# The Brain Gut Disconnect



## eric (Jul 8, 1999)

FYI http://abbc3.hsc.usc.edu/cme/ibs/contents/braingut.html


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## eric (Jul 8, 1999)

"Dr. Mayer has a longstanding interest in clinical and neurobiology aspects of brain-gut interactions in health and disease. He has published more than 110 original articles, numerous review articles and chapters, co-edited two books and organized several interdisciplinary symposia in this area. Dr. Mayer has made seminal contributions to the characterization of physiologic alterations in patients with functional disorders, in particular in the area of visceral pain, stress-induced visceral hyperalgesia and altered brain responses. He has two active R01 grants, one on basic mechanisms of NMDA receptors in visceral nociception, the other on brain and perceptual responses to visceral stimulation. He is P.I. on a subcontract of another RO1 grant on the role of proteinase-activated receptors in neuronal activation, and co-investigator on a RO1 grant (P.I. Lin Chang) dealing with neuroendocrine alteration in IBS and fibromyalgia. Dr. Mayer has served on the editorial boards of the leading journals in digestive diseases, including Gastroenterology, Gut, Digestion and the American Journal of Physiology. He has served as reviewer for a wide range of medical and neuroscience journals and as ad hoc reviewer for national and international funding agencies. He has also served on ad hoc NIH study sections.Dr. Mayer has been involved in an administrative and leadership function in several large interdisciplinary programs at UCLA. He is the Director of the UCLA Center for Neurovisceral Sciences & Women's Health (CNS), a translational research program recently funded by the NIH that is currently viewed as the leading integrated research program in the world in the area of functional digestive disorders. Senior investigators within the CNS perform a wide range of basic and clinical research activities in the area of neurovisceral interactions in health and disease. Research efforts of this program include the study of cellular and molecular mechanisms of chemo- and mechanotransduction of primary afferent nerves; animal studies on stress modulation of visceral pain and associated autonomic responses; human physiology studies on cerebral, autonomic, neuroendocrine, and perceptual responses to visceral stimulation; and health outcomes, quality of life, and epidemiological studies in populations suffering from chronic gastrointestinal disorders. The Center includes more than 15 M.D. and Ph.D. researchers who are supported by individual RO1 grants. Dr. Mayer is the Chair of the recently established UCLA Collaborative Centers for Integrative Medicine, a multidisciplinary and interdepartmental clinical and research program related to different aspects of integrative medicine. Dr. Mayer has trained close to 20 postdoctoral fellows and has played an active role in promoting an integrative model of mind/brain/body interactions in his clinical practice, lectures and publications. Along these lines, he has organized two seminal interdisciplinary symposia on different aspects of mind/brain/body interactions and has published a volume of Progress in Brain Research on this topic." http://ibs.med.ucla.edu/Bios/MayerE.htm He also wroteInflammatory Bowel Disease and Irritable Bowel Syndrome: Separate or Unified?from Current Opinion in GastroenterologyPosted 07/15/2003Sylvie Bradesi, PhD, James A. McRoberts, Ph.D, Peter A. Anton, MD, Emeran A. Mayer, MDAbstract and IntroductionAbstractBoth irritable bowel syndrome and inflammatory bowel diseases share symptoms of altered bowel habits associated with abdominal pain or discomfort. Irritable bowel syndrome has been referred to as a functional bowel disorder, which is diagnosed by a characteristic cluster of symptoms in the absence of detectable structural abnormalities. Inflammatory bowel disease is a heterogeneous group of disorders characterized by various forms of chronic mucosal and/or transmural inflammation of the intestine. In this review, the authors discuss recent evidence suggesting several potential mechanisms that might play a pathophysiologic role in both syndromes. Possible shared pathophysiologic mechanisms include altered mucosal permeability, an altered interaction of luminal flora with the mucosal immune system, persistent mucosal immune activation, alterations in gut motility, and a role of severe, sustained life stressors in symptom modulation. It is proposed that similarities and differences between the two syndromes can best be addressed within the framework of interactions between the central nervous system and the gut immune system. Based on recent reports of low-grade mucosal inflammation in subpopulations of patients meeting current diagnostic criteria for irritable bowel syndrome, therapeutic approaches shown to be effective in inflammatory bowel disease, such as probiotics, antibiotics, and antiinflammatory agents, have been suggested as possible therapies for certain patients with irritable bowel syndrome.Complete article here: http://www.medscape.com/viewarticle/457728_1 Curr Opin Gastroenterol 9(4):336-342, 2003. ï¿½ 2003 Lippincott Williams & Wilkins


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## m_m_forth (Oct 21, 2003)

Eric:This is a fantastic article! I always beieved that cortisol had an effect on IBS. I am, however, baffled by their finding that cortisol levels are 50% lower in IBS patients than in controls. I hope they follow up on this finding.


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## kel1059 (Feb 28, 2003)

black tape on engine warning light??? it might be.


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## eric (Jul 8, 1999)

Realist, I know they are following up on this in many ways and creating CRF drugs to target this in IBS.The cortisol is one reason why a lot of IBSers have problems in the mornings."Readers' ExchangeDefining Stress in IBSFall 2003From Arizona -- Thank you so much for your efforts and support for those of us with GI disorders. Your first issue (Spring 2003) of Digestive Health Matters is both professional and informative. I would like to comment on one of the articles - "The CNS: Center for Neurovisceral Sciences and Women's Health at UCLA." I am encouraged to know that steps are being taken for funding research of IBS and interstitial cystitis. However, it is discouraging that researchers are still expending time and money to research "neurobiological mechanisms by which stress modulates brain-visceral interaction." I realize that stress is a popular theory in the discussion of IBS triggers, however, I believe this is completely backward and it is the chronic pain and totally unreliable bowel function of an IBS sufferer which causes the greatest stress. If research would focus on "fixing" the bowel, no doubt the panic and fear of IBS would be greatly alleviated. Comment from Emeran Mayer, M.D. -- In contrast to the common interpretation of the term "stress" as a psychological phenomenon, it should be understood as any real or perceived perturbation of an organism's homeostasis, or state of harmony or balance. For example, in this viewpoint a severe hemorrhage, starvation, extreme temperature, or worry about the unpredictable onset of abdominal pain all qualify as stressors -- some as "physical" stressors, others as "psychological" stressors. The fear to leave the house in the morning without knowing if one can make it to work without having to stop on the freeway because of an uncontrollable bowel movement, or the fear of experiencing uncontrollable abdominal discomfort during an important business meeting are sufficient stressors to activate the central stress system. The central stress system involves the release of chemical stress mediators in the brain (such as corticotropin releasing factor), which in turn orchestrate an integrated autonomic, behavioral, neuroendocrine, and pain modulatory response. This biological response in turn will alter the way the brain and the viscera interact, and this altered brain-gut interaction can result in worsening of IBS symptoms. Thus, pain and discomfort, fear of these symptoms, activation of the stress response, and modulation of the brain-gut interactions by stress mediators are part of a vicious cycle which need to be interrupted to produce symptom relief. The neurobiology of stress is not a theory, but a topic that can be studied in animal models, and *one of the hottest topics in drug development for treatment of IBS* e.g., substance P antagonists, corticotropin releasing factor antagonists. "


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## eric (Jul 8, 1999)

From - Report on the 5th International Symposium onFunctional Gastrointestinal Disorders"Preliminary work also suggests that there may be family interventions that help reduce the impact of functional GI disorders on children.3 Shin Fukudo, Tohoku University School of Medicine, Japan discussed Possible Genetic Markers in Functional GI Disorders and Treatment Response, an emerging area of research. For some time it has been believed that brain-gut interactions -- autonomous activity in the GI tract and central nervous activity that influences bowel function in response to stressors -- play a major role in the origin and development (pathogenesis) of irritable bowel syndrome (IBS). Studies suggest that IBS patients have hyper-reactive bowels and unusually stress-sensitive brains. Studies by Dr. Fukudo's group include recent use of models to study serotonin (5-HT) reuptake transporter (SERT) genes, cross-cultural studies of 5-HT agents, and the effects of variations in the regions of the DNA strand that are the beginning of a gene (gene promoter regions) on one's responses to stress. Sensitization of the nerves (neurons) in the brain and the gut (intestines) may be due to a genetic effect as well as an acquired effect (resulting from a stimulus). More investigation on exploring genetic markers and therapeutic responses is warranted.4 http://www.iffgd.org/symposium2003factors.html


