Neural Gastric Electrical Stimulation: Future Prospects in Managing Gastric Emptying Disorders

Abstract

Neural gastric electrical stimulation (NGES) is a multi-channel high-energy gastrointestinal stimulation technique that directly activates cholinergic motor neurons to evoke contractions that improve gastric emptying. NGES stimulation superimposes on spontaneous electromechanical activity to generate coordinated propagating contractions. In contrast, the most commonly applied form of gastric electrical stimulation (Enterra), employs paired pulses that stimulate vagal afferent pathways to reduce symptoms of nausea and vomiting, but does not enhance emptying. This review examines the evolution and implementation of NGES, focusing on its potential role as a treatment option to enhance gastric propulsion in gastroparesis and delayed gastric conduit emptying. While initial acute animal studies have shown promising results, continued development of the technology and refinement of stimulation protocols through chronic experiments remains essential for successful clinical translation.

Introduction

Delayed gastric emptying disorders encompass a group of complex conditions characterized by impaired gastric motility, leading to inefficient food movement through the stomach. The condition arises from various medical causes, including idiopathic or diabetic gastroparesis, as well as post-surgical states following upper gastrointestinal cancer resections.¹ Delayed gastric emptying represents a significant clinical challenge, substantially reducing patient quality of life and at present there are limited therapeutic options. Impacts on quality of life include nausea and vomiting associated with the delayed gastric emptying of gastroparesis. While dietary modifications and pharmacological approaches remain first-line treatments, their efficacy is often inadequate, creating an urgent need for alternative therapeutic modalities.

Electrophysiological Basis of Gastric Motility Disorders

Electrophysiological abnormalities are fundamental to understanding the pathogenesis of delayed gastric emptying disorders. The stomach's complex motor function relies on electrical signalling primarily mediated by interstitial cells of Cajal (ICC), which serve as the critical pacemaker cells responsible for generating and propagating gastric slow waves.² These slow waves represent spontaneous rhythmic oscillations occurring at regular intervals with variable electrical potentials.³ Recent advances in high-resolution mapping have enabled detailed visualization of gastric slow waves,⁴ which characteristically originate in the proximal stomach and propagate circumferentially and distally toward the pylorus as depolarization-repolarisation annular bands that cause annular contractions.^5,6 Slow wave propagation is facilitated by low-resistance gap junctions called nexuses, which electrically couple ICCs with each other and adjacent smooth muscle cells.⁷ When these slow waves in the muscle reach a critical depolarization threshold, calcium ions flow into the cells and activate contraction.⁸ Slow waves propagate anisotropically at approximately 3 mm/second, with a marked acceleration to over 7 mm/second in the distal antrum, a conduction speed transition critical for coordinating terminal antral contractions that generate retropulsive mixing of gastric content and aspiration of fluid into the duodenum.^9,10

In conditions such as idiopathic gastroparesis, this electrophysiological orchestration is disrupted due to the progressive loss or dysfunction of ICCs, compromizing the electrical coupling between neural networks and smooth muscle.^11,12 Quantitative studies have demonstrated a significant reduction in ICC density, with counts decreasing from 4.95 ± 1.20 cells/field in healthy controls to 1.67-2.10 cells/field in gastroparetic patients, with this depletion correlating with the presence of gastric electrical dysrhythmias and greater symptom severity.¹³ Gastric dysrhythmia describes the abnormal slow wave activity, where this activity may consist of bradygastria (< 2.4 cycles per minute [cpm]), tachygastria (> 3.7 cpm), retrograde propagation, or conduction blocks wherein wave propagation fails or re-enters abnormally.¹⁴ These abnormalities disrupt coordinated peristalsis and also contribute substantially to symptom burden. Vagus nerve division represents another mechanism underlying motility issues following esophago-gastric procedures, particularly those for esophageal cancer. This neural disruption impacts the control of gastric motility, resulting in disrupted gastric contractions.

Gastric electrical stimulation (GES) has been proposed as a potential solution for gastroparesis,^15,16 aiming to modulate the stomach’s electrical activity, and may also be therapeutic for delayed gastric conduit emptying (DGCE). The development of this technology spans several decades and has evolved through contributions from multiple research groups, predominantly through extensive investigation in animal models, each advancing different aspects of the technology.

