Effect of Auricular Vagal Nerve Electrical Stimulation on Post-Treatment Lyme Disease Syndrome (RavLyme)

Pilot, Effect of Respiratory-Gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) on Post-Treatment Lyme Disease Syndrome

This study is to assess if respiratory-gated auricular vagal nerve stimulation (RAVANS) can improve symptoms of post-treatment Lyme disease syndrome

Study Overview

• Status: Completed
• Conditions: Post-Treatment Lyme Disease Syndrome
• Intervention / Treatment: Device: respiratory-gated auricular vagal afferent nerve stimulation (RAVANS); Device: Sham RAVANS

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 15

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults of all genders ≥ 18 years
2. History of Lyme disease treated with antibiotics, and current PTLDS diagnosed by a physician
3. Evidence of past B. burgdorferi infection based on positive results from both enzyme immunoassay and Western blot testing.
4. Ability to provide informed consent,
5. willing to maintain current PTLDS treatment regimen during participation in the study (if on long-term antibiotics or supplements for PTLDS management).

Exclusion Criteria:

1. History of other neurological disorder that in the judgement of the investigator could interfere with the treatment or the interpretation of the results (e.g., epilepsy, history of stroke, tumor, brain tissue damaging pathologies etc.).
2. Current psychotic disorder (e.g., schizophrenia).
3. Current acute illness or infection (e.g. cold or flu).
4. Current or past history of psychiatric illness; PTSD, depression and anxiety are exclusion criteria only if the conditions are so severe as to have required hospitalization in the past 5 years.
5. History of recurrent vaso-vagal syncope
6. Bradycardia defined as resting heart rate <50bpm
7. Implanted electronic device (e.g., pacemaker, neurostimulator)
8. Use of immunosuppressive medication such as prednisone, TNF medications within 2 weeks of the visit or anticipated use during the study.
9. Current use of anti-inflammatory steroid use.
10. Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RAVANS; active RAVANS, 20 minutes each treatment, 3 times per week for 2 weeks	Device: respiratory-gated auricular vagal afferent nerve stimulation (RAVANS); non-painful electrical stimulation of the auricle; Other Names: transcutaneous vagus nerve stimulation
Sham Comparator: Sham stimulation; Sham-stimulation, 20 minutes each treatment, 3 times per week for 2 weeks	Device: Sham RAVANS; sham stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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)

Secondary Outcome Measures

Outcome Measure	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)
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)

Collaborators and Investigators

• Sponsor: Spaulding Rehabilitation Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2022
• Primary Completion (Actual): August 11, 2024
• Study Completion (Actual): April 25, 2025

Study Registration Dates

• First Submitted: June 9, 2021
• First Submitted That Met QC Criteria: June 23, 2021
• First Posted (Actual): June 24, 2021

Study Record Updates

• Last Update Posted (Actual): February 12, 2026
• Last Update Submitted That Met QC Criteria: January 25, 2026
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vector Borne Diseases; Post-Infectious Disorders; Pathologic Processes; Chronic Disease; Disease Attributes; Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Negative Bacterial Infections; Borrelia Infections; Spirochaetales Infections; Tick-Borne Diseases; Lyme Disease; Pathological Conditions, Signs and Symptoms; Post-Lyme Disease Syndrome
• Other Study ID Numbers: 2021P000566

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO