Cognitive Flexibility Predicts PTSD Symptoms: Observational and Interventional Studies

Introduction: Post-Traumatic Stress Disorder (PTSD) is a prevalent, severe and tenacious psychopathological consequence of traumatic events. Neurobehavioral mechanisms underlying PTSD pathogenesis have been identified, and may serve as risk-resilience factors during the early aftermath of trauma exposure. Longitudinally documenting the neurobehavioral dimensions of early responses to trauma may help characterize survivors at risk and inform mechanism-based interventions. We present two independent longitudinal studies that repeatedly probed clinical symptoms and neurocognitive domains in recent trauma survivors. We hypothesized that better neurocognitive functioning shortly after trauma will be associated with less severe PTSD symptoms a year later, and that an early neurocognitive intervention will improve cognitive functioning and reduce PTSD symptoms.Methods: Participants in both studies were adult survivors of traumatic events admitted to two general hospitals’ emergency departments (EDs) in Israel. The studies used identical clinical and neurocognitive tools, which included assessment of PTSD symptoms and diagnosis, and a battery of neurocognitive tests. The first study evaluated 181 trauma-exposed individuals one-, six-, and 14 months following trauma exposure. The second study evaluated 97 trauma survivors 1 month after trauma exposure, randomly allocated to 30 days of web-based neurocognitive intervention (n = 50) or control tasks (n = 47), and re-evaluated all subjects three- and 6 months after trauma exposure.Results: In the first study, individuals with better cognitive flexibility at 1 month post-trauma showed significantly less severe PTSD symptoms after 13 months (p = 0.002). In the second study, the neurocognitive training group showed more improvement in cognitive flexibility post-intervention (p = 0.019), and lower PTSD symptoms 6 months post-trauma (p = 0.017), compared with controls. Intervention- induced improvement in cognitive flexibility positively correlated with clinical improvement (p = 0.002).Discussion: Cognitive flexibility, shortly after trauma exposure, emerged as a significant predictor of PTSD symptom severity. It was also ameliorated by a neurocognitive intervention and associated with a better treatment outcome. These findings support further research into the implementation of mechanism-driven neurocognitive preventive interventions for PTSD

Structural neuroimaging of hippocampus and amygdala subregions in posttraumatic stress disorder: A scoping review

Numerous studies have explored the relationship between posttraumatic stress disorder (PTSD) and the hippo-campus and the amygdala because both regions are implicated in the disorder’s pathogenesis and pathophysiology. Nevertheless, those key limbic regions consist of functionally and cytoarchitecturally distinct substructures that may play different roles in the etiology of PTSD. Spurred by the availability of automatic segmentation software, structural neuroimaging studies of human hippocampal and amygdala subregions have proliferated in recent years. Here, we present a preregistered scoping review of the existing structural neuroimaging studies of the hippocampus and amygdala subregions in adults diagnosed with PTSD. A total of 3513 studies assessing subregion volumes were identified, 1689 of which were screened, and 21 studies were eligible for this review (total N = 2876 individuals). Most studies examined hippocampal subregions and reported decreased CA1, CA3, dentate gyrus, and subiculum volumes in PTSD. Fewer studies investigated amygdala subregions and reported altered lateral, basal, and central nuclei volumes in PTSD. This review further highlights the conceptual and methodological limitations of the current literature and identifies future directions to increase understanding of the distinct roles of hippocampal and amygdalar subregions in posttraumatic psychopathology

Whole genome identification of Mycobacterium tuberculosis vaccine candidates by comprehensive data mining and bioinformatic analyses

<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium tuberculosis</it>, the causative agent of tuberculosis (TB), infects ~8 million annually culminating in ~2 million deaths. Moreover, about one third of the population is latently infected, 10% of which develop disease during lifetime. Current approved prophylactic TB vaccines (BCG and derivatives thereof) are of variable efficiency in adult protection against pulmonary TB (0%–80%), and directed essentially against early phase infection.</p> <p>Methods</p> <p>A genome-scale dataset was constructed by analyzing published data of: (1) global gene expression studies under conditions which simulate intra-macrophage stress, dormancy, persistence and/or reactivation; (2) cellular and humoral immunity, and vaccine potential. This information was compiled along with revised annotation/bioinformatic characterization of selected gene products and <it>in silico </it>mapping of T-cell epitopes. Protocols for scoring, ranking and prioritization of the antigens were developed and applied.</p> <p>Results</p> <p>Cross-matching of literature and <it>in silico</it>-derived data, in conjunction with the prioritization scheme and biological rationale, allowed for selection of 189 putative vaccine candidates from the entire genome. Within the 189 set, the relative distribution of antigens in 3 functional categories differs significantly from their distribution in the whole genome, with reduction in the Conserved hypothetical category (due to improved annotation) and enrichment in Lipid and in Virulence categories. Other prominent representatives in the 189 set are the PE/PPE proteins; iron sequestration, nitroreductases and proteases, all within the Intermediary metabolism and respiration category; ESX secretion systems, resuscitation promoting factors and lipoproteins, all within the Cell wall category. Application of a ranking scheme based on qualitative and quantitative scores, resulted in a list of 45 best-scoring antigens, of which: 74% belong to the dormancy/reactivation/resuscitation classes; 30% belong to the Cell wall category; 13% are classical vaccine candidates; 9% are categorized Conserved hypotheticals, all potentially very potent T-cell antigens.</p> <p>Conclusion</p> <p>The comprehensive literature and <it>in silico</it>-based analyses allowed for the selection of a repertoire of 189 vaccine candidates, out of the whole-genome 3989 ORF products. This repertoire, which was ranked to generate a list of 45 top-hits antigens, is a platform for selection of genes covering all stages of <it>M. tuberculosis </it>infection, to be incorporated in rBCG or subunit-based vaccines.</p

