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 a delay 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 of each 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 sensory areas 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 developing controls (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 A ttention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopment disorder of childhood affecting between 3% and 5% of school-aged children (1). Since its earliest descriptions, there has been debate as to whether the disorder is a consequence partly of delay in brain maturation or as a complete deviation from the template of typical development (2). Several studies find that brain activity at rest and in response to cognitive probes is similar between children with ADHD and their slightly younger but typically developing peers, evidence congruent with a maturational lag in cortical development (3-5). However, others report a quantitatively distinct neurophysiology, with a unique architecture of the electroencephalogram and some highly anomalous findings in functional imaging studies, more in keeping with ADHD as a deviation from typical development (6-10).In a previous longitudinal study, we found parallel trajectories of gray lobar volume change in children with ADHD and typically developing controls, but more focal changes in cortical maturation occurring at a sublobar level would not be detected by this lobar measure (11). We thus aimed to define the trajectory of cortical development using a measure of cortical thickness that affords exquisite spatial re...

Understanding human cortical maturation is a central goal for developmental neuroscience. Significant advances towards this goal have come from two recent strands of in-vivo structural magnetic resonance imaging (sMRI) research: (i) longitudinal study designs have revealed that factors such as sex, cognitive ability and disease are often better related to variations in the tempo of anatomical change than to variations in anatomy at any one time-point, and (ii) largely cross-sectional applications of new “surface-based morphometry” (SBM) methods have shown how the traditional focus on cortical volume (CV) can obscure information about the two evolutionarily and genetically distinct determinants of CV - cortical thickness (CT) and surface area (SA). Here, by combining these two strategies for the first time, and applying SBM in over 1,250 longitudinally acquired brain scans from 647 healthy individuals aged 3 to 30 years, we deconstruct cortical development to reveal that distinct trajectories of anatomical change are “hidden” within, and give rise to, a curvilinear pattern of CV maturation. Developmental changes in CV emerge through the sexually dimorphic and age-dependent changes in CT and SA. Moreover, SA change itself actually reflects complex interactions between brain size-related changes in exposed cortical “convex hull” area (CHA), and changes in the degree of cortical gyrification, which again vary by age and sex. Knowing of these developmental dissociations, and further specifying their timing and sex-biases provides potent new research targets for basic and clinical neuroscience.

SUMMARY Understanding of human structural brain development has rapidly advanced in recent years, but remains fundamentally “localizational” in nature. Here, we use 376 longitudinally acquired structural brain scans from 108 typically developing adolescents to conduct the first study of coordinated anatomical change within the developing cortex. Correlation in rates of anatomical change was regionally heterogeneous, with fronto-temporal association cortices showing the strongest and most widespread maturational coupling with other cortical areas, and lower-order sensory cortices showing the least. Canonical cortical systems with rich structural and functional interconnectivity showed significantly elevated maturational coupling. Evidence for sexually dimorphic maturational coupling was found within a frontopolar-centered prefrontal system involved in complex decision-making. By providing the first link between cortical connectivity and the coordination of cortical development, we reveal a hitherto unseen property of healthy brain maturation, which may represent a target for neurodevelopmental disease processes, and a substrate for sexually dimorphic behavior in adolescence.

Humans have systematic sex differences in brain-related behavior, cognition, and pattern of mental illness risk. Many of these differences emerge during adolescence, a developmental period of intense neurostructural and endocrine change. Here, by creating "movies" of sexually dimorphic brain development using longitudinal in vivo structural neuroimaging, we show regionally specific sex differences in development of the cerebral cortex during adolescence. Within cortical subsystems known to underpin domains of cognitive behavioral sex difference, structural change is faster in the sex that tends to perform less well within the domain in question. By stratifying participants through molecular analysis of the androgen receptor gene, we show that possession of an allele conferring more efficient functioning of this sex steroid receptor is associated with "masculinization" of adolescent cortical maturation. Our findings extend models first established in rodents, and suggest that in humans too, sex and sex steroids shape brain development in a spatiotemporally specific manner, within neural systems known to underpin sexually dimorphic behaviors.

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