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

 描述(由申请人提供)：能够探测电子和化学之间复杂的相互作用的装置(即。(多巴胺)神经信号体现了基底神经节的大脑回路，这将改善皮质下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及其在控制基底节活动中的主要作用，与许多衰弱障碍有关-运动障碍包括帕金森氏病，精神和情绪障碍，如抑郁和焦虑等。目前的治疗方法疗效有限，而开发更好的恢复策略的能力因我们对这些复杂的大脑电路的有限了解而加剧，包括已知支配所有基底节结构及其在大脑中的投射目标的多巴胺信号的作用。此外，靶向的基底节区域位于脑体积的深处，这限制了可以用来原位监测其活动的方法。第一个目标是利用微制造技术来 制造具有多(4)种不同功能的高纵横比电极，以探索基底节的多方面性质--局部和多点记录和调制电和化学活动。这些“注射电极”将能够记录两种神经电信号 来自药物输注或电刺激部位的致密微阵列电极的活性和多巴胺波动。这种多模式探测器将允许以其电气和化学信号域的形式对细胞类型的特定神经活动进行无与伦比的分析(具有卓越的时间和空间分辨率)，这对于了解病因机制和确定治疗大脑疾病的药物靶点至关重要。在注射电极尖端集成的多电极碳阵列上进行的快速扫描循环伏安法允许在刺激或输注部位近端的几个位置以毫秒级的时间尺度化学记录多巴胺的波动。该注射电极还可以通过自适应地干扰基于检测到的电和化学放电模式的异常活动来改进对病理性大脑状态的修复，以用于闭合环路治疗。第二个目标是验证注射电极装置。在非人类灵长类动物中，将监测局部场电位和棘波活动以及多巴胺的波动，以响应局部传递的刺激。这些研究将与与训练的眼跳眼动任务相关的行为研究结合起来。治疗效果将通过长期使用长期植入帕金森氏病啮齿动物模型的闭环式注射系统的行为和生理神经活动以及生理反应来确定。这些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大脑的异常回路，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神经药理药物的现场高通量筛选以用于药物发现。

 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.