Several neurobiological systems areinvolved in the regulation of stress responses, specifically endocrine andneurotransmitter pathways and networks of brain regions that regulate fearbehavior at conscious and unconscious levels. Pathological changes occur inpatients who develop post traumatic stress disorder that were believed to occuras a consequence of a traumatic experience, downstream from an exposure.However, these abnormalities in patients with PTSD may represent a pre-existing,acquired upstream pathology triggered by trauma exposure. Although biological,psychological and social ramifications of PTSD have been established andinvestigated, there is still much more to understand about the underlyingbiology of the disorder, specifically brain circuitry and neurochemistry. The centralbrain regions that are part of the neural circuitry that mediate stress and aresignificantly altered in patients with PTSD are the amygdala, hippocampus, andmedial prefrontal cortex.
The hippocampus, responsible for memory functions,shows the most significant neurological impact from trauma. Patients with PTSDhave reduced hippocampal volume, making it extremely difficult for them todistinguish between past and present memories or experiences and the ability tocorrectly interpret environmental contexts. Furthermore, severe emotionaltrauma can create detrimental changes in the ventromedial prefrontal cortex,which is responsible for regulating emotional responses that are triggered by theamygdala. There is a decrease in volume and function of the prefrontal cortexin patients with PTSD. This inhibits ability to regulate negative emotions,like fear that commonly occurs in patients triggered by specific stimuli. Thisis why common symptoms of those suffering from post traumatic stress exhibitanxiety, fear, and extreme stress responses, even when confronted with stimulinot directly connected to their past experiences.
The third region, theamygdala, shows an increase in activity in those with PTSD. The amygdala regionprocesses emotions and is highly linked to fear responses. Patients with PTSDexhibit hyperactivity in the amygdala in response to stimuli. This increasespanic, anxiety, and stress when patients hear sounds or narratives or are shownimages that relate to their traumatic past. Neuroanatomic features causereduced volume and activity in the hippocampus of PTSD patients alters stressresponses and extinction. The amygdala shows increased activity, which promoteshypervigilance and impairs discrimination of threat. The cortex in patientswith PTSD show reduced volume, reduced anterior cingulate volume, and decreasedmedial prefrontal activation which leads to dysregulation of executivefunctions and impaired extinction of fear responses. Certainendocrine and neurotransmitter pathways are neurobiological systems thatregulate stress responses.
Patients with PTSD show abnormal regulation ofthyroid hormones and cortisol. The hypothalamic-pituitary-adrenal axis is thecore manager of the neuroendocrine stress response systems. When exposed tostress, corticotropin-releasing hormone (CRH) is secreted from the neurons inthe hypothalamic paraventricular nucleus (PVN) into the hypothalamo-hypophysealportal circulation that stimulates the production and release ofadrenocorticoptropin (ACTH) from the anterior pituitary.
Adrenocorticoptropinin turn causes the release of glucocorticoids from the adrenal cortex thatregulates metabolism and immune/brain function and ultimately manages stressors.The hypothalamic-pituitary-adrenal axis in patients with PTSD showshypocortolism due to increased negative feedback sensitivity of the HPA axis,caused by increased glucocorticoid receptor binding. Additionally, increasedand sustained levels of CRH concentrations are found in the cerebrospinal fluidof PTSD patients. Dysregulation of the HPA axis and reduced hippocampal volumeare fundamental features of PTSD.
The hypothalamic-pituitary-thyroid axis (HPT)is the secondary neuroendocrine feature present in patients with PTSD thatregulates blood level of thyroid hormones. Trauma triggers abnormalities inthyroid hormones; more specifically it increases level of tri-iodothyronine(T3) and thyroxine (T4). In patients with stress-related syndromes, there was adisproportionate level of T3 to T4, suggesting that over time trauma willeventually cause T4 levels to terminate. This abnormal T3:T4 ratio ultimatelycauses an increase in subjective anxiety in patients with PTSD. Neurochemicalfeatures including catecholamines, serotonin, amino acids, and peptides are allneurobiological features of those with post-traumatic stress disorder thatpresent abnormal regulation.
Catecholamine neurotransmitters likenorepinephrine and dopamine are present in high levels in patients with PTSD.This interferes with fear conditioning by the mesolimbic system and increasesarousal, encoding or fear memories, and startle response. Increased levels ofdopamine and norepinephrine also increase blood pressure, response to memories,and heart rate. Serotonin (5HT) is a neurotransmitter produced by tryptophanthat affects stress responses depending on the stressor intensity, receptortype, and region of the brain. Serotonin neurons located on the dorsal rapheare responsible for mediating anxiogenic effects through the 5HT2 receptorsin the amygdala and hippocampus. The 5HT neurons from the median raphé arebelieved to mediate anxiolytic effects through 5HT1A receptors. PTSDpatients with decreased levels of serotonin in their dorsal raphé disturb thedynamic between the hippocampus and the amygdala.
Furthermore, decreasedconcentrations of serotonin in the median raphé compromises anxiolytic effectsand increases vigilance, startle, impulsivity, and memory intrusions. As far asamino acid factors, GABA is the central inhibitory neurotransmitter of thebrain that diminishes behavioral and physiological responses to stressors byinhibiting CRH/NE circuits that are responsible for mediating stress and fearresponse. GABAA receptors increase the inhibitory effects of GABA,that with immense stress, causes alterations of the GABAA /benzodiazepinereceptor complex. Patients with PTSD will present decreased peripheralbenzodiazepine binding sites. Decreased GABA activity will ultimately compromiseanxiolytic effects.
Glutamate is another amino acid and primary excitatoryneurotransmitter that binds to N-methyl D-aspartate (NMDA) receptors that isinvolved in the synaptic plasticity, learning, and memory. Increased levels ofglutamate will lead to derealization and dissociation in patients with immensetrauma. Lastly, peptide neurotransmitters, specifically neuropeptide Y,regulate anxiety and stress. Decreased plasma neuropeptide Y concentrationsupregulates response to stress by leaving corticotropin-releasing hormone andnorepinephrine unopposed. PTSD patients also show increased levels of CSFbeta-endorphin levels, which increases activation of the endogenous opioidsystem that is responsible for symptoms like numbing, dissociation, and stress-inducedanalgesia in PTSD patients.
FK506binding protein 5 (FKBP5) is a co-chaperone of the glucocorticoid receptor(GR), and is highly associated with stress reactivity and post-traumatic stressdisorder risk. Hypothalamus-pituitary-adrenal-axis regulation is also aprominent factor in patients with stress-related disorders like PTSD. Releaseof glucocorticoids aids flight or flight responses, and binding of cortisol tothe glucocorticoid receptor is essential to terminate the stress reaction throughnegative feedback. This shows that glucocorticoid receptor function is key forproper stress response regulation.
FKBP5 binding to GR is key in modulating GRsensitivity and reduces cortisol-binding capacity. PTSD patients presentincreased cortisol release, which leads to more FKBP5 gene expression and areduction in GR sensitivity. Glucocorticoid signaling influences risk of PTSD,memory, and extinction, with genetic variability of FKBP5 influencing PTSDvulnerability. FKBP5 genotype is associated with peritraumatic dissociation,and proves to be a strong risk factor for PTSD development and risk.
