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The Neurobiology of Stress and Emotions, and IBS new
      #14675 - 07/23/03 10:35 AM

Reged: 12/09/02
Posts: 7798
Loc: Seattle, WA

The Neurobiology of Stress and Emotions

By: Emeran A. Mayer, M.D.
UCLA Mind Body Collaborative Research Center, UCLA School of Medicine, California

We often hear the term "stress" associated with functional gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS). Many patients experience a worsening of symptoms during times of severely stressful life events. But what is stress? How often does it occur? How does our body respond to stress? This article explores the mechanisms that link stress and emotions to responses that have evolved to ensure survival and that, in the modern world, affect health—including gastrointestinal function.

Stress is an adaptive response that is not unusual or unique to only certain individuals. In humans and animals, internal mechanisms have developed throughout evolution, which allow the individual to maximize their chances of survival when confronted with a stressor. A stressor in this context is any situation that represents an actual or perceived threat to the balance (homeostasis) of the organism. In a wide variety of real, life threatening situations-such as an actual physical assault or a natural disaster-stress induces a coordinated biological, behavioral, and psychological response.

In many ways, the stress response of an organism can be understood in analogy to the response of a nation confronted with an actual or perceived threat to its stability. As we are all too familiar, such a threat will result in the activation of a series of preprogrammed civilian (economic, security) and military measures, optimizing the chances of the nation to overcome or avoid the threatening situation. On the one hand, the readiness to quickly mount such a response is paramount to the long-term survival of the nation; on the other hand, the longer this response has to be maintained, the greater the toll will be on other functions of the society. We will return to this analogy later.

The organism's stress response often, but not necessarily, includes subjective emotional feelings like fear and/or anger. However, similar responses can also be observed in situations that are perceived as threats but which do not represent actual life-threatening situations, such as public speaking or the memory of a natural disaster. The associated subjective emotion associated with such non-life threatening stressors is frequently referred to as anxiety.

Emotions, stress, and conscious feelings
One environmental situation that triggers a distinct emotional response of the body is a real or perceived threat to the organism. The stressor is the event that triggers this particular response; fear and/or anger is the emotional feeling that may be associated with the bodily response. However, stress and fear are not the only emotions that our organism is programmed to respond to. Emotions are stereotypic patterns of the body, which are triggered by the central nervous system in response to distinct external environmental situations or to the recollection of memories related to such situations. In evolution, the basic mechanisms generating an emotional response of the body evolved long before the conscious feeling of emotions evolved in humans and in non-human primates. The reason for this is simple: Emotional responses are essential for the survival of all living organisms. For example, the emotion of fear and/or anger, and the associated fight or flight response is essential to avoiding harm from an aggressor; the emotion of love (attachment) is essential for bonding between individuals; the emotion of disgust may have evolved initially as food aversion to avoid ingestion of harmful materials.

In these different situations, the body consistently responds in an automatic, stressor-specific way, at times without our being aware of the response. Conscious emotional feelings may or may not be associated when the body responds to a stressful situation. It is important to realize that the frequently associated conscious feelings of emotions, such as fear, anger, sadness, disgust, or love, are not essential to the understanding of the basic biological mechanisms underlying the emotions. As expressed by Joseph E. LeDoux, Ph.D., author of The Emotional Brain, in a concise way: From the perspective of the lover, the conscious feeling of love is the only thing that is relevant. For the scientist who wants to understand the biological mechanism underlying the emotion of love, the biological responses of the organism are the only relevant aspects.

Basic biological mechanisms by which stressors are translated into distinct bodily responses
Whenever an emotion is triggered, a network of brain regions (traditionally referred to as the "limbic system") generates a pattern of stereotypic outputs, which ultimately induce a biological response of the body. The circuits within the brain that generate the emotional responses can be referred to as the emotional motor system (EMS). Via parallel outputs of the autonomic nervous and neuroendocrine systems, the EMS plays out an emotional response in the "theater of the body." For example, every human being produces similar facial expressions associated with specific emotions. Facial expressions of fear, anger, and sadness are so universal that a primal tribe member living in the Amazonian jungle has the identical pattern as a broker at the New York stock exchange. Specific circuits of the emotional motor system have evolved to both generate this stereotypic emotional facial response, as well as instantaneously recognize it when it occurs in somebody else. Other examples of musculoskeletal responses associated with emotions include tightening of muscles or changes in posture.

Even though most of us are completely unaware of it, similar stereotypic emotion-specific responses are also generated within our internal (visceral) organs. In a stressful situation they include responses such as stimulation of the cardiovascular system (increased blood pressure, heart rate, cardiac output) required to prepare the body for the "fight or flight" response. Of particular relevance for those with a functional GI disorder like IBS, is the fact that the emotion of fear is associated with inhibition of upper GI (stomach and duodenum) contractions and secretions, and with stimulation of lower GI (sigmoid colon and rectum) motility and secretions. The former may contribute to a sensation of fullness and lack of appetite, the latter to diarrhea and lower abdominal pain. This response pattern of the digestive tract may have evolved in order to minimize the exposure of the small and large intestine to ingested food and waste material during a time when all energy is shunted toward the skeletomotor system to maximize success of the fight and flight response. Interestingly, when the emotion shifts to anger, the pattern of upper GI activity is reversed, with stimulation of gastric contractions and acid secretion.

The beneficial and detrimental effect of the stress response
In addition to elaborate mechanisms that have evolved to activate the stress response when needed to protect the organism, equally effective mechanisms have evolved to turn it off immediately when no longer needed, or to rapidly habituate to repeated occurrences of the same stressor. Apparently these systems of activation and inactivation of the stress response, which have evolved over millions of years, have been perfected to deal with the daily threats to survival for all organisms involved in the cycle of prey and predators. However, in humans living in modern societies we are increasingly beginning to realize a phenomenon that has been referred to as the wear and tear, or the allostatic load, of stress. This detrimental effect of stress may manifest following a one time severe stressor (life threatening situation), following repeated smaller stressors, or following a major sustained stressor over a period of time.

Let us again take the example of a nation responding to an acute or perceived threat by mounting a massive mobilization of civilian and military resources ("fight response" or "defense reaction"). In the majority of situations, mounting the response will be sufficient to avoid the potential damage, and the country can return to its normal civilian function within a relatively short time. However, if the threat persists, or the response is maintained over a long period of time, there will be substantial costs to the society (i.e., allostatic load) such as the channeling of resources from civilian to military projects, and dealing with psychological and physical impact of military conflicts.

What is the wear and tear of severe, repeated, or sustained chronic stress in humans? The remarkable thing is that in the absence of predisposing "vulnerability" factors (e.g., genetic factors, adverse early life experiences) or in the presence of "resilience" factors (e.g., possibly genetic, strong social support system), a large number of people are remarkably resilient to this wear and tear of chronic stress. However, in the vulnerable person, it has frequently severe consequences. For example, the acute increase in heart rate and blood pressure is an essential response to optimize the physical strength of a threatened organism, but the chronic changes developing with persistent increase in cardiovascular function lead to hypertension and coronary artery disease. An acute increase in vigilance is important to better recognize an enemy, however persistent hypervigilance is associated with a variety of common chronic conditions such as anxiety disorders. Finally, while acute stimulation of the immune system has a beneficial effect, chronic stress can be associated with suppression of cellular immunity, and detrimental effects on health.

Men vs. women: Fight and flight vs. tend and befriend
A problem with research into the biology of stress is that the preponderance of such research has been conducted in males. Prior to 1995, females constituted only about 17% of participants in laboratory studies of physiological and neuroendocrine responses to stress, while in recent years, the gender bias has somewhat decreased.

Could it be that the majority of research studies on the stress response apply only to men, and not to women? In an article, reviewed in May 2000, by the New York Times, a prominent Professor of Psychology from UCLA, Shelley Taylor and colleagues, summarized published scientific evidence from behavioral and biological studies and made a strong argument for differences in the way male and female animals, and men and women, respond to stressful, threatening situations. The authors made the following theoretical assumptions about the evolution of gender-specific stress response patterns:

Traditionally and throughout evolution, males have been selected that mount a successful behavioral response to a threat, which maximizes the survival of self by either defeating the enemy or overcoming the threat. A similar evolutionary advantage exists for males that are able to flee from a superior enemy. However, the same fight and flight response, which is advantageous for the survival of the male individual, puts defenseless and unprotected offspring at significantly greater risk of being harmed.

