Eyal Zadicario

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.

Conservative Visibility and Strong Occlusion for Viewspace Partitioning of Densely Occluded Scenes

Computing the visibility of out‐door scenes is often much harder than of in‐door scenes. A typical urban scene, for example, is densely occluded, and it is effective to precompute its visibility space, since from a given point only a small fraction of the scene is visible. The difficulty is that although the majority of objects are hidden, some parts might be visible at a distance in an arbitrary location, and it is not clear how to detect them quickly. In this paper we present a method to partition the viewspace into cells containing a conservative superset of the visible objects. For a given cell the method tests the visibility of all the objects in the scene. For each object it searches for a strong occluder which guarantees that the object is not visible from any point within the cell. We show analytically that in a densely occluded scene, the vast majority of objects are strongly occluded, and the overhead of using conservative visibility (rather than visibility) is small. These results are further supported by our experimental results. We also analyze the cost of the method and discuss its effectiveness.

Unilateral magnetic resonance guided focused ultrasound thalamotomy for essential tremor: practices and clinicoradiological outcomes

Background Several options exist for surgical management of essential tremor (ET), including radiofrequency lesioning, deep brain stimulation and γ knife radiosurgery of the ventralis intermedius nucleus of the thalamus. Recently, magnetic resonance-guided focused ultrasound (MRgFUS) has been developed as a less-invasive surgical tool aimed to precisely generate focal thermal lesions in the brain. Methods Patients underwent tremor evaluation and neuroimaging study at baseline and up to 6 months after MRgFUS. Tremor severity and functional impairment were assessed at baseline and then at 1 week, 1 month, 3 months and 6 months after treatment. Adverse effects were also sought and ascertained by directed questions, neuroimaging results and neurological examination. Results The current feasibility study attempted MRgFUS thalamotomy in 11 patients with medication-resistant ET. Among them, eight patients completed treatment with MRgFUS, whereas three patients could not complete the treatment because of insufficient temperature. All patients who completed treatment with MRgFUS showed immediate and sustained improvements in tremors lasting for the 6-month follow-up period. Skull volume and maximum temperature rise were linearly correlated (linear regression, p=0.003). Other than one patient who had mild and delayed postoperative balance, no patient developed significant postsurgical complications; about half of the patients had bouts of dizziness during the MRgFUS. Conclusions Our results demonstrate that MRgFUS thalamotomy is a safe, effective and less-invasive surgical method for treating medication-refractory ET. However, several issues must be resolved before clinical application of MRgFUS, including optimal patient selection and management of patients during treatment.

Magnetic resonance imaging-guided focused ultrasound for thermal ablation in the brain: a feasibility study in a swine model.

INTRODUCTIONMagnetic resonance imaging (MRI)-guided focused ultrasound is a novel technique that was developed to enable precise, image-guided targeting and destruction of tumors by thermocoagulation. The system, ExAblate2000, is a focused ultrasound delivery system embedded within the MRI bed of a conventional diagnostic MRI scanner. The device delivers small volumetric sonications from an ultrasound phased array transmitter that converge energy to selectively destroy the target. Temperature maps generated by the MRI scanner verify the location and thermal rise as feedback, as well as thermal destruction. To assess the safety, feasibility, and precision of this technology in the brain, we have used the ExAblate system to create predefined thermal lesions in the brains of pigs. METHODSTen pigs underwent bilateral craniectomy to provide a bone window for the ultrasound beams. Seven to 10 days later, the animals were anesthetized and positioned in the ExAblate system. A predefined, 1-cm3 frontal para ventricular region was delineated as the target and treated with multiple sonications. MRI was performed immediately and 1 week after treatment. The animals were then sacrificed and the brains removed for pathological study. The size of individual sonication points and the location of the lesion were compared between the planned dose maps, posttreatment MRI scans, and pathological specimen. RESULTSHigh-energy sonications led to precise coagulation necrosis of the specified targets as shown by subsequent MRI, macroscopic, and histological analysis. The thermal lesions were sharply demarcated from the surrounding brain with no anatomic or histological abnormalities outside the target. CONCLUSIONMRI-guided focused ultrasound proved a precise and an effective means to destroy anatomically predefined brain targets by thermocoagulation with minimal associated edema or damage to adjacent structures. Contrast-enhanced T1-, T2-, and diffusion-weighted MRI scans may be used for real-time assessment of tissue destruction.

