Simultaneous recording of task-induced changes in blood oxygenation, volume, and flow using diffuse optical imaging and arterial spin-labeling MRI.

Increased neural activity in brain tissue is accompanied by an array of supporting physiological processes, including increases in blood flow and the rates at which glucose and oxygen are consumed. These responses lead to secondary effects such as alterations in blood oxygenation and blood volume, and are ultimately the primary determinants of the amplitude and temporal signature of the blood oxygenation level-dependent (BOLD) signal used prevalently to map brain function. We have performed experiments using a combination of optical and MRI-based imaging methods to develop a more comprehensive picture of the physiological events accompanying activation of primary motor cortex during a finger apposition task. Temporal profiles for changes in tissue hemoglobin concentrations were qualitatively similar to those observed for MRI-based flow and oxygenation signals. Quantitative analysis of these signals revealed peak changes of +16 +/- 2% for HbO, -13 +/- 2% for HbR, +8 +/- 3% for total Hb, +83 +/- 9% for cerebral blood flow, and +1.4 +/- 0.1% for the BOLD MRI signal. A mass balance model was used to estimate the change in rate of oxidative metabolism implied by the optical and flow measurements, leading to a computed value of +47 +/- 5%. It should be noted that the optical and MRI observations may in general reflect changes over different volumes of tissue. The ratio of fractional changes in oxidative metabolism to fractional change in blood flow was found to be 0.56 +/- 0.08, in general agreement with previous studies of flow-metabolism coupling.

Can the cerebral metabolic rate of oxygen be estimated with near-infrared spectroscopy?

We have measured the changes in oxy-haemoglobin and deoxy-haemoglobin in the adult human brain during a brief finger tapping exercise using near-infrared spectroscopy (NIRS). The cerebral metabolic rate of oxygen (CMRO2) can be estimated from these NIRS data provided certain model assumptions. The change in CMRO2 is related to changes in the total haemoglobin concentration, deoxy-haemoglobin concentration and blood flow. As NIRS does not provide a measure of dynamic changes in blood flow during brain activation, we relied on a Windkessel model that relates dynamic blood volume and flow changes, which has been used previously for estimating CMRO2 from functional magnetic resonance imaging (fMRI) data. Because of the partial volume effect we are unable to quantify the absolute changes in the local brain haemoglobin concentrations with NIRS and thus are unable to obtain an estimate of the absolute CMRO2 change. An absolute estimate is also confounded by uncertainty in the flow-volume relationship. However, the ratio of the flow change to the CMRO2 change is relatively insensitive to these uncertainties. For the linger tapping task, we estimate a most probable flow-consumption ratio ranging from 1.5 to 3 in agreement with previous findings presented in the literature, although we cannot exclude the possibility that there is no CMRO2 change. The large range in the ratio arises from the large number of model parameters that must be estimated from the data. A more precise estimate of the flow-consumption ratio will require better estimates of the model parameters or flow information, as can be provided by combining NIRS with fMRI.

Improved mapping of pharmacologically induced neuronal activation using the IRON technique with superparamagnetic blood pool agents.

The use of functional magnetic resonance imaging (fMRI) techniques for evaluation of pharmacologic stimuli has great potential for understanding neurotransmitter dynamics for a number of brain disorders, such as drug abuse, schizophrenia, epilepsy, or neurodegeneration. Unfortunately, blood oxygenation level-dependent (BOLD) imaging at common fields strengths, such as 1.5 or 3 T, has very low sensitivity and contrast-to-noise ratios (CNRs). We demonstrate here the utility of using an intravascular superparamagnetic iron oxide contrast agent with a long plasma half-life for evaluation of hemodynamic changes related to dopaminergic stimuli using amphetamine or the cocaine analog 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT). We refer to this technique as increased relaxation with iron oxide nanoparticles (IRON). Results obtained here show that even at field strengths as high as 4.7 T, one can obtain increases in CNR by factors of 2-3 over BOLD imaging that lead to greater than an order of magnitude increase in statistical power with greatly increased sensitivity to hemodynamic changes in brain regions difficult to observe using BOLD imaging. Furthermore, use of the intravascular contrast agent allows for a meaningful physiologic parameter to be measured (relative cerebral blood volume (rCBV)), compared to conventional BOLD imaging.

