Brain-gut communication: vagovagal reflexes interconnect the two "brains".

The gastrointestinal tract has its own "brain," the enteric nervous system or ENS, that executes routine housekeeping functions of digestion. The dorsal vagal complex in the central nervous system (CNS) brainstem, however, organizes vagovagal reflexes and establishes interconnections between the entire neuroaxis of the CNS and the gut. Thus, the dorsal vagal complex links the "CNS brain" to the "ENS brain." This brain-gut connectome provides reflex adjustments that optimize digestion and assimilation of nutrients and fluid. Vagovagal circuitry also generates the plasticity and adaptability needed to maintain homeostasis to coordinate among organs and to react to environmental situations. Arguably, this dynamic flexibility provided by the vagal circuitry may, in some circumstances, lead to or complicate maladaptive disorders.

Stomach region stimulated determines effects on duodenal motility in rats.

Gastric electrical stimulation (GES) is used clinically to promote proximal GI emptying and motility. In acute experiments, we measured duodenal motor responses elicited by GES applied at 141 randomly chosen electrode sites on the stomach serosal surface. Overnight-fasted (H2O available) anesthetized male rats (n = 81) received intermittent biphasic GES for 5 min (20-s-on/40-s-off cycles; I = 0.3 mA; pw = 0.2 ms; 10 Hz). A strain gauge on the serosal surface of the proximal duodenum of each animal was used to evaluate baseline motor activity and the effect of GES. Using ratios of time blocks compared with a 15-min prestimulation baseline, we evaluated the effects of the 5-min stimulation on concurrent activity, on the 10 min immediately after the stimulation, and on the 15-min period beginning with the onset of stimulation. We mapped the magnitude of the duodenal response (three different motility indices) elicited from the 141 stomach sites. Post hoc electrode site maps associated with duodenal responses suggested three zones similar to the classic regions of forestomach, corpus, and antrum. Maximal excitatory duodenal motor responses were elicited from forestomach sites, whereas inhibitory responses occurred with stimulation of the corpus. Moderate excitatory duodenal responses occurred with stimulation of the antrum. Complex, weak inhibitory/excitatory responses were produced by stimulation at boundaries between stomach regions. Patterns of GES efficacies coincided with distributions of previously mapped vagal afferents, suggesting that excitation of the duodenum is strongest when GES electrodes are situated over stomach concentrations of vagal intramuscular arrays, putative stretch receptors in the muscle wall.

Stomach serosal arteries distinguish gastric regions of the rat.

Because the stomach in situ has few distinctive surface features and changes shape dramatically with food intake, we have used micro-CT imaging combined with two distinct contrast agents to (1) characterize the pattern of arteries, potential landmarks, on the stomach wall and (2) evaluate how meal-related shape changes affect the size of the different regions. Images generated with a contrast agent injected directly into the heart during perfusion enabled a thorough look at the organizational features of the stomach angioarchitecture. The stomach receives its blood supply primarily from two pairs of vessels, the gastric and gastroepiploic arteries. Each of the three regions of the stomach is delineated by a distinctive combination of arterial fields: the corpus, consistent with its dynamic secretory activity and extensive mucosa, is supplied by extensive arterial trees formed by the left and right gastric arteries, travelling, respectively, on the ventral and dorsal stomach surfaces. These major arteries course circularly from the lesser towards the greater curvature, distally along both left (or ventral) and right (or dorsal) walls of the corpus, and branch rostrally to supply the region. The muscular antrum is characterized by smaller arterial branches arising primarily from the right gastroepiploic artery that follows the distal greater curvature and secondarily from small, distally directed arteries supplied by the large vessels of the left and right gastric arteries. The forestomach, essentially devoid of mucosal tissue and separated from the corpus by the limiting ridge, is vascularized predominantly by a network of small arteries issued from the left gastroepiploic artery coursing around the proximal greater curvature, as well as from higher order and smaller branches issued by the gastric and celiac arteries. These distinctive arterial fields appear to distinguish the major gastric regions, irrespective of the degree of fill of the stomach. Volume assessments of stomach compartments were made from images of iodine-stained stomachs. By varying the delay time between eating and perfusion, we were able to probe the emptying behavior of the stomach and demonstrate that the regions of the stomach empty at different rates, thus changing the relative dimensions of the organ regions. Notably, and despite these shape changes, the gastric arteries appear to form a regular, particularly recognizable, and lateralized pattern corresponding to the corpus that should be of use in guiding surgical and experimental interventions.

