Measuring the interaction of meal and gastric secretion: a combined quantitative magnetic resonance imaging and pharmacokinetic modeling approach

Background The stimulation and intragastric accumulation of gastric secretion has been recognized as an important factor in gastroesophageal reflux disease. However, the interaction of gastric secretion and meal emptying has not been fully understood. Current methods to assess gastric secretion are either invasive or unable to provide information on its volume, distribution and dynamics. The aim of this study was to quantify the interaction between meal emptying and meal induced gastric secretion by using quantitative magnetic resonance imaging (MRI) and pharmacokinetic analysis. Methods A chocolate test meal was developed which is secretion stimulating and MRI compatible. Meal emptying and gastric secretion were assessed in fourteen healthy volunteers using a validated quantitative MRI technique. A population based pharmacokinetic model was developed and applied to the extracted volume data, assessing the meal emptying rate, rate of secretion and their interaction. Key Results The test meal continuously induced gastric secretion in all subjects, which partly accumulated at the meal–air interface, forming a ‘secretion layer’ in the proximal stomach. Traditional fitting detected a significant correlation between meal emptying rate and rate of secretion. The pharmacokinetic model quantified this interaction and estimated a 2.3 ± 1 fold higher effect of meal on secretion than vice versa. The efficacy of the emptied meal to produce gastric secretion was 61%. Conclusions & Inferences The combined quantitative MRI and pharmacokinetic model approach allows for the quantification of gastric secretion volume and its interaction on meal emptying. The observed secretion layer might explain previous findings postulating the presence of an intragastric ‘acid pocket’.     

Inter‐observer reproducibility and analysis of gastric volume measurements and gastric emptying assessed with magnetic resonance imaging

Background Magnetic resonance (MR) imaging provides direct, non‐invasive measurements of gastric function and emptying. The inter‐observer variability (IOV) of MR volume measurements and the most appropriate analysis of MR data have not been established. To assess IOV of total gastric volume (TGV) and gastric content volume (GCV) measurements from MR images and the ability of standard power exponential (PowExp), and a novel linear exponential (LinExp) model to describe MR data. Methods Ten healthy volunteers received three different volumes of a liquid nutrient test meal (200–800 mL) on 3 days in a randomized order. Magnetic resonance scans were acquired using a 1.5T system every 1–5 min for 60 min. Total gastric volume and GCV were measured independently by three observers. Volume data were fitted by PowExp and LinExp models to assess postprandial volume change and gastric emptying half time (T₅₀). Key Results An initial rise in GCV and TGV was often observed after meal ingestion, thereafter GCV and TGV decreased in an approximately linear fashion. Inter‐observer variability decreased with greater volumes from 12% at 200 mL to 6% at 600 and 800 mL. Inter‐observer variability for T₅₀ was <5%. PowExp and LinExp models provided comparable estimates of T₅₀; however, only LinExp described dynamic volume change in the early postprandial period. Conclusions & Inferences Gastric MR provides quantitative measurements of postprandial volume change with low IOV, unless the stomach is nearly empty. The novel LinExp model describes the dynamic volume changes in the early postprandial period more accurately than the PowExp model used in existing gastric emptying studies.     

Magnetic resonance imaging as a non-invasive tool to assess gastric emptying in mice

Background

Methods to study gastric emptying in rodents are time consuming or terminal, preventing repetitive assessment in the same animal. Magnetic resonance imaging (MRI) is a non-invasive technique increasingly used to investigate gastrointestinal function devoid of these shortcomings. Here, we evaluated MRI to measure gastric emptying in control animals and in two different models of gastroparesis.

Methods

Mice were scanned using a 9.4 Tesla MR scanner. Gastric volume was measured by delineating the stomach lumen area. Control mice were scanned every 30 min after ingestion of a 0.2 g meal and stomach volume was quantified. The ability of MRI to detect delayed gastric emptying was evaluated in models of morphine-induced gastroparesis and streptozotocin-induced diabetes.

Key Results

Magnetic resonance imaging reproducibly detected increased gastric volume following ingestion of a standard meal and progressively decreased with a half emptying time of 59 ± 5 min. Morphine significantly increased gastric volume measured at t = 120 min (saline: 20 ± 2 vs morphine: 34 ± 5 mm³; n = 8–10; p < 0.001) and increased half emptying time using the breath test (saline: 85 ± 22 vs morphine: 161 ± 46 min; n = 10; p < 0.001). In diabetic mice, gastric volume assessed by MRI at t = 60 min (control: 23 ± 2 mm³; n = 14 vs diabetic: 26 ± 5 mm³; n = 18; p = 0.014) but not at t = 120 min (control: 21 ± 3 mm³; n = 13 vs diabetic: 18 ± 5 mm³; n = 18; p = 0.115) was significantly increased compared to nondiabetic mice.

