Toyohiro Hamaguchi

Correlation between alexithymia and hypersensitivity to visceral stimulation in human

Abstract Empirical studies indicate that alexithymia exacerbates physical illness. However, direct evidence to explain the mechanism of this exacerbation has not been provided. One hypothesis is that alexithymics amplify unpleasant internal signals. In the present study, we investigated how alexithymia influences sensitivity to visceral stimulation in human. In 45 non‐clinical healthy subjects (34 males and 11 females), brain processing of visceral sensation induced by colonic distension was examined using H215O positron emission tomography (PET). Subjective feeling evaluated on an ordinate scale and neuroendocrine response to stimuli were also measured. The degree of alexithymia was determined using the 20‐item of Toronto alexithymia scale (TAS‐20), and the correlation between reaction to stimuli and the scores of TAS‐20 and its three subscales [difficulty to identify feelings (DIF), difficulty to describe feelings (DDF) and external oriented thinking (EOT)] was evaluated. Greater activation was observed during colonic distension in the pregenual anterior cingulate cortex, right insula and midbrain in the 10 (out of 45) subjects that were identified as alexithymic by TAS‐20 scores larger than 61. TAS‐20 scores positively correlated with both activity in the right insula and orbital gyrus and adrenaline levels in the blood in response to stimulation. Subjects with high scores of DIF perceived strong pain, urgency for defecation, stress, anxiety, and slight sleepiness. The present study demonstrates that alexithymia is associated with hypersensitivity to visceral stimulation. This finding supports the somatosensory amplification hypothesized in alexithymics and is important to elucidate the influence of alexithymia on brain‐gut function, particularly to understand the pathophysiology of FGIDs (functional gastrointestinal disorders).

Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention.

BACKGROUND AND AIMS Determining the gene that plays a key role in brain-gut interactions is a crucial step for clarifying the pathophysiology of irritable bowel syndrome (IBS). We previously reported that the 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is related to anxiety in subjects with IBS. The amygdala is more activated during fearful face recognition in individuals with the s allele of 5-HTTLPR. Here, we tested our hypothesis that 5-HTTLPR differentially activates brain regions with colorectal distention in humans. METHODS We enrolled 28 subjects without any organic disease. The study was approved by the Ethics Committee and all subjects gave written informed consent. DNA was extracted from the peripheral blood. The genotype of 5-HTTLPR was determined using polymerase chain reaction. Age, sex, diagnosis-matched individuals with the s/s genotype (n=14) and individuals with the l allele (genotypes l/s, l/l, l/extra-l, n=14) were compared. A barostat bag was inserted to the colorectum and was intermittently inflated with no (0 mm Hg), mild (20 mm Hg), or intense (40 mm Hg) stimulation on a random order. Radioactive H2[(15-)O] saline was injected at bag inflation and then positron emission tomography was performed. Changes in rCBF were analyzed using statistical parametric mapping. RESULTS Individuals with the s/s genotype showed a significantly larger increase in rCBF by colorectal distention from 0 mm Hg to 40 mm Hg than individuals with the l allele. The significantly more activated brain regions in individuals with the s/s genotype were the left anterior cingulate cortex and right parahippocampal gyrus (p<0.0001). The increase in rCBF by colorectal distention of 20 mm Hg compared with 0 mm Hg was significantly larger in the left orbitofrontal cortex of individuals with the s/s genotype than that of individuals with the l allele (p<0.0001). CONCLUSION These data suggest that individuals with a weak function of serotonin transporter respond to gut signals more in emotion-regulating brain regions. Functional gene polymorphism may partially predict the individual effect of a selective serotonin reuptake inhibitor on visceral pain.

Brain activity during distention of the descending colon in humans

Abstract  Brain‐gut interaction is considered to be a major factor in the pathophysiology of irritable bowel syndrome. However, only limited information has been provided on the influence of gastrointestinal tract stimulation on the brain. Our aim in this study was to determine the specific regions of the brain that are responsible for visceral perception and emotion provoked by distention of the descending colon in humans. Fifteen healthy males aged 22 ± 1 participated in this study. Using a colonoscope, a balloon was inserted into the descending colon of each subject. After sham stimulation, the colon was randomly stimulated with bag pressures of 20 and 40 mmHg, and regional cerebral blood flow was measured by [15O] positron emission tomography. The subjects were asked to report visceral perception and emotion using an ordinate scale of 0–10. Colonic distention pressure dependently induced visceral perception and emotion, which significantly correlated with activation of specific regions of the brain including the prefrontal, anterior cingulate, parietal cortices, insula, pons, and the cerebellum. In conclusion, distention of the descending colon induces visceral perception and emotion. These changes significantly correlate with activation of specific regions in the brain including the limbic system and the association cortex, especially the prefrontal cortex.

