Journal CMEs

Print Friendly 

Johanna M. Jarcho, MA, and Emeran A. Mayer, MD

Needs Assessment: Irritable bowel syndrome (IBS) affects up to 15% of the general population and has a major impact on patient quality of life. Psychosocial stressors play an important role in triggering first onset of symptoms and chronic symptom exacerbation. Understanding the association between IBS, stressful life events, and biological mechanisms of underlying altered stress responsiveness should aid physicians in the better treatment of symptoms.

Learning Objectives:

• Explain the general concepts of stress neurobiology and the central role of corticotropin-releasing factor in the integration of the stress response.


Identify evidence on the role of altered stress responsiveness in IBS.


• Evaluate cognitive-behavioral and pharmacologic therapy as IBS treatments that improve symptoms by normalizing enhanced stress responsiveness.


Target Audience: Primary care physicians and psychiatrists.


CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.


Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.


Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.


This activity has been peer-reviewed and approved by Eric Hollander, MD, chair at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: March 20, 2007.


Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.


To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME quiz. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged to measure outcomes for this CME activity. Please submit this posttest by April 1, 2009 to be eligible for credit. Release date: April 1, 2007. Termination date: April 30, 2009. The estimated time to complete all three articles and the quiz is 3 hours.


Primary Psychiatry. 2007;14(4):74-78

Ms. Jarcho is a graduate student in the Department of Psychology and Dr. Mayer is professor in the Departments of Medicine, Physiology, Psychiatry, and Biobehavioral Sciences at the University of California, Los Angeles.

Disclosures: Ms. Jarcho reports no affliation with or financial interest in any organization that may pose a conflict of interest. Dr. Mayer is a consultant to Avera, GlaxoSmithKline, and Novartis; is on the advisory board of GlaxoSmithKline; and receives grant support from Avera, GlaxoSmithKline, the National Institutes of Health, and Novartis.

Please direct all correspondence to: Emeran A. Mayer, MD, Neuroimaging Program, Center for Neurovisceral Sciences & Women’s Health, UCLA, VAGLAHS, Building 115, Room 223, 11301 Wilshire Blvd., Los Angeles, CA 90073; Tel: 310-312-9276; Fax: 310-794-2864; E-mail:


Pre-clinical, clinical, and epidemiologic data support a prominent role of psychosocial stressors in the manifestation of functional gastrointestinal disorders, including irritable bowel syndrome (IBS). Advances in the understanding of stress response and interactions between the brain and digestive system (“brain-gut interactions”) are providing a neurobiologic framework to understanding symptom generation and treatment effects in IBS. This article reviews the current understanding of the central stress response and emotional motor system to provide an overview of studies supporting alterations of these responses in IBS. In addition, the article reviews clinical implications of these concepts.


With an estimated prevalence rate of 10% to 15% in industrialized countries, irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal (GI) disorders.1 IBS is characterized by chronic abdominal pain or discomfort associated with altered bowel habits in the absence of demonstrable structural abnormalities.2 As with other stress sensitive pain disorders (eg, fibromyalgia, chronic pelvic pain), women are more likely affected by IBS than men.3 IBS patients have a profound impairment in health-related quality of life4 and often suffer comorbid psychiatric disorders with anxiety-related disorders being the most prevalent.5

Epidemiologic data suggest that stress plays a prominent role in first onset and exacerbation of established IBS symptoms.6 Vulnerability to the development of IBS or IBS-like symptoms increases with exposure to severe stressors early in life7 and with exposure to major stressful life events at the time of a documented gastroenteric infection (called “postinfectious IBS”).8 Despite much clinical and epidemiologic evidence for the association between psychosocial stressors and IBS, the psychiatric field has remained skeptical on psychological symptom explanations. However, major advances in the understanding of the neurobiology of stress9 as well as the intricate relationship between central stress circuits and GI function6 have resulted in an acceptance of the concept that central stress mediators play a critical role in the cardinal symptoms of IBS. This article reviews the neurobiologic pathways by which stress may affect IBS symptoms, and discusses treatment strategies aimed at modulating these potentially dysfunctional pathways.

