Research Article: The voxel-wise analysis of false negative fMRI activation in regions of provoked impaired cerebrovascular reactivity

Date Published: May 6, 2019

Publisher: Public Library of Science

Author(s): Christiaan Hendrik Bas van Niftrik, Marco Piccirelli, Giovanni Muscas, Martina Sebök, Joseph Arnold Fisher, Oliver Bozinov, Christoph Stippich, Antonios Valavanis, Luca Regli, Jorn Fierstra, Jay Pillai.


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.

Partial Text

Task-evoked blood oxygenation-level dependent functional magnetic resonance imaging (BOLD-fMRI) is based on neurovascular coupling and is widely used to interrogate eloquence of brain areas.[1, 2] Neurovascular coupling is considered to represent the biochemical cascade between neuronal activation and subsequent local cerebral blood flow (CBF) increase.[3] This premise, however, imposes two major challenges for an accurate interpretation of BOLD-fMRI studies. First, the extent and strength of the fMRI signal response to a task-related neuronal activation (for instance finger-tapping) varies considerably between subjects and therefore requires a summation of repeated tests and arbitrary statistical data thresholding. Second, BOLD-fMRI does not directly measure neuronal activity or blood flow, rather it shows the relative change in de-oxyhemoglobin concentration.[4, 5] The intrinsic BOLD-fMRI signal is therefore strongly influenced by CBF, and to a lesser extent changes in metabolism (cerebral metabolic rate of oxygen (CMRO2), and oxygen extraction fraction (OEF)).[2]

We recruited 17 consecutive healthy subjects (age 32±5.5) (ethical institutional approval: Kantonalle Ethikkommission Zürich: KEK-ZH-Nr. 2012–0427). Each subject signed an informed consent form prior to the study and was asked to refrain from heavy exercise, smoking, and caffeine on the day of scanning. The only exclusion criteria was a diagnosed neurological disease.

The data is presented as follows: all BOLD fMRI data (i.e. BOLD-CVR and task based BOLD fMRI signal activation) are given in % BOLD signal change (for BOLD-CVR per mmHg CO2 change) as well as in t-values. T-values are given as it represents the more clinical standard for task-based fMRI, while % BOLD signal change is the more commonly used presentation of BOLD-CVR.

The main finding of this study is that false negative BOLD fMRI signal activation occurs when BOLD-CVR impairment is simulated in healthy subjects. This findings could be consistently reproduced in all participants. The dampened BOLD fMRI signal response reveals yet another major uncertainty of accurate BOLD-fMRI data interpretation. Quantitative voxel-wise analysis of t-values and Δ% signal of BOLD-CVR and fMRI effects were strongly correlated over the whole cerebral motor network, accounting for more than half of the variance. This highlights the importance of the complementary role of BOLD-CVR to identify brain areas at high risk for false negative BOLD fMRI signal activation, in particular for clinical interpretation of fMRI data, e.g. pre-operative planning of brain tumor surgery in eloquent areas. Here it is known that by using low fMRI t-value thresholds more noise is increasingly introduced into the fMRI activation maps, thereby limiting the interpretability of the maps. When in addition the BOLD-CVR is also reduced in these eloquent regions, the fMRI study can be considered insufficient for clinical interpretation. Prior to BOLD-CVR studies in brain tumor patients, this absent fMRI signal activation was considered as a result of adaptive brain plasticity (i.e. lateralization of fMRI signal to the contralateral hemisphere). However, a more feasible explanation is that in the presence of impaired BOLD-CVR, fMRI-“silent” or -“invisible” activation maps may occur because of an absent or at best a minimal BOLD response to an appropriate neural stimulus.[13, 20] Additionally, local mass effect from brain tumors can also have a significant effect on extend of CVR impairment.[15] This may also be true for vascular lesions such as arteriovenous malformations, where arterial-venous shunting can induce a similar effect on BOLD-CVR. Here false negative activation is more likely to occur near such a lesion, potentially increasing the risk of adverse surgical outcomes.[13, 21]

In healthy subjects, false negative BOLD fMRI signal activation can be found when cerebrovascular reactivity is artificially impaired. Our findings highlight the importance of the complementary role of BOLD-CVR to identify brain areas at high risk for false negative BOLD fMRI signal activation.




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