Search

Human brain mapping 43(1), 37-55 (2022). doi:10.1002/hbm.25029 special issue: "Special Issue: The ENIGMA Consortium: the first 10 years / Issue Edited by: P.M. Thompson, N. Jahanshad, L. Schmaal, J.A. Turner, A. Winkler, S.I. Thomopoulos, G.F. Egan, P. Kochunov", Published by Wiley-Liss, New York, NY

Previous Diffusion Tensor Imaging (DTI) studies in children suggest that developmental improvements in inhibitory control is largely mediated by the degree of white matter organisation within a right-lateralised network of fronto-basal-ganglia regions. Recent advances in diffusion imaging analysis now permit greater biological specificity, both in identifying specific fibre populations within a voxel, as well as in the underlying microstructural properties of that white matter. In the present work, employing a novel fixel-based analysis (FBA) framework, we aimed to comprehensively investigate microstructure within the fronto-basal-ganglia circuit in childhood, and its contribution to inhibition performance. Diffusion MRI data were obtained from 43 healthy children and adolescents aged 9–11 years (10.42 ± .41 years, 18 females). Response inhibition for each participant was assessed using the Stop-signal Task (SST) and quantified as a Stop–Signal Reaction Time (SSRT). All steps relevant to FBA were implemented in MRtrix3Tissue, a fork of the MRtrix3 software library. The fronto-basal-ganglia circuit were delineated using probabilistic tractography to identify the tracts connecting the subthalamic nucleus, pre-supplementary motor area and the inferior frontal gyrus. Connectivity-based fixel enhancement (CFE) was then used to assess the association between fibre density (FD) and fibre cross-section (FC) with inhibitory ability. Significant negative associations were identified for FD in both the right and left fronto-basal-ganglia circuit whereby greater FD was associated with better inhibition performance (e.g., reduced SSRTs). This effect was specifically localised to clusters of fixels within white matter proximal to the right subthalamic nucleus. We did not report any meaningful associations between SSRT and FC. Whilst findings are broadly consistent with prior DTI evidence, current results suggest that SSRT is predominantly facilitated by subcortical microstructure of the connections projecting from the subthalamic nucleus to the cortical regions of the network. Our findings extend current understanding of the role of white matter in childhood response inhibition.

Vigilant Attention (VA) is a critical cognitive function allowing to maintain our attention, particularly in redundant or intellectually unchallenging situations. Evidence has shown that, as the brain develops, VA abilities rapidly improve throughout childhood and adolescence. Dietary omega-3 polyunsaturated fats (PUFA), playing a critical role for proper brain development and maturation of cortical regions, may contribute to variations in VA abilities.The present study investigated the effect of dietary omega-3 PUFA intake (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) on resting-state functional connectivity (rsFC) of a meta-analytically defined VA network in 24 neurotypical children and adolescents (7.3-17.2 years) from the Healthy Brain Network databank.Functional MRI and phenotypical information were collected from the Healthy Brain Network databank. Intake of omega-3 DHA and EPA was assessed using a food frequency questionnaire and was adjusted for total calorie intake. Out of scanner VA-related performance was assessed using the VA condition of the Adaptive Cognitive Evaluation tool.Overall, reported intake of omega-3 PUFA was not significantly associated with VA-related performance. Furthermore, energy-adjusted omega-3 intake was not significantly correlated with rsFC within the VA network. A complementary whole-brain analysis revealed that energy-adjusted omega-3 intake was correlated with decreased rsFC between parieto-occipital brain regions.The present study was not able to detect a relationship between dietary omega-3 and rsFC or VA performance.

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.

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.

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.

