Traumatic Predisposition or Neurotoxicity: Examining Hippocampal Volume and PTSD

Traumatic Predisposition or Neurotoxicity: Examining Hippocampal Volume and PTSD





Peter A. Brown


California Institute of Integral Studies
School of Professional Psychology
Clinical Psychology





Table of Contents


Do Smaller Hippocampi predispose PTSD? 1

Hippocampal atrophy in PTSD: The Neurotoxicity Hypothesis 3

Conclusions: A Middle Way? 5

References 7




Traumatic Predisposition or Neurotoxicity: Examining Hippocampal Volume and PTSD


In much of the literature, there is an ongoing debate surrounding two hypotheses regarding subcortical (primarily limbic, hippocampal) relationships to Post Traumatic Stress Disorder (PTSD)/trauma: 1) the predisposition hypothesis, that is, those with smaller hippocampi (to begin with; genetically), are predisposed to the development of the familiar PTSD symptom cluster (intrusiveness/reexperiencing, avoidance, and hyperarousal – see also the DSM-IV-TR, American Psychiatric Association, 2004, pp. 463-8), and 2) the so-called neurotoxicity hypothesis, believed to be that the hippocampus actually atrophies in the post-traumatic brain.

The person suffering from PTSD is likely to have a dysfunctional hippocampus that does not distinguish a safe context from a dangerous one, thereby triggering amygdalic-emotional response (see also Carlson, 2010, p. 607). This subcortical process follows the ‘low road’ in amygdalic connectivity parlance, bypassing the (ventro-)medial prefrontal cortex ((v-)mPFC) which is unable to inhibit these triggers (or is itself impaired); the amygdala is highly connected, both ascending to cortical structures like the vmPFC and descending to other pontine structures including the spinal cord (Zillmer, Spiers, & Culbertson, 2008, p. 150).


Do Smaller Hippocampi predispose PTSD?

According to Sapolsky (2002), pivotal to the predisposition hypothesis is the need for correlation between more severe combat and smaller hippocampi, a finding that Gilbertson and colleagues (2002) did not support (p. 1113). The seminal Gilbertson study found that the hippocampal (and amygdalar) volume in monozygotic twin combat veterans was not only smaller in those who developed PTSD, but that it was likely smaller before combat and predisposed those veterans to traumatic reactions (2002).

Gilbertson and colleagues examined monozygotic twins (combat exposed Vietnam veterans and their stay-home twin brothers) in order to reveal whether or not smaller hippocampal volume post – combat experience was either a pre-existing condition or a direct result of traumatic experience (p. 1242). Demonstrating the superior design of this study and its predictive validity,

[b]ecause monozygotic twins are genetically identical, any differences in hippocampal volume between brothers were
interpreted as evidence for environmental effects, such as stress-induced neurotoxicity [as a result of combat exposure and
not as a result of exposure to combat with a smaller pre-existing hippocampal volume]. Alternatively, any differences in
hippocampal volume between the unexposed brothers of PTSD combat veterans…versus the unexposed brothers of non-
PTSD combat veterans…were taken as evidence for a pre-existing trait...Our results indicate that small hippocampal volume
constitutes a pre-existing vulnerability factor for pathological response to stress.” (pp. 1242-3)

Perhaps most important is the fact that the findings of the study show that combat exposed twins with larger hippocampi did not develop PTSD, thereby arguing “strongly against a stress-neurotoxic interpretation of the hippocampal diminution” (p. 1246).

Although unrelated to the combat veteran population, a recent study of limbic system volume (hippocampi and amygdalae) of adult survivors of childhood abuse with dissociative disorders (dissociative amnesia – DA; dissociative identity disorder – DID) reveals the tenor of etiological hypothesizing about PTSD and brain limbic volume: “Clinical symptoms and cognitive deficits have been frequently related to small hippocampal size of individuals who had been exposed to traumatic stress [i.e. that the traumatic even precipitated an atrophic mechanism], suggesting that hippocampal damage may be a powerful predictor for the severity and chronic character of PTSD [almost postulating that PTSD is so chronic because trauma damages the brain]” (Weniger, Lange, Sachsse, & Irle, 2008, p. 282). Alas, this study concludes with a position straddling the debate: “the small size of the amygdala and hippocampus and impaired cognition seems to be primarily related to PTSD [and not to dissociative disorders, per se, but in comorbid situations, the results are less clear], either by genetic factors or by factors related to suffering from chronic stress” (p. 289).


Hippocampal atrophy in PTSD: The Neurotoxicity Hypothesis

Many studies since the groundbreaking Bremner and colleagues paper in 1995 and the Gurvits and colleagues paper in 1996 (MRI studies showing establishing the initial correlates) established a evidence suggesting that the brain might be damaged due to psychological distress by action of “stress-induced disturbance of the hypothalamic-pituitary-adrenal axis” (Sapolsky as cited in Schmahl, et al., 2009, p. 294), glucocorticoids, and glutamate active in the limbic system (see also Carlson, 2010; Zillmer, et al., 2008). Dr. Alan Schore – in a chapter in Drs. Solomon and Siegel’s Healing Trauma: Attachment, Mind, Body, and Brain (2003) – on early relational trauma, echoes the flavor of the neurotoxic hypothesis, and possibly provides a link to the etiology of the hypothesis itself, if not as the trace of the 1990s “Decade of the Brain” Bremner and Gurvits’ papers, in his descriptions of developmentally toxic states. Schore expounds that developmental neurotoxicity occurs when the caregiver is unresponsive (or abusive) to the child induces hyperaroused states, which produce elevated catecholamines (neuromodulating in times of stress) and “hyperactivation of the excitotoxic N-methyl-D-aspartate (NMDA)-sensitive glutamate receptor, a critical site of neurotoxicity and synapse elimination in early development [due to pruning/synaptic apoptosis]” (Schore, 2003, p. 132). It is in passages such as this that make it easier to see how scientists hypothesized that psychological trauma may cause neurological damage due to neurotoxic activation of corticosteroids leading to hippocampal neuronal death – it was precisely this hypothesis that Gilbertson and colleagues tested, and refuted (2002).

