Widespread infection with SARS-CoV-2 has resulted in millions of people havingPost-COVID. Post-COVID is a complex, non-monolithic disease with diverse clinicalmanifestations. Symptoms range from fatigue, brain fog, muscle aches and shortness ofbreath, affecting multiple organ systems simultaneously. To directly address thismulti-organ component of Post-COVID, innovative treatment methods are urgently needed.One potential treatment that we will investigate in our study, is the intervention viathe vagus nerve, as the cranial nerve plays a central role in communication between thebody and the brain and influences targeted behavior. This innovative approach is based onour clinically relevant findings regarding the effects where acute tVNS increased thelevel of effort (Neuser et al., 2020; Ferstl et al., 2021), specifically targeting a keysymptom of Post-COVID. In the proposed study, the investigators aim to investigate theeffectiveness of transcutaneous vagus nerve stimulation (tVNS) as a non-invasive,self-administered treatment for Post-COVID symptoms at home. To evaluate the clinicallyrelevant effects of repeated taVNS application (high-intensity stimulation), theinvestigators will employ a randomized cross-over design to investigatestimulation-induced changes in fatigue, depression and motivation to work for rewardcompared to low-intensity stimulation and to a control group.
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.
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.
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
Department of Psychiatry & Psychotherapy, University of Tübingen
Tübingen 2820860, Baden-Wurttemberg 2953481, Germany
Nils B. Kroemer, Prof. Dr.
+4922828711151
nils.kroemer@uni-tuebingen.de
Andreas Stengel, Prof. Dr.
+497071 29-86714
andreas.stengel@med.uni-tuebingen.de