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Brain-Gut
      #13958 - 07/14/03 01:59 PM
HeatherAdministrator

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All articles pertaining to brain-gut research should be posted here.



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The gut has a mind of its own new
      #13994 - 07/14/03 04:07 PM
HeatherAdministrator

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The gut has a mind of its own

Operating like the cranial brain and looking uncannily
similar to it, the gut brain is continuously active,
whether we're aware of it or no, writes CHANTAL OUIMET


By CHANTAL OUIMET
Special to The Globe and Mail

Tuesday, December 31, 2002 – Page R7

Ever wonder why you get cramps when you're stressed? Or why you get "butterflies" in your stomach before a job interview? And why your gut tells you not to trust a certain person?

Scientists say it's because the body has two brains -- the familiar one encased in our skull and another more obscure one in our gut. This "second brain," known as the enteric nervous system, is located in our digestive tract and holds about 100-million nerve cells -- more than in our spinal cord.

Less complex and smaller than our cranial brain, this "second brain," which contains between 70 to 85 per cent of the body's immune cells, is an independent data-processing centre handling a complicated circuitry of neurons, neuromodulators and neurotransmitters.

"Every neurotransmitter that exists in our brain, also exists in the gut without exception. The brain in the gut is simply the brain gone south," says Dr. Michael Gershon, author of The Second Brain, and chairman of the department of anatomy and cell biology at Columbia University College of Physicians and Surgeons.

In 1899, anatomists and physiologists studying dogs found that, unlike any other reflex, the continuous push of material through the digestive system continued after nerves linking the brain to the intestines were severed. In other words, they discovered the gut had a mind of its own.

Operating like our brain and looking uncannily similar to it, the gut brain responds to stimulus and is continuously active whether we're aware of it or not. But it doesn't think or feel. Feeling is held in the cerebral cortex of the brain. This "second brain" performs a different role.

"The brain in the head deals with the finer things in life: religion, philosophy, appreciation of art and music, creativity, etc.," says Dr. Gershon. "Whereas the brain in the gut deals with this dirty, messy and disgusting business of digestion. The brain in the head doesn't have to get its hands dirty with that kind of thing since it has delegated the job."

They may have different roles but our two brains are interconnected. One thousand to 2,000 nerve fibres connect them and enable the two to talk. When one gets upset, the other one does too.

"I don't think we could have made that statement a few years ago. . . . We've been finding out that the nerves in the gut independently regulate gut function, but do so in a dialogue with the nerves in our head. It's a nerve-to-nerve discussion," says Keith Sharkey, physiology and biophysics professor at the University of Calgary.

Interest in the gut brain resurfaced in the early 1980s after new technology became available.

"For the first time, we were able to see in elegant and exquisite detail the specific way that nerves went from A to B," explains Prof. Sharkey. "That gives you a chance to ask questions that could not or had not been asked before."

There are approximately 250 research laboratories now studying the enteric nervous system around the world. This new breed of neuroscientists is not only fuelling the present renaissance in the field of neurogastroenterology (study of the nerves entrenched in the lining of the esophagus, stomach, small intestine and colon), but offering insights into malfunctions of both brains.

Scientists have discovered that the gut brain may be involved in gastrointestinal disorders like ulcerative colitis, Crohn's disease and irritable bowel syndrome -- a condition that affects between 15 and 20 per cent of the population.

"Back in the days when . . . I was a medical student, I was taught that these diseases were psychosomatic. . . . But they're a real thing. Your gut can literately drive your brain crazy," notes Dr. Gershon. "If you are walking around with a burning sensation in your upper belly and it feels terrible, you can get pretty anxious. Likewise, if you've got aches and you're on the toilet with diarrhea every five minutes, it can change your personality. But it's more than that."

For many years, individuals (mostly women) with irritable bowel syndrome, a functional disorder characterized by abdominal pain, bloating, flatulence, diarrhea and/or constipation, suffered in silence. Doctors believed the illness was imagined -- all in the head.

"We now know IBS is not psychosomatic. There is an element of the brain controlling the gut which has to be born in the mind. But we now understand that there is also an organic and physiological basis for the functional changes in the little brain," declares Prof. Sharkey.

Dr. Nicholas Diamant, a gastroenterologist at Toronto Western Hospital and an emeritus professor of medicine and physiology at the University of Toronto, agrees that both brains are involved in the disorder.

"The brain sends signals down to the little brain via the spinal cord which acts as a gate for the pain signals," Dr. Diamant says. "The brain may not be closing this gate adequately to modulate and regulate the signals coming up from the gut. Therefore, the brain is letting more signals come up than it normally would."

A study by the Mayo Foundation published this August in Gastroenterology, the official journal of the American Gastroenterological Association, suggested there is genetic determinant that predicts the response to medication of IBS patients with diarrhea-predominant symptoms.

"It has to do with how the body inactivates the [neuro]transmitter serotonin. In some patients, the body inactivation is more efficient and the patient therefore responds better to the medication," explains Dr. Michael Carmilleri, professor of medicine and physiology at the Mayo Clinic in Rochester and one of the authors of the report.

"It's a landmark paper. . . . We are starting to relate changes in the signalling in the 'second brain' to real diseases based not only on functional changes but on genetic studies as well," says Prof. Sharkey.

This July, a drug came on the Canadian market to treat patients (women only) with constipation-predominant IBS. Experts say Tegaserod, known commercially as Zelnorm, is only effective in 60 to 65 per cent of people.

"IBS is defined by a series of symptoms," says Prof. Sharkey. "It's a multiple disease entity. . . . We don't understand it well enough to ever consider a miracle-type cure because it's too complicated for that."

In the case of Crohn's disease and ulcerative colitis (both autoimmune diseases), Dr. Carmilleri says the gut brain may play a role. "There is some interaction between the immune cells in the intestines and the 'second brain.' "

The discovery of the brain-gut connection also allowed scientists to learn what is at the heart of the most visceral human emotions. A gut feeling, for example, isn't just a poetic image used to convey intuition. It arises from the interplay between our two brains.

"It's a "body loop" which is activated every time we are being challenged or stressed. From a lifetime of activating this "body loop" during good or bad situations, we learn to interpret this preverbal feedback as good or bad," says Emeran Mayer, professor of medicine and physiology at the University of California -- Los Angeles.

Butterflies are minor indicators of pain and another example of this close relationship. Prof. Mayer says when one is faced with an anxiety-ridden situation, the brain in our skull sends urgent messages to our "second brain" and throws it off balance. "The big brain also becomes more sensitive to signals from the gut and amplifies them to unpleasant conscious sensations," he wrote. Therefore, one reads this response as gurgling or "butterflies" in the belly.

Stomach cramps, heartburn, diarrhea or constipation due to stress are again an illustration of the gut rising to the level of conscious perception. "The dialogue between the brain in our head and the brain in our gut sometimes goes awry. . . . in such a way that the brain in our gut responds inappropriately to stimulus," says Prof. Sharkey. In turn, the nerves tell the muscles to contract more or less or make the glands secrete more or less fluid.

Not all of the signals sent from the "second brain" to the cranial brain are bad news. "Some of the information that is being sent from the gut to the brain can establish how well the brain in the head works. . . . Your gut doesn't think for you but if it's behaving well, it can contribute to your mood being good," says Dr. Gershon. As a result, this interaction plays a role in dictating behavior and in creating human joy as well as sadness.

Scientists affirm the brain constantly communicates and listens to our "second brain." Its functions are then taken over by the brain with respect to the activation of major emotions such as fear, anxiety, anger, sadness or happiness. There is no direct proof but a lot of suggestive evidence.

"Chemicals released from cells within the 'second brain' . . . can activate vagal sensory neurons (cells high in the neck) which signal back to the brain. These vagal sensory neurons play a prominent role in many emotional processes and it is certainly conceivable that such signals play a role in generating happiness or a sense of well-being. The newborn gets its first sense of well-being from stimulation of the gut and release of chemicals through milk," wrote Prof. Mayer.

Dr. Diamant, a specialist in the mind-body connection, says each person's "second brain" reacts differently. "If you think everybody feels the same thing when the gut does something, you are in deep trouble. You have to consider the whole person and all the baggage they carry. The gut's reaction may be based on many experiences as well as the individual's genetic makeup."

It's an exciting time for scientists because research in the field of neurogastroenterology is still evolving. Even medical students are generally shocked by the "second brain's" complexity. "That hasn't really made it to the textbooks yet," says Prof. Sharkey. "It takes a few years for emerging knowledge to become dogma."

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Brain research in functional gastrointestinal disorders. new
      #14339 - 07/18/03 12:24 PM
HeatherAdministrator

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J Clin Gastroenterol. 2002 Jul;35(1 Suppl):S23-5.

Brain research in functional gastrointestinal disorders.

Ringel Y.

Division of Digestive Diseases and Nutrition, Department of Medicine, University of North Carolina at Chapel Hill, 778 Burnett-Womack, CB# 7080, Chapel Hill, NC 27599-7080, USA. ringel@med.unc.edu

The current understanding is that functional gastrointestinal disorders (FGIDs) result from dysregulation of the bidirectional communication between the gut and the brain (i.e., the brain-gut axis), modulated by various psychosocial and environmental factors (i.e., the biopsychosocial model). This concept has led to a growing interest in the research of brain function in relation to gut motor and sensory function. Brain research on the mechanisms that are involved in the generation of gastrointestinal symptoms includes studies of the gut response to brain stimulation with technique such as transcranial magnetic stimulation or studies of the brain response to gut stimulation by cortical evoked potentials, positron emission tomography, and functional magnetic resonance imaging. Studies using these techniques have shown that visceral/gut sensation involves activation of several brain regions that are associated with various brain functions, including sensation, cognition, and affect. The complexity of the brain response to visceral stimulation and the multidetermined nature of FGIDs make studies of brain function in FGID patients difficult and demands great caution in interpreting their results. Nevertheless, brain research in FGIDs is an emerging field and suggests that patients with irritable bowel syndrome differ from healthy subjects in the way that their brain response to visceral (e.g., rectal) distention. These studies emphasize the role of the central nervous system in conducting and processing visceral signals and suggest that alteration in brain processes involving perception and affective responses might be key factors in the pathogenesis of functional gastrointestinal symptoms.

