Impact of Exercise Training on Pain and Brain Function in Gulf War Veterans

Musculoskeletal pain in soldiers who returned from the Persian Gulf War is a serious problem.
Numerous studies have reported musculoskeletal pain as a primary symptom of sick Gulf
Veterans (GVs), with ~100,000 Veterans (~15%) reporting unresolved pain affecting their
social and professional lives. Pain and other symptoms are often disabling with 1 in 7 United
States Veterans seeking care for war-related health concerns and ~12% receiving disability
compensation. Thus, a significant number of military personnel are no longer able to perform
their duties due to medically unexplained symptoms including pain, fatigue and cognitive
problems. Importantly, recent evidence suggests that chronic pain complaints in most GVs have
not resolved. Similar problems appear to be on the horizon for Veterans from Operations
Enduring and Iraqi Freedom. Understanding the pathophysiological consequences of chronic
muscle pain is important for better determining both the efficacy and mechanism of treatments
aimed at decreasing debilitating symptoms and improving physical function among Veterans
coping with chronic pain.

Given the dearth of experimental data in GVs with chronic musculoskeletal pain (CMP), we have
patterned much of our research in GVs after our research in fibromyalgia (FM), a disorder
with a primary symptom of muscle and joint pain in civilians. Our work and the work of others
suggest that FM pain is produced and maintained by central nervous system (CNS) dysregulation
of nociceptive and pain processes. Our work also suggests that phenomena similar to those
observed in FM may be occurring in GVs with CMP. Like FM patients, GVs with CMP, 1) are more
sensitive to experimental pain stimuli, 2) exhibit exaggerated pain responses following acute
exercise, 3) experience more muscle pain during acute exercise and 4) show augmented brain
responses to both painful and non-painful experimental stimuli. These data suggest that some
of the same pathophysiological mechanisms involved in FM may be maintaining chronic
widespread muscle pain in GVs. Critical unanswered questions include whether promising
treatments for CMP in GVs can affect laboratory measures of pain sensitivity and pain
regulation and whether these changes relate to clinical improvements. We intend to begin to
answer these questions by examining perceptual and brain hemodynamic responses to
standardized painful stimuli and documenting their relationships to clinical outcomes before,
during and upon completion of a viable, novel treatment for CMP.

There are no known efficacious treatments for GVs suffering CMP. Efficacy studies are needed
to begin determining effective treatments for our Veterans following their service of our
country. In FM, exercise training (both aerobic and resistance modes) is widely recognized as
one of the few consistently efficacious treatments, resulting in improved well-being,
increased physical function and in some cases decreased pain. One large scale treatment trial
of aerobic exercise in GVs with chronic multi-symptom illness showed only modest improvements
in pain, fatigue and mental health. We believe this trial had several limitations that
greatly attenuated the treatment's effectiveness; consequently, it is premature to discount
exercise training as a treatment for GVs with CMP. Further, we propose a novel approach that
employs progressive resistance exercise training (RET) to treat GVs with CMP, while obtaining
objective measures of nociceptive function, brain white matter tract pathways and total
physical activity.

In addition to exercise performed as part of a structured training program, physical activity
behaviors are important determinants of physical and mental health. Greater total physical
activity levels are associated with increased physical function, improved mental health,
increased energy and decreased symptoms of chronic pain. To our knowledge, none of the
exercise training trials in FM have actually measured the impact of the exercise training on
physical activity behaviors during daytime hours outside the intervention. It is plausible
that the adoption of a structured exercise training program reduces physical activities
performed during the rest of the day, and that this change in total physical activity could
affect health outcomes. Objective measurement of physical activity will allow us to determine
whether RET increases, decreases or has no impact on total physical activity levels in GVs
with CMP. This will allow us to begin to characterize sub-groups who benefit the most from
RET (e.g. potentially those GVs that maintain or increase their extra-intervention physical
activity). Thus, in addition to supervised RET, we will objectively measure total physical
activity levels outside of the intervention using accelerometers before, during and following
treatment.

In summary, we propose to determine the efficacy of RET for the treatment of CMP and
associated symptoms in GVs. In addition, we will assess the influence of RET on total
physical activity, pain sensitivity and regulation, and brain white matter tracts. By
applying functional neuroimaging techniques in conjunction with pain psychophysics we will
test how the brains of Veterans with CMP respond to sensory stimuli and whether these
responses can be modified by exercise training. We plan to use blood oxygen level dependent
(BOLD) and diffusion tensor imaging (DTI) methods to evaluate the function of brain regions
involved in pain processing and control and the microstructural properties of white matter
tract pathways that connect these regions. In addition, we will determine the influence of
RET on extra-intervention physical activity behaviors, testing a critical and unanswered
question - whether total physical activity levels change as a result of engaging in a RET
program in patients with CMP. The primary goals of this project will be accomplished by
comparing GVs with CMP assigned to either RET or wait-list control (WLC) in a randomized
controlled trial.

Inclusion Criteria:

- Veteran of the Persian Gulf War

- Chronic muscle pain

Exclusion Criteria:

- Regular participation in resistance exercise

- Color blindness

- Claustrophobia

- Medical conditions that could explain the Veteran's pain

- Use of exclusionary drugs 3 weeks prior to testing

- Major depressive disorder with melancholic features

- Substance abuse

- Schizophrenia

- Bipolar disorder