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.

Characterization of elbow flexion torque after nerve reconstruction of patients with traumatic brachial plexus injury.

BACKGROUND: The modified British Medical Research Council muscle grading system remains the primary method for assessing outcomes following surgical intervention despite its subjectivity and numerous inherent flaws. A new objective outcome measure of elbow function in patients with a brachial plexus injury is proposed. METHODS: 11 patients with a reconstructed brachial plexus (nerve reconstruction) and 10 unimpaired control subjects were evaluated. A custom apparatus measuring elbow flexion torque was developed. The subjects were asked to match their elbow flexion torque to a predefined torque. Time taken to achieve this predefined elbow flexion torque (latency) and duration of steady torque output were used as outcome measures. RESULTS: Healthy individuals were better at maintaining and regulating elbow torque. The patients with a brachial plexus injury showed similar latency while increasing their elbow torque (normalized to maximum elbow torque) but lacked the ability to modulate the latency with demand as the healthy subjects. INTERPRETATION: This novel measure provides objective information regarding the patient's ability to control elbow torque after nerve reconstruction.

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.