Kirsten Tillisch

Consumption of Fermented Milk Product With Probiotic Modulates Brain Activity

BACKGROUND & AIMS Changes in gut microbiota have been reported to alter signaling mechanisms, emotional behavior, and visceral nociceptive reflexes in rodents. However, alteration of the intestinal microbiota with antibiotics or probiotics has not been shown to produce these changes in humans. We investigated whether consumption of a fermented milk product with probiotic (FMPP) for 4 weeks by healthy women altered brain intrinsic connectivity or responses to emotional attention tasks. METHODS Healthy women with no gastrointestinal or psychiatric symptoms were randomly assigned to groups given FMPP (n = 12), a nonfermented milk product (n = 11, controls), or no intervention (n = 13) twice daily for 4 weeks. The FMPP contained Bifidobacterium animalis subsp Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp Lactis. Participants underwent functional magnetic resonance imaging before and after the intervention to measure brain response to an emotional faces attention task and resting brain activity. Multivariate and region of interest analyses were performed. RESULTS FMPP intake was associated with reduced task-related response of a distributed functional network (49% cross-block covariance; P = .004) containing affective, viscerosensory, and somatosensory cortices. Alterations in intrinsic activity of resting brain indicated that ingestion of FMPP was associated with changes in midbrain connectivity, which could explain the observed differences in activity during the task. CONCLUSIONS Four-week intake of an FMPP by healthy women affected activity of brain regions that control central processing of emotion and sensation.

Gut/brain axis and the microbiota

Tremendous progress has been made in characterizing the bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. A series of provocative preclinical studies have suggested a prominent role for the gut microbiota in these gut-brain interactions. Based on studies using rodents raised in a germ-free environment, the gut microbiota appears to influence the development of emotional behavior, stress- and pain-modulation systems, and brain neurotransmitter systems. Additionally, microbiota perturbations by probiotics and antibiotics exert modulatory effects on some of these measures in adult animals. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomic nervous system. Limited information is available on how these findings may translate to healthy humans or to disease states involving the brain or the gut/brain axis. Future research needs to focus on confirming that the rodent findings are translatable to human physiology and to diseases such as irritable bowel syndrome, autism, anxiety, depression, and Parkinsons disease.

Gut Microbes and the Brain: Paradigm Shift in Neuroscience

The discovery of the size and complexity of the human microbiome has resulted in an ongoing reevaluation of many concepts of health and disease, including diseases affecting the CNS. A growing body of preclinical literature has demonstrated bidirectional signaling between the brain and the gut microbiome, involving multiple neurocrine and endocrine signaling mechanisms. While psychological and physical stressors can affect the composition and metabolic activity of the gut microbiota, experimental changes to the gut microbiome can affect emotional behavior and related brain systems. These findings have resulted in speculation that alterations in the gut microbiome may play a pathophysiological role in human brain diseases, including autism spectrum disorder, anxiety, depression, and chronic pain. Ongoing large-scale population-based studies of the gut microbiome and brain imaging studies looking at the effect of gut microbiome modulation on brain responses to emotion-related stimuli are seeking to validate these speculations. This article is a summary of emerging topics covered in a symposium and is not meant to be a comprehensive review of the subject.

The Brain-Gut Axis in Abdominal Pain Syndromes

The importance of bidirectional brain-gut interactions in gastrointestinal (GI) illness is increasingly recognized, most prominently in the area of functional GI syndromes such as irritable bowel syndrome (IBS), functional dyspepsia, and functional chest pain. The brain receives a constant stream of interoceptive input from the GI tract, integrates this information with other interoceptive information from the body and with contextual information from the environment, and sends an integrated response back to various target cells within the GI tract. This system is optimized to assure homeostasis of the GI tract during physiological perturbations and to adapt GI function to the overall state of the organism. In health, the great majority of interoceptive information reaching the brain is not consciously perceived but serves primarily as input to autonomic reflex pathways. In patients with functional abdominal pain syndromes, conscious perception of interoceptive information from the GI tract, or recall of interoceptive memories of such input, can occur in the form of constant or recurrent discomfort or pain. This is often associated with alterations in autonomic nervous system output and with emotional changes. A model is proposed that incorporates reported peripheral and central abnormalities in patients with IBS, extrapolates similar alterations in brain-gut interactions to patients with other chronic abdominal pain syndromes, and provides novel treatment targets.

