The Causes of Individual Variation in the Risk and Expression of Post Traumatic Stress Disorder (PTSD)

Abstract

This paper examines the neurobiological causes that may underlie individual variation in the risk and expression of post traumatic stress disorder (PTSD). Aberrant functioning in both the hypothalamic-pituitary-adrenal axis and the neurocircuit consisting of the amygdala, hippocampus, and medial prefrontal cortex, are postulated to be vulnerability factors which predispose certain individuals to possess a higher risk of developing PTSD. As for the individual differences in PTSD expression, laterality differences in gray matter deficits contained in the anterior cingulate cortex may distinguish between chronic and acute PTSD cases, while catecholamine studies suggest that there may be a subset of individuals with a sensitized noradrenergic system and another subset with a sensitized serotonergic system. The discussion then concludes with a proposed study that aims to determine if the aforementioned neurobiological factors correlate with personality traits that have been found to play a role in PTSD risk and expression.

Introduction

The diagnosis of post traumatic stress disorder (PTSD) was formalized in 1980 and it is currently classified under Anxiety Disorders in the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (APA, 2000). PTSD is characterized by persistent feelings of extreme fear, horror, or helplessness following exposure to a traumatic event. The consequences to this exposure are manifested in three symptom clusters: persistent and involuntary reexperiencing of the trauma (e.g. recurring dreams and intrusive thoughts), avoidance of trauma-related stimuli and numbing of general responsiveness (e.g. feeling of detachment or estrangement), and increased arousal (e.g. hypervigilance and exaggerated startle response).

In a nationally representative study conducted in the United States (Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995), it is estimated that although approximately half of the adult population have experienced a traumatic event, not everyone who is exposed to the trauma develops PTSD. Lifetime prevalence in the community stands at 10% for women and 5% for men, and around 30% of those affected go on to develop chronic PTSD (in which symptoms last for at least 3 months). It is critical to note that these statistics should not undermine, and thus "blanket", the heterogeneity within PTSD because the risk of developing PTSD ranges from 1.8% to 65%, depending on the gender of the victim and the nature of the trauma (Davidson, Stein, Shalev, & Yehuda, 2004). Nevertheless, the clear disparity between a 50% chance of trauma exposure and a relatively lower prevalence rate of PTSD highlights the fact that individual responses to trauma vary dramatically. Consequently, such variation raises two very important questions - 1) why only some, and not all, of those who have been exposed to trauma develop PTSD and 2) why not everyone with PTSD behaves the same way. It is both interesting and relevant to study these two questions, as knowing what predisposes certain individuals to PTSD allows us to identify the high-risk groups and hence engage them in selective preventive interventions, which are relatively more cost- and time- efficient than universal interventions (which target the general public). Further, understanding that heterogeneity exists within a PTSD diagnosis reminds us that there is no one method of treatment for PTSD, and different treatments should be developed to target individuals who may exhibit different neurobiological disturbances.

Thus, the aim of this paper is to discuss the causes of individual differences in the risk and expression of PTSD from a neurobiological perspective. In particular, individual variation in PTSD risk will be explained via a primarily neuroanatomical standpoint - with focus on the hypothalamic-pituitary-adrenal axis, amygdala, hippocampus, and medial prefrontal cortex. The causes of individual variation in PTSD expression will be explained via both neuroanatomical and neurochemical standpoints - with focus on the anterior cingulated cortex and the noradrenergic and serotonergic systems. However, it is important to state that any discussion on neuroanatomy cannot be completely divorced from the discussion on neurochemistry. Thus, both viewpoints will overlap in the following analysis and each will contribute significantly to our understanding of risk and expression in PTSD.

Methods

The first step in resource collection for this paper was to peruse the PTSD section in each of the following textbooks - Clinical Neuroscience (Lambert & Kinsley, 2005), Behaviour Disorders of Childhood (Wicks-Nelson & Israel, 2006), and Abnormal Psychology - Clinical Perspectives on Psychological Disorders (Halgin & Whitbourne, 2005). Neuroanatomical and neurochemical correlates of PTSD were taken note of. The next step was to conduct multiple searches using the databases PsychINFO and PUBMED spanning the years 1980 (the year PTSD appeared as a formal diagnosis) to 2007. In the search for PTSD risk information, the keywords entered were "PTSD", "risk", and in combination with one of the following - "HPA", "hippocampus, or "amygdala". In the search for PTSD expression information, the keywords entered were "PTSD", "expression" or "course", and "catecholamine". Additional studies were also identified from the textbooks mentioned above, and a total of seven review studies were utilized in the analysis.

