Adaptive total linear least square method for quantification of mean transit time in brain perfusion MRI

Absolute quantification of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) are of great relevance for clinical applications. One of the widely used methods for quantification of these parameters is gamma-variate fitting. Traditional nonlinear regression methods for gamma-variate fitting are inaccurate and computationally demanding. In this study, we developed an adaptive total least square method (ATSSL) to fit a gamma-variate function to the delayed concentration-time course. For each concentration-time curve, the beginning and ending time point of the curve are adaptively determined online. After the curves were fitted, a robust method for automatically determination of arterial input function (AIF) from whole and region of interest (ROI) was developed. Using the obtained AIF and fitted gamma-variate concentration-time curve, the MTT, CBV, and CBF were calculated by utilizing singular value decomposition algorithm. Computer simulations show that the suggested method is adaptive, reliable, and insensitive to noise. Comparison with the traditional nonlinear regression method indicated that the presented method is more accurate and faster to determine the CBV, CBF and MTT.     

Quantification of cerebral blood flow by bolus tracking and artery spin tagging methods

This study deals with perfusion quantification in healthy volunteers using two types of dynamic magnetic resonance imaging (MRI) methods. Absolute cerebral blood flow (CBF) measurements were performed in 11 subjects by applying both bolus tracking of exogenous contrast agent and non-invasive arterial spin labeling MRI techniques. Both methods produced CBF images with good tissue contrast and CBF values are in good agreement with literature data. The correlation between cerebral blood volume (CBV) and CBF is also discussed.     

Mapping of cerebrovascular reactivity using BOLD magnetic resonance imaging

Blood oxygen level-dependent (BOLD) contrast MRI is a simple non-invasive method of estimating "perfusion," and combined with a vasodilatory stimulus, may allow estimation of cerebral vascular reserve. We compared BOLD carbon dioxide (CO2) reactivity in the middle cerebral artery (MCA) perfusion territory to MCA flow velocity reactivity determined using transcranial Doppler ultrasound (TCD) in 16 patients with unilateral carotid artery stenosis or occlusion. Both BOLD and TCD reactivities were calculated from measurements acquired when the subjects were breathing air, and again when breathing a 6% CO2/air mixture, and were normalized by dividing by the difference in end tidal (ET) CO2. There was a significant correlation between interhemispheric MCA reactivity difference (contralateral-ipsilateral to the stenosis or occlusion) determined by BOLD MRI and TCD (r = 0.75, p < 0.001). In contrast, treating each hemisphere individually, there was no correlation between the absolute BOLD and TCD MCA CO2 reactivities (r = 0.08, p = 0.670). This appeared to be due to a variable BOLD signal change in the non-stenosed hemisphere between subjects, with little change in the normal hemisphere of a few subjects. In one patient, focal regions of reduced reactivity were seen in non-infarcted regions of the stenosed hemisphere, in the borderzones between arterial territories. BOLD reactivity maps provide information on the whole MCA territory reactivity, and may identify small regions of impaired reactivity which are not detected using TCD. However, BOLD reactivity maps only appear to provide semi-quantitative rather than quantitative data.     

Correcting the effects of background microcirculation in the measurement of arterial input functions using dynamic susceptibility contrast MRI of the brain

In dynamic susceptibility contrast MRI, the shape of the arterial input function (AIF) is commonly obtained in the near vicinity of the middle cerebral artery (MCA). However, the tissue regions where the AIF is sampled also have significant perfusion, which contributes to T(2)* changes. We investigate whether correction of this effect will introduce significant changes in the measurement of the AIF and, subsequently, the assessment of the mean transit time (MTT). Clinical dynamic susceptibility data from 13 patients with brain tumors were analyzed. Patients received either single or double doses of Magnevist followed by a saline flush through a power injector. In the correction procedure, DeltaR(2)* was sampled in a region of gray matter approximately 1-2 cm away from the MCA and then subtracted from the DeltaR(2)* sampled in the immediate vicinity of the MCA. We demonstrate that in the brain, this correction of DeltaR(2)* due to tissue perfusion leads to a narrower width of the AIF curve obtained with DeltaR(2)* (mean+/-S.D.=7.3+/-2.0 and 6.4+/-1.7 s, before and after correction, respectively, P<.001 using a two-tailed paired t-test). Furthermore, the peak of the AIF also moved to a slightly earlier time relative to the time of arrival (mean+/-S.D.=4.7+/-0.9 and 4.3+/-0.8 s, before and after correction, with P<.001). With the use of the corrected AIF, the measured MTT had increased values in areas of both gray and white matter.     

