Contents

Summary

Gastric dysrhythmia continues to be a clinical enigma 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 abnormalities are associated with motility disorders have reinvigorated gastric dysrhythmia research. Increasing evidence now suggests that ICC depletion and damage, network disruption and channelopathies may serve as causes of aberrant slow wave initiation and conduction. Histological and high-resolution (HR) electrical mapping studies have recently redefined the normal human ‘gastric conduction system’, providing an improved baseline for dysrhythmia research. Further, the application of HR mapping to dysrhythmia has generated important new insights into the spatiotemporal dynamics of dysrhythmia onset and maintenance, resulting in the emergence of new provisional classification schemes. 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 dysrhythmia. However, for such translational goals, it remains to be seen whether dysrhythmia can be corrected in a way that improves organ function and symptoms in patients.

Introduction

Almost a century has passed since the esteemed physiologist Alvarez made his “little prophesy” that “gastroenterologists would come to rely upon electrical measures for the routine diagnosis of stomach disorders, just as the heart specialist [does]".¹ Despite intensive investigations through the intervening years, Alvarez’s prophesy remains unfulfilled. There continues to be little uptake of gastric electrical diagnostics beyond a few specialist research centres, due to ongoing uncertainty regarding the reliability and value of current clinical tests.^2,3

However, recent progress has been substantial, with technical advances, theoretical insights, and experimental discoveries offering new translational opportunities in gastric electrophysiology. This update evaluates several of these advances and addresses future horizons in the basic and clinical science of gastric dysrhythmia.

The role of ICC

It is now widely accepted that slow waves are generated and propagated by interstitial cells of Cajal (ICC), and this discovery has been accompanied by intense interest in what roles ICC defects may play in disease.^4,5 These advances have critically informed new directions in dysrhythmia research, and reinvigorate clinical interest in evaluating gastric electrical activity.

In the stomach, the strongest evidence for a pathophysiologic role for ICC is in gastroparesis.^6,7 While gastroparesis is multifactorial, and also associated with autonomic, smooth muscle, enteric nervous system and immune cellular changes and fibrosis,^6,8 the ICC loss appears to be of particular significance. ICC abnormalities are the most common histological finding in both idiopathic and diabetic gastroparesis,⁶ and severity of ICC loss has been correlated with severity of gastric retention as well as electrogastrography (EGG) abnormalities.^9,10 Animal model research supports a pathophysiologic role for ICC in gastroparesis; for example, induction of heme oxygenase-1, a cytoprotective molecule against oxidative stress, has been shown to both restore ICC and normalize gastric emptying in non-obese diabetic mice.¹¹

Another emerging ICC research area with implications for dysrhythmia is ion channel defects (channelopathies).¹² Early work in this area has linked mutations in the mechanosensitive Na(v)1.5 sodium channel, encoded by the SCN5A gene and found in human ICC and smooth muscle cells, with irritable bowel syndrome.¹³ Channel defects of this type can substantially modify whole cell slow wave activation,¹⁴ potentially inducing dysrhythmias in a manner analogous to defined types of cardiac dysrhythmia.¹⁵ Further research is needed to determine whether such mechanisms are also important in disorders such as functional dyspepsia.¹⁶

ICC also serve several other functions beside slow wave pacemaking, including mediating neurotransmission, mechanotransduction and establishing smooth muscle resting membrane potential gradients.^4,5 Importantly, ICC pathologies will therefore impact on gastric motility by other pathways beyond just slow wave dysrhythmia.¹⁷

The gastric conduction system

In the normal stomach, ICC generate slow waves synchronously at a common frequency, achieved by their ‘entrainment’ to the highest frequency expressed in their syncytium within the gastric wall.¹⁸ Entrainment is maintained by an underlying frequency gradient intrinsic to ICC, which declines in the aboral direction, as may be revealed by partitioning the stomach into isolated segments.^19,20 It is helpful to consider the pathogenesis of dysrhythmia mechanisms in terms of disruption to normal entrainment (‘disorders of conduction’) or to the intrinsic ICC frequencies (‘disorders of initiation’) (e.g. Figure 1), and each of these abnormalities may in turn promote secondary forms of dysrhythmia (e.g. Figure 2).

Figure 1. An example of the classification schemes for gastric dysrhythmia that are emerging. These are now being based on mechanisms and spatial patterns of slow wave activation. Aberrant initiation relates to abnormalities of intrinsic ICC frequencies, and example activities include stable ectopic pacemakers and unstable regions of ectopic foci. Aberrant conduction involves disruption of the normal slow wave entrainment, and examples include abnormal velocities, conduction blocks, and re-entrant activities.

Figure 2. Examples of secondary gastric dysrhythmia mechanisms. These were observed during multi-electrode (high-resolution) mapping, whereby one class of dysrhythmia may induce secondary dysrhythmic events. (i) Conduction delay or block may give rise to distal ‘escape’ events, due to the inherent automaticity of distal ICC;^7,66 (ii) Conduction inhomogeneity, in the presence of unidirectional block, may give rise to re-entrant slow wave activity;^34,42,66 (iii) Ectopic events in the distal stomach may cause uncoupled areas of tissue, resulting in block of the normal antegrade wavefronts.^7,42,66

In human stomach, an anastomosing network of ICC is distributed throughout the myenteric plexus (ICC-MP), and circular and longitudinal muscle layers (intramuscular ICC; ICC-IM).^21,22 ICC-IM run parallel to the smooth muscle fibres within the muscle layers, forming a loosely connecting network, with a further anatomical subclass of ICC encasing and connecting bundles (ICC-SEP).²² In animal models (but yet to be shown in humans), a decrease in ICC-MP within the pylorus functions as an electrical barrier, helping to isolate gastric and duodenal electrical events.²³

Extracellular recordings remain the primary tool for evaluating in vivo gastric slow wave activation patterns over large tissue areas.²⁴ Classically, gastric slow wave propagation was studied using sparse arrangements of extracellular electrodes, typically up to eight, placed at regular intervals along the GI tract. However, such results were incomplete due to the limitations of sparse sampling, and could be misleading due to spatial aliasing.²⁵ These limitations therefore motivated the introduction of GI high-resolution (HR) electrical mapping by Lammers et al., whereby dense arrays of electrodes were applied to accurately track activation in spatiotemporal detail.^26,27 The analysis of gastric conduction patterns using HR mapping has now yielded a much more accurate description of the normal origin and propagation of gastric slow waves in large animal models and in humans,^25,28,29 serving as a reliable baseline for dysrhythmia investigations.

