Neuropsychological factors associated with performance on the rey-osterrieth complex figure test in children with neurofibromatosis type 1.

Children with neurofibromatosis type 1 (NF1) are at considerable risk for cognitive difficulties, including visuospatial deficits and executive dysfunction. This study aimed to (1) assess the overall performance of children with NF1 on the Rey-Osterrieth Complex Figure Test (RCFT) compared to unaffected siblings and (2) examine neuropsychological predictors of RCFT performance in children with NF1. A retrospective clinical audit was performed on neuropsychological records from a multidisciplinary NF1 Clinic in Australia. We searched for children that had completed an assessment between 2000 and 2015 which included the RCFT and other neuropsychological outcomes in this study. These included the Wechsler Intelligence Scale for Children, Judgment of Line Orientation (JLO), Tower of London test, Conners ADHD Scales, and the Behavioral Rating Inventory of Executive Function (BRIEF). The study population consisted of 191 children with NF1 aged 6-16 years, and 55 unaffected siblings recruited from a separate study. Results revealed that 62% of children with NF1 performed at or below the first percentile on the RCFT copy, which was significantly worse than their unaffected siblings. Visuospatial skills, parent-rated executive abilities, ADHD symptoms, and intellectual skills all predicted poorer performance on the RCFT copy, however the best fitting multiple regression model only contained the JLO, BRIEF Metacognition Index, and chronological age. The JLO emerged as the strongest predictor of RCFT performance. This study provides evidence that visuospatial deficits are a key driver of reduced RCFT performance in NF1 and that executive skills as well as a younger age are also independent predictors of RCFT performance.

Sensory Processing in Children and Adolescents with Neurofibromatosis Type 1.

Despite the evidence of elevated autistic behaviors and co-occurring neurodevelopmental difficulties in many children with neurofibromatosis type 1 (NF1), we have a limited understanding of the sensory processing challenges that may occur with the condition. This study examined the sensory profile of children and adolescents with NF1 and investigated the relationships between the sensory profiles and patient characteristics and neuropsychological functioning. The parent/caregivers of 152 children with NF1 and 96 typically developing children completed the Sensory Profile 2 (SP2), along with standardized questionnaires assessing autistic behaviors, ADHD symptoms, internalizing symptoms, adaptive functioning, and social skills. Intellectual functioning was also assessed. The SP2 data indicated elevated sensory processing problems in children with NF1 compared to typically developing children. Over 40% of children with NF1 displayed differences in sensory registration (missing sensory input) and were unusually sensitive to and unusually avoidant of sensory stimuli. Sixty percent of children with NF1 displayed difficulties in one or more sensory modalities. Elevated autistic behaviors and ADHD symptoms were associated with more severe sensory processing difficulties. This first detailed assessment of sensory processing, alongside other clinical features, in a relatively large cohort of children and adolescents with NF1 demonstrates the relationships between sensory processing differences and adaptive skills and behavior, as well as psychological well-being. Our characterization of the sensory profile within a genetic syndrome may help facilitate more targeted interventions to support overall functioning.

Understanding nonliteral language abilities in children with neurofibromatosis type 1.

OBJECTIVE: Neurofibromatosis Type 1 (NF1) is a genetic syndrome that affects cognitive, behavioral, and social development. Nonliteral language (NLL) comprehension has not been examined in children with NF1. This study examined NLL comprehension in children with NF1 and associated neuropsychological correlates. METHOD: NLL comprehension was examined in children with NF1 (n = 49) and typically developing (TD) controls (n = 27) aged 4-12 years using a novel NLL task. The task assessed comprehension of sarcasm, metaphor, simile, and literal language. Cognitive (Wechsler Scales Composites or the Woodcock-Johnson Test of Cognitive Abilities Revised scaled scores) and behavioral (attention deficit hyperactivity disorder [ADHD] symptoms) correlates of NLL comprehension in children with NF1 were also examined. RESULTS: Children with NF1 demonstrated significantly poorer sarcasm comprehension than TD children and a vulnerability in metaphor comprehension. Simile and literal language comprehension were not significantly different between groups. Working memory difficulties and impulsive/hyperactive ADHD symptoms were associated with a reduced ability to identify sarcasm in NF1, while verbal comprehension, fluid reasoning, and inattentive ADHD symptoms were not. CONCLUSIONS: Results suggest children with NF1 experience challenges in understanding complex NLL comprehension, which are related to reduced working memory and increased impulsivity/hyperactivity. This study provides an initial insight into the figurative language abilities of children with NF1, which should be examined in relation to their social difficulties in future studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Delineating Visual Habituation Profiles in Preschoolers with Neurofibromatosis Type 1 and Autism Spectrum Disorder: A Cross-Syndrome Study.