The fight and flight response should result in the selection of males that maximizes biological mechanisms to assure superior fight or flight responses, such as cardiovascular performance, motor planning, and necessary neuroendocrine responses, such as activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis—systems essential to self-preservation.
Different considerations apply to females:

Compared to males, females make a greater investment initially in pregnancy and nursing, and typically play the primary role in bringing offspring to maturity. Therefore, behavioral responses to threats that were successfully passed on would have been those that protected offspring as well as self.

This maternal investment should result in selection of female stress responses that do not jeopardize the health of both the female and her offspring, and maximize the likelihood that they will survive.

This response pattern should favor the development of biological mechanisms that inhibit the fight and flight response, and shift the individual's attention to caring and tending to the young (attachment behavior) and to forming networks of females for the defense of the group.
Men and women: Biological differences in the stress responses
Based on these considerations, the authors make a convincing argument that high sympathetic nervous system activation (targeted primarily at the cardiovascular system, thereby optimizing physical performance), effective activation of pain inhibition systems (to prevent distraction of fight and flight performance from injury related pain), and high cortisol responses (that mitigate the immune response and repress inflammation) are characteristic biological components of the male stress response. These responses are related to higher male sex hormone levels.

In contrast, in females, greater activation of vagal mechanisms (associated with parasympathetic nervous system "relax and restore" responses and increased gastrointestinal activation), and greater release of oxytocin (a calming hormone amplified by estrogen) and endorphins within the brain will inhibit the underlying fight and flight response, and promote attachment behavior both to the offspring as well as to other females.

Do these differences also apply to the non-life threatening stressors of daily life, and could the differences in biological mechanisms play a role in the well known fact that men are more likely to die of chronic diseases of the cardiovascular system (hypertension, coronary artery disease), while women appear more likely to suffer from a wide range of functional disorders, such as IBS, fibromyalgia, and interstitial cystitis?

What does this have to do with IBS
Converging evidence from different laboratories and research groups are consistent with the concept of an "enhanced stress responsiveness" as a major vulnerability factor in many IBS patients. As outlined above, such an enhanced stress responsiveness may not be obvious to the affected individual, until he or she is exposed to a period of sustained threatening stress (financial or employment problems, divorce, aftermath of a major disaster with consequences on daily life), repeated mild to moderate stressors, or a one time severe (life threatening) type stressor (robbery or physical assault). Under these circumstances the mechanisms that normally turn off the stress response are overwhelmed, and attempts of the nervous system at adaptation or habituation fail. Many of the vulnerability factors for such enhanced stress responsiveness have been identified and many of them occur in a particular vulnerable period of the developing brain (before age 10). Some of the best-studied factors include loss of the primary care giver, distant mother-child relationship, emotional neglect, and physical and verbal or sexual abuse.

In order to understand how a chronically enhanced stress response can produce the cardinal symptoms of IBS (abdominal pain and discomfort associated with altered bowel habits) we have to go back to the earlier section on the emotional motor system: activation of the stress system will stimulate contractions and secretion in the sigmoid colon and rectum. Depending on the specific emotional context (fear vs. anger), the upper GI tract will be either inhibited (fear) or stimulated (anger). In addition, recent research in animals has demonstrated a phenomenon referred to as stress-induced visceral hyperalgesia. What this means is that in vulnerable animals, exposure to an acute moderate stressor will make the colon more sensitive to distension (and the perception of discomfort or pain).

Why do the symptoms go away after one stressful situation has resolved and persist in another? Amongst many factors, anxiety and fear generated by IBSsymptoms themselves are sufficient in many patients to maintain the stress responsiveness in a chronically enhanced state. Some of the more common symptom related anxieties include: Am I close enough to a bathroom when my symptoms come on? Will I be OK for the rest of the day, unless I completely empty my colon in the morning before leaving the house?

What can IBS patients do to guard against the detrimental effects of allostatic load and enhanced stress responsiveness
Based on our current state of knowledge, little can be done in the affected patients to reverse vulnerability factors that have been programmed into our genes or have been hardwired into our nervous system during the first few years in life. Nevertheless, a variety of cognitive and behavioral approaches may be useful in protecting ourselves against the effects of allostatic load, or the wear and tear, of stress. These include: 1) Developing effective coping styles towards life stress and IBS symptoms; 2) Learning to activate mechanisms in the body that oppose the stress response and induce what has been referred to as the "relaxation response" through various relaxation techniques (e.g., breathing exercises, progressive relaxation, hypnosis, meditation); and 3) Moderate but sustained exercise.

A Simple Relaxation Technique
Breathing is the only bodily function that, in the normal state, is fully under automatic control by circuits in the central nervous system, but which can instantly be switched to conscious control. This unique property is probably responsible for the fact that for thousands of years, breathing techniques have been essential components of meditation techniques and healing practices.[1]

Typically, our breathing is either shallow and irregular (chest or thoracic breathing), or deep and regular (abdominal or diaphragmatic). Shallow chest breathing is often associated with muscle tension and distress. Deeper abdominal breathing, on the other hand, is associated with reduced muscle tension and relaxation. There are many breathing techniques that can be quickly and easily learned. While initially the positive effects are often subtle, benefits increase over time. Here is a simple breathing technique to enhance relaxation and release tension:[2]

Sit straight in a comfortable position with your arms and legs uncrossed
Breathe in comfortably into your abdomen. (If your are not used to diaphragmatic breathing, place your palm over your abdomen to feel it rise and fall with each breath.) Pause briefly before you exhale.
Each time your exhale, count silently to yourself, "One…two…three…four."
Repeat this cycle, counting your exhalations in sets of four, for five to ten minutes.
Notice your breathing gradually slowing, your body relaxing, and your mind calming as you practice this breathing technique.

[1] Mayer E. The Neurobiology Basis of Mind Body Medicine, IFFGD, 2000.
[2] Davis M, Eshelman E, McKay M. The Relaxation and Stress Reduction Workbook, MJF Books, 1995.

Source: the International Foundation for Functional Gastrointestinal Disorders (IFFGD). Copyright IFFGD 2001. PO Box 170864, Milwaukee, WI 53217, USA

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The Brain-Gut Connection new
      #19272 - 09/01/03 11:43 AM

Reged: 12/09/02
Posts: 7798
Loc: Seattle, WA

Notes taken from, Patient Heal Thyself by Jordan S. Rubin, NMD, CNC

The Brain-Gut Connection

Why do we get butterflies in our stomach before a performance?

Why does indigestion produce nightmares?

Why are antidepressants now also being used for gastrointestinal ailments?

It turns out that both our gut and our brain originate early in embryogenesis from the same clump of tissue which divides during fetal development. While one section turns into the central nervous system, another piece migrates to become the enteric nervous system. Later the two nervous systems connect via a cable called the vagus nerve -- the longest of all the cranial nerves whose name is derived from Latin, meaning "wandering." The vagus nerve meanders from the brain stem through the neck and finally ends up in the abdomen. There's the brain-gut connection.

Have you ever wondered why an impending job interview can cause an attack of intestinal cramps? And why do anti-depressants targeted for the brain cause nausea or abdominal upset in millions of people who take such drugs? The reason for these common experiences is because each of us literally has two brains --the familiar one encased in our skulls and a lesser-known but vitally important one found in the human gut. Like Siamese twins, the two brains are interconnected; when one gets upset, the other does, too. No wonder people trust their gut. One half of all our nerve cells are located within the gut?

The state of the gut has a profound influence upon our health. It is from the healthy gut that we enjoy neurological and psychological as well as immunological health. This is not to discount the human brain. This is simply to say that the body has two brains -- the second brain being our gut. There is an excellent article on this brain-gut connection called Complex and Hidden Brain in Gut Makes Bellyaches and Butterflies written by Sandra Blakeslee, originally published in the January 23, 1996 issue of The New York Times. I have added a link to her article in the Diet section of the Links page.

How it all Works

The gut's brain, known as the enteric nervous system (ENS), is located in sheaths of tissue lining the esophagus, stomach, small intestine and colon. Considered a single entity, it is packed with neurons, neurotransmitters and proteins that zap messages between neurons or support cells like those found in the brain. It contains a complex circuitry that enables it to act independently, learn, remember and, as the saying goes, produce gut feelings.

In his book The Second Brain, HarperCollins 1998, Dr. Michael Gershon, a professor of anatomy and cell biology at Columbia-Presbyterian Medical Center in New York City, dubs the entire gastrointestinal system the body's second nervous system. "The brain is not the only place in the body that's full of neurotransmitters," says Dr. Gershon. "A hundred million neurotransmitters line the length of the gut, approximately the same number that is found in the brain..." If we add the nerve cells of the esophagus, stomach and large intestine, there are more nerve cells in the gut than there are in the entire remainder of the peripheral nervous system. Nearly every chemical that controls the brain in the head has been identified in the gut, including hormones and neurotransmitters.

