Introduction

Gastrointestinal motility disorders (GMDs) are common along the gut and are one of major causes of functional gastrointestinal (GI) diseases that affect more than 20% of general population and account for more than 40% of patients seen in GI clinic ( ). Typical diseases associated with GMD include gastroesophageal reflux, achalysia, functional dyspepsia, gastroparesis, intestinal pseudo-obstruction, postoperative ileus, irritable bowel syndrome, fecal incontinence, and constipation.

The normal physiological function of the stomach is to accommodate ingested food, store it, and then empty it at an appropriate rate into the duodenum for absorption. There are two major motility actions in the stomach: accommodation reflex action to relax the proximal stomach to accommodate ingested food and antegradely propagated, antral contractions (or peristalsis) to push the ingested food through the pylorus into the duodenum. The relaxation of the proximal stomach is achieved through the activation of the vagus nerve and release of the inhibitory neurotransmitter, nitric oxide. Antral contractions are generated by the activation of the vagal nerve and release of acetylcholine (AcH). The rhythm and propagation of antral contractions are determined by the basic rhythm of the stomach called slow-wave or pace-making activity (3 waves/min in humans).

Currently, treatment options for GMDs have been very limited. Prokinetics were developed to enhance gastric motility, such as cisapride, domperidone, erythromycin, metoclopramide, tegaserod, and prucalopride ( ). However, due to cardiac toxicity or side effects, most of these medications are not available in the United States. Although some of them are available, such as erythromycin, they often do not produce adequate symptom relief that is possibly due to their aggregating effect on gastric accommodation: most of the prokinetic medications impairs gastric accommodation ( ). Accordingly, there is an urgent need for the development of novel therapies for GMDs.

The myoelectrical and neural basis of gastric electrical stimulation (GES) is to modulate the enteric nervous system and/or autonomic functions, or directly modulate myoelectrical rhythm of the stomach. Previous studies have shown that GES can be programmed to alter autonomic functions and thus change gastric motility functions. It is well-known that enhancement or activation of vagal activity improves gastric motility, whereas activation of sympathetic activity inhibits gastric motility. Studies have also been shown that GES with appropriate settings of stimulation parameters is able to alter gastric slow waves or pace-making activities ( ). By normalizing or enhancing gastric slow waves, GES improves gastric motility. Whereas, by impairing gastric slow waves, GES inhibits gastric motility or gastric tone ( ).

In addition to gastric dysmotility, obesity is another disease that is to be addressed with GES in this chapter. Obesity is one of the most prevalent public health problems worldwide. About 1.7 billion individuals in the world are now estimated to be obese (body mass index or BMI ≥ 30 kg/m ² ) and approximately two-thirds of general population in the United States are overweight and of those, about half are obese. The annual medical cost for the treatment of obesity in the United States is estimated to be $147 billion in 2008 ( ). The analysis of five prospective cohort studies suggested that between 275,000 and 325,000 Americans die each year from obesity-related diseases ( ). Obesity is also associated with an increased prevalence of socioeconomic hardship due to a higher rate of disability, early retirement, and widespread discrimination ( ).

The treatment of obesity can be classified into three categories: general measures (diet and exercise), pharmacotherapy, and surgical treatment. Diet and exercise are the first treatment/preventive option for obesity. Although an acceptable weight loss may be achieved with such measures, maintaining weight loss seems to be more difficult, particularly for patients who were treated with caloric restriction. About 50% of patients regain weight within 1 year after treatment and almost all patients regain weight within 5 years ( ). Pharmacotherapy for obesity has been problematic. Various drugs have been developed for the treatment of obesity. These include amphetamine derivatives such as fenfluramine and dexfenfluramine, sibutramine, diethylpropion, mazindol, phentermine, phenylpropanolamine, orlistat, etc. ( ). However, in general, the outcome of medical treatment has been disappointing due to either adverse effects/events (AEs) or a lack of long-term efficacy. Surgical treatment is typically reserved for patients with morbid obesity (BMI > 40) ( ). A number of surgical procedures have been used clinically, including sleeve gastrectomy that restricts food intake, gastric bypass that promotes maldigestion of ingested nutrients, such as Roux-en-Y and biliopancreatic diversion, duodenal switch and gastric banding (called lap-banding if the procedure is done laparoscopically) or adjustable gastric banding ( ). Among these various procedures, Roux-en-Y gastric bypass is the most effective. However, it should be noted that the gastric bypass procedure as well as other surgical procedures have a number of drawbacks: (1) it alters the anatomy of the gut, is irreversible and therefore poses a significant problem in patients who fail to reduce body weight; (2) it involves morbidity and mortality; the mortality rate is about 0.2%–2% and the rate of serious adverse events (SAEs) is about 5%–8% ( ); (3) it impairs micronutrient absorption and results in metabolic and nutritional complications. Nutrient deficiencies following gastric bypass include protein-calorie malnutrition, fat malabsorption, iron deficiency, vitamin B ₁₂ deficiency, folate deficiency, riboflavin deficiency, and calcium deficiency ( ).

