Among functional digestive disorders, the irritable bowel syndrome (IBS) is the most common gastrointestinal disorder seen in primary care and gastroenterology practice. IBS is a functional bowel disorder in which abdominal pain is associated with defecation or a change in bowel habit, with features of disordered defecation and with distension. Pain is the symptom that patients list as their most distressing, and is a major factor in whether they consult physician. Up to 22% of the population reports symptoms consistent with IBS but only 10% of patients present for medical care for evaluation or treatment of their symptoms. Women are four times as likely to present to their doctors. IBS is a chronic disease with an extremely variable course in the general population and fluctuation of symptoms often results for seeking of further health care.

The underlying pathophysiology of IBS is unknown. Three mechanisms are classically involved in the pathophysiology of IBS: psychosocial factors, altered motility and sensory disorders. Neuroimmune interactions are also most likely involved as suggested by IBS manifestations observed after infectious gastroenteritis. In that case, mast cell seems to play a role.

Chronic visceral hyperalgesia, in the absence of detectable organic disease, is implicated in IBS. Indeed, Ritchie (1) reported an increased pain from distension of the pelvic colon by inflating a balloon in IBS patients. In contrast, IBS patients have normal or even increased tolerance to somatic stimuli. The exact location of abnormality of visceral pain processing is not known (Fig.1). Theories of its etiology have range widely from the original view that the disease represents a primary disturbance of gut mucosa to emerging conception of the syndrome as emanating from a complex disordered interaction between the digestive and nervous systems (2). Several lines of evidence suggest a strong modulatory or etiologic role of the central nervous system in the pathophysiology of IBS. A majority of patients associate stressful life events with initiation or exacerbation of symptoms (3). Stress is well known to induce gastrointestinal motility disturbances (4) and to decrease the threshold to visceral pain (5) and has been shown to increase the symptoms of patients with IBS (3). Recent data have shown that the emotional state caused by stress or a psychiatric disorder modifies intestinal reactivity (6). Anxiety and depression have an effect on intestinal transit, since anxiety is associated with increased bowel frequency, and depressed patients tend to be constipated. Behavioral studies, including relaxation (7) and hypnosis (8), and low-dose tricyclic antidepressant have proven efficacious in ameliorating symptoms in patients (9). Symptomatic improvement in IBS patients after hypnotherapy may be in part due to changes in visceral sensitivity (10).

Fig. 1. Visceral hypersensitivity in functional digestive disorders: location-nature of the prima-ry abnormality.

PAIN PROCESSING

Pain is a multidimensional experience including sensory-discriminative (ability to localize a stimulus in space and time and assess its intensity) and affective-motivational (unpleasant and emotional aspects of pain) components. Classically, a lateral pain system (lateral thalamic nuclei and somatosensory cortex) mediates the sensory-discriminative component while a medial pain system (medial thalamic nuclei, anterior cingulated and insular cortices) subserves the affective-motivational component of pain (Fig.2). It has become evident that there may not be a common structure or neuronal master switch for the generation of pain, but rather a distribution parallel network or matrix of cortical and subcortical structures that are subserved with afferent input via distinct anatomical pathways. The results from several groups working on experimentally induced pain in healthy volunteers have shown decreased global blood flow as well as increased regional cerebral blood flow in brain areas typically thought to be important in a) somatosensory processing: SI, SII, and the posterior insular cortex; b) motor processing: cerebellum, puttamen/globus pallidus, supplementary motor cortex, ventral premotor cortex, and the anterior cingulate cortex; c) affective processing: anterior cingulate cortex and insular cortex; d) attentional processing: anterior cingulate cortex, primary somatosensory cortex and the ventral premotor cortex; and e) autonomic functions: anterior cingulate cortex and anterior insular cortex. Anticipatory knowledge increases perception of intestinal distension as compared to mental distraction; thus cognitive processes selectively regulate the sensitivity to gut stimuli. This type of cortical mechanism may be activated by hypnosis, since hypnotherapy modifies perception of rectal distension in patients with IBS without changes in rectal compliance or reflexes and could thus explain the improvement in clinical outcome in patients with IBS. Specific assemblies of coherently activated brain structures are needed to portray all the different aspects of the subjects in pain. The overall picture of activation may thus depend not only on the nature, duration, and intensity of the applied noxious stimulus, but also on the general psychological disposition of the subject and how much intensity and unpleasantness of pain is perceived.

