Tic Disorder, Chronic Motor or Vocal, Tourette Syndrome
Conditions
Keywords
Tourette, tic, Transcutaneous Electric Nerve Stimulation, Median Nerve
Brief summary
A recent report (Morera Maiquez et al 2020) described reduced tic severity in people with Tourette syndrome during 1-minute epochs of median nerve stimulation (MNS) at 10 Hz. Among the various questions still to be answered is the question of whether a device to administer MNS is practical for use in a chronic, real-world setting. This study will recruit participants who complete the clinic-based, blinded, randomized controlled trial, https://clinicaltrials.gov/ct2/show/NCT04731714, to determine the real-world usage and apparent utility of median nerve stimulation in people with chronic tics.
Detailed description
Chronic tic disorders (CTD), including Tourette syndrome (TS), are associated with a substantially reduced quality of life (Evans et al 2016). Medication treatments are no more than 50-60% effective in randomized, controlled trials (RCTs), and are often discontinued due to unacceptable side effects (Thomas and Cavanna 2013). Behavioral therapies require ability to participate in therapy and a specially trained therapist (Scahill et al 2013), but weekly visits to psychologists are impractical for many Americans, especially in rural areas (Lin et al 2016). Patients strongly desire new treatment options (Cuenca et al 2015). In June, 2020, Stephen Jackson's group at the University of Nottingham published a fascinating report in Current Biology on a potential novel treatment for tics (Morera Maiquez et al 2020). The radical new idea arose from observations associating movement inhibition with 8-14 Hz activity in motor cortex. They first showed that rhythmic 12 Hz peripheral stimulation of the median nerve evoked synchronous contralateral EEG activity over primary sensorimotor cortex, whereas arrhythmic stimulation at the same mean rate did not. As hypothesized, median nerve stimulation (MNS) at 12 Hz created small but statistically significant effects on initiation of voluntary movements. Importantly, they also demonstrated that this stimulation did not meaningfully impair concentration, suggesting that the effect did not operate through simple distraction. They went on to test 10 Hz MNS in 19 TS patients, and demonstrated using blinded video ratings a significant reduction in tic number and severity during 1-minute stimulation epochs vs 1-minute no-stimulation epochs. They noted that in some participants, benefit lasted beyond the end of the stimulation epoch \[personal correspondence\]. Videos accompanying the publication showed dramatic benefit during MNS in some subjects. Although the authors appropriately noted the steps needed to generalize these results to clinical practice, news reports already have led a number of TS patients to contact them asking for treatment. The Nottingham group has referred such inquiries from the U.S. to me as leader of our Wash.U. Tourette Association of America (TAA) Center of Excellence. Among the various questions still to be answered is the question of whether such a device would be practical for use in the real world. This study will supply participants with a commercially available transcutaneous electrical nerve stimulation (TENS) units to use for median nerve stimulation as described in the Nottingham study. Participants will be told to use the device as much or as little as desired to see how such stimulation might be utilized in the real world. Here the investigators propose (a) to determine the real-world usage and apparent utility of stimulation in people with chronic tics, and (b) to determine momentary self-rated efficacy and side effects of stimulation. The investigators will also compare results from this study to those from the Peripheral induction of inhibitory brain circuits to treat Tourette's: pilot study, from which participants will be drawn, in order to compare laboratory and real-world efficacy. Aim 1. Determine the real-world usage and apparent utility of stimulation in people with chronic tics. Participants will be allowed to choose when and for how long to use the stimulation, thus simulating how patients would use the stimulation in their daily lives. Aim 2. Determine momentary self-rated efficacy and side effects of stimulation, using surveys taken at the beginning and end of stimulation periods, as well as twice daily when prompted. Aim 3. Compare results of this trial with those from Peripheral induction of inhibitory brain circuits to treat Tourette's: pilot. Participants in this study will have been drawn from completers of the peripheral induction blinded RCT, allowing for clear comparisons between the laboratory conditions of the first study and the real-world conditions of the second. Completion of these Aims will provide practical information that can inform a future, controlled clinical trial of chronic MNS delivered by a portable device.
Interventions
DEVICEActive, self-directed electrical stimulation of the median nerve
Electrical stimulation of the median nerve (12 Hz, pulse width 200µs), initially at the threshold needed to see movement of the right thumb with stimulation. After initial training with the device and education in the rationale for suprathreshold stimulation, participants will choose timing and intensity of stimulation based on their momentary symptom severity and their experience with the treatment since the beginning of the study. Participant can choose right or left median nerve (we will suggest their nondominant hand to minimize interference with daily activities).