Conclusions and Inferences

Our data indicate that MRI is a reliable and reproducible tool to assess gastric emptying in mice and represents a useful technique to study gastroparesis in disease models or for evaluation of pharmacological compounds.     

功能磁共振成像在植物状态研究中的应用

一、植物状态及其研究历程随着现代医疗技术的进步,危重患者的死亡率明显降低,临床上可以见到越来越多的意识障碍患者.1972年由Jennett和Plum在Lancet上首次提出持续性植物状态(vegetative state,VS)的概念,用以取代当时混杂应用的各类名词,如极深度昏迷,运动不能性缄默,永久性、不可逆性或稽延性昏迷、去大脑或去皮层状态等,这一见解以后逐渐为各国学者所采纳.1994年美国PVS多学科专责小组对VS下的定义为:“患者完全失去对自身及周围环境的认知,有睡眠一觉醒周期,下丘脑及脑干的自主功能完全或部分保存”.此类患者死亡率高,致残严重且缺乏有效治疗,给社会及家庭造成沉重的负担,引起了医学界和全社会的广泛关注.     

Gastric motor disturbances in patients with idiopathic rapid gastric emptying

Background The mechanisms of ‘idiopathic’ rapid gastric emptying, which are associated with functional dyspepsia and functional diarrhea, are not understood. Our hypotheses were that increased gastric motility and reduced postprandial gastric accommodation contribute to rapid gastric emptying. Methods Fasting and postprandial (300 kcal nutrient meal) gastric volumes were measured by magnetic resonance imaging (MRI) in 20 healthy people and 17 with functional dyspepsia; seven had normal and 10 had rapid gastric emptying. In 17 healthy people and patients, contractility was analyzed by spectral analysis of a time‐series of gastric cross‐sectional areas. Logistic regression models analyzed whether contractile parameters, fasting volume, and postprandial volume change could discriminate between health and patients with normal or rapid gastric emptying. Key Results While upper gastrointestinal symptoms were comparable, patients with rapid emptying had a higher (P = 0.002) body mass index than normal gastric emptying. MRI visualized propagating contractions at ～3 cpm in healthy people and patients. Compared with controls (0.32 ± 0.04, Mean ± SEM), the amplitude of gastric contractions in the entire stomach was higher (OR 4.1, 95% CI 1.2–14.0) in patients with rapid (0.48 ± 0.06), but not normal gastric emptying (0.20 ± 0.06). Similar differences were observed in the distal stomach. However, the propagation velocity, fasting gastric volume, and the postprandial volume change were not significantly different between patients and controls. Conclusions & Inferences MRI provides a non‐invasive and refined assessment of gastric volumes and contractility in humans. Increased gastric contractility may contribute to rapid gastric emptying in functional dyspepsia.     

Gastric secretion does not affect the reliability of the 13C‐acetate breath test: A validation of the 13C‐acetate breath test by magnetic resonance imaging

Background ¹³C‐Acetate labeled meals are widely used to determine meal emptying by means of analyzing resulting ¹³CO₂ exhalation dynamics. In contrast to the underlying metabolic processes, only few ¹³C breath test meal emptying studies have focused on intragastric processes that may alter ¹³CO₂ exhalation. This work assessed the effect of enhanced gastric secretion on the reliability of half emptying time (t50) measurements by ¹³C‐acetate breath test. Methods ¹³CO₂ exhalation data were acquired in a double‐blind, randomized, cross‐over gastric emptying study in 12 healthy volunteers receiving either pentagastrin or placebo intravenously. The standard method proposed by Ghoos et al. was applied to calculate t50 (t50_Ghoos) from ¹³CO₂ exhalation data, which were compared and tested for agreement to meal half emptying times (t50_MV) from concurrent recorded MRI (magnetic resonance imaging) volume data. In addition, the accumulated gastric secretion volumes during infusion as detected by MRI (AUC_SV₆₀) were correlated with the corresponding cumulative percent ¹³C doses recovered (cPDR₆₀). Key Results t50_Ghoos and t50_MV showed a linear correlation with a slope of 1.1 ± 0.3 (r² = 0.67), however, a positive offset of 136 min for t50_Ghoos. No correlation was detected between AUC_SV₆₀ and cPDR₆₀ (r² = 0.11). Both, breath test and MRI, revealed a prolonged t50 under pentagastrin infusion with median differences in t50_Ghoos of 45[28–84] min (P = 0.002) and t50_MV of 39[28–52] min (P = 0.002). Conclusions & Inferences This study suggests that ¹³CO₂ exhalation after ingestion of a ¹³C‐labeled liquid test meal is not affected by stimulated gastric secretion, but is rather reflecting the dynamics of meal or caloric emptying from the stomach.     

