Sex-based structural and functional MRI outcomes in the rat brain after soman (GD) exposure-induced status epilepticus.

OBJECTIVE

Exposure to the nerve agent, soman (GD), induces status epilepticus (SE), epileptogenesis, and even death. Although rodent models studying the pathophysiological mechanisms show females to be more reactive to soman, no tangible sex differences in brains postexposure have been reported. In this study, we used multimodal imaging using MRI in adult rats to determine potential sex-based biomarkers of soman effects.

METHODS

Male and female Sprague Dawley rats were challenged with 1.2 × LD soman followed by medical countermeasures. Ten weeks later, the brains were analyzed via structural and functional MRI.

RESULTS

Despite no significant sex differences in the initial SE severity after soman exposure, long-term MRI-based structural and functional differences were evident in the brains of both sexes. While T2 MRI showed lesser soman-induced neurodegeneration, large areas of T1 enhancements occurred in females than in males, indicating a distinct pathophysiology unrelated to neurodegeneration. fMRI-based resting-state functional connectivity (RSFC), indicated greater reductions in soman-exposed females than in males, associating with the T1 enhancements (unrelated to neurodegeneration) rather than T2-hyperintensity or T1-hypointensity (representing neurodegeneration). The wider T1 enhancements associating with the decreased spontaneous neuronal activity in multiple resting-state networks in soman-exposed females than males suggest that neural changes unrelated to cellular atrophy impinge on brain function postexposure. Taken together with lower spontaneous neural activity in soman-exposed females, the results indicate some form of neuroprotective state that was not present in males.

SIGNIFICANCE

The results indicate that endpoints other than neurodegeneration may need to be considered to translate sex-based nerve agent effects in humans.