Auditory Stimulation of Slow‐Wave Sleep Promotes Recovery after Brain Injury in an Animal Model

OBJECTIVE: Traumatic brain injury (TBI) significantly reduces the quality of life for millions of survivors worldwide, causing persistent brain tissue damage and cognitive impairments, with no established therapeutic interventions currently available. Slow-wave activity, a hallmark of deep sleep, has been implicated in recovery after TBI, but pharmacological approaches to enhance it lack specificity and scalability, complicating efforts to identify slow-wave activity as a direct mechanistic contributor and severely limiting clinical translation. METHODS: To overcome these limitations, we developed a preclinical closed-loop auditory stimulation (CLAS) paradigm that targets sleep's slow waves, enabling highly specific and temporally precise enhancement of slow-wave activity. Therefore, we delivered 30-ms sound triggers targeting the up-phase of real-time detected slow-waves (upCLAS: TBI n = 8), or no sound stimulation (mockCLAS: non-TBI n = 8, TBI n = 7) during sleep to healthy controls (non-TBI) or brain injured (TBI) rats. Concomitantly, we assessed the ability of upCLAS-enhanced sleep to counteract brain tissue damage (primary outcome) and symptomatic sequelae (secondary outcome) of TBI. RESULTS: Bayesian analysis revealed that sound-mediated slow-wave activity enhancement: (1) reduces diffuse axonal injury, with TBI mockCLAS posterior estimates falling outside the 95% confidence intervals of both other groups, whereas the posterior distributions of TBI upCLAS and non-TBI groups largely overlapped (~13% posterior differences >0), consistent with a negligible effect size between groups; (2) decreases demyelination, with approximately 97% posterior differences >0 between TBI mockCLAS and TBI upCLAS groups, compared to approximately 60% between non-TBI and TBI upCLAS groups; and (3) preserves cognitive ability, with recognition indexes in the novel object recognition test significantly above chance level in non-TBI (*p = 0.031) and TBI upCLAS (*p = 0.026) groups, in contrast to mockCLAS-treated TBI rats (p = 0.156), presenting pronounced cognitive deficit. Furthermore, microglial response to brain injury was increased by deep sleep enhancement, with reduced ionized calcium-binding adaptor molecule 1+ area coverage in TBI upCLAS rats (*p = 0.0445) compared to non-TBI ones. INTERPRETATION: These results unambiguously demonstrate slow-wave activity enhancement confers robust disease modification following TBI while overcoming major limitations of other preclinical approaches. Our findings constitute proof-of-concept that boosted sleep intensity mitigates histopathological and cognitive sequelae of brain trauma, suggesting that a clinically relevant, nonobtrusive, sleep-based therapy may represent a novel therapeutic intervention for TBI survivors. ANN NEUROL 2026.