Focused Ultrasound Thalamotomy for Tremor in Parkinson's Disease: Outcomes in a Large, Prospective Cohort.

BACKGROUND: Magnetic resonance guided focused ultrasound (MRgFUS) is United States Food and Drug Administration approved for the treatment of tremor-dominant Parkinson's disease (TdPD), but only limited studies have been described in practice. OBJECTIVES: To report the largest prospective experience of unilateral MRgFUS thalamotomy for the treatment of medically refractory TdPD. METHODS: Clinical outcomes of 48 patients with medically refractory TdPD who underwent MRgFUS thalamotomy were evaluated. Tremor outcomes were assessed using the Fahn-Tolosa-Marin scale and adverse effects were categorized using a structured questionnaire and clinical exam at 1 month (n = 44), 3 months (n = 34), 1 year (n = 22), 2 years (n = 5), and 3 years (n = 2). Patients underwent magnetic resonance imaging <24 hours post-procedure. RESULTS: Significant tremor control persisted at all follow-ups (P < 0.001). All side effects were mild. At 3 months, these included gait imbalance (38.24%), sensory deficits (26.47%), motor weakness (17.65%), dysgeusia (5.88%), and dysarthria (5.88%), with some persisting at 1 year. CONCLUSIONS: MRgFUS thalamotomy is an effective treatment for sustained tremor control in patients with TdPD. © 2023 International Parkinson and Movement Disorder Society.

Targeted Blood Brain Barrier Opening With Focused Ultrasound Induces Focal Macrophage/Microglial Activation in Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a model of multiple sclerosis (MS). EAE reflects important histopathological hallmarks, dissemination, and diversity of the disease, but has only moderate reproducibility of clinical and histopathological features. Focal lesions are less frequently observed in EAE than in MS, and can neither be constrained to specific locations nor timed to occur at a pre-specified moment. This renders difficult any experimental assessment of the pathogenesis of lesion evolution, including its inflammatory, degenerative (demyelination and axonal degeneration), and reparatory (remyelination, axonal sprouting, gliosis) component processes. We sought to develop a controlled model of inflammatory, focal brain lesions in EAE using focused ultrasound (FUS). We hypothesized that FUS induced focal blood brain barrier disruption (BBBD) will increase the likelihood of transmigration of effector cells and subsequent lesion occurrence at the sonicated location. Lesion development was monitored with conventional magnetic resonance imaging (MRI) as well as with magnetic resonance elastography (MRE) and further analyzed by histopathological means. EAE was induced in 12 6-8 weeks old female C57BL/6 mice using myelin oligodendrocyte glycoprotein (MOG) peptide. FUS-induced BBBD was performed 6, 7, and 9 days after immunization in subgroups of four animals and in an additional control group. MRI and MRE were performed on a 7T horizontal bore small animal MRI scanner. Imaging was conducted longitudinally 2 and 3 weeks after disease induction and 1 week after sonication in control animals, respectively. The scan protocol comprised contrast-enhanced T1-weighted and T2-weighted sequences as well as MRE with a vibration frequency of 1 kHz. Animals were sacrificed for histopathology after the last imaging time point. The overall clinical course of EAE was mild. A total of seven EAE animals presented with focal T2w hyperintense signal alterations in the sonicated hemisphere. These were most frequent in the group of animals sonicated 9 days after immunization. Histopathology revealed foci of activated microglia/macrophages in the sonicated right hemisphere of seven EAE animals. Larger cellular infiltrates or apparent demyelination were not seen. Control animals showed no abnormalities on MRI and did not have clusters of activated microglia/macrophages at the sites targeted with FUS. None of the animals had hemorrhages or gross tissue damage as potential side effects of FUS. EAE-animals tended to have lower values of viscoelasticity and elasticity in the sonicated compared to the contralateral parenchyma. This trend was significant when comparing the right sonicated to the left normal hemisphere and specifically the right sonicated compared to the left normal cortex in animals that underwent FUS-BBBD 9 days after immunization (right vs. left hemisphere: mean viscoelasticity 6.1 vs. 7.2 kPa; p = 0.003 and mean elasticity 4.9 vs. 5.7 kPa, p = 0.024; right vs. left cortex: mean viscoelasticity 5.8 vs. 7.5 kPa; p = 0.004 and mean elasticity 5 vs. 6.5 kPa; p = 0.008). A direct comparison of the biomechanical properties of focal T2w hyperintensities with normal appearing brain tissue did not yield significant results. Control animals showed no differences in viscoelasticity between sonicated and contralateral brain parenchyma. We here provide first evidence for a controlled lesion induction model in EAE using FUS-induced BBBD. The observed lesions in EAE are consistent with foci of activated microglia that may be interpreted as targeted initial inflammatory activity and which have been described as pre-active lesions in MS. Such foci can be identified and monitored with MRI. Moreover, the increased inflammatory activity in the sonicated brain parenchyma seems to have an effect on overall tissue matrix structure as reflected by changes of biomechanical parameters.

