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Attention-deficit/hyperactivity disorder (ADHD) is a prevalent childhood neurodevelopmental disorder. Given the profound brain changes that occur across childhood and adolescence, it is important to identify functional networks that exhibit differential developmental patterns in children with ADHD. This study sought to examine whether children with ADHD exhibit differential developmental trajectories in functional connectivity compared with typically developing children using a network-based approach.This longitudinal neuroimaging study included 175 participants (91 children with ADHD and 84 control children without ADHD) between ages 9 and 14 and up to 3 waves (173 total resting-state scans in children with ADHD and 197 scans in control children). We adopted network-based statistics to identify connected components with trajectories of development that differed between groups.Children with ADHD exhibited differential developmental trajectories compared with typically developing control children in networks connecting cortical and limbic regions as well as between visual and higher-order cognitive regions. A pattern of reduction in functional connectivity between corticolimbic networks was seen across development in the control group that was not present in the ADHD group. Conversely, the ADHD group showed a significant decrease in connectivity between predominantly visual and higher-order cognitive networks that was not displayed in the control group.Our findings show that the developmental trajectories in children with ADHD are characterized by a subnetwork involving different trajectories predominantly between corticolimbic regions and between visual and higher-order cognitive network connections. These findings highlight the importance of examining the longitudinal maturational course to understand the development of functional connectivity networks in children with ADHD.

Sustained attention is a cognitive function with known links to academic success and mental health disorders such as attention/deficit-hyperactivity disorder (ADHD). Several functional networks are critical to sustained attention, however the association between white matter maturation in tracts linking functional nodes and sustained attention in typical and atypical development is unknown. 309 diffusion-weighted imaging scans were acquired from 161 children and adolescents (80 ADHD, 81 control) at up to three timepoints over ages 9-14. A fixel-based analysis approach was used to calculate mean fiber density and fiber-bundle cross section in tracts of interest. Sustained attention was measured using omission errors and response time variability on the out-of-scanner sustained attention to response task. Linear mixed effects models examined associations of age, group and white matter metrics with sustained attention. Greater fiber density in the bilateral superior longitudinal fasciculus (SLF) I and right SLF II was associated with fewer attention errors in the control group only. In ADHD and control groups, greater fiber density in the left ILF and right thalamo-premotor pathway, as well as greater fiber cross-section in the left SLF I and II and right SLF III, was associated with better sustained attention. Relationships were consistent across the age span. Results suggest that greater axon diameter or number in the dorsal and middle SLF may facilitate sustained attention in neurotypical children but does not assist those with ADHD potentially due to disorder-related alterations in this region. Greater capacity for information transfer across the SLF was associated with attention maintenance in 9-14-year-olds regardless of diagnostic status, suggesting white matter macrostructure may also be important for attention maintenance. White matter and sustained attention associations were consistent across the longitudinal study, according with the stability of structural organization over this time. Future studies can investigate modifiability of white matter properties through ADHD medications.

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

BackgroundUndergoing puberty ahead of peers (“earlier pubertal timing”) is an important risk factor for mental health problems during early adolescence. The current study examined pathways between pubertal timing and mental health via connectivity of neural systems implicated in emotional reactivity and regulation (specifically corticolimbic connections) in 9- to 14-year-olds.MethodResearch questions were examined in the Adolescent Brain Cognitive Development (ABCD) Study, a large population representative sample in the United States. Linear mixed models examined associations between pubertal timing and resting-state corticolimbic connectivity. Significant connections were examined as potential mediators of the relationship between pubertal timing and mental health (withdrawn depressed and rule-breaking delinquency) problems. Exploratory analyses interrogated whether the family environment moderated neural risk patterns in those undergoing puberty earlier than their peers.ResultsEarlier pubertal timing was related to decreased connectivity between limbic structures (bilateral amygdala and right hippocampus) and the cingulo-opercular network (CON), as well as between the left hippocampus and ventral attention network (VAN). Corticolimbic connections also mediated the relationship between earlier pubertal timing and increased withdrawn depressed problems (but not rule-breaking delinquency). Finally, parental acceptance buffered against limbic-CON connectivity patterns that were implicated in withdrawn depressed problems in those undergoing puberty earlier than their peers.ConclusionFindings highlight the role of decreased corticolimbic connectivity in mediating pathways between earlier pubertal timing and withdrawn depressed problems, and we present preliminary evidence that the family environment may buffer against these neural risk patterns during early adolescence.

