Neurobiology of Psychiatric Disorders

What is an emotional state?

A neurobiological state produced by coordinated, physiological, behavioural, cognitive responses.
→ they prepare the body to react in a certain way, an internal motive that produces action tendencies

List the major brain regions involved in emotion and anxiety

• Amygdala

• Prefrontal cortex

  • LATERAL: dlPFC + vlPFC

  • MEDIAL: vmPFC + OFC, also mPFC

• Hippocampus

• Ventral striatum (NAc)

• Cingulate gyrus (ACC)

• Insula

• HPA axis

Primary, secondary & tertiary emotional systems (3-parted brain theory)

‘Lizard brain’ = brainstem + cerebellum → primary emotions

• Evolutionary responses hardwired into all animals (born with the ability)

• Innate, automatic, universal

• i.e., body language of threat, autopilot, homeostatic functions, fight or flight, reflexes
  
  ‘Mammal brain’ = subcortical/limbic system → secondary emotions

• Associative learning between stimuli

• Still automatic, but not reflexive

• i.e., emotions, memories, habits, attachments
  
  ‘Human brain’ = neocortex → tertiary emotions

• Flexibility to facilitate social interactions and decision-making, higher order emotions

• Dampens primary and secondary impulses, cognition > emotion

• i.e., language, abstract thought, consciousness, imagination, reasoning, rationalising, guilt, empathy, assessing environment

Amygdala in affective circuitry

NOT the home of fear, but a NOVELTY CENTRE
→ has one of the highest degrees of connectivity, no region is more than 2 steps away

13 nuclei, 3 key regions:

• Basolateral (BLA) complex: lateral nucleus (LA) + basal nucleus (BA) + accessory basal nucleus (AB)

  • Receives sensory information, either directly from sensory pathways or via sensory cortex

  • Performs memory association between stimuli and emotional significance

• Corticomedial

  • Receives olfactory input, odour-related emotional responses (pheromones, food, danger/defence)

  • Ancient and highly conserved, still strong link in humans but more prioritised in other animals

• Central nucleus (CeA):

  • Major output to other subcortical areas like brainstem and hypothalamus for physiological responses

  • Defensive emotional reactions like HR, sweating, freezing

PATHWAYS:

1. High road: sensory information → spinal/cranial nerve → spinal tract → thalamus → cortex → amygdala

   • Cortical analysis produces the generated feeling = subjective emotional experience (requires PFC)

2. Low road: bypasses cortex, straight from thalamus → amygdala

   • Fast, subconscious threat detection = behavioural & physiological response

   • Rapid survival response before you’re consciously aware something’s happening

PFC in affective circuitry

Executive functions, cognitive control over other cognitive regions

Separated into affective and cognitive regions with opposite effects on emotional regulation

MEDIAL = processes POSITIVE affect, emotion, reward value in decision-making and reward learning
→ stimulates action

• OFC: assigns emotional and motivational value to events, information, outcomes, top-down regulation of the amygdala

  • Updates values CONSTANTLY

  • OFC and amygdala receive nearly identical information, humans have greater OFC development that overshadows the amygdala

• vmPFC + mPFC: introspection, social cognition, a broader program of how to behave in the world, context of environment

  • Keeps values for LONGER TERM = beliefs, social relationships, ethics
    

LATERAL = process NEGATIVE affect, encodes punishment and negative feedback, drives analytical thinking in humans
→ inhibits action

• dlPFC + vlPFC: maintain and manipulate information, plan actions, inhibit impulses

Hippocampus in affective circuitry

Integrating contextual information + emotional valence

• Encoding of episodic and contextual memory

  • Emotional memories are much more likely to be encoded, or ‘stick’

• Input from the BLA encoding emotional valence information

• High expression of glucocorticoid receptors, interpretation and termination of stress response

Ventral striatum (NAc) in affective circuitry

• Interface between emotion, motivation, and action (DA regulated circuits)

  • Processes emotional valence

  • Receives inputs from BLA, hippocampus and VTA

• Key role (+ basal ganglia) in stimulus-response habit learning)

  • ‘Habitual’ functions to reduce cognitive load and re-delegate attention

  • Outputs driving motor responses like VP, LH and SNr

ACC in affective circuitry

1. Pregenual (pACC) ← input from medial OFC (positive rewards)

2. Supracallosal or midcingulate (dACC) ← input from lateral OFC (punishment, non-reward)

• Designing and planning the best action for current goal or outcome

  • Strong link to insula (body states), amygdala (emotional salience), oPFC (outcome values), and hippocampus

  • Most adjacent to OFC and insular

• Generates “subjective feeling” from emotional motor associaiton areas

  • Emotional component of physical and emotional pain, suffering (activates same region)

• Monitors conflicts between competing actions, sustaining attention on the one that has the best outcome

Insula in affective circuitry

• , the brain’s response to internal changes

1. Posterior insula: the primary interoceptive cortex
   → visceral sensory input

2. Mid-insula: integrates interoceptive signals with affective and motivational states
   → attaches to affect, how much motivation do I have to do things?

