Insula Network Microstructural Injury Links Low-Level Blast Exposure to Clinical Depression in Military Special Operations Forces Soldiers

Special Operations Forces (SOF) sustain repeated low-level blast (LLB) exposures; while most remain resilient, a subset develop depression, sleep disruption and reduced wellbeing that threaten readiness. We asked whether sub-concussive LLB chronically injures an insula-centered cortico-striato-thalamic network and whether network architecture explains divergent outcomes. In a mouse model parameterized to SOF blast exposure monitoring data, ninety 3-psi blasts over three weeks produced persistent diffusion and connectivity deficits across insular, striatal, pallidal and thalamic nodes, accompanied by tauopathy, neuroinflammation, vascular amyloid, and durable sleep and metabolic abnormalities. In SOF Soldiers, measures of cumulative LLB exposure predicted right insula-striatal diffusion/neurite disruption and increased depression risk. Interventional multi-mediator modeling showed that right insula-striatal microstructural injury mediated the effect of LLB to increase depression risk, while moderator screening identified features that amplify or buffer this mediation, defining risk and resilience zones. These findings enable precision blast-medicine integrating exposure dose, circuit biomarkers and moderator profiles.