Historical Evolution of Gastric Electrical Stimulation

The exploration of electrical stimulation as a therapeutic intervention for gastrointestinal disorders dates back to the mid-20th century. Early investigations sought to manipulate the slow waves governing gastric motility. These efforts focused on using low-frequency gastric pacing in the in the sub-Hertz range with long-duration pulses at physiological frequencies of 3-4 cpm to entrain slow gastric waves (Fig. 1).¹⁷ These low-frequency stimuli likely directly activate ICC or smooth muscle cells without requiring cholinergic neural involvement, as evidenced by the persistence of electrically-induced slow waves even after atropine administration.^7,18 This approach typically employed a single set of bipolar electrodes at the proximal stomach, with stimulation parameters including currents of 2-5 mA or voltage ranges of 1-10 V.^19,20 This approach, however, revealed practical limitations. While acute canine model studies demonstrated the ability to entrain slow waves, even after artificially inducing gastroparesis through vagal disruption,²¹ there was no observed effect on gastric contractions and no measurable improvement in the gastric emptying rate of either liquids or solids.^22-25 The application of gastric pacing in humans with gastroparesis also failed to translate to meaningful improvements in gastric emptying, even though slow-wave entrainment was consistently achieved. In addition to the lack of enhanced emptying, the use of long pulses (10-600 milliseconds) resulted in high energy consumption, exceeding the capabilities of implantable stimulator technology at the time, thereby limiting its viability as a long-term therapeutic option.²⁶

Figure 1.

Gastric pacing: electrode placement and stimulation parameters. The early method investigated to accelerate gastric emptying, with stimulation supplied by a single electrode pair with broad pulses at low frequency.

The subsequent development of a low energy, higher-frequency stimulation system employed short pulses at rates well above physiological norms, typically 10-1200 cpm, enabling the use of a miniaturised subcutaneously implanted pulse generator.^25,27 Enterra Therapy (Medtronic, Minneapolis, MN, USA) is the most widely commercialized application of this high-frequency local GES, receiving Food and Drug Administration humanitarian device approval for medication-resistant gastroparesis (Fig. 2).^28,29 The Enterra system is implanted with a single pair of stimulating electrodes inserted into the muscularis propria along the greater curvature of the stomach, approximately 10 cm proximal to the pylorus and spaced 1 cm apart, targeting the distal corpus and proximal antrum.³⁰ Standard stimulation parameters are defined as 14 Hz pulse pairs every 5 seconds, a pulse width of 330 microseconds, and an amplitude of 5 mA.³¹ The Enterra system has been found to improve symptom control and quality of life in several studies, but does not achieve this through gastric pacing or improved gastric emptying.^26,32-34 Notably, a meta-analysis of 3 trials demonstrated a significant benefit over baseline in symptom burden, with a mean reduction in total symptom severity score of 6.52 (95% CI, 1.32-11.73; P = 0.010). This included a mean reduction of 16.5 vomiting episodes per week (95% CI, 6.17-26.88; P = 0.002) among 57 patients treated with GES.³⁵ The stimulation appears to interact with vagal afferent pathways, suggesting this to be the mechanism for modulating central control to reduce nausea and vomiting.^31,36 The vagus nerves transmit afferent signals from the stomach that that can either increase or decrease nausea and vomiting,^37,38 and the therapeutic efficacy of high-frequency GES to reduce nausea in patients with diabetic and idiopathic gastroparesis has been attributed to its ability to engage gastric vagal afferent fibers.³⁹ Despite its effectiveness in minimizing symptoms,^34,40 the limitation of this mode of stimulation in relation to gastric emptying is that it has not demonstrated consistent improvements in gastric contractility or emptying rates in either animal models or clinical studies of patients with gastroparesis.^24,41,42

Figure 2.

Gastric electrical stimulation: electrode placement and stimulation parameters. High frequency local stimuli, typified by the Enterra system that relieves the nausea and vomiting of gastroparesis but does not accelerate gastric emptying.

