Bruce Naliboff - US grants

[unreadable] DESCRIPTION (provided by applicant): Background: Irritable Bowel Syndrome (IBS) is a common chronic gastrointestinal (Gl) disorder defined by recurrent symptoms of abdominal pain or discomfort associated with alterations in bowel habits, in the absence of a detectable organic cause. Though many IBS patients have extraintestinal symptoms, these are generally not considered under the conventional paradigm. Partly from the lack of effective therapies, 30- 40% of IBS patients turn to complementary and alternative medical (CAM) therapies instead of, or in addition to, conventional treatment. Unlike the western approach, Traditional Chinese Medicine (TCM) views IBS patients as a heterogeneous population whose Gl symptoms are one of many manifestations resulting from a broader underlying multisystemic dysregulation. In TCM patterns of dysregulation, patients are classified into subgroups incorporating both Gl and extraintestinal symptoms. TCM therapies like acupuncture and herbs target these specific patterns. Further, TCM patterns show striking similarity to common presentations of IBS and to emerging concepts of stress neurobiology, particularly allostasis and allostatic load. Despite its core role in the TCM paradigm, few studies explore the nature of patterns of dysregulation. Aims: Building on extensive preliminary data, this proposal seeks to scientifically validate TCM patterns by testing the following hypotheses: 1) TCM patterns can be characterized by distinct pathophysiologic patterns related to specific alterations in stress responsiveness, and 2) TCM patterns can be distinguished by select symptom items. Methods: In Aim 1, we will assess affective, pain, autonomic and neuroendocrine responses to visceral and somatic pain stimuli to identify two distinct patterns (EXCESS and DEFICIENCY) reflecting altered stress responsiveness (allostasis and allostatic load, respectively). In Aim 2, we will assess correlation between patient self-report of select symptom items and TCM expert diagnosis of patients to specific TCM patterns. Conclusions: If these hypotheses are correct, it strongly validates the existence of TCM patterns of dysregulation in IBS, supports that IBS is a heterogeneous, multisystemic disorder contrary to current characterizations, and provides the basis for novel diagnostic and treatment approaches. Given the disappointing results with conventional approaches to multisystemic functional disorders like IBS, this may provide exciting insights and contributions to the classification and treatment of these challenging disorders. [unreadable] [unreadable] [unreadable]

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a common chronic bladder syndrome characterized by bladder pain and discomfort (urgency) and increased frequency of urination. It is associated with significant decrements in health-related quality of life (HRQOL), productivity and increased healthcare costs. There is growing evidence that IC/PBS shares several features with other chronic functional pain disorders like irritable bowel syndrome (IBS) and fibromyalgia, including a history of adverse early life events, a history psychological or physical stressors preceding symptom onset or exacerbation, and the presence of anxiety and/or depression and poor illness coping. These findings suggest a model of IC/PBS development that includes vulnerability factors of childhood trauma interacting with life stress, familial modeling, and poor coping. These factors most likely interact with genetic vulnerabilities for both central and peripheral risk (including affective dysregulation) as well as bladder disease history. The proposed project follows the overall themes for the UCLA MAPP Center using a targeted epidemiology approach to study moderators and mediators of IC/PBS symptoms and symptom impact over a 1-year period in a diverse group of male and female patients. In Aim 1 we will examine IC/PBS patients bi-monthly for 1 year to characterize patients in terms of severity, frequency, and variation in cardinal symptoms, HRQOL, productivity, and healthcare utilization. We will examine concurrent mediators of symptom presentation including stress, coping and symptom-specific anxiety. In Aim 2, we will examine early life vulnerability factors including genetic traits, early life trauma, and familial modeling as moderator variables in the model to test the important hypotheses that these factors are related to adult symptom presentation including comorbidities with affective and other functional pain disorders and response to the mediating variables. In Aim 3, we will apply the same modeling to a sample of IBS patients to test the hypothesis that similar mediators and moderators operate in other functional pain disorders including genetic and early life vulnerabilities and ongoing stressors. Other important outcomes from this project will be the development of a IC/PBS targeted measure of symptom-specific anxiety, data on treatment response as related to the model predictors and new data on symptom variation over an extended period of time. If verified the proposed model of IC/PBS symptom development has important implications for a better understanding of underlying mechanisms as well as for more effective treatment strategies.

