Removing the effects of CSF partial voluming on fitted CBF and arterial transit times using FAIR, a pulsed arterial spin labelling technique.

FAIR, an arterial spin labelling technique, provides non-invasive, quantitative CBF values and arterial transit times deltat. This paper focuses on the negative impact of CSF partial voluming on FAIR results. To understand and solve this problem, we performed a theoretical analysis and a range of simulations. We then acquired FAIR data from a volunteer to illustrate our findings. We found that the determinant effect of CSF is a delayed zero-crossing during inversion recovery. The subtraction of magnitude inversion recovery data in FAIR generates erroneous negative data and distorted fit results: we simulated that for CSF percentages of 0-40%, CBF and deltat will be progressively overestimated by up to 50%. For higher CSF percentages the errors were found to increase steeply. We explored a straightforward solution: taking the magnitude of the FAIR data before fitting. This provided a remarkably strong antidote against the effects of CSF partial voluming: for CSF percentages of 0-40%, simulations now gave CBF values accurate within 1%, and deltat within 5%. The fit remained robust for high CSF fractions. Our analysis and simulations demonstrate that using magnitude FAIR data minimises the detrimental effects of CSF partial voluming. Data from a healthy volunteer illustrate these results.

MR image-guided investigation of regional signal transducers and activators of transcription-1 activation in a rat model of focal cerebral ischemia.

BACKGROUND AND PURPOSE: STAT-1 is a member of a family of proteins called signal transducers and activators of transcription (STATs), and recent studies have shown its involvement in the induction of apoptosis. There is limited information on the role of STAT-1 following stroke. In this study we use MRI measurements of cerebral perfusion and bioenergetic status to target measurements of regional STAT-1 activity. METHODS: Rats were subjected to 60 or 90 min of middle cerebral artery occlusion with and without reperfusion. MRI maps of the apparent diffusion coefficient of water and cerebral blood flow were acquired throughout the study. After the ischemia or reperfusion period, the brain was excised and samples were analyzed by Western blots using anti-phospho-STAT1 and anti-Fas antibodies. Regions were selected for analysis according to their MRI characteristics. RESULTS: Transcriptional factor STAT-1 was enhanced in the lesion core and, to a lesser extent, in the lesion periphery, following ischemia and reperfusion. This level of activity was greater than for ischemia alone. Western blots demonstrated STAT-1 phosphorylation on tyrosine 701 and not serine 727 after ischemia and 3 h of reperfusion. Enhanced expression of the apoptotic death receptor Fas was confirmed after ischemia followed by reperfusion. CONCLUSIONS: This study demonstrates that focal ischemia of the rat brain can induce STAT-1 activation, particularly following a period of reperfusion. The activation occurs not only in the lesion core, but also in the lesion periphery, as identified using MRI. STAT-1 may play an important role in the induction of cell death following stroke.

High field MRI correlates of myelin content and axonal density in multiple sclerosis--a post-mortem study of the spinal cord.

Different MRI techniques are used to investigate multiple sclerosis (MS) in vivo. The pathological specificity of these techniques is poorly understood, in particular their relationship to demyelination and axonal loss. The aim of this study was to evaluate the pathological substrate of high field MRI in post-mortem (PM) spinal cord (SC) of patients with MS. MRI was performed in PMSCs of four MS patients and a healthy subject on a 7 Tesla machine. Quantitative MRI maps (PD; T2; T1; magnetization transfer ratio, MTR; diffusion weighted imaging) were obtained. After scanning, the myelin content and the axonal density of the specimens were evaluated neuropathologically using quantitative techniques. Myelin content and axonal density correlated strongly with MTR, T1, PD, and diffusion anisotropy, but only moderately with T2 and weakly with the apparent diffusion coefficient. Quantitative MR measures provide a promising tool to evaluate components of MS pathology that are clinically meaningful. Further studies are warranted to investigate the potential of new quantitative MR measures to enable a distinction between axonal loss and demyelination and between demyelinated and remyelinated lesions.

