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Background: As Posttraumatic stress disorder (PTSD) in adolescents significantly impacts their well-being, effective treatment is of great importance. Little is known, however, about the novel, multi-modal virtual reality supported, exposure-based psychotherapeutic interventions such as 3MDR in this population. Objective: To describe the 3MDR treatment of an adolescent with PTSD who did not respond to previous exposure-based PTSD interventions. Method: A 14-year-old girl diagnosed with PTSD received six sessions of 3MDR embedded in family therapy. Result: The patient tolerated the 3MDR intervention very well. Personalized music and self-selected pictures appeared to be a good fit, contributing to enhanced engagement in and adherence to the therapy. She no longer met criteria for PTSD post-intervention, and at 18 months follow-up. Conclusion: This case report suggests that 3MDR has potential as a trauma treatment for adolescents with treatment-resistant PTSD. Trauma-focused therapy for youngsters is often complicated, with a high percentage of dropouts. Elements of 3MDR such as walking, self-selected pictures, and personalized music are a good fit, contributing to enhanced engagement in and adherence to 3MDR therapy. 3MDR has potential as a trauma treatment for adolescents with treatment-resistant PTSD. [ABSTRACT FROM AUTHOR]

Objective: Military members and veterans are at elevated risk of treatment‐resistant posttraumatic stress disorder (TR‐PTSD) due to higher rates of exposure to potentially traumatic events during the course of duty. Knowledge of TR‐PTSD is limited, and specific protocols or evidence‐based TR‐PTSD therapies are lacking. Multimodal motion‐assisted memory desensitization and reconsolidation (3MDR) therapy is an emerging intervention for combat‐related TR‐PTSD. The purpose of this study was to preliminarily assess the effectiveness of 3MDR in addressing TR‐PTSD in Canadian military members and veterans. Methods: This study is a longitudinal mixed‐methods clinical trial. English‐speaking military members and veterans aged 18–60 with TR‐PTSD were recruited to participate. The intervention consisted of six sessions of 3MDR therapy. Quantitative data were collected pretreatment, posttreatment, and longitudinally at 1, 3, and 6 months after completion of 3MDR. Results: Results from the first 11 participants to complete the 3MDR protocol exhibited statistically significant improvement (surviving multiple comparison correction) in clinically administered and self‐reported scores for PTSD (CAPS‐5 and PCL‐5), moral injury (MISS‐M‐SF), depression (PHQ‐9), anxiety (GAD‐7), emotional regulation (DERS‐18), and resilience (CD‐RS‐25). Conclusion: The preliminary and exploratory results from this clinical trial support the growing body of literature illustrating 3MDR as an effective treatment for military‐related TR‐PTSD. These results are notable given participants' previous lack of success with frontline psychotherapeutic and pharmacological interventions. Given that there are currently very limited treatment options for TR‐PTSD, 3MDR could prove to be a valuable treatment option for military members and veterans with TR‐PTSD. [ABSTRACT FROM AUTHOR]

Background: In recent years, the delivery of evidence-based therapies targeting posttraumatic stress disorder (PTSD) has been the focus of the Departments of Defense in countries such as Canada, the Netherlands, and the United States. More than 66% of military members continue to experience symptoms of PTSD that significantly impact their daily functioning and quality of life after completing evidence-based treatments. Innovative, engaging, and effective treatments for PTSD are needed. Multimodal motion-assisted memory desensitization and reconsolidation (3MDR) is an exposure-based, virtual reality–supported therapy used to treat military members and veterans with treatment-resistant PTSD. Given the demonstrated efficacy of 3MDR in recently published randomized control trials, there is both an interest in and a need to adapt the intervention to other populations affected by trauma and to improve accessibility to the treatment. Objective: We aimed to further innovate, develop, and validate new and existing hardware and software components of 3MDR to enhance its mobility, accessibility, feasibility, and applicability to other populations affected by trauma, including public safety personnel (PSP), via international collaboration. Methods: This study used a modified Delphi expert consultation method and mixed methods quasi-experimental validation with the purpose of software validation among PSP (first responders, health care providers) participants (N=35). A team of international experts from the Netherlands, the United States, and Canada met on the web on a weekly basis since September 2020 to discuss the adoption of 3MDR in real-world contexts, hardware and software development, and software validation. The evolution of 3MDR hardware and software was undertaken followed by a mixed methods software validation study with triangulation of results to inform the further development of 3MDR. Results: This study resulted in the identification, description, and evolution of hardware and software components and the development of new 3MDR software. Within the software validation, PSP participants widely acknowledged that the newly developed 3MDR software would be applicable and feasible for PSP affected by trauma within their professions. The key themes that emerged from the thematic analysis among the PSP included the desire for occupationally tailored environments, individually tailored immersion, and the applicability of 3MDR beyond military populations. Conclusions: Within the modified Delphi consultation and software validation study, support for 3MDR as an intervention was communicated. PSP participants perceived that 3MDR was relevant for populations affected by trauma beyond military members and veterans. The resulting hardware and software evolution addressed the recommendations and themes that arose from PSP participants. 3MDR is a novel, structured, exposure-based, virtual reality–supported therapy that is currently used to treat military members and veterans with PTSD. Going forward, it is necessary to innovate and adapt 3MDR, as well as other trauma interventions, to increase effectiveness, accessibility, cost-effectiveness, and efficacy among other populations affected by trauma. [ABSTRACT FROM AUTHOR]

