{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T15:45:59Z","timestamp":1793202359765,"version":"4.5.0"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001922","name":"DH | NIHR | Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR130077"],"award-info":[{"award-number":["NIHR130077"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    External trigeminal nerve stimulation (TNS) received US Food and Drug Administration 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. Here we conducted a confirmatory multicenter, double-blind, randomized, sham-controlled, parallel-group, phase 2b RCT to investigate short-term and long-term efficacy (6\u2009months) of real versus sham TNS in 150 children and adolescents with ADHD. Participants were randomized to receive real TNS (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200975, mean age (s.d.)\u2009=\u200912.6 (2.8) years) or sham TNS (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200975, mean age (s.d.)\u2009=\u200912.6 (2.8) years) nightly for approximately 9\u2009hours for 4\u2009weeks. Bilateral stimulation targeted V1 trigeminal branches using battery-powered electrodes applied to the forehead. Sham TNS delivered 30\u2009seconds of stimulation per hour at lower frequency and pulse width. Intention-to-treat analysis showed no significant differential treatment effects on ADHD symptoms (primary outcome) (estimated adjusted mean difference\u2009=\u20090.83; 95% confidence interval: \u20132.47 to 4.13;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.622; Cohen\u2019s\n                    <jats:italic>d<\/jats:italic>\n                    \u2009=\u20090.09). No serious adverse events were reported, and side effects did not differ between groups. In conclusion, TNS is a safe intervention but does not demonstrate clinical efficacy for pediatric ADHD. Trial registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.isrctn.com\/ISRCTN82129325\" ext-link-type=\"uri\">ISRCTN82129325<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-025-04075-x","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T10:02:27Z","timestamp":1768557747000},"page":"582-590","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["External trigeminal nerve stimulation in youth with ADHD: a randomized, sham-controlled, phase 2b trial"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0467-9431","authenticated-orcid":false,"given":"Aldo Alberto","family":"Conti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natali","family":"Bozhilova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3468-1719","authenticated-orcid":false,"given":"Irem Ece","family":"Eraydin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5624-1733","authenticated-orcid":false,"given":"Dominic","family":"Stringer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4473-1134","authenticated-orcid":false,"given":"Lena","family":"Johansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7760-8661","authenticated-orcid":false,"given":"Robert","family":"Marhenke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Bilbow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6259-2079","authenticated-orcid":false,"given":"Sahid","family":"El Masri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Hyde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Giaroli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6650-9449","authenticated-orcid":false,"given":"Holan","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Fiori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1152-5323","authenticated-orcid":false,"given":"Mitul Ashok","family":"Mehta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4830-5893","authenticated-orcid":false,"given":"Paramala","family":"Santosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0318-8865","authenticated-orcid":false,"given":"Ben","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5877-8075","authenticated-orcid":false,"given":"Samuele","family":"Cortese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1410-7701","authenticated-orcid":false,"given":"Katya","family":"Rubia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"4075_CR1","doi-asserted-by":"crossref","first-page":"4823","DOI":"10.1038\/s41380-023-02228-3","volume":"28","author":"S Cortese","year":"2023","unstructured":"Cortese, S. et al. 