WINCS and DBS

描述（由申请人提供）：基底神经节复合体内深部脑刺激（DBS）是治疗帕金森病（PD）运动症状的有效神经外科方法。阐明DBS改善PD和其他靶向疾病预后的机制已成为立体定向和功能神经外科的关键临床目标。为了解决这一问题，我们首次结合了两种强大的技术，特别是功能性磁共振成像（fMRI）和体内神经化学监测来研究dbs介导的基底神经节网络电路的激活。为此，我们开发了一种核磁共振兼容的无线监测设备，用于在大型哺乳动物模型（恒河猴）中植入微传感器，以获得化学分辨的神经递质测量。该设备支持一系列电化学测量，包括快速扫描循环伏安法（FSCV），用于实时监测碳纤维微电极上多巴胺和腺苷释放，以及固定电位安培法，用于监测酶联生物传感器上的谷氨酸。我们的恒河猴模型利用电生理靶向STN植入适当缩小的人类DBS电极，将使我们能够利用功能磁共振成像（fMRI）初步确定在应用临床定义的“治疗性”（tDBS）和“非治疗性”（nDBS） STN刺激时基底节区的主要激活位点。然后，我们将电化学监测STN DBS在fMRI激活识别的大脑区域中引起的谷氨酸、多巴胺和腺苷释放的细胞外水平。最后，我们建议将恒河猴的fMRI和FSCV记录结合起来，通过确定模拟晚期PD的多巴胺消耗和补充以及疾病的药物治疗以及腺苷消耗的后果，来确认谷氨酸、多巴胺和/或腺苷释放与fMRI识别的基底神经节复合体解剖部位之间的因果关系。三个特定目的是：(1)利用fMRI识别STN DBS激活的基底神经节内脑区；(2)量化STN DBS在fMRI识别的脑区中诱发的谷氨酸、多巴胺和腺苷释放；(3)在多巴胺药物消耗和恢复之前、期间和之后，通过fMRI同时关联STN DBS在fMRI识别的区域中诱发的谷氨酸、多巴胺和腺苷释放，以及腺苷减少。我们相信fMRI和电化学的同时结合提供了一种新的和令人兴奋的方法，为STN DBS的治疗作用提供了互补的解剖制图和神经化学监测。

DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) within the basal ganglia complex is an effective neurosurgical approach for treating motoric symptoms of Parkinson's disease (PD). Elucidating DBS mechanisms for improving outcomes in PD and other targeted disorders has become a critical clinical goal in stereotactic and functional neurosurgery. We propose to address this issue by combining for the first time two powerful technologies, notably functional Magnetic Resonance Imaging (fMRI) and in vivo neurochemical monitoring to investigate DBS-mediated activation of basal ganglia network circuitry. For this purpose, we have developed an MRI-compatible wireless monitoring device to obtain chemically resolved neurotransmitter measurements at implanted microsensors in a large mammalian model (rhesus monkey). This device supports an array of electrochemical measurements that includes fast-scan cyclic voltammetry (FSCV) for real-time simultaneous in vivo monitoring of dopamine and adenosine release at carbon-fiber microelectrodes as well as fixed potential amperometry for monitoring of glutamate at enzyme-linked biosensors. Using electrophysiological targeting of the STN to implant appropriately scaled-down human DBS electrodes, our rhesus monkey model will enable us to employ fMRI to initially determine the major sites of activation in the basal ganglia during application of clinically-defined "therapeutic" (tDBS) versus "non-therapeutic" (nDBS) STN stimulation. We will then electrochemically monitor extracellular levels of glutamate, dopamine and adenosine release evoked by STN DBS in the brain areas identified by fMRI activation. Lastly, we propose to combine fMRI and FSCV recordings in the rhesus monkey to confirm a causal relationship between glutamate, dopamine and/or adenosine release and the fMRI-identified anatomical sites in the basal ganglia complex by determining the consequences of dopamine depletion and repletion mimicking advanced PD and pharmacological treatment of the disease, as well as adenosine depletion. The three Specific Aims are (1) identify using fMRI brain regions within the basal ganglia complex activated by STN DBS, (2) quantify glutamate, dopamine and adenosine release evoked by STN DBS of the brain region(s) identified by fMRI, and (3) correlate STN DBS-evoked glutamate, dopamine and adenosine release in the regions identified by fMRI with simultaneous fMRI before, during, and after pharmacological depletion and restoration of dopamine, and reductions in adenosine. We believe that the simultaneous combination of fMRI and electrochemistry offer a new and exciting approach that provides complementary anatomical mapping and neurochemical monitoring implicated in the therapeutic actions of STN DBS.