Imaging Findings in MR Imaging-Guided Focused Ultrasound Treatment for Patients with Essential Tremor

This study reports the imaging findings after focused ultrasound ablation of the intermedius nuclei in patients with essential tremor. Fifteen patients received follow-up MRI studies on 4 occasions after treatment. Maximal lesion size and perilesional edema predicted a good outcome and all lesions showed consistent and typical findings in the days, weeks, and months after treatment. BACKGROUND AND PURPOSE: MR imaging–guided focused sonography surgery is a new stereotactic technique that uses high-intensity focused sonography to heat and ablate tissue. The goal of this study was to describe MR imaging findings pre- and post-ventralis intermedius nucleus lesioning by MR imaging–guided focused sonography as a treatment for essential tremor and to determine whether there was an association between these imaging features and the clinical response to MR imaging–guided focused sonography. MATERIALS AND METHODS: Fifteen patients with medication-refractory essential tremor prospectively gave consent; were enrolled in a single-site, FDA-approved pilot clinical trial; and were treated with transcranial MR imaging–guided focused sonography. MR imaging studies were obtained on a 3T scanner before the procedure and 24 hours, 1 week, 1 month, and 3 months following the procedure. RESULTS: On T2-weighted imaging, 3 time-dependent concentric zones were seen at the site of the focal spot. The inner 2 zones showed reduced ADC values at 24 hours in all patients except one. Diffusion had pseudonormalized by 1 month in all patients, when the cavity collapsed. Very mild postcontrast enhancement was seen at 24 hours and again at 1 month after MR imaging–guided focused sonography. The total lesion size and clinical response evolved inversely compared with each other (coefficient of correlation = 0.29, P value = .02). CONCLUSIONS: MR imaging–guided focused sonography can accurately ablate a precisely delineated target, with typical imaging findings seen in the days, weeks, and months following the treatment. Tremor control was optimal early when the lesion size and perilesional edema were maximal and was less later when the perilesional edema had resolved.

Different magnetic resonance imaging patterns after transcranial magnetic resonance–guided focused ultrasound of the ventral intermediate nucleus of the thalamus and anterior limb of the internal capsule in patients with essential tremor or obsessive-compulsive disorder

OBJECT The authors report different MRI patterns in patients with essential tremor (ET) or obsessive-compulsive disorder (OCD) after transcranial MR-guided focused ultrasound (MRgFUS) and discuss possible causes of occasional MRgFUS failure. METHODS Between March 2012 and August 2013, MRgFUS was used to perform unilateral thalamotomy in 11 ET patients and bilateral anterior limb capsulotomy in 6 OCD patients; in all patients symptoms were refractory to drug therapy. Sequential MR images were obtained in patients across a 6-month follow-up period. RESULTS For OCD patients, lesion size slowly increased and peaked 1 week after treatment, after which lesion size gradually decreased. For ET patients, lesions were visible immediately after treatment and markedly reduced in size as time passed. In 3 ET patients and 1 OCD patient, there was no or little temperature rise (i.e., < 52°C) during MRgFUS. Successful and failed patient groups showed differences in their ratio of cortical-to-bone marrow thickness (i.e., skull density). CONCLUSIONS The authors found different MRI pattern evolution after MRgFUS for white matter and gray matter. Their results suggest that skull characteristics, such as low skull density, should be evaluated prior to MRgFUS to successfully achieve thermal rise.

Minimally invasive treatment of intracerebral hemorrhage with magnetic resonance-guided focused ultrasound.

OBJECT Intracerebral hemorrhage (ICH) is a major cause of death and disability throughout the world. Surgical techniques are limited by their invasive nature and the associated disability caused during clot removal. Preliminary data have shown promise for the feasibility of transcranial MR-guided focused ultrasound (MRgFUS) sonothrombolysis in liquefying the clotted blood in ICH and thereby facilitating minimally invasive evacuation of the clot via a twist-drill craniostomy and aspiration tube. METHODS AND RESULTS In an in vitro model, the following optimum transcranial sonothrombolysis parameters were determined: transducer center frequency 230 kHz, power 3950 W, pulse repetition rate 1 kHz, duty cycle 10%, and sonication duration 30 seconds. Safety studies were performed in swine (n = 20). In a swine model of ICH, MRgFUS sonothrombolysis of 4 ml ICH was performed. Magnetic resonance imaging and histological examination demonstrated complete lysis of the ICH without additional brain injury, blood-brain barrier breakdown, or thermal necrosis due to sonothrombolysis. A novel cadaveric model of ICH was developed with 40-ml clots implanted into fresh cadaveric brains (n = 10). Intracerebral hemorrhages were successfully liquefied (> 95%) with transcranial MRgFUS in a highly accurate fashion, permitting minimally invasive aspiration of the lysate under MRI guidance. CONCLUSIONS The feasibility of transcranial MRgFUS sonothrombolysis was demonstrated in in vitro and cadaveric models of ICH. Initial in vivo safety data in a swine model of ICH suggest the process to be safe. Minimally invasive treatment of ICH with MRgFUS warrants evaluation in the setting of a clinical trial.

