Background

This noninvasive approach attempts to modulate the noradrenergic system of the locus coeruleus by stimulating the vagal nerve. It uses electrodes clipped on the outer ear to stimulate the auricular branch of the vagal nerve. This procedure is under investigation for multiple indications, including mild cognitive impairment in Alzheimer’s disease, and motor and nonmotor symptoms in Parkinson’s disease. Auricular stimulation devices are sold in many countries; however, their efficacy has not been proven.

Locus coeruleus neurons are the sole source of norepinephrine in the brain. They accumulate tau pathology and die early in the course of AD and PD (e.g., Jacobs et al., 2021). The resulting lack of norepinephrine impairs attention, learning, and behavior, and contributes to neuroinflammation (Heneka et al. 2002; Bondareff et al., 1982). Vagal nerve stimulation increases hippocampal and cortical norepinephrine levels, and inhibits seizure-like neuron activity that contributes to cognitive decline.

In human studies, a pilot, one-year open-label study in 17 AD patients reported that one year of vagal stimulation via implanted electrodes was well tolerated, and associated with improvement or stability on the MMSE or clinician impression of change in about three quarters of patients. Just under half of patients saw improvement or stability on the ADAS-Cog (Sjogren et al., 2002; Merrill et al., 2006).

In pilot studies, taVANS showed signs of improving cognition in older people. A single session of taVANS to the ear improved memory scores on a face-name recognition task, compared to a sham stimulation (Jacobs et al., 2015). A follow-up study, reported at the 2020 AAIC, reported a larger effect using respiratory-gated stimulation (Jacobs et al., 2020, abstract). In this variation, electrical stimulation is synchronized with breathing and only occurs during exhalation. This type of stimulation enhanced the effects of taVANS on fMRI BOLD signals in the locus coeruleus and cortical areas, and increased functional connectivity between the locus coeruleus and the cortex, compared to stimulation during inhalation (Sclocco et al., 2019). A comparison of stimulation at different frequencies found 100 Hz most effective at enhancing BOLD signals (Sclocco et al., 2020).

Most side effects of taVANS are mild and transient. In a systematic review, the most common were ear and headache pain, tingling, and skin redness (Kim et al., 2022).

In animal work, brief noninvasive stimulation of the vagal nerve in the necks of APP/PS1 mice changed microglia morphology (Kaczmarczyk et al., 2017). Vagal nerve stimulation was reported to reduce Aβ-induced measures of anxiety and depression (Yesiltepe et al. 2022) improved performance on cognitive tests of spatial memory and learning (Yu et al., 2023). In a rat model of postoperative brain inflammation, taVANS prevented inflammation and neurodegeneration (Cai et al., 2019). Similarly, taVANS was neuroprotective and anti-inflammatory in a rat model of PD (Jiang et al., 2018).

Findings

From 2018 to 2022, a study investigated the effects of taVANS on fMRI BOLD signals in 50 patients with mild cognitive impairment. Unilateral left-side taVANS modified brain connectivity in brain networks associated with cognitive deterioration in people with AD (Murphy et al., 2023). Stimulation of the ear lobe away from the vagal nerves served as a sham control and had no effect. At the 2024 AAIC, these investigators reported that a single session of taVANS did not improve performance on a battery of cognitive tests compared to sham stimulation (abstract).

From 2020-2021, a placebo-controlled trial in China tested transcutaneous auricular stimulation in 60 seniors with mild cognitive impairment. Treatment was for 30 minutes twice a day, five days per week for six months, against a primary out of the MoCA. The placebo was stimulation of the earlobe outside of the vagal nerve range. According to published results, active stimulation increased the MoCA by 3.24 points, compared to 0.33 points change in the sham group. A battery of cognitive tests served as secondary outcomes. Only the auditory verbal learning test performance was significantly better in the active stimulation group (Wang et al., 2022). In a preprint, the authors claim the improvement may have been due to an observed strengthening in functional connectivity between regions in the default mode network (Wang et al., 2023).

In November 2021, a trial called WALLe began at Massachusetts General Hospital testing whether respiratory-gated taVANS could improve cognition in older people. The crossover study plans to enroll 140 people age 60 to 85, to receive sham versus active stimulation while being monitored by fMRI and performing a face-name association task. After that, participants receive two weeks of active or sham stimulation, followed by cognitive testing. The primary outcome is performance on the face-name association test. Secondary outcomes include other cognitive tests, including the Preclinical Alzheimer Cognitive Composite. The study will also evaluate AD and inflammation biomarkers. Completion is planned for February 2026 (Feb 2025 conference news).

The same group is evaluating respiratory-gated taVANS for ulcerative colitis, depression, and chronic pain.

From June 2022 to June 2023, The VINCI-AD trial in Dublin assessed the feasibility, safety and tolerability of taVANS on 40 older adults with amnestic mild cognitive impairment. Participants received 60 minutes of active or sham stimulation, followed by computerized cognitive tests including face-name association, attention, spatial navigation, and RBANS with simultaneous NIRS assessment of brain activity. The study also measured blood markers of inflammation. At the 2023 AAIC, investigators reported interim data on 28 participants (abstract). Seventy-five percent of participants had biomarkers indicating AD. Active taVANS significantly improved recall accuracy in the face-name association compared to baseline or sham stimulation. Virtual spatial navigation during active taVANS was quicker than baseline or sham. Other tests did not change during stimulation.

In people with Parkinson’s disease, 10 sessions of in-office taVANS stimulation over two weeks were safe and feasible (Lench et al., 2023). Small pilot studies indicated that taVANS improved gait and blood flow to motor cortices compared to sham treatment (Zhang et al., 2023; Marano et al., 2022). Ongoing studies, mostly in China, are testing taVANS and on motor and nonmotor symptoms in PD. 

For details on these trials, see clinicaltrials.gov