Laurie A. Keefer, Ph.D. - US grants

DESCRIPTION (provided by applicant): Aim 1 is to determine whether gut-directed hypnotherapy, an established CAM intervention that targets psychological stress, is feasible and acceptable to patients with Ulcerative Colitis (UC). Aim 2 is to estimate effect sizes for gut-directed hypnotherapy on relapse prevention and other clinical disease outcomes in UC. This project is a step towards our long-term goal, which is to help patients with Inflammatory Bowel Diseases (IBD) employ behavioral self-management techniques in order to obtain better disease control, reduce the frequency, severity and duration of flare-ups and achieve improved quality of life. The introduction of maintenance medications has been critical for a portion of patients with respect to increasing time between flares, but relapse prevention methods are limited. IBD patients and their doctors cite stress as a common trigger for relapse. Gut-directed hypnotherapy may impact UC by improving adherence and attention to positive lifestyle factors and altering stress-related physiological and psychological processes that contribute to disease flare and quality of life. 88 UC patients in remission will be randomized to a) 8 weeks of gut directed hypnotherapy + standard care (HYP), b) 8 weeks time/attention control + standard care (TA) or c) standard care alone (SCA). Assessments are repeated at baseline, 8 weeks (post-treatment), 20 weeks, 36 weeks and 52 weeks. Aim 1 Endpoints: 1) proportion of patients who are retained over the trial period in comparison to those who did not complete/enter the trial. We expect that HYP will be feasible and acceptable to at least a subset of patients with inactive UC;2) differences between participants who enroll and those who decline enrollment/drop-out on demographics, disease characteristics, adherence and perceived stress. We expect that there will be differences between groups: HYP >TA >SCA. Aim 2 Endpoints: 1) the proportion of participants in each treatment group that are still in remission at 52 weeks, as determined by daily symptom diaries and physician evaluation. We expect that HYP, when used in conjunction with standard care, may increase the proportion of patients who remain in remission at 1-year follow-up more than either TA or SCA, demonstrating proof of concept that hypnotherapy may positively impact risk of relapse;2) mean number of days to relapse, characteristics of first flare, quality of life, perceived control, perceived stress and adherence: HY P>TA>SCA.

DESCRIPTION (provided by applicant): Thirty to 50 percent of patients diagnosed with gastroesophageal reflux disease (GERD) are not satisfied with symptom control derived from proton pump inhibitors (PPI). This group of patients; PPI non-responders (PPI- NR), pursue further diagnostic procedures and interventions with low yield. This approach is problematic because symptoms are not related to pathologic reflux in at least 50% of PPI-NRs referred for ambulatory reflux testing and therefore it does not lead to improved outcomes or even inform us as to why a patient did not respond to PPI. The development of novel therapies for this group is limited by lack of agreement on the definition of a PPI responder and the lack of a model that accounts for the heterogeneity of continued symptom generation. Our goal is to validate a PPI-NR model that accounts for factors above and beyond pathologic reflux, reducing the need for low-yield ambulatory reflux monitoring and informing the development of novel treatments. Study 1 will provide an equation in which pre-test clinical and questionnaire data sufficiently enables probability estimation for each of 4 reflux phenotypes, derived from ambulatory reflux monitoring. Study 2 will yield a similar equation which will predict one's ability to withdraw PPI therapy when indicated. PUBLIC HEALTH RELEVANCE: Gastroesophageal reflux disease (GERD) is an increasingly common medical condition affecting at least ten percent of the adult US population. Despite the fact that proton pump inhibitors (PPI) are extremely effective, up to 30-50% of patients are unsatisfied with their response and continue to have refractory symptoms. This proposal seeks to identify the reason for continued symptoms and to determine whether a systematic diagnostic protocol will better define treatment strategies for PPI non-responders.

DESCRIPTION (provided by applicant): The goal of this program is to leverage the physiology and psychology expertise and the current resources available at Northwestern University to train predoctoral students in Biomedical Engineering and Psychology and MD and PhD postdoctoral trainees in Gastroenterology, Surgery and Psychology for careers focused on research in functional foregut disorders. The study of functional and motor foregut disorders is complicated and requires a multidisciplinary approach that incorporates an understanding of the mechanical, physiological and inflammatory aspects of gastrointestinal tract function and the cognitive and psychosocial factors that alter symptom response. This training program will build on the successful integration of the Esophageal Center and Center for Psychosocial Research at Northwestern University and also utilize resources from current collaborations with the Center for Healthcare Studies, the Cognitive Brain Mapping Group and translational research colleagues in Allergy-Immunology and Pathology. The fellowship in Gastroenterology and Hepatology, residency program in Surgery and the graduate programs in Engineering and Psychology attract top-notch applicants for these training positions. Each trainee will work with both a primary research mentor and a co-mentor, which will foster interaction between research and clinical faculty and enhance the collaborative aspects of the trainee's research experience. A training program consisting of structured research and mentorship that combines a Master of Science in Clinical Investigation or Public Health degee, seminars, career development programs, and education in the ethical conduct of research has been developed to promote excellence in research focused on functional foregut disorders. We propose to fund one highly qualified predoctoral student and one highly qualified postdoctoral MD or PhD trainee per year for a two-year intensive research experience. Thus, our program will have 4 trainees at steady-state and currently we have the interest from prospective applicants and commitment from our potential mentors, departments and university to support this program.

