The efficacy of external Trigeminal Nerve Stimulation (TNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD): a multi-centre, double-blind, randomized, sham-controlled, parallel-group, phase IIb trial

The efficacy of external Trigeminal Nerve Stimulation (TNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD): a multi-centre, double-blind, randomized, sham-controlled, parallel-group, phase IIb trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The efficacy of external Trigeminal Nerve Stimulation (TNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD): a multi-centre, double-blind, randomized, sham-controlled, parallel-group, phase IIb trial Aldo Alberto Conti, Natali Bozhilova, Irem Ece Eraydin, Dominic Stringer, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6882697/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Jan, 2026 Read the published version in Nature Medicine → Version 1 posted You are reading this latest preprint version Abstract External trigeminal nerve stimulation (TNS) received FDA clearance in 2019 as the first device-based, non-pharmacological treatment for Attention-Deficit/Hyperactivity Disorder (ADHD), based on a small pilot sham-controlled randomized controlled trial (RCT) that reported symptom improvement in 62 children with ADHD. We conducted a confirmatory multi-centre, double-blind, randomized, sham-controlled, parallel-group, phase IIb RCT investigating short and longer-term efficacy (6 months) of real vs sham TNS in 150 children and adolescents with ADHD. Partricipants were randomized to receive real TNS ( n =75, mean age [ SD ]= 12.6 [2.8 years]), or sham TNS ( n =75, mean age [ SD ]= 12.6 [2.8 years]), nightly for 4 weeks. Bilateral stimulation targeted V1 trigeminal branches using battery-powered electrodes applied to the forehead for ~9 hours/night. Sham TNS delivered 30 seconds of stimulation per hour at a lower frequency. Intention to treat analysis (ITT) showed no significant differential treatment effects on ADHD symptoms (estimated adjusted mean difference [ aMD ] = 0.83; 95% Confidence interval [CI] = –2.47 to 4.13; p = 0.622; Cohen’s d = 0.09). No differential treatment effects were observed either on the secondary outcomes covering other symptom scales of ADHD and related clinical problems, as well as cognitive and physiological outcomes, except for a small reduction in mind wandering favouring real TNS ( aMD = –2.17; 95% CI = –4.33 to –0.01; p = 0.049; Cohen’s d = –0.27). Adherence was 94% and compliance 93%. Blinding was successful. No serious adverse events (SAEs) were reported, and side effects did not differ between groups. In conclusion, TNS is a safe intervention but does not demonstrate clinical efficacy for paediatric ADHD. Trial registration: ISRCTN82129325. Health sciences/Diseases/Psychiatric disorders/ADHD Health sciences/Medical research/Clinical trial design/Randomized controlled trials Health sciences/Health care/Therapeutics/Biological therapy Biological sciences/Neuroscience/Cognitive neuroscience/Attention Figures Figure 1 Figure 2 INTRODUCTION Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common neurodevelopmental condition with a prevalence of around 5% in school-age children 1 and is defined by symptoms of inattention and/or hyperactivity/impulsivity that are inconsistent with the developmental stage and significantly impair daily functioning 2 . ADHD is also associated with impairments in executive functions and small but consistent differences in functional and structural brain regions and networks, most prominently involving frontal, striato-thalamic, parieto-temporal and cerebellar regions 3 , 4 . Stimulant medications (including methylphenidate and amphetamine) are first-line treatments for severe ADHD, improving symptoms in ~70% of children, with effect sizes of about 0.8-1.0 in the short-term 5 . However, stimulants can cause side effects, may not be indicated with some associated conditions such as cardiovascular disorders 5 and adherence over time is poor, particularly in adolescence 6 . Furthermore, their longer-term efficacy has not been demonstrated 7 , with imaging studies suggesting brain adaptation 8 and hence, possibly reduced effects with long-term use. Non-stimulant (e.g., atomoxetine, guanfacine or viloxazine), considered second-line medications, have on average lower efficacy than stimulants and can also lead to intolerable side effects 5 . Importantly, users and their families prefer non-pharmacological treatments with better side-effect profiles 9 . Yet, evidence for the efficacy of interventions such as behavioural therapy, cognitive and parent training, dietary changes, and neurofeedback in improving ADHD symptoms remains limited 10 , 4 , 11 . External Trigeminal Nerve stimulation (TNS) was granted clearance by the USA Food and Drug Administration (FDA) in 2019 as the first non-pharmacological treatment for ADHD. TNS is a non-invasive brain stimulation technique that targets the supratrochlear and supraorbital branches of the ophthalmic division (V1) of the trigeminal nerve by delivering an electric current through electrodes placed on the forehead. Sensory inputs from the trigeminal nerve fibres activate the locus coeruleus (LC), raphe nuclei (RN), and nucleus tractus solitarius (NTS) that innervate in a bottom-up manner several other brain regions, most prominently thalamic, frontal and limbic regions 12 , all of which are affected in ADHD 3, 4 . The effects of TNS on the LC and brainstem are thought to enhance attention and arousal mechanisms 13 , which are commonly affected in ADHD 14 . Furthermore, TNS is thought to stimulate the release of neurotransmitters important for arousal, attention, and emotion regulation, particularly noradrenaline, but also dopamine, glutamate, gamma-aminobutyric acid (GABA), and serotonin 12 , 15 all of which have been implicated in ADHD 16 . A recent meta-analysis showed that TNS is safe with good tolerability for neurological and psychiatric conditions 17 . The evidence for FDA clearance was based on a pilot double-blind randomized controlled trial (RCT) in 62 unmedicated children 18 , showing that four weeks of nightly real versus sham TNS significantly decreased parent-rated ADHD symptoms on the ADHD Rating Scale (ADHD-RS) 19 , with medium effect size (Cohen’s d = 0.5). The behavioural effects were correlated with increased electroencephalography (EEG) activity in right inferior/dorsolateral prefrontal cortex 18 , a key region known to be underactive in ADHD 2,3 , 20 , 21 . TNS was well-tolerated, with no severe adverse events and only minor, transient side effects, predominantly headaches and fatigue 18 , 22 . These promising findings call for replication in a definitive, multi-centre trial. Furthermore, the pilot study did not assess effects beyond 4 weeks and was limited to very young children aged 8-12 years (yrs) 18 . To address this need, we conducted a confirmatory multi-centre, double-blind, randomized, sham-controlled, parallel-group, phase IIb trial investigating both short (4 weeks) and longer-term (6 months) efficacy of real vs sham TNS not only in children but also in adolescents with ADHD, a population with particularly high need for alternative treatments due to low medication adherence rates 6 . We hypothesized that 4 weeks of nightly real versus sham TNS in children and adolescents with ADHD would improve core symptoms, as measured by parent-rated scales (primary outcome). Secondary cognitive and clinical outcomes included vigilance, symptoms of depression and anxiety, emotional dysregulation, mind-wandering, and sleep. We also investigated the effect of TNS on arousal via pupillometry and on objective hyperactivity using a wrist-worn device. Mechanisms of action were explored through functional magnetic resonance imaging (fMRI), which will be reported separately. RESULTS Participant data Participants were recruited from September 2022 to November 2024. Of 843 children/adolescents with ADHD and their parents/carers who were interested in the study, 165 provided written informed consent, and 150 (97 males, 64.7%) were enrolled in the study and included in the intention to treat (ITT) analysis (Figure 1). Participants had a mean age ( SD ) of 12.6 years (2.8) and the majority were of white ethnicity ( n =119, 79.3%) and off medication/medication-naïve ( n =91, 60.7%; Table 1). At baseline, 39.3% of participants were on stable stimulant medication, 12.6% were taking other psychotropic medication, and 13.3% were receiving other types of medication (for further demographic and medication information, see Supplementary Table S1 and S2). All participants met criteria for a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 2 ADHD diagnosis. Among them, 133 (88.7%) met criteria for ADHD combined presentation, 16 (10.7%) for ADHD inattentive presentation, and one participant (0.7%) for ADHD hyperactive/impulsive presentation. Comorbid Oppositional Defiant Disorder was present in 54 participants (36%), and Conduct Disorder in four participants (2.7%) (Table 1). At baseline, participants had a mean ( SD ) ADHD-RS total score of 35.3 (9.75), indicating severe ADHD symptomatology (Table 2). Participants were randomly allocated to real TNS ( n =75, mean age [ SD ]= 12.6 [2.8] yrs, off medication/medication-naive [ n =46, 61.3%]) or sham TNS ( n =75, mean age [ SD ]= 12.6 [2.8] yrs), off medication/medication-naive [ n =45, 60%]). One hundred and forty (93.3%) participants adhered to the intervention with only nine participants (real TNS [ n =6, (8%)]; sham TNS [ n =3, (4%)]) discontinuing the intervention permanently prior to the week 4 primary endpoint (Fig. 1 and Supplementary Table S3). One additional participant did not meet the predefined adherence threshold (≥1 hr of device use per night on at least 17 nights), as specified in the statistical analysis plan (SAP) found in the protocol supplementary material 23 . Table 1 . Baseline demographics and clinical characteristics Baseline characteristics ( n ,%) Real TNS ( n =75) Sham TNS ( n =75) Overall ( n =150) Age (Mean, SD) 12.6 (2.8) 12.6 (2.8) 12.6 (2.8) Age (categorized per randomization stratifier) 8-13.5 years old 43 (57.3) 43 (57.3) 86 (57.3) 13.6-19 years old 32 (42.7) 32 (42.7) 64 (42.7) Child sex at birth Male 49 (65.3) 48 (64.0) 97 (64.7) Female 26 (34.7) 27 (36.0) 53 (35.3) ADHD diagnosis per KSADS Combined presentation 66 (88.0) 67 (89.3) 133 (88.7) Inattentive presentation 8 (10.7) 8 (10.7) 16 (10.7) Hyperactive/impulsive presentation 1 (1.3) 0 (0.0) 1 (0.7) Oppositional Disorder per KSADS 26 (34.7) 28 (37.3) 54 (36.0) Conduct Disorder per KSADS 4 (5.3) 0 (0.0) 4 (2.7) Current stimulant medication status On stable medication 29 (38.7) 30 (40.0) 59 (39.3) Off medication/ Naive 46 (61.3) 45 (60.0) 91 (60.7) WASI FSIQ-4 score (Mean (SD)) 105.5 (13.8) 109.8 (13.5) 107.6 (13.8) Child ethnicity White 61 (81.3) 58 (77.3) 119 (79.3) Black, African, Caribbean, or Black British 4 (5.3) 1 (1.3) 5 (3.3) Asian or Asian British 2 (2.7) 5 (6.7) 7 (4.7) Mixed or Multiple ethnic groups 6 (8.0) 9 (12.0) 15 (10.0) Other ethnic groups 2 (2.7) 2 (2.7) 4 (2.7) Handedness Right-handed 60 (80.0) 52 (69.3) 112 (74.7) Left/mixed handed 15 (20) 23 (30.6) 38 (50.6) Index of Multiple Deprivation (Mean (SD)) 6.5 (2.8) 6.8 (2.6) 6.7 (2.7) Site King's College London 54 (72.0) 57 (76.0) 111 (74.0) University of Southampton 21 (28.0) 18 (24.0) 39 (26.0) Note. Categorical variables are presented as the number of participants, with the percentage in parentheses. Continuous variables are reported as mean (standard deviation). The Index of Multiple Deprivation ranges from 0 (most deprived) to 10 (least deprived). ADHD = Attention-Deficit/Hyperactivity Disorder; KSADS = Kiddie Schedule for Affective Disorders and Schizophrenia; TNS = External Trigeminal Nerve Stimulation; WASI FSIQ-4 = Wechsler Abbreviated Scale of Intelligence, Full Scale Intelligence Quotient, Fourth Edition. Primary outcome ADHD-RS total scores decreased in both groups over the 4-week treatment period, followed by a slight increase from week 3 to week 4 (Figure 2 and Table 2). At the week 4 primary endpoint, there was no significant difference between groups (estimated adjusted mean difference [ aMD ] = 0.83; 95% CI = –2.47 to 4.13; p = 0.622; Cohen’s d = 0.09), indicating no evidence of a differential treatment effect between arms (Figure 2 and Table 2). Table 2. Change in ADHD-RS total scores over 4 weeks of real versus sham TNS treatment. Primary Outcome (ADHD-RS) Real TNS (Mean, SD ) Sham TNS (Mean, SD ) aMD (95% CI) Cohen’s d (95% CI) p -value Baseline 35.4 (9.7) 35.2 (9.8) N/A N/A Week 1 26.6 (11.8) 22.9 (11.4) 3.03 (0.45, 5.61) 0.31 (0.05,0.58) N/A Week 2 25.4 (12.6) 22.9 (12.3) 2.30 (-0.25,4.84) 0.24 (-0.03,0.50) N/A Week 3 24.1 (11.9) 22.5 (12.0) 1.56 (-1.24, 4.37) 0.16 (-0.13,0.45) N/A Week 4 26.1 (12.3) 25.0 (12.3) 0.83 (-2.47,4.13) 0.09 (-0.26,0.43) 0.622 Note. ADHD-RS = Attention-Deficit/Hyperactivity Disorder Rating Scale; aMD = Adjusted Mean Difference; CI = Confidence Interval; Cohen’s d = standardised effect size (0.2 = small, 0.5 = medium, 0.8 = large). Secondary outcomes No significant between-group difference was observed for the ADHD-RS total score at 6 months follow-up ( aMD = -0.29; 95% CI = –3.17 to 2.59; p = 0.845; Cohen’s d = -0.03). No significant group differences were observed for most of the other secondary outcomes at week 4 and at 6-month follow-up (Table 3). An exception was the Mind Excessively Wandering Scale (MEWS) total score at week 4, which showed a statistically significant group difference (a MD = –2.17; 95% CI = –4.33 to –0.01; p = 0.049; Cohen’s d = –0.27) in favour of the real TNS arm compared to the sham TNS arm. Teacher ratings (Conners T-S and ADHD-RS-T) were not analysed due to high degree of missing data (80%). Similarly, Columbia-Suicide Severity Rating Scale (C-SSRS) scores were not analysed due to the lack of variation in scores. Descriptive statistics for teacher ratings and C-SSRS scores at baseline, week 4, and at 6 months follow-up are presented in Supplementary Table S4. Table 3 . Values and statistical comparisons of secondary outcome measures at baseline, 4 weeks, and 6 months. Secondary outcomes Mean (SD) [No.] Effect estimates Baseline Week 4 Month 6 Week 4 Month 6 Real TNS ( n =75) Sham TNS ( n =75) Real TNS ( n =73) Sham TNS ( n =74) Real TNS ( n =72) Sham TNS ( n =73) aMD (95% CI) p -value aMD (95% CI) p -value SDQ Hyperactivity/impulsivity/ inattention score (child rated) 7.5 (2.0) [75] 7.5 (2.1) [75] 6.8 (2.3) [73] 7.0 (2.1) [74] 6.6 (2.2) [71] 6.7 (2.1) [73] -0.30 (-0.88, 0.28) 0.308 -0.24 (-0.83, 0.36) 0.433 ARI-P total score (parent rated) 5.5 (3.3) [75] 5.0 (3.2) [75] 3.8 (3.2) [73] 3.9 (3.1) [74] 4.6 (3.1) [72] 4.4 (3.2) [73] -0.36 (-1.15,0.43) 0.374 -0.01 (-0.83, 0.80) 0.974 ARI-S total score (child rated) 4.2 (3.4) [75] 4.0 (3.3) [75] 2.9 (3.2) [73] 3.4 (3.2) [74] 3.3 (2.8) [71] 3.2 (3.0) [73] -0.63 (-1.27, 0.01) 0.052 -0.11 (-0.83, 0.61) 0.766 MEWS total score (child rated) 16.7 (8.1) [75] 17.3 (8.2) [75] 13.4 (8.9) [73] 15.9 (9.8) [74] 15.0 (9.6) [71] 15.9 (8.9) [73] -2.17 (-4.33,-0.01) 0.049 * -0.73 (-3.15, 1.68) 0.553 RCADS-25 total score (child rated) 41.6 (9.0) [74] 42.7 (10.4) [75] 36.9 (7.1) [73] 39.1 (9.1) [74] 38.6 (8.5) [71] 40.7 (10.0) [73] -1.56 (-3.54, 0.41) 0.121 -1.45 (-4.04, 1.15) 0.274 RCADS-25 total score (parent rated) 58.5 (12.6) [73] 56.9 (13.7) [75] 50.3 (10.1) [73] 50.7 (11.7) [74] 55.4 (14.2) [72] 53.3 (11.9) [73] -1.07 (-3.87, 1.73) 0.453 1.41 (-1.95, 4.77) 0.410 Mackworth Vigilance Task (% of Omission errors) 45.8 (23.8) [75] 41.4 (21.7) [74] 36.3 (21.1) [70] 30.1 (21.8) [74] 28.3 (17.0) [64] 25.8 (19.9) [72] 3.62 (-0.73, 7.98) 0.103 -0.15 (-4.90, 4.60) 0.950 Mackworth Vigilance Task (% of Commission errors) 6.8 (8.6) [73] 5.9 (6.6) [75] 4.7 (5.5) [70] 6.8 (12.8) [74] 4.2 (7.0) [64] 5.7 (10.4) [72] 0.95 1 (0.80, 1.13) 0.573 0.90 (0.73, 1.10) 0.283 SDSC total score (parent rated) 49.2 (12.1) [75] 44.0 (9.7) [74] 43.2 (10.0) [73] 39.6 (8.9) [74] 46.1 (12.1) [72] 42.7 (9.7) [72] 1.00 (-1.42, 3.42) 0.417 0.51 (-2.46, 3.47) 0.738 Objective hyperactivity composite score 1 -0.1 (1.7) [73 0.1 (1.7) [74] -0.2 (1.8) [71] 0.2 (1.7) [73] N/A N/A -0.25 (-0.74, 0.24) 0.319 N/A N/A Average pupil diameter at rest 9.5 (1.5) [75] 9.5 (1.6) [75] 9.0 (1.3) [72] 9.3 (1.6) [74] 9.3 (1.4) [65] 9.7 (1.6) [69] -0.25 (-0.58, 0.08) 0.134 -0.30 (-0.65, 0.04) 0.080 Average pupil diameter at task 9.9 (1.6) [75] 10.1 (1.5) [75] 9.5 (1.3) [72] 9.8 (1.6) [74] 9.7 (1.5) [65] 10.0 (1.3) [70] -0.17 (-0.52, 0.18) 0.349 -0.20 (-0.56, 0.16) 0.281 Side effects score (child rated) 12.5 (10.1) [75] 12.3 (9.3) [75] 10.7 (9.5) [75] 11.9 (10.5) [75] 7.5 (7.6) [70] 8.5 (7.1) [73] -1.11 (-3.76, 1.53) 0.410 -1.05 (-3.09, 0.99) 0.314 Side effects score (parent rated) 10.8 (7.9) [75] 8.9 (6.5) [75] 8.7 (6.0) [75] 9.0 (6.8) [75] 7.6 (6.2) [71] 7.2 (6.4) [73] -1.09 (-2.79, 0.61) 0.210 -0.26 (-2.03, 1.52) 0.777 Weight (Kg) 46.7 (13.8) [75] 47.4 (14.4) [75] 47.2 (14.1) [72] 48.1 (14.8) [74] 49.3 (14.4) [65] 49.7 (15.0) [71] -0.39 (-0.83, 0.05) 0.080 0.13 (-0.68, 0.94) 0.754 Pulse (bpm) 78.4 (13.7) [75] 78.5 (14.2) [74 78.0 (12.5) [72] 79.4 (13.7) [74] 78.5 (13.0) [65] 78.1 (14.1) [71] -1.32 (-4.97, 2.32) 0.477 0.79 (-2.96, 4.54) 0.679 Note. aMD = Adjusted Mean Difference; ARI-P = Affective Reactivity Index-Parent Report; ARI-S = Affective Reactivity Index-Self Report; bpm = beats per minute; Kg = kilograms; MEWS = Mind Excessively Wandering Scale; RCADS-25 = Revised Child Anxiety and Depression Scale-25; SD = standard deviation; SDQ = Strengths and Difficulties Questionnaire; SDSC = Sleep Disturbance Scale for Children. 