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 hippocampus 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.

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

Treatment 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.

Self-neuromodulation procedures that regulates limbic-related activity in adjunction to therapy show clinical effectivity in complex PTSD.We present an integrative perspective of neurofeedback embedded in psychotherapy, illustrated by a single case report.A single case provides an illustration of the potential utility of multifaced treatment including psychotherapy with adjunctive neurofeedback.

Amygdala-related electroencephalogram neurofeedback as add-on therapy for treatment-resistant childhood sexual abuse posttraumatic stress disorder: feasibility study.

AIM: Childhood sexual abuse (CSA) among women is an alarmingly prevalent traumatic experience that often leads to debilitating and treatment-refractory posttraumatic stress disorder (PTSD), raising the need for novel adjunctive therapies. Neuroimaging investigations systematically report that amygdala hyperactivity is the most consistent and reliable neural abnormality in PTSD and following childhood abuse, raising the potential of implementing volitional neural modulation using neurofeedback (NF) aimed at down-regulating amygdala activity. This study aimed to reliably probe limbic activity but overcome the limited applicability of functional magnetic resonance imaging (fMRI) NF by using a scalable electroencephalogram NF probe of amygdala-related activity, termed amygdala electrical-finger-print (amyg-EFP) in a randomized controlled trial. METHOD: Fifty-five women with CSA-PTSD who were in ongoing intensive trauma-focused psychotherapy for a minimum of 1 year but still met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) PTSD criteria were randomized to either 10 add-on sessions of amyg-EFP-NF training (test group) or continuing psychotherapy (control group). Participants were blindly assessed for PTSD symptoms before and after the NF training period, followed by self-reported clinical follow-up at 1, 3, and 6 months, as well as one session of amygdala real-time fMRI-NF before and after NF training period. RESULTS: Participants in the test group compared with the control group demonstrated a marginally significant immediate reduction in PTSD symptoms, which progressively improved during the follow-up period. In addition, successful neuromodulation during NF training was demonstrated. CONCLUSION: This feasibility study for patients with treatment-resistant CSA-PTSD indicates that amyg-EFP-NF is a viable and efficient intervention.

Reduced emotion regulatory selection flexibility in post-traumatic stress disorder: converging performance-based evidence from two PTSD populations.

BACKGROUND: Contemporary views of emotion dysregulation in post-traumatic stress disorder (PTSD) highlight reduced ability to flexibly select regulatory strategies according to differing situational demands. However, empirical evidence of reduced regulatory selection flexibility in PTSD is lacking. Multiple studies show that healthy individuals demonstrate regulatory selection flexibility manifested in selecting attentional disengagement regulatory strategies (e.g. distraction) in high-intensity emotional contexts and selecting engagement meaning change strategies (e.g. reappraisal) in low-intensity contexts. Accordingly, we hypothesized that PTSD populations will show reduced regulatory selection flexibility manifested in diminished increase in distraction (over reappraisal) preference as intensity increases from low to high intensity. METHODS: Study 1 compared student participants with high (N = 22) post-traumatic symptoms (PTS, meeting the clinical cutoff for PTSD) and participants with low (N = 22) post-traumatic symptoms. Study 2 compared PTSD diagnosed women (N = 31) due to childhood sexual abuse and matched non-clinical women (N = 31). In both studies, participants completed a well-established regulatory selection flexibility performance-based paradigm that involves selecting between distraction and reappraisal to regulate negative emotional words of low and high intensity. RESULTS: Beyond demonstrating adequate psychometric properties, Study 1 confirmed that relative to the low PTS group, the high PTS group presented reduced regulatory selection flexibility (p = 0.01, ŋ²â‚š= 0.14). Study 2 critically extended findings of Study 1, in showing similar reduced regulatory selection flexibility in a diagnosed PTSD population, relative to a non-clinical population (p = 0.002, ŋ²â‚š= 0.114). CONCLUSIONS: Two studies provide converging evidence for reduced emotion regulatory selection flexibility in two PTSD populations.

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.

Guilt and Shame are two self-related emotions that often emerge following traumatic events and may contribute to the clinical profile of post-traumatic stress disorder (PTSD).Our framework suggests Guilt and Sham driven phenotypes of post-traumatic psychopathology, associated with two self-processing deficiencies related to specific action or global identity, respectively.The proposed phenotypes may inform neuropsychological treatments aiming to restore dysfunctional neural networks, later to be evident in alleviating Guilt and Shame and improving clinical outcomes.

Neural Indices of Emotion Regulatory Implementation Correlate With Behavioral Regulatory Selection: Proof-of-Concept Investigation.

