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Keywords:

  • autonomic function;
  • barostat;
  • brain imaging;
  • gastric electrical stimulation;
  • gastroparesis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict Of Interest
  9. Grants
  10. References

Abstract  The aims were to investigate the effects of gastric electrical stimulation (GES) on autonomic function, gastric distention and tone, and central control mechanisms in gastroparetic patients. Ten gastroparetic patients refractory to standard medical therapy participated in this study and data were collected at baseline, within two weeks before surgery for implantation of GES system, and at follow-up sessions between 6 and 12 weeks after GES therapy was initiated. In each session, electrocardiogram, electrogastrogram (EGG) and gastric barostat measurements were conducted before and after a caloric liquid meal. Positron Emission Tomography (PET) brain scans were performed on a separate day. During GES therapy there was a significant increase in the discomfort threshold for mean pressure from 21 mmHg at baseline to 25 mmHg at follow-up, and for mean volume from 561 mL to 713 mL. A significant increase in the postprandial EGG power (amplitude) was observed between baseline and follow up. The sympathovagal balance was significantly decreased after GES therapy, indicating a significant increase in vagal activity. The cumulative PET data showed an increase in quantitative radioactive counts relative to the standardized data base in both the thalamic and caudate nuclei after chronic GES therapy. We conclude that our data suggest that the symptomatic improvement achieved by GES in gastroparesis is best explained by activation of vagal afferent pathways to influence CNS control mechanisms for nausea and vomiting accompanied by enhanced vagal efferent autonomic function and decreased gastric sensitivity to volume distention which enhances postprandial gastric accommodation.


Abbreviations:
ANS

autonomic nerve, system

CNS

central nerve system

FDG

2-[18F]-fluoro-2-deoxyglucose

GES

gastric electrical stimulation

MDP

minimal distending pressure

PET

positron emission tomography

TSS

total symptom score

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict Of Interest
  9. Grants
  10. References

Gastroparesis is a chronic disorder of gastric motility characterized by delayed gastric emptying of solids without evidence of mechanical obstruction and presents with nausea, early satiety in mild cases and chronic vomiting, dehydration and weight loss in severe cases.1,2 Patients with this condition have frequent hospital admissions, lost employment, and a poor quality of life. The most common treatment for gastroparesis is to use prokinetic agents, such as metoclopramide, erythromycin and domperidone. These agents stimulate gastric motility, i.e., contractility of smooth muscles of the stomach.3,4 However, only two agents (metoclopramide, erythromycin) are currently available in the USA, and side effects from these agents result in up to 40% of patients being unable to tolerate chronic use.1 Those who are refractory to the prokinetic agents often undergo abdominal surgery or endoscopy for placement of a jejunostomy or gastrostomy tube. These tubes are used as either an adjunctive or exclusive route of nutrition but do not eliminate symptoms if oral caloric intake is attempted. Despite active investigation into new therapies, the management of medication-refractory gastroparesis is a challenge for both the clinicians and the affected patients.

Gastric electrical stimulation (GES) is an emerging therapy for refractory gastroparesis.5 Based on the Worldwide Anti-Vomiting Electrical Stimulation Study (WAVESS) data,6 the US FDA approved GES with high frequency and low energy parameters (ENTERRATM Therapy System; Medtronic, Minneapolis, MN, USA) in March 2000 under a Humanitarian Device Exemption for symptomatic relief in patients with diabetic and idiopathic gastroparesis. Since then a number of publications have shown that GES by the Enterra device does produce a significant and sustained improvement in symptoms and nutritional status in most patients with intractable symptomatic gastroparesis.7–10 Because gastric emptying is not consistently improved, and gastric dysrhythmias are not converted to normal rhythm, other reasons to explain the substantial improvement in nausea and vomiting must be considered.10 The aims of our study were to identify possible mechanisms that could help explain how GES is effective in treating nausea and vomiting associated with refractory gastroparesis. We hypothesized that high-frequency GES would do the following: (i) affect autonomic function and improve vagal tone; (ii) enhance relaxation of the proximal stomach, resulting in better accommodation to a meal; (iii) activate central mechanisms for controlling nausea and vomiting.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict Of Interest
  9. Grants
  10. References