The unmet need for stimulation approaches that promote gastric propulsion led to the development of sequential neural stimulation using multiple electrode arrays. This method aims to more closely mimic natural gastric physiology by generating coordinated contractions through precisely timed activation of electrodes placed along the gastric wall (Fig. 3). This technology, termed neural gastric electrical stimulation (NGES), introduces a paradigm shift in conceptualizing stimulation of the gut. Using microprocessor-controlled multichannel stimulators, NGES employs a train of brief electrical square waves of high-energy (8-20 V peak-to-peak) stimulation for 4-16 seconds through strategically placed circumferential electrode arrays.^43,44 Unlike previous techniques that attempt to restore or entrain physiological slow-waves, NGES operates in a way that is not necessarily dependent on slow waves. The brief high-amplitude pulses are capable of overriding the intrinsic rhythmic electrophysiological patterns of the stomach by directly activating local neural networks.⁷ This is achieved through the release of acetylcholine from intramural cholinergic nerve fibers, a mechanism supported by the observation that NGES effects are abolished with atropine administration.⁴⁴ Rather than inducing a single contraction that naturally propagates, NGES achieves propagation of contents by sequentially stimulating discrete regions of the gastric wall, producing a series of spatially and temporally coordinated contractions that closely resemble peristaltic movement. This approach essentially superimposes an artificial pattern of coordinated contractions, independent of the underlying slow wave activity.^7,45 Thus, NGES has the potential to be effective even when ICC are severely compromized or absent, as may occur in idiopathic gastroparesis.¹¹

Figure 3.

Neural gastric electric stimulation: electrode placement and stimulation parameters. Neural gastric electric stimulation utilises sequential stimulation by electrodes placed along the stomach to accelerate emptying.

Research Foundations of Neural Gastric Electrical Stimulation

The foundational work in NGES was pioneered by Mintchev and colleagues at the University of Calgary,^44,46-49 who focused on developing multichannel sequential stimulation from proximal to distal to emulate gastric peristalsis (Table).^50-54 They developed a computational model of gastric activity demonstrating that phase-locked electrical stimulation at sequential sites could reproduce coordinated peristaltic-like contractions, thereby establishing the conceptual framework for NGES.^47,55 Their subsequent experimental validation in anaesthetised canine models between 1998-2000 demonstrated that NGES,^44,48,49 when applied as trains of 20 milliseconds bipolar pulses at 50 Hz, could generate coordinated contractions and significantly accelerate liquid gastric emptying. A series of 4 electrode pairs were spaced at 3-4 cm apart along the gastric axis, with pairs of electrodes diametrically opposing each other on the ventral and dorsal surface of the stomach. The mean half-emptying time of 300 mL of liquid gastric contents was reduced from 25.3 minutes in the absence of stimulation to just 6.7 minutes with NGES in 8 subjects, representing a nearly 4-fold acceleration in gastric emptying.⁴⁴ The group then extended their work in 2000 to solid gastric emptying in the same animal model, demonstrating that phase-locked stimulation could effectively propel gastric contents containing pellets to a greater degree than control subjects without stimulation.⁴⁸

Table.

Summary of Findings for Neural Gastric Electrical Stimulation in Animal Model Research