Predicting Bone Marrow Damage in the Skull After Clinical Transcranial MRI-Guided Focused Ultrasound With Acoustic and Thermal Simulations.

Transcranial MRI-guided focused ultrasound (TcMRgFUS) thermal ablation is a noninvasive functional neurosurgery technique. Previous reports have shown that damage in the skull bone marrow can occur at high acoustic energies. While this damage is asymptomatic, it would be desirable to avoid it. Here we examined whether acoustic and thermal simulations can predict where the thermal lesions in the marrow occurred. Post-treatment imaging was obtained at 3-15 months after 40 clinical TcMRgFUS procedures, and bone marrow lesions were observed after 16 treatments. The presence of lesions was predicted by the acoustic energy with a threshold of 18.1-21.1 kJ (maximum acoustic energy used) and 97-112 kJ (total acoustic energy applied over the whole treatment). The size of the lesions was not always predicted by the acoustic energy used during treatment alone. In contrast, the locations, sizes, and shapes of the heated regions estimated by the acoustic and thermal simulations were qualitatively similar to those of the lesions. The lesions generally appeared in areas that were predicted to have high temperatures. While more work is needed to validate the temperature estimates in and around the skull, being able to predict the locations and onset for lesions in the bone marrow could allow for better distribution of the acoustic energy over the skull. Understanding skull absorption characteristics of TcMRgFUS could also be useful in optimizing transcranial focusing.

Elementwise approach for simulating transcranial MRI-guided focused ultrasound thermal ablation.

This work explored an elementwise approach to model transcranial MRI-guided focused ultrasound (TcMRgFUS) thermal ablation, a noninvasive approach to neurosurgery. Each element of the phased array transducer was simulated individually and could be simultaneously loaded into computer memory, allowing for rapid (~2.5 s) calculation of the pressure field for different phase offsets used for beam steering and aberration correction. We simulated the pressure distribution for 431 sonications in 32 patients, applied the phase and magnitude values used during treatment, and estimated the resulting temperature rise. We systematically varied the relationship between CT (computerized tomography)-derived skull density and the acoustic attenuation and sound speed to obtain the best agreement between the predictions and MR temperature imaging (MRTI). The optimization was validated with simulations of 396 sonications from 40 additional treatments. After optimization, the predicted and measured heating agreed well (R 2: 0.74 patients 1-32; 0.71 patients 33-72). The dimensions and obliquity of the heating in the simulated temperature maps were correlated with the MRTI (R 2: 0.62, 0.74, respectively), but the measured heating was more spatially diffuse. The energy needed to achieve ablation varied by an order of magnitude (3.3-36.1 kJ). While this elementwise approach required more computation time up front (the combined simulation matrices were approximately 4.6 times higher than a single large simulation), it could be performed in parallel on a computing cluster. It allows for rapid calculation of the three-dimensional heating at the focus for different phase and magnitude values on the array. We also show how this approach can be used to optimize the relationship between CT-derived skull density and acoustic properties. While the relationships found here need further validation in a larger patient population, these results demonstrate the promise of this approach to model TcMRgFUS.

Nonthermal ablation of deep brain targets: A simulation study on a large animal model.