Discussion

Causes of individual variation in PTSD risk

The work in both animal and human studies has given insight into the critical contribution of the hypothalamic-pituitary-adrenal (HPA) axis to regulating and promoting adaptive responses to stress (Herman & Cullinan, 1997; McEwen, 1979; Sapolsky, Armanini, Packan, Sutton, & Plotsky 1990; Tsigos & Chrousos, 2002). Given that stress plays an important causal role in the development of PTSD, it is not surprising that HPA axis reactivity is extensively studied in PTSD individuals. Thus, in light of the role of the HPA axis in the stress response, any individual variation in the risk of developing PTSD can be potentially due to individual variation in HPA axis response and functioning.

The neurobiology of the acute stress response as mediated by the HPA axis is summarized as follows: under conditions of stress, both the hippocampus and amygdala activate the hypothalamus, which releases the hormone corticotrophin-releasing factor (CRF). This in turn stimulates the pituitary gland to release adrenocorticotropin hormone (ACTH), which then stimulates the adrenal gland to release cortisol. The role of cortisol is dual - to inhibit the sympathetic nervous system activation (the "fight-or-flight" response which is also launched in times of stress) and to suppress HPA axis activity via negative feedback inhibition. In healthy individuals, the negative feedback mechanism terminates the stress response by restoring basal hormonal levels. However, in individuals with PTSD, there seems to be abnormalities in the regulation of the HPA system (Davidson et al., 2004; Southwick, Yehuda, & Wang, 1998). In particular, the first abnormality is that individuals with PTSD exhibit higher CRF levels than individuals without PTSD, and this CRF hypersecretion is confirmed in both neuroendocrine challenge studies and also studies measuring CRF concentration levels in the cerebrospinal fluid (De Kloet et al., 2006; Southwick et al., 1998). The second abnormality in PTSD individuals is an accompanying decrease in baseline cortisol levels. The decreased cortisol level is widely documented both in a variety of PTSD populations (e.g. war veterans, offspring of Holocaust survivors, rape victims, survivors of automobile accidents, and abuse victims etc), and in a variety of studies using different methods of cortisol measure (Davidson et al., 2004; De Kloet et al., 2006; Southwick et al., 1998). In particular, the review conducted by Southwick et al. (1998) showed that the majority of 24-hour urine and diurnal plasma cortisol studies found lower cortisol levels in PTSD individuals, and that studies which have looked at receptor densities document a greater number of lymphocyte glucocorticoid receptors in PTSD individuals relative to normal or comparison controls, which is consistent with an up-regulation mechanism in response to low circulating levels of cortisol. Thus the recurring characteristic of PTSD is a combination of CRF hypersecretion and low cortisol level. An explanation for this anomaly in PTSD individuals is an enhanced negative feedback mechanism in the HPA axis, in which cortisol receptors in the pituitary are oversensitive (De Kloet et al., 2006; Stein, Yehuda, Koverola, & Hanna, 1997). The enhanced negative feedback then leads to a premature shutdown of the HPA axis, which would prevent the damping down of the sympathetic nervous system and consequently cause prolonged arousal during stress.

Since CRF hypersecretion, low cortisol level, and consequently the enhanced HPA axis feedback regulation are biological correlates of PTSD, it is possible that they serve as either risk factors for PTSD (i.e. present before the trauma), or as after-effects of traumatic stress (i.e. the stress causes a dysfunctional HPA axis response), or even both. There is evidence, however, that supports the idea that enhanced negative feedback in the HPA axis is actually a risk factor that predisposes certain individuals to develop PTSD in response to traumatic stress (Davidson et al, 2004; Southwick et al., 1998; Yehuda et al. 2000). For instance, in their study of cortisol level and PTSD risk in the adult offspring of Holocaust survivors, Yehuda et al. (2000) found that of the Holocaust children who had no PTSD or trauma exposure, those whose parents had PTSD exhibited lower cortisol levels than those whose parents did not have PTSD. This result is in line with the notion that parental PTSD is a putative vulnerability marker for future PTSD. Further, a twin study suggests that genetic factors account for 28% to 32% of the variance in arousal-related PTSD symptoms in war veterans even after adjusting for differences in combat exposure (True et al., 1993).

