| 1. |
- Bednarska, Olga, 1973-, et al.
(author)
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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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In: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 160:9, s. 2004-2012
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Journal article (peer-reviewed)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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| 2. |
- Icenhour, Adriane, et al.
(author)
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Brain functional connectivity is associated with visceral sensitivity in women with Irritable Bowel Syndrome
- 2017
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In: NeuroImage. - : ELSEVIER SCI LTD. - 2213-1582. ; 15, s. 449-457
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Journal article (peer-reviewed)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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| 3. |
- Icenhour, Adriane, et al.
(author)
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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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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Journal article (peer-reviewed)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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| 4. |
- Lasselin, Julie, et al.
(author)
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Mood disturbance during experimental endotoxemia : Predictors of state anxiety as a psychological component of sickness behavior
- 2016
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In: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 57, s. 30-37
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Journal article (peer-reviewed)abstract
- Lipopolysaccharide (LPS) administration is a well-established model to assess afferent immune-to-brain communication and behavioral aspects of inflammation. Nevertheless, only few studies in comparatively small samples have assessed state anxiety as a psychological component of sickness behavior despite possible clinical implications for the pathophysiology of neuropsychiatric conditions. Thus, the goal of the present analyses carried out in a large, pooled dataset from two independent study sites was to analyze the state anxiety response to LPS administration and to investigate predictors (i.e., cytokine changes; pre-existing anxiety and depression symptoms assessed with the Hospital Anxiety and Depression Scale) of the LPS-induced state anxiety changes at different time points after LPS administration. Data from 186 healthy volunteers who participated in one of six randomized, placebo-controlled human studies involving intravenous administration of LPS at doses of 0.4-0.8ng/kg body weight were combined. State anxiety as well as circulating interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-10 concentrations were significantly increased 2h and 3h after LPS administration, with a peak at 2h, and returned to baseline 6h after administration. Greater changes in IL-6 from baseline to 3h after LPS administration significantly and independently predicted a more pronounced LPS-induced state anxiety response. In addition, higher pre-existing subclinical anxiety symptoms significantly predicted a lower increase in state anxiety 3h and 6h after LPS-administration, which was mediated by TNF-α changes. In conclusion, our findings give additional support for a putative role of inflammatory mechanisms in the pathophysiology of stress-related and anxiety disorders and give new insight on the potential role of pre-existing subclinical affective symptoms.
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| 5. |
- Lowén, Mats, 1977-
(author)
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Irritable Bowel Syndrome : Studies of central pathophysiological mechanisms and effects of treatment
- 2015
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Doctoral thesis (other academic/artistic)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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| 6. |
- Norlin, Anna-Karin, 1977-, et al.
(author)
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Fatigue in irritable bowel syndrome is associated with plasma levels of TNF-α and mesocorticolimbic connectivity
- 2021
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In: Brain, behavior, and immunity. - Amsterdam, Netherlands : Elsevier. - 0889-1591 .- 1090-2139. ; 92, s. 211-220
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Journal article (peer-reviewed)abstract
- Irritable bowel syndrome (IBS) is a symptom-based disorder of gut-brain interactions generating abdominal pain. It is also associated with a vulnerability to develop extraintestinal symptoms, with fatigue often reported as one of the most disturbing. Fatigue is related to brain function and inflammation in several disorders, however, the mechanisms of such relations in IBS remain elusive. This study aimed to elucidate fatigue and its association with a resting state network of mesocorticolimbic regions of known importance in fatigue, and to explore the possible role of circulating TNF-α levels in IBS and healthy controls (HC). Resting state functional magnetic resonance imaging (fMRI) was conducted in 88 IBS patients and 47 HC of similar age and gender to investigate functional connectivity between mesocorticolimbic regions. Further, fatigue impact on daily life and plasma levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α), of known relevance to immune activation in IBS, were also measured. The selected mesocorticolimbic regions indeed formed a functionally connected network in all participants. The nucleus accumbens (NAc), in particular, exhibited functional connectivity to all other regions of interest. In IBS, fatigue impact on daily life was negatively correlated with the connectivity between NAc and dorsolateral prefrontal cortex bilaterally (left p = 0.019; right p = 0.038, corrected for multiple comparisons), while in HC, fatigue impact on daily life was positively correlated to the connectivity between the right NAc and anterior middle insula in both hemispheres (left p = 0.009; right p = 0.011). We found significantly higher levels of TNF-α in IBS patients compared to HC (p = 0.001) as well as a positive correlation between TNF-α and fatigue impact on daily life in IBS patients (rho = 0.25, p = 0.02) but not in HC (rho = −0.13, p = 0.37). There was no association between functional connectivity in the mesocorticolimbic network and plasma levels of TNF-α in either group In summary, this novel multimodal study provides the first evidence that the vulnerability to fatigue in IBS is associated with connectivity within a mesocorticolimbic network as well as immune activation. These findings warrant further investigation, both peripherally and potentially with measurements of central immune activation as well.
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| 7. |
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| 8. |
- Witt, Suzanne Tyson, 1979-, et al.
(author)
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Interactions between gut permeability and brain structure and function in health and irritable bowel syndrome
- 2019
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In: NeuroImage. - : Elsevier. - 2213-1582. ; 21
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Journal article (peer-reviewed)abstract
- Changes in brain-gut interactions have been implicated in the pathophysiology of chronic visceral pain in irritable bowel syndrome (IBS). Different mechanisms of sensitization of visceral afferent pathways may contribute to the chronic visceral pain reports and associated brain changes that characterize IBS. They include increased gut permeability and gut associated immune system activation, and an imbalance in descending pain inhibitory and facilitatory mechanisms. In order to study the involvement of these mechanisms, correlations between gut epithelial permeability and live bacterial passage, and structural and functional brain connectivity were measured in women with moderate-to-severe IBS and healthy women. The relationships between gut permeability and functional and anatomical connectivity were significantly altered in IBS compared with the healthy women. IBS participants with lower epithelial permeability reported increased IBS symptoms, which was associated with increased functional and structural connectivity in endogenous pain facilitation regions. The findings suggest that relationships between gut permeability and the brain are significantly altered in IBS and suggest the existence of IBS subtypes based on these interactions.
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