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We assessed the feasibility of supine intraoperative MRI (iMRI) during breast-conserving surgery (BCS), enrolling 15 patients in our phase I trial between 2012 and 2014. Patients received diagnostic prone MRI, BCS, pre-excisional supine iMRI, and postexcisional supine iMRI. Feasibility was assessed based on safety, sterility, duration, and image-quality. Twelve patients completed the study; mean duration = 114 minutes; all images were adequate; no complications, safety, or sterility issues were encountered. Substantial tumor-associated changes occurred (mean displacement = 67.7 mm, prone-supine metric, n = 7). We have demonstrated iMRI feasibility for BCS and have identified potential limitations of prone breast MRI that may impact surgical planning.

Alterations in renal microperfusion play an important role in the development of acute kidney injury with long-term consequences. Here we used contrast-enhanced ultrasonography as a novel method for depicting intra-renal distribution of blood flow. After infusion of microbubble contrast agent, bubbles were collapsed in the kidney and post-bubble destruction refilling was measured in various regions of the kidney. Local perfusion was monitored in vivo at 15, 30, 45, 60 minutes and 24 hours after 28 min of bilateral ischemia in 12 mice. High-resolution, pixel-by-pixel, analysis was performed on each imaging clip using customized software, yielding parametric perfusion maps of the kidney, representing relative blood volume in each pixel. These perfusion maps revealed that outer medullary perfusion decreased disproportionately to the reduction in the cortical and inner medullary perfusion after ischemia. Outer medullary perfusion was significantly decreased by 69% at 60 minutes post-ischemia and remained significantly less (40%) than pre-ischemic levels at 24 hours post-ischemia. Thus, contrast-enhanced ultrasonography with high-resolution parametric perfusion maps can monitor changes in renal microvascular perfusion in space and time in mice. This novel technique can be translated to clinical use in man.

Stereotactic radiosurgery is one of the treatment options for brain metastases. However, there are patients who will progress after radiosurgery. One of the potential treatments for this subset of patients is laser ablation. Image-guided stereotactic biopsy is important to determine the histopathological nature of the lesion. However, this is usually based on preoperative, static images, which may affect the target accuracy during the actual procedure as a result of brain shift. We therefore performed real-time intraoperative MRI-guided stereotactic aspiration and biopsies on two patients with symptomatic, progressive lesions after radiosurgery followed immediately by laser ablation. The patients tolerated the procedure well with no new neurologic deficits. Intraoperative MRI-guided stereotactic biopsy followed by laser ablation is safe and accurate, providing real-time updates and feedback during the procedure.

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.

The authors review methods for image-guided diagnosis and therapy that increase precision in the detection, characterization, and localization of many forms of cancer to achieve optimal target definition and complete resection or ablation. A new model of translational, clinical, image-guided therapy research is presented, and the Advanced Multimodality Image-Guided Operating (AMIGO) suite is described. AMIGO was conceived and designed to allow for the full integration of imaging in cancer diagnosis and treatment. Examples are drawn from over 500 procedures performed on brain, neck, spine, thorax (breast, lung), and pelvis (prostate and gynecologic) areas and are used to describe how they address some of the many challenges of treating brain, prostate, and lung tumors. Cancer 2015;121:817-827. © 2014 American Cancer Society.

For many intraoperative decisions surgeons depend on frozen section pathology, a technique developed over 150 y ago. Technical innovations that permit rapid molecular characterization of tissue samples at the time of surgery are needed. Here, using desorption electrospray ionization (DESI) MS, we rapidly detect the tumor metabolite 2-hydroxyglutarate (2-HG) from tissue sections of surgically resected gliomas, under ambient conditions and without complex or time-consuming preparation. With DESI MS, we identify isocitrate dehydrogenase 1-mutant tumors with both high sensitivity and specificity within minutes, immediately providing critical diagnostic, prognostic, and predictive information. Imaging tissue sections with DESI MS shows that the 2-HG signal overlaps with areas of tumor and that 2-HG levels correlate with tumor content, thereby indicating tumor margins. Mapping the 2-HG signal onto 3D MRI reconstructions of tumors allows the integration of molecular and radiologic information for enhanced clinical decision making. We also validate the methodology and its deployment in the operating room: We have installed a mass spectrometer in our Advanced Multimodality Image Guided Operating (AMIGO) suite and demonstrate the molecular analysis of surgical tissue during brain surgery. This work indicates that metabolite-imaging MS could transform many aspects of surgical care.

Transcranial MRI-guided focused ultrasound (TcMRgFUS) is an old idea but a new technology that may change the entire clinical field of the neurosciences. TcMRgFUS has no cumulative effect, and it is applicable for repeatable treatments, controlled by real-time dosimetry, and capable of immediate tissue destruction. Most importantly, it has extremely accurate targeting and constant monitoring. It is potentially more precise than proton beam therapy and definitely more cost effective. Neuro-oncology may be the most promising area of future TcMRgFUS applications.

Object Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging–guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull. Methods In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm. Results Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina. Conclusions This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in deep brain structures while preserving function in adjacent nerves. Because of low vascularity—and thus a low microbubble concentration—some large white matter tracts appear to have some natural resistance to this type of ablation compared with gray matter. While future work is needed to develop methods of monitoring the procedure and establishing its safety at deep brain targets, the technique does appear to be a potential solution that allows FUS ablation of deep brain targets while sparing adjacent nerve structures.

Burgess et al ( 1 ) present intriguing results of repetitive transient opening of the blood-brain barrier (BBB) in a transgenic mouse model of advanced Alzheimer disease (AD). The results underscore the potential of using magnetic resonance (MR) imaging-guided focused ultrasound and microbubble ultrasonography (US) contrast agents for the disruption of the BBB as a potential long-term therapy to reduce amyloid plaque burden and improve cognitive performance. This daring conclusion that is based on an experimental animal model should now be confirmed in humans. Considering that the technology is commercially available and given the immense clinical need, clinical trials in this AD treatment should be initiated as soon as possible.

