Chronic Tachygastrial Electrical Stimulation ... - Wiley Online Library

Chronic Tachygastrial Electrical Stimulation Reduces Food Intake in Dogs Jing Zhang,* Xiaohong Xu,† and Jiande D.Z. Chen*†

Abstract ZHANG, JING, XIAOHONG XU, AND JIANDE D.Z. CHEN. Chronic tachygastrial electrical stimulation reduces food intake in dogs. Obesity. 2007;15:330 –339. Objective: Tachygastria is known to be associated with gastric hypomotility. This study investigated the effect of tachygastrial electrical stimulation (TES) on food intake and its effects on gastric motility. Research Methods and Procedures: Five experiments were performed to study the effects of TES on gastric slow waves, gastric tone, accommodation, and antral contractions, gastric emptying, acute food intake, and chronic food intake in dogs. Results: TES at tachygastrial frequencies induced tachygastria and reduced normal slow waves. TES significantly reduced gastric tone or induced gastric distention, impaired gastric accommodation, and inhibited antral contractions. TES significantly delayed gastric emptying. Acute TES reduced food intake but did not induce any noticeable symptoms. Chronic TES resulted in a 20% reduction in food intake, and the effect of TES was found to be related to specific parameters. Discussion: TES at the distal antrum results in a significant reduction in food intake in dogs, and this inhibitory effect is probably attributed to TES-induced reduction in proximal gastric tone, gastric accommodation, antral contractility, and gastric emptying. These data suggest a therapeutic potential of the specific method of TES for obesity. Key words: weight loss, gastric pacing, gastric electrical stimulation, gastrointestinal motility

Received for review July 13, 2006. Accepted in final form September 13, 2006. The costs of publication of this article were defrayed, in part, by the payment of page charges. This article must, therefore, be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. *Veterans Research Foundation, VA Medical Center, Oklahoma City, Oklahoma and †Division of Gastroenterology, University of Texas Medical Branch, Galveston, Texas. Address correspondence to Jiande Chen, Division of Gastroenterology, Route 0632, 1108 The Strand, Room 221, Galveston, TX 77555-0632. E-mail: [email protected] Copyright © 2007 NAASO

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Introduction The prevalence of obesity is rising to epidemic proportions around the world at an alarming rate. Obesity is one of the most prevalent public health problems in the United States. According to the National Health and Nutrition Examination Survey, overweight (BMI ⫽ 25.0 to 29.9 kg/ m2) adults now represent 59.4% of the male and 50.7% of the female population in this country, totaling more than 97 million people. The corresponding figures for obesity (BMI ⱖ 30 kg/m2) are ⬃19.5% for men and 25% for women, involving a total of almost 40 million people. Severe obesity or clinically severe obesity (BMI ⱖ 40 kg/m2 or ⬎100 lbs over normal weight) affects more than 15 million Americans (1– 4). It is estimated that more than 300,000 deaths are caused by obesity every year. The treatment of obesity and its primary comorbidities costs the U.S. health care system close to $100 billion each year (5– 8); in addition, consumers spend in excess of $33 billion annually on weight reduction products and services (9). Moreover, obesity is associated with an increased prevalence of socioeconomic hardship because of a higher rate of disability, early retirement, and widespread discrimination (10,11). The traditional treatment of obesity can be classified into three categories: general measures, pharmacotherapy, and surgical treatment. General measures typically are caloric restriction, behavior therapy, and physical activity; although acceptable weight loss may be achieved with such measures, maintaining weight loss seems to be more difficult. Approximately 50% of patients regain weight within 1 year after treatment, and almost all patients regain weight within 5 years (12). Most of the medication for obesity has adverse events, some are approved only for short-term use, and their clinical efficacy is very limited. Surgical treatment is mainly reserved for severely obese patients (13). The operative complications and long-term consequences of the current operative procedures prohibit many people from having surgery. Gastric distention and gastric emptying play an important role in regulating food intake. Several studies have shown that gastric distention acts as a satiety signal to inhibit food intake (14), and rapid gastric emptying is closely related to

