Remotely controlled drug release in deep brain regions of non-human primates.

Many areas of science and medicine would benefit from selective release of drugs in specific regions. Nanoparticle drug carriers activated by focused ultrasound-remotely applied, depth-penetrating energy-may provide such selective interventions. Here, we developed stable, ultrasound-responsive nanoparticles that can be used to release drugs effectively and safely in non-human primates. The nanoparticles were used to release propofol in deep brain visual regions. The release reversibly modulated the subjects' visual choice behavior and was specific to the targeted region and to the released drug. Gadolinium-enhanced MR imaging suggested an intact blood-brain barrier. Blood draws showed normal clinical chemistry and hematology. In summary, this study provides a safe and effective approach to release drugs on demand in selected deep brain regions at levels sufficient to modulate behavior.

Remotely controlled drug release in deep brain regions of non-human primates.

Many areas of science and medicine would benefit from selective release of drugs in specific regions of interest. Nanoparticle drug carriers activated by focused ultrasound-remotely applied, depth-penetrating energy-may provide such selective interventions. Here, we developed stable, ultrasound-responsive nanoparticles that can be used to release drugs effectively and safely in non-human primates. The nanoparticles were used to release propofol in deep brain visual regions. The release reversibly modulated the subjects' visual choice behavior and was specific to the targeted region and to the released drug. Gadolinium-enhanced MRI imaging suggested an intact blood-brain barrier. Blood draws showed normal clinical chemistry and hematology. In summary, this study provides a safe and effective approach to release drugs on demand in selected deep brain regions at levels sufficient to modulate behavior.

Sustained modulation of primate deep brain circuits with focused ultrasonic waves.

BACKGROUND: Transcranial focused ultrasound has the potential to noninvasively modulate deep brain circuits and impart sustained, neuroplastic effects. OBJECTIVE: Bring the approach closer to translations by demonstrating sustained modulation of deep brain circuits and choice behavior in task-performing non-human primates. METHODS: Low-intensity transcranial ultrasound of 30 s in duration was delivered in a controlled manner into deep brain targets (left or right lateral geniculate nucleus; LGN) of non-human primates while the subjects decided whether a left or a right visual target appeared first. While the animals performed the task, we recorded intracranial EEG from occipital screws. The ultrasound was delivered into the deep brain targets daily for a period of more than 6 months. RESULTS: The brief stimulation induced effects on choice behavior that persisted up to 15 minutes and were specific to the sonicated target. Stimulation of the left/right LGN increased the proportion of rightward/leftward choices. These effects were accompanied by an increase in gamma activity over visual cortex. The contralateral effect on choice behavior and the increase in gamma, compared to sham stimulation, suggest that the stimulation excited the target neural circuits. There were no detrimental effects on the animals' discrimination performance over the months-long course of the stimulation. CONCLUSION: This study demonstrates that brief, 30-s ultrasonic stimulation induces neuroplastic effects specifically in the target deep brain circuits, and that the stimulation can be applied daily without detrimental effects. These findings encourage repeated applications of transcranial ultrasound to malfunctioning deep brain circuits in humans with the goal of providing a durable therapeutic reset.

Remus: System for remote deep brain interventions.

Transcranial-focused ultrasound brings personalized medicine to the human brain. Ultrasound can modulate neural activity or release drugs in specific neural circuits but this personalized approach requires a system that delivers ultrasound into specified targets flexibly and on command. We developed a remote ultrasound system (Remus) that programmatically targets deep brain regions with high spatiotemporal precision and in a multi-focal manner. We validated these functions by modulating two deep brain nuclei-the left and right lateral geniculate nucleus-in a task-performing nonhuman primate. This flexible system will enable researchers and clinicians to diagnose and treat specific deep brain circuits in a noninvasive yet targeted manner, thus embodying the promise of personalized treatments of brain disorders.

Comparison between MR and CT imaging used to correct for skull-induced phase aberrations during transcranial focused ultrasound.

