Transcranial magnetic resonance imaging-guided focused ultrasound thalamotomy for tremor: technical note.

Although the use of focused ultrasound (FUS) in neurosurgery dates to the 1950s, its clinical utility was limited by the need for a craniotomy to create an acoustic window. Recent technological advances have enabled efficient transcranial delivery of US. Moreover, US is now coupled with MRI to ensure precise energy delivery and monitoring. Thus, MRI-guided transcranial FUS lesioning is now being investigated for myriad neurological and psychiatric disorders. Among the first transcranial FUS treatments is thalamotomy for the treatment of various tremors. The authors provide a technical overview of FUS thalamotomy for tremor as well as important lessons learned during their experience with this emerging technology.

Focused ultrasound-mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters.

OBJECTIVE The application of pharmacological therapeutics in neurological disorders is limited by the ability of these agents to penetrate the blood-brain barrier (BBB). Focused ultrasound (FUS) has recently gained attention for its potential application as a method for locally opening the BBB and thereby facilitating drug delivery into the brain parenchyma. However, this method still requires optimization to maximize its safety and efficacy for clinical use. In the present study, the authors examined several sonication parameters of FUS influencing BBB opening in small animals. METHODS Changes in BBB permeability were observed during transcranial sonication using low-intensity FUS in 20 adult male Sprague-Dawley rats. The authors examined the effects of FUS sonication with different sonication parameters, varying acoustic pressure, center frequency, burst duration, microbubble (MB) type, MB dose, pulse repetition frequency (PRF), and total exposure time. The focal region of BBB opening was identified by Evans blue dye. Additionally, H & E staining was used to identify blood vessel damage. RESULTS Acoustic pressure amplitude and burst duration were closely associated with enhancement of BBB opening efficiency, but these parameters were also highly correlated with tissue damage in the sonicated region. In contrast, MB types, MB dose, total exposure time, and PRF had an influence on BBB opening without conspicuous tissue damage after FUS sonication. CONCLUSIONS The study aimed to identify these influential conditions and provide safety and efficacy values for further studies. Future work based on the current results is anticipated to facilitate the implementation of FUS sonication for drug delivery in various CNS disease states in the near future.

Neuromodulation with transcranial focused ultrasound.

The understanding of brain function and the capacity to treat neurological and psychiatric disorders rest on the ability to intervene in neuronal activity in specific brain circuits. Current methods of neuromodulation incur a tradeoff between spatial focus and the level of invasiveness. Transcranial focused ultrasound (FUS) is emerging as a neuromodulation approach that combines noninvasiveness with focus that can be relatively sharp even in regions deep in the brain. This may enable studies of the causal role of specific brain regions in specific behaviors and behavioral disorders. In addition to causal brain mapping, the spatial focus of FUS opens new avenues for treatments of neurological and psychiatric conditions. This review introduces existing and emerging FUS applications in neuromodulation, discusses the mechanisms of FUS effects on cellular excitability, considers the effects of specific stimulation parameters, and lays out the directions for future work.

Predicting lesion size during focused ultrasound thalamotomy: a review of 63 lesions over 3 clinical trials.

OBJECTIVE The goal of this study was to improve the predictability of lesion size during focused ultrasound (FUS) thalamotomy procedures. METHODS Treatment profiles and T2-weighted MRI (T2 MRI) studies obtained in 63 patients who participated in 3 clinical trials of FUS thalamotomy from February 2011 to March 2015 were reviewed retrospectively. Four damage estimate models were compared with lesion sizes measured on postprocedural T2 MRI. Models were based on 54°C × 3 seconds, 240 cumulative equivalent minutes at 43°C, and simple thermal threshold analysis, which recorded the maximum diameter that reached a temperature of at least 51°C and 54°C. Energy requirements per °C thermal rise above 37°C were also recorded. RESULTS Lesion diameters from T2 MRI correlated poorly from the day of the procedure to day 1 postprocedure (mean increase 78% [SD 79%]). There was more predictability of lesion size from day 1 to day 30, with a mean reduction in lesion diameter of 11% (SD 24%). Of the 4 models tested, the most correlative model to day 1 findings on T2 MRI was a 51°C threshold. The authors observed an increase in the energy requirement for each subsequent treatment sonication, with the largest percentage increase from treatment sonication 1 to treatment sonication 2 (mean increase 20% in energy required per °C increase in temperature above 37°C). CONCLUSIONS At the margins, 51°C temperature threshold diameters correlated best to lesion diameters measured at day 1 with T2 MRI. The lesion size from T2 MRI decreases from day 1 to day 30 in a predictable manner, much more so than from the day of the procedure to day 1 postprocedure. Energy requirements per °C rise above 37°C continuously increase with each successive sonication.

