• Kristine M Knutson, Stephen J Gotts, Eric M Wassermann, and Jeffrey D Lewis.
• Behavioral Neurology Unit, National Institute of Neurological Disorders and Stroke/National Institutes of Health, Room 7D41, MSC 1440, 10 Center Dr, Bethesda, MD 20892-1440.
• Mil Med. 2020 Sep 18; 185 (9-10): e1750-e1758.

IntroductionThe purpose of this study was to explore the effect of low testosterone level on whole-brain resting state (RS) connectivity in male veterans with symptoms such as sleep disturbance, fatiguability, pain, anxiety, irritability, or aggressiveness persisting after mild traumatic brain injury (mTBI). Follow-up analyses were performed to determine if sleep scores affected the results.Materials And MethodsIn our cross-sectional design study, RS magnetic resonance imaging scans on 28 veterans were performed, and testosterone, sleep quality, mood, and post-traumatic stress symptoms were measured. For each participant, we computed the average correlation of each voxel's time-series with the rest of the voxels in the brain, then used AFNI's 3dttest++ on the group data to determine whether the effects of testosterone level on whole-brain connectivity were significant. We then performed follow-up region of interest-based RS analyses of testosterone, with and without sleep quality as a covariate. The study protocol was approved by the National Institute of Health's Combined Neuroscience Institutional Review Board.ResultsSixteen participants reported repeated blast exposure in theater, leading to symptoms; the rest reported exposure to a single blast or a nonblast TBI. Thirty-three percent had testosterone levels <300 ng/dL. Testosterone level was lower in participants who screened positive for post-traumatic stress disorder compared to those who screened negative, but it did not reach statistical significance. Whole-brain connectivity and testosterone level were positively correlated in the left parahippocampal gyrus (LPhG), especially in its connectivity with frontal areas, the lingual gyrus, cingulate, insula, caudate, and right parahippocampal gyrus. Further analysis revealed that the effect of testosterone on LPhG connectivity is only partially mediated by sleep quality. Sleep quality by itself had an effect on connectivity of the thalamus, cerebellum, precuneus, and posterior cingulate.ConclusionLower testosterone levels were correlated with lower connectivity of the LPhG. Weaknesses of this study include a retrospective design based on self-report of mTBI and the lack of a control group without TBI. Without a control group or pre-injury testosterone measures, we were not able to attribute the rate of low testosterone in our participants to TBI per se. Also testosterone levels were checked only once. The high rate of low testosterone level that we found suggests there may be an association between low testosterone level and greater post-traumatic stress disorder symptoms following deployment, but the causality of the relationships between TBI and deployment stress, testosterone level, behavioral symptomatology, and LPhG connectivity remains to be determined. Our study on men with persistent symptoms postdeployment and post-mTBI may help us understand the role of low testosterone and sleep quality in persistent symptoms and may be important in developing therapeutic interventions. Our results highlight the role of the LPhG, as we found that whole-brain connectivity in that region was positively associated with testosterone level, with only a limited portion of that effect attributable to sleep quality.Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.

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