A tool for monitoring cell type-specific focused ultrasound neuromodulation and control of chronic epilepsy.

Focused ultrasound (FUS) is a powerful tool for noninvasive modulation of deep brain activity with promising therapeutic potential for refractory epilepsy; however, tools for examining FUS effects on specific cell types within the deep brain do not yet exist. Consequently, how cell types within heterogeneous networks can be modulated and whether parameters can be identified to bias these networks in the context of complex behaviors remains unknown. To address this, we developed a fiber Photometry Coupled focused Ultrasound System (PhoCUS) for simultaneously monitoring FUS effects on neural activity of subcortical genetically targeted cell types in freely behaving animals. We identified a parameter set that selectively increases activity of parvalbumin interneurons while suppressing excitatory neurons in the hippocampus. A net inhibitory effect localized to the hippocampus was further confirmed through whole brain metabolic imaging. Finally, these inhibitory selective parameters achieved significant spike suppression in the kainate model of chronic temporal lobe epilepsy, opening the door for future noninvasive therapies.

Improving in situ acoustic intensity estimates using MR acoustic radiation force imaging in combination with multifrequency MR elastography.

PURPOSE: Magnetic resonance acoustic radiation force imaging (MR-ARFI) enables focal spot localization during nonablative transcranial ultrasound therapies. As the acoustic radiation force is proportional to the applied acoustic intensity, measured MR-ARFI displacements could potentially be used to estimate the acoustic intensity at the target. However, variable brain stiffness is an obstacle. The goal of this study was to develop and assess a method to accurately estimate the acoustic intensity at the focus using MR-ARFI displacements in combination with viscoelastic properties obtained with multifrequency MR elastography (MRE). METHODS: Phantoms with a range of viscoelastic properties were fabricated, and MR-ARFI displacements were acquired within each phantom using multiple acoustic intensities. Voigt model parameters were estimated for each phantom based on storage and loss moduli measured using multifrequency MRE, and these were used to predict the relationship between acoustic intensity and measured displacement. RESULTS: Using assumed viscoelastic properties, MR-ARFI displacements alone could not accurately estimate acoustic intensity across phantoms. For example, acoustic intensities were underestimated in phantoms stiffer than the assumed stiffness and overestimated in phantoms softer than the assumed stiffness. This error was greatly reduced using individualized viscoelasticity measurements obtained from MRE. CONCLUSION: We demonstrated that viscoelasticity information from MRE could be used in combination with MR-ARFI displacements to obtain more accurate estimates of acoustic intensity. Additionally, Voigt model viscosity parameters were found to be predictive of the relaxation rate of each phantom's time-varying displacement response, which could be used to optimize patient-specific MR-ARFI pulse sequences.

Benchmark problems for transcranial ultrasound simulation: Intercomparison of compressional wave models.

Computational models of acoustic wave propagation are frequently used in transcranial ultrasound therapy, for example, to calculate the intracranial pressure field or to calculate phase delays to correct for skull distortions. To allow intercomparison between the different modeling tools and techniques used by the community, an international working group was convened to formulate a set of numerical benchmarks. Here, these benchmarks are presented, along with intercomparison results. Nine different benchmarks of increasing geometric complexity are defined. These include a single-layer planar bone immersed in water, a multi-layer bone, and a whole skull. Two transducer configurations are considered (a focused bowl and a plane piston operating at 500 kHz), giving a total of 18 permutations of the benchmarks. Eleven different modeling tools are used to compute the benchmark results. The models span a wide range of numerical techniques, including the finite-difference time-domain method, angular spectrum method, pseudospectral method, boundary-element method, and spectral-element method. Good agreement is found between the models, particularly for the position, size, and magnitude of the acoustic focus within the skull. When comparing results for each model with every other model in a cross-comparison, the median values for each benchmark for the difference in focal pressure and position are less than 10% and 1 mm, respectively. The benchmark definitions, model results, and intercomparison codes are freely available to facilitate further comparisons.