TES Reduces Food Intake in Dogs, Zhang, Xu, and Chen

overeating and obesity (15). In a rodent study, Philips and Powley (14) placed an intragastric balloon and found a reduction of short-term food intake. They also noted that the inhibition of food intake was attributed to gastric distention rather than nutritional content. A number of clinical studies have been performed in patients with severe obesity using an intragastric balloon, and promising short-term (up to 6 months) results on weight loss have been reported (16 –18). However, its long-term use is not promoted because of severe morbidity and complications (16,17). Duggan and Booth (15) published a study that reported that rapid gastric emptying is the major primary cause of the obesity resulting from ventromedial hypothalamic lesions in rats and suggested that therapy for obesity could include slowing of stomach emptying. In patients with obesity, rapid gastric emptying has been frequently reported (19). Inspired by cardiac electrical stimulation and electrical nerve stimulation, a number of investigators have explored the potential of gastric electrical stimulation (GES).1 Recently, the therapeutic potential of GES for gastrointestinal motility disorders has been under intensive study (20). Long-pulse GES at the electrophysiological frequency of the stomach has been applied in an attempt to normalize gastric dysrhythmia in patients with gastroparesis (delayed gastric emptying) and accelerate delayed emptying of the stomach (21–34). Both human and canine studies have shown that the method of long-pulse GES is capable of pacing the stomach and restoring the normal rhythm of gastric electrical activity (32,34). Physiological gastric electrical activity propagates distally from the body to the pylorus with a frequency of 3 cpm in human and controls gastric peristalsis. When there is tachygastria (a frequency of ⬎5 cpm), the stomach is not capable of contracting. In this application, we propose to apply GES at a tachygastrial frequency and place stimulation electrodes in the distal stomach as shown in Figure 1. That is, the tachygastrial electrical stimulation (TES) generates an artificial tachygastria that propagates retrogradely. This artificial pacemaker has two functions: 1) it interrupts the normal distal propagation of regular slow waves, and 2) it paces the gastric slow waves in the distal stomach to a tachygastrial rhythm. These effects will result in a reduction of both gastric tone and gastric peristalsis (Figure 1). However, little is known about the therapeutic role of GES for obesity. The available data were all obtained using the implantable stimulator that was modified from a cardiac pacemaker and was able to generate only short pulses (up to 650 ␮s). The methodology (selection of stimulation parameters and locations) was not physiologically designed, and possible mechanisms were not studied.

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Nonstandard abbreviations: GES, gastric electrical stimulation; TES, tachygastrial electrical stimulation; IGS, implantable gastric stimulation.

Figure 1: TES is equivalent to placing an artificial ectopic pacemaker in the antrum. This artificial ectopic pacemaker results in electrical waves propagating retrogradely from the antrum to the proximal stomach, fighting against the normal and physiological electrical waves that propagate from the proximal to the distal stomach. Consequently, tachygastria is induced, and the regular propagation of gastric electrical waves is impaired, leading to an inhibition of gastric tone and gastric peristalsis.

The specific aims of this study were to investigate the effects of TES on gastric motility (including tachygastria, gastric tone and gastric accommodation, antral contraction, and gastric emptying) and to examine the acute and chronic effects of TES on food intake in dogs.

Research Methods and Procedures Animal Preparation A total of 18 healthy female hound dogs (17 to 25 kg) were used in five separate experiments. After an overnight fast, anesthesia was induced with pentothal (11 mg/kg sodium thiopental intravenously; Abbott Laboratories, North Chicago, IL) and maintained on IsoFlo (2% to 4% isoflurane, inhalation anesthesia; Abbott Laboratories) in oxygen (1 L/min) carrier gases delivered from a ventilator after endotracheal intubation. The dog was monitored by a pulse oximeter. In the first 12 dogs, four pairs of 28-gauge cardiac pacing wires (A&E Medical, Farmingdale, NJ) were implanted on the gastric serosa along the great curvature at an interval of 4 cm, with the most distal pair 2 to 3 cm above the pylorus. The two electrodes in each pair were arranged in the circumferential pattern with a distance of ⬃0.5 to 1.0 cm. The electrodes were penetrated into the subserosal layer and were affixed to the serosa by nonabsorbable sutures. The connecting wires of the electrodes were tunneled through the anterior abdominal wall subcutaneously along the right side of the trunk and placed outside the skin around OBESITY Vol. 15 No. 2 February 2007