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## eric (Jul 8, 1999)

FYIJack Wood, PhDProfessor of Physiology and Internal MedicineChairman Emeritus, Department of PhysiologyThe Ohio State University College of Medicine Dr. Wood was the first to use microelectrodes to record the electrical and synaptic behavior of neurons in the enteric nervous system. He coined the term "brain-in-the-gut" in view of emerging evidence that the enteric nervous system had neurophysiological properties like the brain and spinal cord. In recent years he has focused on signaling interactions between the enteric immune system and the brain-in-the-gut during infectious enteritis and food allergy. In this lecture he shows how the central nervous system, enteric nervous system and intestinal immune system are integrated during physical and emotional stress to produce irritable bowel symptoms of diarrhea and abdominal pain and discomfort. http://www.conference-cast.com/ibs/Lecture...cfm?LectureID=7 Nigel Bunnett, PhDUniversity of California School of MedicineDepartment of Surgery and PhysiologyAccumulating evidence indicates that sensory nerves play a major role in inflammation of multiple tissues, and that communication between the nervous system and mast cells is of particular importance. Dr. Bunnettï¿½s lecture will highlight recent experimental evidence that mast cell proteases signal to sensory nerves through novel receptors that couple to the release of proinflammatory peptides, and that defects in this mechanism result in uncontrolled inflammation and disease. Dr. Bunnett will present evidence that therapies designed to block signaling by neuropeptides and proteases are attractive treatments for inflammation. Inflammation: Role of Sensory Nerves and Mast Cell Mediators http://www.conference-cast.com/ibs/Lecture...dRegLecture.cfm J Neuroimmunol. 2004 Jan;146(1-2):1-12. Related Articles, Links Critical role of mast cells in inflammatory diseases and the effect of acute stress.Theoharides TC, Cochrane DE.Department of Pharmacology and Experimental Therapeutics, Tufts-New England Medical Center, Boston, MA, USAMast cells are not only necessary for allergic reactions, but recent findings indicate that they are also involved in a variety of neuroinflammatory diseases, especially those worsened by stress. In these cases, mast cells appear to be activated through their Fc receptors by immunoglobulins other than IgE, as well as by anaphylatoxins, neuropeptides and cytokines to secrete mediators selectively without overt degranulation. These facts can help us better understand a variety of sterile inflammatory conditions, such as multiple sclerosis (MS), migraines, inflammatory arthritis, atopic dermatitis, coronary inflammation, interstitial cystitis and irritable bowel syndrome, in which mast cells are activated without allergic degranulation.PMID: 14698841 FYIHarvard healthThe Mind and the Immune Systemï¿½Part IOne of the standing mysteries of medicine is the relationship between the mind and physical healthï¿½how feelings, thoughts, attitudes, and behavior are related to physical illness, how psychological and social stress affect the likelihood of developing a disease or the ability to resist it, and how counseling for emotional problems can aid recovery from illness. One of the clues to this mystery lies in the immune system, the network that defends us against microbes and other invaders. Interest in the connections between the brain and the immune system has given birth to the discipline of psychoneuroimmunology. These systems communicate through the sympathetic nervous system and the endocrine glands, especially the hypothalamic-pituitary-adrenal (HPA) axis. Like the immune system, both are dedicated to the defense of the body against stress and danger, and both are directed from the same part of the brain, the hypothalamus. All threeï¿½the immune system, sympathetic nervous system, and HPA axisï¿½respond to some of the same transmitter chemicals. The sympathetic nervous system is part of the autonomic nervous system, which controls involuntary functions like heart rate, digestion, and breathing. The sympathetic nerves serve as an emergency response network, heightening the bodyï¿½s readiness to accept a challenge or escape in the face of danger. The sympathetic nerves are connected to various organs of the immune system, such as the thymus gland, the bone marrow, the spleen, and lymph nodes. Immune cells, including T cells, monocytes, and B cells, have receptors for the neurotransmitters released by sympathetic nerves. Damage to the hypothalamus and loss of sympathetic transmitters impairs the functioning of the immune system. An injection of antigens (foreign substances that activate the immune system) affects the concentration of sympathetic neurotransmitters in the brain. Immune LearningAnimal experiments show that the immune system can ï¿½learnï¿½ by association. In one experiment, rats drank sweetened water containing a drug that causes nausea and depresses the immune system. They became so sick that they avoided sweetened water for some time after the drug was removed. That behavioral conditioning eventually was extinguished (wore off), and they returned to drinking the waterï¿½only to start developing infections at an abnormally high rate. Apparently, by association with the immunosuppressant drug, sugared water was provoking a conditioned response that continued to suppress the ratsï¿½ immune systems even when it no longer affected their behavior. Another experiment involved mice bred to be genetically vulnerable to an autoimmune disease (one in which an overactive immune system attacks the bodyï¿½s own tissues). They were given a flavored solution containing a drug that suppresses the immune system, delaying the onset of the disease. Then most of the drug was removed, but as long as the flavor remained, the rats continued to drink the liquid and resist the disease. The immune system had learned by association to suppress itself when the animals recognized that taste. Conditioned learning can also enhance immune function, as another experiment showed. Mice were repeatedly forced to smell camphor while they were injected with a substance that stimulated the activity of natural killer (NK) cells, a type of white blood cell. When they were exposed to the smell of camphor without the injection, the activity of their NK cells still increased. Hormonal EffectsThe HPA axis regulates the bodyï¿½s activity through the circulation of the blood rather than directly through neural connections. The hypothalamus directs the pituitary gland to produce hormones that travel in the blood to the adrenal glands, where they cause the release of cortisol and other steroids as well as epinephrine (adrenaline) and its chemical relative norepinephrine (both of which also serve as neurotransmitters in the sympathetic system). These stress hormones influence the immune reaction through receptors on immune cells. Adrenaline, which prepares the body for immediate action, stimulates the immune system. One function of cortisol and related hormones (glucocorticoids) is to serve as a feedback mechanism that conserves energy by tuning down the emergency reaction when it is no longer needed. Rising cortisol levels signal the brain to shut down an immune response that threatens to become overactive. Thereï¿½s evidence that stress is associated with depressed immune function in one or another part of the system. In one study, the activity of NK cells declined in medical students preparing for an examination. Those who felt calmer and had a slower heart rate also showed fewer immune changes. In another study, unemployment slowed the multiplication of white blood cells in response to antigens. A survey found that unhappily married women had lower numbers of certain immune cells than women with happy marriages. Elderly people caring for relatives with Alzheimerï¿½s disease have higher than average levels of cortisol and low levels of antibody response to influenza vaccine. Stress delays the production of antibodies in mice infected with influenza virus and suppresses the activity of NK cells in animals inoculated with herpes simplex virus. Social stress can be even more damaging than physical stress. In a report published last year, some mice were put into a cage with a highly aggressive mouse two hours a day for six days. Other mice were kept in tiny cages without food and water for long periods. Both groups of mice were exposed to a bacterial toxin, and the socially stressed animals were twice as likely to die. Severe depression resembles a chronic stress response, and depressed patients often lack the normal daily variation in the production of cortisol. Depressed patients seem to have lower NK cell activity than healthy controls, possibly because of high cortisol levels. In one study, the lymphocytes (a type of white blood cell) of depressed and bereaved persons responded sluggishly to the substances that normally stimulate them to proliferate. Isolation can also suppress immune function. Infant monkeys separated from their mothers, especially if they are caged alone rather than in groups, generate fewer lymphocytes in response to antigens and fewer antibodies in response to viruses. Some studies have found lower NK cell activity in separated and divorced than in married men. NK cell activity also has been found to be lower in medical students who say they are lonely. In a year-long study of people caring for husbands or wives with Alzheimerï¿½s disease, changes in immune function were greatest in those who had the fewest friends and least outside help. In general, good social support is associated with better immune function in the elderly, even after correction for health habits, depression, anxiety, and life stress. The effect of traumatic stress on the immune system has been studied occasionally. According to one report, four months after the passage of Hurricane Andrew in Florida, people in the most heavily damaged neighborhoods showed red uced activity in four out of five immune functions. Similar results were found in a study of hospital employees after an earthquake in Los Angeles. And a report published last year suggested that men with a history of posttraumatic stress disorder (PTSD), even long after apparent recovery, had lower numbers of various immune cells and lower levels of immune activityï¿½possibly indicating a long-lasting suppression of the system. Another study found lower lymphocyte activity in abused women. But itï¿½s not easy to generalize about the effect of stress hormones and sympathetic nervous system activity on immune functioning. Much depends on the individual, the timing, the kind of stress, and the part of the immune system under consideration. The results of studies on depression, for example, are conflicting; it does not consistently suppress any part of the immune system except NK cells. Animal experiments suggest that the nervous system responds differently to acute and chronic stress. The acute stress reaction is often a healthy response to a challenge. But chronic stress may cause the feedback controls to fail, turning the emergency response into a condition that persists when it no longer has any use. Stress hormones and sympathetic activity remain at high levels, suppressing immune function and possibly promoting illness. The immune systems of people who are under chronic stress may also respond abnormally to acute stress. The Difference it MakesWhat matters most is whether the mindï¿½s influence on the immune system has the power to raise or lower the risk of illness or injury. On that issue only a little evidence is available. Healing of injuries. One study found that the wound from a biopsy healed more slowly in women under high emotional stress. In another experiment, a wound healed more slowly in students when it was inflicted before an examination rather than just before vacation. Slow healing has also been found in people caring for Alzheimerï¿½s patients. Colds and flu. Both observation and experiments suggest that stress makes people more susceptible to colds and other respiratory infections. In a one-year study, researchers asked 100 people to keep a diary recording their feelings and events in their lives. They were examined periodically for bacteria in throat cultures and virus antibodies in the blood. Stressful events were four times more likely to come before rather than after new infections. And people who developed a cold or other infection had often been feeling more angry and tense than usual. In an English study published in 1991, 420 people were given nose drops containing a cold virus after answering questions about their personality, health practices, and behavior. They were asked about feelings of frustration, nervousness, anxiety, and depression and about events such as loss of a job or deaths in the family. When the subjects were quarantined and monitored for nine days, those under greater stress were more likely to catch a cold. Researchers have continued to confirm this connection. In a study conducted in the late 1990s at the University of Pittsburgh, 276 healthy adults were given nose drops containing a cold virus. The symptoms were most severe in those who reported a high level of stress in their livesï¿½but only when it was prolonged stress caused by such problems as unemployment and troubled marriages. Resistance to the virus was correlated with strong social support, especially a variety of contacts with family, neighbors, friends, workmates, and fellow members of voluntary organizations. This effect was independent of smoking, alcohol consumption, and quality of sleep. People with the weakest (least diverse) social ties were four times more susceptible to colds than those with the strongest ties. Stress can also interfere with the response to a vaccine. In one study, flu shots were given to 32 people under high stress and 32 under low stress, matched for age, sex, and social class. The vaccine produced higher levels of antibodies in the low-stress group, and the high-stress people were more likely to become infected. The University of Pittsburgh researchers found a close association between difficulties in coping with stress, flu symptoms, and a specific immune response. Fifty-five volunteers were given nose drops containing a flu virus after answering questions about their ability to handle stress in their lives. The people with the most stress-related problems produced higher concentrations of interleukin-6, a chemical messenger that attracts immune cells to the site of an infection. They also produced more mucus (had stuffier noses) and generally developed more serious symptoms in direct proportion to the rise in their interleukin-6 levels. http://www.health.harvard.edu/hhp/article/content.do?id=537


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## eric (Jul 8, 1999)

FYI" *The autonomic nervous system (ANS) is the portion of the nervous system that controls the body's visceral functions, including, but not limited to action of the heart, movement of the gastrointestinal tract and secretion by different glands, among many other vital activities.* It is well known that mental and emotional states can affect visceral function by the ANS. Many research studies have examined the influence of emotions on the ANS utilizing the analysis of heart rate variability, or heart rhythms, which serves as a dynamic window into autonomic function and balance. While the rhythmic beating of the heart at rest was once believed to be monotonously regular, it is now known that the rhythm of a healthy heart under resting conditions is actually surprisingly irregular. These moment-to-moment variations in heart rate are easily overlooked when average heart rate is calculated. Heart rate variability (HRV), derived from the electrocardiogram (ECG), is a measurement of these naturally occurring, beat-to-beat changes in heart rate.Various models propose that HRV is an important indicator of both physiological resiliency and behavioral flexibility, reflecting the individual's capacity to adapt effectively to stress and environmental demands. It has become apparent that while a large degree of instability is detrimental to efficient physiological functioning, too little variation can also be pathological. An optimal level of variability within an organism's key regulatory systems is critical to health. This principle is aptly illustrated by a simple analogy: just as the shifting stance of a tennis player about to receive a serve may facilitate swift adaptation, in healthy individuals, the heart remains similarly responsive and resilient, primed and ready to react when needed.The normal variability in heart rate is due to the synergistic action of two branches of the ANS (the sympathetic and parasympathetic branches), which act in balance through neural, mechanical, humoral and other physiological mechanisms to maintain cardiovascular parameters in their optimal ranges and to permit appropriate reactions to changing external or internal conditions. In a healthy individual, thus, the heart rate estimated at any given time represents the net effect of the parasympathetic (vagus) nerves, which slow heart rate, and the sympathetic nerves, which accelerate it. These changes are influenced by emotions, thoughts and physical exercise. Our changing heart rhythms affect not only the heart but indirectly also the brain's ability to process information, including decision-making, problem-solving and creativity. They also directly affect how we feel. Thus, the study of heart rate variability is a powerful, objective and noninvasive tool to explore the dynamic interactions between physiological, mental, emotional and behavioral processes.The mathematical transformation of HRV data is used to discriminate and quantify sympathetic and parasympathetic activity and total autonomic nervous system activity, reducing the HRV signal into its constituent frequency components and quantifies the relative power of these components. Heart rate variability is a measure of the beat-to-beat changes in heart rate.To summarize:Thoughts and even subtle emotions influence the activity and balance of the autonomic nervous system (ANS).The ANS interacts with our digestive, cardiovascular,immune and hormonal systems and is therefore ideally suited to translate mind states into organ functions/dysfunctions Negative reactions create disorder and imbalance in the ANS. Positive feelings such as appreciation and a state of relaxation create increased order and balance in the ANS, resulting in increased hormonal and immune system balance and more efficient brain function. It has been shown in a number of studies that during mental or emotional stress and physical stress, there is an increase in sympathetic activity and a decrease in parasympathetic activity. This results in increased strain on the heart as well as on the immune and hormonal systems. Increased sympathetic activity is associated with a lower ventricular fibrillation threshold and an increased risk of fibrillation, in contrast to increased parasympathetic activity, which protects the heart." http://ibs.med.ucla.edu/Articles/PatientArticleSm02ANS.htm


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## eric (Jul 8, 1999)