Evaluation of an MRI receive head coil for use in transcranial MR guided focused ultrasound for functional neurosurgery.

BACKGROUND: Trans-cranial MR guided focused ultrasound (tcMRgFUS) ablation targets are <5mm from critical neurological structures, creating a need for improved MR imaging and thermometry. The purpose of this study was to evaluate the performance of a dual-channel radiofrequency receive-only head coil designed specifically for integrated use in tcMRgFUS. METHODS: Imaging used a 3 T MRI and the ExAblate Neuro System (INSIGHTEC Inc., Israel). Sensitivity maps determined receive-only coil uniformity. The head coil was compared to the volume body coil at the level of the thalamus using 1) T2-weighted imaging and 2) multi-echo MR thermometry of volunteers in the transducer helmet. Thermal sonications (40 W, 24s) were acquired in a heating phantom. Thermal maps in were constructed to evaluate temperature uncertainty, focal heating, and temperature evolution. RESULTS: The normalized signal intensity showed up to a 35% variation. On T2wFSE images the SNR with the head coil is improved by 4x in the axial plane, and 3x in sagittal and coronal planes. The head coil provided better visualization of the thalamus and globus pallidus (axial), and of the anterior/posterior commissure, and brain stem/cerebellum (sagittal) compared to the body coil. MR thermometry showed a 4x gain in SNR in the thalamus. Thermometry showed a preserved focal spot with 20 °C temperature rise. The average temperature uncertainty (mean ± std) was reduced from σ T = 0.96 °C ± 0.55 °C for the body coil to σ T = 0.41 °C ± 0.24 °C for the head coil. CONCLUSIONS: Greater SNR from the dual-channel head coil provides access to better treatment day visualization for treatment planning and higher precision intra-operative thermometry.

A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor.

BACKGROUND: Uncontrolled pilot studies have suggested the efficacy of focused ultrasound thalamotomy with magnetic resonance imaging (MRI) guidance for the treatment of essential tremor. METHODS: We enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort). RESULTS: Seventy-six patients were included in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively. CONCLUSIONS: MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.).

High sensitivity MR acoustic radiation force imaging using transition band balanced steady-state free precession.

PURPOSE: MR acoustic radiation force imaging (MR-ARFI) provides a method to visualize the focal spot of a focused ultrasound (FUS) beam without introducing a significant temperature rise. With conventional spoiled MR-ARFI pulse sequences, the ARFI phase always equals the motion-encoded phase. In this work, MR-ARFI using transition band balanced steady-state free precession (bSSFP) is presented, which improves the sensitivity of MR-ARFI with high acquisition speed. THEORY AND METHODS: Motion-encoding gradients (MEG) are inserted into bSSFP sequences for MR-ARFI. By applying an ultrasound pulse during the MEG, motion-encoded phase is generated, which leads to an amplified change in the image phase when operating in the bSSFP transition band. MR-ARFI was performed on a homemade gel phantom using both the proposed technique and a spoiled gradient echo ARFI sequence with identical MEG and FUS, and ARFI images were compared. RESULTS: The bSSFP-ARFI sequence generated an ARFI image phase that is more than 5 times larger than the motion-encoded phase in a few seconds with 2DFT readout. By keeping FUS pulses as short as 1.45 ms, temperature rise was insignificant during the measurement. CONCLUSION: bSSFP-ARFI has enhanced sensitivity compared with conventional MR-ARFI pulse sequences and could provide an efficient way to visualize the focal spot. Magn Reson Med 79:1532-1537, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

A spiral-based volumetric acquisition for MR temperature imaging.

