Advertisement

Prefrontal Cortex Dopamine Transporter Gene Network Moderates the Effect of Perinatal Hypoxic-Ischemic Conditions on Cognitive Flexibility and Brain Gray Matter Density in Children

  • Patrícia Maidana Miguel
    Affiliations
    Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
    Search for articles by this author
  • Lenir Orlandi Pereira
    Affiliations
    Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
    Search for articles by this author
  • Barbara Barth
    Affiliations
    Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada

    Integrated Program in Neuroscience, Faculty of Medicine, McGill University, Montréal, Quebec, Canada
    Search for articles by this author
  • Euclides José de Mendonça Filho
    Affiliations
    Programa de Pós-Graduação em Psicologia, Instituto de Psicologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada
    Search for articles by this author
  • Irina Pokhvisneva
    Affiliations
    Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada
    Search for articles by this author
  • Thao T.T. Nguyen
    Affiliations
    Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada
    Search for articles by this author
  • Elika Garg
    Affiliations
    Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada
    Search for articles by this author
  • Bruna Regis Razzolini
    Affiliations
    Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada

    Integrated Program in Neuroscience, Faculty of Medicine, McGill University, Montréal, Quebec, Canada
    Search for articles by this author
  • Dawn Xin Ping Koh
    Affiliations
    Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore, Singapore
    Search for articles by this author
  • Heather Gallant
    Affiliations
    Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, Ontario, Canada
    Search for articles by this author
  • Roberto Britto Sassi
    Affiliations
    Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
    Search for articles by this author
  • Geoffrey B.C. Hall
    Affiliations
    Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, Ontario, Canada
    Search for articles by this author
  • Kieran John O’Donnell
    Affiliations
    Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada

    Department of Psychiatry, Faculty of Medicine, McGill University, Montréal, Quebec, Canada
    Search for articles by this author
  • Michael J. Meaney
    Affiliations
    Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada

    Integrated Program in Neuroscience, Faculty of Medicine, McGill University, Montréal, Quebec, Canada

    Department of Psychiatry, Faculty of Medicine, McGill University, Montréal, Quebec, Canada

    Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore, Singapore
    Search for articles by this author
  • Patrícia Pelufo Silveira
    Correspondence
    Address correspondence to Patrícia Pelufo Silveira, M.D., Ph.D., Department of Psychiatry, Faculty of Medicine, McGill University, Douglas Hospital Research Centre, 6875 Boulevard LaSalle, Montréal, QC, H4H 1R3, Canada.
    Affiliations
    Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada

    Integrated Program in Neuroscience, Faculty of Medicine, McGill University, Montréal, Quebec, Canada

    Department of Psychiatry, Faculty of Medicine, McGill University, Montréal, Quebec, Canada
    Search for articles by this author

      Abstract

      Background

      Genetic polymorphisms of the dopamine transporter gene (DAT1) and perinatal complications associated with poor oxygenation are risk factors for attentional problems in childhood and may show interactive effects.

      Methods

      We created a novel expression-based polygenic risk score (ePRS) reflecting variations in the function of the DAT1 gene network (ePRS-DAT1) in the prefrontal cortex and explored the effects of its interaction with perinatal hypoxic-ischemic–associated conditions on cognitive flexibility and brain gray matter density in healthy children from two birth cohorts—MAVAN from Canada (n = 139 boys and girls) and GUSTO from Singapore (n = 312 boys and girls).

      Results

      A history of exposure to several perinatal hypoxic-ischemic–associated conditions was associated with impaired cognitive flexibility only in the high-ePRS group, suggesting that variation in the prefrontal cortex expression of genes involved in dopamine reuptake is associated with differences in this behavior. Interestingly, this result was observed in both ethnically distinct birth cohorts. Additionally, parallel independent component analysis (MAVAN cohort, n = 40 children) demonstrated relationships between single nucleotide polymorphism–based ePRS and gray matter density in areas involved in executive (cortical regions) and integrative (bilateral thalamus and putamen) functions, and these relationships differ in children from high and low exposure to hypoxic-ischemic–associated conditions.

