Abstract
The integration of functional magnetic resonance imaging (fMRI) with advanced neuroscience technologies in experimental small animal models offers a unique path to interrogate the causal relationships between regional brain activity and brain-wide network measures-a goal challenging to accomplish in human subjects. This review traces the historical development of the neuromodulation techniques commonly used in rodents, such as electrical deep brain stimulation, optogenetics, and chemogenetics, and focuses on their application with fMRI. We discuss their advantageousness roles in uncovering the signaling architecture within the brain and the methodological considerations necessary when conducting these experiments. By presenting several rodent-based case studies, we aim to demonstrate the potential of the multimodal neuromodulation approach in shedding light on neurovascular coupling, the neural basis of brain network functions, and their connections to behaviors. Key findings highlight the cell-type and circuit-specific modulation of brain-wide activity patterns and their behavioral correlates. We also discuss several future directions and feature the use of mediation and moderation analytical models beyond the intuitive evoked response mapping, to better leverage the rich information available in fMRI data with neuromodulation. Using fMRI alongside neuromodulation techniques provide insights into the mesoscopic (relating to the intermediate scale between single neurons and large-scale brain networks) and macroscopic fMRI measures that correlate with specific neuronal events. This integration bridges the gap between different scales of neuroscience research, facilitating the exploration and testing of novel therapeutic strategies aimed at altering network-mediated behaviors. In conclusion, the combination of fMRI with neuromodulation techniques provides crucial insights into mesoscopic and macroscopic brain dynamics, advancing our understanding of brain function in health and disease. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.