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. Mol. Psychiatry 28, 4823\u20134830 (2023).","journal-title":"Mol. Psychiatry"},{"key":"4075_CR2","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) (American Psychiatric Association Publishing, 2022).","DOI":"10.1176\/appi.books.9780890425787"},{"key":"4075_CR3","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1093\/arclin\/acx055","volume":"33","author":"MA Pievsky","year":"2018","unstructured":"Pievsky, M. A. & McGrath, R. E. The neurocognitive profile of attention-deficit\/hyperactivity disorder: a review of meta-analyses. Arch. Clin. Neuropsychol. 33, 143\u2013157 (2018).","journal-title":"Arch. Clin. Neuropsychol."},{"key":"4075_CR4","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1037\/a0027205","volume":"121","author":"CL Huang-Pollock","year":"2012","unstructured":"Huang-Pollock, C. L., Karalunas, S. L., Tam, H. & Moore, A. N. Evaluating vigilance deficits in ADHD: a meta-analysis of CPT performance. J. Abnorm. Psychol. 121, 360\u2013371 (2012).","journal-title":"J. Abnorm. Psychol."},{"key":"4075_CR5","doi-asserted-by":"crossref","first-page":"100","DOI":"10.3389\/fnhum.2018.00100","volume":"12","author":"K Rubia","year":"2018","unstructured":"Rubia, K. Cognitive neuroscience of attention deficit hyperactivity disorder (ADHD) and its clinical translation. Front. Hum. Neurosci. 12, 100 (2018).","journal-title":"Front. Hum. Neurosci."},{"key":"4075_CR6","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41572-024-00495-0","volume":"10","author":"SV Faraone","year":"2024","unstructured":"Faraone, S. V. et al. Attention-deficit\/hyperactivity disorder. Nat. Rev. Dis. Primers 10, 11 (2024).","journal-title":"Nat. Rev. Dis. Primers"},{"key":"4075_CR7","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/S2215-0366(18)30269-4","volume":"5","author":"S Cortese","year":"2018","unstructured":"Cortese, S. et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry 5, 727\u2013738 (2018).","journal-title":"Lancet Psychiatry"},{"key":"4075_CR8","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S2215-0366(23)00332-2","volume":"11","author":"I Brikell","year":"2024","unstructured":"Brikell, I. et al. ADHD medication discontinuation and persistence across the lifespan: a retrospective observational study using population-based databases. Lancet Psychiatry 11, 16\u201326 (2024).","journal-title":"Lancet Psychiatry"},{"key":"4075_CR9","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1002\/cpt.1186","volume":"104","author":"JM Swanson","year":"2018","unstructured":"Swanson, J. M. Risk of bias and quality of evidence for treatment of ADHD with stimulant medication. Clin. Pharmacol. Ther. 104, 638\u2013643 (2018).","journal-title":"Clin. Pharmacol. Ther."},{"key":"4075_CR10","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1176\/appi.ajp.2011.11060940","volume":"169","author":"P Fusar-Poli","year":"2012","unstructured":"Fusar-Poli, P., Rubia, K., Rossi, G., Sartori, G. & Balottin, U. Striatal dopamine transporter alterations in ADHD: pathophysiology or adaptation to psychostimulants? A meta-analysis. Am. J. Psychiatry 169, 264\u2013272 (2012).","journal-title":"Am. J. Psychiatry"},{"key":"4075_CR11","doi-asserted-by":"crossref","first-page":"105703","DOI":"10.1016\/j.neubiorev.2024.105703","volume":"162","author":"F Isfandnia","year":"2024","unstructured":"Isfandnia, F., El Masri, S., Radua, J. & Rubia, K. The effects of chronic administration of stimulant and non-stimulant medications on executive functions in ADHD: a systematic review and meta-analysis. Neurosci. Biobehav. Rev. 162, 105703 (2024).","journal-title":"Neurosci. Biobehav. Rev."