Emotional overactivity in patients with irritable bowel syndrome.

BACKGROUND: Negativity is often observed in patients with irritable bowel syndrome (IBS). No study has examined their emotional expressiveness as a marker of emotional reactivity. We investigated IBS patients' vulnerability to an emotional load by associating their expressiveness with psychological and neurophysiological assessments. We hypothesized that IBS would be characterized by a lack of expressiveness coupled with high scores in psychological and neurophysiological parameters. METHODS: We assessed the emotional facial expressions (EMFACS), psychological (anxiety, depression, alexithymia), and neurophysiological (cortisol, heart rate variability (HRV)) parameters of 25 IBS patients and 26 healthy controls (HC) while they watched fear-eliciting movie extracts. KEY RESULTS: Overall, the task elicited an increase in state anxiety and consistent HRV responses. However, IBS patients differed from HC as they displayed more sadness and tended to display more rage. Contrary to HC, IBS patients showed an increase in heart rate and a decrease in parasympathetic regulation, reflecting an enhanced responsiveness corroborated by higher scores in depression and state anxiety. Consistent with their higher difficulty in identifying feelings, a component of alexithymia positively correlated with their expressions of rage, they were not aware of their increase in anxiety during the task, whereas HC were. No linear relationship between patients' expressions and their neurophysiological responses was found. CONCLUSIONS & INFERENCES: Irritable bowel syndrome patients displayed greater emotional expressiveness with negative prevalence. This reflects an emotional vulnerability potentially related to low regulation skills and underscores the importance of considering the central dysregulation hypothesis in IBS as a promising avenue of research.

Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease.

Inflammatory bowel disease (IBD), that is Crohn's disease (CD) and ulcerative colitis, affects about 1.5 million persons in the USA and 2.2 million in Europe. The pathophysiology of IBD involves immunological, genetic and environmental factors. The treatment is medico-surgical but suspensive. Anti-TNFα agents have revolutionized the treatment of IBD but have side effects. In addition, a non-negligible percentage of patients with IBD stop or take episodically their treatment. Consequently, a nondrug therapy targeting TNFα through a physiological pathway, devoid of major side effects and with a good cost-effectiveness ratio, would be of interest. The vagus nerve has dual anti-inflammatory properties through its afferent (i.e. hypothalamic-pituitary-adrenal axis) and efferent (i.e. the anti-TNFα effect of the cholinergic anti-inflammatory pathway) fibres. We have shown that there is an inverse relationship between vagal tone and plasma TNFα level in patients with CD, and have reported, for the first time, that chronic vagus nerve stimulation has anti-inflammatory properties in a rat model of colitis and in a pilot study performed in seven patients with moderate CD. Two of these patients failed to improve after 3 months of vagus nerve stimulation but five were in deep remission (clinical, biological and endoscopic) at 6 months of follow-up and vagal tone was restored. No major side effects were observed. Thus, vagus nerve stimulation provides a new therapeutic option in the treatment of CD.

The Place of Stress and Emotions in the Irritable Bowel Syndrome.

Our emotional state can have many consequences on our somatic health and well-being. Negative emotions such as anxiety play a major role in gut functioning due to the bidirectional communications between gut and brain, namely, the brain-gut axis. The irritable bowel syndrome (IBS), characterized by an unusual visceral hypersensitivity, is the most common disorder encountered by gastroenterologists. Among the main symptoms, the presence of current or recurrent abdominal pain or discomfort associated with bloating and altered bowel habits characterizes this syndrome that could strongly alter the quality of life. This chapter will present the physiopathology of IBS and explain how stress influences gastrointestinal functions (permeability, motility, microbiota, sensitivity, secretion) and how it could be predominantly involved in IBS. This chapter will also describe the role of the autonomic nervous system and the hypothalamic-pituitary axis through vagal tone and cortisol homeostasis. An analysis is made about how emotions and feelings are involved in the disruption of homeostasis, and we will see to what extent the balance between vagal tone and cortisol may reflect dysfunctions of the brain-gut homeostasis. Finally, the interest of therapeutic treatments focused on stress reduction and vagal tone enforcement is discussed.

