Magnetic resonance imaging analysis predicts nanoparticle concentration delivered to the brain parenchyma.

Ultrasound in combination with the introduction of microbubbles into the vasculature effectively opens the blood brain barrier (BBB) to allow the passage of therapeutic agents. Increased permeability of the BBB is typically demonstrated with small-molecule agents (e.g., 1-nm gadolinium salts). Permeability to small-molecule agents, however, cannot reliably predict the transfer of remarkably larger molecules (e.g., monoclonal antibodies) required by numerous therapies. To overcome this issue, we developed a magnetic resonance imaging analysis based on the ΔR2* physical parameter that can be measured intraoperatively for efficient real-time treatment management. We demonstrate successful correlations between ΔR2* values and parenchymal concentrations of 3 differently sized (18 nm-44 nm) populations of liposomes in a rat model. Reaching an appropriate ΔR2* value during treatment can reflect the effective delivery of large therapeutic agents. This prediction power enables the achievement of desirable parenchymal drug concentrations, which is paramount to obtaining effective therapeutic outcomes.

Non-thermal focused ultrasound induced reversible reduction of essential tremor in a rat model.

BACKGROUND: Essential tremor (ET) is one of the most common movement disorders of adults, characterized by postural and kinetic tremor. With drug treatment only partially efficient, new treatments are being developed. OBJECTIVES: The goal of this study was to demonstrate the feasibility of non-thermal focused-ultrasound (FUS) to induce tremor-suppression in an ET rat model. METHODS: Harmaline-induced tremor rats were treated with FUS along the inferior olivary (IO) system. EMG was recorded continuously during treatment in order to quantify FUS-induced tremor suppression. T2-weighted MRI was performed immediately following treatment and periodically thereafter. RESULTS: FUS treatment at an intensity of 27.2 W/cm2 (Isppa) induced significant reduction of tremor in 12 out of 13 ET rats. Tremor frequency was reduced from 6.2 ±â€¯2.8 to 2 ±â€¯1 Hz, p < 0.0003. In 6 of the 12 responding rats, tremor was completely suppressed. Response duration was 70 ±â€¯61s, on average. FUS induced motor response, depicted as movement of the tail and/or the limbs synchronized with the FUS sonication, was also demonstrated both in ET rats and in naïve rats when treated in the medulla oblongata region. CONCLUSIONS: These results demonstrate the feasibly for obtaining significant tremor reduction or tremor suppression induced by non-thermal, non-invasive, reversible focused-ultrasound.

Focused Ultrasound-Induced Suppression of Auditory Evoked Potentials in Vivo.

The goal of this study was to determine the feasibility of focused ultrasound-based neuromodulation affecting auditory evoked potentials (AEPs) in animals. Focused ultrasound-induced suppression of AEPs was performed in 22 rats and 5 pigs: Repetitive sounds were produced, and the induced AEPs were recorded before and repeatedly after FUS treatment of the auditory pathway. All treated animals exhibited a decrease in AEP amplitude post-treatment in contrast to animals undergoing the sham treatment. Suppression was weaker for rats treated at 2.3 W/cm2 (amplitudes decreased to 59.8 ± 3.3% of baseline) than rats treated at 4.6 W/cm2 (36.9 ± 7.5%, p <0.001). Amplitudes of the treated pigs decreased to 27.7 ± 5.9% of baseline. This effect lasted between 30 min and 1 mo in most treated animals. No evidence of heating during treatment or later brain damage/edema was observed. These results demonstrate the feasibility of inducing significant neuromodulation with non-thermal, non-invasive, reversible focused ultrasound. The long recovery times may have clinical implications.

Potential of magnetic resonance-guided focused ultrasound for intracranial hemorrhage: an in vivo feasibility study.