Animal neurophysiological studies have identified neural signals within dorsal frontoparietal areas that trace a perceptual decision by accumulating sensory evidence over time and trigger action upon reaching a threshold. Although analogous accumulation-to-bound signals are identifiable on extracranial human electroencephalography, their cortical origins remain unknown. Here neural metrics of human evidence accumulation, predictive of the speed of perceptual reports, were isolated using electroencephalography and related to dorsal frontoparietal network (dFPN) connectivity using diffusion and resting-state functional magnetic resonance imaging. The build-up rate of evidence accumulation mediated the relationship between the white matter macrostructure of dFPN pathways and the efficiency of perceptual reports. This association between steeper build-up rates of evidence accumulation and the dFPN was recapitulated in the resting-state networks. Stronger connectivity between dFPN regions is thus associated with faster evidence accumulation and speeded perceptual decisions. Our findings identify an integrated network for perceptual decisions that may be targeted for neurorehabilitation in cognitive disorders. How efficiently humans make perceptual decisions varies between people. Based on EEG and structural and functional MRI data, Brosnan et al. suggest a role for dorsal frontoparietal network connectivity in the speed of perceptual decisions.

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.

Objective Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. Methods We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. Results There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from −0.18 to 0.18) and would not survive study-wide correction for multiple testing. Conclusion Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait., Journal of Child Psychology and Psychiatry, 62 (10), ISSN:0021-9630, ISSN:1469-7610

Objective: 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. Method: 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). Results: Repetitive and stereotyped behaviors were independently associated with emotional ( p = .02) and conduct ( p = .03) problems, and poorer quality of life ( p = .004). Reciprocal social interaction deficits were independently associated with peer problems ( p = .03). Conclusion: Reciprocal social interaction deficits and repetitive and stereotyped behaviors are important areas that should be focused on in ADHD assessment and treatment.

Puberty triggers a period of structural “re-organization” in the brain, when rising hormone levels act via receptors to influence morphology. However, our understanding of these neuroendocrine processes in humans remains poor. As such, the current longitudinal study characterized development of the human subcortex during puberty, including changes in relation to pubertal (Tanner) stage and hormone (testosterone, dehydroepiandrosterone [DHEA]) levels. Beyond normative group-level patterns of development, we also examined whether individual differences in the rate of pubertal maturation (i.e., “pubertal/hormonal tempo”) were associated with variations in subcortical trajectories. Participants (N = 192; scans = 366) completed up to three waves of MRI assessments between 8.5 and 14.5 years of age. Parents completed questionnaire assessments of pubertal stage at each wave, and adolescents provided hormone samples on a subset of waves. Generalized additive mixture models were used to characterize trajectories of subcortical development. Results showed that development of most subcortical structures was related to pubertal stage, although findings were mostly non-significant when controlling for age. Testosterone and DHEA levels were related to development of the amygdala, hippocampus and pallidum in both sexes, and findings in the amygdala remained significant when controlling for age. Additionally, we found that variability in hormonal (specifically testosterone) tempo was related to right hippocampal development in males, with an accelerated pattern of hippocampal development in those with greater increases in testosterone levels. Overall, our findings suggest prominent hormonal influences on the amygdala and hippocampus, consistent with the prevalence of androgen and estrogen receptors in these regions. We speculate that these findings are most likely reflective of the important role of adrenarcheal processes on adolescent brain development.

Contains fulltext : 243961.pdf (Publisher’s version ) (Closed access) Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful collaborative framework for combining datasets across individual sites. Recently, we have launched the ENIGMA-Sleep working group with the collaboration of several institutes from 15 countries to perform large-scale worldwide neuroimaging and genetics studies for better understanding the neurobiology of impaired sleep quality in population-based healthy individuals, the neural consequences of sleep deprivation, pathophysiology of sleep disorders, as well as neural correlates of sleep disturbances across various neuropsychiatric disorders. In this introductory review, we describe the details of our currently available datasets and our ongoing projects in the ENIGMA-Sleep group, and discuss both the potential challenges and opportunities of a collaborative initiative in sleep medicine.

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.

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.

