Publications by authors named "Daryl Efron"

109 Publications

Neural correlates of irritability in a community sample of children.

J Affect Disord 2021 Sep 5;292:223-226. Epub 2021 Jun 5.

Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; School of Psychology, Deakin University, Geelong, Australia.

Irritability has been associated with aberrant patterns of neural activation, yet little is known about structural brain correlates of irritability. As such, we aimed to investigate associations between irritability and gray matter volume (GMV) in a community sample of children enriched for irritability. The sample comprised children (n=162) aged 9-11 years with and without Attention-Deficit/Hyperactivity Disorder (ADHD), participating in a cohort study with magnetic resonance imaging data available. Mixed effects linear regression analyses tested the associations between irritability symptoms and regional GMV (extracted using Freesurfer). Irritability was associated with smaller gray matter volume across multiple brain regions implicated in executive functioning, and emotion and reward processing including frontal regions and the cingulate.
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http://dx.doi.org/10.1016/j.jad.2021.05.093DOI Listing
September 2021

Potential therapeutic uses of cannabinoids to treat behavioural problems in children and adolescents with developmental disorders.

Authors:
Daryl Efron

Aust J Gen Pract 2021 Jun;50(6):352-355

MBBS, FRACP, MD, Senior Research Fellow, Murdoch [email protected] Research Institute, Vic; Consultant Paediatrician, Royal [email protected] Hospital, Vic; Associate Professor, Department of Paediatrics, University of Melbourne, Vic.

Background: There is a great deal of interest in the potential symptomatic benefits of medicinal cannabis among parents of children and adolescents with developmental disorders.

Objective: This article provides an overview of what is known about medicinal cannabis as a treatment for paediatric developmental disorders.

Discussion: While there is emerging evidence in support of medicinal cannabis for some adult mental health disorders, to date the evidence in children and adolescents is scant. Reports from uncontrolled observational studies suggest that cannabidiol-rich products may be helpful in reducing behavioural problems in autistic youth. Cannabidiol appears to have a relatively benign adverse effect profile and therefore may be worth considering as a treatment option in some cases. Several controlled clinical trials are underway that will provide more definitive information on the therapeutic value of medicinal cannabis in paediatric developmental and behavioural disorders.
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http://dx.doi.org/10.31128/AJGP-01-21-5809DOI Listing
June 2021

Clinicians' perceptions of the Australian Paediatric Mental Health Service System: Problems and solutions.

Aust N Z J Psychiatry 2021 05 18;55(5):494-505. Epub 2021 Jan 18.

Centre for Community Child Health, Murdoch Children's Research Institute and The Royal Children's Hospital Melbourne, Melbourne, VIC, Australia.

Objectives: Despite substantial investment by governments, the prevalence of mental health disorders in developed countries remains unchanged over the past 20 years. As 50% of mental health conditions present before 14 years of age, access to high-quality mental health care for children is crucial. Barriers to access identified by parents include high costs and long wait times, difficulty navigating the health system, and a lack of recognition of the existence and/or severity of the child's mental health disorder. Often neglected, but equally important, are clinician views about the barriers to and enablers of access to high-quality mental health care. We aimed to determine perspectives of Australian clinicians including child and adolescent psychiatrists, paediatricians, psychologists and general practitioners, on barriers and enablers within the current system and components of an optimal system.

Methods: A total of 143 clinicians (approximately 35 each of child and adolescent psychiatrists, paediatricians, child psychologists and general practitioners) from Victoria and South Australia participated in semi-structured phone interviews between March 2018 and February 2019. Inductive content analysis was applied to address the broad study aims.

Findings: Clinician-identified barriers included multi-dimensional family factors, service fragmentation, long wait times and inadequate training for paediatricians and general practitioners. Rural and regional locations provided additional challenges but a greater sense of collaboration resulting from the proximity of clinicians in rural areas, creating an opportunity to develop support networks. Suggestions for an optimal system included novel ways to improve access to child psychiatry expertise, training for paediatricians and general practitioners, and co-located multidisciplinary services.

Conclusion: Within the current mental health system for children, structural, training and workforce barriers prevent optimal access to care. Clinicians identified many practical and systemic ideas to improve the system. Implementation and evaluation of effectiveness and cost effectiveness of these ideas is the next challenge for Australia's children's mental health.
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http://dx.doi.org/10.1177/0004867420984242DOI Listing
May 2021

Impact of the COVID-19 pandemic on the well-being of children with neurodevelopmental disabilities and their parents.

J Paediatr Child Health 2021 05 10;57(5):631-636. Epub 2021 Jan 10.

School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.

Aims: To examine the impact of COVID-19 pandemic on child mental health and socio-emotional and physical well-being (including sleep, diet, exercise, use of electronic media; care giver perceptions of symptoms of child neurodevelopmental disability [NDD] and comorbidities), and care giver mental health and well-being, social support and service use.

Methods: An online cross-sectional self-report survey was distributed via disability service providers and support groups. Care givers of children aged 2-17 years with a NDD were invited to respond to questions on child symptom severity and well-being, parent well-being and service access and satisfaction.

Results: Overall, 302 care givers (94.7% female) completed the survey. Average child age was 9.7 years and 66.9% were male. Worsening of any child NDD or comorbid mental health symptom was reported by 64.5% of respondents and 76.9% reported child health and well-being was impacted by COVID-19. Children were viewing more television and digital media (81.6%), exercising less (68.0%), experiencing reduced sleep quality (43.6%) and had a poorer diet (32.4%). Almost one fifth (18.8%) of families reported an increase in the dosage of medication administered to their child. Parents reported COVID-19 had impacted their own well-being (76.1%). Over half of respondents were not satisfied with services received during COVID-19 (54.8%) and just 30% reported that telehealth works well for their child.

Conclusion: Targeted interventions are required to address worsening child neurodevelopmental disability, mental health symptoms and poor diet, sleep and exercise patterns. Improved access to telehealth services is indicated, as is further research on barriers and enablers of effective telehealth services.
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http://dx.doi.org/10.1111/jpc.15285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014782PMC
May 2021

A longitudinal analysis of puberty-related cortical development.

Neuroimage 2021 03 29;228:117684. Epub 2020 Dec 29.