Mismatch between Cerebral Blood Volume and Flow Index during Transient Focal Ischemia Studied with MRI and Gd-BOPTA

We investigated the regional and temporal changes in cerebral blood volume (CBV), cerebral blood flow (CBF), and vascular transit time in seven mongrel cats during 30 min transient focal ischemia, caused by occlusion of the middle cerebral artery. Dynamic susceptibility contrast magnetic resonance imaging was done at 4.7 T, using fast gradient echo T₂¹ weighted imaging and intravenous injection of gadolinium-BOPTA/Dimeglumine. During occlusion, the areas showing a blood volume change were predominantly within the middle cerebral artery territory and could be divided into areas showing either CBV increases or decreases. The area with decreased blood volume also had decreased blood flow as measured by our flow-based index (p < 0.05) and was located in the central territory of the middle cerebral artery. Peripheral to this region was an area showing increased blood volume but without significant CBF changes (p > 0.05). During reperfusion, the CBF increased in the entire zone showing changes in blood volume during occlusion, and remained significantly elevated until 45 min post-occlusion, while CBV remained elevated in the hyperemic rim for at least 2 h. The presence of a peri-ischemic zone showing flow/volume mismatch identified a region wherein baseline CBF is maintained by means of compensatory vasodilatation, but where the ratio of CBF to CBV is decreased. Dynamic susceptibility contrast magnetic resonance imaging with gadolinium-BOPTA/Dimeglumine may be a valuable technique for the investigation of regional and temporal perturbations of hemodynamics during ischemia and reperfusion.     

Three-vessel study of cerebral blood flow using phase-contrast magnetic resonance imaging: Effect of physical characteristics

The development of phase-contrast magnetic resonance imaging (P-C MRI) provides a noninvasive method for measurement of volumetric blood flow (VFR). We performed P-C MRI to study the effects of physical characteristics on cerebral blood flow. VFR of the left and right internal carotid arteries and basilar artery were measured using P-C MRI and total cerebral blood flow (tCBF) was calculated by summing up the VFR values in the three vessels. Moreover, we investigated the changes in these blood flows as influenced by age, head size, height, weight, body surface area, and handedness. The blood flows were 142 ± 58 ml/min (mean ± standard deviation) in the basilar artery; and 229 ± 86 ml/min in the left, and 223 ± 58 ml/min in the right internal carotid artery; and tCBF was 617 ± 128 ml/min. Significant increases were observed in head size-related change of VFR in the basilar artery (p = .028) and height-related change of tCBF (p = .045). The other characteristics did not significantly influence any VFR. The results suggest that head size and height may reflect CBF, and that these effects should be considered when changes of CBF are diagnosed. Phase-contrast MRI is useful for a noninvasive and rapid analysis of cerebral VFR and has potential for clinical use.     

Assessment of clinical data of nonlinear stochastic deconvolution versus block-circulant singular value decomposition for quantitative dynamic susceptibility contrast magnetic resonance imaging

Dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) allows the noninvasive assessment of brain hemodynamics alterations by quantifying, via deconvolution, the cerebral blood flow (CBF) and mean transit time (MTT). Singular value decomposition (SVD) and block-circulant SVD (cSVD) are the most widely adopted deconvolution method, although they bear some limitations, including unphysiological oscillations in the residue function and bias in the presence of delay and dispersion between the tissue and the arterial input function. A nonlinear stochastic regularization (NSR) has been proposed, which performs better than SVD and cSVD on simulated data both in the presence and absence of dispersion. Moreover, NSR allows to quantify the dispersion level. Here, cSVD and NSR are compared for the first time on a group of nine patients with severe atherosclerotic unilateral stenosis of internal carotid artery before and after carotid stenting to investigate the effect of arterial dispersion. According to region of interest-based analysis, NSR characterizes the pathologic tissue more accurately than cSVD, thus improving the quality of the information provided to physicians for diagnosis. In fact, in 7 (78%) of the 9 subjects, CBF and MTT maps provided by NSR allow to correctly identify the pathologic hemisphere to the physician. Moreover, by emphasizing the difference between pathologic and healthy tissues, NSR may be successfully used to monitor the subject's recovery after the treatment and/or surgery. NSR also generates dispersion level and non-dispersed CBF and MTT maps. The dispersion level provides information on CBF and MTT estimates reliability and may also be used as a clinical indicator of pathological tissue state complementary to CBF and MTT, thus increasing the clinical information provided by DSC-MRI analysis.     

