Post Traumatic Stress Disorder: Mechanisms of Disease

Posttraumatic stress disorder (PTSD) is a dynamic disorder involving fluctuations between contrasting forms of emotional dysregulation.¹ Emotional dysregulation may be due to a complex interplay of key brain regions, namely, the amygdala, hippocampus, prefrontal cortex (PFC), and striatum.^2,3,4 PTSD presents with symptoms that develop following traumatic experience(s)^5,1 and may be associated with structural deficits in stress-regulating brain regions.⁵

In PTSD emotional under-modulation may involve amygdala hyperactivity, as well as PFC and hippocampus hypoactivity,^1,6 which can contribute to symptoms of intrusion and arousal.⁶ Emotional over-modulation may involve PFC hyperactivity, along with amygdala and striatum hypoactivity, associated with symptoms of emotional detachment.^1,4

The amygdala plays an essential role in fear conditioning and fear extinction.³ In the amygdala, fear processing involves two pathways: fear conditioning, influenced by long-term memory and responses to fearful or adversive stimuli,⁷ and fear extinction, for alleviating that learned behavior following the absence of a negative outcome after a fearful or adversive stimulus.^7,8 PTSD is thought to involve an imbalance of activity between the fear extinction and fear conditioning pathways, resulting in aberrant fear response.^7,8,9,10

Monoamine neurotransmitter systems can alter the activity of key brain regions involved in emotional regulation, including the amygdala, PFC, hippocampus, and striatum.¹¹ High norepinephrine (NE) levels can impair PFC function and intensify amygdala activity through activation of α1-adrenoceptors, leading to restricted executive control of emotion.^12,13,14,15 Combined with low serotonin (5-HT) levels, this may impair activity of the fear extinction pathway by altering PFC and hippocampus activity.^16,17 High NE levels combined with low 5-HT levels may increase activation of the fear conditioning pathway.¹⁵ Inhibitory 5-HT-1A receptors in the amygdala reduce fear behaviors,^16,17 excitatory 5-HT-2A receptors increase fear behaviors.¹¹ Dopamine dysfunction in the PFC and striatum may enhance the processing of adversive stimuli and disrupt reward processing.¹⁸

In summary, animal studies indicate that increased α1-adrenoceptor activity combined with decreased 5-HT-1A receptor activity in the amygdala may increase fear responses.^16,19

PTSD is a complex disorder and may involve an imbalance of activity between the fear extinction and fear conditioning pathways in the amygdala.^8,7 Dysfunction of monoamine neurotransmitter systems can disrupt key brain regions involved in emotional regulation, while NE system hyperactivity combined with 5-HT deficits may increase fear responses.^8,7,11

References

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