Brain Activation Associated With Changes in Heart Rate, Heart Rate Variability, and Plasma Catecholamines During Rectal Distention

Objective: To test the hypothesis that gut stimulation provokes autonomic arousal via activation of regional cerebral cortices. How the human brain processes interoceptive signals and forms initial autonomic arousal is one of the key questions to be answered in research on emotion. Methods: Twelve healthy males participated in this study. A barostat bag was inserted in the rectum and intermittently inflated with 0, 20, or 40 mm Hg at random for 80 seconds. H215O positron emission tomography (PET) of the brain, electrocardiography, and blood sampling for catecholamines were performed. Changes in regional cerebral blood flow were interpreted using statistical parametric mapping. Results: Rectal distention with 40 mm Hg induced a significant increase in heart rate, low frequency (LF)/high frequency (HF) ratio of heart rate variability, and plasma adrenaline. Activated brain areas that were associated with increased heart rate during rectal distention were the right insula, right operculum, right dorsolateral prefrontal cortex, putamen, thalamus, periaqueductal gray, and cerebellum (p < .001, uncorrected), whereas those that were associated with an increased LF/HF ratio were the bilateral insula, putamen, thalamus, midbrain, pons, and cerebellum (p < .001, uncorrected). Activated brain areas that were associated with increased plasma adrenaline were the right insula, right orbitofrontal cortex, right parahippocampal gyrus, putamen, thalamus, periaqueductal gray, pons, and cerebellum (p < .001, uncorrected). Conclusion: Our results suggest that the right insula and the related body mapping regions may form the functional module of sympathetic arousal in response to gut stimulation. PET = positron emission tomography; rCBF = regional cerebral blood flow; SPM = statistical parametric mapping; BA = Brodmann’s area; ECG = electrocardiogram; HRV = heart rate variability; HF = high frequency component of HRV; LF = low frequency component of HRV; LF/HF = ratio of LF to HF; ANOVA = analysis of variance; MRI = magnetic resonance imaging.

Effects of personality traits on the manifestations of irritable bowel syndrome

ObjectivePrevious studies have reported that patients with irritable bowel syndrome (IBS) show high neuroticism. However, the precise association between the IBS subtypes and the degree of neuroticism in younger populations is largely unknown. We tested our hypothesis that subjects with diarrhea-predominant IBS may have a higher degree of neuroticism than subjects without IBS or those with other subtypes of IBS. We also verified the additional hypothesis that the severity of neuroticism might be correlated with the severity of IBS in younger populations.MethodsWe conducted a cross-sectional survey of 557 university students, ranging in age from 18 to 21 years. Presence/ absence of IBS and determination of the IBS subtype was by the Rome II Modular Questionnaire, while the severity of IBS was determined by the IBS severity index (IBS-SI). The degree of neuroticism was evaluated using the Maudsely Personality Inventory (MPI). The presence/absence of psychological distress was measured with the K6 scale.ResultsNeuroticism scores in the subjects with diarrhea-predominant IBS were significantly higher than those in the non-IBS subjects or subjects with constipation-predominant IBS. The neuroticism scores were significantly correlated with the IBS-SI scores in all subjects with IBS.ConclusionThese results suggest that neuroticism is involved in the pathophysiology of IBS in young subjects, especially in that of the diarrhea-predominant subtype.

Changes in salivary physiological stress markers induced by muscle stretching in patients with irritable bowel syndrome

