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This study is to assess if respiratory-gated auricular vagal nerve stimulation (RAVANS) can improve symptoms of post-treatment Lyme disease syndrome
Lyme disease is caused by the tick-borne spirochete bacteria Borrelia burgdoferi and is the most common vector borne illness in the US. A subset of individuals with confirmed Lyme disease go on to experience persistent fatigue, pain, and/or neurocognitive difficulties after treatment that are of sufficient severity to impact quality of life and physical functioning. This chronic condition has since been termed post-treatment Lyme disease syndrome (PTLDS). The cause of PTLDS is not known and currently there are no recommended treatments.
We have hypothesized that some cases of PTLDS may be caused by an infection or inflammatory process on or near the neuroimmune vagus nerve, which communicates the detection of peripheral inflammation to the central nervous system and triggers the sickness response circuitry.
Increasing evidence shows that transcutaneous auricular nerve stimulation (taVNS) can significantly reduce multiple symptoms of stress disorder including depression, cognitive impairment, psychomotor retardation, sleep disturbance. Respiratory-gated auricular vagal afferent nerve stimulation(RAVANS), a type of taVNS, which synchronizes stimulation to the respiratory cycle, modulate vagal systems and optimize stimulations and has been shown beneficial effect in pain management.
In this study, we will conduct a randomized, double blinded, sham-controlled pilot study to explore the effect of RAVANS on the symptoms in individuals diagnosed with PTLDS using psychometric measurement, function and cognitive test, and serum biomarkers.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| RAVANS | Experimental | active RAVANS, 20 minutes each treatment, 3 times per week for 2 weeks |
|
| Sham stimulation | Sham Comparator | Sham-stimulation, 20 minutes each treatment, 3 times per week for 2 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) | Device | non-painful electrical stimulation of the auricle |
|
| Measure | Description | Time Frame |
|---|---|---|
| Horowitz Lyme-Multiple Systemic Infectious Disease Syndrome Questionnaire | This 55-item questionnaire evaluates the frequency, severity, and incidence of Lyme symptoms as well as assessing one's perceived overall health. Minimum value:0 Maximum value: 114 The higher number indicates more symptoms | Before treatment (baseline) and Post treatment ( at the end of 2-week treatment) |
| Measure | Description | Time Frame |
|---|---|---|
| Sedentary Behaviors Questionnaire | This 18-item questionnaire asks about the amount of time spent engaged in sedentary behaviors on typical weekdays and weekends. Minimum:0 Maximum:162 The higher scores mean higher sedentary behaviors | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
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Inclusion Criteria:
Exclusion Criteria:
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33144299 | Background | Aranow C, Atish-Fregoso Y, Lesser M, Mackay M, Anderson E, Chavan S, Zanos TP, Datta-Chaudhuri T, Bouton C, Tracey KJ, Diamond B. Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial. Ann Rheum Dis. 2021 Feb;80(2):203-208. doi: 10.1136/annrheumdis-2020-217872. Epub 2020 Nov 3. | |
| 11189027 |
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| ID | Title | Description |
|---|---|---|
| FG000 | RAVANS | active RAVANS, 20 minutes each treatment, 3 times per week for 2 weeks respiratory-gated auricular vagal afferent nerve stimulation (RAVANS): non-painful electrical stimulation of the auricle |
| FG001 | Sham Stimulation | Sham-stimulation, 20 minutes each treatment, 3 times per week for 2 weeks Sham RAVANS: sham stimulation |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | RAVANS | active RAVANS, 20 minutes each treatment, 3 times per week for 2 weeks respiratory-gated auricular vagal afferent nerve stimulation (RAVANS): non-painful electrical stimulation of the auricle |
