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).
ADHD
Attention-Deficit
EF
Executive functions
External transcutaneous Trigeminal Nerve Stimulation
External trigeminal nerve stimulation
Functional magnetic resonance imaging
Hyperactivity Disorder
Supraorbital transcutaneous stimulation
TENS
TNS
Transcutaneous electrical nerve stimulation
Transcutaneous external supraorbital nerve stimulation
Transcutaneous supraorbital nerve stimulation
Trigeminal nerve stimulation
Trigeminal transcutaneous nerve stimulation
eTNS
fMRI
Journal
BMC psychiatry
ISSN: 1471-244X
Titre abrégé: BMC Psychiatry
Pays: England
ID NLM: 100968559
Informations de publication
Date de publication:
30 Apr 2024
30 Apr 2024
Historique:
received:
15
01
2024
accepted:
01
03
2024
medline:
1
5
2024
pubmed:
1
5
2024
entrez:
30
4
2024
Statut:
epublish
Résumé
Attention Deficit/Hyperactivity Disorder (ADHD), if severe, is usually treated with stimulant or non-stimulant medication. However, users prefer non-drug treatments due to side effects. Alternative non-medication treatments have so far only shown modest effects. External trigeminal nerve stimulation (eTNS) is a minimal risk, non-invasive neuromodulation device, targeting the trigeminal system. It was approved for ADHD in 2019 by the USA Food and Drug administration (FDA) based on a small proof of concept randomised controlled trial (RCT) in 62 children with ADHD showing improvement of ADHD symptoms after 4 weeks of nightly real versus sham eTNS with minimal side effects. We present here the protocol of a larger confirmatory phase IIb study testing efficacy, longer-term persistency of effects and underlying mechanisms of action. A confirmatory, sham-controlled, double-blind, parallel-arm, multi-centre phase IIb RCT of 4 weeks of eTNS in 150 youth with ADHD, recruited in London, Portsmouth, and Southampton, UK. Youth with ADHD will be randomized to either real or sham eTNS, applied nightly for 4 weeks. Primary outcome is the change in the investigator-administered parent rated ADHD rating scale. Secondary outcomes are other clinical and cognitive measures, objective hyperactivity and pupillometry measures, side effects, and maintenance of effects over 6 months. The mechanisms of action will be tested in a subgroup of 56 participants using magnetic resonance imaging (MRI) before and after the 4-week treatment. This multi-centre phase IIb RCT will confirm whether eTNS is effective in a larger age range of children and adolescents with ADHD, whether it improves cognition and other clinical measures, whether efficacy persists at 6 months and it will test underlying brain mechanisms. The results will establish whether eTNS is effective and safe as a novel non-pharmacological treatment for ADHD. ISRCTN82129325 on 02/08/2021, https://doi.org/10.1186/ISRCTN82129325 .
Sections du résumé
BACKGROUND
BACKGROUND
Attention Deficit/Hyperactivity Disorder (ADHD), if severe, is usually treated with stimulant or non-stimulant medication. However, users prefer non-drug treatments due to side effects. Alternative non-medication treatments have so far only shown modest effects. External trigeminal nerve stimulation (eTNS) is a minimal risk, non-invasive neuromodulation device, targeting the trigeminal system. It was approved for ADHD in 2019 by the USA Food and Drug administration (FDA) based on a small proof of concept randomised controlled trial (RCT) in 62 children with ADHD showing improvement of ADHD symptoms after 4 weeks of nightly real versus sham eTNS with minimal side effects. We present here the protocol of a larger confirmatory phase IIb study testing efficacy, longer-term persistency of effects and underlying mechanisms of action.
METHODS
METHODS
A confirmatory, sham-controlled, double-blind, parallel-arm, multi-centre phase IIb RCT of 4 weeks of eTNS in 150 youth with ADHD, recruited in London, Portsmouth, and Southampton, UK. Youth with ADHD will be randomized to either real or sham eTNS, applied nightly for 4 weeks. Primary outcome is the change in the investigator-administered parent rated ADHD rating scale. Secondary outcomes are other clinical and cognitive measures, objective hyperactivity and pupillometry measures, side effects, and maintenance of effects over 6 months. The mechanisms of action will be tested in a subgroup of 56 participants using magnetic resonance imaging (MRI) before and after the 4-week treatment.
