Deriving causal relationships in resting-state functional connectivity using SSFO-based optogenetic fMRI

Objective. The brain network has been extensively studied as a collection of brain regions that are functionally inter-connected. However, the study of the causal relationship in brain-wide functional connectivity, which is critical to the brain function, remains challenging. We aim to examine the feasibility of using (SSFO)-based optogenetic functional magnetic resonance imaging to infer the causal relationship (i.e. directional information) in the brain network. Approach. We combined SSFO-based optogenetics with fMRI in a resting-state rodent model to study how a local increase of excitability affects brain-wide neural activity and resting-state functional connectivity (RSFC). We incorporated Pearson's correlation and partial correlation analyses in a graphic model to derive the directional information in connections exhibiting RSFC modulations. Main results. When the dentate gyrus (DG) was sensitized by SSFO activation, we found significantly changed activity and connectivity in several brain regions associated with the DG, particularly in the medial prefrontal cortex Our causal inference result shows an 84%-100% accuracy rate compared to the directional information based on anatomical tracing data. Significance. This study establishes a system to investigate the relationship between local region activity and RSFC modulation, and provides a way to analyze the underlying causal relationship between brain regions.