In sum, the aberrant negative feedback mechanism in the HPA stress response is a possible risk factor for PTSD development. Thus, any individual variation in the HPA response, potentially played out via genetic variation, can possibly explain why only some, but not all, of those individuals who are exposed to traumatic stress develop PTSD.

Another cause of individual variation in PTSD risk has its roots in the neuroanatomical "triad" consisting of the amygdala, hippocampus, and medial prefrontal cortex (mPFC). The amygdala, which is implicated as the key structure in fear conditioning and processing in both animal and human studies, often exhibits enhanced activity in individuals who suffer from PTSD (Hendler et al., 2003; LeDoux, 2000; Shin et al., 2004), and this hyperactivity is seen in both acute and chronic PTSD cases (Armony, Corbo, Clement, & Brunet, 2005). In addition, neuroimaging studies also show that the exaggerated amygdala response (usually the right amygdala) can be elicited by the presentation of either trauma-related stimuli or general negative stimuli to PTSD individuals (Armony et al., 2005; Rauch et al., 2000). Consistent with animal studies, which document hippocampal damage in response to prolonged stress (Sapolsky, 1994; Stein-Behrens, Lin, & Sapolsky, 1994), the hippocampus is also another neuroanatomical area that has been implicated as deficient in human PTSD individuals. In particular, several structural and functional imaging studies conducted on different PTSD populations (i.e. women with childhood sexual abuse and war veterans) show that relative to individuals who are exposed to trauma but do not develop PTSD or to individuals are not exposed to trauma at all, those who are diagnosed with PTSD often show a reduction in hippocampal volume and activation (Bremner et al., 2003; Gilbertson et al., 2002; Rauch, Shin, & Phelps, 2006; Stein, Koverola, Hanna, Torchia, & McClarty, 1997). Using a monozygotic twin study, Gilbertson et al. (2002) investigated if smaller hippocampal volume represents the consequence of traumatic exposure or a pre-trauma, familial vulnerability that predisposes certain individuals to develop PTSD in response to stress. They found evidence for the latter, as severe PTSD twin pairs - both the trauma-exposed and unexposed members - had smaller hippocampi than non-PTSD twin pairs. The third area that is found to exhibit attenuated activity in PTSD is the mPFC, which is implicated in the extinction of the fear response (Lanius et al., 2001; Lindauer et al., 2004; Shin et al., 2004).

With dysfunction in these three neuroanatomical areas - the amygdala, hippocampus, and mPFC - recurring in PTSD research, Rauch et al. (2006) presented a neurocircuitry model involving interactions among these three areas. In particular, amygdala hyperresponsivity mediates hyperarousal and explains the indelible quality of emotional memories related to the trauma; inadequate influence of the mPFC underlies the deficits of fear extinction as well as the capacity to suppress attention and response to trauma related or generally threatening stimuli; lastly, as the hippocampus plays a role in contextual fear conditioning (Rudy, Huff, & Matus-Amat, 2004; Sanders, Wiltgen, & Fanselow, 2003), decreased hippocampal function underlies deficits in identifying safe contexts. In addition, dysfunction in both the amygdala and hippocampus can also increase the risk of developing PTSD and its associated symptoms by their aforementioned roles in influencing HPA axis activity (see above discussion on HPA axis and PTSD). Rauch et al. (2006) posit that this neurocircuitry model represents a pathophysiological pathway, in which the development of PTSD can be conceptualized as a fear-conditioning process which is superimposed on some diathesis that entails dysfunction/deficit in at least one of the three structures. In other words, individual differences in the risk of an aberrant PTSD neurocircuit predispose some individuals to develop PTSD in response to a traumatic stressor.

