Given its key role in sending or mediating sensory information throughout the body to the brain, the vagus nerve has long interested researchers as a target for potential intervention for myriad conditions. Such research has paid off. To date, research on the efficacy of stimulating the vagus nerve has resulted in approval by the Food and Drug Administration (FDA) for the treatment of drug-resistant epilepsy and depression in patients older than 12 years. A broader role for vagus nerve stimulation (VNS) is suggested by ongoing research for conditions such as pain, migraines, chronic inflammatory conditions, and post-stroke recovery
(J Inflamm Res. 2018;11:203–213).
Another potential role may be for improving auditory processing. A number of preclinical and small pilot studies in humans show a potential for pairing VNS with tones to improve auditory processing, such as for patients with tinnitus. Data show that VNS paired with specific tones improved the tinnitus percept in a rat model and reversed the abnormal primary auditory cortex plasticity linked to tinnitus (Nature. 2011;470:101–104). Subsequent pilot clinical studies looked at the feasibility and safety of VNS paired with tones in patients with moderate-to-severe chronic tinnitus (Neuromodulation. 2014;17:170–179; Sci Rep. 2017;7:11960). These studies found that 50% of patients in the VNS-tone paired group showed clinically meaningful improvements in their tinnitus, compared with 28% in the control group after six weeks of treatment.
Now new preclinical research recently reported by researchers at the University of Texas in Dallas shows that this VNS-induced plasticity does not occur only in the primary auditory cortex, but is more widespread and occurs across multiple areas within the auditory pathway (J Neurophysiol. 2019;122:659-671). Building on prior research that focused on VNS-tone pairing therapy in the context of tinnitus, the new research used VNS-tone pairing therapy in rats with normal hearing to examine the neural response to VNS-tone therapy on subcortical and cortical auditory fields.
Although the results are preliminary, the authors suggest that the multiple changes in the auditory pathway found after VNS-tone therapy in their rat model provides a framework for future preclinical and clinical studies.
The study demonstrated that pairing VNS and tones increased both cortical and subcortical plasticity. “Stimulation of the vagus nerve activates neuromodulator release in the brain, and this neuromodulator release paired with sound presentation generates plasticity throughout the auditory system, both cortically and subcortically,” said the study’s senior author, Crystal T. Engineer, PhD, a research assistant professor at The University of Texas at Dallas. “In the current study, we paired vagus nerve stimulation with the presentation of tone and found that the neural representation of the paired sound was enhanced in four auditory fields: the inferior colliculus, the primary auditory cortex, the anterior auditory field, and the posterior auditory field.”
According to Dr. Engineer, the novelty of this research is that pairing VNS and sound presentation has the ability to alter both early and late levels of the auditory pathway. “By pairing VNS with a sound, we are able to manipulate auditory responses specifically to the paired sound, which opens doors to a variety of new therapeutic tools for individuals with auditory processing disorders,” she said.
Although preliminary, the authors suggest that the multiple changes in the auditory pathway found after VNS-tone therapy in their rat model provide a framework for future preclinical and clinical studies.
Therapeutic Effect
Figure 1. Proximity of the cranial nerve nuclei that may account for cross stimulation.
© Evan Oto / Science Source
The proximity of cranial nerve nuclei in the brainstem is only recently being exploited for clinical benefit,” said Sujana Chandrasekhar, MD, a partner with ENT & Allergy Associates, LLP, associate clinical professor of otolaryngology at Icahn School of Medicine at Mount Sinai in New York City, and an associate editor of ENTtoday (see Figure 1).
Saying that the study advances understanding of the cross-responsiveness between the vagus nerve nucleus and the cochlear nucleus, Dr. Chandrasekhar emphasized the need for more research. “The cross-responsiveness seen in VNS may hold promise in the treatment of auditory pathology, including certain subtypes of tinnitus,” she said. However, although the procedure is generally safe, she cautioned that it is not without risk and that future research is necessary before it can potentially be clinically useful.
Bruce Gantz, MD, professor and head of the department of otolaryngology–head and neck surgery at the University of Iowa in Iowa City, expressed strong caution about the use of this technology for auditory problems. Although he said that the pilot study (Sci Rep. 2017;7:11960) reported some support for a larger clinical trial on the use of this technology for tinnitus, he noted that results of a multicenter trial (not yet published) did not yield a clinically significant benefit in reducing tinnitus. “Whether or not stimulation of the vagus nerve would enhance auditory perception in humans needs further evaluation,” he said, “but I am not very enthusiastic at this point following our experience with tinnitus.”
However, J. Thomas Roland, Jr, MD, chair of the department of otolaryngology–head and neck surgery and professor of otolaryngology and neurosurgery at NYU Langone Medical Center in New York City, thinks this is an exciting area of research.
He and his colleagues are working on a rat model in which they are stimulating the locus aurelius deep in the brain via the vagus nerve to examine the effect on auditory tasks. Rats are first deafened and then trained on tasks linked to different tones (J Neurophysiol. 2016;116:844–858; Brain Res. 2018;S0006-8993(18)30324-X). “We found that if we stimulate the locus aurelius, [the rats] learn the auditory tasks three times as fast, and it only takes a few days [of learning] instead of two weeks,” he said. “I don’t know if that is improving their hearing or just improving their brain’s response to hearing.”
Down the road, Dr. Roland said, they’re interested in testing this technology in people with cochlear implants. “We’re looking at this as a future technique to enhance outcomes with a cochlear implant,” he said. That said, his research is focused on using VNS to enhance hearing with a prosthesis such as a cochlear implant, unlike the current study.
As to that research, “I think this is very preliminary and is another step and more evidence that this may be a very viable way to assist people with hearing,” Dr. Roland said. “I’m happy that other researchers are looking at [VNS] from different angles. It has tremendous potential in a relatively noninvasive way to enhance hearing and auditory learning.”
Mary Beth Nierengarten is a freelance medical writer based in Minnesota.