Intermittent theta burst stimulation for attention deficit hyperactivity disorder

Intermittent theta burst stimulation for attention deficit hyperactivity disorder | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (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];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Intermittent theta burst stimulation for attention deficit hyperactivity disorder Brian C. Kavanaugh , Megan M. Vigne , Christopher Legere , Gian DePamphilis , Eric Tirrell , W. Luke Acuff , Joshua Brown , Rich Jones , Anthony Spirito , Linda L. Carpenter doi: https://doi.org/10.1101/2025.09.03.25335033 Brian C. Kavanaugh 1 E.P. Bradley Hospital 2 Brown University, Department of Psychiatry & Human Behavior Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: Brian_Kavanaugh{at}Brown.edu Megan M. Vigne 3 Butler Hospital TMS Clinic and Neuromodulation Research Facility Find this author on Google Scholar Find this author on PubMed Search for this author on this site Christopher Legere 1 E.P. Bradley Hospital Find this author on Google Scholar Find this author on PubMed Search for this author on this site Gian DePamphilis 3 Butler Hospital TMS Clinic and Neuromodulation Research Facility Find this author on Google Scholar Find this author on PubMed Search for this author on this site Eric Tirrell 2 Brown University, Department of Psychiatry & Human Behavior 3 Butler Hospital TMS Clinic and Neuromodulation Research Facility Find this author on Google Scholar Find this author on PubMed Search for this author on this site W. Luke Acuff 3 Butler Hospital TMS Clinic and Neuromodulation Research Facility 4 Providence Veteran’s Association Medical Center, Center for Neurorestoration and Neurotechnology Find this author on Google Scholar Find this author on PubMed Search for this author on this site Joshua Brown 2 Brown University, Department of Psychiatry & Human Behavior 3 Butler Hospital TMS Clinic and Neuromodulation Research Facility Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rich Jones 2 Brown University, Department of Psychiatry & Human Behavior Find this author on Google Scholar Find this author on PubMed Search for this author on this site Anthony Spirito 2 Brown University, Department of Psychiatry & Human Behavior Find this author on Google Scholar Find this author on PubMed Search for this author on this site Linda L. Carpenter 2 Brown University, Department of Psychiatry & Human Behavior 3 Butler Hospital TMS Clinic and Neuromodulation Research Facility Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Data/Code Preview PDF ABSTRACT Objective : Attention deficit hyperactivity disorder (ADHD) is the most diagnosed psychiatric disorder in childhood and often causes lifelong symptom burden. Transcranial magnetic stimulation (TMS) has been investigated in adult ADHD with encouraging findings, although work in pediatric samples remains limited and no ADHD studies have examined the utility of intermittent theta burst stimulation (iTBS). Methods : Twenty-nine adolescents with ADHD and working memory (WM) symptoms were randomized into a sham-controlled, counter-balanced, double-blind, crossover clinical trial of iTBS for adolescent ADHD. Participants completed ten active iTBS sessions (600 pulses per session) and ten sham iTBS sessions to the left dorsolateral prefrontal cortex (DLPFC) at 80% resting motor threshold. Primary outcome variables included safety, feasibility, and change in parent-reported ADHD and WM symptoms. Secondary outcomes consisted of parent and participant-reported affective symptom changes. Results : The protocol was feasible (82% completed all scheduled sessions) and safe (zero serious adverse events). A statistically significant improvement was seen in active versus sham iTBS in parent-reported overall ADHD symptoms, hyperactivity/impulsivity, working memory, anger, depressive symptoms, and anxiety symptoms. Conclusions : iTBS holds promise as a potential future treatment for ADHD, and effects achieved when targeting the left DLPFC may be most robust for transdiagnostic cognitive and affective symptoms. Increasing the number of iTBS sessions per day with accelerated protocols may maximize efficacy and feasibility for teens with ADHD and their parents. Clinicaltrials.gov Identifier: NCT05102864 INTRODUCTION Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that affects approximately 10% of youth and is characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity( 1 , 2 ). Ninety percent of children with ADHD continue to experience residual symptoms into young adulthood, and only 9% experience full recovery in adulthood( 3 ). ADHD is a disorder of delayed cortical maturation particularly characterized by delayed peak thickness in prefrontal regions( 4 ), and meta-analytic findings have shown reduced gray matter volume and task-related hypoactivation in multiple frontoparietal and limbic regions( 5 ). Non-invasive brain stimulation approaches to ADHD show tremendous promise. A recent meta-analysis found a medium effect size for rTMS to the dorsolateral prefrontal cortex (DLPFC) efficacy on overall ADHD symptoms( 6 ). Six of the eight examined studies were completed with adults. In fact, only four ADHD studies have been done in children and/or adolescents (total n=106), including two sham-controlled trials (total n=52)( 7 – 10 ). Utilizing a crossover design (n=9), Weaver and colleagues found no difference between active and sham rTMS in ADHD symptom change