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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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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-�-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 α 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, α�) divided by the standard error of the indirect effect, σα�.[28] Similar to significance testing using the standard normal distribution, z' = α�/σα� is calculated and tested against the critical value from the empirical sampling distribution of the product of coefficients (H0: α�/σα� = 0). The empirical critical value at α = 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 α 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, �0 = 6.4 (95% CI: 4.5-8.2), �VSI = 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, α� = 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, α� = 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, M�lndal, Sweden

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

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

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