PURPOSE: Thermal ablation with transcranial MRI-guided focused ultrasound (FUS) is currently limited to central brain targets because of heating and other beam effects caused by the presence of the skull. Recently, it was shown that it is possible to ablate tissues without depositing thermal energy by driving intravenously administered microbubbles to inertial cavitation using low-duty-cycle burst sonications. A recent study demonstrated that this ablation method could ablate tissue volumes near the skull base in nonhuman primates without thermally damaging the nearby bone. However, blood-brain disruption was observed in the prefocal region, and in some cases, this region contained small areas of tissue damage. The objective of this study was to analyze the experimental model with simulations and to interpret the cause of these effects. METHODS: The authors simulated prior experiments where nonthermal ablation was performed in the brain in anesthetized rhesus macaques using a 220 kHz clinical prototype transcranial MRI-guided FUS system. Low-duty-cycle sonications were applied at deep brain targets with the ultrasound contrast agent Definity. For simulations, a 3D pseudospectral finite difference time domain tool was used. The effects of shear mode conversion, focal steering, skull aberrations, nonlinear propagation, and the presence of skull base on the pressure field were investigated using acoustic and elastic wave propagation models. RESULTS: The simulation results were in agreement with the experimental findings in the prefocal region. In the postfocal region, however, side lobes were predicted by the simulations, but no effects were evident in the experiments. The main beam was not affected by the different simulated scenarios except for a shift of about 1 mm in peak position due to skull aberrations. However, the authors observed differences in the volume, amplitude, and distribution of the side lobes. In the experiments, a single element passive cavitation detector was used to measure the inertial cavitation threshold and to determine the pressure amplitude to use for ablation. Simulations of the detector's acoustic field suggest that its maximum sensitivity was in the lower part of the main beam, which may have led to excessive exposure levels in the experiments that may have contributed to damage in the prefocal area. CONCLUSIONS: Overall, these results suggest that case-specific full wave simulations before the procedure can be useful to predict the focal and the prefocal side lobes and the extent of the resulting bioeffects produced by nonthermal ablation. Such simulations can also be used to optimally position passive cavitation detectors. The disagreement between the simulations and the experiments in the postfocal region may have been due to shielding of the ultrasound field due to microbubble activity in the focal region. Future efforts should include the effects of microbubble activity and vascularization on the pressure field.

Two-dimensional image reconstruction with spectrally-randomized ultrasound signals.

An ultrasound imaging method using unfocused frequency-randomized transmissions and image reconstruction from data received by a single element is experimentally demonstrated. The elements of an ultrasound imaging array are randomly assigned different frequencies and driven by a multicycle sinusoidal burst. The resulting acoustic field is spectrally unique and target localization is possible based on the a priori knowledge of this field. A 64-element phased array driven by arbitrary waveform generators is used in the experiments. Transmission frequencies range from 2.00 to 2.64 MHz with 10 kHz resolution. One element of the array is reserved for receiving backscattered signals and an image is reconstructed from the signals received by this single element. Reconstruction is based on cross-correlation of the received data with transmitted bursts to obtain radial elliptical projections. Multiple projections are obtained from single received data, which are back-projected to obtain an image. Successful target localization is made possible through multiple frequency-randomized acquisitions. The performance of the method is measured using images of a single point target. These images are quantified and analyzed in terms of their point spread function (PSF) and SNR. Optimum imaging parameters, such as the number of acquisitions, transmit burst length, and number of possible receivers, are obtained through further analysis of SNR. Images obtained with the frequency-randomized transmission method compared well with the performance measurements of a typical B-mode acquisition. It is demonstrated that the frequency-randomized method provides images superior to B-mode images in terms of PSF. The two-point discrimination threshold is measured to be 2 mm in the lateral and azimuth directions.

Accelerated focused ultrasound imaging.

One of the most basic trade-offs in ultrasound imaging involves frame rate, depth, and number of lines. Achieving good spatial resolution and coverage requires a large number of lines, leading to decreases in frame rate. An even more serious imaging challenge occurs with imaging modes involving spatial compounding and 3-D/4-D imaging, which are severely limited by the slow speed of sound in tissue. The present work can overcome these traditional limitations, making ultrasound imaging many-fold faster. By emitting several beams at once, and by separating the resulting overlapped signals through spatial and temporal processing, spatial resolution and/or coverage can be increased by many-fold while leaving frame rates unaffected. The proposed approach can also be extended to imaging strategies that do not involve transmit beamforming, such as synthetic aperture imaging. Simulated and experimental results are presented where imaging speed is improved by up to 32-fold, with little impact on image quality. Object complexity has little impact on the method's performance, and data from biological systems can readily be handled. The present work may open the door to novel multiplexed and/or multidimensional protocols considered impractical today.

An intraoperative brain shift monitor using shear mode transcranial ultrasound: preliminary results.

