Focused Ultrasound Neuromodulation of Human In Vitro Neural Cultures in Multi-Well Microelectrode Arrays.

The neuromodulatory effects of focused ultrasound (FUS) have been demonstrated in animal models, and FUS has been used successfully to treat movement and psychiatric disorders in humans. However, despite the success of FUS, the mechanism underlying its effects on neurons remains poorly understood, making treatment optimization by tuning FUS parameters difficult. To address this gap in knowledge, we studied human neurons in vitro using neurons cultured from human-induced pluripotent stem cells (HiPSCs). Using HiPSCs allows for the study of human-specific neuronal behaviors in both physiologic and pathologic states. This report presents a protocol for using a high-throughput system that enables the monitoring and quantification of the neuromodulatory effects of FUS on HiPSC neurons. By varying the FUS parameters and manipulating the HiPSC neurons through pharmaceutical and genetic modifications, researchers can evaluate the neural responses and elucidate the neuro-modulatory effects of FUS on HiPSC neurons. This research could have significant implications for the development of safe and effective FUS-based therapies for a range of neurological and psychiatric disorders.

Tethered spinal cord tension assessed via ultrasound elastography in computational and intraoperative human studies.

BACKGROUND: Tension in the spinal cord is a trademark of tethered cord syndrome. Unfortunately, existing tests cannot quantify tension across the bulk of the cord, making the diagnostic evaluation of stretch ambiguous. A potential non-destructive metric for spinal cord tension is ultrasound-derived shear wave velocity (SWV). The velocity is sensitive to tissue elasticity and boundary conditions including strain. We use the term Ultrasound Tensography to describe the acoustic evaluation of tension with SWV. METHODS: Our solution Tethered cord Assessment with Ultrasound Tensography (TAUT) was utilized in three sub-studies: finite element simulations, a cadaveric benchtop validation, and a neurosurgical case series. The simulation computed SWV for given tensile forces. The cadaveric model with induced tension validated the SWV-tension relationship. Lastly, SWV was measured intraoperatively in patients diagnosed with tethered cords who underwent treatment (spinal column shortening). The surgery alleviates tension by decreasing the vertebral column length. RESULTS: Here we observe a strong linear relationship between tension and squared SWV across the preclinical sub-studies. Higher tension induces faster shear waves in the simulation (R2 = 0.984) and cadaveric (R2 = 0.951) models. The SWV decreases in all neurosurgical procedures (p < 0.001). Moreover, TAUT has a c-statistic of 0.962 (0.92-1.00), detecting all tethered cords. CONCLUSIONS: This study presents a physical, clinical metric of spinal cord tension. Strong agreement among computational, cadaveric, and clinical studies demonstrates the utility of ultrasound-induced SWV for quantitative intraoperative feedback. This technology is positioned to enhance tethered cord diagnosis, treatment, and postoperative monitoring as it differentiates stretched from healthy cords.

Tethered spinal cord syndrome occurs when surrounding tissue attaches to and causes stretching across the spinal cord. People with a tethered cord can experience weakness, pain, and loss of bladder control. Although increased tension in the spinal cord is known to cause these symptoms, evaluating the amount of stretching remains challenging. We investigated the ability of an ultrasound imaging approach to measure spinal cord tension. We studied our method in a computer simulation, a benchtop validation model, and in six people with tethered cords during surgery that they were undergoing to reduce tension. In each phase, the approach could detect differences between stretched spinal cords and spinal cords in a healthy state. Our method could potentially be used in the future to improve the care of people with a tethered cord.

Non-contrast ultrasound image analysis for spatial and temporal distribution of blood flow after spinal cord injury.

Ultrasound technology can provide high-resolution imaging of blood flow following spinal cord injury (SCI). Blood flow imaging may improve critical care management of SCI, yet its duration is limited clinically by the amount of contrast agent injection required for high-resolution, continuous monitoring. In this study, we aim to establish non-contrast ultrasound as a clinically translatable imaging technique for spinal cord blood flow via comparison to contrast-based methods and by measuring the spatial distribution of blood flow after SCI. A rodent model of contusion SCI at the T12 spinal level was carried out using three different impact forces. We compared images of spinal cord blood flow taken using both non-contrast and contrast-enhanced ultrasound. Subsequently, we processed the images as a function of distance from injury, yielding the distribution of blood flow through space after SCI, and found the following. (1) Both non-contrast and contrast-enhanced imaging methods resulted in similar blood flow distributions (Spearman's ρ = 0.55, p < 0.0001). (2) We found an area of decreased flow at the injury epicenter, or umbra (p < 0.0001). Unexpectedly, we found increased flow at the periphery, or penumbra (rostral, p < 0.05; caudal, p < 0.01), following SCI. However, distal flow remained unchanged, in what is presumably unaffected tissue. (3) Finally, tracking blood flow in the injury zones over time revealed interesting dynamic changes. After an initial decrease, blood flow in the penumbra increased during the first 10 min after injury, while blood flow in the umbra and distal tissue remained constant over time. These results demonstrate the viability of non-contrast ultrasound as a clinical monitoring tool. Furthermore, our surprising observations of increased flow in the injury periphery pose interesting new questions about how the spinal cord vasculature reacts to SCI, with potentially increased significance of the penumbra.

Visualizing tactile feedback: an overview of current technologies with a focus on ultrasound elastography.

