Handout for Biology of Mental Disorders (BCS 246)
Session 15 (11/5)

Aggression

• Amygdala
• Damage bilaterally causes Kluver Bucy syndrome with reduced aggressiveness
• Aggression provoked by stimulating amygdala in most animals
• Aggression provoked as above is be inhibited by frontal cortex stimulation (ipselateral)
• Amygdala lesions cause lowering of social dominance rank in colony
• Can be "kindled" easily, as other areas of limbic system, with long lasting behavioral
  changes (aggressiveness, defensiveness)
• EEG spikes related to episodic irritability in humans
• Other brain regions where stimulation causes aggression
• Regions of hypothalamus (medial)
• Areas around fornix in diencephalon (near thalamus, striatum, and hypothalamus)
• Central gray (neuron dense area around cerebral aqueduct in midbrain)
• Ventral posterior lateral nucleus of thalamus
• Areas that may be involved in inhibiting aggression
• Frontal lobes (stimulation can block aggression caused by stimulation in a number of areas)
• Ventrolateral hypothalamus (lesions interfere blocking of aggression by amygdala lesions)
• Medications that have been shown to reduce aggressiveness include: lithium carbonate (salt effective in manic depressive disorder), Tegretol (anticonvulsant, also effective in manic
  depressive disorder), Inderol (beta adrenergic blocker, antihypertensive), antipsychotics
• Unknown how this works, many have speculated on 5HT effects, anti-kindling effects etc.

• JA Gray, based on animal studies, has postulated a behavioral inhibition system (BIS) that
  includes the septohippocampal system
• BIS is affected by internal neurotransmitter release and benzodiazepines (BZ, anxiolytics)
• Stimulation of septum causes anxiety-like behaviors
• Lesions of septum or hippocampus cause behavior much like that seen after BZs
• System as "comparator"
• If stimuli are not found in memory and seen as "safe" signals sent to increase arousal,
  vigilance, defensive behaviors
• Frontal lobes act as comparator for motor programs, and in man, allows for verbal
  influences to predominate over septohippocampal processing
• Possible neural substrate for obsessive symptoms
• Weakness of Gray's theory is the lack of amygdala function
• Ledoux's theory of anxiety
• Based on "neural circuits" of fear and autonomic conditioning in the auditory system
• Evidence for two systems, he feels are related to fear vs. anxiety
• Fear seen as subcortical, involving info flow from auditory ctx -> inf. colliculus ->
  medial geniculate -> amygdala and does not involve association cortex
• Anxiety seen as info flow from auditory cortex -> neocortical auditory system -> amygdala, extended amygdala, autonomic and somatomotor systems, with more delayed route and "refinement" of message"
• For fear, more raw" information assessed in terms of affect by amygdala
• For anxiety, more processed, and hippocampus input particularly allows "cognitive"
  information, and results in "anxiety" linked to specific situations
• Both theorists allow for large impact of ascending amine system (particularly norepinephrine [NE] and serotonin [5HT] in mediation, due to effects on hippocampal "gating" of information
• Medications most effective for acute anxiety are benzodiazepines and barbiturates, with effects on GABA receptor being critical
• Medications effective in chronic anxiety include antidepressants and 5HT receptor agonists and antagonists (agonist at 5HT 1a, antagonists at 5HT 2 and 3)

• Hippocampal cells of CA1 and CA3 very much involved in memory
• May create "spatial maps"
• Critical to either the consolidation of short-term memory or retrieval of information
• NMDA receptor (type of glutamate receptor) crucial to "plasticity" and long-term
  potentiation (LTP)
• Amygdala involved in memory, probably related to affectively influenced memories, which
  are enhanced relative to non-affective
• The stress hormone ACTH is highly bound by hippocampus and may be involved in memory enhancement (? the neurochemical underpinning of cognitive/affective
  enhancement?)
• Pleasurable stimulation may be important to memory consolidation through pathways below
• Memory/cognitive enhancers only in the experimental phases, but DA agonists can be helpful for some, as well as antidepressants if memory impairment related to depression

• Stimulation of certain areas can act as reinforcers and animals with self-stimulated if allowed
• Areas include many regions around Medial Forebrain Bundle (MFB)
• MFB is a trunk of fibers that extend from midbrain to basal forebrain
• Most "active" sites in terms of pleasure are in areas with high concentrations of dopamine
  (DA), norepinephrine (NE)
• Septum, hypothalamus, nucleus accumbens of striatum
• Some areas odd since related to aggression, but "control" over stimuli might be relevant
• All addictive substances have in common the release or enhancement of DA and its effects in critical areas such as the nucleus accumbens (includes stimulants, alcohol, opiates)

• Amygdala (Kluver-Bucy syndrome)
• Septal lesions reverse hypersexuality of KB syndrome (i.e. septum critical to sexual behavior?)
• Penile erection and orgasm in animals related to septal activity
• Anterior hypothalamus critical area for hormonal secretion necessary for normal function
• Monoamines (DA, NE) and serotonin (5HT) involved in normal sexual behavior
• Side effects of psychotropic medication affecting these neurotransmitters include: reduced
  libido, anorgasmia, painful orgasm, priapism

• Dependent on tonic effect of ascending reticular activating system (RAS)
• Extends from medulla to thalamus (intralaminar nucleus part of this system)
• Stimulation of this area causes EEG desynchronization (left/right, and generally less high
  amplitude waveforms)
• Stimulation causes behavioral arousal
• Lesions can lead to "permanent sleep" (I think this is coma!!)
• Other areas, if lesioned (raphe with 5HT cells), cause permanent insomnia
• RAS receives input from adjacent ascending and descending tracts and nuclei, hypothalamus, and limbic system
• RAS sends output to entire cortical mantle, mostly through effects on thalamic nuclei and monaminergic/serotonergic nuclei (NE, DA, 5HT efferents), and to spinal cord, influencing
  motor neurons and sensory afferents

