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所有人类实验都是由新宁健康科学中心的机构研究伦理委员会批准的。
1. 病人识别
<ol>
	<li>与患者或替代决策者进行知情同意。向患者解释与手术相关的潜在不良事件, 如出血和神经功能缺损。</li>
	<li>评估候选患者的 MRgFUS 丘脑。在运动障碍方面有专长的医生应该进行评估。 注意: 重要的是排除鉴别诊断, 如性震颤, 帕金森氏症, 和心理震颤。此外, 神经学家应评估是否已尝试了适当的医疗治疗试验, 病人认为治疗难治性。</li>
	<li>检查是否有禁忌症, 如不能耐受 MRI。</li>
	<li>评估病人的健康状况以及麻醉。 注意: 主动心脏病、肾功能受损、出血倾向是 MRgFUS 的禁忌症。</li>
	<li>作为筛选过程的一部分, 获得血样, 如完整的血细胞计数、电解质、肌酐和凝血板。</li>
	<li>执行完整的神经学检查 (表 1), 并使用震颤 (CRST) 的临床评分表来记录震颤和残疾。还需要管理标准的生活质量等级, 以在基线上捕获这些信息并随着时间的推移跟踪它。</li>
</ol>
2. 成像设置
<ol>
	<li>在治疗前获得 CT 扫描, 以评估颅内钙化和颅骨厚度。 注: CT 扫描应至少有 512 512 分辨率, 1 毫米厚度与零间距, 覆盖整个头骨从顶部到底。</li>
	<li>在治疗前获得 MR 扫描, 排除以前颅内出血或脑瘤等禁忌症。</li>
	<li>使用一个商业上可用的头盔传感器与1024独立的元素, 每一个中央频率650赫和集成3特斯拉先生扫描仪8。MRI 测温可提供目标温度的实时反馈。</li>
</ol>
3. 病人准备
<ol>
	<li>建议病人在接受治疗的当天不要服用必要的震颤药物, 在手术前的半夜不要用嘴做任何事。</li>
	<li>检查病人进入医院, 通常是通过同一天的手术。</li>
	<li>确保整个团队的存在: 神经外科医生, 运动障碍神经学家, 物理学家, 影像技术员, 和麻醉。 注: 麻醉应可用于支持病人在整个过程中的不适, 焦虑, 眩晕/呕吐, 同时保持病人意识在任何时候。</li>
	<li>将吸入设备放在附近进行紧急呼吸道维护和周围静脉输液, 以防药物需要紧急管理。</li>
	<li>连接心率、心电图、血压和氧饱和度的无创监测器。</li>
	<li>如有必要, 插入导尿管, 使病人排空膀胱。</li>
	<li>把毕业的压袜放在病人身上, 以帮助防止下肢深静脉血栓形成。</li>
	<li>仔细地剃毛, 检查头皮病变。</li>
	<li>在神经外科医生的帮助下放置立体定向框架, 并在4针部位应用局部麻醉药 (例如, 如、利多卡因或因)。</li>
	<li>把橡胶隔膜放在病人的头上。 注: 由于传感器和头皮之间的空间充满了脱水, 橡胶隔膜包围病人头部以防止水泄漏。凉爽的水循环, 从头皮上带走任何多余的热量。</li>
	<li>在进入手术室前, 确保病人没有任何铁质成分。</li>
	<li>让病人平躺着, 一头扎进超声波头盔。</li>
	<li>用暖毯盖住病人以防体温过低。 注意: 治疗室的温度约为15° c。</li>
</ol>
4. 丘脑的 Vim 核的靶选择
<ol>
	<li>执行一个初步的3D 定位 MR 扫描和 T2-weighted 序列与至少轴和矢状面在紧接超声之前, 登记病人的前处理 CT/MRI 扫描。</li>
	<li>将新的扫描与前处理的 MRI 和 CT 融合。</li>
	<li>在头皮上的任何病变, 脑、鼻窦和空气中的钙化都是 no-pass 的区域, 这样传感器就可以避免这些特定的区域。</li>
	<li>通过前合 (AC) 和后合 (PC) 选择轴向 T2 加权图像切割的目标。 注意: 有不同的方法来确定和靶向丘脑的 Vim 核。鉴于即使在3T 图像上, Vim 也不可见, 它的位置是相对于已知的解剖地标 (即间接目标) 推断出来的。<ol>
		<li>在 AC 个人计算机线的水平, 开始在 intercommissural 距离的 25%, 在个人计算机之前。这通常是大约6毫米。 注: 人的平均 AC 个人计算机距离是 24-28 毫米, 并且可以范围从 20-30 毫米. 将距离划分为四分之一, 一开始定义¼前后距离的距离, 在 PC 前。</li>
		<li>横向, 选择一个点中点之间的点14毫米侧向中线和点11.5 毫米侧向侧边缘的脑室在水平的 AC PC 飞机。</li>
		<li>根据具体病人的第三脑室的实际长度和宽度和区域解剖进行小的调整。 注: 第三脑室宽度可相差很大, 尤其是在老年患者。重要的是要注意内部胶囊纤维时, 确定侧的建议目标。一个个性化的方法, 考虑到病人的具体解剖, 是至关重要的。</li>
	</ol>
	</li>
</ol>
5。超声波输送
<ol>
	<li>提供一个停止按钮的病人, 使他们可以放弃能量交付在任何时候。</li>
	<li>通过将目标区域的温度提高到大约45° c, 进行低能量的测试超声。</li>
	<li>验证加热量对目标的对准, 并在所有三维度中正确</li>
	<li>进一步增加温度到大约50° c。</li>
	<li>在每次超声后, 对运动动力和感觉进行检查, 并对病人的震颤进行测试。 注意: 在这一点上, 病人可能会经历短暂的头晕, 刺痛和/或麻木。</li>
	<li>根据患者的反应, 调整目标 (即, 如果患者报告 parasthesias), 在增加能量使永久性病变大约 55-60 oC 之前。</li>
	<li>重复超声, 直到震颤降至令人满意的水平。 注:12-29 sonications 的持续时间为 10-二十五年代通常以0、1或2° c 的增量在醒的患者被管理。</li>
</ol>
6. 后处理
<ol>
	<li>治疗后立即进行 T2-weighted MRI 评估病灶大小及相关的影像学表现如水肿。</li>
	<li>一旦满意, 将病人从扫描仪中取出, 并取下框架。</li>
	<li>检查针脚部位是否有出血。几分钟的压力通常会阻止这一点。</li>
	<li>执行另一个神经系统检查 (表 1)。 注: 这项检查是重要的, 以排除任何神经缺损, 如感觉, 虚弱, 语音或视力缺陷。</li>
	<li>让病人在一后单位过夜观察。</li>
	<li>在一天后进行一项 MRI 检查以确认病灶的存在并排除任何不良事件。</li>
	<li>请求评估由神经外科医生, 如果不良事件 (例如, 质量影响成像, 颅内出血, 或降低意识水平) 被发现。</li>
	<li>如果病人做得好, 早上就出院。</li>
</ol>
7. 后续行动
<ol>
	<li>安排病人在治疗后约1周进行第一次随访。</li>
	<li>检查病人的震颤症状, 副作用, 药物改变和神经系统检查。</li>
	<li>执行 CRST 和质量的生活措施, 记录和跟踪震颤和残疾。</li>
	<li>记录任何不良事件, 包括针场感染、运动缺陷、感觉障碍和言语问题。</li>
	<li>如有必要, 请医生对不良事件进行评估。如果病人有一种新的神经缺损来排除颅内出血的原因, 请进行 CT 扫描。</li>
</ol>