A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy.

Magnetic resonance-guided focused ultrasound (MRgFUS) has been used extensively to ablate brain tissue in movement disorders, such as essential tremor. At a lower energy, MRgFUS can disrupt the blood-brain barrier (BBB) to allow passage of drugs. This focal disruption of the BBB can target systemic medications to specific portions of the brain, such as for brain tumors. Current methods to bypass the BBB are invasive, as the BBB is relatively impermeable to systemically delivered antineoplastic agents. Multiple healthy and brain tumor animal models have suggested that MRgFUS disrupts the BBB and focally increases the concentration of systemically delivered antitumor chemotherapy, immunotherapy, and gene therapy. In animal tumor models, combining MRgFUS with systemic drug delivery increases median survival times and delays tumor progression. Liposomes, modified microbubbles, and magnetic nanoparticles, combined with MRgFUS, more effectively deliver chemotherapy to brain tumors. MRgFUS has great potential to enhance brain tumor drug delivery, while limiting treatment toxicity to the healthy brain.

High-intensity focused ultrasound: past, present, and future in neurosurgery.

Since Lynn and colleagues first described the use of focused ultrasound (FUS) waves for intracranial ablation in 1942, many strides have been made toward the treatment of several brain pathologies using this novel technology. In the modern era of minimal invasiveness, high-intensity focused ultrasound (HIFU) promises therapeutic utility for multiple neurosurgical applications, including treatment of tumors, stroke, epilepsy, and functional disorders. Although the use of HIFU as a potential therapeutic modality in the brain has been under study for several decades, relatively few neuroscientists, neurologists, or even neurosurgeons are familiar with it. In this extensive review, the authors intend to shed light on the current use of HIFU in different neurosurgical avenues and its mechanism of action, as well as provide an update on the outcome of various trials and advances expected from various preclinical studies in the near future. Although the initial technical challenges have been overcome and the technology has been improved, only very few clinical trials have thus far been carried out. The number of clinical trials related to neurological disorders is expected to increase in the coming years, as this novel therapeutic device appears to have a substantial expansive potential. There is great opportunity to expand the use of HIFU across various medical and surgical disciplines for the treatment of different pathologies. As this technology gains recognition, it will open the door for further research opportunities and innovation.

Therapeutic strategies to improve drug delivery across the blood-brain barrier.

Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBB's physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor. This review describes the characteristics of the BBB and associated changes wrought by the presence of a tumor. Current strategies for enhancing the delivery of therapies across the BBB to the tumor will be discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it.

Skull bone marrow injury caused by MR-guided focused ultrasound for cerebral functional procedures.

OBJECTIVE: One patient for whom an MR-guided focused ultrasound (MRgFUS) pallidotomy was attempted was discovered to have multiple new skull lesions with the appearance of infarcts on the MRI scan 3 months after his attempted treatment. The authors conducted a retrospective review of the first 30 patients treated with MRgFUS to determine the incidence of skull lesions in patients undergoing these procedures and to consider possible causes. METHODS: A retrospective review of the MRI scans of the first 30 patients, 1 attempted pallidotomy and 29 ventral intermediate nucleus thalamotomies, was conducted. The correlation of the mean skull density ratio (SDR) and the maximum energy applied in the production or attempted production of a brain lesion was examined. RESULTS: Of 30 patients treated with MRgFUS for movement disorders, 7 were found to have new skull lesions that were not present prior to treatment and not visible on the posttreatment day 1 MRI scan. Discomfort was reported at the time of treatment by some patients with and without skull lesions. All patients with skull lesions were completely asymptomatic. There was no correlation between the mean SDR and the presence or absence of skull lesions, but the maximum energy applied with the Exablate system was significantly greater in patients with skull lesions than in those without. CONCLUSIONS: It is known that local skull density, thickness, and SDR vary from location to location. Sufficient energy transfer resulting in local heating sufficient to produce a bone lesion may occur in regions of low SDR. A correlation of lesion location and local skull properties should be made in future studies.

A single case of MRI-guided focused ultrasound ventro-oral thalamotomy for musician's dystonia.

