A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation (taVNS) to manage long COVID symptoms

Abstract

Background Although the coronavirus disease 19 (COVID-19) pandemic has now impacted the world for over two years, the persistent secondary neuropsychiatric effects are still not fully understood. These "long COVID" symptoms, also referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), can persist for months after infection without any effective treatments. Long COVID involves a complex heterogenous symptomology and can lead to disability and limit work. Long COVID symptoms may be due to sustained inflammatory responses and prolonged immune response after infection. Interestingly, vagus nerve stimulation (VNS) may have anti-inflammatory effects, however, until recently, VNS could not be self-administered, at-home, noninvasively. Methods We created a double-blind, noninvasive transcutaneous auricular VNS (taVNS) system that can be self-administered at home with simultaneous remote monitoring of physiological biomarkers and video supervision by study staff. Subsequently, we carried out a pilot (n = 13) randomized, sham-controlled, trial with this system for four weeks to treat nine predefined long covid symptoms (anxiety, depression, vertigo, anosmia, ageusia, headaches, fatigue, irritability, brain fog). No in-person patient contact was needed, with informed consent, trainings, ratings, and all procedures being conducted remotely during the pandemic (2020-2021) and equipment being shipped to individuals' homes. This trial was registered onClinicalTrials.gov under the identifier: NCT04638673. Results Four-weeks of at-home self-administered taVNS (two, one-hour sessions daily, delivered at suprathreshold intensities) was feasible and safe. Although our trial was not powered to determine efficacy as an intervention in a heterogenous population, the trends in the data suggest taVNS may have a mild to moderate effect in reducing mental fatigue symptoms in a subset of individuals. This innovative study demonstrates the safety and feasibility of supervised self-administered taVNS under a fully contactless protocol and suggests that future studies can safely investigate this novel form of brain stimulation at-home for a variety of neuropsychiatric and motor recovery applications.

Conflict of interest statement

Competing interests

MB has equity in Soterix Medical. All other authors declare that they have no relevant competing interests.

Figures

Figure 1. Study Timeline and Overview.

Participants were shipped a taVNS kit to self-administer in their homes. After receiving the kit, they received either two weeks of either active or sham taVNS. Subsequently, all participants received two additional weeks of active taVNS stimulation.

Figure 2. Overview of Stimulation Methodology.

A) we created an at-home taVNS kit that included all the components required to safely self-administer taVNS, as well as real-time monitor safety via physio monitoring. B) taVNS was administered to participant’s left ear, with the anode placed on the cymba conchae of the ear, and the cathode on the tragus.

Figure 3. Remote Monitoring of Self-Administration Feasibility.

We virtually monitored whether participants needed assistance with both the physiology monitoring and the self-administration. As demonstrated in the graphs, most participants were able to self-administer physio and taVNS proficiently within 3 sessions.

Figure 4. Individual Participant Heart Rate Monitoring.

We recorded the mean heart rate (error bars =sem) during the first 6 taVNS sessions in all participants. Regardless of stimulation condition, all participants maintained a safe mean heart rate and did not experience any bradycardia events.

Figure 5. Long-COVID Symptom Improvement by Randomization Group.

In this small sample, taVNS reduced the mean percent of Long-COVID symptoms experienced by participants. During the two-week blinded period, sham taVNS provided no benefit to participants, however during the open label period, those individuals reduced their Long-COVID symptom burden. In the initial active group, we see a marked reduction in Long-COVID symptoms over the course of treatment and follow-up.

Figure 6. Individual Mental Fatigue Score by Condition.

Individuals receiving sham taVNS initially demonstrated no improvement in mental fatigue, however when switched to active taVNS, see a marked reduction. This is like the initial active group, which demonstrates an improvement in mental fatigue throughout the entire course of active taVNS treatment.