      Conclusions

      These findings reveal that the impact of conditions associated with hypoxia-ischemia on brain development and executive functions is moderated by genotypes associated with dopamine signaling in the prefrontal cortex. We discuss the potential impact of innovative genomic and environmental measures for the identification of children at high risk for impaired executive functions.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Giros B.
        • Caron M.G.
        Molecular characterization of the dopamine transporter.
        Trends Pharmacol Sci. 1993; 14: 43-49
        • Mortensen O.V.
        • Amara S.G.
        Dynamic regulation of the dopamine transporter.
        Eur J Pharmacol. 2003; 479: 159-170
        • Minzenberg M.J.
        Pharmacotherapy for attention-deficit/hyperactivity disorder: From cells to circuits.
        Neurotherapeutics. 2012; 9: 610-621
        • Treuer T.
        • Gau S.S.
        • Mendez L.
        • Montgomery W.
        • Monk J.A.
        • Altin M.
        • et al.
        A systematic review of combination therapy with stimulants and atomoxetine for attention-deficit/hyperactivity disorder, including patient characteristics, treatment strategies, effectiveness, and tolerability.
        J Child Adolesc Psychopharmacol. 2013; 23: 179-193
        • Vaughan B.
        • Kratochvil C.J.
        Pharmacotherapy of pediatric attention-deficit/hyperactivity disorder.
        Child Adolesc Psychiatr Clin N Am. 2012; 21: 941-955
        • Piccini P.P.
        Dopamine transporter: Basic aspects and neuroimaging.
        Mov Disord. 2003; 18: S3-S8
        • Sesack S.R.
        • Hawrylak V.A.
        • Matus C.
        • Guido M.A.
        • Levey A.I.
        Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter.
        J Neurosci. 1998; 18: 2697-2708
        • Berridge C.W.
        • Devilbiss D.M.
        • Andrzejewski M.E.
        • Arnsten A.F.
        • Kelley A.E.
        • Schmeichel B.
        • et al.
        Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function.
        Biol Psychiatry. 2006; 60: 1111-1120
        • Devilbiss D.M.
        • Berridge C.W.
        Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness.
        Biol Psychiatry. 2008; 64: 626-635
        • Schmeichel B.E.
        • Berridge C.W.
        Neurocircuitry underlying the preferential sensitivity of prefrontal catecholamines to low-dose psychostimulants.
        Neuropsychopharmacology. 2013; 38: 1078-1084
        • Spencer R.C.
        • Klein R.M.
        • Berridge C.W.
        Psychostimulants act within the prefrontal cortex to improve cognitive function.
        Biol Psychiatry. 2012; 72: 221-227
        • Bahcivan Saydam R.
        • Ayvasik H.B.
        • Alyanak B.
        Executive functioning in subtypes of attention deficit hyperactivity disorder.
        Noro Psikiyatr Ars. 2015; 52: 386-392
        • Martel M.
        • Nikolas M.
        • Nigg J.T.
        Executive function in adolescents with ADHD.
        J Am Acad Child Adolesc Psychiatry. 2007; 46: 1437-1444
        • Marzocchi G.M.
        • Oosterlaan J.
        • Zuddas A.
        • Cavolina P.
        • Geurts H.
        • Redigolo D.
        • et al.
        Contrasting deficits on executive functions between ADHD and reading disabled children.
        J Child Psychol Psychiatry. 2008; 49: 543-552
        • Franke B.
        • Faraone S.V.
        • Asherson P.
        • Buitelaar J.
        • Bau C.H.
        • Ramos-Quiroga J.A.
        • et al.
        The genetics of attention deficit/hyperactivity disorder in adults, a review.
        Mol Psychiatry. 2012; 17: 960-987
        • Cook Jr., E.H.
        • Stein M.A.
        • Krasowski M.D.
        • Cox N.J.
        • Olkon D.M.
        • Kieffer J.E.
        • et al.
        Association of attention-deficit disorder and the dopamine transporter gene.
