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A novel method of quantifying hemodynamic delays to improve hemodynamic response, and CVR estimates in CO2 challenge fMRI.

ABSTRACT: Elevated carbon dioxide (CO2) in breathing air is widely used as a vasoactive stimulus to assess cerebrovascular functions under hypercapnia (i.e., "stress test" for the brain). Blood-oxygen-level-dependent (BOLD) is a contrast mechanism used in functional magnetic resonance imaging (fMRI). BOLD is used to study CO2-induced cerebrovascular reactivity (CVR), which is defined as the voxel-wise percentage BOLD signal change per mmHg change in the arterial partial pressure of CO2 (PaCO2). Besides the CVR, two additional important parameters reflecting the cerebrovascular functions are the arrival time of arterial CO2 at each voxel, and the waveform of the local BOLD signal. In this study, we developed a novel analytical method to accurately calculate the arrival time of elevated CO2 at each voxel using the systemic low frequency oscillations (sLFO: 0.01-0.1 Hz) extracted from the CO2 challenge data. In addition, 26 candidate hemodynamic response functions (HRF) were used to quantitatively describe the temporal brain reactions to a CO2 stimulus. We demonstrated that our approach improved the traditional method by allowing us to accurately map three perfusion-related parameters: the relative arrival time of blood, the hemodynamic response function, and CVR during a CO2 challenge.

SUBMITTER: Yao JF

PROVIDER: S-EPMC8327112 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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A novel method of quantifying hemodynamic delays to improve hemodynamic response, and CVR estimates in CO2 challenge fMRI.

Yao Jinxia Fiona JF Yang Ho-Ching Shawn HS Wang James H JH Liang Zhenhu Z Talavage Thomas M TM Tamer Gregory G GG Jang Ikbeom I Tong Yunjie Y

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20210114 8

Elevated carbon dioxide (CO2) in breathing air is widely used as a vasoactive stimulus to assess cerebrovascular functions under hypercapnia (i.e., "stress test" for the brain). Blood-oxygen-level-dependent (BOLD) is a contrast mechanism used in functional magnetic resonance imaging (fMRI). BOLD is used to study CO2-induced cerebrovascular reactivity (CVR), which is defined as the voxel-wise percentage BOLD signal change per mmHg change in the arterial partial pressure of CO2 (PaCO2). Besides th ...[more]

PMID: 33444087

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Project description:The blood flow response to a vasoactive stimulus demonstrates regional heterogeneity across both the healthy brain and in cerebrovascular pathology. The timing of a regional hemodynamic response is emerging as an important biomarker of cerebrovascular dysfunction, as well as a confound within fMRI analyses. Previous research demonstrated that hemodynamic timing is more robustly characterized when a larger systemic vascular response is evoked by a breathing challenge, compared to when only spontaneous fluctuations in vascular physiology are present (i.e., in resting-state data). However, it is not clear whether hemodynamic delays in these two conditions are physiologically interchangeable, and how methodological signal-to-noise factors may limit their agreement. To address this, we generated whole-brain maps of hemodynamic delays in nine healthy adults. We assessed the agreement of voxel-wise gray matter (GM) hemodynamic delays between two conditions: resting-state and breath-holding. We found that delay values demonstrated poor agreement when considering all GM voxels, but increasingly greater agreement when limiting analyses to voxels showing strong correlation with the GM mean time-series. Voxels showing the strongest agreement with the GM mean time-series were primarily located near large venous vessels, however these voxels explain some, but not all, of the observed agreement in timing. Increasing the degree of spatial smoothing of the fMRI data enhanced the correlation between individual voxel time-series and the GM mean time-series. These results suggest that signal-to-noise factors may be limiting the accuracy of voxel-wise timing estimates and hence their agreement between the two data segments. In conclusion, caution must be taken when using voxel-wise delay estimates from resting-state and breathing-task data interchangeably, and additional work is needed to evaluate their relative sensitivity and specificity to aspects of vascular physiology and pathology.

