Neuron selective modulation of brain circuitry in non-human primates

 描述(申请人提供)：目前所有可用的神经刺激方法要么是侵入性的，要么只能适度定位，而能够克服这些限制的神经刺激方法对于脑回路的研究将是非常有价值的。利用磁共振引导的高强度聚焦超声(MRgHIFU)进行神经刺激是一种很有前途的技术，它可以无创地兴奋或抑制大脑中定义明确的离散体积内的神经活动，从而使磁共振成像(MRI)能够研究大脑电路。我们试图在非人类灵长类动物的躯体感觉和视觉系统中探索这种脑刺激方法，目的是量化和扩展MRgHIFU作为理解神经回路的工具的能力。这一建议的意义在于，超声波有可能被用作神经刺激的研究工具，可以解决其他现有方法的缺点。超声波对神经元的作用机制表明，不同的声脉冲可以根据神经元的离子通道类型选择性地激活神经元，从而允许细胞受到不同的刺激。在我们的前期工作中，我们开发了使用核磁共振测量并随后优化声束的方法，并设计了一种针对猕猴皮质刺激进行优化的换能器阵列。我们将把它集成到高场(7T)人体磁体中，并实施新的方法，以受控的方式经颅聚焦猕猴皮质内的一小束超声波。有了这项技术，我们将利用我们在猕猴行为和神经生理学测量方面的背景，在宏观、中观和微观尺度上量化对行为动物的影响。然后，我们将使用血氧水平依赖的功能磁共振成像(BOLD FMRI)来绘制刺激过程中大脑的S1亚区。具体地说，我们将量化声学参数对BOLD功能磁共振的影响，并使用超声波抑制或刺激皮肤触觉诱发反应，同时成像BOLD信号的后续变化。我们还将使用超声波来唤起激活模式，并研究大脑的细、中、长程回路。基于一种新验证的超声波与神经元相互作用的模型，声脉冲将被设计成兴奋或抑制神经元。该模型将声学诱导的细胞膜振荡与Hodgkin-Huxley动作电位产生模型相结合，并可能提供一种基于神经元离子通道的差异性刺激方法，这将是一种非常强大和史无前例的神经刺激技术。我们建议在一个高度相关的动物中进行简单的实验，以测试该模型在局部区域设计超声波刺激(无论是刺激还是抑制)的实用性，并检查这种刺激产生的大胆的fMRI信号。这些目标的完成将扩展MRgHIFU与功能磁共振成像一起研究神经回路的能力，为这一潜在重要的新方法评估大脑功能铺平道路。

 DESCRIPTION (provided by applicant): All presently available neural stimulation methods are either invasive or can only be moderately localized, and a neurostimulation method that could overcome these limitations would be invaluable for brain circuit investigation. Neural stimulation with magnetic resonance guided high intensity focused ultrasound (MRgHIFU) is a promising technology that can noninvasively excite or inhibit neural activity in well-defined discrete volumes of the brain, subsequently enabling investigation of brain circuits with magnetic resonance imaging (MRI). We seek to explore this brain stimulation method in the somatosensory and visual systems of non- human primates with the goal of quantifying and expanding the capabilities of MRgHIFU as a tool for understanding neural circuits. The significance of this proposal results from the potential for ultrasound to be used as an investigative tool for neural stimulation that can address the shortcomings of other available methods. The mechanism of action of ultrasound on neurons suggests that different acoustic pulses can selectively activate neurons based on their ion channel types, allowing for cells to be differentially stimulated. In our preliminary work, we have developed methods for measuring and subsequently optimizing acoustic beams using MRI and designed a transducer array that is optimized for stimulation of the macaque cortex. We will integrate this into a high-field (7T) human magnet and implement novel methods for transcranially focusing a small burst of ultrasound within the macaque cortex in a controlled manner. With this technology in place, we will leverage our background in behavioral and neurophysiological measurements in macaques to quantify effects at the macro-, meso-, and microscale in behaving animals. We will then use blood oxygen level dependent functional MRI (BOLD fMRI) to map the S1 subregions of the brain during stimulation. Specifically, we will quantify the effect of acoustic parameters on BOLD fMRI and use ultrasound to inhibit or excite the skin tactile evoked response, while imaging the subsequent change in the BOLD signal. We will also use ultrasound to evoke activation patterns, and investigate the fine, middle, and long range circuits of the brain. Acoustic pulses will be designed to excite or inhibit neurons based on a newly validated model of the interaction of ultrasound with neurons. This model couples acoustically induced oscillation of cell membranes to the Hodgkin-Huxley model of action potential generation and may provide a method to differentially stimulate neurons based on their ion channels, which would be a very powerful and unprecedented neurostimulation technology. We propose simple experiments in a highly relevant animal that would test the utility of this model to design ultrasonic stimulation (either exciting or inhibiting) in localized regions and examine the BOLD fMRI signals resulting from such stimulation. The completion of these aims will expand the capabilities of MRgHIFU in conjunction with fMRI for investigating neural circuits, paving this way for this potentially important new approach to the assessment of brain function.