Neurohormonal Benefits of Exercise in Fibromyalgia and PTSD

This study will compare the effects of a 12-week progressive exercise training program on 1)
Fibromyalgia (FM) pain and PTSD symptoms, 2) pain threshold and tolerance, and 3) relevant
biomarkers and neuromodulators including: a) anti-stress, anti-nociceptive, immune modulating
factors such as neuropeptide Y (NPY) and GABAergic neuroactive steroids such as
allopregnanolone and pregnanolone (together termed ALLO) b) factors that upregulate the
expression of NPY and the GABAergic neuroactive steroids, and otherwise modulate
inflammation, such as cortisol, c) excitatory factors such as substance P that directly
promote pain transduction and d) pro-inflammatory cytokines such as IL-6 and IL-8 that not
only increase pain and inflammation, but also contribute to psychological dysfunction (e.g.
anhedonia and depression) via impact on the CNS reward system. This study will focus on
Veterans with FM/PTSD. The study design includes a baseline, acute, 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 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" CPX assessment will occur at week
13 to track changes in psychological and neurobiological factors and to delineate their
impact on pain and PTSD symptoms. Both CPX, maximum load, exercise tests will be performed in
accordance with guidelines published by the American College of Cardiology. Among Veterans
with FM/PTSD, changes in the biomarkers assessed after acute, CPX exercise testing will be
associated with improvements in pain and PTSD symptoms.

Once identified, such biomarkers could be augmented by modification of the exercise regimen
to help enhance the anti-stress hormone levels for the FM/PTSD population and experience
clinically significant reductions in their symptoms. To obtain sufficient power, 36
participants (18/year) will be recruited. Data from this pilot work will be used to
demonstrate feasibility and inform the further development of individually prescribed
exercise regimens and a motivationally based exercise behavior change intervention aimed at
reducing chronic musculoskeletal pain, including FM, and PTSD symptoms in Veterans. In the
short-term, this SPiRE proposal will allow the PI to develop a more effective, motivationally
based, exercise behavior change protocol that fosters long-term exercise adherence in
patients with FM/PTSD. In the long-term, 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 year 2 of the current SPiRE
proposal.

Inclusion Criteria:

- Only Veteran and civilian participants in whom a physical examination and medical
history indicate that the participant meets current diagnostic criteria for FM, as
specified by the American College of Rheumatology, will be eligible for the study.

- Eligible participants who agree to a blood draw for measurement of biomarkers, must be
free of medications and other substances (e.g., illicit drugs and alcohol) that may
alter results for 2-6 weeks depending on the medication and frequency of use (which
must be cleared by MD consultants).

- If on pain medications with short half-lives, participants must be off of them for 5
half-lives before testing, generally about 24 hours.

- Any FM participant with an ICD-10 chronic pain diagnosis of a musculoskeletal
etiology, will also be eligible for inclusion in the study as many individuals with FM
also have such conditions.

- Any participant with a confirmed psychiatric diagnosis of PTSD will be included in the
study. Individuals in the PTSD group must meet diagnostic criteria for current chronic
PTSD (>3 months) as assessed by the CAPS-5, 1-Month Diagnostic Version.

Exclusion Criteria:

- 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 (except for Psychosis NOS due to PTSD-related
sensory hallucinations)

- Untreated bipolar disorder

- Or active suicidal or homicidal ideation requiring clinical intervention

- Individuals with current or past alcohol and/or substance dependence (less than three
months from date of screening assessment) will be excluded

- Individuals seeking interventional pain treatment, such as surgical interventions or
other pain clinic interventions, will also be excluded unless they agree to
participate in the biomarker procedure prior to the start of their pain intervention.

- Finally, participants who have a neuropathic origin to their pain will be excluded.