following 10 daily sessions of 10 Hz to the right DLPFC( 9 ). However, Cao and colleagues( 8 ) found ADHD symptom decrease (i.e., inattention, hyperactivity/impulsivity, and oppositionality) with active TMS (but not with sham TMS) after 30 daily sessions of 10 Hz to the right DLPFC (n=43). In healthy adults, small-effect sized improvements in motor impulsivity are identified when applying rTMS to the left DLPFC, right inferior frontal gyrus, right frontal eye fields, and medial prefrontal cortex( 11 ), and medium-effect sized improvements in temporal impulsivity are identified when targeting the left DLPFC with rTMS( 11 ). Meta-analytic findings across neuropsychiatric disorders have shown that left DLPFC stimulation produces small effects on working memory, but no effect on attention( 12 ). Another meta-analysis of left DLPFC rTMS in ADHD samples found a medium-sized effect on sustained attention( 13 ). Preliminary work with rTMS targeting the right DLPFC( 14 ) has also found beneficial effects on aspects of emotion regulation, and particularly anger in adults with PTSD( 14 ). Similarly, in adults with MDD, irritability is significantly reduced following with intermittent theta burst stimulation (iTBS)( 15 ) to the left DLPFC. iTBS is particularly promising given its non-inferiority to 10 Hz rTMS for treating depression( 16 ), shorter administration time, and feasibility as multiple sessions per day via accelerated iTBS protocols( 17 , 18 ). We conducted a trial of iTBS in adolescents with ADHD with a sham-controlled, double-blind, crossover design. We hypothesized that iTBS would be safe for participants and feasible for participants and their families, and that active iTBS would show superiority to sham in improving core ADHD symptoms, working memory, and emotional symptoms. We also conducted an open-label trial of twice-daily iTBS in a subsample to evaluate the viability of an accelerated iTBS schedule approach. METHODS Design This was a randomized, double-blind, sham-controlled, crossover design clinical trial examining iTBS for adolescent ADHD ( clinicaltrials.gov ; NCT05102864 ). Local Institutional Review Board approval and an investigational device exemption (IDE) from the United States Food and Drug Administration (FDA) were obtained. Thirty-four adolescents (12-18 years old) with ADHD were enrolled from November 2021 to October 2024 ( Figure 1 ). Primary inclusion criteria were: a) a clinical diagnosis of ADHD (confirmed with parent-reported symptoms on the Vanderbilt Assessment Scales), b) parent-reported working memory symptoms (i.e., t-score≥ 60 on the Behavior Rating Inventory of Executive Function– Second Edition [BRIEF-2]), c) full-scale intelligence quotient≥ 80 (based on Wechsler Abbreviated Scales of Intelligence, Second Edition [WASI-II]), and English fluency. Exclusion criteria included active mania, psychosis, substance use, current suicidal ideation, and standard TMS and MRI contraindications including history of seizures, participant or family diagnosis of epilepsy, significant current neurological disorder or intracranial pathology, prior brain injury, significant active medical condition, intracranial implanted metal devices, non-removeable metallic makeup or piercings, and chronic use of medications known to significantly decrease seizure threshold. Participants were not required to discontinue any clinical treatments, including psychostimulant medication, although they were asked to maintain consistency in medications throughout the trial. Download figure Open in new tab Figure 1. CONSORT flow diagram for a study of intermittent theta-burst stimulation (iTBS) for ADHD Participants completed two phases, with iTBS administered during the first 10 visits of each phase. Symptom status was gathered before the first iTBS session, immediately before the 6 th iTBS session, and ∼24 hours after the last session. A washout between phases was 6 weeks, except for one participant who waited four weeks due to sports season conflict. Treatment Intervention 10 iTBS sessions was selected based on prior iTBS studies available at the time of study design( 19 , 20 ) and prior TMS studies utilizing a crossover design to modulate neurocognitive processes( 21 , 22 ). We targeted the left DLPFC given the limited and mixed findings in ADHD targeting the right DLPFC( 8 , 9 ) and the more established left DLPFC findings associated with working memory-related processes( 23 ). Stimulation was delivered using a Nexstim NBT System 2 device with a figure-eight coil. Single pulses were used for mapping the left motor cortex for optional location and determining minimal threshold intensity for eliciting motor evoked potentials (MEPs ≥50 μV) in the contralateral abduces pollicus brevis muscle, with an integrated algorithm over at least 16 trials. The iTBS protocol was administered in 2-second trains of triplet 50 Hz bursts with 8-second rest intervals, for a total of 600 pulses/session, at 80% intensity relative to rMT. Each session lasted approximately three minutes. DLPFC Target Structural MRI scans were completed prior to the first iTBS session. Stimulation was delivered to the left DLPFC target using individual participant MRI-based neuronavigation for coil placement during all sessions ( Figure 2 ). Targeting was well-aligned across participants when examined in standard Montreal Neurological Institute (MNI) coordinates ( Figure 2 ). The left DLPFC target site was identified based on anatomical landmarks per