BIOSCI N165 -- Unit 6

Limbic System

A collection of subcortical brain regions that controls mood and attitude, is involved in storage of highly charged emotional memories, and controls appetite and sleep cycles.

Key components:

• Amygdala – involved in rage, fear, and fight-or-flight; processes fear-related memories

• Hippocampus – plays a key role in long-term memory storage and spatial navigation

• Hypothalamus – regulates and releases hormones along the HPA axis

• Anterior cingulate gyrus – regulates autonomic functions (blood pressure, heart rate) and cognitive functions (reward anticipation, decision-making, empathy, emotion)

• Mammillary bodies & anterior thalamus – also play roles in long-term memory storage

• Additional components: cingulate gyrus, fornix, parahippocampal gyrus, ventral tegmental area, septal nucleus, prefrontal area

Hypothalamus-Pituitary-Adrenal (HPA) Axis

A major part of the neuroendocrine system that controls reactions to stress and regulates many body processes including mood and emotion.

Involves complex feedback interactions among the hypothalamus, pituitary gland, and adrenal glands, and may be abnormal in anxiety and depressive disorders.

May be abnormal in anxiety and depressive disorders.

Depression

A set of neuropsychiatric disorders characterized by a pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities.

Can be a FATAL illness — suicide is the 10th leading cause of death.

SIGECAPS:

• Sleep changes

• Interest loss (Anhedonia)

• Guilt or feeling worthless

• Energy loss

• Concentration problems

• Appetite changes

• Psychomotor changes

• Suicidal thoughts

Anhedonia

The inability to experience pleasure or interest in formerly pleasurable or satisfying activities.

A key symptom of depression.

Psychomotor Agitation

A series of unintentional, purposeless motions stemming from mental tension and anxiety — e.g., pacing, hand-wringing, uncontrolled tongue movements, pulling clothing on and off.

Psychomotor Retardation

Also called psychomotor impairment — a visible slowing of physical activity such as movement and speech.

Major Depressive Disorder

Having 5 or more depressive symptoms that last without remission for at least two weeks.

Often characterized by anhedonia, psychomotor retardation, weight loss, guilt, and insomnia.

Also called unipolar or clinical depression.

Melancholic Depression

The most "classic" type of depression — low mood, insomnia, loss of appetite/weight loss, and anhedonia.

Mood does NOT temporarily improve in response to positive events.

Contrast with atypical depression.

Atypical Depression

A subtype of depression with mood reactivity (mood improves temporarily with positive events), paradoxical anhedonia, significant weight gain or increased appetite, hypersomnia, leaden paralysis (heaviness in limbs), and hypersensitivity to interpersonal rejection.

Leaden Paralysis

A sensation of heaviness in the limbs — a specific symptom associated with atypical depression.

Dysthymia

A less severe but long-lasting depression that lasts for at least two years. Does not meet the full criteria for a major depressive episode.

Also called persistent depressive disorder.

Adjustment Disorder with Depressed Mood

A mood disturbance appearing as a psychological response to an identifiable event or stressor.

Emotional or behavioral symptoms are significant but do NOT meet the criteria for a major depressive episode.

Catatonic Depression

A rare and severe form of major depression involving disturbances of motor behavior.

The patient is mute, immobile, or exhibits purposeless or even bizarre movements.

Catatonia can also occur in schizophrenia and other disorders.

Seasonal Affective Disorder (SAD)

A depressive disorder related to circadian rhythms in which depressive episodes come on in autumn/winter and resolve in spring.

Winter symptoms include intense hunger, weight gain, hypersomnia, and lower mood in the evening.

Treatment: light therapy (phototherapy).

Postpartum Depression

Intense, sustained, and sometimes disabling depression experienced by women within three months after giving birth — can last a year or more. Likely due to sudden withdrawal of placental hormones.

Postpartum psychosis (= postpartum mania) is also possible.

Premenstrual Dysphoric Disorder (PMDD)

Severe, debilitating PMS with an abnormal response to normal hormonal levels.

Genetic component; affects 3-8% of women.

Symptoms start ~1 week before menstruation and abruptly end when it begins.

