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By combining computational, morphological, and functional analyses, this study relates latent markers of associative threat learning to overt post-traumatic stress disorder (PTSD) symptoms in combat veterans. Using reversal learning, we found that symptomatic veterans showed greater physiological adjustment to cues that did not predict what they had expected, indicating greater sensitivity to prediction errors for negative outcomes. This exaggerated weighting of prediction errors shapes the dynamic learning rate (associability) and value of threat predictive cues. The degree to which the striatum tracked the associability partially mediated the positive correlation between prediction-error weights and PTSD symptoms, suggesting that both increased prediction-error weights and decreased striatal tracking of associability independently contribute to PTSD symptoms. Furthermore, decreased neural tracking of value in the amygdala, in addition to smaller amygdala volume, independently corresponded to higher PTSD symptom severity. These results provide evidence for distinct neurocomputational contributions to PTSD symptoms.PTSD symptom severity in combat veterans was associated with enhanced sensitivity to prediction errors and lower neural tracking of value and learning rate, providing evidence for neurocomputational contributions to trauma-related psychopathology.

Purpose of Review Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of synaptic connectivity. Recent Findings Here, we will briefly review evidence that PTSD might be a “synaptic disconnection syndrome” and highlight the importance of this perspective for the emerging therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity. Summary Synaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics.

Post-traumatic stress disorder (PTSD) is a highly prevalent disorder and a highly debilitating condition. Although anhedonia is an important construct of the disorder, the relationship between PTSD and reward functioning is still under-researched. To date, the majority of research on PTSD has focused on fear: fear learning, maintenance, and extinction. Here we review the relevant literature—including clinical observations, self-report data, neuroimaging research, and animal studies—in order to examine the potential effects of post-traumatic stress disorder on the reward system. Our current lack of sufficient insight into how trauma affects the reward system is one possible hindrance to clinical progress. The current review highlights the need for further investigation into the complex relationship between exposure to trauma and the reward system to further our understandings of the ethology of PTSD.

The role of the endocannabinoid system in stress-related psychiatric symptoms has been investigated in many animal and human studies. Although most of these studies consistently report long-lasting effects of prolonged stress and trauma on the endocannabinoid system, the nature and direction of these changes are controversial. We reviewed the available preclinical and clinical studies investigating the endocannabinoid system alterations long after chronic stress and trauma. We propose that the effects of prolonged stress or trauma on the endocannabinoid system are different based on the developmental age of subjects at the time of experiencing the trauma and its repetitiveness and accumulative effects. The current literature consistently demonstrates decreased levels of endocannabinoid ligands and receptors if the trauma occurs in childhood, whereas decreased levels of endocannabinoid ligands and increased levels of cannabinoid receptors are reported when trauma has happened in adulthood. It is important to note that these changes are region-specific in the brain and also there are important sex differences, which are beyond the scope of this review.

Novel pharmacotherapies that improve outcomes for individuals with stress-related psychiatric disorders are needed. The neurohormone oxytocin (OT) is a promising candidate given its influence on the social–emotional brain. In this review, we present an overview of evidence supporting OT’s utility for treating major depressive disorder and posttraumatic stress disorder. We first discuss endogenous OT, which research suggests is not yet a reliable biomarker of stress-related disorders. Second, we review effects of intranasal (IN) OT on processes relevant to stress-related disorders in healthy populations (anhedonia, reward processing, psychosocial stress reactivity, fear/anxiety, and social behavior) and their neurobiological mechanisms (e.g., the salience network and hypothalamic–pituitary–adrenal axis). Third, we present the sparse but promising findings from clinical populations, followed by discussion of critical moderating variables to consider in the service of maximizing the therapeutic potential of OT (e.g., patient sex and child maltreatment). We also identify heterogeneous findings and limitations of existing research, including reliance on single-dose studies in psychiatrically healthy samples and unanswered questions regarding the effectiveness of IN drug delivery and dosing schedules. Well-controlled multidose studies including women and measures of potentially moderating variables are sorely needed and would inform our understanding of the utility of OT for preventing and treating stress-related psychiatric disorders.

Background Accumulating evidence implicates the endocannabinoid system, including variants in the cannabinoid-1 receptor gene (CNR1), in the pathophysiology of posttraumatic stress disorder (PTSD). The synonymous G1359A variant (rs1049353) in the CNR1 gene has been linked to PTSD in individuals exposed to childhood abuse. In this study, the effects of the rs1049353 genotype and childhood abuse on overall PTSD symptoms, as well as PTSD symptom clusters were examined in order to examine how this interaction relates to the phenotypic expression of this disorder. Method Data were analyzed from 1,372 Caucasian U.S. veterans who participated in the National Health and Resilience in Veterans Study. Multivariable analyses were conducted to evaluate the association between rs1049353 genotype, childhood abuse, and their interaction in relation to PTSD symptoms. Results A significant interaction between rs1049353 genotype and childhood abuse was observed, with A allele carriers with histories of childhood abuse reporting greater severity of PTSD symptoms, most notably anxious arousal, relative to G/G homozygotes. Significant main effects of childhood abuse on overall PTSD symptoms, and re-experiencing, emotional numbing, and dysphoric arousal symptom clusters, as well as of A allele carrier status on anxious arousal symptoms were observed. Conclusions Results of this study replicate prior work and suggest that the rs1049353-by-childhood abuse interaction is particularly associated with the manifestation of anxious arousal symptoms of PTSD. Taken together, these findings underscore the importance of considering the phenotypic heterogeneity of PTSD in gene-environment studies of this multifaceted disorder.

