Joe Morishita

Altered Cognitive Function of Prefrontal Cortex During Error Feedback in Patients With Irritable Bowel Syndrome, Based on fMRI and Dynamic Causal Modeling

BACKGROUND & AIMS Patients with irritable bowel syndrome (IBS) have increased activity in the insula and reduced activation of the dorsolateral prefrontal cortex (DLPFC) in response to visceral stimulation. We investigated whether they have latent impairments in cognitive flexibility because of dysfunction in the DLPFC and insula and altered connectivity between brain regions. METHODS We analyzed data from 30 individuals with IBS (15 men; age, 21.7 ± 3.0 y) diagnosed based on Rome III criteria, along with 30 individuals matched for age, sex, and education level (controls). Event-related functional magnetic resonance imaging of the brain was performed to evaluate cognitive flexibility and was assessed by the Wisconsin Card Sorting Test, in which subjects are allowed to change choice criteria, defined as set-shifting in response to error feedback. Brain images were analyzed with statistical parametric mapping 5 and 8 software and dynamic causal modeling. RESULTS Subjects with IBS had significantly more Nelson perseverative errors (P < .05) and set-maintenance difficulties (P < .05) than controls. They also showed significantly decreased activity of the right DLPFC (Brodmanns area 9; P < .001) and right hippocampus (P < .001), and significantly increased activity of the left posterior insula (P < .001) at error feedback during set-shifting. Dynamic causal modeling analysis during set-shifting revealed significantly less connectivity from the DLPFC to pre-supplementary motor area in subjects with IBS, compared with controls (P = .012). CONCLUSIONS Individuals with IBS have latent impairments in cognitive flexibility as a result of altered activity of the DLPFC, insula, and hippocampus, and impaired connectivity between the DLPFC and pre-supplementary motor area.

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.

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.

Su2115 Altered Activation of Cardiac Sympathetic Discharge and Covariated Brain Region During Colorectal Distention With Corticotropin-Releasing Hormone in Irritable Bowel Syndrome

G A A b st ra ct s plasma ghrelin levels at 2 h after ICV UCN. UCN induces c-fos mRNA and Fos protein expression in the supraoptic nucleus, paraventricular nucleus of hypothalamus (PVN), locus coeruleus, solitary tract nucleus (NTS), and ventrolateral nucleus of medulla oblongata (VLM), known to influence sympathetic outflow. Fos expression in NTS was markedly suppressed by coadministration of RKT (control 84 ± 28, UCN 352 ± 130, UCN + RKT 48 ± 15; P , 0.05). UCN-induced Fos expression in VLM was also suppressed by RKT (control 35 ± 10, UCN 289 ± 94, UCN + RKT 133 ± 27), but not significant (P=0.08). RKT also suppressed UCN-induced c-fos expression in PVN. In contrast, the dorsal motor nucleus involved in vagal outflow did not show any changes in Fos and fos expression by RKT. Conclusions: These data indicate that a) RKT inhibits the activity of the neuron of NTS suggesting that RKT inhibits vagal input from the periphery to central nerves. b) As the result of inhibiton of vagal input, activity of hypothalamic satiety center, PVN is suppressed resulting in the inhibition of the sympathetic outflow from the central nerve to the periphery. RKT may restore disturbed appetite and ghrelin secretion through the restoration of balance of central autonomic nervous system.

Sa1441 Do Protease Inhibitors Influence Visceral Pain Sensitivity in Patients With Irritable Bowel Syndrome

