[Show abstract][Hide abstract] ABSTRACT: Gastric dysrhythmia 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 dysrhythmia 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 dysrhythmia research. The application of HR mapping to dysrhythmia has also generated important new insights into the spatiotemporal dynamics of dysrhythmia 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 GI dysrhythmias. 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 dysrhythmogenesis also continue to be elucidated, and a deepening understanding of these mechanisms may open opportunities for drug design for treating dysrhythmias. However, for all translational goals, it still remains to be seen whether dysrhythmia can be corrected in a way that meaningfully improves organ function and symptoms in patients.This article is protected by copyright. All rights reserved.
Clinical and Experimental Pharmacology and Physiology 08/2014; · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim: There is little knowledge about macroscopic electrical propagation in the wall of the urinary bladder. Recording simultaneously from a large number of extracellular electrodes is one technology that could be used to study the patterns of macroscopic electrical propagations. Method: The urinary bladders from 14 guinea pigs were isolated and placed in a organ bath. A 16x4 electrode array was positioned at various sites on the serosal bladder surface and recordings were performed at different intravesical volumes. In four experiments, carbachol (CCH; 10(-6) M), nifedipine (10 mM) or tetrodotoxin (TTX; 10(-6) M) was added to the superfusing fluid. After the experiments, the extracellular signals were analysed and propagation maps constructed. Results: Electrical waves were detected at all sites on the bladder surface and propagated for a limited distance before terminating spontaneously. The majority of waves ( > 90%) propagated in the axial direction (i.e. from dome to base or vice versa). Increase in vesical volume decreased significantly the conduction velocity (from 4.9±1.5 to 2.7±0.7 cm/sec; p< 0.05). CCH increased, nifedipine decreased while TTX had little effect on electrical activities. In addition, a new electrical phenomenon, termed a 'patch', was discovered whereby a simultaneous electrical deflection was detected across an area of the bladder surface. Conclusions: Two types of electrical activities were detected on the bladder surface: a) electrical waves propagating preferentially in the axial direction and b) electrical patches. The propagating electrical waves could form the basis for local spontaneous contractions in the bladder during the filling phase.
American journal of physiology. Renal physiology 06/2014; · 3.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In recent years, it has become possible to record, from a large number of extracellular electrodes, the electrical activities of smooth muscle organs. These recordings, after proper processing and analysis, may reveal origin and propagation of normal and abnormal electrical activities in these organs. Several publications have appeared in the past 5 years describing origin and propagation of slow waves in the stomach of experimental animals and in humans. Furthermore, publications are now starting to appear that describe pathophysiological patterns of propagation and these studies provide us with novel concepts regarding potential mechanisms of arrhythmias in the gut, crucial information if we are ever going to successfully treat patients suffering from such arrhythmias. In this issue of Neurogastroenterology & Motility, Angeli et al. have mapped the slow wave propagation in the porcine small intestine and discovered two types of reentry; functional reentry and circumferential reentry. Next to the descriptions of arrhythmias in the stomach, the fact that reentrant arrhythmias may also occur in the small intestine further extends this new emerging field of gastrointestinal (GI) arrhythmias. In this viewpoint, the relevance of these arrhythmias is further discussed and a few ideas for future research in this field, not necessarily constrained to the GI system, proposed.
Neurogastroenterology and Motility 03/2013; · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
An experimental-theoretical study was performed. High-resolution gastric mapping was performed in pigs during normal activation, pacing, and dysrhythmia. Activation profiles, velocities, and amplitudes were quantified. ICC pathways were theoretically evaluated in a bidomain model. Extracellular potentials were modeled as a function of membrane potentials.
High-velocity, high-amplitude activation was only recorded in the pacemaker region when circumferential conduction occurred. Circumferential propagation accompanied dysrhythmia in 8/8 experiments was faster than longitudinal propagation (8.9 vs 6.9 mm s(-1) ; P = 0.004) and of higher amplitude (739 vs 528 μV; P = 0.007). Simulations predicted that ICC-MP could be the driving network during longitudinal propagation, whereas during ectopic pacemaking, ICC-IM could outpace and activate ICC-MP in the circumferential axis. Experimental and modeling data demonstrated a linear relationship between velocities and amplitudes (P < 0.001).
