| 1. |
- Bednarska, Olga, 1973-
(författare)
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Peripheral and Central Mechanisms in Irritable Bowel Syndrome : in search of links
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Irritable bowel syndrome (IBS) is a chronic visceral pain disorder with female predominance, characterized by recurrent abdominal pain and disturbed bowel habits in the absence of an identifiable organic cause. This prevalent and debilitating disease, which accounts for a substantial economic and individual burden, lacks exact diagnostic tools and effective treatment, since its pathophysiology remains uncertain. The bidirectional and multilayered brain-gut axis is a well-established disease model, however, the interactions between central and peripheral mechanisms along the brain-gut axis remain incompletely understood. One of the welldescribed triggering factors, yet accounting for only a fraction of IBS prevalence, is bacterial gastroenteritis that affects mucosal barrier function. Altered gut microbiota composition as well as disturbed intestinal mucosal barrier function and its neuroimmune regulation have been reported in IBS, however, the impact of live bacteria, neither commensal nor pathogenic, on intestinal barrier has not been studied yet. Furthermore, abnormal central processing of visceral sensations and psychological factors such as maladaptive coping have previously been suggested as centrally-mediated pathophysiological mechanisms of importance in IBS. Brain imaging studies have demonstrated an imbalance in descending pain modulatory networks and alterations in brain regions associated with interoceptive awareness and pain processing and modulation, particularly in anterior insula (aINS), although biochemical changes putatively underlying these central alterations remain poorly understood. Most importantly, however, possible associations between these documented changes on central and peripheral levels, which may as complex interactions contribute to disease onset and chronification of symptoms, are widely unknown.This thesis aimed to investigate the peripheral and central mechanisms in women with IBS compared to female healthy controls (HC) and to explore possible mutual associations between these mechanisms.In Paper I, we studied paracellular permeability and passage of live bacteria, both commensal and pathogenic through colonic biopsies mounted in Ussing chambers. We explored the regulation of the mucosal barrier function by mast cells and the neuropeptide vasoactive intestinal polypeptide (VIP) as well as a correlation between mucosal permeability and gastrointestinal and psychological symptoms. We observed increased paracellular permeability and the passage of commensal and pathogenic live bacteria in patients with IBS compared with HC, which was diminished by blocking the VIP receptors as well as after stabilizing mast cells in both groups. Moreover, higher paracellular permeability was associated with less somatic and psychological symptoms in patients.In Paper II, we aimed to determine the association between colonic mucosa paracellular permeability and structural and resting state functional brain connectivity. We demonstrated different patterns of associations between mucosa permeability and functional and structural brain connectivity in IBS patients compared to HC. Specifically, lower paracellular permeability in IBS, similar to the levels detected in HC, was associated with more severe IBS symptoms and increased functional and structural connectivity between intrinsic brain resting state network and descending pain modulation brain regions. Our findings further suggested that this association between mucosa permeability and functional brain connectivity was mainly mediated by coping strategies.In Paper III, we investigated putative alterations in excitatory and inhibitory neurotransmission of aINS, as the brain’s key node of the salience network crucially involved in cognitive control, in IBS patients relative to HC and addressed possible connections with both symptoms and psychological factors. We found decreased concentrations of the excitatory neurotransmitter Glx in bilateral aINS in IBS patients compared to HC, while inhibitory neurotransmitter GABA+ levels were comparable. Further, we demonstrated hemisphere-specific associations between abdominal pain, coping and aINS excitatory neurotransmitter concentration.In conclusion, this thesis broadens the knowledge on peripheral and central mechanisms in IBS and presents novel findings that bring together the ends of brain-gut axis. Our results depict association between mucosal permeability, IBS symptoms and functional and structural connectivity engaging brain regions involved in emotion and pain modulation as well as underlying neurotransmitter alterations.
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| 2. |
- Bednarska, Olga, 1973-, et al.
(författare)
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Reduced excitatory neurotransmitter levels in anterior insulae are associated with abdominal pain in irritable bowel syndrome
- 2019
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Ingår i: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 160:9, s. 2004-2012
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Tidskriftsartikel (refereegranskat)abstract
- Irritable bowel syndrome (IBS) is a visceral pain condition with psychological comorbidity. Brain imaging studies in IBS demonstratealtered function in anterior insula (aINS), a key hub for integration of interoceptive, affective, and cognitive processes. However,alterations in aINS excitatory and inhibitory neurotransmission as putative biochemical underpinnings of these functional changesremain elusive. Using quantitative magnetic resonance spectroscopy, we compared women with IBS and healthy women (healthycontrols [HC]) with respect to aINS glutamate 1 glutamine (Glx) and g-aminobutyric acid (GABA1) concentrations and addressedpossible associations with symptoms. Thirty-nine women with IBS and 21 HC underwent quantitative magnetic resonancespectroscopy of bilateral aINS to assess Glx and GABA1 concentrations. Questionnaire data from all participants and prospectivesymptom-diary data from patients were obtained for regression analyses of neurotransmitter concentrations with IBS-related andpsychological parameters. Concentrations of Glx were lower in IBS compared with HC (left aINS P , 0.05, right aINS P , 0.001),whereas no group differences were detected for GABA1concentrations. Lower right-lateralized Glx concentrations in patients weresubstantially predicted by longer pain duration, while less frequent use of adaptive pain‐coping predicted lower Glx in left aINS. Ourfindings provide first evidence for reduced excitatory but unaltered inhibitory neurotransmitter levels in aINS in IBS. The results alsoindicate a functional lateralization of aINS with a stronger involvement of the right hemisphere in perception of abdominal pain and ofthe left aINS in cognitive pain regulation. Our findings suggest that glutaminergic deficiency may play a role in pain processing in IBS.
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| 3. |
- Bednarska, Olga, et al.
(författare)
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Vasoactive Intestinal Polypeptide and Mast Cells Regulate Increased Passage of Colonic Bacteria in Patients With Irritable Bowel Syndrome
- 2017
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Ingår i: Gastroenterology. - : W B SAUNDERS CO-ELSEVIER INC. - 0016-5085 .- 1528-0012. ; 153:4, s. 948-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND amp; AIMS: Irritable bowel syndrome (IBS) is associated with intestinal dysbiosis and symptoms of IBS develop following gastroenteritis. We aimed to study the passage of live bacteria through the colonic epithelium, and determine the role of mast cells (MCs) and vasoactive intestinal polypeptide (VIP) in barrier regulation in IBS and healthy individuals. METHODS: Colon biopsies from 32 women with IBS and 15 age-matched healthy women (controls) were mounted in Ussing chambers; we measured numbers of fluorescently labeled Escherichia coli HS and Salmonella typhimurium that passed through from the mucosal side to the serosal side of the tissue. Some biopsies were exposed to agents that block the VIP receptors (VPAC1 and VPAC2) or MCs. Levels of VIP and tryptase were measured in plasma and biopsy lysates. Number of MCs and MCs that express VIP or VIP receptors were quantified by immunofluorescence. Biopsies from an additional 5 patients with IBS and 4 controls were mounted in chambers and Salmonella were added; we studied passage routes through the epithelium by transmission electron microscopy and expression of tight junctions by confocal microscopy. RESULTS: In colon biopsies from patients with IBS, larger numbers of E coli HS and S typhimurium passed through the epithelium than in biopsies from controls (P amp;lt;.0005). In transmission electron microscopy analyses, bacteria were found to cross the epithelium via only the transcellular route. Bacterial passage was reduced in biopsies from patients with IBS and controls after addition of antibodies against VPACs or ketotifen, which inhibits MCs. Plasma samples from patients with IBS had higher levels of VIP than plasma samples from controls. Biopsies from patients with IBS had higher levels of tryptase, larger numbers of MCs, and a higher percentage of MCs that express VPAC1 than biopsies from controls. In biopsies from patients with IBS, addition of Salmonella significantly reduced levels of occludin; subsequent addition of ketotifen significantly reversed this effect. CONCLUSIONS: We found that colonic epithelium tissues from patients with IBS have increased translocation of commensal and pathogenic live bacteria compared with controls. The mechanisms of increased translocation include MCs and VIP.
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| 4. |
- Bonfiglio, F., et al.
(författare)
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Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome
- 2018
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 155:1, s. 168-179
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 x 10(-8)) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0 x 10(-6)). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 x 10(-10) in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKB-KAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.
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| 5. |
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| 6. |
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| 7. |
- Grodzinsky, Ewa, et al.
