Autonomic innervation, including vagus nerve and sympathetic nerves

Afferent and efferent signals are communicated chiefly from the autonomic nervous system which is generally extrinsic to the stomach, ultimately moderating the enteric nervous system which is intrinsic to the stomach . While the stomach does have intrinsic innervation that allows for loco-regional control, the foregut is heavily reliant upon extrinsic signals from the autonomic nervous system; this originates from the caudal brain stem. Autonomic innervation consists of either parasympathetic or sympathetic pathways. Predominantly afferent pathways will be detailed in greater depth in the portion of the chapter dedicated to signaling in the setting of nausea and vomiting ( Fig. 9.2 ).

Brain-gut axis and vomiting .

Any discussion of brain-gut axis dysfunction in gastroparesis must begin with a discussion of the many triggers that can provoke symptoms of gastroparesis such as nausea or vomiting. In this schematic from Sleisinger and Fordtran’s, the pathways of the brain-gut axis are depicted that result in vomiting from a variety of insults.

Parasympathetic innervation, which is responsible for gastric motor function, is largely the domain of the vagus nerve; gastric motor functions are routed through the dorsal motor nerve nucleus. The potency of this vagal control over stomach function has been known for thousands of years up through to the father of gastrointestinal physiology, William Beaumont; there is remarkable conservation of the regulatory mechanisms throughout vertebrate species as well . Over the past several centuries, deliberate perturbation of the vagus nerve has been known to have several consequences. Beaumont himself noted that stress impacted both motor and secretory functions of the stomach (both vagally mediated); severing the vagus nerve dramatically reduces the secretory function of the stomach as well as causes the gastric fundus to inappropriately maintain its tone as well as decreases contractions in the antrum . Regulatory pathways and their actors (such as acetylcholine and nitric oxide) will be discussed as they relate to their end-organ targets as mediated by the enteric nervous system ( Fig. 9.3 ).

It is not just about emptying in gastroparesis .

Brain-gut axis dysregulation in gastroparesis is typically considered from the perspective only of stomach emptying. However, the brain-gut axis also regulates other aspects of gastric motility that, when perturbed, can produce symptoms which are very similar to gastroparesis but actually represent abnormalities in other aspects of stomach function (such as accommodation of the food bolus after passage from the esophagus into the stomach).

The sympathetic nervous system, in contrast, tends to inhibit the secretomotor function of the stomach through a variety of different targets . Input from the sympathetic nervous system arises from fibers in the intermediolateral column of the spinal cord, principally the T6-T9 levels through cholinergic neurons that control post-ganglionic adrenergic neurons within the celiac ganglion, resulting in the sympathetic innervation of the stomach. The sympathetic nervous system influences gastric function through both control of presynaptic vagal input to the nerves of the enteric plexus as well as directly moderating nerves in plexi that control smooth muscle in the stomach ( Fig. 9.4 ).

Nausea versus vomiting.

While nausea and vomiting often occur together, they are mistakenly viewed as being dependent phenomena. There are important distinctions in any disturbance that results in nausea or vomiting, including gastroparesis.

Intrinsic innervation, including the enteric nervous system

The intrinsic innervation of the stomach/the enteric nervous system integrates divergent autonomic signals in order to transmit their excitatory or inhibitory output as these fibers directly penetrate into the gastric wall . The enteric nervous system is the major actor in terms of secretomotor and sensorimotor function of the stomach. It arises from neural crest cells through a combination of different embryologic events including migration, proliferation, differentiation, and synapse formation. The vast majority of nerves of the enteric nervous system in the foregut reside in the myenteric plexus (compared to the rest of the gastrointestinal tract which has ENS nerves residing in greater populations in the submucosal plexus). Various neuron types arise from these neural crest cells including primary afferent neurons, excitatory/inhibitory circular muscle motor neurons, longitudinal muscle motorneurons, ascending/descending interneurons, and secretomotor/vasomotor neurons comprised of Dogiel cells . Local enteric circuits then promote changes in secretion, vascular perfusion, contraction, and relaxation ( Fig. 9.5 ).

