| Obesity has become a global disease. The consequent impact on health and life quality has attracted increasing attention. And more and more obesity patients start seeking therapies proactively. The conventional treatments of obesity include physical exercise, calorie restriction, pharmacotherapy and surgeries, among which surgeries have proven to be the most effective approach. However, due to the associated complications and risks, the vast majority of patients reject to receive surgeries. Thus, it remains an import challenge to find a safe, effective and less invasive treatment of obesity.The mechanism of obesity can be explained in a large part by excessive food intake. It has been shown that gastric motility plays a critical role in the regulation of food intake as well as the intestinal neuroendocrine activity. And the alteration of gastric accommodation and emptying is induced by myoelectrical processes. Based on this knowledge, external electric stimulation has been employed to interfere normal myoelectrical signals and to treat diseases related to gastric motility since 1963. Thirty-two years later, the new concept of implantable gastric stimulation (IGS) was introduced and applied for the first time to obesity treatment. The procedures of IGS include the placement of mucosal gastric electrodes under endoscopy and the generation of electric pulses at certain frequencies in certain patterns, which will then induce satiety and cause weight loss. The operation is simpler and less invasive compared to surgeries. Moreover, it would not alter the normal gastric anatomy or histological structures. IGS has been applied to over 2,000 obesity patients in the world. The results showed weight loss between 5% and 35%. The safety and reliability have also been verified.Despite the abovementioned progress, several issues remain unsolved. First, satisfactory weight loss was only achieved in one third of patients, and the patient-to-patient variability is daunting. Second, the effect is greatly affected by the detailed setting of electrical pulses. Therefore the parameter optimization remains an important challenge in improving IGS. Chen et al., has proposed the retrograde gastric electrical stimulation (RGES) technology, in which electrical stimulation was performed at a tachygastrial frequency through a pair of electrodes put in the distal antrum, reminiscent of an ectopic pacemaker generating tachygastria. In animal experiments, RGES was more effective in the inhibition of antral contraction and gastric emptying. We conducted the first study on RGES in gastric motility and food intake of healthy individuals. The result showed that RGES significantly reduced water and food intake and delayed gastric emptying without noticeable side effects. Therefore RGES seems to be a safe and effective obesity treatment. In this study, we for the first time in China applied RGES to obesity patients and examined its effect on food intake, gastric motility and visceral sensitivity. We also explored and optimized the electrical parameters in RGES treatments and discussed the possible mechanisms underlying the RGES effectiveness. Aims1. Optimizing RGES parameters in obesity patients:placing mucosal gastric electrodes under endoscopy, generating electrical pulses with variable frequencies and patterns and selecting parameters based on effectiveness.2. Examining the effect and side effect of RGES on the food intake, gastric emptying and visceral sensitivity.3. Exploring the mechanism of RGES in treating obesity, and providing useful information for the improvement and further application of RGES in clinic. MethodsSixteen obese volunteers were recruited in this study, including 8 males and 8 females, with a mean age of 37.3±7.85 years, a body weight of 85.7±10.7 kg (78-93 kg) and a body mass index of 32.90±2.99 kg/m2. None of the subjects had any gastrointestinal diseases or symptoms or a history of gastrointestinal surgery.The study was performed on three consecutive days. On the first day, a pair of mucosal gastric electrodes was placed along the great curvature 5cm above the pylorus under endoscopy. RGES from a pulse generator was performed at different output energy. The stimulation pattern was tandem pulses:2s-on and 3s-off, output current:10mA, frequency:40Hz. The initial duration of pulses is lms. If it was well tolerated, an increase by 1ms would be applied every 2 minutes until 20ms. If not, a 0.1ms decrease would be applied every 2 minutes. In this way, optimal pulse duration was selected based on the assessment of gastric motility and visceral sensitization. On the second day, RGES at a tachygastrial frequency of 9 cpm was performed for 30 min at 7am, 1pm and 7pm. The