Subjects

This study was performed in 10 patients (two men and eight women; mean age, 44 years; range, 20–58 years) with severe gastroparesis (seven diabetic, three idiopathic) refractory to standard medical therapies. The entry criteria include: (i) delayed gastric emptying of a solid meal (>10% retention at four hours after eating a low-fat meal) using a standardized 4-hour scintigraphic method;11 (ii) more than seven episodes of vomiting and/or nausea per week; (iii) symptoms of gastroparesis for longer than one year; (iv) refractoriness or intolerance to 2 of 3 classes of prokinetic drugs (cholinergic agonists, motilin receptor agonists, and dopamine receptor antagonists) and 2 of 3 classes of antiemetics (anticholinergics/antihistamines, serotonin receptor antagonists, and dopamine receptor antagonists). Patients with documented organic or intestinal pseudo-obstruction, primary eating or swallowing disorders, chemical dependency, a diagnosis of active malignancy, positive pregnancy test, rumination, cyclic vomiting syndrome or psychogenic vomiting were excluded. The study protocol was approved by the Human Subjects Committee at University of Kansas Medical Center, and written consent forms were obtained from all subjects before the study.

Study protocol

This study consisted of a baseline, within two weeks before implantation of the GES system, and follow-up sessions between 6 and 12 weeks after initiation of GES therapy. In each session, a total symptom score (TSS) derived from 7 upper GI symptom sub-scores (vomiting, nausea, early satiety, bloating, postprandial fullness, epigastric pain, and burning) using a 5-point scale (0 = none, 4 = extremely severe) was assessed, simultaneous measurements of the electrocardiogram (ECG), electrogastrogram (EGG), gastric tone and accommodation were obtained for 30-min before and 60 min after a caloric liquid meal. Additionally, 2-[18F]-fluoro-2-deoxyglucose (FDG) Positron Emission Tomography (PET) scans of the brain were performed during the second study day both at baseline and at follow-up visit, 6 to 12 weeks after initiation of GES therapy.

Surgical and gastric electrical stimulation (GES) techniques

The GES system used in this study consisted of three components: a battery-powered implantable pulse generator (Medtronic Model 3116), two intramuscular electrodes (Model 4300, Medtronic) and an external programmer (Medtronic N’Vision clinician programmer 8840) to adjust the output parameters of the pulse generator. One pair of permanent electrodes (about 1 cm apart) was inserted during laparotomy into the muscularis propria layer on the greater curvature at 9.5 and 10.5 cm proximal to the pylorus. The electrodes were secured to the serosa of the stomach using 5–0 silk sutures and plastic disks. The other end of each electrode was connected to the pulse generator which was positioned in a subcutaneous pocket in the abdominal wall to the right of the midline. The pocket was irrigated with an antibiotic containing solution and the patient was given intravenous antibiotics prior to surgery and for two days postoperatively. Intraoperative endoscopy was performed on all patients to confirm positioning of the electrodes and to exclude any other pathology. The load impedance of the circuit was checked both before and after the GES device was placed in the pocket using the external programmer. The pulse generator was usually activated in the operating room or within 48 h after surgery and initially programmed to standardized parameters: pulse width, 330 μs; (current) amplitude, 5 mA; frequency, 14 Hz; cycle ON: 0.1 s; cycle OFF, 5.0 s. At various intervals of follow-up after the implant, those parameters can be adjusted based on patient’s symptomatic status or changes in impedance reading.

