Beyond BOLD: in search of genuine diffusion fMRI contrast in human brain

Functional Magnetic Resonance Imaging (fMRI) is an essential method to measure brain activity noninvasively. While fMRI almost systematically relies on the blood oxygenation level-dependent (BOLD) contrast, there is an increasing interest in alternative methods that would not rely on neurovascular coupling. A promising but controversial such alternative is diffusion fMRI (dfMRI), which relies instead on dynamic fluctuations in apparent diffusion coefficient (ADC) due to microstructural changes underlying neuronal activity. However, it is unclear whether genuine dfMRI contrast, distinct from BOLD contamination, can be detected in the human brain in physiological conditions. Here, we present the first dfMRI study in humans attempting to minimize all BOLD contamination sources and comparing functional responses at two field strengths (3T and 7T), both for task and resting-state (RS) fMRI. Our study benefits from unprecedented high spatiotemporal resolution and harnesses novel denoising strategies. We report task-induced decrease in ADC with temporal and spatial features distinct from the BOLD response and yielding more specific activation maps. Furthermore, we report dfMRI RS connectivity which, compared to its BOLD counterpart, is essentially free from physiological artifacts and preserves positive correlations but preferentially suppresses anti-correlations, which are likely of vascular origin. A careful acquisition and processing design thus enable the detection of genuine dfMRI contrast on clinical MRI systems. As opposed to BOLD, diffusion functional contrast could be particularly well suited for low-field MRI.