This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (344)  • Contact me when this article is cited  Related Content  • Related article  • Similar articles in JAMA  Topic Collections  • Pediatrics  • Adolescent Medicine  • Psychiatry  • Attention Deficit Hyperactivity Disorder  • Radiologic Imaging  • Magnetic Resonance Imaging  • Alert me on articles by topic  Social Bookmarking   What's this?

F. Xavier Castellanos, MD; Patti P. Lee, MD; Wendy Sharp, MSW; Neal O. Jeffries, PhD; Deanna K. Greenstein, PhD; Liv S. Clasen, PhD; Jonathan D. Blumenthal, MA; Regina S. James, MD; Christen L. Ebens, BA; James M. Walter, MA; Alex Zijdenbos, PhD; Alan C. Evans, PhD; Jay N. Giedd, MD; Judith L. Rapoport, MD

JAMA. 2002;288:1740-1748.

Context  Various anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder (ADHD), with varying methods, small samples, cross-sectional designs, and without accounting for stimulant drug exposure.

Objective  To compare regional brain volumes at initial scan and their change over time in medicated and previously unmedicated male and female patients with ADHD and healthy controls.

Design, Setting, and Participants  Case-control study conducted from 1991-2001 at the National Institute of Mental Health, Bethesda, Md, of 152 children and adolescents with ADHD (age range, 5-18 years) and 139 age- and sex-matched controls (age range, 4.5-19 years) recruited from the local community, who contributed 544 anatomic magnetic resonance images.

Main Outcome Measures  Using completely automated methods, initial volumes and prospective age-related changes of total cerebrum, cerebellum, gray and white matter for the 4 major lobes, and caudate nucleus of the brain were compared in patients and controls.

Results  On initial scan, patients with ADHD had significantly smaller brain volumes in all regions, even after adjustment for significant covariates. This global difference was reflected in smaller total cerebral volumes (-3.2%, adjusted F_1,280 = 8.30, P = .004) and in significantly smaller cerebellar volumes (-3.5%, adjusted F_1,280 = 12.29, P = .001). Compared with controls, previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes (overall F_2,288 = 6.65; all pairwise comparisons Bonferroni corrected, -5.8%; P = .002) and cerebellar volumes (-6.2%, F_2,288 = 8.97, P<.001). Unmedicated children with ADHD also exhibited strikingly smaller total white matter volumes (F_2,288 = 11.65) compared with controls (-10.7%, P<.001) and with medicated children with ADHD (-8.9%, P<.001). Volumetric abnormalities persisted with age in total and regional cerebral measures (P = .002) and in the cerebellum (P = .003). Caudate nucleus volumes were initially abnormal for patients with ADHD (P = .05), but diagnostic differences disappeared as caudate volumes decreased for patients and controls during adolescence. Results were comparable for male and female patients on all measures. Frontal and temporal gray matter, caudate, and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures within the ADHD sample (Pearson coefficients between -0.16 and -0.26; all P values were <.05).

Conclusions  Developmental trajectories for all structures, except caudate, remain roughly parallel for patients and controls during childhood and adolescence, suggesting that genetic and/or early environmental influences on brain development in ADHD are fixed, nonprogressive, and unrelated to stimulant treatment.

Author Affiliations: Child Psychiatry Branch, National Institute of Mental Health (Drs Castellanos, Lee, Greenstein, Clasen, James, Giedd, and Rapoport, Mss Sharp and Ebens, and Messrs Blumenthal and Walter), Biostatistics Branch, National Institute of Neurological Disorders and Stroke (Dr Jeffries), National Institutes of Health, Bethesda, Md; and Montreal Neurological Institute, McGill University, Montreal, Quebec (Drs Zijdenbos and Evans). Dr Castellanos is now with the New York University Child Study Center, New York, NY.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

RELATED ARTICLE

Attention-Deficit/Hyperactivity Disorder
JAMA. 2002;288(14):1804.
PDF  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Research design issues for the use of magnetic resonance imaging machines in brain studies of psychological/psychiatric variables
Czarnolewski
Behav Res Methods 2009;41:1061-1072.
ABSTRACT  

Disrupted Effective Connectivity Between the Medial Frontal Cortex and the Caudate in Adolescent Boys With Externalizing Behavior Disorders
Shannon et al.
Criminal Justice and Behavior 2009;36:1141-1157.
ABSTRACT  

Neural Correlates of Developmental Coordination Disorder: A Review of Hypotheses
Zwicker et al.
J Child Neurol 2009;24:1273-1281.
ABSTRACT  