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.

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.

Alterations in cerebellar morphology relative to controls have been identified in children with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and developmental coordination disorder (DCD). However, it is not clear if common cerebellar regions are affected in each neurodevelopmental disorder and whether cerebellar morphological changes reflect a generic developmental vulnerability, or disorder-specific characteristic. The present study concatenated anatomical MRI scans from five existing cohorts, resulting in data from 252 children between the age of 7 and 12 years (ASD = 58, ADHD = 86, DCD = 22, Controls = 86). The ACAPULCO processing pipeline for cerebellar segmentation was conducted on T1-weighted images. A voxel-wise approach with general linear model was used to compare grey-matter volume of the 27 cerebellar lobules between each clinical group and controls. Our findings revealed that the ADHD group showed lower grey-matter volume in the left Crus I - part of the executive/non-motor portion of the cerebellum, relative to controls (p = 0.02). This no longer remained significant after controlling for medication status. There were no regions of significant differences in volume of the cerebellar lobules in ASD or DCD compared to controls. Future work will conduct harmonisation of behavioural data (cognitive and motor outcomes) across cohorts, enabling more advanced analyses to identify symptom cluster across neurodevelopmental disorders.

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.

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.

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.

Delayed recovery from concussion can dramatically affect a child's social, emotional, and educational development, yet little is known about what causes some children to recover faster than others. The contribution of white matter disruption in children with delayed recovery has been hypothesized, but findings are limited by methodological issues such as: small heterogeneous samples, bias toward children with delayed recovery, and inconsistencies in timing of brain imaging, both within and between studies. The aim of the present study was to assess diffusion neuroimaging correlates of delayed recovery post-concussion in children. A prospective, longitudinal, observational cohort study was conducted at a statewide tertiary pediatric hospital. Forty-three children who presented to the emergency department (ED) with concussion (defined according to the Zurich/Berlin Consensus Statement on Concussion in Sport) underwent magnetic resonance imaging (MRI) at a 2 weeks post-injury and were classified as either normally recovering (n = 26) or delayed recovering (n = 17). Diffusion imaging comparison using voxelwise tract-based spatial statistics (TBSS) analysis found no difference between the groups in fractional anisotropy, axial diffusion, radial diffusion, or mean diffusivity metrics (p > 0.05 threshold-free cluster enhancement [TFCE] corrected). Post-hoc tract-based Bayesian analysis found evidence for the null in 11 unique white matter tracts (Bayes factor >3). These findings indicate that delayed recovery from post-concussive symptoms in children is unlikely to be caused by white matter microstructural damage.

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.

The transition from childhood to adolescence involves important neural function, cognition, and behavior changes. However, the links between maturing brain function and sustained attention over this period could be better understood. This study examined typical changes in network functional connectivity over childhood to adolescence, developmental differences in attention deficit/hyperactivity disorder (ADHD), and how functional connectivity might underpin variability in sustained attention development in a longitudinal sample. A total of 398 resting state scans were collected from 173 children and adolescents (88 ADHD, 85 control) at up to three timepoints across ages 9-14 years. The effects of age, sex, and diagnostic group on changes in network functional connectivity were assessed, followed by relationships between functional connectivity and sustained attention development using linear mixed effects modelling. The ADHD group displayed greater decreases in functional connectivity between salience and visual networks compared with controls. Lower childhood functional connectivity between the frontoparietal and several brain networks was associated with more rapid sustained attention development, whereas frontoparietal to dorsal attention network connectivity related to attention trajectories in children with ADHD alone. Brain network segregation may increase into adolescence as predicted by key developmental theories; however, participants with ADHD demonstrated altered developmental trajectories between salience and visual networks. The segregation of the frontoparietal network from other brain networks may be a mechanism supporting sustained attention development. Frontoparietal to dorsal attention connectivity can be a focus for further work in ADHD.