A multimodality investigation of cerebral hemodynamics and autoregulation in pharmacological MRI

Pharmacological MRI (phMRI) methods have been widely applied to assess the central hemodynamic response to pharmacological intervention as a surrogate for changes in the underlying neuronal activity. However, many psychoactive drugs can also affect cardiovascular parameters, including arterial blood pressure (BP). Abrupt changes in BP or the anesthetic agents used in preclinical phMRI may impair cerebral blood flow (CBF) autoregulation mechanisms, potentially introducing confounds in the phMRI response. Moreover, relative cerebral blood volume (rCBV), often measured in small-animal phMRI studies, may be sensitive to BP changes even in the presence of intact autoregulation. We applied laser Doppler flowmetry and MRI to measure changes in CBF and microvascular CBV induced by increasing doses of intravenous norepinephrine (NE) challenge in the halothane-anesthetized rat. NE is a potent vasopressor that does not cross the blood-brain barrier and mimics the rapid BP changes typically observed with acute drug challenges. We found that CBF autoregulation was maintained over a BP range of 60-120 mmHg. Under these conditions, no significant central rCBV responses were observed, suggesting that microvascular rCBV changes in response to abrupt changes in perfusion pressure are negligible within the autoregulatory range. Larger BP responses were accompanied by significant changes in both CBV and CBF that might confound the interpretation of phMRI results.     

基于功能近红外光谱技术(fNIRs)的帕金森病大鼠模型脑组织特性研究

利用功能近红外光谱技术(functionality near infrared spectroscopy,fNIRs)探索帕金森病(parkin-son's disease,PD)大鼠模型的脑组织功能特性.通过小动物磁共振(magnetic resonance imaging,MRI)和电子计算机断层扫描(computed tomography,CT)对PD大鼠模型进行影像学研究,用fNIRs系统测试大鼠模型脑组织纹状体特征参数.实验结果表明,PD大鼠脑部没有明显的形态结构变化;优化散射系数(reduced scattering coefficient:μ's)、脑血容量(cerobral bloodvolume:CBV)在PD大鼠的纹状体部与对照组间存在显著的差别;fNIRs测量参数(μ's、CBV)与CT灌注(CTP)测定参数[CBF(cerebral blood flow),CBV]之间存在相关性.这些结果表明fNIRs可以作为PD研究的重要参考手段.     

Study of cerebrovascular reserve capacity by magnetic resonance perfusion weighted imaging and photoacoustic imaging

The aim of this work was to assess the feasibility of photoacoustic imaging (PAI) and MR imaging for evaluating the cerebrovascular reserve capacity (CVRC) in animal models. Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHR) were used for MRI. BALB/c mice were used for PAI. MR perfusion weighted imaging (PWI) was performed on a 1.5-T whole-body MR system before and after oral administration of acetazolamide (ACZ). The region of interest (ROI) was chosen in the bilateral frontal lobe for measuring regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV) and mean transit time (MTT). The vessel diameters of the superficial layer of the cortex were measured by PAI in the resting and ACZ-activated mice. The results showed that there was a statistical difference between the resting and ACZ-activated animals in vessel diameter, rCBV and rCBF values. The increments in rCBV and rCBF of WKY rats between resting and ACZ test states were significantly higher than that of SHR. The pathological findings of small arterial walls and lumen of the brain were also different between WKY and SHR rats. The diameters of blood vessels in the superficial layer of the brain measured by PAI were enlarged after the ACZ tolerance test. This result was also observed in the MRI CBV map, where the signal of the vessel in the superficial layer of the cortex became redder after the ACZ stimulation, suggesting the increase of blood flow. It can be concluded that MR PWI and PAI combined with the ACZ test might be useful in evaluating the CVRC and revealing the pathologic changes in cerebral vessels.     

