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Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation
P. Shaw†‡, K. Eckstrand†, W. Sharp†, J. Blumenthal†, J. P. Lerch§, D. Greenstein†, L. Clasen†, A. Evans§, J. Giedd†, and J. L. Rapoport†
†Child Psychiatry Branch, National Institute of Mental Health, Room 3N202, Building 10, Center Drive, Bethesda, MD 20892; and §Montreal Neurological Institute, McGillUniversity, Montreal, QC, Canada H3A 2T5

Edited by Leslie G. Ungerleider, National Institutes of Health, Bethesda, MD, and approved October 5, 2007 (received for review August 17, 2007)

There is controversy over the nature of the disturbance in brain development that underpins attention-deficit/hyperactivity disorder (ADHD). In particular, it is unclear whether the disorder results from adelay in brain maturation or whether it represents a complete deviation from the template of typical development. Using computational neuroanatomic techniques, we estimated cortical thickness at >40,000 cerebral points from 824 magnetic resonance scans acquired prospectively on 223 children with ADHD and 223 typically developing controls. With this sample size, we could define the growth trajectory ofeach cortical point, delineating a phase of childhood increase followed by adolescent decrease in cortical thickness (a quadratic growth model). From these trajectories, the age of attaining peak cortical thickness was derived and used as an index of cortical maturation. We found maturation to progress in a similar manner regionally in both children with and without ADHD, with primary sensoryareas attaining peak cortical thickness before polymodal, high-order association areas. However, there was a marked delay in ADHD in attaining peak thickness throughout most of the cerebrum: the median age by which 50% of the cortical points attained peak thickness for this group was 10.5 years (SE 0.01), which was significantly later than the median age of 7.5 years (SE 0.02) for typically developingcontrols (log rank test (1)2 5,609, P < 1.0 10 20). The delay was most prominent in prefrontal regions important for control of cognitive processes including attention and motor planning. Neuroanatomic documentation of a delay in regional cortical maturation in ADHD has not been previously reported.
cortical development structural neuroimaging

Most of the 446 children in the current study hadrepeated neuroanatomic imaging—112 (25%) had two scans, 88 (20%) had three scans, and 30 (7%) had four or more scans, performed at a mean interval between scans of 2.8 years. Such longitudinal data can be combined with cross-sectional data by using mixedmodel regression to model developmental change, with the longitudinal data being particularly informative. For cortical thickness data, thesimplest trajectory that can be fitted to describe its change over time is a straight line. More complex growth models include distinct phases of increase and decrease in cortical thickness: A quadratic model has two such phases (typically an initial increase that reaches a peak before declining) and a cubic model has three. Derived properties of these developmental curves are frequently used asdevelopmental indices, such as the age at which points of inflection in the curve are attained (16, 17). When considering cortical change, the age at which peak cortical thickness is reached—the point where increase gives way to decrease in cortical thickness—emerges as a particularly useful index. Note that the ability to detect a quadratic or cubic growth model is a prerequisite for defining the age ofpeak cortical thickness; it cannot be determined from a linear model. We thus compared the age of attaining peak cortical thickness in children with and without ADHD to determine whether the disorder is characterized by a delay in cerebral cortical maturation. Results The temporal sequence of cortical maturation, reflected by the age of reaching peak cortical thickness at cortical points where...