Publication Types:
Review
Review, Tutorial

PMID: 12184135 [PubMed - indexed for MEDLINE]
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The gut as a neurological organ. new
      #14342 - 07/18/03 12:28 PM
HeatherAdministrator

Reged: 12/09/02
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Wien Klin Wochenschr. 2001 Sep 17;113(17-18):647-60.

The gut as a neurological organ.

Holzer P, Schicho R, Holzer-Petsche U, Lippe IT.

Department of Experimental and Clinical Pharmacology, University of Graz, Austria.

We refer to the gut as a neurological organ to emphasize the particular importance of the nervous system in the regulation of digestive functions, given that the gastrointestinal tract is innervated by five different classes of neurons: intrinsic enteric neurons, vagal afferents, spinal afferents, parasympathetic efferents and sympathetic efferents. Virtually each aspect of digestive activity is under the regulatory influence of neurons, among which the enteric nervous system (ENS) plays the most important part. The ENS acts like a brain in the gut that functions independently of the central nervous system, contains programmes for a variety of gastrointestinal behaviours and governs the activity of all gastrointestinal effector systems according to need. Intrinsic sensory neurons supply the ENS with the kind of information that this system requires for its autonomic control of digestion, whereas extrinsic afferents notify the brain about any data that are relevant to energy and fluid homeostasis and the sensation of discomfort and pain. Many diseases of the gut, particularly the functional bowel disorders, seem to be related to dysfunction of the ENS and other components of the gastrointestinal innervation. The ENS and extrinsic afferents are hence prime targets for the therapeutic management of gut diseases and for the relief of the pain and discomfort associated with these disorders.

Publication Types:
Review
Review, Tutorial

PMID: 11603099 [PubMed - indexed for MEDLINE]
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Perceptual hyperreactivity to auditory stimuli in patients with irritable bowel syndrome. new
      #14344 - 07/18/03 12:33 PM
HeatherAdministrator

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Scand J Gastroenterol. 2000 Jun;35(6):583-9.

Perceptual hyperreactivity to auditory stimuli in patients with irritable bowel syndrome.

Blomhoff S, Jacobsen MB, Spetalen S, Dahm A, Malt UF.

Dept. of Psychosomatic and Behavioral Medicine. National Hospital, Oslo, Norway.

BACKGROUND: Patients with irritable bowel syndrome (IBS) have abnormal perception of visceral stimuli; however, no study has so far investigated the perception of non-visceral stimuli in IBS. In the present study we used event-related potentials (ERP) to study whether IBS patients differed from healthy controls in processing of auditory stimuli and, if so, how this was influenced by emotions. METHODS: We compared ERPs to auditory stimuli in 40 female diarrhoea-predominant IBS patients without current psychiatric illness with those in 20 healthy controls. Tones were used as standard and target stimuli, and words with emotional content as distractors. Characteristics of the first negative wave (N100) and mean amplitudes in 50-msec time intervals between 150 and 600 msec were assessed. RESULTS: At the frontal midline electrode IBS patients had significantly enhanced N100 amplitude to all stimuli, persisting after adjustment for age, current emotions, and personality traits. They additionally had enhanced waves 200-300 msec and 400-500 msec after stimulus. The latter differences disappeared after adjustment for emotions and personality traits. CONCLUSIONS: In the frontal brain region, IBS patients seem to have a hyperreactivity to auditory stimuli compared with controls. Later elements (P300, N400) of stimulus processing were influenced by emotions and personality traits. These may possibly contribute to changes in intestinal motility caused by stress. The study indicates that aberrant brain functioning may be an element of the irritable bowel syndrome. It may elucidate a mechanism for brain-gut interaction by which psychosocial stress may influence visceral pain perception in non-psychiatric subjects with an intestinal motility disorder and also the efficacy of psychiatric treatment on IBS symptoms.

Publication Types:
Clinical Trial
Controlled Clinical Trial

PMID: 10912657 [PubMed - indexed for MEDLINE]
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Intestinal reactivity to words with emotional content and brain information processing in IBS new
      #14345 - 07/18/03 12:35 PM
HeatherAdministrator

Reged: 12/09/02
Posts: 7799
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Dig Dis Sci. 2000 Jun;45(6):1160-5.

Intestinal reactivity to words with emotional content and brain information processing in irritable bowel syndrome.

Blomhoff S, Spetalen S, Jacobsen MB, Vatn M, Malt UF.

Department of Psychosomatic and Behavioural Medicine, National Hospital, Oslo, Norway.

The intestinal reactivity to emotional experiences is poorly understood. We therefore compared healthy controls with nonpsychiatric irritable bowel syndrome (IBS) patients and IBS patients with comorbid phobic anxiety disorders with respect to rectal wall reactivity during exposure to everyday words with emotional content. We found that 70.3% of the subjects responded either with increased or decreased rectal tone during exposure to anger words, 75.0% when exposed to sadness words, and 76.6% when exposed to anxiety words. We also investigated event-related potentials in the brain to the same stimuli. We observed significant group differences in the frontal brain to sadness (P < 0.001) and anxiety (P = 0.013) distracter words, and threshold significant group difference to anger (P = 0.053) distracter words. Rectal wall reactivity during the word series significantly predicted frontal amplitude to the same word series, indicating a close interaction among mind, brain, and gut.

PMID: 10877232 [PubMed - indexed for MEDLINE]
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Regional cerebral activation in irritable bowel syndrome new
      #14348 - 07/18/03 12:36 PM
HeatherAdministrator

Reged: 12/09/02
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Gastroenterology. 2000 May;118(5):842-8.

Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention.

Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R.

Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232-5340, USA. howard.mertz@mcmail.vanderbilt.edu

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is characterized by visceral hypersensitivity, possibly related to abnormal brain-gut communication. Positron emission tomography imaging has suggested specific central nervous system (CNS) abnormalities in visceral pain processing in IBS. This study aimed to determine (1) if functional magnetic resonance imaging (fMRI) detects CNS activity during painful and nonpainful visceral stimulation; and (2) if CNS pain centers in IBS respond abnormally. METHODS: fMRI was performed during nonpainful and painful rectal distention in 18 patients with IBS and 16 controls. RESULTS: Rectal stimulation increased the activity of anterior cingulate (33/34), prefrontal (32/34), insular cortices (33/34), and thalamus (32/34) in most subjects. In IBS subjects, but not controls, pain led to greater activation of the anterior cingulate cortex (ACC) than did nonpainful stimuli. IBS patients had a greater number of pixels activated in the ACC and reported greater intensity of pain at 55-mm Hg distention than controls. CONCLUSIONS: IBS patients activate the ACC, a critical CNS pain center, to a greater extent than controls in response to a painful rectal stimulus. Contrary to previous reports, these data suggest heightened pain sensitivity of the brain-gut axis in IBS, with a normal pattern of activation.

PMID: 10784583 [PubMed - indexed for MEDLINE]
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The autonomic nervous system in functional bowel disorders. new
      #14350 - 07/18/03 12:40 PM
HeatherAdministrator

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Can J Gastroenterol. 1999 Mar;13 Suppl A:15A-17A.

The autonomic nervous system in functional bowel disorders.

Tougas G.

Digestive Diseases Research Program, Division of Gastroenterology, McMaster University, Hamilton, Canada. tougasg@fhs.mcmaster.ca

Communications along the brain-gut axis involve neural pathways as well as immune and endocrine mechanisms. The two branches of the autonomic nervous system are integrated anatomically and functionally with visceral sensory pathways, and are responsible for the homeostatic regulation of gut function. The autonomic nervous system is also a major mediator of the visceral response to central influences such as psychological stress. As defined, functional disorders comprise a constellation of symptoms, some of which suggest the presence of altered perception, while other symptoms point to disordered gastrointestinal function as the cause of the symptoms. A growing number of reports have demonstrated disordered autonomic function in subgroups of functional bowel patients. While a number of different methods were used to assess autonomic function, the reports point to a generally decreased vagal (parasympathetic) outflow or increased sympathetic activity in conditions usually associated with slow or decreased gastrointestinal motility, while other studies found either an increased cholinergic activity or a decreased sympathetic activity in patients with symptoms compatible with an increased motor activity. Under certain conditions, altered autonomic balance (including low vagal tone and increased sympathetic activity) may alter visceral perception. Autonomic dysfunction may also represent the physiological pathway accounting for many of the extraintestinal symptoms seen in irritable bowel syndrome patients and some of the frequent gastrointestinal complaints reported by patients with disorders such as chronic fatigue and fibromyalgia.

Publication Types:
Review
Review, Tutorial

PMID: 10202203 [PubMed - indexed for MEDLINE]
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Sleep and gastric function in irritable bowel syndrome: derailing the brain-gut axis new
      #14351 - 07/18/03 12:42 PM
HeatherAdministrator

Reged: 12/09/02
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Gut. 1997 Sep;41(3):390-3.