School of Psychology, Deakin University, Melbourne, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, Australia; Developmental Imaging, Murdoch Children's Research Institute, Parkville, Australia.

The brain undergoes extensive structural changes during adolescence, concurrent to puberty-related physical and hormonal changes. While animal research suggests these biological processes are related to one another, our knowledge of brain development in humans is largely based on age-related processes. Thus, the current study characterized puberty-related changes in human brain structure, by combining data from two longitudinal neuroimaging cohorts. Beyond normative changes in cortical thickness, we examined whether individual differences in the rate of pubertal maturation (or "pubertal tempo") was associated with variations in cortical trajectories. Participants (N = 192; scans = 366) completed up to three waves of MRI assessments between 8.5 and 14.5 years of age, as well as questionnaire assessments of pubertal stage at each wave. Generalized additive mixture models were used to characterize trajectories of cortical development. Results revealed widespread linear puberty-related changes across much of the cortex. Many of these changes, particularly within the frontal and parietal cortices, were independent of age-related development. Males exhibiting faster pubertal tempo demonstrated greater thinning in the precuneus and frontal cortices than same-aged and -sex peers. Findings suggest that the unique influence of puberty on cortical development may be more extensive than previously identified, and also emphasize important individual differences in the coupling of these developmental processes.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117684DOI Listing
March 2021

Development of the Fearless, Tearless Transition model of care for adolescents with an intellectual disability and/or autism spectrum disorder with mental health comorbidities.

Dev Med Child Neurol 2021 May 17;63(5):560-565. Epub 2020 Dec 17.

Centre for Community Child Health, The Royal Children's Hospital, Melbourne, VIC, Australia.

Aim: First, to understand the barriers to achieving effective transition and the supports required from the perspective of parents and carers, adolescents with intellectual disability and/or autism spectrum disorder and co-existing mental health disorders (often termed 'dual disability'), and those who provide services to this group. Second, to develop an informed model of shared care to improve the transition of adolescents with dual disabilities.

Method: Carers and a young adult with a dual disability were surveyed about their experience of transition care. Other key stakeholders including paediatricians, general practitioners, and policy makers were also interviewed. These data informed the model of care.

Results: Paediatricians and general practitioners reported difficulties establishing working relationships to foster smooth transitions, and carers reported lacking a regular general practitioner with adequate expertise to care for people with dual disabilities. A process of shared care between paediatricians and general practitioners was developed and initiated by a dedicated transition manager, who assisted with care coordination and service linkages. Standardized clinical assessment tools were also introduced to determine patient and carer support needs.

Interpretation: This study highlights the potential to improve transition outcomes for adolescents with dual disabilities and their carers through early transition planning, consistent methods of assessing patient and carer needs, and shared care.

What This Paper Adds: Adolescents with co-occurring disabilities require a collaborative health and disability service interface. Fearless, Tearless Transition is a new approach to transitioning adolescents with dual disabilities from paediatric to adult care. Carers of adolescents with dual disabilities require support navigating and negotiating services. Engaging general practitioners and paediatricians in shared care early during the transition process is essential.
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http://dx.doi.org/10.1111/dmcn.14766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247054PMC
May 2021

Physical Health, Media Use, and Mental Health in Children and Adolescents With ADHD During the COVID-19 Pandemic in Australia.

J Atten Disord 2020 Dec 17:1087054720978549. Epub 2020 Dec 17.

Deakin University, Geelong, VIC, Australia.

Objective: To examine the impact of COVID-19 restrictions among children with attention-deficit/hyperactivity disorder (ADHD).

Methods: Parents of 213 Australian children (5-17 years) with ADHD completed a survey in May 2020 when COVID-19 restrictions were in place (i.e., requiring citizens to stay at home except for essential reasons).

Results: Compared to pre-pandemic, children had less exercise (Odds Ratio (OR) = 0.4; 95% CI 0.3-0.6), less outdoor time (OR = 0.4; 95% 0.3-0.6), and less enjoyment in activities (OR = 6.5; 95% CI 4.0-10.4), while television (OR = 4.0; 95% CI 2.5-6.5), social media (OR = 2.4; 95% CI 1.3-4.5), gaming (OR = 2.0; 95% CI 1.3-3.0), sad/depressed mood (OR = 1.8; 95% CI 1.2-2.8), and loneliness (OR = 3.6; 95% CI 2.3-5.5) were increased. Child stress about COVID-19 restrictions was associated with poorer functioning across most domains. Most parents (64%) reported positive changes for their child including more family time.

Conclusions: COVID-19 restrictions were associated with both negative and positive impacts among children with ADHD.
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http://dx.doi.org/10.1177/1087054720978549DOI Listing
December 2020

Examining the Educational Gap for Children with ADHD and Subthreshold ADHD.

J Atten Disord 2020 Dec 14:1087054720972790. Epub 2020 Dec 14.

The University of Melbourne, Melbourne, Australia.

Objective: The present study examined the impact of Attention Deficit Hyperactivity Disorder (ADHD) on core educational outcomes in two large community cohorts of Australian school children.

Method: Academic (reading and numeracy) and non-academic (school engagement, attendance, peer victimization, and parental expectations) outcomes were compared between children with ADHD, subthreshold ADHD, and controls when children were in grade 5 (M age = 10.5). Data were drawn from the Longitudinal Study of Australian Children birth cohort (LSAC;  = 3,540) and the Children's Attention Project (CAP;  = 356).

Results: Both subthreshold ADHD and ADHD groups had poorer outcomes on all measures, with medium effects sizes. Differences were not evident between subthreshold ADHD and ADHD groups.

Conclusions: Educational outcomes examined in this study highlight the educational risk for upperprimary school children with ADHD or subthreshold ADHD, in comparison to their peers. Monitoring these outcomes is necessary to inform policy, practice, and intervention.
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http://dx.doi.org/10.1177/1087054720972790DOI Listing
December 2020

Manual dexterity in late childhood is associated with maturation of the corticospinal tract.

Neuroimage 2021 02 19;226:117583. Epub 2020 Nov 19.

