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      Limited usefulness of neurocognitive functioning indices as predictive markers for treatment response to methylphenidate or neurofeedback@home in children and adolescents with ADHD

      1 , * , , 1 , 2 , 3 , 4 , 5 , 1 , 1 , 6 , 7 , 8 , 4 , 9 , 6 , 1 , 7 , 1 , 10 , 11 , 9 , 9 , 9 , 12 , 13 , 6 , 14 , 15 , 1 , 9 , 16 , 17
      Frontiers in Psychiatry
      Frontiers Media S.A.
      neurocognitive functioning, executive functions, ADHD, predictive marker, treatment marker, methylphenidate, neurofeedback

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          Earlier studies exploring the value of executive functioning (EF) indices for assessing treatment effectiveness and predicting treatment response in attention-deficit/hyperactivity disorder (ADHD) mainly focused on pharmacological treatment options and revealed rather heterogeneous results. Envisioning the long-term goal of personalized treatment selection and intervention planning, this study comparing methylphenidate treatment (MPH) and a home-based neurofeedback intervention (NF@Home) aimed to expand previous findings by assessing objective as well as subjectively reported EF indices and by analyzing their value as treatment and predictive markers.


          Children and adolescents ( n = 146 in the per protocol sample) aged 7–13 years with a formal diagnosis of an inattentive or combined presentation of ADHD were examined. We explored the EF performance profile using the Conners Continuous Performance Task (CPT) and the BRIEF self-report questionnaire within our prospective, multicenter, randomized, reference drug-controlled NEWROFEED study with sites in five European countries (France, Spain, Switzerland, Germany, and Belgium). As primary outcome for treatment response, the clinician-rated ADHD Rating Scale-IV was used. Patients participating in this non-inferiority trial were randomized to either NF@home (34–40 sessions of TBR or SMR NF depending on the pre-assessed individual alpha peak frequency) or MPH treatment (ratio: 3:2). Within a mixed-effects model framework, analyses of change were calculated to explore the predictive value of neurocognitive indices for ADHD symptom-related treatment response.


          For a variety of neurocognitive indices, we found a significant pre-post change during treatment, mainly in the MPH group. However, the results of the current study reveal a rather limited prognostic value of neurocognitive indices for treatment response to either NF@Home or MPH treatment. Some significant effects emerged for parent-ratings only.


          Current findings indicate a potential value of self-report (BRIEF global score) and some objectively measured neurocognitive indices (CPT commission errors and hit reaction time variability) as treatment markers (of change) for MPH. However, we found a rather limited prognostic value with regard to predicting treatment response not (yet) allowing recommendation for clinical use. Baseline symptom severity was revealed as the most relevant predictor, replicating robust findings from previous studies.

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          Most cited references70

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          Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents.

          The literature on the prevalence of mental disorders affecting children and adolescents has expanded significantly over the last three decades around the world. Despite the field having matured significantly, there has been no meta-analysis to calculate a worldwide-pooled prevalence and to empirically assess the sources of heterogeneity of estimates.
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            Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data.

            To describe the psychometric properties of the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL) interview, which surveys additional disorders not assessed in prior K-SADS, contains improved probes and anchor points, includes diagnosis-specific impairment ratings, generates DSM-III-R and DSM-IV diagnoses, and divides symptoms surveyed into a screening interview and five diagnostic supplements. Subjects were 55 psychiatric outpatients and 11 normal controls (aged 7 through 17 years). Both parents and children were used as informants. Concurrent validity of the screen criteria and the K-SADS-PL diagnoses was assessed against standard self-report scales. Interrater (n = 15) and test-retest (n = 20) reliability data were also collected (mean retest interval: 18 days; range: 2 to 36 days). Rating scale data support the concurrent validity of screens and K-SADS-PL diagnoses. Interrater agreement in scoring screens and diagnoses was high (range: 93% to 100%). Test-retest reliability kappa coefficients were in the excellent range for present and/or lifetime diagnoses of major depression, any bipolar, generalized anxiety, conduct, and oppositional defiant disorder (.77 to 1.00) and in the good range for present diagnoses of posttraumatic stress disorder and attention-deficit hyperactivity disorder (.63 to .67). Results suggest the K-SADS-PL generates reliable and valid child psychiatric diagnoses.
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              Attention-deficit hyperactivity disorder.

