Referred Percepts in Non-Invasive Trigeminal Nerve Stimulation for Modulating MRI Indices of Cerebrospinal Fluid Movement
DOI: Pending DOI
Synopsis
Noninvasive, temporally patterned electrical stimulation of superficial V1 trigeminal nerve branches, or "Cerebrovascular Pacing™," is an emerging therapy for modulating cerebrospinal fluid (CSF) movement. In 10 healthy awake participants, we characterized sensory percepts from transcutaneous stimulation and assessed MRI indices pre-, during, and post-stimulation. 96% of responses reported sensation distant from the electrode consistent with Aβ fiber recruitment, and 88% reported sleep-tolerable sensations. fMRI BOLD and DTI Low-B both peaked mid-stimulation and returned to baseline before stimulation end. DTI-ALPS indices showed significant increases in perivascular diffusivity (p=0.0155), indicating Cerebrovascular Pacing™ can modulate MRI indices of CSF movement at comfortable levels.
Background
An estimated 2.8 million Americans suffer traumatic brain injuries annually [14]. Immediately after TBI, damage-associated molecular patterns (DAMPs) released into cerebrospinal fluid (CSF) drive inflammation and secondary injury, including a cascade of misfolded and toxic soluble proteins, leading to higher risk of post-concussive syndrome, seizures, dementia, and other neurological disorders. Mechanistically, slow vasomotion drives changes in perivascular volume, passively moving CSF through perivascular spaces and into the parenchyma [5,7]. Trigeminal nerve stimulation (TNS) has been shown to modulate cerebrovascular tone and cerebral blood flow [11,15], with a well-defined safety profile and FDA approval for pediatric ADHD and migraine [2,8]. Existing TNS devices place electrodes just above the eyebrow, where the nerve trunk lies beneath the frontalis and corrugator muscles, requiring charge densities that may activate overlying motor fibers and Aδ nociceptors before engaging the nerve. Cadaveric dissection indicates that the supraorbital and supratrochlear branches of V1 emerge above the muscle and lie subcutaneously superior to the orbital ridge [3,10], where sensory-only branches can be selectively engaged without co-activating overlying motor fibers or skin nociceptors. Whether transcutaneous stimulation at this anatomical location produces referred Aβ sensation without activating Aδ nociceptors has not been characterized in humans.
Methods
In 10 healthy awake participants, we investigated referred percepts from transcutaneous electrical stimulation of the V1 trigeminal nerve and analyzed CSF-related diffusivity (DTI-ALPS and DTI Low-B) and BOLD fMRI changes pre-, during, and post-stimulation. Stimulation was delivered via TENS hydrogel electrodes (Rhythmlink, Columbia, SC) in a current-controlled configuration (500 µs per phase, biphasic, cathodic-leading) in multi-second epochs with gradual linear ramps, titrated to sleep-tolerable Aβ-relevant thresholds before each of three visits. Participants completed a colored pencil survey of sensation intensity and location in the trigeminal dermatome after each visit [1,4,12]. 16 of 24 responses were included after excluding incomplete or mirrored maps. Responses were digitized and analyzed via custom MATLAB image segmentation; intensity values assigned 1-5 per color, with left/right hemisphere differences compared by two-tailed t-test following normality (Shapiro-Wilk) and equal variance (Levene's) testing (α=0.05). Functional images were acquired on a GE SIGNA Premier 3T wide-bore scanner. fMRI BOLD responses were compared across stimulation periods. DTI-ALPS assessed diffusivity along medullary vein perivascular spaces relative to orthogonal fibers as an established glymphatic outflow measure vs. baseline [13]. DTI Low-B assessed brain-wide mean diffusivity in CSF-containing voxels adjacent to major vasculature.
