High Resolution Studies of Oxygen, Carbogen and Carbon Dioxide in the Brain — with Supporting Findings from Peripheral Muscle

Functional MRI (fMRI) is a non-invasive technique widely used to map brain-functions. Nevertheless, its hemodynamic basis and spatial precision with which fMRI reflects sites of neuronal activity are not completely understood. We therefore combined fMRI, based on the blood oxygenation level dependent (BOLD) effect, with optical recording of intrinsic signals (ORIS), a technique, which has a better spatial and temporal resolution. Furthermore, ORIS can distinguish between localized changes in deoxyhemoglobin, and more widespread changes in cerebral blood volume/flow. In gerbils hemodynamic responses over the contralateral barrel cortex were studied with both methods, using identical stimulation of a single vibrissae and identical integration and correlation analysis strategies. Analysis of integration maps and of the spatial distribution and temporal correlation with the block-design of vibrissal stimulation revealed that the BOLD signal, at the site of neuronal activation, does not reflect a depletion of deoxyhemoglobin, as generally assumed. Instead, its positive polarity is likely due to an increase in cerebral blood volume (CBV) whose highly dynamic effect on the BOLD signal exceeds that of the increase in deoxyhemoglobin remaining elevated during prolonged stimulation. This is so, because we show, that blood flow does wash out deoxyhemoglobin but at a rate which is to decrease the deoxyhemoglobin concentration in the voxel below resting level. The wash out causes an accumulation of deoxyhemoglobin in the draining venous side, but at a time window which can be clearly distinguished from the specific activity by applying an analysis strategy based on correlation functions. Therefore, draining veins do not appear as confounding problem. This knowledge could be useful to model the BOLD effect more accurately and improve the spatial resolution of fMRI.

Assessment of lung development and maturity is of utmost importance in prenatal counseling. Blood oxygen level-dependent (BOLD) effect MRI was developed for functional evaluations of organs. To date, no data are available in fetal lungs and nothing is known about the existence of a BOLD effect in the lungs. The aim of our study was to evaluate if a BOLD response could be detected in fetal lungs. From January 2014 to December 2016, 38 healthy pregnant women were prospectively enrolled. After a routine scan on a 1.5-T MRI device (normoxic period), maternal hyperoxia was induced for 5 min before the BOLD sequence (hyperoxic period). R2* was evaluated by fitting average intensity of the signal, both for normoxic (norm) and hyperoxic (hyper) periods. A significant BOLD response was observed after maternal hyperoxia in the lungs with a mean R2* decrease of 12.1 ± 2.5% (p < 0.001), in line with the placenta response with a mean R2* decrease of 19.2 ± 5.9% (p < 0.0001), confirming appropriate oxygen uptake. Conversely, no significant BOLD effect was observed for the brain nor the liver with a mean ∆R2* of 3.6 ± 3.1% (p = 0.64) and 2.8 ± 3.7% (p = 0.23). This study shows for the first time in human that a BOLD response can be observed in the normal fetal lung despite its prenatal "non-functional status." If confirmed in congenital lung and chest malformations, this property could be used in addition to the lung volume for a better prediction of postnatal respiratory status. • Blood oxygen level-dependent (BOLD) effect MRI was developed for functional evaluations of organs and could have interesting implications for the fetal organs. • Assessment of lung development is of utmost importance in prenatal counseling, but to date no data are available in fetal lungs. • BOLD response can be observed in the normal fetal lung opening the way to studies on fetus with pathological lungs.

The purpose of this chapter is to introduce the novice NMR imager to blood oxygen level dependent (BOLD) contrast as well as remind the seasoned veteran of its beauty. Introduction to many of the factors that influence the BOLD signal is given higher priority than pursuing any subset in exquisite detail. Instead, references are given for readers seeking intense investigations into a given aspect. The hope is that this overview inspires the reader with the elegant simplicity of BOLD contrast while not, at first, intimidating too much with the underlying complexity. As one's knowledge of NMR matures so too will one's understanding, appreciation, and application of BOLD MRI. BOLD contrast derives from variations in the magnetic susceptibility of blood due to variations in the concentration of deoxyhemoglobin. These magnetic susceptibility effects produce local magnetic fields around blood vessels that can result in phase dispersion of nearby spins and, therefore, changes in signal intensity in NMR images. After providing brief historical context for BOLD, this chapter will follow the trail of magnetic susceptibility through definition, its source and location in vivo, and how the source and location in vivo interact with anatomical (e.g., blood vessel size) and imaging considerations (e.g., pulse sequence) to influence the BOLD signal. We will conclude by briefly highlighting clinical and preclinical applications using BOLD contrast.

