Robust estimation of dynamic cerebrovascular reactivity using breath-holding fMRI: application in diabetes and hypertension

Breath-holding (BH) tasks during functional magnetic resonance imaging (fMRI) acquisitions are gaining popularity for non-invasive mapping of carbon-dioxide (CO2) driven cerebrovascular reactivity (CVR), which is a valuable clinical marker of vascular function. However, compliance to BH tasks is often unclear, and the ability to record end-tidal CO2 often limited, rendering the optimal analysis of BH fMRI data a challenge. In this work, we demonstrate an adaptive data-driven approach for estimating CVR from BH fMRI data that minimizes errors due to subject non-compliance and regional CVR time delay variability. Building on previous work, we propose a frequency-domain-based approach for CVR estimation without the need for end-tidal CO2 (PETCO2) recordings. CVR amplitude is estimated in units of %ΔBOLD directly from the data-driven BH frequency. Serious deviations from the designed task paradigm were suppressed and thus did not bias the estimated CVR values. We demonstrate our method in detecting regional CVR amplitude and time-lag differences in a group of 56 individuals, consisting of healthy (CTL), hypertensive (HT) and diabetic-hypertensive (DM+HT) groups of similar ages and sex ratios. The CVR amplitude was lowest in HT+DM, and HT had a lower CVR amplitude than CTL regionally but the voxelwise comparison did not yield statistical significance. Notably, we demonstrate that the voxelwise CVR time delay estimated in Fourier domain is a more sensitive marker of vascular dysfunction than CVR amplitude. While HT+DM seems to confer longer CVR delays, HT seems to confer shorter delays than CTL. These are the first MRI-based observations of CVR time delay differences between diabetic-hypertensive patients and healthy controls. These results demonstrate the feasibility of extracting CVR amplitude and CVR time delay using BH challenges without PETCO2 recordings, and the unique clinical value of CVR time-delay information. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Canadian Institutes of Health Research (CIHR) for funding support. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: REB of Baycrest Health Sciences gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data produced in the present study may be made available only according to terms in the research ethics approval.