Mylius and colleagues( 24 ) (See Supplement for further details); The mean E-field max for each session was recorded and averaged across sessions during statistical analyses to check for equal dosing across groups. Download figure Open in new tab Figure 2. Target locations using the Mylius et al., 2013 method Legend . White dots reflect individual participant stimulation target sites plotted on a standardized brain. Black dot reflects the group average MNI coordinates of participants in this study (−40, 36 , 37 ). Randomization/Blinding Participants were randomized 1:1 to receive active iTBS followed by sham iTBS (“Active First”) or sham iTBS followed by active iTBS (“Sham First”). Identical active and sham coils each had a colored label corresponding with their treatment condition. Each participant was assigned to either a “yellow” or “rainbow” condition. The principal investigator and research treatment team remained masked to the condition associated with each coil. Participants were asked to guess if they received “real” or “fake” TMS; most were asked after their first iTBS session, although the first five participants were asked to guess after their first full phase of iTBS (both approaches were analyzed). Clinical Variables The primary efficacy outcome measures were parent-reported: a) National Institute for Children’s Health Quality Vanderbilt Assessment Scale for ADHD( 25 ) (VAS; total score for items 1-18 [“Total ADHD Score”] to assess 9 core inattentive symptoms [“Inattentive Score”] and 9 core hyperactive/impulsive symptoms [“Hyperactive/Impulsive Score”] of ADHD to assess core ADHD symptoms, and b) Working Memory subscale of the Behavior Rating Inventory of Executive Function – Second Edition (BRIEF-2)( 26 ) to assess working memory symptoms. The secondary efficacy outcome measure was the Patient-Reported Outcomes Measurement Information System (PROMIS) participant and parent proxy forms( 27 ) to assess anger, anxiety, depressive symptoms, positive affect, and stress-related symptoms. The PROMIS (parent and participant report) forms were added to the study protocol after the sixth participant, after several parents anecdotally reported that reduced anger and/or irritability was one of the most striking changes observed in their child following completion of the study. Intelligence quotient (IQ) and performance-based executive functions were assessed with the WASI-II (2-Subtest IQ)( 28 ) and NIH Toolbox Cognition Battery( 29 ), respectively ( Table 1 ). Diagnostic status was assessed by parent report based on clinical history; a subset (n=20) completed the Mini International Neuropsychiatric Interview (MINI-KID)( 30 ). Clinical and demographic variables were parent-reported at the enrollment session. Raw scores were utilized for all measures except IQ. View this table: View inline View popup Download powerpoint Table 1. Demographic, clinical, and treatment characteristics of sample, grouped by order in which they received TMS Statistics Primary outcomes included: a) safety b) feasibility, and c) change in parent-reported ADHD and WM symptoms. Secondary outcomes consisted of parent- and participant-reported affective symptom changes. Primary outcomes for safety/feasibility are reported for all enrolled subjects who received at least one stimulation session (n = 29). Given the small sample size and preliminary nature of this study, efficacy analyses were conducted only with the sample of completers (n = 24). A series of two-way repeated measures analyses of covariance (ANCOVA) was conducted with treatment group (i.e., Sham First versus Active First; to account for order effects) and psychostimulant use (i.e., yes/no) as between-subject factors. Treatment condition (active or sham) by time (baseline, post-5 sessions, post-10 sessions) interaction was the primary outcome variable for all parent- and participant-report measures. In statistically significant models, pairwise comparisons of group differences after 5 and 10 sessions examined dose-response relationships. Estimated marginal means (EMMs) and standard errors (SE) are plotted in Figure 2 , while raw score means and standard deviations (SD) are reported in Table 2 . Effect size ([sham change – active change]/pooled SD) and % change were calculated based on the EMMs of the ANCOVAs. Response data generated by the BRIEF-2 and PROMIS forms were recoded so that the “never” option was set to zero prior to calculating change scores. To statistically examine time effects of the accelerated iTBS cohort, a series of two-sided t-tests (as the two cohorts had different treatment length) examined the symptom change between baseline (“Pre-iTBS”) and after 5 days (i.e., 10 iTBS sessions; “Post-10 iTBS”), and at one-week and one-month follow-up (after 10 days was not analyzed as only n=4 received 20 sessions). Statistical significance was set at p<.05. View this table: View inline View popup Download powerpoint Table 2. Clinical outcomes comparing active and sham intermittent theta burst stimulation Open-Label Pilot Study of iTBS Accelerated Schedule After participating in the randomized clinical trial (RCT) described above, all participants in the RCT (regardless of study completion, outcomes) were invited to enter an open-label pilot study to examine the safety, feasibility, and preliminary efficacy of a twice-daily (“accelerated”) iTBS treatment schedule. This pilot study was initiated 2.5 years after opening the randomized crossover trial and enrolled 8 