Cognitive Neuroscience Unit, School of Psychology, Deakin University, Geelong, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; Developmental Imaging, Murdoch Children's Research Institute, Parkville, Australia.

Purpose: Despite the important role of manual dexterity in child development, the neurobiological mechanisms associated with manual dexterity in childhood remain unclear. We leveraged fixel-based analysis (FBA) to examine the longitudinal association between manual dexterity and the development of white matter structural properties in the corticospinal tract (CST).

Methods: High angular diffusion weighted imaging (HARDI) data were acquired for 44 right-handed typically developing children (22 female) aged 9-13 across two timepoints (timepoint 1: mean age 10.5 years ± 0.5 years, timepoint 2: 11.8 ± 0.5 years). Manual dexterity was assessed using the Grooved Pegboard Test, a widely used measure of manual dexterity. FBA-derived measures of fiber density and morphology were generated for the CST at each timepoint. Connectivity-based fixel enhancement and mixed linear modelling were used to examine the longitudinal association between manual dexterity and white matter structural properties of the CST.

Results: Longitudinal mixed effects models showed that greater manual dexterity of the dominant hand was associated with increased fiber cross-section in the contralateral CST. Analyses further demonstrated that the rate of improvement in manual dexterity was associated with the rate of increase in fiber cross-section in the contralateral CST between the two timepoints.

Conclusion: Our longitudinal data suggest that the development of manual dexterity in late childhood is associated with maturation of the CST. These findings significantly enhance our understanding of the neurobiological systems that subserve fine motor development and provide an important step toward mapping normative trajectories of fine motor function against microstructural and morphological development in childhood.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117583DOI Listing
February 2021

Clinical trials with cannabis medicines-guidance for ethics committees, governance officers and researchers to streamline ethics applications and ensuring patient safety: considerations from the Australian experience.

Trials 2020 Nov 17;21(1):932. Epub 2020 Nov 17.

Chris O'Brien Lifehouse Comprehensive Cancer Hospital, Camperdown, New South Wales, Australia.

With cannabis medicines now obtaining legal status in many international jurisdictions (generally on the authorisation of a medical professional), a rapid increase in consumer demand for access to cannabis as a therapeutic option in the treatment and management of a range of indications is being noted. Despite this accessibility, knowledge on optimal use is lacking. Further drug development and clinical trials at regulatory standards are necessary both if a better understanding of the efficacy of cannabis medicines, optimal product formulation and indication-specific dosing is needed and to ensure the broader quality and safety of cannabis medicines in the clinical setting.To enable this, clinical, academic and public calls for the undertaking of rigorous clinical trials to establish an evidence base for the therapeutic use of cannabis medicines have been made internationally. While this commitment to undertake human studies with cannabis medicines is welcomed, it has highlighted unique challenges, notably in the review stages of ethics and governance. This often results in lengthy delays to approval by Human Research Ethics Committees (herein 'HREC', Australia's nomenclature for Institutional Review Boards) and trial commencement. A principal concern in these cases is that in contrast to clinical trials using other more conventional pharmaceutical products, trials of cannabis medicines in humans often involve the use of an investigational product prior to some (or any) of the preclinical and pharmaceutical safety issues being established. This paucity of data around product safety, potential drug interactions, continuity of supply, shelf life and product storage results in apprehension by HRECs and governance bodies to endorse trials using cannabis medicines.This manuscript draws from the experiences of Australian researchers and staff involved in clinical trials of cannabis medicines to describe some of the common difficulties that may be faced in the HREC approval process. It also presents practical advice aimed to assist researchers, HRECs and governance officers navigate this complex terrain. While the authors' experiences are situated within the Australian setting, many of the barriers described are applicable within the international context and thus, the solutions that have been proposed are typically adaptive for use within other jurisdictions.
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http://dx.doi.org/10.1186/s13063-020-04862-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673085PMC
November 2020

How long and how much? Wait times and costs for initial private child mental health appointments.

J Paediatr Child Health 2021 04 10;57(4):526-532. Epub 2020 Nov 10.

Health Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Aim: To determine: (i) wait times and out-of-pocket costs for children attending private specialists for initial mental health appointments; and (ii) whether these differed between specialists working in metropolitan versus rural areas and in low, medium and high socio-economic areas.

Methods: Prospective secret shopper study whereby a researcher posed as a parent seeking an appointment for her child with anxiety or attention-deficit/hyperactivity disorder. We contacted 317 private paediatrician, psychiatrist and psychologist practices in Victoria and South Australia between 12 March and 5 May 2019.

Results: One third (29.8%) of private practices were closed to new referrals. The average wait times for paediatricians, psychiatrists, and psychologists were 44, 41 and 34 days, respectively. Average out-of-pocket costs quoted were AU$120 for paediatricians, AU$176 for psychiatrists and AU$85 for psychologists.

Conclusion: Parents face extensive wait times and substantial out-of-pocket costs when seeking private mental health services for their child.
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http://dx.doi.org/10.1111/jpc.15253DOI Listing
April 2021

Understanding motor difficulties in children with ADHD: A fixel-based analysis of the corticospinal tract.

Prog Neuropsychopharmacol Biol Psychiatry 2021 03 5;105:110125. Epub 2020 Oct 5.

Cognitive Neuroscience Unit, School of Psychology, Deakin University, Geelong, Victoria, Australia; Developmental Imaging, Clinical Sciences, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia.

Aims: Children with attention deficit hyperactivity disorder (ADHD) often present with deficits in fine motor control. The cortico-spinal tract (CST) is critical for voluntary motor control. Although neuroimaging work has identified anomalous microstructural properties in the CST in ADHD, no study to date has attempted to investigate the link between deficits in fine motor performance and microstructural properties of the CST in children with ADHD. This study aimed to address this gap using a novel fixel-based analysis (FBA).

Methods: Participants were 50 right-handed medication naïve children with a history of ADHD and 56 non-ADHD controls aged 9-11 years. Fine motor control was assessed using the Grooved Pegboard task. Children underwent high angular resolution diffusion MRI. Following pre-processing, FBA was performed and the semi-automated deep-learning TractSeg was used to delineate the CST bilaterally. Fibre density (FD), fibre cross-section (FC-log), and fibre density/cross-section (FDC) were extracted for each tract.