The identification of neuronal control pathways supplying effector tissues in the stomach.

The stomach acts as a buffer between the ingestion of food and its processing in the small intestine. It signals to the brain to modulate food intake and it in turn regulates the passage of a nutrient-rich fluid, containing partly digested food, into the duodenum. These processes need to be finely controlled, for example to restrict reflux into the esophagus and to transfer digesta to the duodenum at an appropriate rate. Thus, the efferent pathways that control gastric volume, gastric peristalsis and digestive juice production are critically important. We review these pathways with an emphasis on the identities of the final motor neurons and comparisons between species. The major types of motor neurons arising from gastric enteric ganglia are as follows: immunohistochemically distinguishable excitatory and inhibitory muscle motor neurons; four neuron types innervating mucosal effectors (parietal cells, chief cells, gastrin cells and somatostatin cells); and vasodilator neurons. Sympathetic efferent neurons innervate intramural arteries, myenteric ganglia and gastric muscle. Vagal efferent neurons with cell bodies in the brain stem do not directly innervate gastric effector tissues; they are pre-enteric neurons that innervate each type of gastric enteric motor neuron. The principal transmitters and co-transmitters of gastric motor neurons, as well as key immunohistochemical markers, are the same in rat, pig, human and other species.

Carbohydrates designed with different digestion rates modulate gastric emptying response in rats.

We sought to determine whether design of carbohydrate-based microspheres to have different digestion rates, while retaining the same material properties, could modulate gastric emptying through the ileal brake. Microspheres made to have three slow digestion rates and a rapidly digested starch analogue (maltodextrin) were administrated to rats by gavage and starch contents in the stomach, proximal and distal small intestine, and caecum were measured 2 h post-gavage. A stepwise increase in the amount of starch retained in the stomach was found for microspheres with incrementally slower rates of digestion. Postprandial glycaemic and insulinaemic responses were incrementally lower for the different microspheres than for the rapidly digestible control. A second-meal effect was observed for slowly digestible starch (SDS) microspheres compared to glucose. Thus, dietary slowly digestible carbohydrates were designed to elicit incremental significant changes in gastric emptying, glycaemic and insulinaemic responses, and they may be a means to trigger the ileal brake.

Gastric stimulation drives fast BOLD responses of neural origin.

Functional magnetic resonance imaging (fMRI) is commonly thought to be too slow to capture any neural dynamics faster than 0.1 Hz. However, recent findings demonstrate the feasibility of detecting fMRI activity at higher frequencies beyond 0.2 Hz. The origin, reliability, and generalizability of fast fMRI responses are still under debate and await confirmation through animal experiments with fMRI and invasive electrophysiology. Here, we acquired single-echo and multi-echo fMRI, as well as local field potentials, from anesthetized rat brains given gastric electrical stimulation modulated at 0.2, 0.4 and 0.8 Hz. Such gastric stimuli could drive widespread fMRI responses at corresponding frequencies from the somatosensory and cingulate cortices. Such fast fMRI responses were linearly dependent on echo times and thus indicative of blood oxygenation level dependent nature (BOLD). Local field potentials recorded during the same gastric stimuli revealed transient and phase-locked broadband neural responses, preceding the fMRI responses by as short as 0.5 s. Taken together, these results suggest that gastric stimulation can drive widespread and rapid fMRI responses of BOLD and neural origin, lending support to the feasibility of using fMRI to detect rapid changes in neural activity up to 0.8 Hz under visceral stimulation.

Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections.

