Gregory O'Grady

Origin and propagation of human gastric slow-wave activity defined by high-resolution mapping

Slow waves coordinate gastric motility, and abnormal slow-wave activity is thought to contribute to motility disorders. The current understanding of normal human gastric slow-wave activity is based on extrapolation from data derived from sparse electrode recordings and is therefore potentially incomplete. This study employed high-resolution (HR) mapping to reevaluate human gastric slow-wave activity. HR mapping was performed in 12 patients with normal stomachs undergoing upper abdominal surgery, using flexible printed circuit board (PCB) arrays (interelectrode distance 7.6 mm). Up to six PCBs (192 electrodes; 93 cm(2)) were used simultaneously. Slow-wave activity was characterized by spatiotemporal mapping, and regional frequencies, amplitudes, and velocities were defined and compared. Slow-wave activity in the pacemaker region (mid to upper corpus, greater curvature) was of greater amplitude (mean 0.57 mV) and higher velocity (8.0 mm/s) than the corpus (0.25 mV, 3.0 mm/s) (P < 0.001) and displayed isotropic propagation. A marked transition to higher amplitude and velocity activity occurred in the antrum (0.52 mV, 5.9 mm/s) (P < 0.001). Multiple (3-4) wavefronts were found to propagate simultaneously in the organoaxial direction. Frequencies were consistent between regions (2.83 +/- 0.35 cycles per min). HR mapping has provided a more complete understanding of normal human gastric slow-wave activity. The pacemaker region is associated with high-amplitude, high-velocity activity, and multiple wavefronts propagate simultaneously. These data provide a baseline for future HR mapping studies in disease states and will inform noninvasive diagnostic strategies.

Abnormal initiation and conduction of slow-wave activity in gastroparesis, defined by high-resolution electrical mapping.

BACKGROUND & AIMS Interstitial cells of Cajal (ICC) generate slow waves. Disrupted ICC networks and gastric dysrhythmias are each associated with gastroparesis. However, there are no data on the initiation and propagation of slow waves in gastroparesis because research tools have lacked spatial resolution. We applied high-resolution electrical mapping to quantify and classify gastroparesis slow-wave abnormalities in spatiotemporal detail. METHODS Serosal high-resolution mapping was performed using flexible arrays (256 electrodes; 36 cm(2)) at stimulator implantation in 12 patients with diabetic or idiopathic gastroparesis. Data were analyzed by isochronal mapping, velocity and amplitude field mapping, and propagation animation. ICC numbers were determined from gastric biopsy specimens. RESULTS Mean ICC counts were reduced in patients with gastroparesis (2.3 vs 5.4 bodies/field; P < .001). Slow-wave abnormalities were detected by high-resolution mapping in 11 of 12 patients. Several new patterns were observed and classified as abnormal initiation (10/12; stable ectopic pacemakers or diffuse focal events; median, 3.3 cycles/min; range, 2.1-5.7 cycles/min) or abnormal conduction (7/10; reduced velocities or conduction blocks; median, 2.9 cycles/min; range, 2.1-3.6 cycles/min). Circumferential conduction emerged during aberrant initiation or incomplete block and was associated with velocity elevation (7.3 vs 2.9 mm s(-1); P = .002) and increased amplitudes beyond a low base value (415 vs 170 μV; P = .002). CONCLUSIONS High-resolution mapping revealed new categories of abnormal human slow-wave activity. Abnormalities of slow-wave initiation and conduction occur in gastroparesis, often at normal frequency, which could be missed by tests that lack spatial resolution. Irregular initiation, aberrant conduction, and low amplitude activity could contribute to the pathogenesis of gastroparesis.

Quantification of in vivo colonic motor patterns in healthy humans before and after a meal revealed by high-resolution fiber-optic manometry.

Until recently, investigations of the normal patterns of motility of the healthy human colon have been limited by the resolution of in vivo recording techniques.

Rapid high-amplitude circumferential slow wave propagation during normal gastric pacemaking and dysrhythmias.

Background  Gastric slow waves propagate aborally as rings of excitation. Circumferential propagation does not normally occur, except at the pacemaker region. We hypothesized that (i) the unexplained high‐velocity, high‐amplitude activity associated with the pacemaker region is a consequence of circumferential propagation; (ii) rapid, high‐amplitude circumferential propagation emerges during gastric dysrhythmias; (iii) the driving network conductance might switch between interstitial cells of Cajal myenteric plexus (ICC‐MP) and circular interstitial cells of Cajal intramuscular (ICC‐IM) during circumferential propagation; and (iv) extracellular amplitudes and velocities are correlated.

