These results suggest the contrasting symptom profiles of PTSD and its dissociative subtype (hyper- vs. hypo-emotionality, respectively) may be driven by complementary changes in directed connectivity corresponding to bottom-up defensive fear processing versus enhanced top-down regulation. Hum Brain Mapp 38:5551-5561, 2017. © 2017 Wiley Periodicals, Inc.

BackgroundPosttraumatic stress disorder (PTSD) is associated with hyperarousal and active fight or flight defensive responses. By contrast, the dissociative subtype of PTSD, characterized by depersonalization and derealization symptoms, is frequently accompanied by additional passive or submissive defensive responses associated with autonomic blunting. Here, the periaqueductal gray (PAG) plays a central role in defensive responses, where the dorsolateral (DL‐PAG) and ventrolateral PAG (VL‐PAG) are thought to mediate active and passive defensive responses, respectively.MethodsWe examined PAG subregion (dorsolateral and ventrolateral) resting‐state functional connectivity in three groups: PTSD patients without the dissociative subtype (n = 60); PTSD patients with the dissociative subtype (n = 37); and healthy controls (n = 40) using a seed‐based approach via PickAtlas and SPM12.ResultsAll PTSD patients showed extensive DL‐ and VL‐PAG functional connectivity at rest with areas associated with emotional reactivity and defensive action as compared to controls (n = 40). Although all PTSD patients demonstrated DL‐PAG functional connectivity with areas associated with initiation of active coping strategies and hyperarousal (e.g., dorsal anterior cingulate; anterior insula), only dissociative PTSD patients exhibited greater VL‐PAG functional connectivity with brain regions linked to passive coping strategies and increased levels of depersonalization (e.g., temporoparietal junction; rolandic operculum).ConclusionsThese findings suggest greater defensive posturing in PTSD patients even at rest and demonstrate that those with the dissociative subtype show unique patterns of PAG functional connectivity when compared to those without the subtype. Taken together, these findings represent an important first step toward identifying neural and behavioral targets for therapeutic interventions that address defensive strategies in trauma‐related disorders.

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Exposure to psychological trauma (for example, childhood/early life adversity, exposure to violence or assault, combat exposure, accidents or natural disasters) is known to increase one's risk of developing certain chronic medical conditions. Clinical and population studies provide evidence of systemic inflammatory activity in trauma survivors with various psychiatric and nonpsychiatric conditions. This transdiagnostic meta-analysis quantitatively integrates the literature on the relationship of inflammatory biomarkers to trauma exposure and related symptomatology. We conducted random effects meta-analyses relating trauma exposure to log-transformed inflammatory biomarker concentrations, using meta-regression models to test the effects of study quality and psychiatric symptomatology on the inflammatory outcomes. Across k=36 independent samples and n=14 991 participants, trauma exposure was positively associated with C-reactive protein (CRP), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α (mean rs =0.2455, 0.3067, 0.2890, and 0.2998, respectively). No significant relationships were noted with fibrinogen, IL-2, IL-4, IL-8, or IL-10. In meta-regression models, the presence of psychiatric symptoms was a significant predictor of increased effect sizes for IL-1β and IL-6 (β=1.0175 and 0.3568, respectively), whereas study quality assessment scores were associated with increased effect sizes for IL-6 (β=0.3812). Positive correlations between inflammation and trauma exposure across a range of sample types and diagnoses were found. Although reviewed studies spanned an array of populations, research on any one specific psychiatric diagnosis was generally limited to one or two studies. The results suggest that chronic inflammation likely represents one potential mechanism underlying risk of health problems in trauma survivors.

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Individuals with post‐traumatic stress disorder (PTSD) typically experience states of reliving and hypervigilance; however, the dissociative subtype of PTSD (PTSD+DS) presents with additional symptoms of depersonalization and derealization. Although the insula is critical to emotion processing, its association with these contrasting symptom profiles is yet to be fully delineated. Accordingly, we investigated insula subregion resting‐state functional connectivity patterns among individuals with PTSD, PTSD+DS, and healthy controls. Using SPM12 and PRONTO software, we implemented a seed‐based resting‐state functional connectivity approach, along with multiclass Gaussian process classification machine learning, respectively, in order to evaluate unique patterns and the predictive validity of insula subregion connectivity among individuals with PTSD (n = 84), PTSD+DS (n = 49), and age‐matched healthy controls (n = 51). As compared to PTSD and PTSD+DS, healthy controls showed increased right anterior and posterior insula connectivity with frontal lobe structures. By contrast, PTSD showed increased bilateral posterior insula connectivity with subcortical structures, including the periaqueductal gray. Strikingly, as compared to PTSD and controls, PTSD+DS showed increased bilateral anterior and posterior insula connectivity with posterior cortices, including the left lingual gyrus and the left precuneus. Moreover, machine learning analyses were able to classify PTSD, PTSD+DS, and controls using insula subregion connectivity patterns with 80.4% balanced accuracy (p < .01). These findings suggest a neurobiological distinction between PTSD and its dissociative subtype with regard to insula subregion functional connectivity patterns. Furthermore, machine learning algorithms were able to utilize insula resting‐state connectivity patterns to discriminate between participant groups with high predictive accuracy.

Post-traumatic stress disorder (PTSD), a diagnosis that may follow the experience of trauma, has multiple symptomatic phenotypes. Generally, individuals with PTSD display symptoms of hyperarousal and of hyperemotionality in the presence of fearful stimuli. A subset of individuals with PTSD; however, elicit dissociative symptomatology (i.e., depersonalization, derealization) in the wake of a perceived threat. This pattern of response characterizes the dissociative subtype of the disorder, which is often associated with emotional numbing and hypoarousal. Both symptomatic phenotypes exhibit attentional threat biases, where threat stimuli are processed preferentially leading to a hypervigilant state that is thought to promote defensive behaviors during threat processing. Accordingly, PTSD and its dissociative subtype are thought to differ in their proclivity to elicit active (i.e., fight, flight) versus passive (i.e., tonic immobility, emotional shutdown) defensive responses, which are characterized by the increased and the decreased expression of the sympathetic nervous system, respectively. Moreover, active and passive defenses are accompanied by primarily endocannabinoid-and opioid-mediated analgesics, respectively. Through critical review of the literature, we apply the defense cascade model to better understand the pathological presentation of defensive responses in PTSD with a focus on the functioning of lower-level midbrain and extended brainstem systems. K E Y W O R D Sbrainstem, dissociation, periaqueductal gray, PTSD, trauma | INTRODUC TI ONIn this review, we integrate literature from trauma experiences, the defense cascade, and the threat-response neurocircuitry within a framework of post-traumatic stress disorder (PTSD). We begin by introducing the concepts of the hypothalamic-pituitary-adrenal (HPA) axis, general PTSD, and defensive responses. Following these primers, we discuss the influences of trauma onset and prolonged exposure to trauma and their effects on the development of PTSD and the dissociative subtype of PTSD. Next, we introduce the defense cascade model and its underlying neurocircuitry as described in the animal literature and relate it to PTSD. In addition, we discuss the current state of the neuroimaging literature, which Edited by Sandra Chanraud.All peer review communications can be found with the online version of the article. | 1111TERPOU ET al. suggests that functional alterations are detectable in the midbrain of individuals with PTSD and its dissociative subtype as compared to healthy controls. We conclude by presenting directions for future research and the clinical implications for treatment of persons with PTSD that arise from this review of the extant literature.

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