Why perfusion in neonates with congenital heart defects is negative--technical issues related to pulsed arterial spin labeling

Pulsed arterial spin labeling (PASL) perfusion MRI has unique advantages for measuring cerebral blood flow (CBF) in the pediatric population. In neonates with congenital heart defects (CHDs), however, a considerable number of negative CBF values were observed in PASL perfusion images. A set of specific physiological and biophysical conditions were proposed as plausible explanations for this phenomenon, including small body size, low blood flow, prolonged tracer life time (blood T1) and the "shunt" between pulmonary and systemic circulations in CHD. An optimized PASL scheme with a restricted label volume was proposed, and experimental data demonstrated reduced spurious negative values and lower intersubject variability of perfusion measurements in neonates with CHD as compared to standard PASL sequences.     

A comparison study between the saturation-recovery-T1 and CASL MRI methods for quantitative CBF imaging

The saturation-recovery (SR)-T₁ MRI method for quantitatively imaging cerebral blood flow (CBF) change (ΔCBF) concurrently with the blood oxygenation level dependence (BOLD) alteration has been recently developed and validated by simultaneous measurement of relative CBF change using laser Doppler flowmetry (LDF) in rats at 9.4T. In this study, ΔCBF induced by mildly transient hypercapnia and measured by the SR-T₁ MRI method was rigorously compared with an established perfusion MRI method—continuous arterial spin labeling (CASL) approach in normal and preclinical middle cerebral artery occlusion (MCAo) rat models. The results show an excellent agreement between ΔCBF values measured with these two imaging methods. Moreover, the intrinsic longitudinal relaxation rate (R₁^int) was experimentally determined in vivo in normal rat brains at 9.4T by comparing two independent measures of the apparent longitudinal relaxation rate (R₁^app) and CBF measured by the CSAL approach across a wide range of perfusion. In turn, the R₁^int constant can be employed to calculate the CBF value based on the R₁^app measurement in healthy brain. This comparison study validates the fundamental relationship for linking brain tissue water R₁^app and cerebral perfusion, demonstrates the feasibility of imaging and quantifying both CBF and its change using the SR-T₁ MRI method in vivo.     

MRI based diffusion and perfusion predictive model to estimate stroke evolution.

In this study we present a novel automated strategy for predicting infarct evolution, based on MR diffusion and perfusion images acquired in the acute stage of stroke. The validity of this methodology was tested on novel patient data including data acquired from an independent stroke clinic. Regions-of-interest (ROIs) defining the initial diffusion lesion and tissue with abnormal hemodynamic function as defined by the mean transit time (MTT) abnormality were automatically extracted from DWI/PI maps. Quantitative measures of cerebral blood flow (CBF) and volume (CBV) along with ratio measures defined relative to the contralateral hemisphere (r(a)CBF and r(a)CBV) were calculated for the MTT ROIs. A parametric normal classifier algorithm incorporating these measures was used to predict infarct growth. The mean r(a)CBF and r(a)CBV values for eventually infarcted MTT tissue were 0.70 +/- 0.19 and 1.20 +/- 0.36. For recovered tissue the mean values were 0.99 +/- 0.25 and 1.87 +/- 0.71, respectively. There was a significant difference between these two regions for both measures (p < 0.003 and p < 0.001, respectively). Mean absolute measures of CBF (ml/100g/min) and CBV (ml/100g) for the total infarcted territory were 33.9 +/- 9.7 and 4.2 +/- 1.9. For recovered MTT tissue, the mean values were 41.5 +/- 7.2 and 5.3 +/- 1.2, respectively. A significant difference was also found for these regions (p < 0.009 and p < 0.036, respectively). The mean measures of sensitivity, specificity, positive and negative predictive values for modeling infarct evolution for the validation patient data were 0.72 +/- 0.05, 0.97 +/- 0.02, 0.68 +/- 0.07 and 0.97 +/- 0.02. We propose that this automated strategy may allow possible guided therapeutic intervention to stroke patients and evaluation of efficacy of novel stroke compounds in clinical drug trials.     

