Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

Cortical volume abnormalities in posttraumatic stress disorder: an ENIGMA-psychiatric genomics consortium PTSD workgroup mega-analysis.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

Increased recruitment of cognitive control in the presence of traumatic stimuli in complex PTSD.

A neurocircuitry model of post-traumatic stress disorder (PTSD) suggests increased amygdala responses to emotional stimuli, coupled with hypoactivation of prefrontal regions associated with cognitive control. However, results are heterogenous across different subsamples of PTSD as well as different paradigms. We investigated cognitive control in a classic and emotional Stroop task in 28 female patients with complex PTSD (cPTSD), 28 female trauma-exposed healthy controls (TCs) and 28 female non-trauma-exposed healthy controls (HCs) using functional neuroimaging. Afterwards, we assessed memory function in a spontaneous free recall and recognition task. Patients with cPTSD displayed significantly greater Stroop interference with trauma-related words (as reflected in slower reaction times and increased errors) compared to the other conditions and compared to the TC and HC groups. Moreover, patients with cPTSD showed increased activation in the context of trauma-related words in brain regions associated with cognitive control (dlPFC, vmPFC, dACC) compared to both control groups, and a trend for increased activation in the insula compared to the HC group. Increased recruitment of regions contributing to cognitive control in patients with cPTSD, together with a lack of amygdala response may point to efforts to compensate for emotional distraction caused by the trauma-related words.

Generalisation of fear in PTSD related to prolonged childhood maltreatment: an experimental study.

BACKGROUND: Fear responses are particularly intense and persistent in post-traumatic stress disorder (PTSD), and can be evoked by unspecific cues that resemble the original traumatic event. Overgeneralisation of fear might be one of the underlying mechanisms. We investigated the generalisation and discrimination of fear in individuals with and without PTSD related to prolonged childhood maltreatment. METHODS: Sixty trauma-exposed women with (N = 30) and without (N = 30) PTSD and 30 healthy control participants (HC) underwent a fear conditioning and generalisation paradigm. In a contingency learning procedure, one of two circles of different sizes was associated with an electrical shock (danger cue), while the other circle represented a safety cue. During generalisation testing, online risk ratings, reaction times and fear-potentiated startle were measured in response to safety and danger cues as well as to eight generalisation stimuli, i.e. circles of parametrically varying size creating a continuum of similarity between the danger and safety cue. RESULTS: The increase in reaction times from the safety cue across the different generalisation classes to the danger cue was less pronounced in PTSD compared with HC. Moreover, PTSD participants expected higher risk of an aversive event independent of stimulus types and task. CONCLUSIONS: Alterations in generalisation constitute one part of fear memory alterations in PTSD. Neither the accuracy of a risk judgement nor the strength of the induced fear was affected. Instead, processing times as an index of uncertainty during risk judgements suggested a reduced differentiation between safety and threat in PTSD.

Examining the association between posttraumatic stress disorder and disruptions in cortical networks identified using data-driven methods.

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions.

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder 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 >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2-85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis-Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2-148) 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 with the mean SC of 5000 randomly generated n-region networks. RESULTS: Patients with PTSD, relative to non-PTSD control subjects, 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 SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

Influence of Severity of Type and Timing of Retrospectively Reported Childhood Maltreatment on Female Amygdala and Hippocampal Volume.

Deleterious effects of adverse childhood experiences (ACE) on human brain volume are widely reported. First evidence points to differential effects of ACE on brain volume in terms of timing of ACE. Upcoming studies additionally point towards the impact of different types (i.e., neglect and abuse) of ACE in terms of timing. The current study aimed to investigate the correlation between retrospectively reported severity of type (i.e., the extent to which subjects were exposed to abuse and/or neglect, respectively) and timing of ACE on female brain volume in a sample of prolonged traumatized subjects. A female sample with ACE (N = 68) underwent structural magnetic resonance imaging and a structured interview exploring the severity of ACE from age 3 up to 17 using the "Maltreatment and Abuse Chronology of Exposure" (MACE). Random forest regression with conditional interference trees was applied to assess the impact of ACE severity as well as the severity of ACE type, (i.e. to what extent individuals were exposed to neglect and/or abuse) at certain ages on pre-defined regions of interest such as the amygdala, hippocampus, and anterior cingulate (ACC) volume. Analyses revealed differential type and timing-specific effects of ACE on stress sensitive brain structures: Amygdala and hippocampal volume were affected by ACE severity during a period covering preadolescence and early adolescence. Crucially, this effect was driven by the severity of neglect.

Adverse Childhood Experiences and the Consequences on Neurobiological, Psychosocial, and Somatic Conditions Across the Lifespan.

Introduction: Adverse childhood experiences (ACE) such as sexual and physical abuse or neglect are frequent in childhood and constitute a massive stressor with long-lasting adverse effects on the brain, mental and physical health.The aim of this qualitative review is to present a concise overview of the present literature on the impact of ACE on neurobiology, mental and somatic health in later adulthood. Methods: The authors reviewed the existing literature on the impact of ACE on neurobiology, mental and somatic health in later adulthood and summarized the results for a concise qualitative overview. Results: In adulthood, the history of ACE can result in complex clinical profiles with several co-occurring mental and somatic disorders such as posttraumatic stress disorder, depression, borderline personality disorder, obesity and diabetes. Although a general stress effect in the development of the disorders and neural alterations can be assumed, the role of type and timing of ACE is of particular interest in terms of prevention and treatment of ACE-related mental and somatic conditions. It has been suggested that during certain vulnerable developmental phases the risk for subsequent ACE-related disorders is increased. Moreover, emerging evidence points to sensitive periods and specificity of ACE-subtypes in the development of neurobiological alterations, e.g., volumetric and functional changes in the amygdala and hippocampus. Conclusion: Longitudinal studies are needed to investigate complex ACE-related characteristics and mechanisms relevant for mental and somatic disorders by integrating state of the art knowledge and methods. By identifying and validating psychosocial and somatic risk factors and diagnostic markers one might improve the development of innovative somatic and psychological treatment options for individuals suffering from ACE-related disorders.