Functional magnetic resonance (fMR) imaging of a rat brain tumor model: implications for evaluation of tumor microvasculature and therapeutic response

Functional MR (fMR) imaging techniques based on blood oxygenation level dependent (BOLD) effects were developed and applied to a rat brain tumor model to evaluate the potential utility of the method for characterizing tumor growth and regression following treatment. Rats bearing 9L brain tumors in situ were imaged during inhalation of room air and after administration of 100% oxygen + acetazolamide (ACZ) injected 15 mg/kg intravenously. Pixel-to-pixel fMR maps of normalized signal intensity change from baseline values were calculated from T2 weighted spin echo (SE) images acquired pre- and post- oxygen + ACZ administration. Resultant fMR maps were then compared to gross histological sections obtained from corresponding anatomical regions. Regions containing viable tumor with increased cellular density and localized foci of necrotic tumor cells consistent with hypoxia were visualized in the fMR images as regions with decreased signal intensities, indicating diminished oxyhemoglobin concentration and blood flow as compared to normal brain. Histological regions having peritumor edema, caused by increased permeability of tumor vasculature, were visualized in the fMR images as areas with markedly increased signal intensities. These results suggest that fMR imaging techniques could be further developed for use as a non-invasive tool to assess changes in tumor oxygenation/hemodynamics, and to evaluate the pharmacologic effect of anti-neoplastic drugs.     

Changes in intratumor heterogeneity in blood perfusion in intradermal human melanoma xenografts during tumor growth assessed by DCE-MRI

The purpose of this study was to use dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to search for systematic intratumor heterogeneity in blood perfusion in human melanoma xenografts growing intradermally in BALB/c-nu/nu mice. Six xenografted tumors of an amelanotic human melanoma line (A-07) were included in the study. DCE-MRI was performed daily for 5 days by using spoiled-gradient recalled sequences. Tumor images of E.F (E is initial extraction fraction and F is perfusion) were produced by subjecting DCE-MRI data to Kety analysis. E.F was used as a measure of tumor blood perfusion, since comparative studies have shown that E.F is closely related to blood perfusion in A-07 tumors. The E.F images indicated that the intratumor heterogeneity in blood perfusion was similar in all investigated tumors. The blood perfusion was low in the center of the tumors and increased toward the tumor periphery in the dorsal and ventral direction by a factor of 3-4, but not in the lateral and medial direction. The magnitude of the heterogeneity increased by a factor of approximately 2 during tumor growth. In conclusion, intradermal human melanoma xenografts show significant systematic intratumor heterogeneity in blood perfusion.     

Effects of hyperthermia on bioenergetic status and phosphorus T1S in human melanoma xenografts monitored by 31P-MRS.

Conventional hyperthermia enhances tumor response to radiotherapy through thermal cell inactivation and vascular shut-down, whereas mild hyperthermia potentiates the effect of radiotherapy by improving tumor oxygenation. The work reported here was aimed at investigating whether 31P-magnetic resonance spectroscopy (31P-MRS) measurements of tumor bioenergetic status; i.e., the (PCr + NTPbeta)/Pi resonance ratio, and/or the spin lattice relaxation times, T1s, of the Pi and NTPbeta resonances can be used to distinguish between the effects of conventional and mild hyperthermia. BEX-t human melanoma xenografts were treated at 43.0 degrees C for 15 or 60 min, and bioenergetic status and T1s were measured as function-of-time after treatment. Hyperthermia-induced effects on tumor blood flow was measured by using the 86Rb uptake method. The morphology of the capillary network in treated and untreated tumors was studied by histologic examination. Tumors treated for 15 min showed increased blood flow and dilated capillaries, whereas tumors treated for 60 min showed decreased blood flow and capillary occlusions; i.e., 43.0 degrees C for 15 min was a treatment consistent with mild hyperthermia and 43.0 degrees C for 60 min was consistent with conventional hyperthermia treatment of BEX-t tumors. Bioenergetic status increased after treatment at 43.0 degrees C for 15 min, and decreased after treatment at 43.0 degrees C for 60 min, similar to the blood flow. Likewise, the T1 of the Pi resonance increased after treatment at 43.0 degrees C for 15 min, and decreased after treatment at 43.0 degrees C for 60 min. The T1 of the NTPbeta resonance showed a similar change as the T1 of the Pi resonance, but less pronounced. Consequently, 31P-MRS measurements of tumor bioenergetic status and the T1 of the Pi resonance may perhaps be utilized to distinguish between vascular effects of mild and conventional hyperthermia.     