BACKGROUND: Because of the paucity of effective treatments for intracranial hemorrhage (ICH), the mortality rate remains at 40%-60%. A novel application of magnetic resonance-guided focused ultrasound (MRgFUS) for ICH may offer an alternative noninvasive treatment through the precise delivery of FUS under real-time MR imaging (MRI) guidance. The purpose of the present study was to optimize the parameters for rapid, effective, and safe trans-skull large clot liquefaction using in vivo porcine and ex vivo human skull models to provide a clinically relevant proof of concept. METHODS: The transcranial effectiveness of MRgFUS was tested ex vivo by introducing a porcine blood clot into a human skull, without introducing tissue plasminogen activator (tPA). We used an experimental human head device to deliver pulsed FUS sonications at an acoustic power of 600-900 W for 5-10 seconds. A 3-mL clot was also introduced in a porcine brain and sonicated in vivo with one 5-second pulse of 700 W through a bone window or with 3000 W when treated through an ex vivo human skull. Treatment targeting was guided by MRI, and the tissue temperature was monitored online. Liquefied volumes were measured as hyperintense regions on T2-weighted MR images. RESULTS: In both in vivo porcine blood clot through a craniectomy model and the porcine clot in an ex vivo human skull model targeted clot liquefaction was achieved, with only marginal increase in temperature in the surrounding tissue. CONCLUSIONS: Our results demonstrate the feasibility of fast, efficient, and safe thrombolysis in an in vivo porcine model of ICH and in 2 ex vivo models using a human skull, without introducing tPA. Future studies will further optimize parameters and assess the nature of sonication-mediated versus natural clot lysis, the risk of rebleeding, the potential effect on the adjacent parenchyma, and the chemical and toxicity profiles of resulting lysate particles.

Transcranial magnetic resonance-guided focused ultrasound surgery for trigeminal neuralgia: a cadaveric and laboratory feasibility study.

OBJECT: Transcranial MR-guided focused ultrasound surgery (MRgFUS) is evolving as a treatment modality in neurosurgery. Until now, the trigeminal nerve was believed to be beyond the treatment envelope of existing high-frequency transcranial MRgFUS systems. In this study, the authors explore the feasibility of targeting the trigeminal nerve in a cadaveric model with temperature assessments using computer simulations and an in vitro skull phantom model fitted with thermocouples. METHODS: Six trigeminal nerves from 4 unpreserved cadavers were targeted in the first experiment. Preprocedural CT scanning of the head was performed to allow for a skull correction algorithm. Three-Tesla, volumetric, FIESTA MRI sequences were performed to delineate the trigeminal nerve and any vascular structures of the cisternal segment. The cadaver was positioned in a focused ultrasound transducer (650-kHz system, ExAblate Neuro, InSightec) so that the focus of the transducer was centered at the proximal trigeminal nerve, allowing for targeting of the root entry zone (REZ) and the cisternal segment. Real-time, 2D thermometry was performed during the 10- to 30-second sonication procedures. Post hoc MR thermometry was performed on a computer workstation at the conclusion of the procedure to analyze temperature effects at neuroanatomical areas of interest. Finally, the region of the trigeminal nerve was targeted in a gel phantom encased within a human cranium, and temperature changes in regions of interest in the skull base were measured using thermocouples. RESULTS: The trigeminal nerves were clearly identified in all cadavers for accurate targeting. Sequential sonications of 25-1500 W for 10-30 seconds were successfully performed along the length of the trigeminal nerve starting at the REZ. Real-time MR thermometry confirmed the temperature increase as a narrow focus of heating by a mean of 10°C. Postprocedural thermometry calculations and thermocouple experiments in a phantom skull were performed and confirmed minimal heating of adjacent structures including the skull base, cranial nerves, and cerebral vessels. For targeting, inclusion of no-pass regions through the petrous bone decreased collateral heating in the internal acoustic canal from 16.7°C without blocking to 5.7°C with blocking. Temperature at the REZ target decreased by 3.7°C with blocking. Similarly, for midcisternal targeting, collateral heating at the internal acoustic canal was improved from a 16.3°C increase to a 4.9°C increase. Blocking decreased the target temperature increase by 4.4°C for the same power settings. CONCLUSIONS: This study demonstrates focal heating of up to 18°C in a cadaveric trigeminal nerve at the REZ and along the cisternal segment with transcranial MRgFUS. Significant heating of the skull base and surrounding neural structures did not occur with implementation of no-pass regions. However, in vivo studies are necessary to confirm the safety and efficacy of this potentially new, noninvasive treatment.

Impact of propagating and standing waves on cavitation appearance.

Standing waves play a significant role in the appearance of cavitation phenomena. The goal of this study was to investigate the effect that the relation between standing and propagating waves in a focused field has on acoustic bubble cloud formation. Measurements of the cavitation signals were performed on five different configurations of a hemispheric phased array transducer (230 kHz) representing a wide range of relations between propagating and standing waves. The results show that configurations with a larger propagating component induce bubble clouds at lower pressures than configurations with a larger standing component.