The high-velocity and high-amplitude profile of the normal pacemaker region is due to localized circumferential propagation. Rapid circumferential propagation also emerges during a range of gastric dysrhythmias, elevating extracellular amplitudes and organizing transverse wavefronts. One possible explanation for these findings is bidirectional coupling between ICC-MP and circular ICC-IM networks.
Neurogastroenterology and Motility 07/2012; 24(7):e299-312. · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In contrast to the current state of knowledge of cardiac and of gastrointestinal electrophysiology, our current knowledge of the physiology of the uterus during pregnancy is still very rudimentary. Despite seminal work performed in the past decades, there are still significant areas that we know little about. In this review, some of these areas are explored. For example, although many studies have tried to find the site of the uterus pacemaker, such a site has not yet been found and its mechanism and location remain, to date, a mystery. Similarly, there is much confusion as to the mechanism of propagation of the electrical impulse. Although the existence of gap junctions, connecting neighboring myometrial cells to each other, have been known since 1977, alternative or additional mechanisms are being suggested such as the potential existence of a network of interstitial cells, similar to the one that is functioning in the gut, or the involvement of stretch receptors to synchronize activity and contraction. In recent years, high-resolution studies have been introduced enabling detailed analysis of the location and spatial patterns of propagation. This work is being developed at the in-vitro level in isolated tissues, in the whole organ and in several animal species. Most recently, a surge in new technology enabling high fidelity and high resolution recording from the human uterus through the abdominal wall are being explored which could ultimately lead to new diagnostic tools and a clearer understanding of the physiology of pregnancies and (premature) labor.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
[Show abstract][Hide abstract] ABSTRACT: In a few recent studies, the presence of arrhythmias based on reentry and circus movement of the slow wave have been shown to occur in normal and diseased stomachs. To date, however, reentry has not been demonstrated before in any other part of the gastrointestinal system. No animals had to be killed for this study. Use was made of materials obtained during the course of another study in which 11 rats were treated with streptozotocin and housed with age-matched controls. After 3 and 7 mo, segments of duodenum, jejunum, and ileum were isolated and positioned in a tissue bath. Slow wave propagation was recorded with 121 extracellular electrodes. After the experiment, the propagation of the slow waves was reconstructed. In 10 of a total of 66 intestinal segments (15%), a circus movement of the slow wave was detected. These reentries were seen in control (n = 2) as well as in 3-mo (n = 2) and 7-mo (n = 6) diabetic rats. Local conduction velocities and beat-to-beat intervals during the reentries were measured (0.42 ± 0.15 and 3.03 ± 0.67 cm/s, respectively) leading to a wavelength of 1.3 ± 0.5 cm and a circuit diameter of 4.1 ± 1.5 mm. This is the first demonstration of a reentrant arrhythmia in the small intestine of control and diabetic rats. Calculations of the size of the circuits indicate that they are small enough to fit inside the intestinal wall. Extrapolation based on measured velocities and rates indicate that reentrant arrhythmias are also possible in the distal small intestine of larger animals including humans.
[Show abstract][Hide abstract] ABSTRACT: The number of myenteric interstitial cells of Cajal (ICC-MY), responsible for the generation and propagation of the slow wave in the small intestine, has been shown to decrease in diabetes, suggesting impairment of slow-wave (SW) propagation and related motility. To date, however, this expected decrease in SW propagation has neither been recorded nor analysed. Eleven rats were treated with streptozotocin and housed in pairs with 11 age-matched control animals. After 3 or 7 months, segments of duodenum, jejunum and ileum were isolated and divided into two parts. One part was processed for immediate freezing, cryosectioning and immunoprobing using anti-c-Kit antibody to quantify ICC-MY. The second part was superfused in a tissue bath, and SW propagation was recorded with 121 extracellular electrodes. In addition, a cellular automaton was developed to study the effects of increasing the number of inactive cells on overall propagation. The number of ICC-MY was significantly reduced after 3 months of diabetes, but rebounded to control levels after 7 months of diabetes. Slow-wave frequencies, velocities and extracellular amplitudes were unchanged at any stage of diabetes. The cellular automaton showed that SW velocity was not linearly related to the number of inactive cells. The depletion of ICC-MY is not as severe as is often assumed and in fact may rebound after some time. In addition, at least in the streptozotocin model, the initial reduction in ICC-MY is not enough to affect SW propagation. Diabetic intestinal dysfunction may therefore be more affected by impairments of other systems, such as the enteric system or the muscle cells.