The main goal of brain tumor surgery is to maximize tumor resection while preserving brain function. However, existing imaging and surgical techniques do not offer the molecular information needed to delineate tumor boundaries. We have developed a system to rapidly analyze and classify brain tumors based on lipid information acquired by desorption electrospray ionization mass spectrometry (DESI-MS). In this study, a classifier was built to discriminate gliomas and meningiomas based on 36 glioma and 19 meningioma samples. The classifier was tested and results were validated for intraoperative use by analyzing and diagnosing tissue sections from 32 surgical specimens obtained from five research subjects who underwent brain tumor resection. The samples analyzed included oligodendroglioma, astrocytoma, and meningioma tumors of different histological grades and tumor cell concentrations. The molecular diagnosis derived from mass-spectrometry imaging corresponded to histopathology diagnosis with very few exceptions. Our work demonstrates that DESI-MS technology has the potential to identify the histology type of brain tumors. It provides information on glioma grade and, most importantly, may help define tumor margins by measuring the tumor cell concentration in a specimen. Results for stereotactically registered samples were correlated to preoperative MRI through neuronavigation, and visualized over segmented 3D MRI tumor volume reconstruction. Our findings demonstrate the potential of ambient mass spectrometry to guide brain tumor surgery by providing rapid diagnosis, and tumor margin assessment in near–real time.

Purpose To use intraoperative supine magnetic resonance (MR) imaging to quantify breast tumor deformation and displacement secondary to the change in patient positioning from imaging (prone) to surgery (supine) and to evaluate residual tumor immediately after breast-conserving surgery (BCS). Materials and Methods Fifteen women gave informed written consent to participate in this prospective HIPAA-compliant, institutional review board-approved study between April 2012 and November 2014. Twelve patients underwent lumpectomy and postsurgical intraoperative supine MR imaging. Six of 12 patients underwent both pre- and postsurgical supine MR imaging. Geometric, structural, and heterogeneity metrics of the cancer and distances of the tumor from the nipple, chest wall, and skin were computed. Mean and standard deviations of the changes in volume, surface area, compactness, spherical disproportion, sphericity, and distances from key landmarks were computed from tumor models. Imaging duration was recorded. Results The mean differences in tumor deformation metrics between prone and supine imaging were as follows: volume, 23.8% (range, -30% to 103.95%); surface area, 6.5% (range, -13.24% to 63%); compactness, 16.2% (range, -23% to 47.3%); sphericity, 6.8% (range, -9.10% to 20.78%); and decrease in spherical disproportion, -11.3% (range, -60.81% to 76.95%). All tumors were closer to the chest wall on supine images than on prone images. No evidence of residual tumor was seen on MR images obtained after the procedures. Mean duration of pre- and postoperative supine MR imaging was 25 minutes (range, 18.4-31.6 minutes) and 19 minutes (range, 15.1-22.9 minutes), respectively. Conclusion Intraoperative supine breast MR imaging, when performed in conjunction with standard prone breast MR imaging, enables quantification of breast tumor deformation and displacement secondary to changes in patient positioning from standard imaging (prone) to surgery (supine) and may help clinicians evaluate for residual tumor immediately after BCS.

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a novel combination of technologies that is actively being realized as a noninvasive therapeutic tool for a myriad of conditions. These applications are reviewed with a focus on neurological use. A combined search of PubMed and MEDLINE was performed to identify the key events and current status of MRgFUS, with a focus on neurological applications. MRgFUS signifies a potentially ideal device for the treatment of neurological diseases. As it is nearly real time, it allows monitored provision of treatment location and energy deposition; is noninvasive, thereby limiting or eliminating disruption of normal tissue; provides focal delivery of therapeutic agents; enhances radiation delivery; and permits modulation of neural function. Multiple clinical applications are currently in clinical use and many more are under active preclinical investigation. The therapeutic potential of MRgFUS is expanding rapidly. Although clinically in its infancy, preclinical and early-phase I clinical trials in neurosurgery suggest a promising future for MRgFUS. Further investigation is necessary to define its true potential and impact.

Focused ultrasound surgery (FUS) is a noninvasive image-guided therapy and an alternative to surgical interventions. It presents an opportunity to revolutionize cancer therapy and to affect or change drug delivery of therapeutic agents in new focally targeted ways. In this article the background, principles, technical devices, and clinical cancer applications of image-guided FUS are reviewed.

Malignant brain tumors present a major challenge in neurosurgery not only for their biological behavior but also because of their infiltration in the functioning brain. Currently preferred diagnostic imaging techniques, namely magnetic resonance imaging (MRI),1 have limited sensitivity and specificity to detect the full extent of malignant brain tumors, making it especially difficult to distinguish tumor from peritumoral edema and to recognize low density of tumor cells within otherwise normal brain tissue. Diagnosis, grading of tumors, and treatment rely primarily on neuro-pathological documentation of tissue, including cellular and nuclear morphology, proliferation, necrosis, vascu-larization, and characteristic cytogenetic aberrations.2 Moreover, when single biopsies or sparse surgical samples are used, there may be considerable heterogeneity, leading to sampling error. Surgical pathology-based approaches need to be complemented by improved intraoperative definition of tumors and their margins. This definition will help us obtain samples from appropriate histopathological areas and may provide additional molecular tissue characterization of the tumor. This improved tumor definition will help intraoperative decision making and maximize the extent of tumor resection.3 Surgery remains the first line of treatment for most brain tumor patients, and prognosis for many brain tumors depends significantly on the extent of surgical resection,4–7 but this must be balanced against preservation of functioning cortex and white matter.8–10 In recent years, there has been significant progress in developing imaging and image-guidance platforms for localizing and targeting brain tumors and revealing the full extent of infiltrating tumor with the anatomic and functional definition of involved brain areas.11–13 Frameless stereotaxy and neuro-navigation is key for aiding the neurosurgeon in the coregistration of the individual patient’s anatomy and images. Mass spectrometry is a well-established, sensitive analytical technique used to identify and characterize molecules based on their mass and fragmentation pattern, respectively. The recent adaptation of mass spectrometers and their respective computer applications to accommodate tissue analysis provides simultaneous molecular profiling of hundreds of molecules without the need for radioactive or fluorescent tag.14 An increasing number of studies support the concept of mass spectrometry as an efficient tool to recognize and delineate pathology directly from tissue specimens.15–17 In 2004, desorption electrospray ionization (DESI) was introduced as an ambient desorption/ionization method for mass spectrometry18 and subsequently proven to be applicable to tissue imaging.19,20 The DESI technique is well suited for clinical deployment because it is a soft ionization method that allows the analysis of intact biomolecules and provides direct sampling of the tissue in the ambient environment without specialized sample preparation.21 The present study introduces the integration of DESI mass spectrometry into surgery for in vivo molecular tissue characterization and intraoperative definition of tumor boundaries, without systemic injection of contrast agents. This novel approach will provide complex molecular information during the surgery, complementing preoperative and intraoperative MRI and positron emission tomography (PET) with a potentially more sensitive and specific assessment of tumor boundaries in vivo.

