Characterizing neuroanatomic heterogeneity in people with and without ADHD based on subcortical brain volumes

Abstract

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder in children and adults. Neuroanatomic heterogeneity limits our understanding of the etiology of ADHD. This study aimed to parse neuroanatomic heterogeneity of ADHD, and to determine whether subgroups could be discerned in patients based on subcortical volumes. Methods:Using the dataset from the ENIGMA-ADHD Working Group, we applied exploratory factor analysis (EFA) to subcortical volumes of 993 boys with and without ADHD, and to subsamples of 653 adult men, 400 girls, and 447 women. Factor scores derived from the EFA were used to build networks.A community detection (CD) algorithm clustered participants into subgroups based on the networks.Results: Three factors (basal ganglia, limbic system, and thalamus) were found in boys and men with and without ADHD. The factor structures for girls and women differed from those in males. Given sample size considerations, we concentrated subsequent analyses on males. Male participants could be separated into four communities, though Community 3 was absent in healthy men. Significantly casecontrol differences of subcortical volumes were observed within communities in boys with increased effect sizes, but not in men. While we found no significant differences in ADHD symptom severity between communities in boys or men; affected men in Community 1 and 4 presented comorbidities more frequently than those in other communities. Conclusion:Our results indicate that neuroanatomic heterogeneity in subcortical volumes exists, irrespective of ADHD diagnosis. Effect sizes of case-control differences appear more pronounced at least in some of the subgroups.

Dissecting the heterogeneous subcortical brain volume of Autism spectrum disorder (ASD) using community detection

“…Four communities were observed in boys, three were seen in the samples of male adolescents and adult men, irrespective of ASD status and age; The CD results indicated that the heterogeneity in subcortical brain volumes is nested within normative variability, with different neuroanatomic communities existing in both controls and patients [39]. Importantly, the observed community structure is highly consistent with our recent findings in the ENIGMA-ADHD Working Group [31]. The fact that we observe not only a similar factor structure, but also similar community structure in that sample greatly supports the robustness of our current analysis.…”

“…A study on 404 healthy adults (age range 51-59 years) indicated that subcortical brain volumes could be partitioned into three factors: basal ganglia/thalamus, nucleus accumbens, and a limbic factor [36]. In a recent study of the ENIGMA-ADHD Working Group, we found identical subcortical factor structure as in the current analysis -basal ganglia, limbic system and thalamus -existed in boys and adult men, which was irrespective of ADHD diagnosis and age [31]. Nucleus accumbens receives direct glutamatergic inputs from amygdala and hippocampus, and the nucleus accumbens shell may be regarded as a part of the extended amygdala [37]; this may explain why the nucleus accumbens loads on either the basal ganglia or the limbic factor in the current study.…”

“…Earlier clustering studies have shown that it was possible to stratify a population based on their neuroanatomical profiles, which increased the power to detect case/control differences within each subgroup [30]. Similarly, our recent findings from the ENIGMA-ADHD Working Group also showed distinct subgroups based on subcortical brain patterns present in male participants with and without ADHD [31]. Rather than expecting to find consistent anatomical alterations across the entire ASD population, it may therefore be more reasonable to first stratify both subjects with ASD and healthy controls into more homogeneous subgroups based on their neuroanatomical profiles, and subsequently investigate ASD diagnostic group differences within each subgroup.…”

“…Based on earlier findings in subjects with ADHD, we expected sex difference in subcortical brain volumes organization [31], and given the limited data availability in females (only 145 girls, 45 female adolescents, and 33 women with ASD in ENIGMA-ASD cohort), we decided to only focus on male participants in the current study. We subdivided the full cohort into three subsamples based on age, a subsample comprised of 772 boys with ASD and 733 healthy controls (aged 4-13 years), a subsample of 360 male adolescents with ASD and 321 healthy controls (aged 14-22 years), and a subsample of 221 adult men with ASD and 254 healthy controls (aged >22 years).…”

“…We performed exploratory factor analysis (EFA) to uncover the latent structure underlying the subcortical brain, and reduce the input variables to a more parsimonious model consisting of fewer factors than the total number of subcortical volumes. Following our previously established analysis pipeline [31], covariance matrices and squared multiple correlation were built as prior communality estimates for each subject over all subcortical volumes. Subsequently, maximum likelihood method and oblique rotation were applied to extract factors in the EFA.…”