Cerebrovascular Reactivity Mapping Without Gas Challenges: A Methodological Guide

Cerebrovascular reactivity (CVR) is defined as the ability of vessels to alter their caliber in response to vasoactive factors, by means of dilating or constricting, in order to increase or decrease regional cerebral blood flow (CBF). Importantly, CVR may provide a sensitive biomarker for pathologies where vasculature is compromised. Furthermore, the spatiotemporal dynamics of CVR observed in healthy subjects, reflecting regional differences in cerebral vascular tone and response, may also be important in functional MRI studies based on neurovascular coupling mechanisms. Assessment of CVR is usually based on the use of a vasoactive stimulus combined with a CBF measurement technique. Although transcranial Doppler ultrasound has been frequently used to obtain global flow velocity measurements, MRI techniques are being increasingly employed for obtaining CBF maps. For the vasoactive stimulus, vasodilatory hypercapnia is usually induced through the manipulation of respiratory gases, including the inhalation of increased concentrations of carbon dioxide. However, most of these methods require an additional apparatus and complex setups, which not only may not be well-tolerated by some populations but are also not widely available. For these reasons, strategies based on voluntary breathing fluctuations without the need for external gas challenges have been proposed. These include the task-based methodologies of breath holding and paced deep breathing, as well as a new generation of methods based on spontaneous breathing fluctuations during resting-state. Despite the multitude of alternatives to gas challenges, existing literature lacks definitive conclusions regarding the best practices for the vasoactive modulation and associated analysis protocols. In this work, we perform an extensive review of CVR mapping techniques based on MRI and CO 2 variations without gas challenges, focusing on the methodological aspects of the breathing protocols and corresponding data analysis. Finally, we outline a set of practical guidelines based on generally accepted practices and available data, extending previous reports and encouraging the wider application of CVR mapping methodologies in both clinical and academic MRI settings.