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Stress & the amygdala (PTSD (Treatment (Pharmacotherapy…

- - - - It is clear now that such anatomical system does not function as the emotional control centre through visceral regulation. Instead the amygdala seems to be the key mediator in emotion in the brain and more recently the striatum (particularly ventral striatum as a motor/limbic interface) became of interest
      - Klüver-Bucy syndrome supports notion of a limbic system: Disconnection between sensory and affective properties of stimuli (e.g. Weiskrantz, 1969)
- - - - Conditioned suppression and conditioned freezing (LeDoux et al., 1990)
      - Fear-potentiated startle (Davis et al., 1993)
        
        Conditioned emotional states facilitate the performance of US-specific CRs; CeN plays a particularly important role in this. The fact that CeN lesions disrupt freezing (a BLA-dependent fear response) can be interpreted as evidence for a serial model (no double dissociation) but in fact it may also consistent with the parallel view. To be consistent a major site of convergence of BLA and CeN is required (anterolateral region of bed nucleus has been implicated) (Balleine & Killcross (2006))
      - Caveat: Behavioural deficits (e.g. conditioned freezing) could be an output problem i.e. animals are still terrified but cannot respond. However conditioned suppression experiments address this issue since animals 'over-respond' compared to controls
  - - - More recent evidence challenge this serial view and postulate existence of parallel incentive processing by amygdaloid subnuclei
        
        BLA and CeN both receive sensory inputs and are involved in computations
        
        Killcross et al. (1997): CeN necessary for conditioned suppression (general behaviour) and BLA necessary for conditioned punishment (US-specific)
        
        A double dissociation between BLA and CeN
        
        Caveat: It is possible that a shift from serial to parallel circuit takes place for animals trained on aversive conditioning procedures
- - - - Glucocorticoid-dependent enhancement of memory consolidation depends upon intact NA signalling
        
        Roozendaal et al. (2006): Novelty-induced emotional arousal is simulated by NA release. NA signalling is necessary for glucocorticoid-dependent enhancement of memory consolidation in emotionally arousing experiences
    - - b-adrenergic signalling enhances consolidation of memories (e.g. inhibitory avoidance, conditioned taste aversion) in the amygdala (Hatfield & McGaugh, 1999)
  - - - Stress enhances the function of the amygdala whilst impair the function of other systems (e.g. HC and PFC) (McEwen et al., 2016).
- - - - Expnaded to Foa's fear network (Foa & Rothbaum, 1998)
        
        An entire relapse of the fear network can be triggered as a result of other contextual stimuli which are in reality erroneous associations.
        
        Stimulus generalization leads to hypervigilance and hyperarousal beyond the traumatic context
    - - Trauma memories are encoded in episodic ('verbally accessible memories') and emotional ('situationally accessible memories').
        
        Episodic are hippocampal-dependent. Emotional are amygdala-dependent
        
        Emotional memories (SAMs) are not tied to time --> they are generalized
        
        SAMs are easier to retrieve as they do not require the specific combination of retrieval cues that VAMs require
  - - - High levels of hormone decrease function of HC while enhancing function of AMG
        
        Parallel with Brewin's 'dual representation theory': Shift from hippocampal-dependent memory to amygdala-dependent memory
        
        Structural reorganization (Roozendaal et al., 2009)
        
        Chronic stress leads to reduction in dendritic arborisation of HC neurons and reduced neurogenesis ultimately leading to reduced volume while promoting persistent growth in amygdala. PTSD patients also show reduced HC volumes. Taken together, anatomical loss correlates with behavioural defiit
        
        Again this idea is parallel with theories pushing forth the role of imbalance between hippocampal and amygdala function in PTSD. However a question of directionality: is reduced HC a consequence of stress-related increased glucocorticoid signalling or a susceptibility factor for developing PTSD?
        
        PFC anatomy also affected by chronic stress and PTSD show marked decreases in function of mPFCv and rostral anterior cingulate (Pitman et al., 2012). This can be considered in conjunction with structural findings in dendritic arborisation in prelimbic and infralimbic cortex of rats.
        
        The result may be loss of prefrontal control over amygdala whose behavioural basis may be the observed impairment n extinction learning observed in PTSD patients (Maren & Holmes, 2016)
        
        Again, this is is supported from observations that Atrophy in infralimbic prefrontal neurons following stress is coupled with a reduction in animal's ability to extinguish conditioned fear (Izquierdo et al., 2006)
    - - Switching b/w networks is hypothesized to depend on anterior insula that has altered function in PTSD (Shin et al., 2001). Dysfunction --> impaired switching
        
        Overactivation of salience network: Hyperarousal
        
        Underactivation of salience network: Alexithymia
      - Default mode network: Self-referential processing and anti-correlated with onging tasks i.e. active at rest
        
        Salience network: Recognizing emotional significance of internal and external cues
        
        Central executive network: Cognitive function e.g. workin memory
  - - - Physiological variation
        
        Dysregulated HPA axis response in response to stress in PTSD patients: increased catecholaminergic signalling and CRH expression, but reduced levels of cortisol
        
        The reduced levels of cortisol are counter-acted by increased resistance of GR, leading to exaggerated negative feedback mechanisms and hence slower termination of stress response
        
        Loss of control of glucocorticoid signalling, coupled with enhanced background adrenergic signalling, leads to stronger consolidation of trauma memory and increased likelihood of generalization of trauma memory if HC is functional (Yehuda & LeDoux, 2007)
        
        The interaction between glucocorticoid and noradrenergic signalling in memory consolidation was also suggested by McGaugh (McGaugh, 2004)
      - Genetic variation
        
        GWAS
        
        CRHR1
        
        CAMKV
        
        FKBP5
        
        Bind GR and decreases affinity for glucocorticoids, reducing GR ability to translocate and induce gene transcription and hence reducing control of GR expression. One of the most extensively studied polymorphisms correlating with PTSD.
        
        Genetic variation: High risk allele for enhanced FKBP5 expression
        
        Epigenetic influence: Environmental stressors trigger epigenetic reprogramming (demethylation) of the FKBP5 gene, to enhance its expression (Klengel et al., 2013). This has implications in PTSD
        
        So combined risk from having high risk allele (genetic variation) and epigenetic reprogramming by environmental stressors
        
        Barriers to epigenetic research in mental illness: difficulty in obtaining relevant brain tissue. However, through animal studies we can identify convergent pathways between blood and brain (e.g. more recently glucocorticoid signalling in blood, HC, and AMG)
      - Also not all stressors are the same and prevalence within each stressor type differs greatly
  - - - Antidepressants
      - Adrenergic inhibitors
      - Antipsychotics
    - - Cue exposure therapy
        
        Learning a CS-no fear memory
        
        Caveats: Renewal, Reinstatement, Spontaneous recover as CS-no fear memory tends to be v. context specific (e.g. conditioning to therapist a safety-signal)
        
        EMDR
        
        Also Tetris for 'secondary prevention' (James et al., 2015). This is low risk and hence overcomes the harm:benefit tradeoff that needs to be taken into account considering not all trauma-exposed individuals will develop PTSD
        
        Consolidation blockade?
    - - Prevention programmes to promote good psychological health and adaptive methods for coping in the face of adversity
  - - - Intrusive re-experiencing of traumatic events (e.g. nightmares, flashbacks, unwanted & upsetting memories) which trigger emotional and physiological distres
    - - Conscious avoidance of trauma-related stimuli
    - - In at least 2 ways: inability to recall key features of trauma, exaggerated blame of self, overly negative thoughts about self and world, anhedonia
    - - Hypervigilance, Sleep disturbances, Problems with concentration, Irritability