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PLoS One. 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.

Author information

Department of Neurosurgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Department of Neuroradiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Department of Neurosurgery, Careggi University Hospital, Florence, University of Florence, Florence, Italy.
Department of Anesthesiology, University Health Network, University of Toronto, Toronto, ON, Canada.


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.

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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.

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