The Stress Response

Stress—defined as a real (physical) or perceived (psychological) acute threat to the homeostasis of an organism due to external or internal events—evokes adaptive responses that defend the stability of the internal environment, which assures survival of the organism. This ability to defend homeostasis or maintain stability through change is referred to as allostasis.10

Central stress circuits form a complex neurobiologic system, which comprises multiple brain regions that communicate with one another through positive and negative feedback loops.11 The hypothalamic-pituitary-adrenal (HPA) axis is a critical stress circuit that controls release of glucocorticoids via corticotropin-releasing factor (CRF). CRF, a neuropeptide secreted by neurons in the paraventricular nucleus (PVN) of the hypothalamus and central nucleus of the amygdala, plays a central role in triggering and integrating the central stress response. Noradrenergic inputs from the locus coeruleus to the PVN promote the synthesis and release of CRF.12 Thus, the locus coeruleus receives CRF inputs from the central nucleus of the amygdala, a brain region responsive to threat, which activates noradrenergic input production in the locus coeruleus. Ascending outputs from the locus coeruleus to various forebrain regions, including the prefrontal cortex and the anterior cingulate cortex, play a prominent role in the generation of autonomic and emotional arousal. Hypothalamic CRF binds to receptors at the anterior pituitary gland and stimulates proopiomelanocortin (POMC)-producing cells to release b-endorphin and adrenocorticotrophin (ACTH). ACTH promotes the synthesis and release of glucocorticoids from the adrenal cortex. Following acute stress, glucocorticoids provide negative feedback, which inhibit the biosynthesis and release of CRF in the PVN and ACTH in the anterior pituitary resulting in the termination of stress-induced HPA activation.13

Due to receiving converging inputs from multiple areas of the brain, CRF neurons in the PVN and amygdala are a final common stress pathway that coordinates behavioral, neuroendocrine, and autonomic responses to stress via the emotional motor system (EMS).14 Afferent inputs to the central stress circuits include ascending projections from the brainstem that relay visceral sensory information and descending cortical and limbic pathways, which relay cognitive and emotional information.15 Cortical circuits play an important role in adjusting stress response to the context, the organism’s physiological state, memories of past stressful life events, and beliefs on the subjective meaning of the situation.

The multiple, parallel outputs of the central stress system to various organs and body systems have been referred to as the EMS (Figure).7 These outputs include branches of the autonomic nervous system (ANS), the HPA axis, endogenous pain modulation systems, and neural outputs to the skeletomotor system. Activation of the EMS by a stressor may or may not be associated with a conscious emotional feeling (eg, anxiety or fear). For example, a stressor may produce all the physical manifestations of the stress response, but this physical response may be associated with the feeling of anxiety in one circumstance but not another.

CRF released centrally in response to physical and emotional stressors results in the inhibition of the upper GI tract, stimulation of distal GI motility, secretion and transit (via the ANS), increase in visceral sensitivity (via endogenous pain modulation systems), and suppression of gut immune activity (and increase in HPA axis activity). These GI manifestations of the CRF-induced central stress circuit activation mimic many IBS symptoms, such as visceral hypersensitivity, altered GI transit and secretion, and altered mucosal immune activity.6,16

In the face of severe, prolonged, or chronic stressors, the normally adaptive physiological response to stress can cause damage, exacerbate existing disease, or increase vulnerability to new diseases, becoming maladaptive. These long-term effects of the organism’s accommodation to certain stressors is referred to as allostatic load.17 Stress responses characteristic of allostatic load include blunted or elevated activity in the central system following stress or under basal conditions.17 Early life stress,18 chronic physical or sexual abuse or neglect throughout life, and exposure to a one-time stressor that is perceived as life threatening (eg, rape, combat, or natural disaster),19 have all been associated with development of allostatic load. Whether such “wear and tear” on the central stress circuits results in a dysfunctional stress response, however, is determined not only by the length, severity, and type of stressor experienced by an individual, but also by factors such as genetics, capacity to cope, and environmental support. Literature has described such risk factors to be present in IBS patients.20-22