Detection of α-synuclein lesions in peripheral tissues is a feature of human synucleinopathies of likely pathogenetic relevance and bearing important clinical implications. Experiments were carried out to elucidate the relationship between α-synuclein accumulation in the brain and in peripheral organs, and to identify potential pathways involved in long-distance protein transfer. Results of this in vivo study revealed a route-specific transmission of α-synuclein from the rat brain to the stomach. Following targeted midbrain overexpression of human α-synuclein, the exogenous protein was capable of reaching the gastric wall where it was accumulated into preganglionic vagal terminals. This brain-to-stomach connection likely involved intra- and inter-neuronal transfer of non-fibrillar α-synuclein that first reached the medulla oblongata, then gained access into cholinergic neurons of the dorsal motor nucleus of the vagus nerve and finally traveled via efferent fibers of these neurons contained within the vagus nerve. Data also showed a particular propensity of vagal motor neurons and efferents to accrue α-synuclein and deliver it to peripheral tissues; indeed, following its midbrain overexpression, human α-synuclein was detected within gastric nerve endings of visceromotor but not viscerosensory vagal projections. Thus, the dorsal motor nucleus of the vagus nerve represents a key relay center for central-to-peripheral α-synuclein transmission, and efferent vagal fibers may act as unique conduits for protein transfer. The presence of α-synuclein in peripheral tissues could reflect, at least in some synucleinopathy patients, an ongoing pathological process that originates within the brain and, from there, reaches distant organs innervated by motor vagal projections.

A flexible, thin-film microchannel electrode array device for selective subdiaphragmatic vagus nerve recording.

The vagus nerve (VN) plays an important role in regulating physiological conditions in the gastrointestinal (GI) tract by communicating via the parasympathetic pathway to the enteric nervous system (ENS). However, the lack of knowledge in the neurophysiology of the VN and GI tract limits the development of advanced treatments for autonomic dysfunctions related to the VN. To better understand the complicated underlying mechanisms of the VN-GI tract neurophysiology, it is necessary to use an advanced device enabled by microfabrication technologies. Among several candidates including intraneural probe array and extraneural cuff electrodes, microchannel electrode array devices can be used to interface with smaller numbers of nerve fibers by securing them in the separate channel structures. Previous microchannel electrode array devices to interface teased nerve structures are relatively bulky with thickness around 200 µm. The thick design can potentially harm the delicate tissue structures, including the nerve itself. In this paper, we present a flexible thin film based microchannel electrode array device (thickness: 11.5 µm) that can interface with one of the subdiaphragmatic nerve branches of the VN in a rat. We demonstrated recording evoked compound action potentials (ECAP) from a transected nerve ending that has multiple nerve fibers. Moreover, our analysis confirmed that the signals are from C-fibers that are critical in regulating autonomic neurophysiology in the GI tract.

Fractal Microelectrodes for More Energy-Efficient Cervical Vagus Nerve Stimulation.

Vagus nerve stimulation (VNS) has the potential to treat various peripheral dysfunctions, but the traditional cuff electrodes for VNS are susceptible to off-target effects. Microelectrodes may enable highly selective VNS that can mitigate off-target effects, but they suffer from the increased impedance. Recent studies on microelectrodes with non-Euclidean geometries have reported higher energy efficiency in neural stimulation applications. These previous studies use electrodes with mm/cm-scale dimensions, mostly targeted for myelinated fibers. This study evaluates fractal microelectrodes for VNS in a rodent model (N = 3). A thin-film device with fractal and circle microelectrodes is fabricated to compare their neural stimulation performance on the same radial coordinate of the nerve. The results show that fractal microelectrodes can activate C-fibers with up to 52% less energy (p = 0.012) compared to circle microelectrodes. To the best of the knowledge, this work is the first to demonstrate a geometric advantage of fractal microelectrodes for VNS in vivo.

Mapping the Organization and Morphology of Calcitonin Gene-Related Peptide (CGRP)-IR Axons in the Whole Mouse Stomach.

