Epipharyngeal sensory stimulation is associated with changes in brainstem-cortical functional connectivity and...

Neurostimulation has emerged as a potential approach for modulating autonomic and neuroimmune function. Because epipharyngeal mucosa receives sensory innervation from cranial afferents, mechanical stimulation of this region may engage neural pathways. Epipharyngeal abrasive therapy (EAT) involves mechanical and chemical stimulation of the epipharyngeal mucosa and is used clinically for chronic epipharyngitis; however, its central and systemic effects remain poorly understood. This study aimed to investigate whether epipharyngeal stimulation using EAT is associated with changes in brainstem functional connectivity and circulating proteomic profiles in healthy adults. Participants underwent five EAT sessions at 7-day intervals (Protocol A), with restingstate functional MRI performed before, immediately after, and four weeks after the first session. A subset also underwent a control protocol without EAT (Protocol B). Wholebrainstem seed-to-voxel functional connectivity was analyzed. Paired plasma samples collected before and after the first EAT session were analyzed using the SomaScan 11K assay. Longitudinal analysis identified altered connectivity between the brainstem and subcallosal/medial frontal region, primarily immediately after EAT. A controlled withinsubject analysis identified an EAT-specific increase in connectivity between the brainstem and right temporal pole, extending into the inferior temporal gyrus. Proteomic analysis identified 13 proteins meeting exploratory screening criteria and significant pathway-level enrichment involving RNA metabolism, translation, and extracellular matrix organization. Mechanical and chemical stimulation of the epipharynx was associated with changes in brainstem-cortical functional connectivity and circulating proteomic signatures. These findings suggest that sensory stimulation of the epipharynx may engage cranial sensory afferent-brainstem pathways and contribute to coordinated central neural and peripheral molecular responses.