Pharmacokinetic analysis of glioma compartments with dynamic Gd-DTPA-enhanced magnetic resonance imaging

Dynamic contrast-enhanced magnetic resonance imaging (MRI) is widely used for measuring perfusion and blood volume, especially cerebral blood volume (CBV). In case of blood-brain barrier (BBB) disruption, the conventional techniques only partially determine the pharmacokinetic parameters of contrast medium (CM) exchange between different compartments. Here a modified pharmacokinetic model is applied, which is based on the bidirectional CM exchange between blood and two interstitial compartments in terms of the fractional volumes of the compartments and the vessel permeabilities between them. The evaluation technique using this model allows one to quantify the fractional volumes of the different compartments (blood, cells, slowly and fast enhancing interstitium) as well as the vessel permeabilities and cerebral blood flow (CBF) with a single T1-weighted dynamic MRI measurement. The method has been successfully applied in 25 glioma patients for generating maps of all of these parameters. The fractional volume maps allow for the differentiation of glioma vascularization types. The maps show a good correlation with the histological grading of these tumors. Furthermore, regions with enhanced interstitial volumes are found in high-grade gliomas. Differences in permeability maps of Gd-DTPA apart from BBB disruption do not exist between different tissue types. CBF measured in high-grade glioma is less pronounced than it would be expected from their blood volume. Therefore pharmacokinetic imaging provides an additional tool for glioma characterization.     

Impaired functionality of reperfused brain tissue following short transient focal ischemia in rats

Functional magnetic resonance imaging (fMRI) has been applied to study the consequences of transient focal ischemia on neuronal excitability in the rat brain. The experimental paradigm consisted of measuring the changes in local cerebral blood volume (CBV) induced by systemic infusion of the GABA(A) antagonist bicuculline after occlusion of the middle cerebral artery (MCA) for durations of 5, 15, 30 and 60 min using the intraluminal thread model. fMRI studies were carried out 60 min after successful reperfusion of the ischemic territory. Bicuculline-induced dynamic changes in local CBV were assessed in three brain regions: Parietal cortex, caudate putamen and thalamus. The measured CBV response was negatively correlated with the ischemia duration. Additionally, the three regions showed different vulnerability to the transient MCA occlusion, caudate being the most susceptible followed by parietal cortex and thalamus. The fMRI signals weakly correlated with basal CBF and CBV following reperfusion. Our results indicate that fMRI is a sensitive method to assess functional integrity of the brain. Activation maps allow to quantitatively assess the functionally compromized territory at an early stage following the ischemic event prior to the manifestation of pathomorphological changes.     

Effects of blood ΔR2* non-linearity on absolute perfusion quantification using DSC-MRI: Comparison with Xe-133 SPECT

Purpose

To evaluate whether a non-linear blood ΔR₂*-versus-concentration relationship improves quantitative cerebral blood flow (CBF) estimates obtained by dynamic susceptibility contrast (DSC) MRI in a comparison with Xe-133 SPECT CBF in healthy volunteers.

Material and Methods

Linear as well as non-linear relationships between ΔR₂* and contrast agent concentration in blood were applied to the arterial input function (AIF) and the venous output function (VOF) from DSC-MRI. To reduce partial volume effects in the AIF, the arterial time integral was rescaled using a corrected VOF scheme.

Results

Under the assumption of proportionality between the two modalities, the relationship CBF(MRI) = 0.58CBF(SPECT) (r = 0.64) was observed using the linear relationship and CBF(MRI) = 0.51CBF(SPECT) (r = 0.71) using the non-linear relationship.

Discussion

A smaller ratio of the VOF time integral to the AIF time integral and a somewhat better correlation between global DSC-MRI and Xe-133 SPECT CBF estimates were observed using the non-linear relationship. The results did not, however, confirm the superiority of one model over the other, potentially because realistic AIF signal data may well originate from a combination of blood and surrounding tissue.     

Near-infrared spectroscopy extended with indocyanine green dye dilution for cerebral blood flow measurement: Median values in healthy volunteers

The cerebral blood flow (CBF) is an important vital parameter in neurointensive care. Currently, there is no non-invasive method for its measurement that can easily be applied at the bedside. A new tool to determine CBF is based on near-infrared spectroscopy (NIRS) applied together with indocyanine green (ICG) dye dilution. From a bilateral measurement on selected regions on the head of infrared (IR) absorption at various wavelengths during the dilution maneuver, the vascular perfusion characteristics of the two brain hemispheres can be determined in terms of mean transit time (mtt) of ICG, cerebral blood volume (CBV) and CBF. So far, on nine healthy volunteers, NIRS ICG dye dilution bihemispheric measurements were performed, which yielded to mtt given as median (range) of 9.3 s (5.1–16.3 s), CBV of 3.5 ml/100 g (1.7–4.1 ml/100 g), and CBF of 18.2 ml/(100 g×min) [11.1–48.6 ml/(100 g×min)]. Additionally, the blood flow index (BFI) was calculated with BFI= 13.8 mg/(100 g×s) [6.6–15.2 mg/(100 g×s)]. The Spearman rank correlation coefficient between CBF and BFI was R_S = 0.76. However, as the Bland & Altman plot between CBFNIRS and the CBF_BFI documents, the limits of agreement are rather wide (21.9±6.7). Under physiological conditions in healthy volunteers, no differences could be detected between the hemispheres.     

