Less is more: Smaller hippocampal subfield volumes predict greater improvements in posttraumatic stress disorder symptoms over 2 years.

Posttraumatic stress disorder (PTSD) is a heterogeneous disorder, and symptom severity varies over time. Neurobiological factors that predict PTSD symptoms and their chronicity remain unclear. This study investigated whether the volume of the hippocampus and its subfields, particularly cornu ammonis (CA) 1, CA3, and dentate gyrus, are associated with current PTSD symptoms and whether they predict PTSD symptom changes over 2 years. We examined clinical and structural magnetic resonance imaging measures from 252 trauma-exposed post-9/11 veterans (159 with Time 1 PTSD diagnosis) during assessments approximately 2 years apart. Automated hippocampal subfield segmentation was performed with FreeSurfer Version 7.1, producing 19 bilateral subfields. PTSD symptoms were measured at each assessment using the Clinician-Administered PTSD Scale-IV (CAPS). All models included total intracranial volume as a covariate. First, similar to previous reports, we showed that smaller overall hippocampal volume was associated with greater PTSD symptom severity at Time 1. Notably, when examining regions of interest (CA1, CA3, dentate gyrus), we found that smaller Time 1 hippocampal volumes in the bilateral CA1-body and CA2/3-body predicted decreased PTSD symptom severity at Time 2. These findings were not accounted for by combat exposure or treatment history. Additionally, both Time 1 CA1-body and CA2/3-body volume showed unique associations with changes in avoidance/numbing, but not with changes in reexperiencing or hyperarousal symptoms. This supports a more complex and nuanced relationship between hippocampal structure and PTSD symptoms, where during the posttrauma years bigger may not always mean better, and suggests that the CA1-body and CA2/3-body are important factors in the maintenance of PTSD symptoms. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Characterizing Typhoon-related Posttraumatic Stress Disorder Based on Multimodal Fusion of Structural, Diffusion, and Functional Magnetic Resonance Imaging.

Diagnosing posttraumatic stress disorder (PTSD) using only single-modality images is controversial. We aimed to use multimodal magnetic resonance imaging (MRI) combining structural, diffusion, and functional MRI to possibly provide a more comprehensive viewpoint on the decisive characteristics of PTSD patients. Typhoon-exposed individuals with (n = 26) and without PTSD (n = 32) and healthy volunteers (n = 30) were enrolled. Five MRI features from three modalities, including two resting-state functional MRI (rs-fMRI) features (amplitude of low-frequency fluctuation, ALFF; and regional homogeneity, ReHo), one structural MRI feature (gray matter density, GM), and two diffusion tensor imaging (DTI) features (fractional anisotropy, FA; and mean diffusivity, MD) were investigated simultaneously with a multimodal canonical correlation analysis + joint independent component analysis model to identify abnormalities in the PTSD brain. We identified statistical differences between PTSD patients and healthy controls in terms of 1 rs-fMRI (ALFF, ReHo) alterations in the superior frontal gyrus, precuneus, inferior parietal lobule (IPL), anterior cingulate cortex (ACC), and posterior cingulate cortex (PCC), 2 DTI (FA, MD) changes in the pons, genu, and splenium of the corpus callosum, and 3 Structural MRI abnormalities in the precuneus, IPL, ACC, and PCC. A novel ReHo component was found to distinguish PTSD and trauma-exposed controls, including the precuneus, IPL, middle frontal gyrus, middle occipital gyrus, and cerebellum. This study reveals that PTSD individuals exhibit intertwined functional and structural anomalies within the default mode network. Some alterations within this network may serve as a potential marker to distinguish between PTSD patients and trauma-exposed controls.

Effects of a dissociative drug on fronto-limbic resting-state functional connectivity in individuals with posttraumatic stress disorder: a randomized controlled pilot study.

