Comprehensive elucidation of resting-state functional connectivity in anorexia nervosa by a multicenter cross-sectional study.

BACKGROUND: Previous research on the changes in resting-state functional connectivity (rsFC) in anorexia nervosa (AN) has been limited by an insufficient sample size, which reduced the reliability of the results and made it difficult to set the whole brain as regions of interest (ROIs). METHODS: We analyzed functional magnetic resonance imaging data from 114 female AN patients and 135 healthy controls (HC) and obtained self-reported psychological scales, including eating disorder examination questionnaire 6.0. One hundred sixty-four cortical, subcortical, cerebellar, and network parcellation regions were considered as ROIs. We calculated the ROI-to-ROI rsFCs and performed group comparisons. RESULTS: Compared to HC, AN patients showed 12 stronger rsFCs mainly in regions containing dorsolateral prefrontal cortex (DLPFC), and 33 weaker rsFCs primarily in regions containing cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between anterior cingulate cortex (ACC) and thalamus (p < 0.01, false discovery rate [FDR] correction). Comparisons between AN subtypes showed that there were stronger rsFCs between right lingual gyrus and right supracalcarine cortex and between left temporal occipital fusiform cortex and medial part of visual network in the restricting type compared to the binge/purging type (p < 0.01, FDR correction). CONCLUSION: Stronger rsFCs in regions containing mainly DLPFC, and weaker rsFCs in regions containing primarily cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between ACC and thalamus, may represent categorical diagnostic markers discriminating AN patients from HC.

Systematic reduction of gray matter volume in anorexia nervosa, but relative enlargement with clinical symptoms in the prefrontal and posterior insular cortices: a multicenter neuroimaging study.

Although brain morphological abnormalities have been reported in anorexia nervosa (AN), the reliability and reproducibility of previous studies were limited due to insufficient sample sizes, which prevented exploratory analysis of the whole brain as opposed to regions of interest (ROIs). Objective was to identify brain morphological abnormalities in AN and the association with severity of AN by brain structural magnetic resonance imaging (MRI) in a multicenter study, and to conduct exploratory analysis of the whole brain. Here, we conducted a cross-sectional multicenter study using T1-weighted imaging (T1WI) data collected between May 2014 and February 2019 in Japan. We analyzed MRI data from 103 female AN patients (58 anorexia nervosa restricting type [ANR] and 45 anorexia nervosa binge-purging type [ANBP]) and 102 age-matched female healthy controls (HC). MRI data from five centers were preprocessed using the latest harmonization method to correct for intercenter differences. Gray matter volume (GMV) was calculated from T1WI data of all participants. Of the 205 participants, we obtained severity of eating disorder symptom scores from 179 participants, including 87 in the AN group (51 ANR, 36 ANBP) and 92 HC using the Eating Disorder Examination Questionnaire (EDE-Q) 6.0. GMV reduction were observed in the AN brain, including the bilateral cerebellum, middle and posterior cingulate gyrus, supplementary motor cortex, precentral gyrus medial segment, and thalamus. In addition, the orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), rostral anterior cingulate cortex (ACC), and posterior insula volumes showed positive correlations with severity of symptoms. This multicenter study was conducted with a large sample size to identify brain morphological abnormalities in AN. The findings provide a better understanding of the pathogenesis of AN and have potential for the development of brain imaging biomarkers of AN. Trial Registration: UMIN000017456. https://center6.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000019303 .

Characteristics of disorders of gut-brain interaction in the Japanese population in the Rome Foundation Global Epidemiological Study.