participants into one of two cohorts: n=4 received twice/day iTBS sessions (80% rMT), 1,800 pulses/session, over five consecutive weekdays, to the same left DLPFC target used in the RCT; n=4 received this same twice/daily protocol for ten days (20 total sessions; Supplemental Table 1 ). Symptoms were monitored in the same manner as the RCT: VAS, BRIEF-2 WM subscale, and PROMIS forms were administered pre-iTBS and post-iTBS, and at 1 week and 1 month follow-up. ADHD symptom response was defined as > 50% reduction in parent-reported symptoms from baseline score. ADHD symptom remission was defined as < 6 inattentive parent-reported symptoms occurring often to very often and < 6 hyperactive/impulsive parent-reported symptoms occurring often to very often (i.e., no longer meeting ADHD criteria). RESULTS Clinical Sample As shown in Table 1 , the sample is characterized as a predominantly male, white, and non-Hispanic cohort. Most of the sample had at least one clinical diagnosis in addition to ADHD (79%), particularly anxiety (55%) and depression (38%), most were receiving school-based services (76%), and most were prescribed psychiatric medication (93%), particularly psychostimulants (66%) and antidepressants (48%). Twenty-nine participants were randomized to a treatment group. There were no statistically significant differences between groups at baseline in clinical and demographic variables ( Table 1 ). Symptom status at the start of each phase is provided in Supplemental Table 2 . Safety A total of 11 adverse events (AEs) were documented in the trial, across n=6 participants (over the total iTBS administered sessions of n=567), resulting in a 21% AE per participant rate. Ten of the 11 AEs occurred in the active iTBS phase. Nine of the AEs involved a mild headache or scalp discomfort that naturally subsided, one AE involved mild, transient “brain fog”, and one AE involved moderate, increased behavioral fatigue at school that was later attributed to mononucleosis. There were no serious AEs. One participant (3%) withdrew from the study due to poor tolerability (i.e., secondary to scalp discomfort) of stimulation (during active iTBS; i.e., 97% tolerability of sample). Feasibility Twenty-four of the twenty-nine randomized participants (82%) completed both phases of the study and all study procedures ( Figure 1 ). There was an average washout period between conditions of 8.6 +/- 2.9 weeks (range:4.1-15.4). Further, there was no correlation between length of washout period and symptom status at the start of phase 2 (all p>.05, including when just analyzing the group that received active iTBS in phase 1. Four participants withdrew from the study (3 of 4 while receiving sham iTBS) due to burdens associated with the requirement for daily treatment sessions at the clinic or due to other family or school demands. A total of 3 (10.3%) participants thus withdrew (for any reason) during sham iTBS (including n=1 who withdraw after completing sham iTBS phase) and 2 (6.9%) withdrew during active iTBS. Effectiveness of the Blind When receiving active iTBS first, 50% of the participants guessed correctly (i.e., “real”), and although 82% of participants guessed correctly (“fake”) when sham iTBS (x 2 =2.7, p=0.10). Clinical Outcomes Clinical outcomes were analyzed in the subsample that completed both active and sham phases of the trial (n=24). PROMIS measures (added during the trial) generated data in a subset of n=16. Among completers, a statistically significant difference in symptom change across time was identified between the treatment conditions (i.e., condition x time interaction) for parent-reported working memory symptoms (BRIEF-2 WM subscale; p=0.025; d=0.58; sham change: 7.1% vs active change: 25%), parent-reported overall ADHD symptoms (VAS Total Score; p=0.037; d=-0.48; 13% vs 36% change for sham and active, respectively), and parent-reported hyperactivity/impulsivity (VAS Hyperactivity/Impulsivity Score; p=0.006; d=-0.43; 15% vs 43% change), but not parent-reported inattention (VAS Inattention Score; p=0.18; d=-0.41; 10% vs 27% change; Table 2 & Figure 3.A ). In pairwise condition comparisons in statistically significant models, condition differences were not significant after 5 sessions (p>.05) but were significant after 10 sessions (p<.05, Figure 3.A ). Download figure Open in new tab Figure 3. Clinical outcomes comparing active and sham intermittent theta burst stimulation and clinical outcomes of open-label twice-daily pilot study Legend . A) Sham-controlled clinical trial. Results reflect the repeated measures ANCOVA comparing active and sham iTBS on clinical outcomes. Estimated marginal means from ANCOVA models are displayed here. * p < .05. Pairwise comparisons were only conducted on statistically significant overall ANCOVA models. B) Open-label twice-daily arm. Top: Effect size change in clinical symptoms in open-label pilot study of “accelerated” schedule (two sessions/day) iTBS. Two-sided t-tests examined change between Pre-iTBS and Post-10 iTBS, 1-Week Follow-Up, and 1-Month Follow-Up. *p < .05. Bottom: Raw scores displayed here at each time point for accelerated cohort (n = 8). Half the sample received 10 iTBS sessions (n = 4) and half the sample received 20 iTBS sessions (n = 4). Among secondary outcome measures, a statistically significant condition x time difference was identified for change in parent-reported anger (PROMIS; p=0.01; d=-0.87; −3.2% vs 48% change), for change in parent-reported depressive