Multichannel mapping of in vivo rat uterine myometrium exhibits both high and low frequency electrical activity in non-pregnancy.

The uterus exhibits intermittent electrophysiological activity in vivo. Although most active during labor, the non-pregnant uterus can exhibit activity of comparable magnitude to the early stages of labor. In this study, two types of flexible electrodes were utilized to measure the electrical activity of uterine smooth muscle in vivo in anesthetized, non-pregnant rats. Flexible printed circuit electrodes were placed on the serosal surface of the uterine horn of six anesthetized rats. Electrical activity was recorded for a duration of 20-30 min. Activity contained two components: high frequency activity (bursts) and an underlying low frequency 'slow wave' which occurred concurrently. These components had dominant frequencies of 6.82 ± 0.63 Hz for the burst frequency and 0.032 ± 0.0055 Hz for the slow wave frequency. There was a mean burst occurrence rate of 0.76 ± 0.23 bursts per minute and mean burst duration of 20.1 ± 6.5 s. The use of multiple high-resolution electrodes enabled 2D mapping of the initiation and propagation of activity along the uterine horn. This in vivo approach has the potential to provide the organ level detail to help interpret non-invasive body surface recordings.

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.

Cervical Vagus Nerve Stimulation Disrupts Gastric Slow Wave Activity in Rats.

Cervical vagus nerve stimulation (cVNS) is a promising neuromodulation therapy for treating symptoms of disease in peripheral organs. The rat is a common animal model for studying and trialing new applications of cVNS therapy, but the stomach and its activity in rats is less well characterized than other animals, such as pigs. We sought to investigate the effects of acute, in vivo cVNS on gastric bioelectrical activity as an intermediate step to computational modeling of the effects of cVNS on gastric smooth muscle electromechanical coupling. Here we show a method of detecting bioelectrical gastric slow wave events using a non-linear energy operator. The marked events are compared to the underlying bioelectrical slow wave activity.The mean propagation velocity before stimulation was 0.79 ± 0.31 mm s-1, and the mean interval was 17.4 ± 1.4 s. During cVNS, there was a significant increase in velocity (1.02 ± 0.69 mm s-1; p < 0.001), and decrease in interval (15.4 ± 2.9 s; p = 0.0196). At stimulation onset, premature slow waves were induced at an ectopic pacemaker location and waves originating at the ectopic and initial pacemaker sites continued to collide following the cessation of cVNS.This work forms the basis for more thorough investigation of the effects of cVNS on gastric bioelectrical slow wave activity and consequential smooth muscle contractions in rats. A better understanding of the effects of cVNS on gastric function will allow the refinement of cVNS therapy to target the stomach, and avoid off-target effects on the stomach.Clinical relevance- This work presents a signal processing and analysis approach for the investigation of cervical vagus nerve stimulation on gastric bioelectrical activity in rats. Vagus nerve stimulation may enable the control and amelioration of hunger, gastric emptying, or functional gastric disorders.

Optical Mapping of Virtual Electrode Polarization Pattern and Its Relationship with Pacemaker Location during Gastric Pacing.

Gastric rhythmic contractions are regulated by bioelectrical events known as slow waves (SW). Abnormal SW activity is associated with gastric motility disorders. Gastric pacing is a potential treatment method to restore rhythmic SW activity. However, to date, the efficacy of gastric pacing is inconsistent and the underlying mechanisms of gastric pacing are poorly understood. Optical mapping is widely used in cardiac electrophysiology studies. Its immunity to pacing artifacts offers a distinct advantage over conventional electrical mapping for studying pacing. In the present study, we first found that optical mapping can image pacing-induced virtual electrode polarization patterns in the stomach (adjacent regions of depolarized and hyperpolarized tissue). Second, we found that elicited SWs usually (15 of 16) originated from the depolarized areas of the stimulated region (virtual cathodes). To our knowledge, this is the first direct observation of virtual electrode polarization patterns in the stomach. Conclusions: Optical mapping can image virtual electrode polarization patterns during gastric pacing with high spatial resolution.Clinical Relevance- Gastric pacing is a potential therapeutic method for gastric motility disorders. This study provides direct observation of virtual electrode polarization pattern during gastric pacing and improves our understanding of the mechanisms underlying gastric pacing..