Tissue elasticity remains an essential biomarker of health and is indicative of irregularities such as tumors or infection. The timely detection of such abnormalities is crucial for the prevention of disease progression and complications that arise from late-stage illnesses. However, at both the bedside and the operating table, there is a distinct lack of tactile feedback for deep-seated tissue. As surgical techniques advance toward remote or minimally invasive options to reduce infection risk and hasten healing time, surgeons lose the ability to manually palpate tissue. Furthermore, palpation of deep structures results in decreased accuracy, with the additional barrier of needing years of experience for adequate confidence of diagnoses. This review delves into the current modalities used to fulfill the clinical need of quantifying physical touch. It covers research efforts involving tactile sensing for remote or minimally invasive surgeries, as well as the potential of ultrasound elastography to further this field with non-invasive real-time imaging of the organ's biomechanical properties. Elastography monitors tissue response to acoustic or mechanical energy and reconstructs an image representative of the elastic profile in the region of interest. This intuitive visualization of tissue elasticity surpasses the tactile information provided by sensors currently used to augment or supplement manual palpation. Focusing on common ultrasound elastography modalities, we evaluate various sensing mechanisms used for measuring tactile information and describe their emerging use in clinical settings where palpation is insufficient or restricted. With the ongoing advancements in ultrasound technology, particularly the emergence of micromachined ultrasound transducers, these devices hold great potential in facilitating early detection of tissue abnormalities and providing an objective measure of patient health.

Disruption of the Blood-Spinal Cord Barrier using Low-Intensity Focused Ultrasound in a Rat Model.

Low-intensity focused ultrasound (LIFU) uses ultrasonic pulsations at lower intensities than ultrasound and is being tested as a reversible and precise neuromodulatory technology. Although LIFU-mediated blood-brain barrier (BBB) opening has been explored in detail, no standardized technique for blood-spinal cord barrier (BSCB) opening has been established to date. Therefore, this protocol presents a method for successful BSCB disruption using LIFU sonication in a rat model, including descriptions of animal preparation, microbubble administration, target selection and localization, as well as BSCB disruption visualization and confirmation. The approach reported here is particularly useful for researchers who need a fast and cost-effective method to test and confirm target localization and precise BSCB disruption in a small animal model with a focused ultrasound transducer, evaluate the BSCB efficacy of sonication parameters, or explore applications for LIFU at the spinal cord, such as drug delivery, immunomodulation, and neuromodulation. Optimizing this protocol for individual use is recommended, especially for advancing future preclinical, clinical, and translational work.

Sonodynamic Therapy for the Treatment of Glioblastoma Multiforme in a Mouse Model Using a Portable Benchtop Focused Ultrasound System.

Sonodynamic therapy (SDT) is an application of focused ultrasound (FUS) that enables a sonosensitizing agent to prime tumors for increased sensitivity during sonication. Unfortunately, current clinical treatments for glioblastoma (GBM) are lacking, leading to low long-term survival rates among patients. SDT is a promising method for treating GBM in an effective, noninvasive, and tumor-specific manner. Sonosensitizers preferentially enter tumor cells compared to the surrounding brain parenchyma. The application of FUS in the presence of a sonosensitizing agent generates reactive oxidative species resulting in apoptosis. Although this therapy has been shown previously to be effective in preclinical studies, there is a lack of established standardized parameters. Standardized methods are necessary to optimize this therapeutic strategy for preclinical and clinical use. In this paper, we detail the protocol to perform SDT in a preclinical GBM rodent model using magnetic resonance-guided FUS (MRgFUS). MRgFUS is an important feature of this protocol, as it allows for specific targeting of a brain tumor without the need for invasive surgeries (e.g., craniotomy). The benchtop device used here can focus on a specific location in three dimensions by clicking on a target on an MRI image, making target selection a straightforward process. This protocol will provide researchers with a standardized preclinical method for MRgFUS SDT, with the added flexibility to change and optimize parameters for translational research.

Automatic detection of foreign body objects in neurosurgery using a deep learning approach on intraoperative ultrasound images: From animal models to first in-human testing.

Objects accidentally left behind in the brain following neurosurgical procedures may lead to life-threatening health complications and invasive reoperation. One of the most commonly retained surgical items is the cotton ball, which absorbs blood to clear the surgeon's field of view yet in the process becomes visually indistinguishable from the brain parenchyma. However, using ultrasound imaging, the different acoustic properties of cotton and brain tissue result in two discernible materials. In this study, we created a fully automated foreign body object tracking algorithm that integrates into the clinical workflow to detect and localize retained cotton balls in the brain. This deep learning algorithm uses a custom convolutional neural network and achieves 99% accuracy, sensitivity, and specificity, and surpasses other comparable algorithms. Furthermore, the trained algorithm was implemented into web and smartphone applications with the ability to detect one cotton ball in an uploaded ultrasound image in under half of a second. This study also highlights the first use of a foreign body object detection algorithm using real in-human datasets, showing its ability to prevent accidental foreign body retention in a translational setting.

Towards standardization of the parameters for opening the blood-brain barrier with focused ultrasound to treat glioblastoma multiforme: A systematic review of the devices, animal models, and therapeutic compounds used in rodent tumor models.

Glioblastoma multiforme (GBM) is a deadly and aggressive malignant brain cancer that is highly resistant to treatments. A particular challenge of treatment is caused by the blood-brain barrier (BBB), the relatively impermeable vasculature of the brain. The BBB prevents large molecules from entering the brain parenchyma. This protective characteristic of the BBB, however, also limits the delivery of therapeutic drugs for the treatment of brain tumors. To address this limitation, focused ultrasound (FUS) has been safely utilized to create transient openings in the BBB, allowing various high molecular weight drugs access to the brain. We performed a systematic review summarizing current research on treatment of GBMs using FUS-mediated BBB openings in in vivo mouse and rat models. The studies gathered here highlight how the treatment paradigm can allow for increased brain and tumor perfusion of drugs including chemotherapeutics, immunotherapeutics, gene therapeutics, nanoparticles, and more. Given the promising results detailed here, the aim of this review is to detail the commonly used parameters for FUS to open the BBB in rodent GBM models.