Consumption of 2 Green Kiwifruits Daily Improves Constipation and Abdominal Comfort-Results of an International Multicenter Randomized Controlled Trial.

INTRODUCTION: Consumption of green kiwifruit is known to relieve constipation. Previous studies have also reported improvements in gastrointestinal (GI) comfort. We investigated the effect of consuming green kiwifruit on GI function and comfort. METHODS: Participants included healthy controls (n = 63), patients with functional constipation (FC, n = 60), and patients with constipation-predominant irritable bowel syndrome (IBS-C, n = 61) randomly assigned to consume 2 green kiwifruits or psyllium (7.5 g) per day for 4 weeks, followed by a 4-week washout, and then the other treatment for 4 weeks. The primary outcome was the number of complete spontaneous bowel movements (CSBM) per week. Secondary outcomes included GI comfort which was measured using the GI symptom rating scale, a validated instrument. Data (intent-to-treat) were analyzed as difference from baseline using repeated measures analysis of variance suitable for AB/BA crossover design. RESULTS: Consumption of green kiwifruit was associated with a clinically relevant increase of ≥ 1.5 CSBM per week (FC; 1.53, P < 0.0001, IBS-C; 1.73, P = 0.0003) and significantly improved measures of GI comfort (GI symptom rating scale total score) in constipated participants (FC, P < 0.0001; IBS-C, P < 0.0001). No significant adverse events were observed. DISCUSSION: This study provides original evidence that the consumption of a fresh whole fruit has demonstrated clinically relevant increases in CSBM and improved measures of GI comfort in constipated populations. Green kiwifruits are a suitable dietary treatment for relief of constipation and associated GI comfort.

Insula Activity to Visceral Stimulation and Endocrine Stress Responses as Associated With Alexithymia in Patients With Irritable Bowel Syndrome.

OBJECTIVE: Few studies have investigated associations between alexithymia and physiological mechanisms in psychosomatic diseases. We examined associations between alexithymia and 1) perception and brain processing of visceral stimulation and 2) the endocrine responses to corticotrophin-releasing hormone (CRH) in healthy individuals and patients with irritable bowel syndrome (IBS). METHODS: The study included 29 patients with IBS and 35 age- and sex-matched healthy controls (HCs). Alexithymia was measured using the 20-item Toronto Alexithymia Scale (TAS-20). Brain responses to rectal distention and its anticipation were measured by functional magnetic resonance imaging and analyzed at a voxel-level threshold of puncorrected < .001 combined with a cluster-level threshold of pFWE-corrected < .05. On a different day, plasma adrenocorticotropic hormone and cortisol responses after intravenous CRH administration were measured. RESULTS: TAS-20 scores did not differ significantly between patients with IBS and HCs (p = .18). TAS-20 scores correlated positively with the individual rectal discomfort thresholds (ßrobust = 0.49, p = .03) and negatively with the rating of fear before rectal distention (ßrobust = -1.63, p = .04) in patients with IBS but not in HCs. Brain responses to rectal distention in the right insula and other brain regions were positively associated with TAS-20 scores to a greater extent in patients with IBS than in HCs. Individuals with higher TAS-20 scores (both patients with IBS and HCs) demonstrated stronger adrenocorticotropic hormone responses to CRH administration (F(4,224) = 3.54, p = .008). CONCLUSION: Higher alexithymia scores are associated with stronger physiological responses, but lower anticipatory fear ratings and higher discomfort thresholds, particularly in patients with IBS.

Imaging Brain Mechanisms of Functional Somatic Syndromes: Potential as a Biomarker?