Nociceptive afferent axons innervate the stomach and send signals to the brain and spinal cord. Peripheral nociceptive afferents can be detected with a variety of markers [e.g., substance P (SP) and calcitonin gene-related peptide (CGRP)]. We recently examined the topographical organization and morphology of SP-immunoreactive (SP-IR) axons in the whole mouse stomach muscular layer. However, the distribution and morphological structure of CGRP-IR axons remain unclear. We used immunohistochemistry labeling and applied a combination of imaging techniques, including confocal and Zeiss Imager M2 microscopy, Neurolucida 360 tracing, and integration of axon tracing data into a 3D stomach scaffold to characterize CGRP-IR axons and terminals in the whole mouse stomach muscular layers. We found that: 1) CGRP-IR axons formed extensive terminal networks in both ventral and dorsal stomachs. 2) CGRP-IR axons densely innervated the blood vessels. 3) CGRP-IR axons ran in parallel with the longitudinal and circular muscles. Some axons ran at angles through the muscular layers. 4) They also formed varicose terminal contacts with individual myenteric ganglion neurons. 5) CGRP-IR occurred in DiI-labeled gastric-projecting neurons in the dorsal root and vagal nodose ganglia, indicating CGRP-IR axons were visceral afferent axons. 6) CGRP-IR axons did not colocalize with tyrosine hydroxylase (TH) or vesicular acetylcholine transporter (VAChT) axons in the stomach, indicating CGRP-IR axons were not visceral efferent axons. 7) CGRP-IR axons were traced and integrated into a 3D stomach scaffold. For the first time, we provided a topographical distribution map of CGRP-IR axon innervation of the whole stomach muscular layers at the cellular/axonal/varicosity scale.

A novel statistical methodology for quantifying the spatial arrangements of axons in peripheral nerves.

A thorough understanding of the neuroanatomy of peripheral nerves is required for a better insight into their function and the development of neuromodulation tools and strategies. In biophysical modeling, it is commonly assumed that the complex spatial arrangement of myelinated and unmyelinated axons in peripheral nerves is random, however, in reality the axonal organization is inhomogeneous and anisotropic. Present quantitative neuroanatomy methods analyze peripheral nerves in terms of the number of axons and the morphometric characteristics of the axons, such as area and diameter. In this study, we employed spatial statistics and point process models to describe the spatial arrangement of axons and Sinkhorn distances to compute the similarities between these arrangements (in terms of first- and second-order statistics) in various vagus and pelvic nerve cross-sections. We utilized high-resolution transmission electron microscopy (TEM) images that have been segmented using a custom-built high-throughput deep learning system based on a highly modified U-Net architecture. Our findings show a novel and innovative approach to quantifying similarities between spatial point patterns using metrics derived from the solution to the optimal transport problem. We also present a generalizable pipeline for quantitative analysis of peripheral nerve architecture. Our data demonstrate differences between male- and female-originating samples and similarities between the pelvic and abdominal vagus nerves.

Spinal afferent innervation in flat-mounts of the rat stomach: anterograde tracing.

The dorsal root ganglia (DRG) project spinal afferent axons to the stomach. However, the distribution and morphology of spinal afferent axons in the stomach have not been well characterized. In this study, we used a combination of state-of-the-art techniques, including anterograde tracer injection into the left DRG T7-T11, avidin-biotin and Cuprolinic Blue labeling, Zeiss M2 Imager, and Neurolucida to characterize spinal afferent axons in flat-mounts of the whole rat stomach muscular wall. We found that spinal afferent axons innervated all regions with a variety of distinct terminal structures innervating different gastric targets: (1) The ganglionic type: some axons formed varicose contacts with individual neurons within myenteric ganglia. (2) The muscle type: most axons ran in parallel with the longitudinal and circular muscles and expressed spherical varicosities. Complex terminal structures were observed within the circular muscle layer. (3) The ganglia-muscle mixed type: some individual varicose axons innervated both myenteric neurons and the circular muscle, exhibiting polymorphic terminal structures. (4) The vascular type: individual varicose axons ran along the blood vessels and occasionally traversed the vessel wall. This work provides a foundation for future topographical anatomical and functional mapping of spinal afferent axon innervation of the stomach under normal and pathophysiological conditions.

Organization and morphology of calcitonin gene-related peptide-immunoreactive axons in the whole mouse stomach.