1 Reported beta estimate is back-transformed following log transformation of this outcome due to skewness of residuals. The back-transformed estimate given here is a geometric mean ratio for this outcome instead of a mean difference. *Significant at p <0.05. Complier Average Causal Effect Analysis The Complier Average Causal Effect (CACE) analysis showed no significant group difference for the ADHD-RS total score at the week 4 primary endpoint in participants that would comply with the assigned treatment (mean difference [ MD ] = 1.12; 95% CI = –1.38 to 3.61; p = 0.381; Cohen’s d = 0.12) consistent with the ITT analysis (Supplementary Table S5) . Subgroup analysis on non-medicated participants The pre-specified subgroup analysis of participants who were off medication/medication-naïve at baseline found no significant group difference for the ADHD-RS total score at week 4 ( MD = 0.68; 95% CI = -3.59 to 4.95; p = 0.755; Cohen’s d = 0.07; Supplementary Table S6). Post-hoc analyses For comparability of findings with the previous pilot RCT 18 , a post-hoc analysis was conducted including only participants in the same age group (8-12 yrs). No significant group difference was observed for ADHD-RS total score at the week 4 primary endpoint ( aMD = 0.55; 95% CI = -3.73 to 4.83; p = 0.80) for this subgroup (Supplementary Table S7). Given our observation that younger children had difficulties in understanding the MEWS items, we conducted a post-hoc subgroup analysis in older adolescents (14–18 yrs) where we were more confident in their comprehension of the scale statements, to test whether we would still observe the effect. No significant group difference was observed for MEWS total score at week 4 ( aMD = 0.28; 95% CI = -3.65 to 4.21; p = 0.89; Supplementary Table S8). Blinding At the end of week 1 and week 4 of the TNS treatment period, children/adolescents, parents/carers, and researchers were asked to guess treatment allocation. Blinding appeared successful at week 1, with high rates of “don’t know” responses across children (40%), parents (50%), and researchers (75.3%). Among children in the real TNS group, 45.3% guessed they were receiving the real treatment and 12% guessed sham. In the sham TNS group, 45.3% guessed real and 17.3% guessed sham. For parents in the real TNS group, 40% believed their child was receiving the real treatment and 16% guessed sham; in the sham group, 21.3% guessed real and 22.7% guessed sham. For researchers in the real TNS group, 10.7% guessed real and 10.7% guessed sham; in the sham group, 12.0% guessed real and 16% guessed sham. Blinding remained successful for most participants at week 4, with “don’t know” responses still reported by 34.9% of children, 33.6% of parents, and 53.0% of researchers. Among those who did guess at week 4, guesses were balanced across treatment groups: for children in the real TNS group, 37.8% guessed real and 28.4% guessed sham; for children in the sham TNS group, 32% guessed real and 29.3% guessed sham. For parents in the real TNS group, 37.8% guessed real and 32.4% guessed sham; for parents in the sham TNS group, 21.3% guessed real and 38.7% guessed sham. For researchers in the real TNS group, 13.5% guessed real and 28.4% guessed sham; in the sham group, 13.3% guessed real and 36.0% guessed sham (for further details see Supplementary Table S9). Safety At week 4, the most reported side effects were having trouble sleeping, feeling drowsy/sleepy, headaches, and feeling nervous/hyper; however, the majority of these side effects were rated as mild by participants (Supplementary Table S10) and common in children with ADHD.). As illustrated in Table 3, side effects rates and pulse (bpm) did not differ between treatment groups. The most commonly reported adverse device effects (ADEs) were headaches (real TNS = 21.3%, sham TNS = 17.3%), and difficulties falling asleep or sleep disturbances (real TNS = 20%, sham TNS = 9.3%). Other reported ADEs included physiological symptoms (real TNS = 13.3%, sham TNS =5.3%), grumpiness or irritability (real TNS = 4%, sham TNS = 5.3%), tearfulness, sadness or depression (real TNS = 1.3%, sham TNS = 6.7%), tiredness, demotivation or joylessness (real TNS = 4%, sham TNS = 1.3%), and frustration (real TNS = 4%, sham TNS = 1.3%; see Supplementary Tables S11–S15 and Supplementary Figure S1). No serious adverse events (SAEs), serious adverse device effects (SADEs), nor unanticipated serious adverse device effects (USADEs) were reported, and no participants withdrew from the trial due to adverse events (AEs). Six participants discontinued treatment but remained in the trial. Three stopped on their own due to side effects (nightmares, sleep issues, increased hyperactivity – all in the real arm), while three were withdrawn on our clinician’s advice (SC, PS) for safety reasons (sham: unrelated head injury, emotional sensitivity; real: recurring nosebleeds that stopped shortly after discontinuation). The majority of parents (97%) and children (92.5%) reported no or only mild side effects on the acceptability questionnaire administered at week 4. Similarly, most parents (89.8%) and children (82.3%) indicated no or only mild burden on the same questionnaire (Supplementary Table S16). DISCUSSION This multi-centre, double-blind, randomized, parallel-group, confirmatory phase IIb study tested the efficacy of 4 weeks nightly use of real versus sham TNS on ADHD clinical symptoms and related problems. We found no differential effects of real versus sham TNS on the primary outcome, the parent-rated ADHD-RS score, nor on any secondary outcomes except for ratings on the MEWS, evaluating mind-wandering, which showed improvement in the real versus sham TNS group. Adherence (94%) and reported compliance (93%) were extremely high, likely reflecting the current preference of parents and users for non-pharmacological treatments 9 . Safety was high, with no serious adverse events, and side effects were comparable across arms. Acceptability was also high. Blinding was successful. The findings of this large double-blind, multicentre RCT do not provide support for TNS as an effective treatment for ADHD. If anything, the sham group had numerically reduced ADHD symptoms on the ADHD-RS at week one with an effect size of 0.3. This conflicts with the positive findings from the previous pilot RCT of TNS in children with ADHD that showed an improvement in ADHD symptoms with medium effect size for real versus sham TNS with almost the same protocol with respect to trial duration (4 weeks) and dose/nightly settings 18 . However, a key distinction of our study is the improved design of the sham condition, which is likely responsible for the apparent successful blinding after 4 weeks of treatment. While the RCT of McGough et al. 18 applied no stimulation at all in the sham TNS condition, in our RCT, the sham TNS group received 30s stimulation at a lower frequency, followed by 570s without stimulation, for every hour of stimulation. This likely improved blinding over the previous RCT. Notably, in the trial of McGough et al. 18 , blinding was successful after 1 week. However, participants/parents were not asked about their blinding at the end of the four-week trial, when unblinding was more likely. Evidence shows that the placebo effect is greater in trials involving technology, such as neurofeedback 24 and neurostimulation, as well as in studies with younger age groups, larger sample sizes, multi-site designs and higher baseline symptom severity (ADHD severity was an inclusion criterion in this trial) 25 . This is furthermore enhanced by a nocebo effect in those that realise they are in the sham condition 26 . In our trial, both groups improved in ADHD symptoms by 26% (real) and 29% (sham). Given that a significant number of participants in both groups believed they were in the active condition, the observed effects may reflect a neurotechnology-induced placebo effect or “neuro-enchantment” or “neuro-suggestion” 27 . Alternative explanations are a regression to the mean, potential baseline severity symptom inflation, as parents were aware of severity criteria for trial entry, or non-specific beneficial effects of staff interaction 25 . It could also potentially be argued that sham conditions sharing features with the intervention may dilute its effects and hence compromise its validity. However, the sham stimulation had lower frequency and pulse width, and it is unlikely that 30s of stimulation every hour with such low frequency and pulse width would have led to an improvement in symptoms. Another difference with respect to the previous pilot RCT 18 is that we included long-term medicated children (39.3%) and a larger age range of children and adolescents of 8-18 yrs, while the previous study was restricted to non-medicated children (8-12 yrs).Medication could potentially mask effects or interact with TNS. However, our subgroup analysis in non-medicated children & adolescents also showed no effect, nor did a post hoc analysis in the same age range as the one used in the previous study 18 (see supplementary Tables S6 and S7). The only positive finding of real versus sham TNS was an improvement in the MEWS mind-wandering scale after 4 weeks. Given that increased mind-wandering is a core feature of ADHD 28-30 , this may represent a meaningful benefit of the treatment. However, this needs to be considered in the context of negative findings in all other 16 measures, and a possible Type I error due to multiple testing. Also, the younger children in the trial had difficulty understanding the MEWS items, which, although validated in children 31 , were originally designed for adults with ADHD 32 . A post hoc analysis of older adolescents aged 14-18 years who we are more confident understood the MEWS items, however, showed no effect (see supplementary Table S8). The RCT also showed no effect on a key measure of vigilance/sustained attention that is typically impaired in children with ADHD. While an open-label pilot study of TNS reported a significant reduction in flanker task incongruent reaction times after eight weeks of treatment 22 , this finding was not replicated in the subsequent double-blind pilot RCT 18 . In that trial 18 , only participants classified as TNS responders showed reductions in behavioural measures of working memory, which predicted treatment response and correlated with symptom improvement. However, performance on computerized cognitive tasks, including working memory and Stroop tests, did not predict treatment response 33 . We also found no effect on objective wrist-held measures of hyperactivity nor on pupil diameter, a key physiological measure of arousal and autonomic nervous system (ANS) activity. The lack of treatment-induced pupil dilation suggests that TNS may not significantly influence the ANS, thus challenging its proposed bottom-up mechanisms of action through the LC and brainstem 13 . In line with a previous meta-analysis of TNS across neurological and psychiatric conditions 17 , and the earlier pilot study 18 , safety was excellent, with no group differences in side effects and no serious adverse events. Acceptability was also excellent with most participants reporting mild or no burden. TNS is hence very safe and tolerable but unfortunately not effective for youth with ADHD. The study population was very representative of the general UK population in terms of race/ethnicity, with 79,3% identifying as white (81% in the Census 2021; Ethnic group, England and Wales - Office for National Statistics), and 20.7 % from other ethnic groups (18.7% in the Census 2021). While this RCT study was rigorously conducted, with an improved control condition over previous trials 18,22 , it had some limitations. Due to low teacher participation and therefore a high rate of missing data on teacher ratings (80%), we did not have the power to analyse teacher ratings and potential treatment-related changes in participants’ inattentive and/or impulsive/hyperactive behaviours within school settings. Parent ratings are subject to various biases, including those related to parental stress and demographic factors 34,35 . Also, while adherence was very high (94%), it was self-reported and may have been overestimated due to social desirability bias 36 . The inclusion of medication could have been a confound, but as discussed above, the effects remained the same in non-medicated participants. In summary, this rigorously controlled multicentre RCT found that despite high compliance and adherence, four weeks of nightly TNS did not improve core symptoms nor related clinical and cognitive features in children and adolescents with ADHD. These negative findings on TNS extend largely negative findings using other neurostimulation techniques in children and adults with ADHD, including transcranial magnetic and direct current stimulation 10,37-41 . This large multi-centre RCT contrasts with the positive symptom improvements reported in the pilot trial that informed FDA clearance for TNS 18 , highlighting the critical importance of robust sham control conditions and expectation management to minimise placebo effects in neurostimulation research. In conclusion, while TNS is a safe intervention, it does not demonstrate clinical efficacy for paediatric ADHD. METHODS Trial design This UK multi-centre (King’s College London; University of Southampton), phase IIb, double-blind, parallel group, sham-controlled confirmatory RCT was pre-registered (trial registration: ISRCTN82129325). Participants were randomized to either active TNS or sham TNS (1:1). For protocol details, see 23 . The trial was approved by the West Midlands–Solihull NHS Research Ethics Committee (REC; Ref: 21/WN/0169; IRAS: 299703) and the Medicines and Healthcare products Regulatory Agency (MHRA; Ref: CI/2022/0003/GB). It was conducted in accordance with the Declaration of Helsinki 1975 and is reported following CONSORT guidelines 42 . Independent oversight of the trial was provided by a Data Monitoring and Ethics Committee (DMEC) and a Trial Steering Committee (TSC). Randomization and blinding Randomization was done by minimization by sex (male/female), medication status (on medication; off medication/naïve), site (London, Southampton) and age (8–13.5 years; 13.6-19 years) using a validated, online, web-based system from King’s Clinical Trials unit (KCTU) 23 . Participants, parents/carers, postdoctoral research associates (RAs), Principal Investigator (PI), Co-Investigators (Co-Is), and analysts were blinded to treatment arm except for the trial manager (LJ) and trial manager assistants (SEM and JH), who trained participants/parents on the device use, but did not conduct research assessments and were prohibited from sharing the information with other team members. Analysts were blinded until after database lock. Blinding was assessed by a questionnaire administered to participants, parents/carers, and researchers after 1 and 4 weeks of TNS treatment. Participants One hundred and fifty children and adolescents (8-18 years) with ADHD were recruited from public and private clinics in (Greater) London, Southampton and Portsmouth, nationwide parent and ADHD support groups, general practitioners (GPs), National Health System (NHS) Consent for Contact (C4C) research directory, and social media. Inclusion criteria were: a clinical and/or research DSM-5 ADHD diagnosis (semi-structured interview: Kiddie-Schedule for Affective Disorders and Schizophrenia [K-SADS] 43 ; a score >= 24 on the investigator-scored parent-rated ADHD-RS; IQ above 70 (Wechsler Abbreviated Scale of Intelligence [WASI-II] 44 ; being able to speak sufficient English (parents and children); be either medication-naïve, willing to come off their stimulant medication for one week before participation, or willing to be on stable stimulant medication for the 4 week RCT duration. Exclusion criteria were: comorbidity