"Do what you do best" conveys an intuition about the association between ability and preference. In the field of emotion regulation, ability and preference are manifested in two central stages, namely, implementation and selection of regulatory strategies, which to date have been mainly studied separately. Accordingly, the present proof-of-concept study wished to provide preliminary evidence for an association between neural indices of implementation ability and behavioral selection preferences. In this pilot study, participants performed a classic neuroimaging regulatory implementation task that examined their ability (neurally reflected in the degree of amygdala modulation) to execute two central regulatory strategies, namely, attentional distraction and cognitive reappraisal while viewing negative images. Then participants performed a separate, classic behavioral selection task that examined their choice preferences for using distraction and reappraisal while viewing negative images. Confirming our conceptual framework, we found that exclusively for distraction, which has been associated with robust amygdala modulation, a decrease in amygdala activity during implementation (i.e., enhanced ability) was associated with enhanced preference to behaviorally select distraction [r(15) = -0.69, p = 0.004]. These preliminary findings link between two central emotion regulatory stages, suggesting a clue of the adaptive association between neural ability and behavioral preference for particular regulatory strategies.

COVID-19 epidemic-induced changes in mood and anxiety mediate the relationship between resilience and symptoms of depression and generalized anxiety in sexual assault survivors.

BACKGROUND: Sexual assault survivors are a vulnerable sub-population that might be severely affected by the COVID-19 pandemic, yet received little research attention during this global crisis. Higher levels of resilience are generally associated with lower symptoms of depression and anxiety and are thus considered as promoting adjustment to stress. Here, we tested the associations between resilience, depression, and anxiety symptoms among sexual assault survivors during the COVID-19 epidemic. Pandemic-induced changes in mood and anxiety were also examined as potential mediators of the relations between resilience and clinical symptoms of depression and anxiety. METHODS: At the pandemic onset, 83 sexual assault survivors (66 females, average age=37.68±10.90 years) undergoing treatment at a specialized psychiatric outpatient clinic completed a survey aimed at identifying patients in distress during the lockdown. The survey included a battery of questionnaires assessing resilience, pandemic-induced changes in mood and anxiety, and clinical symptoms of depression and generalized anxiety. RESULTS: Resilience scores were significantly negatively correlated with both depression and generalized anxiety symptoms. Furthermore, pandemic-induced changes in mood and anxiety significantly mediated these effects. LIMITATIONS: Due to the cross-sectional study design, a temporal relationship between pandemic induced changes (mood and anxiety) and clinical symptoms (depression and generalized anxiety) could not be determined. CONCLUSIONS: Our findings highlight the need to develop interventions for reducing situational changes in mood and anxiety during periods of acute stress, while increasing resilience factors, in order to decrease the burden of stress on sexual assault survivors' mental health during the pandemic and beyond.

Neurobehavioral moderators of post-traumatic stress disorder (PTSD) trajectories: study protocol of a prospective MRI study of recent trauma survivors.

Background: Post-traumatic stress disorder (PTSD) is triggered by distinct events and is therefore amenable to studies of its early pathogenesis. Longitudinal studies during the year that follows trauma exposure revealed typical symptom trajectories leading to either recovery or protracted PTSD. Thezneurobehavioral correlates of early PTSD symptoms' trajectories have not been longitudinally explored. Objective: To present the rationale and design of a longitudinal study exploring the relationship between evolving PTSD symptoms and co-occurring cognitive functioning and structural and functional brain imaging parameters. Method: Adult civilians consecutively admitted to a general hospital emergency room (ER) for traumatic injury will be screened for early PTSD symptoms suggestive of chronic PTSD risk, and consecutively evaluated 1, 6 and 14 months following the traumatic event. Consecutive assessments will include structured clinical interviews for PTSD and comorbid disorders, self-reported depression and anxiety symptoms, a web-based assessment of cognitive domains previously linked with PTSD (e.g., memory, executive functions, cognitive flexibility), high-resolution structural MRI of both grey and white matter, functional resting-state connectivity, and fMRI tasks examining emotional reactivity and regulation, as well as motivation processing and sensitivity to risk and reward. Data analyses will explore putative cognitive predictors of non-remitting PTSD, and brain structural and functional correlates of PTSD persistence or recovery. Conclusion: This work will longitudinally document patterns of brain structures, connectivity, and functioning, predictive of (or associated with) emerging PTSD during the critical first year of after the traumatic event. It will thereby inform our understanding of the disorder's pathogenesis and underlying neuropathology. Challenges to longitudinal MRI studies of recent survivors, and methodological choices used to optimize the study's design are discussed.

