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      Distinct effects of childhood ADHD and cannabis use on brain functional architecture in young adults

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          Abstract

          One of the most salient long-term implications of a childhood diagnosis of ADHD is an increased risk for substance use, abuse, or dependence in adolescence and adulthood. The extent to which cannabis use affects ADHD-related alterations in brain functional organization is unknown, however. To address this research gap, we recruited a sample of 75 individuals aged 21–25 years with and without a childhood diagnosis of ADHD Combined Type, who were either frequent users or non-users of cannabis. These participants have been followed longitudinally since age 7–9.9 years as part of a large multi-site longitudinal study of ADHD, the Multimodal Treatment Study of Children with ADHD (MTA). We examined task-independent intrinsic functional connectivity (iFC) within 9 functional networks using a 2 × 2 design, which compared four groups of participants: (1) individuals with a childhood diagnosis of ADHD who currently use cannabis ( n = 23); (2) individuals with ADHD who do not currently use cannabis ( n = 22); (3) comparisons who currently use cannabis ( n = 15); and (4) comparisons who do not currently use cannabis ( n = 15). The main effects of childhood ADHD were primarily weakened iFC in networks supporting executive function and somatomotor control. Contrary to expectations, effects of cannabis use were distinct from those of diagnostic group and no interactions were observed. Exploratory brain-behavior analyses suggested that ADHD-related effects were primarily linked with poorer neurocognitive performance. Deficits in the integrity of functional networks supporting executive function and somatomotor control are consistent with the phenotypic and neurocognitive features of ADHD. Our data suggest that cannabis use does not exacerbate ADHD-related alterations, but this finding awaits replication in a larger sample. Longitudinal neuroimaging studies are urgently required to delineate the neurodevelopmental cascade that culminates in positive and negative outcomes for those diagnosed with ADHD in childhood.

          Highlights

          • Alterations in functional organization persist in those with childhood ADHD.

          • Network alterations can be linked with specific aspects of the ADHD phenotype.

          • Cannabis use does not appear to exacerbate ADHD-related alterations.

          • Longitudinal studies are required to capture the long-term impact of cannabis use.

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          Cognitive control and right ventrolateral prefrontal cortex: reflexive reorienting, motor inhibition, and action updating.

          Delineating the functional organization of the prefrontal cortex is central to advancing models of goal-directed cognition. Considerable evidence indicates that specific forms of cognitive control are associated with distinct subregions of the left ventrolateral prefrontal cortex (VLPFC), but less is known about functional specialization within the right VLPFC. We report a functional MRI meta-analysis of two prominent theories of right VLPFC function: stopping of motor responses and reflexive orienting to abrupt perceptual onsets. Along with a broader review of right VLPFC function, extant data indicate that stopping and reflexive orienting similarly recruit the inferior frontal junction (IFJ), suggesting that IFJ supports the detection of behaviorally relevant stimuli. By contrast, other right VLPFC subregions are consistently active during motor inhibition, but not reflexive reorienting tasks, with posterior-VLPFC being active during the updating of action plans and mid-VLPFC responding to decision uncertainty. These results highlight the rich functional heterogeneity that exists within right VLPFC. © 2011 New York Academy of Sciences.
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            Prospective association of childhood attention-deficit/hyperactivity disorder (ADHD) and substance use and abuse/dependence: a meta-analytic review.

            Given the clinical and public health significance of substance disorders and the need to identify their early risk factors, we examined the association of childhood attention-deficit/hyperactivity disorder (ADHD) with substance use (nicotine, alcohol, marijuana) and abuse/dependence outcomes (nicotine, alcohol, marijuana, cocaine, other). To strengthen a potential causal inference, we meta-analyzed longitudinal studies that prospectively followed children with and without ADHD into adolescence or adulthood. Children with ADHD were significantly more likely to have ever used nicotine and other substances, but not alcohol. Children with ADHD were also more likely to develop disorders of abuse/dependence for nicotine, alcohol, marijuana, cocaine, and other substances (i.e., unspecified). Sex, age, race, publication year, sample source, and version of the Diagnostic and Statistical Manual of Mental Disorders (DSM) used to diagnose ADHD did not significantly moderate the associations with substance outcomes that yielded heterogeneous effect sizes. These findings suggest that children with ADHD are significantly more likely to develop substance use disorders than children without ADHD and that this increased risk is robust to demographic and methodological differences that varied across the studies. Finally, few studies addressed ADHD and comorbid disruptive behavior disorders (DBD), thus preventing a formal meta-analytic review. However, we qualitatively summarize the results of these studies and conclude that comorbid DBD complicates inferences about the specificity of ADHD effects on substance use outcomes. Copyright © 2011 Elsevier Ltd. All rights reserved.
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              Clinical and functional outcome of childhood attention-deficit/hyperactivity disorder 33 years later.