Results: Children with ADHD performed significantly worse than non-ADHD children on the Grooved Pegboard task when using their non-dominant hand. They also demonstrated widespread significantly lower diffusion metrics in both CSTs compared to non-ADHD controls. However, no correlations were observed between Grooved Pegboard performance and diffusion metrics for the CST in either hemisphere.

Conclusions: While we failed to detect a significant relationship between fine motor skill and FBA metrics in either group, this paper extends previous work by showing that children with ADHD and reduced fine motor competence demonstrate atypical microstructure within the CST relative to non-ADHD controls.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110125DOI Listing
March 2021

ADHD at Age 7 and Functional Impairments at Age 10.

Pediatrics 2020 11 6;146(5). Epub 2020 Oct 6.

Murdoch Children's Research Institute, Parkville, Victoria, Australia.

Background And Objectives: Attention-deficit/hyperactivity disorder (ADHD) cohort studies have typically involved clinical samples and have usually recruited children across wide age ranges, limiting generalizability across complexity and developmental stage. We compared academic, emotional-behavioral and social functioning at age 10, and predictors of outcomes, in a nonreferred cohort of children recruited at age 7, between those with full-syndrome (FS) ADHD and controls with no ADHD.

Methods: This was a prospective cohort study with a 3-year follow-up period. Children were recruited from 43 socioeconomically diverse schools in Melbourne, Australia. Multi-informant outcomes at age 10 were academic functioning (Wide Range Achievement Test 4; Social Skills Improvement System), emotional-behavioral functioning (Strengths and Difficulties Questionnaire total), and social functioning (Strengths and Difficulties Questionnaire peer problems). Outcomes were compared across the groups by using adjusted random-effects linear regression analyses.

Results: In total, 477 children (62% male) were recruited at a mean (SD) age of 7.3 years (0.4). There were 179 participants with FS ADHD, 86 with ST ADHD, and 212 controls. Sample retention was 78.2% at 3-year follow-up. Both the FS and ST groups were functioning worse than controls on almost all outcome measures. The best predictors of outcome for children with ADHD were working memory (academic outcome, < .001), ADHD symptom severity (emotional-behavioral outcome, parent: < .001; teacher: < .01), and autism spectrum disorder symptoms (emotional-behavioral outcome, parent = .003; social outcome, parent = .001).

Conclusions: Children with FS and ST ADHD at age 7 experience persisting functional impairments across domains at age 10. The predictors identified at age 7 present potential targets for intervention to ameliorate impairments.
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http://dx.doi.org/10.1542/peds.2020-1061DOI Listing
November 2020

Persistence of disruptive mood dysregulation disorder in children with attention-deficit/hyperactivity disorder.

J Affect Disord 2021 01 28;278:502-505. Epub 2020 Sep 28.

Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; School of Psychology, Deakin University, Geelong, Australia.

Disruptive mood dysregulation disorder (DMDD) is common in children with ADHD yet it is not known how persistent DMDD is in this population. As such we aimed to investigate the persistence of disruptive mood dysregulation disorder (DMDD) in a community sample of children with ADHD. The sample comprised children (n = 136) participating in a cohort study with data available at age 7 and age 10. DMDD status was ascertained using proxy items from the Diagnostic Interview Schedule for Children, Version IV. Of those with DMDD at age 7 (n = 30), eight (21.1%) had DMDD that persisted at age 10. In the first study investigating the longitudinal course of DMDD in ADHD one in five children with ADHD+DMDD at age 7 continued to meet diagnostic criteria for DMDD three years later.
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http://dx.doi.org/10.1016/j.jad.2020.09.109DOI Listing
January 2021

Longitudinal patterns of white matter fibre density and morphology in children are associated with age and pubertal stage.

Dev Cogn Neurosci 2020 10 28;45:100853. Epub 2020 Aug 28.

Developmental Imaging, Murdoch Children's Research Institute, Parkville, Australia; Department of Paediatrics, University of Melbourne, Parkville, Australia.

The pubertal period involves dynamic white matter development. This period also corresponds with rapid gains in higher cognitive functions including attention, as well as increased risk of developing mental health difficulties. This longitudinal study comprised children aged 9-13 years (n = 130). Diffusion magnetic resonance imaging (dMRI) data were acquired (b = 2800s/mm, 60 directions) at two time-points. We derived measures of fibre density and morphology using the fixel-based analysis framework and performed a tract-based mixed-effects modelling analysis to understand patterns of white matter development with respect to age, sex, pubertal stage, and the change in pubertal stage. We observed significant increases in apparent fibre density across a large number of white matter pathways, including major association and commissural pathways. We observed a linear relationship between pubertal stage and fibre density and morphology in the right superior longitudinal fasciculus, and fibre morphology in the right inferior longitudinal fasciculus. Finally, we report a significant interaction between the change in pubertal stage and age in the development of fibre density, for left-lateralised association tracts. Overall, white matter development across ages 9-13 years involves the expansion of major white matter fibre pathways, with key association pathways linked with pubertal stage.
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http://dx.doi.org/10.1016/j.dcn.2020.100853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498759PMC
October 2020

Longitudinal Trajectories of Sustained Attention Development in Children and Adolescents with ADHD.

J Abnorm Child Psychol 2020 12;48(12):1529-1542

Department of Paediatrics, The University of Melbourne, Melbourne, Australia.

The present study characterizes changes in sustained attention ability over ages 9-14, and whether longitudinal trajectories of attention development differ between persistent ADHD, remitted ADHD and control groups. The Sustained Attention to Response Task (SART) was administered to 120 children with ADHD and 123 controls on three occasions between ages 9 and 14. Trajectories of sustained attention development, indicated by changes in SART performance (standard deviation of response time [SDRT], omission errors, and ex-Gaussian parameters sigma and tau), were examined using generalized additive mixed models. For all measures there was a significant main effect of age; response time variability and number of omission errors improved linearly as children aged. However, children with ADHD had significantly greater SDRT, tau and omission errors than controls across waves. There were no significant group differences in sigma, indicating that the greater overall response time variability (SDRT) observed in ADHD was likely driven by more intermittent long responses (larger tau). Trajectories of sustained attention performance did not differ between children with persistent ADHD or ADHD in remission. Longitudinal trajectories of sustained attention development are comparable between ADHD and controls, however children with ADHD (regardless of remission status) display a performance deficit equivalent to typical controls 1-3 years younger. Findings highlight the need for continued clinical support for children in remission from ADHD and provide support for tau as an endophenotype of ADHD.
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http://dx.doi.org/10.1007/s10802-020-00698-5DOI Listing
December 2020

A pilot randomised placebo-controlled trial of cannabidiol to reduce severe behavioural problems in children and adolescents with intellectual disability.

