1000 Section - Transcranial temporal interference stimulation reduces neuroinflammation and neurological dysfunction after traumatic brain injury by enhancing AQP4-mediated glymphatic drainage

Objectives : Traumatic brain injury (TBI) often causes severe cerebral edema, inflammation, and impaired waste clearance. Glymphatic system dysfunction is closely linked to secondary injury after TBI. While transcranial temporal interference stimulation (tTIS) can reduce neuroinflammation and aid recovery, its precise mechanisms remain unclear.

Design: Mice subjected to TBI via the controlled cortical impact (CCI) model were treated with daily 20-minute tTIS sessions over a 3-day period.We assessed tTIS effects on motor/cognitive function, blood-brain barrier integrity, astrocyte activation, and AQP4-mediated glymphatic function. In vitro, a co-culture system of astrocytes with neurons/endothelial cells was established. Lipopolysaccharide (LPS) activated astrocytes, and the effects of AQP4 knockout or polarity restoration on neurovascular damage and neuroplasticity were evaluated.

Results: tTIS significantly reduced neuroinflammation and tissue damage after TBI, promoting neural repair and functional recovery. Mechanistically, tTIS appeared to restore AQP4-mediated glymphatic flow, enhancing clearance of water/metabolic waste and supporting repair. In vitro, restoring AQP4 polarity—not knockout—inhibited LPS-induced A1 astrocyte polarization and promoted the A2 phenotype. It also reduced abnormal reactive oxygen species production in neurons/endothelial cells and decreased neuronal apoptosis induced by activated astrocytes.

Conclusion: tTIS may alleviate neuroinflammation and enhance recovery after TBI by restoring AQP4-mediated glymphatic function, reducing A1 astrocytes, and promoting A2 astrocyte expression. These findings elucidate tTIS's neuroprotective mechanisms and suggest novel strategies for TBI rehabilitation.