• Dependent on superior parietal lobes
• Right side "modulates" attention bilaterally or more critical in integrating bilateral info
• Left side "modulates" attention predominantly on right side
• Basal ganglia important in attentional function
• Anterior cingulate critical to attention

• Mesulam makes point of stating that paralimbic and heteromodal cortex critical for formation of " internal template", with a gradient of communication from limbic to cortical areas and no specific area of "gating"
• Trimble emphasizes entorhinal cortex/parahippocampal gyrus as site through which highly processed neocortical information is passed to hippocampus and from her to other "limbic" structures. He states this is a two way "gate", allowing limbic information to flow back to cortex
• Greater emphasis on a low "band-width" gate, with regional specificity, where information is passed (though this is newer text, the tracing experiments support Mesulam's view, with this area possibly more critical to consolidating information for memory than all info passing

• Focus on integration of emotion and motoric activity, based on
• Motor abnormalities in patients with psychiatric syndromes (depression/mania with reduced/excess activity; tic and other motoric hyperactivity syndromes in patients with
  ADHD, OCD, and schizophrenia)
• Motor abnormalities follow the level of psychopathology
• Traditional motor syndromes have high comorbidity of psychiatric syndromes (Parkinson's, Huntington's, Tourette's, Wilson's disease etc.)
• Neural circuits defined for motor system have close parallels in limbic regions
• Information from limbic system (especially amygdala, hippocampus) critical for putting present in context of memory and applying an affective "valence" respectively
• Ventral (limbic) basal ganglia critical to emotional/motoric integration
• Inputs from amygdala and hippocampus
• May be critical to "gating" information in cortico-striatal-pallidal-thalamic circuits, and hence the outflow to both the motor and association cortex (including frontal ctx)
• Emotion (positive/negative) may be critical to the ability to initiate new and appropriate motor behavior as well as curtail an ongoing "program" that is no longer appropriate respectively
• Hemispheric specialization of emotion
• Damage to right hemisphere more likely to result in sensory inattention, aprosody (lack of affective color of speech), emotional unconcern, and reduced ability to detect emotional cues
• Anesthesia of left hemisphere more likely to result in depression, with right sided anesthesia often causing euphoria
• ? Left hemisphere may be more "linear categorical" in its processing with the right being more holistic and non-linear (this is still unclear)

• Careful history taking for diagnosis is critical and most often neglected aspect of work up
• 3rd party input crucial (family, friends, support group who knows patient etc.)
• Personality style and development dissociated from onset of pathologic process
• Frequent failure to do this
• Must get background, then focus on point of departure from typical functioning to onset of new process resulting in psychiatric attention
• Differential diagnosis and search for etiology (many causes of psychiatric symptoms that need identification and elimination of offending factor)
• Do not see distinction of functional vs. structural being as clear as Trimble makes it
• There are structured clinical interviews that assure diagnosis is made with appropriate ruling out of other psychiatric syndromes, as well as symptom rating scales to assess change
• Typical laboratory work up (not to be memorized!!!, but psychiatrists better know this)
• Basic serum tests, including: blood counts, renal functions, liver functions, test for acute inflammatory process (ESR), syphilis screen, vitamin B12 and folate levels, thyroid functions
• Sometimes: glucose tolerance test, serum copper if Wilson's disease suspected, antinuclear antibody if autoimmune disorder suspected, EEG, and MRI of head if suspect seizure disorder, first episode of psychosis, focal neurologic findings, change from treatment responsive to refractory
• Research approaches and technology
• Epidemiologic studies for examining incidence of disorders, relation to demographics, stability over time, whether accessing care professionals etc.
• Longitudinal studies of patients with disorder to examine comorbidity issues, changes over time within patients, response to treatment over time, predictors of prognosis etc.
• Genetic factors
• Family studies, twin studies, identical or monozygotic (MZ) vs. dizygotic (DZ) twin studies (concordance rates, best are adoption studies [raised together vs. apart])
• Genetic linkage studies
• Neuroendocrine function
• Prolactin levels, cortisol level after giving agent that should decrease it (dexamethasone suppression test), TRH stimulation test (to see responsiveness of hypothalamus), prolactin levels (prolactin release under dopaminergic control)
• Challenge studies
• Ex. Growth hormone response to apomorphine (dopamine agonist)
• Behavioral response to serotonin agonist/antagonist, serotonin depleting diet etc.
• Response to yohimbine (NE agonist)
• EEG and ERP studies (cortical brain electrical activity, averaged EEG due to stimuli)
• Abnormalities, relation to clinical picture, prediction of response, challenge studies
• Neuroimaging for structural and functional changes
• CT scan, MRI, MRS, fMRI, PET, SPECT scanning

Limbic Structure                   Behavioral Influence
Cingulate                          Maternal behavior, play, vocalization
Hippocampus                        Memory, anxiety
Amygdala                           Fear/anxiety, aggression, sex, mood, memory for emotional events
Septum	                           Pleasure
Hypothalamus                       Eating, drinking, sex, aggression, hormonal control
Reticular activating system (RAS)  Arousal, sleep-wake cycle
Entorhinal cortex                  Memory, sensory integration
Ventral striatum                   Motivation