Ultrasound-Enhanced Drug Transport and Distribution in the Brain

Drug delivery in the brain is limited by slow drug diffusion in the brain tissue. This study tested the hypothesis that ultrasound can safely enhance the permeation of drugs in the brain. In vitro exposure to ultrasound at various frequencies (85 kHz, 174 kHz, and 1 MHz) enhanced the permeation of tritium-labeled molecules with molecular weight up to 70 kDa across porcine brain tissue. A maximum enhancement of 24-fold was observed at 85 kHz and 1,200 J/cm2. In vivo exposure to 1-MHz ultrasound further demonstrated the ability of ultrasound to facilitate molecule distribution in the brain of a non-human primate. Finally, ultrasound under conditions similar to those used in vivo was shown to cause no damage to plasmid DNA, siRNA, adeno-associated virus, and fetal rat cortical neurons over a range of conditions. Altogether, these studies demonstrate that ultrasound can increase drug permeation in the brain in vitro and in vivo under conditions that did not cause detectable damage

Directed evolution of a magnetic resonance imaging contrast agent for noninvasive imaging of dopamine

The development of molecular probes that allow in vivo imaging of neural signaling processes with high temporal and spatial resolution remains challenging. Here we applied directed evolution techniques to create magnetic resonance imaging (MRI) contrast agents sensitive to the neurotransmitter dopamine. The sensors were derived from the heme domain of the bacterial cytochrome P450-BM3 (BM3h). Ligand binding to a site near BM3h's paramagnetic heme iron led to a drop in MRI signal enhancement and a shift in optical absorbance. Using an absorbance-based screen, we evolved the specificity of BM3h away from its natural ligand and toward dopamine, producing sensors with dissociation constants for dopamine of 3.3–8.9 μM. These molecules were used to image depolarization-triggered neurotransmitter release from PC12 cells and in the brains of live animals. Our results demonstrate the feasibility of molecular-level functional MRI using neural activity–dependent sensors, and our protein engineering approach can be generalized to create probes for other targets.Charles A. Dana Foundation. Brain and Immuno-ImagingRaymond and Beverley Sackler FoundationNational Institutes of Health (U.S.) (grant R01-DA28299)National Institutes of Health (U.S.) (grant DP2-OD2441)National Institutes of Health (U.S.) (grant R01-GM068664)Jacobs Institute for Molecular Engineering for Medicine. Jacobs Institute for Molecular Engineering for MedicineNational Institutes of Health (U.S.) (grant R01-DE013023

Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound

The purpose of this study was to investigate the effects on the brain of multiple sessions of blood-brain barrier (BBB) disruption using focused ultrasound (FUS) in combination with micro-bubbles over a range of acoustic exposure levels. Six weekly sessions of FUS, using acoustical pressures between 0.66 and 0.80 MPa, were performed under magnetic resonance guidance. The success and degree of BBB disruption was estimated by signal enhancement of post-contrast T1-weighted imaging of the treated area. Histopathological analysis was performed after the last treatment. The consequences of repeated BBB disruption varied from no indications of vascular damage to signs of micro-hemorrhages, macrophage infiltration, micro-scar formations and cystic cavities. The signal enhancement on the contrast-enhanced T1-weighted imaging had limited value for predicting small-vessel damage. T2-weighted imaging corresponded well with the effects on histopathology and could be used to study treatment effects over time. This study demonstrates that repeated BBB disruption by FUS can be performed with no or limited damage to the brain tissue

Pulse duration and peak intensity during focused ultrasound surgery: Theoretical and experimental effects in rabbit brain in vivo

The goal of this study was to establish the exposure parameters that will generate predictable thermally induced lesions in brain. In addition, the accuracy of a theoretical model for prediction of the lesion size was tested. To do this, 160 adult rabbits were sonicated (frequency 0.936 and 1.72 MHz) and then sacrificed at various intervals after the sonications. The results showed that predictable thermal lesions could be induced if the exposure durations were between 0.5 and 2 s. Dimensions of the necrosed tissue volume were roughly predictable by the theoretical calculations based on purely thermal effects. Shorter sonications required higher intensities (above 3700 W cm-2 at 1.72 MHz) resulting in mechanical effects with extensive vascular damage. Lesion size varied more at longer exposures (5 and 10 s), perhaps due to the increased effect of tissue perfusion. As a conclusion, focused ultrasound can be used for destruction of tissues deep in brain without causing undesirable mechanical effects, if the exposure parameters are selected properly. © 1994

Histologic effects of high intensity pulsed ultrasound exposure with subharmonic emission in rabbit brain in vivo

In this study, the threshold for subharmonic emission during in vivo sonication of rabbit brain was investigated. In addition, the histologic effects of pulsed sonication above this threshold were studied. Two spherically curved focused ultrasound transducers with a diameter of 80 mm and a radius of curvature of 70 mm were used in the sonications. The operating frequencies of the transducers were 0.936 and 1.72 MHz. The sonication duration was varied between 0.001 and 1 s and the repetition frequency between 0.1 and 5 Hz. The threshold for subharmonic emission at the frequency of 0.936 MHz was found to be approximately 2000 W cm-2 and 3600 W cm-2 for pulse durations of 1 s and 0.001 s, respectively. The threshold was approximately 1.5-fold as high at a frequency of 1.72 MHz. However, there was considerable variation from experiment to experiment. The multiple pulse experiments at a frequency of 1.72 MHz and an intensity of 7000 W cm-2 showed that the histologic effects ranged from no observable damage of the tissue, to blood-brain barrier breakage, to local haemorrhagia, to local destruction of the tissue, to gross hemorrhage resulting in the death of the animal. The severity of the tissue damage increased as the pulse duration, number of pulses and their repetition frequency increased. The results indicate that the end point of the tissue damage may be controlled by selecting the sonication parameters. Such control over tissue effects can have several different applications when brain disorders are treated. © 1995

Designing digital transformation of department educational environment

Digital transformation of modern educational environment is stipulated by recently occurred changes and intellectualization of information systems of various ecosystems. The aim of this study is development of methodology of design and implementation of digital technologies oriented at integral automation of department educational environment. Using the methods of system analysis, project management and simulation, the content and structure of digital component of this environment were analyzed, aiming at efficient formation of high-quality professional competences of graduates. The experimental results allow to substantiate composition of the required functional units. On the basis of the obtained data, the project concept of department educational environment is proposed, the activity of which is supported by integrated automation system of all information processes. Scientific novelty of the performed study is determined by that the existing automation system of educational environment in fact does not impact department level of information processes. On the basis of analysis of information processes of department level and existing technologies of their automation, a new methodological approach is proposed to conceptualization, development and implementation of fully functional digitalization system of department educational environment. The significance of the proposed approach is comprised of opportunity to integrate digital and content components of educational environment for improvement of education quality