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Irritable Bowel Syndrome: Studies of central pathophysiological mechanisms and effects of treatment
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background and aims

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by abdominal pain and altered bowel habits. The societal costs of the disorder are significant, as are its negative effects on quality of life. Medical treatment options are limited, but psychological treatments such as hypnotherapy have proven to be effective. Important pathophysiological mechanisms include disturbances in brain processing of visceral sensation and expectation of visceral sensation. Increased sensation of stimuli (hypersensitivity) is present in a subset of IBS patients to distensions in the lower part of the gastrointestinal tract, indicating a probable important pathophysiological mechanism in IBS. The overall aim of the thesis was to further study the central pathophysiological mechanisms involved in IBS. Specifically, we aimed to identify differences in brain response to standardized repeated rectal distensions and expectation of these stimuli between IBS patients (with or without perceptual rectal hypersensitivity), and healthy controls. Furthermore, we aimed to investigate IBS patients´ brain responses to standardized rectal distensions and expectation of these stimuli after either a successful course hypnotherapy or educational intervention.

Methods

Functional magnetic resonance imaging (fMRI) data were acquired and analyzed from 15 IBS patients with visceral hypersensitivity, and 18 IBS patients with normal visceral sensitivity (papers I and II). In paper III, fMRI data were analyzed from IBS patients who reported significant symptom reduction after either a course of hypnotherapy, or an educational intervention. FMRI data from IBS patients and healthy controls were also compared.

Results

The findings reported in papers I and II suggest, that the differences in brain response between IBS patients with and without rectal hypersensitivity, can be explained by changes in brain response during the course of the experiment. Even though the brain responses were similar between groups during the early phase of the experiment, they became substantially different during the late phase. The IBS patients with rectal hypersensitivity demonstrated increased brain response in several brain regions and networks involved in visceral sensation and processing. In contrast, IBS patients with normal rectal sensitivity exhibited reduced brain response during the late phase of the experiment. As reported in paper III, similar symptom reduction was achieved for both treatments. The symptomatic improvement was associated with a reduction of response in the anterior insula, indicating an attenuated awareness of the stimuli. The hypnotherapy group had a reduction of response in the posterior insula, indicating less input to the brain, possibly due to changed activity in endogenous pain modulatory systems. In patients who reported significant symptom reduction following treatment, the brain response to rectal distension got more similar to that observed in healthy controls.

Conclusions

The results from papers I and II indicate that a subpopulation of IBS patients lacks the ability to habituate to repeated rectal distensions and expectation of these stimuli. Results from paper III indicate that the abnormal processing of visceral stimuli in IBS can be altered, and that the treatments probably had a normalizing effect on the central processing abnormality of visceral signals in IBS.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. , 62 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1472
National Category
Neurology Radiology, Nuclear Medicine and Medical Imaging Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:liu:diva-122144DOI: 10.3384/diss.diva-122144ISBN: 978-91-7685-983-4 (print)OAI: oai:DiVA.org:liu-122144DiVA: diva2:862078
Public defence
2015-11-06, Berzeliussalen, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2015-10-20 Created: 2015-10-20 Last updated: 2016-04-24Bibliographically approved
List of papers
1. Brain Responses to Visceral Stimuli Reflect Visceral Sensitivity Thresholds in Patients With Irritable Bowel Syndrome
Open this publication in new window or tab >>Brain Responses to Visceral Stimuli Reflect Visceral Sensitivity Thresholds in Patients With Irritable Bowel Syndrome
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2012 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 142, no 3, 463-472 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND & AIMS:

Only a fraction of patients with irritable bowel syndrome (IBS) have increased perceptual sensitivity to rectal distension, indicating differences in processing and/or modulation of visceral afferent signals. We investigated the brain mechanisms of these perceptual differences.

METHODS:

We analyzed data from 44 women with IBS and 20 female healthy subjects (controls). IBS symptom severity was determined by a severity scoring system. Anxiety and depression symptoms were assessed using the hospital anxiety and depression score. Blood oxygen level-dependent signals were measured by functional magnetic resonance imaging during expectation and delivery of high (45 mmHg) and low (15 mmHg) intensity rectal distensions. Perception thresholds to rectal distension were determined in the scanner. Brain imaging data were compared among 18 normosensitive and 15 hypersensitive patients with IBS and 18 controls. Results were reported significant if peak P-values were ≤.05, with family-wise error correction in regions of interest.

RESULTS:

The subgroups of patients with IBS were similar in age, symptom duration, psychological symptoms, and IBS symptom severity. Although brain responses to distension were similar between normosensitive patients and controls, hypersensitive patients with IBS had greater activation of insula and reduced deactivation in pregenual anterior cingulate cortex during noxious rectal distensions, compared to controls and normosensitive patients with IBS. During expectation of rectal distension, normosensitive patients with IBS had more activation in right hippocampus than controls.

CONCLUSIONS:

Despite similarities in symptoms, hyper- and normosensitive patients with IBS differ in cerebral responses to standardized rectal distensions and their expectation, consistent with differences in ascending visceral afferent input.