        Am J Hum Genet. 1995; 56: 993-998
        • Cornish K.M.
        • Manly T.
        • Savage R.
        • Swanson J.
        • Morisano D.
        • Butler N.
        • et al.
        Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample.
        Mol Psychiatry. 2005; 10: 686-698
        • de Azeredo L.A.
        • Rovaris D.L.
        • Mota N.R.
        • Polina E.R.
        • Marques F.Z.
        • Contini V.
        • et al.
        Further evidence for the association between a polymorphism in the promoter region of SLC6A3/DAT1 and ADHD: Findings from a sample of adults.
        Eur Arch Psychiatry Clin Neurosci. 2014; 264: 401-408
        • Gaiteri C.
        • Ding Y.
        • French B.
        • Tseng G.C.
        • Sibille E.
        Beyond modules and hubs: the potential of gene coexpression networks for investigating molecular mechanisms of complex brain disorders.
        Genes Brain Behav. 2014; 13: 13-24
        • Ramanan V.K.
        • Shen L.
        • Moore J.H.
        • Saykin A.J.
        Pathway analysis of genomic data: Concepts, methods, and prospects for future development.
        Trends Genet. 2012; 28: 323-332
        • Biederman J.
        • Faraone S.V.
        Attention-deficit hyperactivity disorder.
        Lancet. 2005; 366: 237-248
        • Getahun D.
        • Rhoads G.G.
        • Demissie K.
        • Lu S.E.
        • Quinn V.P.
        • Fassett M.J.
        • et al.
        In utero exposure to ischemic-hypoxic conditions and attention-deficit/hyperactivity disorder.
        Pediatrics. 2013; 131: e53-e61
        • Zhu T.
        • Gan J.
        • Huang J.
        • Li Y.
        • Qu Y.
        • Mu D.
        Association between perinatal hypoxic-ischemic conditions and attention-deficit/hyperactivity disorder: A meta-analysis.
        J Child Neurol. 2016; 31: 1235-1244
        • Sucksdorff M.
        • Lehtonen L.
        • Chudal R.
        • Suominen A.
        • Gissler M.
        • Sourander A.
        Lower Apgar scores and Caesarean sections are related to attention-deficit/hyperactivity disorder.
        Acta Paediatr. 2018; 107: 1750-1758
        • Miguel P.M.
        • Deniz B.F.
        • Deckmann I.
        • Confortim H.D.
        • Diaz R.
        • Laureano D.P.
        • et al.
        Prefrontal cortex dysfunction in hypoxic-ischaemic encephalopathy contributes to executive function impairments in rats: Potential contribution for attention-deficit/hyperactivity disorder.
        World J Biol Psychiatry. 2018; 19: 547-560
        • O'Donnell K.A.
        • Gaudreau H.
        • Colalillo S.
        • Steiner M.
        • Atkinson L.
        • Moss E.
        • et al.
        The maternal adversity, vulnerability and neurodevelopment project: Theory and methodology.
        Can J Psychiatry. 2014; 59: 497-508
        • Soh S.E.
        • Chong Y.S.
        • Kwek K.
        • Saw S.M.
        • Meaney M.J.
        • Gluckman P.D.
        • et al.
        Insights from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) cohort study.
        Ann Nutr Metab. 2014; 64: 218-225
        • Silveira P.P.
        • Pokhvisneva I.
        • Parent C.
        • Cai S.
        • Rema A.S.S.
        • Broekman B.F.P.
        • et al.
        Cumulative prenatal exposure to adversity reveals associations with a broad range of neurodevelopmental outcomes that are moderated by a novel, biologically informed polygenetic score based on the serotonin transporter solute carrier family C6, member 4 (SLC6A4) gene expression.
        Dev Psychopathol. 2017; 29: 1601-1617
        • Hari Dass S.A.
        • McCracken K.
        • Pokhvisneva I.
        • Chen L.M.
        • Garg E.
        • Nguyen T.T.T.
        • et al.
        A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regions.
        EBioMedicine. 2019; 42: 188-202
        • Linnet K.M.
        • Dalsgaard S.
        • Obel C.