[Show abstract][Hide abstract] ABSTRACT: The significance of gastric dysrhythmias remains uncertain. Progress requires a better understanding of dysrhythmic behaviors, including the slow wave patterns that accompany or promote them. The aim of this study was to use high-resolution spatiotemporal mapping to characterize and quantify the initiation and conduction of porcine gastric dysrhythmias.
High-resolution mapping was performed on healthy fasted weaner pigs under general anesthesia. Recordings were made from the gastric serosa using flexible arrays (160-192 electrodes; 7.6mm spacing). Dysrhythmias were observed to occur in 14 of 97 individual recordings (from 8 of 16 pigs), and these events were characterized, quantified and classified using isochronal mapping and animation.
All observed dysrhythmias originated in the corpus and fundus. The range of dysrhythmias included incomplete conduction block (n=3 pigs; 3.9±0.5cpm; normal range: 3.2±0.2cpm) complete conduction block (n=3; 3.7±0.4cpm), escape rhythm (n=5; 2.0±0.3cpm), competing ectopic pacemakers (n=5, 3.7±0.1cpm) and functional re-entry (n=3, 4.1±0.4cpm). Incomplete conduction block was observed to self-perpetuate due to retrograde propagation of wave fragments. Functional re-entry occurred in the corpus around a line of unidirectional block. 'Double potentials' were observed in electrograms at sites of re-entry and at wave collisions.
Intraoperative multi-electrode mapping of fasted weaner healthy pigs detected dysrhythmias in 15% of recordings (from 50% of animals), including patterns not previously reported. The techniques and findings described here offer new opportunities to understand the nature of human gastric dysrhythmias.
Neurogastroenterology and Motility 06/2011; 23(9):e345-55. · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated the propagation of electrical impulses in a reversible, complete or partial unilateral ureteral obstruction model in vivo.
In Wistar rats the left mid ureter was completely (8) or partially (7) occluded and released after 24 hours. We recorded electrical activity of the left and right ureter before, during and after obstruction at different stages up to 2 weeks after obstruction using a high resolution, 64 extracellular electrode probe.
Complete obstruction in the left proximal ureter caused an immediate increase in frequency from a mean ± SEM of 14.8 ± 1.3 to 18.6 ± 1.7 per minute (p <0.05), followed by a 1.4 ± 0.9 per minute decrease (p <0.001). Within the first 2 days after reversal velocity gradually decreased from 1.82 ± 0.12 to 0.79 ± 0.17 cm per second (p <0.001). Release of obstruction gradually restored frequency and velocity, which returned to baseline at 2 weeks. Generally the alterations in rats with complete and partial obstruction were similar but they were less marked in those with partial obstruction. Distal to the obstruction site the impulses disappeared (38%) or propagated retrograde (43%) at some stage in the post-obstruction period. These abnormal impulse propagations also gradually disappeared in the post-obstruction stage.
After complete or partial ureteral obstruction there were immediate, significant changes in the propagation of electrical impulses in the proximal and distal left ureter, which were generally less marked after partial than after complete obstruction. Reversal of obstruction resulted in the gradual disappearance of this abnormality in 2 weeks.
The Journal of urology 02/2011; 185(2):744-50. · 4.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the propagation of the electrical impulses in a unilateral ureteric obstruction model using a high-resolution technique in vivo.
In Wistar rats (n= 15), the left mid-ureter was occluded and the electrical activity was recorded from the proximal and distal part of the obstructed ureter and from the right ureter at different times up to 2 weeks post-obstruction using 64 extracellular electrodes.