<ol>
	<li>Louis, E. D., Ottman, R., Hauser, W. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=How+common+is+the+most+common+adult+movement+disorder?+Estimates+of+the+prevalence+of+essential+tremor+throughout+the+world.">How common is the most common adult movement disorder? Estimates of the prevalence of essential tremor throughout the world.</a> Mov Disord. 13, 5-10 (1998).</li><li>Louis, E. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Treatment+of+essential+tremor:+are+there+issues+we+are+overlooking?.">Treatment of essential tremor: are there issues we are overlooking?.</a> Front Neurol. 2, 91 (2011).</li><li>Zesiewicz, T. A., Encarnacion, E., Hauser, R. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Management+of+essential+tremor.">Management of essential tremor.</a> Curr Neurol Neurosci Rep. 2 (4), 324-330 (2002).</li><li>Yu, H., Neimat, J. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+treatment+of+movement+disorders+by+deep+brain+stimulation.">The treatment of movement disorders by deep brain stimulation.</a> Neurotherapeutics. 5 (1), 26-36 (2008).</li><li>Niranjan, A., Raju, S. S., Kooshkabadi, A., Monaco, E., Flickinger, J. C., Lunsford, L. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stereotactic+radiosurgery+for+essential+tremor:+Retrospective+analysis+of+a+19-year+experience.">Stereotactic radiosurgery for essential tremor: Retrospective analysis of a 19-year experience.</a> Movement Disorders: Mov Disord. , (2017).</li><li>Lipsman, N., Schwartz, M. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MR-guided+focused+ultrasound+thalamotomy+for+essential+tremor:+a+proof-of-concept+study.">MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study.</a> The Lancet. Neurology. 12 (5), 462-468 (2013).</li><li>Elias, W. J., Lipsman, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Randomized+Trial+of+Focused+Ultrasound+Thalamotomy+for+Essential+Tremor.">A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor.</a> N Engl J Med. 375 (8), 730-739 (2016).</li><li>Hynynen, K., Jolesz, F. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Demonstration+of+potential+noninvasive+ultrasound+brain+therapy+through+an+intact+skull.">Demonstration of potential noninvasive ultrasound brain therapy through an intact skull.</a> Ultrasound Med Biol. 24 (2), 275-283 (1998).</li><li>Hamani, C., Lozano, A. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hardware-related+complications+of+deep+brain+stimulation:+a+review+of+the+published+literature.">Hardware-related complications of deep brain stimulation: a review of the published literature.</a> Stereotact Funct Neurosurg. 84, 248-251 (2006).</li><li>Lim, S. Y., Hodaie, M., Fallis, M., Poon, Y. Y., Mazzella, F., Moro, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gamma+knife+thalamotomy+for+disabling+tremor:+a+blinded+evaluation.">Gamma knife thalamotomy for disabling tremor: a blinded evaluation.</a> Arch Neurol. 67, 584-588 (2010).</li><li>King, N. K. K., Krishna, V., Basha, D., Elias, G., Sammartino, F., Hodaie, M., Lozano, A. M., Hutchison, W. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Microelectrode+recording+findings+within+the+tractography-defined+ventral+intermediate+nucleus.">Microelectrode recording findings within the tractography-defined ventral intermediate nucleus.</a> J Neurosurg. 126, 1669-1675 (2017).</li></ol>

