Persistent Hypersensitivity after Repeat Concussion is Associated with Chronic Cognitive Dysfunction

Persistent sensory hypersensitivity is a common but under-recognized feature of post-concussion syndrome (PCS) following mild traumatic brain injury (mTBI), and may contribute to chronic cognitive complaints. However, the mechanistic relationship between long-term sensory dysregulation and cognitive dysfunction after repeat concussion remains poorly understood. Here, we used an experimental repeated closed-head injury (rCHI-5x), in young adult mouse model targeting the frontal cortex at 8-weeks of age to test whether chronic sensory processing abnormalities contribute to cognitive impairment under increased sensory load chronically at 8-10 weeks post-injury (4-months old). rCHI mice exhibited significant sensory dysfunction across multiple modalities, including increased tactile sensitivity, tactile avoidance, and impaired habituation to auditory startle, despite the absence of gross structural brain damage and preserved learning and memory under low-demand conditions. While spatial learning and working memory in the Barnes maze were intact, rCHI mice displayed increased perseveration and reduced cognitive flexibility. However, these cognitive deficits emerged only when auditory and tactile sensory distractors were introduced during testing, unmasking impairments that were not evident under baseline conditions. Within-animal statistical analyses found strong associations between the severity of sensory hypersensitivity, impaired sensory habituation, and deficits in cognitive flexibility in rCHI mice, but not in sham controls. These findings indicate that chronic sensory dysregulation following repeat mild concussion is not merely a secondary symptom, but a primary contributor to cognitive impairment under conditions of increased sensory load. Together, this work identifies persistent sensory processing and gating dysfunction as a key driver of PCS-related cognitive deficits and reveals that targeting sensory circuitry for therapeutic neuromodulation may offer functional rescue across multiple domains, extending beyond sensory symptoms to improve higher-order cognitive performance.