DISCUSSION
CONCLUSIONS
This multi-centre phase IIb RCT will confirm whether eTNS is effective in a larger age range of children and adolescents with ADHD, whether it improves cognition and other clinical measures, whether efficacy persists at 6 months and it will test underlying brain mechanisms. The results will establish whether eTNS is effective and safe as a novel non-pharmacological treatment for ADHD.
TRIAL REGISTRATION
BACKGROUND
ISRCTN82129325 on 02/08/2021, https://doi.org/10.1186/ISRCTN82129325 .
Identifiants
pubmed: 38689273
doi: 10.1186/s12888-024-05650-1
pii: 10.1186/s12888-024-05650-1
doi:
Types de publication
Journal Article
Clinical Trial Protocol
Randomized Controlled Trial
Clinical Trial, Phase II
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
326Subventions
Organisme : National Institute for Health and Care Research
ID : NIHR130077
Organisme : National Institute for Health and Care Research
ID : NIHR130077
Organisme : National Institute for Health and Care Research
ID : NIHR130077
Organisme : National Institute for Health and Care Research
ID : NIHR130077
Organisme : National Institute for Health and Care Research
ID : NIHR130077
Organisme : National Institute for Health and Care Research
ID : NIHR130077
Organisme : National Institute for Health and Care Research
ID : NIHR130077
Organisme : National Institute for Health and Care Research
ID : NIHR130077
Organisme : National Institute for Health and Care Research
ID : NIHR130077
Organisme : National Institute for Health and Care Research
ID : NIHR130077
Informations de copyright
© 2024. The Author(s).
Références
American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Washington, D.C.: American Psychiatric Publishing; 2013.
Rubia K. Cognitive Neuroscience of Attention Deficit Hyperactivity Disorder (ADHD) and Its Clinical Translation. Front Hum Neurosci. 2018;12:100.
pubmed: 29651240
pmcid: 5884954
doi: 10.3389/fnhum.2018.00100
Rubia K, Westwood S, Aggensteiner PM, Brandeis D. Neurotherapeutics for Attention Deficit/Hyperactivity Disorder (ADHD): A Review. Cells. 2021;10(8):2156.
pubmed: 34440925
pmcid: 8394071
doi: 10.3390/cells10082156
Faraone SV, Banaschewski T, Coghill D, Zheng Y, Biederman J, Bellgrove MA, et al. The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder. Neurosci Biobehav Rev. 2021;128:789–818.
pubmed: 33549739
pmcid: 8328933
doi: 10.1016/j.neubiorev.2021.01.022
Faraone SV, A. BM, Isabell B, S C, Catharina H, Chris H, et al. Update on Attention-Deficit/Hyperactivity Disorder. Nature Reviews. 2024;10(11):1–21.
Cortese S, Adamo N, Del Giovane C, Mohr-Jensen C, Hayes AJ, Carucci 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. 2018;5(9):727–38.
pubmed: 30097390
pmcid: 6109107
doi: 10.1016/S2215-0366(18)30269-4
Cunill R, Castells X, Tobias A, Capella D. Efficacy, safety and variability in pharmacotherapy for adults with attention deficit hyperactivity disorder: a meta-analysis and meta-regression in over 9000 patients. Psychopharmacology. 2016;233(2):187–97.
pubmed: 26446868
doi: 10.1007/s00213-015-4099-3
Aston-Jones G, Cohen JD. Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance. J Comp Neurol. 2005;493(1):99–110.
pubmed: 16254995
doi: 10.1002/cne.20723
McGough JJ, Sturm A, Cowen J, Tung K, Salgari GC, Leuchter AF, et al. Double-Blind, Sham-Controlled, Pilot Study of Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 2019;58(4):403-11.e3.
pubmed: 30768393
pmcid: 6481187
doi: 10.1016/j.jaac.2018.11.013
Cook IA, Espinoza R, Leuchter AF. Neuromodulation for depression: invasive and noninvasive (deep brain stimulation, transcranial magnetic stimulation, trigeminal nerve stimulation). Neurosurg Clin N Am. 2014;25(1):103–16.
