Anxiety Disorders: Mayer EA

Mayer EA, Tillisch K, Bradesi S. · Department of Medicine, Center for Neurovisceral Sciences and Women's Health, David Geffen School of Medicine at UCLA, Los Angeles, CA 90073, USA. · Aliment Pharmacol Ther. · Pubmed #16948804 No free full text.

Abstract: BACKGROUND: The importance of bi-directional brain-gut interactions in gastrointestinal illness is increasingly being recognized, most prominently in the area of functional gastrointestinal disorders. Numerous current and emerging therapies aimed at normalizing brain-gut interactions are a focus of interest, particularly for irritable bowel syndrome and functional dyspepsia. METHODS: A literature search was completed for preclinical and clinical studies related to central modulation of gastrointestinal functions and published in English between 1980 and 2006. RESULTS: Existing data, while sparse, support the use of different classes of antidepressant drugs, including tricyclics, and selective and non-selective serotonin reuptake inhibitors in irritable bowel syndrome. Serotonin receptor agonists and antagonists with peripheral and possibly central effects are effective in treating specific subtypes of irritable bowel syndrome. Based largely on theoretical and preclinical evidence, several novel compounds that selectively target receptors at multiple levels within the brain-gut axis such as neurokinin, somatostatin and corticotropin-releasing factor receptor antagonists are promising. CONCLUSIONS: This review discusses the rationale for modulation of the brain-gut axis in the treatment of functional gastrointestinal disorders and highlights the most promising current and future therapeutic strategies.

Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Lydiard RB, Mayer EA, Anonymous00102. · Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston 29425-0742, USA. · J Clin Psychiatry. · Pubmed #12108822 No free full text.

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Mayer EA, Craske M, Naliboff BD. · Department of Medicine, University of California, Los Angeles, USA. · J Clin Psychiatry. · Pubmed #12108819 No free full text.

Abstract: Functional disorders of the digestive system, such as irritable bowel syndrome, are often associated with affective disorders, such as depression, anxiety, panic, and posttraumatic stress disorder (PTSD). Some of these associations are observed not only in clinical populations, but also in population-based samples, suggesting a relationship with pathophysiologic mechanisms underlying both gastrointestinal (GI) dysfunction and certain affective disorders. Sustained and acute life-threatening stressors play an important role in the onset and modulation of GI symptoms as well as in the development of affective disorders and PTSD. A neurobiological model is proposed that attempts to explain the development of visceral hypersensitivity, the neuroendocrine and autonomic dysfunction characteristic of functional GI disorders, as well as the overlap with affective disorders.

Mayer EA. · Division of Digestive Diseases, University of California Los Angeles School of Medicine, USA. · Am J Med. · Pubmed #10588168 No free full text.

Abstract: In response to perceived or experienced change that is considered threatening to the individual, the central nervous system mounts a stereotypic response that decreases the sensitivity to pain, modulates the autonomic nervous system outflow, and activates the hypothalamic-pituitary-adrenal (HPA) axis. This response of the "emotional motor system" may or may not be associated with the conscious experience of feelings of fear or anxiety. Alterations in these response systems (either up- or downregulation) may produce symptoms, such as viscero-somatic hypersensitivity, altered bowel habits, or increased anxiety.

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. · J Neurosci. · Pubmed #18184777 links to  free full text

Abstract: 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.

Twiss C, Kilpatrick L, Craske M, Buffington CA, Ornitz E, Rodríguez LV, Mayer EA, Naliboff BD. · Department of Urology, Center for Neurobiology of Stress, Los Angeles, California, USA. · J Urol. · Pubmed #19286199 No free full text.

Abstract: PURPOSE: Hypersensitivity to visceral stimuli in interstitial cystitis/painful bladder syndrome may result from enhanced responsiveness of affective circuits (including the amygdala complex) and associated central pain amplification. Potentiation of the eyeblink startle reflex under threat is mediated by output from the amygdala complex and, therefore, represents a noninvasive marker to study group differences in responsiveness in this brain circuit. MATERIALS AND METHODS: Acoustic startle responses were examined in female patients with interstitial cystitis/painful bladder syndrome (13) and healthy controls (16) during context threat (application of muscle stimulation electrodes to the lower abdomen overlying the bladder), and cued conditions for safety (no stimulation possible), anticipation and imminent threat of aversive abdominal stimulation over the bladder. RESULTS: Patients showed significantly greater startle responses during nonimminent threat conditions (baseline, safe and anticipation periods) while both groups showed similar robust startle potentiation during the imminent threat condition. Higher rates of anxiety and depression symptoms in the patient group did not account for the group differences in startle reflex magnitude. CONCLUSIONS: Compared to controls, female patients with interstitial cystitis/painful bladder syndrome showed increased activation of a defensive emotional circuit in the context of a threat of abdominal pain. This pattern is similar to that previously reported in patients with anxiety disorders as well as those with irritable bowel syndrome. Since these circuits have an important role in central pain amplification related to affective and cognitive processes, these results support the hypothesis that the observed abnormality may be involved in the enhanced perception of bladder signals associated with interstitial cystitis/painful bladder syndrome.

