© Springer Science+Business Media New York 2015
Marilyn P. Safir, Helene S. Wallach and Albert “Skip” Rizzo (eds.)Future Directions in Post-Traumatic Stress Disorder10.1007/978-1-4899-7522-5_22. Neurobiological Risk Factors and Predictors of Vulnerability and Resilience to PTSD
(1)
Department of Psychiatry, Rambam Health Care Campus, Haifa, Israel
(2)
Faculty of Medicine, Technion IIT, Haifa, Israel
Keywords
PTSD riskPTSD resiliencePsychosocial factorsNeurobiological factorsGenetic factorsIntroduction
Risk factors for PTSD may be classified in three temporal domains: pre-traumatic, peri-traumatic, and posttraumatic factors.
Pre-traumatic factors predispose an individual to developing PTSD. These include various neurobiological, anatomic, and genetic variables. Peri-traumatic factors are those linked to the actual traumatic occurrence and reflect greater stress responses. Posttraumatic factors are related to the long-term course of the trauma response, including the coping abilities of the survivors and their support network (Ozer, Best, Lipsey, & Weiss, 2003). Currently, the vast majority of the posttraumatic risk factors that have been delineated are psychosocial and not biological. The scope of the current chapter focuses on neurobiological and genetic vulnerability and resilience factors of PTSD.
Pre-traumatic Risk Factors
Neurobiological Factors
Much attention in PTSD research has focused on the two predominant biological systems involved in stress responses: the noradrenergic system and the corticotrophin releasing hormone (CRH) stress response. Under normal conditions, in the presence of a stressor, the sympathetic nervous system is activated, causing norepinephrine (NE) to be released from the locus ceruleus (LC). This in turn produces a number of physiological responses, such as vasoconstriction of peripheral blood flow, increased blood flow to the heart, increased respiratory rate, and pupillary dilation—the so-called “fight or flight” response. However, there is a large body of evidence that suggests this functioning is altered, and there may, in fact, be hyperactive noradrenergic function in PTSD.
The amygdala has received particular attention in research into emotional memory. Cahill and McGaugh (1996) used positron emission tomography (PET) to demonstrate that enhanced activity in the amygdala during viewing of emotionally arousing films influenced subsequent recall of the arousing material, although this was not true of neutral material. Subsequently, research has shown that both the emotional valence of the stimulus and the level of arousal at the time of encoding into memory appear to be important factors in the process of memory consolidation (Zald, 2003). As such, in the presence of an emotionally arousing stimulus, sensory information received by the basolateral nucleus of the amygdala (BLA) is amalgamated along with information from other brain structures to form an emotional association with memory of the stimulus. Input from the BLA is then transmitted, via the central nucleus of the amygdala, to other neural structures, including the hypothalamus, effecting motor, and autonomic responses. In this way, the amygdala plays a critical role in fear conditioning, by creating the association that links a potential threat to a fear response.
The amygdala is also thought to modulate consolidation of emotional memories in the hippocampus, and this process is significantly influenced by the noradrenergic system. In a pivotal study by Cahill, Prins, Weber, and McGaugh (1994), administration of a central β-adrenergic antagonist (propranolol) prior to viewing a series of emotional slides resulted in selectively impairing effects on recall of emotional material; recall of neutral material was unaffected. Building on this, van Stegeren et al. (2005) conducted a functional magnetic resonance imaging (fMRI) study, comparing memory retrieval in a group of healthy controls that received either propranolol or placebo prior to viewing emotional and neutral pictures. van Stegeren et al. demonstrated that, following placebo administration, amygdala activation increased in response to emotional pictures, but this response decreased following propranolol, suggesting that NE is an important modulator of amygdala activation. As such, enhanced noradrenergic activity seen in patients with PTSD may act to increase amygdala activation, intensifying the fear conditioning process, which may partially explain why these individuals avoid thoughts, feelings, or physical triggers that remind them of the trauma. Increased amygdala activation with acquisition of fear responses, and a failure of the medial prefrontal cortex to properly mediate extinction, is hypothesized to underlie symptoms of PTSD.
Interestingly, resilience to PTSD may be associated with relatively decreased amygdala activation (Osuch, Willis, Bluhm, Ursano, & Drevets, 2008), and amygdala lesions may reduce the occurrence of PTSD (Armony, Corbo, Clement, & Brunet, 2005). In support of the potential role of amygdala in PTSD, some studies have reported that amygdala activation is positively correlated with PTSD symptom severity (Dickie, Brunet, Akerib, & Armony, 2008). Similarly, response to cognitive-behavioral treatment is associated with a decrease in amygdala activation (Peres et al., 2007), and relatively higher pre-treatment amygdala activation is predictive of a less favorable response to cognitive-behavioral therapy (Bryant et al., 2008).
One study using positron emission tomography (PET) and [11C]-carfentanil reported diminished mu-opioid receptor binding in the extended amygdala in trauma-exposed individuals with and without PTSD (Liberzon et al., 2007). Another study found decreased [11C]-flumazenil binding in the left amygdala in PTSD subjects compared with trauma-exposed control participants, consistent with altered gamma amino-butyric acid (GABA)ergic function in this disorder (Geuze et al., 2008).
As mentioned above, another critical brain structure implicated in PTSD is the hippocampus, which has an essential role in the formation and retrieval of episodic and declarative memories. The hippocampus is linked reciprocally to the amygdala and is subject to altered noradrenergic function via NE’s actions on the amygdala. A review of evidence from animal studies showed that chronic stress was associated with dendritic atrophy in the CA3 region of the hippocampus and the medial prefrontal cortex (mPFC), as well as decreased neurogenesis (Kuroda & McEwen, 1998). One commonly cited observation in individuals with PTSD is a finding of decreased hippocampal volumes, which was initially postulated to reflect atrophy secondary to chronic stress and glucocorticoid overexposure. More recently, however, Kasai et al. (2008) employed an impressively designed twin study of brain morphometrics and PTSD. In the latter study, two classifications of twin pairs were used. One classification included sets of twins in which one twin was combat-exposed in Vietnam and diagnosed with PTSD, while his co-twin was unexposed to combat and did not have PTSD (co-twin was termed “high risk”). The second classification included sets of twins in which one twin was combat-exposed in Vietnam and did not have PTSD while his co-twin was not exposed to combat and did not have PTSD (co-twin termed “low risk”). Combat-exposed twins with PTSD had less gray matter volume in the hippocampus, pregenual anterior cingulate cortex, and bilateral insular regions compared to combat-exposed twins without PTSD. In addition, a Diagnosis by Exposure interaction revealed less gray matter volume in the pregenual anterior cingulate cortex of combat-exposed PTSD twins compared to the other three twin groups (Kasai et al., 2008). This finding suggests that lower gray matter volume is a consequence of combat stress exposure and subsequent PTSD and not of genetic factors.
