WINCS and DBS

描述（由申请人提供）：基底神经节复合体内的脑深部电刺激（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机制以改善PD和其他靶向疾病的结局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种强大的技术来解决这个问题，特别是功能性磁共振成像（fMRI）和体内神经化学监测，以研究DBS介导的基底神经节网络电路的激活。 为此，我们开发了一种兼容MRI的无线监测设备，以在大型哺乳动物模型（恒河猴）中植入的微传感器上获得化学分辨的神经递质测量值。 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），用于在碳纤维微电极上实时同时体内监测多巴胺和腺苷的释放，以及用于在酶联生物传感器上监测谷氨酸的固定电位安培法。 使用电生理靶向的小脑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采用功能磁共振成像，以初步确定在应用临床定义的“治疗”（tDBS）与“非治疗”（nDBS）小脑刺激期间，基底神经节中的主要激活部位。 然后，我们将电化学监测谷氨酸，多巴胺和腺苷释放的细胞外水平引起的脑功能磁共振成像激活的脑区的DBS。 最后，我们建议结合联合收割机和FSCV记录在恒河猴，以确认谷氨酸，多巴胺和/或腺苷释放和fMRI确定的解剖部位在基底神经节复合体通过确定的后果多巴胺耗尽和充满模仿先进的PD和药物治疗的疾病，以及腺苷耗尽之间的因果关系。 这三个特定目的是（1）使用fMRI识别由DBS激活的基底神经节复合体内的脑区域，（2）量化由DBS诱发的fMRI识别的脑区域的谷氨酸、多巴胺和腺苷释放，以及（3）将DBS诱发的谷氨酸、多巴胺和腺苷释放与fMRI识别的区域中的同时fMRI之前、期间、以及在药理学消耗和多巴胺恢复以及腺苷减少之后。 我们认为，同时结合功能磁共振成像和电化学提供了一个新的和令人兴奋的方法，提供互补的解剖映射和神经化学监测牵连的治疗作用的DBS。

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.