Atypical habituation to repetitive information has been commonly reported in Autism Spectrum Disorder (ASD) but it is not yet clear whether similar abnormalities are present in Neurofibromatosis Type 1 (NF1). We employed a cross-syndrome design using a novel eye tracking paradigm to measure habituation in preschoolers with NF1, children with idiopathic ASD and typically developing (TD) children. Eye movements were recorded to examine fixation duration to simultaneously presented repeating and novel stimuli. Children with NF1 showed a bias for longer look durations to repeating stimuli at the expense of novel stimuli, and slower habituation in NF1 was associated with elevated ASD traits. These findings could indicate aberrant modulation of bottom-up attentional networks that interact with the emergence of ASD phenotypes.

Sex- and age-related differences in autistic behaviours in children with neurofibromatosis type 1.

This study investigated sex and age differences in autistic behaviours in children with neurofibromatosis type 1 (NF1) who scored within the clinical range on the Social Responsiveness Scale - Second Edition (T score ≥ 60). Thirty-four males and 28 females (3-16 years) were assessed with the Autism Diagnostic Observation Schedule - Second Edition and Autism Diagnostic Interview - Revised. Across both measures, males exhibited greater social communication deficits relative to females. Age-related abatement of social communication difficulties was observed for males but not females. Conversely, no sex differences were found for restricted/repetitive behaviours, which were stable over time for both males and females. The findings are discussed within the context of broader neurodevelopmental considerations that are common in NF1.

A randomized controlled trial of remote microphone listening devices to treat auditory deficits in children with neurofibromatosis type 1.

BACKGROUND: A high proportion of patients with neurofibromatosis type 1 (NF1) present with functional hearing deficiency as a result of neural abnormality in the late auditory brainstem. METHODS: In this randomized, two-period crossover study, we investigated the hypothesis that remote-microphone listening devices can ameliorate hearing and communication deficits in affected school-aged children (7-17 years). Speech perception ability in background noise was evaluated in device-active and inactive conditions using the CNC-word test. Participants were then randomized to one of two treatment sequences: (1) inactive device for two weeks (placebo), followed by active device use for two weeks, or (2) active device for 2 weeks, followed by inactive device for 2 weeks. Listening and communication ratings (LIFE-R Questionnaire) were obtained at baseline and at the end of each treatment phase. RESULTS: Each participant demonstrated functional hearing benefits with remote-microphone use. All showed a speech perception in noise increase when the device was activated with a mean phoneme-score difference of 16.4% (p < 0.001) and reported improved listening/communication abilities in the school classroom (mean difference: 23.4%; p = 0.017). DISCUSSION: Conventional hearing aids are typically ineffective as a treatment for auditory neural dysfunction, making sounds louder, but not clearer for affected individuals. In this study, we demonstrate that remote-microphone technologies are acceptable/tolerable in pediatric patients with NF1 and can ameliorate their hearing deficits. CONCLUSION: Remote-microphone listening systems offer a viable treatment option for children with auditory deficits associated with NF1.

Delineating the autistic phenotype in children with neurofibromatosis type 1.

BACKGROUND: Existing research has demonstrated elevated autistic behaviours in children with neurofibromatosis type 1 (NF1), but the autistic phenotype and its relationship to other neurodevelopmental manifestations of NF1 remains unclear. To address this gap, we performed detailed characterisation of autistic behaviours in children with NF1 and investigated their association with other common NF1 child characteristics. METHODS: Participants were drawn from a larger cross-sectional study examining autism in children with NF1. The population analysed in this study scored above threshold on the Social Responsiveness Scale-Second Edition (T-score ≥ 60; 51% larger cohort) and completed the Autism Diagnostic Interview-Revised (ADI-R) and/or the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2). All participants underwent evaluation of their intellectual function, and behavioural data were collected via parent questionnaires. RESULTS: The study cohort comprised 68 children (3-15 years). Sixty-three per cent met the ADOS-2 'autism spectrum' cut-off, and 34% exceeded the more stringent threshold for 'autistic disorder' on the ADI-R. Social communication symptoms were common and wide-ranging, while restricted and repetitive behaviours (RRBs) were most commonly characterised by 'insistence on sameness' (IS) behaviours such as circumscribed interests and difficulties with minor changes. Autistic behaviours were weakly correlated with hyperactive/impulsive attention deficit hyperactivity disorder (ADHD) symptoms but not with inattentive ADHD or other behavioural characteristics. Language and verbal IQ were weakly related to social communication behaviours but not to RRBs. LIMITATIONS: Lack of genetic validation of NF1, no clinical diagnosis of autism, and a retrospective assessment of autistic behaviours in early childhood. CONCLUSIONS: Findings provide strong support for elevated autistic behaviours in children with NF1. While these behaviours were relatively independent of other NF1 comorbidities, the importance of taking broader child characteristics into consideration when interpreting data from autism-specific measures in this population is highlighted. Social communication deficits appear similar to those observed in idiopathic autism and are coupled with a unique RRB profile comprising prominent IS behaviours. This autistic phenotype and its relationship to common NF1 comorbidities such as anxiety and executive dysfunction will be important to examine in future research. Current findings have important implications for the early identification of autism in NF1 and clinical management.