symptoms (PROMIS; p=0.007; d=-0.62; 12% vs 57% change), and for change in parent-reported anxiety symptoms (PROMIS; p<.001; d=-0.98; −28% vs 53% change). No statistically significant group differences were identified on the five PROMIS participant-reported subscales or on the PROMIS parent-reported positive affect or stress subscales ( Table 2 & Figure 3.A ). Open Label Pilot Study of Accelerated Schedule No adverse events (AEs) or early discontinuations occurred during twice daily iTBS in either the 5- or 10-day group (each n=4). One participant only tolerated stimulation intensity up to 45% MT for all visits. When examining the pooled cohorts (n=8) after 5 days of treatment, we observed categorical ADHD symptom response (i.e., >50% reduction from baseline VAS score) in one participant, and this response status persisted at one-month follow-up. Following 10 days of twice daily iTBS, three out of four (75%) participants experienced categorical ADHD symptom response and also ADHD symptom remission (i.e., <6 inattentive and <6 hyperactive/impulsive-type symptoms rated as occurring ‘often to very often’) that persisted at one-month follow-up. In a series of t-tests examining pre-versus post-iTBS differences, statistically significant change after iTBS was observed in parent-reported total ADHD symptoms, working memory symptoms, anxiety symptoms, as well as participant-reported anger symptoms (n=8; all p<.05; Figure 3B ). At one-week follow-up (n=8), statistically significant change was similarly observed in parent-rated total ADHD symptoms, working memory symptoms, anger symptoms, depressive symptoms, and anxiety symptoms. No statistically significant change from baseline persisted at one-month follow-up in the full cohort. DISCUSSION This is the first study, to our knowledge, that has investigated iTBS for ADHD. Using a randomized, sham-controlled, double-blind, crossover design in adolescents with ADHD, we found that active iTBS to the left DLPFC was safe and feasible, and, consistent with our hypothesis, superior to sham in improving core ADHD clinical features, including symptoms related to working memory, hyperactivity/impulsivity, and anger. Twenty-one percent of the randomized sample reported experiencing at least one non-serious, transient AE but no participant had a serious AE. All AEs were considered expected and typical for TMS, largely consistent with prior child/adolescent ADHD-TMS studies( 7 – 10 ) and adult TMS studies. AEs included headache (22%), discomfort (11%), and pain (24%)( 31 ). Twenty-four (83%) of the randomized sample completed the protocol (i.e., 17% discontinuation rate), which is consistent with prior child/adolescent ADHD-TMS clinical trials( 7 , 8 ). Regarding preliminary efficacy, this is the third sham-controlled trial of rTMS efficacy in pediatric ADHD and the first to use iTBS. One of these prior studies found that 30 sessions of active rTMS (n=43; 10 Hz), but not sham rTMS, led to improvements in inattention, hyperactivity/impulsivity, and oppositionality( 8 ), while the other study (n=9; 10 Hz) did not find an effect on ADHD symptoms after 10 sessions of active rTMS( 9 ). A recent meta-analysis of rTMS in ADHD across the lifespan found a standardized mean difference of .45 for efficacy in reducing ADHD symptoms( 6 ). This is highly consistent with findings reported here that also showed a medium effect size (d=.41-.48) for efficacy of iTBS on core ADHD symptoms. Most prior rTMS ADHD therapy trials have targeted the right DLPFC with scalp-based measurements (predominantly the “5 cm rule”), while the current study targeted the left DLPFC via individual MRI-based neuronavigation to an anatomically defined target. We utilized the working memory and the iTBS literature for selecting protocol parameters( 19 , 20 , 23 ) given the TMS-ADHD literature was mixed at the time of study design( 8 , 9 ). The lack of similarity across studies makes it difficult to determine whether either of the targets (left versus right DLPFC) or targeting methods (5-cm, scalp-based versus MRI-based neuronavigation to anatomical target) are superior in optimizing efficacy for treatment of core ADHD symptoms. Related, we observed preliminary evidence of a dose-response relationship with the number of iTBS sessions in the RCT, in that there was no significant effect on any primary symptoms after 5 sessions, but the active versus sham iTBS differences emerged after 10 sessions for ADHD and WM symptoms. Future studies should test longer protocols than the current standard 10-session protocol. The strongest effects in this study were not on core ADHD features, but rather on transdiagnostic and co-occurring symptoms, particularly parent-reported working memory (d=.58), anger (d=.87), depression (d=.62), and anxiety (d=.98). A published meta-analysis of data from adult trials showed a small effect of rTMS on performance-based working memory( 12 ). Two prior studies have found that iTBS improved participant-reported anger symptoms (right DLPFC target) and participant-reported irritability symptoms (left DLPFC target) in adult PTSD( 14 ) and MDD( 15 ), respectively, with current findings extending prior work to show this effect is also observed in adolescent ADHD. While current effects on parent-reported anxiety and depression are consistent with the known effects of rTMS on adult anxiety( 32 ) and depression( 33 ), and even adolescent anxiety( 34 ) and depression( 35 ), no effects were found for participant-reported