是一个发明专利和专利申请相关的 neuroablation 与聚焦超声。NL 和 FUSF 曾担任过聚焦超声基础的有偿顾问。FUSF 是一个独立的非营利性组织, 其目标是聚焦超声技术及其应用的研究进展。YM、YH、BS、MLS 和 NS 没有要声明的冲突。

MRgFUS 在高强度能非造成颅内病变。目前高强度 MRgFUS 与连续波模式的650赫已优化的热消融深脑结构, 如 Vim 丘脑。MRgFUS 的使用与现有的技术, 如 DBS, 伽玛刀放射外科手术, 或射频消融治疗难治性 ET。DBS 是一个开放的手术程序, 可以与潜在的设备相关的并发症, 包括硬件故障, 破损, 和电池损耗。射频消融也是一个开放的过程, 并与脑电极的跨皮质通路有关。虽然伽玛刀是一种非侵入性的替代品, 伽玛刀...

原发性震颤 (ET) 是最常见的运动障碍, 在个人40岁或更旧的1中患病率高达4%。它的特点是姿势和意图震颤的频率约 4-7 赫兹。它通常影响上肢, 以及头部和声音, 但也可以看到在腿上。ET 可能会严重削弱, 影响日常生活的简单活动的管理能力。15-25% 的患者由于 ET 的原因被迫过早退休, 60% 的患者不申请工作或晋升, 因为无法控制的晃动2。尽管一线医疗疗法的有效性, 如心得安或扑3, 很大比例的病人不能容忍或不耐医疗治疗。在尝试了至少两种药物后仍然有症状和严重残疾的病人, 或者是那些产生难以忍受的副作用的患者, 被认为是药物难治的。
医学上难治性 ET 的病例符合手术治疗的条件。靶向丘脑的鮈中间 (Vim) 核, 一个关键的小脑-马达中继结构, 与深脑刺激 (DBS)4电极或射频消融可以帮助缓解震颤5,6。然而, 两者都是开放式神经外科手术, 潜在的并发症, 包括感染和出血。DBS 还包括长期植入的颅内电极和电池超过胸大肌。此外, 病人需要麻醉剂, 在 DBS 的情况下, 一般的麻醉剂, 以及医院的停留范围从一天到几天不等。
MR 引导下聚焦超声 (MRgFUS) 是一种新兴的无创技术治疗各种神经和精神疾病。该装置由一个头盔, 其聚焦超过1000超声光束从独立的传感器通过完整的头骨。高强度的 MRgFUS 能在靶处产生热, 导致凝血坏死。multi-centered 丘脑的随机假对照试验显示, 47% 的震颤评分在12月7时持续改善。这一结果导致了对 MRgFUS 的监管批准作为一种治疗方式和随后增加 MRgFUS 的临床医生的医疗的震颤管理。该协议详细介绍了患者的选择、准备和超声的步骤, 以及患者随访的重要因素。