Br J Clin Pharmacol 2021 02 1;87(2):436-446. Epub 2020 Jul 1.

Monash University, Clayton, Victoria, Australia.

Aims: Severe behavioural problems (SBP) are a major contributor to morbidity in children with intellectual disability (ID). Medications used to treat SBP in ID are associated with a high risk of side effects. Cannabidiol has potential therapeutic effects in SBP. This pilot study aimed to investigate the feasibility of conducting a randomised placebo-controlled trial of cannabidiol to reduce SBP in children with ID.

Methods: This is a double-blind, placebo-controlled, two-armed, parallel-design, randomised controlled trial of cannabidiol in children aged 8-16 years with ID and SBP. Participants were randomised 1:1 to receive either 98% cannabidiol in oil (Tilray, Canada) or placebo orally for 8 weeks. The dose was up-titrated over 9 days to 20 mg/kg/day in two divided doses, with a maximum dose of 500 mg twice/day. The feasibility and acceptability of all study components were assessed.

Results: Eight children were randomised, and all completed the full study protocol. There were no serious adverse events or drop-outs. Protocol adherence for key study components was excellent: study visits 100%, medication adherence 100%, blood tests 92% and questionnaire completion 88%. Parents reported a high degree of acceptability with the study design. All parents reported they would recommend the study to other families with children with similar problems. There was an efficacy signal in favour of active drug.

Conclusions: The findings suggest that the study protocol is feasible and acceptable to patients with ID and SBP and their families.
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http://dx.doi.org/10.1111/bcp.14399DOI Listing
February 2021

Reduced fine motor competence in children with ADHD is associated with atypical microstructural organization within the superior longitudinal fasciculus.

Brain Imaging Behav 2021 Apr;15(2):727-737

Cognitive Neuroscience Unit, School of Psychology, Deakin University, Geelong, Victoria, Australia.

Recent work in healthy adults suggests that white matter organization within the superior longitudinal fasciculus (SLF) may, at least partly, explain individual differences in fine motor skills. The SLF is also often implicated in the neurobiology underlying attention deficit hyperactivity disorder (ADHD) as part of the attention network connecting frontal and parietal regions. While ADHD is primarily characterized by inattention, impulsivity and/or hyperactivity, atypical fine motor control is a common comorbid feature. This study aimed to investigate the association between reduced fine motor skills in ADHD and microstructural properties within the SLF. Participants were 55 right-handed children with ADHD and 61 controls aged 9-11 years. Fine motor control was assessed using the Grooved Pegboard task. Children underwent high angular resolution diffusion MRI. Following pre-processing, constrained spherical deconvolution tractography was performed to delineate the three SLF branches bilaterally. Children with ADHD showed significantly poorer fine motor performance relative to controls in the non-dominant hand, indicated by significantly slower left handed Grooved Pegboard task performance. This slower response time for the non-dominant (left) hand was significantly associated with reduced apparent fibre density within the right SLF I, and reduced right SLF I, II and III volume. This finding was independent of spatial attention performance. These data support previous reports indicating that children with ADHD have poorer fine motor performance than controls in their non-dominant hand, and indicates that the neurobiological basis for impaired fine motor control may involve white matter properties within the contralateral SLF. This suggests that white matter properties in fronto-parietal areas may have broader implications than attention.
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http://dx.doi.org/10.1007/s11682-020-00280-zDOI Listing
April 2021

Head Motion During MRI Predicted by out-of-Scanner Sustained Attention Performance in Attention-Deficit/Hyperactivity Disorder.

J Atten Disord 2021 Aug 19;25(10):1429-1440. Epub 2020 Mar 19.

The University of Melbourne, Victoria, Australia.

To characterize head movements in children with ADHD using an ex-Gaussian distribution and examine associations with out-of-scanner sustained attention. Fifty-six children with ADHD and 61 controls aged 9 to 11 years completed the Sustained Attention to Response Task (SART) and resting-state functional magnetic resonance imaging (fMRI). In-scanner head motion was calculated using ex-Gaussian estimates for mu, sigma, and tau in delta variation signal and framewise displacement. Sustained attention was evaluated through omission errors and tau in response time on the SART. Mediation analysis revealed that out-of-scanner attention lapses (omissions during the SART) mediated the relationship between ADHD diagnosis and in-scanner head motion (tau in delta variation signal), indirect effect: = 1.29, 95% confidence interval (CI) = [0.07, 3.15], accounting for 29% of the association. Findings suggest a critical link between trait-level sustained attention and infrequent large head movements during scanning (tau in head motion) and highlight fundamental challenges in measuring the neural basis of sustained attention.
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http://dx.doi.org/10.1177/1087054720911988DOI Listing
August 2021

Does cannabidiol reduce severe behavioural problems in children with intellectual disability? Study protocol for a pilot single-site phase I/II randomised placebo controlled trial.

BMJ Open 2020 03 8;10(3):e034362. Epub 2020 Mar 8.

Health Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.

Introduction: Severe behavioural problems (SBPs) are a common contributor to morbidity and reduced quality of life in children with intellectual disability (ID). Current medication treatment for SBP is associated with a high risk of side effects. Innovative and safe interventions are urgently needed. Anecdotal reports and preliminary research suggest that medicinal cannabis may be effective in managing SBP in children with developmental disabilities. In particular, cannabidiol (CBD) may be a plausible and safe alternative to current medications. Families who are in urgent need of solutions are seeking cannabis for their ID children with SBP. However there is no evidence from randomised controlled trials to support the use of CBD for SBP. This pilot study aims to investigate the feasibility of conducting a randomised placebo-controlled trial of CBD to improve SBP in children with ID.

