Safety and performance of TCI pumps in a magnetic resonance imaging environment.

Target controlled infusion (TCI) devices can be associated with significant safety concerns when used during magnetic resonance imaging (MRI). We tested the safety and compatibility of newer TCI systems in a 3-Tesla MRI environment. Two Asena PK and two Agilia TCI pumps were used to administer TCI propofol (at target blood concentrations of 0.5 and 6.0 µg.ml⁻¹) using the Marsh model under magnetic fields of up to 50 G with a T2-weighted sequence. We assessed the devices for projectile risk, accuracy of drug delivery, alarm function and effects on MR image quality. Both devices did not demonstrate any significant deflection at the tested field strengths, and performed within acceptable limits (cumulative error in total delivered volume < 3%; maximum 10-min interval error < 10%). The Asena pump caused minor artefacts on MR images. The TCI pumps tested perform well and safely implement pharmacokinetic software in a high magnetic field.

Use of magnetic resonance imaging for anatomical phenotyping of the R6/2 mouse model of Huntington's disease.

Huntington's disease (HD) is a fatal, inherited neurodegenerative CAG disorder characterized by marked brain atrophy. We used magnetic resonance imaging (MRI) with manual volumetry for three dimensional (3D) morphological phenotyping of ex vivo brains of R6/2 mice, the most commonly used model of HD. High resolution 3D images were acquired for 18 week old wild-type (WT) and R6/2 mice. Although overall brain volumes were the same between genotypes, decreases in volumes were found in the cortex and striatum of R6/2 mice, with significant volume increases in the lateral ventricles and globus pallidus. There was no change in the volume of the amygdala, internal capsule or hippocampal formation. There was a significant increase in signal intensity in the globus pallidus, amygdala, cortex and striatum in R6/2 mice that may reflect neuronal atrophy. This study clearly shows the potential of MRI for morphological phenotyping of rodent models of HD and other neurological diseases. Having obtained proof-of-principle for the technique using ex vivo tissue, it is now our intention to carry out in vivo measurement of developing pathology in HD transgenic mice, and correlate this with behavioral deficits.

Voxel-based morphometry in the R6/2 transgenic mouse reveals differences between genotypes not seen with manual 2D morphometry.

The R6/2 mouse is the most common mouse model used for Huntington's disease (HD), a fatal, inherited neurodegenerative CAG disorder characterized by marked brain atrophy. We scanned 47 R6/2 transgenic and 42 wildtype (WT) ex vivo mouse brains at 18 weeks of age using high resolution, three-dimensional magnetic resonance imaging (MRI) for automated voxel-based morphometry (VBM) analysis. We found differences between genotypes in specific brain structures. Many of these changes were bilateral and were found in regions known to be involved in the behavioral deficits present in both R6/2 mice and HD patients. In particular, changes were evident in the basal ganglia, hippocampus, cortex and hypothalamus. In the striatum, changes were heterogenous and reminiscent of striosomal distribution. Changes were also seen in the cerebellum, as might be expected in a mouse carrying a repeat length typical of juvenile onset HD. Many of these changes were not detected by manual 2D morphometry from the same MR images. These data indicate that VBM will be a valuable technique for in vivo measurement of developing pathology in HD transgenic mice, and may be particularly useful for correlating histologically undetectable changes with behavioral deficits.

T2*-weighted MRI versus oxygen extraction fraction PET in acute stroke.

BACKGROUND: Mapping high oxygen extraction fraction (OEF) in acute stroke is of considerable interest to depict the at-risk tissue. Being sensitive to deoxyhemoglobin, T2*-weighted MRI has been suggested as a potential marker of high OEF. METHODS: We compared T2*-weighted images from pre-contrast arrival perfusion scans against quantitative positron emission tomography in 5 patients studied 7-21 h after onset of carotid territory stroke. OEF and T2* signal were obtained in the voxels with significantly high OEF. RESULTS: All patients showed increased OEF. No significant relationship between OEF and T2*-weighted signal was found either within or between subjects. CONCLUSION: We found no indication that T2*-weighted MRI in the way implemented in this investigation was sensitive to high OEF in acute stroke.

Responses of human frontal cortex to surprising events are predicted by formal associative learning theory.