Musician's dystonia (MD) is a type of focal hand dystonia that develops only while playing musical instruments and interferes with skilled and fine movements. Lesioning of the ventro-oral (Vo) nucleus of the thalamus (Vo-thalamotomy) using radiofrequency can cause dramatic improvement in MD symptoms. Focused ultrasound (FUS) can make intracranial focal lesions without an incision. The authors used MRI-guided FUS (MRgFUS) to create a lesion on the Vo nucleus to treat a patient with MD. Tubiana's MD scale (TMDS) was used to evaluate the condition of musical play ranging from 1 to 5 (1: worst, 5: best). The patient was a 35-year-old right-handed man with involuntary flexion of the right second, third, and fourth fingers, which occurred while playing a classical guitar. Immediately after therapeutic sonications of FUS Vo-thalamotomy, there was dramatic improvement in the MD symptoms. The TMDS scores before; at 0 and 1 week after; and at 1, 3, 6, and 12 months after MRgFUS Vo-thalamotomy were 1, 4, 4, 5, 5, 5, and 5, respectively. No complications were observed. Focused ultrasound Vo-thalamotomy can be an effective treatment for MD.

Noninvasive neuromodulation and thalamic mapping with low-intensity focused ultrasound.

OBJECTIVE Ultrasound can be precisely focused through the intact human skull to target deep regions of the brain for stereotactic ablations. Acoustic energy at much lower intensities is capable of both exciting and inhibiting neural tissues without causing tissue heating or damage. The objective of this study was to demonstrate the effects of low-intensity focused ultrasound (LIFU) for neuromodulation and selective mapping in the thalamus of a large-brain animal. METHODS Ten Yorkshire swine ( Sus scrofa domesticus) were used in this study. In the first neuromodulation experiment, the lemniscal sensory thalamus was stereotactically targeted with LIFU, and somatosensory evoked potentials (SSEPs) were monitored. In a second mapping experiment, the ventromedial and ventroposterolateral sensory thalamic nuclei were alternately targeted with LIFU, while both trigeminal and tibial evoked SSEPs were recorded. Temperature at the acoustic focus was assessed using MR thermography. At the end of the experiments, all tissues were assessed histologically for damage. RESULTS LIFU targeted to the ventroposterolateral thalamic nucleus suppressed SSEP amplitude to 71.6% ± 11.4% (mean ± SD) compared with baseline recordings. Second, we found a similar degree of inhibition with a high spatial resolution (∼ 2 mm) since adjacent thalamic nuclei could be selectively inhibited. The ventromedial thalamic nucleus could be inhibited without affecting the ventrolateral nucleus. During MR thermography imaging, there was no observed tissue heating during LIFU sonications and no histological evidence of tissue damage. CONCLUSIONS These results suggest that LIFU can be safely used to modulate neuronal circuits in the central nervous system and that noninvasive brain mapping with focused ultrasound may be feasible in humans.

Enhancement of antitumor activity by using 5-ALA-mediated sonodynamic therapy to induce apoptosis in malignant gliomas: significance of high-intensity focused ultrasound on 5-ALA-SDT in a mouse glioma model.

OBJECTIVEHigh invasiveness of malignant gliomas frequently causes early local recurrence of the tumor, resulting in extremely poor outcome. To control such recurrence, novel therapies targeted toward infiltrating glioma cells around the tumor border are required. Here, the authors investigated the antitumor activity of sonodynamic therapy (SDT) combined with a sonosensitizer, 5-aminolevulinic acid (5-ALA), on malignant gliomas to explore the possibility for clinical use of 5-ALA-mediated SDT (5-ALA-SDT).METHODSIn vitro cytotoxicity of 5-ALA-SDT was evaluated in U87 and U251 glioma cells and in U251Oct-3/4 glioma stemlike cells. Treatment-related apoptosis was analyzed using flow cytometry and TUNEL staining. Intracellular reactive oxygen species (ROS) were measured and the role of ROS in treatment-related cytotoxicity was examined by analysis of the effect of pretreatment with the radical scavenger edaravone. Effects of 5-ALA-SDT with high-intensity focused ultrasound (HIFU) on tumor growth, survival of glioma-transplanted mice, and histological features of the mouse brains were investigated.RESULTSThe 5-ALA-SDT inhibited cell growth and changed cell morphology, inducing cell shrinkage, vacuolization, and swelling. Flow cytometric analysis and TUNEL staining indicated that 5-ALA-SDT induced apoptotic cell death in all gliomas. The 5-ALA-SDT generated significantly higher ROS than in the control group, and inhibition of ROS generation by edaravone completely eliminated the cytotoxic effects of 5-ALA-SDT. In the in vivo study, 5-ALA-SDT with HIFU greatly prolonged survival of the tumor-bearing mice compared with that of the control group (p < 0.05). Histologically, 5-ALA-SDT produced mainly necrosis of the tumor tissue in the focus area and induced apoptosis of the tumor cells in the perifocus area around the target of the HIFU-irradiated field. The proliferative activity of the entire tumor was markedly decreased. Normal brain tissues around the ultrasonic irradiation field of HIFU remained intact.CONCLUSIONSThe 5-ALA-SDT was cytotoxic toward malignant gliomas. Generation of ROS by the SDT was thought to promote apoptosis of glioma cells. The 5-ALA-SDT with HIFU induced tumor necrosis in the focus area and apoptosis in the perifocus area of the HIFU-irradiated field, whereas the surrounding brain tissue remained normal, resulting in longer survival of the HIFU-treated mice compared with that of untreated mice. These results suggest that 5-ALA-SDT with HIFU may present a less invasive and tumor-specific therapy, not only for a tumor mass but also for infiltrating tumor cells in malignant gliomas.

