Recent Changes

Wednesday, August 23

  1. page Hyperthyroidism edited ... 2. radioactive iodine 3. surgery Etiology - Unknown, but probably immunologic Signs and S…
    ...
    2. radioactive iodine
    3. surgery
    Etiology
    - Unknown, but probably immunologic
    Signs and Symptoms of Hyperthyroidism
    - Nervousness, inc activity
    - Increased perspiration, heat intolerance
    - Fatigue, weakness
    - Increased appetite, weight loss
    - Insomnia
    - Frequent bowel movements
    - Goiter
    - Tachycardia, atrial fibrillation
    - Warm, moist skin
    - Tremor
    - Stare
    in Grave’s disease
    - Exophthalmos
    -Ocular muscle weakness
    - Pretibial edema
    - Non-pitting, pruritic edema
    x-Diagnosis1toc21 Diagnostic Testing
    - Decreased TSH
    - Elevated free T4
    - Elevated T3 uptake
    - Elevated T3
    x-Treatment1toc31 Biomedical Treatment
    - Anti-thyroid agents - propylthiouracil
    - Radioactive iodine
    - Surgery
    Chinese Medicine Etiology
    -Internal damage of the seven emotions
    -Unregulated eating and drinking
    -Aging
    -Enduring disease
    Pattern Differentiation
    Qi stagnation and Phlegm Congealing
    Primary Symptoms: Goiter swelling in the front of the neck that is soft and not painful, possible exophthalmia
    Secondary Symptoms: Emotional depression, frequent suspicion, irritability, easy anger
    Tongue: Pale red, thin slimy coat
    Pulse: Wiry (bowstring), slippery
    Treatment Principles: Course the Liver, rectify Qi, transform phlegm, scatter nodulation
    Acupuncture Treatment: LR-3, ST-40, TW-13, SI-16, LI-17, SI-17, CV-22
    Herbal Treatment:Xiao Chai Hu Tang + Xiao Yao San (Minor Bupleurum Decoction + Rambling Powder)
    [Xia Ku Cao 15g, Mu Li 12g, Zhe Bei Mu 12g, Fu Ling 12g, Chai Hu 9g, Dang Shen 9g, Bai Zhu 9g, Dang Gui 9g, Bai Shao 9g, Kun Bu 9g, Ban Xia 9g, Chen Pi 6g, Gan Cao 6g, Da Zao 3pc, Sheng Jiang 3 slices]
    Modifications:
    Depressive heat + Xuan Shen 15g, Huang Qin 12g
    Increased appetite + Shi Gao 15g, Zhi Mu 9g
    Hand or finger tremors + Jiang Can 15g, Chan Tui 15g
    Liver Fire Flaring Upward
    Primary Symptoms: Marked goiter that is soft and not painful, possible exophthalmia
    Secondary Symptoms: Emotional tension, irritability, impetuosity, red face, headache, dizziness, tinnitus, hand and tongue trembling, palpitations, insomnia, thirst, profuse drinking, bitter taste
    Tongue: Red tongue, yellow coat
    Pulse: Wiry (bowstring), rapid
    Treatment Principles: Clear the Liver and drain fire, transform phlegm, scatter nodulation
    Acupuncture Treatment: LR-2, GB-34, TW-13, SI-16, LI-17, SI-17, CV-22
    Herbal Treatment:Long Dan Xie Gan Tang Jia Jian (Gentiana Drain the Liver Decoction Plus Modifications)
    [Xia Ku Cao 15g, Xuan Shen 15g, Sheng Di 12g, Mu Li 12g, Long Gu 12g, Ban Xia 12g, Fu Ling 12g, Zhe Bei Mu 12g, Chai Hu 9g, Huang Qin 9g, Zhi Zi 9g, Dang Gui 9g, Hai Zao 9g, Kun Bu 9g, Chen Pi 6g, Gan Cao 6g]
    Modifications:
    Hand or finger tremors + Shi Jue Ming 15g, Gou Teng 9g, Bai Shao 9g
    Fatigue + Huang Qi 20g
    Oral thirst, profuse drinking +Mai Men Dong 12g, Tian Hua Fen 12g
    Pain and distention in the eyes + Bai Zhi 15g, Gou Qi Zi 15g, Shi Chang Pu 9g, Ci Ji Li 9g
    Yin Deficiency, Yang Excess
    Primary Symptoms: Goiter, possible exophthalmia, possible nodulations
    Secondary Symptoms: 5 palm heat, insonia, profuse dreams, dizziness, blurred vision, palpitations, restlessness, easy sweating, hot flashes, malar flush, shaking hands, tinnitus, increased food intake but emaciation, lack of strength
    Tongue: Red tongue, scanty coat
    Pulse: Wiry (bowstring), fine, rapid
    Treatment Principles: Enrich Yin, subdue Yang, transform phlegm, scatter nodulation
    Acupuncture Treatment: LR-3, HT-7, KI-7, TW-13, SI-16, LI-17, SI-17, ST-9
    Herbal Treatment:Tian Wan Bu Xin Dan + Yi Guan Jian (Heavenly Emperor Supplement the Heart Elixir + One Link Decoction)
    [Sheng Di 15g, Xuan Shen 15g, Huang Yaso Zi 15g, Mai Men Dong 12g, Tian Men Dong 12g, Gou Qi Zi 12g, Suan Zao Ren 12g, Long Gu 12g, Mu Li 12g, Fu Ling 12g, Chuan Lian Zi 9g, Yuan Zhi 9g, Wu Weri Zi 9g, Bai Zi Rren 9g, Ban Xia 9g, Hai Zao 9g, Kun Bu 9g, Chen Pi 6g, Huang Lian 3g]
    Modifications:
    Severe Yin deficiency + Gui Ban 12g, He Shou Wu 12g, Nu Zhen Zi 12g
    Severe deficiency fire +Huang Bai 9g
    Sudden Liver fire engendering wind +Gou Teng 15g, Jiang Can 9g
    leukopenia + Hu Zhang 12g, Gui Ban 12g
    Qi and Yin Dual Deficiency
    Primary Symptoms: Spirit lassitude and fatigue, shortness of breath,, dizziness, tinnitus, palpitations, emaciation, lack of strength
    Secondary Symptoms: Dry rough eyes, pale lusterless complexion with possible malar flush, restlessness, insomnia, impaired memory, dry mouth and throat, possible tremors of hand and tongue
    Tongue: Red tongue, thin or peeling coat
    Pulse: Vacuous, rapid
    Treatment Principles: Boost the Qi, nourish Yin
    Acupuncture Treatment: BL-15, BL-18, BL-20, BL-23, TW-13, SI-16, SI-17, LI-17
    Herbal Treatment:Jia Kang Zhing Fang (Heavy Hyperthyroid Formula)
    [Huang Qo 30-45g, Xia Ku Cao 30g, He Shou Wu 20g, Sheng Di 15g, Bai Shao 12g, Xiang Fu 12g]]
    Modifications:
    Bulging, distending eyes + Gou Qi Zi 15g, Bai Jie Zi 9g, Ze Xie 9g, Lai Fu Zi 9g, Di Gu Pi 9g, Ci Ji Li 9g
    Severe palpitations, shortness of breath + Sheng Mai San
    Yin deficiency with stirring of wind + Gui Ban 15gm Bie Jia 15g, Zhen Zhu Mu 15g

    ========================================================
    IBIS:
    (view changes)
    7:22 pm

Friday, August 4

  1. page Amygdala edited The amygdala has been implicated in the generation of the most rudimentary and the most profound…

    The amygdala has been implicated in the generation of the most rudimentary and the most profound of human emotions, including fear, sexual desire, rage, religious ecstasy, or at a more basic level, determining if something might be good to eat. The amygdala is implicated in the seeking of loving attachments and the formation of long term emotional memories. It contains neurons which become activated in response to the human face, and which become activated in response to the direction of someone else's gaze. Chemical systems within the amygdala include opiate, lutenizing hormone, vasopressin, somatostatin, and corticotropin releasing factor The amygdala can be likened to the chief executive of the limbic system, weilding enormous power over the hypothalamic impulses via the stria terminalis, medial forebrain bundle, and amygdalafugal pathways.. The amygdala is also directly connected to the hippocampus, with which it interacts in regard to memory. The influence of the amygdala can become so significant that it is able to overwhelm the neocortex and thus gain control over behavior when emotions run high.
    The amygdala is buried within the depths of the anterior-inferior temporal lobe and consists of several major nuclear groups including the cortical-medial, central, paralaminar, lateral, basal, and accessory basal nucleus which can roughly be grouped as medial and basolateral nuclei. The medial group (or cortico-medial amygdala) is involved in olfaction, sexual, and motor activity (via its interconnections with the striatum). In females, the medial amygdala is a principle site for uptake of the female sex hormone, estrogen, and contains a high concentration of leutenizing hormones which are important during pregnancy and nursing. In addition, the medial (and lateral) regions are rich in cells containing enkephalins, and opiate receptors can be found throughout the amygdala and the amygdala becomes exceedingly active when experiencing a craving for pleasure such as drugs. The basolateral amygdala is the most cortex-like, subserving pleasure circuits and relying on excitatory neurotransmitters, e.g., glutamate--whereas the local-circuit (interneurons) rely on the inhibitory transmitters, e.g., GABA. This is intimately involved in all aspects of emotional activity.It is highly important in analyzing information received and transferring information back to the neocortex so that further elaboration may be carried out at the neocortical level. It is through the lateral division that emotional meaning and significance can be assigned to as well as extracted from that which is experienced.
    Possible Symptoms Associated with Amygdala Damage
    -Docility
    -Intractible aggression or fear
    -Inability to recognize faces
    -Blunted emotions
    -Lack of emotional speech
    -Incapacity to respond appropriately to socially emotional stimuli (social-emotional agnosia)
    -Difficulty maintaining attention
    -Inability to sing, convey melodic information or to properly enunciate via vocal inflection (right sided injury)
    -Prolonged, repeated, and inappropriate sexual behavior and/or masturbation
    -High risk behavior,reduced loss aversion (e.g.gambling)
    -Memory deficits
    -Tendency to react to every stimuli
    -Tendency to put objects into the mouth

    Laterality
    The right cerebral hemisphere appears to maintain more extensive as well as bilateral interconnections with the limbic system.
    (view changes)
    8:04 pm
  2. page hypothalamus edited ... nervous system. The The hypothalamus integrates ... certain systems. Blood pressu…
    ...
    nervous system.
    The

    The
    hypothalamus integrates
    ...
    certain systems.
    Blood pressure and electrolyte composition are maintained by control of drinking and salt appetite.
    Body temperature is regulated by control of metabolic thermogenesis and behaviors that seek to warm or cool the individual.
    ...
    Medial
    Medial preoptic nucleus
    ...
    from the adenohypophysis
    Contains
    adenohypophysis. Contains the sexually
    ...
    which releases GnRH, differential development between sexes is based upon in utero testosterone levelsGnRH.
    Supraoptic nucleus (SO)
    oxytocin release
    vasopressin

    Oxytocin release, Vasopressin
    release
    Paraventricular nucleus* (PV)
    corticotropin-releasing hormonerelease
    oxytocin release
    vasopressin release[9]
    nucleus
    Corticotropin-releasing hormone

    Anterior hypothalamic nucleus (AH)
    thermoregulation
    panting
    sweating
    thyrotropin

    Thermoregulation, panting, sweating, thyrotropin
    inhibition
    Suprachiasmatic

    Suprachiasmic
    nucleus (SC)
    vasopressin release
    Circadian

    Vasopressin release, circadian
    rhythms
    Lateral
    Lateral preoptic nucleus
    Lateral nucleus(LT)
    thirst
    Nucleua
    Thirst
    and hunger
    ...
    supraoptic nucleus (SO)
    vasopressin

    Vasopressin
    release
    Tuberal
    Medial
    ...
    hypothalamic nucleus (DM)
    Blood Pressure
    Heart Rate
    GI
    pressure, heart rate, GI stimulation
    Ventromedial nucleus (VM)
    satiety
    neuroendocrine

    Satiety, neuroendocrine
    control
    Arcuate nucleus(AR)nucleus
    Growth hormone-releasing hormone (GHRH)
    feeding
    Dopamine
    releleasing hormone (GHRH), feeding, dopamine
    Lateral
    Lateral nucleus(LT)
    thirst and
    nucleus
    Thirst,
    hunger
    Lateral tuberal nuclei
    Posterior
    Medial
    Mammillary nuclei (part ofmammillary bodies) (MB)
    memory

    Memory

    Posterior nucleus (PN)
    Increase

    Increased
    blood pressure
    pupillary dilation
    shivering
    pressure, pupillary dilation, shivering
    Lateral
    Lateral nucleus(LT)
    Secreted hormone
    Abbreviation
    nucleus
    Hormone

    Produced by
    Effect
    Thyrotropin-releasing hormone
    (Prolactin-releasing hormone)
    TRH, TRF, or PRH
    (TRH)
    Parvocellular neurosecretory neurons
    Stimulate-Stimulates thyroid-stimulating hormone
    ...
    anterior pituitary (primarily)
    Stimulate

    -Stimulate
    prolactin release
    ...
    pituitary
    Dopamine
    (Prolactin-inhibiting hormone)
    DA or PIH
    (DA)
    Dopamine neurons of the arcuate nucleus
    Inhibit-Inhibits prolactin release
    ...
    hormone-releasing hormone
    GHRH
    Neuroendocrineneurons
    (GRHR)
    neurons
    of the Arcuate nucleus
    Stimulate

    Stimulates
    Growth hormone
    ...
    pituitary
    Somatostatin
    (growth hormone-inhibiting hormone)
    SS, GHIH, or SRIF
    (SS)
    Neuroendocrine cells of the Periventricular nucleus
    InhibitInhibits Growth hormone
    ...
    anterior pituitary
    Inhibit

    Inhibits
    thyroid-stimulating hormone
    ...
    anterior pituitary
    Gonadotropin-releasing

    Gonadotrophin – releasing
    hormone
    GnRH or LHRH
    (GnRH)
    Neuroendocrine cells of the Preoptic area
    Stimulate-Stimulates follicle-stimulating hormone
    ...
    anterior pituitary
    Stimulate

    -Stimulate
    luteinizing hormone
    ...

    Corticotropin-releasing hormone
    CRH or CRF
    (CRH)
    Parvocellular neurosecretory neurons
    Stimulate-Stimulate adrenocorticotropic hormone (ACTH) release fromanteriorfrom anterior pituitary
    Oxytocin
    Magnocellular neurosecretory cells
    Uterine-Uterine contraction
    Lactation

    -Lactation
    (letdown reflex)
    Vasopressin
    (antidiuretic hormone)
    ADH or AVP

    Vasopressin/antidiuretic hormone (ADH)

    Magnocellular neurosecretory neurons
    ...
    tubuleand collecting duct inductin the kidney
    ...
    concentrated urine
    Lateral vs Medial Hypothalamic Lesion Effects
    Lateral Lesion
    -Aphagia, adipsia (no motivation to eat or drink)
    -Attenuated sense of pleasure and emotional responsiveness
    -Pathological laughter and crying
    -Passiveness, inability to become aggressive
    Medial Lesion
    -Hyperphagia, severe obesity (especially ventromedial)
    -Pathological laughter and crying
    -Aggressive or attack behavior, rage-like outbursts, propensity toward violence

    (view changes)
    7:07 pm
  3. page Limbic System edited {http://brainmind.com/images/BrainMindLimbicSystem101.jpg} Limbic Limbic System Overview ... …
    {http://brainmind.com/images/BrainMindLimbicSystem101.jpg} Limbic
    Limbic
    System Overview
    ...
    of loving attachments. Indeed, the limbic system not only controls the capacity to experience love and sorrow, but it governs and monitors internal homeostasis and basic needs such as hunger and thirst
    The
    attachments.The structures and
    ...
    limbic system.
    However, over the course of evolution a mantle of neocortex began to develop and enshroud the limbic system; evolving at first to serve limbic needs in a way that would maximize the survival of the organism, and to more efficiently, effectively, and safely satisfy limbic needs and impulses. In consequence, the frontal, temporal, parietal, and occipital lobes evolved covered with a neocortical mantle, that in humans would come to be associated with the conscious, rational mind. Sometimes, however, even in the most rational of humans, emotions can hijack the logical mind, and the neocortex, and even peaceful people might be impelled to murder even those they love.
    Indeed,
    Indeed, the old
    ...
    the neocortex. Although over the course of evolution a new brain (neocortex) has developed, Homo sapiens sapiens ("the wise may who knows he is wise") remains a creature of emotion.
    FUNCTIONAL OVERVIEW
    ...
    axonal pathways. With the exception of the cingulate which is referred to as "transitional" cortex (mesocortex) and consists of five layers, the hypothalamus, amygdala, hippocampus, septal nuclei are considered allocortex, consisting of at most, 3 layers.
    The hypothalamus could be considered the most "primitive" aspect of the limbic system, though in fact the functioning of this sexually dimorphic structure is exceedingly complex. The hypothalamus regulates internal homeostasis including the experience of hunger and thirst, can trigger rudimentary sexual behaviors or generate feelings of extreme rage or pleasure. In conjunction with the pituitary the hypothalamus is a major manufacturer/secretor of hormones and other bodily humors, including those involved in the stress response and feelings of depression.
    The amygdala has been implicated in the generation of the most rudimentary and the most profound of human emotions, including fear, sexual desire, rage, religious ecstasy, or at a more basic level, determining if something might be good to eat. The amygdala is implicated in the seeking of loving attachments and the formation of long term emotional memories. It contains neurons which become activated in response to the human face, and which become activated in response to the direction of someone else's gaze. The amygdala also acts directly on the hypothalamus via the stria terminalis, medial forebrain bundle, and amygdalafugal pathways, and in this manner can control hypothalamic impulses. The amygdala is also directly connected to the hippocampus, with which it interacts in regard to memory.
    ...
    that unlike the amygdala and other structures,
    ...
    overlying entorhinal cortex--a five layered mesocortex. As is well known, thecortex. The hippocampus is
    ...
    associated memories.
    The septal nuclei is in part an evolutionary and developmental outgrowth of the hippocampus, and the hypothalamus, and links these two structures along with the brainstem. It consists of both lateral and medial segments; i.e. the lateral and medial septal nuclei. Presumably these interconnections allow the septal nuclei to exert modulatory influences on hippocampal regarding memory functioning and arousal. The septal nuclei is also interconnected with and shares a counterbalancing relationship with the amygdala, particularly in regard to hypothalamic activity and emotional and sexual arousal. For example, whereas the amygdala promotes indiscriminate contact seeking, and perhaps promiscuous sexual activity, the septal nuclei inhibits these tendencies thus assisting in the formation of selective and more enduring emotional attachments.

    The septal nuclei can produce extremes of emotion, including explosive violence, known as "septal rage."
    The septal nuclei is in part an evolutionary and developmental outgrowth of the hippocampus, and the hypothalamus, and in fact acts to link the hippocampus with the hypothalamus as well as with the brainstem. It consists of both lateral and medial segments; i.e. the lateral and medial septal nuclei. Presumably, via these interconnections, the septal nuclei exerts modulatory influences on the hippocampus in regard to memory functioning and arousal.
    The septal nuclei is also interconnected with and shares a counterbalancing relationship with the amygdala particularly in regard to hypothalamic activity and emotional and sexual arousal. For example, whereas the amygdala promotes indiscriminate contact seeking, and perhaps promiscuous sexual activity, the septal nuclei inhibits these tendencies thus assisting in the formation of selective and more enduring emotional attachments.
    The
    anterior cingulate
    ...
    cortex, or rather, mesocortex (also referred to as "paleocortex") as it consists of five layers (MacLean, 1990). The anterior cingulatemesocortex. It is intimately
    ...
    misery, and anxiety, and is directly implicated in theanxiety. The evolution and
    ...
    of maternal behavior. Itbehavior is also directly related to this structure. The anterior cingulate is also
    ...
    periaqueductal gray. ThusThus, the anterior
    ...
    mother-infant bond.
    Also

    The olfactory bulb and olfactory system are also
    implicated in
    ...
    the limbic system are the olfactory bulb and olfactory system, thesystem. The limbic striatum
    HYPOTHALAMUS
    The hypothalamus is an exceedingly ancient structure and unlike most other brain regions it has remained somewhat similar in structure throughout phylogeny and apparently over the course of evolution. Located in the most medial aspect of the brain, along the walls and floor of the 3rd ventricle, this nucleus is fully functional at birth and is the central core from which all emotions derive their motive force. Indeed, the hypothalamus is highly involved in all aspects of emotional, reproductive, vegetative, endocrine, hormonal, visceral and autonomic functions and mediates or exerts significant or controlling influences on eating, drinking, sleeping and the experience of pleasure, rage, and aversion.
    (view changes)
    4:07 pm
  4. page Limbic System edited ... HUNGER & THIRST The lateral and medial region are highly involved in monitoring internal …
    ...
    HUNGER & THIRST
    The lateral and medial region are highly involved in monitoring internal homeostasis and motivating the organism to respond to internal needs such as hunger and thirst (Anand & Brobeck, 1951; Bernardis & Bellinger 2007; Hetherington & Ranson, 1940). For example, both nuclei appear to contain receptors which are sensitive to the body's fat content (lipostatic/caloric receptors) and to circulating metabolites (e.g. glucose) which together indicate the need for food and nourishment. For example, when food is digested, the viscera secretes various hormones which act on the alimentary tract, which in turn stimulates the solitary tract (ST) which projects directly to the hypothalamus. However, in the absence of food, the viscera also begins to secrete various hormones which when coupled changes in caloric blood levels, signals to the hypothalamus the need for food. The lateral hypothalamus also appears to contain osmoreceptors (Joynt, 1966) which determine if water intake should be altered.
    {http://brainmind.com/images/hypocenters.gif}
    Electophysiologically, it has been determined that the hypothalamus not only become highly active immediately prior to and while the organism is eating or drinking, but the lateral region alters it's activity when the subject is hungry and simply looking at food (Hamburg, 1971; Rolls et. al., 1976). In fact, if the lateral hypothalamus is electrically stimulated a compulsion to eat and drink results (Delgado & Anand, 1953). Conversely, if the lateral area is destroyed bilaterally there results aphagia and adipsia so severe animals will die unless force fed (Anand & Brobeck, 1951; Hetherington & Ranson, 1940; Teitelbaum & Epstein, 1962).
    If the medial hypothalamus is surgically destroyed, inhibitory influences on the lateral region appear to be abolished such that hypothalamic hyperphagia and severe obesity result (Anand & Brobeck, 1951; Hoebel & Tetelbaum, 1966; Teitelbaum, 1961). Hence, the medial area seems to act as a satiaty center; but, a center that can be overridden.
    ...
    CIRCADIAN RHYTHM GENERATION & SEASONAL AFFECTIVE DISORDER
    As noted in chapter 5, during the initial stages of cerebral evolution, the dorsal hypothalmus (like the dorsal thalamus, dorsal hippocampus, dorsal midbrain) was likely fashioned, at least in part, from photosensitive cells located in the anterior head region. Given the daily and seasonal changes in light vs darkness, nuclei in the midbrain-pons, and in the hypothalamus, became sensitive to and capable of generating rhythmic hormonal, neurotransmitter, and motoric activities. It is the hypothalamus, however, the suprachiasmatic nucleus (SCN) in particular, which appears to be the "master clock" for the generation of circadian rhythms; rhythms which have a period length of 24 hours (Aronson et al. 2013; Morin 2014).
    {http://brainmind.com/images/ch3rythm.jpg}
    In humans and other species, the SCN (and the midbrain superior colliculus) is a direct recipient of retinal axons. It also receives indirect visual projections from the lateral geniculate nucleus of the thalamus (see Morin 2014). In this regard, the visual system appears to act to synchronize the SCN (and probably the midbrain-pons) to function in accordance with seasonal and day to day variations in the light/dark ratio. However, the SCN does not "see" per se, nor can it detect visual features, as its main concern is adjusting mood, and activity in regard to light intensity as related to rhythm generation.
    There is thus some evidence which suggests that when the SCN of the hypothalamus is deprived of (or unable to effectively respond to) sufficient light, although rhythm generation is not grossly effected (Morin 2014), individuals may become depressed; a condition referred to as Seasonal Affective Disorder (SAD). That is, the hypothalamus (and midbrain-pons) appear to decrease those hormonal and neurochemical activities normally associated with activation and high (daytime) activity thus resulting in depression.
    (view changes)
    3:44 pm
  5. page Limbic System edited The {http://brainmind.com/images/BrainMindLimbicSystem101.jpg} Limbic System Hypothalamus, …

    The
    {http://brainmind.com/images/BrainMindLimbicSystem101.jpg} Limbic System
    Hypothalamus, Septal Nuclei,
    Amygdala, Hippocampus
    Emotion and the Unconscious Mind
    R. Gabriel Joseph, Ph.D.
    {http://brainmind.com/images/BrainMindLimbicSystem101.jpg}
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    Limbic
    System Overview
    ...
    and thirst (Bernardis & Bellinger 2007; Gloor 1992, 2010; Joseph, 1990, 1992, 2000a; LeDoux 1992, 2012; MacLean, 1973, 1990; Rolls, 1984, 1992; Smith et al. 1990), including even the cravings for pleasure-inducing drugs (Childress, et al., 2009).
    The structures and nuclei of the limbic system are exceedingly ancient, some of which began to evolve over 450 million years ago. Over the course of evolution, these emotional structures have expanded in size, some becoming increasingly cortical in response to increased environmental opportunities and demands. In fact, as the neocortical forebrain expanded and until as recently as 50 million years ago, the cerebrum of the ancestral line that would eventually give rise to humans, was dominated by the limbic system.
    {http://brainmind.com/images/CortexLimbic.jpg}
    However, over the course of evolution a mantle of neocortex began to develop and enshroud the limbic system; evolving at first to serve limbic needs in a way that would maximize the survival of the organism, and to more efficiently, effectively, and safely satisfy limbic needs and impulses. In consequence, the frontal, temporal, parietal, and occipital lobes evolved covered with a neocortical mantle, that in humans would come to be associated with the conscious, rational mind. Sometimes, however, even in the most rational of humans, emotions can hijack the logical mind, and the neocortex, and even peaceful people might be impelled to murder even those they love.
    ...
    of emotion. Humans have not completely emerged from the phylogenetic swamps of their original psychic existence.
    {http://brainmind.com/images/LimbicRage1.jpg}
    Hence, due to these limbic roots, humans not uncommonly behave "irrationally" or in the "heat of passion," and get into fights, have sex with or scream and yell at strangers thus act at the behest of their immediate desires; sometimes falling "madly in love" and at other times, acting in a blind rage such that even those who are 'loved" may be slaughtered and murdered.
    Indeed, emotion is a potentially powerful overwhelming force that warrants and yet resists control-- as something irrational that can happen to a someone ("you make me so angry") and which can temporarily hijack, overwhelm, and snuff out the "rational mind."
    The schism between the rational and the emotional is real, and is due to the raw energy of emotion having it's source in the nuclei of the ancient limbic lobe -- a series of structures which first make their phylogenetic appearance over a hundred million years before humans walked upon this earth and which continue to control and direct human behavior.

    FUNCTIONAL OVERVIEW
    ...
    massive axonal pathways (Gloor, 2010; MacLean, 1990; Risvold & Swanson, 2012).pathways. With the
    ...
    3 layers.
    {http://brainmind.com/images/LimbicSystem888.jpg}

    The hypothalamus could be considered the most "primitive" aspect of the limbic system, though in fact the functioning of this sexually dimorphic structure is exceedingly complex. The hypothalamus regulates internal homeostasis including the experience of hunger and thirst, can trigger rudimentary sexual behaviors or generate feelings of extreme rage or pleasure. In conjunction with the pituitary the hypothalamus is a major manufacturer/secretor of hormones and other bodily humors, including those involved in the stress response and feelings of depression.
    {http://brainmind.com/images/LimbicSystemEmotions.jpg} TheThe amygdala has
    The hippocampus is unique in that unlike the amygdala and other structures, almost all of its input from the neocortex is relayed via the overlying entorhinal cortex--a five layered mesocortex. As is well known, the hippocampus is exceedingly important in memory, acting to place various short-term memories into long-term storage. Presumably the hippocampus encodes new information during the storage and consolidation (long-term storage) phase, and assists in the gating of afferent streams of information destined for the neocortex by filtering or suppressing irrelevant sense data which may interfere with memory consolidation. Moreover, it is believed that via the development of long-term potentiation the hippocampus is able to track information as it is stored in the neocortex, and to form conjunctions between synapses and different brain regions which process and store associated memories.
    {http://cosmology.com/images/LimbicCoverEbook1epub.jpg} TheThe septal nuclienuclei can produce
    ...
    of the hippocampus (Ariens Kappers, et al., 1936; Gloor, 2010),hippocampus, and the
    ...
    with the brainstem (Andy & Stephan, 1968; Risvold & Swanson, 2012; Swanson & Cowan, 1979;).brainstem. It consists
    ...
    medial septal nuclei (Ariens Kappers, et al., 1936).nuclei. Presumably, via
    ...
    functioning and arousal (Gloor, 2010).arousal.
    The septal
    ...
    and sexual arousal (Andy & Stephan, 1968; Swanson & Cowan, 1979).arousal. For example,
    ...
    enduring emotional attachments (Joseph, 1992a, 2009b).
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    attachments.
    The anterior cingulate is considered a transitional cortex, or rather, mesocortex (also referred to as "paleocortex") as it consists of five layers (MacLean, 1990). The anterior cingulate is intimately interconnected with the hypothalamus, amygdala, septal nuclei, and hippocampus, and participates in memory and emotion including the experience of pain, misery, and anxiety, and is directly implicated in the evolution and expression of maternal behavior. It is also the most vocal aspect of the brain, becomes active during language tasks, and generates emotional-melodic aspects of speech which is expressed via interconnections with the right and left frontal speech areas, and the vocalization center in the midbrain periaqueductal gray. Thus the anterior cingulate is implicated in the more cognitive aspects of social-emotional behavior including language and the establishment of long term attachments beginning with the mother-infant bond.
    {http://brainmind.com/images/OlfactoryLimbic748.jpg}
    Also implicated in the functioning of the limbic system are the olfactory bulb and olfactory system, the limbic striatum (nucleus accumbens, olfactory tubercle, substantia innominata, ventral caudate and putamen), the orbital frontal and inferior temporal lobes and the midbrain monoamine system. These systems and structures are also directly connected or separated by only a single synapse, and which tend to become aroused not only as a function of emotional arousal, but in reaction to olfactory input which continues to exert profound effects on the human limbic system, and upon human behavior.
    {http://cosmology.com/images/LimbicCoverEbook1epub.jpg}
    HYPOTHALAMUS
    ...
    course of evolution (Crosby et al. 1966).evolution. Located in
    ...
    autonomic functions (Alam et al., 2011; Johnson & Gross, 2013; Markakis & Swanson, 2010; Sherin, et al., 2012; Smith et al. 1990) and mediates
    ...
    and aversion.
    {http://brainmind.com/images/HypothalamicNuclei45.jpg}
    In

    In
    fact, almost
    ...
    to its influences (Swanson, 2007).influences. Moreover, the
    ...
    of the neuroaxis (Markakis & Swanson, 2010).neuroaxis. Through the
    ...
    it controls.
    {http://brainmind.com/images/HypothalamusBrainstem1.jpg}

    Certain areas of the diencephalon, midbrain, and brainstem, are exceedingly exceedingly sensitive to hormones, humors, and peptides circulating within the blood plasma, and the cerebrospinal fluids; chemosensory information which is used for maintaining homeostasis. Broadly considered, these chemosensory sensitive areas are generally located near or surrounding the cerebral ventricles (Johnson & Gross, 2013) and they tend not to be effected by the so called "blood brain barrier;" referred to as circumventricular organs (CVOs). There are perhaps dozens of CVO's at least 8 of which are located in or near the ventricular systems which feed the brainstem and diencephalon including the hypothalamus, pineal gland and pituitary (Johnson & Gross, 2013).
    The hypothalamus, however, does not act solely through the blood supply or via cerebrospinal fluid, and its also receives sensory information synaptically, and often indirectly, as is the case with the majority of olfactory fibers. In general, sensory stimuli reach the hypothalamus from a variety of routes. These include the solitary tract of the brainstem, a structure which receives, processes, and transmits data received principally from the vagus and glosopharyngeal cranial nerves. Through this pathway the lateral hypothalamus is informed about cardivocascular activities, respiration, and taste. These pathways are also bidirectional (Swanson, 2007). Other major pathways include the medial forebrain bundle (which contains axons from a variety of different cellular groups) and the stria terminalis through which the amygdala and hypothalamus interact. The hypothalamus also maintains massive interactive pathways with the frontal lobes and septal nuclei (Risvold & Swanson, 2012).
    {http://brainmind.com/images/HypothalamicPaths18.gif}
    Broadly considered, the hypothalamus consists of three longitudinal subdivisions which extend along its anterior to posterior axis. These are the medial, lateral, and periventricular (Swanson, 2007). The periventricular zone is concerned with neuroendocrine regulation, whereas the lateral and medial zones are concerned with affective states, including hunger and thirst. These zones, in turn can be further subdivided into subnuclei.
    Phylogenetically, structurally, and embryologically the hypothalamus is traditionally considered part of the diencephalon. During embryological development it emerges from the diencephalic vessicle of the neural tube along with those anterior-lateral evaginations which become the optic nerves and retina of the eye, as well as the pituitary gland (ventrally) and the pineal gland and thalamus (dorsally). There is some dispute, however, over the developmental patterns of the hypothalamus, as some scientists believe that it develops from the outside in (the "hollow hypothalamus hypothesis").
    On the other hand, the hypothalamus originates from the medially situated neuroepithelium, and thus begins its developmental journey in a medial (or rather paramedial) to lateral arc, such that it appears that the medial hypothalamus is fashioned (and matures) in advance of the lateral hypothalamus.
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    From an evolutionary perspective, however, the hypothalamus appears to have dual (forebrain - midbrain) origins; that is emerging from the dorsal (visual) midbrain, and the olfactory forebrain, which together, and over the course of evolution, gave rise to the ventral, medial, lateral and preoptic hypothalamus. Nevertheless, in modern mammals and humans, the olfactory origins are no longer directly apparent, particularly in that most olfactory fibers reach the hypothalamus indirectly; e.g. via the amygdala and piriform cortex.
    {http://brainmind.com/images/OlfactoryHypothalamus.jpg}
    The hypothalamus is exceedingly responsive to olfactory (and pheromonal) input. Perhaps reflecting this partial and putative olfactory origin is the fact that this structure utilizes chemical (hormonal, humoral) molecules to communicate with other areas of the brain, and reacts to these same molecules as well as olfactory cues, including those directly related to sexual status.
    It is this olfactory-chemical origin and sensitivity which in turn may explain why portions of the hypothalamus (like the amygdala) are also sexually dimorphic and reacts to pheromonal sensory stimuli including those which signal sexual status. That is, structurally and functionally the hypothalamus of males and females are stucturally dissimilar (Bleier et al. 1982; Dorner, 1976; Gorski et al. 1978; Rainbow et al. 1982; Raisman & Field, 1971, 1973) and perform different functions depending on if one is a man or a woman, and if a woman is sexually receptive, pregnant, or lactating. For example, the sexually dimorphic supraoptic and paraventricular nuclei project (via the infundibular stalk) to the posterior lobe of the pituitary which may then secrete oxytocin--a chemical which can trigger uterine contractions as well as milk production in lactating females (and which can thus make nursing a pleasurable experience). The male hypothalamus/pituitary does not perform this function.
    SEXUAL DIMORPHISM IN THE HYPOTHALAMUS
    ...
    as the amygdala (Bleier et al. 1982; Dorner, 1976; Gorski et al. 1978; Rainbow et al. 1982; Raisman & Field, 1971, 1973).
    {http://brainmind.com/images/HypothalamicNuclei78.jpg}
    Indeed
    amygdala.
    Indeed
    it has
    ...
    and dendritic development, (Allen et al. 1989; Blier et al. 1982; Gorski et al. 1978; Rainbow et al. 1982; Raisman & Field, 1971, 1973; Swaab & fliers, 2005).development.
    This is
    ...
    cognitive functioning (Barnett & Meck, 1990; Beatty, 1992; Dawson et al. 1975; Harris, 1978; Joseph, et al. 1978; Stewart et al. 1975).
    {http://brainmind.com/images/HormonalChanges65.jpg}
    {http://brainmind.com/images/HypothalamusHormones87.jpg} {http://brainmind.com/images/bodyHypothalamus.jpg} {http://brainmind.com/images/endocrine47.jpg}

    For example, if the testes are removed prior to differentiation, or if a chemical blocker of testosterone is administered thus preventing this hormone from reaching target cells in the limbic system, not only does the female pattern of neuronal development occur, but males so treated behave and process information in a manner similar to females (e.g., Joseph et al. 1978); i.e. they develop female brains and think and behave in a manner similar to females. Conversely, if females are administered testosterone during this critical period, the male pattern of differentiation and behavior results (see Gerall et al. 1992 for review).
    That the preoptic and other hypothalamic regions are sexually dimorphic is not surprising in that it has long been known that this area is extremely important in controlling the basal output of gonadotrophins in females prior to ovulation and is heavily involved in mediating cyclic changes in hormone levels (e.g. FSH, LH, estrogen, progesterone). Chemical and electrical stimulation of the preoptic and ventromedial hypothalamic nuclei also triggers sexual behavior and even sexual posturing in females and males (Hart et al., 2005; Lisk, 1967, 1971) and, in female primates, even maternal behavior (Numan, 2005). In fact, dendritic spine density of ventromedial hypothalamic neurons varies across the estrus cycle (Frankfurt et al., 1990) and thus presumably during pregnancy and while nursing.
    {http://brainmind.com/images/PenisRock.jpg} {http://brainmind.com/images/peniscactus.jpg} InIn primates, electrical
    ...
    gonadal atrophy.
    {http://brainmind.com/images/treepenis8022.jpg} Hence,

    Hence,
    it is
    Specifically, the hypothalamic neurons secrete gonadotropin-releasing hormone, which acts on the anterior lobe of the pituitary which secretes gonadotropins. However, given that in females, this is a cyclic event, whereas in males sperms are constantly reproduced, is further evidence of the sexual dimorphism of the hypothalamus.
    Although the etiology of homosexuality remains in question, it has been shown that the ventromedial and anterior nuclei of the hypothalamus of male homosexuals demonstrate the female pattern of development (Levay, 1991; Swaab, 1990). When coupled with the evidence of male vs female and homosexual differences in the anterior commissure which links the temporal lobe and sexually dimorphic amygdala (see below) as well as the similarity between male homosexuals and women in regard to certain cognitive attributes including spatial-perceptual capability (see below), this raises the possibility that male homosexuals are in possession of limbic system that is more "female" than "male" in functional as well as structural orientation.
    ...
    LATERAL & VENTROMEDIAL HYPOTHALAMIC NUCLEI
    Although consisting of several nuclear subgroups, the lateral and medial (ventromedial) hypothalamic nuclei play particularly important roles in the control of the automonic nervous system, the experience of pleasure and aversion, eating and drinking, and raw (undirected) emotionality. They also appear to share a somewhat antagnistic relationship.
    {http://brainmind.com/images/HypothalamusSympathetic.jpg}
    For example, the medial hypothalamus controls parasympathetic activities (e.g. reduction in heart rate, increased peripheral circulation) and exerts a dampening effect on certain forms of emotional/motivational arousal. The lateral hypothalamus mediates sympathetic activity (increasing heart rate, elevation of blood pressure) and is involved in controlling the metabolic and somatic correlates of heightened emotionality (Smith et al. 1990). In this regard, the lateral and medial region act to exert counterbalancing influences on each other.
    {http://brainmind.com/images/lateralHypothalamus500.gif}
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}

    HUNGER & THIRST
    The lateral and medial region are highly involved in monitoring internal homeostasis and motivating the organism to respond to internal needs such as hunger and thirst (Anand & Brobeck, 1951; Bernardis & Bellinger 2007; Hetherington & Ranson, 1940). For example, both nuclei appear to contain receptors which are sensitive to the body's fat content (lipostatic/caloric receptors) and to circulating metabolites (e.g. glucose) which together indicate the need for food and nourishment. For example, when food is digested, the viscera secretes various hormones which act on the alimentary tract, which in turn stimulates the solitary tract (ST) which projects directly to the hypothalamus. However, in the absence of food, the viscera also begins to secrete various hormones which when coupled changes in caloric blood levels, signals to the hypothalamus the need for food. The lateral hypothalamus also appears to contain osmoreceptors (Joynt, 1966) which determine if water intake should be altered.
    {http://brainmind.com/images/hypocenters.gif}
    {http://brainmind.com/images/rys0504.gif} Electophysiologically,Electophysiologically, it has
    If the medial hypothalamus is surgically destroyed, inhibitory influences on the lateral region appear to be abolished such that hypothalamic hyperphagia and severe obesity result (Anand & Brobeck, 1951; Hoebel & Tetelbaum, 1966; Teitelbaum, 1961). Hence, the medial area seems to act as a satiaty center; but, a center that can be overridden.
    Specifically, with ventromedial lesions, animals not only eat more, but the intervals between meals becomes shorter such that they eat more meals. Thus they begin to gain weight. In part this is also due to changes in the sympathetic nervous system which increases vagal activity, thus signaling the need for more food. As noted, the ST is bidirectional.
    ...
    again become obese (Hoebel & Tetelbaum, 1966).
    {http://brainmind.com/images/anorexia55.jpg} {http://brainmind.com/images/anorexia11.jpg}
    {http://brainmind.com/images/obese01456.jpg} Overall,
    obese.
    Overall,
    it appears
    In part, these nuclei exert these differential influences on eating and drinking via motivational/emotional influences they exert on other brain nuclei (e.g. via reward or punishment). However, it should be stressed that there are a number of other structures and hormones and peptides involved, including the pancreatic islets, and insulin secretion.
    PLEASURE & REWARD
    ...
    1952, Heath (cited by Maclean, 1969) reported what
    ...
    orbital frontal lobes (Brady, 1960; Lilly, 1960; Olds & Forbes, 1981; Stein & Ray, 1959; Waraczynski et al. 2007).
    {http://brainmind.com/images/selfstimulationrat.jpg} {http://brainmind.com/images/ratSelfStimulating.jpg} {http://brainmind.com/images/OlfactoryHypothalamus21.jpg} In
    lobes.
    In
    mapping the
    Electrophysiological studies of single lateral hypothalamic neurons indicate that these cells become highly active in response to rewarding food items (Nakamura & Ono, 1986). In fact, many of these cells will become aroused by neutral stimuli repeatedly associated with reward such as a cue-tone --even in the absence of the actual reward (Nakamura & Ono, 1986; Ono et al. 1980). However, this ability to form associations appears to be secondary to amygdaloid activation (Fukuda et al. 2007) which in turn influences hypothalamic functioning.
    Nevertheless, if the lateral region is destroyed the experience of pleasure and emotional responsiveness is almost completely attenuated. For example, in primates, faces become blank and expressionless, whereas if the lesion is unilateral, a marked neglect and indifference regarding all sensory events occurring on the contralateral side occurs (Marshall & Teitelbaum, 1974). Animals will in fact cease to eat and will die.
    ...
    The hypothalamus, via it's rich interconnections with other limbic regions including the neocortex and frontal lobes, it able to mobilize and motivate the organism to either cease or continue to behave. Nevertheless, at the level of the hypothalamus, the emotional states elicited are very primitive, diffuse, undirected and unrefined.
    The organism feels pleasure in general, or aversion/unpleasure in general. Higher order emotional reactions (e.g. desire, love, hate, etc.) require the involvement of other limbic regions as well as neocortical participation.
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    Emotional functioning at the level of the hypothalamus is not only quite limited and primitive, it is also largely reflexive. For example, when induced via stimulation, the moment the electrical stimulus is turned off the emotion elicited is immediately abolished. In contrast, true emotions (which require other limbic interactions) are not simply turned on or off but can last from minutes to hours to days and weeks before completely dissipating.
    Nevertheless, in humans, disturbances of hypothalamic functioning (e.g. due to an irritating lesion such as tumor) can give rise to seemingly complex, higher order behavioral-emotional reactions, such as pathological laughter and crying which occurs uncontrollably. However, in some cases when patients are questioned, they may deny having any feelings which correspond to the emotion displayed (Davison & Kelman, 1939; Ironside, 1956; Martin, 1950). In part, these reactions are sometimes due to disinhibitory release of brainstem structures involved in respiration, whereas in other instances the resulting behavior is caused by hypothalamic triggering of other limbic nuclei.
    ...
    HYPOTHALAMIC RAGE
    Stimulation of the lateral hypothalamus can induce extremes in emotionality, including intense attacks of rage accompanied by biting and attack upon any moving object (Flynn et al. 1971; Gunne & Lewander, 1966; Wasman & Flynn, 1962). If this nucleus is destroyed, aggressive and attack behavior is abolished (Karli & Vergness, 1969). Hence, the lateral hypothalamus is responsible for rage and aggressive behavior.
    {http://brainmind.com/images/rage22.jpg} AsAs noted, the
    In man, inflammation, neoplasm, and compression of the hypothalamus have also been noted to give rise to rage attacks (Pilleri & Poeck, 1965), and surgical manipulations or tumors within the hypothalamus have been observed to elicit manic and rage-like outbursts (Alpers, 1940). These appear to be release phenomenon, however. That is, rage, attack, aggressive, and related behaviors associated with the hypothalamus appears to be under the inhibitory influence of higher order limbic nuclei such as the amygdala and septum (Siegel & Skog, 1970). When the controlling pathways between these areas are damaged (i.e. disconnection) sometimes these behaviors are elicited.
    For example, Pilleri and Poeck (1965) described a man with severe damage throughout the cerebrum including the amygdala, hippocampus, cingulate, but with complete sparing of the hypothalamus who continually reacted with howling, growling, and baring of teeth in response to noise, a slight touch, or if approached. Hence, the hypothalamus being released responds reflexively in an aggressive-like non-specific manner to any stimulus. Lesions of the frontal-hypothalamic pathways have been noted to result in severe rage reactions as well (Fulton & Ingraham, 1929; Kennard, 1945).
    ...
    As noted in chapter 5, during the initial stages of cerebral evolution, the dorsal hypothalmus (like the dorsal thalamus, dorsal hippocampus, dorsal midbrain) was likely fashioned, at least in part, from photosensitive cells located in the anterior head region. Given the daily and seasonal changes in light vs darkness, nuclei in the midbrain-pons, and in the hypothalamus, became sensitive to and capable of generating rhythmic hormonal, neurotransmitter, and motoric activities. It is the hypothalamus, however, the suprachiasmatic nucleus (SCN) in particular, which appears to be the "master clock" for the generation of circadian rhythms; rhythms which have a period length of 24 hours (Aronson et al. 2013; Morin 2014).
    {http://brainmind.com/images/ch3rythm.jpg}
    {http://brainmind.com/images/clocks1.jpg} InIn humans and
    ...
    rhythm generation.
    {http://brainmind.com/images/HypoSCN1.jpg} {http://brainmind.com/images/HypoSCN2.jpg} There

    There
    is thus
    For example, the hypothalamic-pituitary axis secretes melatonin in phase with the circadian rhythm. Phase-delayed rhythms in plasma melatonin secretion have been repeatedly noted in most (but not all) studies of individuals with SADs (see Wirz-Justice et al. 2013, for review). However, with light therapy, not only is the depression relieved but the melatonin secretions return to normal. This is significant for melatonin is derived from tryptophan via serotonin and low serotonin levels have been directly linked to depression (e.g. Van Pragg 1982).
    {http://brainmind.com/images/HypothalamicPituitary31.jpg} ThereThere is some
    ...
    within the brainstem (Chaouloff 2013; however, see Morin 2014),brainstem, which in
    ...
    abnormally effected.
    {http://brainmind.com/images/HypothalamicPaths18.gif} On

    On
    the other
    ...
    influenced by latitude (e.g. Margnusson & Stefansson 2013; Wirz-Justice et al. 2013).latitude. There is
    ...
    on the hypothalamus (Chauloff 2013).hypothalamus. For example,
    ...
    alterations in serotonin (see Chauloff 2013, for review);serotonin; as well as norepinephrine (Swann et al. 2014) which has
    THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS
    The hypothalamic, pituitary, adrenal system (HPA) is critically involved in the adaption to stressful changes in the external or internal environment. For example, in response to fear, anger, anxiety, disapointment, and even hope, the hypothalamus begins to release corticotropin releasing factor (CRF) which activates the andenohypophysis which begins secreting ACTH which stimulates the adrenal cortex which secretes cortisol (Fink, 2009).
    These events in turn appear to be under the modulating influences of norepinephrine. That is, as stress increases, NE levels decrease, which triggers the activation of the HPA axis. As is well known, low levels of NE are associated with depression.
    {http://brainmind.com/images/HYPOTHLamus1005.jpg}
    {http://brainmind.com/images/Pituitary33.jpg} Normally,
    Normally, cortisol secretion
    Among certain subgroups suffering from depression, it appears that this entire feedback regulatory system and thus the HPA axis is disrupted (Carrol et al. 1976; Sachar et al. 1973). This results in the hypersecretion of ACTH and cortisol with a corresponding decrease in NE; which results in NE induced depression. It was these findings which led to the development of the Dexamethasone suppression test over 25 years ago.
    Via the administration of Dexamethasone (a synthetic corticosteroid) it was determined that many depressed individuals have excess cortisol, and an increased frequency of cortisol secretory episodes (Carrol et al. 1976; Sachar et al. 1973; Swann et al. 2014). Moreover, those who demonstrate excess cortisol were found to respond to NE potentiating agents, whereas those who were depressed but with normal cortisol, responded best to serotonin potentiating compounds (Van Pragg 1982).
    ...
    superimposed over depression (see Swann et al. 2014).depression. These "mixed
    ...
    of their illness (Swann et al. 2014).illness.
    As noted, the hypothalamus may greatly influence circadian activities within the midbrain and pons, and thus the rhythmical secretion of various neurotransmitters. For example, corticotropin-releasing factor acts directly on the locus coeruleus (Valentino et al. 1983) which manufactures NE, and on the raphe thereby influencing serotonin release. These findings suggest a disturbance in circadian or rhythmical control of hypothalamic and midbrain-pontine activity can give rise to depression, or mixed mania in some individuals; women in particular.
    {http://brainmind.com/images/StressHypothalam.jpg}
    Lateralization.
    ...
    and left hemisphere (Robinson 1979).hemisphere. Greater right
    ...
    also been reported (Gerendai, 1984),reported, which in
    PSYCHIC MANIFESTIONS OF HYPOTHALAMIC ACTIVITY: THE ID
    Phylogenetically and from an evolutionary perspective, the appearance and development of the hypothalamus predates the differentation of all other limbic nuclei, e.g., amygdala, septal nucleus, hippocampus (Andy & Stephan, 1961; Brown, 1983; Herrick, 1925; Humphrey, 1972). It constitutes the most primitive, archaic, reflexive, and purely biological aspect of the psyche.
    ...
    The lateral and medial nuclei exert counterbalancing influences which serve to modulate activity occurring in the other. As described by Freud (1911), the pleasure principale not only serves to maximize pleasant experiences, but acts to keep the psyche as a whole free from high levels of excitation (be they pleasurable or unpleasant).
    Like the hypothalamus, the pleasure principle is present from birth and for some time thereafter the search for pleasure is manifested in an unrestricted manner and with a great deal of intensity as there are no oppositional forces (except those between the lateral and medial regions) to counter it's strivings. Indeed, higher order limbic nuclei have yet to mature.
    ...
    acceptance of quiescence (McGraw, 1969; Milner, 1967; Piaget, 1952; Spitz & Wolf, 1946).quiescence.
    It is only with the further differentiation and maturation of higher order limbic nuclei (e.g. amygdala, septal nucleus, hippocampus) that the infant begins to achieve some awareness of external reality and begins to form memories as well as differentiate and associate externally occurring events and individuals.
    AMYGDALA
    {http://brainmind.com/images/LimbicAmyagdala10.jpg}
    In
    In contrast to
    ...
    to the organism (Gaffan 1992; Gloor 1960, 1992, 2010; LeDoux 1992; Morris et al., 2012; Rolls, 1984, 1992 Steklis & Kling, 2005; Kling & Brothers 1992; Ursin & Kaada 1960).organism. This includes
    ...
    to eat.
    {http://brainmind.com/images/amygdala2001.jpg} {http://brainmind.com/images/AmygdalaEmotionaCircuit45.jpg} In

    In
    fact, amygdaloid
    ...
    to eat (Fukuda et al. 2007; Gaffan et al. 1992; O'Keefe & Bouma, 1969; Ono et al. 1980; Ono & Nishijo, 1992) including even
    ...
    anterior cingulate) activity (Childress, et al., 2009).
    {http://brainmind.com/images/AmygdalaDrugs7.jpg} Belying
    activity.
    elying
    its involvement
    ...
    steroid activity (Bubenik & Brown, 1973; Nishizuka & Arai, 1981; see also Simerly, 1990).
    {http://brainmind.com/images/amygdala201.jpg} The
    .
    The
    amygdala is
    ...
    of the face (Gloor, 1992; Halgren, 1992; Kling & Brothers 1992; Morris et al., 2012; Rolls, 1984, 1992).face. In fact,
    ...
    emotions they convey (Hasselmo, Rolls, & Baylis, 1989, Heit et al., 1988; Kawashima, et al., 2009; Rolls, 1984).convey. For example,
    ...
    making eye-to-eye contact (Kawashima, et al., 2009).contact.
    Moreover, the
    ...
    altering its activity (Morris et al., 2012),activity, whereas injury
    ...
    to recognize faces (Young, Aggleton, & Hellawell,2011).faces. With bilateral
    ...
    stimuli is abolished (Lilly, Cummings, Benson, & Frankel, 1983; LeDoux, 2012; Marlowe, Mancall, Thomas,1975; Scott, Young, Calder, Hellawell, Aggleton, & Johnson, 2010; Terzian & Ore, 1955).
    {http://brainmind.com/images/insulaamygdalabrain.jpg} {http://brainmind.com/images/Amygdala2004.gif} Single
    abolished.
    ingle
    amygdaloid neurons
    ...
    to this structure (Dreifuss, et al., 1968).
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    {http://brainmind.com/images/ColoredLimbicSystem34.jpg}
    {http://brainmind.com/images/AmygdalaNuclei3.jpg} {http://brainmind.com/images/amygdalabypass.gif} Direct
    structure.
    Direct
    stimulation of
    ...
    the medial hypothalamus (Dreifuss, et al., 1968).hypothalamus. By contrast,
    ...
    same hypothalamic neurons (Dreifuss, et al., 1968).neurons. Hence, whereas
    ...
    the hypothalamic nuclues (Dreifuss, et al., 1968; Joseph, 1992a; Gloor, 2010).nuclues. Indeed, the
    ...
    aggressive defensive reactions (De vito & Smith, 1982; Hess, 1949).reactions. As indicated
    ...
    to this area (De vito & Smith, 1982).area. And, when
    ...
    hypothalamus becomes activated (Dreifuss, et al., 1968),activated, and defensive
    However, this system is also interactional, especially in regard to sexual activity, fear, anger, hunger, and stress. For example, the hypothalamus can stimulate the amygdala which may then survey the environment so that internal needs may be met, and/or they may act in concert regarding sexual behavior, the stress response, and so on.
    OVERVIEW: AMYGDALA STRUCTURAL FUNCTIONAL ORGANIZATION
    ...
    basal nucleus (Amaral et al., 1992; Stephan & Andy, 1977).. Different authors
    ...
    and Andy (1977) assign the
    ...
    et al., (1977) subdivided the
    ...
    different schemes.
    {http://brainmind.com/images/Amygdala222.jpg} For

    For
    our purposes
    ...
    primates and humans (Amaral et al. 1992; Herrick, 1925; Humphrey, 1972; McDonald 1992; Stephan & Andy, 1977).humans. Of its
    ...
    transmitters, e.g., GABA (Fallon & Ciofi, 1992).GABA.
    The lateral
    ...
    the pleasure circuit (Olds & Forbes, 1981).circuit. By contrast,
    ...
    other subcortical structures (Amaral et al. 1992; Stephan & Andy, 1977).structures.
    Evolution & Embryology
    ...
    of this asymmetry (Murphy et al., 2007).asymmetry. Moreover, over
    ...
    other amygdaloid nuclei (Stephan & Andy, 1977)--thatnuclei--that is, when
    ...
    as the claustrum (Gilles et al., 1983),claustrum, became separated
    ...
    auditory cortex.
    {http://brainmind.com/images/LimbicAmyagdala11.jpg} {http://brainmind.com/images/LimbicAmyagdala12.jpg} The

    The
    amygdala, therefore,
    ...
    course of evolution (Stephan & Andy, 1977),evolution, and has
    ...
    the left (Murphy et al., 2007) which in
    ...
    dominance for emotion (chapter 10).emotion.
    Intrinsic & Extrinsic Organization: The Flow of Information
    ...
    different anatomical interconnections (Amaral et al., 1992; Stephan & Andy, 1977).interconnections. And, they
    ...
    which are excitatory (Rolls, 1992) andexcitatoryand use glutamate (Fallon & Ciofi, 1992) and which
    ...
    to the hippocampus (Amaral et al., 1992).hippocampus.
    Local circuit
    ...
    inhibitory transmitter GABA (Fallon & Ciofi, 1992).GABA. Considered rather
    ...
    temporal lobes (Amarral et al., 1992; Krettek & Price, 1978; Stephan & Andy, 1977; van Hoesen, et al., 1981).. However, the
    ...
    pyramidal axons (Amaral et al, 1992; Carlsen et al. 1982; Gloor, 1955; McDonald 1992; Russchen, 1982; Swanson & Cowan, 1979).
    {http://brainmind.com/images/AmygdalaOutputs2.jpg} It

    It
    appears that
    ...
    influences.
    Moreover, as detailed in chapter 12, the amygdala
    ...
    to the amygdala" (Goor, 2010).amygdala". Moreover, it
    ...
    a seizure.
    {http://brainmind.com/images/AmygdalaPathways130.jpg} In

    In
    addition, the
    ...
    to the amygdala (Amaral et al, 1992; Carlsen et al. 1982; Gloor, 1955; Krettek & Price, 1978; McDonald 1992; Russchen, 1982; Swanson & Cowan, 1979; Stephan & Andy, 1977).amygdala. In addition,
    ...
    evident in primates (Amaral et al., 1992).primates. Hence, this
    The Amygdala-Striatum
    ...
    the lateral ventricle (Humphrey, 1972).ventricle. Specifically, around
    ...
    striatum will emerge (Gilles et al., 1983; Humphrey, 1968).
    {http://brainmind.com/images/ThalamicProjection.jpg}
    Approximately
    emerge.
    Approximately
    one week
    ...
    the amygdala (Gilles et al., 1983; Humphrey, 1968).
    {http://brainmind.com/images/AmygdalaStriatum32.gif} Thus

    Thus
    initially these
    ...
    limbic striatum (Heimer & Alheid, 1991) and through
    ...
    the "striatum accessorium" (Gloor, 2010).accessorium".
    By contrast,the
    ...
    via the striatum (Heimer & Alheid, 1991; Mogenson & Yang, 1991).
    {http://brainmind.com/images/LimbicStriatum0.jpg}
    striatum.
    THE MEDIAL AMYGDALA
    ...
    the septal nucleus (Amaral et al, 1992; Carlsen et al. 1982; Gloor, 1955; McDonald 1992; Russchen, 1982; Swanson & Cowan, 1979).nucleus. The stria
    ...
    vs females (Allen & Gorksi 1992) which suggests
    ...
    is sexually differentiated (Nishizuka & Arai, 1981; see also Simerly, 1990),differentiated, such that
    ...
    of steroidal activity (Nishizuka & Arai, 1981; Simerly, 1990).activity. In fact,
    ...
    total volume (Filipek, et al., 2014) whereas in
    ...
    presence of testosterone (Breedlove & Cooke, 2009).testosterone.
    The female
    ...
    leutenizing hormones (Stopa et al., 1991) which are
    ...
    highest during proestrus (Simerly, 1990).proestrus. Moreover, the
    ...
    are sexually differentiated (e.g. Allen et al., 1989; Gorski, et al., 1978; Le Vay, 1991; Raisman & Field, 1971), anddifferentiatedand which when
    ...
    specific behaviors (Hart et al., 2005; Lisk, 1967, 1971; MacLean, 1973) and, in
    ...
    even maternal behavior (Numan, 2005).behavior. These amygdala
    ...
    are excitatory.
    {http://brainmind.com/images/AmygdalaNuclei3.jpg}
    Because