        • Wisborg K.
        • Henriksen T.B.
        • Rodriguez A.
        • et al.
        Maternal lifestyle factors in pregnancy risk of attention deficit hyperactivity disorder and associated behaviors: Review of the current evidence.
        Am J Psychiatry. 2003; 160: 1028-1040
        • Smith T.F.
        • Schmidt-Kastner R.
        • McGeary J.E.
        • Kaczorowski J.A.
        • Knopik V.S.
        Pre- and perinatal ischemia-hypoxia, the ischemia-hypoxia response pathway, and ADHD risk.
        Behav Genet. 2016; 46: 467-477
        • Leinonen E.
        • Gissler M.
        • Haataja L.
        • Rahkonen P.
        • Andersson S.
        • Metsaranta M.
        • et al.
        Low Apgar scores at both one and five minutes are associated with long-term neurological maorbidity.
        Acta Paediatr. 2018; 107: 942-951
        • Kramer M.S.
        • Platt R.W.
        • Wen S.W.
        • Joseph K.S.
        • Allen A.
        • Abrahamowicz M.
        • et al.
        A new and improved population-based Canadian reference for birth weight for gestational age.
        Pediatrics. 2001; 108: E35
        • Kramer M.S.
        • Platt R.
        • Yang H.
        • McNamara H.
        • Usher R.H.
        Are all growth-restricted newborns created equal(ly)?.
        Pediatrics. 1999; 103: 599-602
        • Distefano C.
        • Zhu M.
        • Mîndrilă D.
        Understanding and using factor scores: Considerations for the applied researcher.
        Pract Assess Res Eval. 2009; 14: 1-11
        • Jazbec S.
        • Pantelis C.
        • Robbins T.
        • Weickert T.
        • Weinberger D.R.
        • Goldberg T.E.
        Intra-dimensional/extra-dimensional set-shifting performance in schizophrenia: Impact of distractors.
        Schizophr Res. 2007; 89: 339-349
        • Zelazo P.D.
        The Dimensional Change Card Sort (DCCS): A method of assessing executive function in children.
        Nat Protoc. 2006; 1: 297-301
        • Khadka S.
        • Pearlson G.D.
        • Calhoun V.D.
        • Liu J.
        • Gelernter J.
        • Bessette K.L.
        • et al.
        Multivariate imaging genetics study of MRI gray matter volume and SNPs reveals biological pathways correlated with brain structural differences in attention deficit hyperactivity disorder.
        Front Psychiatry. 2016; 7: 128
        • Liu J.
        • Ghassemi M.M.
        • Michael A.M.
        • Boutte D.
        • Wells W.
        • Perrone-Bizzozero N.
        • et al.
        An ICA with reference approach in identification of genetic variation and associated brain networks.
        Front Hum Neurosci. 2012; 6: 21
        • Galili T.
        • O'Callaghan A.
        • Sidi J.
        • Sievert C.
        heatmaply: an R package for creating interactive cluster heatmaps for online publishing.
        Bioinformatics. 2018; 34: 1600-1602
        • Demontis D.
        • Walters R.K.
        • Martin J.
        • Mattheisen M.
        • Als T.D.
        • Agerbo E.
        • et al.
        Discovery of the first genome-wide significant risk loci for ADHD.
        Nat Genet. 2019; 51: 63-75
        • Gatley S.J.
        • Pan D.
        • Chen R.
        • Chaturvedi G.
        • Ding Y.S.
        Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters.
        Life Sci. 1996; 58: 231-239
        • Thakur G.A.
        • Grizenko N.
        • Sengupta S.M.
        • Schmitz N.
        • Joober R.
        The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD.
        BMC Psychiatry. 2010; 10: 50
        • Cheadle J.
        • Goosby B.J.
        Birth weight, cognitive development, and life chances: A comparison of siblings from childhood into early adulthood.
        Soc Sci Res. 2010; 39: 570-584
        • Lee H.
        • Barratt M.S.
        Cognitive development of preterm low birth weight children at 5 to 8 years old.