              Attention-deficit hyperactivity disorder (ADHD) is a disorder of inattention, impulsivity, and hyperactivity that affects 8-12% of children worldwide. Although the rate of ADHD falls with age, at least half of children with the disorder will have impairing symptoms in adulthood. Twin, adoption, and molecular genetic studies show ADHD to be highly heritable, and other findings have recorded obstetric complications and psychosocial adversity as predisposing risk factors. Converging evidence from animal and human studies implicates the dysregulation of frontal-subcortical-cerebellar catecholaminergic circuits in the pathophysiology of ADHD, and molecular imaging studies suggest that abnormalities of the dopamine transporter lead to impaired neurotransmission. Studies during the past decade have shown the safety and effectiveness of new non-stimulant drugs and long-acting formulations of methylphenidate and amfetamine. Other investigations have also clarified the appropriate role of targeted psychosocial treatments in the context of ongoing pharmacotherapy.

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                Front Psychiatry
                Front Psychiatry
                Front. Psychiatry
                Frontiers in Psychiatry
                Frontiers Media S.A.
                12 January 2024
                : 14
                : 1331004
                [1] 1Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University , Mannheim, Germany
                [2] 2UNIR Health Sciences School and Medical Center and UNIR-itei, CIBERSAM , Madrid, Spain
                [3] 3Department of Neuroscience, Campus Biotech CISA-Université de Genève , Genève, Switzerland
                [4] 4Child and Adolescent Psychiatry Department and Child Brain Institute, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris and Universite Paris Cite , Paris, France
                [5] 5myBrain Technologies , Paris, France
                [6] 6Unit of Child and Adolescent Psychiatry (MPEA1), CHU Montpellier-Saint Eloi Hospital, University of Montpellier , Montpellier, France
                [7] 7Mensia Technologies , Paris, France
                [8] 8Child and Adolescent Psychiatry, Erasme Academic Hospital, Université Libre de Bruxelles , Bruxelles, Belgium
                [9] 9Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich , Zurich, Switzerland
                [10] 10Clinique des Grangettes, Chêne-Bougeries , Geneva, Switzerland
                [11] 11Unit of Child and Adolescent Psychiatry, Hospices civils de Lyon, Hôpital Femme Mère Enfant , Bron Cedex, France
                [12] 12SANPSY, USR 3413, CNRS , Bordeaux, France
                [13] 13Clinique du Sommeil, CHU Pellegrin , Bordeaux Cedex, France
                [14] 14Development and Trajectories, INSERM CESP U 1018 Psychiatry , Montpellier, France
                [15] 15CESP, INSERM U 1018, Paul Brousse Hospital , Villejuif, France
                [16] 16Neuroscience Center Zurich, University of Zurich and ETH Zurich , Zurich, Switzerland
                [17] 17Zurich Center for Integrative Human Physiology, University of Zurich , Zurich, Switzerland
                Author notes

                Edited by: Charlotte Lotta Borg Skoglund, Uppsala University, Sweden

                Reviewed by: Luke Norman, National Institute of Mental Health (NIH), United States

                Sergio Luis Schmidt, Rio de Janeiro State Federal University, Brazil

                *Correspondence: Anna Kaiser, anna.kaiser@ 123456zi-mannheim.de
                Copyright © 2024 Kaiser, Aggensteiner, Blasco Fontecilla, Ros, Acquaviva, Attal, Banaschewski, Baumeister, Bousquet, Bussalb, Delhaye, Delorme, Drechsler, Goujon, Häge, Mayaud, Mechler, Menache, Revol, Tagwerker, Walitza, Werling, Bioulac, Purper-Ouakil and Brandeis.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 31 October 2023
                : 29 December 2023
                Page count
                Figures: 6, Tables: 2, Equations: 0, References: 70, Pages: 14, Words: 10176
                Funded by: EU H2020
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. AB reports grants from EU H2020 SME research and innovation grant N°684,809 during the conduct of the study. HB is the recipient of a MINECO grant (2019–2021). In 2019, he was the recipient of a PHUH intensification grant. He also received funding from a clinical trial sponsored by Janssen (ESKETINSUI2002). LM reports grants from EC H2020 SME Biomarker and personal fees from Mensia Technologies during the conduct of the study. SW’s work was supported in the last years by the Swiss National Science Foundation (SNF), diff. EU FP7s, HSM Hochspezialisierte Medizin of the Kanton Zurich, Switzerland, Bfarm Germany, ZInEP, Hartmann Müller Stiftung, Olga Mayenfisch, Gertrud Thalmann, Vontobel, Unicentia, Erika Schwarz, Heuberg Fonds, National Government of Health (BAG), Gesundheitsförderung Schweiz and Horizon Europe. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.
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                Clinical Psychology & Psychiatry
                neurocognitive functioning,executive functions,adhd,predictive marker,treatment marker,methylphenidate,neurofeedback


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