    Because
    the medial
    ...
    and clitoral tumenence (Kling and Brothers, 1992; MacLean, 1990; Robinson and Mishkin, 1968; Stoffels et al., 1980), thrusing,tumenence, thrusting, sexual moaning,
    ...
    responses, and orgasm (Backman and Rossel, 1984; Currier, Little, Suess and Andy, 1971; Freemon and Nevis,1969; Warneke, 1976; Remillard et al., 1983; Shealy and Peel, 1957).orgasm.
    In addition,
    ...
    the amygdala (Atweh & Kuhar, 1977; Fallon & Ciofi, 1992; Uhl et al. 1978) and the
    ...
    pleasure inducing drgus,drugs, such as cocaine (Childress et al., 2009).cocaine. In this
    LATERAL AMYGDALA
    ...
    including the brinstem (Aggleton et al. 1980; Amaral et al. 1992; Carlsen et al. 1982; Dreifuss et al., 1968; Gloor, 1955, 1960, 2010; Klinger & Gloor, 1960; McDonald 1992; Mehler, 1980; Russchen, 1982).brainstem. Lateral amygdala
    ...
    startle response (Amaral et al., 1992; Davis et al., 2010) as well
    ...
    the pyramidal tract (Amaral et al., 1992).tract. It also
    ...
    the lateral hypothalamus (Mehler, 1980).
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    hypothalamus.
    In general, whereas the medial amygdala is highly involved in motor, olfactory and sexual functioning, the lateral division is intimately involved in all aspects of emotional activity. Hence, it's rich interconnections with the lateral and medial hypothalamus, and the neocortex and those brainstem centers controlling the visceral aspects of affective-motor behavior.
    {http://brainmind.com/images/InputAmygdala13.jpg} TheThe lateral amygdala
    ...
    and emotional significance (Gloor 1992; Herzog & Van Hoesen 1976; Kling et al., 2007; Machne & Segundo, 1956; Mesulam & Mufson, 1982; O'Keefe & Bouma, 1969; Rolls 1992; Steklis & Kling, 2005; Turner et al., 1980; Van Hoesen, 1981).significance. Gustatory and
    ...
    this vicinity (Amaral et al. 1992; Fukuda et al., 2007; Maclean, 1949; Ono et al., 1980) as is
    ...
    parietal cortex (Amaral et al. 1992; McDonald 1992; O'Keefe & Bouma, 1969; Pandya et al. 1973) through which
    The lateral amygdala is highly important in analyzing information received and transferring information back to the neocortex so that further elaboration may be carried out at the neocortical level. It is through the lateral division that emotional meaning and significance can be assigned to as well as extracted from that which is experienced.
    The amygdala, overall, maintains a functionally interdependent relationship with the hypothalamus. It is able to modulate and even control rudimentary emotional forces governed by the hypothalamic nucleus. However, it also acts as the behest of hypothalamically induced drives. For example, if certain nutritional requirements need to be meet, the hypothalamus signals the amygdala which then surveys the external enviornment for something good to eat or drink.
    ...
    time period (Dreifuss et. al. 1968; Rolls 1992).. The amygdala
    ...
    may be attained.attained.\
    ATTENTION
    ...
    were to appear (Gloor, 1955, 1960, 1992; Kaada, 1951; Kapp et al., 1992; Rolls 1992; Ursin & Kaasa, 1960).appear.
    In part,
    ...
    throughout the thalamus (Aggleton et al., 1980; LeDoux, 2012; McDonald, 1992; Russchen, 1982),thalamus, as well
    ...
    to happen (Halgren 1992; Kapp et al., 1992; Ursin & Kaasa, 1960).. The EEG
    ...
    significantly alters (Bagshaw & Benzies, 1968; Kapp et al. 2014; Ursin & Kaada, 1960) and the
    ...
    may freeze (Gloor, 1960; Kapp et al., 1992) -- reactions
    Once a stimulus of potential interest is detected, the amygdala then acts to analyze its emotional-motivational importance and will act to alert other nuclei such as the hypothalamus, brainstem, and striatum, so that appropriate action may take place.
    FEAR, RAGE & AGGRESSION
    Initially, electrical stimulation of the amygdala produces sustained attention and orienting reactions. If the stimulation continues the subject may begin to experience, wariness, fear and/or rage (Cendes et al. 2014; Davis et al., 2010; Gloor 1992; Halgren 1992; LeDoux, 2012; Rosen & Schulkin, 2012; Ursin & Kaada, 1960). When fear follows the attention response, the pupils dilate and the subject will cringe, withdraw, and cower. This cowering reaction in turn may give way to extreme fear and/or panic such that the animal will attempt to take flight.
    {http://brainmind.com/images/AmygdalaActivation.jpg} AmongAmong humans, the
    ...
    and abnormal activation (Davis et al., 2010; Gloor, 1992, Halgren, 1992; LeDoux, 2012; Rosen & Schulkin, 2012).activation. Moreover, unlike
    ...
    licking, and chewing (Anand & Dua, 1955; Ursin & Kaada, 1960).chewing. Indeed, some
    ...
    human will attack (Egger & Flynn, 1963; Gunne & Lewander, 1966; Mark et al., 1972 Ursin & Kaada, 1960; Zbrozyna, 1963).attack. Unlike hypothalamic
    Moreover, rage and attack will persist well beyond the termination of the electrical stimulation of the amygdala. In fact, the amygdala remains electrophysiologically active for long time periods even after a stimulus has been removed (be it external-perceptual, or internal-electrical) such that is appears to contine to process--in the abstract--information even when that information is no longer observable (O'Keefe & Bouma, 1969).
    The amygdala, in addition to sustained electrophysiological activity, has been shown to be heavily involved in the maintenance of behavioral responsiveness even in the absence of an immediately tangible or visible objective or stimulus (O'Keefe & Bouma, 1969). This includes motivating the organism to engage in the seeking of hidden objects or continuing a certain activity in anticipation of achieving some particular long term goal. At a more immediate level, the amygdala is probably very important in object permanance (i.e. the keeping of an object in mind when it is no longer visible) and concrete or abstract anticipation. Anticipation is, of course, very important in the prolongation of emotional states such as fear or anger, as well as the generation of more complex emotions such as anxiety. In this regard, the amygdala is probably important not only in regard to emotion, but in the maintanance of mood states.
    Fear and rage reactions have also been triggered in humans following depth electrode stimulation of the amygdala (Chapman, 1960; Chapman et al., 1954; Heath et al. 1955; Mark et al. 1972). Mark et al. (1972) describe one female patient who following amygdaloid stimulation became irritable and angry, and then enraged. Her lips retracted, there was extreme facial grimmacning, threatening behavior, and then rage and attack--all of which persisted well beyond stimulus termination.
    Similarly, Schiff et al. (1982) describe a man who developed intractable aggression following a head injury and damage (determined via depth electrode) to the amygdala (i.e. abnormal electrical activity). Subsequently, he became easily enraged, sexually preoccupied (although sexually hypoactive), and developed hyper-religiosity and psuedo-mystical ideas. Tumors invading the amygdala have been reported to trigger rage attacks (Sweet et al. 1960; Vonderache, 1940).
    ...
    horrifying results. A famous example of this is Charles Whitman, who in 1966 climbed a tower at the University of Texas and began to indiscriminantly kill people with a rifle (Whitman Case File # M968150. Austin Police Department, Texas, The Texas Department of Public Safety, File #4-38).
    Case Study in Amygdala-Aggression: Charles Whitman
    Charles Whitman was born on June 24, 1941 and even before entering grade school had shown exceptional intellectual promise, was well liked by neighbors and had already shown some mastery of the piano, which he "loved to play." At the age of six he was administered the Stanford Binet tests of intellectual ability and obtained an IQ of 138; thus scoring at the 99.9% rank. He also became enamored by guns; his father being described as a gun fanatic. According to his father, "Charlie could plug a squirrel in the eye by the time he was sixteen." However, Charlie loved animals, was somewhat religiously oriented as a child, was very athlectic, was described as "handsome" and "fun" and "high spirited" and was in many respects the "all American boy." He became an Eagle Scout at age 12, and receiving national recognition as being the youngest Eagle Scout in the world. Within 15 months he had earned 21 merit badges. While in high school he continued these activites, also pitching for the baseball team and managing the football team. After high school he joined the Marines and was described as "the kind of guy you would want around if you went into combat." It was while in the Marines that he got married, and it was during this period that began to show the first subtle signs that something might be amiss.
    He began having occassional bursts of anger. He threatened to "kick the teeth out" of another Marine, was court marshalled, consigned to the brig for 30 days, and reduced in rank. He also began taking copious notes, and developed what is referred to as "hypergraphia" excessive writing--a disturbance associated with the amygdala (Joseph, 2009b).
    Incessantly he began to write and leave himself notes, ranging from the mundane, to the tremendous love he felt for his wife. "Received a call from Kathy... it was fabulous, she sounds so wonderful. I love her so much... I will love her to the day I die. She is the best thing I have in life. My Most Precious Possession."
    {http://brainmind.com/images/CharlesWhitman24.jpg}
    Increasingly, however, he was having trouble with his temper and composed notes offering self-advice as to how to control his growing temper and rage attacks. "CONTROL your anger" he wrote, "Don't let it prove you the fool. SMILE--Its contagious. DON'T be belligerent. STOP cursing. CONTROL your passion; DON'T LET IT lead YOU."
    On February 4, 1964, he purchased a diary. According to Charles: "I opened this diary of my daily events as a result of the peace of mind or release of feelings that I experienced when I started making notes of my daily events...."
    Nevertheless, he also continued to excell and although he had been Court marshalled, he also won a scholarship to attend the University of Texas and to attend classes while still in the Marines. He also became increasingly religious and would often have discussions with his school mates about the nature of God--hyperreligiousness also being associated with an abnormality involving the amygdala (see chapter 9). And, although he was attending classes, he also began to perform volunteer work, while simultaneously holding a part time job, and at times felt overwhelmed with energy, almost manic--mania also being associated with the amygdala (Strakowski et al., 2009) as well as the frontal lobes (Joseph, 1986a, 1988a, 2009a). And, he continued to be well liked and admired. His supervisor at the bank, E. R. Hendricks, described Charles "as a truly outstanding person. Very likeable. Neat. Nice looking... A great guy."
    However, Charles also began suffering terrible headaches, and one day lost his temper in class, pulling a male student bodily from his chair and tossing him from the classroom. Apparently he felt considerable remorse. He also continued to have frequent bouts of anger and on occasion, difficulty concentrating, and was beginning to over eat--increased food consumption being associated with a disturbance of the hypothalamus. Moreover, he began having periods where he couldn't sleep for days at a time--yet another disturbance associated with the hypothalamus, a major sleep center. Charles also realized that something was wrong, and continued writing copious notes to himself, reminding himself to be nice, to control his apetitite, and especially to control temper. But his temper was getting out of control and Charles was gaining weight.
    A close friend, Elaine Fuess, also noticed that something was amiss. "Even when he looked perfectly normal, he gave you the feeling of trying to control something in himself. He knew he had a temper, and he hated this in himself. He hated the idea of cruelty in himself and tried to suppress it."
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    Charles Whitman finally sought professional help and consulted a staff psychiatrist, at the University of Texas Health Center about his periodic and uncontrollable violent impulses. Charles was referred to Dr. Heatly. According to the report written by Dr. Heatly about his session with Whitman, a report which was distributed to the media: "This massive, muscular youth seemed to be oozing with hostility as he initiated the hour with the statement that something was happening to him and he didn't seem to be himself...." Whitman "could talk for long periods of time and develop overt hostility while talking, and then during the same narration show signs of weeping.... Past history revealed a youth who... grew up in Florida where his father was a very successful plumbing contractor... who achieved considerable wealth. He identified his father as being brutal, domineering, and extremely demanding of the other three members of the family." Whitman "married four or five years ago, and served a hitch in the Marines.... He referred to several commendable achievements during his Marine service, but also made reference to a court martial for fighting which resulted in being reduced several grades to private. In spite of this he received a scholarship to attend the University for two years and remained a Marine at the same time... He expressed himself as being very fond of his wife, but admitted that he had on two occasions assaulted his wife physically. He said he has made an intense effort to avoid losing his temper with her... His real concern is with himself at the present moment. He readily admits having overwhelming periods of hostility with a very minimum of provocation... he... also... made vivid reference to thinking about going up on the tower with a deer rifle and start shooting people. ....He was told to make an appointment for the same day next week."
    Instead, Charles apparently decided to climb the tower and to begin killing people. But not before first contacting the police and asking to be arrested. As Charles had not committed a crime, the desk sergeant instead suggested that he see a psychiatrist.
    Several days prior to climbing the tower, Charles Whitman wrote himself a letter:
    "I don't quite understand what it is that compels me to type this letter.... I don't really understand myself these days... Lately I have been a victim of many unusual and irrational thoughts. These thoughts constantly recur, and it requires a tremendous mental effort to concentrate. I consulted Dr. Cochrum at the University Health Center and asked him to recommend someone that I could consult with about some psychiatric disorders I felt I had.... I talked to a doctor once for about two hours and tried to convey to him my fears that I felt overcome by overwhelming violent impulses. After one session I never saw the Doctor again, and since then I have been fighting my mental turmoil alone, and seemingly to no avail. After my death I wish that an autopsy would be performed to see if there is any visible physical disorder. I have had tremendous headaches in the past and have consumed two large bottles of Excedrin in the past three months."
    On August 1, 1966, one day before climbing the tower at the University of Texas, Charles Whitman paid a visit to his mother, who greeted him outside her penthouse and introduced him to the night watchman who noticed that Charles was carrying a big black attache case. According to police reports, Charles must have immediately attacked his mother after they entered the penthouse, and then brutally beat, strangled, and stabbed her to death, crushing the back of her head, smashing her hands, and stabbing her in the chest with a huge hunting knife.
    Later, neighbors told police that the only sounds they heard were that of a "child crying and whimpering," which they found puzzling as no child lived in the penthouse.
    After brutally murdering his mother, Charles cleaned up the mess, and placed her in bed with a notepad laying across and covering up the massive wound in her chest. Charles had left a note. It read: "To Whom It May Concern: I have just taken my mother's life. I am very upset over having done it. However, I feel that if there is a heaven she is definitely there now... I am truly sorry... Let there be no doubt in your mind that I loved this woman with all my heart."
    After killing his mother, Charles returned home, planning on killing his wife "as painlessly as possible.," as he explained in yet another note:
    "It was after much thought that I decided to kill my wife, Kathy, tonight....I love her dearly, and she has been a fine wife to me as any man could ever hope to have. I cannot rationally pinpoint any specific reason for doing this..."
    Apparently she was sleeping, and after removing the blankets to expose her nude body, he viciously stabbed her repeatedly with his huge hunting knife, leaving five gaping holes in her chest. She died instantly.
    Charles wrote another note which he left with the body: "I imagine it appears that I brutally killed both of my loved ones. I was only trying to do a quick thorough job... If my life insurance policy is valid please pay off my debts... donate the rest anonymously to a mental health foundation. Maybe research can prevent further tragedies of this type."
    And then he added a post script beneath his signature: "Give our dog to my in-laws. Tell them Kathy loved "Schoci" very much."
    {http://brainmind.com/images/WhitmanTexasTower.jpg} The next morning Charles Whitman climbed the University tower carrying several guns, a sawed off shotgun, and a high powered hunting rifle, and for the next 90 minutes he shot at everything that moved, killing 14, wounding 38.
    He was finally killed by a police sharp shooter.
    {http://brainmind.com/images/Whitmandead4.jpg} Post-mortem autopsy of his brain revealed a glioblastoma multiforme tumor the size of a walnut, erupting from beneath the thalamus, impacting the hypothalamus, extending into the temporal lobe and compressing the amygdaloid nucleus (Charles J. Whitman Catastrophe, Medical Aspects. Report to Governor, 9/8/66).

    DOCILITY & AMYGDALOID DESTRUCTION
    Bilateral destruction of the amygdala usually results in increased tameness, docility, and reduced aggressiveness in cats, monkeys and other animals (Schreiner & Kling, 1956; Weiskrantz, 1956; Vochteloo & Koolhaas, 2007), including purportedly ferocious creatures such as the agoutie and lynxe (Schreiner & Kling, 1956). In man, bilateral amygdala destruction (via neurosurgery) has been reported to reduce and/or eliminate paroxysmal aggressive and violent behavior (Terzian & Ore, 1955).
    ...
    EMOTIONAL LANGUAGE & THE AMYGDALA
    Although cries and vocalizations indicative of rage or pleasure have been elicited via hypothalamic stimulation, of all limbic nuclei the amygdala is the most vocally active--particularly the lateral division (Robinson, 1967). In humans and animals a wide range of emotional sounds have been evoked through amygdala activation, such as sounds indicative of pleasure, sadness, happiness, and anger (Robinson, 1967; Ursin & Kaada, 1960). The human amygdala can produce as well as perceive emotional vocalizations (Halgren, 1992; Heit, Smith, & Halgren, 1988).
    {http://brainmind.com/images/JosephRightLanguage.jpg}
    Conversely, in humans, destruction limited to the amygdala (Freeman & Williams 1952, 1963), the right amygdala in particular, has abolished the ability to sing, convey melodic information or to properly enunciate via vocal inflection. Similar disturbances occur with right hemisphere damage (chapter 10). Indeed, when the right temporal region (including the amygdala) has been grossly damaged or surgically removed, the ability to perceive, process, or even vocally reproduce most aspects of musical and emotional auditory input is significanlty curtailed (Chapter 21).
    AMYGDALA, THE ANTERIOR COMMISSURE, SEXUALITY & EMOTION,
    When the amygdala or the bed nuclei for the anterior commissure of both cerebral hemispheres are damaged, hyperactivated, or completely inhibited a striking disturbance in sexual and social behavior is evident (Brown & Schaffer, 1888; Gloor, 1960; Kluver & Bucy, 1939; Terzian & Ore, 1955; Schriner & Kling, 1953). Specifically, humans, non-human primates, and felines who have undergone bilateral amygdalectomies will engage in prolonged, repeated, and inappropriate sexual behavior and masturbation including repeated sexual acts with members of different species (e.g. a cat with a dog, a dog with a turtle, etc.).
    {http://brainmind.com/images/KluverBucy101.jpg}
    When activated from seizures, patients may involuntarily behave in a sexual manner and even engage in what appears to be intercourse with an imaginary partner. This abnormality is one aspect of a complex of symptoms sometimes referred to as the Kluver-Bucy syndrome.
    {http://brainmind.com/images/AnteriorCommAmyg.jpg} AsAs noted, portions
    Moreover, despite myths to the contrary, females, regardless of species, are more sexually active than males, on average (see chapter 8)--that is, when they are in estrus-- and the human female is capable of experiencing multiple orgasms of increasing intensity--which may also be a function of sex differences in the amygdala. That is, since female primate amygdala neurons are more numerous and packed more closely together (Bubenik & Brown, 1973; Nishizuka & Arai, 1981), and as smaller, tightly packed neurons demonstrate enhanced electrical excitability, lower response thresholds, and increase susceptibility to kindling and thus hyper-excitation, the amygdala therefore is likely largely responsible for sex differences in emotionality and sexuality.
    Indeed, electrical stimulation of the medial amygdala results in sex related behavior and activity. In females this includes ovulation, uterine contractions and lactogenetic responses, and in males penile erections (Robinson & Mishkin, 1968; Shealy & Peele, 1957). Moreover, in rats and other animals, kindling induced in the amygdala can trigger estrus and produce prolonged female sexual behavior.
    {http://brainmind.com/images/AmygdalAnteriorC.jpg} Moreover,Moreover, the anterior
    ...
    than males.
    {http://brainmind.com/images/SexAmygdala.jpg} In

    In
    contrast, whereas
    Although environmental influences can shape and sculpt behavior and the functional organization of the brain (chapter 28), most sex differences are innate and shared by other species (see chapters 7 & 8); a direct consequence of the presence or absence of testosterone during adulthood and fetal development (see Gerall et al. 1992; Joseph 2013, Joseph et al. 1978) and the sexual differentiation of the limbic system.
    THE LIMBIC SYSTEM & TESTOSTERONE
    In large part these and related sex differences in aggressiveness are also a consequence of the relatively higher concentrations of the activating hormone, testosterone flowing through male bodies and brains. The overarching influence of neurological and hormonal predispositions are also indicated by studies which have shown that females who have been prenatally exposed to high levels of masculinizing hormones (i.e. androgens) behave similar to males even in regard to spatial abilities (Joseph et al. 1978; see Gerall et al. 1992). They are also more aggressive and engage in more rough and tumble play as compared to normal females (Money & Ehrhardt, 1972; Ehrhardt & Baker, 1974; Reinisch, 1974) and this is also true of other species such as dogs, wolves, gorillas, baboons, and chimpanzees.
    {http://brainmind.com/images/LimbicAmyagdala12.jpg} Similarly,Similarly, female primates
    SEXUAL ORIENTATION & HETEROSEXUAL DESIRE
    As noted, the amygdala surveys the environment searching out stimuli, events, or individuals which are emotionally, sexually or motivationally significant. Moreover, it contains facial recognition neurons which are sensitive to different facial expressions and which are capable of determining the sex of the individual being viewed and which become excited when looking at a male vs female face (Leonard et al. 2005; Rolls 1984). In this regard, the amygdala can act to discern and detect potential sexual partners and then motivate sex-appropriate behavior culminating in sexual intercourse and orgasm.
    ...
    The amygdaloid nucleaus via its rich interconnections with other brain regions is able to sample and influence activity occurring in other parts of the cerebrum and add emotional color to ones perceptions. As such it is highly involved in the assimilation and association of divergent emotional, motivational, somesthetic, visceral, auditory, visual, motor, olfactory and gustatory stimuli. Thus it is very concerned with learning, memory, and attention, and can generate reinforcement for certain behaviors. Moreover, via reward or punishment it can promote the encoding, storage and later retrieval of particular types of information. That is, learning often involved reward and it is via the amygdala (in concert with other nuclei) that emotional consequences can be attributed to certain events, actions, or experiences, as well as extracted from the world of possibility so that it can be attended to and remembered.
    Lastly, as is evident from studies of individuals with abnormal activity or seizures originating in or involving this nuclei, the amygdala is able to overwhelm the neocortex and thus gain control over behavior. As based on electrophysiological studies, the amygdala seems capable of literally turning off the neocortex (such as occurs during a seizure) at least for brief time periods. That is, the amygdala can induce electrophysiological slow wave theta activity in the neocortex which indicates low levels of arousal (see below) as well as high voltage fast activity. In the normal brain it probably exerts similar influences such that at times individuals (i.e. their neocortex) "lose control" over themselves and respond in a highly emotionally charged manner.
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    In consequence, after they "explode" or respond "irrationally" they (that is, the neocortex of the left hemisphere) are likely to wonder aloud: "I don't know what came over me."
    But we know the answer: The Limbic System.
    {http://brainmind.com/images/LimbicAmyagdala11.jpg}

    HIPPOCAMPUS
    Memory & Attention
    The hippocampus (Ammon's Horn" or the "sea horse") is an elongated structure located within the inferior medial wall of the temporal lobe (posterior to the amygdala) and surrounds, in part, the lateral ventricle. In humans it consists of an anterior and posterior region and depending on the angle at which it is viewed, could be construed as shaped somewhat like an old fashion telephone receiver, or a "sea horse."
    {http://brainmind.com/images/HippocampusSeahorse.jpg}
    The hippocampus consists of a number of subcomponents, and adjoining structures, such as the parahippocampal gyrus, entorhinal and perirhinal cortex and the uncus (which it shares with the amygdala) are considered by some to be subdivisions, whereas the main body of the hippocampus consists of the dentate gyrus, the subiculum, and sectors referred to as CA1, CA2, CA3, CA4.
    {http://brainmind.com/images/HippocampusLayers1.jpg} TheThe uncus is
    ...
    the hippocampus.
    {http://brainmind.com/images/hippocampus34.jpg}

    HIPPOCAMPAL AROUSAL, ATTENTION & INHIBITORY INFLUENCES
    Various authors have assigned the hippocampus a major role in information processing, including memory, new learning, cognitive mapping of the environment, voluntary movement toward a goal, as well as attention, behavioral arousal, and orienting reactions (Douglas, 1967; Eichenbaum et al. 2014; Enbert & Bonhoeffer, 2009; Frisk & Milner, 1990; Grastayan et al., 1959; Green & Arduini, 1954; Isaacson, 1982; Milner, 1966, 1970, 1971; Nishitani, et al., 2009; Olton et al. 1978; Routtenberg, 1968; Squire, 1992; Victor & Agamanolis, 1990; Xu et al., 2012). For example, hippocampal cells greatly alter their activity in response to certain spatial correlates, particularly as an animal moves about in its environment (Nadel, 1991; O'Keefe, 1976; Olton et al., 1978; Wilson & McNaughton, 2013). It also developes slow wave theta activity during arousal (Green & Arduini, 1954) or when presented with noxious or novel stimuli (Adey et al.1960)--at least in non-humans.
    ...
    These findings suggest when the neocortex is highly stimulated the hippocampus, in order to monitor what is being received and processed, functions at a level much lower in order not to become overwhelmed. When the neocortex is not highly aroused, the hippocampus presumably compensates by increasing its own level of arousal so as to tune in to information that is being processed at a low level of intensity.
    Hence, in situations where both the cortex and the hippocampus become desynchronized, there results distractability and hyperresponsiveness such that the subject becomes overwhelmed, confused, and may orient to and approach several stimuli (Grastyan et al., 1959). Attention, learning, and memory functioning are decreased. Situations such as this sometimes also occur when individuals are highly anxious or repetitively emotionally or physically traumatized (see chapter 30).
    {http://brainmind.com/images/EntorhinalCortex.jpg} TheThe hippocampus consists
    ...
    entorhinal cortex.
    {http://brainmind.com/images/HippocampusEntorhinal.jpg} Hence,

    Hence,
    the hippocampus
    There is also evidence to suggest that the hippocampus may act so as to reduce extremes in cortical arousal. For example, whereas stimulation of the reticular activating system augments cortical arousal and EEG evoked potentials, hippocampal stimulation reduces or inhibits these potentials such that cortical responsiveness and arousal is dampened (Feldman, 1962; Redding, 1967). On the otherhard, if cortical arousal is at a low level, hippocampal stimulation often results in an augmentation of the cortical evoked potential (Redding, 1967).
    {http://brainmind.com/images/HippocampusPathways3.jpg} TheThe hippocampus also
    It is thus likely that the hippocampus may act to influence information reception and storage at the neocortical level as well as possibly reduce extremes in cortical arousal (be they too low or high) perhaps by activating inhibitory circuits in the dorsal medial nucleus, thus ensuring that the neocortex is not over or underwhelmed when engaged in the reception and processing of information. This is an important attribute since very high or very low states of excitation are incompatible with alertness and selective attention as well as the ability to learn and retain information (Joseph et al. 1981; Lupien & McEwen, 2010; Sapolsky, 2012).
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    Aversion & Punishment.
    In many ways, the hippocampus appears to act in concert with the medial hypothalamus and septal nuclei (with which it maintains rich interconnections) so as to also prevent extremes in emotional arousal and thus maintain a state of quiet alertness (or quiescence). Moreover, similar to the results following stimulation of the medial hypothalamus, it has been reported that the subjective components of aversive emotion in humans is correlated with electrophysiological alternations in the hippocampus and septal area (Heath, 1976).
    ...
    LEARNING & MEMORY: THE HIPPOCAMPUS
    The hippocampus is most usually associated with learning and memory encoding, e.g. long term storage and retrieval of newly learned information (Enbert & Bonhoeffer, 2009; Fedio & Van Buren, 1974; Frisk & Milner, 1990; Milner, 1966; 1970; Nunn et al., 2009; Penfield & Milner, 1958; Rawlins, 2005; Scoville & Milner, 1957; Squire, 1992; Victor & Agamanolis, 1990) particularly the anterior regions. Hence, if the hippocampus has been damaged the ability to convert short term memories into long term memories (i.e. anterograde amnesia), becomes significantly impaired in humans (MacKinnon & Squire, 1989; Nunn et al., 2009; Squire, 1992; Victor & Agamanolis, 1990) as well as primates (Zola-Morgan & Squire, 1984, 2005a, 1986). In humans, memory for words, passages, conversations, and written material is also significantly impacted, particularly with left hippocampal destruction (Frisk & Milner, 1990; Squire, 1992).
    {http://brainmind.com/images/Hippocampusmemory1.jpg} BilateralBilateral destruction of
    ...
    anterograde amnesia). For example, one such individual who underwent bilateral destruction of this nuclei (H.M.), was subsequently found to have almost completely lost the ability to recall anything experienced after surgery. If you introduced yourself to him, left the room, and then returned a few minutes later he would have no recall of having met or spoken to you. Dr. Brenda Milner has worked with H.M. for almost 20 years and yet she is an utter stranger to him.
    {http://brainmind.com/images/HippocampusSeptal.jpg} {http://brainmind.com/images/hippocampus101.jpg}
    {http://brainmind.com/images/HMHippocampus.jpg} H.M. is in fact so amnesic for everything that has occurred since his surgery (although memory for events prior to his surgery is comparatively exceedingly well preserved), that every time he rediscovers that his favorite uncle died (actually a few years before his surgery) he suffers the same grief as if he had just been informed for the first time.
    H.M., although without memory for new (non-motor) information, has adequate intelligence, is painfully aware of his deficit and constantly apologizes for his problem. "Right now, I'm wondering" he once said, "Have I done or said anything amiss?" You see, at this moment everything looks clear to me, but what happened just before? That's what worries me. It's like waking from a dream. I just don't remember...Every day is alone in itself, whatever enjoyment I've had, and whatever sorrow I've had...I just don't remember" (Blakemore, 1977, p.96).
    Presumably

    Presumably
    the hippocampus
    ...
    learning) is attenuated (Douglas, 1967).attenuated.
    THE SEPTAL NUCLEI
    HIPPOCAMPAL & SEPTAL INTERACTIONS
    The septal nuclei consists of medial and lateral nuclei, and can be further subdivided into several nuclear components (Ariens Kappers et al., 1936; Swanson & Cowan, 1979), such as the nucleus of the diagonal band of Broca. The septal nuclei is an evolutionary derivative of the hippocampus and the hypothalamus, and in the human brain is richly interconnected with both structures including the amygdala, and the substantia innomminata (SI) which is a major memory center, and which manufactures ACh--a transmitter directly implicated in memory (Gage et al., 1983; Olton, 1990). Andy and Stephan (1968) and Swanson and Cowan (1979) considered the bed nucleus of the stria terminals (which gives rise to a major pathway linking the septal nuclei, and amygdala and hypothalamus) as part of the septal nuclei, whereas others (Gloor, 2010) consider it to be part of the "extended amygdala." Likewise, some consider the nucleus accumbens as part of the septal nuclei, and others consider it part of the "extended amygdala;" i.e. the limbic striatum.
    {http://brainmind.com/images/ColoredLimbicSystem34.jpg}
    As noted the septal nuclei is massively interconnected with the hippocampus as well as with the entorhinal cortex (Swanson & Cowan, 1979) via a number of pathways, including the fornix. Directly implicating the septal nuclei in the memory functioning of the hippocampus is the finding that septal activation of this structure results in ACh secretion (Gage et al., 1983), whereas septal grafts into the hippocampus improves learning and memory (Gage et al., 1986). Conversely, lesions of the fimbria-fornix septal-hippocampal pathway results ACh depletion throughout the hippocampus (Gage et al., 1983; Olton, 1990), as well as loss of norepinephrine and serotonin coupled with memory loss (Olton, 1990).
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    {http://brainmind.com/images/HippocampusPathways3.jpg}

