Cortical Thickness, Cortico-Amygdalar Networks, and Externalizing Behaviors in Healthy Children

BACKGROUND Fronto-amygdalar networks are implicated in childhood psychiatric disorders characterized by high rates of externalizing (aggressive, noncompliant, oppositional) behavior. Although externalizing behaviors are distributed continuously across clinical and nonclinical samples, little is known about how brain variations may confer risk for problematic behavior. Here, we studied cortical thickness, amygdala volume, and cortico-amygdalar network correlates of externalizing behavior in a large sample of healthy children. METHODS Two hundred ninety-seven healthy children (6-18 years; mean = 12 ± 3 years), with 517 magnetic resonance imaging scans, from the National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development, were studied. Relationships between externalizing behaviors (measured with the Child Behavior Checklist) and cortical thickness, amygdala volume, and cortico-amygdalar structural networks were examined using first-order linear mixed-effects models, after controlling for age, sex, scanner, and total brain volume. Results significant at p ≤ .05, following multiple comparison correction, are reported. RESULTS Left orbitofrontal, right retrosplenial cingulate, and medial temporal cortex thickness were negatively correlated with externalizing behaviors. Although amygdala volume alone was not correlated with externalizing behaviors, an orbitofrontal cortex-amygdala network predicted rates of externalizing behavior. Children with lower levels of externalizing behaviors exhibited positive correlations between orbitofrontal cortex and amygdala structure, while these regions were not correlated in children with higher levels of externalizing behavior. CONCLUSIONS Our findings identify key cortical nodes in frontal, cingulate, and temporal cortex associated with externalizing behaviors in children; and indicate that orbitofrontal-amygdala network properties may influence externalizing behaviors, along a continuum and across healthy and clinical samples.

[1]  Efstathios D. Gennatas,et al.  Network-level structural covariance in the developing brain , 2010, Proceedings of the National Academy of Sciences.

[2]  A. Damasio,et al.  The return of Phineas Gage: clues about the brain from the skull of a famous patient. , 1994, Science.

[3]  Alan C. Evans,et al.  Longitudinal mapping of cortical thickness and clinical outcome in children and adolescents with attention-deficit/hyperactivity disorder. , 2006, Archives of general psychiatry.

[4]  Kelly N. Botteron,et al.  Right Anterior Cingulate Cortical Thickness and Bilateral Striatal Volume Correlate with Child Behavior Checklist Aggressive Behavior Scores in Healthy Children , 2011, Biological Psychiatry.

[5]  D. Louis Collins,et al.  Towards accurate, automatic segmentation of the hippocampus and amygdala from MRI by augmenting ANIMAL with a template library and label fusion , 2010, NeuroImage.

[6]  Alan C. Evans,et al.  The NIH MRI study of normal brain development , 2006, NeuroImage.

[7]  John O. Willis,et al.  Wechsler Abbreviated Scale of Intelligence , 2014 .

[8]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[9]  Matthew K Nock,et al.  Lifetime prevalence, correlates, and persistence of oppositional defiant disorder: results from the National Comorbidity Survey Replication. , 2007, Journal of child psychology and psychiatry, and allied disciplines.

[10]  D. Shohamy,et al.  Ventromedial prefrontal-subcortical systems and the generation of affective meaning , 2012, Trends in Cognitive Sciences.

[11]  Arthur W Toga,et al.  Behavioral/Systems/Cognitive Amygdala Reactivity in Healthy Adults Is Correlated with Prefrontal Cortical Thickness , 2010 .

[12]  Michael Frankfurter,et al.  Applied Longitudinal Data Analysis Modeling Change And Event Occurrence , 2016 .

[13]  Alan C. Evans,et al.  Testosterone-related cortical maturation across childhood and adolescence. , 2012, Cerebral cortex.

[14]  P. Nopoulos,et al.  Behavioral effects of congenital ventromedial prefrontal cortex malformation , 2011, BMC neurology.

[15]  C. Edelbrock,et al.  Child Behavior Checklist (CBCL) , 1983 .

[16]  P. Diggle Analysis of Longitudinal Data , 1995 .

[17]  G L Shulman,et al.  INAUGURAL ARTICLE by a Recently Elected Academy Member:A default mode of brain function , 2001 .

[18]  Katya Rubia,et al.  “Cool” Inferior Frontostriatal Dysfunction in Attention-Deficit/Hyperactivity Disorder Versus “Hot” Ventromedial Orbitofrontal-Limbic Dysfunction in Conduct Disorder: A Review , 2011, Biological Psychiatry.

[19]  Alan C. Evans,et al.  Automated 3-D extraction and evaluation of the inner and outer cortical surfaces using a Laplacian map and partial volume effect classification , 2005, NeuroImage.

[20]  C. Shapiro,et al.  Child Behavior Checklist (CBCL), 1½–5 , 2011 .

[21]  C. Lamm,et al.  Neural Changes Associated with Treatment Outcome in Children with Externalizing Problems , 2011, Biological Psychiatry.

[22]  J. Singer,et al.  Applied Longitudinal Data Analysis , 2003 .

[23]  J. Rosenbaum,et al.  The child behavior checklist broad-band scales predict subsequent psychopathology: A 5-year follow-up. , 2008, Journal of anxiety disorders.