(författare)
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More negative self-esteem and inferior coping strategies among patients diagnosed with IBS compared with patients without IBS - a case-control study in primary care
- 2015
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Ingår i: BMC Family Practice. - : BioMed Central. - 1471-2296. ; 16:6
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIrritable Bowel Syndrome (IBS) is a chronic, relapsing gastrointestinal disorder,that affects approximately 10% of the general population and the majority are diagnosed in primary care. IBS has been reported to be associated with altered psychological and cognitive functioning such as mood disturbances, somatization, catastrophizing or altered visceral interoception by negative emotions and stress. The aim was to investigate the psychosocial constructs of self-esteem and sense of coherence among IBS patients compared to non-IBS patients in primary care. MethodsA case–control study in primary care setting among IBS patients meeting the ROME III criteria (n = 140) compared to controls i.e. non-IBS patients (n = 213) without any present or previous gastrointestinal complaints. The data were collected through self-reportedquestionnaires of psychosocial factors. ResultsIBS-patients reported significantly more negative self-esteem (p < 0.001), lower scores for positive self-esteem (p < 0.001), and lower sense of coherence (p < 0.001) than the controls. The IBS-cases were also less likely to report ‘good’ health status (p < 0.001) and less likely to report a positive belief in the future (p < 0.001). After controlling for relevant confounding factors in multiple regressions, the elevation in negative self-esteem among IBS patients remained statistically significant (p =0.02), as did the lower scores for sense of coherence among IBS cases (p = 0.04). ConclusionsThe more frequently reported negative self-esteem and inferior coping strategies among IBS patients found in this study suggest the possibility that psychological therapies might be helpful for these patients. However these data do not indicate the causal direction of the observed associations. More research is therefore warranted to determine whether these psychosocial constructs are more frequent in IBS patients.
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| 8. |
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| 9. |
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| 10. |
- Henstrom, M., et al.
(författare)
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Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome
- 2018
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 67:2, s. 263-270
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Tidskriftsartikel (refereegranskat)abstract
- Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucraseisomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p. Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.
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| 11. |
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| 12. |
- Icenhour, Adriane, et al.
(författare)
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Brain functional connectivity is associated with visceral sensitivity in women with Irritable Bowel Syndrome
- 2017
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Ingår i: NeuroImage. - : ELSEVIER SCI LTD. - 2213-1582. ; 15, s. 449-457
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Tidskriftsartikel (refereegranskat)abstract
- Increased perception of visceral stimuli is a key feature of Irritable Bowel Syndrome (IBS). While altered resting-state functional connectivity (rsFC) has been also reported in IBS, the relationship between visceral hypersensitivity and aberrant rsFC is unknown. We therefore assessed rsFC within the salience, sensorimotor and default mode networks in patients with and without visceral hypersensitivity and in healthy controls (HCs). An exploratory resting-state functional magnetic resonance imaging study was performed in 41 women with IBS and 20 HCs. Group independent component analysis was used to derive intrinsic brain networks. Rectal thresholds were determined and patients were subdivided into groups with increased (hypersensitive IBS, N = 21) or normal (normosensitive IBS, N= 20) visceral sensitivity. Between-group comparisons of rsFC were carried-out using region-of-interest analyses and peak rsFC values were extracted for correlational analyses. Relative to normosensitive IBS, hypersensitive patients showed increased positive rsFC of pregenual anterior cingulate cortex and thalamus within the salience network and of posterior insula within the sensorimotor network. When compared to both hypersensitive IBS and HCs, normosensitive IBS showed decreased positive rsFC of amygdala and decreased negative rsFC in dorsal anterior insula within the DMN. DMN and sensorimotor network rsFC were associated with rectal perception thresholds, and rsFC in posterior insula was correlated with reported symptom severity in IBS. Our exploratory findings suggest that visceral sensitivity in IBS is related to changes in FC within resting-state networks associated with interoception, salience and sensory processing. These alterations may play an important role in hypervigilance and hyperalgesia in IBS.
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| 13. |
- Icenhour, Adriane, et al.