The mediating role of ADHD symptoms between executive function and social skills in children with neurofibromatosis type 1.

Children with neurofibromatosis type 1 (NF1) often experience executive dysfunction, attention deficit/hyperactivity disorder (ADHD) symptoms and poor social skills, however, the nature of the relationships between these domains in children with NF1 is unclear. This study investigated these relationships using primary caregiver ratings of executive functions, ADHD symptoms and social skills in children with NF1. Participants were 136 children with NF1 and 93 typically developing (TD) controls aged 3-15 years recruited from 3 multidisciplinary neurofibromatosis clinics in Melbourne and Sydney, Australia, and Washington DC, USA. Mediation analysis was performed on primary outcome variables: parent ratings of executive functions (Behavior Rating Inventory of Executive Function, Metacognition Index), ADHD symptoms (Conners-3/Conners ADHD Diagnostic and Statistical Manual for Mental Disorders Scales) and social skills (Social Skills Improvement System-Rating Scale), adjusting for potential confounders (full scale IQ, sex, and social risk). Results revealed significantly poorer executive functions, elevated ADHD symptoms and reduced social skills in children with NF1 compared to controls. Poorer executive functions significantly predicted elevated ADHD symptoms and poorer social skills. Elevated ADHD symptoms significantly mediated the relationship between executive functions and social skills problems although did not fully account for social dysfunction. This study provides evidence for the importance of targeting ADHD symptoms as part of future interventions aimed at promoting prosocial behaviors in children with NF1.

Auditory Dysfunction Among Individuals With Neurofibromatosis Type 1.

Importance: Neurofibromatosis type 1 (NF1) affects hearing through disruption of central auditory processing. The mechanisms, functional severity, and management implications are unclear. Objective: To investigate auditory neural dysfunction and its perceptual consequences in individuals with NF1. Design, Setting, and Participants: This case-control study included children and adults with NF1 and control participants matched on age, sex, and hearing level. Patients were recruited through specialist neurofibromatosis and neurogenetic outpatient clinics between April and September 2019. An evaluation of auditory neural activity, monaural/binaural processing, and functional hearing was conducted. Diffusion-weighted magnetic resonance imaging (MRI) data were collected from a subset of participants (10 children with NF1 and 10 matched control participants) and evaluated using a fixel-based analysis of apparent fiber density. Main Outcomes and Measures: Type and severity of auditory dysfunction evaluated via laboratory testing and questionnaire data. Results: A total of 44 participants (18 [41%] female individuals) with NF1 with a mean (SD) age of 16.9 (10.7) years and 44 control participants (18 [41%] female individuals) with a mean (SD) age of 17.2 (10.2) years were included in the study. Overall, 11 participants (25%) with NF1 presented with evidence of auditory neural dysfunction, including absent, delayed, or low amplitude electrophysiological responses from the auditory nerve and/or brainstem, compared with 1 participant (2%) in the control group (odds ratio [OR], 13.03; 95% CI, 1.59-106.95). Furthermore, 14 participants (32%) with NF1 showed clinically abnormal speech perception in background noise compared with 1 participant (2%) in the control group (OR, 20.07; 95% CI, 2.50-160.89). Analysis of diffusion-weighted MRI data of participants with NF1 showed significantly lower apparent fiber density within the ascending auditory brainstem pathways. The regions identified corresponded to the neural dysfunction measured using electrophysiological assessment. Conclusions and Relevance: The findings of this case-control study could represent new neurobiological and clinical features of NF1. Auditory dysfunction severe enough to impede developmental progress in children and restrict communication in older participants is a common neurobiological feature of the disorder.

Cognition, ADHD Symptoms, and Functional Impairment in Children and Adolescents With Neurofibromatosis Type 1.