Gastric anisotropy

Velocity anisotropy has proven to be an important finding from HR mapping studies for dysrhythmia interpretation, whereby extracellular slow waves in the region of the normal gastric pacemaker show a much higher velocity and amplitude activity than events in the surrounding corpus (∼2.5× in humans).^25,28 The reason for the high velocity and amplitude pacemaker pattern was only recently resolved in a combined theoretical-experimental study,³⁰ aided by novel methods for analysing the spatial properties of slow wave activation.^31,32,33 The high local velocity is the consequence of the fact that the impulse propagates from the pacemaker area initially and predominantly in the circumferential direction.³⁰ In human stomach, propagation in the circumferential direction is ∼2.5× faster than in the longitudinal direction (termed ‘anisotropic’ propagation). The accompanying increase in extracellular amplitudes is due to changes in current distribution associated with the higher impulse velocity.³⁰ By the time slow waves reach the mid to lower corpus, however, they have formed into complete ring wavefronts, such that the rapid circumferential conduction ceases, and wavefronts propagate with slower antegrade activation towards the pylorus.^25,30

Velocity anisotropy is critical to the interpretation of dysrhythmic activity, because disorders of both initiation and conduction disrupt normal gastric ring wavefronts.^7,30 This allows ‘ectopic circumferential propagation’ to emerge, such that dysrhythmias are characterized by high-velocity wavefronts and high-amplitude signals local to their source, which directly determines the patterns of dysrhythmic activation. This anisotropy also plays a key role in the maintenance and stability of dysrhythmic patterns, such as slow wave re-entry³⁴ (recently reviewed by Cheng et al., 2013³⁵).

It is not yet known which ICC network structures underlie the anisotropic properties outlined above. There are likely to be two complimentary gastric conduction pathways active, supporting circumferential conduction at high velocity and longitudinal conduction at low velocity.³⁶ For humans, it was recently proposed that within a bidirectionally-coupled ICC system, the leading network might switch between ICC-MP (dominant during longitudinal conduction) and ICC-IM (dominant during circumferential conduction), depending on the presence or absence of complete gastric ring wavefronts.³⁰ This theory awaits validation, but could offer mechanistic insights into dysrhythmogenesis. For example, slow wave frequencies are known to increase in ICC-IM at sites of sustained cholinergic stimulation,³⁷ which could then act as sites of dysrhythmic initiation within a bidirectionally-coupled system.

Electrogastrography and dysrhythmia

Much of what is known about gastric dysrhythmia, particularly in human disease, continues to be derived from electrogastrography (EGG). EGG is a non-invasive test and is relatively simple to perform,³⁸ but the signals are currently difficult to relate to the underlying slow waves. In addition, EGG signals are of low amplitude and susceptible to motion artifacts, necessitating use of bipolar electrodes, tight band-pass filtering (e.g. 0.016 - 0.3 Hz), careful attention to noise discrimination, and ideally, concurrent motion sensing.³⁹

EGG recordings are typically taken before and after a test meal, and analysed variables include the dominant slow wave frequency and its consistency, dominant power (reflecting signal amplitude and regularity over time), the ‘fasting-fed power ratio’ (the dominant power increases after a test meal in normal subjects), as well as measures of signal instability.^3,38 Analysis of the EGG waveform morphology has no defined role, but EGG may also be applied to detect ‘gastric uncoupling’ (where discrete areas of the stomach are entrained to different sources and frequencies),⁴⁰ particularly using modern multichannel approaches (e.g. four bipolar electrodes).⁴¹

The normal frequency range defined by EGG is around 2.4 – 3.7 cycles/min, with frequency abnormalities outside this range classed as bradygastria, tachygastria, or non-specific.^3,38 However, a limitation of this approach is that it is not yet certain how and from where the gastric slow wave potentials actually summate to form the EGG signal, especially since it has now been shown that there may be 3-5 slow waves propagating at any time in the stomach.^25,28 This issue is even more problematic during dysrhythmias, when different frequencies may be simultaneously active in multiple uncoupled gastric regions.^7,42

Several decades of EGG investigations have produced an extensive literature associating electrical abnormalities with gastric disorders (Table 1). Multiple studies have also demonstrated that hyperglycaemia is associated with dysrhythmia, possibly contributing to dysrhythmia in diabetic gastroparesis,^43,44 leading to recommendations that blood glucose be tested and normalized prior to testing.³ EGG abnormalities have also been associated with chronic renal failure,⁴⁵ anorexia nervosa (after a prolonged period),⁴⁶ and chronic intestinal pseudo-obstruction.⁴⁷

Table 1. Published associations between electrogastrography measures and gastric disorders.

In terms of symptoms, the strongest association with EGG-diagnosed frequency abnormality is with nausea and vomiting.⁴⁸ Dysrhythmia is common when vomiting is likely, as seen in chronic unexplained nausea and vomiting,^49,50 after chemotherapy,⁵¹ in motion sickness,⁵² and in nausea of pregnancy.⁵³ Indeed, physiological evidence suggests that myoelectrical derangements may be part of the normal physiological sequence of vomiting.^54,55,56 Some controversy remains, however, as to whether dysrhythmia is truly a cause of nausea and vomiting, or merely an associated epiphenomenon. More research on this point is needed, but it is notable that gastric electrical pacing therapy may have potential to both revert dysrhythmia and reduce nausea, suggesting dysrhythmia does have a role in symptom genesis.⁵⁷ A pathogenic role for dysrhythmia in the motion sickness induced by circular vection,⁵⁸ has also been suggested by the fact that the rhythm disturbances arise 1-2 minute before symptoms, and their severity correlates with nausea intensity.⁴⁸ Additionally, in patients with gastroparesis, the resolution of nausea and vomiting has been associated with improvements in EGG abnormalities.⁵⁹

