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Diffusion functional magnetic resonance imaging (dfMRI) is a promising technique to map functional activations by acquiring diffusion‐weighed spin‐echo images. In previous studies, dfMRI showed higher spatial accuracy at activation mapping compared to classic functional MRI approaches. However, it remains unclear whether dfMRI measures result from changes in the intracellular/extracellular environment, perfusion, and/or T 2  values. We designed an acquisition/quantification scheme to disentangle such effects in the motor cortex during a finger‐tapping paradigm. dfMRI was acquired at specific diffusion weightings to selectively suppress perfusion and free‐water diffusion, then time series of the apparent diffusion coefficient (ADC‐fMRI) and of intravoxel incoherent motion (IVIM) effects were derived. ADC‐fMRI provided ADC estimates sensitive to changes in perfusion and free‐water volume, but not to T 2 /T 2 * values. With IVIM modeling, we isolated the perfusion contribution to ADC, while suppressing T 2  effects. Compared to conventional gradient‐echo blood oxygenation level‐dependent fMRI, activation maps obtained with dfMRI and ADC‐fMRI had smaller clusters, and the spatial overlap between the three techniques was below 50%. Increases of perfusion fractions were observed during task in both dfMRI and ADC‐fMRI activations. Perfusion effects were more prominent with ADC‐fMRI than with dfMRI but were significant in less than 25% of activation regions. IVIM modeling suggests that the sensitivity to task of dfMRI derives from a decrease of intracellular/extracellular diffusion and an increase of the pseudo‐diffusion signal fraction, leading to different, more confined spatial activation patterns compared to classic functional MRI.

On the sensitivity of the diffusion MRI signal to brain activity in response to a motor cortex paradigm