Chanikarn Power

Nonthermal ablation with microbubble-enhanced focused ultrasound close to the optic tract without affecting nerve function

OBJECT Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging-guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull. METHODS In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm. RESULTS Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina. CONCLUSIONS This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in deep brain structures while preserving function in adjacent nerves. Because of low vascularity--and thus a low microbubble concentration--some large white matter tracts appear to have some natural resistance to this type of ablation compared with gray matter. While future work is needed to develop methods of monitoring the procedure and establishing its safety at deep brain targets, the technique does appear to be a potential solution that allows FUS ablation of deep brain targets while sparing adjacent nerve structures.

Targeted, noninvasive blockade of cortical neuronal activity

Here we describe a novel method to noninvasively modulate targeted brain areas through the temporary disruption of the blood-brain barrier (BBB) via focused ultrasound, enabling focal delivery of a neuroactive substance. Ultrasound was used to locally disrupt the BBB in rat somatosensory cortex, and intravenous administration of GABA then produced a dose-dependent suppression of somatosensory-evoked potentials in response to electrical stimulation of the sciatic nerve. No suppression was observed 1–5 days afterwards or in control animals where the BBB was not disrupted. This method has several advantages over existing techniques: it is noninvasive; it is repeatable via additional GABA injections; multiple brain regions can be affected simultaneously; suppression magnitude can be titrated by GABA dose; and the method can be used with freely behaving subjects. We anticipate that the application of neuroactive substances in this way will be a useful tool for noninvasively mapping brain function, and potentially for surgical planning or novel therapies.

Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

Significance Focused ultrasound is currently the only method of reversible blood–brain barrier disruption for targeted drug delivery without incision or radiation. A significant challenge for its clinical translation is a lack of reliable real-time treatment control. Here a closed-loop, real-time control paradigm is shown capable of sustaining stable microbubble oscillations at a preset level while minimizing microbubble behavior that may result in vascular damage. Tested at clinically relevant frequency in healthy and tumor-bearing rats, our approach enables targeted delivery of predefined drug concentrations within a therapeutically effective range in both normal tissue and glioma, while maintaining a safe exposure level. It can be readily implemented clinically for delivering chemotherapeutics or other agents and potentially applied to other cavitation-enhanced ultrasound therapies. Cavitation-facilitated microbubble-mediated focused ultrasound therapy is a promising method of drug delivery across the blood–brain barrier (BBB) for treating many neurological disorders. Unlike ultrasound thermal therapies, during which magnetic resonance thermometry can serve as a reliable treatment control modality, real-time control of modulated BBB disruption with undetectable vascular damage remains a challenge. Here a closed-loop cavitation controlling paradigm that sustains stable cavitation while suppressing inertial cavitation behavior was designed and validated using a dual-transducer system operating at the clinically relevant ultrasound frequency of 274.3 kHz. Tests in the normal brain and in the F98 glioma model in vivo demonstrated that this controller enables reliable and damage-free delivery of a predetermined amount of the chemotherapeutic drug (liposomal doxorubicin) into the brain. The maximum concentration level of delivered doxorubicin exceeded levels previously shown (using uncontrolled sonication) to induce tumor regression and improve survival in rat glioma. These results confirmed the ability of the controller to modulate the drug delivery dosage within a therapeutically effective range, while improving safety control. It can be readily implemented clinically and potentially applied to other cavitation-enhanced ultrasound therapies.

Transcranial cavitation-mediated ultrasound therapy at sub-MHz frequency via temporal interference modulation

Sub-megahertz transmission is not usually adopted in pre-clinical small animal experiments for focused ultrasound (FUS) brain therapy due to the large focal size. However, low frequency FUS is vital for preclinical evaluations due to the frequency-dependence of cavitation behavior. To maximize clinical relevance, a dual-aperture FUS system was designed for low-frequency (274.3 kHz) cavitation-mediated FUS therapy. Combining two spherically curved transducers provides significantly improved focusing in the axial direction while yielding an interference pattern with strong side lobes, leading to inhomogeneously distributed cavitation activities. By operating the two transducers at slightly offset frequencies to modulate this interference pattern over the period of sonication, the acoustic energy was redistributed and resulted in a spatially homogenous treatment profile. Simulation and pressure field measurements in water were performed to assess the beam profiles. In addition, the system performance was dem...

Targeted delivery of GABA via ultrasound-induced blood-brain barrier disruption blocks somatosensory-evoked potentials

This study investigated whether targeted delivery of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA), a small molecule (103 Da) that normally does not reach the brain with systemic administration, can temporarily block brain activity after ultrasound-induced blood-brain barrier (BBB) disruption.

Ultrasound-mediated delivery of gadolinium and fluorescent-labeled liposomes through the blood-brain barrier

The main objective of this study was to examine liposome extravasation across the BBB as a function of size after disruption via ultrasound and microbubbles. The liposomes were labeled with gadolinium (Gd) and fluorophore, thus enabling detection of extravasated liposomes via MRI in vivo and fluorescence methods in tissue, respectively. Liposomes labeled with gadolinium and fluorophore were prepared using lipid film hydration and extrusion to two different sizes (~80 nm and ~140 nm). Animals were divided into two groups based on the use of particle sizes. FUS–BBB disruption was produced in one hemisphere in 10 mice. Particles were injected before sonication. Sonications (0.69 MHz at 0.68 MPa) were performed in two locations combine with Definity (10 μl/kg). Acoustic emissions were recorded during FUS. T1 & T2*-weighted MRI were used to confirm Gd leakage and damage detection respectively. Mice were euthanized 5–24 h after FUS and post-process for fluorescence measurement. In sonicated area, Gd-leakage was...

Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system

The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. The method presents new opportunities for the use of drugs and for the study of the brain.