PROJECT SUMMARY The goal of the Butler Hospital COBRE Center for Neuromodulation parent award is to support interdisciplinary clinical-translational brain research by creating the key infrastructure to support the careers of interdisciplinary investigators with as overall objective to advance the use of noninvasive neuromodulation in circuit-based therapies for neuropsychiatric disorders, including posttraumatic stress disorder. In doing so, the COBRE Center for Neuromodulation addresses the pressing need for innovative and effective treatments for people struggling with psychiatric disorders. The current proposal builds upon this overarching objective. Specifically, the proposed administrative supplement aims to test the feasibility and acceptability of a four-week course of noninvasive cranial electrotherapy stimulation (CES) as well as establish an early signal of CES effects on homeostatic functioning in a sample of firefighter first responders. Firefighters are at ultra-high risk for developing posttraumatic stress disorder due to the nature of their occupation which has both dire personal as well as economic, workforce- related consequences. Therefore, there is an urgent need for an effective preventative intervention for posttraumatic stress disorder. This is scientifically challenging, and current intervention strategies that aim to prevent the development of posttraumatic stress disorder have either had little to modest success (e.g., pharmacotherapy) or are unrealistic to implement when the source of trauma is one's occupation and thus unavoidable (e.g., psychotherapy). The repeated exposure to traumatic events regularly faced by firefighters puts them at risk for homeostatic dysregulation, contributing to the pathogenesis of posttraumatic stress disorder. CES is thought to reestablish physiological homeostasis, thus reducing the negative consequences of (repeated) traumatic stress. However, despite literature on CES effectiveness to improve symptoms of anxiety, insomnia, and depression, the mechanism of CES effects on homeostatic functioning remains rather hypothetical with little direct evidence to date. In addition, the application of CES should be carefully integrated with firefighter work schedules. Even though CES carries little to no side effects and can be done safely outside the clinic, its usage would be restricted to off-duty days which raises important questions about CES feasibility and acceptability in firefighters. Ultimately, the long-term goal of this line of work is to develop an effective, easily deployable, proactive intervention to prevent the development of posttraumatic stress disorder in first responders. To test feasibility, acceptability, and early signal of CES homeostasis, we have assembled a collaborative partnership between investigators of the Butler Hospital COBRE for Neuromodulation and the Rhode Island Hospital COBRE on Opioids and Overdose. Both the COBRE for Neuromodulation and the COBRE on Opioids and Overdose are in Rhode Island within a 10-minute driving distance. This proximity permits a close partnership between investigators. The proposed complimentary and interdisciplinary team will leverage expertise on the pathogenesis of posttraumatic stress disorder and methodological strengths from the fields of psychiatry (Dr. Fukuda), cognitive neuropsychiatry (Dr. van ’t Wout-Frank), and clinical psychology (Dr. Weiss) to propose the use of CES as a novel approach to posttraumatic stress disorder prevention. Dr. Fukuda, Principal Investigator on a pilot project supported through the COBRE Center for Neuromodulation, and Dr. van ’t Wout-Frank, Project Leader within the COBRE Center for Neuromodulation, provide the expertise in posttraumatic stress disorder, infrastructure to support the administration of CES as a noninvasive brain stimulation technique, and in assessing its effects via measuring brain activity and (psycho)physiology, including the stress hormone cortisol and heart rate variability. However, the COBRE Center for Neuromodulation at Butler Hospital does not currently include investigators with the combined expertise in posttraumatic stress disorder and advanced skills to assess the effects of noninvasive brain stimulation techniques in a naturalistic and near real-time manner. This additional critical expertise comes from Dr. Weiss, a Project Leader affiliated with the COBRE on Opioids and Overdose through Rhode Island Hospital, who will lead the implementation of ecological momentary assessments to naturalistically and in near real-time assess the effects of CES. This team is uniquely poised to preliminarily, yet comprehensively, assess whether and how CES would be beneficial for prevention of posttraumatic stress disorder based on ecological monitoring of subjective (i.e., negative and positive affect, fatigue) and objective biometric indices of stress responses (i.e., heart rate variability, cortisol, quality of sleep) and neural circuit changes (i.e., thalamic functioning and default mode network structural and functional connectivity). The proposed project allows the building and strengthening of new collaborations between investigators from two distinct Centers of Biomedical Research Excellence to expand and strengthen scientific resources and expertise for future grant submissions to address the critical need to prevent posttraumatic stress disorder in those in high-risk occupations such as firefighter first responders.

PROJECT NARRATIVE Despite an urgent need for interventions that can prevent the development of posttraumatic stress disorder (PTSD) in firefighter first responders who, due to the nature of their occupation, are at ultrahigh risk for PTSD and its profound consequences, current preventative approaches suffer from low rates of efficacy or difficulties with implementation. Cranial electrotherapy stimulation (CES), a noninvasive brain stimulation technique that is FDA approved for treatment of anxiety, insomnia, and depression, offers substantial promise as a proactive preventative intervention for PTSD because of its hypothesized ability to reestablish homeostasis, a process that becomes dysregulated in individuals who develop PTSD. The proposed study is an administrative supplement that combines the unique strengths and knowledge of a complimentary team of scientists from two distinct Centers of Biomedical Research Excellence to test whether CES is feasible and acceptable in firefighters as well as obtain early signal of CES efficacy to change subjective and objective indices of homeostatic functioning to allow a long-term collaboration with the ultimate goal to develop a safe, effective, and easily deployable intervention to prevent PTSD in first responders.