Unraveling Sleep-Dependent Glymphatic Disruption: Insights into Impaired Oxyhemoglobin-Water Dynamics in Mild Traumatic Brain Injury

Sujasha Gupta, PhD, Will Coon, PhD, Franck Amyot, PhD, Angeliki Pollatou, Adriana Penafiel, BS, Clara Scholl, PhD, Elizabeth Metzger, MSPH, J. Kent Werner Jr., MD, PhD

Introduction: The glymphatic system plays a crucial role in clearing metabolic waste from the brain during sleep, with dysfunction linked to amyloid beta (Aβ) plaque accumulation, particularly in conditions like mild traumatic brain injury (mTBI). Impaired glymphatic clearance in mTBI may contribute to neurodegeneration and cognitive decline, making it critical to identify early biomarkers of dysfunction. This study investigates a novel surrogate marker of glymphatic clearance in mTBI by examining sleep-related fluctuations in oxyhemoglobin (HbO) and water dynamics, using their phase differences as proxies for flow alterations. Additionally, by leveraging near-infrared spectroscopy (fNIRS) and Electroencephalography (EEG), we aim to characterize oscillatory patterns of HbO and water in cardiac and respiratory frequency ranges, providing insight into how neurovascular disruptions may underlie glymphatic impairment in mTBI.

Materials and Methods: We used near-infrared spectroscopy (fNIRS) to track HbO and water concentration changes during sleep in mTBI (N=9) and healthy (N=18) controls, alongside electroencephalography (EEG) recordings. After removing movement artifacts, we applied the Modified Beer-Lambert Law (MBLL) to compute HbO and water fluctuations. We then analyzed their spectra in respiratory and cardiac frequency ranges, isolating the periodic component by removing aperiodic power. 

Results and Discussion: In healthy participants, HbO and water showed a 180-degree phase difference across sleep stages, increasing in deep sleep, but this pattern was absent in mTBI. Post-hoc analysis revealed significant phase shift differences (P<0.05; d=1.30) during N3 and Wake in healthy subjects, with no such differences in mTBI. Spectral analysis further showed significantly lower (P<0.05) cardiac frequency power in mTBI compared to healthy controls in REM (cohen’s d = 1.33 for water and d = 1.09 for HbO) and N3 stage of sleep (d = 1.12 for water and d = 1.22 for HbO) .

Conclusion: This suggests mTBI disrupts water flux, possibly glymphatic function, particularly in deep sleep, a phase crucial for waste clearance. Additionally, in REM sleep, TBI subjects show reduced cardiac frequency range bandpower, indicating impaired autonomic regulation. These findings highlight mTBI’s impact on glymphatic clearance and its link to HbO and water dynamics during sleep, underscoring the therapeutic potential of targeting glymphatic function and sleep in mTBI recovery.

DISCLAIMER/CONFLICT OF INTEREST: The project was funded by CDMRP. The opinions and assertions expressed herein are those of the author(s) and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences or the Department of Defense. Neither I nor my family members have a financial interest in any commercial product, service, or organization providing financial support for this research