To confirm prior cross-sectional findings and clarify discrepancies in the literature, sophisticated computational image analysis methods were employed to examine highly localized changes in cortical thickness in a well-matched sample of child and adolescent subjects with ADHD compared to typically developing controls. Mean cortical gray matter thickness was significantly reduced in ADHD (> 6%). Examination of cortical thickness performed at high spatial resolution showed that subjects with ADHD exhibit robust (up to 20%) and widespread cortical thinning over large areas of anterior and posterior association cortices, including aspects of primary motor cortex and with predominant sparing of primary sensory regions. No brain region showed significantly increased thickness in subjects with ADHD compared to age-matched controls. Standard volumetric analyses of brain tissue compartments were consistent with the majority of earlier reports where subjects with ADHD exhibited smaller brain and gray matter volumes with respect to healthy controls.9-12
White matter volumes, however, were significantly larger in ADHD as consistent with some prior observations,46
but conflicting with others.13
Cortical thickness represents the number, size, density, and arrangement of cells (neurons and neuroglia and nerve fibers) within the cortical mantle.47, 48
Age-inappropriate cortical thinning may thus reflect changes in the integrity of the neuropil stemming from disturbances in neural/synaptic development and pruning. White matter changes may also influence cortical thickness since myelinated fibers extend into the cortex. However, cortical thickness may be over or underestimated in imaging data since it is not certain to what extent gray/white and gray/CSF boundaries match actual tissue boundaries in the living brain. Signal intensity thresholds used for tissue segmentation may also vary across studies. Notwithstanding, if image parameters and pre-processing are the same for all participants, differences between diagnostic groups should remain relative since thickness or brain tissue voxel counts are biased in the same direction for all subjects.
Prominent ADHD-related cortical thinning was observed over much of dorso-lateral, orbito and mesial frontal cortices encompassing the cingulate and aspects of premotor and motor cortex, antero-lateral and mesial temporal cortices, lateral occipital cortices, medial parietal cortices, and left lateral parietal cortex. These findings are largely consistent, although more pervasive, than results from a landmark study investigating both cross-sectional and longitudinal changes of cortical thickness in child and adolescent ADHD.21
Specifically, Shaw et al.21
using completely automated procedures observed significant global cross-sectional reductions of laminar thickness in subjects with ADHD (n=163) compared to healthy controls (n=166) that were localized bilaterally to dorsal and mesial prefrontal cortices including the cingulate and antero- and mesial temporal cortices. Notably, without correction for IQ or mean cortical thickness, this prior study observed widespread sub-threshold cortical thinning and no regions of increased cortical thickness over much of the remaining cortex. Furthermore, when averaged within 56 probabilistic gyral boundaries, subjects with ADHD exhibited significant cortical thinning in almost all regions implicated in the current investigation including parietal and occipital cortex.
After controlling for differences in general intellectual ability, significant observations of cortical thinning were slightly less pronounced in ADHD [, panels B and D], although effects still spanned the same areas of cortex. These findings may be explained in part by a loss of degrees of freedom, indicate that localized cortical thinning more closely relates to intellectual ability, or suggest that the neurobehavioral disturbances in ADHD are not dissociable from ADHD-related test taking difficulties.49
These results are again consistent with the findings of Shaw and colleagues,21
although the investigators additionally included mean cortical thickness in their statistical model, which may serve to remove ADHD-related variance for the regional effects of interest. Moreover, their study participants were of higher general intellectual ability (> 10 points) on average than those included in this study. Thus, our findings of somewhat more pronounced cortical thinning in ADHD may relate to the severity of the disorder or could be attributable to methodological differences, where in spite of smaller sample sizes, our study may have benefited from using both manual and automated methods to match gyral anatomy across subjects with less spatial smoothing.
Our findings and those of Shaw et al.21
contrast with another earlier study of cortical thickness that failed to show significant regional cortical thinning in child and adolescent ADHD, although significant reductions of intracranial volume, surface area and cortical folding were observed.24
Since sample sizes were similar, differences in results are most likely accounted for by methodological differences and/or differences in the clinical characteristics of subjects. For example, Wolosin et al.24
used automated methods to estimate and compare mean cortical thickness across the cortical mantle and within 34 gyral-based regions, where individual brain volumes appear to have been rescaled into a Talairach coordinate space. Thus, it is possible that if applied, scaling, or alternatively the lack of control for overall brain size may have influenced results. Moreover, as noted by Shaw et al.21
cortical thickness reductions in ADHD do not appear to conform well to prescribed gyral regions, thus averaging thickness across coarsely registered gyral areas may serve to decrease rather than to increase statistical power. Differences in exclusionary criteria for comorbid diagnoses may also have contributed to discrepancies in prior findings. In a post-hoc analysis, Wolosin et al.24
reported a trend for mean cortical thinning bilaterally when children comorbid for ADHD and ODD (38%) were compared with controls separately.
