Beat Werner

High-intensity focused ultrasound for noninvasive functional neurosurgery

Transcranial magnetic resonance (MR)‐guided high‐intensity focused ultrasound (tcMRgHIFU) implies a novel, noninvasive treatment strategy for various brain diseases. Nine patients with chronic neuropathic pain were treated with selective medial thalamotomies. Precisely located thermal ablations of 4mm in diameter were produced at peak temperatures of 51°C to 60°C under continuous visual MR guidance and MR thermometry. The resulting lesions are clearly visible on follow‐up MR imaging. All treatments were well tolerated, without side effects or neurological deficits. This is the first report on successful clinical application of tcMRgHIFU in functional brain disorders, portraying it as safe and reliable for noninvasive neurosurgical interventions. Ann Neurol 2009;66:858–861

Transcranial magnetic resonance imaging–guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain

OBJECT Recent technological developments open the field of therapeutic application of focused ultrasound to the brain through the intact cranium. The goal of this study was to apply the new transcranial magnetic resonance imaging-guided focused ultrasound (tcMRgFUS) technology to perform noninvasive central lateral thalamotomies (CLTs) as a treatment for chronic neuropathic pain. METHODS In 12 patients suffering from chronic therapy-resistant neuropathic pain, tcMRgFUS CLT was proposed. In 11 patients, precisely localized thermal ablations of 3-4 mm in diameter were produced in the posterior part of the central lateral thalamic nucleus at peak temperatures between 51 ° C and 64 ° C with the aid of real-time patient monitoring and MR imaging and MR thermometry guidance. The treated neuropathic pain syndromes had peripheral (5 patients) or central (6 patients) origins and covered all body parts (face, arm, leg, trunk, and hemibody). RESULTS Patients experienced mean pain relief of 49% at the 3-month follow-up (9 patients) and 57% at the 1-year follow-up (8 patients). Mean improvement according to the visual analog scale amounted to 42% at 3 months and 41% at 1 year. Six patients experienced immediate and persisting somatosensory improvements. Somatosensory and vestibular clinical manifestations were always observed during sonication time because of ultrasound-based neuronal activation and/or initial therapeutic effects. Quantitative electroencephalography (EEG) showed a significant reduction in EEG spectral overactivities. Thermal ablation sites showed sharply delineated ellipsoidal thermolesions surrounded by short-lived vasogenic edema. Lesion reconstructions (18 lesions in 9 patients) demonstrated targeting precision within a millimeter for all 3 coordinates. There was 1 complication, a bleed in the target with ischemia in the motor thalamus, which led to the introduction of 2 safety measures, that is, the detection of a potential cavitation by a cavitation detector and the maintenance of sonication temperatures below 60 ° C. CONCLUSIONS The authors assert that tcMRgFUS represents a noninvasive, precise, and radiation-free neurosurgical technique for the treatment of neuropathic pain. The procedure avoids mechanical brain tissue shift and eliminates the risk of infection. The possibility of applying sonication thermal spots free from trajectory restrictions should allow one to optimize target coverage. The real-time continuous MR imaging and MR thermometry monitoring of targeting accuracy and thermal effects are major factors in optimizing precision, safety, and efficacy in an outpatient context.

First noninvasive thermal ablation of a brain tumor with MR-guided focusedultrasound

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) allows for precisethermal ablation of target tissues. While this emerging modality is increasinglyused for the treatment of various types of extracranial soft tissue tumors, ithas only recently been acknowledged as a modality for noninvasive neurosurgery.MRgFUS has been particularly successful for functional neurosurgery, whereas itsclinical application for tumor neurosurgery has been delayed for varioustechnical and procedural reasons. Here, we report the case of a 63-year-oldpatient presenting with a centrally located recurrent glioblastoma who wasincluded in our ongoing clinical phase I study aimed at evaluating thefeasibility and safety of transcranial MRgFUS for brain tumor ablation. Applying25 high-power sonications under MR imaging guidance, partial tumor ablationcould be achieved without provoking neurological deficits or other adverseeffects in the patient. This proves, for the first time, the feasibility ofusing transcranial MR-guided focused ultrasound to safely ablate substantialvolumes of brain tumor tissue.

