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SPECIAL REPORTS AND REVIEWS Brain-Gut Axis in Health and Disease QASIM AZIZ and DAVID G. THOMPSON Department of Medicine, Section of Gastroenterology, University of Manchester, Manchester, England Because it is common to experience gastrointestinal (GI) symptoms such as diarrhea, dyspepsia, and abdominal discomfort in response to alterations in emo- tional state, clinicians have long appreciated that the brain modulates gut function.1 This association, however, began to be explored critically only in the 19th and the early 20th century by Beaumont,2 Pavlov,3 and Cannon4 and later by Wolf and Wolff,5 who showed not only that external sensory events eliciting strong emotional reac- tions can alter the function of the alimentary canal but also that different emotional states produced different patterns of GI motor function. Because the experimental design of these early studies was not always as rigorous as would be expected today and the methodology used is now considered archaic, their validity has been questioned. Nevertheless, a close relationship between emotional state and GI function is repeatedly reported by patients with functional bowel disorders.6,7 Furthermore, studies in healthy volunteers have also shown alterations in GI function when they are subjected to experimental stressors.8 More tangible evidence for the brain’s influence on GI function comes from reports of alterations in gut function after lesions of the central nervous system (CNS). For instance, brain stem can produce alterations in small bowel motility,9 and dysphagia can occur in stroke patients.10 Spinal cord transection can lead to gastric distention with delay of postprandial gastric emptying of liquids and ileus.11 Bilateral resection of sacral nerves during removal of sacral tumors can lead to disruption of anal function leading to incontinence,12 and bilateral truncal vagotomy is well known to result in postprandial bloating, abdominal pain, and diarrhea.13 Despite unequivocal evidence of the brain’s influence on gut function, our ability to study human brain gut interactions in vivo has been restricted until recently by the lack of noninvasive neurophysiological techniques. However, with recent advances in neuroscience, func- tional brain imaging techniques have become available that not only allow objective assessment of sensorimotor pathways between the brain and the periphery but also provide information about the functional neuroanatomy of the brain, enabling the acquisition of real-time images of brain function. These techniques have found diverse applications. For instance, psychologists are now able to study brain physiology during the performance of com- plex mental tasks involving memory and cognition,14,15 and psychiatrists have gained insight into devastating mental illnesses such as schizophrenia.16 Neurophysiolo- gists are studying the brain’s processing of somatosensory, visual, and auditory information,17,18 and neurosurgeons are able to identify the homunculus in patients before stereotactic surgery, thereby avoiding damage to function- ally important areas.19 The availability of functional brain imaging techniques has also opened up an exciting new area of GI research and allowed gastroenterologists to explore the CNS control of human gut function in health and disease. The aim of this review is to introduce the readers to the basic principles, advantages, and limitations of functional brain imaging techniques and to bring them up to date with studies of the human brain-gut axis in health and disease. Review of the Anatomy and Physiology of the Brain-Gut Axis Gut function is modulated by both extrinsic and intrinsic neural pathways.20–22 The intrinsic innervation is provided by neurons of the myenteric and the submu- cous plexi, and the extrinsic innervation is provided by Abbreviations used in this paper: CEP, cortical evoked potential; CPG, central pattern generator; DMN, dorsal motor nucleus; DRG, dorsal root ganglia; EMG, electromyography; ENS, enteric nervous system; fMRI, functional magnetic resonance imaging; GI, gastroin- testinal; IBS, irritable bowel syndrome; MEG, magnetoencephalogra- phy; MRI, magnetic resonance imaging; NA, nucleus ambiguus; NTS, nucleus of solitary tract; PBN, parabrachial nuclei; PET, positron emission tomography; SQUID, superconducting quantum interfer- ence device; TCMS, transcranial magnetic stimulation; WDRMN, wide dynamic range mechanonociceptors. r 1998 by the American Gastroenterological Association 0016-5085/98/$3.00 GASTROENTEROLOGY 1998;114:559–578