},{"key":"4075_CR12","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/s40271-015-0112-5","volume":"8","author":"NK Schatz","year":"2015","unstructured":"Schatz, N. K. et al. Systematic review of patients\u2019 and parents\u2019 preferences for ADHD treatment options and processes of care. Patient 8, 483\u2013497 (2015).","journal-title":"Patient"},{"key":"4075_CR13","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.3390\/cells10082156","volume":"10","author":"K Rubia","year":"2021","unstructured":"Rubia, K., Westwood, S., Aggensteiner, P. M. & Brandeis, D. Neurotherapeutics for attention deficit\/hyperactivity disorder (ADHD): a review. Cells 10, 2156 (2021).","journal-title":"Cells"},{"key":"4075_CR14","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s42234-023-00128-z","volume":"9","author":"K Powell","year":"2023","unstructured":"Powell, K. et al. Trigeminal nerve stimulation: a current state-of-the-art review. Bioelectron. Med. 9, 30 (2023).","journal-title":"Bioelectron. Med."},{"key":"4075_CR15","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.brainres.2016.03.001","volume":"1645","author":"G Aston-Jones","year":"2016","unstructured":"Aston-Jones, G. & Waterhouse, B. Locus coeruleus: from global projection system to adaptive regulation of behavior. Brain Res. 1645, 75\u201378 (2016).","journal-title":"Brain Res."},{"key":"4075_CR16","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.3390\/biomedicines11092392","volume":"11","author":"B Mercante","year":"2023","unstructured":"Mercante, B., Enrico, P. & Deriu, F. Cognitive functions following trigeminal neuromodulation. Biomedicines 11, 2392 (2023).","journal-title":"Biomedicines"},{"key":"4075_CR17","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.neubiorev.2019.11.001","volume":"108","author":"A Bellato","year":"2020","unstructured":"Bellato, A., Arora, I., Hollis, C. & Groom, M. J. Is autonomic nervous system function atypical in attention deficit hyperactivity disorder (ADHD)? A systematic review of the evidence. Neurosci. Biobehav. Rev. 108, 182\u2013206 (2020).","journal-title":"Neurosci. Biobehav. Rev."},{"key":"4075_CR18","doi-asserted-by":"publisher","unstructured":"Faraone, S. V. & Radonji\u0107, N. V. Neurobiology of attention deficit hyperactivity disorder. in Tasman\u2019s Psychiatry 1\u201328 (Springer, 2023); https:\/\/doi.org\/10.1007\/978-3-030-42825-9_33-1","DOI":"10.1007\/978-3-030-42825-9_33-1"},{"key":"4075_CR19","doi-asserted-by":"crossref","first-page":"4025","DOI":"10.1038\/s41380-023-02227-4","volume":"28","author":"SJ Westwood","year":"2023","unstructured":"Westwood, S. J. et al. Clinical and cognitive effects of external trigeminal nerve stimulation (eTNS) in neurological and psychiatric disorders: a systematic review and meta-analysis. Mol. Psychiatry 28, 4025\u20134043 (2023).","journal-title":"Mol. Psychiatry"},{"key":"4075_CR20","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.jaac.2018.11.013","volume":"58","author":"JJ McGough","year":"2019","unstructured":"McGough, J. J. et al. Double-blind, sham-controlled, pilot study of trigeminal nerve stimulation for attention-deficit\/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 58, 403\u2013411 (2019).","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"4075_CR21","doi-asserted-by":"crossref","unstructured":"DuPaul, G.J., Power, T.J., Anastopoulos, A.D. & Reid, R. ADHD Rating Scale-5 for Children and Adolescents: Checklists, Norms, and Clinical Interpretation (Guilford Press, 2016).","DOI":"10.1037\/t05638-000"},{"key":"4075_CR22","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1017\/S0033291720000574","volume":"50","author":"S Lukito","year":"2020","unstructured":"Lukito, S. et al. Comparative meta-analyses of brain structural and functional abnormalities during cognitive control in attention-deficit\/hyperactivity disorder and autism spectrum disorder. Psychol. Med. 50, 894\u2013919 (2020).","journal-title":"Psychol. Med."