Sequence optimization to reduce velocity offsets in cardiovascular magnetic resonance volume flow quantification - A multi-vendor study

PurposeEddy current induced velocity offsets are of concern for accuracy in cardiovascular magnetic resonance (CMR) volume flow quantification. However, currently known theoretical aspects of eddy current behavior have not led to effective guidelines for the optimization of flow quantification sequences. This study is aimed at identifying correlations between protocol parameters and the resulting velocity error in clinical CMR flow measurements in a multi-vendor study.MethodsNine 1.5T scanners of three different types/vendors were studied. Measurements were performed on a large stationary phantom. Starting from a clinical breath-hold flow protocol, several protocol parameters were varied. Acquisitions were made in three clinically relevant orientations. Additionally, a time delay between the bipolar gradient and read-out, asymmetric versus symmetric velocity encoding, and gradient amplitude and slew rate were studied in adapted sequences as exploratory measurements beyond the protocol. Image analysis determined the worst-case offset for a typical great-vessel flow measurement.ResultsThe results showed a great variation in offset behavior among scanners (standard deviation among samples of 0.3, 0.4, and 0.9 cm/s for the three different scanner types), even for small changes in the protocol. Considering the absolute values, none of the tested protocol settings consistently reduced the velocity offsets below the critical level of 0.6 cm/s neither for all three orientations nor for all three scanner types. Using multilevel linear model analysis, oblique aortic and pulmonary slices showed systematic higher offsets than the transverse aortic slices (oblique aortic 0.6 cm/s, and pulmonary 1.8 cm/s higher than transverse aortic). The exploratory measurements beyond the protocol yielded some new leads for further sequence development towards reduction of velocity offsets; however those protocols were not always compatible with the time-constraints of breath-hold imaging and flow-related artefacts.ConclusionsThis study showed that with current systems there was no generic protocol which resulted into acceptable flow offset values. Protocol optimization would have to be performed on a per scanner and per protocol basis. Proper optimization might make accurate (transverse) aortic flow quantification possible for most scanners. Pulmonary flow quantification would still need further (offline) correction.

Noninvasive functional neurosurgery using transcranial MR imaging-guided focused ultrasound

UNLABELLED Transcranial magnetic resonance imaging-guided focused ultrasound (tcMRgFUS) is a novel technique to supplement the spectrum of established neurosurgical interventions. In contrast to traditional ablative procedures, tcMRgFUS is noninvasive and entirely imaging-guided with continuous temperature measurements at and around the target in real time. It has no trajectory restrictions and does not involve ionizing radiation. Since no device is implanted into the brain or the body, there is no restriction to future diagnostic work-up with MR imaging. The ability to treat a variety of chronic, therapy-resistant neurological diseases by precisely focusing ultrasound energy to desired targets in the thalamus, subthalamus and basal ganglia while avoiding collateral tissue damage is certainly attractive. Ongoing clinical studies on over 130 patients with neuropathic pain, essential tremor, Parkinsons disease and obsessive-compulsive disorder are very promising and demonstrate that ultrasound energy can precisely be focused through the intact skull, without overheating it. Varying the ultrasound parameters allows not only to ablate pathological tissue, or silence dysfunctional neuronal circuits, but also to modulate neural functions, as shown in preclinical studies. CONCLUSION Transcranial magnetic resonance imaging-guided focused ultrasound is a novel, noninvasive, alternative treatment option for patients with therapy-resistant movement disorders, such as essential tremor and Parkinsons disease.

Prolonged survival upon ultrasound-enhanced doxorubicin delivery in two syngenic glioblastoma mouse models

Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans with a very poor prognosis. Chemotherapeutical treatment of GBMs is limited by the blood-brain barrier (BBB). This physical and metabolic barrier separates the blood from the brain parenchyma and prevents the entry of toxins but also of potentially useful chemotherapeutics from the blood into the brain. Microbubble-enhanced focused ultrasound (MB-FUS) has been proposed to disrupt locally and reversibly the BBB to facilitate diffusion of drugs from the micro vasculature into brain tissue. The present study investigates the feasibility and the safety of such an approach in two syngenic mouse models of GBM (GL261 and SMA-560). Local doxorubicin (DOX) concentration in MB-FUS sonicated normal brain tissue as well as in brain tumor tissue was increased as compared to the unsonicated control tissue in the contralateral hemisphere. Moreover, ultrasound mediated BBB disruption, in combination with DOX therapy, resulted in a significant increase of survival and in a slower disease progression in the two syngenic GBM mouse models. In conclusion, our results confirm that MB-ultrasound might ultimately be an effective technology to improve the therapy of GBM, and they provide for the first time evidence that combining MB-FUS with DOX treatment is effective in syngenic mouse models for GBM which can serve as preclinical models to study the impact of immune system on the therapeutic application of MB-FUS chemotherapy.

