Post-Treatment Lyme Disease Syndrome
Conditions
Brief summary
This study is to assess if respiratory-gated auricular vagal nerve stimulation (RAVANS) can improve symptoms of post-treatment Lyme disease syndrome
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.
Interventions
DEVICErespiratory-gated auricular vagal afferent nerve stimulation (RAVANS)
non-painful electrical stimulation of the auricle
DEVICESham RAVANS
sham stimulation
Sponsors
Spaulding Rehabilitation Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
randomized, double blinded, sham-controlled
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Horowitz Lyme-Multiple Systemic Infectious Disease Syndrome Questionnaire | Before treatment (baseline) and Post treatment ( at the end of 2-week treatment) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sedentary Behaviors Questionnaire | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) | 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 |
| Fatigue Symptom Inventory | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) | 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 |
| Brief Pain Inventory-Pain 24 Hours | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) | 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 |
| Beck Depression Inventory | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) | This questionnaire evaluates current depressive symptoms. Minimum value: 0 Maximum value: 63 The higher scores mean higher depressive symptoms |
| Beck Anxiety Inventory | Before treatment (at baseline) and after treatment (at the end of 2-week treatment) | This questionnaire evaluates current anxiety symptoms. Minimum value: 0 Maximum value: 63 The higher scores mean higher anxiety symptoms |
| Pittsburgh Sleep Quality Index | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) | This 9-item questionnaire assesses sleep quality and patterns of sleep. Minimum value: 0 Maximum value: 21 The higher scores mean poorer sleep quality |
| Timed Up and Go | Before treatment ( baseline) and Post treatment (at the end of 2-week treatment) | Measures the time it takes for a person to stand up from a chair, walk 3 meter, turn, walk back, and sit down again. |
| Time to Complete 4 Meters at Usual Walking Speed, | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) | Measure usual walk speed |
| NIH Toolbox Cognition Battery (NIHTB-CB) | Before treatment (at baseline) and Post treatment (at the end of 2-week treatment) | 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. |
| Serum Level of Inflammatory Cytokines-IL6 | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) | To determine if RAVANS treatment affects the level of inflammation |
| Serum Level of Inflammatory Cytokines-IL10 | Before treatment (at baseline) and after treatment (at the end of 2-week treatment) | To determine if RAVANS treatment affects the level of inflammation |
| Serum Level of Inflammatory Cytokines-TNF Alfa | Before treatment (baseline) and Post treatment (at the end of 2-week treatment) | To determine if RAVANS treatment affects the level of inflammation |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 8 |
| Sham stimulation Sham-stimulation, 20 minutes each treatment, 3 times per week for 2 weeks
Sham RAVANS: sham stimulation | 7 |
| Total | 15 |
Baseline characteristics
| Characteristic | RAVANS | Sham stimulation | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 5 Participants | 11 Participants |
| Age, Continuous | 50.3 years STANDARD_DEVIATION 18.1 | 59.1 years STANDARD_DEVIATION 12.6 | 54.4 years STANDARD_DEVIATION 15.9 |
| Functional Comorbidity Index | 15.1 units on a scale STANDARD_DEVIATION 1.21 | 14.6 units on a scale STANDARD_DEVIATION 2.4 | 14.8 units on a scale STANDARD_DEVIATION 1.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 7 Participants | 15 Participants |
| Region of Enrollment United States | 8 participants | 7 participants | 15 participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 7 |
