Connectomic Disturbances in Attention-Deficit/Hyperactivity Disorder: A Whole-Brain Tractography Analysis

BACKGROUND Few studies have sought to identify, in a regionally unbiased way, the precise cortical and subcortical regions that are affected by white matter abnormalities in attention-deficit/hyperactivity disorder (ADHD). This study aimed to derive a comprehensive, whole-brain characterization of connectomic disturbances in ADHD. METHODS Using diffusion tensor imaging, whole-brain tractography, and an imaging connectomics approach, we characterized altered white matter connectivity in 71 children and adolescents with ADHD compared with 26 healthy control subjects. White matter differences were further delineated between patients with (n = 40) and without (n = 26) the predominantly hyperactive/impulsive subtype of ADHD. RESULTS A significant network comprising 25 distinct fiber bundles linking 23 different brain regions spanning frontal, striatal, and cerebellar brain regions showed altered white matter structure in ADHD patients (p < .05, family-wise error-corrected). Moreover, fractional anisotropy in some of these fiber bundles correlated with attentional disturbances. Attention-deficit/hyperactivity disorder subtypes were differentiated by a right-lateralized network (p < .05, family-wise error-corrected) predominantly linking frontal, cingulate, and supplementary motor areas. Fractional anisotropy in this network was also correlated with continuous performance test scores. CONCLUSIONS Using an unbiased, whole-brain, data-driven approach, we demonstrated abnormal white matter connectivity in ADHD. The correlations observed with measures of attentional performance underscore the functional importance of these connectomic disturbances for the clinical phenotype of ADHD. A distributed pattern of white matter microstructural integrity separately involving frontal, striatal, and cerebellar brain regions, rather than direct frontostriatal connectivity, appears to be disrupted in children and adolescents with ADHD.

[1]  W. Tseng,et al.  White matter tract integrity of frontostriatal circuit in attention deficit hyperactivity disorder: Association with attention performance and symptoms , 2014, Human brain mapping.

[2]  John L Bradshaw,et al.  White‐matter abnormalities in attention deficit hyperactivity disorder: A diffusion tensor imaging study , 2009, Human brain mapping.

[3]  F. Xavier Castellanos,et al.  Large-scale brain systems in ADHD: beyond the prefrontal–striatal model , 2012, Trends in Cognitive Sciences.

[4]  Yong He,et al.  Probabilistic Diffusion Tractography and Graph Theory Analysis Reveal Abnormal White Matter Structural Connectivity Networks in Drug-Naive Boys with Attention Deficit/Hyperactivity Disorder , 2013, The Journal of Neuroscience.

[5]  A. Mack,et al.  Gray Matter Volume Abnormalities in ADHD: Voxel-Based Meta-Analysis Exploring the Effects of Age and Stimulant Medication , 2013 .

[6]  Jeremy D. Schmahmann,et al.  Diffusion spectrum magnetic resonance imaging (DSI) tractography of crossing fibers , 2008, NeuroImage.

[7]  Nikos Makris,et al.  Towards Conceptualizing a Neural Systems-Based Anatomy of Attention-Deficit/Hyperactivity Disorder , 2009, Developmental Neuroscience.

[8]  Yong He,et al.  BrainNet Viewer: A Network Visualization Tool for Human Brain Connectomics , 2013, PloS one.

[9]  S. Haber,et al.  The Reward Circuit: Linking Primate Anatomy and Human Imaging , 2010, Neuropsychopharmacology.

[10]  Dirk J. Heslenfeld,et al.  Diffusion tensor imaging in attention deficit/hyperactivity disorder: A systematic review and meta-analysis , 2012, Neuroscience & Biobehavioral Reviews.

[11]  O. Sporns.  Discovering the Human Connectome , 2012 .

[12]  Xiaoping Hu,et al.  The effects of connection reconstruction method on the interregional connectivity of brain networks via diffusion tractography , 2012, Human brain mapping.

[13]  Sarah Durston,et al.  Differentiating Frontostriatal and Fronto-Cerebellar Circuits in Attention-Deficit/Hyperactivity Disorder , 2011, Biological Psychiatry.

[14]  Klaus Scheffler,et al.  Structural and functional imaging approaches in attention deficit/hyperactivity disorder: Does the temporal lobe play a key role? , 2010, Psychiatry Research: Neuroimaging.

[15]  Eric A Youngstrom,et al.  Meta-analysis of intellectual and neuropsychological test performance in attention-deficit/hyperactivity disorder. , 2004, Neuropsychology.

[16]  Y. Zang,et al.  Methylphenidate Normalizes Resting-State Brain Dysfunction in Boys With Attention Deficit Hyperactivity Disorder , 2013, Neuropsychopharmacology.

[17]  Conor Liston,et al.  Atypical Prefrontal Connectivity in Attention-Deficit/Hyperactivity Disorder: Pathway to Disease or Pathological End Point? , 2011, Biological Psychiatry.

[18]  E. Bullmore,et al.  Disrupted Axonal Fiber Connectivity in Schizophrenia , 2011, Biological Psychiatry.

[19]  F Xavier Castellanos,et al.  Brain development and ADHD. , 2006, Clinical psychology review.

[20]  Alan C. Evans,et al.  Psychostimulant treatment and the developing cortex in attention deficit hyperactivity disorder. , 2009, The American journal of psychiatry.

[21]  P. Strick,et al.  The cerebellum communicates with the basal ganglia , 2005, Nature Neuroscience.

[22]  George Bush,et al.  Attention-Deficit/Hyperactivity Disorder and Attention Networks , 2010, Neuropsychopharmacology.

