Clarifying the Origin of Biological Abnormalities in PTSD Through the Study of Identical Twins Discordant for Combat Exposure

Harvard University, Cambridge, Massachusetts, United States
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 08/2006; 1071(1):242-54. DOI: 10.1196/annals.1364.019
Source: PubMed


A biological abnormality found to be associated with posttraumatic stress disorder (PTSD) may be, among other things, a pretrauma vulnerability factor, that is, it may have been present prior to the event's occurrence and increased the individual's likelihood of developing PTSD upon traumatic exposure. Alternately, it may be an acquired PTSD sign, that is, it may have developed after the traumatic exposure, along with the PTSD. We have studied pairs of Vietnam combat veterans and their noncombat-exposed, identical twins in an effort to resolve these competing origins. Combat veterans were diagnosed as current PTSD or non-PTSD (i.e., never had). Average heart rate responses (HRRs) to a series of sudden, loud-tone presentations were larger in Vietnam combat veteran twins with PTSD, but these larger responses were not shared by their noncombat-exposed cotwins, whose responses were similar to those of the non-PTSD combat veterans and their noncombat-exposed cotwins. These results suggest that larger HRRs to sudden, loud tones represent an acquired sign of PTSD. In contrast, increased neurological soft signs (NSSs), diminished hippocampal volume, and presence of abnormal cavum septum pellucidum (CSP) were found in Vietnam combat veteran twins with PTSD and their "high-risk," unexposed cotwins compared to Vietnam combat veteran twins without PTSD and their "low-risk," unexposed cotwins. These results support the conclusion that the latter abnormalities represent antecedent, familial vulnerability factors for developing chronic PTSD upon exposure to a traumatic event.

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Available from: Scott P Orr, Oct 05, 2015
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    • "Several potential PTSD biomarkers including disturbances in hormones or neurotransmitter systems, impaired physiological responses to stimuli, and structural or functional brain abnormalities have been investigated (Lanius et al., 2002; Yehuda et al., 2002; Karl et al., 2006; Pitman et al., 2006; Geuze et al., 2008; Kovacic et al., 2008; Eckart et al., 2011; Zolad and Diamond, 2013); yet, none have previously emerged as definitive PTSD biomarkers. Indeed, to be useful, a PTSD biomarker must first be both reproducible and highly accurate; many previously proposed biomarkers meet one but not both of these criteria. "
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    ABSTRACT: Intact cognitive functions rely on synchronous neural activity; conversely, alterations in synchrony are thought to underlie psychopathology. We recently demonstrated that anomalies in synchronous neural interactions (SNI) determined by magnetoencephalography represent a putative PTSD biomarker. Here we develop and apply a regression-based diagnostic algorithm to further validate SNI as a PTSD biomarker in 432 veterans (235 controls; 138 pure PTSD; 59 PTSD plus comorbid disorders). Correlation coefficients served as proximities in multidimensional scaling (MDS) to obtain a two-dimensional representation of the data. In addition, least absolute shrinkage and selection operator (LASSO) regression was used to derive a diagnostic algorithm for PTSD. Performance of this algorithm was assessed by the area under the receiver operating characteristic (ROC) curves, sensitivity, and specificity in 1000 randomly divided testing and validation datasets and in independent samples. MDS revealed that individuals with PTSD, regardless of comorbid psychiatric conditions, are highly distinct from controls. Similarly, application of the LASSO regression-derived prediction model demonstrated remarkable classification accuracy (AUCs≥0.93 for men, AUC=0.82 for women). Neural functioning in individuals with PTSD, regardless of comorbid psychiatric diagnoses, can be used as a diagnostic test to determine patient disease status, further validating SNI as a PTSD biomarker.
    Psychiatry Research: Neuroimaging 11/2014; 231(1). DOI:10.1016/j.pscychresns.2014.11.007 · 2.42 Impact Factor
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    • "Cross-sectional studies have associated decreased hippocampal volume, especially in the cornu ammonis region 3 and the dentate gyrus of the hippocampus, with PTSD [20,21]. Stronger evidence for decreased hippocampal volume as a true predisposing factor for PTSD comes from monozygotic twin studies [22,23], although decreases in hippocampal volume may also be acquired post-trauma [24,25]. Functionally, declarative memory deficits have been identified in humans with PTSD [26,27] and animal lesion studies have found the hippocampus to be vital for developing contextual fear memory [28]. "
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    ABSTRACT: Posttraumatic Stress Disorder (PTSD) is a prevalent, chronic, and disabling anxiety disorder that may develop following exposure to a traumatic event. The majority of individuals with PTSD often have comorbid psychiatric conditions such as major depression, generalized anxiety disorder, and substance use disorders, and are at increased risk for suicide. Despite the public health significance of PTSD, relatively little is known about the etiology or pathophysiology of this disorder, and pharmacotherapy development to date has been largely opportunistic instead of mechanism-based. One promising target for modulation is Tropomyosin Receptor Kinase B (TrkB), the receptor for Brain-Derived Neurotrophic Factor (BDNF), a signaling pathway important for neuronal plasticity, survival, and growth. The following discusses how genetic and environmental alterations to this signaling pathway may contribute to anatomical and functional changes in the hippocampus, amygdala, anterior cingulate cortex, ventromedial prefrontal cortex, and the nucleus accumbens. Changes in these brain regions may in turn contribute to the predisposition to or maintenance of some of the clinical manifestations of PTSD, including intrusive memories, hyperarousal, increased fear, and emotional numbing.
    10/2013; 2013(S4). DOI:10.4172/2167-1044.S4-006
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    • "Our participants consisted of male Vietnam combat veterans with and without PTSD, and their non-combat exposed monozygotic twins. The contributions of familial vulnerability and trauma exposure to biological abnormalities in this study population have been investigated by Pitman and colleagues [28]. Gilbertson et al. [29] demonstrated that total hippocampal volumes were about 10% smaller in men with severe PTSD, compared to men who did not have PTSD. "
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    ABSTRACT: Background PTSD is associated with reduction in hippocampal volume and abnormalities in hippocampal function. Hippocampal asymmetry has received less attention, but potentially could indicate lateralised differences in vulnerability to trauma. The P300 event-related potential component reflects the immediate processing of significant environmental stimuli and has generators in several brain regions including the hippocampus. P300 amplitude is generally reduced in people with PTSD. Methods Our study examined hippocampal volume asymmetry and the relationship between hippocampal asymmetry and P300 amplitude in male monozygotic twins discordant for Vietnam combat exposure. Lateralised hippocampal volume and P300 data were obtained from 70 male participants, of whom 12 had PTSD. We were able to compare (1) combat veterans with current PTSD; (2) their non-combat-exposed co-twins; (3) combat veterans without current PTSD and (4) their non-combat-exposed co-twins. Results There were no significant differences between groups in hippocampal asymmetry. There were no group differences in performance of an auditory oddball target detection task or in P300 amplitude. There was a significant positive correlation between P300 amplitude and the magnitude of hippocampal asymmetry in participants with PTSD. Conclusions These findings suggest that greater hippocampal asymmetry in PTSD is associated with a need to allocate more attentional resources when processing significant environmental stimuli.
    Biology of Mood and Anxiety Disorders 12/2012; 2(1):21. DOI:10.1186/2045-5380-2-21
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