<table><tbody><tr><td>InSightec ExAblate Neuro system</td><td>InSightec</td><td></td><td>The ExAblate Neuro consists of a helmet transducer with 1,024 independent elements, each with central frequency 650 kHz and is integrated with a 3 Tesla MR scanner.</td></tr><tr><td>3 Tesla MRI scanner</td><td></td><td></td><td></td></tr><tr><td>MRI compatible Cosman-Roberts-Wells (CRW) stereotactic frame</td><td></td><td></td><td></td></tr><tr><td>20 mL of 1% lidocaine with 1:100,000 epinephrine</td><td></td><td></td><td></td></tr><tr><td>hair shaver/clipper</td><td></td><td></td><td></td></tr><tr><td>warming blanket</td><td></td><td></td><td></td></tr><tr><td>compression stockings</td><td></td><td></td><td></td></tr></tbody></table>

mri-guided focused ultrasound thalamotomy for patients with medically-refractory essential tremor

原发性震颤 (ET) 是成人最常见的震颤类型。et 不会导致预期寿命下降, 但与 et 相关的残疾对生活质量、情绪、功能活动和社会化有重大影响。患者患有 ET 不充分治疗一线药物可能有资格替代策略, 如深脑刺激, 射频消融, 和 MRI 引导聚焦超声 (MRgFUS)。高强度 MRgFUS 是一种新兴的治疗 ET 的方式, 它对病人的吸引力在于它是无创的, 并且与短暂的恢复时间有关, 因为病人在治疗后的一天回家。虽然 MRgFUS 中心仍然是有限的, 这将成为重要的临床医生考虑 MRgFUS 作为一种治疗替代, 特别是在病人的情况下, 开放手术是禁忌。本文概述了病人选择、设备设置、超声和后处理后续行动的步骤, 以及在执行 MRgFUS 过程时需要注意的关键步骤。

长期减少的震颤在治疗下肢是平均50% 在3月和40% 在12月。治疗成功可以立即评估后, 超声通过影像学发现的一个病灶在 Vim (图 1) 和性能的临床措施, 如手绘螺旋测试 (图 2)。此外, 术中 MR 热成像提供 real-time 反馈的目标温度。当温度达到 55-60 ° c 时, 预计会出现永久性病变。
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MRI-guided Focused Ultrasound Thalamotomy for Patients with Medically-refractory Essential Tremor

高强度 MRI 引导聚焦超声是一种新兴的无创技术, 精确蚀脑组织。它已被证明是安全和有效的治疗医用难治性本质震颤。本文介绍了丘脑从病人选择到设备设置到后处理随访的协议。

MRI 引导下聚焦超声丘脑治疗难治性原发性震颤

Essential tremor (ET) is the most common type of tremor in adults. While ET does not result in decreased life expectancy, the disabilities associated with ...

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13.9K 次观看.  Sunnybrook Health Sciences Centre. 高强度 MRI 引导聚焦超声是一种新兴的无创技术, 精确蚀脑组织。它已被证明是安全和有效的治疗医用难治性本质震颤。本文介绍了丘脑从病人选择到设备设置到后处理随访的协议。

视频: MRI-guided Focused Ultrasound Thalamotomy for Patients with Medically-refractory Essential Tremor

Contrast Ultrasound Targeted Treatment of Gliomas in Mice via Drug-Bearing Nanoparticle Delivery and Microvascular Ablation

