Ultrasound neuromodulation holds promise as a non-invasive technique for neuromodulation of the central nervous system. However, much remains to be determined about how the technique can be transformed into a useful technology, including the effect of ultrasound frequency. Previous studies have demonstrated neuromodulation in vivo using frequencies less than 1 MHz, with a trend towards improved efficacy with lower frequency. However, using higher frequencies could offer improved ultrasound spatial resolution. We investigate the ultrasound neuromodulation effects in mice at various frequencies both below and above 1 MHz and find that frequencies up to 2.9 MHz can still be effective for generating motor responses, but also confirm that as frequency increases, sonications require significantly more intensity to achieve equivalent efficacy. We argue that our results provide evidence that favors either a particle displacement or a cavitation-based mechanism for the phenomenon of ultrasound neuromodulation.

Background: Recent studies in a variety of animal models including rodents, monkeys, and humans suggest that transcranial focused ultrasound (tFUS) has considerable promise for noninvasively modulating neural activity with the ability to target deep brain structures. However, concerns have been raised that motor responses evoked by tFUS may be due to indirect activation of the auditory pathway rather than direct activation of motor circuits. Objective: In this study, we sought to examine the involvement of peripheral auditory system activation from tFUS stimulation applied to elicit motor responses. The purpose was to determine to what extent ultrasound induced auditory artifact could be a factor in ultrasound motor neuromodulation. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflicts of interest No potential conflict of interest was reported by the authors. Declaration of interest We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm that any aspect of the work covered in this manuscript that has involved either experimental animals or human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript.

Recent studies in a variety of animal models including rodents, monkeys, and humans suggest that transcranial focused ultrasound (tFUS) has considerable promise for noninvasively modulating neural activity with the ability to target deep brain structures. However, concerns have been raised that motor responses evoked by tFUS may be due to indirect activation of the auditory pathway rather than direct activation of motor circuits. In this study, tFUS-induced electromyography (EMG) signals were recorded and analyzed in wild-type (WT) normal hearing mice and two strains of genetically deaf mice to examine the involvement of the peripheral auditory system in tFUS-stimulated motor responses. In addition, auditory brainstem responses (ABRs) were measured to elucidate the effect of the tFUS stimulus envelope on auditory and motor responses. We also varied the tFUS stimulation duration to measure its effect on motor response duration. We show, first, that the sharp edges in a tFUS rectangular envelope stimulus activate the peripheral afferent auditory pathway and, second, that smoothing these edges eliminates the auditory responses without affecting the motor responses in normal hearing WT mice. We further show that by eliminating peripheral auditory activity using two different strains of deaf knockout mice, motor responses are the same as in normal hearing WT mice. Finally, we demonstrate a high correlation between tFUS pulse duration and EMG response duration. These results support the concept that tFUS-evoked motor responses are not a result of stimulation of the peripheral auditory system.

Objectives Essential Tremor (ET) is one of the most common neurologic conditions, and conservative measures are frequently suboptimal. Recent data from a multi-institution, randomized controlled clinical trial demonstrated that Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thalamotomy improves upper limb tremor in medically refractory ET. This study assesses the cost-effectiveness of this novel therapy in comparison to existing procedural options. Methods PubMed and Cochrane Library searches were performed for studies of MRgFUS, Deep Brain Stimulation (DBS), and Stereotactic Radiosurgery (SRS) for ET. Pre-and post-operative tremor-related disability scores were collected from 32 studies involving 83 MRgFUS, 615 DBS, and 260 SRS cases. Utility (defined as percent change in functional disability) was calculated, and Medicare reimbursements were collected as a proxy for societal cost -costs of MRgFUS for ET were derived from a combination of available costs of approved indications and SRS costs where appropriate. A decision and cost-effectiveness analysis was then constructed, implementing meta-analytic techniques. Results MRgFUS thalamotomy resulted in significantly higher utility scores compared with DBS and SRS based on estimates of Medicare reimbursement (p < 0.001). MRgFUS was also the most inexpensive procedure out of the three (p < 0.001). Conclusions Preliminary experience with MRgFUS for ET suggests that this novel therapeutic may be more effective than available alternatives and potentially less costly for society. It thus will likely "dominate" DBS and SRS as a more cost-effective option for medically refractory ET. Our findings support further investigation of MRgFUS for ET and broad adoption. Objectives The ventral intermediate nucleus (VIM) is not visible on conventional Magnetic Resonance Imaging (MRI).A novel method for tractography-based VIM identification has recently been described. We report the short-term clinical results of prospective VIM targeting with tractography in a cohort of patients undergoing Focused Ultrasound thalamotomy. Methods All patients underwent structural and diffusion weighted imaging (60 diffusion directions, 2 mm isovoxel) with 3 Tesla MRI scanner (Philips Ingenia CX). The images were processed using streamline tractography (Stealth Viz, Medtronic Inc.). The lateral and posterior borders of VIM were defined by tracking the pyramidal tract and medial lemniscus respectively. A VIM region of interest (ROI) was placed 3 mm away from these borders (Figs. 1, 2 and 3). The structural connectivity of this VIM ROI was confirmed to the motor cortex (M1) and cerebellum. The coordinates of tractography-based VIM in relation to posterior commissure were noted for surgical targeting. The parameters analyzed include a clinical tremor scale (pre-, intraoperative, and post operative), operative time, and number of sonications. Results Tractography-based VIM targeting was successful in 7 out of 8 patients. The coordinates of tractography-based VIM were significantly different from...

As novel cancer treatments become available, the need to quickly and accurately evaluate whether these treatments are effective remains unaddressed. Obtaining earlier feedback on the efficacy of a cancer therapy could prevent a poor treatment outcome by switching to a more effective therapy sooner. Levels of circulating tumor DNA (ctDNA) have been found to be prognostic of tumor progression, suggesting that a non-invasive liquid biopsy assay could provide longitudinal ctDNA measurements that accurately track tumor progression. However, while there is interest in using existing minimal residual disease (MRD) detection and treatment selection liquid biopsy assays for treatment monitoring applications, they both suffer from limitations in their ability to precisely and sensitively quantify trends in tumor progression over the course of treatment. In addition, tumor-informed MRD detection assays are often infeasible for treatment monitoring due to unavailability of the initial tissue sample. We have developed and validated a novel methylation-based liquid biopsy assay for pan-cancer treatment monitoring without the need to obtain a sample from the tumor itself. Methylation has long been shown to be a strong and consistent biomarker for cancer, and because tumor tissue has widespread differential methylation across the genome compared to normal tissue, we are able to overcome molecule sampling limitations. In analytical validation, our assay could detect as small changes as 0.05%, e.g., an elevation of tumor fraction from 0.5% to 0.55%, a level of precision that is an order-of-magnitude better than any available assays. Next, we tested our assay on clinical specimens by measuring ctDNA in serially collected blood samples from subjects with cancer. As would be expected from the high level of precision, we were able to successfully demonstrate the predictive power of ctDNA measurements for clinical outcomes. These results from our methylation-based liquid biopsy assay open the path to earlier and extremely precise treatment monitoring for oncologists and their patients. Citation Format: Patrick Peiyong Ye, Robb Viens, Xavier Bower, Shan Riku, David Tsao, Oguzhan Atay. Novel methylation-based, tissue-free ctDNA assay accurately quantifies longitudinal tumor burden changes for precision treatment monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 526.