High-energy pacing inhibits slow-wave dysrhythmias in the small intestine.

The motility of the gastrointestinal tract is coordinated in part by rhythmic slow waves, and disrupted slow-wave patterns are linked to functional motility disorders. At present, there are no treatment strategies that primarily target slow-wave activity. This study assessed the use of pacing to suppress glucagon-induced slow-wave dysrhythmias in the small intestine. Slow waves in the jejunum were mapped in vivo using a high-resolution surface-contact electrode array in pigs (n = 7). Glucagon was intravenously administered to induce hyperglycemia. Slow-wave propagation patterns were categorized into antegrade, retrograde, collision, pacemaker, and uncoupled activity. Slow-wave characteristics such as period, amplitude, and speed were also quantified. Postglucagon infusion, pacing was applied at 4 mA and 8 mA and the resulting slow waves were quantified spatiotemporally. Antegrade propagation was dominant throughout all stages with a prevalence of 55 ± 38% at baseline. However, glucagon infusion resulted in a substantial and significant increase in uncoupled slow waves from 10 ± 8% to 30 ± 12% (P = 0.004) without significantly altering the prevalence of other slow-wave patterns. Slow-wave frequency, amplitude, and speed remained unchanged. Pacing, particularly at 8 mA, significantly suppressed dysrhythmic slow-wave patterns and achieved more effective spatial entrainment (85%) compared with 4 mA (46%, P = 0.039). This study defined the effect of glucagon on jejunal slow waves and identified uncoupling as a key dysrhythmia signature. Pacing effectively entrained rhythmic activity and suppressed dysrhythmias, highlighting the potential of pacing for gastrointestinal disorders associated with slow-wave abnormalities.NEW & NOTEWORTHY Glucagon was infused in pigs to induce hyperglycemia and the resulting slow-wave response in the intact jejunum was defined in high resolution for the first time. Subsequently, with pacing, the glucagon-induced dysrhythmias were suppressed and spatially entrained for the first time with a success rate of 85%. The ability to suppress slow-wave dysrhythmias through pacing is promising in treating motility disorders that are associated with intestinal dysrhythmias.

Mapping the rat gastric slow-wave conduction pathway: bridging in vitro and in vivo methods, revealing a loosely coupled region in the distal stomach.

Rhythmic electrical events, termed slow waves, govern the timing and amplitude of phasic contractions of the gastric musculature. Extracellular multielectrode measurement of gastric slow waves can be a biomarker for phenotypes of motility dysfunction. However, a gastric slow-wave conduction pathway for the rat, a common animal model, is unestablished. In this study, the validity of extracellular recording was demonstrated in vitro with simultaneous intracellular and extracellular recordings and by pharmacological inhibition of slow waves. The conduction pathway was determined by in vivo extracellular recordings while considering the effect of motion. Slow-wave characteristics [means (SD)] varied regionally having higher amplitude in the antrum than the distal corpus [1.03 (0.12) mV vs. 0.75 (0.31) mV; n = 7; P = 0.025 paired t test] and faster propagation near the greater curvature than the lesser curvature [1.00 (0.14) mm·s-1 vs. 0.74 (0.14) mm·s-1; n = 9 GC, 7 LC; P = 0.003 unpaired t test]. Notably, in some subjects, separate wavefronts propagated near the lesser and greater curvatures with a loosely coupled region occurring in the area near the distal corpus midline at the interface of the two wavefronts. This region had either the greater or lesser curvature wavefront propagating through it in a time-varying manner. The conduction pattern suggests that slow waves in the rat stomach form annular wavefronts in the antrum and not the corpus. This study has implications for interpretation of the relationship between slow waves, the interstitial cells of Cajal network structure, smooth muscles, and gastric motility.NEW & NOTEWORTHY Mapping of rat gastric slow waves showed regional variations in their organization. In some subjects, separate wavefronts propagated near the lesser and greater curvatures with a loosely coupled region near the midline, between the wavefronts, having a varying slow-wave origin. Furthermore, simultaneous intracellular and extracellular recordings were concordant and independent of movement artifacts, indicating that extracellular recordings can be interpreted in terms of their intracellular counterparts when intracellular recording is not possible.