pubmed: 24262903
doi: 10.1016/j.nec.2013.10.002
Aucoin R, Lewthwaite H, Ekstrom M, von Leupoldt A, Jensen D. Impact of trigeminal nerve and/or olfactory nerve stimulation on activity of human brain regions involved in the perception of breathlessness. Respir Physiol Neurobiol. 2023;311: 104036.
pubmed: 36804472
doi: 10.1016/j.resp.2023.104036
McGough JJ, Loo SK, Sturm A, Cowen J, Leuchter AF, Cook IA. An eight-week, open-trial, pilot feasibility study of trigeminal nerve stimulation in youth with attention-deficit/hyperactivity disorder. Brain Stimul. 2015;8(2):299–304.
pubmed: 25533244
doi: 10.1016/j.brs.2014.11.013
Adler LD, Nierenberg AA. Review of medication adherence in children and adults with ADHD. Postgrad Med. 2010;122(1):184–91.
pubmed: 20107302
doi: 10.3810/pgm.2010.01.2112
Dupaul DG, Power TJ, Anastopoulos AD, Reid R. ADHD Rating Scale-IV: Checklists, Norms, and Clinical Interpretations. New York: Guilford; 1998.
Goodman R. The strengths and difficulties questionnaire: A research note. J Child Psychol Psychiatry. 1997;38(5):581–6.
pubmed: 9255702
doi: 10.1111/j.1469-7610.1997.tb01545.x
Conners K. Conners 3rd Edition. Manual. Toronto, Ontario, Canada: Multi-Health Systems; 2008.
Stringaris A, Goodman R, Ferdinando S, Razdan V, Muhrer E, Leibenluft E, Brotman MA. The Affective Reactivity Index: a concise irritability scale for clinical and research settings. J Child Psychol Psychiatry. 2012;53(11):1109–17.
pubmed: 22574736
pmcid: 3484687
doi: 10.1111/j.1469-7610.2012.02561.x
Mowlem FD, Skirrow C, Reid P, Maltezos S, Nijjar SK, Merwood A, et al. Validation of the Mind Excessively Wandering Scale and the Relationship of Mind Wandering to Impairment in Adult ADHD. J Atten Disord. 2019;23(6):624–34.
pubmed: 27255536
doi: 10.1177/1087054716651927
Chorpita BF, Yim L, Moffitt C, Umemoto LA, Francis SE. Assessment of symptoms of DSM-IV anxiety and depression in children: a revised child anxiety and depression scale. Behav Res Ther. 2000;38(8):835–55.
pubmed: 10937431
doi: 10.1016/S0005-7967(99)00130-8
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, 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. 2011;168(12):1266–77.
pubmed: 22193671
pmcid: 3893686
doi: 10.1176/appi.ajp.2011.10111704
Rubia K, Smith A, Brammer M, Taylor E. Performance of children with Attention Deficit Hyperactivity Disorder (ADHD) on a test battery for impulsiveness. Child Neuropsychol. 2007;30(2):659–95.
Lichstein KL, Riedel BW, Richman SL. The Mackworth Clock Test: a computerized version. J Psychol. 2000;134(2):153–61.
pubmed: 10766107
doi: 10.1080/00223980009600858
Bruni O, Ottaviano S, Guidetti V, Romoli M, Innocenzi M, Cortesi F, Giannotti F. The Sleep Disturbance Scale for Children (SDSC). Construction and validation of an instrument to evaluate sleep disturbances in childhood and adolescence. J Sleep Res. 1996;5(4):251–61.
Christakou A, Murphy C, Chantiluke C, Cubillo A, Smith A, Giampietro V, et al. Disorder-specific functional abnormalities during sustained attention in youth with Attention Deficit Hyperactivity Disorder (ADHD) and with Autism. Mol Psychiatry. 2013;18(2):236–44.
pubmed: 22290121
doi: 10.1038/mp.2011.185
Cubillo A, Smith A, Barrat N, Giampietro V, Simmons A, Brammer M, Rubia K. Drug-specific laterality effects on frontal lobe activation of Atomoxetine and Methylphenidate in ADHD boys during working memory Psychol Medicine. 2013;44(3):633–46.