RATIONALE: A subanesthetic dose of ketamine, a non-competitive N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist, elicits dissociation in individuals with posttraumatic stress disorder (PTSD), who also often suffer from chronic dissociative symptoms in daily life. These debilitating symptoms have not only been linked to worse PTSD trajectories, but also to increased resting-state functional connectivity (RSFC) between medial prefrontal cortex (mPFC) and amygdala, supporting the conceptualization of dissociation as emotion overmodulation. Yet, as studies were observational, causal evidence is lacking. OBJECTIVES: The present randomized controlled pilot study examines the effect of ketamine, a dissociative drug, on RSFC between mPFC subregions and amygdala in individuals with PTSD. METHODS: Twenty-six individuals with PTSD received either ketamine (0.5mg/kg; n = 12) or the control drug midazolam (0.045mg/kg; n = 14) during functional magnetic resonance imaging (fMRI). RSFC between amygdala and mPFC subregions, i.e., ventromedial PFC (vmPFC), dorsomedial PFC (dmPFC) and anterior-medial PFC (amPFC), was assessed at baseline and during intravenous drug infusion. RESULTS: Contrary to pre-registered predictions, ketamine did not promote a greater increase in RSFC between amygdala and mPFC subregions from baseline to infusion compared to midazolam. Instead, ketamine elicited a stronger transient decrease in vmPFC-amygdala RSFC compared to midazolam. CONCLUSIONS: A dissociative drug did not increase fronto-limbic RSFC in individuals with PTSD. These preliminary experimental findings contrast with prior correlative findings and call for further exploration and, potentially, a more differentiated view on the neurobiological underpinning of dissociative phenomena in PTSD.

Altered functional connectivity between cortical networks associated with inhibitory control in trauma-exposed females.

Post-traumatic stress disorder (PTSD) is associated with impaired inhibitory control and alterations in large-scale brain network connectivity. However, few studies to date have examined the construct of inhibitory control as it relates to resting-state functional connectivity (rsFC) in a population with PTSD or trauma-exposure. The present study investigated the relationship between impaired inhibitory control and rsFC within the default mode network (DMN), central executive network (CEN), and salience network (SN) in a sample of females exposed to interpersonal trauma with and without PTSD (n = 67). Participants completed a classic Color-Word Stroop task as a measure of inhibitory control and two resting-state fMRI scans. We conducted voxelwise rsFC analyses with seed regions in the DMN, CEN, and SN and voxelwise linear regression analyses to examine the relationship between inhibitory control and rsFC of these networks across the sample. Better Stroop performance was negatively associated with total self-reported PTSD symptoms. An analysis of PTSD symptom clusters indicated that better Stroop performance was also associated with re-experiencing and hyperarousal symptoms, but not avoidance PTSD symptoms. Decreased coupling between the CEN and the DMN was associated with better inhibitory control in this sample of trauma-exposed females. These findings lend support to the hypothesis that efficient switching between these networks may contribute to better performance on cognitive and attentional tasks in trauma-exposed individuals.

Altered longitudinal trajectory of default mode network connectivity in healthy youth with subclinical depressive and posttraumatic stress symptoms.

The default mode network (DMN) plays a crucial role in internal self-processing, rumination, and social functions. Disruptions to DMN connectivity have been linked with early adversity and the emergence of psychopathology in adolescence and early adulthood. Herein, we investigate how subclinical psychiatric symptoms can impact DMN functional connectivity during the pubertal transition. Resting-state fMRI data were collected annually from 190 typically-developing youth (9-15 years-old) at three timepoints and within-network DMN connectivity was computed. We used latent growth curve modeling to determine how self-reported depressive and posttraumatic stress symptoms predicted rates of change in DMN connectivity over the three-year period. In the baseline model without predictors, we found no systematic changes in DMN connectivity over time. However, significant modulation emerged after adding psychopathology predictors; greater depressive symptomatology was associated with significant decreases in connectivity over time, whereas posttraumatic stress symptoms were associated with significant increases in connectivity over time. Follow-up analyses revealed that these effects were driven by connectivity changes involving the dorsal medial prefrontal cortex subnetwork. In conclusion, these data suggest that subclinical depressive and posttraumatic symptoms alter the trajectory of DMN connectivity, which may indicate that this network is a nexus of clinical significance in mental health disorders.