Recording and analysis of heart rate variability (HRV) and EGG

After the patient fasted for at least 12 h, one-channel ECG and one channel EGG were simultaneously measured using the UFI Bio-Amplifier with a cut-off frequency of 100 Hz (UFI; Morro Bay, CA, USA)12 and a portable battery-operated recorder (Digitrapper EGG, Synectics Medical; Irving, TX, USA),13 respectively. After preparing the electrodes sites, with an abrasive paste and electroconductive gel, two ECG electrodes were attached to the left and right side shoulders below the clavicle, midway between the shoulder and the upper sternum and the third on the left last intercostal space. The ECG signal was digitized online at a sampling frequency of 6000 Hz with the sound card installed on the PC and further down-sampled to 500 Hz. To avoid motion artifact, the patients were asked to lie quietly in supine position on the bed and try to be as still as possible during the recording period. Analysis of autonomic function was accomplished through power spectral analysis of heart rate variability which was derived from ECG data obtained in the fasting state. The following parameters were computed from the ECG recordings using a validated program:12 (i) mean of heart rate, (ii) the percentage of power in low frequency band (0.04–0.15 Hz), PL which was calculated as the ratio between the area under the curve in the low frequency range of 0.04–0.15 Hz and the area under the curve in the frequency range of 0.04–0.50 Hz, (iii) the percentage of power in the high frequency band (0.15–0.50 Hz), PH which was calculated as the ratio between the area under the curve in the high frequency range of 0.15–0.50 Hz and the area under the curve in the frequency range of 0.04–0.50 Hz, and (iv) PL/PH, which measures sympathovagal balance, with higher values indicating greater overall sympathetic dominance.

The following EGG parameters in the fasting state and in the fed state were computed using spectral analysis methods:13 (i) dominant frequency, defined as the frequency at which the power spectrum of an EGG recording had a peak power in the range of 0.5 to 9 cycles per minute (cpm); (ii) dominant power, defined as the power at the dominant frequency in the power spectrum of the EGG recording; (iii) change in postprandial EGG dominant power, which was defined as the difference between the dominant powers before and after the meal; (iv) the percentage of normal slow waves defined as the percent time during which regular 2–4 cpm slow waves were present over the entire observation period; and, (v) the percentage of dysrhythmias defined as the percent time during which frequencies of either >4 (tachygastria) or <2 cpm (bradygastria) were recorded.

Gastric barostat study

After an overnight fast for at least 12 h, a double-lumen polyvinyl tube, with a finely folded adherent plastic bag (1200-mL capacity; maximal diameter: 17 cm), was introduced through the mouth and secured to the patient’s chin with adhesive tape. The polyvinyl tube was then connected to a programmable barostat device (G & J Electronics, Ontario, Canada). The position of the bag in the gastric fundus was considered appropriate once a slight resistance was met (reaching the fundic wall and diaphragm). The patient was then positioned in a supine manner on a bed to keep him or her comfortable. After a 15-min adaptation period, minimal distending pressure (MDP) was first determined by increasing intra-bag pressure by 1 mmHg every 1.5 min until a volume of 30 mL was reached.14 (i) Assessment of Perception: subsequently, isobaric distensions were performed in stepwise increments of 2 mmHg starting from MDP, each lasting for 2 min, while the corresponding intragastric volume was recorded. Patients were instructed to score their perception of upper abdominal sensations at the end of every distending step, using a graphic rating scale that combines verbal descriptors on a scale graded 0–6. The end point of each sequence of distensions was established at an intra-bag volume of 1000 mL, or when the patient reported more marked discomfort or pain (score 5 or 6). This pressure level equilibrated the intra-abdominal pressure. Discomfort threshold was defined as the first level of pressure and corresponding volume that provoked a score of 5 or more. Pressure thresholds are expressed both as pressure relative to MDP and as absolute pressures. (ii) Assessment of Gastric Accommodation: After a 15-min adaptation period with the bag completely deflated, the pressure level was set at MDP +2 mmHg for 75 min. After 15 min, the patient ingested a liquid meal (Boost, 240 kcal). In all patients, gastric tone measurement was continued for 60 min after the meal. The amplitude of the meal-induced fundal relaxation was calculated by subtracting the difference between the average volume during the 15-min period before and the 60-min period after the administration of the meal.14

Positron emission tomography (PET) imaging of brain

The patients were asked to fast for at least 4 h prior to this study. Diabetic patients had their glucose blood levels checked prior to the injection of 2-[18F]-fluoro-2-deoxyglucose (FDG). If their blood glucose level, just prior to injection, was greater than 200 mg dL−1 or below 70 mg dL−1, the patient’s study was rescheduled. Venous access was obtained via an indwelling catheter or butterfly needle. Then, twenty minutes after the patient had been placed in an environment controlled for light and sound, 10 mCi of FDG were injected intravenously. Forty-five minutes thereafter, brain metabolic activity data was acquired in the 2D mode using a Discovery ST PET/CT scanner (GE Healthcare –Americas, Milwaukee, WI, USA). Quantitative radioactive count data from 240 separate areas of the brain of each patient were displayed as 47 anatomical regions and compared to a standardized database, which was derived from the FDG-PET brain scans of 50 asymptomatic subjects acquired at a major research medical center in the United States and licensed as a commercial package under the name Neuro Q.15

