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 2016-2017, our group has focused on identical twins oen affected by ADHD, the other unaffected- as well as completing a long term study that examined why some indiviudals grow out of ADHD while others do not. Research accomplshments. Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for ADHD (Chen, 2017) The study of monozygotic twins discordant for attention deficit hyperactivity disorder can disentgale genetic from epigenetic mechanisms that contribute to the disorder. First, using in vivo neuroanatomic imaging on 14 pairs of monozygotic twins we found that discordance for the disorder is mirrored by differing dimensions of deep brain structures (the striatum and cerebellum), but not the cerebral cortex. Next, using whole-blood DNA from the same twins, we found a significant enrichment of epigenetic differences in genes expressed in these 'discordant' brain structures. Specifically, there is differential methylation of probes lying in the striatal and cerebellar genes. Notably, gene sets pertaining to the cerebral cortex (which did not differ in volume between affected and unaffected twins) were not enriched by differentially methylated probes. Genotypic differences between the twin pairs-such as copy number and rare, single-nucleotide variants-did not contribute to phenotypic discordance. Pathway analyses of the genes implicated by the most differentially methylated probes implicated -aminobutyric acid (GABA), dopamine and serotonin neurotransmitter systems. The study illustrates how neuroimaging can help guide the search for epigenomic mechanisms in neurodevelopmental disorders. The Heritability of Structural and Functional Brain Connectivity in Families Affected by ADHD (Sudre, 2017) Despite its high heritability, few risk genes have been identified for attention-deficit/hyperactivity disorder (ADHD). We sought to identify the structural and functional connections that are heritable and pertinent to ADHD through recruiting members of extended multigenerational families enriched for ADHD. Heritability and association with ADHD symptoms were estimated in 24 extended multigenerational families. We found that more symptoms of hyperactivity/impulsivity and inattention were associated with decreased functional connectivity within the default mode network. Some cross-modal correlations were purely phenotypic. A genetic cross-modal correlation was seen between the ventral attention network and radial diffusivity of the right inferior fronto-occipital fasciculus. Analysis of data on multigenerational extended and nuclear families identified the features of structural and functional connectivity that are both significantly heritable and associated with ADHD. Shared genetic factors account for some phenotypic correlations between functional and structural connections. This work helps to prioritize the facets of the brain's connectivity for future genomic studies. Response Inhibition in a Neuroimaging Study (Szekely, 2017). Understanding the neural processes tied to the adult outcome of childhood attention deficit hyperactivity disorder (ADHD) could guide novel interventions to improve its clinical course. It has been argued that normalization of prefrontal cortical activity drives remission from ADHD, while anomalies in subcortical processes are fixed, present even in remission. Using multimodal neuroimaging of inhibitory processes we tested these hypotheses in adults followed since childhood, contrasting remitted against persistent ADHD. We scanned 35 persistent ADHD, 35 remitted ADHD, and 47 never affected adult participants with functional MRI, magnetoencephalography, or both during a response inhibition task. In fMRI analyses, during inhibition, right caudate anomalies reflected a childhood ADHD history and were present even among those who remitted. By contrast, differences related to adult outcome emerged in cortical and cerebellar regions. The persistent ADHD group showed under-activation, whereas the remitted ADHD group did not differ significantly from the never-affected group. Magnetoencephalography showed that the association between adult symptom severity and prefrontal neuronal activity was confined to the time window covering the act of inhibition. By combining fMRI and magnetoencephalography, the location and time window of neuronal activity that underpins the adult outcome of ADHD was pinpointed. Thus, the cortico-cerebellar processes tied to the clinical course of ADHD are separated from the subcortical processes that are not.

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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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