Cavitation Feedback Control of Focused Ultrasound Blood-Brain Barrier Opening for Drug Delivery in Patients with Parkinson's Disease.

Authors: Huang Y, Meng Y, Pople CB, Bethune A, Jones RM, Abrahao A, Hamani C, Kalia SK, Kalia LV, Lipsman N, Hynynen K

Magnetic resonance-guided focused ultrasound (MRgFUS), in conjunction with circulating microbubbles, is an emerging technology that can transiently enhance the permeability of the blood-brain barrier (BBB) locally and non-invasively to facilitate targeted drug delivery to the brain. In this clinical trial, the feasibility and safety of BBB modulation in the putamen were evaluated for biweekly therapeutic agent delivery in patients with Parkinson's disease. The performance of the clinical MRgFUS system's cavitation feedback controller for active power modulation throughout the exposures was examined. The putamen was targeted unilaterally by an ExAblate Neuro MRgFUS system operating at 220 kHz. Definity microbubbles were infused via a saline bag gravity drip at a rate of 4 µL/kg per 5 min. A cavitation emissions-based feedback controller was employed to modulate the acoustic power automatically according to prescribed target cavitation dose levels. BBB opening was measured by Gadolinium (Gd)-enhanced T1-weighted MR imaging, and the presence of potential micro-hemorrhages induced by the exposures was assessed via T2*-weighted MR imaging. A total of 12 treatment sessions were carried out across four patients, with target cavitation dose levels ranging from 0.20-0.40. BBB permeability in the targeted putamen was elevated successfully in all treatments, with a 14% ± 6% mean increase in Gd-enhanced T1-weighted MRI signal intensity relative to the untreated contralateral side. No indications of red blood cell extravasations were observed on MR imaging scans acquired one day following each treatment session. The cavitation emissions-based feedback controller was effective in modulating acoustic power levels to ensure BBB permeability enhancement while avoiding micro-hemorrhages, however, further technical advancements are warranted to improve its performance for use across a wide variety of brain diseases.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To evaluate the feasibility and safety of MRgFUS-mediated transient blood–brain barrier opening in the putamen for biweekly therapeutic delivery in Parkinson’s patients and to assess the performance of a cavitation emissions-based feedback controller.

Animal model / Human subject Homo sapiens (human patients), strain: N/A, age: None, sex: None

Disease model Parkinson's disease

MRI or image guidance method Magnetic resonance-guided focused ultrasound (MRgFUS) using an ExAblate Neuro system with MRI guidance (Gd-enhanced T1-weighted and T2*-weighted imaging) and a cavitation emissions-based feedback controller for acoustic power modulation

Targeted brain region(s) Putamen

Target coordinates None in the paper text; only 'putamen' (unilateral) is reported.

Cargo name and characteristics Gadolinium-based MRI contrast agent (small-molecule paramagnetic contrast agent used for T1-weighted imaging to assess blood–brain barrier opening; systemically administered)

Route of administration Intravenous (Definity microbubbles infused via a saline bag gravity drip at 4 µL/kg per 5 min; gadolinium contrast for imaging was also administered intravenously)

Outcomes and Safety

Summary of Outcomes MRgFUS with circulating microbubbles transiently and safely increased BBB permeability in the targeted putamen (mean 14% ± 6% Gd-enhanced signal increase) across treatments without MRI-detected micro-hemorrhages, using a cavitation-feedback controller to modulate acoustic power.

Duration of biological effect 1 day

Safety-related matter Post-treatment MRI showed no micro-hemorrhages or red blood cell extravasation, indicating the procedure was safe and the cavitation feedback controller effectively avoided hemorrhagic adverse effects.

Brain Region

Ultrasound Parameters

Ultrasound instrument ExAblate Neuro MRgFUS system (220 kHz)

FUS Frequency 220 kHz

FUS Mode pulsed

Duration of a single FUS session None.

Treatment frequency multiple sessions

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