(författare)
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Elucidating the putative link between prefrontal neurotransmission, functional connectivity, and affective symptoms in irritable bowel syndrome
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Altered neural mechanisms are well-acknowledged in irritable bowel syndrome (IBS), a disorder of brain-gut-communication highly comorbid with anxiety and depression. As a key hub in corticolimbic inhibition, medial prefrontal cortex (mPFC) may be involved in disturbed emotion regulation in IBS. However, aberrant mPFC excitatory and inhibitory neurotransmission potentially contributing to psychological symptoms in IBS remains unknown. Using quantitative magnetic resonance spectroscopy (qMRS), we compared mPFC glutamate + glutamine (Glx) and gamma-aminobutyric acid (GABA+) concentrations in 64 women with IBS and 32 age-matched healthy women (HCs) and investigated their association with anxiety and depression in correlational and subgroup analyses. Applying functional magnetic resonance imaging (fMRI), we explored whether altered neurotransmission was paralleled by aberrant mPFC resting-state functional connectivity (FC). IBS patients did not differ from HCs with respect to mPFC GABA+ or Glx levels. Anxiety was positively associated with mPFC GABA+ concentrations in IBS, whereas Glx was unrelated to psychological or gastrointestinal symptoms. Subgroup comparisons of patients with high or low anxiety symptom severity and HCs revealed increased GABA+ in patients with high symptom severity, and lower mPFC FC with adjacent anterior cingulate cortex (ACC), a crucial region of emotion modulation. Our findings provide novel evidence that altered prefrontal inhibitory neurotransmission may be linked to anxiety in IBS.
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| 14. |
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| 15. |
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| 16. |
- Jones, Michael P., et al.
(författare)
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Gastrointestinal recall questionnaires compare poorly with prospective patient diaries for gastrointestinal symptoms : data from population and primary health centre samples
- 2019
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Ingår i: European Journal of Gastroenterology and Hepathology. - : Lippincott Williams & Wilkins. - 0954-691X .- 1473-5687. ; 31:2, s. 163-169
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Tidskriftsartikel (refereegranskat)abstract
- Background: Clinical understanding of gastrointestinal symptoms is commonly based on patient reports of symptom experience. For diagnosis and treatment choices to be appropriate, symptom reports need to be accurate. We examined the agreement between questionnaire recall and prospective diary enumeration of symptoms relevant to the irritable bowel syndrome.Patients and methods: Data are reported from a randomly selected general population sample (n=238) and also a primary healthcare centre (PHC) sample (n=503, 10 PHCs). All the patients completed the questionnaires, which included Rome III-qualifying irritable bowel syndrome items and a stool and symptom diary over either 7 or 14 days. Agreement between retrospective questionnaire reports and prospective diaries was evaluated.Results: Concordance between questionnaires and diaries was highest for the simple construct of the occurrence of abdominal pain, although after adjusting for possible chance, agreement was only moderate in the general population sample. More complex constructs, such as pain relieved by defecation, yielded poorer concordance. In general, concordance was stronger among PHC respondents than in the general population sample.Conclusion: Concordance between questionnaires and diaries was generally poor and related to the complexity of the symptom construct and the type of respondent. The information used to classify individuals based on patient self-report may be unreliable, and therefore, more effort is needed to develop data collection instruments.
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| 17. |
- Jung, Christian, et al.
(författare)
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A comparison of very old patients admitted to intensive care unit after acute versus elective surgery or intervention
- 2019
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Ingår i: Journal of critical care. - : W B SAUNDERS CO-ELSEVIER INC. - 0883-9441 .- 1557-8615. ; 52, s. 141-148
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to evaluate differences in outcome between patients admitted to intensive care unit (ICU) after elective versus acute surgery in a multinational cohort of very old patients (80 years; VIP). Predictors of mortality, with special emphasis on frailty, were assessed.Methods: In total, 5063 VIPs were induded in this analysis, 922 were admitted after elective surgery or intervention, 4141 acutely, with 402 after acute surgery. Differences were calculated using Mann-Whitney-U test and Wilcoxon test. Univariate and multivariable logistic regression were used to assess associations with mortality.Results: Compared patients admitted after acute surgery, patients admitted after elective surgery suffered less often from frailty as defined as CFS (28% vs 46%; p < 0.001), evidenced lower SOFA scores (4 +/- 5 vs 7 +/- 7; p < 0.001). Presence of frailty (CFS >4) was associated with significantly increased mortality both in elective surgery patients (7% vs 12%; p = 0.01), in acute surgery (7% vs 12%; p = 0.02).Conclusions: VIPs admitted to ICU after elective surgery evidenced favorable outcome over patients after acute surgery even after correction for relevant confounders. Frailty might be used to guide clinicians in risk stratification in both patients admitted after elective and acute surgery.