Altered dynamic functional connectivity associates with post-traumatic stress disorder.

Research has been looking into neural pathophysiology of post-traumatic stress disorder (PTSD) and dynamic functioning connectivity (dFC) applying resting state functional magnetic resonance imaging (rs-fMRI). Previous studies showed that PTSD related impairments are associated with alterations distributed across different brain regions and disorganized functional connectivity, especially in Default Mode Network and the cerebellar area. In this study, we specifically looked into dFC on a whole brain level, and we focused on critical regions such as DMN and cerebellum. To explore the characteristics of dFC among patients with PTSD, we collected rs-fMRI data from 27 PTSD patients and 30 healthy controls. The study also added a control group of 33 trauma-exposed individuals to further look into trauma impact. Utilizing group spatial independent component analysis (ICA), the dynamic properties on whole brain level were detected with sliding time window approach, and k-means clustering. Two reoccurring FC "States" were identified, with connections being more concentrated on a within-network level in one state and more strongly inter-connected in the other state. Abnormalities in dFC were found within DMN, between DMN and cerebellum, and between DMN and visual network for PTSD patients. The findings were in accordance with the study hypothesis that the dFC alterations might point to deficits in emotional modulation and dysfunctional self-referential thought. Abnormalities in dFC among PTSD patients might also be indicators of PTSD symptoms including depression and anxiety, hypervigilance, impaired cognitive functioning and self-referential information processing.

Longitudinal volumetric evaluation of hippocampus and amygdala subregions in recent trauma survivors.

The hippocampus and the amygdala play a central role in post-traumatic stress disorder (PTSD) pathogenesis. While alternations in volumes of both regions have been consistently observed in individuals with PTSD, it remains unknown whether these reflect pre-trauma vulnerability traits or acquired post-trauma consequences of the disorder. Here, we conducted a longitudinal panel study of adult civilian trauma survivors admitted to a general hospital emergency department (ED). One hundred eligible participants (mean age = 32.97 ± 10.97, n = 56 females) completed both clinical interviews and structural MRI scans at 1-, 6-, and 14-months after ED admission (alias T1, T2, and T3). While all participants met PTSD diagnosis at T1, only n = 29 still met PTSD diagnosis at T3 (a "non-Remission" Group), while n = 71 did not (a "Remission" Group). Bayesian multilevel modeling analysis showed robust evidence for smaller right hippocampus volume (P+ of ~0.014) and moderate evidence for larger left amygdala volume (P+ of ~0.870) at T1 in the "non-Remission" group, compared to the "Remission" group. Subregion analysis further demonstrated robust evidence for smaller volume in the subiculum and right CA1 hippocampal subregions (P+ of ~0.021-0.046) in the "non-Remission" group. No time-dependent volumetric changes (T1 to T2 to T3) were observed across all participants or between groups. Results support the "vulnerability trait" hypothesis, suggesting that lower initial volumes of specific hippocampus subregions are associated with non-remitting PTSD. The stable volume of all hippocampal and amygdala subregions does not support the idea of consequential, progressive, stress-related atrophy during the first critical year following trauma exposure.

Study on the changes of Structural Covariance Network in post-traumatic stress disorder.

The topological properties of functional brain networks in post-traumatic stress disorder (PTSD) have been thoroughly examined, whereas the topology of structural covariance networks has been researched much less. Based on graph theoretical approaches, we investigated the topological architecture of structural covariance networks among PTSD, trauma-exposed controls (TEC), and healthy controls (HC) by constructing covariance networks driven by inter-regional correlations of cortical thickness. Structural magnetic resonance imaging (sMRI) scans and clinical scales were performed on 27 PTSD, 33 TEC, and 29 HC subjects. Group-level structural covariance networks were established using pearson correlations of cortical thickness between 68 brain areas, and the graph theory method was utilized to study the global and nodal properties. PTSD and HC subjects did not differ at the global level. When PTSD subjects were compared to TEC subjects, they had significantly higher clustering coefficient (p = .014) and local efficiency (p = .031). Nodes having different nodal centralities between groups did not pass the false-discovery rate correction at the node level. According to the structural brain network topological characteristics discovered in this study, PTSD manifests differently compared to the TEC group. In the PTSD group, the SCN keeps the small-world characteristics, but the degree of functional separation is enhanced. The TEC group's reduced small worldness and the tendency for brain network randomization could be signs of trauma recovery.