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: 9378397 [PubMed - indexed for MEDLINE]
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Gut Feelings: The Surprising Link Between Mood and Digestion new
      #14674 - 07/23/03 10:31 AM
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Gut Feelings: The Surprising Link Between Mood and Digestion

Chris Woolston

CONSUMER HEALTH INTERACTIVE

• Listening to your gut
• The stress alarm
• Functional disease in a dysfunctional world
• Setting your mind on relief

If you've ever felt your insides twist in knots before a big speech, you know the stomach listens carefully to the brain. In fact, the entire digestive system is closely tuned to a person's emotions and state of mind, says William E. Whitehead, PhD, a professor of medicine and an adjunct professor of psychology at the University of North Carolina. People with irritable bowel syndrome often suffer flare-ups during times of stress and anxiety, and even perfectly healthy people can worry their way to stomach pain, nausea, diarrhea, constipation, or other problems. Even if a doctor can't find anything physically wrong, the misery is real.

In the past -- back when scientists believed the mind and the body operated as separate entities -- some physicians wrote off digestive distress with no sign of organic disease as being "all in the head." But in recent years, that wall has crumbled. Doctors now see intricate links between the nervous system and the digestive system. The two realms constantly exchange streams of chemical and electrical messages, and anything that affects one is likely to affect the other. The connections between the two systems are so tight that scientists often refer to them as one entity: the brain-gut axis. (The brain-gut axis is a hot topic in medicine. In the summer of 2001, more than 100 researchers from around the world gathered in Los Angeles for a convention called "2001: A Brain-Gut Odyssey.") For people suffering from persistent digestive troubles unconnected to disease, such research suggests that reducing stress, depression, and anxiety may go a long way toward calming the gut.

Listening to your gut
It may surprise many people to learn that the gut actually contains as many neurons (nerve cells) as the spinal cord. In an article in the medical journal Gut, author J. D. Woods and colleagues compare this network -- known as the enteric nervous system, or ENS -- to a "local mini-brain" storing a library of programs for different patterns of gut behavior." Woods and colleagues compare the ENS to a microcomputer with its own independent software, "whereas the brain is like a larger mainframe with extended memory and processing circuits that receive information from and issue commands to the enteric computer."

With all these messages, the connection between the brain and the digestive system is a busy two-way street. The central nervous system releases chemicals (acetylcholine and adrenaline) that tell the stomach when to produce acid, when to churn, and when to rest. Similar signals help guide the movements of the intestines. The digestive system responds by sending electrical messages to the brain, creating such sensations as hunger, fullness, pain, nausea, discomfort, and possibly sadness and joy.

As strange as it sounds, our guts just might help shape our moods, says Emeran Mayer, MD, a gastroenterologist and the chairman of the new Mind-Body Collaborative Research Center at the University of California at Los Angeles. Mayer points to the vagus nerve, essentially a large electrical cable that runs between the brain and the digestive system. "Doctors once believed the nerve's main job was controlling acid production in the stomach," Mayer says. "But 95 percent of the fibers go the other direction -- from the gut to the brain."

Nobody knows exactly what messages travel along this cable, but scientists have found that stimulating the nerve at different frequencies can cause either anxiety or a strong sense of well being. Perhaps the term "gut feeling" isn't just a figure of speech after all.

Mayer suggests another intriguing possibility: Prozac and similar antidepressants may actually work on the gut, not the brain. Drugs known as SSRIs (short for selective serotonin reuptake inhibitors) ease depression by enhancing levels of serotonin. Most experts assume it's the extra serotonin in the brain that helps improve mood. But 95 percent of the serotonin in the body actually lies within the digestive system. Perhaps, Mayer says, SSRIs do their job by boosting serotonin in the gut and changing the signals along the vagus nerve.

The stress alarm
Whatever messages may be passing back and forth, they can easily become garbled in times of stress. When the brain senses a threat, real or imagined, it sounds the alarm by flooding the body with adrenaline and another hormone called CRF (short for corticotropin-releasing factor). These hormones trigger the "fight or flight" response -- helpful back in the days when humans had to run from lions, but a potential liability when we lose a job or go through a divorce.

If you suffer from frequent emotional distress -- perhaps because of extreme stress, depression, or anxiety -- the unrelenting flood of adrenaline and CRF will take a toll on your digestive system. For one thing, the hormones can make the cells in the stomach and intestines extra-sensitive to pain. As a result, normal contractions and movements can become excruciating. The new signals can also disrupt the motion of the intestines, causing bouts of constipation or diarrhea.

Functional disease in a dysfunctional world
Because of the close connection between the brain and many abdominal disorders, a multinational team of investigators, specialists, and federal research agencies convened in the mid-1980s to develop criteria for diagnosing more than 20 digestive disorders known as "Functional Gastrointestinal Disorders," or FGIDs. A "functional" disease, in this case, means a disturbance in GI function that it isn't related to any injury, infection, or other obvious physical problem. These criteria, which include persistent constipation, diarrhea, bloating, abdominal pain, or irritable bowel syndrome unrelated to diagnosable physical disorder, was recently updated by an international team known as the Rome II Committee, which called for a classification system of these disorders based on clusters of common symptoms.

Among the disorders the committee examined is irritable bowel syndrome (IBS), a very common and perplexing malady often characterized by painful cramps, bloating, and constipation alternating with diarrhea. If you have "functional" IBS, you may feel that "dysfunctional" is a much more apt term.

Emotional distress alone can't cause IBS -- the source of the disorder is still unknown -- but stress or a mood disorder may worsen the symptoms. In fact, few other conditions provide such a clear illustration of the link between the mind and the body. One recent Australian study found that chronic distress -- arising from such traumas as divorce, lawsuits, serious illnesses, or job troubles -- accounted for 97 percent of all changes in IBS symptoms. Interestingly, short-term swings in mood don't seem to have much effect on IBS, which explains why many people still suffer symptoms on relatively calm, relaxing days.

In a similar manner, strange messages along the gut-brain axis also seem to be a major cause of "functional" dyspepsia, or indigestion. People with dyspepsia often experience the discomfort of constant ulcer pain without actually having ulcers. Stress definitely makes the symptoms worse, but the effect isn't nearly as dramatic as with irritable bowel syndrome. If adding stress to functional dyspepsia is like throwing woodchips on a fire, combining stress with IBS is like dousing a blaze with gasoline.

The influence of the mind on the gut goes beyond functional diseases. For instance, people with Crohn's disease or ulcerative colitis -- two conditions with clearly physical origins -- often suffer flareups during times of emotional stress. And in a recent survey, 68 percent of people with basically healthy digestive systems said stress gives them stomachaches.

Setting your mind on relief
So what can you do if your mind and your digestive system aren't getting along? One thing you shouldn't do is suffer silently. Ask your doctor if you would be a good candidate for cognitive behavioral therapy, interpersonal therapy, relaxation therapy, or another form of counseling. In several studies, these treatments have been shown to give IBS patients more relief than standard medical therapies. You might even consider hypnosis or self-hypnosis.

While rarely used in the United States, hypnosis is a popular -- and apparently effective -- treatment for IBS in Europe, Whitehead says. Preliminary studies suggest it may also help ease functional dyspepsia.

It's worth noting that Prozac and other SSRIs may help calm the stomach. Small doses of a tricyclic antidepressant -- too small to affect mood -- can lessen stomach pain, presumably by blocking pain messages.

There's another reason to go to the doctor: Simply hearing you're not crazy or gravely ill may be a great source of comfort. "Reassurance from a physician is probably the most effective treatment [for IBS]," Mayer says.

Supportive docs will never go out of style, but even better treatments for IBS and other functional disorders may soon be on the way. Researchers are currently studying medications designed to block the release of CRF, the hormone that helps translate stress into stomach trouble. Mayer says the medication may be available in a little more than a year.

But you don't have to wait that long to get better. Do what you can to avoid stress and work closely with your doctor. With a little luck, your gut feelings will be much more pleasant.

-- Chris Woolston, M.S., is a health and medical writer with a master's degree in biology. He is a contributing editor at Consumer Health Interactive, and was the staff writer at Hippocrates, a magazine for physicians. He has also covered science issues for Time Inc. Health, WebMD, and the Chronicle of Higher Education. His reporting on occupational health earned him an award from the northern California Society of Professional Journalists.



References

D.A. Drossman. The functional gastroinestinal disorders and the Rome II process. Gut, September 1999, Volume 45, Supplement II.

Babette S. Duncan, Pharm.D., Walter "Buzz" Stewart, Ph.D., MPH. Gastrointestinal Disorders. Innovative Medical Research (IMR), AdvancePCS.

Emeran Mayer, telephone interview.

Rome II: A Multinational Consensus Document on Functional Gastrointestinal Disorders. Gut: An International Journal of Gastroenterology and Hepatology. September 1999, No. II, Vol. 45.

UCLA-The Inside TRAK. Does stress cause IBS or similar disorders in other
parts of the GI tract?

J.D. Wood et al. Fundamentals of neurogastroenterology. Gut, September 1999. Volume 45. Supplement II.

William Whitehead, telephone interview.

Wilhelmsen I. The role of psychosocial factors in gastrointestinal
disorders. Gut. December 2000


Wilhelmsen I. Brain-gut axis as an example of the bio-psycho-social model.
Gut.


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Reviewed by George W. Meyer, MD, FACP, a staff gastroenterologist at Kaiser Permanente in Sacramento, Calif.; and John Inadomi, MD, a gastroenterologist and assistant professor of medicine at the University of Michigan Medical Center.