Learning depends on surprise and is not engendered by predictable occurrences. In this functional magnetic resonance imaging (fMRI) study of causal associative learning, we show that dorsolateral prefrontal cortex (DLPFC) is associated specifically with the adjustment of inferential learning on the basis of unpredictability. At the outset, when all associations were unpredictable, DLPFC activation was maximal. This response attenuated with learning but, subsequently, activation here was evoked by surprise violations of the learned association. Furthermore, the magnitude of DLPFC response to a surprise event was sensitive to the relationship that had been learned and was predictive of subsequent behavioral change. In short, the physiological response properties of right DLPFC satisfied specific predictions made by associative learning theory.

Improved delineation of glioma margins and regions of infiltration with the use of diffusion tensor imaging: an image-guided biopsy study.

BACKGROUND AND PURPOSE: The efficacy of radiation therapy, the mainstay of treatment for malignant gliomas, is limited by our inability to accurately determine tumor margins. As a result, despite recent advances, the prognosis remains appalling. Because gliomas preferentially infiltrate along white matter tracks, methods that show white matter disruption should improve this delineation. In this study, results of histologic examination from samples obtained from image-guided brain biopsies were correlated with diffusion tensor images. METHODS: Twenty patients requiring image-guided biopsies for presumed gliomas were imaged preoperatively. Patients underwent image-guided biopsies with multiple biopsies taken along a single track that went into normal-appearing brain. Regions of interest were determined from the sites of the biopsies, and diffusion tensor imaging findings were compared with glioma histology. RESULTS: Using diffusion tissue signatures, it was possible to differentiate gross tumor (reduction of the anisotropic component, q > 12% from contralateral region), from tumor infiltration (increase in the isotropic component, p > 10% from contralateral region). This technique has a sensitivity of 98% and specificity of 81%. T2-weighted abnormalities failed to identify the margin in half of all specimens. CONCLUSION: Diffusion tensor imaging can better delineate the tumor margin in gliomas. Such techniques can improve the delineation of the radiation therapy target volume for gliomas and potentially can direct local therapies for tumor infiltration.

Development of a combined microPET-MR system.

As evidenced by the success of PET-CT, there are many benefits from combining imaging modalities into a single scanner. The combination of PET and MR offers potential advantages over PET-CT, including improved soft tissue contrast, access to the multiplicity of contrast mechanisms available to MR, simultaneous imaging and fast MR sequences for motion correction. In addition, PET-MR is more suitable than PET-CT for cancer screening due to the elimination of the radiation dose from CT. A key issue associated with combining PET and MR is the fact that the performance of the photomultiplier tubes (PMTs) used in conventional PET detectors is degraded in the magnetic field required for MR. Two approaches have been adopted to circumvent that issue: retention of conventional, magnetic field-sensitive PMT-based PET detectors by modification of other features of the MR or PET system, or the use of new, magnetic field-insensitive devices in the PET detectors including avalanche photo-diodes (APDs) and silicon photomultipliers (SiPMs). Taking the former approach, we are assembling a modified microPET Focus 120 within a gap in a novel, 1T superconducting magnet. The PMTs are located in a low magnetic field (approximately 30mT) through a combination of magnet design and the use of fiber optic 'bundles'. Two main features of the modified PET system have been tested, namely the effect of using long fiber optic bundles in the PET detector, and the impact of magnetic field upon the performance of the position sensitive PMTs. The design of a modified microPET-MR system for small animal imaging is completed, and assembly and testing is underway.

Physiological thresholds for irreversible tissue damage in contusional regions following traumatic brain injury.