"Revisiting IBS: Perspectives for the New Millennium --------------------------------------------------------------------------------Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that affects millions of Americans. Care for patients with IBS often falls to the primary care physician. The pathophysiology of the disorder is still not entirely clear, and current treatment options are ineffective in many patients. At the 2000 American College of Gastroenterology's Annual Meeting, attendees convened for the presentations of three experts in the field, who outlined the latest research on the pathogenesis and treatment of this clinically challenging condition.This program was sponsored by the University of Kentucky through an unrestricted educational grant from Novartis Pharmaceuticals Corporation and Bristol-Myers Squibb Company.--------------------------------------------------------------------------------Brain Imaging: CNS Abnormalities in Patients with IBSThe lack of a clearcut pathophysiology and an often noted association between physical and psychological symptoms has led some clinicians to dismiss irritable bowel syndrome (IBS) as a condition that is "all in their head." However recent findings showing CNS abnormalities in patients with IBS may offer a new perspective on the etiology of this debilitating condition, characterized by abdominal discomfort and pain and altered bowel habits. Until recently, the presence and severity of IBS were measured only by gut function and the subjective perceptions of the patient. "Now, the use of functional brain imaging techniques is contributing to an increased under- standing of the pathophysiology of this disease and new target areas for treatment," said Emeran A. Mayer, MD, Professor of Medicine, Physiology, and Biobehavioral Sciences, and Director of the CURE Neuroenteric Disease Program at the University of California, Los Angeles.Pathophysiology of IBSIBS is a disease that develops as the result of an abnormally altered brain-gut interaction (Table 1). One manifestation of this alteration consists of aberrant output patterns of the emotional motor system, a part of the limbic system in the brain, in response to external (psychosocial) or internal (immune, nutrient) stressors. Outputs from the limbic system in the form of autonomic, pain modulatory, and neuroendocrine responses can be modu- lated by cognitive factors, such as the beliefs, thoughts, and emotions of the patient. Aberrant output of the emotional motor system in large part accounts for the constellation of symptoms that makes up IBS. "A hyperresponsiveness of circuits in the brain may be one common link to both the abnormal responses to internal inflammatory stressors and external psychosocial stressors," Dr. Mayer explained. Treatment is chosen with consideration of altered motility, visceral hypersensitivity, and the brain's role in modulating these factors. The autonomic regulatory systems affect not only muscle cells in the gut, but also other cell types, such as mast cells, enterochromaffin cells, and nerve cells of the enteric nervous system. Responses of some of these cells to autonomic modulation, for example in the form of tryptase secretion by mast cells or serotonin secretion by enterochromaffin cells, may play a role in the modulation of visceral afferent sensitivity. According to Dr. Mayer, such mechanisms may play a role in the development of stress-induced visceral hyperalgesia. Another form of visceral hypersensitivity may be related to altered arousal or hypervigilance toward visceral sensations. Such hypervigilance can result in decreased tolerance to balloon distension and lower discomfort thresholds. A cognitive factor involved in the development of hypervigilance is an increased threat appraisal of visceral sensations.Functional Brain Imaging TechniquesRecently, functional brain imaging techniques have been used to assess directly the activation of certain regions of the brain in response to visceral stimulation. Today, these techniques, particularly functional magnetic resonance imaging, are being used to assess activation of brain circuits that process visceral afferent information from the gut. Dr. Mayer noted that there are distinct but overlapping brain circuits that relate to subjective perception of gut sensations, autonomic responses, and pain modulatory responses. Even in terms of subjective gut sensations, different overlapping circuits are present for intensity coding of the stimulus; threat appraisal of the stimulus; and attribution of primary affect, or "unpleasantness". Both serial and parallel pathways are involved in the processing of visceral sensory information and the control of descending modulatory systems. Input from the gut is derived from multiple channels, such as spinothalamic, vagal, and dorsal column pathways; different regions of the brain then code for intensity, appraise the threat of the stimulus, and determine the level of attention the brain attributes to the stimulus and the unpleasantness the patient experiences. These processes are modulated both by the stress- or arousal- activated system and by recollection of past experiences.Intensity Coding, Threat Appraisal, and UnpleasantnessIntensity coding. As visceral sensory information is delivered via the spinal cord, it is encoded for intensity in the anterior aspects of the insula, or visceral sensory cortex. PET scan studies of somatic and visceral experimental pain have shown that the insula most objectively and reliably encodes information. Interestingly, studies have also demonstrated a greater activation of the insula in male IBS patients, compared with female patients, when exposed to the same stimulus intensity. Threat appraisal and unpleasantness. The information that reaches the insula is "appraised" in the dorsal aspects of the anterior cingulate cortex. Blood flow changes in this part of the brain may also correlate with attentional processes and the subjective unpleasantness ratings in response to a somatic stimulus. The ventral (perigenual) cingulate cortex, which is rich in muopioid receptors, functions to encode the affective quality of the stimulus. In a study by Mayer and colleagues, rectal and sigmoid distension resulted in a lower activation of the ventral anterior cingulate cortex in patients with IBS compared with healthy controls, but an increased activation of the dorsal aspects of the anterior cingulate. Increased activation of an unspecified region of the anterior cingulate was also reported by Mertz and colleagues, in a functional MRI study. Modulatory factors. Finally, the CNS processing of sensory experience may be simultaneously modulated by two parallel pathways: memory-based modulation and stress- or arousal-induced modulation. The posterior parietal cortex, or sensory association cortex, forms a network with the hippocampus and the amygdala (the brain's memory centers) as well as with the lateral prefrontal cortex. Somatic pain studies have shown that, in response to a stimulus, the recall of a similar past event, along with subsequent interpretation of this memory in the lateral prefrontal cortex, plays a major role in the threat appraisal of a sensory experience. The second modulatory effect is the stress- or arousal-induced response. The pontine locus ceruleus is activated in response to potentially threatening experiences. This region then projects to nearly all other regions of the brain that receive visceral input, causing secretions of norepinephrine and arousal of these sections of the brain. When the secretion of norepinephrine is excessive, these target regions are inhibited. It is of interest that descending projections from the locus coeruleus complex to the sacral spinal cord appear to play a major role in the modulation of distal colonic motor and secretory function.ConclusionBrain imaging and other studies of IBS pathophysiology indicate that the perception of gut stimuli and altered autonomic responses to these stimuli are affected by activation of various parts of the brain, resulting in increased attention to these stimuli, greater unpleasantness of the subjective experience, greater threat appraisal, and greater arousal in response to visceral sensations. Further study may lead to new developments in treatment for persons with IBS. --------------------------------------------------------------------------------Table 1. Clinical Relevance of Altered Brain-Gut InteractionAltered attentional mechanisms o Greater awareness of normally subliminal visceral afferent stimuliAltered affective stimulus processing o Greater unpleasantness of visceral sensations, including heartburn, bloating, fullness, abdominal pain, incomplete rectal evacuationAltered threat appraisal o Leads to fears such as not being close enough to a bathroom anything eaten may trigger abdominal painEnhanced arousal o Shared by clinical conditions frequently overlapping IBS, such as anxiety, panic disorder and PTSD o Arousal reduced by sedatives, anxiolytics, low-dose tricyclics o May respond to relaxation exercises" http://cp.yahoo.net/search/cache?p=ibs+sym.../pcp2000_01.htm


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## eric (Jul 8, 1999)

