Computational Models of Deep Brain Stimulation of the Cerebellothalamic and Subthalamopallidal Pathways

项目总结/摘要 帕金森氏病是第二常见的神经退行性疾病，在美国每年估计有59，000例新发病例，随着人口老龄化，预计将对社会造成重大的经济和社会负担。脑深部电刺激是FDA批准的PD治疗方法，但尽管生活质量显著改善，DBS治疗往往不一致，并可能导致认知和运动副作用。这可能是由于缺乏对介导DBS治疗效果的潜在机制和结构途径的理解。该项目旨在确定负责改善STN DBS震颤的途径。从长远来看，这项研究将完善DBS靶向，并提高我们对PD病理学的整体理解。 第一个目标是开发三维的、患者特定的解剖和纤维束成像模型。将对10名患者和2条纤维通路进行建模。将使用磁共振图像（MRI）来定义相关结构的几何形状和相关纤维通路（即小脑丘脑和丘脑下苍白球通路）的轨迹，并将使用计算机断层扫描来确定DBS电极的位置。这将产生10个患者特定的计算解剖模型，包括用于DBS建模的纤维束成像。 第二个目的是确定优先激活每个特定通路的刺激参数。 轴突将使用电缆理论建模，其轨迹将由概率纤维束成像确定。将使用多变量统计分析来分析响应于刺激的轴突激活。 数值优化算法将用于确定优先激活一种通路（即小脑丘脑或丘脑下丘脑通路）的特定刺激范例。该目标的结果将是一组患者特异性刺激参数，其理论上将优先激活特定的纤维通路。 第三个目的是评估这些选择性刺激范例对震颤的临床结果，以确定每种通路激活的效果。将进行定量运动评估，以评估优先激活结局。我们假设，特定纤维通路的优先激活将导致不同的临床结果，包括治疗益处的变化。此外，我们假设，小脑丘脑通路的调制是必要的和足够的震颤控制。这一目标的完成将导致更好地理解与小脑丘脑和丘脑下丘脑途径的优先激活相关的结果。 这项研究的成功完成将促进我们对特定纤维通路的激活如何在PD患者中产生治疗效果的理解。

Project Summary/Abstract Parkinson’s disease is the second most common neurodegenerative disorder, with an estimated 59,000 new cases per year in the US, and as populations age it is expected to impose significant financial and social burden on society. Deep brain stimulation is an FDA approved treatment for PD, but despite a marked improvement in quality of life, DBS therapy is often inconsistent and can result in both cognitive and motor side effects. This may be due to a lack of understanding of the underlying mechanisms and structural pathways that mediate the therapeutic effects of DBS. This project seeks to identify the pathways responsible for the tremor improvements in STN DBS. In the long term, this research will refine DBS targeting and improve our overall understanding of the PD pathology. The first aim is to develop three-dimensional, patient-specific anatomical and tractography models. Ten patients and two fiber pathways will be modeled. Magnetic resonance images (MRI) will be used to define the geometry of relevant structures and the trajectory of relevant fiber pathways (i.e. cerebellothalamic and subthalamopallidal pathways), and computed tomography scans will be used to determine the location of the DBS electrode. This will result in ten patient-specific computational anatomical models including fiber tractography for use in DBS modeling. The second aim is to identify stimulation parameters that preferentially activate each specific pathway. Axons will be modeled using cable theory and their trajectories will be determined by probabilistic tractography. Multivariate statistical analyses will be used to analyze axon activation in response to stimulation. A numerical optimization algorithm will be used to determine specific stimulation paradigms that preferentially activate one pathway (i.e. the cerebellothalamic or subthalamopallidal pathway). The outcome of this aim will be a set of patient-specific stimulation parameters that will theoretically preferentially activate a specific fiber pathway. The third aim is to evaluate the clinical outcomes of these selective stimulation paradigms with regard to tremor to determine the effects of activation of each pathway. Quantitative motor assessments will be performed to assess preferential activation outcomes. We hypothesize that preferential activation of specific fiber pathways will result in different clinical outcomes, including variation in therapeutic benefit. Further, we hypothesize that modulation of the cerebellothalamic pathway is necessary and sufficient for tremor control. The completion of this aim will result in an improved understanding of the outcomes associated with preferential activation of the cerebellothalamic and subthalamopallidal pathways. Successful completion of this research will advance our understanding of how activation of specific fiber pathways can produce a therapeutic effect in PD patients.