Another documented EGG abnormality is the loss of normal power increase after a test meal observed in gastroparetic patients.⁶⁰ The EGG signal is considered summative of slow wave activity and smooth muscle potentials and/or contractions.⁶¹ The normal post-prandial power increase may therefore reflect increased electromechanical activity, and/or perhaps gastric distension,^62,63 while its loss in gastroparesis may reflect reduced electromechanical activity,⁶³ potentially related to hypomotility or reduced current density output caused by ICC loss.⁶⁴ Consistent with this latter hypothesis, a recent extracellular study has shown reduced serosal slow wave amplitudes in patients with gastroparesis.⁷

Despite the many studies showing the potential value of EGG, clinical adoption remains weak. In addition to the limitations outlined above, EGG is perceived as having incomplete sensitivity and specificity, inconsistent associations with symptoms, and there are uncertainties regarding its functional significance and role in management.^2,3 The positive predictive value of EGG for normal gastric emptying ranges from 65-100% in published studies (average 85%), and from 50-81% for predicting abnormal gastric emptying (average 65%).³ But it should be noted that EGG and gastric emptying tests likely reflect and characterize different patient subgroups. More significantly, additional work is needed to define validated roles for EGG in therapeutic algorithms.³ There is also considerable scope to further refine the principles and practice of EGG, through biophysical modelling, technical advances, and basic experimental studies.⁶⁵

New insights into dysrhythmia from HR mapping

The advent of HR mapping has been a major advance in gastric dysrhythmia research. The first HR analyses of slow wave dysrhythmias were performed in dogs in 2008, reporting novel abnormalities of both initiation (e.g. focal or ectopic activities) and conduction (e.g. re-entrant propagations) as mechanisms of antral tachygastrias.⁴² These concepts were extended in a subsequent porcine study, demonstrating that complex slow wave abnormalities also underlie tachygastria in the corpus, including re-entry, self-perpetuating conduction block, and ectopic initiation, and showing ‘escape rhythms’ in bradygastria.⁶⁶ These two studies are representative of a new era for gastric dysrhythmia, in which modern methods of cardiac rhythm analysis are brought to bear to achieve accurate analyses of dysrhythmic onset and maintenance.⁶⁷

Clinical translation of HR mapping was recently achieved in a study of patients with idiopathic and diabetic gastroparesis, providing the first spatially-detailed description of human dysrhythmic patterns.⁷ Whereas previous studies had focused almost exclusively on human abnormalities of slow wave initiation (e.g. ectopic activity), this study demonstrated that conduction abnormalities (e.g. slow conduction and conduction blocks) were also prevalent in gastroparesis. These conduction abnormalities could be a consequence of ICC loss, which results in network remodelling and haphazard or delayed conduction.^64,68 The complex dysrhythmic propagation patterns described in this recent study also have pathophysiologic implications, because disorganised patterns such as competing pacemakers, colliding wavefronts, retrograde propagation, and uncoupling, must be highly disruptive to gastric mixing and motility, in a manner akin to cardiac fibrillation disrupting cardiac contractility and output. This notion is supported by canine studies that show slow wave dysrhythmia impairs gastric contractions and induces hypomotility.^69,70

With a range of abnormalities now being discovered and examined by HR mapping, early attempts are being made to classify these dysrhythmias. In their canine study,⁴² Lammers et al. proposed a first classification mostly based on rate and rhythm, very similar to what is used in cardiac arrhythmias.⁷¹ In contrast, in the human gastroparesis mapping study,⁷ the changes in rate were less dramatic, and dysrhythmias were classified in patterns of propagation, as elucidated by HR mapping (e.g. Figure 1). The limited alterations in slow wave rate during human dysrhythmia is important, because it means that many such abnormalities could be missed by tests relying predominantly on frequency analysis, perhaps partly explaining the limited sensitivity of EGG.

Given that the HR mapping analysis of dysrhythmias has only recently begun, there may well be additional types of dysrhythmias to be discovered and analysed, and it therefore seems premature at present to suggest a complete or comprehensive classification system. Furthermore, future classifications could also be based directly on the mechanisms of these dysrhythmias, as is starting to occur in the nascent field of small intestine dysrhythmias.^34,72

Despite its advantages, a major limitation of HR mapping is that all studies to date have been performed in fasted anaesthetised subjects subjected to laparotomy. While routine anaesthesia is substantially unlikely to alter slow wave activity (reviewed by O'Grady et al., 2013²⁷), this research context is limiting because mechanical and nutrient factors are likely to be significant in slow wave dysrhythmogenesis. For example, balloon distension of the antrum can provoke dysrhythmias,⁷³ as can duodenal perfusion with lipid and protein rich solutions,⁴⁸ suggesting that it would also be productive to evaluate dysrhythmias in the post-prandial period, as occurs with EGG. Major technical advances would be required to achieve multi-electrode mapping in fed awake subjects (discussed below).

Neurohormonal influences and therapies

Multiple neurohormonal factors have shown potential to induce gastric dysrhythmias, some of which are discussed here. Hormonal factors that may affect slow wave rhythms include insulin, cholecystokinin, pentagastrin, and glucagon.⁴⁸ Administration of progesterone and estrogen to non-pregnant women, in levels equivalent to that occurring in the pregnant state, can also induce gastric dysrhythmia and nausea,⁷⁴ and adrenalin and noradrenalin have also been shown to be dysrhythmogenic in susceptible individuals and animals.^48,70 In general, however, the clinical significance of these associations remains quite uncertain. For example, while female sex steroids can induce dysrhythmias, and dysrhythmias are associated with nausea and vomiting in pregnancy,⁵³ proof of causality within this chain of events is lacking.