This complex circuitry provides the brain in the gut with the means to act independently. Proof of this can be seen in stroke victims whose brain stem cells, which control swallowing, have been destroyed. If this occurs, a surgeon has to create an opening in the abdominal wall, so that feeding can be accomplished by manually inserting foods directly into the stomach. Once the food is in the stomach, digestion and absorption can take place, even in individuals who are brain dead. The central nervous system is needed for swallowing and for defecation, but from the time the food is swallowed to the moment its remains are expelled from the anus, the gut is in charge.

The Sleep-Gut Connection

As light is shed on the circuitry between the two brains, researchers are beginning to understand why people act and feel the way they do. The brain and gut are so much alike that during our sleeping hours, both have natural 90-minute cycles. For the brain, this slow wave sleep is interrupted by periods of rapid eye movement sleep in which dreams occur. For the gut, the 90-minute cycles also involve slow waves of muscle contractions but, as with REM intervals, these are punctuated by short bursts of rapid muscle movement. Could it be that both brains influence each other? The answer is probably yes. REM sleep is a sleep phase characterized by arousal, altered activity of the autonomic nervous system and altered colon (large intestine) function.

We also know that patients with bowel problems tend to have abnormal REM sleep. Poor sleep has been reported by many perhaps a majority of, patients with irritable bowel syndrome (lBS) and non-ulcerative dyspepsia (also known as "sour stomach") who complain of awakening tired and unrefreshed in the morning. Even after patients awake from what they describe as a "sound sleep," they report a general feeling of tiredness and fatigue.

Abnormal REM sleep is reduced by low-dose treatment with the anti-depressant amitryptiline, which has also been shown to be effective in treating lBS and non-ulcerative dyspepsia. Many drugs designed to affect the brain also affect the gut. For example, the gut is loaded with the neurotransmitter serotonin. In fact, more serotonin is produced there than anywhere else in the body. Serotonin is linked with initiation of peristalsis.

The Anxiety-Gut Connection

About 25% of people taking fluoxetine (Prozac) and other types of similar-acting antidepressants experience gastrointestinal problems such as nausea, diarrhea and constipation. The problem with these drugs is that they prevent uptake of serotonin by cells that should be using it. While this enables the depressed person to have more serotonin in the brain, less is available for use by the cells of the gastrointestinal tract. "Serotonin is calming to the digestive tract, initiates peristaltic and secretory reflexes," notes nutritionist June Butlin, M.Sc., Ph.D. "Long-term use or the wrong dosage may cause fluctuations between nausea, vomiting, constipation and diarrhea, and can cause depression, anxiety, insomnia, and fluctuations in appetite."

In a study reported in The New York Times article, Dr. Gershon and his colleagues explain Prozac's side effects on the gut. They mounted a section of guinea pig colon on a stand and put a small pellet in the 'mouth' end. The isolated colon whips the pellet down to the 'anal' end of the column, just as it would inside an animal. When the researchers put a small amount of Prozac into the colon, the pellet "went into high gear," Dr. Gerhson explained to the paper. "The drug doubled the speed at which the pellet passed through the colon, which would explain why some people get diarrhea," the paper says. No wonder, in small doses, Prozac is used to treat chronic constipation.

Although a little is beneficial for constipation, a lot is not. When the Gershon team greatly increased the amount of Prozac in the guinea pig colon, the pellet stopped moving at all. Hence, a little cures constipation; a lot causes it. Prozac stimulates sensory nerves, thus can also cause nausea.

The gut has opiate receptors much like the brain. "Not surprisingly, drugs like morphine and heroin that are thought to act on the central nervous system also attach to the gut's opiate receptors, producing constipation," notes pain management specialist Michael Loes, M.D., M.D.(H.), author of The Healing Response (Freedom Press 2002) "Both brains," he says, "can be addicted to opiates."

Many Alzheimer's and Parkinson's disease patients are constipated. A sickness we think of as primarily affecting the brain or central nervous system also impacts the gut.

Our gut also helps us in some amazing ways. The gut also produces chemicals called benzodiazepines. These are the same chemicals found in anti-anxiety drugs like Valium, and these are the same chemicals that alleviate pain. Perhaps our gut is truly our body's anxiety and pain reliever. While we are not sure whether the gut synthesizes benzodiazepine from chemicals in our foods, bacterial actions, or both, we know that in times of extreme pain, the gut goes into overdrive, delivering benzodiazepine to the brain. The result is to render the patient unconscious or at least reduce the pain, says Dr. Anthony Basile, a neurochemist in the Neuroscience Laboratory at the National Institutes of Health in Bethesda, Maryland.

A Bit of Background

Throughout the world's healing and mystical traditions, the belly is seen as an important center of energy and consciousness. You've probably noticed that many of India's great spiritual adepts sport prodigious bellies. These tremendous tummies are thought to be full of prana. Hence, Indian artists often depict their deities with a paunch.

In China, the gentle art of tai chi emphasizes the lower abdomen as a reservoir for energy. Tai chi teacher Kenneth Cohen, author of The Way of Qigong (Ballantine Books 1997), explains that it's possible to strengthen the abdominals by learning how to compact qi (prana) into the belly. "From the Chinese viewpoint," he says, "the belly is considered the dan tian or 'field of the elixir,' where you plant the seeds of long life and wisdom."

Lastly, in Biblical times, the seat of emotion, which we call the heart, is actually referring to the bowels. That thought in itself conjures up an image of a young Romeo sending a love note to his Juliet saying, "You move me."

In all seriousness, most people today completely ignore gut health. As a result, they are experiencing health problems that could be overcome if they knew that they centered in their gut. So I guess the thing to remember is, as Dr. Gershon puts it, "Take care of your gut and your gut will take care of you."

Notes taken from, Patient Heal Thyself by Jordan S. Rubin, NMD, CNC

Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

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Images Show a Snub Really Is Like Kick in the Gut new
      #24042 - 10/20/03 03:43 PM

Reged: 12/09/02
Posts: 7798
Loc: Seattle, WA

Images Show a Snub Really Is Like Kick in the Gut
Thu Oct 9, 2003

By Maggie Fox, Health and Science Correspondent

WASHINGTON (Reuters) - The feeling is familiar to anyone who has been passed over in picking teams or snubbed at a party -- a sickening, almost painful feeling in the stomach.

Well, it turns out that "kicked in the gut" feeling is real, U.S. scientists said on Thursday.

Brain imaging studies show that a social snub affects the brain precisely the way visceral pain does.

"When someone hurts your feelings, it really hurts you," said Matt Lieberman, a social psychologist at the University of California, Los Angeles, who worked on the study.

"I wouldn't want to be quoted as saying that physical pain and social pain are the same thing, but it seems that some of the same things are going on," he said in a telephone interview.

"In the English language we use physical metaphors to describe social pain like 'a broken heart' and 'hurt feelings,"' added Naomi Eisenberger, a graduate student who did much of the work. "Now we see that there is good reason for this."

Working with Kipling Williams, a psychology professor at Macquarie University in Sydney, Australia, Lieberman and Eisenberger set up a brain imaging test of 13 volunteers to find out how social distress affects the brain.

They used functional magnetic imaging -- a type of scan that allows the brain's activity to be viewed "live." The 13 volunteers were given a task that they did not know related to an experiment in social snubbing.

Writing in the journal Science, Lieberman and Eisenberger said the brains of the volunteers lit up when they were rejected in virtually the same way as a person experiencing physical pain.

"It would be odd if social pain looked like the exact same thing as someone-breaking-your-arm pain," Lieberman said. "What it does look like is visceral pain."

In other words -- like being punched in the stomach.

The area affected is the anterior cingulate cortex, a part of the brain known to be involved in the emotional response to pain.

In the experiment, the volunteers were asked to play a computer game. They believed they were playing two other people, but in fact played a set computer program.

"It looked like a ball being thrown around between the three people," Lieberman said.

Eventually, the game excludes the player. "For the next 45 throws they don't get thrown the ball," Lieberman said.

"It is just heartbreaking to watch. They keep indicating that they are ready to be thrown to. This really affects the person afterwards. They report feeling social distress."

The functional magnetic imaging verifies the physical basis of this feeling.

Social interaction is important to survival, so it would make sense that people would evolve to have a strong emotional response to being included socially, Lieberman said.

"For any mammal, all the needs that people typically think of as necessary for survival -- food, shelter, avoiding physical harm -- your caregiver gives you access to those needs," Lieberman said.