Effect of vasodilator hydralazine on tumor microvascular random flow and blood volume as measured by intravoxel incoherent motion (IVIM) weighted MRI in conjunction with Gd-DTPA-Albumin enhanced MRI.

We studied the effect of hydralazine on tumor blood volume fraction and microvascular random flow velocity magnitude by IVIM weighted MRI in conjunction with dynamic Gd-DTPA-Albumin enhanced MRI. Blood volume fraction maps were obtained from the dynamic Gd-DTPA-Albumin enhanced MRI measurements. The average blood volume fraction of R3230 AC adenocarcinoma decreased from 0.125 +/- 0.022 (s.d.) ml/g to 0.105 +/- 0.018 (s.d.) ml/g (p < 0.001) after the administration of hydralazine at a dose of 5 mg/kg. The microvascular random flow velocity magnitude maps were obtained from the IVIM weighted MRI signals by utilizing the Gd-DTPA-Albumin measured blood volume fractions as an input in the compartmental modeling analysis of the IVIM weighted MRI signal. The random-directional microvascular flow induced MRI signal attenuation was separated from the molecular diffusion induced signal attenuation. Flow induced attenuation was more significant after the administration of hydralazine. The mean microvascular random flow velocity magnitude increased from 0.52 +/- 0.15 (s.d.) mm/sec to 0.73 +/- 0.23 (s.d.) mm/sec (p < 0.05) in the presence of the above blood volume fraction change.     

Effects of cocaine on blood flow and oxygen metabolism in the rat brain: implications for phMRI

The effects of cocaine on cerebral blood flow and tissue oxygen levels in the rat brain were investigated with concurrent laser Doppler flowmetry and fluorescence quenching spectroscopy. Responses elicited by mild hypercapnia were used as calibration to assess the effects of cocaine on oxidative metabolism. Intravenous cocaine challenge of 0.5 mg/kg induced significant increases in tissular oxygenation and perfusion in all regions investigated (primary motor cortex, medial prefrontal cortex and dorsal striatum). Mild hypercapnia, a challenge that affects haemodynamics but not metabolism, elicited comparable changes in blood flow but substantially larger changes in tissue oxygen levels. These differences in tissue oxygen build-up suggest that increased oxidative metabolism is a significant component of the cerebral metabolic response to acute cocaine challenge. The implications for the interpretation of pharmacological MRI data are discussed.     

Dynamic contrast-enhanced MRI of vascular changes induced by the VEGF-signalling inhibitor ZD4190 in human tumour xenografts

Dynamic contrast-enhanced magnetic resonance imaging (DCEMRI) was used to examine the acute effects of treatment with an inhibitor of vascular endothelial growth factor (VEGF) signaling. ZD4190 is an orally bioavailable inhibitor of VEGF receptor-2 (KDR) tyrosine kinase activity, which elicits broad-spectrum antitumour activity in preclinical models following chronic once-daily dosing. Nude mice, bearing established (0.5-1.0 mL volume) human prostate (PC-3), lung (Calu-6) and breast (MDA-MB-231) tumor xenografts, were dosed with ZD4190 (p.o.) using a 1 day (0 and 22 h) or 7 day (0, 24, 48, 72, 96,120,144, and 166 h) treatment regimen. DCEMRI was employed 2 h after the last dose of ZD4190, using the contrast agent gadopentetate dimeglumine. Dynamic data were fit to a compartmental model to obtain voxelwise K(trans), the transfer constant for gadopentetate into the tumor. K(trans) was averaged over the entire tumor, and a multi-threshold histogram analysis was also employed to account for tumor heterogeneity. Reductions in K(trans) reflect reductions in flow, in endothelial surface area, and/or in vascular permeability. A vascular input function was obtained for each mouse simultaneously with the tumor DCEMRI data. ZD4190 treatment produced a dose-dependent (12.5-100 mg x kg(-1) per dose) reduction in K(trans) in PC-3 prostate tumors. At 100 mg x kg(-1), the largest concentration examined, ZD4190 reduced K(trans) in PC-3 tumors by 31% following 2 doses (1 day treatment regimen; p < 0.001) and by 53% following 8 doses (7 day regimen; p < 0.001). Comparative studies in the three models using a showed similar reductions in K(trans) for the lung and breast tumors using the histogram analysis, although the statistical significance was lost when K(trans) was averaged over the entire tumor. Collectively these studies suggest that DCEMRI using gadopentetate may have potential clinically, for monitoring inhibition of VEGF signaling in solid tumors.     