Transcranial MR-guided focused ultrasound (TcMRgFUS) provides a potential noninvasive alternative to surgical resection and for other treatments for brain disorders. Use of low-frequency ultrasound provides several advantages for TcMRgFUS, but is potentially limited by reflection and standing wave effects that may cause secondary hotspots within the skull cavity. The purpose of this work was to use volumetric magnetic resonance temperature imaging (MRTI) and ex vivo human skulls filled with tissue-mimicking phantom material to search for heating distant from the focal point that may occur during sonication with a TcMRgFUS system as a result of reflections or standing wave effects. Heating during 120-s sonications was monitored within the entire skull volume for 12 different locations in two different skulls. The setup used a hemispheric array operating at 220 kHz. Multiple sonications were delivered at each location while varying the MRTI slice positions to provide full coverage of the skull cavity. An automated routine was used evaluate the MRTI to detect voxel regions that appeared to be heated by ultrasound. No secondary hotspots with a temperature rise of 15% or more of the focal heating were found. The MRTI noise level prevented the identification of possible hotspots with a lower temperature rise. These results suggest that significant secondary heating by this TcMRgFUS system at points distant from the focal point are not common.

Rationale and Objectives: MR-guided Focused Ultrasound Surgery (MRgFUS) is an evolving thermoablative technique for treatment of benign and malignant soft tissue tumors. The feasibility and effectiveness of this non-invasive method has been tested by several investigators by treating uterine fibroid. The aim of the present study was to evaluate early and mid-term efficacy of MRgFUS treatment using MR imaging follow-ups. Materials and Methods: 38 patients with uterine fibroids were enrolled and treated by MRgFUS in a single center. MRI follow-up exams were performed 3 and 6 months after the procedure. Total fibroid volumes (FV) and non-perfused volumes (NPV) were compared and evaluated over time. Results: There was a significant reduction of FV at 3- and 6-month follow-ups (10±19%, p=0.022 and 19±29%, pConclusion: This study suggests that MRgFUS can effectively coagulate uterine fibroid tissue. Smaller UFs can be most effectively treated within reasonable time with the used equipment.

Thermal ablation is an established treatment for tumor. The merging of newly developed imaging techniques has allowed precise targeting and real-time thermal mapping. This article provides an overview of the image-guided thermal ablation techniques in the treatment of uterine fibroids. Background on uterine fibroids, including epidemiology, histology, symptoms, imaging findings and current treatment options, is first outlined. After describing the principle of magnetic resonance thermal imaging, we introduce the applications of image-guided thermal therapies, including laser ablation, radiofrequency ablation, cryotherapy and particularly the newest, magnetic resonance-guided focused ultrasound surgery, and how they apply to uterine fibroid treatment.

The field of magnetic resonance imaging-guided high-intensity focused ultrasound surgery (MRgFUS) is a rapidly evolving one, with many potential applications in neurosurgery. The first of 3 articles on MRgFUS, this article focuses on the historical development of the technology and its potential applications in modern neurosurgery. The evolution of MRgFUS has occurred in parallel with modern neurological surgery, and the 2 seemingly distinct disciplines share many of the same pioneering figures. Early studies on focused ultrasound treatment in the 1940s and 1950s demonstrated the ability to perform precise lesioning in the human brain, with a favorable risk-benefit profile. However, the need for a craniotomy, as well as the lack of sophisticated imaging technology, resulted in limited growth of high-intensity focused ultrasound for neurosurgery. More recently, technological advances have permitted the combination of high-intensity focused ultrasound along with magnetic resonance imaging guidance to provide an opportunity to effectively treat a variety of central nervous system disorders. Although challenges remain, high-intensity focused ultrasound-mediated neurosurgery may offer the ability to target and treat central nervous system conditions that were previously extremely difficult to address. The remaining 2 articles in this series will focus on the physical principles of modern MRgFUS as well as current and future avenues for investigation.

Real-time functional MRI (rtfMRI) has been used as a basis for brain–computer interface (BCI) due to its ability to characterize region-specific brain activity in real-time. As an extension of BCI, we present an rtfMRI-based brain–machine interface (BMI) whereby 2-dimensional movement of a robotic arm was controlled by the regulation (and concurrent detection) of regional cortical activations in the primary motor areas. To do so, the subjects were engaged in the right- and/or left-hand motor imagery tasks. The blood oxygenation level dependent (BOLD) signal originating from the corresponding hand motor areas was then translated into horizontal or vertical robotic arm movement. The movement was broadcasted visually back to the subject as a feedback. We demonstrated that real-time control of the robotic arm only through the subjects’ thought processes was possible using the rtfMRI-based BMI trials.

The simultaneous acquisition of electroencephalogram (EEG) and functional MRI (fMRI) signals is potentially advantageous because of the superior resolution that is achieved in both the temporal and spatial domains, respectively. However, ballistocardiographic artifacts along with the ocular artifacts are a major obstacle for the detection of the EEG signatures of interest. Since the sources corresponding to these artifacts are independent from those producing the EEG signatures, we applied the Infomax-based independent component analysis (ICA) technique to separate the EEG signatures from the artifacts. The isolated EEG signatures were further utilized to model the canonical hemodynamic response functions (HRFs). Subsequently, the brain areas from which these EEG signatures originated were identified as locales of activation patterns from the analysis of fMRI data. Upon the identification and subsequent evaluation of brain areas generating interictal epileptic discharge (IED) spikes from an epileptic subject, the presented method was successfully applied to detect the theta- and alpha-rhythms that are sleep onset related EEG signatures along with the subsequent neural circuitries from a sleep deprived volunteer. These results suggest that the ICA technique may be useful for the preprocessing of simultaneous EEG-fMRI acquisitions, especially when a reference paradigm is unavailable.

To retrospectively assess the magnetic resonance (MR) imaging predictors of success at reducing uterine leiomyoma volume and achieving patient symptom relief 12 months after MR imaging-guided focused ultrasound surgery.This single-center retrospective analysis of 71 symptomatic fibroids in 66 women was approved by the institutional review board and was HIPAA-compliant. Patients were treated with MR imaging-guided focused ultrasound surgery. The volume of treated fibroid and nonperfused volume (NPV) were calculated with software, while symptom outcome was assessed with a symptom severity score (SSS). Fibroids were classified as hyperintense or hypointense relative to skeletal muscle on pretreatment T2-weighted MR images.Baseline volume of treated fibroids was 255.5 cm(3) +/- 201.7 (standard deviation), and baseline SSS was 61.5 +/- 14.9. Both pretreatment fibroid signal intensity (SI) and posttreatment NPV predicted 12-month volume reduction independently: Fibroids with an NPV of at least 20% or with low SI both showed significantly larger volume reduction (17.0% +/- 13.0 and 17.2% +/- 20.1, respectively) than fibroids with an NPV less than 20% or with high SI (10.7% +/- 18.2 and no significant change, respectively). Patients whose fibroids demonstrated an NPV of at least 20% also experienced a larger decrease in SSS than did patients with fibroids with an NPV less than 20% (50.1% +/- 19.8 vs 32.6% +/- 29.9).Fibroids with low SI on pretreatment T2-weighted MR images were more likely to shrink than were ones with high SI. The larger the NPV immediately after treatment, the greater the volume reduction and symptom relief were. These findings may help both in selecting appropriate patients for MR-guided focused ultrasound surgery and in predicting patient outcome.