But there also seems to be a defense mechanism to prevent the pain of rejection from becoming overwhelming.

"We also saw this area in the prefrontal cortex. The more it is active in response to pain, the less subjective pain you feel," Lieberman said. "This part of the brain inhibits the more basic response."

In the volunteers, those who had the most activity here reported the least distress in response to the snub.

It seemed to be involved in consciously thinking about the pain, Lieberman said, but said the area needed more study.

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Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

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The human enteric nervous system new
      #69651 - 05/11/04 07:10 PM

Reged: 12/09/02
Posts: 7798
Loc: Seattle, WA

Neurogastroenterology and Motility
Official Journal of the European Society of Neurogastroenterology and Motility and the American Motility Society

Edited by:

Michael Camilleri and Michael Schemann

Print ISSN: 1350-1925
Online ISSN: 1365-2982
Issues per Volume: Bi-monthly
Current Volume: 16

ISI Journal Citation Reports® Ranking: 2002: 17/45 (Gastroent & Hepatol); 24/138 (Clin Neurol); 92/197 (Neurosci)
Impact Factor: 2.083

Volume 16: Supplement 1
The human enteric nervous system

M. Schemann
M. Neunlist

Decades of work in animal models have demonstrated that the enteric nervous system (ENS) plays a key role in controlling gut functions. Recent advances made it possible to extend such studies to the ENS of man in health and even in disease. Such studies have already provided new insights into the pathophysiology of inflammatory and possibly functional bowel diseases. Studies on human ENS revealed both important similarities and differences between the ENS of man and of experimental animals. Here we summarize the current state of knowledge of the electrophysiology and neurochemistry of the human ENS, including relevant reflex mediated functions in the human gut. Additionally, we review disease associated changes in human ENS properties. Finally, we highlight some research areas that hold special promise in advancing our understanding of the human ENS.

Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

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Irritable bowel syndrome: a model of the brain-gut interactions new
      #73278 - 05/25/04 12:28 PM

Reged: 12/09/02
Posts: 7798
Loc: Seattle, WA

Irritable bowel syndrome: a model of the brain-gut interactions

Agata Mulak , Bruno Bonaz

Brain-gut interactions are increasingly recognized as underlying pathomechanisms of functional gastrointestinal disorders. Bi-directional communication between the central nervous system (CNS) and the enteric nervous system (ENS) occurs both in health and disease. Various CNS- and gut-directed stressors stimulate the brain-gut axis. Processes modulating responsiveness to stressors along the brain-gut axis involve neural pathways, the immunological, and endocrinological mechanisms. Disturbances at every level of neural control of the gastrointestinal tract can affect modulation of gastrointestinal motility, secretion, immune functions as well as perception and emotional response to visceral events. ENS function, central processing, and autonomic regulation play an important role in the brain-gut dialogue. Stress and emotions may trigger neuroimmune and neuroendocrine reactions via the brain-gut axis. Various non-site specific neurotransmitters influence gastrointestinal, endocrine and immune function, as well as human behavior and emotional state, depending on their location. The physiology of the digestive tract, the subjective experience of symptom, health behavior, and treatment outcome are strongly affected by psychosocial factors. Recently, a biopsychosocial model of IBS containing physiological, emotional, cognitive and behavioral components has been proposed. Rapid progress in neurogastroenterology, using new brain imaging techniques, should bring better understanding of the brain-gut axis and open new therapeutic perspectives.

Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

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Brain activity during distention of the descending colon in humans new
      #88759 - 07/11/04 02:07 PM

Reged: 12/09/02
Posts: 7798
Loc: Seattle, WA

Neurogastroenterology and Motility
Official Journal of the European Society of Neurogastroenterology and Motility and the American Motility Society

Edited by:

Michael Camilleri and Michael Schemann

Print ISSN: 1350-1925
Online ISSN: 1365-2982
Frequency: Bi-monthly
Current Volume: 16
ISI Journal Citation Reports® Ranking: 2002: 17/45 (Gastroent & Hepatol); 24/138 (Clin Neurol); 92/197 (Neurosci)
Impact Factor: 2.083


Table of Contents > Issue > Abstract

Volume 16: Issue 3
Brain activity during distention of the descending colon in humans

T. Hamaguchi
M. Kano
H. Rikimaru
M. Kanazawa
M. Itoh
K. Yanai
S. Fukudo


Brain-gut interaction is considered to be a major factor in the pathophysiology of irritable bowel syndrome. However, only limited information has been provided on the influence of gastrointestinal tract stimulation on the brain. Our aim in this study was to determine the specific regions of the brain that are responsible for visceral perception and emotion provoked by distention of the descending colon in humans. Fifteen healthy males aged 22 ± 1 participated in this study. Using a colonoscope, a balloon was inserted into the descending colon of each subject. After sham stimulation, the colon was randomly stimulated with bag pressures of 20 and 40 mmHg, and regional cerebral blood flow was measured by [15O] positron emission tomography. The subjects were asked to report visceral perception and emotion using an ordinate scale of 0–10. Colonic distention pressure dependently induced visceral perception and emotion, which significantly correlated with activation of specific regions of the brain including the prefrontal, anterior cingulate, parietal cortices, insula, pons, and the cerebellum. In conclusion, distention of the descending colon induces visceral perception and emotion. These changes significantly correlate with activation of specific regions in the brain including the limbic system and the association cortex, especially the prefrontal cortex.

Article Type: Original Article
Page range: 299 - 309

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Visceral Sensitivity Index: Development and Validation of a GI Symptom-Specific Anxiety Scale new
      #92812 - 07/24/04 01:54 PM

Reged: 12/09/02
Posts: 7798
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From Alimentary Pharmacology & Therapeutics

The Visceral Sensitivity Index: Development and Validation of a Gastrointestinal Symptom-Specific Anxiety Scale

Posted 07/15/2004

J. S. Labus; R. Bolus; L. Chang; I. Wiklund; J. Naesdal; E. A. Mayer; B. D. Naliboff

Summary and Introduction
Background: Anxiety related to gastrointestinal sensations, symptoms or the contexts in which these may occur is thought to play a significant role in the pathophysiology as well as in the health outcomes of patients with irritable bowel syndrome.
Aim: To develop a valid and reliable psychometric instrument that measures gastrointestinal symptom-specific anxiety.
Methods: External and internal expert panels as well as a patient focus group evaluated a large pool of potential item stems gathered from the psychological and gastrointestinal literature. Potential scale items were then administered to 96 patients diagnosed with irritable bowel syndrome along with a set of validating questionnaires. Final item selection was based upon rigorous empirical criteria and the psychometric properties of the final scale were examined.
Results: A final unidimensional 15-item scale, the Visceral Sensitivity Index, demonstrated excellent reliability as well as good content, convergent, divergent and predictive validity.
Conclusions: The findings suggest that the Visceral Sensitivity Index is a reliable, valid measure of gastrointestinal symptom-specific anxiety that may be useful for clinical assessment, treatment outcome studies, and mechanistic studies of the role of symptom-related anxiety in patients with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is characterized by chronic abdominal pain or discomfort associated with altered bowel habits. It is the most common of the functional gastrointestinal (GI) disorders (10-15% prevalence)[1] and has an impact on disease-related quality of life (QoL) comparable with that of depression and chronic renal failure.[2] Converging clinical, epidemiological and experimental evidence is consistent with a pathophysiological model of IBS that is multifactorial and includes a prominent role for altered central stress responses. This evidence includes the association of IBS symptom exacerbations with certain stressful[3-5] or traumatic[6] life events, frequently reported comorbidity with anxiety disorders, in particular panic disorder and post-traumatic stress disorder,[7] and efficacy of pharmacological and non-pharmacological treatments targeted at the stress circuitry of the central nervous system (CNS).[8,9]

While peripheral changes in the gut may contribute to overall IBS symptoms in some patients, an altered sensitivity or responsiveness of the emotional motor system (EMS) has been proposed to play an important role in the mediation of autonomic and neuroendocrine responses, as well as pain modulation in response to stressful life events.[10] It has previously been suggested that GI symptom-specific anxiety (GSA) may be an important endogenous stressor perpetuating IBS symptoms, even in the absence of external stressors.[11] Similar models of symptom-related anxiety have been shown to play an important role in symptom maintenance and treatment response in other syndromes including chronic pain and panic disorder.[12-14] Most importantly, pathological anxiety directed towards bodily sensations may be present even in patients who do not meet DSM-IV criteria for anxiety disorders.[15,16] Thus, while IBS patients generally are found to have psychiatric comorbidity in the form of anxiety disorders of up to 40%,[9] a much larger number may show GSA, making the overall prevalence of all types of anxiety in these patients much higher.