Functional magnetic resonance imaging (fMRI) has become a powerful tool for investigating the working human brain based on the blood oxygenation level dependent (BOLD) effect on the MR signal. However, despite the widespread use of fMRI techniques for mapping brain activation, the basic physiological mechanisms underlying the observed signal changes are still poorly understood. Arterial spin labeling (ASL) techniques, which measure cerebral blood flow (CBF) and the BOLD effect simultaneously, provide a useful tool for investigating these physiological questions. In this paper, recent results of studies manipulating the baseline CBF both pharmacologically and physiologically will be discussed. These data are consistent with a feed-forward mechanism of neurovascular coupling, and suggest that the CBF change itself may be a more robust reflection of neural activity changes than the BOLD effect. Consistent with these data, a new thermodynamic hypothesis is proposed for the physiological function of CBF regulation: maintenance of the [O 2 ]/[CO 2 ] concentration ratio at the mitochondria in order to preserve the free energy available from oxidative metabolism. A kinetic model based on this hypothesis provides a reasonable quantitative description of the CBF changes associated with neural activity and altered blood gases (CO 2 and O 2 ).

Characterizing the Relationship between BOLD Contrast and Regional Cerebral Blood Flow Measurements by Varying the Stimulus Presentation Rate

The blood oxygen level dependent (BOLD) effect that provides the contrast in functional magnetic resonance imaging (fMRI) has been demonstrated to affect the linewidth of spectral peaks as measured with magnetic resonance spectroscopy (MRS) and through this, may be used as an indirect measure of cerebral blood flow related to neural activity. By acquiring MR-spectra interleaved with frames without water suppression, it may be possible to image the BOLD effect and associated metabolic changes simultaneously through changes in the linewidth of the unsuppressed water peak. The purpose of this study was to implement this approach with the MEGA-PRESS sequence, widely considered to be the standard sequence for quantitative measurement of GABA at field strengths of 3 T and lower, to observe how changes in both glutamate (measured as Glx) and GABA levels may relate to changes due to the BOLD effect. MR-spectra and fMRI were acquired from the occipital cortex (OCC) of 20 healthy participants whilst undergoing intrascanner visual stimulation in the form of a red and black radial checkerboard, alternating at 8 Hz, in 90 s blocks comprising 30 s of visual stimulation followed by 60 s of rest. Results show very strong agreement between the changes in the linewidth of the unsuppressed water signal and the canonical haemodynamic response function as well as a strong, negative, but not statistically significant, correlation with the Glx signal as measured from the OFF spectra in MEGA-PRESS pairs. Findings from this experiment suggest that the unsuppressed water signal provides a reliable measure of the BOLD effect and that correlations with associated changes in GABA and Glx levels may also be measured. However, discrepancies between metabolite levels as measured from the difference and OFF spectra raise questions regarding the reliability of the respective methods.

Negative Dip in BOLD fMRI Is Caused by Blood Flow— Oxygen Consumption Uncoupling In Humans

Brain activation is known to lead to enhanced perfusion which, together with other physiological changes (e.g. blood volume, oxygen consumption), results in a decreased deoxyhaemoglobin concentration in regions of neuronal activity (Ogawa et al. 1990). This effect is referred to as the BOLD (blood oxygenation level dependent) effect and is by far the most commonly used method for fMRI studies and manifests itself as a slight increase in the strongly T2* (or T2) weighted MR images used for fMRI studies. BOLD signal changes occur both in the tissue (extra-vascular BOLD effect) and within the vasculature (intra-vascular BOLD effect). Non-BOLD related intra-vascular signal changes can also occur within larger vessels due to in-flow effects.

Clinically, development of anti-angiogenic drugs for cancer therapy is pivotal. Longitudinal monitoring of tumour angiogenesis can help clinicians determine the effectiveness of anti-angiogenic therapy. Blood oxygen level dependent (BOLD) effect has been widely used for functional imaging and tumour oxygenation assessment. In this study, the BOLD effect is investigated under different levels of oxygen inhalation for the development of a novel angiographic MRI technique, blood oxygen level dependent angiography (BOLDangio). Under short-term (<10 min) generalized hypoxia induced by inhalation of 8% oxygen, we measure BOLD contrast as high as 25% from vessels at 9.4T using a simple gradient echo (GRE) pulse sequence. This produces high-resolution 2D and 3D maps of normal and tumour brain vasculature in less than 10 minutes. Additionally, this technique reliably detects metastatic tumours and tumour-induced intracranial hemorrhage. BOLDangio provides a sensitive research tool for MRI of vasculature under normal and pathological conditions. Thus, it may be applied as a simple monitoring technique for measuring the effectiveness of anti-angiogenic drugs in a preclinical environment.

