Noninvasive ultrasound neuromodulation for functional brain mapping

描述(由申请人提供)：脑图工具对于我们理解大脑以及诊断功能障碍都是必不可少的。一种非侵入性、精确地刺激人脑内任何三维轨迹的方法，无论在临床上还是在科学上都将是革命性的。如果与现代脑功能成像方法兼容，这种改进的刺激工具可以支持前所未有的探索人类大脑功能和连接的研究。在临床上，它可以支持新的筛查/诊断策略，并改进对抑郁症、帕金森氏症和癫痫等疾病的治疗，这些疾病正变得越来越频繁地使用侵入性刺激方法(例如，使用脑深部刺激电极；DBS)。脉冲超声(US)能量可用于调节大脑电路活动，并具有在大脑任何位置实现毫米空间分辨率的定向刺激所需的特性。我们的目标是将超声神经调节转化为人类，并开发将超声诱导的神经调节与当前的神经成像和电生理学方法相结合的技术。我们建议开发的方法将在诊断医学中建立一个新的范式，并广泛适用于神经疾病，以及提高我们理解大脑综合功能的能力。具体目标1.开发确定UNMOD最佳脉冲波形的硬件和软件平台。里程碑：将US刺激与电生理和功能磁共振数据采集相结合的硬件和软件平台，以建立一种系统的方法来分析最佳超声神经调制(UNMOD)刺激参数空间。具体目标2。利用超声波通过颅骨进行深层神经刺激的聚焦和扫描策略的发展。里程碑：使用多种超声源的神经调节策略，可提高激活的空间分辨率， 减少不必要的热效应，提高激活效率。特定的目标3。在灵长类动物的大脑中测试局部神经刺激策略。我们将使用这个模型来测试在特定目标1和2中开发的方法。里程碑：在灵长类动物中的概念验证以及在人类身上测试最佳聚焦和扫描策略的选择。具体目的4.人体同时进行超声神经刺激、功能磁共振成像和脑电记录。里程碑：UNMOD、功能磁共振成像和人类脑电记录的成功整合。在第一阶段SBIR的成功结束时，我们将开发出一些关键技术，用于将人类脑功能图与非侵入性超声神经调节相结合。这些包括通过头骨刺激目标大脑区域的能力，在灵长类动物中的概念验证，以及在人类中成功地整合UNMOT、功能磁共振成像和EEG。我们将在第二阶段使用这项技术来比较健康人和患有神经疾病的人的功能脑图。 公共卫生相关性： 脑图工具对于了解大脑以及诊断大脑功能障碍至关重要。与目前的有创刺激方法不同，我们建议使用超声波来精确地刺激大脑的某些部分，而不是非侵入性的。开发的方法将建立诊断医学的新范式，广泛适用于抑郁症、帕金森氏症和癫痫等神经疾病，并提高我们了解大脑综合功能的能力。

DESCRIPTION (provided by applicant): Brain mapping tools are essential for both our understanding the brain as well as diagnosing dysfunction. A method to noninvasively and precisely stimulate any three-dimensional locus within the human brain would be transformative, both clinically and scientifically. If compatible with modern functional brain imaging methods, such an improved stimulation tool could support unprecedented studies exploring human brain function and connectivity. Clinically, it could support novel screening/diagnostic strategies and improved treatments for diseases such as depression, Parkinson's, and epilepsy which are becoming more frequently treated using invasive stimulation methods (for example with deep-brain stimulating electrodes; DBS). Pulsed ultrasound (US) energy can be used to modulate brain circuit activity and has the characteristics required to achieve targeted stimulation with millimeter spatial resolution anywhere in the brain. Our goal is to translate ultrasound neuromodulation to humans and develop technologies to combine ultrasound-induced neuromodulation with current neuroimaging and electrophysiology methods. The methods we propose to develop will establish a new paradigm in diagnostic medicine and be broadly applicable to neurological disorders as well as increase our ability to understand integrative functions of the brain. Specific Aim 1. Development of a hardware and software platform for identifying optimal pulsed UNMOD waveforms. Milestone: Hardware and software platform that integrates US stimulation with electrophysiological and fMRI data acquisition to establish a systematic approach for assaying the optimal ultrasound neuromodulation (UNMOD) stimulus parameter space. Specific Aim 2. Development of focusing and scanning strategies for deep neurostimulation through the skull using ultrasound. Milestone: Neuromodulation strategies using multiple sources of ultrasound that offer an improvement in spatial resolution of activation, decrease undesirable thermal effects, and increase in activation efficiency. Specific Aim3. Testing focal neurostimulation strategies in the primate brain. We will use this model to test approaches developed in Specific Aims 1 and 2. Milestone: Proof of concept in primates and the selection of optimal focusing and scanning strategies to be tested in humans. Specific Aim 4. Simultaneous ultrasound nerve stimulation, fMRI imaging and EEG recordings in humans. Milestone: Successful integration of UNMOD, fMRI imaging and EEG recordings in humans. At the successful conclusion of this Phase I SBIR we will have developed a number of key technology pieces for translating functional brain mapping with noninvasive ultrasound neuromodulation in humans. These include the ability to stimulate targeted brain regions through the skull, a proof of concept in primates, and successful integration of UNMOT, fMRI and EEG in humans. We will be poised in Phase II to use this technique to compare the functional brain maps of healthy individuals with ones suffering from neurological disorders. PUBLIC HEALTH RELEVANCE: Brain mapping tools are essential for understanding the brain as well as diagnosing brain dysfunction. We propose to use ultrasound to precisely stimulate parts of the brain, noninvasively, in contrast to current invasive stimulation methods. The methods developed will establish a new paradigm in diagnostic medicine, be broadly applicable to neurological disorders such as depression, Parkinson's, and epilepsy, and increase our ability to understand integrative functions of the brain.