Transcutaneous Vagus Nerve Stimulation (tVNS) for Improved Recovery After Exertion.

Official title

Transcutaneous Vagus Nerve Stimulation (tVNS) for Improved Recovery After Exertion in Patients With Long/Post-COVID.

Overview

Widespread infection with SARS-CoV-2 has resulted in millions of people having Post-COVID. Post-COVID is a complex, non-monolithic disease with diverse clinical manifestations. Symptoms range from fatigue, brain fog, muscle aches and shortness of breath, affecting multiple organ systems simultaneously. To directly address this multi-organ component of Post-COVID, innovative treatment methods are urgently needed. One potential treatment that we will investigate in our study, is the intervention via the vagus nerve, as the cranial nerve plays a central role in communication between the body and the brain and influences targeted behavior. This innovative approach is based on our clinically relevant findings regarding the effects where acute tVNS increased the level of effort (Neuser et al., 2020; Ferstl et al., 2021), specifically targeting a key symptom of Post-COVID. In the proposed study, the investigators aim to investigate the effectiveness of transcutaneous vagus nerve stimulation (tVNS) as a non-invasive, self-administered treatment for Post-COVID symptoms at home. To evaluate the clinically relevant effects of repeated taVNS application (high-intensity stimulation), the investigators will employ a randomized cross-over design to investigate stimulation-induced changes in fatigue, depression and motivation to work for reward compared to low-intensity stimulation and to a control group.

Detailed description

The proposed study aims to advance the understanding of Post-COVID treatment using a randomized cross-over design to evaluate the taVNS-induced changes over 12 weeks. A hundred twenty patients diagnosed with Long/Post-COVID are randomly assigned to one of three groups related to the two arms of the study ("Monitoring with low/high-intensity stimulation" vs. Monitoring without stimulation"). In the treatment group, forty patients will start with high-intensity taVNS for 6 weeks, then switch to low-intensity stimulation for an additional 6 weeks. Another 40 patients begin with low-intensity stimulation for 6 weeks, followed by high-intensity taVNS stimulation. The control group ("Monitoring without stimulation") is able to receive taVNS after participation in the study.

The treatment group and the control group will participate in the same monitoring procedures. All participants will attend an initial laboratory session to complete several baseline assessments, including questionnaires, measuring energy expenditure via indirect calorimetry and completing a body silhouette task. Blood samples are taken at every session to evaluate changes in metabolic and inflammatory markers. To assess the motivation to work for rewards, the investigators employ an effort-based-cost-benefit paradigm (Effort Allocation Task). All these lab assessments will be repeated after 6 and 12 weeks to evaluate stimulation-induces changes in primary and secondary outcomes. In addition, all participants are given a cardio bracelet to monitor physiological parameters (e.g. heart rate, heart rate variability, breathing, skin conductance, step counts) over the study period. Over the 12 weeks, the treatment group will self-administer taVNS for four hours daily in a targeted manner, anticipating forthcoming exertion and stimulating in anticipation of an effortful event to enhance the patients' motivational drive and recovery. Another essential part of the study is the monitoring over the 12 weeks. All participants will complete daily ecological momentary assessments via smartphone to monitor their mental states. In addition, participants will perform once a day one of two discounting games (effort or temporal discounting task) to investigate changes in their decision behavior over time. The effort discounting task is essential to assess the motivation of post-COVID patients to pursue subjectively effortful situations over the 12 weeks.