| BG001 | Sham Stimulation |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Horowitz Lyme-Multiple Systemic Infectious Disease Syndrome Questionnaire | This 55-item questionnaire evaluates the frequency, severity, and incidence of Lyme symptoms as well as assessing one's perceived overall health. Minimum value:0 Maximum value: 114 The higher number indicates more symptoms | Posted | Mean | Standard Deviation | score on a scale | Before treatment (baseline) and Post treatment ( at the end of 2-week treatment) |
|
within the study period-2 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | RAVANS | active RAVANS, 20 minutes each treatment, 3 times per week for 2 weeks respiratory-gated auricular vagal afferent nerve stimulation (RAVANS): non-painful electrical stimulation of the auricle |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment | nausea during stimulation |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Qing Mei Wang, MD, PhD | Spaulding Rehabilitation Hospital | (617) 952-5299 | wang.qingmei@mgh.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 29, 2023 | Aug 9, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000077342 | Post-Lyme Disease Syndrome |
| ID | Term |
|---|---|
| D008193 | Lyme Disease |
| D016905 | Gram-Negative Bacterial Infections |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
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randomized, double blinded, sham-controlled
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| Sham RAVANS | Device | sham stimulation |
|
| Fatigue Symptom Inventory |
This non-diagnosis-specific questionnaire measures the severity of fatigue symptoms and how much these factors interfere with the subjects' lives. Minimum value:0 Maximum value:127 The higher scores mean higher fatigue symptoms |
| Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
| Brief Pain Inventory-Pain 24 Hours | This 15-item questionnaire assesses the location, severity, and type of current pain, using analogue scales and body diagrams. Subscale-pain 24 hours describes the pain at its worst in the past 24 hours. Minimum value:0 Maximum value: 10 The higher scores means higher pain level | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
| Beck Depression Inventory | This questionnaire evaluates current depressive symptoms. Minimum value: 0 Maximum value: 63 The higher scores mean higher depressive symptoms | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
| Beck Anxiety Inventory | This questionnaire evaluates current anxiety symptoms. Minimum value: 0 Maximum value: 63 The higher scores mean higher anxiety symptoms | Before treatment (at baseline) and after treatment (at the end of 2-week treatment) |
| Pittsburgh Sleep Quality Index | This 9-item questionnaire assesses sleep quality and patterns of sleep. Minimum value: 0 Maximum value: 21 The higher scores mean poorer sleep quality | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
| Timed Up and Go | Measures the time it takes for a person to stand up from a chair, walk 3 meter, turn, walk back, and sit down again. | Before treatment ( baseline) and Post treatment (at the end of 2-week treatment) |
| Time to Complete 4 Meters at Usual Walking Speed, | Measure usual walk speed | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
| NIH Toolbox Cognition Battery (NIHTB-CB) | The following cognitive domains are assessed: executive function (Flanker inhibitory control and attention); cognitive flexibility (Dimensional Change Card Sort); working memory (List Sorting); short-term memory (Picture Sequence), processing speed (Pattern Comparison), Picture vocabulary and Oral Reading Recognition Tests. An overall composite score that combines these outcomes (Total Cognition Composite Score) is reported here. The higher value means better cognitive function. A score at or near 100 indicates ability that is average compared with others nationally. Scores around 115 suggest above-average cognitive ability, while scores around 130 suggest superior ability (in the top 2 percent nationally, based on Toolbox normative data). Conversely, a score around 85 suggests below-average cognitive ability, and a score in the range of 70 or below suggests significant impairment. | Before treatment (at baseline) and Post treatment (at the end of 2-week treatment) |
| Serum Level of Inflammatory Cytokines-IL6 | To determine if RAVANS treatment affects the level of inflammation | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