When patients present with persistent bodily complaints that cannot be explained by a symptom-linked organic pathology (medically unexplained symptoms), they are diagnosed with 'functional' somatic syndromes (FSS). Despite their prevalence, the management of FSS is notoriously challenging in clinical practice. This may be because FSS are heterogeneous disorders in terms of etiopathogenesis. They include patients with primarily peripheral dysfunction, primarily centrally driven somatic symptoms, and a mix of both. Brain-imaging studies, particularly data-driven pattern recognition methods using machine learning algorithms, could provide brain-based biomarkers for these clinical conditions. In this review, we provide an overview of our brain imaging data on brain-body interactions in one of the most well-known FSS, irritable bowel syndrome (IBS), and discuss the possible development of a brain-based biomarker for FSS. Anticipation of unpredictable pain, which commonly elicits fear in FSS patients, induced increased activity in brain areas associated with hypervigilance during rectal distention and non-distention conditions in IBS. This was coupled with dysfunctional inhibitory influence of the medial prefrontal cortex (mPFC) and pregenual anterior cingulate cortex (pACC) on stress regulation systems, resulting in the activated autonomic nervous system (ANS) and neuroendocrine system stimulated by corticotropin-releasing hormone (CRH). IBS subjects with higher alexithymia, a risk factor for FSS, showed stronger activity in the insula during rectal distention but reduced subjective sensitivity. Reduced top-down regulation of the ANS and CRH system by mPFC and pACC, discordance between the insula response to stimulation and subjective sensation of pain, and stronger threat responses in hypervigilance-related areas may be a candidate brain-based biomarker.

Influence of Uncertain Anticipation on Brain Responses to Aversive Rectal Distension in Patients With Irritable Bowel Syndrome.

OBJECTIVE: We investigated whether certainty and uncertainty of impending aversive visceral sensation differently modulate regional brain activity, both during anticipation and visceral sensation in irritable bowel syndrome (IBS) patients compared with healthy controls. METHODS: Twenty-six IBS patients (14 women) and 29 healthy controls (15 women) were enrolled in a functional magnetic resonance imaging study. Participants received rectal distention at an individually titrated severe discomfort level that was preceded by visual cues to induce certain (100% chance of distention), uncertain (50% chance), and safe (0% chance) anticipation. RESULTS: Subjective ratings of anticipatory fear before and discomfort during distention were similar between IBS and control participants under cued certainty and uncertainty (p > .05). Uncertain anticipation compared with certain anticipation induced greater activation of anterior midcingulate cortex, thalamus, and visual processing areas in IBS patients compared with controls. Rectal distention after the uncertain, but not certain, cue induced higher activity in the posterior- and midcingulate cortices and the precuneus in IBS compared with controls. Controls exhibited bilateral insula activation during the nondistention period after the uncertain cue compared with the safe cue. IBS patients failed to produce this response, which was possibly due to elevated bilateral insular responses during nondistention after the safe cue. Brain data were significant at a voxel-level threshold of puncorrected value of less than .005 combined with a cluster-level threshold of pFWE-corrected value of less than .05. CONCLUSIONS: Preceding uncertainty differentially modulates the brain processing of physiologically identical rectal stimulation in IBS patients. Cue-dependent alterations in brain responses may underlie hypervigilance to visceral sensations in IBS patients.

Association between disturbance of self-organization and irritable bowel syndrome in Japanese population using the international trauma questionnaire.

Disturbance of self-organization (DSO) is defined by affective dysregulation, negative self-concept, and disturbances in relationships. Along with post-traumatic stress disorder (PTSD), DSO is a part of complex post-traumatic stress disorder (CPTSD), which often results from childhood trauma and has life-long consequences. We investigated the association between CPTSD, PTSD, DSO, childhood adversity, and irritable bowel syndrome (IBS). Individuals with IBS exhibited markedly higher prevalences of DSO, CPTSD, and PTSD symptoms and higher trauma scores compared with healthy individuals. The odds of having IBS were 3.718 and 1.924 times greater for those with DSO symptoms (p < .001) and CPTSD symptoms (p = .005), respectively. IBS severity was highest in the DSO group, followed by the CPTSD, PTSD, and non-DSO/CPTSD/PTSD groups. DSO symptoms mediate the impact of childhood adversity on IBS symptoms, explaining half of this effect, whereas PTSD symptoms do not. These findings suggest a significant role of DSO in the development of IBS.

Sex differences in brain response to anticipated and experienced visceral pain in healthy subjects.