Rubia K, Smith AB, Brammer MJ, Toone B, Taylor E. Abnormal brain activation during inhibition and error detection in medication-naive adolescents with ADHD. Am J Psychiatry. 2005;162(6):1067–75.
pubmed: 15930054
doi: 10.1176/appi.ajp.162.6.1067
Alegria AA, Wulff M, Brinson H, Barker GJ, Norman LJ, Brandeis D, et al. Real-Time fMRI Neurofeedback in Adolescents with Attention Deficit Hyperactivity Disorder. Hum Brain Mapp. 2017;38(6):3190–209.
pubmed: 28342214
pmcid: 5434828
doi: 10.1002/hbm.23584
Westwood SJ, Criaud M, Lam SL, Lukito S, Wallace-Hanlon S, Kowalczyk OS, 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. 2021:1–16.
Lam SL, Criaud M, Lukito S, Westwood SJ, Agbedjro D, Kowalczyk OS, et al. Double-Blind, Sham-Controlled Randomized Trial Testing the Efficacy of fMRI Neurofeedback on Clinical and Cognitive Measures in Children With ADHD. Am J Psychiatry. 2022;179(12):947–58.
pubmed: 36349428
pmcid: 7614456
doi: 10.1176/appi.ajp.21100999
Kaufman J, Birmaher B, Brent D, Rao U, Ryan ND. Schedule for Affective Disorders and Schizophrenia for School-age Children- present and lifetime version (K-SADS-PL). Pittsburgh: University of Pittsburgh Press; 1996.
Wechsler D. Wechsler Abbreviated Scale of Intelligence- Second Edition (WASI-II). San Antonio, Texas: APA PsycTests; 2011.
Antal A, Alekseichuk I, Bikson M, Brockmöller J, Brunoni AR, Chen R, et al. Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines. Clin Neurophysiol. 2017;128(9):1774–809.
pubmed: 28709880
pmcid: 5985830
doi: 10.1016/j.clinph.2017.06.001
Shiozawa P, Silva ME, Carvalho TC, Cordeiro Q, Brunoni AR, Fregni F. Transcutaneous vagus and trigeminal nerve stimulation for neuropsychiatric disorders: a systematic review. Arq Neuropsiquiatr. 2014;72(7):542–7.
pubmed: 25054988
doi: 10.1590/0004-282X20140061
Cook IA, Abrams M, Leuchter AF. Trigeminal Nerve Stimulation for Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder. Neuromodulation. 2016;19(3):299–305.
pubmed: 26818103
doi: 10.1111/ner.12399
Veale JF. Edinburgh Handedness Inventory - Short Form: a revised version based on confirmatory factor analysis. Laterality. 2014;19(2):164–77.
pubmed: 23659650
doi: 10.1080/1357650X.2013.783045
Cubillo A, Smith A, Barrett N, Simmons A, Brammer M, V. G, Rubia K. Shared and drug-specific effects of Atomoxetine and Methylphenidate on inhibitory brain dysfunction in medication-naive ADHD boys. Cerebral Cortex. 2014;24(1):174–85.
Kowalczyk O, Cubillo A, Smith ABS, Barrett N, Giampietro V, Brammer M, et al. Methylphenidate and atomoxetine normalise fronto-parietal underactivation during sustained attention in ADHD adolescents Eur Neuropsychopharmacol. 2019;29(10):1102–16.
pubmed: 31358436
Westwood SJ, Conti AA, Tang W, Xue S, Cortese S, Rubia K. Clinical and cognitive effects of external trigeminal nerve stimulation (eTNS) in neurological and psychiatric disorders: a systematic review and meta-analysis. Mol Psychiatry. 2023;28(10):4025–43.
doi: 10.1038/s41380-023-02227-4
pubmed: 37674019
pmcid: 10827664
Jakobsen JC, Gluud C, Wetterslev J, Winkel P. When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts. BMC Med Res Methodol. 2017;17(1):162.
pubmed: 29207961
pmcid: 5717805
doi: 10.1186/s12874-017-0442-1
Waschbusch DA, Cunningham CE, Pelham WE, Rimas HL, Greiner AR, Gnagy EM, et al. A discrete choice conjoint experiment to evaluate parent preferences for treatment of young, medication naive children with ADHD. J Clin Child Adolesc Psychol. 2011;40(4):546–61.