Treatment may include low-dose antidepressants taken only during the symptomatic week.

Monoamine Hypothesis

An early hypothesis that depression results from abnormalities in monoamine neurotransmitters (serotonin, norepinephrine, dopamine), based on the observation that medications affecting these neurotransmitters have psychological side effects.

Note: a 2022 study questioned the serotonin role.

Biological Cause of Depression

Specific monoamine hypothesis – the more targeted theory that depression results from pre-synaptic and/or post-synaptic changes specifically in noradrenergic (norepinephrine) and/or serotonergic (5-HT) pathways

Cognitive Model of Depression (A.T. Beck)

Depressed patients hold pessimistic views of themselves, the world, and the future, with recurrent patterns of depressive thinking and disordered information processing (e.g., exaggerating bad experiences, minimizing good ones).

This model led directly to the development of CBT.

Psychosocial Cause of Depression

Learned Hopelessness Theory

A model of depression in which the patient loses hope that life will get better (possibly based on early life experiences) and believes negative experiences are due to stable, global reasons — e.g., "I didn't get the job because I'm stupid" vs. "the interview didn't go well."

Psychosocial Cause of Depression

Cognitive Behavioral Therapy (CBT)

An empirically tested psychotherapy for treating depression and anxiety in which patients are taught to alter recurrent patterns of depressive thinking to restore normal information processing.

Targets the triangle: Thoughts → Feelings → Behaviors.

Best combined with medication.

Also helpful for bipolar disorder

SSRIs (Selective Serotonin Reuptake Inhibitors)

Antidepressant drugs that block the reuptake of serotonin so that more serotonin is available to act on receptors in the brain.

Selective for serotonin compared to MAOIs and tricyclics.

Example: Prozac (fluoxetine). Can take 6-8 weeks for effect.

MAOIs (Monoamine Oxidase Inhibitors)

Antidepressant medications that cause a general increase in monoamine neurotransmitters (serotonin, norepinephrine, dopamine). One of the oldest antidepressant classes.

Carries dietary risks (dangerous interactions with tyramine-containing foods).

Electroconvulsive Shock Therapy (ECT)

Electric shock therapy used for refractory (hard-to-treat) depression.

A grand mal seizure is induced in a sedated patient to "reboot" the brain. Administered 3 days/week for 2-3 weeks, then monthly maintenance. ~100,000/year in the US.

Mild memory loss and fatigue on treatment day.

Deep Brain Stimulation (DBS)

Therapy for severe depression in which electrodes are implanted into the basal ganglia (as in Parkinson's disease) and stimulate at a patient-specific frequency.

Can have IMMEDIATE effects — symptoms may reappear rapidly when turned off.

Also used for severe OCD and Tourette's.

Mania

A psychological state characterized by DIG FAST:

• Distractibility — Attention is easily drawn to unimportant or irrelevant external stimuli

• Indiscretion — Excessive involvement in risky, impulsive, or high-consequence behaviors

• Grandiosity — Inflated self-esteem, grand or exaggerated beliefs in one's special powers, importance, or abilities

• Flight of Ideas — Racing thoughts or a subjective experience that thoughts are moving very fast

• Activity increase — Increased goal-directed activity (socially, at work, or sexually) or physical psychomotor agitation

• Sleep deficit — Decreased need for sleep

• Talkativeness — Pressured speech

Can include psychosis.

Dangerous due to extreme risk-taking.

Pressured Speech

A symptom of mania characterized by an intense pressure to keep talking — rapid, non-stop speech and talkativeness.

A "flight of ideas" is the thought equivalent of pressured speech.

Hypomania

A mood state characterized by persistent disinhibition and euphoric mood, but generally less severe than full mania.

Characterized by extreme energy, talkative flight of creative ideas (pressurized speech for thoughts), and confidence.

Distinguished from mania by the ABSENCE of psychosis and grandiosity, and lesser impact on functioning.

Bipolar I

Episodes of severe depression alternate with MANIA.

The most severe form of bipolar disorder.

Bipolar II

Episodes of severe depression alternate with HYPOMANIA (not full mania).

