Huang Yuexi, Meng Ying, Pople Christopher B, Bethune Allison, Jones Ryan M, Abrahao Agessandro, Hamani Clement, Kalia Suneil K, Kalia Lorraine V, Lipsman Nir, Hynynen Kullervo
Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
Division of Neurosurgery, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada.
Pharmaceutics. 2022 Nov 26;14(12):2607. doi: 10.3390/pharmaceutics14122607.
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.
磁共振引导聚焦超声（MRgFUS）结合循环微泡，是一种新兴技术，可局部且非侵入性地瞬时增强血脑屏障（BBB）的通透性，以促进向脑内的靶向给药。在这项临床试验中，评估了在帕金森病患者中每两周进行一次治疗剂递送时，壳核中血脑屏障调节的可行性和安全性。检查了临床MRgFUS系统的空化反馈控制器在整个照射过程中进行有功功率调制的性能。使用ExAblate Neuro MRgFUS系统以220 kHz的频率单侧靶向壳核。通过盐水袋重力滴注以每5分钟4 μL/kg的速率注入Definity微泡。采用基于空化发射的反馈控制器，根据规定的目标空化剂量水平自动调节声功率。通过钆（Gd）增强的T1加权磁共振成像测量血脑屏障开放情况，并通过T2*加权磁共振成像评估照射引起的潜在微出血情况。对4名患者共进行了12次治疗，目标空化剂量水平为0.20 - 0.40。在所有治疗中，靶向壳核的血脑屏障通透性均成功提高，相对于未治疗的对侧，Gd增强T1加权MRI信号强度平均增加了14%±6%。在每次治疗后一天获取的磁共振成像扫描中未观察到红细胞外渗的迹象。基于空化发射的反馈控制器在调节声功率水平以确保血脑屏障通透性增强同时避免微出血方面是有效的，然而，需要进一步的技术进步来提高其在各种脑部疾病中的应用性能。