Women demonstrate higher pain sensitivity and prevalence of chronic visceral pain conditions such as functional gastrointestinal disorders than men. The role of sex differences in the brain processing of visceral pain is still unclear. In 16 male and 16 female healthy subjects we compared personality, anxiety levels, skin conductance response (SCR), and brain processing using functional MRI during anticipation and pain induced by esophageal distension at pain toleration level. There was no significant difference in personality scores, anxiety levels, SCR, and subjective ratings of pain between sexes. In group analysis, both men and women demonstrated a similar pattern of brain activation and deactivation during anticipation and pain consistent with previous reports. However, during anticipation women showed significantly greater activation in the cuneus, precuneus, and supplementary motor area (SMA) and stronger deactivation in the right amygdala and left parahippocampal gyrus, whereas men demonstrated greater activation in the cerebellum. During pain, women demonstrated greater activation in the midcingulate cortex, anterior insula, premotor cortex, and cerebellum and stronger deactivation in the caudate, whereas men showed increased activity in the SMA. The pattern of brain activity suggests that, during anticipation, women may demonstrate stronger limbic inhibition, which is considered to be a cognitive modulation strategy for impending painful stimulation. During pain, women significantly activate brain areas associated with the affective and motivation components of pain. These responses may underlie the sex differences that exist in pain conditions, whereby women may attribute more emotional importance to painful stimuli compared with men.

Effects of preceding stimulation on brain activation in response to colonic distention in humans.

OBJECTIVE: It has been suggested that the pattern of distension (moderate following mild and vice versa) might influence brain activation and the experience of hypersensitivity, offset analgesia, and anticipation. Nevertheless, how the pattern of stimulation affects sensitization and/or desensitization to visceral stimulation remains unknown. METHODS: In 45 nonclinical healthy participants (12 women, 33 men; 20-26 years old), brain processing of visceral sensation induced by colonic distension was examined using H2(15)O positron emission tomography. Subjective feelings regarding the stimuli were also measured. The descending colon was stimulated using six patterns of three bag pressures (0, 20, and 40 mm Hg). To evaluate the neural sensitization to visceral stimulation arising from the precedence effect, the effects of a 20- or 40-mm Hg distention after a sham or 20- or 40-mm Hg distension were analyzed using statistical parametric mapping. The level of significance was set at a voxelwise level of p < .0001, with cluster extent sizes of k > 50. RESULTS: The midbrain, insula, and cerebellum, were more strongly activated by a 20-mm Hg distension with a preceding 40-mm Hg distention than by a 20-mm Hg distention without a preceding stimulation (p < .0001). Conversely, a sham stimulation after the experience of an intense stimulation activated the midcingulate cortex, compared with a sham stimulation without the experience of actual visceral stimulation (p < .0001). CONCLUSIONS: By directly comparing different patterns of visceral stimuli, preceding visceral stimuli may affect neural sensitization and/or desensitization in humans, including elevated midbrain, insula, and midcingulate cortex.

Neuroticism influences brain activity during the experience of visceral pain.

BACKGROUND & AIMS: One particularly important individual dynamic known to influence the experience of pain is neuroticism, of which little is known about in visceral pain research. Our aim was to study the relationship between neuroticism, psychophysiologic response, and brain processing of visceral pain. METHODS: Thirty-one healthy volunteers (15 male; age range, 22-38 years) participated in the study. The Eysenck Personality Questionnaire was used to assess neuroticism. Skin conductance level, pain ratings, and functional magnetic resonance imaging data were acquired during anticipation of pain and painful esophageal distention. The effect of neuroticism was assessed using correlation analysis. RESULTS: There was a wide spread of neuroticism scores (range, 0-22) but no influence of neuroticism on skin conductance level and pain tolerance or pain ratings. However, a positive correlation between brain activity and neuroticism during anticipation was found in regions associated with emotional and cognitive pain processing, including the parahippocampus, insula, thalamus, and anterior cingulate cortex. These regions showed a negative correlation with neuroticism during pain (P < .001). CONCLUSIONS: This study provides novel data suggesting higher neuroticism is associated with engagement of brain regions responsible for emotional and cognitive appraisal during anticipation of pain but reduced activity in these regions during pain. This may reflect a maladaptive mechanism in those with higher neuroticism that promotes overarousal during anticipation and avoidance coping during pain.