the splanchnic ‘‘sympathetic’’ and vagal-sacral ‘‘parasym- pathetic’’ nerves (Figure 1). The proximal esophagus22,23 and the external anal sphincter22,24 are composed of striated muscle with sparse intrinsic innervation so that motor function in these regions is regulated almost entirely by extrinsic control. The rest of the GI tract, in contrast, is composed of smooth muscle, controlled largely by the intrinsic plexi that receive modulatory influence from the extrinsic innervation. Intrinsic Innervation The enteric nervous system (ENS) is an integrative system of neurons with structural complexity and func- tional heterogeneity similar to those of the brain and the spinal cord. The principal role of the ENS is to control and coordinate GI functions such as motility, secretion, mucosal transport, and blood flow that are necessary for normal digestive processes.25–28 The ENS performs these functions via motor neurons located within its ganglia, which form the final common pathway to the effector cells of the GI tract. Although specialized ‘‘command’’ motor neurons that form intrinsic neural circuits for the control of GI motility receive some inputs from the CNS via parasympathetic and sympathetic pathways, the func- tion of most motor neurons is predominantly coordinated by sensory neurons and interneurons located within the ENS. Extrinsic Innervation Vagal (parasympathetic) innervation. The vagus nerve conveys information between the viscera and the brain stem. It contains both afferent and efferent nerves and, in humans, innervates the entire gut except the distal third of the colon.22,29 Vagal afferent pathways. Of the fibers within the vagal trunks, 70%–90% are unmyelinated afferent neu- rons with cell bodies located in the nodose ganglia22,29–31 lying just below the jugular foramen. The nodose ganglia display a crude viscerotopic organization corresponding to the rostrocaudal organization of the alimentary canal, sensory neurons projecting to the soft palate and pharynx being located superiorly, whereas those projecting to the lower GI tract are located more inferiorly.32 Vagal afferent fibers from the nodose ganglia terminate in the brain stem within the medial division of the nucleus of solitary tract (NTS), where they also display rostrocaudal viscero- topic organization within distinct subnuclei32,33 (Figure 2). Vagal afferents have a low threshold of response34,35 to mechanical stimulation and are saturated at levels of stimulation well within the physiological range. They are therefore believed to mediate nonnoxious physiological sensations such as satiety and nausea. Recently, however, a role for vagal afferents in the modulation of nociception has been established. Experimental studies suggest that vagal afferents acting via the brain stem exert both inhibitory and excitatory influences on spinal nociceptive transmission.36,37 Loss of such influences may be respon- sible for the altered sensation experienced by patients after vagotomy. Vagal motor pathways. The vagal motor nuclei comprise the nucleus ambiguus (NA) and the dorsal motor nucleus (DMN).20,22,32,33 The NA is located in the ventrolateral medulla and has rostrocaudally aligned subdivisions. Within the NA, the striated musculature of upper GI tract has a distinct pattern of representation so Figure 1. Schematic representation of the intrinsic and extrinsic innervation of the smooth muscle region of the gut shows dual extrinsic innervation via vagal and spinal pathways. Figure 2. The bulbar and suprabulbar projections of vagal and spinal afferent pathways. Vagal afferents terminate in the NTS from where projections ascend via the PBN to the thalamus, limbic, and the insular cortices. Spinal afferents ascend in the spinothalamic tract and the dorsal columns. The spinothalamic tracts ascend to the thalamus, and the dorsal columns ascend to the nucleus gracilus and cuneatus in the rostral medulla, from where they project to the thalamus via the medial lemniscus. From the thalamus, projections ascend to the primary somatosensory and insular cortices. 560 AZIZ AND THOMPSON GASTROENTEROLOGY Vol. 114, No. 3
that different populations of neurons project to the pharynx, larynx, and the upper esophagus.32,33,38 Den- drites from the subdivisions of the NA project into the surrounding reticular formation where they form net- works for coordinating complex motor events such as swallowing.33,38 The DMN is the source of efferents to the smooth muscle region of the gut that synapse with the neurons of the myenteric plexus.20,22,33 Within the DMN, motoneu- rons innervating specific abdominal viscera show topo- graphic organization.33,39 The DMN motoneurons also show extensive dendritic arborizations allowing coordina- tion of efferent activity throughout the rostrocaudal extent of the nucleus.33 Dendrites from the DMN that innervate specific viscera also terminate within the NTS, where they overlap with their respective primary sensory neurons leading to organ-specific monosynaptic interac- tion between the two structures.33 Vagovagal reflexes. GI function is modulated by a number of vagally mediated reflexes including gastrogas- tric, enterogastric, hepatopancreatic, and gastrocolic re- flexes.20,22,40 The circuitry for these reflexes is organized in the medulla, where vagal afferents are integrated with