              CONTEXT Prospective studies of childhood attention-deficit/hyperactivity disorder (ADHD) have not extended beyond early adulthood. OBJECTIVE To examine whether children diagnosed as having ADHD at a mean age of 8 years (probands) have worse educational, occupational, economic, social, and marital outcomes and higher rates of ongoing ADHD, antisocial personality disorder (ASPD), substance use disorders (SUDs), adult-onset psychiatric disorders, psychiatric hospitalizations, and incarcerations than non-ADHD comparison participants at a mean age of 41 years. DESIGN Prospective, 33-year follow-up study, with masked clinical assessments. SETTING Research clinic. PARTICIPANTS A total of 135 white men with ADHD in childhood, free of conduct disorder, and 136 men without childhood ADHD (65.2% and 76.4% of original cohort, respectively). MAIN OUTCOME MEASURES Occupational, economic, and educational attainment; marital history; occupational and social functioning; ongoing and lifetime psychiatric disorders; psychiatric hospitalizations; and incarcerations. RESULTS Probands had significantly worse educational, occupational, economic, and social outcomes; more divorces; and higher rates of ongoing ADHD (22.2% vs 5.1%, P < .001), ASPD (16.3% vs 0%, P < .001), and SUDs (14.1% vs 5.1%, P = .01) but not more mood or anxiety disorders (P = .36 and .33) than did comparison participants. Ongoing ADHD was weakly related to ongoing SUDs (ϕ = 0.19, P = .04), as well as ASPD with SUDs (ϕ = 0.20, P = .04). During their lifetime, probands had significantly more ASPD and SUDs but not mood or anxiety disorders and more psychiatric hospitalizations and incarcerations than comparison participants. Relative to comparisons, psychiatric disorders with onsets at 21 years or older were not significantly elevated in probands. Probands without ongoing psychiatric disorders had worse social, but not occupational, functioning. CONCLUSIONS The multiple disadvantages predicted by childhood ADHD well into adulthood began in adolescence, without increased onsets of new disorders after 20 years of age. Findings highlight the importance of extended monitoring and treatment of children with ADHD.
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                Author and article information

                Contributors
                Journal
                Neuroimage Clin
                Neuroimage Clin
                NeuroImage : Clinical
                Elsevier
                2213-1582
                15 September 2016
                2017
                15 September 2016
                : 13
                : 188-200
                Affiliations
                [a ]School of Psychology, Trinity College Dublin, Dublin, Ireland
                [b ]Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland
                [c ]Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
                [d ]Center for Neurodevelopmental Disorders, Child Study Center, New York University Langone Medical Center, New York, NY, USA
                [e ]Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA
                [f ]National Adoption & Fostering Team, Michael Rutter Center, Maudsley Hospital, London, UK
                [g ]University of Wisconsin-Milwaukee, Psychology Department, 2441 E. Hartford Ave, Milwaukee, WI, USA
                [h ]Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, ML10006 Cincinnati, OH, USA
                [i ]Center for Human Development, University of California, San Diego, La Jolla, CA, USA
                [j ]Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA
                [k ]Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
                [l ]Department of Radiology, University of California, San Diego, La Jolla, CA, USA
                [m ]Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
                [n ]Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
                [o ]Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA
                [p ]Department of Psychiatry, Columbia University, New York, NY, USA
                [q ]Department of Psychiatry and Human Behavior, School of Medicine, University of California Irvine, Irvine, CA, USA
                [r ]Department of Psychology, University of California-Berkeley, Berkeley, CA, USA
                [s ]Child Development Center, University of California, Irvine, Irvine, CA, USA
                Author notes
                [* ]Corresponding author at: Trinity College Institute of Neuroscience, School of Psychology, Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin 2, Ireland; Center for Neurodevelopmental Disorders, Child Study Center, NYU Langone Medical Center, New York, NY 10016, USA.Trinity College Institute of Neuroscience, School of Psychology, Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin 2, IrelandCenter for Neurodevelopmental DisordersChild Study CenterNYU Langone Medical CenterNew YorkNY10016USA clare.kelly@ 123456tcd.ie clare.kelly@ 123456nyumc.org
                [1]

