Michiko Kano

Imaging of central itch modulation in the human brain using positron emission tomography.

The unpleasantness of itching is reduced by cooling. Although previous research suggests the presence of a central itch modulation system, there is little documentation about the modulation system in the brain. In the present study, we investigated the modulating system of the itching sensation in human brains using positron emission tomography and H2 15O. The significant increases of regional cerebral blood flow caused by histamine stimuli using iontophoresis were observed in the anterior cingulate cortex (BA24), the thalamus, the parietal cortex (BA40 and BA7), the dorsolateral prefrontal cortex (BA46) and the premotor cortex (BA6). We did not observe any changes in the secondary somatosensory cortex (S2) during the itching stimulus, corresponding to the previous imaging studies concerning itching. Activation in these areas related to itching stimuli was decreased by a simultaneous stimulation of itching and cold pain (the dual stimuli), as compared to itching alone. Interestingly, the midbrain, including periaqueductal gray matter (PAG), was only activated during the dual stimuli. PAG is well known to be a modulating noxious stimulus. Here we hypothesize that the activation of PAG may also be related to the itch modulation. These findings indicate that the modified brain activities in the PAG, the cingulate, the frontal and the parietal cortex might be associated with the itch modulation in the central nervous system and that the S2 might not be primarily involved in processing the itching perception in the brain since the activity of S2 was not observed in any concentration of itching stimuli.

Patients and nonconsulters with irritable bowel syndrome reporting a parental history of bowel problems have more impaired psychological distress

Little is known about the prevalence and risk factors for development of irritable bowel syndrome (IBS) in Japan. In the United States, it is reported that heredity and social learning contribute to the development of IBS. Our aims were (1) to estimate the prevalence of IBS, (2) to confirm that subjects with IBS are more likely to have parents with a history of bowel problems, (3) to confirm that gastroenteritis is a risk factor for IBS, and (4) to determine whether these two risk factors interact with psychological distress. Prevalence was estimated from a sample of 417 young adults seen for annual health screening examinations. To evaluate risk factors related to consulting physicians, the 46 subjects who fulfilled Rome II diagnostic criteria for IBS but denied ever having seen a physician about these symptoms (IBS non-consulters) were compared to the 317 subjects who did not meet the criteria for IBS (controls) and to a group of 56 patients diagnosed with IBS by gastroenterologists (IBS patients). All subjects completed the Gastrointestinal Symptoms Rating Scale, the State-Trait Anxiety Inventory, the Self-Rating Depression Scale, the Perceived Stress Scale, and the SF-36 quality of life scale. Fourteen and two-tenths percent (15.5% of females and 12.9% of males) of the community sample met the criteria for IBS diagnosis, of whom 22% consulted physicians. IBS patients and IBS nonconsulters were more likely than controls to have a parental history (33.9 vs. 12.6%, P < 0:001, for patients and 26.1 vs. 12.6%, P < 0:01, for nonconsulters) and were more likely to report an infective history compared to controls (44.6 vs. 16.1%, P < 0:001, for patients and 32.6 vs. 16.1%, P < 0:01, for nonconsulters). Two-way analysis of variance showed that the parental history was associated with a significantly greater impact on symptoms of indigestion, diarrhea, constipation, state and trait anxiety, and the SF-36 scales for social functioning and role emotional and that an infective history was associated with a greater impact on bodily pain. Both a parental history of bowel problems and a history of acute gastroenteritis are significant risk factors for development of IBS in Japan, as reported for the United States. Moreover, patients with such a family history show more psychological distress than other patients.

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.

Exaggerated motility of the descending colon with repetitive distention of the sigmoid colon in patients with irritable bowel syndrome

Background. Visceral hypersensitivity is one of the mechanisms of irritable bowel syndrome (IBS), but it does not explain the entire symptomatology, i.e., altered bowel habit with abdominal pain relieved by defecation. We tested our hypothesis that an abnormal link between luminal stimulation and mural response may have some role in the pathophysiology of IBS. Methods. Patients with IBS (n = 10, median 21 years old, 5 male patients, 5 female patients) and healthy control subjects (n = 10, median 21 years old, 5 men, 5 women) were studied. A manometric catheter with three transducers was inserted to the descending colon and a balloon was placed in the distal sigmoid colon. Another catheter with three transducers was inserted to the duodenum. After baseline for 30 min, the sigmoid colon was stimulated by balloon distention for 30 min followed by recovery for 30min. Balloon distention was repeated 100 times, and each stimulation consisted of a 5-s inflation and a 10-s deflation, with a volume of 50 ml maximum. The sensory threshold of balloon inflation was then examined, and plasma adrenocorticotropic hormone (ACTH) was measured with radioimmunoassay. Results. Repetitive colonie distention induced a significant increase in motility indices (mmHg s/s%) of the descending colon in the IBS patients (from 118 ± 25 to 333 ± 108, P < 0.05) but not of those in controls (from 90 ± 16 to 89 ± 19). A significant group difference (P < 0.05), period effect (P < 0.02), and group X period interactions (P < 0.01) were detected with two-way ANOVA. Duodenal motility indices in controls were significantly reduced by colonic distention (from 169 ± 25 to 104 ± 14, P < 0.01), but those in the IBS patients were not (from 156 ± 17 to 124 ± 20). The sensory threshold of balloon inflation in the IBS patients (74 ± 10 ml) was significantly lower than that in controls (125 ± 6 ml, P < 0.001). There was no significant difference in plasma ACTH levels between the IBS patients and controls. Conclusions. Repetitive distention of the distal sigmoid colon below the sensory threshold induced orad exaggerated motility of the colon in IBS patients. The distention inhibited motility of the small intestine in healthy subjects, but this inhibition was blunted in IBS patients. These results suggest that IBS patients may have not only visceral hypersensitivity, but also an abnormal intestinal reflex.