Background As provisions of mental healthcare services to military and veteran populations increases the risk to service providers developing secondary traumatic stress (STS), efforts are needed to examine the impact of delivering novel interventions which may include 3MDR. As a virtual-reality supported intervention, 3MDR exposes the patient, therapist and operator to graphic and sensory stimuli (i.e. narratives, imagery, smells, and music) in the course of the intervention. 3MDR is actively being researched at multiple sites internationally within military and veteran populations. It is, therefore, crucial to ensure the safety and wellbeing of 3MDR therapists and operators who are exposed to potentially distressing sensory stimuli. Objective The purpose of this study is to qualitatively examine the impact and experiences of STS amongst therapists and operators in delivering 3MDR. For this study, impact will be defined as therapists or operators experiencing perceived STS as a result of delivering 3MDR. Methods This exploratory qualitative study recruited 3MDR therapists and operators (N = 18) from Canada, the Netherlands, the United Kingdom, and the United States who had previously delivered 3MDR therapy. Telephone or video-conferencing interviews were used to gather data that was subsequently transcribed and thematically analyzed. Results Four themes emerged among the therapists (n = 13) and operators (n = 5): (1) personal cost and benefits of 3MDR, (2) professional paradox of a 3MDR therapist, (3) perceived effect of 3MDR on patients, and (4) recommendations for future 3MDR use. Conclusions STS was not noted to be a significant challenge for 3MDR therapists and operators. Future research may investigate optimal means of providing training and ongoing support for 3MDR therapists and operators. HIGHLIGHTS Secondary Traumatic Stress was not noted to be a significant challenge for 3MDR therapists and operators Future research may investigate optimal means of providing training and ongoing support for 3MDR therapists and operators

Background: Military members and veterans exhibit higher rates of injuries and illnesses such as posttraumatic stress disorder (PTSD) because of their increased exposure to combat and other traumatic scenarios. Novel treatments for PTSD are beginning to emerge and increasingly leverage advances in gaming and other technologies, such as virtual reality. Without assessing the degree of technology acceptance and perception of usability to the end users, including the military members, veterans, and their attending therapists and staff, it is difficult to determine whether a technology-based treatment will be used successfully in wider clinical practice. The Unified Theory of Acceptance and Use of Technology model is commonly used to address the technology acceptance and usability of applications in 5 domains. Objective: Using the Unified Theory of Acceptance and Use of Technology model, the purpose of this study was to determine the technology acceptance and usability of multimodal motion-assisted memory desensitization and reconsolidation (3MDR) on a virtual reality system in the primary user group (military members and veterans with treatment-resistant PTSD, 3MDR therapists, and virtual reality environment operators). Methods: This mixed methods embedded pilot study included military members (n=3) and veterans (n=8) with a diagnosis of combat-related PTSD, as well as their therapists (n=13) and operators (n=5) who completed pre-post questionnaires before and on completion of 6 weekly sessions of 3MDR. A partial least squares structural equation model was used to analyze the questionnaire results. Qualitative data from the interviews were assessed using thematic analysis. Results: Effort expectancy, which was the most notable predictor of behavioral intention, increased after a course of 3MDR with the virtual reality system, whereas all other constructs demonstrated no significant change. Participants' expectations of the technology were met, as demonstrated by the nonsignificant differences in the pre-post scores. The key qualitative themes included feasibility and function, technical support, and tailored immersion. Conclusions: 3MDR via a virtual reality environment appears to be a feasible, usable, and accepted technology for delivering 3MDR to military members and veterans who experience PTSD and 3MDR therapists and operators who facilitate their treatment. [ABSTRACT FROM AUTHOR]