symptoms. This may reflect variable self-awareness and/or underreporting of symptoms phenomenon in ADHD( 36 ). Alternatively, iTBS effects may not manifest in core emotional experiences but rather in cognitive control or behavioral manifestations of affect that are observed by parents. Additionally, alternative spatial targets should be examined for maximal targeting of core ADHD symptoms. While the left DLPFC may be optimal for working memory and mood, the right pre-SMA may be more optimal for inhibition and impulse control( 11 , 37 ), while the right the left superior frontal gyrus may be more optimal for core ADHD feature targeting( 5 ). Importantly, 14% of the sample withdrew from the study due to the demands of attending daily sessions. Although most of these families were receiving sham iTBS at the time of their withdrawal, we do think these findings are critical in treatment development. This protocol only administered 600 pulses per day (i.e., 3 minutes). Given the rapidly growing literature on safety and efficacy of protocols that administer numerous iTBS sessions per day( 18 ), we conducted an open-label trial of twice-daily iTBS (3,600 pulses per day) for 5 or 10 days to previously enrolled participants in the clinical trial. In this small, sample of teens not naïve to iTBS, we found that twice-daily iTBS was safe (i.e., no AEs), feasible (no withdrawals), tolerated (i.e., 88% of the sample tolerated 80% MT), and effective for acutely improving parent-rated ADHD, working memory, and mood symptoms. In this small sample that received 36,000 pulses (20 total sessions), we observed a 75% response and remission rate of ADHD that persisted for at least one month (n= 3/4). Accelerated iTBS will likely show improved feasibility and comparable efficacy to traditional once per day iTBS for ADHD, although further work with large samples, sham-controlled trials, and treatment-naïve participants is needed. There are several limitations to this study. First, the study had a modest sample size and a crossover design, so effect sizes may be an overestimation of true effects. Second, the DLPFC targeting approach used in this study has not previously been utilized in ADHD research, so an optimal or ideal cortical target for ADHD remains unknown. Third, consistent with other clinical trials in ADHD samples, self-report measures of ADHD were not collected from participants in this study, so results are dependent on parent observations and not internal experiences related to ADHD. Fourth, as this was a relatively short iTBS course (total 10 sessions), the optimal dose of iTBS for ADHD remains unknown. Finally, no long-term follow-up data was collected in the primary trial, so it remains unknown whether symptom improvement will persist. Data Availability Data are available upon request Declaration of Interests LLC has received support (through contracts with Butler Hospital) from Neuronetics, Affect Neuro, Janssen, Neurolief, Nexstim, and Biosynapse. She has received consulting income from Neuronetics, Janssen, Sage Therapeutics, Otsuka, Neurolief, and Magnus Medical. JCB receives financial support as an editorial stipend from Elsevier. BK, CL, GD, WA, ET, AS, MV, and RJ have no conflicts of interest. BK is supported by K23MH129853 and P20GM130452. Supplemental Section Targeting Mylius et al method uses anatomical landmarks on participant MRI to identify a left DLPFC target location corresponding with the BA46/BA9 junction in the Talairach atlas. It is identified as the location on the left middle frontal gyrus corresponding with the center of a line separating the anterior and middle thirds of the gyrus, and verified by anatomical placement on sagittal, coronal, and axial planes. The Nexstim NBT System 2 software uses structural MRI data to generate an accurate 3D model of a person’s head and brain structures, with co-registration of landmarks on their head with landmarks on their structural MRI to allow tracking of the TMS coil position with respect to the underlying cortex. All participants wore a neoprene EEG cap (64 electrodes) during resting Motor Threshold (rMT) and iTBS treatment procedures for consistency across sessions (as some visits involved EEG recording). The Nexstim device models the induced E-field maximum (V/m) value on the cortical surface based on the individual participant’s anatomical MRI data and the physics of the coil. View this table: View inline View popup Download powerpoint Supplemental Table 1. Basic characteristics of open-label cohort View this table: View inline View popup Download powerpoint Supplemental Table 2. Pre-iTBS primary clinical symptom status for each phase/coil Acknowledgements This trial was funded by the NARSAD Brain & Behavior Research Foundation and the Carol Peterson Foundation. REFERENCES 1. ↵ American Psychiatric Association . Diagnostic and statistical manual of mental disorders (5th ed.) . Arlington, VA : American Psychiatric Publishing ; 2013 . 2. ↵ Li Y , Yan X , Li Q , Li Q , Xu G , Lu J , et al. Prevalence and Trends in Diagnosed ADHD Among US Children and Adolescents, 2017-2022 . JAMA Netw Open . 2023 ; 6 ( 10 ): e2336872 . OpenUrl 3. ↵ Sibley MH , Arnold LE , Swanson JM , Hechtman LT , Kennedy TM , Owens E , et al. Variable Patterns of Remission From ADHD in the Multimodal Treatment Study of ADHD . Am J Psychiatry . 2022 ; 179 ( 2 ): 142 – 51 . OpenUrl PubMed 4. ↵ Shaw P , Eckstrand K , Sharp W , Blumenthal J , Lerch JP , Greenstein D , et al. Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation . PNAS . 2007 ; 104 : 19649 – 54 . OpenUrl Abstract / FREE Full Text 5. ↵ Yu M , Gao X , Niu X , Zhang M , Yang Z , Han S , et al. Meta-analysis of structural and functional alterations of brain in patients with attention-deficit/hyperactivity disorder . Front Psychiatry . 2022 ; 13 : 1070142 . 6. ↵ Han Y , Wei ZY , Zhao N , Zhuang Q , Zhang H , Fang HL , et al. Transcranial magnetic stimulation in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis of cortical excitability and therapeutic efficacy . Front Psychiatry . 2025 ; 16 : 1544816 . 7. ↵ Cao P , Xing J , Cao Y , Cheng Q , Sun X , Kang Q , et al. Clinical effects of repetitive transcranial magnetic stimulation combined with atomoxetine in the treatment of attention-deficit hyperactivity disorder . Neuropsychiatr Dis Treat . 2018 ; 14 : 3231 – 40 . OpenUrl PubMed 8. ↵ Cao P , Wang L , Cheng Q , Sun X , Kang Q , Dai L , et al. Changes in serum miRNA-let-7 level in children with attention deficit hyperactivity disorder treated by repetitive transcranial magnetic stimulation or atomoxetine: An exploratory trial . Psychiatry Res . 2019 ; 274 : 189 – 94 . OpenUrl PubMed 9. ↵ Weaver L , Rostain AL , Mace W , Akhtar U , Moss E , O’Reardon JP . Transcranial magnetic stimulation (TMS) in the treatment of attention-deficit/hyperactivity disorder in adolescents and young adults: a pilot study . J ECT . 2012 ; 28 ( 2 ): 98 – 103 . OpenUrl CrossRef PubMed 10. ↵ Gomez L , Vidal B , Morales L , Baez M , Maragoto C , Galvizu R , et al. Low frequency repetitive transcranial magnetic stimulation in children with attention deficit/hyperactivity disorder. Preliminary results . Brain Stimul . 2014 ; 7 ( 5 ): 760 – 2 . OpenUrl PubMed 11. ↵ Yang CC , Vollm B , Khalifa N . The Effects of rTMS on Impulsivity in Normal Adults: a Systematic Review and Meta-Analysis . Neuropsychol Rev . 2018 ; 28 ( 3 ): 377 – 92 . OpenUrl CrossRef PubMed 12. ↵ Kan RLD , Padberg F , Giron CG , Lin TTZ , Zhang BBB , Brunoni AR , et al. Effects of repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex on symptom domains in neuropsychiatric disorders: a systematic review and cross-diagnostic meta-analysis . Lancet Psychiatry . 2023 ; 10 ( 4 ): 252 – 9 . OpenUrl PubMed 13. ↵ Chen YH , Liang SC , Sun CK , Cheng YS , Tzang RF , Chiu HJ , et al. A meta-analysis on the therapeutic efficacy of repetitive transcranial magnetic stimulation for cognitive functions in attention-deficit/hyperactivity disorders . BMC Psychiatry . 2023 ; 23 ( 1 ): 756 . OpenUrl PubMed 14. ↵ van ‘t Wout-Frank M , Shea MT , Sorensen DO , Faucher CR , Greenberg BD , Philip NS . A Secondary Analysis on Effects of Theta Burst Transcranial Magnetic Stimulation to Reduce Anger in Veterans With Posttraumatic Stress Disorder . Neuromodulation . 2021 ; 24 ( 5 ): 870 – 8 . OpenUrl PubMed 15. ↵ Ng E , Abramian M , Nestor SM , Rabin JS , Hamani C , Lipsman N , et al. Impact of intermittent theta burst repetitive transcranial magnetic stimulation on irritability: A retrospective analysis of patients with major depressive disorder . Transcranial Magnetic Stimulation . 2025 ; 3 . 16. ↵ Blumberger DM , Vila-Rodriguez F , Thorpe KE , Feffer K , Noda Y , Giacobbe P , et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial . Lancet . 2018 ; 391 ( 10131 ): 1683 – 92 . OpenUrl CrossRef PubMed 17. ↵ Huang YZ , Edwards MJ , Rounis E , Bhatia KP , Rothwell JC . Theta burst stimulation of the human motor cortex . Neuron . 2005 ; 45 ( 2 ): 201 – 6 . OpenUrl CrossRef PubMed Web of Science 18. ↵ Cole EJ , Stimpson KH , Bentzley BS , Gulser M , Cherian K , Tischler C , et al. Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression . Am J Psychiatry . 2020 ; 177 ( 8 ): 716 – 26 . OpenUrl CrossRef PubMed 19. ↵ Philip NS , Barredo J , Aiken E , Larson V , Jones RN , Shea MT , et al. Theta-Burst Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder . Am J Psychiatry . 2019 ; 176 ( 11 ): 939 – 48 . OpenUrl CrossRef PubMed 20. ↵ Li CT , Chen MH , Juan CH , Huang HH , Chen LF , Hsieh JC , et al. Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study . Brain . 2014 ; 137 (Pt 7 ): 2088 – 98 . OpenUrl CrossRef PubMed 21. ↵ Hermiller MS , Karp E , Nilakantan AS , Voss JL . Episodic memory improvements due to noninvasive stimulation targeting the cortical-hippocampal network: A replication and extension experiment . Brain Behav . 2019 ; 9 ( 12 ): e01393 . OpenUrl CrossRef PubMed 22. ↵ Nilakantan AS , Mesulam MM , Weintraub S , Karp EL , VanHaerents S , Voss JL . Network-targeted stimulation engages neurobehavioral hallmarks of age-related memory decline . Neurology . 2019 ; 92 ( 20 ): e2349 – e54 . OpenUrl PubMed 23. ↵ Brunoni AR , Vanderhasselt MA . Working memory improvement with non-invasive brain stimulation of the dorsolateral prefrontal cortex: a systematic review and meta-analysis . Brain Cogn . 2014 ; 86 : 1 – 9 . OpenUrl CrossRef PubMed Web of Science 24. ↵ Mylius V , Ayache SS , Ahdab R , Farhat WH , Zouari HG , Belke M , et al. Definition of DLPFC and M1 according to anatomical landmarks for navigated brain stimulation: inter-rater reliability, accuracy, and influence of gender and age . Neuroimage . 2013 ; 78 : 224 – 32 . OpenUrl CrossRef PubMed 25. ↵ Wolraich ML , Lambert W , Doffing MA , Bickman L , Simmons T , Worley K . Psychometric properties of the Vanderbilt ADHD diagnostic parent rating scale in a referred population . J Pediatr Psychol . 