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 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, 346 new subjects were enrolled, and a further 216 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) The wiring of the brain in adult ADHD. ADHD is far from being a problem confined to childhood, but rather it persists into adulthood in between 20-40% of individuals. Problems with attention tend to be more prominent than hyperactivity-impulsivity in adults and are a major cause of impairment for the individuals in the workplace and in interpersonal relationships. Understanding the neural basis of the variable outcome is not only a public health priority but could also help stimulate novel treatment approaches to promote remission from ADHD. We recently found that severity of adult inattentive symptoms of ADHD was linked with differing developmental trajectories within the cortical components of multiple neural networks supporting attention and cognitive control. A logical next step is to examine the properties of the white matter tracts that constitute the structural connections within these neural systems. This can be attained using diffusion tensor imaging (DTI), which obtains measures related to white matter microstructure- such as fractional anisotropy. Seventy-five young adults, 32 with ADHD persisting from childhood and 43 with symptom remission were contrasted against 74 never-affected comparison subjects. We found that greater adult inattention, but not hyperactivity-impulsivity was associated with significantly lower measures of white matter organization in several major white matter tracts. The anomalies the principle anomalies are identified within neural systems which support facets of attentional control (the inferior fronto-occipital fasciculus) and hot cognitive-affective processes (the uncincate fasciculus), each perhaps contributing to the complex symptom profile of ADHD. This informs our understanding of the multiple pathways that may lead to adult ADHD. Additionally, others have reported that white matter organization is enhanced in response to therapies which bolster sustained attention and improve emotion regulation. Thus mapping changes in white matter microstructure might serve as a biomarker to help evaluate the efficacy and potentially understand the mechanisms of novel interventions. 2) Problems with the regulation of emotions in ADHD. Although it has long been recognized that many individuals with ADHD also have difficulties with emotion regulation, no consensus has been reached on how to conceptualize this clinically challenging domain. Our team in collaboration with leading experts in the field of child psychiatry thus examined the current literature using both quantitative and qualitative methods. Three key findings emerged. First, emotion dysregulation was found to be prevalent in ADHD throughout the lifespan and a major contributor to impairment. Second, emotion dysregulation in ADHD arose from deficits in orienting toward, recognizing, and/or allocating attention to emotional stimuli;these deficits implicate dysfunction within a wide spread brain network, incorporating the striatum, amygdala and medial prefrontal cortical network. Third, while current treatments for ADHD often also ameliorate emotion dysregulation, a focus on this combination of symptoms could help us reframe clinical questions and could stimulate novel therapeutic approaches. As an extension of this work, we are currently delineating the course of symptoms of emotional dysregulation throughout childhood in our cohort, linking symptom course with the development of the underlying brain systems. 3) Ongoing genomic projects. In earlier work, our group demonstrated atypical anatomic development of interconnected brain structures in childhood ADHD- specifically, a lower velocity of growth of the prefrontal cortex (lateral prefrontal and paralimbic regions) and the (ventral) striatum. These brain regions form neural circuits supporting many of the behavioral characteristics of ADHD. I further demonstrated that these developmental trajectories are dimensional, that is quantitative traits that characterize the entire childhood population. Thus, as behavioral problems with impulse and motor control increase in typically developing children, the growth trajectories of key fronto-striatal regions more closely resemble those seen in children with the full syndrome of ADHD. My Section is now looking for genetic variants that influence the growth of these structures, mapping genetic varation throughout the entire genome. This could throw light onto the biological mechanisms underlying dysregulated control of impulses and attention. 4) Ongoing social scientific projects. ADHD is embedded in an array of social contexts that include the family, schools and the larger community. While the family has attracted a great deal of research interest in ADHD, there has been less study of relationships with peers. To address this relative neglect, we have completed a systematic review and meta-analysis of the problems that children with ADHD face in relating to peers. 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. We are extending this work by leveraging advances in the quantification of social behavior and structures. This allows us to map a childs position within positive peer networks defined through being friendly or helpful to one another, or more problematic peer network defined by disliking and being hurtful to one another. Using a longitudinal approach, we are asking whether early ADHD problems predict later difficulties in interpersonal relationships (reflected by less optimal positions within different peer networks- such as being marginalized in helping networks). Demonstrating a link over time would bolster the case for early intervention for ADHD to help prevent later interpersonal problems.

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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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