Methods And Analysis: This is a single-site, double-blind, parallel-group, randomised, placebo-controlled pilot study of 10 participants comparing 98% CBD oil with placebo in reducing SBP in children aged 8-16 years with ID. Eligible participants will be randomised 1:1 to receive either CBD 20 mg/kg/day or placebo for 8 weeks. Data will be collected regarding the feasibility and acceptability of all study components, including recruitment, drop-out rate, study visit attendance, protocol adherence and the time burden of parent questionnaires. Safety outcomes and adverse events will be recorded. All data will be reported using descriptive statistics. These data will inform the design of a full scale randomised controlled trial to evaluate the efficacy of CBD in this patient group.

Ethics And Dissemination: This protocol has received ethics approval from the Royal Children's Hospital ethics committee (Human Research Ethics Committee no. 38236). Results will be disseminated through peer-reviewed journals, professional networks, conferences and social media.

Trial Registration Number: ACTRN12618001852246.
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http://dx.doi.org/10.1136/bmjopen-2019-034362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064134PMC
March 2020

Patterns of long-term ADHD medication use in Australian children.

Arch Dis Child 2020 06 14;105(6):593-597. Epub 2020 Jan 14.

Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.

Objective: Adherence to attention-deficit/hyperactivity disorder (ADHD) medication treatment is often suboptimal. This can compromise patient outcomes. We aimed to describe the patterns of ADHD medication use in Australian children, and characteristics associated with patterns of use.

Design: Dispensing data were analysed for all redeemed prescriptions of methylphenidate, dexamphetamine and atomoxetine between May 2002 and March 2015 from waves 1 to 6 of the Longitudinal Study of Australian Children (n=4634, age 4-5 years at wave 1). Medication coverage was defined as the proportion of time between the first and the last redeemed prescriptions in which the child was taking medication. Associations between predictor variables (child sex, ADHD symptom severity, age at first prescription, family socioeconomic status (SES), single parent status, parent education and parent mental health) and medication coverage were examined using regression analyses.

Results: 166 (3.6%) children had ever redeemed a prescription for an ADHD medication. Boys had higher odds of having taken ADHD medication than girls (OR=3.9; 95% CI 2.7 to 5.7). The mean medication coverage was 59.8%. Medication coverage was lower in children from families of lower SES (β=4.0; 95% CI 0.2 to 7.8, p=0.04). Medication coverage was relatively high in the first year of prescription, then decreased progressively, only increasing again after 5 or 6 years of treatment.

Conclusions: Children with ADHD from socially disadvantaged families were less likely to receive medication consistently. Prescribers need to continue to support families over many years to ensure medication is used consistently for children with ADHD.
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http://dx.doi.org/10.1136/archdischild-2019-317997DOI Listing
June 2020

Does the treatment of anxiety in children with Attention-Deficit/Hyperactivity Disorder (ADHD) using cognitive behavioral therapy improve child and family outcomes? Protocol for a randomized controlled trial.

BMC Psychiatry 2019 11 13;19(1):359. Epub 2019 Nov 13.

Murdoch Children's Research Institute, Parkville, Vic, Australia.

Background: Up to 60% of children with Attention-Deficit/Hyperactivity Disorder (ADHD) meet diagnostic criteria for at least one anxiety disorder, including Social, Generalized and/or Separation Disorder. Anxiety in children with ADHD has been shown to be associated with poorer child and family functioning. Small pilot studies suggest that treating anxiety in children with ADHD using cognitive-behavioral therapy (CBT) has promising benefits. In a fully powered randomized controlled trial (RCT), we aim to investigate the efficacy of an existing CBT intervention adapted for children with ADHD and comorbid anxiety compared with usual care.

Methods: This RCT is recruiting children aged 8-12 years (N = 228) from pediatrician practices in Victoria, Australia. Eligibility criteria include meeting full diagnostic criteria for ADHD and at least one anxiety disorder (Generalized, Separation or Social). Eligible children are randomized to receive a 10 session CBT intervention (Cool Kids) versus usual clinical care from their pediatrician. The intervention focuses on building child and parent skills and strategies to manage anxiety and associated impairments including cognitive restructuring and graded exposure. Minor adaptations have been made to the delivery of the intervention to meet the needs of children with ADHD including increased use of visual materials and breaks between activities. The primary outcome is change in the proportion of children meeting diagnostic criteria for an anxiety disorder at 5 months randomization. This will be assessed via diagnostic interview with the child's parent (Anxiety Disorders Interview Schedule for Children V) conducted by a researcher blinded to intervention condition. Secondary outcomes include a range of child (e.g., anxiety symptoms, ADHD severity, behavior, quality of life, sleep, cognitive functioning, school attendance) and parent (e.g., mental health, parenting behaviors, work attendance) domains of functioning assessed at 5 and 12 months post-randomization. Outcomes will be analyzed using logistic and mixed effects regression.

Discussion: The results from this study will provide evidence on whether treating comorbid anxiety in children with ADHD using a CBT approach leads to improvements in anxiety and/or broader functional outcomes.

Trial Registration: This trial was prospectively registered: Current Controlled Trials ISRCTN59518816 (https://doi.org/10.1186/ISRCTN59518816). The trial was first registered 29/9/15 and last updated 15/1/19.
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http://dx.doi.org/10.1186/s12888-019-2276-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854614PMC
November 2019

The Association Between Autism Symptoms and Child Functioning in a Sample With ADHD Recruited From the Community.

J Atten Disord 2021 06 11;25(8):1129-1134. Epub 2019 Nov 11.

Deakin University, Melbourne, Victoria, Australia.