2003 ; 28 ( 8 ): 559 – 67 . OpenUrl CrossRef PubMed Web of Science 26. ↵ Gioia G , Isquith , P. K. , Guy , S. C. , & Kenworthy , L. Behavior rating inventory of executive function, second edition, professional manual . Lutz, FL : Psychological Assessment Resources ; 2015 . 27. ↵ Hanmer J , Jensen RE , Rothrock N , HealthMeasures T . A reporting checklist for HealthMeasures’ patient-reported outcomes: ASCQ-Me, Neuro-QoL, NIH Toolbox, and PROMIS . J Patient Rep Outcomes . 2020 ; 4 ( 1 ): 21 . OpenUrl PubMed 28. ↵ Wechsler D. Wechsler Abbreviated Scale of Intelligence (2nd ed.) . San Antonio, TX : The Psychological Corporation ; 2011 . 29. ↵ Gershon RC , Wagster , M. V. , Hendrie , H. C. , Fox , N. A. , Cook , K. F. , & Nowinski , C. J. NIH Toolbox for assessment of neurological and behavioral function . Neurology . 2013 ; 80 ( 11 Suppl 3 ): S2 – 6 . OpenUrl CrossRef PubMed 30. ↵ Hogberg C , Billstedt , E. , Bjorck , C. , Bjorck , P. , Ehlers , S. , Gustle , L. , Hellner , C. , Hook , H. , Serlachius , E. , Svensson , M. A. , Larsson , J. Diagnostic validty of MINI-KID disorder classifications in specialized child and adolescent psychiatric outpatient clinics in Sweden . BMC Psychiatry . 2019 ; 19 : 142 – 52 . OpenUrl PubMed 31. ↵ Wang WL , Wang SY , Hung HY , Chen MH , Juan CH , Li CT . Safety of transcranial magnetic stimulation in unipolar depression: A systematic review and meta-analysis of randomized-controlled trials . J Affect Disord . 2022 ; 301 : 400 – 25 . OpenUrl CrossRef PubMed 32. ↵ Parikh TK , Strawn JR , Walkup JT , Croarkin PE . Repetitive Transcranial Magnetic Stimulation for Generalized Anxiety Disorder: A Systematic Literature Review and Meta-Analysis . Int J Neuropsychopharmacol . 2022 ; 25 ( 2 ): 144 – 6 . OpenUrl CrossRef PubMed 33. ↵ Berlim MT , McGirr A , Rodrigues Dos Santos N , Tremblay S , Martins R. Efficacy of theta burst stimulation (TBS) for major depression: An exploratory meta-analysis of randomized and sham-controlled trials . J Psychiatr Res . 2017 ; 90 : 102 – 9 . OpenUrl CrossRef PubMed 34. ↵ Croarkin PE , Dojnov A , Middleton VJ , Bowman J , Kriske J , Donachie N , et al. Accelerated 1 Hz dorsomedial prefrontal transcranial magnetic stimulation for generalized anxiety disorder in adolescents and young adults: A case series . Brain Stimul . 2024 ; 17 ( 2 ): 269 – 71 . OpenUrl PubMed 35. ↵ Qiu H , Liang K , Lu L , Gao Y , Li H , Hu X , et al. Efficacy and safety of repetitive transcranial magnetic stimulation in children and adolescents with depression: A systematic review and preliminary meta-analysis . J Affect Disord . 2023 ; 320 : 305 – 12 . OpenUrl PubMed 36. ↵ Steward KA , Tan A , Delgaty L , Gonzales MM , Bunner M . Self-Awareness of Executive Functioning Deficits in Adolescents With ADHD . J Atten Disord . 2017 ; 21 ( 4 ): 316 – 22 . OpenUrl PubMed 37. ↵ Rae CL , Hughes LE , Weaver C , Anderson MC , Rowe JB . Selection and stopping in voluntary action: a meta-analysis and combined fMRI study . Neuroimage . 2014 ; 86 : 381 – 91 . OpenUrl CrossRef PubMed Web of Science View the discussion thread. Back to top Previous Next Posted September 05, 2025. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Intermittent theta burst stimulation for attention deficit hyperactivity disorder Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Intermittent theta burst stimulation for attention deficit hyperactivity disorder Brian C. Kavanaugh , Megan M. Vigne , Christopher Legere , Gian DePamphilis , Eric Tirrell , W. Luke Acuff , Joshua Brown , Rich Jones , Anthony Spirito , Linda L. Carpenter medRxiv 2025.09.03.25335033; doi: https://doi.org/10.1101/2025.09.03.25335033 Share This Article: Copy Citation Tools Intermittent theta burst stimulation for attention deficit hyperactivity disorder Brian C. Kavanaugh , Megan M. Vigne , Christopher Legere , Gian DePamphilis , Eric Tirrell , W. Luke Acuff , Joshua Brown , Rich Jones , Anthony Spirito , Linda L. Carpenter medRxiv 2025.09.03.25335033; doi: https://doi.org/10.1101/2025.09.03.25335033 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Psychiatry and Clinical Psychology Subject Areas All Articles Addiction Medicine (568) Allergy and Immunology (863) Anesthesia (299) Cardiovascular Medicine (4426) Dentistry and Oral Medicine (443) Dermatology (382) Emergency Medicine (607) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1507) Epidemiology (15222) Forensic Medicine (30) Gastroenterology (1123) Genetic and Genomic Medicine (6589) Geriatric Medicine (667) Health Economics (997) Health Informatics (4525) Health Policy (1368) Health Systems and Quality Improvement (1612) Hematology (540) HIV/AIDS (1264) Infectious Diseases (except HIV/AIDS) (15910) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (145) Nephrology (667) Neurology (6588) Nursing (346) Nutrition (998) Obstetrics and Gynecology (1143) Occupational and Environmental Health (956) Oncology (3331) Ophthalmology (971) Orthopedics (369) Otolaryngology (420) Pain Medicine (435) Palliative Medicine (129) Pathology (663) Pediatrics (1690) Pharmacology and Therapeutics (691) Primary Care Research (710) Psychiatry and Clinical Psychology (5440) Public and Global Health (9221) Radiology and Imaging (2195) Rehabilitation Medicine and Physical Therapy (1369) Respiratory Medicine (1196) Rheumatology (593) Sexual and Reproductive Health (710) Sports Medicine (529) Surgery (711) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9ffefee718924807',t:'MTc3OTQ4NjE5OA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();