Our results are also partially conflicting with a previous study employing a similar approach to align cortical anatomy, but that measured cortical gray matter density to show increased density in posterior temporal/anterior parietal regions in ADHD youth with respect to controls19
. However, this prior investigation did observe cortical surface deformations in prefrontal and anterior temporal regions suggestive of local brain tissue reductions that are consistent with our results. Though cortical thickness and cortical gray matter density measures may be associated, gray matter density measures reflect the number of voxels classifying as gray matter with respect to voxels classifying as other tissue types (white matter and CSF) both within and outside the cortical mantle and may thus be influenced by changes in other tissue characteristics perhaps accounting for discrepancies in findings.
ADHD-related cortical thinning was less pronounced and spatially pervasive after removing participants receiving stimulant mediation from the sample. However, we cannot be sure whether the similar, although less extensive spatial pattern of results may be attributable to more severe cortical thinning in subjects receiving medication or simply reflect the loss of statistical power by reducing the sample size by approximately one third. Some larger structural imaging studies10
suggest that morphometric abnormalities in ADHD are largely independent of comorbidities and medication exposure, although further longitudinal assessments appear warranted.
ADHD is associated with impairments in executive function including deficits in working memory, planning, set shifting and inhibitory/cognitive control suggesting the involvement of prefrontal regions and subcortical circuits.5, 49, 50
The developmentally inappropriate symptoms of inattention, impulsivity and restlessness in ADHD also implicate disturbances in prefrontal as well as parietal networks. Moreover, predominant disturbances of neural activity within fronto-striatal and fronto-parietal circuits have been reported via meta-analysis of the functional neuroimaging literature in ADHD.51
Thus, our observations of pervasive cortical thinning within dorsolateral, orbitofrontal, and medial frontal regions, and parietal cortex suggest that abnormalities in neural cytoarchitecture may constitute a biological basis for the clinical and neuropsychological profiles of ADHD.
In spite of an emphasis of the role of executive functioning and inhibitory control in ADHD, the existing literature also indicates that ADHD is associated with a heterogeneous neurocognitive profile where deficits in executive function do not present in all individuals and other functional systems are implicated.49, 52, 53
For example, some neuropsychological and electrophysiological studies suggest earlier, more generalized deficits in information processes such as in visual-spatial functioning, attention allocation and response preparation involving temporo-striatal and/or temporo-parietal networks.54-56
Prior studies also implicate altered mesiolimbic circuitry in ADHD (orbitofrontal, anterior cingulate, ventral striatum and medial temporal regions) as associated with reward, reinforcement and motivational behaviors.56
Finally, disruptions in temporo-occipital ‘ventral stream’ and parieto-occipital ‘dorsal stream’ pathways involved in object recognition/manipulation and visual-attention and analysis that underlie most cognitive processes have been implicated in ADHD, although less widely examined.57, 58
As consistent with the presentation of neurocognitve deficits, our observations of cortical thinning in anterior- and ventral temporal regions and in temporo-occipital cortex similarly suggest a complex neuroanatomical profile of ADHD extending beyond frontal and subcortical circuits.
There are several limitations associated with the current investigation. Firstly, female subjects with ADHD were underrepresented. Although prevalence is higher in males, the core features of ADHD appear similar across sex10
, but developmental processes may differ by sex. Secondly, it is common for ADHD to present with other diagnoses, where ODD is the most common coexistent condition.5
Unfortunately, we were not able to address the potential confounding effects of comorbid disorders in the current study, since such analyses would have been underpowered and thus uninformative. However, an argument can be made that controlling for conditions such as ODD may remove variance that overlaps with ADHD.49
Thirdly, our cross-sectional study design did not allow us to address group differences with respect to age. Finally, the experiments performed here did not include investigation of the cerebellum and subcortical regions, also widely implicated in the disorder.
In summary, analysis strategies that enable the mapping of cortical thickness deficits with high spatial accuracy and resolution, revealed highly significant (FDR corrected p < .0006) cortical thinning over wide areas of cortex in a well-matched sample of children and adolescents with ADHD compared to typically developing controls. These results confirm and expand upon an earlier study of cortical thickness in ADHD.21
Although this study could not address whether cortical thinning is associated with a developmental delay in ADHD as previously suggested,22
our results support that when taking age into account, cortical thinning represents a robust imaging marker of the disorder. Since the observed pattern of cortical thinning is most consistent with a model of ADHD that points to deficits in multiple functional systems, future studies may focus on clarifying the nature of potential structure-function relationships.