Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1: a study protocol for a randomised placebo-controlled crossover trial

Natalie A Pride, Belinda Barton, Paul Hutchins, David R Coghill, Mayuresh S Korgaonkar, Stephen J C Hearps, Melissa Rouel, Stephanie Malarbi, Kathryn N North, Jonathan M Payne

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    Abstract

    INTRODUCTION: Dopamine dysregulation has been identified as a key modulator of behavioural impairment in neurofibromatosis type 1 (NF1) and a potential therapeutic target. Preclinical research demonstrates reduced dopamine in the brains of genetically engineered NF1 mouse strains is associated with reduced spatial-learning and attentional dysfunction. Methylphenidate, a stimulant medication that increases dopaminergic and noradrenergic neurotransmission, rescued the behavioural and dopamine abnormalities. Although preliminary clinical trials have demonstrated that methylphenidate is effective in treating attention deficit hyperactivity disorder (ADHD) symptoms in children with NF1, its therapeutic effect on cognitive performance is unclear. The primary aim of this clinical trial is to assess the efficacy of methylphenidate for reducing attention deficits, spatial working memory impairments and ADHD symptoms in children with NF1.

    METHODS AND ANALYSIS: A randomised, double-blind, placebo-controlled trial of methylphenidate with a two period crossover design. Thirty-six participants with NF1 aged 7-16 years will be randomised to one of two treatment sequences: 6 weeks of methylphenidate followed by 6 weeks of placebo or; 6 weeks of placebo followed by 6 weeks of methylphenidate. Neurocognitive and behavioural outcomes as well as neuroimaging measures will be completed at baseline and repeated at the end of each treatment condition (week 6, week 12). Primary outcome measures are omission errors on the Conners Continuous Performance Test-II (attention), between-search errors on the Spatial Working Memory task from the Cambridge Neuropsychological Test Automated Battery (spatial working memory) and the Inattentive and Hyperactivity/Impulsivity Symptom Scales on the Conners 3-Parent. Secondary outcomes will examine the effect of methylphenidate on executive functions, attention, visuospatial skills, behaviour, fine-motor skills, language, social skills and quality of life.

    ETHICS AND DISSEMINATION: This trial has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.

    TRIAL REGISTRATION NUMBER: ACTRN12611000765921.

    Original languageEnglish
    Pages (from-to)e021800
    JournalBMJ Open
    Volume8
    Issue number8
    DOIs
    Publication statusPublished - 30 Aug 2018

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    Methylphenidate
    Neurofibromatosis 1
    Child Behavior
    Cross-Over Studies
    Cognition
    Placebos
    Short-Term Memory
    Dopamine
    Attention Deficit Disorder with Hyperactivity
    Institutional Ethics
    Clinical Trials
    Motor Skills
    Impulsive Behavior
    Neuropsychological Tests
    Executive Function
    Therapeutic Uses
    Neuroimaging
    Synaptic Transmission
    Publications
    Language

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    Pride, Natalie A ; Barton, Belinda ; Hutchins, Paul ; Coghill, David R ; Korgaonkar, Mayuresh S ; Hearps, Stephen J C ; Rouel, Melissa ; Malarbi, Stephanie ; North, Kathryn N ; Payne, Jonathan M. / Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1 : a study protocol for a randomised placebo-controlled crossover trial. In: BMJ Open. 2018 ; Vol. 8, No. 8. pp. e021800.
    @article{75f5978a55bd4caeb08565ad84bd5893,
    title = "Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1: a study protocol for a randomised placebo-controlled crossover trial",
    abstract = "INTRODUCTION: Dopamine dysregulation has been identified as a key modulator of behavioural impairment in neurofibromatosis type 1 (NF1) and a potential therapeutic target. Preclinical research demonstrates reduced dopamine in the brains of genetically engineered NF1 mouse strains is associated with reduced spatial-learning and attentional dysfunction. Methylphenidate, a stimulant medication that increases dopaminergic and noradrenergic neurotransmission, rescued the behavioural and dopamine abnormalities. Although preliminary clinical trials have demonstrated that methylphenidate is effective in treating attention deficit hyperactivity disorder (ADHD) symptoms in children with NF1, its therapeutic effect on cognitive performance is unclear. The primary aim of this clinical trial is to assess the efficacy of methylphenidate for reducing attention deficits, spatial working memory impairments and ADHD symptoms in children with NF1.METHODS AND ANALYSIS: A randomised, double-blind, placebo-controlled trial of methylphenidate with a two period crossover design. Thirty-six participants with NF1 aged 7-16 years will be randomised to one of two treatment sequences: 6 weeks of methylphenidate followed by 6 weeks of placebo or; 6 weeks of placebo followed by 6 weeks of methylphenidate. Neurocognitive and behavioural outcomes as well as neuroimaging measures will be completed at baseline and repeated at the end of each treatment condition (week 6, week 12). Primary outcome measures are omission errors on the Conners Continuous Performance Test-II (attention), between-search errors on the Spatial Working Memory task from the Cambridge Neuropsychological Test Automated Battery (spatial working memory) and the Inattentive and Hyperactivity/Impulsivity Symptom Scales on the Conners 3-Parent. Secondary outcomes will examine the effect of methylphenidate on executive functions, attention, visuospatial skills, behaviour, fine-motor skills, language, social skills and quality of life.ETHICS AND DISSEMINATION: This trial has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.TRIAL REGISTRATION NUMBER: ACTRN12611000765921.",
    author = "Pride, {Natalie A} and Belinda Barton and Paul Hutchins and Coghill, {David R} and Korgaonkar, {Mayuresh S} and Hearps, {Stephen J C} and Melissa Rouel and Stephanie Malarbi and North, {Kathryn N} and Payne, {Jonathan M}",
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    Pride, NA, Barton, B, Hutchins, P, Coghill, DR, Korgaonkar, MS, Hearps, SJC, Rouel, M, Malarbi, S, North, KN & Payne, JM 2018, 'Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1: a study protocol for a randomised placebo-controlled crossover trial', BMJ Open, vol. 8, no. 8, pp. e021800. https://doi.org/10.1136/bmjopen-2018-021800

    Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1 : a study protocol for a randomised placebo-controlled crossover trial. / Pride, Natalie A; Barton, Belinda; Hutchins, Paul; Coghill, David R; Korgaonkar, Mayuresh S; Hearps, Stephen J C; Rouel, Melissa; Malarbi, Stephanie; North, Kathryn N; Payne, Jonathan M.

    In: BMJ Open, Vol. 8, No. 8, 30.08.2018, p. e021800.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1

    T2 - a study protocol for a randomised placebo-controlled crossover trial

    AU - Pride, Natalie A

    AU - Barton, Belinda

    AU - Hutchins, Paul

    AU - Coghill, David R

    AU - Korgaonkar, Mayuresh S

    AU - Hearps, Stephen J C

    AU - Rouel, Melissa

    AU - Malarbi, Stephanie

    AU - North, Kathryn N

    AU - Payne, Jonathan M

    N1 - © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

    PY - 2018/8/30

    Y1 - 2018/8/30

    N2 - INTRODUCTION: Dopamine dysregulation has been identified as a key modulator of behavioural impairment in neurofibromatosis type 1 (NF1) and a potential therapeutic target. Preclinical research demonstrates reduced dopamine in the brains of genetically engineered NF1 mouse strains is associated with reduced spatial-learning and attentional dysfunction. Methylphenidate, a stimulant medication that increases dopaminergic and noradrenergic neurotransmission, rescued the behavioural and dopamine abnormalities. Although preliminary clinical trials have demonstrated that methylphenidate is effective in treating attention deficit hyperactivity disorder (ADHD) symptoms in children with NF1, its therapeutic effect on cognitive performance is unclear. The primary aim of this clinical trial is to assess the efficacy of methylphenidate for reducing attention deficits, spatial working memory impairments and ADHD symptoms in children with NF1.METHODS AND ANALYSIS: A randomised, double-blind, placebo-controlled trial of methylphenidate with a two period crossover design. Thirty-six participants with NF1 aged 7-16 years will be randomised to one of two treatment sequences: 6 weeks of methylphenidate followed by 6 weeks of placebo or; 6 weeks of placebo followed by 6 weeks of methylphenidate. Neurocognitive and behavioural outcomes as well as neuroimaging measures will be completed at baseline and repeated at the end of each treatment condition (week 6, week 12). Primary outcome measures are omission errors on the Conners Continuous Performance Test-II (attention), between-search errors on the Spatial Working Memory task from the Cambridge Neuropsychological Test Automated Battery (spatial working memory) and the Inattentive and Hyperactivity/Impulsivity Symptom Scales on the Conners 3-Parent. Secondary outcomes will examine the effect of methylphenidate on executive functions, attention, visuospatial skills, behaviour, fine-motor skills, language, social skills and quality of life.ETHICS AND DISSEMINATION: This trial has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.TRIAL REGISTRATION NUMBER: ACTRN12611000765921.

    AB - INTRODUCTION: Dopamine dysregulation has been identified as a key modulator of behavioural impairment in neurofibromatosis type 1 (NF1) and a potential therapeutic target. Preclinical research demonstrates reduced dopamine in the brains of genetically engineered NF1 mouse strains is associated with reduced spatial-learning and attentional dysfunction. Methylphenidate, a stimulant medication that increases dopaminergic and noradrenergic neurotransmission, rescued the behavioural and dopamine abnormalities. Although preliminary clinical trials have demonstrated that methylphenidate is effective in treating attention deficit hyperactivity disorder (ADHD) symptoms in children with NF1, its therapeutic effect on cognitive performance is unclear. The primary aim of this clinical trial is to assess the efficacy of methylphenidate for reducing attention deficits, spatial working memory impairments and ADHD symptoms in children with NF1.METHODS AND ANALYSIS: A randomised, double-blind, placebo-controlled trial of methylphenidate with a two period crossover design. Thirty-six participants with NF1 aged 7-16 years will be randomised to one of two treatment sequences: 6 weeks of methylphenidate followed by 6 weeks of placebo or; 6 weeks of placebo followed by 6 weeks of methylphenidate. Neurocognitive and behavioural outcomes as well as neuroimaging measures will be completed at baseline and repeated at the end of each treatment condition (week 6, week 12). Primary outcome measures are omission errors on the Conners Continuous Performance Test-II (attention), between-search errors on the Spatial Working Memory task from the Cambridge Neuropsychological Test Automated Battery (spatial working memory) and the Inattentive and Hyperactivity/Impulsivity Symptom Scales on the Conners 3-Parent. Secondary outcomes will examine the effect of methylphenidate on executive functions, attention, visuospatial skills, behaviour, fine-motor skills, language, social skills and quality of life.ETHICS AND DISSEMINATION: This trial has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.TRIAL REGISTRATION NUMBER: ACTRN12611000765921.

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    DO - 10.1136/bmjopen-2018-021800

    M3 - Article

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    SP - e021800

    JO - BMJ Open

    JF - BMJ Open

    SN - 2044-6055

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