Fear, Anxiety Disorders and Amygdala PSY391S March 29, 2006 John Yeomans

Limbic System Anatomy Oldest areas of telencephalon, bordering diencephalon. Limbic means "border". Connections with olfactory and taste systems, hypothalamus (visceral & emotional). Transition from subcortex (e.g. amygdala) to 3-4 layered cortex (e.g. hippocampus) to 6-layered neocortex. Interconnections--"Papez Circuit"

Amygdala and Conditioned Fear Unconditioned fear mediated through PAG.

Extended Amygdala and Emotions Subcortical parts of limbic system. Amygdala, BNST, Basal Forebrain (olfactory tubercle, Ventral pallidum, septum and basal n.), n. accumbens. Fear and emotion learning (amygdala), sex and maternal behavior (medial amygdala, BNST, ventral pallidum), and reward learning (n. accumbens).

Monogamous voles have more Vasopressin in their Ventral Pallidum. Young et al.

Bed Nucleus and Gender Identity Central n. of BNST is sexually dimorphic in humans—larger in males by 44%. 6 transgendered males had smaller BNSTc. Not related to partner preference. No differences in MPO areas that are sexually dimorphic. Correlation, not causal link.

Early Studies Temporal lobe lesions (Klüver-Bucy Syndrome) lead to tame monkeys, fearless and hypersexual. Temporal lobe epilepsy leads to emotional auras and behaviors. Stimulation of amygdala leads to attack, rage or positive affect. Stimulation of hippocampal region leads to experiential reports "deja vu".

CS Tone, US shock

LeDoux, Davis Deep superior colliculus Startle Fear Potentiation

Fear Learning Unlearned emotional responses activated through PAG (central gray), SC, BNST and hypothalamus. Associations between CS and US occur in lateral and basolateral n. Fast CS auditory path via thalamus, slow CS path via auditory cortex. Context associations via hippocampus.

/ Deep SC

Pharmacology of Fear and Anxiety Fear inhibited by benzodiazepines (GABA A agonists) in amygdala. Fear activated by glutamate. Panic activated by CCK B in amygdala. Stress/anxiety activated by CRH in BNST. Peripheral effects of stress hormones (CRH  ACTH  cortisol) and central effects on limbic system.

Anxiety Disorders I Phobias: Specific fears, often learned. Treated by psychotherapy “progressive desensitization”. Panic attacks: Severe sympathetic overreactions to uncomfortable situations. Usually treated with tranquillizers and psychotherapy. Amygdala? Post-traumatic stress: Fear brought on by specific trauma, e.g., violence or accident. Nightmares. Generalized anxiety: Persistent excessive worries, associated with depression. Treated with SSRIs or tranquillizers.

Posttraumatic Stress Disorder

Anxiety Disorders II Obsessive-compulsive disorders: Uncontrollable and irrational desire to perform repetitive tasks, e.g. washing, or checking for safety. Overactivity in striatum. Treated with neuroleptics. Tourette’s Syndrome: Uncontrollable tics, either motor or verbal. Treated with neuroleptics.

Frontal Cortex and Emotions Orbital, medial prefrontal and cingulate. Conscious processing of rewards and punishers. Important in depression (fMRI) and SSRI antidepressant actions. Long-term planning of emotions, motives and actions. Weak lateralization of emotions in right frontal cortex.

Areas Changed by Emotions (fMRI) Yellow--Orbitofrontal Blue--Anterior Cingulate Green--Posterior Cingulate Purple--Insula Red--Amygdala

Depression Irrational feelings of failure and hopelessness, loss of appetites, loss of energy, sleep disorders. Treated with selective serotonin reuptake inhibitors, benzodiazepines, and/or cognitive psychotherapy. SSRIs take weeks to work, perhaps due to stimulation of neurogenesis in hippocampus. Often associated with generalized anxiety, and can be treated with tranquilizers short term.

Brain Changes Increased activity in amygdala, mediodorsal thalamus, medial orbitofrontal cortex. Benzodiazepines inhibit amygdala and many other areas. SSRIs inhibit orbitofrontal cortex. Also, activate hypothalamus feeding/energy system for weight loss. Cognitive therapy inhibits anterior cingulate. Electroconvulsive shock still used occasionally, e.g. suicide, poor drug effect. Cingulotomy less often (pain and depression).

Cingulate and Depression Cingulotomy (cutting fibers of anterior cingulate) relieves persistent pain and depression. Stimulation of subgenual anterior cingulate (Area 25) relieves persistent depression in a few treatment-resistant people.

Bipolar Disorder Manic-depression (now called “bipolar disorder”) results in severe mood swings from high to low. Usually cyclic, with shorter highs of great energy, self-confidence and destructive behaviors (spending, gambling, escapades), followed by longer periods of depression. Treated with lithium, which effectively smooths out highs and lows, but mechanism still unknown. Widespread brain changes.

Schizophrenia Positive symptoms: hallucination and delusions. Loss of contact with reality. Negative symptoms: social withdrawal, poor grooming. Cognitive symptoms: poor intellectual functioning. Positive symptoms treated by D2 blockers (typical neuroleptics). Negative symptoms also treated with atypical neuroleptics (e.g. clozapine) but mechanism still unknown.

Brain Changes Dopamine system or receptors? Amphetamine psychosis. Phencyclidine (PCP) psychosis suggests that NMDA inhibition also important. Low frontal cortex activity. Changes in hippocampus organization. Reduction in cortical mass, and hippocampal/ amygdala mass, with enlargement of ventricles. Causes? Strongly genetic, but many genes. Environment—Drug taking, prenatal viruses (cytokines slow brain development in pregnancy?)

Male vs. Females More females than males have depression and some anxiety disorders. More males have schizophrenia, with earlier onset and greater severity. Estrogens may be protective factor, because some women get schizophrenia at menopause.