Implications of neurovascular uncoupling in functional magnetic resonance imaging (fMRI) of brain tumors

Abstract

Functional magnetic resonance imaging (fMRI) serves as a critical tool for presurgical mapping of eloquent cortex and changes in neurological function in patients diagnosed with brain tumors. However, the blood-oxygen-level-dependent (BOLD) contrast mechanism underlying fMRI assumes that neurovascular coupling remains intact during brain tumor progression, and that measured changes in cerebral blood flow (CBF) are correlated with neuronal function. Recent preclinical and clinical studies have demonstrated that even low-grade brain tumors can exhibit neurovascular uncoupling (NVU), which can confound interpretation of fMRI data. Therefore, to avoid neurosurgical complications, it is crucial to understand the biophysical basis of NVU and its impact on fMRI. Here we review the physiology of the neurovascular unit, how it is remodeled, and functionally altered by brain cancer cells. We first discuss the latest findings about the components of the neurovascular unit. Next, we synthesize results from preclinical and clinical studies to illustrate how brain tumor induced NVU affects fMRI data interpretation. We examine advances in functional imaging methods that permit the clinical evaluation of brain tumors with NVU. Finally, we discuss how the suppression of anomalous tumor blood vessel formation with antiangiogenic therapies can "normalize" the brain tumor vasculature, and potentially restore neurovascular coupling.

Keywords: Neurovascular; angiogenesis; cancer; cooption; coupling; functional magnetic resonance imaging.

Figure 1.

The healthy and cancer-disrupted neurovascular unit: Immunofluorescently labeled elements of (a) the healthy neurovascular unit in a tissue section from a murine brain showing GFAP labeled astrocytes (green channel), DAPI labeled cell nuclei (blue channel), and autofluorescing erythrocytes or RBCs (red channel). The dense vascular coverage of the astrocytes is immediately apparent as is the intimate contact between the astrocytic endfeet and neurovascular endothelium. (b) Disrupted neurovascular unit in a 9L brain tumor bearing murine brain section, wherein one can not only see a dearth of astrocytic coverage (green channel) of the tumor vessels (dextran-TRITC label in red channel) but also displaced astrocytic endfeet. All images were acquired at 20× magnification.

Figure 2.

The emergent role of the endothelium in neurovascular uncoupling: Perfusion of blood vessels before and after light dye treatment. Before the light treatment, vasculature was (a) illuminated by 534 nm light, and (b) a map of the total hemoglobin (ΔHbT) constructed, clearly indicating blood flow in the vessels. The light-dye method selectively disrupted endothelial cells, so treatment (c) reduced dilation in the pial arteries, as demonstrated by the significantly decreased levels of ΔHbT. This absence of vascular response after endothelial disruption suggested that the endothelium plays an essential role in neurovascular coupling. Adapted with permission from Hillman et al.

Figure 3.

Imaging cerebral autoregulation at the microvascular spatial scale: Data from “microvascular-scale” in vivo optical imaging illustrating the autoregulatory hemodynamic response of the cerebrovasculature. (a) Laser speckle contrast (LSC) derived “baseline” or “resting” cerebral blood flow (CBF_rest) map computed from the average over the first 2 min during room air breathing. (b) Time courses illustrating relative in vivo changes in deoxyhemoglobin (red trace) and CBF (green trace) in response to carbogen (95% O₂, 5% CO₂) inhalation. The carbogen inhalation (i.e. “Stim”) is shown as a solid black pulse train. The waveforms shown correspond to the 20 × 20 pixel ROI indicated by the red box in (a). Maps of (c) peak CBF response (CBF_max) and (d) the maximal change in deoxyhemoglobin (-ΔdHb_max) in response to the carbogen challenge. Scale and color bars are shown where appropriate.

Figure 4.

Neurovascular uncoupling in the tumor-affected brain hemisphere relative to the unaffected contralateral hemisphere: Cerebrovascular reactivity (CVR) maps overlaid on T2 FLAIR images obtained on a 7T MRI system during performance of a breath-hold task for a patient with a low-grade oligoastrocytoma (WHO grade II). The CVR maps were generated using a general linear model analysis in which the breath-hold hypercapnia state was contrasted with the baseline normal breathing blocks. Notice that within and in the immediate vicinity of the tumor, there is abnormally decreased and in some areas absent CVR (arrow) relative to the normal contralateral hemisphere. This is an indication of the presence of neurovascular uncoupling (NVU). All CVR maps were thresholded at a z-score > 1.0.

Figure 5.

Neurovascular uncoupling in task-based and resting-state fMRI: A patient with a low-grade (WHO grade II) non-enhancing oligodendroglioma underwent fMRI at (a) 3T, and (b) ultra-high field 7T. Both fMRI maps were registered and overlaid on T2 FLAIR images. (a) Vertical tongue movement task activation map (blue arrow) at 3T thresholded at a z-score > 4.5. (b) The resting-state fMRI map displaying sensorimotor activation (blue arrow) derived from an independent component analysis (ICA) with order of 30, thresholded at z-score > 5.0. The white arrow points to the expected areas of sensorimotor cortex activation in all panels. Both task-based and resting-state fMRI methods demonstrated NVU.

Figure 6.

Brain tumors disrupt the normal inter- and intra-hemispheric resting-state functional connectivity due to neurovascular uncoupling: Correlation coefficient (CC) matrices illustrating the resting state functional connectivity for (a) regions-of-interest (ROI) from a 9L brain tumor-bearing mouse; (b) ROI from a healthy mouse. (c) The “difference” CC matrix between tumor-bearing and normal mouse ROIs illustrating the inter-ROI connectivity most affected by the presence of a tumor. To visually represent the resting state connectivity between murine brain regions, we generated force-directed spatial graphs using the Kamada-Kawai (KK) algorithm. In this spatial graph, each brain ROI was represented by a node and the strength of the connectivity between ROI represented by the thickness of the edge. The end result was a KK plot corresponding to the CC matrices in (a) and (b), respectively. (d) KK plot for a brain tumor-bearing mouse; (e) KK plot for a normal mouse. (f) Overlaying the KK-plots in (d) and (e) illustrates the alterations in resting state connectivity between tumor-bearing and normal brains. ROI labels have been omitted in (f) for clarity.