Fear Response Mechanisms

Communication to the Amygdala

• The thalamus plays a role in communication to the amygdala
• The hippocampus can be activated as part of the process of learning about the cause of fear and how it can be avoided
• The pre-frontal cortex can exert top-down control over cognitive responses or behaviors to a potential fear-causing stimulus
• The serotonin-releasing nucleus in the brainstem (raphe nucleus) can have a global modulatory effect on mood, memory, and fear + stress responses
• The noradrenergic, serotonergic, and dopaminergic pathways all have important nuclei in the brainstem and cross-talk to each other

Noradrenergic Pathway

• Neurotransmitter: Noradrenaline (also known as Norepinephrine)
• Origin: Locus coeruleus in the brainstem
• Function: Regulates mood, attention, arousal, and stress response; involved in the "fight or flight" response
• Clinical Significance: Dysregulation of noradrenergic pathways is implicated in various psychiatric disorders such as depression, anxiety disorders, and attention deficit hyperactivity disorder (ADHD)

Serotonergic Pathway

• Neurotransmitter: Serotonin (also known as 5-hydroxytryptamine or 5-HT)
• Origin: Raphe nuclei in the brainstem
• Function: Regulates mood, emotion, appetite, sleep, and various cognitive functions; involved in modulating anxiety, aggression, and impulsivity
• Clinical Significance: Imbalances in serotonin levels are associated with mood disorders such as depression and anxiety, as well as obsessive-compulsive disorder (OCD) and eating disorders

Dopaminergic Pathway

• Neurotransmitter: Dopamine
• Origin: Substantia nigra and ventral tegmental area (VTA) in the brain
• Function: Regulates mood, emotion, motivation, and reward processing
• Clinical Significance: Over-activation of the direct pathway and poor activation of the indirect pathway may be implicated in certain disorders; higher-dose SSRIs may mediate their positive impact on these circuits

Basal Ganglia

• A group of nuclei in the brain involved in movement control and cognition
• Components:
  • Input nuclei: Putamen, Caudate, Nucleus accumbens
  • Associated nuclei: Globus pallidus externa, Substantia nigra pars compacta, Subthalamic nucleus
  • Output nuclei: Globus pallidus interna, Substantia nigra pars reticulata

Eating Disorders

• Anorexia Nervosa and Bulimia Nervosa
• Lifetime prevalence: 1% for anorexia and 2-4% for bulimia in the female population
• Higher risk factors:
  • Display "perfectionist" traits
  • Past history of sexual abuse
  • Feel a lack of control in other dimensions of life
  • Expectations regarding weight (e.g. athletes, gymnasts, dancers)

Anorexia Diagnostic Criteria

• Restriction of energy intake relative to requirements, leading to a significantly low body weight in the context of age, sex, developmental trajectory, and physical health
• Intense fear of gaining weight or of becoming fat, or persistent behavior that interferes with weight gain, even though at a significantly low weight
• Disturbance in the way in which one's body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or persistent lack of recognition of the seriousness of the current low body weight

Bulimia Diagnostic Criteria

• Recurrent episodes of binge-eating, characterized by:
  • Eating, in a single period of time, an amount of food that is larger than what most individuals would eat during a similar period of time and under similar circumstances
  • A sense of lack of control over eating during the episode

Bipolar Disorders

• Epidemiology: 1.5% of the Canadian population experiences bipolar disorder
• Clinical Features:
  • Mania, Hypomania, Depression
  • Cyclical changes between these states
  • Manic psychosis, which may include delirium
• Subtypes:
  • Bipolar 1: At least 1 manic episode and usually depressive episodes
  • Bipolar 2: Major depressive episodes with at least 1 hypomanic episode

Bipolar Disorders - DDX

• Exclusion of hyperthyroidism and stimulant drug abuse
• Clinical diagnosis based on DSM-5 criteria
• At least 1 episode of mania/hypomania lasting for at least 4 consecutive days AND be present most of the day, almost every day
• 3 or more symptoms of mania:
  • Inflated self-esteem or grandiosity
  • Decreased need for sleep
  • More talkative than usual or pressure to keep talking
  • Flight of ideas or subjective experience that thoughts are racing
  • Distractibility
  • Increase in goal-directed activity or psychomotor agitation
  • Excessive involvement in activities that have a high potential for painful consequences

