这项工作得到了加拿大自然科学与工程研究委员会发现资助、INNOVAIT 计划、卡明医学研究基金、加拿大创新基金会（项目 36703）、霍奇基斯脑研究所 CAPRI 资助和阿尔伯塔省帕金森协会资助的部分支持。GBP 感谢加拿大卫生研究所 （FDN-143290） 和阿尔伯塔省校园创新主席计划的支持。

高精度 TUS：使用声学和热仿真进行规划和执行

作者没有需要声明的利益冲突。

在这种方法中，执行特定于主题的模拟以预测和评估将 TUS 应用于大脑可能产生的热和机械效应。参与者之间的数据集必须保持独立并仔细记录，因为使用不正确的扫描或数据文件会导致模拟不准确。当收集大量参与者扫描并一起执行规划时，确保正确标记图像和文件夹并在排序和保存文件时谨慎进行非常重要。
为了准确地执行仿真，必须对头骨进行正确建模，以获得对声学...

常用的非侵入性神经刺激技术包括经颅直流电刺激 （tDCS） 和经颅磁刺激 （TMS）。然而，两者都具有有限的穿透深度和较低的精度 1,2。相比之下，经颅超声 （TUS） 是一种新兴的非侵入性技术，能够增强或抑制神经元活动 3,4,5 并以毫米级精度靶向皮质或皮质下结构 6,7。使用啮齿动物4、8、9、兔子10、绵羊5、11、猪6 和非人灵长类动物7、12、13、14 的动物模型显示了 TUS 的有效性和安全性。研究表明，针对不同的大脑区域可以引起大鼠的肢体运动8 、猪的体感诱发电位 （SSEP）6 、非人灵长类动物的视觉运动活动12、认知和动机决策13 的变化以及其他行为变化。在人类中，已观察到 TUS 在针对初级运动皮层 15,16 时改变运动诱发电位 （MEP） 和反应时间任务的表现，在针对体感皮层 17 和感觉丘脑18 时改变触觉辨别任务和 SSEP 的表现。组织学分析显示，猪6、绵羊 5,11、兔子 10 和非人灵长类动物14 没有与 TUS 相关的肉眼或微观结构变化，也没有发现与其他非侵入性神经刺激技术显着不同的副作用19。
TUS 使用频率在 200 kHz 和 700 kHz 之间的脉冲低强度聚焦超声来产生瞬态神经调节效果。原位典型的空间峰值脉搏平均强度 （Isppa） 为 10 W/cm2 或更低，报告的人类占空比（超声开启的时间百分比）在 0.5% 到 70% 之间 20,21,22,23,24。尽管已经提出 TUS 神经调控的机制主要涉及脂质膜的机械搅动，导致离子通道打开 25,26,27，但可能的热和空化效应不容忽视。它们通过机械 （MI） 和热 （TI） 指数进行评估。MI 描述了 TUS 将发生的预测的空化相关生物效应，而 TI 描述了超声应用后组织内的潜在温度升高28,29。此外，改变频率和输入强度也会导致 MI 和 TI 发生变化。频率越高，空间分辨率越好，发生机械生物效应的可能性越小;然而，它们在组织中具有更强的吸收能力，这增加了温度升高的可能性28。或者，相同强度的较低频率会增加 MI。同样，增加强度往往会增加机械和热生物效应的程度30。因此，在实验之前，必须对所有将要实施的 TUS 参数进行仔细的规划和仿真。
规划 TUS 实验需要确定目标和目标轨迹，以及热仿真和声学仿真的性能。仿真有助于优化机械效应并减轻 TUS 对组织的热影响。他们需要了解颅骨加热的预测、超声在焦点处的压力振幅、局灶矫正以及颅骨和皮肤内的其他加热。充分的模拟可确保焦点到达感兴趣的目标，并遵循国际经颅超声刺激安全和标准联盟 （ITRUSST）31 推荐的生物物理安全指南规定的超声使用安全参数，这些指南基于 FDA 和加拿大卫生部的建议。最近的研究还强调了动物和人类伴随 TUS 32,33,34 的听觉混杂效应，因此 TUS 刺激可以激活大脑中的听觉通路以引发反应 32,33,34。啮齿动物的听觉神经横断32 （transection of the auditory nerves）、去除耳蜗液32 （cochlear fluid） 或化学性耳聋33 （chemical deafness） 已被用来减少动物的这些影响。在人类中，通过耳机管理听觉音调已被用于有效掩盖来自 TUS 的听觉噪声，控制 TUS 诱导的听觉活动混淆34。这突出了在假刺激条件下控制听觉噪声的必要性，这必须纳入协议规划、设计和实施中。
在这里，我们提供了有关如何适当完成在人体中进行 TUS 神经调控实验所需的准备（第 1 步、第 2 步）、规划（第 3 步）、模拟（第 4 步）和 TUS 交付（第 5 步）的指南。