Development of Cortical Asymmetry in Typically Developing Children and Its Disruption in Attention-Deficit/Hyperactivity Disorder
Shaw et al.
Arch Gen Psychiatry 2009;66:888-896.
ABSTRACT | FULL TEXT  

Sensitivity and Specificity of Long Wave Infrared Imaging for Attention-Deficit/Hyperactivity Disorder
Coben and Myers
J Atten Disord 2009;13:56-65.
ABSTRACT  

Attention-Deficit Disorders and Epilepsy in Childhood: Incidence, Causative Relations and Treatment Possibilities
Kaufmann et al.
J Child Neurol 2009;24:727-733.
ABSTRACT  

Validation and Extension of the Endophenotype Model in ADHD Patterns of Inheritance in a Family Study of Inhibitory Control
Goos et al.
Am. J. Psychiatry 2009;166:711-717.
ABSTRACT | FULL TEXT  

Comorbidities in Pediatric Epilepsy: Beyond ``Just'' Treating the Seizures
Hamiwka and Wirrell
J Child Neurol 2009;24:734-742.
ABSTRACT  

Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis
Simon et al.
Br. J. Psychiatry 2009;194:204-211.
ABSTRACT | FULL TEXT  

Dopamine-Dependent Periadolescent Maturation of Corticostriatal Functional Connectivity in Mouse
Galinanes et al.
J. Neurosci. 2009;29:2496-2509.
ABSTRACT | FULL TEXT  

Age-related grey matter volume correlates of response inhibition and shifting in attention-deficit hyperactivity disorder
McAlonan et al.
Br. J. Psychiatry 2009;194:123-129.
ABSTRACT | FULL TEXT  

Psychostimulant Treatment and the Developing Cortex in Attention Deficit Hyperactivity Disorder
Shaw et al.
Am. J. Psychiatry 2009;166:58-63.
ABSTRACT | FULL TEXT  

Basal Ganglia Volume and Shape in Children With Attention Deficit Hyperactivity Disorder
Qiu et al.
Am. J. Psychiatry 2009;166:74-82.
ABSTRACT | FULL TEXT  

Evidence of Developmental Alterations in Cortical and Subcortical Regions of Children With Attention-Deficit/Hyperactivity Disorder: A Multivoxel In Vivo Phosphorus 31 Spectroscopy Study
Stanley et al.
Arch Gen Psychiatry 2008;65:1419-1428.
ABSTRACT | FULL TEXT  

Age-related changes in motor subtle signs among girls and boys with ADHD
Cole et al.
Neurology 2008;71:1514-1520.
ABSTRACT | FULL TEXT  

Practice Parameter for the Assessment and Treatment of Children and Adolescents With Attention-Deficit/Hyperactivity Disorder
Focus 2008;6:401-426.
ABSTRACT | FULL TEXT  

Attention-Deficit Hyperactivity Disorder (ADHD): Does New Research Support Old Concepts?
Furman
J Child Neurol 2008;23:775-784.
ABSTRACT  

Pediatric Functional Magnetic Resonance Imaging (fMRI): Issues and Applications
O'Shaughnessy et al.
J Child Neurol 2008;23:791-801.
ABSTRACT  

Age of Methylphenidate Treatment Initiation in Children With ADHD and Later Substance Abuse: Prospective Follow-Up Into Adulthood
Mannuzza et al.
Am. J. Psychiatry 2008;165:604-609.
ABSTRACT | FULL TEXT  

Attention and Executive Systems Abnormalities in Adults with Childhood ADHD: A DT-MRI Study of Connections
Makris et al.
Cereb Cortex 2008;18:1210-1220.
ABSTRACT | FULL TEXT  

Vestibular Stimulation for ADHD: Randomized Controlled Trial of Comprehensive Motion Apparatus
Clark et al.
J Atten Disord 2008;11:599-611.
ABSTRACT  

Functional Magnetic Resonance Imaging of Methylphenidate and Placebo in Attention-Deficit/Hyperactivity Disorder During the Multi-Source Interference Task
Bush et al.
Arch Gen Psychiatry 2008;65:102-114.
ABSTRACT | FULL TEXT  

Neuro-anatomic evidence for the maturational delay hypothesis of ADHD
Rubia
Proc. Natl. Acad. Sci. USA 2007;104:19663-19664.
FULL TEXT  

From the Cover: Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation
Shaw et al.
Proc. Natl. Acad. Sci. USA 2007;104:19649-19654.
ABSTRACT | FULL TEXT  