The RESET (Reconsolidation, Exposure, and Short-term Emotional Transformation) clinical protocol is an intensive, structured trauma-focused intervention designed to treat post-traumatic stress disorder (PTSD) within six daily sessions. While Prolonged Exposure (PE) therapy remains a leading evidence-based treatment, challenges such as high dropout rates and relapses highlight the need for innovative approaches. This paper outlines RESET's theoretical foundations, session structure, and clinical implementation, offering a detailed framework for its integration into psychotrauma practice. RESET integrates principles of memory reconsolidation, exposure therapy, and psychodynamic case formulation to facilitate the rapid processing and integration of traumatic memories. The protocol includes psychoeducation, targeted exposure, dynamic case formulation, and guided trauma processing, providing a comprehensive yet time-efficient intervention. By leveraging memory reconsolidation mechanisms within an intensive treatment format, RESET has the potential to enhance therapeutic engagement, reduce dropout, optimize PTSD symptom reduction, and foster sustained emotional processing. Its structured design ensures feasibility and adherence while maintaining the efficacy of traditional PTSD treatments. Ongoing clinical trials are evaluating RESET's effectiveness across diverse populations, positioning it as both a scalable stand-alone intervention and a valuable adjunct to long-term psychotherapies.

Posttraumatic stress disorder (PTSD) is one of the most common psychiatric disorders among veterans returning tfrom Iraq and Afghanistan. Little research has examined variables that may mediate the relation between PTSD and aspects of social functioning, such as relationship satisfaction and family functioning. In this cross-sectional study, a total of 164 veterans who were seeking VA primary care or mental health care within one year after returning from Iraq and/or Afghanistan were screened for PTSD and completed a series of questionnaires that assessed social functioning, coping, and life satisfaction. Results showed that the 86 (52%) veterans who screened positive for PTSD reported greater difficulties in their relationships with romantic partners, less cohesion in their families, less social support, poorer social functioning, and lower life satisfaction compared to other treatment-seeking veterans. Less social support from the community, excessive worry, decreased acceptance of change, and lower availability of secure relationships mediated the association between PTSD and poor social functioning. The relation between PTSD and lower partner satisfaction was mediated by greater cognitive social avoidance and lower availability of secure relationships. These results suggest that psychotherapeutic interventions that address these mediating variables may help improve social functioning in treatment-seeking veterans with PTSD.

RationaleA 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.ObjectivesThe present randomized controlled pilot study examines the effect of ketamine, a dissociative drug, on RSFC between mPFC subregions and amygdala in individuals with PTSD.MethodsTwenty-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.ResultsContrary 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.ConclusionsA 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.

Background Chronic stress and related physiological responses are known to have deleterious effects on neural integrity. Combat exposure is a notoriously pathogenic stressor, and with over 2 million U.S. troops deployed to active combat zones since 2001, there is an urgent need to advance our understanding of its potential neural impact. Previous evidence suggests structural alterations in posttraumatic stress disorder (PTSD) and more recent studies have explored cortical thinning specifically. This preliminary study investigates the impact of combat exposure on cortical thickness, controlling for history of early life stress and age. Methods Twenty-one combat-exposed Veterans with PTSD and 20 non-PTSD combat-exposed controls (mean age 32.7) completed the Combat Exposure Scale, Childhood Trauma Questionnaire, and structural magnetic resonance imaging in a Siemens 3T TIM trio system. General linear model was used to examine the effect of combat exposure on cortical thickness, controlling for early life trauma exposure and age using cluster-wise correction (p < 0.05). Results This preliminary study found a negative correlation between combat exposure severity (CES) and cortical thickness in the left superior temporal and left rostral middle frontal regions, as well as an interaction between PTSD diagnosis status and CES, in the superior temporal/insular region showing a stronger negative correlation between CES and cortical thickness in the non-PTSD group. Conclusions Though caution should be taken with interpretation given the preliminary nature of the findings, the results indicate combat exposure may affect cortical structure beyond possible alterations due to early life stress exposure or PTSD psychopathology. Though replication in larger samples is required, these results provide useful information regarding possible neural biomarkers and treatment targets for combat-related psychopathology as well as highlighting the pathogenic effects of combat.