White Matter Microstructure Is Associated with Serum Neuroactive Steroids and Psychological Functioning

Abstract

Military service members are at increased risk for mental health issues, and comorbidity with mild traumatic brain injury (mTBI) is common. Largely overlapping symptoms between conditions suggest a shared pathophysiology. The present work investigates the associations among white matter microstructure, psychological functioning, and serum neuroactive steroids that are part of the stress-response system. Diffusion-weighted brain imaging was acquired from 163 participants (with and without military affiliation) and free-water-corrected fractional anisotropy (FA_T) was extracted. Associations between serum neurosteroid levels of allopregnanolone (ALLO) and pregnenolone (PREGNE), psychological functioning, and whole-brain white matter microstructure were assessed using regression models. Moderation models tested the effect of mTBI and comorbid post-traumatic stress disorder (PTSD) and mTBI on these associations. ALLO is associated with whole-brain white matter FA_T (β = 0.24, t = 3.05, p = 0.006). This association is significantly modulated by PTSD+mTBI comorbidity (β = 0.00, t = 2.50, p = 0.027), although an mTBI diagnosis alone did not significantly impact this association (p = 0.088). There was no significant association between PREGNE and FA_T (p = 0.380). Importantly, lower FA_T is associated with poor psychological functioning (β = -0.19, t = -2.35, p = 0.020). This study provides novel insight into a potential common pathophysiological mechanism of neurosteroid dysregulation underlying the high risk for mental health issues in military service members. Further, comorbidity of PTSD and mTBI may bring the compensatory effects of the brain's stress response to their limit. Future research is needed to investigate whether neurosteroid regulation may be a promising tool for restoring brain health and improving psychological functioning.

Keywords: diffusion tensor imaging; mild traumatic brain injury; military service members; neuroactive steroids; post-traumatic stress disorder; psychological functioning.

FIG. 1.

Whole-brain white matter tractography. This figure shows the whole-brain white matter of one participant derived from the fiber clustering output (in the sagittal and coronal plane).

FIG. 2.

Neuropsychiatric comorbidities. (a) (Venn diagram) and (b) (UpSet plot) display the comorbid neuropsychiatric disorders in the present sample (n = 163). Particularly, participants with both PTSD and mTBI have high numbers of comorbidity with alcohol/drug addiction and depression. mTBI, Mild traumatic brain injury; PTSD, Post-traumatic stress disorder..

FIG. 3.

Association between allopregnanolone (ALLO) and whole-brain FA_T. This figure illustrates the significant moderating effect of PTSD+mTBI comorbidity on the association between ALLO (pg/mL) and whole-brain FA_T. mTBI, Mild traumatic brain injury; PTSD, Post-traumatic stress disorder; FA_T, Fractional anisotropy _Tissue

FIG. 4.

Summary of findings. This figure illustrates the significant associations between allopregnanolone (ALLO) and whole-brain white matter and between whole-brain white matter and psychological functioning. Comorbidity of PTSD and mTBI significantly alters the strength of the observed relation between ALLO and whole-brain white matter. PTSD, Post-traumatic stress disorder; mTBI, Mild traumatic brain injury.

FIG. 5.

Association between psychological functioning and whole-brain FA_T. This figure shows the association between the psychological functioning and whole brain FA_T (β = -0.20, t = -2.38, p = 0.019). Lower scores on the psychological functioning scale represent better functioning. Scores are standardized z-scores with a mean of 0 and a standard deviation of 1.