Intrusive experiences in posttraumatic stress disorder: Treatment response induces changes in the directed functional connectivity of the anterior insula.

BACKGROUND: One of the core features of posttraumatic stress disorder (PTSD) is re-experiencing trauma. The anterior insula (AI) has been proposed to play a crucial role in these intrusive experiences. However, the dynamic function of the AI in re-experiencing trauma and its putative modulation by effective therapy need to be specified. METHODS: Thirty PTSD patients were enrolled and exposed to traumatic memory reactivation therapy. Resting-state functional magnetic resonance imaging (fMRI) scans were acquired before and after treatment. To explore AI-directed influences over the rest of the brain, we referred to a mixed model using pre-/posttreatment Granger causality analysis seeded on the AI as a within-subject factor and treatment response as a between-subject factor. To further identify correlates of re-experiencing trauma, we investigated how intrusive severity affected (i) causality maps and (ii) the spatial stability of other intrinsic brain networks. RESULTS: We observed changes in AI-directed functional connectivity patterns in PTSD patients. Many within- and between-network causal paths were found to be less influenced by the AI after effective therapy. Insular influences were found to be positively correlated with re-experiencing symptoms, while they were linked with a stronger default mode network (DMN) and more unstable central executive network (CEN) connectivity. CONCLUSION: We showed that directed changes in AI signaling to the DMN and CEN at rest may underlie the degree of re-experiencing symptoms in PTSD. A positive response to treatment further induced changes in network-to-network anticorrelated patterns. Such findings may guide targeted neuromodulation strategies in PTSD patients not suitably improved by conventional treatment.

Preliminary evidence on the neural correlates of timing deficit in post-traumatic stress disorder.

It has recently been suggested that a deficit in time processing may be considered a cognitive marker of Post-Traumatic Stress Disorder (PTSD). However, the neural correlates of this cognitive deficit in PTSD remain unknown. Voxel-based morphometry and supra-second perceptual time processing data from 8 participants with PTSD and 19 healthy controls have been examined. In line with previous investigations, PTSD patients overestimated the duration of the displayed stimuli. Moreover, their time estimation was more variable than that of controls. Critically, compared to controls, a higher grey matter volume was reported in most of neural regions of PTSD canonically associated with supra-second perceptual timing. These data provide preliminary evidence that the abnormal neuroplasticity of this neural network may be responsible for the altered experience of time in PTSD.

Recientemente se ha sugerido que un déficit en el procesamiento del tiempo puede considerarse un marcador cognitivo del trastorno de estrés postraumático (TEPT). Sin embargo, los correlatos neuronales de este déficit cognitivo en el TEPT siguen siendo desconocidos. Se ha examinado la morfometría basada en vóxeles y los datos de procesamiento del tiempo de percepción en supra-segundos de 8 participantes con TEPT y 19 controles sanos. De acuerdo con investigaciones anteriores, los pacientes con TEPT sobrestimaron la duración de los estímulos mostrados. Además, su estimación del tiempo fue más variable que la de los controles. Críticamente, en comparación con los controles, se reportó un mayor volumen de materia gris en la mayoría de las regiones neuronales del TEPT canónicamente asociado con el tiempo perceptual en supra-segundos. Estos datos proporcionan evidencia preliminar de que la neuroplasticidad anormal de esta red neuronal puede ser responsable de la experiencia alterada del tiempo en el TEPT.

Machine learning for post-traumatic stress disorder identification utilizing resting-state functional magnetic resonance imaging.

