Brain Function in Gulf War Illness (GWI) and Associated Mental Health Comorbidities

Abstract

GWI has affected a substantial number of Gulf War (GW) veterans. The disease involves several organ systems among which the brain is most prominent. Neurological, cognitive and mood-related (NCM) symptoms frequently dominate and are at the root of chronic ill-health and disability in veterans suffering from GWI. In addition, such symptoms frequently co-occur with diagnosable mental health disorders, predominantly posttraumatic stress disorder (PTSD). Here we investigated the possibility that increased GWI severity leads, above a threshold, to a diagnosable mental health disorder (excluding psychosis). For this purpose, we used, in separate analyses, symptom severity scores and resting-state brain functional connectivity patterns, as determined by magnetoencephalography (MEG). Two-hundred-thirty GW-era veterans participated in this study. They completed diagnostic interviews to establish the presence of GWI and assess mental health status. This distinguished 3 groups: healthy controls (N = 41), veterans with GWI and no mental illness (GWI group, N = 91), and veterans with both GWI and mental health disorder (GWI+MH, N = 98). For each veteran, symptom severity scores in the 6 GWI domains (fatigue, pain, NCM, skin, gastrointestinal, respiratory) were available as well as 9 summary measures of the distribution of Synchronous Neural Interactions (SNI) derived from the MEG recordings. We tested the hypothesis that, in the presence of GWI, the appearance of a diagnosable mental health disorder may depend on GWI symptom severity. For that purpose, we performed a logistic regression on the GWI population, where the presence (or absence) of the MH disorder was the dependent variable and the age- and gender-adjusted GWI severity in the 6-symptom domains were the predictors. The outcome was the probability that a participant will have MH disorder or not. Similarly, we tested the hypothesis that the presence of the MH disorder can be predicted by the SNI distribution patterns by performing a second logistic regression as above but with the 9 SNI measures as predictors. We found GWI symptom severity differed significantly across groups (GWI+MH > GWI > Control). SNI distributions of the GWI group also differed significantly from the other groups in a systematic hemispheric pattern, such that the presence of GWI involved predominantly the left hemisphere, and presence of mental health disorders involved, in addition, the right hemisphere. Both logistic regressions yielded highly significant outcomes, demonstrating that both GWI symptom severity and SNI distribution measures can predict the presence of MH disorder in GWI. Remarkably, the prediction probabilities for MH presence derived from the symptom-based and SNI-based logistic regressions were positively and highly statistically significantly correlated. Taken together, both objective (neural) and subjective (symptoms) indices suggest that GWI is distinct from healthy controls and varies in severity in a continuum that leads, at the higher end, to a diagnosable MH disorder. The positive correlation between the GWI symptom-based and brain-based predicted classifications provides a key link between GWI symptom severity and synchronous neural interactions in the context of mental illness.

Keywords: Gulf War Illness (GWI); Magnetoencephalography; Posttraumatic Stress Disorder (PTSD); Veterans.

Figure 1:

Overall (mean ± SEM) of GWI symptom severity per group.

Figure 2:

Specific GWI symptom severity (mean ± SEM) per group.

Figure 3:

Pie plots of the data in Table 2 where the radius of the pie is proportional to the overall symptom severity. GI, gastrointestinal; NCM, neurological-cognitive-mood.

Figure 4:

PCL score is plotted against GWI severity score for the Control (blue), GWI (green) and GWI+MH (magenta) groups. (See text for details).

Figure 5:

Scree plot from factor analysis of symptom severity in the Control group. F, fatigue; P, pain; N, neurocognitive-mood; S, skin; G, gastrointestinal; R, respiratory. Signs (positive, negative) indicate the sign of loading of a specific symptom onto the corresponding component with absolute value of component score > 0.4.

Figure 6:

Scree plot from factor analysis of symptom severity in the GWI group.

Figure 7:

Scree plot from factor analysis of symptom severity in the GWI+MH group.

Figure 8:

The probability of presence of mental health disorder is plotted against the weighted sum of the 6 GWI severity, where the weights are the coefficients provided by the logistic regression. (see text for details.) Vertical green lines indicate participants without mental health problems; horizontal magenta lines indicate participants with mental health problems.

Figure 9:

ROC curve yielded by the logistic regression of presence/absence of mental health disorder against the severity of the 6 GWI symptoms, adjusted for age and gender. (See text for details.)

Figure 10:

Derived Group configuration from the weighted MDS analysis of 100 bootstraps. (Normalized Raw Stress = 0.00025, Dispersion Accounted For = 0.99975.) See text for details.

Figure 11:

Lines indicate SNIs in the left and right hemisphere exceeding a nominal threshold of P < 0.01 (uncorrected) in the Control vs. GWI ANCOVA (F-test). There is a left hemispheric preponderance. A, anterior; P, posterior; L, left; R, right. (See text for details.)

Figure 12:

Lines indicate SNIs in the left and right hemisphere exceeding a nominal threshold of P < 0.01 (uncorrected) in the Control vs. GWI+MH ANCOVA (F-test). Compared to plot in Fig. 10, there is an increased left hemispheric involvement and a more prominent involvement of the right hemisphere. (See text for details.)

Figure 13:

Lines indicate interhemispheric SNIs exceeding a nominal threshold of P < 0.01 (uncorrected) in the Control vs. GWI ANCOVA (F-test).

Figure 14:

Lines indicate interhemispheric SNIs exceeding a nominal threshold of P < 0.01 (uncorrected) in the Control vs. GWI ANCOVA (F-test). Compared to plot in Fig. 12, there is an increased left hemispheric involvement and a more prominent involvement of the right hemisphere. (See text for details.)

Figure 15:

The probability of presence of mental health disorder is plotted against the weighted sum of the 9 SNI measures, where the weights are the coefficients provided by the logistic regression. (see text for details.) Vertical green lines indicate participants without mental health problems; horizontal magenta lines indicate participants with mental health problems.

Figure 16:

ROC curve yielded by the logistic regression of presence/absence of mental health disorder against the 9 SNI measures, adjusted for age and gender. (See text for details.)

Figure 17:

Proposed framework of the various factors involved in GWI. Abbreviations as in Fig. 5. Symptoms exceeding threshold (in green) indicate diagnosable disease.