with any major psychiatric disorder as assessed on the K-SADS (except for conduct/oppositional defiant disorder, mild anxiety and mild depression, which scored below threshold on the K-SADS), enuresis and encopresis, alcohol and substance abuse, neurological abnormalities, medicated with atomoxetine or guanfacine (as it may interfere with TNS mechanisms), any other non-pharmacological treatments, dermatitis, and TNS contraindications such as implanted cardiac or neurostimulation systems, head-implanted metallic or electronic devices, and body-worn devices. Children/adolescents and their parents/carers provided both digital and written informed consents/assents and were reimbursed for travel costs and received up to £350 (£450 if they were enrolled in the fMRI sub-study). For details, see the protocol 23 . Procedures Participants were screened for eligibility via two online and one in-person appointments at King’s College London (KCL) Institute of Psychiatry, Psychology, and Neuroscience (IoPPN) or the University of Southampton Centre for Innovation and Mental Health (CIMH). Online screening included study information sheets and device explanations, digital consents, and parents/carers K-SADS interviews. In-person screening included IQ testing (WASI-II), children/adolescents K-SADS interviews, mock fMRI, fMRI task training, and written informed consents/assents. During the 2-3-hour baseline assessment, participants and parents/carers completed measures of ADHD symptoms, depression and anxiety, sleep, mind wandering, emotional dysregulation, and suicidality. Children/adolescents performed neurocognitive tasks (30–40 min), pupillometry during one of the tasks, and wore an Empatica E4 wristband to assess objective hyperactivity and autonomic functions. Vital signs and anthropometrics (height and weight) were recorded, and those participants who enrolled in the fMRI sub-study underwent a 1-hour scan. Teachers were contacted prior to the assessment to provide ADHD ratings. Participants were randomized (1:1) to active or sham TNS at the end of the baseline assessment, and both parents/carers and participants were instructed on device use and daily sleep diaries for the 4-week treatment. Weekly online assessments (20–30 min) included ADHD ratings from parents/carers, side effect and adverse event reporting, and a blinding questionnaire completed during the Week 1 assessment. At week 4 (2–3 hrs, in-person), participants returned the TNS device and repeated baseline tasks. Weight, hyperactivity, and vital signs were reassessed, and acceptability and blinding questionnaires were completed. Participants who underwent an fMRI scan at baseline also underwent an fMRI scan during this assessment. Teachers were asked to provide ADHD ratings. The 6-month follow-up (1-2 hrs, in-person) replicated prior baseline and week-4 assessments, except for fMRI and Empatica E4 measurements. Concomitant medications were recorded throughout the trial. Intervention Real and sham TNS was performed with the Monarch TNS System (NeuroSigma, Inc, Los Angeles, CA). Participants needed to use the stimulator for ~8 hrs during sleep. Each night, participants or their parents applied the disposable self-adhesive patch electrodes connected to the stimulator across their child’s forehead to provide bilateral stimulation of V1 trigeminal nerve branches. The real TNS used 120Hz repetition frequency with a 250 μs pulse width, and a duty cycle of 30s/30s off (total 240min in 8 hours). Stimulator settings were established at baseline (and adjusted each night) by titration in 0.2 mA increments ranging from 0 to a safe maximum of 10mA to identify a stimulation level that was perceptible but below the participants’ subjective level of pain/discomfort. The sham Monarch TNS system was identical in current, appearance, and user interface but the electrical stimulation flowed for 30s every hour at a lower frequency (2Hz) and 50 μs pulse width and was then routed through the internal resistor instead of the electrical patch, thus still draining battery to maintain blinding (total 4min in 8 hours). The 30s of real stimulation every hour in the sham condition was added to further enhance blinding 23 , which was successful in the previous trial without any stimulation in the sham condition 18 . The scalp adjusts very quickly to the stimulation, and the switch-off is not noticeable. To further protect blinding, participants were counselled that stimulation may not be perceptible, and that most people would not feel the stimulation after some time because of scalp adaptation. Technical support was provided by the trial manager (LJ. For details, see the protocol 23 ). Safety Safety was assessed through a weekly side-effect questionnaire adapted for TNS 18 , a weekly open-ended adverse event form completed by participants and their parents/carers, and vital signs (blood pressure and pulse) measured at baseline, week 4, and at 6 months follow-up. Outcome measures The primary outcome measure was the investigator-scored, parent-rated ADHD-RS total score 19 collected at eligibility, baseline and weekly throughout the four-week trial. Secondary outcome measures were collected at baseline, week 4, and at 6 months follow-up and included the following rating scales: teacher-rated ADHD-RS (school version) 45 , Conners Teacher Rating Scale short form T-S 46 , child-reported Strength and Difficulties Questionnaire (SDQ) 47 , parent and child-reported Affective Reactivity Index (ARI) 48 , parent and child-reported Child and Adolescent Anxiety and Depression scale (RCADS-25) 49 , child-reported Columbia Suicide Severity Rating Scale (C-SSRS) 50 , child-reported Mind Excessively Wandering Scale (MEWS) 32 , parent-reported Sleep Disturbance Scale for Children (SDSC) 51 , and the investigator scored parent-rated ADHD-RS 19 at 6 months follow-up. Vigilance (omission and commission errors) was assessed using the Mackworth Clock Task 52 . Pupillometry data were recorded with the Tobii Pro Nano screen-based eye-tracking device (Tobii AB, Stockholm, Sweden) during a 1-minute resting condition and a cognitive task. Objective hyperactivity, defined as the composite score of both the intensity (g) and frequency (g) of movement, was assessed at baseline and week 4 using a 3-axis accelerometer embedded in the Empatica E4 wristband device (Empatica Srl, Milan, Italy). Other measures included an acceptability questionnaire filled out by participants and their parents/carers at the end of the treatment. Details regarding other secondary outcome measures of executive functions, physiological, and fMRI measures are described in the study protocol 23 and will be published elsewhere. Sample size justification The estimated sample size of 128 participants (64:64) was calculated using a baseline to post-treatment correlation of 0.5, 90% power, 5% type I error, and an anticipated effect size of 0.5 for a reduction in ADHD symptoms at 4 weeks 18 . The number of participants was inflated to 150 (75:75) to account for a loss to follow-up rate of 15% 23 . Statistical analysis Analyses were performed in Stata 18 (College Station, TX: StataCorp LLC) following a prespecified statistical analysis plan which can be found as supplementary material to the published protocol 23 . For the primary analysis a longitudinal linear mixed model was used, fitting 4-week ADHD symptom scores as a continuous outcome, with continuous time as a covariate using actual time of assessments and an interaction between time and trial arm to estimate effects at week 1, 2,3 and 4 using post-estimation. A random intercept was included as well as a random slope over time for each participant and an adjustment for fixed effects of baseline ADHD-RS score, site, age (8–13.5 years; 13.6-19 years), gender, and medication status. An adjusted mean difference ( aMD ) was calculated between the treatment groups with associated 95% confidence intervals (95% CI) and p -value (for week 4 only). A separate model was used to investigate treatment differences at 6-months timepoint by including time as a categorical variable, as treatment differences at follow-up were not expected to follow the same linear time trend. For the analysis of secondary outcomes, we utilized mixed models for repeated measures (MMRM) with time included as a categorical variable and the same covariates as for the primary analysis. An intention-to-treat (ITT) approach was used for both primary and secondary analyses. No adjustment for multiple timepoints was performed as we pre-specified the primary outcome at week 4 53 . Statistical significance for all analyses was p <0.05. Cohen’s d was calculated using the pooled baseline standard deviation of each measure. A separate analysis of the primary outcome was carried out to estimate the treatment effect in those participants who adhered to the intervention, using a complier average causal effect analysis. Further details on the statistical methods can be found in the Supplement and the protocol paper and its supplement 23 . Declarations The author has provided a link to the data, https://doi.org/10.6084/m9.figshare.29414744.v1 Data availability There are no contractual agreements in place to restrict data availability. Once the results of the trial have been reported, a data sharing dataset will be available. All data sharing requests should be submitted to Prof Katya Rubia (corresponding author). Funding This project (NIHR130077) is funded by the [Efficacy and Mechanism Evaluation (EME) Programme/Better Methods, Better Research (BMBR) programme], an MRC and NIHR partnership. The views expressed in this publication are those of the authors and not necessarily those of the MRC, NIHR or the Department of Health and Social Care. The design, management, analysis and reporting of the study are independent of the funder and the device manufacturer. KR and MM are supported by the NIHR Biomedical Research Centre at South London and Maudsley NHS foundation Trust and King’s College London (BRC). SC and KR are also supported by NIHR grant NIHR203684. SC is an NIHR Research Professor (NIHR303122) funded by the NIHR for this research project. SC is also supported by NIHR203035, NIHR128472, RP-PG-0618-20003 and by grant 101095568-HORIZONHLTH- 2022-DISEASE-07-03 from the European Research Executive Agency. BC has received funding from NIHR (EME, HTA, PHR, HSDR, RfPB), CRUK, MRC. SP has received funding from NIHR Invention for Innovation (i4i) Programme, MRC Clinical Academic Research Partnerships, NIHR HTA, and NIHR PGfAR. This study is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration South London (NIHR ARC South London) at King's College Hospital NHS Foundation Trust. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR or the UK Department of Health and Social Care. Competing interests KR has received a grant from Takeda Pharmaceuticals for another project. SC has received reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health (ACAMH) in relation to lectures delivered for ACAMH, the Canadian AADHD Alliance Resource, the British Association of Psychopharmacology, Healthcare Convention and CCM Group team for educational activity on ADHD and has received honoraria from Medice. MAM has received research funding from Takeda Pharmaceuticals, Johnson and Johnson, Lundbeck, Boehringer Ingelheim and SoseiHeptares. He also acted as a consultant for Neurocrine, Lundbeck, Boehringer Ingelheim and SoseiHeptares. Dr Giovanni Giaroli has received speaker honoraria from Takeda Pharmaceuticals. PS reports research funding from the British Heart Foundation, Reverse Rett, Newron Pharmaceuticals, HealthTracker, and Anavex Life Sciences Corporation; consulting fees from Anavex Life Sciences Corporation; honoraria and reimbursement for travel and accommodation expenses from the Egyptian Psychiatry Association, Acadia Pharmaceuticals Inc, and Neurogene Inc; and stocks from HealthTracker Ltd. BC has received funding from the Nuffield Foundation, Alzheimer’s Research UK, LifeARC and Mundipharma. FF has received stocks from HealthTracker Ltd. DS, AAC, NB, IEE, RM, AB, S E-M, JH, HL and LJ have no financial interests to declare. Acknowledgement Many thanks to all the participants and their parents/carers for their time and support for the project. Recruitments were made through the CAMHS clinics within the following NHS trusts: South London and Maudsley NHS Foundation Trust, Hampshire and Isle of wight Healthcare (previously known as SOLENT NHS Trust), Central and North-West London NHS Foundation Trust, Oxleas NHS Foundation Trust and South-West London and St George’s Mental Health NHS Trust. In addition, recruitment was made by private clinics from the Giaroli Centre and the Assessment Team. The project received support for the study by CRN South London and CRN Wessex, in particular Keira O’Brien. Many thanks to ADHD Foundation trust and ADDISS (ADHD Information Services) who advertised the study on their social media as well as other local ADHD support groups in the South-East of England. Valuable advice and support have been provided throughout the trial by the study dedicated PPI group (Michele Reilly, Co-ordinator Lambeth ADHD Support Group, Faduma Mahamed Ali, Zaynab Hassan Ali, Harry Reynolds, Jane Reynolds). In addition, further help was given by Sidra Zahid. We are also grateful for the advice and support given throughout the trial by the DMEC committee (Professor David Daley, Drs Aditya Sharma and Dr Adrian Cook) and the Trial Steering Committee (TSC) (Professor Richard Morriss, Dr Jody Warner-Rogers, Dr Anthony James, Dr Rachel Evans, Mrs Beverley Nolker and Mason Nolker). This study was supported by the United Kingdom Clinical Research Collaboration-registered King's Clinical Trials Unit at King's Health Partners, which is part funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King's College London and the NIHR Evaluation, Trials and Studies Coordinating Centre. A particular thanks to Merry Martin who helped with data analysis. Authorship contributions statement Grant funding was obtained by KR (PI), SC, BC, PS, MAM (Co-Is) who conceived and designed the study. SC was PI lead for the Southampton site. 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The Sleep Disturbance Scale for Children (SDSC) Construct ion and validation of an instrument to evaluate sleep disturbances in childhood and adolescence. Journal of sleep research 5 , 251-261 (1996). Lichstein, K.L., Riedel, B.W. & Richman, S.L. The mackworth clock test: A computerized version. The Journal of psychology 134 , 153-161 (2000). 10.1080/00223980009600858 Li, G. , et al. An introduction to multiplicity issues in clinical trials: the what, why, when and how. International journal of epidemiology 46 , 746-755 (2017). 10.1093/ije/dyw320 Additional Declarations Yes there is potential Competing Interest. Competing interests KR has received a grant from Takeda Pharmaceuticals for another project. SC has received reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health (ACAMH) in relation to lectures delivered for ACAMH, the Canadian AADHD Alliance Resource, the British Association of Psychopharmacology, Healthcare Convention and CCM Group team for educational activity on ADHD and has received honoraria from Medice. MAM has received research funding from Takeda Pharmaceuticals, Johnson and Johnson, Lundbeck, Boehringer Ingelheim and SoseiHeptares. He also acted as a consultant for Neurocrine, Lundbeck, Boehringer Ingelheim and SoseiHeptares. Dr Giovanni Giaroli has received speaker honoraria from Takeda Pharmaceuticals. PS reports research funding from the British Heart Foundation, Reverse Rett, Newron Pharmaceuticals, HealthTracker, and Anavex Life Sciences Corporation; consulting fees from Anavex Life Sciences Corporation; honoraria and reimbursement for travel and accommodation expenses from the Egyptian Psychiatry Association, Acadia Pharmaceuticals Inc, and Neurogene Inc; and stocks from HealthTracker Ltd. BC has received funding from the Nuffield Foundation, Alzheimer’s Research UK, LifeARC and Mundipharma. FF has received stocks from HealthTracker Ltd. DS, AAC, NB, IEE, RM, AB, S E-M, JH, HL and LJ have no financial interests to declare. Supplementary Files ATTENSNatureMedicinesupplementV.3.0FINAL.docx Supplementary Material CONSORT2025ATTENSmainpaper16.06.25.docx CONSORT Checklist nrreportingsummaryV.2.0.docx Reporting Summary nreditorialpolicychecklistV.2.0.docx Editorial Policy Checklist Cite Share Download PDF Status: Published Journal Publication published 16 Jan, 2026 Read the published version in Nature Medicine → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6882697","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":472507797,"identity":"106cd837-a4cc-463d-98b6-7e109057e163","order_by":0,"name":"Aldo Alberto Conti","email":"","orcid":"","institution":"King's College London, Institute of Psychiatry, Psychology \u0026 Neuroscience","correspondingAuthor":false,"prefix":"","firstName":"Aldo","middleName":"Alberto","lastName":"Conti","suffix":""},{"id":472507798,"identity":"ee346820-4031-43bb-b32a-e08b8193e433","order_by":1,"name":"Natali Bozhilova","email":"","orcid":"","institution":"King's 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Rubia","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYBACCRjDgJmB8WEDgwWYw9iAVwszXAuzYQPUCCK1MDCwSRKlRbL9/DGJHwz3ErezMz+rnFEjwcDffoBNcgYeLdI8yWySPQzFiTub2cxubjgmwSBxJoFNcgMeLXIMyWwSPAwJiRsOM5jdfNgAdNgNoAsf4NPC/5hN8g9YC/u3QpAWeUJapCWS2aQhtvCYMW4EajEAacHnMMkZj42tZQwSjHc28xRLzjgmwWN4JrHZEp/3Jc4nPrz5piJBdjv/8Y0fe2ps5OSOHz54swePFiBgkQBFCgzwEIgVMGD+QEjFKBgFo2AUjHAAAFwfRiimgRbtAAAAAElFTkSuQmCC","orcid":"","institution":"King's College London, Institute of Psychiatry, Psychology \u0026 Neuroscience","correspondingAuthor":true,"prefix":"","firstName":"Katya","middleName":"","lastName":"Rubia","suffix":""}],"badges":[],"createdAt":"2025-06-12 18:45:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6882697/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6882697/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41591-025-04075-x","type":"published","date":"2026-01-16T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85723229,"identity":"3e45450d-9a77-4e00-91b4-464d1eb0e9e2","added_by":"auto","created_at":"2025-07-01 06:05:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":357275,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCONSORT diagram. \u003c/strong\u003eEnrolment, group allocation, and analysis.