High resolution MRI of the brain at 4.7 Tesla using fast spin echo imaging.

Over recent years, high field MR scanners (3 T and above) have become increasingly widespread due to potential advantages such as higher signal-to-noise ratio. However, few examples of high resolution images covering the whole brain in reasonable acquisition times have been published to date and none have used fast spin echo (FSE), a sequence commonly employed for the acquisition of T(2) weighted images at 1.5 T. This is mostly due to the increased technical challenges associated with uniform signal generation and the increasingly restrictive constraints of current safety guidelines at high field. We investigated 10 volunteers using an FSE sequence optimized to the 4.7 T environment. This sequence allows the acquisition of 17- and 34-slice data sets with an in-plane resolution of approximately 500 microm x 500 microm and a slice thickness of 2 mm, in 5 min 40 s and 11 min 20 s, respectively. The images appear T(2) weighted, although the contrast is due to the combined effects of chosen echo time, magnetization transfer, direct radio frequency saturation and diffusion as well as the T(1) and T(2) relaxation times of the tissue. The result is an excellent detailed visualization of anatomical structures, demonstrating the great potential of 4.7 T MRI for clinical applications. This paper shows that, with careful optimization of sequence parameters, FSE imaging can be used at high field to generate images with high spatial resolution and uniform contrast across the whole brain within the prescribed power deposition limits.

Simultaneous noninvasive measurement of CBF and CBV using double-echo FAIR (DEFAIR).

A new method for measuring cerebral blood flow (CBF) and cerebral blood volume (CBV) noninvasively using MRI is presented. The approach is based on the technique of arterial spin labelling (ASL), in which CBF-based contrast is generated by controlled modulation of the longitudinal magnetization of the blood. The proposed method also uses differences in T(2) between tissue and blood to differentiate the two compartments and allow assessment of the relative size of each. Two successive EPI images are acquired following spin preparation using either a slice-selective or global inversion pulse, and the technique is therefore referred to as double-echo FAIR (DEFAIR). DEFAIR is demonstrated in the normal gerbil brain and during hypothermia, where reductions of both CBF and CBV are known to occur. It is also shown theoretically that this method can be extended to include a measurement of oxygen extraction fraction. The main drawbacks of the technique are the long acquisition time and relatively low sensitivity to hemodynamic changes compared to conventional qualitative T2(*)-weighted BOLD contrast, which may limit its applicability and practical use in monitoring functional cerebral activation. However, the technique can be used repetitively in longer-term time course studies due to its noninvasive and quantitative nature.

Acute changes in MRI diffusion, perfusion, T(1), and T(2) in a rat model of oligemia produced by partial occlusion of the middle cerebral artery.

Oligemic regions, in which the cerebral blood flow is reduced without impaired energy metabolism, have the potential to evolve toward infarction and remain a target for therapy. The aim of this study was to investigate this oligemic region using various MRI parameters in a rat model of focal oligemia. This model has been designed specifically for remote-controlled occlusion from outside an MRI scanner. Wistar rats underwent remote partial MCAO using an undersize 0.2 mm nylon monofilament with a bullet-shaped tip. Cerebral blood flow (CBF(ASL)), using an arterial spin labeling technique, the apparent diffusion coefficient of water (ADC), and the relaxation times T(1) and T(2) were acquired using an 8.5 T vertical magnet. Following occlusion there was a decrease in CBF(ASL) to 35 +/- 5% of baseline throughout the middle cerebral artery territory. During the entire period of the study there were no observed changes in the ADC. On occlusion, T(2) rapidly decreased in both cortex and basal ganglia and then normalized to the preocclusion values. T(1) values rapidly increased (within approximately 7 min) on occlusion. In conclusion, this study demonstrates the feasibility of partially occluding the middle cerebral artery to produce a large area of oligemia within the MRI scanner. In this region of oligemic flow we detect a rapid increase in T(1) and decrease in T(2). These changes occur before the onset of vasogenic edema. We attribute the acute change in T(2) to increased amounts of deoxyhemoglobin; the mechanisms underlying the change in T(1) require further investigation.