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the right hypochondrium for the attachment to the recorder or the stimulator (World Precision Instruments, Sarasota, FL). In 6 of the 12 dogs, a cannula was placed in the duodenum, 20 cm beyond the pylorus, for the assessment of gastric emptying. In the other 6 dogs, a gastric cannula instead of a duodenum cannula was placed 10 cm above the pylorus for the assessment of antral motility. In the last six dogs, a custom-made implantable stimulator (Transneuronix, Mt. Arlington, NJ) was placed in a pouch under the abdominal skin. The implantable stimulator was connected to a lead with bipolar electrodes on its tip (Transneuronix). The lead was placed in the antrum 6 cm above the pylorus along the greater curvature. The distance between the bipolar electrodes was ⬃0.6 cm. No temporary cardiac pacing wire or cannula was placed in these animals. Immediately after the surgical procedure, the dog was transferred to a recovery cage after receiving medications for postoperative pain control. The study was initiated after the dogs were completely recovered from the surgery (usually 2 weeks after the surgery). The study was approved by the Institutional Animal Care and Use Committees of the University of Texas Medical Branch (Galveston, TX) and the Animal Committee of the Veterans Affairs Medical Center (Oklahoma City, OK). Experimental Protocol The study was composed of five separate experiments. Experiment 1. Tachygastria is known to cause gastric hypomotility (or absence of peristalsis). The first experiment was performed in six dogs with the gastric cannula (the cannula was not used in this experiment) to study the effects of TES on gastric slow waves. One distal pair 2 to 4 cm above the pylorus (E1; Figure 2) was used for electrical stimulation. Each study session was composed of nine periods. After a 30-minute baseline recording, TES (pulse width: 100 ms, pulse amplitude: 6 mA; Figure 3) with a different tachygastrial frequency (7 cycles/min; 9, 14, and 18 cpm) was initiated. Each stimulation period lasted 20 minutes, followed by a 20-minute recovery period. Experiment 2. The second experiment was performed in six dogs with the gastric cannula to study the effects of TES on gastric tone and antral contractions. Gastric volume was recorded under a constant minimal distending pressure (plus 2 mm Hg) for 30 minutes at baseline, 30 minutes with TES, and 60 minutes after a liquid meal of Boost (237 mL, 240 kcal; total fat, 4.0 grams; total carbohydrate, 41.0 grams; protein, 10.0 grams; Boost; Mead Johnson Nutritionals, Evansville, IN) with TES. TES was performed at a frequency of 9 cpm, a pulse width of 200 ms, and an amplitude of 6 mA. In the control session performed on a separate day, gastric tone was recorded for 30 minutes at baseline and 60 minutes after the same test meal; no TES was performed. In the experiment with the measurement of antral contractions, each dog was fed with one can of solid dog food. 332