Brain responses to uncertainty about upcoming rectal discomfort in quiescent Crohn's disease - a fMRI study.

BACKGROUND: Patients with Crohn's disease (CD) in remission are exposed to chronic psychological distress, due to the constant risk of relapse. This permanent situation of anticipation and uncertainty can lead to anxiety, which may, in turn, trigger relapse. We aimed to investigate the effects of uncertainty on behavioral and brain responses to anticipation of visceral discomfort in quiescent CD patients. METHODS: Barostat-controlled rectal distensions were preceded by cued uncertain or certain anticipation in nine CD patients and nine matched healthy volunteers. Brain responses obtained before distension across the different anticipation conditions in regions of interest (ROI) involved in (anticipation of) pain were measured using functional magnetic resonance imaging and compared between CD and controls. The association between anxiety-related psychological variables and cerebral anticipatory activity was tested. KEY RESULTS: During uncertainty, CD patients had significantly stronger activations than controls in the cingulate cortex, insula, amygdala, and thalamus with trends in the hippocampus, prefrontal, and secondary somatosensory cortex. In patients, brain responses to uncertainty in the majority of ROI correlated positively with gastrointestinal symptom-specific anxiety, trait-anxiety, and intolerance of uncertainty. CONCLUSIONS & INFERENCES: In a context of uncertainty regarding occurrence of uncomfortable visceral sensations, CD is associated with excessive reactivity in brain regions known to be involved in sensory, cognitive and emotional aspects of pain processing and modulation, and threat appraisal. Our findings contribute to a better understanding of the role of emotional and cognitive processes in CD. This may, in turn, lead to the development of new (psycho)therapeutic approaches for management of symptoms and related anxiety.

Vagal tone: effects on sensitivity, motility, and inflammation.

The vagus nerve (VN) is a key element of the autonomic nervous system. As a mixed nerve, the VN contributes to the bidirectional interactions between the brain and the gut, i.e., the brain-gut axis. In particular, after integration in the central autonomic network of peripheral sensations such as inflammation and pain via vagal and spinal afferents, an efferent response through modulation of preganglionic parasympathetic neurons of the dorsal motor nucleus of the vagus and/or preganglionic sympathetic neurons of the spinal cord is able to modulate gastrointestinal nociception, motility, and inflammation. A low vagal tone, as assessed by heart rate variability, a marker of the sympatho-vagal balance, is observed in functional digestive disorders and inflammatory bowel diseases. To restore a normal vagal tone appears as a goal in such diseases. Among the therapeutic tools, such as drugs targeting the cholinergic system and/or complementary medicine (hypnosis, meditation…), deep breathing, physical exercise, VN stimulation (VNS), either invasive or non-invasive, appears as innovative. There is new evidence in the current issue of this Journal supporting the role of VNS in the modulation of gastrointestinal functions.

Chronic vagus nerve stimulation in Crohn's disease: a 6-month follow-up pilot study.

The vagus nerve (VN) is a link between the brain and the gut. The VN is a mixed nerve with anti-inflammatory properties through the activation of the hypothalamic-pituitary-adrenal axis by its afferents and by activating the cholinergic anti-inflammatory pathway through its efferents. We have previously shown that VN stimulation (VNS) improves colitis in rats and that the vagal tone is blunted in Crohn's disease (CD) patients. We thus performed a pilot study of chronic VNS in patients with active CD. Seven patients under VNS were followed up for 6 months with a primary endpoint to induce clinical remission and a secondary endpoint to induce biological (CRP and/or fecal calprotectin) and endoscopic remission and to restore vagal tone (heart rate variability). Vagus nerve stimulation was feasible and well-tolerated in all patients. Among the seven patients, two were removed from the study at 3 months for clinical worsening and five evolved toward clinical, biological, and endoscopic remission with a restored vagal tone. These results provide the first evidence that VNS is feasible and appears as an effective tool in the treatment of active CD.

The link between negative affect, vagal tone, and visceral sensitivity in quiescent Crohn's disease.