Study	Animal (sample)/design	Stimulation electrodes	Stimulation parameters	Outcome
Mintchev et al,44 1998	Canine model (8) Non-recoverable	4 rings of bipolar electrodes 4 cm apart located on antrum (proximally 6 electrodes; distally 2 electrodes); active electrodes and ground electrodes were alternatively arranged in each circumferential set	Amplitude: 14 V (peak-to-peak) Frequency: 50 Hz Pulse width: 20 msec “Sequential electrode activation; 4 sec on-time/4 sec off-time (electrode cycle time 32 sec)”	Strong artificial contractions were observed by sequential stimulation. Significantly reduced mean half-emptying time of liquid from 25.3 min without stimulation to 6.7 min with stimulation (P < 0.01).
Mintchev et al,49 1999	Canine model (4) Non-recoverable	4 rings of bipolar electrodes 4 cm apart located on antrum (proximally 6 electrodes; distally 2 electrodes); active electrodes and ground electrodes were alternatively arranged in each circumferential set	Amplitude: 14 V (peak-to-peak) Frequency: 50 Hz Pulse width: 20 msec “Sequential electrode activation; 4 sec on-time/4 sec off-time (electrode cycle time 32 sec)”	Strong artificially propagated contractions were observed. Spectral changes on electrogastrography with stimulation: normogastric activity (3-7 cpm) decreased, while low-frequency (1-3 cpm) and high-frequency (7-12 cpm) components increased.
Mintchev et al,48 2000	Canine model (9) Non-recoverable “Pyloroplasty performed as part of acute experiment”	4-6 rings of bipolar electrodes 3-4 cm apart located on antrum (proximally 6 electrodes; distally 2 electrodes) “Varying distances between sets were selected to mimic distally increasing propagation velocity of spontaneously contracting stomach.”	Amplitude: 6-12 V (peak-to-peak), gradually decreasing from proximal to distal Frequency: 50 Hz Pulse width: 20 msec “Stimulation train duration decreased progressively from 16 sec proximally to 4 sec distally with partially overlapping electrode activation (electrode cycle time 32 sec).”	Strong artificially propagated contractions were observed. Significantly accelerated solid gastric content emptying as measured by monitoring number of expelled radiopaque markers (P <0.01).
Chen et al,55 2000	Canine model (8) Non-recoverable	4 rings of bipolar electrodes 4 cm apart along greater curvature (2 electrodes per set)	Amplitude: 0.4-1 mA (proximal 1 mA; distal 0.4 mA) Frequency: 10% > intrinsic Pulse width: 40 msec “Phase-shifted sequential electrode activation based on intrinsic slow wave propagation delays.”	Significantly accelerated liquid gastric content emptying at 60 min from 190.8 without stimulation to 241.0 mL with stimulation (P < 0.05).
Chen et al,56 2005	Canine model (8) Recoverable	4 rings of bipolar electrodes 4 cm apart along greater curvature (2 electrodes per set)	Amplitude: 0.4-1 mA (proximal 1 mA; distal 0.4 mA) Frequency: 10% > intrinsic Pulse width: 40 msec “Phase-shifted sequential electrode activation based on intrinsic slow wave propagation delays.”	Significantly accelerated liquid gastric content emptying of 121.0% at 30 min and 93.9% at 60 min following stimulation, in comparison to without stimulation (P < 0.05).
Song et al,54 2005	Canine model (7) Recoverable	2 rings of bipolar electrodes 10 cm apart (2 electrodes per set)	Frequency: 10% > intrinsic Amplitude: 0.6-1 mA (proximal 1 mA; distal 0.6 mA) Pulse width: 200 msec “Phase-shifted dual-channel stimulation synchronised to intrinsic slow wave propagation”	Significantly accelerated liquid gastric content emptying at multiple time points compared to vasopressin-only and single-channel GES, increasing emptying at 30, 60, and 90 min postprandially (P < 0.05), while also normalising gastric dysrhythmias.
Jalilian et al,51 2007	Canine model (9) Non-recoverable	2 sets of bipolar electrode pairs implanted on antrum (2 electrodes per set)	Amplitude: 8-16 V (peak-to-peak) Frequency: 50 Hz Pulse width: NS “Sequential electrode activation of 4 channels with programmable 1-999 sec ON-time, 2-9999 sec OFF-time, 0-100% overlap”	Local non-propagated contractions as measured with force transducers correlated with higher amplitudes. Pre-pyloric stimulation resulted in retrograde peristalsis.
Onen et al,45 2007	Canine model (5) Non-recoverable	2 sets of bipolar electrode pairs implanted on antrum (2 electrodes per set)	Amplitude: 8-16V (peak-to-peak) Frequency: 50 Hz Pulse width: 20 msec “Sequential electrode activation; 8 sec on-time/82 sec off-time; 50% overlap (electrode cycle time 90 sec)”	Motility index increased with higher voltage parameters but was unaffected by variations across duty cycles. Ideal settings for strong and energy-efficient contractions are: 12-16 V, 50 Hz, 60% duty cycle.
Arriagada et al,52 2011	Canine model (4) Non-recoverable	4 rings of bipolar electrodes 3 cm apart located on antrum (proximally 6 electrodes; distally 2 electrodes); electrode axis transversely positioned	Amplitude: 20 V (peak-to-peak) Frequency: 50 Hz Pulse width: NS “Sequential electrode activation; 6 sec on-time/off-time programmable (1-1024 sec); 0% overlap (feedback-triggered)”	Implantable feedback-controlled stimulator detected gastric distension through changes in gastric tissue impedance. Feedback-controlled stimulator generated lumen-occluding contractions.

cpm, cycles per minute; NS, not stated; GES, gastric electrical stimulation.