| other Total, other adverse events | 3 / 8 | 1 / 7 |
| serious Total, serious adverse events | 0 / 8 | 0 / 7 |
Outcome results
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
Time frame: Before treatment (baseline) and Post treatment ( at the end of 2-week treatment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVANS | Horowitz Lyme-Multiple Systemic Infectious Disease Syndrome Questionnaire | Before Treatment | 50.5 score on a scale | Standard Deviation 21.3 |
| RAVANS | Horowitz Lyme-Multiple Systemic Infectious Disease Syndrome Questionnaire | Post Treatment | 33.8 score on a scale | Standard Deviation 17.3 |
| Sham stimulation | Horowitz Lyme-Multiple Systemic Infectious Disease Syndrome Questionnaire | Before Treatment | 44.8 score on a scale | Standard Deviation 14.1 |
| Sham stimulation | Horowitz Lyme-Multiple Systemic Infectious Disease Syndrome Questionnaire | Post Treatment | 25.6 score on a scale | Standard Deviation 9.9 |
p-value: 0.07ANOVA
p-value: 0.039t-test, 2 sided
p-value: 0.037t-test, 2 sided
Secondary
Beck Anxiety Inventory
This questionnaire evaluates current anxiety symptoms. Minimum value: 0 Maximum value: 63 The higher scores mean higher anxiety symptoms
Time frame: Before treatment (at baseline) and after treatment (at the end of 2-week treatment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVANS | Beck Anxiety Inventory | Before Treatment | 19.5 score on a scale | Standard Deviation 11.1 |
| RAVANS | Beck Anxiety Inventory | Post Treatment | 11.5 score on a scale | Standard Deviation 9.9 |
| Sham stimulation | Beck Anxiety Inventory | Post Treatment | 9.3 score on a scale | Standard Deviation 6.2 |
| Sham stimulation | Beck Anxiety Inventory | Before Treatment | 13.1 score on a scale | Standard Deviation 0.8 |
p-value: 0.29ANOVA
p-value: 0.038t-test, 2 sided
p-value: 0.08t-test, 2 sided
Secondary
Beck Depression Inventory
This questionnaire evaluates current depressive symptoms. Minimum value: 0 Maximum value: 63 The higher scores mean higher depressive symptoms
Time frame: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVANS | Beck Depression Inventory | Before Treatment | 42.1 score on a scale | Standard Deviation 12.9 |
| RAVANS | Beck Depression Inventory | Post Treatment | 33.7 score on a scale | Standard Deviation 14.6 |
| Sham stimulation | Beck Depression Inventory | Before Treatment | 33.3 score on a scale | Standard Deviation 10.9 |
| Sham stimulation | Beck Depression Inventory | Post Treatment | 28 score on a scale | Standard Deviation 4.9 |
p-value: 0.93ANOVA
p-value: 0.02t-test, 2 sided
p-value: 0.17t-test, 2 sided
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
Time frame: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVANS | Brief Pain Inventory-Pain 24 Hours | Before Treatment | 5.6 score on a scale | Standard Deviation 2.1 |
| RAVANS | Brief Pain Inventory-Pain 24 Hours | Post Treatment | 4.8 score on a scale | Standard Deviation 3.3 |
| Sham stimulation | Brief Pain Inventory-Pain 24 Hours | Before Treatment | 6.4 score on a scale | Standard Deviation 2.2 |
| Sham stimulation | Brief Pain Inventory-Pain 24 Hours | Post Treatment | 4.4 score on a scale | Standard Deviation 2.9 |
p-value: 0.35ANOVA
p-value: 0.59t-test, 2 sided
p-value: 0.073t-test, 2 sided
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
Time frame: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVANS | Fatigue Symptom Inventory | Before Treatment | 89.4 score on a scale | Standard Deviation 20.6 |
| RAVANS | Fatigue Symptom Inventory | Post Treatment | 66.8 score on a scale | Standard Deviation 31.4 |
| Sham stimulation | Fatigue Symptom Inventory | Before Treatment | 65.4 score on a scale | Standard Deviation 34.3 |
| Sham stimulation | Fatigue Symptom Inventory | Post Treatment | 44.3 score on a scale | Standard Deviation 22.9 |
p-value: 0.92ANOVA
p-value: 0.053t-test, 2 sided
p-value: 0.069t-test, 2 sided
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.