We are developing minimally-invasive contrast agent microbubble based therapeutic approaches in which the permeabilization and/or ablation of the microvasculature are controlled by varying ultrasound pulsing parameters.  Specifically, we are testing whether such approaches may be used to treat malignant brain tumors through drug delivery and microvascular ablation.  Preliminary studies have been performed to determine whether targeted drug-bearing nanoparticle delivery can be facilitated by the ultrasound mediated destruction of "composite" delivery agents comprised of 100nm poly(lactide-co-glycolide) (PLAGA) nanoparticles that are adhered to albumin shelled microbubbles. We denote these agents as microbubble-nanoparticle composite agents (MNCAs). When targeted to subcutaneous C6 gliomas with ultrasound, we observed an immediate 4.6-fold increase in nanoparticle delivery in MNCA treated tumors over tumors treated with microbubbles co-administered with nanoparticles and a 8.5 fold increase over non-treated tumors. Furthermore, in many cancer applications, we believe it may be desirable to perform targeted drug delivery in conjunction with ablation of the tumor microcirculation, which will lead to tumor hypoxia and apoptosis. To this end, we have tested the efficacy of non-theramal cavitation-induced microvascular ablation, showing that this approach elicits tumor perfusion reduction, apoptosis, significant growth inhibition, and necrosis. Taken together, these results indicate that our ultrasound-targeted approach has the potential to increase therapeutic efficiency by creating tumor necrosis through microvascular ablation and/or simultaneously enhancing the drug payload in gliomas.

Insonation of microbubbles is a promising strategy for tumor ablation at reduced time-averaged acoustic powers, as well as for the targeted delivery of therapeutics. The purpose of the present study is to develop low duty cycle ultrasound pulsing strategies and nanocarriers to maximize non-thermal microvascular ablation and payload delivery to subcutaneous C6 gliomas.

超声造影有针对性的治疗胶质瘤的小鼠通过药物轴承纳米粒子交付和微血管消融

We are developing minimally-invasive contrast agent microbubble based therapeutic approaches in which the permeabilization and/or ablation of the ...

科研

生物工程

Evaluation of the Feasibility, Safety, and Accuracy of an Intraoperative High-intensity Focused Ultrasound Device for Treating Liver Metastases

Today, the only potentially curative option in patients with colorectal liver metastases is surgery. However, liver resection is feasible in less than 20% of patients. Surgery has been widely used in association with radiofrequency, cryotherapy, or microwaves to expand the number of treatments performed with a curative intent. Nevertheless, several limitations have been documented when using these techniques (i.e., a traumatic puncture of the parenchyma, a limited size of lesions, and an inability to monitor the treatment in real-time).High-intensity focused ultrasound (HIFU) technology can achieve precise ablations of biological tissues without incisions or radiation. Current HIFU devices are based on an extracorporeal approach with limited access to the liver. We have developed a HIFU device designed for intraoperative use. The use of a toroidal transducer enables an ablation rate (10 cm3&#183;min-1) higher than any other treatment and is independent of perfusion.
The feasibility, safety, and accuracy of intraoperative HIFU ablation were evaluated during an ablate-and-resect prospective study. This clinical phase I and IIa study was performed in patients undergoing hepatectomy for liver metastases. The HIFU treatment was performed on healthy tissue scheduled for resection.Liver metastases measuring less than 20 mm will be targeted during phase IIb (currently ongoing). This set-up allows the real-time evaluation of HIFU ablation while protecting participating patients from any adverse effects related to this new technique.
Fifteen patients were included in phase I&#8211;IIa and 30 HIFU ablations were safely created within 40 s and with a precision of 1&#8211;2 mm. The average dimensions of the HIFU ablations were 27.5 x 21.0 mm2, corresponding to a volume of approximately 7.5 cm3. The aim of the ongoing phase IIb is to ablate metastases of less than 20 mm in diameter with a 5 mm margin.

Here, we present an ablate-and-resect prospective study to evaluate the feasibility, safety, and accuracy of intraoperative high-intensity focused ultrasound ablation in patients undergoing hepatectomy for liver metastases.

术中高强度聚焦超声装置治疗肝转移的可行性、安全性和准确性评价

Today, the only potentially curative option in patients with colorectal liver metastases is surgery. However, liver resection is feasible in less than 20% ...