Measurement of the extracellular volume of human melanoma xenografts by contrast enhanced magnetic resonance imaging

The magnitude of the extracellular volume fraction (ECV) of tumors is of importance for the transport of macromolecular therapeutic agents from the vessel wall to the tumor cells. The aim of this study was to develop a method for measurement of tumor ECV by contrast enhanced MRI. Tumors of two human amelanotic melanoma xenograft lines (A-07 and R-18) grown intradermally in Balb/c nu/nu mice were used as model system, and muscle tissue was used as control. The renal arteries of the mice were ligated prior to i.v. administration of Gd-DTPA, and an MRI protocol for calculating Gd-DTPA concentration in tissue was followed. ECV was calculated from the Gd-DTPA concentrations in the tissue and in a plasma sample. In muscle tissue, the concentration reached a constant level after 1 min and the ECV was calculated to be 0.12 (+/- 0.01), consistent with values reported in the literature. Individual tumors showed large differences in the uptake of Gd-DTPA. The Gd-DTPA concentration in the tissue at 40 min after the Gd-DTPA administration was used to calculate tumor ECV. The ECV was found to differ significantly among regions of individual tumors and among individual tumors. The ECV ranged from 0.075 to 0.33 for A-07 tumors and from 0.016 to 0.097 for R-18 tumors. The intra- and intertumor heterogeneity in ECV was confirmed by histologic findings, showing that contrast enhanced MRI is suitable for non-invasive studies of the ECV in experimental tumors without necrosis.     

BOLD MRI response to hypercapnic hyperoxia in patients with meningiomas: correlation with Gadolinium-DTPA uptake rate

Because meningiomas tend to recur after (partial) surgical resection, radiotherapy is increasingly being applied for the treatment of these tumors. Radiation dose levels are limited, however, to avoid radiation damage to the surrounding normal tissue. The radiosensitivity of tumors can be improved by increasing tumor oxygen levels. The aim of this study was to investigate if breathing a hyperoxic hypercapnic gas mixture could improve the oxygenation of meningiomas. Blood oxygen level-dependent magnetic resonance imaging and dynamic Gadolinium (Gd)-DTPA contrast-enhanced MRI were used to assess changes in tumor blood oxygenation and vascularity, respectively. Ten meningioma patients were each studied twice; without and with breathing a gas mixture consisting of 2% CO(2) and 98% O(2). Values of T(2)* and the Gd-DTPA uptake rate k(ep) were calculated under both conditions. In six tumors a significant increase in the value of T(2)* in the tumor was found, suggesting an improved tumor blood oxygenation, which exceeded the effect in normal brain tissue. Contrarily, two tumors showed a significant T(2)* decrease. The change in T(2)* was found to correlate with both k(ep) and with the change in k(ep). The presence of both vascular effects and oxygenation effects and the heterogeneous response to hypercapnic hyperoxia necessitates individual assessment of the effects of breathing a hyperoxic hypercapnic gas mixture on meningiomas. Thus, the current MRI protocol may assist in radiation treatment selection for patients with meningiomas.     