Some functional neuroimaging studies have reported decreased hippocampal activation during symptomatic states (Bremner et al., 1999) and during memory tasks that involve neutral or emotional stimuli (Moores et al., 2008). One study in 2010 found reduced glucose metabolic rate in the hippocampus at rest (Molina, Isoardi, Prado, & Bentolila, 2010), and another reported that successful treatment was related to increased hippocampal activation (Peres et al., 2007). Other studies, however, have reported increased activation in the hippocampus in PTSD (Werner et al., 2009) or a positive correlation between hippocampal activation and PTSD symptom severity (Shin et al., 2004).
Hippocampal volumes have been inversely associated with verbal memory deficits (Bremner et al., 1995), combat exposure severity (Gurvits et al., 1996), dissociative symptom severity (Bremner et al., 2003), depression severity (Villarreal et al., 2002), and PTSD symptom severity (Bremner et al., 2003). Spectroscopy studies have reported decreased N-acetyl aspartate (NAA) in the hippocampus, often interpreted as consistent with decreased neuronal integrity (Ham et al., 2007). Furthermore, NAA levels in the pregenual ACC were negatively correlated with the severity of reexperiencing symptoms (Ham et al., 2007). The results of some studies suggest that hippocampal volumes may increase following treatment with serotonin reuptake inhibitors (Bossini et al., 2007).
With regard to neurochemistry, one PET study found decreased [11C]-flumazenil binding in the hippocampus (as well as thalamus and cortical areas) suggesting diminished benzodiazepine–GABA function in the hippocampus in PTSD (Geuze et al., 2008).
Although not originally included in early neurocircuitry models, the dorsal anterior cingulated cortex (dACC) and insular cortex may have a role in PTSD as well. Recent studies have suggested that the dACC is hyperresponsive in PTSD, perhaps underlying exaggerated fear learning. The findings of several studies suggest diminished volumes or gray matter densities in the ACC in PTSD (Kasai et al., 2008), and smaller ACC volumes have been associated with greater PTSD symptom severity (Woodward et al., 2006). Enhanced resting metabolic activity in the dACC/MCC appears to represent a familial risk factor for developing PTSD after exposure to psychological trauma (Shin et al., 2009).
Functional neuroimaging studies of PTSD have reported decreased activation or failure to activate the medial prefrontal cortex (mPFC) (including the right ACC, medial frontal gyrus, and subcallosal cortex) during traumatic script-driven imagery (Shin et al., 2004), the presentation of trauma-related stimuli (Hou et al., 2007), and negative, non-traumatic stimuli (Phan, Britton, Taylor, Fig, & Liberzon, 2006). Furthermore, mPFC activation appears to be inversely correlated with PTSD symptom severity (Dickie et al., 2008) and positively correlated with pre-scan cortisol levels (Liberzon et al., 2007). Finally, increased mPFC activation following treatment has been positively associated with symptomatic improvement (Felmingham et al., 2007).
Relative to comparison groups, increased activation in the insular cortex has been found in PTSD during script-driven imagery (Lanius et al., 2007), fear conditioning and extinction (Bremner et al., 2005), the retrieval of emotional or neutral stimuli (Whalley, Rugg, Smith, Dolan, & Brewin, 2009), aversive smells and painful stimuli (Geuze et al., 2007), and the performance of an emotional Stroop task (Shin et al., 2001). Insular cortex activation has been found to be positively correlated with measures of symptom severity (Osuch et al., 2001) and post-scan plasma adrenocorticotropic hormone levels (Liberzon et al., 2007). Although greater insular activation in PTSD has been confirmed by a recent voxel-wise meta-analysis (Etkin & Wager, 2007), a few studies have reported either no group differences in insular activation or relatively decreased activation in PTSD (Moores et al., 2008).
Genetic Factors
Several major genotypes have been linked either to risk for developing, or resilience to, PTSD following trauma exposure (Broekman, Olff, & Boer, 2007). Prior candidate gene association studies have identified genes related to the HPA axis, the ascending brainstem LC noradrenergic system, and the limbic amygdalar frontal pathway that mediates fear processing (Charney, Shin, & Phelps, 2006 ). Within the latter anatomical systems, association studies have implicated the serotonin, dopamine, glucocorticoid receptor (GR), GABA, apolipoprotein (APO), brain-derived neurotrophic factor (BDNF), and neuropeptide Y (NPY) systems in the genetic contribution to the onset of PTSD symptoms following a traumatic event.
Early evidence of a genetic contribution to development of PTSD following trauma exposure came in the form of familial transmission studies (Davidson, Tupler, Wilson, & Connor, 1998), followed by twin studies. Moreover, twin studies suggested a heritability component for susceptibility to experience trauma as well as for the development of PTSD symptoms following a trauma event (True et al., 1993). Later twin studies identified potential biomarkers for PTSD such as hippocampal volume (Gilbertson et al., 2002) and altered acoustic startle responses (Orr et al., 2003). Thus, examination of 3,000–4,000 twin pairs from the Vietnam Twin Registry revealed that approximately 32–35 % of the variance of PTSD symptoms could be attributed to inherited influences upon exposure to combat (Chantarujikapong et al., 2001).