OBJECTIVE: Preoperative magnetic resonance imaging (MRI), functional MRI, diffusion tensor MRI, magnetic resonance spectroscopy, and positron-emission tomographic scans may be aligned to intraoperative MRI to enhance visualization and navigation during image-guided neurosurgery. However, several effects (both machine- and patientinduced distortions) lead to significant geometric distortion of intraoperative MRI. Therefore, a precise alignment of these image modalities requires correction of the geometric distortion. We propose and evaluate a novel method to compensate for the geometric distortion of intraoperative 0.5-T MRI in image-guided neurosurgery. METHODS: In this initial pilot study, 11 neurosurgical procedures were prospectively enrolled. The scheme used to correct the geometric distortion is based on a nonrigid registration algorithm introduced by our group. This registration scheme uses image features to establish correspondence between images. It estimates a smooth geometric distortion compensation field by regularizing the displacements estimated at the correspondences. A patient-specific linear elastic material model is used to achieve the regularization. The geometry of intraoperative images (0.5 T) is changed so that the images match the preoperative MRI scans (3 T). RESULTS: We compared the alignment between preoperative and intraoperative imaging using 1) only rigid registration without correction of the geometric distortion, and 2) rigid registration and compensation for the geometric distortion. We evaluated the success of the geometric distortion correction algorithm by measuring the Hausdorff distance between boundaries in the 3-T and 0.5-T MRIs after rigid registration alone and with the addition of geometric distortion correction of the 0.5-T MRI. Overall, the mean magnitude of the geometric distortion measured on the intraoperative images is 10.3 mm with a minimum of 2.91 mm and a maximum of 21.5 mm. The measured accuracy of the geometric distortion compensation algorithm is 1.93 mm. There is a statistically significant difference between the accuracy of the alignment of preoperative and intraoperative images, both with and without the correction of geometric distortion (P 0.001). CONCLUSION: The major contributions of this study are 1) identification of geometric distortion of intraoperative images relative to preoperative images, 2) measurement of the geometric distortion, 3) application of nonrigid registration to compensate for geometric distortion during neurosurgery, 4) measurement of residual distortion after geometric distortion correction, and 5) phantom study to quantify geometric distortion.

Purpose This study was performed to define the rectal dose constraint that would predict late rectal bleeding requiring argon plasma coagulation (APC) following prostate brachy mono-therapy. Methods and materials Between February 1999 and April 2002, 91 patients with low risk prostate cancer underwent permanent I 125 radioactive seed implantation without the use of supplemental external beam radiation or androgen suppression therapy. Patients received both CT and MRI scans 6 weeks postimplant for evaluation of dosimetry. The CT and MRI scans were fused. Rectal volumes were contoured on the T2 weighted MR images. For those patients requiring APC, the date on which a patient reported rectal bleeding was recorded. A Cox regression analysis was performed to assess whether there was a significant association between the rectal volume (continuous) exceeding 100 Gy time rectal bleeding. Comparisons of estimates of rectal bleeding requiring APC were made using a 2-sided log rank test. Results There was a significant association (hazard ratio = 5.6 [95% confidence interval: 1.3, 23.8]; P = 0.002) between the rectal volume exceeding 100 Gy and rectal bleeding requiring APC. After a median follow-up of 4.25 (1–6) years, no patient with less than a median value of 8 cc of rectum exceeding 100 Gy required APC, whereas 20% ( P = 0.004) were estimated to require APC within 3 years following treatment. Conclusions Keeping the rectal volume receiving more than 100 Gy below 8 cc will minimize the risk of rectal bleeding requiring APC following I 125 permanent prostate brachy mono-therapy.

We report an automated method to simultaneously monitor blood‐oxygenation‐level‐dependent (BOLD) MR signals from multiple cortical areas in real‐time. Individual brain anatomy was normalized and registered to a pre‐segmented atlas in standardized anatomical space. Subsequently, using real‐time fMRI (rtfMRI) data acquisition, localized BOLD signals were measured and displayed from user‐selected areas labeled with anatomical and Brodmann's Area (BA) nomenclature. The method was tested on healthy volunteers during the performance of hand motor and internal speech generation tasks employing a trial‐based design. Our data normalization and registration algorithm, along with image reconstruction, movement correction and a data display routine were executed with enough processing and communication bandwidth necessary for real‐time operation. Task‐specific BOLD signals were observed from the hand motor and language areas. One of the study participants was allowed to freely engage in hand clenching tasks, and associated brain activities were detected from the motor‐related neural substrates without prior knowledge of the task onset time. The proposed method may be applied to various applications such as neurofeedback, brain‐computer‐interface, and functional mapping for surgical planning where real‐time monitoring of region‐specific brain activity is needed. Hum Brain Mapp 2008. © 2007 Wiley‐Liss, Inc.

The combination of the imaging abilities of magnetic resonance imaging (MRI) with the ability to delivery energy to targets deep in the body noninvasively with focused ultrasound presents a disruptive technology with the potential to significantly affect healthcare. MRI offers precise targeting, visualization, and quantification of temperature changes and the ability to immediately evaluate the treatment. By exploiting different mechanisms, focused ultrasound offers a range of therapies, ranging from thermal ablation to targeted drug delivery. This article reviews recent preclinical and tests clinical of this technology.

Objective The software requirements for computer-aided navigation tools in image-guided therapy become increasingly complex as a result of new imaging and tracking hardware, novel application areas and regulatory restrictions. The objective of this work was to develop a new software framework to meet the needs of emerging image-guided procedures and therapies that require multi-modal imaging and tracking.