Background and Aims: Several studies have reported that gastric scintigraphy is a useful and non-invasive modality to assess the gastric motility, especially gastric emptying. Recently, many researchers have suggested that the measuring gastric emptying in addition to gastric accommodation is essential to evaluate gastric motility. Gastric accommodation is considered as postprandial relaxation of the proximal stomach. However, we have little knowledge of gastric scintigraphy to assess gastric accommodation. Accordingly, we aimed to clarify the usefulness of gastric scintigraphy in the assessment of gastric accommodation in comparison with gastric barostat which is a gold standard modality. Patients and Methods: Seventeen healthy volunteers (male/female 10/ 7; mean age 33.8 ± 10.5 years) were enrolled in this study. Test meal consisted of curry with rice; radiolabeled 99mTc (37 MBq) was used for scintigraphy. Volunteers ingested the test meal in the upright position with scintigraphic images recorded over time. Radioactivity in the upper-third andwhole stomachwas calculated to evaluate gastric accommodation. In the barostat procedure, a gastric balloon was inserted nasally and distended after a liquid meal ingestion (250 ml, 375 kcal). The maximal volume of distending balloon was measured to evaluate gastric accommodation. Thereafter, we investigated the correlation between scintigraphic and barostat accommodation. We next validated the reproducibility and intraand inter-observer variation for the scintigraphic test. Finally, we evaluated the diagnostic performance of scintigraphy using sumatriptan which delays gastric emptying and improves gastric accommodation as a positive control. The scintigraphic test was repeated in the same volunteers after one week. Data were evaluated by three investigators. Results: Accommodation measured with scintigraphy and barostat correrlated (r=0.524, p<0.05). For the scintigraphic test, sumatriptan significantly increased (51.5 ± 16.4 %) gastric accommodation compared with the control (38.4 ± 13.8 %) (p<0.01). Moreover, sumatriptan significantly delayed the gastric emptying (50 % half emptying time) at 60, 90, 120 and 150 min after the experimental start, respectively (p<0.05). The data obtained from repeated scintigraphic tests was highly reproducible (r=0.75) with significant differences observed among the investigators (r=0.90). Conclusions: Gastric scintigraphy is a useful modality to assess gastric accommodation and emptying.

Corticotropin-releasing hormone exaggerates regional brain activity and adrenocorticotropic hormone and cortisol release during colorectal distention in men

Zic2 is a causal gene of holoprosencephaly (a dysgenesis of medial forebrain). Although it is broadly expressed in CNS, there was a difficulty to fully show its role due to its critical role in early embryogenesis. Here we developed a conditionally targeted Zic2 mutant mice and clarified its role in the development of dorsal cochlear nucleus (DCoN) and in the auditory function of mature mice. Soon after the neural tube closure, Zic2 and its close relatives (Zic1 and Zic3) are differentially expressed in hindbrain region along the rostrocaudal axis. Zic2 expression was dominant in the DCoN forming region. In Zic2 hypomorphic mutants (60% of wild type level), slight reduction of DCoN size was observed whereas the DCoN size reduction was severe in the midbrainhindbrain restricted Zic2 conditional knockout (CKO). Both granule cells and unipolar brush cells were decreased in DCoN. We observed the increased acoustic startle response and the altered auditory brain stem responses in both Zic2 hypomorphic and Zic2 CKO animals. Furthermore, we measured the activities of the primary auditory cortices during various sound stimuli application by means of autofluorescence imaging. These results indicated that optimal Zic2 gene dosage is a critical parameter for the auditory neural circuit formation and the auditory function. Further analyses using the Zic2 mutants would be beneficial for understanding physiological regulation of auditory information processing in mammalian. Research fund: RIKEN BSI funds.

Increased activation of ventromedial prefrontal cortex during decision making in irritable bowel syndrome

It has well known that potential for immunity in human body is decreased under a stress. While, macrophages (M s) play an important role for immunoresponse. Cytokines are also affected by a stressed condition. The specific alternation of rhythm in temperature (SART) stress is one kind of environmental stress, induced by repeated sudden changes in ambient temperature. The SART-stressed animals are vagotonia-type autonomic imbalance model and have chronic stress symptoms. Therefore, it is supposed that the relationship between the autonomic nervous system, the endocrine system and the immune system breaks down in SART-stressed animals. In this work, to clear the relationships between stress and natural immunity, we investigated the change for immunoresponce in SART stressed mice using as an indicator for the number and the activity of alveolar M s. Male ddY mice, weighing 20–30 g, were used. The bronchoalveolar lavage fluid (BALF) was obtained by washing lungs with phosphate-buffered saline under urethane anesthesia. Histological samples were prepared from mice lung after fixation by 4% paraformaldehyde perfusion. M fraction was obtained from the pellet by centrifugation of BALF. Number and phagocytotic activity of M s in stressed group were significantly decreased in comparison with those in unstressed and cold stressed group. The amounts of inflammatory cytokines, IL-1 , IL-6 and TNF, in BALF were significantly reduced in the SARTstressed group. We obtained the similar result in the culture medium of M s for 48 hours from the SART-stressed group, that is, the amounts of cytokines except IL-1 was reduced. Repeated oral administration of antianxiety drug, diazepam, attenuated the reduction of the number of M , phagocytotic activity and the amount of cytokines in BALF, which observed in the SART-stressed mice. These results suggest that the immune function in SART stressed mice under a repeated change in ambient temperature may be decreased.

Effect of repetitive transcranial magnetic stimulation on rectal function and emotion in humans

Background A previous brain imaging study demonstrated activation of the right dorsolateral prefrontal cortex (DLPFC) during visceral nociception, and this activation was associated with anxiety. We hypothesized that functional modulation of the right DLPFC by repetitive transcranial magnetic stimulation (rTMS) can reveal the actual role of right DLPFC in brain–gut interactions in humans.