Cerebral ischaemia appears to be an important mechanism of secondary neuronal injury in traumatic brain injury (TBI) and is an important predictor of outcome. To date, the thresholds of cerebral blood flow (CBF) and cerebral oxygen utilization (CMRO(2)) for irreversible tissue damage used in TBI studies have been adopted from experimental and clinical ischaemic stroke studies. Identification of irreversibly damaged tissue in the acute phase following TBI could have considerable therapeutic and prognostic implications. However, it is questionable whether stroke thresholds are applicable to TBI. Therefore, the aim of this study was to determine physiological thresholds for the development of irreversible tissue damage in contusional and pericontusional regions in TBI, and to determine the ability of such thresholds to accurately differentiate irreversibly damaged tissue. This study involved 14 patients with structural abnormalities on late-stage MRI, all of whom had been studied with (15)O PET within 72 h of TBI. Lesion regions of interest (ROI) and non-lesion ROIs were constructed on late-stage MRIs and applied to co-registered PET maps of CBF, CMRO(2) and oxygen extraction fraction (OEF). From the entire population of voxels in non-lesion ROIs, we determined thresholds for the development of irreversible tissue damage as the lower limit of the 95% confidence interval for CBF, CMRO(2) and OEF. To test the ability of a physiological variable to differentiate lesion and non-lesion tissue, we constructed probability curves, demonstrating the ability of a physiological variable to predict lesion and non-lesion outcomes. The lower limits of the 95% confidence interval for CBF, CMRO(2) and OEF in non-lesion tissue were 15.0 ml/100 ml/min, 36.7 mumol/100 ml/min and 25.9% respectively. Voxels below these values were significantly more frequent in lesion tissue (all P < 0.005, Mann-Whitney U-test). However, a significant proportion of lesion voxels had values above these thresholds, so that definition of the full extent of irreversible tissue damage would not be possible based upon single physiological thresholds. We conclude that, in TBI, the threshold of CBF below which irreversible tissue damage consistently occurs differs from the classical CBF threshold for stroke (where similar methodology is used to define such thresholds). The CMRO(2) threshold is comparable to that reported in the stroke literature. At a voxel-based level, however (and in common with ischaemic stroke), the extent of irreversible tissue damage cannot be accurately predicted by early abnormalities of any single physiological variable.

Enhanced visualization and quantification of magnetic resonance diffusion tensor imaging using the p:q tensor decomposition.

Many scalar measures have been proposed to quantify magnetic resonance diffusion tensor imaging (MR DTI) data in the brain. However, only two parameters are commonly used in the literature: mean diffusion (D) and fractional anisotropy (FA). We introduce a visualization technique which permits the simultaneous analysis of an additional five scalar measures. This enhanced diversity is important, as it is not known a priori which of these measures best describes pathological changes for brain tissue. The proposed technique is based on a tensor transformation, which decomposes the diffusion tensor into its isotropic (p) and anisotropic (q) components. To illustrate the use of this technique, diffusion tensor imaging was performed on a healthy volunteer, a sequential study in a patient with recent stroke, a patient with hydrocephalus and a patient with an intracranial tumour. Our results demonstrate a clear distinction between different anatomical regions in the normal volunteer and the evolution of the pathology in the patients. In the normal volunteer, the brain parenchyma values for p and q fell into a narrow band with 0.976

Imaging of cerebral blood flow and metabolism in brain injury in the ICU.

The heterogeneity of the initial insult and subsequent pathophysiology has made both the study of human head injury and design of randomised controlled trials exceptionally difficult. The combination of multimodality bedside monitoring and functional brain imaging positron emission tomography (PET) and magnetic resonance (MR), incorporated within a Neurosciences Critical Care Unit, provides the resource required to study critically ill patients after brain injury from initial ictus through recovery from coma and rehabilitation to final outcome. Methods to define cerebral ischemia in the context of altered cerebral oxidative metabolism have been developed, traditional therapies for intracranial hypertension re-evaluated and bedside monitors cross-validated. New modelling and analytical approaches have been developed.

A comparison of the early development of ischaemic damage following permanent middle cerebral artery occlusion in rats as assessed using magnetic resonance imaging and histology.