},{"key":"4075_CR23","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1016\/j.neubiorev.2012.08.003","volume":"36","author":"H Hart","year":"2012","unstructured":"Hart, H., Radua, J., Mataix-Cols, D. & Rubia, K. Meta-analysis of fMRI studies of timing in attention-deficit hyperactivity disorder (ADHD). Neurosci. Biobehav. Rev. 36, 2248\u20132256 (2012).","journal-title":"Neurosci. Biobehav. Rev."},{"key":"4075_CR24","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1001\/jamapsychiatry.2013.277","volume":"70","author":"H Hart","year":"2013","unstructured":"Hart, H., Radua, J., Nakao, T., Mataix-Cols, D. & Rubia, K. Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit\/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects. JAMA Psychiatry 70, 185\u2013198 (2013).","journal-title":"JAMA Psychiatry"},{"key":"4075_CR25","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1001\/jamapsychiatry.2016.0700","volume":"73","author":"LJ Norman","year":"2016","unstructured":"Norman, L. J. et al. Structural and functional brain abnormalities in attention-deficit\/hyperactivity disorder and obsessive-compulsive disorder: a comparative meta-analysis. JAMA Psychiatry 73, 815\u2013825 (2016).","journal-title":"JAMA Psychiatry"},{"key":"4075_CR26","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.brs.2014.11.013","volume":"8","author":"JJ McGough","year":"2015","unstructured":"McGough, J. J. et al. An eight-week, open-trial, pilot feasibility study of trigeminal nerve stimulation in youth with attention-deficit\/hyperactivity disorder. Brain Stimul. 8, 299\u2013304 (2015).","journal-title":"Brain Stimul."},{"key":"4075_CR27","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.neubiorev.2018.07.010","volume":"92","author":"NS Bozhilova","year":"2018","unstructured":"Bozhilova, N. S., Michelini, G., Kuntsi, J. & Asherson, P. Mind wandering perspective on attention-deficit\/hyperactivity disorder. Neurosci. Biobehav. Rev. 92, 464\u2013476 (2018).","journal-title":"Neurosci. Biobehav. Rev."},{"key":"4075_CR28","doi-asserted-by":"crossref","DOI":"10.1186\/s12888-024-05650-1","volume":"24","author":"K Rubia","year":"2024","unstructured":"Rubia, K. et al. The efficacy of real versus sham external trigeminal nerve stimulation (eTNS) in youth with attention-deficit\/hyperactivity disorder (ADHD) over 4 weeks: a protocol for a multi-centre, double-blind, randomized, parallel-group, phase IIb study (ATTENS). BMC Psychiatry 24, 326 (2024).","journal-title":"BMC Psychiatry"},{"key":"4075_CR29","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1037\/amp0000118","volume":"72","author":"RT Thibault","year":"2017","unstructured":"Thibault, R. T. & Raz, A. The psychology of neurofeedback: clinical intervention even if applied placebo. Am. Psychol. 72, 679\u2013688 (2017).","journal-title":"Am. Psychol."},{"key":"4075_CR30","doi-asserted-by":"crossref","first-page":"3915","DOI":"10.1038\/s41380-024-02638-x","volume":"29","author":"NTM Huneke","year":"2024","unstructured":"Huneke, N. T. M. et al. Placebo effects in randomized trials of pharmacological and neurostimulation interventions for mental disorders: an umbrella review. Mol. Psychiatry 29, 3915\u20133925 (2024).","journal-title":"Mol. Psychiatry"},{"key":"4075_CR31","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1159\/000540791","volume":"93","author":"W Rief","year":"2024","unstructured":"Rief, W. & Wilhelm, M. Nocebo and placebo effects and their implications in psychotherapy. Psychother. Psychosom. 93, 298\u2013303 (2024).","journal-title":"Psychother. Psychosom."},{"key":"4075_CR32","doi-asserted-by":"crossref","unstructured":"Thibault, R. T., Veissi\u00e8re, S., Olson, J. A. & Raz, A. Treating ADHD with suggestion: neurofeedback and placebo therapeutics. J. Atten. Disord. 