Analysis of tracer transit in rat brain after carotid artery and femoral vein administrations using linear system theory

Determination of tissue perfusion rates by MRI bolus tracking methods relies on the central volume principle which states that tissue blood flow is given by the tissue blood volume divided by the mean tracer transit time (MTT). Accurate determination of the MTT requires knowledge of the arterial input function which in MRI experiments is usually not known, especially when using small animals. The problem of unknown arterial input can be circumvented in animal experiments by directly injecting the contrast agent into a feeding artery of the tissue of interest. In the present article the passage of magnetite nanoparticles through the rat cerebral cortex is analyzed after injection into the internal carotid artery. The results are discussed in the framework of linear system theory using a one-compartment model for brain tissue and by using the well characterized γ-variate function to describe the tissue concentration profile of the contrast agent. The results obtained from the intra-arterial tracer administration experiments are then compared with the commonly used intra-venous injection of the contrast agent in order to estimate the contribution of the peripheral circulation to the MTT values in the latter case. The experiments were analyzed using a two-compartment model and the γ-variate function. As an application perfusion rates in normal and ischemic cerebral cortex of hypertensive rats were estimated in a model of focal cerebral ischemia. The results indicate that peripheral circulation has a significant influence on the MTT values and thus on the perfusion rates, which cannot be neglected.     

Comparison of MR perfusion imaging and microsphere measurements of regional cerebral blood flow in a rat model of middle cerebral artery occlusion

The purpose of this investigation was to correlate magnetic resonance (MR) perfusion measurements with absolute regional cerebral blood flow (rCBF) in a rat model of focal ischemia. The MR perfusion measurements were made using dynamic first-pass bolus tracking of a susceptibility contrast agent, whereas rCBF was measured using radioactive microspheres. Two simple MR perfusion parameters, the maximum change in ( ) and time delay to ( ), were derived from the signal intensity versus time curves on a pixel-to-pixel basis, without applying curve-fitting procedures or tracer kinetic theory. In each hemisphere, and were compared with the rCBF measurements in four selected regions of interest. Sixteen MR bolus tracking series were performed in 12 rats with occlusion of the middle cerebral artery. In all of the individual series there was a significant correlation (.0001 ≤ p ≤ .02) between and the microsphere rCBF measurements, with correlation coefficients ranging from .784 to .983. Pooling the data resulted in a correlation coefficient of .809 (p = .0001). There was a nonlinear correlation between the and rCBF. For both parameters there was considerable variation between different measurements regarding both the slope of the regression line and its intercept with the y-axis. Our results justify the use of as a relative measure of perfusion during acute cerebral ischemia. Because of the interindividual variation, calibration of MR perfusion measurements for the estimation of absolute flow values must be considered unreliable. The may have physiological relevance as a marker of collateral flow.     

Direct measurement of oxygen extraction with fMRI using 6% CO2 inhalation

The blood-oxygenation-level-dependent (BOLD) signal is an indirect hemodynamic signal that is sensitive to cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen. Therefore, the BOLD signal amplitude and dynamics cannot be interpreted unambiguously without additional physiological measurements, and thus, there remains a need for a functional magnetic resonance imaging (fMRI) signal, which is more closely related to the underlying neuronal activity. In this study, we measured CBF with continuous arterial spin labeling, CBV with an exogenous contrast agent and BOLD combined with intracortical electrophysiological recording in the primary visual cortex of the anesthetized monkey. During inhalation of 6% CO2, it was observed that CBF and CBV are not further increased by a visual stimulus, although baseline CBF for 6% CO2 is below the maximal value of CBF. In contrast, the electrophysiological response to the stimulation was found to be preserved during hypercapnia. As a consequence, the simultaneously measured BOLD signal responds negatively to a visual stimulation for 6% CO2 inhalation in the same voxels responding positively during normocapnia. These observations suggest that the fMRI response to a sensory stimulus for 6% CO2 inhalation occurs in the absence of a hemodynamic response, and it therefore directly reflects oxygen extraction into the tissue.