Posttraumatic Stress Disorder (PTSD) is a much studied medical condition that can affect anyone at any time when the individual is subjected to undue trauma, fear, stress, or other abnormal situations like war where all the above probably occur sometimes simultaneously. Military personnel, dating back centuries (references can be found about such experiences as early as 3139 BC from the Mahabharat War) experienced neurological/psychological trauma as a result of the atrocities witnessed in war.
The Greek historian Herotodus writes a lot about PTSD, according to a presentation by Mylea Charvat to the Veterans Administration. One soldier, fighting in the battle of Marathon in 490 BC, reportedly went blind after the man standing next to him was killed, even though the blinded soldier "was wounded in no part of his body." So, while it is understood that PTSD can be caused by many factors, it is hard to image anyone more prone to the condition than a Veteran who has battlefield experience.
Post Traumatic Stress Disorder is an anxiety disorder with significant functional impairment. In coming to grips with Electric shockPTSD in the last couple of centuries we have seen it called many things…battle fatigue, shell shock, neurasthenia/hysteria, soldier's heart, irritable heart, and even such benign terms as nostalgia and homesickness. As early as WWI they tried to "treat shell shock" by using the "Bergonic Chair" for giving electric shock treatment for psychological effect, in psycho-neurotic cases." This lead to many returning warriors since WWI, simply going "underground" or into a shell to keep others from recognizing the effects war had on them.
This leads us to the long-term consequences of PTSD and has lead researchers to study what is possibly an underlying genetic vulnerability (or alteration) that can be laid at the doorstep of this debilitating condition. To this end three primary neuronal systems have been investigated:
The hypothalamic-pituitary-adrenal (HPA) axis
The locus coeruleus-noradrenergic (LC) system
The neurocircuitry interconnecting the limbic system and frontal cortex.
The initial investigations into main effects of possible "candidate genes" thought to be associated with PTSD risk have been negative, but studies examining the interaction of genetic polymorphisms in predicting PTSD have produced several positive results which have increased our understanding of risk and resilience in the aftermath of trauma. Polymorphism involves one of two or more variations of a particular DNA sequence. NOTE: Polymorphism refers to a principle in biology in which an organism or species can have many different forms or stages.
As scientists study how these variations in the human genome correlate with disease and drug response, promising new research that addresses genetic modification have been proposed that can begin to explain the enduring impact during key, often early, developmental periods on gene expression.
This has lead to associating inherited biomarkers by closely monitoring traits of PTSD within this highly complex psychiatric disorder, so as to better understand the underlying genetics and neural pathways that are involved, particularly in how such gene modification becomes a factor that may be inherited for generations to come. Research is also looking at promising targets for clearly following the neurobiology pathway of PTSD improving treatment and possible interventions.
Why is the hereditary factor so important? "If the risk for PTSD following traumatic exposure is associated with an underlying genetic vulnerability, it would be expected that biological relatives (family) of an individual with PTSD would have a higher risk of developing the disorder following trauma exposure than similarly traumatized non-relatives. Family studies of PTSD have demonstrated this finding. Specifically, PTSD diagnosis was more frequent in adult children of Holocaust survivors with PTSD as compared to children of Holocaust survivors without PTSD (Yehuda et al., 2001). A similar finding has been reported in adult children of Cambodian refugees whose parents had PTSD (Sack et al., 1995 )." Obviously, if we know there is a hereditary factor to consider, early interventions would be most desirable.
The report from the Elsevier Journal goes on to state, "A limitation of family studies is that PTSD cannot be assessed in those individuals who are not exposed to trauma, and therefore, it cannot be known whether they would have developed PTSD in response to trauma. This can have the effect of falsely lowering the estimated risk for PTSD. An even more significant limitation of family studies is that because family members share both genetic and environmental similarities, these studies cannot differentiate between a genetic versus environmental basis for the increased prevalence within a family pedigree." [Skelton, K., et al., PTSD and gene variants: New pathways and new thinking, Neuropharmacology (2011), doi:10.1016/j.neuropharm.2011.02.013]
Going back to our three primary neuronal systems listed above, The HPA axis (hypothalamic-pituitary-adrenal) is ptsdcomprised of neural (mental) and endocrine (secretion of hormons) structures that coordinate the response or reaction to stress. It activates the LC-noradrenergic system which has been implicated in the over-consolidation of fear memories in the aftermath of traumatic exposure (O’Carroll et al., 1999; Southwick et al., 1999; Southwick et al., 2002).