Furthermore, psychiatric morbidity in families has been identified as a risk factor for PTSD. Early work by Davidson et al. (1998) demonstrated that alcohol, depression, and anxiety disorders were commonly reported by first-degree family members of probands with PTSD. In addition, work by Yehuda and Bierer (2008) as well as Yehuda, Bell, Bierer, and Schmeidler (2008) showed that parental PTSD is a significant risk factor for PTSD in children. For example, PTSD diagnosis was more frequent in adult offspring of Holocaust survivors with PTSD when compared to offspring of Holocaust survivors without PTSD (Yehuda et al., 2008). Neuroendocrine analyses of offspring of Holocaust-exposed parents with PTSD have revealed lower urinary and salivary cortisol levels and increased plasma cortisol suppression, following low dose dexamethasone administration, compared to children of survivors without PTSD (Yehuda & Bierer, 2008). Similarly, the offspring of mothers with PTSD, who were pregnant at the time of the 9/11 terrorist attacks, also exhibit lower cortisol levels (Brand, Engel, Canfield, & Yehuda, 2006). The negative correlation between offspring cortisol levels and maternal PTSD suggests that epigenetic mechanisms contribute to the intergenerational transmission of PTSD risk.
Dysregulation of brain serotonergic systems has been implicated in the pathophysiology of PTSD (Davis, Clark, Kramer, Moeller, & Petty, 1999). Studies have suggested that serotonin transporter (SERT) genetic polymorphisms contribute to an individual’s response to a traumatic event (Lee et al., 2005). The SERT gene, mapped to chromosome 17q11.1–q12, contains a polymorphism (5HTTLPR) within the promoter region such that there is a long L allele and a short S allele (Heils et al., 1996). SERT expression at the presynaptic membrane and 5-HT uptake activity is significantly greater in carriers of the long allele when compared to carriers of the short allele (Heils et al., 1996).
The data from the 2004 Florida Hurricanes study showed that low expression (s) variant of the 5-HTTLPR increased risk of post-hurricane PTSD, but only under high stress conditions of high hurricane exposure and low social support (Koenen et al., 2009). It was further investigated whether rs4606, a single nucleotide polymorphism (SNP) of regulator of G-protein signaling 2 (RGS2), and low social support moderated risk for post-hurricane and lifetime PTSD. This polymorphism was associated with lifetime PTSD symptoms under conditions of lifetime exposure to a traumatic event (other than the current hurricane) and low social support (Koenen et al., 2009). It was also demonstrated that county-level crime rate and percent unemployment modified the association between the 5-HTTLPR genotype and PTSD; low expression allele carriers (s) were at increased risk for PTSD in high environmental stress conditions (high unemployment; high crime), and were at decreased risk for PTSD in low-risk environments (low unemployment, low crime) (Koenen et al., 2009). These findings underscored the importance of the interactions between genes and the environment to produce the symptoms of PTSD. Sayin et al. (2010) observed a positive association between the s allele and severity of PTSD and hyperarousal symptoms. In a prospective study of emergency department physical trauma patients, Thakur, Joober, and Brunet (2009) found that 5-HTTLPR was not significantly associated with initial risk for PTSD diagnosis. To examine the variant’s association with PTSD chronicity, the authors compared participants continuing to evidence PTSD at 12 months with those who no longer met criteria for PTSD at 12 months. Findings supported excess l/l genotypes in chronic PTSD patients compared with a group of acute PTSD patients and exposed nonpatients. The results of this study suggest that predictors of onset may differ from predictors of chronicity. Additionally, the 5-HTTLPR polymorphism has been found to be triallelic in that a third functional allele LG, has been identified (Nakamura, Ueno, Sano, & Tanabe, 2000). Accordingly, investigations that have examined only the insertion/deletion may have included less transcriptionally efficient variants in their “l” allele groups. Yet another serotonergic polymorphism, a G → A substitution (rs6311) in serotonin receptor 2A (5-HT2A), was examined in a sample of Koreans by Lee, Kwak, Paik, Kang, and Lee (2007) and in a sample of Americans by Mellman et al. (2009). Both reported an increased risk of PTSD associated with the G allele, although Lee et al. (2007) observed this effect only among women.
The increasingly prevalent finding of an interaction between the 5-HTTLPR polymorphism and stressful life events as a vulnerability factor to depressive illnesses (Caspi et al., 2003) has spurred further explorations of this interaction with other psychiatric illnesses. Stein, Schork, and Gelernter (2008) investigated the relationship between the 5-HTTLPR polymorphism, childhood maltreatment, and anxiety sensitivity (AS). AS has been defined as the fear of anxiety-related symptoms such that an individual who fears his/her symptoms will lead to an adverse event (e.g., cardiac arrest) (Bernstein & Zvolensky, 2007). In the aforementioned study, Stein et al. found a significant association between childhood maltreatment, as measured by the Childhood Trauma Questionnaire (CTQ), and 5-HTTLPR genotype. More specifically, homozygotes with the S allele who also had a higher degree of maltreatment exhibited higher AS scores compared to heterozygotes and homozygous L carriers. Based on this association, the authors of the Stein study suggest that anxiety sensitivity may represent an intermediate phenotype for anxiety, depression, and their comorbidity (Stein et al., 2008). Xie et al. (2009) observed a significant interaction between variation in 5-HTTLPR and adult and/or child trauma for risk of lifetime PTSD. More specifically, increased risk of PTSD was evidenced in “s” allele carriers who experienced childhood and adulthood trauma. Moreover, some fMRI studies found increased amygdala reactivity to fearful stimuli in healthy subjects carrying the S allele (Hariri et al., 2002).
PTSD pathophysiology may also reflect altered dopaminergic and noradrenergic neurotransmission (Glover et al., 2003). Genetic variants of the dopamine beta-hydroxylase gene (DBH) represent a likely candidate for examinations of genetic contributions to anxiety disorders, because of the role this enzyme plays in converting dopamine to norepinephrine as part of catecholamine synthesis (Bloom, 1982). Plasma DBH activity is regulated by genetic factors (Mustapic et al., 2007). More specifically, individual differences in DBH activity (approximately 35–52 % of the variance) are influenced by an SNP in the 5′ flanking region of DBH-1021C/T variant (rs1611115) (Zabetian et al., 2001). Mustapic et al. (2007) suggest that genotype-mediated plasma DBH activity may serve as a biomarker for an individual’s response to trauma (i.e., vulnerability to developing PTSD).