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>128-channel amplifier unit</td>
			<td>Image Guided Therapy</td>
			<td></td>
			<td>This unit drives the H-317 transducer</td>
		</tr>
		<tr>
			<td>24-channel head coil</td>
			<td>General Electric</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>3D printer</td>
			<td>Raise3D</td>
			<td>Pro2</td>
			<td>Filament thickness of 1.75mm.</td>
		</tr>
		<tr>
			<td>3T MRI scanner</td>
			<td>General Electric</td>
			<td>Discovery 750 HD</td>
			<td>MR Console version DV26.0_R05_2008</td>
		</tr>
		<tr>
			<td>BabelBrain</td>
			<td>Samuel Pichardo (University of Calgary)</td>
			<td>Version 0.3.0</td>
			<td>Accessible at https://github.com/ProteusMRIgHIFU/BabelBrain. Executes thermal and acoustic simulations.</td>
		</tr>
		<tr>
			<td>Blender</td>
			<td>Blender Foundation</td>
			<td>Version 3.4.1</td>
			<td>Accessible at https://www.blender.org. Blender is called automatically by BabelBrain.</td>
		</tr>
		<tr>
			<td>Brainsight</td>
			<td>Rogue Research</td>
			<td>Version 2.5.2</td>
			<td>Used for target identification, trajectory planning, and execution of TUS delivery sessions.</td>
		</tr>
		<tr>
			<td>Chair and chin/head holder</td>
			<td>Rogue Research</td>
			<td></td>
			<td>To be used during TUS delivery session to ensure stability of participant&#8217;s head for optimized targeting.</td>
		</tr>
		<tr>
			<td>Custom-made coupling cone</td>
			<td>University of Calgary team</td>
			<td></td>
			<td>3D printed cone in acrylonitrile butadiene styrene (ABS), only required for H-317 transducer.</td>
		</tr>
		<tr>
			<td>dcm2niix</td>
			<td>Chris Rorden (University of South Carolina)&#160;</td>
			<td>Version 1.0.20220720</td>
			<td>Accessible at https://github.com/rordenlab/dcm2niix/releases. Used for pre-processing subject MR images.</td>
		</tr>
		<tr>
			<td>Fiducials and headband or glasses</td>
			<td>Brainsight, Rogue Research&#160;</td>
			<td>ST-1325 (subject tracker), LCT-583 (large coil tracker)</td>
			<td>Headband or glasses can be interchangeably used.</td>
		</tr>
		<tr>
			<td>Headphones</td>
			<td>Beats</td>
			<td>Fit Pro True Wireless Earbuds</td>
			<td>Wireless Bluetooth earbuds with disposable tips.</td>
		</tr>
		<tr>
			<td>MacBookPro</td>
			<td>Apple</td>
			<td>M2 Max, 16&#8221;, 64GB RAM</td>
			<td>Computer for completing trajectory planning and simulations</td>
		</tr>
		<tr>
			<td>SimNIBS</td>
			<td>Axel Thielscher (Technical University of Denmark)</td>
			<td>Version 4.0.0</td>
			<td>Accessible at https://simnibs.github.io/simnibs/build/html.index.html</td>
		</tr>
		<tr>
			<td>Syringe(s)</td>
			<td></td>
			<td>10 mL, 60 mL</td>
			<td>Used to add additional ultrasound gel to fill air pockets.</td>
		</tr>
		<tr>
			<td>Transducer</td>
			<td>Sonicconcepts</td>
			<td>H-317</td>
			<td>Other supported transducers include CTX_500 (NeuroFUS, Sonicconcepts), Single element, H-246 (Sonicconcepts), and Bsonix (Brainsonix)</td>
		</tr>
		<tr>
			<td>Transducer film</td>
			<td>Sonicconcepts</td>
			<td>Polyurethane membrane</td>
			<td>Interface between transducer and the subject</td>
		</tr>
		<tr>
			<td>Ultrasound gel</td>
			<td>Wavelength</td>
			<td>Clear Ultrasound Gel</td>
			<td>Coupling medium.</td>
		</tr>
		<tr>
			<td>Windows Laptop</td>
			<td>Acer</td>
			<td>Aspire A717-71G, Intel Core i7-7700HQ, 16 GB RAM</td>
			<td>System used to control 128-channel amplifier and generate sound through the headphones</td>
		</tr>
	</tbody>
</table>

