A Preliminary Model of Gastrointestinal Electromechanical Coupling

Du, Peng; Poh, Yong Cheng; Lim, Jee Lean; Gajendiran, Viveka; OrGrady, G.; Buist, Martin L.; Pullan, Andrew J.; Cheng, Leo K.

doi:10.1109/tbme.2011.2166155

Cited by 22 publications

(9 citation statements)

References 19 publications

(36 reference statements)

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“…by acetylcholine-binding to muscarinic receptors 53 , 54 . If ICC spread sufficient current to depolarize the SMC above the threshold for VDCC, Ca 2+ increases which induces contraction 55 . Our characterization of light-induced currents in ChR2 expressing SMC, the resulting Ca 2+ transients and isometric force measurements prove that these currents are sufficient to reach the threshold potential of VDCC.…”

Section: Discussionmentioning

confidence: 99%

Direct optogenetic stimulation of smooth muscle cells to control gastric contractility

et al. 2021

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Rationale: Antral peristalsis is responsible for gastric emptying. Its failure is called gastroparesis and often caused by dysfunction of enteric neurons and interstitial cells of Cajal (ICC). Current treatment options, including gastric electrical stimulation, are non-satisfying and may improve symptoms but commonly fail to restore gastric emptying. Herein, we explore direct optogenetic stimulation of smooth muscle cells (SMC) via the light-gated non-selective cation channel Channelrhodopsin2 (ChR2) to control gastric motor function. Methods: We used a transgenic mouse model expressing ChR2 in fusion with eYFP under the control of the chicken-β-actin promoter. We performed patch clamp experiments to quantify light-induced currents in isolated SMC, Ca 2+ imaging and isometric force measurements of antral smooth muscle strips as well as pressure recordings of intact stomachs to evaluate contractile responses. Light-induced propulsion of gastric contents from the isolated stomach preparation was quantified in video recordings. We furthermore tested optogenetic stimulation in a gastroparesis model induced by neuronal- and ICC-specific damage through methylene blue photo-toxicity. Results: In the stomachs, eYFP signals were restricted to SMC in which blue light (460 nm) induced inward currents typical for ChR2. These depolarizing currents led to contractions in antral smooth muscle strips that were stronger than those triggered by supramaximal electrical field stimulation and comparable to those evoked by global depolarization with high K + concentration. In the intact stomach, panoramic illumination efficiently increased intragastric pressure achieving 239±46% (n=6) of the pressure induced by electrical field stimulation and triggered gastric transport. Within the gastroparesis model, electric field stimulation completely failed but light still efficiently generated pressure waves. Conclusions: We demonstrate direct optogenetic stimulation of SMC to control gastric contractility. This completely new approach could allow for the restoration of motility in gastroparesis in the future.

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Section: Discussionmentioning

confidence: 99%

Direct optogenetic stimulation of smooth muscle cells to control gastric contractility

et al. 2021

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“…Existing models have modeled the spatial dynamics of ENS and slow wave behavior by spacing subpopulations of cells longitudinally (Lin et al, 2006, Chambers et al, 2008, Du et al, 2011, Chambers et al, 2014). In our model, sensory and motor subnetworks were spatially distributed along the simulated GI tract to reflect GI anatomy and interneuron projection lengths in small rodents (Brookes et al, 1997, Permezel and Webling, 1971).…”

Section: Methodsmentioning

confidence: 99%

“…Additional models were developed to study neural control of motility, including models for segmentation and migrating motor complexes (Chambers et al, 2008, Thomas et al, 2004). Separate models captured electrical slow waves that arise from the interaction between interstitial cells of Cajal (ICC) and smooth muscle fibers, but these models did not consider enteric neurons or neuromuscular junctions (Edwards and Hirst, 2003, Edwards and Hirst, 2006, Edwards and Hirst, 2005, Edwards et al, 1999, Hirst et al, 2006, Du et al, 2016, Du et al, 2011). Despite these efforts, there is no model that includes all the components necessary to capture the effect of electrical stimulation on gut motility, including conductance-based models of the electrical activity of enteric neurons and ICC-driven slow wave propagation through smooth muscle.…”

Section: Introductionmentioning

confidence: 99%

Electrical stimulation of gut motility guided by anin silicomodel

2017

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Objective Neuromodulation of the central and peripheral nervous systems is becoming increasingly important for treating a diverse set of diseases—ranging from Parkinson’s Disease and epilepsy to chronic pain. However, neuromodulation of the gastrointestinal (GI) tract has achieved relatively limited success in treating functional GI disorders, which affect a significant population, because the effects of stimulation on the enteric nervous system (ENS) and gut motility are not well understood. Here we develop an integrated neuromechanical model of the ENS and assess neurostimulation strategies for enhancing gut motility, validated by in vivo experiments. Approach The computational model included a network of enteric neurons, smooth muscle fibers, and interstitial cells of Cajal, which regulated propulsion of a virtual pellet in a model of gut motility. Main results Simulated extracellular stimulation of ENS-mediated motility revealed that sinusoidal current at 0.5 Hz was more effective at increasing intrinsic peristalsis and reducing colon transit time than conventional higher frequency rectangular current pulses, as commonly used for neuromodulation therapy. Further analysis of the model revealed that the 0.5 Hz sinusoidal currents were more effective at modulating the pacemaker frequency of interstitial cells of Cajal. To test the predictions of the model, we conducted in vivo electrical stimulation of the distal colon while measuring bead propulsion in awake rats. Experimental results confirmed that 0.5 Hz sinusoidal currents were more effective than higher frequency pulses at enhancing gut motility. Significance This work demonstrates an in silico GI neuromuscular model to enable GI neuromodulation parameter optimization and suggests that low frequency sinusoidal currents may improve the efficacy of GI pacing.

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“…The capability of recording Ca 2+ transients at the tissue level could also lead to the development of new electromechanical models (Du et al, 2011 ; Singh et al, 2014 ; Malysz et al, 2017 ). This is critical because motility is a functional consequence of slow wave activation, and ICC have been shown to exhibit significant mechano-sensitivity (Beyder et al, 2010 ), which has been studied using a mathematical cell model (Poh et al, 2012 ).…”

Section: Final Remarks and Future Directionmentioning

confidence: 99%

Progress in Mathematical Modeling of Gastrointestinal Slow Wave Abnormalities

Calder

Angeli

et al. 2018

Front. Physiol.

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Gastrointestinal (GI) motility is regulated in part by electrophysiological events called slow waves, which are generated by the interstitial cells of Cajal (ICC). Slow waves propagate by a process of “entrainment,” which occurs over a decreasing gradient of intrinsic frequencies in the antegrade direction across much of the GI tract. Abnormal initiation and conduction of slow waves have been demonstrated in, and linked to, a number of GI motility disorders. A range of mathematical models have been developed to study abnormal slow waves and applied to propose novel methods for non-invasive detection and therapy. This review provides a general outline of GI slow wave abnormalities and their recent classification using multi-electrode (high-resolution) mapping methods, with a particular emphasis on the spatial patterns of these abnormal activities. The recently-developed mathematical models are introduced in order of their biophysical scale from cellular to whole-organ levels. The modeling techniques, main findings from the simulations, and potential future directions arising from notable studies are discussed.

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A Preliminary Model of Gastrointestinal Electromechanical Coupling

Cited by 22 publications

References 19 publications

Direct optogenetic stimulation of smooth muscle cells to control gastric contractility

Direct optogenetic stimulation of smooth muscle cells to control gastric contractility

Electrical stimulation of gut motility guided by anin silicomodel

Progress in Mathematical Modeling of Gastrointestinal Slow Wave Abnormalities

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