Serotonin transporter gene promoter polymorphism and alexithymia.

BACKGROUND: Recent neurobiological studies have reported that alexithymia may result from altered brain function related to emotional processing. Serotonin (5-hydroxytryptamine, 5-HT) has been shown to regulate central nervous system development associated with psychological processing. We investigated the possibility that polymorphism of the 5-HT transporter-linked promoter region (5-HTTLPR) is associated with alexithymia. METHODS: This study included 304 healthy Japanese volunteers (148 males, 156 females). The subjects were categorized according to genotype (L/L, L/S, S/S) and results of the 20-item Toronto Alexithymia Scale (TAS-20), State-Trait Anxiety Inventory (STAI) and Self-Rating Depression Scale (SDS). RESULTS: Subjects with the L/L genotype showed significantly higher TAS-20 scores, as well as significantly higher scores on the difficulty identifying feeling (DIF) subscale, than those with the L/S or S/S genotype (p < 0.05). There was a gender difference in the association between 5-HTTLPR genotype and DIF score. Female subjects with the L/L genotype showed significantly higher DIF scores than those with the L/S or S/S genotype (p ≤ 0.001). Neither STAI nor SDS was significantly associated with the 5-HTTLPR genotype. CONCLUSION: These results suggest a link between low synaptic 5-HT and alexithymia.

Histamine Neuroimaging in Stress-Related Disorders.

Although histamine plays a major role in animal models of stress-related disorders, human neuroimaging data are sparse. Histamine H1 receptors in the human brain were first imaged by Professor Kazuhiko Yanai in 1992 by using 11C-doxepin, a potent ligand of H1 receptors, and positron emission tomography (PET). Subsequent work revealed that H1 receptors are reduced in the prefrontal and anterior cingulate cortices in patients with major depressive disorders. A sex difference in H1 receptor binding in the brain has also been found, with women exhibiting more abundant H1 receptor binding than men. Moreover, female patients with anorexia nervosa show higher H1 receptor binding in the amygdala and lentiform nucleus. These studies also found an inverse correlation of depression scores with H1 receptor binding. Histamine is considered to play a major role in the pathophysiology of irritable bowel syndrome (IBS), a representative disorder of brain-gut interactions. Along these lines, hypnotic suggestion dramatically changes the waveforms of viscerosensory cerebral evoked potentials in response to electrical rectal stimulation and these changes are modified by the administration of H1 antagonist. The direction of the H1 antagonist-induced changes in the viscerosensory cerebral evoked potentials differs between IBS patients and healthy controls. Thus, histamine likely plays an important role in stress-related disorders. Further histamine brain imaging studies of humans are warranted.

Neural substrates of decision making as measured with the Iowa Gambling Task in men with alexithymia.

OBJECTIVE: Individuals with alexithymia have a reduced ability to use their feelings to guide their behavior appropriately in social situations. To reveal the capacity to use emotional signals in alexithymia under conditions of uncertainty, this study investigates neural substrates and performance on the Iowa Gambling Task (IGT), which was developed to assess decision making based on emotion-guided evaluation. METHODS: The participants were 10 men with alexithymia and 13 without. Alexithymia was assessed by the 20-item Toronto Alexithymia Scale. Regional cerebral blood flow (rCBF) was measured by [¹5O]-H2O positron emission tomography during four trials of the IGT and two visuomotor control tasks. RESULTS: The participants with alexithymia failed to learn an advantageous decision-making strategy, with performance differing significantly from the nonalexithymic group in the fourth IGT trial (p = .029). Comparing performance between the IGT and the control tasks, both groups showed brain activation in the dorsolateral frontal area, inferior frontal lobe, pre-supplementary motor area, inferior parietal lobe, fusiform gyrus, and cerebellum. Men with alexithymia showed lower rCBF in the medial frontal area (Brodmann area [BA] 10) and higher rCBF in the caudate and occipital areas in the first and second IGT trials, which are within a learning phase according to test performance data. All brain data were significant at p ≤ .001, uncorrected. CONCLUSIONS: BA10 activity may be associated with using internal signals accompanying affective evaluation of the stimuli, which is crucial for successful decision making. Reduced BA10 activity in participants with alexithymia suggests that they may not use an emotion-based biasing signal to lead to advantageous decision making.