PURPOSE: To develop a rapid pulse sequence for volumetric MR thermometry. METHODS: Simulations were carried out to assess temperature deviation, focal spot distortion/blurring, and focal spot shift across a range of readout durations and maximum temperatures for Cartesian, spiral-out, and retraced spiral-in/out (RIO) trajectories. The RIO trajectory was applied for stack-of-spirals 3D imaging on a real-time imaging platform and preliminary evaluation was carried out compared to a standard 2D sequence in vivo using a swine brain model, comparing maximum and mean temperatures measured between the two methods, as well as the temporal standard deviation measured by the two methods. RESULTS: In simulations, low-bandwidth Cartesian trajectories showed substantial shift of the focal spot, whereas both spiral trajectories showed no shift while maintaining focal spot geometry. In vivo, the 3D sequence achieved real-time 4D monitoring of thermometry, with an update time of 2.9-3.3 s. CONCLUSION: Spiral imaging, and RIO imaging in particular, is an effective way to speed up volumetric MR thermometry. Magn Reson Med 79:3122-3127, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Transcranial MRI-guided high-intensity focused ultrasound for treatment of essential tremor: A pilot study on the correlation between lesion size, lesion location, thermal dose, and clinical outcome.

BACKGROUND: Transcranial MR-guided high-intensity focused ultrasound (tcMRgFUS) is a promising noninvasive method to treat medication-refractory essential tremor. PURPOSE/HYPOTHESIS: To define the correlation between lesion size after ablation, thermal dose, and clinical outcome in tcMRgFUS treatment of essential tremor. STUDY TYPE: Retrospective. POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL: Eight patients with medication-refractory essential tremor were treated using a tcMRgFUS system at 3T. FIELD STRENGTH/SEQUENCE: T2 -weighted images were acquired immediately and at 1 year posttreatment at 3T. ASSESSMENT: An atlas of the thalamic nuclei and dose maps were warped to the posttreatment images. The thermal dose, the immediate posttreatment lesion volume and 1-year final lesion volume, and the volumes confined inside the ventral division of the ventral lateral posterior thalamic nucleus (VLpv) were correlated to clinical outcome at 1 month and 1 year using Pearson's coefficient. The spatial region of treatment correlating with maximal clinical outcome was derived in a normalized space from average maps of clinical tremor score improvement at 1 year. STATISTICAL TESTS: Statistical significance was assessed using the Wilcoxon two-tailed rank test. RESULTS: The correlations between thermal dose, lesion volume posttreatment and at 1 year, and outcome at 1 year were good (r = 0.73, 0.65, 0.73, respectively), and were slightly better than at 1 month (r = 0.57, 0.49, 0.65). Reducing the measurement to include only the portion within the VLpv did not significantly modify the correlations (P = 0.09). The center of the spatial region of treatment was found in the anterior commissure - posterior commissure plane, 14.3 mm lateral from the midline, and 8.3 mm rostral to the posterior commissure. DATA CONCLUSION: In this pilot study a good correlation was found between the size of the lesion, the thermal dose, and the clinical outcome in patients treated for essential tremor with ablation of the VLpv with tcMRgFUS. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2017.

Specialized volumetric thermometry for improved guidance of MRgFUS in brain.

PURPOSE: MR thermometry is critical for safe and effective transcranial focused ultrasound. The current single-slice MR thermometry sequence cannot achieve all desired treatment monitoring requirements. We propose an approach in which the imaging requirements of different aspects of treatment monitoring are met by optimizing multiple sequences. METHODS: Imaging requirements were determined for three stages of MR-guided focused ultrasound brain treatment: 1) focal spot localization, 2) focal spot monitoring, and 3) background monitoring. Multiple-echo spiral thermometry sequences were optimized for each set of requirements and then validated with in vivo signal-to-noise ratio measurements and with phantom heating experiments. RESULTS: Each of the proposed sequences obtained better precision than the current two-dimensional Fourier transform (2DFT) thermometry sequence. Five-slice focal spot localization achieved two-fold better resolution with 1.9-fold better precision but two-fold longer acquisition compared to 2DFT. Five-slice focal monitoring achieved 2.1-fold better precision with similar speed but 12% larger voxels than 2DFT. Full-brain background monitoring was demonstrated in both axial (7.1 s) and sagittal (11.4 s) orientations. Phantom heating time curves were consistent across all sequences after correcting for resolution. CONCLUSION: Multiple-echo spiral imaging significantly improves MR thermometry efficiency, enabling multiple-slice monitoring. Optimizing multiple specialized sequences provides better performance than can be achieved by any single sequence. Magn Reson Med 78:508-517, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Treatment of Low-Flow Vascular Malformations of the Extremities Using MR-Guided High Intensity Focused Ultrasound: Preliminary Experience.

