ConnSearch: A framework for functional connectivity analysis designed for interpretability and effectiveness at limited sample sizes

Functional connectivity studies increasingly turn to machine learning methods, which typically involve fitting a connectome-wide classifier, then conducting post hoc interpretation analyses to identify the neural correlates that best predict a dependent variable. However, this traditional analytic paradigm suffers from two main limitations. First, even if classifiers are perfectly accurate, interpretation analyses may not identify all the patterns expressed by a dependent variable. Second, even if classifiers are generalizable, the patterns implicated via interpretation analyses may not replicate. In other words, this traditional approach can yield effective classifiers while falling short of most neuroscientists' goals: pinpointing the neural correlates of dependent variables. We propose a new framework for multivariate analysis, ConnSearch, which involves dividing the connectome into components (e.g., groups of highly connected regions) and fitting an independent model for each component (e. g., a support vector machine or a correlation-based model). Conclusions about the link between a dependent variable and the brain are based on which components yield predictive models rather than on interpretation analysis. We used working memory data from the Human Connectome Project (N = 50-250) to compare ConnSearch with four existing connectome-wide classification/interpretation methods. For each approach, the models attempted to classify examples as being from the high-load or low-load conditions (binary labels). Relative to traditional methods, ConnSearch identified neural correlates that were more comprehensive, had greater consistency with the WM literature, and better replicated across datasets. Hence, ConnSearch is wellpositioned to be an effective tool for functional connectivity research.