Recent Advances in Pathophysiology of Irritable Bowel SyndromeDepartment of Behavioral Medicine, Tohoku University Graduate School of MedicineShin Fukudo, M.D., PhD.The gastrointestinal tract has autonomous activity and responds to the luminal stimuli moment-to-moment. Since theWalter B. Cannon's era, it also has been known that central nervous activity influences on the bowel function. Recentadvances in research clearly demonstrate mutual and reciprocal interactions between these two organs. These phenomena,the brain-gut interactions, are believed to play a major role in pathogenesis of functional gastrointestinal disorders.Irritable bowel syndrome (IBS) is a prototype of functional gastrointestinal disorders. The brain-to-gut effects and thegut-to-brain effects are supposed to form complex circuits.Psychosocial stress is known to exacerbate IBS symptoms. Drossman et al. reported that stress affected bowelfunction in 84 % of IBS subjects or induced abdominal pain in 69% of them. Whitehead et al. confirmed that IBSsubjects showed steeper slope of regression line relating stress to bowel symptoms, suggesting they have a greaterreactivity to stress. To see the effect of of mental stress on the bowel motility, we loaded mirror tracing stress to theIBS patients. The IBS patients showed higher colonic motility index during and after stress than the controls. Welganet al. reported anger increased frequency of myoelectrical activity and motility of the colon in the IBS patients. Thesetwo independent data express the stress-induced pathophysiology of colonic motility in the IBS patients.Simultaneous manometric measurements in the duodenum during and after the mental arithmetic stress expressed lessphase I, period of quiescence, and phase III, period of powerful rhythmic contractions with 11-12 cycle per min, ofmigrating motor complex in the IBS patients. Phase II, period of contractions with irregular intervals, prolonged moreprominently in the IBS patients. Twenty-four hrs prolonged recording in duodenal motility in the IBS patients disclosedexistence of dysmotility patterns during phase II. They were burst activity and clustered contractions. Arousal of thebrain has great impact on duodenal motility. In most individuals, either in the IBS patients or the controls, phase II isdominant during the awake, while it attenuates during the sleep.Dysmotility patterns more than 15 min of duration were limited in the IBS patients during the awake, suggestingprogrammed function of the enteric nervous system is disturbed by perturbations from the brain. Motility patterns of thesmall bowel during sleep were normal in the IBS patients.Power spectral analyses of electroencephalogram (EEG) demonstrated that stress decreased a-power and increasedb-power in the IBS patients and the controls. However, in the IBS patients, these changes were enhanced. Thesefindings implies that the IBS patients may have sensitive brain to stress. Moreover, abnormal sleep patterns of rapid eyemovement (REM) in the IBS patients are also reported by Kumar et al.- 113 ---------------------------------------------------------------------------------Page 2 ??????? ?????? 2002From these observations, the IBS patients are suggested to have stress-sensitive brain and hyper-reactive bowel. Manyneurotransmitters are supposed to be involved in these mechanisms. Corticotropin-releasing hormone (CRH) is one ofthe most plausible candidates to play a crucial role in pathogenesis of IBS. CRH is a 41-amino acids-peptide producedmainly in the hypothalamus and distributed in the colon. Stress releases hypothalamic CRH, resulting pituitary secretionof adrenocorticotropic hormone (ACTH). In rodents, CRH antagonists inhibits stress-induced alterations in the colonicmotility. Exogenous administration of CRH, intracerebroventricularly or intravenously, accelerates colonic transit. CRHmildly provokes colonic motility in humans. While in the IBS patients, CRH stimulates colonic motility moreprominently. ACTH secretion to CRH in the IBS patients is also exaggerated.Recently, studies on gut-to-brain direction are more focused on the research. That is because progressive knowledgedemonstrates that the brain plays a major role in the integration of the signal derived from the peripheral organs. Thesestudies are performed mainly using the barostat technique. Visceral hyperalgesia in the IBS patients are first reported byRichie and his group, replicated by Whitehead, and further investigated by Mayer et al. Repetitive mechanicalstimulation of the sigmoid colon provoked increase in colonic motility in the descending colon of the IBS patients,suggesting visceral hyperalgesia and simultaneous abnormal intramural reflex. Cerebral evoked potentials, as shown inthe first negative1-positive1-negative2-triphasic waves, were obtained using EEG recordings during the gut stimulation.IBS patients have abnormal patterns of viscerosensory evoked potentials. IBS patients were reported to have abnormalactivation patterns of the regional cerebral blood flow in response to the mechanical distention of the rectum.In this context, the IBS patients have stress-sensitive brain, hyper-reactive bowel motility, and visceral hyperalgesia toa larger or lesser extent. The initial involved point may be either. This notion is also supported by the report fromRead's group in the Lancet. When acute enterocolitis hits the bowel, patients with high scores for anxiety, depression,somatization, and neurotic trait become IBS. Once the vicious cycle is formed, visceral hyperalgesia will changeintramural reflex as well as brain neurotransmitter release, resulting exaggerated stress-sensitivity. Therapeutic approachfor IBS should be performed along these knowledge. Further investigations on reciprocal brain-gut interaction in IBS iswarranted.- 114 - http://cp.yahoo.net/search/cache?p=+hyper+...ng/07806192.pdf Altered Visceral Perception Modulation Confirmed In Irritable Bowel PatientsA DGReview of :"Irritable bowel syndrome patients show enhanced modulation of visceral perception by auditory stress."American Journal of Gastroenterology01/29/2003By Elda HauschildtPatients with irritable bowel syndrome (IBS) have altered stress-induced modulation of visceral perception, confirms research from the United States.Investigators, from the University of California at Los Angeles, found that IBS patients rate visceral stimulus during stress significantly higher in terms of intensity and unpleasantness than do healthy controls."IBS patients also reported higher ratings of stress, anger and anxiety during the stress compared with the relaxing condition, whereas controls had smaller and non-significant subjective responses," they explain.Symptoms from IBS are known to be sensitive to psychological stressors. This could occur because of enhanced responsiveness of the emotional motor system, a network of brain circuits modulating arousal, viscerosomatic perception and autonomic responses associated with emotional response, the researchers point out.Rectal balloon distension during experimentally induced psychological stress was used to test psychological reactions in 15 IBS patients and 14 healthy controls to assess whether IBS patients demonstrate altered perceptual response. The mild stress condition involved dichotomous listening to two conflicting types of music. The control condition also involved listening but to relaxing nature sounds. Stress and relation stimuli were delivered over a 10-minute listening period preceding and during rectal distensions. Intensity and unpleasantness ratings measured included visceral sensation, subjective emotional response and heart rate. Neuro-endocrine measures were also taken.The investigators found that unlike healthy controls, IBS patients gave significantly higher ratings of the visceral stimulus in terms of intensity and unpleasantness. American Journal of Gastroenterology, 2003; 98: 135-143. "Irritable bowel syndrome patients show enhanced modulation of visceral perception by auditory stress." http://www.docguide.com/news/content.nsf/n...52568880078C249


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## eric (Jul 8, 1999)