water load test, food intake test and scintigraphic gastric emptying test were performed to assess the efficacy of RGES. The protocol for the third day was the same as the second day except that RGES was replaced with sham RGES (current=0). The subjects were blinded about the sham or actual RGES and the parameters of RGES. On the fourth day, the mucosal gastric electrodes were taken out.The study was divided into three parts. Part one aimed to test the effect of RGES on the quantity of food intake. On each day patients were starved for 6 hours and were then provided with the same food with measurable calories. Patients were asked to intake as much food as they could to achieved similar degrees of satiety. The quantity and calories were recorded. We required patients to finish food intake in 20 minutes. RGES was started with the, pulse duration 30 minutes prior to the food intake and last throughout the process. The results from true and sham RGES were then compared.Part two was designed to examine the effect of RGES on gastric emptying. After 6-hour starvation, patients were asked to take food and water labeled with 99mTc within 10 minutes. RGES with the optimal pulse duration was started 30 minutes prior to the process and last till 2 hours after the food intake. Relevant results such as the half-emptying time, the gastric retention rates at 60 and 120 minutes were recorded.In Part three, we evaluated the visceral sensitivity to RGES. Through the systematic alteration of electric stimulation (pulse duration) as described above, we observed and scored the symptoms induced by initial, varying and maximum tolerable RGES strength in each patient. We also investigated the correlation between the symptoms that reflect the visceral sensitivity and the alterations of water load and gastric emptying. All 16 subjects completed the 3-day study with good compliance. No complication occurred during and after the experiments.Part 1:The effect of RGES on food intake. Patients were allowed to take food till satiety. After converting food quantity to calories, RGES reduced intake by 28% compared to the sham RGES (689.93±194.84 kcal vs.963.94±193.84 cal, p<0.001). The symptom scores before, after and 30-minute post meals were significantly increased by RGES (1.2±1.3 vs.0±0, P<0.002; 6.4±0.7 vs.5.2±1.5, P=0.016; 4.9±1.0 vs.1.9±1.5, P<0.001).Part 2:The effect of RGES on gastric emptying. Short-term RGES did not exhibit effect on either the half-emptying time or the food retention rate of solid meal at 60 minutes and 120 minutes. (109±26min vs.103±31min, P=0.329; 63.37±9.75% vs.59.73±12.87%, P=0.087; 42.22±13.97% vs.38.33±16.87%, P=0.095). We divided all 16 patients into fast (emptying) and slow (emptying) groups using the median gastric emptying time. When given short term RGES, six out of eight patients in the fast group exhibited increased half emptying time. Only 3 out of 8 patients in the slow group showed similar reaction, suggesting some kind of bi-directional regulation of gastric emptying by RGES. We divided all patients into two groups by gender and found RGES delayed gastric emptying of male patients(P=0.045) but had no effect on female patients(P=0.166).We also found RGES could delay gastric emptying of low BMI groups but have no effect on high BMI groups.Part 3:The correlation between visceral sensitivity and gastric accommodation and emptying. RGES induced a series of symptoms associated with dyspepsia. The minimum strength of RGES that was sensible to the patients was 299±169smA, the maximum tolerable strength was 562±314smA. Overall, there was a great patient-to-patient variability in visceral sensitivity. We also noticed an invert correlation between the minimum sensible RGES strength and the induced water intake reduction. On the other hand, no such correlation was observed with gastric emptying. The visceral sensitivity was independent of skin sensitivity to electric stimulation. In short, our results suggested the need to individualize RGES parameters in future studies. Conclusions1. RGES significantly reduced the food intake of obesity patients.2. RGES might exert its effect in a bi-directional fashion of gastric emptying in obesities.It can delay gastric emptying of female and low BMI obesities.3. RGES induces side effects. For patients with higher visceral sensitivity, RGES could effectively decrease water load. The optimization of RGES parameters, however, could not achieve through electrical stimulations on skins.4. Obesity patients exhibited highly variable sensitivity to RGES. The temporary mucosal gastric electrodes might be used to select and optimize parameters for long-term RGES. |
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