    The septal nucleus in part regulate hippocampal memory-related activity not only by stimulating ACh and other neurotransmitter production (Gage et al., 1983, 1986), but as it provides excitatory input and inhibitory-GABAnergic-- especially from the medial septal nuclei which in general exerts inhibitory influences not only on the hippocampus but the amygdala and hypothalamus. In general, it is supposed that the excitatory-inhibitory influences on the hippocampus (like those on the amygdala and hypothalamus) serve to modulate activity and prevent extremes in arousal (Joseph, 1992a, 2012b, 2009d). This is accomplished in part not only through the interconnections maintained with the amygdala, hypothalamus and entorhinal cortex, but the brainstem reticular formation (Petsche et al., 1965)--with which the hippocampus is also connected directly and via the entorhinal cortex.
    Septal influences on hippocampal/entorhinal arousal is also indicated by fluctuations in rhythmic slow activity (theta), which is generated by both the hippocampus and entorhinal cortex (Alonso & Garcia-Austt, 2007). As detailed in chapter 14, theta is an indication of hippocampal arousal (Green & Arduini, 1954; Petsche et al., 1965; Vanderwolf, 1992) and is associated with learning and memory (O'Keefe & Nadel, 1978). Theta is a robust electrophysiological phenomenon which has been found in the hippocampus of most species studied, including monkeys (Stewart & Fxx, 1990) and humans (Sano et al., 1970); though in primates it seems to differ from the theta rhythm of non-primates (see Gloor, 2010).
    O'Keefe and Nadel (1978) believe that theta plays an important role in creating the spatial maps that are maintained by hippocampal "place" neurons; i.e. pyramidal neurons which are attuned to specific environmental features and landmarks and the animals place in that environment as they move about. Moreover, long term potentiation (LTP) which is associated with learning and memory, is generated in those neurons demonstrating theta or activity that is at the "theta frequency" (Staubli & Lynch, 2007).
    Neurons of the septal nucleus which innervate the hippocampus fluctuate in activity in parallel with changes in the theta rhythm (Petsche et al., 1965), whereas septal lesions abolish hippocampal theta (Green & Arduini, 1954). It has long been believed that septal neurons act as an interface between the reticular formation and the hippocampus (Petsche et al., 1965) and in conjunction with its connections with the amygdala and hypothalamus, therefore modulate hippocampal arousal as well as learning and memory.
    {http://brainmind.com/images/SeptalHippAmyg.gif}
    HIPPOCAMPAL & AMYGDALOID INTERACTIONS: MEMORY
    It has been argued that significant impairments involving short-term memory and motor learning, cannot be produced by lesions supposedly restricted to the hippocampus (Horel, 1978; see also commentary in Eichenbaum et al. 2014); though in fact it is impossible to create such "restricted" lesions. Nevetheless, ignoring for the moment that inconvenient fact, in some instances with supposed restricted lesions, good recall of new information is possible for at least several minutes (Horel, 1978; Penfield & Milner, 1958; Squire 1992).
    ...
    The amygdala becomes particularly active when recalling personal and emotional memories (Halgren, 1992; Heath, 1964; Penfield & Perot, 1963), and in response to cognitive and context determined stimuli regardless of their specific emotional qualities (Halgren, 1992). However, once these emotional memories are formed, it sometimes requires the specific emotional or associated visual context to trigger their recall (Rolls, 1992; Halgren, 1992). If those cues are not provided or ceased to be available, the original memory may not be triggered and may appear to be forgotten or repressed. However, even emotional context can trigger memory (see also Halgren, 1992) in the absence of specific cognitive cues.
    Similarly, it is also possible for emotional and non-emotional memories to be activated in the absence of active search and retrieval, and thus without hippocampal or frontal lobe participation. Recognition memory which may be triggered by contextual or emotional cues. Indeed, there are a small group of neurons in the amygdala, as well as a larger group in the inferior temporal lobe which are involved in recognition memory (Murray, 1992; Rolls, 1992). Because of amygdaloid sensitivity to visual and emotional cues, even long forgotten memories may be evoked via recognition, even when search and retrieval repeatedly fail to activate the relevant memory store.
    {http://brainmind.com/images/amygdala%20hippocampus22.jpg}
    According to Gloor (1992), "a perceptual experience similar to a previous one can through activation of the isocortical population involved in the original experience recreate the entire matrix which corresponds to it and call forth the memory of the original event and an appropriate affective response through the activation of amygdaloid neurons." This can occur "at a relatively non-cognitive (affective) level, and thus lead to full or partial recall of the original perceptual message associated with the appropriate affect."
    In this regard, it appears that the amygdala is responsible for emotional memory formation whereas the hippocampus is concerned with storing verbal-visual-spatial and contextual details in memory. Thus, in rats and primates damage to the hippocampus can impair retention of context, and contextual fear conditioning, but it has no effect on the retention of the fear itself or the fear reaction to the original cue (Kim & Fanselow 1992; Phillips & LeDoux 1992, 2012; Rudy & Morledge 2014). In these instances, fear-memory is retained due to preservation of the amygdala. However, when both the amygdala and hippocampus are damaged, striking and profound disturbances in memory functioning result (Kesner & Andrus, 1982; Mishkin, 1978).
    {http://brainmind.com/images/HippocampusAmygdalaNetwork5.jpg}
    Therefore, the role of the amygdala in memory and learning seems to involve activities related to reward, orientation, and attention, as well as emotional arousal and social-emotional recognition (Gloor, 1992, 2010; Rolls, 1992; Sarter & Markowitsch, 2005). If some event is associated with positive or negative emotional states it is more likely to be learned and remembered. That is, reward increases the probability of attention being paid to a particular stimulus or consequence as a function of its association with reinforcement (Gaffan 1992; Douglas, 1967; Kesner & Andrus, 1982).
    Moreover, the amygdala appears to reinforce and maintain hippocampal activity via the identification of motivationally significant information and the generation of pleasurable rewards (through action on the lateral hypothalamus). However, the amygdala and hippocampus act differentially in regard to the effects of positive vs. negative reinforcement on learning and memory, particularly when highly stressed or repetitively aroused in a negative fashion. For example, whereas the hippocampus produces theta in response to noxious stimuli the amygdala increases its activity following the reception of a reward (Norton, 1970).
    ...
    It is now very well known that lesions involving the mesial-inferior temporal lobes (i.e. destruction or damage to the amygdala/hippocampus) of the left cerebral hemisphere typically produce significant disturbances involving verbal memory--particularly as constrasted with individuals with right sided destruction. Left sided damage disrupts the ability to recall simple sentences, complex verbal narrative passages, or to learn verbal paired-associates or a series of digits (Frisk & Milner 1990; Milner, 1966, 1970, 1971; Squire 1992).
    In contract, right temporal destruction typically produces deficits involving visual memory, such as the learning and recall of geometic patterns, visual or tactile mazes, locations, objects, emotional sounds, or human faces (Corkin, 1965; Milner, 1965; Nunn et al., 2009; Kimura, 1963). Right sided damage also disrupts the ability to recognize (via recall) olfactory stimuli (Rausch et al. 1977), or recall emotional passages or personal memories (Cimino et al., 1991; Wechsler, 1973).
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    It appears, therefore, that the left amygdala and hippocampus are highly involved in processing and/or attending to verbal information, whereas the right amygdala/hippocampus is more involved in the learning, memory and recollection of non-verbal, visual-spatial, environmental, emotional, motivational, tactile, olfactory, and facial information. These issues and the differing roles of these nuclei in memory formation, as well as amnesia and repression will be discussed in greater detail in chapters 29, 30.
    THE PRIMARY PROCESS
    ...
    For example, stimulation of the right amygdala produces complex visual hallucinations, body sensations, deja vu, illusions, as well as gustatory and alimentary experiences (Weingarten et al. 1977), whereas Freeman and Williams (1963) have reported that the surgical removal of the right amygdala in one patient abolished hallucinations. Stimulation of the right hippocampus has also been associated with the production of memory- and dream-like hallucinations (Halgren et al. 1978; Horowitz et al. 1968).
    The amygdala also becomes activated in response to bizarre stimuli (Halgren, 1992). Conversely, if activated to an abnormal degree, it may in turn produce bizarre memories and abnormal perceptual experiences. In fact, the amygdala contributes in large part to the production of very sexual as well as bizarre, unusual and fearful memories and mental phenomenon including dissociative states, feelings of depersonalization, and hallucinogenic and dream-like recollections (Bear, 1979; Gloor, 1986, 1992, 2010; Horowitz et al. 1968; Mesulam, 1981; Penfield & Perot, 1963; Weingarten et al. 1977; Williams, 1956). In addition, sexual feelings and related activity and behavior are often evoked by amygdala stimulation and temporal lobe seizures (Halgren, 1992; Jacome, et al. 1980; Gloor, 1986, 2010; Remillard, et al. 1983; Robinson & Mishkin, 1968; Shealy & Peele, 1957), including memories of sexual intercourse (Gloor 1990) or severe emotional trauma and abuse (Gloor, 2010).
    ...
    left their body (Bear 1979; Gloor 1986, 1992; Horowitz, Adams & Rutkin 1968; MacLean 1990; Mesulam 1981; Penfield & Perot 1963; Schenk, & Bear 1981; Weingarten, et al. 1977; Williams 1956).body.
    LSD.
    As is well known, LSD can elicit profound hallucinations involving all spheres of experience. Following the administration of LSD high amplitude slow waves (theta) and bursts of paroxysmal spike discharges occurs in the hippocampus and amygdala (Chapman & Walter, 1965; Chapman et al. 1963), but with little cortical abnormal activity. In both humans and chimps, when the temporal lobes, amygdala and hippocampus are removed, LSD ceased to produce hallucinatory phenomena (Baldwin et al. 1959; Serafintides, 1965). Moreover, LSD induced hallucinations are significantly reduced when the right vs. left temporal lobe has been surgically ablated (Serafintides, 1965).
    {http://brainmind.com/images/HippocampusAmygdala42.jpg}
    Overall, it appears that the amygdala, hippocampus, and the neocortex of the temporal lobe are highly interactionally involved in the production of hallucinatory experiences. Presumably, it is the neocortex of the temporal lobe which acts to interpret this material (Penfield & Perot, 1963) as perceptual phenomena. Indeed, it is the interrelated activity of the temporal lobes, hippocampus and amygdala which not only produce memories and hallucinations, but dreams. In fact, the amygdalas involvement in all aspects of emotion and sexual functioning, including associated memories, the production of overwhelming fear as well as bizarre and dream-like mental phenomenon, may well account for why this type of unusual stimuli, including personal and innocuous memories also appears in dreams.
    DREAMING
    ...
    Nevertheless, the cry does not produce the immediately desire relief or reduction in tension. There is thus a pressure on the limbic system and the organism to engage in environmental surveillance so as to meet the needs monitored by the hypothalamus.
    Over the course of the first months of life, as the amygdala and then hippocampus develop, the organism begins to develop an eye that not only sees outward, but which can register and recall events, objects, people, etc., associated with tension reduction, pleasure and the satiaty of the infants internal needs (e.g. the taste, smell, feeling of mother's breast and milk, the experience of sucking and relief, etc.). This is called learning.
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    With the maturation of these two limbic nuclei the infant is increasingly able to differentiate what occurs in the external environment based on hypothalamically monitored needs and the emotional/motivational significance of that which is experienced. The infant can now orient, selectively attend, determine what brings satisfaction, and store this information in memory.
    PRIMARY IMAGERY
    ...
    Since the hypothalamus (which monitors internal homeostasis) is not conscious that the dream images experienced are not real, it initially accepts the memory/dream images transmitted from the amygdala and hippocampus and ceases to cry, i.e. it responds to the imagined sources of nourishment just as it responds to a cue-tone associated with a food reward (Nakamuar & Ono, 1986; Ono et al., 1980). However, the hypothalamus is not long fooled, for the primary process does not offer effective long lasting relief from tension. As the pain of hunger remains and increases, limbic activity is increased, and the image falls away to be replaced by a cry of hunger (Joseph, 1982). The amygdala and hippocampus are thus forced to renew their surveillance of the environment in search of sources of tension reduction. Cognitive development is thus promoted.
    "Whatever was thought of (desired) was simply imagined in an hallucinatory form, as still happens today with our dream-thoughts every night. This attempt at satisfaction by means of hallucination was abandoned only in consequence of the absence of the expected gratification, because of the disappointment experienced. Instead, the mental apparatus had to decide to form a conception of the real circumstances in the outer world and to exert itself to alter them...The increased significance of external reality heightened the significance also of the sense-organs directed towards the outer word, and of the consciousness attached to them; the later now learned to comprehend the qualities of sense in addition to the qualities of pleasure and "pain" which hitherto had alone been of interest to it. A special function was instituted which had periodically to search the outer word in order that its data might be already familiar if an urgent need should arise; this function was attention. Its activity meets the sense-impressions halfway, instead of awaiting their appearance. At the same time there was probably introduced a system of notation, whose task was to deposit the results of this periodical activity of consciousness--a part of that which we call memory" (Freud, 1911, pp. 410-411).
    THE LIMBIC SYSTEM
    Foundations of Social, Sexual, Emotional Behavior, love & Memory
    THE BRAIN RESEARCH LABORATORY
    I. The Evolution of the Olfactory/Limbic SystemII. Hypothalamus
    A. Lateral & Ventromedial Hypothalamic nuclei
    B. Hunger & Thrist
    C. Pleasure & Reward
    D. Emotion Incontinence: Laughter & Rage
    III. Psychological Manifestations of Hypothalamic Activity
    IV. Amygdala
    A. Medial & Lateral Amygdala Nuclei
    B. The Amygdala & Hypothalamus
    C. Fear, Rage, Aggression
    D. Social-Emotional Agnosia
    V. Septal Nuclei
    A. Rage & Quiescence
    B. Contact Comfort & Septal Social Functioning
    VI. Emotional Attachment & Amygdala-Septal Interactions
    A. Limbic Abnormalities in Love & Socialization Skills
    VII. The Cingulate Gyrus
    A. The Evolution of Maternal Care
    VIII. Limbic Language
    A. Limbic Localization of Emotional Sound Production
    B. Limbic Language & Mother-Infant Vocalization
    IX. Sexual Differentiation of the Hypothalamus & Amygdala
    A. Sex Differences in Language & Cognition
    B. Sex Differences in Emotion
    X. Hippocampus
    A. Arousal, Attention & Inhibition
    B. Learning & Memory
    C. Hippocampal & Amygdala Interactions: Memory
    D. Visual & Verbal Memory
    THE LIMBIC SYSTEM is buried within the depths of the cerebrum and consists of a collection of ancient brain structures which are preeminent in the mediation and expression of emotional, motivational, sexual, and social behavior. The limbic system is involved in learning and the formation of new memories, monitors internal homeostasis and basic needs such as hunger and thirst, controls the secretion of hormones involved in pregnancy and reactions to stress, and even makes possible the ability to experience orgasm, depression, fear, rage, and love.
    Broadly, these limbic system nuclei include the hypothalamus, amygdala, hippocampus, septal nuclei, and cingulate gyrus. Also related to limbic system functioning are portions of the reticular activating system, the orbital frontal and inferior temporal lobes, as well as parts of the thalamus and cerebellum. Indeed, the limbic system is not only exceedingly ancient but originally provided the foundation for the development and evolution of much of the brain.
    I. THE EVOLUTION OF THE OLFACTORY/LIMBIC SYSTEM
    About 1 billion years ago a cellular metamorphosis of paramount importance resulted in the creation of a completely unique type of cell, the neuron. These nerve cells in turn were especially responsive to light as well as chemical (olfactory and pheromonal) messages. Over the course of evolution, as the number of secreting and transmitting nerve cells that a creatures possessed increased, a network of interlinked neurons, called the "nerve net" was soon fashioned. Soon tiny neural ganglia, composed of colonies of similarly functioning nerve cells began to form in the anterior head region of various ancient and primitive creatures.
    By time the first vertebrates and fish begin to swim the oceans, around 500 million years ago, the first primitive lobes of the brain had also become fashioned through the collectivization of these neural ganglia. This included the olfactory-limbic lobe (the forebrain), which was concerned with the detection of olfactory/pheromonal chemicals that might betray the presence of a predators, prey, or a mate; the optic lobe/tectum of the midbrain which was responsive to visual messages, and the hindbrain which was concerned with movement. By 450,000 years ago, the first sharks had acquired a limbic system, which they, like modern humans, still possess today.
    II. HYPOTHALAMUS
    The hypothalamus is an exceedingly ancient structure and unlike most other brain regions it has maintained a striking similarity in structure throughout phylogeny and apparently over the course of evolution. The hypothalamus is fully functional at birth and is highly involved in all aspects of endocrine, hormonal, visceral and autonomic functions and mediates or exerts controlling influences on eating, drinking, the experience of pleasure, rage, and aversion. The hypothalamus is the central core from which all emotions derive their motive force.
    The hypothalamus is also sexually differentiated. That is, structurally and functionally the hypothalamus of men and women are sexually dissimilar.
    A. LATERAL & VENTROMEDIAL HYPOTHALAMIC NUCLEI
    Although the hypothalamus consists of several distinct regions and subgroups, the lateral and medial (ventromedial) hypothalamic nuclei play particularly important roles in almost all aspects of emotion and internal homeostasis. They also appear to share a somewhat antagonistic relationship and act to exert counterbalancing influences on each other.
    For example, the medial hypothalamus controls parasympathetic activities (e.g. reduction in heart rate, increased peripheral circulation) and exerts a dampening effect on certain forms of emotional/motivational arousal. The lateral hypothalamus mediates sympathetic activity (increasing heart rate, elevation of blood pressure) and is involved in controlling the metabolic and somatic correlates of heightened emotionality.
    B. HUNGER & THIRST
    The lateral and medial region are highly involved in monitoring internal needs such as hunger and thirst. For example, both nuclei contain receptors which are sensitive to the body's fat content (lipostatic receptors) and to circulating metabolites such as glucose, which together indicate the need for food and nourishment. The lateral hypothalamus also appears to contain osmoreceptors which determine if water intake should be altered. Both hypothalamic nuclei also become highly active immediately prior to and while the organism is eating or drinking.
    For example, the lateral region alters it's activity when the subject is hungry and simply looking at food. If the lateral hypothalamus is electrically stimulated a compulsion to eat and drink results. Conversely, if the lateral area is destroyed there results aphagia and adipsia so severe animals will die of starvation. If the medial hypothalamus is surgically destroyed, inhibitory influences on the lateral region appear to be abolished such that hypothalamic hyperphagia and severe obesity result.
    Overall, it appears that the lateral hypothalamus is involved in the initiation of eating and acts to maintain a lower weight limit such that when the limit is reached the organism is stimulated to eat.
    Conversely, the medial regions seems to be involved in setting a higher weight limit such that when these levels are approached it triggers the cessation of eating. That is, the medial area seems to act as a satiety center; but, a center that can be overridden. In part, these nuclei exert these differential influences on eating and drinking via motivational/emotional influences they exert on other brain nuclei (e.g. via reward or punishment).
    C. PLEASURE & REWARD.
    In 1952, R.G. Heath reported what was then considered remarkable. Electrical stimulation near the septal nuclei elicited feelings of pleasure in human subjects: "I have a glowing feeling. I feel good!" Subsequently, in 1954 James Olds and Peter Milner reported that rats would tirelessly press a lever in order to receive electrical stimulation via tiny electrodes planted in this same region. Olds and Milner, in fact, concluded that stimulation in this region of the brain "has an effect which is apparently equivalent to that of a conventional primary reward." Even hungry animals would demonstrate a preference for self-stimulation over food.
    Feelings of pleasure have since been obtained following electrical excitation to a number of diverse limbic areas including the olfactory bulbs, amygdala, hippocampus, cingulate gyrus, the basal ganglia, thalamus, reticular formation, medial forebrain bundle, and orbital frontal lobes. However, the greatest area of concentration and the highest rates of self-stimulatory activity were found to occur in the lateral hypothalamus. Indeed, according to Olds, animals "would continue to stimulate as rapidly as possible until physical fatigue forced them to slow or to sleep."
    More recently, the lateral hypothalamus (as well as the amygdala and other limbic nuclei) have been found to have nerve cells which produce and are responsive to opiate-like substances, i.e. enkephalins. Hence, when an individual is injected to with various narcotic substances, it is these limbic nuclei which respond with feelings of pleasure.
    In contrast to the lateral hypothalamus and it's involvement in pleasurable self-stimulation, activation of the medial hypothalamus is so aversive that subjects will work to reduce it --apparently so as to obtain relief (e.g. active avoidance).
    In this regard, when considering behavior such as eating, it might be postulated that when upper weight limits (or nutritional requirements) are met, the medial hypothalamus becomes activated which in turn leads to behavior which terminates it's activation (e.g. cessation of eating). In fact, it is probably in this manner that the hypothalamus is able to exert considerable influence on a variety of behaviors, either acting to reward one's actions, or to generate feelings of aversion so that one is less likely to act in a similar manner in the future.
    D. EMOTIONAL INCONTINENCE: LAUGHTER & RAGE
    Although highly involved in all aspects of emotion and motivational functioning, the emotional states elicited by the hypothalamus are very primitive, diffuse, undirected and unrefined, being limited to pleasure in general, or aversion/unpleasure in general. It is for this reason that ancient and primitive animals are also very limited in their ability to express and perceive emotion. Higher order emotional reactions (e.g. desire, love, hate, etc.) require the involvement of other limbic regions as well as the participation of the more recently evolved regions of the brain, the neocortex (i.e. "new brain").
    Nevertheless, due to its involvement in the generation of positive and negative emotions, not surprisingly, when the hypothalamus has been injured or is made to function abnormally, extremely positive or negative reactions can also be elicited, including rage and uncontrolled laughter. For example, laughter has been noted to occur with hilarious or obscene speech--usually as a prelude to stupor or death--in cases where tumor has infiltrated the hypothalamus. In several instances it has been reported that in the course of neurosurgery involving the hypothalamus, patients "became lively, talkative, joking, and whistling each time the hypothalamus was manipulated."
    In one case, the patient became excited and began to sing. Some individuals with hypothalamic damage have in fact died laughing. However, such patients claim that their laughter does not reflect there true feelings. Hence, laughter in these instances has been referred to as "sham mirth." Moreover, the type of emotional reaction elicited is dependent on which region of the hypothalamus has been injured or activated.
    Stimulation of the lateral hypothalamus, for example, can induce extremes in emotionality, including intense attacks of rage accompanied by biting and attack upon any moving object. If this nucleus is destroyed, aggressive and attack behavior is abolished.
    Hence, the lateral hypothalamus is responsible for rage and aggressive behavior, including attack and predatory actions, which coincides with its involvement with eating. In contrast, stimulation of the medial region counters the lateral hypothalamus such that rage reactions are reduced or eliminated. If the medial region is destroyed there results lateral hypothalamic release and the triggering of extreme savagery.
    Nevertheless, like "sham mirth", rage reactions elicited in response to direct electrical activation of the hypothalamus immediately and completely dissipate when the stimulation is removed. As such, these outbursts have been referred to as "sham rage".
    III. PSYCHOLOGICAL MANIFESTATIONS OF HYPOTHALAMIC ACTIVITY
    Phylogenetically and from an evolutionary perspective, the appearance and development of the hypothalamus predates the emergence and differentiation of all other limbic nuclei, e.g., amygdala, septal nucleus, hippocampus. It constitutes the most primitive, archaic, reflexive, and purely biological aspect of the psyche.
    Biologically the hypothalamus serves the body tissues by attempting to maintain internal homeostasis and by providing for the immediate discharge of tensions in an almost reflexive manner. Hence, as based on studies of lateral and medial hypothalamic functioning, it appears to act reflexively, in an almost on/off manner so as to seek or maintain the experience of pleasure and escape or avoid unpleasant, noxious conditions.
    Emotions elicited by the hypothalamus are largely undirected, short-lived, and unconnected with events occurring within the external environment, being triggered reflexively and without concern or understanding regarding consequences. Direct contact with the real world is quite limited and almost entirely indirect as the hypothalamus is largely concerned with the internal environment of the organism. It has no sense of morals, danger, values, logic, etc., and cannot feel or express love or hate. Although quite powerful, hypothalamic emotions are largely undifferentiated, consisting of feelings such as pleasure, unpleasure, aversion, rage, hunger, thirst, etc.
    As the hypothalamus is concerned with the internal environment much of it's activity occurs outside conscious-awareness. Moreover, being involved in maintaining internal homeostasis, via, for example, it's ability to reward or punish the organism with feelings of pleasure or aversion, it tends to serve what Sigmund Freud described as the "pleasure principle".
    IV. AMYGDALA
    In contrast to the primitive hypothalamus, the amygdala is preeminent in the control and mediation of all higher order emotional and motivational activities, including the capacity to form emotional attachments and to feel love. Neurons located in the amygdala are able to monitor and abstract from the sensory array stimuli that are of motivational significance so as to organize and express appropriate feelings and behaviors. This includes the ability to discern and express even subtle social-emotional nuances such as friendliness, fear, affection, distrust, anger, etc., and at a more basic level, determine if something might be good to eat. In fact, amygdaloid neurons respond selectively to the flavor of certain preferred foods, as well as to the sight or sound of something that might be especially desirable to eat.
    Moreover, some neurons located in the amygdala are responsive to faces and facial emotions conveyed by others. Many neurons are also able to respond to visual, tactual, olfactory, and auditory stimuli simultaneously. Hence, many amygdaloid neurons are predominantly polymodal, responding to a variety of stimuli from different modalities. It is in this manner that the amygdala has come to be involved not only in emotion, but attention, and learning and memory, for multimodal assimilation of various sensory impressions occurs in this region.
    A. MEDIAL & LATERAL AMYGDALA NUCLEI
    The amygdala is buried within the depths of the anterior-inferior temporal lobe and consists of two major nuclear groups. These are a phylogenetically ancient anteromedial group (or medial amygdala) which is involved in olfaction, pheromonal perception, and motor activity (via rich interconnections with the basal ganglia), and a relatively newer basolateral division (lateral amygdala) which is maximally developed among humans.
    Like the lateral and medial hypothalamus, the medial and lateral amygdala are rich in opiate receptors and cells containing enkephalins and both subserve different functions. For example, the medial amygdala is highly involved in motor, olfactory and sexual functioning, whereas the lateral division is intimately involved in all aspects of higher order emotional activity including the generation of selective attention. That is, the amygdala acts to perform environmental surveillance and can trigger orienting responses as well as mediate the maintenance of attention if something of interest or importance were to appear. Hence, electrical stimulation of the lateral division can initiate quick and/or anxious glancing and searching movements of the eyes and head such that the organism appears aroused and highly alert as if in expectation of something that is going to happen.
    Indeed, via its rich interconnections with the inferior, middle, and superior temporal lobes, as well as other neocortical regions, the lateral amygdala is able to sample and influence the auditory, somesthetic, and visual information being received and processed in these areas, as well as scrutinize this information for motivational and emotional significance. It is through the lateral division that emotional meaning and significance can be assigned to as well as extracted from that which is experienced.
    B. THE AMYGDALA & HYPOTHALAMUS
    The amygdala, overall, maintains a functionally interdependent relationship with the hypothalamus. It is able to modulate and even control rudimentary emotional forces governed by the hypothalamic nucleus. However, it also acts as the behest of hypothalamically induced drives. For example, if certain nutritional requirements need to be meet, the hypothalamus signals the amygdala which then surveys the external environment for something good to eat. On the other hand, if the amygdala via environmental surveillance were to discover a potentially threatening stimulus such as a predator, it acts to excite and drive the hypothalamus as well as the motor centers, so that the organism is mobilized to take appropriate action.
    When the hypothalamus is activated by the amygdala, instead of responding in an on/off manner, cellular activity continues for an appreciably longer time period. The amygdala can tap into the reservoir of emotional energy mediated by the hypothalamus so that certain ends may be attained.
    C. FEAR, RAGE & AGGRESSION
    Initially, electrical stimulation of the amygdala produces sustained attention and orienting reactions. If the stimulation continues fear and/or rage reactions are elicited. When fear follows the attention response, the pupils dilate and the subject will cringe, withdraw, and cower. This cowering reaction in turn may give way to extreme fear and/or panic such that the animal will attempt to take flight.
    Among humans, the fear response is one of the most common manifestations of amygdaloid electrical stimulation. Moreover, unlike hypothalamic on/off emotional reactions, attention and fear reactions can last up to several minutes after the stimulation is withdrawn. In addition to behavioral manifestations of heightened emotionality, amygdaloid stimulation can also result in intense changes in emotional facial expression. This includes facial contortions, baring of the teeth, dilation of the pupils, widening or narrowing of the eye-lids, flaring of the nostrils, tearing, as well as sniffing, licking, and chewing. In fact, epileptic seizure activity in this area (i.e. temporal lobe epilepsy) often induces involuntary chewing, and smacking of the lips and licking.
    In many instances, rather than fear, stimulation of the amygdala results in anger, irritation, and rage which seems to gradually build up until finally the animal or human will attack. Unlike hypothalamic "sham rage", amygdaloid activation results in attacks directed at something real, or, in the absence of an actual stimulus, at something imaginary. Moreover, rage and attack will persist well beyond the termination of the electrical stimulation of the amygdala.
    In fact, the amygdala remains electrophysiologically active for long time periods even after a stimulus has been removed (be it external-perceptual, or internal-electrical) such that is appears to continue to process--in the abstract--information even when that information is no longer observable. Moreover, tumors in this area can trigger violent rage attacks. A famous example of this is Charles Whitman, who in 1966 climbed a tower at the University of Texas carrying a high powered hunting rifle and for the next 90 minutes shot at everything that moved, killing 14, wounding 38. Post-mortem autopsy of his brain revealed a glioblastoma multiforme tumor the size of a walnut compressing the amygdaloid nucleus.
    D. SOCIAL-EMOTIONAL AGNOSIA
    Among primates and mammals, bilateral destruction of the amygdala significantly disturbs the ability to determine and identify the motivational and emotional significance of externally occurring events, to discern social-emotional nuances conveyed by others, or to select what behavior is appropriate given a specific social context. Bilateral destruction of both amygdalas (located in the right and left temporal lobe) usually results in increased tameness, docility, and reduced aggressiveness in cats, monkeys and other animals and humans. It also lowers responsiveness to aversive and social stimuli, and reduces fearfulness, competitiveness, dominance, and social interest. Indeed, this condition is so pervasive that subjects seem to have tremendous difficulty discerning the meaning or recognizing the significance of even common objects -- a condition sometimes referred to as "psychic blindness", or, the "Kluver-Bucy syndrome". However, it is important to note that although Drs. Kluver and Bucy reported this in 1937, this condition had first been reported in 1888 by Drs. Brown and Shaefer.
    Like an infant (who similarly is without a fully functional amygdala), individuals with bilateral amygdala destruction engage in extreme orality and will indiscriminately pick up various objects and place them in their mouth regardless of its appropriateness. There is a repetitive quality to this behavior, for once they put it down they seem to have forgotten that they had just explored it, and will immediately pick it up and place it again in their mouth as if it were a completely unfamiliar object.
    Hence, humans as well as animals with bilateral amygdala destruction, although able to see and interact with their environment, respond in an emotionally blunted manner, and seem unable to recognize what they see, feel, and experience. Things seem stripped of meaning. This condition pervades all aspects of higher level social-emotional functioning including the ability to appropriately interact with loved ones. As might be expected, maternal behavior is severely affected. According to Dr. A. Kling, mothers will behave as if their "infant were a strange object be be mouthed, bitten and tossed around as though it were a rubber ball".
    Among primates who have undergone bilateral amygdaloid removal, once they are released from captivity and allowed to return to their social group, a social-emotional agnosia becomes readily apparent as they no longer respond to or seem able to appreciate or understand emotional or social nuances. Indeed, they appear to have little or no interest in social activity and persistently attempt to avoid contact with others. If approached they withdraw, and if followed they flee. Indeed, they behave as if they have no understanding of what is expected of them or what others intend or are attempting to convey, even when the behavior is quite friendly and concerned. Among adults with bilateral lesions, total isolation seems to be preferred.
    It is thus apparent that the amygdala, in conjunction with other limbic tissue, such as septal nuclei and the more recently evolved transitional limbic cortex, the cingulate gyrus, is highly involved in all aspects of social and emotional functioning. In fact, as argued by Dr. R. Joseph in a number of articles, it appears that the differential maturation of these limbic structures, in particular, that of the amygdala, septal nuclei, and cingulate gyrus, are responsible for seeking contact comfort and forming of emotional and loving attachments during infancy.
    V. SEPTAL NUCLEI
    The septal nuclei, like the amygdala is very ancient, and appears to develop out of the hypothalamus. Phylogenetically and presumably, ontogentically, it seems to mature following the development of the amygdala, but at about the same time as the hippocampus, a limbic system structure involved in the formation of memory. The septal nuclei also increases in relative size and complexity as we ascend the ancestral tree, attaining its greatest degree of development in humans.
    The septal nuclei lies in the medial portions of the hemispheres, just anterior to the hypothalamus, and maintains rich interconnections with all regions of the limbic system. Unfortunately, unlike other limbic tissue, the functioning of the septal nuclei is still not well understood. Nevertheless, it appears to maintain a complementary relationship with the hippocampus, but an oppositional, and sometimes antagonistic relationship with the amygdala. For example, the amygdala appears to act so as to either facilitate or inhibit septal functioning whereas septal influences on the amygdala are largely inhibitory. However, in large part, the amygdala and septal nuclei appear to exert the majority of their counterbalancing influences on the emotional functioning of the hypothalamus with which they both maintain rich interconnections.
    A. RAGE & QUIESCENCE
    A primary activity of the septal nucleus appears to be that of reducing extremes in emotionality and arousal, and maintaining the organism in state of quiescence and readiness to respond. Stimulation of the septum acts to reduce blood pressure and heart rate, induces andrenocortical secretion, counters lateral hypothalamic self-stimulatory activity, inhibits aggressive behavior and suppresses the expression of rage reactions following hypothalamic stimulation.
    If the septal nucleus is destroyed, these counterbalancing influences are removed such that initially there results dramatic increases in aggressive behavior. In fact, bilateral lesions of the septal nuclei can trigger explosive emotional reactivity to tactile, visual, or auditory stimulation such that the animal may attempt to attack or run away. However, if the amygdala is subsequently destroyed, the septal rage and emotional reactivity are completely attenuated. However, when the amygdala remains intact, septal lesions appear to result in a loss of modulatory and inhibitory restraint.
    B. CONTACT COMFORT & SEPTAL SOCIAL FUNCTIONING
    Although initially destruction of the septal nuclei results in rage reactions, within a few weeks this aggressiveness subsides and/or completely disappears. However, a generalized tendency to over respond and a generalized failure to inhibit emotional responsiveness persists, and animals so effected tend to demonstrate an extreme and indiscriminate need for social and physical contact. That is, in contrast to amygdaloid lesions which produce a severe social-emotional agnosia and social avoidance, septal lesions produce a dramatic and persistent increase in social cohesiveness.
    These findings suggest that the normal, intact amygdala appears to promote social behavior whereas the septal nucleus seems to counter socializing tendencies. Hence, with destruction of the septal nuclei (which results in a release of the amygdala), the drive for social contact appears to be irresistible such that persistent attempts to make physical contact occurs--even with species quite unlike their own.
    For example, septal lesioned rats, unlike normals, will readily seek out mice (to which they are normally indifferent) or rabbits (which they usually avoid). If presented with a choice of an empty (safe) chamber or one containing a cat, septal lesioned rats persistently attempt to huddle and crawl upon this normally feared creature, even when the cat is acting perturbed. If a group of septally lesioned animals are placed together, extreme huddling results.
    So intense is this need for contact comfort following septal lesions, that if other animals are not available they will seek out blocks of wood, old rags, bare wire frames or walls.
    Among humans with right sided or bilateral disturbances in septal functioning (such as due to seizure activity being generated in this region), a behavior referred to as "stickiness" is sometimes observed. Such individuals seek to make repeated, prolonged, and often inappropriate contact with anyone who is available or who happens to be near by so as to tell them stories, jokes or merely pass the time. Moreover, they refuse to take a "hint," and do not depart unless given a direct request to do so.
    VI. EMOTIONAL ATTACHMENT & AMYGDALA-SEPTAL INTERACTIONS
    Physical, social and emotional interaction and contact during infancy is critically important to the child's well being as well as his or her neurological, sensory, cognitive, intellectual, social and emotional development. Indeed, babies need their "mamas" and all the love and attendant physical and emotional interaction they can get. The more an infant is held, stroked and spoken to, and the greater the visual divergence of his surroundings, the greater will be its resilience and capability to adapt to negative emotional and physical onslaughts and to withstand stressful extremes later in life. In fact, the very cells of the nervous system will prosper by growing larger and more complex.
    So great is the need for stimulation that until 6-7 months of age most children will eagerly and indiscriminately seek social and physical contact from anyone including complete strangers. Indiscriminate social interaction is not merely a manifestation of friendliness but serves a specific purpose: it maximizes opportunities for social and physical contact and interaction. Like hunger and the desire for food (which is mediated by the hypothalamus) there is a physical drive and hunger for social, emotional, and physical stimulation (which is mediated by the amygdala).
    At about 7 months of age the infant becomes more discriminate in his or her interactions and it is during this time period that a very real and specific attachment (e.g. to one's mother) becomes progressively more intense and stable. This does not mean that prior to this period the mother is not highly important to the infant, but rather maximal social interaction takes precedence during the first critical months of life. In other words, the baby needs more contact than a single mother is capable of providing.
    After these specific attachments such as to mother have been formed, most children increasingly begin to show anxiety, fear and even flight reactions at the approach of a stranger. By one year of age 90% of children respond aversively to strangers. This also serves a purpose for it maximizes the bond with mother and insures that a child who can crawl and maneuver through space does not indiscriminately attach to and wander off with a stranger.
    Thus the infants initial seeking of indiscriminate social contact is followed at a later age by progressively narrowed contact seeking. According to a theory developed by Dr. R. Joseph, these stages of emotional development coincide with the maturation of different nuclei in the limbic system of the brain; the amygdala, septal nuclei and cingulate gyrus.
    As noted, the septal nucleus and amygdala often act in balanced opposition. That is, the septal nuclei appears to be highly involved in social and intimate contact seeking, but in a fashion quite different from the amygdala. The normal amygdala, which matures before the septal region promotes social contact seeking, whereas the normal, undamaged septal nuclei, which matures later, acts to inhibit and restrict these tendencies so that they are directed and focused (such as upon one person), rather than being generalized and indiscriminate. These two regions of the brain, in conjunction with the cingulate gyrus are highly interactive and crucially important in the formation of our first and earliest attachments, as well as those later in life.
    It is these same limbic nuclei which later in life are involved in the ability to feel love (as well as hate and anger) for, and attachment to, a loved one. That is, the limbic system controls the basic aspects of emotion, such as love, hate, anger, rage, fear, pleasure, the desire to bond together, as well as biological drives, including hunger, thirst, and even the capacity to experience orgasm during sex. Often all these impulses and needs at one time or another becomes associated with mother or the primary caretaker, and later in life (to a considerable degree), with a spouse. Even the presence or absence of mother can at one time or another elicit these responses (e.g. rage when the infant is not being held or fed).
    Similarly, due to limbic attachment, the rejecting actions of a mate elicit limbic reactions including infantile feelings of rage and abandonment. That is, the amygdala striving to maintain the bonds of love responds with rage when the bond is severed, and the hypothalamus, feeling likewise, responds similarly. Even the murderous desire to kill one's spouse can be elicited. Indeed, loss of love, such as occurs when a relationship ends, seconded only by jealousy and money are prime elicitors of such murderous feelings and are due to the high involvement of the limbic system in all affairs of the heart.
    A. LIMBIC ABNORMALITIES IN LOVE & SOCIALIZATION SKILLS
    If contact with others is restricted during the early phases of infant development, then the ability to interact successfully with others at a later stage of of life is retarded. That is, the infant and child must experience love and nurturance during this time period, otherwise these limbic nuclei will not develop and interact normally. If these interactional needs are not met during this critical period of development, gross abnormalities can result. Children will lose the ability to form emotional attachments with others, sometimes for the rest of their lives.
    This is even true among non-human animals. Kittens which are not handled or stroked by humans soon become "wild" and unapproachable even when they have otherwise been exposed to people on a daily basis. Similarly, young children and infants who are separated from their parents and who fail to receive necessary loving and social stimulation are also affected adversely. They have difficulty forming emotional attachments and even their brains may not properly develop. If not adequately physically and emotionally stimulated, the child may even die.
    In other words, if a child is not firmly attached to a mother figure and has been neglected early in life, the ability to form attachments increasingly narrows and then disappears, possibly forever. The child becomes attached to no one and its ability to form loving attachments later in life will be abnormal if drastic countermeasures are not taken. This is because cells in the amygdala, not receiving sufficient and appropriate stimulation begin to die and atrophy from disuse; just like a muscle if unused. "Use it or lose it." Once these limbic neurons die or if certain interconnections between different regions are not maintained, they are no longer able to respond appropriately to physical, emotional and social interaction.
    VII. THE CINGULATE GYRUS A. THE EVOLUTION OF MATERNAL CARE
    As noted, most creatures, including sharks, amphibians, reptiles and fish, possess a limbic system, consisting of an amygdala, hippocampus, hypothalamus, and septal nuclei. It is these limbic nuclei which enable a group of fish to congregate together, i.e. to school, or for reptiles (creatures who first began to roam the planet about 300 million years ago) to form territories and very loosely organized social aggregates consisting of an alpha male and female, several sub-females, and a few juveniles. Such creatures, however, although sometimes showing parental investment, generally do not provide long term care for their young and do not produce complex meaningful vocalizations, although, like amphibians they do produce very limited socially meaningful sounds, which in turn appear to be generated and perceived by limbic nuclei such as the amygdala.
    Nevertheless, although in possession of a limbic system, reptiles, and other non-mammalian species are lacking the more recently acquired cingulate cortex which appears to have begun to evolve around 250 million years ago when reptiles diverged to form repto-mammals (the therapsids) who in turn evolved into mammals and then primates. It was with the appearance of the repto-mammals that the first evidence of suckling of infants and long term maternal care came into being. Indeed, it has been postulated by Paul Maclean (who in fact coined the term "limbic system") as well as by Dr. R. Joseph, that the cingulate (in conjunction with the amygdala and septal nuclei) is largely responsible for the appearance of maternal feelings, and the evolution of the family.
    However, primates and other mammals, in addition to limbic and transitional limbic cingulate cortex, are also equipped with the six to seven layered neocortex which evolved approximately 100 million years ago and which covers the old brain like a shroud. However, like the amygdala, the cingulate has reached its maximal size among humans and maintains rich interconnections with the neocortex as well as with the older portions of the limbic system such as the amygdala and hippocampus.
    Among humans and lower mammals, destruction of the anterior cingulate results a loss of fear, lack of maternal responsiveness and severe alterations in socially appropriate behavior. Humans will often become initially mute and socially unresponsive, and when they speak, their vocal melodic-inflectional patterns and the emotional sounds they produce sound abnormal.
    Animals, such as monkeys who have suffered cingulate destruction will also become mute, will cease to groom or show acts of affection and will treat their fellow monkeys as if they were inanimate objects. For example, they may walk upon and over them as if they were part of the floor or some obstacle rather than a fellow being. In other words, their behavior is more typical of a reptile than a primate. Maternal behavior is also abolished following cingulate destruction, and the majority of infants soon die from lack of care.
    More importantly, when the cingulate cortex is electrically stimulated, the separation cry, similar if not identical to that produced by an infant, is elicited. In fact, it appears that the cingulate, in conjunction with the amygdala and other limbic tissue are not only responsible for the development of long term infant care, but the initial production of what would become language. This has been referred to by Joseph as "limbic language." In fact, be it humans or reptiles the limbic system is preeminent in the mediation, production, and comprehension of emotional-social sounds, including sex differences in their production.
    VIII. LIMBIC LANGUAGE
    Phylogenetically and ontogenetically, the original impetus to vocalize springs forth from roots buried within the depths of the ancient "limbic lobe" a term coined by Papez in 1937. Although non-humans do not have the capacity to speak, they still vocalize, and these vocalizations are primarily limbic in origin being evoked in situations involving sexual arousal, terror, anger, flight, helplessness, and separation from the primary caretaker when young.
    The first vocalizations of human infants are similarly emotional in origin and limbically mediated, consisting predominantly of sounds indicative of pleasure and displeasure. Indeed, these sounds and cries are produced soon after birth, indicating they are innate, and are produced even by infants born deaf and blind. Similarly, apes and monkeys reared in isolation or with surgically muted mothers also produce appropriately sounding complex emotional calls in order to convey a wealth of information, including the presence of danger. Moreover, they will respond to these same calls with appropriate reactions, even when they had never before been heard.
    A. LIMBIC LOCALIZATION OF EMOTIONAL SOUND PRODUCTION
    Emotional cries and warning calls have been produced via electrode stimulation of wide areas throughout the limbic system. Nevertheless, the type of cry elicited, in general, depends upon which limbic nuclei has been activated. For example, portions of the septal nuclei, hippocampus, and medial hypothalamus have been repeatedly shown to be generally involved in the generation of negative and unpleasant mood states, whereas the lateral hypothalamus and amygdala, and portions of the septal nuclei, are associated with pleasurable feelings.
    Not surprisingly, areas associated with pleasurable sensations often give rise, when sufficiently stimulated, to pleasurable calls, whereas those linked to negative mood states, will trigger cries of alarm and shrieking. However, of all limbic nuclei, the amygdala and cingulate gyrus appear to be the most vocal.
    In humans and animals a wide range of emotional sounds have been evoked through amygdala activation, including those indicative of pleasure, sadness, happiness, and anger. Conversely, in humans, destruction limited to the amygdala, the right amygdala in particular, has abolished the ability to sing, convey melodic information or to enunciate properly via vocal inflection and can result in great changes in pitch and the timbre of speech. Even the capacity to perceive and respond appropriately to social-emotional cues is abolished.
    However, in the cingulate gyrus, completely different emotional calls can be elicited from electrodes which are immediately adjacent, and, the calls do not always correlate with the mood state. This suggests considerable flexibility within the cingulate which also appears to have the capability of producing emotional sounds that are not reflective of mood. This suggests a high degree of voluntary control within the cingulate. However, of the many sounds produced, the separation cry of the infant is one of the most significant, particularly in regard to the evolution of language. It is from the cingulate where the separation cry is most frequently elicited.
    B. LIMBIC LANGUAGE & MOTHER-INFANT VOCALIZATION
    Among social terrestrial vertebrates the production of sound is very important in regard to infant care, for if an infant becomes lost, separated, or in danger, a mother would have no way of quickly knowing this by smell alone. Such information would have to be conveyed via a cry of distress or a sound indicative of separation fear and anxiety. It would be the production of these sounds which would cause a mother to come running to the rescue. Hence, the first forms of limbic social-emotional communication was probably produced in a maternal context.
    Indeed, considerable vocalizing typically occurs between human and non-human mammalian mothers and their infants, and the infants of many species, including primates, will often sing along or produced sounds in accompaniment to those produced by their mothers. In fact, among primates, females are more likely to vocalize and utter alarm calls when they are near their infants versus non-kin, and vice versa, and adult males are more likely to call or cry when in the presence of their mother or an adult female vs an adult male. Similarly, infant primates will loudly protest when separated from their mother so long as she is in view and will quickly cease to vocalize when isolated. It thus appears that the purpose of these vocalizations are to elicit a response from the mother.
    Hence, the production of emotional sounds appears to be limbically linked and associated with maternal-infant care, and with interactions with an adult female. In fact, human females in general tend to vocalize more so than males and their speech tends to be perceived as friendlier and more social.
    It is important to note, however, that the hypothalamus, septal nuclei, as well as the periquaductal gray (which is located in the midbrain) are also important components in the formulation of limbic language. Given the role of these limbic nuclei in sex related differences in cognition and behavior, it is perhaps highly likely that they may contribute to sex differences in language as well.
    IX. SEXUAL DIFFERENTIATION OF THE HYPOTHALAMUS & AMYGDALA
    As is well known, sexual differentiation is strongly influenced by the presence or absence of gonadal androgen hormones during certain critical periods of prenatal development in many species including humans. However, not only are the external genitalia and other physical features sexually differentiated but certain regions of the brain have also been found to be sexually dimorphic and differentially sensitive to steroids, particularly the amygdala and the preoptic area and medial nucleus of the hypothalamus. Specifically, the presence or absence of the male hormone, testosterone, during this critical neonatal period, directly effects and determines the pattern of interconnections between the amygdala and hypothalamus, between axons and dendrites in these nuclei, and thus the organization of specific neural circuits. In the absence of testosterone, the female pattern of neuronal development occurs.
    That various limbic regions, such as the preoptic and medial (ventromedial) hypothalamus are sexually differentiated is not surprising in that it has long been known that this area is extremely important in controlling the basal output of gonadotrophins in females prior to ovulation and is heavily involved in mediating cyclic changes in hormone levels (e.g. estrogen, progesterone). Chemical and electrical stimulation of these nuclei also triggers sexual behavior and even sexual posturing in females and males.
    Moreover, In primates, electrical stimulation of the preoptic area increases sexual behavior in males, and significantly increases the frequency of erections, copulations and ejaculations, we well as pelvic thrusting followed by an explosive discharge of semen even in the absence of a mate. Conversely, lesions to these nuclei eliminates male sexual behavior and results in gonadal atrophy.
    Similarly, electrical stimulation of the amygdala, the medial division in particular, results in sex related behavior and activity. In females this includes ovulation, uterine contractions and lactogenetic responses, and in males penile erections.
    Conversely, damage to the amygdala bilaterally, often results in heightened and indiscriminate sexual activity. For example, primates and other animals (while in captivity) will engage in excessive masturbation and genital manipulation and will repeatedly attempt to copulate even with species other than their own (e.g. a cat with a dog, a dog with a turtle, etc.) regardless of their sex. Hence, with bilateral destruction, animals are not only overly active sexually, but are unable to identify appropriate partners. Conversely, with abnormal activity involving the amygdala, such as due to temporal lobe epilepsy, sensations of sexual excitement, and even sexual behavior sometimes leading to orgasm, may also occur as a function of seizures originating in the temporal lobe.
    A. SEX DIFFERENCES IN LANGUAGE & COGNITION
    Hence, it thus appears that the limbic system is not only involved in all aspects of emotion, including sexual behavior, and the production of emotional speech, but that these same limbic nuclei may be responsible for sex differences in thought, feeling and even language. For example, it has been argued by that sex differences in language, emotion, and cognitive capability may represent the differential effects of early hormonal influences on various limbic system nuclei as well as within the neocortex. Indeed, the administration of testosterone to infant females during these early critical periods, or the castration of infant males will completely reverse sex differences in behavior and cognition.
    For example, it is well known that men, boys, and even male rats demonstrate superior spatial-perceptual abilities, such as in maze learning, as compared to females. If testosterone is not present during these early critical periods, these superiorities are reversed. On the other hand, women and young girls are clearly superior in regard to various aspects of language, including those related to social and emotional functioning. It is likely that these superiorities, like those of the male, are also related to early hormonal influences on limbic organization.
    Consider for example intonation and pitch. Women tend to employ 5-6 different variations and to utilize the higher registers when conversing. They are also more likely to employ glissando or sliding effects between stressed syllables, and they tend to talk faster as well. Men tend to be more monotone, employing 2-3 variations on average, most of which hovers around the lower registers. Even when trying to emphasize a point males are less likely to employ melodic extremes but instead tend to speak louder.
    B. SEX DIFFERENCES IN EMOTION
    As has been demonstrated in a number of recent studies, women are also more emotionally expressive, and are more perceptive in regard to comprehending emotional verbal nuances. This superior female sensitivity even includes the comprehension of emotional faces, and the ability to feel and express empathy. In fact, from childhood to adulthood women appear to be much more emotionally expressive than males in general.
    Indeed, given woman's role in rearing children, and the role of the limbic system in promoting maternal care and communication, it seems rather natural that they are much more sensitive to and expressive of these nuances. Presumably, these differences reflect sex related differences in the structure and function of the male vs female limbic system.
    Indeed, although sex differences in the structure of the cingulate have not yet been reported, consider for example, the anterior commissure, a bundle of fibers which acts to interconnect the two amygdalas and inferior temporal lobes. This fiber pathway is 18% larger in the female vs the male brain. Given the preimmanent role of the amygdala in emotionality and sound production, as well as evidence indicating that this nuclei is sexually dimorphic, this latter finding of an enlargement in the anterior commissure may be yet another reason why females are more emotionally expressive, receptive, and tend to employ a wider range of melodic pitch when they speak. Moreover, given the intimate role of the amygdala with the hippocampus, it is possible that sexual differentiation of this and other limbic nuclei may be responsible for sex differences in spatial-perceptual abilities and other cognitive differences as well.
    X. HIPPOCAMPUS
    A. AROUSAL, ATTENTION & INHIBITION
    The hippocampus is an elongated structure located within the inferior medial wall of the temporal lobe, posterior to the amygdala and is shaped somewhat like a telephone receiver. It consists of an anterior and posterior region, and is richly interconnected with the septal nuclei (which in some ways acts as a relay nucleus for the hippocampus), as well as the cingulate gyrus and amygdala. And among animals it has been also been found to be sexually differentiated.
    Various authors have assigned the hippocampus a major role in information processing, including memory, new learning, spatial mapping of the environment, voluntary movement toward a goal, as well as in attention and behavioral arousal. For example, hippocampal cells greatly alter their activity in response to certain spatial correlates, particularly as an animal moves about in its environment. It is also intimately involved in the encoding and memory storage of spatial, as well as verbal, emotional, and other forms of information. However, few studies have implicated the hippocampus in emotional functioning per se, although responses such as "anxiety" or "bewilderment" have been observed when directly electrically stimulated.
    Over the course of evolution the hippocampus has become modified and many of its functions have come to be hierarchically mediated, controlled, or at least, influenced by activity occurring within the neocortex, with which it maintains rich interconnections. Due to this interrelationship the hippocampus is able to monitor as well as exert reciprocal influences over neocortical functioning which it monitors.
    For example, when the neocortex becomes highly activated, the hippocampus functions at a much lower level of arousal in order not to become overwhelmed. When the neocortex is not highly aroused, the hippocampus presumably compensates by increasing its own level of arousal so as to tune in to information that is being processed at a low level of neocortical intensity. However, in situations where both the neocortex and the hippocampus become highly aroused and activated, the individual becomes easily distracted, hyper responsive, and overwhelmed, confused, and disoriented. Attention, learning, and memory functioning are also decreased due to this interference in the ability to selectively maintain attention. Situations such as this sometimes sometimes occur when individuals are highly anxious or upset.
    Unfortunately, under conditions of extreme and repetitive stress and arousal, the hippocampus may be injured and the victim may suffer varying degrees of memory loss.
    There is also evidence to suggest that the hippocampus may act so as to reduce extremes in neocortical arousal. For example, whereas stimulation of the reticular activating system augments cortical arousal and EEG evoked potentials, hippocampal stimulation reduces or inhibits these potentials such that cortical responsiveness and arousal is dampened.
    On the other hand, if neocortical arousal is at a low level, hippocampal stimulation often results in an augmentation of the neocortical evoked EEG potential, thus increasing arousal levels. It is presumably in this manner that the hippocampus can exert influence on what is being processed in the neocortex so as to control selective attention and maintain concentration. Again, this aids in learning and the retention of significant information via selective attention or the filtering of irrelevant forms of input that might otherwise become processed and attended to.
    The hippocampus thus prevents the neocortex from becoming overwhelmed or inattentive, and may act to increase neocortical arousal so that it is sufficiently activated. This is because very high or very low states of excitation are incompatible with alertness and selective attention as well as the ability to learn and retain information. When the hippocampus is damaged or destroyed, animals have great difficulty inhibiting behavioral responsiveness or shifting attention. The ability to shift from one set of perceptions to another, or to change behavioral patterns is disrupted and the organism becomes overwhelmed by a particular mode of input. Learning, memory, as well as attention, are greatly compromised. Again, the hippocampus (as well as the amygdala) may be injured under these conditions--a function of the massive release of stress hormones which attack and injure pyramidal cells.
    B. LEARNING & MEMORY
    The hippocampus is thus associated with learning and memory encoding (e.g. long term storage and retrieval of newly learned information), particularly the anterior regions. Of course, many other brain areas such as the mammillary bodies, dorsal medial nucleus of the thalamus, etc., are also important in memory functioning. Nevertheless, the hippocampus, in conjunction with the amygdala, appears to be preeminent in this regard.
    It is now well known that bilateral destruction of the anterior hippocampus results in striking and profound disturbances involving memory and new learning i.e. anterograde amnesia. For example, one such individual who underwent bilateral destruction of this nuclei (H.M.), was subsequently found to have almost completely lost the ability to recall anything experienced after surgery. If you introduced yourself to him, left the room, and then returned a few minutes later he would have no recall of having met or spoken to you. Dr. Brenda Milner has worked with H.M. for almost 20 years and yet she is an utter stranger to him. However, events that occurred for up to two years before his surgery was also somewhat disrupted.
    Nevertheless, H.M. is in fact so amnesic for everything that has occurred since his surgery, that every time he rediscovers that his favorite uncle died (years after his surgery) he suffers the same grief as if he had just been informed for the first time. Even so, although without memory for new (non-motor) information, H.M. has adequate intelligence, is painfully aware of his deficit and constantly apologizes for his problem. "Right now, I'm wondering" he once said, "Have I done or said anything amiss?" You see, at this moment everything looks clear to me, but what happened just before? That's what worries me. It's like waking from a dream. I just don't remember...Every day is alone in itself, whatever enjoyment I've had, and whatever sorrow I've had...I just don't remember."
    As noted above, presumably the hippocampus acts to protect memory and the encoding of new information during the storage and consolidation phase via the gating of afferent streams of information and the filtering/exclusion (or dampening) of irrelevant and interfering stimuli. When the hippocampus is damaged there results input overload, the brain is overwhelmed by irrelevant stimuli, and the consolidation phase of memory is disrupted such that relevant information is not properly stored or even attended to. Consequently, the ability to form associations (e.g. between stimulus and response) or to alter preexisting schemas (such as occurs during learning) is attenuated.
    C. HIPPOCAMPAL & AMYGDALOID INTERACTIONS: MEMORY
    The amygdaloid nucleus via its rich interconnections with other brain regions is able to sample and influence activity occurring in other parts of the cerebrum and add emotional color to ones perceptions. As such it is highly involved in the assimilation and association of divergent emotional, motivational, somesthetic, visceral, auditory, visual, motor, olfactory and gustatory stimuli. Thus it is very concerned with learning, memory, and attention, and can generate reinforcement for certain behaviors.
    Moreover, via reward or punishment it can promote the encoding, storage and later retrieval of particular types of information. That is, learning often involves reward and it is via the amygdala (in concert with other nuclei) that emotional consequences can be attributed to certain events, actions, or experiences, as well as extracted from the world of possibility so that it can be attended to and remembered. Indeed, the amygdala, in conjunction with the hippocampus, is extremely important in learning and memory, and both are richly interconnected.
    The amygdala thus seems to reinforce and maintain hippocampal activity via the identification of motivationally and emotionally significant information and the generation of pleasurable rewards (through action on the lateral hypothalamus). This is because reward increases the probability of attention being paid to a particular stimulus or consequence as a function of its association with reinforcement. As such, events which are positively, or negatively reinforced, are more likely to be remembered; the exception being that high levels of arousal can interfere with memory.
    Hence, the hippocampus acts to reduce or enhance extremes in arousal associated with information reception and storage in memory, whereas the amygdala acts to identify the social-emotional-motivational characteristics of the stimuli as well as to generate (in conjunction with the hippocampus) appropriate emotional rewards so that learning and memory will be reinforced. Thus, we find that when both the amygdala and hippocampus are damaged, or under conditions of prolonged and repetitive stress, striking and profound disturbances in memory functioning result.
    D. VISUAL & VERBAL MEMORY
    It is now very well known that lesions involving the inferior temporal lobes and the amygdala/hippocampus of the left cerebral hemisphere typically produce significant disturbances involving verbal memory. Left sided damage disrupts the ability to recall simple sentences, complex verbal narrative passages, or to learn verbal paired-associates or a series of digits.
    In contrast, right temporal, amygdala-hippocampal destruction typically produces deficits involving visual and spatial memory, such as the learning and recall of geometric patterns, visual mazes, human faces, or even where some object was placed the night before. Right sided damage also disrupts the ability to recall olfactory stimuli, emotional sounds and passages, or sounds from the environment.
    Hence, the left amygdala/hippocampus is highly involved in processing and/or attending to verbal information, whereas the right amygdala/hippocampus is more involved in the learning, memory and recollection of non-verbal, visual-spatial, environmental, emotional, motivational, and facial information. However, as noted above, the limbic system, including the hippocampus, is sexually differentiated, which in turn appears to effect the ability to attend to and recall spatial vs emotional and verbal information. In this regard, the male limbic system appears to have conferred an advantage in the processing of spatial information, whereas the female limbic system is more adept at expressing, processing and possibly recalling emotionally laden visual and verbal stimuli.
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    AMYGDALA (LIMBIC) STRIATUM:
    The amygdala is concerned with all aspects of emotion, including fighting, fleeing, feeding, and fornicating. Thus the amygdala is greatly concerned with emotional behavior and stereotyped emotional movements.
    Early in the course of vertebrate evolution, motor functioning was the province of the spinal cord, brainstem, cerebellum, and forebrain (see chapter 5), just as it is in modern species including humans. Much of the forebrain, however, consisted of the olfactory bulbs and tracts, and the amygdalostriatal gray which was both dorsal and venterally located and contained at its central-posterior-dorsal core, the hippocampus. The amygdalostriatal gray was dominated by the olfactory system, and reacted to olfactory impulses by feeding, fighting, fleeing, or engaging in sexual behavior. Although the amygdalostriatal gray became separate structures once terrestrial vertebrates had evolved (Gloor, 1997, MacLean, 1990; Stephans, 1984; Ulinsky, 1990), the striatum and related structures collectively referred to as the basal ganglia, continued to govern all aspects of affectively triggered gross motor behavior, just as they do in modern humans, albeit in conjunction with the brainstem, cerebellum, spinal cord and cranial nerve nuclei, as well as the thalamus, and the primary, secondary and supplementary motor areas of the frontal lobes.
    Structural Overview
    Thus the amygdala is part of the basal ganglia which is composed of several major nuclei which include the corpus (or dorsal) striatum ("striped bodies") i.e., the caudate and putamen which are extensively interconnected and which project to a variety of brain areas including the immediately adjacent globus pallidus ("pale globe"). The dorsal globus pallidus although related to the hypothalamus and midbrain, is in many respects coextensive and appears to merge with the putamen giving the entire structure the appearance of a camera lens.
    The dorsal striatum is also intimately related to the amgydala, receiving massive input from this structure but providing little in return.
    [-INSERT FIGURES 2 & 3 ABOUT HERE-]
    As noted the amydalostriatal gray consisted of both dorsal and ventral components, and so too does the human striatum--also referred to as the limbic (ventral) striatum. The substantia innominata, nucleus accumbens, olfactory tubercle constitute the limbic striatum. The inferior ventral globus pallidus (also referred to as the ventral pallidum or substantia innominata) is also part of the limbic (ventral) striatum and in fact eventually merges with the centro-medial amygdala and receives extensive projections from the lateral amygdala, the olfactory tubercle, and nucleus accumbens.
    In addition, the "motor thalamus," the orbital and medial frontal lobes and medial supplementary motor area, hippocampus (as well as the central and medial amygdala), are richly interconnected with and constitute major components of the basal ganglia. However, as noted in chapter 12, the basal ganglia (i.e. the corpus and limbic striatum and globus pallidus) evolved out of the olfactory-amygdala and in many respects it could be considered part of the limbic system (Heimer & Alheid, 1991; MacLean, 1990).
    Intimately linked and thus part of the basal ganglia is the substantia nigra and the midbrain tegmentum, which feed dopamine to the corpus and limbic striatum. Specifically, the nigrostriatal DA (A-9) cell group projects from the substantia nigra to the dorsal caudate and putamen and the medial frontal lobes (Ellison, 1994; Fibiger & Phillips, 1986; Parent & Hazrati 1995), although some fibers also innervate the limbic striatum. It is the nigro-(dorsal)-striatal system which is thought to be related to motor functions including the production of stereotyped and routine actions.
    [-INSERT FIGURE 4 ABOUT HERE-]
    The mesolimbic DA systems originates in the ventral midbrain tegmentum (A10 DA cell group) and sends fibers to the amygdala, septal area, hippocampus, frontal cortical areas, including the ventral caudate-putamen, nucleus accumbens and substantia innominata (Le Moal & Simon 1991; Olton et al. 1991; Zaborszky et al. 1991), although some fibers also innervate the dorsal striatum. The mesolimbic DA system is believed to be related to emotion, mood, memory, and reward, including locomotor survival related activities such as running and even "galloping" (Ellison, 1994; Fibiger & Phillips, 1986; Le Moal & Simon 1991).
    THE AMYGDALA, EMOTION, MEMORY, PSYCHOSIS, & THE BASAL GANGLIA
    As detailed in chapter 13, early in the course of animal evolution, the amydala and striatum formed a composite dorsal/ventral amygdala-striatum, these structures being pushed apart and become distinct one animals began to live on land. For example, it can be surmised, based on the brain of a "living fossil" the shark, that 450 millions B.P., that the majority of the forebrain in cartilaginous animals, consisted of a dorsal and ventral amygdala-striatum, the striatoamygdaloid gray, such that the amygdala and striatum were enmeshed forming a dorsal lateral/ventral lobe, an organization pattern that is also evident in cyclostromes, fish, and (to a much lesser degree) in tailed amphibians (urodela). The dorsal/ventral amygdala/striatum formed a composite allocortical structure that was dominated by the olfactory system (Haberly, 1990; Smeets, 1990; Ulinksi, 1990).
    The striatoamygdaloid gray (or "dorsal pallium") performed motor functions that in some respects mirrored those of the brainstem which was dominated by the vestibular system and to a lesser extent, the visual system; one of the major differences being that the olfactory-forebrain was provided with a crucial "pregnant interval" before it need respond, which enabled it to beocme a thinking machine whereas the brainstem remained reflexive.
    As animals emerged from the sea and began to live on dry land, the amygdala and striatum were pushed apart due to the increased important of motor functioning and as the olactory bulb expanded as did its forebrain pathways, so as to adapt to living in a world of smell. With the evolution of amphibians (the tailless anura) the amygdala and the striatum (and much later the hippocampus and striatum) became semi-separate structures (Herrick, 1925; Nieuwenhuys & Meek, 1990ab; Stephan & Andy, 1977; Ulinksi, 1990) which nevertheless remained tightly linked, the striatum responding to amygdala impulses which were directed to the brainstem. As these structures expanded and were pushed further apart, the dorsal aspect became a rudimentary dorsal striatum, and the ventral aspect became the ventral (limbic) striatum.
    Ontogeny often replicates phylogeny and this amygdala-striatal separation is also repeated over the course of embrylogical development. For example, around the sixth week of fetal development immature neuroblasts migrate in massive numbers from the ventricular lining, and congregate in the more caudal portion of the emerging forebrain, thus forming an arc shaped "striatal ridge" from which the primordial amygdala will emerge (Gilles et al., 1983; Humphrey, 1968). Approximately one week after the formation of the amygdala, this primordial striatum begins to differentiate and balloon outward. Thus both the striatum and amygdala are derived from the arc shaped "striatal ridge," the caudal portion giving rise to the primordial amgydala at about the 6th week of gestation, and the basal portion later giving rise to the primordial striatum which initially overlies and is contiguous with the amygdala (Gilles et al., 1983; Humphrey, 1968). Over the ensuing weeks, these structures are pushed further apart thus again, replicating phylogeny.
    [-INSERT FIGURE 9 & 10 ABOUT HERE-]
    Nevertheless, they do not completely separate, and the medial amygdala remains extensively interconnected with the limbic (ventral) striatum. As noted, the substantia innominata (ventral globus pallidus/nucleus basalis) merges with the centro-medial amygdala and receives extension projections from the lateral amygdala. In addition, the lateral amygdala id directly connected with the corpus striatum, via the so called "tail of the caudate." However, as these connnections are predominantly from the amygdala to the striatum and not vice versa, the caudate could be considered the bulbous "tail" end of the amygdala.
    [-INSERT FIGURE 11 ABOUT HERE-]
    In fact the human corpus and limbic striatum are sandwiched between the posterior/ventral medial/lateral "tail" and the extended centro-medial "nose" (or internal shoulder) of this nucleus. And, these structures, being derivatives of the amygdala, respond to amygdala impulses, as they receive extensive amygdala projections (Gloor, 1955; Klingler & Gloor, 1960; Krettek & Price, 1978)--projections which are not reciprocated. The the right and left amygdala povides ipsilateral connections.
    The amygdala (as well as the anterior cingulate, lateral hypothalamus, and hippocampus), therefore is able to exert considerable influence on the basal ganglia which appears to have evolved out of the amygdala in order to serve as an emotional-motor interface so that amygdala needs and impulses may be acted on in a flexible manner These are functions the basal ganglia (the limbic striatum in particular) continues to perform in humans as well as other creatures (e.g., MacLean, 1990; Mogenson 1991).
    For example, the basal ganglia is exceedingly important in the stereotyped and species specific motoric expression of social and emotional states such as running away in fear, biting defensively, or via ballistic movements (hitting, kicking) or as manifested through facial expression, posture, muscle tone, or gesture (Mogenson & Yang, 1991; MacLean, 1990; Rapoport 1991). Because humans possess basically the same basal ganglia and limbic system, when happy, sad, angry, and so on, the facial and body musculature assumes the same readily identifiable emotional postures and expression regardless of culture or racial orgins (Ekman 1993; Eibl-Ebesfedlt, 1990; However, see Russell 1994).
    [-INSERT FIGURE 12 ABOUT HERE-]
    Because of this similarity in basal ganglia functional architecture, regardless of culture or race (and in many respects, mammalian species) if frightened, angry, or in the process of being assaulted, animals or humans may similarly engage in (ballistic) hitting and kicking, or biting, and/or all of the above, depending on context, mood and situational variables (including play). However, in contrast to the brainstem and cerebellum which provides reflexive and stereotyped motor programs that can be performed without thinking, the basal ganglia is capable of considerable flexibility in regard to motor-emotional expression, and is exceedingly responsive to the organisms motivational and emotional state -via its extensive interconnections with the limbic system.
    Thus, the striatum contains cells which selectively respond to motivationally significant stimuli, including novel and familiar variables that are rewarding or punishing (Rolls & Williams, 1987; Schneider & Lidsky, 1981). Striatal neurons can also react differently to familiar stimuli depending on their reinforcement properties, and many neurons will in fact increase their responsiveness as stimuli approach the mouth, and/or touch the face and mouth (Rolls & Williams, 1987; Schneider & Lidsky, 1981). Some striatal neurons also respond when making tongue and lip movements (e.g. licking) and during arm movements toward a food item (Rolls & Williams, 1987).
    These findings suggest the striatum is involved in orienting and guiding movements toward the mouth presumably so that a desired object can be licked, sucked on, chewed, and consumed. In this regard the striatum could be considered a primary motor center which enables various limbic desires, needs, and impulses such as hunger, to be satisfied.
    The limbic striatum (e.g. the nucleus accumbens) and the mesolimbic DA system which projects to these nuclei also appear to be highly involved in mediating feelings of pleasure including the rewarding effects of amphetamine, cocaine and opiates (see Ellison, 1994; Hakan et al. 1994; Koob et al. 1991). These effects (including the aversiveness of opiate withdrawal) are probably due not only to the presence of opiate, DA, and related receptors, but the rich interconnections maintained with the amygdala as well as the lateral hypothalamus (Kelsey & Arnold 1994; Olton et al. 1991; Zaborszky et al. 1991) which constitute part of the "pleasure circuit" maintained by the medial forebrain bundle (Olds & Forbes, 1981; see also chapter 13).
    However, animals will also work in order to self-administer opiates directly into the accumbens (Koob et al. 1991; Olds & Forbes 1981). Conversely, lesions to the nucleus accumbens may disrupt the capacity to experience pleasure or the rewarding effects of opiates and cocaine (Koob et al. 1991); or to engage in complex coordinated defensive acts (see below).
    Catatonia, Parkinson's Disease, & Psychosis.
    Lesions to the corpus striatum and lenticular nucleus (putamen and globus pallidus) can attenuate one's capacity to motorically express their emotions via the musculature; e.g. the face may become frozen and mask-like. These latter motor disturbances are well known symptoms associated with Parkinson's disease, a disturbance directly linked to dopamine deficiency (Fahn, 1999) and neuronal degeneration not only in the putamen (Goto, et al. 1990; Kish, et al. 1988; see also Hauser et al., 1999), but within the limbic striatum, i.e. the nucleus accumbens (see Rolls & Williams, 1987), as well as in the supplementary motor areas and medial frontal lobe -which maintains rich interconnections with the striatum.
    However, when chemical or structural lesions extend beyond the basal ganglia and come to include the medial frontal lobe, not only might an individual suffer motor rigidity, they may become catatonic and experience extreme difficulty responding to external or internally mediated impulses (Joseph, 1999a). Various aspects of this symptom complex also characterize those with Parkinson's disease (see below).
    Other disturbances associated with striatal abnormalities include Huntington's chorea, ballismus, restless leg syndrome, sensory neglect and apathy, obsessive compulsive disorders, mania, depression, "schizophrenia" and related psychotic states (Aylward et al. 1994; Baxter et al. 1992; Caplan, et al. 1990; Castellanos et al. 1994; Chakos et al. 1994; Davis, 1958; Deicken et al. 1995; Ellison, 1994; Rauch et al. 1994; Richfield, et al. 1987; Turjanski, et al., 1999). Severe memory loss and social-emotional agnosia and an inability to recongize friends or loved ones is also characteristic of striatal abnormalities, particularly disturbances involving the limbic striatum.
    Thus although the basal ganglia is often viewed and described as a major motor center (detailed below), the functional capacities and symptoms associated with this group of nuclei are quite diverse, and vary depending on the nuclei and chemical neurotransmitters involved as well as the laterality, location, and extent of any lesion.
    THE AMYGDALA, STRIATUM, SMA, & LIFE THREATENING FEAR & AROUSAL
    In situations involving exceedingly high levels of arousal coupled with extreme fear, the individual may simply freeze and attentional functioning may become so exceedingly narrow that little or nothing is perceived and cognitive activity may be almost completely (albeit temporarily) abolished (see chapter 30). These behaviors are apparently under the control of the amygdala which can trigger a "freezing" reaction and a complete arrest of ongoing behavior (Gloor, 1960; Kapp et al. 1992; Ursin & Kaada, 1960) via these brainstem/striatal interconnections. This is part of the amygdala attention response, which at lower levels of excitation may be followed by anxious glancing about, an increase in respiration and heart rate, pupil dilation, and perhaps cringing and cowering or flight (Gloor, 1960; Ursin & Kaada, 1960).
    Among humans, the fear response is one of the most common manifestations of amygdaloid stimulation (Gloor, 1990; Halgren, 1992; Williams, 1956). However, if arousal levels continue to increase, subjects do not merely freeze in response to increased fear, they may become catatonic; a condition which may be secondary to dopamine and serotonin depletion and amygdaloid influences on the SMA as well as the striatum; nuclei which are intimately interconnected.
    For example, in response to extreme fear, "one tendency is to remain motionless, which reaches its extreme form in death-feigning in certain animals and sometimes produces the waxy flexibility of catatonics" (Miller, 1951). The affected individual becomes psychologically and emotionally numb and unresponsive which is coupled with a complete blocking off of cognition. Moreover, the individual may resist and fail to respond to attempts at assistance (Krystal, 1988; Miller, 1951; Stern, 1951).
    The airline industry has referred to this as "frozen panic states" (Krystal, 1988), a condition sometimes seen in air and sea disasters. For example, in mass disasters, 10-25% of the victims will become frozen, stunned, and immobile, and will fail to take any action to save their lives, such as attempting to evacuate a burning or sinking craft even though they have been uninjured (see Krystal, 1988).
    According to Krystal (1988) with increasing fear "there is also a progressive loss of the ability to adjust, to take the initiative or defensive action, or act on one's own behalf... that starts with a virtual complete blocking of the ability to feel emotions and pain, and progresses to inhibition of other mental functions" (Krystal, 1988, p. 151).
    Evolutionary Significance of Rigidity.
    Catatonic panic states are prevalent in the animal kingdom, and constitute a life preserving reaction that is apparently mediated by the amygdala and striatum. That is, by freezing and not moving, predators may fail to take note of their presence.
    Catatonia, coupled with emotional and "psychological" numbing, also represents a total surrender reaction, usually as a prelude (and hopeful guarantee) of a painless death when attacked by predators or invaders. That is, the prey may cease to run or fight and simply stand still or lie down and allow predators to literally eat them alive. Or, in the case of humans as sometimes occurs during war and genocidal mass murders, passively allow themselves to be marched into a ditch and shot.
    According to Krystal (1988, p. 144), "thousands of European Jews obeyed orders in an automatonlike fashion, took off their clothes, and together with their children decended into a pit, lay down on top of the last layers of corpses, and waited to be machine-gunned," all the while seemingly almost petrified with fear and/or completely numb as to what was going on around them.
    Presumably this numbing is made possible via the massive secretion of opiates within the amygdala and basal ganglia, whereas the rigidity and loss of the will to resist is a consequence of overwhelming fear and hyper-amygdala influences on the medial frontal lobe and corpus and limbic striatum.
    Once prey have sighted a predator, some animals, however, instead of running in fear, will simply "freeze," fall to the ground, and lie stiff, rigid, and motionless as if dead. Unless exceedingly hungry, many predators will avoid eating creatures which appear to be already dead (i.e. unresponsive).
    As sometimes occurs to potential victims during mass killings (e.g. the 1994 Rwanda civil war between the Hutus and the Tutus) humans too, will sometimes fall down as if dead and may remain frozen, stiff and and unmoving for long time periods even though they may not have been harmed (Krystal 1988). Indeed, sometimes these individuals are believed to be dead even by rescuers or those who are clearing away and burying bodies.
    Presumably it is via connections with the basal ganglia and medial frontal lobes that the amygdala is able to induce these catatonic states, which in part is also dependent on dopamine. For example, it has been demonstrated that under extremely stressful conditions the striatal and frontal lobe DA system is adversely affected (see Le Moal & Simon 1991).
    IMPLICATIONS REGARDING PARKINSON'S DISEASE
    [-INSERT FIGURE 17 ABOUT HERE-]
    As noted, many of the functions originally associated with the basal ganglia have been subsumed by the neocortex, and damage to the frontal lobes can produce essentially similar symptoms as seen following caudate destruction; including stiffness, rigidity, and difficulty initiating movement (see chapter 19).
    Given that the medial frontal lobes, corpus and limbic striatum, and amygdala are extensively interconnected, and given the powerful influences of the limbic system on all aspects of behavior, it thus appears that when exceedingly aroused or emotionally stressed, the amygdala is able to inhibit (or overactivate) the frontal-striatal motor centers which (in addition to the amygdala) are simultaneously undergoing DA depletion (which in turn results in hyperactivation of these nuclei including the amygdala; see Le Moal & Simon 1991). When this occurs, the organism may fall and cease to move, blink or even breathe (or breathe only shallowly and slowly). The creature therefore appears to be in a state of rigor mortis and thus dead (i.e. catatonic).
    Overall, these amygdala-basal ganglia-medial frontal lobe-fear induced frozen and catatonic states are exceedingly adaptive; that is, unless the hapless victim is in a burning airplane or sinking ship.
    Although not as dramatic or severe, similar states occur with biochemical abnormalities involving the dopamine pathways from the substantia nigra which not only feed the caudate, but the medial frontal lobes and the amygdala. Specifically, loss of DA (or excessive amygdaloid arousal) results in motor neuron hyperactivity and tonic EMG activity and thus limb and facial rigidity; conditions which also afflict those with Parkinson's disease.
    In that some of these same exact "semi-frozen" and akinetic states are present in many of those with Parkinson's disease, and given that affected individuals are sometimes described as excessively aroused and/or unable to relax, and to suffer from heightened autonomic nervous system activity (Stacy & Jankovic, 1992) this raises the possibility that the amygdala and related limbic nuclei may significantly contribute to the development of this disorder. Indeed, as noted, destruction of the amygdala prior to chemically lesioning the corpus striatum prevents the development of Parkinsonian symptoms.
    [-INSERT FIGURE 18 ABOUT HERE-]
    PARKINSON'S DISEASE
    The basal ganglia plays a major role in controlling and facilitating specific movements, as well as inhibiting unwanted movements (Marsden & Obesco 1994; Turjanski, et al., 1999). The basal ganglia is also directly implicated in the generation of a variety of movement disorders, including chorea, ballismus, restless leg syndrome, rigidity, stiffness, and Parkinson's disease.
    Parkinson's disease is a progressive degenerative disorder characterized by rigidity and shuffling gait, stooped posture, generalized slowness and stiffness of movement, and a loss of facial emotional expression, as well as a loss of spontaneity and flexibility in making postural adjustments when eating, going to the toilet, or having sex. Moreover, many Parkinson's patients experience not only rigidity and akinesia, but suffer from episodic freezing of movement (Dietz, et al. 1990; Pascual-Leone, et al. 1994), a tendency to easily fall (Stacy & Jankovic 1992) an impairment of "righting reflexes" (Calne 1994), and a reduced capacity to blink (Freedman 1992) and even to breathe (Stacy & Jankovic, 1992); similar to the frozen panic states and induced catatonia.
    Hypophonia (reduced voice volume) dysarthria and a tendency to speak in a monotone, micrographia (small handwriting), and a 4-8 c/sec. ("pill rolling") resting tremor (exacerbated by stress) involving antagonistic muscles are common (Freedman, 1992; Stacy & Jankovic, 1992). Depression, changes in personality and slowed thought processes are also not unusual among Parkinson's patients (Walters, 1999). Parkinsonism can result following neurological trauma or vascular abnormalities (Koller, 1987; Murrow et al. 1990) or isolated lesions to the substantia nigra (Stern, 1966) and can therefore arise from a number of different causes including infection and toxic exposure. Parkinson's disease may also overlap with other striatal disturbances such as Alzheimers disease (Calne 1994). Indeed, sigificant cognitive deficits are not unusual among those with Parkinson's disease (Freedman, 1992; Rajput 1992); i.e. subcortical dementia.
    Parkinson's disease usually begins after age 60 (though the first signs may appear during the early 40's), effects about 2% of the population (Koller, 1987) and is usually characterized by a massive loss of up to 80-85% of the dopamine neurons in the substantia nigra and an 80% decrease in striatal DA, with DA depletion greatest in the putamen (Goto, et al. 1990; Kish, et al. 1988). In fact, transplanting fetal nigral tissue into the putamen, can result in increased dlurodopa intake and some long-term clinical improvement (Hauser et al., 1999).
    Hence, whereas the substantia nigra DA system is directly implicated, the mesolimbic pathways and limbic striatum are only a mild factor and are only mildly effected in this disorder.
    STRIATAL IMBALANCE & PARKINSON'S DISEASE
    The differential involvement of the nigrostriatal vs mesolimbic DA system raises the possibility that whereas the corpus striatum and medial frontal lobes are negatively impacted, the amygdala and limbic striatum may continue to function normally -due to preservation of the mesolimbic DA system. However, because the normal balance between these various nuclei is disrupted, amygdala influences received within the SMA and corpus striatum may in fact overwhelm and massively inhibit (or over activate) these nuclei thereby giving rise to Parkinsonian symptoms (see Le Moal & Simon 1991 for related discussion); i.e. rigidity, a tendency to fall coupled with reduced blinking and disturbed righting reflexes, etc.
    In addition to DA in the genesis of Parkinsonian symptoms, significant reductions in opiate receptors within the putamen as well as the globus pallidus have also been reported (Goto et al. 1990), such that neurons involved in the experience of "reward" are effected. This selective loss of "reward" neurons suggests a a reduction in the capacity of the basal ganglia to receive pleasurable or positive emotional input as might be provided not only by opiates, but via the lateral amygdala and lateral hypothalamus.
    Possibly, because striatal neurons associated with negative feelings states may be selectively preserved in Parkinson's disease, the basal ganglia (but not the amygdala, hypothalamus, or neocortex) may respond as if in a highly aroused negative state (e.g. fearful, stressed) even when that is not the case. Adding to this imbalance would be the relative preservation of the mesolimbic DA system, and the continued input from the medial amygdala into the corpus and limbic striatum -the medial amygdala being more involved in the generation of unpleasant including fearful mood states (chapter 13)
    Indeed, loss of corpus striatal DA and/or excessive amygdaloid arousal is directly associated with the development of tonic EMG activity, motor neuron hyperactivity and thus excessive tonic excitation of the musculature and limb rigidity; i.e. Parkinson's symptoms. Conversely, excess striatal DA can result in chorea and excessive movement as well as psychosis.
    THE SMA & PARKINSON'S DISEASE
    It has been reported that many patients with Parkinson's disease display reductions in norepinephrine (NE) as well as DA throughout the upper layers of the motor, premotor, and medial frontal lobes (Gasper et al. 1991; Hornykieciz, 1982). NE (and 5HT) depletion also occurs following heightened emotional states, including extreme fear, prolonged stress and heightened arousal, and with amygdala hyperactivation. As noted, individuals with Parkinson's disease are also sometimes described as excessively aroused and/or unable to relax, and to suffer from heightened autonomic nervous system activity and gastrointestinal disturbances (Stacy & Jankovic, 1992) --disturbances which also implicate the amygdala and excessive limbic system arousal. Conversely, the autonomic nervous sytem of those who suffer from Alzheimer's disease have been characterized has hypoactive (Borson et al. 1992); the limbic striatum being implicated in Alzheimer's disease.
    The SMA typically becomes functionally activated prior to movement (chapter 19) and well before the caudate or putamen with which it is interconnected. When Parkinson's patients attempt to make repetitive movements, SMA functional activity is abnormally reduced as is putamen activity (Playford et al. 1992). This suggests that in addition to the corpus striatum one of the major regions of the neuroaxis involved in the "will" to move and the capacity to prepare to move; i.e. the SMA, is dysfunctional in those suffering from Parkinson's disease. Thus the SMA and medial frontal lobes as well as the corpus striatum, DA system, and amygdala, are implicated in the genesis of this disorder (e.g. Playford et al. 1992).
    Consider, for example, that Parkinson's patient's have difficulty using both hands to perform two different movements (e.g. squeeze a ball with one hand, draw a triangle with the other). Rather, they tend to perform one action, then switch to the other (Caligiuri et al. 1992). SMA dysfunction can result in similar disturbances (see chapter 19). Similarly, the ability of Parkinson's patients to engage in sequential and repetitive movements (Playford et al. 1992), or to simultaneously engage in separate movements such as walking, turning, and talking (Stacy & Jankovic 1992) is severely effected; a disorder which is also associated with frontal lobe abnormalities.
    THE HIPPOCAMPUS & SMA
    The striatum is also innervated by the hippocampus which is involved not only in memory, but spatial and cognitive mapping of the environment (chapters 13, 14). Thus the corpus striatum presumably relies on hippocampal (as well as parietal lobe) input in order to coordinate movement in visual-space.
    It is noteworthy that Parkinson's patients find it easier to perform movements that are cued or guided by external visual stimuli, whereas those which are internally generated are more severely effected (Dietz, et al. 1990). Hence, perhaps those striatal neurons which normally receive and integrate hippocampal input may also be dysfunctional.
    However, the role of the hippocampus appears to be minimal in the development of Parkinson's disease, at least in those cases without memory loss or dementia. Instead, the beneficial effect of external cues again raises the specter of significant medial frontal lobe and SMA involvement.
    For example, lesions to the medial frontal lobes can result in an inability to internally generate movements whereas external environmental and visual cues can exert an almost "magnetic" effect on limb activation and patients may involuntarily respond and react to external stimuli by reaching, grasping, or utilizing whatever objects may be near (see chapter 19). In contrast, the lateral frontal lobes are involved in externally driven movements (chapter 19).
    Hence, Parkinson's patients are possibly better able to "move" in response to visual stimuli presumably because of preserved lateral frontal lobe functioning and the loss of inhibitory SMA control -which (in part) accounts for their difficulty internally "willing" purposeful and fluid movements.
    DA, ACh, & STRIATAL IMBALANCE.
    The DA and cholinergic, ACh system appear to exert counterbalancing influences. For example, loss of nigrostriatal DA results in increased ACh, neuron hyperactivity (see Aghanjanian & Bunney, 1977; Bloom et al. 1965) and tonic EMG activity and thus limb rigidity which can be reversed by anti-cholinergic drugs (Klockgether, et al., 1987). That is, drugs which decrease ACh and those which increase DA, can ameliorate Parkinsons symptoms (Fahn, 1999), which suggests these two transmitters play oppositional and balancing roles (see Stoof et al. 1992). Moreover, ACh can be inceased by drugs that decrease DA, and can be decreased by drugs which increase DA (reviewed by Stoof et al. 1992).
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    DA normally inhibits ACh release and increases GABA activity. The DA system appears to exert an controlling influences not only on GABA but ACh neurons in the striatum (Le Moal & Simon 1991). Hence, reductions in DA result in decreased GABA activity and increased limbic striatal arousal and ACh activity, and reduced corpus striatal arousal and reduced GABA activity (see Stoof et al. 1992). Under these latter conditions the subject becomes rigid.
    However, under conditions where striatal DA is depleted, the excessive release of ACh creates excessive neural activity (Aghanjanian & Bunney, 1977; Bloom, et al. 1965) which in turn may be manifested in the form of excessive motor actions; i.e. ballismus, chorea, if the medial and ventral globus pallidus-subthalamic circuit is effected, or hypomovement and Parkinson's symptoms if the corpus striatum and dorsal globus pallidus is effected.
    For example, fluctuations in DA levels can either act to excite or inhibit motor and related cognitive-memory activity within the limbic striatum (Le Moal & Simon 1991; Mogenson & Yang 1991). However, with high levels of limbic striatal DA (and/or amygdala) activity, coupled with reduced GABA, animals may appear hyperactive and engage in running, "galloping," and biting, and related movements.
    Presumably these latter actions are due to inhibitory release (a consequence of striatal dysfunction or hyperactivation), and thus the triggering of brainstem motor programs that subserve these specific behavioral acts. These same stimulus (predator) released actions, across evolution, and across most animal species, are directly related to the functional integrity of the limbic system and striatum, and the capacity to survive when living in close proximity to predators, the elements, and cospecies. Actions without thought are in fact the province not of the basal ganglia, but the brainstem, which is why these and related motor programs are stored within brainstem nuclei (see chapter 17).
    The Amygdala, Temporal Lobe & DA.
    Psychotic disturbances, including "schizophrenia" need not involve the basal ganglia or DA dysfunction, as disorders of thought and mood may also appear following frontal or temporal lobe damage (chapter 19, 21). However, with frontal lobe damage the basal ganglia and SMA are often effected, whereas the amygdala is implicated in temporal lobe related psychotic states.
    Indeed, abnormal DA as well as norepinephrine (NE) and serotonin (5HT) have been reported in the amygdala of those diagnosed as psychotic (Spoont 1993; Stevens 1992). In addition, a gross asymmetry in the post-mortem levels of mesolimbic DA has been noted in the brains of those diagnosed as schizophrenic (reviewed in Le Moal & Simon 1991). Specifically, an increase in DA has been noted in the central amygdala and in the striatum of the left hemisphere, whereas DA levels within the right cerebral are similar to normals.
    In fact, the left amygdala and left temporal lobe (Flor-Henry, 1969; Perez, et al. 1985; Stevens, 1992) have long been thought to be a major component in the pathophysiology of psychosis and schizophrenia (Heath, 1954; Stevens, 1973; Torey & Peterson, 1974). For example, abnormal activity as well as size decrements have been noted in the left amygdala (Flor-Henry, 1969; Perez, et al. 1985) as well as the left inferior temporal lobe in schizophrenic patients (see Stevens, 1992). Spiking has also been observed in the amygdala of psychotic individuals who are experiencing emotional and psychological stress (see Halgren, 1992).
    In this regard it has been suggested that stress, particularly when experienced prenatally may be responsible, in some cases, for the development of DA abnormalities (see Le Moal & Simon 1991), whereas adverse early environmental experiences and trauma may contribute to the development of kindling, spiking and abnormal amygdala functioning (see chapters 28, 30). As noted, Parkinson's symptoms in some respects also resemble the effects of chronic stress and an inability to relax.
    THE LIMBIC STRIATUM, MEMORY & ALZHEIMER'S DISEASE
    THE LIMBIC STRIATUM, DA, 5HT, ACH, NE, & MEMORY
    The limbic striatum consists of the nucleus accumbens, olfactory tubericle, the extended (centro-medial) amygdala, as well as the ventral aspects of the caudate, putamen and globus pallidus (-substantia innomminata).
    The nucleus accumbens is located immediately beneath the anterior portion of the caudate and from a microscopic level appears to be part of the ventral caudate (Olton et al. 1991; Zaborszky et al. 1991). However, it maintains extensive interconnections with the amygdala as well as the hippocampus via the fimbria-fornix fiber bundle (DeFrance et al. 1985), which implicates this nuclei in memory functioning and probably the learning of visual-spatial and perhaps social-affective relationships.
    Similarly, the dorsal portion of the substantia innominata ("great unknown") merges (dorsally) with the ventral globus pallidus (and ventrally with the centro-medial amygdala), and maintains interconnections with the accumbens, hippocampus, lateral amygdala, and dorsal medial (DM) nucleus of the thalamus (Young et al. 1984; Zaborszky et al. 1991) -the DM being involved in regulating neocortical arousal and information reception as well as memory (see chapter 19).
    Like the accumbens, the substantia innominata (SI) is also important in memory functioning and has been implicated as one of the principle sites (along with the nucleus basallis) for the initial development of Alzheimers disease (see Olton et al. 1991; Zaborszky et al. 1991, for review of related details).
    The nuclei of the limbic striatum are also interconnected with the lateral and medial hypothalamus, brainstem reticular formation, and the frontal and inferior temporal lobes (Everitt & Robbins, 1992; Groenewegen, et al. 1991; Heimer & Alheid, 1991; Kelly, et al. 1982; Mogenson & Yang 1991; Olton et al. 1991; Parent & Hazrati 1995; Van Hoesen, et al. 1981; Zaborszky et al. 1991). The limbic striatum is able, therefore, to exert widespread effects on neocortical and subcortical structures.
    As noted, the limbic striatum receives DA from the mesolimbic system as does the amygdala. The amygdala also sends axons that terminate in striatal neurons immediately adjacent to those innervated by mesolimbic DA neurons (Kelly et al. 1982; Yim & Mogenson, 1983, 1989). Thus, a complex interactional loop is formed between these nuclei, the integrity of which, in part is dependent on the mesolimbic DA system which can act on the amygdala, hippocampus and limbic striatum simultaneously so as to modulate striatal reception of amygdala (Maslowski-Cobuzzi & Napier, 1994) and hippocampal excitatory signals, and regulate the transmission of accumbens input into the SI. Alterations in mesolimbic DA activity, therefore, can significantly influence limbic striatal, amygdala and hippocampal activity as well as the motoric expression of limbic impulses.
    For example, depletions in mesolimbic DA can disrupt motor and social-emotional memory functioning; a condition compounded by DA influences on acetylcholine (ACh) neurons, and the effects of striatal DA on the reception of hippocampal, amygala, and neocortical input.
    Indeed, the limbic striatum (and limbic system) contain high densities of ACh neurons which are involved in memory as well as motor functioning (Olton et al. 1991; McGaugh et al. 1992; Zaborszky et al. 1991). In fact, of all striatal nuclei, densities of DA (and ACh) neurons are highest within the (SI) and nucleus accumbens (Meredith et al. 1989) which in turn greatly influences the SI (which is a major source of neocortical ACh), as does the amygdala (Yim & Mogenson 1983) and hippocampus; i.e. these signals converge on the SI.
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    Like the striatum, the hippocampus (and the amygdala) also receives meso-limbic DA input and contains D1 and D2 receptors (Camps et al. 1990) as well as ACh. ACh influences on neuronal activity can be excitory or inhibitory depending on the resting membrain potential of the receiving neuron (Ajima et al. 1990) as well as concurrent DA activity. Specifically, mesolimbic DA mediated signals are relayed from the accumbens to ACh neurons in the SI which in turn project to DM and the neocortex, the frontal lobes in particular (Mogenson & Yang 1991; Olton et al. 1991; Zaborszky et al. 1991). However, the DA and cholinergic, ACh system appear to exert counterbalancing influences.
    For example, ACh is usually inhibited by DA. By contrast, DA depletion results increased ACh and neuron hyperactivity (see Aghanjanian & Bunney, 1977; Bloom et al. 1965; Klockgether, et al., 1987) which can greatly disrupt cognitive and memory functioning as well as motor activities, unless reversed by anti-cholinergic drugs. In fact, damage to this DA/cholinergic system can result in Alzheimers disease (Olton et al. 1991; Zaborszky et al. 1991).
    As per memory functioning, it appears that mesolimbic DA modulates the reception of hippocampal (motor-spatial) input into the accumbens which projects to the SI (which in turn distributes these influences, perhaps via ACh) to the neocortex). DA accomplishes this via inhibitory influences on ACh and facilitation of the GABA system which appears to exert inhibitory influences within the striatum and the transmission of impulses from the nucleus accumbens (and amygdala/hippocampus) to the SI. Therefore, if the inhibitory influences of GABA and ACh on the SI are dampened, the SI becomes activated and memory functioning may be enhanced or disrupted at the neocortical level as this nucleus exerts widespread ACh influences on the cerebrum. Thus fluctuations in DA levels can either act to excite or inhibit cognitive-memory activity within the limbic striatum (see Mogenson & Yang 1991) as well as the corpus striatum (Packard & White 1991) and the neocortex.
    However, also of importance in this memory-striatal neural network is (5HT) serotonin (McLoughlin et al. 1994; Mogenson & Yang 1991) and (NE) norepinephrine (Roozendaal & Cools, 1994). For example, NE levels have been shown to fluctuate within the amygdala and nucleus accumbens when presented with novel stimuli (Cools et al. 1991) and during information acquisition. Presumably NE levels within the accumbens can regulate or influence the reception of amygdala and hippocampal impulses within the accumbens and SI which in turn projects to the neocortex and, in this regard, may act to shunt amygdala-hippocampal impulses to discrete or wide areas of the cerebrum.
    Specifically, high alpha-NE activity is associated with reduced amygdala input, whereas low beta NE may reduce hippocampal input into the striatum. Conditions such as these, however, are most likely to result when stressed or traumatized in which case it is possible for amygdala (and thus emotional) input to be received in, learned, and expressed by the striatum in the absence of hippocampal participation (see Rozzendaal & Cools 1994). It is conditions such as these that can give rise to amnesia with preserved learning (see chapters 14, 30).
    However, in some cases, it is also possible for both the alpha and beta NE system to be effected simultaneously such that amygdala and hippocampal input to the limbic striatum are inhibited in which case profound memory loss may result (see Rozzendaal & Cools 1994). Similar disturbances are associated with the serotonin (5HT) system (McLoughlin et al. 1994).
    Depletion of 5HT can significantly effect the capacity to inhibit irrelevant sensory input (at the level of the brainstem, amygdala, basal ganglia, and neocortex). Hence, 5HT abnormalities or depletion typically results in confusion and sensory overload and in some instances the production of hallucinations (see chapter 30).
    Thus disruption of the mesolimbic DA system and/or severe disruptions in the 5HT system in turn interferes with the hippocampal-limbic striatal memory system (Packard & White 1991) and can create neuronal hyperactivity -a condition which interferes with perceptual and hippocampal- memory-SI-amygdala functioning. In this regard it is noteworthy that the central 5HT system is severely disrupted among those with severe memory loss and Alzheimer's disease (McLoughlin et al. 1994) and that calcification of the globus pallidus/SI can induce visual and auditory hallucinations as well as cognitive deterioration (Lauterbach et al. 1994).
    OVERVIEW: ALZHEIMER'S DISEASE
    Alzhiemer's disease is associated with a profound loss of memory and cognitive and intellectual functioning, including, at its later stages, an inability to recognize friends, loved one's or their own personal identity. Alzhiemer's disease is estimated to afflict approximately 10% of those over age 65, and 50% of those over 85.
    In its later stages, Alzhiemer's disease is associated with profound loss of cerebral functional capacity, coupled with neural degeneration and a loss of neurons and the development of amyloid (senile) plaque and neurofibrillary tangles. Because structures such as the substantia innominata, amygdala, and entorhinal cortex have been injured (Morrison et al. 1990; Gomez-Isla, et al., 2000; Rapoport 1990) it is thought that the destruction of this tissue and adjacent tissue accounts for the loss of memory, and social-emotional, facial recognition, and related visual abnormalities, including visual agnosia (Giannakoulos, et al., 1999).
    However, because there is no single factor that has been implicated, and due to the number of associated disturbances, it has been argued that Alzheimer's disease and associated cognitive and memory disturbances are due to a "global cortico-cortical disconnection" syndrome (see Morrison et al. 1990; Rapoport 1990). Nevertheless, for the purposes of this chapter, the striatal contribution to this disorder will be emphasized.
    MEMORY & ALZHEIMER'S DISEASE
    As detailed in chapter 15, the amygdala and hippocampus provide massive input to the limbic striatum as well as the dorsal medial nucleus of the thalamus (DM) , the frontal lobes and reticular activating system, as does the accumbens and SI (see Heimer & Alheid, 1991; Koob et al. 1991; Mogenson & Yang 1991; Zaborszky et al. 1991). As noted, these nuclei, including the overlying entorhinal cortex, play a significant role in memory and the gating of information destined for the neocortex and appear to be part of a massive neural network designed to control information processing and to establish memory related neural networks (see also chapter 14). Presumably the nucleus accumbens apparently acts to integrate hippocampal and amygdala input, which is then transmitted to the SI which is also the recipient of limbic impulses concerned with cognitive, memory, and motoric activities (see Mogenson & Yang 1991).
    In part, it appears that the accumbens and SI play an inhibitory (filtering) role on information processing, and may exert inhibitory (and counterbalancing) influences on the the medial frontal lobes, the DM, and corpus striatum (see Mogenson & Yang 1991). The amygdala exerts similar influences on these nuclei (chapter 15) and is also able to inhibit the SI and accumbens.
    However, the role of the limbic striatum in cognitive and memory related activity also includes the learning of reward-related and aversion processes, the facilitation of approach and withdrawal responses and the memorization of where a reward or aversive stimulus was previously received (Everitt et al. 1991; Kelsey & Arnold 1994). In this regard the nucleus accumbens and SI are dependent on the medial and lateral amgydala, especially in the learning of negative experiences (Kelsey & Arnold 1994).
    As noted, the SI is the primary source of neocortical cholinergic innervation (Carpenter 1991) and appears to be concerned with integrating social-emotional and cognitive input with motor memories and then storing them perhaps within the SI as well as within the neocortex. Hence, if the SI is lesioned the cholinergic projection system is disrupted, and cognitive as well as social-emotional memory functioning is negatively impacted.
    Since the SI merges with and becomes coextensive with the centromedial amygdala (Heimer & Alheid 1991),and is an amygdala derivative, not suprisingly, a significant loss of neurons, neurofibrillary changes and senile plaques have been found in the amygdala (and hippocampus, Rapoport 1990), as well as in the SI, in patients with Alzheimer's disease and those suffering from degenerative disorders and memory loss (Herzog & Kemper, 1980; Mann, 1992; Sarter & Markowitsch, 1985). Degeneration in the amygdala would also account for the social-emotional agnosia and prosopagnosia that is common in the advanced states of Alzhiemer's disease; i.e. failure to recognize or remember loved ones (chapter 13).
    WIDESPREAD NEURONAL DEATH & ALZHEIMER'S
    Neuronal loss has also been reported in the entorhinal and parahippocampal areas of the inferior temporal lobe (see Morrison et al. 1990; Rapoport 1990) within which is buried the hippocampus and amygdala. Specifically, in addition to senile plaques, neurofibrillary tangles, a 40% to 60% loss of neurons during the early stages of this disease have been found in layers 4 and 2 of the entorhinal cortex (Gomez-Isla, et al., 2000)--the gateway to the hippocampus. Destruction of this tissue and adjacent tissue would also result in memory, social-emotional, facial recognition, and related visual abnormalities, including visual agnosia, as recently demonstrated among those with Alzheimer's disease (Giannakoulos, et al., 1999).
    Indeed, among those with Alzheimer's disease, widespread atrophy, amyloid plaques, tangles, and metabolic disturbances have been noted in a variety of cortical areas with relative preservation of the motor and primary receiving areas (Rapoport 1990). Based on these findings it has been argued that Alzheimer's disease and associated cognitive and memory disturbances are due to a "global cortico-cortical disconnection" syndrome (see Morrison et al. 1990; Rapoport 1990); i.e., a loss of neurons in and interconnections with association neocortex, which in part would account for the cognitive deterioration.
    The initiation of this deteriorative process may well be in the SI, and it may be due to an olfactory borne infection due to viral or bacterial invasion. That is, these bacterial or viral agents may enter the olfactory system and invade those structures directly innervated by the olfactory nerves, i.e. the amygdala, entorhinal cortex, and SI (Joseph, 1998d). On the other hand, or perhaps related to this scenario, are findings suggesting a genetic foundation for this disorder, such that defects in at least four specific genes (located on chromosomes 1, 14, and 21) may be responsible (Levy-Lehad et al., 1995; Saunders et al., 1993).
    Given the likelihood that the limbic striatum and olfactory-limbic structures may be selectively involved in the early stages of Alzheimers, and given the fact that the SI provides cholinergic input to the neocortex, then the subsequent and progressive loss of SI (and amygdala) neurons might result in a progressive deterioration and cell death within the neocortex such that otherwise healthy neurons are killed. That is, since the SI contains high concentrations of cholinergic neurons which in turn project to widespread areas throughout the neocortex (reviewed in Carpenter 1991), perhaps the initial cell loss within the SI (also referred to as the nucleus basalis), may trigger further cell death in healthy neurons (which project to or receive fibers from the affected cells) which essentially become "pruned" and drop out form disuse.
    Defective Axonal Transport.
    There is evidence which indicates that perhaps due to head injury, drug or toxic exposure, or perhaps the loss of synaptic junctions (due to the death of unhealthy cells and dendritic retraction), axonal transport becomes defective due to the death of its target neuron. However, if a healthy cell cannot discharge and exchange information it too may die, thus leading to a domino effect and thus widespread cell death (see Burke et al. 1992). That is, due to the loss of terminal synaptic junctions (due to cell death) or to other chemical abnormalties including defects in microtubule assembly (which participates in neuronal transmission), axonal transport becomes dysfunctional as the receiving cell and it's dendrite have died. Hence, there is a buildup of toxic oxidatative metabolites and naturally occurring neurotoxins in the healthy cell body that project to the dead cell, which causes the normal cell to die as well. This would result in a progressive loss of neurons such that widespread areas of the cerebrum soon become effected.
    Presumably this what may occur if the limbic striatum becomes abnormal and cells within the SI and accumbens begin to die. As the disturbance and deterioration spreads, cognitive, emotional, memory and related abnormalities including Parkinsonian symptoms begin to appear and become progressively worse as neocortical, striatal, and limbic neurons die and drop out.
    LIMBIC & CORPUS STRIATAL COUNTERBALANCING INFLUENCES
    The limbic and corpus striatum are richly interconnected and send projections to many of the same brain areas. However, due to differential input from the amygdala and DA systems, these nuclei exert tremendous counterbalancing influences on each other and their associated neural networks. For example, the centro-medial as well as the basolateral amygdala projects to and exerts excitatory influences on the the limbic striatum (Maslowski-Cobuzzi & Napier, 1994; Yim & Mogenson 1982), whereas the medial and posterior-lateral amygdala projects to the corpus striatum and the ventral and dorsal globus pallidus. Via these dual interconnections, the amygdala can exert simultaneous and even oppositional influences on these nuclei.
    In addition, the corpus striatum receives the bulk of its DA from the nigrostriatal systems, whereas the limbic striatum receives DA from the mesolimbic DA system (see Fibiger & Phillips, 1986 for review) -transmitter systems which interact at the level of the brainstem, limbic system, striatum, and neocortex (Maslowski-Cobuzzi & Napier, 1994). For example, it has been shown mesolimbic DA can act on the amygdala and limbic striatum simultaneously so as to modulate striatal reception of amygdala excitatory signals (Maslowski-Cobuzzi & Napier, 1994).
    However, because the corpus and limbic striatum are largely (but not completely) innervated by different clusters of midbrain DA neurons, reductions or increases in one DA system can exert profound influences on those neurons innervated by the others -for example, by eliminating inhibitory or counterbalancing influences. Thus depletion of DA in the nigrostriatal (but not the mesolimbic) pathways can result in increased activity within the limbic striatum (see Yim & Mogenson, 1983, 1989) and medial amygdala, but deceased activity within the corpus striatum. If this occurs, movement programming may be disrupted resulting in rigidity or tremors -a consequence, in part, of an imbalance in amygdala-DA-striatal activation.
    Conversely, mesolimbic DA depletion can result in enhanced corpus striatal activity and decreased limbic striatal and lateral amygdala and hippocampal activity, such that motor and social-emotional memory functioning may be disrupted; a condition compounded by DA influences on acetylcholine (ACh) neurons and the reception of hippocampal, amygala, and neocortical input within the striatum. Hence, the functioning of the limbic or corpus striatum can be severely disrupted even when the functional integrity of its own neurotransmitter systems are otherwise intact; i.e. due to a loss of counterbalancing influences.
    CONCLUDING STATEMENT: THE AMYGDALA
    The basal ganglia motor circuit, as conceptualized and described in this chapter, consists of multiple neural networks involving the caudate, putamen, globus pallidus, limbic striatum, motor thalamus, subthalamus, brainstem, SMA, pre-motor and primary motor areas, and the amygdala.
    Unfortunately, the role of the amygdala in movement is often ignored by investigators (and almost all textbooks) although all aspects of the motor circuit are directly or indirectly innervated by this nuclei and respond to amygdala mediated impulses. Although the amygdala can be surgically destroyed bilaterally without significantly effecting normal motor functioning, in many instances the amygdala is implicated in the genesis of abnormal motor activities and may play a significant role in striatal dysfunction and the development of Parkinson's and related diseases.
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    LIMBIC LANGUAGE
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  6. page Limbic System edited The Limbic System Hypothalamus, Septal Nuclei, Amygdala, Hippocampus Emotion and the Unconsci…