Causes of individual variation in PTSD expression

A DSM-IV-TR diagnosis of PTSD requires the specification of whether it is an acute (duration of symptoms is less than 3 months), a chronic (duration of symptoms is 3 months or more), or a delayed onset (onset of symptoms is at least 6 months post-trauma) case. The observation that some individuals experience relief after a given period of time whereas others suffer from post traumatic stress even after many years following the trauma (Breslau et al., 1998) draws attention to the fact that the expression of PTSD can be heterogeneous in its duration. It appears that the study of the anterior cingulate cortex (ACC), which is slowly gaining the interest of PTSD researchers who utilize structural and functional imaging, may provide some insight into this issue of PTSD symptom duration.

The ACC is a component of the frontal lobes that is implicated in the processing of emotional and cognitive information and is also thought to have inhibitory projections to the amygdala (Allman, Hakeem, Erwin, Nimchinsky, & Hof, 2001; Bush, Luu, & Posner, 2000). Two studies which used voxel-based morphometry to study gray matter volumes in the ACCs of PTSD individuals reveal that acute and chronic cases of PTSD can potentially be differentiated via laterality differences in ACC gray matter anomalies. The first study (Yamasue et al., 2003) measured gray matter volume in the ACCs of individuals with PTSD and those without PTSD approximately five years after the Tokyo subway sarin attack. The researchers found reduced gray matter volume in the left-dorsal ACC of the group who developed chronic PTSD. On the other hand, the second study (Corbo, Clement, Armony, Pruessner, & Brunet, 2005) measured gray matter density in the ACCs of individuals who developed acute PTSD (duration of symptoms less than 4 weeks post-trauma) and also in healthy controls. Corbo et al. (2005) found significantly reduced gray matter density in the right pregenual ACC of those who developed acute PTSD. Thus, it appears that individuals with chronic PTSD show deficits in the left ACC while those with acute PTSD show deficits in the right ACC. However, given that both studies were conducted on different national populations who experienced very different types of trauma, it is definitely too premature to conclude that laterality differences in ACC gray matter reduction can predict if an individual who is diagnosed with PTSD will exhibit an acute or chronic course. Nevertheless, the role of ACC in PTSD symptom expression appears promising and thus should certainly receive much more attention in current PTSD research.

Besides the aforementioned laterality differences in ACC gray matter deficits, individuals differences in the catecholamine receptor systems have also been postulated to be

associated with different neurobiological subtypes of PTSD. In particular, the noradrenergic system has been the one of the most extensively studied neural systems in individuals who suffer from PTSD. As mentioned, debilitating PTSD symptoms include intense fear, anxiety, hypervigilance, and intrusive memories or flashbacks. Thus, it is not surprising that noradrenaline, or norepinephrine (NE), is a major focal point in PTSD research because it has been linked to fear, anxiety, vigilance, and memory consolidation (Abercrombie & Jacobs, 1987; Grant, Aston-Jones, & Redmond; 1988; Levine, Litto, & Jacobs, 1990; McGaugh, 1990; Pitman, 1989; Squire, 1986). 24-hour urine NE excretion is significantly elevated (Kosten, Mason, Giller, Ostroff, & Harkness, 1987; Yehuda, Southwick, Giller, Ma, & Mason, 1992) and platelet alpha2-adrenergic receptor number is significantly decreased in combat veterans with PTSD compared with normal controls (Perry, Giller, & Southwick, 1987). In some studies of NE in PTSD, yohimbine hydrochloride is often used as a probe of central and peripheral NE reactivity. Yohimbine is an alpha2-adrenergic receptor antagonist that activates NE neurons by blocking the presynaptic alpha2-adrenergic autoreceptor. It has been found that yohimbine administration produces panic attacks in 60%-70% and flashbacks in 30%-40% of PTSD individuals (Southwick et al., 1993; Bremner et al. 1993). This anxiogenic and PTSD behavioural response to yohimbine, which acts primarily on the NE system, suggests that the NE system might be hyperreactive in some PTSD individuals.