vagal efferents. The functional specificity and heterogene- ity of vagovagal reflexes is due to the structural organiza- tion within the NTS and DMN, which are not compart- mentalized into distinct anatomic units but are composed of relatively unspecialized neurons, topographically orga- nized into partially overlapping zones corresponding to different nerve branches. The NTS and DMN are effec- tively fused together and, because of the orthogonal organization of the sensory and motor neurons, have an architectural organization of a lattice.40 This organization may be responsible for the specificity of GI reflexes because each intersecting node of this lattice could organize a specific reflex. The heterogeneity of these reflexes is probably due to the fact that each nerve branch within this lattice is capable of carrying multiple modali- ties of information, so that the intersection of the lattice that represents the gastrogastric reflex would mediate chemical, mechanical, and secretory responses. Higher CNS control of vagal nuclei. The brain stem vagal nuclei provide the circuitry for the basic reflex control of GI function, but they are also modulated by higher brain regions.20,22,31,41,42 The NTS acts as a relay for the vast amount of information arriving to it from abdominal viscera and, in turn, sends out a large ramifying fiber network to higher centers while also receiving information from these centers. There are four levels of output from the NTS.41–44 The first is a direct projection to the autonomic motor nuclei involving both the parasympathetic and the sympathetic preganglionic neurons in the DMN/NA and the interomediolateral cell column of the spinal cord, respectively. These projections provide an anatomic substrate for short autonomic reflex loops. Second, the NTS sends relays to the motor components of ingestion found in the trigeminal, facial, hypoglossal nuclei and also the NA. Third, visceral information is relayed to more rostral regions of the brain stem such as the parabrachial nuclei (PBN), which in turn is connected to higher brain centers. Fourth, long projections terminate in the thalamus, hypothalamus, and limbic and insular cortical regions that mediate autonomic, neuroendocrine, and behavioral functions (Figure 2). Vagal motor nuclei have numerous reciprocal connec- tions with other brain regions such as area postrema, the PBN, hypothalamus, amygdala, and the orbitofrontal, insular, and infralimbic-anterior cingulate cortex.20,41–43 These connections integrate sensory input arriving from the NTS with the descending influences from the higher brain centers and provide the circuitry for visceral reflex loops; allow integration of GI, cardiovascular, and respira- tory activities that occurs in autonomic reflexes such as vomiting; and also provide the conduit through which various emotions and environmental influences modulate gut function. Sacral (parasympathetic) innervation of the GI tract. Projections from preganglionic neurons located in the intermediate grey matter of the cord segments S1–S5 innervate the distal colon, rectum, and internal anal sphincters via pelvic ganglia from where postganglionic pelvic nerve fibers innervate the enteric ganglia.20,22,45,46 Interneurons in the sacral autonomic nuclei receive projections from the colon via the pelvic nerve afferents, whose cell bodies lie in dorsal root ganglia (DRG) and then send projections to the preganglionic neurons to form the spinal reflex that regulates colonic motility and defecation. Supraspinal sites such as the cerebral cortex, pons, and medullary reticular formation also send projec- tions to the sacral cord and exert a modulatory influence on colonic function.20,47 Spinal pathways innervating the GI tract. Al- though in the past both afferent and efferent spinal innervation of the GI tract were referred to as ‘‘sympa- thetic,’’48 it is now usual to refer to visceral afferents running in the spinal cord as ‘‘spinal visceral afferents’’ and to restrict the term ‘‘sympathetic innervation’’ to the spinal efferent innervation.29 Spinal visceral afferent nerves. Spinal visceral affer- ents constitute 5%–10% of all afferent fibers in the thoracic and lumber dorsal nerve roots.20,22,29,49–51 Most March 1998 BRAIN–GUT AXIS 561