Modification of rectal function and emotion by repetitive transcranial magnetic stimulation in humans.

Gut microbiota may affect function of the dorsolateral prefrontal cortex (DLPFC). However, there have been a few studies on modification of brain-gut interactions with repetitive transcranial magnetic stimulation (rTMS) to the DLPFC. We hypothesized that stimulation of the right or left DPFC by rTMS modifies the brain-gut interactions in humans. Subjects were 25 healthy males. Viscerosensory evoked potential (VEP) with sham (0 mA) or actual (30 mA) electrical stimulation (ES) of the rectum was taken after sham, low frequency rTMS at 0.1 Hz, and high frequency rTMS at 10 Hz to the right or left DLPFC. Rectal tone was measured with a rectal barostat. Visceral perception and emotion were analyzed using ordinates scale, rectal barostat, and viscerosensory evoked potential. Low frequency rTMS to the right DLPFC significantly reduced the visceral sensation and emotion composite score evoked by ES at 30 mA (p < 0.05). Plasma ACTH was significantly increased by high frequency rTMS to the right or left DLPFC (p < 0.05). Rectal fine contractions were significantly induced by low frequency rTMS to the right or left DLPFC and high frequency rTMS to the right DLPFC (p < 0.05). These results suggest that stimulation of the right or left DPFC by rTMS modifies the brain-gut interactions in humans.

Concordant pattern of the HPA axis response to visceral stimulation and CRH administration.

The physiological and psychological mechanisms explaining the individual variability in the stress response are poorly understood. We tested the hypothesis that hypothalamic-pituitary- adrenal (HPA) axis responses to colorectal stimulation affect HPA axis reactivity to corticotropin-releasing hormone (CRH), the visceral pain threshold, and perceived stress. We examined 31 healthy volunteers and 27 individuals with irritable bowel syndrome. According to the ACTH response to colorectal stimulation, the participants were classified into three groups: flattened, decreased, and increased. We found significant differences in the abdominal pain threshold, discomfort threshold, and sensitivity to anxiety among the groups. There were significant differences in the ACTH change and peak level after CRH administration among the groups. The area under the curve of the cortisol response to CRH was significantly different among the groups. The increased group showed a higher basal ACTH level, earlier peak level in the CRH administration test, and higher stress rating during the experiment. The increased group had an exaggerated psychological and physiological stress response, whereas the decreased group had a higher anticipatory endocrine response, stress, and sensitivity to anxiety. Further studies are needed to determine factors including gut microbiota on the individual difference in HPA response.

Effect of autogenic training on general improvement in patients with irritable bowel syndrome: a randomized controlled trial.

Autogenic training (AT) is a useful and comprehensive relaxation technique. However, no studies have investigated the effects of AT on irritable bowel syndrome (IBS). In this study we tested the hypothesis that AT improves symptoms of IBS. Twenty-one patients with IBS were randomly assigned to AT (n = 11, 5 male, 6 female) or control therapy (n = 10, 5 male, 5 female). AT patients were trained intensively, while the control therapy consisted of discussions about patients' meal habits and life styles. All patients answered a question related to adequate relief (AR) of IBS symptoms and four questionnaires: Self-induced IBS Questionnaire (SIBSQ), Self-reported Depression Scale (SDS), State-Trait Anxiety Inventory (STAI), and Medical Outcome Short Form 36 Health Survey (SF-36). The proportion of AR in the last AT session in the AT group (9/11, 81.8%) was significantly higher than that in the controls (3/10, 30.0%, Chi-square test, p = 0.048). Two subscales of the SF-36, i.e., social functioning and bodily pain, were significantly improved in the AT group (p < 0.05) as compared to the control group. Role emotional (p = 0.051) and general health (p = 0.068) showed a tendency for improvement in the AT group. AT may be useful in the treatment of IBS by enhancing self-control.