Highlights • Fibre properties derived from fixel-based analysis are sensitive to development. • Age-related patterns are consistent with previous diffusion tensor studies. • Pubertal stage correlates with fibre density and morphology in the right SLF. • Pubertal stage correlates with fibre morphology in the right ILF. • Pubertal progression interacts with age for longitudinal fibre density changes., 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/mm2, 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.

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

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.

Objective: To characterize head movements in children with ADHD using an ex-Gaussian distribution and examine associations with out-of-scanner sustained attention. Method: 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. Results: 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: B = 1.29, 95% confidence interval (CI) = [0.07, 3.15], accounting for 29% of the association. Conclusion: 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.

The development of Vigilant Attention (VA), the ability to focus and maintain our attention to repetitive and cognitively unchallenging tasks over time, has been investigated for more than a decade. The development of this critical executive function across the lifespan has been characterised by a rapid improvement in VA performance throughout childhood and adolescence, a steady improvement in adulthood and a slow decline in older adulthood. However, the development of the neural correlates of VA in children and adolescents remains poorly understood. Using a cross-sectional design, the present study used a meta-analytically defined VA network in children and adolescents to explore the developmental trend of the resting-state functional connectivity (rsFC) within the VA network across two independent cohorts. The results showed a linear and non-linear decrease of rsFC between the left and right VA brain regions across age. However, the results could not be reproduced in the replication cohort, potentially due to a smaller sample size. Based on previous findings from behavioural studies, the present findings suggest that changes in rsFC may underlie a developmental shift in cognitive strategies in neurotypical children and adolescents.

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.

Children born very preterm (VP; C and BS > FS, respectively. There were no significant group differences in neuronal activation for FS > C. However, BS > FS revealed that VP children had significantly greater activation in the left middle frontal gyrus, in the left superior parietal gyrus and right cerebellar tonsil, and significantly less activation in the right precentral and postcentral gyrus and left insula compared with controls. Taken together these results suggest that VP children at 13 years of age show an atypical neuronal activation during spatial WM, specifically related to manipulation of spatial information in WM. It is unclear whether these findings reflect delayed maturation and/or recruitment of alternative neuronal networks as a result of neuroplasticity. Hum Brain Mapp 38:6172-6184, 2017. © 2017 Wiley Periodicals, Inc.

BackgroundDeficits in social cognition may be among the most profound and disabling sequelae of paediatric traumatic brain injury (TBI); however, the neuroanatomical correlates of longitudinal outcomes in this domain remain unexplored. This study aimed to characterize social cognitive outcomes longitudinally after paediatric TBI, and to evaluate the use of sub-acute diffusion tensor imaging (DTI) to predict these outcomes.MethodsThe sample included 52 children with mild complex-severe TBI who were assessed on cognitive theory of mind (ToM), pragmatic language and affective ToM at 6- and 24-months post-injury. For comparison, 43 typically developing controls (TDCs) of similar age and sex were recruited. DTI data were acquired sub-acutely (mean = 5.5 weeks post-injury) in a subset of 65 children (TBI = 35; TDC = 30) to evaluate longitudinal prospective relationships between white matter microstructure assessed using Tract-Based Spatial Statistics and social cognitive outcomes.ResultsWhole brain voxel-wise analysis revealed significantly higher mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in the sub-acute TBI group compared with TDC, with differences observed predominantly in the splenium of the corpus callosum (sCC), sagittal stratum (SS), dorsal cingulum (DC), uncinate fasciculus (UF) and middle and superior cerebellar peduncles (MCP & SCP, respectively). Relative to TDCs, children with TBI showed poorer cognitive ToM, affective ToM and pragmatic language at 6-months post-insult, and those deficits were related to abnormal diffusivity of the sCC, SS, DC, UF, MCP and SCP. Moreover, children with TBI showed poorer affective ToM and pragmatic language at 24-months post-injury, and those outcomes were predicted by sub-acute alterations in diffusivity of the DC and MCP.ConclusionsAbnormal microstructure within frontal-temporal, limbic and cerebro-cerebellar white matter may be a risk factor for long-term social difficulties observed in children with TBI. DTI may have potential to unlock early prognostic markers of long-term social outcomes.