More common than Bipolar I.

Cyclothymia

A milder, chronic cycling form of bipolar disorder in which DYSTHYMIA alternates with HYPOMANIA.

Mixed Affective Disorder

A disorder in which manic AND depressive symptoms occur SIMULTANEOUSLY (rather than alternating).

Symptoms include agitation, impulsiveness, anxiety, restlessness, rage, insomnia, suicidal ideation, pressured speech, and racing thoughts.

Lithium

The element lithium (Li, atomic number 3) used to treat bipolar disorder as a MOOD STABILIZER — prevents mania.

Must be carefully managed because it is TOXIC. Discovered accidentally by Dr. Cade after WWII.

Must be used WITH an antidepressant, not alone.

Antidepressants in Bipolar Disorder

Antidepressants (e.g., SSRIs) can be used for bipolar disorder ONLY with a mood stabilizer.

Using an antidepressant ALONE may push the patient from depression INTO a manic episode. A mood stabilizer (e.g., lithium) must also be prescribed.

Anxiety

Diffuse, vague feelings of fear and apprehension.

Everyone experiences it — it becomes a problem when it is irrational, uncontrollable, and/or disruptive.

Anxiety and depression are increasingly viewed as related disorders existing along a continuum. There is approximately a 60% co-occurrence of anxiety with depression. Genetic factors plus environmental triggers play a role in both.

Anxiety Disorder

A set of disorders in which the normal anxiety response is inappropriately provoked by homeostatic imbalance.

Characterized by a physiological state including racing heart, sweating, etc. About 60% co-occur with depression.

Physiological Causes

• Low levels of GABA — GABA is the primary inhibitory neurotransmitter in the brain; low GABA is associated with anxiety disorders

• Role of the amygdala — limbic system structure that controls the fear response and processes fear-related memories; supports species-specific fear responses

• HPA axis dysregulation and cortisol (stress response)

Other Factors

• Genetic predisposition plus environmental triggers

• Childhood trauma (especially linked to GAD)

• ~60% co-occurrence with depression

Phobia

An intense, irrational fear of a specific thing (e.g., object, event/situation, social setting) that interferes with normal behavior. May develop through classical conditioning.

More commonly diagnosed in females than males.

Specific Phobia vs. Social Phobia

Specific phobia: fear of a specific object (e.g., animals, blood, heights).

Social phobia: fear of failing or being embarrassed in public (e.g., public speaking, meeting new people, eating in public).

Considered phobic only if fears INTERFERE with normal behavior.

Generalized Anxiety Disorder (GAD)

Chronic anxiety, worry, and tension INDEPENDENT of a clear external cause for at least 6 months.

Patients anticipate disaster and are overly concerned about health, money, family, or work.

Women 2x more than men.

Physical symptoms: headaches, stomachaches, muscle tension, trembling, irritability

Genetically related to major depression; childhood trauma also implicated.

Obsessive-Compulsive Disorder (OCD)

An anxiety disorder characterized by obsessive, distressing, intrusive thoughts (obsessions) and related compulsions which attempt to neutralize the obsessions.

Cause: heightened activity of the caudate nucleus of the basal ganglia.

Obsession — irrational, disturbing thoughts that intrude into consciousness

Compulsion — irresistible, repetitive actions performed to alleviate obsessions (most commonly checking and washing)

Obsession vs. Compulsion

Obsession: irrational, disturbing thoughts that intrude into consciousness.

Compulsion: irresistible, repetitive actions performed to alleviate obsessions. Most common compulsions are checking and washing.

OCD & the Caudate Nucleus

OCD is associated with HEIGHTENED neural activity in the caudate nucleus of the basal ganglia — a region associated with initiation of learned, habitual motor activities. SSRIs reduce caudate activity.

DBS targeting the basal ganglia can also help severe cases.

Note: OCD and Tourette's syndrome BOTH involve changes in the caudate nucleus.

Panic Disorder

A disorder characterized by recurring panic attacks (feelings of helpless terror) and persistent fear of having them.