Visual motion processing investigated using contrast agent-enhanced fMRI in awake behaving monkeys.

To reduce the information gap between human neuroimaging and macaque physiology and anatomy, we mapped fMRI signals produced by moving and stationary stimuli (random dots or lines) in fixating monkeys. Functional sensitivity was increased by a factor of approximately 5 relative to the BOLD technique by injecting a contrast agent (monocrystalline iron oxide nanoparticle [MION]). Areas identified as motion sensitive included V2, V3, MT/V5, vMST, FST, VIP, and FEF (with moving dots), as well as V4, TE, LIP, and PIP (with random lines). These regions sensitive for moving dots are largely in agreement with monkey single unit data and (except for V3A) with human fMRI results. Moving lines activate some regions that have not been previously implicated in motion processing. Overall, the results clarify the relationship between the motion pathway and the dorsal stream in primates.

Functional magnetic resonance imaging of reorganization in rat brain after stroke.

Functional recovery after stroke has been associated with brain plasticity; however, the exact relationship is unknown. We performed behavioral tests, functional MRI, and histology in a rat stroke model to assess the correlation between temporal changes in sensorimotor function, brain activation patterns, cerebral ischemic damage, and cerebrovascular reactivity. Unilateral stroke induced a large ipsilateral infarct and acute dysfunction of the contralateral forelimb, which significantly recovered at later stages. Forelimb impairment was accompanied by loss of stimulus-induced activation in the ipsilesional sensorimotor cortex; however, local tissue and perfusion were only moderately affected and cerebrovascular reactivity was preserved in this area. At 3 days after stroke, extensive activation-induced responses were detected in the contralesional hemisphere. After 14 days, we found reduced involvement of the contralesional hemisphere, and significant responses in the infarction periphery. Our data suggest that limb dysfunction is related to loss of brain activation in the ipsilesional sensorimotor cortex and that restoration of function is associated with biphasic recruitment of peri- and contralesional functional fields in the brain.

Regional sensitivity and coupling of BOLD and CBV changes during stimulation of rat brain.

Functional MRI of rat brain was performed at 2 Tesla following intravenous injection of cocaine in order to 1) determine if changes in CBV and changes in BOLD signal were regionally coupled in brain parenchyma, and 2) compare the sensitivities of these imaging methods across different brain structures. Percent changes in CBV and BOLD relaxation rate were spatially and temporally coupled during this graded brain activation. The use of contrast agent increased functional sensitivity in all parenchymal brain structures, with a strong but predictable dependence on the resting-state blood volume fraction. Magn Reson Med 45:443-447, 2001.

The accuracy of near infrared spectroscopy and imaging during focal changes in cerebral hemodynamics.

Near infrared spectroscopy (NIRS) can detect changes in the concentrations of oxy-hemoglobin ([HbO]) and deoxy-hemoglobin ([Hb]) in tissue based upon differential absorption at multiple wavelengths. The common analysis of NIRS data uses the modified Beer-Lambert law, which is an empirical formulation that assumes global concentration changes. We used simulations to examine the errors that result when this analysis is applied to focal hemodynamic changes, and we performed simultaneous NIRS measurements during a motor task in adult humans and a neonate to evaluate the dependence of the measured changes on detector-probe geometry. For both simulations and in vivo measurements, the wide range of NIRS results was compared to an imaging analysis, diffuse optical tomography (DOT). The results demonstrate that relative changes in [HbO] and [Hb] cannot, in general, be quantified with NIRS. In contrast to that method, DOT analysis was shown to accurately quantify simulated changes in chromophore concentrations. These results and the general principles suggest that DOT can accurately measure changes in [Hb] and [HbO], but NIRS cannot accurately determine even relative focal changes in these chromophore concentrations. For the standard NIRS analysis to become more accurate for focal changes, it must account for the position of the focal change relative to the source and detector as well as the wavelength dependent optical properties of the medium.