Naliboff BD, Waters AM, Labus JS, Kilpatrick L, Craske MG, Chang L, Negoro H, Ibrahimovic H, Mayer EA, Ornitz E. · Center for Neurobiology of Stress, Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA, Los Angeles, California, USA. · Psychosom Med. · Pubmed #18842745 No free full text.

Abstract: BACKGROUND AND AIMS: Visceral hypersensitivity and symptom severity in Irritable Bowel Syndrome (IBS) are both exacerbated by stress. The eye-blink startle response represents a noninvasive measure of central defensive responding. Evidence for central hyperexcitability was studied in IBS patients by examining potentiation of the startle reflex to a nociceptive threat. METHODS: Acoustic startle responses were examined in female IBS patients (n = 42) and healthy controls (n = 22) during cued periods in which an aversive abdominal or biceps stimulation was impossible (safe), possible (imminent threat) or anticipated (period just before the imminent threat), and during a threatening context (muscle stimulation pads attached but no cues for stimulation). RESULTS: Both groups showed potentiation of startle responses during the imminent threat condition compared with both the anticipation and safe conditions. Compared with controls, IBS subjects showed significantly larger startle responses during anticipation and imminent threat conditions after receiving an initial aversive stimulation. There were no group differences during the context threat manipulation. Moreover, in IBS patients but not controls, higher neuroticism was associated with larger startle responses during safe and anticipation conditions but not imminent threat, whereas anxiety symptoms were negatively associated with startle magnitude during imminent threat. CONCLUSIONS: Female IBS patients show increased startle responses to threat of aversive stimulation at both abdominal and nonabdominal sites compared with controls. The data represent the first demonstration of altered threat potentiated startle in a functional pain condition and provide support for the use of these paradigms in further evaluation of affective mechanisms in these disorders.

Ringel Y, Drossman DA, Leserman JL, Suyenobu BY, Wilber K, Lin W, Whitehead WE, Naliboff BD, Berman S, Mayer EA. · UNC Center for Functional GI and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina, USA. · Gastroenterology. · Pubmed #18242208 No free full text.

Abstract: BACKGROUND & AIMS: Abuse history is common in irritable bowel syndrome (IBS) and is associated with greater pain reporting, psychologic distress, and poorer health outcome. These effects may be mediated by enhanced responses to aversive visceral stimuli. We investigated the effects of IBS and abuse history on pain reporting and brain activation in response to rectal distentions. METHODS: Ten female patients with IBS and 10 controls were included. Half of patients in each group reported a history of abuse. Brain functional magnetic resonance imaging (fMRI) images and pain ratings were obtained during rectal distentions. Statistical parametric mapping identified activation in subregions of the dorsal cingulate cortex and covariation with rated pain. RESULTS: (1) Distention-elicited pain correlated with anxiety and activation of the posterior (PCC) and middle (MCC) dorsal cingulate subregions. (2) Subjects with a history of abuse showed greater activation in the left MCC (P = .022; t = 5.61) and PCC (P = .033; t = 5.00) than subjects without abuse. (3) Those with IBS and abuse reported greater pain than all others (P = .004), had more activity in the left MCC (P = .021; t = 5.29) and PCC (P = .049; t = 4.81), and had less activity in the left supragenual anterior cingulate (sACC) (P = .01; t = 4.86). CONCLUSIONS: Pain ratings during rectal distention are associated with activation of dorsal cingulate regions implicated in homeostatic afferent processing, and prior abuse enhances this activation. Patients with IBS and abuse report more pain, greater MCC/PCC activation, and reduced activity of a region implicated in pain inhibition and arousal (sACC). These findings suggest a possible explanation for the clinical observation of greater pain reporting and poorer outcome in IBS patients with a history of abuse.