Copyright of European Journal of Psychotraumatology is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Military members and Veterans are at risk of developing combat-related, treatment-resistant posttraumatic stress disorder (TR-PTSD) and moral injury (MI). Conventional trauma-focused therapies (TFTs) have shown limited success. Novel interventions including Multi-modal Motion-assisted Memory Desensitization and Reconsolidation therapy (3MDR) may prove successful in treating TR-PTSD.Objective: To qualitatively study the experiences of Canadian military members and Veterans with TR-PTSD who received the 3MDR intervention.Methods: This study explored qualitative data from a larger mixed-method waitlist control trial testing the efficacy of 3MDR in military members and veterans. Qualitative data were recorded and collected from 3MDR sessions, session debriefings and follow-up interviews up to 6 months post-intervention; the data were then thematically analyzed.Results: Three themes emerged from the data: (1) the participants' experiences with 3MDR; (2) perceived outcomes of 3MDR; and (3) keys to successful 3MDR treatment. Participants expressed that 3MDR provided an immersive environment, active engagement and empowerment. The role of the therapist as a coach and “fireteam partner” supports the participants' control over their therapy. The multi-modal nature of 3MDR, combining treadmill-walking toward self-selected trauma imagery with components of multiple conventional TFTs, was key to helping participants engage with and attribute new meaning to the memory of the traumatic experience.Discussion: Preliminary thematic analysis of participant experiences of 3MDR indicate that 3MDR has potential as an effective intervention for combat-related TR-PTSD, with significant functional, well-being and relational improvements reported post-intervention.Conclusion: Military members and Veterans are at risk of developing TR-PTSD, with worse outcomes than in civilians. Further research is needed into 3MDR and its use with other trauma-affected populations.

Introduction: Military members and Veterans are at risk of developing combat-related, treatment-resistant posttraumatic stress disorder (TR-PTSD) and moral injury (MI). Conventional trauma-focused therapies (TFTs) have shown limited success. Novel interventions including Multi-modal Motion-assisted Memory Desensitization and Reconsolidation therapy (3MDR) may prove successful in treating TR-PTSD. Objective: To qualitatively study the experiences of Canadian military members and Veterans with TR-PTSD who received the 3MDR intervention. Methods: This study explored qualitative data from a larger mixed-method waitlist control trial testing the efficacy of 3MDR in military members and veterans. Qualitative data were recorded and collected from 3MDR sessions, session debriefings and follow-up interviews up to 6 months post-intervention; the data were then thematically analyzed. Results: Three themes emerged from the data: (1) the participants' experiences with 3MDR; (2) perceived outcomes of 3MDR; and (3) keys to successful 3MDR treatment. Participants expressed that 3MDR provided an immersive environment, active engagement and empowerment. The role of the therapist as a coach and "fireteam partner" supports the participants' control over their therapy. The multi-modal nature of 3MDR, combining treadmill-walking toward self-selected trauma imagery with components of multiple conventional TFTs, was key to helping participants engage with and attribute new meaning to the memory of the traumatic experience. Discussion: Preliminary thematic analysis of participant experiences of 3MDR indicate that 3MDR has potential as an effective intervention for combat-related TR-PTSD, with significant functional, well-being and relational improvements reported post-intervention. Conclusion: Military members and Veterans are at risk of developing TR-PTSD, with worse outcomes than in civilians. Further research is needed into 3MDR and its use with other trauma-affected populations. [ABSTRACT FROM AUTHOR]

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.

Some post-traumatic stress disorder (PTSD) patients do not benefit from imaginal exposure therapy. One possible approach to reach such patients are virtual trauma interventions. Herein, a qualitative scoping review was conducted. Different types of virtual trauma exposure interventions were identified. For each type of virtual trauma exposure interventions it was examined in detail: (1) which in sensu trauma exposure approach serves as therapeutic framework, how it was transferred into virtual reality, and if it was manualized; (2) which hardware and software were used; (3) whether the influence of spatial and social presence on the efficacy of virtual trauma interventions have been measured, and (4) whether the efficacy of virtual trauma interventions for PTSD patients having imagination difficulties was evaluated. These research questions were analyzed qualitatively. Accordingly, an extensive literature search was conducted using the databases Web of Science, PsycINFO, LIVIVO, PTSDpubs, and PubMed for scientific articles published between January 2013 and July 2020. Only studies aimed to reduce PTSD symptoms using virtual trauma interventions were included. The literature search was not limited to a specific study design, treatment/intervention method, or a minimum sample size. Eighteen studies were identified, which reported three different virtual trauma intervention approaches, namely, virtual reality exposure therapy (VRET), multi-modular motion-assisted memory desensitization and reconsolidation (3MDR), and action-centered exposure therapy (ACET). Seven randomized controlled trials (RCTs), two pilot studies, and one case study were focused on VRET; while two RCTs, one pilot study, and three case studies focused on 3MDR, and two case studies on ACET. Regarding the first research question (1), the results show that VRET is based on prolonged exposure, aiming for a virtual re-creation of the patient's traumatic recounting. Several treatment protocols exist for VRET. 3MDR is based on eye movement desensitization and reprocessing, aiming to reduce the patient's avoidance behavior. In 3MDR patients walk toward individualized trauma-related symbolic images in a cave automatic virtual environment (CAVE). One treatment protocol exists for 3MDR. ACET is based on the inhibitory learning theory, aiming for active interactions with a virtual trauma-associated environment to alter the anxiety structure through new secondary inhibitory learning. One treatment protocol exists for ACET. For the second research question (2), the results indicate that all VRET studies used head-mounted displays (HMDs) with a virtual version of the Iraq/Afghanistan or the World Trade Center attacks, while 3MDR studies utilized two different versions of a CAVE with personalized trauma-related images, and the ACET studies used HMDs with virtual street scenarios. For the third research question (3), the results demonstrate that the influence of spatial or social presence on the efficacy of virtual trauma interventions was not examined in any of the included studies. Similarly, for the fourth research question (4), the results show that empirical evidence for the efficacy of virtual trauma interventions on PTSD patients having imagination difficulties was lacking. Therefore, such empirical studies are needed to fill these research gaps.