(413 kcal; 13.2 oz; crude protein, 8.0%; crude fat, 6.0%; crude fiber, 1.5%; moisture, 78.0%; Pedigree; Kal Kan Foods, Vernon, CA). After eating, antral contractions were measured using a water-perfused manometric catheter with four side holes at an interval of 1 cm placed in the distal antrum using the gastric cannula (C-1; Figure 2). The recording was composed of three 30-minute consecutive postprandial periods: baseline, TES, and recovery. TES was performed with a frequency of 9 cpm, a pulse width of 300 ms, and an amplitude of 6 mA. (Electrode E2 was used for electrical stimulation.) Experiment 3. The third experiment was performed in six dogs with the duodenal cannula (C-2; Figure 2) to study the effects of TES on gastric emptying. The study was composed of two sessions in a random order with at least a 72-hour lapse between the two sessions. The animals were acclimated to a restraining sling before the experiment and were fasted overnight before each session. Thirty minutes after the dog was put into the restraining sling, either no stimulation or stimulation was initiated, and 30 minutes later, the dog was fed with liquid food (a can of Boost, 237 mL, 240 kcal) mixed with 100 mg phenol red, no stimulation or stimulation was continuously applied for another 90 minutes, and gastric chime emptied from the stomach was collected every 15 minutes for 90 minutes. TES was performed at a tachygastrial frequency of 9 cpm, a pulse width of 100 ms, and an amplitude of 2 mA (this value was lower than most of the other studies) through E2 (Figure 2) electrodes that were 6 to 7 cm above pylorus. Experiment 4. The fourth experiment was designed to study the effect of TES on acute food intake, water intake, and signs/symptoms, performed in six dogs with the gastric cannula (the cannula was not used). This study was composed of a TES and a control session (no stimulation) on two different days. TES was performed at a frequency of 9 cpm, pulse width of 100 ms, and an amplitude of 2 mA. Before each study, the dogs were deprived of food for 28 hours and deprived of water for 16 to 22 hours. TES or no stimulation was initiated at the beginning of the experiment, and 30 minutes later, 2 kg (more than any dog could consume at a time) regular solid food (gross energy, 4.33 kcal/g; calories provided by 27.8% protein, 23.3% fat, and 49.0% carbohydrates; Laboratory diet, PMI Nutrition International, Brentwood, MO) and sufficient water were offered for 1 hour with TES or no stimulation. No exoteric disturbances were present during the study. At the end of the experiments, the leftover food and water were removed and weighed. Four noticeable signs/symptoms (salivation; licking tongue; murmuring: whine, growl, bark, yelp; and movement) were recorded and separately graded from 0 to 3 (0: none; 1: mild; 2: moderate; 3: severe) during the study. A total symptom score was obtained in each study session. Experiment 5. The fifth experiment was designed to study the chronic effect of GES on food intake and effects of


various stimulation parameters. It was performed in six dogs with the custom-made implantable stimulator. The study was initiated 2 weeks after the surgery. The first 2 weeks of the study served as an acclimation period during which the animals were only given unlimited food (1 kg or more than animal could consume one time) during 9:00 AM to 11:00 AM daily. Similarly, during the next 6 months of the study, the animals were only given unlimited food from 9:00 to 11:00 AM. No food was given at other times. Water was given regularly. During the 6-month study period, the stimulator was programmed randomly to one of the following set of the parameters: pulse width of 100 ms and pulse frequency of 10 or 15 cpm; pulse width of 300 ms and pulse frequency of 8, 10, or 15 cpm; pulse width of 500 ms and pulse frequency of 10, 12, and 15 cpm. The stimulation voltage was fixed at 2.5 V. Each setting was used three times, and each time it was used continuously for a period of 1 week. There were also 6 individual weeks during which no stimulation was performed, and these six periods were randomly but relatively evenly distributed within the 6-month study period. Electrical stimulation was performed between 9:00 AM and 11:00 AM, during which the food was given. The stimulator was programmed using a Remote Wonder that is connected to a PC. Measurements and Analysis Gastric Slow Waves. Gastric myoelectrical activities were recorded from two pairs of gastric serosal electrodes (E2 and E3) using a multichannel recorder (Acknowledge III, EOG 100A; Biopac Systems, Santa Barbara, CA) with a cut-off frequency of 35 Hz. All signals were displayed on a computer monitor, digitized at a frequency of 100 Hz, and saved on a hard disk. The recorded myoelectrical signal was filtered by a digital low-pass filter with a cut-off frequency of 1 Hz and down-sampled at 2 Hz. Gastric myoelectrical activity is composed of rhythmic slow waves with a frequency of 4 to 6 cycles/min and spikes with a frequency of ⬃2 to 10 Hz. The recorded signal after low-pass filter (a cut-off frequency of 1 Hz) was composed of only slow waves as spikes were filtered out. A previously validated spectral analysis method was used to calculate the percentage of normal 4- to 6-cpm slow waves and the percentage of tachygastria (⬎6 cpm) (35). Gastric Tone/Gastric Distention. Before the experiments, all of the dogs were fasted overnight with free access to water. A noncompliant polyethylene balloon (700 mL, 10 cm, finely folded) attached to a catheter was introduced into the stomach through the gastric cannula (C-1), placed in the proximal stomach. The other side of the catheter (with double lumen polyvinyl) was connected to a computerdriven programmable barostat device (G & J Electronics, Willowdale, Ontario, Canada). A constant intragastric pressure was set, with the minimal distending pressure ⫹ 2 mm Hg (range, 4 to 6 mm Hg, with a mean of 5 mm Hg).