In addition to playing a possible role in the pathophysiology of IBS, GSA may play a role in the unexpected severe impairment of disease-related QoL reported by these patients.[2,17] A recent analysis of specific factors contributing to the QoL impairment in IBS patients found worries about symptoms to be a highly significant predictor of QoL impairment.[17]

Finally, symptom-related anxiety may respond particularly well to therapies such as anxiolytics, 5-HT3 receptor antagonists, and other centrally targeted compounds such as corticotropin-releasing factor receptor and neurokinin-1 receptor antagonists, as well as various cognitive behavioural therapies. A reduction of this anxiety may play an important role in improving global end-points commonly used in IBS trials, and these global end-points, as well as QoL measures may be greatly influenced by a reduction in symptom-related anxiety. In the current study, a measure of GSA is developed and support for the psychometric properties of this instrument is provided.


Section 1 of 4 Next Page: Materials and Methods

Materials and Methods
In the following section, the specific steps taken to develop the rationale and items for the new scale are presented and the methods for the validation study are described.

Construct Definition
The GSA was operationalized based on previous conceptualizations of anxiety sensitivity (AS)[18] and biobehavioural models as applied to IBS.[9] Specifically, the GSA construct was thought to comprise five dimensions of GI-related cognitions and behaviours:

Worry: obsessive, negative, catastrophic thoughts, either learned or innate, reflecting a negative, future-oriented perspective on GI symptoms and their impact.

Fear: learned responses to previously innocuous physical sensation(s) that have been paired with a painful or aversive stimulus; often unassociated with feelings of anxiety.

Vigilance: an increased awareness of, attention to, and increased perceived relevance of GI-specific sensations resulting in a decreased ability to attend to other internal or external stimuli.

Sensitivity: heightened perception of GI-specific sensations and symptoms under a variety of conditions including eating and stress.

Avoidance: increased safety behaviours, rituals, and seeking reassurance to GI-specific sensations.

As triggers for these behaviours and cognitions may be interoceptive (e.g. experience of GI sensations) or contextual (e.g. environmental cues related to GI sensations), item generation was based on considerations regarding stimulus origin as well as affective, cognitive, or behaviour manifestations of the dimensions.

Item Generation and Refinement
Validated and widely used instruments in the psychological and IBS literature (e.g. Cognitive Scale-Functional Bowel Disorders,[19] Pain Anxiety Symptoms Scale,[20] IBS - QoL[21]) were reviewed for item structure and content thought to be reflective of the dimensions described above. In most cases, the reviewed instruments contained items that were intended to measure a general construct (e.g. trait anxiety) but were not context-specific (i.e. anxieties pertaining to GI sensations or experiences). In these instances, the stem of appropriate items were selected and modified to increase relevance. In some instances, selected items thought to be extremely relevant to the current development of the Visceral Sensitivity Index (VSI) were found as part of larger multidimensional instruments on QoL. Additional sample items were recommended based on the clinical observations of the authors. Items were constructed as questions or statements that could be presented in a self-report format. The resulting 86 sample items were presented to panels of external and internal experts in IBS as well as a focus group of patients with IBS to address content and face validity issues.

External panel. Seven physicians (QA, CB, DD, RF, TL, MS and DW) and two psychologist practitioners/researchers (MC, MH, see Acknowledgements) were asked, via mail, to assist in the evaluation of the items. After being provided with a theoretical rationale for the development effort, the operational definitions of the measurement domains, the sample of items, a set of instructions, and a score sheet, the panellists evaluated each item on the basis of (i) its 'relevance' to the concept of GSA as portrayed in the definitions provided, (ii) its 'conciseness', in terms of its ability to capture and adequately present to patients the focal thought of the statement as succinctly as possible, and (ii) its 'clarity', vis-à-vis its level of understanding for the typical patient with IBS that they saw in their research and/or practice. A 5-point ordinal scale (5 = excellent, 4 = very good, 3 = fair, 2 = poor, 1 = very poor) was used for each rating and panellists provided an explanation of why and what suggestions they might make to improve the item receiving a rating of poor or very poor. Finally, they were asked to contribute additional items where they thought it would be relevant.

Internal panel. A second panel comprised of three of the authors (EM, BN and LC) was brought together and replicated the activities of the external panel. These panelists were also asked to assess the items with regard to the perceiveddimension that the item stem was intending to cover. Results from both panels were tabulated and used in the final selection process as described below.

Patient focus group. A 2.5-h focus group, moderated by one of the authors (RB) was convened to review the items and address eventual questionnaire format. Eleven participants (ages 22-63) meeting Rome II diagnostic criteria[22] for IBS were recruited by advertisement and gave their reactions to selected items and formats. Consensus of the focus group was that items were best understood if item stems were formatted as statements (e.g. I always try to relieve my bowels before I leave the house in the morning), and the response alternatives were given as ordinal categories from 'strongly agree' to 'strongly disagree'. Based on the focus group results and comments from the expert panels, 90 potential items were generated (i.e. four additional items were added based on comments made by the panellists). Each item was scored on a 6-point Likert Scale (0 = strongly disagree to 5 = strongly agree). The responses to negatively worded items were reverse scored so that a higher score for each item indicated greater GSA.

Validation Study Methods
Participants. A total of 100 patients with a documented history of IBS were recruited via advertisement. Patients were mailed a questionnaire battery (see Appendix) and instructions. A nurse followed up with late responders.

Measures. In order to assess concurrent and predictive validity for the candidate GSA items, as well as degree of socially desirable responding, participants were administered the 90 GSA items, a bowel symptom questionnaire (BSQ), which includes multiple items regarding symptom severity, quality, and bowel habit information[23] and the Social Desirability Response Set (SDRS).[24] In addition, two well-known measures of anxiety, the Hospital Anxiety and Depression Scale (HAD)[25] and Anxiety Sensitivity Index (ASI),[26] were administered.

The HAD is a self-assessment mood scale specifically designed for use in non-psychiatric settings.[25] It is a well-validated brief inventory for assessment of symptoms of anxiety and depression. The HAD is one of the most widely used psychological symptom questionnaires to document clinical symptoms of state anxiety, depression and somatization.

The ASI[26] is the most widely used self-report measure of AS, the tendency to respond fearfully to the bodily sensations of anxiety rather than a predisposition to respond anxiously to a wide range of external stressors.[18] The ASI is a well-validated multidimensional instrument assessing panic-specific somatic sensations (i.e. heart palpitations), cognitive dyscontrol (i.e. inability to concentrate), and fear of publicly observable dysfunction (e.g. sweating).[27] Conceptualized as a stable personality trait, AS has been conceptually and empirically distinguished from trait anxiety.[18]

Statistical Analysis
Item means and discrimination indices were calculated as were the items' correlation with symptom severity (as measured from the BSQ) and general anxiety (as measured by the HAD) and the items ratings from the expert panellists. Item retention for the final scale was guided by the following criteria:

Acceptable item content and face validity: two of three internal panellists rated item relevance as at least very good (>/=4) and agreed upon the item's dimension (e.g. worry, avoidance).

Sufficient variation: item did not demonstrate distributional floor or ceiling effects (i.e. a mean difficulty <1 or >3).

Maximize internal consistency: only items with a moderate correlation (>/=0.45) with the total scale were retained.

Optimize eventual predictive and concurrent validity: items correlating with symptom severity but evidencing only a moderate relationship with general state anxiety were included (so as not to exhibit excessive convergent validity with this construct).

Factor analysis was used to assess construct internal consistency, reliability and validity of the final selected scale items. Specifically, principal components analysis with varimax rotation was applied to determine the maximum number and nature of the factors comprising of the final scale. Reliability of the final scale was assessed using Cronbach's &#945; and the mean inter-item correlation, an indicator of item homogeneity in a scale. Validity of the final scale was examined using bivariate correlations and linear regression. In addition, path analysis was used to determine the potential mediating effect of GSA. The significance of mediation was evaluated using the empirical sampling distribution of the product of the coefficients (the estimate of the intervening variable or the indirect effect, &#945;ß) divided by the standard error of the indirect effect, &#963;&#945;ß.[28] Similar to significance testing using the standard normal distribution, z' = &#945;ß/&#963;&#945;ß is calculated and tested against the critical value from the empirical sampling distribution of the product of coefficients (H0: &#945;ß/&#963;&#945;ß = 0). The empirical critical value at &#945; = 0.05 is 0.97. This test is considered the most powerful method for testing intervening effects.[28] In addition, 95% confidence intervals for the indirect effects were calculated based upon normal distribution theory.

