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• We compared breath-hold CVR maps made using CO 2 , RVT, and the global BOLD signal. • All show good agreement in CVR amplitude and delay provided CO 2 data are "sufficient". • We define "sufficient" CO 2 data quality as relative power >50% in the task frequency. • RVT or the global signal can map relative CVR parameters if CO 2 data are insufficient. • Offers solution to map breath-hold CVR when CO 2 data are unavailable or unreliable. Cerebrovascular reactivity (CVR), defined as the cerebral blood flow response to a vasoactive stimulus, is an imaging biomarker with demonstrated utility in a range of diseases and in typical development and aging processes. A robust and widely implemented method to map CVR involves using a breath-hold task during a BOLD fMRI scan. Recording end-tidal CO 2 (P ET CO 2) changes during the breath-hold task is recommended to be used as a reference signal for modeling CVR amplitude in standard units (%BOLD/mmHg) and CVR delay in seconds. However, obtaining reliable P ET CO 2 recordings requires equipment and task compliance that may not be achievable in all settings. To address this challenge, we investigated two alternative reference signals to map CVR amplitude and delay in a lagged general linear model (lagged-GLM) framework: respiration volume per time (RVT) and average gray matter BOLD response (GM-BOLD). In 8 healthy adults with multiple scan sessions, we compare spatial agreement of CVR maps from RVT and GM-BOLD to those generated with P ET CO 2. We define a threshold to determine whether a P ET CO 2 recording has "sufficient" quality for CVR mapping and perform these comparisons in 16 datasets with sufficient P ET CO 2 and 6 datasets with insufficient P ET CO 2. When P ET CO 2 quality is sufficient, both RVT and GM-BOLD produce CVR amplitude maps that are nearly identical to those from P ET CO 2 (after accounting for differences in scale), with the caveat they are not in standard units to facilitate between-group comparisons. CVR delays are comparable to P ET CO 2 with an RVT regressor but may be underestimated with the average GM-BOLD regressor. Importantly, when P ET CO 2 quality is insufficient, RVT and GM-BOLD CVR recover reasonable CVR amplitude and delay maps, provided the participant attempted the breath-hold task. Therefore, our framework offers a solution for achieving high quality CVR maps in both retrospective and prospective studies where sufficient P ET CO 2 recordings are not available and especially in populations where obtaining reliable measurements is a known challenge (e.g., children). Our results have the potential to improve the accessibility of CVR mapping and to increase the prevalence of this promising metric of vascular health. [ABSTRACT FROM AUTHOR]

• We propose adding a short breathing task to the start of a resting state fMRI scan • This protocol facilitates mapping of cerebrovascular reactivity and hemodynamic lag • This practical modification adds vascular insight to typical resting state fMRI • Protocol is sensitive to pathology, and modeling lag is crucial for interpretation Cerebrovascular reactivity (CVR), defined here as the Blood Oxygenation Level Dependent (BOLD) response to a CO 2 pressure change, is a useful metric of cerebrovascular function. Both the amplitude and the timing (hemodynamic lag) of the CVR response can bring insight into the nature of a cerebrovascular pathology and aid in understanding noise confounds when using functional Magnetic Resonance Imaging (fMRI) to study neural activity. This research assessed a practical modification to a typical resting-state fMRI protocol, to improve the characterization of cerebrovascular function. In 9 healthy subjects, we modelled CVR and lag in three resting-state data segments, and in data segments which added a 2–3 minute breathing task to the start of a resting-state segment. Two different breathing tasks were used to induce fluctuations in arterial CO 2 pressure: a breath-hold task to induce hypercapnia (CO 2 increase) and a cued deep breathing task to induce hypocapnia (CO 2 decrease). Our analysis produced voxel-wise estimates of the amplitude (CVR) and timing (lag) of the BOLD-fMRI response to CO 2 by systematically shifting the CO 2 regressor in time to optimize the model fit. This optimization inherently increases gray matter CVR values and fit statistics. The inclusion of a simple breathing task, compared to a resting-state scan only, increases the number of voxels in the brain that have a significant relationship between CO 2 and BOLD-fMRI signals, and improves our confidence in the plausibility of voxel-wise CVR and hemodynamic lag estimates. We demonstrate the clinical utility and feasibility of this protocol in an incidental finding of Moyamoya disease, and explore the possibilities and challenges of using this protocol in younger populations. This hybrid protocol has direct applications for CVR mapping in both research and clinical settings and wider applications for fMRI denoising and interpretation. [ABSTRACT FROM AUTHOR]