    The Limbic System
    Hypothalamus, Septal Nuclei,
    Amygdala, Hippocampus
    Emotion and the Unconscious Mind
    R. Gabriel Joseph, Ph.D.
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    Limbic System Overview
    Buried within the depths of the cerebrum are several large aggregates of limbic structures and nuclei which are preeminent in the control and mediation of memory, emotion, learning, dreaming, attention, and arousal, and the perception and expression of emotional, motivational, sexual, and social behavior including the formation of loving attachments. Indeed, the limbic system not only controls the capacity to experience love and sorrow, but it governs and monitors internal homeostasis and basic needs such as hunger and thirst (Bernardis & Bellinger 2007; Gloor 1992, 2010; Joseph, 1990, 1992, 2000a; LeDoux 1992, 2012; MacLean, 1973, 1990; Rolls, 1984, 1992; Smith et al. 1990), including even the cravings for pleasure-inducing drugs (Childress, et al., 2009).
    The structures and nuclei of the limbic system are exceedingly ancient, some of which began to evolve over 450 million years ago. Over the course of evolution, these emotional structures have expanded in size, some becoming increasingly cortical in response to increased environmental opportunities and demands. In fact, as the neocortical forebrain expanded and until as recently as 50 million years ago, the cerebrum of the ancestral line that would eventually give rise to humans, was dominated by the limbic system.
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    However, over the course of evolution a mantle of neocortex began to develop and enshroud the limbic system; evolving at first to serve limbic needs in a way that would maximize the survival of the organism, and to more efficiently, effectively, and safely satisfy limbic needs and impulses. In consequence, the frontal, temporal, parietal, and occipital lobes evolved covered with a neocortical mantle, that in humans would come to be associated with the conscious, rational mind. Sometimes, however, even in the most rational of humans, emotions can hijack the logical mind, and the neocortex, and even peaceful people might be impelled to murder even those they love.
    Indeed, the old limbic brain has not been replaced and is not only predominant in regard to all aspects of motivational and emotional functioning, but is capable of completely overwhelming "the rational mind" due in part to the massive axonal projections of limbic system to the neocortex. Although over the course of evolution a new brain (neocortex) has developed, Homo sapiens sapiens ("the wise may who knows he is wise") remains a creature of emotion. Humans have not completely emerged from the phylogenetic swamps of their original psychic existence.
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    Hence, due to these limbic roots, humans not uncommonly behave "irrationally" or in the "heat of passion," and get into fights, have sex with or scream and yell at strangers thus act at the behest of their immediate desires; sometimes falling "madly in love" and at other times, acting in a blind rage such that even those who are 'loved" may be slaughtered and murdered.
    Indeed, emotion is a potentially powerful overwhelming force that warrants and yet resists control-- as something irrational that can happen to a someone ("you make me so angry") and which can temporarily hijack, overwhelm, and snuff out the "rational mind."
    The schism between the rational and the emotional is real, and is due to the raw energy of emotion having it's source in the nuclei of the ancient limbic lobe -- a series of structures which first make their phylogenetic appearance over a hundred million years before humans walked upon this earth and which continue to control and direct human behavior.
    FUNCTIONAL OVERVIEW
    In general, the primary structures of the limbic system include the hypothalamus, amygdala, hippocampus, septal nuclei, and anterior cingulate gyrus; structures which are directly interconnected by massive axonal pathways (Gloor, 2010; MacLean, 1990; Risvold & Swanson, 2012). With the exception of the cingulate which is referred to as "transitional" cortex (mesocortex) and consists of five layers, the hypothalamus, amygdala, hippocampus, septal nuclei are considered allocortex, consisting of at most, 3 layers.
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    The hypothalamus could be considered the most "primitive" aspect of the limbic system, though in fact the functioning of this sexually dimorphic structure is exceedingly complex. The hypothalamus regulates internal homeostasis including the experience of hunger and thirst, can trigger rudimentary sexual behaviors or generate feelings of extreme rage or pleasure. In conjunction with the pituitary the hypothalamus is a major manufacturer/secretor of hormones and other bodily humors, including those involved in the stress response and feelings of depression.
    {http://brainmind.com/images/LimbicSystemEmotions.jpg} The amygdala has been implicated in the generation of the most rudimentary and the most profound of human emotions, including fear, sexual desire, rage, religious ecstasy, or at a more basic level, determining if something might be good to eat. The amygdala is implicated in the seeking of loving attachments and the formation of long term emotional memories. It contains neurons which become activated in response to the human face, and which become activated in response to the direction of someone else's gaze. The amygdala also acts directly on the hypothalamus via the stria terminalis, medial forebrain bundle, and amygdalafugal pathways, and in this manner can control hypothalamic impulses. The amygdala is also directly connected to the hippocampus, with which it interacts in regard to memory.
    The hippocampus is unique in that unlike the amygdala and other structures, almost all of its input from the neocortex is relayed via the overlying entorhinal cortex--a five layered mesocortex. As is well known, the hippocampus is exceedingly important in memory, acting to place various short-term memories into long-term storage. Presumably the hippocampus encodes new information during the storage and consolidation (long-term storage) phase, and assists in the gating of afferent streams of information destined for the neocortex by filtering or suppressing irrelevant sense data which may interfere with memory consolidation. Moreover, it is believed that via the development of long-term potentiation the hippocampus is able to track information as it is stored in the neocortex, and to form conjunctions between synapses and different brain regions which process and store associated memories.
    {http://cosmology.com/images/LimbicCoverEbook1epub.jpg} The septal nuclie can produce extremes of emotion, including explosive violence, known as "septal rage."
    The septal nuclei is in part an evolutionary and developmental outgrowth of the hippocampus (Ariens Kappers, et al., 1936; Gloor, 2010), and the hypothalamus, and in fact acts to link the hippocampus with the hypothalamus as well as with the brainstem (Andy & Stephan, 1968; Risvold & Swanson, 2012; Swanson & Cowan, 1979;). It consists of both lateral and medial segments; i.e. the lateral and medial septal nuclei (Ariens Kappers, et al., 1936). Presumably, via these interconnections, the septal nuclei exerts modulatory influences on the hippocampus in regard to memory functioning and arousal (Gloor, 2010).
    The septal nuclei is also interconnected with and shares a counterbalancing relationship with the amygdala particularly in regard to hypothalamic activity and emotional and sexual arousal (Andy & Stephan, 1968; Swanson & Cowan, 1979). For example, whereas the amygdala promotes indiscriminate contact seeking, and perhaps promiscuous sexual activity, the septal nuclei inhibits these tendencies thus assisting in the formation of selective and more enduring emotional attachments (Joseph, 1992a, 2009b).
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    The anterior cingulate is considered a transitional cortex, or rather, mesocortex (also referred to as "paleocortex") as it consists of five layers (MacLean, 1990). The anterior cingulate is intimately interconnected with the hypothalamus, amygdala, septal nuclei, and hippocampus, and participates in memory and emotion including the experience of pain, misery, and anxiety, and is directly implicated in the evolution and expression of maternal behavior. It is also the most vocal aspect of the brain, becomes active during language tasks, and generates emotional-melodic aspects of speech which is expressed via interconnections with the right and left frontal speech areas, and the vocalization center in the midbrain periaqueductal gray. Thus the anterior cingulate is implicated in the more cognitive aspects of social-emotional behavior including language and the establishment of long term attachments beginning with the mother-infant bond.
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    Also implicated in the functioning of the limbic system are the olfactory bulb and olfactory system, the limbic striatum (nucleus accumbens, olfactory tubercle, substantia innominata, ventral caudate and putamen), the orbital frontal and inferior temporal lobes and the midbrain monoamine system. These systems and structures are also directly connected or separated by only a single synapse, and which tend to become aroused not only as a function of emotional arousal, but in reaction to olfactory input which continues to exert profound effects on the human limbic system, and upon human behavior.
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    HYPOTHALAMUS
    The hypothalamus is an exceedingly ancient structure and unlike most other brain regions it has remained somewhat similar in structure throughout phylogeny and apparently over the course of evolution (Crosby et al. 1966). Located in the most medial aspect of the brain, along the walls and floor of the 3rd ventricle, this nucleus is fully functional at birth and is the central core from which all emotions derive their motive force. Indeed, the hypothalamus is highly involved in all aspects of emotional, reproductive, vegetative, endocrine, hormonal, visceral and autonomic functions (Alam et al., 2011; Johnson & Gross, 2013; Markakis & Swanson, 2010; Sherin, et al., 2012; Smith et al. 1990) and mediates or exerts significant or controlling influences on eating, drinking, sleeping and the experience of pleasure, rage, and aversion.
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    In fact, almost every region of the cerebrum interacts with and communicates with the hypothlamus and is subject to its influences (Swanson, 2007). Moreover, the hypothalamus utilizes the blood supply to transmit hormonal and humoral messages to peripheral organs as well as other brain structures and utilizes the blood supply to receive information as well, thus bypassing the synaptic route utilized by almost all other regions of the neuroaxis (Markakis & Swanson, 2010). Through the blood supply (as well as via the cerebrospinal fluid), the hypothalamus not only regulates, but is subject to feedback regulation by the same structures that it controls.
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    Certain areas of the diencephalon, midbrain, and brainstem, are exceedingly exceedingly sensitive to hormones, humors, and peptides circulating within the blood plasma, and the cerebrospinal fluids; chemosensory information which is used for maintaining homeostasis. Broadly considered, these chemosensory sensitive areas are generally located near or surrounding the cerebral ventricles (Johnson & Gross, 2013) and they tend not to be effected by the so called "blood brain barrier;" referred to as circumventricular organs (CVOs). There are perhaps dozens of CVO's at least 8 of which are located in or near the ventricular systems which feed the brainstem and diencephalon including the hypothalamus, pineal gland and pituitary (Johnson & Gross, 2013).
    The hypothalamus, however, does not act solely through the blood supply or via cerebrospinal fluid, and its also receives sensory information synaptically, and often indirectly, as is the case with the majority of olfactory fibers. In general, sensory stimuli reach the hypothalamus from a variety of routes. These include the solitary tract of the brainstem, a structure which receives, processes, and transmits data received principally from the vagus and glosopharyngeal cranial nerves. Through this pathway the lateral hypothalamus is informed about cardivocascular activities, respiration, and taste. These pathways are also bidirectional (Swanson, 2007). Other major pathways include the medial forebrain bundle (which contains axons from a variety of different cellular groups) and the stria terminalis through which the amygdala and hypothalamus interact. The hypothalamus also maintains massive interactive pathways with the frontal lobes and septal nuclei (Risvold & Swanson, 2012).
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    Broadly considered, the hypothalamus consists of three longitudinal subdivisions which extend along its anterior to posterior axis. These are the medial, lateral, and periventricular (Swanson, 2007). The periventricular zone is concerned with neuroendocrine regulation, whereas the lateral and medial zones are concerned with affective states, including hunger and thirst. These zones, in turn can be further subdivided into subnuclei.
    Phylogenetically, structurally, and embryologically the hypothalamus is traditionally considered part of the diencephalon. During embryological development it emerges from the diencephalic vessicle of the neural tube along with those anterior-lateral evaginations which become the optic nerves and retina of the eye, as well as the pituitary gland (ventrally) and the pineal gland and thalamus (dorsally). There is some dispute, however, over the developmental patterns of the hypothalamus, as some scientists believe that it develops from the outside in (the "hollow hypothalamus hypothesis").
    On the other hand, the hypothalamus originates from the medially situated neuroepithelium, and thus begins its developmental journey in a medial (or rather paramedial) to lateral arc, such that it appears that the medial hypothalamus is fashioned (and matures) in advance of the lateral hypothalamus.
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    From an evolutionary perspective, however, the hypothalamus appears to have dual (forebrain - midbrain) origins; that is emerging from the dorsal (visual) midbrain, and the olfactory forebrain, which together, and over the course of evolution, gave rise to the ventral, medial, lateral and preoptic hypothalamus. Nevertheless, in modern mammals and humans, the olfactory origins are no longer directly apparent, particularly in that most olfactory fibers reach the hypothalamus indirectly; e.g. via the amygdala and piriform cortex.
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    The hypothalamus is exceedingly responsive to olfactory (and pheromonal) input. Perhaps reflecting this partial and putative olfactory origin is the fact that this structure utilizes chemical (hormonal, humoral) molecules to communicate with other areas of the brain, and reacts to these same molecules as well as olfactory cues, including those directly related to sexual status.
    It is this olfactory-chemical origin and sensitivity which in turn may explain why portions of the hypothalamus (like the amygdala) are also sexually dimorphic and reacts to pheromonal sensory stimuli including those which signal sexual status. That is, structurally and functionally the hypothalamus of males and females are stucturally dissimilar (Bleier et al. 1982; Dorner, 1976; Gorski et al. 1978; Rainbow et al. 1982; Raisman & Field, 1971, 1973) and perform different functions depending on if one is a man or a woman, and if a woman is sexually receptive, pregnant, or lactating. For example, the sexually dimorphic supraoptic and paraventricular nuclei project (via the infundibular stalk) to the posterior lobe of the pituitary which may then secrete oxytocin--a chemical which can trigger uterine contractions as well as milk production in lactating females (and which can thus make nursing a pleasurable experience). The male hypothalamus/pituitary does not perform this function.
    SEXUAL DIMORPHISM IN THE HYPOTHALAMUS
    As is well known, sexual differentiation is strongly influenced by the presence or absence of gonadal steriod hormones during certain critical periods of prenatal development in many species including humans. Not only are the external genitalia and other physical features sexually differentiated but certain regions of the brain have also been found to be sexually dimorphic and differentially senstitive to steriods, particularly the preoptic area and ventromedial nucleus of the hypothalamus, as well as the amygdala (Bleier et al. 1982; Dorner, 1976; Gorski et al. 1978; Rainbow et al. 1982; Raisman & Field, 1971, 1973).
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    Indeed it has now been well established that the amygdala and the hypothalamus (specifically the anterior commissure, anterior-preoptic, ventromedial and suprachiasmatic nuclei) are sexually differentiated and have sex specific patterns of neuronal and dendritic development, (Allen et al. 1989; Blier et al. 1982; Gorski et al. 1978; Rainbow et al. 1982; Raisman & Field, 1971, 1973; Swaab & fliers, 2005).
    This is a consequence of the presence or absence of testosterone during fetal development in humans, or soon after birth in some species such as rodents. Specifically, the presence or absence of the male hormone, testosterone during this critical neonatal period, directly effects and determines the growth and pattern of interconnections between the amygdala and hypothalamus, between axons and dendrites in these nuclei as well as the hippocampus, septal nuclei, olfactory system (ref), and thus the organization of specific neural circuits. In the absence of testosterone, the female pattern of neuronal development occurs. Indeed, it is the presence or absence of testosterone during these early critical periods that appear to be responsible for neurological alterations which greatly effect sex differences in thinking, sexual orientation, aggression, and cognitive functioning (Barnett & Meck, 1990; Beatty, 1992; Dawson et al. 1975; Harris, 1978; Joseph, et al. 1978; Stewart et al. 1975).
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    For example, if the testes are removed prior to differentiation, or if a chemical blocker of testosterone is administered thus preventing this hormone from reaching target cells in the limbic system, not only does the female pattern of neuronal development occur, but males so treated behave and process information in a manner similar to females (e.g., Joseph et al. 1978); i.e. they develop female brains and think and behave in a manner similar to females. Conversely, if females are administered testosterone during this critical period, the male pattern of differentiation and behavior results (see Gerall et al. 1992 for review).
    That the preoptic and other hypothalamic regions are sexually dimorphic is not surprising in that it has long been known that this area is extremely important in controlling the basal output of gonadotrophins in females prior to ovulation and is heavily involved in mediating cyclic changes in hormone levels (e.g. FSH, LH, estrogen, progesterone). Chemical and electrical stimulation of the preoptic and ventromedial hypothalamic nuclei also triggers sexual behavior and even sexual posturing in females and males (Hart et al., 2005; Lisk, 1967, 1971) and, in female primates, even maternal behavior (Numan, 2005). In fact, dendritic spine density of ventromedial hypothalamic neurons varies across the estrus cycle (Frankfurt et al., 1990) and thus presumably during pregnancy and while nursing.
    {http://brainmind.com/images/PenisRock.jpg} {http://brainmind.com/images/peniscactus.jpg} In primates, electrical stimulation of the preoptic area increases sexual behavior in males, and significantly increases the frequency of erections, copulations and ejaculations, we well as pelvic thrusting followed by an explosive discharge of semen even in the absence of a mate (Hart, et al., 2005; Maclean, 1973). Conversely, lesions to the preoptic and posterior hypothalamus eliminates male sexual behavior and results in gonadal atrophy.
    {http://brainmind.com/images/treepenis8022.jpg} Hence, it is thus rather clear than the ability to sexually reproduce is dependent on the functional integrity of the hypothalamus. In fact, it is via the hypothalamus acting on the pituitary, that gonadotropins come to be released. Gonadotropins control the production and/or release of gametes; i.e. ova and sperm.
    Specifically, the hypothalamic neurons secrete gonadotropin-releasing hormone, which acts on the anterior lobe of the pituitary which secretes gonadotropins. However, given that in females, this is a cyclic event, whereas in males sperms are constantly reproduced, is further evidence of the sexual dimorphism of the hypothalamus.
    Although the etiology of homosexuality remains in question, it has been shown that the ventromedial and anterior nuclei of the hypothalamus of male homosexuals demonstrate the female pattern of development (Levay, 1991; Swaab, 1990). When coupled with the evidence of male vs female and homosexual differences in the anterior commissure which links the temporal lobe and sexually dimorphic amygdala (see below) as well as the similarity between male homosexuals and women in regard to certain cognitive attributes including spatial-perceptual capability (see below), this raises the possibility that male homosexuals are in possession of limbic system that is more "female" than "male" in functional as well as structural orientation.
    It is also interesting to note that the sexually dimorphic preoptic region contains thermosensitive neurons, and controls the physiological and behavior responses to excessive external cold or heat. That is, it is responsible for internal thermoregulation and thus heat loss or retention (Alam et al., 2011). Although we can only speculate, it may well be sex differences in this structure which accounts (at least in part) for the stereotypical differences in male vs female perceptions of cold, and why, stereotypically, females (despite their extra-layers of heat-retaining fat) are more likely to insist on elevating room temperature.
    LATERAL & VENTROMEDIAL HYPOTHALAMIC NUCLEI
    Although consisting of several nuclear subgroups, the lateral and medial (ventromedial) hypothalamic nuclei play particularly important roles in the control of the automonic nervous system, the experience of pleasure and aversion, eating and drinking, and raw (undirected) emotionality. They also appear to share a somewhat antagnistic relationship.
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    For example, the medial hypothalamus controls parasympathetic activities (e.g. reduction in heart rate, increased peripheral circulation) and exerts a dampening effect on certain forms of emotional/motivational arousal. The lateral hypothalamus mediates sympathetic activity (increasing heart rate, elevation of blood pressure) and is involved in controlling the metabolic and somatic correlates of heightened emotionality (Smith et al. 1990). In this regard, the lateral and medial region act to exert counterbalancing influences on each other.
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    HUNGER & THIRST
    The lateral and medial region are highly involved in monitoring internal homeostasis and motivating the organism to respond to internal needs such as hunger and thirst (Anand & Brobeck, 1951; Bernardis & Bellinger 2007; Hetherington & Ranson, 1940). For example, both nuclei appear to contain receptors which are sensitive to the body's fat content (lipostatic/caloric receptors) and to circulating metabolites (e.g. glucose) which together indicate the need for food and nourishment. For example, when food is digested, the viscera secretes various hormones which act on the alimentary tract, which in turn stimulates the solitary tract (ST) which projects directly to the hypothalamus. However, in the absence of food, the viscera also begins to secrete various hormones which when coupled changes in caloric blood levels, signals to the hypothalamus the need for food. The lateral hypothalamus also appears to contain osmoreceptors (Joynt, 1966) which determine if water intake should be altered.
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    {http://brainmind.com/images/rys0504.gif} Electophysiologically, it has been determined that the hypothalamus not only become highly active immediately prior to and while the organism is eating or drinking, but the lateral region alters it's activity when the subject is hungry and simply looking at food (Hamburg, 1971; Rolls et. al., 1976). In fact, if the lateral hypothalamus is electrically stimulated a compulsion to eat and drink results (Delgado & Anand, 1953). Conversely, if the lateral area is destroyed bilaterally there results aphagia and adipsia so severe animals will die unless force fed (Anand & Brobeck, 1951; Hetherington & Ranson, 1940; Teitelbaum & Epstein, 1962).
    If the medial hypothalamus is surgically destroyed, inhibitory influences on the lateral region appear to be abolished such that hypothalamic hyperphagia and severe obesity result (Anand & Brobeck, 1951; Hoebel & Tetelbaum, 1966; Teitelbaum, 1961). Hence, the medial area seems to act as a satiaty center; but, a center that can be overridden.
    Specifically, with ventromedial lesions, animals not only eat more, but the intervals between meals becomes shorter such that they eat more meals. Thus they begin to gain weight. In part this is also due to changes in the sympathetic nervous system which increases vagal activity, thus signaling the need for more food. As noted, the ST is bidirectional.
    Normally the hypothalamus can act via the ST and thus the vagal complex and can signal satiation. However, with medial destruction, the ST becomes hyperactive thus inducing parasympathetic overactivity which induces more rapid gastric emptying and the rapid storage of ingested calories. Because these calories are rapidly stored, caloric blood levels are reduced and the lateral hypothalamus is stimulated to begin eating again--which explains the increased frequency of meals. In fact, if animals that have become obese following ventromedial lesions are starved back to their normal weight, once they are allowed free access to food, they again become obese (Hoebel & Tetelbaum, 1966).
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    {http://brainmind.com/images/obese01456.jpg} Overall, it appears that the lateral hypothalamus is involved in the intitation of eating and acts to maintain a lower weight limit such that when the limit is reached the organism is stimulated to eat. Conversely, the medial regions seems to be involved in setting a higher weight limit such that when these levels are approached it triggers the cessation of eating.
    In part, these nuclei exert these differential influences on eating and drinking via motivational/emotional influences they exert on other brain nuclei (e.g. via reward or punishment). However, it should be stressed that there are a number of other structures and hormones and peptides involved, including the pancreatic islets, and insulin secretion.
    PLEASURE & REWARD
    In 1952, Heath (cited by Maclean, 1969) reported what was then considered remarkable. Electrical stimulation near the septal nuclei elicited feelings of pleasure in human subjects: "I have a glowing feeling. I feel good!" Subsequently, Olds and Milner (1954) reported that rats would tirelessly perform operants to receive electrical stimulation in this same region and concluded that stimulation "has an effect which is apparently equivalent to that of a conventional primary reward." Even hungry animals would demonstrate a preference for self-stimulation over food.
    Feelings of pleasure (as demonstrated via self-stimulation) have been obtained following excitation to a number of diverse limbic areas including the olfactory bulbs, amygdala, hippocampus, cingulate, substantia nigra (a major source of dopamine), locus coeruleus (a major source of norepinephrine), raphe nucleus (serotonin), caudate, putamen, thalamus, reticular formation, medial forebrain bundle, and orbital frontal lobes (Brady, 1960; Lilly, 1960; Olds & Forbes, 1981; Stein & Ray, 1959; Waraczynski et al. 2007).
    {http://brainmind.com/images/selfstimulationrat.jpg} {http://brainmind.com/images/ratSelfStimulating.jpg} {http://brainmind.com/images/OlfactoryHypothalamus21.jpg} In mapping the brain for positive loci for self-stimulation, Olds (1956) found that the medial forebrain bundle (MFB) was a major pathway which supported this activity. Although the MFB interconnects the hippocampus, hypothalamus, septum, amygdala, orbital frontal lobes (areas which give rise to self-stimulation), Olds discovered in its course up to the lateral hypothalamus reward sites become more densely packed. Moreover, the greatest area of concentration and the highest rates of self-stimulatory activity were found to occur not in the MFB but in the lateral hypothalamus (Olds, 1956; Olds & Forbes, 1981). Indeed, animals "would contine to stimulate as rapidly as possible until physical fatigue forced them to slow or to sleep" (Olds, 1956).
    Electrophysiological studies of single lateral hypothalamic neurons indicate that these cells become highly active in response to rewarding food items (Nakamura & Ono, 1986). In fact, many of these cells will become aroused by neutral stimuli repeatedly associated with reward such as a cue-tone --even in the absence of the actual reward (Nakamura & Ono, 1986; Ono et al. 1980). However, this ability to form associations appears to be secondary to amygdaloid activation (Fukuda et al. 2007) which in turn influences hypothalamic functioning.
    Nevertheless, if the lateral region is destroyed the experience of pleasure and emotional responsiveness is almost completely attenuated. For example, in primates, faces become blank and expressionless, whereas if the lesion is unilateral, a marked neglect and indifference regarding all sensory events occurring on the contralateral side occurs (Marshall & Teitelbaum, 1974). Animals will in fact cease to eat and will die.
    AVERSION
    In contrast to the lateral hypothalamus and it's involvement in pleasurable self-stimulation, activation of the medial hypothalamus is apparently so aversive that subjects will work to reduce it (Olds & Forbes, 1981). Hence, electrical stimulation of the medial region leads to behavior which terminates the stimulation--apparently so as to obtain relief (e.g. active avoidance). In this regard, when considering behavior such as eating, it might be postulated that when upper weight limits (or nutritional requirements) are met, the medial region becomes activated which in turn leads to behavior (e.g. cessation of eating) which terminates its activation.
    It is possible, however, that medial hypothalamic activity may also lead to a state of quiescence such that the organism is motivated to simply cease to respond or to behave. In some instances this quiescent state may be physiologically neutral, whereas in other situations medial hypothalamic activity may be highly aversive. Quiescence is also associated with parasympathetic activity which is mediated by the medial area.
    HYPOTHALAMIC DAMAGE & EMOTIONAL INCONTINENCE: LAUGHTER & RAGE
    When electrically stimulated, the hypothalamus responds by triggering two seemly oppositional feeling states, i.e. pleasure and unpleasure/aversion. The generation of these emotional reactions in turn influences the organism to respond so as to increase or decrease what is being experienced.
    The hypothalamus, via it's rich interconnections with other limbic regions including the neocortex and frontal lobes, it able to mobilize and motivate the organism to either cease or continue to behave. Nevertheless, at the level of the hypothalamus, the emotional states elicited are very primitive, diffuse, undirected and unrefined.
    The organism feels pleasure in general, or aversion/unpleasure in general. Higher order emotional reactions (e.g. desire, love, hate, etc.) require the involvement of other limbic regions as well as neocortical participation.
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    Emotional functioning at the level of the hypothalamus is not only quite limited and primitive, it is also largely reflexive. For example, when induced via stimulation, the moment the electrical stimulus is turned off the emotion elicited is immediately abolished. In contrast, true emotions (which require other limbic interactions) are not simply turned on or off but can last from minutes to hours to days and weeks before completely dissipating.
    Nevertheless, in humans, disturbances of hypothalamic functioning (e.g. due to an irritating lesion such as tumor) can give rise to seemingly complex, higher order behavioral-emotional reactions, such as pathological laughter and crying which occurs uncontrollably. However, in some cases when patients are questioned, they may deny having any feelings which correspond to the emotion displayed (Davison & Kelman, 1939; Ironside, 1956; Martin, 1950). In part, these reactions are sometimes due to disinhibitory release of brainstem structures involved in respiration, whereas in other instances the resulting behavior is caused by hypothalamic triggering of other limbic nuclei.
    UNCONTROLLED LAUGHTER
    Pathological laughter has frequently been reported to occur with hypophyseal and midline tumors involving the hypothalamus, aneurysm in this vicinity, hemorrhage, astrocytoma or pappiloma of the 3rd ventricle (resulting in hypothalamic compression), as well as surgical manipulation of this nucleus (Davison & Kelman, 1939; Dott, 1938; Foerster & Gabel, 1933; Martin, 1950; Money & Hosta, 1967; Ironside, 1956; List, Dowman, & Bagheiv, 1958).
    For example, Martin (1950, p.455) describes a man who while "attending his mother's funeral was seized at the graveside with an attack of uncontrollable laughter which embarrassed and distressed him considerably." Although this particular attack dissipated, it was soon accompanied by several further fits of laughter and he died soon thereafter. Post-mortem a large ruptured aneurysm was found, compressing the mammillary bodies and hypothalamus.
    In a similar case (Anderson, 1936; Cited by Martin, 1950), a patient literally died laughing following the eruption of the posterior communicating artery which resulted in compression (via hemorrhage) of the hypothalamus. "She was shaken by laughter and could not stop: short expirations followed each other in spasms, without the patient being able to make an adequate inspiration of air, she became cyanosed and nothing could stop the spasm of laughter which eventually became noiseless and little more than a grimace. After 24 hours of profound coma she died."
    Because laughter in these instances has not been accompanied by corresponding feeling states, this pseudo-emotional condition has been referred to as "sham mirth" (Martin, 1950). However, in some cases, abnormal stimulation in this region (such as due to compression effects from neoplasm) has triggered corresponding emotions and behaviors -- presumably due to activation of other limbic nuclei.
    For example, laughter has been noted to occur with hilarious or obscene speech--usually as a prelude to stupor or death--in cases where tumor has infiltrated the hypothlamus (Ironside, 1956). In several instances it has been reported by one group of neurosurgeons (Foerster & Gagel, 1933) that while swabbing the blood from the floor of the 3rd ventricle, patients "became lively, talkative, joking, and whistling each time the infundibular region of the hypothalamus was manipulated." In one case, the patient became excited and began to sing.
    HYPOTHALAMIC RAGE
    Stimulation of the lateral hypothalamus can induce extremes in emotionality, including intense attacks of rage accompanied by biting and attack upon any moving object (Flynn et al. 1971; Gunne & Lewander, 1966; Wasman & Flynn, 1962). If this nucleus is destroyed, aggressive and attack behavior is abolished (Karli & Vergness, 1969). Hence, the lateral hypothalamus is responsible for rage and aggressive behavior.
    {http://brainmind.com/images/rage22.jpg} As noted, the lateral maintains an oppositional relationship with the medial hypothalamus. Hence, stimulation of the medial region counters the lateral area such that rage reactions are reduced or eliminated (Ingram, 1952; Wheately, 1944), whereas if the medial is destroyed there results lateral hypothalamic release and the triggering of extreme savagery.
    In man, inflammation, neoplasm, and compression of the hypothalamus have also been noted to give rise to rage attacks (Pilleri & Poeck, 1965), and surgical manipulations or tumors within the hypothalamus have been observed to elicit manic and rage-like outbursts (Alpers, 1940). These appear to be release phenomenon, however. That is, rage, attack, aggressive, and related behaviors associated with the hypothalamus appears to be under the inhibitory influence of higher order limbic nuclei such as the amygdala and septum (Siegel & Skog, 1970). When the controlling pathways between these areas are damaged (i.e. disconnection) sometimes these behaviors are elicited.
    For example, Pilleri and Poeck (1965) described a man with severe damage throughout the cerebrum including the amygdala, hippocampus, cingulate, but with complete sparing of the hypothalamus who continually reacted with howling, growling, and baring of teeth in response to noise, a slight touch, or if approached. Hence, the hypothalamus being released responds reflexively in an aggressive-like non-specific manner to any stimulus. Lesions of the frontal-hypothalamic pathways have been noted to result in severe rage reactions as well (Fulton & Ingraham, 1929; Kennard, 1945).
    Nevertheless, like "sham mirth", rage reactions elicited in response to direct electrical activation of the hypothalamus immediately and completely dissipate when the stimulation is removed. As such, these outbursts have been referred to as "sham rage".
    CIRCADIAN RHYTHM GENERATION & SEASONAL AFFECTIVE DISORDER
    As noted in chapter 5, during the initial stages of cerebral evolution, the dorsal hypothalmus (like the dorsal thalamus, dorsal hippocampus, dorsal midbrain) was likely fashioned, at least in part, from photosensitive cells located in the anterior head region. Given the daily and seasonal changes in light vs darkness, nuclei in the midbrain-pons, and in the hypothalamus, became sensitive to and capable of generating rhythmic hormonal, neurotransmitter, and motoric activities. It is the hypothalamus, however, the suprachiasmatic nucleus (SCN) in particular, which appears to be the "master clock" for the generation of circadian rhythms; rhythms which have a period length of 24 hours (Aronson et al. 2013; Morin 2014).
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    {http://brainmind.com/images/clocks1.jpg} In humans and other species, the SCN (and the midbrain superior colliculus) is a direct recipient of retinal axons. It also receives indirect visual projections from the lateral geniculate nucleus of the thalamus (see Morin 2014). In this regard, the visual system appears to act to synchronize the SCN (and probably the midbrain-pons) to function in accordance with seasonal and day to day variations in the light/dark ratio. However, the SCN does not "see" per se, nor can it detect visual features, as its main concern is adjusting mood, and activity in regard to light intensity as related to rhythm generation.
    {http://brainmind.com/images/HypoSCN1.jpg} {http://brainmind.com/images/HypoSCN2.jpg} There is thus some evidence which suggests that when the SCN of the hypothalamus is deprived of (or unable to effectively respond to) sufficient light, although rhythm generation is not grossly effected (Morin 2014), individuals may become depressed; a condition referred to as Seasonal Affective Disorder (SAD). That is, the hypothalamus (and midbrain-pons) appear to decrease those hormonal and neurochemical activities normally associated with activation and high (daytime) activity thus resulting in depression.
    For example, the hypothalamic-pituitary axis secretes melatonin in phase with the circadian rhythm. Phase-delayed rhythms in plasma melatonin secretion have been repeatedly noted in most (but not all) studies of individuals with SADs (see Wirz-Justice et al. 2013, for review). However, with light therapy, not only is the depression relieved but the melatonin secretions return to normal. This is significant for melatonin is derived from tryptophan via serotonin and low serotonin levels have been directly linked to depression (e.g. Van Pragg 1982).
    {http://brainmind.com/images/HypothalamicPituitary31.jpg} There is some evidence which suggests that the hypothalamus (and the midbrain) may act to regulate serotonin release within the brainstem (Chaouloff 2013; however, see Morin 2014), which in turn may explain why serotonin levels rhythmically fluctuate (e.g. such as during the sleep cycle), or become abnormal when denied sufficient light; i.e. the production of serotonin by the raphe nucleus (in the pons) is abnormally effected.
    {http://brainmind.com/images/HypothalamicPaths18.gif} On the other hand, numerous studies have reported that SADs and major depression occurs most often during the Spring and not the winter, and is not influenced by latitude (e.g. Margnusson & Stefansson 2013; Wirz-Justice et al. 2013). There is also some suggestion that abnormal temperature perception, or aging within the SCN may be responsible for the genesis of SADs and related depressive disorders. For example, age related changes in the SCN have been noted to adversely effect circadian rhythm generation as well as metabolic and peptide activity (Aronson et al. 2013). In consequence, rest vs active cycles also become abnormal, with reductions in arousal and activity; i.e. the patient becomes depressed.
    It is also possible, however, that although light therapy can assist in alleviating depressive symptoms associated with SADs, that the deregulation of the SCN (and melatonin/serotonin) might be unrelated to light, temperature, or aging, but may be a consequence of stress on the hypothalamus (Chauloff 2013). For example, the hypothalamic-pituitary axis is tightly linked with and in fact mediates stress induced alterations in serotonin (see Chauloff 2013, for review); as well as norepinephrine (Swann et al. 2014) which has also been repeatedly implicated in the genesis of depression.
    THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS
    The hypothalamic, pituitary, adrenal system (HPA) is critically involved in the adaption to stressful changes in the external or internal environment. For example, in response to fear, anger, anxiety, disapointment, and even hope, the hypothalamus begins to release corticotropin releasing factor (CRF) which activates the andenohypophysis which begins secreting ACTH which stimulates the adrenal cortex which secretes cortisol (Fink, 2009).
    These events in turn appear to be under the modulating influences of norepinephrine. That is, as stress increases, NE levels decrease, which triggers the activation of the HPA axis. As is well known, low levels of NE are associated with depression.
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    {http://brainmind.com/images/Pituitary33.jpg} Normally, cortisol secretion is subject to the tonic influences of NE; whereas cortisol can indirectly reduce NE synthesis. Thus a feedback system is maintained via the interaction of these substances (in conjuction with ACTH). Moreover, cortisol and NE levels fluctuate in reverse, and thus maintain a reciprocal relationship with the circadian rhythm; i.e. in oppositional fashion they increase and then decrease throughout the day and evening.
    Among certain subgroups suffering from depression, it appears that this entire feedback regulatory system and thus the HPA axis is disrupted (Carrol et al. 1976; Sachar et al. 1973). This results in the hypersecretion of ACTH and cortisol with a corresponding decrease in NE; which results in NE induced depression. It was these findings which led to the development of the Dexamethasone suppression test over 25 years ago.
    Via the administration of Dexamethasone (a synthetic corticosteroid) it was determined that many depressed individuals have excess cortisol, and an increased frequency of cortisol secretory episodes (Carrol et al. 1976; Sachar et al. 1973; Swann et al. 2014). Moreover, those who demonstrate excess cortisol were found to respond to NE potentiating agents, whereas those who were depressed but with normal cortisol, responded best to serotonin potentiating compounds (Van Pragg 1982).
    It is also noteworthy that dexamethason nonsuppression rates are increased in mania; specifically "mixed manic" states which consist of lability, grandiosity, and lability superimposed over depression (see Swann et al. 2014). These "mixed manic" individuals also display elevated NE levels but respond poorly to lithium and show higher levels of cortisol during the depressed phase of their illness (Swann et al. 2014).
    As noted, the hypothalamus may greatly influence circadian activities within the midbrain and pons, and thus the rhythmical secretion of various neurotransmitters. For example, corticotropin-releasing factor acts directly on the locus coeruleus (Valentino et al. 1983) which manufactures NE, and on the raphe thereby influencing serotonin release. These findings suggest a disturbance in circadian or rhythmical control of hypothalamic and midbrain-pontine activity can give rise to depression, or mixed mania in some individuals; women in particular.
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    Lateralization.
    Although scant, there is some evidence which suggests that the right hypothalamus may be more heavily involved in the control of neuroendocrine functioning, particularly in females. Females are also far more likelyt to suffer from depression and from SADs. Moreover, right cerebral dysfunction can reduce NE levels in both the right and left hemisphere (Robinson 1979). Greater right hypothalamic concentration of substances such as LHRH (luteinizing hormone) has also been reported (Gerendai, 1984), which in turn is a "female" hormone involved in lactation and pregnancy.
    PSYCHIC MANIFESTIONS OF HYPOTHALAMIC ACTIVITY: THE ID
    Phylogenetically and from an evolutionary perspective, the appearance and development of the hypothalamus predates the differentation of all other limbic nuclei, e.g., amygdala, septal nucleus, hippocampus (Andy & Stephan, 1961; Brown, 1983; Herrick, 1925; Humphrey, 1972). It constitutes the most primitive, archaic, reflexive, and purely biological aspect of the psyche.
    Biologically the hypothalamus serves the body tissues by attempting to maintain internal homeostasis and by providing for the immediate discharge of tenions in an almost reflexive manner. Hence, as based on studies of lateral and medial hypothalamic functioning, it appears to act reflexively, in an almost on/off manner so as to seek or maintain the experience of pleasure and escape or avoid unpleasant, noxious conditions.
    Emotions elicited by the hypothalamus are largely undirected, short-lived, being triggered reflexively and without concern or understanding regarding consequences; that is, unless chronically stressed or aroused. Nevertheless, direct contact with the real world is quite limited and almost entirely indirect as the hypothalamus is largely concerned with the internal environment of the organism. Although it receives and responds to light, it cannot "see." It has no sense of morals, danger, values, logic, etc., and cannot feel or express love or hate. Although quite powerful, hypothalamic emotions are largely undifferentiated, consisting of feelings such as pleasure, unpleasure, aversion, rage, hunger, thirst, etc.
    As the hypothalamus is concerned with the internal enviornment much of it's activity occurs outside conscious-awareness. Moreover, being involved in maintaining internal homeostasis, via, for example, it's ability to reward or punish the organism with feelings of pleasure or aversion, it tends to serve what Freud (1911) has described as the pleasure principle.
    THE PLEASURE PRINCIPLE
    The lateral and medial nuclei exert counterbalancing influences which serve to modulate activity occurring in the other. As described by Freud (1911), the pleasure principale not only serves to maximize pleasant experiences, but acts to keep the psyche as a whole free from high levels of excitation (be they pleasurable or unpleasant).
    Like the hypothalamus, the pleasure principle is present from birth and for some time thereafter the search for pleasure is manifested in an unrestricted manner and with a great deal of intensity as there are no oppositional forces (except those between the lateral and medial regions) to counter it's strivings. Indeed, higher order limbic nuclei have yet to mature.
    Functionally isolated, the hypothalamus at birth has no way of reducing tension or mobilizing the organism for any form of effective action. It is helpless. When tensions associated with immediate needs (e.g. hunger or thirst) become unpleasant the only response available to the hypothalamus is to cry and make rage-like vocalizations. When satiated, the hypothalamus can only respond with a feeling state suggesting pleasure or at least quiescence. Indeed, as is well known, for the first few months of life the infants awareness largely consists of a very restricted matrix involving tactile, visceral (hunger) and kinesthetic sensations, where emotionally the infant is capable of screaming, crying, or demonstrating very rudimentary features of pleasure, i.e. an attitude of acceptance of quiescence (McGraw, 1969; Milner, 1967; Piaget, 1952; Spitz & Wolf, 1946).
    It is only with the further differentiation and maturation of higher order limbic nuclei (e.g. amygdala, septal nucleus, hippocampus) that the infant begins to achieve some awareness of external reality and begins to form memories as well as differentiate and associate externally occurring events and individuals.
    AMYGDALA
    {http://brainmind.com/images/LimbicAmyagdala10.jpg}
    In contrast to the primitive hypothalamus, the more recently developed amygdala (the "almond") is preeminent in the control and mediation of all higher order emotional and motivational activities. Via it's rich interconnections with various neocortical and subcortical regions, amygdaloid neurons are able to monitor and abstract from the sensory array stimuli that are of motivational significance to the organism (Gaffan 1992; Gloor 1960, 1992, 2010; LeDoux 1992; Morris et al., 2012; Rolls, 1984, 1992 Steklis & Kling, 2005; Kling & Brothers 1992; Ursin & Kaada 1960). This includes the ability to discern and express even subtle social-emotional nuances such as friendliness, fear, love, affection, distruct, anger, etc., and at a more basic level, determine if something might be good to eat.
    {http://brainmind.com/images/amygdala2001.jpg} {http://brainmind.com/images/AmygdalaEmotionaCircuit45.jpg} In fact, amygdaloid neurons respond selectively to the flavor of certain preferred foods, as well as to the sight or sound of something that might be especially desirable to eat (Fukuda et al. 2007; Gaffan et al. 1992; O'Keefe & Bouma, 1969; Ono et al. 1980; Ono & Nishijo, 1992) including even the sight of drugs that induce extreme pleasure.
    For example, it has been shown, using positron emission tomography, that detoxified cocaine users not only respond to a cocaine video with cocaine craving, but with increased amygdala (and anterior cingulate) activity (Childress, et al., 2009).
    {http://brainmind.com/images/AmygdalaDrugs7.jpg} Belying its involvement in emotion, including the pleasure associated with cocaine usage, is the unique chemical anatomy of the amygdala, which is rich in a variety of neuropetides including enkephalins and beta-endorphins as well as opiate receptors (Atweh & Kuhar, 1977; Fallon & Ciofi, 1992; Uhl et al. 1978). In fact, of all brain regions, the greates concentration of opiate receptors is found within the human amygdala. Other chemical systems include lutenizing hormone, vasopressin, somatostatin, and corticotropin releasing factor (Fallon & Ciofi, 1992) --indications of its involvement in stress and sexuality, especially female sexuality. The primate amygdala is sexually differentiated with male and female patterns of dendritic organization and steroid activity (Bubenik & Brown, 1973; Nishizuka & Arai, 1981; see also Simerly, 1990).
    {http://brainmind.com/images/amygdala201.jpg} The amygdala is exceedingly responsive to social and emotional stimuli as conveyed vocally, through touch, sight, and via the expressions of the face (Gloor, 1992; Halgren, 1992; Kling & Brothers 1992; Morris et al., 2012; Rolls, 1984, 1992). In fact, the amygdala, as well as the overlying (and partly coextensive) temporal lobe, contains neurons which respond selectively to smiles and to the eyes, and which can differentiate between male and female faces and the emotions they convey (Hasselmo, Rolls, & Baylis, 1989, Heit et al., 1988; Kawashima, et al., 2009; Rolls, 1984). For example, the left amygdala acts to discriminate the direction of another person's gaze, whereas the right amygdala becomes activated while making eye-to-eye contact (Kawashima, et al., 2009).
    Moreover, the normal human amygdala typically responds to frightened faces by altering its activity (Morris et al., 2012), whereas injury to the amygdala disrupts the ability to recognize faces (Young, Aggleton, & Hellawell,2011). With bilateral destruction, emotional speech production and the capacity to respond appropriately to social emotionally stimuli is abolished (Lilly, Cummings, Benson, & Frankel, 1983; LeDoux, 2012; Marlowe, Mancall, Thomas,1975; Scott, Young, Calder, Hellawell, Aggleton, & Johnson, 2010; Terzian & Ore, 1955).
    {http://brainmind.com/images/insulaamygdalabrain.jpg} {http://brainmind.com/images/Amygdala2004.gif} Single amygdaloid neurons receive a considerable degree of topographic input, and are predominatly polymodal, responding to a variety of stimuli from different modalities simultaneously (Amaral et al. 1992; O'Keefe & Bouma, 1969; Ono & Nishijo, 1992; Perryman, Kling, & Lloyd, 2007; Rolls 1992; Sawa & Delgado, 1963; Schutze et al. 2007; Turner et al. 1980; Ursin & Kaasa, 1960; Van Hoesen, 1981). The amygdala is also very sensitive to somesthetic input and physical contact such that even a slight touch in a very circumscribed area of the body can produce amygdaloid excitation. Overall, because emotional, motivational, and multimodal assimilation of various sensory impressions occurs in this region, it is also involved in attention, learning, and memory (Gloor, 2010; Halgren, 1992; LeDoux, 2012).
    Moreover, through the massive interconnections maintained with the lateral and medial (ventromedial) hypothalamus, the amygdala is able to act directly on this structure, driving the hypothalamus, so to speak, and thus tapping into its emotional reserviour so that its ends may be met. Indeed, it is able to modulate hypothalamic activity through inhibitory and excitatory projections to this structure (Dreifuss, et al., 1968).
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    {http://brainmind.com/images/ColoredLimbicSystem34.jpg}
    {http://brainmind.com/images/AmygdalaNuclei3.jpg} {http://brainmind.com/images/amygdalabypass.gif} Direct stimulation of the basolateral amygdala and the ventral amydalofugal pathway excites the principle neurons of the medial hypothalamus (Dreifuss, et al., 1968). By contrast, stimulation of the medial (ventro-medial) amygdala and the stria terminalis pathway, inhibits these same hypothalamic neurons (Dreifuss, et al., 1968). Hence, whereas the lateral amydala exerts excitatory influences on the hypothalamus, the medial amygdala exerts inhibitory influences, and can thus control, or at least exert excitatory/inhibitory and thus modulatory influences on hunger, thirst, sexual arousal, rage, etc., as well as hormonal, endocrine, and other functions associated with the hypothalamic nuclues (Dreifuss, et al., 1968; Joseph, 1992a; Gloor, 2010). Indeed, the amygdala can be likened to the chief executive of the limbic system and weilds enormous power via its control over the hypothalamus.
    For example, in the cat and monkey, stimulation of the border area between the lateral and medial hypothalamus can trigger aggressive defensive reactions (De vito & Smith, 1982; Hess, 1949). As indicated by radioactive tracers, both the lateral and medial amygdala projection to this area (De vito & Smith, 1982). And, when the amygdala is electrically activated, the hypothalamus becomes activated (Dreifuss, et al., 1968), and defensive and aggressive reactions can be triggered.
    However, this system is also interactional, especially in regard to sexual activity, fear, anger, hunger, and stress. For example, the hypothalamus can stimulate the amygdala which may then survey the environment so that internal needs may be met, and/or they may act in concert regarding sexual behavior, the stress response, and so on.
    OVERVIEW: AMYGDALA STRUCTURAL FUNCTIONAL ORGANIZATION
    The amygdala is buried within the depths of the anterior-inferior temporal lobe and consists of several major nuclear groups including what has been referred to as the "extended amygdala." These include the cortical-medial, central, paralaminar, lateral, basal, and acessory basal nucleus (Amaral et al., 1992; Stephan & Andy, 1977). Different authors propose different divisions and link them differently. For example, Stephan and Andy (1977) assign the cortical division to the basolateral amydala, and the central division to the medial division. Price et al., (1977) subdivided the amygdala into basolateral, corticomedial and central amygdaloid nuclei. Others propose yet different schemes.
    {http://brainmind.com/images/Amygdala222.jpg} For our purposes we will primarily focus on the "medial" and the basolateral subdivisions. The phylogenetically ancient medial group (or cortico-medial amygdala) is involved in olfaction, sexual, and motor activity (via its interconnections with the striatum), and the relatively newer basolateral division (lateral amygdala) is most fully developed in primates and humans (Amaral et al. 1992; Herrick, 1925; Humphrey, 1972; McDonald 1992; Stephan & Andy, 1977). Of its various subdivisions, the basolateral amygdala is the most "cortex-like. However, being allocortex it contains three layers (vs 7 for the neocortex) with layer 2 containing pyramidal neurons which rely on excitatory neurotransmitters, e.g., glutamate--whereas the local-circuit (interneurons) rely on the inhibitory transmitters, e.g., GABA (Fallon & Ciofi, 1992).
    The lateral amydala utilizes the ventral amygdalofugal pathway and less so the stria terminalis to influence the hypothalamus. The lateral amygdala also relies on the medial forebrain bundle which is the pathway subserving the pleasure circuit (Olds & Forbes, 1981). By contrast, the medial amygdala relies on the stria terminalis, and less so the amygdalofugal pathway to influences the hypothalamus. Through these pathways, these diferent subdivions of the amygdala can act to modulate activity in the hypothalamus, septal nuclei, and other subcortical structures (Amaral et al. 1992; Stephan & Andy, 1977).
    Evolution & Embryology
    In humans, the right amygdala is also larger than the left amygdala, with the basolateral portion contributing to most of this asymmetry (Murphy et al., 2007). Moreover, over the course of evolution, and in the transition from amphibians to reptiles, to mammals and then humans, the basolateral amygdala appears to have grown the most in size as compared to other amygdaloid nuclei (Stephan & Andy, 1977)--that is, when considered only in regard to its subtemporal diminsions. However, it also appears that the medial amygdala may have contributed to the evolution of the piriform cortex, and then the evolution of the 4 to 5 layered mesocortex, which when layered upon the 3-layered allocortical piriform cortex, gave rise to the neocortex of the temporal lobe. Hence, the expansion of the medial amydala may not be apparent as that expansion is represented as mesocortex and neocortex.
    Moreover, it appears that the medial group was broken up over the course of evolution such that structures such as the claustrum (Gilles et al., 1983), became separated and is now situated beneath the auditory cortex of the superior temporal lobe. Indeed, the claustrum which is very cortical in organization, may well act as an interface between the auditory cortex and the amygdala, processing and relaying auditory impulses to and fro, and may have, in addition to the medial amygdala, contributed to the evolution of the auditory cortex.
    {http://brainmind.com/images/LimbicAmyagdala11.jpg} {http://brainmind.com/images/LimbicAmyagdala12.jpg} The amygdala, therefore, has definitely increased in size over the course of evolution (Stephan & Andy, 1977), and has become increasingly cortical, has contributed to the evolution of mesocortex and neocortex (which is thus a cortical extension of the neocortex, maintaining extensive interconnections). In addition, the right amygdala is larger than the left (Murphy et al., 2007) which in turn may contribute to right hemisphere dominance for emotion (chapter 10).
    Intrinsic & Extrinsic Organization: The Flow of Information
    Like the lateral and medial hypothalamus, the medial and basolateral (hereafter referred to as the lateral) amygdaloid nuclei subserve different functions and maintain different anatomical interconnections (Amaral et al., 1992; Stephan & Andy, 1977). And, they can be subdivided into additional subnuclei. As noted, they also contain pyramidal neurons which are excitatory (Rolls, 1992) and use glutamate (Fallon & Ciofi, 1992) and which project throughout the neocortex as well as to the hippocampus (Amaral et al., 1992).
    Local circuit neurons are mostly stellate-like and chandelier cells, which account for about 30% of the amydala's neurons and which use the inhibitory transmitter GABA (Fallon & Ciofi, 1992). Considered rather broadly and simplistically, these local circuit neurons are organized in such a fashion that they appear to project information from the the lateral to the basal amygdala, and from the lateral basal to the medial and central amygdala which transmits, via pyramid and local-circuit neurons to the uncus, piriform cortex, medial temporal cortex, entrohinal cortex, anterior hippocampus, and via pyramidal neurons to the striatum, the septal nuclei, hypothalamus, cingulate, medial dorsal nucleus of the thalamus, brainstem, and throughout the frontal and temporal lobes (Amarral et al., 1992; Krettek & Price, 1978; Stephan & Andy, 1977; van Hoesen, et al., 1981). However, the lateral amygdala also projects to the septal nuclei, hypothalamus, corpus striatum, dorsal medial thalamus, brainstem, and throughout the neocortex via pyramidal axons (Amaral et al, 1992; Carlsen et al. 1982; Gloor, 1955; McDonald 1992; Russchen, 1982; Swanson & Cowan, 1979).
    {http://brainmind.com/images/AmygdalaOutputs2.jpg} It appears that much of the input from the neocortex is directed at the lateral amygdala (the exception being auditory cortex which also projects to the medial amygdala). Hence, in certain respects, at least at the level of the neocortex, it appears that there is an almost circular stream of activity, from lateral/basal to medial/central to neocortex to lateral/basal. However, subcortically, both the lateral and medial project to many of the same exact structures, often providing counterbalancing excitatory/inhibitory influences.
    Moreover, as detailed in chapter 12, the amygdala receives significant projections directly from the olfactory bulb. In act, "the olfactory system is the only sensory system in which first- and second-order central sensory neurons project directly to the amygdala" (Goor, 2010). Moreover, it receives projections from the gustatory system. Smell and taste thus converge in the amygdala, which may explain why some patients with temporal lobe epilepsy experience terrible odors and tasts as part of the aura which announces the onset of a seizure.
    {http://brainmind.com/images/AmygdalaPathways130.jpg} In addition, the secondary and in particular the association and multi-modal assimilation areas, including the orbital frontal lobe, project directly to the amygdala (Amaral et al, 1992; Carlsen et al. 1982; Gloor, 1955; Krettek & Price, 1978; McDonald 1992; Russchen, 1982; Swanson & Cowan, 1979; Stephan & Andy, 1977). In addition, as is evident from dissecting the human brain, the amygdala maintains significant reciprocal connections with the primary auditory area and Wernicke's area--and similar projections are evident in primates (Amaral et al., 1992). Hence, this structure receives simple and complex auditory, as well as fully formed perceptions from the neocortex which feeds the amygdala this information which it then analyzes for social, sexual, gustatory, and emotional significance.
    The Amygdala-Striatum
    Emybryologically, the medial amygdala is the first portion of the basal ganglia (limbic) striatal complex to appear during development, being formed via neuroblast migration from the epithilium of the lateral ventricle (Humphrey, 1972). Specifically, around the sixth week of fetal development immature neuroblasts migrate in massive numbers from the ventricular lining, and congregate in the more caudal portion of the emerging forebrain, thus forming an arc shaped "striatal ridge" from which the primordial amygdala and striatum will emerge (Gilles et al., 1983; Humphrey, 1968).
    {http://brainmind.com/images/ThalamicProjection.jpg}
    Approximately one week after the formation of the amygdala, this primordial amygdala-striatum begins to differentiate and balloon outward to also create the striatum. That is, both the striatum and amygdala are derived from the arc shaped "striatal ridge," the caudal portion giving rise to the primordial amgydala at about the 6th week of gestation, and the basal portion later giving rise to the primordial striatum which initially overlies and is contiguous with the amygdala (Gilles et al., 1983; Humphrey, 1968).
    {http://brainmind.com/images/AmygdalaStriatum32.gif} Thus initially these structures are contiguous. However, over the ensuing weeks, these structures are pushed apart as the forebrain and its interconnections form. However, although they are pushed apart and may even break up into semi-separate islands (or rather, penninsulas) the amgydala maintains connnections with what is referred to as the "extended amygdala," i.e., the limbic striatum (Heimer & Alheid, 1991) and through what is called the "tail of the caudate" maintains massive interconnections with the corpus striatum
    Specifically, the tail of the caudate nucleus (as it circles in an arc from the frontal to temporal lobe) terminates and merges with the medial and in particular, the lateral amygdala. Hence, the lateral amygdala has also been referred to the "striatum limitans, and the "striatum accessorium" (Gloor, 2010).
    By contrast,the medial amygdala (or rather, the central division of the medial amygdala, central-medial amygdala) extends almost imperceptibly around the fundus of the entorhinal sulcus, and merges with the substantia innominata of the limbic striatum. The amygdala, therefore, is in fact part of the basal ganglia and is heavily involved in motivating and coordinating gross, or whole body motor activity via the striatum (Heimer & Alheid, 1991; Mogenson & Yang, 1991).
    {http://brainmind.com/images/LimbicStriatum0.jpg}
    THE MEDIAL AMYGDALA
    The medial amygdala receives fibers from the olfactory tract, and via a rope of fibers called the stria terminalis projects directly to and receives fibers from the medial hypothalamus (via which it exerts inhibitory influences) as well as the septal nucleus (Amaral et al, 1992; Carlsen et al. 1982; Gloor, 1955; McDonald 1992; Russchen, 1982; Swanson & Cowan, 1979). The stria terminals is significantly larger and thicker in males vs females (Allen & Gorksi 1992) which suggests that information and impulse exchange (or inhibition) between the hypothalamus and amygdala is different in men vs women. Moreover, in humans, the amygdala in general is large in males than in females, and in primates, the medial amygdala is sexually differentiated (Nishizuka & Arai, 1981; see also Simerly, 1990), such that the male amygdala contains a greater number of synaptic connections and shows different patterns of steroidal activity (Nishizuka & Arai, 1981; Simerly, 1990). In fact, the human amygdala is 16% larger in the male in total volume (Filipek, et al., 2014) whereas in male rats, the medial amygdala is 65% larger than the female amygdala and grows or shrinks in the presence of testosterone (Breedlove & Cooke, 2009).
    The female medial amygdala is a principle site for uptake of the female sex hormone, estrogen, and contains a high concentration of leutenizing hormones (Stopa et al., 1991) which are important during pregnancy and nursing. In fact, the female medial amygdala fluctuates immunoreactive activity during estrus cycle, being highest during proestrus (Simerly, 1990). Moreover, the medial amygdala projects directly to the ventromedial hypothalamus and the preoptic area of the hypothalamus which, as noted above, are sexually differentiated (e.g. Allen et al., 1989; Gorski, et al., 1978; Le Vay, 1991; Raisman & Field, 1971), and which when activated produce sex specific behaviors (Hart et al., 2005; Lisk, 1967, 1971; MacLean, 1973) and, in primates, even maternal behavior (Numan, 2005). These amygdala to hypothalamic synapses are excitatory.
    {http://brainmind.com/images/AmygdalaNuclei3.jpg}
    Because the medial amygdala is sexually differentiated, and through its massive connections with the hypothalamus and preoptic area, as well as the striatum which controls gross motor and limb movements, when activated, male vs female sexual behavior can be triggered. These amygdala-induced sexual behariors include sexual posturing, penile erection and clitoral tumenence (Kling and Brothers, 1992; MacLean, 1990; Robinson and Mishkin, 1968; Stoffels et al., 1980), thrusing, sexual moaning, ejaculation, as well as ovulation, uterine contractions, lactogenetic responses, and orgasm (Backman and Rossel, 1984; Currier, Little, Suess and Andy, 1971; Freemon and Nevis,1969; Warneke, 1976; Remillard et al., 1983; Shealy and Peel, 1957).
    In addition, the medial (and lateral) regions are rich in cells containing enkephalins, and opiate receptors can be found throughout the amygdala (Atweh & Kuhar, 1977; Fallon & Ciofi, 1992; Uhl et al. 1978) and the amygdala becomes exceedingly active when experiencing a craving for pleasure inducing drgus, such as cocaine (Childress et al., 2009). In this regard, the amygdala is capable of inducing extreme feelings of pleasure as well as motivating the individual to engage in pleasure-seeking behaviors such as sexual activity.
    LATERAL AMYGDALA
    With the evolutionary ascent of primates the lateral division of the amygdala progressively expands and differentiates. The lateral amygdala contributes fibers to the stria terminalis and gives rise to the amygdalofugal pathway via which it projects to the lateral and medial hypothalamus (upon which it exerts inhibitory and excitatory influences respectively), the dorsal medial thalamus (which is involved in memory, attention and arousal), the limbic and corpus striatum, as well as other subcortical regions including the brinstem (Aggleton et al. 1980; Amaral et al. 1992; Carlsen et al. 1982; Dreifuss et al., 1968; Gloor, 1955, 1960, 2010; Klinger & Gloor, 1960; McDonald 1992; Mehler, 1980; Russchen, 1982). Lateral amygdala brainstem projection pathways include the dopamine producing substantia nigra, the vocalizing periaqueductal gray, the pontine tegmentum which includes and area that triggers the startle response (Amaral et al., 1992; Davis et al., 2010) as well as visceral nuclei such as those controlling blood pressure, respiration, vosodilation and constriction and so on. It also sends some fibers into the spinal cord, where they travel along with those of the pyramidal tract (Amaral et al., 1992). It also receives fibers from the medial forebrain bundle which in turn has it's site of origin in the lateral hypothalamus (Mehler, 1980).
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    In general, whereas the medial amygdala is highly involved in motor, olfactory and sexual functioning, the lateral division is intimately involved in all aspects of emotional activity. Hence, it's rich interconnections with the lateral and medial hypothalamus, and the neocortex and those brainstem centers controlling the visceral aspects of affective-motor behavior.
    {http://brainmind.com/images/InputAmygdala13.jpg} The lateral amygdala maintains rich interconnections with the inferior, middle, and superior temporal lobes, as well as the insular temporal region, which in turn allows it to sample and influence the auditory, somesthetic, and visual information being received and processed in these areas, as well as scrutinize this information for motivational and emotional significance (Gloor 1992; Herzog & Van Hoesen 1976; Kling et al., 2007; Machne & Segundo, 1956; Mesulam & Mufson, 1982; O'Keefe & Bouma, 1969; Rolls 1992; Steklis & Kling, 2005; Turner et al., 1980; Van Hoesen, 1981). Gustatory and respiratory sense are also re-represented in this vicinity (Amaral et al. 1992; Fukuda et al., 2007; Maclean, 1949; Ono et al., 1980) as is the capacity to influence (via sensory analysis) food and water intake. The lateral division also maintains rich interconnections with cingulate gyrus, orbital and medial frontal lobes and the parietal cortex (Amaral et al. 1992; McDonald 1992; O'Keefe & Bouma, 1969; Pandya et al. 1973) through which it able to influence emotional expression and receive complex somesthetic information.
    The lateral amygdala is highly important in analyzing information received and transferring information back to the neocortex so that further elaboration may be carried out at the neocortical level. It is through the lateral division that emotional meaning and significance can be assigned to as well as extracted from that which is experienced.
    The amygdala, overall, maintains a functionally interdependent relationship with the hypothalamus. It is able to modulate and even control rudimentary emotional forces governed by the hypothalamic nucleus. However, it also acts as the behest of hypothalamically induced drives. For example, if certain nutritional requirements need to be meet, the hypothalamus signals the amygdala which then surveys the external enviornment for something good to eat or drink.
    On the other hand, if the amygdala via environmental surveilance were to discover a potentially threatening stimulus, it acts to excite and drive the hypothalamus so that the organism is mobilized to take appropriate action. as noted, direct stimulation of the basolateral amygdala and the ventral amydalofugal pathway excites the principle neurons of the ventromedial hypothalamus (Dreifuss, et al., 1968). When the hypothalamus is activated by the amygdala, instead of responding in an on/off manner, cellular activity continues for an appreciably longer time period (Dreifuss et. al. 1968; Rolls 1992). The amygdala can tap into the reservoir of emotional energy mediated by the hypothalamus so that certain ends may be attained.
    ATTENTION
    The amygdala acts to perform environmental surveilance and can trigger orienting responses as well as mediate the maintanance of attention if something of interest or importance were to appear (Gloor, 1955, 1960, 1992; Kaada, 1951; Kapp et al., 1992; Rolls 1992; Ursin & Kaasa, 1960).
    In part, the attention response can be triggered by amygdala activation of the brainstem, frontal lobes, and the dorsal medial nucleus (DMN) of the thalamus, each of which is implicated in arousal (see chapter 19). The DMN, for example, in conjunction with the frontal lobe, acts to gate and regulate the flow of information destined for the neocortex (Joseph, 2009a). The amydala, being provided thalamic, brainstem, as well as neocortical input (as well as projecting to these nuclei), is therefore able to directly influence the DMN so that attention can be directed to particular percepts (and emotional significance attached). In fact, the projections of the amygdala to extend well beyond the DMN, but extends throughout the thalamus (Aggleton et al., 1980; LeDoux, 2012; McDonald, 1992; Russchen, 1982), as well as throughout the neocortex .
    Electrical stimulation of the lateral amygdala, therefore, can initiate quick and/or anxious glancing and searching movements of the eyes and head such that the organism appears aroused and highly alert as if in expectation of something that is going to happen (Halgren 1992; Kapp et al., 1992; Ursin & Kaasa, 1960). The EEG becomes desynchronized (indicating arousal), heart rate becomes depressed, respiration patterns change, and the galvanic skin response significantly alters (Bagshaw & Benzies, 1968; Kapp et al. 2014; Ursin & Kaada, 1960) and the animal may freeze (Gloor, 1960; Kapp et al., 1992) -- reactions which characteristically accompany the orienting response of most species.
    Once a stimulus of potential interest is detected, the amygdala then acts to analyze its emotional-motivational importance and will act to alert other nuclei such as the hypothalamus, brainstem, and striatum, so that appropriate action may take place.
    FEAR, RAGE & AGGRESSION
    Initially, electrical stimulation of the amygdala produces sustained attention and orienting reactions. If the stimulation continues the subject may begin to experience, wariness, fear and/or rage (Cendes et al. 2014; Davis et al., 2010; Gloor 1992; Halgren 1992; LeDoux, 2012; Rosen & Schulkin, 2012; Ursin & Kaada, 1960). When fear follows the attention response, the pupils dilate and the subject will cringe, withdraw, and cower. This cowering reaction in turn may give way to extreme fear and/or panic such that the animal will attempt to take flight.
    {http://brainmind.com/images/AmygdalaActivation.jpg} Among humans, the fear response is one of the most common manifestations of amygdaloid electrical stimulation and abnormal activation (Davis et al., 2010; Gloor, 1992, Halgren, 1992; LeDoux, 2012; Rosen & Schulkin, 2012). Moreover, unlike hypothalamic on/off emotional reactions, attention and fear reactions can last up to several minutes after the stimulation is withdrawn.
    In addition to behavioral manifestations of heightened emotionality, amygdaloid stimulation can result in intense changes in emotional facial expression. This includes crying and facial contortions such as baring of the teeth, dilation of the pupils, widening or narrowing of the eye-lids, flaring of the nostrils, as well as sniffing, licking, and chewing (Anand & Dua, 1955; Ursin & Kaada, 1960). Indeed, some of the behavioral manifestations of a seizure in this vicinity (i.e. temporal lobe epilepsy) typically include throat and mouth movements, including chewing, smacking of the lips, licking, and swallowing--a consequence, perhaps of amygdala activation of the brainstem periaqueductal gray and nuclei subserving mastication.
    In many instances patients or animals will react defensively and with anger, irritation, and rage which seems to gradually build up until finally the animal or human will attack (Egger & Flynn, 1963; Gunne & Lewander, 1966; Mark et al., 1972 Ursin & Kaada, 1960; Zbrozyna, 1963). Unlike hypothalamic "sham rage", amygdaloid activation results in attacks directed at something real, or, in the absence of an actual stimulus, at something imaginary. There have been reported instances of patient's suddenly lashing out and even attempting to attack those close by, while in the midst of a temporal lobe seizure (Saint-Hilaire et al., 1980), and/or attacking, kicking, and destroying furniture and other objects (Ashford et al., 1980).
    Moreover, rage and attack will persist well beyond the termination of the electrical stimulation of the amygdala. In fact, the amygdala remains electrophysiologically active for long time periods even after a stimulus has been removed (be it external-perceptual, or internal-electrical) such that is appears to contine to process--in the abstract--information even when that information is no longer observable (O'Keefe & Bouma, 1969).