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=0.43 years, 31 female) at 3.0T (60 diffusion gradient directions, b-value=2800 s/mm 2 ). 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.

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.

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

Background Children with Attention-Deficit Hyperactivity Disorder (ADHD) appear to have a higher risk of language problems compared with typically developing children, although the types of language problems experienced are less clear. This review aims to establish the types of language problems experienced by children with ADHD according to systematically reviewed literature and determine the empirical evidence for language problems in children with ADHD compared with non-ADHD controls. Methods A standardized search protocol was used on databases: CINAHL, Medline, and PsychINFO. We identified studies with the following inclusion criteria: (a) confirmed ADHD status at the time of the study, (b) inclusion of a non-ADHD control group, (c) use of a validated language measure, and (d) age ≤ 18. t-Tests, Pearson's r, and Hedges g effect sizes (ES) were calculated using summary statistics. Random effects meta-analyses were conducted for the language domain suitable for analysis. Publication bias was investigated using both the trim and fill and p-curve techniques. Results Twenty-one studies were included in the systematic review (ADHD = 1,209; Control = 1,101), within which 60 of 68 separate analyses found significant differences between the ADHD and control group on the language measures (p

Childhood and adolescence coincide with rapid structural and functional maturation of brain networks implicated in Theory of Mind (ToM); however, the impact of paediatric traumatic brain injury (TBI) on the development of these higher order skills is not well understood. ToM can be partitioned intoconative ToM, defined as the ability to understand how indirect speech acts involving irony and empathy are used to influence the mental or affective state of the listener; andaffective ToM, concerned with understanding that facial expressions are often used for social purposes to convey emotions that we want people to think we feel. In a sample of 84 children with mild-severe TBI and 40 typically developing controls, this study examined the effect of paediatric TBI on affective and conative ToM; and evaluated the respective contributions of injury-related factors (injury severity/lesion location) and non-injury-related environmental variables (socio-economic status (SES)/family functioning) to long-term ToM outcomes. Results showed that the poorest ToM outcomes were documented in association with mild-complicated and moderate TBI, rather than severe TBI. Lesion location and SES did not significantly contribute to conative or affective ToM. Post-injury family affective responsiveness was the strongest and most significant predictor of conative ToM. Results suggest that clinicians should exercise caution when prognosticating based on early clinical indicators, and that group and individual-level outcome prediction should incorporate assessment of a range of injury- and non-injury-related factors. Moreover, the affective quality of post-injury family interactions represents a potentially modifiable risk factor, and might be a useful target for family-centred interventions designed to optimise social cognitive outcomes after paediatric TBI.

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.

To date, there has been relatively little research into how the neurobiological mechanisms of sleep regulation may be affected in attention deficit hyperactivity disorder (ADHD). This chapter gives a broad overview of the neurobiology of sleep and explores possible neurobiological processes that may explain the association between sleep problems and ADHD. The chapter discusses the reciprocal inhibition between a system that promotes wakefulness, attention, and alertness, and a system that induces sleep. It highlights the nuclei and neurotransmitters of the ascending arousal system and the sleep-inducing system, and the mechanisms that drive the transition between the two systems. It also covers the homeostatic and circadian regulation that drives sleep to occur. This summary of the growing literature reveals that anomalies in particular neural circuitry or neurotransmitter systems may contribute to both difficulties in the regulation of sleep and the behavioral and cognitive deficits that characterize ADHD, however, the relationship may not be straightforward.

© 2019 Elsevier Inc. Neuroethics is central to the Australian Brain Initiative's aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative.

