Publications by authors named "Timothy J Silk"

41 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

White matter tract signatures of fiber density and morphology in ADHD.

Cortex 2021 05 3;138:329-340. Epub 2021 Mar 3.

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

Previous studies investigating white matter organization in attention deficit hyperactivity disorder (ADHD) have adopted diffusion tensor imaging (DTI). However, attempts to derive pathophysiological models from this research have had limited success, possibly reflecting limitations of the DTI method. This study investigated the organization of white matter tracts in ADHD using fixel based analysis (FBA), a fiber specific analysis framework that is well placed to provide novel insights into the pathophysiology of ADHD. High angular diffusion weighted imaging and clinical data were collected in a large paediatric cohort (N = 144; 76 with ADHD; age range 9-11 years). White matter tractography and FBA were performed across 14 white matter tracts. Permutation based inference testing (using FBA derived measures of fiber density and morphology) assessed differences in white matter tract profiles between children with and without ADHD. Analysis further examined the association between white matter properties and ADHD symptom severity. Relative to controls, children with ADHD showed reduced white matter connectivity along association and projection pathways considered critical to behavioral control and motor function. Increased ADHD symptom severity was associated with reduced white matter organization in fronto-pontine fibers projecting to and from the supplementary motor area. Providing novel insight into the neurobiological foundations of ADHD, this is the first research to uncover fiber specific white matter alterations across a comprehensive set of white matter tracts in ADHD using FBA. Findings inform pathophysiological models of ADHD and hold great promise for the consistent identification and systematic replication of brain differences in this disorder.
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http://dx.doi.org/10.1016/j.cortex.2021.02.015DOI Listing
May 2021

Childhood conduct problems are associated with reduced white matter fibre density and morphology.

J Affect Disord 2021 02 12;281:638-645. Epub 2020 Nov 12.

School of Psychology, Deakin University, Geelong, Australia; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, The University of Melbourne, Parkville, Australia. Electronic address:

Childhood conduct problems are an important public health issue as these children are at-risk of adverse outcomes. Studies using diffusion Magnetic Resonance Imaging (dMRI) have found that conduct problems in adults are characterised by abnormal white-matter microstructure within a range of white matter pathways underpinning socio-emotional processing, while evidence within children and adolescents has been less conclusive based on non-specific diffusion tensor imaging metrics. Fixel-based analysis (FBA) provides measures of fibre density and morphology that are more sensitive to developmental changes in white matter microstructure. The current study used FBA to investigate whether childhood conduct problems were related both cross-sectionally and longitudinally to microstructural alterations within the fornix, inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), and the uncinate fasciculus (UF). dMRI data was obtained for 130 children across two time-points in a community sample with high levels of externalising difficulties (age: time-point 1 = 9.47 - 11.86 years, time-point 2 = 10.67 -13.45 years). Conduct problems were indexed at each time-point using the Conduct Problems subscale of the parent-informant Strengths and Difficulties Questionnaire (SDQ). Conduct problems were related to lower fibre density in the fornix at both time-points, and in the ILF at time-point 2. We also observed lower fibre cross-section in the UF at time-point 1. The change in conduct problems did not predict longitudinal changes in white-matter microstructure across time-points. The current study suggests that childhood conduct problems are related to reduced fibre-specific microstructure within white matter fibre pathways implicated in socio-emotional functioning.
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http://dx.doi.org/10.1016/j.jad.2020.11.098DOI Listing
February 2021

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

Associations Between Limbic System White Matter Structure and Socio-Emotional Functioning in Children with ADHD + ASD.

J Autism Dev Disord 2021 Aug;51(8):2663-2672

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

Children with attention deficit/hyperactivity disorder (ADHD) combined with autism spectrum disorder (ASD) symptoms (ADHD + ASD) have poorer social and emotional functioning than those with ADHD alone. However, no studies have specifically examined the associations between ASD symptoms, measures of social and emotional functioning and limbic system white matter microstructure. Tractography on the cingulum, uncinate fasciculus and fornix were performed for 151 children with (N = 78) and without (N = 73) ADHD. Participants in the ADHD group who scored 11 or above on the Social Communication Questionnaire were classified as the ADHD + ASD group (N = 16). Significant differences in mean cingulum FA were present between the control group and the ADHD (all) group, however, no significant differences were seen between the ADHD and ADHD + ASD groups. Despite this, significant associations were seen between mean FA of the left cingulum and emotional problems for the ADHD + ASD group. Results give greater insights into the specific biological basis of emotional problems in the ADHD + ASD group, indicating that the cingulum may play a role.
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http://dx.doi.org/10.1007/s10803-020-04738-3DOI Listing
August 2021

Meta-analysis of the neural correlates of vigilant attention in children and adolescents.

