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However, an undesired feature of this measure is that there exist large variations in CVR values across individuals, which is mainly attributed to physiological factors. Here, we test the hypothesis that caffeine, a widely consumed neurostimulant, has a significant effect on CVR measured with MRI. Sixteen young healthy participants were enrolled and categorized into caffeine-naive (N = 8) and caffeine-habituated (N = 8) groups based on their caffeine consumption habits. CVR was assessed via CO2 inhalation using two different MRI methods, phase-contrast (PC) cerebral blood flow (CBF), and T2*-EPI Blood-Oxygenation-Level-Dependent (BOLD)-MRI. Each participant underwent two MRI sessions, one before and the other after an oral administration of 200 mg of caffeine. Additionally, venous oxygenation (Yv) was measured using T2-Relaxation-Under-Spin-Tagging (TRUST) MRI. For basal physiological parameters, a significant caffeine-induced CBF decrease was observed in both naive (p = 0.002) and habituated (p &amp;lt; 0.001) groups. The caffeine-naive group exhibited a 31.2 \u00b1 14.1% reduction in basal CBF, whereas the caffeine-habituated group showed a 16.7 \u00b1 5.0% reduction, revealing significant differences between groups (p = 0.04). A similar observation was seen in basal Yv, with caffeine-naive participants showing a greater (p = 0.02) reduction (21.5 \u00b1 8.9%) than the habituated participants (7.6 \u00b1 10.1%). CBF-CVR decreased significantly in both groups: from 4.5 \u00b1 0.9 to 3.0 \u00b1 0.9 %CBF\/mmHg of CO2 (33.3 \u00b1 14.1%, p &amp;lt; 0.001) in the caffeine-naive group, and from 5.1 \u00b1 1.5 to 3.7 \u00b1 1.3 %CBF\/mmHg of CO2 (27.3 \u00b1 16.0%, p = 0.009) in the caffeine-habituated group. No significant differences were observed between groups in terms of the extent of CVR reduction (p = 0.23). BOLD-CVR showed modest reduction after caffeine administration, from 0.17 \u00b1 0.04 %\/mmHg to 0.15 \u00b1 0.05 %\/mmHg (14.1 \u00b1 16.8%, p = 0.02). There was no difference between the participant groups in terms of BOLD-CVR reduction following caffeine consumption. This study suggests that investigations using CVR as a disease marker may benefit from accounting for the caffeine consumption and\/or its blood concentration in the participants.<\/jats:p>","DOI":"10.1162\/imag.a.103","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T20:01:48Z","timestamp":1753214508000},"update-policy":"https:\/\/doi.org\/10.1162\/mitpressjournals.corrections.policy","source":"Crossref","is-referenced-by-count":2,"title":["The dependence of CO2 cerebrovascular reactivity (CVR) on caffeine"],"prefix":"10.1162","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6669-5584","authenticated-orcid":false,"given":"Dinil Sasi","family":"Sankaralayam","sequence":"first","affiliation":[{"name":"The Russell H. Morgan Department of Radiology & Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuimei","family":"Xu","sequence":"additional","affiliation":[{"name":"The Russell H. Morgan Department of Radiology & Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyi","family":"Hu","sequence":"additional","affiliation":[{"name":"The Russell H. Morgan Department of Radiology & Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States"},{"name":"Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhay","family":"Moghekar","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dengrong","family":"Jiang","sequence":"additional","affiliation":[{"name":"The Russell H. Morgan Department of Radiology & Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Hu","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiying","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology & Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3871-1564","authenticated-orcid":false,"given":"Hanzhang","family":"Lu","sequence":"additional","affiliation":[{"name":"The Russell H. Morgan Department of Radiology & Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States"},{"name":"Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States"},{"name":"F.M. Kirby Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"281","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"issue":"5","key":"2025080815555794000_IMAG.a.103-b1","doi-asserted-by":"crossref","first-page":"R1473","DOI":"10.1152\/ajpregu.91008.2008","article-title":"Integration of cerebrovascular CO2 reactivity and chemoreflex control of breathing: Mechanisms of regulation, measurement, and interpretation","volume":"296","author":"Ainslie","year":"2009","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2025080815555794000_IMAG.a.103-b2","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.neuroimage.2016.06.010","article-title":"The BOLD cerebrovascular reactivity response to progressive hypercapnia in young and elderly","volume":"139","author":"Bhogal","year":"2016","journal-title":"Neuroimage"},{"issue":"5","key":"2025080815555794000_IMAG.a.103-b3","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.jocn.2006.03.019","article-title":"The effect of caffeine on dilated cerebral circulation and on diagnostic CO2 reactivity testing","volume":"14","author":"Blaha","year":"2007","journal-title":"J Clin Neurosci"},{"issue":"1","key":"2025080815555794000_IMAG.a.103-b4","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.neuroimage.2011.12.017","article-title":"Quantitative measurement of cerebral physiology using respiratory-calibrated MRI","volume":"60","author":"Bulte","year":"2012","journal-title":"Neuroimage"},{"key":"2025080815555794000_IMAG.a.103-b5","doi-asserted-by":"crossref","first-page":"1179069518785151","DOI":"10.1177\/1179069518785151","article-title":"Regional cerebrovascular reactivity and cognitive performance in healthy aging","volume":"12","author":"Catchlove","year":"2018","journal-title":"J Exp Neurosci"},{"issue":"3","key":"2025080815555794000_IMAG.a.103-b6","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.neuroimage.2008.09.057","article-title":"Caffeine\u2019s effects on cerebrovascular reactivity and coupling between cerebral blood flow and oxygen metabolism","volume":"44","author":"Chen","year":"2009","journal-title":"Neuroimage"},{"issue":"4","key":"2025080815555794000_IMAG.a.103-b7","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1002\/jmri.25833","article-title":"Spatial distribution of flow and oxygenation in the cerebral venous drainage system","volume":"47","author":"De Vis","year":"2018","journal-title":"Journal of Magnetic Resonance Imaging"},{"key":"2025080815555794000_IMAG.a.103-b8","doi-asserted-by":"crossref","DOI":"10.1016\/B978-0-12-375083-9.00033-7","article-title":"Caffeine. 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