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.

Functional and anatomical gastric regions and their relations to motility control.

The common occurrence of gastric disorders, the accelerating emphasis on the role of the gut-brain axis, and development of realistic, predictive models of gastric function, all place emphasis on increasing understanding of the stomach and its control. However, the ways that regions of the stomach have been described anatomically, physiologically, and histologically do not align well. Mammalian single compartment stomachs can be considered as having four anatomical regions fundus, corpus, antrum, and pyloric sphincter. Functional regions are the proximal stomach, primarily concerned with adjusting gastric volume, the distal stomach, primarily involved in churning and propelling the content, and the pyloric sphincter that regulates passage of chyme into the duodenum. The proximal stomach extends from the dome of the fundus to a circumferential band where propulsive waves commence (slow waves of the pacemaker region), and the distal stomach consists of the pacemaker region and the more distal regions that are traversed by waves of excitation, that travel as far as the pyloric sphincter. Thus, the proximal stomach includes the fundus and different extents of the corpus, whereas the distal stomach consists of the remainder of the corpus and the antrum. The distributions of aglandular regions and of specialized glands, such as oxyntic glands, differ vastly between species and, across species, have little or no relation to anatomical or functional regions. It is hoped that this review helps to clarify nomenclature that defines gastric regions that will provide an improved basis for drawing conclusions for different investigations of the stomach.

A Computational Model of Biophysical Properties of the Rat Stomach Informed by Comprehensive Analysis of Muscle Anatomy.

An anatomically based 3D computational model of the rat stomach was developed using experimental muscle thickness measurements and muscle fiber orientations for the longitudinal muscle (LM) and circular muscle (CM) layers. First, 15 data points corresponding to the measurements were registered on the dorsal and ventral faces of the serosal surface of an averaged 3D rat stomach model. A thickness field representing the varying wall thickness was fitted to the surface and nodal points were projected outwards (for the LM layer) and inwards (for the CM layer) to create 2 new surfaces. In addition, a computational volume mesh was created and fiber orientation in each tetrahedral element was computed using a Laplace-Dirichlet rule-based algorithm and a simulation was performed to validate the model. The stomach model successfully represented the experimental measurements with a thickness in the range of 11.7-52.9 µm and 40.6-276.5 µm in the LM and CM layers, respectively, while the variation across the stomach was in agreement with the reported values. Similarly, the generated fiber orientations matched with the investigated fiber data and successfully resembled the observed properties such as the hairpin-like structure formed by the LM fibers in the fundus. Bioelectrical simulation using the developed model was successfully converged and reflected the properties of normal antegrade activity. In conclusion, a 3D computational model of the rat stomach was successfully developed and tested for in-silico studies. The model will be used in future studies to assess parameters in electrical therapies and to investigate the structure-function relationship in gastric motility. Clinical Relevance - Electrical stimulation is an emerging therapy for functional motility disorders. The 3D model of rat stomach developed in this study could provide accurate assessment of the efficacy of a vast range of stimulation parameters via in-silico studies and could aid in the adaptation of electrical therapies to clinical settings.

In vivo multi-channel measurement of electrical activity of the non-pregnant rat uterus.

In the uterus, the characteristics of smooth muscle contraction and the electrical activity that drives this contraction depends on hormonal cycles, and pregnancy status. Smooth muscle contraction is initiated by a change in membrane electrical potential, due to the flux of ions in and out of the intracellular space. Chains of action potentials throughout a section of muscle can result in coordinated contraction events. In this study, flexible printed circuit electrode arrays were applied to measure the bioelectric signals on the surface of a rat uterus in vivo. Variations in the electrical activity were quantified, including intermittent periods of activity and inactivity, which contain both slow-wave type activity (0.039 Hz ±0.017 Hz) and faster, spike-like activity (3.26 Hz ±0.27 Hz). The spike activity initiated at the ovarian end of the uterine horn, spreading towards the cervical end with a propagation velocity of 5.34 ± 2.32 mm [Formula: see text]. In conclusion, this pilot study outlines a new method of in vivo measurement of uterine electrical activity in rats. Clinical Relevance- Measurement of bioelectrical data using in vivo techniques provides insight into the electromechanical function of uterine smooth muscle, which could provide insights into what drives coordinated contraction in the uterus.