Purpose: To prospectively assess patient response (after 12 months) to magnetic resonance (MR) imaging–guided focused ultrasound surgery in treatment of uterine leiomyomas by using two treatment protocols. Materials and Methods: This prospective clinical trial was approved by institutional review boards and was HIPAA compliant. After giving informed consent, patients with symptomatic leiomyomas were consecutively enrolled and treated at one of five U.S. centers by using an original or a modified protocol. Outcomes were assessed with the symptom severity score (SSS) obtained at baseline and 3, 6, and 12 months after treatment. Adverse events (AEs) were recorded. Statistical analysis included Student t test, Fisher exact test, analysis of covariance, Spearman correlation, and logistic regression. Results: One hundred sixty patients had a mean SSS of 62.1 ± 16.3 (standard deviation) at baseline, which decreased to 35.5 ± 19.5 at 3 months (P < .001) and to 32.3 ± 19.8 at 6 months (P < .001) and was 32.7 ± 21....

Schizophrenia is characterized by deficits in cognition as well as visual perception. There have, however, been few magnetic resonance imaging (MRI) studies of the occipital lobe as an anatomically defined region of interest in schizophrenia. To examine whether or not patients with chronic schizophrenia show occipital lobe volume abnormalities, we measured gray matter volumes for both the primary visual area (PVA) and the visual association areas (VAA) using MRI based neuroanatomical landmarks and three-dimensional information. PVA and VAA gray matter volumes were measured using high-spatial resolution MRI in 25 male patients diagnosed with chronic schizophrenia and in 28 male normal controls. Chronic schizophrenia patients showed reduced bilateral VAA gray matter volume (11%), compared with normal controls, whereas patients showed no group difference in PVA gray matter volume. These results suggest that reduced bilateral VAA may be a neurobiological substrate of some of the deficits observed in early visual processing in schizophrenia.

OBJECT Transcranial MRI-guided focused ultrasound (TcMRgFUS) is an emerging noninvasive alternative to surgery and radiosurgery that is undergoing testing for tumor ablation and functional neurosurgery. The method is currently limited to central brain targets due to skull heating and other factors. An alternative ablative approach combines very low intensity ultrasound bursts and an intravenously administered microbubble agent to locally destroy the vasculature. The objective of this work was to investigate whether it is feasible to use this approach at deep brain targets near the skull base in nonhuman primates. METHODS In 4 rhesus macaques, targets near the skull base were ablated using a clinical TcMRgFUS system operating at 220 kHz. Low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes in conjunction with the ultrasound contrast agent Definity, which was administered as a bolus injection or continuous infusion. The acoustic power level was set to be near the inertial cavitation threshold, which was measured using passive monitoring of the acoustic emissions. The resulting tissue effects were investigated with MRI and with histological analysis performed 3 hours to 1 week after sonication. RESULTS Thirteen targets were sonicated in regions next to the optic tract in the 4 animals. Inertial cavitation, indicated by broadband acoustic emissions, occurred at acoustic pressure amplitudes ranging from 340 to 540 kPa. MRI analysis suggested that the lesions had a central region containing red blood cell extravasations that was surrounded by edema. Blood-brain barrier disruption was observed on contrast-enhanced MRI in the lesions and in a surrounding region corresponding to the prefocal area of the FUS system. In histology, lesions consisting of tissue undergoing ischemic necrosis were found in all regions that were sonicated above the inertial cavitation threshold. Tissue damage in prefocal areas was found in several cases, suggesting that in those cases the sonication exceeded the inertial cavitation threshold in the beam path. CONCLUSIONS It is feasible to use a clinical TcMRgFUS system to ablate skull base targets in nonhuman primates at time-averaged acoustic power levels at least 2 orders of magnitude below what is needed for thermal ablation with this device. The results point to the risks associated with the method if the exposure levels are not carefully controlled to avoid inertial cavitation in the acoustic beam path. If methods can be developed to provide this control, this nonthermal approach could greatly expand the use of TcMRgFUS for precisely targeted ablation to locations across the entire brain.

Molecular imaging is the next frontier in image-guided therapy promising to increase surgical precision. In vivo molecular imaging modalities, such as positron emission tomography (PET) and magnetic resonance spectroscopy (MRS), can already enhance the diagnostic value of magnetic resonance imaging alone and refine surgical planning. In centers where these modalities are available for intraoperative use, PET and MRS can also improve the detection of residual tumor but with significant surgical time delays. The field of molecular imaging is witnessing the development of tools that could eventually be placed in the hands of the surgeon for direct assessment of the surgical field. Optical methods, such as variations of fluorescence imaging, can both increase contrast to reveal tissue microstructures or target specific cells using molecular probes. Mass spectrometry offers a new modality for molecular imaging in image-guided surgery by providing detailed information of the chemical makeup of surgical tissue without the need for molecular probes. Each modality offers a unique view. It is our hope to see a day when the surgeon will have the opportunity to select among molecular imaging modalities to meet specific surgical goals.

In this article, we report efforts to integrate a number of state-of-the-art technologies for MRI-guided neurosurgery at the Brigham and Women's Hospital (BWH) in Boston. These include advanced intraoperative imaging, image registration, visualization, navigation, minimally invasive ablative therapies, and robotics. This is part of a multidisciplinary Image-Guided Therapy Program that comprises several key research thrusts, including the surgical planning laboratory, magnetic resonance therapy (MRT), focused ultrasound surgery, thermal ablation, and neurosurgery

Previously, activation of vesicular transport in the brain microvasculature was shown to be one of the mechanisms of focused ultrasound-induced blood-brain barrier (BBB) opening. In the present study, we aimed to estimate the rate of the transendothelial vesicular traffic after focused ultrasound sonication in the rabbit brain, using ultrastructural morphometry and horseradish peroxidase (HRP) as a tracer. In the capillaries, the mean endothelial pinocytotic densities (the number of HRP-containing vesicles per μm2 of the cell cytoplasm) were 0.9 and 1.05 vesicles/μm2 1 h after sonication with ultrasound frequencies of 0.69 and 0.26 MHz, respectively. In the arterioles, these densities were 1.63 and 2.43 vesicles/μm2, values 1.8 and 2.3 times higher. In control locations, the densities were 0.7 and 0.14 vesicles/μm2 for capillaries and arterioles, respectively. A small number of HRP-positive vesicles were observed in the venules. Focal delivery of HRP tracer was also observed in light microscopy. The results indicate that the precapillary microvessels play an important role in macromolecular transcytoplasmic traffic through the ultrasound-induced BBB modulation, which should be considered in the future development of trans-BBB drug delivery strategies. (E-mail: nsheikov@bwh.harvard.edu)