The volume inside the intragastric bag was continuously recorded and saved on a computer. Antral Contraction. Antral contractile activities were recorded from the four pressure sensors of 1 cm apart attached to the manometric catheter using a PC polygraph HR system (Synectics Medical, Stockholm, Sweden) and a microcapillary infusion system (model 8; Medtronic Synectic, Stockholm, Sweden). All recordings were displayed on a computer monitor. We used the number of contractions per minute as a parameter to represent the contractile strength of the distal stomach. It was visually counted from the tracings. A contraction was defined as a positive increase in pressure of ⬎8 mm Hg from the baseline. Gastric Emptying. The liquid test meal was evenly mixed with phenol red, and gastric emptying was determined by the assessment of the amount of phenol red in each collection obtained from the duodenal cannula. For each collection of the gastric effluent, the volume was recorded, and a sample of 5 mL was taken and stored in a freezer. The samples were analyzed all together at the end of the study using a spectrophotometer. Gastric emptying was assessed by computing the amount of phenol red recovered from each collection of the gastric effluent using a previously validated method (36). Food Intake. In Experiment 5, food intake was averaged over a period of 1 week (either control period without stimulation or stimulation using one set of parameters). The amount of daily food intake during the control period was averaged over all six periods, whereas the amount of food intake during TES with each stimulation setting was averaged over all three periods with the same setting. To compare the difference between the control periods and the stimulation periods, all values of food intake were averaged over all periods with stimulation. Statistical Analysis Data were reported as mean ⫾ SE. One-way ANOVA was used to compare the difference among nine periods in Experiment 1 and among the three periods in Experiment 2. Paired Student’s t test was used to study the difference in any two study sessions in Experiment 2 (gastric tone), Experiment 3, the difference between any two study periods in Experiment 2, or the difference between the control session and the TES session in Experiments 4 and 5. The pairwise analyses were performed only if the ANOVA revealed significant p values. p ⬍ 0.05 was regarded as a significant difference.

Results TES Induced Tachygastria Gastric myoelectrical recording showed that TES at 7 and 14 cpm induced a complete entrainment (the gastric slow waves were phased-locked with stimuli). The percentage of OBESITY Vol. 15 No. 2 February 2007

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Figure 4: Tachygastria induced by TES at various stimulation frequencies in dogs. A significant increase in tachygastria was noted with TES. It was also found that TES at 7 or 14 cpm induced a higher percentage of tachygastria.

Figure 2: Experimental model. E1–E4, electrodes; C-1, gastric cannula; C-2, duodenal cannula.

entrainment time was 64.5 ⫾ 3.5% with TES at 7 cpm and 53.2 ⫾ 5.9% with TES at 14 cpm. No complete entrainment was found during TES at 9 and 18 cpm. TES at tachygastrial frequencies significantly reduced the percentage of normal slow waves and induced tachygastria. The percentage of normal slow waves (4 to 6 cpm) was 82.4 ⫾ 6% at baseline, 13.7 ⫾ 3.8% (p ⬍ 0.001) with TES at 7 cpm, 18.5 ⫾ 10.2% (p ⬍ 0.001) with TES at 9 cpm, 8.3 ⫾ 3.4% (p ⬍ 0.001) with TES at 14 cpm, and 12.2 ⫾ 4.8% (p ⬍ 0.001) with TES at 18 cpm. The percentage of tachygastria was significantly higher with TES than baseline 1.9 ⫾ 1.3% (p ⬍ 0.001) and significantly higher with TES at 7 (78.1 ⫾ 4.6%) and 14 cpm (76.9 ⫾ 6.8%) than TES at other frequencies (52.8 ⫾ 6.2% at 9 cpm; 55.6 ⫾ 8.4% at 18 cpm; p ⬍ 0.05; Figure 4). TES Reduced Gastric Tone and Gastric Accommodation Barostat study results showed that TES consistently increased the intragastric balloon volume in all tested animals.

