Non-invasive brain stimulation and glymphatic function: an aquaporin-4 perspective

The glymphatic system is a brain-wide fluid transport network in which cerebrospinal fluid enters along periarterial spaces, exchanges with interstitial fluid within the parenchyma, supports the redistribution and clearance of interstitial solutes, and drains toward meningeal and extracranial lymphatic pathways. Aquaporin-4 (AQP4), a water channel highly enriched at perivascular astrocytic endfeet, forms a polarized astroglial membrane interface that facilitates water exchange across the gliovascular compartment and critically shapes glymphatic transport. While non-invasive brain stimulation has been widely studied for its effects on neural circuits and network activity, its potential role in regulating brain fluid homeostasis and waste clearance has only recently gained attention. Accumulating evidence suggests that rhythmic sensory stimulation, transcranial ultrasound stimulation, and transcranial magnetic stimulation may influence glymphatic transport through effects on neural oscillations, neurovascular coupling, vascular pulsatility, vasomotion, meningeal lymphatic drainage, and astrocytic endfoot organization. This review summarizes the anatomical and functional basis of the glymphatic system, the membrane targeting and polarization of AQP4, and current evidence on non-invasive brain stimulation-mediated glymphatic modulation from an AQP4-centered perspective.