WINCS and DBS

描述(申请人提供)：基底节复合体内的脑深部刺激(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改善帕金森病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。我们建议通过首次结合两项强大的技术来解决这个问题，特别是功能磁共振成像(FMRI)和体内神经化学监测，以研究DBS介导的基底节网络回路的激活。为此，我们开发了一种与MRI兼容的无线监测设备，以获得在大型哺乳动物模型(恒河猴)中植入的微型传感器上的化学分辨神经递质测量。该设备支持一系列电化学测量，包括用于实时同时监测碳纤维微电极上的多巴胺和腺苷释放的快速扫描循环伏安法(FSCV)，以及用于监测酶连接生物传感器上的谷氨酸的固定电位安培法。使用STN的电生理靶向植入适当缩小的人类DBS电极，我们的恒河猴模型将使我们能够使用fMRI初步确定临床定义的“治疗性”(TDBS)与“非治疗性”(NDBS)STN刺激期间基底节的主要激活部位。然后，我们将电化学监测STN DBS在通过fMRI激活识别的大脑区域中诱发的细胞外谷氨酸、多巴胺和腺苷释放水平。最后，我们建议结合恒河猴的fMRI和FSCV记录，通过确定多巴胺耗竭和重复的后果来确定谷氨酸、多巴胺和/或腺苷的释放与基底神经节复合体中fMRI确定的解剖位置之间的因果关系，以模拟晚期PD和疾病的药物治疗，以及腺苷耗竭。这三个具体目标是：(1)利用功能磁共振确定STN DBS激活的基底节复合体内的脑区域；(2)定量由功能磁共振确定的STN DBS(S)脑区域引起的谷氨酸、多巴胺和腺苷的释放；以及(3)在药物耗竭和多巴胺恢复以及腺苷减少之前、期间和之后，将由STN DBS引起的谷氨酸、多巴胺和腺苷的释放与同时的fMRI相关联。我们相信，fMRI和电化学的同时结合提供了一种新的令人兴奋的方法，提供了与STN DBS的治疗行为有关的补充解剖标测和神经化学监测。

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.