Spatial response of jejunal pacing defined by a novel high-resolution multielectrode array.

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. 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. 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. 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.NEW & NOTEWORTHY A novel surface-contact electrode array customized for the small intestine anatomy enabled simultaneous pacing and high-resolution response mapping. The spatial response of small intestine bioelectrical activity to pacing was mapped for the first time in vivo. Antegrade and circumferential pacing achieved spatial entrainment over 70% of the time and their induced pattern was held for 4-6 cycles postpacing at high energy (4 mA, 100 ms, at ∼2.7 s which corresponds to 1.1 × intrinsic frequency).

The bioelectrical conduction system around the ileocecal junction defined through in vivo high-resolution mapping in rabbits.

Coordinated contractions across the small and large intestines via the ileocecal junction (ICJ) are critical to healthy gastrointestinal function and are in part governed by myoelectrical activity. In this study, the spatiotemporal characteristics of the bioelectrical conduction across the ICJ and its adjacent regions were quantified in anesthetized rabbits. High-resolution mapping was applied from the terminal ileum (TI) to the sacculus rotundus (SR), across the ICJ and into the beginning of the large intestine at the cecum ampulla coli (AC). Orally propagating slow wave patterns in the SR did not entrain the TI. However, aborally propagating patterns from the TI were able to entrain the SR. Bioelectrical activity was recorded within the ICJ and AC, revealing complex interactions of slow waves, spike bursts, and bioelectrical quiescence. This suggests the involvement of myogenic coordination when regulating motility between the small and large intestines. Mean slow wave frequency between regions did not vary significantly (13.74-17.16 cycles/min). Slow waves in the SR propagated with significantly faster speeds (18.51 ± 1.57 mm/s) compared with the TI (14.05 ± 2.53 mm/s, P = 0.0113) and AC (9.56 ± 1.56 mm/s, P = 0.0001). Significantly higher amplitudes were observed in both the TI (0.28 ± 0.13 mV, P = 0.0167) and SR (0.24 ± 0.08 mV, P = 0.0159) within the small intestine compared with the large intestine AC (0.03 ± 0.01 mV). We hypothesize that orally propagating slow waves facilitate a motor-brake pattern in the SR to limit outflow into the ICJ, similar to those previously observed in other gastrointestinal regions.NEW & NOTEWORTHY Competing slow wave pacemakers were observed in the terminal ileum and sacculus rotundus. Prevalent oral propagation in the sacculus rotundus toward the terminal ileum potentially acts as a brake mechanism limiting outflow. Slow waves and periods of quiescence at the ileocecal junction suggest that activation may depend on the coregulatory flow and distention pathways. Slow waves and spike bursts in the cecum impart a role in the coordination of motility.

Targeted ablation of gastric pacemaker sites to modulate patterns of bioelectrical slow wave activation and propagation in an anesthetized pig model.

Gastric motility is coordinated by underlying bioelectrical slow waves. Gastric dysrhythmias occur in gastrointestinal (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 anesthetized pigs. Radiofrequency ablation was performed in a square formation surrounding the pacemaker site. Postablation 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 five of those cases. Histological analysis showed that ablation lesions extended through the entire depth of the muscle layer. Immunohistochemical staining confirmed localized 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.NEW & NOTEWORTHY This study presents gastric ablation as a novel tool for modulating gastric bioelectrical activation, including eliminating the normal gastric pacemaker site as well as abnormal ectopic pacemaker sites underlying gastric dysrhythmias. Targeted application of radiofrequency ablation was able to eliminate these pacemaker sites 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.