| Serum Level of Inflammatory Cytokines-IL10 | To determine if RAVANS treatment affects the level of inflammation | Before treatment (at baseline) and after treatment (at the end of 2-week treatment) |
| Serum Level of Inflammatory Cytokines-TNF Alfa | To determine if RAVANS treatment affects the level of inflammation | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
| Background |
| Dantzer R, Konsman JP, Bluthe RM, Kelley KW. Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent? Auton Neurosci. 2000 Dec 20;85(1-3):60-5. doi: 10.1016/S1566-0702(00)00220-4. |
| 9801384 | Background | Ek M, Kurosawa M, Lundeberg T, Ericsson A. Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins. J Neurosci. 1998 Nov 15;18(22):9471-9. doi: 10.1523/JNEUROSCI.18-22-09471.1998. |
| 29236732 | Background | Embers ME, Hasenkampf NR, Jacobs MB, Tardo AC, Doyle-Meyers LA, Philipp MT, Hodzic E. Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding. PLoS One. 2017 Dec 13;12(12):e0189071. doi: 10.1371/journal.pone.0189071. eCollection 2017. |
| 28541256 | Background | Garcia RG, Lin RL, Lee J, Kim J, Barbieri R, Sclocco R, Wasan AD, Edwards RR, Rosen BR, Hadjikhani N, Napadow V. Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal afferent nerve stimulation in migraine patients. Pain. 2017 Aug;158(8):1461-1472. doi: 10.1097/j.pain.0000000000000930. |
| 29459836 | Background | Kong J, Fang J, Park J, Li S, Rong P. Treating Depression with Transcutaneous Auricular Vagus Nerve Stimulation: State of the Art and Future Perspectives. Front Psychiatry. 2018 Feb 5;9:20. doi: 10.3389/fpsyt.2018.00020. eCollection 2018. |
| 22568773 | Background | Napadow V, Edwards RR, Cahalan CM, Mensing G, Greenbaum S, Valovska A, Li A, Kim J, Maeda Y, Park K, Wasan AD. Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. Pain Med. 2012 Jun;13(6):777-89. doi: 10.1111/j.1526-4637.2012.01385.x. Epub 2012 May 8. |
| 23790471 | Background | VanElzakker MB. Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis. Med Hypotheses. 2013 Sep;81(3):414-23. doi: 10.1016/j.mehy.2013.05.034. Epub 2013 Jun 19. |
| 32974369 | Background | Zubcevik N, Mao C, Wang QM, Bose EL, Octavien RN, Crandell D, Wood LJ. Symptom Clusters and Functional Impairment in Individuals Treated for Lyme Borreliosis. Front Med (Lausanne). 2020 Aug 21;7:464. doi: 10.3389/fmed.2020.00464. eCollection 2020. |
Sham-stimulation, 20 minutes each treatment, 3 times per week for 2 weeks
Sham RAVANS: sham stimulation
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Functional Comorbidity Index | The Functional Comorbidity Index (FCI) is a tool developed to predict physical function in adults based on their pre-existing chronic health conditions. The FCI is an unweighted, self-reported index of 18 specific chronic conditions. Each condition is scored on a binary scale with 1 point given for the presence of a condition and 0 for the absence. The sum of the individual condition scores yields FCU score; range, 0 to 18. A score of 0 indicates no comorbidities, while a score of 18 indicates the highest burden of comorbid conditions related to physical function. | Mean | Standard Deviation | units on a scale |
|
|
|
|
| Secondary | Sedentary Behaviors Questionnaire | This 18-item questionnaire asks about the amount of time spent engaged in sedentary behaviors on typical weekdays and weekends. Minimum:0 Maximum:162 The higher scores mean higher sedentary behaviors | Posted | Mean | Standard Deviation | score on a scale | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
|
|
|
|
| Secondary | Fatigue Symptom Inventory | This non-diagnosis-specific questionnaire measures the severity of fatigue symptoms and how much these factors interfere with the subjects' lives. Minimum value:0 Maximum value:127 The higher scores mean higher fatigue symptoms | Posted | Mean | Standard Deviation | score on a scale | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
|
|
|
|
| Secondary | Brief Pain Inventory-Pain 24 Hours | This 15-item questionnaire assesses the location, severity, and type of current pain, using analogue scales and body diagrams. Subscale-pain 24 hours describes the pain at its worst in the past 24 hours. Minimum value:0 Maximum value: 10 The higher scores means higher pain level | Posted | Mean | Standard Deviation | score on a scale | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
|
|
|
|