Five patients with painful vascular malformations of the extremities that were refractory to standard treatment and were confirmed as low-flow malformations on dynamic contrast-enhanced magnetic resonance (MR) imaging were treated with MR imaging-guided high intensity focused ultrasound. Daily maximum numeric rating scale scores for pain improved from 8.4 ± 1.5 to 1.6 ± 2.2 (P = .004) at a median follow-up of 9 months (range, 4-36 mo). The size of the vascular malformations decreased on follow-up MR imaging (median enhancing volume, 8.2 mL [0.7-10.1 mL] before treatment; 0 mL [0-2.3 mL] after treatment; P = .018) at a median follow-up of 5 months (range, 3-36 mo). No complications occurred.

Improved MRI thermometry with multiple-echo spirals.

PURPOSE: Low-bandwidth PRF shift thermometry is used to guide HIFU ablation treatments. Low sampling bandwidth is needed for high signal-to-noise ratio with short acquisition times, but can lead to off-resonance artifacts. In this work, improved multiple-echo thermometry is presented that allows for high bandwidth and reduced artifacts. It is also demonstrated with spiral sampling, to improve the trade-off between resolution, speed, and measurement precision. METHODS: Four multiple-echo thermometry sequences were tested in vivo, one using two-dimensional Fourier transform (2DFT) sampling and three using spirals. The spiral sequences were individually optimized for resolution, for speed, and for precision. Multifrequency reconstruction was used to correct for off-resonance spiral artifacts. Additionally, two different multiecho temperature reconstructions were compared. RESULTS: Weighted combination of per-echo phase differences gave significantly better precision than least squares off-resonance estimation. Multiple-echo 2DFT sequence obtained precision similar to single-echo 2DFT, while greatly increasing sampling bandwidth. The multiecho spiral acquisitions achieved 2× better resolution, 2.9× better uncertainty, or 3.4× faster acquisition time, without negatively impacting the other two design parameters as compared to single-echo 2DFT. CONCLUSION: Multiecho spiral thermometry greatly improves the capabilities of temperature monitoring, and could improve transcranial treatment monitoring capabilities. Magn Reson Med 76:747-756, 2016. © 2015 Wiley Periodicals, Inc.

Correcting heat-induced chemical shift distortions in proton resonance frequency-shift thermometry.

PURPOSE: To reconstruct proton resonance frequency-shift temperature maps free of chemical shift distortions. THEORY AND METHODS: Tissue heating created by thermal therapies such as focused ultrasound surgery results in a change in proton resonance frequency that causes geometric distortions in the image and calculated temperature maps, in the same manner as other chemical shift and off-resonance distortions if left uncorrected. We propose an online-compatible algorithm to correct these distortions in 2DFT and echo-planar imaging acquisitions, which is based on a k-space signal model that accounts for proton resonance frequency change-induced phase shifts both up to and during the readout. The method was evaluated with simulations, gel phantoms, and in vivo temperature maps from brain, soft tissue tumor, and uterine fibroid focused ultrasound surgery treatments. RESULTS: Without chemical shift correction, peak temperature and thermal dose measurements were spatially offset by approximately 1 mm in vivo. Spatial shifts increased as readout bandwidth decreased, as shown by up to 4-fold greater temperature hot spot asymmetry in uncorrected temperature maps. In most cases, the computation times to correct maps at peak heat were less than 10 ms, without parallelization. CONCLUSION: Heat-induced proton resonance frequency changes create chemical shift distortions in temperature maps resulting from MR-guided focused ultrasound surgery ablations, but the distortions can be corrected using an online-compatible algorithm. Magn Reson Med 76:172-182, 2016. © 2015 Wiley Periodicals, Inc.