Bremner JD, Bolus R, Mayer EA. · Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia 30306, USA. · J Nerv Ment Dis. · Pubmed #17468680 No free full text.

Abstract: Childhood trauma is an important public health problem, but there are limitations in our ability to measure childhood abuse. The purpose of this study was to develop a self-report instrument for the assessment of childhood trauma that is valid but simple to administer. A total of 288 subjects with and without trauma and psychiatric disorders were assessed with the Early Trauma Inventory-Self Report (ETI-SR), an instrument for the assessment of physical, emotional, and sexual abuse, as well as general traumas, which measures frequency, onset, emotional impact, and other variables. Validity and consistency of the ETI-SR using different methods of scoring was assessed. The ETI-SR was found to have good validity and internal consistency. No method was found to be superior to the simple method of counting the number of items endorsed as having ever occurred in terms of validity. Some items were found to be redundant or not necessary for the accurate measurement of trauma severity within specific domains. Subsequent analyses with a shortened checklist of items showed acceptable validity and internal consistency. These findings suggest that the ETI-SR is a valid measure of early trauma, and suggest future directions for a shortened version of the ETI-SR that could be more easily incorporated into clinical research studies and practice settings.

Tillisch K, Labus JS, Naliboff BD, Bolus R, Shetzline M, Mayer EA, Chang L. · CNS/WH: Center for Neurovisceral Sciences & Women's Health, Department of Medicine, UCLA, and the VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. · Am J Gastroenterol. · Pubmed #15784038 No free full text.

Abstract: BACKGROUND: Due to a wide range of symptom patterns, patients with irritable bowel syndrome (IBS) are often subgrouped by bowel habit. However, the IBS subgroup with alternating bowel habits (IBS-A) has been poorly characterized. OBJECTIVES: (i) To determine a set of bowel habit symptom criteria, which most specifically identifies IBS patients with an alternating bowel habit, (ii) to describe IBS-A bowel symptom patterns, and (iii) to compare clinical characteristics among IBS-A, constipation-predominant (IBS-C), and diarrhea-predominant IBS (IBS-D). METHODS: One thousand one hundred and two Rome I positive IBS patients were analyzed. Three sets of potential criteria for IBS-A were developed and compared by multirater Kappa test. Gastrointestinal, psychological, extraintestinal symptoms, and health-related quality of life were compared in IBS-A, IBS-C, and IBS-D using chi(2) test and analysis of variance (ANOVA). RESULTS: Stool consistency was determined to be the most specific criteria for alternating bowel habits. IBS-A patients reported rapid fluctuations in bowel habits with short symptom flares and remissions. There was a greater prevalence of psychological and extraintestinal symptoms in the IBS-A subgroup compared to IBS-C and IBS-D. No differences were seen between bowel habit subtypes in health-related quality of life. CONCLUSIONS: IBS-A patients have rapidly fluctuating symptoms and increased psychological comorbidity, which should be taken into account for clinical practice and clinical trials.

Longstreth GF, Bolus R, Naliboff B, Chang L, Kulich KR, Carlsson J, Mayer EA, Naesdal J, Wiklund IK. · Department of Gastroenterology, Kaiser Permanente Medical Center, San Diego, California, USA. · Eur J Gastroenterol Hepatol. · Pubmed #15756093 No free full text.

Abstract: OBJECTIVE: To develop a disease-specific questionnaire to capture the impact of irritable bowel syndrome (IBS) and its treatment on patients' lives, the Irritable Bowel Syndrome Impact Scale (IBS-IS). PATIENTS AND METHODS: One hundred and fifty-five IBS patients participated (126 (81%) female; age (mean+/-SD) 45.5+/-12.4 years). We developed the initial 39 items from the literature, available IBS-specific instruments and input from physicians, nurses and patients. We deleted IBS-IS items with a high ceiling effect, items that measured a different construct and items showing a high correlation (r>0.90) with another item and with Rasch analysis, leaving 26 items. We then applied exploratory factor analysis to examine domain groupings. Subjects completed the IBS-IS instrument, the Gastrointestinal Symptom Rating Scale for IBS (GSRS-IBS), Short Form-36 (SF-36), Visceral Sensitivity Index (VSI), and Hospital Anxiety and Depression (HAD) scale. Internal consistency, construct validity and discriminate validity were assessed. RESULTS: The 26 items represented five domains: fatigue, impact on daily activities, sleep disturbance, emotional distress and eating habits. The internal consistency reliability for the domains was 0.87 to 0.96. Most associations between similar constructs in the IBS-IS, GSRS-IBS, SF-36, VSI, and HAD were >0.40. Each IBS-IS domain score decreased with increasing IBS symptom severity (P<0.05), and the patients scored >5 score units lower than a US general population scored on all eight SF-36 dimensions. CONCLUSION: The IBS-IS is a short, user-friendly instrument with excellent psychometric properties that has potential usefulness for clinical trials.

