Cortical gradient perturbation in attention deficit hyperactivity disorder correlates with neurotransmitter-, cell type-specific and chromosome- transcriptomic signatures

Abstract

Neurofunctional dysregulations in spatially discrete areas or isolated pathways have been suggested as neural markers for attention deficit hyperactivity disorder (ADHD). However, multiscale perspectives into the neurobiological underpins of ADHD spanning multiple biological systems remain sparse. This points to the need of multi-levels of analysis encompassing brain functional organization and its correlation with molecular and cell-specific transcriptional signatures are stressed. Here, we capitalized on diffusion mapping embedding model to derive the functional connectome gradient, and deployed multivariate partial least square (PLS) method to uncover the enrichment of neurotransmitomic, cellular and chromosomal connectome-transcriptional signatures of ADHD. Compared to typical control, ADHD children presented connectopic cortical perturbations in lateral orbito-frontal and superior temporal regions, which had also been validated in another independent sample. This gradient-derived variants in ADHD further aligned spatially with distributions of GABAA/BZ and 5-HT2A receptors and co-varied with genetic transcriptional expression. Cognitive decoding and gene-expression annotation showed the correlates of these variants in memory, emotional regulation and spatial attention. Moreover, the gradient-derived transcriptional signatures of ADHD exhibited enriched expression of oligodendrocyte precursors and endothelial cells, and were mainly involved as variants of chromosome 18, 19 and X. In conclusion, our findings bridged in-vivo neuroimging assessed functional brain organization patterns to a multi-level molecular pathway in ADHD, possibly shedding light on the interrelation of biological systems that may coalesce to the emergence of this disorder.

Bridging gaps in brain disconnection in childhood ADHD: From macroscale connectomes to microscale biological architectures

“…In the study of this issue by Chen et al 1 they attempted to address an important question on the intricate neuropathological landscape of ADHD through a comprehensive macro-micro-molecular perspective. Leveraging human neuroimaging data from the ADHD-200 initiative repository, they examined resting-state functional connectivity in ADHD children and matched typically developing cohorts.…”

“…One key domain that the current results suggest should be studied further is to delve into the neuropathological mechanisms underlying brain connectome aberrations in ADHD linked to microscale neurotransmitter and genetic transcriptomic profiles derived from independent populations. 2 One novel aspect of the Chen et al 1 study design attempts to bridge a gap between macroscale brain connectome aberrations and farreaching microscale/cellular biological architectures. Given there are many factors and sources that could account for the associations of connectome gradient changes with neurotransmitter and transcriptomic profiles, it would be wise to disentangle the specificity of neurotransmitomic, type-specific and chromosome-level signatures in relation to ADHD rather than other disorders in future studies.…”