| Secondary | Beck Depression Inventory | This questionnaire evaluates current depressive symptoms. Minimum value: 0 Maximum value: 63 The higher scores mean higher depressive symptoms | Posted | Mean | Standard Deviation | score on a scale | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
|
|
|
|
| Secondary | Beck Anxiety Inventory | This questionnaire evaluates current anxiety symptoms. Minimum value: 0 Maximum value: 63 The higher scores mean higher anxiety symptoms | Posted | Mean | Standard Deviation | score on a scale | Before treatment (at baseline) and after treatment (at the end of 2-week treatment) |
|
|
|
|
| Secondary | Pittsburgh Sleep Quality Index | This 9-item questionnaire assesses sleep quality and patterns of sleep. Minimum value: 0 Maximum value: 21 The higher scores mean poorer sleep quality | Posted | Mean | Standard Deviation | score on a scale | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
|
|
|
|
| Secondary | Timed Up and Go | Measures the time it takes for a person to stand up from a chair, walk 3 meter, turn, walk back, and sit down again. | Posted | Mean | Standard Deviation | seconds | Before treatment ( baseline) and Post treatment (at the end of 2-week treatment) |
|
|
|
| Secondary | Time to Complete 4 Meters at Usual Walking Speed, | Measure usual walk speed | Posted | Mean | Standard Deviation | seconds | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
|
|
|
| Secondary | NIH Toolbox Cognition Battery (NIHTB-CB) | The following cognitive domains are assessed: executive function (Flanker inhibitory control and attention); cognitive flexibility (Dimensional Change Card Sort); working memory (List Sorting); short-term memory (Picture Sequence), processing speed (Pattern Comparison), Picture vocabulary and Oral Reading Recognition Tests. An overall composite score that combines these outcomes (Total Cognition Composite Score) is reported here. The higher value means better cognitive function. A score at or near 100 indicates ability that is average compared with others nationally. Scores around 115 suggest above-average cognitive ability, while scores around 130 suggest superior ability (in the top 2 percent nationally, based on Toolbox normative data). Conversely, a score around 85 suggests below-average cognitive ability, and a score in the range of 70 or below suggests significant impairment. | Posted | Mean | Standard Deviation | score on a scale | Before treatment (at baseline) and Post treatment (at the end of 2-week treatment) |
|
|
|
|
| Secondary | Serum Level of Inflammatory Cytokines-IL6 | To determine if RAVANS treatment affects the level of inflammation | Posted | Mean | Standard Deviation | fg/ml | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
|
|
|
| Secondary | Serum Level of Inflammatory Cytokines-IL10 | To determine if RAVANS treatment affects the level of inflammation | Posted | Mean | Standard Deviation | fg/ml | Before treatment (at baseline) and after treatment (at the end of 2-week treatment) |
|
|
|
| Secondary | Serum Level of Inflammatory Cytokines-TNF Alfa | To determine if RAVANS treatment affects the level of inflammation | Posted | Mean | Standard Deviation | fg/ml | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) |
|
|
|
| 0 |
| 8 |
| 0 |
| 8 |
| 3 |
| 8 |
| EG001 | Sham Stimulation | Sham-stimulation, 20 minutes each treatment, 3 times per week for 2 weeks Sham RAVANS: sham stimulation | 0 | 7 | 0 | 7 | 1 | 7 |
| Dizziness | General disorders | Non-systematic Assessment | mild dizziness during treatment |
|
| Headache | General disorders | Non-systematic Assessment |
|
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| D007239 | Infections |
| D001899 | Borrelia Infections |
| D013145 | Spirochaetales Infections |
| D017282 | Tick-Borne Diseases |
| D000079426 | Vector Borne Diseases |
| D000094025 | Post-Infectious Disorders |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Superiority |
| t-test, 2 sided | 0.069 | Superiority |
| Superiority |
| t-test, 2 sided | 0.069 | Superiority |
| Superiority |
| t-test, 2 sided | 0.073 | Superiority |
| Superiority |
| t-test, 2 sided | 0.17 | Superiority |
| Superiority |
| t-test, 2 sided | 0.08 | Superiority |
| Superiority |
| t-test, 2 sided | 0.15 | Superiority |
| Superiority |
| t-test, 2 sided | 0.06 | Superiority |