Several studies examined the association between SNPs of the dopamine receptor D2 (DRD2) region and chronic PTSD, for instance (Voisey et al., 2009). A number of studies such as (Comings, Muhleman, & Gysin, 1996) found a positive association between risk and a SNP commonly known as TaqIA within the coding region of the ankyrin repeat and kinase domain containing 1 (ANKK1) gene, located downstream of DRD2. Some studies examined a variable number tandem repeat (VNTR) in a dopamine transporter gene (DAT1), and both reported an increased risk of PTSD with nine 40-bp repeats compared with ten repeats despite differences in traumatic exposure across studies (Segman et al., 2002). Finally, a VNTR in the gene encoding the dopamine receptor D4 (DRD4) was examined in relation to PTSD diagnosis and symptoms within 3 months of exposure to a flood (Dragan & Oniszczenko, 2009). Findings supported significantly higher levels of avoidance/numbing symptoms in carriers of the long (seven or eight repeats) allele, as well as higher levels of PTSD symptoms as measured by a questionnaire indexing the intensity of PTSD symptoms.
In general, these genetic association studies have revealed that (1) it is unlikely that specific anxiety disorders are associated with a single genetic variant, (2) there is a complex interaction between genetic and environmental factors, and (3) many of the identified genetic polymorphisms are in the regulatory promoter regions and not necessarily in the coding regions (Smoller, Gardner-Schuster, & Covino, 2008). Thus, future investigations aimed at identifying genetic contributions to PTSD should examine multiple susceptibility loci (including total genome analyses) (Shalev & Segman, 2008) and should employ expanded gene X environment (GxE) investigations.
Increased HPA axis reactivity (Ham et al., 2007) and elevated GR sensitivity (Yehuda, Golier, Yang, & Tischler, 2004) have been recurrently demonstrated in patients with PTSD. In particular, the experience of child abuse appears to pathologically alter the function of the HPA axis (Heim, Newport, Mletzko, Miller, & Nemeroff, 2008). Depressed patients who have a history of childhood adversity show elevated secretion of adrenocorticotropic hormone (ACTH) and cortisol in response to a laboratory stress test (Heim et al., 2000), as well as with neuroendocrine challenge tests including the dexamethasone-corticotropin-releasing factor (CRF) test (Heim et al., 2008). More recently reported data (McGowan et al., 2009) identified epigenetic regulation of glucocorticoid receptors (GR) in postmortem tissue from individuals with a history of child abuse. These data indicate that trauma exposure during childhood persistently alters the endogenous stress response, acting principally upon CRH and its downstream effectors, suggesting that a GxE interaction at this locus may be important in mediating the effects of childhood trauma exposure on adult risk for depression.
One study examined a population that reported high levels of exposure to childhood physical, sexual, and emotional abuse. Fifteen SNPs spanning 57 kb of the CRH receptor1 (CRHR1) were examined. Significant GxE interactions with multiple individual SNPs were identified, as well as with a common haplotype spanning intron 1 of the CRHR1 locus that modify adult risk of depression in the presence of childhood trauma exposure. Specific CRHR1 polymorphisms (rs7209436, rs110402, and rs242924) appeared to moderate the effect of child abuse on the risk for adult depressive symptomatology but did not influence risk for adult posttraumatic stress symptomatology. These data suggest that a GxE interaction is important for the expression of depressive symptoms in adults with CRHR1 risk or protective alleles who have a history of child abuse (Amstadter et al., 2010).
FKBP5 is a co-chaperone component of the GR heterocomplex (Binder, 2009) that plays a key role in the regulation of GR sensitivity and hence the expression of glucocorticoid-responsive genes by virtue of its participation in an ultrashort, intracellular negative feedback loop regulating GR activity (Vermeer, Hendriks-Stegeman, van der Burg, van Buul-Offers, & Jansen, 2003). Clinical research has identified FKBP5 alleles associated with variation in GR resistance in depressed patients (Binder et al., 2004) that are also associated with elevated peri-traumatic dissociation in medically injured children (Koenen et al., 2005), a psychological response to trauma which is predictive of PTSD risk in adults (Ozer et al., 2003). The level of FKBP5 expression in peripheral blood mononuclear cells at 4 months post-trauma exposure is predictive of PTSD diagnosis in trauma survivors (Segman et al., 2005). Most recently, gene expression analysis from a study of subjects with PTSD following the World Trade Center Attacks found that FKBP5 showed reduced expression in PTSD, consistent with enhanced GR responsiveness (Yehuda, 2009). Further, FKBP5 polymorphisms were examined in association with level of adult PTSD symptomatology (Binder et al., 2008). This cross-sectional study examined genetic and psychological risk factors for PTSD using a verbally presented survey, combined with SNP genotyping, in a randomly chosen sample of nonpsychiatric clinic patients who experienced significant levels of childhood abuse as well as non-child abuse trauma. It was shown that although FKBP5 SNPs did not directly predict PTSD outcome, or interact with level of non-child abuse trauma to predict PTSD, four SNPs in the FKBP5 locus significantly interacted with the severity of child abuse to predict level of adult PTSD (Binder et al., 2008).
One possible explanation for these findings is that a critical period exists for the normative development of a theoretic emotional regulatory system. It has been proposed that during sufficiently supported childhood development, an amygdala-dependent emotional circuit develops that is able to appropriately differentiate threatening from nonthreatening environmental stimuli. In contrast, when child abuse is combined with these biological risk factors, amygdala development may be altered through interactions of elevated stress/cortisol and genetic risk/resilience factors such as described with variation in FKBP5 or CRHR1. This developmental interaction may lead to an amygdala-dependent emotional circuit that is always primed for stress responsiveness. In the case of child maltreatment with combined genetic risk, this emotion circuit is unable to appropriately differentiate threat. Thus, in the presence of an adult trauma these individuals may be at a higher risk for PTSD or other trauma-related psychopathology, such as depression.
No significant associations were reported between chronic PTSD and variation in genes encoding glucocorticoid receptor (GCCR) (Bachmann et al., 2005), neuropeptide Y (NPY) (Lappalainen et al., 2002), or BDNF (Zhang et al., 2006).
Lu et al. (2008) reported a significant association between lifetime PTSD and one of four SNPs in CNR1 (cannabinoid receptor 1) among parents and a haplotype of two CNR1 SNPs among parents of youth with attention-deficit/hyperactivity disorder.