Recent developments in diffusion-weighted imaging (DWI) have enabled the pathological changes that occur during cerebral ischaemia to be studied. The present studies utilised DWI to investigate the development of early ischaemic changes following permanent middle cerebral artery (MCA) occlusion in the rat, which represents a model of stroke. An increased DWI signal was seen in the region of the occluded MCA and this was detectable as early as 1 h postocclusion. DWI images were obtained at nine stereotactic levels throughout the brain, providing a quantifiable measure of the volume of increased signal intensity in each animal. At 1 h post-MCA occlusion the hyperintense areas were seen in the frontoparietal cortex and lateral caudate nucleus; these areas represent the core of the infarct and no protection is seen with any compounds in these areas. There was a progressive increase in the area of hyperintensity up to 4 h post-MCA occlusion, and at this time point the hyper-intensity was seen in the dorsolateral cortex and caudate nucleus. At 4 h post-MCA occlusion there was a significant correlation between the volume of hemispheric and cortical ischaemic damage measured using DWI and histology. Thus, it appears that the increased DWI signal seen during the early time points after MCA occlusion was demarcating tissue that was destined for infarction. The area beyond the hyperintense region at 1 h represents the so-called "penumbral" region, because with increasing time (post-MCA occlusion) this area became incorporated into the infarct. There was also a slight increase in infarct size between 4 and 24 h, when assessed using DWI or histology, although two groups of animals were being compared, as opposed to the time-course study, in which just one group of animals was used. At 24 h post-MCA occlusion there was a good correlation between DWI, histology, and conventional T2 weighted imaging. There was no further increase in size of the infarct between 24 h and 7 days as assessed using histology and T2-weighted imaging. DWI could not be used to quantify infarct volume at 7 days because there was no uniform signal in the damaged area. At 7 days the area of infarction actually appeared to be darker in the diffusion-weighted images. The hyperintensity seen in diffusion-weighted images appears to decrease some time between 24 h and 7 days.(ABSTRACT TRUNCATED AT 400 WORDS)

Linear coupling between functional magnetic resonance imaging and evoked potential amplitude in human somatosensory cortex.

The interpretation of task-induced functional imaging of the brain is critically dependent on understanding the relationship between observed blood flow responses and the underlying neuronal changes. However, the exact nature of this neurovascular coupling relationship remains unknown. In particular, it is unclear whether blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) responses principally reflect neuronal synaptic activity. In order to address this issue directly in humans, we measured the increase in somatosensory evoked potential amplitude and fMRI BOLD changes to increases in intensity of median nerve electrical stimulation in five healthy non-anaesthetized subjects. We found that mean N20-P22 amplitudes increased significantly with stimulus intensity in all subjects, as did fMRI BOLD percentage signal intensity change. Moreover, the intensity of the BOLD signal was found to correlate linearly with evoked potential amplitude in four of the five subjects studied. This suggests that the BOLD response correlates with synchronized synaptic activity, which is the major energy consuming process of the cortex.

Magnetic resonance imaging protocol optimization for evaluation of hyaline cartilage in the distal interphalangeal joint of fingers.

RATIONALE AND OBJECTIVES: To identify a single magnetic resonance imaging (MRI) protocol that will provide optimal signal-to-noise ratio, resolution, and image contrast with minimal susceptibility artifacts and that will allow clear delineation and visualization of cartilage, fluid, bone, tendons, and ligaments within the distal interphalangeal (DIP) joint of the human hand. METHODS: A highly optimized 2.4 T MRI system was constructed from a 31-cm horizontal bore magnet, using a solenoid radiofrequency coil. This was used to study the DIP joints of 16 healthy, asymptomatic volunteers. RESULTS: A range of image contrast protocols were explored, including spin-echo T1 and T2, field echo, chemical shift suppression to give water only images, and magnetization transfer. Susceptibility variations were explored by changing the field strength from 0.6 to 2.4 T. A spin-echo protocol with TR = 1500 msec and TE = 30 msec can routinely produce images with resolution 0.075 x 0.150 for a slice thickness of 1 mm in 13 minutes. That protocol can visualize simultaneously compact and trabecular bone, two layers of cartilage, synovial fluid, and synovium within the joint, tendons and ligaments, and the volar plate. CONCLUSIONS: Although the contrast is not fully optimized for any one tissue, the spin echo protocol (TR = 1500, TE = 30) provides sagittal MR images, which clearly delineate the major structures of interest within the DIP joint, and which will be used in future studies to compare changes in the DIP joint because of aging or osteoarthritis. Experience gained by applying the above methods to a total of 16 healthy, asymptomatic volunteers has enabled a single sequence to be identified, which although not optimized for any one tissue, nevertheless visualized simultaneously and clearly delineated compact and trabecular bone, two layers of cartilage, synovial fluid, and synovium within the joint.

Evaluation of an MRI-based protocol for cell implantation in four patients with Huntington's disease.