Fig. 2. Lateral and medial pain system pathways

BRAIN MAPPING OF PAIN PROCESSING

In animals, it is possible to map neuronal pathways activated by visceral pain using the expression of immediate early genes as represented by c-fos (11, 12). Recently, a major advance in the understanding of the central mechanisms of pain processing has evolved from application of functional imaging techniques, represented by positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These techniques have by now become the method of choice for functional brain mapping to characterize the central processing of somatic pain (13, 14). Regional blood flow and metabolism are modulated by neuronal activity (15). Oxygen consumption increases slightly during activation (less than 10%) while blood flow increases much more (up to 50%). Indeed, PET as well as fMRI may be used to study changes in blood flow or flow-related phenomena in human subjects in vivo. Both techniques monitor changes of synaptic activity in a population of cells. These changes may be due to excitation or inhibition. Monitoring of regional cerebral blood flow with PET or fMRI thus mainly reflects neuronal and more specifically (pre-) synaptic activity (16). The most common approach to fMRI of brain activation has been the one using blood oxygen level dependent (BOLD) contrast (17). This technique uses the paramagnetic susceptibility of deoxyhemoglobin, due to the presence of four unpaired electrons, to become slightly magnetized in the presence of the magnetic field of the MRI scanner. Deoxyhemoglobin is confined to red cells and is a natural endogenous paramagnetic contrast agent present in the blood at high concentration and modulated by variations in oxygen supply (blood flow) and oxygen utilization (tissue metabolism). During brain activation the large increase in blood flow which overcompensates a small increase in oxygen consumption, results in a net decrease in the blood deoxyhemoglobin concentration which, in turns, leads to a small (a few percent), but measurable signal increase. BOLD-based fMRI is sensitive to tissue deoxyhemoglobin content, which is determined by the rates of oxygen consumption and cerebral blood flow. During increased local neuronal activity, it is accepted that regional blood flow increases without a commensurate increase in oxygen consumption. The resultant decrease in regional deoxyhemoglobin generates susceptibility gradients giving rise to the BOLD-fMRI signal increase. BOLD has been found to be consistent with cerebral-blood-flow-based functional maps generated by PET or by perfusion-based magnetic resonance imaging technique. Unlike PET, fMRI provides rich information regarding temporal fluctuations of the fMRI signal. MRI does not show any ionizing radiation and thus offers the great advantage of being repeatable on the same subject. MRI do not require radiochemistry laboratories and are available in most hospitals. FMRI has a greater sensitivity, a better spatial and temporal resolution and is more widely available than PET. High resolution anatomical images and functional images can be obtained during the same session using the same imaging modality and functional and anatomical images can be easily matched. The possibility of alternating activation and rest periods (paradigm) increases the contrast-to-noise ratio.