The measurement of diffusion and perfusion in biological systems using magnetic resonance imaging.

The aim of this review is to describe two recent developments in the use of magnetic resonance imaging (MRI) in the study of biological systems: diffusion and perfusion MRI. Diffusion MRI measures the molecular mobility of water in tissue, while perfusion MRI measures the rate at which blood is delivered to tissue. Therefore, both these techniques measure quantities which have direct physiological relevance. It is shown that diffusion in biological systems is a complex phenomenon, influenced directly by tissue microstructure, and that its measurement can provide a large amount of information about the organization of this structure in normal and diseased tissue. Perfusion reflects the delivery of essential nutrients to tissue, and so is directly related to its status. The concepts behind the techniques are explained, and the theoretical models that are used to convert MRI data to quantitative physical parameters are outlined. Examples of current applications of diffusion and perfusion MRI are given. In particular, the use of the techniques to study the pathophysiology of cerebral ischaemia/stroke is described. It is hoped that the biophysical insights provided by this approach will help to define the mechanisms of cell damage and allow evaluation of therapies aimed at reducing this damage.

Cerebral tissue water spin-spin relaxation times in human neonates at 2.4 tesla: methodology and the effects of maturation.

Using a 4-echo spin-echo sequence, cerebral T2 was measured in specific anatomic regions in eleven healthy newborn infants, whose gestational plus postnatal ages (GPAs) lay between 37 and 42 weeks. For a region in the pons, T2 was 141+/-9 ms (mean +/- standard deviation), and no significant dependence upon GPA was seen. In the thalamus mean T2 was 136+/-13 ms, and T2 demonstrated a significant negative linear dependence upon age (r = 0.690; p < 0.02). In periventricular and frontal regions, mean T2 were 217+/-33, and 228+/-32 ms respectively, and more marked negative linear correlations with age were observed (r = 0.833; p < 0.001 and r = 0.722; p < 0.02). For these regions, the rate of T2 decrease with age appeared to be related to known patterns of myelination. For the parietal region studied, mean T2 was 204+/-34 ms, no significant dependence upon GPA being seen. T2 shows promise as an objective measure of cerebral development in the perinatal period.

R'2 measured in trabecular bone in vitro: relationship to trabecular separation.

Measurement of key parameters of the microstructure of trabecular bone is critical to the study of osteoporosis and bone strength. Density based methods cannot provide this information, and give only the total amount of bone present, and not its arrangement. Magnetic resonance imaging has shown the potential to provide information related to the microarchitecture of the trabecular bone matrix. Twelve samples (8 x 8 x 8 mm3 bone cubes) were cut from sheep vertebrae such that the trabeculae ran either parallel or perpendicular to each face. Detailed measurements of the structure of these bone cubes were made by histomorphometry, and compared to R'2 and R*2 measured with a spin and gradient-echo sequence, Partially Refocused Interleaved Multiple Echo, at 1.5 Tesla. The precision of the R'2 measurement (% coefficient of variation) was 8.7+/-5.1, and 7.7+/-4.3 for R*2. Uncorrected values of R'2 and R*2 were significantly correlated to density measured by quantitative computed tomography (r = 0.87, p = 0.0005, and r = 0.90, p = 0.0002, respectively), and trabecular bone area measured by histomorphometry (r = 0.80, p = 0.002, and r = 0.83, p = 0.0008, respectively). Density correction was effected by imaging the same slice of bone in two orientations (90 degrees and 0 degrees ) to the main magnetic field. For both R'2 and R*2 there was a significant difference between measurements in the 90 degrees and 0 degrees orientations (p < 0.01). The difference between the two values was used, and termed R'2net or R*2net. The net parameters were independent of bone mass. R'2net and R*2net were significantly correlated to trabecular separation (p < 0.05) with r = -0.58 and r = -0.62, respectively. These results demonstrate the ability of magnetic resonance imaging to characterize a key measure of the trabecular microstucture. An increase in trabecular separation has important biomechanical consequences in osteoporosis. This result also strengthens the hypothesis that the sensitivity of R'2 to osteoporosis-related bone changes is due to magnetic susceptibility effects in which rapid transitions between bone and marrow create local magnetic field inhomogeneities that result in an increase in R'2 values.