The amygdala, part of the limbic system within the temporal lobe, plays a primary role in threat detection and elaborating conditioned and unconditioned fear responses, including behavioral responses and activation of the HPA axis (Davis, 1992). The activity of the amygdale, an almond-shape set of neurons located deep in the brain's medial temporal lobe is shown to play a key role in the processing of emotions. The amygdala forms part of the limbic system which is a set of evolutionarily primitive brain structures located on top of the brainstem and buried under the cortex. Limbic system structures are involved in many of our emotions and motivations, particularly those that are related to survival like fear and anger and is regulated in a "top-down" fashion by the medial prefrontal cortex which can function in an inhibitory manner to extinguish conditioned fear responses (Milad and Quirk, 2002; Vidal-Gonzalez et al., 2006; Peters et al., 2009).
Each of these Neural systems interact in the development and maintenance of fear conditioning, and have been the focus of candidate genes studies into the neurobiology of PTSD.
Despite clear evidence of HPA axis disturbance in PTSD, initial investigations into main effects of candidate genes that impact on this system have not been very revealing. For example, a study of the glucocorticoid receptor gene demonstrated no significant association between two polymorphisms in this gene and a diagnosis of PTSD (Bachmann et al., 2005).
Given that PTSD is a psychiatric disorder that, by definition, requires exposure to a specific environmental event (trauma), and that individuals vary in their phenotypic response (the observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences) to the event, with only a minority of individuals subsequently developing PTSD, the genetic basis of this disorder is likely to be better illustrated by studies of gene-environment interactions rather than studies of the main effects of genes.
Studies have recently demonstrated an interaction between polymorphisms in FKBP5 , a gene which impacts on HPA axis function by regulating GR (glucocorticoid receptor gene expression-hormonal response to stress) activity, and childhood environment to predict severity of PTSD. "FKBP5 is a co-chaperone protein that interacts with another molecular chaperone, hsp90, and is part of the mature GR heterocomplex. It regulates GR sensitivity and nuclear translocation of GRs such that reduced activity of FKBP5 increases GR sensitivity." (Hubler and Scammell, 2004).
Polymorphisms in FKBP5 have previously been reported to be associated with peri-traumatic dissociation in medically ill children, a symptom which is predictive of the development of PTSD (Koenen et al., 2005b). In a study of over 700 highly traumatized, inner city, African-American subjects recruited from primary care clinics (Binder et al., 2008), four polymorphisms of theFKBP5 gene were demonstrated to interact with severity of childhood abuse to predict the severity of adult PTSD symptoms.
Two additional G x E (Gene and Environment) studies focused on genes which may have a broad impact within the brain. Gamma-Aminobutyric Acid (GABA) is the major inhibitory neurotransmitter in the brain. A recent study reported a significant interaction between three single nucleotide (organic molecules that form the building blocks of DNA and RNA) polymorphisms in the GABA alpha-2 receptor gene and severity of childhood trauma in predicting adult PTSD. (Nelson et al., 2009).
G-proteins (known as guanosine nucleotide-binding proteins), are a family of proteins involved in transmitting signals from a variety of different signals from outside a cell to the inside of the cell. They regulate a wide variety of activities, receptors and transporters in the brain. G-protein signaling 2 (RGS2) is a member of a protein family that facilitates the deactivation of G-proteins, thereby decreasing G protein-coupled receptor signaling (Neubig and Siderovski, 2002). Amstadter et al. (2009a).
In a study of 2004 Florida hurricane populations by Amstader it was found there was a significant association between a specific genotype of the RGS2 gene and post-hurricane PTSD in adults exposed to high environmental stress (high exposure to hurricanes and low social support), as well as an association between this genotype and a diagnosis of lifetime PTSD in adults with prior trauma exposure and low social support.
Epigenetic modification describes an environmentally induced change in DNA which alters the function rather than the structure of a gene. These changes can be specific to critical developmental periods. They can be stable, site-specific, long-lasting, and may be inter-generationally transmitted…meaning inherited from generation to generation (Meaney and Szyf, 2005; Yehuda and Bierer, 2009). The biological mechanism of epigenetic modification most often involves methylation (the addition of a methyl group) of cytosine within a gene, which typically reduces gene expression (Novik, Nimmrich et al. ,2002)
Enough of the scientific stuff for now… The important thing to remember when studying the effect of PTSD on one's genetic make-up is that research must focus on how stress may alter gene function rather that gene structure.
In Part 2 we will look at possible ways to address these genetic markers of Post Traumatic Stress Disorder, which could well provide long term solutions. To those suffering PTSD, such outside-the-box thinking would be most welcome.