Fundamentals of Neurogastroenterology: Basic Science

The focus of neurogastroenterology in Rome II was the enteric nervous system (ENS). To avoid duplication with Rome II, only advances in ENS neurobiology after Rome II are reviewed together with stronger emphasis on interactions of the brain, spinal cord, and the gut in terms of relevance for abdominal pain and disordered gastrointestinal function. A committee with expertise in selective aspects of neurogastroenterology was invited to evaluate the literature and provide a consensus overview of the Fundamentals of Neurogastroenterology textbook as they relate to functional gastrointestinal disorders (FGIDs). This review is an abbreviated version of a fuller account that appears in the forthcoming book, Rome III. This report reviews current basic science understanding of visceral sensation and its modulation by inflammation and stress and advances in the neurophysiology of the ENS. Many of the concepts are derived from animal studies in which the physiologic mechanisms underlying visceral sensitivity and neural control of motility, secretion, and blood flow are examined. Impact of inflammation and stress in experimental models relative to FGIDs is reviewed as is human brain imaging, which provides a means for translating basic science to understanding FGID symptoms. Investigative evidence and emerging concepts implicate dysfunction in the nervous system as a significant factor underlying patient symptoms in FGIDs. Continued focus on neurogastroenterologic factors that underlie the development of symptoms will lead to mechanistic understanding that is expected to directly benefit the large contingent of patients and care-givers who deal with FGIDs. The focus of neurogastroenterology in Rome II was the enteric nervous system (ENS). To avoid duplication with Rome II, only advances in ENS neurobiology after Rome II are reviewed together with stronger emphasis on interactions of the brain, spinal cord, and the gut in terms of relevance for abdominal pain and disordered gastrointestinal function. A committee with expertise in selective aspects of neurogastroenterology was invited to evaluate the literature and provide a consensus overview of the Fundamentals of Neurogastroenterology textbook as they relate to functional gastrointestinal disorders (FGIDs). This review is an abbreviated version of a fuller account that appears in the forthcoming book, Rome III. This report reviews current basic science understanding of visceral sensation and its modulation by inflammation and stress and advances in the neurophysiology of the ENS. Many of the concepts are derived from animal studies in which the physiologic mechanisms underlying visceral sensitivity and neural control of motility, secretion, and blood flow are examined. Impact of inflammation and stress in experimental models relative to FGIDs is reviewed as is human brain imaging, which provides a means for translating basic science to understanding FGID symptoms. Investigative evidence and emerging concepts implicate dysfunction in the nervous system as a significant factor underlying patient symptoms in FGIDs. Continued focus on neurogastroenterologic factors that underlie the development of symptoms will lead to mechanistic understanding that is expected to directly benefit the large contingent of patients and care-givers who deal with FGIDs. Neurogastroenterology is an emerging area of scientific and clinical subspecialization that was introduced in the early 1990s. Neurogastroenterology encompasses basic and clinical research dealing with function and dysfunction of the gastrointestinal (GI) tract and its neural innervation. In Rome II, attention was focused on the enteric nervous system (ENS) and neuroeffector mechanisms as they relate to functional gastrointestinal disorders (FGIDs).1Wood J.D. Alpers D.H. Andrews P.L.R. Fundamentals of neurogastroenterology basic science.in: Drossman D.A. Talley N.J. Thompson W.G. Corazziari E. Whitehead W.E. The functional gastrointestinal disorders: diagnosis, pathophysiology and treatment: a multinational consensus. Degnon Associates, McLean, VA2000: 31-90Google Scholar, 2Wood J.D. Alpers D.H. Andrews P.L.R. Fundamentals of neurogastroenterology.Gut. 