The relationship between gastric pH and the emptying of solid, semisolid and liquid meals

The effect of three different meal constituents, solid, semisolid and liquid, on gastric pH, recorded in the proximal and distal stomach, was evaluated in a prospective study of 20 normal volunteers. The solid and liquid were ingested together as one meal and the semisolid as another. Simultaneous recordings of the rate of gastric emptying of the isotopically labelled meal constituents and the gastric pH were made. The rate of gastric emptying was more rapid for the liquid and semisolid constituents (t_1/2= 35.6, range 9.8–103.3 min and 47.4, range 33.5–120 min, respectively) than for the solid meal constituent (t_1/2= 72.0, range 45.0–103.8 min), P < 0.01. Both the combined meal of solid and liquid and the semisolid meal produced a higher pH response in the proximal stomach than in the distal stomach (5.2, range 2.4–6.1 vs 2.9, range 0.8–5.3 and 5.9, range 4.3–6.6 vs 4.3, range 1.1–5.9), P < 0.01. There were significant correlations between the rate of gastric emptying of all three meal constituents and the decline phase in the gastric pH recorded at both the proximal and distal probes, P < 0.01 (Pearson's correlation). The strongest correlations were found between the rate of gastric emptying and the gastric pH recorded in the proximal stomach. The decline phase of gastric pH followed the emptying of semisolid more closely than the emptying of either solid or liquid.     

A novel MRI-based three-dimensional model of stomach volume,surface area,and geometry in response to gastric filling and emptying

Background

Gastric motility and accommodation have a critical role in maintaining normal gastrointestinal homeostasis. Different modalities can be adopted to quantify those processes, that is, scintigraphy to measure emptying time and intragastric Barostat for accommodation assessment. However, magnetic resonance imaging (MRI) can assess the same parameters noninvasively without ionizing radiation. Our study aimed to develop a detailed three-dimensional (3D) MRI model of the stomach to describe gastric volumes, surface areas, wall tension distribution, and interobserver agreement.

Methods

Twelve healthy volunteers underwent an MRI protocol of six axial T2-weighted acquisitions. Each dataset was used to construct a 3D model of the stomach: First, the volumes of the whole stomach, gastric liquid, and air were segmented. After landmark placing, a raw 3D model was generated from segmentation data. Subsequently, irregularities were removed, and the model was divided into compartments. Finally, surface area and 3D geometry parameters (inverse curvatures) were extracted. The inverse curvatures were used as a proxy for wall tension distribution without measuring the intragastric pressure.

Key Results

The model was able to describe changes in volume and surface geometry for each compartment with a distinct pattern in response to filling and emptying. The surface tension was distributed nonhomogeneously between compartments and showed dynamical changes at various time points.

Conclusion & Inferences

The presented model offers a detailed tool for evaluating gastric volumes, surface geometry, and wall tension in response to filling and emptying and will provide insights into gastric emptying and accommodation in diseases such as diabetic gastroparesis.     

Effects of clonidine and sumatriptan on postprandial gastric volume response, antral contraction waves and emptying: an MRI study