Schematic of nausea and vomiting in the central nervous system .

This is a simplified schematic from Babic et al. which demonstrates the varying inputs into the central nervous system in nausea and vomiting, including the central role of the nucleus tractus solitaries (NTS). Structures listed include the area postrema (AP), vestibular nucleus (Vestibular N), facial nucleus (Facial N), dorsal motor nucleus of the vagus (DMV), the nucleus ambiguous (N Amb), ventral respiratory group (VRG), and the parabrachial nucleus (Parabrachial N). Full discussion of all such pathways is beyond the scope of this chapter, and can be reviewed in the cited references.

It is only through integrated control of the above structures and nerves that the stomach can undergo appropriate secretomotor and sensorimotor function . It ensures that appropriate parts of the stomach are contracting, relaxing, secreting, are adequately perfused to allow for the complicated process of digestion. It is no surprise, then, that processes such as neuropathy arising from diabetes or loss of ENS cells can provoke the abnormalities and symptoms of gastroparesis. Normal function is accomplished by a more intricate connection of the stomach ENS with brainstem and cranial nerve/spinal structures due to the inability of the ENS to control as precisely through loco-regional mechanisms as compared to other parts of the gastrointestinal tract. Yet, it is important to put in perspective that despite this more controlled function of the ENS that the vast majority of the vagus nerve fibers to the stomach (90%) are afferent and sensory which means that the brain can only control based on input it receives via the vagus from the ENS. Those efferent fibers use acetylcholine to simultaneously stimulate controlled excitatory and inhibitory contractions of the stomach smooth muscle via nicotinic receptors on the post synaptic myenteric neurons. In general, contractile responses are mediated by cholinergic nerves acting upon smooth muscle. Relaxation mediated by the vagus nerve is accomplished by the release of nitric oxide, adenosine triphosphate, and vaso-active intestinal peptide.

Gastric fundus and the stomach reservoir

When food passes from the esophagus into the gastric cardia and fundus, it requires relaxation of the normal vagus-mediated tone to allow for the proximal stomach to perform its chief meal-related duty: gastric accommodation . In addition to providing more room for additional food bolus to pass from the esophagus, gastric accommodation allows for the controlled passage of food into the distal esophagus where the next steps of digestion occur . There have been attempts to manipulate gastric accommodation in experimental models which subtly hint at mechanisms behind aberrant brain-gut modulation of gastric accommodation. For example, in normal healthy subjects, transcutaneous stimulation improves gastric accommodation that is deliberately impaired with a bolus of cold contents . By provoking pain in the form of a clothespin clipped to the ear, this results in impaired post-prandial stomach volumes . In addition to pain and discomfort, psychosocial factors have also been shown to have an impact on gastric accommodation. Those patients suffering from anxiety have both reduced and slower increases in gastric volume . Anorexia nervosa adolescents have been found to have impaired gastric accommodation . Prior sexual abuse/trauma can also provoke changes in gastric accommodation . Pharmacologic therapy exists to address gastric accommodation difficulties, which will be described further as it relates to brain-gut axis modulatory targets.

Gastric antrum and stomach emptying

In normal gastric function, food passes from an adequately accommodating fundus into the distal body/antrum where food is further broken down and exposed to gastric secretions that continue digestion by way of contraction waves . Actual passage of stomach contents into the proximal duodenum, however, is dependent on a multitude of factors that can only be measured as a gastric emptying time in routine clinical practice: antral contractions, as well as relaxation of the pylorus and the proximal duodenum . Abnormalities in the vagus nerve or in the enteric nervous system can result in hypomotility in the antrum that reduce gastric emptying time and provoke symptoms through sensorimotor disturbance. Several of these will be described later in this chapter and their pathways highlighted by a focused discussion of current pharmacotherapy and surgical interventions which address brain-gut dysfunction in gastroparesis. While delays in stomach emptying can be associated with hyperglycemia, medications, and post-surgical complications, as with gastric accommodation, delayed gastric emptying can be provoked by psychosocial stress. In one study with healthy volunteers, participants were shown to have dyspeptic symptoms associated with delays in gastric emptying due to auditory stress .

