Neurobiological Underpinnings of Trauma-related Psychopathology

The understanding and treatment of trauma-related psychopathology is a crucial challenge in the field of global mental health today. The etiology and mechanisms of two common trauma-related symptoms – intrusive re-experiencing and dissociative symptomatology – are still not well understood. The present work aims to advance the understanding of these phenomena by investigating their neurobiological underpinnings in two disorders: depersonalization/derealization disorder (DPD), in which dissociation depicts the core feature, and the dissociative subtype of posttraumatic stress disorder (PTSD-D), in which dissociative symptomatology and intrusive re-experiencing co-occur and correlate in regard to their severity. Alterations in fiber tract networks in white matter, which are crucial for communicating between brain regions, have not yet been investigated in DPD or PTSD-D. In Study I, white matter network alterations were explored in 23 patients with DPD compared to 23 matched healthy controls. Results yielded relatively lower structural connectivity in left and right temporal regions in DPD, which have previously been associated with dissociative symptomatology in DPD and in other disorders. Furthermore, a trend indicated alterations in a fronto-limbic circuit, which a neurobiological model proposes underlies dissociation in DPD as well as PTSD-D. In Study II, we tested whether fronto-limbic circuits are also altered in PTSD-D (n=23) compared to ‘classic’ PTSD patients (n=19) using the same analysis pipeline as in Study I. No respective white matter changes were detected on a network level in PTSD-D. However, subsequent exploratory analyses revealed alterations in two subcortical networks comprising a limbic-thalamic circuit and low-level motor regions, respectively. The limbic-thalamic network is crucial for declarative and spatial mnemonic processes, which according to dual memory models play a crucial role for the development of intrusive memories. We tested the respective memory model in Study III and confirmed for the first time empirically, that spatial-contextual (allocentric) memory ability is negatively associated with severity of intrusive memories in 33 patients with PTSD. The findings of the present work indicate that (1) dissociation in DPD is underpinned by different alterations in structural connectivity than in PTSD-D and (2) dissociative and intrusive memories are associated with aberrations in similar sub-cortical circuits, supporting the notion that in PTSD-D, a lower state of consciousness exacerbates de-contextualization of the traumatic content, resulting in heightened intrusive symptomatology. Clinical implications of our findings are discussed

Neurobiological Underpinnings of Trauma-related Psychopathology

The understanding and treatment of trauma-related psychopathology is a crucial challenge in the field of global mental health today. The etiology and mechanisms of two common trauma-related symptoms – intrusive re-experiencing and dissociative symptomatology – are still not well understood. The present work aims to advance the understanding of these phenomena by investigating their neurobiological underpinnings in two disorders: depersonalization/derealization disorder (DPD), in which dissociation depicts the core feature, and the dissociative subtype of posttraumatic stress disorder (PTSD-D), in which dissociative symptomatology and intrusive re-experiencing co-occur and correlate in regard to their severity. Alterations in fiber tract networks in white matter, which are crucial for communicating between brain regions, have not yet been investigated in DPD or PTSD-D. In Study I, white matter network alterations were explored in 23 patients with DPD compared to 23 matched healthy controls. Results yielded relatively lower structural connectivity in left and right temporal regions in DPD, which have previously been associated with dissociative symptomatology in DPD and in other disorders. Furthermore, a trend indicated alterations in a fronto-limbic circuit, which a neurobiological model proposes underlies dissociation in DPD as well as PTSD-D. In Study II, we tested whether fronto-limbic circuits are also altered in PTSD-D (n=23) compared to ‘classic’ PTSD patients (n=19) using the same analysis pipeline as in Study I. No respective white matter changes were detected on a network level in PTSD-D. However, subsequent exploratory analyses revealed alterations in two subcortical networks comprising a limbic-thalamic circuit and low-level motor regions, respectively. The limbic-thalamic network is crucial for declarative and spatial mnemonic processes, which according to dual memory models play a crucial role for the development of intrusive memories. We tested the respective memory model in Study III and confirmed for the first time empirically, that spatial-contextual (allocentric) memory ability is negatively associated with severity of intrusive memories in 33 patients with PTSD. The findings of the present work indicate that (1) dissociation in DPD is underpinned by different alterations in structural connectivity than in PTSD-D and (2) dissociative and intrusive memories are associated with aberrations in similar sub-cortical circuits, supporting the notion that in PTSD-D, a lower state of consciousness exacerbates de-contextualization of the traumatic content, resulting in heightened intrusive symptomatology. Clinical implications of our findings are discussed

Neural correlates of acute post-traumatic dissociation:a functional neuroimaging script-driven imagery study

Background: Current neurobiological models of post-traumatic stress disorder (PTSD) assume excessive medial frontal activation and hypoactivation of cortico-limbic regions as neural markers of post-traumatic dissociation. Script-driven imagery is an established experimental paradigm that is used to study acute dissociative reactions during trauma exposure. However, there is a scarcity of experimental research investigating neural markers of dissociation; findings from existing script-driven neuroimaging studies are inconsistent and based on small sample sizes. Aims: The current aim was to identify the neural correlates of acute post-traumatic dissociation by employing the script-driven imagery paradigm in combination with functional magnetic resonance imaging. Method: Functional neuroimaging data was acquired in 51 female patients with PTSD with a history of interpersonal childhood trauma. Blood-oxygen-level-dependent response during the traumatic (versus neutral) autobiographical memory recall was analysed, and the derived activation clusters were correlated with dissociation measures. Results: During trauma recall, enhanced activation in the cerebellum, occipital gyri, supramarginal gyrus and amygdala was identified. None of the derived clusters correlated significantly with dissociative symptoms, although patients reported increased levels of acute dissociation following the paradigm. Conclusions: The present study is one of the largest functional magnetic resonance imaging investigations of dissociative neural biomarkers in patients with PTSD undergoing experimentally induced trauma confrontation to elicit symptom-specific brain reactivity. In light of the current reproducibility crisis prominent in neuroimaging research owing to costly and time-consuming data acquisition, the current (null) findings highlight the difficulty of extracting reliable neurobiological biomarkers for complex subjective experiences such as dissociation

