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.

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.

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.

Photobiomodulation prevents PTSD-like memory impairments in rats.

A precise fear memory encoding a traumatic event enables an individual to avoid danger and identify safety. An impaired fear memory (contextual amnesia), however, puts the individual at risk of developing posttraumatic stress disorder (PTSD) due to the inability to identify a safe context when encountering trauma-associated cues later in life. Although it is gaining attention that contextual amnesia is a critical etiologic factor for PTSD, there is no treatment currently available that can reverse contextual amnesia, and whether such treatment can prevent the development of PTSD is unknown. Here, we report that (I) a single dose of transcranial photobiomodulation (PBM) applied immediately after tone fear conditioning can reverse contextual amnesia. PBM treatment preserved an appropriately high level of contextual fear memory in rats revisiting the "dangerous" context, while control rats displayed memory impairment. (II) A single dose of PBM applied after memory recall can reduce contextual fear during both contextual and cued memory testing. (III) In a model of complex PTSD with repeated trauma, rats given early PBM interventions efficiently discriminated safety from danger during cued memory testing and, importantly, these rats did not develop PTSD-like symptoms and comorbidities. (IV) Finally, we report that fear extinction was facilitated when PBM was applied in the early intervention window of memory consolidation. Our results demonstrate that PBM treatment applied immediately after a traumatic event or its memory recall can protect contextual fear memory and prevent the development of PTSD-like psychopathological fear in rats.

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.

Stability of hippocampal subfield volumes after trauma and relationship to development of PTSD symptoms.

BACKGROUND: The hippocampus plays a central role in post-traumatic stress disorder (PTSD) pathogenesis, and the majority of neuroimaging research on PTSD has studied the hippocampus in its entirety. Although extensive literature demonstrates changes in hippocampal volume are associated with PTSD, fewer studies have probed the relationship between symptoms and the hippocampus' functionally and structurally distinct subfields. We utilized data from a longitudinal study examining post-trauma outcomes to determine whether hippocampal subfield volumes change post-trauma and whether specific subfields are significantly associated with, or prospectively related to, PTSD symptom severity. As a secondary aim, we leveraged our unique study design sample to also investigate reliability of hippocampal subfield volumes using both cross-sectional and longitudinal pipelines available in FreeSurfer v6.0. METHODS: Two-hundred and fifteen traumatically injured individuals were recruited from an urban Emergency Department. Two-weeks post-injury, participants underwent two consecutive days of neuroimaging (time 1: T1, and time 2: T2) with magnetic resonance imaging (MRI) and completed self-report assessments. Six-months later (time 3: T3), participants underwent an additional scan and were administered a structured interview assessing PTSD symptoms. First, we calculated reliability of hippocampal measurements at T1 and T2 (automatically segmented with FreeSurfer v6.0). We then examined the prospective (T1 subfields) and cross-sectional (T3 subfields) relationship between volumes and PTSD. Finally, we tested whether change in subfield volumes between T1 and T3 explained PTSD symptom variability. RESULTS: After controlling for sex, age, and total brain volume, none of the subfield volumes (T1) were prospectively related to T3 PTSD symptoms nor were subfield volumes (T3) associated with current PTSD symptoms (T3). Tl - T2 reliability of all hippocampal subfields ranged from good to excellent (intraclass correlation coefficient (ICC) values > 0.83), with poorer reliability in the hippocampal fissure. CONCLUSION: Our study was a novel examination of the prospective relationship between hippocampal subfield volumes in relation to PTSD in a large trauma-exposed urban sample. There was no significant relationship between subfield volumes and PTSD symptoms, however, we confirmed FreeSurfer v6.0 hippocampal subfield segmentation is reliable when applied to a traumatically-injured sample, using both cross-sectional and longitudinal analysis pipelines. Although hippocampal subfield volumes may be an important marker of individual variability in PTSD, findings are likely conditional on the timing of the measurements (e.g. acute or chronic post-trauma periods) and analysis strategy (e.g. cross-sectional or prospective).

Altered basal forebrain BOLD signal variability at rest in posttraumatic stress disorder: A potential candidate vulnerability mechanism for neurodegeneration in PTSD.

