Beyond BOLD: Evidence for diffusion fMRI contrast in the human brain distinct from neurovascular response

Functional Magnetic Resonance Imaging (fMRI) is an essential method to measure brain activity non-invasively. 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, i.e. neuromorphological coupling. 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 BOLD contamination sources and comparing functional responses at two field strengths (3T and 7T). Our study benefits from unprecedented high spatio-temporal resolution, harnesses novel denoising strategies and examines characteristics of not only task but also resting-state dfMRI. 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 resting-state functional 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.