Figure 3: TES stimulus. A, amplitude in milliamperes; F, frequency in cpm (cycles per minute); W, width in milliseconds.

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The mean fasting gastric volume was elevated from the baseline value of 104.6 ⫾ 22.2 to 308.8 ⫾ 42.4 mL during TES (a 200% increase) and 453.8 ⫾ 44.2 mL after the meal. A typical example showing the distention of the stomach with TES and the test meal is presented in Figure 5. In comparison with the control session, the gastric accommodation (volume difference between pre- and postmeal) was significantly reduced with TES (145.1 ⫾ 24.3 vs. 267.1 ⫾ 28.9 mL, p ⫽ 0.001). The postprandial volume of the stomach did not show any difference with or without TES. TES Inhibited Antral Contractions TES significantly inhibited antral contractions, and the effect persisted during the 30-minute recovery period without TES. A substantial decrease in the number of contractions per minute and the amplitude of contraction was shown with TES. As shown in Figure 6, the frequency of the contraction was 4.57 contractions/min at baseline before TES, reduced to 0.11 contractions/min during TES (p ⬍ 0.0001), and recovered to 1.90 contractions/min (p ⬍ 0.02 vs. TES). A typical example showing the inhibition of antral

Figure 5: Gastric volume (milliliters) at baseline, during TES, and after a test meal with TES in a dog. A substantial increase in gastric volume was noted immediately after the initiation of TES, which was continued until the end of the study. The ingestion of a liquid meal led to a further increase in gastric volume.


Figure 6: # p ⬍ 0.005 vs. baseline; * p ⬍ 0.0001 vs. baseline; ⌬ p ⬍ 0.02 vs. recovery.

contractions is presented in Figure 7. During TES, most of contractions were completely inhibited. TES Delayed Gastric Emptying TES significantly delayed gastric emptying. Compared with the baseline session, gastric emptying was significantly delayed in the TES session at 30 (28.5 ⫾ 7.5% vs. 36.1 ⫾ 7.9%, p ⬍ 0.006), 45 (37.1 ⫾ 7.6% vs. 47.7 ⫾ 7.5%, p ⬍ 0.02), 60 (43.8 ⫾ 8.6% vs. 54.6 ⫾ 8.1%, p ⬍ 0.03), 75 (47.8 ⫾ 8.2% vs. 57.9 ⫾ 7.3%, p ⬍ 0.02), and 90 minutes (51.5 ⫾ 7.5% vs. 62.1 ⫾ 6.2%, p ⬍ 0.02; Figure 8). Acute TES on Food Intake TES resulted in a significant reduction in food intake in comparison with the control session (227.3 ⫾ 38.6 vs.

Figure 8: Effect of TES on percentage of gastric emptying. At a very low amplitude of 2 mA, gastric emptying was slightly delayed with TES. However, this marginal delay in gastric emptying was associated with a substantial decrease (⬃30%) in acute food intake.

317.6 ⫾ 27.5 grams, p ⬍ 0.004) but had no significant effect on water intake. Furthermore, TES did not induce any remarkable symptoms compared with the control session. Chronic TES Reduced Food Intake in Dogs The average daily food intake was 517 ⫾ 18 grams during the control week and 422 ⫾ 22 grams during the weeks with TES (p ⬍ 0.0007). TES resulted in a reduction

Figure 7: Effects of TES at a tachygastrial frequency on gastric slow waves and contractions in a healthy dog (2-minute recording). The top four channels were gastric myoelectrical activities recorded using implanted serosal electrodes (E1–E4). The bottom tracing shows gastric contractions measured from a pressure sensor placed in the distal stomach (C-1). Vertical bar indicates the initiation of electrical stimulation through Channel 3. Before stimulation, normal distally propagated slow waves and regular gastric contractions were seen; after stimulation, the frequency of gastric slow wave in Channel 4 was paced into a higher frequency, and gastric contractions were diminished.