Puberty is linked to mental health problems during adolescence, and in particular, the timing of puberty is thought to be an important risk factor. This study developed a new measure of pubertal timing using multiple pubertal features and nonlinear associations with age and investigated its association with mental health problems. Using the Adolescent Brain Cognitive Development (ABCD) cohort, we implemented three models of pubertal timing by predicting chronological age from i) observed physical development, ii) hormones (testosterone and dehydroepiandrosterone [DHEA]), and iii) a combination of the two, using a supervised machine learning method (n ∼9,900). Accuracy of the new models, and their associations with mental health problems were evaluated. The new pubertal timing measure performed better in capturing age variance compared to a commonly used method, and the physical measure accounted for more variance in mental health, such that earlier pubertal timing was associated with higher symptoms. This study demonstrates the utility for a new model of pubertal timing and suggests that physical maturation may play a predominant role in predicting mental health problems in early adolescence.

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.

Susceptibility weighted imaging (SWI) and resting state functional magnetic resonance imaging have been highlighted as two novel neuroimaging modalities that have been underutilized when attempting to predict whether a child with concussion will recover normally or have a delayed recovery course. This study aimed to investigate whether there was a difference between children who recover normally from a concussion and children with delayed recovery in terms of SWI lesion burden and resting state network makeup. Forty-one children who presented to the emergency department of a tertiary level pediatric hospital with concussion participated in this study as a part of a larger prospective, longitudinal observational cohort study into concussion assessment and recovery. Children underwent neuroimaging 2 weeks post-injury and were classified as either normally recovering (n = 27), or delayed recovering (n = 14) based on their post-concussion symptoms at 2 weeks post-injury. No participants showed lesions detected using SWI; therefore, no group differences could be assessed. No between-group resting state network differences were uncovered using dual regression analysis. These findings, alongside previously published work, suggest that potential causes of delayed recovery from concussion may not be found using current neuroimaging paradigms.

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.

BACKGROUND AND OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) cohort studies have typically involved clinical samples and have usually recruited children across wide age ranges, limiting generalizability across complexity and developmental stage. We compared academic, emotional-behavioral and social functioning at age 10, and predictors of outcomes, in a nonreferred cohort of children recruited at age 7, between those with full-syndrome (FS) ADHD and controls with no ADHD. METHODS: This was a prospective cohort study with a 3-year follow-up period. Children were recruited from 43 socioeconomically diverse schools in Melbourne, Australia. Multi-informant outcomes at age 10 were academic functioning (Wide Range Achievement Test 4; Social Skills Improvement System), emotional-behavioral functioning (Strengths and Difficulties Questionnaire total), and social functioning (Strengths and Difficulties Questionnaire peer problems). Outcomes were compared across the groups by using adjusted random-effects linear regression analyses. RESULTS: In total, 477 children (62% male) were recruited at a mean (SD) age of 7.3 years (0.4). There were 179 participants with FS ADHD, 86 with ST ADHD, and 212 controls. Sample retention was 78.2% at 3-year follow-up. Both the FS and ST groups were functioning worse than controls on almost all outcome measures. The best predictors of outcome for children with ADHD were working memory (academic outcome, P < .001), ADHD symptom severity (emotional-behavioral outcome, parent: P < .001; teacher: P < .01), and autism spectrum disorder symptoms (emotional-behavioral outcome, parent P = .003; social outcome, parent P = .001). CONCLUSIONS: Children with FS and ST ADHD at age 7 experience persisting functional impairments across domains at age 10. The predictors identified at age 7 present potential targets for intervention to ameliorate impairments.

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.

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.

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

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.

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.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).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.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.

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

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.