BRAIN MAPPING OF VISCERAL PAIN

In contrast to the central processing of somatic pain, few imaging studies have been performed in order to evaluate the central processing of visceral pain in healthy subjects and in patients as represented by myocardial ischemia (18) or processing of painful and non-painful esophageal sensations (19). The first study depicting brain processing of intestinal pain has been published in 1997 by Silverman et al (20). Using PET to explore neural correlates of visceral pain induced by rectal pressure, the authors observed some differences in cerebral activation between healthy subjects and patients with IBS. If healthy subjects activated the anterior cingulate cortex (ACC), the patients with IBS didn’t. In contrast, patients presented an activation of the left prefrontal cortex (PFC). The authors considered these findings as being consistent with an IBS model that includes both the exaggerated activation of a vigilance network (PFC) and a failure in activation of brain regions involved in pain inhibition (ACC). These findings implicate differences in the way the brain of IBS patients function in response to visceral pain. fMRI is a non-invasive method that presents good spatial and temporal resolutions, and the matching of functional and anatomical MR imaging data is straightforward. Using fMRI, we first characterized cerebral loci activated by a rectal distension in healthy volunteers (21). Activations were detected within the ACC (Brodmann areas 24 and 32), the dorsolateral prefrontal cortex (DLPFC), the insular cortex (IC), the primary somato-sensory and motor cortices (Brodmann areas 3, 2, 1, and 4), the inferior parietal lobule (angular gyrus and supramarginal gyrus, Brodmann areas 39 and 40), the posterior cingulate gyrus (Brodmann areas 30 and 31) and the extrastriate visual cortex (Brodmann areas 18 and 19). A significant right-hemispheric predominance of responses was observed within the PFC and IC. The activation patterns observed in this study support the hypothesis that the cerebral processing of visceral pain involves multiple components, in strong similarity with the central processing of somatic pain. This study was considered as a first step towards the identification of possible aberrations in the activation patterns of patients suffering from visceral hypersensitivity as represented by IBS patients. In a recent study, using fMRI performed during nonpainful and painful rectal distension in controls and patients with IBS, Mertz et al (22) observed that in IBS subjects, but not in controls, pain led to a greater activation of the ACC than did nonpainful stimuli. These data are in contrast to the findings of Mayer’s group who used PET. It does suggest an up-regulation of afferent sensitivity to pain, which could be caused by either increased sensitivity to visceral stimulation at the primary splanchnic afferent neuron or by increased sensitivity of the CNS pain-processing center in the ACC in IBS patients. We also performed a study on IBS patients using fMRI, we showed that these patients present alterations in the central processing of rectal pain (23). Indeed, using the same procedure as previously described (21), we observed a lack of activation in cerebral structures normally activated in healthy volunteers (ACC and PFC) while we observed significant deactivations (i.e. pixels in which the MR signal levels were significantly lower during noxious stimulation than in the absence of pain) in the right hemisphere, within the posterior part of the insular cortex, the amygdala and within the striatum (putamen). These results provide additional ground to the hypothesis that the CNS plays a significant role in the pathophysiology of IBS patients (Fig.3). Our findings are different than the ones of Mayer’s group (20), who used PET, and the ones recently obtained by Mertz et al (22), using fMRI. If we didn’t observe any activation in the PFC, as observed in the Silverman’s study, we also didn’t observe any activation of the ACC; this finding being closed to the one observed by Silverman. Our protocol is different that the ones of Silverman and Mertz in the sense that we didn’t use a barostat but the maximal tolerable volume (MTV) of the rectum which is a validated method exploring the sensitivity of the rectum (24). In the Mertz’s study, it is note that only six 5-mm-thick slices were acquired while 20 in our study. On the other hand the regions of interest were identified and circled on the high-resolution anatomic images by a senior neuroradiologist, who was blinded to the identity of the patient and to the active pixels. In our study, we did not specifically assess anxiety or vigilance in our subjects, but administered a series of 3 distensions. There was no difference between the first and the third stimulus that might indicate progressive anticipation of stimuli. Furthermore the subjects were not aware of the order of stimuli sets (inflation vs. deflation). While it is very unlikely that differences across studies arise from the use of different imaging techniques (PET vs. fMRI) or from subtle differences in data processing, the particular paradigms and parameters (duration, intensity….) of the noxious stimuli applied may account for some of the discrepancies. Attentional processes could possibly explain part of the variability observed. Avoidance of hypervigilance is a particularly difficult problem in this form of research.