        J Dev Behav Pediatr. 1993; 14: 242-249
        • Yang S.
        • Platt R.W.
        • Kramer M.S.
        Variation in child cognitive ability by week of gestation among healthy term births.
        Am J Epidemiol. 2010; 171: 399-406
        • Saha S.
        • Barnett A.G.
        • Buka S.L.
        • McGrath J.J.
        Maternal age and paternal age are associated with distinct childhood behavioural outcomes in a general population birth cohort.
        Schizophr Res. 2009; 115: 130-135
        • Raizada R.D.
        • Kishiyama M.M.
        Effects of socioeconomic status on brain development, and how cognitive neuroscience may contribute to levelling the playing field.
        Front Hum Neurosci. 2010; 4: 3
        • Patra K.
        • Greene M.M.
        • Patel A.L.
        • Meier P.
        Maternal education level predicts cognitive, language, and motor outcome in preterm infants in the second year of life.
        Am J Perinatol. 2016; 33: 738-744
        • Kang H.J.
        • Kawasawa Y.I.
        • Cheng F.
        • Zhu Y.
        • Xu X.
        • Li M.
        • et al.
        Spatio-temporal transcriptome of the human brain.
        Nature. 2011; 478: 483-489
        • Mehta M.A.
        • Manes F.F.
        • Magnolfi G.
        • Sahakian B.J.
        • Robbins T.W.
        Impaired set-shifting and dissociable effects on tests of spatial working memory following the dopamine D2 receptor antagonist sulpiride in human volunteers.
        Psychopharmacology (Berl). 2004; 176: 331-342
        • Yang P.
        • Chung L.C.
        • Chen C.S.
        • Chen C.C.
        Rapid improvement in academic grades following methylphenidate treatment in attention-deficit hyperactivity disorder.
        Clin Neurophysiol. 2004; 58: 37-41
        • Agudelo J.A.
        • Galvez J.M.
        • Fonseca D.J.
        • Mateus H.E.
        • Talero-Gutierrez C.
        • Velez-Van-Meerbeke A.
        Evidence of an association between 10/10 genotype of DAT1 and endophenotypes of attention deficit/hyperactivity disorder.
        Neurologia. 2015; 30: 137-143
        • Bellgrove M.A.
        • Barry E.
        • Johnson K.A.
        • Cox M.
        • Daibhis A.
        • Daly M.
        • et al.
        Spatial attentional bias as a marker of genetic risk, symptom severity, and stimulant response in ADHD.
        Neuropsychopharmacology. 2008; 33: 2536-2545
        • Franke B.
        • Hoogman M.
        • Arias Vasquez A.
        • Heister J.G.
        • Savelkoul P.J.
        • Naber M.
        • et al.
        Association of the dopamine transporter (SLC6A3/DAT1) gene 9–6 haplotype with adult ADHD.
        Am J Med Genet B Neuropsychiatr Genet. 2008; 147B: 1576-1579
        • Jaber M.
        • Jones S.
        • Giros B.
        • Caron M.G.
        The dopamine transporter: A crucial component regulating dopamine transmission.
        Mov Disord. 1997; 12: 629-633
        • Vaughan R.A.
        • Foster J.D.
        Mechanisms of dopamine transporter regulation in normal and disease states.
        Trends Pharmacol Sci. 2013; 34: 489-496
        • Zhu J.
        • Reith M.E.
        Role of the dopamine transporter in the action of psychostimulants, nicotine, and other drugs of abuse.
        CNS Neurol Disord Drug Targets. 2008; 7: 393-409
        • Ketzer C.R.
        • Gallois C.
        • Martinez A.L.
        • Rohde L.A.
        • Schmitz M.
        Is there an association between perinatal complications and attention-deficit/hyperactivity disorder-inattentive type in children and adolescents?.
        Braz J Psychiatry. 2012; 34: 321-328
        • Milberger S.
        • Biederman J.
        • Faraone S.V.
        • Guite J.
        • Tsuang M.T.
        Pregnancy, delivery and infancy complications and attention deficit hyperactivity disorder: issues of gene-environment interaction.
        Biol Psychiatry. 1997; 41: 65-75