Early detection of post-traumatic stress disorder (PTSD) is essential for proper treatment of the patients to recover from this disorder. The aligned purpose of this study was to investigate the performance deviations in regions of interest (ROI) of PTSD than the healthy brain regions, to assess interregional functional connectivity and applications of machine learning techniques to identify PTSD and healthy control using resting-state functional magnetic resonance imaging (rs-fMRI). The rs-fMRI data of 10 ROI was extracted from 14 approved PTSD subjects and 14 healthy controls. The rs-fMRI data of the selected ROI were used in ANOVA to measure performance level and Pearson's correlation to investigate the interregional functional connectivity in PTSD brains. In machine learning approaches, the logistic regression, K-nearest neighbor (KNN), support vector machine (SVM) with linear, radial basis function, and polynomial kernels were used to classify the PTSD and control subjects. The performance level in brain regions of PTSD deviated as compared to the regions in the healthy brain. In addition, significant positive or negative functional connectivity was observed among ROI in PTSD brains. The rs-fMRI data have been distributed in training, validation, and testing group for maturity, implementation of machine learning techniques. The KNN and SVM with radial basis function kernel were outperformed for classification among other methods with high accuracies (96.6%, 94.8%, 98.5%) and (93.7%, 95.2%, 99.2%) to train, validate, and test datasets, respectively. The study's findings may provide a guideline to observe performance and functional connectivity of the brain regions in PTSD and to discriminate PTSD subject using only the suggested algorithms.

Psychoradiological abnormalities in treatment-naive noncomorbid patients with posttraumatic stress disorder.

BACKGROUND: Neuroimaging studies in posttraumatic stress disorder (PTSD) have identified various alterations in white matter (WM) microstructural organization. However, it remains unclear whether these are localized to specific regions of fiber tracts, and what diagnostic value they might have. This study set out to explore the spatial profile of WM abnormalities along defined fiber tracts in PTSD. METHODS: Diffusion tensor images were obtained from 77 treatment-naive noncomorbid patients with PTSD and 76 demographically matched trauma-exposed non-PTSD (TENP) controls. Using automated fiber quantification, tract profiles of fractional anisotropy, axial diffusivity, mean diffusivity, and radial diffusivity were calculated to evaluate WM microstructural organization. Results were analyzed by pointwise comparisons, by correlation with symptom severity, and for diagnosis-by-sex interactions. Support vector machine analyses assessed the ability of tract profiles to discriminate PTSD from TENP. RESULTS: Compared to TENP, PTSD showed lower fractional anisotropy accompanied by higher radial diffusivity and mean diffusivity in the left uncinate fasciculus, and lower fractional anisotropy accompanied by higher radial diffusivity in the right anterior thalamic radiation. Tract profile alterations were correlated with symptom severity, suggesting a pathophysiological relevance. There were no significant differences in diagnosis-by-sex interaction. Tract profiles allowed individual classification of PTSD versus TENP with significant accuracy, of potential diagnostic utility. CONCLUSIONS: These findings add to the knowledge of the neuropathological basis of PTSD. WM alterations based on a tract-profile quantification approach are a potential biomarker for PTSD.

Adverse childhood experiences associate with early post-trauma thalamus and thalamic nuclei volumes and PTSD development in adulthood.

Adverse childhood experiences (ACEs) potentially contribute to posttraumatic stress disorder (PTSD) after adult trauma exposure, but underlying brain changes remain unclear. The present study tested relationships between ACEs, whole thalamus and thalamic nuclei volumes, and post-trauma stress symptoms (PTSS) after adult trauma. Trauma survivors (n = 101) completed the Childhood Trauma Questionnaire (CTQ), the PTSD checklist-special stressor version 5 (PCL), and a structural magnetic resonance imaging (sMRI) scan within post-trauma 2 weeks. At post-trauma 3 months, survivors completed a second PCL survey and a PTSD diagnosis interview using the Clinician-Administered PTSD Scale (CAPS). CTQ scores significantly positively correlated with PCL scores at post-trauma 2 weeks and 3 months (respective p's < 0.01 and < 0.001). CTQ scores significantly negatively correlated with whole thalamus and 7 thalamic nuclei volumes at post-trauma 2 weeks in the PTSD (N = 50), but not the non-PTSD (N = 51) group. Whole thalamus and 22 nuclei volumes significantly negatively correlated with PCL scores at post-trauma 3 months in the PTSD, but not the non-PTSD group. These results suggest ACEs negatively influence early post-trauma thalamic volumes which, in turn, are negatively associated with PTSS in survivors who develop PTSD.