Sponsors
National Center for Advancing Translational Sciences (NCATS)
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All participants will receive MNS at 12 Hz, pulse width 200µs. After initial threshold determination and training on device usage, individual participants will choose duration and intensity of treatment depending on their momentary symptom severity and history of response to treatment.
Eligibility
Sex/Gender
ALL
Age
15 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Completed participation in the study called Peripheral induction of inhibitory brain circuits to treat Tourette's: pilot * Informed consent by adult participant, or assent by child and informed consent by guardian
Exclusion criteria
* Has an implanted device that could be affected by electrical current * Pregnancy known to participant or (for children) to the parent * Severe or unstable systemic illness * Factors (such as exaggerated symptom report) that in the judgment of the principal investigator may make the outcome measures inaccurate * Judged by investigator to be unlikely to complete study procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Discomfort | Recorded every time the device was turned off, and every time the participant was prompted by a text to fill out the survey if the device was on when the text was received, up to 4 weeks. | Mean discomfort while using the stimulator, on a 0-3 scale adapted from the Clinical Global Impression - Improvement \[CGI-I\] Efficacy Index. Specifically, the prompt was How much DISCOMFORT did the stimulation cause?, and the participant selected one of the following responses: 0 = NO discomfort 1. = discomfort noticeable, but not severe enough to concern me or to turn it off 2. = enough discomfort, impairment of functioning or social embarrassment that I would only keep it on if the benefit was considerable 3. = caused discomfort, impairment of functioning or social embarrassment to a degree that any treatment benefit was not worth leaving it on Higher values represent a worse outcome. Discomfort was reported at the end of each stimulation period, and at random times twice daily between 9a.m. and 9p.m. when prompted by text message, if the device was on when the text was received. |
| Time Spent Using the Device Per Day of Use | At study conclusion, up to 4 weeks | Number of minutes per day the device was used, only counting days in which the device was turned on, over the four-week period after the initial visit |
| Time Spent Using the Device (Days Per Week) | At study conclusion, up to 4 weeks | Number of days per week the device was used |
| Plan to Continue MNS (Median Nerve Stimulation) | At study conclusion, up to 1 month | Answered yes (from options yes / no / maybe) to the question, Do you expect to continue to use the stimulator? |
| Change in Tic Frequency With Stimulation | Recorded every time the device was turned on and every time it was turned off, up to 4 weeks | Change in self-reported tic frequency on the frequency item (score range from 0 = no tics \[better\] to 5 = always \[worse\]) from the Yale Global Tic Severity Scale (YGTSS) from the beginning to the end of each stimulation period. Participants were instructed to answer this question every time they turned on the device and every time they turned it off, every day for 4 weeks. The difference between the turning off score and the previous turning on score was averaged across all ratings completed during the 4 weeks of the trial. The wording of the score anchors is provided at https://osf.io/7pjk4 . |
| Change in Tic Intensity With Stimulation | Recorded every time the device was turned on and every time it was turned off, up to 4 weeks | Change in self-reported tic intensity on the intensity item (score range from 0 = no tics \[better\] to 5 = severe intensity \[worse\]) from the Yale Global Tic Severity Scale (YGTSS) from the beginning to the end of each stimulation period. Participants were instructed to answer this question every time they turned on the device and every time they turned it off, every day for 4 weeks. The difference between the turning off score and the previous turning on score was averaged across all ratings completed during the 4 weeks of the trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CGI Efficacy Index: Side Effects | At study conclusion, up to 4 weeks | Overall discomfort from stimulation throughout the study period. The prompt for this survey question was: On average, over the course of the study, how much DISCOMFORT did the stimulation cause? (If discomfort is the wrong word, please substitute any negative effects or side effects of stimulation.) Participants chose one of the following answers: 0 no discomfort 1. discomfort noticeable, but not severe enough to concern me or to turn it off 2. enough discomfort, impairment of functioning or social embarrassment that I would only keep it on if the benefit was considerable 3. caused discomfort, impairment of functioning or social embarrassment to a degree that any treatment benefit was not worth leaving it on On this scale, lower numbers represent a better outcome. |
