tES synchronization of slow oscillations in N3 sleep decreases brain electrical impedance: implications for improved brain waste clearance

Abstract The age-related impairment of glial-lymph (glymphatic) mechanisms for brain waste clearance has been suspected as a causal factor in the accumulation of toxic metabolites, including amyloid beta and tau proteins in Alzheimer’s Disease and alpha synuclein in Parkinson’s Disease and Lewy Body Dementia. Because electrical current at low frequencies flows preferentially through extracellular space (ECS), measures of brain electrical impedance may track changes over time in ECS as a function of cerebrospinal fluid (CSF) dynamics that are important to brain waste clearance in sleep. We applied a single-frequency measure of electrical impedance in a study of transcranial electrical stimulation (tES) to enhance deep N3 sleep in healthy adults, using a novel method for estimating the intracranial impedance compartment through separately estimating and subtracting the electrode-skin impedance. The results suggest that, regardless of tES, brain impedance slowly decreases over the course of the night’s sleep versus waking, with a marked decrease in rapid eye movement (REM). Furthermore, the therapeutic tES protocol (applied to synchronize and enhance slow oscillations of N3) resulted in significant brain impedance decreases in the transition from N2 to N3 (as well as in REM), consistent with the fast magnetic resonance imaging (MRI )evidence of respiration-linked CSF inflow at these intervals. Statement of Significance Sleep appears to be a critical period for the brain’s removal of metabolic waste products through its lymph system, which involves both perivascular cerebrospinal fluid (CSF) flow, transport of CSF through the extracellular space of the parenchyma, and glial (aquaporin 4 end feet) transfer across the blood–brain barrier. The decline of waste removal with the decline of stage N3 sleep in aging may be relevant to the neurodegeneration leading to dementia. The present results suggest that transcranial electrical stimulation strategically applied at key sleep stages, such as the N2-N3 transition, may not only enhance the duration of N3 and rapid eye movement sleep, but may facilitate the transient extracellular space expansion driven by cardiac pulses and respiration that supports brain waste clearance in healthy sleep.