visceral afferents pass via prevertebral and paravertebral ganglia en route to the spinal cord. Collaterals to the prevertebral ganglia from visceral afferents participate in the mediation of local autonomic reflexes. Spinal afferents have cell bodies in the DRG at the cervical, thoracic, and upper lumbar spine. These afferents are predominantly unmyelinated C and A d fibers and show sensitivity to both mechanical and chemical stimuli. Spinal mechanore- ceptive afferents are present predominantly in the muscu- lar layer, serosal layer, and the mesentery of the gut.29 Innervation of different viscera shows considerable segmen- tal overlap in the spinal cord, which probably explains the poor viscerotopic localization of sensation in the GI tract. The convergence of visceral and spinal afferents in the dorsal horn of the spinal cord is thought to be the basis for the referral of visceral sensation to somatic struc- tures.50,52,53 Visceral afferent information is transmitted proximally along the spinal cord via a number of tracts of which the spinothalamic tracts and the dorsal columns are the most important20,29,49,52,53 (Figure 2). The lateral spinotha- lamic neurons mediate the sensory-discriminative aspects of pain, whereas the medial spinothalamic neurons mediate the motivational-affective aspects of pain.49,54,55 In contrast to conventional wisdom that the dorsal columns do not mediate visceral afferent information, recent evidence from human studies now suggests that is not so, because posterior midline myelotomy that inter- rupts the dorsal columns alleviates pelvic visceral pain in patients with colon cancer.56 Additional visceral afferent information is also carried in the spinoreticular, spinomes- encephalic, and spinosolitary tracts,49,52,57 which project to the thalamus via relays in the brain stem (e.g., the NTS) and in the midbrain.58 These pathways are respon- sible for the integration of somatic and visceral input from wide areas of the body, and they also allow afferent information encoded within vagal afferents to modulate afferent information encoded within spinal afferents.36,37 From the thalamus, sensory information passes to the insular cortex, the primary somatosensory cortex, and the prelimbic, limbic, and infralimbic areas of the medial prefrontal cortex.58,59 Although spinal afferents are usually only thought of as pathways for transmission of nociceptive information to the CNS,29,49,51,54,55 the majority of afferents have stimulus response functions that cover both physiological and nociceptive ranges of stimulation.29,35,60,61 This suggests that the quality of visceral sensation must depend on the intensity of discharge within the spinal visceral afferent fibers. There are several extensive review articles on the role of visceral afferents in the mediation of GI sensation in health and disease.36,37,49,51,62,63 Sympathetic efferent pathways. The GI tract receives efferent neural input from the cervical, thoracic, and lumbar segments of the spinal cord.20,22 The pregangli- onic (cholinergic) neurons have cell bodies in the interme- diate gray region of the thoracolumbar spinal cord and terminate in the spinal ganglia. The postganglionic (noradrenergic) neurons to the stomach, small intestine, and proximal large intestine are located in the celiac- superior mesenteric ganglion, the remainder of the large intestine is innervated by the inferior mesenteric gan- glion, and the rectum is innervated by the pelvic ganglion. Postganglionic neurons project to the ganglia of the myenteric plexus and inhibit GI function via inhibition of the release of acetylcholine from submucous and myenteric neurons.20,22,64 Modulation of sympathetic neuron function. Sympa- thetic neurons of the prevertebral ganglia also receive synaptic input from enteric neural and spinal visceral afferents, which mediate peripheral regulatory reflexes such as the intestino-intestinal inhibitory reflex.64,65 Furthermore, stimulation of the hypothalamus increases colonic motility, whereas stimulation of the medial forebrain bundle and anterior sigmoid, orbital, and cingulate gyri of the cerebral cortex inhibits colonic motility.20,66 These supraspinal influences on colonic function are likely to be mediated via descending modu- lation of spinal preganglionic neurons. Innervation of the striated muscle regions of the GI tract. Both swallowing and defecation are under conscious control, suggesting strong CNS influence on the striated musculature involved in these acts.22 Neural control of swallowing. Swallowing is a com- plex sensorimotor event requiring the coordinated contrac- tion of muscles both in the buccopharynx and the esophagus.22,67,68 The neural control of swallowing re- quires integration at the brainstem swallowing center of peripheral afferent inputs with inputs from the cortical swallowing centers (Figure 3).20,67–71 Numerous studies have confirmed that once swallowing is initiated by stimulation of either an afferent pathway or voluntarily, the entire motor sequence of peristalsis proceeds even in the absence of peripheral feedback from an accompanying bolus. This suggests that the neural control of swallowing is governed by a central pattern generator (CPG), which organizes the sequential excitation of motor neurons controlling swallowing muscles.67–71 In mammals, the swallowing center is located bilaterally in the medulla and the pons and consists of three functional components: an afferent component, and efferent component, and a complex organizing system of interneurons forming the CPG. The afferent component comprises fibers within the 562 AZIZ AND THOMPSON GASTROENTEROLOGY Vol. 114, No. 3