Gastrointestinal system: Gastrointestinal system

The functions of the gastrointestinal (GI) tract include digestion, absorption, excretion, and protection. In this review, we focus on the electrical activity of the stomach and small intestine, which underlies the motility of these organs, and where the most detailed systems descriptions and computational models have been based to date. Much of this discussion is also applicable to the rest of the GI tract. This review covers four major spatial scales: cell, tissue, organ, and torso, and discusses the methods of investigation and the challenges associated with each. We begin by describing the origin of the electrical activity in the interstitial cells of Cajal, and its spread to smooth muscle cells. The spread of electrical activity through the stomach and small intestine is then described, followed by the resultant electrical and magnetic activity that may be recorded on the body surface. A number of common and highly symptomatic GI conditions involve abnormal electrical and/or motor activity, which are often termed functional disorders. In the last section of this review we address approaches being used to characterize and diagnose abnormalities in the electrical activity and how these might be applied in the clinical setting. The understanding of electrophysiology and motility of the GI system remains a challenging field, and the review discusses how biophysically based mathematical models can help to bridge gaps in our current knowledge, through integration of otherwise separate concepts. Copyright

Biophysically Based Modeling of the Interstitial Cells of Cajal: Current Status and Future Perspectives

Gastrointestinal motility research is progressing rapidly, leading to significant advances in the last 15 years in understanding the cellular mechanisms underlying motility, following the discovery of the central role played by the interstitial cells of Cajal (ICC). As experimental knowledge of ICC physiology has expanded, biophysically based modeling has become a valuable tool for integrating experimental data, for testing hypotheses on ICC pacemaker mechanisms, and for applications in in silico studies including in multiscale models. This review is focused on the cellular electrophysiology of ICC. Recent evidence from both experimental and modeling domains have called aspects of the existing pacemaker theories into question. Therefore, current experimental knowledge of ICC pacemaker mechanisms is examined in depth, and current theories of ICC pacemaking are evaluated and further developed. Existing biophysically based ICC models and their physiological foundations are then critiqued in light of the recent advances in experimental knowledge, and opportunities to improve these models are identified. The review concludes by examining several potential clinical applications of biophysically based ICC modeling from the subcellular through to the organ level, including ion channelopathies and ICC network degradation.

Circumferential and functional re‐entry of in vivo slow‐wave activity in the porcine small intestine

Slow‐waves modulate the pattern of small intestine contractions. However, the large‐scale spatial organization of intestinal slow‐wave pacesetting remains uncertain because most previous studies have had limited resolution. This study applied high‐resolution (HR) mapping to evaluate intestinal pacesetting mechanisms and propagation patterns in vivo.

Mapping and Modeling Gastrointestinal Bioelectricity: From Engineering Bench to Bedside

A key discovery in gastrointestinal motility has been the central role played by interstitial cells of Cajal (ICC) in generating electrical slow waves that coordinate contractions. Multielectrode mapping and multiscale modeling are two emerging interdisciplinary strategies now showing translational promise to investigate ICC function, electrophysiology, and contractions in the human gut.

Improved signal processing techniques for the analysis of high resolution serosal slow wave activity in the stomach

High resolution electrical mapping of slow waves on the stomach serosa has improved our understanding of gastric electrical activity in normal and diseased states. In order to assess the signals acquired from high resolution mapping, a robust framework is required. Our framework is semi-automated and allows for rapid processing, analysis and interpretation of slow waves via qualitative and quantitative measures including isochronal activation time mapping, and velocity and amplitude mapping. Noise removal techniques were validated for raw recorded signals, where three filters were evaluated for baseline drift removal and three filters for removal of high frequency interference. For baseline drift removal, the Gaussian moving median filter was most effective, while for eliminating high frequency interference the Savitzky Golay filter was the most effective. Methods for assessing slow wave velocity and amplitude were investigated. To estimate slow wave velocity, a finite difference approach with interpolation and smoothing was used. To evaluate the slow wave amplitude and width, a peak and trough method based on Savitzky Golay derivative filters was used. Together, these methods constitute a significantly improved framework for analyzing gastric high resolution mapping data.

Recent progress in gastric arrhythmia: Pathophysiology, clinical significance and future horizons

Gastric arrhythmia continues to be of uncertain diagnostic and therapeutic significance. However, recent progress has been substantial, with technical advances, theoretical insights and experimental discoveries offering new translational opportunities. The discoveries that interstitial cells of Cajal (ICC) generate slow waves and that ICC defects are associated with dysmotility have reinvigorated gastric arrhythmia research. Increasing evidence now suggests that ICC depletion and damage, network disruption and channelopathies may lead to aberrant slow wave initiation and conduction. Histological and high‐resolution (HR) electrical mapping studies have now redefined the human ‘gastric conduction system’, providing an improved baseline for arrhythmia research. The application of HR mapping to arrhythmia has also generated important new insights into the spatiotemporal dynamics of arrhythmia onset and maintenance, resulting in the emergence of new provisional classification schemes. Meanwhile, the strong associations between gastric functional disorders and electrogastrography (EGG) abnormalities (e.g. in gastroparesis, unexplained nausea and vomiting and functional dyspepsia) continue to motivate deeper inquiries into the nature and causes of gastrointestinal arrhythmias. In future, technical progress in EGG methods, new HR mapping devices and software, wireless slow wave acquisition systems and improved gastric pacing devices may achieve validated applications in clinical practice. Neurohormonal factors in arrhythmogenesis also continue to be elucidated and a deepening understanding of these mechanisms may open opportunities for drug design for treating arrhythmias. However, for all translational goals, it remains to be seen whether arrhythmia can be corrected in a way that meaningfully improves organ function and symptoms in patients.