Neural Substrates of Decision Making in Irritable Bowel Syndrome

Aim: Patients with irritable bowel syndrome (IBS) show exaggerated sensorimotor function of the gastrointestinal tract against stress. However, emotion-cognition sequence of IBS is largely unknown. The emotional experience begins from the unconscious level and “gut feelings” may be used as somatic marker that guides decision making (Bechara, A, et al Science 1997). We hypothesized that brain processing in individuals with IBS, during decision making, is different from that of healthy controls, due to increased activity of the insula and ventromedial prefrontal cortex (vmPFC) and altered connectivity among brain regions. Methods: Subjects were individuals with IBS (n=30, 15 men and 15 women, aged 21.5 ± 2.2) diagnosed with Rome III criteria. IBS subtypes were 8 constipation, 14 diarrhea, and 8mixed. Age-, sex-, and education-matched controls (n = 30) were compared. All subjects scored Wechsler Adult Intelligence Scale-III (WAIS-III). Using PHILIPS 3.0T Scanner, eventrelated functional magnetic resonance imaging (fMRI) was performed to determine the specific location and pattern of activation in the brain during the IOWA Gambling Task (IGT). Subjects must select 100 cards, one at a time, from 4 identical-looking decks, labelled A, B, C, and D. We obtained behavioural data, which entailed the number of selections from ‘advantageous’ (card C and D) vs. ‘disadvantageous’ (card A and B) decks during the IGT. We counted the total number of card selections from the advantageous minus disadvantageous ((C + D)-(A +B)) decks for each block of 20 cards. This is net score. Decision-making reaction times were also examined. Each time a card was selected, the participant received a monetary reward. During the control task, subjects were presented with 4 decks of cards labeled E, F, G and H, and were instructed to pick a card from a specific deck. Brain image was analyzed with statistical parametric mapping 8. We compared BOLD activity of the two groups during card selection in the decision-making and control task. Results: IBS subjects showed no difference in WAIS-III, reaction time and net scores. IBS subjects had significantly more one of advantageous card selections (p < 0.05) and gaining money (p < 0.05). Brain imaging data revealed that IBS subjects showed significantly less activity in the left anterior insula (p < 0.005) and significantly more activity in the right vmPFC (p < 0.005) during decision making conditions than controls. Conclusion: Conversely to visceral stimulation-induced insular activation, insula in IBS subjects is likely to be inactivated during decision making task. These findings suggest that individuals with IBS show advantageous decision making due to more activity of vmPFC.

M1309 Virtual Visual Stress Enhances Gastric Hypersensitivity in Functional Dyspepsia

[Background] Psychological stress is one of the strong triggers that induce gastric symptoms in functional dyspepsia. Previously we reported that in healthy subjects virtual stress induced increase of gastric volume and gastric hypersensitivity, which relate to the pathophysiology of functional dyspepsia. [Aim] We tested our hypothesis that psychological stress can induce excessive changes of gastric volume and sensation in functional dyspepsia than in healthy subjects. [Subjects & Methods] Nine functional dyspepsia non-consulters (FD) and 9 healthy subjects (HS) were recruited in this study. Virtual visual stress (VS) was loaded with a 3D roller coaster movie for 10 minutes by the head-mounted display. Gastric volume and compliance were measured by barostat technique during the virtual stress session. At the beginning and end of the VS session, gastric perception was evaluated by barostat bag distention, then 3 perception thresholds were defined (first sensation (F), discomfort (D), and pain (P)). Subjective gastric perception and stress sensation during the stress were evaluated on the gastric symptom questionnaires consisted of 7 graded ordinate scales. [Results] During VS, FD reported higher stress sensation than in HC (p=0.0163, ANOVA). VS induced gastric volume increase both in FD and in HS (p=0.001). However, the changes of gastric volume in FD were not different in HS (p=0.88, ANOVA). Basal gastric perceptional thresholds were significantly lower in FD than in HS (p<0.001). After VS session, gastric perceptional thresholds significantly decreased in both FD and HS (p<0.001 ANOVA, vs. basal thresholds). Nausea symptom was moderate but remarkably induced in FD during VS compared with HS. [Summary] Virtual stress remarkably reduced gastric perceptional thresholds in functional dyspepsia, which suggested that psychological stress induce gastric symptoms by enhancing gastric hypersensitivity. Effects of VS on gastric volume and perception in FD and HS