Neural influences may also promote or suppress dysrhythmia. As discussed above, cholinergic stimulation may modulate intrinsic ICC frequencies, potentially inducing dysrhythmias.³⁷ Additionally, anticholinergic agents, such as atropine and scopolamine, can inhibit tachygastria and reduce nausea during circular vection, implying a cholinergic influence, which is likely to be centrally-mediated.^52,75 Phentolamine has also been shown to blunt nausea and tachygastria induced by circular vection and ephedrine infusion, implying that α-adrenergic pathways are also involved.^48,52 Dysrhythmias induced by gastric antral distension, by contrast, cannot be inhibited by anticholinergic administration,⁷³ and other influences could also be active in this context, such as mechanosensitive ion channels within the ICC network.⁷⁶

Paracrine factors are also known to induce gastric dysrhythmias, such as the endogenous prostaglandin E2,⁷⁷ which may act through EP3 receptors with chronotropic responses mediated by IP3 generation.⁷⁸ Indomethacin has been shown to reduce dysrhythmia in hyperglycaemia, among other conditions,⁷⁹ but the clinical applicability and safety of prostaglandin synthesis inhibitors in dysrhythmia management currently remains uncertain.

Finally, dopamine and serotonin pathways have also been associated with gastric dysrhythmia pathogenesis. Domperidone, cisapride and ondansetron are all known to stabilize gastric rhythm; however, it is unclear whether these are simply associations or pharmacologic mechanisms of action.⁴⁸ Interestingly, ginger has similar effects, mediated by unknown means.⁸⁰

Advances in gastric dysrhythmia monitoring devices

Future advances in gastric dysrhythmia research will continue to be underpinned by technical advances, and some of these opportunities are addressed here. To date, human HR mapping studies have been facilitated by a flexible printed-circuit-board (PCB) electrode platform.⁸¹ Besides being flexible, these arrays are cheap to mass-produce, are readily sterilized and potentially disposable. However, their relatively low SNR can make signal interpretation problematic in the electrically-noisy clinical environment, and further refinements to human serosal mapping arrays will be important.

Data management remains a major technical challenge in HR mapping research, with vast volumes of electrograms being recorded in each study. This problem has been partly overcome through a recent series of signal processing advances, which have generated an efficient data analysis package (‘GEMS’) that is largely automated when data quality is sufficient.⁸² The backend of this analysis package is supported by a number of signal processing algorithms specifically developed for slow wave identification; these include validated algorithms for filtering,⁸³ identifying slow wave activation times,⁸⁴ grouping and mapping propagation cycles,⁸⁵ and mapping amplitude and velocity fields.^31,32 Efforts are also underway to apply similar methods in real-time, allowing live mapping during experiments or clinical studies.⁸⁶

To progress the goal of HR mapping dysrhythmias in conscious fed patients, Farajadivar et al. recently presented the first telemetric platform for wireless slow wave data acquisition and transmission.⁸⁷ In future, wireless transmission could be coupled with secure mucosal recording methods (e.g. Coleski & Hasler, 2009⁸⁸), allowing detailed clinical studies to be performed over several days and in the awake state.

Gastric pacing (i.e. low-frequency stimulation to entrain slow waves) has shown potential to revert dysrhythmias, modulate symptoms, and accelerate gastric emptying,⁵⁷ and continues to be explored as a treatment modality. In a recent porcine study, HR mapping was applied to evaluate the effects of gastric pacing on slow wave entrainment in spatiotemporal detail,⁸⁹ and it would be valuable to reproduce this work in humans. An endoscopically-implantable gastric stimulation device was recently proposed that could reduce invasiveness.⁹⁰

Another critical advance will be development of effective devices for endoscopic HR mapping, which holds the potential for a routinely deployable diagnostic device. This task is complicated by the high impedance of the gastric mucosa, which attenuates signals that are already low in amplitude. However, past efforts at mucosal recordings in humans show that the approach is feasible (e.g. Coleski & Hasler, 2009;⁸⁸ Monges & Salducci, 1970⁹¹), and we anticipate that endoscopic prototypes will be proposed within the coming years. Laparoscopic approaches are also being developed, which could be usefully applied to investigate the consequences of operative procedures on slow wave activity.⁹²

Concluding remarks

Despite substantial recent progress, gastric dysrhythmia remains a clinical enigma, with uncertain pathogenesis, pathophysiology, and therapeutic implications. Many lines of enquiry must be further developed before we will know the full potential of Alvarez’s “little prophesy” that “gastroenterologists would come to rely upon electrical measures for the routine diagnosis of stomach disorders". However, like Alvarez, we continue to see significant unmet potential in this field. The ultimate test will be to show that dysrhythmias can be reversed in a way that meaningfully improves organ function and symptoms for the benefit of patients. In light of the many advances discussed here, such a goal may finally be within reach.

Acknowledgements

The authors are supported by the NZ Health Research Council, the NIH (R01 DK64775), the Riddet Institute, the NZ Rutherford Foundation Trust, and the Marsden Fund.

References

1.  Alvarez WC. The electrogastrogram and what it shows. JAMA 1922; 78:1116-1119.

2.  Bortolotti M. Electrogastrography: a seductive promise, only partially kept. Am. J. Gastroenterol. 1998; 93:1791-1794.

3.  Parkman HP, Hasler WL, Barnett JL, Eaker EY. Electrogastrography: a document prepared by the gastric section of the American Motility Society Clinical GI Motility Testing Task Force. Neurogastroenterol. Motil. 2003; 2003:89-102.

4.  Farrugia G. Interstitial cells of Cajal in health and disease. Neurogastroenterol. Motil. 2008; 20:54-63.

5.  Huizinga JD, Zarate N, Farrugia G. Physiology, injury, and recovery of interstitial cells of Cajal: basic and clinical science. Gastroenterology 2009; 137:1548-1556.

6.  Grover M, Farrugia G, Lurken MS, Bernard CE, Faussone-Pellegrini MS, Smyrk TC, Parkman HP, Abell TL, Snape WJ, Hasler WL, Ünalp-Arida A, Nguyen L, Koch KL, Calles J, Lee L, Tonascia J, Hamilton FA, Pasricha PJ. Cellular changes in diabetic and idiopathic gastroparesis. Gastroenterology 2011; 140:1575-85.e8.

7.  O'Grady G, Angeli TR, Du P, Lahr C, Lammers WJ, Windsor JA, Abell TL, Farrugia G, Pullan AJ, Cheng LK. Abnormal initiation and conduction of slow wave activity in gastroparesis, defined by high-resolution electrical mapping. Gastroenterology 2012; 143:589-598.