Acute Posttraumatic Symptoms Are Associated With Multimodal Neuroimaging Structural Covariance Patterns: A Possible Role for the Neural Substrates of Visual Processing in Posttraumatic Stress Disorder.

BACKGROUND: Although aspects of brain morphology have been associated with chronic posttraumatic stress disorder (PTSD), limited work has investigated multimodal patterns in brain morphology that are linked to acute posttraumatic stress severity. In the present study, we utilized multimodal magnetic resonance imaging to investigate if structural covariance networks (SCNs) assessed acutely following trauma were linked to acute posttraumatic stress severity. METHODS: Structural magnetic resonance imaging data were collected around 1 month after civilian trauma exposure in 78 participants. Multimodal magnetic resonance imaging data fusion was completed to identify combinations of SCNs, termed structural covariance profiles (SCPs), related to acute posttraumatic stress severity collected at 1 month. Analyses assessed the relationship between participant SCP loadings, acute posttraumatic stress severity, the change in posttraumatic stress severity from 1 to 12 months, and depressive symptoms. RESULTS: We identified an SCP that reflected greater gray matter properties of the anterior temporal lobe, fusiform face area, and visual cortex (i.e., the ventral visual stream) that varied curvilinearly with acute posttraumatic stress severity and the change in PTSD symptom severity from 1 to 12 months. The SCP was not associated with depressive symptoms. CONCLUSIONS: We identified combinations of multimodal SCNs that are related to variability in PTSD symptoms in the early aftermath of trauma. The identified SCNs may reflect patterns of neuroanatomical organization that provide unique insight into acute posttraumatic stress. Furthermore, these multimodal SCNs may be potential candidates for neural markers of susceptibility to both acute posttraumatic stress and the future development of PTSD.

Evaluation of gray matter reduction in patients with typhoon-related posttraumatic stress disorder using causal network analysis of structural MRI.

BACKGROUND: The structural changes recent-onset posttraumatic stress disorder (PTSD) subjects were rarely investigated. This study was to compare temporal and causal relationships of structural changes in recent-onset PTSD with trauma-exposed control (TEC) subjects and non-TEC subjects. METHODS: T1-weighted magnetic resonance images of 27 PTSD, 33 TEC and 30 age- and sex-matched healthy control (HC) subjects were studied. The causal network of structural covariance was used to evaluate the causal relationships of structural changes in PTSD patients. RESULTS: Volumes of bilateral hippocampal and left lingual gyrus were significantly smaller in PTSD patients and TEC subjects than HC subjects. As symptom scores increase, reduction in gray matter volume began in the hippocampus and progressed to the frontal lobe, then to the temporal and occipital cortices (p < 0.05, false discovery rate corrected). The hippocampus might be the primary hub of the directional network and demonstrated positive causal effects on the frontal, temporal and occipital regions (p < 0.05, false discovery rate corrected). The frontal regions, which were identified to be transitional points, projected causal effects to the occipital lobe and temporal regions and received causal effects from the hippocampus (p < 0.05, false discovery rate corrected). CONCLUSIONS: The results offer evidence of localized abnormalities in the bilateral hippocampus and remote abnormalities in multiple temporal and frontal regions in typhoon-exposed PTSD patients.

The DRD2 Taq1A polymorphism moderates the effect of PTSD symptom severity on the left hippocampal CA3 volume: a pilot study.