Is MR-guided High-intensity Focused Ultrasound a Feasible Treatment Modality for Desmoid Tumors?

BACKGROUND: MR-guided high-intensity focused ultrasound is a noninvasive treatment modality that uses focused ultrasound waves to thermally ablate tumors within the human body while minimizing side effects to surrounding healthy tissues. This technology is FDA-approved for certain tumors and has potential to be a noninvasive treatment option for extremity soft tissue tumors. Development of treatment modalities that achieve tumor control, decrease morbidity, or both might be of great benefit for patients. We wanted to assess the potential use of this technology in the treatment of extremity desmoid tumors. QUESTIONS/PURPOSES: (1) Can we use MR-guided high-intensity focused ultrasound to accurately ablate a predetermined target volume within a human cadaver extremity? (2) Does MR-guided high-intensity focused ultrasound treatment stop progression and/or cause regression of extremity desmoid tumors? METHODS: Simulated tumor volumes in four human cadavers, created by using plastic markers, were ablated using a commercially available focused ultrasound system. Accuracy was determined in accordance with the International Organization of Standards location error by measuring the farthest distance between the ablated tissue and the plane corresponding to the target. Between 2012 and 2014, we treated nine patients with desmoid tumors using focused ultrasound ablation. Indications for this were tumor-related symptoms or failure of conventional treatment. Of those, five of them were available for MRI followup at 12 months or longer (mean, 18.2 months; range, 12-23 months). The radiographic and clinical outcomes of five patients who had desmoid tumors treated with focused ultrasound were prospectively recorded. Patients were assessed preoperatively with MRI and followed at routine intervals after treatment with MRI scans and clinical examination. RESULTS: The ablation accuracy for the four cadaver extremities was 5 mm, 3 mm, 8 mm, and 8 mm. Four patients' tumors became smaller after treatment and one patient has slight progression at the time of last followup. The mean decrease in tumor size determined by MRI measurements was 36% (95% confidence interval, 7%-66%). No patient has received additional adjuvant systemic or local treatment. Treatment-related adverse events included first- and second-degree skin burns occurring in four patients, which were managed successfully without further surgery. CONCLUSIONS: This preliminary investigation provides some evidence that MR-guided high-intensity focused ultrasound may be a feasible treatment for desmoid tumors. It may also be of use for other soft tissue neoplasms in situations in which there are limited traditional treatment options such as recurrent sarcomas. Further investigation is necessary to better define the indications, efficacy, role, and long-term oncologic outcomes of focused ultrasound treatment. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Voltage-based device tracking in a 1.5 Tesla MRI during imaging: initial validation in swine models.

PURPOSE: Voltage-based device-tracking (VDT) systems are commonly used for tracking invasive devices in electrophysiological cardiac-arrhythmia therapy. During electrophysiological procedures, electro-anatomic mapping workstations provide guidance by integrating VDT location and intracardiac electrocardiogram information with X-ray, computerized tomography, ultrasound, and MR images. MR assists navigation, mapping, and radiofrequency ablation. Multimodality interventions require multiple patient transfers between an MRI and the X-ray/ultrasound electrophysiological suite, increasing the likelihood of patient-motion and image misregistration. An MRI-compatible VDT system may increase efficiency, as there is currently no single method to track devices both inside and outside the MRI scanner. METHODS: An MRI-compatible VDT system was constructed by modifying a commercial system. Hardware was added to reduce MRI gradient-ramp and radiofrequency unblanking pulse interference. VDT patches and cables were modified to reduce heating. Five swine cardiac VDT electro-anatomic mapping interventions were performed, navigating inside and thereafter outside the MRI. RESULTS: Three-catheter VDT interventions were performed at >12 frames per second both inside and outside the MRI scanner with <3 mm error. Catheters were followed on VDT- and MRI-derived maps. Simultaneous VDT and imaging was possible in repetition time >32 ms sequences with <0.5 mm errors, and <5% MRI signal-to-noise ratio (SNR) loss. At shorter repetition times, only intracardiac electrocardiogram was reliable. Radiofrequency heating was <1.5°C. CONCLUSION: An MRI-compatible VDT system is feasible.

