NEUROANATOMICAL CORRELATES OF CHILD BEHAVIOR CHECKLIST AGGRESSIVE BEHAVIOR SCORES IN TYPICALLY DEVELOPING CHILDREN Simon Ducharme MD (260287392) Department of Psychiatry McGill University, Montréal Manuscript‐Based Thesis submitted on September 2011 “A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of M.Sc. in Psychiatry” ©Simon Ducharme, 2011 1 TABLE OF CONTENTS 1. English Abstract……………………………………………………………..3 2. Résumé en français…………………………………………………………5 3. Acknowledgements………………………………………………………...7 4. Preface……………………………………………………………………….....10 4.1 Definitions………………………………………………………..10 4.2 Neurobiology of Aggression……………………………….13 4.3 Anterior Cingulate Cortex………………………………….16 4.4 Orbito‐Frontal Cortex………………………………………..16 5. Rationale of the Research………………………………………………18 5. Contributions of Authors………………………………………………..22 6. Manuscript…………………………………………………………………….23 6.1 Introduction………………………………………………………25 6.2 Methods…………………………………………………………….28 6.3 Results…………………………………………………………...….33 6.4 Discussion………………………………………………………….36 6.5 Acknowledgements and Disclosures……………………42 6.6 Tables and Figures……………………………………………...43 6.7 Supplemental Material………………………………………..48 7. Postface………………………………………………………………………….55 7.1 Integrative Models……………………………………………...60 8. Final Conclusions…………………………………………………………….65 9. Elements of Originality.……………………………………………………66 10. References……………………………………………………………………67 2 ENGLISH ABSTRACT Background: The anterior cingulate cortex (ACC), orbito‐frontal cortex (OFC) and basal ganglia have been implicated in the neurobiology of pathological aggression. They are thought to be the structures involved in top‐down regulation of impulses from the limbic system. This study aimed at identifying neuroanatomical correlates of impulsive aggression in healthy children. Methods: Data from 193 representative 6‐18 year‐old healthy children were obtained from the NIH MRI Study of Normal Brain Development after a blinded quality control (1). Cortical thickness and subcortical volumes were obtained with automated software. Aggression levels were measured with the Aggressive Behavior scale (AGG) of the Child Behavior Checklist (CBCL). AGG scores were regressed against cortical thickness and basal ganglia volumes using first and second‐order linear models while controlling for age, gender, scanner site and total brain volume. ‘Gender by AGG’ interactions were analyzed. Whole brain random field theory corrections for multiple comparisons were implemented. Results: There were positive associations between bilateral striatal volumes and AGG scores (right: r=0.238, p=0.001; left: r=0.188, p=0.01). A significant association was found with right ACC and subgenual ACC cortical thickness in a second‐order linear model (p<0.05, corrected). High AGG scores were associated with a relatively 3 thin right ACC cortex. An ‘AGG by gender’ interaction trend was found in bilateral OFC and ACC associations with AGG scores. Conclusion: This study shows the existence of relationships between impulsive aggression in healthy children and the structure of the striatum and right ACC. It also suggests the existence of gender specific patterns of association in OFC/ACC grey matter. These results may guide research on oppositional‐defiant and conduct disorders. KEYWORDS: Aggression, Cortical Thickness, Anterior Cingulate Cortex, Orbito‐ Frontal Cortex, Striatum, Magnetic Resonance Imaging (MRI) 4 RÉSUMÉ EN FRANÇAIS Contexte: Le cortex cingulaire antérieur (CCA), le cortex orbito‐frontal (COF) et les noyaux gris centraux ont été identifiés dans les recherches sur la neurobiologie de l’agressivité pathologique. Ces structures seraient impliquées dans la régulation ‘top­down’ des impulsions produites dans le système limbique. Le but de cette étude était d’identifier les corrélations neuroanatomiques de l’agressivité impulsive chez les enfants en santé ayant un développement normal. Méthodologie: Les données de 193 sujets de 6 à 18 ans ont été obtenues de l’étude NIH MRI Study of Normal Brain Development après un contrôle visuel de qualité des données (1). L’épaisseur corticale et les volumes sous‐corticaux ont été obtenus avec des programmes automatisés. Le niveau d’agressivité a été mesuré avec l’échelle de comportements agressifs (AGG) obtenue du questionnaire Child Behavior Checklist. Les scores de AGG ont été analysés en régression linéaire avec l’épaisseur corticale et le volume des noyaux gris centraux en utilisant des modèles de premier et de deuxième ordre, et en contrôlant pour les effets de l’âge, du sexe, du numéro de scanner et du volume cérébral total. L’interaction ‘AGG X sexe’ a aussi été analysée. Une correction statistique de type random field theory pour comparaisons multiples a été appliquée aux résultats. 