Stress and IBS

A variety of stressors play a role in the development of IBS and the symptom experience among affected patients. There is a substantial overlap in the type of stressors associated with allostatic load and those that affect IBS symptoms. Epidemiologic data indicate that physical, sexual, and psychological abuse are more common among patients with IBS than in the general population,23 which suggests that severe stress experienced as an adult, but particularly during childhood, may increase the likelihood of developing IBS. Similar to allostatic load, individual differences in genetic predisposition and coping style may increase IBS susceptibility. For example, psychological stress, such as the break-up of a close relationship,24 or physical stress, including interoceptive stressors of the digestive system,25 normally cause transient alterations in stress responsiveness, but can trigger the onset of IBS symptoms in a subset of individuals. Patients already affected by IBS commonly report an exacerbation of symptoms when faced with these stressors.26 Finally, for many IBS patients, the chronic positive feedback loop of conditioned fear responses to interoceptive stimuli or contextually conditioned stimuli of symptom-generated stressors may play a primary role in symptom chronicity.27 This article briefly reviews evidence supporting the presence of alterations in central stress circuits and EMS output in IBS.

Alterations of HPA Axis Function in IBS

Although not entirely consistent, numerous studies have described altered HPA system function in IBS patients.28 Under basal conditions, patients with IBS have elevated serum cortisol at mid-day29 and urine cortisol in the evening,30 but blunted 24-hour salivary cortisol31,32 and plasma CRF levels.33 Perceptual hypersensitivity to noxious rectosigmoid stimulation has been shown to be associated with elevated CRF, ACTH, and cortisol responses in some studies,33,34 and blunted cortisol responses and normal ACTH responses in other studies.31,33 Moreover, psychological stressors produce greater elevation of CRF and ACTH levels in IBS patients than in control groups.31,35 Although inconsistent in directionality, the reported patterns of HPA system alteration are consistent with outcomes derived from allostatic load.17

Alterations in ANS Function in IBS

Psychological, interoceptive, and cutaneous stress result in a greater acceleration in transit for IBS patients than in control groups8,36 as well as prolonged reduction of rectomucosal blood flow,37 which suggests an exaggerated and protracted ANS response to stress. IBS patients and non-patients also have different cardioautonomic responses to interoceptive stress.38 The hyper-responsiveness of gut motility and blood flow to various stressors and alterations in cardioautonomic tone may be related to heightened responsiveness of the ANS. This finding is illustrated by the greater colonic motility and greater colonic suppression in IBS patients in response to exogenous CRF39 and CRF receptor antagonists,40 respectively. In addition, persistence of inflammatory mucosal changes after eradication of infectious organisms41 and increased intestinal permeability and hyperplasia of enterochromaffin cells in patients with post-infectious IBS may be partially related to altered ANS function.42

Alterations in Endogenous IBS Pain Modulation

Studies confirm that IBS patients show enhanced perceptual responses to visceral stimuli (“visceral hypersensitivity”).43,44 IBS patients have lower rectal and sigmoid colon discomfort thresholds and report greater intensity and unpleasantness ratings during distension than non-patients.45,46 This is particularly true when distension is paired with noxious somatic stimulation.37 Whether IBS patients have generalized abnormalities in pain perception, however, has been a topic of controversy. Compared to non-patients, IBS patients had decreased sensitivity to various somatic stimuli (eg, electrical stimulation, heat, cold, and pressure) in some studies,47,48 and hyperalgesia in other studies.49,50 These differences may be related to variability in experimental protocols and patient selection. For example, the presence of fibromyalgia, a functional pain condition commonly seen in conjunction with IBS, is likely to alter somatic pain sensitivity in IBS patients, which leads to somatic pain thresholds lower than those observed in controls.47

Functional brain imaging has identified alterations in the central nervous system that further suggest the hypersensitivity to visceral stimuli that IBS patients experience is associated with central inhibitory deficits.51 The brain can both inhibit and facilitate spinal cord excitability thereby regulating the amount of peripheral sensory information reaching the central nervous system. Neuroimaging studies have demonstrated that while IBS patients and non-patients activate similar brain regions in response to rectosigmoidal stimulation, activation is greater for IBS patients in a subset of regions with functional connections to the HPA axis. These regions are associated with the upregulation of attention as well as the experience of unpleasantness and threat, including the dorsal anterior cingulate cortex, hypothalamus, and amygdala.52-54 In anticipation of rectal stimulation, healthy women inhibit activity in these similar brain regions, while IBS patients do not. This anticipatory decrease in activity is associated with the activation of brain regions during rectosigmoidal stimulation, which are known to inhibit negative affect and reduce pain.55 Decreased activation in the dorsal pons of IBS patients during stimulation also suggests deficits in descending pain modulation systems.53 Together, data indicate that patients may have increased affective and attentional responses to actual or anticipated visceral stimuli (hypervigilance) as well as a decreased capacity to inhibit descending pain.

