Simulations of spinal cord recruitment to optimize bioelectronic interventions for lower urinary tract control

模拟脊髓募集以优化下尿路控制的生物电子干预措施

• 批准号: 10207979
• 负责人: Robert A Gaunt
• 金额: $ 88.78万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207979
• 关键词: 3-Dimensional; Afferent Neurons; Anatomic Models; Anatomy; Area; Axon; Behavior; Behavioral; Bladder; Catheterization; Communities; Complex; Computer Models; Coupled; Data; Data Set; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Electrophysiology (science); Elements; Felis catus; Fiber; Frequencies; Functional disorder; Goals; Image; Implant; Injury; Intervention; Lower urinary tract; Magnetic Resonance Imaging; Measures; Medicine; Methods; Modeling; Neurostimulation procedures of spinal cord tissue; Organ; Pathway interactions; Pelvis; Pharmacologic Substance; Play; Population; Property; Reflex action; Resolution; Role; Sacral spinal cord structure; Spinal; Spinal Cord; Structural Models; Structure; Techniques; Time; Tissue Model; United States; Urination; base; biophysical model; dorsal column; economic impact; improved; models and simulation; neural recruitment; neuroregulation; novel therapeutics; open source; pressure; recruit; sciatic nerve; sensory input; side effect; simulation; spinal reflex; tool; ultra high resolution

Lower urinary tract (LUT) dysfunction occurs in 20-40% of the global population and has an economic impact measured in tens of billions of dollars every year in the United States. This field desperately needs new therapies as current treatments, such as clean intermittent catheterization and pharmaceuticals, have significant side effects. Epidural spinal cord stimulation (SCS) provides a potential solution. SCS is a rapidly growing area of bioelectronic medicine, with tens of thousands of implants occurring each year in the United States. While SCS normally activates the dorsal columns, this technique can also be used to recruit primary sensory neurons as they enter the spinal cord through the dorsal rootlets. These sensory inputs play a crucial role in regulating bladder function6 and activating these primary sensory neurons can have powerful effects on bladder behavior. Through ongoing SPARC efforts, our team has established that high-resolution SCS can selectively recruit sacral afferents leading to both micturition and continence reflexes. These data support our ultimate translational goal to develop a SGS therapy to improve bladder function after injury and disease. However, a critical gap remains to understand, develop and optimize these neuromodulation therapies. There are no models that accurately represent the complex sacral spinal anatomy, and previous modelling efforts have consistently ignored the dorsal rootlets. In this project, we will develop functionalized, anatomically accurate models of the cat sacral spinal cord. including the dorsal rootlets, and validate these models using electrophysioloqical data acquired under an existing SPARC effort. Task 1: Create a pipeline for anatomically accurate, ultra-high resolution finite element models of the cat sacral spinal cord Accurate anatomy is critical for biophysical models of stimulation-evoked neural recruitment. However, these structures have been underappreciated in modelling efforts, in part due to their anatomical complexity. We will use diffusion tensor imaging (DTI) and structural magnetic resonance imaging to acquire detailed anatomy of the sacral spinal cord in the cat, including dorsal and ventral rootlet fiber pathways and develop a pipeline within o2S2PARC segment these images and create finite element method (FEM) models of these tissues. Year 1: Imaging dataset of sacral spinal cord in one cat and preliminary pipeline. Year 2: Imaging datasets for four spinal cords to validate anatomical model creation pipeline. Task 2: Create finite element models, functionalized with computational axon models, and validate recruitment using existing electrophysiological data We will use Sim4Life and the o2S2PARC platform to mesh and populate simplified and anatomically accurate spinal cord models with populations of pelvic, pudenda! and sciatic nerve axons that project into the cord. DTI data will be used to create realistic 3D axon trajectories and the model will be validated using existing data (OT2OD024908). Year 1: Functionalized model of simplistic spinal cord and simulated effects of epidural stimulation. Year 2: Functionalized model of anatomically accurate sacral spinal cord with validated recruitment properties. Task 3: Model spinal reflexes that simulate frequency-dependent excitatory and inhibitory bladder activity SCS at different frequencies on the same contact can evoke opposing effects on bladder pressure through spinal reflexes. To model this effect we will extend SCS recruitment models to include, for the first time, computational models of spinal reflexes that reproduce observed behavioral effects. This will create functionalized finite element models that can predict the effects of stimulation frequency on a target organ. Year 1: Reflex model structure defined and coupled to finite element stimulations. Year 2: Completed functional simulations of bladder behavior, driven by SCS, that reproduce frequency-dependent effects. This project will create credible (https://bit.ly/2NFeYLj) open-source and community extensible tools, models and simulations to improve SGS-based neuromodulation therapies to enhance treatments for people living with lower urinary tract dysfunction.

