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.

下尿路（LUT）功能障碍发生在20-40%的全球人口中， 在美国，每年数百亿美元的经济影响。这一领域 迫切需要新的治疗方法，如清洁间歇性导管插入术 和药物都有很大的副作用。硬膜外脊髓电刺激（SCS） 提供了一个潜在的解决方案。SCS是一个快速发展的生物电子医学领域， 每年在美国发生的数千例植入手术。当SCS正常激活时 背柱，这项技术也可以用来招募初级感觉神经元，因为它们 通过背根进入脊髓。这些感官输入在以下方面起着至关重要的作用： 调节膀胱功能6并激活这些初级感觉神经元， 对膀胱行为的影响通过持续的SPARC努力，我们的团队已经建立了高分辨率 SCS可以选择性地募集骶神经传入，导致排尿和排尿 反射这些数据支持我们的最终转化目标，即开发SGS疗法， 损伤和疾病后的膀胱功能。然而，一个关键的差距仍然是理解，发展， 并优化这些神经调节疗法。没有模型能准确地代表 复杂的骶骨脊柱解剖结构，以前的建模工作一直忽略了 背根在这个项目中，我们将开发功能化的，解剖学上准确的模型， 猫骶髓包括背根，并验证这些模型使用 电生理学数据在现有的电生理学努力下获得。 任务1：为解剖学上精确的超高分辨率有限元创建管道 猫骶髓模型 准确的解剖结构是刺激诱发神经募集的生物物理模型的关键。 然而，在建模工作中，这些结构一直被低估，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（MRI）。 共振成像，以获得猫骶脊髓的详细解剖结构，包括 背侧和腹侧小根纤维通路，并在o2 S2 PARC段内形成管道， 图像并创建这些组织的有限元方法（FEM）模型。第1年：成像数据集 一只猫的骶髓和初步管道。第2年：四个脊柱的成像数据集 用于验证解剖模型创建管道的软线。 任务2：创建有限元模型，用计算轴突模型功能化， 使用现有电生理数据验证招募 我们将使用Sim 4Life和o2 S2 PARC平台来网格化和填充简化的 解剖学上精确的脊髓模型，包括骨盆和阴部！和坐骨神经 轴突伸入脊髓DTI数据将用于创建逼真的3D轴突轨迹， 将使用现有数据（OT 2 OD 024908）对模型进行验证。第一年：功能化模型 简单的脊髓和硬膜外刺激的模拟效果。第二年：功能化模型 解剖学上准确的骶骨脊髓，具有经验证的募集特性。 任务3：模拟频率依赖性兴奋和抑制的脊髓反射模型 膀胱活动 在相同接触上以不同频率的SCS可以引起对膀胱压力的相反影响 通过脊髓反射。为了模拟这种效应，我们将扩展SCS招募模型， 这是第一次，脊髓反射的计算模型再现了观察到的行为 方面的影响.这将创建功能化有限元模型，可以预测 目标器官上的刺激频率。第1年：定义Reflex模型结构并与之耦合 有限元仿真第2年：完成膀胱行为的功能模拟， 通过SCS，再现频率依赖效应。 该项目将创建可信的（https：//bit.ly/2NFeYLj）开源和社区可扩展 工具、模型和模拟，以改善基于SGS的神经调节疗法， 治疗下尿路功能障碍的患者。