Childhood and adolescence are critical periods for maturation of neurobiological processes that underlie complex social and emotional behavior including Theory of Mind (ToM). While structural correlates of ToM are well described in adults, less is known about the anatomical regions subsuming these skills in the developing brain or the impact of cerebral insult on the acquisition and establishment of high-level social cognitive skills. This study aimed to examine the differential influence of age-at-insult and brain pathology on ToM in a sample of children and adolescents with traumatic brain injury (TBI). Children and adolescents with TBI (n = 112) were categorized according to timing of brain insult: (i) middle childhood (5-9 years; n = 41); (ii) late childhood (10-11 years; n = 39); and (iii) adolescence (12-15 years; n = 32) and group-matched for age, gender, and socioeconomic status to a typically developing (TD) control group (n = 43). Participants underwent magnetic resonance imaging including a susceptibility-weighted imaging (SWI) sequence 2-8 weeks postinjury and were assessed on a battery of ToM tasks at 6- and 24-months after injury. Results showed that for adolescents with TBI, social cognitive dysfunction at 6- and 24-months postinjury was associated with diffuse neuropathology and a greater number of lesions detected using SWI. In the late childhood TBI group, we found a time-dependent emergence of social cognitive impairment, linked to diffuse neuropathology. The middle childhood TBI group demonstrated performance unrelated to SWI pathology and comparable to TD controls. Findings indicate that the full extent of social cognitive deficits may not be realized until the associated skills reach maturity. Evidence for brain structure-function relationships suggests that the integrity of an anatomically distributed network of brain regions and their connections is necessary for the acquisition and establishment of high-level social cognitive skills.

Background Dysthymic disorder (DD) is a depressive disorder characterised by persistent low and/or irritable mood and has been identified as a major risk factor for developing major depressive disorder (MDD). MDD and DD have been associated with executive function difficulties of working memory and attention. Little is known about how executive function networks in the brain are affected in children and adolescents with MDD and even less in DD. This study used fMRI and two spatial working memory paradigms to investigate associated brain function in young people with DD and an age-, gender- and IQ- matched typically developing group. Methods Nineteen male patients with DD (mean age 11.2±1.5 years) diagnosed according to DSM-IV criteria and 16 typically developing boys (mean age 10.5±1.1 years) performed a mental rotation and a delay-match to sample (DMTS) task while undergoing fMRI. All participants were medication-naive at the time of testing. Results Compared to typically developing young people, the DD group showed less activation in left frontal regions including left ventro- and dorsolateral prefrontal cortices (PFC) during mental rotation. Medial frontal regions including dorsomedial PFC, anterior cingulate cortex and frontal pole also showed relatively reduced activation. During the DMTS task patients showed significantly more activation in the right precuneus and posterior cingulate cortex. Limitations This was a cross-sectional study with a small sample limiting the generalizability of the results. Conclusions The results complement previous findings in adults with MDD that have shown differential activation of left PFC regions during working memory tasks. Additionally, altered function of cortical midline structures in young patients with DD was identified. This supports findings in children, adolescents and adults with MDD suggesting that the pathophysiology of depressive disorders extends to DD as a risk factor for MDD and exhibits continuity over the lifespan.

Atypical asymmetries of spatial attention have been reported in children with attention deficit hyperactivity disorder (ADHD) and may be exacerbated by non-spatial factors such as attentional capacity. Although preliminary evidence suggests that asymmetries of attention in ADHD may be modifiable by the psychostimulant, methylphenidate, further placebo-controlled studies are required. This study first aimed to confirm recent evidence that increasing non-spatial processing load at fixation can unmask a spatial gradient of target detection in children with ADHD but not Controls. Second, we used placebo-controlled randomised trial methodology to ask whether 20 mg of methylphenidate (MPH) could remediate any load-dependent asymmetry of spatial attention in adolescents with ADHD. Twelve male adolescents with ADHD were assessed twice in a double-blind, randomized design, under either placebo or an acute dose of methylphenidate. Thirteen typically developing adolescent Controls completed a single session under placebo. Participants completed a computer-based task in which they monitored a centrally presented rapid serial visual presentation stream for a probe stimulus, while also responding to brief peripheral events. The attentional load of the central task was manipulated by varying the target instructions but not the physical stimuli or the frequency of targets. Between-group analyses under placebo conditions indicated that increased attentional load induced a spatial gradient for target detection in the ADHD but not Controls, such that load slowed response times for left, but not, right hemi-field targets. This load-dependent spatial asymmetry in the adolescents with ADHD was abolished by administration of methylphenidate. Methylphenidate may “normalise” target detection between the hemi-fields in ADHD via enhancement of the right-lateralised ventral attention networks that support non-spatial attention.