Significant G × E interactions for risk of PTSD were reported in studies of GABRA2 (γ-aminobutyric acid A receptor, α2) (Nelson et al., 2009) and COMT (catechol-O-methyltransferase) (Breslau, Davis, Peterson, & Schultz, 2000). Several variants of GABRA2 interacted with composite lifetime history of trauma exposure (Nelson et al., 2009), while a well-characterized amino acid substitution (Val158Met) in COMT interacted with the number of traumatic event types (Kolassa, Kolassa, Ertl, Papassotiropoulos, & De Quervain, 2010). A single study examined the association between the commonly investigated APOE variation and PTSD symptoms among PTSD veterans (Freeman, Roca, Guggenheim, Kimbrell, & Griffin, 2005). The APOE ε2 allele was associated with higher reexperiencing scores (Freeman et al., 2005).
HPA Axis
The HPA axis and immune system communicate in a complex feedback system that can be disrupted following the experience of a traumatic event. Children who experienced permanent or long-term separations from parents, or parental death, have been found to have increases in basal salivary cortisol concentrations (Pfeffer, Altemus, Heo, & Jiang, 2007) and cortisol nonsuppression in the dexamethasone-suppression test (Weller, Weller, Fristad, & Bowes, 1990), but decreased morning cortisol concentrations are seen in some cases of separation (Flinn, Quinlan, Decker, Turner, & England, 1996 ) and in studies of institutionalized children (Gunnar, Morison, Chisholm, & Schuder, 2001). Two more recent studies of university students with less severe forms of loss have found attenuation of the cortisol response to CRH stimulation in subjects with a childhood history of parental divorce,(Bloch, Peleg, Koren, Aner, & Klein, 2007) and a decreased awakening cortisol response in students with a history of either parental separation/divorce or death of a very close friend or relative (Meinlschmidt & Heim, 2005). It was found that childhood parental loss was associated with increased cortisol responses to the Dex/CRH test. It was also demonstrated that patients with major depressive episode (MDE) had the highest plasma cortisol levels and patients with MDE+PTSD, the levels were the lowest, with healthy volunteers (HVs) having intermediate levels compared with the other two groups. Furthermore, there was a significant increase in cortisol after dl-fenfluramine administration in each of the three groups of patients, but hormonal response to dl-fenfluramine failed to discriminate between MDE, MDE+PTSD, and HVs. The findings did not detect a relationship between suicidal behavior and HPA function regardless of comorbid PTSD (Oquendo et al., 2003).
Domestic violence survivors with a sole diagnosis of PTSD show a very strong hypersuppression of cortisol following administration of a low (0.5 mg) dexamethasone dose (Yehuda et al., 1993). In particular, these findings lend support to the idea of a dysregulation in the HPA axis, and perhaps to enhanced negative feedback inhibition in PTSD (Yehuda, 2002).
Lower levels of cortisol and altered HPA axis functioning have been observed in traumatized women without PTSD (Ganzel et al., 2007). In PTSD patients, female gender was associated with lower cortisol levels in a meta-analysis (Meewisse, Reitsma, de Vries, Gersons, & Olff, 2007). In addition, lower waking salivary cortisol levels have been reported in samples of men and women with PTSD (Wessa, Rohleder, Kirschbaum, & Flor, 2006).
Women with PTSD demonstrated significantly elevated cortisol levels compared to abused women without PTSD when exposed to personalized scripts of childhood abuse, with the greatest magnitude of elevations during and shortly after exposure to the trauma scripts. During recovery, cortisol levels in the PTSD group dropped significantly to a level similar to the non-PTSD group. Taken together, these findings are consistent with findings of increased negative feedback sensitivity (Elzinga, Schmahl, Vermetten, van Dyck, & Bremner, 2003).
Comorbid MDD may further alter cortisol levels in PTSD subjects. PTSD participants with comorbid MDD exhibited lower plasma cortisol levels compared to participants with only MDD (Oquendo et al., 2003), and lower continuous plasma levels compared to healthy subjects (Yehuda, Teicher, Trestman, Levengood, & Siever, 1996), and also lower urinary levels in those women with lifetime PTSD and comorbid MDD compared to controls (Young & Breslau, 2004). Following stimulation with dexamethasone and CRH, PTSD+MDD subjects exhibited lower levels of adrenocorticotropin hormone compared to PTSD-MDD subjects (de Kloet et al., 2008).
In healthy subjects, delta sleep activity peaks in the first half of the night and is temporally associated with the nadir of cortisol output (Steiger, 2002). Multiple studies have shown that increased hypothalamic CRF release is associated with disturbed sleep and particularly with decreased delta sleep activity (Neylan et al., 2003). In turn, treatment with a CRF receptor antagonist increased delta sleep in depressed patients (Held et al., 2004). It was demonstrated that PTSD subjects had diminished ACTH response and a less pronounced decrease of delta sleep to an indirect CRF challenge with metyrapone (Neylan et al., 2003). Further, PTSD subjects had significantly less delta sleep, but no significant differences in total sleep time, sleep maintenance, rapid eye movements (REM) sleep latency, or REM density compared to control subjects. By blocking the last step of cortisol synthesis, metyrapone acutely reduces cortisol levels and attenuates cortisol-mediated feedback inhibition at the pituitary, hypothalamus, and hippocampus, while increasing the release of hypothalamic CRF. Therefore, an attenuated increase of ACTH and a diminished decrease of delta sleep after metyrapone in subjects with PTSD could be explained by chronic increased CRF activity and downregulated CRF receptors.
The evidence supporting the role of increased hypothalamic CRF associated with decreased delta sleep includes the following: (1) hypercortisolemic depression is associated with increased hypothalamic CRF and decreased delta sleep (Steiger, 2002), (2) there is a strong inverse relationship between delta sleep and pulsatile cortisol release (Vgontzas et al., 1999), (3) exogenous cortisol infusion, which reduces CRF in the hypothalamus, increases delta sleep (Friess, Tagaya, Grethe, Trachsel, & Holsboer, 2004), (4) metyrapone administration, which leads to an increase in hypothalamic CRF, causes a decrease in delta sleep (Neylan et al., 2003), and (5) rats with genetically reduced hypothalamic CRF spent more time in delta sleep than genetically intact rats (Opp, 1997).