Individuals with posttraumatic stress disorder (PTSD) are at increased risk for the development of various forms of dementia. Nevertheless, the neuropathological link between PTSD and neurodegeneration remains unclear. Degeneration of the human basal forebrain constitutes a pathological hallmark of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. In this seed-based resting-state (rs-)fMRI study identifying as outcome measure the temporal BOLD signal fluctuation magnitude, a seed-to-voxel analyses assessed temporal correlations between the average BOLD signal within a bilateral whole basal forebrain region-of-interest and each whole-brain voxel among individuals with PTSD (n = 65), its dissociative subtype (PTSD+DS) (n = 38) and healthy controls (n = 46). We found that compared both with the PTSD and healthy controls groups, the PTSD+DS group exhibited increased BOLD signal variability within two nuclei of the seed region, specifically in its extended amygdaloid region: the nucleus accumbens and the sublenticular extended amygdala. This finding is provocative, because it mimics staging models of neurodegenerative diseases reporting allocation of neuropathology in early disease stages circumscribed to the basal forebrain. Here, underlying candidate etiopathogenetic mechanisms are neurovascular uncoupling, decreased connectivity in local- and large-scale neural networks, or disrupted mesolimbic dopaminergic circuitry, acting indirectly upon the basal forebrain cholinergic pathways. These abnormalities may underpin reward-related deficits representing a putative link between persistent traumatic memory in PTSD and anterograde memory deficits in neurodegeneration. Observed alterations of the basal forebrain in the dissociative subtype of PTSD point towards the urgent need for further exploration of this region as a potential candidate vulnerability mechanism for neurodegeneration in PTSD.

Alterations in hippocampal subfield and amygdala subregion volumes in posttraumatic subjects with and without posttraumatic stress disorder.

The hippocampus and amygdala are important structures in the posttraumatic stress disorder (PTSD); however, the exact relationship between these structures and stress or PTSD remains unclear. Moreover, they consist of several functionally distinct subfields/subregions that may serve different roles in the neuropathophysiology of PTSD. Here we present a subregional profile of the hippocampus and amygdala in 145 survivors of a major earthquake and 56 non-traumatized healthy controls (HCs). We found that the bilateral hippocampus and left amygdala were significantly smaller in survivors than in HCs, and there was no difference between survivors with (n = 69) and without PTSD (trauma-exposed controls [TCs], n = 76). Analyses revealed similar results in most subfields/subregions, except that the right hippocampal body (in a head-body-tail segmentation scheme), right presubiculum, and left amygdala medial nuclei (Me) were significantly larger in PTSD patients than in TCs but smaller than in HCs. Larger hippocampal body were associated with the time since trauma in PTSD patients. The volume of the right cortical nucleus (Co) was negatively correlated with the severity of symptoms in the PTSD group but positively correlated with the same measurement in the TC group. This correlation between symptom severity and Co volume was significantly different between the PTSD and TCs. Together, we demonstrated that generalized smaller volumes in the hippocampus and amygdala were more likely to be trauma-related than PTSD-specific, and their subfields/subregions were distinctively affected. Notably, larger left Me, right hippocampal body and presubiculum were PTSD-specific; these could be preexisting factors for PTSD or reflect rapid posttraumatic reshaping.

Neural changes following equine-assisted therapy for posttraumatic stress disorder: A longitudinal multimodal imaging study.

BACKGROUND: While effective treatments for posttraumatic stress disorder (PTSD) exist, many individuals, including military personnel and veterans fail to respond to them. Equine-assisted therapy (EAT), a novel PTSD treatment, may complement existing PTSD interventions. This study employs longitudinal neuro-imaging, including structural magnetic resonance imaging (sMRI), resting state-fMRI (rs-fMRI), and diffusion tensor imaging (DTI), to determine mechanisms and predictors of EAT outcomes for PTSD. METHOD: Nineteen veterans with PTSD completed eight weekly group sessions of EAT undergoing multimodal MRI assessments before and after treatment. Clinical assessments were conducted at baseline, post-treatment and at 3-month follow-up. RESULTS: At post-treatment patients showed a significant increase in caudate functional connectivity (FC) and reduction in the gray matter density of the thalamus and the caudate. The increase of caudate FC was positively associated with clinical improvement seen immediately at post-treatment and at 3-month follow-up. In addition, higher baseline caudate FC was associated with greater PTSD symptom reduction post-treatment. CONCLUSIONS: This exploratory study is the first to demonstrate that EAT can affect functional and structural changes in the brains of patients with PTSD. The findings suggest that EAT may target reward circuitry responsiveness and produce a caudate pruning effect from pre- to post-treatment.

Decreased functional connectivity of hippocampal subregions and methylation of the NR3C1 gene in Han Chinese adults who lost their only child.

