The Relevance of Neurocircuitry-Based TMS EEG Biomarkers and EVs in Next Generation Versatile Therapeutic Approaches of the Human Glymphatic System: A Hypothesis-Driven Perspective

ABSTRACT: This Perspective paper is motivated by a novel understanding of the human glymphatic system (GS) functional anatomy, its critical role in Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative and autoimmune disorders, as well as by novel therapeutic possibilities critically relevant in enhancing the GS function and its healing. Non-invasive transcranial magnetic stimulation (TMS) technology and administration of cell-free extracellular vesicles (EVs) in clinical conditions may well constitute potentially synergistic, versatile, and effective next generation neurotherapeutic approaches to treat human GS dysfunctions. Brain stimulation approaches, such as TMS, act upon brain circuits, which have been strongly considered candidate endophenotypes and factual targets in neuromodulation interventions using multimodal neuroimaging. The dorsolateral prefrontal cortex (DLPFC) has been proposed as a potential target for neuromodulating the GS, a fluid-compartment mechanism involved in waste disposal that is not entirely elucidated in humans, yet considered of critical importance for the normal functioning of the brain and a key factor for its dysfunction in such neurodegenerative conditions as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Likewise, EVs have been proposed as potential GS therapeutic agents, given their capability to traverse the blood-brain barrier (BBB), reduce neuroinflammation, increase cellular communication and central nervous system (CNS) homeostasis, and promote healing. The combined effect of TMS-EEG (TMS-Electroencephalography), and EV approach is putatively complementary, and thus we envision their combined use as a promising, versatile, and potentially effective next generation neurotherapeutic strategy to treat human GS dysfunctions and to become a powerful asset in the treatment of neurodegenerative and autoimmune disorders. Furthermore, anatomically accurate neuroimaging-based navigation of TMS and the assessment of GS functionality via diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) enable precision-medicine personalized interventions in these disorders. On these grounds, we formulate a hypothesis-driven conceptual framework connecting neurocircuitry-based neuromodulation, EV-mediated neuroimmune effects, and DTI-ALPS assessable glymphatic function to identify directions for future experimental and translational clinical research.