The mechanism by which CRF might decrease delta sleep is not known. One possible explanation is that an increase in hypothalamic CRF release effects other brain areas involved in sleep or arousal. This possibility is supported by studies showing that not only extrahypothalamic CRF neurons but also neurons from the hypothalamus (Valentino, Page, Van Bockstaele, & Aston-Jones, 1992) project to the LC, which may be a point of integration between neurohormonal and neurotransmitter CRF systems (Koob, 1999). It is possible that stimulation of the LC by way of CRF neurons from the hypothalamus is of sufficient magnitude to affect delta sleep. However, other constituents that parallel cortisol release from the adrenal gland, such as dehydroepiandrosterone (DHEA), could be involved in sleep regulation. Consistent with this hypothesis, DHEA has been associated with sleep.
DHEA and DHEA sulphate ester (DHEA-S) are produced by the adrenal cortex and under normal conditions DHEA levels are closely correlated with cortisol. However, an imbalance of cortisol/DHEA secretion may occur when an individual experiences chronic stress (Raison & Miller, 2003). DHEA-S is more abundant than DHEA in plasma and saliva, and exerts effects at glutamate and GABA receptors that may contribute to PTSD symptoms. DHEA also modulates actions of the immune system, resulting in reduced Th1 immune activities, similar to cortisol (Schuld et al., 2000). Higher DHEA levels among participants with PTSD have been reported (Olff, de Vries, Guzelcan, Assies, & Gersons, 2007), as well as higher DHEA-S (Rasmusson et al., 2004); however a lower level was reported in traumatized individuals that were highly comorbid with MDD and PTSD (Kanter et al., 2001). DHEA administration has been shown to reduce MDD symptoms in depressed individuals (Hsiao, 2006), indicating a possible mechanism for symptom improvement. DHEA levels following HPA axis stimulation were inversely related to negative mood among women with chronic PTSD such that higher levels of depressive symptoms were related to lower production of DHEA (Rasmusson et al., 2004). Sondergaard, Hansson, and Theorell (2002) reported that DHEA levels were lower in participants with PTSD and MDD compared to participants with PTSD and no MDD.
Activation of the Immune System
Indicators of immune activation have been observed in studies of individuals suffering from PTSD. These include increased circulating inflammatory markers, increased reactivity to antigen skin tests, lower natural killer cell activity, and lower total T lymphocyte counts. Certain pro-inflammatory cytokines are able to induce neurochemical and behavioral changes that resemble some key features of PTSD (Pace & Heim, 2010).
The majority of studies in adults with PTSD have reported increased pro-inflammatory cytokine levels in plasma including TNF-α (von Kanel et al., 2007), IL-1β (Spivak et al., 1997), IL-6 (Maes et al., 1999), IL-8 (Song, Zhou, Guan, & Wang, 2007), and stimulated levels of IL-6 (Rohleder, Joksimovic, Wolf, & Kirschbaum, 2004) and INFγ (Woods et al., 2005). Maes et al. (1999) also reported that IL-6 receptor levels were higher in individuals with PTSD and comorbid MDD compared to PTSD participants without MDD. In addition, salivary secretory IgA (sIgA), an immunoglobulin that protects mucosal surfaces from upper respiratory infection, was lower in chronically stressed persons (Ng et al., 2004) including women with PTSD (Woods et al., 2005), possibly resulting in exposure to additional antigens that require an inflammatory immune response.
Following a stressor, cortisol increases and results in suppression of Th1 cytokines by binding to glucocorticoid (GC) receptors in lymphocytes, resulting in downregulation of inflammatory activities (Raison & Miller, 2003). The immune system also affects HPA axis function in an effort to protect the individual. Th1 cytokines stimulate the HPA axis resulting in increased cortisol and a reduction in Th1 immune activities (Raison & Miller, 2003).
Rohleder et al. (2004) reported lower cortisol levels and greater whole blood IL-6 production in male and female Bosnian war refugees with PTSD, as did Pervanidou et al. (2007), who linked elevated evening cortisol and morning serum IL-6 with PTSD development in children following a motor vehicle accident. Together, these studies provide evidence of insufficient glucocorticoid signaling in PTSD sufferers, such that impaired feedback regulation of stress responses and HPA axis activity may be linked to greater pro-inflammatory immune responsiveness (Raison & Miller, 2003).
Peri-traumatic Factors
These factors reflect stress response during and immediately following the traumatic event.
Physical Injury
Desborough found that surgery-associated tissue injury results in activation of the HPA axis and that increased plasma concentrations of cortisol can be detected shortly following the start of surgery (Desborough, 2000). These findings suggest that tissue injury elicits a hypothalamic endocrine response, independent of the context in which it was inflicted (Shavit et al., 2005). Thus, it is plausible to assume that concurrent physical and psychological stresses may have an additive effect on HPA-axis activity, especially among people with hypersensitive cortisol receptors. The additive effects of injury and trauma on cortisol release may raise the likelihood that an overactive negative feedback pathway will eventually lead to suboptimal HPA-axis activity and prolongation of the stress response.
Substance P, a peptide known as neurokinin 1, has been implicated in transmitting sensory pain impulses to receptors in the spinal cord, and from there to the brain. Moreover, elevated Substance P levels have been shown to be related to persistent and intense regional pain after minor injury or surgery (Schinkel et al., 2006). Thus, it is possible that Substance P increases the risk for PTSD by prolonging the stressful effects of chronic and intense pain.
Intense bodily pain, with its accompanying neurobiological and psychological effects, can be an integral part of the posttraumatic experience for critically injured trauma survivors. Under certain circumstances, physical pain may even be a powerful enough stressor to serve as the primary cause of PTSD (Schreiber & Galai-Gat, 1993). The co-occurrence of PTSD, and chronic pain in particular, has been well documented in the literature (Gayle Beck, Gudmundsdottir, & Shipherd, 2003). The overlap between regulation of pain and emotion lends credence to the theory that pain may be a stimulus for PTSD. By the same token, hyperarousal, stress intolerance, and selective attention typical of PTSD may aggravate pain (Buchwald, Goldberg, Noonan, Beals, & Manson, 2005). The modest correlations between pain and injury severity suggest that the effect of injury on pain is moderated by multiple mechanisms, such as attentional bias, pain sensitivity, anxiety sensitivity, and depression (Asmundson, Coons, Taylor, & Katz, 2002).