Time frame: Before treatment (at baseline) and Post treatment (at the end of 2-week treatment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVANS | NIH Toolbox Cognition Battery (NIHTB-CB) | Before Treatment | 109.8 score on a scale | Standard Deviation 7.6 |
| RAVANS | NIH Toolbox Cognition Battery (NIHTB-CB) | Post Treatment | 118.7 score on a scale | Standard Deviation 9.2 |
| Sham stimulation | NIH Toolbox Cognition Battery (NIHTB-CB) | Before Treatment | 107.2 score on a scale | Standard Deviation 4.7 |
| Sham stimulation | NIH Toolbox Cognition Battery (NIHTB-CB) | Post Treatment | 113.6 score on a scale | Standard Deviation 9.1 |
p-value: 0.42ANOVA
p-value: 0.001t-test, 2 sided
p-value: 0.06t-test, 2 sided
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
Time frame: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVANS | Pittsburgh Sleep Quality Index | Before Treatment | 13.8 score on a scale | Standard Deviation 4.2 |
| RAVANS | Pittsburgh Sleep Quality Index | Post Treatment | 9.8 score on a scale | Standard Deviation 5.7 |
| Sham stimulation | Pittsburgh Sleep Quality Index | Before Treatment | 9.0 score on a scale | Standard Deviation 4.2 |
| Sham stimulation | Pittsburgh Sleep Quality Index | Post Treatment | 8.0 score on a scale | Standard Deviation 3.9 |
p-value: 0.04ANOVA
p-value: 0.007t-test, 2 sided
p-value: 0.15t-test, 2 sided
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
Time frame: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVANS | Sedentary Behaviors Questionnaire | Before Treatment | 55.8 score on a scale | Standard Deviation 11.5 |
| RAVANS | Sedentary Behaviors Questionnaire | Post Treatment | 48.8 score on a scale | Standard Deviation 22.5 |
| Sham stimulation | Sedentary Behaviors Questionnaire | Before Treatment | 49.5 score on a scale | Standard Deviation 8.4 |
| Sham stimulation | Sedentary Behaviors Questionnaire | Post Treatment | 52.6 score on a scale | Standard Deviation 12.4 |
p-value: 0.38ANOVA
p-value: 0.79t-test, 2 sided
p-value: 0.069t-test, 2 sided
Secondary
Serum Level of Inflammatory Cytokines-IL10
To determine if RAVANS treatment affects the level of inflammation
Time frame: Before treatment (at baseline) and after treatment (at the end of 2-week treatment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVANS | Serum Level of Inflammatory Cytokines-IL10 | Before Treatment | 668 fg/ml | Standard Deviation 293 |
| RAVANS | Serum Level of Inflammatory Cytokines-IL10 | Post Treatment | 616 fg/ml | Standard Deviation 159 |
| Sham stimulation | Serum Level of Inflammatory Cytokines-IL10 | Before Treatment | 742 fg/ml | Standard Deviation 308 |
| Sham stimulation | Serum Level of Inflammatory Cytokines-IL10 | Post Treatment | 713 fg/ml | Standard Deviation 217 |
Secondary
Serum Level of Inflammatory Cytokines-IL6
To determine if RAVANS treatment affects the level of inflammation
Time frame: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVANS | Serum Level of Inflammatory Cytokines-IL6 | Before Treatment | 1897 fg/ml | Standard Deviation 1658 |
| RAVANS | Serum Level of Inflammatory Cytokines-IL6 | Post Treatment | 2798 fg/ml | Standard Deviation 2391 |
| Sham stimulation | Serum Level of Inflammatory Cytokines-IL6 | Before Treatment | 2648 fg/ml | Standard Deviation 1920 |
| Sham stimulation | Serum Level of Inflammatory Cytokines-IL6 | Post Treatment | 2044 fg/ml | Standard Deviation 661 |
Secondary
Serum Level of Inflammatory Cytokines-TNF Alfa
To determine if RAVANS treatment affects the level of inflammation
Time frame: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVANS | Serum Level of Inflammatory Cytokines-TNF Alfa | Before Treatment | 473 fg/ml | Standard Deviation 95 |
| RAVANS | Serum Level of Inflammatory Cytokines-TNF Alfa | Post Treatment | 485 fg/ml | Standard Deviation 107 |
| Sham stimulation | Serum Level of Inflammatory Cytokines-TNF Alfa | Before Treatment | 492 fg/ml | Standard Deviation 137 |
| Sham stimulation | Serum Level of Inflammatory Cytokines-TNF Alfa | Post Treatment | 470 fg/ml | Standard Deviation 135 |
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.
Time frame: Before treatment ( baseline) and Post treatment (at the end of 2-week treatment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVANS | Timed Up and Go | Before Treatment | 10.5 seconds | Standard Deviation 3.5 |
| RAVANS | Timed Up and Go | Post Treatment | 9.5 seconds | Standard Deviation 2.8 |
| Sham stimulation | Timed Up and Go | Before Treatment | 9.3 seconds | Standard Deviation 2.4 |
| Sham stimulation | Timed Up and Go | Post Treatment | 8.6 seconds | Standard Deviation 1.7 |
Secondary
Time to Complete 4 Meters at Usual Walking Speed,
Measure usual walk speed
Time frame: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAVANS | Time to Complete 4 Meters at Usual Walking Speed, | Before Treatment | 4.9 seconds | Standard Deviation 1.1 |
| RAVANS | Time to Complete 4 Meters at Usual Walking Speed, | Post Treatment | 4.2 seconds | Standard Deviation 0.9 |
| Sham stimulation | Time to Complete 4 Meters at Usual Walking Speed, | Before Treatment | 4.6 seconds | Standard Deviation 0.6 |
| Sham stimulation | Time to Complete 4 Meters at Usual Walking Speed, | Post Treatment | 4.3 seconds | Standard Deviation 1 |