    The amygdala, in addition to sustained electrophysiological activity, has been shown to be heavily involved in the maintenance of behavioral responsiveness even in the absence of an immediately tangible or visible objective or stimulus (O'Keefe & Bouma, 1969). This includes motivating the organism to engage in the seeking of hidden objects or continuing a certain activity in anticipation of achieving some particular long term goal. At a more immediate level, the amygdala is probably very important in object permanance (i.e. the keeping of an object in mind when it is no longer visible) and concrete or abstract anticipation. Anticipation is, of course, very important in the prolongation of emotional states such as fear or anger, as well as the generation of more complex emotions such as anxiety. In this regard, the amygdala is probably important not only in regard to emotion, but in the maintanance of mood states.
    Fear and rage reactions have also been triggered in humans following depth electrode stimulation of the amygdala (Chapman, 1960; Chapman et al., 1954; Heath et al. 1955; Mark et al. 1972). Mark et al. (1972) describe one female patient who following amygdaloid stimulation became irritable and angry, and then enraged. Her lips retracted, there was extreme facial grimmacning, threatening behavior, and then rage and attack--all of which persisted well beyond stimulus termination.
    Similarly, Schiff et al. (1982) describe a man who developed intractable aggression following a head injury and damage (determined via depth electrode) to the amygdala (i.e. abnormal electrical activity). Subsequently, he became easily enraged, sexually preoccupied (although sexually hypoactive), and developed hyper-religiosity and psuedo-mystical ideas. Tumors invading the amygdala have been reported to trigger rage attacks (Sweet et al. 1960; Vonderache, 1940).
    The amygdals appears capable of not only triggering and steering hypothalamic activity but acting on higher level neocortical processes so that individuals form emotional ideas . Indeed, the amygdala is able to overwhelm the neocortex and the rest of the brain so so that the person not only forms emotional ideas but responds to them, sometimes with vicious, horrifying results. A famous example of this is Charles Whitman, who in 1966 climbed a tower at the University of Texas and began to indiscriminantly kill people with a rifle (Whitman Case File # M968150. Austin Police Department, Texas, The Texas Department of Public Safety, File #4-38).
    Case Study in Amygdala-Aggression: Charles Whitman
    Charles Whitman was born on June 24, 1941 and even before entering grade school had shown exceptional intellectual promise, was well liked by neighbors and had already shown some mastery of the piano, which he "loved to play." At the age of six he was administered the Stanford Binet tests of intellectual ability and obtained an IQ of 138; thus scoring at the 99.9% rank. He also became enamored by guns; his father being described as a gun fanatic. According to his father, "Charlie could plug a squirrel in the eye by the time he was sixteen." However, Charlie loved animals, was somewhat religiously oriented as a child, was very athlectic, was described as "handsome" and "fun" and "high spirited" and was in many respects the "all American boy." He became an Eagle Scout at age 12, and receiving national recognition as being the youngest Eagle Scout in the world. Within 15 months he had earned 21 merit badges. While in high school he continued these activites, also pitching for the baseball team and managing the football team. After high school he joined the Marines and was described as "the kind of guy you would want around if you went into combat." It was while in the Marines that he got married, and it was during this period that began to show the first subtle signs that something might be amiss.
    He began having occassional bursts of anger. He threatened to "kick the teeth out" of another Marine, was court marshalled, consigned to the brig for 30 days, and reduced in rank. He also began taking copious notes, and developed what is referred to as "hypergraphia" excessive writing--a disturbance associated with the amygdala (Joseph, 2009b).
    Incessantly he began to write and leave himself notes, ranging from the mundane, to the tremendous love he felt for his wife. "Received a call from Kathy... it was fabulous, she sounds so wonderful. I love her so much... I will love her to the day I die. She is the best thing I have in life. My Most Precious Possession."
    {http://brainmind.com/images/CharlesWhitman24.jpg}
    Increasingly, however, he was having trouble with his temper and composed notes offering self-advice as to how to control his growing temper and rage attacks. "CONTROL your anger" he wrote, "Don't let it prove you the fool. SMILE--Its contagious. DON'T be belligerent. STOP cursing. CONTROL your passion; DON'T LET IT lead YOU."
    On February 4, 1964, he purchased a diary. According to Charles: "I opened this diary of my daily events as a result of the peace of mind or release of feelings that I experienced when I started making notes of my daily events...."
    Nevertheless, he also continued to excell and although he had been Court marshalled, he also won a scholarship to attend the University of Texas and to attend classes while still in the Marines. He also became increasingly religious and would often have discussions with his school mates about the nature of God--hyperreligiousness also being associated with an abnormality involving the amygdala (see chapter 9). And, although he was attending classes, he also began to perform volunteer work, while simultaneously holding a part time job, and at times felt overwhelmed with energy, almost manic--mania also being associated with the amygdala (Strakowski et al., 2009) as well as the frontal lobes (Joseph, 1986a, 1988a, 2009a). And, he continued to be well liked and admired. His supervisor at the bank, E. R. Hendricks, described Charles "as a truly outstanding person. Very likeable. Neat. Nice looking... A great guy."
    However, Charles also began suffering terrible headaches, and one day lost his temper in class, pulling a male student bodily from his chair and tossing him from the classroom. Apparently he felt considerable remorse. He also continued to have frequent bouts of anger and on occasion, difficulty concentrating, and was beginning to over eat--increased food consumption being associated with a disturbance of the hypothalamus. Moreover, he began having periods where he couldn't sleep for days at a time--yet another disturbance associated with the hypothalamus, a major sleep center. Charles also realized that something was wrong, and continued writing copious notes to himself, reminding himself to be nice, to control his apetitite, and especially to control temper. But his temper was getting out of control and Charles was gaining weight.
    A close friend, Elaine Fuess, also noticed that something was amiss. "Even when he looked perfectly normal, he gave you the feeling of trying to control something in himself. He knew he had a temper, and he hated this in himself. He hated the idea of cruelty in himself and tried to suppress it."
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    Charles Whitman finally sought professional help and consulted a staff psychiatrist, at the University of Texas Health Center about his periodic and uncontrollable violent impulses. Charles was referred to Dr. Heatly. According to the report written by Dr. Heatly about his session with Whitman, a report which was distributed to the media: "This massive, muscular youth seemed to be oozing with hostility as he initiated the hour with the statement that something was happening to him and he didn't seem to be himself...." Whitman "could talk for long periods of time and develop overt hostility while talking, and then during the same narration show signs of weeping.... Past history revealed a youth who... grew up in Florida where his father was a very successful plumbing contractor... who achieved considerable wealth. He identified his father as being brutal, domineering, and extremely demanding of the other three members of the family." Whitman "married four or five years ago, and served a hitch in the Marines.... He referred to several commendable achievements during his Marine service, but also made reference to a court martial for fighting which resulted in being reduced several grades to private. In spite of this he received a scholarship to attend the University for two years and remained a Marine at the same time... He expressed himself as being very fond of his wife, but admitted that he had on two occasions assaulted his wife physically. He said he has made an intense effort to avoid losing his temper with her... His real concern is with himself at the present moment. He readily admits having overwhelming periods of hostility with a very minimum of provocation... he... also... made vivid reference to thinking about going up on the tower with a deer rifle and start shooting people. ....He was told to make an appointment for the same day next week."
    Instead, Charles apparently decided to climb the tower and to begin killing people. But not before first contacting the police and asking to be arrested. As Charles had not committed a crime, the desk sergeant instead suggested that he see a psychiatrist.
    Several days prior to climbing the tower, Charles Whitman wrote himself a letter:
    "I don't quite understand what it is that compels me to type this letter.... I don't really understand myself these days... Lately I have been a victim of many unusual and irrational thoughts. These thoughts constantly recur, and it requires a tremendous mental effort to concentrate. I consulted Dr. Cochrum at the University Health Center and asked him to recommend someone that I could consult with about some psychiatric disorders I felt I had.... I talked to a doctor once for about two hours and tried to convey to him my fears that I felt overcome by overwhelming violent impulses. After one session I never saw the Doctor again, and since then I have been fighting my mental turmoil alone, and seemingly to no avail. After my death I wish that an autopsy would be performed to see if there is any visible physical disorder. I have had tremendous headaches in the past and have consumed two large bottles of Excedrin in the past three months."
    On August 1, 1966, one day before climbing the tower at the University of Texas, Charles Whitman paid a visit to his mother, who greeted him outside her penthouse and introduced him to the night watchman who noticed that Charles was carrying a big black attache case. According to police reports, Charles must have immediately attacked his mother after they entered the penthouse, and then brutally beat, strangled, and stabbed her to death, crushing the back of her head, smashing her hands, and stabbing her in the chest with a huge hunting knife.
    Later, neighbors told police that the only sounds they heard were that of a "child crying and whimpering," which they found puzzling as no child lived in the penthouse.
    After brutally murdering his mother, Charles cleaned up the mess, and placed her in bed with a notepad laying across and covering up the massive wound in her chest. Charles had left a note. It read: "To Whom It May Concern: I have just taken my mother's life. I am very upset over having done it. However, I feel that if there is a heaven she is definitely there now... I am truly sorry... Let there be no doubt in your mind that I loved this woman with all my heart."
    After killing his mother, Charles returned home, planning on killing his wife "as painlessly as possible.," as he explained in yet another note:
    "It was after much thought that I decided to kill my wife, Kathy, tonight....I love her dearly, and she has been a fine wife to me as any man could ever hope to have. I cannot rationally pinpoint any specific reason for doing this..."
    Apparently she was sleeping, and after removing the blankets to expose her nude body, he viciously stabbed her repeatedly with his huge hunting knife, leaving five gaping holes in her chest. She died instantly.
    Charles wrote another note which he left with the body: "I imagine it appears that I brutally killed both of my loved ones. I was only trying to do a quick thorough job... If my life insurance policy is valid please pay off my debts... donate the rest anonymously to a mental health foundation. Maybe research can prevent further tragedies of this type."
    And then he added a post script beneath his signature: "Give our dog to my in-laws. Tell them Kathy loved "Schoci" very much."
    {http://brainmind.com/images/WhitmanTexasTower.jpg} The next morning Charles Whitman climbed the University tower carrying several guns, a sawed off shotgun, and a high powered hunting rifle, and for the next 90 minutes he shot at everything that moved, killing 14, wounding 38.
    He was finally killed by a police sharp shooter.
    {http://brainmind.com/images/Whitmandead4.jpg} Post-mortem autopsy of his brain revealed a glioblastoma multiforme tumor the size of a walnut, erupting from beneath the thalamus, impacting the hypothalamus, extending into the temporal lobe and compressing the amygdaloid nucleus (Charles J. Whitman Catastrophe, Medical Aspects. Report to Governor, 9/8/66).
    DOCILITY & AMYGDALOID DESTRUCTION
    Bilateral destruction of the amygdala usually results in increased tameness, docility, and reduced aggressiveness in cats, monkeys and other animals (Schreiner & Kling, 1956; Weiskrantz, 1956; Vochteloo & Koolhaas, 2007), including purportedly ferocious creatures such as the agoutie and lynxe (Schreiner & Kling, 1956). In man, bilateral amygdala destruction (via neurosurgery) has been reported to reduce and/or eliminate paroxysmal aggressive and violent behavior (Terzian & Ore, 1955).
    In some creatures, however, bilateral ablation of the amygdala has been reported to al least initially result in increased aggressive reponding (Bard & Mountcastle, 1948), and if sufficiently aroused or irritated, even the most placid of amygdalectomized animals can be induced to fiercely fight (Fuller et al. 1957).
    However, these aggressive responses are very short-lived and appear to be reflexively mediated by the hypothalamus. Hence, these findings (and the data reviewed above) suggests that true aggressive feelings including violent moods, are dependent upon activation of the amygdala.
    SOCIAL-EMOTIONAL AGNOSIA
    Among primates and mammals, bilateral destruction of the amygdala significantly disturbs the ability to determine and identify the motivational and emotional significance of externally occuring events, to discern social-emotional nuances conveyed by others, or to select what behavior is appropriate given a specific social context (Bunnel, 1966; Fuller et al. 1957; Gloor, 1960; Kling & Brothers 1992; Kluver & Bucy, 1939; Lilly et al., 1983; Marlowe et al., 1975; Scott et al., 2010; Terzian & Ore, 1955; Weiskrantz, 1956). Bilateral lesions lower responsiveness to aversive and social stimuli, reduce aggressiveness, fearfullness, competitiveness, dominance, and social interest (Rosvold et al. 1954). This condition is so pervasive that subjects have tremendous diffficulty discerning the meaning or recognizing the significance of even common objects -- a condition sometimes referred to as "psychic blindness", or, the "Kluver-Bucy syndrome" (Lilly et al., 1983; Marlowe et al., 1975; Terzian & Ore, 1955).
    Thus, animals with bilateral amygdaloid destruction, although able to see and interact with their environment, may respond in an emotionally blunted manner, and seem unable to recognize what they see, feel, and experience. Things seem stripped of meaning. Like an infant (who similarly is without a fully functional amygdala), individuals with this condition engage in extreme orality and will indiscriminantly pick up various objects and place them in their mouth regardless of its appropriateness. There is a repetitive quality to this behavior, for once they put it down they seem to have forgotten that they had just explored it, and will immediately pick it up and place it again in their mouth as if it were a completely unfamiliar object.
    Although ostensibly exploratory, there is thus a failure to learn, to remember, to discern motivational significance, to habituate with repeated contact, or to discriminate between appropriate vs inappropriate stimuli. Rather, when the amygdala has been removed bilaterally the organism reverts to the most basic and primitive modes of object and social-emotional interaction (Brown & Schaffer, 1888; Gloor, 1960; Kluver & Bucy, 1939; Weiskrantz, 1956) such that even the ability to appropriately interact with loved ones is impaired (Lilly et al., 1983; Marlowe et al., 1975; Terzian & Ore, 1955).
    For example, Terzian & Ore (1955) described a young man who following bilateral removal of the amygdala subsequently demonstrated an inability to recognize anyone, including close friends, relatives and his mother. He ceased to repond in an emotional manner to his environment and seemed unable to recognize feelings expressed by others. He also demonstrated many features of the Kluver-Bucy syndrome (perserverative oral "exploratory" behavior and psychic blindness), as well as an insatiable appetite. In addition, he became extremely socially unresponsive such that he preferred to sit in isolation, well away from others.
    Among primates who have undergone bilateral amygdaloid removal, once they are released from captivity and allowed to return to their social group, a social-emotional agnosia becomes readily apparent as they no longer respond to or seem able to appreciate or understand emotional or social nuances. Indeed, they appear to have little or no interest in social acitivity and persistently attempt to avoid contact with others (Dicks et al. 1969; Jonason & Enloe, 1971; Kling & Brothers 1992; Jonason et al. 1973). If approached they withdraw, and if followed they flee.
    Indeed, they behave as if they have no understanding of what is expected of them or what others intend or are attempting to convey, even when the behavior is quite friendly and concerned. Among adults with bilateral lesions, total isolation seems to be preferred.
    In addition, they no longer display appropriate social or emotional behaviors, and if kept in captivity will fall in dominance in a group or competitive situation -- even when formerly dominant (Bunnel, 1966; Dicks et al., 1969; Fuller et al., 1957; Jonason & Enloe, 1971; Jonason et al., 1973; Rosvold et al. 1954).
    As might be expected, maternal behavior is severly affected. According to Kling (1972), mothers will behave as if their "infant were a strange object be be mouthed, bitten and tossed around as though it were a rubber ball".
    EMOTIONAL LANGUAGE & THE AMYGDALA
    Although cries and vocalizations indicative of rage or pleasure have been elicited via hypothalamic stimulation, of all limbic nuclei the amygdala is the most vocally active--particularly the lateral division (Robinson, 1967). In humans and animals a wide range of emotional sounds have been evoked through amygdala activation, such as sounds indicative of pleasure, sadness, happiness, and anger (Robinson, 1967; Ursin & Kaada, 1960). The human amygdala can produce as well as perceive emotional vocalizations (Halgren, 1992; Heit, Smith, & Halgren, 1988).
    {http://brainmind.com/images/JosephRightLanguage.jpg}
    Conversely, in humans, destruction limited to the amygdala (Freeman & Williams 1952, 1963), the right amygdala in particular, has abolished the ability to sing, convey melodic information or to properly enunciate via vocal inflection. Similar disturbances occur with right hemisphere damage (chapter 10). Indeed, when the right temporal region (including the amygdala) has been grossly damaged or surgically removed, the ability to perceive, process, or even vocally reproduce most aspects of musical and emotional auditory input is significanlty curtailed (Chapter 21).
    AMYGDALA, THE ANTERIOR COMMISSURE, SEXUALITY & EMOTION,
    When the amygdala or the bed nuclei for the anterior commissure of both cerebral hemispheres are damaged, hyperactivated, or completely inhibited a striking disturbance in sexual and social behavior is evident (Brown & Schaffer, 1888; Gloor, 1960; Kluver & Bucy, 1939; Terzian & Ore, 1955; Schriner & Kling, 1953). Specifically, humans, non-human primates, and felines who have undergone bilateral amygdalectomies will engage in prolonged, repeated, and inappropriate sexual behavior and masturbation including repeated sexual acts with members of different species (e.g. a cat with a dog, a dog with a turtle, etc.).
    {http://brainmind.com/images/KluverBucy101.jpg}
    When activated from seizures, patients may involuntarily behave in a sexual manner and even engage in what appears to be intercourse with an imaginary partner. This abnormality is one aspect of a complex of symptoms sometimes referred to as the Kluver-Bucy syndrome.
    {http://brainmind.com/images/AnteriorCommAmyg.jpg} As noted, portions of the hypothalamus and amygdala are sexually dimorphic; i.e. there are male and female amygdaloid nuclei (Bubenik & Brown, 1973; Nishizuka & Arai, 1981). In humans the male amygdala is 16% larger (Filipek, et al., 2014), and in male rats the medial amygdala is 65% larger than the female amygdala (Breedlove & Cooke, 2009), and the male amygdala grows or shrinks in the presence of testosterone--findings which may be related to sex differences in sexuality and aggression. Moreover, female amygdala neurons are smaller and more numerous, and densely packed than those of the male (Bubenik & Brown, 1973; Nishizuka & Arai, 1981), and smaller, densely packed neurons fire more easily and frequently than larger ones--which may contribute to the fact that females are more emotional and more easily frightened than males (chapters 7,13,15), as the amygdala is a principle structure involved in evoking feelings of fear (Davis et al., 2010; Gloor, 2010; LeDoux, 2012).
    Moreover, despite myths to the contrary, females, regardless of species, are more sexually active than males, on average (see chapter 8)--that is, when they are in estrus-- and the human female is capable of experiencing multiple orgasms of increasing intensity--which may also be a function of sex differences in the amygdala. That is, since female primate amygdala neurons are more numerous and packed more closely together (Bubenik & Brown, 1973; Nishizuka & Arai, 1981), and as smaller, tightly packed neurons demonstrate enhanced electrical excitability, lower response thresholds, and increase susceptibility to kindling and thus hyper-excitation, the amygdala therefore is likely largely responsible for sex differences in emotionality and sexuality.
    Indeed, electrical stimulation of the medial amygdala results in sex related behavior and activity. In females this includes ovulation, uterine contractions and lactogenetic responses, and in males penile erections (Robinson & Mishkin, 1968; Shealy & Peele, 1957). Moreover, in rats and other animals, kindling induced in the amygdala can trigger estrus and produce prolonged female sexual behavior.
    {http://brainmind.com/images/AmygdalAnteriorC.jpg} Moreover, the anterior commissure, the band of axonal fibers which interconnects the right and left amygdala/temporal lobe is sexually differentiated. Like the corpus callosum, the anterior commissure is responsible for information transfer as well as inhibition within the limbic system. Specifically, the female anterior commissure is 18% larger than in the male (Allen & Gorski 1992). It has been argued that the increased capacity of the right and left female amygdala to communicate (via the anterior commissure) coupled with the more numerous and more densely packed neurons within the female amygdala (which in turn would decrease firing thresholds and enhance communication), and the sex diffferences in the hypothalamus, would also predispose females to be more emotionally and socially sensitive, perceptive, and expressive (Joseph 2013). Hence, these limbic sex differences induces her to be less aggressive and more compassionate and maternal, and affects her sexuality, feelings of dependency and nurturance, and desire to maintain and form attachments in a manner different than males.
    {http://brainmind.com/images/SexAmygdala.jpg} In contrast, whereas the right and left female amygdala are provided a communication advantage not shared by males, the "male" amygdala in turn may be more greatly influenced by the (medial) hypothalamus via the stria terminalis which is larger in men than women (Allen & Gorski 1992). As noted, the male medial amygdala is larger than its female counterpart (Breedlove & Cooke, 2009) and changes in size in response to testosterone, which is significant as the medial nuclei (and testosterone) is directly implicated in negative and aggressive behaviors (see above).
    Although environmental influences can shape and sculpt behavior and the functional organization of the brain (chapter 28), most sex differences are innate and shared by other species (see chapters 7 & 8); a direct consequence of the presence or absence of testosterone during adulthood and fetal development (see Gerall et al. 1992; Joseph 2013, Joseph et al. 1978) and the sexual differentiation of the limbic system.
    THE LIMBIC SYSTEM & TESTOSTERONE
    In large part these and related sex differences in aggressiveness are also a consequence of the relatively higher concentrations of the activating hormone, testosterone flowing through male bodies and brains. The overarching influence of neurological and hormonal predispositions are also indicated by studies which have shown that females who have been prenatally exposed to high levels of masculinizing hormones (i.e. androgens) behave similar to males even in regard to spatial abilities (Joseph et al. 1978; see Gerall et al. 1992). They are also more aggressive and engage in more rough and tumble play as compared to normal females (Money & Ehrhardt, 1972; Ehrhardt & Baker, 1974; Reinisch, 1974) and this is also true of other species such as dogs, wolves, gorillas, baboons, and chimpanzees.
    {http://brainmind.com/images/LimbicAmyagdala12.jpg} Similarly, female primates and mammals who have been exposed to testosterone during neonatal development display an altered sexual orientation, as well as significantly higher levels of activity, competitiveness, combativeness and belligerence (Mitchell, 1979). Nevertheless, it is important to re-emphasize that it is generally the presence or absence of testosterone during the critical period of neuronal differentiation which determines if one is in possession of a "male" vs "female" limbic system.
    SEXUAL ORIENTATION & HETEROSEXUAL DESIRE
    As noted, the amygdala surveys the environment searching out stimuli, events, or individuals which are emotionally, sexually or motivationally significant. Moreover, it contains facial recognition neurons which are sensitive to different facial expressions and which are capable of determining the sex of the individual being viewed and which become excited when looking at a male vs female face (Leonard et al. 2005; Rolls 1984). In this regard, the amygdala can act to discern and detect potential sexual partners and then motivate sex-appropriate behavior culminating in sexual intercourse and orgasm.
    That is, an individual who possess a "male" limbic system is likely to view the female face, body and genitalia as sexually arousing because the amygdala and limbic system responds with pleasure when stimulated by these particular features. Conversely, male physical features are likely to excite and sexually stimulate the limbic systems possessed by heterosexual females and homosexual males (Joseph, 2013). This is because, at a very basic level emotional, sexual, and motivational perceptual/behavioral functioning becomes influenced and guided by the anatomical sexual bias of the host.
    OVERVIEW: THE AMYGDALA
    Over the course of early evolutionary development, the hypothalamus reigned supreme in the control and expression of raw and reflexive emotionality, i.e., pleasure, displeasure, aversion, and rage. Largely, however, it has acted as an eye turned inward, monitoring internal homeostasis and concerned with basic needs. With the development of the amygdala, the organism was now equipped with an eye turned outward so that the external emotional features of reality could be tested and ascertained. When signalled by the hypothalamus the amygdala begins to search the sensory array for appropriate emotional-motivational stimuli until what is desired is discovered and attended to.
    However, with the differentiation of the amygdala, emotional functioning also became differentiated and highly refined. The amygdala hierarchically wrested control of emotion from the hypothalamus.
    The amygdala is primary in regard to the perception and expression of most aspects of emotionality, including fear, aggression, pleasure, happiness, sadness, etc., and in fact assigns emotional or motivational significance to that which is experienced. It can thus induce the organism to act on something seen, felt, heard, or anticipated. The integrity of the amygdala is essential in regard to the anylysis of social-emotional nuances, the organization and mobilization of the persons internal motivational status regarding these cues, as well as the mediation of higher order emotional expression and impluse control. When damaged or functionally compromised, social-emotional functioning becomes grossly disturbed.
    The amygdaloid nucleaus via its rich interconnections with other brain regions is able to sample and influence activity occurring in other parts of the cerebrum and add emotional color to ones perceptions. As such it is highly involved in the assimilation and association of divergent emotional, motivational, somesthetic, visceral, auditory, visual, motor, olfactory and gustatory stimuli. Thus it is very concerned with learning, memory, and attention, and can generate reinforcement for certain behaviors. Moreover, via reward or punishment it can promote the encoding, storage and later retrieval of particular types of information. That is, learning often involved reward and it is via the amygdala (in concert with other nuclei) that emotional consequences can be attributed to certain events, actions, or experiences, as well as extracted from the world of possibility so that it can be attended to and remembered.
    Lastly, as is evident from studies of individuals with abnormal activity or seizures originating in or involving this nuclei, the amygdala is able to overwhelm the neocortex and thus gain control over behavior. As based on electrophysiological studies, the amygdala seems capable of literally turning off the neocortex (such as occurs during a seizure) at least for brief time periods. That is, the amygdala can induce electrophysiological slow wave theta activity in the neocortex which indicates low levels of arousal (see below) as well as high voltage fast activity. In the normal brain it probably exerts similar influences such that at times individuals (i.e. their neocortex) "lose control" over themselves and respond in a highly emotionally charged manner.
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    In consequence, after they "explode" or respond "irrationally" they (that is, the neocortex of the left hemisphere) are likely to wonder aloud: "I don't know what came over me."
    But we know the answer: The Limbic System.
    {http://brainmind.com/images/LimbicAmyagdala11.jpg}
    HIPPOCAMPUS
    Memory & Attention
    The hippocampus (Ammon's Horn" or the "sea horse") is an elongated structure located within the inferior medial wall of the temporal lobe (posterior to the amygdala) and surrounds, in part, the lateral ventricle. In humans it consists of an anterior and posterior region and depending on the angle at which it is viewed, could be construed as shaped somewhat like an old fashion telephone receiver, or a "sea horse."
    {http://brainmind.com/images/HippocampusSeahorse.jpg}
    The hippocampus consists of a number of subcomponents, and adjoining structures, such as the parahippocampal gyrus, entorhinal and perirhinal cortex and the uncus (which it shares with the amygdala) are considered by some to be subdivisions, whereas the main body of the hippocampus consists of the dentate gyrus, the subiculum, and sectors referred to as CA1, CA2, CA3, CA4.
    {http://brainmind.com/images/HippocampusLayers1.jpg} The uncus is a bulbar allocortical protrusion located in the anterior-inferior medial part of the temporal lobe, and consists of both the hippocampus and amygdala which become fused in forming this structure. That is the ventral-medial portion of the amygdala becomes fused with the head of the hippocampus, such that the uncus consists of both allocortex and mesocortex--the entorhinal cortex which shrouds the hippocampus.
    {http://brainmind.com/images/hippocampus34.jpg}
    HIPPOCAMPAL AROUSAL, ATTENTION & INHIBITORY INFLUENCES
    Various authors have assigned the hippocampus a major role in information processing, including memory, new learning, cognitive mapping of the environment, voluntary movement toward a goal, as well as attention, behavioral arousal, and orienting reactions (Douglas, 1967; Eichenbaum et al. 2014; Enbert & Bonhoeffer, 2009; Frisk & Milner, 1990; Grastayan et al., 1959; Green & Arduini, 1954; Isaacson, 1982; Milner, 1966, 1970, 1971; Nishitani, et al., 2009; Olton et al. 1978; Routtenberg, 1968; Squire, 1992; Victor & Agamanolis, 1990; Xu et al., 2012). For example, hippocampal cells greatly alter their activity in response to certain spatial correlates, particularly as an animal moves about in its environment (Nadel, 1991; O'Keefe, 1976; Olton et al., 1978; Wilson & McNaughton, 2013). It also developes slow wave theta activity during arousal (Green & Arduini, 1954) or when presented with noxious or novel stimuli (Adey et al.1960)--at least in non-humans.
    However, few studies have implicated this nucleus as important in emotional functioning per se, although responses such as "anxiety" or "bewilderment" have been observed when directly electrically stimulated (Kaada et al. 1953). Indeed, in response to persistent and repeated instances of stress and unpleasant emotional arousal, the hippocampus appears to cease to participate in cognitive, emotional, or memory processing (chapter 30). Thus the role of the hippocampus in emotion is quite minimal.
    AROUSAL
    Hippocampal-neocortical interactions. Desynchronization of the cortical EEG is associated with high levels of arousal and information input. As the level of input increases, the greater is the level of cortical arousal (Como et al. 1979; Joseph et al. 1981; Joseph, 2012b, 2009d). However, when arousal levels become too great, efficienty in information processing, memory, new learning, and attention become compromised as the brain becomes overwhelmed (Joseph, 2012b, 2009d; Joseph et al., 1981; Lupien & McEwen, 2010; Sapolsky, 2012).
    When the neocortex becomes desynchronised (indicating cortical arousal), the hippocampus often (but not always) developes slow wave theta activity (Grastyan et al., 1959; Green & Arduni, 1954) such that it appears to be functioning at a much lower level of arousal--as demonstrated in non-humans. Conversely, when cortical arousal is reduced to a low level (indicated by EEG synchrony), the hippocampal EEG often becomes desynchronized.
    These findings suggest when the neocortex is highly stimulated the hippocampus, in order to monitor what is being received and processed, functions at a level much lower in order not to become overwhelmed. When the neocortex is not highly aroused, the hippocampus presumably compensates by increasing its own level of arousal so as to tune in to information that is being processed at a low level of intensity.
    Hence, in situations where both the cortex and the hippocampus become desynchronized, there results distractability and hyperresponsiveness such that the subject becomes overwhelmed, confused, and may orient to and approach several stimuli (Grastyan et al., 1959). Attention, learning, and memory functioning are decreased. Situations such as this sometimes also occur when individuals are highly anxious or repetitively emotionally or physically traumatized (see chapter 30).
    {http://brainmind.com/images/EntorhinalCortex.jpg} The hippocampus consists of 3 layers, layer 2 consisting of pyramidal neurons which provide excitatory output and thus act to activate and arouse target tissues; via the transmitters glutamate and aspartic acid. In addition, the entorhinal cortex provides excitatory input into the hippocampus--input which is derived from the neocortex; using again, aspartic and glutamate acid (reviewed in Gloor, 2010). Specifically, it appears that the hippocampus interacts with the neocortex is regard to arousal via the dorsal medial nucleus of the thalamus, the septal nuclei, the hypothalamus, amygdala and brainstem--structures with which it maintains direct interconnections. As per the neocortex, this sheet of tissue is also innervated by these structures, and by the entorhinal cortex.
    {http://brainmind.com/images/HippocampusEntorhinal.jpg} Hence, the hippocampus serves as a major component of an excitatory interface and can be aroused by neocortical activity (via the entorhinal cortex), and can provide excitatory input to directly to subcortical structures and indirectly to the neocortex (via the entorhinal cortex and dorsal medial nucleus). However, if the neocortex becomes excessively aroused, so to might the hippocampus, and vice versa. Under excessively arousing conditions, however, hippocampal pyramidal neurons may become inhibited or even damaged (Lupien & McEwen, 2010; Sapolsky, 2012), thus resulting in loss of memory.
    There is also evidence to suggest that the hippocampus may act so as to reduce extremes in cortical arousal. For example, whereas stimulation of the reticular activating system augments cortical arousal and EEG evoked potentials, hippocampal stimulation reduces or inhibits these potentials such that cortical responsiveness and arousal is dampened (Feldman, 1962; Redding, 1967). On the otherhard, if cortical arousal is at a low level, hippocampal stimulation often results in an augmentation of the cortical evoked potential (Redding, 1967).
    {http://brainmind.com/images/HippocampusPathways3.jpg} The hippocampus also exerts desynchronizing or synchronizing influences on various thalamic nuclei (e.g., the dorsal medial thalamus) which in turn augments or decreases activity in this region (Green & Adey, 1956; Guillary, 1955; Nauta, 1956, 1958). As the dorsal medial thalamus is the major relay nucleus to the neocortex, the hippocampus therefore appears able to block or enhance information transfer to various neocortical areas (that is, in conjunction with the frontal lobe, see chapter 19). Indeed, it may be acting to insure that certain percepts are stored in memory at the level of the neocortex (Gloor, 2010; Squire 1992) by modulating cortical activity.
    It is thus likely that the hippocampus may act to influence information reception and storage at the neocortical level as well as possibly reduce extremes in cortical arousal (be they too low or high) perhaps by activating inhibitory circuits in the dorsal medial nucleus, thus ensuring that the neocortex is not over or underwhelmed when engaged in the reception and processing of information. This is an important attribute since very high or very low states of excitation are incompatible with alertness and selective attention as well as the ability to learn and retain information (Joseph et al. 1981; Lupien & McEwen, 2010; Sapolsky, 2012).
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    Aversion & Punishment.
    In many ways, the hippocampus appears to act in concert with the medial hypothalamus and septal nuclei (with which it maintains rich interconnections) so as to also prevent extremes in emotional arousal and thus maintain a state of quiet alertness (or quiescence). Moreover, similar to the results following stimulation of the medial hypothalamus, it has been reported that the subjective components of aversive emotion in humans is correlated with electrophysiological alternations in the hippocampus and septal area (Heath, 1976).
    The hippocampus also appears to be heavily involved in the modulation of reactions to frustrations or mild punishment (Gray, 1970, 1990), particularly in regard to single trial but not multiple trial learning. For example, the hippocampus responds with trains of slow theta waves when presented with noxious stimuli but habituates or ceases to respond with repeated presentation. It is likely, however, that these physiological responses are secondary to activity within the amygdala and hypothalamus which then effects hippocampal functioning.
    ATTENTION & INHIBITION
    The hippocampus participates in the elicitation of orienting reactions and the maintainance of an aroused state of attention (Foreman & Stevens, 2007; Grastayan et al., 1959; Green & Arduini, 1954; Nishitani, et al., 2009; Routtenberg, 1968). When exposed to novel stimuli or when engaged in active searching of the environment, hippocampal theta appears (Adey, et al. 1960). However, with repeated presentations of a novel stimulus the hippocampus habituates and theta disappears (Adey et al. 1960). Thus, as information is attended to, recognized, and presumably learned and/or stored in memory, hippocampal participation diminishes. Theta also appears during the early stages of learning as well as when engaged in selective attention and the making of discriminant responses (Grastyan et al. 1959).
    When the hippocampus is damaged or destroyed, animals have great difficulty inhibiting behavioral responsiveness or shifting attention. For example, Clark and Issacson (1965) found that animals with hippocampal lesions could not learn to wait 20 seconds between bar presses if first trained to respond to a continous schedule. There is an inability to switch from a continous to a discontinous pattern, such that a marked degree of perseveration and inability to change sets or inhibit a pattern of behavior once initiated occurs (Douglas, 1967; Ellen, et al. 1964). Habituation is largely abolished and the ability to think or respond divergently is disrupted. Disinhibition due to hippocampal damage can even prevent the learning of a passive avoidance task, such as simple ceasing to move (Kimura, 1958).
    Hence, when coupled with the evidence presented above, it appears that the hippocampus acts to possibly selectively enhance or diminish areas of neural excitation which in turn allows for differential selective attention and differential responding, as well as the storage and consolidation of information into long term memory. When damaged, the ability to shift from one set of perceptions to another, or to change behavioral patterns is disrupted and the organism becomes overwhelmed by a particular mode of input. Learning, memory, as well as attention, are greatly compromised.
    LEARNING & MEMORY: THE HIPPOCAMPUS
    The hippocampus is most usually associated with learning and memory encoding, e.g. long term storage and retrieval of newly learned information (Enbert & Bonhoeffer, 2009; Fedio & Van Buren, 1974; Frisk & Milner, 1990; Milner, 1966; 1970; Nunn et al., 2009; Penfield & Milner, 1958; Rawlins, 2005; Scoville & Milner, 1957; Squire, 1992; Victor & Agamanolis, 1990) particularly the anterior regions. Hence, if the hippocampus has been damaged the ability to convert short term memories into long term memories (i.e. anterograde amnesia), becomes significantly impaired in humans (MacKinnon & Squire, 1989; Nunn et al., 2009; Squire, 1992; Victor & Agamanolis, 1990) as well as primates (Zola-Morgan & Squire, 1984, 2005a, 1986). In humans, memory for words, passages, conversations, and written material is also significantly impacted, particularly with left hippocampal destruction (Frisk & Milner, 1990; Squire, 1992).
    {http://brainmind.com/images/Hippocampusmemory1.jpg} Bilateral destruction of the anterior hippocampus results in striking and profound disturbances involving memory and new learning (i.e. anterograde amnesia). For example, one such individual who underwent bilateral destruction of this nuclei (H.M.), was subsequently found to have almost completely lost the ability to recall anything experienced after surgery. If you introduced yourself to him, left the room, and then returned a few minutes later he would have no recall of having met or spoken to you. Dr. Brenda Milner has worked with H.M. for almost 20 years and yet she is an utter stranger to him.
    {http://brainmind.com/images/HippocampusSeptal.jpg} {http://brainmind.com/images/hippocampus101.jpg}
    {http://brainmind.com/images/HMHippocampus.jpg} H.M. is in fact so amnesic for everything that has occurred since his surgery (although memory for events prior to his surgery is comparatively exceedingly well preserved), that every time he rediscovers that his favorite uncle died (actually a few years before his surgery) he suffers the same grief as if he had just been informed for the first time.
    H.M., although without memory for new (non-motor) information, has adequate intelligence, is painfully aware of his deficit and constantly apologizes for his problem. "Right now, I'm wondering" he once said, "Have I done or said anything amiss?" You see, at this moment everything looks clear to me, but what happened just before? That's what worries me. It's like waking from a dream. I just don't remember...Every day is alone in itself, whatever enjoyment I've had, and whatever sorrow I've had...I just don't remember" (Blakemore, 1977, p.96).
    Presumably the hippocampus acts to protect memory and the encoding of new information during the storage and consolidation phase via the gating of afferent streams of information and the filtering/exclusion (or dampening) of irrelevant and interfering stimuli. When the hippocampus is damaged there results input overload, the neuroaxis is overwhelmed by neural noise, and the consolidation phase of memory is disrupted such that relevant information is not properly stored or even attented to. Consequently, the ability to form associations (e.g. between stimulus and response) or to alter preexisting schemas (such as occurs during learning) is attenuated (Douglas, 1967).
    THE SEPTAL NUCLEI
    HIPPOCAMPAL & SEPTAL INTERACTIONS
    The septal nuclei consists of medial and lateral nuclei, and can be further subdivided into several nuclear components (Ariens Kappers et al., 1936; Swanson & Cowan, 1979), such as the nucleus of the diagonal band of Broca. The septal nuclei is an evolutionary derivative of the hippocampus and the hypothalamus, and in the human brain is richly interconnected with both structures including the amygdala, and the substantia innomminata (SI) which is a major memory center, and which manufactures ACh--a transmitter directly implicated in memory (Gage et al., 1983; Olton, 1990). Andy and Stephan (1968) and Swanson and Cowan (1979) considered the bed nucleus of the stria terminals (which gives rise to a major pathway linking the septal nuclei, and amygdala and hypothalamus) as part of the septal nuclei, whereas others (Gloor, 2010) consider it to be part of the "extended amygdala." Likewise, some consider the nucleus accumbens as part of the septal nuclei, and others consider it part of the "extended amygdala;" i.e. the limbic striatum.
    {http://brainmind.com/images/ColoredLimbicSystem34.jpg}
    As noted the septal nuclei is massively interconnected with the hippocampus as well as with the entorhinal cortex (Swanson & Cowan, 1979) via a number of pathways, including the fornix. Directly implicating the septal nuclei in the memory functioning of the hippocampus is the finding that septal activation of this structure results in ACh secretion (Gage et al., 1983), whereas septal grafts into the hippocampus improves learning and memory (Gage et al., 1986). Conversely, lesions of the fimbria-fornix septal-hippocampal pathway results ACh depletion throughout the hippocampus (Gage et al., 1983; Olton, 1990), as well as loss of norepinephrine and serotonin coupled with memory loss (Olton, 1990).
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    The septal nucleus in part regulate hippocampal memory-related activity not only by stimulating ACh and other neurotransmitter production (Gage et al., 1983, 1986), but as it provides excitatory input and inhibitory-GABAnergic-- especially from the medial septal nuclei which in general exerts inhibitory influences not only on the hippocampus but the amygdala and hypothalamus. In general, it is supposed that the excitatory-inhibitory influences on the hippocampus (like those on the amygdala and hypothalamus) serve to modulate activity and prevent extremes in arousal (Joseph, 1992a, 2012b, 2009d). This is accomplished in part not only through the interconnections maintained with the amygdala, hypothalamus and entorhinal cortex, but the brainstem reticular formation (Petsche et al., 1965)--with which the hippocampus is also connected directly and via the entorhinal cortex.
    Septal influences on hippocampal/entorhinal arousal is also indicated by fluctuations in rhythmic slow activity (theta), which is generated by both the hippocampus and entorhinal cortex (Alonso & Garcia-Austt, 2007). As detailed in chapter 14, theta is an indication of hippocampal arousal (Green & Arduini, 1954; Petsche et al., 1965; Vanderwolf, 1992) and is associated with learning and memory (O'Keefe & Nadel, 1978). Theta is a robust electrophysiological phenomenon which has been found in the hippocampus of most species studied, including monkeys (Stewart & Fxx, 1990) and humans (Sano et al., 1970); though in primates it seems to differ from the theta rhythm of non-primates (see Gloor, 2010).
    O'Keefe and Nadel (1978) believe that theta plays an important role in creating the spatial maps that are maintained by hippocampal "place" neurons; i.e. pyramidal neurons which are attuned to specific environmental features and landmarks and the animals place in that environment as they move about. Moreover, long term potentiation (LTP) which is associated with learning and memory, is generated in those neurons demonstrating theta or activity that is at the "theta frequency" (Staubli & Lynch, 2007).
    Neurons of the septal nucleus which innervate the hippocampus fluctuate in activity in parallel with changes in the theta rhythm (Petsche et al., 1965), whereas septal lesions abolish hippocampal theta (Green & Arduini, 1954). It has long been believed that septal neurons act as an interface between the reticular formation and the hippocampus (Petsche et al., 1965) and in conjunction with its connections with the amygdala and hypothalamus, therefore modulate hippocampal arousal as well as learning and memory.
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    HIPPOCAMPAL & AMYGDALOID INTERACTIONS: MEMORY
    It has been argued that significant impairments involving short-term memory and motor learning, cannot be produced by lesions supposedly restricted to the hippocampus (Horel, 1978; see also commentary in Eichenbaum et al. 2014); though in fact it is impossible to create such "restricted" lesions. Nevetheless, ignoring for the moment that inconvenient fact, in some instances with supposed restricted lesions, good recall of new information is possible for at least several minutes (Horel, 1978; Penfield & Milner, 1958; Squire 1992).
    Moreover, there is considerable evidence which strongly suggests that the hippocampus plays an interdependent role with the amygdala in regard to memory (Gloor 1992, 2010; Halgren 1992; Kesner & Andrus, 1982; Mishkin, 1978; Murray 1992; Sarter & Markowitsch, 2005); particularly in that they are richly interconnected, merge at the uncus, and exert mutual excitatory influences on one another. For example, it appears that the amygdala is responsible for storing the emotional aspects and personal reactions to events in memory, whereas the hippocampus acts to store the cognitive, visual, and contextual variables (chapter 14) whereas that the amygdala activates the hippocampus by providing excitatory input (Gloor, 1955, 2010).
    Specifically, the amygdala plays a particularly important role in memory and learning when activities are related to reward and emotional arousal (Gaffan 1992; Gloor 1992, 2010; Halgren 1992; LeDoux 1992, 2012; Kesner 1992; Rolls 1992; Sarter & Markowitsch, 2005). Thus, if some event is associated with positive or negative emotional states it is more likely to be learned and remembered.
    The amygdala becomes particularly active when recalling personal and emotional memories (Halgren, 1992; Heath, 1964; Penfield & Perot, 1963), and in response to cognitive and context determined stimuli regardless of their specific emotional qualities (Halgren, 1992). However, once these emotional memories are formed, it sometimes requires the specific emotional or associated visual context to trigger their recall (Rolls, 1992; Halgren, 1992). If those cues are not provided or ceased to be available, the original memory may not be triggered and may appear to be forgotten or repressed. However, even emotional context can trigger memory (see also Halgren, 1992) in the absence of specific cognitive cues.
    Similarly, it is also possible for emotional and non-emotional memories to be activated in the absence of active search and retrieval, and thus without hippocampal or frontal lobe participation. Recognition memory which may be triggered by contextual or emotional cues. Indeed, there are a small group of neurons in the amygdala, as well as a larger group in the inferior temporal lobe which are involved in recognition memory (Murray, 1992; Rolls, 1992). Because of amygdaloid sensitivity to visual and emotional cues, even long forgotten memories may be evoked via recognition, even when search and retrieval repeatedly fail to activate the relevant memory store.
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    According to Gloor (1992), "a perceptual experience similar to a previous one can through activation of the isocortical population involved in the original experience recreate the entire matrix which corresponds to it and call forth the memory of the original event and an appropriate affective response through the activation of amygdaloid neurons." This can occur "at a relatively non-cognitive (affective) level, and thus lead to full or partial recall of the original perceptual message associated with the appropriate affect."
    In this regard, it appears that the amygdala is responsible for emotional memory formation whereas the hippocampus is concerned with storing verbal-visual-spatial and contextual details in memory. Thus, in rats and primates damage to the hippocampus can impair retention of context, and contextual fear conditioning, but it has no effect on the retention of the fear itself or the fear reaction to the original cue (Kim & Fanselow 1992; Phillips & LeDoux 1992, 2012; Rudy & Morledge 2014). In these instances, fear-memory is retained due to preservation of the amygdala. However, when both the amygdala and hippocampus are damaged, striking and profound disturbances in memory functioning result (Kesner & Andrus, 1982; Mishkin, 1978).
    {http://brainmind.com/images/HippocampusAmygdalaNetwork5.jpg}
    Therefore, the role of the amygdala in memory and learning seems to involve activities related to reward, orientation, and attention, as well as emotional arousal and social-emotional recognition (Gloor, 1992, 2010; Rolls, 1992; Sarter & Markowitsch, 2005). If some event is associated with positive or negative emotional states it is more likely to be learned and remembered. That is, reward increases the probability of attention being paid to a particular stimulus or consequence as a function of its association with reinforcement (Gaffan 1992; Douglas, 1967; Kesner & Andrus, 1982).
    Moreover, the amygdala appears to reinforce and maintain hippocampal activity via the identification of motivationally significant information and the generation of pleasurable rewards (through action on the lateral hypothalamus). However, the amygdala and hippocampus act differentially in regard to the effects of positive vs. negative reinforcement on learning and memory, particularly when highly stressed or repetitively aroused in a negative fashion. For example, whereas the hippocampus produces theta in response to noxious stimuli the amygdala increases its activity following the reception of a reward (Norton, 1970).
    TEMPORAL LOBES & LATERALITY.
    It is now very well known that lesions involving the mesial-inferior temporal lobes (i.e. destruction or damage to the amygdala/hippocampus) of the left cerebral hemisphere typically produce significant disturbances involving verbal memory--particularly as constrasted with individuals with right sided destruction. Left sided damage disrupts the ability to recall simple sentences, complex verbal narrative passages, or to learn verbal paired-associates or a series of digits (Frisk & Milner 1990; Milner, 1966, 1970, 1971; Squire 1992).
    In contract, right temporal destruction typically produces deficits involving visual memory, such as the learning and recall of geometic patterns, visual or tactile mazes, locations, objects, emotional sounds, or human faces (Corkin, 1965; Milner, 1965; Nunn et al., 2009; Kimura, 1963). Right sided damage also disrupts the ability to recognize (via recall) olfactory stimuli (Rausch et al. 1977), or recall emotional passages or personal memories (Cimino et al., 1991; Wechsler, 1973).
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    It appears, therefore, that the left amygdala and hippocampus are highly involved in processing and/or attending to verbal information, whereas the right amygdala/hippocampus is more involved in the learning, memory and recollection of non-verbal, visual-spatial, environmental, emotional, motivational, tactile, olfactory, and facial information. These issues and the differing roles of these nuclei in memory formation, as well as amnesia and repression will be discussed in greater detail in chapters 29, 30.
    THE PRIMARY PROCESS
    AMYGDALA & PLEASURE
    The amygdala maintains a functionally interdependent relationship with the hypothalamus in regard to emotional, sexual, autonomic, consumatory and motivational concerns. It is able to modulate and even control rudimentary emotional forces governed by the hypothalamic nucleus. However, the amygdala also acts at the behest of hypothalamically induced drives. For example, if certain nutritional requirements need to be meet, the hypothalamus signals the amygdala which then surveys the external environment for something good to eat (Joseph, 1982, 1992a). On the other hard, if the amygdala via environmental surveillance were to discover a potentially threatening stimulus, it acts to excite and drive the hypothalamus as well as the basal ganglia so that the organism is mobilized to take appropriate action.
    When the hypothalamus is activated by the amygdala, instead of responding in an on/off manner, cellular activity continues for an appreciably longer time period (Dreifuss et. al., 1968). The amygdala can tap into the reservoir of emotional energy mediated by the hypothalamus so that certain ends may be attained (Joseph, 1982, 1992a)
    AMYGDALA & HIPPOCAMPAL INTERACTIONS DURING INFANCY
    HALLUCINATIONS
    The amygdal-hippocampal complex, particularly that of the right hemisphere, is very important in the production and recollection of non-linguistic and verbal-emotional images associated with past experience. In fact direct electrical stimulation of the temporal lobes, hippocampus and particularly the amygdala (Gloor, 1990, 2010) not only results in the recollection of images, but in the creation of fully formed visual and auditory hallucinations (Gloor 1992, 2010; Halgren 1992; Halgren et al., 1978; Horowitz et al., 1968; Malh et al., 1964; Penfield & Perot, 1963), as well as feelings of familiarity (e.g. deja vus).
    Indeed, it has long been know that tumors invading specific regions of the brain can trigger the formation of hallucinations which range from the simple (flashing lights) to the complex. The most complex forms of hallucination, however, are associated with tumors within the most anterior portion of the temporal lobe (Critchley, 1939; Gibbs, 1951; Gloor 1992, 2010; Halgren 1992; Horowitz et al. 1968; Tarachow, 1941); i.e. the region containing the amygdala and anterior hippocampus.
    Similarly, electrical stimulation of the anterior lateral temporal cortical surface results in visual hallucinations of people, objects, faces, and various sounds (Gloor 1992, 2010; Halgren 1992; Horowitz et al., 1968)--particularly the right temporal lobe (Halgren et al. 1978). Depth electrode stimulation and thus direct activation of the amygdala and/or hippocampus is especially effective.
    For example, stimulation of the right amygdala produces complex visual hallucinations, body sensations, deja vu, illusions, as well as gustatory and alimentary experiences (Weingarten et al. 1977), whereas Freeman and Williams (1963) have reported that the surgical removal of the right amygdala in one patient abolished hallucinations. Stimulation of the right hippocampus has also been associated with the production of memory- and dream-like hallucinations (Halgren et al. 1978; Horowitz et al. 1968).
    The amygdala also becomes activated in response to bizarre stimuli (Halgren, 1992). Conversely, if activated to an abnormal degree, it may in turn produce bizarre memories and abnormal perceptual experiences. In fact, the amygdala contributes in large part to the production of very sexual as well as bizarre, unusual and fearful memories and mental phenomenon including dissociative states, feelings of depersonalization, and hallucinogenic and dream-like recollections (Bear, 1979; Gloor, 1986, 1992, 2010; Horowitz et al. 1968; Mesulam, 1981; Penfield & Perot, 1963; Weingarten et al. 1977; Williams, 1956). In addition, sexual feelings and related activity and behavior are often evoked by amygdala stimulation and temporal lobe seizures (Halgren, 1992; Jacome, et al. 1980; Gloor, 1986, 2010; Remillard, et al. 1983; Robinson & Mishkin, 1968; Shealy & Peele, 1957), including memories of sexual intercourse (Gloor 1990) or severe emotional trauma and abuse (Gloor, 2010).
    Moreover, intense activation of the temporal lobe and amygdala has been reported to give rise to a host of sexual, religious and spiritual experiences; and chronic hyperstimulation (i.e. seizure activity) can induce some individuals to become hyper-religious or visualize and experience ghosts, demons, angels, and even God, as well as claim demonic and angelic possession or the sensation of having left their body (Bear 1979; Gloor 1986, 1992; Horowitz, Adams & Rutkin 1968; MacLean 1990; Mesulam 1981; Penfield & Perot 1963; Schenk, & Bear 1981; Weingarten, et al. 1977; Williams 1956).
    LSD.
    As is well known, LSD can elicit profound hallucinations involving all spheres of experience. Following the administration of LSD high amplitude slow waves (theta) and bursts of paroxysmal spike discharges occurs in the hippocampus and amygdala (Chapman & Walter, 1965; Chapman et al. 1963), but with little cortical abnormal activity. In both humans and chimps, when the temporal lobes, amygdala and hippocampus are removed, LSD ceased to produce hallucinatory phenomena (Baldwin et al. 1959; Serafintides, 1965). Moreover, LSD induced hallucinations are significantly reduced when the right vs. left temporal lobe has been surgically ablated (Serafintides, 1965).
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    Overall, it appears that the amygdala, hippocampus, and the neocortex of the temporal lobe are highly interactionally involved in the production of hallucinatory experiences. Presumably, it is the neocortex of the temporal lobe which acts to interpret this material (Penfield & Perot, 1963) as perceptual phenomena. Indeed, it is the interrelated activity of the temporal lobes, hippocampus and amygdala which not only produce memories and hallucinations, but dreams. In fact, the amygdalas involvement in all aspects of emotion and sexual functioning, including associated memories, the production of overwhelming fear as well as bizarre and dream-like mental phenomenon, may well account for why this type of unusual stimuli, including personal and innocuous memories also appears in dreams.
    DREAMING
    When hallucinations follow depth electrode or cortical stimulation, much of the material experienced is very dream-like (Gloor 1990, 1992; Halgren et al., 1978; Malh et al., 1964; Penfield & Perot 1963) and consists of recent perceptions, ideas, feelings, and other emotions which are similarly illusionary and dream-like. Indeed, the right amygdala, hippocampus, and the right hemisphere in general (Broughton, 1982; Goldstein et al., 1972; Hodoba, 1986; Humphrey & Zangwill, 1961; Kerr & Foulkes, 1978; Meyer et al. 2007) also appear to be involved in the production of deam imagery as well as REM sleep (chapter 10). For example stimulation of the amygdala triggers and increases ponto-geniculo-occipital paradoxical activity during sleep (Calvo, et al. 2007), which in turn is associated with REM and dreaming. In addition, during REM, the hippocampus begins to produce slow wave, theta activity (Jouvet, 1967; Olmstead, Best, & Mays, 1973; Robinson et al. 1977), which is associated with long-term potentiation which is associated with learning and memory (see chapter 14). Presumably, during REM, the hippocampus and amygdala act as a reservoir from which various images, emotions, words, and ideas are drawn and incorporated into the matrix of dream-like activity being woven by the right hemisphere. It is probably just as likely that the right hippocampus and amygdala serve as a source from which material is drawn during the course of a daydream.
    The Right Hemisphere & Dreams.
    There have been reports of patients with right cerebral damage, hypoplasia and abnormalities in the corpus callosum who have ceased dreaming altogether, suffer a loss of hypnogic imagery or tend to dream only in words (Botez et al. 2005; Humphrey & Zangwill, 1951; Kerr & Foulkes, 1981; Murri et al. 1984). However, there have also been some report that when the left hemisphere has been damaged, particularly the posterior portions (i.e. aphasic patients), the ability to verbally report and recall dreams also is greatly attenuated (e.g., Murri et al. 1984). Of course, aphasics have difficulty describing much of anything, let alone their dreams.
    Electrophysiologically the right hemisphere also becomes highly active during REM, whereas, conversely, the left brain becomes more active during N-REM (Goldstein et al. 1972; Hodoba, 1986). Similarly, measurements of cerebral blood flow have shown an increase in the right temporal regions during REM sleep and in subjects who upon wakening report visual, hypnagogic, hallucinatory and auditory dreaming (Meyer et al. 2007). Interestingly, abnormal and enhanced activity in the right temporal and temporal-occipital area acts to increase dreaming and REM sleep for an atypically long time period (Hodoba, 1986). Hence, it appears that there is a specific complementary relationship between REM sleep and right temporal electrophysiological activity.
    Interestingly, daydreams appear to follow the same 90-120 minute cycle that characterize the fluctuation between REM and NREM periods, as well as fluctuations in mental capabilities associated with the right and left hemisphere (Broughton, 1982; Kripke & Sonneschein 1973). That is, the cerebral hemisphere tend to oscillate in activity every 90-120 minutes -- a cycle which appears to correspond to the REM-NREM cycle and the appearance of day and night dreams.
    Forgotten Dreams.
    Most individuals, however, have difficulty recalling their dreams. This may seem paradoxical considering that hippocampal theta is being produced. However, this is theta punctuated by high levels of desychronized activity, which is not conducive to learning. In this regard, theta activity may represent the reverberating activity of neural circuits formed during the day, such that the residue of day time memories come to be inserted into the dream. Conversely, due to the high level of desychronization occuring in the hippocampus (as it is so highly aroused), although it contributes images and the days memories, it does not participate in storing these dream-like experiences into memory.
    Consider the results from temporal lobe, amygdala, and hippocampal electrical stimulation on memory recall and the production of hallucinations. Although personal memories are often activated at low intensities of stimulation (memories which are verified not only by the patient but family), if stimulation is sufficiently intense, the memory instead will become dreamlike and populated by hallucinated and cartoon like characters (Halgren, et al. 1978). That is, at low levels of stimulation memories are triggered but these memories become increasingly dream-like with high levels of activity. Moreover, once these high levels of stimulation are terminated, patients soon become verbally amnesic and fail to verbally recall having had these experiences (Gloor, 1992; Horowitz, et al. 1968). However, these memories can be later recalled if subjects are provided with specific contextual cues (Horowitz, et al. 1968). The same can occur during the course of the day when a fragment of a conversation, or some other experience, suddenly triggers the recall of a dream from the previous night which had otherwise been completely forgotten. Presumably it had seemingly been forgotten because the hippocampus did not participate in their storage and thus could not assist in their retrieval (see chapters 29, 20).
    There is also some evidence to suggest that different regions of the hippocampus show different levels of arousal during paradoxical sleep. For example, it appears that the posterior hippocampus becomes activated during paradoxical sleep and shows theta activity, whereas the more anterior portions become inhibited (Olmstead et al. 1973). As the anterior portions are more involved in new learning (at least in humans), whereas the posterior hippocampus is more concerned with old and well established memories, this would suggest that the posterior hippocampus is contributing older or already established memories to the content of the dream--which explains why theta, which is associated with learning and memory, is also produced during the dream--that is, it is replaying various fragmentary memories. Conversely, the inhibition of the anterior region would prevent this dream material from becoming re-memorized.
    DREAMS & INFANCY
    In the newborn, and up until approximately 6-9 months, there are two distinct stages of sleep which correspond to REM and N-REM periods demonstrated by adults (Berg & Berg, 1978; Dreyfus-Brisac & Monod, 1975; Parmelee et al. 1967). Among infants, however, REM occur during wakefulness as well as during sleep. In fact, REM can be observed when the eyes are open, when the infant is crying, fussing, eating, or sucking (Emde & Metcalf, 1970). Moreover, REM is also observed to occur within a few moments after an infant begins to engage in nutritional sucking and appears identical to that which occurs during sleep (Emde & Metcalf, 1970).
    The production of REM during waking in some respects seems paradoxical. Nevertheless, it might be safe to assume that like an adult, when the infant is in REM, he or she is dreaming, or at least, in a dream-like state. Possibly, this state corresponds to what Freud has described as the Primary Process. That is, when produced when the infant is crying or fussing, it is dreaming of whatever relief it seeks. Correspondingly, REM which occurs while eating or sucking may have to do with the limbic structures which are involved not only in the production of dream-like activity, but the identification, learning and retention of motivationally significant information (i.e. the amygdala and hippocampus).
    Presumably this relationship is a consequence of REM as well as eating and sucking being mediated, in part, by the amygdala as well as other limbic nuclei, which are also concerned with forming motivationally significant memories. Hence, when hungry, the hypothalamus becomes aroused which activates the amygdala which is responsible for the performing environmental surveillance so as to attend, orient to, identify and approach motivationally significant stimuli and eat. However, because the infants brain is so immature and as its resources for meeting its limbic needs are quite rudimentary, under certain conditions prolonged hypothalamus induced amygdala activation results in the formation and recall of relevant memories which may be experienced as hallucinations of the desired object. That is, previously formed neural networks become activated and the infant begins to dream and hallucinate food and will then suck and smack its lips as if eating or sucking when it is awake, in REM, and there is no food present.
    THE PRIMARY PROCESS
    The hypothalamus, our exceedingly ancient and primitive Id, has an eye that only sees inward. It can tell if the body needs nourishment but cannot determine what might be good to eat. It can feel thirst, but has no way of slacking this desire. The hypothalamus can only say: "I want", "I need", and can only signal pleasure and displeasure. However, being the seat of pleasure, the hypothalamus can be exceedingly gracious in rewarding the organism when its needs are met. Conversely, when its needs go unmet it can respond not only with displeasure and feelings of aversion, but with undirected fury and rage. It can cause the organism to cry out.
    Nevertheless, the cry does not produce the immediately desire relief or reduction in tension. There is thus a pressure on the limbic system and the organism to engage in environmental surveillance so as to meet the needs monitored by the hypothalamus.
    Over the course of the first months of life, as the amygdala and then hippocampus develop, the organism begins to develop an eye that not only sees outward, but which can register and recall events, objects, people, etc., associated with tension reduction, pleasure and the satiaty of the infants internal needs (e.g. the taste, smell, feeling of mother's breast and milk, the experience of sucking and relief, etc.). This is called learning.
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    With the maturation of these two limbic nuclei the infant is increasingly able to differentiate what occurs in the external environment based on hypothalamically monitored needs and the emotional/motivational significance of that which is experienced. The infant can now orient, selectively attend, determine what brings satisfaction, and store this information in memory.
    PRIMARY IMAGERY
    Although admittedly we have no direct knowledge as to the psychic interactions in the neonate, it does seem reasonable to assume that as the neocortex and underlying structures and fiber pathways mature, neural "prgroams" are formed which correspond to the repeated registration of experiences which are deemed significant (e.g. pleasurable). That is, neural pathways which are repetitively fired, deactivated or activated in response to specific sensory and affective activities and experiences, become associated with that activity, such that an associated neural circuit is formed (chapter 14); i.e. a memory is created. Eventually, if this circuit is reactivated, the "learned" pattern is reexperienced; i.e. the organism remembers.
    Thus, infants as young as 2 days of age can learn to suck at the mere sight of a bottle (see Piaget, 1954) and in order to receive milk as a reinforcement, infants can even modify their sucking response (Sameroff & Cameron, 1979). Hence, they are susceptible to classical conditioning (Sameroff & Cavanagh, 1979), although the possibility of operant conditioning has not been established. Nevertheless, the fact that they can recognize the bottle and suck (as well as cry and shed tears) indicates that various regions of the limbic system, especially that of the amygdala is functional and that learning and the creation of specific, context specific neural circuits have been formed very early in life.
    Thus, when the amygdala/hippocampus are stimulated by a hungry hypothalamus, the events and images associated with past experiences of pleasure can not only be searched out externally, but recalled in imaginal form. For example, as an infant experiences hunger and stomach contractions as well as it own cries of displeasure, these states become associated with the sound, smell, taste, etc. of mother and her associated movement and other stimuli which accompany being fed (cf Piaget, 1952, pp. 37, 407-408). Repetitively experienced, the sequence from hunger to satiety evokes and becomes associated with the activation of certain neural pathways and the creation of a specific neural network subserving that memory (chapter 14).
    Eventually, when the infant becomes hungry, if prolonged there is the possibility that the entire neural sequence associated with hunger and feeding (i.e. hunger, mother, food, satiaty), may become involuntarily triggered and activated (via association) such that an "image" of being fed is experienced. The activation of these rudimentary and infantile memory-images is probably what consititutes, at least in part, the primary process.
    Behaviorally this is manifested by REM and via sucking and tongue movements as if eating, when in fact there is no food present (cf, Piaget, 1952). That is, when hungry, the infant will begin to cry, rapid eye movement (REM) might be observed, and then the infant will stop crying and smack its lips and make sucking movement (mediated by the amygdala) as if it were being fed. The infant experiences the experience of being fed in the form of a dream (Joseph, 1982) or hallucination, although it is awake.
    In that the brain of the human infant is quite immature for in fact several years, which in turn restricts information reception and processing (chapters 23-28), and given the limited amount of reality contact infants are able to achieve, these rudimentary memories and images (even when occurring during waking, i.e. REM), are probably indistinguishable from actual experience simply because they are experience.
    Like a dream, when replayed, the infant presumalby reexperiences to some degree the sensations, emotions, etc., originally linked to tension reduction. Thus, the young infant, as yet unable to distinguish between representation and reality, responds to the image as reality (Freud, 1900, 1911), even while awake--as manifested by REM. When hunger is prolonged the association linked to feeding are triggered and for a brief time period the infant behaves as if its hunger has been sated. Reality is replaced by an image, or rather, a "dream". This is the primary process.
    Since the hypothalamus (which monitors internal homeostasis) is not conscious that the dream images experienced are not real, it initially accepts the memory/dream images transmitted from the amygdala and hippocampus and ceases to cry, i.e. it responds to the imagined sources of nourishment just as it responds to a cue-tone associated with a food reward (Nakamuar & Ono, 1986; Ono et al., 1980). However, the hypothalamus is not long fooled, for the primary process does not offer effective long lasting relief from tension. As the pain of hunger remains and increases, limbic activity is increased, and the image falls away to be replaced by a cry of hunger (Joseph, 1982). The amygdala and hippocampus are thus forced to renew their surveillance of the environment in search of sources of tension reduction. Cognitive development is thus promoted.
    "Whatever was thought of (desired) was simply imagined in an hallucinatory form, as still happens today with our dream-thoughts every night. This attempt at satisfaction by means of hallucination was abandoned only in consequence of the absence of the expected gratification, because of the disappointment experienced. Instead, the mental apparatus had to decide to form a conception of the real circumstances in the outer world and to exert itself to alter them...The increased significance of external reality heightened the significance also of the sense-organs directed towards the outer word, and of the consciousness attached to them; the later now learned to comprehend the qualities of sense in addition to the qualities of pleasure and "pain" which hitherto had alone been of interest to it. A special function was instituted which had periodically to search the outer word in order that its data might be already familiar if an urgent need should arise; this function was attention. Its activity meets the sense-impressions halfway, instead of awaiting their appearance. At the same time there was probably introduced a system of notation, whose task was to deposit the results of this periodical activity of consciousness--a part of that which we call memory" (Freud, 1911, pp. 410-411).