A novel method for tracking nitrogen kinetics in vivo under hyperbaric conditions using radioactive nitrogen-13 gas and positron emission tomography.

Decompression sickness (DCS) is caused by gaseous nitrogen dissolved in tissues forming bubbles during decompression. To date, no method exists to identify nitrogen within tissues, but with advances in positron-emission tomography (PET) technology, it may be possible to track gaseous radionuclides into tissues. We aimed to develop a method to track nitrogen movement in vivo and under hyperbaric pressure that could then be used to further our understanding of DCS using nitrogen-13 (13N2). A single anesthetized female Sprague-Dawley rat was exposed to 625 kPa, composed of air, isoflurane, and 13N2 for 10 min. The PET scanner recorded 13N2 during the hyperbaric exposure with energy windows of 250-750 keV. The PET showed an increase in 13N2 concentration in the lung, heart, and abdominal regions, which all reached a plateau after ∼4 min. This showed that it is possible to gain noninvasive in vivo measurements of nitrogen kinetics through the body while at hyperbaric pressures. Tissue samples showed radioactivity above background levels in the blood, brain, liver, femur, and thigh muscle when assessed using a γ counter. The method can be used to evaluate an array of challenges to our understanding of decompression physiology by quantifying nitrogen load through γ counts of 13N2, and signal intensity of the PET. Further development of the method will improve the specificity of the measured outcomes, and enable it to be used with larger mammals, including humans.NEW & NOTEWORTHY This article describes a method for the in vivo quantification and tracking of nitrogen through the mammalian body whilst exposed to hyperbaric pressure. The method has the potential to further our understanding of decompression sickness, and quantitatively evaluate the effectiveness of both the treatment and prevention of decompression sickness.

Prospective motion correction using tracking coils.

Intracavity imaging coils provide higher signal-to-noise than surface coils and have the potential to provide higher spatial resolution in shorter acquisition times. However, images from these coils suffer from physiologically induced motion artifacts, as both the anatomy and the coils move during image acquisition. We developed prospective motion-correction techniques for intracavity imaging using an array of tracking coils. The system had <50 ms latency between tracking and imaging, so that the images from the intracavity coil were acquired in a frame of reference defined by the tracking array rather than by the system's gradient coils. Two-dimensional gradient-recalled and three-dimensional electrocardiogram-gated inversion-recovery-fast-gradient-echo sequences were tested with prospective motion correction using ex vivo hearts placed on a moving platform simulating both respiratory and cardiac motion. Human abdominal tests were subsequently conducted. The tracking array provided a positional accuracy of 0.7 ± 0.5 mm, 0.6 ± 0.4 mm, and 0.1 ± 0.1 mm along the X, Y, and Z directions at a rate of 20 frames-per-second. The ex vivo and human experiments showed significant image quality improvements for both in-plane and through-plane motion correction, which although not performed in intracavity imaging, demonstrates the feasibility of implementing such a motion-correction system in a future design of combined tracking and intracavity coil.

Development and validation of a computational method to predict unintended auditory brainstem response during transcranial ultrasound neuromodulation in mice.

