Testing the Efficacy of Contrast-Enhanced Ultrasound in Detecting Transplant Rejection Using a Murine Model of Heart Transplantation.

One of the key unmet needs to improve long-term outcomes of heart transplantation is to develop accurate, noninvasive, and practical diagnostic tools to detect transplant rejection. Early intragraft inflammation and endothelial cell injuries occur prior to advanced transplant rejection. We developed a novel diagnostic imaging platform to detect early declines in microvascular perfusion (MP) of cardiac transplants using contrast-enhanced ultrasonography (CEUS). The efficacy of CEUS in detecting transplant rejection was tested in a murine model of heart transplants, a standard preclinical model of solid organ transplant. As compared to the syngeneic groups, a progressive decline in MP was demonstrated in the allografts undergoing acute transplant rejection (40%, 64%, and 92% on days 4, 6, and 8 posttransplantation, respectively) and chronic rejection (33%, 33%, and 92% on days 5, 14, and 30 posttransplantation, respectively). Our perfusion studies showed restoration of MP following antirejection therapy, highlighting its potential to help monitor efficacy of antirejection therapy. Our data suggest that early endothelial cell injury and platelet aggregation contributed to the early MP decline observed in the allografts. High-resolution MP mapping may allow for noninvasive detection of heart transplant rejection. The data presented have the potential to help in the development of next-generation imaging approaches to diagnose transplant rejection.

Design and development of a mobile image overlay system for needle interventions.

Previously, a static and adjustable image overlay systems were proposed for aiding needle interventions. The system was either fixed to a scanner or mounted over a large articulated counterbalanced arm. Certain drawbacks associated with these systems limited the clinical translation. In order to minimize these limitations, we present the mobile image overlay system with the objective of reduced system weight, smaller dimension, and increased tracking accuracy. The design study includes optimal workspace definition, selection of display device, mirror, and laser source. The laser plane alignment, phantom design, image overlay plane calibration, and system accuracy validation methods are discussed. The virtual image is generated by a tablet device and projected into the patient by using a beamsplitter mirror. The viewbox weight (1.0 kg) was reduced by 8.2 times and image overlay plane tracking precision (0.21 mm, STD = 0.05) was improved by 5 times compared to previous system. The automatic self-calibration of the image overlay plane was achieved in two simple steps and can be done away from patient table. The fiducial registration error of the physical phantom to scanned image volume registration was 1.35 mm (STD = 0.11). The reduced system weight and increased accuracy of optical tracking should enable the system to be hand held by the physician and explore the image volume over the patient for needle interventions.

Automatic Segmentation of Breast Carcinomas from DCE-MRI using a Statistical Learning Algorithm.

Segmenting regions of high angiogenic activity corresponding to malignant tumors from DCE-MRI is a time-consuming task requiring processing of data in 4 dimensions. Quantitative analyses developed thus far are highly sensitive to external factors and are valid only under certain operating assumptions, which need not be valid for breast carcinomas. In this paper, we have developed a novel Statistical Learning Algorithm for Tumor Segmentation (SLATS) for automatically segmenting cancer from a region selected by the user on DCE-MRI. In this preliminary study, SLATS appears to demonstrate high accuracy (78%) and sensitivity (100%) in segmenting cancers from DCE-MRI when compared to segmentations performed by an expert radiologist. This may be a useful tool for delineating tumors for image-guided interventions.

Needle artifact localization in 3T MR images.

This work explores an image-based approach for localizing needles during MRI-guided interventions, for the purpose of tracking and navigation. Susceptibility artifacts for several needles of varying thickness were imaged, in phantoms, using a 3 tesla MRI system, under a variety of conditions. The relationship between the true needle positions and the locations of artifacts within the images, determined both by manual and automatic segmentation methods, have been quantified and are presented here.

DTI and MTR abnormalities in schizophrenia: analysis of white matter integrity.

