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

非侵入性地干扰人类大脑深处的特定fic区的能力将使研究人员和临床医生 目的：研究特定fic脑结构与行为之间的因果关系。现代无创神经调节 技术使人类大脑皮层能够受到干扰，但这种方法同时具有非侵入性、局部性和 能够扰乱大脑深层回路的能力仍然难以捉摸。该项目的目标是开发一种非侵入性和 能够干扰人类大脑深部个体核团的聚焦技术。这样的技术有能力 通过对因果关系的系统研究，使临床和实验室的神经科学发生革命性的变化 神经回路和区域行为之间的关系，而这些区域是当前技术无法访问的。 研究这些因果关系需要有能力扰乱个人大脑深部核团，同时监测 对病人的症状或行为产生的影响。经颅超声可以通过聚焦来实现这项技术 声波通过完整的头骨传到脑深部结构。经颅超声对深部靶向能力的研究 高强度聚焦超声已彻底显示了大脑结构，同时保留了介入组织。 利用超声波携带的热能消融丘脑4-5毫米体积的治疗方法。这些 治疗是门诊的，不需要切开。在低得多的强度下，超声波已被证明可以调节 无明显fi的神经活动不能在温度下增加。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。 超声波可以直接或通过使用纳米颗粒载体来调节神经活动，纳米颗粒载体旨在释放 神经调节药物暴露在足够的fi超声压力下。超声神经调节器的临床翻译-- fi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 研究人员选择符合给定试验或治疗限制的超声方案。这个项目的目标是 是对两种超声神经调节方法的effi准确性和安全性进行系统的描述。 在最相关的临床前模型中，非人类灵长类动物，虽然目标是大脑深层结构，但侧向基因- 腹侧核(LGN)。这项研究将测量每个超声波刺激如何改变猕猴的行为 在一项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、量化的中枢神经- 调节效应。当没有施加刺激时，任务作为安全的敏感指标，这是一个衡量标准 辅以磁共振成像。 该项目的培训目标是促进申请者过渡到利用超声波的独立研究 以更好地了解和治疗神经系统疾病。该方案为申请者提供系统方面的培训 神经科学和在清醒、行为受试者中设计和执行超声神经调节实验。 这种结合将使研究人员能够设计和执行未来的超声波神经调节实验 探索大脑深层结构在人类行为和疾病中的作用。

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.