Developing a comprehensive model for peripheral nerve stimulation of gastrointestinal function

总结 五分之一的人患有某种形式的功能性胃肠和动力障碍（FGIMD）， 肠神经系统（ENS）功能障碍引起的疾病，包括肠易激综合征， 大便失禁、便秘、消化不良等。药物干预在很大程度上是不成功的 管理这些条件。最近，电骶神经刺激（SNS）已成为一种替代方法 治疗FGIMD。然而，骶神经如何支配和调节ENS是未知的，因此临床医生 不得不求助于一组经验刺激参数，希望缓解不同的（有时相反的） 条件，结果非常不一致。 本研究的目的是了解骶神经是如何支配和调节肠神经的。 神经系统我们提出了三种假设的机制，通过SNS调节肠道动力：SNS 调节[a]肠神经元、[B]平滑肌和/或[c]内在起搏细胞。挑战在于 没有特定的工具，如药理学阻断剂、转基因动物模型等，可以区分 这三种假设的机制。 为了克服这一挑战，我们将建立第一个整合骶神经的计算模型， ENS和GI运动。对于每个假设的机制，计算机模拟框架将预测不同的神经元， 肌肉放电模式，然后可以通过c-Fos+免疫作图在体内进行实验验证， 活体结肠成像。计算机模拟框架还将预测SNS期间的运动模式， 在清醒的动物体内植入运动传感器进行验证。一旦SNS-ENS的基本机制 界面理解，我们将使用改进的计算机模型来优化SNS参数， 增加或减少结肠运动，随后进行体内验证。 总之，我们将联合收割机计算建模和体内实验相结合，以确定骶骨如何 神经支配和调节ENS和GI运动。我们的模型将提供基本的理解 外周神经如何与器官接口，这可推广到其他类型的外周神经， 迷走神经该模型还将使我们能够测试特定刺激模式可以 用于治疗下消化道系统的不同疾病，而不是使用目前的一刀切， 偶然的方法。

SUMMARY One in five people suffer from some form of functional gastrointestinal and motility disorders (FGIMD), a group of diseases caused by malfunction of the enteric (gut) nervous system (ENS), including irritable bowel syndrome, fecal incontinence, constipation, dyspepsia, and others. Pharmaceutical intervention is largely unsuccessful at managing these conditions. Recently, electrical sacral nerve stimulation (SNS) has emerged as an alternative therapy for FGIMD. However, how the sacral nerves innervate and modulate the ENS is unknown, so clinicians have to resort to one set of empirical stimulation parameters in hopes of relieving different (sometimes opposite) conditions, with very inconsistent outcomes. The objective of this project is to understanding how the sacral nerves innervate and modulate the enteric nervous system. We pose three hypothetical mechanisms through which SNS modulates gut motility: SNS modulates [a] enteric neurons, [b] smooth muscle, and / or [c] intrinsic pacemaker cells. The challenge is that there is no specific tool, such as pharmacological blockers, transgenic animal models, etc., that can distinguish these three hypothetical mechanisms in vivo. To overcome this challenge, we will build the first computational model that integrates the sacral nerves, the ENS, and GI motility. For each hypothetic mechanism, the in silico framework will predict distinct neuron and muscle firing patterns, which can then be experimentally validated in vivo by c-Fos+ immunomapping and intravital colon imaging. The in silico framework will also predict motility patterns during SNS, which will be validated by implantable motility sensors in awake animals. Once the fundamental mechanism of the SNS-ENS interface is understood, we will use the improved in silico model to optimize SNS parameters that maximally increase or decrease colonic motility, followed by in vivo validation. In summary, we will combine computational modeling and in vivo experiments to determine how the sacral nerves innervate and modulate the ENS and GI motility. Our model will provide fundamental understanding of how peripheral nerves interface with an organ, which is generalizable to other types of peripheral nerves such as the vagus nerve. The model will also enable us to test the hypothesis that specific stimulation patterns can be delivered to treat different conditions in the lower GI system, rather than using the current one-size-fits-all, hit-or-miss approach.