Localized gastric distension disrupts slow-wave entrainment leading to temporary ectopic propagation: a high-resolution electrical mapping study.

Gastric distension is known to affect normal slow-wave activity and gastric function, but links between slow-wave dysrhythmias and stomach function are poorly understood. Low-resolution mapping is unable to capture complex spatial properties of gastric dysrhythmias, necessitating the use of high-resolution mapping techniques. Characterizing the nature of these dysrhythmias has implications in the understanding of postprandial function and the development of new mapping devices. In this two-phase study, we developed and implemented a protocol for measuring electrophysiological responses to gastric distension in porcine experiments. In vivo, serosal high-resolution electrical mapping (256 electrodes; 36 cm2) was performed in anaesthetized pigs (n = 11), and slow-wave pattern, velocity, frequency, and amplitude were quantified before, during, and after intragastric distension. Phase I experiments (n = 6) focused on developing and refining the distension mapping methods using a surgically inserted intragastric balloon, with a variety of balloon types and distension protocols. Phase II experiments (n = 5) used barostat-controlled 500-mL isovolumetric distensions of an endoscopically introduced intragastric balloon. Dysrhythmias were consistently induced in all five gastric distensions, using refined distension protocols. Dysrhythmias appeared 23 s (SD = 5 s) after the distension and lasted 129 s (SD = 72 s), which consisted of ectopic propagation originating from the greater curvature in the region of distension. In summary, our results suggest that distension disrupts gastric entrainment, inducing temporary ectopic slow-wave propagation. These results may influence the understanding of the postprandial stomach and electrophysiological effects of gastric interventions.NEW & NOTEWORTHY This study presents the discovery of temporary dysrhythmic ectopic pacemakers in the distal stomach caused by localized gastric distension. Distension-induced dysrhythmias are an interesting physiological phenomenon that can inform the design of new interventional and electrophysiological protocols for both research and the clinic. The observation of distension-induced dysrhythmias also contributes to our understanding of stretch-sensitivity in the gut and may play an important role in normal and abnormal postprandial physiology.

Bulk phase resource ratio alters carbon steel corrosion rates and endogenously produced extracellular electron transfer mediators in a sulfate-reducing biofilm.

Desulfovibrio alaskensis G20 biofilms were cultivated on 316 steel, 1018 steel, or borosilicate glass under steady-state conditions in electron-acceptor limiting (EAL) and electron-donor limiting (EDL) conditions with lactate and sulfate in a defined medium. Increased corrosion was observed on 1018 steel under EDL conditions compared to 316 steel, and biofilms on 1018 carbon steel under the EDL condition had at least twofold higher corrosion rates compared to the EAL condition. Protecting the 1018 metal coupon from biofilm colonization significantly reduced corrosion, suggesting that the corrosion mechanism was enhanced through attachment between the material and the biofilm. Metabolomic mass spectrometry analyses demonstrated an increase in a flavin-like molecule under the 1018 EDL condition and sulfonates under the 1018 EAL condition. These data indicate the importance of S-cycling under the EAL condition, and that the EDL is associated with increased biocorrosion via indirect extracellular electron transfer mediated by endogenously produced flavin-like molecules.

Sharp transition in the immunoimmobilization of E. coli O157:H7.