The emesis motor cascade

While the vomiting and nausea associated with gastroparesis is definitively part of the pathophysiology of the disorder, nausea/vomiting remain normal physiologic mechanisms in response to disease ranging from mechanical obstruction to infection. The afferent components involved in nausea and vomiting will be discussed later in this chapter as they relate to the brain-gut axis. In terms of the motor response to pathways provoking vomiting, it proceeds along a well-organized cascade to result in the forceful expulsion of foregut contents . As emesis centers are triggered, the stomach relaxes and foregut peristalsis ceases. Other anatomic structures, though, are necessary to ensure that vomiting occurs. For example, the diaphragm and the intercostal muscles contract in a spasmodic fashion to allow for increased intra-abdominal pressure. Not only has peristalsis stopped during an episode of vomiting, retrograde contractions from the small bowel push contents into the stomach which is allowed to pass through into the esophagus by way of relaxation of the lower esophageal sphincter. At the same time, protective reflexes occur within the pharynx to reduce the chance of aspiration of foregut contents into the respiratory tree. The combination of these events result in vomiting.

Stomach motor function in between meals

Motor function in the stomach also occurs independently of meals, principally through the migratory motor complex (MMC) . In the fasting state, the MMC consists of a coordinated cyclical pattern of contraction of the foregut. The three phases of MMC activity include: phase I which is characterized by a lack of contractile activity; phase II and phase III consist of propagating contractions which serve various functions in the foregut including preventing dysbiosis as well as to clear the stomach of indigestible particles.

Nausea and vomiting in the brain

While gastroparesis has distinct disease pathology with a well-defined diagnostic criteria, its symptoms display a wide overlap with other nausea and vomiting and functional disorders (such as chronic unexplained nausea and vomiting) which likely reflects common pathophysiologic mechanisms . As a greater appreciation has developed for gastroparesis being in part due to a disordered brain-gut axis, it is important to consider separately the central nervous system’s role in any state associated with nausea and/or vomiting from the motor elements of the foregut that are involved with these symptoms. Such a distinction is artificial as the afferent and efferent signals sent between the brain and the gut ultimately act in a coordinated fashion to provoke nausea and vomiting.

In the central nervous system (CNS), several structures have been identified as being involved in nausea and vomiting. These include the chemoreceptor trigger zone in the area postrema and the vomiting center in the medulla . Vagal afferents from the gastrointestinal tract, vestibular stimulation, and cerebral structures can provoke disturbances in these CNS structures which can provoke nausea and vomiting . Experimental manipulation of study subjects to provoke nausea and vomiting has been performed since the 19th century when apomorphine (a dopamine agonist) was used to prove such symptoms . It has been shown that apomorphine does stimulate the chemoreceptor trigger zone and can provoke gastric emptying delay with metoclopramide abolishing this motility abnormality which has been known as early as the 1970s .

Functional brain connectivity has been studied for conditions that are associated with nausea and vomiting. Functional MRI (fMRI) has been able to identify CNS structures that are associated with diseases as diverse as motion sickness and cyclic vomiting syndrome that have significant symptom overlap with gastroparesis. Structures that have been implicated with fMRI in nausea have included the amygdala, putamen, dorsal pons, and various parts of the cerebral cortex which is not surprising given the need for the body to process such symptoms and attempt to modify behavior as a result of this CNS input . Unfortunately, although a Rome working team report has recognized for over a decade the promise that neuroimaging could have in the study of functional gastrointestinal disorders, use of such technology remains limited to the research realm with limited clinical application .

Finally, endoconnabonids, including CB ₁ and CB ₂ are thought to have predominantly CNS-localization although they are also found in the gastrointestinal tract, with multiple possible mechanisms provoked by receptor activation including inhibition of dopamine and acetylcholine release and indirect inhibition of opioid-, serotonin-, and gamma-aminobutyric acid (GABA) receptors .

