Neurobiological and Psychological Benefits of Exercise in Chronic Pain and PTSD (EXCPPTSD)

The wars in Iraq and Afghanistan are creating a new generation of Veterans, including an increasing number of women Veterans, who present with comorbid PTSD and chronic pain conditions from recent deployment-related physical injuries and exposure to psychological trauma. Health behavior change has become increasingly important in treating these conditions and proactively preventing long-term negative health sequelae, in order to benefit these Veterans directly and reduce the growing challenges to our healthcare system. The proposed CDA-2 program of research will use an innovative translational research approach to study whether a chronic progressive -based exercise program will reduce chronic pain in patients with PTSD and to elucidate and modify potential PTSD-related deficiencies in neurobiological and psychological responses to exercise to optimize the physical and psychological benefits of exercise for these individuals.

Due to the COVID-19 pandemic, and after consultation with the appropriate research oversight, all study procedures are temporarily suspended as of 3/15/20. This study will explicitly compare the effects of a 12-week progressive exercise training program on 1) the clinical symptoms of chronic pain and PTSD, 2) pain threshold and tolerance, and 3) anti-stress, anti-nociceptive neurohormones such as neuropeptide Y (NPY) and allopregnanolone/pregnanolone (ALLO) in Veterans with chronic pain/PTSD compared to healthy comparison participants. The revised study design includes a baseline cardiopulmonary exercise assessment (CPX) that will inform the exercise prescription for a 12-week "progressive exercise" training program, comprised of three 30-45 minute exercise sessions per week (walking or running, depending on the ability/capacity of the participant). Exercise sessions will be initially supervised by an exercise physiologist in the Clinical Studies Unit (CSU) at the VA Boston Healthcare System and then each participant will transition into the home. Weekly telephone calls by the PI will provide additional motivational support and assistance with problem solving. Implementation of the prescribed exercise regimen will also be supported by the use of heart rate and actigraph monitors programmed for the participant to achieve their prescribed heart rate range (HRR). Finally, an "endpoint" maximum load exercise assessment will occur at week 13 in order to track measurable change for both psychological and neurobiological factors and to delineate their impact on pain indices and PTSD symptomatology. Both maximum load exercise tests will be performed in accordance with guidelines published by the American College of Cardiology. Measures of pain, pain tolerance (via the cold pressor test) will be implemented 30 minutes before and 30 minutes after exercise testing as well as at a midpoint "check-in" at which self-report questionnaires will also be repeated. Based on the PI's earlier research, the role of exercise motivation and self-efficacy on changes in perceived pain and pain tolerance will be correlated with changes in NPY and ALLO levels, pre and post exercise. It is anticipated that differences in biological responses to aerobic and anaerobic exercise between healthy participants and those with chronic pain/PTSD will predict differences in the psychological and pain-reducing benefits of aerobic and anaerobic exercise. Once identified, such factors could be augmented by modification of the exercise regimen in order to help enhance the ant-stress hormone levels for the pain/PTSD population and experience clinically significant reductions in their symptoms. In order to obtain sufficient power as well as accounting for an expected drop-out rate of 18-20%, the proposed recruitment is 30 participants per condition (total of 60 participants). Data from this pilot work will be used to compute effect sizes in support of a future clinical trial incorporating individually prescribed exercise regimens and a motivationally based exercise behavior change intervention aimed at reducing pain and PTSD symptoms in our Veterans. Advanced education and training is sought by this CDA-2 award applicant in four broad areas: 1) psychophysiology of chronic pain and PTSD with a sub-focus on sex differences, 2) the neurobiology of chronic stress, PTSD, and pain, 3) exercise physiology and 4) the neuropsychology and neurobiology of traumatic brain injury (TBI). The combination of didactic and experiential training in these areas will serve the PI's long-term goal of becoming an independent scientist/practitioner in the VA focused on development of improved treatments for health conditions co-morbid with PTSD such as chronic pain and mild TBI. In the shorter-term, this CDA-2 will allow the PI to develop a more effective, motivationally based, exercise behavior change protocol that fosters long-term exercise compliance in patients with chronic pain/PTSD. This intervention will be used as an adjunct to cognitive interventions for these disorders to be further developed and studied via a larger VA, NIH, or DOD-funded grant for which the PI will apply in years 4-5 of the CDA2.

Chronic Musculoskeletal Pain, Posttraumatic Stress Disorder (PTSD), Mild or Moderate Traumatic Brain Injury

This study includes two groups: Trauma-exposed healthy controls and individuals suffering from both chronic musculoskeletal pain and PTSD. Those who meet diagnostic criteria for Chronic pain and PTSD will be assigned to that group. Those who are trauma exposed and do not meet criteria for Chronic Pain and PTSD will be assigned to the trauma-exposed control group.

