Evaluating the dependence of ADC-fMRI on haemodynamics in breath-hold and resting-state conditions

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Abstract
Apparent diffusion coefficient (ADC)-fMRI offers a promising functional contrast, capable of mapping neuronal activity directly in both grey and white matter. However, previous studies have shown that diffusion-weighted fMRI (dfMRI), from which ADC-fMRI derives, is influenced by blood-oxygen level dependent (BOLD) effects, leading to a concern that the dfMRI contrast is still rooted in neurovascular rather than neuromorphological coupling. Mitigation strategies have been proposed to remove vascular contributions while retaining neuromorphological coupling, by: i) analysing ADC timecourses calculated from two interleaved diffusion-weightings, known as ADC-fMRI; ii) using b-values of at least 200 s mm−2; and iii) using a sequence compensated for cross-terms with fluctuating background field gradients associated with blood oxygenation. Respiration-induced haemodynamic fluctuations, which are dissociated from neural activity, are an excellent test-bed for the robustness of ADC-fMRI to vascular contributions. In this study, we investigate the association between end-tidal CO2 and ADC-fMRI, in comparison with dfMRI and BOLD, in both breath-hold and resting-state paradigms in the human brain. We confirm a strong dependence of the BOLD signal on respiration, and a pattern of delayed haemodynamic response in white matter. While dfMRI mitigates much of the vascular contribution, it retains some association with respiration, as expected. Conversely, ADC-fMRI is mostly unaffected by vascular contribution, exhibiting minimal correlation between expired CO2 and ADC timeseries, as well as low inter- and intra-subject reproducibility in correlation maps. These findings validate ADC-fMRI as a predominantly non-vascular contrast sensitive to microstructural dynamics, enabling whole-brain functional imaging unconstrained by vascular confounds.
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Funding Information
  • Swiss Secretariat for Research and Innovation (‘FIREPATH’ MB22.00032)
  • SNSF (194260)
  • Swedish Cancer Society (22 0592 JIA)

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