Background and Purpose: Gastric pacing has shown preclinical success in modulating bioelectrical slow wave activity and has potential as a novel therapy for functional motility disorders. However, the translation of pacing techniques to the small intestine remains preliminary. This paper presents the first high-resolution framework for simultaneous pacing and response mapping of the small intestine. Methods: A novel surface-contact electrode array, capable of simultaneous pacing and high-resolution mapping of the pacing response was developed and applied in vivo on the proximal jejunum of pigs. Pacing parameters including the input energy and pacing electrode orientation were systematically evaluated and the efficacy of pacing was determined by analyzing spatiotemporal characteristics of entrained slow waves. Histological analysis was conducted to determine if the pacing resulted in tissue damage. Results: A total of 54 studies were conducted on 11 pigs and pacemaker propagation patterns were successfully achieved at both low (2 mA, 50 ms) and high (4 mA, 100 ms) energy levels with the pacing electrodes oriented in the antegrade, retrograde and circumferential directions. The high energy level performed significantly better (p=0.014) in achieving spatial entrainment. Comparable success (greater than 70%) was achieved when pacing in the circumferential and antegrade pacing directions, and no tissue damage was observed at the pacing sites. Conclusion: This study defined the spatial response of small intestine pacing in vivo revealing effective pacing parameters for slow wave entrainment in the jejunum. Intestinal pacing now awaits translation to restore disordered slow wave activity associated with motility disorders.
Gastric pacing and stimulation strategies were first proposed in the 1960s to treat motility disorders. However, there has been relatively limited clinical translation of these techniques. Experimental investigations have been critical in advancing our understanding of the control mechanisms that innervate gut function. In this review, we will discuss the use of pacing to modulate the rhythmic slow wave conduction patterns generated by interstitial cells of Cajal in the gastric musculature. In addition, the use of gastric high-frequency stimulation methods that target nerves in the stomach to either inhibit or enhance stomach function will be discussed. Pacing and stimulation protocols to modulate gastric activity, effective parameters and limitations in the existing studies are summarized. Mathematical models are useful to understand complex and dynamic systems. A review of existing mathematical models and techniques that aim to help refine pacing and stimulation protocols are provided. Finally, some future directions and challenges that should be investigated are discussed.
Gastric motility is coordinated by underlying bioelectrical slow waves. Gastric dysrhythmias occur in GI motility disorders, but there are no validated methods for eliminating dysrhythmias. We hypothesized that targeted ablation could eliminate pacemaker sites in the stomach, including dysrhythmic ectopic pacemaker sites. In vivo high-resolution serosal electrical mapping (16×16 electrodes; 6×6 cm) was applied to localize normal and ectopic gastric pacemaker sites in 13 anaesthetised pigs. Radiofrequency ablation was performed in a square formation surrounding the pacemaker site. Post-ablation high-resolution mapping revealed that ablation successfully induced localized conduction blocks after 18 min (SD 5). Normal gastric pacemaker sites were eliminated by ablation (n=6), resulting in the emergence of a new pacemaker site immediately distal to the original site in all cases. Ectopic pacemaker sites were similarly eliminated by ablation in all cases (n=7), and the surrounding mapped area was then entrained by normal antegrade activity in 5 of those cases. Histological analysis showed that ablation lesions extended through the entire depth of the muscle layer. Immunohistochemical staining confirmed localised interruption of the interstitial cell of Cajal (ICC) network through the ablation lesions. This study demonstrates that targeted gastric ablation can effectively modulate gastric electrical activation, including eliminating ectopic sites of slow wave activation underlying gastric dysrhythmias, without disrupting surrounding conduction capability or tissue structure. Gastric ablation presents a powerful new research tool for modulating gastric electrical activation and may likely hold therapeutic potential for disorders of gastric function.
The interstitial cells of Cajal (ICC) form interconnected networks throughout the gastrointestinal (GI) tract. ICC act as the pacemaker cells that initiate the rhythmic bioelectrical slow waves and intermediary between the GI musculature and nerves, both of which are critical to GI motility. Disruptions to the number of ICC and the integrity of ICC networks have been identified as a key pathophysiological mechanism in a number of clinically challenging GI disorders. The current analyses of ICC generally rely on either functional recordings taken directly from excised tissue or morphological analysis based on images of labeled ICC, where the structural‐functional relationship is investigated in an associative manner rather than mechanistically. On the other hand, computational physiology has played a significant role in facilitating our understanding of a number of physiological systems in both health and disease, and investigations in the GI field are beginning to incorporate several mathematical models of the ICC. The main aim of this review is to present the major modeling advances in GI electrophysiology, in order to introduce a multi‐scale framework for mathematically quantifying the functional consequences of ICC degradation at both cellular and tissue scales. The outcomes will inform future investigators utilizing modeling techniques in their studies. This article is categorized under: Metabolic Diseases > Computational Models
Introduction-The network of Interstitial Cells of Cajal (ICC) plays a plethora of key roles in maintaining, coordinating, and regulating the contractions of the gastrointestinal (GI) smooth muscles. Several GI functional motility disorders have been associated with ICC degradation. This study extended a previously reported 2D morphological analysis and applied it to 3D spatial quantification of three different types of ICC networks in the distal stomach guided by confocal imaging and machine learning methods. The characterization of the complex changes in spatial structure of the ICC network architecture contributes to our understanding of the roles that different types of ICC may play in postprandial physiology, pathogenesis, and/or amelioration of GI dsymotility-bridging structure and function. Methods-A validated classification method using Trainable Weka Segmentation was applied to segment the ICC from a confocal dataset of the gastric antrum of a transgenic mouse, followed by structural analysis of the segmented images. Results-The machine learning model performance was compared to manually segmented subfields, achieving an area under the receiver-operating characteristic (AUROC) of 0.973 and 0.995 for myenteric ICC (ICC-MP; n = 6) and intramuscular ICC (ICC-IM; n = 17). The myenteric layer in the distal antrum increased in thickness (from 14.5 to 34 lm) towards the lesser curvature, whereas the thickness decreased towards the lesser curvature in the proximal antrum (17.7 to 9 lm). There was an increase in ICC-MP volume from proximal to distal antrum (406,960 ± 140,040 vs. 559,990 ± 281,000 lm 3 ; p = 0.000145). The % of ICC volume was similar for ICC-LM and for ICC-CM between proximal (3.6 ± 2.3% vs. 3.1 ± 1.2%; p = 0.185) and distal antrum (3.2 ± 3.9% vs. 2.5 ± 2.8%; p = 0.309). The aver-age % volume of ICC-MP was significantly higher than ICC-IM at all points throughout sample (p < 0.0001). Conclusions-The segmentation and analysis methods provide a high-throughput framework of investigating the structural changes in extended ICC networks and their associated physiological functions in animal models.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.