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Figure 9: Daily food intake in five dogs during 1 week with TES (On) and 1 week without TES (Off). The TES was composed of single long pulses with a frequency of 9 cpm, width of 100 ms, and amplitude of 6 mA and delivered through a specially developed portable stimulator attached to the back of the dogs.

of ⬃20% in food intake (Figure 9). Figure 10 shows the effects of various stimulation parameters. The changes in food intake were the difference between the control weeks and the stimulation weeks. It can be seen from the figure that a pulse width of 100 or 300 ms resulted in a better reduction in daily food intake than 500 ms. In addition, with the pulse width of 100 or 300 ms, an increase in stimulation frequency seemed to yield a higher reduction in food intake. According to the amount of food intake reduction and the p values, the setting of 100 ms, 15 cpm, and 2.5 V and the setting of 300 ms, 15 cpm, and 2.5 V were the best choices. If the consumption of energy is also taken into consideration, the setting of 100 ms, 15 cpm, and 2.5 V would be the optimal one among those tested.

Discussion In this study, we showed that TES at the distal antrum induced tachygastria, reduced gastric tone or induced gas-

Figure 10: Percent changes in food intake with TES of various sets of stimulation parameters. 100 ms, 300 ms, and 500 ms represent width. Frequency (ppm) is shown on the bars. Voltage, P1 to P8 is 2.5 V. * p ⬍ 0.05 vs. control; ** p ⬍ 0.03 vs. control; # p ⬍ 0.01 vs. control.

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tric distention, impaired gastric accommodation, antral motility, and gastric emptying, and both acutely and chronically reduced food intake in dogs without inducing any noticeable symptoms. These data suggest the therapeutic potential of TES at the distal antrum for obesity. The TES method proposed in this study was based on the physiology and pathophysiology of gastric motility. The method of stimulation was designed to impair gastric motility and thereby to reduce food intake. First, it was proposed to induce tachygastria, which is known to be associated with gastric hypomotility. The results of this study showed an induction of tachygastria. It was further shown that TES at 7 or 14 cpm was able to completely entrain the gastric slow wave at a frequency of 7 cpm, whereas stimulation at other frequencies was not able to completely entrain gastric slow waves. These data suggest a maximal paceable frequency of 7 cpm in dogs, and tachygastrial stimulation might be more effective and efficient at a stimulation frequency of 7 cpm. Second, the introduction of tachygastria with TES resulted in an inhibition of antral contractions as expected. Postprandial antral contractions were substantially inhibited with TES, and the inhibition in antral motility was correlated with the induced-tachygastria as shown in a separate study (37). It was previously shown that antral motility was completely inhibited when the percentage of induced tachygastria was ⬎25%. The inhibition of antral motility was mediated through ␣- and ␤-adrenergic pathways (37). Third, gastric emptying was delayed with TES. Delayed of gastric emptying was previously reported with retrograde electrical stimulation at physiological frequency (38). The mechanism involved in the delayed gastric emptying induced with the retrograde stimulation is by reversing the propagation direction of antral peristalsis. The TES method proposed in this study is more potent than the retrograde stimulation because it not only reverses the propagation direction of the antral contractions or slow waves but also inhibits antral motility by inducing tachygastria. Although gastric emptying was mildly delayed with TES in this study, a more severe delay could be induced with TES at a higher stimulation output (39). These data also suggest that a mild delay in gastric emptying may be sufficient in reducing food intake because similar TES parameters led to a significant reduction in acute and chronic intake of food in dogs. As mentioned previously, gastric emptying is accelerated in most patients with obesity (40), and the slowing of gastric emptying is hypothetically beneficial to obesity because this would prolong the next meal time and the feeling of postprandial fullness. Additionally, TES was found to reduce the tone of the proximal stomach or induce gastric distention. As stated earlier, gastric distention is associated with satiety. In a separate study, electrical stimulation-induced gastric distention was found to be inversely correlated to the amount of