Nociceptive afferent axons innervate the stomach and send signals to the brain and spinal cord. Peripheral nociceptive afferents can be detected with a variety of markers (e.g., substance P [SP] and calcitonin gene-related peptide [CGRP]). We recently examined the topographical organization and morphology of SP-immunoreactive (SP-IR) axons in the whole mouse stomach muscular layer. However, the distribution and morphological structure of CGRP-IR axons remain unclear. We used immunohistochemistry labeling and applied a combination of imaging techniques, including confocal and Zeiss Imager M2 microscopy, Neurolucida 360 tracing, and integration of axon tracing data into a 3D stomach scaffold to characterize CGRP-IR axons and terminals in the whole mouse stomach muscular layers. We found that: (1) CGRP-IR axons formed extensive terminal networks in both ventral and dorsal stomachs. (2) CGRP-IR axons densely innervated the blood vessels. (3) CGRP-IR axons ran in parallel with the longitudinal and circular muscles. Some axons ran at angles through the muscular layers. (4) They also formed varicose terminal contacts with individual myenteric ganglion neurons. (5) CGRP-IR occurred in DiI-labeled gastric-projecting neurons in the dorsal root and vagal nodose ganglia, indicating CGRP-IR axons were visceral afferent axons. (6) CGRP-IR axons did not colocalize with tyrosine hydroxylase or vesicular acetylcholine transporter axons in the stomach, indicating CGRP-IR axons were not visceral efferent axons. (7) CGRP-IR axons were traced and integrated into a 3D stomach scaffold. For the first time, we provided a topographical distribution map of CGRP-IR axon innervation of the whole stomach muscular layers at the cellular/axonal/varicosity scale.

Rapid stimulus-bound suppression of intake in response to an intraduodenal nonnutritive sweetener after training with nutritive sugars predicting malaise.

In a previous report (Schier et al., Am J Physiol Regul Integr Comp Physiol 301: R1557-R1568, 2011), we demonstrated with a new behavioral procedure that rats exhibit stimulus-bound suppression of intake in response to an intraduodenal (ID) bitter tastant predicting subsequent malaise. With the use of the same modified taste aversion procedure, the present experiments evaluated whether the sweet taste properties of ID stimuli are likewise detected and encoded. Thirsty rats licked at sipper spouts for hypotonic NaCl for 30 min and received brief (first 6 min) yoked ID infusions of either the same NaCl or an isomolar lithium chloride (LiCl) solution in each session. An intestinal taste cue was mixed directly into the LiCl infusate for aversion training. Results showed that rats failed to detect intestinal sweet taste alone (20 mM Sucralose) but clearly suppressed licking in response to a nutritive sweet taste stimulus (234 mM sucrose) in the intestine that had been repeatedly paired with LiCl. Rats trained with ID sucrose in LiCl subsequently generalized responding to ID Sucralose alone at test. Replicating this, rats trained with ID Sucralose in compound with 80 mM Polycose rapidly suppressed licking to the 20 mM Sucralose alone in a later test. Furthermore, ID sweet taste signaling did not support the rapid negative feedback of sucrose or Polycose on intake when their digestion and transport were blocked. Together, these results suggest that other signaling pathways and/or transporters engaged by caloric carbohydrate stimuli potentiate detection of sweet taste signals in the intestine.

Automatic assessment of human gastric motility and emptying from dynamic 3D magnetic resonance imaging.

BACKGROUND: Time-sequenced magnetic resonance imaging (MRI) of the stomach is an emerging technique for non-invasive assessment of gastric emptying and motility. However, an automated and systematic image processing pipeline for analyzing dynamic 3D (ie, 4D) gastric MRI data has not been established. This study uses an MRI protocol for imaging the stomach with high spatiotemporal resolution and provides a pipeline for assessing gastric emptying and motility. METHODS: Diet contrast-enhanced MRI images were acquired from seventeen healthy humans after they consumed a naturalistic contrast meal. An automated image processing pipeline was developed to correct for respiratory motion, to segment and compartmentalize the lumen-enhanced stomach, to quantify total gastric and compartmental emptying, and to compute and visualize gastric motility on the luminal surface of the stomach. KEY RESULTS: The gastric segmentation reached an accuracy of 91.10 ± 0.43% with the Type-I error and Type-II error being 0.11 ± 0.01% and 0.22 ± 0.01%, respectively. Gastric volume decreased 34.64 ± 2.8% over 1 h where the emptying followed a linear-exponential pattern. The gastric motility showed peristaltic patterns with a median = 4 wave fronts (range 3-6) and a mean frequency of 3.09 ± 0.07 cycles per minute. Further, the contractile amplitude was stronger in the antrum than in the corpus (antrum vs. corpus: 5.18 ± 0.24 vs. 3.30 ± 0.16 mm; p < 0.001). CONCLUSIONS & INFERENCES: Our analysis pipeline can process dynamic 3D MRI images and produce personalized profiles of gastric motility and emptying. It will facilitate the application of MRI for monitoring gastric dynamics in research and clinical settings.