RATIONALE AND OBJECTIVES: The hippocampus, especially the CA1, CA3, and dentate gyrus (DG) subfields, is reported to be associated with post-traumatic stress disorder (PTSD) after trauma. However, neuroimaging studies of the associations between PTSD and hippocampal subfield volumes have failed to yield consistent findings. The aim of this study is to examine whether the dopamine D2 receptor (DRD2) Taq1A polymorphism, which is associated with both hippocampal function and PTSD, moderated the association between PTSD severity and hippocampal CA1, CA3 and DG volumes. METHODS: T1-weighted images were acquired from 142 trauma survivors from the 2008 Wenchuan earthquake using a 3.0-T magnetic resonance imaging system. Hippocampal subfield segmentations were performed with FreeSurfer v6.0. We used the simple moderation model from the PROCESS v3.4 tool for SPSS 23.0 to examine the association between the rs1800497 polymorphism, PTSD severity, and hippocampal CA3 and DG volumes. RESULTS: A significant genotype × PTSD symptom severity interaction was found for the left CA3 volume (ΔF = 5.01, p = 0.008, ΔR2 = 0.05). Post hoc, exploratory analyses deconstructing the interaction revealed that severe PTSD symptomatology were associated with reduced left CA3 volume among TC heterozygotes (t = - 2.86, p = 0.005). CONCLUSIONS: This study suggests that DRD2 Taq1A polymorphism moderates the association between PTSD symptomatology and left CA3 volume, which promotes an etiological understanding of the hippocampal atrophy at the subfield level. This highlights the complex effect of environmental stress, and provides possible mechanism for the relationship between the dopaminergic system and hippocampal function in PTSD.

Long-term molecular differences between resilient and susceptible mice after a single traumatic exposure.

BACKGROUND AND PURPOSE: Post-traumatic stress disorder (PTSD) is a heterogeneous disorder induced by trauma, resulting in severe long-term impairments of an individual's mental health. PTSD does not develop in every individual and, thus, some individuals are more resilient. However, the underlying molecular mechanisms are poorly understood. Here, we aimed to elucidate these processes. EXPERIMENTAL APPROACH: We used a single-trauma PTSD model in mice to induce long-term maladaptive behaviours and profiled the mice 4 weeks after trauma into resilient or susceptible individuals. The classification of phenotype was based on individual responses in different behavioural experiments. We analysed microbiome, circulating endocannabinoids, and long-term changes in brain phospholipid and transcript levels. KEY RESULTS: We found many molecular differences between resilient and susceptible individuals across multiple molecular domains, including lipidome, transcriptome and gut microbiome. Some differences were stable even several weeks after the trauma, indicating the long-term impact of traumatic stimuli on the organism's physiology. Furthermore, the integration of these multilayered molecular data revealed that resilient and susceptible individuals have very distinct molecular signatures across various physiological systems. CONCLUSION AND IMPLICATIONS: Trauma induced individual-specific behavioural responses that, in combination with a longitudinal characterisation of mice, could be used to identify distinct sub-phenotypes within the trauma-exposed group. These groups differed significantly not only in their behaviour but also in specific molecular aspects across a variety of tissues and brain regions. This approach may reveal new targets and predictive biomarkers for the pharmacological treatment and prognosis of stress-related disorders. LINKED ARTICLES: This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc.

Long-term adjustment of hepatic lipid metabolism after chronic stress and the role of FGF21.

Chronic stress leads to post-traumatic stress disorder (PTSD) and metabolic disorders including fatty liver. We hypothesized that stress-induced molecular mechanisms alter energy metabolism, thereby promoting hepatic lipid accumulation even after a stress-free recovery period. In this context, we investigated fibroblast growth factor-21 (FGF21) as protective for energy and glucose homeostasis. FGF21 knockout mice (B6.129S6(SJL)-Fgf21tm1.2Djm; FGF21KO) and control mice (C57BL6; WT) were subjected to chronic variable stress. Mice were examined directly after acute intervention (Cvs) and long-term after 3 months of recovery (3mCvs). In WT, Cvs reduced insulin sensitivity and hepatic lipid accumulation, whilst fatty acid uptake increased. FGF21KO mice responded to Cvs with improved glucose tolerance, insulin resistance but liver triglycerides and plasma lipids were unaltered. Hepatic gene expression was specifically altered by genotype and stress e.g. by PPARa and SREBP-1 regulated genes. The stress-induced alteration of hepatic metabolism persisted after stress recovery. In hepatocytes at 3mCvs, differential gene regulation and secreted proteins indicated a genotype specific progression of liver dysfunction. Overall, at 3mCvs FGF21 was involved in maintaining mitochondrial activity, attenuating de novo lipogenesis, increased fatty acid uptake and histone acetyltransferase activity. Glucocorticoid release and binding to the FGF21 promoter may contribute to prolonged FGF21 release and protection against hepatic lipid accumulation. In conclusion, we showed that stress favors fatty liver disease and FGF21 protected against hepatic lipid accumulation after previous chronic stress loading by i) restored physiological function, ii) modulated gene expression via DNA-modifying enzymes, and iii) maintained energy metabolism.