8.  Faussone-Pellegrini MS, Grover M, Pasricha PJ, Bernard CE, Lurken MS, Smyrk TC, Parkman HP, Abell TL, Snape WJ, Hasler WL, Ünalp-Arida A, Nguyen L, Koch KL, Calles J, Lee L, Tonascia J, Hamilton FA, Farrugia G. Ultrastructural differences between diabetic and idiopathic gastroparesis. J. Cell. Mol. Med. 2012;16:1573-1581.

9.  Grover M, Bernard CE, Pasricha PJ, Lurken MS, Faussone-Pellegrini MS, Smyrk TC, Parkman HP, Abell TL, Snape WJ, Hasler WL, McCallum RW, Nguyen L, Koch KL, Calles J, Lee L, Tonascia J, Ünalp-Arida A, Hamilton FA, Farrugia G. Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium. Neurogastroenterol. Motil. 2012; 24:531-9, e249.

10.  Lin Z, Sarosiek I, Forster J, Damjanov I, Hou Q, McCallum RW. Association of the status of interstitial cells of Cajal and electrogastrogram parameters, gastric emptying and symptoms in patients with gastroparesis. Neurogastroenterol. Motil. 2010; 22:56-61, e10.

11.  Choi KM, Gibbons SJ, Nguyen TV, Stoltz GJ, Lurken MS, Ordog T, Szurszewski JH, Farrugia G.` Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis. Gastroenterology 2008; 135:2055-64, 2064.e1.

12.  Beyder A, Farrugia G. Targeting ion channels for the treatment of gastrointestinal motility disorders. Therap. Adv. Gastroenterol. 2012; 5:5-21.

13.  Saito YA, Strege PR, Tester DJ, Locke GR 3rd, Talley NJ, Bernard CE, Rae JL, Makielski JC, Ackerman MJ, Farrugia G. Sodium channel mutation in irritable bowel syndrome: evidence for an ion channelopathy. Am. J. Physiol. Gastrointest. Liver Physiol. 2009; 296:G211-G218.

14.  Poh YC, Beyder A, Strege PR, Farrugia G, Buist ML. Quantification of gastrointestinal sodium channelopathy. J. Theor. Biol. 2012; 293:41-48.

15.  Richter S, Brugada P. Role of Mapping in Channelopathies: Brugada Syndrome, Long-QT Syndrome, and Idiopathic VF. In: Shenasa M, Hindricks G, Borggrefe M, Breithardt G, eds. Cardiac Mapping, Third Edition. Oxford, UK.: Wiley-Blackwell; 2009.

16.  Jung KT, Park H, Kim JH, Shin DJ, Joung BY, Lee MH, Jang YS. The relationship between gastric myoelectric activity and SCN5A mutation suggesting sodium channelopathy in patients with Brugada syndrome and functional dyspepsia - a pilot study. J. Neurogastroenterol. Motil. 2012; 18:58-63.

17.  Klein S, Seidler B, Kettenberger A, Sibaev A, Rohn M, Feil R, Allescher HD, Vanderwinden JM, Hofmann F, Schemann M, Rad R, Storr MA, Schmid RM, Schneider G, Saur D. Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity. Nat. Commun. 2013; 4:1630.

18.  van Helden DF, Laver DR, Holdsworth J, Imtiaz MS. The generation and propagation of gastric slow waves. Clin. Exp. Pharmacol. Physiol. 2010;37:516-524.

19.  Kelly KA, Code CF. Canine gastric pacemaker. Am. J. Physiol. 1971;220:112-118.

20.  Hinder RA, Kelly KA. Human gastric pacesetter potential. Site of origin, spread, and response to gastric transection and proximal gastric vagotomy. Am. J. Surg. 1977; 133:29-33.

21.  Torihashi S, Horisawa M, Watanabe Y. c-Kit immunoreactive interstitial cells in the human gastrointestinal tract. J. Auton. Nerv. Syst. 1999; 75:38-50.

22.  Rhee PL, Lee JY, Son HJ, Kim JJ, Rhee JC, Kim S, Koh SD, Hwang SJ, Sanders KM, Ward SM. Analysis of pacemaker activity in the human stomach. J. Physiol. 2011; 589:6105-6118.

23.  Wang XY, Lammers WJ, Bercik P, Huizinga JD. Lack of pyloric interstitial cells of Cajal explains distinct peristaltic motor patterns in stomach and small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 2005; 289:G539-G549.

24.  Angeli TR, Du P, Paskaranandavadivel N, Janssen PW, Beyder A, Lentle RG, Bissett IP, Cheng LK, O'Grady G. The bioelectrical basis and validity of gastrointestinal extracellular slow wave recordings. J. Physiol. 2013; 591:4567-4579.

25.  O’Grady G, Du P, Cheng LK, et al. Origin and propagation of human gastric slow wave activity defined by high-resolution mapping. Am. J. Physiol. Gastrointest. Liver Physiol. 2010; 299:585-592.

26.  Lammers WJ, al-Kais A, Singh S, Arafat K, el-Sharkawy TY. Multielectrode mapping of slow-wave activity in the isolated rabbit duodenum. J. Appl. Physiol. 1993; 74:1454-1461.

27.  O’Grady G, Angeli T, Lammers WJ. The principles and practice of gastrointestinal high-resolution mapping. In: Cheng LK, Farrugia G, Pullan AJ, eds. New Advances in Gastrointestinal Motility Research. New York: Springer; 2013. pp. 51-69.

28.  Lammers WJ, Ver Donck L, Stephen B, Smets D, Schuurkes JA. Origin and propagation of the slow wave in the canine stomach: the outlines of a gastric conduction system. Am. J. Physiol. Gastrointest. Liver Physiol. 2009; 296:1200-1210.

29.  Egbuji JU, O’Grady G, Du P, Cheng LK, Lammers WJ, Windsor JA, Pullan AJ. Origin, propagation and regional characteristics of porcine gastric slow wave activity determined by high-resolution mapping. Neurogastroenterol. Motil. 2010; 22:e292-e300.

30.  O’Grady G, Du P, Paskaranandavadivel N, Angeli TR, Lammers WJ, Asirvatham SJ, Windsor JA, Farrugia G, Pullan AJ, Cheng LK. Rapid high-amplitude circumferential slow wave conduction during normal gastric pacemaking and dysrhythmia. Neurogastroenterol. Motil. 2012; 24:e299-e312.