Although autism spectrum disorder (ASD) symptoms are associated with poorer functioning in children with attention-deficit/hyperactivity disorder (ADHD), it is unclear which ASD symptom domains are most impairing. This study investigated whether specific ASD symptom domains were associated with child functioning in children with ADHD. Parents of 164 children with ADHD completed a diagnostic interview to assess ADHD and comorbidities. Parents reported on ASD symptoms (Social Communication Questionnaire) and child quality of life (Pediatric Quality of Life Inventory 4.0). Parents and teachers completed the Strengths and Difficulties Questionnaire (emotional, conduct, and peer problems). Repetitive and stereotyped behaviors were independently associated with emotional ( = .02) and conduct ( = .03) problems, and poorer quality of life ( = .004). Reciprocal social interaction deficits were independently associated with peer problems ( = .03). Reciprocal social interaction deficits and repetitive and stereotyped behaviors are important areas that should be focused on in ADHD assessment and treatment.
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http://dx.doi.org/10.1177/1087054719886352DOI Listing
June 2021

ADHD and emotional engagement with school in the primary years: Investigating the role of student-teacher relationships.

Br J Educ Psychol 2020 Jun 26;90 Suppl 1:193-209. Epub 2019 Oct 26.

Murdoch Children's Research Institute, Parkville, Victoria, Australia.

Background: Attention deficit hyperactivity disorder (ADHD) is consistently associated with poor school-level outcomes. Although school engagement is recognized as a protective factor associated with increased academic achievement, school retention/completion, and student well-being in the general population, little research has focused on school engagement in children with ADHD.

Aims: To explore a model of the relationships between ADHD symptoms at age 7, student-teacher closeness and conflict at age 10, and emotional engagement with school at age 10 and 12.

Sample: Participants were 498 grade one children (mean age = 7.3), recruited from 43 socio-economically diverse government primary schools in Melbourne. Follow-up occurred at 36 months (mean age = 10.5) and 54 months (mean age = 12.0).

Methods: Data were drawn from a controlled community-based longitudinal study examining the long-term effects of ADHD on children's behaviour, learning, and day-to-day living. Data were collected via direct assessment and child, parent, and teacher surveys.

Results: Path analysis revealed a significant, negative relationship between ADHD symptoms and emotional engagement with school, which was partially mediated by student-teacher conflict. This remained significant after controlling for differences in ADHD status (ADHD, high-risk, or control group), ADHD medication use, and socio-economic status.

Conclusions: These findings highlight the negative impact of ADHD symptoms on children's emotional engagement with school. Given the role of student-teacher conflict in mediating this relationship, interventions aiming to reduce conflict in the student-teacher relationship may promote school engagement for students with ADHD, with potential to improve longer-term outcomes.
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http://dx.doi.org/10.1111/bjep.12316DOI Listing
June 2020

Assessment and management of tic disorders and Tourette syndrome by Australian paediatricians.

J Paediatr Child Health 2020 Jan 17;56(1):136-141. Epub 2019 Jun 17.

Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Aim: The diagnosis and management of tic disorders and Tourette syndrome (TS) can be challenging. A better understanding of current approaches by paediatricians is important to inform research and education to improve patient outcomes. We aimed to investigate current assessment and management practices for tics/TS by Australian paediatricians.

Methods: An online survey was sent to members of the Australian Paediatric Research Network. Primary outcomes of interest included assessment processes, referrals, behavioural interventions and pharmacological management. Four scenarios were presented to elicit information regarding treatment of different types of cases.

Results: Of 340 eligible paediatricians, 139 (41%) responded, with 116 (84%) reporting that they diagnose and manage tics/TS as part of their practice. Questionnaires were used more to identify comorbidities (43%) than to quantify tics (12%). Referrals were most likely to be made to psychologists. Medication was considered important in the management of TS by 45% of respondents, with clonidine identified as the first-choice medication by 69%. There was wide variation in both the pharmacological and behavioural management strategies reported.

Conclusions: There is substantial practice variation among Australian paediatricians in the assessment and management of patients referred with tics/TS. This may reflect insufficient evidence regarding best practice, as well as limited training in this area. There is a need for improved education of Australian paediatricians in the assessment and management of tics/TS, as well as further research to identify optimal treatments.
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http://dx.doi.org/10.1111/jpc.14541DOI Listing
January 2020

Characterisation of depressive symptoms in young children with and without attention deficit hyperactivity disorder.

Eur Child Adolesc Psychiatry 2019 Sep 29;28(9):1183-1192. Epub 2019 Jan 29.

School of Psychology, Deakin University, Geelong, VIC, Australia.

Depressive symptoms and attention deficit hyperactivity disorder (ADHD) are prevalent and commonly co-occur in childhood. To assist with early identification of depression in children with ADHD, we aimed to: (1) use factor analysis to determine whether the construct of depression is measured consistently in those with and without ADHD; and (2) determine whether overall depressive symptoms and specific depressive symptoms were elevated in children with ADHD relative to controls. Participants comprised a community-based sample of 179 children with ADHD (51% Combined presentation, 35% Inattentive presentation) and 212 non-ADHD controls aged 6-8 years. Participants were screened for ADHD and underwent a structured diagnostic interview which confirmed ADHD status and assessed depressive symptoms. The factor structure of depressive symptoms was similar, enabling comparisons between the two groups to be made. Eighteen children with ADHD (10%) and three control participants (1%) experienced either MDD or subthreshold MDD. Children with ADHD experienced more depressive symptoms than controls (Cohen's d =1.19, p < 0.001), with the following symptoms elevated in children with ADHD relative to controls: sadness (32% vs. 14%, p < 0.001), irritability (52% vs. 19%, p < 0.001), insomnia (56% vs. 22%, p < 0.001), psychomotor agitation (53% vs. 9%, p < 0.001), feeling bad about oneself (50% vs. 24%, p < 0.001), difficulty concentrating (75% vs. 14%, p < 0.001) and making decisions (56% vs. 17%, p < 0.001). This study provides support for the occurrence of depressive symptoms in children with ADHD as young as six and highlights the importance of early assessment for depressive symptoms in children with ADHD.
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http://dx.doi.org/10.1007/s00787-018-01274-5DOI Listing
September 2019

A network analysis approach to ADHD symptoms: More than the sum of its parts.

PLoS One 2019 18;14(1):e0211053. Epub 2019 Jan 18.

School of Psychology, Deakin University, Geelong, Australia.