The frequency, complications and aetiology of ADHD in new onset paediatric epilepsy
Hermann et al.
Brain 2007;130:3135-3148.
ABSTRACT | FULL TEXT  

Size at Birth and Motor Activity During Stress in Children Aged 7 to 9 Years
Schlotz et al.
Pediatrics 2007;120:e1237-e1244.
ABSTRACT | FULL TEXT  

Bihemispheric Leftward Bias in a Visuospatial Attention-Related Network
Siman-Tov et al.
J. Neurosci. 2007;27:11271-11278.
ABSTRACT | FULL TEXT  

Understanding decision-making deficits in neurological conditions: insights from models of natural action selection
Frank et al.
Phil Trans R Soc B 2007;362:1641-1654.
ABSTRACT | FULL TEXT  

Polymorphisms of the Dopamine D4 Receptor, Clinical Outcome, and Cortical Structure in Attention-Deficit/Hyperactivity Disorder
Shaw et al.
Arch Gen Psychiatry 2007;64:921-931.
ABSTRACT | FULL TEXT  

Functional Connectivity of Frontal Cortex in Healthy and ADHD Children Reflected in EEG Coherence
Murias et al.
Cereb Cortex 2007;17:1788-1799.
ABSTRACT | FULL TEXT  

Attention-Deficit/Hyperactivity Disorder: Diagnosis, Lifespan, Comorbidities, and Neurobiology
Spencer et al.
J Pediatr Psychol 2007;32:631-642.
ABSTRACT | FULL TEXT  

Stressing About Posttraumatic Stress Disorder
Steen and Hamer
Pediatrics 2007;120:232-234.
FULL TEXT  

Cortical Thinning of the Attention and Executive Function Networks in Adults with Attention-Deficit/Hyperactivity Disorder
Makris et al.
Cereb Cortex 2007;17:1364-1375.
ABSTRACT | FULL TEXT  

Cerebellar Development and Clinical Outcome in Attention Deficit Hyperactivity Disorder
Mackie et al.
Am. J. Psychiatry 2007;164:647-655.
ABSTRACT | FULL TEXT  

Evidence-based guidelines for management of attention-deficit/hyperactivity disorder in adolescents in transition to adult services and in adults: recommendations from the British Association for Psychopharmacology
Nutt et al.
J Psychopharmacol 2007;21:10-41.
ABSTRACT  

Increased Prevalence of ADHD in Turner Syndrome with No Evidence of Imprinting Effects
Russell et al.
J Pediatr Psychol 2006;31:945-955.
ABSTRACT | FULL TEXT  

Volumetric MRI differences in treatment-naive vs chronically treated children with ADHD.
Pliszka et al.
Neurology 2006;67:1023-1027.
ABSTRACT | FULL TEXT  

The adult psychiatrist's dilemma: psychostimulant use in attention deficit/hyperactivity disorder
Ashton et al.
J Psychopharmacol 2006;20:602-610.
ABSTRACT  

Hippocampus and Amygdala Morphology in Attention-Deficit/Hyperactivity Disorder.
Plessen et al.
Arch Gen Psychiatry 2006;63:795-807.
ABSTRACT | FULL TEXT  

From Behavior to Cognition to the Brain and Back: What Have We Learned From Functional Imaging Studies of Attention Deficit Hyperactivity Disorder?
Casey and Durston, Ph.d.
Am. J. Psychiatry 2006;163:957-960.
FULL TEXT  

Task-Specific Hypoactivation in Prefrontal and Temporoparietal Brain Regions During Motor Inhibition and Task Switching in Medication-Naive Children and Adolescents With Attention Deficit Hyperactivity Disorder
Smith et al.
Am. J. Psychiatry 2006;163:1044-1051.
ABSTRACT | FULL TEXT  

Longitudinal Mapping of Cortical Thickness and Clinical Outcome in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder.
Shaw et al.
Arch Gen Psychiatry 2006;63:540-549.
ABSTRACT | FULL TEXT  

Marijuana use is associated with a reorganized visual-attention network and cerebellar hypoactivation
Chang et al.
Brain 2006;129:1096-1112.
ABSTRACT | FULL TEXT  

What Is Attention-Deficit Hyperactivity Disorder (ADHD)?
Furman
J Child Neurol 2005;20:994-1002.
ABSTRACT  

The genetics of attention deficit hyperactivity disorder
Thapar et al.
Hum Mol Genet 2005;14:R275-R282.
ABSTRACT | FULL TEXT  

