This report details progress towards our overarching aim of understanding the interplay between behavioral, social, genetic and brain factors in development. The initial focus is on attention deficit hyperactivity disorder (ADHD), the most common psychiatric disorder of childhood that often persists into adulthood. In 2017-2018, our group has focused on (1) examining the neural substrates that accompany remission from ADHD; (2) using the brain as a phenotype in genome wide association study; (3) using data from multigenerational familis affected by ADHD to parse the neuroanatomic correlates of cognition in the disorder; (4) using multiochort data to map the development of the cerebellum in ADHD. Research accomplishments. 1. The brain in those with remitted Many children do not simply outgrow attention deficit hyperactivity disorder (ADHD). The disorder often persists and affects around one in 40 adults, presenting a major public health challenge. Defining the mechanisms that underpin this variable clinical outcome could stimulate novel approaches to boost recovery in ADHD. In a recent study, reported in Proceedings of the National Academy of Science, we mapped the brain's functional architecture in 205 young adults followed clinically since childhood. We find clinically significant inattention persisting from childhood has a disruptive effect on the functional connections within and between the brain's major networks. These disruptions are similar whether defined through direct observation of neuronal activity or measures of hemodynamic change. By contrast, adults who remit from childhood ADHD showed typical brain connectivity, suggesting convergence toward typical brain function may underpin recovery. Such work complements our earlier studies that found that adults who had remitted also did not differ from those who have never had ADHD in white matter microstructure, cortical anatomy or cerebral cortical function during a task of response inhibition. 2. A genome wide association study of brain growth. Genomewide association studies (GWASs) are unraveling the genetics of adult brain neuroanatomy as measured by crosssectional anatomic magnetic resonance imaging (aMRI). However, the genetic mechanisms that shape childhood brain development are, as yet, largely unexplored. In this study we identify common genetic variants associated with childhood brain development as defined by longitudinal aMRI. Genomewide single nucleotide polymorphism (SNP) data were determined in two cohorts: one enriched for attentiondeficit/hyperactivity disorder (ADHD) (LONG cohort: 458 participants; 119 with ADHD) and the other from a populationbased cohort (Generation R: 257 participants). The growth of the brain's major regions (cerebral cortex, white matter, basal ganglia, and cerebellum) and one region of interest (the right lateral prefrontal cortex) were defined on all individuals from two aMRIs, and a GWAS and a pathway analysis were performed. In addition, association between polygenic risk for ADHD and brain growth was determined for the LONG cohort. For white matter growth, GWAS metaanalysis identified a genomewide significant intergenic SNP (rs12386571, P = 9.09 109), near AKR1B10. This gene is part of the aldoketo reductase superfamily and shows neural expression. No enrichment of neural pathways was detected and polygenic risk for ADHD was not associated with the brain growth phenotypes in the LONG cohort that was enriched for the diagnosis of ADHD. The study illustrates the use of a novel brain growth phenotype defined in vivo for further study. The findings were recently published in Genetic Epidemiology (Szekely et al, 2018). 3. Family studies of the brain in ADHD. While the neuroanatomic substrates of symptoms of attention deficit hyperactivity disorder (ADHD) have been investigated, less is known about the neuroanatomic correlates of cognitive abilities pertinent to the disorder, particularly in adults. Here we define the neuroanatomic correlates of key cognitive abilities and determine if there are associations with histories of psychostimulant medication (Muster et al, Psychological Medicine, 2018).. We acquired neuroanatomic magnetic resonance imaging data from 264 members of 60 families. Using linear mixed model regression, we tested for associations between cognitive abilities (working memory, information processing, intelligence, and attention), symptoms and both cortical and subcortical volumes. Symptom severity was associated with spatial working memory, processing speed, and a measure of impulsive responding; these associations did not vary with age (all p > 0.1). The neuroanatomic correlates of ADHD symptoms overlapped significantly with those of working memory and information processing. Psychostimulant medication history was associated with neither cognitive skills nor with a brain-cognition relationships. 