Obsessive-compulsive disorder (OCD) is a chronic, relapsing anxiety disorder. To date, neuroimaging investigations of OCD have been variable and few studies have examined paediatric populations. Eight children with OCD and 12 typically developing children matched for age, gender, handedness and performance IQ underwent a high resolution T1-weighted structural magnetic resonance imaging (MRI) scan. A voxel-based morphometry (VBM) protocol (using DARTEL) compared the brains of the paediatric OCD children with those of typically developing children. Overall, children with OCD demonstrated significantly lower intra-cranial volume (ICV) and grey- and white-matter volumes. ICV was significantly reduced (∼9%) in the OCD group compared with the typically developing group. The VBM analysis demonstrated lower volumes in widespread grey matter in bilateral frontal, cingulate, temporal-parietal, occipital-frontal and right precuneus regions for OCD. Lower white matter volume was found bilaterally in the cingulate and occipital cortex, right frontal and parietal and left temporal regions, and the corpus callosum. In summary, this study provides further evidence of brain dysmorphology in paediatric OCD patients. In addition to fronto-striatal-thalamic neural networks, abnormalities in other brain regions, such as the parietal lobe and corpus callosum, were demonstrated. These brain regions may play an additional role in the pathophysiology of OCD.

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.

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 R2=.60) compared with MD (median R2=.39), FA (median R2=.27), AD (median R2=.14), and RD (median R2=.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.

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.

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.

Background: The symptom profile and neuropsychological functioning of individuals with Attention Deficit/\udHyperactivity Disorder (ADHD), change as they enter adolescence. It is unclear whether variation in brain structure and\udfunction parallels these changes, and also whether deviations from typical brain development trajectories are associated\udwith differential outcomes. This paper describes the Neuroimaging of the Children’s Attention Project (NICAP), a\udcomprehensive longitudinal multimodal neuroimaging study. Primary aims are to determine how brain structure and\udfunction change with age in ADHD, and whether different trajectories of brain development are associated with\udvariations in outcomes including diagnostic persistence, and academic, cognitive, social and mental health outcomes.\udMethods/Design: NICAP is a multimodal neuroimaging study in a community-based cohort of children with and\udwithout ADHD. Approximately 100 children with ADHD and 100 typically developing controls will be scanned at a\udmean age of 10 years (range; 9–11years) and will be re-scanned at two 18-month intervals (ages 11.5 and 13 years\udrespectively). Assessments include a structured diagnostic interview, parent and teacher questionnaires, direct child\udcognitive/executive functioning assessment and magnetic resonance imaging (MRI). MRI acquisition techniques,\udcollected at a single site, have been selected to provide optimized information concerning structural and functional\udbrain development.\udDiscussion: This study will allow us to address the primary aims by describing the neurobiological development of\udADHD and elucidating brain features associated with differential clinical/behavioral outcomes. NICAP data will also be\udexplored to assess the impact of sex, ADHD presentation, ADHD severity, comorbidities and medication use on brain\uddevelopment trajectories. Establishing which brain regions are associated with differential clinical outcomes, may allow\udus to improve predictions about the course of ADHD.

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.