Evidence suggests that IBS patients are hypersensitive to visceral stimuli and that central stress circuits play an important role in facilitating this sensitization.

Clinical Implications

If hyper-responsiveness of central stress circuits play an important role in IBS symptoms, therapeutic approaches that are successful in treating other stress-sensitive disorders should also be effective in treating IBS patients. Centrally acting drugs, such as benzodiazepines, tricyclic antidepressants, selective serotonin reuptake inhibitors, and norepinephrine serotonin reuptake inhibitors are commonly used for IBS treatment and are considered effective therapies. However, their effectiveness is typically not strongly supported by clinical trials.56 Results from studies using the cognitive-behavioral approach to treatment suggest that, in selected patient populations, these strategies may be equally effective as available pharmacologic approaches.57 Based on the pathophysiologic concept, cognitive-behavioral therapy (CBT) and centrally targeted pharmacologic approaches may be effective because both approaches result in a normalization of central stress responsiveness, albeit through different mechanisms. While CBT enhances inhibitory cortical (or cognitive) control of hyperactive limbic circuits, centrally targeted pharmacologic therapies may directly reduce limbic hyperactivity. As demonstrated for psychiatric disorders including the treatment of depression, the combination of CBT and pharmacologic approaches may have synergistic therapeutic effects on symptoms.58 Recently developed antagonists aimed at the central neurokinin 1 and CRF receptors are currently being evaluated in early clinical trials.56 If successful in reducing IBS symptoms, these results would strongly support the crucial role of stress hyper-responsiveness in IBS pathophysiology.


Epidemiologic and pre-clinical evidence supports an important role of stress in the pathophysiology of IBS. Many of the symptoms and systemic alterations in IBS patients can be seen as GI manifestations of enhanced central stress response circuits. Genetic and environmental risk factors associated with enhanced stress responsiveness and vulnerability to IBS-specific symptoms are likely critical in explaining the overall syndrome. Therapies aimed at normalizing enhanced stress responsiveness, and thereby IBS symptoms, include CBT as well as recently developed pharmacologic therapies that target signaling systems involved in the central stress response, such as neurokinin 1, CRF receptor antagonists, and non-selective reuptake inhibitors. PP


1. American College of Gastroenterology Functional Gastrointestinal Disorders Task Force. Evidence-based position statement on the management of irritable bowel syndrome in North America. Am J Gastroenterol. 2002;97(11 suppl):S1-S5.

2. Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 2006;130(5):1377-1390.

3. Saito YA, Schoenfeld P, Locke GR 3rd. The epidemiology of irritable bowel syndrome in North America: a systematic review. Am J Gastroenterol. 2002;97(8):1910-1915.

4. Spiegel BM, Gralnek IM, Bolus R, et al. Clinical determinants of health-related quality of life in patients with irritable bowel syndrome. Arch Intern Med. 2004;164(16):1773-1780.

5. Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology. 2002;122(4):1140-1156.

6. Mayer EA. The neurobiology of stress and gastrointestinal disease. Gut. 2000;47(6):861-869.

7. Mayer EA, Naliboff BD, Chang L, Coutinho SV. V. Stress and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2001;280(4):G519-G524.

8. Gwee KA, Collins SM, Read NW, et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut. 2003;52(4):523-526.

9. Tache Y, Martinez V, Wang L, Million M. CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity: implications for irritable bowel syndrome. Br J Pharmacol. 2004;141(8):1321-1330.

10. Sterling P, Eyer J. Allostasis: a new paradigm to explain arousal pathology. In: Fisher S, Reason J, eds. Handbook of Life Stress, Cognition, and Health. New York, NY: John Wiley & Sons; 1988:629-649.

11. Makino S, Hashimoto K, Gold PW. Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress. Pharmacol Biochem Behav. 2002;73(1):147-158.

12. Plotsky PM, Cunningham ET Jr, Widmaier EP. Catecholaminergic modulation of corticotropin-releasing factor and adrenocorticotropin secretion. Endocr Rev. 1989;10(4):437-458.