This work focuses on immobilization of living enterohemorrhagic Escherichia coli O157:H7 on a gold surface as a function of the concentration of antibody tethered to the surface in the physiological environment of the organisms. Experiments are conducted using antibodies raised against bacterial surface lipopolysaccharides (LPS) tethered to gold-coated silicon wafers at surface concentrations spanning a range from submonolayers of antibodies to full coverage, an estimated 1 antibody per ∼100 nm(2). A careful optimization of surface chemistry is conducted to obtain the most efficient tethering of the antibodies to the surface. The mechanism of immobilizing the bacteria is antibody-antigen interactions between the tethered antibodies on the surface and the bacterial surface LPS firmly attached to the bacteria. This type of attachment is known as immunoimmobilization. The experiments suggest no noticeable bacterial attachment until the surface antibody concentration reaches ∼70% of a full monolayer of coverage. Above this critical antibody density, a sharp increase in immunoimmobilized bacteria is observed as they populate nearly 80% to 100% of the available surface area, reaching ∼1.2 cells/10 µm(2). This sharp increase in population is tentatively explained in terms of the minimum number of antibody-antigen interactions required per bacterium to immobilize the cell. This critical number is estimated to be ∼6000-8000 antibodies per bacterium (having a 1 µm(2) footprint on the surface) under the assumption that a full monolayer of antibodies is about 1 antibody per ∼100 nm(2). However, the large majority of the 6000-8000 antibodies are not expected to participate in antibody-antigen interactions, in that the loose LPS in solution will saturate many of these antibodies before bacteria have a chance to interact with them. Furthermore, the geometric considerations will further restrict the majority of the active antibodies from interacting with the surface antigens of the cell, reducing its effective contact area with the antibodies considerably.

Three-Dimensional Fractal Analysis of the Interstitial Cells of Cajal Networks of Gastrointestinal Tissue Specimens.

Introduction: Several functional gastrointestinal disorders (FGIDs) have been associated with the degradation or remodeling of the network of interstitial cells of Cajal (ICC). Introducing fractal analysis to the field of gastroenterology as a promising data analytics approach to extract key structural characteristics that may provide insightful features for machine learning applications in disease diagnostics. Fractal geometry has advantages over several physically based parameters (or classical metrics) for analysis of intricate and complex microstructures that could be applied to ICC networks. Methods: In this study, three fractal structural parameters: Fractal Dimension, Lacunarity, and Succolarity were employed to characterize scale-invariant complexity, heterogeneity, and anisotropy; respectively of three types of gastric ICC network structures from a flat-mount transgenic mouse stomach. Results: The Fractal Dimension of ICC in the longitudinal muscle layer was found to be significantly lower than ICC in the myenteric plexus and circumferential muscle in the proximal, and distal antrum, respectively (both p < 0.0001). Conversely, the Lacunarity parameters for ICC-LM and ICC-CM were found to be significantly higher than ICC-MP in the proximal and in the distal antrum, respectively (both p < 0.0001). The Succolarity measures of ICC-LM network in the aboral direction were found to be consistently higher in the proximal than in the distal antrum (p < 0.05). Conclusions: The fractal parameters presented here could go beyond the limitation of classical metrics to provide better understanding of the structural-functional relationship between ICC networks and the conduction of gastric bioelectrical slow waves.

Optimization of pacing parameters to entrain slow wave activity in the pig jejunum.

Pacing has been proposed as a therapy to restore function in motility disorders associated with electrical dysrhythmias. The spatial response of bioelectrical activity in the small intestine to pacing is poorly understood due to a lack of high-resolution investigations. This study systematically varied pacing parameters to determine the optimal settings for the spatial entrainment of slow wave activity in the jejunum. An electrode array was developed to allow simultaneous pacing and high-resolution mapping of the small intestine. Pacing parameters including pulse-width (50, 100 ms), pulse-amplitude (2, 4, 8 mA) and pacing electrode orientation (antegrade, retrograde, circumferential) were systematically varied and applied to the jejunum (n = 15 pigs). Pulse-amplitudes of 4 mA (p = 0.012) and 8 mA (p = 0.002) were more effective than 2 mA in achieving spatial entrainment while pulse-widths of 50 ms and 100 ms had comparable effects (p = 0.125). A pulse-width of 100 ms and a pulse-amplitude of 4 mA were determined to be most effective for slow wave entrainment when paced in the antegrade or circumferential direction with a success rate of greater than 75%. These settings can be applied in chronic studies to evaluate the long-term efficacy of pacing, a critical aspect in determining its therapeutic potential.