Abstract Gastric emptying (GE) may be driven by tonic contraction of the stomach (‘pressure pump’) or antral contraction waves (ACW) (‘peristaltic pump’). The mechanism underlying GE was studied by contrasting the effects of clonidine (α₂‐adrenergic agonist) and sumatriptan (5‐HT₁ agonist) on gastric function. Magnetic resonance imaging provided non‐invasive assessment of gastric volume responses, ACW and GE in nine healthy volunteers. Investigations were performed in the right decubitus position after ingestion of 500 mL of 10% glucose (200 kcal) under placebo [0.9% NaCl intravenous (IV) and subcutaneous (SC)], clonidine [0.01 mg min^?1 IV, max 0.1 mg (placebo SC)] or sumatriptan [6 mg SC (placebo IV)]. Total gastric volume (TGV) and gastric content volume (GCV) were assessed every 5 min for 90 min, interspersed with dynamic scan sequences to measure ACW activity. During gastric filling, TGV increased with GCV indicating that meal volume dictates initial relaxation. Gastric contents volume continued to increase over the early postprandial period due to gastric secretion surpassing initial gastric emptying. Clonidine diminished this early increase in GCV, reduced gastric relaxation, decreased ACW frequency compared with placebo. Gastric emptying (GE) rate increased. Sumatriptan had no effect on initial GCV, but prolonged gastric relaxation and disrupted ACW activity. Gastric emptying was delayed. There was a negative correlation between gastric relaxation and GE rate (r² = 49%, P < 0.001), whereas the association between ACW frequency and GE rate was inconsistent and weak (r² = 15%, P = 0.05). These findings support the hypothesis that nutrient liquid emptying is primarily driven by the ‘pressure pump’ mechanism.     

Ghrelin prevents levodopa-induced inhibition of gastric emptying and increases circulating levodopa in fasted rats

Background Levodopa (l ‐dopa) is the most commonly used treatment for alleviating symptoms of Parkinson’s disease. However, l ‐dopa delays gastric emptying, which dampens its absorption. We investigated whether ghrelin prevents l ‐dopa action on gastric emptying and enhances circulating l ‐dopa in rats. Methods Gastric emptying of non‐nutrient methylcellulose/phenol red viscous solution was determined in fasted rats treated with orogastric or intraperitoneal (i.p.) l ‐dopa, or intravenous (i.v.) ghrelin 10 min before orogastric l ‐dopa. Plasma l ‐dopa and dopamine levels were determined by high pressure liquid chromatography. Plasma acyl ghrelin levels were assessed by radioimmunoassay. Fos expression in the brain was immunostained after i.v. ghrelin (30 μg kg^?1) 10 min before i.p. l ‐dopa. Key Results Levodopa (5 and 15 mg kg^?1) decreased significantly gastric emptying by 32% and 62%, respectively, when administered orally, and by 91% and 83% when injected i.p. Ghrelin (30 or 100 μg kg^?1, i.v.) completely prevented l ‐dopa’s (15 mg kg^?1, orogastrically) inhibitory action on gastric emptying and enhanced plasma l ‐dopa and dopamine levels compared with vehicle 15 min after orogastric l ‐dopa. Levodopa (5 mg kg^?1) did not modify plasma acyl ghrelin levels at 30 min, 1, and 2 h after i.v. injection. Levodopa (15 mg kg^?1, i.p.) induced Fos in brain autonomic centers, which was not modified by i.v. ghrelin. Conclusions & Inferences Ghrelin counteracts l ‐dopa‐induced delayed gastric emptying but not Fos induction in the brain and enhances circulating l ‐dopa levels. Potential therapeutic benefits of ghrelin agonists in Parkinson’s disease patients treated with l ‐dopa remain to be investigated.     

Advances in the physiology of gastric emptying

There have been many recent advances in the understanding of various aspects of the physiology of gastric motility and gastric emptying. Earlier studies had discovered the remarkable ability of the stomach to regulate the timing and rate of emptying of ingested food constituents and the underlying motor activity. Recent studies have shown that two parallel neural circuits, the gastric inhibitory vagal motor circuit (GIVMC) and the gastric excitatory vagal motor circuit (GEVMC), mediate gastric inhibition and excitation and therefore the rate of gastric emptying. The GIVMC includes preganglionic cholinergic neurons in the DMV and the postganglionic inhibitory neurons in the myenteric plexus that act by releasing nitric oxide, ATP, and peptide VIP. The GEVMC includes distinct gastric excitatory preganglionic cholinergic neurons in the DMV and postganglionic excitatory cholinergic neurons in the myenteric plexus. Smooth muscle is the final target of these circuits. The role of the intramuscular interstitial cells of Cajal in neuromuscular transmission remains debatable. The two motor circuits are differentially regulated by different sets of neurons in the NTS and vagal afferents. In the digestive period, many hormones including cholecystokinin and GLP‐1 inhibit gastric emptying via the GIVMC, and in the inter‐digestive period, hormones ghrelin and motilin hasten gastric emptying by stimulating the GEVMC. The GIVMC and GEVMC are also connected to anorexigenic and orexigenic neural pathways, respectively. Identification of the control circuits of gastric emptying may provide better delineation of the pathophysiology of abnormal gastric emptying and its relationship to satiety signals and food intake.     