Cortex 2020 11 25;132:374-385. Epub 2020 Aug 25.

Centre & Discipline of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia; Telethon Kids Institute, Perth, Western Australia, Australia; Department of Child and Adolescent Psychiatry, Psychosomatic Medicine and Psychotherapy, Jena University Hospital, Friedrich Schiller University, Jena, Germany.

Vigilant Attention (VA), defined as the ability to maintain attention to cognitively unchallenging activities over a prolonged period of time, is critical to support higher cognitive functions and many behaviours in our everyday life. Evidence has shown that VA rapidly improves throughout childhood and adolescence until young adulthood and tends to decline in older adulthood. Although neuroimaging studies have extensively investigated this cognitive function in adults, the neural correlates of VA in neurotypical children and adolescents remain unclear. The current meta-analysis reviewed and examined functional neuroimaging studies in paediatric populations that used behavioural tasks involving VA. The selected studies (N = 25) were analyzed using the activation likelihood estimation method. Findings showed convergence of activation in mainly right-lateralized brain areas, including dorsomedial frontal cortex and parieto-temporal areas, and are consistent with previous literature on the neural correlates of VA. Results are discussed in terms of their functional and developmental implications for VA in children and adolescents.
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http://dx.doi.org/10.1016/j.cortex.2020.08.008DOI 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

The Role of Sleep in the Relationship Between ADHD Symptoms and Stop Signal Task Performance.

J Atten Disord 2020 Jul 24:1087054720943290. Epub 2020 Jul 24.

Murdoch Children's Research Institute, Melbourne, Australia.

ADHD commonly occurs with sleep problems and secondary cognitive impairments such as inhibitory control. Sleep problems may explain attentional lapses and inhibition performance variability in children with ADHD. This study applied Bayesian analyses to examine the relationship between ADHD symptoms, sleep problems, and inhibition. Participants included 73 children with ADHD and 73 non-ADHD controls, aged 10.5 to 13.5 years. The Stop Signal Task measured inhibition. Sleep problems were measured with the Adolescent Sleep Wake Scale and parent-report. ADHD symptoms are associated with sleep problems and reaction time variability, however, sleep problems accounted for more variance in inhibition performance than both hyperactive and inattentive symptoms. Sleep problems account for inhibition performance over and above ADHD symptom severity in children with and without ADHD diagnoses. This suggests clinical utility in assessing sleep in children with manifestations of ADHD, and interventions targeting sleep problems concurrently with behavioral symptoms. This further adds to the discussion on overdiagnosis of ADHD due to behavioral presentations of underlying sleep disorders. Treatment for phenotypes of ADHD could be enhanced by targeting sleep problems, in addition to inhibition deficits and attentional lapses.
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http://dx.doi.org/10.1177/1087054720943290DOI Listing
July 2020

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

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

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

Multimodal Structural Neuroimaging Markers of Brain Development and ADHD Symptoms.

Am J Psychiatry 2019 01 17;176(1):57-66. Epub 2018 Sep 17.

From Developmental Imaging, Clinical Sciences, Murdoch Children's Research Institute, Melbourne, Australia; Population Health, Murdoch Children's Research Institute, Melbourne; the Royal Children's Hospital, Melbourne; the Department of Paediatrics, University of Melbourne, Melbourne; the Judith Lumley Centre, La Trobe University, Melbourne; the School of Psychology, Deakin University, Geelong, Australia; and the Melbourne School of Psychological Sciences, University of Melbourne, Melbourne.

Objective: Attention deficit hyperactivity disorder (ADHD) is a multifactorial disorder with diverse associated risk factors and comorbidities. In this study, the authors sought to understand ADHD from a dimensional perspective and to identify neuroanatomical correlates of traits and behaviors that span diagnostic criteria.

Methods: Multimodal neuroimaging data and multi-informant cognitive and clinical data were collected in a densely phenotyped pediatric cohort (N=160; 70 with ADHD; age range, 9-12 years). Multivariate analysis identified associations between clinical and cognitive factors and multimodal neuroimaging markers (across tissue volume, cortical thickness, cortical area, and white matter microstructure). The resulting imaging markers were validated in an independent cohort (N=231; 132 with ADHD; age range, 7-18 years).

Results: Four novel patterns of neuroanatomical variation that related to phenotypic variation were identified. The first imaging pattern captured association of head size with sex, socioeconomic status, and mathematics and reading performance. The second pattern captured variation associated with development and showed that individuals with delayed development were more likely to be receiving ADHD medication. The third pattern was associated with hyperactivity, greater comorbidities, poorer cognition, lower parental education, and lower quality of life. The fourth pattern was associated with a particular profile of poorer cognition and irritability independent of ADHD. The authors further demonstrated that these imaging patterns could predict variation in age and ADHD symptoms in an independent cohort.