Autonomic dysfunction and mood disorders are frequently described in Crohn's disease (CD) and are known to influence visceral sensitivity. We addressed the link between vagal tone, negative affect, and visceral sensitivity in CD patients without concomitant features of irritable bowel syndrome (IBS). Rectal distensions to a discomfort threshold of 70% and onset of pain were performed in nine CD patients in remission and eight healthy controls. Autonomic parameters were evaluated with heart rate variability and electrodermal reactivity. We showed that CD patients had (i) higher scores of depressive symptomatology (12 ± 3 in patients vs 4 ± 1 in controls on the Center for Epidemiologic Studies-Depression Scale; p = 0.038), (ii) reduced vagal tone (HF 257 ± 84 ms(2) vs 1607 ± 1032 ms(2) , p = 0.043; LF 455 ± 153 ms(2) vs 1629 ± 585 ms(2) , p = 0.047), (iii) decreased sympathetic reactivity during an aversive stimulus, and (iv) higher tolerance to rectal distension pressures (43 ± 3 mmHg vs 30 ± 2 mmHg, p = 0.002) and low sensitivity index scores. In conclusion, our results provide preliminary evidence that patients with quiescent CD, in the absence of IBS, are hyposensate to experimental rectal distension. These data provide further evidence that anxiety and depressive symptomatology in addition to autonomic dysfunction modulate visceral pain perception in quiescent CD patients in the absence of IBS.

Oxyntomodulin and glicentin are potent inhibitors of the fed motility pattern in small intestine.

Glicentin (GLIC) and oxyntomodulin (OXM or GLIC 33-69) are gut hormones which regulate digestion. They are known to reduce digestive secretions and to delay gastric emptying. Their biological activities on intestinal motility are still unknown. The effect of a systemic GLIC or OXM increase was investigated in rats on the food intake, the postprandial myoelectrical activity of small intestine and the orocaecal transit. An OXM or GLIC i.v. infusion was applied during the 5 min preceding food onset and during the first 15 min of food intake. This determined a three- to fourfold increase of the preprandial OXM-GLIC level. The OXM or GLIC plasma increase did not modify food intake. OXM infusion slowed down gastric emptying when the stomach contained 3/4 of the ingested food (before T 3 h). The quantity of food delivered in jejunum was subsequently smaller (P < 0.05). In the small intestine, the duration of postprandial myoelectrical activity (50-60 min g(-1) of ingested food) was reduced by 70% (P < 0.001) on duodenum or jejunum and by 54% (P < 0.01) on ileum in OXM-treated rats. An interdigestive motility profile was settled and an acceleration of both gastric emptying and transit rate was thereafter evidenced (after T 3 h). GLIC also reduced the duration of the postprandial myoelectrical activity on duodenum and jejunum (65 and 63% respectively, P < 0.05), but was not as efficient as OXM on ileum. In pathological states such as acute adult gastroenteritis, OXM and GLIC exhibit a two- to fivefold increase in their plasma concentrations. The present findings suggest that OXM and GLIC could, in that disease, contribute to exclude pathogens, due to their joined action on gut motility.

Therapeutic perspectives for melatonin agonists and antagonists.

Melatonin is a neurohormone synthesized in the pineal gland during the dark period in all species, including humans. The diversity and differences in melatonin receptor distribution in the brain and extracerebral organs suggest multiple functional roles for melatonin. Administration of melatonin agonists reduces neophobia and treatment with a melatonin antagonist during the dark period reverses the anxiolytic-like effect of endogenous melatonin. Chronic treatment with agonists prevents various perturbations induced by chronic mild stress. Melatonin in vivo directly constricts cerebral arterioles in rats and decreases the lower limit of cerebral blood flow autoregulation, suggesting that melatonin may diminish the risk of hypoperfusion-induced cerebral ischemia. At the extracerebral level, melatonin regulates intestinal motility in rats. The intestinal postprandial motor response is shorter in the dark phase than in the light phase and this reduction is reversed in animals pretreated with a melatonin antagonist. Moreover, melatonin reduces the duration of cholecystokinin excitomotor effect. Endogenous melatonin may modulate intestinal motility to coordinate intestinal functions such as digestion and transit and control the metabolism of the animal. An adipocyte melatonin binding site may also participate in this control. Melatonin is involved in a wide range of physiological functions. The question remains as to whether evolution, adaptation and diurnal life have modified the physiological role of melatonin in humans. Moreover, the functional role of each of the receptor subtypes has to be characterized to design selective ligands to treat specific diseases.