| Mean Therapeutic Effect During Stimulator Use | At study conclusion, up to 4 weeks | Mean self-rated therapeutic effect (from the modified CGI Efficacy Index) when device is on, reported at the end of the study. Specifically, the prompt for this question was On average, over the course of the study, how much did your tics IMPROVE during stimulation? Participants chose one of the following answers: 0 Unchanged or worse 1. Minimal - Slight improvement that doesn't decrease the overall impact of symptoms. 2. Moderate - Decided improvement. Partial remission of symptoms 3. Marked - Vast improvement. Complete or nearly complete remission of all symptoms On this scale, higher numbers represent a better outcome. |
| Change in Self-reported Tic Severity | At beginning of study participation or up to 2 weeks prior, and again at end of study participation up to 4 weeks | Self-rated tic severity over the past week using the Adult Tic Questionnaire (ATQ), first rating at (or within 2 weeks prior to) the beginning of study participation and second rating at the end of study participation. Higher ATQ scores reflect a worse outcome. For each tic present in the past week, its severity score is the sum of its frequency score (0-4, 4 worst, occurring almost all the time during the day) and its intensity score (0-4, 4 worst). The ATQ severity score is the sum of the severity score for each of up to 27 tics present in the past week. The minimum possible severity score on the ATQ is 0, indicating that no tics were present in the past week. The maximum possible severity score on the ATQ indicates is 216, indicating that a tic of each of the 27 types listed was present in the past week, each with an item severity score of 8 = 4 + 4. |
| Self-reported Duration of MNS Benefit, in Minutes | Monitored over the entire period of study participation, up to 4 weeks | On the survey at the end of study participation, the relevant question asked: On average, over the course of the study, how long do you think the improvement in your tics lasted after you turned off the device? Give answer in minutes. Enter 0 (zero) if improvement with stimulation stopped immediately when you turned the device off. On this item, higher answers indicate a better outcome. |
| CGI-I (Clinical Global Impression--Improvement) | At study conclusion, up to 4 weeks | Overall impact of the stimulation on symptoms throughout the study period: 1. = Very much improved - nearly all better; good level of functioning; minimal symptoms; represents a very substantial change 2. = Much improved - notably better with significant reduction of symptoms; increase in the level of functioning but some symptoms remain 3. = Minimally improved - slightly better with little or no clinically meaningful reduction of symptoms. Represents very little change in basic clinical status, level of care, or functional capacity 4. = No change - symptoms remain essentially unchanged 5. = Minimally worse - slightly worse but may not be clinically meaningful; may represent very little change in basic clinical status, level of care, or functional capacity 6. = Much worse - clinically significant increase in symptoms and diminished functioning 7. = Very much worse - severe exacerbation of symptoms and loss of functioning On this scale, lower numbers indicate a better outcome. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from those 32 participants who completed an in person RCT (randomized controlled trial; registration number NCT04731714). One RCT participant did not choose to participate in this open-label extension. Recruitment occurred between November 2021 and April 2022.
Participants by arm
| Arm | Count |
|---|---|
| Active MNS Active, self-directed electrical stimulation of the median nerve: Electrical stimulation of the median nerve (12 Hz, pulse width 200µs), initially at the threshold needed to see movement of the right thumb with right median nerve stimulation. After initial training with the device and education in the rationale for suprathreshold stimulation, participants will choose timing and intensity of stimulation based on their momentary symptom severity and their experience with the treatment since the beginning of the study. Participant can choose right or left median nerve (we will suggest their nondominant hand to minimize interference with daily activities). | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 4 |
Baseline characteristics
| Characteristic | Active MNS |
|---|---|
| Age, Continuous | 34.5 years STANDARD_DEVIATION 16.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Region of Enrollment United States | 31 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 31 |
| other Total, other adverse events | 4 / 31 |
| serious Total, serious adverse events | 0 / 31 |
Outcome results
Primary
Change in Tic Frequency With Stimulation
Change in self-reported tic frequency on the frequency item (score range from 0 = no tics \[better\] to 5 = always \[worse\]) from the Yale Global Tic Severity Scale (YGTSS) from the beginning to the end of each stimulation period. Participants were instructed to answer this question every time they turned on the device and every time they turned it off, every day for 4 weeks. The difference between the turning off score and the previous turning on score was averaged across all ratings completed during the 4 weeks of the trial. The wording of the score anchors is provided at https://osf.io/7pjk4 .