IBS and rem sleepGastroenterology. 1992 Jul;103(1):12-7. Related Articles, Links Abnormal REM sleep in the irritable bowel syndrome.Kumar D, Thompson PD, Wingate DL, Vesselinova-Jenkins CK, Libby G.Gastrointestinal Science Research Unit, London Hospital Medical College, England.Motor abnormalities of the small bowel that occur only during the waking state have been reported in the irritable bowel syndrome (IBS), suggesting that central nervous system arousal is a necessary condition for expression of the disorder and that it may reflect inappropriate brain-gut interaction. This possible relationship was explored further by synchronous polysomnography and recording of upper small bowel motility in six healthy subjects and six patients with IBS. During sleep, there was no difference in the patterns of intestinal motility between the two groups. There was no difference between the rapid eye movement (REM) latency or number of REM episodes, but the proportion of REM sleep was markedly increased (36.5% +/- 5.7% vs. 18.2% +/- 5.7%; P less than 0.01) in the IBS group, although the duration of sleep was similar (468 +/- 13 minutes in IBS vs. 444 +/- 10 minutes in controls; P greater than 0.1). Sleep apnea was detected in three of six patients with IBS but was not seen in controls. The data are consistent with the model of IBS as a disorder of brain-gut interaction.PMID: 1612320Nippon Rinsho. 1992 Nov;50(11):2703-11. Related Articles, Links Brain-gut interactions in irritable bowel syndrome: physiological and psychological aspectFukudo S, Muranaka M, Nomura T, Satake M.Department of Psychosomatic Medicine, Tohoku University School of Medicine.Recent advances in the investigation of brain-gut interaction in irritable bowel syndrome (IBS) were reviewed. Brain is suggested to play an important role in the pathophysiology of IBS on the basis of the following evidence. (1) Stress often induces major symptoms of IBS patients (Drossman et al., 1982), simultaneously with colonic hypermotility (Fukudo et al., 1987) or dysmotility of the small intestine (Kumar et al., 1985). (2) IBS patients rarely express symptoms or small intestinal dysmotility during sleep (Kellow et al., 1990). (3) IBS patients complain of more pain with balloon distension of the colon or rectum than normal controls; visceral perception is enhanced in IBS (Whitehead et al., 1990). (4) IBS patients often show psychoneurotic symptoms and extra-colonic somatic symptoms (Young et al., 1976). (5) There are some animal (Williams et al, 1987) or human (Dinan et al, 1990) experiments which indicate the possible involvement of brain peptide or brain monoamine in IBS. (6) Dysrhythmia or increased beta power in electroencephalogram is observed more often in IBS patients than in the normal controls (Fukudo et al, 1991) in addition to abnormal REM sleep in IBS patients (Kumar et al., 1992). These observations support our hypothesis that not only the gut but also the brain show dysfunction and exaggerated responsivity to the stimuli in IBS. Further research on brain-gut interaction in IBS is warranted.Publication Types: Review Review Literature PMID: 1337564Am J Gastroenterol. 2002 Dec;97(12):3147-53. Related Articles, Links Autonomic functioning during REM sleep differentiates IBS symptom subgroups.Thompson JJ, Elsenbruch S, Harnish MJ, Orr WC.Lynn Institute for Healthcare Research, Oklahoma City, Oklahoma 73112, USA.OBJECTIVE: The aim of this study was to investigate autonomic activity by means of heart rate variability analysis in a sample of irritable bowel syndrome (IBS) patients, allowing stratification into IBS symptom subgroups. METHODS: Thirty-three female IBS patients (mean age 37 yr) and 21 healthy female controls (mean age 38 yr) participated. Patients were stratified into 16 subjects with only lower bowel symptoms (IBS only) and 17 subjects with both lower bowel and dyspeptic symptoms (IBS+D). The protocol included standard polysomnography to assess stages of sleep with concomitant electrocardiographic measurement of beat-to-beat intervals of the cardiac cycle. Fifteen-min segments were selected from presleep waking, stage 2 of non-rapid eye movement (REM), and REM sleep and analyzed by spectral analysis of heart rate variability to calculate the high-frequency band, a measure of vagal tone, and the low-frequency/high-frequency ratio, an indicator of sympathovagal balance. RESULTS: The high-frequency band power during REM sleep was significantly lower, indicating substantial vagal withdrawal in IBS-only patients compared with IBS+D patients and controls. The low-frequency/high-frequency band ratio was significantly higher during REM sleep for IBS-only patients. CONCLUSIONS: IBS-only patients had greater sympathetic dominance, indicated by elevated low-frequency/high-frequency band ratio, during REM sleep because of vagal withdrawal. Autonomic functioning, unique to REM sleep, differentiates IBS symptom subgroups, suggesting that autonomic functioning during REM sleep may be a useful biological marker to identify IBS patient subgroups.PMID: 12492202 Gut. 1997 Sep;41(3):390-3. Related Articles, Links Sleep and gastric function in irritable bowel syndrome: derailing the brain-gut axis.Orr WC, Crowell MD, Lin B, Harnish MJ, Chen JD.Thomas N. Lynn Institute for Healthcare Research, INTEGRIS Baptist Medical Center of Oklahoma, Oklahoma City 73112, USA.BACKGROUND: Recently, several studies have shown an alteration in bowel function during sleep in patients with irritable bowel syndrome (IBS), and a recent study also suggests a remarkable increase in rapid eye movement (REM) sleep. These studies have suggested that an alteration in CNS function may play an important role in the pathogenesis of IBS. AIMS: To confirm the presence of an alteration in REM sleep in patients with IBS and to assess the relation between sleep and a non-invasive measure of gastric functioning, the electrogastrogram (EGG). PATIENTS: Ten patients with IBS and 10 age and sex matched normal volunteers. METHODS: All subjects slept one night in the sleep laboratory and underwent polysomnographic monitoring to determine sleep patterns, and recording of the EGG from surface electrodes. RESULTS: The IBS group had a notable and significant increase in the percentage and duration of REM sleep (p 0.05). The control group had a decrease in the amplitude of the dominant EGG frequency from waking to non-REM sleep (p 0.05), and a subsequent increase in the amplitude from non-REM to REM sleep (p 0.05). No such changes were noted in the patients with IBS. CONCLUSIONS: Results confirmed the enhancement of REM sleep in patients with IBS and suggested an intrinsic alteration in autonomic and CNS functioning in patients with IBS.PMID: 9378397Sleep. 2003 Sep15;26(6):747-52. Related Articles, Links Polysomnographic and actigraphic evidence of sleep fragmentation in patients with irritable bowel syndrome.Rotem AY, Sperber AD, Krugliak P, Freidman B, Tal A, Tarasiuk A.Soroka University Medical Center, Beer-Sheva, Israel.STUDY OBJECTIVE: To characterize the function and quality of sleep in patients with irritable bowel syndrome (IBS). DESIGN: A prospective study with a historic comparison group. SETTING: A regional hospital that also serves as a tertiary referral center. PATIENTS: Eighteen patients with IBS and a comparison group of 20 matched adults with mild benign snoring. INTERVENTIONS: A polysomnography study and a wrist actigraphy study. MEASUREMENTS: All subjects underwent sleep studies and completed self-report questionnaires (IBS severity, psychosocial variables, sleep function, and Epworth Sleepiness Scale). Fourteen IBS and 11 comparison patients underwent actigraphy. RESULTS: The IBS patients had more than 70% less slow-wave stage sleep (4.5 +/- 7.3% vs 19.3 +/- 12.9%; P = 0.006), compensated by increased stage 2 sleep (72.2 +/- 6.6% vs 60.1 +/- 16.8%; P = 0.01). The IBS group had significant sleep fragmentation with a significantly higher arousal and awakening index (P 0.001), a longer wake period after sleep onset (P = 0.02), and more downward shifts to lighter sleep stages (P = 0.01). The 4-night actigraphy study supported the polysomnography findings. The sleep fragmentation index was significantly higher (P = 0.008) in the IBS group. The IBS patients reported greater daytime sleepiness (9.0 +/- 4.8 vs 6.4 +/- 4.8, Epworth Sleepiness Scale score, P 0.01) and greater impairment in quality of life, which correlated significantly with the sleep fragmentation indexes. The difference between the groups was not due to differences in baseline anxiety/depression levels. CONCLUSIONS: Patients with IBS have impaired sleep quality, reduced slow-wave sleep activity, and significant sleep fragmentation. The cause-and-effect relationship of these findings with patients' daytime symptoms should be studied further.PMID: 14572130


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## m_m_forth (Oct 21, 2003)

I'd say there's methodological flaws with that REM sleep study. I study Circadian Rhythms and sleep. I know that many people with IBS also have depression. I also know that people with depression have a larger amount of REM sleep. I think perhaps they'd need to narrow their subject pool and try again. Plus, I recently measured my own REM sleep and I am right on normal there (I know I'm only one subject, but it's something). Hmmmmm.


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## eric (Jul 8, 1999)