BackgroundPsychophysiological processing has been reported to play a crucial role in irritable bowel syndrome (IBS) but there has been no report on modulation of the stress marker chromogranin A (CgA) resulting from muscle stretching. We hypothesized that abdominal muscle stretching as a passive operation would have a beneficial effect on a biochemical index of the activity of the sympathetic/adrenomedullary system (salivary CgA) and anxiety.MethodsFifteen control and eighteen untreated IBS subjects underwent experimental abdominal muscle stretching for 4 min. Subjects relaxed in a supine position with their knees fully flexed while their pelvic and trunk rotation was passively and slowly moved from 0 degrees of abdominal rotation to about 90 degrees or the point where the subject reported feeling discomfort.Changes in the Gastrointestinal Symptoms Rating Scale (GSRS), State Trait Anxiety Inventory (STAI), Self-rating Depression Scale (SDS), ordinate scale and salivary CgA levels were compared between controls and IBS subjects before and after stretching. A three-factor analysis of variance (ANOVA) with period (before vs. after) as the within-subject factor and group (IBS vs. Control), and sex (men vs. female) as the between-subject factors was carried out on salivary CgA.ResultsCgA showed significant interactions between period and groups (F[1, 31] = 4.89, p = 0.03), and between groups and sex (F[1, 31] = 4.73, p = 0.03). Interactions between period and sex of CgA secretion were not shown (F[1, 3] = 2.60, p = 0.12). At the baseline, salivary CgA in IBS subjects (36.7 ± 5.9 pmol/mg) was significantly higher than in controls (19.9 ± 5.5 pmol/mg, p < 0.05). After the stretching, salivary CgA significantly decreased in the IBS group (25.5 ± 4.5 pmol/mg), and this value did not differ from that in controls (18.6 ± 3.9 pmol/mg).ConclusionOur results suggest the possibility of improving IBS pathophysiology by passive abdominal muscle stretching as indicated by CgA, a biochemical index of the activity of the sympathetic/adrenomedullary system.

Classical conditioned response of rectosigmoid motility and regional cerebral activity in humans

Abstract  The relationship between the central processes of classical conditioning and conditioned responses of the gastrointestinal function is incompletely understood in humans. We tested the hypothesis that the rectosigmoid motility becomes conditioned with anticipatory painful somatosensory stimulus and that characteristic brain areas become activated during anticipation. In nine right‐handed healthy male subjects, a loud buzzer (CS, conditional stimulus) was paired with painful transcutaneus electrical nerve stimulation to the right hand (unconditional stimulus). Rectosigmoid muscle tone measured by the barostat as the intrabag volume, phasic contractions of the bowel measured as the number of phasic volume events (PVEs), and regional cerebral blood flow assessed by positron emission tomography (PET), were measured before and after conditioning. Following conditional trials, the bag volume after CS alone did not show significant changes between before and after the stimulus, but the number of PVEs after 2‐minute interval of the CS alone was significantly greater than that before the stimulus (P < 0.05). The PET data showed the conditioning elicited significant cerebral activation of the prefrontal, anterior cingulate, parietal and insula cortices (P ≤ 0.001, uncorrected). Rectosigmoid motility can be conditioned with increase in phasic contractions in humans.

Differential Activation in Amygdala and Plasma Noradrenaline during Colorectal Distention by Administration of Corticotropin-Releasing Hormone between Healthy Individuals and Patients with Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) often comorbids mood and anxiety disorders. Corticotropin-releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis, but it is not clear how CRH agonists change human brain responses to interoceptive stimuli. We tested the hypothesis that brain activation in response to colorectal distention is enhanced after CRH injection in IBS patients compared to healthy controls. Brain H215O- positron emission tomography (PET) was performed in 16 male IBS patients and 16 age-matched male controls during baseline, no distention, mild and intense distention of the colorectum using barostat bag inflation. Either CRH (2 μg/kg) or saline (1:1) was then injected intravenously and the same distention protocol was repeated. Plasma adrenocorticotropic hormone (ACTH), serum cortisol and plasma noradrenaline levels were measured at each stimulation. At baseline, CRH without colorectal distention induced more activation in the right amygdala in IBS patients than in controls. During intense distention after CRH injection, controls showed significantly greater activation than IBS patients in the right amygdala. Plasma ACTH and serum cortisol secretion showed a significant interaction between drug (CRH, saline) and distention. Plasma noradrenaline at baseline significantly increased after CRH injection compared to before injection in IBS. Further, plasma noradrenaline showed a significant group (IBS, controls) by drug by distention interaction. Exogenous CRH differentially sensitizes brain regions of the emotional-arousal circuitry within the visceral pain matrix to colorectal distention and synergetic activation of noradrenergic function in IBS patients and healthy individuals.

Effect of baseline self-efficacy on physical activity and psychological stress after a one-week pedometer intervention

Physical activity and psychological stress were hypothesized to improve more in participants with high self-efficacy than in those with low and medium self-efficacy, after a one-week intervention. 39 female university students participated. The intervention had two steps: a lecture on self-monitoring and goal setting (160 min.) and a one-week pedometer intervention. Analyses were conducted on tertile groups according to self-efficacy at baseline. Pedometer step counts were higher in the high self-efficacy group than in the low self-efficacy group after intervention. Helplessness decreased time dependently after intervention only in the high-self-efficacy group. Because physical activity improved more in the high self-efficacy group after a one-week intervention, one hypothesis was supported.

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 H215O 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.