BACKGROUND: Losing one's only child is a major traumatic life event that may lead to post-traumatic stress disorder (PTSD); however, the underlying mechanisms of its psychological consequences remain poorly understood. Here, we investigated subregional hippocampal functional connectivity (FC) networks based on resting-state functional magnetic resonance imaging and the deoxyribonucleic acid methylation of the human glucocorticoid receptor gene (NR3C1) in adults who had lost their only child. METHODS: A total of 144 Han Chinese adults who had lost their only child (51 adults with PTSD and 93 non-PTSD adults [trauma-exposed controls]) and 50 controls without trauma exposure were included in this fMRI study (age: 40-67 years). FCs between hippocampal subdivisions (four regions in each hemisphere: cornu ammonis1 [CA1], CA2, CA3, and dentate gyrus [DG]) and methylation levels of the NR3C1 gene were compared among the three groups. RESULTS: Trauma-exposed adults, regardless of PTSD diagnosis, had weaker positive FC between the left hippocampal CA1, left DG, and the posterior cingulate cortex, and weaker negative FC between the right CA1, right DG, and several frontal gyri, relative to healthy controls. Compared to non-PTSD adults, PTSD adults showed decreased negative FC between the right CA1 region and the right middle/inferior frontal gyri (MFG/IFG), and decreased negative FC between the right DG and the right superior frontal gyrus and left MFG. Both trauma-exposed groups showed lower methylation levels of the NR3C1 gene. CONCLUSIONS: Adults who had lost their only child may experience disrupted hippocampal network connectivity and NR3C1 methylation status, regardless of whether they have developed PTSD.

Do somatic symptoms relate to PTSD and gender after earthquake exposure? A cross-sectional study on young adult survivors in Italy.

OBJECTIVE: Increasing evidence confirms a strict relationship between mental disorders and physical health. Particularly, stressful life events and post-traumatic stress disorder (PTSD) have been closely correlated with various physical disorders and somatic symptoms, such as chronic pain, gastrointestinal disorders, and headaches. The aim of this study was to investigate the emergence of somatic symptoms in a sample of young adult survivors 21 months after exposure to the L'Aquila 2009 earthquake, with particular attention to PTSD and gender impact. METHODS: Four hundred and fifty high-school senior students (253 male and 197 female) exposed to the 2009 L'Aquila earthquake, 21 months earlier, were enrolled and evaluated by the Trauma and Loss Spectrum Self-Report (TALS-SR), for symptomatological PTSD, and the Mood Spectrum Self-Report-Lifetime Version (MOODS-SR) "rhythmicity and vegetative functions" domain, for somatic symptoms. RESULTS: Significantly higher rates of endorsement of the MOODS-SR somatic symptoms emerged in survivors with PTSD compared to those without. Females reported higher rates of endorsement of at least one MOODS-SR somatic symptom compared to males; however, a Decision Tree model and a two-way analysis of variance model confirmed a significant effect of PTSD only. A multivariate logistical regression showed a significant association between the presence of at least one MOOD-SR somatic symptom and re-experiencing and maladaptive coping TALS-SR domains. CONCLUSION: This study corroborates a relevant impact of symptomatological PTSD, across both the genders, on somatic symptoms occurring in young adults after months from exposure to a massive earthquake.

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.

Dysregulation of miR-15a-5p, miR-497a-5p and miR-511-5p Is Associated with Modulation of BDNF and FKBP5 in Brain Areas of PTSD-Related Susceptible and Resilient Mice.

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder occurring in susceptible individuals following a traumatic event. Understanding the mechanisms subserving trauma susceptibility/resilience is essential to develop new effective treatments. Increasing evidence suggests that non-coding RNAs, such as microRNAs (miRNAs), may play a prominent role in mediating trauma susceptibility/resilience. In this study, we evaluated the transcriptional expression of two key PTSD-related genes (FKBP5 and BDNF) and the relative targeting miRNAs (miR-15a-5p, miR-497a-5p, miR-511-5p, let-7d-5p) in brain areas of PTSD-related susceptible and resilient mice identified through our recently developed mouse model of PTSD (arousal-based individual screening (AIS) model). We observed lower transcript levels of miR-15a-5p, miR-497a-5p, and miR-511a-5p in the hippocampus and hypothalamus of susceptible mice compared to resilient mice, suggesting that the expression of these miRNAs could discriminate the two different phenotypes of stress-exposed mice. These miRNA variations could contribute, individually or synergically, to the inversely correlated transcript levels of FKBP5 and BDNF. Conversely, in the medial prefrontal cortex, downregulation of miR-15a-5p, miR-511-5p, and let-7d-5p was observed both in susceptible and resilient mice, and not accompanied by changes in their mRNA targets. Furthermore, miRNA expression in the different brain areas correlated to stress-induced behavioral scores (arousal score, avoidance-like score, social memory score and PTSD-like score), suggesting a linear connection between miRNA-based epigenetic modulation and stress-induced phenotypes. Pathway analysis of a miRNA network showed a statistically significant enrichment of molecular processes related to PTSD and stress. In conclusion, our results indicate that PTSD susceptibility/resilience might be shaped by brain-area-dependent modulation of miRNAs targeting FKBP5, BDNF, and other stress-related genes.