Statistical analysis

Positron emission tomography results are reported as ±SD from the mean and ± change in percentage of quantitative counts from the mean, where the mean is derived from an asymptomatic control group of 50 subjects used to establish the norms for the proprietary data base (NeuroQ). All other data are reported as mean ± SEM unless otherwise stated. Analyses were performed using Student’s t-test and Wilcoxon signed-rank test where appropriate.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict Of Interest
  9. Grants
  10. References

Seven upper GI symptom sub-scores and TSS are summarized in Table 1. Six of 7 upper GI symptom sub-scores (except for epigastric pain) were significantly reduced after GES therapy.

Table 1.   Results of gastroparetic symptom responses (mean ± SEM)
 Before GESDuring GESP-value (t-test)
  1. TSS (Total Symptom Score) derived from 7 upper GI symptom sub-scores (vomiting, nausea, early satiety, bloating, postprandial fullness, epigastric pain and burning) using a 5-point scale (0 = none, 4 = extremely severe) before and after initiation of GES (Gastric Electrical Stimulation).

Nausea score (0–4)3.8 ± 0.11.7 ± 0.40.002
Vomiting score (0–4)3.2 ± 0.41.8 ± 0.50.02
Early satiety (0–4)3.2 ± 0.32.0 ± 0.50.04
Bloating3.5 ± 0.22.0 ± 0.50.04
Fullness3.5 ± 0.22.0 ± 0.50.03
Epigastric pain3.0 ± 0.41.3 ± 0.50.06
Epigastric burning2.8 ± 0.30.7 ± 0.40.008
TSS in severity (0–28)23.1 ± 0.811.5 ± 2.60.004

Effects on autonomic function and EGG

The results of heart rate (HR), percentages of power in the low frequency band (PL) (0.04–0.15 Hz), power in the high frequency band (PH) (0.15–0.50 Hz) and power ratio (PL/PH) are summarized in Table 2. Fig. 1 shows individual percentages of power in the low-frequency band and (B) in high-frequency band derived from heart rate variability before and after GES.

Table 2.   Comparison of heart rate and parameters of heart rate variability (mean ± SEM) before and during gastric electrical stimulation (GES)
 Mean HR (beats min−1) PL (%) PH (%) PL/PH
  1. GES, gastric electrical stimulation; HR, heart rate; PL, the percentage of power in the low frequency band; PH, the percentage of power in high frequency band; NS, not significant.

  2. *Wilcoxon signed-rank test.

Before GES98.7 ± 6.269 ± 1231 ± 92.2 ± 0.6
During GES88.2 ± 5.434 ± 566 ± 60.5 ± 0.1
P-values*NSNS0.040.04
image

Figure 1.  (A) Individual percentages of power in the low-frequency band and (B) in high-frequency band derived from heart rate variability before and during gastric electrical stimulation (GES) (Mean data also included for comparison).

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The sympathovagal balance (PL/PH) was significantly decreased after GES therapy (2.2 ± 0.6 vs 0.5 ± 0.2), indicating a significant increase in vagal activity during GES. The mean symptom reduction in TSS was substantially higher in seven patients who had a decrease in the sympathovagal balance than that in three patients who had an increase in the sympathovagal balance (59%vs 26%).

Table 3 summarizes the EGG parameters at baseline and at follow-up visit. It can be seen that high-frequency GES had no significant effects on rhythms of gastric electrical activity but significantly increased the postprandial EGG power change from 0.3 ± 0.8 dB at baseline to 3.6 ± 0.7 dB at follow-up.

