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Page 6 of 20 Choi et al. Cancer Drug Resist. 2026;9:12

typically at wavelengths above 800 nm - to stimulate neural and glial function while minimizing thermal
damage . Among its various effects, tNIR has been shown to increase the contractility and pumping
[52]
function of mLVs, thereby promoting ISF and CSF clearance from the brain [52,54] . In addition, tNIR induces
local vasodilation and relaxation of blood vessels and mLVs through nitric oxide (NO) release, which further
enhances glymphatic flow .
[54]

Electromagnetic stimulation methods such as transcranial direct current stimulation (tDCS) and repetitive
transcranial magnetic stimulation (rTMS) have also been shown to promote glymphatic transport [55,56] . These
modalities have been clinically used as a complementary therapy for neurological disorders, including
Alzheimer’s disease, aiding amyloid-β clearance. tDCS typically delivers ~2 mA of direct current between two
scalp electrodes for several tens of minutes and has been shown to modulate astrocytic inositol
[55]
trisphosphate (IP )/Ca signaling, thereby improving CSF–ISF exchange. Similarly, rTMS applies rapidly
2+
3
changing magnetic fields generated by a scalp-mounted coil, inducing electric currents in cortical tissue that
augment glymphatic transport by modulating astrocytic reactivity, AQP4 polarization, and mLV dilation .
[56]
Recent studies suggest that low-frequency vibration or subtle mechanical stimulation can promote CSF
dynamics and potentially enhance mLVs function [57,58] . Observations that CSF movement is influenced by
physiological oscillations - cardiac pulsation and respiration - raise the possibility that externally replicating
these rhythms may facilitate lymphatic clearance. Vijayakrishnan Nair et al. used neck-region functional
MRI (fMRI) to demonstrate that human CSF movement is simultaneously and synchronously driven by
low-frequency (< 1 Hz) hemodynamic oscillations and respiration . In a complementary animal study, Choi
[57]
et al. showed that low-frequency (2 Hz) auricular vagus nerve stimulation (aVNS) increases arterial
vasomotion and enhances CSF influx along the branches of the middle cerebral artery, demonstrating a
noninvasive method to modulate intracranial fluid flow .
[58]

Among these stimulation modalities, US offers a uniquely advantageous profile for glymphatic modulation
because it delivers acoustic energy with high spatial precision, enabling targeted stimulation of deep brain
structures that regulate CSF–ISF exchange [59-61] . Its mechanical effects - localized pressure oscillations and
micro-vibrations of vessel walls - can directly enhance arterial pulsatility, a primary driver of glymphatic
influx. Furthermore, low-intensity US combined with microbubbles can transiently and reversibly modulate
BBB permeability, further influencing perivascular fluid movement . Unlike optical, electrical, or magnetic
[62]
stimulation, focused US can access specific vascular regions with millimeter-scale accuracy, and its
stimulation parameters (e.g., frequency, pulse pattern, duty cycle) can be precisely tuned to optimize
glymphatic clearance. These characteristics position US as a powerful and flexible tool for both mechanistic
research and potential therapeutic augmentation of glymphatic function.

The different glymphatic flow modulation methods and their key characteristics are summarized in Table 1.

STUDIES ON US-MODULATED GLYMPHATIC TRANSPORT
Building on the unique strengths of US, recent studies have begun to characterize how US actively alters
glymphatic transport. These investigations span diverse experimental frameworks, including MRI, optical
imaging, and molecular assays, collectively demonstrating that US can enhance CSF influx, promote CSF–ISF
exchange, and accelerate metabolic waste clearance. Importantly, several studies have further identified the
biophysical and molecular pathways through which US exerts these effects.

Aryal et al. investigated US-induced enhancement of intrathecal drug delivery using both small- and
large-molecule agents . They focused on the problem of limited drug penetration into the brain
[38]
parenchyma following intrathecal administration, despite its potential to bypass the BBB, which blocks more

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