PROJECT SUMMARY Chronic digestive illness affecting the esophagus, including gastroesophageal reflux disease (GERD), eosinophilic esophagitis (EoE), achalasia and functional dysphagia are common and pose a significant economic burden. These are heterogeneous conditions whose pathophysiology occurs on a wide spectrum based on degree of abnormal acid exposure, motor dysfunction, bolus retention and degree of esophageal hypersensitivity. Symptom-to-physiology correlations are poor, indicating that other processes influence symptom experience. Almost half of patients continue to experience symptoms despite first-line treatments, leaving these patients with inadequate treatment options. There is a need for more personalized interventions targeting the bolus transit system that operate subconsciously to suppress the perception of bolus transit and muscle contraction. Centrally-mediated psychological processes such as esophageal hypervigilance, catastrophizing, and visceral hypersensitivity drive symptom experience, independent of acid exposure, motility function, or eosinophilia histology. Autonomic nervous system (ANS) arousal, the physiological ?fight-or-flight? response to fear and hypervigilance, perpetuates these psychological processes. Heart rate variability (HRV), or the variation in time intervals between heart beats, serves as a biomarker for overall ANS functioning. Higher HRV is indicative of a greater ability to adapt to stressful situations, such as when experiencing esophageal symptoms. A less studied, yet important construct is cognitive flexibility, or the ability to appropriately shift thoughts and adapt behavior. Cognitive flexibility is a modifiable construct that if improved through training, can improve outcomes and prepare patients for behavioral treatments who may otherwise be poor responders. We aim to characterize the degree of cognitive flexibility in well-defined patient populations based on mechanical and physiological phenotypes derived from our biophysiologic modeling CORE. Then, we aim to evaluate heart rate variability biofeedback (HRVB), a novel intervention for these four patient groups. Patients will be stratified by cognitive flexibility level, with those identified as low undergoing Cognitive Remediation Therapy (CRT), a brief intervention using cognitive exercises to improve thinking strategies. We hypothesize applying HRVB to target ANS arousal in real-time, as the symptoms are being experienced, will be effective in increasing HRV, decreasing symptoms, and improving quality of life. We also expect HRVB will decrease esophageal hypervigilance in comparison to controls. We hypothesize CRT will be a feasible and acceptable intervention for esophageal patients, and will be associated with positive changes in cognitive flexibility, decreased symptoms, and improved quality of life. Finally, we aim to develop an integrative predictive model using biomarkers of esophageal distensibility, measures of HRV and measures of cognitive flexibility to define management and outcomes. The results will have implications for current and future behavioral interventions for individuals with chronic esophageal disorders.

Project Summary/Abstract Irritable Bowel Syndrome (IBS) is a chronic and costly digestive condition characterized by abdominal pain and altered bowel habits (diarrhea, constipation, or mixed type). IBS is a disorder of brain-gut dysregulation, including the amplification of normal gut signals at the level of the brain. Yet most medical therapies for IBS to date have focused on symptom management and dietary change with only minor improvements in symptoms, especially in moderate to severe cases. Brain targeted therapies that improve perception of gut signals are effective and increasingly utilized. One of these therapies, gut-directed hypnotherapy, presents a significant problem of access for individuals seeking treatment. Current delivery models require access to qualified providers who offer scientifically validated protocols specifically designed for IBS. Access is severely limited to only a few major academic institutions in urban settings. Furthermore, gut-directed hypnotherapy requires a substantial time and cost commitment from patients. To address the problem of patient access, metaMe, a small business, has developed a new solution through a digital hypnosis program that allows patients to connect with a highly qualified therapist and receive the hypnosis intervention from their own home on their own schedule, including evenings or weekends, at less than a fifth of the cost of traditional therapy. In this Phase I proposal, metaMe and its research partners will demonstrate that the digital hypnosis program is feasible and acceptable to patients.