Bradesi S, Schwetz I, Ennes HS, Lamy CM, Ohning G, Fanselow M, Pothoulakis C, McRoberts JA, Mayer EA. · Department of Medicine, Center for Neurovisceral Sciences and Women's Health, David Geffen School of Medicine at University of California, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073, USA. · Am J Physiol Gastrointest Liver Physiol. · Pubmed #15746211 links to  free full text

Abstract: Chronic stress plays an important role in the development and exacerbation of symptoms in functional gastrointestinal disorders. To better understand the mechanisms underlying this relationship, we aimed to characterize changes in visceral and somatic nociception, colonic motility, anxiety-related behavior, and mucosal immune activation in rats exposed to 10 days of chronic psychological stress. Male Wistar rats were submitted daily to either 1-h water avoidance (WA) stress or sham WA for 10 consecutive days. The visceromotor response to colorectal distension, thermal somatic nociception, and behavioral responses to an open field test were measured at baseline and after chronic WA. Fecal pellets were counted after each WA stress or sham WA session as a measure of stress-induced colonic motility. Colonic samples were collected from both groups and evaluated for structural changes and neutrophil infiltration, mast cell number by immunohistochemistry, and cytokine expression by quantitative RT-PCR. Rats exposed to chronic WA (but not sham stress) developed persistent visceral hyperalgesia, whereas only transient changes in somatic nociception were observed. Chronically stressed rats also exhibited anxiety-like behaviors, enhanced fecal pellet excretion, and small but significant increases in the mast cell numbers and the expression of IL-1beta and IFN-gamma. Visceral hyperalgesia following chronic stress persisted for at least a month. Chronic psychological stress in rats results in a robust and long-lasting alteration of visceral, but not somatic nociception. Visceral hyperalgesia is associated with other behavioral manifestations of stress sensitization but was only associated with minor colonic immune activation arguing against a primary role of mucosal immune activation in the maintenance of this phenomenon.

Naliboff BD, Mayer M, Fass R, Fitzgerald LZ, Chang L, Bolus R, Mayer EA. · Center for Neurovisceral Sciences & Women's Health, Department of Medicine, UCLA, Los Angeles, CA, USA. · Psychosom Med. · Pubmed #15184707 links to  free full text

Abstract: OBJECTIVE: Psychosocial stressors have been associated with exacerbations of symptoms in functional and inflammatory disorders of the gastrointestinal tract. The present longitudinal study tests the general hypothesis that life stressors can exacerbate symptoms in patients with chronic heartburn. METHODS: Sixty subjects with current heartburn symptoms were recruited by community advertisement and assessed for presence of stressful life events retrospectively over the preceding 6 months and prospectively for 4 months. Symptom severity by daily diary, quality of life, and psychological symptoms of anxiety, depression, and vital exhaustion were also measured. RESULTS: The presence of a severe, sustained life stress during the previous 6 months significantly predicted increased heartburn symptoms during the following 4 months. In addition, symptoms showed a strong, independent correlation with vital exhaustion. Affective and subjective stress ratings were not strongly related to heartburn severity; however, anxiety showed the strongest relationship to impaired quality of life and depression to heartburn medication use. CONCLUSIONS: As with other chronic conditions such as irritable bowel syndrome (IBS), heartburn severity appears to be most responsive to major life events and not an accumulation of more minor stressors or fluctuations in mood. In addition, vital exhaustion, which may in part result from sustained stress, may represent the psychophysiological symptom complex most closely associated with heartburn exacerbation. Potential mechanisms for these results include increased level and frequency of esophageal acid exposure, inhibition of gastric emptying of acid, or stress-induced hypersensitivity.