5 Résultats: Une association positive a été trouvée entre les scores de AGG et le volume du striatum bilatéralement (droite: r=0.238, p=0.001; gauche: r=0.188, p=0.01). Une association significative était aussi présente entre AGG et l’épaisseur corticale du CCA droit et du CCA sous‐géniculé droit dans un modèle linéaire de deuxième ordre (p<0.05, corrigé). Les scores AGG élevés étaient associés à un CCA droit relativement mince. Une tendance d’association entre l’épaisseur corticale et l’interaction ‘AGG X sexe’ a aussi été trouvée dans le COF et le CCA bilatéralement. Conclusion: Cette étude démontre l’existence d’une relation entre l’agressivité impulsive chez les enfants en santé et la structure anatomique du striatum, ainsi que du CCA droit. Elle suggère également l’existence de patterns d’associations spécifiques au sexe dans la matière grise du COF et du CCA. Ces résultats pourraient guider la recherche clinique sur le trouble oppositionnel avec provocation et le trouble des conduites. MOTS CLÉS: Agressivité, Épaisseur corticale, Cortex cingulaire antérieur, Cortex orbito‐frontal, Striatum, Imagerie par résonance magnétique (IRM) 6 ACKNOWLEDGEMENTS The design of the NIH MRI Study of Normal Brain Development and data collection were performed by a multisite network called the Brain Development Cooperative Group*, which includes the Montreal Neurological Institute as the Data Coordinating Centre. The design of the current study on impulsive aggression and statistical analyses described in the manuscript were performed by the author of this thesis under the supervision of Dr. Sherif Karama and Dr. Alan C. Evans. The author acknowledges the help and support of other members of the McConnell Brain Imaging Centre, including Dr. Claude Lepage (member of staff), Dr. D. Louis Collins (member of staff), Samir Das (member of staff), Dr. Hooman Ganjavi (fellow student) and Dr. Tuong‐Vi Nguyen (fellow student). There were no research assistants involved in this study. The author also wants to thank US collaborators including Dr. James J. Hudziak and Matthew D. Albaugh at the University of Vermont, in addition to Dr. Kelly N. Botteron at Washington University for their intellectual contribution to the design of the study and editorial review of the submitted manuscript. Finally, the author wants to recognize Dr. Sherif Karama and Dr. Alan C. Evans for their close supervision and precious advices at every steps of this masters’ project. 7 *Brain Development Cooperative Group Key personnel from the six pediatric study centers are as follows: Children’s Hospital Medical Center of Cincinnati, Principal Investigator William S. Ball, M.D., Investigators Anna Weber Byars, Ph.D., Mark Schapiro, M.D., Wendy Bommer, R.N., April Carr, B.S., April German, B.A., Scott Dunn, R.T.; Children’s Hospital Boston, Principal Investigator Michael J. Rivkin, M.D., Investigators Deborah Waber, Ph.D., Robert Mulkern, Ph.D., Sridhar Vajapeyam, Ph.D., Abigail Chiverton, B.A., Peter Davis, B.S., Julie Koo, B.S., Jacki Marmor, M.A., Christine Mrakotsky, Ph.D., M.A., Richard Robertson, M.D., Gloria McAnulty, Ph.D; University of Texas Health Science Center at Houston, Principal Investigators Michael E. Brandt, Ph.D., Jack M. Fletcher, Ph.D., Larry A. Kramer, M.D., Investigators Grace Yang, M.Ed., Cara McCormack, B.S., Kathleen M. Hebert, M.A., Hilda Volero, M.D.; Washington University in St. Louis, Principal Investigators Kelly Botteron, M.D., Robert C. McKinstry, M.D., Ph.D., Investigators William Warren, Tomoyuki Nishino, M.S., C. Robert Almli, Ph.D., Richard Todd, Ph.D., M.D., John Constantino, M.D.; University of California Los Angeles, Principal Investigator James T. McCracken, M.D., Investigators Jennifer Levitt, M.D., Jeffrey Alger, Ph.D., Joseph O’Neil, Ph.D., Arthur Toga, Ph.D., Robert Asarnow, Ph.D., David Fadale, B.A., Laura Heinichen, B.A., Cedric Ireland B.A.; Children’s Hospital of Philadelphia, Principal Investigators Dah‐Jyuu Wang, Ph.D. and Edward Moss, Ph.D., Investigators Robert A. Zimmerman, M.D., and Research Staff Brooke Bintliff, B.S., Ruth Bradford, Janice Newman, M.B.A. The Principal Investigator of the data coordinating center at McGill University is Alan C. Evans, Ph.D., Investigators Rozalia Arnaoutelis, B.S., G. Bruce Pike, Ph.D., D. Louis Collins, 8 Ph.D., Gabriel Leonard, Ph.D., Tomas Paus, M.D., Alex Zijdenbos, Ph.D., and Research Staff Samir Das, B.S., Vladimir Fonov, Ph.D., Luke Fu, B.S., Jonathan Harlap, Ilana Leppert, B.E., Denise Milovan, M.A., Dario Vins, B.C.,, and at Georgetown University, Thomas Zeffiro, M.D., Ph.D. and John Van Meter, Ph.D. Ph.D. Investigators at the Neurostatistics Laboratory, Harvard University/McLean Hospital, Nicholas Lange, Sc.D., and Michael P. Froimowitz, M.S., work with data