Object The goal of this study was to explore the feasibility of using low-frequency magnetic resonance (MR) image–guided focused ultrasound as a noninvasive method for the temporary disruption of the blood–brain barrier (BBB) at targeted locations. Methods Rabbits were placed inside a clinical 1.5-tesla MR imaging unit, and sites in their brains were targeted for 20-second burst sonications (frequency 260 kHz). The peak pressure amplitude during the burst varied between 0.1 and 0.9 MPa. Each sonication was performed after an intravenous injection of an ultrasound contrast agent (Optison). The disruption of the BBB was evaluated with the aid of an injection of an MR imaging contrast agent (MAG-NEVIST). Additional tests involving the use of MION-47, a 20-nm magnetic nanoparticle contrast agent, were also performed. The animals were killed at different time points between 3 minutes and 5 weeks postsonication, after which light or electron microscopic evaluation was performed. The threshold for BBB disruption was approximately 0.2 MPa. More than 80% of the brain sites sonicated showed BBB disruption when the pressure amplitude was 0.3 MPa; at 0.4 MPa, this percentage was greater than 90%. Tissue necrosis, ischemia, and apoptosis were not found in tissue in which the pressure amplitude was less than 0.4 MPa; however, in a few areas of brain tissue erythrocytes were identified outside blood vessels following exposures of 0.4 MPa or higher. Survival experiments did not show any long-term adverse events. Conclusions These results demonstrate that low-frequency ultrasound bursts can induce local, reversible disruption of the BBB without undesired long-term effects. This technique offers a potential noninvasive method for targeted drug delivery in the brain aided by a relatively simple low-frequency device.

Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/c-erbB2) monoclonal antibody, has been used successfully in patients with breast cancer. However, in patients with brain metastasis, the blood–brain barrier limits its use, and a different delivery method is needed to treat these patients. Here, we report that Herceptin can be delivered locally and noninvasively into the mouse central nervous system through the blood–brain barrier under image guidance by using an MRI-guided focused ultrasound blood–brain barrier disruption technique. The amount of Herceptin delivered to the target tissue was correlated with the extent of the MRI-monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. Histological changes attributable to this procedure were minimal. This method may represent a powerful technique for the delivery of macromolecular agents such as antibodies to treat patients with diseases of the central nervous system.

MRI-guided and monitored focused ultrasound thermal surgery of brain through intact skull was tested in three rhesus monkeys. The aim of this study was to determine the amount of skull heating in an animal model with a head shape similar to that of a human. The ultrasound beam was generated by a 512 channel phased array system (Exablate ® 3000, InSightec, Haifa, Israel) that was integrated within a 1.5-T MR-scanner. The skin was pre-cooled by degassed temperature controlled water circulating between the array surface and the skin. Skull surface temperature was measured with invasive thermocouple probes. The results showed that by applying surface cooling the skin and skull surface can be protected, and that the brain surface temperature becomes the limiting factor. The MRI thermometry was shown to be useful in detecting the tissue temperature distribution next to the bone, and it should be used to monitor the brain surface temperature. The acoustic intensity values during the 20 s sonications were adequate for thermal ablation in the human brain provided that surface cooling is used. © 2006 Elsevier Ireland Ltd. All rights reserved.

To retrospectively evaluate magnetic resonance (MR) imaging-based thermometry and thermal dosimetry during focused ultrasound treatments of uterine leiomyomas (ie, fibroids).All patients gave written informed consent for the focused ultrasound treatments and the current HIPAA-compliant retrospective study, both of which were institutional review board approved. Thermometry performed during the treatments of 64 fibroids in 50 women (mean age, 46.6 years +/- 4.5 [standard deviation]) was used to create thermal dose maps. The areas that reached dose values of 240 and 18 equivalent minutes at 43 degrees C were compared with the nonperfused regions measured on contrast material-enhanced MR images by using the Bland-Altman method. Volume changes in treated fibroids after 6 months were compared with volume changes in nontreated fibroids and with MR-based thermal dose estimates.While the thermal dose estimates were shown to have a clear relationship with resulting nonperfused regions, the nonperfused areas were, on average, larger than the dose estimates (means of 1.9 +/- 0.7 and 1.2 +/- 0.4 times as large for areas that reached 240- and 18-minute threshold dose values, respectively). Good correlation was observed for smaller treatment volumes at the lower dose threshold (mean ratio, 1.0 +/- 0.3), but for larger treatment volumes, the nonperfused region extended to locations within the fibroid that clearly were not heated. Variations in peak temperature increase were as large as a factor of two, both between patients and within individual treatments. On average, the fibroid volume reduction at 6 months increased as the ablated volume estimated by using the thermal dose increased.Study results showed good correlation between thermal dose estimates and resulting nonperfused areas for smaller ablated volumes. For larger treatment volumes, nonperfused areas could extend within the fibroid to unheated areas.

Semantic priming refers to a reduction in the reaction time to identify or make a judgment about a stimulus that has been immediately preceded by a semantically related word or picture and is thought to result from a partial overlap in the semantic associates of the two words. A semantic priming lexical decision task using spoken words was presented in event-related fMRI and behavioral paradigms. Word pairs varied in terms of semantic relatedness and the connectivity between associates. Thirteen right-handed subjects underwent fMRI imaging and 10 additional subjects were tested in a behavioral version of the semantic priming task. It was hypothesized priming would be greatest, reaction time fastest, and cortical activation reduced the most for related word pairs of high connectivity, followed by related word pairs of low connectivity, and then by unrelated word pairs. Behavioral and fMRI results confirmed these predictions. fMRI activity located primarily in bilateral posterior superior and middle temporal regions showed modulation by connectivity and relatedness. The results suggest that these regions are involved in semantic processing.

To retrospectively assess the main variables that affect the complete magnetic resonance (MR) imaging-guided resection of supratentorial low-grade gliomas.Institutional review board approval was obtained for this retrospective HIPAA-compliant study, with the requirement for informed consent waived. Data from 101 patients (61 men, 40 women; mean age, 39 years; age range, 18-72 years) who had nonenhancing supratentorial mass lesions that were histopathologically diagnosed as low-grade (World Health Organization grade II) gliomas and consecutively underwent surgery with intraoperative MR imaging guidance were analyzed. There were 21 low-grade astrocytomas, 64 oligodendrogliomas, and 16 mixed oligoastrocytomas. Initial and residual tumor volumes were measured on intraoperative T2-weighted MR images and three-dimensional spoiled gradient-echo MR images. The anatomic relationships between the tumor and eloquent cortical and/or subcortical regions and the influence of these relationships on the extent of resection were analyzed on the basis of preoperative MR imaging findings. Summary measures, univariate Fisher exact test and t test, and multivariate logistic regression analyses were performed.Tumor volume ranged from 2.7-231.0 mL. Univariate analyses revealed the following tumor characteristics to be significant predictive variables of incomplete tumor resection: diffuse tumor margin on T2-weighted MR images, oligodendroglioma or oligoastrocytoma histopathologic type, and large tumor volume (P.05 for all). Tumor involvement of the following structures was associated with incomplete resection: corpus callosum, corticospinal tract, insular lobe, middle cerebral artery, motor cortex, optic radiation, visual cortex, and basal ganglia (P.05 for all). Multivariate analyses revealed that incomplete tumor resection was due to tumor involvement of the corticospinal tract (P.01), large tumor volume (P.01), and oligodendroglioma histopathologic type (P = .02).The main variables associated with incomplete tumor resection in 101 patients were identified by using statistical predictive analyses.