Antidepressants

• SNRI's (Serotonin & Norepinephrine Reuptake Inhibitors):
  • Examples: Venlafaxine (Effexor), Amitriptyline (Elavil)
• SSRI's (Selective Serotonin Reuptake Inhibitors):
  • Examples: Fluoxetine (Prozac)
• MAOI's (Monoamine Oxidase Inhibitors):
  • Examples: Trazodone (Desyrel), Bupropion (Wellbutrin, Zyban)

Anxiety Disorders

• Specific Phobia: 12-16% prevalence; characterized by immediate fear/anxiety response to a stimulus, active avoidance or endurance with intense anxiety, fear out of proportion to actual danger, and recognition of excessive fear.
• Social Anxiety Disorder: 2-7% prevalence; marked and persistent fear of social or performance situations, fear of being judged or evaluated, and avoidance of situations.

Post-Traumatic Stress Disorder (PTSD)

• Causes: exposure to actual death, threatened death, physical or sexual violence, or serious injury; can occur in people who have witnessed or experienced traumatic events.
• Symptoms: recurrent, involuntary, and intrusive memories of the event; avoidance of stimuli associated with the event; negative changes in mood and cognition.

Eating Disorders

• Dangers: significant physical harm, including hypotension, bradycardia, dysrhythmias, congestive heart failure, and vitamin deficiencies.
• Types: Anorexia Nervosa, Bulimia Nervosa, Binge Eating Disorder.

Benzodiazepines

• Mechanism of action: facilitate binding of GABA to GABA receptors, leading to anxiolytic, hypnotic, and anti-seizure effects.
• Examples: Diazepam (Valium), Triazolam (Halcion).

Mania and Hypomania

• Mania: increased talkativeness, rapid speech, decreased need for sleep, racing thoughts, distractibility, and increased goal-directed activity; may include elevated mood, mood lability, impulsivity, and grandiosity.
• Hypomania: similar to mania, but with shorter duration (at least 4 days) and less severe impairment.

Major Depressive Disorder (MDD)

• Epidemiology: predicted to be the 2nd leading cause of disability worldwide by 2030; 4.7-5.4% prevalence in Canada.
• Risk Factors: exposure to traumatic life events, chronic pain, low income, lack of social support, and family history.
• Clinical Features: mood symptoms (feeling sad, low self-esteem), physical symptoms (lack of energy, changes in appetite), and cognitive symptoms (slow thinking, difficulty concentrating).
• Diagnostic Criteria: at least 5 symptoms, including depressed mood and anhedonia, must be present most of the day, every day, for at least 2 weeks.

Neurobiology of MDD

• Monoamine Hypothesis: altered levels of monoamine neurotransmitters, such as serotonin and noradrenaline, contribute to depression.
• Stress-induced Depression Hypothesis: chronic stress leads to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to depression.
• Other theories: neurotrophic/neuroplasticity hypothesis, cytokine hypothesis/neuroinflammation hypothesis, and circadian hypothesis.

Antidepressants

• Mechanism of action: increase levels of neurotransmitters, such as serotonin and noradrenaline, to improve mood.
• Types: Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), Monoamine Oxidase Inhibitors (MAOIs), and others.
• Adverse effects: include increased risk of suicide, serotonin syndrome, and overdose effects.

Fear Response and Regulation

• The thalamus plays a role in communication to the amygdala
• The hippocampus can be activated as part of the process of learning about the cause of fear and how it can be avoided
• The pre-frontal cortex can exert top-down control over cognitive responses or behaviors to a potential fear-causing stimulus
• The serotonin-releasing nucleus in the brainstem (raphe nucleus) has a global modulatory effect on mood, memory, and fear + stress responses

Noradrenergic Pathway

• Neurotransmitter: Noradrenaline (also known as norepinephrine)
• Origin: Locus coeruleus in the brainstem
• Function: Regulates mood, attention, arousal, and stress response; involved in "fight or flight" response
• Clinical Significance: Dysregulation is implicated in depression, anxiety disorders, and attention deficit hyperactivity disorder (ADHD)