Connecting the brain and gut: The vagus nerve

During “normal” nausea and vomiting, it is known that reduced gastric motility is associated with a vagal non-adrenergic non-cholinergic link . Afferent signals from the vagus nerve bring signals from the gut to the nucleus of the solitary tract which relays the signals to the central pattern generator resulting in multiple downstream pathways which are again relayed by the vagus nerve . What follows is a discussion of the neurocircuits mediated by the vagus nerve which result in nausea, vomiting, or nausea and vomiting combined.

The nucleus of the solitary tract integrates input not only from the gastrointestinal tract via the vagus nerve but also from other afferents which can provoke the sensation of nausea and vomiting, including the hypothalamus, the cerebellum, various cranial nerves such as the pharyngeal, glossopharyngeal and trigeminal nerves and the cerebral cortex . Vagal afferent fibers from the gastrointestinal relay to the central nervous system signals via the dorsal vagal complex which consists of the nucleus of the solitary tract, the area postrema (associated with the fourth ventricle of the brain) and the dorsal motor nucleus of the vagus . These nerves have their cell bodies in the nodose ganglion and connect to the nucleus of the solitary tract via glutamatergic synapses and make their second-order neuronal connections here . Integrated neuronal responses are sent via the dorsal motor nucleus to the gastrointestinal tract through efferent vagal nerve fibers; these are cholinergic nerves . Once efferent vagal fibers reach their target in the gastrointestinal tract they induce either a cholinergic response that promotes muscle contraction or the aforementioned “non-adrenergic non-cholinergic” pathway that results in smooth muscle relaxation by release of either nitric oxide or vasoactive intestinal peptide .

Given the intimate control the vagus nerve has on appropriate sensorimotor function and brain-gut regulation of the stomach, it is not surprising that vagus pathology contributes directly to gastroparesis pathophysiology. As previously discussed, what is unique about gastrointestinal innervation compared to other organ systems is the ability of loco-regional regulation to generally maintain function. However, various vagal neuropathies highlight the role that this nerve has in being the central mediator of brain-gut communication.

The classic example of a vagus neuropathy resulting in brain-gut axis dysfunction and gastroparesis is the surgical vagotomy/iatrogenic injury of the vagus nerve and its branches. “Post-surgical gastroparesis syndrome” refers to delayed gastric emptying secondary to typically in the upper abdomen/thoracic cavities that occurs due to gastric atony without evidence of mechanical obstruction . The central pathology is thought to arise from the loss of parasympathetic control which results in disruption of tonic contractions in the fundus and a weakening of antral peristalsis . Various operations have been described as provoking gastroparesis, including truncal vagotomy and antrectomy , lung transplantation gastric bypass and anti-reflux procedures such as fundoplication .

Other interventions have been described as provoking pathology similar to post-surgical gastroparesis due to brain-gut axis dysfunction secondary to vagus nerve injury. Atrial radiofrequency ablation is one such intervention . In such an iatrogenic complication, vagus nerve-mediated damage results from the structure being an innocent bystander passing posterior to the left atrium. Posterior ablation is performed in order to address the tachyarrhythmia, possibly perturbing brain-gut signaling of all downstream gastrointestinal organs.

An emerging wave of technology flips the “brain-gut” paradigm by using stimulation of the vagus nerve to modulate afferent signaling to improve disease related to pain or central nervous dysfunction which likely overlap with pathways responsible for the symptoms associated with gastroparesis. For example, vagus nerve stimulation can moderate the brain connectivity thought to contribute to migraines . Auricular acupuncture to stimulate the vagus nerve has even been studied to reduce doses of general anesthesia used during surgeries . Given the limited pharmacotherapy to improve the sensory abnormalities associated with gastroparesis, this points to a potential treatment avenue for the management of brain-gut dysfunction.

Enteric nervous system abnormalities in gastroparesis

While post-surgical gastroparesis is a syndrome thought to be due to vagus nerve injury, surgical interventions can induce gastroparesis through other mechanisms . For example, pylorus-sparing pancreatoduodenectomy can result in gastroparesis in part due to compromised gastric phase III activity resulting from reduced levels of motilin after duodenectomy. Another post-surgical mechanism of enteric nervous system injury that results in gastroparesis is damage to the interstitial cells of Cajal (ICC) due to ischemic injury.