31.  Paskaranandavadivel N, Cheng LK, Du P, O’Grady G, Pullan AJ. Improved signal processing techniques for the analysis of high resolution serosal slow wave activity in the stomach. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2011; 2011:1737-1740.

32.  Paskaranandavadivel N, O’Grady G, Du P, Pullan AJ, Cheng LK. An improved method for the estimation and visualization of velocity fields from gastric high-resolution electrical mapping. IEEE Trans. Biomed. Eng. 2012; 59:882-889.

33.  Du P, O'Grady G, Paskaranandavadivel N, Angeli TR, Lahr C, Abell TL, Cheng LK, Pullan AJ. Quantification of velocity anisotropy during gastric electrical arrhythmia. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2011; 2011:4402-4405.

34.  Angeli TR, O'Grady G, Du P, Paskaranandavadivel N, Pullan AJ, Bissett IP, Cheng LK. Circumferential and functional re-entry of in vivo slow-wave activity in the porcine small intestine. Neurogastroenterol. Motil. 2013; 25:e304-e314.

35.  Cheng LK, Du P, O’Grady G. Mapping and modeling gastrointestinal bioelectricity: from engineering bench to bedside. Physiology (Bethesda) 2013; 28:310-317.

36.  Hirst GD, Garcia-Londono AP, Edwards FR. Propagation of slow waves in the guinea-pig gastric antrum. J. Physiol. 2006; 571:165-177.

37.  Forrest AS, Ordog T, Sanders KM. Neural regulation of slow-wave frequency in the murine gastric antrum. Am. J. Physiol. Gastrointest. Liver Physiol. 2006;290:G486-G495.

38.  Yin J, Chen JD. Electrogastrography: methodology, validation and applications. J. Neurogastroenterol. Motil. 2013; 19:5-17.

39.  Verhagen MAMT, van Schelven LJ, Samsom M, Smout AJPM. Pitfalls in the analysis of electrogastrographic recordings. Gastroenterology 1999; 177:453-460.

40.  Mintchev MP, Otto SJ, Bowes KL. Electrogastrography can recognise gastric electrical uncoupling in dogs. Gastroenterology 1997; 112:2006-2011.

41.  Simonian HP, Panganamamula K, Chen JZ, Fisher RS, Parkman HP. Multichannel electrogastrography (EGG) in symptomatic patients: a single center study. Am. J. Gastroenterol. 2004; 99:478-485.

42.  Lammers WJEP, Ver Donck L, Stephen B, Smets D, Schuurkes JAJ. Focal activities and re-entrant propagations as mechanisms of gastric tachyarrhythmias. Gastroenterology 2008; 135:1601-1611.

43.  Abell TL, Malagelada JR. Glucagon-evoked gastric dysrhythmias in humans shown by an improved electrogastrographic technique. Gastroenterology 1985; 88:1932-1940.

44.  Jebbink RJ, Samsom M, Bruijs PP, Bravenboer B, Akkermans LM, Vanberge-Henegouwen GP, Smout AJ. Hyperglycemia induces abnormalities of gastric myoelectrical activity in patients with type I diabetes mellitus. Gastroenterology 1994; 107:1390-1397.

45.  Lin X, Mellow MH, Southmayd L, Pan J, Chen JD. Impaired gastric myoelectrical activity in patients with chronic renal failure. Dig. Dis. Sci. 1997; 42:898-906.

46.  Abell TL, Malagelada JR, Lucas AR, Brown ML, Camilleri M, Go VL, Azpiroz F, Callaway CW, Kao PC, Zinsmeister AR, et al. Gastric electromechanical and neurohormonal function in anorexia nervosa. Gastroenterology 1987; 93:958-965.

47.  Debinski HS, Ahmed S, Milla PJ, Kamm MA. Electrogastrography in chronic intestinal pseudoobstruction. Dig. Dis. Sci. 1996; 41:1292-1297.

48.  Owyang C, Hasler WL. Physiology and pathophysiology of the interstitial cells of Cajal: from bench to bedside. VI. Pathogenesis and therapeutic approaches to human gastric dysrhythmias. Am. J. Physiol. Gastrointest. Liver Physiol. 2002; 283:G8-15.

49.  You CH, Lee KY, Chey WY, Menguy R. Electrogastrographic study of patients with unexplained nausea, bloating, and vomiting. Gastroenterology 1980; 79:311-314.

50.  Geldof H, van der Schee EJ, van Blankenstein M, Grashuis JL. Electrogastrographic study of gastric myoelectrical activity in patients with unexplained nausea and vomiting. Gut 1986; 27:799-808.

51.  Song J, Zhong DX, Qian W, Hou XH, Chen JD. Short pulse gastric electrical stimulation for cisplatin-induced emesis in dogs. Neurogastroenterol Motil. 2011; 23:468-74, e178.

52.  Hasler WL, Kim MS, Chey WD, Stevenson V, Stein B, Owyang C. Central cholinergic and alpha-adrenergic mediation of gastric slow wave dysrhythmias evoked during motion sickness. Am. J. Physiol. Gastrointest. Liver Physiol. 1995; 268:G539-G547.

53.  Koch KL, Stern RM, Vasey M, Botti JJ, Creasy GW, Dwyer A. Gastric dysrhythmias and nausea of pregnancy. Dig. Dis. Sci. 1990; 35:961-968.

54.  Lee KY, Park HJ, Chey WY. Studies on mechanism of retching and vomiting in dogs. Effect of peripheral dopamine blocker on myoelectric changes in antrum and upper small intestine. Dig. Dis. Sci. 1985; 30:22-28.

55.  Lang IM, Sarna SK. Motor and myoelectric activity associated with vomiting, regurgitation, and nausea. Comprehensive Physiology. American Physiological Society; 1989. pp. 1179-1198.

56.  Ueno T, Chen JD. Vomiting and gastric electrical dysrhythmia in dogs. Scand. J. Gastroenterol. 2004; 39:344-352.

57.  McCallum RW, Chen JD, Lin Z, Schirmer BD, Williams RD, Ross RA. Gastric pacing improves emptying and symptoms in patients with gastroparesis. Gastroenterology 1998; 114:456-461.