Diffusion tensor imaging (DTI) studies in schizophrenia demonstrate lower anisotropic diffusion within white matter due either to loss of coherence of white matter fiber tracts, to changes in the number and/or density of interconnecting fiber tracts, or to changes in myelination, although methodology as well as localization of such changes differ between studies. The aim of this study is to localize and to specify further DTI abnormalities in schizophrenia by combining DTI with magnetization transfer imaging (MTI), a technique sensitive to myelin and axonal alterations in order to increase specificity of DTI findings. 21 chronic schizophrenics and 26 controls were scanned using Line-Scan-Diffusion-Imaging and T1-weighted techniques with and without a saturation pulse (MT). Diffusion information was used to normalize co-registered maps of fractional anisotropy (FA) and magnetization transfer ratio (MTR) to a study-specific template, using the multi-channel daemon algorithm, designed specifically to deal with multidirectional tensor information. Diffusion anisotropy was decreased in schizophrenia in the following brain regions: the fornix, the corpus callosum, bilaterally in the cingulum bundle, bilaterally in the superior occipito-frontal fasciculus, bilaterally in the internal capsule, in the right inferior occipito-frontal fasciculus and the left arcuate fasciculus. MTR maps demonstrated changes in the corpus callosum, fornix, right internal capsule, and the superior occipito-frontal fasciculus bilaterally; however, no changes were noted in the anterior cingulum bundle, the left internal capsule, the arcuate fasciculus, or inferior occipito-frontal fasciculus. In addition, the right posterior cingulum bundle showed MTR but not FA changes in schizophrenia. These findings suggest that, while some of the diffusion abnormalities in schizophrenia are likely due to abnormal coherence, or organization of the fiber tracts, some of these abnormalities may, in fact, be attributed to or coincide with myelin/axonal disruption.

Future perspectives in intraoperative imaging.

Of all the advances in imaging science in the past twenty years, none has had a greater impact than Magnetic Resonance Imaging. Since its introduction as a diagnostic tool in the mid-1980's, MRI has evolved into the premier neuroimaging modality, and with the addition of higher field magnets, we are able to achieve spatial resolution of such superb quality that even the most exquisite details of the brain anatomy can be visualized. With the implementation of intraoperative, neurosurgical MRI, we can not only monitor brain shifts and deformations; we can achieve intraoperative navigation using intraoperative image updates. In the future, intraoperative MRI can be used not only to localize, target, and resect brain tumors and other lesions but also to fully comprehend the surrounding cortical and white matter functional anatomy. In addition to the inclusion of new imaging methods such as diffusion tensor imaging, new therapeutic methods will be applied. Especially encouraging are the promising results in MRI-guided Focused Ultrasound Surgery, in which the non-invasive thermal ablation of tumors is monitored and controlled by MRI. With the clinical introduction of these advances, intraoperative MRI is changing the face of Neurosurgery today.

Surgical navigation in the open MRI.

The introduction of MRI into neurosurgery has opened multiple avenues, but also introduced new challenges. The open-configuration intraoperative MRI installed at the Brigham and Women's Hospital in 1996 has been used for more than 500 open craniotomies and beyond 100 biopsies. Furthermore the versatile applicability, employing the same principles, is evident by its frequent use in other areas of the body. However, while intraoperative scanning in the SignaSP yielded unprecedented imaging during neurosurgical procedures their usage for navigation proved bulky and unhandy. To be fully integrated into the procedure, acquisition and display of intraoperative data have to be dynamic and primarily driven by the surgeon performing the procedure. To use the benefits of computer-assisted navigation systems together with immediate availability of intraoperative imaging we developed a software package. This "3D Slicer" has been used routinely for biopsies and open craniotomies. The system is stable and reliable. Pre- and intraoperative data can be visualized to plan and perform surgery, as well as to accommodate for intraoperative deformations, "brain shift", by providing online data acquisition.

Non-invasive opening of BBB by focused ultrasound.

Blood brain barrier (BBB) is a major barrier for delivering therapeutic agents in the brain. In this study we investigated the feasibility of open the BBB by using focused ultrasound. Rabbit brains were exposed to pulsed focused ultrasound while injecting ultrasound contrast agent containg microbubbles intravenously. The BBB opening was measured after the sonications by injecting MRI contrast agent i.v. and evaluating the local enhancement in the brain. Low ultrasound powers and pressure amplitudes were found to cause focal enhancement. Before sacrificing the animals trypan blue was also injected i.v.. After the sacrifice of the animals blue spots were found in the brain in the sonicated locations. This method may have potential for targeted delivery of macromolecules in the brain.

Voxel-based morphometric analysis of gray matter in first episode schizophrenia.

