Biological Basis of Post-Traumatic Stress - Essay Example

?Biological Basis of Post-Traumatic Stress Stress can be defined as "a particular relationship between the person and the environment that is appraised by the person as taxing or exceeding his or her resources and endangering his or her well-being" (Lazarus & Folkman, 1984). The stress felt after a traumatic event that involved actual, threatened death or serious injury, or a threat to the physical reliability of a person or others, is seen in people with post-traumatic stress (PTS). The abnormality seen in individuals with stress can be observed and measured on all major systems of the body including the neural system, endocrine system and the immune system. The Hypothalamic-Pituitary-Adrenal (HPA) axis plays a key regulatory function in the body, which controls all three systems mentioned above. Cortisol is a major hormone of the HPA axis and is the primary stress hormone in the body. Disturbance of glutamatergic, serotonergic, and adrenergic systems is also an important cause of the structural and functional abnormalities which can give stress. The immune system is mutually regulated by the neural and endocrine systems and can also be affected by PTS. PTS often co-occurs with various inflammatory diseases, likely due to HPA axis dysregulation affecting the immune system (Tucker et al., 2004). An increasing body of evidence indicates that posttraumatic stress is associated with major forms of cardiovascular disease including those attributed to atherosclerosis such as coronary heart disease and thromboembolic stroke. Persons with PTS have also been reported to be more likely to have hypertension, hyperlipidemia, obesity, which can precipitate to cardiovascular diseases (McFarlane, 2010). Knowledge of the biological changes with PTS has led to the development of new treatments that offer more comprehensive management of PTS and enable patients to enjoy an improved quality of life. No genes have been pin-pointed so far for the disorder, but there are a few epigenetic changes seen in such patients. Prevalence estimates from epidemiological studies suggest that the majority of individuals have been exposed to at least one potentially-traumatic event (PTE) during their lifetime. Some of them are resilient and recover rapidly following exposure, but some may develop chronic psychopathology, most commonly post-traumatic stress. Although a disease of central nervous system, it has a peripheral involvement too. The hypothalamic-pituitary-adrenal (HPA) axis is the central coordinator of the mammalian neuroendocrine stress response systems, and as such, it has been a major focus of scrutiny in patients with PTS. In short, the HPA axis is made up of hypothalamus components, anterior pituitary, and the adrenal glands. Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. PACAP blood levels increase in heavily traumatized patients and is sex specific. These sex-specific effects may occur via estrogen regulation (Ressler, et al. 2011). Upon exposure to stress, neurons in the hypothalamus secrete corticotropin-releasing hormone (CRH) into the circulation, which stimulates the production and release of adrenocorticotropin hormone from the anterior pituitary. Adrenocorticotropin hormone in turn stimulates the release of glucocorticoids from the adrenal cortex which then modulates metabolism as well as immune and brain function. Several brain pathways modulate HPA axis activity. The hippocampus and prefrontal cortex is known to inhibit, whereas the amygdala and aminergic brain stem neurons stimulate corticotropin-releasing hormone neurons. Smaller mean bilateral amygdala volume and reduced gray matter density in the left anterior cingulate cortex has also been noted in humans having history of PTS (Rogers et al., 2009). It has also been reported that the hippocampal volumes of PTS patients are relatively low and this is attributed to apoptosis of hippocampal neurons, apoptosis-related proteins and genes of Bcl-2 and Bax in rats (Li, Han, Liu, & Shi, 2010). Engdahl et al (2010) show that PTS could be a temporal lobe syndrome with incorrect communication between temporal lobe and other parts of the brain. This lateralized temporal-posterior pattern of miscommunication is very similar but weakened in patients with PTS. In addition, glucocorticoids exert negative feedback control of the HPA axis by regulating hippocampal and paraventricular nucleus neurons. Sustained glucocorticoid exposure can have adverse effects on the health of the hippocampal neurons. An increasing body of evidence indicates that posttraumatic stress is associated with major forms of cardiovascular disease including those attributed to atherosclerosis such as coronary heart disease and thromboembolic stroke. Persons with PTS can have hypertension, hyperlipidemia, obesity, and cardiovascular disease (McFarlane, 2010). Increased activity of the sympathoadrenal axis might contribute to cardiovascular disease through the effects of catecholamines on the heart, vasculature, and platelet function. Platelet function is altered by elevated levels of circulating catecholamines. Platelets play an important role in blood clot formation. Catecholamines, (including dopamine, adrenaline and nor adrenaline) which act on alpha-2a receptors on platelet membranes, have been shown to increase platelet aggregation and other changes in platelet function (Bedi & Arora, 2001). Karlovic et al. (2004) have