Objective: We examined the contribution of attention and executive cognitive processes to ADHD symptomatology in NF1, as well as the relationships between cognition and ADHD symptoms with functional outcomes. Methods: The study sample consisted of 141 children and adolescents with NF1. Children were administered neuropsychological tests that assessed attention and executive function, from which latent cognitive variables were derived. ADHD symptomatology, adaptive skills, and quality of life (QoL) were assessed using parent-rated questionnaires. Path analyses were conducted to test relationships among cognitive functioning, ADHD symptomatology, and functional outcomes. Results: Significant deficits were observed on all outcome variables. Cognitive variables did not predict ADHD symptomatology. Neither did they predict functional outcomes. However, elevated ADHD symptomatology significantly predicted functional outcomes. Conclusion: Irrespective of cognitive deficits, elevated ADHD symptoms in children with NF1 negatively impact daily functioning and emphasize the importance of interventions aimed at minimizing ADHD symptoms in NF1.

Profiling the Word Reading Abilities of School-Age Children with Neurofibromatosis Type 1.

OBJECTIVE: Reading difficulties are one of the most significant challenges for children with neurofibromatosis type 1 (NF1). The aims of this study were to identify and categorize the types of reading impairments experienced by children with NF1 and to establish predictors of poor reading in this population. METHOD: Children aged 7-12 years with NF1 (n = 60) were compared with typically developing children (n = 36). Poor word readers with NF1 were classified according to impairment type (i.e., phonological, surface, mixed), and their reading subskills were compared. A hierarchical multiple regression was conducted to identify predictors of word reading. RESULTS: Compared to controls, children with NF1 demonstrated significantly poorer literacy abilities. Of the 49 children with NF1 classified as poor readers, 20 (41%) were classified with phonological dyslexia, 24 (49%) with mixed dyslexia, and 5 (10%) fell outside classification categories. Children with mixed dyslexia displayed the most severe reading impairments. Stronger working memory, better receptive language, and fewer inattentive behaviors predicted better word reading skills. CONCLUSIONS: The majority of children with NF1 experience deficits in key reading skills which are essential for them to become successful readers. Weaknesses in working memory, receptive language, and attention are associated with reading difficulties in children with NF1.

Generation of four iPSC lines from Neurofibromatosis Type 1 patients.

We describe the generation and characterisation of four human induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMC) from individuals with neurofibromatosis type (NF1). PBMC reprogramming was performed using a non-integrative Sendai virus containing the reprogramming factors OCT4, SOX2, MYC and KLF4. All iPSC lines exhibited a normal karyotype, and pluripotency was validated by flow cytometry (EPCAM, TRA-1-81, SSEA1 and CD9) and immunofluorescence (OCT4 and Nanog). Differentiation of the cells into the three embryonic germ layers was confirmed using immunofluorescence. These iPSC lines are a valuable pre-clinical resource to study the molecular mechanisms underlying NF1.

Social skills and autism spectrum disorder symptoms in children with neurofibromatosis type 1: evidence for clinical trial outcomes.

AIM: We examined key features of two outcome measures for social dysfunction and autism spectrum disorder traits, the Social Responsiveness Scale, Second Edition (SRS-2) and the Social Skills Improvement System - Rating Scales (SSIS-RS), in children with neurofibromatosis type 1 (NF1). The aim of the study was to provide objective evidence as to which behavioural endpoint should be used in clinical trials. METHOD: Cross-sectional behavioural and demographic data were pooled from four paediatric NF1 tertiary referral centres in Australia and the United States (N=122; 65 males, 57 females; mean age [SD] 9y 2mo [3y], range 3-15y). RESULTS: Distributions of SRS-2 and SSIS-RS scores were unimodal and both yielded deficits, with a higher proportion of severely impaired scores on the SRS-2 (16.4%) compared to the SSIS-RS (8.2%). Pearson's product-moment correlations revealed that both questionnaires were highly related to each other (r=-0.72, p<0.001) and to measures of adaptive social functioning (both p<0.001). Both questionnaires were significantly related to attention-deficit/hyperactivity disorder symptoms, but only very weakly associated with intelligence. INTERPRETATION: The SRS-2 and SSIS-RS capture social dysfunction associated with NF1, suggesting both may be suitable choices for assessing social outcomes in this population in a clinical trial. However, careful thought needs to be given to the nature of the intervention when selecting either as a primary endpoint. WHAT THIS PAPER ADDS: The Social Responsiveness Scale, Second Edition yielded a large deficit relative to population norms. The Social Skills Improvement System - Rating Scales yielded a moderate deficit relative to population norms. Both scales were highly correlated, suggesting that they are measuring a unitary construct.

Visual spatial learning outcomes for clinical trials in neurofibromatosis type 1.

