Investigation of the neurovascular coupling in positive and negative BOLD responses in human brain at 7T

Decreases in stimulus-dependent blood oxygenation level dependent (BOLD) signal and their underlying neurovascular origins have recently gained considerable interest. In this study a multi-echo, BOLD-corrected vascular space occupancy (VASO) functional magnetic resonance imaging (fMRI) technique was used to investigate neurovascular responses during stimuli that elicit positive and negative BOLD responses in human brain at 7 T. Stimulus-induced BOLD, cerebral blood volume (CBV), and cerebral blood flow (CBF) changes were measured and analyzed in ‘arterial’ and ‘venous’ blood compartments in macro- and microvasculature. We found that the overall interplay of mean CBV, CBF and BOLD responses is similar for tasks inducing positive and negative BOLD responses. Some aspects of the neurovascular coupling however, such as the temporal response, cortical depth dependence, and the weighting between ‘arterial’ and ‘venous’ contributions, are significantly different for the different task conditions. Namely, while for excitatory tasks the BOLD response peaks at the cortical surface, and the CBV change is similar in cortex and pial vasculature, inhibitory tasks are associated with a maximum negative BOLD response in deeper layers, with CBV showing strong constriction of surface arteries and a faster return to baseline. The different interplays of CBV, CBF and BOLD during excitatory and inhibitory responses suggests different underlying hemodynamic mechanisms

High-resolution CMRO2 in gray matter of macaque visual cortex

Commonly used fMRI signals measure local vascular and neural changes, with the former underlying a certain degree of spatiotemporal blurring. To minimize the latter, methods can be used that are less sensitive to partial volume effects. One such methodology capitalizes on high resolution, voxel-by-voxel CMRO2 measurements. Here we combined such measurements with so-called calibrated BOLD methodology to acquire CBF and BOLD maps during visual stimulation. Calibration was done by estimating a normalization factor (M) assessed in hypercapnia conditions, reflecting the upper limit of BOLD signal-changes. Quantitative description and interpretation of the data was done by using a model with parameters α, relating relative changes of CBV to CBF according to Grubb’s law (α=0.38), and β linking blood oxygenation to relaxivity (β=1.5). To improve the model, α was selected to account for changes in venous CBV only (α=0.23), i.e. to account for CBV-changes that are relevant to the BOLD signal, rather than to total CBV alterations. Alternatively, the model was compared to a more detailed model and showed highest accuracy with α=0.14 β=0.91. We determined the CMRO2 in anesthetized macaques at 7T high resolution to separate the visually induced percent changes in CMRO2 (CMRO2) in gray matter from white matter and vessel signals. We subsequently repeated the calculations using the aforementioned α β parameters in order to reassess the robustness of the results. CBF and BOLD signals were acquired simultaneously with a triple-echo sequence. The CMRO2 changes, M and n (ratio of fractional CBF to CMRO2) were calculated in V1 and V2. At a resolution of 1x1x3 mm3, the average CMRO2 was 12±5 (mean ± sem) with M=0.29 ± 0.05. The coupling constant n was 2.1 ± 0.4. Similar values were obtained for α=0.23. The calibration constant M slightly increased using α=0.14 β=0.91 but remained consistent with the value of 0.3-0.4 in gray matter at 7T. CMRO2 changes n were not very sensitive to the choice of parameters. For resolution of 0.5x0.5x3mm3 the results suggested higher CMRO2 changes in gray matter than in white matter with a possible peak in layer IV, being the main input layer in macaque monkey. CBF and BOLD percent changes during visual stimulation and hypercapnic challenge were increased at a resolution of 0.5x0.5x3mm3 compared to 1x1x3 mm3. In conclusion, using the calibrated BOLD method, we found high-resolution CMRO2 changes of 12-14 and coupling ratios of 1.8-2.1, and demonstrated differences in CMRO2 measured in gray and white matter. The reported results were found to be robust and insensitive to changes in the α β parameters at high field

Decreased Cerebral Blood Volume and Flow in Areas with Negative BOLD Indicates the Mechanism for Negative BOLD May Be Stimulus- and Area-Specific

In earlier work, we showed increased CBV in regions with negative BOLD responses. This seems to disagree with work in cats where CBV was decreased in areas with negative BOLD. Here, we used a full-field checkerboard stimulus and show decreased CBV and CBF in areas that show negative BOLD responses. However, this type of negative BOLD signals occurred in peripheral V1 and extrastriate visual cortex. Our results suggest that different mechanisms for negative BOLD exist and that these may be area-dependent