Time frame: Recorded every time the device was turned on and every time it was turned off, up to 4 weeks
Population: All participants with at least one on-off survey pair during the study period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active MNS | Change in Tic Frequency With Stimulation | All participants turning ON surveys | 3.1 score on a scale | Standard Deviation 1 |
| Active MNS | Change in Tic Frequency With Stimulation | All participants turning OFF surveys | 2.1 score on a scale | Standard Deviation 1.1 |
p-value: <0.001t-test, 2 sided
Comparison: Correlation of this Outcome measure (change in tic frequency with stimulation during this study) with the change in tic frequency (measured as the number of 10-second tic-free intervals) during active, rhythmic stimulation in the randomized, controlled trial of MNS that all participants had previously completed.p-value: 0.3395% CI: [-0.22, 0.56]Regression, Linear
Primary
Change in Tic Intensity With Stimulation
Change in self-reported tic intensity on the intensity item (score range from 0 = no tics \[better\] to 5 = severe intensity \[worse\]) from the Yale Global Tic Severity Scale (YGTSS) from the beginning to the end of each stimulation period. Participants were instructed to answer this question every time they turned on the device and every time they turned it off, every day for 4 weeks. The difference between the turning off score and the previous turning on score was averaged across all ratings completed during the 4 weeks of the trial.
Time frame: Recorded every time the device was turned on and every time it was turned off, up to 4 weeks
Population: All participants with at least one on-off survey pair during the study period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active MNS | Change in Tic Intensity With Stimulation | All participants turning ON surveys | 2.9 score on a scale | Standard Deviation 0.8 |
| Active MNS | Change in Tic Intensity With Stimulation | All participants turning OFF surveys | 2.0 score on a scale | Standard Deviation 1.1 |
p-value: <0.001Wilcoxon (Mann-Whitney)
Comparison: Correlation of this Outcome measure (change in tic intensity during this study) with change in tic intensity during active, rhythmic stimulation during the randomized, controlled trial that all participants had previously completed.p-value: 0.0895% CI: [-0.05, 0.66]Regression, Linear
Primary
Discomfort
Mean discomfort while using the stimulator, on a 0-3 scale adapted from the Clinical Global Impression - Improvement \[CGI-I\] Efficacy Index. Specifically, the prompt was How much DISCOMFORT did the stimulation cause?, and the participant selected one of the following responses: 0 = NO discomfort 1. = discomfort noticeable, but not severe enough to concern me or to turn it off 2. = enough discomfort, impairment of functioning or social embarrassment that I would only keep it on if the benefit was considerable 3. = caused discomfort, impairment of functioning or social embarrassment to a degree that any treatment benefit was not worth leaving it on Higher values represent a worse outcome. Discomfort was reported at the end of each stimulation period, and at random times twice daily between 9a.m. and 9p.m. when prompted by text message, if the device was on when the text was received.
Time frame: Recorded every time the device was turned off, and every time the participant was prompted by a text to fill out the survey if the device was on when the text was received, up to 4 weeks.
Population: All participants who completed the discomfort question at least once during the study after initial training.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active MNS | Discomfort | 1.0 units on a scale |
Primary
Plan to Continue MNS (Median Nerve Stimulation)
Answered yes (from options yes / no / maybe) to the question, Do you expect to continue to use the stimulator?
Time frame: At study conclusion, up to 1 month
Population: All participants who completed the final survey
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active MNS | Plan to Continue MNS (Median Nerve Stimulation) | 21 Participants |
Primary
Time Spent Using the Device (Days Per Week)
Number of days per week the device was used
Time frame: At study conclusion, up to 4 weeks
Population: All participants enrolled in study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active MNS | Time Spent Using the Device (Days Per Week) | 1.5 days per week |
Primary
Time Spent Using the Device Per Day of Use
Number of minutes per day the device was used, only counting days in which the device was turned on, over the four-week period after the initial visit
Time frame: At study conclusion, up to 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active MNS | Time Spent Using the Device Per Day of Use | 49.6 minutes per day |
Secondary
CGI Efficacy Index: Side Effects
Overall discomfort from stimulation throughout the study period. The prompt for this survey question was: On average, over the course of the study, how much DISCOMFORT did the stimulation cause? (If discomfort is the wrong word, please substitute any negative effects or side effects of stimulation.) Participants chose one of the following answers: 0 no discomfort 1. discomfort noticeable, but not severe enough to concern me or to turn it off 2. enough discomfort, impairment of functioning or social embarrassment that I would only keep it on if the benefit was considerable 3. caused discomfort, impairment of functioning or social embarrassment to a degree that any treatment benefit was not worth leaving it on On this scale, lower numbers represent a better outcome.
