Developing a comprehensive model for peripheral nerve stimulation of gastrointestinal function

摘要 五分之一的人患有某种形式的功能性胃肠道和动力障碍(FGIMD)， 肠道(肠道)神经系统(ENS)故障引起的疾病，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不成功 管理这些情况。近年来，电刺激(Sns)已成为一种新的治疗方法。 FGIMD的治疗。然而，骶神经是如何支配和调节脊神经的，这一点尚不清楚，所以临床医生 我不得不求助于一套经验刺激参数，希望缓解不同的(有时是相反的) 条件，结果非常不一致。 这个项目的目标是了解骶神经是如何支配和调节肠道的。 神经系统。我们提出了三种SNS调节肠道运动的假想机制： 调节[a]肠神经元、[b]平滑肌和/或[c]固有起搏细胞。挑战在于 没有特定的工具，如药物阻滞剂、转基因动物模型等，可以区分 这三种假说机制在体内。 为了克服这一挑战，我们将建立第一个整合了骶神经的计算模型，即 ENS和胃肠动力。对于每一种假说机制，电子框架将预测不同的神经元和 肌肉放电模式，然后可以在体内通过c-Fos+免疫映射和 活体结肠成像。In Silico框架还将预测SNS期间的运动模式，这将是 通过在清醒动物身上植入的运动传感器进行验证。曾经是SNS-ENS的基本机制 界面是理解的，我们将使用改进的硅胶模型来最大限度地优化SNS参数 增加或降低结肠动力，随后进行体内验证。 总之，我们将结合计算模型和活体实验来确定骶骨是如何 神经支配和调节ENS和GI的运动。我们的模型将提供对 周围神经如何与器官连接，这可推广到其他类型的周围神经，如 作为迷走神经。该模型还将使我们能够测试特定刺激模式可以 提供用于治疗较低GI系统中的不同情况，而不是使用当前的一刀切， 命中或未命中方法。

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.