22, 707\u2212711 (2018).","DOI":"10.1177\/1087054718770012"},{"key":"4075_CR33","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/s41380-021-01134-w","volume":"27","author":"SV Faraone","year":"2022","unstructured":"Faraone, S. V. et al. Placebo and nocebo responses in randomised, controlled trials of medications for ADHD: a systematic review and meta-analysis. Mol. Psychiatry 27, 212\u2013219 (2022).","journal-title":"Mol. Psychiatry"},{"key":"4075_CR34","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/mp.2011.185","volume":"18","author":"A Christakou","year":"2013","unstructured":"Christakou, A. et al. Disorder-specific functional abnormalities during sustained attention in youth with attention deficit hyperactivity disorder (ADHD) and with autism. Mol. Psychiatry 18, 236\u2013244 (2013).","journal-title":"Mol. Psychiatry"},{"key":"4075_CR35","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/s41386-022-01408-z","volume":"48","author":"LJ Norman","year":"2023","unstructured":"Norman, L. J., Sudre, G., Price, J., Shastri, G. G. & Shaw, P. Evidence from \u2018big data\u2019 for the default-mode hypothesis of ADHD: a mega-analysis of multiple large samples. Neuropsychopharmacology 48, 281\u2013289 (2023).","journal-title":"Neuropsychopharmacology"},{"key":"4075_CR36","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1007\/s10578-023-01557-2","volume":"56","author":"TJ Dekkers","year":"2025","unstructured":"Dekkers, T. J. et al. Does mind-wandering explain ADHD-related impairment in adolescents? Child Psychiatry Hum. Dev. 56, 346\u2013357 (2025).","journal-title":"Child Psychiatry Hum. Dev."},{"key":"4075_CR37","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1177\/1087054719865781","volume":"25","author":"J Lanier","year":"2021","unstructured":"Lanier, J., Noyes, E. & Biederman, J. Mind wandering (internal distractibility) in ADHD: a literature review. J. Atten. Disord. 25, 885\u2013890 (2021).","journal-title":"J. Atten. Disord."},{"key":"4075_CR38","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1111\/bjc.12241","volume":"59","author":"MA Frick","year":"2020","unstructured":"Frick, M. A., Asherson, P. & Brocki, K. C. Mind-wandering in children with and without ADHD. Br. J. Clin. Psychol. 59, 208\u2013223 (2020).","journal-title":"Br. J. Clin. Psychol."},{"key":"4075_CR39","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1177\/1087054716651927","volume":"23","author":"FD Mowlem","year":"2019","unstructured":"Mowlem, F. D. et al. Validation of the mind excessively wandering scale and the relationship of mind wandering to impairment in adult ADHD. J. Atten. Disord. 23, 624\u2013634 (2019).","journal-title":"J. Atten. Disord."},{"key":"4075_CR40","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.jaac.2020.09.021","volume":"60","author":"SK Loo","year":"2021","unstructured":"Loo, S. K. et al. Trigeminal nerve stimulation for attention-deficit\/hyperactivity disorder: cognitive and electroencephalographic predictors of treatment response. J. Am. Acad. Child Adolesc. Psychiatry 60, 856\u2013864 (2021).","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"4075_CR41","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1037\/pas0000627","volume":"30","author":"AD Anastopoulos","year":"2018","unstructured":"Anastopoulos, A. D. et al. Impact of child and informant gender on parent and teacher ratings of attention-deficit\/hyperactivity disorder. Psychol. Assess. 30, 1390\u20131394 (2018).","journal-title":"Psychol. Assess."},{"key":"4075_CR42","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.psychres.2018.03.083","volume":"264","author":"AL Vazquez","year":"2018","unstructured":"Vazquez, A. L., Sibley, M. H. & Campez, M. Measuring impairment when diagnosing adolescent ADHD: differentiating problems due to ADHD versus other sources. Psychiatry Res. 264, 407\u2013411 (2018).","journal-title":"Psychiatry Res."},{"key":"4075_CR43","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1007\/s13142-015-0315-2","volume":"5","author":"MJ Stirratt","year":"2015","unstructured":"Stirratt, M. J. et al. Self-report measures of medication adherence behavior: recommendations on optimal use. Transl. Behav. Med. 5, 470\u2013482 (2015).","journal-title":"Transl. Behav. Med."