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    Summary of key evidence on transcutaneous electrical stimulation of the trigeminal nerve for ADHD

    Study 1 McGough JJ (2019)

    Study details

    Study type

    RCT

    Country

    US

    Recruitment period

    Not reported

    Study population and number

    n=62 (32 active treatment; 30 sham)

    Children aged 8 to 12 with ADHD.

    Age and sex

    Active group: mean 10.3 years; 60% male

    Patient selection criteria

    Inclusion criteria: Children aged 8 to 12 years with Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) ADHD, based on the Kiddie Schedule for Affective Disorders and Schizophrenia and clinical interview, minimum total of 24 on the clinician-administered parent ADHD-IV Rating Scale, baseline CGI-S Score of 4 or more, estimated full-scale IQ of 85 or more, and able to cooperate with electroencephalography and other study procedures.

    Exclusion criteria: current major depression or autism spectrum disorder, lifetime psychosis, mania, seizure disorder, or head injury with loss of consciousness, or baseline suicidality.

    Technique

    Trigeminal nerve stimulation (Monarch eTNS System, NeuroSigma) nightly during sleep for 4 weeks. Children were followed for an additional week without treatment to analyse whether the treatment effect persisted.

    Children were medicine free for at least 1 month prior to participation and remained so throughout the trial.

    Parents applied patches across their child's forehead to provide bilateral stimulation of V1 trigeminal branches for approximately 8 hours nightly. Patches were removed each morning. The active condition used a 120-Hz repetition frequency, with 250-μs pulse width, and a duty cycle of 30 seconds on/30 seconds off. Stimulator current settings between 2 and 4 milli-amperes (range: 0 to 10) were established at baseline by titration. Each night parents turned on the device, pressed the 'up' button until the stimulation was uncomfortable or until the device reached the maximum current, and then pressed 'down' to reduce it by one 0.1mA step.

    Follow up

    5 weeks

    Conflict of interest/source of funding

    Conflict of interest: One author had served as part of the management team of NeuroSigma, Inc. and has been allocated stock options.

    Source of funding: Supported by National Institute of Mental Health grant. Study devices and some materials were provided by NeuroSigma, Inc. in response to an investigator-initiated request.

    Analysis

    Follow up issues: Outcomes were assessed weekly or at baseline and week 4 and 5. One person randomised to the sham group withdrew after 3 weeks. One additional participant in each group withdrew between weeks 4 and 5. qEEG data for 3 participants were excluded due to excessive movement artifact.

    Study design issues: This RCT assessed the outcomes of TNS for children with ADHD. People were recruited through community advertisements and internet postings. Randomisation was 1:1, using random block lengths of 4 and 6, to active or sham TNS. Participants, parents, and staff were blinded (except for 1 staff member who managed the study devices). To maintain the blind, active and sham systems were identical in appearance and operation, and participants were informed via a scripted presentation that 'pulses may come so fast or so slowly that the nerves in the forehead might or might not detect a sensation'. Outcomes included (see Outcome measures for full descriptions):

    • Primary: ADHD-RS – clinician-completed, based on clinical information and parental interview.

    • Secondary behavioural:

      • Clinician-completed: CGI-I, CDRS.

      • Parent-completed: BRIEF Scales, Conners Global Index, CSHQ, ARI, and MASC.

      • Teacher-completed: Conners Global Index.

    • qEEG

    • Safety: including adverse events, parent-completed Side Effects Rating Scales, and clinician-completed C-SSRS.

    For statistical analysis, a general linear mixed model was used with treatment group (active vs. sham), time (in weeks), and group-by-time interactions to test for differential treatment effects as primary predictors, along with subject level random intercepts. This accounts for repeated measures and for missing data. Categorical outcomes were assessed using chi square. Effect size differences between groups were estimated using Cohen's d and NNT. For Cohen's d, cut-off values for small, medium, and large effects were defined as 0.2, 0.5, and 0.8, respectively. For NNT, small, medium, and large effects were defined as 9, 4, and 2, respectively. ADHD-RS was identified as the primary outcome a priori. However, there was no hierarchical testing of endpoints or adjustment for multiple comparisons. p<0.05 was considered statistically significant.

    Study population issues: There were no statistically significant differences between the groups for age, sex, race/ethnicity, height, weight, vital signs, IQ, ADHD subtype, or baseline behavioural ratings.

    Key efficacy findings

    ADHD-RS

    Number of people analysed: 32 active treatment; 30 sham

    • In the active treatment group, ADHD-RS total scores decreased from 32.1 (SD 6.3) at baseline to 23.39 (7.88) at week 4. In the sham group, ADHD-RS total scores decreased from 32.8 (SD 6.2) at baseline to 27.50 (8.08) at week 4.