Fig.3. fMRI study of rectal pain in patients with irritable bowel syndrome (IBS) (Group analysis): Abnormal central processing of visceral pain, as represented by deactivations in the right insular cortex (black circles), the right amygdala (gray circles), and the right putamen (white circles).

BRAIN NUCLEI INVOLVED IN VISCERAL PAIN PROCESSING: ANATOMICAL AND FUNCTIONAL CHARACTERISTICS

1. The amygdala is a nuclear located inside the temporal lobe, deep to the uncus. The overall function of the amygdala is to assign emotional significance to a current experience especially as that experience relates to anxiety and fear (25, 26). Electrical stimulation of the amygdala in humans elicits feelings of fear and anxiety as well as autonomic reactions consistent with fear (27). Sensory information from the external environment reaches the amygdala through the sensory cortex while other fibers arrive from the insula cortex (IC), which provides sensory information from the internal environment. Projections from the amygdala go to cortical areas involved in the perception of anxiety and fear, including the orbital cortex, temporal pole, and hippocampus as well as the cingulate gyrus and subcortical areas including the medio-dorsal nucleus of the thalamus which projects fibers to all areas of the prefrontal cortex (PFC). Connections with the PFC and cingulate gyrus allow for appreciation of the emotion, for memory of the emotional situation and for the formulation of appropriate somatic and autonomic responses. Thus there is a direct and indirect route from the lateral amygdala to the PFC. Connections with the hypothalamus provide a route by which the amygdala can regulate autonomic tone. A behaviorally sensitive region in which a large number of amygdala efferents terminate is the ventral striatum, which includes the nucleus accumbens. Connections with the hippocampus may provide the substrate for learning the emotional significance of specific spatial and sensory cue stimuli. The amygdala-hippocampus system may assess the magnitude of a particular threat based on past experience. The hippocampal formation is critical in the storage and recall of memory events. Close ties between the hippocampus, amygdala, and PFC links specific situations with emotions. The amygdala is believed to attach emotional significance to specific incoming somatic and visceral sensory stimuli. The amygdala can search for past stimuli of a similar nature in order to tag the current stimulus with the same emotion. Other afferents arise from brainstem areas that are related to visceral sensations, taste and pain. Efferents from the amygdala terminate in the hypothalamus, mainly in the ventromedial nucleus, which is related to feeding behavior. Hypothalamic efferents influenced by the amygdala include those that regulate the anterior pituitary. Projections from the amygdala to the hypothalamus as well as reciprocal hypothalamic-prefrontal connections are the basis of the endocrine, autonomic, and behavioral reactions to anxiety-producing situations. The amygdala receives input from brainstem autonomic sensory nuclei (nuclei tractus solitarii, parabrachial nuclei). Efferents from the central nucleus terminate in the dorsal motor nucleus of the vagus as well as other brainstem parasympathetic motor nuclei and in the brainstem reticular formation, including the periaqueductal gray. Other efferents also control autonomic activity by way of efferent fibers to the hypothalamus. The amygdala is closely tied with the emotional responsiveness of parasympathetic tone. It copes with environmental challenges by promoting responses that have been successful in the past and by assigning emotional significance to current events. Fight or flight responses or defensive freezing behaviors can be elicited by the amygdala and its connections with the periaqueductal gray (PAG). The amygdala plays a key role in monitoring the level of autonomic tone by way of feedback from viscera. Connections with the brainstem autonomic motor nuclei provide a route by which the amygdala directly modifies the autonomic nervous system. Rats with a lesion in the amygdala fail to benefit from procedures that normally improve response to conditioned stimuli. People with a bilateral destruction of the amygdala have a loss of fear. The sensation of anxiety is appreciated in the orbital PFC and possibly the cingulate gyrus by way of projections from the amygdala. The location of the amygdala with respect to the PFC and autonomic centers is consistent with the role it plays in learning relationships between stimuli and socially important behavior. The descending raphe spinal pathway that regulates incoming pain signals is also a target of fibers from the amygdala. The vagus nerve monitors the internal environment and contributes to visceral tone. Visceral sensory information is passed to the solitary and parabrachail nuclei of the brainstem. Other interoceptive information is channeled through the nucleus prepositus hypoglossi and nucleus paragiganto-cellularis. The subsequent activation of the locus coeruleus increases the level of anxiety as controlled by the amygdala. The parabrachial nucleus receives and integrates incoming visceral signals. Overactivity of the parabrachial/locus coeruleus axis may be responsible for spontaneous and nocturnal panic attacks. The locus coeruleus may play an important role in mediating anticipatory anxiety by way of its connections with the amygdala. The amygdala has been shown to respond to many distinct types of affective stimuli, including reward and punishment feedback in animals. In humans, winning and losing situations can be considered as reward and punishment experiences, respectively. The role of the amygdala is to translate information about the moment-to-moment state of subjective emotional intensity into the modulation of long-term memory, but only for the most emotionally intensive experiments. The determinant of amygdala laterality in influencing memory for emotional events is an important area for future studies. Laterality could relate to gender difference, activity in the left amygdala being predominant in females. 2. The anterior cingulate cortex (ACC) forms a large region around the genu of the corpus callosum. The ACC lies in a position of filter and control the relationship between the emotional limbic system and the skeletomotor and autonomic portions of the nervous system. It is considered to be a key element in the rostral limbic system. A majority of the ACC consists of Brodmann’s area 24. The others areas correspond to area 25 (the paragenu area) and area 32 (prelimbic area). Subdivisions of the ACC deal with different aspects of emotionally related behavior, including the motor aspects of those behaviors. The posterior prelimbic area (Brodmann’s area 32) and the more posterior portion of Brodmann’s area 24 are called the cognitive division. More anterior portions, including area 25 and 33 (paragenu area) and anterior area 24 have been termed the affect division (28). The affect division regulates autonomic and endocrine functions, assesses motivational and emotional content of internal and external stimuli, and plays a role in maternal-infant interactions. The cognitive division of the ACC includes the skeletomotor and nociceptive regions and is involved in response selection and in cognitive aspects of problem solving. The ACC is important in providing motivation and in selecting appropriate skeletomotor responses to internal and external stimuli, including socially relevant stimuli. The ACC is involved with planning motor activity (premotor function) and with memory and the selection of motor and autonomic responses associated with affect, including responses to painful stimuli. The ACC and parietal cortex may interact closely during directed attention. Activity in the ACC occurs well in advance of the execution of the behavior, suggesting that it functions in an executive and planning capacity. The strategic anatomical location of the cingulate suggests that it plays an important gating (executive) function in goal directed behavior, motivation, and neurovegetative functions. The ACC is associated with motivation and the initiation of behavior (29). The ACC along with the basal ganglia represent the anterior attention system. This system plays an executive role in selecting and controlling various brain areas in order to perform complex cognitive tasks. This system can, for example, scan available visual objects and select those with particular properties defined by a set of instructions. It works by recruiting and controlling the posterior attention system as well as other brain systems. One region under its executive control can be the dorsolateral PFC in which past events are represented and transformed as a part of working memory (30). Stimulation of the ACC elicits autonomic related responses, including pupillary, cardiovascular, respiratory, gastrointestinal, and urinary changes, but without integrated forms of behavior. Electrical stimulation in different parts of the ACC evokes different emotions, including euphoria, fear, pleasure, and agitation (31). Lesions of the ACC may produce contralateral neglect, and blood flow in some limbic structures including the ACC. The ACC has been reported to be significantly more active in patients with obsessive-compulsive disorders.

