Mechanistic underpinnings of trigeminal nerve stimulation for enhancing neuropsychological function in dementia

The National Institute on Aging awarded The Feinstein Institutes For Medical Research $460,625 on September 1, 2026, under the Aging Research program (CFDA 93.866) to investigate the mechanistic underpinnings of electrical trigeminal nerve stimulation for enhancing neuropsychological function in dementia.

The project addresses neuropsychiatric symptoms—including anxiety and depression—that affect up to 80 percent of dementia patients and significantly contribute to cognitive decline and reduced quality of life. The research focuses on vascular cognitive impairment and dementia (VCID), the second most common dementia type after Alzheimer's disease, which is particularly vulnerable to psychological stress. The recipient will conduct mechanistic research on how electrical trigeminal nerve stimulation may alleviate neuropsychiatric symptoms in VCID by enhancing serotonergic signaling. Preliminary findings in rat models of VCID indicate that expression of serotonin, CGRP, and CFOS in the amygdala is significantly reduced and correlates with anxiety- and depression-like behaviors, suggesting trigeminal nerve stimulation as a potential noninvasive neuromodulatory intervention for addressing the underlying pathophysiology of neuropsychiatric dysfunction in VCID.

Performance occurs at The Feinstein Institutes' location in Manhasset, New York. The project runs from September 1, 2026, through August 31, 2028.

Abstract

Neuropsychiatric symptoms, such as anxiety and depression, affect up to 80% of dementia patients, significantly contributing to cognitive decline and reduced quality of life. Vascular cognitive impairment and dementia (vcid), the second most common type of dementia after alzheimer's disease, is particularly vulnerable to psychological stress, as even acute anxiety-induced cortisol imbalances exacerbate vascular damage, further impairing cerebrovascular function and accelerating cognitive decline. Despite the significant impact of neuropsychiatric dysfunction in vcid, targeted therapies remain unavailable, underscoring the urgent need for novel approaches to address its underlying pathophysiology. The trigeminal nerve, the largest cranial nerve, is strategically positioned to modulate cortical and subcortical structures involved in cognition, emotion, and behavior. IT transmits sensory information to the thalamus and somatosensory cortex while projecting to brainstem nuclei, including the raphe nucleus, the primary source of serotonin, which influences higher brain regions like the amygdala, crucial for emotional processing. Despite its potential, the role of the trigeminal nerve in enhancing serotonergic signaling remains uninvestigated. Electrical trigeminal nerve stimulation (TNS) is a promising noninvasive neuromodulatory technique with proven safety and efficacy in treating psychological disorders; however, its underlying mechanisms remain largely speculative, and its effects on neuropsychiatric symptoms in dementia have yet to be explored. Our recent findings indicate that TNS may alleviate neuropsychiatric symptoms in vcid by enhancing serotonergic signaling: (i) in a RAT model of vcid, expression of serotonin, cgrp, and cfos in the amygdala is significantly reduced, correlating with anxiety- and depression-like behaviors; (II) TNS increases serotonin, cgrp, and cfos expression in the amygdala of healthy brains; (III) TNS reverses vcid-induced reductions in these markers in the raphe nucleus in dementia models. Building on our preliminary findings and existing neuroanatomical evidence of TNS effects, we hypothesize that TNS enhances serotonergic neurotransmission via a dual mechanism: acutely, by activating neuronal CA2⁺ channels in the amygdala and raphe nucleus to trigger immediate, CA2⁺- dependent serotonin exocytosis; and chronically, by eliciting cgrp release from trigeminal afferents, which amplifies CA2⁺ influx and upregulates serotonin biosynthesis to sustain elevated serotonergic tone. We propose two specific aims: (1) to define the dose-response relationship and molecular mechanism of TNS- induced serotonin release in the healthy brain; (2) to evaluate the therapeutic efficacy and mechanism of TNS in alleviating and neuropsychiatric symptoms in a RAT model of vcid. This project is highly innovative, leveraging a novel bioelectronic approach to target fundamental neurotransmitter dysregulation in dementia.