Asymmetry emerges as a dynamic cortical process: a relative increase in right prefrontal cortical thickness with age is balanced against a relative gain in the left occipital cortex. The results partly explain how the adult right prefrontal and left occipital biases arise from the infantile pattern of cortical asymmetries, where hemispheric biases have been found to be essentially reversed4
or to only partially resemble adult asymmetry.12,13,15
The similar rates of changing asymmetry in the anterior and posterior regions is congruent with the high correlation found in a cross-sectional adult study between right frontal and left occipital cortical expansion using a deformation-based morphometric approach.61
The findings relate to a change in relative thickness of the right and left hemispheres: our earlier work35,62
and that of others63-65
has shown that the cortex becomes thinner bilaterally throughout most of late childhood and adolescence. Herein, we demonstrate that the rate of this thinning differs by hemisphere: there is more rapid cortical thinning in the left hemisphere in the prefrontal regions (resulting in a relatively thicker right prefrontal cortex), with the reverse pattern in posterior regions. Some studies suggest that more rapid thinning is associated with the acquisition of cognitive skills63,66
and is a characteristic of cortical change in children with higher general intelligence.36
Thus, more rapid thinning in the left ventrolateral prefrontal cortex may support the refinement during adolescence of cognitive skills supported by this region.67
However, others have argued that an increase with age in right inferior frontal activation is characteristic of the development of key cognitive skills68
(including cognitive control), illustrating the complexity of forging links between structure and function. The salience of the right inferior frontal gyrus in response inhibition is demonstrated by deficits in this key cognitive skill in adults who have lesions of this area, and, notably, similar deficits are found in those with ADHD.60,69,70
It is also not clear what, if any, psychological processes supported by the posterior parietal and occipital cortex would show a similar age-related shift in lateralized cortical activity. We can equally only speculate about the evolutionary significance of the findings. It is unknown whether this age-related shift in asymmetry is more prominent in humans than in other species or, indeed, whether shifting asymmetry is a uniquely human feature.71
Perhaps the changing asymmetries in most humans might reflect a plastic cortical substrate that could be advantageous in adaptation to early central nervous system insults.
Cortical asymmetries have been delineated using lobar, sublobar, and voxel-level estimates of cortical volumes, gray matter density, and cortical shape and thickness. We can, thus, compare the patterns of childhood and young adult asymmetry from this study, represented by the initial (age 4 years) and final (age 21 years) “stills” in against a wealth of data. The pattern of young adult cortical asymmetry resembles the picture reported in the only other cortical thickness study,25
particularly in the location of relatively thicker right anterior cortex. Like wise, rightward prefrontal and leftward occipital cortical surface expansion, defined in terms of distance from a central point in the brain, have been reported and overlap with the regions showing increased cortical thickness by adulthood in the present study.17
Resultsofvoxel-based morphometric studies9,10
are also consistent, although they report more extensive asymmetries, particularly right-hemispheric asymmetry, which extends from the prefrontal to the temporoparietal regions. Left-hemispheric asymmetry is frequently reported in posterior language areas,9,20-22
and the left posterior superior temporal gyrus is thicker in young adults in the present cohort (although the most pronounced asymmetry is centered on the angular gyrus and immediately posterior to the Wernicke area). We did not find a similar left-hemispheric bias in the anterior speech areas, congruent with some studies using metrics of cortical thickness,25
but not others.23,24
Asymmetries of the motor cortex that occur below the resolution capacity of conventional MRI are reported,72
as are some gross asymmetries,73
although we did not confirm these.
As mentioned earlier, the infantile and childhood pattern of asymmetry is either essentially reversed4
or lacks the right prefrontal13-15
or left occipital bias.12,14
Comparison with the “childhood” picture of asymmetry () confirms this reversed pattern of adult asymmetries, with relatively thicker right occipital and left or-bito-inferior prefrontal regions.