1999; 45: II6-II16Crossref PubMed Google Scholar Also relevant are the central nervous system (CNS) mechanisms that process and interpret the incoming sensory information that gives rise to visceral pain and influence the autonomic sympathetic and parasympathetic outflows that, together with the ENS, control and coordinate digestive functions. Clinical gastroenterology translates basic discovery into the diagnosis and treatment of FGIDs and includes the impact of inflammation and psychological state on brain-gut interactions. This report continues the “fundamentals” with a primary focus on interactions of the brain, spinal cord, ENS, and gut and the relevance for abdominal pain and disordered GI function. GI afferents mediate reflexes that control motility, secretion, and blood flow and also modulate immune responses.3Beyak M.J. Bulmer D.C.E. Jiang W. Keating C.D. Rong W. Grundy D. Extrinsic sensory afferent nerves innervating the gastrointestinal tract.in: Johnson L.R. Barrett K.E. Ghishan F.K. Merchant J.L. Said H.M. Wood J.D. Physiology of the gastrointestinal tract. 4th ed. Elsevier, San Diego, CA2006: 685-726Google Scholar Moreover, sensory information reaching the CNS gives rise to both painful and nonpainful sensation and influences feeding and illness behavior. Heightened visceral sensitivity is a hallmark of FGIDs. Whether the hypersensitivity reflects transmission of aberrant sensory signals to the brain, normal signals that are interpreted inappropriately by the brain, or a combination of both remains an unresolved question. Vagal and spinal afferent nerve fibers transmit sensory information from the GI tract to the CNS. Vagal afferents have cell bodies in nodose ganglia and enter the brainstem. Cell bodies of spinal afferents are located in dorsal root ganglia and project to the dorsal horn of the spinal cord and the dorsal column nuclei. Spinal afferents are broadly subdivided into splanchnic and pelvic afferents that follow the paths of sympathetic and parasympathetic efferents to the gut wall. Somatic afferents, which innervate the striated musculature of the pelvic floor, project to the sacral spinal cord via the pudendal nerve. Peripheral endings of vagal and spinal sensory neurons terminate within the musculature, mucosal epithelium, and ganglia of the ENS.3Beyak M.J. Bulmer D.C.E. Jiang W. Keating C.D. Rong W. Grundy D. Extrinsic sensory afferent nerves innervating the gastrointestinal tract.in: Johnson L.R. Barrett K.E. Ghishan F.K. Merchant J.L. Said H.M. Wood J.D. Physiology of the gastrointestinal tract. 4th ed. Elsevier, San Diego, CA2006: 685-726Google Scholar Spinal afferents also terminate in the serosa and mesenteric attachments and form a dense network around mesenteric blood vessels and their intramural tributaries. Vagal afferent endings in the mucosa are in close association with the lamina propria adjacent to the mucosal epithelium, where they directly monitor the chemical nature of luminal contents either directly following passage across the epithelium or indirectly via paracrine input from enteroendocrine cells in the epithelium.3Beyak M.J. Bulmer D.C.E. Jiang W. Keating C.D. Rong W. Grundy D. Extrinsic sensory afferent nerves innervating the gastrointestinal tract.in: Johnson L.R. Barrett K.E. Ghishan F.K. Merchant J.L. Said H.M. Wood J.D. Physiology of the gastrointestinal tract. 4th ed. Elsevier, San Diego, CA2006: 685-726Google Scholar Luminal nutrients, for example, cross the epithelium by various transport mechanisms to reach the afferent nerve terminals in the lamina propria. In addition, luminal nutrients act before absorption to cause the release of messenger molecules (eg, cholecystokinin and serotonin [5-HT]) from enteroendocrine cells in the mucosa. These molecules in turn act on afferent terminals that lie in close proximity in the lamina propria.4Berthoud H.R. Kressel M. Raybould H.E. Neuhuber W.L. Vagal sensors in the rat duodenal mucosa distribution and structure as revealed by in vivo Di1-tracing.Anat Embryol (Berl). 1995; 191: 203-212Crossref PubMed Google Scholar, 5Kirkup A.J. Brunsden A.M. Grundy D. Receptors and transmission in the brain-gut axis: potential for novel therapies I. Receptors on visceral afferents.Am J Physiol. 