Effect of melatonin on motility pattern of small intestine in rats and its inhibition by melatonin receptor antagonist S 22153.

Melatonin is synthesized during the night by the pineal gland. Recently, melatonin binding sites have been identified in the gut. Despite few studies, the physiological role of melatonin in gut function remains unclear. The objective of the present study was to investigate the effects of melatonin in the regulation of intestinal motility by using the melatonin receptor antagonist S 22153 in rats. Twenty-four male Wistar rats (400 +/- 25 g) were equipped with intraparietal electrodes along the small intestine. Rats were subjected to a 12:12 hr light:dark schedule. During the dark phase, intestinal migrating motor complexes (MMCs) frequency increased (P < 0.05) by 20% in the duodenum and in the jejunum compared with daylight. This effect is due to a significant reduction in the irregular spiking activity (ISA) of MMCs. Concurrently, at night, the duration of the postprandial motor response is reduced by 30% in the duodenum and 50% in the jejunum and ileum. The administration of S 22153 (2 mg/kg sc) at night suppressed these nocturnal variations and restored the daylight values. In contrast, S 22153 was ineffective during daylight whatever the digestive state. Administration of melatonin (1 mg/kg iv) during the preprandial state, 3 hr after light onset, decreased (-80%) the duration of the ISA of MMCs at the three intestinal levels. During the satiety phase, melatonin administered 10 min before or 15 min after food onset induced the appearance of a transitory preprandial-like motor profile in the entire small intestine. In contrast, when administered at the end of the meal it was ineffective. Preprandial and postprandial melatonin effects were prevented by S 22153 pretreatment. In conclusion, these findings reveal, first, that endogenous melatonin is physiologically involved in the pre- and postprandial changes of intestinal motility at night. Second, exogenous melatonin produces pharmacological effects on pre- and postprandial intestinal motility. In both cases, the action of melatonin corresponds to an inhibition of ISA and a reinforcement of the cyclic MMC pattern.

Release of guanylin immunoreactivity from the isolated vascularly perfused rat colon.

The intestinal peptide guanylin regulates the electrolyte/water transport in the intestinal epithelium. The aim of the present study was to investigate the mechanisms that modulate its secretion in the isolated vascularly perfused rat colon by using a specific guanylin RIA. Intraarterial infusion of bethanechol (10(-4) M) or bombesin (10(-7) M) elicited a significant 6-fold increase in the release of guanylin immunoreactivity (G-IR) in the lumen. Bombesin-stimulated G-IR secretion was strongly reduced by tetrodotoxin, whereas atropine had no effect. VIP (10(-7) M) induced a moderate release of G-IR, whereas substance P, calcitonin gene-related peptide, peptide YY, somatostatin, and neurotensin were without effect. Dimethyl-PGE2 (1.4 x 10(-5) M) or interleukin-1beta (2.5 x 10(-10) M) induced a 3-fold increase in G-IR in the lumen, whereas the degranulator compound bromolasalocid did not stimulate guanylin secretion. Forskolin (10(-5) M) or sodium nitroprusside (10(-4)-10(-3) M) induced a significant release of G-IR. In contrast, PMA (10(-7) M) or ionophore A23187 (10(-6) M) did not modify basal secretion of G-IR. Upon stimulation of guanylin release with bombesin or bethanechol, an increase in G-IR in the portal effluent was also detected. The release of G-IR in the portal effluent was 40-fold lower than that of G-IR into the luminal perfusate. Additionally, analysis with gel chromatography revealed that the immunoreactive material released in the lumen or in the portal effluent coeluted with the 15-amino acid peptide originally isolated from rat intestine. In conclusion, the present data suggest that the enteric nervous system and immune cells may modulate guanylin release from the rat colon. The release of guanylin in the lumen and portal effluent suggests that this peptide may exert both luminal/paracrine and hormonal effects.