Table 3.   Comparison of EGG parameters (mean ± SEM) before and during gastric electrical stimulation (GES)
 Preprandial EGGPostprandial EGGδP (dB)
DF (cpm)N (%)T (%)B (%)DF (cpm)N (%)T (%)B (%)
  1. DF, dominant frequency of the EGG; δP, postprandial EGG dominant power change; N, 2–4 cpm normal slow waves; T, tachygastria; B, bradygastria; GES, gastric electrical stimulation.

  2. *P < 0.05 compared to before GES (t-test).

Before GES3.3 ± 0.575 ± 517 ± 48 ± 42.9 ± 0.180 ± 313 ± 37 ± 20.3 ± 0.8
During GES2.8 ± 0.273 ± 822 ± 75 ± 23.2 ± 0.574 ± 615 ± 411 ± 43.6 ± 0.7*

Effect on gastric tone and accommodation

After GES therapy there was a significant increase in the discomfort threshold for pressure from 20.5 ± 1.7 mmHg at baseline to 24.8 ± 2.1 mmHg at follow-up, and for volume from 561.1 ± 52.5 mL at baseline to 713.3 ± 79.2 mL (P < 0.05) (Fig. 2). Also, a change in the amplitude of gastric accommodation to the meal was observed between baseline (38.2 ± 18.6 mL) and follow up (68.1 ± 29.1 mL), although it did not achieve statistical significance (P = 0.2 by Wilcoxon signed-rank test, see Fig. 3). Seven patients who had an increase in gastric accommodation had a mean of 61% reduction in TSS. This is substantially higher than a mean of 14% reduction in the three patients who had a decrease in gastric accommodation. Moreover five of the seven (71%) patients who had an increase in gastric accommodation had a ≥ 50% TSS reduction and the three patients who had a decrease in gastric accommodation had a < 50% TSS reduction.

image

Figure 2.  Individual results of (A) pressure pain thresholds and (B) volume pain thresholds measured by gastric barostat before and during gastric electrical stimulation (GES). Mean data also included for comparison.

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image

Figure 3.  Individual results of the degree of gastric accommodation to a meal measured by the gastric barostat before and during gastric electrical stimulation (GES). Mean data also included for comparison.

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Changes in cerebral activity on positron emission tomography (PET) images

In our study, quantitative radioactive counts per second (CPS), which directly reflect glucose metabolic activity and thus brain activity, were measured before and during GES from 47 specific regions of each patient’s brain and were compared to the same regions of a standardized FDG-PET brain database obtained from 50 asymptomatic age and gender matched subjects. Comparing the metabolic activity in both the right and left thalami before and after GES showed an average percent change increase in metabolic activity in the thalami bilaterally (P = 0.13, see Table 4) which is equivalent to a confidence level of 87%. Comparing the change in the standard deviation (SD) from the asymptomatic population database, there was an increase in SD from the norm in the right thalamus from −0.69 to 0.06 SD (P = 0.08, or a confidence level of 92%), and in the left thalamus from −1.25 to 0.22 SD (P = 0.10, or a confidence level of 90%). The metabolic activity in left caudate before and after GES showed an average percent change increase in metabolic activity (P = 0.08, see Table 4), which is equivalent to a confidence level of 92%; the SD change increased from −1.44 to 0.04 SD (P = 0.07, or a confidence level of 93%) (Table 4). Four of seven patients (57%) who had an increase in thalamic activity had >50% reduction in TSS. Only one of the three patients (33%) who had a decrease in thalamic activity had >50% reduction in TSS. Fig. 4 is an example of PET brain images from a gastroparetic patient before (left panel) and during GES therapy at 3-month follow-up visit (right panel).

Table 4.   Results of positron emission tomography (PET) imaging of the brain summarizing the percent changes in metabolic activity in the thalamic and the caudate nuclei between baseline and during chronic gastric electrical stimulation (GES), based on analysis of the mean and standard deviation (SD) data
 Right caudateLeft caudateRight thalamusLeft thalamus
Change (%)SDChange (%)SDChange (%)SDChange (%)SD
  1. GES, gastric electrical stimulation.