BACKGROUND: Transcranial ultrasound stimulation (TUS) is a promising noninvasive neuromodulation modality. The inadvertent and unpredictable activation of the auditory system in response to TUS obfuscates the interpretation of non-auditory neuromodulatory responses. OBJECTIVE: The objective was to develop and validate a computational metric to quantify the susceptibility to unintended auditory brainstem response (ABR) in mice premised on time frequency analyses of TUS signals and auditory sensitivity. METHODS: Ultrasound pulses with varying amplitudes, pulse repetition frequencies (PRFs), envelope smoothing profiles, and sinusoidal modulation frequencies were selected. Each pulse's time-varying frequency spectrum was differentiated across time, weighted by the mouse hearing sensitivity, then summed across frequencies. The resulting time-varying function, computationally predicting the ABR, was validated against experimental ABR in mice during TUS with the corresponding pulse. RESULTS: There was a significant correlation between experimental ABRs and the computational predictions for 19 TUS signals (R2 = 0.97). CONCLUSIONS: To reduce ABR in mice during in vivo TUS studies, 1) reduce the amplitude of a rectangular continuous wave envelope, 2) increase the rise/fall times of a smoothed continuous wave envelope, and/or 3) change the PRF and/or duty cycle of a rectangular or sinusoidal pulsed wave to reduce the gap between pulses and increase the rise/fall time of the overall envelope. This metric can aid researchers performing in vivo mouse studies in selecting TUS signal parameters that minimize unintended ABR. The methods for developing this metric can be adapted to other animal models.

Focused ultrasound-induced inhibition of peripheral nerve fibers in an animal model of acute pain.

BACKGROUND: Moderate-to-severe acute pain is prevalent in many healthcare settings and associated with adverse outcomes. Peripheral nerve blockade using traditional needle-based and local anesthetic-based techniques improves pain outcomes for some patient populations but has shortcomings limiting use. These limitations include its invasiveness, potential for local anesthetic systemic toxicity, risk of infection with an indwelling catheter, and relatively short duration of blockade compared with the period of pain after major injuries. Focused ultrasound is capable of inhibiting the peripheral nervous system and has potential as a pain management tool. However, investigations of its effect on peripheral nerve nociceptive fibers in animal models of acute pain are lacking. In an in vivo acute pain model, we investigated focused ultrasound's effects on behavior and peripheral nerve structure. METHODS: Focused ultrasound was applied directly to the sciatic nerve of rats just prior to a hindpaw incision; three control groups (focused ultrasound sham only, hindpaw incision only, focused ultrasound sham+hindpaw incision) were also included. For all four groups (intervention and controls), behavioral testing (thermal and mechanical hyperalgesia, hindpaw extension and flexion) took place for 4 weeks. Structural changes to peripheral nerves of non-focused ultrasound controls and after focused ultrasound application were assessed on days 0 and 14 using light microscopy and transmission electron microscopy. RESULTS: Compared with controls, after focused ultrasound application, animals had (1) increased mechanical nociceptive thresholds for 2 weeks; (2) sustained increase in thermal nociceptive thresholds for ≥4 weeks; (3) a decrease in hindpaw motor response for 0.5 weeks; and (4) a decrease in hindpaw plantar sensation for 2 weeks. At 14 days after focused ultrasound application, alterations to myelin sheaths and nerve fiber ultrastructure were observed both by light and electron microscopy. DISCUSSION: Focused ultrasound, using a distinct parameter set, reversibly inhibits A-delta peripheral nerve nociceptive, motor, and non-nociceptive sensory fiber-mediated behaviors, has a prolonged effect on C nociceptive fiber-mediated behavior, and alters nerve structure. Focused ultrasound may have potential as a peripheral nerve blockade technique for acute pain management. However, further investigation is required to determine C fiber inhibition duration and the significance of nerve structural changes.

Changes in the Cerebello-Thalamo-Cortical Network After Magnetic Resonance-Guided Focused Ultrasound Thalamotomy.