Cavitation-enhanced nonthermal ablation in deep brain targets: feasibility in a large animal model.

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.

Nonthermal ablation in the rat brain using focused ultrasound and an ultrasound contrast agent: long-term effects.

OBJECTIVE Thermal ablation with transcranial MRI-guided focused ultrasound (FUS) is currently under investigation as a less invasive alternative to radiosurgery and resection. A major limitation of the method is that its use is currently restricted to centrally located brain targets. The combination of FUS and a microbubble-based ultrasound contrast agent greatly reduces the ultrasound exposure level needed to ablate brain tissue and could be an effective means to increase the "treatment envelope" for FUS in the brain. This method, however, ablates tissue through a different mechanism: destruction of the microvasculature. It is not known whether nonthermal FUS ablation in substantial volumes of tissue can safely be performed without unexpected effects. The authors investigated this question by ablating volumes in the brains of normal rats. METHODS Overlapping sonications were performed in rats (n = 15) to ablate a volume in 1 hemisphere per animal. The sonications (10-msec bursts at 1 Hz for 60 seconds; peak negative pressure 0.8 MPa) were combined with the ultrasound contrast agent Optison (100 µl/kg). The rats were followed with MRI for 4-9 weeks after FUS, and the brains were examined with histological methods. RESULTS Two weeks after sonication and later, the lesions appeared as cyst-like areas in T2-weighted MR images that were stable over time. Histological examination demonstrated well-defined lesions consisting of a cyst-like cavity that remained lined by astrocytic tissue. Some white matter structures within the sonicated area were partially intact. CONCLUSIONS The results of this study indicate that nonthermal FUS ablation can be used to safely ablate tissue volumes in the brain without unexpected delayed effects. The findings are encouraging for the use of this ablation method in the brain.

Intraparenchymal ultrasound application and improved distribution of infusate with convection-enhanced delivery in rodent and nonhuman primate brain.

OBJECT Convection-enhanced delivery (CED) is an effective drug delivery method that delivers high concentrations of drugs directly into the targeted lesion beyond the blood-brain barrier. However, the drug distribution attained using CED has not satisfactorily covered the entire targeted lesion in tumors such as glioma. Recently, the efficacy of ultrasound assistance was reported for various drug delivery applications. The authors developed a new ultrasound-facilitated drug delivery (UFD) system that enables the application of ultrasound at the infusion site. The purpose of this study was to demonstrate the efficacy of the UFD system and to examine effective ultrasound profiles. METHODS The authors fabricated a steel bar-based device that generates ultrasound and enables infusion of the aqueous drug from one end of the bar. The volume of distribution (Vd) after infusion of 10 ml of 2% Evans blue dye (EBD) into rodent brain was tested with different frequencies and applied voltages: 252 kHz/30 V; 252 kHz/60 V; 524 kHz/13 V; 524 kHz/30 V; and 524 kHz/60 V. In addition, infusion of 5 mM gadopentetate dimeglumine (Gd-DTPA) was tested with 260 kHz/60 V, the distribution of which was evaluated using a 7-T MRI unit. In a nonhuman primate (Macaca fascicularis) study, 300 µl of 1 mM Gd-DTPA/EBD was infused. The final distribution was evaluated using MRI. Two-sample comparisons were made by Student t-test, and 1-way ANOVA was used for multiple comparisons. Significance was set at p < 0.05. RESULTS After infusion of 10 µl of EBD into the rat brain using the UFD system, the Vds of EBD in the UFD groups were significantly larger than those of the control group. When a frequency of 252 kHz was applied, the Vd of the group in which 60 V was applied was significantly larger than that of the group in which 30 V was used. When a frequency of 524 kHz was applied, the Vd tended to increase with application of a higher voltage; however, the differences were not significant (1-way ANOVA). The Vd of Gd-DTPA was also significantly larger in the UFD group than in the control group (p < 0.05, Student t-test). The volume of Gd-DTPA in the nonhuman primate used in this study was 1209.8 ± 193.6 mm(3). This volume was much larger than that achieved by conventional CED (568.6 ± 141.0 mm(3)). CONCLUSIONS The UFD system facilitated the distribution of EBD and Gd-DTPA more effectively than conventional CED. Lower frequency and higher applied voltage using resonance frequencies might be more effective to enlarge the Vd. The UFD system may provide a new treatment approach for CNS disorders.

