Development of cortical asymmetry in typically developing children and its disruption in attention-deficit/hyperactivity disorder

Abstract

Context: Just as typical development of anatomical asymmetries in the human brain has been linked with normal lateralization of motor and cognitive functions, disruption of asymmetry has been implicated in the pathogenesis of neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD). No study has examined the development of cortical asymmetry using longitudinal neuroanatomical data.

Objective: To delineate the development of cortical asymmetry in children with and without ADHD.

Design: Longitudinal study.

Setting: Government Clinical Research Institute.

Participants: A total of 218 children with ADHD and 358 typically developing children, from whom 1133 neuroanatomical magnetic resonance images were acquired prospectively.

Main outcome measures: Cortical thickness was estimated at 40 962 homologous points in the left and right hemispheres, and the trajectory of change in asymmetry was defined using mixed-model regression.

Results: In right-handed typically developing individuals, a mean (SE) increase in the relative thickness of the right orbitofrontal and inferior frontal cortex with age of 0.011 (0.0018) mm per year (t(337) = 6.2, P < .001) was balanced against a relative left-hemispheric increase in the occipital cortical regions of 0.013 (0.0015) mm per year (t(337) = 8.1, P < .001). Age-related change in asymmetry in non-right-handed typically developing individuals was less extensive and was localized to different cortical regions. In ADHD, the posterior component of this evolving asymmetry was intact, but the prefrontal component was lost.

Conclusions: These findings explain the way that, in typical development, the increased dimensions of the right frontal and left occipital cortical regions emerge in adulthood from the reversed pattern of childhood cortical asymmetries. Loss of the prefrontal component of this evolving asymmetry in ADHD is compatible with disruption of prefrontal function in the disorder and demonstrates the way that disruption of typical processes of asymmetry can inform our understanding of neurodevelopmental disorders.

Figure 1

Differences between left and right cortical thickness at each age. Red and yellow areas indicate a thicker left cortex; blue and purple areas, a thicker right cortex. Note the changing asymmetries in the right orbitofrontal and inferior frontal regions and in the left posterior temporo-occipital cortex.

Figure 2

A, Regions with a significant (at false discovery rate–adjusted P<.05) increase in relative right-hemispheric thickness with age. B, Regions with an increase in relative left-hemispheric thickness with age. L indicates left; R, right.

Figure 3

Comparison of regions with significantly (P<.05) changing asymmetry with age in right-handed and non–right-handed typically developing individuals. The groups were strictly matched, which explains the lesser extent of the changing asymmetry with age in the right-handed typically developing cohort compared with the entire right-handed group shown in Figure 2.

Figure 4

Regions where there was a significant interaction of sex with changing asymmetry. A, Regions where males had a greater decrease with age in asymmetry (left [L] minus right [R]), indicating relative right-hemispheric gain; females showed the opposite pattern of an increase with age in asymmetry, indicative of a relative left-hemispheric gain. B, Superior temporal region where the reverse pattern occurred.

Figure 5

Differences between left and right cortical thickness at each age for the right-handed attention-deficit/hyperactivity disorder cohort. Red and yellow areas indicate a thicker left cortex; blue and purple areas, a thicker right cortex. Note the essential absence of changing asymmetries in the right orbitofrontal and inferior frontal regions. The left posterior temporo-occipital cortex shows a similar pattern of changing asymmetry with age as in the typically developing group.

Figure 6

Regions where asymmetry at study entry differed between individuals with attention-deficit/hyperactivity disorder treated vs not treated with psychostimulant drugs. Results are shown at an unadjusted P<.05; the group difference did not survive correction for multiple comparisons.