The Glymphatic System: From Basic Research Advances to Non-Invasive Brain Stimulation Applications-A Narrative Review

The glymphatic system (GS) is a pathway for waste clearance in the brain and a promising therapeutic target for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). GS function is governed by multiple interacting factors, such as aquaporin-4 (AQP4) polarization, cerebral arterial pulsatility, and the integrity of meningeal lymphatic vessels (MLVs). Despite growing recognition of the importance of the GS, effective strategies to actively and non-invasively enhance glymphatic function have long been lacking. In recent years, non-invasive neuromodulatory approaches-most notably focused ultrasound (FUS), repetitive transcranial magnetic stimulation (rTMS), and transcranial photobiomodulation (tPBM)-have emerged as novel strategies to modulate GS activity. Growing evidence suggests that these interventions can enhance glymphatic transport by influencing key regulatory mechanisms, including cerebrovascular dynamics, AQP4 expression and localization, and meningeal lymphatic drainage. In this review, we summarize current experimental advances in non-invasive, external alterations of the GS, discuss underlying mechanisms and translational challenges, and highlight the therapeutic potential of GS modulation in neurological diseases characterized by impaired waste clearance. However, further research about the function and dysfunction of the GS in humans is needed to evaluate the findings from animal studies and thereby fill the translational gap in the human pathophysiology of the GS.