Polyconnectomic Scoring of Functional Connectivity Patterns Across Eight Neuropsychiatric and Three Neurodegenerative Disorders.

Background: Neuropsychiatric and neurodegenerative disorders involve diverse changes in brain functional connectivity. As an alternative to approaches that search for specific mosaic patterns of affected connections and networks, we used polyconnectomic scoring to quantify disorder-related whole-brain connectivity signatures into interpretable, personalized scores.

Methods: The polyconnectomic score (PCS) measures the extent to which an individual's functional connectivity mirrors the whole-brain circuitry characteristics of a trait. We computed PCSs for 8 neuropsychiatric conditions (attention-deficit/hyperactivity disorder, anxiety-related disorders, autism spectrum disorder, obsessive-compulsive disorder, bipolar disorder, major depressive disorder, schizoaffective disorder, and schizophrenia) and 3 neurodegenerative conditions (Alzheimer's disease, frontotemporal dementia, and Parkinson's disease) across 22 datasets with resting-state functional magnetic resonance imaging data from 10,667 individuals (5325 patients, 5342 control participants). We also examined PCSs in 26,673 individuals from the population-based UK Biobank cohort.

Results: PCSs were consistently higher in out-of-sample patients across 6 of the 8 neuropsychiatric and across all 3 investigated neurodegenerative disorders ([minimum, maximum]: area under the receiver operating characteristic curve = [0.55, 0.73], false discovery rate-corrected p [p] = [1.8 × 10, 4.5 × 10]). Individuals with elevated PCS levels for neuropsychiatric conditions exhibited higher neuroticism (p < 9.7 × 10), lower cognitive performance (p < 5.3 × 10), and lower general well-being (p < 9.7 × 10).

Conclusions: Our findings reveal generalizable whole-brain connectivity alterations in brain disorders. Polyconnectomic scoring effectively aggregates disorder-related signatures across the entire brain into an interpretable, participant-specific metric. A toolbox is provided for PCS computation.