Quantitative Meta-analysis Identifies Brain Regions Activated During Rectal Distension in Irritable Bowel Syndrome

BACKGROUND AND AIMS The responsiveness of the central nervous system is altered in patients with irritable bowel syndrome (IBS). However, because of variations in experimental paradigms, analytic techniques, and reporting practices, little consensus exists on brain responses to visceral stimulation. We aimed to identify brain regions consistently activated by supraliminal rectal stimulation in IBS patients and healthy subjects (controls) by performing a quantitative meta-analysis of published studies. METHODS Significant foci from within-group statistical parametric maps were extracted from published neuroimaging studies that employed rectal distension. Voxel-based activation likelihood estimation was applied, pooling the results and comparing them across groups. RESULTS Across studies, there was consistent activation in regions associated with visceral afferent processing (ie, thalamus, insula, anterior midcingulate) among IBS patients and controls, but considerable differences in the extent and specific location of foci. IBS patients differed from controls in that there were more consistent activations in regions associated with emotional arousal (pregenual anterior cingulate cortex, amygdala) and activation of a midbrain cluster, a region playing a role in endogenous pain modulation. Controls showed more consistent activation of the medial and lateral prefrontal cortex. CONCLUSIONS Patients with IBS have greater engagement of regions associated with emotional arousal and endogenous pain modulation, but similar activation of regions involved in processing of visceral afferent information. Controls have greater engagement of cognitive modulatory regions. These results support a role for central nervous system dysregulation in IBS. These findings provide specific targets for guiding development of future neuroimaging protocols to more clearly define altered brain-gut interactions in IBS.

Regional Gray Matter Density Changes in Brains of Patients With Irritable Bowel Syndrome

BACKGROUND & AIMS Several studies have examined structural brain changes associated with chronic pain syndromes, including irritable bowel syndrome (IBS), but study sample sizes have been small and heterogeneous. METHODS We used magnetic resonance imaging-based techniques, voxel-based morphometry, and cortical thickness analysis to examine brain anatomical differences in a relatively large, tightly screened sample of IBS patients (n = 55); we compared data with that from healthy persons (controls; n = 48). RESULTS IBS was associated with decreased gray matter density (GMD) in widespread areas of the brain, including medial prefrontal and ventrolateral prefrontal cortex, posterior parietal cortex, ventral striatum, and thalamus. Compared with controls, we observed increased GMD in patients with IBS in the pregenual anterior cingulate cortex and the orbitofrontal cortex, as well as trends in the posterior insula/secondary somatosensory cortex, (para)hippocampus, and left dorsolateral prefrontal cortex. In accounting for anxiety and depression, we found that several of the regions involved in affective processing no longer differed between patients with IBS and controls, whereas the differences in prefrontal and posterior parietal cortices remained. The areas of decreased GMD associated with IBS were largely consistent across clinical subgroups, based on predominant bowel habit and pain predominance of symptoms. No overall or regional differences were observed in cortical thickness between patients with IBS and controls. CONCLUSIONS Changes in density of gray matter among regions involved in cognitive/evaluative functions are specifically observed in patients with IBS, whereas changes in other areas of the brain can be explained by levels of anxiety and depression.

Impact of mindfulness-based stress reduction training on intrinsic brain connectivity

The beneficial effects of mindful awareness and mindfulness meditation training on physical and psychological health are thought to be mediated in part through changes in underlying brain processes. Functional connectivity MRI (fcMRI) allows identification of functional networks in the brain. It has been used to examine state-dependent activity and is well suited for studying states such as meditation. We applied fcMRI to determine if Mindfulness-Based Stress Reduction (MBSR) training is effective in altering intrinsic connectivity networks (ICNs). Healthy women were randomly assigned to participate in an 8-week Mindfulness-Based Stress Reduction (MBSR) training course or an 8-week waiting period. After 8 weeks, fMRI data (1.5T) was acquired while subjects rested with eyes closed, with the instruction to pay attention to the sounds of the scanner environment. Group independent component analysis was performed to investigate training-related changes in functional connectivity. Significant MBSR-related differences in functional connectivity were found mainly in auditory/salience and medial visual networks. Relative to findings in the control group, MBSR subjects showed (1) increased functional connectivity within auditory and visual networks, (2) increased functional connectivity between auditory cortex and areas associated with attentional and self-referential processes, (3) stronger anticorrelation between auditory and visual cortex, and (4) stronger anticorrelation between visual cortex and areas associated with attentional and self-referential processes. These findings suggest that 8 weeks of mindfulness meditation training alters intrinsic functional connectivity in ways that may reflect a more consistent attentional focus, enhanced sensory processing, and reflective awareness of sensory experience.

Sex specific alterations in autonomic function among patients with irritable bowel syndrome

Background: Irritable bowel syndrome (IBS) is associated with increased psychological symptoms, early life stressors, and alterations in visceral perception and brain responses to noxious visceral stimuli. The autonomic nervous system (ANS) is a likely mediator for these brain-gut interactions. The few studies directly examining ANS measures have been suggestive of alterations in some IBS patients, but no studies to date have examined the potentially critical variables of sex differences or response to visceral stimulation. Aims: (1) To test differences in ANS function during rest and during a visceral stressor (rectosigmoid balloon distension) between IBS patients and healthy control subjects. (2) To examine the role of sex on the autonomic responses of IBS patients. Methods: Baseline autonomic measures were evaluated from 130 Rome I positive IBS patients and 55 healthy control subjects. Data were also collected from a subset of 46 IBS patients and 16 healthy control subjects during a sigmoid balloon distension study. Heart rate variability measures of peak power ratio (PPR) and peak power high frequency (PPHF) were analysed to assess sympathetic balance and parasympathetic response, respectively. Peripheral sympathetic response was measured by skin conductance. Results: IBS patients showed a greater skin conductance response to visceral distension than controls. IBS patients had higher PPR and lower PPHF across conditions. Male IBS patients had higher skin conductance and PPR than females and lower PPHF. Conclusions: IBS patients have altered autonomic responsiveness to a visceral stressor, with increased sympathetic and decreased parasympathetic activity. These differences are predominantly seen in males.

Characterization of the alternating bowel habit subtype in patients with irritable bowel syndrome.

BACKGROUND:Due to a wide range of symptom patterns, patients with irritable bowel syndrome (IBS) are often subgrouped by bowel habit. However, the IBS subgroup with alternating bowel habits (IBS-A) has been poorly characterized.OBJECTIVES:(i) To determine a set of bowel habit symptom criteria, which most specifically identifies IBS patients with an alternating bowel habit, (ii) to describe IBS-A bowel symptom patterns, and (iii) to compare clinical characteristics among IBS-A, constipation-predominant (IBS-C), and diarrhea-predominant IBS (IBS-D).METHODS:One thousand one hundred and two Rome I positive IBS patients were analyzed. Three sets of potential criteria for IBS-A were developed and compared by multirater Kappa test. Gastrointestinal, psychological, extraintestinal symptoms, and health-related quality of life were compared in IBS-A, IBS-C, and IBS-D using χ2 test and analysis of variance (ANOVA).RESULTS:Stool consistency was determined to be the most specific criteria for alternating bowel habits. IBS-A patients reported rapid fluctuations in bowel habits with short symptom flares and remissions. There was a greater prevalence of psychological and extraintestinal symptoms in the IBS-A subgroup compared to IBS-C and IBS-D. No differences were seen between bowel habit subtypes in health-related quality of life.CONCLUSIONS:IBS-A patients have rapidly fluctuating symptoms and increased psychological comorbidity, which should be taken into account for clinical practice and clinical trials.

Brain responses to visceral stimuli reflect visceral sensitivity thresholds in patients with irritable bowel syndrome.

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.