Conclusions: The findings suggest that ADHD presentation may arise from a summation of several clinical, developmental, or cognitive factors, each with a distinct neuroanatomical foundation. This informs the neurobiological foundations of ADHD and highlights the value of detailed phenotypic data in understanding the neurobiology underlying neurodevelopmental disorders.
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http://dx.doi.org/10.1176/appi.ajp.2018.18010034DOI Listing
January 2019

Development of white matter fibre density and morphology over childhood: A longitudinal fixel-based analysis.

Neuroimage 2018 12 22;183:666-676. Epub 2018 Aug 22.

Developmental Imaging, Murdoch Children's Research Institute, Parkville, Australia; School of Psychology, Deakin University, Geelong, Australia.

Purpose: White matter fibre development in childhood involves dynamic changes to microstructural organisation driven by increasing axon diameter, density, and myelination. However, there is a lack of longitudinal studies that have quantified advanced diffusion metrics to identify regions of accelerated fibre maturation, particularly across the early pubertal period. We applied a novel longitudinal fixel-based analysis (FBA) framework, in order to estimate microscopic and macroscopic white matter changes over time.

Methods: Diffusion-weighted imaging (DWI) data were acquired for 59 typically developing children (27 female) aged 9-13 years  at two time-points approximately 16 months apart (time-point 1: 10.4 ± 0.4 years, time-point 2: 11.7 ± 0.5 years). Whole brain FBA was performed using the connectivity-based fixel enhancement method, to assess longitudinal changes in fibre microscopic density and macroscopic morphological measures, and how these changes are related to sex, pubertal stage, and pubertal progression. Follow-up analyses were performed in sub-regions of the corpus callosum to confirm the main findings using a Bayesian repeated measures approach.

Results: There was a statistically significant increase in fibre density over time localised to medial and posterior commissural and association fibres, including the forceps major and bilateral superior longitudinal fasciculus. Increases in fibre cross-section were substantially more widespread. The rate of fibre development was not associated with age or sex. In addition, there was no significant relationship between pubertal stage or progression and longitudinal fibre development over time. Follow-up Bayesian analyses were performed to confirm the findings, which supported the null effect of the longitudinal pubertal comparison.

Conclusion: Using a novel longitudinal fixel-based analysis framework, we demonstrate that white matter fibre density and fibre cross-section increased within a 16-month scan rescan period in specific regions. The observed increases might reflect increasing axonal diameter or axon count. Pubertal stage or progression did not influence the rate of fibre development in the early stages of puberty. Future work should focus on quantifying these measures across a wider age range to capture the full spectrum of fibre development across the pubertal period.
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http://dx.doi.org/10.1016/j.neuroimage.2018.08.043DOI Listing
December 2018

Age, sex, and puberty related development of the corpus callosum: a multi-technique diffusion MRI study.

Brain Struct Funct 2018 Jul 5;223(6):2753-2765. Epub 2018 Apr 5.

Department of Paediatrics, Melbourne Medical School, The University of Melbourne, Parkville, Australia.

The corpus callosum is integral to the central nervous system, and continually develops with age by virtue of increasing axon diameter and ongoing myelination. Magnetic resonance imaging (MRI) techniques offer a means to disentangle these two aspects of white matter development. We investigate the profile of microstructural metrics across the corpus callosum, and assess the impact of age, sex and pubertal development on these processes. This study made use of two independent paediatric populations. Multi-shell diffusion MRI data were analysed to produce a suite of diffusion tensor imaging, neurite orientation dispersion and density imaging, and apparent fibre density (AFD) metrics. A multivariate profile analysis was performed for each diffusion metric across ten subdivisions of the corpus callosum. All diffusion metrics significantly varied across the length of the corpus callosum. AFD exhibited a strong relationship with age across the corpus callosum (partial η = 0.65), particularly in the posterior body of the corpus callosum (partial η = 0.72). In addition, females had significantly higher AFD compared with males, most markedly in the anterior splenium (partial η = 0.14) and posterior genu (partial η = 0.13). Age-matched pubertal group differences were localised to the splenium. We present evidence of a strong relationship between apparent fibre density and age, sex, and puberty during development. These results are consistent with ex vivo studies of fibre morphology, providing insights into the dynamics of axonal development in childhood and adolescence using diffusion MRI.
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http://dx.doi.org/10.1007/s00429-018-1658-5DOI Listing
July 2018

White matter microstructure in boys with persistent depressive disorder.