Building upon these findings, Jalilian et al⁵¹ demonstrated the feasibility of wireless external control of gastrointestinal motility via an implantable NGES device, marking a significant step toward clinical translation in 2007. Arriagada et al⁵² subsequently advanced this work by integrating a feedback control system into the implantable device, enabling dynamic modulation of stimulation in response to changes in gastric volume, monitored by tissue impedance changes. Such feedback-based control holds promise not only for reducing battery consumption but also for mitigating tissue accommodation by preventing overstimulation and nerve fatigue.

While NGES has shown promise in preclinical models, its application in humans remains limited. To date, only a single human case has been attempted in a 32-year-old female with severe gastroparesis undergoing laparotomy and planned gastrectomy.⁴⁴ Four circumferential electrodes were temporarily placed to produce the high-frequency NGES parameters of the aforementioned studies.^{44,48,51,56,57} While gastric emptying was not assessed, the stimulation successfully produced visible, strong circumferential contractions under direct observation. This proof-of-concept case illustrates the feasibility of NGES in humans.

In contrast to this high-frequency NGES paradigm, the University of Texas research group explored the efficacy of NGES using low-frequency (~3 cpm, just above slow wave rate), long-pulse (40 milliseconds) stimulation.^50,53,54,58 Through a series of preclinical studies in canine models, Chen et al^55,56 demonstrated that applying multi-channel stimulation at a frequency just above the intrinsic slow wave rate was able to successfully achieve electrical entrainment in all subjects. This entrainment also translated to improved mean liquid gastric emptying at 60 minutes, showing a statistically significant increase from 190.8 mL without stimulation to 241.0 mL post-stimulation.⁵⁰ A follow-up study in 2005 confirmed this efficacy in a chronic recoverable study of canines, with a 121.0% improvement in gastric emptying at 30 minutes and 93.9% at 60 minutes when compared to controls.⁵³ In both studies, 4 pairs of stimulating electrodes were implanted along the greater curvature at the serosa at 4 cm intervals, each pair spaced 0.5-1.0 cm apart, with the most distal pair positioned approximately 4 cm proximal to the pylorus. The 4-channel stimulation protocol used 40 milliseconds pulses delivered at 10% above the intrinsic gastric slow wave frequency, with stimulation amplitude tapered from 1 mA at the most proximal site to 0.4 mA at the most distal to create a gradient of activation along the gastric axis to prevent retrograde propagation of the stimulation current. Song et al⁵⁴ applied similar principles in their recovery study using dogs, implementing a 2-channel GES approach to address vasopressin-induced delayed gastric emptying. The stimulation phase shift was calibrated to match the intrinsic propagation delay of gastric slow waves, allowing electrical activation to more closely replicate physiological coordination. Sequential 2-channel stimulation in this model significantly improved gastric emptying of a 100 mL water-based test meal, as measured via an intestinal cannula, increasing the average 60- and 90-minute emptied volume from 54.0 mL and 80.3 mL in the no-stimulation session to 75.3 mL and 90.8 mL with dual-channel stimulation, respectively.⁵⁴ Despite showing promising results in animal studies, these low-frequency, long-pulse stimulation protocols for NGES have yet to be translated into human studies.

Technical Implementation of Neural Gastric Electrical Stimulation

The effectiveness of NGES relies heavily on electrode placement. A typical configuration involves 2-6 circumferential positioned electrode assemblies implanted subserosally, along the gastric axis.^44,47 The most distal electrode is positioned at least 2 cm proximal to the pylorus, deliberately avoiding immediate pyloric placement as studies have shown that direct pyloric stimulation results in the counterproductive effect of delayed gastric emptying.^59,60

A defining innovation of NGES is its phase-locked sequential stimulation strategy, which delivers precisely timed electrical pulses across successive electrode sites from proximal to distal regions.²¹ This controlled, consecutive activation of each electrode pair stimulates coordinated contractions of the gastric muscle wall, enabling deliberate manipulation of contraction direction and velocity. The result is a seamless, artificially generated peristaltic-like movement that minimizes zones of stasis and promotes effective gastric emptying.⁴⁵

Standard operational parameters for NGES, as initially described by Mintchev et al,⁵² include pulse widths of 20 milliseconds, stimulation frequencies around 50 Hz, train durations (on-time) of 2-10 seconds, and inter-train pauses (off-time) ranging from 8 seconds to 1 hour. Voltage amplitudes typically vary from 2-20 V peak-to-peak.