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6882697/v1/5881136d489f199d5ba667ab.png"},{"id":85723227,"identity":"4f8afc18-7f92-47ef-8e49-3bbfccdc01b4","added_by":"auto","created_at":"2025-07-01 06:05:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":76982,"visible":true,"origin":"","legend":"\u003cp\u003eTemporal ADHD-RS plot showing raw means by trial arm over time with 95% confidence intervals.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6882697/v1/e5e13a6c32f90693be795ee8.png"},{"id":100468325,"identity":"81fb7395-ef5e-4378-962c-6bea9843eade","added_by":"auto","created_at":"2026-01-17 08:08:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2111084,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6882697/v1/9a264375-0018-4f4c-8ab5-a3a66330779f.pdf"},{"id":85723235,"identity":"1d806b54-a543-4742-bb97-c7dc749c9aa4","added_by":"auto","created_at":"2025-07-01 06:05:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":328979,"visible":true,"origin":"","legend":"Supplementary Material","description":"","filename":"ATTENSNatureMedicinesupplementV.3.0FINAL.docx","url":"https://assets-eu.researchsquare.com/files/rs-6882697/v1/b23abb05c1081d19d57afa5b.docx"},{"id":85723233,"identity":"4b09713d-2f30-4217-afc5-bdc0a9a6d66c","added_by":"auto","created_at":"2025-07-01 06:05:31","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":34507,"visible":true,"origin":"","legend":"CONSORT Checklist","description":"","filename":"CONSORT2025ATTENSmainpaper16.06.25.docx","url":"https://assets-eu.researchsquare.com/files/rs-6882697/v1/a484dbea86300a472857b236.docx"},{"id":85723231,"identity":"0993c879-10ad-4529-bd0e-84e1fa73586c","added_by":"auto","created_at":"2025-07-01 06:05:31","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":353381,"visible":true,"origin":"","legend":"Reporting Summary","description":"","filename":"nrreportingsummaryV.2.0.docx","url":"https://assets-eu.researchsquare.com/files/rs-6882697/v1/538d90524c2b8108c1c1a7e6.docx"},{"id":85723232,"identity":"c64aff07-5358-49c2-b750-296d7d8d1ba6","added_by":"auto","created_at":"2025-07-01 06:05:31","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":205458,"visible":true,"origin":"","legend":"Editorial Policy Checklist","description":"","filename":"nreditorialpolicychecklistV.2.0.docx","url":"https://assets-eu.researchsquare.com/files/rs-6882697/v1/beaecf12d4671d9e29c1e338.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nCompeting interests\r\nKR has received a grant from Takeda Pharmaceuticals for another project. SC has received reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health (ACAMH) in relation to lectures delivered for ACAMH, the Canadian AADHD Alliance Resource, the British Association of Psychopharmacology, Healthcare Convention and CCM Group team for educational activity on ADHD and has received honoraria from Medice. MAM has received research funding from Takeda Pharmaceuticals, Johnson and Johnson, Lundbeck, Boehringer Ingelheim and SoseiHeptares. He also acted as a consultant for Neurocrine, Lundbeck, Boehringer Ingelheim and SoseiHeptares. Dr Giovanni Giaroli has received speaker honoraria from Takeda Pharmaceuticals. PS reports research funding from the British Heart Foundation, Reverse Rett, Newron Pharmaceuticals, HealthTracker, and Anavex Life Sciences Corporation; consulting fees from Anavex Life Sciences Corporation; honoraria and reimbursement for travel and accommodation expenses from the Egyptian Psychiatry Association, Acadia Pharmaceuticals Inc, and Neurogene Inc; and stocks from HealthTracker Ltd. BC has received funding from the Nuffield Foundation, Alzheimer’s Research UK, LifeARC and Mundipharma. FF has received stocks from HealthTracker Ltd.\r\nDS, AAC, NB, IEE, RM, AB, S E-M, JH, HL and LJ have no financial interests to declare.","formattedTitle":"The efficacy of external Trigeminal Nerve Stimulation (TNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD): a multi-centre, double-blind, randomized, sham-controlled, parallel-group, phase IIb trial","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAttention-Deficit/Hyperactivity Disorder (ADHD) is the most common neurodevelopmental condition with a prevalence of around 5% in school-age children\u003csup\u003e1\u003c/sup\u003e and is defined by symptoms of inattention and/or hyperactivity/impulsivity that are inconsistent with the developmental stage and significantly impair daily functioning \u003csup\u003e2\u003c/sup\u003e. ADHD is also associated with impairments in executive functions and small but consistent differences in functional and structural brain regions and networks, most prominently involving frontal, striato-thalamic, parieto-temporal and cerebellar regions\u003csup\u003e3\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e. Stimulant medications (including methylphenidate and amphetamine) are first-line treatments for severe ADHD, improving symptoms in ~70% of children, with effect sizes of about 0.8-1.0 in the short-term\u0026nbsp;\u003csup\u003e5\u003c/sup\u003e. However, stimulants can cause side effects, may not be \u0026nbsp;indicated with some associated conditions such as cardiovascular disorders\u0026nbsp;\u003csup\u003e5\u003c/sup\u003e and adherence over time is poor, particularly in adolescence\u0026nbsp;\u003csup\u003e6\u003c/sup\u003e. Furthermore, their longer-term efficacy has not been demonstrated\u0026nbsp;\u003csup\u003e7\u003c/sup\u003e, with imaging studies suggesting brain adaptation\u003csup\u003e8\u003c/sup\u003e and hence, possibly reduced effects with long-term use. Non-stimulant (e.g., atomoxetine, guanfacine or viloxazine), considered second-line medications, have on average lower efficacy than stimulants and can also lead to intolerable side effects\u0026nbsp;\u003csup\u003e5\u003c/sup\u003e. Importantly, users and their families prefer non-pharmacological \u0026nbsp;treatments with better side-effect profiles\u0026nbsp;\u003csup\u003e9\u003c/sup\u003e. Yet, evidence for the efficacy of interventions such as behavioural therapy, cognitive and parent training, dietary changes, and neurofeedback in improving ADHD symptoms remains limited\u0026nbsp;\u003csup\u003e10\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e \u003csup\u003e4\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e \u003csup\u003e11\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExternal Trigeminal Nerve stimulation (TNS) was granted clearance by the USA Food and Drug Administration (FDA) in 2019 as the first non-pharmacological treatment for ADHD. TNS is a non-invasive brain stimulation technique that targets the supratrochlear and supraorbital branches of the ophthalmic division (V1) of the trigeminal nerve by delivering an electric current through electrodes placed on the forehead. \u0026nbsp;Sensory inputs from the trigeminal nerve fibres activate the locus coeruleus (LC), raphe nuclei (RN), and nucleus tractus solitarius (NTS) that innervate in a bottom-up manner several other brain regions, most prominently thalamic, frontal and limbic regions \u003csup\u003e12\u003c/sup\u003e, all of which are affected in ADHD \u003csup\u003e3,\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e. The effects of TNS on the LC and brainstem are thought to enhance attention and arousal mechanisms \u003csup\u003e13\u003c/sup\u003e,\u0026nbsp;which are commonly affected in ADHD\u0026nbsp;\u003csup\u003e14\u003c/sup\u003e. \u0026nbsp;Furthermore, TNS is thought to stimulate the release of neurotransmitters important for arousal, attention, and emotion regulation, particularly noradrenaline, but also dopamine, glutamate, gamma-aminobutyric acid (GABA), and serotonin\u0026nbsp;\u003csup\u003e12\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e15\u003c/sup\u003e all of which have been implicated in ADHD \u0026nbsp;\u003csup\u003e16\u003c/sup\u003e. A recent meta-analysis showed that TNS is safe with good tolerability for neurological and psychiatric conditions\u0026nbsp;\u003csup\u003e17\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe evidence for FDA clearance was based on a pilot double-blind randomized controlled trial (RCT) in 62 unmedicated children \u003csup\u003e18\u003c/sup\u003e, showing that four weeks of nightly real versus sham TNS significantly decreased parent-rated ADHD symptoms on the ADHD Rating Scale (ADHD-RS) \u003csup\u003e19\u003c/sup\u003e, with medium effect size (Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e = 0.5). The behavioural effects were correlated with increased electroencephalography (EEG) activity in right inferior/dorsolateral prefrontal cortex \u003csup\u003e18\u003c/sup\u003e, a key region known to be underactive \u0026nbsp;in ADHD \u003csup\u003e2,3 ,\u003c/sup\u003e\u003csup\u003e20\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e21\u003c/sup\u003e.\u0026nbsp;TNS was well-tolerated, with no severe adverse events and only minor, transient side effects, predominantly headaches and fatigue \u0026nbsp;\u003csup\u003e18\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e22\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThese promising findings call for replication in a definitive, multi-centre trial. Furthermore, the pilot study did not assess \u0026nbsp;effects beyond 4 weeks and was limited to very young children aged 8-12 years (yrs) \u003csup\u003e18\u003c/sup\u003e. To address this need, we conducted a confirmatory multi-centre, double-blind, randomized, sham-controlled, parallel-group, phase IIb trial investigating both short (4 weeks) and longer-term (6 months) efficacy \u0026nbsp;of real vs sham TNS not only in children but also in adolescents with ADHD,\u0026nbsp;a population with particularly high need for alternative treatments due to low medication adherence rates\u0026nbsp;\u003csup\u003e6\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe hypothesized that 4 weeks of nightly real versus sham TNS in children and adolescents with ADHD would improve core symptoms, as measured by parent-rated scales (primary outcome). Secondary cognitive and clinical outcomes included vigilance, symptoms of depression and anxiety, emotional dysregulation, mind-wandering, and sleep. We also investigated the effect of TNS on arousal via pupillometry and on objective hyperactivity using a wrist-worn device. Mechanisms of action were explored through functional magnetic resonance imaging (fMRI), which will be reported separately.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eParticipant data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants were recruited from September 2022 to November 2024. Of 843 children/adolescents with ADHD and their parents/carers who were interested in the study, 165 provided written informed consent, and 150 (97 males, 64.7%) were enrolled in the study and included in the intention to treat (ITT) analysis (Figure 1). Participants had a mean age (\u003cem\u003eSD\u003c/em\u003e) of 12.6 years (2.8) and the majority were of white ethnicity (\u003cem\u003en\u003c/em\u003e=119, 79.3%) and off medication/medication-na\u0026iuml;ve (\u003cem\u003en\u003c/em\u003e=91, 60.7%; Table 1). At baseline, 39.3% of participants were on stable stimulant medication, 12.6% were taking other psychotropic medication, and 13.3% were receiving other types of medication (for further demographic and medication information, see Supplementary Table S1 and S2). All participants met criteria for a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) \u003csup\u003e2\u003c/sup\u003e ADHD diagnosis. Among them, 133 (88.7%) met criteria for ADHD combined presentation, 16 (10.7%) for ADHD inattentive presentation, and one participant (0.7%) for ADHD hyperactive/impulsive presentation. Comorbid Oppositional Defiant Disorder was present in 54 participants (36%), and Conduct Disorder in four participants (2.7%) (Table 1). At baseline, participants had a mean (\u003cem\u003eSD\u003c/em\u003e) ADHD-RS total score of 35.3 (9.75), indicating severe ADHD symptomatology (Table 2).\u003c/p\u003e\n\u003cp\u003eParticipants were randomly allocated to real TNS (\u003cem\u003en\u003c/em\u003e=75, mean age [\u003cem\u003eSD\u003c/em\u003e]= 12.6 [2.8] yrs, off medication/medication-naive [\u003cem\u003en\u003c/em\u003e=46, 61.3%]) or sham TNS (\u003cem\u003en\u003c/em\u003e=75, mean age [\u003cem\u003eSD\u003c/em\u003e]= 12.6 [2.8] yrs), off medication/medication-naive [\u003cem\u003en\u003c/em\u003e=45, 60%]). One hundred and forty (93.3%) participants adhered to the intervention with only nine participants (real TNS [\u003cem\u003en\u003c/em\u003e=6, (8%)]; sham TNS [\u003cem\u003en\u003c/em\u003e=3, (4%)]) discontinuing the intervention permanently prior to the week 4 primary endpoint (Fig. 1 and Supplementary Table S3). One additional participant did not meet the predefined adherence threshold (\u0026ge;1 hr of device use per night on at least 17 nights), as specified in the statistical analysis plan (SAP) found in the protocol supplementary material \u003csup\u003e23\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e. Baseline demographics and clinical characteristics\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline characteristics (\u003cem\u003en\u003c/em\u003e,%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eReal TNS (\u003cem\u003en\u003c/em\u003e=75)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSham TNS (\u003cem\u003en\u003c/em\u003e=75)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eOverall (\u003cem\u003en\u003c/em\u003e=150)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (Mean, SD) \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12.6 (2.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12.6 (2.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12.6 (2.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (categorized per randomization stratifier)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 8-13.5 years old\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e43 (57.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e43 (57.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e86 (57.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 13.6-19 years old\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e32 (42.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e32 (42.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e64 (42.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eChild sex at birth \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Male\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e49 (65.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e48 (64.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e97 (64.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Female\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e26 (34.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e27 (36.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e53 (35.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eADHD diagnosis per KSADS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Combined presentation\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e66 (88.