Cerebrovascular and Glymphatic Dysfunction in Sickle Cell Disease: Evidence from a 40 Hz Gamma Sensory Stimulation Study in Mice

Abstract This pilot study used the Berkeley HbSS humanized mouse model of sickle cell disease (SCD) to assess whether audiovisual 40 Hz gamma sensory stimulation (40 Hz GSS) may serve as a non-pharmacologic approach to reduce chronic pain in SCD. HbSS and HbAA (control) mice received daily one-hour 40 Hz GSS or sham conditions for six weeks and were assessed weekly in the von Frey and forelimb grip strength assays. At baseline, HbSS mice displayed mechanical hypersensitivity and grip strength deficits compared to HbAA controls. Over six weeks, 40 Hz GSS normalized both von Frey and grip strength responses in HbSS mice to levels indistinguishable from HbAA, whereas HbSS sham mice remained impaired. These findings support 40 Hz GSS as a promising, low-cost, non-pharmacological, and non-invasive adjunctive strategy for treating SCD-related chronic pain that may help reduce reliance on opioid analgesics and improve quality of life for those with SCD.