The purpose of this study was to evaluate our surgical protocol for the preparation and delivery of suspensions of fetal tissue into the diseased human brain. We implanted suspensions of human fetal striatal anlage into the right caudate and putamen of four patients with Huntington's disease. Postoperative 3 tesla MR imaging confirmed accurate graft placement. Variability in graft survival was noted and the MR signal changes over 6 months revealed persistent hyperintense signal on T2-weighted images. Our results are consistent with those described by other groups and indicate that our surgical protocol is safe, accurate, and reproducible.

A comparative study of acquisition schemes for diffusion tensor imaging using MRI.

This study has investigated the effects of the selection of the diffusion-weighted (DW) gradient directions on the precision of a diffusion tensor imaging (DTI) experiment. The theoretical analysis provided a quantitative framework in which the noise performance of DTI schemes could be assessed objectively and for the development of novel DTI schemes, which employ multiple DW gradient directions. This generic framework was first applied to the examination of two commonly used DTI schemes, which employed 6 DW gradient directions and hitherto were used indiscriminately under the sole condition of noncollinearity. It was then used to design and assess a novel 12-DW-gradient-direction DTI protocol, which employed the same total number of DW acquisitions as the two conventional schemes (12). This theoretical investigation was then corroborated using rigorous simulation and DTI experiments on both an isotropic phantom and a healthy human brain. Both the theoretical and the experimental analysis demonstrated that the two conventional schemes showed a significantly different noise performance and that use of the new multiple-DW-gradient-direction scheme clearly improved the precision of the DTI measurements.

Visualization by magnetic resonance imaging of focal cartilage lesions in the excised mini-pig knee.

This study showed that magnetic resonance imaging can be used to visualize partial thickness cartilage lesions, 0.7 x 10 mm in area and 0.5 mm in depth, surgically induced in the femur (femoropatellar compartment) of a mini-pig knee joint. Formalin-fixed joints, intact as well as disarticulated, were studied by high resolution imaging using a 2.35 T, 31 cm horizontal-bore superconducting magnet. The two-dimensional and three-dimensional spatial resolutions achievable were as follows: 0.12 x 0.23 mm (two-dimensional) and 0.35 x 0.35 x 0.35 mm (three-dimensional) for the intact joint, and 0.08 x 0.08 mm (two-dimensional) and 0.14 x 0.14 x 0.27 mm (three-dimensional) for the disarticulated joint. These results demonstrate that magnetic resonance imaging, together with edge detection and volume rendering, can be used to visualize focal cartilage lesions.

Serial MRI, functional recovery, and long-term infarct maturation in a non-human primate model of stroke.

We have examined the effects of permanent middle cerebral artery occlusion (pMCAO) in marmoset monkeys over 5 months, using behavioural and magnetic resonance imaging (MRI) techniques. Three marmosets were trained on behavioural tests before pMCAO. Shortly after surgery, these marmosets were scanned with T2-weighted (T2W) and diffusion-weighted (DW) MRI. Three, 10 and 20 weeks after surgery, these marmosets were re-tested on the behavioural tasks and had further MRI sessions to monitor lesion development. This was followed by histological analysis. All these marmosets had a persistent contralesional motor deficit and a spatial neglect which resolved over the 20 weeks of testing. Percentage infarct volume assessed by MRI on the day of surgery and at 20 weeks matched the percentage infarct volume measured histologically at 20 weeks. However, the apparent infarct size at 3 weeks was considerably less than that measured by histological analysis or that measured at the other MRI time points. Additional histological analysis of the brains of two further marmosets removed 3 weeks after pMCAO found considerable infiltration by lipid filled macrophages into the ischaemic zone which may have caused an MRI "fogging" effect leading to an apparent reduction in infarct volume.

Magnetic resonance imaging compatibility testing of intracranial pressure probes. Technical note.