Endogenous opioids, which inhibit pain and reduce panic, are secreted after prolonged exposure to severe stress. Siegfried, Frischknecht, and Nunes de Souza (1990) showed that both excessive endogenous opioids and NE affect the storage of experience in explicit memory. Based on these findings, it has been proposed that the dissociative reactions in people responding to trauma may be analogous to the opioid-mediated analgesia that occurs in animals after prolonged exposure to severe uncontrollable stress (van der Kolk, Greenberg, Boyd, & Krystal, 1985). In support of this hypothesis, research has shown that as late as two decades after the original trauma, individuals with PTSD developed opioid-mediated analgesia in response to a stimulus resembling the traumatic stressor (Pitman, van der Kolk, Orr, & Greenberg, 1990). Moreover, they showed that change in pain perception was the best predictor of PTSD. While the exact nature of the relationship between increased levels of endogenous opioids and PTSD symptoms is not fully understood, it is reasonable to postulate that the enhanced risk for PTSD following injury is mediated, at least in part, by increased levels of endogenous opioids. Preliminary support for this hypothesis comes from a study (Nishith, Griffin, & Poth, 2002) that compared battered and non-battered traumatized women. The study found that the presence of stress-induced analgesia in battered women 1-month post-trauma predicted an increase in the severity of PTSD 3 months later (Nishith et al., 2002).
The secretion of pro-inflammatory cytokines is suppressed by glucocorticoids and stimulated by catecholamines. As previously mentioned, patients with PTSD commonly have decreased cortisol levels and increased catecholamine levels (Baker et al., 2001). Thus, low glucocorticoid signaling among injured PTSD-prone individuals may result in elevated levels of pro-inflammatory cytokines (Raison & Miller, 2003). Elevated levels of cytokines may contribute to PTSD by increasing anxiety, depression, and sleep disturbances. Baker et al. (2001) found elevated cerebrospinal fluid concentrations of interleukin-6 in patients with PTSD versus normal controls. Finally, higher levels of interleukin-6 may also explain the higher frequency of physical complaints in PTSD patients (Baker, Mendenhall, Simbartl, Magan, & Steinberg, 1997).
As far as psychological mechanisms are concerned, the most direct hypothesis is that bodily injury intensifies the perceived threat to one’s life or physical integrity during the trauma. According to the literature (Shalev, 1992), the perceived level of danger by trauma survivors is a better predictor of PTSD than the objective severity of the traumatic event. However, this hypothesis may be overly simplistic due to data suggesting that the heightened level of perceived threat is not directly correlated with the severity of injury (Koren, Norman, Cohen, Berman, & Klein, 2005). These findings suggest that the effect of bodily injury on perceived threat is moderated by other factors, such as sense of control and the ability to effectively function and cope during the traumatic event.
Disfigured trauma survivors may be more likely to exhibit avoidant behaviors due to self-consciousness about their appearance, or in response to negative reactions from others about their appearance. One study involving female patients with burn injuries or digital amputation found that the degree of cosmetic disfigurement correlated with symptoms of avoidance and emotional numbing (Fukunishi, 1999).
Hospitalization, and ensuing medical procedures, may constitute secondary stressors that can increase the risk for PTSD, even in patients who were not highly traumatized by the initial traumatic event. For example, increased levels of disturbing memories have been found in patients hospitalized in intensive care units for medical conditions that were not caused by traumatic events (Buchwald et al., 2005).
Traumatic Brain Injury
Traumatic brain injury (TBI) is commonly associated with loss of consciousness or impaired memory (retrograde amnesia) and thus potentially serves as a natural model for the study of memory and its role in the development of PTSD. Some of the studies that focused on TBI have provided evidence that traumatic events involving TBI are associated with reduced prevalence of PTSD, consistent with the view that TBI and PTSD are incompatible. It has been suggested (Gil, Caspi, Ben-Ari, Koren, & Klein, 2005) that amnesia for the traumatic event minimizes the possibility of establishing any cognitive representation of the trauma, thus reducing the likelihood of intrusive symptoms.
However, several studies suggest that PTSD is fairly prevalent among TBI patients. These studies indicate that loss of consciousness may not guarantee protection from trauma-related intrusive memories or PTSD (Ohry, Rattok, & Solomon, 1996). Although head injury seemed to be associated with reduced frequency of fear, helplessness, and intrusive memories 1-month post-trauma, there was no difference in the likelihood of a diagnosis of PTSD between trauma survivors with and without head injury at 6-month follow-up (Bryant & Harvey, 1998).
A similar trend was observed in a study that explored the relationship between mild TBI, amnesia, and PTSD among 307 consecutive admissions to a Level one Trauma Center (Creamer, O’Donnell, & Pattison, 2005). This highlights the fact that both ASD and PTSD may develop following trauma despite amnesia for the event.
In another study, Gil et al. (2005) examined the relationship between memory of traumatic event (MTE) and subsequent development of PTSD in a prospective design. One hundred twenty subjects, hospitalized for observation after sustaining a mild TBI, were assessed immediately after the trauma and were followed up for 6 months. The results yielded a bimodal distribution of MTE, with most participants reporting either very good MTE or total lack of MTE. Overall, 14 % of the participants met full criteria for PTSD at 6 months. However, participants with MTE were significantly more likely to develop PTSD than those without MTE, with the difference attributable primarily to the reexperiencing cluster. MTE within the first 24 h was a strong predictor of PTSD 6 months after the traumatic event. However, it should be noted that, albeit less frequently, PTSD was nonetheless present even in the absence of explicit memory of the event, indicating that TBI and PTSD are not mutually exclusive, even in the absence of MTE.
A possible mechanism to account for findings that PTSD occurs without explicit memory of the event is that emotionally charged traumatic memories are initially processed via brain circuits that bypass cortical structures and are mediated primarily through the amygdala and related brain structures, resulting in the formation of implicit (unconscious) memories. In addition, stress-induced secretion of glucocorticoids, which have been shown to impair hippocampal functioning, may disrupt the formation of explicit memory (LeDoux, 1998).