Reperfusion in a gerbil model of forebrain ischemia using serial magnetic resonance FAIR perfusion imaging.

BACKGROUND AND PURPOSE: Existing methods for the quantitative measurement of the changing cerebral blood flow (CBF) during reperfusion suffer from poor spatial or temporal resolution. The aim of this study was to implement a recently developed MRI technique for quantitative perfusion imaging in a gerbil model of reperfusion. Flow-sensitive alternating inversion recovery (FAIR) is a noninvasive procedure that uses blood water as an endogenous tracer. METHODS: Bilateral forebrain ischemia of 4 minutes' duration was induced in gerbils (n=8). A modified version of FAIR with improved time efficiency was used to provide CBF maps with a time resolution of 2.8 minutes after recirculation had been initiated. Quantitative diffusion imaging was also performed at intervals during the reperfusion period. RESULTS: On initiating recirculation after the transient period of ischemia, the FAIR measurements demonstrated either a symmetrical, bilateral pattern of flow impairment (n=4) or an immediate side-to-side difference that became apparent with respect to the cerebral hemispheres in the imaged slice (n=4). The flow in each hemisphere displayed a pattern of recovery close to the preocclusion level or, alternatively, returned to a lower level before displaying a delayed hypoperfusion and a subsequent slow recovery. The diffusion measurements during this latter response suggested the development of cell swelling during the reperfusion phase in the striatum. CONCLUSIONS: The CBF during the reperfusion period was monitored with a high time resolution, noninvasive method. This study demonstrates the utility of MRI techniques in following blood flow changes and their pathophysiological consequences.

In vivo MRI measurements of bone quality in the calcaneus: a comparison with DXA and ultrasound.

Magnetic resonance imaging (MRI) has shown promise in the assessment of bone architecture. The precision and feasibility of MRI measurements in osteoporosis in vivo have been assessed in this study. T2' was calculated from measurements of T2 and T2* in the calcaneus of 32 postmenopausal women using a gradient-echo sequence PRIME (Partially Refocused Interleaved Multiple Echo). This sequence allows the measurement of T2 and T2* in one acquisition. In vivo measurements of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were made in the calcaneus, spine and femoral neck. The ultrasound parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were also measured in the calcaneus. These three techniques have not previously been compared in the same study population. The precision of the MRI technique was poor relative to the DXA and ultrasound techniques, with a CV of 6.9% +/- 4.4% for T2' and 5.5% +/- 3.6% for T2*. Approximately 4% of this is due to system error as determined by phantom measurements. The postmenopausal women were classified as having low BMD if they had a lumbar spine (L2-4) BMD of less than 0.96 g/cm2 (more than 2 standard deviations below normal peak bone mass). Calcaneal T2' was significantly correlated with calcaneal BMD (r = -0.79, p < 0.0001), BUA (r = -0.59, p = 0.0004) and SOS (r = -0.58, p = 0.0006). T2' was significantly different in postmenopausal women with normal BMD and those with low BMD (p < 0.01). However, the difference was of only borderline significance (p < 0.06) after adjustment for age and years since menopause.

Implementation of quantitative FAIR perfusion imaging with a short repetition time in time-course studies.

Flow-sensitive alternating inversion recovery (FAIR) is a pulsed arterial spin labeling magnetic resonance imaging method for perfusion quantification. In its standard implementation for quantification with full longitudinal relaxation between acquisitions, its use in time-course investigations of rapidly changing flow values is limited. The time efficiency can be improved by decreasing the repetition time but quantification becomes problematic. This situation is further complicated if a whole-body radiofrequency transmit coil is not used since fresh blood spins will flow in from outside the coil. To alleviate these problems, the use of global pre-saturation is proposed. The resulting expression for the flow signal depends on the relationship between the imaging parameters and the coil inflow time and can be significantly simplified under certain combinations of these parameters. With this implementation of FAIR, quantitative flow maps of gerbil brains were obtained with a 3 minute time resolution in a study of the effects of reperfusion. The pre-occlusion flow measurements were in good agreement with values obtained by the standard FAIR implementation and by other techniques, but the low values following occlusion were underestimated due to the increased transit times.