Transcranial focused ultrasound with the InSightec Exablate system uses thermal ablation for the treatment of movement and mood disorders and blood brain barrier disruption for tumor therapy. The system uses computed tomography (CT) images to calculate phase corrections that account for aberrations caused by the human skull. This work investigates whether magnetic resonance (MR) images can be used as an alternative to CT images to calculate phase corrections. Phase corrections were calculated using the gold standard hydrophone method and the standard of care InSightec ray tracing method. MR binary image mask, MR-simulated-CT (MRsimCT), and CT images of three ex vivo human skulls were supplied as inputs to the InSightec ray tracing method. The degassed ex vivo human skulls were sonicated with a 670 kHz hemispherical phased array transducer (InSightec Exablate 4000). 3D raster scans of the beam profiles were acquired using a hydrophone mounted on a 3-axis positioner system. Focal spots were evaluated using six metrics: pressure at the target, peak pressure, intensity at the target, peak intensity, positioning error, and focal spot volume. Targets at the geometric focus and 5 mm lateral to the geometric focus were investigated. There was no statistical difference between any of the metrics at either target using either MRsimCT or CT for phase aberration correction. As opposed to the MRsimCT, the use of CT images for aberration correction requires registration to the treatment day MR images; CT misregistration within a range of ± 2 degrees of rotation error along three dimensions was shown to reduce focal spot intensity by up to 9.4%. MRsimCT images used for phase aberration correction for the skull produce similar results as CT-based correction, while avoiding both CT to MR registration errors and unnecessary patient exposure to ionizing radiation.

Improving Transcranial Acoustic Targeting: The Limits of CT-Based Velocity Estimates and the Role of MR.

Transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) enables the noninvasive treatment of the deep brain. This capacity relies on the ability to focus acoustic energy through the in-tact skull, a feat that requires accurate estimates of the acoustic velocity in individual patient skulls. In current practice, these estimates are generated using a pretreatment computed tomography (CT) scan and then registered to a magnetic resonance (MR) dataset on the day of the treatment. Treatment safety and efficacy can be improved by eliminating the need to register the CT data to the MR images and by improving the accuracy of acoustic velocity measurements. In this study, we examine the capacity of MR to supplement or replace CT as a means of estimating velocity in the skull. We find that MR can predict velocity with less but comparable accuracy to CT. We then use micro-CT imaging to better understand the limitations of Hounsfield unit (HU)-based estimates of velocity, demonstrating that the macrostructure of pores in the skull contributes to the acoustic velocity of the bone. We find evidence that detailed T2 measurements provide information about pore macrostructure similar to the information obtained with micro-CT, offering a potential clinical mechanism for improving patient-specific estimates of acoustic velocity in the human skull.

Acoustic properties across the human skull.

Transcranial ultrasound is emerging as a noninvasive tool for targeted treatments of brain disorders. Transcranial ultrasound has been used for remotely mediated surgeries, transient opening of the blood-brain barrier, local drug delivery, and neuromodulation. However, all applications have been limited by the severe attenuation and phase distortion of ultrasound by the skull. Here, we characterized the dependence of the aberrations on specific anatomical segments of the skull. In particular, we measured ultrasound propagation properties throughout the perimeter of intact human skulls at 500 kHz. We found that the parietal bone provides substantially higher transmission (average pressure transmission 31 ± 7%) and smaller phase distortion (242 ± 44 degrees) than frontal (13 ± 2%, 425 ± 47 degrees) and occipital bone regions (16 ± 4%, 416 ± 35 degrees). In addition, we found that across skull regions, transmission strongly anti-correlated (R=-0.79) and phase distortion correlated (R=0.85) with skull thickness. This information guides the design, positioning, and skull correction functionality of next-generation devices for effective, safe, and reproducible transcranial focused ultrasound therapies.

Transcranial focused ultrasound phase correction using the hybrid angular spectrum method.