13. Canny BJ, Funder JW, Clarke IJ. Glucocorticoids regulate ovine hypophysial portal levels of corticotropin-releasing factor and arginine vasopressin in a stress-specific manner. Endocrinology. 1989;125(5):2532-2539.

14. Holstege G, Bandler R, Saper CB, eds. The Emotional Motor System. Amsterdam, the Netherlands: Elsevier Publishing Company; 1996:3-6.

15. Sawchenko PE, Brown ER, Chan RK, et al. The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress. Prog Brain Res. 1996;107:201-222.

16. Valentino RJ, Miselis RR, Pavcovich LA. Pontine regulation of pelvic viscera: pharmacological target for pelvic visceral dysfunction. Trends Pharmacol Sci. 1999;20(6):253-260.

17. McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338(3):171-179.

18. Ladd CO, Huot RL, Thrivikraman KV, et al. Long-term behavioral and neuroendocrine adaptations to adverse early experience. In: Mayer EA, Saper CB, eds. The Biological Basis for Mind Body Interactions, Vol. 122. Amsterdam, the Netherlands: Elsevier Publishing Company; 2000:81-103.

19. Stam R, Akkermans LM, Wiegant VM. Trauma and the gut: interactions between stressful experience and intestinal function. Gut. 1997;40(6):704-709.

20. Lackner JM, Gurtman MB. Pain catastrophizing and interpersonal problems: a circumplex analysis of the communal coping model. Pain. 2004;110(3):597-604.

21. Park MI, Camilleri M. Genetics and genotypes in irritable bowel syndrome: implications for diagnosis and treatment. Gastroenterol Clin North Am. 2005;34(2):305-317.

22. Locke GR 3rd, Weaver AL, Melton LJ 3rd, Talley NJ. Psychosocial factors are linked to functional gastrointestinal disorders: a population based nested case-control study. Am J Gastroenterol. 2004;99(2):350-357.

23. Talley NJ, Fett SL, Zinsmeister AR, Melton LJ 3rd. Gastrointestinal tract symptoms and self-reported abuse: a population-based study. Gastroenterology. 1994;107(4):1040-1049.

24. Creed F, Craig T, Farmer R. Functional abdominal pain, psychiatric illness, and life events. Gut. 1988; 29(2):235-242.

25. Spiller RC. Postinfectious irritable bowel syndrome. Gastroenterology. 2003;124(6):1662-1671.

26. Bennett EJ, Tennant CC, Piesse C, Badcock CA, Kellow JE. Level of chronic life stress predicts clinical outcome in irritable bowel syndrome. Gut. 1998;43(2):256-261.

27. Fendt M, Fanselow MS. The neuroanatomical and neurochemical basis of conditioned fear. Neurosci Biobehav Rev. 1999;23(5):743-760.

28. Chang L. Neuroendocrine and neuroimmune markers in IBS: pathophysiological role or epiphenomenon? Gastroenterology. 2006;130(2):596-600.

29. Dinan TG, Barry S, Ahkion S, Chua A, Keeling PW. Assessment of central noradrenergic functioning in irritable bowel syndrome using a neuroendocrine challenge test. J Psychosom Res. 1990;34(5):575-580.

30. Heitkemper M, Jarrett M, Cain K, et al. Increased urine catecholamines and cortisol in women with irritable bowel syndrome. Am J Gastroenterol. 1996;91(5):906-913.

31. Munakata J, Mayer EA, Chang L, et al. Autonomic and neuroendocrine responses to recto-sigmoid stimulation. Gastroenterology. 1998;114(suppl 1):A808.

32. Bohmelt AH, Nater UM, Franke S, Hellhammer DH, Ehlert U. Basal and stimulated hypothalamic-pituitary-adrenal axis activity in patients with functional gastrointestinal disorders and healthy controls. Psychosom Med. 2005;67(2):288-294.

33. Posserud I, Agerforz P, Ekman R, Bjornsson ES, Abrahamsson H, Simren M. Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress. Gut. 2004;53(8):1102-1108.

34. Walter SA, Aardal-Eriksson E, Thorell LH, Bodemar G, Hallbook O. Pre-experimental stress in patients with irritable bowel syndrome: high cortisol values already before symptom provocation with rectal distensions. Neurogastroenterol Motil. 2006;18(12):1069-1077.