癌症研究

MRI-guided Disruption of the Blood-brain Barrier using Transcranial Focused Ultrasound in a Rat Model

Focused ultrasound (FUS) disruption of the blood-brain barrier (BBB) is an increasingly investigated technique for circumventing the BBB1-5. The BBB is a significant obstacle to pharmaceutical treatments of brain disorders as it limits the passage of molecules from the vasculature into the brain tissue to molecules less than approximately 500 Da in size6. FUS induced BBB disruption (BBBD) is temporary and reversible4 and has an advantage over chemical means of inducing BBBD by being highly localized. FUS induced BBBD provides a means for investigating the effects of a wide range of therapeutic agents on the brain, which would not otherwise be deliverable to the tissue in sufficient concentration. While a wide range of ultrasound parameters have proven successful at disrupting the BBB2,5,7, there are several critical steps in the experimental procedure to ensure successful disruption with accurate targeting. This protocol outlines how to achieve MRI-guided FUS induced BBBD in a rat model, with a focus on the critical animal preparation and microbubble handling steps of the experiment.

Microbubble-mediated focused ultrasound disruption of the blood-brain barrier (BBB) is a promising technique for non-invasive targeted drug delivery in the brain1-3. This protocol outlines the experimental procedure for MRI-guided transcranial BBB disruption in a rat model.

MRI引导下的破坏血脑屏障在大鼠模型经颅聚焦超声

Focused ultrasound (FUS) disruption of the blood-brain barrier (BBB) is an increasingly investigated technique for circumventing the BBB1-5. The BBB is a ...

医学

MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial prefrontal cortex (dmPFC) in patients with major depressive disorder (MDD). Technicians used a neuronavigation system to process patient MRIs to generate a 3-dimensional head model. The head model was subsequently used to identify patient-specific stimulatory targets. The dmPFC was stimulated daily for 20 sessions. Stimulation intensity was titrated to address scalp pain associated with rTMS. Weekly assessments were conducted on the patients using the Hamilton Rating Scale for Depression (HamD17) and Beck Depression Index II (BDI-II). Treatment-resistant MDD patients achieved significant improvements on both HAMD and BDI-II. Of note, angled, double-cone coil rTMS at 120% resting motor threshold allows for optimal stimulation of deeper midline prefrontal regions, which results in a possible therapeutic application for MDD. One major limitation of the rTMS field is the heterogeneity of treatment parameters across studies, including duty cycle, number of pulses per session and intensity. Further work should be done to clarify the effect of stimulation parameters on outcome. Future dmPFC-rTMS work should include sham-controlled studies to confirm its clinical efficacy in MDD.

Here we outline the procedure for MRI-guided repetitive transcranial magnetic stimulation to the dorsomedial prefrontal cortex as an experimental treatment for major depressive disorder.

MRI引导dmPFC-rTMS治疗作为治疗难治性抑郁症

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial ...

Sonodynamic Therapy for the Treatment of Glioblastoma Multiforme in a Mouse Model Using a Portable Benchtop Focused Ultrasound System

Sonodynamic therapy (SDT) is an application of focused ultrasound (FUS) that enables a sonosensitizing agent to prime tumors for increased sensitivity during sonication. Unfortunately, current clinical treatments for glioblastoma (GBM) are lacking, leading to low long-term survival rates among patients. SDT is a promising method for treating GBM in an effective, noninvasive, and tumor-specific manner. Sonosensitizers preferentially enter tumor cells compared to the surrounding brain parenchyma. The application of FUS in the presence of a sonosensitizing agent generates reactive oxidative species resulting in apoptosis. Although this therapy has been shown previously to be effective in preclinical studies, there is a lack of established standardized parameters. Standardized methods are necessary to optimize this therapeutic strategy for preclinical and clinical use. In this paper, we detail the protocol to perform SDT in a preclinical GBM rodent model using magnetic resonance-guided FUS (MRgFUS). MRgFUS is an important feature of this protocol, as it allows for specific targeting of a brain tumor without the need for invasive surgeries (e.g., craniotomy). The benchtop device used here can focus on a specific location in three dimensions by clicking on a target on an MRI image, making target selection a straightforward process. This protocol will provide researchers with a standardized preclinical method for MRgFUS SDT, with the added flexibility to change and optimize parameters for translational research.

Here, we describe a protocol that details how to perform sonodynamic therapy in an in vivo mouse glioblastoma model using magnetic resonance-guided focused ultrasound.

使用便携式台式聚焦超声系统治疗小鼠模型中多形性胶质母细胞瘤的声动力疗法

Sonodynamic therapy (SDT) is an application of focused ultrasound (FUS) that enables a sonosensitizing agent to prime tumors for increased sensitivity ...