High-Energy Pacing in the Jejunum Elicits Pulsatile Segmental Contractions.

OBJECTIVE: Compromised bowel function is associated with a range of motility disorders such as post-operative ileus and chronic intestinal pseudo-obstruction. Disordered or weak motility compromise the efficient movement of luminal contents necessary for digestion and nutrient absorption. This study investigated the potential of high-energy pacing to enhance contractions in the proximal jejunum of the small intestine. METHODS: Pacing pulse parameters (pulse-width: 100 ms, 200 ms, 400 ms, pulse-amplitude: 4 mA, 6 mA, 8 mA) were systematically varied in the in vivo porcine jejunum (n = 7) and the induced contractile responses were evaluated using a video mapping system. Localized segmental contractions were quantified by measuring the intestinal diameter and thereby computing the strain. The impact of pacing parameters on contractile strain was investigated. Finally, histological studies were conducted on paced tissue to assess for potential tissue damage. RESULTS: Segmental contractions were successfully induced at all pulse-settings and evaluated across 67 pacing sessions. In response to pacing, the intestine segment at the site of pacing contracted, with diameter reduced by 6-18%. Contractile response significantly increased with increasing pulse-amplitude. However, with increasing pulse-width, the increase in contractile response was significant only between 100 ms and 400 ms. Histology showed no tissue damage occurred when maximal pacing energy (pulse-amplitude = 4-8 mA, pulse-width = 400 ms, 5 minute duration) was applied. CONCLUSION: High-energy pacing induced periodic segmental contractions in response to pacing pulses and the contractile strain was proportional to the energy applied on the intestine. The ability to enhance motility through pacing may hold promising therapeutic potential for bowel disorders and awaits clinical translation. SIGNIFICANCE: Small intestine pacing elicits localized segmental contractions which increase in magnitude with increasing pulse settings. This study marks the first adaptation of video mapping techniques to track the pacing response in the small intestine.

Electromechanical Response of Mesenteric Ischemia Defined Through Simultaneous High-Resolution Bioelectrical and Video Mapping.

Intestinal motility is governed in part by bioelectrical slow-waves and spike-bursts. Mesenteric ischemia is a substantial clinical challenge, but its electrophysiological and contractile mechanisms are not well understood. Simultaneous high-resolution bioelectrical and video mapping techniques were used to capture the changes in slow-waves, spike-bursts, and contractile activity during baseline, ischemia, and reperfusion periods. Experiments were performed on anesthetized pigs where intestinal contractions were quantified using surface strain and diameter measurements, while slow-wave and spike-bursts were quantified using frequency and amplitude. Slow-waves entrainment within the ischemic region diminished during ischemia, resulting in irregular slow-wave activity and a reduction in the frequency from 12.4 ± 3.0 cycles-per-minute (cpm) to 2.5 ± 2.7 cpm (p = 0.0006). At the end of the reperfusion period, normal slow-wave entrainment was observed at a frequency of 11.5 ± 2.9 cpm. There was an increase in spike-burst activity between the baseline and ischemia periods (1.1 ± 1.4 cpm to 8.7 ± 3.3 cpm, p = 0.0003) along with a spasm of circumferential contractions. At the end of the reperfusion period, the frequency of spike-bursts decreased to 2.7 ± 1.4 cpm, and contractions subsided. The intestine underwent tonal contraction during ischemia, with the diameter decreasing from 29.3 ± 2.6 mm to 21.2 ± 6.2 mm (p = 0.0020). At the end of the reperfusion period, the intestinal diameter increased to 27.3 ± 3.9 mm. The decrease in slow-wave activity, increase in spike-bursts, and tonal contractions can objectively identify ischemic segments in the intestine. It is anticipated that the use of electrophysiological slow-wave and spike-burst biomarkers, along with contractile measures, could identify mesenteric ischemia in surgical settings and allow an objective biomarker for successful revascularization.