58.  Stern RM, Koch KL, Steward WR, Lindblad IM. Spectral analysis of tachygastria recorded during motion sickness. Gastroenterology 1987; 92:92-97.

59.  Koch KL, Stern RM, Stewart WR, Vasey MW. Gastric emptying and gastric myoelectrical activity in patients with diabetic gastroparesis: effect of long-term domperidone treatment. Am. J. Gastroenterol. 1989; 84:1069-1075.

60.  Chen JD, Lin Z, Pan J, McCallum RW. Abnormal gastric myoelectrical activity and delayed gastric emptying in patients with symptoms suggestive of gastroparesis. Dig. Dis. Sci. 1996; 41:1538-1545.

61.  Smout AJPM, Van der schee EJ, Grashuis JL. What is measured in electrogastrography? Dig. Dis. Sci. 1980; 25:179-187.

62.  Mintchev MP, Kingma YJ, Bowes KL. Accuracy of cutaneous recordings of gastric electrical activity. Gastroenterology 1993; 104:1273-1280.

63.  Lin Z, Chen JD, Schirmer BD, McCallum RW. Postprandial response of gastric slow waves: correlation of serosal recordings with the electrogastrogram. Dig. Dis. Sci. 2000; 45:645-651.

64.  Du P, O'Grady G, Gibbons SJ, Yassi R, Lees-Green R, Farrugia G, Cheng LK, Pullan AJ. Tissue-specific mathematical models of slow wave entrainment in wild-type and 5-HT2B knockout mice with altered interstitial cell of Cajal networks. Biophys. J. 2010; 98:1772-1781.

65.  Du P, O’Grady G, Cheng LK, Pullan AJ. A multi-scale model of the electrophysiological basis of the human electrogastrogram. Biophys. J. 2010; 99:2784-2792.

66.  O'Grady G, Egbuji JU, Du P, Lammers WJ, Cheng LK, Windsor JA, Pullan AJ. High-resolution spatial analysis of slow wave initiation and conduction in porcine gastric dysrhythmia. Neurogastroenterol. Motil. 2011; 23:e345-e355.

67.  Lammers WJ. Arrhythmias in the gut. Neurogastroenterol. Motil. 2013; 25:353-357.

68.  Gao J, Du P, O'Grady G, Archer R, Farrugia G, Gibbons SJ, Cheng LK. Numerical metrics for automated quantification of interstitial cell of Cajal network structural properties. J. R. Soc. Interface. 2013; 10:20130421.

69.  Xing J, Qian L, Chen J. Experimental gastric dysrhythmias and its correlation with in vivo gastric muscle contractions. World J. Gastroenterol. 2006; 12:3994-3998.

70.  You CH, Chey WY. Study of electromechanical activity of the stomach in humans and in dogs with particular attention to tachygastria. Gastroenterology 1984; 86:1460-1468.

71.  Waldo AL, Wit AL. Mechanisms of cardiac arrhythmias. Lancet 1993; 341:1189-1193.

72.  Lammers WJ, Stephen B, Karam SM. Functional reentry and circus movement arrhythmias in the small intestine of normal and diabetic rats. Am. J. Physiol. Gastrointest. Liver Physiol. 2012; 302:G684-G689.

73.  Ladabaum U, Koshy SS, Woods ML, Hooper FG, Owyang C, Hasler WL. Differential symptomatic and electrogastrographic effects of distal and proximal human gastric distension. Am. J. Physiol. 1998; 275:G418-G424.

74.  Walsh JW, Hasler WL, Nugent CE, Owyang C. Progesterone and estrogen are potential mediators of gastric slow-wave dysrhythmias in nausea of pregnancy. Am. J. Physiol. 1996; 270:G506-G514.

75.  Uijtdehaage SH, Stern RM, Koch KL. Effects of scopolamine on autonomic profiles underlying motion sickness susceptibility. Aviat. Space Environ. Med. 1993; 64:1-8.

76.  Beyder A, Rae JL, Bernard C, Strege PR, Sachs F, Farrugia G. Mechanosensitivity of Nav1.5, a voltage-sensitive sodium channel. J. Physiol. 2010; 588:4969-4985.

77.  Kim CH, Zinsmeister AR, Malagelada JR. Mechanisms of canine gastric dysrhythmia. Gastroenterology 1987; 92:993-999.

78.  Forrest AS, Hennig GW, Jokela-Willis S, Park CD, Sanders KM. Prostaglandin regulation of gastric slow waves and peristalsis. Am. J. Physiol. Gastrointest. Liver Physiol. 2009; 296:G1180-G1190.

79.  Hasler WL, Soudah HC, Dulai G, Owyang C. Mediation of hyperglycemia-evoked gastric slow-wave dysrhythmias by endogenous prostaglandins. Gastroenterology 1995; 108:727-736.

80.  Lien HC, Sun WM, Chen YH, Kim H, Hasler W, Owyang C. Effects of ginger on motion sickness and gastric slow-wave dysrhythmias induced by circular vection. Am. J. Physiol. Gastrointest. Liver Physiol. 2003; 284:G481-G489.

81.  Du P, O'Grady G, Egbuji JU, Lammers WJ, Budgett D, Nielsen P, Windsor JA, Pullan AJ, Cheng LK. High-resolution mapping of in vivo gastrointestinal slow wave activity using flexible printed circuit board electrodes: methodology and validation. Ann. Biomed. Eng. 2009; 37:839-846.

82.  Yassi R, O'Grady G, Paskaranandavadivel N, Du P, Angeli TR, Pullan AJ, Cheng LK, Erickson JC. The gastrointestinal electrical mapping suite (GEMS): Software for analysing and visualising gastrointestinal (multi-electrode) recordings in spatiotemporal detail. BMC Gastroenterol. 2012; 12:60.

83.  Paskaranandavadivel N, O’Grady G, Du P, Cheng LK. Comparison of filtering methods for extracellular gastric slow wave recordings. Neurogastroenterol. Motil. 2013;25:79-83.