Next Page: Results

A total of 96 patients (75 female, 21 male), ranging in age from 19 to 79 years (49.4 ± 13.6, mean ± s.d.), completed questionnaires. On average, patients reported an initial IBS diagnosis at age 39 ± 15.2 and reported a mean IBS duration of 11.4 ± 10.4 years. Table 1 contains a more detailed description of the sample.

Final Item Selection
After meeting the retention criteria, items were assessed on the basis of content overlap (i.e. when items had redundant content one was dropped) and domain coverage, to yield the final item set of 15-items (see Table 2). The final 15-items were subjected to factor analysis to assess construct internal consistency, reliability and validity. One main factor accounted for 51% of the variance. A minor factor (items 2, 6, 7 and 10) accounted for an additional 8% of the total variance. However, only items 7 and 10 loaded uniquely on this factor rendering interpretation untenable. Forcing a single factor solution resulted in loadings of 0.47-0.81 for the 15-items and supported a unidimensional measure. Given this outcome, the entire 15-item scale was labelled the VSI and was evaluated for reliability and validity as a single scale based on the sum of the individual item scores.

The VSI demonstrated a high level of internal consistency. Cronbach's &#945; was estimated at 0.93 and the mean inter-item correlation of the VSI was 0.47 (further supporting a unidimensional scale). Table 2 contains the item-total correlations which ranged from 0.49 to 0.77. Additionally, SDRS scores were not correlated with VSI scores, r(95) = -0.02, ns, suggesting that participant responses did not appear to be influenced by a desire to present in a favourable light.

Table 3 contains the mean scores and bivariate correlations between the VSI, HAD anxiety subscale, ASI, and current IBS symptom severity (past week). Scores on the VSI, HAD anxiety subscale, and ASI as well as symptom severity were not correlated with age, sex, predominant bowel habit, or age of first diagnosis. Duration of IBS evidenced a small negative correlation with VSI scores, r (91) = -0.22, P < 0.05, suggesting that higher GSA was associated with shorter duration of IBS symptoms. However, the duration variable was positively skewed and the significant negative correlation was not robust to logarithm transformation, r (91) = -0.19, ns. The relationship between ASI and duration of illness demonstrated similar results.

To examine the relationship between the VSI and severity of IBS symptoms, symptom severity in the past week was regressed simultaneously onto the ASI, HAD, and the VSI. Results indicated that the VSI total score was the strongest independent predictor (of the three anxiety scales) of current IBS symptom severity, accounting for 24% of the variance (adjusted R2) in symptom severity scores, ß0 = 6.4 (95% CI: 4.5-8.2), ßVSI = 0.12 (0.08-0.17), F (1, 94) = 30.4, P < 0.001. For example, for every 10-point decrease on the VSI a 1.2-point decrease on the 20-point symptom scale is anticipated. After controlling for VSI score neither the ASI or HAD measure explained a significant amount of the variance remaining in symptom severity demonstrating that the VSI is the key predictor of symptoms among these anxiety measures.

Path analysis was applied to examine a potential mediating effect for GSA, see Figure 1. The impact of the ASI on symptom severity through the mediator, GSA, was significant, &#945;ß = 0.14 (95% CI: 0.08-0.20). The test for intervening effects indicated significant mediating effects for GSA, z' = 4.03 (95% critical value = 0.97). As can be seen in Figure 1 (Model a), the direct effect of ASI on symptom severity controlling for GSA was not significant, c' = -0.06 (-0.14-0.02). Despite the negative coefficient for the direct effect estimate, neither examination of the confidence intervals nor significance testing indicated evidence of significant suppression effects.

Referring to Figure 1 (Model b), the impact of state anxiety, as measured by the HAD, on symptom severity through the mediator, GSA was significant, &#945;ß = 0.31 (0.11-0.51). Again, the test for intervening effects indicated that mediating effect for GSA was statistically significant, z' = 3.02 and accounted for 70% of the effect of state anxiety on symptom severity. The direct effect of state anxiety was not statistically significant, c' = 0.13 (-0.14 to 0.39).

Although, the results suggested that the effect of ASI and the effects of state anxiety on symptom severity were completely mediated by GSA, a sample size of 96 was inadequate to detect small effects (i.e. ESr = 0.20). Arguably, an effect contributing 4% or less to the variance in symptom severity may not be clinically relevant.


Next Page: Discussion

In the current study, we report the development and validation of a novel instrument for the assessment of GSA. We describe a unidimensional 15-item scale, the VSI, which demonstrates excellent reliability as well as good content, convergent, divergent and predictive validity. There is growing evidence that psychological factors including certain forms of stress are at least partially responsible for maintenance and exacerbation of IBS symptoms. In addition, IBS sufferers, especially those who seek medical attention, have increased levels of affective symptoms, in particular anxiety.[4,9,29] However, the majority of IBS sufferers do not reach criteria for an affective disorder and many report normal levels of anxiety on standardized scales. We have hypothesized that GSA and not general anxiety (or depression) may be the best marker of the characteristic cognitive and affective processes in IBS. The VSI is a readily administered 15-item self-report questionnaire designed to measure GSA in IBS including the unique aspects of fear, anxiety and hypervigilance that can accompany misappraisals of GI-specific sensations and discomfort. Empirical validation in 96 patients with moderate to very severe IBS supported a unidimensional scale and strong internal reliability. Face validity was supported by patient focus group and expert opinion endorsing the relevance of items to IBS and the concept of GSA. The VSI was shown to have high levels of convergent validity with other anxiety measures including the HAD anxiety subscale and the ASI. The scale was not influenced by social desirability, age, sex or duration of illness. In addition, it is not influenced by predominant bowel habit.

Supporting the predictive validity of the VSI, the regression analysis indicated a significant relationship with IBS symptom severity even after controlling for the other anxiety measures. While state anxiety assessed by the HAD and AS measured by the ASI were associated with IBS symptom severity, the path analyses indicated it is most parsimonious to view these relationships as mediated through GSA. Similar findings reported in studies of chronic somatic pain suggest that symptom-specific anxiety measures have greater utility for understanding symptom severity than more general measures of AS.[14,30,31] The results support a multifactorial model in which there are both general and specific mechanisms of AS.[32] In this model, trait anxiety or neuroticism represents a general mechanism (or higher order factor) which can predispose an individual to develop symptom-specific anxiety (and accompanying hypersensitivity) such as that measured by the VSI. A variety of physiological or psychosocial factors including trauma, modelling, and acute illness may be important in the development of symptom-specific anxiety in vulnerable individuals.[33,34] Although related, each of these mechanisms may have their own underlying central circuitry. For example, providing preliminary support for a GI-specific domain of AS, Verne et al.[35] reported IBS patients when compared with controls rated much higher fear and anxiety to rectal but not cutaneous pain and this was associated with greater prefrontal cortex activity in IBS patients.

Proposed Use for the VSI
Some recent models of functional GI disorders have proposed that CNS networks such as the EMS play a key role in the modulation of perceptual responses to visceral sensations and GI motility, hypothalamic-pituitary-adrenal axis dysregulation, and possibly as a consequence, immune modulation.[8] GSA may be a sensitive marker for the mental processes associated with activation of the EMS and therefore the VSI could be an important tool in mechanistic investigations in IBS. Based on this model, we propose several specific hypotheses regarding the role of GSA in IBS and related functional GI disorders that may be tested directly using the VSI.

The high comorbidity of IBS with other functional GI disorders has been hypothesized to result from shared gut-related mechanisms, such as dysmotility, or immune activation.[29] Alternatively, psychological factors such as somatization or stress responsiveness may explain this high comorbidity, and SA might be a key construct in this model.[9,29] For example, this model predicts that patients with non-functional GI disorders (inflammatory bowel disease, cancer) will score relatively low on the VSI despite significant symptom severity while patients with other functional GI disorders such as functional dyspepsia or non-cardiac chest pain and especially patients with multiple disorders will score high as a result of generalized anxiety about of GI sensations.

It is hypothesized that IBS symptoms are influenced by both external stressors such as major life events[9] and internal stressors including conditioned and unconditioned over-responsiveness to GI-specific sensations. The importance of internal stressors in symptom maintenance and exacerbation has not been directly tested as a result of lack of instrumentation. However, studies using both measures of life stress and the VSI may help to determine the relative importance of these two factors in IBS symptoms and QoL.

We would expect that VSI scores would be related to perceptual responses to experimental GI-specific stimuli supporting the hypothesis that GSA may lead to increased perception of GI-specific stimuli and symptoms through facilitation of pain transmission.