    THE LIMBIC SYSTEM
    Foundations of Social, Sexual, Emotional Behavior, love & Memory
    ...
    Language is both emotional and grammatically descriptive, limbic and neocortical. It is precisely because all humans possess a limbic system which is organized, and which develops in an identical fashion, that a listener is able to comprehend not only the content and grammar of what is said, but the emotion and melody of how it is said --what a speaker feels, even when that speaker is a cooing, gooing, babbling infant.
    +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
    The Limbic System
    Hypothalamus, Septal Nuclei,
    Amygdala, Hippocampus
    Emotion and the Unconscious Mind
    R. Gabriel Joseph, Ph.D.
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    Limbic System Overview
    Buried within the depths of the cerebrum are several large aggregates of limbic structures and nuclei which are preeminent in the control and mediation of memory, emotion, learning, dreaming, attention, and arousal, and the perception and expression of emotional, motivational, sexual, and social behavior including the formation of loving attachments. Indeed, the limbic system not only controls the capacity to experience love and sorrow, but it governs and monitors internal homeostasis and basic needs such as hunger and thirst (Bernardis & Bellinger 2007; Gloor 1992, 2010; Joseph, 1990, 1992, 2000a; LeDoux 1992, 2012; MacLean, 1973, 1990; Rolls, 1984, 1992; Smith et al. 1990), including even the cravings for pleasure-inducing drugs (Childress, et al., 2009).
    The structures and nuclei of the limbic system are exceedingly ancient, some of which began to evolve over 450 million years ago. Over the course of evolution, these emotional structures have expanded in size, some becoming increasingly cortical in response to increased environmental opportunities and demands. In fact, as the neocortical forebrain expanded and until as recently as 50 million years ago, the cerebrum of the ancestral line that would eventually give rise to humans, was dominated by the limbic system.
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    However, over the course of evolution a mantle of neocortex began to develop and enshroud the limbic system; evolving at first to serve limbic needs in a way that would maximize the survival of the organism, and to more efficiently, effectively, and safely satisfy limbic needs and impulses. In consequence, the frontal, temporal, parietal, and occipital lobes evolved covered with a neocortical mantle, that in humans would come to be associated with the conscious, rational mind. Sometimes, however, even in the most rational of humans, emotions can hijack the logical mind, and the neocortex, and even peaceful people might be impelled to murder even those they love.
    Indeed, the old limbic brain has not been replaced and is not only predominant in regard to all aspects of motivational and emotional functioning, but is capable of completely overwhelming "the rational mind" due in part to the massive axonal projections of limbic system to the neocortex. Although over the course of evolution a new brain (neocortex) has developed, Homo sapiens sapiens ("the wise may who knows he is wise") remains a creature of emotion. Humans have not completely emerged from the phylogenetic swamps of their original psychic existence.
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    Hence, due to these limbic roots, humans not uncommonly behave "irrationally" or in the "heat of passion," and get into fights, have sex with or scream and yell at strangers thus act at the behest of their immediate desires; sometimes falling "madly in love" and at other times, acting in a blind rage such that even those who are 'loved" may be slaughtered and murdered.
    Indeed, emotion is a potentially powerful overwhelming force that warrants and yet resists control-- as something irrational that can happen to a someone ("you make me so angry") and which can temporarily hijack, overwhelm, and snuff out the "rational mind."
    The schism between the rational and the emotional is real, and is due to the raw energy of emotion having it's source in the nuclei of the ancient limbic lobe -- a series of structures which first make their phylogenetic appearance over a hundred million years before humans walked upon this earth and which continue to control and direct human behavior.
    FUNCTIONAL OVERVIEW
    In general, the primary structures of the limbic system include the hypothalamus, amygdala, hippocampus, septal nuclei, and anterior cingulate gyrus; structures which are directly interconnected by massive axonal pathways (Gloor, 2010; MacLean, 1990; Risvold & Swanson, 2012). With the exception of the cingulate which is referred to as "transitional" cortex (mesocortex) and consists of five layers, the hypothalamus, amygdala, hippocampus, septal nuclei are considered allocortex, consisting of at most, 3 layers.
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    The hypothalamus could be considered the most "primitive" aspect of the limbic system, though in fact the functioning of this sexually dimorphic structure is exceedingly complex. The hypothalamus regulates internal homeostasis including the experience of hunger and thirst, can trigger rudimentary sexual behaviors or generate feelings of extreme rage or pleasure. In conjunction with the pituitary the hypothalamus is a major manufacturer/secretor of hormones and other bodily humors, including those involved in the stress response and feelings of depression.
    {http://brainmind.com/images/LimbicSystemEmotions.jpg} The amygdala has been implicated in the generation of the most rudimentary and the most profound of human emotions, including fear, sexual desire, rage, religious ecstasy, or at a more basic level, determining if something might be good to eat. The amygdala is implicated in the seeking of loving attachments and the formation of long term emotional memories. It contains neurons which become activated in response to the human face, and which become activated in response to the direction of someone else's gaze. The amygdala also acts directly on the hypothalamus via the stria terminalis, medial forebrain bundle, and amygdalafugal pathways, and in this manner can control hypothalamic impulses. The amygdala is also directly connected to the hippocampus, with which it interacts in regard to memory.
    The hippocampus is unique in that unlike the amygdala and other structures, almost all of its input from the neocortex is relayed via the overlying entorhinal cortex--a five layered mesocortex. As is well known, the hippocampus is exceedingly important in memory, acting to place various short-term memories into long-term storage. Presumably the hippocampus encodes new information during the storage and consolidation (long-term storage) phase, and assists in the gating of afferent streams of information destined for the neocortex by filtering or suppressing irrelevant sense data which may interfere with memory consolidation. Moreover, it is believed that via the development of long-term potentiation the hippocampus is able to track information as it is stored in the neocortex, and to form conjunctions between synapses and different brain regions which process and store associated memories.
    {http://cosmology.com/images/LimbicCoverEbook1epub.jpg} The septal nuclie can produce extremes of emotion, including explosive violence, known as "septal rage."
    The septal nuclei is in part an evolutionary and developmental outgrowth of the hippocampus (Ariens Kappers, et al., 1936; Gloor, 2010), and the hypothalamus, and in fact acts to link the hippocampus with the hypothalamus as well as with the brainstem (Andy & Stephan, 1968; Risvold & Swanson, 2012; Swanson & Cowan, 1979;). It consists of both lateral and medial segments; i.e. the lateral and medial septal nuclei (Ariens Kappers, et al., 1936). Presumably, via these interconnections, the septal nuclei exerts modulatory influences on the hippocampus in regard to memory functioning and arousal (Gloor, 2010).
    The septal nuclei is also interconnected with and shares a counterbalancing relationship with the amygdala particularly in regard to hypothalamic activity and emotional and sexual arousal (Andy & Stephan, 1968; Swanson & Cowan, 1979). For example, whereas the amygdala promotes indiscriminate contact seeking, and perhaps promiscuous sexual activity, the septal nuclei inhibits these tendencies thus assisting in the formation of selective and more enduring emotional attachments (Joseph, 1992a, 2009b).
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    The anterior cingulate is considered a transitional cortex, or rather, mesocortex (also referred to as "paleocortex") as it consists of five layers (MacLean, 1990). The anterior cingulate is intimately interconnected with the hypothalamus, amygdala, septal nuclei, and hippocampus, and participates in memory and emotion including the experience of pain, misery, and anxiety, and is directly implicated in the evolution and expression of maternal behavior. It is also the most vocal aspect of the brain, becomes active during language tasks, and generates emotional-melodic aspects of speech which is expressed via interconnections with the right and left frontal speech areas, and the vocalization center in the midbrain periaqueductal gray. Thus the anterior cingulate is implicated in the more cognitive aspects of social-emotional behavior including language and the establishment of long term attachments beginning with the mother-infant bond.
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    Also implicated in the functioning of the limbic system are the olfactory bulb and olfactory system, the limbic striatum (nucleus accumbens, olfactory tubercle, substantia innominata, ventral caudate and putamen), the orbital frontal and inferior temporal lobes and the midbrain monoamine system. These systems and structures are also directly connected or separated by only a single synapse, and which tend to become aroused not only as a function of emotional arousal, but in reaction to olfactory input which continues to exert profound effects on the human limbic system, and upon human behavior.
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    HYPOTHALAMUS
    The hypothalamus is an exceedingly ancient structure and unlike most other brain regions it has remained somewhat similar in structure throughout phylogeny and apparently over the course of evolution (Crosby et al. 1966). Located in the most medial aspect of the brain, along the walls and floor of the 3rd ventricle, this nucleus is fully functional at birth and is the central core from which all emotions derive their motive force. Indeed, the hypothalamus is highly involved in all aspects of emotional, reproductive, vegetative, endocrine, hormonal, visceral and autonomic functions (Alam et al., 2011; Johnson & Gross, 2013; Markakis & Swanson, 2010; Sherin, et al., 2012; Smith et al. 1990) and mediates or exerts significant or controlling influences on eating, drinking, sleeping and the experience of pleasure, rage, and aversion.
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    In fact, almost every region of the cerebrum interacts with and communicates with the hypothlamus and is subject to its influences (Swanson, 2007). Moreover, the hypothalamus utilizes the blood supply to transmit hormonal and humoral messages to peripheral organs as well as other brain structures and utilizes the blood supply to receive information as well, thus bypassing the synaptic route utilized by almost all other regions of the neuroaxis (Markakis & Swanson, 2010). Through the blood supply (as well as via the cerebrospinal fluid), the hypothalamus not only regulates, but is subject to feedback regulation by the same structures that it controls.
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    Certain areas of the diencephalon, midbrain, and brainstem, are exceedingly exceedingly sensitive to hormones, humors, and peptides circulating within the blood plasma, and the cerebrospinal fluids; chemosensory information which is used for maintaining homeostasis. Broadly considered, these chemosensory sensitive areas are generally located near or surrounding the cerebral ventricles (Johnson & Gross, 2013) and they tend not to be effected by the so called "blood brain barrier;" referred to as circumventricular organs (CVOs). There are perhaps dozens of CVO's at least 8 of which are located in or near the ventricular systems which feed the brainstem and diencephalon including the hypothalamus, pineal gland and pituitary (Johnson & Gross, 2013).
    The hypothalamus, however, does not act solely through the blood supply or via cerebrospinal fluid, and its also receives sensory information synaptically, and often indirectly, as is the case with the majority of olfactory fibers. In general, sensory stimuli reach the hypothalamus from a variety of routes. These include the solitary tract of the brainstem, a structure which receives, processes, and transmits data received principally from the vagus and glosopharyngeal cranial nerves. Through this pathway the lateral hypothalamus is informed about cardivocascular activities, respiration, and taste. These pathways are also bidirectional (Swanson, 2007). Other major pathways include the medial forebrain bundle (which contains axons from a variety of different cellular groups) and the stria terminalis through which the amygdala and hypothalamus interact. The hypothalamus also maintains massive interactive pathways with the frontal lobes and septal nuclei (Risvold & Swanson, 2012).
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    Broadly considered, the hypothalamus consists of three longitudinal subdivisions which extend along its anterior to posterior axis. These are the medial, lateral, and periventricular (Swanson, 2007). The periventricular zone is concerned with neuroendocrine regulation, whereas the lateral and medial zones are concerned with affective states, including hunger and thirst. These zones, in turn can be further subdivided into subnuclei.
    Phylogenetically, structurally, and embryologically the hypothalamus is traditionally considered part of the diencephalon. During embryological development it emerges from the diencephalic vessicle of the neural tube along with those anterior-lateral evaginations which become the optic nerves and retina of the eye, as well as the pituitary gland (ventrally) and the pineal gland and thalamus (dorsally). There is some dispute, however, over the developmental patterns of the hypothalamus, as some scientists believe that it develops from the outside in (the "hollow hypothalamus hypothesis").
    On the other hand, the hypothalamus originates from the medially situated neuroepithelium, and thus begins its developmental journey in a medial (or rather paramedial) to lateral arc, such that it appears that the medial hypothalamus is fashioned (and matures) in advance of the lateral hypothalamus.
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    From an evolutionary perspective, however, the hypothalamus appears to have dual (forebrain - midbrain) origins; that is emerging from the dorsal (visual) midbrain, and the olfactory forebrain, which together, and over the course of evolution, gave rise to the ventral, medial, lateral and preoptic hypothalamus. Nevertheless, in modern mammals and humans, the olfactory origins are no longer directly apparent, particularly in that most olfactory fibers reach the hypothalamus indirectly; e.g. via the amygdala and piriform cortex.
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    The hypothalamus is exceedingly responsive to olfactory (and pheromonal) input. Perhaps reflecting this partial and putative olfactory origin is the fact that this structure utilizes chemical (hormonal, humoral) molecules to communicate with other areas of the brain, and reacts to these same molecules as well as olfactory cues, including those directly related to sexual status.
    It is this olfactory-chemical origin and sensitivity which in turn may explain why portions of the hypothalamus (like the amygdala) are also sexually dimorphic and reacts to pheromonal sensory stimuli including those which signal sexual status. That is, structurally and functionally the hypothalamus of males and females are stucturally dissimilar (Bleier et al. 1982; Dorner, 1976; Gorski et al. 1978; Rainbow et al. 1982; Raisman & Field, 1971, 1973) and perform different functions depending on if one is a man or a woman, and if a woman is sexually receptive, pregnant, or lactating. For example, the sexually dimorphic supraoptic and paraventricular nuclei project (via the infundibular stalk) to the posterior lobe of the pituitary which may then secrete oxytocin--a chemical which can trigger uterine contractions as well as milk production in lactating females (and which can thus make nursing a pleasurable experience). The male hypothalamus/pituitary does not perform this function.
    SEXUAL DIMORPHISM IN THE HYPOTHALAMUS
    As is well known, sexual differentiation is strongly influenced by the presence or absence of gonadal steriod hormones during certain critical periods of prenatal development in many species including humans. Not only are the external genitalia and other physical features sexually differentiated but certain regions of the brain have also been found to be sexually dimorphic and differentially senstitive to steriods, particularly the preoptic area and ventromedial nucleus of the hypothalamus, as well as the amygdala (Bleier et al. 1982; Dorner, 1976; Gorski et al. 1978; Rainbow et al. 1982; Raisman & Field, 1971, 1973).
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    Indeed it has now been well established that the amygdala and the hypothalamus (specifically the anterior commissure, anterior-preoptic, ventromedial and suprachiasmatic nuclei) are sexually differentiated and have sex specific patterns of neuronal and dendritic development, (Allen et al. 1989; Blier et al. 1982; Gorski et al. 1978; Rainbow et al. 1982; Raisman & Field, 1971, 1973; Swaab & fliers, 2005).
    This is a consequence of the presence or absence of testosterone during fetal development in humans, or soon after birth in some species such as rodents. Specifically, the presence or absence of the male hormone, testosterone during this critical neonatal period, directly effects and determines the growth and pattern of interconnections between the amygdala and hypothalamus, between axons and dendrites in these nuclei as well as the hippocampus, septal nuclei, olfactory system (ref), and thus the organization of specific neural circuits. In the absence of testosterone, the female pattern of neuronal development occurs. Indeed, it is the presence or absence of testosterone during these early critical periods that appear to be responsible for neurological alterations which greatly effect sex differences in thinking, sexual orientation, aggression, and cognitive functioning (Barnett & Meck, 1990; Beatty, 1992; Dawson et al. 1975; Harris, 1978; Joseph, et al. 1978; Stewart et al. 1975).
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    For example, if the testes are removed prior to differentiation, or if a chemical blocker of testosterone is administered thus preventing this hormone from reaching target cells in the limbic system, not only does the female pattern of neuronal development occur, but males so treated behave and process information in a manner similar to females (e.g., Joseph et al. 1978); i.e. they develop female brains and think and behave in a manner similar to females. Conversely, if females are administered testosterone during this critical period, the male pattern of differentiation and behavior results (see Gerall et al. 1992 for review).
    That the preoptic and other hypothalamic regions are sexually dimorphic is not surprising in that it has long been known that this area is extremely important in controlling the basal output of gonadotrophins in females prior to ovulation and is heavily involved in mediating cyclic changes in hormone levels (e.g. FSH, LH, estrogen, progesterone). Chemical and electrical stimulation of the preoptic and ventromedial hypothalamic nuclei also triggers sexual behavior and even sexual posturing in females and males (Hart et al., 2005; Lisk, 1967, 1971) and, in female primates, even maternal behavior (Numan, 2005). In fact, dendritic spine density of ventromedial hypothalamic neurons varies across the estrus cycle (Frankfurt et al., 1990) and thus presumably during pregnancy and while nursing.
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    {http://brainmind.com/images/peniscactus.jpg} In primates, electrical stimulation of the preoptic area increases sexual behavior in males, and significantly increases the frequency of erections, copulations and ejaculations, we well as pelvic thrusting followed by an explosive discharge of semen even in the absence of a mate (Hart, et al., 2005; Maclean, 1973). Conversely, lesions to the preoptic and posterior hypothalamus eliminates male sexual behavior and results in gonadal atrophy.
    {http://brainmind.com/images/treepenis8022.jpg} Hence, it is thus rather clear than the ability to sexually reproduce is dependent on the functional integrity of the hypothalamus. In fact, it is via the hypothalamus acting on the pituitary, that gonadotropins come to be released. Gonadotropins control the production and/or release of gametes; i.e. ova and sperm.
    Specifically, the hypothalamic neurons secrete gonadotropin-releasing hormone, which acts on the anterior lobe of the pituitary which secretes gonadotropins. However, given that in females, this is a cyclic event, whereas in males sperms are constantly reproduced, is further evidence of the sexual dimorphism of the hypothalamus.
    Although the etiology of homosexuality remains in question, it has been shown that the ventromedial and anterior nuclei of the hypothalamus of male homosexuals demonstrate the female pattern of development (Levay, 1991; Swaab, 1990). When coupled with the evidence of male vs female and homosexual differences in the anterior commissure which links the temporal lobe and sexually dimorphic amygdala (see below) as well as the similarity between male homosexuals and women in regard to certain cognitive attributes including spatial-perceptual capability (see below), this raises the possibility that male homosexuals are in possession of limbic system that is more "female" than "male" in functional as well as structural orientation.
    It is also interesting to note that the sexually dimorphic preoptic region contains thermosensitive neurons, and controls the physiological and behavior responses to excessive external cold or heat. That is, it is responsible for internal thermoregulation and thus heat loss or retention (Alam et al., 2011). Although we can only speculate, it may well be sex differences in this structure which accounts (at least in part) for the stereotypical differences in male vs female perceptions of cold, and why, stereotypically, females (despite their extra-layers of heat-retaining fat) are more likely to insist on elevating room temperature.
    LATERAL & VENTROMEDIAL HYPOTHALAMIC NUCLEI
    Although consisting of several nuclear subgroups, the lateral and medial (ventromedial) hypothalamic nuclei play particularly important roles in the control of the automonic nervous system, the experience of pleasure and aversion, eating and drinking, and raw (undirected) emotionality. They also appear to share a somewhat antagnistic relationship.
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    For example, the medial hypothalamus controls parasympathetic activities (e.g. reduction in heart rate, increased peripheral circulation) and exerts a dampening effect on certain forms of emotional/motivational arousal. The lateral hypothalamus mediates sympathetic activity (increasing heart rate, elevation of blood pressure) and is involved in controlling the metabolic and somatic correlates of heightened emotionality (Smith et al. 1990). In this regard, the lateral and medial region act to exert counterbalancing influences on each other.
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    HUNGER & THIRST
    The lateral and medial region are highly involved in monitoring internal homeostasis and motivating the organism to respond to internal needs such as hunger and thirst (Anand & Brobeck, 1951; Bernardis & Bellinger 2007; Hetherington & Ranson, 1940). For example, both nuclei appear to contain receptors which are sensitive to the body's fat content (lipostatic/caloric receptors) and to circulating metabolites (e.g. glucose) which together indicate the need for food and nourishment. For example, when food is digested, the viscera secretes various hormones which act on the alimentary tract, which in turn stimulates the solitary tract (ST) which projects directly to the hypothalamus. However, in the absence of food, the viscera also begins to secrete various hormones which when coupled changes in caloric blood levels, signals to the hypothalamus the need for food. The lateral hypothalamus also appears to contain osmoreceptors (Joynt, 1966) which determine if water intake should be altered.
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    {http://brainmind.com/images/rys0504.gif} Electophysiologically, it has been determined that the hypothalamus not only become highly active immediately prior to and while the organism is eating or drinking, but the lateral region alters it's activity when the subject is hungry and simply looking at food (Hamburg, 1971; Rolls et. al., 1976). In fact, if the lateral hypothalamus is electrically stimulated a compulsion to eat and drink results (Delgado & Anand, 1953). Conversely, if the lateral area is destroyed bilaterally there results aphagia and adipsia so severe animals will die unless force fed (Anand & Brobeck, 1951; Hetherington & Ranson, 1940; Teitelbaum & Epstein, 1962).
    If the medial hypothalamus is surgically destroyed, inhibitory influences on the lateral region appear to be abolished such that hypothalamic hyperphagia and severe obesity result (Anand & Brobeck, 1951; Hoebel & Tetelbaum, 1966; Teitelbaum, 1961). Hence, the medial area seems to act as a satiaty center; but, a center that can be overridden.
    Specifically, with ventromedial lesions, animals not only eat more, but the intervals between meals becomes shorter such that they eat more meals. Thus they begin to gain weight. In part this is also due to changes in the sympathetic nervous system which increases vagal activity, thus signaling the need for more food. As noted, the ST is bidirectional.
    Normally the hypothalamus can act via the ST and thus the vagal complex and can signal satiation. However, with medial destruction, the ST becomes hyperactive thus inducing parasympathetic overactivity which induces more rapid gastric emptying and the rapid storage of ingested calories. Because these calories are rapidly stored, caloric blood levels are reduced and the lateral hypothalamus is stimulated to begin eating again--which explains the increased frequency of meals. In fact, if animals that have become obese following ventromedial lesions are starved back to their normal weight, once they are allowed free access to food, they again become obese (Hoebel & Tetelbaum, 1966).
    {http://brainmind.com/images/anorexia55.jpg}
    {http://brainmind.com/images/anorexia11.jpg}
    {http://brainmind.com/images/obese01456.jpg} Overall, it appears that the lateral hypothalamus is involved in the intitation of eating and acts to maintain a lower weight limit such that when the limit is reached the organism is stimulated to eat. Conversely, the medial regions seems to be involved in setting a higher weight limit such that when these levels are approached it triggers the cessation of eating.
    In part, these nuclei exert these differential influences on eating and drinking via motivational/emotional influences they exert on other brain nuclei (e.g. via reward or punishment). However, it should be stressed that there are a number of other structures and hormones and peptides involved, including the pancreatic islets, and insulin secretion.
    PLEASURE & REWARD
    In 1952, Heath (cited by Maclean, 1969) reported what was then considered remarkable. Electrical stimulation near the septal nuclei elicited feelings of pleasure in human subjects: "I have a glowing feeling. I feel good!" Subsequently, Olds and Milner (1954) reported that rats would tirelessly perform operants to receive electrical stimulation in this same region and concluded that stimulation "has an effect which is apparently equivalent to that of a conventional primary reward." Even hungry animals would demonstrate a preference for self-stimulation over food.
    Feelings of pleasure (as demonstrated via self-stimulation) have been obtained following excitation to a number of diverse limbic areas including the olfactory bulbs, amygdala, hippocampus, cingulate, substantia nigra (a major source of dopamine), locus coeruleus (a major source of norepinephrine), raphe nucleus (serotonin), caudate, putamen, thalamus, reticular formation, medial forebrain bundle, and orbital frontal lobes (Brady, 1960; Lilly, 1960; Olds & Forbes, 1981; Stein & Ray, 1959; Waraczynski et al. 2007).
    {http://brainmind.com/images/selfstimulationrat.jpg}
    {http://brainmind.com/images/ratSelfStimulating.jpg}
    {http://brainmind.com/images/OlfactoryHypothalamus21.jpg} In mapping the brain for positive loci for self-stimulation, Olds (1956) found that the medial forebrain bundle (MFB) was a major pathway which supported this activity. Although the MFB interconnects the hippocampus, hypothalamus, septum, amygdala, orbital frontal lobes (areas which give rise to self-stimulation), Olds discovered in its course up to the lateral hypothalamus reward sites become more densely packed. Moreover, the greatest area of concentration and the highest rates of self-stimulatory activity were found to occur not in the MFB but in the lateral hypothalamus (Olds, 1956; Olds & Forbes, 1981). Indeed, animals "would contine to stimulate as rapidly as possible until physical fatigue forced them to slow or to sleep" (Olds, 1956).
    Electrophysiological studies of single lateral hypothalamic neurons indicate that these cells become highly active in response to rewarding food items (Nakamura & Ono, 1986). In fact, many of these cells will become aroused by neutral stimuli repeatedly associated with reward such as a cue-tone --even in the absence of the actual reward (Nakamura & Ono, 1986; Ono et al. 1980). However, this ability to form associations appears to be secondary to amygdaloid activation (Fukuda et al. 2007) which in turn influences hypothalamic functioning.
    Nevertheless, if the lateral region is destroyed the experience of pleasure and emotional responsiveness is almost completely attenuated. For example, in primates, faces become blank and expressionless, whereas if the lesion is unilateral, a marked neglect and indifference regarding all sensory events occurring on the contralateral side occurs (Marshall & Teitelbaum, 1974). Animals will in fact cease to eat and will die.
    AVERSION
    In contrast to the lateral hypothalamus and it's involvement in pleasurable self-stimulation, activation of the medial hypothalamus is apparently so aversive that subjects will work to reduce it (Olds & Forbes, 1981). Hence, electrical stimulation of the medial region leads to behavior which terminates the stimulation--apparently so as to obtain relief (e.g. active avoidance). In this regard, when considering behavior such as eating, it might be postulated that when upper weight limits (or nutritional requirements) are met, the medial region becomes activated which in turn leads to behavior (e.g. cessation of eating) which terminates its activation.
    It is possible, however, that medial hypothalamic activity may also lead to a state of quiescence such that the organism is motivated to simply cease to respond or to behave. In some instances this quiescent state may be physiologically neutral, whereas in other situations medial hypothalamic activity may be highly aversive. Quiescence is also associated with parasympathetic activity which is mediated by the medial area.
    HYPOTHALAMIC DAMAGE & EMOTIONAL INCONTINENCE: LAUGHTER & RAGE
    When electrically stimulated, the hypothalamus responds by triggering two seemly oppositional feeling states, i.e. pleasure and unpleasure/aversion. The generation of these emotional reactions in turn influences the organism to respond so as to increase or decrease what is being experienced.
    The hypothalamus, via it's rich interconnections with other limbic regions including the neocortex and frontal lobes, it able to mobilize and motivate the organism to either cease or continue to behave. Nevertheless, at the level of the hypothalamus, the emotional states elicited are very primitive, diffuse, undirected and unrefined.
    The organism feels pleasure in general, or aversion/unpleasure in general. Higher order emotional reactions (e.g. desire, love, hate, etc.) require the involvement of other limbic regions as well as neocortical participation.
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    Emotional functioning at the level of the hypothalamus is not only quite limited and primitive, it is also largely reflexive. For example, when induced via stimulation, the moment the electrical stimulus is turned off the emotion elicited is immediately abolished. In contrast, true emotions (which require other limbic interactions) are not simply turned on or off but can last from minutes to hours to days and weeks before completely dissipating.
    Nevertheless, in humans, disturbances of hypothalamic functioning (e.g. due to an irritating lesion such as tumor) can give rise to seemingly complex, higher order behavioral-emotional reactions, such as pathological laughter and crying which occurs uncontrollably. However, in some cases when patients are questioned, they may deny having any feelings which correspond to the emotion displayed (Davison & Kelman, 1939; Ironside, 1956; Martin, 1950). In part, these reactions are sometimes due to disinhibitory release of brainstem structures involved in respiration, whereas in other instances the resulting behavior is caused by hypothalamic triggering of other limbic nuclei.
    UNCONTROLLED LAUGHTER
    Pathological laughter has frequently been reported to occur with hypophyseal and midline tumors involving the hypothalamus, aneurysm in this vicinity, hemorrhage, astrocytoma or pappiloma of the 3rd ventricle (resulting in hypothalamic compression), as well as surgical manipulation of this nucleus (Davison & Kelman, 1939; Dott, 1938; Foerster & Gabel, 1933; Martin, 1950; Money & Hosta, 1967; Ironside, 1956; List, Dowman, & Bagheiv, 1958).
    For example, Martin (1950, p.455) describes a man who while "attending his mother's funeral was seized at the graveside with an attack of uncontrollable laughter which embarrassed and distressed him considerably." Although this particular attack dissipated, it was soon accompanied by several further fits of laughter and he died soon thereafter. Post-mortem a large ruptured aneurysm was found, compressing the mammillary bodies and hypothalamus.
    In a similar case (Anderson, 1936; Cited by Martin, 1950), a patient literally died laughing following the eruption of the posterior communicating artery which resulted in compression (via hemorrhage) of the hypothalamus. "She was shaken by laughter and could not stop: short expirations followed each other in spasms, without the patient being able to make an adequate inspiration of air, she became cyanosed and nothing could stop the spasm of laughter which eventually became noiseless and little more than a grimace. After 24 hours of profound coma she died."
    Because laughter in these instances has not been accompanied by corresponding feeling states, this pseudo-emotional condition has been referred to as "sham mirth" (Martin, 1950). However, in some cases, abnormal stimulation in this region (such as due to compression effects from neoplasm) has triggered corresponding emotions and behaviors -- presumably due to activation of other limbic nuclei.
    For example, laughter has been noted to occur with hilarious or obscene speech--usually as a prelude to stupor or death--in cases where tumor has infiltrated the hypothlamus (Ironside, 1956). In several instances it has been reported by one group of neurosurgeons (Foerster & Gagel, 1933) that while swabbing the blood from the floor of the 3rd ventricle, patients "became lively, talkative, joking, and whistling each time the infundibular region of the hypothalamus was manipulated." In one case, the patient became excited and began to sing.
    HYPOTHALAMIC RAGE
    Stimulation of the lateral hypothalamus can induce extremes in emotionality, including intense attacks of rage accompanied by biting and attack upon any moving object (Flynn et al. 1971; Gunne & Lewander, 1966; Wasman & Flynn, 1962). If this nucleus is destroyed, aggressive and attack behavior is abolished (Karli & Vergness, 1969). Hence, the lateral hypothalamus is responsible for rage and aggressive behavior.
    {http://brainmind.com/images/rage22.jpg} As noted, the lateral maintains an oppositional relationship with the medial hypothalamus. Hence, stimulation of the medial region counters the lateral area such that rage reactions are reduced or eliminated (Ingram, 1952; Wheately, 1944), whereas if the medial is destroyed there results lateral hypothalamic release and the triggering of extreme savagery.
    In man, inflammation, neoplasm, and compression of the hypothalamus have also been noted to give rise to rage attacks (Pilleri & Poeck, 1965), and surgical manipulations or tumors within the hypothalamus have been observed to elicit manic and rage-like outbursts (Alpers, 1940). These appear to be release phenomenon, however. That is, rage, attack, aggressive, and related behaviors associated with the hypothalamus appears to be under the inhibitory influence of higher order limbic nuclei such as the amygdala and septum (Siegel & Skog, 1970). When the controlling pathways between these areas are damaged (i.e. disconnection) sometimes these behaviors are elicited.
    For example, Pilleri and Poeck (1965) described a man with severe damage throughout the cerebrum including the amygdala, hippocampus, cingulate, but with complete sparing of the hypothalamus who continually reacted with howling, growling, and baring of teeth in response to noise, a slight touch, or if approached. Hence, the hypothalamus being released responds reflexively in an aggressive-like non-specific manner to any stimulus. Lesions of the frontal-hypothalamic pathways have been noted to result in severe rage reactions as well (Fulton & Ingraham, 1929; Kennard, 1945).
    Nevertheless, like "sham mirth", rage reactions elicited in response to direct electrical activation of the hypothalamus immediately and completely dissipate when the stimulation is removed. As such, these outbursts have been referred to as "sham rage".
    CIRCADIAN RHYTHM GENERATION & SEASONAL AFFECTIVE DISORDER
    As noted in chapter 5, during the initial stages of cerebral evolution, the dorsal hypothalmus (like the dorsal thalamus, dorsal hippocampus, dorsal midbrain) was likely fashioned, at least in part, from photosensitive cells located in the anterior head region. Given the daily and seasonal changes in light vs darkness, nuclei in the midbrain-pons, and in the hypothalamus, became sensitive to and capable of generating rhythmic hormonal, neurotransmitter, and motoric activities. It is the hypothalamus, however, the suprachiasmatic nucleus (SCN) in particular, which appears to be the "master clock" for the generation of circadian rhythms; rhythms which have a period length of 24 hours (Aronson et al. 2013; Morin 2014).
    {http://brainmind.com/images/ch3rythm.jpg}
    {http://brainmind.com/images/clocks1.jpg} In humans and other species, the SCN (and the midbrain superior colliculus) is a direct recipient of retinal axons. It also receives indirect visual projections from the lateral geniculate nucleus of the thalamus (see Morin 2014). In this regard, the visual system appears to act to synchronize the SCN (and probably the midbrain-pons) to function in accordance with seasonal and day to day variations in the light/dark ratio. However, the SCN does not "see" per se, nor can it detect visual features, as its main concern is adjusting mood, and activity in regard to light intensity as related to rhythm generation.
    {http://brainmind.com/images/HypoSCN1.jpg}
    {http://brainmind.com/images/HypoSCN2.jpg} There is thus some evidence which suggests that when the SCN of the hypothalamus is deprived of (or unable to effectively respond to) sufficient light, although rhythm generation is not grossly effected (Morin 2014), individuals may become depressed; a condition referred to as Seasonal Affective Disorder (SAD). That is, the hypothalamus (and midbrain-pons) appear to decrease those hormonal and neurochemical activities normally associated with activation and high (daytime) activity thus resulting in depression.
    For example, the hypothalamic-pituitary axis secretes melatonin in phase with the circadian rhythm. Phase-delayed rhythms in plasma melatonin secretion have been repeatedly noted in most (but not all) studies of individuals with SADs (see Wirz-Justice et al. 2013, for review). However, with light therapy, not only is the depression relieved but the melatonin secretions return to normal. This is significant for melatonin is derived from tryptophan via serotonin and low serotonin levels have been directly linked to depression (e.g. Van Pragg 1982).
    {http://brainmind.com/images/HypothalamicPituitary31.jpg} There is some evidence which suggests that the hypothalamus (and the midbrain) may act to regulate serotonin release within the brainstem (Chaouloff 2013; however, see Morin 2014), which in turn may explain why serotonin levels rhythmically fluctuate (e.g. such as during the sleep cycle), or become abnormal when denied sufficient light; i.e. the production of serotonin by the raphe nucleus (in the pons) is abnormally effected.
    {http://brainmind.com/images/HypothalamicPaths18.gif} On the other hand, numerous studies have reported that SADs and major depression occurs most often during the Spring and not the winter, and is not influenced by latitude (e.g. Margnusson & Stefansson 2013; Wirz-Justice et al. 2013). There is also some suggestion that abnormal temperature perception, or aging within the SCN may be responsible for the genesis of SADs and related depressive disorders. For example, age related changes in the SCN have been noted to adversely effect circadian rhythm generation as well as metabolic and peptide activity (Aronson et al. 2013). In consequence, rest vs active cycles also become abnormal, with reductions in arousal and activity; i.e. the patient becomes depressed.
    It is also possible, however, that although light therapy can assist in alleviating depressive symptoms associated with SADs, that the deregulation of the SCN (and melatonin/serotonin) might be unrelated to light, temperature, or aging, but may be a consequence of stress on the hypothalamus (Chauloff 2013). For example, the hypothalamic-pituitary axis is tightly linked with and in fact mediates stress induced alterations in serotonin (see Chauloff 2013, for review); as well as norepinephrine (Swann et al. 2014) which has also been repeatedly implicated in the genesis of depression.
    THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS
    The hypothalamic, pituitary, adrenal system (HPA) is critically involved in the adaption to stressful changes in the external or internal environment. For example, in response to fear, anger, anxiety, disapointment, and even hope, the hypothalamus begins to release corticotropin releasing factor (CRF) which activates the andenohypophysis which begins secreting ACTH which stimulates the adrenal cortex which secretes cortisol (Fink, 2009).
    These events in turn appear to be under the modulating influences of norepinephrine. That is, as stress increases, NE levels decrease, which triggers the activation of the HPA axis. As is well known, low levels of NE are associated with depression.
    {http://brainmind.com/images/HYPOTHLamus1005.jpg}
    {http://brainmind.com/images/Pituitary33.jpg} Normally, cortisol secretion is subject to the tonic influences of NE; whereas cortisol can indirectly reduce NE synthesis. Thus a feedback system is maintained via the interaction of these substances (in conjuction with ACTH). Moreover, cortisol and NE levels fluctuate in reverse, and thus maintain a reciprocal relationship with the circadian rhythm; i.e. in oppositional fashion they increase and then decrease throughout the day and evening.
    Among certain subgroups suffering from depression, it appears that this entire feedback regulatory system and thus the HPA axis is disrupted (Carrol et al. 1976; Sachar et al. 1973). This results in the hypersecretion of ACTH and cortisol with a corresponding decrease in NE; which results in NE induced depression. It was these findings which led to the development of the Dexamethasone suppression test over 25 years ago.
    Via the administration of Dexamethasone (a synthetic corticosteroid) it was determined that many depressed individuals have excess cortisol, and an increased frequency of cortisol secretory episodes (Carrol et al. 1976; Sachar et al. 1973; Swann et al. 2014). Moreover, those who demonstrate excess cortisol were found to respond to NE potentiating agents, whereas those who were depressed but with normal cortisol, responded best to serotonin potentiating compounds (Van Pragg 1982).
    It is also noteworthy that dexamethason nonsuppression rates are increased in mania; specifically "mixed manic" states which consist of lability, grandiosity, and lability superimposed over depression (see Swann et al. 2014). These "mixed manic" individuals also display elevated NE levels but respond poorly to lithium and show higher levels of cortisol during the depressed phase of their illness (Swann et al. 2014).
    As noted, the hypothalamus may greatly influence circadian activities within the midbrain and pons, and thus the rhythmical secretion of various neurotransmitters. For example, corticotropin-releasing factor acts directly on the locus coeruleus (Valentino et al. 1983) which manufactures NE, and on the raphe thereby influencing serotonin release. These findings suggest a disturbance in circadian or rhythmical control of hypothalamic and midbrain-pontine activity can give rise to depression, or mixed mania in some individuals; women in particular.
    {http://brainmind.com/images/StressHypothalam.jpg}
    Lateralization.
    Although scant, there is some evidence which suggests that the right hypothalamus may be more heavily involved in the control of neuroendocrine functioning, particularly in females. Females are also far more likelyt to suffer from depression and from SADs. Moreover, right cerebral dysfunction can reduce NE levels in both the right and left hemisphere (Robinson 1979). Greater right hypothalamic concentration of substances such as LHRH (luteinizing hormone) has also been reported (Gerendai, 1984), which in turn is a "female" hormone involved in lactation and pregnancy.
    PSYCHIC MANIFESTIONS OF HYPOTHALAMIC ACTIVITY: THE ID
    Phylogenetically and from an evolutionary perspective, the appearance and development of the hypothalamus predates the differentation of all other limbic nuclei, e.g., amygdala, septal nucleus, hippocampus (Andy & Stephan, 1961; Brown, 1983; Herrick, 1925; Humphrey, 1972). It constitutes the most primitive, archaic, reflexive, and purely biological aspect of the psyche.
    Biologically the hypothalamus serves the body tissues by attempting to maintain internal homeostasis and by providing for the immediate discharge of tenions in an almost reflexive manner. Hence, as based on studies of lateral and medial hypothalamic functioning, it appears to act reflexively, in an almost on/off manner so as to seek or maintain the experience of pleasure and escape or avoid unpleasant, noxious conditions.
    Emotions elicited by the hypothalamus are largely undirected, short-lived, being triggered reflexively and without concern or understanding regarding consequences; that is, unless chronically stressed or aroused. Nevertheless, direct contact with the real world is quite limited and almost entirely indirect as the hypothalamus is largely concerned with the internal environment of the organism. Although it receives and responds to light, it cannot "see." It has no sense of morals, danger, values, logic, etc., and cannot feel or express love or hate. Although quite powerful, hypothalamic emotions are largely undifferentiated, consisting of feelings such as pleasure, unpleasure, aversion, rage, hunger, thirst, etc.
    As the hypothalamus is concerned with the internal enviornment much of it's activity occurs outside conscious-awareness. Moreover, being involved in maintaining internal homeostasis, via, for example, it's ability to reward or punish the organism with feelings of pleasure or aversion, it tends to serve what Freud (1911) has described as the pleasure principle.
    THE PLEASURE PRINCIPLE
    The lateral and medial nuclei exert counterbalancing influences which serve to modulate activity occurring in the other. As described by Freud (1911), the pleasure principale not only serves to maximize pleasant experiences, but acts to keep the psyche as a whole free from high levels of excitation (be they pleasurable or unpleasant).
    Like the hypothalamus, the pleasure principle is present from birth and for some time thereafter the search for pleasure is manifested in an unrestricted manner and with a great deal of intensity as there are no oppositional forces (except those between the lateral and medial regions) to counter it's strivings. Indeed, higher order limbic nuclei have yet to mature.
    Functionally isolated, the hypothalamus at birth has no way of reducing tension or mobilizing the organism for any form of effective action. It is helpless. When tensions associated with immediate needs (e.g. hunger or thirst) become unpleasant the only response available to the hypothalamus is to cry and make rage-like vocalizations. When satiated, the hypothalamus can only respond with a feeling state suggesting pleasure or at least quiescence. Indeed, as is well known, for the first few months of life the infants awareness largely consists of a very restricted matrix involving tactile, visceral (hunger) and kinesthetic sensations, where emotionally the infant is capable of screaming, crying, or demonstrating very rudimentary features of pleasure, i.e. an attitude of acceptance of quiescence (McGraw, 1969; Milner, 1967; Piaget, 1952; Spitz & Wolf, 1946).
    It is only with the further differentiation and maturation of higher order limbic nuclei (e.g. amygdala, septal nucleus, hippocampus) that the infant begins to achieve some awareness of external reality and begins to form memories as well as differentiate and associate externally occurring events and individuals.
    AMYGDALA
    {http://brainmind.com/images/LimbicAmyagdala10.jpg}
    In contrast to the primitive hypothalamus, the more recently developed amygdala (the "almond") is preeminent in the control and mediation of all higher order emotional and motivational activities. Via it's rich interconnections with various neocortical and subcortical regions, amygdaloid neurons are able to monitor and abstract from the sensory array stimuli that are of motivational significance to the organism (Gaffan 1992; Gloor 1960, 1992, 2010; LeDoux 1992; Morris et al., 2012; Rolls, 1984, 1992 Steklis & Kling, 2005; Kling & Brothers 1992; Ursin & Kaada 1960). This includes the ability to discern and express even subtle social-emotional nuances such as friendliness, fear, love, affection, distruct, anger, etc., and at a more basic level, determine if something might be good to eat.
    {http://brainmind.com/images/amygdala2001.jpg}
    {http://brainmind.com/images/AmygdalaEmotionaCircuit45.jpg} In fact, amygdaloid neurons respond selectively to the flavor of certain preferred foods, as well as to the sight or sound of something that might be especially desirable to eat (Fukuda et al. 2007; Gaffan et al. 1992; O'Keefe & Bouma, 1969; Ono et al. 1980; Ono & Nishijo, 1992) including even the sight of drugs that induce extreme pleasure.
    For example, it has been shown, using positron emission tomography, that detoxified cocaine users not only respond to a cocaine video with cocaine craving, but with increased amygdala (and anterior cingulate) activity (Childress, et al., 2009).
    {http://brainmind.com/images/AmygdalaDrugs7.jpg} Belying its involvement in emotion, including the pleasure associated with cocaine usage, is the unique chemical anatomy of the amygdala, which is rich in a variety of neuropetides including enkephalins and beta-endorphins as well as opiate receptors (Atweh & Kuhar, 1977; Fallon & Ciofi, 1992; Uhl et al. 1978). In fact, of all brain regions, the greates concentration of opiate receptors is found within the human amygdala. Other chemical systems include lutenizing hormone, vasopressin, somatostatin, and corticotropin releasing factor (Fallon & Ciofi, 1992) --indications of its involvement in stress and sexuality, especially female sexuality. The primate amygdala is sexually differentiated with male and female patterns of dendritic organization and steroid activity (Bubenik & Brown, 1973; Nishizuka & Arai, 1981; see also Simerly, 1990).
    {http://brainmind.com/images/amygdala201.jpg} The amygdala is exceedingly responsive to social and emotional stimuli as conveyed vocally, through touch, sight, and via the expressions of the face (Gloor, 1992; Halgren, 1992; Kling & Brothers 1992; Morris et al., 2012; Rolls, 1984, 1992). In fact, the amygdala, as well as the overlying (and partly coextensive) temporal lobe, contains neurons which respond selectively to smiles and to the eyes, and which can differentiate between male and female faces and the emotions they convey (Hasselmo, Rolls, & Baylis, 1989, Heit et al., 1988; Kawashima, et al., 2009; Rolls, 1984). For example, the left amygdala acts to discriminate the direction of another person's gaze, whereas the right amygdala becomes activated while making eye-to-eye contact (Kawashima, et al., 2009).
    Moreover, the normal human amygdala typically responds to frightened faces by altering its activity (Morris et al., 2012), whereas injury to the amygdala disrupts the ability to recognize faces (Young, Aggleton, & Hellawell,2011). With bilateral destruction, emotional speech production and the capacity to respond appropriately to social emotionally stimuli is abolished (Lilly, Cummings, Benson, & Frankel, 1983; LeDoux, 2012; Marlowe, Mancall, Thomas,1975; Scott, Young, Calder, Hellawell, Aggleton, & Johnson, 2010; Terzian & Ore, 1955).
    {http://brainmind.com/images/insulaamygdalabrain.jpg}
    {http://brainmind.com/images/Amygdala2004.gif} Single amygdaloid neurons receive a considerable degree of topographic input, and are predominatly polymodal, responding to a variety of stimuli from different modalities simultaneously (Amaral et al. 1992; O'Keefe & Bouma, 1969; Ono & Nishijo, 1992; Perryman, Kling, & Lloyd, 2007; Rolls 1992; Sawa & Delgado, 1963; Schutze et al. 2007; Turner et al. 1980; Ursin & Kaasa, 1960; Van Hoesen, 1981). The amygdala is also very sensitive to somesthetic input and physical contact such that even a slight touch in a very circumscribed area of the body can produce amygdaloid excitation. Overall, because emotional, motivational, and multimodal assimilation of various sensory impressions occurs in this region, it is also involved in attention, learning, and memory (Gloor, 2010; Halgren, 1992; LeDoux, 2012).
    Moreover, through the massive interconnections maintained with the lateral and medial (ventromedial) hypothalamus, the amygdala is able to act directly on this structure, driving the hypothalamus, so to speak, and thus tapping into its emotional reserviour so that its ends may be met. Indeed, it is able to modulate hypothalamic activity through inhibitory and excitatory projections to this structure (Dreifuss, et al., 1968).
    {http://brainmind.com/images/LimbicCoverEbook1epub.jpg}
    {http://brainmind.com/images/ColoredLimbicSystem34.jpg}
    {http://brainmind.com/images/AmygdalaNuclei3.jpg}
    {http://brainmind.com/images/amygdalabypass.gif} Direct stimulation of the basolateral amygdala and the ventral amydalofugal pathway excites the principle neurons of the medial hypothalamus (Dreifuss, et al., 1968). By contrast, stimulation of the medial (ventro-medial) amygdala and the stria terminalis pathway, inhibits these same hypothalamic neurons (Dreifuss, et al., 1968). Hence, whereas the lateral amydala exerts excitatory influences on the hypothalamus, the medial amygdala exerts inhibitory influences, and can thus control, or at least exert excitatory/inhibitory and thus modulatory influences on hunger, thirst, sexual arousal, rage, etc., as well as hormonal, endocrine, and other functions associated with the hypothalamic nuclues (Dreifuss, et al., 1968; Joseph, 1992a; Gloor, 2010). Indeed, the amygdala can be likened to the chief executive of the limbic system and weilds enormous power via its control over the hypothalamus.
    For example, in the cat and monkey, stimulation of the border area between the lateral and medial hypothalamus can trigger aggressive defensive reactions (De vito & Smith, 1982; Hess, 1949). As indicated by radioactive tracers, both the lateral and medial amygdala projection to this area (De vito & Smith, 1982). And, when the amygdala is electrically activated, the hypothalamus becomes activated (Dreifuss, et al., 1968), and defensive and aggressive reactions can be triggered.
    However, this system is also interactional, especially in regard to sexual activity, fear, anger, hunger, and stress. For example, the hypothalamus can stimulate the amygdala which may then survey the environment so that internal needs may be met, and/or they may act in concert regarding sexual behavior, the stress response, and so on.
    OVERVIEW: AMYGDALA STRUCTURAL FUNCTIONAL ORGANIZATION
    The amygdala is buried within the depths of the anterior-inferior temporal lobe and consists of several major nuclear groups including what has been referred to as the "extended amygdala." These include the cortical-medial, central, paralaminar, lateral, basal, and acessory basal nucleus (Amaral et al., 1992; Stephan & Andy, 1977). Different authors propose different divisions and link them differently. For example, Stephan and Andy (1977) assign the cortical division to the basolateral amydala, and the central division to the medial division. Price et al., (1977) subdivided the amygdala into basolateral, corticomedial and central amygdaloid nuclei. Others propose yet different schemes.
    {http://brainmind.com/images/Amygdala222.jpg} For our purposes we will primarily focus on the "medial" and the basolateral subdivisions. The phylogenetically ancient medial group (or cortico-medial amygdala) is involved in olfaction, sexual, and motor activity (via its interconnections with the striatum), and the relatively newer basolateral division (lateral amygdala) is most fully developed in primates and humans (Amaral et al. 1992; Herrick, 1925; Humphrey, 1972; McDonald 1992; Stephan & Andy, 1977). Of its various subdivisions, the basolateral amygdala is the most "cortex-like. However, being allocortex it contains three layers (vs 7 for the neocortex) with layer 2 containing pyramidal neurons which rely on excitatory neurotransmitters, e.g., glutamate--whereas the local-circuit (interneurons) rely on the inhibitory transmitters, e.g., GABA (Fallon & Ciofi, 1992).
    The lateral amydala utilizes the ventral amygdalofugal pathway and less so the stria terminalis to influence the hypothalamus. The lateral amygdala also relies on the medial forebrain bundle which is the pathway subserving the pleasure circuit (Olds & Forbes, 1981). By contrast, the medial amygdala relies on the stria terminalis, and less so the amygdalofugal pathway to influences the hypothalamus. Through these pathways, these diferent subdivions of the amygdala can act to modulate activity in the hypothalamus, septal nuclei, and other subcortical structures (Amaral et al. 1992; Stephan & Andy, 1977).
    Evolution & Embryology
    In humans, the right amygdala is also larger than the left amygdala, with the basolateral portion contributing to most of this asymmetry (Murphy et al., 2007). Moreover, over the course of evolution, and in the transition from amphibians to reptiles, to mammals and then humans, the basolateral amygdala appears to have grown the most in size as compared to other amygdaloid nuclei (Stephan & Andy, 1977)--that is, when considered only in regard to its subtemporal diminsions. However, it also appears that the medial amygdala may have contributed to the evolution of the piriform cortex, and then the evolution of the 4 to 5 layered mesocortex, which when layered upon the 3-layered allocortical piriform cortex, gave rise to the neocortex of the temporal lobe. Hence, the expansion of the medial amydala may not be apparent as that expansion is represented as mesocortex and neocortex.
    Moreover, it appears that the medial group was broken up over the course of evolution such that structures such as the claustrum (Gilles et al., 1983), became separated and is now situated beneath the auditory cortex of the superior temporal lobe. Indeed, the claustrum which is very cortical in organization, may well act as an interface between the auditory cortex and the amygdala, processing and relaying auditory impulses to and fro, and may have, in addition to the medial amygdala, contributed to the evolution of the auditory cortex.
    {http://brainmind.com/images/LimbicAmyagdala11.jpg}
    {http://brainmind.com/images/LimbicAmyagdala12.jpg} The amygdala, therefore, has definitely increased in size over the course of evolution (Stephan & Andy, 1977), and has become increasingly cortical, has contributed to the evolution of mesocortex and neocortex (which is thus a cortical extension of the neocortex, maintaining extensive interconnections). In addition, the right amygdala is larger than the left (Murphy et al., 2007) which in turn may contribute to right hemisphere dominance for emotion (chapter 10).
    Intrinsic & Extrinsic Organization: The Flow of Information
    Like the lateral and medial hypothalamus, the medial and basolateral (hereafter referred to as the lateral) amygdaloid nuclei subserve different functions and maintain different anatomical interconnections (Amaral et al., 1992; Stephan & Andy, 1977). And, they can be subdivided into additional subnuclei. As noted, they also contain pyramidal neurons which are excitatory (Rolls, 1992) and use glutamate (Fallon & Ciofi, 1992) and which project throughout the neocortex as well as to the hippocampus (Amaral et al., 1992).
    Local circuit neurons are mostly stellate-like and chandelier cells, which account for about 30% of the amydala's neurons and which use the inhibitory transmitter GABA (Fallon & Ciofi, 1992). Considered rather broadly and simplistically, these local circuit neurons are organized in such a fashion that they appear to project information from the the lateral to the basal amygdala, and from the lateral basal to the medial and central amygdala which transmits, via pyramid and local-circuit neurons to the uncus, piriform cortex, medial temporal cortex, entrohinal cortex, anterior hippocampus, and via pyramidal neurons to the striatum, the septal nuclei, hypothalamus, cingulate, medial dorsal nucleus of the thalamus, brainstem, and throughout the frontal and temporal lobes (Amarral et al., 1992; Krettek & Price, 1978; Stephan & Andy, 1977; van Hoesen, et al., 1981). However, the lateral amygdala also projects to the septal nuclei, hypothalamus, corpus striatum, dorsal medial thalamus, brainstem, and throughout the neocortex via pyramidal axons (Amaral et al, 1992; Carlsen et al. 1982; Gloor, 1955; McDonald 1992; Russchen, 1982; Swanson & Cowan, 1979).
    {http://brainmind.com/images/AmygdalaOutputs2.jpg} It appears that much of the input from the neocortex is directed at the lateral amygdala (the exception being auditory cortex which also projects to the medial amygdala). Hence, in certain respects, at least at the level of the neocortex, it appears that there is an almost circular stream of activity, from lateral/basal to medial/central to neocortex to lateral/basal. However, subcortically, both the lateral and medial project to many of the same exact structures, often providing counterbalancing excitatory/inhibitory influences.
    Moreover, as detailed in chapter 12, the amygdala receives significant projections directly from the olfactory bulb. In act, "the olfactory system is the only sensory system in which first- and second-order central sensory neurons project directly to the amygdala" (Goor, 2010). Moreover, it receives projections from the gustatory system. Smell and taste thus converge in the amygdala, which may explain why some patients with temporal lobe epilepsy experience terrible odors and tasts as part of the aura which announces the onset of a seizure.
    {http://brainmind.com/images/AmygdalaPathways130.jpg} In addition, the secondary and in particular the association and multi-modal assimilation areas, including the orbital frontal lobe, project directly to the amygdala (Amaral et al, 1992; Carlsen et al. 1982; Gloor, 1955; Krettek & Price, 1978; McDonald 1992; Russchen, 1982; Swanson & Cowan, 1979; Stephan & Andy, 1977). In addition, as is evident from dissecting the human brain, the amygdala maintains significant reciprocal connections with the primary auditory area and Wernicke's area--and similar projections are evident in primates (Amaral et al., 1992). Hence, this structure receives simple and complex auditory, as well as fully formed perceptions from the neocortex which feeds the amygdala this information which it then analyzes for social, sexual, gustatory, and emotional significance.
    The Amygdala-Striatum
    Emybryologically, the medial amygdala is the first portion of the basal ganglia (limbic) striatal complex to appear during development, being formed via neuroblast migration from the epithilium of the lateral ventricle (Humphrey, 1972). Specifically, around the sixth week of fetal development immature neuroblasts migrate in massive numbers from the ventricular lining, and congregate in the more caudal portion of the emerging forebrain, thus forming an arc shaped "striatal ridge" from which the primordial amygdala and striatum will emerge (Gilles et al., 1983; Humphrey, 1968).
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    Approximately one week after the formation of the amygdala, this primordial amygdala-striatum begins to differentiate and balloon outward to also create the striatum. That is, both the striatum and amygdala are derived from the arc shaped "striatal ridge," the caudal portion giving rise to the primordial amgydala at about the 6th week of gestation, and the basal portion later giving rise to the primordial striatum which initially overlies and is contiguous with the amygdala (Gilles et al., 1983; Humphrey, 1968).
    {http://brainmind.com/images/AmygdalaStriatum32.gif} Thus initially these structures are contiguous. However, over the ensuing weeks, these structures are pushed apart as the forebrain and its interconnections form. However, although they are pushed apart and may even break up into semi-separate islands (or rather, penninsulas) the amgydala maintains connnections with what is referred to as the "extended amygdala," i.e., the limbic striatum (Heimer & Alheid, 1991) and through what is called the "tail of the caudate" maintains massive interconnections with the corpus striatum
    Specifically, the tail of the caudate nucleus (as it circles in an arc from the frontal to temporal lobe) terminates and merges with the medial and in particular, the lateral amygdala. Hence, the lateral amygdala has also been referred to the "striatum limitans, and the "striatum accessorium" (Gloor, 2010).
    By contrast,the medial amygdala (or rather, the central division of the medial amygdala, central-medial amygdala) extends almost imperceptibly around the fundus of the entorhinal sulcus, and merges with the substantia innominata of the limbic striatum. The amygdala, therefore, is in fact part of the basal ganglia and is heavily involved in motivating and coordinating gross, or whole body motor activity via the striatum (Heimer & Alheid, 1991; Mogenson & Yang, 1991).
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    THE MEDIAL AMYGDALA
    The medial amygdala receives fibers from the olfactory tract, and via a rope of fibers called the stria terminalis projects directly to and receives fibers from the medial hypothalamus (via which it exerts inhibitory influences) as well as the septal nucleus (Amaral et al, 1992; Carlsen et al. 1982; Gloor, 1955; McDonald 1992; Russchen, 1982; Swanson & Cowan, 1979). The stria terminals is significantly larger and thicker in males vs females (Allen & Gorksi 1992) which suggests that information and impulse exchange (or inhibition) between the hypothalamus and amygdala is different in men vs women. Moreover, in humans, the amygdala in general is large in males than in females, and in primates, the medial amygdala is sexually differentiated (Nishizuka & Arai, 1981; see also Simerly, 1990), such that the male amygdala contains a greater number of synaptic connections and shows different patterns of steroidal activity (Nishizuka & Arai, 1981; Simerly, 1990). In fact, the human amygdala is 16% larger in the male in total volume (Filipek, et al., 2014) whereas in male rats, the medial amygdala is 65% larger than the female amygdala and grows or shrinks in the presence of testosterone (Breedlove & Cooke, 2009).
    The female medial amygdala is a principle site for uptake of the female sex hormone, estrogen, and contains a high concentration of leutenizing hormones (Stopa et al., 1991) which are important during pregnancy and nursing. In fact, the female medial amygdala fluctuates immunoreactive activity during estrus cycle, being highest during proestrus (Simerly, 1990). Moreover, the medial amygdala projects directly to the ventromedial hypothalamus and the preoptic area of the hypothalamus which, as noted above, are sexually differentiated (e.g. Allen et al., 1989; Gorski, et al., 1978; Le Vay, 1991; Raisman & Field, 1971), and which when activated produce sex specific behaviors (Hart et al., 2005; Lisk, 1967, 1971; MacLean, 1973) and, in primates, even maternal behavior (Numan, 2005). These amygdala to hypothalamic synapses are excitatory.
    {http://brainmind.com/images/AmygdalaNuclei3.jpg}
    Because the medial amygdala is sexually differentiated, and through its massive connections with the hypothalamus and preoptic area, as well as the striatum which controls gross motor and limb movements, when activated, male vs female sexual behavior can be triggered. These amygdala-induced sexual behariors include sexual posturing, penile erection and clitoral tumenence (Kling and Brothers, 1992; MacLean, 1990; Robinson and Mishkin, 1968; Stoffels et al., 1980), thrusing, sexual moaning, ejaculation, as well as ovulation, uterine contractions, lactogenetic responses, and orgasm (Backman and Rossel, 1984; Currier, Little, Suess and Andy, 1971; Freemon and Nevis,1969; Warneke, 1976; Remillard et al., 1983; Shealy and Peel, 1957).
    In addition, the medial (and lateral) regions are rich in cells containing enkephalins, and opiate receptors can be found throughout the amygdala (Atweh & Kuhar, 1977; Fallon & Ciofi, 1992; Uhl et al. 1978) and the amygdala becomes exceedingly active when experiencing a craving for pleasure inducing drgus, such as cocaine (Childress et al., 2009). In this regard, the amygdala is capable of inducing extreme feelings of pleasure as well as motivating the individual to engage in pleasure-seeking behaviors such as sexual activity.
    LATERAL AMYGDALA
    With the evolutionary ascent of primates the lateral division of the amygdala progressively expands and differentiates. The lateral amygdala contributes fibers to the stria terminalis and gives rise to the amygdalofugal pathway via which it projects to the lateral and medial hypothalamus (upon which it exerts inhibitory and excitatory influences respectively), the dorsal medial thalamus (which is involved in memory, attention and arousal), the limbic and corpus striatum, as well as other subcortical regions including the brinstem (Aggleton et al. 1980; Amaral et al. 1992; Carlsen et al. 1982; Dreifuss et al., 1968; Gloor, 1955, 1960, 2010; Klinger & Gloor, 1960; McDonald 1992; Mehler, 1980; Russchen, 1982). Lateral amygdala brainstem projection pathways include the dopamine producing substantia nigra, the vocalizing periaqueductal gray, the pontine tegmentum which includes and area that triggers the startle response (Amaral et al., 1992; Davis et al., 2010) as well as visceral nuclei such as those controlling blood pressure, respiration, vosodilation and constriction and so on. It also sends some fibers into the spinal cord, where they travel along with those of the pyramidal tract (Amaral et al., 1992). It also receives fibers from the medial forebrain bundle which in turn has it's site of origin in the lateral hypothalamus (Mehler, 1980).
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    In general, whereas the medial amygdala is highly involved in motor, olfactory and sexual functioning, the lateral division is intimately involved in all aspects of emotional activity. Hence, it's rich interconnections with the lateral and medial hypothalamus, and the neocortex and those brainstem centers controlling the visceral aspects of affective-motor behavior.
    {http://brainmind.com/images/InputAmygdala13.jpg} The lateral amygdala maintains rich interconnections with the inferior, middle, and superior temporal lobes, as well as the insular temporal region, which in turn allows it to sample and influence the auditory, somesthetic, and visual information being received and processed in these areas, as well as scrutinize this information for motivational and emotional significance (Gloor 1992; Herzog & Van Hoesen 1976; Kling et al., 2007; Machne & Segundo, 1956; Mesulam & Mufson, 1982; O'Keefe & Bouma, 1969; Rolls 1992; Steklis & Kling, 2005; Turner et al., 1980; Van Hoesen, 1981). Gustatory and respiratory sense are also re-represented in this vicinity (Amaral et al. 1992; Fukuda et al., 2007; Maclean, 1949; Ono et al., 1980) as is the capacity to influence (via sensory analysis) food and water intake. The lateral division also maintains rich interconnections with cingulate gyrus, orbital and medial frontal lobes and the parietal cortex (Amaral et al. 1992; McDonald 1992; O'Keefe & Bouma, 1969; Pandya et al. 1973) through which it able to influence emotional expression and receive complex somesthetic information.
    The lateral amygdala is highly important in analyzing information received and transferring information back to the neocortex so that further elaboration may be carried out at the neocortical level. It is through the lateral division that emotional meaning and significance can be assigned to as well as extracted from that which is experienced.
    The amygdala, overall, maintains a functionally interdependent relationship with the hypothalamus. It is able to modulate and even control rudimentary emotional forces governed by the hypothalamic nucleus. However, it also acts as the behest of hypothalamically induced drives. For example, if certain nutritional requirements need to be meet, the hypothalamus signals the amygdala which then surveys the external enviornment for something good to eat or drink.
    On the other hand, if the amygdala via environmental surveilance were to discover a potentially threatening stimulus, it acts to excite and drive the hypothalamus so that the organism is mobilized to take appropriate action. as noted, direct stimulation of the basolateral amygdala and the ventral amydalofugal pathway excites the principle neurons of the ventromedial hypothalamus (Dreifuss, et al., 1968). When the hypothalamus is activated by the amygdala, instead of responding in an on/off manner, cellular activity continues for an appreciably longer time period (Dreifuss et. al. 1968; Rolls 1992). The amygdala can tap into the reservoir of emotional energy mediated by the hypothalamus so that certain ends may be attained.
    ATTENTION
    The amygdala acts to perform environmental surveilance and can trigger orienting responses as well as mediate the maintanance of attention if something of interest or importance were to appear (Gloor, 1955, 1960, 1992; Kaada, 1951; Kapp et al., 1992; Rolls 1992; Ursin & Kaasa, 1960).
    In part, the attention response can be triggered by amygdala activation of the brainstem, frontal lobes, and the dorsal medial nucleus (DMN) of the thalamus, each of which is implicated in arousal (see chapter 19). The DMN, for example, in conjunction with the frontal lobe, acts to gate and regulate the flow of information destined for the neocortex (Joseph, 2009a). The amydala, being provided thalamic, brainstem, as well as neocortical input (as well as projecting to these nuclei), is therefore able to directly influence the DMN so that attention can be directed to particular percepts (and emotional significance attached). In fact, the projections of the amygdala to extend well beyond the DMN, but extends throughout the thalamus (Aggleton et al., 1980; LeDoux, 2012; McDonald, 1992; Russchen, 1982), as well as throughout the neocortex .
    Electrical stimulation of the lateral amygdala, therefore, can initiate quick and/or anxious glancing and searching movements of the eyes and head such that the organism appears aroused and highly alert as if in expectation of something that is going to happen (Halgren 1992; Kapp et al., 1992; Ursin & Kaasa, 1960). The EEG becomes desynchronized (indicating arousal), heart rate becomes depressed, respiration patterns change, and the galvanic skin response significantly alters (Bagshaw & Benzies, 1968; Kapp et al. 2014; Ursin & Kaada, 1960) and the animal may freeze (Gloor, 1960; Kapp et al., 1992) -- reactions which characteristically accompany the orienting response of most species.
    Once a stimulus of potential interest is detected, the amygdala then acts to analyze its emotional-motivational importance and will act to alert other nuclei such as the hypothalamus, brainstem, and striatum, so that appropriate action may take place.
    FEAR, RAGE & AGGRESSION
    Initially, electrical stimulation of the amygdala produces sustained attention and orienting reactions. If the stimulation continues the subject may begin to experience, wariness, fear and/or rage (Cendes et al. 2014; Davis et al., 2010; Gloor 1992; Halgren 1992; LeDoux, 2012; Rosen & Schulkin, 2012; Ursin & Kaada, 1960). When fear follows the attention response, the pupils dilate and the subject will cringe, withdraw, and cower. This cowering reaction in turn may give way to extreme fear and/or panic such that the animal will attempt to take flight.
    {http://brainmind.com/images/AmygdalaActivation.jpg} Among humans, the fear response is one of the most common manifestations of amygdaloid electrical stimulation and abnormal activation (Davis et al., 2010; Gloor, 1992, Halgren, 1992; LeDoux, 2012; Rosen & Schulkin, 2012). Moreover, unlike hypothalamic on/off emotional reactions, attention and fear reactions can last up to several minutes after the stimulation is withdrawn.
    In addition to behavioral manifestations of heightened emotionality, amygdaloid stimulation can result in intense changes in emotional facial expression. This includes crying and facial contortions such as baring of the teeth, dilation of the pupils, widening or narrowing of the eye-lids, flaring of the nostrils, as well as sniffing, licking, and chewing (Anand & Dua, 1955; Ursin & Kaada, 1960). Indeed, some of the behavioral manifestations of a seizure in this vicinity (i.e. temporal lobe epilepsy) typically include throat and mouth movements, including chewing, smacking of the lips, licking, and swallowing--a consequence, perhaps of amygdala activation of the brainstem periaqueductal gray and nuclei subserving mastication.
    In many instances patients or animals will react defensively and with anger, irritation, and rage which seems to gradually build up until finally the animal or human will attack (Egger & Flynn, 1963; Gunne & Lewander, 1966; Mark et al., 1972 Ursin & Kaada, 1960; Zbrozyna, 1963). Unlike hypothalamic "sham rage", amygdaloid activation results in attacks directed at something real, or, in the absence of an actual stimulus, at something imaginary. There have been reported instances of patient's suddenly lashing out and even attempting to attack those close by, while in the midst of a temporal lobe seizure (Saint-Hilaire et al., 1980), and/or attacking, kicking, and destroying furniture and other objects (Ashford et al., 1980).
    Moreover, rage and attack will persist well beyond the termination of the electrical stimulation of the amygdala. In fact, the amygdala remains electrophysiologically active for long time periods even after a stimulus has been removed (be it external-perceptual, or internal-electrical) such that is appears to contine to process--in the abstract--information even when that information is no longer observable (O'Keefe & Bouma, 1969).