This group will receive baseline and endpoint maximum load exercise testing which will inform their individualized exercise prescription (based on a progressive methodology) of aerobic exercise training aimed at meeting specific heart rate ranges over time (increasing up to 80% of maximum HRR between the midpoint and endpoint (6-12 weeks).

This group will receive baseline and endpoint maximum load exercise testing which will inform their individualized exercise prescription (based on a progressive methodology) of aerobic exercise training aimed at meeting specific heart rate ranges over time (increasing up to 80% of maximum HRR between the midpoint and endpoint (6-12 weeks).

Each study group will perform a baseline maximum load exercise test which will inform the individualized exercise prescription for the participant. Based on a progressive methodology, the participant will engage in 12 weeks of exercise of their choice (walking, running, cycling or swimming) with the goal of working towards a maximum heart rate range of 80% between weeks 6 and 12 of the study.

To be administered at: Screening Evaluation & Endpoint 13 week exercise test sessions This 30-item structured interview is designed to assess both the 17 symptoms of PTSD and the 8 hypothesized associated features. The scale yields a dichotomous diagnosis of PTSD, and also provides a continuous score of frequency and severity for each symptom. In addition, a behaviorally anchored probe question is provided for each symptom to increase the reliability of administration. The CAPS-5 is currently in the process of being validated however its previous version demonstrated excellent sensitivity (.81) and specificity (.95).57

Change from Baseline: West Haven=Yale Multidimensional Pain Inventory- Interference Subscale (WHY-MPI)

The WHY-MPI has been demonstrated to be applicable across a variety of clinical pain conditions. Its brevity, validity/ reliability, self-report nature and ease of scoring make it ideal for both clinical and research purposes. The WHY-MPI is sensitive to change following rehabilitation. Please note only the interference subscale of the WHY-MPI will be administered in this study.

Inclusion Criteria: Only Veteran and civilian participants in whom a physical examination, medical history, EKG, and baseline laboratory studies including urine toxicology screens indicate that maximum load exercise testing will be safe will be included in this study. Participants must be free of medications and other substances, (e.g., illicit drugs and alcohol) with effects that could hinder data interpretation for 2-6 weeks depending on the medication and frequency of use (which must be cleared by the PI's primary mentor). If on pain medications with short half-lives, must be off of them for 5 half-lives before testing, generally about 24 hours. Any participant with an ICD9 chronic pain diagnosis, with a musculoskeletal etiology, as confirmed by the study rehab medicine doctor, will be allowed for inclusion in the study. Also, any participant with a confirmed psychiatric diagnosis of PTSD (PTSD/chronic pain group) or have trauma exposure without a diagnosis of PTSD other psychiatric conditions or chronic pain (healthy comparison group) will also be included in the study. Individuals in the PTSD groups must meet for current chronic PTSD (>3 months ) as assessed by the CAPS 1-Month Diagnostic Version. Healthy trauma exposed individuals must have met criteria for an A1 event, but not necessarily A2. Finally, healthy, trauma-exposed control participants with a maximum of one major depressive episode in their past will be included in the study. Exclusion Criteria: Veteran and civilian participants will be excluded from participation in the study if they have: a life threatening or acute physical illness (e.g., cancer) current schizophreniform illnesses or bipolar disorder or active suicidal or homicidal ideation requiring clinical intervention. Women participants who are pregnant or are intending to become pregnant within the next six months will be excluded from participation. Individuals with current or past alcohol and/or substance dependence (less than three months from date of screening assessment) will be excluded. Healthy individuals with current partial PTSD -- or presently healthy individuals with a past or lifetime diagnosis of PTSD greater than one major depressive episode or diagnosis of another serious psychiatric illness in their past, e.g.: bipolar disorder or a schizophreniform disorder except for Psychosis not otherwise specified due to PTSD-related sensory hallucinations. Individuals seeking pain treatment such as surgical interventions or who have a neuropathic origin to their pain will also be excluded. Participants with chronic pain concerns that cannot tolerate exercising in a reclining bike and those who have had a clinical history of coronary artery disease or positive stress test Uncontrolled cardiac arrhythmia Moderate-to-severe aortic stenosis Severe arterial hypertension (systolic >200 mmHg, diastolic>110 mm Hg) More than first degree atrioventricular block also will be excluded from participation. Finally, participants who screen positive by answering all four items on the TBI assessment, will be excluded from participation.

This is a VA single site study. There are no plans to share the data outside of VA Boston Healthcare System, unless specifically requested by authorized officials of VA, once the study has ended.