Voxel-based morphometry (VBM) may afford a more rapid and extensive survey of gray matter abnormalities in schizophrenia than manually drawn region of interest (ROI) analysis, the current gold standard in structural MRI. Unfortunately, VBM has not been validated by comparison with ROI analyses, nor used in first-episode patients with schizophrenia or affective psychosis, who lack structural changes associated with chronicity. An SPM99-based implementation of VBM was used to compare a group of 16 patients with first-episode schizophrenia and a group of 18 normal controls and, as a further comparison, 16 first-episode patients with affective psychosis. All groups were matched for age and handedness. High spatial resolution structural images were normalized to the SPM99 template and then segmented, smoothed, and subjected to an ANCOVA. Schizophrenia vs control group comparisons: Voxel-by-voxel comparison of gray matter densities showed that only the left STG region was significantly different when corrected for multiple comparisons (P <.05), consistent with our previously reported manual ROI results. Analysis of the extent of voxel clusters, replicated with permutation analyses, revealed group differences in bilateral anterior cingulate gyri and insula (not previously examined by us with manually drawn ROI) and unilateral parietal lobe, but not in medial temporal lobe (where our ROI analysis had shown differences). However, use of a smaller smoothing kernel and a small volume correction revealed left-sided hippocampal group differences. Affective psychosis comparisons: When the same statistical thresholding criteria were used, no significant differences between affective psychosis patients and controls were noted. Since a major interest was whether patients with affective psychosis shared some anatomical abnormalities with schizophrenia, we applied a small volume correction and searched within the regions that were significantly less dense in schizophrenia compared to control subjects. With this statistical correction, the insula showed, bilaterally, the same pattern of differences in affective disorder subjects as that in schizophrenic subjects, whereas both left STG and left hippocampus showed statistical differences between affectives and schizophrenics, indicating the abnormalities specific to first-episode schizophrenia. These findings suggest both the promise and utility of VBM in evaluating gray matter abnormalities. They further suggest the importance of comparing VBM findings with more traditional ROI analyses until the reasons for the differences between methods are determined.

3D visualisation of the middle ear and adjacent structures using reconstructed multi-slice CT datasets, correlating 3D images and virtual endoscopy to the 2D cross-sectional images.

The 3D imaging of the middle ear facilitates better understanding of the patient's anatomy. Cross-sectional slices, however, often allow a more accurate evaluation of anatomical structures, as some detail may be lost through post-processing. In order to demonstrate the advantages of combining both approaches, we performed computed tomography (CT) imaging in two normal and 15 different pathological cases, and the 3D models were correlated to the cross-sectional CT slices. Reconstructed CT datasets were acquired by multi-slice CT. Post-processing was performed using the in-house software "3D Slicer", applying thresholding and manual segmentation. 3D models of the individual anatomical structures were generated and displayed in different colours. The display of relevant anatomical and pathological structures was evaluated in the greyscale 2D slices, 3D images, and the 2D slices showing the segmented 2D anatomy in different colours for each structure. Correlating 2D slices to the 3D models and virtual endoscopy helps to combine the advantages of each method. As generating 3D models can be extremely time-consuming, this approach can be a clinically applicable way of gaining a 3D understanding of the patient's anatomy by using models as a reference. Furthermore, it can help radiologists and otolaryngologists evaluating the 2D slices by adding the correct 3D information that would otherwise have to be mentally integrated. The method can be applied to radiological diagnosis, surgical planning, and especially, to teaching.

Processing and visualization for diffusion tensor MRI.

This paper presents processing and visualization techniques for Diffusion Tensor Magnetic Resonance Imaging (DT-MRI). In DT-MRI, each voxel is assigned a tensor that describes local water diffusion. The geometric nature of diffusion tensors enables us to quantitatively characterize the local structure in tissues such as bone, muscle, and white matter of the brain. This makes DT-MRI an interesting modality for image analysis. In this paper we present a novel analytical solution to the Stejskal-Tanner diffusion equation system whereby a dual tensor basis, derived from the diffusion sensitizing gradient configuration, eliminates the need to solve this equation for each voxel. We further describe decomposition of the diffusion tensor based on its symmetrical properties, which in turn describe the geometry of the diffusion ellipsoid. A simple anisotropy measure follows naturally from this analysis. We describe how the geometry or shape of the tensor can be visualized using a coloring scheme based on the derived shape measures. In addition, we demonstrate that human brain tensor data when filtered can effectively describe macrostructural diffusion, which is important in the assessment of fiber-tract organization. We also describe how white matter pathways can be monitored with the methods introduced in this paper. DT-MRI tractography is useful for demonstrating neural connectivity (in vivo) in healthy and diseased brain tissue.

Prefrontal cortex, negative symptoms, and schizophrenia: an MRI study.