A variety of treatment modalities proposed for IBS may have a direct impact on GSA including cognitive and educational interventions,[36] and certain centrally targeted medications. Even the global effectiveness of more peripherally acting interventions may depend in a significant way on their ability to change the pattern of cognitive and conditioned responses to GI-specific sensations. The VSI may therefore be an important tool for studying the mechanism of treatment change in a variety of circumstances and ultimately for matching patient characteristics to appropriate interventions.

The current results indicate the VSI should have significant utility as a brief, valid measure of GSA in IBS. Further, empirical work to support the initial reliability and validity should include replication in other IBS patient samples, known validity studies examining healthy individuals and other patient groups with functional and non-functional GI symptoms, convergent/divergent validity studies with other measures thought to have important explanatory roles in IBS (e.g. measures of negative affect and abuse), and assessment of sensitivity to treatment outcome/change.


The authors thank the panel of experts who rated the items: Qasim Aziz, Charles Bernstein, Michelle Craske, Douglas Drossman, Ronnie Fass, Margaret Heitkemper, Tony Lembo, Max Schmulson and Dave Williams; Cathy Liu for data management; and Teresa Olivas for her editorial assistance in the preparation of the manuscript.

Funding Information

Supported in part by P50 DK64539, NR007768, and funds from AstraZeneca R&D, Sweden.

Reprint Address

Dr E. A. Mayer, Center for Neurovisceral Sciences and Women's Health, VAGLAHS, Bldg 115, Rm. 223, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA. E-mail:

J. S. Labus;*§ R. Bolus;* L. Chang;*† I. Wiklund;†† J. Naesdal;†† E. A. Mayer;*†‡§¶ B. D. Naliboff*¶**

*Center for Neurovisceral Sciences and Women's Health; Departments of †Medicine, ‡Physiology, §Psychiatry and Biobehavioral Sciences and ¶Brain Research Institute, David Geffen School of Medicine at UCLA; **VA GLA Healthcare System, Los Angeles, CA; ††AstraZeneca R&D, Mölndal, Sweden

Aliment Pharmacol Ther 20(1):89-97, 2004. © 2004 Blackwell Publishing

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Alterations of sensori-motor functions of the digestive tract in the pathophysiology of IBS new
      #105358 - 09/12/04 03:44 PM

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Alterations of sensori-motor functions of the digestive tract in the pathophysiology of irritable bowel syndrome

Michel Delvaux MD, PhD,

Department of Internal Medicine and Digestive Pathology, CHU de Brabois, F-54511 Vandoeuvre-les-Nancy, France

Available online 18 August 2004.

Pathophysiology of irritable bowel syndrome (IBS) is based upon multiple factors that have been organised in a comprehensive model centred around the brain–gut axis. The brain–gut axis encompasses nerve pathways linking the enteric and the central nervous systems and contains a large proportion of afferent fibres. Functionally and anatomically, visceral nerves are divided in to two categories: the parasympathetic pathways distributing to the upper gut through the vagi and to the hindgut, through the pelvic and pudendal nerves, and the sympathetic pathways, arising form the spinal cord and distributing to the midgut via the paravertebral ganglia.

Several abnormalities of gut sensori-motor function have been described in patients with IBS. Abnormal motility patterns have been described at the intestinal and colonic levels. Changes in colonic motility are mainly related to bowel disturbances linked to IBS but do not correlate with pain. More recently, visceral hypersensitivity has been recognised as a main characteristic of patients with IBS. It is defined by an exaggerated perception of luminal distension of various segments of the gut and related to peripheral changes in the processing of visceral sensations as well as modulation of perception by centrally acting factors including mood and stress.

Viscero-visceral reflexes link the two edges of the brain–gut axis and may account for the origin of symptoms in some pathological conditions. Recent advances in the understanding of the role of myenteric plexus allowed recognition of several neurotransmitters involved at the level of both the afferent and efferent pathways. Targeting the receptors of these neurotransmitters is a promising way for development of new treatments for IBS.

Best Practice & Research Clinical Gastroenterology
Volume 18, Issue 4 , August 2004, Pages 747-771

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Serotonin receptors and transporters — roles in normal and abnormal gastrointestinal motility new
      #120100 - 11/08/04 04:38 PM

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Alimentary Pharmacology and Therapeutics

Edited by:
R.E. Pounder and W.L. Peterson

ISI Journal Citation Reports® Ranking: 2003: 8/47 (Gastroenterology & Hepatology); 32/184 (Pharmacology & Pharmacy)
Impact Factor: 3.529


Volume 20: Supplement 7

Review article: serotonin receptors and transporters — roles in normal and abnormal gastrointestinal motility

M. D. Gershon


The gut is the only organ that can display reflexes and integrative neuronal activity even when isolated from the central nervous system. This activity can be triggered by luminal stimuli that are detected by nerves via epithelial intermediation.

Epithelial enterochromaffin cells act as sensory transducers that activate the mucosal processes of both intrinsic and extrinsic primary afferent neurones through their release of 5-hydroxytryptamine (5-HT). Intrinsic primary afferent neurones are present in both the submucosal and myenteric plexuses. Peristaltic and secretory reflexes are initiated by submucosal intrinsic primary afferent neurones, which are stimulated by 5-HT acting at 5-HT1P receptors.

5-HT acting at 5-HT4 receptors enhances the release of transmitters from their terminals and from other terminals in prokinetic reflex pathways. Signalling to the central nervous system is predominantly 5-HT3 mediated, although serotonergic transmission within the enteric nervous system and the activation of myenteric intrinsic primary afferent neurones are also 5-HT3 mediated. The differential distribution of 5-HT receptor subtypes makes it possible to use 5-HT3 antagonists and 5-HT4 agonists to treat intestinal discomfort and motility.

5-HT3 antagonists alleviate the nausea and vomiting associated with cancer chemotherapy and the discomfort from the bowel in irritable bowel syndrome; however, because 5-HT-mediated fast neurotransmission within the enteric nervous system and the stimulation of mucosal processes of myenteric intrinsic primary afferent neurones are 5-HT3 mediated, 5-HT3 antagonists tend to be constipating and should be used only when pre-existing constipation is not a significant component of the problem to be treated.

In contrast, 5-HT4 agonists, such as tegaserod, are safe and effective in the treatment of irritable bowel syndrome with constipation and chronic constipation. They do not stimulate nociceptive extrinsic nerves nor initiate peristaltic and secretory reflexes. Instead, they rely on natural stimuli to activate reflexes, which they strengthen by enhancing the release of transmitters in prokinetic pathways.

Finally, when all the signalling by 5-HT is over, its action is terminated by uptake into enterocytes or neurones, which is mediated by the serotonin reuptake transporter. In inflammation, serotonergic signalling is specifically diminished in the mucosa.

Transcripts encoding tryptophan hydroxylase-1 and serotonin reuptake transporter are both markedly decreased. Successive potentiation of 5-HT and/or desensitization of its receptor could account for the symptoms seen in diarrhoea-predominant and constipation-predominant irritable bowel syndrome, respectively.

Symptoms associated with the down-regulation of the serotonin reuptake transporter in the human mucosa in irritable bowel syndrome are similar to the symptoms associated with the knockout of the serotonin reuptake transporter in mice. The observation that molecular defects occur in the human gut in irritable bowel syndrome strengthens the hand of those seeking to legitimize the disease. At least it is not 'all in your head'. The bowel contributes.

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Pathophysiology of IBS and Serotonin Signaling new
      #191949 - 07/05/05 03:22 PM

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Pathophysiology of IBS and Serotonin Signaling

From: IBS: Improving Diagnosis, Serotonin Signaling, and Implications for Treatment CME

Authors: Lucinda Harris, MD; Lin Chang, MD

Abnormal GI Motility
The pathophysiology of IBS has evolved tremendously over the last 50 years. IBS was previously considered a disorder primarily due to abnormal intestinal motility. In the 1950s, a study by Thomas Almy[22] demonstrated that gut motility was increased in both normal individuals and patients with IBS when presented with a stressful situation. Subsequent research demonstrated that patients with IBS had increased motility abnormalities related to meals (ie, after eating) compared with control subjects.[23,24] Studies have also demonstrated GI motility abnormalities, such as clustered contractions, prolonged propagated contractions, and high-amplitude propagating contractions more commonly in patients with IBS compared with healthy individuals.[25-28] Although these motility abnormalities may be, but are not always, associated with IBS symptoms, there does not appear to be a consistent motility abnormality to explain the etiology of symptoms in all patients, and therefore, they are not currently used as diagnostic markers.