Project description:Background and purposeThe BOLD signal amplitude as a response to a hypercapnia stimulus is commonly used to assess cerebrovascular reserve. Despite recent advances, the implementation remains cumbersome and alternative ways to assess hemodynamic impairment are desirable. Resting-state BOLD signal fluctuations (rsBOLD) have been proposed however data on its sensitivity and dependence on baseline venous cerebral blood volume (vCBV) is limited. The primary aim of this study was to compare the effect sizes of resting-state and hypercapnia induced BOLD signal changes in the detection of hemodynamic impairment. The second aim of the study was to assess the dependence of BOLD signal variability on vCBV.Materials and methodsFifteen patients with internal carotid artery occlusive disease and 15 matched healthy controls were included in this study. The BOLD signal was derived from a dual-echo gradient-echo echo-planar sequence during hypercapnia (HC) and hyperoxia (HO) gas modulations. BOLD (fractional) amplitude of low frequency fluctuations ((f)ALFF) was compared to HC-BOLD, BOLD response delays derived from time delay analysis and ΔBOLD in response to progressively increasing HC. Effect sizes (i.e. the standard mean difference between patients and controls) were calculated. HO-BOLD was used to estimate vCBV, and its contribution to the variability in rsBOLD signal was evaluated.ResultsThe effect sizes of ALFF and fALFF (0.61 and 0.72) were lower than the effect sizes related to hypercapnia-based hemodynamic assessment analysis; 1.62, 1.56 and 0.90 for HC-BOLD, BOLD response delays and ΔBOLD in response to progressively increasing HC. A moderate relation was found between (f)ALFF and HC-BOLD in controls (R2 of 0.61 and 0.42), but this relation decreased in patients (R2 of 0.33 and 0.15). (f)ALFF did not differ between patients and controls whereas HC-BOLD did (p < 0.005). The ΔBOLD response to progressively increasing HC was significantly different in between patients and controls for ΔEtCO2 values ≥ 2 mmHg (at +2 mmHg F(1, 18) = 5.85, p = 0.026). Up to 31% and 53% of the variance in the ALFF and HC-BOLD spatial distribution could be explained by HO-BOLD.ConclusionALFF and fALFF demonstrated a moderate effect size to detect hemodynamic impairment whereas the effect size was large for methods employing a hypercapnia-based vascular stress stimulus. Based on our analysis of BOLD signal change as a response to a progressively increasing hypercapnia stimulus we can argue that a hypercapnia stimulus of at least 2 mmHg above baseline EtCO2 is necessary to evaluate hemodynamic impairment. We also demonstrated that a substantial amount of information imbedded in the rsBOLD and HC-BOLD was explained by HO-BOLD. HO-BOLD can serve as a proxy for vCBV and this thus indicates that one should be careful when adopting these techniques in disease cases with compromised CBV.

Project description:Conventional functional magnetic resonance imaging (FMRI) group analysis makes two key assumptions that are not always justified. First, the data from each subject is condensed into a single number per voxel, under the assumption that within-subject variance for the effect of interest is the same across all subjects or is negligible relative to the cross-subject variance. Second, it is assumed that all data values are drawn from the same Gaussian distribution with no outliers. We propose an approach that does not make such strong assumptions, and present a computationally efficient frequentist approach to FMRI group analysis, which we term mixed-effects multilevel analysis (MEMA), that incorporates both the variability across subjects and the precision estimate of each effect of interest from individual subject analyses. On average, the more accurate tests result in higher statistical power, especially when conventional variance assumptions do not hold, or in the presence of outliers. In addition, various heterogeneity measures are available with MEMA that may assist the investigator in further improving the modeling. Our method allows group effect t-tests and comparisons among conditions and among groups. In addition, it has the capability to incorporate subject-specific covariates such as age, IQ, or behavioral data. Simulations were performed to illustrate power comparisons and the capability of controlling type I errors among various significance testing methods, and the results indicated that the testing statistic we adopted struck a good balance between power gain and type I error control. Our approach is instantiated in an open-source, freely distributed program that may be used on any dataset stored in the universal neuroimaging file transfer (NIfTI) format. To date, the main impediment for more accurate testing that incorporates both within- and cross-subject variability has been the high computational cost. Our efficient implementation makes this approach practical. We recommend its use in lieu of the less accurate approach in the conventional group analysis.

Dataset Information

A novel method of quantifying hemodynamic delays to improve hemodynamic response, and CVR estimates in CO2 challenge fMRI.

Publications

A novel method of quantifying hemodynamic delays to improve hemodynamic response, and CVR estimates in CO2 challenge fMRI.

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