Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task.
Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task.
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DOI：
10.1371/journal.pone.0125911
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ferrera VP
中科院分区：
文献类型：
--
作者：
Downs ME;Buch A;Sierra C;Karakatsani ME;Teichert T;Chen S;Konofagou EE;Ferrera VP
聚焦超声（FUS）与静脉注射微泡（MB）相结合是一种非侵入性技术，已被证明可以在包括非人类灵长类动物（NHP）在内的多种体内模型中可靠地打开血脑屏障（BBB）（增加其渗透性）。该程序已显示出临床和基础科学应用的前景，但在 NHP 中长期应用的安全性和潜在神经学影响需要在对该物种有效的参数（500kHz、200–400 kPa、4–5μm MB、2 分钟超声处理）下进行进一步研究。在这项研究中，我们在 4-20 个月内使用 FUS 和全身注射 MB 反复打开 4 个 NHP 基底神经节尾状核和壳核区域的 BBB。我们使用 MRI 检测脑部水肿或出血来评估 FUS 与 MB 手术的安全性。对比增强 T1 加权 MRI 序列显示目标区域开口的成功率为 98%。 T2 加权和 SWI 序列表明大多数病例没有水肿。我们使用触摸屏显示器上呈现的带有奖励幅度偏差的随机点运动任务，通过视觉、认知、动机和运动功能的定量认知测试，研究了 FUS 与 MB 程序的潜在神经学影响。在 FUS 和 MB 手术当天，任务期间的反应时间显着增加。这种增加在手术后 4-5 天内恢复到基线。视觉运动辨别阈值不受影响。我们的结果表明，FUS 与 MB 可以是一种安全的方法，可以在 NHP 中重复打开基底神经节的 BBB，长达 20 个月，并且使用的参数不会产生任何长期的负面生理或神经学影响。
Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500kHz, 200–400 kPa, 4–5μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4–20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of’ visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4–5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used.
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影响因子：
3.5
作者：
Baseri B;Choi JJ;Deffieux T;Samiotaki G;Tung YS;Olumolade O;Small SA;Morrison B;Konofagou EE
通讯作者：
Konofagou EE
影响因子：
19.7
作者：
Hynynen, K;McDannold, N;Jolesz, FA
通讯作者：
Jolesz, FA
影响因子：
3.1
作者：
Groenewegen HJ
通讯作者：
Groenewegen HJ
影响因子：
64.8
作者：
Lauwereyns, J;Watanabe, K;Hikosaka, O
通讯作者：
Hikosaka, O
DOI：
10.1038/mtna.2012.64
发表时间：
2013-02-19
期刊：
Molecular therapy. Nucleic acids
影响因子：
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作者：
通讯作者：
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