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. 2019 May 6;14(5):e0215294.
doi: 10.1371/journal.pone.0215294. eCollection 2019.

The Voxel-Wise Analysis of False Negative fMRI Activation in Regions of Provoked Impaired Cerebrovascular Reactivity

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Free PMC article

The Voxel-Wise Analysis of False Negative fMRI Activation in Regions of Provoked Impaired Cerebrovascular Reactivity

Christiaan Hendrik Bas van Niftrik et al. PLoS One. .
Free PMC article

Abstract

Task-evoked Blood-oxygenation-level-dependent (BOLD-fMRI) signal activation is widely used to interrogate eloquence of brain areas. However, data interpretation can be improved, especially in regions with absent BOLD-fMRI signal activation. Absent BOLD-fMRI signal activation may actually represent false-negative activation due to impaired cerebrovascular reactivity (BOLD-CVR) of the vascular bed. The relationship between impaired BOLD-CVR and BOLD-fMRI signal activation may be better studied in healthy subjects where neurovascular coupling is known to be intact. Using a model-based prospective end-tidal carbon dioxide (CO2) targeting algorithm, we performed two controlled 3 tesla BOLD-CVR studies on 17 healthy subjects: 1: at the subjects' individual resting end-tidal CO2 baseline. 2: Around +6.0 mmHg CO2 above the subjects' individual resting baseline. Two BOLD-fMRI finger-tapping experiments were performed at similar normo- and hypercapnic levels. Relative BOLD fMRI signal activation and t-values were calculated for BOLD-CVR and BOLD-fMRI data. For each component of the cerebral motor-network (precentral gyrus, postcentral gyrus, supplementary motor area, cerebellum und fronto-operculum), the correlation between BOLD-CVR and BOLD-fMRI signal changes and t-values was investigated. Finally, a voxel-wise quantitative analysis of the impact of BOLD-CVR on BOLD-fMRI was performed. For the motor-network, the linear correlation coefficient between BOLD-CVR and BOLD-fMRI t-values were significant (p<0.01) and in the range 0.33-0.55, similar to the correlations between the CVR and fMRI Δ%signal (p<0.05; range 0.34-0.60). The linear relationship between CVR and fMRI is challenged by our voxel-wise analysis of Δ%signal and t-value change between normo- and hypercapnia. Our main finding is that BOLD fMRI signal activation maps are markedly dampened in the presence of impaired BOLD-CVR and highlights the importance of a complementary BOLD-CVR assessment in addition to a task-evoked BOLD fMRI to identify brain areas at risk for false-negative BOLD-fMRI signal activation.

Conflict of interest statement

The RespirAct is currently a non-clinical research tool approved by Health Canada, assembled, and made available by Thornhill Research Inc. (TRI), a spin-off company from the University Health Network, to research institutions to enable CVR studies. J.A.F. is the Chief Scientist and director of TRI. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Illustration of the combined BOLD-CVR and task-evoked BOLD-fMRI study protocol in one subject.
Top: Fig 1A and 1B show the CO2 (grey dotted line) and mean BOLD signal time course (black line) during a BOLD-CVR study at CO2 baseline (A) versus hypercapnia (B), respectively. Note that the BOLD signal follows the CO2 increase from normocapnia and quickly returns to baseline levels. However, during hypercapnia, the mean BOLD signal increase with CO2 rise is less than in normocapnia. Bottom: Fig 1C and 1D show the CO2 time course during a task-evoked BOLD-fMRI block protocol. The black short lines represent the task phase of the protocol. The ability of precise CO2 control with the MPET method produced a constant CO2 level at CO2 baseline (C) versus hypercapnia (D), respectively.
Fig 2
Fig 2. Schematic overview of the analysis pipeline.
1) Representation of the raw BOLD-fMRI data obtained from the MRI system. 2) From the raw BOLD-fMRI images t-value maps are then calculatedusing a mass-univariate general linear model within SPM12. 3) By using a predetermined t-value threshold of 3.43, all significant voxels of each t-value map are combined into a significant-t-value binary mask, i.e. a combined T-map. 4)This map is then overlaid onto the predefined ROIsto determine the significant t-values within each ROI. 5)The BOLD-CVR and fMRI Δ%signal maps for the normocapnic condition are calculated and the values of the combined significant t-value voxels for each region of interest are scatter-plotted. 6)The BOLD-CVR and fMRI Δ%signal maps for the hypercapnic condition are calculated and the values of the combined significant t-value voxels for each region of interest are scatter-plotted. Abbreviations: Blood oxygenation-level dependent cerebrovascular reactivity (BOLD-CVR, defined as %signal change/mmHg CO2 change). Functional MRI (fMRI, defined as %signal change).
Fig 3
Fig 3. Upper row: Scatterplot of the t-values obtained from the BOLD-CVR and the fMRI finger tapping data.
Lower row: Scatterplot of BOLD-CVR % signal change and %fMRI signal change for each ROI and subject. Each red and blue point represents the average value of a ROI of a single subject during either normocpanie (blue) or hypercapnia (red). Black line: least square error linear fit of each scatterplot. Abbreviations: BOLD: blood oxygenation-level dependent; -CVR: cerebrovascular reactivity, CO2: carbon dioxide, %fMRI: mean percent BOLD signal changes, ROI: Region of Interest.
Fig 4
Fig 4. The fMRI t-values are represented as a function of the BOLD-CVR (relative BOLD fMRI signal change per mmHg CO2).
Each red and blue point represents the average value of a ROI of a single subject during either normocpanie (blue) or hypercapnia (red). Black line: least square error linear fit of each scatterplot. Abbreviations: BOLD: blood oxygenation-level dependent; -CVR: cerebrovascular reactivity, CO2: carbon dioxide, %fMRI: mean percent BOLD signal changes, ROI: Region of Interest.
Fig 5
Fig 5. Scatterplot of the voxel-wise t-value of the task-evoked fMRI (y-axis) and BOLD CVR data (x-axis) for an illustrative subject.
For each ROI, only the voxels which were significantly activated in at least one of the two finger-tapping fMRI data are plotted. The drop in t-values from normo- to hyper-capnia below the threshold (here 3.43) is clearly visible. This is known as false negative activation, implying the limitation of the task-evoked fMRI by the remaining BOLD-CVR, especially with a fixed threshold.

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Grant support

Christiaan Hendrik Bas van Niftrik and Jorn Fierstra are supported by the Swiss Cancer League (KFS-3975-08-2016-R) and by Forschungskredit; Postdoc. Zurich University FK-16-040. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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