    • Total ADHD-RS scores showed statistically significant group-by-time interaction, indicating a difference in the treatment groups (F=8.12, df=1/228, p=0.005).

      • There was no statistically significant group-by-time2 ('time2' represents the change in slope after the initial week) interaction, indicating an equal levelling-off of improvement following week 1.

    • Estimated Cohen's d at week 4 was 0.50, suggesting a medium treatment effect.

    • Week 4 scores in active vs. sham groups were 23.39 (7.88) and 27.50 (8.08) respectively. After discontinuation, week 5 scores were 25.52 (7.84) and 29.11 (7.79), respectively.

      • The time effect was statistically significant (F=6.23, df=1/57, p=0.02), with a non-statistically significant trend for group differences (F=4.18, df=1/57, p=0.05), but no statistically significant group-by-time interaction (F=0.12, df=1/57, p=0.73), suggesting both groups deteriorated at similar rates.

      • Cohen's d at Week 5 was 0.46, suggesting maintenance of a medium treatment effect 1 week after treatment cessation.

    CGI-I

    Number of people analysed: 32 active treatment; 30 sham

    • There was a statistically significant greater improvement in CGI-I scores with active treatment compared to sham (X2=8.75, df=1/168, p=0.003).

      • Improvement rates for active vs. sham were 25% vs. 13%, 34% vs. 15%, 47% vs. 12%, and 52% vs. 14% based on raw CGI-I at weeks 1, 2, 3, and 4.

    • NNT based on CGI-I at week 4 was 3.

    • After discontinuation, Week 5 CGI-I ratings showed 13% improved in active vs.7% improved in sham groups compared to baseline (X2=0.53, df=1, p=0.46).

    Other outcome measures

    Number of people analysed: 32 active treatment; 30 sham

    • Statistically significant group-by-time interactions were not observed for the parent-completed Conners Global Index, MASC-Parent Report, MASC Child Report, CDRS, BRIEF, CSHQ, teacher-completed Conners Global Index, and ARI scales.

    qEEG

    Number of people analysed: 30 active treatment; 26 sham

    • There were statistically significant group-by-time effects for frequency bands in the right frontal (F4 delta, theta, beta, gamma) and frontal midline (Fz gamma) channels.

    • Week 4 changes in right frontal (F4 theta, beta bands) and frontal midline (Fz Gamma 1) regions were statistically significantly associated with changes in ADHD-RS total and hyperactive/impulsive scores (r's range −.34 to −.41).

    Key safety findings

    Number of people analysed: 32 active treatment; 30 sham

    There were no serious adverse events in either group and no participant withdrew for adverse events.

    • C-SSRS showed no responses suggestive of suicidality.

    • The following side effects were endorsed on the administered rating scale at some point during the study:

    Side Effect

    Participants Reporting (%)

    Active (N=32)

    Sham (N=30)

    n

    %

    n

    %

    Trouble sleeping

    6

    19

    5

    17

    Nightmares

    2

    6

    0

    0

    Drowsy

    7

    22

    4

    13

    Hyperactive

    13

    41

    19

    63

    Fatigue

    4

    13

    1

    3

    Feels strange

    0

    0

    2

    7

    Tingling

    1

    3

    0

    0

    Headache

    4

    13

    0

    0

    Stuffy nose

    5

    16

    6

    20

    Muscle cramps

    1

    3

    1

    3

    Muscle twitch

    0

    0

    2

    7

    Tremor

    0

    0

    1

    3

    Slurred speech

    0

    0

    1

    3

    Rapid heartbeat

    1

    3

    0

    0

    Out of breath

    1

    3

    1

    3

    Nausea

    1

    3

    0

    0

    Stomach ache

    2

    6

    1

    3

    Constipation

    3

    9

    2

    7

    Frequent urination

    2

    6

    0

    0

    Frequent sweating

    1

    3

    1

    3

    Decreased appetite

    1

    3

    1

    3

    Increased appetite

    6

    19

    2

    7

    Skin rash

    2

    6

    0

    0

    Finding words

    0

    0

    2

    7

    Apathy

    2

    6

    2

    7

    Clenching teeth

    4

    13

    2

    7

    • The following adverse events were spontaneously reported:

    Adverse Event

    Participants Reporting, n (%)

    Active (N=32)

