Electrical stimulation of gut motility guided by an in silico model

Abstract

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.

Figure 1. Computational model of gut motility simulates peristalsis

(a) Illustration of pellet moving through a section of the GI tract. Illustration is not drawn to scale. (b) Network of model enteric neurons, smooth muscle, and ICC. SN: sensory neuron, AI: ascending interneuron, DI: descending interneuron, IN: inhibitory motor neuron, EN: excitatory motor neuron, CM: circular muscle fiber. (c) Pellet position over time, along with raster plots of sensory neuron action potentials and circular muscle fiber contractions, as functions of position.

Figure 2. Electrical stimulation reduces transit time

(a) Pellet position, circular muscle activity, and sensory neuron activity over time during 14 Hz, 200 μs pulse stimulation at 1 mA. (b) Sensory neuron action potentials during pulse stimulation in (a). (c) Circular muscle subthreshold oscillations during pulse stimulation in (a). (d) Pellet position, circular muscle activity, and sensory neuron activity over time during 14 Hz sine stimulation at 1 mA.

Figure 3. Characterizing sine wave stimulation over a range of frequencies

Pellet position, circular muscle activity, and sensory neuron activity during (a) 0.5 Hz, (b) 5 Hz, and (c) 50 Hz sine wave stimulation at 1 mA. (d) Motility speed as percent control for each of the sine wave stimulation frequencies. (e) Comparing motility speed between the optimal sine wave stimulation (0.5 Hz) and 14 Hz and 0.5 Hz pulse stimulation.

Figure 4. Role of ICC in electrical stimulation of gut motility

(a) Threshold current required to entrain ICC pacemaker frequency to match sine stimulation frequency. Transmembrane potential of the ICC at position ^L/₄ in the model of motility during (b) no stimulation, (c) 0.5 Hz sine wave stimulation, and (d) 0.5 Hz, 200 μs pulse stimulation at 1 mA. Pellet position, circular muscle activity, and sensory neuron activity during 0.5 Hz, 1 mA sine wave stimulation with electrical stimulation (e) influencing enteric neurons and smooth muscle, but not ICC, and (f) influencing only ICC, but not enteric neurons and smooth muscle.

Figure 5. Effects of stimulation in intermediate and advanced models of motility

Motility speed (% control) is compared in the intermediate expanded model between (a) 0.5 Hz, 5 Hz, and 50 Hz sine wave stimulation and (b) 14 Hz and 0.5 Hz pulse stimulation at 1 mA. In the advanced model, motility speed (% control) is compared between (c) 0.5 Hz, 5 Hz, and 50 Hz sine wave stimulation and (d) 14 Hz and 0.5 Hz pulse stimulation at 1 mA. N = 9 for all groups; error bars show standard error.

Figure 6. Effects of electrical stimulation on colonic transit time in awake rats

(a) Individual trials for bead propulsion time during sine wave stimulation. (b) Summary statistics for mean motility speed as percent control during sine wave stimulation. (c) Individual trials for bead propulsion time during 0.5 Hz sine wave stimulation compared to pulse stimulation. (d) Summary statistics comparing mean motility speed as percent control between 0.5 Hz sine wave and pulse stimulation. N = 7 for all groups; error bars show standard error. Star (★) denotes significant difference between control (unstimulated) and experimental (stimulated) groups, as determined by two-tailed, paired t-test. Dagger (†) denotes significantly different from all other groups, as determined by ANOVA and Tukey HSD post hoc testing.