We present a new algorithm to register 3-D preoperative magnetic resonance (MR) images to intraoperative MR images of the brain which have undergone brain shift. This algorithm relies on a robust estimation of the deformation from a sparse noisy set of measured displacements. We propose a new framework to compute the displacement field in an iterative process, allowing the solution to gradually move from an approximation formulation (minimizing the sum of a regularization term and a data error term) to an interpolation formulation (least square minimization of the data error term). An outlier rejection step is introduced in this gradual registration process using a weighted least trimmed squares approach, aiming at improving the robustness of the algorithm. We use a patient-specific model discretized with the finite element method in order to ensure a realistic mechanical behavior of the brain tissue. To meet the clinical time constraint, we parallelized the slowest step of the algorithm so that we can perform a full 3-D image registration in 35 s (including the image update time) on a heterogeneous cluster of 15 personal computers. The algorithm has been tested on six cases of brain tumor resection, presenting a brain shift of up to 14 mm. The results show a good ability to recover large displacements, and a limited decrease of accuracy near the tumor resection cavity.

Objective. Medical classification accuracy studies often yield continuous data based on predictive models for treatment outcomes. A popular method for evaluating the performance of diagnostic tests is the receiver operating characteristic (ROC) curve analysis. The main objective was to develop a global statistical hypothesis test for assessing the goodness-of-fit (GOF) for parametric ROC curves via the bootstrap.Design. A simple log (or logit) and a more flexible Box-Cox normality transformations were applied to untransformed or transformed data from two clinical studies to predict complications following percutaneous coronary interventions (PCIs) and for image-guided neurosurgical resection results predicted by tumor volume, respectively. We compared a non-parametric with a parametric binormal estimate of the underlying ROC curve. To construct such a GOF test, we used the non-parametric and parametric areas under the curve (AUCs) as the metrics, with a resulting p value reported.Results. In the interventional cardiology example, logit and Box-Cox transformations of the predictive probabilities led to satisfactory AUCs (AUC = 0.888; p = 0.78, and AUC = 0.888; p = 0.73, respectively), while in the brain tumor resection example, log and Box-Cox transformations of the tumor size also led to satisfactory AUCs (AUC = 0.898; p = 0.61, and AUC = 0.899; p = 0.42, respectively). In contrast, significant departures from GOF were observed without applying any transformation prior to assuming a binormal model (AUC = 0.766; p = 0.004, and AUC=0.831; p = 0.03), respectively.Conclusions. In both studies the p values suggested that transformations were important to consider before applying any binormal model to estimate the AUC. Our analyses also demonstrated and confirmed the predictive values of different classifiers for determining the interventional complications following PCIs and resection outcomes in image-guided neurosurgery.

The history of MR-guided FUS demonstrates the need for merging advanced therapy technology with advanced imaging. Without the ability of MR imaging to localize the tumor margins and without the temperature-sensitive imaging that provides the closed-loop control of energy deposition, this method is inadequate for most clinical applications. Given these limitations,high-intensity focused ultrasound initially appeared to have a narrow application area and was not able to compete with other surgical or ablation methods. Today, MR imaging-guided FUS has become a safe and effective means of performing probe-delivered thermal ablations and minimally invasive surgery. Moreover, it has the potential to replace treatments that use ionizing radiation such as radiosurgery and brachytherapy. Although the cost of integrating"big ticket" MR imaging systems with complex and expensive phased arrays is high, this expenditure will largely be offset by eliminating hospitalization and anesthesia and by reducing complications. In effect, an investment in this emerging technology will ultimately redound to the benefit of the health care delivery system and, most important, to the patient. The FUS system provides a safe, repeatable treatment approach for benign tumors (eg, uterine fibroid and breast fibroadenoma) that do not require an aggressive approach. MR-guided FUS can also be used for debulking cancerous tissue. It has already been tested as a breast cancer treatment; its application for other malignancies in the brain, liver, and prostate is under development. MR-guided FUS offers an attractive alternative to conventional surgery because it incorporates intraoperative MR imaging, which provides far more precise target definition than is possible with the surgeon's direct visualization of the lesion. MR-guided FUS is undeniably the most promising interventional MR imaging method in the field of image-guided therapy today. It is applicable not only in the thermal coagulative treatment of tumors but also in several other medical situations for which invasive surgery or radiation may not be treatment options. The use of FUS for treating vascular malformation or functional disorders of the brain is also exciting. It is uniquely applicable for image-guided therapy using targeted drug delivery methods and gene therapy. Further advances in this technology will no doubt improve energy deposition and reduce treatment times. In the near future, FUS will offer a viable alternative to conventional surgery and radiation therapy; in the longer-term, it may also enable a host of targeted treatment methods aimed at eradicating or arresting heretofore intractable diseases such as certain brain malignancies and forms of epilepsy.

1 From the Dept of Radiology, Vanderbilt Univ Medical Ctr, RR-1223, MCN, 1161 21st Ave South, Nashville, TN 37232-2675 (C.L.P.); Dept of Radiology, Univ of Michigan Health Systems, Ann Arbor (H.P.C.); Dept of Radiology, Univ of Texas M.D. Anderson Cancer Ctr, Houston (J.G.G.); Dept of Radiology, Univ of Chicago, Ill (M.L.G.); Dept of Radiology, Duke Univ Medical Ctr, Durham, NC (J.A.I.); Dept of Radiology, Brigham and Women’s Hosp, Harvard Medical School, Boston, Mass (F.A.J.); Dept of Radiology, Univ of Massachusetts Medical School, Worcester (K.K.); Imaging Sciences Program, NIH, Bethesda, Md (K.C.P.L.); Dept of Radiology, David Geffen School of Medicine at UCLA, Los Angeles, Calif (M.M.G.); Dept of Radiology, Stanford Univ School of Medicine, Calif (S.N.); Diagnostic Radiology Dept, NIH, Bethesda, Md (R.M.S.); and Inst for Technology Assessment and Dept of Radiology, Massachusetts General Hosp, Harvard Medical School, Boston, and Dept of Health Policy and Management, Harvard School of Public Health, Boston, Mass (G.S.G.). Supported in part by grants from NIBIB (1 R13 EB003553-01) and the Whitaker Foundation.Received Nov 4, 2004; revision requested Dec 13; revision received Jan 23, 2005; accepted Feb 1. Address correspondence to C.L.P. (e-mail: leon.partain@vanderbilt.edu).