First published August 27, 2001
Last updated July 17, 2003
Copyright © 2001 Consumer Health Interactive

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

Introduction
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
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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

http://immune.altmedangel.com/gutbrain.htm



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Images Show a Snub Really Is Like Kick in the Gut new
      #24042 - 10/20/03 03:43 PM
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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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The human enteric nervous system new
      #69651 - 05/11/04 07:10 PM
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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.

http://www.blackwellpublishing.com/abstract.asp?ref=1350-1925&vid=16&iid=1&aid=12&s=1&site=1

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

Agata Mulak , Bruno Bonaz

Summary:
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.

http://www.docguide.com/news/content.nsf/PaperFrameSet?OpenForm&refid=2&id=48DDE4A73E09A969852568880078C249&c=&newsid=8525697700573E1885256E76006051C8&u=http://www.medscimonit.com/medscimonit/modules.php?name=Current_Issue&d_op=summary&id=4126&ref=/news/content.nsf/SearchResults?openform&Query=ibs&so=date&id=48DDE4A73E09A969852568880078C249

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



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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




Abstract

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

http://www.blackwellpublishing.com/abstract.asp?ref=1350-1925&vid=16&iid=3&aid=6&s=&site=1



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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
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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
Summary
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.

Introduction
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.




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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

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.

Reliability
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.

Validity
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.




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Next Page: Discussion

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.

Acknowledgements

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: emayer@ucla.edu.

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

http://www.medscape.com/viewarticle/482645?src=mp

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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

http://www.mdlinx.com/GILinx/thearts.cfm?artid=1041730&specid=13&ok=yes

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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



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Volume 20: Supplement 7

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

M. D. Gershon

Abstract

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.

http://www.mdlinx.com/GILinx/thearts.cfm?artid=1095562&specid=13&ok=yes

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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.


http://www.medscape.com/viewarticle/463521_3

Copyright © 2003 Medscape.

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A Neurobiology of Sensitivity? new
      #267543 - 06/04/06 12:16 PM
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A Neurobiology of Sensitivity? New Study Suggests a Link
Between Environmental Sensitivity and Anomalous Perceptions

Vienna, Virginia (April 24, 2006) – People with a 'sensitive' personality type are far more likely to report apparitional experience, according to a paper in the current issue of the Journal of the Society for Psychical Research. Such persons commonly report longstanding allergies, chronic pain and fatigue, depression, migraine headaches, or sensitivity to light, sound, and smell. These individuals are also more likely to report that immediate family members suffered from the same conditions. The survey raises the question of whether a 'neurobiology of sensitivity' could underlie reports of apparitional experience occurring across societies and throughout history.

Sixty-two self-described 'sensitives' participated in the study, along with 50 individuals serving as controls who did not profess any outstanding forms of sensitivity. Persons in the former group were 3.5 times as likely, on average, to assert that they'd had an apparitional experience (defined as perceiving something that could not be verified as being physically present through normal means). Sensitive persons were also 2.5 times as likely to indicate that an immediate family member was affected by similar physical, mental or emotional conditions.

Overall, 8 of the 54 factors asked about in the survey were found to be significant in the makeup of a sensitive personality:

Being female
Being a first-born or only child
Being single
Being ambidextrous
Appraising oneself as imaginative
Appraising oneself as introverted
Recalling a plainly traumatic event (or events) in childhood
Maintaining that one affects - or is affected by – lights, computers, and other electrical appliances in an unusual way.

Additionally, synesthesia – the scientifically recognized condition of overlapping senses, such as hearing colors or tasting shapes – was reported by approximately 10% of the sensitive group but not at all among controls.

This finding gives added weight to the possibility that apparitional perceptions stem from an underlying neurobiology of sensitivity.

"It seems quite possible," writes study author Michael Jawer, "that certain individuals are, from birth onward, disposed to a number of conditions, illnesses, and perceptions that, in novelty as well as intensity, distinguish them from the general population. If so, apparitional experience might have a bona fide neurobiological basis that makes it accessible to scientific inquiry."

The paper is posted online at http://cogprints.org/4846/. The Society for Psychical Research, founded in 1882 by a distinguished group of Cambridge University scholars, is the foremost British organization for the scientific study of anomalous perceptions. Its website is http://www.spr.ac.uk/.


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An international study of irritable bowel syndrome: Family relationships and mind-body attributions new
      #267544 - 06/04/06 12:28 PM
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Social Science & Medicine 62 (2006) 2838–2847

An international study of irritable bowel syndrome: Family
relationships and mind-body attributions

Mary-Joan Gersona,, Charles D. Gerson, Richard A. Awad, Christine Dancey, Pierre Poitrase, Piero Porcellif, Ami D. Sperberg

Irritable bowel syndrome (IBS) is a functional gastrointestinal illness, characterized by potentially debilitating symptoms without pathologic findings, often associated with psychological conditions. Little is known about the psychosocial aspects of this condition on an international scale. A total of 239 patients in eight countries were given a series of psychological and medical questionnaires, including IBS activity, relationships with significant others, beliefs regarding the etiology of symptoms, and assessment of quality of life. There were highly significant associations between IBS severity and all other measures. Symptoms were worse if relationship conflict was high and if attributions about illness were physiological rather than psychological. Symptoms were less severe if relationship depth and support were high, and illness was viewed as psychological. Implications for treatment are discussed.

r 2005 Elsevier Ltd. All rights reserved.

Full study is available in PDF format. Mind Body Survey

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The Effectiveness of Hypnotherapy in the Management of Irritable Bowel Syndrome new
      #288015 - 10/26/06 10:16 AM
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From Alimentary Pharmacology & Therapeutics

The Effectiveness of Hypnotherapy in the Management of Irritable Bowel Syndrome

Posted 10/03/2006

S. Wilson; T. Maddison; L. Roberts; S. Greenfield; S. Singh


Aim: To systematically review the literature evaluating hypnotherapy in the management of irritable bowel syndrome (IBS).

Methods: Electronic databases were searched (Cochrane Library, Medline, CINAHL, AMED, Embase, PsycINFO, CISCOM, TRIP and the Social Science Citation index), bibliographic references scanned and main authors contacted. No restrictions were placed on language or publication year. Eligible studies involved adults with IBS using single-component hypnotherapy. All studies, except single case or expert opinion, were sought and all patient-related outcomes eligible.

Results: Out of 299 unique references identified, 20 studies (18 trials of which four were randomized, two controlled and 12 uncontrolled) and two case series were eligible. These tended to demonstrate hypnotherapy as being effective in the management of IBS. Numbers of patients included were small. Only one trial scored more than four out of eight on internal validity.

Conclusion: The published evidence suggests that hypnotherapy is effective in the management of IBS. Over half of the trials (10 of 18) indicated a significant benefit. A randomized placebo-controlled trial of high internal validity is necessary to establish the effectiveness of hypnotherapy in the management of IBS. Until such a trial is undertaken, this form of treatment should be restricted to specialist centres caring for the more severe forms of the disorder.

Introduction
Irritable bowel syndrome (IBS) is a chronic disorder affecting 10-20% of the population.[1,2] It is estimated that a general practitioner in the UK sees eight patients with IBS every week[3] and these patients constitute up to 50% of gastroenterology referrals.[4-7] The quality of life (QOL) of patients with IBS is surprisingly poor, particularly in the population seeking professional health care,[8] with over 40% of those referred to hospital out-patients reporting avoidance of some activities[9] and some studies have indicated that the impact of IBS on QOL is as great as that observed for congestive heart failure[10] and stroke.[11] Health service costs, both direct[12,13] and indirect,[14-16] are high.

Conventional therapy leaves up to 25% of sufferers without relief of symptoms[17] and many patients have been reported to turn to alternative therapies.[18]'Gut-directed hypnotherapy' (GDH), a type of hypnosis, is one of the alternative therapies most frequently reported to have a demonstrable beneficial therapeutic impact on IBS symptoms.[19,20] GDH is based on the use of hypnotic induction, using progressive relaxation and other techniques, followed by imagery directed towards control and normalization of gut function.[20] Therapy also aims to teach autohypnosis, to enable patients to manage their own symptoms without ongoing reliance on primary or secondary care, although occasional refresher sessions may be required.

The first paper to report an evaluation of GDH in the management of IBS was published 20 years ago[20] and indicated a significant benefit over placebo, in patients referred to a specialist centre for the management of refractory IBS. A more recent audit of patients treated in this hypnotherapy unit, reported that GDH may also confer longer term benefits and reduced health care costs as a result of lower consultation rates and medication use.[21] Such studies suggest benefits would be achieved by the more widespread use of GDH in the management of IBS.

Four reviews of the published evidence relating to the role of hypnotherapy in the management of IBS have been previously published with conflicting conclusions.[22-25] The first review[24] concluded that hypnotherapy was effective in the management of refractory IBS, with suggested models of implementation focusing on the training of primary and community care staff (nurses, physiotherapists and occupational therapists). However, this review limited searches to only one database (CISCOM) and no detail was provided with respect to the search strategy or years searched, how inclusion criteria were applied, how judgements of validity were made or the process of data extraction. Spanier's review aimed to determine the effectiveness of alternative therapies,[25] including hypnotherapy, for the treatment of IBS but was also limited to only one bibliographic database (Medline) and excluded all non-English language studies; language restrictions may compromise the validity of a systematic review, but potentially more so in the areas of alternative therapy where major developments have occurred outside of the English speaking world.[26] This review concluded that the studies identified (n = 3) were of poor quality and further research was necessary to determine the efficacy of hypnotherapy. Two recent reviews have included differing studies; Tan et al.[22] included six controlled trials and concluded that hypnosis consistently produces significant results, and, Whitehead[23] included five controlled studies and concluded that hypnosis has a substantial therapeutic impact on IBS.

The number of primary studies and reviews suggesting that GDH may have significant value in the management of IBS and the lack of a high quality systematic review, provided the impetus to conduct this systematic review, which addresses the question of whether hypnotherapy is effective in the management of IBS.



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Section 1 of 4 Next Page: Methods



S. Wilson*, T. Maddison*, L. Roberts*, S. Greenfield* & S. Singh† on Behalf of the Birmingham IBS Research Group

*Division of Primary Care, Public & Occupational Health, Department of Primary Care and General Practice, University of Birmingham, Birmingham B15 2TT, UK
†Good Hope NHS Trust, Birmingham B75 7RR, UK


Competing Interests: None of the authors have any competing interests to declare.


Aliment Pharmacol Ther. 2006;24(5):769-780. ©2006 Blackwell Publishing


http://www.medscape.com/viewarticle/543563

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Stress, the Brain-Gut Axis, and IBS new
      #311401 - 07/17/07 11:34 AM
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Stress and the Emotional Motor System (EMS)
eCAM Advance Access published online on May 17, 2007
eCAM, doi:10.1093/ecam/nem046

Min/Body Psychological Treatments for Irritable Bowel Syndrome
Bruce D. Naliboff1,2,3, Michael P. Fresé1,2,3 and Lobsang Rapgay2
1UCLA Center for Neurovisceral Sciences and Women's Health, 2Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA and 3Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA, USA




A variety of experimental and clinical studies support the model described above. In general, IBS patients show altered perception of visceral events that is characterized by hypervigilance, hypersensitivity and increased autonomic arousal (16,17). While peripheral GI factors may play a role in subsets of patients with IBS (e.g. post-infectious IBS), there is converging clinical and neurobiologic research to suggest that enhanced central stress responsiveness involving anxiety may provide a specific mechanism for enhanced visceral sensitivity found in these disorders (11). GI symptom-specific anxiety may be an especially important variable leading to increased pain sensitivity, hypervigilance and poor coping (18,19). Mild psychologic stress increases visceral perception in IBS patients but not in healthy controls (20) and IBS symptoms are exacerbated following stressful life events (21). We have also recently shown that visceral-specific anxiety appears to be particularly important in IBS and may be the primary element in mediating the impact between changes in symptom severity and changes in quality of life in IBS sufferers (18). Recent brain imaging findings have now begun to show the central circuitry that may underlie many of the observations described above (22). For example, patients with IBS during visceral stimulation show increased activation in the anterior cingulate cortex, a brain region involved in vigilance and discomfort during physical and social situations (23).

http://ecam.oxfordjournals.org/cgi/content/full/nem046v1#SEC3



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Colonic Hypersensitivity in IBS - Brain or Gut? new
      #314950 - 09/13/07 12:04 PM
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Gut 2007;56:1202-1209
Copyright © 2007 BMJ Publishing Group Ltd & British Society of Gastroenterology


Increased colonic pain sensitivity in irritable bowel syndrome is the result of an increased tendency to report pain rather than increased neurosensory sensitivity

Spencer D Dorn1, Olafur S Palsson1, Syed I M Thiwan1, Motoyori Kanazawa2, W Crawford Clark3, Miranda A L van Tilburg1, Douglas A Drossman1, Yolanda Scarlett1, Rona L Levy4, Yehuda Ringel1, Michael D Crowell5, Kevin W Olden6 and William E Whitehead1

1 Center for Functional GI and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2 Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
3 Department of Psychiatry, Columbia University, New York, NY, USA
4 School of Social Work, University of Washington, Seattle, WA, USA
5 Mayo Clinic Scottsdale, Scottsdale, AZ, USA
6 Division of Gastroenterology, University of Arkansas, Little Rock, AR, USA


ABSTRACT
Objective: The aim was to determine whether lower visceral pain thresholds in irritable bowel syndrome (IBS) primarily reflect physiological or psychological factors.

Methods: Firstly, 121 IBS patients and 28 controls underwent balloon distensions in the descending colon using the ascending methods of limits (AML) to assess pain and urge thresholds. Secondly, sensory decision theory analysis was used to separate physiological from psychological components of perception: neurosensory sensitivity (p(A)) was measured by the ability to discriminate between 30 mm Hg vs 34 mm Hg distensions; psychological influences were measured by the report criterion—that is, the overall tendency to report pain, indexed by the median intensity rating for all distensions, independent of intensity. Psychological symptoms were assessed using the Brief Symptom Inventory (BSI).

Results: IBS patients had lower AML pain thresholds (median: 28 mm Hg vs 40 mm Hg; p<0.001), but similar neurosensory sensitivity (median p(A): 0.5 vs 0.5; p = 0.69; 42.6% vs 42.9% were able to discriminate between the stimuli better than chance) and a greater tendency to report pain (median report criterion: 4.0 ("mild" pain) vs 5.2 ("weak" pain); p = 0.003). AML pain thresholds were not correlated with neurosensory sensitivity (r = –0.13; p = 0.14), but were strongly correlated with report criterion (r = 0.67; p<0.0001). Report criterion was inversely correlated with BSI somatisation (r = –0.26; p = 0.001) and BSI global score (r = –0.18; p = 0.035). Similar results were seen for the non-painful sensation of urgency.

Conclusion: Increased colonic sensitivity in IBS is strongly influenced by a psychological tendency to report pain and urge rather than increased neurosensory sensitivity.

http://gut.bmj.com/cgi/content/abstract/56/9/1202?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Firstly%2C+it+underscores+the+importance+of+accounting+for+psychological+factors+w&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT


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Daily stress and gastrointestinal symptoms in women with irritable bowel syndrome new
      #320209 - 12/06/07 04:41 PM
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Nurs Res. 2007 Nov-Dec;56(6):399-406.

Daily stress and gastrointestinal symptoms in women with irritable bowel syndrome.Hertig VL, Cain KC, Jarrett ME, Burr RL, Heitkemper MM.

Department of Biobehavioral Nursing & Health Systems, University of Washington, Seattle, WA 98195, USA.

BACKGROUND: Stress has been implicated as contributing to the initiation and exacerbation of bowel and discomfort symptoms in patients with irritable bowel syndrome (IBS).

OBJECTIVE: To examine the relationships of daily self-reported stress to gastrointestinal (GI) and psychological distress symptoms both across women and within woman in a comparison group of women without IBS and among subgroups of women with IBS.

METHODS: Women with IBS (n = 181; age = 18-49 years) who were divided into subgroups based on bowel pattern (constipation, n = 52; diarrhea, n = 67; alternating, n = 62) were compared to a group of women without IBS (n = 48). Self-report stress measures; abdominal (abdominal pain, bloating, and intestinal gas), bowel pattern (constipation, diarrhea), and intestinal gas; and psychological (anxiety and depression) distress symptoms were obtained daily over 1 month. Across-women and within-woman analyses were used.

RESULTS: There were significant across-women correlations among mean daily stress, psychological distress, and GI symptoms in the total IBS group and the IBS bowel pattern subgroups. The across-women relationships between daily stress and GI symptoms were diminished when anxiety and depression were controlled in the analyses. Within-woman analyses showed little evidence of relationship between day-to-day variations in stress and day-to-day variations in GI symptoms; however, stress was strongly related to anxiety and depression.

DISCUSSION: Gastrointestinal symptom distress is associated with self-reported stress in women with IBS. Psychological distress moderates the effects of stress on GI symptoms. The IBS treatment protocols that incorporate strategies that decrease stress and psychological distress are likely to reduce GI symptoms.

PMID: 18004186 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=18004186&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

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Women With IBS Can't Switch Off Pain Response new
      #322639 - 01/18/08 12:39 PM
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J Neurosci. 2008 Jan 9;28(2):349-59.

Reduced brainstem inhibition during anticipated pelvic visceral pain correlates with enhanced brain response to the visceral stimulus in women with irritable bowel syndrome.

Berman SM, Naliboff BD, Suyenobu B, Labus JS, Stains J, Ohning G, Kilpatrick L, Bueller JA, Ruby K, Jarcho J, Mayer EA.

Department of Medicine, University of California, Los Angeles Center for Neurovisceral Sciences and Women's Health, David Geffen School of Medicine at University of California, Los Angeles, 90073, USA.

Cognitive factors such as fear of pain and symptom-related anxiety play an important role in chronic pain states. The current study sought to characterize abnormalities in preparatory brain response before aversive pelvic visceral distention in irritable bowel syndrome (IBS) patients and their possible relationship to the consequences of distention. The brain functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) response to anticipated and delivered mild and moderate rectal distention was recorded from 14 female IBS patients and 12 healthy controls. During cued anticipation of distention, activity decreased in the insula, supragenual anterior cingulate cortex (sACC), amygdala, and dorsal brainstem (DBS) of controls.

IBS patients showed less anticipatory inactivation. Group differences were significant in the right posterior insula and bilateral DBS. Self-rated measures of negative affect during scanning were higher in patients than controls (p < 0.001), and the anticipatory BOLD decreases in DBS were inversely correlated with these ratings.

During subsequent distention, both groups showed activity increases in insula, dorsal ACC, and DBS and decreases in the infragenual ACC. The increases were more extensive in patients, producing significant group differences in dorsal ACC and DBS. The amplitude of the anticipatory decrease in the pontine portion of DBS was associated with greater activation during distention in right orbitofrontal cortex and bilateral sACC.

Both regions have been associated previously with corticolimbic inhibition and cognitive coping. Deficits in preparatory inhibition of DBS, including the locus ceruleus complex and parabrachial nuclei, may interfere with descending corticolimbic inhibition and contribute to enhanced brain responsiveness and perceptual sensitivity to visceral stimuli in IBS.

PMID: 18184777 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/pubmed/18184777?ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

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Mind/Body psychological treatments for irritable bowel syndrome new
      #343425 - 03/18/09 05:47 PM
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Evid Based Complement Alternat Med. 2008 Mar;5(1):41-50.

Mind/Body psychological treatments for irritable bowel syndrome.

Naliboff BD, Fresé MP, Rapgay L.

UCLA Center for Neurovisceral Sciences and Women's Health, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA and Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA, USA.

