Faculty Bibliography

Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.

Epigenetic mechanisms play a role in the detrimental effects of traumatic stress and the development of post-traumatic stress disorder (PTSD). However, it is unknown whether successful treatment of PTSD restores these epigenetic marks. This study investigated longitudinal changes of blood-based genome-wide DNA methylation levels in relation to trauma-focused psychotherapy for PTSD in soldiers that obtained remission (N = 21), non-remitted PTSD patients (N = 23), and trauma-exposed military controls (N = 23). In an independent prospective cohort, we then examined whether these DMRs were also relevant for the development of deployment-related PTSD (N = 85). Successful treatment of PTSD was accompanied by significant changes in DNA methylation at 12 differentially methylated regions (DMRs) in the genes: APOB, MUC4, EDN2, ZFP57, GPX6, CFAP45, AFF3, TP73, UBCLP1, RPL13P, and two intergenic regions (p values < 0.0001 were confirmed using permutation and sensitivity analyses). Of the 12 DMRs related to PTSD symptom reduction, consistent prospective evidence was found for ZFP57 methylation changes related to changing PTSD symptoms (B = -0.84, t = -2.49, p = 0.014). Increasing ZFP57 methylation related to PTSD symptom reduction was present over and above the relation with symptoms, suggesting that psychological treatments exert biological effects independent of symptom reduction. Together, these data provide longitudinal evidence that ZFP57 methylation is involved in both the development and successful treatment of deployment-related PTSD. This study is a first step to disentangle the interaction between psychological and biological systems to identify genomic regions relevant for the etiology and treatment of stress-related disorders such as PTSD.

BACKGROUND:Heart Rate Variability Biofeedback (HRVB) is a treatment in which patients learn self-regulation of a physiological dysregulated vagal nerve function. While the therapeutic approach of HRVB is promising for a variety of disorders, it has not yet been regularly offered in a mental health treatment setting. AIM:To provide a systematic review about the efficacy of HRV-Biofeedback in treatment of anxiety, depression, and stress related disorders. METHOD:Systematic review in PubMed and Web of Science in 2020 with terms HRV, biofeedback, Post-Traumatic Stress Disorder (PTSD), depression, panic disorder, and anxiety disorder. Selection, critical appraisal, and description of the Random Controlled Trials (RCT) studies. Combined with recent meta-analyses. RESULTS:The search resulted in a total of 881 studies. After critical appraisal, nine RCTs have been selected as well as two other relevant studies. The RCTs with control groups treatment as usual, muscle relaxation training and a "placebo"-biofeedback instrument revealed significant clinical efficacy and better results compared with control conditions, mostly significant. In the depression studies average reduction at the Beck Depression Inventory (BDI) scale was 64% (HRVB plus Treatment as Usual (TAU) versus 25% (control group with TAU) and 30% reduction (HRVB) at the PSQ scale versus 7% (control group with TAU). In the PTSD studies average reduction at the BDI-scale was 53% (HRV plus TAU) versus 24% (control group with TAU) and 22% (HRVB) versus 10% (TAU) with the PTSD Checklist (PCL). In other systematic reviews significant effects have been shown for HRV-Biofeedback in treatment of asthma, coronary artery disease, sleeping disorders, postpartum depression and stress and anxiety. CONCLUSION:This systematic review shows significant improvement of the non-invasive HRVB training in stress related disorders like PTSD, depression, and panic disorder, in particular when combined with cognitive behavioral therapy or different TAU. Effects were visible after four weeks of training, but clinical practice in a longer daily self-treatment of eight weeks is more promising. More research to integrate HRVB in treatment of stress related disorders in psychiatry is warranted, as well as research focused on the neurophysiological mechanisms.

Only a few studies have investigated the welfare of animals participating in animal-assisted interventions (AAIs). Most of these studies focus on dogs in therapeutic settings. There are, however, also dogs-service dogs-that are employed to continuously support a single human. Because the welfare of these service dogs is important for the sustainability of their role, the aim of this study was to investigate their stress response to service dog training sessions. To do this, we took repeated salivary cortisol samples from dogs who participated in a training session (n = 19). Samples were taken just after arrival at the training ground, before training, after training, and after a period of free play. Our results showed that mean cortisol levels in all samples were relatively low (between 1.55 ± 1.10 and 2.73 ± 1.47 nmol/L) compared to similar studies. Analysis further showed that samples taken before and after participation in the training's session did not differ from one another. Mean cortisol levels in both situations were additionally lower than those upon arrival at the training site and after a period of free play. This led to the conclusion that the dogs in our study did not seem to experience training as stressful.

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

Background: A novel intervention, Multi-modular motion-assisted memory desensitization and reconsolidation (3MDR), aims to reduce avoidance and improve engagement for patients with posttraumatic stress disorder (PTSD) who did not sufficiently respond to previous treatments. It has been found to effectively reduce PTSD symptoms for veterans with treatment-resistant PTSD. Symptomatic measures alone might not capture all treatment effects, and addition of qualitative outcomes may provide deeper understanding of treatment processes and treatment-induced changes. Objective: To study the perspectives of veterans with treatment-resistant PTSD on 3MDR treatment processes and effects and explore the relation of their experiences to PTSD symptom improvement. Method: A convergent parallel mixed methods design was applied. For the qualitative part, open-ended question interviews were conducted until data saturation was reached (N = 10). Thematic analysis, rooted in grounded theory, was performed. Quantitative data included pre- to posttreatment responder status based on a structured clinical interview for PTSD. Results: Treatment processes endorsed by the veterans were engaging, regulating distress, feeling supported, facing traumatic memories, allowing emotions, associating, and disengaging from trauma. In terms of effects, veterans reported positive changes following 3MDR, including openness, new learning, self-understanding, closure, and reintegration. High comparability across themes was observed for responders and non-responders, except for the themes closure and reintegration, which were reported more often or more in depth by responders. Conclusions: Veterans indicated 3MDR treatment processes that complied with its aims of breaking through avoidance and increasing engagement, thereby facilitating traumatic memory retrieval and processing. However, this did not necessarily translate into PTSD symptom improvement for all veterans. Walking towards trauma-related pictures was highlighted as unique component of 3MDR and connected to specific treatment processes and effects. Positive changes following 3MDR were experienced outside the domain of PTSD symptom improvement, implicating that 3MDR may beneficially impact veterans beyond symptom changes alone.