    Sham (N=30)

    n

    %

    n

    %

    Anxiety

    0

    0

    1

    3

    Bronchitis

    1

    3

    0

    0

    Headache

    3

    9

    1

    3

    Itching

    1

    3

    0

    0

    Lightheaded

    1

    3

    0

    0

    Mouth pain

    0

    0

    1

    3

    Nausea

    1

    3

    0

    0

    Nightmares

    0

    0

    1

    3

    Poor appetite

    1

    3

    0

    0

    Rash

    1

    3

    0

    0

    Rhinitis

    2

    6

    2

    6

    Skin whitening/ discoloration

    1

    3

    1

    3

    Stomach ache

    2

    6

    1

    3

    Tooth pain

    1

    3

    0

    0

    Upper respiratory infection

    3

    9

    3

    10

    Vomiting

    1

    3

    0

    0

    Wrist sprain

    0

    0

    1

    3

    Study 2 Loo SK (2021)

    Study details

    Study type

    Secondary analysis of McGough, 2019 (Study 1)

    Country

    US

    Recruitment period

    Not reported

    Study population and number

    n=51 (25 responders and 26 non-responders)

    Children aged 8 to 12 with ADHD.

    Age and sex

    Responders: mean 10.5 years, 44% male; non-responders: mean 10.1 years; 88% male

    Patient selection criteria

    As described in McGough, 2019 (Study 1).

    After the 1-week discontinuation period, participants assigned to sham were given the option to crossover into 4 weeks of open-label active treatment. The sample for this study was then comprised of the people originally randomised to active treatment, and the people randomised to sham who chose to crossover.

    Technique

    As described in McGough, 2019 (Study 1).

    Follow up

    Up to 9 weeks

    Conflict of interest/source of funding

    Conflict of interest: One author reported expert witness testimony for 2 pharmaceutical companies and honoraria from another company.

    Source of funding: Supported by National Institute of Mental Health grant. Study devices and some materials were provided by NeuroSigma, Inc. in response to an investigator-initiated request.

    Analysis

    Follow up issues: Data was available for 51 total people (31 active treatment; 20 sham crossover).

    Study design issues: This secondary analysis of McGough (2019) evaluated whether baseline cognitive or EEG characteristics were predictors of positive response and associated with ADHD symptom reduction within the original RCT sample. The sample was divided into responders and non-responders. Responders were those with a 25% or greater reduction in ADHD-RS score from baseline and the end of active treatment (week 4 for people randomised to active treatment and week 9 for the people randomised to sham who chose to crossover). Non-responders were those with a less than 25% reduction in ADHD-RS score. Outcome measures (in addition to those described in McGough, 2019) included (see Outcome measures for full descriptions):

    • CBCL, WISC-4 and Digit Span subtest, WRAT, SWM, Flanker Task, and resting state EEG.

    Analysis of variance (ANOVA) was used to identify baseline differences between responders and non-responders. Two analyses were used to then predict response status: linear regression analyses for prediction of post-treatment ADHD-RS Total scores and receiver operating characteristics curve analysis to determine area under the curve for prediction of responder status. Significant baseline predictors of ADHD symptoms were then tested for TNS treatment-related change by responder status and time (pre-/post-TNS) using repeated measures ANOVAs.

    Pearson correlations between baseline predictors and ADHD symptoms were used to characterize degree of change occurring in both variables with TNS treatment. Partial eta squared was used as the measure of effect size and was interpreted as follows: small: 0.01, medium: 0.06, large: 0.14. Two procedures were used to control for multiple comparisons: only variables that were significant at p<0.05 in the baseline profile were further tested for prediction of treatment outcomes and treatment related change; and a p-value of p<0.01 was used as the threshold for statistical significance in subsequent analyses.

    Study population issues: Responders and non-responders did not differ on any demographic or baseline clinical variables, including age, gender, IQ, or socioeconomic status.

    Key efficacy findings

    Responder baseline profile

    Number of people analysed: 51

    • Responders had statistically significantly lower scores on baseline Wide Range Achievement Test (WRAT) Spelling (F(1,49)=4.6, p=0.04) and Math (F(1,49)=4.1, p=0.05).

    • Responders had statistically significantly worse cognitive functioning relative to non-responders on:

      • CBCL Sluggish Cognitive Tempo index (F(1, 49)=7.3, p=0.009)

      • BRIEF:

        • Initiate (F(1, 49)=7.2, p=0.01)

        • Working Memory (F(1, 49)=20.7, p<0.001)

        • Planning (F(1,49)=17.8, p<0.001)

        • Organisation (F(1, 49)=5.9, p=0.02)

        • Metacognition (F(1, 49)=14.9, p<0.001)

        • General Executive Composite (GEC; [F(1,49)=5.8, p=0.02]).