84.  Erickson JC, O'Grady G, Du P, Obioha C, Qiao W, Richards WO, Bradshaw LA, Pullan AJ, Cheng LK. Falling-edge, variable threshold (FEVT) method for the automated detection of gastric slow wave events in serosal high-resolution electrical recordings. Ann. Biomed. Eng. 2010; 38:1511-1529.

85.  Erickson JC, O’Grady G, Du P, Egbuji JU, Pullan AJ, Cheng LK. Automated cycle partitioning and visualization of high-resolution activation time maps of gastric slow wave recordings: the region growing using polynomial surface-estimate stabilization (REGROUPS) algorithm. Ann. Biomed. Eng. 2011; 39:469-483.

86.  Bull S, O’Grady G, Cheng LK, Pullan AJ. A framework for the online analysis of multi-electrode gastric slow wave recordings. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2011; 2011:1741-1744.

87.  Farajidavar A, O’Grady G, Rao SM, Cheng LK, Abell T, Chiao JC. A miniature bidirectional telemetry system for in vivo gastric slow wave recordings. Physiol. Meas. 2012; 33:N29-N37.

88.  Coleski R, Hasler WL. Coupling and propagation of normal and dysrhythmic gastric slow waves during acute hyperglycaemia in healthy humans. Neurogastroenterol. Motil. 2009; 21:492-9, e1.

89.  O'Grady G, Du P, Lammers WJ, Egbuji JU, Mithraratne P, Chen JD, Cheng LK, Windsor JA, Pullan AJ. High-resolution entrainment mapping for gastric pacing: a new analytic tool. Am. J. Physiol. Gastrointest. Liver Physiol. 2010; 298:314-321.

90.  Deb S, Tang SJ, Abell TL, Rao S, Huang WD, To SD, Lahr C, Chiao JC. An endoscopic wireless gastrostimulator (with video). Gastrointest. Endosc. 2012; 75:411-415.e1.

91.  Monges H, Salducci J. A method of recording the gastric electrical activity in man. Am. J. Dig. Dis. 1970; 15:271.

92.  O'Grady G, Du P, Egbuji JU, Lammers WJ, Wahab A, Pullan AJ, Cheng LK, Windsor JA. A novel laparoscopic device for measuring gastrointestinal slow-wave activity. Surg. Endosc. 2009; 23:2842-2848.

93.  Brzana RJ, Koch KL, Bingaman S. Gastric myoelectrical activity in patients with gastric outlet obstruction and idiopathic gastroparesis. Am. J. Gastroenterol. 1998; 93:1803-1809.

94.  Chen J, McCallum RW. Gastric slow wave abnormalities in patients with gastroparesis. Am. J. Gastroenterol. 1992; 87:477-482.

95.  Lin ZY, McCallum RW, Schirmer BD, Chen JD. Effects of pacing parameters on entrainment of gastric slow waves in patients with gastroparesis. Am. J. Physiol. 1998; 274:G186-G191.

96.  Chen JD, Schirmer BD, McCallum RW. Serosal and cutaneous recordings of gastric myoelectrical activity in patients with gastroparesis. Am. J. Physiol. 1994; 266:G90-G98.

97.  Bortolotti M, Sarti P, Barara L, Brunelli F. Gastric myoelectrical activity in patients with chronic idiopathic gastroparesis. J. Gastrointest. Motil. 1990; 2:104-108.

98.  Abell TL, Familoni B, Voeller G, Werkman R, Dean P, Waters B, Smalley D, Salameh JR. Electrophysiologic, morphologic, and serologic features of chronic unexplained nausea and vomiting: lessons learned from 121 consecutive patients. Surgery 2009; 145:476-485.

99.  You CH, Chey WY, Lee KY, Menguy R, Bortoff A. Gastric and small intestinal myoelectric dysrhythmia associated with chronic intractable nausea and vomiting. Ann. Intern. Med. 1981; 95:449-451.

100.  Leahy A, Besherdas K, Clayman C, Mason I, Epstein O. Abnormalities of the electrogastrogram in functional gastrointestinal disorders. Am. J. Gastroenterol. 1999; 94:1023-1028.

101.  Lin Z, Eaker EY, Sarosiek I, McCallum RW. Gastric myoelectrical activity and gastric emptying in patients with functional dyspepsia. Am. J. Gastroenterol. 1999; 94:2384-2389.

102.  Sha W, Pasricha PJ, Chen JD. Rhythmic and spatial abnormalities of gastric slow waves in patients with functional dyspepsia. J. Clin. Gastroenterol. 2009; 43:123-129.

103.  Lin X, Levanon D, Chen JD. Impaired postprandial gastric slow waves in patients with functional dyspepsia. Dig. Dis. Sci. 1998; 43:1678-1684.

104.  Pfaffenbach B, Adamek RJ, Bartholomaus C, Wegener M. Gastric dysrhythmias and delayed gastric emptying in patients with functional dyspepsia. Dig. Dis. Sci. 1997; 42:2094-2099.

105.  Lin X, Chen JZ. Abnormal gastric slow waves in patients with functional dyspepsia assessed by multichannel electrogastrography. Am. J. Physiol. Gastrointest. Liver Physiol. 2001; 280:G1370-G1375.

106.  Leahy A, Besherdas K, Clayman C, Mason I, Epstein O. Gastric dysrhythmias occur in gastro-oesophageal reflux disease complicated by food regurgitation but not in uncomplicated reflux. Gut 2001; 48:212-215.

107.  Cucchiara S, Salvia G, Borrelli O, Ciccimarra E, Az-Zeqeh N, Rapagiolo S, Minella R, Campanozzi A, Riezzo G. Gastric electrical dysrhythmias and delayed gastric emptying in gastroesophageal reflux disease. Am. J. Gastroenterol. 1997; 92:1103-1108.

108.  Chen CL, Lin HH, Huang LC, Huang SC, Liu TT. Electrogastrography differentiates reflux disease with or without dyspeptic symptoms. Dig. Dis. Sci. 2004; 49:715-719.

109.  Chong SK. Electrogastrography in cyclic vomiting syndrome. Dig. Dis. Sci. 1999; 44:64S-73S.

110.  Liberski SM, Koch KL, Atnip RG, Stern RM. Ischemic gastroparesis: resolution after revascularization. Gastroenterology 1990; 99:252-257.