J Affect Disord 2017 10 13;221:11-16. Epub 2017 Jun 13.

Developmental Imaging, Murdoch Childrens Research Institute, Parkville, Australia.

Background: Persistent depressive symptoms in children and adolescents are considered a risk factor for the development of major depressive disorder (MDD) later in life. Previous research has shown alterations in white matter microstructure in pediatric MDD but discrepancies exist as to the specific tracts affected. The current study aimed to improve upon previous methodology and address the question whether previous findings of lower fractional anisotropy (FA) replicate in a sample of children with persistent depressive disorder characterized by mild but more chronic symptoms of depression.

Methods: White matter microstructure was examined in 25 boys with persistent depressive disorder and 25 typically developing children. Tract specific analysis implemented with the Diffusion Tensor Imaging - ToolKit (DTI-TK) was used to probe fractional anisotropy (FA) in eleven major white matter tracts.

Results: Clusters within the left uncinate, inferior fronto-occipital and cerebrospinal tracts showed lower FA in the clinical group. FA in the left uncinate showed a negative association with self-reported symptoms of depression.

Conclusions: The results demonstrate lower FA in several white matter tracts in children with persistent depressive disorder. These findings support the contention that early onset depression is associated with altered white matter microstructure, which may contribute to the maintenance and recurrence of symptoms.
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http://dx.doi.org/10.1016/j.jad.2017.06.020DOI Listing
October 2017

White matter alterations at pubertal onset.

Neuroimage 2017 08 19;156:286-292. Epub 2017 May 19.

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

Recent neurodevelopmental research supports the contribution of pubertal stage to local and global grey and white matter remodelling. Little is known, however, about white matter microstructural alterations at pubertal onset. This study investigated differences in white matter properties between pre-pubertal and pubertal children using whole brain fixel-based analysis (FBA) of the microscopic density and macroscopic cross-section of fibre bundles. Diffusion-weighted imaging data were acquired for 74 typically developing children (M=10.4, SD=.43 years, 31 female) at 3.0T (60 diffusion gradient directions, b-value=2800s/mm). Group comparisons of fibre density (FD) and fibre cross-section (FC) were made between age-matched pre-pubertal and pubertal groups, and post-hoc analyses were performed on regions of interest (ROIs) defined in the splenium, body and genu of the corpus callosum. Significant fixel-wise differences in FD were observed between the pubertal groups, where the pubertal group had significantly higher FD compared with age-matched pre-pubertal children, localised to the posterior corpus callosum. Post-hoc analyses on mean FD in the corpus callosum ROIs revealed group differences between the pubertal groups in the splenium, but not body or genu. The observed higher apparent fibre density in the splenium suggests that pubertal onset coincides with white matter differences explained by increasing axon diameter. This may be an important effect to account for over pubertal development, particularly for group studies where age-matched clinical and typical populations may be at various stages of puberty.
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http://dx.doi.org/10.1016/j.neuroimage.2017.05.017DOI Listing
August 2017

Uncovering the neuroanatomical correlates of cognitive, affective and conative theory of mind in paediatric traumatic brain injury: a neural systems perspective.

Soc Cogn Affect Neurosci 2017 09;12(9):1414-1427

Australian Centre for Child Neuropsychological Studies, Murdoch Childrens Research Institute, Parkville, VIC, Australia.

Deficits in theory of mind (ToM) are common after neurological insult acquired in the first and second decade of life, however the contribution of large-scale neural networks to ToM deficits in children with brain injury is unclear. Using paediatric traumatic brain injury (TBI) as a model, this study investigated the sub-acute effect of paediatric traumatic brain injury on grey-matter volume of three large-scale, domain-general brain networks (the Default Mode Network, DMN; the Central Executive Network, CEN; and the Salience Network, SN), as well as two domain-specific neural networks implicated in social-affective processes (the Cerebro-Cerebellar Mentalizing Network, CCMN and the Mirror Neuron/Empathy Network, MNEN). We also evaluated prospective structure-function relationships between these large-scale neural networks and cognitive, affective and conative ToM. 3D T1- weighted magnetic resonance imaging sequences were acquired sub-acutely in 137 children [TBI: n = 103; typically developing (TD) children: n = 34]. All children were assessed on measures of ToM at 24-months post-injury. Children with severe TBI showed sub-acute volumetric reductions in the CCMN, SN, MNEN, CEN and DMN, as well as reduced grey-matter volumes of several hub regions of these neural networks. Volumetric reductions in the CCMN and several of its hub regions, including the cerebellum, predicted poorer cognitive ToM. In contrast, poorer affective and conative ToM were predicted by volumetric reductions in the SN and MNEN, respectively. Overall, results suggest that cognitive, affective and conative ToM may be prospectively predicted by individual differences in structure of different neural systems-the CCMN, SN and MNEN, respectively. The prospective relationship between cerebellar volume and cognitive ToM outcomes is a novel finding in our paediatric brain injury sample and suggests that the cerebellum may play a role in the neural networks important for ToM. These findings are discussed in relation to neurocognitive models of ToM. We conclude that detection of sub-acute volumetric abnormalities of large-scale neural networks and their hub regions may aid in the early identification of children at risk for chronic social-cognitive impairment.
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http://dx.doi.org/10.1093/scan/nsx066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629820PMC
September 2017

Neurite density index is sensitive to age related differences in the developing brain.