2001; 280: G787-G794PubMed Google Scholar Vagal afferent endings in the GI wall are classified as either intramuscular arrays or intraganglionic laminar endings. Intramuscular arrays are distributed within the muscle sheets running parallel to the long axes of the muscle fibers,6Fox E.A. Phillips R.J. Martinson F.A. Baronowsky E.A. Powley T.L. Vagal afferent innervation of smooth muscle in the stomach and duodenum of the mouse morphology and topography.J Comp Neurol. 2000; 428: 558-576Crossref PubMed Scopus (64) Google Scholar where they appear to make direct contact with the muscle fibers and also form appositions with intramuscular interstitial cells of Cajal. Intraganglionic laminar endings are basket-like structures associated with myenteric ganglia in the ENS. The location of intraganglionic laminar endings between the circular and longitudinal muscle layers exposes them to the shearing forces generated during muscle stretch or contraction and determines their function as low-threshold mechanoreceptors.7Zagorodnyuk V.P. Chen B.N. Brookes S.J. Intraganglionic laminar endings are mechano-transduction sites of vagal tension receptors in the guinea-pig stomach.J Physiol. 2001; 534: 255-268Crossref PubMed Scopus (122) Google Scholar Intraganglionic laminar endings are also present in the pelvic supply to the rectal musculature.8Lynn P.A. Olsson C. Zagorodnyuk V. Costa M. Brookes S.J. Rectal intraganglionic laminar endings are transduction sites of extrinsic mechanoreceptors in the guinea pig rectum.Gastroenterology. 2003; 125: 786-794Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Their location in regions from which graded sensory experiences can arise in response to investigator-applied stimuli (eg, balloon distention) leads to a suggestion that these endings may signal nonpainful sensations of fullness. Spinal afferents have multiple receptive fields extending over relatively wide areas of bowel.3Beyak M.J. Bulmer D.C.E. Jiang W. Keating C.D. Rong W. Grundy D. Extrinsic sensory afferent nerves innervating the gastrointestinal tract.in: Johnson L.R. Barrett K.E. Ghishan F.K. Merchant J.L. Said H.M. Wood J.D. Physiology of the gastrointestinal tract. 4th ed. Elsevier, San Diego, CA2006: 685-726Google Scholar Afferent endings in the serosa and mesenteric attachments respond to distortion of the viscera during distention and contraction. Other endings detect changes in the submucosal chemical milieu following injury, ischemia, or infection and may play a role in generating hypersensitivity to distention and muscle contraction.5Kirkup A.J. Brunsden A.M. Grundy D. Receptors and transmission in the brain-gut axis: potential for novel therapies I. Receptors on visceral afferents.Am J Physiol. 2001; 280: G787-G794PubMed Google Scholar Intramural spinal afferent fibers have collateral branches that innervate blood vessels and enteric ganglia. These contain and release neurotransmitters during local axon reflexes that influence GI blood flow, motility, and secretory reflexes.9Maggi C.A. Meli A. The sensory-efferent function of capsaicin-sensitive sensory neurons.Gen Pharmacol. 1988; 19: 1-43Crossref PubMed Google Scholar Spinal afferents en route to the spinal cord also give off collaterals that innervate prevertebral sympathetic ganglia.10Szurszewski J.H. Miller S.H. Physiology of prevertebral sympathetic ganglia.in: Johnson L.R. Barrett K.E. Ghishan F.K. Merchant J.L. Said H.M. Wood J.D. Physiology of the gastrointestinal tract. 4th ed. Elsevier, San Diego, CA2006: 603-628Google Scholar The same sensory information is thereby transmitted to information-processing circuits in the spinal cord, ENS, and prevertebral ganglia. Calcitonin gene-related peptide and substance P are important neurotransmitters in this sensory pathway, and both of these peptides are implicated in the induction of neurogenic inflammation.11Holzer P. Neural regulation of gastrointestinal blood flow.in: Johnson L.R. Barrett K.E. Ghishan F.K. Merchant J.L. Said H.M. Wood J.D. Physiology of the gastrointestinal tract. 