Our ability to remember locations in space (spatial working memory) and our ability to direct attention to those locations (spatial attention) are two fundamental and closely related cognitive processes. A growing body of behavioural evidence suggests that spatial working memory and spatial attention share common resources, while neuroimaging studies show some overlap in the neural regions that mediate these two cognitive functions. The current study used fMRI to directly examine the extent to which spatial working memory and spatial attention rely on common underlying neural mechanisms. Twenty healthy participants underwent functional MRI while performing a dual task of spatial working memory incorporating a visual search task during the working memory retention interval. Working memory and visual search task loads were parametrically modulated. A wide network of prefrontal, premotor, and parietal regions showed increasing activity with increased spatial working memory load. Of these areas, part of the right supramarginal gyrus, lying along the intraparietal sulcus, showed a significant interaction such that the neural activity associated with spatial working memory load was significantly attenuated as visual search load in the dual task was increased. This interaction suggests that this part of the supramarginal gyrus, along the intraparietal sulcus, is critical for mediating both spatial working memory and shifts in spatial attention.

ADHD is associated with spatial working memory deficits, thought to be subserved by dysfunction of neural circuits. In this study we aimed to further examine fronto-parietal dysfunction in ADHD by examining brain activation associated with the Raven’s Progressive Matrices task, a visuo-spatial pattern sequencing task involving relational reasoning and thereby placing high-demand loading on the prefrontal cortex. Functional MRI was conducted on twelve right-handed 8–12 year old boys with ADHD-combined type and 12 right-handed, age and performance IQ-matched, healthy boys as they completed items from the Raven’s Progressive Matrices. Our findings further confirm striatum and parietal lobe dysfunction in ADHD. Furthermore, dysfunction in lateral prefrontal regions was found. In addition to lateral prefrontal, striatum and posterior parietal regions, the temporal lobe was also less active. These findings suggest deficits in a widespread ‘functional network’ in ADHD that may be fundamental for visuo-spatial information processing and relational reasoning.

Attention deficit hyperactivity disorder, combined type (ADHD-CT) is associated with spatial working memory deficits. These deficits are known to be subserved by dysfunction of neural circuits involving right prefrontal, striatal and parietal brain regions. This study determines whether decreased right prefrontal, striatal and parietal activation with a mental rotation task shown in adolescents with ADHD-CT is also evident in children with ADHD-CT. A cross-sectional study of 12 pre-pubertal, right-handed, 8-12-year-old boys with ADHD-CT and 12 pre-pubertal, right-handed, performance IQ-matched, 8-12-year-old healthy boys, recruited from local primary schools, was completed. Participants underwent functional magnetic resonance imaging while performing a mental rotation task that requires spatial working memory. The two groups did not differ in their accuracy or response times for the mental rotation task. The ADHD-CT group showed significantly less activation in right parieto-occipital areas (cuneus and precuneus, BA 19), the right inferior parietal lobe (BA 40) and the right caudate nucleus. Our findings with a child cohort confirm previous reports of right striatal-parietal dysfunction in adolescents with ADHD-CT. This dysfunction suggests a widespread maturational deficit that may be developmental stage independent.

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.

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.

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.

Objective: Individuals with autism spectrum disorders typically have normal visuospatial abilities but impaired executive functioning, particularly in abilities related to working memory and attention. The aim of this study was to elucidate the functioning of frontoparietal networks underlying spatial working memory processes during mental rotation in persons with autism spectrum disorders. Method: Seven adolescent males with normal IQ with an autism spectrum disorder and nine age- and IQ-matched male comparison subjects underwent functional magnetic resonance imaging scans while performing a mental rotation task. Results: The autism spectrum disorders group showed less activation in lateral and medial premotor cortex, dorsolateral prefrontal cortex, anterior cingulate gyrus, and caudate nucleus. Conclusions: The finding of less activation in prefrontal regions but not in parietal regions supports a model of dysfunction of frontostriatal networks in autism spectrum disorders.