Neuroimage 2017 03 11;148:373-380. Epub 2017 Jan 11.

Murdoch Childrens Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia. Electronic address:

Purpose: White matter development during childhood and adolescence is characterised by increasing white matter coherence and organisation. Commonly used scalar metrics, such as fractional anisotropy (FA), are sensitive to multiple mechanisms of white matter change and therefore unable to distinguish between mechanisms that change during development. We investigate the relationship between age and neurite density index (NDI) from neurite orientation dispersion and density imaging (NODDI), and the age-classification accuracy of NDI compared with FA, in a developmental cohort.

Method: Diffusion-weighted imaging data from 72 children and adolescents between the ages of 4-19 was collected (M=10.42, SD=3.99, 36 male). We compared NODDI metrics against conventional DTI metrics (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD] and radial diffusivity [RD]) in terms of their relationship to age. An ROC analysis was also performed to assess the ability of each metric to classify older and younger participants.

Results: NDI exhibited a stronger relationship with age (median R=.60) compared with MD (median R=.39), FA (median R=.27), AD (median R=.14), and RD (median R=.35) in a high proportion of white matter tracts. When participants were divided into an older and younger group, NDI achieved the best classification (median area under the curve [AUC]=.89), followed by MD (median AUC=.81), FA (median AUC=.80), RD (median AUC=.81), and AD (median AUC=.64).

Conclusion: Our results demonstrate the sensitivity of NDI to age-related differences in white matter microstructural organisation over development. Importantly, NDI is more sensitive to such developmental changes compared to commonly used DTI metrics. This knowledge provides justification for implementing NODDI metrics in developmental studies.
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http://dx.doi.org/10.1016/j.neuroimage.2017.01.023DOI Listing
March 2017

The effect of single-dose methylphenidate on resting-state network functional connectivity in ADHD.

Brain Imaging Behav 2017 Oct;11(5):1422-1431

School of Psychological Sciences, Monash University, Melbourne, Australia.

We examined the effect of a single dose of methylphenidate (MPH) on whole brain functional connectivity, assessed using resting state functional MRI (rsfMRI), in young people with ADHD. 16 young people with ADHD participated in two rsfMRI scans in a randomized, placebo-controlled study with an acute dose of MPH (20 mg). 15 typically developing controls also performed the task under placebo conditions. The network-based statistic (NBS) was used to identify differential connectivity patterns between the MPH and placebo conditions in the ADHD group. Mean connectivity of the resulting sub-network was examined in the ADHD and control groups. Resting state functional connectivity (RSFC) analysis revealed significantly reduced connectivity under MPH compared to placebo in young people with ADHD. Findings were robust across a range of thresholds. No sub-networks of increased connectivity were found at any threshold. Mean connectivity of the identified sub-network was significantly higher in ADHD individuals in the placebo condition compared to controls, however there was no difference between MPH condition and controls. We demonstrated a significant MPH-related reduction in RSFC in a large, robust network primarily involving occipital, temporal and cerebellar regions, and visual, executive and default mode networks. These findings suggest that MPH is 'normalising' a higher RSFC in young people with ADHD. This study is a novel addition to the understanding of treatment effects on the brain in ADHD.
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http://dx.doi.org/10.1007/s11682-016-9620-8DOI Listing
October 2017

Uncovering cortico-striatal correlates of cognitive fatigue in pediatric acquired brain disorder: Evidence from traumatic brain injury.

Cortex 2016 10 16;83:222-30. Epub 2016 Aug 16.

Australian Centre for Child Neuropsychological Studies, Murdoch Childrens Research Institute, Melbourne, Australia; Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia; Department of Psychology, Royal Children's Hospital, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia.