The ACC is involved in visceromotor control. The cortex just below the genu of the corpus callosum (infralimbic cortex) regulates autonomic behavior. This region is included in the affect region of the ACC and has been called part of the « ventral anterior cingulate system » as well as visceral motor cortex. It is reciprocally connected with the visceral sensory cortex of the insular area (32). It receives a large input from the amygdala and has efferent fibers that project to visceromotor centers, including the PAG, the solitary nucleus, the dorsal motor nucleus of the vagus, the reticular formation motor nuclei, and the thoracic sympathetic lateral horn. It also receives dopaminergic fibers from the ventral tegmental area of the midbrain. The ACC is not the anatomical site where emotion is experiences, but it does contribute to the overall emotional response by activation of visceral and somatic states that are important in the experience of emotion (33). Vocalizations emitted by animals in response to threat, attack, or fear arise from this region. Since stimulation of the PAG of the midbrain can produce these same vocalizations, the projections from the infralimbic area to the PAG may be critical in transmitting the signals from the affect division of the ACC to the brainstem. Stimulation of the infralimbic region of the ACC in animals results in marked changes in blood pressure, and heart and respiratory rates as well gonadal and adrenocortical hormone secretion, thirst, penile erection, and aggression. These areas appear to be involved in the autonomic responses seen during classical conditioning, suggesting that memory for these associations may be integrated here. In humans, stimulation of the infralimbic region results in changes in autonomic tone.