    • Responders had statistically significantly lower right frontal spectral power in the theta (4-7 Hz [F(1,45)=9.2, p=0.004]) and alpha (8-12 Hz; [F(1,45)=9.2, p=0.004]) bands.

    Prediction of treatment response

    Number of people analysed: 51

    • The measures that differed significantly at baseline were then tested for whether the baseline score was predictive of end of treatment ADHD-RS Total Score.

    • The following measures were statistically significant predictors of end of treatment ADHD-RS Total score:

      • CBCL Sluggish Cognitive Tempo (β=-0.40, 95% CI -0.68 to -0.14, p=0.004)

      • BRIEF Working Memory (β=-0.40, 95% CI -0.70 to -0.14, p=0.004), Planning (β=-0.36, 95% CI -0.51 to -0.08, p=0.01) and Metacognition (β=-0.32, 95% CI -0.57 to -0.04, p=0.02)

      • EEG right-frontal theta (β=0.43, 95% CI 0.2 to 1.1, p=0.005) and alpha band power (β=0.45, 95% CI 0.3 to 1.2], p=0.003).

    TNS treatment-related change in cognitive function and EEG power

    Number of people analysed: 28 (EEG); 51 (BRIEF scores)

    • Among responders, TNS treatment resulted in right frontal theta- and alpha-band power increase that was not seen in the non-responders (F4 theta: F(1, 25)=4.4, p=0.05, F4 alpha: F(1, 25)=4.1, p=0.06, partial eta squared=0.18: large effect size).

      • Treatment-related change in F4 theta was moderately correlated with ADHD symptom change but this was not statistically significant (r=0.3, p=0.14).

    • Statistically significant group-by-time interactions indicated that TNS responders showed treatment related improvement in BRIEF that were not observed in non-responders:

      • Metacognition (F(1,45)=38.6, p<0.001, partial eta squared=0.47: large effect size)

      • Working Memory (F(1,45)=41.1, p<0.001, partial eta squared=0.48: large effect size)

      • Initiate (F(1,45)=18.3, p<0.001, partial eta squared=0.29: large effect size)

      • Planning (F(1,45)=36.7, p=0.001, partial eta squared=0.51: large effect size)

      • Organisation (F(1,45)=19, p=0.001, partial eta squared=0.30: large effect size)

      • Treatment-related change in these BRIEF variables and ADHD-RS Total scores were very strongly correlated, with Pearson r's ranging from 0.65 (Planning, p=6.5E-7) to 0.79 (Working memory, p =3.0E-11).

    • BRIEF Working Memory score was the strongest predictor (AUC=0.83, p=0.003).

    Key safety findings

    Safety findings were reported in McGough, 2019 (Study 1).

    Study 3 McGough JJ (2015)

    Study details

    Study type

    Single arm, open-label trial

    Country

    US

    Recruitment period

    Not reported.

    Study population and number

    n=24

    Children aged 7 to 14 with ADHD.

    Age and sex

    Mean 10.3 years; 92% male

    Patient selection criteria

    Inclusion criteria: Children aged 7 to 14 years with DSM-IV ADHD as assessed with the Kiddie Schedule for Affective Disorders and Schizophrenia; minimum baseline scores of 12 on both the inattentive and hyperactive/impulsive subscales of the investigator-completed Parent ADHD-RS; baseline CGI-S rating 4 or more; no current use of medicine with central nervous system effects; and a parent able and willing to complete all required ratings and monitor proper use of the TNS device.

    Exclusion criteria: levels of ADHD-related impairment that required immediate medication management; current diagnoses of pervasive developmental or depressive disorders; current suicidality; and lifetime histories of psychosis, mania, or seizure disorder.

    Technique

    Trigeminal nerve stimulation (EMS7500 Stimulator, TENS Products, Inc. Granby, CO) nightly during sleep for 8 weeks.

    Parents applied patches across their child's forehead to provide bilateral stimulation of V1 trigeminal branches for 7 to 9 hours nightly. Patches were removed each morning. The active condition used a 120-Hz repetition frequency, with 250-μs pulse width, and a duty cycle of 30 seconds on/30 seconds off. Stimulator current settings between 2 and 4 milli-amperes (range: 0 to 10) were established at baseline by titration.

    Follow up

    8 weeks

    Conflict of interest/source of funding

    Conflict of interest: Not reported.

    Source of funding: This study was funded in part by an investigator-initiated research grant from NeuroSigma, Inc., the manufacturers of the Monarch eTNS device.