High resolution CMRO2 in visual cortex of macaca mulatta

Current fMRI-methods are based on changes in cerebral blood flow and/or oxygenation. Since these methods measure hemodynamic signals, changes in BOLD or CBF may not always accurately reflect changes in the actual energy use of the brain. We determined CMRO2 in macaques during visual stimulation at high resolution. The CMRO2values and the ratio of fractional CBF and CMRO2 changes were consistent with those reported in the literature

fMRI at high spatial resolution implications for BOLD-models

As high-resolution functional magnetic resonance imaging (fMRI) and fMRI of cortical layers become more widely used, the question how well high-resolution fMRI signals reflect the underlying neural processing, and how to interpret laminar fMRI data becomes more and more relevant. High-resolution fMRI has shown laminar differences in cerebral blood flow (CBF), volume (CBV), and neurovascular coupling. Features and processes that were previously lumped into a single voxel become spatially distinct at high resolution. These features can be vascular compartments such as veins, arteries, and capillaries, or cortical layers and columns, which can have differences in metabolism. Mesoscopic models of the blood oxygenation level dependent (BOLD) response therefore need to be expanded, for instance, to incorporate laminar differences in the coupling between neural activity, metabolism and the hemodynamic response. Here we discuss biological and methodological factors that affect the modeling and interpretation of high-resolution fMRI data. We also illustrate with examples from neuropharmacology and the negative BOLD response how combining BOLD with CBF- and CBV-based fMRI methods can provide additional information about neurovascular coupling, and can aid modeling and interpretation of high-resolution fMRI

Laminar differences in functional oxygen metabolism in monkey visual cortex measured with calibrated fMRI

Summary: Blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) of cortical layers relies on the hemodynamic response and is biased toward large veins on the cortical surface. Functional changes in the cerebral metabolic rate of oxygen (ΔCMRO2) may reflect neural cortical function better than BOLD fMRI, but it is unknown whether the calibrated BOLD model for functional CMRO2 measurement remains valid at high resolution. Here, we measure laminar ΔCMRO2 elicited by visual stimulation in macaque primary visual cortex (V1) and find that ΔCMRO2 peaks in the middle of the cortex, in agreement with autoradiographic measures of metabolism. ΔCMRO2 values in gray matter are similar as found previously. Reductions in CMRO2 are associated with veins at the cortical surface, suggesting that techniques for vein removal may improve the accuracy of the model at very high resolution. However, our results show feasibility of laminar ΔCMRO2 measurement, providing a physiologically meaningful metric of laminar functional metabolism

Validation of a patient-specific one-dimensional model of the systemic arterial tree

Reymond P, Bohraus Y, Perren F, Lazeyras F, Stergiopulos N. Validation of a patient-specific one-dimensional model of the systemic arterial tree. Am J Physiol Heart Circ Physiol 301: H1173-H1182, 2011. First published May 27, 2011; doi:10.1152/ajpheart.00821.2010.-The aim of this study is to develop and validate a patient-specific distributed model of the systemic arterial tree. This model is built using geometric and hemodynamic data measured on a specific person and validated with noninvasive measurements of flow and pressure on the same person, providing thus a patient-specific model and validation. The systemic arterial tree geometry was obtained from MR angiographic measurements. A nonlinear viscoelastic constitutive law for the arterial wall is considered. Arterial wall distensibility is based on literature data and adapted to match the wave propagation velocity of the main arteries of the specific subject, which were estimated by pressure waves traveling time. The intimal shear stress is modeled using the Witzig-Womersley theory. Blood pressure is measured using applanation tonometry and flow rate using transcranial ultrasound and phase-contrast-MRI. The model predicts pressure and flow waveforms in good qualitative and quantitative agreement with the in vivo measurements, in terms of wave shape and specific wave features. Comparison with a generic one-dimensional model shows that the patient-specific model better predicts pressure and flow at specific arterial sites. These results obtained let us conclude that a patient-specific one-dimensional model of the arterial tree is able to predict well pressure and flow waveforms in the main systemic circulation, whereas this is not always the case for a generic one-dimensional model

Haemodynamics in the mouse aortic arch computed from MRI-derived velocities at the aortic root

Mice are widely used to investigate atherogenesis, which is known to be influenced by stresses related to blood flow. However, numerical characterization of the haemodynamic environment in the commonly studied aortic arch has hitherto been based on idealizations of inflow into the aorta. Our purpose in this work was to numerically characterize the haemodynamic environment in the mouse aortic arch using measured inflow velocities, and to relate the resulting shear stress patterns to known locations of high- and low-lesion prevalence. Blood flow velocities were measured in the aortic root of C57/BL6 mice using phase-contrast MRI. Arterial geometries were obtained by micro-CT of corrosion casts. These data were used to compute blood flow and wall shear stress (WSS) patterns in the arch. WSS profiles computed using realistic and idealized aortic root velocities differed significantly. An unexpected finding was that average WSS in the high-lesion-probability region on the inner wall was actually higher than the WSS in the low-probability region on the outer wall. Future studies of mouse aortic arch haemodynamics should avoid the use of idealized inflow velocity profiles. Lesion formation does not seem to uniquely associate with low or oscillating WSS in this segment, suggesting that other factors may also play a role in lesion localization