Is PTSD-Phenotype Associated with HPA-Axis Sensitivity?: The Endocannabinoid System in Modulating Stress Response in Rats.

Endocannabinoids play a role in adaptation to stress and regulate the release of glucocorticoids in stressed and unstressed conditions. We recently found that basal corticosterone pulsatility may significantly impact the vulnerability for developing post-traumatic-stress-disorder (PTSD), suggesting that the endocannabinoid system may contribute to its development. To examine this, we exposed rats to predator scent stress (PSS). Behavioral reactions were recorded seven days post-PSS. Cerebrospinal fluid (CSF) was collected from anesthetized rats shortly after PSS exposure to determine the levels of 2-arachidonoyl glycerol (2-AG) and anandamide (AEA). To correlate between endocannabinoids and corticosterone levels, rats were placed in metabolic cages for urine collection. To assess the levels of endocannabinoids in specific brain regions, rats' brains were harvested one day after behavioral analysis for staining and fluorescence quantification. Moreover, 2-AG was elevated in the CSF of PTSD-phenotype rats as compared with other groups and was inversely correlated with corticosterone urinary secretion. Eight days post-PSS exposure, hippocampal and hypothalamic 2-AG levels and hippocampal AEA levels were significantly more reduced in the PTSD-phenotype group compared to other groups. We posit that maladaptation to stress, which is propagated by an abnormal activation of endocannabinoids, mediates the subsequent stress-induced behavioral disruption, which, later, reduces neuronal the expression of endocannabinoids, contributing to PTSD symptomology.

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.

Is PTSD-Phenotype Associated with HPA-Axis Sensitivity? Feedback Inhibition and Other Modulating Factors of Glucocorticoid Signaling Dynamics.

Previously, we found that basal corticosterone pulsatility significantly impacts the vulnerability for developing post-traumatic stress disorder (PTSD). Rats that exhibited PTSD-phenotype were characterized by blunted basal corticosterone pulsatility amplitude and a blunted corticosterone response to a stressor. This study sought to identify the mechanisms underlining both the loss of pulsatility and differences in downstream responses. Serial blood samples were collected manually via jugular vein cannula at 10-min intervals to evaluate suppression of corticosterone following methylprednisolone administration. The rats were exposed to predator scent stress (PSS) after 24 h, and behavioral responses were assessed 7 days post-exposure for retrospective classification into behavioral response groups. Brains were harvested for measurements of the glucocorticoid receptor, mineralocorticoid receptor, FK506-binding protein-51 and arginine vasopressin in specific brain regions to assess changes in hypothalamus-pituitary-adrenal axis (HPA) regulating factors. Methylprednisolone produced greater suppression of corticosterone in the PTSD-phenotype group. During the suppression, the PTSD-phenotype rats showed a significantly more pronounced pulsatile activity. In addition, the PTSD-phenotype group showed distinct changes in the ventral and dorsal CA1, dentate gyrus as well as in the paraventricular nucleus and supra-optic nucleus. These results demonstrate a pre-trauma vulnerability state that is characterized by an over-reactivity of the HPA and changes in its regulating factors.

Modulation of PARP-1 Activity in a Broad Time Window Attenuates Memorizing Fear.

The amygdala plays a critical role in the acquisition and consolidation of fear-related memories. Recent studies have demonstrated that ADP-ribosylation of histones, accelerated by PARPs, affects the chromatin structure and the binding of chromatin remodeling complexes with transcription factors. Inhibition of PARP-1 activity during the labile phase of re-consolidation may erase memory. Accordingly, we investigated the possibility of interfering with fear conditioning by PARP-1 inhibition. Herein, we demonstrate that injection of PARP-1 inhibitors, specifically into the CeA or i.p., in different time windows post-retrieval, attenuates freezing behavior. Moreover, the association of memory with pharmacokinetic timing of PARP inhibitor arrival to the brain enabled/achieved attenuation of a specific cue-associated memory of fear but did not hinder other memories (even traumatic events) associated with other cues. Our results suggest using PARP-1 inhibitors as a new avenue for future treatment of PTSD by disrupting specific traumatic memories in a broad time window, even long after the traumatic event. The safety of using these PARP inhibitors, that is, not interfering with other natural memories, is an added value.

The cerebellum under stress.