Intracranial inertial cavitation threshold and thermal ablation lesion creation using MRI-guided 220-kHz focused ultrasound surgery: preclinical investigation.

OBJECT: In biological tissues, it is known that the creation of gas bubbles (cavitation) during ultrasound exposure is more likely to occur at lower rather than higher frequencies. Upon collapsing, such bubbles can induce hemorrhage. Thus, acoustic inertial cavitation secondary to a 220-kHz MRI-guided focused ultrasound (MRgFUS) surgery is a serious safety issue, and animal studies are mandatory for laying the groundwork for the use of low-frequency systems in future clinical trials. The authors investigate here the in vivo potential thresholds of MRgFUS-induced inertial cavitation and MRgFUS-induced thermal coagulation using MRI, acoustic spectroscopy, and histology. METHODS: Ten female piglets that had undergone a craniectomy were sonicated using a 220-kHz transcranial MRgFUS system over an acoustic energy range of 5600-14,000 J. For each piglet, a long-duration sonication (40-second duration) was performed on the right thalamus, and a short sonication (20-second duration) was performed on the left thalamus. An acoustic power range of 140-300 W was used for long-duration sonications and 300-700 W for short-duration sonications. Signals collected by 2 passive cavitation detectors were stored in memory during each sonication, and any subsequent cavitation activity was integrated within the bandwidth of the detectors. Real-time 2D MR thermometry was performed during the sonications. T1-weighted, T2-weighted, gradient-recalled echo, and diffusion-weighted imaging MRI was performed after treatment to assess the lesions. The piglets were killed immediately after the last series of posttreatment MR images were obtained. Their brains were harvested, and histological examinations were then performed to further evaluate the lesions. RESULTS: Two types of lesions were induced: thermal ablation lesions, as evidenced by an acute ischemic infarction on MRI and histology, and hemorrhagic lesions, associated with inertial cavitation. Passive cavitation signals exhibited 3 main patterns identified as follows: no cavitation, stable cavitation, and inertial cavitation. Low-power and longer sonications induced only thermal lesions, with a peak temperature threshold for lesioning of 53°C. Hemorrhagic lesions occurred only with high-power and shorter sonications. The sizes of the hemorrhages measured on macroscopic histological examinations correlated with the intensity of the cavitation activity (R2 = 0.74). The acoustic cavitation activity detected by the passive cavitation detectors exhibited a threshold of 0.09 V·Hz for the occurrence of hemorrhages. CONCLUSIONS: This work demonstrates that 220-kHz ultrasound is capable of inducing a thermal lesion in the brain of living swines without hemorrhage. Although the same acoustic energy can induce either a hemorrhage or a thermal lesion, it seems that low-power, long-duration sonication is less likely to cause hemorrhage and may be safer. Although further study is needed to decrease the likelihood of ischemic infarction associated with the 220-kHz ultrasound, the threshold established in this work may allow for the detection and prevention of deleterious cavitations.

Minimally invasive techniques for epilepsy surgery: stereotactic radiosurgery and other technologies.

Minimally invasive surgical techniques for the treatment of medically intractable epilepsy, which have been developed by neurosurgeons and epileptologists almost simultaneously with standard open epilepsy surgery, provide benefits in the traditional realms of safety and efficacy and the more recently appreciated realms of patient acceptance and costs. In this review, the authors discuss the shortcomings of the gold standard of open epilepsy surgery and summarize the techniques developed to provide minimally invasive alternatives. These minimally invasive techniques include stereotactic radiosurgery using the Gamma Knife, stereotactic radiofrequency thermocoagulation, laser-induced thermal therapy, and MRI-guided focused ultrasound ablation.