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| 18. |
- Jönsson, Daniel, 1984-, et al.
(författare)
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Visual analysis for understanding irritable bowel syndrome
- 2019
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Ingår i: Biomedical visualisation. - Cham : Springer. - 9783030193843 - 9783030193850 ; , s. 111-122
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Bokkapitel (refereegranskat)abstract
- The cause of irritable bowel syndrome (IBS), a chronic disorder characterized by abdominal pain and disturbed bowel habits, is largely unknown. It is believed to be related to physical properties in the gut, central mechanisms in the brain, psychological factors, or a combination of these. To understand the relationships within the gut-brain axis with respect to IBS, large numbers of measurements ranging from stool samples to functional magnetic resonance imaging are collected from patients with IBS and healthy controls. As such, IBS is a typical example in medical research where research turns into a big data analysis challenge. In this chapter we demonstrate the power of interactive visual data analysis and exploration to generate an environment for scientific reasoning and hypothesis formulation for data from multiple sources with different character. Three case studies are presented to show the utility of the presented work.
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| 19. |
- Lowén, Mats B. O., et al.
(författare)
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Deficient habituation to repeated rectal distensions in irritable bowel syndrome patients with visceral hypersensitivity
- 2015
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 27:5, s. 646-655
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 20. |
- Lowén, Mats, 1977-
(författare)
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Irritable Bowel Syndrome : Studies of central pathophysiological mechanisms and effects of treatment
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and aimsIrritable 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.MethodsFunctional 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.ResultsThe 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.ConclusionsThe 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.
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| 21. |
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| 22. |
- Lundengård, Karin, 1985-
(författare)
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Mechanistic modelling - a BOLD response to the fMRI information loss problem
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Functional Magnetic Resonance Imaging (fMRI) is a common technique for imaging brain activity in humans. However, the fMRI signal stems from local changes in oxygen level rather than from neuronal excitation. The change in oxygen level is referred to as the Blood Oxygen Level Dependent (BOLD) response, and is connected to neuronal excitation and the BOLD response are connected by the neurovascular coupling. The neurons affect the oxygen metabolism, blood volume and blood flow, and this in turn controls the shape of the BOLD response. This interplay is complex, and therefore fMRI analysis often relies on models. However, none of the previously existing models are based on the intracellular mechanisms of the neurovascular coupling. Systems biology is a relatively new field where mechanistic models are used to integrate data from many different parts of a system in order to holistically analyze and predict system properties. This thesis presents a new framework for analysis of fMRI data, based on mechanistic modelling of the neurovascular coupling, using systems biology methods. Paper I presents the development of the first intracellular signaling model of the neurovascular coupling. Using models, a feed-forward and a feedback hypothesis are tested against each other. The resulting model can mechanistically explain both the initial dip, the main response and the post-peak undershoot of the BOLD response. It is also fitted to estimation data from the visual cortex and validated against variations in frequency and intensity of the stimulus. In Paper II, I present a framework for separating activity from noise by investigating the influence of the astrocytes on the blood vessels via release of vasoactive sub- stances, using observability analysis. This new method can recognize activity in both measured and simulated data, and separate differences in stimulus strength in simulated data. Paper III investigates the effects of the positive allosteric GABA modulator diazepam on working memory in healthy adults. Both positive and negative BOLD was measured during a working memory task, and activation in the cingulate cortex was negatively correlated to the plasma concentration of diazepam. In this area, the BOLD response had decreased below baseline in test subjects with >0.01 mg/L diazepam in the blood. Paper IV expands the model presented in Paper I with a GABA mechanism so that it can describe neuronal inhibition and the negative BOLD response. Sensitization of the GABA receptors by diazepam was added, which enabled the model to explain how changes to the BOLD response described in Paper III could occur without a change in the balance between the GABA and glutamate concentrations.The framework presented herein may serve as the basis for a new method for identification of both brain activity and useful potential biomarkers for brain diseases and disorders, which will bring us a deeper understanding of the functioning of the human brain.
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| 23. |
- Molinder, Herdis, et al.
(författare)
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How individuals with the irritable bowel syndrome describe their own symptoms before formal diagnosis
- 2015
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Ingår i: Upsala Journal of Medical Sciences. - : Taylor & Francis. - 0300-9734 .- 2000-1967. ; 120:4, s. 276-279
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To investigate how individuals fulfilling the Rome II criteria for irritable bowel syndrome (IBS) spontaneously described their symptoms. Method: From a general population, 1,244 randomly sampled adults were asked to describe their gastrointestinal symptoms (if any) verbally, in their own words, at a semi-structured interview. Their own descriptions were sorted into five symptom clusters. The participants independently completed a written questionnaire (the Rome II Modular Questionnaire (RMIIMQ)). Results: A total of 601 participants reported at least one gastrointestinal symptom, and 128 had IBS according to the RMIIMQ. After exclusion of organic causes, previously diagnosed IBS, or additional gastrointestinal diagnosis, 81 participants with IBS according to RMIIMQ remained. Five participants (6%) described symptoms included in the full definition of IBS, but none fulfilled the Rome II criteria completely. Abdominal pain or other IBS-related symptoms were reported by 64 (79%), and 12 (15%) did not report any IBS-like symptom. Conclusion: Previously undiagnosed individuals, who fulfil criteria for Rome II-IBS, often express their complaints in words that do not fit into the current diagnostic criteria.
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| 24. |
- Nichols, Hazel B., et al.
(författare)
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The Premenopausal Breast Cancer Collaboration : A Pooling Project of Studies Participating in the National Cancer Institute Cohort Consortium
- 2017
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : AMER ASSOC CANCER RESEARCH. - 1055-9965 .- 1538-7755. ; 26:9, s. 1360-1369
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Forskningsöversikt (refereegranskat)abstract
- Breast cancer is a leading cancer diagnosis among premenopausal women around the world. Unlike rates in postmenopausal women, incidence rates of advanced breast cancer have increased in recent decades for premenopausal women. Progress in identifying contributors to breast cancer risk among premenopausal women has been constrained by the limited numbers of premenopausal breast cancer cases in individual studies and resulting low statistical power to subcategorize exposures or to study specific subtypes. The Premenopausal Breast Cancer Collaborative Group was established to facilitate cohort-based analyses of risk factors for premenopausal breast cancer by pooling individuallevel data from studies participating in the United States National Cancer Institute Cohort Consortium. This article describes the Group, including the rationale for its initial aims related to pregnancy, obesity, and physical activity. We also describe the 20 cohort studies with data submitted to the Group by June 2016. The infrastructure developed for this work can be leveraged to support additional investigations.
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| 25. |
- Norlin, Anna-Karin, et al.
(författare)
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Cortisol levels in hair are altered in irritable bowel syndrome - A case control study in primary care.
- 2017
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Ingår i: Journal of Psychosomatic Research. - : Elsevier BV. - 0022-3999 .- 1879-1360. ; 93, s. 69-75
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Stress is an important component in the pathophysiology of irritable bowel syndrome (IBS). Long term Hypothalamus Pituitary Adrenal (HPA)-axis activity can be studied by measuring hair cortisol concentrations (HCC). Some previous studies have indicated a dysregulated HPA-axis in IBS patients, but cortisol levels in hair have not yet been studied. We investigated whether HCC and self-reported stress differentiate IBS patients from controls.METHODS: In a cross-sectional study within 10 Swedish Primary Health Care Centers we compared patients in working age with active IBS to patients without GI complaints. The participants donated hair samples and completed questionnaires including a scale of self-reported perceived stress (PSS). 169 Rome III-fulfilling IBS patients and 316 non-IBS patients were available for final analyses.RESULTS: IBS patients had significantly lower HCC, median=16.3pg/mg, IQR=26.9pg/mg, compared to non-IBS patients, median=22.8pg/mg, IQR=29.1pg/mg. There was also a difference in the distribution of HCC quintiles between the two groups, with 30.2% IBS patients and 14.2% of non-IBS patients in the lowest quintile of HCC. PSS was higher among IBS patients with a mean (SD) total score of 25.3 (8.0) compared to controls 21.4, (7.5). Quintiles of HCC and PSS stayed significantly but very weakly related to IBS (B=-0.332, Std error=0.146, p<0.005) in multivariable analyses.CONCLUSION: This study suggests a possible suppression of the HPA-axis activity in a considerable portion of IBS patients.
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