Therapeutic devices for probing electrical and chemical activity in deep brain disorders

 描述（由申请人提供）：能够探测电气和化学（即，包含基底神经节脑回路的多巴胺）神经信号将改善基于皮质下的疾病的治疗方法和阐明其病理生理机制的能力。神经活性化学物质多巴胺，沿着其在控制基底神经节操作中的主要作用，与许多使人衰弱的疾病有关-运动障碍，包括帕金森病，精神和情绪障碍，如抑郁和焦虑，目前的治疗效果有限，而开发更好的恢复策略的能力由于我们对这些复杂的大脑回路的有限理解而加剧，包括已知多巴胺信号传导支配所有基底神经节结构，沿着它们的投射靶点穿过大脑。此外，靶向基底神经节区域位于脑体积深处，这限制了可以用于原位监测其活性的方法。第一个目标是采用微细加工技术， 制造具有多个（4）不同功能的高纵横比电极，以探测基底神经节的多面性质-电和化学活性的局部和多部位记录和调制。这些“注射电极”将能够记录电神经 活动和多巴胺的波动从一个密集的微阵列的电极网站在该网站的药物输注或电刺激。这种多模式探针将允许无与伦比的分析（具有上级时间和空间分辨率）的细胞类型的特定的神经活动的形式，其电气和化学信号传导域的理解病因机制和确定药物的大脑疾病的目标。快速扫描循环伏安法在多电极碳阵列集成在注射器尖端允许化学记录的多巴胺波动在毫秒的时间尺度在几个网站接近刺激或输液的网站。注射极还可以通过基于用于闭环治疗的检测到的电和化学放电模式自适应地干扰异常活动来提供对病理性脑状态的改善的补救。第二个目的是验证注射电极装置。在非人灵长类动物中，将监测局部场电位和尖峰活动沿着多巴胺波动，以响应局部递送的刺激。这些研究将结合与训练扫视眼球运动任务相关的行为研究。通过测量长期植入帕金森氏病啮齿动物模型中的闭环注射电极系统的长期使用期间的行为和生理神经活动沿着生理反应来确定治疗功效。拟议的研究将产生先进的工具，从多个功能领域探测大脑，并以局部和有效的方式改善异常的大脑回路，并可能揭示对基底神经节功能至关重要的重要神经化学机制。此外，所产生的装置可应用于原位高通量筛选神经药理学试剂用于药物发现。

 DESCRIPTION (provided by applicant): Devices capable of probing the elaborate interactions between electrical and chemical (ie. dopamine) neural signals that embody the basal ganglia brain circuits will improve treatment approach of subcortically based disorders and ability to elucidate their pathophysiological mechanisms. The neuroactive chemical, dopamine, along with its major role in controlling basal ganglia operations, are implicated in many debilitating disorders- movement disorders including Parkinson's disease, psychiatric and mood disorders such as depression and anxiety, etc. Current treatment have limited efficacy while the ability to develop better restorative strategies is aggravated by our limited understanding of these complex brain circuits including the role of dopamine signaling known to innervate all basal ganglia structures along with their projection targets across the brain. Furthermore, the targeted basal ganglia areas are situated deep in the brain volume, which limits the methods that can be employed to monitor its activity in situ. The first aim is to employ microfabrication techniques to manufacture high aspect ratio electrodes with multiple (4) different functions to probe the multifaceted nature of the basal ganglia-local and multi-site recording and modulation of electrical and chemical activity. These "injectrodes" will be able to record both electrical neural activity and dopamine fluctuations from a dense micro- array of electrode sites at the site of drug infusion or electrical stimulation. This multimodal probe will allow unparalleled analysis (with superior temporal and spatial resolution) of cell-type specific neural activity in the form o their electrical and chemical signaling domains-essential to understand etiological mechanisms and identify drug targets for brain disorders. Fast scan cyclic voltammetry performed at multi-electrode carbon arrays integrated at the injectrode tip allows for chemical recording of dopamine fluctuations at millisecond timescales at several sites proximal to the site of stimulation or infusion. The injectrode may also afford improved remediation of pathological brain states by adaptively disturbing the aberrant activity based on detected electrical and chemical discharge patterns for closed-loop treatment. The second aim is to validate the injectrode device. Local field potentials and spike activity along with dopamine fluctuations will be monitored in response to locally delivered stimuli in nonhuman primates. These studies will be combined with behavioral studies related to trained saccadic eye movement tasks. Therapeutic efficacy will be determined by measuring both behavioral and physiological neural activity along with physiological response during the long term use of the closed-loop injectrode systems as chronically implanted in rodent models of Parkinson's disease. The proposed studies will generate advanced tools to probe the brain from multiple functional domains and ameliorate aberrant brain circuits in a localized and efficacious manner and may reveal important neurochemical mechanisms critical to basal ganglia functionality. Furthermore, the generated devices may be applied towards in situ high throughput screening of neuropharmacological agents for drug discovery.