Approaches to Brain Stress Testing: BOLD Magnetic Resonance Imaging with Computer-Controlled Delivery of Carbon Dioxide

Background: An impaired vascular response in the brain regionally may indicate reduced vascular reserve and vulnerability to ischemic injury. Changing the carbon dioxide (CO2) tension in arterial blood is commonly used as a cerebral vasoactive stimulus to assess the cerebral vascular response, changing cerebral blood flow (CBF) by up to 5-11 percent/mmHg in normal adults. Here we describe two approaches to generating the CO2 challenge using a computer-controlled gas blender to administer: i) a square wave change in CO2 and, ii) a ramp stimulus, consisting of a continuously graded change in CO2 over a range. Responses were assessed regionally by blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI). Methodology/Principal Findings: We studied 8 patients with known cerebrovascular disease (carotid stenosis or occlusion) and 2 healthy subjects. The square wave stimulus was used to study the dynamics of the vascular response, while the ramp stimulus assessed the steady-state response to CO2. Cerebrovascular reactivity (CVR) maps were registered by color coding and overlaid on the anatomical scans generated with 3 Tesla MRI to assess the corresponding BOLD signal change/mmHg change in CO2, voxel-by-voxel. Using a fractal temporal approach, detrended fluctuation analysis (DFA) maps of the processed raw BOLD signal per voxel over the same CO2 range were generated. Regions of BOLD signal decrease with increased CO2 (coded blue) were seen in all of these high-risk patients, indicating regions of impaired CVR. All patients also demonstrated regions of altered signal structure on DFA maps (Hurst exponents less than 0.5; coded blue) indicative of anti-persistent noise. While 'blue' CVR maps remained essentially stable over the time of analysis, 'blue' DFA maps improved. Conclusions/Significance: This combined dual stimulus and dual analysis approach may be complementary in identifying vulnerable brain regions and thus constitute a regional as well as global brain stress test.