Non-invasive neuromodulation using low-intensity transcranial focused ultrasound in the human brain

低强度聚焦超声(LIFUS)是一种新兴但强大的非侵入性人脑神经调节方法。与经颅磁刺激(TMS)和经颅直流电刺激相比，LIFUS更有针对性，可以到达更深的地方。只有几项研究在动物和人类身上测试了LIFUS。LIFUS对人脑的影响尚不清楚。重要的是，不同的LIFUS参数和脑可塑性的诱导还没有被系统地研究。我们将系统地研究LIFUS对人脑的神经调节作用。健康的受试者将被招募。目的1采用单脉冲和成对脉冲TMS，研究脉冲重复频率、强度、占空比、超声时间等不同参数对运动皮质(M1)兴奋性、皮层内易化回路和抑制回路的影响。AIM 2将评估LIFUS如何影响从其他大脑区域到运动皮质的连接。LIFUS将被应用于小脑，以调节小脑-丘脑皮质通路，而TMS将被应用于对侧M1。同样，LIFUS到M1和TMS到对侧M1将测试大脑半球间的连接。进一步的研究将测试后顶叶皮质和背侧运动前皮质与M1的联系。AIM 3将评估LIFUS的功能后果。受试者将在M1的LIFUS期间执行一项提示反应时任务。当受试者执行停止信号任务时，将LIFUS应用于右额下回和补充前运动区，以测试抑制功能。目的4用诱导脑可塑性来评估LIFUS的后遗症。LIFUS在常规列车和theta猝发模式中将应用于M1。TMS将在LIFUS后80分钟内评估M1的变化。AIM 5将测试LIFUS如何改变大脑功能连接。我们将LIFUS应用于MRI中的M1、小脑、运动前皮质或顶后皮质，并评估静息状态的功能磁共振成像(FMRI)的变化。目标6将检测调节LIFUS效果的神经递质。正常受试者将被单剂量服用作用机制已知的药物，包括卡马西平(钠离子通道阻滞剂)、尼莫地平(L型钙通道阻滞剂)、劳拉西潘(增加GABA传递)、右美沙芬(N-甲基-D-天冬氨酸受体拮抗剂)或安慰剂。每种药物的效果将与安慰剂进行比较。这将是第一个全面和系统地研究LIFUS神经调节的研究。拟议中的研究将确定最佳参数，并确定LIFUS对人脑神经调节的影响和潜在机制。这将导致LIFUS的开发和采用，成为神经科学研究中了解和非侵入性调节大脑功能和连接的有价值的工具。

Low-intensity focused ultrasound (LIFUS) is an emerging but powerful method for non-invasive neuromodulation of the human brain. Compared to transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, LIFUS is more focal and can reach greater depths. Only a few studies have tested LIFUS in animals and humans. How LIFUS affects the human brain remains unclear. Importantly, different LIFUS parameters and induction of brain plasticity have not been systematically investigated. We will systematically investigate the neuromodulatory effects of LIFUS in the human brain. Healthy subjects will be recruited. Aim 1 will investigate the effects of different parameters of LIFUS including pulse repetition frequency, intensity, duty cycle, sonication duration on the excitability, intracortical facilitatory and inhibitory circuits in the motor cortex (M1) using single and paired pulse TMS. Aim 2 will assess how LIFUS affects connections to the motor cortex from other brain areas. LIFUS will be applied to the cerebellum to modulate the cerebello-thalamocortical pathway while TMS is applied to the contralateral M1. Similarly, LIFUS to M1 and TMS to the contralateral M1 will test interhemispheric connections. Further studies will test the connections of the posterior parietal cortex and dorsal premotor cortex to M1. Aim 3 will assess the functional consequences of LIFUS. Subjects will perform a cued reaction time task during LIFUS of M1. Inhibitory functions will be tested by applying LIFUS to the right inferior frontal gyrus and the presupplementary motor area while subjects perform a stop signal task. Aim 4 will use induce brain plasticity to assess the after effects of LIFUS. LIFUS in regular trains and in theta burst pattern will be applied the M1. Changes in M1 will be assessed by TMS up to 80 min after LIFUS. Aim 5 will test how LIFUS changes functional brain connectivity. We will apply LIFUS to the M1, cerebellum, premotor cortex or posterior parietal cortex in the MRI and assess changes resting state functional magnetic resonance imaging (fMRI). Aim 6 will examine the neurotransmitters mediating the effects of LIFUS. Normal subjects will be administered a single dose of a drug with known mechanism of action including carbamazepine (Na+ channel blocker), nimodipine (L-type Ca2+ channel blocker), lorazepam (increases GABA transmission), dextromethorphan (NMDA receptor antagonist) or placebo. The effects of each drug will be compared to that of placebo. This will be the first study to comprehensively and systematically examine LIFUS for neuromodulation. The proposed studies will define the optimal parameters, and determine the effects and the underlying mechanisms of LIFUS for neuromodulation in the human brain. It will lead to the development and adoption of LIFUS as a valuable tool in neuroscience research to understand and non-invasively modulate brain functions and connectivity.