shown abnormal changes in lipid profile (cholesterol, high density lipoproteins (HDL), Low density lipoproteins (LDL)) of people with PTS compared with patients having major depression. The above studies show that the peripheral biological processes is involved in stress. All these results are based on epidemiological studies or animal model based studies, more prospective studies are needed, with elegantly designed experiments in human. Although post-traumatic stress is a complicated CNS syndrome, recent studies suggest that peripheral blood mononuclear cells could cause and/or worsen PTS. Several experimental animal models have shown that peripheral blood mononuclear cell activity can cause hippocampal volume loss and PTS-like symptoms. Monocytes are a type of white blood cells, and are responsible for inflammation. One of the several studies shows that a traumatic event can trigger peripheral cells to migrate, cause inflammation, and decrease nerve cell growth, leading to CNS volume loss (Bechmann et al., 2005). Stress confers an increased risk for disorders with an inflammatory etiology. Altered transcriptional control of monocyte gene expression could contribute to exaggerated inflammatory activity in stress with altered glucocorticoid receptor (GR) expression and function in peripheral blood mononuclear cells (O'Donovan et al., 2011). However, researcher have identified T cells, especially CD4+ T cell, as novel players in coping with psychological stress, and offers immunization with a myelin-related peptide, for example connexin32, as a new therapeutic approach to alleviate chronic consequences of acute psychological trauma, such as those found in posttraumatic stress disorder (Lewitus, Cohen & Schwartz, 2008). CD4+ T cell are lymphocytes, also called T helper cells that do not directly kill infected host cells or pathogens, but rather help other cells like cytotoxic T cells in killing the infected cells or the pathogen. Even the complement system is altered in PTS. PTS is characterized by over activation of the complement classical pathway, lower activation of the complement alternative pathway and over activation of the terminal pathway. A human study provides further evidence on the involvement of the inflammatory component in pathogenesis of stress, done by haemolytic assays. (Hovhannisyan, Mkrtchyan, Sukiasian, & Boyajyan, 2010). Stress can have epigenetic component to it. Epigenetic alterations of the brain-derived neurotrophic factor (Bdnf) gene have been identified in rats. Hippocampal Bdnf DNA methylation is a cellular mechanism underlying the cause of persistent reasoning deficits which are prominent features of the pathophysiology of some types of stress (Roth, Zoladz, Sweatt, & Diamond, 2011). A single nucleotide polymorphism (DBH rs1611115) has been identified in the dopamine ?-hydroxylase (sD?H) enzyme, which converts dopamine to epinephrine but no associations between sD?H and PTS diagnosis or symptom severity were found in this civilian sample. DNA methylation patterns in genomic repetitive elements, LINE-1 and Alu, also show perturbation compared to controls, suggesting them as resilience or vulnerability factors (Rusiecki, et al. 2012). Stress can be multifactorial and one of the factors is trauma. Post-traumatic stress, as the literature shows, can have central as well as peripheral players. Not only is the brain affected in stress, but peripheral systems like cardiovascular and immune systems are also affected. It also has a genetic and epigenetic component to it. These researches do promise some treatment for the various forms of stress in general. Most of the studies are epidemiological or based on animal models. More human based prospective studies, although not very likely, are warranted. These studies are also not likely because of lack of proper control group; every human being might be under some sort of stress, although not very obvious. Research examining the mechanism of how traumatic events are linked to peripheral blood functions and related biomarkers, may offer improved diagnoses and treatments for stress. Future work targeting, for example the PACAP/PAC1 receptor system, may lead to novel and robust biomarkers. These studies can also help us to increase our understanding of the neural mechanisms underlying pathological responses to stress. Potential therapeutic targets towards the prevalent and debilitating stress conditions are in urgent need. Although psychological therapies are available for stress, the biological, psychological, and sociological modalities of treatment should not remain mutually exclusive. All three combined may restrict stress at some level. References Bechmann, I., Goldmann, J., Kovac, A. D., Kwidzinski, E., Simburger, E., Naftolin, F., . . . & Priller, J. (2005). Circulating monocytic cells infiltrate layers of anterograde axonal degeneration where they transform into microglia. FASEB J, 19, 647–649. Bedi, U.S., & Arora, R. (2007). Cardiovascular manifestations of posttraumatic stress disorder. J National Med Assoc, 99, 642-649 Engdahl, B., Leuthold, A.C., Tan, H.R., Lewis, S.M., Winskowski, A.M., Dikel, T.N., & Georgopoulos, A.P. (2010). Post-traumatic stress disorder: a right temporal lobe syndrome? J Neural Eng, 7(6), 066005. Hovhannisyan, L.P., Mkrtchyan, G.M., Sukiasian, S.H., & Boyajyan, A.S. (2010). Alterations in the complement cascade in post-traumatic stress disorder. 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