BACKGROUND: The aims were to use Japanese data from the Rome Foundation Global Epidemiological Study (RFGES) to test the hypotheses that severity of gastrointestinal (GI) symptoms and psychosocial disturbance are ordered as Rome IV irritable bowel syndrome (IBS) > Rome III IBS > DGBI, not IBS > others. METHODS: Subjects were 2504 Japanese in the RFGES. We assessed DGBI/IBS diagnoses with Rome IV/III, IBS Symptom Severity Scale (IBS-SSS), Patient Health Questionnaire (PHQ) for anxiety/depression and non-GI somatic symptoms, PROMIS-10 for quality of life (QOL), Work Productivity and Activity Impairment (WPAI) Questionnaire, parts of Self-reported IBS Questionnaire (SIBSQ) for meal effect and stress effect, Food Frequency Questionnaire, and medication questions. KEY RESULTS: The prevalence of Rome IV DGBI was as follows; IBS-C 0.5%, IBS-D 0.8%, IBS-M 0.8%, IBS-U 0.1%, unspecified functional bowel disorder 10.7%, postprandial distress syndrome 2.2%, and epigastric pain syndrome 0.3%. Rome III IBS prevalence; IBS-C 3.0%, IBS-D 3.1%, IBS-M 2.7%, and IBS-U 0.6%. Comparison among Rome IV IBS (n = 54), Rome III IBS (n = 197), other DGBI (n = 746), others (n = 1389) revealed significant order as Rome IV IBS > Rome III IBS > other DGBI > others in IBS-SSS, anxiety/depression, activity impairment, non-GI symptoms, physical QOL, mental QOL, exacerbated symptoms by meals and perceived stress (all p < 0.001). CONCLUSIONS & INFERENCES: These findings support the study hypotheses. Data from Japan as a culturally homogenous country suggest Rome IV IBS is more severe and hence has more gut-brain psychobehavioral involvement than Rome III IBS.

Automatic adaptive emotion regulation is associated with lower emotion-related activation in the frontoparietal cortex and other cortical regions with multi-componential organization.

Although some researchers consider automatic adaptive emotion regulation to be an automatized strategy whereas others consider it to be implicit disengagement of deliberative process, to date, its neural correlates have been poorly investigated. In addition, the valence specificity of automatic adaptive emotion regulation and levels of activation relative to the neutral condition are controversial; the former is relevant to the attribution of resilient emotion regulation to positivity bias or emotional stability, and the latter to determining whether regulation is based on emotion-specific or emotion-non-specific processes. In this functional magnetic resonance imaging (fMRI) study, we presented positive and negative emotional pictures to healthy young participants and investigated the neural correlates of automatic adaptive emotion regulation in spontaneous emotional response. A significant negative trait effect (i.e., regression coefficient) on activation was identified both for positive and negative emotional responses in various cortical regions. A cluster analysis identified three clusters among these regions based on the valence specificity of the trait effect and level of activation relative to neutral stimuli. Cluster 1 included regions in the sensorimotor cortex characterized by negative emotion-specific decreases in activation relative to neutral stimuli in adaptive individuals. Cluster 2 included several cortical regions including the bilateral dorsal executive network, anterior cingulate, and inferior frontal gyrus, which were characterized by valence-independent decreases in activation in adaptive individuals. Cluster 3 included the bilateral ventrolateral and dorsomedial prefrontal cortices, right insula, and other posterior regions, which were characterized by increased activation for negative stimuli in non-adaptive individuals. These findings support the assumption that automatic adaptive emotion regulation involves the implicit disengagement of deliberative process and suggest the relevance of different cortical networks to the potential emotion- and valence-specificity of adaptive regulation.

Impact of mindfulness tendency and physical activity on brain-gut interactions.

BACKGROUND: Irritable bowel syndrome (IBS) is a disorder of brain-gut interactions characterized by abdominal pain and bowel dysfunction. Exercise and mindfulness have been reported to be effective on IBS, but there has been no study of their interaction. In this study, we hypothesized that exercise and mindfulness interactively affect the severity of IBS symptoms. METHODS: Subjects were 703 adolescents with 590 women and 113 men. Their IBS status was evaluated with Rome III Diagnostic Questionnaire and IBS Severity Index (IBS-SI). They also fulfilled past exercise experience, athletic performance and exercise enthusiasm, International Physical Activity Questionnaire (IPAQ), Mindful Attention Awareness Scale (MAAS), Kessler 6 Scale (K6), and Perceived Stress Scale (PSS). Statistical analysis was performed using SPSS v25. RESULTS: In this population, 184 (158 women and 26 men, 14.1%) subjects had Rome III IBS symptoms. IBS subjects scored significantly less in exercise enthusiasm at high school (p = 0.017) and MAAS (p < 0.001) and significantly more K6 (p < 0.001) and PSS (p < 0.001) than non-IBS. The two-way ANOVA on IBS-SI showed a significant main effect of MAAS (p < 0.001) and interaction between MAAS and IPAQ (p = 0.008). CONCLUSION: It is suggested that mindfulness per se decreases IBS severity, but that mindfulness and physical activity interactively affect the severity. Further studies on how to design interventional trials for IBS patients with mindfulness and physical exercise are warranted.

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.

Oxytocin antagonist induced visceral pain and corticotropin-releasing hormone neuronal activation in the central nucleus of the amygdala during colorectal distention in mice.