pipeline for planning and execution of transcranial ultrasound neuromodulation experiments in humans

经颅超声刺激 （TUS） 是一种新兴的非侵入性神经调控技术，能够高精度地操纵皮层和皮层下结构。进行涉及人类的实验需要仔细规划声学和热仿真。此规划对于调整骨与超声束形状和轨迹的干扰以及确保 TUS 参数满足安全要求至关重要。获取 T1 和 T2 加权以及具有 1 mm 各向同性分辨率的零时间回波 （ZTE） 磁共振成像 （MRI） 扫描（或者计算机断层扫描 X 射线 （CT） 扫描）用于颅骨重建和模拟。使用神经导航平台进行目标和轨迹映射。SimNIBS 用于颅骨、皮肤和脑组织的初始分割。TUS 的模拟是通过 BabelBrain 工具进行的，该工具使用 ZTE 扫描生成头骨的合成 CT 图像，并将其转换为声学特性。我们使用具有电动转向功能的相控阵超声换能器。调整 Z 方向转向以确保达到目标深度。规划工具还支持其他传感器配置。运行热模拟以确保温度和机械指数要求符合 FDA 建议的人体 TUS 声学指南。在 TUS 交付过程中，机械臂使用无框架立体定向定位系统协助传感器移动到所需位置。