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e67 (89.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e133 (88.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Inattentive presentation\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (10.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (10.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16 (10.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Hyperactive/impulsive presentation\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (1.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (0.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOppositional Disorder per KSADS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e26 (34.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e28 (37.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e54 (36.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eConduct Disorder per KSADS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (5.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (2.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCurrent stimulant medication status \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; On stable medication\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e29 (38.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e30 (40.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e59 (39.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Off medication/ Naive\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e46 (61.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e45 (60.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e91 (60.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eWASI FSIQ-4 score (Mean (SD)) \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e105.5 (13.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e109.8 (13.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e107.6 (13.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eChild ethnicity \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; White\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e61 (81.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e58 (77.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e119 (79.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Black, African, Caribbean, or Black British\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (5.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (1.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (3.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Asian or Asian British\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (2.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (6.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (4.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Mixed or Multiple ethnic groups\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (8.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (12.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15 (10.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Other ethnic groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (2.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (2.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (2.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHandedness \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Right-handed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e60 (80.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e52 (69.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e112 (74.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Left/mixed handed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15 (20)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e23 (30.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e38 (50.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIndex of Multiple Deprivation (Mean (SD)) \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6.5 (2.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6.8 (2.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6.7 (2.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSite \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; King\u0026apos;s College London\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e54 (72.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e57 (76.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e111 (74.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; University of Southampton\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21 (28.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18 (24.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39 (26.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eNote.\u0026nbsp;\u003c/strong\u003eCategorical variables are presented as the number of participants, with the percentage in parentheses. Continuous variables are reported as mean (standard deviation). The Index of Multiple Deprivation ranges from 0 (most deprived) to 10 (least deprived). ADHD = Attention-Deficit/Hyperactivity Disorder; KSADS = Kiddie Schedule for Affective Disorders and Schizophrenia; TNS = External Trigeminal Nerve Stimulation; WASI FSIQ-4 = Wechsler Abbreviated Scale of Intelligence, Full Scale Intelligence Quotient, Fourth Edition.\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eADHD-RS total scores decreased in both groups over the 4-week treatment period, followed by a slight increase from week 3 to week 4 (Figure 2 and Table 2). At the week 4 primary endpoint, there was no significant difference between groups (estimated adjusted mean difference [\u003cem\u003eaMD\u003c/em\u003e] = 0.83; 95% CI = \u0026ndash;2.47 to 4.13; \u003cem\u003ep\u003c/em\u003e = 0.622; Cohen\u0026rsquo;s\u003cem\u003e\u0026nbsp;d\u003c/em\u003e = 0.09), indicating no evidence of a differential treatment effect between arms (Figure 2 and Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eChange in ADHD-RS total scores over 4 weeks of real versus sham TNS treatment.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"654\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary Outcome (ADHD-RS)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReal TNS \u0026nbsp; \u0026nbsp; (Mean, \u003cem\u003eSD\u003c/em\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSham TNS \u0026nbsp;(Mean, \u003cem\u003eSD\u003c/em\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;aMD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCohen\u0026rsquo;s \u003cem\u003ed\u0026nbsp;\u003c/em\u003e\u0026nbsp; \u0026nbsp;(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e35.4 (9.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e35.2 (9.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eWeek 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e26.6 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e22.9 (11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e3.03\u003c/p\u003e\n \u003cp\u003e(0.45, 5.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.31 \u0026nbsp; \u0026nbsp;(0.05,0.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eWeek 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e25.4 (12.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e22.9 (12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e2.30\u003c/p\u003e\n \u003cp\u003e(-0.25,4.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003cp\u003e(-0.03,0.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eWeek 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e24.1 (11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e22.5 (12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.56\u003c/p\u003e\n \u003cp\u003e(-1.24, 4.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003cp\u003e(-0.13,0.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eWeek 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e26.1 (12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e25.0 (12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003cp\u003e(-2.47,4.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003cp\u003e(-0.26,0.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.622\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eNote.\u0026nbsp;\u003c/strong\u003eADHD-RS = Attention-Deficit/Hyperactivity Disorder Rating Scale; aMD = Adjusted Mean Difference; CI = Confidence Interval; Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e = standardised effect size (0.2 = small, 0.5 = medium, 0.8 = large).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo significant between-group difference was observed for the ADHD-RS total score at 6 months follow-up (\u003cem\u003eaMD\u003c/em\u003e = -0.29; 95% CI = \u0026ndash;3.17 to 2.59; \u003cem\u003ep\u003c/em\u003e = 0.845; Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e = -0.03). No significant group differences were observed for most of the other secondary outcomes at week 4 and at 6-month follow-up (Table 3). An exception was the Mind Excessively Wandering Scale (MEWS) total score at week 4, which showed a statistically significant group difference (a\u003cem\u003eMD\u003c/em\u003e = \u0026ndash;2.17; 95% CI = \u0026ndash;4.33 to \u0026ndash;0.01; p = 0.049; Cohen\u0026rsquo;s d = \u0026ndash;0.27) in favour of the real TNS arm compared to the sham TNS arm. Teacher ratings (Conners T-S and ADHD-RS-T) were not analysed due to high degree of missing data (80%). Similarly, Columbia-Suicide Severity Rating Scale (C-SSRS) scores were not analysed due to the lack of variation in scores. Descriptive statistics for teacher ratings and C-SSRS scores at baseline, week 4, and at 6 months follow-up are presented in Supplementary Table S4.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e. Values and statistical comparisons of secondary outcome measures at baseline, 4 weeks, and 6 months.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSecondary outcomes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"6\" style=\"width: 519px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean (SD) [No.]\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 315px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEffect estimates\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 176px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 175px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeek 4\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 167px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMonth 6\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeek 4\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMonth 6\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReal TNS (\u003cem\u003en\u003c/em\u003e=75)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSham TNS\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003cem\u003en\u003c/em\u003e=75)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReal TNS\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003cem\u003en\u003c/em\u003e=73)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSham TNS\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003cem\u003en\u003c/em\u003e=74)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReal TNS\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003cem\u003en\u003c/em\u003e=72)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSham TNS\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003cem\u003en\u003c/em\u003e=73)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eaMD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eaMD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSDQ Hyperactivity/impulsivity/ inattention score (child rated)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e7.5 (2.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e7.5 (2.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e6.8 (2.3)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e7.0 (2.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e6.6 (2.2)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[71]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e6.7 (2.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-0.30\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-0.88, 0.28)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.308\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-0.24\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-0.83, 0.36)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.433\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eARI-P total score (parent rated)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e5.5 (3.3)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e5.0 (3.2)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e3.8 (3.2)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e3.9 (3.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.6 (3.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[72]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e4.4 (3.2)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-0.36\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-1.15,0.43)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.374\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-0.01 \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-0.83, 0.80)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.974\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eARI-S total score (child rated)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e4.2 (3.4)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e4.0 (3.3)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e2.9 (3.2)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e3.4 (3.2)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.3 (2.8)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[71]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e3.2 (3.0)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-0.63\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-1.27, 0.01)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.052\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-0.11\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-0.83, 0.61)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.766\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMEWS total score (child rated)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e16.7 (8.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e17.3 (8.2)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e13.4 (8.9)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e15.9 (9.8)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e15.0 (9.6)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[71]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e15.9 (8.9)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-2.17\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-4.33,-0.01)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;0.049\u003cstrong\u003e*\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-0.73\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-3.15, 1.68)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.553\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRCADS-25 total score (child rated)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e41.6 (9.0)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e42.7 (10.4)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e36.9 (7.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e39.1 (9.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e38.6 (8.5)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[71]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e40.7 (10.0)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-1.56\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-3.54, 0.41)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.121\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-1.45\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-4.04, 1.15)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.274\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRCADS-25 total score (parent rated)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e58.5 (12.6)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e56.9 (13.7)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e50.3 (10.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e50.7 (11.7)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e55.4 (14.2)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[72]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e53.3 (11.9)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-1.07\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-3.87, 1.73)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.453\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1.41\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-1.95, 4.77)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.410\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMackworth Vigilance Task \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; (% of Omission errors)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e45.8 (23.8)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e41.4 (21.7)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e36.3 (21.