    Analysis

    Follow up issues: Two participants were lost to follow up prior to Visit 4 outcome assessments, one each at Visits 2 and 3. One further participant was lost to follow up after Visit 6.

    Study design issues: This single arm, open-label trial was a pilot study of the use of TNS for ADHD. Children were recruited and followed prospectively. Outcomes included (see Outcome measures for full descriptions):

    • Primary behavioural: investigator-completed Parent ADHD-RS

    • Secondary behavioural: investigator-completed CGI-I, and the parent-completed Conners Global Index, and CSHQ.

    • Cognitive: computer-based ANT and SWM, parent-competed BRIEF, MASC, and participant-completed CDI.

    • Potential side effects and adverse events were assessed with weekly parent-completed Side Effect Ratings Scales and open-ended Adverse Event Inquiries with parents conducted by study investigators.

    The safety population included all participants with at least 1 night's exposure to TNS. The treatment population included all participants with outcomes data at week 4, the first post-baseline point at which primary behavioural and cognitive outcomes were obtained. Behavioural and cognitive measures were assessed for change over time with the general linear mixed model. p<0.05 was considered statistically significant. No adjustments for multiple comparisons were made.

    Key efficacy findings

    ADHD-RS

    Number of people analysed: 22

    • There was a statistically significant decrease in ADHD-RS scores from baseline to week 8 follow up (F=42.5, df=2/40, p<0.0001).

    CGI-I

    Number of people analysed: 22

    • There was a statistically significant decrease in CGI-I scores from baseline to week 8 follow up (F=6.89, df=8/140, p<0.0001).

    • 64% met response criteria (improved or very much improved) at week 4, and 71% met these criteria at week 8.

    Anxiety and depression

    Number of people analysed: 22

    • There were statistically significant improvements in dimensional CDI scores (F=3.40, df=2/38, p=0.04).

    • There were no statistically significant changes in self-reported MASC scores (p=0.82).

    Cognitive functioning

    Number of people analysed: 22

    • BRIEF:

      • There were statistically significant improvements in 7 of 11 BRIEF subscales, including Inhibit (p=0.004), BRI Index (p=0.03), Working memory, (p=0.0004), Plan/organise (p=0.004), Monitor (p=0.003), MI index (p=0.0008), and Global exec composite (p=0.002).

      • There were no statistically significant improvements in 4 of 11 BRIEF subscales, including Shift, Emotional control, Initiate, and Organisation materials (all p>0.05).

    • ANT:

      • There was a statistically significant decrease in ANT incongruent reaction time from baseline to 8-week follow up (p=0.006)

      • There were no statistically significant changes in ANT neutral reaction time, neutral accuracy, congruent reaction time, congruent accuracy, and incongruent accuracy (all p>0.05).

    • SWM:

      • There were no statistically significant changes in SWM subscales from baseline to 8-week follow up.

    CSHQ

    Number of people analysed: 22

    • There were statistically significant improvements in CSHQ scores for Sleep Anxiety (p=0.03), Total Bedtime Problems (p<0.0001), and Total Sleep Problems (p<0.0001) from baseline to 8-week follow up.

    • There were no statistically significant improvements in CSHQ scores for Bedtime resistance Sleep onset delay, Sleep duration, Night wakings, Parasomnias, Disordered breathing, Daytime sleepiness, Total sleep behaviour problems, and Total problems daytime sleepiness (all p≥0.05).

    Key safety findings

    Number of people analysed: 24

    • The following adverse events were spontaneously reported and considered related or potentially related to treatment:

      • Eye twitch, n=1

      • Headache, n=2

    • The following adverse events were rated 'moderate' or 'severe' on the Side Effects Rating Scale and reported at least once by at least 5% of participants:

    Side effect

    Number reporting

    %

    Trouble sleeping

    7

    29

    Nightmares

    5

    21

    Feeling drowsy

    5

    21

    Feeling nervous

    14

    58

    Weakness or fatigue

    5

    21

    Irritable

    10

    42

    Poor memory*

    11

    46

    Trouble concentrating*

    22

    92

    Feeling strange or unreal

    2

    8

    Headache

    3

    13

    Stuffy nose

    6

    24

    Drooling

    2

    8

    Muscle twitch

    2

    8

    Trouble sitting still*

    17

    71

    Poor concentration*

    17

    71

    Slurred speech

    2

    8

    Stomach discomfort

    2

    8

    Excess sweating

    2

    8

    Weight gain

    2

    8

    Diminished mental acuity/sharpness

    3

    13

    Difficulty finding words

    2

    8

    Apathy/emotional indifference

    3

    13

    *ADHD symptom.