The dissociative subtype of posttraumatic stress disorder is associated with subcortical white matter network alterations

Posttraumatic stress disorder (PTSD) is characterized by intrusions, avoidance, and hyperarousal while patients of the dissociative subtype (PTSD-D) experience additional dissociative symptoms. A neurobiological model proposes hyper-inhibition of limbic structures mediated by prefrontal cortices to underlie dissociation in PTSD. Here, we tested whether functional alterations in fronto-limbic circuits are underpinned by white matter network abnormalities on a network level. 23 women with PTSD-D and 19 women with classic PTSD participated. We employed deterministic diffusion tractography and graph theoretical analyses. Mean fractional anisotropy (FA) was chosen as a network weight and group differences assessed using network-based statistics. No significant white matter network alterations comprising both frontal and limbic structures in PTSD-D relative to classic PTSD were found. A subsequent whole brain exploratory analysis revealed relative FA alterations in PTSD-D in two subcortical networks, comprising connections between the left amygdala, hippocampus, and thalamus as well as links between the left ventral diencephalon, putamen, and pallidum, respectively. Dissociative symptom severity in the PTSD-D group correlated with FA values within both networks. Our findings suggest fronto-limbic inhibition in PTSD-D may present a dynamic neural process, which is not hard-wired via white matter tracts. Our exploratory results point towards altered fiber tract communication in a limbic-thalamic circuit, which may underlie (a) an initial strong emotional reaction to trauma reminders before conscious regulatory processes are enabled and (b) deficits in early sensory processing. In addition, aberrant structural connectivity in low-level motor regions may present neural correlates for dissociation as a passive threat-response

Allocentric spatial memory performance predicts intrusive memory severity in posttraumatic stress disorder

BACKGROUND: Posttraumatic stress disorder (PTSD) is characterised by distressing trauma-related memories. According to the dual representation theory, intrusive memories arise from strengthened egocentric encoding and a poor contextual encoding, with spatial context requiring allocentric processing. Contextualization of mental imagery is proposed to be formed hierarchically through the ventral visual stream (VVS) to the hippocampal formation. Here, we tested this notion by investigating whether neuronal aberrations in structures of the VVS or in the hippocampus, as well as allocentric memory performance are associated with intrusive memory severity. METHODS: The sample comprised 33 women with PTSD due to childhood trauma. Allocentric memory performance was measured with the virtual Town Square Task and T1-weighted images acquired on a 3T Siemens Scanner. Intrusive memories were evoked by presenting an audio script describing parts of their trauma (script-driven imagery). RESULTS: Using hierarchical linear regression analysis, we found a significant association between lower intrusive memory severity and higher allocentric spatial memory, controlling for age, working memory, and general visuospatial ability. No significant association was found between cortical thickness of VVS structures, hippocampal volume and intrusive memory severity. Post hoc exploratory analyses revealed a negative correlation between years since index trauma and left hippocampal volume. LIMITATIONS: Our results are based on correlational analyses, causality cannot be inferred. CONCLUSION: This study supports the dual representation theory, which emphasizes the role of allocentric spatial memory for the contextualization of mental imagery in PTSD. Clinical implications are discussed

Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups

Background: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. Method: Adult subjects (N = 2229; 56.2% male) aged 18–69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age − chronological age) controlling for chronological age, sex, and scan site. Results: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. Discussion: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan

Assessment of Brain Age in Posttraumatic Stress Disorder: Findings from the ENIGMA PTSD and Brain Age Working Groups

Background Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. Method Adult subjects (N = 2229; 56.2% male) aged 18–69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age − chronological age) controlling for chronological age, sex, and scan site. Results BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. Discussion Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder:Results from the ENIGMA-PGC PTSD Consortium

BACKGROUND: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). METHODS: Neuroimaging and clinical data were aggregated from 29 research sites in >1,300 PTSD cases and >2,000 trauma-exposed controls (age 6.2-85.2 years) by the ENIGMA-PGC PTSD working group. Cortical regions in the network were rank-ordered by effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2 to 148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared to the mean SC of 5,000 randomly generated n-region networks. RESULTS: Patients with PTSD, relative to non-PTSD controls, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex and age modulated covariance differences of PTSD-related structural networks. CONCLUSIONS: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The structural covariance networks that are perturbed in PTSD comport with converging evidence from resting state functional connectivity networks and networks impacted by inflammatory processes, and stress hormones in PTSD

A Comparison of Methods to Harmonize Cortical Thickness Measurements Across Scanners and Sites

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LME INT), (2) LME that models both site-specific random intercepts and age-related random slopes (LME INT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2–81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3–85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ 2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ 2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ 2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects