Further Characterization of Human Brain Processing of Viscero-Sensation: The Role of Gender and a Word of Caution

See article on page 1738.

A series of recent studies have indicated measurable,gender-related, differences in human brain activity

in response to visceral and somatic stimulation. Thesefindings are mainly due to a better understanding of theinteraction between the gastrointestinal tract and thecerebral cortex facilitated by recent advances in brainimaging technologies such as positron emission tomog-raphy (PET) and functional magnetic resonance imaging(fMRI). A considerable amount of investigative effortusing these new technologies has been directed at a morethorough understanding of irritable bowel syndrome(IBS). An example of one of these interesting studiesappears in this issue of GASTROENTEROLOGY. The thrustof this article by Naliboff et al.,1 further elaborates thedifferences in cortical response between genders duringperceived rectal distention in IBS patients. Gender-re-lated differences in brain response to lower gut stimula-tion in healthy individuals,2 as well as IBS patients3 havebeen reported previously. The findings of the presentarticle corroborates the reproducibility of some but notall of these previous findings in IBS patients. Although,from the recent body of work emerges a clearer outline ofneurophysiologic and perception-related processes thatmay help explain gender differences in the prevalence offunctional bowel disorders, our enthusiasm in interpret-ing these findings must be tempered by realizing thelimitations of available brain imaging techniques.

It is important to remember that there is considerabledisagreement in the published data concerning the gen-eral features of cortical response to visceral stimulation inboth healthy, as well as patient, populations. Further-more, gender differences in cortical response to somato-sensation have also been reported previously,4 however,similar to studies of viscero-sensation, there exists dis-agreement among these studies with regard to gender-related differences in regions of brain activity.5,6 Thesediscrepancies must further mitigate our interpretation ofthe results obtained using current brain imaging modal-ities and experimental methods used in these investiga-tions.

Interpretation of the results of brain imaging studiesof viscero-sensation using distention protocols entailsseveral methodological concerns. (A) Spatial resolution ofthe imaging modality may not be adequate for precise

assignment of observed cortical activity to a particularanatomic region. For example, the blood flow increasesmeasured using PET occur within 3 to 5 mm of theactivated neurons.7,8 These spatial limitations are withinthe window of distances that separate many corticalstructures. (B) Speculation on the network and sequenceof cortical activity in response to rectal distention wouldrequire an imaging system rapid enough to delineate theinitiation of brain activity in temporal domains that liefar below the 1–3 second time lag of PET responsesignals. Even fMRI with its better spatial (approximately1 mm) and temporal (40–100 microseconds for a singleecho planar slice) resolution would be hard pressed tosystematically dissect the cortical network activated dur-ing visceral stimulation. These limitations thereforeshould be considered in any discussion to avoid specificassignment of the activated cortical regions that may bebeyond the resolution of the technique. (C) With regardto visceral stimulation using distention techniques, theability to deliver a comparable distention pressure ap-plied to the gut wall is an important consideration forinterpretation of the obtained brain imaging results.Interpretation of the observed brain activity in responseto gut distention may not be reliable if the similarity ofthe applied pressure among groups cannot be ascer-tained. The most commonly used devices for applying apressure stimulus to the rectal wall are a controllablepressure delivery system such as a computer-controlledbarostatic air pump and a catheter-affixed, distensiblechamber such as an elastic balloon or infinitely compliantbag. The distending devices used in the brain imagingstudies of rectal distention reported in the literatureconsist of either infinitely compliant polyethylenebags2,9,10 or latex balloons.3,11–15 Great care must betaken if the pressure within the bag or balloon is beingused as a quantifier of the force per unit area applied tothe rectal wall. In the case of a latex balloon, the momentthe balloon begins to stretch, there is a residual pressuregenerated within the balloon that is reflective of thephysical characteristics of the balloon wall rather thanthe rectal wall. Alternatively, an infinitely compliantpolyethylene bag that is large enough to expand to therectal walls generates no residual pressure within the bagthus any pressure reading from within the bag is a directmeasure of the force per unit area on the rectal wall. Ifthe polyethylene bag is used, it must be of sufficientvolume to fill the rectal chamber without reaching the

June 2003 EDITORIALS 1975

distensible limit of the bag since, at this limit, thematerial characteristics of the bag contribute greatly tothe measured intra-bag pressure. (D) Applying the sameintra-balloon pressure results in distention of the balloonto a fixed diameter. At this diameter, the pressure ap-plied to the intestinal wall is influenced by the diameterof the organ in which the balloon is inflated. Theoreti-cally, since the organ diameter may vary in individuals,the pressure applied to the organ wall using such a fixedballoon diameter may not be the same among studiedsubjects and may therefore produce a different response.(E) Another issue for consideration relates to potentialinfluence of differences in the background of the studysubjects. This difficulty mainly includes the heteroge-neous background of subjects in terms of emotional state,psychological conditions, and previous life experiencesthat can influence a subject’s response to an experimentalprotocol such as rectal distention. These difficulties mayexplain some of the reasons that, at times, similarlydesigned experiments performed in a similar group ofpatients have yielded different results. Applying moredetailed selection criteria, possibly including standardtesting, may help select a more uniform study popula-tion.

In addition to these difficulties, there is considerabledisagreement and confusion in the published literatureregarding the cortical distribution of activity associatedwith rectal distention in health and disease, as well asbetween genders. While activation of the anterior cin-gulate gyrus (ACG), insula, prefrontal and sensory cor-tices have been reported in response to rectal distentionin various studies the findings have not been in concor-dance with regard to the distribution and intensity ofthese regional cortical activities. For example, in thecurrent study by Naliboff et al., the authors report“trends” toward gender-related differences in greater ac-tivation of the insula in males compared to no significantactivation of this cortical region in females. This findingis consistent with previous reports in a smaller group ofIBS patients3 but is in contrast to observations in alargely female (16 women and 2 men) group of IBSpatients9 and in healthy controls using fMRI2 whereininsular activity in females was reported to be associatedwith perceived rectal distention. These inconsistenciescould be due to differences in recording techniques,stimulation methods, the intensity of stimuli, as well asthe applied statistical criteria making direct comparisonbetween these studies difficult. Despite these difficulties,there is no doubt that there are some gender-relateddifferences in the cortical activity associated with viscero-sensation in both healthy individuals, as well as IBS

patients. The pathophysiological role of these differences,if any, in the higher prevalence of IBS among females,remains to be elucidated.

There has been considerable advancement in our un-derstanding of intestinal viscero-sensation since the ad-vent of modern brain imaging techniques; however, im-portant issues and critical questions remain unexamined.Arriving at a consensus on the key issues regarding thelimitations and discrepancies alluded to above will allowfor a more direct comparison of future studies and facil-itate more rapid acquisition of necessary information.Some of these issues include comparable distentionmethods, uniform patient psychological screening tech-niques, and limiting criteria that are sensitive to thespatial and temporal limitations of the imaging modalityfor identifying regions of cortical activity. The existenceof, as yet, unexamined issues as well as the need to cometo a consensus on critical matters of experimental designnecessitates an underlying philosophy of restraint andcaution when interpreting the results of functional brainimaging studies.

MARK KERNREZA SHAKERDigestive Disease CenterDivision of Gastroenterology and HepatologyMedical College of WisconsinMilwaukee, Wisconsin

References1. Naliboff BD, Berman S, Chang L, Derbyshire SWG, Suyenobu B,

Vogt BA, Mandelkern M, Mayer EA. Sex-related differences in IBSpatients: central processing of visceral stimuli. Gastroenterology2003;124:1738–1747.

2. Kern MK, Jaradeh S, Arndorfer RC, Jesmanowicz A, Hyde J,Shaker R. Gender differences in cortical representation of rectaldistension in healthy humans. Am J Physiol 2001;281:G1512–G1523.

3. Berman S, Munakata J, Naliboff BD, Chang L, Mandelkern M,Silveman D, Kovalik E, Mayer EA. Gender differences in regionalbrain response to visceral pressure in IBS patients. Eur J Pain2000;4:157–172.

4. Paulson PE, Minoshima S, Morrow TJ, Casey KL. Gender differ-ences in pain perception and patterns of cerebral activationduring noxious heat stimulation in humans. Pain 1998;76:223–229.

5. Beccerra I, Comite A, Breiter H, Gonzalez RG, Borsook D. Differ-ential CNS activation following a noxious thermal stimulus in menand women. Soc Neurosci Abstr 1998;24:1136.

6. Derbyshire SWG, Jones AKP, Townsend D, Gyulai F, Smith GS,Firestone L. Gender differences in the central response to paincontrolled for stimulus intensity. Soc Neurosci Abstr 1998;24:528.

7. Malonek D, Dirnagl U, Lindauer U, Yamada K, Kanno I, Grinvald A.Vascular imprints of neuronal activity: relationship between thedynamics of cortical blood flow, oxygenation and volume changesfollowing sensory stimulation. Proc Natl Acad Sci U S A 1997;94:14826–14831.

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8. Kinehan PE, Noll DC. A direct comparison between whole-brainPET and BOLD fMRI measurements of single-subject activationresponse. NeuroImage 1999;9:430–438.

9. Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, KesslerR. Regional cerebral activation in irritable bowel syndrome andcontrol subjects with painful and nonpainful rectal distension.Gastroenterology 2000;118:842–848.