较低的尿路（LUT）功能障碍发生在20-40％的全球人口中，并且具有 在美国，经济影响每年以数百亿美元的速度衡量。这个领域 迫切需要新疗法作为当前治疗，例如干净的间歇性导管插入术 和药物具有显着的副作用。硬膜外脊髓刺激（SCS） 提供了潜在的解决方案。 SCS是生物电子医学的快速生长的领域，有数十个 每年在美国发生的数千个植入物。而SC通常激活 背侧柱，该技术也可用于募集主要感觉神经元 通过背侧根进入脊髓。这些感官输入在 调节膀胱功能6并激活这些主要感觉神经元可以具有强大的 对膀胱行为的影响。通过正在进行的SPARC努力，我们的团队确定了高分辨率 SC可以有选择地募集s骨传入，导致排尿和延续 反射。这些数据支持我们开发SGS治疗以改善的最终转化目标 受伤和疾病后的膀胱功能。但是，还有一个关键的差距仍然要理解，发展 并优化这些神经调节疗法。没有准确代表的模型 复杂的骨脊柱解剖结构以及以前的建模工作一直忽略 背根。在这个项目中，我们将开发功能化的，解剖学精确的模型 猫骨脊髓。包括背部根，并使用 在现有的SPARC工作中获取的电潜可数据。 任务1：为解剖上准确的超高分辨率有限元创建管道 猫脊髓的模型 准确的解剖学对于刺激诱发神经募集的生物物理模型至关重要。 但是，这些结构在建模方面被低估了，部分原因是它们 解剖复杂性。我们将使用扩散张量成像（DTI）和结构磁 共振成像以获取猫中s骨脊髓的详细解剖学，包括 背侧和腹侧根纤维途径并在O2S2PARC段中开发管道 图像并创建这些组织的有限元方法（FEM）模型。 1年：成像数据集 一只猫和初步管道中的骨脊髓。第二年：四个脊柱的成像数据集 启用解剖模型创建管道的绳索。 任务2：创建有限元模型，使用计算轴突模型功能化，并且 使用现有电生理数据验证招聘 我们将使用SIM4LIFE和O2S2PARC平台进行网格和填充简化和填充 具有骨盆，Pudenda种群的解剖学精确脊髓模型！和坐骨神经 将轴突投射到电线中。 DTI数据将用于创建现实的3D轴突轨迹和 该模型将使用现有数据（OT2OD024908）进行验证。 1年：功能化模型 硬膜外刺激的简单脊髓和模拟作用。第二年：功能化模型 具有验证特性的解剖学精确的脊髓。 任务3：模型脊柱反射，模拟频率依赖性兴奋性和抑制作用 膀胱活动 在同一接触时以不同频率的SC会引起对膀胱压力的相反影响 通过脊柱反射。为了建模这种效果，我们将扩展SCS招聘模型以包括， 首次，脊柱反射的计算模型会重现观察到的行为 效果。这将创建功能化的有限元模型，以预测 目标器官上的刺激频率。 1年：反射模型结构定义并耦合到 有限元刺激。第二年：完成膀胱行为的功能模拟，驱动 通过SCS，这种再现依赖频率的效应。 该项目将创建可信（https://bit.ly/2nfeylj）开放源和社区可扩展 工具，模型和模拟以改善基于SGS的神经调节疗法以增强 尿路功能障碍的患者的治疗。