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[70]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e30.1 (21.8)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e28.3 (17.0)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[64]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e25.8 (19.9)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[72]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e3.62\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-0.73, 7.98)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.103\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-0.15\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-4.90, 4.60)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.950\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMackworth Vigilance Task \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; (% of Commission errors)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e6.8 (8.6)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e5.9 (6.6)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e4.7 (5.5)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[70]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e6.8 (12.8)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.2 (7.0)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[64]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e5.7 (10.4)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[72]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e0.95\u003csup\u003e1\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(0.80, 1.13)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.573\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.90\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(0.73, 1.10)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.283\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSDSC total score (parent rated)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e49.2 (12.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e44.0 (9.7)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e43.2 (10.0)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e39.6 (8.9)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e46.1 (12.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[72]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e42.7 (9.7)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[72]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1.00\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-1.42, 3.42)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.417\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.51\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-2.46, 3.47)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.738\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eObjective hyperactivity composite score\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e-0.1 (1.7)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.1 (1.7)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-0.2 (1.8)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[71]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.2 (1.7)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eN/A\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eN/A\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-0.25\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-0.74, 0.24)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.319\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eN/A\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eN/A\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAverage pupil diameter at rest\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e9.5 (1.5)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e9.5 (1.6)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e9.0 (1.3)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[72]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e9.3 (1.6)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e9.3 (1.4)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[65]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e9.7 (1.6)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[69]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-0.25\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-0.58, 0.08)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.134\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-0.30\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-0.65, 0.04)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.080\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAverage pupil diameter at task\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e9.9 (1.6)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e10.1 (1.5)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e9.5 (1.3)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[72]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e9.8 (1.6)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e9.7 (1.5)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[65]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e10.0 (1.3)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[70]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-0.17\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-0.52, 0.18)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.349\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-0.20\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-0.56, 0.16)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.281\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSide effects score (child rated)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e12.5 (10.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e12.3 (9.3)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e10.7 (9.5)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e11.9 (10.5)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e7.5 (7.6)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[70]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e8.5 (7.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-1.11\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-3.76, 1.53)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.410\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-1.05\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-3.09, 0.99)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.314\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSide effects score (parent rated)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e10.8 (7.9)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e8.9 (6.5)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e8.7 (6.0)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e9.0 (6.8)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e7.6 (6.2)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[71]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e7.2 (6.4)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[73]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-1.09\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-2.79, 0.61)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.210\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-0.26\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-2.03, 1.52)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.777\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeight (Kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e46.7 (13.8)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e47.4 (14.4)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e47.2 (14.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[72]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e48.1 (14.8)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e49.3 (14.4)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[65]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e49.7 (15.0)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[71]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-0.39\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-0.83, 0.05)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.080\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.13\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-0.68, 0.94)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.754\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePulse (bpm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e78.4 (13.7)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[75]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e78.5 (14.2)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e78.0 (12.5)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[72]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e79.4 (13.7)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[74]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e78.5 (13.0)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[65]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e78.1 (14.1)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[71]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-1.32\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-4.97, 2.32)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.477\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.79\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-2.96, 4.54)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e0.679\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eNote.\u003c/strong\u003e aMD = Adjusted Mean Difference; ARI-P = Affective Reactivity Index-Parent Report; ARI-S = Affective Reactivity Index-Self Report; bpm = beats per minute; Kg = kilograms; MEWS = Mind Excessively Wandering Scale; RCADS-25 = Revised Child Anxiety and Depression Scale-25; SD = standard deviation; SDQ = Strengths and Difficulties Questionnaire; SDSC = Sleep Disturbance Scale for Children.\u003csup\u003e1\u003c/sup\u003eReported beta estimate is back-transformed following log transformation of this outcome due to skewness of residuals. The back-transformed estimate given here is a geometric mean ratio for this outcome instead of a mean difference. *Significant at \u003cem\u003ep\u003c/em\u003e \u0026lt;0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComplier Average Causal Effect Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Complier Average Causal Effect (CACE) analysis showed no significant group difference for the ADHD-RS total score at the week 4 primary endpoint in participants that would comply with the assigned treatment (mean difference [\u003cem\u003eMD\u003c/em\u003e] = 1.12; 95% CI = \u0026ndash;1.38 to 3.61;\u003cem\u003e\u0026nbsp;p\u003c/em\u003e = 0.381; Cohen\u0026rsquo;s \u003cem\u003ed\u0026nbsp;\u003c/em\u003e= 0.12) consistent with the ITT analysis (Supplementary Table S5)\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup analysis on non-medicated participants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pre-specified subgroup analysis of participants who were off medication/medication-na\u0026iuml;ve at baseline found no significant group difference for the ADHD-RS total score at week 4 (\u003cem\u003eMD\u003c/em\u003e = 0.68; 95% CI = -3.59 to 4.95; \u003cem\u003ep\u003c/em\u003e = 0.755; Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e = 0.07; Supplementary Table S6). \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePost-hoc analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor comparability of findings with the previous pilot RCT \u003csup\u003e18\u003c/sup\u003e, a post-hoc analysis was conducted including only participants in the same age group (8-12 yrs). No significant group difference was observed for ADHD-RS total score at the week 4 primary endpoint (\u003cem\u003eaMD\u003c/em\u003e = 0.55; 95% CI = -3.73 to 4.83; \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.80) for this subgroup (Supplementary Table S7).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGiven our observation that younger children had difficulties in understanding the MEWS items, we conducted a post-hoc subgroup analysis in older adolescents (14\u0026ndash;18 yrs) where we were more confident in their comprehension of the scale statements, to test whether we would still observe the effect. No significant group difference was observed for MEWS total score at week 4 (\u003cem\u003eaMD\u003c/em\u003e = 0.28; 95% CI = -3.65 to 4.21; \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.89; Supplementary Table S8).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBlinding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the end of week 1 and week 4 of the TNS treatment period, children/adolescents, parents/carers, and researchers were asked to guess treatment allocation. Blinding appeared successful at week 1, with high rates of \u0026ldquo;don\u0026rsquo;t know\u0026rdquo; responses across children (40%), parents (50%), and researchers (75.3%). Among children in the real TNS group, 45.3% guessed they were receiving the real treatment and 12% guessed sham. In the sham TNS group, 45.3% guessed real and 17.3% guessed sham. For parents in the real TNS group, 40% believed their child was receiving the real treatment and 16% guessed sham; in the sham group, 21.3% guessed real and 22.7% guessed sham. For researchers in the real TNS group, 10.7% guessed real and 10.7% guessed sham; in the sham group, 12.0% guessed real and 16% guessed sham.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBlinding remained successful for most participants at week 4, with \u0026ldquo;don\u0026rsquo;t know\u0026rdquo; responses still reported by 34.9% of children, 33.6% of parents, and 53.0% of researchers. Among those who did guess at week 4, guesses were balanced across treatment groups: for children in the real TNS group, 37.8% guessed real and 28.4% guessed sham; for children in the sham TNS group, 32% guessed real and 29.3% guessed sham. For parents in the real TNS group, 37.8% guessed real and 32.4% guessed sham; for parents in the sham TNS group, 21.3% guessed real and 38.7% guessed sham. For researchers in the real TNS group, 13.5% guessed real and 28.4% guessed sham; in the sham group, 13.3% guessed real and 36.0% guessed sham (for further details see Supplementary Table S9).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt week 4, the most reported side effects were having trouble sleeping, feeling drowsy/sleepy, headaches, and feeling nervous/hyper;\u0026nbsp;however, the majority of these side effects were rated as mild by participants\u0026nbsp;(Supplementary Table S10) and common in children with ADHD.).\u0026nbsp;As illustrated in Table 3, side effects rates and pulse (bpm) did not differ between treatment groups.\u0026nbsp;The most commonly reported adverse device effects (ADEs) were headaches (real TNS = 21.3%, sham TNS = 17.3%), and difficulties falling asleep or sleep disturbances (real TNS = 20%, sham TNS = 9.3%). Other reported ADEs included physiological symptoms (real TNS = 13.3%, sham TNS =5.3%), grumpiness or irritability (real TNS = 4%, sham TNS = 5.3%), tearfulness, sadness or depression (real TNS = 1.3%, sham TNS = 6.7%), tiredness, demotivation or joylessness (real TNS = 4%, sham TNS = 1.3%), and frustration (real TNS = 4%, sham TNS = 1.3%;\u0026nbsp;see Supplementary Tables S11\u0026ndash;S15 and Supplementary Figure S1).\u0026nbsp;No serious adverse events (SAEs), serious adverse device effects (SADEs), nor unanticipated serious adverse device effects (USADEs) were reported, and no participants withdrew from the trial due to adverse events (AEs). Six participants discontinued treatment but remained in the trial. Three stopped on their own due to side effects (nightmares, sleep issues, increased hyperactivity \u0026ndash; all in the real arm), while three were withdrawn on our clinician\u0026rsquo;s advice (SC, PS) for safety reasons (sham: unrelated head injury, emotional sensitivity; real: recurring nosebleeds that stopped shortly after discontinuation).\u003c/p\u003e\n\u003cp\u003eThe majority of parents (97%) and children (92.5%) reported no or only mild side effects on the acceptability questionnaire administered at week 4. Similarly, most parents (89.8%) and children (82.3%) indicated no or only mild burden on the same questionnaire (Supplementary Table S16).