Baseline−0.030.24−0.13−1.44−0.07−0.69−0.12−1.25
During GES0.060.570.0030.040.0040.060.020.22
P-value0.200.200.080.070.130.080.130.10
image

Figure 4.  Results of positron emission tomography (PET) images of brain before (left panel) and during gastric electrical stimulation (GES) (right panel). Arrows indicate the increased counts and the change in color scale in the thalamus after GES while another arrow identifies the caudate nucleus as a reference point.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict Of Interest
  9. Grants
  10. References

This study identifies enhanced vagal activity, a significant increase in the discomfort threshold for both pressure and volume changes in the stomach, and increased thalamic activity during chronic high-frequency GES therapy. These observations augment previous reports on the purported mechanisms of high-frequency GES therapy.10,20,21,27–29

The autonomic nervous system (ANS) is involved in the modulation of normal gastrointestinal function. It consists of extrinsic control exerted by the parasympathetic and sympathetic nervous system.16 A number of methods have been developed to assess specific aspects of autonomic nervous function. In recent years the development of techniques based on the autonomic modulation of heart rate function have largely replaced other methods because of their simplicity and validity as markers of vagal as well as sympathetic function.17,18 The power spectral analysis of the heart rate variability (HRV) derived from the electrocardiogram now provides a simple and accurate measure of the respective outflow of the vagal and sympathetic branches of the ANS.19 Preliminary studies in animals using spectral analysis of HRV have shown that short-pulse GES significantly increased vagal activity at a frequency four times the intrinsic slow-wave frequency20,21 and is mediated via the vagal efferent pathway.21 These short-pulse and high-frequency stimulation parameters have been used in previous clinical trials6–10 and in clinical practice. In this current study, we used power spectral analysis of heart rate variability derived from raw ECG recordings to assess the effect of GES on autonomic function and found that the sympathovagal balance (power in the low frequency band/power in high frequency band) was significantly decreased during GES therapy, attributing to an increase in vagal activity. To our knowledge, this is the first study to demonstrate that these stimulation parameters would evoke a similar change in vagal activity in humans as previously observed in the dog.20,21

Previous studies have shown that many patients with gastroparesis have impaired gastric accommodation to a meal or balloon distention22,23 and heightened visceral perception.24,25 Samsom et al.23 reported a decreased postprandial increase in the volume of the gastric fundus which was inversely correlated with bloating, suggesting that impaired relaxation of the proximal stomach may play a role in the genesis of the sensation. In diabetic patients with moderately severe gastroparesis, Kumar et al.26 reported hypersensitivity to gastric distention in 42% of subjects. In the present study, we used a gastric barostat to measure the gastric distention and tone and demonstrated that after GES therapy there was a significant increase in the discomfort threshold for both pressure and volume, as well as a substantial increase in the amplitude of gastric accommodation to a meal, suggesting that modulation of enhanced gastric accommodation to a meal and decreased sensitivity to gastric distention by GES may be one of the mechanisms by which this intervention improves gastroparetic symptoms. Our results are supported by the data both from a canine model27 and gastroparetic patients.28

FDG-PET brain scans have been used to discern regional glucose metabolic activity as a reflection of brain activity for over 30 years.29 This technique has become so well established, for example, that currently Medicare coverage is provided for discriminating Alzheimer’s Dementia (AD) from frontal-temporal dementia (FTD). Regional differences in brain activity can be detected by quantitatively measuring the number of radioactive counts per second given off by the radioactive glucose analogue FDG.

In the current study, quantitative analysis of imaged cerebral activity using FDG-PET indicated that GES increased thalamic and caudate nuclei activity. The confidence levels of 87% and 93% achieved in this study indicate that the changes observed in the PET scan data are evidence of a real and meaningful increase in the metabolism of the thalamus and caudate nuclei in response to chronic neurostimulation by GES therapy. Identification of this increased thalamic activity in both thalami demonstrates that FDG-PET scanning can detect a GES-induced change in CNS function. This is particularly important because others have not been able to find a significant change in cerebral glucose metabolism during GES in gastroparetic patients.30 For example, Sanmiguel et al.30 reported in a recent abstract that no significant change in brain cortical glucose metabolism was observed between the two study sessions (stimulator in ON or OFF position on two separate days) using FDG-PET scans in 10 gastroparetic patients with GES therapy (range: 1–24 months). The following factors might have lead to the contradictory results: (i) the two study sessions in Sanmiguel’s study were performed on two separate days at follow-up of GES ranging from 1 to 24 months. It has been shown that two to three months may be required before sustained improvement from GES is observed.6,8 Therefore one month may be too short to judge response to GES; (ii) the methods of PET brain imaging analysis were different. In the present study, a commercially available package under the name Neuro Q15 was used to assess human brain scans through quantitative analysis of 240 brain regions comparing the patient’s scan to the scans of an asymptomatic control group (N = 50). Data was expressed as standard deviation (SD) from normal mean pixel values and percent below the normal mean lying within 47 standardized regions of interest (S-ROI).15 It is not clear how the PET data were analyzed in the previous study.30