10. Bouras EP, O’Brien TJ, Camilleri M, O’Conner MK, Mullan BP.Cerebral topography of rectal stimulation using single photonemission tomography. Am J Physiol 1999;277:G687–G694.

11. Baciu MV, Bonaz BL, Papillon E, Bost RA, LeBas JF, Fournet J,Segebarth CM. Central processing of rectal pain: a functional MRimaging study. Am J Neuroradiol 1999;20:1920–1924.

12. Hobday DI, Aziz Q, Thacker N, Hollander I, Jackson A, ThompsonDG. A study of the cortical processing of ano-rectal sensationusing functional MRI. Brain 2001;124:361–368.

13. Lotze M, Wietek B, Birbaumer N, Ehrhardt J, Grodd W, Enck P.

Cerebral activation during anal and rectal stimulation. NeuroIm-age 2001;14:1027–1034.

14. Bonaz B, Baciu M, Papillon E, Bost R, Gueddah N, LeBas JF,Fournet J, Segebarth C. Central processing of rectal pain inpatients with irritable bowel syndrome: an fMRI study. Am JGastroenterol 2002;97:654–661.

15. Silverman DHS, Munakata JA, Ennes H, Mandelkern MA, Hoh CK,Mayer EA. Regional cerebral activity in normal and pathologicalperception of visceral pain. Gastroenterology 1997;112:64–72.

Address reprint requests to: Reza Shaker, M.D., Digestive DiseaseCenter, Division of Gastroenterology and Hepatology, Medical Collegeof Wisconsin, Milwaukee, Wisconsin 53226. e-mail: rshaker@mcw.edu; fax: (414) 456-6214.

© 2003 by the American Gastroenterological Association0016-5085/03/$30.00

doi:10.1016/S0016-5085(03)00554-7

Prevention of Post-ERCP Pancreatitis: Pharmacologic Solutionor Patient Selection and Pancreatic Stents?

See article on page 1786.

Pancreatitis is a complication that has plagued endo-scopic retrograde cholangiopancreatography (ERCP)

since its inception. Pancreatitis occurs after ERCP in1%–30% of cases, varying with case mix, patient sus-ceptibility, the endoscopist, the definition of pancreati-tis, and the thoroughness of follow-up. Pancreatitis canrange in severity from mild, with a 1- or 2-day hospitalstay and a full recovery, to severe and life threatening,with permanent disability or death. Several approacheshave been taken toward avoiding this all-too-commoncomplication. In this editorial, we will attempt to putinto perspective the relative importance of each ap-proach, including the study published in this issue ofGASTROENTEROLOGY by Murray et al.1

The first approach is pharmacologic prevention ofpost-ERCP pancreatitis. Such a holy grail has beensought for many years.2–7 Rationale has centered oninterrupting various postulated mechanisms of injury.Some are unique to pancreatitis resulting from ERCP,including instrumental trauma to the pancreatic sphinc-ter with obstruction to flow of pancreatic juice andhydrostatic injury, introduced infection, and acinar tox-icity resulting from contrast exposure. Others are inher-ent to all forms of acute pancreatitis, including prema-ture intracellular activation of proteolytic enzymes, andthe inflammatory cascade, including chemokines andproinflammatory cytokines that lead to local and sys-

temic inflammatory response. Although appealing intheory, the history of attempts to find the ideal drug isfamiliar: First 1 agent, then another, appears promisingin animal studies and then in preliminary human studies.Initial single-center randomized trials suggest efficacy,followed by conflicting results from other centers. Dis-appointment ultimately ensues once larger, multicenterstudies are conducted. The list of agents that have gonethrough this sequence is long (Table 1), including thelatest contenders of platelet-activating factor inhibitorsand interleukin 10. Meta-analyses suggest that 2 agentsare effective in preventing post-ERCP pancreatitis.5 One,somatostatin, is an antisecretory agent, whereas theother, gabexate, is a protease inhibitor. The caveats arethat both drugs are not available in North America and,to be effective, both agents must be administered beforeERCP and continued for a 12-hour infusion afterward.When administered as a single dose, neither agent hasbeen consistently effective.5 The economic and logisticalviability of a 12-hour infusion of an expensive drug ishighly questionable in today’s environment, especiallywhen 13–27 patients must be treated to prevent a singlecase of pancreatitis.5 Thus, to date, a drug that is con-sistently effective in a single dose has not been found.

The second approach to post-ERCP pancreatitis is theuse of epidemiologic analyses to identify patient- andprocedure-related risk factors so that ERCP can beavoided or technique modified in high-risk patients.8

Recent prospective, large-scale multivariate analyseshave taught us that risk of post-ERCP pancreatitis is

June 2003 EDITORIALS 1977