There is increasing recognition that magnetic resonance (MR) imaging and spectroscopy may provide important information in the assessment of patients with acute brain injury. However, optimum care of the acutely head injured patient requires monitoring of intracranial pressure (ICP). Although many monitoring modalities have been integrated into commercially available MR-compatible systems, there have been no reports of commonly used intraparenchymal ICP sensors in an MR environment. The authors describe the use of an ICP micromanometer probe in an MR environment, with a fiberoptic connection that interfaces the probe with a commercially available MR-compatible monitoring system. Phantom studies were performed to demonstrate the safety and compatibility of the modified MR system at 0.5 tesla. The safety of the device was assessed in relation to its interaction with the static, gradient, and radiofrequency fields used in MR imaging. The MR compatibility was documented by demonstrating that its performance was unaffected by the operation of imaging sequences and by showing that there was no degradation of the diagnostic quality of imaging data obtained during ICP monitoring.

Geometrical models of left ventricular contraction from MRI of the normal and spontaneously hypertensive rat heart.

This study develops a quantitative analysis and model for the differences in left ventricular dynamics in normal and spontaneously hypertensive rats, as determined using non-invasive magnetic resonance imaging (MRI). We emerge with a characterization of the geometrical changes in the left ventricle resulting from hypertension. In addition, the techniques we have adopted are potentially applicable to the study of other disease models for important human cardiac pathologies. A gradient-echo multislice imaging sequence (echo time 4.3 ms) achieved complete image coverage of the heart at high time resolution (13 ms) through the cardiac cycle. Cardiac anatomy in two age-matched groups of young adult (8 and 12 weeks old) normal Wistar-Kyoto (WKY, n = 8) and spontaneously hypertensive rats (SHR, n = 8) was imaged in synchrony with the electrocardiographic R wave in defined planes both parallel and perpendicular to the principal cardiac axis. The transverse left ventricular image sections were circularly symmetrical; this permitted application of different analytical models for the three-dimensional geometry of the epi- and endocardial borders. An ellipsoidal figure of revolution offered an effective description of the three-dimensional left ventricular geometry throughout the cardiac cycle in both normal WKY and SHR animals. The model successfully characterized both the dynamic changes in the shape of the left ventricle through the cardiac cycle and the pathological alterations resulting from spontaneous hypertension. The elliptical model also formed the basis of a simple stress distribution analysis. Such parametric descriptions thus provided a useful alternative to more complex finite element analyses of cardiac function. The eccentricity of the ventricle was characterized by an ellipticity factor a, where a = 1 for a sphere and a < 1 for a prolate ellipsoid. At end systole, the endocardial surface of the left ventricle gave a = 0.43+/-0.02 and 0.49+/-0.02 for the WKY and SHR animals respectively (probability, P < 0.05). At end diastole, the endocardial surface of the left ventricle gave a = 0.58+/-0.02 and 0.63+/-0.02 for the WKY and SHR animals respectively (P < 0.05). Such a difference in ventricular shape was a potential adaptation to increased blood pressure. Hypertension thus altered the left ventricular ellipticity to give a more spherical geometry compared with the normal rats.

Potential role of NovoSeven in the prevention of rebleeding following aneurysmal subarachnoid haemorrhage.

Rebleeding following aneurysmal subarachnoid haemorrhage is a major factor contributing to unfavourable outcome. Antifibrinolytic agents reduce the rate of rebleeding but increase the risk of cerebral ischaemia and infarction and hence provide no overall benefit. To address the theoretical concern that recombinant activated factor VII (NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) might increase the risk of cerebral ischaemia while stabilizing the clot at the site of aneurysmal rupture, an open-label, dose-escalation safety study has been developed in collaboration with the UK Spontaneous Intracranial Haemorrhage Group. The trial design includes the recruitment of 15 patients (aged 18 years or over) in good grade with subarachnoid haemorrhage verified by computerized tomography scan or lumbar puncture. Safety evaluation includes clinical observation, monitoring of laboratory variables, positron emission tomography (PET) scanning (rCBF, rOEF, rCMRO2) and transcranial Doppler ultrasound. To date, ten patients have been recruited [NovoSeven 80 microg/kg single bolus (n = 2), NovoSeven 80 microg/kg single bolus followed by continuous infusion at 3.5 microg/kg per h (n = 2) or 7 microg/kg per h (n = 1), or control (n = 5)]. Clinical observation, transcranial Doppler ultrasound and PET studies revealed no evidence of cerebral ischaemia in the first nine patients treated with NovoSeven. The last patient developed middle cerebral artery branch thrombosis contralateral to the aneurysm. The study is currently suspended pending further investigation.