Simultaneous measurement of perfusion and oxygenation changes using a multiple gradient-echo sequence: application to human muscle study

We have developed a magnetic resonance imaging (MRI) technique based on a multiple gradient-echo sequence designed to probe perfusion and oxygenation simultaneously within skeletal muscle. Processing of the images acquired at successive echo times (TEs) generates two functional maps: one of the signal intensity (SI) extrapolated to zero echo time, which is sensitive to perfusion; and a second one of R21, which reflects oxygenation. An advantage of the processing procedure lies in the selection of tissue of interest through the profile of T₂1 decay, leading to automatic rejection of pixels containing small vessels. This allows a more specific assessment of tissue perfusion and oxygenation. This technique was demonstrated successfully during post-ischemic reactive hyperemia in human calf. A perfusion peak of 123 mL ×100 g⁻¹ × min⁻¹ was measured immediately after ischemia, whereas R21 value showed an 11.5% decrease at the same time, essentially reflecting blood oxygenation changes. Differences in the time courses of reperfusion and re-oxygenation were observed, oxygenation presenting a slower recovery. The mechanisms responsible for such a differential dynamic response are discussed.     

Quantitative assessment of intracranial tumor response to dexamethasone using diffusion, perfusion and permeability magnetic resonance imaging

There is increasing interest in obtaining quantitative imaging parameters to aid in the assessment of tumor responses to treatment. In this study, the feasibility of performing integrated diffusion, perfusion and permeability magnetic resonance imaging (MRI) for characterizing responses to dexamethasone in intracranial tumors was assessed. Eight patients with glioblastoma, five with meningioma and three with metastatic carcinoma underwent MRI prior to and 48-72 h following dexamethasone administration. The MRI protocol enabled quantification of the volume transfer constant (K(trans)), extracellular space volume fraction (nu(e)), plasma volume fraction (nu(p)), regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), longitudinal relaxation time (T(1)) and mean diffusivity (D(av)). All subjects successfully completed the imaging protocol for the presteroid and poststeroid scans. Significant reductions were observed after the treatment for K(trans), nu(e) and nu(p) in enhancing tumor as well as for T(1) and D(av) in the edematous brain in glioblastoma; on the other hand, for meningioma, significant differences were seen only in edematous brain T(1) and D(av). No significant difference was observed for any parameter in metastatic carcinoma, most likely due to the small sample size. In addition, no significant difference was observed for enhancing tumor rCBF and rCBV in any of the tumor types, although the general trend was for rCBV to be reduced and for rCBF to be more variable. The yielded parameters provide a wealth of physiologic information and contribute to the understanding of dexamethasone actions on different types of intracranial tumors.     

Effects of different levels of hypercapnic hyperoxia on tumour R(2)* and arterial blood gases

The hypercapnia induced by carbogen (95% O(2)/5% CO(2)) breathing, which is being re-evaluated as a clinical radiosensitiser, causes patient discomfort and hence poor compliance. Recent preclinical and clinical studies have indicated that the CO(2) content might be lowered without compromising increased tumour oxygenation and radiosensitisation. This preclinical study was designed to see if lower levels of hypercapnia could evoke similar decreases in the transverse relaxation rate R(2)* of rodent tumours to those seen with carbogen breathing. The response of rat GH3 prolactinomas to 1%, 212% and 5% CO(2) in oxygen, and 100% O(2) breathing, was monitored by non-invasive multi-gradient echo MRI to quantify R(2)*. As the oxygenation of haemoglobin is proportional to the blood p(a)O(2) and therefore in equilibrium with tissue pO(2), R(2)* is a sensitive indicator of tissue oxygenation. Hyperoxia alone decreased R(2)* by 13%, whilst all three hypercapnic hyperoxic gases decreased R(2)* by 29%. Breathing 1% CO(2) in oxygen evoked the same decrease in R(2)* as carbogen. The DeltaR(2)* response is primarily consistent with an increase in blood oxygenation, though localised increases in tumour blood flow were also identified in response to hypercapnia. The data support the concept that levels of hypercapnia can be reduced without loss of enhanced oxygenation and hence potential radiotherapeutic benefit.     