The second catecholamine system that has been studied in PTSD research, though not

to the extent of NE, is serotonin (5-HT). Altered 5-HT activity following severe stress or trauma has been reported in both animal and human studies. (Arora, Fitchner, & O'Connor, 1993; Shimizu, Take, Hori, & Oomura, 1992; Wright, Ismail, Upton, & Marsden, 1991). Low 5-HT activity in humans is also associated with aggression, impulsivity, and suicide - behaviors that often are reported in combat veterans with PTSD (Brown & Linnoila, 1990; Stanley & Stanley, 1990). In addition, platelet 5-HT uptake is significantly decreased in individuals with PTSD compared with normal controls (Arora et al., 1993) and selective serotonin reuptake inhibitors (SSRIs) have been found to be moderately efficacious in treating the full range of PTSD-specific symptoms in a subgroup of traumatized individuals. (Shay, 1992; Nagy, Morgan, Southwick, & Charney, 1993; Van der Kolk et al., 1994).

Thus, while yohimbine clearly causes pronounced symptom effects in PTSD individuals, it is unclear whether other anxiogenic probes that alter the function of different neurotransmitter systems would produce similar reactions. Consequently, the Southwick et al. (1997) study tested the specificity of the yohimbine response in combat veterans with PTSD and evaluated the potential serotonergic (5-HT) contributions to trauma-related symptoms. Yohimbine (a probe for NE activity), meta-chlorophenylpiperazine (m-CPP - a probe for 5-HT activity), and saline solution were administered intravenously over 3 separate test days to combat veterans with PTSD and to healthy controls. The researchers found that yohimbine induced panic attacks in 42% and flashbacks in 31% of the individuals who had PTSD, while m-CPP induced panic attacks in 31% and flashbacks in 27% of the same population. It is important to note that yohimbine-induced and m-CPP-induced panic attacks tended to occur in different individuals - only 19% with drug-induced panic attacks had the attacks on both test days; the remaining 81% had their panic attacks following either yohimbine or m-CPP administration, but not both. This suggests that although all individuals with drug-induced panic attacks showed elevation in PTSD symptoms (e.g. detachment, flashbacks etc) relative to the controls, there is the possibility that at least 2 biological subtypes of PTSD exist - one characterized by sensitized NE function and the other by sensitized 5-HT function. Since these two neurochemical systems each implicate different behaviours, it seems plausible that the two PTSD subtypes, if existent, will express behavioural differences.

Conclusion

In sum, the above discussion postulates that the neurobiological causes of individual differences in PTSD risk are - an enhanced negative feedback system in the HPA axis stress response (accompanied by low circulating cortisol level) and an aberrant fear-conditioning neurocircuit consisting of the amygdala, hippocampus, and mPFC. Individual differences in PTSD expression, on the other hand, may be determined by laterality differences in ACC gray matter deficits and differential responses to different neurotransmitter systems.

These solutions are best seen as tentative answers, and not irrefutably conclusive ones, to the questions of why only some individuals develop PTSD after trauma exposure, and why those who eventually develop PTSD may exhibit differences in behavioural and biological responses. This caution is definitely warranted because comparing and contrasting PTSD research inevitably involves several limitations. Firstly, the studies discussed above were conducted on a heterogeneous group of PTSD individuals. Many studies involved Vietnam War veterans in the United States, while others had rape victims, automobile accident survivors, and offspring of Holocaust survivors as subjects. Since the nature of the traumatic cause was so different in each population, assembling all of them into one homogeneous group (with the uniform diagnosis label "PTSD") for the sake of convenience in the discussion of individual differences will decrease the validity of any conclusions drawn. Secondly, for reasons of practicality, many studies were unable to exclude PTSD individuals who were on medication for their condition or who exhibited comorbidity with other disorders like major depression. This inevitably introduces confounds into the results obtained from such studies. Thirdly, while the primary focus in this paper is causality of individual differences, PTSD research, like most areas of clinical research, is plagued with the problem of directionality. Since ethical constraints prevent researchers from exposing normal and healthy humans to stressors which are comparable in magnitude to natural disasters and wars, almost all of the PTSD studies conducted on humans are retrospective. This means that the neurobiological features that have been put forward as causing PTSD and its manifestation may very well be consequences of the trauma and not predisposing factors which exist before the trauma. Lastly, individual differences may actually be minimized in PTSD research because most studies tend to focus on only one set of PTSD individuals (i.e. chronic cases only or acute cases only, but seldom both), or they do not distinguish between differences within the same PTSD population (i.e. chronic vs. acute cases, internalizing vs. externalizing subtypes). The evidence for the PTSD internalizing and externalizing subtypes comes from research in personality (Miller, 2003; Miller, Greif, & Smith, 2003; Miller, Kaloupek, Dillon, & Keane, 2004), and thus was not mentioned in the above discussion on the neurobiological causes of different PTSD expressions. However, it appears that combining the two separate lines of PTSD research - personality and neurobiology - might be the key to gaining a more comprehensive and valid view of individual differences in PTSD risk and expression. Further, the heritability and stability of personality have been documented, and specific trait dispositions have been linked to structural and biochemical brain systems. Thus, a hypothetical study utilizing this approach has been proposed for future research and it will be discussed towards the end of this section.