Currently, the goal of treatment for those with irritable bowel syndrome (IBS) is to improve the quality of life through a reduction in symptoms. While the majority of treatment approaches involve the use of traditional medicine, more and more patients seek out a non-drug approach to managing their symptoms. Current forms of non-drug psychologic or mind/body treatment for IBS include hypnotherapy, cognitive behavioral therapy and brief psychodynamic psychotherapy, all of which have been proven efficacious in clinical trials. We propose that incorporating the constructs of mindfulness and acceptance into a mind/body psychologic treatment of IBS may be of added benefit due to the focus on changing awareness and acceptance of one's own state which is a strong component of traditional and Eastern healing philosophies.

PMID: 18317547 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/pubmed/18317547?ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

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Olfactory and gustatory function in irritable bowel syndrome new
      #356745 - 03/16/10 11:24 AM
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Eur Arch Otorhinolaryngol. 2009 Dec 30.

Olfactory and gustatory function in irritable bowel syndrome.

Steinbach S, Reindl W, Kessel C, Ott R, Zahnert T, Hundt W, Heinrich P, Saur D, Huber W.

Department of Otorhinolaryngology, Philipps University, Deutschhausstrasse 3, 35037, Marburg, Germany,

Irritable bowel syndrome (IBS) is the most common, functional disorder diagnosed by gastroenterologists. It is still unclear whether IBS has a central etiology, e.g., hyperreactivity of the brain, or a peripheral etiology, e.g., stimulation of olfactory/gustatory receptors on enterochromaffin cells, followed by serotonin release and changed gut motility. Testing the odor identification (ID), odor discrimination (DIS) and odor threshold (THR) as well as the total taste and the taste qualities "sweet", "sour", "salty" and "bitter" should be of help for determining the etiology. To our knowledge, this is the first study investigating the olfactory/gustatory function in IBS patients. The olfactory/gustatory function of 43 patients (32 women, 11 men) suffering from IBS as defined by the ROME III criteria was investigated by means of validated tests (Sniffin' Sticks and taste strips). Compared to normative data, scores of THR were decreased and scores of ID and DIS were increased in IBS patients. Additionally, when compared to normative data, there was no difference in the taste function of IBS patients. Assuming that THR reflects more the peripheral olfactory function, whereas ID and DIS are influenced by central activity, and that taste did not differ in IBS patients compared to normative data, this supports the idea of a central etiology of IBS.

PMID: 20041259 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/20041259

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Brain-gut axis dysfunction in IBS new
      #356746 - 03/16/10 11:27 AM
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Gastroenterol Clin Biol. 2009 Feb;33 Suppl 1:S48-58.

Brain-gut axis dysfunction

Bonaz B, Sabate JM.

Clinique Universitaire d'Hépato-Gastroentérologie et Stress et Interactions neuro-Digestives, Grenoble Institut des Neurosciences (GIN, Centre de Recherche INSERM U836-UJF-CEA-CHU), CHU de Grenoble, BP217, 38043 Grenoble cedex 09, France.

There is a bidirectional relation between the central nervous system and the digestive tract, i.e., the brain-gut axis. Numerous data argue for a dysfunction of the brain-gut axis in the pathophysiology of irritable bowel syndrome (IBS). Visceral hypersensitivity is a marker of IBS as well as of an abnormality of the brain-gut axis. This visceral hypersensitivity is peripheral and/or central in origin and may be the consequence of digestive inflammation or an anomaly of the nociceptive message treatment at the spinal and/or supraspinal level. Stress is involved in the genesis and maintenance of IBS. Disturbances of the autonomic nervous system are observed in IBS as a consequence of brain-gut axis dysfunction. The contribution of the neurosciences, in particular brain imaging techniques, has contributed to the better understanding of IBS physiopathology. The better knowledge of brain-gut axis dysfunction has therapeutic implications, either through drugs and/or cognitive and behavioral therapies.

PMID: 19303539 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/19303539

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Women With IBS Show Changes In Their Brains new
      #359993 - 07/28/10 11:01 AM
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Study finds structural brain alterations in patients with irritable bowel syndrome

A large academic study has demonstrated structural changes in specific brain regions in female patients with irritable bowel syndrome (IBS), a condition that causes pain and discomfort in the abdomen, along with diarrhea, constipation or both. A collaborative effort between UCLA and Canada's McGill University, the study appears in the July issue of the journal Gastroenterology. The findings show that IBS is associated with both decreases and increases in grey matter density in key areas of the brain involved in attention, emotion regulation, pain inhibition and the processing of visceral information.

IBS affects approximately 15 percent of the U.S. population, primarily women. Currently, the condition is considered by the medical field to be a "functional" syndrome of the digestive tract not working properly rather than an "organic" disorder with structural organ changes. Efforts to identify structural or biochemical alterations in the gut have largely been unsuccessful. Even though the pathophysiology is not completely understood, it is generally agreed that IBS represents an alteration in brain-gut interactions. These study findings, however, show actual structural changes to the brain, which places IBS in the category of other pain disorders, such as lower back pain, temporomandibular joint disorder, migraines and hip pain — conditions in which some of the same anatomical brain changes have been observed, as well as other changes.

A recent, smaller study suggested structural brain changes in IBS, but a larger definitive study hadn't been completed until now. "Discovering structural changes in the brain, whether they are primary or secondary to the gastrointestinal symptoms, demonstrates an 'organic' component to IBS and supports the concept of a brain-gut disorder," said study author Dr. Emeran Mayer, professor of medicine, physiology and psychiatry at the David Geffen School of Medicine at UCLA." Also, the finding removes the idea once and for all that IBS symptoms are not real and are 'only psychological.'The findings will give us more insight into better understanding IBS."

Researchers employed imaging techniques to examine and analyze brain anatomical differences between 55 female IBS patients and 48 female control subjects. Patients had moderate IBS severity, with disease duration from one to 34 years (average 11 years). The average age of the participants was 31. Investigators found both increases and decreases of brain grey matter in specific cortical brain regions. Even after accounting for additional factors such as anxiety and depression, researchers still discovered differences between IBS patients and control subjects in areas of the brain involved in cognitive and evaluative functions, including the prefrontal and posterior parietal cortices, and in the posterior insula, which represents the primary viscerosensory cortex receiving sensory information from the gastrointestinal tract.

"The grey-matter changes in the posterior insula are particularly interesting since they may play a role in central pain amplification for IBS patients," said study author David A. Seminowicz, Ph.D., of the Alan Edwards Centre for Research on Pain at McGill University. "This particular finding may point to a specific brain difference or abnormality that plays a role in heightening pain signals that reach the brain from the gut." Decreases in grey matter in IBS patients occurred in several regions involved in attentional brain processes, which decide what the body should pay attention to. The thalamus and midbrain also showed reductions, including a region — the periaqueductal grey — that plays a major role in suppressing pain. "Reductions of grey matter in these key areas may demonstrate an inability of the brain to effectively inhibit pain responses," Seminowicz said. The observed decreases in brain grey matter were consistent across IBS patient sub-groups, such as those experiencing more diarrhea-like symptoms than constipation. "We noticed that the structural brain changes varied between patients who characterized their symptoms primarily as pain, rather than non-painful discomfort," said Mayer, director of the UCLA Center for Neurobiology of Stress. "In contrast, the length of time a patient has had IBS was not related to these structural brain changes." Mayer added that the next steps in the research will include exploring whether genes can be identified that are related to these structural brain changes. In addition, there is a need to increase the study sample size to address male-female differences and to determine if these brain changes are a cause or consequence of having IBS.

The study was funded by the National Institutes of Health. Additional authors include M. Catherine Bushnell, Ph.D., of McGill University, and Jennifer B. Labus, Joshua A. Bueller, Kirsten Tillisch and Bruce D. Naliboff, Ph.D., all of UCLA.

Author:
Rachel Champeau

http://www.semel.ucla.edu/news/10/jul/22/study-finds-structural-brain-alterations-patients-irritable-bowel-syndrome


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Does bacteria connect the brain and the gut? new
      #370313 - 09/27/13 11:44 AM
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Anxiety In Your Head Could Come From Your Gut

Sept. 12, 2013
By SUSAN DONALDSON JAMES


Dr. James Greenblatt, a Boston-area psychiatrist, had a puzzling case: a teenager arrived in his office with severe obsessive–compulsive disorder (OCD), as well as attention deficit hyperactivity disorder (ADHD) and an array of digestive problems.

"Mary's parents had been running around for many years and she'd had a poor response to medicine," said Greenblatt, founder of Comprehensive Psychiatric Resources Inc. in Waltham, Mass. "When a patient doesn't respond, that's a red flag."

Greenblatt first did a simple urine test for the metabolite HPHPA, the chemical byproduct of the clostridia bacteria, and found that it was elevated. He put her on a course of high-powered probiotics to boost her good bacteria, followed by antibiotics, and her levels began to "dramatically" go down, he said.

After six months, Mary's symptoms began to disappear. And by a year, they were gone. Today, three years later, Mary is a senior in high school and has no sign of either mental disorder.

Read about the ins and outs of gut bacteria.

Greenblatt does not practice alternative medicine; his expertise is in psychopharmacology and he is a clinical faculty member at Tufts Medical School.

"I start with integrative medicine, but I have my prescription pad right by my side," he told ABCNews.com.

Greenblatt, like many others, are beginning to recognize the power of healthy gut bacteria. The average adult carries up to five pounds of bacteria -- trillions of microbes -- in their digestive tract alone.

A recent study in the journal Science showed that thin and fat people have different bacteria -- a discovery that could lead to weight-loss programs. Doctors have also been using fecal transplants to seniors when their gastrointestinal health is compromised in nursing home living.

