Safe focused ultrasound-mediated blood-brain barrier opening is driven primarily by transient reorganization of tight junctions.

Unlabelled: Focused ultrasound (FUS) with microbubbles opens the blood-brain barrier (BBB) to allow targeted drug delivery into the brain. The mechanisms by which endothelial cells (ECs) respond to either low acoustic pressures known to open the BBB transiently, or high acoustic pressures that cause brain damage, remain incompletely characterized. Here, we use a mouse strain where tight junctions between ECs are labelled with eGFP and apply FUS at low (450 kPa) and high (750 kPa) acoustic pressures, after which mice are sacrificed at 1 or 72 hours.

Characterization of Microbubble Cavitation in Theranostic Ultrasound-mediated Blood-Brain Barrier Opening and Gene Delivery.

Rationale: The characterization of microbubble activity has proven critical in assessing the safety and efficacy of ultrasound-mediated blood-brain barrier (BBB) opening and drug and gene delivery. In this study, we build upon our previous work on theranostic ultrasound (ThUS)-mediated BBB opening (ThUS-BBBO) and conduct for the first time a comprehensive characterization of the role of microbubble cavitation in ThUS-BBBO, as well as its impact on gene delivery with adeno-associated viruses (AAV).

Methods: A repurposed imaging phased array was used throughout the study to generate focused transmits and record microbubble activity through high-resolution power cavitation imaging (PCI).

ENHANCING TRANSCRANIAL FOCUSED ULTRASOUND TREATMENT PLANNING WITH SYNTHETIC CT FROM ULTRA-SHORT ECHO TIME (UTE) MRI: A MULTI-TASK DEEP LEARNING APPROACH.

Utilizing a multi-task deep learning framework, this study generated synthetic CT (sCT) images from a limited dataset of Ultrashort echo time (UTE) MRI for transcranial focused ultrasound (tFUS) planning. A 3D Transformer U-Net was employed to produce sCT images that closely replicated actual CT scans, demonstrated by an average Dice coefficient of 0.868 for morphological accuracy.

Physician-Patient Communication about Novel Drugs and High-Risk Medical Devices.

Background: After a new drug or medical device is approved by the US Food and Drug Administration (FDA), physician-patient communication about benefits and risks is critical, including whether the product was approved through an expedited pathway based on limited evidence. In addition, physician reporting of drug- and device-related adverse events in real-world use is necessary to have a complete safety profile. We studied physician-reported communication and safety-reporting practices related to drugs and devices.

Low hemoglobin causes hematoma expansion and poor intracerebral hemorrhage outcomes.

Objectives: Although lower hemoglobin levels associate with worse intracerebral hemorrhage (ICH) outcomes, causal drivers for this relationship remain unclear. We investigated the hypothesis that lower hemoglobin relates to increased hematoma expansion (HE) risk and poor outcomes using human observational data and assessed causal relationships using a translational murine model of anemia and ICH.

Methods: ICH patients with baseline hemoglobin measurements and serial CT neuroimaging enrolled between 2010-2016 to a multicenter, prospective observational cohort study were studied.

Feasibility of Hologram-Assisted Bilateral Blood-Brain Barrier Opening in Non-Human Primates.

Focused ultrasound (FUS) and microbubbles facilitate blood-brain barrier opening (BBBO) noninvasively, transiently, and safely for targeted drug delivery. Unlike state-of-the-art approaches, in this study, we demonstrate for the first time the simultaneous, bilateral BBBO in non-human primates (NHPs) using acoustic holograms at caudate and putamen structures. The simple and low-cost system with a single-element FUS transducer and 3-D printed acoustic hologram was guided by neuronavigation and a robotic arm.

Funding of evidence included within public comments submitted to inform Medicare national coverage determinations.

The Centers for Medicare & Medicaid Services (CMS) relies on public comments submitted in response to proposed national coverage determinations to assist the agency in determining the coverage of items and services for Medicare beneficiaries. In a cross-sectional study, we characterized the cited evidence and what funding supported the cited evidence submitted in public comments to CMS for all therapeutic medical device national coverage determinations finalized between June 2019 and June 2022. Of 681 public comments, 159 (23%) cited at least 1 identifiable published scientific journal article.

Transcranial Functional Ultrasound Imaging Detects Focused Ultrasound Neuromodulation Induced Hemodynamic Changes in Mouse and Nonhuman Primate Brains .

Focused ultrasound (FUS) is an emerging noinvasive technique for neuromodulation in the central nervous system (CNS). To evaluate the effects of FUS-induced neuromodulation, many studies used behavioral changes, functional magnetic resonance imaging (fMRI) or electroencephalography (EEG). However, behavioral readouts are often not easily mapped to specific brain activity, EEG has low spatial resolution limited to the surface of the brain and fMRI requires a large importable scanner that limits additional readouts and manipulations.

Physicians' Perspectives On FDA Regulation Of Drugs And Medical Devices: A National Survey.

Physicians' knowledge of Food and Drug Administration (FDA) approval processes is important in informing clinical decisions and patient discussions. Among a randomly selected national sample of 509 internists, cardiologists, and oncologists, 41 percent reported moderate or better understanding of the FDA's drug approval process, and 17 percent reported moderate or better understanding of the FDA's medical device approval process. Nearly all physicians thought that randomized, blinded trials that met primary endpoints should be very important factors required to secure regulatory approval.

Cardiac coronary tomography angiography (CCTA) use across geographical regions in the USA and the UK: a cross-sectional study.