A Benchtop Approach to the Location Specific Blood Brain Barrier Opening using Focused Ultrasound in a Rat Model

Stereotaxic surgery is the gold standard for localized drug and gene delivery to the rodent brain. This technique has many advantages over systemic delivery including precise localization to a target brain region and reduction of off target side effects. However, stereotaxic surgery is highly invasive which limits its translational efficacy, requires long recovery times, and provides challenges when targeting multiple brain regions. Focused ultrasound (FUS) can be used in combination with circulating microbubbles to transiently open the blood brain barrier (BBB) in millimeter sized regions. This allows intracranial localization of systemically delivered agents that cannot normally cross the BBB. This technique provides a noninvasive alternative to stereotaxic surgery. However, to date this technique has yet to be widely adopted in neuroscience laboratories due to the limited access to equipment and standardized methods. The overall goal of this protocol is to provide a benchtop approach to FUS BBB opening (BBBO) that is affordable and reproducible and can therefore be easily adopted by any laboratory.

Focused ultrasound with microbubble agents can open the blood brain barrier focally and transiently. This technique has been used to deliver a wide range of agents across the blood brain barrier. This article provides a detailed protocol for the localized delivery to the rodent brain with or without MRI guidance.

在鼠模型中使用聚焦超声波打开位置特定血脑屏障开口的台面方法

Stereotaxic surgery is the gold standard for localized drug and gene delivery to the rodent brain. This technique has many advantages over systemic ...

神经科学

A High-Throughput Image-Guided Stereotactic Neuronavigation and Focused Ultrasound System for Blood-Brain Barrier Opening in Rodents

The blood-brain barrier (BBB) has been a major hurdle for the treatment of various brain diseases. Endothelial cells, connected by tight junctions, form a physiological barrier preventing large molecules (&#62;500 Da) from entering the brain tissue. Microbubble-mediated focused ultrasound (FUS) can be used to induce a transient local BBB opening, allowing larger drugs to enter the brain parenchyma.
In addition to large-scale clinical devices for clinical translation, preclinical research for therapy response assessment of drug candidates requires dedicated small animal ultrasound setups for targeted BBB opening. Preferably, these systems allow high-throughput workflows with both high-spatial precision as well as integrated cavitation monitoring, while still being cost effective in both initial investment and running costs.
Here, we present a bioluminescence and X-ray guided stereotactic small animal FUS system that is based on commercially available components and fulfills the aforementioned requirements. A particular emphasis has been placed on a high degree of automation facilitating the challenges typically encountered in high-volume preclinical drug evaluation studies. Examples of these challenges are the need for standardization in order to ensure data reproducibility, reduce intra-group variability, reduce sample size and thus comply with ethical requirements and decrease unnecessary workload. The proposed BBB system has been validated in the scope of BBB opening facilitated drug delivery trials on patient-derived xenograft models of glioblastoma multiforme and diffuse midline glioma.

The blood-brain barrier (BBB) can be temporarily disrupted with microbubble-mediated focused ultrasound (FUS). Here, we describe a step-by-step protocol for high-throughput BBB opening in vivo using a modular FUS system accessible for non-ultrasound experts.

高通量图像引导立体定向神经导航和聚焦超声系统，用于在啮齿动物中打开血脑屏障

The blood-brain barrier (BBB) has been a major hurdle for the treatment of various brain diseases. Endothelial cells, connected by tight junctions, form a ...

Targeted Neuronal Injury for the Non-Invasive Disconnection of Brain Circuitry

Surgical intervention can be quite effective for treating certain types of medically intractable neurological diseases. This approach is particularly useful for disorders in which identifiable neuronal circuitry plays a key role, such as epilepsy and movement disorders. Currently available surgical modalities, while effective, generally involve an invasive surgical procedure, which can result in surgical injury to non-target tissues. Consequently, it would be of value to expand the range of surgical approaches to include a technique that is both non-invasive and neurotoxic.
Here, a method is presented for producing focal, neuronal lesions in the brain in a non-invasive manner. This approach utilizes low-intensity focused ultrasound together with intravenous microbubbles to transiently and focally open the Blood Brain Barrier (BBB). The period of transient BBB opening is then exploited to focally deliver a systemically administered neurotoxin to a targeted brain area. The neurotoxin quinolinic acid (QA) is normally BBB-impermeable, and is well-tolerated when administered intraperitoneally or intravenously. However, when QA gains direct access to brain tissue, it is toxic to the neurons. This method has been used in rats and mice to target specific brain regions. Immediately after MRgFUS, successful opening of the BBB is confirmed using contrast enhanced T1-weighted imaging. After the procedure, T2 imaging shows injury restricted to the targeted area of the brain and the loss of neurons in the targeted area can be confirmed post-mortem utilizing histological techniques. Notably, animals injected with saline rather than QA do demonstrate opening of the BBB, but dot not exhibit injury or neuronal loss. This method, termed Precise Intracerebral Non-invasive Guided surgery (PING) could provide a non-invasive approach for treating neurological disorders associated with disturbances in neural circuitry.

