title: Altered neural connectivity during response inhibition in adolescents with attention-deficit/hyperactivity disorder and their unaffected siblings.
abstract: BACKGROUND
  Response inhibition is one of the executive functions impaired in attention-deficit/hyperactivity disorder (ADHD). Increasing evidence indicates that altered functional and structural neural connectivity are part of the neurobiological basis of ADHD. Here, we investigated if adolescents with ADHD show altered functional connectivity during response inhibition compared to their unaffected siblings and healthy controls.
  
  
  METHODS
  Response inhibition was assessed using the stop signal paradigm. Functional connectivity was assessed using psycho-physiological interaction analyses applied to BOLD time courses from seed regions within inferior- and superior frontal nodes of the response inhibition network. Resulting networks were compared between adolescents with ADHD (N = 185), their unaffected siblings (N = 111), and controls (N = 125).
  
  
  RESULTS
  Control subjects showed stronger functional connectivity than the other two groups within the response inhibition network, while subjects with ADHD showed relatively stronger connectivity between default mode network (DMN) nodes. Stronger connectivity within the response inhibition network was correlated with lower ADHD severity, while stronger connectivity with the DMN was correlated with increased ADHD severity. Siblings showed connectivity patterns similar to controls during successful inhibition and to ADHD subjects during failed inhibition. Additionally, siblings showed decreased connectivity with the primary motor areas as compared to both participants with ADHD and controls.
  
  
  CONCLUSIONS
  Subjects with ADHD fail to integrate activation within the response inhibition network and to inhibit connectivity with task-irrelevant regions. Unaffected siblings show similar alterations only during failed stop trials, as well as unique suppression of motor areas, suggesting compensatory strategies. These findings support the role of altered functional connectivity in understanding the neurobiology and familial transmission of ADHD.
authors.affiliation: Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands ; Centre for Cognitive Neuroimaging, Donders Institute for Brain Cognition and Behavior, Nijmegen, The Netherlands.
authors.forename: Daan
authors.initials: D
authors.lastname: van Rooij
authors.affiliation: Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Catharina A
authors.initials: CA
authors.lastname: Hartman
authors.affiliation: Centre for Cognitive Neuroimaging, Donders Institute for Brain Cognition and Behavior, Nijmegen, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Mennes
authors.affiliation: Department of Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Oosterlaan
authors.affiliation: Departments of Human Genetics and Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Karakter Child and Adolescent Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Nanda
authors.initials: N
authors.lastname: Rommelse
authors.affiliation: Department of Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Heslenfeld
authors.affiliation: Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: Karakter Child and Adolescent Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands ; Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain Cognition and Behavior, Nijmegen, The Netherlands.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.affiliation: Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Hoekstra
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000503:physiopathology*; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007266:Inhibition, Psychological; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology*; D035781:Siblings
keywords: ADHD; ADHD, attention deficit/hyperactivity disorder; CD, conduct disorder; Connectivity; DMN, default mode network; GEE, generalized estimating equations; ICV, intraindividual coefficient of variance; ODD, oppositional defiant disorder; PPI; RD, reading disorder; ROI, region of interest; Response inhibition; SI, supplementary information; SSRT, stop-signal reaction time; SST, Stop-signal task; Siblings; WM, white matter