ASHP Therapeutic Position Statement on the Appropriate Use of Medications in the Treatment of Attention-Deficit/Hyperactivity Disorder in Pediatric Patients
Dopheide
Am J Health Syst Pharm 2005;62:1502-1509.
FULL TEXT  

A Theory Explaining Biological Correlates of Criminality
Ellis
European Journal of Criminology 2005;2:287-315.
ABSTRACT  

Abnormal Brain Activation During Inhibition and Error Detection in Medication-Naive Adolescents With ADHD
Rubia et al.
Am. J. Psychiatry 2005;162:1067-1075.
ABSTRACT | FULL TEXT  

Children Experience Cognitive Decline Despite Reversal of Brain Atrophy One Year After Resolution of Cushing Syndrome
Merke et al.
J. Clin. Endocrinol. Metab. 2005;90:2531-2536.
ABSTRACT | FULL TEXT  

Brain Volume in Pediatric Patients with Sickle Cell Disease: Evidence of Volumetric Growth Delay?
Steen et al.
Am. J. Neuroradiol. 2005;26:455-462.
ABSTRACT | FULL TEXT  

Attention Deficit-Hyperactivity Disorder
Rappley
NEJM 2005;352:165-173.
FULL TEXT  

Atypical white matter volume development in children following craniospinal irradiation
Reddick et al.
Neuro Oncol Duke 2005;7:12-19.
ABSTRACT  

Short-Term Efficacy of Methylphenidate: A Randomized, Double-Blind, Placebo-Controlled Trial Among Survivors of Childhood Cancer
Mulhern et al.
JCO 2004;22:4795-4803.
ABSTRACT | FULL TEXT  

The Effects of Methylphenidate on Neural Systems of Attention in Attention Deficit Hyperactivity Disorder
Shafritz et al.
Am. J. Psychiatry 2004;161:1990-1997.
ABSTRACT | FULL TEXT  

Attention-Deficit Hyperactivity Disorder (ADHD)
Voeller
J Child Neurol 2004;19:798-814.
ABSTRACT  

Response Inhibition in Adolescents Diagnosed With Attention Deficit Hyperactivity Disorder During Childhood: An Event-Related fMRI Study
Schulz et al.
Am. J. Psychiatry 2004;161:1650-1657.
ABSTRACT | FULL TEXT  

Attention-Deficit/Hyperactivity Disorder in Adults
Wilens et al.
JAMA 2004;292:619-623.
FULL TEXT  

Learning problems, delayed development, and puberty
Wright and Zecker
Proc. Natl. Acad. Sci. USA 2004;101:9942-9946.
ABSTRACT | FULL TEXT  

Meanings and causes in ADHD * Author's reply
Double and Taylor
Br. J. Psychiatry 2004;184:453-454.
FULL TEXT  

Incentive-Elicited Brain Activation in Adolescents: Similarities and Differences from Young Adults
Bjork et al.
J. Neurosci. 2004;24:1793-1802.
ABSTRACT | FULL TEXT  

Amygdala and Hippocampal Volumes in Adolescents and Adults With Bipolar Disorder
Blumberg et al.
Arch Gen Psychiatry 2003;60:1201-1208.
ABSTRACT | FULL TEXT  

Anatomic Brain Abnormalities in Monozygotic Twins Discordant for Attention Deficit Hyperactivity Disorder
Castellanos et al.
Am. J. Psychiatry 2003;160:1693-1696.
ABSTRACT | FULL TEXT  

Evidence of Brain Overgrowth in the First Year of Life in Autism
Courchesne et al.
JAMA 2003;290:337-344.
ABSTRACT | FULL TEXT  

Neural Substrates of Decision Making in Adults With Attention Deficit Hyperactivity Disorder
Ernst et al.
Am. J. Psychiatry 2003;160:1061-1070.
ABSTRACT | FULL TEXT  

INTERFACE BETWEEN NEUROLOGY AND PSYCHIATRY IN CHILDHOOD
Baird and Santosh
J. Neurol. Neurosurg. Psychiatry 2003;74:i17-22.
FULL TEXT  

Biologic Basis of ADHD
JWatch Pediatrics 2003;2003:13-13.
FULL TEXT  

Brain Volume Abnormalities in Attention Deficit Hyperactivity Disorder
Millichap
AAP Grand Rounds 2003;9:1-2.
FULL TEXT  

Biologic Basis of ADHD
JWatch Psychiatry 2002;2002:10-10.
FULL TEXT  

Link Found Between ADHD and Brain Size
Arehart-Treichel
Psychiatr. News 2002;37:21-21.
FULL TEXT