Activation of neurons containing oxytocin and corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) of the hypothalamus, the anterior cingulate cortex (ACC), and the central nucleus of the amygdala (CeA) during colorectal distention (CRD) is likely to play a crucial role in animal models of irritable bowel syndrome (IBS). Earlier studies in rodents showed that the microbiome is involved in social behavior via oxytocin expression in the brain. However, the detailed mechanism of visceral sensation and oxytocin is largely unknown. We tested the following hypotheses: (1) that oxytocin neurons in the PVN are activated by CRD, and (2) that the activation of oxytocin neurons by CRD is related to anxiety-like behavior, visceral perception, and an activation of CRH CeA neurons or ACC neurons. Oxytocin antagonist caused visceral hypersensitivity and anxiety-like behavior. In the PVN, oxytocin neurons were activated by CRD. Noxious CRD activated the CeA, basolateral nucleus of the amygdala (BLA), and ACC. High-dose oxytocin antagonist suppressed ACC activity and activated CRH CeA neurons. These results support our hypotheses. Oxytocin likely regulates CRH CeA neurons in an inhibitory manner and the ACC in an excitatory manner. Further research into the interaction of oxytocin and CRH in visceral pain and anxiety is warranted.

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.

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.

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.

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.

Altered brain and gut responses to corticotropin-releasing hormone (CRH) in patients with irritable bowel syndrome.

Stress is a known trigger of irritable bowel syndrome (IBS) and exacerbates its gastrointestinal symptoms. However, underlying the physiological mechanism remains unknown. Here, we investigated hypothalamic-pituitary-adrenal (HPA) axis, colonic motility, and autonomic responses to corticotropin-releasing hormone (CRH) administration as well as brain activity alterations in IBS. The study included 28 IBS patients and 34 age and sex-matched healthy control subjects. IBS patients demonstrated greater adrenocorticotropic hormone (ACTH) responses to CRH than control subjects. Male IBS patients had greater increases in colonic motility than male HCs after CRH. Female IBS patients showed altered sympathovagal balance and lower basal parasympathetic tone relative to female control subjects. Brain responses to rectal distention were measured in the same subjects using functional magnetic resonance imaging, and their associations with individual ACTH responses to CRH were tested. A negative association between ACTH response to CRH and activity in the pregenual anterior cingulate cortex (pACC) during rectal distention was identified in controls but not in IBS patients. Impaired top-down inhibitory input from the pregenual ACC to the HPA axis may lead to altered neuroendocrine and gastrointestinal responses to CRH. Centrally acting treatments may dampen the stress induced physical symptoms in IBS.

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.

Relationship between Job Stress and Hypo-high-density Lipoproteinemia of Chinese Workers in Shanghai: The Rosai Karoshi Study.

BACKGROUND: Karoshi, or death due to overwork, has now become a serious social problem in China. Worsening of cardiovascular risks by stress might initiate karoshi. Many studies have examined the relationship between job stress and obesity, hypertension, and type 2 diabetes mellitus, but less evidence exists for dyslipidemia like hypo-high-density lipoproteinemia (hypo-HDL). The aim of this study was to investigate the relationship between job stress and hypo-HDL of Chinese workers in Shanghai. METHODS: We studied 2219 Chinese workers in Shanghai, who participated in the Japan-China cooperative study for the prevention of karoshi. A questionnaire was administered to examine the lifestyle characteristics, job category, weekly working hours, and job stress. Job demand and job control were quantified using the National Institute for Occupational Safety and Health questionnaire. Modified job strain measure was defined by the combination of low job control and high demand. Hypo-HDL was defined as plasma high-density lipoprotein cholesterol concentration of <1.04 mmol/L (40 mg/dl). Multivariate logistic regression analysis was performed for hypo-HDL as a dependent variable. RESULTS: Modified job strain was not related to hypo-HDL either in men or women. In men, multivariate adjusted odds ratio (OR) for having hypo-HDL was significantly higher in the lowest job control tertile compared with the highest job control tertile (OR = 1.39, 95% confidence interval [CI] 1.03-1.87, P = 0.034). In the same model, a similar trend was observed for women, but it did not reach a statistically significant level (OR = 1.51, 95% CI, 0.88-2.56, P = 0.132). CONCLUSION: A low level of job control but not modified job strain was significantly related to higher prevalence of hypo-HDL of Chinese workers in Shanghai.