4. Collaborative studies of the brain in ADHD Our group led a multicohort study using longitudinal data, to characterize cerebellar development. Growth trajectories of the cerebellar vermis, hemispheres and white matter were estimated using piecewise linear regression from 1,656 youth; of whom 63% had longitudinal data, totaling 2,914 scans. Diagnostic differences in growth were confined to the corpus medullare (cerebellar white matter). The ADHD group showed slower growth in early childhood compared to the typically developing group. This reversed in late childhood, with faster growth in ADHD in the left corpus medullare. The findings are consistent with the concept of ADHD as a disorder of the brain's structural connections, formed partly by developing cortico-cerebellar white matter tracts (Shaw et al, Journal of Child Psychology and Psychiatry, 2018). In another collaborative study, we asked if autism-spectrum disorders (ASD), ADHD and schizophrenia share neuroanatomical variations (Park et al 2018). We used measures of cortical anatomy to estimate the spatial overlap of neuroanatomical variation using traditional univariate methods and developed a novel methodology to determine whether cortical deficits specifically target or are enriched within functional resting-state networks. We found cortical anomalies were preferentially enriched across functional networks rather than clustering spatially. Specifically, cortical thickness showed significant enrichment between patients with Autism Spectrum Disorders (ASD) and those with ADHD in the default mode network, between patients with ASD and those with schizophrenia in the frontoparietal and limbic networks, and between patients with ADHD and those with schizophrenia in the ventral attention network. Our data has also contributed to several international consortia. For example, we provided data to the Enhancing NeuroImaging Genetics through Meta-Analysis Consortium for a study on lateratliy differences in the brain (published in the Proceedings of the National Academy of Science). We have also participated in efforts to harmonize the methods used to ascertain quality of images obtained on different scanners at different sites (White et al, Human Brain mapping 2018).

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Human Genome Research
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Park, Min Tae M; Raznahan, Armin; Shaw, Philip et al. (2018) Neuroanatomical phenotypes in mental illness: identifying convergent and divergent cortical phenotypes across autism, ADHD and schizophrenia. J Psychiatry Neurosci 43:170094
White, Tonya; Jansen, Philip R; Muetzel, Ryan L et al. (2018) Automated quality assessment of structural magnetic resonance images in children: Comparison with visual inspection and surface-based reconstruction. Hum Brain Mapp 39:1218-1231
Kong, Xiang-Zhen; Mathias, Samuel R; Guadalupe, Tulio et al. (2018) Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium. Proc Natl Acad Sci U S A 115:E5154-E5163
Chen, Y-C; Sudre, G; Sharp, W et al. (2018) Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder. Mol Psychiatry 23:683-690
Shaw, Philip; Ishii-Takahashi, Ayaka; Park, Min Tae et al. (2018) A multicohort, longitudinal study of cerebellar development in attention deficit hyperactivity disorder. J Child Psychol Psychiatry 59:1114-1123
Szekely, Eszter; Sudre, Gustavo P; Sharp, Wendy et al. (2017) Defining the Neural Substrate of the Adult Outcome of Childhood ADHD: A Multimodal Neuroimaging Study of Response Inhibition. Am J Psychiatry 174:867-876
Shaw, Philip; Ahn, Kwangmi; Rapoport, Judith L (2017) Good News for Screening for Adult Attention-Deficit/Hyperactivity Disorder. JAMA Psychiatry 74:527
Sudre, Gustavo; Choudhuri, Saadia; Szekely, Eszter et al. (2017) Estimating the Heritability of Structural and Functional Brain Connectivity in Families Affected by Attention-Deficit/Hyperactivity Disorder. JAMA Psychiatry 74:76-84
Hoogman, Martine; Bralten, Janita; Hibar, Derrek P et al. (2017) Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis. Lancet Psychiatry 4:310-319
Shaw, Philip (2016) Quantifying the Benefits and Risks of Methylphenidate as Treatment for Childhood Attention-Deficit/Hyperactivity Disorder. JAMA 315:1953-5

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