Some post-traumatic stress disorder (PTSD) patients do not benefit from imaginal exposure therapy. One possible approach to reach such patients are virtual trauma interventions. Herein, a qualitative scoping review was conducted. Different types of virtual trauma exposure interventions were identified. For each type of virtual trauma exposure interventions it was examined in detail: (1) which in sensu trauma exposure approach serves as therapeutic framework, how it was transferred into virtual reality, and if it was manualized; (2) which hardware and software were used; (3) whether the influence of spatial and social presence on the efficacy of virtual trauma interventions have been measured, and (4) whether the efficacy of virtual trauma interventions for PTSD patients having imagination difficulties was evaluated. These research questions were analyzed qualitatively. Accordingly, an extensive literature search was conducted using the databases Web of Science, PsycINFO, LIVIVO, PTSDpubs, and PubMed for scientific articles published between January 2013 and July 2020. Only studies aimed to reduce PTSD symptoms using virtual trauma interventions were included. The literature search was not limited to a specific study design, treatment/intervention method, or a minimum sample size. Eighteen studies were identified, which reported three different virtual trauma intervention approaches, namely, virtual reality exposure therapy (VRET), multi-modular motion-assisted memory desensitization and reconsolidation (3MDR), and action-centered exposure therapy (ACET). Seven randomized controlled trials (RCTs), two pilot studies, and one case study were focused on VRET; while two RCTs, one pilot study, and three case studies focused on 3MDR, and two case studies on ACET. Regarding the first research question (1), the results show that VRET is based on prolonged exposure, aiming for a virtual re-creation of the patient's traumatic recounting. Several treatment protocols exist for VRET. 3MDR is based on eye movement desensitization and reprocessing, aiming to reduce the patient's avoidance behavior. In 3MDR patients walk toward individualized trauma-related symbolic images in a cave automatic virtual environment (CAVE). One treatment protocol exists for 3MDR. ACET is based on the inhibitory learning theory, aiming for active interactions with a virtual trauma-associated environment to alter the anxiety structure through new secondary inhibitory learning. One treatment protocol exists for ACET. For the second research question (2), the results indicate that all VRET studies used head-mounted displays (HMDs) with a virtual version of the Iraq/Afghanistan or the World Trade Center attacks, while 3MDR studies utilized two different versions of a CAVE with personalized trauma-related images, and the ACET studies used HMDs with virtual street scenarios. For the third research question (3), the results demonstrate that the influence of spatial or social presence on the efficacy of virtual trauma interventions was not examined in any of the included studies. Similarly, for the fourth research question (4), the results show that empirical evidence for the efficacy of virtual trauma interventions on PTSD patients having imagination difficulties was lacking. Therefore, such empirical studies are needed to fill these research gaps. [ABSTRACT FROM AUTHOR]

