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 110 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. ReResearch accomplishments. 1) Mapping the development of brain and behavior in ADHD. Childhood ADHD persists into adulthood in around half of those affected, constituting a major public health challenge. No known demographic, clinical, or neuropsychological factors robustly explain the clinical course, directing our focus to the brain. We looked at the possibility that there are links between how the brain develops and the clinical course of ADHD. We focused on the developmental trajectory of the cerebral cortex. We followed 92 individuals with childhood ADHD (entering the study at a mean of 10 years) conducting clinical assessments repeatedly as they grew into adulthood (the final assessment was at a mean age of 24 years). We also obtained anatomic magnetic brain resonance images on all participants in childhood and adulthood allowing us to link the trajectory of brain development with clinical outcome. We found that childhood ADHD persisted into adulthood in 40% of our participants and that adult symptom severity was linked to cortical trajectories. Specifically, as the number of adult symptoms increased, particularly inattentive symptoms, so did the rate of cortical thinning in the medial and dorsolateral prefrontal cortex. These are key regions in the control of attention. For each increase of one symptom of adult ADHD, the rate of cortical thinning increased by .0018 mm/year, representing a 5.6% change over the mean rate of thinning for the entire group. These differing trajectories resulted in a convergence toward typical dimensions among those who remitted and a fixed, nonprogressive deficit in persistent ADHD. Notably, cortical thickening or minimal thinning in these regions was found exclusively among individuals who remitted. In summary, we found that adult ADHD status is linked with the developmental trajectories of cortical components of networks supporting attention, cognitive control, and the default mode network. This informs our understanding of the developmental pathways to adult ADHD. 2) Mapping the development of the basal ganglia in ADHD. The basal ganglia are implicated in the etiology of ADHD, but little is known of their development in the disorder. The basal ganglia are core components of richly interconnected loops that connect the cortex and thalamus, supporting many cognitive processes impaired in ADHD. We mapped basal ganglia development from childhood into late adolescence using methods that define surface morphology at a millimeter level of spatial resolution. Surface morphology of the basal ganglia was defined from 869 neuroanatomic magnetic resonance images acquired on 270 youth with ADHD and 270 age and sex matched typically developing controls. Three novel findings emerged from this study. First, we found a diagnostic difference in developmental trajectories of one part of the basal ganglia- the ventral striatum. This region shows progressive expansion in typically developing children, but showed surface contraction in ADHD. This ventral striatal region plays an important role in processing rewards, which can impaired in thsoe with ADHD. Second, multiple areas of the basal gnaglia showed surface area reductions in ADHD which are fixed and do not progress with age, including the head and tail of the caudate and inferior-posterior putamen. These regions support executive function and motor planning functions which are also impaired in ADHD. Third, we found no links between treatment with psychostimulants and the development of basal ganglia. In this study we were able to define the trajecotires of striatal development for each idniviudal, thus providing a powerful development phenotype for future gneomic studies. 3) Ongoing projects. We have started a series of projects to explore the problems with social behavior and emotion regulation seen in many individuals with ADHD. ADHD is embedded in an array of social contexts that include the family, schools and the larger community. We recently completed a systematic review and meta-analysis of the problems that children with ADHD face in navigating the social world. We showed that social behavioral factors- such as a child's position within peer networks and behavior towards others within these networks- may be a relatively specific expression of the disorder. We found that the structures of peer friendships formed by children with ADHD are often atypical. Children with ADHD experience more peer rejection, less peer acceptance and tend to inhabit the periphery of their peer groups, associating with peers with behavioral challenges. This is a distinct peer network structure from that seen in children who have autism or severe emotional problems. At a social cognitive level, children with ADHD have impaired emotion recognition and subtle deficits in ability to reason about the thoughts and feelings of others. These social cognitive deficits are generally less severe than those seen in children with autism, and have qualitative differences from those seen among children with oppositional defiant and conduct disorder. This review prompts us to move from viewing ADHD solely as a property of the individual child. Rather, a fuller picture of the disorder emerges when we consider the social behavioral expression of the disorder, incorporating facets such as the structure and function of a childs social networks. This approach will both refine our phenotype of ADHD for future genomic studies and provide novel approaches to treatment. A second aligned project examines the makred overlap between ADHD and difficulties with emotion regulation. Through a systematic review and meta-analysis of the current literature, three main themes emerged. Firstly, problems in regulating emotions are highly prevalent in ADHD throughout the lifespan and are a major contributor to overall impairment. Secondly, emotional dysregulation in ADHD may arise from deficits in orienting towards, recognizing and allowing attention to emotional stimuli, deficits that implicate dysfunction within large scale brain networks (amygdalo-medial prefrontal cortical networks). Finally while current treatments for ADHD often also ameliorate associate emotional dysregulation, there is still a need for novel treatment approaches. A major challenge we plan to tackle in 2014 is to integrate our detailed clinical characteristization with multi-modal neuroimaging, genomics and increasingly refined analyses of social behavior and emotional well-being.

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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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