Stress-related psychiatric conditions are one of the main causes of disability in developed countries. They account for a large portion of resource investment in stress-related disorders, become chronic, and remain difficult to treat. Research on the neurobehavioral effects of stress reveals how changes in certain brain areas, mediated by a number of neurochemical messengers, markedly alter behavior. The cerebellum is connected with stress-related brain areas and expresses the machinery required to process stress-related neurochemical mediators. Surprisingly, it is not regarded as a substrate of stress-related behavioral alterations, despite numerous studies that show cerebellar responsivity to stress. Therefore, this review compiles those studies and proposes a hypothesis for cerebellar function in stressful conditions, relating it to stress-induced psychopathologies. It aims to provide a clearer picture of stress-related neural circuitry and stimulate cerebellum-stress research. Consequently, it might contribute to the development of improved treatment strategies for stress-related disorders.

Acceptance and commitment therapy for breast cancer survivors with fear of cancer recurrence: A 3-arm pilot randomized controlled trial.

BACKGROUND: Fear of cancer recurrence (FCR) has a profound negative impact on quality of life (QOL) for many cancer survivors. Breast cancer survivors (BCS) are particularly vulnerable, with up to 70% reporting clinically significant FCR. To the authors' knowledge, evidence-based interventions for managing FCR are limited. Acceptance and commitment therapy (ACT) promotes psychological flexibility in managing life's stressors. The current study examined the feasibility and preliminary efficacy of group-based ACT for FCR in BCS. METHODS: Post-treatment BCS (91 patients with stage I-III disease) with clinical FCR randomly were assigned to ACT (6 weekly 2-hour group sessions), survivorship education (SE; 6 weekly 2-hour group sessions), or enhanced usual care (EUC; one 30-minute group coaching session with survivorship readings). FCR severity (primary outcome) and avoidant coping, anxiety, post-traumatic stress, depression, QOL, and other FCR-related variables (secondary outcomes) were assessed at baseline (T1), after the intervention (T2), 1 month after the intervention (T3), and 6 months after the intervention (T4) using intent-to-treat analysis. RESULTS: Satisfactory recruitment (43.8%) and retention (94.5%) rates demonstrated feasibility. Although each arm demonstrated within-group reductions in FCR severity over time, only ACT produced significant reductions at each time point compared with baseline, with between-group differences at T4 substantially favoring ACT over SE (Cohen d for effect sizes, 0.80; P < .001) and EUC (Cohen d, 0.61; P < .01). For 10 of 12 secondary outcomes, only ACT produced significant within-group reductions across all time points. By T4, significant moderate to large between-group comparisons favored ACT over SE and EUC with regard to avoidant coping, anxiety, depression, QOL, and FCR-related psychological distress. CONCLUSIONS: Group-based ACT is a feasible and promising treatment for FCR and associated outcomes in BCS that warrants testing in larger, fully powered trials.

Anterior hippocampal volume predicts affect-focused psychotherapy outcome.

BACKGROUND: The hippocampus plays an important role in psychopathology and treatment outcome. While posterior hippocampus (PH) may be crucial for the learning process that exposure-based treatments require, affect-focused treatments might preferentially engage anterior hippocampus (AH). Previous studies have distinguished the different functions of these hippocampal sub-regions in memory, learning, and emotional processes, but not in treatment outcome. Examining two independent clinical trials, we hypothesized that anterior hippocampal volume would predict outcome of affect-focused treatment outcome [Interpersonal Psychotherapy (IPT); Panic-Focused Psychodynamic Psychotherapy (PFPP)], whereas posterior hippocampal volume would predict exposure-based treatment outcome [Prolonged Exposure (PE); Cognitive Behavioral Therapy (CBT); Applied Relaxation Training (ART)]. METHODS: Thirty-five patients with posttraumatic stress disorder (PTSD) and 24 with panic disorder (PD) underwent structural magnetic resonance imaging (MRI) before randomization to affect-focused (IPT for PTSD; PFPP for PD) or exposure-based treatments (PE for PTSD; CBT or ART for PD). AH and PH volume were regressed with clinical outcome changes. RESULTS: Baseline whole hippocampal volume did not predict post-treatment clinical severity scores in any treatment. For affect-focused treatments, but not exposure-based treatments, anterior hippocampal volume predicted clinical improvement. Smaller AH correlated with greater affect-focused treatment improvement. Posterior hippocampal volume did not predict treatment outcome. CONCLUSIONS: This is the first study to explore associations between hippocampal volume sub-regions and treatment outcome in PTSD and PD. Convergent results suggest that affect-focused treatment may influence the clinical outcome through the 'limbic' AH, whereas exposure-based treatments do not. These preliminary, theory-congruent, therapeutic findings require replication in a larger clinical trial.