                The Multimodal Treatment Study of Children with ADHD (MTA) was a National Institute of Mental Health (NIMH) cooperative agreement randomized clinical trial, continued under an NIMH contract as a follow-up study and finally under a National Institute on Drug Abuse (NIDA) contract. Collaborators from NIMH: Benedetto Vitiello, M.D. (Child & Adolescent Treatment and Preventive Interventions Research Branch), Joanne B. Severe, M.S. (Clinical Trials Operations and Biostatistics Unit, Division of Services and Intervention Research), Peter S. Jensen, M.D. (currently at REACH Institute and Mayo Clinic), L. Eugene Arnold, M.D., M.Ed. (currently at Ohio State University), Kimberly Hoagwood, Ph.D. (currently at Columbia); previous contributors from NIMH to the early phases: John Richters, Ph.D. (currently at National Institute of Nursing Research); Donald Vereen, M.D. (currently at NIDA). Principal investigators and co-investigators from the sites are: University of California, Berkeley/San Francisco: Stephen P. Hinshaw, Ph.D. (Berkeley), Glen R. Elliott, Ph.D., M.D. (San Francisco); Duke University Medical Center: Karen C. Wells, Ph.D., Jeffery N. Epstein, Ph.D. (currently at Cincinnati Children's Hospital Medical Center), Desiree W. Murray, Ph.D.; previous Duke contributors to early phases: C. Keith Conners, Ph.D. (former PI); John March, M.D., M.P.H.; University of California, Irvine: James Swanson, Ph.D., Timothy Wigal, Ph.D.; previous contributor from UCLA to the early phases: Dennis P. Cantwell, M.D. (deceased); New York University: Howard B. Abikoff, Ph.D.; Montreal Children's Hospital/ McGill University: Lily Hechtman, M.D.; New York State Psychiatric Institute/Columbia University/Mount Sinai Medical Center: Laurence L. Greenhill, M.D. (Columbia), Jeffrey H. Newcorn, M.D. (Mount Sinai School of Medicine). University of Pittsburgh: Brooke Molina, Ph.D., Betsy Hoza, Ph.D. (currently at University of Vermont), William E. Pelham, Ph.D. (PI for early phases, currently at Florida International University). Follow-up phase statistical collaborators: Robert D. Gibbons, Ph.D. (University of Illinois, Chicago); Sue Marcus, Ph.D. (Mt. Sinai College of Medicine); Kwan Hur, Ph.D. (University of Illinois, Chicago). Original study statistical and design consultant: Helena C. Kraemer, Ph.D. (Stanford University). Collaborator from the Office of Special Education Programs/US Department of Education: Thomas Hanley, Ed.D. Collaborator from Office of Juvenile Justice and Delinquency Prevention/Department of Justice: Karen Stern, Ph.D. Additional investigators for Neuroimaging Substudy: Leanne Tamm, Ph.D., PI (Cincinnati Children's Hospital Medical Center), James Bjork, Ph.D. (Division of Clinical Neuroscience and Behavioral Research, NIDA; currently at Virginia Commonwealth University), Daniel Mathalon, M.D., Ph.D. (UC San Francisco), Allen Song, Ph.D. (Duke), Bradley Peterson, M.D. (Columbia), Steven Potkin, M.D. & Claudia Buss, Ph.D. (UC Irvine), Katerina Velanova, Ph.D. (Pittsburgh), Neuroimaging Consultants: Susan Tapert, Ph.D. & Joshua Kuperman, Ph.D. (UC San Diego), BJ Casey, Ph.D. & Leah Sommerville, Ph.D. (Sackler Institute, Cornell), Krista Lisdahl, Ph.D. (University of Wisconsin-Milwaukee). Neuroimaging Analysis and Interpretation: Terry Jernigan, Ph.D. & Anders Dale, Ph.D. (UC San Diego), F. Xavier Castellanos, M.D. & Clare Kelly, Ph.D. (New York University).

                Article
                S2213-1582(16)30170-X
                10.1016/j.nicl.2016.09.012
                5153452
                27995073
                f7b14884-9834-44c1-9234-68699ac0ca92
                © 2016 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 22 June 2016
                : 4 September 2016
                : 15 September 2016
                Categories
                Regular Article

                adhd,cannabis,marijuana,fmri,functional connectivity,neurocognitive

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