Atherosclerotic disease remains concealed for many years and becomes clinically overt only when the growth of atherosclerotic plaques and the adverse remodeling of the arterial wall reach a critical stage that results in impairment of blood flow, ischemia, and angina. Large epicardial arteries have a diameter ranging from a few millimeters to ≈500 μm and are visible at coronary angiography. Prearterioles (diameter from ≈500 to ≈100 μm) and arterioles (diameter <100 μm) are beyond the resolution of current angiographic systems and hence are not visible at angiography. Each compartment is regulated by distinct mechanisms, and vascular resistance is distributed in series along the coronary vascular bed.1 The oxygen supply to the myocardium is determined by arterial oxygen saturation and myocardial extraction, which are relatively fixed in normal perfusion conditions. At constant distending pressure, variations of flow in epicardial coronary arteries can be achieved by means of intracoronary injection of arteriolar vasodilators.2 Near maximal hyperemia can be achieved using coronary vasodilators such as adenosine or dipyridamole, which induce vasodilatation, mainly in the coronary microcirculation. The functional severity of a stenosis cannot be estimated by anatomic imaging such as x-ray coronary angiography or multislice computed tomography, and, in addition, diffuse atherosclerosis and extensive arterial remodeling may contribute to the dissociation of anatomic and functional measurements of coronary stenosis severity. Therefore, the functional significance of coronary stenoses can only be evaluated by measures of coronary flow, and commonly the flow reserve, which is the ratio of nonregulated maximum (hyperemic) and autoregulated (resting) flow. This characterization requires accurate quantitative measurements of pressure and/or flow and can be estimated invasively as fractional flow reserve2 or measured noninvasively with positron emission tomography (PET).3 Articles see p 32 and 41 The relationship between resting and hyperemic myocardial blood flow and severity of coronary …

Brain response to visual stimulation can be probed quantitatively using functional magnetic resonance spectroscopy (fMRS), which relies on the blood oxygenation level dependent (BOLD) contrast mechanism. BOLD effect in fMRS is associated with changes in the areas, widths, and heights of the MR spectra. This study investigated the effect of spectral averaging scheme (NEX value) on BOLD changes in the spectra. Using a visual stimulus at 8 Hz in single and interleaved stimulation paradigms, the BOLD effects in spectra acquired from the occipital brain region of three healthy volunteers (mean age ± SD = 32.7 ± 3.5 years) were compared for two fMRS data sets acquired with two NEX values (“2” and “8”) available on a 3 T MR scanner. BOLD signal changes were estimated as percentage changes in spectral areas, heights, and widths of six cerebral metabolites and water using the SAGE software package (version 7). There was a general trend of lower BOLD effects with NEX = 8 in both stimulation paradigms. In the single stimulation paradigm, NEX = 8 was associated with significantly lower N-acetyl aspartate (NAA) spectral height (p = 0.03), creatine (p = 0.04) and choline (p = 0.02) spectral widths, and NAA (p = 0.03), water (p &lt; 0.01), and glutamate (p = 0.02) spectral areas. In the interleaved stimulation paradigm, NEX = 8 was associated with significantly lower glutamate spectral height (p = 0.02), water (p = 0.03), and glutamine (p = 0.03) spectral widths, but there was no significant difference in all spectral areas between the two NEX values. Even though the two NEX values offered some differences in observable BOLD effects, their spectral areas were not significantly different in the interleaved visual stimulation experiments.

A theoretical framework is presented for converting Blood Oxygenation Level Dependent (BOLD) images to brain temperature maps, based on the idea that disproportional local changes in cerebral blood flow (CBF) as compared with cerebral metabolic rate of oxygen consumption (CMRO₂) during functional brain activity, lead to both brain temperature changes and the BOLD effect. Using an oxygen limitation model and a BOLD signal model, we obtain a transcendental equation relating CBF and CMRO₂ changes with the corresponding BOLD signal, which is solved in terms of the Lambert W function. Inserting this result in the dynamic bioheat equation describing the rate of temperature changes in the brain, we obtain a nonautonomous ordinary differential equation that depends on the BOLD response, which is solved numerically for each brain voxel. Temperature maps obtained from a real BOLD dataset registered in an attention to visual motion experiment were calculated, obtaining temperature variations in the range: (-0.15, 0.1) which is consistent with experimental results. The statistical analysis revealed that significant temperature activations have a similar distribution pattern than BOLD activations. An interesting difference was the activation of the precuneus in temperature maps, a region involved in visuospatial processing, an effect that was not observed on BOLD maps. Furthermore, temperature maps were more localized to gray matter regions than the original BOLD maps, showing less activated voxels in white matter and cerebrospinal fluid.