Reversed bowel segments for the treatment of short bowel syndrome: assessment of their minimal length in correlation with electromyographic pattern in the rat.

Reversal of a distal intestinal loop is a surgical therapy intended to cure rapid intestinal transit in short bowel syndrome. To be active, a reversed loop must present a retrograde propagation of electromyographic patterns and must not be so long as to cause total obstruction. The aim of the current study was to propose methods to calculate the minimal length of the intestinal reversed loop taking into consideration the two previous conditions. Intestinal electromyograms were recorded in 65 rats at short-term (4 days after surgery) and ten rats at long-term (50 days after surgery). Control rats demonstrated that the preprandial regular spiking activity (RSA) of the migrating myoelectrical complex (MMC) extended simultaneously a definite part of the intestine which corresponds to the minimal length to reverse. A similar result can be obtained from a trigonometric representation. Whatever the method, the minimal lengths allowing the recording of RSA decreased along the rat intestine from 6 cm (proximal jejunum) to 4 cm (distal ileum). The experiments demonstrated that shorter loops did not present the preprandial RSA. In conclusion, the minimal reversed length depends on intestinal electromyographic parameters and, thereby, on the intestinal level.

Nycthemeral variations of cholecystokinin action on intestinal motility in rats: effects of melatonin and S 20928, a melatonin receptor antagonist.

The aim of the present work was to investigate the impact of the light-dark cycle on CCK intestinal motor effect and to evaluate the consequence of the melatonin treatment and the melatonin receptors blockade on CCK action. The peripheral administration of CCK-8s (5 microg/kg iv) during the fasted state induces an irregular spiking activity corresponding to an excitation of intestinal motility on the duodenum, the jejunum and the ileum. The duration of this excitomotor effect is shorter in the dark phase only on the duodenum (-60%) and the jejunum (-40) compared to the light phase. During the light phase, melatonin (1 mg/kg iv) administered, 10 min prior to CCK-8s, reduces the duration of CCK-8s excitomotor effect only on the duodenum (-42%) and the jejunum (-52%). On the opposite, during the dark phase, the blockade of melatonin receptors by S 20928 (1 mg/kg sc), 60 min prior CCK-8s, restores the excitomotor effect of CCK-8s to its diurnal values. In conclusion, the action of the neurohormone CCK on intestinal motility follows a biological rhythm related to the light-dark cycle. Melatonin, released by the pineal gland at night, seems to be physiologically involved in this modulation.

Peripheral neurotensin participates in the modulation of pre- and postprandial intestinal motility in rats.

The present study was undertaken to determine whether neurotensin is involved in the regulation of the intestinal postprandial motor response and, if so, whether the regulatory pathway depends upon peripheral or central neurotensin secretion. Neurotensin, injected by the i.v. route (5 micrograms/kg) during the fasting state, induced firstly an increased irregular spiking activity during 30-40 min. This effect was followed by an increase of frequency of the myoelectrical complexes during 60 min. When injected by the i.c.v. route, neurotensin (0.5 microgram/kg) reinforced the fasting motility pattern of the small intestine after a latency of 70 min. Neurotensin was ineffective on the colon. The neurotensin receptor antagonist SR 48692 (200 micrograms/kg i.v.) reduced the duration of the postprandial motor response of the small intestine and blocked the late postprandial phase on the proximal colon while it suppressed the early postprandial phase on the distal colon. When administered i.c.v. (20 micrograms/kg), SR 48692 had no effect. It is concluded that neurotensin modulates intestinal postprandial motility essentially by a peripheral regulatory pathway. Endogenous neurotensin is involved in the maintenance of the postprandial motility pattern on the small intestine and the proximal colon while it is involved in the initiation of this response on the distal colon. This suggests that endogenous neurotensin acts via both endocrine and nervous mechanisms.

[Magnetic resonance imaging and x-ray computed tomography in advanced cancer of the oral cavity. A comparative clinical, radiological and morphological study]. / Apport de l'imagerie par résonance magnétique et de la tomodensitométrie dans les cancers avancés de la cavité buccale. Etude comparative clinique, radiologique, morphologique.

