Cortical morphometric inverse divergence in attention-deficit/hyperactivity disorder correlates with...

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Attention-deficit/hyperactivity disorder (ADHD) involves widespread brain alterations, but macroscale and microscale mechanisms remain unclear.
• Shared neurobiological pathways between the full ADHD cohort and the combined subtype (ADHD-C) require further investigation.

Purpose of the Study:

• To investigate the relationship between macroscale cortical organization and microscale molecular mechanisms in ADHD.
• To identify shared neurobiological underpinnings between the full ADHD cohort and the ADHD-C subtype.

Main Methods:

• Analysis of 176 ADHD patients (105 ADHD-C, 71 ADHD inattentive) and 176 controls using the ADHD-200 dataset.
• Quantification of cortical similarity using Morphometric Inverse Divergence (MIND) networks.
• Partial least squares (PLS) regression to link MIND differences to cortical gene expression, assessing functional enrichment, cell-type, and developmental specificity.

Main Results:

• ADHD-C subtype showed increased regional MIND values, indicating greater morphological homogeneity, particularly in temporal and parietal cortices.
• MIND alterations correlated with a transcriptomic signature (PLS1+) enriched in mitochondrial metabolic pathways, with specific cortical layer (Layer V) and developmental stage (fetal to infancy) specificity.
• Shared PLS1-related genes and functional pathways were observed between the full ADHD cohort and the ADHD-C group, with neurons showing enrichment in the full ADHD cohort and trend-level associations in ADHD-C.

Conclusions:

• The study connects macroscale cortical abnormalities to microscale transcriptional regulation in ADHD, especially in ADHD-C.
• Shared genetic and functional profiles between ADHD and ADHD-C highlight common pathological processes.
• Provides novel insights into the neurodevelopmental mechanisms underlying ADHD.