Using the localized spin-echo (1)H MRS technique, the water resonance and methyl resonance peaks of the cerebral metabolites N-acetylaspartate (NAA at 2.0 ppm) and phosphocreatine/creatine (Cr at 3.0 ppm) were studied in the human visual cortex to detect and quantify the blood oxygenation level dependent (BOLD) effect during visual stimulation at 4 T. Significant BOLD effects, which reflect the increases of spectral peak height (H) accompanied by the decreases of spectral linewidth (Deltaupsilon(1/2)), were observed in NAA (H: 2.5%; Deltaupsilon(1/2): -1.7%) and Cr (H: 3.1%; Deltaupsilon(1/2): -1.8%) as well as in water (H: 3.1%; Deltaupsilon(1/2): -2.3%). Because NAA and Cr mainly exist in the brain cells, the BOLD effects on these cerebral metabolite resonances only measure the susceptibility component spreading into the extravascular cellular compartment. In contrast, water is affected in the intra- and the extravascular compartments. Therefore, the water signal measures the BOLD effects in both compartments. BOLD responses in water were similar to those observed in metabolites. The similarity indicates that the susceptibility spreading into the extravascular parenchyma contributed significantly to the observed BOLD effects at 4 T. Finally, taking advantage of the higher NMR sensitivity at 4 T, the feasibility of measuring BOLD effects on cerebral metabolites by localized (1)H MRS is demonstrated.

A theoretical framework is presented for converting Blood Oxygenation Level Dependent (BOLD) images to temperature maps, based on the idea that disproportional local changes in cerebral blood flow (CBF) as compared with cerebral metabolic rate of oxygen consumption (CMRO2) during functional brain activity, lead to both brain temperature changes and the BOLD effect. Using an oxygen limitation model and a BOLD signal model we obtain a transcendental equation relating CBF and CMRO2 changes with the corresponding BOLD signal, which is solved in terms of the Lambert W function. Inserting this result in the dynamic bio-heat equation describing the rate of temperature changes in the brain, we obtain a non autonomous ordinary differential equation that depends on the BOLD response, which is solved numerically for each brain voxel. In order to test the method, temperature maps obtained from a real BOLD dataset are calculated showing temperature variations in the range: (-0.15, 0.1) which is consistent with experimental results. The method could find potential clinical uses as it is an improvement over conventional methods which require invasive probes and can record only few locations simultaneously. Interestingly, the statistical analysis revealed that significant temperature variations are more localized than BOLD activations. This seems to exclude the use of temperature maps for mapping neuronal activity as areas where it is well known that electrical activity occurs (such as V5 bilaterally) are not activated in the obtained maps. But it also opens questions about the nature of the information processing and the underlying vascular network in visual areas that give rise to this result.

THE BOLD EFFECT The previous chapters described magnetic resonance imaging (MRI) techniques for measuring cerebral blood flow and blood volume. By introducing contrast agents or manipulating the magnetization of arterial blood before it arrives in a tissue voxel, the MR signal becomes sensitive to aspects of local tissue perfusion. Such techniques are clinically valuable for investigating disorders characterized by perfusion abnormalities, such as stroke and tumors, and these techniques have also seen limited use in investigations of normal brain function. But the functional magnetic resonance imaging (fMRI) technique that has created a revolution in research on the basic functions of the healthy human brain is based on an intrinsic sensitivity of the magnetic resonance (MR) signal to local changes in perfusion and metabolism. When neural activity increases in a region of the brain, the local MR signal produced in that part of the brain increases by a small amount due to changes in blood oxygenation. This Blood Oxygenation Level Dependent (BOLD) effect is the basis for most of the fMRI studies done today to map patterns of activation in the working human brain. The BOLD effect is most pronounced on gradient echo (GRE) images, indicating that the effect is primarily an increase of the local value of T . The fact that the oxygenation of the blood has a measurable effect on the MR signal from the surrounding tissue was discovered by Ogawa and co-workers imaging a rat model at 7T (Ogawa et al., 1990). They found that the MR signal around veins decreased when the oxygen content of the inspired air was reduced, and the effect was reversed when the oxygen was returned to normal values.