The InSightec Exablate system is the standard of care used for transcranial focused ultrasound ablation treatments in the United States. The system calculates phase corrections that account for aberrations caused by the human skull. This work investigates whether skull aberration correction can be improved by comparing the standard of care InSightec ray tracing method with the hybrid angular spectrum (HAS) method and the gold standard hydrophone method. Three degassed ex vivo human skulls were sonicated with a 670 kHz hemispherical phased array transducer (InSightec Exablate 4000). Phase corrections were calculated using four different methods (straight ray tracing, InSightec ray tracing, HAS, and hydrophone) and were used to drive the transducer. 3D raster scans of the beam profiles were acquired using a hydrophone mounted on a 3-axis positioner system. Focal spots were evaluated using six metrics: pressure at the target, peak pressure, intensity at the target, peak intensity, positioning error, and focal spot volume. For three skulls, the InSightec ray tracing method achieved 52 ± 21% normalized target intensity (normalized to hydrophone), 76 ± 17% normalized peak intensity, and 0.72 ± 0.47 mm positioning error. The HAS method achieved 74 ± 9% normalized target intensity, 81 ± 9% normalized peak intensity, and 0.35 ± 0.09 mm positioning error. The InSightec-to-HAS improvement in focal spot targeting provides promise in improving treatment outcomes. These improvements to skull aberration correction are also highly relevant for the applications of focused ultrasound neuromodulation and blood brain barrier opening, which are currently being translated for human use.

Acoustic Attenuation: Multifrequency Measurement and Relationship to CT and MR Imaging.

Transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) is gaining significant acceptance as a noninvasive treatment for motion disorders and shows promise for novel applications such as blood-brain barrier opening for tumor treatment. A typical procedure relies on CT-derived acoustic property maps to simulate the transfer of ultrasound through the skull. Accurate estimates of the acoustic attenuation in the skull are essential to accurate simulations, but there is no consensus about how attenuation should be estimated from CT images and there is interest in exploring MR as a predictor of attenuation in the skull. In this study, we measure the acoustic attenuation at 0.5, 1, and 2.25 MHz in 89 samples taken from two ex vivo human skulls. CT scans acquired with a variety of X-ray energies, reconstruction kernels, and reconstruction algorithms, and MR images acquired with ultrashort and zero echo time sequences are used to estimate the average Hounsfield unit value, MR magnitude, and T2* value in each sample. The measurements are used to develop a model of attenuation as a function of frequency and each individual imaging parameter.

A rapid beam simulation framework for transcranial focused ultrasound.

Transcranial focused ultrasound is a non-invasive therapeutic modality that can be used to treat essential tremor. Beams of energy are focused into a small spot in the thalamus, resulting in tissue heating and ablation. Here, we report on a rapid 3D numeric simulation framework that can be used to predict focal spot characteristics prior to the application of ultrasound. By comparing with magnetic resonance proton resonance frequency shift thermometry (MR thermometry) data acquired during treatments of essential tremor, we verified that our simulation framework can be used to predict focal spot position, and with patient-specific calibration, predict focal spot temperature rise. Preliminary data suggests that lateral smearing of the focal spot can be simulated. The framework may also be relevant for other therapeutic ultrasound applications such as blood brain barrier opening and neuromodulation.

Prolonged heating in nontargeted tissue during MR-guided focused ultrasound of bone tumors.