Place, publisher, year, edition, pages
Elsevier, 2012
Keyword
Barostat; Visceral Sensitivity; Functional MRI; Anticipation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-73455 (URN)10.1053/j.gastro.2011.11.022 (DOI)000300774700024 ()
Note

funding agencies|County Council of Ostergotland, Sweden||Lions Forskningsfond for Folksjukdomar||Bengt Ihresfond, Svenska Lakaresallskapet||Magnus Bergvall fond||National Institutes of Health| DK 64531 DK 48351 K23 DK73451 |

Available from: 2012-01-04 Created: 2012-01-04 Last updated: 2017-12-08Bibliographically approved
2. Deficient habituation to repeated rectal distensions in irritable bowel syndrome patients with visceral hypersensitivity
Open this publication in new window or tab >>Deficient habituation to repeated rectal distensions in irritable bowel syndrome patients with visceral hypersensitivity
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2015 (English)In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 27, no 5, 646-655 p.Article in journal (Refereed) Published
Abstract [en]

Background Irritable bowel syndrome (IBS) patients show evidence of altered central processing of visceral signals. One of the proposed alterations in sensory processing is an altered engagement of endogenous pain modulation mechanisms. The aim was to test the hypothesis that IBS patients with (IBS-S) and without visceral hypersensitivity (IBS-N) differ in their ability to engage endogenous pain modulation mechanism during habituation to repeated visceral stimuli.

Methods Brain blood oxygen level dependent (BOLD) response was measured during repeated rectal distension and its anticipation in 33 IBS patients with and without visceral hypersensitivity and 18 healthy controls (HCs). BOLD response to early and late phase of the distension series was compared within and between groups.

Key Results While BOLD response was similar during the early phase of the experiment, IBS-S showed greater BOLD response than IBS-N and HCs during the late phase of the distension series. IBS-S showed increasing BOLD response both to the anticipation and delivery of low intensity rectal distensions in brain regions including insula, anterior and mid cingulate cortex. IBS-N showed decreasing BOLD response to repeated rectal distensions in brain regions including insula, prefrontal cortex and amygdala.

Conclusions & Inferences These findings are consistent with compromised ability of IBS-S to respond to repeated delivery of rectal stimuli, both in terms of sensitization of sensory pathways and habituation of emotional arousal. The fact that both IBS subgroups met Rome criteria, and did not differ in terms of reported symptom severity demonstrates that similar symptom patterns can result from different underlying neurobiological mechanisms.

Keyword
irritable bowel syndrome, brain-gut interaction, fMRI, visceral sensitivity
National Category
Gastroenterology and Hepatology Neurosciences
Identifiers
urn:nbn:se:liu:diva-122143 (URN)10.1111/nmo.12537 (DOI)000364742000007 ()25777251 (PubMedID)
Note

Funding agencies: County Council of Ostergotland, Sweden; National Institute of Health [DK 64531]

Available from: 2015-10-20 Created: 2015-10-20 Last updated: 2017-12-01Bibliographically approved
3. Effect of hypnotherapy and educational intervention on brain response to visceral stimulus in the irritable bowel syndrome
Open this publication in new window or tab >>Effect of hypnotherapy and educational intervention on brain response to visceral stimulus in the irritable bowel syndrome
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2013 (English)In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 37, no 12, 1184-1197 p.Article in journal (Refereed) Published
Abstract [en]

Background Gut-directed hypnotherapy can reduce IBS symptoms, but the mechanisms underlying this therapeutic effect remain unknown. Aim To determine the effect of hypnotherapy and educational intervention on brain responses to cued rectal distensions in IBS patients. Methods Forty-four women with moderate-to-severe IBS and 20 healthy controls (HCs) were included. Blood oxygen level dependent (BOLD) signals were measured by functional Magnetic Resonance Imaging (fMRI) during expectation and delivery of high- (45mmHg) and low-intensity (15mmHg) rectal distensions. Twenty-five patients were assigned to hypnotherapy (HYP) and 16 to educational intervention (EDU). Thirty-one patients completed treatments and posttreatment fMRI. Results Similar symptom reduction was achieved in both groups. Clinically successful treatment (all responders) was associated with significant BOLD attenuation during high-intensity distension in the dorsal and ventral anterior insula (cluster size 142, P=0.006, and cluster size 101, P=0.005 respectively). Moreover HYP responders demonstrated a prepost treatment BOLD attenuation in posterior insula (cluster sizes 59, P=0.05) while EDU responders had a BOLD attenuation in prefrontal cortex (cluster size 60, P=0.05). Prepost differences for expectation conditions were almost exclusively seen in the HYP group. Following treatment, the brain response to distension was similar to that observed in HCs, suggesting that the treatment had a normalising effect on the central processing abnormality of visceral signals in IBS. Conclusions The abnormal processing and enhanced perception of visceral stimuli in IBS can be normalised by psychological interventions. Symptom improvement in the treatment groups may be mediated by different brain mechanisms. Clinical trial number: NCT01815164.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-94599 (URN)10.1111/apt.12319 (DOI)000319295100006 ()
Note

Funding Agencies|County Council of Ostergotland||Lions forskningsfond for folksjukdomar||Svenska Lakaresallskapets forskningsfond||NIDDK|DK048351|

Available from: 2013-06-27 Created: 2013-06-27 Last updated: 2017-12-06

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