[24]  Judith Rumsey,et al.  The NIH MRI study of normal brain development: Performance of a population based sample of healthy children aged 6 to 18 years on a neuropsychological battery , 2007, Journal of the International Neuropsychological Society.

[25]  Alan C. Evans,et al.  Total and regional brain volumes in a population-based normative sample from 4 to 18 years: the NIH MRI Study of Normal Brain Development. , 2012, Cerebral cortex.

[26]  R. Loeber,et al.  Oppositional defiant and conduct disorder: a review of the past 10 years, part I. , 2000, Journal of the American Academy of Child and Adolescent Psychiatry.

[27]  A. Dale,et al.  Distinct genetic influences on cortical surface area and cortical thickness. , 2009, Cerebral cortex.

[28]  E. Leibenluft,et al.  Abnormal ventromedial prefrontal cortex function in children with psychopathic traits during reversal learning. , 2008, Archives of general psychiatry.

[29]  Michael C. Stevens,et al.  Cortical Thickness and Folding Deficits in Conduct-Disordered Adolescents , 2012, Biological Psychiatry.

[30]  Avshalom Caspi,et al.  Neurocognitive impairments in boys on the life-course persistent antisocial path. , 2005, Journal of abnormal psychology.

[31]  M. Catani,et al.  Altered connections on the road to psychopathy , 2009, Molecular Psychiatry.

[32]  D. Louis Collins,et al.  Evidence for a cerebral cortical thickness network anti-correlated with amygdalar volume in healthy youths: Implications for the neural substrates of emotion regulation , 2013, NeuroImage.

[33]  D. Shaw,et al.  Early externalizing behavior problems: Toddlers and preschoolers at risk for later maladjustment , 2000, Development and Psychopathology.

[34]  M. Catani,et al.  Frontotemporal white-matter microstructural abnormalities in adolescents with conduct disorder: a diffusion tensor imaging study , 2012, Psychological Medicine.

[35]  R. C. Oldfield The assessment and analysis of handedness: the Edinburgh inventory. , 1971, Neuropsychologia.

[36]  AC Evans,et al.  Positive association between cognitive ability and cortical thickness in a representative US sample of healthy 6 to 18 year-olds , 2009, NeuroImage.

[37]  T. Achenbach,et al.  National survey of problems and competencies among four- to sixteen-year-olds: parents' reports for normative and clinical samples. , 1991, Monographs of the Society for Research in Child Development.

[38]  D. Shaffer,et al.  NIMH Diagnostic Interview Schedule for Children Version IV (NIMH DISC-IV): description, differences from previous versions, and reliability of some common diagnoses. , 2000, Journal of the American Academy of Child and Adolescent Psychiatry.

[39]  C. Fahim,et al.  Neuroanatomy of childhood disruptive behavior disorders. , 2011, Aggressive behavior.

[40]  Steven Robbins,et al.  An unbiased iterative group registration template for cortical surface analysis , 2007, NeuroImage.

[41]  M Knapp,et al.  Financial cost of social exclusion: follow up study of antisocial children into adulthood , 2001, BMJ : British Medical Journal.

[42]  Karama S,et al.  Positive association between cognitive ability and cortical thickness in a representative US sample of healthy 6 to 18 year-olds , 2009, NeuroImage.

[43]  Deanna Greenstein,et al.  Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study , 2007, The Lancet Neurology.

[44]  R. Buckner,et al.  Functional-Anatomic Fractionation of the Brain's Default Network , 2010, Neuron.

[45]  D. Louis Collins,et al.  Automatic 3‐D model‐based neuroanatomical segmentation , 1995 .

[46]  Alan C. Evans,et al.  Mapping anatomical correlations across cerebral cortex (MACACC) using cortical thickness from MRI , 2006, NeuroImage.

[47]  E. Bullmore,et al.  Imaging structural co-variance between human brain regions , 2013, Nature Reviews Neuroscience.

[48]  K. Worsley,et al.  Unified univariate and multivariate random field theory , 2004, NeuroImage.

[49]  Alan C. Evans,et al.  A nonparametric method for automatic correction of intensity nonuniformity in MRI data , 1998, IEEE Transactions on Medical Imaging.

[50]  Alan C. Evans,et al.  Cortical development in typically developing children with symptoms of hyperactivity and impulsivity: support for a dimensional view of attention deficit hyperactivity disorder. , 2011, The American journal of psychiatry.

[51]  Alan C. Evans,et al.  Erratum to “Positive association between cognitive ability and cortical thickness in a representative US sample of healthy 6 to 18 year-olds” [Intelligence 37/2 145–155] , 2009 .

[52]  D. Pine,et al.  Reduced amygdala–orbitofrontal connectivity during moral judgments in youths with disruptive behavior disorders and psychopathic traits , 2011, Psychiatry Research: Neuroimaging.

[53]  N. Rempel-Clower,et al.  Role of Orbitofrontal Cortex Connections in Emotion , 2007, Annals of the New York Academy of Sciences.

[54]  A. Mechelli,et al.  Size matters: increased grey matter in boys with conduct problems and callous-unemotional traits. , 2009, Brain : a journal of neurology.

[55]  R. Blair,et al.  The amygdala and ventromedial prefrontal cortex: functional contributions and dysfunction in psychopathy , 2008, Philosophical Transactions of the Royal Society B: Biological Sciences.

[56]  Alan C. Evans,et al.  Cortical thickness analysis examined through power analysis and a population simulation , 2005, NeuroImage.