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis multi-centre, double-blind, randomized, parallel-group, confirmatory phase IIb study tested the efficacy of 4 weeks nightly use of real versus sham TNS on ADHD clinical symptoms and related problems. We found no differential effects of real versus sham TNS on the primary outcome, the parent-rated ADHD-RS score, nor on any secondary outcomes except for ratings on the MEWS, evaluating mind-wandering, which showed improvement in the real versus sham TNS group. Adherence (94%) and reported compliance (93%) were extremely high, likely reflecting the current preference of parents and users for non-pharmacological \u0026nbsp; treatments \u003csup\u003e9\u003c/sup\u003e. Safety was high, with no serious adverse events, and side effects were comparable across arms. Acceptability was also high. Blinding was successful.\u003c/p\u003e\n\u003cp\u003eThe findings of this large double-blind, multicentre RCT do not provide support for TNS as an effective treatment for ADHD. If anything, the sham group had numerically reduced ADHD symptoms on the ADHD-RS at week one with an effect size of 0.3. This conflicts with the positive findings from the previous pilot RCT of TNS in children with ADHD that showed an improvement in ADHD symptoms with medium effect size for real versus sham TNS with almost the same protocol with respect to trial duration (4 weeks) and dose/nightly settings \u003csup\u003e18\u003c/sup\u003e. However, a key distinction of our study is the improved design of the sham condition, which is likely responsible for the apparent successful blinding after 4 weeks of treatment. While the RCT of McGough et al.\u003csup\u003e18\u003c/sup\u003e applied no stimulation at all in the sham TNS condition, in our RCT, the sham TNS group received 30s stimulation at a lower frequency,\u0026nbsp;followed by\u0026nbsp;570s without stimulation, for every hour of stimulation. This likely improved blinding over the previous RCT. Notably, in the trial of McGough et al.\u003csup\u003e18\u003c/sup\u003e, blinding was successful after 1 week. However, participants/parents were not asked about their blinding at\u0026nbsp;the end of the four-week trial,\u0026nbsp;when unblinding was more likely. Evidence shows that the placebo effect is greater in trials involving technology, such as neurofeedback\u0026nbsp;\u003csup\u003e24\u003c/sup\u003e and neurostimulation, as well as in studies with younger age groups, larger sample sizes, multi-site designs and higher baseline symptom severity (ADHD severity\u0026nbsp;was an inclusion criterion in this trial)\u0026nbsp;\u003csup\u003e25\u003c/sup\u003e. This is furthermore enhanced by a nocebo effect in those that realise they are in the sham condition\u0026nbsp;\u003csup\u003e26\u003c/sup\u003e. In our trial, both groups improved in ADHD symptoms by 26% (real) and 29% (sham). Given that \u0026nbsp;a significant number of participants in both groups believed they were in the active condition,\u0026nbsp;the observed effects may reflect\u0026nbsp;a neurotechnology-induced placebo effect or \u0026ldquo;neuro-enchantment\u0026rdquo; or \u0026ldquo;neuro-suggestion\u0026rdquo;\u003csup\u003e27\u003c/sup\u003e. Alternative explanations are a regression to the mean, potential baseline severity symptom inflation, as parents were aware of severity criteria for trial entry, or non-specific beneficial effects of staff interaction\u003csup\u003e25\u003c/sup\u003e. It could also potentially be argued that sham conditions sharing features with the intervention may dilute its effects and hence compromise its validity. However, the sham stimulation had lower frequency and pulse width, and it is unlikely that 30s of stimulation every hour with such low frequency and pulse width would have led to an improvement in symptoms.\u003c/p\u003e\n\u003cp\u003eAnother difference with respect to the previous pilot RCT \u003csup\u003e18\u003c/sup\u003e is that we included long-term medicated children (39.3%) and a larger age range of children and adolescents of 8-18 yrs, while the previous study was restricted to non-medicated children (8-12 yrs).Medication could potentially mask effects or interact with TNS. However, our subgroup analysis in non-medicated children \u0026amp; adolescents also showed no effect, nor did a post hoc analysis in the same age range as the one used in the previous study\u003csup\u003e18\u003c/sup\u003e (see supplementary Tables S6 and \u0026nbsp;S7).\u003c/p\u003e\n\u003cp\u003eThe only positive finding of real versus sham TNS was an improvement in the MEWS mind-wandering scale after 4 weeks. \u0026nbsp;Given that increased mind-wandering is a core feature of ADHD\u003csup\u003e28-30\u003c/sup\u003e, this\u0026nbsp;may represent a meaningful benefit of the treatment.\u0026nbsp;However, this needs to be considered in the context of negative findings in all other 16 measures, and a possible Type I error due to multiple testing. Also, the younger children in the trial had difficulty understanding the MEWS items, which, although validated in children\u0026nbsp;\u003csup\u003e31\u003c/sup\u003e, were originally designed for adults with ADHD\u0026nbsp;\u003csup\u003e32\u003c/sup\u003e. A post hoc analysis of older adolescents aged 14-18 years who we are more confident understood the MEWS items, however, showed no effect (see supplementary Table S8).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe RCT also showed no effect on a key measure of vigilance/sustained attention that is typically impaired in children with ADHD. While an open-label pilot study of TNS reported a significant reduction in flanker task incongruent reaction times after eight weeks of treatment \u003csup\u003e22\u003c/sup\u003e, this finding was not replicated in the subsequent double-blind pilot RCT \u003csup\u003e18\u003c/sup\u003e. In that trial \u003csup\u003e18\u003c/sup\u003e, only participants classified as TNS responders showed reductions in behavioural measures of working memory, which predicted treatment response and correlated with symptom improvement. However, performance on computerized cognitive tasks, including working memory and Stroop tests, did not predict treatment response \u003csup\u003e33\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;We also found no effect on objective wrist-held measures of hyperactivity nor on pupil diameter, a key physiological measure of arousal and autonomic nervous system (ANS) activity. The lack of treatment-induced pupil dilation suggests that TNS may not significantly influence the ANS, thus challenging its proposed bottom-up mechanisms of action through the LC and brainstem \u003csup\u003e13\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;In line with a previous meta-analysis of TNS across neurological and psychiatric conditions\u003csup\u003e17\u003c/sup\u003e, and the earlier pilot study \u003csup\u003e18\u003c/sup\u003e, safety was excellent, with no group differences in side effects and no serious adverse events. Acceptability was also excellent with most participants reporting mild or no burden. \u0026nbsp;TNS is hence very safe and tolerable but unfortunately not effective for youth with ADHD. The study population was very representative of the general UK population in terms of race/ethnicity, with 79,3% identifying as white (81% in the Census 2021; Ethnic group, England and Wales - Office for National Statistics), and 20.7 % from other ethnic groups (18.7% in the Census 2021).\u003c/p\u003e\n\u003cp\u003eWhile this RCT study was rigorously conducted, with an improved control condition over previous trials\u003csup\u003e18,22\u003c/sup\u003e, it had some limitations. Due to low teacher participation and therefore a high rate of missing data on teacher ratings (80%), we did not have the power to analyse teacher ratings and potential treatment-related changes in participants\u0026rsquo; inattentive and/or impulsive/hyperactive behaviours within school settings. Parent ratings are subject to various biases, including those related to parental stress and demographic factors\u003csup\u003e34,35\u003c/sup\u003e . Also, while adherence was very high (94%), \u0026nbsp;it was self-reported and may have been overestimated due to social desirability bias \u003csup\u003e36\u003c/sup\u003e. The inclusion of medication could have been a confound, but as discussed above, the effects remained the same in non-medicated participants.\u003c/p\u003e\n\u003cp\u003eIn summary, this rigorously controlled multicentre RCT found that despite high compliance and adherence, four weeks of nightly TNS did not improve core symptoms nor related clinical and cognitive features in children and adolescents with ADHD. These negative findings on TNS extend largely negative findings using other neurostimulation techniques in children and adults with ADHD, including transcranial magnetic and direct current stimulation \u003csup\u003e10,37-41\u003c/sup\u003e . This large multi-centre RCT contrasts with the positive symptom improvements reported in the pilot trial that informed FDA clearance for TNS \u003csup\u003e18\u003c/sup\u003e , highlighting the critical importance of robust sham control conditions and expectation management to minimise placebo effects in neurostimulation research. In conclusion, while TNS is a safe intervention, it does not demonstrate clinical efficacy for paediatric ADHD.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eTrial design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis UK multi-centre (King\u0026rsquo;s College London; University of Southampton), phase IIb, double-blind, parallel group, sham-controlled confirmatory RCT was pre-registered (trial registration: ISRCTN82129325). Participants were randomized to either active TNS or sham TNS (1:1). For protocol details, see\u003csup\u003e23\u003c/sup\u003e .\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe trial was approved by the West Midlands\u0026ndash;Solihull NHS Research Ethics Committee (REC; Ref: 21/WN/0169; IRAS: 299703) and the Medicines and Healthcare products Regulatory Agency (MHRA; Ref: CI/2022/0003/GB). It was conducted in accordance with the Declaration of Helsinki 1975 and is reported following CONSORT guidelines \u003csup\u003e42\u003c/sup\u003e. Independent oversight of the trial was provided by a Data Monitoring and Ethics Committee (DMEC) and a Trial Steering Committee (TSC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization and blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRandomization was done by minimization by sex (male/female), medication status (on medication; off medication/na\u0026iuml;ve), site (London, Southampton) and age (8\u0026ndash;13.5 years; 13.6-19 years) using a validated, online, web-based system from King\u0026rsquo;s Clinical Trials unit (KCTU) \u003csup\u003e23\u003c/sup\u003e. Participants, parents/carers, postdoctoral research associates (RAs), Principal Investigator (PI), Co-Investigators (Co-Is), and analysts were blinded to treatment arm except for the trial manager (LJ) and trial manager assistants (SEM and JH), who trained participants/parents on the device use, but did not conduct research assessments and were prohibited from sharing the information with other team members. Analysts were blinded until after database lock. Blinding was assessed by a questionnaire administered to participants, parents/carers, and researchers after 1 and 4 weeks of TNS treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOne hundred and fifty children and adolescents (8-18 years) with ADHD were recruited from public and private clinics in (Greater) London, Southampton and Portsmouth, nationwide parent and ADHD support groups, general practitioners (GPs), National Health System (NHS) Consent for Contact (C4C) research directory, and social media. Inclusion criteria were: a clinical and/or research DSM-5 ADHD diagnosis (semi-structured interview: Kiddie-Schedule for Affective Disorders and Schizophrenia [K-SADS]\u003csup\u003e43\u003c/sup\u003e; a score \u0026gt;= 24 on the investigator-scored parent-rated ADHD-RS; IQ above 70 (Wechsler Abbreviated Scale of Intelligence [WASI-II]\u003csup\u003e44\u003c/sup\u003e; being able to speak sufficient English (parents and children); be either medication-na\u0026iuml;ve, willing to come off their stimulant medication for one week before participation, or willing to be on stable stimulant medication for the 4 week RCT duration. Exclusion criteria were: comorbidity with any major psychiatric disorder as assessed on the K-SADS (except for conduct/oppositional defiant disorder, mild anxiety and mild depression, which scored below threshold on the K-SADS), enuresis and encopresis, alcohol and substance abuse, neurological abnormalities, medicated with atomoxetine or guanfacine (as it may interfere with TNS mechanisms), any other non-pharmacological treatments, dermatitis, and TNS contraindications such as implanted cardiac or neurostimulation systems, head-implanted metallic or electronic devices, and body-worn devices.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChildren/adolescents and their parents/carers provided both digital and written informed consents/assents and were reimbursed for travel costs and received up to \u0026pound;350 (\u0026pound;450 if they were enrolled in the fMRI sub-study). For details, see the protocol \u003csup\u003e23\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedures\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants were screened for eligibility via two online and one in-person appointments at King\u0026rsquo;s College London (KCL) Institute of Psychiatry, Psychology, and Neuroscience (IoPPN) or the University of Southampton Centre for Innovation and Mental Health (CIMH). Online screening included study information sheets and device explanations, digital consents, and parents/carers K-SADS interviews. In-person screening included IQ testing (WASI-II), children/adolescents K-SADS interviews, mock fMRI, fMRI task training, and written informed consents/assents. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring the 2-3-hour baseline assessment, participants and parents/carers completed measures of ADHD symptoms, depression and anxiety, sleep, mind wandering, emotional dysregulation, and suicidality. Children/adolescents performed neurocognitive tasks (30\u0026ndash;40 min), pupillometry during one of the tasks, and wore an Empatica E4 wristband to assess objective hyperactivity and autonomic functions. Vital signs and anthropometrics (height and weight) were recorded, and those participants who enrolled in the fMRI sub-study underwent a 1-hour scan. Teachers were contacted prior to the assessment to provide ADHD ratings. Participants were randomized (1:1) to active or sham TNS at the end of the baseline assessment, and both parents/carers and participants were instructed on device use and daily sleep diaries for the 4-week treatment.\u003c/p\u003e\n\u003cp\u003eWeekly online assessments (20\u0026ndash;30 min) included ADHD ratings from parents/carers, side effect and adverse event reporting, and a blinding questionnaire completed during the Week 1 assessment.\u003c/p\u003e\n\u003cp\u003eAt week 4 (2\u0026ndash;3 hrs, in-person), participants returned the TNS device and repeated baseline tasks. Weight, hyperactivity, and vital signs were reassessed, and acceptability and blinding questionnaires were completed. Participants who underwent an fMRI scan at baseline also underwent an fMRI scan during this assessment. Teachers were asked to provide ADHD ratings.