During neurosurgical procedures the objective of the neurosurgeon is to achieve the resection of as much diseased tissue as possible while achieving the preservation of healthy brain tissue. The restricted capacity of the conventional operating room to enable the surgeon to visualize critical healthy brain structures and tumor margin has lead, over the past decade, to the development of sophisticated intraoperative imaging techniques to enhance visualization. However, both rigid motion due to patient placement and nonrigid deformations occurring as a consequence of the surgical intervention disrupt the correspondence between preoperative data used to plan surgery and the intraoperative configuration of the patient's brain. Similar challenges are faced in other interventional therapies, such as in cryoablation of the liver, or biopsy of the prostate. We have developed algorithms to model the motion of key anatomical structures and system implementations that enable us to estimate the deformation of the critical anatomy from sequences of volumetric images and to prepare updated fused visualizations of preoperative and intraoperative images at a rate compatible with surgical decision making. This paper reviews the experience at Brigham and Women's Hospital through the process of developing and applying novel algorithms for capturing intraoperative deformations in support of image guided therapy.

The purpose of this study was to test the hypothesis that burst ultrasound in the presence of an ultrasound contrast agent can disrupt the blood-brain barrier (BBB) with acoustic parameters suitable for completely noninvasive exposure through the skull. The 10-ms exposures were targeted in the brains of 22 rabbits with a frequency of 690 kHz, a repetition frequency of 1 Hz, and peak rarefactional pressure amplitudes up to 3.1 MPa. The total exposure (sonication) time was 20 s. Prior to each sonication, a bolus of ultrasound contrast agent was injected intravenously. Contrast-enhanced MR images were obtained after the sonications to detect localized BBB disruption via local enhancement in the brain. Brain sections were stained with HE, TUNEL, and vanadium acid fuchsin (VAF)-toluidine blue staining. In addition, horseradish peroxidase (HRP) was injected into four rabbits prior to sonications and transmission electron microscopy was performed. The MRI contrast enhancement demonstrated BBB disruption at pressure amplitudes starting at 0.4 MPa with approximately 50%; at 0.8 MPa, 90%; and at 1.4 MPa, 100% of the sonicated locations showed enhancement. The histology findings following 4 h survival indicated that brain tissue necrosis was induced in approximately 70-80% of the sonicated locations at a pressure amplitude level of 2.3 MPa or higher. At lower pressure amplitudes, however, small areas of erythrocyte extravasation were seen. The electron microscopy findings demonstrated HRP passage through vessel walls via both transendothelial and paraendothelial routes. These results demonstrate that completely noninvasive focal disruption of the BBB is possible.

MRI-guided neurosurgery not only represents a technical challenge but a transformation from conventional hand-eye coordination to interactive navigational operations. In the future, multimodality-based images will be merged into a single model, in which anatomy and pathologic changes are at once distinguished and integrated into the same intuitive framework. The long-term goals of improving surgical procedures and attendant outcomes, reducing costs, and achieving broad use can be achieved with a three-pronged approach: 1. Improving the presentation of preoperative and real-time intraoperative image information 2. Integrating imaging and treatment-related technology into therapy delivery systems 3. Testing the clinical utility of image guidance in surgery The recent focus in technology development is on improving our ability to understand and apply medical images and imaging systems. Areas of active research include image processing, model-based image analysis, model deformation, real-time registration, real-time 3D (so-called "four-dimensional") imaging, and the integration and presentation of image and sensing information in the operating room. Key elements of the technical matrix also include visualization and display platforms and related software for information and display, model-based image understanding, the use of computing clusters to speed computation (ie, algorithms with partitioned computation to optimize performance), and advanced devices and systems for 3D device tracking (navigation). Current clinical applications are successfully incorporating real-time and/or continuously up-dated image-based information for direct intra-operative visualization. In addition to using traditional imaging systems during surgery, we foresee optimized use of molecular marker technology, direct measures of tissue characterization (ie, optical measurements and/or imaging), and integration of the next generation of surgical and therapy devices (including image-guided robotic systems). Although we expect the primary clinical thrusts of MRI-guided therapy to remain in neurosurgery, with the possible addition of other areas like orthopedic, head, neck, and spine surgery, we also anticipate increased use of image-guided focal thermal ablative methods (eg, laser, RF, cryoablation, high-intensity focused ultrasound). By validating the effectiveness of MRI-guided therapy in specific clinical procedures while refining the technology that serves as its underpinning at the same time, we expect many neurosurgeons will eventually embrace MRI as their intraoperative imaging choice. Clearly, intraoperative MRI offers several palpable advantages. Most important among these are improved medical outcomes, shorter hospitalization, and better and faster procedures with fewer complications. Certain economic and practical barriers also impede the large-scale use of intraoperative MRI. Although there has been a concerted technical effort to increase the benefit/cost ratio by gathering more accurate information, designing more localized and less invasive treatment devices, and developing better methods to orient and position therapy end-effectors, further research is needed. Indeed, the drive to improve and upgrade technology is ongoing. Specifically, in the context of the real-time representation of the patient's anatomy, we have improved the quality and utility of the information presented to the surgeon, which, in turn, contributes to more successful surgical outcomes. We can also expect improvements in intraoperative imaging systems as well as increased use of nonimaging sensors and robotics to facilitate more widespread use of intraoperative MRI.

A number of minimally invasive methods have been tested for the thermal ablation of liver tumors as an alternative to surgical resection. The use of focused ultrasound transducers to ablate deep tumors offers the first completely noninvasive alternative to these techniques. By increasing the flexibility of this technology with modern phased-array transducer design and by combining it with magnetic resonance imaging for targeting and online guidance, a powerful tool results with the potential to offer treatment to a larger population of patients, to reduce trauma to the patient, and to reduce the cost of treatment. In this article, we review previous work with focused ultrasound in the liver and recent experimental results with magnetic resonance imaging guidance.

The integration of imaging and thermal therapy can provide a minimally invasive or even noninvasive alternative to breast surgery for small tumors. Ongoing trials seek to show safety and efficacy for laser, radiofrequency, microwave, cryoablation, and focused ultrasound surgery. To be successful, these therapies must achieve equivalent or even greater efficacy as surgical outcomes and must demonstrate total ablation of the dominant lesion with negative margins, while sparing normal tissue beyond the target tissue. Procedures have been validated by histopathology subsequent to resection.