OBJECTIVE: Various methods of intraoperative structural monitoring during neurosurgery are used to localize lesions after brain shift and to guide surgically introduced probes such as biopsy needles or stimulation electrodes. With its high temporal resolution, portability, and nonionizing mode of radiation, ultrasound has potential advantages over other existing imaging modalities for intraoperative monitoring, yet ultrasound is rarely used during neurosurgery largely because of the craniotomy requirement to achieve sufficiently useful signals. METHODS: Prompted by results from recent studies on transcranial ultrasound, a prototype device that aims to use the shear mode of transcranial ultrasound transmission for intraoperative monitoring was designed, constructed, and tested with 10 human participants. Magnetic resonance images were then obtained with the device spatially registered to the magnetic resonance imaging (MRI) reference coordinates. Peaks in both the ultrasound and MRI signals were identified and analyzed for both spatial localization and signal-to-noise ratio (SNR). RESULTS: The first results aimed toward validating the prototype device with MRI showed an excellent correlation (n = 38; R(2) = 0.9962) between the structural localization abilities of the two modalities. In addition, the overall SNR of the ultrasound backscatter signals (n = 38; SNR = 25.4 +/- 5.2 dB, mean +/- SD) was statistically equivalent to that of the MRI data (n = 38; SNR = 22.5 +/- 4.8 dB). CONCLUSIONS: A statistically significant correlation of localized intracranial structures between intraoperative transcranial ultrasound monitoring and MRI data was achieved with 10 human participants. We have shown and validated a prototype device incorporating transcranial shear mode ultrasound for clinical monitoring applications.

The effects of desiccation on skull bone sound speed in porcine models.

Pre- and postdesiccation sound speeds through ex vivo porcine skull specimens were determined by time-of-flight measurements with propagated broadband pulses centered at 0.97 MHz (Os 12.7 mm, -6-dB band-width = 58%). The measured longitudinal sound speed in the 13 porcine samples (predesiccation average sound speed = 1727 +/- 57 ms(-1)) changed by a statistically significant +2.3% after deionized water reconstitution (paired t-test, alpha = 0.05, p = 0.0332).

A magnetic resonance imaging-compatible, large-scale array for trans-skull ultrasound surgery and therapy.

OBJECTIVE: Advances in ultrasound transducer array and amplifier technologies have prompted many intriguing scientific proposals for ultrasound therapy. These include both mildly invasive and noninvasive techniques to be used in ultrasound brain surgery through the skull. In previous work, it was shown how a 500-element hemisphere-shaped transducer could correct the wave distortion caused by the skull with a transducer that operates at a frequency near 0.8 MHz. Because the objective for trans-skull focusing is its ultimate use in a clinical context, a new hemispheric phased-array system has now been developed with acoustic parameters that are optimized to match the values determined in preliminary studies. METHODS: The transducer was tested by focusing ultrasound through ex vivo human skulls and into a brain phantom by means of a phase-adaptive focusing technique. Simultaneously, the procedure was monitored by the use of magnetic resonance guidance and thermometry. RESULTS: The ultrasound focus of a 500-element 30-cm-diameter, 0.81-MHz array could be steered electronically through the skull over a volume of approximately 30 x 30 x 26 mm. Furthermore, temperature monitoring of the inner and outer surfaces of the skull showed that the array could coagulate targeted brain tissue without causing excessive skull heating. CONCLUSIONS: The successful outcome of these experiments indicates that intensities high enough to destroy brain tissue can be produced without excessive heating of the surrounding areas and without producing large magnetic resonance noise and artifacts.

500-element ultrasound phased array system for noninvasive focal surgery of the brain: a preliminary rabbit study with ex vivo human skulls.

The aim of this study was to test a prototype MRI-compatible focused ultrasound phased array system for trans-skull brain tissue ablation. Rabbit thigh muscle and brain were sonicated with a prototype, hemispherical 500-element ultrasound phased array operating at frequencies of 700-800 kHz. An ex vivo human skull sample was placed between the array and the animal tissue. The temperature elevation during 20-30-sec sonications was monitored using MRI thermometry. The induced focal lesions were observed in T2 and contrast-enhanced T1-weighted fast spin echo images. Whole brain histology evaluation was performed after the sonications. The results showed that sharp temperature elevations can be produced both in the thigh muscle and in the brain. High-power sonications (600-1080 W) produced peak temperatures up to 55 degrees C and focal lesions that were consistent with thermal tissue damage. The lesion size was found to increase with increasing peak temperature. The device was then modified to operate in the orientation that will be used in the clinic and successfully tested in phantom experiments. As a conclusion, this study demonstrates that it is possible to create ultrasound-induced lesions in vivo through a human skull under MRI guidance with this large-scale phased array.