        • Wiggs K.
        • Elmore A.L.
        • Nigg J.T.
        • Nikolas M.A.
        Pre- and perinatal risk for attention-deficit hyperactivity disorder: Does neuropsychological weakness explain the link?.
        J Abnorm Child Psychol. 2016; 44: 1473-1485
        • Miguel P.M.
        • Schuch C.P.
        • Rojas J.J.
        • Carletti J.V.
        • Deckmann I.
        • Martinato L.H.
        • et al.
        Neonatal hypoxia-ischemia induces attention-deficit hyperactivity disorder-like behavior in rats.
        Behav Neurosci. 2015; 129: 309-320
        • Giannopoulou I.
        • Pagida M.A.
        • Briana D.D.
        • Panayotacopoulou M.T.
        Perinatal hypoxia as a risk factor for psychopathology later in life: The role of dopamine and neurotrophins.
        Hormones (Athens). 2018; 17: 25-32
        • Froudist-Walsh S.
        • Bloomfield M.A.P.
        • Veronese M.
        • Kroll J.
        • Karolis V.
        • Jauhar S.
        • et al.
        The effect of perinatal brain injury on dopaminergic function and hippocampal volume in adult life.
        Elife. 2017; 6: e29088
        • Botellero V.L.
        • Skranes J.
        • Bjuland K.J.
        • Haberg A.K.
        • Lydersen S.
        • Brubakk A.M.
        • et al.
        A longitudinal study of associations between psychiatric symptoms and disorders and cerebral gray matter volumes in adolescents born very preterm.
        BMC Pediatr. 2017; 17: 45
        • Suffren S.
        • Angulo D.
        • Ding Y.
        • Reyes P.
        • Marin J.
        • Hernandez J.T.
        • et al.
        Long-term attention deficits combined with subcortical and cortical structural central nervous system alterations in young adults born small for gestational age.
        Early Hum Dev. 2017; 110: 44-49
        • Lean R.E.
        • Melzer T.R.
        • Bora S.
        • Watts R.
        • Woodward L.J.
        Attention and regional gray matter development in very preterm children at age 12 years.
        J Int Neuropsychol Soc. 2017; 23: 539-550
        • Fall S.
        • Querne L.
        • Le Moing A.G.
        • Berquin P.
        Individual differences in subcortical microstructure organization reflect reaction time performances during a flanker task: A diffusion tensor imaging study in children with and without ADHD.
        Psychiatry Res. 2015; 233: 50-56
        • Ferreira P.E.
        • Palmini A.
        • Bau C.H.
        • Grevet E.H.
        • Hoefel J.R.
        • Rohde L.A.
        • et al.
        Differentiating attention-deficit/hyperactivity disorder inattentive and combined types: a (1)H-magnetic resonance spectroscopy study of fronto-striato-thalamic regions.
        J Neural Transm (Vienna) J Neural Transm (Vienna). 2009; 116: 623-629
        • Kim B.N.
        • Lee J.S.
        • Cho S.C.
        • Lee D.S.
        Methylphenidate increased regional cerebral blood flow in subjects with attention deficit/hyperactivity disorder.
        Yonsei Med J. 2001; 42: 19-29
        • Schmitt A.
        • Malchow B.
        • Hasan A.
        • Falkai P.
        The impact of environmental factors in severe psychiatric disorders.
        Front Neurosci. 2014; 8

      Linked Article

      • Assessing the Candidates
        Biological PsychiatryVol. 86Issue 8
        • Preview
          In a bygone era, a plethora of studies assessed the relationship between single, or perhaps several, polymorphisms in key “candidate” genes, and various clinical phenotypes including disease susceptibility (1), brain imaging measures (2), cognitive function (2), and treatment response (3), among others. The strength of the candidates was established—not through a series of crowded debates but via evidence of preexisting biological plausibility or, in some cases, limited functional data derived from in vitro or in vivo assays.
        • Full-Text
        • PDF