The contribution of diverse and stable functional connectivity edges to brain-behavior associations

Resting-state functional connectivity (FC) has received considerable attention in the study of brain-behavior associations. However, the low generalizability of brain-behavior studies is a common challenge due to the limited sample- to-feature ratio. In this study, we aimed to improve the generalizability of brain-behavior associations in resting-state FC by focusing on diverse and stable edges, i.e., edges that show both high between-subject and low within-subject variability. We used resting-state data from 1003 participants with multiple fMRI sessions from the Human Connectome Project to group FC edges in terms of between-subject and within-subject variability. We found that resting-state FC variability was dominated by stable individual factors. Furthermore, diverse and stable edges were primarily part of heteromodal associative networks, and we showed that diverse stable regions are associated with a domain-general cognitive core. We used canonical correlation analysis (CCA) combined with feature selection and principal component analysis (PCA) to investigate the impact of edge selection on the strength and generalizability of brain-behavior associations. Surprisingly, selection based on edge stability did not significantly affect the results, but diverse edges were more informative than uniform edges in two of the three parcellations tested. Regardless, using all edges resulted in the highest strength and generalizability of canonical correlations. Our simulations suggest that under certain circumstances a combination of feature selection and PCA could improve the generalizability of the results, depending on the sample size and the information value of the features. The lack of improvement in generalizability with selection of stable edges may be due to unreliable estimation of within-subject edge variability or because within-subject edge variability is not related to the information value of the edges for brain-behavior associations. In other words, unstable edges may be equally informative as stable ones. ### Competing Interest Statement J.D.M. and A.A. consult for and hold equity with Neumora (formerly BlackThorn Therapeutics), Manifest Technologies, and are co-inventors on the following patents: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No. PCT/US2119/022110, filed March 13, 2019 and Murray JD, Anticevic A, Martin, WJ:Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No. 16/149,903 filed on October 2, 2018, U.S. Application for PCT International Application No. 18/054,009 filed on October 2, 2018. G.R. consults for and holds equity with Neumora (formerly BlackThorn Therapeutics) and Manifest Technologies. A.M. has previously consulted for Neumora (formerly BlackThorn Therapeutics).