The objective of this prospective study is to assess the impact of magnetic resonance imaging (MRI) and computed tomography (CT) as compared to physical examination in the choice of type of surgery for advanced intraoral cancers (with or without resection of the mandibula). From 1990 to 1993, we operated on 21 intraoral malignant tumors with segmental resection of the mandibula followed by a histological examination. The preoperative evaluation consisted of an MRI (n = 8), a CT (n = 8) or both (n = 5). MRI suspected an infiltration of the bone in 9 cases, CT in 4 and physical examination in 16. This was histologically confirmed in 6 of the 21 patients only. MRI and CT both have a high sensitivity, as does physical examination, but neither have a good specificity (physical examination: 5 true positive, 4 true negative, 11 false positive, 1 false negative; MRI: 4 true positive, 4 true negative, 5 false positive, 0 false negative; CT: 3 true positive, 7 true negative, 3 false positive, 0 false negative). In conclusion, the decision of a mandibular resection can only be taken after a careful physical examination, including palpation under general anesthesia in a fully relaxed patient. This is best accomplished during the pretherapy bronchoesophagoscopy, routinely performed for the detection of synchronous second primary tumors using toluidin blue as a vital staining method. If this initial evaluation gives a suspicion of a massive infiltration of the mandible, an MRI, rather than a CT, should be performed to determine the extent of the resection because of a high rate of artefacts with CT.

Melatonin is involved in cholecystokinin-induced changes of ileal motility in rats.

The aim of this study was to determine, in the rat, the interaction between melatonin and cholecystokinin in the regulation of the ileal interdigestive motility. This was analyzed by the chronic electromyography technique. Ileal motility was defined by the presence of intermittent spike bursts corresponding to the contractile activity of the organ. In control rats, these spike bursts were organized in cyclic myoelectrical complexes. Each complex is characterized by two successive spiking activity phases: the irregular phase (ISA) followed by the regular phase (RSA). Pinealectomy suppressed the RSA phase so ileal motility was constituted only by the ISA phase. When melatonin (1 mg/kg i.v.) was injected into pinealectomized rats, RSA phases were immediately and definitively restored. RSA phases were also re-established when the "alimentary" type of cholecystokinin receptors (CCKA) were blocked by selective antagonists such as L364,718 or SR27897 (1 mg/kg i.v.). The latter had better brain accessibility than L364,718. Unlike the effects of melatonin, the effect of these antagonists was neither immediate (the latency is longer for L364,718 than for SR27897) nor definitive. In control rats, cholecystokinin (5 micrograms/kg i.v.) induced a characteristic long-lasting (29 +/- 2 min) excitomotor effect on the ileum. This effect was suppressed in pinealectomized rats and was restored after melatonin treatment. These results suggest that, via the central nervous system, melatonin is involved in the modulation of cholecystokinin action on ileal motility.

A possible interaction between serotonin and cholecystokinin-8 in the ileo-colonic motor responses to feeding in rats.

The effects of cholecystokinin (CCK)-A, CCK-B, and 5-hydroxytryptamine-2 (5-HT2) receptor antagonists on the postprandial myoelectric activity of the ileum and the proximal and distal colon in rats were studied. After L364,718, a CCK-A receptor antagonist, or ritanserin, 5-HT2 receptor antagonist, the duration of the ileal postprandial motor pattern was reduced by 60%. In contrast, L365,260, a CCK-B receptor antagonist, had no effect. In the distal colon, the postprandial response was inhibited by CCK-A, CCK-B, and 5-HT2 receptor antagonists, whereas they were inactive in the proximal colon. CCK-8 administered at the end of the meal suppressed the inhibitory effect of ritanserin on the ileum and the distal colon. These results suggest that, in rats, CCK-8 is involved in the control of the ileal motor response to feeding through CCK-A receptors and in that of the distal colon through both CCK-A and CCK-B receptors. Serotonin seems to play a role in CCK-8 control through 5-HT2 receptors.