Perhaps, though, the major pathologies driving enteric nervous system dysfunction in gastroparesis are infiltrative processes, auto-immune phenomena, or small fiber neuropathies (e.g. that can be due to metabolic conditions such as diabetes). That local processes within the gastric wall (containing the enteric nervous system) could result in gastroparesis has been known for some time. When examining full thickness biopsies in patients suffering from gastroparesis compared to healthy controls, there were multiple enteric nervous system abnormalities including reductions in nerve cell bodies/ganglion cells as well as increased abnormalities or frank reduction in the interstitial cells of Cajal . In another study, 83% of diabetic patients had some histology abnormality, with a reduction in ICC paired with abnormal immune infiltration (measured by CD45 and CD68 staining) and decreased nerve fibers; there remained the possibility even differentiating gastroparesis types by type of enteric nervous system pathology, as there was a greater decrease in neuronal nitric oxide synthase in idiopathic vs diabetic gastroparesis . “Idiopathic” gastroparesis has been thought in part to be due to such changes in the enteric nervous system triggered as a result of viral infections such as cytomegalovirus or Epstein-Barr virus .

Disturbances in the ENS have also been shown to have some clinical correlation. For example, in diabetic patients, abnormal ICC density and morphology was associated with delayed gastric emptying, although it did not correlate with severity . In contrast, in idiopathic gastroparesis, myenteric immune infiltration and severity of nausea complaints has been found . Similar abnormalities have been posited for gastroparesis associated with infiltrative disorders like systemic sclerosis . Unfortunately at the current time these do not have management implications.

Diseases like Parkinson disease highlight other disturbances in the enteric nervous system that can result in gastroparesis due to brain-gut axis pathology along its entire length: it reminds us that the entire axis works as a unit from the central nervous system to the walls of the GI tract. Parkinson disease (PD) is associated with widespread gastrointestinal motility abnormalities, although the CNS-related manifestations are generally more prominent . Brain-gut abnormalities related to PD effect skeletal/striated muscle and can provoke dysphagia. PD also impacts gastrointestinal smooth muscle with prior studies showing changes in the enteric nervous system analogous to other impacted organ systems: namely reduction in dopamine and perturbed myenteric and submucosal enteric nervous plexi due to Lewy body deposition and alpha-synuclein (albeit these studies typically have focused on the lower gastrointestinal tract versus the foregut) . As part of global gastrointestinal dysmotility, it is known that delayed gastric emptying can be component of PD although the heterogeneity of studies characterizing this association make it harder to draw meaningful conclusions as it relates to management of gastroparesis in these patients .

Traditional pharmacologic therapy

Pharmacologic therapy has unfortunately been limited in gastroparesis, although it remains the first line of treatment. Often times, they may have a combined sensory or motor modulation of the brain-gut axis which may result either in improved emptying or reduction of symptoms (or both). The agents variably impact central nervous system processing of nausea/vomiting, can locally effect the enteric nervous system, or can directly stimulate improved motor function; often times, a single drug may impact various components of the brain-gut axis.

Dopamine receptor antagonism has been an early target of brain-gut, including the use of agents like metoclopramide and domperidone. Such antagonism has effects on the central nervous system in the form of modulation of the chemoreceptor trigger zone in the area postrema as well as receptors in the vomiting center . This antagonism can also increase lower esophageal sphincter and gastric tone and cause increased intragastric pressure with enhanced gastric contractility which help to promote emptying .

Similar to dopamine receptor antagonism, 5HT ₃ antagonism is thought to contribute to metoclopramide’s ability to address gastroparesis symptoms also through targeting the vomiting center . Ondansetron and granisetron are also 5HT ₃ antagonists used in diabetic-related nausea which are thought to act on receptors in vagal afferents projecting to the brainstem, area postrema, nucleus solitarius, and the dorsal motor nucleus of the vagus – all structures implicated in stimulating emesis .