A review of numerical and experimental compensation techniques for skull-induced phase aberrations in transcranial focused ultrasound

Abstract The development of phased array transducers and their integration with magnetic resonance (MR) guidance and thermal monitoring has established transcranial MR-guided focused ultrasound (tcMRgFUS) as an attractive non-invasive modality for neurosurgical interventions. The presence of the skull, however, compromises the efficiency of transcranial FUS (tcFUS) therapy, as its heterogeneous nature and acoustic characteristics induce significant phase aberrations and energy attenuation, especially at the higher acoustic frequencies employed in tcFUS thermal therapy. These aberrations may distort and shift the acoustic focus as well as induce heating at the patient’s scalp and skull bone. Phased array transducers feature hundreds of elements that can be driven individually, each with its own phase and amplitude. This feature allows for compensation of skull-induced aberrations by calculation and application of appropriate phase and amplitude corrections. In this paper, we illustrate the importance of precise refocusing and provide a comprehensive review of the wide variety of numerical and experimental techniques that have been used to estimate these corrections.

Numerical simulations of clinical focused ultrasound functional neurosurgery

A computational model utilizing grid and finite difference methods were developed to simulate focused ultrasound functional neurosurgery interventions. The model couples the propagation of ultrasound in fluids (soft tissues) and solids (skull) with acoustic and visco-elastic wave equations. The computational model was applied to simulate clinical focused ultrasound functional neurosurgery treatments performed in patients suffering from therapy resistant chronic neuropathic pain. Datasets of five patients were used to derive the treatment geometry. Eight sonications performed in the treatments were then simulated with the developed model. Computations were performed by driving the simulated phased array ultrasound transducer with the acoustic parameters used in the treatments. Resulting focal temperatures and size of the thermal foci were compared quantitatively, in addition to qualitative inspection of the simulated pressure and temperature fields. This study found that the computational model and the simulation parameters predicted an average of 24 ± 13% lower focal temperature elevations than observed in the treatments. The size of the simulated thermal focus was found to be 40 ± 13% smaller in the anterior-posterior direction and 22 ± 14% smaller in the inferior-superior direction than in the treatments. The location of the simulated thermal focus was off from the prescribed target by 0.3 ± 0.1 mm, while the peak focal temperature elevation observed in the measurements was off by 1.6 ± 0.6 mm. Although the results of the simulations suggest that there could be some inaccuracies in either the tissue parameters used, or in the simulation methods, the simulations were able to predict the focal spot locations and temperature elevations adequately for initial treatment planning performed to assess, for example, the feasibility of sonication. The accuracy of the simulations could be improved if more precise ultrasound tissue properties (especially of the skull bone) could be obtained.

Comparison of temperature processing methods for monitoring focused ultrasound ablation in the brain

To investigate the performance of different reconstruction methods for monitoring temperature changes during transcranial magnetic resonance imaging (MRI)‐guided focused ultrasound (MRgFUS).

Unilateral cerebellothalamic tract ablation in essential tremor by MRI-guided focused ultrasound

Objective: To report results of a prospective trial of unilateral transcranial MRI-guided focused ultrasound (MRIgFUS) ablation of the cerebellothalamic tract in essential tremor (ET). Methods: This was a prospective, uncontrolled, single-center interventional study. Patients with ET fulfilling criteria for interventional therapy received unilateral ablation of the cerebellothalamic tract (CTT) by MRIgFUS. Motor symptoms, manual dexterity, cognition, and quality of life were assessed before intervention and at 48 hours and 1, 3, and 6 months after intervention. Rating of standardized video recordings was blinded for evaluation time points. Primary outcome was the change in unilateral hand tremor score of the treated hand. Results: Six patients received MRIgFUS ablation of the CTT contralateral to the treated hand. Repeated-measures comparison determined a statistically significant 83% reduction (before vs 6 months after intervention mean ± SD; absolute reduction; 95% confidence interval) in the unilateral treated hand subscore (14.3 ± 4.9 vs 2.5 ± 2.6; 11.8; 8.4–15.2; p < 0.001), while quality of life improved by 52% (50.5 ± 19.4 vs 24.8 ± 11.4; 25.7; 3.5–47.28; p = 0.046). Measures for manual dexterity, attention and coordination, and overall cognition were unchanged. Transient side effects (n = 3) were ipsilateral hand clumsiness and mild gait instability for up to 3 months. Conclusions: Unilateral MRIgFUS lesioning of the CTT was highly efficacious in reducing contralateral hand tremor in ET without affecting fine motor function and dexterity over 6 months of follow-up. Adverse effects were mild and transient. Classification of evidence: This study provides Class IV evidence that for patients with ET, transcranial MRIgFUS ablation of the cerebellothalamic tract improves tremor.