},{"key":"4075_CR44","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/S2215-0366(24)00360-2","volume":"12","author":"EG Ostinelli","year":"2025","unstructured":"Ostinelli, E. G. et al. Comparative efficacy and acceptability of pharmacological, psychological, and neurostimulatory interventions for ADHD in adults: a systematic review and component network meta-analysis. Lancet Psychiatry 12, 32\u201343 (2025).","journal-title":"Lancet Psychiatry"},{"key":"4075_CR45","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1002\/pchj.544","volume":"11","author":"K Rubia","year":"2022","unstructured":"Rubia, K. Neurotherapeutics for ADHD: do they work? Psych. J. 11, 419\u2013427 (2022).","journal-title":"Psych. J."},{"key":"4075_CR46","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.jpsychires.2022.08.022","volume":"155","author":"M Schertz","year":"2022","unstructured":"Schertz, M. et al. Transcranial direct current stimulation (tDCS) in children with ADHD: a randomized, sham-controlled pilot study. J. Psychiatr. Res. 155, 302\u2013312 (2022).","journal-title":"J. Psychiatr. Res."},{"key":"4075_CR47","first-page":"497","volume":"53","author":"SJ Westwood","year":"2023","unstructured":"Westwood, S. J. et al. Transcranial direct current stimulation (tDCS) combined with cognitive training in adolescent boys with ADHD: a double-blind, randomised, sham-controlled trial. Psychol. Med. 53, 497\u2013512 (2023).","journal-title":"Psychol. Med."},{"key":"4075_CR48","doi-asserted-by":"crossref","first-page":"E14","DOI":"10.1503\/jpn.190179","volume":"46","author":"SJ Westwood","year":"2021","unstructured":"Westwood, S. J., Radua, J. & Rubia, K. Noninvasive brain stimulation in children and adults with attention-deficit\/hyperactivity disorder: a systematic review and meta-analysis. J. Psychiatry Neurosci. 46, E14\u2013E33 (2021).","journal-title":"J. Psychiatry Neurosci."},{"key":"4075_CR49","doi-asserted-by":"crossref","first-page":"726","DOI":"10.7326\/0003-4819-152-11-201006010-00232","volume":"152","author":"KF Schulz","year":"2010","unstructured":"Schulz, K. F., Altman, D. G., Moher, D. & CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann. Intern. Med. 152, 726\u2013732 (2010).","journal-title":"Ann. Intern. Med."},{"key":"4075_CR50","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1097\/00004583-199707000-00021","volume":"36","author":"J Kaufman","year":"1997","unstructured":"Kaufman, J. et al. Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J. Am. Acad. Child Adolesc. Psychiatry 36, 980\u2013988 (1997).","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"4075_CR51","doi-asserted-by":"crossref","unstructured":"Wechsler, D. Wechsler Abbreviated Scale of Intelligence https:\/\/psycnet.apa.org\/doi\/10.1037\/t15170-000 (American Psychological Association, 1999).","DOI":"10.1037\/t15170-000"},{"key":"4075_CR52","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1056\/NEJMra1917069","volume":"383","author":"S Cortese","year":"2020","unstructured":"Cortese, S. Pharmacologic treatment of attention deficit\u2013hyperactivity disorder. N. Engl. J. Med. 383, 1050\u20131056 (2020).","journal-title":"N. Engl. J. Med."},{"key":"4075_CR53","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1080\/09297040600770761","volume":"13","author":"K Rubia","year":"2007","unstructured":"Rubia, K., Smith, A. & Taylor, E. Performance of children with attention deficit hyperactivity disorder (ADHD) on a test battery of impulsiveness. Child Neuropsychol. 13, 276\u2013304 (2007).","journal-title":"Child Neuropsychol."},{"key":"4075_CR54","doi-asserted-by":"crossref","unstructured":"DuPaul, G. J., Power, T. J., Anastopoulos, A. D. & Reid, R. ADHD Rating Scale-IV: School Checklist https:\/\/psycnet.apa.org\/doi\/10.1037\/t00680-000 (American Psychological Association, 1998).","DOI":"10.1037\/t00680-000"},{"key":"4075_CR55","unstructured":"Conners, C. K. Conners, Third Edition (Conners 3) (Western Psychological Services, 2008)."