Cocaine activation discriminates dopaminergic projections by temporal response: an fMRI study in Rat.

We applied a sensitive new functional magnetic resonance imaging technique to identify the pattern and determinants of cocaine-induced brain activation in drug-naive rats. At doses greater than 0.1 mg/kg iv, cocaine produced robust activation throughout cortex with the largest magnitude increase in frontal neocortex. Additionally, we detected selective activation within dopamine-innervated subcortical regions including dorsomedial and ventrolateral striatum, nucleus accumbens region, and dorsal thalamus. Although dose response was similar among activated regions, temporal response differentiated regions along distinct anatomical boundaries with basal ganglia and limbic cortical structures, reaching maximum activation later than frontal neocortex. Pharmacological specificity was demonstrated by blocking cocaine-induced activation with SCH-23390, a selective D1 antagonist. Our data demonstrate the utility of fMRI to identify spatiotemporal patterns of cocaine-induced brain activation and implicate D1 dopaminergic mechanisms in acute cocaine action.

MRI measurement of the temporal evolution of relative CMRO(2) during rat forepaw stimulation.

This study reports the first measurement of the relative cerebral metabolic rate of oxygen utilization (rCMRO(2)) during functional brain activation with sufficient temporal resolution to address the dynamics of blood oxygen level-dependent (BOLD) MRI signal. During rat forepaw stimulation, rCMRO(2) was determined in somatosensory cortex at 3-sec intervals, using a model of BOLD signal and measurements of the change in BOLD transverse relaxation rate, the resting state BOLD transverse relaxation rate, relative cerebral blood flow (rCBF), and relative cerebral blood volume (rCBV). Average percentage changes from 10 to 30 sec after onset of forepaw stimulation for rCBF, rCBV, rCMRO(2), and BOLD relaxation rate were 62 +/- 16, 17 +/- 2, 19 +/- 17, and -26 +/- 12, respectively. A poststimulus undershoot in BOLD signal was quantitatively attributed to the temporal mismatch between changes in blood flow and volume, and not to the role of oxygen metabolism. Magn Reson Med 42:944-951, 1999.

Cerebrovascular dynamics of autoregulation and hypoperfusion. An MRI study of CBF and changes in total and microvascular cerebral blood volume during hemorrhagic hypotension.

BACKGROUND AND PURPOSE: To determine how cerebral blood flow (CBF), total and microvascular cerebral blood volume (CBV), and blood oxygenation level-dependent (BOLD) contrast change during autoregulation and hypotension using hemodynamic MRI. METHODS: Using arterial spin labeling and steady-state susceptibility contrast, we measured CBF and changes in both total and microvascular CBV during hemorrhagic hypotension in the rat (n=9). RESULTS: We observed CBF autoregulation for mean arterial blood pressure (MABP) between 50 and 140 mm Hg, at which average CBF was 1.27+/-0.44 mL. g(-1). min(-1) (mean+/-SD). During autoregulation, total and microvascular CBV changes were small and not significantly different from CBF changes. Consistent with this, no significant BOLD changes were observed. For MABP between 10 and 40 mm Hg, total CBV in the striatum increased slightly (+7+/-12%, P<0.05) whereas microvascular CBV decreased (-15+/-17%, P<0.01); on the cortical surface, total CBV increases were larger (+21+/-18%, P<0.01) and microvascular CBV was unchanged (3+/-22%, P>0.05). With severe hypotension, both total and microvascular CBV decreased significantly. Over the entire range of graded global hypoperfusion, there were increases in the CBV/CBF ratio. CONCLUSIONS: Parenchymal CBV changes are smaller than those of previous reports but are consistent with the small arteriolar fraction of total blood volume. Such measurements allow a framework for understanding effective compensatory vasodilation during autoregulation and volume-flow relationships during hypoperfusion.

Vascular filters of functional MRI: spatial localization using BOLD and CBV contrast.