Decreased histamine H1 receptor binding in the brain of depressed patients

The central histaminergic neuron system modulates the wakefulness, sleep–awake cycle, appetite control, learning and memory, and emotion. Previous studies have reported changes in neuronal histamine release and its metabolism under stress conditions in the mammalian brain. In this study, we examined, using positron emission tomography (PET) and [11C]‐doxepin, whether the histaminergic neuron system is involved in human depression. Cerebral histamine H1 receptor (H1R) binding was measured in 10 patients with major depression and in 10 normal age‐matched subjects using PET and [11C]‐doxepin. Data were calculated by a graphical analysis on voxel‐by‐voxel and ROI (region of interests) basis. Binding potential (BP) values for [11C]‐doxepin binding in the frontal and prefrontal cortices, and cingulate gyrus were significantly lower in the depressed patients than those in the normal control subjects. There was no area of the brain where [11C]‐doxepin binding was significantly higher in the depressed patients than in the controls. ROI‐based analysis also revealed that BP values for [11C]‐doxepin binding in the frontal cortex and cingulate gyrus decreased in proportion to self‐rating depressive scales scores. The results of this study demonstrate that depressed patients have decreased brain H1R binding and that this decrease correlates with the severity of depression symptoms. It is therefore suggested that the histaminergic neuron system plays an important role in the pathophysiology of depression and that its modulation may prove to be useful in the treatment of depression.

Histamine H1 receptors in schizophrenic patients measured by positron emission tomography

Increasing evidence has shown that the histaminergic neuron system is implicated in the pathophysiology of schizophrenia. The aim of this study was to compare the distribution of histamine H1 receptors between schizophrenics and normal human subjects in vivo using positron emission tomography (PET). H1 receptor binding was measured in 10 normal subjects and 10 medicated schizophrenic patients by PET and [11C] doxepin, a radioligand for the H1 receptor. The binding potential (BP=Bmax/K(D)) of [11C] doxepin for available brain H1 receptors was calculated by a graphical analysis on voxel-by-voxel basis and compared between schizophrenics and normal subjects using the regions of interest (ROIs) and the statistical parametrical mapping (SPM99). BP values for H1 receptors in the frontal and prefrontal cortices and the cingulate gyrus were significantly lower among the schizophrenic patients than among the control subjects. On the contrary, there were no areas of the brain where H1 receptors were significantly higher among the schizophrenic patients than the control subjects. The results of our study suggest that the central histaminergic neuron system could be involved in the pathophysiology of schizophrenia, although further studies are needed to confirm this hypothesis.

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.

Increased brain histamine H1 receptor binding in patients with anorexia nervosa.

BACKGROUND The central histaminergic neuron system modulates various brain functions, including eating behavior. We hypothesized that women have higher density of histamine H1 receptor (H1R) in the limbic system than men and that the density of central H1R is increased in patients with anorexia nervosa (AN). METHODS Subjects were 12 female AN patients, 12 healthy female subjects, and 11 healthy male subjects. Positron emission tomography with H1R radioligand [(11)C]doxepin was performed on all subjects and regions of interest based analysis was conducted to evaluate brain H1R binding potential (BP). Abnormal eating behavior, depression, and anxiety of subjects were evaluated using the Eating Attitude Test-26 (EAT-26), Self-Rating Depression Scale (SDS), and State-Trait Anxiety Inventory (STAI), respectively. RESULTS Binding potential of [(11)C]doxepin in female subjects was significantly higher than that in male subjects at the following brain sites: amygdala, hippocampus, medial prefrontal cortex, orbitofrontal cortex, and temporal cortex. Anorexia nervosa patients showed significantly higher BP of [(11)C]doxepin in the amygdala and lentiform nucleus than the control female subjects. In AN patients, BP of [(11)C]doxepin in the amygdala and thalamus negatively correlated with EAT-26 scores. There was a significant negative correlation between BP of [(11)C]doxepin and SDS or STAI scores in the amygdala, anterior cingulate cortex, and orbitofrontal cortex of AN patients. CONCLUSIONS These findings support the hypothesis that women have higher H1R density in the limbic system than men and suggest that AN patients may have higher expression of H1R in the limbic brain, particularly in the amygdala.

Role of histaminergic neurons in hypnotic modulation of brain processing of visceral perception

Abstract  Modulating visceral sensation of the body is important to the understanding of emotion formation. Molecules that act during hypnosis and modify visceral pain perception are not known. We tested our hypothesis that hypnotic suggestion changes electrophysiological processing of visceroafferent signals in the human brain and that these conditions are in part dependent on histaminergic neurons. Twelve healthy male subjects were studied on two separate days: a day of treatment with histamine H1 receptor antagonist (d‐chlorpheniramine 100 μg kg−1, intravenously) and another day of that with placebo (saline, the same amount) in a randomized order. We recorded cortical evoked potentials to 100 rectal electrical stimuli after neutral, hyperalgesic or analgesic hypnotic suggestions as given to modulate the visceral perception. Analgesic suggestion reduced the amplitude of the deepest positive peak of viscerosensory evoked potential. Administration of histamine H1 antagonist diminished the attenuation of viscerosensory evoked potential by analgesic suggestion. Our results suggest that central pain modulatory system in the brain is activated by hypnotic suggestion and that brain histamine is a mediator in the hypnotic modulation of visceral sensory pathway as well as in the control of consciousness level. These findings lead us to possible new treatment for control of visceral perception.