Clinical Applications

Given the success of early animal model testing in generating coordinated gastric contractions and accelerated gastric emptying, there is significant promise for NGES in clinical practice. Several demographic and clinical trends underscore the growing need for advanced motility treatments. Recent epidemiological data reveal that gastroparesis prevalence may be significantly underestimated, affecting up to 267.7 per 100 000 individuals,⁶¹ with hospitalisations increasing by over 300% in the past 2 decades.⁶² The aetiology of gastric emptying disorders is heterogeneous, and encompasses idiopathic (36%), diabetic (29%), and postsurgical (13%) causes, alongside secondary forms linked to neurological and autoimmune disease.⁶³ The increasing global prevalence of diabetes, ageing populations and iatrogenic causes are expected to further compound this burden.^64-68

The clinical need is evidenced by the widespread adoption of Enterra therapy that, despite not influencing gastric emptying, remains a sought-after treatment option to treat the symptoms of medication-refractory gastroparesis.³⁰ Along with the simultaneous advances in multimodal oncological care, there is now a growing population of esophagogastric cancer survivors experiencing the functional complications of a gastric conduit reconstruction. The emerging challenge of DGCE has limited treatment options and is among the greatest detriment to esophagogastric cancer survivors’ quality of life.⁶⁹ These chronic delayed emptying disorders pose a substantial burden, not only through their emotional and psychological impact on patients but also through their considerable strain on healthcare resources.

A distinct advantage of NGES is its autonomous efficacy. Unlike other stimulation strategies that rely on the presence of intact and responsive slow wave activity, NGES directly induces contractions by overriding native myoelectrical activity, enabling it to function across a broad spectrum of gastric motility disorders. As such, the scope for patient selection may be broad, with suitable candidates including individuals who experience debilitating symptoms of delayed gastric emptying, regardless of underlying aetiology.

Technological advancements in energy efficiency and minimally-invasive surgery in the current era have also advanced the concept of NGES toward clinical feasibility. Modern systems are now compatible with compact, subcutaneously implantable pulse generators, eliminating the need for bulky hardware and enabling less invasive implantation. Importantly, multichannel NGES consumes only 1-15% of the energy required by traditional single-lead systems, owing to its use of efficient electrode configuration and sequential stimulation pattern that minimize power demands.^54,58 Emerging innovations such as impedance-based feedback systems, which activate stimulation only when needed, offer the potential to significantly extend battery life, reducing the frequency of device replacement and improving long-term viability. As the field moves toward more adaptive stimulation protocols, NGES stands to become a practical, durable solution for patients with complex and refractory gastric motility disorders. Complementing these advances in device technology, the growing adoption of laparoscopic and robotic-assisted surgical techniques has made potential reintervention for implanting a gastric stimulator increasingly feasible and acceptable. These minimally invasive approaches are associated with shorter operative times, faster postoperative recovery, reduced perioperative morbidity, and improved patient satisfaction,⁷⁰ thereby lowering the threshold for implantation procedures if necessary. Recent work by Schiemer et al⁷¹ has laid important groundwork for translating gastrointestinal electrostimulation from preclinical models to human trials, with the interdisciplinary development of a protocol that describes surgical implantation strategies. This framework demonstrates the feasibility of implanting multi-segmental gastric stimulators using laparoscopic and robotic-assisted approaches, providing a concrete pathway toward first-in-human trials.