The spatial distributions of functional activation of rat somatosensory cortex by forepaw stimulation were quantitatively compared using blood oxygen level dependent (BOLD) signal and signal weighted by cerebral blood volume (CBV). The BOLD contrast to noise (CNR) distribution showed a significant dorsal shift with respect to the CBV method at fields strengths of 2 T (0.69 +/- 0.09 mm) and 4.7 T (0.44 +/- 0.15 mm). These shifts were attributed to the gradient of resting state blood volume across somatosensory cortex and the different CNR characteristics of the two image methods. The underlying principles suggest that the CBV method has a more uniform sensitivity to percent changes in functional indicators (blood volume or deoxygenated hemoglobin) across regions of variable resting state CBV. Magn Reson Med 42:591-598, 1999.

Evidence of a cerebrovascular postarteriole windkessel with delayed compliance.

A pronounced temporal mismatch was observed between the responses of relative cerebral blood volume (rCBV) measured by magnetic resonance imaging and relative cerebral blood flow measured by laser-Doppler flowmetry in rat somatosensory cortex after electrical forepaw stimulation. The increase of relative cerebral blood flow after stimulus onset and decrease after stimulus cessation were accurately described with a single exponential time constant of 2.4 +/- 0.8 seconds. In contrast, rCBV exhibited two distinct and nearly sequential processes after both onset and cessation of stimulation. A rapid change of rCBV (1.5 +/- 0.8 seconds) occurring immediately after onset and cessation was not statistically different from the time constant for relative cerebral blood flow. However, a slow phase of increase (onset) and decrease (cessation) with an exponential time constant of 14 +/- 13 seconds began approximately 8 seconds after the rapid phase of CBV change. A modified windkessel model was developed to describe the temporal evolution of rCBV as a rapid elastic response of capillaries and veins followed by slow venous relaxation of stress. Venous delayed compliance was suggested as the mechanism for the poststimulus undershoot in blood oxygen-sensitive magnetic resonance imaging signal that has been observed in this animal model and in human data.

Investigation of the early response to rat forepaw stimulation.

The role of relative cerebral blood volume (rCBV) in the early response of blood oxygenation level-dependent (BOLD) signal following sensory stimulation was assessed. Magnetic resonance imaging (MRI) measurements of rCBV and BOLD signal as a function of time (t) were compared with relative cerebral blood flow (rCBF) obtained by laser doppler flowmetry during a repeated epoch of rat forepaw stimulation in which 6 sec of electrical stimulation followed 54 sec of rest. rCBF(t) exceeded rCBV(t) in somatosensory cortex at all time points and reached a maximal increase (60%) during a 6 sec stimulation that was much higher than maximal rCBV (10%). An initial dip was not observed in BOLD signal, which showed a delay with respect to rCBF that was roughly consistent with the cerebral blood transit time.

NMR imaging of changes in vascular morphology due to tumor angiogenesis.

Tumor-sprouted vessels are greater in both number and diameter in comparison to their healthy counterparts. A novel technique based on magnetic susceptibility contrast mechanisms that are sensitive to varying sizes of blood vessels is presented to measure differences between the relaxation rates (1/T2 and 1/T2*) in a rat glioma model and normal cerebral cortex. deltaR2 and deltaR2*, the differences between relaxation rates precontrast and postcontrast agent injection, were measured for an intravascular equilibrium contrast agent (MION) at various echo times. Since deltaR2*/deltaR2 increases as vessel size increases, this ratio can be used as a measure of the average vessel size within an ROI or a voxel. The stability and longevity of the contrast agent within the vasculature were verified (n = 2 trials), and the ratio of deltaR2*/deltaR2 between the tumor and normal cortex was measured to be 1.9+/-0.2 (n = 4, echo time = 20 ms, and susceptibility difference (deltachi) approximately 10(-6)). This ratio compared favorably to a predicted ratio determined using histologically determined vessel sizes and theoretical Monte Carlo modeling results (1.9+/-0.1). Maps of the ratio of deltaR2*/deltaR2 were also made on a pixel-by-pixel basis. These techniques support the hypothesis that susceptibility contrast MRI can provide useful quantitative metrics of in vivo tumor vascular morphology.