Reduced capillary perfusion and permeability in human tumour xenografts treated with the VEGF signalling inhibitor ZD4190: an in vivo assessment using dynamic MR imaging and macromolecular contrast media

We describe the use of perfusion-permeability magnetic resonance imaging (ppMRI) to study hemodynamic parameters in human prostate tumor xenografts, following treatment with the vascular endothelial growth factor-A (VEGF) receptor tyrosine kinase inhibitor, ZD4190. Using a macromolecular contrast agent (P792), a fast MR imaging protocol and a compartmental data analysis, we were able to demonstrate a significant simultaneous reduction in tumor vascular permeability, tumor vascular volume and tumor blood flow (43%, 30% and 42%, respectively) following ZD4190 treatment (100 mg/kg orally, 24 h and 2 h prior to imaging). This study indicates that MR imaging can be used to measure multiple hemodynamic parameters in tumors, and that tumor vascular permeability, volume and flow, can change in response to acute treatment with a VEGF signaling inhibitor.     

Thymidine-modulated 5-fluorouracil metabolism in liver and RIF-1 tumors studied by 19F magnetic resonance spectroscopy.

19F Magnetic resonance spectroscopy was used to study the impact of the biochemical modulator thymidine (TdR) on the 5-fluorouracil (5FU) metabolism in the livers and radiation-induced fibrosarcoma (RIF-1) tumors of 5FU-treated C3H mice. The liver spectra measured after administration of 5FU (65 or 130 mg/kg IP) showed the 5 FU resonance and its catabolites alpha-fluoro-beta-ureidopropionic acid and alpha-fluoro-beta-alanine. At the latter dose, fluoronucleotide signal was also detected. The liver spectra of TdR-pretreated (500 mg/kg, IP) mice showed additional signals of fluoronucleotide and fluoronucleoside at both 5FU doses, while alpha-fluoro-beta-alanine was not detected. TdR pretreatment increased the half-life of 5FU in livers from 24 +/- 2 to 126 +/- 46 SEM min at the 5FU dose of 65 mg/kg and from 28 +/- 2 to 95 +/- 22 min at the 130 mg/kg dose (P less than .1 and P less than .01, respectively). TdR-pretreated mice had higher 5FU anabolite (fluoronucleotide + fluoronucleoside) levels in their RIF-1 tumors than nonpretreated mice that received the same 5FU doses (56 +/- 15 SEM vs. 0 arbitrary units at the 5FU dose of 65 mg/kg, and 88 +/- 21 vs. 10 +/- 3 arbitrary units at 130 mg/kg 5FU; P less than .0001). The percentage drop in tumor volume was enhanced in the mice that received TdR, from 27 +/- 4 SEM to 52 +/- 2 at the 5 FU dose of 65 mg/kg and from 24 +/- 3 to 65 +/- 4 at the 130-mg/kg dose (P less than .0001, both).     

Intravenous administration of Gd-DTPA prior to DWI does not affect the apparent diffusion constant

MRI measurements of water diffusion and blood perfusion are increasingly used for the evaluation of organ functionality and tissue viability (e.g., in tumors). While diffusion-weighted imaging is performed without contrast agents, measurement of blood perfusion is normally performed based on the administration of paramagnetic substances such as gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA). Simultaneous measurements of these two parameters are often preferred. However, it may be argued that Gd-DTPA causes constriction of small blood vessels or alters hemodynamic parameters such as blood viscosity, thereby corrupting subsequent measurements of the apparent diffusion constant (ADC). The objective of the current study was to investigate the possible changes in the ADC in tumors following intravenous administration of 0.2 and 0.4 mmol/kg of Gd-DTPA in mice. The study was conducted with C3H mouse mammary carcinomas inoculated in the right foot of the animal subjects. The results were compared with findings in a sham group, demonstrating that Gd-DTPA had no significant impact on the ADC as measured in a 7-T animal system.     