The ACC is involved in nociception. The ACC is a major component of the medial pain system. The area of the ACC involved in pain lies behind and below the skeletomotor control region. Neurons in this region respond to noxious stimuli. The regions seems to have no localizing value since noxious stimuli applied anywhere on the body result in activation of these neurons. This generalized activation, coupled with the fact that the ACC receives projections from medially located diffuse thalamic nuclei as opposed to laterally located relay nuclei makes the ACC part of the medial pain system (34). The ACC appears to be involved in specifying the affective content of the noxious stimulus, in selecting a motor response to the stimulus, and with learning associated with the prediction and avoidance of noxious stimuli. It is speculated that the ACC organizes appropriate response to pain. One response to pain is the inhibition of activity in the PFC during noxious stimulation (28). The ACC projects to the midbrain PAG, an area known to regulate pain perception. These findings are consistent with the data showing that cingulotomy may be particularly effective in otherwise refractory pain. The ACC is activated by application of noxious stimuli (35). Response to noxious heat stimulus was seen to increase activity in the controlateral ACC in human subjects. Blood flow increases were observed in the ACC during application of noxious stimuli, while at the same time prefrontal cortex blood flow was seen to decrease. A lesion surgically introduced in the anterior cingulum bilaterally is referred to as cingulotomy. Patients suffering from chronic pain who were treated with cingulotomy reported that they continued to feel the pain but that the pain did not bother them and did not trigger an adverse emotional reaction. Psychiatric patients who received surgical lesions of the cingulate cortex or cingulum, or both, reported relief from chronic, intractable pain.

3. The Dorsolateral prefrontal cortex (DLPFC) receives input from the motor cortex as well as from the multimodal sensory convergence areas of the parietal and temporal lobes. In contrast to the orbital cortex, the connections of the DLPFC place it in a position to evaluate and regulate information from the somatic sensory system that can be used by the motor cortex to effect a response. The DLPC has been described as a place « where past and future meet ». It looks backward in time to create memories from sensory input and looks forward in time to assemble a motor plan of action (36). The DLPFC is heavily involved in working memory. Studies indicate that the events that take place in the DLPFC make up what is considered working memory (37). The DLPFC samples and regulates the flow of information to the motor by way of direct connections with the motor cortex and indirect connections with the mediodorsal and reticular nuclei of the thalamus. The reticular thalamic nucleus regulates and directs sensory information to the cortex. In contrast, the projections from the orbital region to the motor cortex regulate arousal and control the degree to which the limbic system influences motor behavior. The DLPFC monitors and adjusts behavior. The more superior portions of the DLPFC direct behavior in terms of sequential or temporal cues. More inferior portions regulate behavior in terms of spatial cues. Neurons involved with memory (~40% of total) decrease their firing rate over time after a stimulus. In contrast, neurons involved with encoding a motor response (60% of total) increase their firing rate as the time to act approaches. Working memory allows the representations to be manipulated and associated with other ideas and with incoming information in order to guide behavior. There appears to be no one locus of a central executive processor. Instead, visuospatial processing takes place in the DLPFC. The working memory for faces and objects takes place in more lateral and inferior regions of the prefrontal cortex. Finally, semantic encoding and verbal representations are found in more inferior, insular, and anterior prefrontal regions. Lesions of the dorsolateral area cause abnormalities in complex psychological functions, which are classified as executive function deficits. The patient demonstrates difficulties in planning, feedback, learning, sequencing, establishing, maintaining, and changing a set behavior.