4th ed. Elsevier, San Diego, CA2006: 817-840Google Scholar Sensory transduction ultimately depends on the modulation of ion channels and/or receptors on the sensory nerve terminal.3Beyak M.J. Bulmer D.C.E. Jiang W. Keating C.D. Rong W. Grundy D. Extrinsic sensory afferent nerves innervating the gastrointestinal tract.in: Johnson L.R. Barrett K.E. Ghishan F.K. Merchant J.L. Said H.M. Wood J.D. Physiology of the gastrointestinal tract. 4th ed. Elsevier, San Diego, CA2006: 685-726Google Scholar Mechanosensitivity may arise indirectly following the release of chemical mediators such as adenosine triphosphate (ATP), which in turn can act on purinergic receptors present on afferent nerve terminals. Alternatively, there may be direct activation via mechanosensitive ion channels in the afferent nerve terminals.5Kirkup A.J. Brunsden A.M. Grundy D. Receptors and transmission in the brain-gut axis: potential for novel therapies I. Receptors on visceral afferents.Am J Physiol. 2001; 280: G787-G794PubMed Google Scholar Mechanical deformation of the nerve ending leads to the opening or closing of the ion channels, which depolarizes the terminal to threshold for action potential firing and transmission of the sensory information to the CNS. Vagal mechanoreceptors generally have low distention thresholds of activation, as indicated by responses to increases in distending pressures of a few millimeters of mercury and maximal firing frequencies occurring within physiologic levels of distention.3Beyak M.J. Bulmer D.C.E. Jiang W. Keating C.D. Rong W. Grundy D. Extrinsic sensory afferent nerves innervating the gastrointestinal tract.in: Johnson L.R. Barrett K.E. Ghishan F.K. Merchant J.L. Said H.M. Wood J.D. Physiology of the gastrointestinal tract. 4th ed. Elsevier, San Diego, CA2006: 685-726Google Scholar However, some vagal fibers can convey information about high-intensity mechanical stimulation and may also respond to noxious chemical stimulation.12Gebhart G.F. Pathobiology of visceral pain: molecular mechanisms and therapeutic implications IV. Visceral afferent contributions to the pathobiology of visceral pain.Am J Physiol. 2000; 278: G834-G838PubMed Google Scholar Spinal afferents are classified as low-threshold, high-threshold, or silent mechanoreceptors.13Sengupta J.N. Gebhart G.F. Gastrointestinal afferent fibers and sensation.in: Johnson L.R. Alpers D.H. Christensen J. Jacobson E.D. Walsh J.H. Physiology of the gastrointestinal tract. 3rd ed. Raven, New York, NY1994: 423-482Google Scholar Low-threshold afferents respond to physiologic levels of distention and continue to encode excessive levels of distention that evoke pain in humans and pain behavior in animals. High-threshold afferents respond to higher levels of distention that are in the noxious range. Silent nociceptors do not respond at all in the normal intestine but become responsive to distention when the intestine is injured or inflamed.12Gebhart G.F. Pathobiology of visceral pain: molecular mechanisms and therapeutic implications IV. Visceral afferent contributions to the pathobiology of visceral pain.Am J Physiol. 2000; 278: G834-G838PubMed Google Scholar This kind of receptor behavior illustrates how mechanosensitivity is not fixed, either in terms of the threshold for sensory activation or the relationship between stimulus and response. Injury and inflammation decrease the threshold and increase the magnitude of the response for a given stimulus, a phenomenon known as peripheral sensitization.14Cervero F. Laird J.M. Role of ion channels in mechanisms controlling gastrointestinal pain pathways.Curr Opin Pharmacol. 2003; 3: 608-612Crossref PubMed Scopus (26) Google Scholar Inflammatory sensitization underlies the perception of a normally innocuous stimulus as being painful and exaggerates the intensity of pain experienced during a painful stimulus (ie, hypersensitivity). Sensitizing mediators are released by a plethora of cell types, including blood platelets, leukocytes, lymphocytes, macrophages, mast cells, glia, fibroblasts, blood vessels, muscle, epithelial cells, and neurons. Several mediators can be released from a single cell type to act either directly on the sensory nerve terminal or indirectly by stimulating the release of agents from other cells in a series of cascades. A battery of chemical mediators, including biogenic amines, purines, prostanoids, proteases, and cytokines, act in a promiscuous manner on a range of receptors