Objective classification biomarkers that are developed using resting-state functional magnetic resonance imaging (rs-fMRI) data are expected to contribute to more effective treatment for psychiatric disorders. Unfortunately, no widely accepted biomarkers are available at present, partially because of the large variety of analysis pipelines for their development. In this study, we comprehensively evaluated analysis pipelines using a large-scale, multi-site fMRI dataset for major depressive disorder (MDD). We explored combinations of options in four sub-processes of the analysis pipelines: six types of brain parcellation, four types of functional connectivity (FC) estimations, three types of site-difference harmonization, and five types of machine-learning methods. A total of 360 different MDD classification biomarkers were constructed using the SRPBS dataset acquired with unified protocols (713 participants from four sites) as the discovery dataset, and datasets from other projects acquired with heterogeneous protocols (449 participants from four sites) were used for independent validation. We repeated the procedure after swapping the roles of the two datasets to identify superior pipelines, regardless of the discovery dataset. The classification results of the top 10 biomarkers showed high similarity, and weight similarity was observed between eight of the biomarkers, except for two that used both data-driven parcellation and FC computation. We applied the top 10 pipelines to the datasets of other psychiatric disorders (autism spectrum disorder and schizophrenia), and eight of the biomarkers exhibited sufficient classification performance for both disorders. Our results will be useful for establishing a standardized pipeline for classification biomarkers.

Recent studies have revealed that resting state functional connectivity is associated with major depressive disorder (MDD). However, the relationship between functional connectivity and clinical measures for the detailed assessment of depression remains unclear. The objective of our study is thus to associate functional connectivity of depressed patients and healthy controls with their individual clinical measures, using a statistical method called partial least squares analysis (PLS). We demonstrated that this method could predict certain clinical measures based on a limited number of functional connections and provided benefits to the prediction performance through incorporation of the subject's age and the estimation of multiple measures simultaneously. Generalizability of the prediction model was assured through leave one out cross validation. The results showed that for BDI-II and SHAPS the most contributing connections concerned cuneus, precuneus and middle frontal cortex and areas of the cerebellum. While the relationship was similar for PANAS(n), it showed its strongest relation with functional connection between calcarine and insula.

To understand the brain mechanisms involved in reward prediction on different time scales, we developed a Markov decision task that requires prediction of both immediate and future rewards, and ana- lyzed subjects’ brain activities using functional MRI. We estimated the time course of reward prediction and reward prediction error on different time scales from subjects' performance data, and used them as the explanatory variables for SPM analysis. We found topog- raphic maps of different time scales in medial frontal cortex and striatum. The result suggests that different cortico-basal ganglia loops are specialized for reward prediction on different time scales.