One may question whether “deliberate disruption” of MTE might prove therapeutically beneficial in trauma survivors. It may be predicted that psychological interventions which enhance the traumatic memory may produce less favorable outcome. Indeed, a single-session debriefing—a session that often leads to reconstruction of the trauma—was found to be associated with a less positive outcome when compared with nonintervention. A randomized controlled trial in which some traffic accident victims were given a single 1-h debriefing intervention, and others no intervention, was followed up after 4 months and again after 3 years. At 4 months, the intervention group was found to have marginally (though mostly nonsignificantly) poorer outcome (Hobbs, Mayou, Harrison, & Worlock, 1996). Measures of psychiatric symptoms, travel anxiety, and level of functioning were all significantly worse for patients in the intervention group at 3-year follow-up (Mayou, Ehlers, & Hobbs, 2000).
Sijbrandij, Olff, Reitsma, Carlier, and Gersons (2006) carried out a further study on debriefing, in which trauma survivors were given emotional debriefing, educational debriefing, or no intervention, 2 weeks after the traumatic event. Follow-up was carried out at several time intervals following the intervention. This study showed that although scores on PTSD, anxiety, and depression measures decreased over time, there was no significant difference between the groups on any of the measures. It seems as if, in line with the “amnestic hypothesis,” psychological interventions that interfere with the amnesia/repression process should not be routinely used, as this may impede the powerful spontaneous recovery process. This line of reasoning also suggests that pharmacological intervention, that is associated with a decrease in consolidation of the traumatic memory, might be beneficial and vice versa—interventions that are associated with enhancing the traumatic memory would be associated with a worse outcome.
Early administration of benzodiazepines (BNZ) was found to be associated with a less favorable outcome in two small studies (Mellman, Bustamante, David, & Fins, 2002), (Gelpin, Bonne, Peri, Brandes, & Shalev, 1996). Data supporting this trend was also found in the animal model of PTSD. In this study (Matar, Cohen, Kaplan, & Zohar, 2006), although both early and late administrations of BNZ (alprazolam) were associated with decreased anxiety in the short term, only the early BNZ group displayed an increase in PTSD-like behavior (as expressed by the anxiety scale) when the rats were exposed a month later to the traumatic cue. One possible explanation for these sequelae of early BNZ administration might be related to its effect on the HPA axis; BNZ abolishes the cortisol response and, therefore, might attenuate the natural response—increased cortisol levels, an increase associated with a decrease in the fear index (Soravia et al., 2006).
The only medications with specific indication for PTSD are selective serotonin reuptake inhibitors (SSRIs). However, they were only tested several months (and in many cases years) after exposure. Would early administration of SSRIs immediately after exposure have a preventive effect? The potential role of SSRIs in hippocampal neurogenesis (Santarelli et al., 2003) along with open naturalistic clinical observations enabled examination of this question in a PTSD animal model (Matar et al., 2006). Results were quite promising and suggested that early administration of SSRI (sertraline, in this case) was associated with a significant decrease in PTSD-like behavior.
Other possible interventions that might be considered for PTSD prophylaxis are the use of medications that act to suppress catecholamine activity of sympathetic arousal, such as proponalol and guanfacine. A double-blind study examined the severity of acute PTSD symptoms among subjects who received propranolol 40 mg (believed to interfere with memory consolidation) 6-h post-trauma compared with severity of symptoms among participants who received placebos (Pitman et al., 2002). Results showed that the experimental group tended to exhibit lower levels of PTSD symptoms 10 days following the traumatic event. If further corroborated, these findings could support the notion that not only does lack of MTE protect against development of PTSD, but that pharmacologically induced disruption of consolidation of traumatic memories can be therapeutically beneficial for some trauma survivors.
Early Activation of Specific Genes
Gene expression profiling during the triggering and development of PTSD may be informative of its onset and course. Strategies for discovering multiple susceptibility loci may stem from studies such as that conducted by Levi et al. (2005). They examined peripheral gene expression and identified a cluster of differential genes 4 months following a traumatic event, a time frame consistent with the development of a pathological disease state. The differentiated clusters identified in this study included those that are related to amygdala activity, apoptosis, and neural plasticity. The authors suggest that these clusters, if replicable, may represent a starting point from which future whole genome studies can be initiated.
PTSD is associated with decreased activity in the dorsolateral prefrontal cortex (DLPFC), the brain region that regulates working memory and preparation and selection of fear responses. DLPFC, including Brodmann area 46 (BA46), is one of the three regions of prefrontal cortex, which regulates working memory and execution of fear responses (Cohen et al., 2004). This brain region has been correlated with structural and functional alterations and treatment response in patients with PTSD. In children with PTSD symptoms, decreased volume of gray matter in the DLPFC is correlated with increased functional impairment (Cohen et al., 2004). Adult patients with PTSD core symptoms (i.e., re-experiencing, avoidance) were markedly improved by treatment with 10-Hz repetitive transcranial magnetic stimulation over the right DLPFC (Cohen et al., 2004).
One possibility is that functional and structural changes in the brain may result from mitochondria-centered responses to repeated or chronic harmful stresses (Manoli et al., 2007). Mitochondrial dysfunctions are increasingly recognized as key components in stress-related mental disorders (Manoli et al., 2007). Human brain DLPFC including BA46 is involved in regulation of working memory and preparation and selection of fear responses, and has been correlated with both structural and functional alterations and treatment response of patients with PTSD (Cohen et al., 2004). In one study (Su et al., 2008), the authors applied human mitochondria-focused cDNA microarrays (hMitChip3) to PTSD brain samples and have successfully identified expression signatures, canonical pathways, molecular networks, and drug targets of neurological disease- and psychological/psychiatric disorder-related genes that are dysregulated in the DLPFC BA46. These results indicate mitochondrial dysfunction is involved in neuronal function and survival in the DLPFC BA46, and may prove useful for development of methods for diagnosis, prevention, and treatment of PTSD (Su et al., 2008). Moreover, unsupervised clusters of 12 DLPFC BA46 RNA samples, based solely on expression similarities of informative 800 mitochondria-focused genes, clearly distinguish PTSD brains from controls. Demonstration that a highly significant number of oxidative phosphorylation genes were dysregulated in PTSD brains’ BA46, strongly suggests the presence of at least energy deficiency in this brain region (Su et al., 2008).
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