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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., Competing Interests: Competing interests: DRC has received grants and personal fees from Shire Pharmaceutical Company and Vifor Pharma; personal fees from Janssen-Cilag, Eli Lilly, Novartis, Flynn Pharma, Medice Arzneimittel Pütter and Oxford University Press outside the submitted work. All other authors declare that they have no competing interests., (© 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.)

This study reviewed evidence for cognitive impairments in trauma-exposed children with and without PTSD. Twenty-seven studies were eligible for meta-analysis, totalling 1526 participants, including 412 trauma-exposed children (PTSD unknown), 300 children with PTSD (PTSD+), 323 children without PTSD (PTSD-), and 491 trauma-naive controls. Eligible studies mostly investigated familial-maltreatment trauma ( k = 22). Trauma-exposed children (PTSD unknown) performed more poorly overall than controls ( d = −0.57). Cognitive deficits were seen in PTSD+ compared to controls, including a large effect size (ES) for general intelligence ( d = −0.88), moderate ESs for language/verbal ( d = −0.65), visuospatial ( d = −0.53), information processing ( d = −0.62), learning and memory ( d = −0.67), and executive skills ( d = −0.52). PTSD+ showed poorer general intelligence ( d = −0.28) and visuospatial skills ( d = −0.42) compared to PTSD-, whilst PTSD- showed poorer executive function ( d = −0.23) and learning and memory ( d = −0.61) compared to controls. In conclusion, trauma-exposed children showed cognitive deficits compared to controls, although greatest deficits were associated with PTSD diagnosis. [ABSTRACT FROM AUTHOR]