Realist that is interesting.I only pulled a few sleep studies out. There are more.also since you study this, you might like this site. Its an excellent sleep website. http://www.sleephomepages.org/sleepsyllabus/intro.html Stress and the GutDr. Howard MertzAssociate Professor of Medicine and RadiologyVanderbilt UniversityStress is a ubiquitous condition that affects all people. Stress can be mental or physical, although in the context of this article the focus will be mental stress. Mental stress involves challenge, threat or worry about future adverse events. Such stress activates the brainï¿½s stress response systems, which in turn effect the body. Many of the bodyï¿½s major systems are altered by stress (cardiovascular, muscular, urinary, gastrointestinal, sweat glands, etc) often with adverse consequences. Gastrointestinal function is particularly influenced by stress. Common gastrointestinal symptoms due to stress are heartburn, indigestion, nausea and vomiting, diarrhea, constipation and associated lower abdominal pain. These symptoms and the alterations in intestinal function that cause them are becoming understood. Gastrointestinal Stress Reactions in Animals and CRFIn animals such as rats, stress can be induced in experimental situations. When rats are wrap restrained, or placed on a small platform surrounded by water they become stressed. During these situations, alterations in motility of the gut occur. The upper gut, including the stomach and small intestine, exhibits markedly reduced transit. This may be a defense mechanism to promote vomiting and reduce oral intake. Conversely the large bowel motility increases with increased stool output and transit speed. This may be a defense mechanism to eliminate toxins. We have learned that a hormone called corticotropin releasing factor (CRF) influences these changes. CRF is released from nerve cells in the hypothalamus of the brain. These nerve cells release the hormone via long processes into other parts of the brain such as the locus ceruleus, where arousal and autonomic nervous system changes are mediated. In rats, injection of CRF blockers into the brain fluid diminishes the stress induced motility changes in the gut. CRF directly injected into the brain fluid mimics the stress response closely (Figure 1). CRF also stimulates the gut directly via CRF-1 and CRF-2 receptors. CRF-1 receptors stimulate colonic contractions, while CRF-2 receptors reduce upper gut activity. Antagonists to CRF-1 receptors are currently being tested for treatment of depression, and may become available for testing in functional bowel disorders as well.Brain Areas Involved in Stress ReactionTwo of the primary brain regions involved in stress reactivity are the hypothalamus and the locus ceruleus. Activation of the hypothalamus by stress is likely to be mediated in part by the limbic brain (particularly the amygdala and hippocampus) and partly by the locus ceruleus in the brainstem. The locus ceruleus and the hypothalamus actually stimulate each other, creating the potential for a vicious cycle, where a stress reaction in one region stimulates the other, which in turn stimulates the first to react even more. The limbic system is a group of connected and related brain regions that mediate emotions and flight or fight attitudes. The limbic or ï¿½emotional brainï¿½ is more primitive by evolutionary standards, and is not necessarily under control by the higher intellectual cortex. This system receives sensory and higher cortical inputs, calls upon memories and determines the threat level imposed by a stimulus. The amygdala for instance is a limbic structure in the base of the brain that is important in anger and rage. In cats, electrical stimulation of the amygdala causes hissing, back arching and the hair to stand on end, typical of anger and defense postures in cats. In animals that have damage to the amygdala a placid state results in which anger cannot be induced. Inputs to the amygdala are thought to originate from the hippocampus, the cingulate cortex and other parts of the limbic sytem. The locus ceruleus is located in the pontine portion of the brainstem. The locus ceruleus is the source of most of the stimulant neurotransmitter norepinephrine in the nervous system. Cells here project to other brain areas, releasing norepinephrine to activate other systems and increase arousal and alertness. Release of norepinephrine increases heart rate, blood pressure and primes the muscles and nervous system for fight or flight. This reaction is not helpful in routine stress of daily activities. If the stress reaction is excessive or the perceived threat too frequent, tachycardia (racing heart), hypertension, muscle tension, bowel spasms and dyspepsia can result.Hypothalamic-Pituitary-Adrenal AxisCRF release is the first step in activation of the hypothalamic-pituitary-adrenal axis (HPA axis) involved in stress response. This is the major endocrine (hormonal) response system to stress. Release of CRF by the hypothalamus stimulates the pituitary gland immediately underneath it. The pituitary gland responds to CRF by release of adreno-corticotropic hormone (ACTH) to stimulate adrenal gland secretion of the stress hormone cortisol. Cortisol promotes fluid and salt retention and impairs inflammation, functions helpful in the short term during flight or fight situations or injury. Again, if the HPA system is activated too frequently adverse health outcomes such as hypertension (from salt retention) and impaired immune function (from excess cortisol) may result. The CRF system and the norepinephrine systems work together to respond to stress with resultant changes in bodily functions that prepare for flight or fight. (Figure 2) Gastrointestinal Stress Response in HumansHumans respond to stress in similar ways to animals. A variety of human studies indicate stress promotes decreased gastric emptying and accelerated colonic transit in normal volunteers. A pioneering study by Almy measured colonic contractions during flexible sigmoidoscopy. The volunteers were told that a cancer was found, leading to abrupt increases in colonic contractions, which resolved after the hoax was explained. Other stressors such as ball-sorting, driving in city traffic and mentally challenging listening tasks similarly increase colonic contractions and reduce gastric motility. Recent data also indicates that intestinal sensitivity increases with stress compared to relaxation. This effect may lower the threshold for sensing intestinal events. In gastroesophageal reflux for example, psychological stressors can increase heartburn symptoms. Analysis of the esophageal pH (measurement of acid) indicates that the amount of reflux doesnï¿½t increase during stress, but the probability of feeling a reflux as heartburn does increase. In one small study of normal controls, intravenous infusion of CRF induced greater rectal sensitivity to balloon distension. It may be that the sensitizing effects of stress on the gut are partly mediated by the stress hormone CRF. Irritable Bowel Syndrome and Functional DyspepsiaTwo of the major causes of uncomfortable or painful intestinal symptoms are irritable bowel syndrome (IBS) and functional dyspepsia. IBS occurs in approximately 12% of people world-wide. Dyspepsia (indigestion/upper abdominal discomfort) is also very common. The majority of dyspepsia is functional, that is not associated with ulcers, gallstones, reflux esophagitis or cancer. In both of these common disorders, motility and sensory changes are present which mimic the stress state. Both disorders demonstrate hypersensitivity of the gut (either stomach or intestine). Both disorders demonstrate alterations in motor function of the gut typical of stress and CRF-induced changes. In functional dyspepsia the stomach generally has mildly reduced emptying and reduced accommodation of meals. In IBS, colonic contractions are generally increased. Furthermore, IBS subjects appear to have increased stress responsiveness in the gut. In one study, IBS patients and healthy controls both underwent ambulatory motility recordings in the colon. Both groups were confronted on return to the lab (ï¿½youï¿½re lateï¿½, ï¿½you came to the wrong windowï¿½, ï¿½now the study may need to be repeatedï¿½). Colonic motility jumped up in the IBS patients during confrontation, but not in healthy volunteers.(Figure 3) IBS patients may also have greater sensitivity to the stress hormone CRF. Infusion of CRF intravenously to IBS patients and controls in one study caused significantly greater colonic motor responses in IBS patients. Another study indicates that listening stress increases rectal sensitivity to balloon distension in IBS patients but not controls. It appears both intestinal motility and sensory responses to stress are heightened in IBS patients. These alterations are likely to cause symptoms such as diarrhea and intestinal cramps due to increased contractions of the gut and increased sensitivity of the gut during stress. The chemical mediators of these changes are not yet established, although alterations in CRF release or CRF receptors may be implicated to some extent in functional bowel diseases.IBS (and other functional bowel symptoms) are generally worsened by stress. In fact recent research has indicated that IBS symptoms tend to resolve in those without major psychosocial stressors. Conversely, symptoms are persistent in subjects with ongoing ï¿½threateningï¿½ psychosocial stressors. The onset of IBS and functional dyspepsia often begin with bereavement, abuse or other major negative life events. Emotional distress is very common in IBS patients, particularly those who seek medical treatment for the condition. Anxiety and depression are significantly increased in IBS patient populations, present in nearly 40%. Psychosocial distress appears much less common in IBS sufferers who do not seek medical care. Population based surveys, however, do still suggest tendencies toward emotional reactivity in people with IBS. Accordingly, stress modification, psychotherapy and hypnosis appear helpful for IBS and functional dyspeptic symptoms. Tricyclic antidepressants also appear effective for IBS and other functional bowel symptoms, even in low doses. Recent evidence indicates the drugs may work by reducing the brainï¿½s response to intestinal pain during stress. Sedatives such as the benzodiazepine Librium can reduce the effect of stress on the gut. During ball sorting challenge, Librium blunts the colonic motor response to mental stress in IBS patients. This effect may explain the benefits of combined sedative-anti-spasmodic drugs for IBS.SummaryThere is much yet to learn about the effects of stress on the gastrointestinal tract. The exact neural and hormonal pathways that mediate excess gut sensitivity and altered contractility during stress are not defined. Where these pathways are excessive or dysfunctional in IBS, functional dyspepsia and other GI disorders is unclear. Specific neurotransmitters are likely to underlie the gastrointestinal stress reaction, and may be amenable to pharmacologic blockade. Psychological therapies are likely to blunt the stress response as well. New tools such as brain imaging to study brain responses to stressors and drugs, and molecular biology to study function of neurotransmitters and their receptors are likely to lead to better understanding of the stress response and its role in disease states. Based on this knowledge, advances in pharmacology may lead to better drug therapies to address these important health problems.www.med.unc.edu/wrkunits/...elcome.htmFYIFrom Medscape GastroenterologyMEDLINE Abstracts: Serotonin Signaling and Visceral Hypersensitivity in IBSPosted 10/23/2003 What's new concerning the role of serotonin signaling and mechanisms of visceral hypersensitivity in the pathophysiology of irritable bowel syndrome (IBS)? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Gastroenterology.--------------------------------------------------------------------------------Serotonin and Its Implication for the Management of Irritable Bowel SyndromeGershon MDRev Gastroenterol Disord. 2003;3(suppl 2):S25-S34Our understanding of the enteric nervous system (ENS) has evolved from the "classical" view, in which the brain controls all enteric behavior, to the current view, which holds that enteric innervation is one of local control within the bowel, modified by a bidirectional "dialogue" with the brain. The ENS independently controls enteric reflexes through intrinsic primary afferent neurons, which monitor intraluminal conditions. This monitoring is accomplished through the use of enteroendocrine cells in the mucosa, the best known of which are the serotonin-containing enterochromaffin cells. This article describes the roles that serotonin, specific serotonin-receptor subtypes, and the serotonin reuptake transporter play in the ENS and in the communication between the ENS and central nervous system. The way in which these findings have implicated serotonin in irritable bowel syndrome is discussed.Systematic Review: Serotonergic Modulators in the Treatment of Irritable Bowel Syndrome--Influence on Psychiatric and Gastrointestinal SymptomsKilkens TO, Honig A, Rozendaal N, Van Nieuwenhoven MA, Brummer RJAliment Pharmacol Ther. 2003 ;17:43-51Background: Both central and peripheral serotonergic modulators are used in the treatment of irritable bowel syndrome. The majority of patients with irritable bowel syndrome presenting to a gastroenterologist demonstrate affective dysregulation. Serotonin may play a regulatory role in both gastrointestinal motility and sensitivity, as well as in affective dysregulation, in irritable bowel syndrome.Aim: To analyse, systematically, randomized controlled trials studying the influence of serotonergic modulators on both gastrointestinal and psychiatric symptoms in irritable bowel syndrome, in order to elucidate baseline irritable bowel syndrome symptomatology and possible differential effects of serotonergic modulation on this symptomatology.Methods: A standardized qualitative analysis was performed of studies investigating the influence of serotonergic modulators on both gastrointestinal and psychiatric symptoms in irritable bowel syndrome using a blind review approach. The studies were ranked according to their total quality score (maximum 100 points).Results: Eleven studies fulfilled the entry criteria, six of which scored above 55 points. An association between gastroenterological and psychiatric changes was present in five of the six studies.Conclusions: The results strengthen the serotonergic association between gastroenterological and psychiatric symptoms. Adjusted guidelines for combined gastrointestinal and psychiatric assessments are recommended in order to further elucidate the serotonergic interaction between gastrointestinal and psychiatric symptoms.Tegaserod and Other Serotonergic Agents: What Is the Evidence?Chey WDRev Gastroenterol Disord. 2003;3(suppl 2):S35-S40Through effects on gastrointestinal motor and secretory function as well as visceral sensation, serotonin (5-HT) plays a key role in the pathogenesis of irritable bowel syndrome (IBS). In particular, 5-HT3 and 5-HT4 receptors appear to be very important in IBS. This article critically appraises the evidence supporting the use of the 5-HT3 receptor antagonist alosetron in the treatment of women with diarrhea-predominant IBS. The safety profile and restricted-use program for alosetron is also reviewed. This discussion is followed by a comprehensive review of the efficacy and safety data in support of tegaserod for women with constipation-predominant IBS.Sex Differences of Brain Serotonin Synthesis in Patients With Irritable Bowel Syndrome Using Alpha-11C Methyl-L-Tryptophan, Positron Emission Tomography and Statistical Parametric MappingNakai A, Kumakura Y, Boivin M, et alCan J Gastroenterol. 2003;17:191-196Background: Irritable bowel syndrome (IBS) is the most common functional bowel disorder and has a strong predominance in women. Recent data suggest that the brain may play an important role in the pathophysiology of IBS in the brain-gut axis. It is strongly suspected that serotonin (5-HT), a neurotransmitter found in the brain and gut, may be related to the pathophysiology of IBS. It is reported that a 5-HT3 antagonist is effective only in female patients with diarrhea-predominant IBS.Objective: In the present study, 5-HT synthesis was measured using positron emission tomography, with alpha-11 Cmethyl-L-tryptophan as the tracer, in patients with IBS. The aim of the present study was to compare 5-HT synthesis in the IBS patients with that in the controls, and to compare 5-HT synthesis between male and female IBS patients.Methods: Six male and six female nonconstipated IBS patients were scanned. Age-matched healthy volunteers were scanned as controls. Eighty minute dynamic scans were performed. Functional 5-HT synthesis images were analyzed using statistical parametric mapping.Results: 5-HT synthesis was greater only in the female IBS patients in the right medial temporal gyrus (multimodal sensory association cortex) compared with the female controls (P 0.001).Conclusions: The greater brain 5-HT synthesis in the female IBS patients than in the controls may be related to the pathological visceral pain processing of the IBS patients, a larger female predominance of the disorder, and the sex difference of the efficacy of the 5-HT3 antagonist in treatment.Sex-Related Differences in IBS Patients: Central Processing of Visceral StimuliNaliboff BD, Berman S, Chang L, et alGastroenterology. 2003;124:1738-1747Background & Aims: Women have a higher prevalence of irritable bowel syndrome (IBS) and possible differences in response to treatment, suggesting sex-related differences in underlying pathophysiology. The aim of this study was to determine possible sex-related differences in brain responses to a visceral and a psychological stressor in IBS.Methods: Regional cerebral blood flow measurements using H(2)(15)O positron emission tomography were compared across 23 female and 19 male nonconstipated patients with IBS during a visceral stimulus (moderate rectal inflation) and a psychological stimulus (anticipation of a visceral stimulus).Results: In response to the visceral stimulus, women showed greater activation in the ventromedial prefrontal cortex, right anterior cingulate cortex, and left amygdala, whereas men showed greater activation of the right dorsolateral prefrontal cortex, insula, and dorsal pons/periaqueductal gray. Similar differences were observed during the anticipation condition. Men also reported higher arousal and lower fatigue.Conclusions: Male and female patients with IBS differ in activation of brain networks concerned with cognitive, autonomic, and antinociceptive responses to delivered and anticipated aversive visceral stimuli.Functional Brain Imaging in Irritable Bowel Syndrome With Rectal Balloon-Distention by Using fMRIYuan YZ, Tao RJ, Xu B, et alWorld J Gastroenterol. 2003;9:1356-1360Aim: Irritable bowel syndrome (IBS) is characterized by abdominal pain and changes in stool habits. Visceral hypersensitivity is a key factor in the pathophysiology of IBS. The aim of this study was to examine the effect of rectal balloon-distention stimulus by blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) in visceral pain center and to compare the distribution, extent, and intensity of activated areas between IBS patients and normal controls.Methods: Twenty-six patients with IBS and eleven normal controls were tested for rectal sensation, and the subjective pain intensity at 90 ml and 120 ml rectal balloon-distention was reported by using Visual Analogue Scale. Then, BOLD-fMRI was performed at 30 ml, 60 ml, 90 ml, and 120 ml rectal balloon-distention in all subjects.Results: Rectal distention stimulation increased the activity of anterior cingulate cortex (35/37), insular cortex (37/37), prefrontal cortex (37/37), and thalamus (35/37) in most cases. At 120 ml of rectal balloon-distention, the activation area and percentage change in MR signal intensity of the regions of interest (ROI) at IC, PFC, and THAL were significantly greater in patients with IBS than that in controls. Score of pain sensation at 90 ml and 120 ml rectal balloon-distention was significantly higher in patients with IBS than that in controls.Conclusion: Using fMRI, some patients with IBS can be detected having visceral hypersensitivity in response to painful rectal balloon-distention. fMRI is an objective brain imaging technique to measure the change in regional cerebral activation more precisely. In this study, IC and PFC of the IBS patients were the major loci of the CNS processing of visceral perception.Role of Visceral Sensitivity in the Pathophysiology of Irritable Bowel SyndromeDelvaux MGut. 2002;51(suppl 1):i67-i71Visceral hypersensitivity has been recognised as a characteristic of patients with irritable bowel syndrome (IBS). It may be involved in the pathogenesis of abdominal pain/discomfort, and seems to result from the sensitisation of nerve afferent pathways originating from the gastrointestinal tract. From a clinical point of view, hypersensitivity, although frequent, is not a constant finding among patients with IBS and cannot therefore be considered as a diagnostic marker of the condition. The advances made in understanding visceral hypersensitivity in patients with IBS are reviewed: the factors that influence abdominal distension are defined and different therapeutic perspectives are examined.www.medscape.com/viewarti...02/7001/-1


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## eric (Jul 8, 1999)

bump


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## bonniei (Jan 25, 2001)

Interesting study about immune system and learning.


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## eric (Jul 8, 1999)

"The brain-gut axis refers to the continuous back and forth interactions of information and feedback that take place between the gastrointestinal tract, and the brain and spinal cord (which together comprise the central nervous system). These interrelated feedback circuits can influence brain processes and bowel functions -- affecting pain perception, thoughts and one's appraisal of symptoms, gut sensitivity, secretions, inflammatory responses, and motility. The brain-gut circuits can be activated by an external or internal factor or stimulus that makes a demand on the system, such as a stressful event, an injury, an emotional thought or feeling, or even the ingestion of food. Symptoms of functional GI disorders may result from a maladaptive response to stimuli at some point within the complex interactions that take place along the brain-gut axis. " http://www.iffgd.org/symposium2003brain-gut.html


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