Effects of Handedness and Sex
Less of the cortex in non–right-handed typically developing participants shows age-related change in asymmetry, a result that is compatible with those of adult studies, including one that used cortical thickness, which generally find reduced left occipital6,8
or right prefrontal74
asymmetry in non–right-handed individuals.9
In the present study, this finding cannot be attributed to differences in group sizes or demographic differences between the right-handed and non–right-handed groups because groups were matched for number of MRIs, age, and sex. The findings are compatible with the absence or silencing of genes in non–right-handed individuals driving hemispheric asymmetries and lateralization of function. Some progress has already been made in identifying such genes.28,29,75
For example, the Lim domain only 4 gene (LMO4
) is differentially expressed in the right and left hemisphere at different stages of human fetal development.76
The identification of such asymmetrically expressed genes and the other mechanisms driving asymmetry may give insights into not only the processes of typical lateralization but also the consequences of its disruption.
Some, but not all,10,17
adult studies find males to have more leftward hemispheric asymmetry,8,18
especially around the planum temporal9,19
and perhaps the postcentral gyrus.73,77
This finding is congruent with the regions showing an increased leftward bias with age in males but not with the present finding of increased postcentral gyrus leftward bias in females.
We can only speculate about the functional significance of the disrupted evolution of typical asymmetry in the orbito-inferior frontal gyral region. In one of the few functional studies to examine directly anomalous lateralization of activation in ADHD,33
single-photon emission computed tomography demonstrated decreased right and increased left dorsolateral prefrontal cortical perfusion during response inhibition in individuals with clinically severe ADHD compared with those with mild ADHD, suggesting that anomalous prefrontal lateralization may characterize the disorder. Disrupted development of prefrontal asymmetry might contribute to the consistent findings of anomalous prefrontal activation in the disorder during tasks of cognitive control.32,78
The dimensions of the right inferior frontal gyrus in ADHD may also change during development: whereas reduced volume is reported in childhood ADHD, one study79
noted an increase in volume in adolescents with the disorder.
We recently reported evidence of delayed cortical maturation in frontotemporal regions in the same cohort of children with ADHD as measured by a later age of attaining peak cortical thickness (representing the point at which childhood increase gives way to adolescent decrease in cortical thickness).38
The anomalous evolving prefrontal cortical asymmetry in ADHD nestles with in this overall delay of cortical maturation of both hemispheres in the disorder.
This reflection-based approach relies on identification of the interhemispheric asymmetry plane, and artifacts can arise where the falx curves, as in the occipital pole.80
This affects mainly the posteromedial cortical wall, where cortical thickness asymmetry findings must be interpreted with caution, but spares the lateral cortical surfaces, where the most prominent findings lie. Possible errors arising from the lack of total homology in cortical surfaces such as the planum temporale21
are attenuated by the use of spatial surface smoothing, which diminishes the effects of small regional shape differences.
Nearly all of the participants were treated with psychostimulants at some stage during the study, and, thus, it was not possible to longitudinally compar emedicated and unmedicated ADHD groups. We note, however, that at study entry, individuals with ADHD divided by medication status differed little in the pattern of cortical asymmetry, and the regions showing possible medication effects lay outside the regions that demonstrate changing asymmetry with age. In addition, we recently reported that during adolescence, when a higher proportion of individuals were unmedicated, psychostimulant drug treatment was associated with highly regional differences in cortical change confined to the left dorsolateral and right medial precentral gyrus regions, which do not show significant change in asymmetry with age.81
Nonetheless, in the present observational study, we cannot exclude the possibility that psychostimulants or, indeed, nonpharmacologic interventions do not affect the pattern of changing asymmetry in ADHD.
We demonstrate a “flip” in cortical asymmetries during typical development: a relatively thicker left anterior and right posterior cortex in childhood develops into the well-established adult asymmetries of a thicker right anterior and left posterior cortex. Disruptions of this process cast light on the pathogenesis of neurodevelopmental disorders.