    The amygdala, in addition to sustained electrophysiological activity, has been shown to be heavily involved in the maintenance of behavioral responsiveness even in the absence of an immediately tangible or visible objective or stimulus (O'Keefe & Bouma, 1969). This includes motivating the organism to engage in the seeking of hidden objects or continuing a certain activity in anticipation of achieving some particular long term goal. At a more immediate level, the amygdala is probably very important in object permanance (i.e. the keeping of an object in mind when it is no longer visible) and concrete or abstract anticipation. Anticipation is, of course, very important in the prolongation of emotional states such as fear or anger, as well as the generation of more complex emotions such as anxiety. In this regard, the amygdala is probably important not only in regard to emotion, but in the maintanance of mood states.
    Fear and rage reactions have also been triggered in humans following depth electrode stimulation of the amygdala (Chapman, 1960; Chapman et al., 1954; Heath et al. 1955; Mark et al. 1972). Mark et al. (1972) describe one female patient who following amygdaloid stimulation became irritable and angry, and then enraged. Her lips retracted, there was extreme facial grimmacning, threatening behavior, and then rage and attack--all of which persisted well beyond stimulus termination.
    Similarly, Schiff et al. (1982) describe a man who developed intractable aggression following a head injury and damage (determined via depth electrode) to the amygdala (i.e. abnormal electrical activity). Subsequently, he became easily enraged, sexually preoccupied (although sexually hypoactive), and developed hyper-religiosity and psuedo-mystical ideas. Tumors invading the amygdala have been reported to trigger rage attacks (Sweet et al. 1960; Vonderache, 1940).
    The amygdals appears capable of not only triggering and steering hypothalamic activity but acting on higher level neocortical processes so that individuals form emotional ideas . Indeed, the amygdala is able to overwhelm the neocortex and the rest of the brain so so that the person not only forms emotional ideas but responds to them, sometimes with vicious, horrifying results. A famous example of this is Charles Whitman, who in 1966 climbed a tower at the University of Texas and began to indiscriminantly kill people with a rifle (Whitman Case File # M968150. Austin Police Department, Texas, The Texas Department of Public Safety, File #4-38).
    Case Study in Amygdala-Aggression: Charles Whitman
    Charles Whitman was born on June 24, 1941 and even before entering grade school had shown exceptional intellectual promise, was well liked by neighbors and had already shown some mastery of the piano, which he "loved to play." At the age of six he was administered the Stanford Binet tests of intellectual ability and obtained an IQ of 138; thus scoring at the 99.9% rank. He also became enamored by guns; his father being described as a gun fanatic. According to his father, "Charlie could plug a squirrel in the eye by the time he was sixteen." However, Charlie loved animals, was somewhat religiously oriented as a child, was very athlectic, was described as "handsome" and "fun" and "high spirited" and was in many respects the "all American boy." He became an Eagle Scout at age 12, and receiving national recognition as being the youngest Eagle Scout in the world. Within 15 months he had earned 21 merit badges. While in high school he continued these activites, also pitching for the baseball team and managing the football team. After high school he joined the Marines and was described as "the kind of guy you would want around if you went into combat." It was while in the Marines that he got married, and it was during this period that began to show the first subtle signs that something might be amiss.
    He began having occassional bursts of anger. He threatened to "kick the teeth out" of another Marine, was court marshalled, consigned to the brig for 30 days, and reduced in rank. He also began taking copious notes, and developed what is referred to as "hypergraphia" excessive writing--a disturbance associated with the amygdala (Joseph, 2009b).
    Incessantly he began to write and leave himself notes, ranging from the mundane, to the tremendous love he felt for his wife. "Received a call from Kathy... it was fabulous, she sounds so wonderful. I love her so much... I will love her to the day I die. She is the best thing I have in life. My Most Precious Possession."
    {http://brainmind.com/images/CharlesWhitman24.jpg}
    Increasingly, however, he was having trouble with his temper and composed notes offering self-advice as to how to control his growing temper and rage attacks. "CONTROL your anger" he wrote, "Don't let it prove you the fool. SMILE--Its contagious. DON'T be belligerent. STOP cursing. CONTROL your passion; DON'T LET IT lead YOU."
    On February 4, 1964, he purchased a diary. According to Charles: "I opened this diary of my daily events as a result of the peace of mind or release of feelings that I experienced when I started making notes of my daily events...."
    Nevertheless, he also continued to excell and although he had been Court marshalled, he also won a scholarship to attend the University of Texas and to attend classes while still in the Marines. He also became increasingly religious and would often have discussions with his school mates about the nature of God--hyperreligiousness also being associated with an abnormality involving the amygdala (see chapter 9). And, although he was attending classes, he also began to perform volunteer work, while simultaneously holding a part time job, and at times felt overwhelmed with energy, almost manic--mania also being associated with the amygdala (Strakowski et al., 2009) as well as the frontal lobes (Joseph, 1986a, 1988a, 2009a). And, he continued to be well liked and admired. His supervisor at the bank, E. R. Hendricks, described Charles "as a truly outstanding person. Very likeable. Neat. Nice looking... A great guy."
    However, Charles also began suffering terrible headaches, and one day lost his temper in class, pulling a male student bodily from his chair and tossing him from the classroom. Apparently he felt considerable remorse. He also continued to have frequent bouts of anger and on occasion, difficulty concentrating, and was beginning to over eat--increased food consumption being associated with a disturbance of the hypothalamus. Moreover, he began having periods where he couldn't sleep for days at a time--yet another disturbance associated with the hypothalamus, a major sleep center. Charles also realized that something was wrong, and continued writing copious notes to himself, reminding himself to be nice, to control his apetitite, and especially to control temper. But his temper was getting out of control and Charles was gaining weight.
    A close friend, Elaine Fuess, also noticed that something was amiss. "Even when he looked perfectly normal, he gave you the feeling of trying to control something in himself. He knew he had a temper, and he hated this in himself. He hated the idea of cruelty in himself and tried to suppress it."
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    Charles Whitman finally sought professional help and consulted a staff psychiatrist, at the University of Texas Health Center about his periodic and uncontrollable violent impulses. Charles was referred to Dr. Heatly. According to the report written by Dr. Heatly about his session with Whitman, a report which was distributed to the media: "This massive, muscular youth seemed to be oozing with hostility as he initiated the hour with the statement that something was happening to him and he didn't seem to be himself...." Whitman "could talk for long periods of time and develop overt hostility while talking, and then during the same narration show signs of weeping.... Past history revealed a youth who... grew up in Florida where his father was a very successful plumbing contractor... who achieved considerable wealth. He identified his father as being brutal, domineering, and extremely demanding of the other three members of the family." Whitman "married four or five years ago, and served a hitch in the Marines.... He referred to several commendable achievements during his Marine service, but also made reference to a court martial for fighting which resulted in being reduced several grades to private. In spite of this he received a scholarship to attend the University for two years and remained a Marine at the same time... He expressed himself as being very fond of his wife, but admitted that he had on two occasions assaulted his wife physically. He said he has made an intense effort to avoid losing his temper with her... His real concern is with himself at the present moment. He readily admits having overwhelming periods of hostility with a very minimum of provocation... he... also... made vivid reference to thinking about going up on the tower with a deer rifle and start shooting people. ....He was told to make an appointment for the same day next week."
    Instead, Charles apparently decided to climb the tower and to begin killing people. But not before first contacting the police and asking to be arrested. As Charles had not committed a crime, the desk sergeant instead suggested that he see a psychiatrist.
    Several days prior to climbing the tower, Charles Whitman wrote himself a letter:
    "I don't quite understand what it is that compels me to type this letter.... I don't really understand myself these days... Lately I have been a victim of many unusual and irrational thoughts. These thoughts constantly recur, and it requires a tremendous mental effort to concentrate. I consulted Dr. Cochrum at the University Health Center and asked him to recommend someone that I could consult with about some psychiatric disorders I felt I had.... I talked to a doctor once for about two hours and tried to convey to him my fears that I felt overcome by overwhelming violent impulses. After one session I never saw the Doctor again, and since then I have been fighting my mental turmoil alone, and seemingly to no avail. After my death I wish that an autopsy would be performed to see if there is any visible physical disorder. I have had tremendous headaches in the past and have consumed two large bottles of Excedrin in the past three months."
    On August 1, 1966, one day before climbing the tower at the University of Texas, Charles Whitman paid a visit to his mother, who greeted him outside her penthouse and introduced him to the night watchman who noticed that Charles was carrying a big black attache case. According to police reports, Charles must have immediately attacked his mother after they entered the penthouse, and then brutally beat, strangled, and stabbed her to death, crushing the back of her head, smashing her hands, and stabbing her in the chest with a huge hunting knife.
    Later, neighbors told police that the only sounds they heard were that of a "child crying and whimpering," which they found puzzling as no child lived in the penthouse.
    After brutally murdering his mother, Charles cleaned up the mess, and placed her in bed with a notepad laying across and covering up the massive wound in her chest. Charles had left a note. It read: "To Whom It May Concern: I have just taken my mother's life. I am very upset over having done it. However, I feel that if there is a heaven she is definitely there now... I am truly sorry... Let there be no doubt in your mind that I loved this woman with all my heart."
    After killing his mother, Charles returned home, planning on killing his wife "as painlessly as possible.," as he explained in yet another note:
    "It was after much thought that I decided to kill my wife, Kathy, tonight....I love her dearly, and she has been a fine wife to me as any man could ever hope to have. I cannot rationally pinpoint any specific reason for doing this..."
    Apparently she was sleeping, and after removing the blankets to expose her nude body, he viciously stabbed her repeatedly with his huge hunting knife, leaving five gaping holes in her chest. She died instantly.
    Charles wrote another note which he left with the body: "I imagine it appears that I brutally killed both of my loved ones. I was only trying to do a quick thorough job... If my life insurance policy is valid please pay off my debts... donate the rest anonymously to a mental health foundation. Maybe research can prevent further tragedies of this type."
    And then he added a post script beneath his signature: "Give our dog to my in-laws. Tell them Kathy loved "Schoci" very much."
    {http://brainmind.com/images/WhitmanTexasTower.jpg} The next morning Charles Whitman climbed the University tower carrying several guns, a sawed off shotgun, and a high powered hunting rifle, and for the next 90 minutes he shot at everything that moved, killing 14, wounding 38.
    He was finally killed by a police sharp shooter.
    {http://brainmind.com/images/Whitmandead4.jpg} Post-mortem autopsy of his brain revealed a glioblastoma multiforme tumor the size of a walnut, erupting from beneath the thalamus, impacting the hypothalamus, extending into the temporal lobe and compressing the amygdaloid nucleus (Charles J. Whitman Catastrophe, Medical Aspects. Report to Governor, 9/8/66).
    DOCILITY & AMYGDALOID DESTRUCTION
    Bilateral destruction of the amygdala usually results in increased tameness, docility, and reduced aggressiveness in cats, monkeys and other animals (Schreiner & Kling, 1956; Weiskrantz, 1956; Vochteloo & Koolhaas, 2007), including purportedly ferocious creatures such as the agoutie and lynxe (Schreiner & Kling, 1956). In man, bilateral amygdala destruction (via neurosurgery) has been reported to reduce and/or eliminate paroxysmal aggressive and violent behavior (Terzian & Ore, 1955).
    In some creatures, however, bilateral ablation of the amygdala has been reported to al least initially result in increased aggressive reponding (Bard & Mountcastle, 1948), and if sufficiently aroused or irritated, even the most placid of amygdalectomized animals can be induced to fiercely fight (Fuller et al. 1957).
    However, these aggressive responses are very short-lived and appear to be reflexively mediated by the hypothalamus. Hence, these findings (and the data reviewed above) suggests that true aggressive feelings including violent moods, are dependent upon activation of the amygdala.
    SOCIAL-EMOTIONAL AGNOSIA
    Among primates and mammals, bilateral destruction of the amygdala significantly disturbs the ability to determine and identify the motivational and emotional significance of externally occuring events, to discern social-emotional nuances conveyed by others, or to select what behavior is appropriate given a specific social context (Bunnel, 1966; Fuller et al. 1957; Gloor, 1960; Kling & Brothers 1992; Kluver & Bucy, 1939; Lilly et al., 1983; Marlowe et al., 1975; Scott et al., 2010; Terzian & Ore, 1955; Weiskrantz, 1956). Bilateral lesions lower responsiveness to aversive and social stimuli, reduce aggressiveness, fearfullness, competitiveness, dominance, and social interest (Rosvold et al. 1954). This condition is so pervasive that subjects have tremendous diffficulty discerning the meaning or recognizing the significance of even common objects -- a condition sometimes referred to as "psychic blindness", or, the "Kluver-Bucy syndrome" (Lilly et al., 1983; Marlowe et al., 1975; Terzian & Ore, 1955).
    Thus, animals with bilateral amygdaloid destruction, although able to see and interact with their environment, may respond in an emotionally blunted manner, and seem unable to recognize what they see, feel, and experience. Things seem stripped of meaning. Like an infant (who similarly is without a fully functional amygdala), individuals with this condition engage in extreme orality and will indiscriminantly pick up various objects and place them in their mouth regardless of its appropriateness. There is a repetitive quality to this behavior, for once they put it down they seem to have forgotten that they had just explored it, and will immediately pick it up and place it again in their mouth as if it were a completely unfamiliar object.
    Although ostensibly exploratory, there is thus a failure to learn, to remember, to discern motivational significance, to habituate with repeated contact, or to discriminate between appropriate vs inappropriate stimuli. Rather, when the amygdala has been removed bilaterally the organism reverts to the most basic and primitive modes of object and social-emotional interaction (Brown & Schaffer, 1888; Gloor, 1960; Kluver & Bucy, 1939; Weiskrantz, 1956) such that even the ability to appropriately interact with loved ones is impaired (Lilly et al., 1983; Marlowe et al., 1975; Terzian & Ore, 1955).
    For example, Terzian & Ore (1955) described a young man who following bilateral removal of the amygdala subsequently demonstrated an inability to recognize anyone, including close friends, relatives and his mother. He ceased to repond in an emotional manner to his environment and seemed unable to recognize feelings expressed by others. He also demonstrated many features of the Kluver-Bucy syndrome (perserverative oral "exploratory" behavior and psychic blindness), as well as an insatiable appetite. In addition, he became extremely socially unresponsive such that he preferred to sit in isolation, well away from others.
    Among primates who have undergone bilateral amygdaloid removal, once they are released from captivity and allowed to return to their social group, a social-emotional agnosia becomes readily apparent as they no longer respond to or seem able to appreciate or understand emotional or social nuances. Indeed, they appear to have little or no interest in social acitivity and persistently attempt to avoid contact with others (Dicks et al. 1969; Jonason & Enloe, 1971; Kling & Brothers 1992; Jonason et al. 1973). If approached they withdraw, and if followed they flee.
    Indeed, they behave as if they have no understanding of what is expected of them or what others intend or are attempting to convey, even when the behavior is quite friendly and concerned. Among adults with bilateral lesions, total isolation seems to be preferred.
    In addition, they no longer display appropriate social or emotional behaviors, and if kept in captivity will fall in dominance in a group or competitive situation -- even when formerly dominant (Bunnel, 1966; Dicks et al., 1969; Fuller et al., 1957; Jonason & Enloe, 1971; Jonason et al., 1973; Rosvold et al. 1954).
    As might be expected, maternal behavior is severly affected. According to Kling (1972), mothers will behave as if their "infant were a strange object be be mouthed, bitten and tossed around as though it were a rubber ball".
    EMOTIONAL LANGUAGE & THE AMYGDALA
    Although cries and vocalizations indicative of rage or pleasure have been elicited via hypothalamic stimulation, of all limbic nuclei the amygdala is the most vocally active--particularly the lateral division (Robinson, 1967). In humans and animals a wide range of emotional sounds have been evoked through amygdala activation, such as sounds indicative of pleasure, sadness, happiness, and anger (Robinson, 1967; Ursin & Kaada, 1960). The human amygdala can produce as well as perceive emotional vocalizations (Halgren, 1992; Heit, Smith, & Halgren, 1988).
    {http://brainmind.com/images/JosephRightLanguage.jpg}
    Conversely, in humans, destruction limited to the amygdala (Freeman & Williams 1952, 1963), the right amygdala in particular, has abolished the ability to sing, convey melodic information or to properly enunciate via vocal inflection. Similar disturbances occur with right hemisphere damage (chapter 10). Indeed, when the right temporal region (including the amygdala) has been grossly damaged or surgically removed, the ability to perceive, process, or even vocally reproduce most aspects of musical and emotional auditory input is significanlty curtailed (Chapter 21).
    AMYGDALA, THE ANTERIOR COMMISSURE, SEXUALITY & EMOTION,
    When the amygdala or the bed nuclei for the anterior commissure of both cerebral hemispheres are damaged, hyperactivated, or completely inhibited a striking disturbance in sexual and social behavior is evident (Brown & Schaffer, 1888; Gloor, 1960; Kluver & Bucy, 1939; Terzian & Ore, 1955; Schriner & Kling, 1953). Specifically, humans, non-human primates, and felines who have undergone bilateral amygdalectomies will engage in prolonged, repeated, and inappropriate sexual behavior and masturbation including repeated sexual acts with members of different species (e.g. a cat with a dog, a dog with a turtle, etc.).
    {http://brainmind.com/images/KluverBucy101.jpg}
    When activated from seizures, patients may involuntarily behave in a sexual manner and even engage in what appears to be intercourse with an imaginary partner. This abnormality is one aspect of a complex of symptoms sometimes referred to as the Kluver-Bucy syndrome.
    {http://brainmind.com/images/AnteriorCommAmyg.jpg} As noted, portions of the hypothalamus and amygdala are sexually dimorphic; i.e. there are male and female amygdaloid nuclei (Bubenik & Brown, 1973; Nishizuka & Arai, 1981). In humans the male amygdala is 16% larger (Filipek, et al., 2014), and in male rats the medial amygdala is 65% larger than the female amygdala (Breedlove & Cooke, 2009), and the male amygdala grows or shrinks in the presence of testosterone--findings which may be related to sex differences in sexuality and aggression. Moreover, female amygdala neurons are smaller and more numerous, and densely packed than those of the male (Bubenik & Brown, 1973; Nishizuka & Arai, 1981), and smaller, densely packed neurons fire more easily and frequently than larger ones--which may contribute to the fact that females are more emotional and more easily frightened than males (chapters 7,13,15), as the amygdala is a principle structure involved in evoking feelings of fear (Davis et al., 2010; Gloor, 2010; LeDoux, 2012).
    Moreover, despite myths to the contrary, females, regardless of species, are more sexually active than males, on average (see chapter 8)--that is, when they are in estrus-- and the human female is capable of experiencing multiple orgasms of increasing intensity--which may also be a function of sex differences in the amygdala. That is, since female primate amygdala neurons are more numerous and packed more closely together (Bubenik & Brown, 1973; Nishizuka & Arai, 1981), and as smaller, tightly packed neurons demonstrate enhanced electrical excitability, lower response thresholds, and increase susceptibility to kindling and thus hyper-excitation, the amygdala therefore is likely largely responsible for sex differences in emotionality and sexuality.
    Indeed, electrical stimulation of the medial amygdala results in sex related behavior and activity. In females this includes ovulation, uterine contractions and lactogenetic responses, and in males penile erections (Robinson & Mishkin, 1968; Shealy & Peele, 1957). Moreover, in rats and other animals, kindling induced in the amygdala can trigger estrus and produce prolonged female sexual behavior.
    {http://brainmind.com/images/AmygdalAnteriorC.jpg} Moreover, the anterior commissure, the band of axonal fibers which interconnects the right and left amygdala/temporal lobe is sexually differentiated. Like the corpus callosum, the anterior commissure is responsible for information transfer as well as inhibition within the limbic system. Specifically, the female anterior commissure is 18% larger than in the male (Allen & Gorski 1992). It has been argued that the increased capacity of the right and left female amygdala to communicate (via the anterior commissure) coupled with the more numerous and more densely packed neurons within the female amygdala (which in turn would decrease firing thresholds and enhance communication), and the sex diffferences in the hypothalamus, would also predispose females to be more emotionally and socially sensitive, perceptive, and expressive (Joseph 2013). Hence, these limbic sex differences induces her to be less aggressive and more compassionate and maternal, and affects her sexuality, feelings of dependency and nurturance, and desire to maintain and form attachments in a manner different than males.
    {http://brainmind.com/images/SexAmygdala.jpg} In contrast, whereas the right and left female amygdala are provided a communication advantage not shared by males, the "male" amygdala in turn may be more greatly influenced by the (medial) hypothalamus via the stria terminalis which is larger in men than women (Allen & Gorski 1992). As noted, the male medial amygdala is larger than its female counterpart (Breedlove & Cooke, 2009) and changes in size in response to testosterone, which is significant as the medial nuclei (and testosterone) is directly implicated in negative and aggressive behaviors (see above).
    Although environmental influences can shape and sculpt behavior and the functional organization of the brain (chapter 28), most sex differences are innate and shared by other species (see chapters 7 & 8); a direct consequence of the presence or absence of testosterone during adulthood and fetal development (see Gerall et al. 1992; Joseph 2013, Joseph et al. 1978) and the sexual differentiation of the limbic system.
    THE LIMBIC SYSTEM & TESTOSTERONE
    In large part these and related sex differences in aggressiveness are also a consequence of the relatively higher concentrations of the activating hormone, testosterone flowing through male bodies and brains. The overarching influence of neurological and hormonal predispositions are also indicated by studies which have shown that females who have been prenatally exposed to high levels of masculinizing hormones (i.e. androgens) behave similar to males even in regard to spatial abilities (Joseph et al. 1978; see Gerall et al. 1992). They are also more aggressive and engage in more rough and tumble play as compared to normal females (Money & Ehrhardt, 1972; Ehrhardt & Baker, 1974; Reinisch, 1974) and this is also true of other species such as dogs, wolves, gorillas, baboons, and chimpanzees.
    {http://brainmind.com/images/LimbicAmyagdala12.jpg} Similarly, female primates and mammals who have been exposed to testosterone during neonatal development display an altered sexual orientation, as well as significantly higher levels of activity, competitiveness, combativeness and belligerence (Mitchell, 1979). Nevertheless, it is important to re-emphasize that it is generally the presence or absence of testosterone during the critical period of neuronal differentiation which determines if one is in possession of a "male" vs "female" limbic system.
    SEXUAL ORIENTATION & HETEROSEXUAL DESIRE
    As noted, the amygdala surveys the environment searching out stimuli, events, or individuals which are emotionally, sexually or motivationally significant. Moreover, it contains facial recognition neurons which are sensitive to different facial expressions and which are capable of determining the sex of the individual being viewed and which become excited when looking at a male vs female face (Leonard et al. 2005; Rolls 1984). In this regard, the amygdala can act to discern and detect potential sexual partners and then motivate sex-appropriate behavior culminating in sexual intercourse and orgasm.
    That is, an individual who possess a "male" limbic system is likely to view the female face, body and genitalia as sexually arousing because the amygdala and limbic system responds with pleasure when stimulated by these particular features. Conversely, male physical features are likely to excite and sexually stimulate the limbic systems possessed by heterosexual females and homosexual males (Joseph, 2013). This is because, at a very basic level emotional, sexual, and motivational perceptual/behavioral functioning becomes influenced and guided by the anatomical sexual bias of the host.
    OVERVIEW: THE AMYGDALA
    Over the course of early evolutionary development, the hypothalamus reigned supreme in the control and expression of raw and reflexive emotionality, i.e., pleasure, displeasure, aversion, and rage. Largely, however, it has acted as an eye turned inward, monitoring internal homeostasis and concerned with basic needs. With the development of the amygdala, the organism was now equipped with an eye turned outward so that the external emotional features of reality could be tested and ascertained. When signalled by the hypothalamus the amygdala begins to search the sensory array for appropriate emotional-motivational stimuli until what is desired is discovered and attended to.
    However, with the differentiation of the amygdala, emotional functioning also became differentiated and highly refined. The amygdala hierarchically wrested control of emotion from the hypothalamus.
    The amygdala is primary in regard to the perception and expression of most aspects of emotionality, including fear, aggression, pleasure, happiness, sadness, etc., and in fact assigns emotional or motivational significance to that which is experienced. It can thus induce the organism to act on something seen, felt, heard, or anticipated. The integrity of the amygdala is essential in regard to the anylysis of social-emotional nuances, the organization and mobilization of the persons internal motivational status regarding these cues, as well as the mediation of higher order emotional expression and impluse control. When damaged or functionally compromised, social-emotional functioning becomes grossly disturbed.
    The amygdaloid nucleaus via its rich interconnections with other brain regions is able to sample and influence activity occurring in other parts of the cerebrum and add emotional color to ones perceptions. As such it is highly involved in the assimilation and association of divergent emotional, motivational, somesthetic, visceral, auditory, visual, motor, olfactory and gustatory stimuli. Thus it is very concerned with learning, memory, and attention, and can generate reinforcement for certain behaviors. Moreover, via reward or punishment it can promote the encoding, storage and later retrieval of particular types of information. That is, learning often involved reward and it is via the amygdala (in concert with other nuclei) that emotional consequences can be attributed to certain events, actions, or experiences, as well as extracted from the world of possibility so that it can be attended to and remembered.
    Lastly, as is evident from studies of individuals with abnormal activity or seizures originating in or involving this nuclei, the amygdala is able to overwhelm the neocortex and thus gain control over behavior. As based on electrophysiological studies, the amygdala seems capable of literally turning off the neocortex (such as occurs during a seizure) at least for brief time periods. That is, the amygdala can induce electrophysiological slow wave theta activity in the neocortex which indicates low levels of arousal (see below) as well as high voltage fast activity. In the normal brain it probably exerts similar influences such that at times individuals (i.e. their neocortex) "lose control" over themselves and respond in a highly emotionally charged manner.
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    In consequence, after they "explode" or respond "irrationally" they (that is, the neocortex of the left hemisphere) are likely to wonder aloud: "I don't know what came over me."
    But we know the answer: The Limbic System.
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    HIPPOCAMPUS
    Memory & Attention
    The hippocampus (Ammon's Horn" or the "sea horse") is an elongated structure located within the inferior medial wall of the temporal lobe (posterior to the amygdala) and surrounds, in part, the lateral ventricle. In humans it consists of an anterior and posterior region and depending on the angle at which it is viewed, could be construed as shaped somewhat like an old fashion telephone receiver, or a "sea horse."
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    The hippocampus consists of a number of subcomponents, and adjoining structures, such as the parahippocampal gyrus, entorhinal and perirhinal cortex and the uncus (which it shares with the amygdala) are considered by some to be subdivisions, whereas the main body of the hippocampus consists of the dentate gyrus, the subiculum, and sectors referred to as CA1, CA2, CA3, CA4.
    {http://brainmind.com/images/HippocampusLayers1.jpg} The uncus is a bulbar allocortical protrusion located in the anterior-inferior medial part of the temporal lobe, and consists of both the hippocampus and amygdala which become fused in forming this structure. That is the ventral-medial portion of the amygdala becomes fused with the head of the hippocampus, such that the uncus consists of both allocortex and mesocortex--the entorhinal cortex which shrouds the hippocampus.
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    HIPPOCAMPAL AROUSAL, ATTENTION & INHIBITORY INFLUENCES
    Various authors have assigned the hippocampus a major role in information processing, including memory, new learning, cognitive mapping of the environment, voluntary movement toward a goal, as well as attention, behavioral arousal, and orienting reactions (Douglas, 1967; Eichenbaum et al. 2014; Enbert & Bonhoeffer, 2009; Frisk & Milner, 1990; Grastayan et al., 1959; Green & Arduini, 1954; Isaacson, 1982; Milner, 1966, 1970, 1971; Nishitani, et al., 2009; Olton et al. 1978; Routtenberg, 1968; Squire, 1992; Victor & Agamanolis, 1990; Xu et al., 2012). For example, hippocampal cells greatly alter their activity in response to certain spatial correlates, particularly as an animal moves about in its environment (Nadel, 1991; O'Keefe, 1976; Olton et al., 1978; Wilson & McNaughton, 2013). It also developes slow wave theta activity during arousal (Green & Arduini, 1954) or when presented with noxious or novel stimuli (Adey et al.1960)--at least in non-humans.
    However, few studies have implicated this nucleus as important in emotional functioning per se, although responses such as "anxiety" or "bewilderment" have been observed when directly electrically stimulated (Kaada et al. 1953). Indeed, in response to persistent and repeated instances of stress and unpleasant emotional arousal, the hippocampus appears to cease to participate in cognitive, emotional, or memory processing (chapter 30). Thus the role of the hippocampus in emotion is quite minimal.
    AROUSAL
    Hippocampal-neocortical interactions. Desynchronization of the cortical EEG is associated with high levels of arousal and information input. As the level of input increases, the greater is the level of cortical arousal (Como et al. 1979; Joseph et al. 1981; Joseph, 2012b, 2009d). However, when arousal levels become too great, efficienty in information processing, memory, new learning, and attention become compromised as the brain becomes overwhelmed (Joseph, 2012b, 2009d; Joseph et al., 1981; Lupien & McEwen, 2010; Sapolsky, 2012).
    When the neocortex becomes desynchronised (indicating cortical arousal), the hippocampus often (but not always) developes slow wave theta activity (Grastyan et al., 1959; Green & Arduni, 1954) such that it appears to be functioning at a much lower level of arousal--as demonstrated in non-humans. Conversely, when cortical arousal is reduced to a low level (indicated by EEG synchrony), the hippocampal EEG often becomes desynchronized.
    These findings suggest when the neocortex is highly stimulated the hippocampus, in order to monitor what is being received and processed, functions at a level much lower in order not to become overwhelmed. When the neocortex is not highly aroused, the hippocampus presumably compensates by increasing its own level of arousal so as to tune in to information that is being processed at a low level of intensity.
    Hence, in situations where both the cortex and the hippocampus become desynchronized, there results distractability and hyperresponsiveness such that the subject becomes overwhelmed, confused, and may orient to and approach several stimuli (Grastyan et al., 1959). Attention, learning, and memory functioning are decreased. Situations such as this sometimes also occur when individuals are highly anxious or repetitively emotionally or physically traumatized (see chapter 30).
    {http://brainmind.com/images/EntorhinalCortex.jpg} The hippocampus consists of 3 layers, layer 2 consisting of pyramidal neurons which provide excitatory output and thus act to activate and arouse target tissues; via the transmitters glutamate and aspartic acid. In addition, the entorhinal cortex provides excitatory input into the hippocampus--input which is derived from the neocortex; using again, aspartic and glutamate acid (reviewed in Gloor, 2010). Specifically, it appears that the hippocampus interacts with the neocortex is regard to arousal via the dorsal medial nucleus of the thalamus, the septal nuclei, the hypothalamus, amygdala and brainstem--structures with which it maintains direct interconnections. As per the neocortex, this sheet of tissue is also innervated by these structures, and by the entorhinal cortex.
    {http://brainmind.com/images/HippocampusEntorhinal.jpg} Hence, the hippocampus serves as a major component of an excitatory interface and can be aroused by neocortical activity (via the entorhinal cortex), and can provide excitatory input to directly to subcortical structures and indirectly to the neocortex (via the entorhinal cortex and dorsal medial nucleus). However, if the neocortex becomes excessively aroused, so to might the hippocampus, and vice versa. Under excessively arousing conditions, however, hippocampal pyramidal neurons may become inhibited or even damaged (Lupien & McEwen, 2010; Sapolsky, 2012), thus resulting in loss of memory.
    There is also evidence to suggest that the hippocampus may act so as to reduce extremes in cortical arousal. For example, whereas stimulation of the reticular activating system augments cortical arousal and EEG evoked potentials, hippocampal stimulation reduces or inhibits these potentials such that cortical responsiveness and arousal is dampened (Feldman, 1962; Redding, 1967). On the otherhard, if cortical arousal is at a low level, hippocampal stimulation often results in an augmentation of the cortical evoked potential (Redding, 1967).
    {http://brainmind.com/images/HippocampusPathways3.jpg} The hippocampus also exerts desynchronizing or synchronizing influences on various thalamic nuclei (e.g., the dorsal medial thalamus) which in turn augments or decreases activity in this region (Green & Adey, 1956; Guillary, 1955; Nauta, 1956, 1958). As the dorsal medial thalamus is the major relay nucleus to the neocortex, the hippocampus therefore appears able to block or enhance information transfer to various neocortical areas (that is, in conjunction with the frontal lobe, see chapter 19). Indeed, it may be acting to insure that certain percepts are stored in memory at the level of the neocortex (Gloor, 2010; Squire 1992) by modulating cortical activity.
    It is thus likely that the hippocampus may act to influence information reception and storage at the neocortical level as well as possibly reduce extremes in cortical arousal (be they too low or high) perhaps by activating inhibitory circuits in the dorsal medial nucleus, thus ensuring that the neocortex is not over or underwhelmed when engaged in the reception and processing of information. This is an important attribute since very high or very low states of excitation are incompatible with alertness and selective attention as well as the ability to learn and retain information (Joseph et al. 1981; Lupien & McEwen, 2010; Sapolsky, 2012).
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    Aversion & Punishment.
    In many ways, the hippocampus appears to act in concert with the medial hypothalamus and septal nuclei (with which it maintains rich interconnections) so as to also prevent extremes in emotional arousal and thus maintain a state of quiet alertness (or quiescence). Moreover, similar to the results following stimulation of the medial hypothalamus, it has been reported that the subjective components of aversive emotion in humans is correlated with electrophysiological alternations in the hippocampus and septal area (Heath, 1976).
    The hippocampus also appears to be heavily involved in the modulation of reactions to frustrations or mild punishment (Gray, 1970, 1990), particularly in regard to single trial but not multiple trial learning. For example, the hippocampus responds with trains of slow theta waves when presented with noxious stimuli but habituates or ceases to respond with repeated presentation. It is likely, however, that these physiological responses are secondary to activity within the amygdala and hypothalamus which then effects hippocampal functioning.
    ATTENTION & INHIBITION
    The hippocampus participates in the elicitation of orienting reactions and the maintainance of an aroused state of attention (Foreman & Stevens, 2007; Grastayan et al., 1959; Green & Arduini, 1954; Nishitani, et al., 2009; Routtenberg, 1968). When exposed to novel stimuli or when engaged in active searching of the environment, hippocampal theta appears (Adey, et al. 1960). However, with repeated presentations of a novel stimulus the hippocampus habituates and theta disappears (Adey et al. 1960). Thus, as information is attended to, recognized, and presumably learned and/or stored in memory, hippocampal participation diminishes. Theta also appears during the early stages of learning as well as when engaged in selective attention and the making of discriminant responses (Grastyan et al. 1959).
    When the hippocampus is damaged or destroyed, animals have great difficulty inhibiting behavioral responsiveness or shifting attention. For example, Clark and Issacson (1965) found that animals with hippocampal lesions could not learn to wait 20 seconds between bar presses if first trained to respond to a continous schedule. There is an inability to switch from a continous to a discontinous pattern, such that a marked degree of perseveration and inability to change sets or inhibit a pattern of behavior once initiated occurs (Douglas, 1967; Ellen, et al. 1964). Habituation is largely abolished and the ability to think or respond divergently is disrupted. Disinhibition due to hippocampal damage can even prevent the learning of a passive avoidance task, such as simple ceasing to move (Kimura, 1958).
    Hence, when coupled with the evidence presented above, it appears that the hippocampus acts to possibly selectively enhance or diminish areas of neural excitation which in turn allows for differential selective attention and differential responding, as well as the storage and consolidation of information into long term memory. When damaged, the ability to shift from one set of perceptions to another, or to change behavioral patterns is disrupted and the organism becomes overwhelmed by a particular mode of input. Learning, memory, as well as attention, are greatly compromised.
    LEARNING & MEMORY: THE HIPPOCAMPUS
    The hippocampus is most usually associated with learning and memory encoding, e.g. long term storage and retrieval of newly learned information (Enbert & Bonhoeffer, 2009; Fedio & Van Buren, 1974; Frisk & Milner, 1990; Milner, 1966; 1970; Nunn et al., 2009; Penfield & Milner, 1958; Rawlins, 2005; Scoville & Milner, 1957; Squire, 1992; Victor & Agamanolis, 1990) particularly the anterior regions. Hence, if the hippocampus has been damaged the ability to convert short term memories into long term memories (i.e. anterograde amnesia), becomes significantly impaired in humans (MacKinnon & Squire, 1989; Nunn et al., 2009; Squire, 1992; Victor & Agamanolis, 1990) as well as primates (Zola-Morgan & Squire, 1984, 2005a, 1986). In humans, memory for words, passages, conversations, and written material is also significantly impacted, particularly with left hippocampal destruction (Frisk & Milner, 1990; Squire, 1992).
    {http://brainmind.com/images/Hippocampusmemory1.jpg} Bilateral destruction of the anterior hippocampus results in striking and profound disturbances involving memory and new learning (i.e. anterograde amnesia). For example, one such individual who underwent bilateral destruction of this nuclei (H.M.), was subsequently found to have almost completely lost the ability to recall anything experienced after surgery. If you introduced yourself to him, left the room, and then returned a few minutes later he would have no recall of having met or spoken to you. Dr. Brenda Milner has worked with H.M. for almost 20 years and yet she is an utter stranger to him.
    {http://brainmind.com/images/HippocampusSeptal.jpg}
    {http://brainmind.com/images/hippocampus101.jpg}
    {http://brainmind.com/images/HMHippocampus.jpg} H.M. is in fact so amnesic for everything that has occurred since his surgery (although memory for events prior to his surgery is comparatively exceedingly well preserved), that every time he rediscovers that his favorite uncle died (actually a few years before his surgery) he suffers the same grief as if he had just been informed for the first time.
    H.M., although without memory for new (non-motor) information, has adequate intelligence, is painfully aware of his deficit and constantly apologizes for his problem. "Right now, I'm wondering" he once said, "Have I done or said anything amiss?" You see, at this moment everything looks clear to me, but what happened just before? That's what worries me. It's like waking from a dream. I just don't remember...Every day is alone in itself, whatever enjoyment I've had, and whatever sorrow I've had...I just don't remember" (Blakemore, 1977, p.96).
    Presumably the hippocampus acts to protect memory and the encoding of new information during the storage and consolidation phase via the gating of afferent streams of information and the filtering/exclusion (or dampening) of irrelevant and interfering stimuli. When the hippocampus is damaged there results input overload, the neuroaxis is overwhelmed by neural noise, and the consolidation phase of memory is disrupted such that relevant information is not properly stored or even attented to. Consequently, the ability to form associations (e.g. between stimulus and response) or to alter preexisting schemas (such as occurs during learning) is attenuated (Douglas, 1967).
    THE SEPTAL NUCLEI
    HIPPOCAMPAL & SEPTAL INTERACTIONS
    The septal nuclei consists of medial and lateral nuclei, and can be further subdivided into several nuclear components (Ariens Kappers et al., 1936; Swanson & Cowan, 1979), such as the nucleus of the diagonal band of Broca. The septal nuclei is an evolutionary derivative of the hippocampus and the hypothalamus, and in the human brain is richly interconnected with both structures including the amygdala, and the substantia innomminata (SI) which is a major memory center, and which manufactures ACh--a transmitter directly implicated in memory (Gage et al., 1983; Olton, 1990). Andy and Stephan (1968) and Swanson and Cowan (1979) considered the bed nucleus of the stria terminals (which gives rise to a major pathway linking the septal nuclei, and amygdala and hypothalamus) as part of the septal nuclei, whereas others (Gloor, 2010) consider it to be part of the "extended amygdala." Likewise, some consider the nucleus accumbens as part of the septal nuclei, and others consider it part of the "extended amygdala;" i.e. the limbic striatum.
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    As noted the septal nuclei is massively interconnected with the hippocampus as well as with the entorhinal cortex (Swanson & Cowan, 1979) via a number of pathways, including the fornix. Directly implicating the septal nuclei in the memory functioning of the hippocampus is the finding that septal activation of this structure results in ACh secretion (Gage et al., 1983), whereas septal grafts into the hippocampus improves learning and memory (Gage et al., 1986). Conversely, lesions of the fimbria-fornix septal-hippocampal pathway results ACh depletion throughout the hippocampus (Gage et al., 1983; Olton, 1990), as well as loss of norepinephrine and serotonin coupled with memory loss (Olton, 1990).
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    The septal nucleus in part regulate hippocampal memory-related activity not only by stimulating ACh and other neurotransmitter production (Gage et al., 1983, 1986), but as it provides excitatory input and inhibitory-GABAnergic-- especially from the medial septal nuclei which in general exerts inhibitory influences not only on the hippocampus but the amygdala and hypothalamus. In general, it is supposed that the excitatory-inhibitory influences on the hippocampus (like those on the amygdala and hypothalamus) serve to modulate activity and prevent extremes in arousal (Joseph, 1992a, 2012b, 2009d). This is accomplished in part not only through the interconnections maintained with the amygdala, hypothalamus and entorhinal cortex, but the brainstem reticular formation (Petsche et al., 1965)--with which the hippocampus is also connected directly and via the entorhinal cortex.
    Septal influences on hippocampal/entorhinal arousal is also indicated by fluctuations in rhythmic slow activity (theta), which is generated by both the hippocampus and entorhinal cortex (Alonso & Garcia-Austt, 2007). As detailed in chapter 14, theta is an indication of hippocampal arousal (Green & Arduini, 1954; Petsche et al., 1965; Vanderwolf, 1992) and is associated with learning and memory (O'Keefe & Nadel, 1978). Theta is a robust electrophysiological phenomenon which has been found in the hippocampus of most species studied, including monkeys (Stewart & Fxx, 1990) and humans (Sano et al., 1970); though in primates it seems to differ from the theta rhythm of non-primates (see Gloor, 2010).
    O'Keefe and Nadel (1978) believe that theta plays an important role in creating the spatial maps that are maintained by hippocampal "place" neurons; i.e. pyramidal neurons which are attuned to specific environmental features and landmarks and the animals place in that environment as they move about. Moreover, long term potentiation (LTP) which is associated with learning and memory, is generated in those neurons demonstrating theta or activity that is at the "theta frequency" (Staubli & Lynch, 2007).
    Neurons of the septal nucleus which innervate the hippocampus fluctuate in activity in parallel with changes in the theta rhythm (Petsche et al., 1965), whereas septal lesions abolish hippocampal theta (Green & Arduini, 1954). It has long been believed that septal neurons act as an interface between the reticular formation and the hippocampus (Petsche et al., 1965) and in conjunction with its connections with the amygdala and hypothalamus, therefore modulate hippocampal arousal as well as learning and memory.
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    HIPPOCAMPAL & AMYGDALOID INTERACTIONS: MEMORY
    It has been argued that significant impairments involving short-term memory and motor learning, cannot be produced by lesions supposedly restricted to the hippocampus (Horel, 1978; see also commentary in Eichenbaum et al. 2014); though in fact it is impossible to create such "restricted" lesions. Nevetheless, ignoring for the moment that inconvenient fact, in some instances with supposed restricted lesions, good recall of new information is possible for at least several minutes (Horel, 1978; Penfield & Milner, 1958; Squire 1992).
    Moreover, there is considerable evidence which strongly suggests that the hippocampus plays an interdependent role with the amygdala in regard to memory (Gloor 1992, 2010; Halgren 1992; Kesner & Andrus, 1982; Mishkin, 1978; Murray 1992; Sarter & Markowitsch, 2005); particularly in that they are richly interconnected, merge at the uncus, and exert mutual excitatory influences on one another. For example, it appears that the amygdala is responsible for storing the emotional aspects and personal reactions to events in memory, whereas the hippocampus acts to store the cognitive, visual, and contextual variables (chapter 14) whereas that the amygdala activates the hippocampus by providing excitatory input (Gloor, 1955, 2010).
    Specifically, the amygdala plays a particularly important role in memory and learning when activities are related to reward and emotional arousal (Gaffan 1992; Gloor 1992, 2010; Halgren 1992; LeDoux 1992, 2012; Kesner 1992; Rolls 1992; Sarter & Markowitsch, 2005). Thus, if some event is associated with positive or negative emotional states it is more likely to be learned and remembered.
    The amygdala becomes particularly active when recalling personal and emotional memories (Halgren, 1992; Heath, 1964; Penfield & Perot, 1963), and in response to cognitive and context determined stimuli regardless of their specific emotional qualities (Halgren, 1992). However, once these emotional memories are formed, it sometimes requires the specific emotional or associated visual context to trigger their recall (Rolls, 1992; Halgren, 1992). If those cues are not provided or ceased to be available, the original memory may not be triggered and may appear to be forgotten or repressed. However, even emotional context can trigger memory (see also Halgren, 1992) in the absence of specific cognitive cues.
    Similarly, it is also possible for emotional and non-emotional memories to be activated in the absence of active search and retrieval, and thus without hippocampal or frontal lobe participation. Recognition memory which may be triggered by contextual or emotional cues. Indeed, there are a small group of neurons in the amygdala, as well as a larger group in the inferior temporal lobe which are involved in recognition memory (Murray, 1992; Rolls, 1992). Because of amygdaloid sensitivity to visual and emotional cues, even long forgotten memories may be evoked via recognition, even when search and retrieval repeatedly fail to activate the relevant memory store.
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    According to Gloor (1992), "a perceptual experience similar to a previous one can through activation of the isocortical population involved in the original experience recreate the entire matrix which corresponds to it and call forth the memory of the original event and an appropriate affective response through the activation of amygdaloid neurons." This can occur "at a relatively non-cognitive (affective) level, and thus lead to full or partial recall of the original perceptual message associated with the appropriate affect."
    In this regard, it appears that the amygdala is responsible for emotional memory formation whereas the hippocampus is concerned with storing verbal-visual-spatial and contextual details in memory. Thus, in rats and primates damage to the hippocampus can impair retention of context, and contextual fear conditioning, but it has no effect on the retention of the fear itself or the fear reaction to the original cue (Kim & Fanselow 1992; Phillips & LeDoux 1992, 2012; Rudy & Morledge 2014). In these instances, fear-memory is retained due to preservation of the amygdala. However, when both the amygdala and hippocampus are damaged, striking and profound disturbances in memory functioning result (Kesner & Andrus, 1982; Mishkin, 1978).
    {http://brainmind.com/images/HippocampusAmygdalaNetwork5.jpg}
    Therefore, the role of the amygdala in memory and learning seems to involve activities related to reward, orientation, and attention, as well as emotional arousal and social-emotional recognition (Gloor, 1992, 2010; Rolls, 1992; Sarter & Markowitsch, 2005). If some event is associated with positive or negative emotional states it is more likely to be learned and remembered. That is, reward increases the probability of attention being paid to a particular stimulus or consequence as a function of its association with reinforcement (Gaffan 1992; Douglas, 1967; Kesner & Andrus, 1982).
    Moreover, the amygdala appears to reinforce and maintain hippocampal activity via the identification of motivationally significant information and the generation of pleasurable rewards (through action on the lateral hypothalamus). However, the amygdala and hippocampus act differentially in regard to the effects of positive vs. negative reinforcement on learning and memory, particularly when highly stressed or repetitively aroused in a negative fashion. For example, whereas the hippocampus produces theta in response to noxious stimuli the amygdala increases its activity following the reception of a reward (Norton, 1970).
    TEMPORAL LOBES & LATERALITY.
    It is now very well known that lesions involving the mesial-inferior temporal lobes (i.e. destruction or damage to the amygdala/hippocampus) of the left cerebral hemisphere typically produce significant disturbances involving verbal memory--particularly as constrasted with individuals with right sided destruction. Left sided damage disrupts the ability to recall simple sentences, complex verbal narrative passages, or to learn verbal paired-associates or a series of digits (Frisk & Milner 1990; Milner, 1966, 1970, 1971; Squire 1992).
    In contract, right temporal destruction typically produces deficits involving visual memory, such as the learning and recall of geometic patterns, visual or tactile mazes, locations, objects, emotional sounds, or human faces (Corkin, 1965; Milner, 1965; Nunn et al., 2009; Kimura, 1963). Right sided damage also disrupts the ability to recognize (via recall) olfactory stimuli (Rausch et al. 1977), or recall emotional passages or personal memories (Cimino et al., 1991; Wechsler, 1973).
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    It appears, therefore, that the left amygdala and hippocampus are highly involved in processing and/or attending to verbal information, whereas the right amygdala/hippocampus is more involved in the learning, memory and recollection of non-verbal, visual-spatial, environmental, emotional, motivational, tactile, olfactory, and facial information. These issues and the differing roles of these nuclei in memory formation, as well as amnesia and repression will be discussed in greater detail in chapters 29, 30.
    THE PRIMARY PROCESS
    AMYGDALA & PLEASURE
    The amygdala maintains a functionally interdependent relationship with the hypothalamus in regard to emotional, sexual, autonomic, consumatory and motivational concerns. It is able to modulate and even control rudimentary emotional forces governed by the hypothalamic nucleus. However, the amygdala also acts at the behest of hypothalamically induced drives. For example, if certain nutritional requirements need to be meet, the hypothalamus signals the amygdala which then surveys the external environment for something good to eat (Joseph, 1982, 1992a). On the other hard, if the amygdala via environmental surveillance were to discover a potentially threatening stimulus, it acts to excite and drive the hypothalamus as well as the basal ganglia so that the organism is mobilized to take appropriate action.
    When the hypothalamus is activated by the amygdala, instead of responding in an on/off manner, cellular activity continues for an appreciably longer time period (Dreifuss et. al., 1968). The amygdala can tap into the reservoir of emotional energy mediated by the hypothalamus so that certain ends may be attained (Joseph, 1982, 1992a)
    AMYGDALA & HIPPOCAMPAL INTERACTIONS DURING INFANCY
    HALLUCINATIONS
    The amygdal-hippocampal complex, particularly that of the right hemisphere, is very important in the production and recollection of non-linguistic and verbal-emotional images associated with past experience. In fact direct electrical stimulation of the temporal lobes, hippocampus and particularly the amygdala (Gloor, 1990, 2010) not only results in the recollection of images, but in the creation of fully formed visual and auditory hallucinations (Gloor 1992, 2010; Halgren 1992; Halgren et al., 1978; Horowitz et al., 1968; Malh et al., 1964; Penfield & Perot, 1963), as well as feelings of familiarity (e.g. deja vus).
    Indeed, it has long been know that tumors invading specific regions of the brain can trigger the formation of hallucinations which range from the simple (flashing lights) to the complex. The most complex forms of hallucination, however, are associated with tumors within the most anterior portion of the temporal lobe (Critchley, 1939; Gibbs, 1951; Gloor 1992, 2010; Halgren 1992; Horowitz et al. 1968; Tarachow, 1941); i.e. the region containing the amygdala and anterior hippocampus.
    Similarly, electrical stimulation of the anterior lateral temporal cortical surface results in visual hallucinations of people, objects, faces, and various sounds (Gloor 1992, 2010; Halgren 1992; Horowitz et al., 1968)--particularly the right temporal lobe (Halgren et al. 1978). Depth electrode stimulation and thus direct activation of the amygdala and/or hippocampus is especially effective.
    For example, stimulation of the right amygdala produces complex visual hallucinations, body sensations, deja vu, illusions, as well as gustatory and alimentary experiences (Weingarten et al. 1977), whereas Freeman and Williams (1963) have reported that the surgical removal of the right amygdala in one patient abolished hallucinations. Stimulation of the right hippocampus has also been associated with the production of memory- and dream-like hallucinations (Halgren et al. 1978; Horowitz et al. 1968).
    The amygdala also becomes activated in response to bizarre stimuli (Halgren, 1992). Conversely, if activated to an abnormal degree, it may in turn produce bizarre memories and abnormal perceptual experiences. In fact, the amygdala contributes in large part to the production of very sexual as well as bizarre, unusual and fearful memories and mental phenomenon including dissociative states, feelings of depersonalization, and hallucinogenic and dream-like recollections (Bear, 1979; Gloor, 1986, 1992, 2010; Horowitz et al. 1968; Mesulam, 1981; Penfield & Perot, 1963; Weingarten et al. 1977; Williams, 1956). In addition, sexual feelings and related activity and behavior are often evoked by amygdala stimulation and temporal lobe seizures (Halgren, 1992; Jacome, et al. 1980; Gloor, 1986, 2010; Remillard, et al. 1983; Robinson & Mishkin, 1968; Shealy & Peele, 1957), including memories of sexual intercourse (Gloor 1990) or severe emotional trauma and abuse (Gloor, 2010).
    Moreover, intense activation of the temporal lobe and amygdala has been reported to give rise to a host of sexual, religious and spiritual experiences; and chronic hyperstimulation (i.e. seizure activity) can induce some individuals to become hyper-religious or visualize and experience ghosts, demons, angels, and even God, as well as claim demonic and angelic possession or the sensation of having left their body (Bear 1979; Gloor 1986, 1992; Horowitz, Adams & Rutkin 1968; MacLean 1990; Mesulam 1981; Penfield & Perot 1963; Schenk, & Bear 1981; Weingarten, et al. 1977; Williams 1956).
    LSD.
    As is well known, LSD can elicit profound hallucinations involving all spheres of experience. Following the administration of LSD high amplitude slow waves (theta) and bursts of paroxysmal spike discharges occurs in the hippocampus and amygdala (Chapman & Walter, 1965; Chapman et al. 1963), but with little cortical abnormal activity. In both humans and chimps, when the temporal lobes, amygdala and hippocampus are removed, LSD ceased to produce hallucinatory phenomena (Baldwin et al. 1959; Serafintides, 1965). Moreover, LSD induced hallucinations are significantly reduced when the right vs. left temporal lobe has been surgically ablated (Serafintides, 1965).
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    Overall, it appears that the amygdala, hippocampus, and the neocortex of the temporal lobe are highly interactionally involved in the production of hallucinatory experiences. Presumably, it is the neocortex of the temporal lobe which acts to interpret this material (Penfield & Perot, 1963) as perceptual phenomena. Indeed, it is the interrelated activity of the temporal lobes, hippocampus and amygdala which not only produce memories and hallucinations, but dreams. In fact, the amygdalas involvement in all aspects of emotion and sexual functioning, including associated memories, the production of overwhelming fear as well as bizarre and dream-like mental phenomenon, may well account for why this type of unusual stimuli, including personal and innocuous memories also appears in dreams.
    DREAMING
    When hallucinations follow depth electrode or cortical stimulation, much of the material experienced is very dream-like (Gloor 1990, 1992; Halgren et al., 1978; Malh et al., 1964; Penfield & Perot 1963) and consists of recent perceptions, ideas, feelings, and other emotions which are similarly illusionary and dream-like. Indeed, the right amygdala, hippocampus, and the right hemisphere in general (Broughton, 1982; Goldstein et al., 1972; Hodoba, 1986; Humphrey & Zangwill, 1961; Kerr & Foulkes, 1978; Meyer et al. 2007) also appear to be involved in the production of deam imagery as well as REM sleep (chapter 10). For example stimulation of the amygdala triggers and increases ponto-geniculo-occipital paradoxical activity during sleep (Calvo, et al. 2007), which in turn is associated with REM and dreaming. In addition, during REM, the hippocampus begins to produce slow wave, theta activity (Jouvet, 1967; Olmstead, Best, & Mays, 1973; Robinson et al. 1977), which is associated with long-term potentiation which is associated with learning and memory (see chapter 14). Presumably, during REM, the hippocampus and amygdala act as a reservoir from which various images, emotions, words, and ideas are drawn and incorporated into the matrix of dream-like activity being woven by the right hemisphere. It is probably just as likely that the right hippocampus and amygdala serve as a source from which material is drawn during the course of a daydream.
    The Right Hemisphere & Dreams.
    There have been reports of patients with right cerebral damage, hypoplasia and abnormalities in the corpus callosum who have ceased dreaming altogether, suffer a loss of hypnogic imagery or tend to dream only in words (Botez et al. 2005; Humphrey & Zangwill, 1951; Kerr & Foulkes, 1981; Murri et al. 1984). However, there have also been some report that when the left hemisphere has been damaged, particularly the posterior portions (i.e. aphasic patients), the ability to verbally report and recall dreams also is greatly attenuated (e.g., Murri et al. 1984). Of course, aphasics have difficulty describing much of anything, let alone their dreams.
    Electrophysiologically the right hemisphere also becomes highly active during REM, whereas, conversely, the left brain becomes more active during N-REM (Goldstein et al. 1972; Hodoba, 1986). Similarly, measurements of cerebral blood flow have shown an increase in the right temporal regions during REM sleep and in subjects who upon wakening report visual, hypnagogic, hallucinatory and auditory dreaming (Meyer et al. 2007). Interestingly, abnormal and enhanced activity in the right temporal and temporal-occipital area acts to increase dreaming and REM sleep for an atypically long time period (Hodoba, 1986). Hence, it appears that there is a specific complementary relationship between REM sleep and right temporal electrophysiological activity.
    Interestingly, daydreams appear to follow the same 90-120 minute cycle that characterize the fluctuation between REM and NREM periods, as well as fluctuations in mental capabilities associated with the right and left hemisphere (Broughton, 1982; Kripke & Sonneschein 1973). That is, the cerebral hemisphere tend to oscillate in activity every 90-120 minutes -- a cycle which appears to correspond to the REM-NREM cycle and the appearance of day and night dreams.
    Forgotten Dreams.
    Most individuals, however, have difficulty recalling their dreams. This may seem paradoxical considering that hippocampal theta is being produced. However, this is theta punctuated by high levels of desychronized activity, which is not conducive to learning. In this regard, theta activity may represent the reverberating activity of neural circuits formed during the day, such that the residue of day time memories come to be inserted into the dream. Conversely, due to the high level of desychronization occuring in the hippocampus (as it is so highly aroused), although it contributes images and the days memories, it does not participate in storing these dream-like experiences into memory.
    Consider the results from temporal lobe, amygdala, and hippocampal electrical stimulation on memory recall and the production of hallucinations. Although personal memories are often activated at low intensities of stimulation (memories which are verified not only by the patient but family), if stimulation is sufficiently intense, the memory instead will become dreamlike and populated by hallucinated and cartoon like characters (Halgren, et al. 1978). That is, at low levels of stimulation memories are triggered but these memories become increasingly dream-like with high levels of activity. Moreover, once these high levels of stimulation are terminated, patients soon become verbally amnesic and fail to verbally recall having had these experiences (Gloor, 1992; Horowitz, et al. 1968). However, these memories can be later recalled if subjects are provided with specific contextual cues (Horowitz, et al. 1968). The same can occur during the course of the day when a fragment of a conversation, or some other experience, suddenly triggers the recall of a dream from the previous night which had otherwise been completely forgotten. Presumably it had seemingly been forgotten because the hippocampus did not participate in their storage and thus could not assist in their retrieval (see chapters 29, 20).
    There is also some evidence to suggest that different regions of the hippocampus show different levels of arousal during paradoxical sleep. For example, it appears that the posterior hippocampus becomes activated during paradoxical sleep and shows theta activity, whereas the more anterior portions become inhibited (Olmstead et al. 1973). As the anterior portions are more involved in new learning (at least in humans), whereas the posterior hippocampus is more concerned with old and well established memories, this would suggest that the posterior hippocampus is contributing older or already established memories to the content of the dream--which explains why theta, which is associated with learning and memory, is also produced during the dream--that is, it is replaying various fragmentary memories. Conversely, the inhibition of the anterior region would prevent this dream material from becoming re-memorized.
    DREAMS & INFANCY
    In the newborn, and up until approximately 6-9 months, there are two distinct stages of sleep which correspond to REM and N-REM periods demonstrated by adults (Berg & Berg, 1978; Dreyfus-Brisac & Monod, 1975; Parmelee et al. 1967). Among infants, however, REM occur during wakefulness as well as during sleep. In fact, REM can be observed when the eyes are open, when the infant is crying, fussing, eating, or sucking (Emde & Metcalf, 1970). Moreover, REM is also observed to occur within a few moments after an infant begins to engage in nutritional sucking and appears identical to that which occurs during sleep (Emde & Metcalf, 1970).
    The production of REM during waking in some respects seems paradoxical. Nevertheless, it might be safe to assume that like an adult, when the infant is in REM, he or she is dreaming, or at least, in a dream-like state. Possibly, this state corresponds to what Freud has described as the Primary Process. That is, when produced when the infant is crying or fussing, it is dreaming of whatever relief it seeks. Correspondingly, REM which occurs while eating or sucking may have to do with the limbic structures which are involved not only in the production of dream-like activity, but the identification, learning and retention of motivationally significant information (i.e. the amygdala and hippocampus).
    Presumably this relationship is a consequence of REM as well as eating and sucking being mediated, in part, by the amygdala as well as other limbic nuclei, which are also concerned with forming motivationally significant memories. Hence, when hungry, the hypothalamus becomes aroused which activates the amygdala which is responsible for the performing environmental surveillance so as to attend, orient to, identify and approach motivationally significant stimuli and eat. However, because the infants brain is so immature and as its resources for meeting its limbic needs are quite rudimentary, under certain conditions prolonged hypothalamus induced amygdala activation results in the formation and recall of relevant memories which may be experienced as hallucinations of the desired object. That is, previously formed neural networks become activated and the infant begins to dream and hallucinate food and will then suck and smack its lips as if eating or sucking when it is awake, in REM, and there is no food present.
    THE PRIMARY PROCESS
    The hypothalamus, our exceedingly ancient and primitive Id, has an eye that only sees inward. It can tell if the body needs nourishment but cannot determine what might be good to eat. It can feel thirst, but has no way of slacking this desire. The hypothalamus can only say: "I want", "I need", and can only signal pleasure and displeasure. However, being the seat of pleasure, the hypothalamus can be exceedingly gracious in rewarding the organism when its needs are met. Conversely, when its needs go unmet it can respond not only with displeasure and feelings of aversion, but with undirected fury and rage. It can cause the organism to cry out.
    Nevertheless, the cry does not produce the immediately desire relief or reduction in tension. There is thus a pressure on the limbic system and the organism to engage in environmental surveillance so as to meet the needs monitored by the hypothalamus.
    Over the course of the first months of life, as the amygdala and then hippocampus develop, the organism begins to develop an eye that not only sees outward, but which can register and recall events, objects, people, etc., associated with tension reduction, pleasure and the satiaty of the infants internal needs (e.g. the taste, smell, feeling of mother's breast and milk, the experience of sucking and relief, etc.). This is called learning.
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    With the maturation of these two limbic nuclei the infant is increasingly able to differentiate what occurs in the external environment based on hypothalamically monitored needs and the emotional/motivational significance of that which is experienced. The infant can now orient, selectively attend, determine what brings satisfaction, and store this information in memory.
    PRIMARY IMAGERY
    Although admittedly we have no direct knowledge as to the psychic interactions in the neonate, it does seem reasonable to assume that as the neocortex and underlying structures and fiber pathways mature, neural "prgroams" are formed which correspond to the repeated registration of experiences which are deemed significant (e.g. pleasurable). That is, neural pathways which are repetitively fired, deactivated or activated in response to specific sensory and affective activities and experiences, become associated with that activity, such that an associated neural circuit is formed (chapter 14); i.e. a memory is created. Eventually, if this circuit is reactivated, the "learned" pattern is reexperienced; i.e. the organism remembers.
    Thus, infants as young as 2 days of age can learn to suck at the mere sight of a bottle (see Piaget, 1954) and in order to receive milk as a reinforcement, infants can even modify their sucking response (Sameroff & Cameron, 1979). Hence, they are susceptible to classical conditioning (Sameroff & Cavanagh, 1979), although the possibility of operant conditioning has not been established. Nevertheless, the fact that they can recognize the bottle and suck (as well as cry and shed tears) indicates that various regions of the limbic system, especially that of the amygdala is functional and that learning and the creation of specific, context specific neural circuits have been formed very early in life.
    Thus, when the amygdala/hippocampus are stimulated by a hungry hypothalamus, the events and images associated with past experiences of pleasure can not only be searched out externally, but recalled in imaginal form. For example, as an infant experiences hunger and stomach contractions as well as it own cries of displeasure, these states become associated with the sound, smell, taste, etc. of mother and her associated movement and other stimuli which accompany being fed (cf Piaget, 1952, pp. 37, 407-408). Repetitively experienced, the sequence from hunger to satiety evokes and becomes associated with the activation of certain neural pathways and the creation of a specific neural network subserving that memory (chapter 14).
    Eventually, when the infant becomes hungry, if prolonged there is the possibility that the entire neural sequence associated with hunger and feeding (i.e. hunger, mother, food, satiaty), may become involuntarily triggered and activated (via association) such that an "image" of being fed is experienced. The activation of these rudimentary and infantile memory-images is probably what consititutes, at least in part, the primary process.
    Behaviorally this is manifested by REM and via sucking and tongue movements as if eating, when in fact there is no food present (cf, Piaget, 1952). That is, when hungry, the infant will begin to cry, rapid eye movement (REM) might be observed, and then the infant will stop crying and smack its lips and make sucking movement (mediated by the amygdala) as if it were being fed. The infant experiences the experience of being fed in the form of a dream (Joseph, 1982) or hallucination, although it is awake.
    In that the brain of the human infant is quite immature for in fact several years, which in turn restricts information reception and processing (chapters 23-28), and given the limited amount of reality contact infants are able to achieve, these rudimentary memories and images (even when occurring during waking, i.e. REM), are probably indistinguishable from actual experience simply because they are experience.
    Like a dream, when replayed, the infant presumalby reexperiences to some degree the sensations, emotions, etc., originally linked to tension reduction. Thus, the young infant, as yet unable to distinguish between representation and reality, responds to the image as reality (Freud, 1900, 1911), even while awake--as manifested by REM. When hunger is prolonged the association linked to feeding are triggered and for a brief time period the infant behaves as if its hunger has been sated. Reality is replaced by an image, or rather, a "dream". This is the primary process.
    Since the hypothalamus (which monitors internal homeostasis) is not conscious that the dream images experienced are not real, it initially accepts the memory/dream images transmitted from the amygdala and hippocampus and ceases to cry, i.e. it responds to the imagined sources of nourishment just as it responds to a cue-tone associated with a food reward (Nakamuar & Ono, 1986; Ono et al., 1980). However, the hypothalamus is not long fooled, for the primary process does not offer effective long lasting relief from tension. As the pain of hunger remains and increases, limbic activity is increased, and the image falls away to be replaced by a cry of hunger (Joseph, 1982). The amygdala and hippocampus are thus forced to renew their surveillance of the environment in search of sources of tension reduction. Cognitive development is thus promoted.
    "Whatever was thought of (desired) was simply imagined in an hallucinatory form, as still happens today with our dream-thoughts every night. This attempt at satisfaction by means of hallucination was abandoned only in consequence of the absence of the expected gratification, because of the disappointment experienced. Instead, the mental apparatus had to decide to form a conception of the real circumstances in the outer world and to exert itself to alter them...The increased significance of external reality heightened the significance also of the sense-organs directed towards the outer word, and of the consciousness attached to them; the later now learned to comprehend the qualities of sense in addition to the qualities of pleasure and "pain" which hitherto had alone been of interest to it. A special function was instituted which had periodically to search the outer word in order that its data might be already familiar if an urgent need should arise; this function was attention. Its activity meets the sense-impressions halfway, instead of awaiting their appearance. At the same time there was probably introduced a system of notation, whose task was to deposit the results of this periodical activity of consciousness--a part of that which we call memory" (Freud, 1911, pp. 410-411).

