Digital Twin Control Framework Uncovers Individualized Cross-Scale Links Between Functional Connectivity Deviations,...

Autism spectrum disorder (ASD) is hallmarked by pronounced inter-individual heterogeneity in brain function and clinical manifestations. Conventional neuroimaging studies yield highly inconsistent findings, as extrinsic confounding factors and intrinsic disease heterogeneity mask ASD-specific functional connectivity (FC) signatures, hampering the identification of individualized neural mechanisms linked to symptom severity.

We developed a digital twin control analytical framework based on deep contrastive learning. By comparing each ASD participant with their matched digital twin control, we quantified individual-specific FC deviations. Principal component analysis was applied to extract the core aberrant pattern, followed by multi-dimensional analyses and validation including clinical correlation, transcriptomic decoding, neurotransmitter and mitochondrial co-localization, as well as disease and cognitive enrichment.

The model effectively disentangled disease‑related from non‑disease‑related variations. The identified dominant aberrant FC pattern was significantly associated with Autism Diagnostic Observation Schedule (ADOS) communication scores, suggesting its associated with to communication impairment. This pattern showed convergent associations with synaptic pathways, excitatory/inhibitory neuronal signatures, critical developmental windows and subcortical structures, and exhibited negative spatial association with multiple neurotransmitter systems and mitochondrial respiratory complexes. Biological validation further supported its ASD specificity and communication‑related cognitive relevance.

Leveraging the twin control analytical framework, this study provides an exploratory cross-scale framework linking individualized FC deviations with clinical, transcriptomic, neurochemical, and mitochondrial maps. The findings indicate that communication difficulties in ASD may partly arise from multi-scale disturbances in neural integration, social-perceptual processing and activity-dependent cellular energy regulation.