In interpreting attention-deficit/hyperactivity disorder (ADHD) symptoms, categorical and dimensional approaches are commonly used. Both employ binary symptom counts which give equal weighting, with little attention to the combinations and relative contributions of individual symptoms. Alternatively, symptoms can be viewed as an interacting network, revealing the complex relationship between symptoms. Using a novel network modelling approach, this study explores the relationships between the 18 symptoms in the Diagnostic Statistical Manual (DSM-5) criteria and whether network measures are useful in predicting outcomes. Participants were from a community cohort, the Children's Attention Project. DSM ADHD symptoms were recorded in a face-to-face structured parent interview for 146 medication naïve children with ADHD and 209 controls (aged 6-8 years). Analyses indicated that not all symptoms are equal. Frequencies of endorsement and configurations of symptoms varied, with certain symptoms playing a more important role within the ADHD symptom network. In total, 116,220 combinations of symptoms within a diagnosis of ADHD were identified, with 92% demonstrating a unique symptom configuration. Symptom association networks highlighted the relative importance of hyperactive/impulsive symptoms in the symptom network. In particular, the 'motoric'-type symptoms as well as interrupts as a marker of impulsivity in the hyperactive domain, as well as loses things and does not follow instructions in the inattentive domain, had high measures of centrality. Centrality-measure weighted symptom counts showed significant association with clinical but not cognitive outcomes, however the relationships were not significantly stronger than symptom count alone. The finding may help to explain heterogeneity in the ADHD phenotype.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211053PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338383PMC
October 2019

Prevalence and Predictors of Medication Use in Children with Attention-Deficit/Hyperactivity Disorder: Evidence from a Community-Based Longitudinal Study.

J Child Adolesc Psychopharmacol 2019 02 1;29(1):50-57. Epub 2018 Dec 1.

3 Department of Health Services, Murdoch Children's Research Institute, Parkville, Australia.

Objectives: To determine, in a community-based sample of primary school-aged children meeting diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD), (1) the proportion of children with ADHD treated with medication; (2) predictors of medication use; and (3) the association between medication use and psychological service utilization.

Methods: Grade 1 children with ADHD were recruited through 43 schools in Melbourne, Australia, using a two-stage screening and case confirmation procedure. Parent report of medication treatment, clinician diagnosis, and psychological service use were collected at ages 7 and 10 years. Medication use was analyzed by ADHD subtype. Predictors of medication treatment examined included ADHD symptom severity and persistence, externalizing comorbidities, poor academic performance, and social disadvantage. Unadjusted and adjusted logistic regression were used to identify the predictors of medication status.

Results: One hundred seventy-nine children with ADHD were recruited. At baseline, 17.3% had been clinically diagnosed with ADHD, increasing to 37.7% at age 10 years. At baseline, 13.6% were taking ADHD medications, increasing to 25.6% at age 10. Children with the combined and hyperactive-impulsive subtypes were more likely to be taking medication than those with inattentive subtype (age 7: p = 0.002; age 10: p = 0.03). ADHD symptom severity (Conners 3 ADHD Index) at baseline was concurrently and prospectively associated with medication use at both ages (both p = 0.01), and ADHD symptom severity at age 10 was also associated with medication use at age 10 (p = 0.01). Baseline area-level disadvantage was associated with medication use at age 7 (p = 0.04). At 10 years, children receiving medication were more likely, compared with those who were not, to be receiving psychological services (p = 0.001).

Conclusions: In this study, only a minority of children meeting diagnostic criteria for ADHD were diagnosed clinically or treated with ADHD medication by age 10. The strongest predictors of medication treatment were ADHD symptom severity and area disadvantage.
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http://dx.doi.org/10.1089/cap.2018.0095DOI Listing
February 2019

Maternal postnatal mental health and offspring symptoms of ADHD at 8-9 years: pathways via parenting behavior.

Eur Child Adolesc Psychiatry 2019 Jul 16;28(7):923-932. Epub 2018 Nov 16.

Murdoch Children's Research Institute, 50 Flemington Road, Parkville, Melbourne, 3052, Australia.

Exposure to maternal mental health problems during pregnancy and the first year of life has been associated with the development of ADHD. One pathway through which maternal mental health may influence children's outcomes is via its effects on parenting. This study aimed to investigate the mediating role of parenting behavior in the pathway between maternal postnatal distress and later symptoms of ADHD in the child. Biological mothers living with their children participating in the Longitudinal Study of Australian Children with data available from waves 1 (child age 3-12 months) and 5 (child age 8-9 years) were included in the current study (n = 3456). Postnatal distress was assessed by parent report at wave 1. Parenting warmth, hostility and consistency were assessed by parent report at wave 5. ADHD status at wave 5 was ascertained by parent report of the child having a diagnosis of ADHD/ADD or by elevated ADHD symptoms by both parent and teacher report. There was evidence of an indirect pathway from maternal postnatal distress to child ADHD at age 8-9 years via parenting hostility, but not through parenting warmth or consistency, even after accounting for concurrent maternal mental health. Our findings highlight the importance of early identification and intervention for maternal postnatal distress, as treatment may prevent mothers from developing hostile parenting practices and also disrupt the pathway to ADHD in their offspring.
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http://dx.doi.org/10.1007/s00787-018-1254-5DOI Listing
July 2019

Tics and Tourette syndrome.

J Paediatr Child Health 2018 10;54(10):1148-1153

Department of Paediatric Neurology, University of Sydney, Sydney, New South Wales, Australia.

Tourette syndrome is a heterogeneous disorder. The genetic basis is complex, and both in utero and ex utero environmental factors may modify the phenotypic expression of the disorder. Inflammation related to aberrations in immune activation appears to play a pathogenic role in some cases. Multiple neurochemical pathways are involved. Rather than being a pure movement problem, tics are now understood to also have a sensory component. This has resulted in new psychological therapeutic strategies and other potential treatments. Furthermore, comorbidities are common, particularly attention-deficit hyperactivity disorder, anxiety and obsessive-compulsive disorder, and often cause more difficulties than the tics. The approach to treatment is dependent on the degree and types of impairment. For many patients, education, acceptance and understanding are all that is needed. In more severe cases, psychological and/or pharmacological interventions may be indicated. In this article, the clinical features and pathophysiology of Tourette syndrome are reviewed, and a pragmatic management approach is discussed.
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http://dx.doi.org/10.1111/jpc.14165DOI Listing
October 2018
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