Advancing simultaneous fMRI-multiphoton imaging technique to study brain function and connectivity across different scales at ultrahigh field

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PROJECT SUMMARY Understanding the neural circuitry and signaling in health or diseased brain requires new tools that can image neuronal activity and functional connectivity with superior spatiotemporal precision across various scales from individual and population of neural cells and microvessel at microscopic scale, neural circuits and cortical layers/columns, and functional connectivity at mesoscopic (or laminar) scale to neural networks at macroscopic scale and the nervous system level. Functional magnetic resonance imaging (fMRI) based on the blood- oxygenation-level-dependent (BOLD) contrast has gained a prominent position in neuroscience, and it is the only neuroimaging modality that can noninvasively map human neuronal activity and dynamic change to the level of neural computational units, and image functional connectivity and resting-state networks (RSNs) covering the entire brain. However, the fMRI BOLD signal is determined by a complex interplay between vascular and metabolic changes, thus, indirectly reflecting neuronal activity. The inference of underlying neuronal activity on the fMRI BOLD signal can be affected by many unknown factors at microscopic and mesoscopic scales. Although great efforts have been made to study the correlation between fMRI signals and neuronal activity, the neurophysiology origin of the BOLD signal and its specificity in mapping neuronal activity and functional connectivity at cortical lamina level remains elusive. To tackle technical challenges and address critical neuroimaging and neuroscience questions, we have formed an interdisciplinary team with experts in the ultrahigh-field (UHF) fMRI and multi-photon microscopy imaging research fields from two research institutions to develop the world first MRI fully compatible volumetric two-photon microscopy imaging (VTPMI) system, which works in one of the highest field animal MRI scanners at 16.4T Tesla. This novel VTPMI-fMRI multimodal neuroimaging system will make it possible to simultaneously measure key neurophysiological information related to activities and dynamics of excitatory/inhibitory neurons, astrocytes, different sized vessels, and ultrahigh-resolution fMRI data, thus enables delineation of cell- and layer- specific neuronal activity in the living brain. The VTPMI-fMRI technology developed in this project will be employed to study the neuro-vascular correlation and the specificity of resting-state fMRI BOLD signals for mapping the layer-specific functional connectivity in anesthetized and awake brains, with particular emphasis on investigating the roles of inhibitory interneurons. The findings and knowledge from this project will be transformative and beneficial for understanding and interpreting the human fMRI BOLD signals at the fine scale of fundamental computational units.