Resting state functional connectivity of the pain matrix and default mode network in irritable bowel syndrome: a graph theoretical analysis.

Irritable bowel syndrome (IBS) is a functional disorder of brain-gut interactions. Differential brain responses to rectal distention between IBS and healthy controls (HCs) have been demonstrated, particularly in the pain matrix and the default mode network. This study aims to compare resting-state functional properties of these networks between IBS patients and HCs using graph analysis in two independent cohorts. We used a weighted graph analysis of the adjacency matrix based on partial correlations between time series in the different regions in each subject to determine subject specific graph measures. These graph measures were normalized by values obtained in equivalent random networks. We did not find any significant differences between IBS patients and controls in global normalized graph measures, hubs, or modularity structure of the pain matrix and the DMN in any of our two independent cohorts. Furthermore, we did not find consistent associations between these global network measures and IBS symptom severity or GI-specific anxiety but we found a significant difference in the relationship between measures of psychological distress (anxiety and/or depressive symptoms) and normalized characteristic path length. The responses of these networks to visceral stimulation rather than their organisation at rest may be primarily disturbed in IBS.

Common and distinct neural representations of aversive somatic and visceral stimulation in healthy individuals.

Different pain types may be encoded in different brain circuits. Here, we examine similarities and differences in brain processing of visceral and somatic pain. We analyze data from seven fMRI studies (N = 165) and five types of pain and discomfort (esophageal, gastric, and rectal distension, cutaneous thermal stimulation, and vulvar pressure) to establish and validate generalizable pain representations. We first evaluate an established multivariate brain measure, the Neurologic Pain Signature (NPS), as a common nociceptive pain system across pain types. Then, we develop a multivariate classifier to distinguish visceral from somatic pain. The NPS responds robustly in 98% of participants across pain types, correlates with perceived intensity of visceral pain and discomfort, and shows specificity to pain when compared with cognitive and affective conditions from twelve additional studies (N = 180). Pre-defined signatures for non-pain negative affect do not respond to visceral pain. The visceral versus the somatic classifier reliably distinguishes somatic (thermal) from visceral (rectal) stimulation in both cross-validation and independent cohorts. Other pain types reflect mixtures of somatic and visceral patterns. These results validate the NPS as measuring a common core nociceptive pain system across pain types, and provide a new classifier for visceral versus somatic pain.

Parasympathetic activity correlates with subjective and brain responses to rectal distension in healthy subjects but not in non-constipated patients with irritable bowel syndrome.

The nociceptive and autonomic nervous systems (ANS) are significantly intertwined. Decoupling of these systems may occur in pathological pain conditions, including irritable bowel syndrome (IBS). We investigated ANS activity and its association with visceral perception and brain activity during rectal distention in 27 patients with non-constipated IBS and 33 controls by assessing heart rate variability (HRV) using electrocardiography at rest, before, and during colorectal distention. Brain responses to colorectal distention were measured using functional magnetic resonance imaging and correlated with individual ANS function parameters. The IBS group displayed blunted sympathovagal balance [low/high-frequency ratio (LF:HF) of HRV] in response to colorectal distention compared with controls (P = 0.003). In controls, basal parasympathetic tone (HF component of HRV) was significantly negatively correlated with toleration threshold to the rectal distention, but not in patients with IBS (group comparison P = 0.04). Further, a positive correlation between baseline HF values and neural responses to rectal distension was found in the right caudate, bilateral dorsolateral anterior cingulate cortex, and pregenual anterior cingulate cortex in the control group but not in the IBS group. The results indicate abnormal interactions between ANS activity and the brain mechanisms underlying visceral perception in patients with IBS.

Understanding Neurogastroenterology From Neuroimaging Perspective: A Comprehensive Review of Functional and Structural Brain Imaging in Functional Gastrointestinal Disorders.