Objective: Increased use of CT imaging has been identified as a key component of unsustainable rising healthcare costs in the USA and globally. Understanding evidence and its relation to imaging coverage policies can help identify patterns of variation to better inform high value care initiatives. This cross-sectional study evaluates regional differences in US utilisation of cardiac coronary tomography angiography (CCTA) and compares use in the USA and England.

A Critical Examination of Independent Medical Review Decision-making for Cardiovascular Procedures Shows Low Rate of Evidence Citation in Reviews.

Background: The California Independent Medical Review (IMR) program was created in 2001 to provide an independent, external evaluation of insurers' denials of coverage of health services.

Objective: We sought to evaluate the quality and comprehensiveness of data used to support IMR decision-making between 2015 and 2020.

Results: Of the 159 cases submitted to IMR regarding denials of cardiovascular procedures, 52% of these denials were overturned by IMR, thus restoring coverage.

Focused ultrasound-mediated brain genome editing.

Gene editing in the brain has been challenging because of the restricted transport imposed by the blood-brain barrier (BBB). Current approaches mainly rely on local injection to bypass the BBB. However, such administration is highly invasive and not amenable to treating certain delicate regions of the brain.

Focused ultrasound mitigates pathology and improves spatial memory in Alzheimer's mice and patients.

Bilateral sonication with focused ultrasound (FUS) in conjunction with microbubbles has been shown to separately reduce amyloid plaques and hyperphosphorylated tau protein in the hippocampal formation and the entorhinal cortex in different mouse models of Alzheimer's disease (AD) without any therapeutic agents. However, the two pathologies are expressed concurrently in human disease. Therefore, the objective of this study is to investigate the effects of repeated bilateral sonications in the presence of both pathologies.

Real-Time Passive Acoustic Mapping With Enhanced Spatial Resolution in Neuronavigation-Guided Focused Ultrasound for Blood-Brain Barrier Opening.

Objective: Passive acoustic mapping (PAM) provides the spatial information of acoustic energy emitted from microbubbles during focused ultrasound (FUS), which can be used for safety and efficacy monitoring of blood-brain barrier (BBB) opening. In our previous work with a neuronavigation-guided FUS system, only part of the cavitation signal could be monitored in real time due to the computational burden although full-burst analysis is required to detect transient and stochastic cavitation activity. In addition, the spatial resolution of PAM can be limited for a small-aperture receiving array transducer.

Using a novel rapid alternating steering angles pulse sequence to evaluate the impact of theranostic ultrasound-mediated ultra-short pulse length on blood-brain barrier opening volume and closure, cavitation mapping, drug delivery feasibility, and safety.

Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is a noninvasive, safe and reversible technique for targeted drug delivery to the brain. Most preclinical systems developed to perform and monitor BBB opening are comprised of a separate geometrically focused transducer and passive cavitation detector (PCD) or imaging array. This study builds upon previous work from our group developing a single imaging phased array configuration for simultaneous BBB opening and monitoring called theranostic ultrasound (ThUS), leveraging ultra-short pulse lengths (USPLs) and a novel rapid alternating steering angles (RASTA) pulse sequence design for simultaneous bilateral sonications with target-specific USPL.

Relationships of Hemoglobin Concentration, Ischemic Lesions, and Clinical Outcomes in Patients With Intracerebral Hemorrhage.

Background: Hemoglobin concentration and diffusion-weighted imaging (DWI) ischemic lesions are separately known to be associated with poor intracerebral hemorrhage (ICH) outcomes. While hemoglobin concentrations have known relationships with ischemic stroke, it is unclear whether hemoglobin concentration is associated with DWI ischemic lesions after ICH. We sought to investigate the hypothesis that hemoglobin concentrations would associate with DWI lesions after ICH and further investigated their relationships with clinical outcomes.

Focused ultrasound-mediated brain genome editing.

Gene editing in the mammalian brain has been challenging because of the restricted transport imposed by the blood-brain barrier (BBB). Current approaches rely on local injection to bypass the BBB. However, such administration is highly invasive and not amenable to treating certain delicate regions of the brain.

Non-invasive optogenetics with ultrasound-mediated gene delivery and red-light excitation.

Optogenetics has revolutionized the capability of controlling genetically modified neurons in vitro and in vivo and has become an indispensable neuroscience tool. Using light as a probe for selective neuronal activation or inhibition and as a means to read out neural activity has dramatically enhanced our understanding of complex neural circuits. However, a common limitation of optogenetic studies to date is their invasiveness and spatiotemporal range.

Transcranial Theranostic Ultrasound for Pre-Planning and Blood-Brain Barrier Opening: A Feasibility Study Using an Imaging Phased Array In Vitro and In Vivo.

Unlabelled: Focused ultrasound (FUS) for blood-brain barrier (BBB) opening is a safe, reversible and non-invasive strategy for targeted drug delivery to the brain, however extensive pre-planning strategies are necessary for successful FUS-mediated BBB opening through the structurally complex primate skull.

Objective: This study aims to demonstrate a pre-planning pipeline consisting of transcranial simulations and in vitro experimentation used to inform synchronous BBB opening and power cavitation imaging (PCI) with a single theranostic ultrasound (TUS) phased array.

Methods: Acoustic wave propagation simulation findings of pressure attenuation and focal shift through clinical-CT and micro-CT-based primate skull models were compared, while the latter were used to determine the impact of beam steering angle on focal shift and pressure attenuation.