Objective: In recent years, transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) has been established as a potential treatment option for movement disorders, including essential tremor (ET). So far, however, little is known about the impact of tcMRgFUS on structural connectivity. The objective of this study was to detect microstructural changes in tremor- and motor-related white matter tracts in ET patients treated with tcMRgFUS thalamotomy. Methods: Eleven patients diagnosed with ET were enrolled in this tcMRgFUS thalamotomy study. For each patient, 3 Tesla magnetic resonance imaging (3T MRI) including structural and diffusion MRI were acquired and the Clinical Rating Scale for Tremor was assessed before the procedure as well as 1 year after the treatment. Diffusion MRI tractography was performed to identify the cerebello-thalamo-cortical tract (CTCT), the medial lemniscus, and the corticospinal tract in both hemispheres on pre-treatment data. Pre-treatment tractography results were co-registered to post-treatment diffusion data. Diffusion tensor imaging (DTI) metrics, including fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD), were averaged across the tracts in the pre- and post-treatment data. Results: The mean value of tract-specific DTI metrics changed significantly within the thalamic lesion and in the CTCT on the treated side (p < 0.05). Changes of DTI-derived indices within the CTCT correlated well with lesion overlap (FA: r = -0.54, p = 0.04; MD: r = 0.57, p = 0.04); RD: r = 0.67, p = 0.036). Further, a trend was seen for the correlation between changes of DTI-derived indices within the CTCT and clinical improvement (FA: r = 0.58; p = 0.062; MD: r = -0.52, p = 0.64; RD: r = -0.61 p = 0.090). Conclusions: Microstructural changes were detected within the CTCT after tcMRgFUS, and these changes correlated well with lesion-tract overlap. Our results show that diffusion MRI is able to detect the microstructural effects of tcMRgFUS, thereby further elucidating the treatment mechanism, and ultimately to improve targeting prospectively. Impact statement The results of this study demonstrate microstructural changes within the cerebello-thalamo-cortical pathways 1 year after MR-guided focused ultrasound thalamotomy. Even more, microstructural changes within the cerebello-thalamo-cortical pathways correlated significantly with clinical outcome. These findings do not only highly emphasize the need of new targeting strategies for MR-guided focused ultrasound thalamotomy but also help to elucidate the treatment mechanism of it.

Dose-dependent effects of high intensity focused ultrasound on compound action potentials in an ex vivo rodent peripheral nerve model: comparison to local anesthetics.

BACKGROUND: In animal models, focused ultrasound can reversibly or permanently inhibit nerve conduction, suggesting a potential role in managing pain. We hypothesized focused ultrasound's effects on action potential parameters may be similar to those of local anesthetics. METHODS: In an ex vivo rat sciatic nerve model, action potential amplitude, area under the curve, latency to 10% peak, latency to 100% peak, rate of rise, and half peak width changes were assessed after separately applying increasing focused ultrasound pressures or concentrations of bupivacaine and ropivacaine. Focused ultrasound's effects on nerve structure were examined histologically. RESULTS: Increasing focused ultrasound pressures decreased action potential amplitude, area under the curve, and rate of rise, increased latency to 10% peak, and did not change latency to 100% peak or half peak width. Increasing local anesthetic concentrations decreased action potential amplitude, area under the curve, and rate of rise and increased latency to 10% peak, latency to 100% peak, and half peak width. At the highest focused ultrasound pressures, nerve architecture was altered compared with controls. DISCUSSION: While some action potential parameters were altered comparably by focused ultrasound and local anesthetics, there were small but notable differences. It is not evident if these differences may lead to differences in clinical pain effects when focused ultrasound is applied in vivo or if focused ultrasound pressures that result in clinically relevant changes damage nerve structures. Given the potential advantages of a non-invasive technique for managing pain conditions, further investigation may be warranted in an in vivo pain model.