Cognitive fatigue is among the most profound and disabling sequelae of pediatric acquired brain disorders, however the neural correlates of these symptoms in children remains unexplored. One hypothesis suggests that cognitive fatigue may arise from dysfunction of cortico-striatal networks (CSNs) implicated in effort output and outcome valuation. Using pediatric traumatic brain injury (TBI) as a model, this study investigated (i) the sub-acute effect of brain injury on CSN volume; and (ii) potential relationships between cognitive fatigue and sub-acute volumetric abnormalities of the CSN. 3D T1 weighted magnetic resonance imaging sequences were acquired sub-acutely in 137 children (TBI: n = 103; typically developing - TD children: n = 34). 67 of the original 137 participants (49%) completed measures of cognitive fatigue and psychological functioning at 24-months post-injury. Results showed that compared to TD controls and children with milder injuries, children with severe TBI showed volumetric reductions in the overall CSN package, as well as regional gray matter volumetric change in cortical and subcortical regions of the CSN. Significantly greater cognitive fatigue in the TBI patients was associated with volumetric reductions in the CSN and its putative hub regions, even after adjusting for injury severity, socioeconomic status (SES) and depression. In the first study to evaluate prospective neuroanatomical correlates of cognitive fatigue in pediatric acquired brain disorder, these findings suggest that post-injury cognitive fatigue is related to structural abnormalities of cortico-striatal brain networks implicated in effort output and outcome valuation. Morphometric magnetic resonance imaging (MRI) may have potential to unlock early prognostic markers that may assist to identify children at elevated risk for cognitive fatigue post-TBI.
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http://dx.doi.org/10.1016/j.cortex.2016.07.020DOI Listing
October 2016

Recovery of White Matter following Pediatric Traumatic Brain Injury Depends on Injury Severity.

J Neurotrauma 2017 02 22;34(4):798-806. Epub 2016 Sep 22.

1 Developmental Imaging, Clinical Sciences, Murdoch Childrens Research Institute , Melbourne, Australia .

Previous studies in pediatric traumatic brain injury (TBI) have been variable in describing the effects of injury severity on white-matter development. The present study used diffusion tensor imaging to investigate prospective sub-acute and longitudinal relationships between early clinical indicators of injury severity, diffusion metrics, and neuropsychological outcomes. Pediatric patients with TBI underwent magnetic resonance imaging (MRI) (n = 78, mean [M] = 10.56, standard deviation [SD] = 2.21 years) at the sub-acute stage after injury (M = 5.55, SD = 3.05 weeks), and typically developing children were also included and imaged (n = 30, M = 10.60, SD = 2.88 years). A sub-set of the patients with TBI (n = 15) was followed up with MRI 2 years post-injury. Diffusion MRI images were acquired at sub-acute and 2-year follow-up time points and analyzed using Tract-Based Spatial Statistics. At the sub-acute stage, mean diffusivity and axial diffusivity were significantly higher in the TBI group compared with matched controls (p < 0.05). TBI severity significantly predicted diffusion profiles at the sub-acute and 2-year post-injury MRI. Patients with more severe TBI also exhibited poorer information processing speed at 6-months post-injury, which in turn correlated with their diffusion metrics. These findings highlight that the severity of the injury not only has an impact on white-matter microstructure, it also impacts its recovery over time. Moreover, findings suggest that sub-acute microstructural changes may represent a useful prognostic marker to identify children at elevated risk for longer term deficits.
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http://dx.doi.org/10.1089/neu.2016.4584DOI Listing
February 2017

Global and local grey matter reductions in boys with ADHD combined type and ADHD inattentive type.

Psychiatry Res Neuroimaging 2016 Aug 20;254:119-26. Epub 2016 Jun 20.

Academic Child Psychiatry Unit, Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville Australia; Developmental Imaging, Murdoch Childrens Research Institute, Parkville, Australia. Electronic address:

Attention-deficit/hyperactivity disorder (ADHD) has reliably been associated with global grey matter reductions but local alterations are largely inconsistent with perhaps the exception of the caudate nucleus. The aim of this study was to examine local and global brain volume differences between typically developing children (TD) and children with a diagnosis of ADHD. We also addressed whether these parameters would differ between children with the ADHD-combined type (ADHD-C) and those with the ADHD-inattentive type (ADHD-I). Using an ROI approach caudate volume differences were also examined. 79 boys between the ages of 8 and 17 participated in the study. Of those 33 met diagnostic criteria for the ADHD-C and 15 for the ADHD-I subtype. 31 boys were included in the TD group. Structural magnetic resonance imaging data were analysed using voxel-based morphometry. The ADHD group had significantly lower global and local grey matter volumes within clusters in the bilateral frontal, right parietal and right temporal regions compared to TD. A significant group by age interaction was found for right caudate nucleus volume. No differences between the ADHD-C and ADHD-I groups were found. Right caudate nucleus volume and age are more strongly related in ADHD than in TD consistent with previous research.
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http://dx.doi.org/10.1016/j.pscychresns.2016.06.008DOI Listing
August 2016

Altered structural connectivity in ADHD: a network based analysis.