Neural regulation of slow waves and phasic contractions in the distal stomach: a mathematical model.

Objective.Neural regulation of gastric motility occurs partly through the regulation of gastric bioelectrical slow waves (SWs) and phasic contractions. The interaction of the tissues and organs involved in this regulatory process is complex. We sought to infer the relative importance of cellular mechanisms in inhibitory neural regulation of the stomach by enteric neurons and the interaction of inhibitory and excitatory electrical field stimulation.Approach.A novel mathematical model of gastric motility regulation by enteric neurons was developed and scenarios were simulated to determine the mechanisms through which enteric neural influence is exerted. This model was coupled to revised and extended electrophysiological models of gastric SWs and smooth muscle cells (SMCs).Main results.The mathematical model predicted that regulation of contractile apparatus sensitivity to intracellular calcium in the SMC was the major inhibition mechanism of active tension development, and that the effect on SW amplitude depended on the inhibition of non-specific cation currents more than the inhibition of calcium-activated chloride current (kiNSCC= 0.77 vs kiAno1= 0.33). The model predicted that the interaction between inhibitory and excitatory neural regulation, when applied with simultaneous and equal intensity, resulted in an inhibition of contraction amplitude almost equivalent to that of inhibitory stimulation (79% vs 77% decrease), while the effect on frequency was overall excitatory, though less than excitatory stimulation alone (66% vs 47% increase).Significance.The mathematical model predicts the effects of inhibitory and excitatory enteric neural stimulation on gastric motility function, as well as the effects when inhibitory and excitatory enteric neural stimulation interact. Incorporation of the model into organ-level simulations will provide insights regarding pathological mechanisms that underpin gastric functional disorders, and allow forin silicotesting of the effects of clinical neuromodulation protocols for the treatment of these disorders.

Biotrapping Ureolytic Bacteria on Sand to Improve the Efficiency of Biocementation.

Microbially induced calcium carbonate precipitation (MICP) has emerged as a novel technology with the potential to produce building materials through lower-temperature processes. The formation of calcium carbonate bridges in MICP allows the biocementation of aggregate particles to produce biobricks. Current approaches require several pulses of microbes and mineralization media to increase the quantity of calcium carbonate minerals and improve the strength of the material, thus leading to a reduction in sustainability. One potential technique to improve the efficiency of strength development involves trapping the bacteria on the aggregate surfaces using silane coupling agents such as positively charged 3-aminopropyl-methyl-diethoxysilane (APMDES). This treatment traps bacteria on sand through electrostatic interactions that attract negatively charged walls of bacteria to positively charged amine groups. The APMDES treatment promoted an abundant and immediate association of bacteria with sand, increasing the spatial density of ureolytic microbes on sand and promoting efficient initial calcium carbonate precipitation. Though microbial viability was compromised by treatment, urea hydrolysis was minimally affected. Strength was gained much more rapidly for the APMDES-treated sand than for the untreated sand. Three injections of bacteria and biomineralization media using APMDES-treated sand led to the same strength gain as seven injections using untreated sand. The higher strength with APMDES treatment was not explained by increased calcium carbonate accrual in the structure and may be influenced by additional factors such as differences in the microstructure of calcium carbonate bridges between sand particles. Overall, incorporating pretreatment methods, such as amine silane coupling agents, opens a new avenue in biomineralization research by producing materials with an improved efficiency and sustainability.

Computational models of autonomic regulation in gastric motility: Progress, challenges, and future directions.