},{"key":"4075_CR56","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1111\/j.1469-7610.1997.tb01545.x","volume":"38","author":"R Goodman","year":"1997","unstructured":"Goodman, R. The Strengths and Difficulties Questionnaire: a research note. J. Child Psychol. Psychiatry 38, 581\u2013586 (1997).","journal-title":"J. Child Psychol. Psychiatry"},{"key":"4075_CR57","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1111\/j.1469-7610.2012.02561.x","volume":"53","author":"A Stringaris","year":"2012","unstructured":"Stringaris, A. et al. The Affective Reactivity Index: a concise irritability scale for clinical and research settings. J. Child Psychol. Psychiatry 53, 1109\u20131117 (2012).","journal-title":"J. Child Psychol. Psychiatry"},{"key":"4075_CR58","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/S0005-7967(99)00130-8","volume":"38","author":"BF Chorpita","year":"2000","unstructured":"Chorpita, B. F., Yim, L., Moffitt, C., Umemoto, L. A. & Francis, S. E. Assessment of symptoms of DSM-IV anxiety and depression in children: a revised child anxiety and depression scale. Behav. Res. Ther. 38, 835\u2013855 (2000).","journal-title":"Behav. Res. Ther."},{"key":"4075_CR59","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1176\/appi.ajp.2011.10111704","volume":"168","author":"K Posner","year":"2011","unstructured":"Posner, K. et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am. J. Psychiatry 168, 1266\u20131277 (2011).","journal-title":"Am. J. Psychiatry"},{"key":"4075_CR60","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/j.1365-2869.1996.00251.x","volume":"5","author":"O Bruni","year":"1996","unstructured":"Bruni, O. et al. The Sleep Disturbance Scale for Children (SDSC). Construction and validation of an instrument to evaluate sleep disturbances in childhood and adolescence. J. Sleep Res. 5, 251\u2013261 (1996).","journal-title":"J. Sleep Res."},{"key":"4075_CR61","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1080\/00223980009600858","volume":"134","author":"KL Lichstein","year":"2000","unstructured":"Lichstein, K. L., Riedel, B. W. & Richman, S. L. The Mackworth Clock Test: a computerized version. J. Psychol. 134, 153\u2013161 (2000).","journal-title":"J. Psychol."},{"key":"4075_CR62","first-page":"746","volume":"46","author":"G Li","year":"2017","unstructured":"Li, G. et al. An introduction to multiplicity issues in clinical trials: the what, why, when and how. Int. J. Epidemiol. 46, 746\u2013755 (2017).","journal-title":"Int. J. Epidemiol."},{"key":"4075_CR63","doi-asserted-by":"publisher","unstructured":"Conti, A. A. et al. 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 (ATTENS). figshare https:\/\/doi.org\/10.6084\/m9.figshare.29414744.v1 (2025).","DOI":"10.6084\/m9.figshare.29414744.v1"}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-04075-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-04075-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-04075-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T18:04:13Z","timestamp":1771783453000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-04075-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,16]]},"references-count":63,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["4075"],"URL":"https:\/\/doi.org\/10.1038\/s41591-025-04075-x","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-6882697\/v1","asserted-by":"object"}]},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,16]]},"assertion":[{"value":"12 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"S.C. 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. M.A.M. has received research funding from Takeda Pharmaceuticals, Johnson and Johnson, Lundbeck, Boehringer Ingelheim and Nxera. He also acted as a consultant for Neurocrine, Lundbeck, Boehringer Ingelheim and Nxera. G.G. has received speaker honoraria from Takeda Pharmaceuticals. P.S. 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. F.F. is a shareholder and the Chief Technical Officer of HealthTracker, Ltd. B.C. has received funding from LifeARC and Mundipharma. K.R., D.S., A.A.C., N.B., I.E.E., R.M., A.B., S.E.M., J.H., H.L. and L.J. have no financial interests to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}