\u003c/p\u003e\n\u003cp\u003eThe 6-month follow-up (1-2 hrs, in-person) replicated prior baseline and week-4 assessments, except for fMRI and Empatica E4 measurements. Concomitant medications were recorded throughout the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eReal and sham TNS was performed with the Monarch TNS System (NeuroSigma, Inc, Los Angeles, CA). Participants needed to use the stimulator for ~8 hrs during sleep. Each night, participants or their parents applied the disposable self-adhesive patch electrodes connected to the stimulator across their child\u0026rsquo;s forehead to provide bilateral stimulation of V1 trigeminal nerve branches. The real TNS used 120Hz repetition frequency with a 250 \u0026mu;s \u0026nbsp;pulse width, and a duty cycle of 30s/30s off (total 240min in 8 hours). Stimulator settings were established at baseline (and adjusted each night) by titration in 0.2 mA increments ranging from 0 to a safe maximum of 10mA to identify a stimulation level that was perceptible but below the participants\u0026rsquo; subjective level of pain/discomfort. The sham Monarch TNS system was identical in current, appearance, and user interface but the electrical stimulation flowed for 30s every hour at a lower frequency (2Hz) and 50 \u0026mu;s pulse width and was then routed through the internal resistor instead of the electrical patch, thus still draining battery to maintain blinding (total 4min in 8 hours). The 30s of real stimulation every hour in the sham condition was added to further enhance blinding \u003csup\u003e23\u003c/sup\u003e, which was successful in the previous trial without any stimulation in the sham condition \u003csup\u003e18\u003c/sup\u003e. The scalp adjusts very quickly to the stimulation, and the switch-off is not noticeable. To further protect blinding, participants were counselled that stimulation may not be perceptible, and that most people would not feel the stimulation after some time because of scalp adaptation. Technical support was provided by the trial manager (LJ. For details, see the protocol \u003csup\u003e23\u003c/sup\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSafety was assessed through a weekly side-effect questionnaire adapted for TNS \u003csup\u003e18\u003c/sup\u003e, a weekly open-ended adverse event form completed by participants and their parents/carers, and vital signs (blood pressure and pulse) measured at baseline, week 4, and at 6 months follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome measures\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome measure was the investigator-scored, parent-rated ADHD-RS total score \u003csup\u003e19\u003c/sup\u003e collected at eligibility, baseline and weekly throughout the four-week trial. Secondary outcome measures were collected at baseline, week 4, and at 6 months follow-up and included the following rating scales: teacher-rated ADHD-RS (school version) \u003csup\u003e45\u003c/sup\u003e, Conners Teacher Rating Scale short form T-S \u003csup\u003e46\u003c/sup\u003e, child-reported Strength and Difficulties Questionnaire (SDQ) \u003csup\u003e47\u003c/sup\u003e, parent and child-reported Affective Reactivity Index (ARI) \u003csup\u003e48\u003c/sup\u003e , parent and child-reported Child and Adolescent Anxiety and Depression scale (RCADS-25) \u003csup\u003e49\u003c/sup\u003e, child-reported Columbia Suicide Severity Rating Scale (C-SSRS) \u003csup\u003e50\u003c/sup\u003e, child-reported Mind Excessively Wandering Scale (MEWS) \u003csup\u003e32\u003c/sup\u003e, parent-reported Sleep Disturbance Scale for Children (SDSC) \u003csup\u003e51\u003c/sup\u003e, and the investigator scored parent-rated ADHD-RS \u003csup\u003e19\u003c/sup\u003e at 6 months follow-up. Vigilance (omission and commission errors) was assessed using the Mackworth Clock Task \u003csup\u003e52\u003c/sup\u003e. Pupillometry data were recorded with the Tobii Pro Nano screen-based eye-tracking device (Tobii AB, Stockholm, Sweden) during a 1-minute resting condition and a cognitive task. Objective hyperactivity, defined as the composite score of both the intensity (g) and frequency (g) of movement, was assessed at baseline and week 4 using a 3-axis accelerometer embedded in the Empatica E4 wristband device (Empatica Srl, Milan, Italy). Other measures included an acceptability questionnaire filled out by participants and their parents/carers at the end of the treatment.\u003c/p\u003e\n\u003cp\u003eDetails regarding other secondary outcome measures of executive functions, physiological, and fMRI measures are described in the study protocol \u003csup\u003e23\u003c/sup\u003e and will be published elsewhere.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size justification\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe estimated sample size of 128 participants (64:64) was calculated using a baseline to post-treatment correlation of 0.5, 90% power, 5% type I error, and an anticipated effect size of 0.5 for a reduction in ADHD symptoms at 4 weeks\u003csup\u003e18\u003c/sup\u003e. The number of participants was inflated to 150 (75:75) to account for a loss to follow-up rate of 15% \u003csup\u003e23\u003c/sup\u003e. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalyses were performed in Stata 18 (College Station, TX: StataCorp LLC) following a prespecified statistical analysis plan which can be found as supplementary material to the published protocol \u003csup\u003e23\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;For the primary analysis a longitudinal linear mixed model was used, fitting 4-week ADHD symptom scores as a continuous outcome, with continuous time as a covariate using actual time of assessments and an interaction between time and trial arm to estimate effects at week 1, 2,3 and 4 using post-estimation. A random intercept was included as well as a random slope over time for each participant and an adjustment for fixed effects of baseline ADHD-RS score, site, age (8\u0026ndash;13.5 years; 13.6-19 years), gender, and medication status. An adjusted mean difference (\u003cem\u003eaMD\u003c/em\u003e) was calculated between the treatment groups with associated 95% confidence intervals (95% CI) and \u003cem\u003ep\u003c/em\u003e-value (for week 4 only). \u0026nbsp;A separate model was used to investigate treatment differences at 6-months timepoint by including time as a categorical variable, as treatment differences at follow-up were not expected to follow the same linear time trend. For the analysis of secondary outcomes, we utilized mixed models for repeated measures (MMRM) with time included as a categorical variable and the same covariates as for the primary analysis. An intention-to-treat (ITT) approach was used for both primary and secondary analyses. No adjustment for multiple timepoints was performed as we pre-specified the primary outcome at week 4 \u003csup\u003e53\u003c/sup\u003e. Statistical significance for all analyses was \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05. Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e was calculated using the pooled baseline standard deviation of each measure.\u003c/p\u003e\n\u003cp\u003eA separate analysis of the primary outcome was carried out to estimate the treatment effect in those participants who adhered to the intervention, using a complier average causal effect analysis. Further details on the statistical methods can be found in the Supplement and the protocol paper and its supplement\u003csup\u003e23\u003c/sup\u003e.\u003csup\u003e\u0026nbsp;\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe author has provided a link to the data, https://doi.org/10.6084/m9.figshare.29414744.v1\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no contractual agreements in place to restrict data availability. \u0026nbsp;Once the results of the trial have been reported, a data sharing dataset will be available. All data sharing requests should be submitted to Prof Katya Rubia (corresponding author).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project (NIHR130077) is funded by the [Efficacy and Mechanism Evaluation (EME) Programme/Better Methods, Better Research (BMBR) programme], an MRC and NIHR partnership. The views expressed in this publication are those of the authors and not necessarily those of the MRC, NIHR or the Department of Health and Social Care. The design, management, analysis and reporting of the study are independent of the funder and the device manufacturer. KR and MM are supported by the NIHR Biomedical Research Centre at South London and Maudsley NHS foundation Trust and King\u0026rsquo;s College London (BRC).\u0026nbsp;SC and KR are also supported by\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eNIHR grant NIHR203684. SC is an NIHR Research Professor (NIHR303122) funded by the NIHR for this research project. SC is also supported by NIHR203035, NIHR128472, RP-PG-0618-20003\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eand by grant\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e101095568-HORIZONHLTH- 2022-DISEASE-07-03 from the European Research Executive Agency. BC has received funding from NIHR (EME, HTA, PHR, HSDR, RfPB), CRUK, MRC. SP has received funding from NIHR Invention for Innovation (i4i) Programme, MRC Clinical Academic Research Partnerships, NIHR HTA, and NIHR PGfAR.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration South London (NIHR ARC South London) at King\u0026apos;s College Hospital NHS Foundation Trust. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR or the UK Department of Health and Social Care.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKR has received a grant from Takeda Pharmaceuticals for another project. SC has received reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health (ACAMH) in relation to lectures delivered for ACAMH, the Canadian AADHD Alliance Resource, the British Association of Psychopharmacology, Healthcare Convention and CCM Group team for educational activity on ADHD and has received honoraria from Medice. MAM has received research funding from Takeda Pharmaceuticals, Johnson and Johnson, Lundbeck, Boehringer Ingelheim and SoseiHeptares. He also acted as a consultant for Neurocrine, Lundbeck, Boehringer Ingelheim and SoseiHeptares. Dr Giovanni Giaroli has received speaker honoraria from Takeda Pharmaceuticals. PS reports research funding from the British Heart Foundation, Reverse Rett, Newron Pharmaceuticals, HealthTracker, and Anavex Life Sciences Corporation; consulting fees from Anavex Life Sciences Corporation; \u0026nbsp;honoraria and reimbursement for travel and accommodation expenses from the Egyptian Psychiatry Association, Acadia Pharmaceuticals Inc, and Neurogene Inc; and stocks from HealthTracker Ltd. BC has received funding from the Nuffield Foundation, Alzheimer\u0026rsquo;s Research UK, LifeARC and Mundipharma. FF has received stocks from HealthTracker Ltd.\u003c/p\u003e\n\u003cp\u003eDS, AAC, NB, IEE, RM, AB, S E-M, JH, HL and LJ have no financial interests to declare.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMany thanks to all the participants and their parents/carers for their time and support for the project. Recruitments were made through the CAMHS clinics within the following NHS trusts: South London and Maudsley NHS Foundation Trust, Hampshire and Isle of wight Healthcare (previously known as SOLENT NHS Trust), Central and North-West London NHS Foundation Trust, Oxleas NHS Foundation Trust and South-West London and St George\u0026rsquo;s Mental Health NHS Trust. In addition, recruitment was made by private clinics from the Giaroli Centre and the Assessment Team. The project received support for the study by CRN South London and CRN Wessex, in particular Keira O\u0026rsquo;Brien. Many thanks to ADHD Foundation trust and ADDISS (ADHD Information Services) who advertised the study on their social media as well as other local ADHD support groups in the South-East of England. Valuable advice and support have been provided throughout the trial by the study dedicated PPI group (Michele Reilly, Co-ordinator Lambeth ADHD Support Group, Faduma Mahamed Ali, Zaynab Hassan Ali, Harry Reynolds, Jane Reynolds). In addition, further help was given by Sidra Zahid. We are also grateful for the advice and support given throughout the trial by the DMEC committee (Professor David Daley, Drs Aditya Sharma and Dr Adrian Cook) and the Trial Steering Committee (TSC) (Professor Richard Morriss, Dr Jody Warner-Rogers, Dr Anthony James, Dr Rachel Evans, Mrs Beverley Nolker\u0026nbsp;and Mason Nolker).\u003c/p\u003e\n\u003cp\u003eThis study was supported by the United Kingdom Clinical Research Collaboration-registered King\u0026apos;s Clinical Trials Unit at King\u0026apos;s Health Partners, which is part funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King\u0026apos;s College London and the NIHR Evaluation, Trials and Studies Coordinating Centre. A particular thanks to Merry Martin who helped with data analysis.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship contributions statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGrant funding was obtained by KR (PI), SC, BC, PS, MAM (Co-Is) who conceived and designed the study. SC was PI lead for the Southampton site. AAC, NB recruited and tested all participants at the London site, IEE at the Southampton site. RM assisted IEE. LJ managed the trial and administered device training and technical support, assisted by SEM and JH. DS and BC wrote the statistical analysis plan, analysed the data and wrote the statistical report. SC and PS were responsible for all clinical aspects of the study. GG, HL assisted with recruitment. FF analysed the Empatica E4 physiological data. AAC, NB, IEE and KR wrote the first draft of the MS. All authors edited the MS.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCortese, S.\u003cem\u003e, et al.\u003c/em\u003e Incidence, prevalence, and global burden of ADHD from 1990 to 2019 across 204 countries: data, with critical re-analysis, from the Global Burden of Disease study. \u003cem\u003eMol Psychiatry\u003c/em\u003e \u003cstrong\u003e28\u003c/strong\u003e, 4823-4830 (2023). 10.1038/s41380-023-02228-3\u003c/li\u003e\n\u003cli\u003eAmerican Psychiatric Association. \u003cem\u003eDiagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR (TM))\u003c/em\u003e, (American Psychiatric Association Publishing, Washington, D.C, 2022).\u003c/li\u003e\n\u003cli\u003eRubia, K. 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We conducted a confirmatory multi-centre, double-blind, randomized, sham-controlled, parallel-group, phase IIb RCT investigating short and longer-term efficacy (6 months) of real vs sham TNS in 150 children and adolescents with ADHD. Partricipants were randomized to receive real TNS (\u003cem\u003en\u003c/em\u003e=75, mean age [\u003cem\u003eSD\u003c/em\u003e]= 12.6 [2.8 years]), or sham TNS (\u003cem\u003en\u003c/em\u003e=75, mean age [\u003cem\u003eSD\u003c/em\u003e]= 12.6 [2.8 years]), nightly for 4 weeks. Bilateral stimulation targeted V1 trigeminal branches using battery-powered electrodes applied to the forehead for ~9 hours/night. Sham TNS delivered 30 seconds of stimulation per hour at a lower frequency. Intention to treat analysis (ITT) showed no significant differential treatment effects on ADHD symptoms (estimated adjusted mean difference [\u003cem\u003eaMD\u003c/em\u003e] = 0.83; 95% Confidence interval [CI] = –2.47 to 4.13; \u003cem\u003ep\u003c/em\u003e= 0.622; Cohen’s \u003cem\u003ed\u003c/em\u003e = 0.09). No differential treatment effects were observed either on the secondary outcomes covering other symptom scales of ADHD and related clinical problems, as well as cognitive and physiological outcomes, except for a small reduction in mind wandering favouring real TNS (\u003cem\u003eaMD\u003c/em\u003e = –2.17; 95% CI = –4.33 to –0.01; \u003cem\u003ep\u003c/em\u003e = 0.049; Cohen’s \u003cem\u003ed\u003c/em\u003e = –0.27). Adherence was 94% and compliance 93%. Blinding was successful. No serious adverse events (SAEs) were reported, and side effects did not differ between groups. In conclusion, TNS is a safe intervention but does not demonstrate clinical efficacy for paediatric ADHD. Trial registration: ISRCTN82129325.\u003c/p\u003e","manuscriptTitle":"The efficacy of external Trigeminal Nerve Stimulation (TNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD): a multi-centre, double-blind, randomized, sham-controlled, parallel-group, phase IIb trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-01 06:05:26","doi":"10.21203/rs.3.rs-6882697/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nm","sideBox":"Learn more about [Nature Medicine](http://www.nature.com/nm/)","snPcode":"","submissionUrl":"","title":"Nature Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0a846e72-1386-465a-9d30-b69c5c4455b7","owner":[],"postedDate":"July 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":50178200,"name":"Health sciences/Diseases/Psychiatric disorders/ADHD"},{"id":50178201,"name":"Health sciences/Medical research/Clinical trial design/Randomized controlled trials"},{"id":50178202,"name":"Health sciences/Health care/Therapeutics/Biological therapy"},{"id":50178203,"name":"Biological sciences/Neuroscience/Cognitive neuroscience/Attention"}],"tags":[],"updatedAt":"2026-01-17T08:07:55+00:00","versionOfRecord":{"articleIdentity":"rs-6882697","link":"https://doi.org/10.1038/s41591-025-04075-x","journal":{"identity":"nature-medicine","isVorOnly":false,"title":"Nature Medicine"},"publishedOn":"2026-01-16 05:00:00","publishedOnDateReadable":"January 16th, 2026"},"versionCreatedAt":"2025-07-01 06:05:26","video":"","vorDoi":"10.1038/s41591-025-04075-x","vorDoiUrl":"https://doi.org/10.1038/s41591-025-04075-x","workflowStages":[]},"version":"v1","identity":"rs-6882697","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6882697","identity":"rs-6882697","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}