Application of magnetic resonance imaging to measure fasting and postprandial volumes in humans

Abstract  Our aims were to measure the gastric volume response in excess of ingested meal volume (i.e. gastric accommodation), contribution of swallowed air to this excess, day-to-day variability of gastric volumes measured by MRI and their relationship to volumes measured by single-photon-emission computed tomography (SPECT). In 20 healthy volunteers, fasting and postprandial gastric volumes were measured after technetium^99m-pertechnetate labeling of the gastric mucosa by SPECT and separately by MRI, using 3D gradient echo and 2D half-Fourier acquisition single-shot turbo spin echo (HASTE) sequences. Ten of these subjects had a second MRI exam to assess intra-individual variation. Thereafter, another 10 subjects had two MRI studies during which they ingested the nutrient in 30 or 150 mL aliquots. During MRI, the postprandial gastric volume change exceeded the ingested meal volume by 106 ± 12 mL (Mean ± SEM). The HASTE and gradient echo sequences distinguished air from fluid under fasting and postprandial conditions respectively. This postprandial excess mainly comprised air (61 ± 5 mL), which was not significantly different when ingested as 30 or 150 mL aliquots. Fasting and postprandial gastric volumes measured by MRI were generally reproducible within subjects. During SPECT, postprandial volumes increased by 158 ± 18 mL; gastric volumes measured by SPECT were higher than MRI. MRI measures gastric volumes with acceptable performance characteristics; the postprandial excess primarily consists of air, which is not affected by the mode of ingestion. Gastric volumes are technique specific and differ between MRI and SPECT.     

脑功能磁共振成像研究进展

主要综述fMRI产生的历史、成像原理、成像技术和方法、已经取得的成绩以及将来研究发展的方向等。fMRI产生技术广泛应用的20世纪90年代,主要受快速成像技术的影响,从有创走向无创,从而受到神经、认知和心理科学领域的极大关注。fMRI原理是根据神经元兴奋后局部氧耗与血流增幅不一致,而BOLD效应机制成像,间接显示神经元活动。成像主要采用平面回波成像（EPI）和快速小角度激发（FLASH）技术、二者在时间和空间分辨率上各有优劣。最后几年来,fMRI技术对脑功能的研究已取得了巨大的成绩,估计将在这一领域继续拥有非常重要的地位。将来fMRI可能主要在BOLD效应的生理过程、临床应用以及高场磁体的应用等领域进一步展开。     

Characterization of gastric volume responses and liquid emptying in functional dyspepsia and health by MRI or barostat and simultaneous 13C-acetate breath test

Abstract The assessment of gastric accommodation and emptying by different methodologies provides inconsistent results. We aimed to compare magnetic resonance imaging (MRI), barostat and ¹³C‐acetate breath test (BT) for the assessment of gastric volume responses and emptying in healthy controls (HC) and patients with functional dyspepsia (FD). Eight HC and eight FD patients underwent: (i) continuous BT with simultaneous MRI in the upright position after ingestion of isocaloric, 300 kcal, 200 and 800 mL meals, both labelled with 100 mg of ¹³C‐acetate; and (ii) BT with gastric barostat after ingestion of the 200 mL meal. MRI measured total gastric volume and gastric content volume (GCV) at baseline, after filling and during emptying. Meal emptying half‐times (T½) for MRI and BT were calculated (mean ± SD). We found: (i) Initial GCV was lower in FD than in HC (762 ± 22 vs 810 ± 52 mL, P < 0.04) after the 800 mL meal but not the 200 mL meal. T½_MRI was shorter for the 800 mL than the 200 mL meal (P < 0.001), but similar in HC and FD (200 mL: HC 117 ± 30 min vs FD 138 ± 42 min, ns; 800 mL: HC 71 ± 16 min vs FD 78 ± 27 min, ns). In contrast, T½_BT was similar between meals and groups (200 mL: HC 111 ± 11 min vs FD 116 ± 19 min; 800 mL: HC 114 ± 14 min vs FD: 113 ± 17 min). (ii) Barostat measurements showed similar postprandial volume increases between groups. We conclude that direct measurements by MRI provide a sensitive, non‐invasive assessment of gastric accommodation and emptying after a meal. In contrast to MRI, BT did not detect faster emptying of high‐volume compared to low‐volume liquid nutrient meals in HC or FD.