Visceral Hypersensitivity
The initial clinical observations that led to the hypothesis that patients with IBS have visceral hypersensitivity include recurring abdominal pain, tenderness during palpation of the sigmoid colon on physical examination, and excessive pain during endoscopic evaluation of the sigmoid colon. Experimental evidence suggests that a variety of perceptual alterations exist in patients with IBS: visceral hypersensitivity involving the upper and lower GI tract, as well as a heightened perception of physiologic intestinal contractions. Multiple studies using various balloon distension paradigms have reported lowered colorectal perceptual thresholds, increased sensory ratings, and viscerosomatic referral areas in patients with IBS compared with healthy individuals.[29-33] By contrast, most studies have demonstrated that patients with IBS do not exhibit generalized hypersensitivity to noxious somatic stimulation.[30,34,35] At least 2 underlying, distinct mechanisms contribute to the visceral hypersensitivity in IBS: a hypervigilance towards expected aversive events arising from the viscera, and a hyperalgesia that is inducible by sustained noxious visceral stimulation.[32]

Central Nervous System Modulation
In the 1980s and 1990s, a greater appreciation for the role of the "brain-gut" axis was achieved, and it was recognized that patients with IBS had a dysregulation between these 2 areas.[36] In general, brain-gut interactions play a key role in the modulation of GI functioning in health and disease. Signals from the brain to the gut play an important role in ensuring optimal digestive function, reflex regulation of the GI tract, and modulation of mood states. Proposed alterations in the brain-gut axis in IBS are best supported by recent findings in functional neuroimaging studies. Using distal colonic stimulation, several studies have demonstrated alterations in regional brain activation in patients with IBS compared with healthy control subjects.[37,38] These brain regions include the anterior and midcingulate cortices, insula, and dorsal pons (in the region of the periaqueductal grey) -- which are some of the most consistently activated brain areas in response to visceral as well as somatic nociceptive stimuli.

One area that is consistently activated to a greater degree in patients with IBS compared with control subjects is the anterior midcingulate cortex, a brain region concerned with cognitive processing of sensory input, including attentional processes and response selection. Furthermore, midcingulate activation correlates with the subjective unpleasantness of visceral and somatic pain. These observations suggest that patients with IBS may fail to use central nervous system downregulating mechanisms in response to incoming or anticipated visceral pain. They further show altered activation or deactivation of brain areas involved in the emotional or cognitive processing of visceral stimuli, ultimately resulting in the amplification of pain perception.

Role of Stress and Psychological Factors in IBS
Stress is widely believed to play a major role in the pathophysiology and clinical presentation of IBS. It has been postulated that in the predisposed individual, sustained stress can result in permanent increased stress responsiveness of central stress circuits and vulnerability to develop functional and affective disorders.[39] Stress may be central (eg, psychological distress) or peripheral (eg, infection, surgery) in origin. Numerous studies indicate that patients with IBS report more lifetime and daily stressful events, including abuse, compared with patients with organic GI conditions or healthy individuals.[1] In addition, in patients with IBS, stress is strongly associated with symptom onset, exacerbation, and severity. Even though the effects of stress on gut function are universal, patients with IBS appear to have greater reactivity to stress compared with healthy individuals.[40]

A large proportion of patients with IBS or other functional bowel disorders have concurrent psychological disturbances, particularly those with severe symptoms or those seen in tertiary care referral centers. Psychosocial factors have been recognized to modify the illness experience and influence healthcare utilization and treatment outcome. These psychosocial factors include a history of emotional, sexual, or physical abuse, stressful life events, chronic social stress, anxiety disorders, or maladaptive coping styles.[1] A current conceptual model regarding the role of psychosocial factors and stress in IBS suggests that adverse life experiences (past and present) influence stress responsiveness, physiologic responses, and susceptibility to developing and exacerbating this functional disorder via amplification of brain-gut interactions.

Role of Immune or Inflammatory Mediators
IBS-like symptoms have been reported in 7% to 30% of patients who have had a recent history of proven bacterial gastroenteritis; this has been termed postinfectious IBS (PI-IBS).[41] A subset of patients with IBS can trace the development of their symptoms to an episode of infectious diarrhea, primarily bacterial[42] or amebic,[43] and possibly even viral,[44] in etiology. Risk factors for PI-IBS include female sex, duration of acute diarrheal illness, and the presence of significant life stressors occurring around the time of the infection.[41]

Investigators have found that there are colonic mucosal abnormalities in PI-IBS. One study compared rectal mucosal cellularity and intestinal permeability in patients at 2, 6, and 12 weeks and 1 year after an acute infection with Campylobacter enteritis with those of patients with a history of PI-IBS and healthy controls.[45] Compared with controls, patients with a previous Campylobacter infection were found to have increased numbers of intraepithelial lymphocytes and EC cells and increased intestinal permeability, even after 1 year, as did the patients with PI-IBS. When the secretory granules of the EC cells were evaluated, patients with PI-IBS had granules containing mainly serotonin. The EC cells in healthy control subjects had granules containing primarily PYY, a peptide associated with antisecretory effects. It is conceivable that these findings play a role in the GI symptoms (eg, diarrhea, mucus in the stool) in at least a subset of patients with IBS.

Role of Serotonin in GI Function and IBS
The ENS plays a key role in regulation of both gut motility and secretion. A number of neuropeptides are involved in regulation of motility and secretion, including serotonin, which can modulate both of these functions. Ninety-five percent of serotonin is found in the gut, with 90% localized within the EC cells and 10% in the enteric neurons. Serotonin is an important mediator of the peristaltic reflex. The excitatory 5-HT1P, 5-HT3, and 5-HT4 receptors have been found to be particularly important in modulating this motor activity. Following mucosal stimulation (eg, mechanical or chemical stimulation), serotonin is released from EC cells. Serotonin acts on the 5-HT1P receptor located on the terminals of IPANs within the submucosal plexus. 5-HT4 receptors are located on the presynaptic terminals of these afferent nerves and, when activated, facilitate the release of acetylcholine and calcitonin gene-related peptide (CGRP).[3] Following activation of interneurons within the ENS, acetylcholine and substance P are released from enteric motor neurons proximally (orad), which leads to a contractual response. Release of vasoactive intestinal peptide and nitric oxide distally (caudad) result in relaxation in the gut. Peristaltic activity of the gut then occurs. 5-HT3 receptors are located on enteric nerves within the myenteric plexus as well as on vagal and spinal afferents. These receptors are thought to play a role in other intestinal reflexes and modulation of nonpainful (eg, nausea) and painful sensations, respectively.

Serotonin Reuptake Transporter
There is likely an evolutionary advantage to having physiologic mechanisms that regulate serotonin levels and activity, because it could be quite harmful without these regulatory mechanisms.[3] One of the primary mechanisms the body has for regulating availability of serotonin within the extracellular space is the serotonin reuptake transporter (SERT). SERT is present in the brain and gut. The amount of serotonin reuptake that occurs from the extracellular space is genetically determined and is based on whether there are long, short, or heterozygous polymorphisms in the promoter for synthesis of SERT. For instance, homozygosity for the short variant and presence of the heterozygous variant result in less transcript, less protein expression, and thus, less reuptake of serotonin. SERT activity is obviously an important factor influencing serotonin availability to act on postsynaptic receptors, and would possibly affect the response to serotonergic medications such as SSRIs, in the treatment of depression, and to the novel agents tegaserod and alosetron, for IBS.

Camilleri and colleagues[46] hypothesized that differences in SERT polymorphisms in patients may influence a patient's response to the 5-HT3 antagonist alosetron. It was noted that there were both sex effects and interindividual effects in the way that the medication worked in patients, slowing intestinal transit in some with IBS more than in others. Therefore, a small study of 30 patients (15 women) with IBS with diarrhea was performed in which the patients were given alosetron 1 mg orally twice daily for 6 weeks and their colonic transit measured via scintigraphy at the end of treatment. Only 23 (12 women) of these patients actually submitted blood for analysis, but 8 long homozygous, 4 short homozygous, and 11 heterozygous SERT polymorphisms were identified. When colonic transit was measured, the patients with a long homozygous polymorphism (associated with more serotonin reuptake, ie, there is conceivably less serotonin around to stimulate the gut and peristalsis and therefore gut motility is slowed) had greater slowing of colonic transit with alosetron than heterozygotes. The importance of SERT and its effect on colonic transit response to alosetron on its clinical efficacy, as well as the vulnerability to adverse events associated with the drug, such as constipation and ischemic colitis, need to be examined.

Copyright © 2003 Medscape.

Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

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