The goal of the protocol is to provide a method for producing non-invasive neuronal lesions in the brain. The method utilizes Magnetic Resonance-guided Focused Ultrasound (MRgFUS) to open the Blood Brain Barrier in a transient and focal manner, in order to deliver a circulating neurotoxin to the brain parenchyma.

脑回路非侵入性断开的靶向神经元损伤

Surgical intervention can be quite effective for treating certain types of medically intractable neurological diseases. This approach is particularly ...

Focused Ultrasound Induced Blood-Brain Barrier Opening for Targeting Brain Structures and Evaluating Chemogenetic Neuromodulation

Acoustically Targeted Chemogenetics (ATAC) allows for the noninvasive control of specific neural circuits. ATAC achieves such control through a combination of focused ultrasound (FUS) induced blood-brain barrier opening (FUS-BBBO), gene delivery with adeno-associated viral (AAV) vectors, and activation of cellular signaling with engineered, chemogenetic, protein receptors and their cognate ligands. With ATAC, it is possible to transduce both large and small brain regions with millimeter precision using a single noninvasive ultrasound application. This transduction can later allow for a long-term, noninvasive, device-free neuromodulation in freely moving animals using a drug. Since FUS-BBBO, AAVs, and chemogenetics have been used in multiple animals, ATAC should also be scalable for the use in other animal species. This paper expands upon a previously published protocol and outlines how to optimize the gene delivery with FUS-BBBO to small brain regions with MRI-guidance but without a need for a complicated MRI-compatible FUS device. The protocol, also, describes the design of mouse targeting and restraint components that can be 3D-printed by any lab and can be easily modified for different species or custom equipment. To aid reproducibility, the protocol describes in detail how the microbubbles, AAVs, and venipuncture were used in ATAC development. Finally, an example data is shown to guide the preliminary investigations of studies utilizing ATAC.

This protocol delineates steps necessary for the gene delivery through focused ultrasound blood brain barrier (BBB) opening, evaluation of the resulting gene expression, and measurement of neuromodulation activity of chemogenetic receptors through histological tests.

聚焦超声诱导血脑屏障打开，用于靶向大脑结构和评估化学遗传神经调控

Acoustically Targeted Chemogenetics (ATAC) allows for the noninvasive control of specific neural circuits. ATAC achieves such control through a ...

Real-Time Magnetic Resonance Guided Focused Ultrasound for Painful Bone Metastases

Bones are one of the most common sites of cancer metastasis, which usually causes pain and impairs quality of life. Radiation therapy combined with opioids is the standard treatment for painful bone metastases. This treatment achieves effective pain control in 60&#8722;74% of patients, but limited treatment choices with limited benefits are available for recurrent or residual painful bone metastases after radiotherapy. More than 40% of patients still experience moderate to severe bone pain after reirradiation. Magnetic resonance-guided focused ultrasound (MRgFUS) combines high-intensity focused ultrasound, which achieves thermal ablation of bone metastases and subsequent pain reduction, with real-time magnetic resonance (MR) thermometry to monitor the temperature of anatomic MR images, with an accuracy of 1 &#176;C, spatial resolution of 1 mm, and temporal resolution within 3 s. As well as being increasingly used clinically for controlling metastatic bone pain, the use of MRgFUS for other diseases has also been tested. However, the use of MR software as a thermometer is the only technique available to verify the accuracy of the software and assure energy delivery. Here, we describe an efficient method of quality assurance we developed for thermal detection and energy delivery before each MRgFUS treatment and also propose a modified workflow to expedite the treatment course as well as to reduce patients&#39; pain during the procedure.

Magnetic resonance could offer real-time monitoring of the position and temperature of focused ultrasound in thermal ablation for painful bone metastases, regardless of cancer type or previous local treatments. Our innovative method of quality assurance could facilitate the application of this effective and safe treatment.

Bones are one of the most common sites of cancer metastasis, which usually causes pain and impairs quality of life. Radiation therapy combined with ...