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TY - JOUR

T1 - Brainmarker-I Differentially Predicts Remission to Various Attention-Deficit/Hyperactivity Disorder Treatments

T2 - A Discovery, Transfer, and Blinded Validation Study

AU - Voetterl, Helena

AU - van Wingen, Guido

AU - Michelini, Giorgia

AU - Griffiths, Kristi R.

AU - Gordon, Evian

AU - DeBeus, Roger

AU - Korgaonkar, Mayuresh S.

AU - Loo, Sandra K.

AU - Palmer, Donna

AU - Breteler, Rien

AU - Denys, Damiaan

AU - Arnold, L. Eugene

AU - du Jour, Paul

AU - van Ruth, Rosalinde

AU - Jansen, Jeanine

AU - van Dijk, Hanneke

AU - Arns, Martijn

N1 - Funding Information: KRG and MSK have received research funding from Takeda Pharmaceutical Company (Japan) and Shire (Australia) for work unrelated to that presented in this manuscript. EG is founder and receives income as Chief Executive Officer and Chairman for Brain Resource Ltd. He has stock options in Brain Resource Ltd. RD has received research funding from the National Institute of Mental Health, has served on the Board of Directors for the International Society for Neurofeedback and Research, and has a clinic in North Carolina where he performs neurofeedback, among other clinical services. DP has received income and stock options with the role of science and data processing manager as an employee with Brain Resource Ltd. RB is the owner of EEG Resource, a neurofeedback/psychology practice. LEA has received research funding from Axial, Curemark, Forest, Lilly, Myndlift, Neuropharm, Novartis, Noven, Otsuka, Roche/Genentech, Shire, Ethiopia, Supernus, and YoungLiving (as well as the National Institutes of Health and Autism Speaks); has consulted with CHADD Publishing, Neuropharm, Organon, Pfizer, Sigma-Tau, Shire, Ethiopia, Tris Pharma, and Waypoint; and has been on advisory boards for Arbor, Ironshore, Novartis, Noven, Otsuka, Pfizer, Roche, Seaside Therapeutics, and Sigma-Tau. RvR holds stock in neuroCare Group AG. MA is an unpaid chairman of the nonprofit Brainclinics Foundation, a minority shareholder in neuroCare Group (Munich, Germany), and a coinventor on four patent applications related to electroencephalography, neuromodulation, and psychophysiology but receives no royalties related to these patents; Research Institute Brainclinics received research and consultancy funding from neuroCare Group (Munich, Germany), Brainify.ai (United States), and Urgotech (France) and equipment support from Deymed, neuroConn, and Magventure. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: We would like to express our gratitude to Mark Koppenberg for the design and editing of figures and tables. A previous version of this article was published as a preprint on Research Square: https://www.researchsquare.com/article/rs-736917/v1. KRG and MSK have received research funding from Takeda Pharmaceutical Company (Japan) and Shire (Australia) for work unrelated to that presented in this manuscript. EG is founder and receives income as Chief Executive Officer and Chairman for Brain Resource Ltd. He has stock options in Brain Resource Ltd. RD has received research funding from the National Institute of Mental Health, has served on the Board of Directors for the International Society for Neurofeedback and Research, and has a clinic in North Carolina where he performs neurofeedback, among other clinical services. DP has received income and stock options with the role of science and data processing manager as an employee with Brain Resource Ltd. RB is the owner of EEG Resource, a neurofeedback/psychology practice. LEA has received research funding from Axial, Curemark, Forest, Lilly, Myndlift, Neuropharm, Novartis, Noven, Otsuka, Roche/Genentech, Shire, Ethiopia, Supernus, and YoungLiving (as well as the National Institutes of Health and Autism Speaks); has consulted with CHADD Publishing, Neuropharm, Organon, Pfizer, Sigma-Tau, Shire, Ethiopia, Tris Pharma, and Waypoint; and has been on advisory boards for Arbor, Ironshore, Novartis, Noven, Otsuka, Pfizer, Roche, Seaside Therapeutics, and Sigma-Tau. RvR holds stock in neuroCare Group AG. MA is an unpaid chairman of the nonprofit Brainclinics Foundation, a minority shareholder in neuroCare Group (Munich, Germany), and a coinventor on four patent applications related to electroencephalography, neuromodulation, and psychophysiology but receives no royalties related to these patents; Research Institute Brainclinics received research and consultancy funding from neuroCare Group (Munich, Germany), Brainify.ai (United States), and Urgotech (France) and equipment support from Deymed, neuroConn, and Magventure. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2022 Society of Biological Psychiatry

PY - 2023/1

Y1 - 2023/1

N2 - Background: Attention-deficit/hyperactivity disorder is characterized by neurobiological heterogeneity, possibly explaining why not all patients benefit from a given treatment. As a means to select the right treatment (stratification), biomarkers may aid in personalizing treatment prescription, thereby increasing remission rates. Methods: The biomarker in this study was developed in a heterogeneous clinical sample (N = 4249) and first applied to two large transfer datasets, a priori stratifying young males (<18 years) with a higher individual alpha peak frequency (iAPF) to methylphenidate (N = 336) and those with a lower iAPF to multimodal neurofeedback complemented with sleep coaching (N = 136). Blinded, out-of-sample validations were conducted in two independent samples. In addition, the association between iAPF and response to guanfacine and atomoxetine was explored. Results: Retrospective stratification in the transfer datasets resulted in a predicted gain in normalized remission of 17% to 30%. Blinded out-of-sample validations for methylphenidate (n = 41) and multimodal neurofeedback (n = 71) corroborated these findings, yielding a predicted gain in stratified normalized remission of 36% and 29%, respectively. Conclusions: This study introduces a clinically interpretable and actionable biomarker based on the iAPF assessed during resting-state electroencephalography. Our findings suggest that acknowledging neurobiological heterogeneity can inform stratification of patients to their individual best treatment and enhance remission rates.

AB - Background: Attention-deficit/hyperactivity disorder is characterized by neurobiological heterogeneity, possibly explaining why not all patients benefit from a given treatment. As a means to select the right treatment (stratification), biomarkers may aid in personalizing treatment prescription, thereby increasing remission rates. Methods: The biomarker in this study was developed in a heterogeneous clinical sample (N = 4249) and first applied to two large transfer datasets, a priori stratifying young males (<18 years) with a higher individual alpha peak frequency (iAPF) to methylphenidate (N = 336) and those with a lower iAPF to multimodal neurofeedback complemented with sleep coaching (N = 136). Blinded, out-of-sample validations were conducted in two independent samples. In addition, the association between iAPF and response to guanfacine and atomoxetine was explored. Results: Retrospective stratification in the transfer datasets resulted in a predicted gain in normalized remission of 17% to 30%. Blinded out-of-sample validations for methylphenidate (n = 41) and multimodal neurofeedback (n = 71) corroborated these findings, yielding a predicted gain in stratified normalized remission of 36% and 29%, respectively. Conclusions: This study introduces a clinically interpretable and actionable biomarker based on the iAPF assessed during resting-state electroencephalography. Our findings suggest that acknowledging neurobiological heterogeneity can inform stratification of patients to their individual best treatment and enhance remission rates.

KW - ADHD

KW - Biomarker

KW - EEG

KW - Stratified psychiatry

UR - http://www.scopus.com/inward/record.url?scp=85129935066&partnerID=8YFLogxK

U2 - 10.1016/j.bpsc.2022.02.007

DO - 10.1016/j.bpsc.2022.02.007

M3 - Article

C2 - 35240343

VL - 8

SP - 52

EP - 60

JO - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

JF - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

SN - 2451-9022

IS - 1

ER -