And now, scientists think there may be a link between what's in your gut and what's in your head, suggesting that bacteria may play a role in disorders such as anxiety, schizophrenia and autism. In some patients, the strep bacterium has been linked to OCD in a condition known as PANDAS.

Strep throat can trigger obsessive-compulsive disorder.

A study published in Nutritional Neuroscience from The Great Plains Laboratory, has shown that HPHPA levels are much higher in the urine of autistic children. Those treated with antibiotics effective against the bacteria clostridia show a decrease in symptoms.

Babies are born with a sterile digestive tract and first acquire their bacteria while traveling through the birth canal and get more in breast milk and in the world outside the womb through contact with other people.

Greenblatt said he had treated hundreds of patients for dysbiosis, a condition of microbial imbalances on or inside the body. "It's a more common scenario than we know," he said.

Scientists are so far unable to identify every strain of bacteria, but they can test for the chemical byproducts that they produce, according to Greenblatt.

He said he checks every patient for HPHPA with a simple organic acid urine test before moving ahead with medications to treat symptoms.

"Eight out of 10 people are fine," he said. "But in the two patients where it's elevated, it can have profound effects on the nervous system."

"I don't know why this test isn't done on every psychiatric patient," he said. 'I question that every day."

HPHPA causes deactivation of an enzyme so that dopamine cannot be converted to the neurotransmitter neuroepinephrine, Greenblatt said, and that causes a build-up of dopamine.

"We know elevated levels in the dopamine gene cause agitation," he said, citing medical literature and case studies.

In one 2010 study at McMaster University in Canada, published in the journal Communicative and Integrative Biology, scientists found a link between intestinal microbiota and anxiety-like behavior.

Researchers compared the behaviors of normal 8-week-old mice and those whose guts were stripped of microbes. Those without bacteria showed higher levels of risk-taking and the stress hormone cortisol. They also had altered levels of the brain chemical BDNF, which has been linked to anxiety and depression in humans.

Researchers believe that in the immediate postnatal period, the "gut bacteria" have an impact on not just the immune system, but the development of the neuroendocrine and metabolic systems. Presence of microbiota regulates the "set point" for hypothalamic-pituitary-adrenal axis activity.

Research into the importance of gut bacteria is "well-established," and two other later studies have reaffirmed the McMaster study, according to its co-author Jane Foster, associate professor of neuroscience and behavioral science and part of the McMaster University & Brain-Body Institute.

"The gut bacteria talk to the brain in multiple ways through either the immune system or the enteric nervous system," said Foster. "It's sort of like if you imagine a mesh network and you took your intestinal tract and wrapped that like a hot dog bun outside a hot dog. There are more neurons that directly surround your GI tract than in the whole spinal cord."

However, while using probiotics may help a "subset of patients," she said, it's not a "magic bullet." Early life stresses, nutrition and building a strong immune system all play an important role in a person's mental health, she said.

Key life transitions -- adolescence and menopause, for example -- are when "big changes" are going on in the gut-brain relationship and probiotics might be helpful in building stronger resilience.

"Anyone who has a mental health disorder that coincides with a GI disorder is a good candidate for probiotics," she said.

One such candidate was Adam Johnson, who since the age of 5 has struggled with ADHD, anxiety and some mood disorders, and has been treated with a variety of medications.

"We know now he had too much stimulation and realize his brain worked differently than everyone else's," said his mother, Kay Lynn Johnson of Massachusetts.

Continue reading this article here http://abcnews.go.com/Health/anxiety-head-gut/story?id=20229136


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How the Gut's Second Brain Influences Mood and Well-Being new
      #371284 - 07/15/14 03:08 PM
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Think Twice: How the Gut's "Second Brain" Influences Mood and Well-Being

As Olympians go for the gold in Vancouver, even the steeliest are likely to experience that familiar feeling of "butterflies" in the stomach. Underlying this sensation is an often-overlooked network of neurons lining our guts that is so extensive some scientists have nicknamed it our "second brain".

A deeper understanding of this mass of neural tissue, filled with important neurotransmitters, is revealing that it does much more than merely handle digestion or inflict the occasional nervous pang. The little brain in our innards, in connection with the big one in our skulls, partly determines our mental state and plays key roles in certain diseases throughout the body.

Although its influence is far-reaching, the second brain is not the seat of any conscious thoughts or decision-making.

"The second brain doesn't help with the great thought processes…religion, philosophy and poetry is left to the brain in the head," says Michael Gershon, chairman of the Department of Anatomy and Cell Biology at New York–Presbyterian Hospital/Columbia University Medical Center, an expert in the nascent field of neurogastroenterology and author of the 1998 book The Second Brain (HarperCollins).

Technically known as the enteric nervous system, the second brain consists of sheaths of neurons embedded in the walls of the long tube of our gut, or alimentary canal, which measures about nine meters end to end from the esophagus to the anus. The second brain contains some 100 million neurons, more than in either the spinal cord or the peripheral nervous system, Gershon says.

This multitude of neurons in the enteric nervous system enables us to "feel" the inner world of our gut and its contents. Much of this neural firepower comes to bear in the elaborate daily grind of digestion. Breaking down food, absorbing nutrients, and expelling of waste requires chemical processing, mechanical mixing and rhythmic muscle contractions that move everything on down the line.

Thus equipped with its own reflexes and senses, the second brain can control gut behavior independently of the brain, Gershon says. We likely evolved this intricate web of nerves to perform digestion and excretion "on site," rather than remotely from our brains through the middleman of the spinal cord. "The brain in the head doesn't need to get its hands dirty with the messy business of digestion, which is delegated to the brain in the gut," Gershon says. He and other researchers explain, however, that the second brain's complexity likely cannot be interpreted through this process alone.

"The system is way too complicated to have evolved only to make sure things move out of your colon," says Emeran Mayer, professor of physiology, psychiatry and biobehavioral sciences at the David Geffen School of Medicine at the University of California, Los Angeles (U.C.L.A.). For example, scientists were shocked to learn that about 90 percent of the fibers in the primary visceral nerve, the vagus, carry information from the gut to the brain and not the other way around. "Some of that info is decidedly unpleasant," Gershon says.

The second brain informs our state of mind in other more obscure ways, as well. "A big part of our emotions are probably influenced by the nerves in our gut," Mayer says. Butterflies in the stomach—signaling in the gut as part of our physiological stress response, Gershon says—is but one example. Although gastrointestinal (GI) turmoil can sour one's moods, everyday emotional well-being may rely on messages from the brain below to the brain above. For example, electrical stimulation of the vagus nerve—a useful treatment for depression—may mimic these signals, Gershon says.

Given the two brains' commonalities, other depression treatments that target the mind can unintentionally impact the gut. The enteric nervous system uses more than 30 neurotransmitters, just like the brain, and in fact 95 percent of the body's serotonin is found in the bowels. Because antidepressant medications called selective serotonin reuptake inhibitors (SSRIs) increase serotonin levels, it's little wonder that meds meant to cause chemical changes in the mind often provoke GI issues as a side effect. Irritable bowel syndrome—which afflicts more than two million Americans—also arises in part from too much serotonin in our entrails, and could perhaps be regarded as a "mental illness" of the second brain.

Scientists are learning that the serotonin made by the enteric nervous system might also play a role in more surprising diseases: In a new Nature Medicine study published online February 7, a drug that inhibited the release of serotonin from the gut counteracted the bone-deteriorating disease osteoporosis in postmenopausal rodents. (Scientific American is part of Nature Publishing Group.) "It was totally unexpected that the gut would regulate bone mass to the extent that one could use this regulation to cure—at least in rodents—osteoporosis," says Gerard Karsenty, lead author of the study and chair of the Department of Genetics and Development at Columbia University Medical Center.

Serotonin seeping from the second brain might even play some part in autism, the developmental disorder often first noticed in early childhood. Gershon has discovered that the same genes involved in synapse formation between neurons in the brain are involved in the alimentary synapse formation. "If these genes are affected in autism," he says, "it could explain why so many kids with autism have GI motor abnormalities" in addition to elevated levels of gut-produced serotonin in their blood.

Down the road, the blossoming field of neurogastroenterology will likely offer some new insight into the workings of the second brain—and its impact on the body and mind. "We have never systematically looked at [the enteric nervous system] in relating lesions in it to diseases like they have for the" central nervous system, Gershon says. One day, perhaps there will be well-known connections between diseases and lesions in the gut's nervous system as some in the brain and spinal cord today indicate multiple sclerosis.

Cutting-edge research is currently investigating how the second brain mediates the body's immune response; after all, at least 70 percent of our immune system is aimed at the gut to expel and kill foreign invaders.

U.C.L.A.'s Mayer is doing work on how the trillions of bacteria in the gut "communicate" with enteric nervous system cells (which they greatly outnumber). His work with the gut's nervous system has led him to think that in coming years psychiatry will need to expand to treat the second brain in addition to the one atop the shoulders.

So for those physically skilled and mentally strong enough to compete in the Olympic Games—as well as those watching at home—it may well behoove us all to pay more heed to our so-called "gut feelings" in the future.


http://www.scientificamerican.com/article/gut-second-brain/

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Perceived stress higher among patients with IBS new
      #372457 - 09/08/15 03:08 PM
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Patients with irritable bowel syndrome had significantly higher perceived stress compared with healthy controls, according to data presented at the AGA's 2015 James W. Freston Conference in Chicago.

The purpose of this study was threefold: to assess physiological markers of stress response in patients with IBS vs. healthy controls; to identify correlations between reported stress and physiological markers in patients with IBS; and to determine the effects of weight, sex and IBS type on these stress-related variables.