expressed on any one sensory ending. Three distinct processes are involved in the actions of these substances on visceral afferent nerves. First, by direct activation of receptors coupled to the opening of ion channels present on nerve terminals, the terminals are depolarized and firing of impulses is initiated. The second is by sensitization that develops in the absence of direct stimulation and results in hyperexcitability to both chemical and mechanical modalities. Sensitization may involve postreceptor signal transduction that includes G protein–coupled alterations in second messenger systems that in turn lead to phosphorylation of membrane receptors and ion channels that control excitability of the afferent endings. The third is by genetic changes in the phenotype of mediators, channels, and receptors expressed by the afferent nerve; for example, a change in the ligand-binding characteristics or coupling efficiency of newly expressed receptors might alter the sensitivity of the afferent terminals. Neurotrophins, in particular nerve growth factor and glial-derived neurotropic factor, influence different populations of visceral afferents and play an important role in adaptive responses to nerve injury and inflammation.15Barreau F. Cartier C. Ferrier L. Fioramonti J. Bueno L. Nerve growth factor mediates alterations of colonic sensitivity and mucosal barrier induced by neonatal stress in rats.Gastroenterology. 2004; 127: 524-534Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Peripheral sensitization can occur rapidly and be short-lived because the changes taking place at the level of the sensory nerve terminal are dependent on release of one or more algesic mediators. However, in the event of sustained tissue injury or inflammatory states, changes in gene expression can occur that prolong peripheral sensitization. These changes include alterations in those genes that determine the amount and pattern of neurotransmitters released from the sensory nerve terminals in the spinal cord and the brain, thereby altering the CNS processing of sensory information.5Kirkup A.J. Brunsden A.M. Grundy D. Receptors and transmission in the brain-gut axis: potential for novel therapies I. Receptors on visceral afferents.Am J Physiol. 2001; 280: G787-G794PubMed Google Scholar Peripheral sensitization integrated with central sensitization of this nature is undoubtedly a significant factor determining the sensations of abdominal pain and discomfort associated with FGIDs. Visceral afferents constitute only 10% of all afferent inflow into the spinal cord, yet they have widespread termination in laminae I, II, V, and X of the dorsal horn.16Ness T.J. Gebhart G.F. Visceral pain a review of experimental studies.Pain. 1990; 41: 167-234Abstract Full Text PDF PubMed Scopus (334) Google Scholar Input from visceral and somatic sensory fields converges onto the same neurons in the dorsal horn, dorsal column nuclei, and supraspinal centers.17Berkley K.J. Hubscher C.H. Wall P.D. Neuronal responses to stimulation of the cervix, uterus, colon, and skin in the rat spinal cord.J Neurophysiol. 1993; 69: 545-556PubMed Google Scholar, 18Al-Chaer E.D. Lawand N.B. Westlund K.N. Willis W.D. Visceral nociceptive input into the ventral posterolateral nucleus of the thalamus a new function for the dorsal column pathway.J Neurophysiol. 1996; 76: 2661-2674PubMed Google Scholar, 19Al-Chaer E.D. Lawand N.B. Westlund K.N. Willis W.D. Pelvic visceral input into the nucleus gracilis is largely mediated by the postsynaptic dorsal column pathway.J Neurophysiol. 1996; 76: 2675-2690PubMed Google Scholar, 20Al-Chaer E.D. Lawand N.B. Westlund K.N. Willis W.D. Pelvic visceral input into the nucleus gracilis is largely mediated by the postsynaptic dorsal column pathway.J Neurophysiol. 1996; 76: 2675-2690PubMed Google Scholar Viscerovisceral convergence of sensory information onto the same neurons also occurs in the spinal cord. For example, pelvic visceral inputs from colon and rectum, bladder, uterine cervix, and vagina all converge onto the same second-order spinal neurons.16Ness T.J. Gebhart G.F. Visceral pain a review of experimental studies.Pain. 1990; 41: 167-234Abstract Full Text PDF PubMed Scopus (334) Google Scholar, 17Berkley K.J. Hubscher C.H. Wall P.D. Neuronal responses to stimulation of the cervix, uterus, colon, and skin in the rat spinal cord.J Neurophysiol. 