Consistent with the studies on hyperalgesia, activation within the PFC has invariably been described in studies on experimental C-nociceptor-mediated pain and unpleasant itch. The signal processing within the PFC shares similar mechanisms during hyperalgesia and C-nociceptor pain. In general the prefrontal responses are interpreted as a consequence of encoding (left) and retrieval (right) of episodic memory and cognitive evaluation and planning, involving behavioral and attentional organization during pain. The PFC is closely connected with the posterior parietal association cortex. They both project to numerous common cortical and subcortical regions and PF and parietal responses to target stimuli often operate in concert. Thus, activation in the PFC may indicate associated processes of cognitive appraisal and evaluation, attention, self-awareness, and other unspecified mental processing of the perceived pain.

4. The insula lies deep within the lateral fissure. It consists of several long gyri located more caudally, paralleling the lateral fissure, and five short gyri located more rostrally. It is made up of an anterior and posterior region divided by the middle cerebral artery that passes across the surface of the insular cortex. It has connections with many limbic-related structures, including the entorhinal area, hippocampus, amygdala and PFC as well as with the motor cortex and basal ganglia. The insular cortex also has interconnections with the sensory association areas and is considered the cortical viscerosensory area. It has been suggested to be a gateway between the somatosensory areas and the limbic system and has been included as a component of the limbic integration cortex (38). The temporal pole, the orbital PFC, and the insula are recognized as components of the paralimbic cortex. The anterior insula along with adjacent frontal opercular cortex, especially on the dominant side, represents a primary gustatory area. This area corresponds closely with Brodmann’s area 43 (39). The posterior insula has been identified as the cardiac control cortex (40). It plays a role in the appreciation of emotional aspects of pain. The insula is also a component of the articulatory loop, which is important in processing verbal material. Blood flow has been reported to increase during anticipatory anxiety in the anterior insular area, which is postulated to serve as an internal alarm center. Recalled sadness in normal subjects produces activation of the anterior insula. Results suggest that the anterior insular cortex participates in the emotional response to particularly distressing cognitive or interoceptive sensory stimuli. Activation of the insular cortex may reflect its role in cardiac control. The insula also responds to gustatory stimuli. The insula has a role in the control of autonomic function. There are considerable reciprocal connections between the ventroposterior regions of the thalamus and the insular cortex, and this organization is consistent with the relay-site role of the thalamus proposed from the results obtained from animals studies. Indeed, by lesioning areas of the insular cortex, they were able to observe subsequent degeneration in the mediobasal nucleus and the mediobasal region of the VPM. There are connections between the insular cortex and the mediodorsal and ventroposteromedial regions of the thalamus. HRP injection into general visceral regions of the insula cortex resulted in staining of the parvocellular region of the VPL nucleus of the thalamus. Previous electrophysiological studies, in animals and humans demonstrate asymmetry in the cortical representation of visceral inputs.


CONCLUSION

Brain imaging techniques are useful tools to depict abnormal loci of cerebral activation in patients with functional digestive disorders with a special interest for IBS. IBS patients have an abnormal central processing of visceral pain. The main abnormalities are essentially depicted in the ACC, IC, DLPFC and amygdala. Reversal effects of chemical compounds targeting these abnormalities either at a peripheral or a central level should be of interest.


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