Time frame: At study conclusion, up to 4 weeks
Population: All participants who completed the final survey.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active MNS | CGI Efficacy Index: Side Effects | 1.2 units on a scale | Standard Deviation 1 |
Secondary
CGI-I (Clinical Global Impression--Improvement)
Overall impact of the stimulation on symptoms throughout the study period: 1. = Very much improved - nearly all better; good level of functioning; minimal symptoms; represents a very substantial change 2. = Much improved - notably better with significant reduction of symptoms; increase in the level of functioning but some symptoms remain 3. = Minimally improved - slightly better with little or no clinically meaningful reduction of symptoms. Represents very little change in basic clinical status, level of care, or functional capacity 4. = No change - symptoms remain essentially unchanged 5. = Minimally worse - slightly worse but may not be clinically meaningful; may represent very little change in basic clinical status, level of care, or functional capacity 6. = Much worse - clinically significant increase in symptoms and diminished functioning 7. = Very much worse - severe exacerbation of symptoms and loss of functioning On this scale, lower numbers indicate a better outcome.
Time frame: At study conclusion, up to 4 weeks
Population: All participants who completed the final survey.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Active MNS | CGI-I (Clinical Global Impression--Improvement) | 3.1 units on a scale |
Secondary
Change in Self-reported Tic Severity
Self-rated tic severity over the past week using the Adult Tic Questionnaire (ATQ), first rating at (or within 2 weeks prior to) the beginning of study participation and second rating at the end of study participation. Higher ATQ scores reflect a worse outcome. For each tic present in the past week, its severity score is the sum of its frequency score (0-4, 4 worst, occurring almost all the time during the day) and its intensity score (0-4, 4 worst). The ATQ severity score is the sum of the severity score for each of up to 27 tics present in the past week. The minimum possible severity score on the ATQ is 0, indicating that no tics were present in the past week. The maximum possible severity score on the ATQ indicates is 216, indicating that a tic of each of the 27 types listed was present in the past week, each with an item severity score of 8 = 4 + 4.
Time frame: At beginning of study participation or up to 2 weeks prior, and again at end of study participation up to 4 weeks
Population: All participants with ATQ scores both at baseline and during final survey (those who completed final survey more than 4 weeks after completing the study were excluded).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active MNS | Change in Self-reported Tic Severity | baseline score | 35.4 units on a scale | Standard Deviation 16.7 |
| Active MNS | Change in Self-reported Tic Severity | final survey score | 34.6 units on a scale | Standard Deviation 22.5 |
p-value: 0.84Paired Sample t-Test, 2-Sided
Secondary
Mean Therapeutic Effect During Stimulator Use
Mean self-rated therapeutic effect (from the modified CGI Efficacy Index) when device is on, reported at the end of the study. Specifically, the prompt for this question was On average, over the course of the study, how much did your tics IMPROVE during stimulation? Participants chose one of the following answers: 0 Unchanged or worse 1. Minimal - Slight improvement that doesn't decrease the overall impact of symptoms. 2. Moderate - Decided improvement. Partial remission of symptoms 3. Marked - Vast improvement. Complete or nearly complete remission of all symptoms On this scale, higher numbers represent a better outcome.
Time frame: At study conclusion, up to 4 weeks
Population: All participants who completed the final survey.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Active MNS | Mean Therapeutic Effect During Stimulator Use | 1.5 units on a scale |
Secondary
Self-reported Duration of MNS Benefit, in Minutes
On the survey at the end of study participation, the relevant question asked: On average, over the course of the study, how long do you think the improvement in your tics lasted after you turned off the device? Give answer in minutes. Enter 0 (zero) if improvement with stimulation stopped immediately when you turned the device off. On this item, higher answers indicate a better outcome.
Time frame: Monitored over the entire period of study participation, up to 4 weeks
Population: All participants who answered this question on the final survey
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active MNS | Self-reported Duration of MNS Benefit, in Minutes | 15 minutes |