Cognitive problems are common in children with neurofibromatosis type 1, representing a significant source of lifelong morbidity. Assessment of cognitive function has been challenging in the setting of clinical trials. Spatial learning deficits may be an important target for cognitive interventions. We leveraged a large, international cognitive study in affected children with NF1 treated with lovastatin to assess spatial learning using the "Arena Maze", a portable, computerized task that allows for retesting in the same environment. As with the parent study, spatial learning assessed with this task did not improve with lovastatin treatment.

Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1.

OBJECTIVE: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility. METHODS: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. RESULTS: Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. INTERPRETATION: These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.

Understanding autism spectrum disorder and social functioning in children with neurofibromatosis type 1: protocol for a cross-sectional multimodal study.

INTRODUCTION: Children with the single-gene disorder neurofibromatosis type 1 (NF1) appear to be at an increased risk for autism spectrum disorder (ASD) and exhibit a unique social-cognitive phenotype compared with children with idiopathic ASD. A complete framework is required to better understand autism in NF1, from neurobiological levels through to behavioural and functional outcomes. The primary aims of this study are to establish the frequency of ASD in children with NF1, examine the social cognitive phenotype, investigate the neuropsychological processes contributing to ASD symptoms and poor social functioning in children with NF1, and to investigate novel structural and functional neurobiological markers of ASD and social dysfunction in NF1. The secondary aim of this study is to compare the neuropsychological and neurobiological features of ASD in children with NF1 to a matched group of patients with idiopathic ASD. METHODS AND ANALYSIS: This is an international, multisite, prospective, cross-sectional cohort study of children with NF1, idiopathic ASD and typically developing (TD) controls. Participants will be 200 children with NF1 (3-15 years of age), 70 TD participants (3-15 years) and 35 children with idiopathic ASD (7-15 years). Idiopathic ASD and NF1 cases will be matched on age, sex and intelligence. All participants will complete cognitive testing and parents will rate their child's behaviour on standardised questionnaires. Neuroimaging will be completed by a subset of participants aged 7 years and older. Children with NF1 that screen at risk for ASD on the parent-rated Social Responsiveness Scale 2nd Edition will be invited back to complete the Autism Diagnostic Observation Scale 2nd Edition and Autism Diagnostic Interview-Revised to determine whether they fulfil ASD diagnostic criteria. ETHICS AND DISSEMINATION: This study has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.

Australian Genomics: A Federated Model for Integrating Genomics into Healthcare.

Australian Genomics is a national collaborative research partnership of more than 80 organizations piloting a whole-of-system approach to integrating genomics into healthcare that is based on federation principles. The aim of Australian Genomics is to assess the application of genomic testing in healthcare at the translational interface between research and clinical delivery, with an emphasis on robust evaluation of outcomes. It encompasses two bodies of work: a research program prospectively providing genomic testing through exemplar clinical projects in rare diseases, cancers, and reproductive carrier screening and interdependent programs for advancing the diagnostic, health informatics, regulatory, ethical, policy, and workforce infrastructure necessary for the integration of genomics into the Australian health system.

Attention to faces in social context in children with neurofibromatosis type 1.

AIM: To examine visual attention to faces within social scenes in children with neurofibromatosis type 1 (NF1) and typically developing peers. METHOD: Using eye-tracking technology we investigated the time taken to fixate on a face and the percentage of time spent attending to faces relative to the rest of the screen within social scenes in 24 children with NF1 (17 females, seven males; mean age 10y 4mo [SD 1y 9mo]). Results were compared with those of 24 age-matched typically developing controls (11 females, 13 males; mean age 10y 3mo [SD 2y]). RESULTS: There was no significant between-group differences in time taken to initially fixate on a face (p=0.617); however, children with NF1 spent less time attending to faces within scenes than controls (p=0.048). Decreased attention to faces was associated with elevated autism traits in children with NF1. INTERPRETATION: Children with NF1 spend less time attending to faces than typically developing children when presented in social scenes. Our findings contribute to a growing body of literature suggesting that abnormal face processing is a key aspect of the social-cognitive phenotype of NF1 and appears to be related to autism spectrum disorder traits. Clinicians should consider the impact of reduced attention to faces when designing and implementing treatment programmes for social dysfunction in this population. WHAT THIS PAPER ADDS: Children with neurofibromatosis type 1 (NF1) demonstrated atypical gaze behaviour when attending to faces. NF1 gaze behaviour was characterized by normal initial fixation on faces but shorter face dwell time. Decreased attention to faces was associated with elevated autism traits in the sample with NF1.

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

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.