Early changes in water diffusion, perfusion, T1, and T2 during focal cerebral ischemia in the rat studied at 8.5 T.

The time evolution of water diffusion, perfusion, T1, and T2 is investigated at high magnetic field (8.5 T) following permanent middle cerebral artery occlusion in the rat. Cerebral blood flow maps were obtained using arterial spin tagging. Although the quantitative perfusion measurements in ischemic tissue still pose difficulties, the combined perfusion and diffusion data nevertheless distinguish between a "moderately affected area," with reduced perfusion but normal diffusion; and a "severely affected area," in which both perfusion and diffusion are significantly reduced. Two novel magnetic resonance imaging observations are reported, namely, a decrease in T2 and an increase in T1, both within the first few minutes of ischemia. The rapid initial decrease in T2 is believed to be associated with an increase in deoxyhemoglobin levels, while the initial increase in T1 may be related to several factors, such as flow effects, an alteration in tissue oxygenation, and changes in water environment.

Rapid T2* mapping using interleaved echo planar imaging.

Magnetic resonance imaging methods that are sensitive to T2* are widely used in the study of blood oxygenation changes, most notably in functional studies of the brain. In these studies the signal intensity change in T2*-weighted imaging is related to the coupling of cerebral blood flow and metabolism. Rapid measurement of T2* itself would offer a valuable method to quantify blood oxygenation changes indirectly and monitor their time course. An interleaved echoplanar imaging (EPI) sequence is presented here that allows maps of T2* to be generated in a few seconds. The sequence benefits from reduced geometric distortion and an improved point spread function compared with single-shot EPI. A comparison among a set of T2*-weighted interleaved EPI images, single-shot EPI, and conventional gradient-echo and spin-echo methods is made using a compartmentalized doped water phantom. The interleaved sequence yields accurate T2* values when compared with reference measurements made using the slower gradient-echo technique. Data acquired from the rat brain at 2.35 T prior to and during an anoxic challenge show, with high temporal resolution, the reduction in T2* associated with increased levels of deoxyhemoglobin.

Use of mitochondrial inhibitors to demonstrate that cytochrome oxidase near-infrared spectroscopy can measure mitochondrial dysfunction noninvasively in the brain.

The use of near-infrared spectroscopy to measure noninvasively changes in the redox state of cerebral cytochrome oxidase in vivo is controversial. We therefore tested these measurements using a multiwavelength detector in the neonatal pig brain. Exchange transfusion with perfluorocarbons revealed that the spectrum of cytochrome oxidase in the near-infrared was identical in the neonatal pig, the adult rat, and in the purified enzyme. Under normoxic conditions, the neonatal pig brain contained 15 micromol/L deoxyhemoglobin, 29 micromol/L oxyhemoglobin, and 1.2 micromol/L oxidized cytochrome oxidase. The mitochondrial inhibitor cyanide was used to determine whether redox changes in cytochrome oxidase could be detected in the presence of the larger cerebral hemoglobin concentration. Addition of cyanide induced full reduction of cytochrome oxidase in both blooded and bloodless animals. In the blooded animals, subsequent anoxia caused large changes in hemoglobin oxygenation and concentration but did not affect the cytochrome oxidase near-infrared signal. Simultaneous blood oxygenation level-dependent magnetic resonance imaging measurements showed a good correlation with near-infrared measurements of deoxyhemoglobin concentration. Possible interference in the near-infrared measurements from light scattering changes was discounted by simultaneous measurements of the optical pathlength using the cerebral water absorbance as a standard chromophore. We conclude that, under these conditions, near-infrared spectroscopy can accurately measure changes in the cerebral cytochrome oxidase redox state.