The present study measured prefrontal cortical gray and white matter volume in chronic, male schizophrenic subjects who were characterized by a higher proportion of mixed or negative symptoms than previous patients that we have evaluated. Seventeen chronic male schizophrenic subjects and 17 male control subjects were matched on age and handedness. Regions of interest (ROI) were measured using high-resolution magnetic resonance (MR) acquisitions consisting of contiguous 1.5-mm slices of the entire brain. No significant differences were found between schizophrenic and control subjects in mean values for prefrontal gray matter volume in either hemisphere. However, right prefrontal white matter was significantly reduced in the schizophrenic group. In addition, right prefrontal gray matter volume was significantly correlated with right hippocampal volume in the schizophrenic, but not in the control group. Furthermore, an analysis in which the current data were combined with those from a previous study showed that schizophrenic subjects with high negative symptom scores had significantly smaller bilateral white matter volumes than those with low negative symptom scores. White matter was significantly reduced in the right hemisphere in this group of schizophrenic subjects. Prefrontal volumes were also associated with negative symptom severity and with volumes of medial-temporal lobe regions - two results that were also found previously in schizophrenic subjects with mostly positive symptoms. These results underscore the importance of temporal-prefrontal pathways in the symptomatology of schizophrenia, and they suggest an association between prefrontal abnormalities and negative symptoms.

Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits.

PURPOSE: To determine if focused ultrasound beams can be used to locally open the blood-brain barrier without damage to surrounding brain tissue and if magnetic resonance (MR) imaging can be used to monitor this procedure. MATERIALS AND METHODS: The brains of 18 rabbits were sonicated (pulsed sonication) in four to six locations, with temporal peak acoustic power ranging from 0.2 to 11.5 W. Prior to each sonication, a bolus of ultrasonographic (US) contrast agent was injected into the ear vein of the rabbit. A series of fast or spoiled gradient-echo MR images were obtained during the sonications to monitor the temperature elevation and potential tissue changes. Contrast material-enhanced MR images obtained minutes after sonications and repeated 1-48 hours later were used to depict blood-brain barrier opening. Whole brain histologic evaluation was performed. RESULTS: Opening of the blood-brain barrier was confirmed with detection of MR imaging contrast agent at the targeted locations. The lowest power levels used produced blood-brain barrier opening without damage to the surrounding neurons. Contrast enhancement correlated with the focal signal intensity changes in the magnitude fast spoiled gradient-echo MR images. CONCLUSION: The blood-brain barrier can be consistently opened with focused ultrasound exposures in the presence of a US contrast agent. MR imaging signal intensity changes may be useful in the detection of blood-brain barrier opening during sonication.

A functional magnetic resonance imaging study of auditory mismatch in schizophrenia.

OBJECTIVE: Previous research has noted functional and structural temporal lobe abnormalities in schizophrenia that relate to symptoms such as auditory hallucinations and thought disorder. The goal of the study was to determine whether the functional abnormalities are present in schizophrenia at early stages of auditory processing. METHOD: Functional magnetic resonance imaging activity was examined during the presentation of the mismatch stimuli, which are deviant tones embedded in a series of standard tones. The mismatch stimuli are used to elicit the mismatch negativity, an early auditory event-related potential. Ten patients with schizophrenia and 10 comparison subjects were presented the mismatch stimuli condition and a control condition in which only one tone was presented repeatedly. RESULTS: The superior temporal gyrus showed the most prevalent and consistent activation. The superior temporal gyrus showed less activation in the schizophrenic subjects than in the comparison subjects only during the mismatch stimuli condition. CONCLUSIONS: This result is consistent with those of mismatch negativity event-related potential studies and suggests that early auditory processing is abnormal in chronic schizophrenia.

MR imaging-guided prostate biopsy with surgical navigation software: device validation and feasibility.

Magnetic resonance (MR) imaging--guided prostate biopsy in a 0.5-T open imager is described, validated in phantom studies, and performed in two patients. The needles are guided by using fast gradient-recalled echo and T2-weighted fast spin-echo images. Surgical navigation software provided T2-weighted images critical to targeting the peripheral zone and the tumor. MR imaging can be used to guide prostate biopsy.

Normal brain and brain tumor: multicomponent apparent diffusion coefficient line scan imaging.

Magnetic resonance line scan diffusion imaging of the brain, with diffusion weighting between 5 and 5,000 sec/mm(2), was performed in healthy subjects and patients with a 1.5-T machine. For each voxel, biexponential signal decay fits produced two apparent diffusion constants and respective signal amplitudes. Images based on these parameters show potential for use in the differentiation of gray and white matter, edema, and tumor.