The researchers analyzed data from 37 patients with IBS and 69 healthy controls who completed the Perceived Stress Scale (PSS) and had fasting peripheral whole-blood specimens collected. PSS scores were 14.81 ± 6.57 for patients with IBS compared with 10.84 ± 6.23 for healthy controls (P = .003). Sex and weight did not affect PSS scores, whereas IBS subtype had an effect (P = .05). PSS scores and serum cortisol were negatively correlated (r = –0.23; P = .02). Correlations between PSS scores and intra-abdominal fat or body fat percentage were not significant.

The investigators concluded that patients with IBS have higher perceived stress than healthy controls, and that "peripheral indicators of the stress response system were found to be negatively correlated with baseline values of self-reported perceived stress. Such findings lend support to alterations of the stress response system in patients with IBD; subjects who reported increased levels of perceived stress displayed diminished levels of cortisol in comparison to their less stressed counterparts."

Baseline PSS scores were found to be significantly different between patients with IBS and healthy controls, and they were somewhat influenced by IBS type, but "although an effect of body weight and sex upon PSS scores was not found, trends were noted in the association of body fat percent and visceral adiposity," they added. "These findings warrant further inquiry, as to the potential mechanism of increased stress among subgroups of this patient population." – by Adam Leitenberger

Reference:

Weaver KR, et al. Physiological correlates of perceived stress in patients with IBS. Presented at: James W. Freston Conference; Aug. 29-30, 2015; Chicago.


http://www.healio.com/gastroenterology/irritable-bowel-syndrome/news/online/%7B965ddf43-b43f-410a-9251-6248b2d47f18%7D/perceived-stress-higher-among-patients-with-ibs

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Gut bacteria may play a role in regulating myelination in the brain's prefrontal cortex new
      #372535 - 10/26/15 03:04 PM
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Microbe-free mice have hypermyelination of the prefrontal cortex


author name
by Kristina Fiore
Staff Writer, MedPage Today


Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Note that this mouse study found increased myelination in certain brain areas when gut microbiota were eradicated.

CHICAGO -- Gut bacteria may play a role in regulating myelination in the prefrontal cortex (PFC), researchers reported here.

Microbe-free mice had greater expression of myelin-related genes and hypermyelination in the PFC compared with control animals, Alan Hoban, PhD, of University College Cork in Ireland, and colleagues presented at a poster session at the Society for Neuroscience meeting here.
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"These animals have no microbiota, so it could be that a lack of signals from the gut aren't check-pointing oligodendrocytes, since we saw with the hypermyelinated fibers was they had so many more wraps of myelin," Hoban told MedPage Today. "That means the oligodendrocytes may be excessively turning, and whatever is missing from the gut signaling to the brain is not telling them to stop -- but that's a very broad interpretation," he cautioned.

The past decade has brought an influx of research on the role of microbiota in gut-brain interactions, including mounting evidence that mood can be impacted by the intestinal flora. But other work has also suggested that gut bugs could play a role in conditions such as autism spectrum disorder (ASD), Parkinson's, and even demyelinating disorders of the central nervous system, including multiple sclerosis.

"MS is an autoimmune disease, so we were interested in how the microbiota may be driving this," Hoban told MedPage Today.

He and his colleagues conducted genome-wide RNA sequencing in the PFC of control mice, microbe-free mice, and mice that were previously microbe-free but were re-colonized.

They conducted RNA sequencing to evaluate differential gene expression, and then validated that data with qRT-PCR. They also conducted transmission electron microscopy in order to quantify myelin thickness relative to axonal diameter, known as the g-ratio. And finally, they did Western blot analysis to assess the expression of proteins from myelin component genes in the PFC.
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Overall, they found that microbe-free mice had increased myelin gene expression, but only in the PFC -- not in five other brain regions including the cerebellum, hippocampus, amygdala, striatum, and frontal cortex.

"We examined a lot of different regions ... and we found that it was solely the PFC that displayed an increase in myelin gene expression," Hoban said.

Expression of myelinating genes was not heightened in any brain regions in control animals, nor in mice that had their microbiota restored, which suggests that myelin processing problems could be repaired, the researchers said.

Hoban and the paper's senior author John Cryan, PhD, also of University College Cork, noted that the hypermyelination seen in animals without gut bacteria "tells us the microbiome provides a break on myelination."

Indeed, the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis cannot be induced in microbe-free mice, Cryan said.

In addition to the gene expression patterns, the researchers conducted transmission electron microscopy and saw greater myelination of axons, as measured by a higher lamina number and greater myelin diameter.

The findings were also confirmed on Western blot, which revealed a greater expression of proteins from myelin component genes in the PFC in microbe-free animals.

Cryan said the next steps are trying to figure out the mechanisms behind the relationship between gut bacteria and myelination in the PFC.

"What could be driving these changes, and why is it specific to the PFC?" Cryan said. "We need to see what signals the microbiome is sending. We need to look at metabolites, at the vagus nerve and the other connections, and see whether we can recapitulate it with certain strategies or certain bacterial strains."

"We know that colonization of the entire microbiome has an effect, but what if we wanted to put back a single bacteria" to impact myelin regulation, he added.

Cryan noted that the concept of the microbiome having an influence on neurologic and psychiatric processes is relatively new and may still have its critics, but "we're slowly beginning to find that all of the fundamental processes of brain function are somehow being regulated by the microbiome."

"These findings encourage a multidisciplinary approach" to understanding disease processes for conditions like multiple sclerosis in order to develop better therapies, Cryan said.

Hoban disclosed no financial relationships with industry.

Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner
This report is part of a 12-month Curriculum In Context series.

last updated 10.26.2015

Primary Source
Society for Neuroscience
Source Reference: Hoban AE, et al "Regulation of myelination in the prefrontal cortex by the microbiota" SFN 2015; Abstract 162.08.



http://www.medpagetoday.com/MeetingCoverage/SFN/54276?xid=nl_mpt_DHE_2015-10-26&eun=g379602d0r

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There’s a ‘second brain’ in your gut — and it’s smarter than you think new
      #373609 - 07/07/17 04:46 PM
HeatherAdministrator

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There's a 'second brain' in your gut — and it's smarter than you think

By Erin Van Der Meer
7/6/17

We tend to think of the brain as the control centre of the human body.

While that is the case, scientists are making new discoveries about a second, smaller brain in the gut that can function independently of the brain in our skulls.

The "second brain" or enteric nervous system (ENS) is a network of around half a billion nerve cells and neurons (about the same amount as the brain of an adult cat) in the gut wall, responsible for controlling the gastrointestinal system.

Scientists are confident learning more about it could solve gut health issues like IBS and constipation, and shed more light on the link between the gut and mental health.
Meet your second brain

Most of us have experienced the feeling of "butterflies" in the tummy when we're nervous, or our stomach "dropping" upon hearing bad news.

But this communication between the brain and the ENS isn't just one way.

Not only is the ENS involved with appetite control, signalling to the brain when we're full, but an emerging area of research suggests the second brain can affect many parts of the "main" or "big" brain, including how it processes thoughts and emotions.

Medical professionals have long been aware of the link between anxiety and depression and digestion issues like irritable bowel syndrome (IBS), thinking the former caused the latter.

But increasingly it seems to be the other way around, as studies show irritation in the gastrointestinal system can trigger mental changes.

"The gut and the brain have a bi-directional relationship; they are interconnected primarily via the vagus nerve which is able to transfer chemical messages between the two," explains Coach's go-to gut health expert, accredited practicing dietitian and founder of Travelling Dietitian Kara Landau.

"Poor gut health has been shown to lead to inflammation throughout the body; and inflammation has been shown to be associated with depression and anxiety.

"Considering our gut sends out chemical messages of its own separate from the brain, including producing around 90 percent of our mood calming neurotransmitter, serotonin, it is no surprise that having a healthy gut has been shown to be associated with enhanced mood regulation."
The potential to solve gut issues

A new study led by the Francis Crick Institute in London mapped the ENS in order to make sense of the complicated system, with the aim of identifying the cause of common gut and digestive issues, like IBS and constipation.

"Now that we have a better understanding of how the enteric nervous system is built and works, we can start to look at what happens when things go wrong, particularly during the critical stages of embryo development or early life," said Reena Lasrado, first author of the paper and researcher at the Crick Institute.

"Perhaps mistakes in the blueprint used to build the neural networks of the gut are the basis of common gastrointestinal problems."

Better understanding the ENS is also likely to help people who are overweight or obese due to overeating, as Landau explains.

"If this system is defective, correct signaling may be impeded.

"This could lead to poorer appetite regulatory hormone signaling between the gut and the brain, and therefore result in increased hunger or a decrease in satiety cues, and therefore overeating or gaining weight."
How to maintain a healthy gut brain

The evidence of the gut-mood connection is still in the early stages, but it's clear maintaining a healthy gut is crucial for mental wellbeing and overall health.

"Having a healthy gut ensures maximum nutrient absorption can take place, which supports proper hormone production and regulation, which benefits mood regulation," Landau explains.

"Ensuring we consume a gut supportive diet, high in probiotic and prebiotic-rich foods and beverages, and low in added sugar and artificial ingredients, is a great place to start.

So what should you eat to help your second brain function optimally?

"Fermented foods, probiotic-enhanced products — that are still live and able to successfully colonise in our gut — as well as prebiotic dietary fibre rich foods and resistant starch rich foods are all going to be beneficial for overall gut integrity.

"Some of the richest sources of prebiotics and resistant starch are chicory root, Jerusalem artichoke, onions and garlic, and green banana flour."

Topping fruit with natural yoghurt, mixing sauerkraut in a salad or ordering some kimchi at a Korean restaurant are also simple ways to make your gut brain smile.

http://coach.nine.com.au/2017/07/06/16/30/gut-brain-enteric-nervous-system?utm_source=newsletter&utm_medium=click&utm_campaign=2271

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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!

Edited by Heather (07/17/17 04:36 PM)

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