Neurobiological and Psychological Benefits of Exercise in Chronic Pain and PTSD

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 the 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 symptoms in patients with varying degrees of PTSD symptom severity 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 examine the effects of a 12-week progressive exercise training program on 1) the clinical symptoms of chronic pain and varying degrees of PTSD symptom severity, 2) anti-stress, anti-nociceptive neurohormones such as allopregnanolone + pregnanolone (ALLO +PA) in Veterans with trauma exposure, chronic pain and varying degrees of PTSD symptom severity. 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. Intermittent 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 symptomatology will be implemented 30 minutes before and 30 minutes after exercise testing at baseline and endpoint. It is anticipated that differences in biological responses to aerobic and anaerobic exercise as illustrated by variability among the participants, with varying degrees of PTSD symptom severity, 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, the proposed recruitment is 23 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 to moderate 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 trauma-exposure, chronic pain and varying degrees of PTSD symptom severity.. 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.

Eligibility Criteria:
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

  * or have trauma exposure without a diagnosis of PTSD but some symptoms of PTSD, including subthreshold PTSD
  * other psychiatric conditions
* Individuals must meet for current chronic PTSD (\>3 months ) as assessed by the CAPS 1-Month Diagnostic Version.

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.
* individuals without PTSD who have had 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.