Transdiagnostic neural correlates of post-traumatic stress disorder and mild traumatic brain injury

Post-traumatic stress disorder and mild traumatic brain injury are highly comorbid and share overlapping cognitive and affective symptoms linked to frontolimbic circuitry. However, it remains unclear whether symptom severity reflects shared neural mechanisms across diagnoses or whether mild traumatic brain injury modifies these relationships. We used functional MRI to examine transdiagnostic associations between brain activity, functional connectivity and symptom burden in 109 combat veterans. Because symptom measures were highly intercorrelated, analyses were interpreted within a symptom-dimensional framework. Participants passively viewed negative and neutral images, and associations with symptom severity were examined across the full sample, with group-by-symptom interactions tested secondarily. Greater symptom burden was associated with increased negative versus neutral responses in ventral visual regions, including lateral occipital and fusiform cortices, with additional effects in frontal regions. A single dorsal visual region showed the opposite pattern, with reduced differentiation driven by decreased responses to negative images. Despite robust task-related activation of limbic regions, symptom severity was not associated with activation in the amygdala or insula. However, functional connectivity analyses identified a positive association between post-traumatic stress disorder symptom severity and right amygdala-ventromedial prefrontal cortex connectivity (P-FDR = 0.0134), with no significant group-by-symptom interaction (F(3,101) = 0.742, P = 0.530). Mild traumatic brain injury-associated symptom severity was positively associated with right insula-right supramarginal gyrus connectivity (P-FDR = 0.0348). Although a significant group-by-symptom interaction was observed (F(3,101) = 3.270, P = 0.0243), pairwise comparisons did not survive correction for multiple comparisons, and the effect was not robust across sensitivity analyses. Sensitivity analyses indicated that these connectivity findings primarily reflect shared symptom variance rather than measure-specific effects. Overall, symptom burden was associated with modulation of visual-affective and frontolimbic circuits during emotional processing, with effects largely consistent across diagnostic groups. These findings support a transdiagnostic framework and identify visual-affective and amygdala-ventromedial prefrontal cortex circuitry as candidate targets for mechanistic and interventional studies.