Post-COVID-19 Syndrome
Conditions
Keywords
Post-COVID-19 Syndrome, taVNS, effort, fatigue, heart rate
Brief summary
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
DEVICEtranscutaneous 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.
BEHAVIORALMonitoring
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.
DEVICEcardiowatch 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.
Sponsors
University Hospital Tuebingen
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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 \< 30 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase | Changes in invigoration to work for rewards are operationalized as the relative increase in the frequency of button presses on an Xbox controller during the first seconds of the trial in the Effort Allocation Task. |
| Stimulation-induced changes in symptoms of depression | Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase | Changes in symptoms of depression are measured via the Montgomery Asberg Depression Scale. The MADRS comprises 10 items rated on a scale from 0 to 6 to compute a sum score with higher scores indicating severe symptoms of depression. |
| Stimulation-induced changes in physical and mental aspects of fatigue | Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase | Changes in fatigue are measured by the Chalder Fatigue scale. The CFS comprises 11 questions rated on a 4-point Likert scale to compute a sum score. It will be measured three times six weeks apart. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stimulation-induced changes in heart rate variability | during 6-week tVNS compared to during 6-week low-intensity stimulation phase | Changes in heart rate variability are measured by a cardiowatch bracelet to evaluate autonomic nervous system activity. It will be measured over three months daily. |
| Stimulation-induced changes in physical activity | during 6-week tVNS compared to during 6-week low-intensity stimulation phase | Changes in physical activity are measured by step count per day, which are recorded by the cardiowatch bracelet. It will be measured over three months daily. |
| Stimulation-induced changes in wanting the monetary rewards | Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase | Changes in wanting monetary rewards are measured via a visual analogue scale rating after each effortful trial in the Effort Allocation Task. It will be measured three times six weeks apart. |
| Stimulation-induced changes in exertion | Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase | Changes in exertion are measured via a visual analogue scale rating after each effortful trial. It will be measured three times six weeks apart. |
| Stimulation-induced changes in the motivation to invest effort: the discounting rate reflecting rewards devalued by effort | during 6-week tVNS compared to during 6-week low-intensity stimulation phase | Changes in the motivation to invest effort is quantified by estimating the participant-specific discounting factor (k) and the inverse temperature parameter (β), which are derived by fitting the participant's observed choice behavior in the effort discounting task to discounting models. It will be measured at least twice a week over three months. |
| Stimulation-induced changes in metabolic and inflammatory markers | Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase | Metabolic hormone levels and inflammatory markers are assessed from blood samples. It will be measured three times six weeks apart. |
| Stimulation-induced changes in health-related quality of life | Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase | Changes in health-related quality of life are measured by the Short-Form-12 health survey (SF-12), consisting of 12 questions (weighted sum score). It will be measured three times six weeks apart. |
| Stimulation-induced changes in mood and mood response to effort | Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase | Changes in positive and negative mood ratings are measured with the questions of the Positive and Negative Affect Schedule (PANAS) questionnaire on visual analog scales (0-100) four times within each experimental session. For each assessment (4x3 time points), all items will be included in the analyses as repeated measures for NA and PA, respectively. |
| Stimulation-induced changes in maintenance:the average relative frequency across the complete trial to gain monetary rewards in the Effort Allocation Task. | Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase | Changes in motivation to work for rewards are operationalized as the average relative increase in the frequency of button presses on an Xbox controller across the complete trial in the Effort allocation task. |
| Stimulation-induced changes in heart rate | during 6-week tVNS compared to during 6-week low-intensity stimulation phase | Changes in heart rate are measured by a cardiowatch bracelet depending on physical activity phases |
| Stimulation-induced changes in effort utility | Pre-treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase | Effort utility will be calculated as the correlation between trial-wise wanting ratings and effort maintenance (i.e., average button press frequency over the trial). |
| stimulation-induced changes in self-reported depressive symptoms | Pre treatment vs. after 6-week tVNS vs. after 6-week low-intensity stimulation phase | Changes in self-reported depressive symptoms will be assessed using the Beck Depression Inventory-II (BDI-II). The BDI consists of 20 items and a sum score is calculated across all items. |
| Stimulation-induced changes in HR | During 6-week tVNS compared to during 6-week low-intensity stimulation phase | HR is measured continuously with the CardioWatch bracelet during the intervention phases between sessions. HR parameters will be calculated for \~1 h time intervals in which participants reported being at rest each day, to compare changes in resting HR. |
Countries
Germany
Contacts
PRINCIPAL_INVESTIGATORNils B. Kroemer, Prof. Dr.
Department of Psychiatry & Psychotherapy, University of Tübingen,Tübingen, 72076
PRINCIPAL_INVESTIGATORAndreas J. Fallgatter, Prof. Dr.
Department of Psychiatry & Psychotherapy, University of Tübingen,Tübingen, 72076
Outcome results
None listed