Approaches to brain stress testing: BOLD magnetic resonance imaging with computer-controlled delivery of carbon dioxide

Abstract

Background: An impaired vascular response in the brain regionally may indicate reduced vascular reserve and vulnerability to ischemic injury. Changing the carbon dioxide (CO(2)) 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 CO(2) challenge using a computer-controlled gas blender to administer: i) a square wave change in CO(2) and, ii) a ramp stimulus, consisting of a continuously graded change in CO(2) 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 CO(2). 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 CO(2), voxel-by-voxel. Using a fractal temporal approach, detrended fluctuation analysis (DFA) maps of the processed raw BOLD signal per voxel over the same CO(2) range were generated. Regions of BOLD signal decrease with increased CO(2) (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.

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following conflicts: Gas control used to enable this study was via a computerized gas blender (RespirAct™, Thornhill Research Inc., Toronto, Canada) custom built for the University Health Network to enable such research. TRI is a for profit spin off of the University Health Network. JAF, DJM and JD are inventors of the RespirAct™ and shareholders in TRI. Should the RespirAct™ become a commercial product, JAF, DJM and JD could gain financially. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Response to square wave CO2 stimulus – CVR and DFA maps.

These data are from a patient who underwent the square wave sequence and ramp sequence (Figure 2) in the same sitting. Not shown in this image is the end-tidal O2 tension which is stable over time at normal values (approximately 100 mmHg). The CO2 stimulus is shown in the first column – start, middle and end during the two-minute stimulus. The first 45-second square wave pulse was to aid in time sequencing of the BOLD signal and CO2 stimulus. Time is on the x-axis and end-tidal CO2 in mmHg on the y-axis. The yellow and magenta vertical markers highlight the center of the CO2 durations analyzed in the square wave sequence. The highlighted red lines are the points where the CO2 tension was correlated to the MR–BOLD signal for the CVR analysis. The second column shows the corresponding CVR maps. The color key to the right of the image is upper red +0.56 arbitrary BOLD units/mmHg in CO2 tension – deep blue −0.56. The third column shows the corresponding DFA maps. For the DFA maps the BOLD signal analysis was based on output as interpolated between the yellow and magenta markers. The color key to the right of the image is brown – 1.5 Hurst units, pink – 1.0 Hurst units, white – 0.5 Hurst units and deep blue – 0 Hurst units. ‘Blue’ DFA was defined as less than 0.5 Hurst units and indicates anti-persistent noise. The percentage of ‘blue’ DFA voxels noticeably decreased over time. The step change in end-tidal CO2 is 8 mmHg.

Figure 2. Response to ramp CO2 stimulus – CVR and DFA maps.

The CO2 ramp stimulus is shown in the first column. The duration of the ramp stimulus increases by row. Not shown in this image is the end-tidal O2 tension which is stable over time at normal values (approximately 100 mmHg). The yellow and magenta vertical markers highlight the center of the CO2 durations analyzed in the square wave sequence. The highlighted red lines demonstrate the interpolated points where the CO2 tension was correlated to the MR–BOLD signal for the DFA analysis. The CVR maps are shown in second column and the DFA maps in the third column. In the first time period CVR map (row 1, column 2) the deep saturation of red signal indicates initial very high responsiveness (steep slope) within these areas suggesting these voxels are on the steep linear portion of the sigmoidal CO2 response curve. In the DFA map (row 1, column 3) these areas are noticeably brown with a Hurst exponent of 1.5 indicating very high time memory. The ramp change in end-tidal CO2 examined is 8 mmHg. The color keys are as in Figure 1.

Figure 3. Density histograms over time for the square wave stimulus for CVR and DFA maps.

The square wave sequence is shown in the first column, as defined in Figure 1. The second column shows the density histograms for the CVR output range shown on the x-axis (−0.56–0.56 BOLD units/mmHg CO2). The third column shows the density histograms for the DFA output range shown on the x-axis (0–1.5 Hurst exponent units). The red bell-shaped curves seen with the histograms are best normal curve fit to the histogram data. For the square wave sequences from start, middle and end, the mean and coefficient of variation for the CVR maps were 0.207, 0.855; 0.209, 0.871; and 0.227, 0.175 respectively, and for the DFA maps 0.947, 0.269; 1.06, 0.224; and 1.09, 0.222.

Figure 4. Density histograms over time for the ramp stimulus for CVR and DFA maps.

For the ramp sequences from start, middle and end, the mean and coefficient of variation for the CVR maps were 0.113, 2.203; 0.151, 1.197; and 0.116, 1.422 respectively and for the DFA maps 0.847, 0.432; 0.929, 0.355; and 0.951, 0.237. Same color coding as in Figure 3.

Figure 5. Change in percentage of ‘blue’ voxels over time in CVR and DFA maps.

Mean percentage of ‘blue’ voxels for the CVR (0 to −0.56 BOLD units/mmHg CO2) and DFA (0.5 to 0 Hurst exponent units) maps for the 8 patients with carotid steno-occlusive disease. All patients had square wave CO2 stimuli. A significant difference in mean percentage of ‘blue’ voxels was seen between CVR and DFA for the end time period.

Figure 6. Vigorous hemodynamic response to CO2 ramp stimulus.

Hemodynamic response to ramp CO2 stimulus in a 60 year old healthy subject. Note the marked blood pressure and cerebral blood flow velocity response to increased CO2 persisting past the stimulus peak. Legend abbreviations – etPCO2; end-tidal partial pressure of carbon dioxide, MCAv; middle cerebral artery velocity, MAP; mean arterial pressure, HR; heart rate, right and left O2; cerebral O2 saturation.

Figure 7. Muted hemodynamic response to CO2 ramp stimulus.

Hemodynamic response to ramp CO2 stimulus in a 31 year old healthy subject. A much-attenuated response is seen in this individual. Same legend abbreviations as in Figure 6.