Line scan diffusion tensor MRI of the cervical spinal cord in preterm infants.

Line scan diffusion tensor magenetic resonance imaging (DT-MRI) of the cervical spinal cord was demonstrated in vivo for unsedated preterm (gestational age 24-30 weeks at birth), very low birthweight (birthweight 620-1300 g) infants at postmenstrual ages from 29-40 weeks. Scalar invariant measures of diffusion [apparent diffusion coefficient (ADC) and relative anisotropy (RA)] determined from a cervical cord region of interest in each case are reported, characterizing the maturational status of the normal third trimester and newborn spinal cord. Mean ADC of 11 infants was 1.2 +/- 0.1 microm(2)/msec and the mean RA was 24.3 +/- 4.9%. Normal infant cord neural fiber tract morphology was visualized using a mapping of the predominant diffusion tensor eigenvector. Potential clinical applications of line scan DT-MRI of the spinal cord of preterm and term newborns for assessment of spinal cord injury are discussed. J. Magn. Reson. Imaging 2001;13:949-953.

An integrated visualization system for surgical planning and guidance using image fusion and an open MR.

A surgical guidance and visualization system is presented, which uniquely integrates capabilities for data analysis and on-line interventional guidance into the setting of interventional MRI. Various pre-operative scans (T1- and T2-weighted MRI, MR angiography, and functional MRI (fMRI)) are fused and automatically aligned with the operating field of the interventional MR system. Both pre-surgical and intra-operative data may be segmented to generate three-dimensional surface models of key anatomical and functional structures. Models are combined in a three-dimensional scene along with reformatted slices that are driven by a tracked surgical device. Thus, pre-operative data augments interventional imaging to expedite tissue characterization and precise localization and targeting. As the surgery progresses, and anatomical changes subsequently reduce the relevance of pre-operative data, interventional data is refreshed for software navigation in true real time. The system has been applied in 45 neurosurgical cases and found to have beneficial utility for planning and guidance. J. Magn. Reson. Imaging 2001;13:967-975.

Dynamic imaging with multiple resolutions along phase-encode and slice-select dimensions.

An implementation is reported of an imaging method to obtain MUltiple Resolutions along Phase-encode and Slice-select dimensions (MURPS), which enables dynamic imaging of focal changes using a graded, multiresolution approach. MURPS allows one to trade spatial resolution in part of the volume for improved temporal resolution in dynamic imaging applications. A unique method of Hadamard slice encoding is used, enabling the varying of the phase encode and slice resolution while maintaining a constant effective TR throughout the entire 3-D volume. MURPS was implemented using a gradient-recalled echo sequence, and its utility was demonstrated for MR temperature monitoring. In this preliminary work, it has been shown that changes throughout a large volume can be effectively monitored in times that would normally only permit dynamic imaging in one or a very few slices.

Serial intraoperative magnetic resonance imaging of brain shift.

OBJECTIVE: A major shortcoming of image-guided navigational systems is the use of preoperatively acquired image data, which does not account for intraoperative changes in brain morphology. The occurrence of these surgically induced volumetric deformations ("brain shift") has been well established. Maximal measurements for surface and midline shifts have been reported. There has been no detailed analysis, however, of the changes that occur during surgery. The use of intraoperative magnetic resonance imaging provides a unique opportunity to obtain serial image data and characterize the time course of brain deformations during surgery. METHODS: The vertically open intraoperative magnetic resonance imaging system (SignaSP, 0.5 T; GE Medical Systems, Milwaukee, WI) permits access to the surgical field and allows multiple intraoperative image updates without the need to move the patient. We developed volumetric display software (the 3D Slicer) that allows quantitative analysis of the degree and direction of brain shift. For 25 patients, four or more intraoperative volumetric image acquisitions were extensively evaluated. RESULTS: Serial acquisitions allow comprehensive sequential descriptions of the direction and magnitude of intraoperative deformations. Brain shift occurs at various surgical stages and in different regions. Surface shift occurs throughout surgery and is mainly attributable to gravity. Subsurface shift occurs during resection and involves collapse of the resection cavity and intraparenchymal changes that are difficult to model. CONCLUSION: Brain shift is a continuous dynamic process that evolves differently in distinct brain regions. Therefore, only serial imaging or continuous data acquisition can provide consistently accurate image guidance. Furthermore, only serial intraoperative magnetic resonance imaging provides an accurate basis for the computational analysis of brain deformations, which might lead to an understanding and eventual simulation of brain shift for intraoperative guidance.