    (view changes)
    2:57 pm

Thursday, August 3

  1. page Cranial Nerves edited I – Olfactory Nerve The olfactory nerve is not a cranial nerve, in the strictest sense, as it byp…
    I – Olfactory Nerve
    The olfactory nerve is not a cranial nerve, in the strictest sense, as it bypasses the brainstem. It is a complex axonal pathway that projects to many structures including the amygdala, entorhinal cortex, hypothalamus, orbital frontal lobes and dorsal medial cortex. It is, however, associated with many brainstem functions as it receives information regarding smell and taste. The nerve begins in the olfactory endothelium where cells turnover rapidly and a cells life is only about two days. It then passes through the cribriform plate where it is prone to injury or shearing before reaching the olfactory bulb then projecting to the amygdala, hippocampus, thalamus, orbital frontal lobes and insula. If an injury occurs the cribriform plate may fracture, the nerve may be severed, and the meninges may rupture. If this happens an individual may not only lose their loss of smell (asnosmia), but may also develop a cerebrospinal fistula in which cerebrospinal fluid drips or gushes into the nose. Is asnosmia is unilateral then the individual will likely not notice the loss and each nostril should be assessed individually. Dysosmia, or a perversion of the sense of smell may also occur due to partial injuries to the olfactory bulbs or a tumor. Olfactory hallucinations are associated with tumors, seizure activity, as well as head injuries involving the inferior temporal lobes.
    II - Optic Nerve
    All visual impulses from the retina to the brain are transmitted via the optic nerves. Injuries to these pathways create visual defects. If these defects are restricted to either the right or left visual field only they are called homonymous, if bilateral, heteronymous. Heteroonymous defects suggest either an injury to both hemispheres or to the retina or optic nerve before reaching the optic chiasm. Homonymous symptoms indicate the injury can be localized to one side of the optic tract or radiations within one cerebral hemisphere. Complete destruction of the optic tract results in homonymous neglect to the left or right, whereas a partial injury may creat a quadratic homonymous defect. Temporal lobe injuries are associated with upper quadrant defects, while injuries to the superior parietal lobe is associated with lower quadrant defects.
    III – Oculomotor Nerve
    Innervation of all ocular rotary muscles, with the exception of the lateral rectus and superior oblique muscles, is provided by the oculomotor nerve. This includes the medial, superior, inferior recti, inferior oblique muscles. The intraocular and smooth muscles of the pupil (ciliary and pupilloconstrictor muscles) are also innervated by this nerve, as is the levator palprebrae muscle which raises the eyelid. If damaged there may be an inability to rotate the eye upward downward, or inward. The pupil may also not respond to direct light and there may be ptosis (drooping) of the eyelid due to weakness of levator palpebrae.
    IV – Trochlear Nerve
    Located just caudal to the inferior colliculi, the trochlear nerve innervates the superior oblique muscle of the eye. This allows for depression, abduction and intorsion of the eyeball so that an individual can look downward or inward. This is the most common cranial nerve to be damaged from head trauma.
    V – Trigeminal
    The trigeminal nerve is the largest of the cranial nerves. It innervates the trigeminal nucleus within the medulla to control jaw closure, chewing, grinding, and lateral movement of the jaw. In concert with the facial nerve, it impacts muscles involved in facial expression. Pathology of this nerve tract can cause difficulty in chewing. In severe cases ipsilateral atrophy and complete paralysis of of the temporal or masseter muscle(s) may occur. Somatic afferent parts of the nerve mediate general sensory input such as temperature, touch, and pain from the face, teeth, mouth, and mucus membranes of the nose, cheek, tongue and sinuses. The sometimes intensely painful condition known as trigeminal neuralgia is an instance of this.
    VI -Abducens
    Primarily concerned with horizontal eye movement, the abducens nerve ascend the brainstem to terminate at the oculomotor complex and innervate the lateral rectus muscle of the eye. This works alongside the pontine center for lateral gaze with eye movements outward to the right or left. It is also linked to the pontine/midbrain center for vertical gaze and is a part of a collection of fibers which form a loop tying into the facial nerve. An injury to the 6th cranial nerve can cause lateral gaze paralysis or paralysis of the lateral rectus muscle which results in horizontal diplopia (double vision)
    VII – Facial
    The 7th cranial nerve controls motor control of the face. This includes the ability to raise eyebrows, movement of the lips, closure of the auditory canals and gustatory sensation. The facial nerve also innervates the taste buds of the anterior 2/3 of the tongue, which if injured, can cause a loss in taste sensation. The stapedius muscle, which inhibits the movement of the ossicles to dampen excessive sound. Should the stapedius become paralyzed an individual may experience sounds as too loud, intolerable or painful. Other symptoms associated with an injury to this nerve include lip retraction, eyebrow lifting, eyelid closure paralysis (Bell's Palsy), inability to wrinkle one's forehead, purse lips or show their teeth. There may be a drooping of the corner of the mouth.
    VIII – Vestibular
    The vestibular portion of the 8th cranial nerve innervates the labyrinth and the macules of the saccule and urticle as well as the ampullae of the semicircular canals. The primary function of this nerve is to determine the body's position in visual-space in order to maintain equilibrium during movement. Changes in fluid balance in the semicircular canals allows the brain to determine changes in position. As a result, if there is an injury to the vestibular receptors or central connections an individual can experience abnormal sensations of movement, vertigo, nausea, tendencies to fall, dizziness, and motion sickness. Hearing problems including deafness or tinnitus which may be described as hearing buzzing, humming, whistling, roaring, hissing or clicking can also occur. They may feel as though they are being pulled to one side or lean/veer to one side when walking. In order to mediate postural reflexes, the vestibular nerve has rich interconnections with cranial nerves III, IV, and VI which subserve eye movement. Nystagmus or difficulty focussing when moving or when an object is moving can thus result from injury as well
    IX – Glossopharyngeal
    Closely related to the vagus nerve, the 9th cranial nerve receives tactile, thermal, and pain sensations from the tongue and helps to form the gustatory nucleus. It also receives information about carotid artery pressure via fibers from the carotid sinus. All of this information is transmitted to the solitary nucleus which then contributes to the vagus nerve. Together the 9th and 10th cranial nerves can influence heart rate and arterial blood pressure. Lesions here will usually result in loss of taste and sensation in the posterior 1/3 of the tongue, a loss of gag reflex, and carotid sinus reflex. Swallow or coughing may become intensely painful.
    X – Vagus
    Actually a complex mix of nerves, the vagus innervates a number of structures including the larynx, pharynx, trachea, esophagus, epiglottis, external auditory meatus, and viscera in the thoracic and abdominal cavities. As such, important bodily functions such as swallowing, breathing, speaking, movement of the palate, pharynx and larynx are all within its influence. It is also responsible for the swinging of the soft palate upward to seal off the oropharynx from the nasopharynx when swallowing, whistles, or talks. An injury can cause palate weakness and pseudobulbal palsy. Speech can be severely affected as well if fluids get into the nasal passages, in which case speech will becomes excessively nasal in nature. Due to it's long-reaching influence on a wide range of structures many other symptoms may develop from injury to the vagus nerve, incuding gastroparesis, hyperarousal, smooth muscle cramping, IBS, weight gain, depression, bradycardia, chronic inflammation, nutritional deficiencies and seizures.
    XI – Spinal Accessory Nerve
    Two distinct segments of this nerve exist. The cranial portion, along with the vagus nerve, forms the inferior laryngeal nerve going to the larynx. The spinal portion of this nerve innervates the sternocleidomastoid (SCM) and upper trapezius muscles to help turn the head and elevate the shoulders. As a results, if this nerve becomes injured one's shoulders may sag on the affected side or the individual may show weakness in turning the head. This is particularly true against resistance.
    XII – Hypoglossal Nerve
    Located in the caudal medulla, the hypoglossal nerve controls movement of the tongue by innervating the relevant skeletal muscle. If the nerve is damaged the skeletal musculature will not properly move the tongue and weakness or atrophy can result. Tongue strength can be tested by placing one's tongue on one side of the cheek and pressing against a practitioners finger when it is placed on the outside of the cheek. Lower motor neuron pathology may cause unilateral atrophy, fasciculation or fibrillation and paralysis that results in an obvious deviation toward the paralytic side when the tongue is protruded.
    The Cranial Nerves – Pathology and Symptoms
    I - Olfactory
    Loss of smell/taste, risk of cerebrospinal fluid fistula
    II - Optic
    Visual defects including blindness, neglect, etc.
    III - Oculomotor
    Ptosis, pupil unresponsive to direct light, inability to move eye downward, upward, or inward
    IV - Trochlear
    Inability to move eye in order to look in downward or inward direction
    V - Trigeminal
    Face pain, difficulty chewing, atrophy or paralysis of temporal or masseter muscles
    VI - Abducens
    Lateral gaze paralysis, horizontal diplopia
    VII -Facial
    Bells' Palsy, facial paralysis or flaccidity, eyebrow raising, eyelid closure paralysis, taste loss in anterior 2/3 of tongue, sounds may seem too loud or painful
    VIII -Vestibular
    Vertigo, nauea, dizziness, leaning or veering to one side when walking, unsteadiness, abnormal sensations of movement, tinnitus, nystagmus, difficulty focusing on objects when they are moving or when walking
    IX -Glossopharyngeal
    Loss of taste/sensation in posterior 1/3 of tongue, loss of gag reflex and carotid sinus reflex, painful swallowing or cough
    X - Vagus
    Pseudobulbar palsy, difficulty swallowing/dysphagia, slurred speech, palate weakness, gastroparesis, hyperarousal, smooth muscle cramping, IBS, weight gain, depression, bradycardia, chronic inflammation, nutritional deficiencies, seizures
    XI – Spinal Accessory
    Ipsilateral sagging shoulder(s), weakness in turning head (esp. against resistance)
    XII - Hypoglossal
    Tongue weakness/atropy/deviation
    Acupuncture Considerations
    A number of points have demonstrated by fMRI studies a correlation to brain activity in the temporal lobes10
    Activating:
    Pons: GB-34, GB-39
    Caudate nucleus: GB-34, GB-39
    Superior Collicus: GB-37
    Deactivating:
    Basal Gyrus: ST-36
    George Soulie De Morant13 notes indications for brain regions according to his extensive studies of the medicine in Chinaprior to the communist revolution when much of the information was either politically streamlined or lost. According to hisstudies points had been found to influence brainstem structures.
    Pons
    Tonifying
    Dispersing
    ST-11
    SP-6, SP-9
    HT-6, HT-8
    KI-6, KI-10, KI-17, KI-19, KI-20
    PC-1
    GB-20
    LR-5
    Medulla Oblongata
    Tonifying
    Dispersing
    LU-1, LU-7
    LI-6
    ST-4, ST-14, ST-16, ST-22, ST-32, ST-33, ST-42, ST-44
    SP-21
    HT-6
    SI-8, SI-19
    BL-11, BL-51, BL-52, BL-54, BL-66
    KI-1, KI-7, KI-21, KI-25
    PC-2
    TW-19
    GB-4, GB-5 (opposite), GB-20, GB-25, GB-26 GB-34, GB-35, GB-37
    LR-4, LR-13
    CV-9, CV-17
    GV-1, GV-10, GV-13, GV-18
    KI-2
    TW-10
    LR-2
    Autonomic Nervous System
    Sympathetic Tonifying ST-41 PC-8 TW-5 GB-20
    Parasympathetic Tonifying: ST-21 BL-10 CV-12 GV-20
    Parasympathetic Dispersing: PC-8

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Monday, July 31

  1. page Temporal Lobes edited ... The temporal lobes are highly susceptible to injury from a variety of causes, including head i…
    ...
    The temporal lobes are highly susceptible to injury from a variety of causes, including head injury, stroke, tumor, and epilepsy. In part, this susceptibility is due to the position of the temporal lobe within the skull. With whiplash injuries, or if the skull is struck from the back or the front, the temporal lobes will slam into the inside of the skull and may be ripped, torn, and sheared. These are called coup and contra coupe injuries.
    The inferior temporal lobes are also slow to mature which in turn increases the likelihood that abnormal neural networks may be formed in response to adverse early experience. Hence, not surprisingly, abnormal early environmental influences, including profound traumatic stress, can induce language, emotional, and memory disorders including repression for childhood experiences, as well as severe psychiatric abnormalities including schizophrenia and dissociative phenomenon; disturbances which implicate the temporal lobes as well as the amygdala and hippocampus.
    {http://brainmind.com/images/coupFrontalTemporal.jpg} {Temporal Lobe Chapter.pdf}
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    2:26 pm

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