Noting the polarity of hypotheses, in another recent study (Woodward, et al., 2006) examined hippocampal volume, PTSD, and alcoholism in combat veterans and found the opposite of Gilbertson and colleagues (2002): that PTSD uncomplicated by alcoholism did not show smaller hippocampal volumes, also drawing attention to the fact that in over 80% of the Gilbertson and colleague twins (one combat veteran, the other not) the brothers suffered from clinically significant alcoholism (Woodward, et al., 2006, p. 679). In another study (the Vietnam Era Twin Registry), upon which many of the combat veteran studies were based, also found genetic vulnerability to combat exposure/PTSD and alcoholism (p. 679). Interestingly, Sapolsky (2002), another researcher in this specialized area of research, and who was published in the same issue as the original Gilbertson study, noted that the alcoholism comorbidity confound was effectively ruled out because the twins (one combat, the other stayed home) had statistically (and genetically) identical hippocampi (p. 1112). The debate on comorbidity of alcoholism in both the Woodward and colleagues (2006) study and the Gilbertson and colleagues (2002) study seems to be a moot point, but there is still criticism despite the evidence. Interestingly, Schmahl and colleagues (2009) “did not find significant influence of [many common comorbidities, such as] eating disorders, agoraphobia, social phobia, substance abuse, or major depression” (p. 294). Finally, the Schmahl and colleagues findings suggest that the debate continues, that it is unclear how volumetric changes occur and that there may be a “supra-additive effect” on brain volume, when both (the studied) Borderline Personality Disorder and traumatic experience and/or PTSD are present (p. 294) (as PTSD is present in 60-70% of BPD patients, Zanarini, et al.; Zimmermann & Mattia as cited in Schmahl, et al., 2009, p. 289).

It seems clear that the debate is also one reminiscent of the nature-nurture question, in that there seems to be both genetic and environmental factors involved. Interestingly enough, Carlson (2010) reports that a few studies have identified genes thought to determine susceptibility to PTSD development, including those responsible for production of dopamine D2 receptors, dopamine transporters, and 5-HT transporters (Nugent, Amstadter, & Koenen as cited in Carlson, 2010, p. 607) (short allele promoter 5-HTT – increased stress sensitivity, proneness to depression/anxiety, see also Carlson, 2010, pp. 578-9 and 607). While perhaps promising and certainly interesting, Carlson’s line of thinking seems rather speculative and does not seem to control for many parsimonious and confounding variables, not to mention generalizability.


Conclusions: A Middle Way?

A final point that raises yet other possibilities in this ongoing debate regarding etiology of hippocampal volume correlates of PTSD, is that in a recent study, Hera and colleagues (2008) experimented with PTSD and cancer survivors in a very well designed study that found that there was no correlation (at 12 months post-diagnosis of cancer – considered a particularly insidious source of trauma) of smaller hippocampi and PTSD, but there was correlation with intrusive symptoms of PTSD (p. 307; see also DSM-IV-TR, APA, 2000). Further, the study seems to refute the predisposition hypothesis, while not exactly confirming the neurotoxic, in that “[t]he… negative findings [i.e., absence of smaller hippocampi in cancer survivors with PTSD]… may indicate that a smaller hippocampal volume is not likely to predispose cancer subjects [italics added] to developing PTSD” (Hera, et al., 2008, p. 305). The authors offered the hypothesis that intrusive symptomology (not full-blown PTSD) in cancer patients may have alternative neuropathophysiologic underpinnings, yet undetermined – suggestive of a possible separate cancer-related PTSD construct, featuring the intrusive symptom cluster (p. 307).

The relevance of the debate between neurotoxic responses to trauma versus preexisting small hippocampi is manifold. It is clear that the evidence goes both ways and that further research is needed. That said, the traumatology specialty might be able to use both hypotheses in the development of innovative applications in prevention and treatment of PTSD, possibly even modification of the PTSD construct, on biopsychological bases. For example, Sapolsky (2002) suggests that small volumetric hippocampi become the modern “flat foot” disqualification for military service, a sort of heart-murmur-like rule-out precluding a soldier from serving in combat (p. 1113). He further suggests that, should the neurotoxicity hypothesis stand, the field might develop a kind of post-traumatic golden hour of response along with antidote to the cascade of glucocorticoids and glutamate in the brain (p. 1113), perhaps reminiscent of propranolol preventative treatments (Pitman, et al., 2004, pp. 241-2).

Which ever way this baby and its bathwater go, it is clear that the best the field has at present is a controversy aiming at a simple solution to a very complex problem. There is some hope, evidenced by preliminary single case findings from researchers treating patients with PTSD with Eye Movement Desensitization and Reprocessing (EMDR) for 90 minutes per week for 8 weeks, that psychotherapy increased total baseline hippocampal volume by some 11% (albeit, this is a rather anecdotally) (Letizia, 2007, pp. 475-6). Perhaps future research, triangulation of data, pluralistic integration, comorbidity studies, longitudinal research, and even epidemiological research (as well as further treatment outcomes with larger sample sizes than the Letizia, 2007, example) will pave the way for refined theories applicable to the biopsychological treatment of PTSD.




References

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