This study aimed to characterize the nature and impact of disruptive mood dysregulation disorder (DMDD) in children with attention-deficit/hyperactivity disorder (ADHD) including its co-occurrence with other comorbidities and its independent influence on daily functioning. Children with ADHD (6-8 years) were recruited through 43 Melbourne schools, using a 2-stage screening (parent and teacher Conners 3 ADHD index) and case-confirmation (Diagnostic Interview Schedule for Children, Version IV; [DISC-IV]) procedure. Proxy DMDD diagnosis was confirmed via items from the oppositional defiant disorder (ODD) and major depressive disorder modules of the DISC-IV. Outcome domains included comorbid mental health disorders, academic functioning, social functioning, child and family quality of life, parent mental health, and parenting behaviors. Unadjusted and adjusted linear and logistic regression were used to compare children with comorbid ADHD and DMDD and children with ADHD without DMDD. Thirty-nine out of 179 children (21.8 %) with ADHD had comorbid DMDD. Children with ADHD and DMDD had a high prevalence of ODD (89.7 %) and any anxiety disorder (41.0 %). Children with ADHD and DMDD had poorer self-control and elevated bullying behaviors than children with ADHD without DMDD. Children with ADHD and DMDD were similar to children with ADHD in the other domains measured when taking into account other comorbidities including ODD. One in five children with ADHD in their second year of formal schooling met criteria for DMDD. There was a very high diagnostic overlap with ODD; however, the use of a proxy DMDD diagnosis containing items from the ODD module of the DISC-IV may have artificially inflated the comorbidity rates. DMDD added to the burden of ADHD particularly in the area of social functioning.

Numerous studies have shown that Major Depressive Disorder (MDD) in adults is associated with deficits in cognitive control. Particularly, impairment on executive function (EF) tasks has been observed. Research into EF deficits in children and adolescents with MDD has reported mixed results and it is currently unclear whether paediatric MDD is characterised by impairments in EF and attention. PsycInfo, Scopus and Medline were systematically searched to identify all studies that have investigated EF and attention in paediatric depressive disorders between 1994 and 2014. 33 studies meeting inclusion/exclusion criteria were identified. While across different domains of EF some studies identified a deficit in the clinical group, the majority of studies failed to find deficits in response inhibition, attentional set shifting, selective attention, verbal working memory, and verbal fluency. More research is needed to clarify the relationship between depressive disorders in children and adolescents and spatial working memory processing, sustaining attention, planning, negative attentional bias and measures of ‘hot’ EF. There is little support for EF deficits in paediatric depression. However, there are numerous methodological problems that may account for null findings. Alternatively, chronicity and/or severity of symptoms may explain discrepancies between cognitive deficits in adult and paediatric MDD. Recommendations for future studies are discussed.

Theory of Mind (ToM) forms an integral component of socially skilled behavior, and is critical for attaining developmentally appropriate goals. The protracted development of ToM is mediated by increasing connectivity between regions of the anatomically distributed ‘mentalizing network’, and may be vulnerable to disruption from pediatric traumatic brain injury (TBI). The present study aimed to evaluate the post-acute effects of TBI on first-order ToM, and examine relations between ToM and both local and global indices of macrostructural damage detected using susceptibility-weighted imaging (SWI). 104 children and adolescents with TBI and 43 age-matched typically developing (TD) controls underwent magnetic resonance imaging including a susceptibility-weighted imaging (SWI) sequence 2–8 weeks post-injury and were assessed on cognitive ToM tasks at 6-months after injury. Compared to TD controls and children with mild-moderate injuries, children with severe TBI showed significantly poorer ToM. Moreover, impairments in ToM were related to diffuse neuropathology, and parietal lobe lesions. Our findings support the vulnerability of the immature social brain network to disruption from TBI, and suggest that global macrostructural damage commonly associated with traumatic axonal injury (TAI) may contribute to structural disconnection of anatomically distributed regions that underlie ToM. This study suggests that SWI may be a valuable imaging biomarker to predict outcome and recovery of social cognition after pediatric TBI.