Abstract
BackgroundWe recently reported that six alleles from class II genes of the Human Leukocyte Antigen (HLA) confer protection from Gulf War Illness (GWI) (Georgopoulos et al., 2015). The most significant effect is exerted on Neurological-Cognitive-Mood (NCM), Pain, and Fatigue symptoms, such that higher number of copies of the protective alleles are associated with lower symptom severity. Here we tested the hypothesis that this effect is exerted by modulating the strength of neural synchronicity. MethodsEighty-one Gulf War veterans (65 with GWI and 16 healthy controls) underwent a magnetoencephalography (MEG) scan to assess the strength of brain synchronicity by computing zero-lag crosscorrelations (and their Fisher z transforms) between prewhitened MEG time series. A high-resolution HLA genotyping determined the number of copies, k, of the 6 protective alleles above in each participant. We tested the hypothesis above by regressing NCM, Pain and Fatigue symptom severity against the interaction term, k×z (HLA-related effect), while including z (non-HLA-related effect), gender and age as covariates. The k×z and z terms assessed HLA- and non-HLA-related effects, respectively, of neural synchronicity on symptom severity. The distributions of these effects in sensor space were visualized using statistical heatmaps. FindingsWe found significant, graded HLA- and non-HLA-related effects: (a) NCM>Pain>Fatigue for HLA-related effects, (b) NCM>Fatigue>Pain for non-HLA-related effects, and (c) HLA-related>non-HLA-related effects for all symptoms. These effects had widespread but distinct distributions in sensor space that allowed the orderly separation of the 6 terms (3 symptom domains×2 HLA factors) in a multidimensional plot, where one dimension separated the symptoms and the other the HLA relation. InterpretationThese findings demonstrate the presence of substantial, widespread, distinct and orderly HLA- and non-HLA-related neural influences on NCM, Pain and Fatigue symptom severity in GWI. FundingU.S. Department of Veterans Affairs and University of Minnesota.
Highlights
Gulf War Illness (GWI) is a disorder that affects multiple systems and is manifested by various combinations and severities of at least 6 different kinds of symptoms, including Neurological-Cognitive-Mood (NCM), pain, fatigue, skin rashes, gastrointestinal, and respiratory symptoms (Institute of Medicine, 2000, 2006, 2010)
We studied a total of 81 veterans, 16 controls (15 men, 1 woman; age range 43–71 y; 54.9 ± 10.2 y, mean ± SD) and 65 GWI (63 men, 2 women; age range 39–76 y; 50.8 ± 7.9 y). (This is the same group studied in Georgopoulos et al, 2015, less one GWI participant for whom we did not have MEG scan.) All participants had deployed during the Gulf War and were free of autoimmune disease, including multiple sclerosis, lupus, rheumatoid arthritis, psoriasis, Sjögren's syndrome, or Graves disease
The two groups in this study differed substantially in their composition regarding the counts of 6 Human Leukocyte Antigen (HLA) protective alleles (Table 1): controls had higher counts, whereas GWI participants had lower counts, without a single participant with 2 alleles
Summary
Gulf War Illness (GWI) is a disorder that affects multiple systems and is manifested by various combinations and severities of at least 6 different kinds of symptoms, including Neurological-Cognitive-Mood (NCM), pain, fatigue, skin rashes, gastrointestinal, and respiratory symptoms (Institute of Medicine, 2000, 2006, 2010). The k × z and z terms assessed HLA- and non-HLA-related effects, respectively, of neural synchronicity on symptom severity. The distributions of these effects in sensor space were visualized using statistical heatmaps. Interpretation: These findings demonstrate the presence of substantial, widespread, distinct and orderly HLA- and non-HLA-related neural influences on NCM, Pain and Fatigue symptom severity in GWI.
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