Symptoms: palpitations, sweating, trembling, chest pain, choking, nausea, dizziness, fear of losing control or dying.

Often leads to agoraphobia as a secondary result.

Agoraphobia

An anxiety disorder often precipitated by fear of having a panic attack in a setting with no easy means of escape.

Sufferers may avoid public or unfamiliar places.

Often develops as a result of panic disorder.

Post-Traumatic Stress Disorder (PTSD)

An anxiety disorder in which patients experience symptoms following a traumatic event (e.g., war, rape, assault).

Symptoms: nightmares and flashbacks, increased arousal (sleeplessness, hypervigilance), depression, irritability, and avoidance of stimuli associated with the traumatic event.

Symptoms last > 1 month.

GABA & Anxiety

Anxiety disorders are associated with LOW levels of GABA (the primary inhibitory neurotransmitter in the brain).

Anxiolytics modulate GABA receptors to increase general neural inhibition. SSRIs may also have effects on GABA circuits.

Amygdala & Anxiety

The amygdala is a limbic system structure that controls the fear response and processes fear-related memories. It supports species-specific fear responses and is associated with stimulus salience.

The amygdala plays a key role in the development and maintenance of anxiety disorders.

Anxiolytics (Anti-anxiety medications)

Medications that produce a short-acting reduction in anxiety (e.g., Ativan, Xanax, Valium). Modulate GABA receptors to increase general neural inhibition.

SHORT-TERM USE ONLY — significant addiction risk.

Most useful for rapid onset, short-term problems like phobias and panic attacks.

Beta-Blockers for Anxiety

Medications that stop the PHYSICAL symptoms of anxiety (e.g., slow heart rate). When physical symptoms stop, the cognitive anxiety response also stops.

Used in cardiovascular medicine as well.

Useful for short-term, situational anxiety.

DBS for Severe OCD

Deep brain stimulation (DBS) targeting the basal ganglia can have dramatic improvement for severe, refractory OCD.

The role of the basal ganglia in habit-forming behavior may be directly related to OCD compulsions.

Also used for Tourette's syndrome and severe depression.

Brain Areas involved in Depression

• Prefrontal & orbitofrontal cortex – “BROKEN CEO”

  • Inability to make decisions, poor judgement, feeling like nothing matters

  • Underactive

• Anterior cingulate cortex – “MALFUNCTIONING BRAKES”

  • Excessive worrying, rumination (obsessive thinking), inability to regulate sadness

  • Fails to regulate emotional heartache

• Hypothalamus – “STRESS FACTORY”

  • Feeling chronically stressed, having trouble sleeping, changes in appetite

  • Excess cortisol, HPA Axis reactivity

• Serotonergic pathways - likely through influences on dopamine pathways

• Suprachiasmatic nucleus – “INTERNAL CLOCK”

  • Sleep changes, linked to SAD

  • Dysfunctional circadian rhythm

• Basal ganglia & Reward pathways – “REWARD DROUGHT”

  • Anhedonia

  • Pleasure pathways clogged/deficient

• Hippocampus — “SHRINKING HARD DRIVE”

  • Memory problems, difficulty concentrating

  • Stress → excess cortisol → shrinkage

Tricyclic antidepressants

Named for their three-ring chemical structure; work on serotonin and norepinephrine

Higher side effects; also used from the 1950s–80s as one of only two available classes

Noradrenergic serotonergic reuptake inhibitors (NSRIs)

Similar to SSRIs but affect both serotonin and norepinephrine (norepinephrine = noradrenaline, the neurotransmitter of the noradrenergic pathway)

Transcranial magnetic stimulation (TMS)

Induces an electrical current in the brain, but can only affect surface cortical regions

FDA approved in 2008; still somewhat experimental; considered like a surface-level DBS, but minimal risk

Other Medications for Bipolar disorder

• Mood stabilizers — used to prevent mania; essential component of bipolar treatment

• Anticonvulsants (anti-seizure medications) — generally lower neural activity brain-wide; may help as mood stabilizers

• Antipsychotic medications — used for manic agitation; typically act to directly or indirectly lower dopamine; essentially the same antipsychotics used for schizophrenia