This research project is a follow-up to the prior VA-funded study that found that chronic
fatigue reported by many Gulf War veterans may be a symptom of dysfunctional cardiovascular
stress response regulation. Specifically, ill veterans had diminished autonomic responses
during demanding psychosocial tasks involving high level cognitive processing and emotional
stress. There was a close relationship between clinical status of ill veterans and their
inability to mount an appropriate physiological response under stress. The main objective of
the present investigation is to determine the specific mechanism through which this
abnormality may contribute to Gulf War-related chronic fatigue. We also observed that Gulf
veterans with posttraumatic stress disorder (PTSD) had the most dampened autonomic
activation to stressors involving higher brain activities. The second major focus of this
study is to explore the role of a psychiatric disorder, specifically PTSD, as a factor in
abnormalities in stress response regulation. This aspect of the study may also provide
pertinent information as to the role of stress of military deployment as a contributing
factor in post-Gulf War illnesses.
Objective: Our previous VA-funded study found that chronic fatigue reported by some Gulf
War veterans may be a symptom of dysfunctional cardiovascular stress response regulation.
Specifically, ill veterans had diminished autonomic responses during tasks involving higher
brain activities, including cognitive processing and psychosocial stress. Gulf veterans with
posttraumatic stress disorder (PTSD) had the most dampened autonomic activation to stressors
involving higher brain activities. There was a close relationship between the clinical
status of ill veterans and their inability to mount an appropriate physiological response
under stress. The main objective of the present investigation is to determine the specific
mechanism through which this abnormality may contribute to Gulf War-related chronic fatigue.
The second major focus of this study is to explore the role of stress of military deployment
as a contributing factor in post-Gulf War illnesses.
Research Plan: The research plan is to establish the mechanisms of blood pressure
hyporeactivity in Gulf War veterans with chronic fatigue and PTSD. Two possibilities are
being examined: one, that abnormal cardiovascular responses to stressors involve reduced
responsiveness of the major cardiovascular effector systems, the peripheral arterial
vasculature and the heart, to sympathetic stimulation; and two, that the locus of
abnormality is in the brain, resulting in inadequate activation of the sympathetic nervous
system during stressful behavioral activities. The role of wartime stress will be examined
by specifically focusing on abnormalities in stress response regulation associated with Gulf
Methods: This study is being performed on four groups of Gulf War veterans, including those
with symptoms that fulfill the 1994 CDC case definition for chronic fatigue syndrome (CFS),
those with PTSD, those who have both CFS and PTSD, and healthy control veterans. A total of
90 veterans will be studied. The study protocol uses standard laboratory procedures to
characterize abnormalities in regulation of cardiovascular function using selective
pharmacological and behavioral challenges. Performance of central mechanisms of sympathetic
activation during mental challenge is evaluated by measuring increases in plasma
catecholamines, epinephrine and norepinephrine, during social-evaluative speech stressor.
Collected plasma samples are analyzed using high performance liquid chromatography assays.
The hypotheses of target organ dysfunction are evaluated using graded intravenous infusions
of two drugs, phenylephrine and dobutamine, and by measuring the resultant cardiovascular
responses. Phenylephrine and dobutamine are synthetic catecholamines, analogues of
endogenous chemical messenger substances released by sympathetic nerve fibers and by adrenal
medulla during stress response activation. Phenylephrine is an alpha-adrenergic agonist that
increases blood pressure by constricting peripheral blood vessels. Dobutamine is
beta-adrenergic agonist that stimulates myocardium to increase force of contraction and
cardiac output. Stimulus-response curves for vasoconstrictor and inotropic adrenergic
receptor mechanisms are constructed, from which measures of vasomotor and cardiac function,
and autonomic reflex mechanisms are derived.
Clinical Relevance: Our research has suggested that there is a biomedical marker in Gulf
veterans with illnesses characterized by severe unexplained chronic fatigue -- a diminished
cardiovascular reactivity to cognitive stressors. Although this problem was served in all
veterans with fatiguing illness, it was worst in the subset of those veterans who also had
PTSD. Our data also suggested that the markedly diminished cardiovascular response to stress
exhibited by this group may contribute to their functional impairment. The present
investigation will determine (1) whether this impairment is due to PTSD, to the medical
disorder of unexplained severe fatigue, or to an interaction between the two diagnoses, and
(2) where in the system of blood pressure regulation lies the cause of abnormal stress
responses. This work, therefore, may lead to better understanding of the causes of Gulf War
Illnesses as well as ways to treat them.
- All former military personnel who participated in the Gulf War campaign and who meet
the criteria for inclusion will be eligible to participate in the study.
- Subjects with medical conditions that could explain their symptoms or with
CDC-defined psychiatric exclusions (schizophrenia, mania, bulimia, and substance
abuse disorders) will not participate in the study.
- Other exclusions will be pregnancy, traumatic brain injury, or a history of any form
of cardiovascular disease or related symptoms.
- Other restrictions on participation will include any medication that impact on
cardiovascular autonomic control, benzodiazepines, and antibiotics.
- Subjects taking nonsteroidal anti-inflammatory/analgesic agents, mild short-acting
hypnotics, and SSRIs will be accepted into the study, but will be requested to
withdraw from their medications with the agreement and under the supervision of their
physician. These subjects will be scheduled for the study after a washout period of