Concussion pathophysiology: From biomechanical insult to clinical phenotype - or is injury truly the beginning?

Mild traumatic brain injury (mTBI) is associated with substantial morbidity worldwide. Emerging evidence demonstrates that both impact- and blast-related mTBI produce diffuse microstructural and functional alterations, e.g., diffuse axonal injury, astroglial and microglial activation, cerebrovascular dysfunction, and neurometabolic disturbance. Rotational acceleration in impact injury preferentially induces white matter shear. Blast overpressure exerts prominent effects at cerebrovascular interfaces, particularly within perivascular spaces (PVS). These biomechanical differences may yield distinct early injury phenotypes but converge on shared downstream cascades involving ionic disequilibrium, excitotoxicity, mitochondrial dysfunction, inflammation, and impaired cerebral blood flow regulation. The glymphatic system has emerged as a potential mechanistic bridge between acute injury and chronic symptomatology. Experimental and clinical studies demonstrate altered aquaporin-4 polarization, increased PVS burden, impaired solute clearance, elevated inflammatory markers, and tau pathology following mTBI. Increased PVS burden has been linked to persistent cognitive deficits and overall post-concussive symptom burden, suggesting a role of glymphatic dysfunction in long-term outcomes. However, biomarker-phenotype correlations remain modest across cognitive, headache, sleep, and affective domains. In this review, we summarize the existing evidence for biological alterations following mTBI and discuss a systems-based framework in which mTBI functions as a "second hit," destabilizing neural networks with variable pre-injury vulnerability. Under this model, chronic phenotypes may reflect interactions between injury-induced pathophysiology and host-specific risk factors, rather than direct linear effects of tissue damage alone. Integrating advanced neuroimaging, molecular biomarkers, and longitudinal phenotyping may clarify mechanistic pathways and inform targeted resilience-building interventions.