1993; 69: 545-556PubMed Google Scholar The low density of visceral nociceptors, the phenomenon of viscerovisceral convergence, and the functional divergence of visceral input within the CNS probably all contribute to the poor localization of visceral pain to a specific bodily region. Visceral nociceptive information is transmitted centrally via spinothalamic, spinohypothalamic, spinosolitary, spinoreticular, and spinoparabrachial tracts, all in the anterolateral quadrant of the spinal cord. In addition, a recently discovered pathway in the dorsal columns, which involves mainly postsynaptic neurons, is also involved in viscerosensory processing and visceral pain transmission.18Al-Chaer E.D. Lawand N.B. Westlund K.N. Willis W.D. Visceral nociceptive input into the ventral posterolateral nucleus of the thalamus a new function for the dorsal column pathway.J Neurophysiol. 1996; 76: 2661-2674PubMed Google Scholar, 19Al-Chaer E.D. Lawand N.B. Westlund K.N. Willis W.D. Pelvic visceral input into the nucleus gracilis is largely mediated by the postsynaptic dorsal column pathway.J Neurophysiol. 1996; 76: 2675-2690PubMed Google Scholar, 20Al-Chaer E.D. Lawand N.B. Westlund K.N. Willis W.D. Pelvic visceral input into the nucleus gracilis is largely mediated by the postsynaptic dorsal column pathway.J Neurophysiol. 1996; 76: 2675-2690PubMed Google Scholar, 21Al-Chaer E.D. Feng Y. Willis W.D. Comparative study of viscerosomatic input onto postsynaptic dorsal column and spinothalamic tract neurons in the primate.J Neurophysiol. 1999; 82: 1876-1882PubMed Google Scholar, 22Willis W.D. Al-Chaer E.D. Quast M.J. Westlund K.N. A visceral pain pathway in the dorsal column of the spinal cord.Proc Natl Acad Sci U S A. 1999; 96: 7675-7679Crossref PubMed Scopus (115) Google Scholar, 23Hirshberg R.M. Al-Chaer E.D. Lawand N.B. Westlund K.N. Willis W.D. Is there a pathway in the posterior funiculus that signals visceral pain?.Pain. 1996; 67: 291-305Abstract Full Text PDF PubMed Scopus (100) Google Scholar, 24Kim Y.S. Kwon S.J. High thoracic midline dorsal column myelotomy for severe visceral pain due to advanced stomach cancer.Neurosurgery. 2000; 46: 85-90Crossref PubMed Google Scholar, 25Al-Chaer E.D. Westlund K.N. Willis W.D. Nucleus gracilis an integrator for visceral and somatic information.J Neurophysiol. 1997; 78: 521-527PubMed Google Scholar Pain signals in the dorsal columns are then transmitted via the ipsilateral dorsal column nuclei (ie, nucleus gracilis and nucleus cuneatus) to the contralateral ventroposterolateral nucleus of the thalamus. Stimulation of the posterior columns in a patient with severe irritable bowel syndrome (IBS) evokes an immediate increase in the intensity of abdominal pain.27Malcolm A. Phillips S.F. Kellow J.E. Cousins M.J. Direct clinical evidence for spinal hyperalgesia in a patient with irritable bowel syndrome.Am J Gastroenterol. 2001; 96: 2427-2431Crossref PubMed Google Scholar The evidence suggests that dorsal column pathways have a major role in visceral nociceptive transmission. Central sensitization is believed to be the mechanism underlying secondary hyperalgesia, which is a phenomenon of increased pain sensitivity in regions distant to the site of injury or inflammation. Secondary hyperalgesia results from altered mechanisms of synaptic transmission in the spinal cord, which leads to a decrease in threshold, increased responsiveness, and an expansion of spinal neuronal receptive fields.28Al-Chaer E.D. Westlund K.N. Willis W.D. Sensitization of postsynaptic dorsal column neuronal responses by colon inflammation.Neuroreport. 1997; 8: 3267-3273Crossref PubMed Google Scholar Central sensitization might contribute to the visceral hypersensitivity to distention found in patients with IBS. The changes in synaptic transmission persist beyond the period of initial injury or inflammation and can be associated with altered bowel function.29Al-Chaer E.D. Kawasaki M. Pasricha P.J. A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development.Gastroenterology. 