In the left ureter, impulses propagated in an antegrade direction at a frequency of 15.5 ± 1.3/min and a velocity of 1.6 ± 0.1 cm/s. Immediately post-obstruction, the proximal part showed an increase in frequency (19.1 ± 2.5/min; P < 0.05) followed by a gradual decrease (at 2 weeks: 2.5 ± 1.2/min; P < 0.001). The velocity of these impulses decreased gradually (at 2 weeks: 0.5 ± 0.1 cm/s; P < 0.05). Distally, the antegrade propagations gradually disappeared and, at 1 week, 33% of ureters showed retrograde impulses and 67% displayed no electrical activity. The frequency of both antegrade and retrograde impulses distal to the obstruction dropped immediately after obstruction so that, at 1 day, it was 1.0 ± 0.3 and 1.5 ± 0.2/min, respectively (P < 0.01 for both). The velocity of these antegrade and retrograde impulses showed a significant rise throughout the post-obstruction period. The right ureter showed only a transient increase in frequency from 18.7 ± 2.7 to 30.3 ± 6.1/min (P < 0.05).
Using this high-resolution technique, it is concluded that, after ureteric obstruction, there were immediate and significant changes in the propagation of electrical impulses in the proximal and distal left ureter and in the right ureter, all of which behaved differently. This data may provide a better insight into the electrophysiological function of the normal and obstructed ureter.
BJU International 11/2010; 108(2 Pt 2):E36-42. · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pig is a popular model for gastric electrophysiology studies. However, its normal baseline gastric activity has not been well characterized. High-resolution (HR) mapping has recently enabled an accurate description of human and canine gastric slow wave activity, and was employed here to define porcine gastric slow wave activity.
Fasted pigs underwent HR mapping following anesthesia and laparotomy. Flexible printed-circuit-board arrays were used (160-192 electrodes; spacing 7.62 mm). Anterior and posterior surfaces were mapped simultaneously. Activation times, velocities, amplitudes and frequencies were calculated, and regional differences evaluated.
Mean slow wave frequency was 3.22 ± 0.23 cpm. Slow waves propagated isotropically from the pacemaker site (greater curvature, mid-fundus). Pacemaker activity was of higher velocity (13.3 ± 1.0 mm s(-1)) and greater amplitude (1.3 ± 0.2 mV) than distal fundal activity (9.0 ± 0.6 mm s(-1), 0.9 ± 0.1 mV; P < 0.05). Velocities and amplitudes were similar in the distal fundus, proximal corpus (8.4 ± 0.8 mm s(-1), 1.0 ± 0.1 mV), distal corpus (8.3 ± 0.8 mm s(-1), 0.9 ± 0.2 mV) and antrum (6.8 ± 0.6 mm s(-1), 1.1 ± 0.2 mV). Activity was continuous across the anterior and posterior gastric surfaces.
This study has quantified normal porcine gastric slow wave activity at HR during anesthesia and laparotomy. The pacemaker region was associated with high-amplitude, high-velocity slow wave activity compared to the activity in the rest of the stomach. The increase in distal antral slow wave velocity and amplitude previously described in canines and humans is not observed in the pig. Investigators should be aware of these inter-species differences.
Neurogastroenterology and Motility 10/2010; 22(10):e292-300. · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The hypothesis was put forward by Thuneberg that rhythmically contracting interstitial cells of Cajal (ICC) were sensing stretch of the musculature and that this information was transmitted to smooth muscle cells via peg and socket contacts. The present study provides the evidence for the contractile nature of ICC as perceived by Thuneberg. The contractile activity is shown by video frame subtraction and by tracking areas of interest in sequential video frames. Thuneberg used neonatal ICC in culture maintained between two coverslips thereby allowing growth factors to quickly reach optimal concentrations. Contractions of ICC were seen to precede smooth muscle contractions. In addition, strong contractions were observed solely in branches of ICC. It is hoped that this communication will stimulate discussion about the contractile nature of ICC and that this phenomenon will eventually find its place amongst the physiological properties of the ICC networks of the gut musculature.
The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 09/2010; 293(9):1543-52. · 1.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.