Brain Imaging Behav 2017 Jun;11(3):846-858

Developmental Imaging, Royal Children's Hospital, Murdoch Childrens Research Institute, Melbourne, 3052, Australia.

Attention deficit/hyperactivity disorder (ADHD) is increasingly being viewed as a dysfunction of distributed brain networks rather than focal abnormalities. Here we investigated the structural brain network differences in children and adolescents with ADHD and healthy controls, using graph theory metrics to describe the anatomic networks and connectivity patterns, and the Network Based Statistic (NBS) to isolate the network components that differ between the two groups. Using DWI high-angular resolution diffusion imaging ('HARDI'), whole brain tractography was conducted on 21 ADHD-combined type boys (m 13.3 ± 1.9 yrs) and 21 typically developing boys (m 14.8 ± 2.1 yrs). This study presents a comprehensive structural network investigation in ADHD covering a range of commonly used methodologies, including both streamline and probabilistic tractography, tensor and constrained spherical deconvolution (CSD) models, as well as different edge weighting methods at a range of densities and t-thresholds. Using graph metrics, ADHD was associated with local neighbourhoods that were more modular and interconnected than controls, where there was a decrease in the global, long-range connections, indicating reduced communication between local, specialised networks in ADHD. ADHD presented with a sub-network of stronger connectivity encompassing bilateral frontostriatal connections as well as left occipital, temporal, and parietal regions, of which the white matter microstructure was associated with ADHD symptom severity. Probabilistic tractography using CSD and the Hagmann weighting method produced that highest stability and most robust network differences across t-thresholds. It demonstrates topological organisation disruption in distributed neural networks in ADHD, supportive of the theory of maturation delay in ADHD.
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http://dx.doi.org/10.1007/s11682-016-9559-9DOI Listing
June 2017

Cortical morphometry in attention deficit/hyperactivity disorder: Contribution of thickness and surface area to volume.

Cortex 2016 09 21;82:1-10. Epub 2016 May 21.

School of Psychological Sciences, Monash University, Melbourne, Australia.

Although lower brain volume is a consistent neuroimaging finding in attention deficit hyperactivity disorder (ADHD), we lack an understanding of whether this effect is driven by changes in cortical thickness or surface area, which are governed by distinct neurodevelopmental processes. This study examined ADHD-control differences in cortical thickness, surface area and volume, and tests whether thickness and surface area mediates any observed volume differences. Magnetic resonance imaging (MRI) data was collected from 35 males with ADHD-combined type and 35 typically developing control participants aged 9-17 years. Morphometric measures were examined for between group differences and the specific contribution of surface area and thickness to group differences in volume tested using mediation analysis. Individuals with ADHD had smaller total cortical volume (7.3%), surface area (4.3%), and mean cortical thickness (2.8%) compared to controls. Differences were pronounced in frontal and parietal lobes. Variance in volume as a function of ADHD diagnosis was accounted for at least in part by the relationship between diagnosis and each of cortical thickness and surface area, with regional variation in the relative contributions of these measures. The surface area of the precuneus was a major driver of volume differences, attesting to the potential relevance of this region for neurodevelopment in ADHD. Both surface area and cortical thickness play a significant mediating role in determining diagnostic differences in volume, with regional variation in the contribution of thickness and surface area to those volume differences, highlighting the importance of examining both cortical thickness and surface area in examining ADHD.
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http://dx.doi.org/10.1016/j.cortex.2016.05.012DOI Listing
September 2016

Developmental brain trajectories in children with ADHD and controls: a longitudinal neuroimaging study.

BMC Psychiatry 2016 Mar 11;16:59. Epub 2016 Mar 11.

Murdoch Childrens Research Institute, Melbourne, Australia.

Background: The symptom profile and neuropsychological functioning of individuals with Attention Deficit/Hyperactivity Disorder (ADHD), change as they enter adolescence. It is unclear whether variation in brain structure and function parallels these changes, and also whether deviations from typical brain development trajectories are associated with differential outcomes. This paper describes the Neuroimaging of the Children's Attention Project (NICAP), a comprehensive longitudinal multimodal neuroimaging study. Primary aims are to determine how brain structure and function change with age in ADHD, and whether different trajectories of brain development are associated with variations in outcomes including diagnostic persistence, and academic, cognitive, social and mental health outcomes.