Ongoing ingestive behavior is rapidly suppressed by a preabsorptive, intestinal "bitter taste" cue.

The discovery that cells in the gastrointestinal (GI) tract express the same molecular receptors and intracellular signaling components known to be involved in taste has generated great interest in potential functions of such post-oral "taste" receptors in the control of food intake. To determine whether taste cues in the GI tract are detected and can directly influence behavior, the present study used a microbehavioral analysis of intake, in which rats drank from lickometers that were programmed to simultaneously deliver a brief yoked infusion of a taste stimulus to the intestines. Specifically, in daily 30-min sessions, thirsty rats with indwelling intraduodenal catheters were trained to drink hypotonic (0.12 M) sodium chloride (NaCl) and simultaneously self-infuse a 0.12 M NaCl solution. Once trained, in a subsequent series of intestinal taste probe trials, rats reduced licking during a 6-min infusion period, when a bitter stimulus denatonium benzoate (DB; 10 mM) was added to the NaCl vehicle for infusion, apparently conditioning a mild taste aversion. Presentation of the DB in isomolar lithium chloride (LiCl) for intestinal infusions accelerated the development of the response across trials and strengthened the temporal resolution of the early licking suppression in response to the arrival of the DB in the intestine. In an experiment to evaluate whether CCK is involved as a paracrine signal in transducing the intestinal taste of DB, the CCK-1R antagonist devazepide partially blocked the response to intestinal DB. In contrast to their ability to detect and avoid the bitter taste in the intestine, rats did not modify their licking to saccharin intraduodenal probe infusions. The intestinal taste aversion paradigm developed here provides a sensitive and effective protocol for evaluating which tastants-and concentrations of tastants-in the lumen of the gut can control ingestion.

Gastric neurons in the nucleus tractus solitarius are selective to the orientation of gastric electrical stimulation.

Objective.Gastric electrical stimulation (GES) is a bioelectric intervention for gastroparesis, obesity, and other functional gastrointestinal disorders. In a potential mechanism of action, GES activates the nerve endings of vagal afferent neurons and induces the vago-vagal reflex through the nucleus tractus solitarius (NTS) in the brainstem. However, it is unclear where and how to stimulate in order to optimize the vagal afferent responses.Approach.To address this question with electrophysiology in rats, we applied mild electrical currents to two serosal targets on the distal forestomach with dense distributions of vagal intramuscular arrays (IMAs) that innervated the circular and longitudinal smooth muscle layers. During stimulation, we recorded single and multi-unit responses from gastric neurons in NTS and evaluated how the recorded responses depended on the stimulus orientation and amplitude.Main results.We found that NTS responses were highly selective to the stimulus orientation for a range of stimulus amplitudes. The strongest responses were observed when the applied current flowed in the same direction as the IMAs in parallel with the underlying smooth muscle fibers. Our results suggest that gastric neurons in NTS may encode the orientation-specific activity of gastric smooth muscles relayed by vagal afferent neurons.Significance.This finding suggests that the orientation of GES is critical to effective engagement of vagal afferents and should be considered in light of the structural phenotypes of vagal terminals in the stomach.

Human organ donor-derived vagus nerve biopsies allow for well-preserved ultrastructure and high-resolution mapping of myelinated and unmyelinated fibers.