GES, developed for the treatment of obesity, can be classified into three categories based on their effects: neural GES (nGES) is supposed to act on nerves to induce satiety, excitatory GES (eGES) to enhance gastric motility, and inhibitory GES (iGES) to inhibit gastric motility to enhance satiety or reduce food intake. Compared with the surgical therapies, GES is much less invasive and, most importantly, reversible and adjustable over time. During GES clinical studies, patients, physicians, and surgeons have shown great enthusiasm toward GES. However, controlled studies of GES for obesity, using weight loss as their primary endpoint, have failed to reach significance. The aim of this chapter is to critically review various methods of GES that have been applied for treating obesity and provide insight into a viable GES therapy for obesity.

Gastric Motility and Food Intake

Methods of Gastric Electrical Stimulation

A number of different methods of GES have been reported in the literature. They can be classified into different groups based on stimulus configurations or functionalities of stimulation. Based on stimulation pulses, GES can be classified as long pulses, short pulses, and pulse trains ( ).

Long-pulse stimulation : This method is most frequently reported in the literature (but mostly limited to animals) because it is able to “pace” or entrain natural slow waves. In this method, the electrical stimulus is composed of repetitive single pulses with a pulse width in the order of milliseconds (10–600 ms), and a stimulation frequency in the vicinity or in the order of the physiological frequency of the gastric slow wave. It is also called low-frequency/high-energy GES ( ).

Short-pulse stimulation : In contrast to long-pulse stimulation, the pulse width in this method is substantially shorter and is in the order of a few hundred microseconds (μs). The stimulation frequency is usually a few times higher than the physiological frequency of the gastric slow wave.

Trains of short pulses : In this method, the stimulus is composed of repetitive trains of short pulses with an on-period and off-period. This kind of stimulation has been frequently used in nerve stimulation. Commercially available implantable stimulators are capable of generating trains of pulses with a pulse width of below 1 ms. Recently, however, a number of implantable pulse generators have been developed for clinical trials or animal research that are capable of generating pulses with a pulse width of >1 ms ( ).

According to the effects of GES on gastric motility, GES can be classified into the following categories:

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  eGES or excitatory GES : Any method of GES that enhances gastric motility is called eGES. According to this definition, eGES is able to pace gastric slow waves (gastric intrinsic myoelectrical activity), enhance gastric contractions, and/or accelerate gastric emptying. In the method of eGES, long pulses are typically used and the frequency of the stimulation should be the same as or slightly higher than the frequency of the intrinsic gastric slow waves. Examples of eGES include gastric pacing that normalize gastric dysrhythmia and synchronized GES that enhances antral contractions and speeds up gastric emptying ( ). This method is typically used for treating GMDs ( ). Long-pulse eGES at the electrophysiological frequency of the stomach has been applied to normalize gastric dysrhythmia in patients with gastroparesis (delayed gastric emptying) and accelerate delayed emptying of the stomach ( ). Both human and canine studies have shown that the method of long-pulse eGES is capable of pacing the stomach and restoring the normal rhythm of gastric myoelectrical activity ( ). Improvement in clinical symptoms of dyspepsia and gastric emptying has also been reported using long-pulse GES at the physiological frequency. However, no implantable device is available to assess the long-term effects of this method for the treatment of gastric motor disorders.

  In the method of pulse train GES, if the pulse width is in the order of a few ms or higher, it is also capable of enhancing or intruding gastric contractions. Two examples are the one proposed by Mintchev et al. ( ) and the device called the Tantalus ( ). In both of these methods, pulse trains are given at a frequency (number of trains/min) that is in the vicinity of or lower than the physiological frequency of the intrinsic gastric contractions or synchronized with the intrinsic gastric contractions. Both of these methods have been reported to induce or enhance gastric contraction/emptying ( ).

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  nGES or neural GES : Any method of GES that has no direct effects on gastric motility is called nGES. In this method, the stimuli of GES are usually composed of short pulses. Although this method of GES does not alter gastric motility, it typically changes neural activities. The method that has been used clinically for the treatment of nausea and vomiting in patients with gastroparesis (called Enterra therapy) can be classified as nGES as it does not effectively alter gastric slow waves, antral contractions, or gastric emptying ( ). The antiemetic effect of Enterra therapy is discussed in detail in other chapters of this volume. If GES uses short pulses or trains of short pulses with a width of <1 ms, it may also be called nGES because GES with these parameters do not alter gastric motility directly.

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  iGES or inhibitory GES : Any method of GES that inhibits gastric motility, such as inhibiting gastric tone, contractions, and/or emptying, is called iGES. Two methods of GES can be called iGES: (1) long-pulse GES that inhibits motility (typically the stimulation frequency is in the tachygastrial range); (2) pulse train GES that inhibits motility (typically the pulse width is >1 ms). The inhibition of gastric motility has been linked to reduced food intake and therefore iGES is expected to be an appropriate method for the treatment of obesity.