A Rat Model of Post-Traumatic Stress Syndrome Causes Phenotype-Associated Morphological Changes and Hypofunction of the Adrenal Gland.

BACKGROUND: Rats exposed to chronic predator scent stress mimic the phenotype of complex post-traumatic stress disorder (PTSD) in humans, including altered adrenal morphology and function. High- and low-anxiety phenotypes have been described in rats exposed to predator scent stress (PSS). This study aimed to determine whether these high- and low-anxiety phenotypes correlate with changes in adrenal histomorphology and corticosteroid production. METHODS: Rats were exposed to PSS for ten days. Thirty days later, the rats' anxiety index (AI) was assessed with an elevated plus-maze test. Based on differences in AI, the rats were segregated into low- (AI ≤ 0.8, n = 9) and high- (AI > 0.8, n = 10) anxiety phenotypes. Plasma corticosterone (CORT) concentrations were measured by ELISA. Adrenal CORT, desoxyCORT, and 11-dehydroCORT were measured by high-performance liquid chromatography. After staining with hematoxylin and eosin, adrenal histomorphometric changes were evaluated by measuring the thickness of the functional zones of the adrenal cortex. RESULTS: Decreased plasma CORT concentrations, as well as decreased adrenal CORT, desoxyCORT and 11-dehydroCORT concentrations, were observed in high- but not in low-anxiety phenotypes. These decreases were associated with increases in AI. PSS led to a significant decrease in the thickness of the zona fasciculata and an increase in the thickness of the zona intermedia. The increase in the thickness of the zona intermedia was more pronounced in low-anxiety than in high-anxiety rats. A decrease in the adrenal capsule thickness was observed only in low-anxiety rats. The nucleus diameter of cells in the zona fasciculata of high-anxiety rats was significantly smaller than that of control or low-anxiety rats. CONCLUSION: Phenotype-associated changes in adrenal function and histomorphology were observed in a rat model of complex post-traumatic stress disorder.

The Molecular Biology of Susceptibility to Post-Traumatic Stress Disorder: Highlights of Epigenetics and Epigenomics.

Exposure to trauma is one of the most important and prevalent risk factors for mental and physical ill-health. Excessive or prolonged stress exposure increases the risk of a wide variety of mental and physical symptoms. However, people differ strikingly in their susceptibility to develop signs and symptoms of mental illness after traumatic stress. Post-traumatic stress disorder (PTSD) is a debilitating disorder affecting approximately 8% of the world's population during their lifetime, and typically develops after exposure to a traumatic event. Despite that exposure to potentially traumatizing events occurs in a large proportion of the general population, about 80-90% of trauma-exposed individuals do not develop PTSD, suggesting an inter-individual difference in vulnerability to PTSD. While the biological mechanisms underlying this differential susceptibility are unknown, epigenetic changes have been proposed to underlie the relationship between exposure to traumatic stress and the susceptibility to develop PTSD. Epigenetic mechanisms refer to environmentally sensitive modifications to DNA and RNA molecules that regulate gene transcription without altering the genetic sequence itself. In this review, we provide an overview of various molecular biological, biochemical and physiological alterations in PTSD, focusing on changes at the genomic and epigenomic level. Finally, we will discuss how current knowledge may aid us in early detection and improved management of PTSD patients.