[23]  Edward T. Bullmore,et al.  Connectivity differences in brain networks , 2012, NeuroImage.

[24]  Deepti Bathula,et al.  Altered white matter microstructure in children with attention-deficit/hyperactivity disorder. , 2011, Journal of the American Academy of Child and Adolescent Psychiatry.

[25]  N. Ryan,et al.  Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. , 1997, Journal of the American Academy of Child and Adolescent Psychiatry.

[26]  Andrew Zalesky,et al.  Altered Functional Brain Connectivity in a Non-Clinical Sample of Young Adults with Attention-Deficit/Hyperactivity Disorder , 2012, The Journal of Neuroscience.

[27]  Jian Wang,et al.  Changes of Brain Structure and Function in ADHD Children , 2011, Brain Topography.

[28]  Edward T. Bullmore,et al.  Whole-brain anatomical networks: Does the choice of nodes matter? , 2010, NeuroImage.

[29]  R. Passingham,et al.  Attention to Intention , 2004, Science.

[30]  Eileen Luders,et al.  Reduced white matter integrity in attention-deficit hyperactivity disorder , 2008, Neuroreport.

[31]  B. Horta,et al.  The worldwide prevalence of ADHD: a systematic review and metaregression analysis. , 2007, The American journal of psychiatry.

[32]  G. McCarthy,et al.  Functional organization of human supplementary motor cortex studied by electrical stimulation , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[33]  E Wyllie,et al.  Functional anatomy of the human supplementary sensorimotor area: results of extraoperative electrical stimulation. , 1994, Electroencephalography and clinical neurophysiology.

[34]  M. Hallett,et al.  The cerebellum in Parkinson’s disease , 2013, Brain : a journal of neurology.

[35]  P. Haggard.  Conscious intention and motor cognition , 2005, Trends in Cognitive Sciences.

[36]  Nikos Makris,et al.  Attention and executive systems abnormalities in adults with childhood ADHD: A DT-MRI study of connections. , 2008, Cerebral cortex.

[37]  Gary Glover,et al.  Frontostriatal connectivity and its role in cognitive control in parent-child dyads with ADHD. , 2007, The American journal of psychiatry.

[38]  Oussama Kebir,et al.  Candidate genes and neuropsychological phenotypes in children with ADHD: review of association studies. , 2009, Journal of psychiatry & neuroscience : JPN.

[39]  Sung-Zoon Cho,et al.  A STUDY OF THE DEVELOPMENT AND STANDARDIZATION OF ADHD DIAGNOSTIC SYSTEM , 2000 .

[40]  Narender Ramnani,et al.  Frontal Lobe and Posterior Parietal Contributions to the Cortico-cerebellar System , 2011, The Cerebellum.

[41]  S. Petersen,et al.  Concepts and principles in the analysis of brain networks , 2011, Annals of the New York Academy of Sciences.

[42]  Alan C. Evans,et al.  Development of cortical asymmetry in typically developing children and its disruption in attention-deficit/hyperactivity disorder. , 2009, Archives of general psychiatry.

[43]  L M Greenberg,et al.  Developmental normative data on the test of variables of attention (T.O.V.A.). , 1993, Journal of child psychology and psychiatry, and allied disciplines.

[44]  Adrian Angold,et al.  Relations Between Continuous Performance Test Performance Measures and ADHD Behaviors , 2003, Journal of abnormal child psychology.

[45]  A. Arnsten,et al.  Neurobiological circuits regulating attention, cognitive control, motivation, and emotion: disruptions in neurodevelopmental psychiatric disorders. , 2012, Journal of the American Academy of Child and Adolescent Psychiatry.

[46]  L. Cocchi,et al.  Decreased Functional Brain Connectivity in Adolescents with Internet Addiction , 2013, PloS one.

[47]  Thomas E. Nichols,et al.  Nonparametric permutation tests for functional neuroimaging: A primer with examples , 2002, Human brain mapping.

[48]  Young Shin Kim,et al.  The reliability and validity of Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version- Korean version (K-SADS-PL-K). , 2004, Yonsei medical journal.

[49]  A. Pfefferbaum,et al.  MR Diffusion Tensor Imaging: A Window into White Matter Integrity of the Working Brain , 2010, Neuropsychology Review.

[50]  John A. Sweeney,et al.  Diffusion Tensor Imaging Study of White Matter Fiber Tracts in Pediatric Bipolar Disorder and Attention-Deficit/Hyperactivity Disorder , 2009, Biological Psychiatry.

[51]  Edward T. Bullmore,et al.  Network-based statistic: Identifying differences in brain networks , 2010, NeuroImage.

[52]  A. Ashley-Koch,et al.  SNPs in dopamine D2 receptor gene (DRD2) and norepinephrine transporter gene (NET) are associated with continuous performance task (CPT) phenotypes in ADHD children and their families , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[53]  Kerstin Konrad,et al.  Is the ADHD brain wired differently? A review on structural and functional connectivity in attention deficit hyperactivity disorder , 2010, Human brain mapping.

[54]  B. J. Casey,et al.  Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder. , 1997, Journal of the American Academy of Child and Adolescent Psychiatry.

[55]  H. Hart,et al.  Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects. , 2013, JAMA psychiatry.

[56]  M. Rietschel,et al.  Adolescent impulsivity phenotypes characterized by distinct brain networks , 2012, Nature Neuroscience.

[57]  Danielle S. Bassett,et al.  Conserved and variable architecture of human white matter connectivity , 2011, NeuroImage.