Dynamic functional imaging of relative cerebral blood volume during rat forepaw stimulation.

Dynamic measurements of regional changes in cerebral blood volume (CBV) were performed in rat models of hypercarbia and focal neuronal activation using T2-weighted imaging after injection of an intravascular contrast agent with a very long blood half-life. Calculated percent CBV change during hypercarbia was consistent with literature results from other non-invasive modalities. Equivalent percent CBV increases were found using spin- and gradient-echo images, suggesting proportional changes in blood volume for capillaries and small veins. During electrical stimulation of rat forepaw, focal CBV response to stimulation (24+/-4%) was significantly delayed relative to blood oxygen level dependent (BOLD) signal after both onset and cessation of stimulation. Poststimulus CBV decay was temporally consistent with the BOLD poststimulus undershoot. The use of exogenous agent increased the functional contrast-to-noise ratio relative to BOLD imaging by 5.7+/-1.3 at a magnetic field strength of 2 Tesla and 1.5+/-0.2 at 4.7 Tesla.

Dynamic liver imaging with iron oxide agents: effects of size and biodistribution on contrast.

In vivo effective relaxation rates in normal rat liver were evaluated for four dextran coated iron oxide agents: monocrystalline iron oxide nanocolloid (MION) with a mean particle diameter of 3.9 nm, a polycrystalline agent (PION) with a larger mean diameter of 12 nm, and these two agents labeled with the asialofetuin (ASF) protein for high hepatocytic receptor binding affinity (MION-ASF and PION-ASF). Using echo planar imaging at 2 Tesla, dose response was measured with measured with high temporal resolution for 3 h after injection of agent, and by comparing with relaxivities in vitro and in brain, dominant in vivo contrast phenomena were elucidated. While transverse relaxivity for PION-ASF exceeded that for MION-ASF by almost a factor of 2 in solution, relaxation rates in vivo became equivalent. Liver relaxation using non-ASF agents was consistent with rapid water exchange between vascular and extravascular compartments, which dominated relaxation as a result of agent accumulation in Kupffer cells.

MRI measurements of water diffusion and cerebral perfusion: their relationship in a rat model of focal cerebral ischemia.

The aim of this study was to examine the quantitative relationship between changes in apparent diffusion coefficient (ADC) and transverse relaxivity (delta R2*) measurements of relative perfusion deficits within the gradients of a focal ischemic insult. Sixty minutes after permanent occlusion of the middle cerebral artery, rats (n = 7) were subjected to spin echo diffusion-weighted scans followed by fast low-angle shot (FLASH) perfusion-sensitive scans. Diffusion-weighted images showed clear ischemic lesions in the affected basal ganglia and cortex. Ischemic deficits were demonstrated as a decrease in first-pass transit of injected boluses of gadodiamide. ADC maps were generated and regions of interest (ROIs) were obtained to span the range of ADC reductions from the lesion center or core to the periphery or penumbra. Corresponding ROIs from the bolus injection images were used to calculate perfusion indexes relative to contralateral levels as ratios of delta R2* integrals and ratios of delta R2* peak values. In all animals, the degree of ADC reductions was related to the degree of delta R2* perfusion deficits, ranging from severe ischemia in the core of the lesion to intermediate and moderate changes toward the lesion periphery. In the ischemic periphery, ADC reductions were linearly correlated with delta R2* peak ratios. However, no significant correlation was found between ADC reductions and delta R2* integral ratios. These data suggest that magnetic resonance measurements of ADC and delta R2* peak ratios can be used to quantitatively assess the variable gradients in focal ischemia, including potentiallyn critical areas at risk in the ischemic periphery.

Neuroprotection with NBQX in rat focal cerebral ischemia. Effects on ADC probability distribution functions and diffusion-perfusion relationships.

