The Section on Neurobehavioral Clinical Research was established in the Social and Behavioral Research Branch of the NHGRI in October 2011. This report details progress towards its aim of understanding the interplay between behavioral, social, genetic and brain factors in early human development. The initial focus is on attention deficit hyperactivity disorder (ADHD), the most common psychiatric disorder of childhood. Children with ADHD and typically developing children have clinical, behavioral, neuropsychological assessments along with brain imaging (using a magnetic resonance scanner). These assessments are repeated yearly as the child grows into adolescence and adulthood. In the past year, a new protocol was approved, 120 new subjects were enrolled, and a further 95 subjects returned for re-assessment, and we started to collect detailed behavioral and social data on all participants including details of friendships and the family environment. Research accomplishments. 1) Defining the nature of the disruption in brain development in ADHD. We previously reported that ADHD is characterized by a delay in the age at which the phase of childhood increase in the thickness of the cortex of the brain (its grey matter) gives way to an adolescent phase of thinning. We further asked whether a similar developmental delay is found in the other major determinant of cortical structure, namely the surface of the cortex. Using brain imaging data collected on 234 children with ADHD and 231 children who were unaffected, we defined how the cortical surfaces changed with age. We found that the overall pattern of development was similar between children with and without ADHD. However, surface area development was delayed in ADHD. For the prefrontal cortex, the majority of cortical points had attained their peak surface area by around age 14 in children with ADHD. This was significantly later than the age by which the most of the cortical surfaces had matured in typically developing children (around age 12.5). This study suggests that ADHD is not on the list of disorders that have deficits of either just surface area or cortical thickness, such as dyslexia and autism. This, in turn, has implications for the mechanisms that underpin ADHD. For example, deficits in cortical thickness but not surface area have been linked with mutations of certain genes which impact on the earliest stages of neuronal growth (such as Pax6 and Id4). Our finding of a congruent delay in both cortical thickness and surface area in ADHD points instead to a more global disturbance in the mechanisms that guide cortical maturation. These findings will inform our future genetic studies. 2) Demonstrating neurobiological continuity between the syndrome of ADHD and those with symptoms of the disorder. Our second major completed research project addressed the considerable epidemiological and behavioral evidence that ADHD is best considered dimensionally, lying at the extreme end of a continuous distribution. We thus asked whether cortical development in typically developing children with symptoms of hyperactivity and impulsivity resembles that found in the full syndrome of ADHD. Specifically we examined whether the slower rate of cortical thinning during late childhood and adolescence which we previously found in ADHD, is also linked to the severity of symptoms of hyperactivity and impulsivity in typically developing children. A total of 193 typically developing children with 389 brain images and varying levels of symptoms of hyperactivity and impulsivity were contrasted with 197 children with ADHD. Typically developing youth with higher levels of hyperactive and impulsive symptoms had a slower rate of cortical thinning, predominantly in prefrontal cortical regions. As the number of symptoms of hyperactivity and impulsivity increased, the rate of cortical thinning became slower. Children with the full syndrome of ADHD had the slowest rate of cortical thinning. This study provides the first neurobiological evidence for dimensionality of ADHD. The disturbances in cortical trajectories related to the symptoms of ADHD emerge as an excellent targets for future genetic studies, given that they are a continuously distributed feature present in the entire population. 3) The effects of parental age on brain structure. We have completed a project examining the impact of the age at which a parent has a child on the childs brain development. It is well established that the age at which a parent has a child impacts the child's behavior and risk for mental illness. It appears that this risk is curvilinear, with both age extremes associated with lower intelligence and increased risk of some neuropsychiatric disorders. Little is known of the brain mechanisms underpinning this phenomenon. We extracted grey matter volumes, surface areas, and cortical thickness from 489 neuroanatomic magnetic resonance images acquired on 171 youth and determined the association between parental age and offspring's neuroanatomy. We found that grey matter volume increased with both advancing paternal and maternal age until around the early 30s after which it fell. Paternal age effects were more pronounced on cortical surface area, whereas maternal age impacted more on cortical thickness. There were no significant effects of parental age on white matter volumes. These parental age effects on brain structure may form part of the link between parental age extremes and suboptimal behavioral and psychiatric outcomes. Conclusions and ongoing projects. While this research has demonstrated the role of the brain in ADHD, the disorder is embedded in an array of social contexts that include the family, schools and the larger community. The next stage of our research is to define the influence of these environmental variables on the course of the disorder. Most research to date has focused on relatively stable aspects of the social environment, such as socio-economic class. We are examining more dynamic aspects of a child's social surroundings, such as changes in the child's social network or family environment, that may prove to be powerful determinants of the disorder's clinical course. This work will be complemented by genetic studies that take advantage of the detailed characterization of children with ADHD that we have already accomplished.

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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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