Cortical morphometric inverse divergence in attention-deficit/hyperactivity disorder correlates with cell-type-specific, laminar-specific and developmental transcriptomic signatures

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition with widespread brain structure alterations. However, the relationship between macroscale cortical organization and microscale molecular mechanisms remains unclear, particularly regarding the neurobiological mechanisms shared between the full ADHD cohort and its combined subtype (ADHD-C). METHODS: We analyzed 176 patients with ADHD (105 ADHD-C, 71 ADHD inattentive subtype) and 176 matched typically developing (TD) controls from the ADHD-200 dataset. Morphometric Inverse Divergence (MIND) networks quantified cortical similarity. Partial least squares (PLS) regression linked case-control MIND differences to cortical gene expression, assessing functional enrichment, cell-type specificity, and developmental trajectories. RESULTS: Neuroanatomically, the ADHD-C subtype exhibited widespread increases in regional MIND values, particularly in temporal and parietal cortices, reflecting greater inter-regional morphological homogeneity. PLS regression revealed that these MIND alterations were spatially correlated with a specific transcriptomic signature (PLS1+). These PLS1+ genes were significantly enriched in mitochondria-related metabolic pathways and showed distinct cortical layer specificity (notably layer V) and developmental stage specificity (from late fetal to late infancy stages). Regarding cell-type specificity, while PLS1+ genes in the full ADHD cohort were significantly enriched in excitatory and inhibitory neurons, the ADHD-C subtype showed similar but trend-level associations. Importantly, the full ADHD cohort and the ADHD-C group shared numerous PLS1-related genes and broad functional pathway enrichment commonalities. CONCLUSIONS: This study links macroscale cortical abnormalities to microscale transcriptional regulation, with pronounced alterations in ADHD-C. The shared genetic and functional profiles between ADHD and its combined subtype underscore common pathological processes, providing novel insights into the neurodevelopmental mechanisms of ADHD.