DESCRIPTION (provided by applicant): Mind-Body treatments such as meditation, yoga or hypnosis have been shown to improve subjective symptoms in several persistent pain disorders including Irritable Bowel Syndrome (IBS). However, objective, reliable measures than can help identify treatment response (biomarkers) have not been developed. A biomarker can support clinical endpoints and be used to more fully assess mechanisms and outcomes in Mind-Body clinical trials, as well as compare various Complementary and Integrative Medicine treatments, and help to target specific treatments to patients most likely to benefit. Recently identified functional and structural brain imaging abnormalities in patients with IBS and other chronic pain disorders are attractive biomarker candidates but have yet to be validated. For example, alterations in the spatiotemporal pattern of spontaneous brain oscillations during rest and in the functional connections between brain regions during pain expectation as well as changes in the structural density in prefrontal brain areas have been identified in IBS by our group. Correlations of clinical symptom severity with some of these brain abnormalities have also been shown. Based on these preliminary findings, we propose a step-wise process, following established guidelines for biomarker validation, to determine the following: Aim 1: Develop and validate structural and functional brain alterations as candidate biomarkers of CAM related treatment change in IBS. Each proposed biomarker will be validated by its ability to differentiate between patients and healthy controls (HC), its correlation with subjective symptom severity, and its stability over time. Our proposed candidate biomarkers include: increased right anterior insula contributions to low frequency power in the resting state, altered connectivity of the amygdala during anticipation of pain, and a structural marker of decreased prefrontal cortex gray matter. Aim 2: Validate optimal biomarker candidates from Aim 1 by assessment of their relationship to treatment responsiveness in IBS patients following Mindfulness Based Stress Reduction (MBSR). Aim 3: Determine the generality of optimal biomarkers from Aims 1 and 2 by examining relationship of factors such as sex, age, co-morbid pain symptoms, and/or baseline disease severity as moderators of the utility of the biomarker to be associated with initial and three month outcomes. These Aims will be accomplished in two studies. The first will examine 75 IBS patients and 30 healthy controls during a single imaging session with 30 of the IBS subjects returning for a second session 2-4 weeks later to test the hypotheses for Aim 1. The second study will test 50 IBS patients before and after the MBSR program with imaging and symptom questionnaires to test the hypotheses for Aims 2 and 3.

DESCRIPTION (provided by applicant): Mind-Body treatments such as meditation, yoga or hypnosis have been shown to improve subjective symptoms in several persistent pain disorders including Irritable Bowel Syndrome (IBS). However, objective, reliable measures than can help identify treatment response (biomarkers) have not been developed. A biomarker can support clinical endpoints and be used to more fully assess mechanisms and outcomes in Mind-Body clinical trials, as well as compare various Complementary and Integrative Medicine treatments, and help to target specific treatments to patients most likely to benefit. Recently identified functional and structural brain imaging abnormalities in patients with IBS and other chronic pain disorders are attractive biomarker candidates but have yet to be validated. For example, alterations in the spatiotemporal pattern of spontaneous brain oscillations during rest and in the functional connections between brain regions during pain expectation as well as changes in the structural density in prefrontal brain areas have been identified in IBS by our group. Correlations of clinical symptom severity with some of these brain abnormalities have also been shown. Based on these preliminary findings, we propose a step-wise process, following established guidelines for biomarker validation, to determine the following: Aim 1: Develop and validate structural and functional brain alterations as candidate biomarkers of CAM related treatment change in IBS. Each proposed biomarker will be validated by its ability to differentiate between patients and healthy controls (HC), its correlation with subjective symptom severity, and its stability over time. Our proposed candidate biomarkers include: increased right anterior insula contributions to low frequency power in the resting state, altered connectivity of the amygdala during anticipation of pain, and a structural marker of decreased prefrontal cortex gray matter. Aim 2: Validate optimal biomarker candidates from Aim 1 by assessment of their relationship to treatment responsiveness in IBS patients following Mindfulness Based Stress Reduction (MBSR). Aim 3: Determine the generality of optimal biomarkers from Aims 1 and 2 by examining relationship of factors such as sex, age, co-morbid pain symptoms, and/or baseline disease severity as moderators of the utility of the biomarker to be associated with initial and three month outcomes. These Aims will be accomplished in two studies. The first will examine 75 IBS patients and 30 healthy controls during a single imaging session with 30 of the IBS subjects returning for a second session 2-4 weeks later to test the hypotheses for Aim 1. The second study will test 50 IBS patients before and after the MBSR program with imaging and symptom questionnaires to test the hypotheses for Aims 2 and 3.