The stomach is extensively innervated by the vagus nerve and the enteric nervous system. The mechanisms through which this innervation affects gastric motility are being unraveled, motivating the first concerted steps towards the incorporation autonomic regulation into computational models of gastric motility. Computational modeling has been valuable in advancing clinical treatment of other organs, such as the heart. However, to date, computational models of gastric motility have made simplifying assumptions about the link between gastric electrophysiology and motility. Advances in experimental neuroscience mean that these assumptions can be reviewed, and detailed models of autonomic regulation can be incorporated into computational models. This review covers these advances, as well as a vision for the utility of computational models of gastric motility. Diseases of the nervous system, such as Parkinson's disease, can originate from the brain-gut axis and result in pathological gastric motility. Computational models are a valuable tool for understanding the mechanisms of disease and how treatment may affect gastric motility. This review also covers recent advances in experimental neuroscience that are fundamental to the development of physiology-driven computational models. A vision for the future of computational modeling of gastric motility is proposed and modeling approaches employed for existing mathematical models of autonomic regulation of other gastrointestinal organs and other organ systems are discussed.

Reconstruction of the human lower esophageal sphincter based on ultra-mill imaging for biomechanical analysis.

Introduction: The lower esophageal sphincter (LES) controls the passage into the stomach and prevents reflex of contents into the esophagus. Dysfunctions of this region typically involves impairment of muscular function, leading to diseases including gastro-esophageal reflux disease and achalasia. The main objective of this study was to develop a finite element model from a unique human LES dataset reconstructed from an ultra-mill imaging setup, and then to investigate the effect of anatomical characteristics on intraluminal pressures. Methods: A pipeline was developed to generate a mesh from a set of input images, which were extracted from a unique ultra-mill sectioned human LES. A total of 216 nodal points with cubic Hermite basis function was allocated to reconstruct the LES, including the longitudinal and circumferential muscles. The resultant LES mesh was used in biomechanical simulations, utilizing a previously developed LES mathematical model based on the Visible Human data to calculate intraluminal pressures. Anatomical and functional comparisons were made between the Ultra-mill and Visible human models. Results: Overall, the Ultra-mill model contained lower cavity (1,796 vs. 5,400 mm3) and muscle (1,548 vs. 15,700 mm3) volumes than the Visible Human model. The Ultra-mill model also developed a higher basal pressure (13.8 vs. 14.7 mmHg) and magnitude of pressure (19.8 vs. 18.9 mmHg) during contraction. Out of all the geometric transformations (i.e., uniform enlargement of volume, lengthening along the center-axis, dilation of the diameter, and increasing muscle thickness), the muscle volume was found to be the main contributor of basal and magnitude of pressures. Increases in length also caused proportional increases to pressures, while dilation of diameter had a less influential reverse effect. Discussion: The findings provide information on interindividual variability in LES pressure and demonstrates that anatomy has a large influence on pressures. This model forms the basis of more complex simulations involving food bolus transport and predicting LES dysfunctions.

MRI Derived Simulations of Flow Patterns in the Stomach.

A framework to simulate the flow in the stomach using subject-specific motility patterns and geometries was developed. Dynamic 2D magnetic resonance images (MRIs) were obtained. Motility parameters such as contraction speed and occlusion were quantified, and 3D stomach geometries were reconstructed using a semi-automated approach. Computational fluid dynamics (CFD) simulations were performed, and flow patterns were investigated. The stomach of both subjects had distinct anatomical features with computed volumes of 789 mL and 619 mL. For the one subject, the occlusion (i.e., normalized contraction size) was 12% while it was around 25% for the other subject. Contraction speeds were also different (1.9-2.8 mm/s vs 3.0-5.1 mm/s) for each subject. CFD simulations resulted in unsteady laminar flow for both subjects with average velocities of 2.1 and 3.2 mm/s. While antegrade flow was mainly observed in the simulations, a retropulsive jet was also present in both stomachs. The versatile framework developed within this study would allow the generation of CFD models of gastric motility from dynamic MRIs.Clinical Relevance- Subject-specific models of flow patterns informed by gastric motility features can elucidate the impact of contractions and anatomical variations on digestion. Such models can inform therapies to treat gastric dysfunctions and improve their efficacy.

Evaluation of Pacing Parameters to Induce Contractions in the Small Intestine.