The vagus nerve provides motor, sensory, and autonomic innervation of multiple organs, and electrical vagus nerve stimulation (VNS) provides an adjunctive treatment option for e.g. medication-refractory epilepsy and treatment-resistant depression. The mechanisms of action for VNS are not known, and high-resolution anatomical mapping of the human vagus nerve is needed to better understand its functional organization. Electron microscopy (EM) is required for the detection of both myelinated and unmyelinated axons, but access to well-preserved human vagus nerves for ultrastructural studies is sparse. Intact human vagus nerve samples were procured intra-operatively from deceased organ donors, and tissues were immediately immersion fixed and processed for EM. Ultrastructural studies of cervical and sub-diaphragmatic vagus nerve segments showed excellent preservation of the lamellated wall of myelin sheaths, and the axolemma of myelinated and unmyelinated fibers were intact. Microtubules, neurofilaments, and mitochondria were readily identified in the axoplasm, and the ultrastructural integrity of Schwann cell nuclei, Remak bundles, and basal lamina was also well preserved. Digital segmentation of myelinated and unmyelinated axons allowed for determination of fiber size and myelination. We propose a novel source of human vagus nerve tissues for detailed ultrastructural studies and mapping to support efforts to refine neuromodulation strategies, including VNS.

Acute effects of vagus nerve stimulation parameters on gastric motility assessed with magnetic resonance imaging.

BACKGROUND: Vagus nerve stimulation (VNS) is an emerging bioelectronic therapy for regulating food intake and controlling gastric motility. However, the effects of different VNS parameters and polarity on postprandial gastric motility remain incompletely characterized. METHODS: In anesthetized rats (N = 3), we applied monophasic electrical stimuli to the left cervical vagus and recorded compound nerve action potential (CNAP) as a measure of nerve response. We evaluated to what extent afferent or efferent pathway could be selectively activated by monophasic VNS. In a different group of rats (N = 13), we fed each rat a gadolinium-labeled meal and scanned the rat stomach with oral contrast-enhanced magnetic resonance imaging (MRI) while the rat was anesthetized. We evaluated the antral and pyloric motility as a function of pulse amplitude (0.13, 0.25, 0.5, 1 mA), width (0.13, 0.25, 0.5 ms), frequency (5, 10 Hz), and polarity of VNS. KEY RESULTS: Monophasic VNS activated efferent and afferent pathways with about 67% and 82% selectivity, respectively. Primarily afferent VNS increased antral motility across a wide range of parameters. Primarily efferent VNS induced a significant decrease in antral motility as the stimulus intensity increased (R = -.93, P < .05 for 5 Hz, R = -.85, P < .05 for 10 Hz). The VNS with either polarity tended to promote pyloric motility to a greater extent given increasing stimulus intensity. CONCLUSIONS AND INFERENCES: Monophasic VNS biased toward the afferent pathway is potentially more effective for facilitating occlusive contractions than that biased toward the efferent pathway.

An emerging method to noninvasively measure and identify vagal response markers to enable bioelectronic control of gastroparesis symptoms with gastric electrical stimulation.

BACKGROUND: Gastric electrical stimulation (GES) can be a life-changing, device-based treatment option for drug-resistant nausea and vomiting associated with diabetic or idiopathic gastroparesis (GP). Despite over two decades of clinical use, the mechanism of action remains unclear. We hypothesize a vagal mechanism. NEW METHOD: Here, we describe a noninvasive method to investigate vagal nerve involvement in GES therapy in 66 human subjects through the compound nerve action potential (CNAP). RESULTS: Of the 66 subjects, 28 had diabetic GP, 35 had idiopathic GP, and 3 had postsurgical GP. Stimulus charge per pulse did not predict treatment efficacy, but did predict a significant increase in total symptom score in type 1 diabetics as GES stimulus charge per pulse increased (p < 0.01), representing a notable side effect and providing a method to identify it. In contrast, the number of significant left and right vagal fiber responses that were recorded directly related to patient symptom improvement. Increased vagal responses correlated with significant decreases in total symptom score (p < 0.05). COMPARISON WITH EXISTING METHOD(S): We have developed transcutaneous recording of cervical vagal activity that is synchronized with GES in conscious human subjects, along with methods of discriminating the activity of different nerve fiber groups with respect to conduction speed and treatment response. CONCLUSIONS: Cutaneous vagal CNAP analysis is a useful technique to unmask relationships among GES parameters, vagal recruitment, efficacy and side-effect management. Our results suggest that CNAP-guided GES optimization will provide the most benefit to patients with idiopathic and type 1 diabetic gastroparesis.