Influence of Passive Stretching on Inhibition of Disuse Atrophy and Hemodynamics of Rat Soleus Muscle

The purpose of this study was to determine the influence of passive stretching on inhibition of disuse atrophy and hemodynamics among longitudinal regions of the rat soleus muscle. Disuse muscle atrophy was induced by hindlimb suspension for two weeks. Muscle blood flow was evaluated using thallium-201 (²⁰¹Tl) which is a radiotracer that has been reported to be useful to assess blood perfusion in skeletal muscle. Thirty-nine male Wistar rats were divided randomly into 5 groups: control (C: n = 10), a group with hindlimb suspension (HS: n = 7), a group with hindlimb suspension and stretching (ST: n = 7), a group receiving only a single session of stretching after the hindlimb suspension period that was killed just after stretching (HSB: n = 7), and a group receiving only a single session of stretching hindlimb suspension and stretching period that was killed just after stretching (STB: n = 8). From the results of the cross-sectional area (CSA) and the capillary-to-fiber ratio (C/F), muscle atrophy and inhibition of atrophy were shown more in proximal than in distal regions of experimental groups. These results suggest that the alterations of the C/F and CSA were different among muscle regions in experimental groups. These differences may depend on the level of stretching. Moreover, alteration of blood flow resulting from alteration of the mechanical environment had little influence on muscle atrophy or inhibition of atrophy.     

Intratumor heterogeneity in perfusion in human melanoma xenografts measured by contrast-enhanced magnetic resonance imaging

The perfusion in tumors shows substantial spatial heterogeneity compared to that in normal tissues. The aim of the present study was to evaluate the intratumor heterogeneity in perfusion in tumors of two amelanotic human melanoma xenograft lines, A-07 and R-18, grown intradermally in Balb/c nu/nu mice. A non-invasive contrast-enhanced magnetic resonance imaging method yielding results in absolute values was applied. The perfusion was determined in manually defined regions of interest, corresponding to a whole tumor or to subregions of a tumor. The mean perfusion and the intertumor heterogeneity in perfusion were similar for the two tumor lines. For whole A-07 tumors, the perfusion ranged from 0.089 mL/(g . min) to 0.20 mL/(g . min) [mean: 0.15 mL/(g . min)], and for whole R-18 tumors, from 0.030 mL/(g . min) to 0.17 mL/(g . min) [mean: 0.13 mL/(g . min)]. The intratumor heterogeneity, on the other hand, was estimated to be 6.4 times larger in A-07 tumors than in R-18 tumors. The highest perfusion values, up to 0.69 mL/(g . min), were found in subregions of A-07 tumors. The intratumor heterogeneity was substantially larger than the intertumor heterogeneity in A-07 tumors, whereas in R-18 tumors, the intratumor heterogeneity was similar to the intertumor heterogeneity. These observations imply that measurements of mean tumor perfusion may have limited value as a predictive assay for outcome of treatment.     

Biexponential analysis of intravoxel incoherent motion in calf muscle before and after exercise: Comparisons with arterial spin labeling perfusion and T2

PurposeThis study aimed to clarify exercise-induced changes in intravoxel incoherent motion (IVIM) parameters obtained from diffusion-weighted imaging (DWI) of the calf muscle, as well as the relationships between IVIM parameters, perfusion, and water content in muscle tissue.Materials and methodsThirteen healthy volunteers underwent IVIM-DWI, arterial spin labeling (ASL), and multi-echo spin-echo T₂ mapping of the right calf on a 3.0-T magnetic resonance imaging scanner before and after performing dorsiflexion exercise. From the data, we derived the perfusion-related diffusion coefficient (D^⁎), perfusion component fraction (F), blood flow parameter (FD^⁎), and restricted diffusion coefficient (D) in the tibialis anterior muscle. The muscle blood flow (MBF) and transverse relaxation time (T₂) were also calculated from the ASL and multi-echo spin-echo data, respectively. We compared the parameters measured before and after exercise and assessed the relationship of each IVIM-derived perfusion parameter (D^⁎, F, and FD^⁎) with MBF and each diffusion parameter (D and ADC) or F with T₂.ResultsNotably, all these parameters were significantly increased after exercise. Before exercise, the FD^⁎ exhibited a significant positive correlation with the MBF, whereas no significant correlation was observed between D^⁎ or F and MBF. After exercise, both D^⁎ and FD^⁎ exhibited significant positive correlations with MBF, whereas F was not significantly correlated with MBF. Additionally, D was significantly correlated with T₂ after exercise, but not before exercise. No significant correlations were found between ADC and T₂ either before or after exercise.ConclusionsThe IVIM analyses before and after exercise enable the simultaneous evaluation of exercise-induced changes in perfusion and water diffusion in the muscle and increases the body of information on muscle physiology.     