Results
96% of participant responses across three visits reported sensation distant from the electrode, and 88% indicated stimulation was comfortable and sleep-tolerable; no participants reported noxious or painful percepts. Manually scored intensities indicated 46% of responses were bilaterally dominant, while 29% and 25% were left- or right-dominant, respectively. Mean intensities were 3.61±1.11 AU (left) and 3.43±1.51 AU (right); automatically segmented responses show broad referred sensation across the trigeminal dermatome with no significant hemispheric difference (p=0.076). Sensation heatmaps, hemisphere comparisons, qualitative descriptor word clouds, and tolerability survey responses are summarized in Figure 1. In our functional imaging analysis, fMRI BOLD and DTI Low-B showed stim-correlated increases in BOLD signal and perivascular mean diffusivity around major arteries, both peaking approximately halfway through the stimulation epoch and returning to baseline before stimulation ended. The DTI-ALPS index showed a statistically significant increase (stim to baseline, p=0.0155), with a magnitude consistent with a substantial fraction of the change reported during natural sleep [16]. fMRI demonstrated consistent statistically significant bilateral BOLD increases in somatosensory cortex in all subjects, with broad symmetric responses including prefrontal cortex across the cohort, consistent with activation of the TSN-NTS-VTA-PFC pathway. Together, these results indicate Cerebrovascular Pacing™ can modulate MRI indices of cerebrospinal fluid movement at comfortable stimulation levels.
Figure 1 depicts participant-reported sensations elicited by noninvasive trigeminal nerve stimulation. (A) Aggregated heatmap of the participant drawn sensation intensities across the trigeminal dermatome, with color indicating the relative frequency and intensity of sensation reports at each region (scale: 1–5 AU). (B) Mean sensation intensity (AU) for right and left hemisphere. The hemispheric difference was not statistically significant (P = 0.0756). (C) Word cloud of qualitative descriptors provided by participants following stimulation, with font size proportional to reporting frequency. Common descriptors included "comfortable," "vibratory," "not painful," "light," and "pins and needles." (D) Binary survey responses evaluating stimulation tolerability. Nearly all participants reported referred sensations distant to the electrode site in the trigeminal dermatome indicative of Aβ percepts (96%), described the stimulation as comfortable (88%), and indicated they could sleep at the stimulation intensity (88%). No responses rated the stimulation as noxious or painful (0%).
Discussion
This work evaluates reported percepts from sleep-tolerable, noninvasive, temporally patterned trigeminal nerve stimulation. Previously, it was unknown whether the current from surface electrodes was sufficient to activate large-diameter sensory fibers without activating Aδ nociceptors in cutaneous tissue [3]. Cadaveric dissection indicates that the supraorbital and supratrochlear branches are small in diameter with complex branching morphology susceptible to nociceptive percepts directly under the electrode [10]. Aβ sensory fibers within the trigeminal nerve trunk are presumed to elicit a referred sensation radiating throughout the dermatome into the forehead and crown, while Aδ activation produces focal perception of pinching at the point of activation. Our results indicate a window for selective sensory fiber activation, corroborated by broad bilateral fMRI BOLD changes along expected trigeminal pathways and statistically significant increases in DTI-ALPS indices measuring CSF diffusivity. These data further suggest that understanding habituation at the axon, synapse, and centrally will be critical to inform temporal patterning needed to reliably induce slow vasomotion over extended periods associated with brain clearance. Future work will examine stimulation timing relative to sleep, blood biomarkers, patient-reported outcome measures (PRoMs), and MRI measures in TBI populations.
Disclosures
Special thanks to the UW clinical coordination team, WITNe collaborators, and the UW WIMR Imaging Services Core. Funded by DARPA Targeted Neuroplasticity Training Program, NIH U18EB029251, and Wisconsin Alumni Research Foundation. CM is CEO and equity holder of NeuraWorx. KC and JKT are paid consultants of NeuraWorx. KAL and JW are co-founders and equity holders of NeuraWorx. Nothing further to disclose by any author(s) related to this work. The Cerebrovascular Pacing™ System, a proprietary neuromodulation platform, is being developed at NeuraWorx Medical Technologies, Inc.
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