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

University Hospital Tuebingen

Status: Not yet enrolling

Conditions: Post-COVID-19 Syndrome

Treatments: Device: cardiowatch bracelet; Device: transcutaneous vagus nerve stimulation; Behavioral: Monitoring

Study type: Interventional

Funder types: Other

Identifiers

NCT06510985

TUE012_tvns_longCovid

Details and patient eligibility

About

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.

Full 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.

Enrollment: 120 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

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120 participants in 2 patient groups

Monitoring with high/low-intensity stimulation

Experimental group

Description:

The cross-over design includes one group which starts with high-intensity stimulation (n = 40) and another group, who starts with low-intensity stimulation (n = 40). The first group receives at first high-intensity for 6 weeks, followed by a low-intensity stimulation phase for 6 weeks. To control for placebo effects, other forty individuals start with the 6-week low-intensity stimulation phase followed by 6 weeks of high-intensity tVNS stimulation phase.

Treatment:

Behavioral: Monitoring

Device: transcutaneous vagus nerve stimulation

Device: cardiowatch bracelet

Monitoring without stimulation

Experimental group

Description:

Another group of patients is included as a control group (n = 40) undergoing 'treatment as usual' for Long/Post Covid. This group of participants receive the same monitoring throughout their participation during 12 weeks as the Stimulation-Group. As there is no standardized treatment protocol for Long/Post Covid, 'treatment as usual' implies a supportive approach. This group of participants have the option to receive taVNS stimulation after participating in the study.

Treatment:

Behavioral: Monitoring

Device: cardiowatch bracelet