Mathematical Modeling of Gastric Slow Waves During Electrical Field Stimulation.

While neural modulation has been trialed as a therapy for functional gastric motility disorders, a computational model that guides stimulation protocol does not exist. In this work, a mathematical model of gastric slow wave activity, which incorporates the effects of neurotransmitter release during electrical field stimulation (EFS), was developed. Slow wave frequency responses due to the release of acetylcholine and slow wave amplitude responses due to the release of nitric oxide were modeled. The model was calibrated using experimental data from literature. A sensitivity analysis was conducted, which showed that the model yielded stable, periodic solutions for EFS frequencies in the range 0-20 Hz. A 25% increase in the input parameter (EFS frequency) from 5 Hz to 6.25 Hz resulted in a 5.2% increase in slow wave frequency and a 3.2 % decrease in slow wave amplitude. Simulated EFS showed that, for stimulation at 15 Hz, with blocking of the nitrergic neurotransmitter pathway the slow wave increased from the no stimulation scenario in frequency by only 2.4x compared to 2.7x when the nitrergic pathway was not blocked. A 21 % reduction in slow wave amplitude occurred when the cholinergic pathway was blocked, compared to a 46% reduction when no neurotransmitter pathways were blocked. Clinical relevance - This mathematical model is a step towards successful computational modeling of the effects ther-apeutic neural stimulation on the stomach. The model is also a tool for understanding of the physiology of neural stimulation.

Wet-printing of PEDOT:PSS Microelectrodes for Gastric Slow Wave Recording.

Bioelectrical slow waves are fundamental to maintaining the normal motility of the gastrointestinal tract. Slow wave abnormalities are associated with several major digestive disorders. High-resolution electrical mapping arrays have been used to investigate pathological slow wave abnormalities. However, conventional electrode substrate materials are opaque with high mechanical modulus, which leads to non-compliance and sub-par contact with the organ, without additional manipulations. Here we developed highly conformal and transparent conducting polymer electrode arrays using the extrusion wet-printing technique. The performance of electrodes for the electrophysiological recording of the gastric slow wave was validated using in a pig model, against a previously validated reference array over 100 s recording window. The conducting polymer electrodes registered comparable frequency to the reference array ( 3.31±0.20 cpm vs. 3.27±0.07 cpm, p = 0.067), with lower amplitude ( 372±237 vs. ), and signal to noise ratio ( 10.92±7.83 vs. [Formula: see text]). Further adjustments to the deposition parameters and contact material will improve the performance of the conducting polymer array for future experimental applications. Clinical Relevance- These conducting polymer electrodes provide better compliance and minimized mechanical mismatch to the gut tissue thus allowing long-term monitoring and stimulation of the gut. This could be potentially extended to other organs as well.

Design of Pressure Sensor Arrays to Assess Electrode Contact Pressure During In Vivo Recordings in the Gut.

The gastrointestinal (GI) tract is in part controlled by slow wave electrical activity. Recordings of slow waves with high-resolution (HR) electrode arrays are used to characterize normal and abnormal conduction pathways. Improving the quality of these electrical recordings is important for developing a better understanding of abnormal activity. Contact pressure is one factor that can affect the quality of electrical recordings. We compared the performance of two pressure sensing devices for measuring HR electrode array contact pressure. A Velostat-based sensor array was custom designed and built in a 4 × 2 conguration (area: 30 mm2 per sensor) to be integrated into electrical recordings. Commercially available FlexiForce A201 sensors were used to compare to the Velostat-based sensors. Benchtop testing of these sensors was performed; the error of the Velostat-based sensors (14-31%) was better than that of the FlexiForce sensors (20-49%) within a range of 2666-6666 Pa. The Velostat-based sensors were also more repeatable than the FlexiForce sensors over the same pressure range. Simultaneous pressure and slow wave recordings were performed in vivo on a rabbit small intestine. The Velostat-based sensors were able to resolve spatiotemporal changes in contact pressure in the range of 0-10 000 Pa.