Nearly 30% of the approximately 700,000 military personnel who served in Operation Desert Storm (1990–1991) have developed Gulf War Illness, a condition that presents with symptoms such as cognitive impairment, autonomic dysfunction, debilitating fatigue and chronic widespread pain that implicate the central nervous system. A hallmark complaint of subjects with Gulf War Illness is post-exertional malaise; defined as an exacerbation of symptoms following physical and/or mental effort. To study the causal relationship between exercise, the brain, and changes in symptoms, 28 Gulf War veterans and 10 controls completed an fMRI scan before and after two exercise stress tests to investigate serial changes in pain, autonomic function, and working memory. Exercise induced two clinical Gulf War Illness subgroups. One subgroup presented with orthostatic tachycardia (n = 10). This phenotype correlated with brainstem atrophy, baseline working memory compensation in the cerebellar vermis, and subsequent loss of compensation after exercise. The other subgroup developed exercise induced hyperalgesia (n = 18) that was associated with cortical atrophy and baseline working memory compensation in the basal ganglia. Alterations in cognition, brain structure, and symptoms were absent in controls. Our novel findings may provide an understanding of the relationship between the brain and post-exertional malaise in Gulf War Illness.

BackgroundGulf War exposures in 1990 and 1991 have caused 25% to 30% of deployed personnel to develop a syndrome of chronic fatigue, pain, hyperalgesia, cognitive and affective dysfunction.MethodsGulf War veterans (n = 31) and sedentary veteran and civilian controls (n = 20) completed fMRI scans for diffusion tensor imaging. A combination of dolorimetry, subjective reports of pain and fatigue were correlated to white matter diffusivity properties to identify tracts associated with symptom constructs.ResultsGulf War Illness subjects had significantly correlated fatigue, pain, hyperalgesia, and increased axial diffusivity in the right inferior fronto-occipital fasciculus. ROC generated thresholds and subsequent binary regression analysis predicted CMI classification based upon axial diffusivity in the right inferior fronto-occipital fasciculus. These correlates were absent for controls in dichotomous regression analysis.ConclusionThe right inferior fronto-occipital fasciculus may be a potential biomarker for Gulf War Illness. This tract links cortical regions involved in fatigue, pain, emotional and reward processing, and the right ventral attention network in cognition. The axonal neuropathological mechanism(s) explaining increased axial diffusivity may account for the most prominent symptoms of Gulf War Illness.

The subjective experience of cognitive dysfunction (“fibrofog”) is common in fibromyalgia. This study investigated the relation between subjective appraisal of cognitive function, objective cognitive task performance, and brain activity during a cognitive task using functional magnetic resonance imaging (fMRI). Sixteen fibromyalgia patients and 13 healthy pain-free controls completed a battery of questionnaires, including the Multiple Ability Self-Report Questionnaire (MASQ), a measure of self-perceived cognitive difficulties. Participants were evaluated for working memory performance using a modified N-back working memory task while undergoing Blood Oxygen Level Dependent (BOLD) fMRI measurements. Fibromyalgia patients and controls did not differ in working memory performance. Subjective appraisal of cognitive function was associated with better performance (accuracy) on the working memory task in healthy controls but not in fibromyalgia patients. In fibromyalgia patients, increased perceived cognitive difficulty was positively correlated with the severity of their symptoms. BOLD response during the working memory task did not differ between the groups. BOLD response correlated with task accuracy in control subjects but not in fibromyalgia patients. Increased subjective cognitive impairment correlated with decreased BOLD response in both groups but in different anatomic regions. In conclusion, “fibrofog” appears to be better characterized by subjective rather than objective impairment. Neurologic correlates of this subjective experience of impairment might be separate from those involved in the performance of cognitive tasks.

About 25% of 1990-1991 Persian Gulf War veterans experience disabling fatigue, widespread pain, and cognitive dysfunction termed Gulf War illness (GWI) or Chronic Multisymptom Illness (CMI). A leading theory proposes that wartime exposures initiated prolonged production of reactive oxygen species (ROS) and central nervous system injury. The endogenous antioxidant L-carnosine (β-alanyl-L-histidine) is a potential treatment since it is a free radical scavenger in nervous tissue. To determine if nutritional supplementation with L-carnosine would significantly improve pain, cognition and fatigue in GWI, a randomized double blind placebo controlled 12 week dose escalation study involving 25 GWI subjects was employed. L-carnosine was given as 500, 1000, and 1500 mg increasing at 4 week intervals. Outcomes included subjective fatigue, pain and psychosocial questionnaires, and instantaneous fatigue and activity levels recorded by ActiWatch Score devices. Cognitive function was evaluated by WAIS-R digit symbol substitution test. Carnosine had 2 potentially beneficial effects: WAIS-R scores increased significantly, and there was a decrease in diarrhea associated with irritable bowel syndrome. No other significant incremental changes were found. Therefore, 12 weeks of carnosine (1500 mg) may have beneficial cognitive effects in GWI. Fatigue, pain, hyperalgesia, activity and other outcomes were resistant to treatment.

Gulf War Illness affects 25–30% of American veterans deployed to the 1990–91 Persian Gulf War and is characterized by cognitive post-exertional malaise following physical effort. Gulf War Illness remains controversial since cognitive post-exertional malaise is also present in the more common Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An objective dissociation between neural substrates for cognitive post-exertional malaise in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome would represent a biological basis for diagnostically distinguishing these two illnesses. Here, we used functional magnetic resonance imaging to measure neural activity in healthy controls and patients with Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome during an N-back working memory task both before and after exercise. Whole brain activation during working memory (2-Back > 0-Back) was equal between groups prior to exercise. Exercise had no effect on neural activity in healthy controls yet caused deactivation within dorsal midbrain and cerebellar vermis in Gulf War Illness relative to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. Further, exercise caused increased activation among Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients within the dorsal midbrain, left operculo-insular cortex (Rolandic operculum) and right middle insula. These regions-of-interest underlie threat assessment, pain, interoception, negative emotion and vigilant attention. As they only emerge post-exercise, these regional differences likely represent neural substrates of cognitive post-exertional malaise useful for developing distinct diagnostic criteria for Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.