BACKGROUND: Thermal dosimetry during MR-guided focused ultrasound (MRgFUS) of bone tumors underpredicts ablation zone. Intraprocedural understanding of heat accumulation near bone is needed to prevent undesired treatment of nontargeted tissue. HYPOTHESIS: Temperature decay rates predict prolonged, spatially varying heating during MRgFUS bone treatments. STUDY TYPE: Prospective case series. PATIENTS: Nine patients with localized painful bone tumors (five bone metastasis, four osteoid osteomas), were compared with five patients with uterine fibroid tumors treated using MRgFUS. FIELD STRENGTH/SEQUENCE: Proton resonance frequency shift thermometry using 2D-GRE with echo-planar imaging at 3 T. ASSESSMENT: Tissue response was derived by fitting data from extended thermometry acquisitions to a decay model. Decay rates and time to peak temperature (TTP) were analyzed in segmented zones between the bone target and skin. Decay rates were used to calculate intersonication cooling times required to return to body temperature; these were compared against conventional system-mandated cooling times. STATISTICAL TESTS: Kolmogorov-Smirnov tests for normality, and Student's t-test was used to compare decay rates. Spatial TTP delay and predicted cooling times used Wilcoxon signed rank tests. P < 0.05 was significant. RESULTS: Tissue decay rates in bone tumor patients were 3.5 times slower than those in patients with fibroids (τbone = 0.037 ± 0.012 vs. τfibroid = 0.131 ± 0.010, P < 0.05). Spatial analysis showed slow decay rates effecting baseline temperature as far as 12 mm away from the bone surface, τ4 = 0.015 ± 0.026 (median ± interquartile range [IQR]). Tissue within 9 mm of bone experienced delayed TTP (P < 0.01). In the majority of bone tumor treatments, system-predicted intersonication cooling times were insufficient for nearby tissue to return to body temperature (P = 0.03 in zone 4). DATA CONCLUSION: MRgFUS near bone is susceptible to long tissue decay rates, and unwanted cumulative heating up to 1.2 cm from the surface of the bone. Knowledge of decay rates may be used to alter treatment planning and intraprocedural thermal monitoring protocols to account for prolonged heating by bone. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2019;50:1526-1533.

Measurements of the Relationship Between CT Hounsfield Units and Acoustic Velocity and How It Changes With Photon Energy and Reconstruction Method.

Transcranial magnetic resonance-guided focused ultrasound continues to gain traction as a noninvasive treatment option for a variety of pathologies. Focusing ultrasound through the skull can be accomplished by adding a phase correction to each element of a hemispherical transducer array. The phase corrections are determined with acoustic simulations that rely on speed of sound estimates derived from CT scans. While several studies have investigated the relationship between acoustic velocity and CT Hounsfield units (HUs), these studies have largely ignored the impact of X-ray energy, reconstruction method, and reconstruction kernel on the measured HU, and therefore the estimated velocity, and none have measured the relationship directly. In this paper, 91 ex vivo human skull fragments from two skulls are imaged by 80 CT scans with a variety of energies and reconstruction methods. The average HU from each fragment is found for each scan and correlated with the speed of sound measured using a through transmission technique in that fragment. As measured by the -squared value, the results show that CT is able to account for 23%-53% of the variation in velocity in the human skull. Both the X-ray energy and the reconstruction technique significantly alter the -squared value and the linear relationship between HU and speed of sound in bone. Accounting for these variations will lead to more accurate phase corrections and more efficient transmission of acoustic energy through the skull.

Improving thermal dose accuracy in magnetic resonance-guided focused ultrasound surgery: Long-term thermometry using a prior baseline as a reference.

PURPOSE: To investigate thermal dose volume (TDV) and non-perfused volume (NPV) of magnetic resonance-guided focused ultrasound (MRgFUS) treatments in patients with soft tissue tumors, and describe a method for MR thermal dosimetry using a baseline reference. MATERIALS AND METHODS: Agreement between TDV and immediate post treatment NPV was evaluated from MRgFUS treatments of five patients with biopsy-proven desmoid tumors. Thermometry data (gradient echo, 3T) were analyzed over the entire course of the treatments to discern temperature errors in the standard approach. The technique searches previously acquired baseline images for a match using 2D normalized cross-correlation and a weighted mean of phase difference images. Thermal dose maps and TDVs were recalculated using the matched baseline and compared to NPV. RESULTS: TDV and NPV showed between 47%-91% disagreement, using the standard immediate baseline method for calculating TDV. Long-term thermometry showed a nonlinear local temperature accrual, where peak additional temperature varied between 4-13°C (mean = 7.8°C) across patients. The prior baseline method could be implemented by finding a previously acquired matching baseline 61% ± 8% (mean ± SD) of the time. We found 7%-42% of the disagreement between TDV and NPV was due to errors in thermometry caused by heat accrual. For all patients, the prior baseline method increased the estimated treatment volume and reduced the discrepancies between TDV and NPV (P = 0.023). CONCLUSION: This study presents a mismatch between in-treatment and post treatment efficacy measures. The prior baseline approach accounts for local heating and improves the accuracy of thermal dose-predicted volume.