Serotonergic Pathway

• Neurotransmitter: Serotonin (also known as 5-hydroxytryptamine or 5-HT)
• Origin: Raphe nuclei in the brainstem
• Function: Regulates mood, emotion, appetite, sleep, and various cognitive functions; involved in modulating anxiety, aggression, and impulsivity
• Clinical Significance: Imbalances are associated with mood disorders such as depression and anxiety, as well as obsessive-compulsive disorder (OCD) and eating disorders

Dopaminergic Pathway

• Neurotransmitter: Dopamine
• Origin: Substantia nigra and ventral tegmental area (VTA) in the brain
• Function: Involved in regulating mood, motivation, and reward processing

Benzodiazepines and Adverse Effects

• General warnings/precautions associated with the use of hypnotics to treat insomnia include:
  • Abnormal thinking and behavioral changes
  • Visual and auditory hallucinations, "sleep-X" events
  • The need to evaluate for an underlying primary psychiatric and/or medical illness for the insomnia
• Hypnotic use coupled with an underlying primary disorder can cause:
  • Worsening of insomnia, worsening of depression (including suicidal thoughts), etc.

Benzodiazepine Antagonist

• Flumazenil = BDZ antagonist
• Competitive inhibitor of BDZ
• Therapeutic uses include:
  • Removal of effects of BDZ once therapeutic effects no longer needed
  • Treatment of BDZ OD
• Caution with multi-drug overdose
• Shorter duration of action than BDZ

Depression and Bipolar Disorders

Definitions

• Psychosis: Hallucination (without insight), delusion, or hallucination (without insight) and delusion; loss of contact with external reality
• Delirium: Acute, fluctuating change in attention (reduced) and consciousness including disorganized thoughts
• Depressive Episode: Experience of low or depressed mood, loss of interest in most activities, and additional possible symptoms
• Mania: Increased talkativeness, rapid speech, decreased need for sleep, racing thoughts, distractibility, increase in goal-direct activity, psychomotor agitation
• Hypomania: Differentiating factors from mania: duration (at least 4 days), does not cause major deficit in social or occupational functioning

Major Depressive Disorder (MDD)

• Epidemiology:
  • Predicted to be the 2nd leading cause of disability worldwide by 2030
  • 4.7-5.4% of the population experience MDD in Canada
  • Risk factors: exposure to traumatic life events, chronic pain and disorders, low income, increased caregiver burden, lack of social support, family history
• Clinical Features:
  • Mood symptoms: feeling sad/low, lack of interest in general, anhedonia, low self-esteem, feelings of guilt or worthlessness, suicidal thoughts
  • Physical symptoms: lack of energy/tired, difficulty sleeping, restless/agitated, weight loss/gain, low libido
  • Cognitive symptoms: slow thinking, difficulty concentrating, forgetfulness, difficulty planning, difficulty making decisions
• Diagnostic Criteria (DSM-5):
  • Category A: must include the first two components and a total of 5 or more components
  • Depressed mood and anhedonia must be present most of the day, every day for at least 2 weeks in a row

Bipolar Disorders

• Epidemiology: 1.5% of the population experience bipolar disorder in Canada
• Clinical Features:
  • Mania
  • Hypomania
  • Depression (most of the time spent in depressive state)
  • Cyclical changes between these states are common
• DDX:
  • Exclusion of hyperthyroidism (TSH and T4)
  • Exclusion of stimulant drug abuse (blood/urine)
  • Clinical based on DSM-5
• Bipolar Disorder 1:
  • At least 1 episode of mania/hypomania lasting for at least 4 consecutive days AND be present most of the day, almost every day
  • 3 or more symptoms (representing sig change from norm) of mania
  • Cause significant impairment or necessitates hospitalization

This quiz covers the neural pathways and brain regions involved in the fear response, including the thalamus, hippocampus, pre-frontal cortex, and raphe nucleus. Learn how these structures interact to regulate fear and anxiety.