3. Anterior insula ( ACC): links bodily/emotional awareness to cognitive control, unconscious ‘gut feelings’
   → combine with cognitive processes, decision-making, conscious experiences, evaluating action options

   • Adjacent to ACC and PFC

HPA axis in affective circuitry

PFC has top-down inhibition over amygdala
↓
Amygdala identifies threats
↓
Projects to hypothalamus
↓ CRH
Anterior pituitary
↓ ACTH
Adrenal cortex
↓ Glucocorticoids

Amg, PFC and HiF all contain GRs

• Cortisol ↑ amygdala activity, ↓ PFC & HiF activity

• Cortisol generates an integrated response by influencing the degree of APH activity

  • Severe acute stress creates temporary amygdala > PFC imbalance to allow automatic, reflexive survival response

  • Chronic stress can cause hormonal imbalance and structural changes
    (i.e., dendritic shrinkage in HiF and PFC, amygdala enlargement)

Connections in the amygdala-PFC-hippocampal circuit that support affective behaviour

AMYGDALA: emotionally relevant stimuli, automatic responses

↓ _{(sends information to be evaluated and regulated)} ↑ _{(top-down regulating, flexible updating of value, conflict monitoring)}

PFC: assigning value to potential outcomes, decision-making, updating/extinction learning

↓ _{(guides memory search, encodes bias)} ↑ _{(memory retrieval)}

HIPPOCAMPUS: episodic and contextual memory

↓ _{(context/scenario to form emotional memories)} ↑ _{(amygdala activation enhances encoding but causes narrow attention)}

[to AMYGDALA]

Roles of default mode vs salience networks in affective processing and threat detection

Default Mode Network (DMN) = PCC + mPFC + precuneus + angular gyrus + PHC + inferior parietal lobule
→ at rest, daydreaming, rumination, social cognition, self-referential thought, planning

Salience Network (SN) = dACC + amygdala + SN + VTA + insula (bilateral anterior)
→ mediator, identifies relevant stimuli, regulates emotional vs cognitive resources

Executive Control Network (ECN) = dlPFC + PPC + aPFC
→ goal-directed behaviour, action execution after stimuli detection, working memory, external tasks

Role of amygdala vs PFC in different types of fear

AMYGDALA: detects threats and initiates automatic, defensive behaviours

act in opposition

PFC: regulates amygdala via top-down inhibition, evaluates whether fear response is appropriate using context

Basic circuitry of Pavlovian fear conditioning

with respect to amygdala

Inputs:

• LOW ROAD: thalamic sensory information → amygdala

• HIGH ROAD: cortically processed sensory information → amygdala

  • From medial PFC:
    - Prelimbic (PL) → BA and CeA = fear expression
    - Infralimbic (IL) → CeA = fear inhibition/extinction

• Contextual and spatial information from hippocampus → amygdala

Outputs:

• Brainstem: physiological responses like freeze, startle, increased respiration (PAG, PnC, PBN)

• Hypothalamus: triggers HPA axis (via PVN) and SNS (via LH)

• Basal forebrain: arousal and attention

Modulatory regions:

• mPFC/OFC: overrides/regulates amygdala fear response

• Hippocampus modulates: response based on context, extinction recall

• VTA: dopaminergic projections facilitate plasticity during fear learning

• LC: enhances consolidation via NAD, drives arousal during threat

Related symptoms of altered system circuits in psychiatric disorders

• PTSD/depressive disorders: in HPA axis, elevated cortisol and structural changes (hippocampal and PFC atrophy, amygdala enlargement)

• Mood disorders/emotional dysregulation: overactive amygdala, lack of top-down regulation by PFC

• Major depressive disorder: medial < lateral OFC imbalance

  • Lateral overconnectivity causes negative thoughts and ruminations

  • Medial underactivity causes apathy, reduced pleasure and motivation

  • Brain analyses most events as negative, encoding punishment

Barrett’s Theory of Constructed Emotion

The purpose of the brain is not learning but to ‘run a budget for the body’ = maintain homeostasis

1. The brain is a predictive system, serves allostasis (maintains stability by anticipating and predicting → comparing → adjusting to environment)
   → the best model of managing energy consumption and resources is predictive, not reactive

2. The brain is degenerative, no region or network is uniquely responsible for a single function or emotion
   → natural selection prefers high complexity systems = more robust, multiple different structures can perform the same function