35. Elsenbruch S, Lucas A, Holtmann G, et al. Public speaking stress-induced neuroendocrine responses and circulating immune cell redistribution in irritable bowel syndrome. Am J Gastroenterol. 2006;101(10):2300-2307.

36. Mayer EA, Craske M, Naliboff BD. Depression, anxiety, and the gastrointestinal system. J Clin Psychiatry. 2001;62(suppl 8):28-36.

37. Murray CD, Flynn J, Ratcliffe L, Jacyna MR, Kamm MA, Emmanuel AV. Effect of acute physical and psychological stress on gut autonomic innervation in irritable bowel syndrome. Gastroenterology. 2004;127(6):1695-1703.

38. Tillisch K, Mayer EA, Labus JS, Stains J, Chang L, Naliboff BD. Sex specific alterations in autonomic function among patients with irritable bowel syndrome. Gut. 2005;54(10):1396-1401.

39. Fukudo S, Nomura T, Hongo M. Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome. Gut. 1998;42(6):845-849.

40. Sagami Y, Shimada Y, Tayama J, et al. Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome. Gut. 2004;53(7):958-964.

41. Gwee KA, Leong YL, Graham C, et al. The role of psychological and biological factors in postinfective gut dysfunction. Gut. 1999;44(3):400-406.

42. Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. 2000;47(6):804-811.

43. Naliboff B, Mayer EA. Sensational developments in the irritable bowel. Gut. 1996;39(5):770-771.

44. Whitehead WE, Palsson OS. Is rectal pain sensitivity a biological marker for irritable bowel syndrome: psychological influences on pain perception. Gastroenterology. 1998;115(5):1263-1271.

45. Whitehead WE, Holtkotter B, Enck P, et al. Tolerance for rectosigmoid distention in irritable bowel syndrome. Gastroenterology. 1990;98(5 pt. 1):1187-1192.

46. Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA. Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology. 1995;109(1):40-52.

47. Chang L, Mayer EA, Johnson T, FitzGerald LZ, Naliboff B. Differences in somatic perception in female patients with irritable bowel syndrome with and without fibromyalgia. Pain. 2000;84(2-3):297-307.

48. Accarino AM, Azpiroz F, Malagelada JR. Selective dysfunction of mechanosensitive intestinal afferents in irritable bowel syndrome. Gastroenterology. 1995;108(3):636-643.

49. Verne GN, Robinson ME, Price DD. Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome. Pain. 2001;93(1):7-14.

50. Rodrigues AC, Nicholas Verne G, Schmidt S, Mauderli AP. Hypersensitivity to cutaneous thermal nociceptive stimuli in irritable bowel syndrome. Pain. 2005;115(1-2):5-11.

51. Mayer EA, Naliboff BD, Craig AD. Neuroimaging of the brain-gut axis: from basic understanding to treatment of functional GI disorders. Gastroenterology. 2006;131(6):1925-1942.

52. Silverman DH, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology. 1997;112(1):64-72.

53. Naliboff BD, Derbyshire SW, Munakata J, et al. Cerebral activation in patients with irritable bowel syndrome and control subjects during rectosigmoid stimulation. Psychosom Med. 2001;63(3):365-375.

54. Derbyshire SW. A systematic review of neuroimaging data during visceral stimulation. Am J Gastroenterol. 2003;98(1):12-20.

55. Berman SM, Naliboff BD, Suyenobu B, et al. Abnormal CNS response to anticipation of visceral distention in female patients with irritable bowel syndrome (IBS): an fMRI study. Paper presented at: Annual Meeting of Digestive Diseases Week; May 23, 2006; Los Angeles, California.

56. Mayer EA, Tillisch K, Bradesi S. Modulation of the brain-gut axis as a therapeutic approach in gastrointestinal disease. Aliment Pharmacol Ther. 2006;24(6):919-933.

57. Lackner JM, Mesmer C, Morley S, Dowzer C, Hamilton S. Psychological treatments for irritable bowel syndrome: a systematic review and meta-analysis. J Consult Clin Psychol. 2004;72(6):1100-1113.

58. Keller MB, McCullough JP, Klein DN, et al. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med. 2000;342(20):1462-1470.