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: 10469840
• 负责人: Robert A Gaunt
• 金额: $ 75.37万
• 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/10469840
• 关键词: Simulations; spinal; cord; recruitment; optimize

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，并具有 在美国，每年以数百亿美元衡量的经济影响。此字段 作为当前的治疗方法，迫切需要新的治疗方法，例如清洁的间歇导尿术 和药品，都有明显的副作用。硬膜外脊髓刺激(SCS) 提供了一个潜在的解决方案。SCS是生物电子医学的一个快速增长的领域，有数十个 每年在美国发生的数以千计的植入手术。而SCS通常会激活 背柱，这项技术也可以用来招募初级感觉神经元 通过背根进入脊髓。这些感官输入在以下方面起着关键作用 调节膀胱功能和激活这些初级感觉神经元可以有强大的 对膀胱行为的影响。通过SPARC的持续努力，我们的团队已经建立了高分辨率 SCS可以选择性地招募导致排尿和控制的骶部传入 条件反射。这些数据支持我们的最终翻译目标，即开发一种SGS疗法来改善 损伤和疾病后的膀胱功能。然而，仍有一个严重的差距需要理解、发展 并优化这些神经调节疗法。没有模型可以准确地代表 复杂的骶椎解剖结构和以前的建模工作一直忽略了 背根细根。在这个项目中，我们将开发功能化的、解剖学上准确的 猫腰段脊髓。包括背根，并使用以下方法验证这些模型 在现有SPARC努力下获得的电生理数据。 任务1：为解剖学上精确的超高分辨率有限元创建管道 猫腰段脊髓模型的建立 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。 然而，这些结构在建模工作中一直被低估，部分原因是它们的 解剖上的复杂性。我们将使用扩散张量成像(DTI)和结构磁学 磁共振成像以获得猫骶椎脊髓的详细解剖，包括 背根和腹根纤维通路并在o2s2PARC节段内形成一条管道 图像，并创建这些组织的有限元方法(FEM)模型。第1年：图像数据集 一只猫的骶髓和初步管道。第2年：四个脊柱的成像数据集 验证解剖模型创建管道的绳索。 任务2：创建具有计算轴突模型功能的有限元模型，以及 使用现有电生理数据验证招募 我们将使用Sim4Life和o2S2PARC平台来网格化和填充简化的 解剖学上准确的脊髓模型和骨盆、阴部的种群！和坐骨神经 投射到脊髓中的轴突。DTI数据将用于创建逼真的3D轴突轨迹和 该模型将使用现有数据(OT2OD024908)进行验证。第1年：功能化模型 单纯的脊髓和模拟硬膜外刺激的效果。第2年：功能化模式 解剖学上准确的骶髓，具有有效的募集特性。 任务3：模拟脊髓反射，模拟频率相关的兴奋性和抑制性 膀胱活动 同一触点上不同频率的SCS可能会对膀胱压力产生相反的影响 通过脊椎反射。为了模拟这一影响，我们将扩展SCS招聘模型，以包括： 第一次，再现观察到的行为的脊髓反射的计算模型 效果。这将创建功能化的有限元模型，可以预测 对靶器官的刺激频率。第1年：定义反射模型结构并将其与 有限元刺激。第2年：完成膀胱行为的功能模拟，受驱动 通过SCS，这复制了频率依赖的效应。 该项目将创建可信的(https://bit.ly/2NFeYLj)开源和社区可扩展 改进基于SGS的神经调节疗法的工具、模型和模拟以增强 下尿路功能障碍患者的治疗。

项目成果

A systematic review of computational models for the design of spinal cord stimulation therapies: from neural circuits to patient-specific simulations.

对脊髓刺激疗法设计的计算模型的系统回顾：从神经回路到患者特异性模拟。

• DOI: 10.1113/jp282884
• 发表时间: 2023
• 期刊: The Journal of physiology
• 作者: Liang,Lucy;Damiani,Arianna;DelBrocco,Matteo;Rogers,EvanR;Jantz,MariaK;Fisher,LeeE;Gaunt,RobertA;Capogrosso,Marco;Lempka,ScottF;Pirondini,Elvira
• 通讯作者: Pirondini,Elvira

An Open-source Computational Model of Neurostimulation of the Spinal Pudendo-Vesical Reflex for the Recovery of Bladder Control After Spinal Cord Injury.

用于脊髓损伤后膀胱控制恢复的脊髓阴部膀胱反射神经刺激的开源计算模型。

• DOI: 10.1109/embc48229.2022.9871195
• 发表时间: 2022
• 期刊: Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference
• 作者: Fang,Xiaoqi;Collins,Scott;Nanivadekar,AmeyaC;Jantz,Maria;Gaunt,RobertA;Capogrosso,Marco
• 通讯作者: Capogrosso,Marco

A Computational Study of Lower Urinary Tract Nerve Recruitment with Epidural Stimulation of the Lumbosacral Spinal Cord.

腰骶脊髓硬膜外刺激下尿路神经复张的计算研究。

• DOI: 10.1109/embc48229.2022.9871292
• 发表时间: 2022
• 期刊: Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference
• 作者: Jantz,MariaK;Liang,Lucy;Damiani,Arianna;Fisher,LeeE;Newton,Taylor;Neufeld,Esra;Hitchens,TKevin;Pirondini,Elvira;Capogrosso,Marco;Gaunt,RobertA
• 通讯作者: Gaunt,RobertA