pubmed: 21722027
pmcid: 3982876
doi: 10.1080/15374416.2011.581617
Wang G-J, Volkow ND, Wigal T, Kollins SH, Newcorn JH, Telang F, et al. Long-Term Stimulant Treatment Affects Brain Dopamine Transporter Level in Patients with Attention Deficit Hyperactive Disorder. Plos One. 2013;8(5):e63023.
pubmed: 23696790
pmcid: 3655054
doi: 10.1371/journal.pone.0063023
Swanson JM. Debate: Are Stimulant Medications for Attention-Deficit/Hyperactivity Disorder Effective in the Long Term? (Against). J Am Acad Child Adolesc Psychiatry. 2019;58(10):936–8.
pubmed: 31515165
doi: 10.1016/j.jaac.2019.07.001
Loo SK, Salgari GC, Ellis A, Cowen J, Dillon A, McGough JJ. Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder: Cognitive and Electroencephalographic Predictors of Treatment Response. J Am Acad Child Adolesc Psychiatry. 2021;60(7):856-64.e1.
pubmed: 33068751
doi: 10.1016/j.jaac.2020.09.021
Joshi S, Li Y, Kalwani RM, Gold JI. Relationships between Pupil Diameter and Neuronal Activity in the Locus Coeruleus, Colliculi, and Cingulate Cortex. Neuron. 2016;89(1):221–34.
pubmed: 26711118
doi: 10.1016/j.neuron.2015.11.028
Aston-Jones G, Waterhouse B. Locus coeruleus: From global projection system to adaptive regulation of behavior. Brain Res. 2016;1645:75–8.
pubmed: 26969408
pmcid: 4969192
doi: 10.1016/j.brainres.2016.03.001
De Cicco V, Tramonti Fantozzi MP, Cataldo E, Barresi M, Bruschini L, Faraguna U, Manzoni D. Trigeminal, Visceral and Vestibular Inputs May Improve Cognitive Functions by Acting through the Locus Coeruleus and the Ascending Reticular Activating System: A New Hypothesis. Front Neuroanat. 2017;11:130.
pubmed: 29358907
doi: 10.3389/fnana.2017.00130
Sara SJ, Bouret S. Orienting and reorienting: the locus coeruleus mediates cognition through arousal. Neuron. 2012;76(1):130–41.
pubmed: 23040811
doi: 10.1016/j.neuron.2012.09.011
Bellato A, Arora I, Hollis C, Groom MJ. Is autonomic nervous system function atypical in Attention Deficit Hyperactivity Disorder (ADHD)? A systematic review of the evidence. Neurosci Biobehav Rev. 2020;108:182–206.
pubmed: 31722229
doi: 10.1016/j.neubiorev.2019.11.001
Di Lenola D, Coppola G, Serrao M, Di Lorenzo C, Pierelli F. O024.Transcutaneous supraorbital nerve stimulation enhances somatosensory thalamic activity in migraine between attacks: a central mechanism of clinical efficacy? J Headache Pain. 2015;16(Suppl 1):160.
doi: 10.1186/1129-2377-16-S1-A160
Willoch F, Gamringer U, Medele R, Steude U, Tolle TR. Analgesia by electrostimulation of the trigeminal ganglion in patients with trigeminopathic pain: a PET activation study. Pain. 2003;103(1–2):119–30.
pubmed: 12749966
doi: 10.1016/s0304-3959(02)00423-2
Magis D, D’Ostilio K, Thibaut A, De Pasqua V, Gerard P, Hustinx R, et al. Cerebral metabolism before and after external trigeminal nerve stimulation in episodic migraine. Cephalalgia. 2017;37(9):881–91.
pubmed: 27342225
doi: 10.1177/0333102416656118
Russo A, Tessitore A, Esposito F, Marcuccio L, Giordano A, Conforti R, et al. Pain processing in patients with migraine: an event-related fMRI study during trigeminal nociceptive stimulation. J Neurol. 2012;259(9):1903–12.
pubmed: 22349864
doi: 10.1007/s00415-012-6438-1
Kovacs S, Peeters R, De Ridder D, Plazier M, Menovsky T, Sunaert S. Central effects of occipital nerve electrical stimulation studied by functional magnetic resonance imaging. Neuromodulation. 2011;14(1):46–55 (discussion 6-7).
pubmed: 21992162
doi: 10.1111/j.1525-1403.2010.00312.x