BACKGROUND:Military members are at elevated risk of operational stress injuries, including posttraumatic stress disorder (PTSD) and moral injury. Although psychotherapy can reduce symptoms, some military members may experience treatment-resistant PTSD. Multimodular motion-assisted memory desensitization and reconsolidation (3MDR) has been introduced as a virtual reality (VR) intervention for military members with PTSD related to military service. The 3MDR intervention incorporates exposure therapy, psychotherapy, eye movement desensitization and reconsolidation, VR, supportive counselling, and treadmill walking. OBJECTIVE:The objective of this study is to investigate whether 3MDR reduces PTSD symptoms among military members with combat-related treatment-resistant PTSD (TR-PTSD); examine the technology acceptance and usability of the Computer Assisted Rehabilitation ENvironment (CAREN) and 3MDR interventions by Canadian Armed Forces service members (CAF-SMs), veterans, 3MDR clinicians, and operators; and evaluate the impact on clinicians and operators of delivering 3MDR. METHODS:This is a mixed-methods waitlist controlled crossover design randomized controlled trial. Participants include both CAF-SMs and veterans (N=40) aged 18-60 years with combat-related TR-PTSD (unsuccessful experience of at least 2 evidence-based trauma treatments). Participants will also include clinicians and operators (N=12) who have been trained in 3MDR and subsequently utilized this intervention with patients. CAF-SMs and veterans will receive 6 weekly 90-minute 3MDR sessions. Quantitative and qualitative data will be collected at baseline and at 1, 3, and 6 months postintervention. Quantitative data collection will include multiomic biomarkers (ie, blood and salivary proteomic and genomic profiles of neuroendocrine, immune-inflammatory mediators, and microRNA), eye tracking, electroencephalography, and physiological data. Data from outcome measures will capture self-reported symptoms of PTSD, moral injury, resilience, and technology acceptance and usability. Qualitative data will be collected from audiovisual recordings of 3MDR sessions and semistructured interviews. Data analysis will include univariate and multivariate approaches, and thematic analysis of treatment sessions and interviews. Machine learning analysis will be included to develop models for the prediction of diagnosis, symptom severity, and treatment outcomes. RESULTS:This study commenced in April 2019 and is planned to conclude in April 2021. Study results will guide the further evolution and utilization of 3MDR for military members with TR-PTSD and will have utility in treating other trauma-affected populations. CONCLUSIONS:The goal of this study is to utilize qualitative and quantitative primary and secondary outcomes to provide evidence for the effectiveness and feasibility of 3MDR for treating CAF-SMs and veterans with combat-related TR-PTSD. The results will inform a full-scale clinical trial and stimulate development and adaptation of the protocol to mobile VR apps in supervised clinical settings. This study will add to knowledge of the clinical effectiveness of 3MDR, and provide the first comprehensive analysis of biomarkers, technology acceptance and usability, moral injury, resilience, and the experience of clinicians and operators delivering 3MDR. TRIAL REGISTRATION/BACKGROUND:ISRCTN Registry 11264368; http://www.isrctn.com/ISRCTN11264368. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)/UNASSIGNED:DERR1-10.2196/20620.

INTRODUCTION/BACKGROUND:Interest in the use of psychedelic substances for the treatment of mental disorders is increasing. Processes that may affect therapeutic change are not yet fully understood. Qualitative research methods are increasingly used to examine patient accounts; however, currently, no systematic review exists that synthesizes these findings in relation to the use of psychedelics for the treatment of mental disorders. OBJECTIVE:To provide an overview of salient themes in patient experiences of psychedelic treatments for mental disorders, presenting both common and diverging elements in patients' accounts, and elucidating how these affect the treatment process. METHODS:We systematically searched the PubMed, MEDLINE, PsycINFO, and Embase databases for English-language qualitative literature without time limitations. Inclusion criteria were qualitative research design; peer-reviewed studies; based on verbalized patient utterances; and a level of abstraction or analysis of the results. Thematic synthesis was used to analyze and synthesize results across studies. A critical appraisal of study quality and methodological rigor was conducted using the Critical Appraisal Skills Programme (CASP). RESULTS:Fifteen research articles, comprising 178 patient experiences, were included. Studies exhibited a broad heterogeneity in terms of substance, mental disorder, treatment context, and qualitative methodology. Substances included psilocybin, lysergic acid diethylamide (LSD), ibogaine, ayahuasca, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Disorders included anxiety, depression, eating disorders, post-traumatic stress disorder, and substance use disorders. While the included compounds were heterogeneous in pharmacology and treatment contexts, patients reported largely comparable experiences across disorders, which included phenomenological analogous effects, perspectives on the intervention, therapeutic processes and treatment outcomes. Comparable therapeutic processes included insights, altered self-perception, increased connectedness, transcendental experiences, and an expanded emotional spectrum, which patients reported contributed to clinically and personally relevant responses. CONCLUSIONS:This review demonstrates how qualitative research of psychedelic treatments can contribute to distinguishing specific features of specific substances, and carry otherwise undiscovered implications for the treatment of specific psychiatric disorders.