Mapping of brain activation in response to pharmacological agents using fMRI in the rat

Functional MRI (fMRI) was used to investigate the effects of psychotropic compound activity in the rat brain in vivo. The effects of dizocilpine (MK-801) an N-methyl-D-aspartate receptor antagonist and m-chlorophenylpiperazine (mCPP), a 5-HT(2b/2c)-receptor agonist on rat brain activity were investigated over a time interval of about 1 h and the results were compared to published glucose utilisation and cerebral blood flow data. Signal magnitude increases were observed predominantly in limbic regions following MK-801 administration (0.5 mg/kg i.v) whereas signal decreases were restricted to neocortical areas; a characteristic, time dependent pattern of regional changes evolved from the thalamic nuclei to cortical regions. In contrast, mCPP (25 mg/kg i.p) produced gradual signal intensity increases in limbic and motor regions with signal decreases restricted to the visual, parietal and motor cortices. The results from both compounds show remarkable similarity with autoradiographic measurements of cerebral blood flow and glucose uptake. These experiments suggest that the spatio-temporal capabilities of fMRI may be applied to the in vivo investigation of psychoactive compound activity with potential for clinical applications.     

Simultaneous blood flow and oxygenation measurements using an off-the-shelf spectrometer

Blood oxygenation and flow are both important parameters in a living body. In this Letter, we introduce a simple configuration to simultaneously measure blood flow and oxygenation using an off-the-shelf spectrometer. With the integration time of 10 ms, flow phantom measurements, a liquid blood phantom test, and an arm cuff occlusion paradigm were performed to validate the feasibility of the system. We expect this proof-of-concept study would be widely adopted by other researchers for acquiring both blood flow and oxygenation changes due to its straightforward configuration and the possibility of multimodal measurement.     

Mapping of the cerebral response to acetazolamide using graded asymmetric spin echo EPI

Cerebral vascular reactivity in different regions of the rat brain was quantitatively characterized by spatial and temporal measurements of blood oxygenation level-dependent (BOLD)-fMRI signals following intravenous administration of the carbonic anhydrase inhibitor acetazolamide: this causes cerebral vasodilatation through a cerebral extracellular acidosis that spares neuronal metabolism and vascular smooth muscle function, thus separating vascular and cerebral metabolic events. An asymmetric spin echo-echo planar imaging (ASE-EPI) pulse sequence sensitised images selectively to oxygenation changes in the microvasculature; use of a surface coil receiver enhanced image signal-to-noise ratios (SNRs). Image SNRs and hardware integrity were verified by incorporating quality assurance procedures; cardiorespiratory stability in the physiological preparations were monitored and maintained through the duration of the experiments. These conditions made it possible to apply BOLD contrast fMRI to map regional changes in cerebral perfusion in response to acetazolamide administration. Thus, fMRI findings demonstrated cerebral responses to acetazolamide that directly paralleled the known physiological actions of acetazolamide and whose time courses were similar through all regions of interest, consistent with acetazolamide's initial distribution in brain plasma, where it affects cerebral haemodynamics by acting at cerebral capillary endothelial cells. However, marked variations in the magnitude of the responses suggested relative perfusion deficits in the hippocampus and white matter regions correlating well with their relatively low vascularity and the known vulnerability of the hippocampus to ischaemic damage.