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Neuronal activity results in a local increase in blood flow. This concept serves as the basis for functional MRI. Still, this approach remains indirect and may fail in situations interfering with the neurovascular coupling mechanisms (drugs, anesthesia). Here we establish that water molecular diffusion is directly modulated by underlying neuronal activity using a rat forepaw stimulation model under different conditions of neuronal stimulation and neurovascular coupling. Under nitroprusside infusion, a neurovascular-coupling inhibitor, the diffusion response and local field potentials were maintained, whereas the hemodynamic response was abolished. As diffusion MRI reflects interactions of water molecules with obstacles (e.g., cell membranes), the observed changes point to a dynamic modulation of the neural tissue structure upon activation, which remains to be investigated. These findings represent a significant shift in concept from the current electrochemical and neurovascular coupling principles used for brain imaging, and open unique avenues to investigate mechanisms underlying brain function.

Imaging based on blood flow dynamics is widely used to study sensory processing. Here we investigated the extent to which local neuronal and capillary responses (two-photon microscopy) are correlated to mesoscopic responses detected with fast ultrasound (fUS) and BOLD-fMRI. Using a specialized chronic olfactory bulb preparation, we report that sequential imaging of the same mouse allows quantitative comparison of odour responses, imaged at both microscopic and mesoscopic scales. Under these conditions, functional hyperaemia occurred at the threshold of neuronal activation and fUS-CBV signals could be detected at the level of single voxels with activation maps varying according to blood velocity. Both neuronal and vascular responses increase non-linearly as a function of odour concentration, whereas both microscopic and mesoscopic vascular responses are linearly correlated to local neuronal calcium. These data establish strengths and limits of mesoscopic imaging techniques to report neural activity.