2000; 119: 1276-1285Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar, 30Saab C.Y. Park Y.C. Al-Chaer E.D. Thalamic modulation of visceral nociceptive processing in adult rats with neonatal colon irritation.Brain Res. 2004; 1008: 186-192Crossref PubMed Scopus (18) Google Scholar Glutamate and substance P are the main neurotransmitters released during the spinal processing of visceral pain. Both N-methyl-d-aspartate and non–N-methyl-d-aspartate glutamate receptors and neurokinin receptors are implicated in the synaptic mechanisms underlying central sensitization. At the level of the spinal cord, inputs from nonnociceptive and nociceptive afferent pathways interact to modify transmission of nociceptive information to higher brain centers. The brain itself has modulatory systems that affect the conscious perception of incoming sensory stimuli. Spinal visceral nociceptive transmission is subject to modification by descending modulatory influences from supraspinal structures (eg, periaqueductal gray, nucleus raphe magnus, locus ceruleus, nuclei reticularis gigantocellularis, and the ventrobasal complex of the thalamus). Descending modulation is sometimes inhibitory, facilitatory, or both, depending on the context of the visceral stimulus or the intensity of the descending signal.30Saab C.Y. Park Y.C. Al-Chaer E.D. Thalamic modulation of visceral nociceptive processing in adult rats with neonatal colon irritation.Brain Res. 2004; 1008: 186-192Crossref PubMed Scopus (18) Google Scholar The descending influence from the ventromedial medulla is mediated mainly by pathways traveling in the dorsolateral spinal cord31Zhuo M. Gebhart G.F. Facilitation and attenuation of a visceral nociceptive reflex from the rostroventral medulla in the rat.Gastroenterology. 2002; 122: 1007-1019Abstract Full Text Full Text PDF PubMed Google Scholar and can be inhibitory or facilitatory based on stimulus intensity. In contrast, descending control from the thalamus is context specific in that it may facilitate or inhibit spinal nociceptive processing depending on the presence or absence of central sensitization.31Zhuo M. Gebhart G.F. Facilitation and attenuation of a visceral nociceptive reflex from the rostroventral medulla in the rat.Gastroenterology. 2002; 122: 1007-1019Abstract Full Text Full Text PDF PubMed Google Scholar Serotonergic, noradrenergic, and, to a lesser extent, dopaminergic projections are major components of descending modulatory pathways. Exaggeration of descending facilitative signals from the brain may partly explain the visceral hypersensitivity that is found in a subset of patients with IBS.27Malcolm A. Phillips S.F. Kellow J.E. Cousins M.J. Direct clinical evidence for spinal hyperalgesia in a patient with irritable bowel syndrome.Am J Gastroenterol. 2001; 96: 2427-2431Crossref PubMed Google Scholar Conscious experience of sensation is a multifaceted process that involves a complex interaction between sensory-discriminative, affective, and cognitive dimensions. Functional brain imaging techniques make it possible to study the complex interaction between a number of cortical and subcortical areas involved in sensory experience and may in the future help determine whether sensory dysfunction in patients with FGIDs is due to disordered sensory detection and transmission in the periphery (eg, tissue injury or inflammation), aberrant processing of sensory information in the brain, or a combination of these peripheral and central factors. The functional brain imaging techniques of functional magnetic resonance imaging and positron emission tomography, both of which rely on measurements of blood flow in cortical and subcortical areas where increased metabolic activity occurs in response to sensory experience, are used to identify a network of brain areas that process GI sensation.32Aziz Q. Andersson J.L. Valind S. Sundin A. Hamdy S. Jones A.K. Foster E.R. Langstrom B. Thompson D.G. Identification of human brain loci processing esophageal sensation using positron emission tomography.Gastroenterology. 1997; 113: 50-59Abstract Full Text PDF PubMed Scopus (176) Google Scholar, 33Ladabaum U. Minoshima S. Hasler W.L. Cross D. Chey W.D. Owyang C. Gastric distention correlates with activation of multiple cortical and subcortical regions.Gastroenterology. 2001; 120: 369-376Abstract Full Te