Hypothalamic-pituitary-adrenal axis functioning has been related to treatment outcome in posttraumatic stress disorder (PTSD). Previous studies have primarily focused on cortisol levels before and after a course of therapy and findings have not been fully consistent. This study investigated session-related cortisol levels in veterans with treatment-resistant PTSD over the course of a novel motion-assisted virtual reality exposure therapy and aimed to determine whether cortisol levels were related to changes in PTSD symptom severity. Veterans (N = 22) received six exposure sessions during which salivary cortisol samples were collected pre-session, post-session and in the late afternoon following sessions. PTSD symptom severity was assessed by structured clinical interviews at pre- and post-treatment. Average cortisol levels were compared between responders and non-responders. Linear regression analyses were conducted with PTSD symptom change as criterion variable, average cortisol levels as predictor, and timing of sampling and baseline PTSD symptoms as covariates. Responders to treatment tended to have higher average cortisol levels at pre-session (p = 0.064) and post-session (p = 0.050) compared to non-responders. Higher average pre-session and post-session cortisol levels predicted greater PTSD symptom improvement (pre: b = −1.83, p = 0.009; post: b = −3.57, p = 0.004). This study provides preliminary evidence for session-related cortisol as biomarker of response to exposure-based therapies for PTSD. Higher cortisol levels may have facilitated fear extinction and reconsolidation, and may indicate increased physiological stress activation necessary for appropriate treatment engagement. Further work involving comparable methodology is encouraged to establish session-related cortisol as biomarker and to determine the mechanisms through which it interacts with treatment outcome. [ABSTRACT FROM AUTHOR]

Objective: To explore the potential efficacy of multi‐modular motion‐assisted memory desensitization and reprocessing (3MDR) in British military veterans with treatment‐resistant service‐related PTSD. Methods: Exploratory single‐blind, randomized, parallel arm, cross‐over controlled trial with nested process evaluation to assess fidelity, adherence and factors that influence outcome. Results: A total of 42 participants (all male) were randomized with 83% retention at 12 weeks and 86% at 26 weeks. The difference in mean Clinician‐Administered PTSD Scale for DSM‐5 scores between the immediate and delayed 3MDR arms was −9.38 (95% CI −17.33 to −1.44, P = 0.021) at 12 weeks and −3.59 (−14.39 to 7.20, P = 0.513) at 26 weeks when both groups had received 3MDR. The likely effect size of 3MDR was found to be 0.65. Improvements were maintained at 26‐week follow‐up. 3MDR was found to be acceptable to most, but not all, participants. Several factors that may impact efficacy and acceptability of 3MDR were identified. Conclusion: 3MDR is a promising new intervention for treatment‐resistant PTSD with emerging evidence of effect. [ABSTRACT FROM AUTHOR]

Copyright of European Journal of Psychotraumatology is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Although the symptoms of Post-Traumatic Stress Disorder (PTSD) in the general and military population seem very similar, combat-related PTSD (cr-PTSD) is typically thought to be more severe due to the repeated and prolonged exposure of traumatic events. Therapeutic adherence is reported a problem in military populations compromising treatment efficacy. Therefore, a new potential supplementary treatment is specially designed for patients with cr-PTSD. This intervention is called Military Motion Memory Desensitization and Reprocessing (3MDR). The treatment incorporates key elements of successful treatments as Virtual Reality Exposure (VRE) and Eye Movement Desensitization Reprocessing (EMDR) and adds motion to the condition. We aimed at designing a treatment procedure that preserved dual task processing principle, yet introduced new engagement by performing the desensitization during motion by to walking on a treadmill. Moreover, we aimed at exposure to real high-affect pictures of deployment setting. Subjects walk a repetitive cycle while walking and viewing high affect pictures of deployment scenes. Dual task processing was maintained by an oscillating ball. Aspects of presence are adhered to, to maximize possible positive outcome. METHOD: Two veterans with chronic PTSD, received four weekly sessions of 3MDR therapy. The indicator of effectiveness was difference in CAPS (Clinical Administrated PTSD Scale)-score. The treatment was designed on the Computer Assisted Rehabilitation Environment (CAREN) facility. RESULTS: The 3MDR treatment did further decrease PTSD symptoms. Patients were highly satisfied about the treatment and had no attention to drop out. CONCLUSION: The results of the two cases suggest that the 3MDR treatment is a successful, more additional treatment that goes further into the patients affect where other treatment may stagnate. The presence was highly appreciated. Further research with more patients needs to be performed to obtain more reliable results. [ABSTRACT FROM AUTHOR]

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: ISRCTN Registry 11264368; http://www.isrctn.com/ISRCTN11264368., International Registered Report Identifier (irrid): DERR1-10.2196/20620., (©Chelsea Jones, Lorraine Smith-MacDonald, Antonio Miguel-Cruz, Ashley Pike, Marieke van Gelderen, Liana Lentz, Maria Y Shiu, Emily Tang, Jeffrey Sawalha, Andrew Greenshaw, Shawn G Rhind, Xin Fang, Adrian Norbash, Rakesh Jetly, Eric Vermetten, Suzette Brémault-Phillips. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 29.10.2020.)