This review provides a comprehensive overview of brain imaging studies of the brain-gut interaction in functional gastrointestinal disorders (FGIDs). Functional neuroimaging studies during gut stimulation have shown enhanced brain responses in regions related to sensory processing of the homeostatic condition of the gut (homeostatic afferent) and responses to salience stimuli (salience network), as well as increased and decreased brain activity in the emotional response areas and reduced activation in areas associated with the top-down modulation of visceral afferent signals. Altered central regulation of the endocrine and autonomic nervous responses, the key mediators of the brain-gut axis, has been demonstrated. Studies using resting-state functional magnetic resonance imaging reported abnormal local and global connectivity in the areas related to pain processing and the default mode network (a physiological baseline of brain activity at rest associated with self-awareness and memory) in FGIDs. Structural imaging with brain morphometry and diffusion imaging demonstrated altered gray- and white-matter structures in areas that also showed changes in functional imaging studies, although this requires replication. Molecular imaging by magnetic resonance spectroscopy and positron emission tomography in FGIDs remains relatively sparse. Progress using analytical methods such as machine learning algorithms may shift neuroimaging studies from brain mapping to predicting clinical outcomes. Because several factors contribute to the pathophysiology of FGIDs and because its population is quite heterogeneous, a new model is needed in future studies to assess the importance of the factors and brain functions that are responsible for an optimal homeostatic state.

The gut-brain axis in health neuroscience: implications for functional gastrointestinal disorders and appetite regulation.

Over the past few years, scientific interest in the gut-brain axis (i.e., the bidirectional communication system between the gastrointestinal tract and the brain) has exploded, mostly due to the identification of the gut microbiota as a novel key player in this communication. However, important progress has also been made in other aspects of gut-brain axis research, which has been relatively underemphasized in the review literature. Therefore, in this review, we provide a comprehensive, although not exhaustive, overview of recent research on the functional neuroanatomy of the gut-brain axis and its relevance toward the multidisciplinary field of health neuroscience, excluding studies on the role of the gut microbiota. More specifically, we first focus on irritable bowel syndrome, after which we outline recent findings on the role of the gut-brain axis in appetite and feeding regulation, primarily focusing on the impact of subliminal nutrient-related gut-brain signals. We conclude by providing future perspectives to facilitate translation of the findings from gut-brain axis neuroscientific research to clinical applications in these domains.

Relationship between sympathoadrenal and pituitary-adrenal response during colorectal distention in the presence of corticotropin-releasing hormone in patients with irritable bowel syndrome and healthy controls.

Corticotropin-releasing hormone (CRH) mediates stress responses in the brain-gut axis. Administration of CRH modulates brain activation, for example by controlling the autonomic nervous system in response to colorectal distention. Here, we investigated the relationship between sympathoadrenal and hypothalamic-pituitary-adrenal (HPA) responses to colorectal distention in patients with irritable bowel syndrome (IBS). We enrolled 32 patients with IBS (16 women and 16 men) and 32 healthy subjects (16 women and 16 men), and randomly divided them between CRH and saline injection groups. The patients randomly underwent no (0 mmHg), mild (20 mmHg), or strong (40 mmHg) colorectal distension. CRH (2 µg/kg) or saline was then administered via injection, and the distention protocol was repeated. The heart rate (HR) and HR variability (HRV; calculated as the low [LF] to high frequency [HF] peak ratio, LF/HF) were analyzed using electrocardiography. Plasma noradrenaline, adrenaline, adrenocorticotropic hormone (ACTH), and cortisol levels were measured at the time of each distention. Plasma adrenaline levels were shown to be associated with plasma ACTH levels in HCs injected with CRH during distention using structural equation modeling analysis. Patients with IBS injected with placebo during distention displayed a closer association between these two parameters than those injected with CRH. Generalized estimating equation analysis revealed a significant distention × group × drug interaction for HF power. Moreover, there was a strong correlation between adrenaline and HRV upon CRH injection in controls, but not patients with IBS. The relationship between HPA-sympathoadrenal responses and CRH levels during colorectal distention differs between patients with IBS and controls. Modulation of adrenal gland activity in response to ACTH stimulation may contribute to the brain-gut pathophysiology characteristic of IBS.