BACKGROUND AND PURPOSE: We have previously shown that treatment with glutamate receptor antagonists after focal ischemia can partially reverse acute lesions measured with diffusion-weighted MRI. The goal of this study was to examine the quantitative nature of these effects of neuroprotection. METHODS: Rats were subjected to permanent occlusion of the middle cerebral artery under halothane anesthesia and treated with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (30 mg/kg IP; two doses given immediately after ischemia and 1 hour after ischemia) or given injections of saline. Diffusion-weighted MRI scans were performed to map the changes in water diffusivity during the first 3 hours after ischemia. Apparent diffusion coefficients (ADCs) within the ischemic hemisphere were calculated, and ischemic changes were expressed as absolute reductions and as a percentage of contralateral mean values. Relative perfusion deficits in the ischemic hemisphere were assessed with dynamic MRI of transient changes in transverse relaxation rates (delta R2*). RESULTS: Analysis with ADC probability distribution functions showed that focal ischemia was present with gradients in ADC reductions emanating from the center to the periphery of the lesion. Ischemic evolution in control rats was manifested as a progressive shift of the probability distribution functions over time. NBQX treatment resulted in a reverse shift of these probability functions. By 3 hours after occlusion, probability distribution functions were significantly improved in treated rats (P < .05). Because of the temporal evolution of the probability distribution functions, ADC thresholds that correlated with histological outcomes of infarction changed over time. NBQX did not alter the cerebral perfusion index, measured as delta R2* peak values. CONCLUSIONS: The results indicate that ADC probability distribution functions can be used to quantitatively evaluate the effects of neuroprotective treatment on the gradients of injury in focal cerebral ischemia. The probability functions also allow for intrasubject comparisons and may therefore be useful for exploring therapeutic windows.

Improving MR quantification of regional blood volume with intravascular T1 contrast agents: accuracy, precision, and water exchange.

The goal of this work was to develop a comprehensive understanding of the relationship between vascular proton exchange rates and the accuracy and precision of tissue blood volume estimates using intravascular T1 contrast agents. Using computer simulations, the effects of vascular proton exchange and experimental pulse sequence parameters on measurement accuracy were quantified. T1 and signal measurements made in a rat model implanted with R3230 mammary adenocarcinoma tumors demonstrated that the theoretical findings are biologically relevant; data demonstrated that over-simplified exchange models may result in measures of tumor, muscle, and liver blood volume fractions that depend on experimental parameters such as the vascular contrast concentration. As a solution to the measurement of blood volume in tissues with exchange that is unknown, methods that minimize exchange rate dependence were examined. Simulations that estimated both the accuracy and precision of such methods indicated that both the inversion recovery and the transverse-spoiled gradient echo methods using a "no-exchange" model provide the best trade-off between accuracy and precision.

Dynamic Gd-DTPA enhanced MRI measurement of tissue cell volume fraction.

A new technique for measuring tissue cellular volume fraction, based on an improved modeling of the dynamic distribution of Gd-DTPA and the effect of proton exchange, is described. This technique uses peak T1 enhancement and blood Gd-DTPA concentration to compute tissue cellular volume fraction. The feasibility of this technique is demonstrated with computer simulations that explore the limits of the simplifying assumptions (small vascular space, slow vascular-extravascular proton exchange), and by direct comparison of MR and radionuclide cell fraction measurements made in muscle, liver, and tumor tissue in a rat model. The computer simulations demonstrate that with slow to intermediate vascular proton exchange and vascular fractions less than 10% the error in our cell fraction measurements typically remains less than 10%. Consistent with this prediction, a direct comparison between MR and radionuclide measurements of cell fraction demonstrates mean percent differences of less than 10%:1.9% in muscle (n = 4); 9% in liver (n = 1) and 9.5% in tumor (n = 4). Similarly, for all rats studied, the MR-measured cell fractions (muscle (0.92 +/- 0.04, n = 20); liver (0.76 +/- 0.11, n = 9); whole tumor (0.69 +/- 0.15, n = 22)) agree with the cell fraction values reported in the literature. In general, the authors' results demonstrate the feasibility of a simple method for measuring tissue cell fraction that is robust across a broad range of vascular volume, flow, and exchange conditions. Consequently, this method may prove to be an important means for evaluating the response of tumors to therapy.