‘Looping’—an exploration mechanism in a dark open field

The behavior of Tristrams jird (a species of gerbil) in an illuminated open field resembled that of other rodents, comprising round trips to a home base and alternating between periods of progression (locomoting) and of stopping. In this study, we compared the characteristics of exploration in a dark arena with exploration by the same individuals in a lit arena. In the dark arena, stopping episodes were brief and fewer, suggesting almost continuous locomotion by the rodents. The clear distinction between progression and stopping that had characterized locomotion in an illuminated arena, thus diminished in the dark. There was also no apparent home base in the dark and traveling consisted in moving in a circular path, closing a loop to a recently traveled place that varied from one loop to the next. Locomotion in the dark may thus be regarded as a set of loops (round trips) to a continuously shifting home base, whereas with lights on the round trips converge to a home base using visible environmental landmarks. We suggest that a similar looping mechanism may be applicable to the behavior of hippocampal rats displaying hyperactivity and diversified locomotion, reminiscent of that seen in jirds in a dark arena.

Transcranial magnetic resonance–guided focused ultrasound surgery for trigeminal neuralgia: a cadaveric and laboratory feasibility study

OBJECT Transcranial MR-guided focused ultrasound surgery (MRgFUS) is evolving as a treatment modality in neurosurgery. Until now, the trigeminal nerve was believed to be beyond the treatment envelope of existing high-frequency transcranial MRgFUS systems. In this study, the authors explore the feasibility of targeting the trigeminal nerve in a cadaveric model with temperature assessments using computer simulations and an in vitro skull phantom model fitted with thermocouples. METHODS Six trigeminal nerves from 4 unpreserved cadavers were targeted in the first experiment. Preprocedural CT scanning of the head was performed to allow for a skull correction algorithm. Three-Tesla, volumetric, FIESTA MRI sequences were performed to delineate the trigeminal nerve and any vascular structures of the cisternal segment. The cadaver was positioned in a focused ultrasound transducer (650-kHz system, ExAblate Neuro, InSightec) so that the focus of the transducer was centered at the proximal trigeminal nerve, allowing for targeting of the root entry zone (REZ) and the cisternal segment. Real-time, 2D thermometry was performed during the 10- to 30-second sonication procedures. Post hoc MR thermometry was performed on a computer workstation at the conclusion of the procedure to analyze temperature effects at neuroanatomical areas of interest. Finally, the region of the trigeminal nerve was targeted in a gel phantom encased within a human cranium, and temperature changes in regions of interest in the skull base were measured using thermocouples. RESULTS The trigeminal nerves were clearly identified in all cadavers for accurate targeting. Sequential sonications of 25-1500 W for 10-30 seconds were successfully performed along the length of the trigeminal nerve starting at the REZ. Real-time MR thermometry confirmed the temperature increase as a narrow focus of heating by a mean of 10°C. Postprocedural thermometry calculations and thermocouple experiments in a phantom skull were performed and confirmed minimal heating of adjacent structures including the skull base, cranial nerves, and cerebral vessels. For targeting, inclusion of no-pass regions through the petrous bone decreased collateral heating in the internal acoustic canal from 16.7°C without blocking to 5.7°C with blocking. Temperature at the REZ target decreased by 3.7°C with blocking. Similarly, for midcisternal targeting, collateral heating at the internal acoustic canal was improved from a 16.3°C increase to a 4.9°C increase. Blocking decreased the target temperature increase by 4.4°C for the same power settings. CONCLUSIONS This study demonstrates focal heating of up to 18°C in a cadaveric trigeminal nerve at the REZ and along the cisternal segment with transcranial MRgFUS. Significant heating of the skull base and surrounding neural structures did not occur with implementation of no-pass regions. However, in vivo studies are necessary to confirm the safety and efficacy of this potentially new, noninvasive treatment.