Non-invasive, Deep Brain, and Focal Neuromodulation in Nonhuman Primates

非人类灵长类动物的非侵入性深部脑部和局灶神经调节

• 批准号: 10300004
• 负责人: Taylor D Webb
• 金额: $ 7.14万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-04 至 2023-05-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300004
• 关键词: Acoustics; Ambulatory Care; Anatomy; Animal Model; Basal Ganglia; Behavior; Behavioral; Brain; Brain region; Caliber; Cell Nucleus; Choice Behavior; Clinic; Clinical; Contralateral; Decision Making; Devices; Diagnosis; Discrimination; Disease; Dreams; Essential Tremor; Exposure to; FDA approved; Focused Ultrasound; Focused Ultrasound Therapy; Frequencies; Future; Goals; Hemorrhage; Human; Individual; Investigation; Ipsilateral; Laboratories; Lateral Geniculate Body; Lesion; Literature; Location; Macaca; Macaca mulatta; Magnetic Resonance Imaging; Measures; Mechanics; Mediating; Methods; Monitor; Monkeys; Neurosciences; Outpatients; Patients; Pharmaceutical Preparations; Physicians; Pre-Clinical Model; Primates; Procedures; Property; Protocols documentation; Rattus; Research; Research Personnel; Research Training; Role; Safety; Sonication; Specificity; Stimulus; Structure; Surgical incisions; Symptoms; System; Techniques; Technology; Temperature; Thalamic structure; Time; Tissues; Training; Ultrasonic wave; Ultrasonics; Ultrasonography; Universities; Utah; Visual; Visual Perception; Visual system structure; awake; clinical translation; comparative efficacy; cranium; design; experience; experimental study; head-to-head comparison; medication safety; millimeter; nanoparticle; nervous system disorder; neural circuit; neuroregulation; nonhuman primate; pressure; relating to nervous system; sound; training opportunity

The ability to non-invasively perturb specific regions deep in the human brain would enable researchers and clinicians to study the causal relationships between specific brain structures and behavior. Current non-invasive neuromodulatory techniques enable the perturbation of the human cortex but a method that is simultaneously non-invasive, focal, and capable of perturbing deep brain circuits remains elusive. The goal of this project is to develop a non-invasive and focal technique capable of perturbing individual deep brain nuclei in humans. Such a technique has the capacity to revolutionize neuroscience in both the clinic and the laboratory by enabling the systematic study of causal relationships between neural circuits and behavior in regions that are inaccessible with current technologies. Investigating these causal relationships requires the capacity to perturb individual deep brain nuclei while monitoring the resulting impact on a patient's symptoms or behaviors. Transcranial ultrasound can enable this technique by focusing acoustic waves to deep brain structure through the intact skull. The capacity of transcranial ultrasound to target deep brain structures while sparing intervening tissue has been thoroughly demonstrated by high intensity focused ultrasound treatments in which the thermal energy carried by ultrasound is used to ablate a 4-5 mm volume in the thalamus. These treatments are outpatient and require no incision. At much lower intensities, ultrasound has been shown to modulate neural activity without significant increases in temperature. The combination of these properties makes ultrasound an ideal technology for developing non-invasive, deep brain, and focal neuromodulation techniques. Ultrasound can modulate neural activity directly or through the use of nanoparticle carriers designed to release a neuromodulatory drug when exposed to sufficient ultrasound pressure. Clinical translation of ultrasonic neuromodu- lation requires characterizing the relative efficacy and safety of these techniques. Such a comparison would enable researchers to select ultrasound protocols that meet the constraints of a given trial or treatment. The goal of this project is to provide a systematic characterization of the efficacy and safety of both ultrasonic neuromodulation approaches in the most relevant pre-clinical model, nonhuman primates, while targeting a deep brain structure, the lateral genic- ulate nucleus (LGN). The investigation will measure how each ultrasound stimulus changes a macaque's behavior during a commonly used visual discrimination task. The task provides a single signed, quantitative metric of the neu- romodulatory effects. When no stimulus is applied, the task serves as a sensitive indicator of safety, a metric which is supplemented with MR imaging. The training goal of the project is to facilitate the applicant's transition to independent research that leverages ultrasound to better understand and treat neurological disorders. The proposal provides the applicant with training in systems neuroscience and the design and execution of ultrasonic neuromodulation experiments in awake, behaving subjects. This combination will enable the investigator to design and execute future ultrasonic neuromodulation experiments exploring the role of deep brain structures in human behavior and disease.

非侵入性干扰人脑深处特定区域的能力将使研究人员和临床医生能够 研究特定大脑结构和行为之间的因果关系。目前非侵入性神经调节 这些技术能够扰动人类皮层，但同时是非侵入性的、局部的， 能够扰乱大脑深层回路的东西仍然是个谜该项目的目标是开发一种非侵入性的， 一种能够扰乱人类大脑深部单个核团的聚焦技术。这种技术能够 通过对因果关系的系统研究，在临床和实验室中彻底改变神经科学 神经回路和行为之间的联系是目前技术无法触及的。 调查这些因果关系需要有能力扰乱个别的脑深部核团，同时监测大脑中的神经元。 对患者的症状或行为产生影响。经颅超声可以通过聚焦 声波通过完整的头骨传递到大脑深处经颅超声靶向深部的能力 高强度聚焦超声已经彻底证实了大脑结构，同时保留了介入组织 其中由超声携带的热能用于消融丘脑中的4-5 mm体积的治疗。这些 治疗是门诊的，不需要切开。在低得多的强度下，超声波已经被证明可以调节 神经活动没有明显的温度升高。这些特性的结合使超声波成为一种 开发非侵入性、脑深部和局灶性神经调节技术的理想技术。 超声波可以直接调节神经活动，也可以通过使用纳米颗粒载体来调节神经活动， 当暴露于足够的超声压力时，神经调节药物。超声神经模块的临床翻译- 因此，需要确定这些技术的相对有效性和安全性。这样的比较将使 研究人员可以选择满足给定试验或治疗限制的超声方案。这个项目的目标 旨在提供两种超声神经调节方法的有效性和安全性的系统表征 在最相关的临床前模型中，非人灵长类动物，虽然靶向深部脑结构，但横向基因- 髓核（LGN）。这项研究将测量每一次超声波刺激如何改变猕猴的行为 在一个常用的视觉辨别任务中。该任务提供了一个单一的有符号的，定量的指标， 调节作用当不施加刺激时，任务作为安全性的敏感指标， 并辅以磁共振成像。 该项目的培训目标是促进申请人过渡到利用超声的独立研究 来更好地理解和治疗神经系统疾病。该提案为申请人提供系统培训 神经科学以及在清醒的行为主体中设计和执行超声波神经调节实验。 这种组合将使研究人员能够设计和执行未来的超声神经调节实验 探索大脑深层结构在人类行为和疾病中的作用。