Hazlett-Stevens H, Craske MG, Mayer EA, Chang L, Naliboff BD. · Department of Psychology/298, University of Nevada, Reno, NV 89557, USA. · J Psychosom Res. · Pubmed #14642979 No free full text.

Abstract: OBJECTIVE: Relationships between presence of irritable bowel syndrome (IBS) and generalized anxiety disorder (GAD), chronic worry, neuroticism, anxiety sensitivity and anxiety about visceral sensations were examined among university students. METHODS: College student participants were administered self-report diagnostic measures of IBS and GAD, the Penn State Worry Questionnaire (PSWQ), the Neuroticism subscale of the Eysenck Personality Questionnaire, the Anxiety Sensitivity Index (ASI) and five additional items designed to measure visceral anxiety. RESULTS: The prevalence of IBS and its associated characteristics among students were similar to previous community survey studies, with the exception of lower symptom severity in the university sample. IBS was associated with a higher frequency of GAD and greater worry, neuroticism, anxiety sensitivity and visceral anxiety. Logistic regression analyses further showed that the measure of anxiety specific to visceral sensations was the strongest predictor of IBS diagnostic status. CONCLUSIONS: While various aspects of anxiety appear related to IBS, specific anxiety about visceral sensations appears to be the most significant factor. Implications of the associations between anxiety-related variables, particularly anxiety about visceral sensations, are discussed.

Berman SM, Naliboff BD, Chang L, Fitzgerald L, Antolin T, Camplone A, Mayer EA. · CURE Digestive Diseases Research Center, Department of Medicine, University of California, Los Angeles 90073, USA. · Am J Gastroenterol. · Pubmed #12425550 No free full text.

Abstract: OBJECTIVE: Irritable bowel syndrome (IBS) is a common functional disorder characterized by enhanced perceptual sensitivity and hypervigilance toward afferent signals from the viscera. We hypothesize that the increased responsiveness of IBS patients is a generalized phenomenon applying to stimuli other than visceral and attempt to demonstrate increased responsiveness to sounds as measured by the P1 scalp potential. METHODS: Event-related potentials were recorded from IBS patients and control subjects in an auditory task requiring detection of rare pitch targets in a designated ear. Visual words served as targets in an additional block. RESULTS: Compared to control subjects, IBS patients displayed a robust increase in the amplitude of the P1 scalp potential elicited by both attended and unattended sounds. CONCLUSIONS: Enhanced P1 indicates preattentive central nervous system dishabituation in response to repeated sounds. A generalized preattentive increase in central nervous system reactivity may be a feature that IBS shares with several anxiety disorders that frequently co-occur in these patients.

Fass R, Fullerton S, Tung S, Mayer EA. · UCLA/CURE Neuroenteric Disease Program, Department of Medicine, UCLA, Los Angeles, California, USA. · Am J Gastroenterol. · Pubmed #10811327 No free full text.

Abstract: OBJECTIVE: Sleep deprivation can lower visceral perception thresholds and nonregenerative sleep has been implicated as an etiological factor in chronic hyperalgesia syndromes. The aims of our study were to quantify the self-reported prevalence and type of sleep disturbances in patients with different functional bowel disorders (FBD) and to determine if this prevalence is related to involvement of the upper or lower gastrointestinal (GI) tract, perceived disease severity, or psychological comorbidity. METHODS: We enrolled 505 new FBD patients from an academic referral center specializing in functional GI disorders and 247 community based healthy controls. All patients and controls were prospectively evaluated by validated bowel symptom and sleep questionnaires. A psychological profile was obtained by SCL-90R. RESULTS: We found that 68% of functional dyspepsia (FD), 71.2% of irritable bowel syndrome (IBS)+FD, 50.2% of IBS, and 55.1% of the normal subjects reported having sleep disturbances. Waking up repeatedly during the night and waking up in the morning feeling tired or not rested were the most commonly reported sleep patterns; 57.2% of the patients reported that their abdominal ache awakened them from sleep during the night. Self-reported sleep disturbance was directly related to the perceived intensity of GI symptoms. Self-reported sleep disturbances were equally common in both male (57%) and female (58.4%) FBD patients. There was no significant difference between the mean anxiety and depression scores between patients with and without sleep dysfunction. CONCLUSIONS: FD patients, but not IBS patients, reported sleep disturbances more frequently than healthy control subjects. Abdominal pain or discomfort that awaken FBD patients from sleep during the night were common, and thus a poor discriminating factor between organic and functional disorders.