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Neuroscientific account of Guilt- and Shame-Driven PTSD phenotypes

Background: Guilt and Shame, two core self-related emotions, often emerge following trauma and play an important role in the development and maintenance of post-traumatic stress disorder (PTSD). Importantly, Guilt and Shame exhibit specific focal and non-specific global impacts of trauma on self-perception, respectively. Objective and Methods: Integrating psychological theories with neuroscientific knowledge, we suggest a scheme of two diverging clinical phenotypes of PTSD, associated with distinct self-related processes and differential functionality of relevant neural networks. Proposal: The Guilt-driven phenotype is characterized by preoccupation with negative self-attributes of one's actions in the traumatic event. It involves altered functionality of both the salience network (SN) and the default-mode network (DMN), associated with heightened interoceptive signalling and ruminative introspection which may lead to hyperarousal and intrusive symptoms, respectively. On the contrary, the Shame-driven phenotype is characterized by global, identity-related negative self-attributions. It involves altered functionality of both the SN and the DMN, associated with blunted interoceptive signalling and diminished introspection which may result in withdrawal and anhedonia symptoms together with dissociative experiences, respectively. Conclusion: The proposed PTSD phenotypes may inform neuropsychological therapeutic interventions (e.g. self-focused psychotherapy and neuromodulation) aiming to restore the function of large-scale self-related neural processing

Evaluating web-based cognitive-affective remediation in recent trauma survivors: study rationale and protocol

Background: The immediate aftermath of traumatic events is a period of enhanced neural plasticity, following which some survivors remain with post-traumatic stress disorder (PTSD) whereas others recover. Evidence points to impairments in emotional reactivity, emotion regulation, and broader executive functions as critically contributing to PTSD. Emerging evidence further suggests that the neural mechanisms underlying these functions remain plastic in adulthood and that targeted retraining of these systems may enhance their efficiency and could reduce the likelihood of developing PTSD. Administering targeted neurocognitive training shortly after trauma exposure is a daunting challenge. This work describes a study design addressing that challenge. The study evaluated the direct effects of cognitive remediation training on neurocognitive mechanisms that hypothetically underlay PTSD, and the indirect effect of this intervention on emerging PTSD symptoms. Method: We describe a study rationale, design, and methodological choices involving: (a) participants’ enrolment; (b) implementation and management of a daily self-administered, web-based intervention; (c) reliable, timely screening and assessment of treatment of eligible survivors; and (d) defining control conditions and outcome measures. We outline the rationale of choices made regarding study sample, timing of intervention, measurements, monitoring participants’ adherence, and ways to harmonize and retain interviewers’ fidelity and mitigate eventual burnout by repeated contacts with recently traumatized survivors. Conclusion: Early web-based interventions targeting causative mechanisms of PTSD can be informed by the model presented in this paper

Integration of limbic self-neuromodulation with psychotherapy for complex post-traumatic stress disorder: treatment rationale and case study

ABSTRACTTreatment Rationale: Exposure to repeated sexual trauma, particularly during childhood, often leads to protracted mental health problems. Childhood adversity is specifically associated with complex posttraumatic stress disorder (PTSD) presentation, which is particularly tenacious and treatment refractory, and features severe emotion dysregulation. Augmentation approaches have been suggested to enhance treatment efficacy in PTSD thus integrating first-line psychotherapy with mechanistically informed self-neuromodulation procedures (i.e. neurofeedback) may pave the way to enhanced clinical outcomes. A central neural mechanism of PTSD and emotion dysregulation involves amygdala hyperactivity that can be volitionally regulated by neurofeedback. We outline a treatment rationale that includes a detailed justification for the potential of combining psychotherapy and NF and delineate mechanisms of change. We illustrate key processes of reciprocal interactions between neurofeedback engagement and therapeutic goals.Case Study: We describe a clinical case of a woman with complex PTSD due to early and repetitive childhood sexual abuse using adjunctive neurofeedback as an augmentation to an ongoing, stable, traditional treatment plan. The woman participated in (a) ten sessions of neurofeedback by the use of an fMRI-inspired EEG model of limbic related activity (Amygdala Electrical-Finger-Print; AmygEFP-NF), (b) traditional weekly individual psychotherapy, (c) skills group. Before and after NF training period patient was blindly assessed for PTSD symptoms, followed by a 1, 3- and 6-months self-report follow-up. We demonstrate mechanisms of change as well as the clinical effectiveness of adjunctive treatment as indicated by reduced PTSD symptoms and improved daily functioning within this single case.Conclusions: We outline an integrative neuropsychological framework for understanding the unique mechanisms of change conferring value to conjoining NF applications with trauma-focused psychotherapy in complex PTSD