Fear, Anxiety and Stress

Fear

  • Classical Fear Learning:
    • Cued Fear: Pair tone with a light foot shock repeatedly in animals.
    • In humans, pair a colored square with a loud noise or shock; measure Galvanic skin conductance response (SCR).
    • Depends on the amygdala.
  • Mechanism:
    • Threatening stimuli activate the basolateral amygdala, which activates the central amygdala.
    • Central amygdala activity leads to:
      • Freezing of limb movements.
      • Sympathetic nervous system activation.
      • Increased vigilance.
    • The periaqueductal gray (PAG) is involved in pain modulation and defensive behaviors.
  • Learning:
    • Repeated pairings of a tone and shock allow the tone to activate the lateral amygdala, leading to central amygdala activation and fear circuitry.
  • Amygdala Damage:
    • Bilateral damage leads to no signs of fear, inability to recall fear experiences, and inability to recognize facial expressions of fear.
  • Conditioning:
    • Repeated pairing of a neutral stimulus (tone) with an unconditional stimulus (shock) leads to the tone alone eliciting freezing.
    • Effective with "delay conditioning”.
  • Extinction:
    • Fear responses can be extinguished but may spontaneously recover.
    • Presentation of the CS alone leads to learning an additional association: CS-No US.
    • The brain gains a new (safe) association (Tone: No shock).
  • The ventromedial prefrontal cortex (vmPFC) is critical for extinction learning and recall. Rodent analog of vmPFC is Infralimbic cortex (IL).
  • Acquisition of Cued-Fear:
    • Children, adolescents, and adults can easily form cued-fear associations.
    • Adolescents show less cued fear extinction and less infralimbic (IL) cortical activity during extinction.
  • Spontaneous Recovery of Fear Memory:
    • Preadolescent mice show no spontaneous recovery of fear.
    • Preadolescent "fear extinction" is due to greater susceptibility to interference from competing association (tone = no shock), not simple decay of memory.
  • Contextual Fear:
    • Adolescents appear fearless; they show no contextual fear.
    • Delayed Retrieval of Contextual Fear Memory

Anxiety Disorders

  • Characterized by excessive fear and anxiety in the absence of true danger/threat.
    • Examples: Posttraumatic stress disorder (PTSD), Social anxiety disorder, Specific phobias, Generalized anxiety disorder.
  • High amygdala reactivity is typical in individuals with social anxiety, specific phobias, and generalized anxiety disorder.
  • Those with PTSD show reduced responsivity of the ventromedial prefrontal cortex.
  • Psychological and Drug Therapies:
    • Psychological therapies: systematic desensitization/exposure therapy & cognitive behavioral therapy.
    • Drug therapies include selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines.

Preclinical Findings inform treatement

  • vmPFC is essential for fear extinction - the basis for exposure /desensitization therapy.
  • During adolescence, there are peak changes in limbic circuitry involved in emotion reactivity while prefrontal circuitry involved in emotion regulation is still slowly developing.
  • Efficacy of CBT with exposure appears diminished during adolescence
  • Reconsolidation of Memory
    • Memories are dynamic and malleable.
    • Memory reconsolidation is the process of previously consolidated memories being recalled and actively consolidated during protein synthesis.
  • Reconsolidation Update Paradigm
    • Reminder cue followed by delay prior to extinction results in pattern similar to that seen for cue never paired with shock (CS-).
  • Reconsolidation update leads to reduced fear memory in adults AND adolescents
  • Clinical Implications (Optimizing Cognitive Behavioral Therapy)
    • Remind patient why they are there (reminder cue)
    • Establish positive/safe rapport (~10 minute delay for protein synthesis sweet spot)
    • Then begin exposure/desensitization
  • Combining cued and contextual fear extinction diminishes cued fear memory in adolescents. Implications for use of virtual reality in clinical interventions
  • During adolescence, surge in amygdala projections to PL may explain sustained cued fear (diminished cued fear extinction) while surge in the hippocampus projections to PL may explain lack of contextual fear.

Stress

  • Stress: Any type of change that causes physical, emotional, or psychological strain.
  • HPA Axis:
    • The hypothalamus, pituitary, and adrenal gland make up the hypothalamic-pituitary-adrenal (HPA) axis.
    • Controls release of the body’s key stress hormones from the adrenal glands.
  • Response to Stressor:
    • Corticotropin-releasing hormone (CRH) is released from the hypothalamus.
    • Triggers release of adrenocorticotropic hormone (ACTH) from the anterior pituitary.
    • Results in the release of glucocorticoid stress hormones from the adrenal cortex.
  • Negative Feedback:
    • High glucocorticoid levels cause the hypothalamus to release less CRH and the pituitary to release less ACTH.
    • Reduces glucocorticoid release from the adrenal cortex.
  • Glucocorticoid Stress Hormones can elevate Anxiety
    • Mice lacking glucocorticoid receptors in the brain look "fearless" / less threatened / less "anxious" when placed in stressful conditions.
  • Glucocorticoids produce brain changes related to increased amygdala activity and reduced prefrontal and hippocampal activity
  • Allostatic Load: "Wear and tear" on the body with repeated responses to stressful situations.
  • Chronic Stress induces or worsens medical conditions in the brain and body (depression, cardiovascular, and neurodegenerative diseases, and cancer).
  • Factors for resilience to stress: social support & perspective that both positive and negative life experiences can lead to personal growth.
  • Early Life Experiences Influence How an Individual Responds to Stress in Adulthood: epigenetics