While various centers have recently adopted pylorus-targeted therapies, such as pyloromyotomy and balloon dilation to manage gastric motility disorders, these interventions address only one aspect of the pathophysiology underlying delayed gastric emptying.^72,73 These procedures aim to relieve pyloric resistance, reflecting the historical assumption that compromised gastric emptying is due primarily to pyloric spasm. Recent work, however, emphasises that gastric reservoir tone, compliance, and peristalsis are also critical for effective emptying, all of which are factors that pyloric interventions fail to address,⁷⁴ which may contribute to their limited long-term efficacy.⁷⁵ NGES, which may be combined with pyloric therapy, offers a more comprehensive approach by modulating these broader neuromuscular mechanisms to restore more physiological gastric function.

Future Directions

The development of implantable NGES devices, as demonstrated by Jalilian et al,⁵¹ marks a crucial step toward clinical advancement. This will facilitate the next phase of chronic studies which are much needed to evaluate the safety and tolerability of NGES in a controlled recoverable setting.

Several critical development priorities must be addressed, however, to support the successful clinical translation of NGES. Foremost among these is the need to define optimal stimulation protocols given significant variability across existing studies in terms of pulse width, frequency, amplitude, and electrode sequencing. A second priority involves evaluating battery longevity under both continuous stimulation and when stimulation is timed to activate during digestion, as this will directly inform device lifespan and replacement schedules.^51,76 The third key area for investigation involves clarifying the role of pyloric function in modulating the efficacy of NGES. Pyloric dysfunction is increasingly recognized as a contributor to impaired gastric outflow in gastroparesis and DGCE.^73,77 Given the potential symptomatic benefit, it remains unclear whether pyloric drainage procedures should routinely be combined with NGES or reserved for specific patient subgroups. A fourth priority to address is to optimize electrode and lead designs. The system requires multiple leads, and there is the possible need to access the lesser sac to implant stimulation leads on both the ventral and dorsal gastric surfaces. However, further research is needed to determine whether stimulation on both gastric surfaces is necessary, as restricting lead placement to the ventral surface alone could simplify surgery. Recent innovations in miniaturization of neural interfaces, wireless energy delivery, and biocompatible implantable materials may also help overcome technological barriers and address the challenges of design, supporting the future development of NGES for long-term clinical use.^78,79

While gastric stimulation technology initially received limited clinical adoption due to perceived market constraints and the availability of prokinetic agents, emerging evidence now demonstrates a substantial and growing clinical burden associated with gastric motility disorders. The increasing prevalence of gastroparesis, driven largely by rising rates of diabetes, an aging population and iatrogenic causes, presents both a pressing therapeutic challenge and an opportunity for innovation.^64-66,80 Prokinetic agents were also once considered a viable mainstay of treatment, although their long-term efficacy is limited, and approximately 20-30% of patients remain refractory to standard therapies.^81,82 In this evolving clinical landscape, NGES represents a promising, and scalable, intervention for an expanding patient population.

The long-term implementation of NGES would necessitate structured follow-up protocols, with periodic device assessments to ensure ongoing functionality. A troubleshooting algorithm would need to be developed to evaluate potential hardware failures when patients present with concerning symptoms or diminished therapeutic efficacy. Drawing from established practices for other neurostimulation implants,^83,84 this framework would likely incorporate device interrogation to evaluate impedance, alongside abdominal X-ray compared against baseline postoperative imaging,⁸⁵ to detect lead displacement, breakage, or migration. Establishing such protocols will be essential for safe chronic use of NGES.

Several emerging therapeutic applications of NGES technology warrant investigation beyond its primary role in gastric emptying disorders. One area of interest involves employing NGES principles for colonic stimulation to improve intestinal transit for constipation.⁸⁶ Another possible avenue is the use of retrograde sequential activation as a potential therapy for obesity, as it has been shown to disrupt normal slow wave rhythms and induce slow wave uncoupling, physiological changes that ultimately delay gastric emptying and enhance early satiety signalling.⁸⁷

Conclusion

NGES has the potential to be a transformative shift in the management of gastric motility disorders by offering a novel approach to elicit coordinated contractions through direct neural activation rather than attempting to entrain existing slow waves. The development of NGES from initial proof-of-concept experiments to advanced systems incorporating real-time feedback control also marks significant progress toward clinical translation. While initial animal studies have demonstrated impressive results, continued development of this approach in chronic recoverable models will provide important new therapeutic options for patients with gastric motility disorders.