Commonly used non-invasive neurostimulation techniques include transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS). However, both have limited penetration depth and low precision1,2. By contrast, transcranial ultrasound (TUS) is an emerging non-invasive technique capable of enhancing or suppressing neuronal activity3,4,5 and targeting cortical or subcortical structures at millimeter precision6,7. Animal models using rodents4,8,9, rabbits10, sheep5,11, swine6, and nonhuman primates7,12,13,14 have shown the efficacy and safety of TUS. Studies have demonstrated that targeting various brain regions can elicit limb movements8 in rats, somatosensory evoked potentials (SSEPs) in swine6, and changes in visuomotor activity12, cognitive, and motivational decision-making in nonhuman primates13 among other changes in behavior. In humans, TUS has been observed to change motor evoked potentials (MEPs)&#160;and performance on a reaction time task when targeting the primary motor cortex15,16 and altered performance on a tactile discrimination task and SSEPs when targeting the somatosensory cortex17 and sensory thalamus18. Histological analyses have revealed no gross or microscopic structural changes associated with TUS in swine6, sheep5,11, rabbits10, and nonhuman primates14, and no side effects have been seen that significantly differ from other non-invasive neurostimulation techniques19.
TUS uses pulsed low-intensity focused ultrasound at a frequency between 200 kHz and 700 kHz to produce a transient neuromodulatory effect. The typical spatial-peak pulse-average intensity (Isppa) in situ is 10 W/cm2 or less, with reported duty cycles (percentage of time when ultrasound is on) ranging from 0.5% to 70% in humans20,21,22,23,24. Although the mechanisms of TUS neuromodulation have been proposed to mainly involve mechanical agitation of lipid membranes leading to the opening of ion channels25,26,27, possible thermal and cavitation effects cannot be ignored. They are assessed through mechanical (MI) and thermal (TI) indices. The MI describes the predicted cavitation-related bioeffects that will occur with TUS, whereas the TI describes the potential temperature increase within tissues following ultrasound application28,29. Furthermore, changing the frequency and input intensity also causes the MI and TI to change. Higher frequencies have better spatial resolution and decrease the probability of mechanical bio-effects; however, they have stronger absorption in the tissue, which increases the potential for temperature rise28. Alternatively, lower frequencies at the same intensity increase the MI. Similarly, increasing the intensity tends to increase the magnitude of mechanical and thermal bio-effects30. It is, therefore, imperative that careful planning and simulation be performed before experimentation sessions for all TUS parameters that will be implemented.
Planning a TUS experiment requires the identification of the target and trajectory of interest and the performance of thermal and acoustic simulations. Simulations assist in optimizing mechanical effects and mitigating the thermal effects of TUS on tissues. They require understanding the prediction of skull heating, pressure amplitude of the ultrasound at the focal point, focal correction, and other heating within the skull and skin. Adequate simulation ensures the focal point will reach the target of interest and safety parameters for ultrasound use set out by the safety guidelines on biophysical safety as recommended by the International Transcranial Ultrasonic Stimulation Safety and Standards Consortium (ITRUSST)31, which are based on FDA and Health Canada recommendations, are followed. Recent studies have also highlighted an auditory confounding effect accompanied by TUS32,33,34 in animals and humans, whereby TUS stimulation can activate auditory pathways in the brain to elicit responses32,33,34. Transection of the auditory nerves32, removal of cochlear fluid32, or chemical deafness33 in rodents have been employed to diminish these effects in animals. In humans, administering an auditory tone through headphones has been used to effectively mask auditory noise from TUS, controlling for the TUS-induced auditory activity confound34. This highlights the need to control for auditory noise in sham stimulation conditions, which must be incorporated into protocol planning, design, and implementation.
Here, we present a guide on how to appropriately complete the preparation (step 1, step 2), planning (step 3), simulations (step 4), and TUS delivery (step 5) required to perform TUS neuromodulation experiment in humans.

作者聚焦：推进人脑调节 - 经颅超声刺激实验的优化方案

用于规划和执行人体经颅超声神经调控实验的管道

Our research aims to understand the details of transcranial ultrasound stimulation to cause measurable effects in humans, including parameter specifications and its ability to modulate deep brain structures. Our protocol streamlines the planning steps required to complete transcranial ultrasound stimulation experiments in humans. It is efficient, easy to use, and involves using open source accessible planning tools.Our recent findings have shed light on the effect of optimal parameter selection in transcranial ultrasound stimulation to achieve neuronal inhibition. This will help in developing and designing future experiments in humans, significantly contributing to our understanding and advancement of this technology.

图 7 显示了我们其中一项研究42 的比较会话样本，其中两个不同的参与者采用特定的超声参数（基频为 250 kHz，超声处理持续时间为 120 s，脉冲重复频率 （PRF） 为 100 Hz，占空比为 10%，ISPPA 为 5 W/cm²）。在这项研究中，从神经系统健康的受试者那里获得了具有 1 mm 各向同性分辨率的 T1-、T2-w 和 ZTE MRI 扫描。TMS 针对初级运动皮层 （M1），以评估不同 ...

经颅超声刺激 （TUS） 是一种新兴的非侵入性神经调控技术，需要仔细规划声学和热模拟。该方法描述了图像处理和超声模拟管道，用于高效、用户友好、简化的人体 TUS 实验规划。

Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation technique capable of manipulating both cortical and subcortical ...

pipeline-for-planning-execution-transcranial-ultrasound

Research

JoVE Journal

Neuroscience

Pipeline for Planning and Execution of Transcranial Ultrasound Neuromodulation Experiments in Humans

599 次观看.  University of Calgary. 我们的研究旨在了解经颅超声刺激对人类造成可测量影响的细节，包括参数规格及其调节深部大脑结构的能力。我们的方案简化了在人体中完成经颅超声刺激实验所需的计划步骤。它高效、易于使用，并且涉及使用开源可访问的规划工具。我们最近的研究结果揭示了经颅超声刺激中最佳参数选择对实现神经元抑制的影响。这将有助于开发和设计...