Methods/design: NICAP is a multimodal neuroimaging study in a community-based cohort of children with and without ADHD. Approximately 100 children with ADHD and 100 typically developing controls will be scanned at a mean age of 10 years (range; 9-11years) and will be re-scanned at two 18-month intervals (ages 11.5 and 13 years respectively). Assessments include a structured diagnostic interview, parent and teacher questionnaires, direct child cognitive/executive functioning assessment and magnetic resonance imaging (MRI). MRI acquisition techniques, collected at a single site, have been selected to provide optimized information concerning structural and functional brain development.

Discussion: This study will allow us to address the primary aims by describing the neurobiological development of ADHD and elucidating brain features associated with differential clinical/behavioral outcomes. NICAP data will also be explored to assess the impact of sex, ADHD presentation, ADHD severity, comorbidities and medication use on brain development trajectories. Establishing which brain regions are associated with differential clinical outcomes, may allow us to improve predictions about the course of ADHD.
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http://dx.doi.org/10.1186/s12888-016-0770-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4787204PMC
March 2016

Theory of mind mediates the prospective relationship between abnormal social brain network morphology and chronic behavior problems after pediatric traumatic brain injury.

Soc Cogn Affect Neurosci 2016 Apr 21;11(4):683-92. Epub 2016 Jan 21.

Australian Centre for Child Neuropsychological Studies, Murdoch Childrens Research Institute, Melbourne, Australia, Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia, Department of Psychology, Royal Children's Hospital, Melbourne, Australia.

Childhood and adolescence coincide with rapid maturation and synaptic reorganization of distributed neural networks that underlie complex cognitive-affective behaviors. These regions, referred to collectively as the 'social brain network' (SBN) are commonly vulnerable to disruption from pediatric traumatic brain injury (TBI); however, the mechanisms that link morphological changes in the SBN to behavior problems in this population remain unclear. In 98 children and adolescents with mild to severe TBI, we acquired 3D T1-weighted MRIs at 2-8 weeks post-injury. For comparison, 33 typically developing controls of similar age, sex and education were scanned. All participants were assessed on measures of Theory of Mind (ToM) at 6 months post-injury and parents provided ratings of behavior problems at 24-months post-injury. Severe TBI was associated with volumetric reductions in the overall SBN package, as well as regional gray matter structural change in multiple component regions of the SBN. When compared with TD controls and children with milder injuries, the severe TBI group had significantly poorer ToM, which was associated with more frequent behavior problems and abnormal SBN morphology. Mediation analysis indicated that impaired theory of mind mediated the prospective relationship between abnormal SBN morphology and more frequent chronic behavior problems. Our findings suggest that sub-acute alterations in SBN morphology indirectly contribute to long-term behavior problems via their influence on ToM. Volumetric change in the SBN and its putative hub regions may represent useful imaging biomarkers for prediction of post-acute social cognitive impairment, which may in turn elevate risk for chronic behavior problems.
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http://dx.doi.org/10.1093/scan/nsw007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814797PMC
April 2016

Abnormal asymmetry in frontostriatal white matter in children with attention deficit hyperactivity disorder.

Brain Imaging Behav 2016 12;10(4):1080-1089

School of Psychological Sciences, Monash University, Melbourne, 3800, Australia.

A growing body of work utilizing structural and functional brain imaging and neurocognitive measures of executive and attentional function indicates anomalous asymmetry in ADHD. This study examined the white-matter volume and diffusion properties of frontostriatal tracts, as a function of hemisphere, in ADHD and healthy controls. Forty-three young males (21 ADHD-Combined Type and 22 controls) aged 10-18 years underwent structural and diffusion weighted MRI. Tractography applying constrained spherical deconvolution (CSD) was used to construct frontostriatal tracts between each of caudate and putamen and each of dorsolateral prefrontal, ventrolateral prefrontal and orbitofrontal cortices (DLPFC, VLPFC and OFC) in each hemisphere, to examine both volumetric and diffusion microstructure properties. Young people with ADHD did not show the right hemisphere lateralization of volume in the Caudate-VLPFC and Caudate-DLPFC tracts that was evident in controls, however the ADHD group displayed a pronounced lateralization to the left for fractional anisotropy in the Putamen-VLPFC tracts. The degree of volume asymmetry did not correlate with symptom severity; however fractional anisotropy (FA) values that were more strongly lateralized to the left in the Putamen-VLPFC white matter were associated with greater symptom severity. ADHD was associated with anomalous hemispheric asymmetries in both tract volume and underlying white-matter microstructure in major fibre tracts of the frontostriatal system. Our observations of both weaker lateralization to the right in terms of tract volume and stronger lateralization to the left in terms of FA values for the ADHD group, suggests that previous inconsistencies in the literature may reflect the influence of such asymmetries.
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http://dx.doi.org/10.1007/s11682-015-9470-9DOI Listing
December 2016
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