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23 Jul 2020

Hoogman M et al. Hum Brain Mapp 2020; Epub ahead of print

Two of the main shortcomings of neuroimaging studies in ADHD and autism spectrum disorder (ASD) are the small sample sizes employed and the heterogeneity of methods used. The ENIGMA-ADHD and ENIGMA-ASD working groups were founded in 2013 and 2014, respectively, with a common goal to address these limitations. There is considerable overlap in the occurrence of ADHD and ASD, and the collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together.

The initial projects undertaken by both working groups focused on analyses of subcortical brain volume, and cortical thickness and surface area analyses.

Subcortical and cortical measures – key findings

In the ENIGMA-ADHD working group’s first project, the volumes of subcortical structures and the total intracranial volume (ICV) were compared between individuals with ADHD (n = 1713) and without ADHD (n = 1529).* Data were collected at 23 sites and there was an overall age range of 4–63 years. Results for the total sample showed significant but small differences in the total volume of the nucleus accumbens (Cohen’s d = –0.15), amygdala (d = –0.19), caudate nucleus (d = –0.11), hippocampus (d = –0.11), putamen (d = –0.14) and ICV (d = –0.10), where individuals with ADHD had smaller volumes than those without ADHD. When age groups were considered, case–control differences were only significant in children (aged <15 years).

The second main analysis of the ENIGMA-ADHD working group covered the cortex. Since completion of its subcortical project, ENIGMA-ADHD had grown to 36 sites, and 2246 individuals with ADHD and 1934 individuals without ADHD were included in the cortical project. Results showed, on average, lower surface area in frontal, cingulate and temporal regions in the analysis of children with ADHD versus children without ADHD, with the largest case–control effect sizes in the youngest group of children. The largest effect was found for total surface area (d = –0.21). Lower cortical thickness values were found for the fusiform gyrus and temporal pole in children with ADHD compared with children without ADHD. Further study revealed that symptoms of inattention were negatively associated with total surface area. In addition, sibling comparison data suggested that familial factors, genes and/or shared environment may play a role in the cortical differences observed in ADHD.

The ENIGMA-ASD working group collected data at 52 sites, including a total of 1571 individuals with ASD and 1651 individuals without ADHD. Small but significant deficits were found in the subcortical volumes of the pallidum (d = –0.08), putamen (d = –0.10), amygdala (d = –0.08) and nucleus accumbens (d = –0.13). Cortical analysis showed no detectable differences in regional and total surface areas. However, individuals with ASD showed greater cortical thickness in frontal brain areas and lower cortical thickness in temporal/occipital brain areas (d = –0.21 to d = 0.2).

Subcortical and cortical measures – overlap and differences between ADHD and ASD

The main results from the analyses of the ENIGMA-ADHD and -ASD working groups revealed several distinct patterns, although the analyses were limited by the lack of full ASD symptomatology/diagnosis coverage in the ADHD cohorts and vice versa. The next logical step was to repeat these analyses on the combined data from the two working groups. This analysis included 2271 individuals with ADHD, 1771 with ASD, 2323 with obsessive-compulsive disorder and 5827 individuals without these conditions; analysis was subdivided by age into children (<12 years), adolescents (12–17 years) and adults (≥18 years).

Taken together, the separate and combined working group analyses indicated that there are unique cortical features in each disorder, but also considerable overlap between the two disorders, specifically when considering cortical thickness. Subcortical volumes were similarly affected in both ASD and ADHD, although the effect sizes over all age strata remained quite small.

Secondary projects within ENIGMA-ADHD and ENIGMA-ASD

Researchers within the ENIGMA collaboration are encouraged to perform additional analyses on the collected data to address alternative research questions, or to use the network to test new analytic strategies and methods. For ENIGMA-ADHD and ENIGMA-ASD, there are four projects with overlapping objectives on the topics of laterality, machine learning, stratification and virtual histology, as well as a project within ENIGMA-ADHD focused on the cerebellum. These projects are at various stages of analysis and publication.

In summary, the ENIGMA collaboration found that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. In addition, cortical analyses identified unique differences in each disorder, as well as considerable overlap between the two, specifically in cortical thickness. Ongoing projects derived from these collaborations are examining alternative research questions, such as brain laterality, prediction of case–control status and anatomical heterogeneity. These projects illustrate the importance of combining expertise to boost the understanding of ADHD and ASD in relation to the brain.

Read more about the collaborative neuroscience of the ENIGMA working groups here


*Detailed instructions for analysis and quality control can be found on the ENIGMA website

Hoogman M, van Rooij D, Klein M, et al. Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: the ENIGMA adventure. Hum Brain Mapp 2020; Epub ahead of print.

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