This hypothetical study is based on an interesting three-factor personality model postulated by Miller (2003). In his thorough review of all studies which examined the interface between personality and PTSD, Miller (2003) posits that the three broad-band personality traits that have been emphasized in personality and psychopathology research - negative emotionality (NEM), positive emotionality (PEM), and constraint/inhibition (CON) also play significant roles in PTSD. NEM refers to dispositions towards negative moods and emotions and a tendency towards adversarial interactions with others. It has also been conceptualized as a "generalized biological vulnerability" - a non-specific predictor of a broad class of psychopathology called "internalizing disorders", which includes anxiety and depression. An anxiety-prone personality, in turn, may increase the risk of developing stress-related disorders like PTSD (Geeres,Van Gurp, Wiegant, & Stam, 2006). PEM refers to the capacity to experience positive emotions and tendencies towards active involvement in social and work environments. CON is characterized by planfulness, harm-avoidance, restraint, and prudence. The Miller (2003) model specifically states that high NEM is the primary personality risk factor in PTSD development, whereas low PEM and low CON serve as moderating factors that influence PTSD expression. In particular, a premorbid personality characterized by high NEM coupled with low PEM predisposes a trauma-exposed individual to develop the "internalizing PTSD subtype" (symptoms expressed as anxiety, depression, and social avoidance), while a premorbid personality characterized by high NEM coupled with low CON predicts an "externalizing PTSD subtype" (symptoms expressed as impulsivity, aggression, antisociality, and substance abuse).

The aforementioned personality model can be used to devise a hypothetical study that combines both the personality and neurobiological approaches to study PTSD risk and expression. The proposed study has a prospective longitudinal research design that aims to track a high-risk group of individuals before and after a traumatic exposure. At the beginning of the study (before the trauma), responses in the HPA axis and the amygdala-hippocampus-mPFC neurocircuit should be measured to see if low cortisol levels and aberrant brain activity in the neurocircuit brain areas actually exist even before the trauma. In addition, activity in the ACC should be assessed, and anxiogenic probes (like yohimbine and m-CPP to test NE and 5-HT receptor reactivity respectively) and personality questionnaires (which assess a broad range of traits including NEM, PEM, and CON) should also be administered. After the traumatic exposure, all these measures should be taken again. Given the roles of NE in internalizing behaviours like anxiety and of 5-HT in externalizing behaviours like aggression, it will be important to note if NE system dysregulation and 5-HT system dysregulation predict the PTSD internalizing subtype and the PTSD externalizing subtype respectively. The existence of such correlations supports the notion that individual variation in PTSD expression may be explained by sensitivity to different neurochemical systems. It might also be interesting to see if NEM, which is a risk factor for PTSD, may actually correlate with responses in the HPA axis and the neurocircuit.

In conclusion, this paper attempts to answer the questions of why not all individuals who have been exposed to trauma develop PTSD and why not everyone with PTSD behaves the same way. However, the solutions presented are by no means definitive or conclusive.

In the future, differing approaches within the field of PTSD research can collaborate in a concerted effort to provide a more comprehensive and valid view of this debilitating disorder.

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