Neuron selective modulation of brain circuitry in non-human primates

非人类灵长类动物脑回路的神经元选择性调节

• 批准号: 9148240
• 负责人: Charles F Caskey
• 金额: $ 45.63万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9148240
• 关键词: Acoustics; Action Potentials; Address; Animal Model; Animals; Architecture; Area; Behavioral; Biological Neural Networks; Brain; Brain Mapping; Cell membrane; Cells; Charge; Coupled; Couples; Development; Devices; Electric Capacitance; Electroconvulsive Therapy; Electrodes; Electroencephalography; Electrophysiology (science); Event; Focused Ultrasound Therapy; Foundations; Functional Magnetic Resonance Imaging; Generations; Goals; Hodgkin-Huxley model; Human; Image; Investigation; Ion Channel; Macaca; Magnetic Resonance; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mechanics; Membrane; Metabolic; Methods; Modeling; Monoclonal Antibody R24; Neurons; Pattern; Performance; Physiologic pulse; Procedures; Property; Resolution; Safety; Scheme; Signal Transduction; Skin; Spottings; Stimulus; System; Tactile; Technology; Testing; Thalamic structure; Transcranial magnetic stimulation; Transducers; Translating; Translations; Ultrasonic Transducer; Ultrasonics; Ultrasonography; Visual; Visual Cortex; Visual system structure; Work; base; behavior measurement; behavioral response; blood oxygen level dependent; brain circuitry; brain volume; design; image guided; imaging system; improved; mathematical model; model design; neural circuit; neural stimulation; neuroimaging; neurophysiology; neuroregulation; next generation; nonhuman primate; novel; novel strategies; optogenetics; public health relevance; relating to nervous system; research study; response; somatosensory; tool

 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.

 描述（由申请人提供）： 所有目前可用的神经刺激方法要么是侵入性的，要么只能适度局部化，并且可以克服这些限制的神经刺激方法对于脑回路研究将是无价的。利用磁共振引导的高强度聚焦超声（MRgHIFU）的神经刺激是一种有前途的技术，其可以无创地激发或抑制脑的明确定义的离散体积中的神经活动，随后使得能够利用磁共振成像（MRI）研究脑回路。我们寻求在非人灵长类动物的体感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。这一建议的重要性来自于超声作为神经刺激的研究工具的潜力，可以解决其他可用方法的缺点。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，从而使细胞受到不同的刺激。在我们的初步工作中，我们已经开发出测量和随后优化使用MRI声束的方法，并设计了一个换能器阵列，优化猕猴皮层的刺激。我们将把它集成到一个高场（7T）的人类磁铁，并实施新的方法，以可控的方式在猕猴皮层内经颅聚焦一个小的超声波脉冲。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来量化行为动物在宏观、中观和微观尺度上的影响。然后，我们将使用血氧水平依赖功能性MRI（BOLD fMRI）来映射刺激期间大脑的S1子区域。具体来说，我们将量化声学参数对BOLD功能磁共振成像的影响，并使用超声波来抑制或激发皮肤触觉诱发反应，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，并研究大脑的精细，中期和长期回路。声脉冲将被设计为基于超声波与神经元相互作用的新验证模型来激励或抑制神经元。该模型将声学诱导的细胞膜振荡耦合到动作电位产生的Hodgkin-Huxley模型，并且可以提供基于其离子通道差异刺激神经元的方法，这将是一种非常强大且前所未有的神经刺激技术。我们提出了一个简单的实验，在高度相关的动物，将测试该模型的效用，设计超声波刺激（无论是兴奋或抑制）在局部区域，并检查BOLD功能磁共振成像信号从这样的刺激。这些目标的完成将扩大MRgHIFU与fMRI结合研究神经回路的能力，为这种潜在的重要的新方法评估大脑功能铺平道路。