food intake; that is, more distention, less food intake, similar to the findings reported in the literature (41). Intragastric balloon was reported to be effective in reducing food intake and leading to a short-term weight loss of up to 6 months (42,43). Distention of the stomach may also activate stretch receptors, sending a satiety signal to the brain. In a previous study, neural activity in the nucleus of solitary tract was found to be activated with GES of similar parameters (44), suggesting that vagal afferent mechanisms are involved with GES or TES. Involvement of hypothalamic neuronal and hormonal activities has also been reported with GES (45,46). Most interestingly, food intake was found to be significantly and substantially reduced with both acute and chronic TES. These data suggest the therapeutic potential of TES for treating obesity. The reduction in food intake is believed to be attributed to the effects of TES on gastric motility described in the previous paragraphs. Although the effects of TES on gastric tone and antral motility have been reported to be stimulation energy dependent (47), i.e., TES with a higher stimulation output is more effective, the chronic study revealed that the pulse widths of 100 or 300 ms were actually better than 500 ms. TES with a pulse width of 500 ms resulted in inconsistent reduction in food intake, whereas TES with a pulse width of 100 or 300 ms yielded a significant and substantial reduction in food intake. In addition, it was also found that the pulse frequency should be at least 10 cpm or higher for TES to produce significant and consistent reduction in food intake. Taking into consideration the results presented in this study and the energy requirements, it is apparent that the parameter set of 100 ms, 15 cpm, and 2.5 V was the best among those tested in this study. Another method of GES called implantable gastric stimulation (IGS) has recently been proposed for obesity (48). In that method, the stimulation electrodes are placed along the lesser curvature, and the stimulus is composed of trains of short pulses with a train on time of 2 seconds and off time of 3 seconds. With a train, there are a number of pulses with a frequency of 40 Hz, pulse width of ⬃0.3 ms, and an amplitude of 6 mA. This method was not shown to be capable of pacing the gastric slow waves or acutely inducing tachygastria. However, chronic IGS (1-month continuous stimulation) was reported to impair postprandial gastric slow waves (49). IGS was also reported to induce gastric distention and inhibit antral contractions. However, its effects on gastric motility were not as potent as TES, and IGS does not alter gastric emptying. The first human study using IGS for the treatment of severe obesity was performed in 1995 with a substantial and sustained weight loss (48). Thereafter, IGS for obesity has been studied in different institutions around the world (50 –52). To explore the clinical feasibility of the proposed TES, a preliminary clinical study has been performed in healthy volunteers using the method TES through a pair of mucosal

electrodes placed temporarily under endoscopy. Similarly, it was found that TES delayed gastric emptying and reduced acute food intake in healthy volunteers (53). Furthermore, it was noticed that different individuals showed different sensitivity to TES, and gastric emptying was more severely impaired in those who were more sensitive to TES (54). Needless to say, chronic clinical studies are to be performed in obese patients to assess the therapeutic role of TES in treating obesity. No commercially available devices are suited for the long-pulse TES proposed in this study. Currently available devices are able to generate pulses with a width of only ⬍2 ms. These devices are suitable to activate cardiac muscles or nerves because their response time is usually in the order of microseconds or a few hundred microseconds. To activate smooth muscles, pulses with a width in the order of milliseconds or a few hundred milliseconds are needed for electrical stimulation. In this study, the effective pulse width was ⬃100 ms. Accordingly, a new generation of implantable stimulators is needed for electrical stimulation to effectively alter smooth muscle functions. In this study, a prototype implantable stimulator was developed and used. While the detailed description of the design and development of the stimulator is beyond the scope of this study, the chronic use of the device and the significant reduction in food intake achieved with the device at least indicate the feasibility of developing an implantable stimulator capable of generating long pulses. It should also be mentioned that the implantable device used in this study was charge balanced. That is, there was a small compensation current to balance the charges after each pulse. If this was not done, the electrodes might be eroded or even resolved after chronic use. In this study, the stimulation electrodes were examined at the end of the chronic study when the animals were killed, and no erosion was noted. Similarly, the stationary stimulation device used in this study was also charge balanced. In conclusion, TES with long pulses at the distal antrum results in a significant reduction in food intake in dogs, and this inhibitory effect is probably attributed to TES-induced reduction in proximal gastric tone, gastric accommodation, antral contractility, and gastric emptying. These data suggest a therapeutic potential of this specific method of TES for obesity. Further clinical studies are warranted to investigate such a clinical potential.

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