Antecedentes: Los trastornos de estrés postraumático (TEPT) son desencadenados por distintos eventos y son por lo tanto susceptibles para estudios de su patogénesis temprana. Los estudios longitudinales durante el año que sigue la exposición al trauma revelan trayectorias de síntomas típicos que llevan tanto a la recuperación como al TEPT prolongado. Los correlatos neuroconductuales de las trayectorias de los síntomas tempranos del TEPT no han sido explorados longitudinalmente.Objetivo: Se presenta la justificación y el diseño de un estudio longitudinal explorando la relación entre los síntomas del TEPT en evolución y la co-ocurrencia del funcionamiento cognitivo y los parámetros de las imágenes cerebrales estructurales y funcionales.Método: Los adultos civiles ingresados consecutivamente a una sala de emergencia (ER en su sigla en inglés) de un hospital general por lesión traumática serán tamizados por los síntomas tempranos del TEPT sugerentes de riesgo de TEPT crónico, y evaluados consecutivamente a los uno, seis, y catorce meses luego del evento traumático. Las evaluaciones consecutivas incluirán entrevistas clínicas estructuradas para el TEPT y los trastornos comórbidos, auto-reporte de los síntomas de depresión y ansiedad, una evaluación online de los dominios cognitivos vinculados previamente con el TEPT (por ej., memoria, funciones cognitivas, flexibilidad cognitiva), MRI estructural de alta definición para tanto la materia blanca como para la gris, conectividad en estado de descanso funcional, y tareas de MRI funcional (fMRI en su sigla en inglés) examinando la reactividad emocional y la regulación, como también el procesamiento de la motivación y la sensibilidad al riesgo y a la recompensa. Los análisis de los datos explorarán supuestos predictores cognitivos del TEPT no remitidos, y los correlatos estructurales y funcionales del cerebro de la persistencia o recuperación del TEPT.Conclusión: Este trabajo documentará longitudinalmente los patrones de las estructuras cerebrales, conectividad, y predicción funcional de, o asociado con TEPT emergente durante el primer año crítico, luego de un evento traumático. Así, informará nuestro entendimiento de la patogénesis del trastorno y la neuropatología de base. Se discuten los desafíos de los estudios longitudinales de MRI con sobrevivientes recientes, y las decisiones metodológicas usadas para optimizar el diseño del estudio.

Internet-delivered computerized cognitive & affective remediation training for the treatment of acute and chronic posttraumatic stress disorder: Two randomized clinical trials.

Treatment of posttraumatic stress disorder (PTSD) is time and cost-intensive. New, readily implementable interventions are needed. Two parallel randomized clinical trials tested if cognitive/affective computerized training improves cognitive/affective functions and PTSD symptoms in acute (N = 80) and chronic PTSD (N = 84). Adults age 18-65 were recruited from an Israeli hospital emergency room (acute) or from across the United States (chronic). Individuals were randomized to an active intervention (acute N = 50, chronic N = 48) that adaptively trains cognition and an affective positivity bias, or a control intervention (acute N = 30, chronic N = 36) of engaging computer games. Participants, blind to assignment, completed exercises at home for 30 min/day over 30 days (acute) or 45 min/day over 45 days (chronic). Primary outcomes were computerized cognitive/affective function metrics. Secondary outcomes were Clinician-Administered PTSD Scale (CAPS) total scores. In chronic PTSD, the active arm demonstrated facilitated speed of fearful face identification (F = 20.96, q < 0.001; d = 1.21) and a trend towards improvement in total PTSD symptoms (F = 2.91, p = 0.09, d = 0.47), which was due to improvement in re-experiencing symptoms (F = 6.14, p = 0.015; d = 0.73). Better cognitive performance at baseline moderated the training effect and was associated with more favorable improvements on both metrics. Cognitive and affective training does not have widespread benefit on symptoms and cognitive/affective functions in PTSD. Future studies targeting re-experiencing a priori, stratifying on cognitive capacity, and with modified methods to infer on mechanisms and optimized training parameters may be warranted. ClinicalTrials.gov Identifiers: NCT01694316 &NCT02085512.

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.

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.

El período inmediatamente posterior a los eventos traumáticos es un período de mayor plasticidad neuronal, después del cual algunos sobrevivientes siguen con trastorno de estrés postraumático (TEPT) mientras que otros se recuperan. La evidencia señala que las deficiencias en reactividad emocional, regulación de las emociones y funciones ejecutivas más amplias contribuyen de manera crítica al TEPT. La evidencia que comienza a hacer su aparición sugiere además que los mecanismos neuronales que subyacen a estas funciones siguen siendo plásticos en la edad adulta y que la reeducación específica de estos sistemas puede mejorar su eficacia y reducir la probabilidad de desarrollar un TEPT. La administración de entrenamiento neurocognitivo específico poco después de la exposición al trauma es un desafío desalentador. Este trabajo describe un diseño de estudio que aborda ese desafío. El estudio evaluó los efectos directos del entrenamiento en reparación cognitiva sobre los mecanismos neurocognitivos que hipotéticamente subyacen al TEPT y el efecto indirecto de esta intervención en los síntomas de TEPT que surgen. Método: Describimos una justificación para el estudio, unas opciones de diseño y una metodología que implican (a) inscribir a los participantes; (b) implementar y administrar una intervención diaria autoadministrada, basada en la web; (c) detectar y evaluar, de modo oportuno y fiable, el tratamiento de los sobrevivientes que resultan elegibles; y (d) definir las condiciones de control y las medidas de los resultados. Resumimos la justificación de las decisiones que se tomaron con respecto a la muestra del estudio, el momento de la intervención, las mediciones, el seguimiento del compromiso de los participantes y el modo de armonizar y retener la fidelidad de los entrevistadores y mitigar el agotamiento debido al contacto repetido con sobrevivientes recientemente traumatizados. Conclusión: las intervenciones tempranas basadas en la web que se dirigen a los mecanismos que causan el TEPT pueden basarse en el modelo presentado en este documento.