Postoperative ileus and chronic intestinal pseudo-obstruction are intestinal motility disorders that can compromise bowel function resulting in a significant reduction in quality of life and prolonged hospital stays. While medication and nutritional support provides relief for some patients, a significant patient population remains untreated. Therefore, alternative treatment options are required. A novel framework that enables small intestine pacing and video mapping of the contractile response was developed. Pacing pulse parameters (pulse-period: 2.7, 10 s, pulse-width: 100, 400 ms, and pulse-amplitude: 4, 6, 8 mA) were systematically varied to investigate the effect of pacing on the small intestine contractility. The contractile response was quantified by computing the strain of the intestinal diameter at the pacing site. The framework was applied in vivo on porcine jejunal loops (n=4) where segmental contractions were induced in response to pacing pulses. Strain increased with increasing pulse-amplitude and pulse-width, while pacing at a period of 2.7 s elicited higher contractile strains compared to pacing at a period of 10 s at all settings (e.g., -0.18 ± 0.06 vs 0.12 ± 0.06 at 8 mA, 400 ms). For a pulse-width of 100 ms, the contractile strain continued to increase with increasing pulse-amplitude, while the induced strain was comparable for all pulse-amplitudes when paced with high pulse-width (400 ms). Therefore, pacing is an effective tool in modulating the intensity of segmental contractions.Clinical Relevance- Different pacing parameters can define contraction intensity and frequency in the small intestine. This is of therapeutic potential for treating motility disorders such as post-operative ileus and chronic intestinal pseudo-obstruction.

Atrous spatial pyramid pooling and multi-image data fusion for smooth muscle segmentation in upper gastrointestinal sphincters.

Gastrointestinal (GI) sphincters provide critical roles in regulating the transport of contents along the GI tract. Dysfunctions of GI sphincters are associated with a range of major digestive disorders. Despite their importance, the microstructures of GI sphincters are not well investigated. While micro-computed tomography (µ-CT) provides detailed 3D images, conventional segmentation methods rely on manual correction, which is both time-consuming and prone to human error. This study proposes a segmentation method using atrous spatial pyramid pooling (ASPP), which helps in capturing different effective fields of view from a given input feature map, thereof providing finer local and global information for a given pixel. Additionally, we explored the use of multi-species data fusion to make the model more generalized. The proposed segmentation network incorporating ASPP and multi-species data fusion improved the segmentation of sphincter muscle images. Specifically, it increased the dice score and Jaccard index by 3.7% and 5.8%, respectively, while reducing the variance compared to conventional methods.Clinical relevance- Techniques developed in this study will inform µ-CT segmentation of human upper GI sphincters for detailed structural analysis of muscular dysfunction.

Quantification of the Regional Properties of Gastric Motility Using Dynamic Magnetic Resonance Images.

Goal: To quantify the regional properties of gastric motility from free-breathing dynamic MRI data. Methods: Free-breathing MRI scans were performed on 10 healthy human subjects. Motion correction was applied to reduce the respiratory effect. A stomach centerline was automatically generated and used as a reference axis. Contractions were quantified and visualized as spatio-temporal contraction maps. Gastric motility properties were reported separately for the lesser and greater curvatures in the proximal and distal regions of the stomach. Results: Motility properties varied in different regions of the stomach. The mean contraction frequencies for the lesser and greater curvatures were both 3.1±0.4 cycles per minute. The contraction speed was significantly higher on the greater curvature than the lesser curvature (3.5±0.7 vs 2.5±0.4 mm/s, p<0.001) while contraction size on both curvatures was comparable (4.9±1.2 vs 5.7±2.4 mm, p = 0.326). The mean gastric motility index was significantly higher in the distal greater curvature (28.13±18.89 mm2/s) compared to the other regions of the stomach (11.16-14.12 mm2/s). Conclusions: The results showed the effectiveness of the proposed method for visualization and quantification of motility patterns from MRI data.