Interventions

• Device transcutaneous vagus nerve stimulation
  The study employs a CE-certified tVNS® E device, ensuring European safety standards (EU regulation 2017/745 on medical devices). This device features a stimulation cycle of 28 seconds on and 32 seconds off, with a 25 Hz impulse frequency. For the high-intensity group, the stimulation intensity will be individually adjusted in the session before starting the high-intensity tVNS stimulation at home. Recommended daily usage is max. 4 hours, after which it automatically shuts off.
• Behavioral Monitoring
  Participants are monitored over 12 weeks using a combination of questionnaires and ecological momentary assessment. This approach allows for a comprehensive assessment of the patient's health and well-being.
• Device cardiowatch bracelet
  The study employs the medically certified cardiowatch bracelet from Corsano (CE-MDR medical certification, FDA 510 (k) cleared) for continuous monitoring of vital signals, such as heart rate, heart rate variability, breathing rate, SpO2, physical activity and sleep.

Primary outcome measures

• Stimulation-induced changes in invigoration: frequency of button presses during the first seconds of the trial to gain monetary rewards in the Effort Allocation Task. [Time frame: Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase]
• Stimulation-induced changes in symptoms of depression [Time frame: Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase]
• Stimulation-induced changes in physical and mental aspects of fatigue [Time frame: Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase]

Secondary outcome measures (11)

• Stimulation-induced changes in heart rate variability [Time frame: during 6-week tVNS compared to during 6-week low-intensity stimulation phase]
• Stimulation-induced changes in physical activity [Time frame: during 6-week tVNS compared to during 6-week low-intensity stimulation phase]
• Stimulation-induced changes in wanting the monetary rewards [Time frame: Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase]
• Stimulation-induced changes in exertion [Time frame: Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase]
• Stimulation-induced changes in the motivation to invest effort: the discounting rate reflecting rewards devalued by effort [Time frame: during 6-week tVNS compared to during 6-week low-intensity stimulation phase]
• Stimulation-induced changes in resting energy expenditure [Time frame: Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase]
• Stimulation-induced changes in metabolic and inflammatory markers [Time frame: Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase]
• Stimulation-induced changes in health-related quality of life [Time frame: Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase]
• Stimulation-induced changes in mood [Time frame: Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase]
• Stimulation-induced changes in maintenance:the average relative frequency across the complete trial to gain monetary rewards in the Effort Allocation Task. [Time frame: Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase]
• Stimulation-induced changes in heart rate [Time frame: during 6-week tVNS compared to during 6-week low-intensity stimulation phase]

Eligibility criteria

Inclusion criteria

• individuals who have previously tested positive for SARS-CoV-2 infection (preferred PCR-Test) or have a medically confirmed history of COVID-19 (preferred SARS-CoV-2 Antibody-test) and have persistent symptoms (including Post-COVID) .
• clinical diagnoses made by physician: individuals are included with at least one persistent symptom for at least 4 weeks (Long-COVID) or at least 8 weeks (Post-COVID) following the SARS-CoV-2 infections, such as fatigue, shortness of breath, brain fog, headaches, irritability, cognitive difficulties, muscle or joint pain, sleep disturbances, etc.
• Participants should not have an alternative explanation for their persistent symptoms, ruling out other medical or psychiatric conditions.

Exclusion criteria

• lack of capacity for consent
• insufficient German language skills: Participants must have sufficient (B2 German) language skills to understand the informed consent form, study procedures, and questionnaires.
• Intensive Care Unit treatment during COVID-19 infection
• BMI > 18.5 \& BMI < 35 kg/m2

Lifetime (according to DSM 5):

• brain injury, stroke, epilepsy, or history of seizures
• schizophrenia
• bipolar disorder
• severe substance use disorders, except tobacco
• cardiac arrhythmia, coronary heart disease
• 12-month prevalence: pregnancy or nursing

Additional exclusion criteria for a safe application of tVNS:

• active implant (pacemaker, cochlear implant, implanted electrode device) and cerebral shunts
• required permanent use of left-sided hearing aid
• ear infections, open wounds, or impaired skin at electrode sites

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Single blind

Primary purpose

Treatment

Study locations

Germany · 1 center

• Department of Psychiatry & Psychotherapy, University of Tübingen — Tübingen

Identifiers

NCT: NCT06510985 · TUE012_tvns_longCovid

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