Neuroanatomy shows that the vagus nerve is comprised of motor, parasympathetic, and sensory components,31 with the majority being visceral afferents.32 Primary sensory axons from the ganglia that convey afferent signals from the abdominal viscera via the vagus nerve terminate in the solitary tract nucleus (STN), which lies in the dorsal medulla, just caudal to the pons. Afferent neural pathways project from the STN to: (i) the reticular formation, and thence to the thalamus, and (ii) the preoptic hypothalamic area.33 Activation of vagal afferents can increase pain thresholds.32 Using PET/MRI33 and fMRI34 in studies utilizing a different form of vagal stimulation, Komisaruk et al. were able to demonstrate an increased signal in the region of the STN and preoptic hypothalamus. In these studies, the afferent vagal signal also reduced somatic pain perception.

In summary, our findings show an improvement in symptomatology and increased gastric accommodation with GES. Furthermore our data show that GES increases vagal efferent activity based on the power spectral analysis of heart rate variability (HRV). With an 87% confidence level, our study also shows increased metabolic activity in the thalami. We postulate this activation of the thalami reflects stimulation of the visceral afferent component of the vagal nerve fibers transmitting impulses to the STN, which then project to the thalami via the reticular formation and in turn exert an inhibitory influence on nausea and vomiting control mechanisms. Furthermore, we postulate that it is this GES stimulation of the visceral afferent component of the vagal nerve fibers that increases the efferent vagal tone, either directly via a reflex pathway in the STN or via secondary pathways originating in the STN. We do not know whether the mechanism of improved symptomatology in our GES treated gastroparetic patients is due to the enhanced vagal autonomic function causing the increased gastric accommodation we demonstrated or whether enhanced vagal autonomic function simulates a postprandial adaptation and decreased gastric sensitivity to volume distention. An additional consideration would be that the afferent neural pathway projecting from the STN to the preoptic hypothalamic area reduces somatic pain perception. The effects could be due to a combination of all three mechanisms. Given the limitations of PET resolution and the primarily white matter tract involvement of the medulla and hypothalamus, fMRI may be better suited for the pursuit of the exact neural pathways involved in the CNS. In addition, a larger number of patients will need to be studied with the caveat that the better resolution of fMRI would have to be balanced against the risks of putting a patient with a pulse generator and pacing leads into a powerful magnetic field.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict Of Interest
  9. Grants
  10. References

This work was supported in part by Medtronic, Inc., Minneapolis, MN, USA. We would like to thank Warren Starkebaum and the Medtronic Gastroenterology and Urology Groups. The authors would like to acknowledge the following individuals for their contributions: Katherine Roeser, Pernilla Foran, LPN, Teri Lavenbarg, RN and Irene King as well as faculty, fellows and nursing staff in the Division of Gastroenterology. We also wish to acknowledge Dr. Robert Twillman in psychology and pain management, and Zachary Collins, M.D., James Traylor, BS, CNMT and Christine McMillin, AS, CNMT in the Division of Nuclear Medicine.

Conflict Of Interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict Of Interest
  9. Grants
  10. References

The authors have no conflict of interest to declare.

Grants

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict Of Interest
  9. Grants
  10. References

This work was supported in part by Medtronic, Inc., Minneapolis, MN, USA.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict Of Interest
  9. Grants
  10. References
  • 1
    Soykan I, Sivri B, Sarosiek I, McCallum RW. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci 1998; 43: 2398404.
  • 2
    Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association medical position statement: diagnosis and treatment of gastroparesis. Gastroenterology 2004; 127: 258991.
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