5HT ₄ agonism is an additional mechanism of metoclopramide action and remain an attractive target for multiple gastrointestinal tract diseases due to their presence throughout the GI tract . These receptors have provided the rationale for the efficacy of other medications such as cisapride and tegaserod (although given concern for toxicity, their use has been either severely restricted or the medication has been completely withdrawn) . Prucalopride, only recently available in the United States but has been available in other parts of the world for the treatment of constipation, is a 5HT ₄ agonist that shows promise in being effective in the management of gastroparesis symptoms and emptying .

Neurokinin-1 receptor antagonism has been another option for pharmacotherapy given the concern regarding side effect profiles from dopamine and 5HT ₃ antagonism as well as 5HT ₄ agonism. Neuorkinin-1 receptors are found in both the sensory and vagal nerve of the nuclei and are components of both afferent (e.g. of discomfort) and efferent (e.g., gastric motor response) signals that are perturbed in gastroparesis . Aprepitant is an NK-1 antagonist that appears to improve both symptoms as well as motor function .

In terms of medications that tend to have more of an impact on motor function in gastroparesis, the traditional target has been motilin receptor agonism and this is represented chiefly by erythromycin, which promotes gastric emptying by increasing phasic contractions in the antrum through cholinergic activity and promotes relaxation in the pylorus therefore promoting stomach emptying . The chief limitation is the phenomenon of tachyphylaxis which limits long term efficacy . Ghrelin receptors have been gaining traction as another target for gastroparesis medical management and are also thought to be more prokinetic . Synthetic analogs of ghrelin like relamorelin have been shown to improve stomach emptying in gastroparesis, although it is not available yet for routine clinical use .

Neuromodulation and visceral hypersensitivity: Another approach to moderating the brain-gut axis in gastroparesis

Beyond this traditional sensorimotor dysfunction paradigm for the management of brain-gut dysfunction in gastroparesis, use of medications with chiefly neuromodulatory properties remains an intriguing avenue for treatment especially in patients who remain unexpectedly symptomatic despite relatively minor/moderate delays in gastric emptying. The term “neuromodulator” refers to broad class of agents with includes antidepressants or anti-epileptic agents (among others) that is used to treat a multitude of functional gastrointestinal disorders (FGIDs) . Mirtazapine, for example, has been shown to reduce vomiting and nausea in gastroparesis patients, although upwards of one-fifth had to discontinue due to medication side effect . The antipsychotic haloperidol has been studied for the use of acute exacerbations of gastroparesis presenting in the emergency department . However, the NORIG study showed that use of nortriptyline, a tricyclic antidepressant often used in FGID management did not improve symptoms . The anxiolytic buspirone (a 5HT _1A receptor agonist) is thought to not only improve gastric accommodation but also symptoms (albeit in dyspepsia) which may be independent of is psychoactive properties; this has been extrapolated as being potentially beneficial in gastroparesis patients as well .

Along the lines of neuro/psychoactive agents being used to manage acute exacerbations and chronic gastroparesis-related symptoms, there is the intriguing possibility that a phenomenon known as “visceral hypersensitivity” may impact symptom severity. When considering the sensorimotor function of the brain-gut axis and its afferent and efferent outputs, there is one critical observation that has been made as it relates to both upper (i.e. dyspepsia) and lower (i.e. irritable bowel syndrome) FGIDs: there is limited correlation between severity of motor delay and the severity of the patient’s symptoms . There have been several visceral sensation abnormalities that have been posited, such as accommodation, compliance, wall tension, and hypersensitivity/hyperalgesia/allodynia as playing a role in a multitude of functional gastro-intestinal disease that all end up being variants of pathology in the same brain-gut axes that regulate the varying portions of the gastrointestinal tract . The challenge of employing visceral hypersensitivity as an explanation for pain/discomfort in gastroparesis is that the manner in which these parameters are measured are not usually employed in clinical management but in the realm of research. For example, barostats have been used to study the role that impaired accommodation of the gastric fundus may have in the manifestation of gastroparesis-related symptom severity , although standardized nutrient drink tests may be a useful surrogate . Yet, neither this technology nor the nutrient drink test traditionally have universal roles in the diagnosis/management of gastroparesis ( Fig. 9.6 ).

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