Genomes and Genes
Central and Peripheral Autonomic Responses in Irritable Bowel Syndrome
Principal Investigator: Kirsten Tillisch
Abstract: Irritable Bowel Syndrome (IBS) is the most common functional gastrointestinal disorder, leading to significant impact on both patients and society. The cardinal IBS symptoms of pain, discomfort and altered bowel habits likely arise from a combination of stress modulated alterations in autonomic nervous system (ANS) regulation of the gut and altered perception of visceral stimuli. The role of central stress networks in this process has been supported by neuroimaging data. This Mentored Career Development Proposal is designed to provide the candidate with skills to integrate the rapidly emerging techniques of neuroimaging, ANS analysis, and clinical skills in gastroenterology to perform cutting edge translational research in functional gastrointestinal disorders. Acquisition of these skills will occur during work on a series of hypothesis driven clinical projects with experts in the field, and with didactic training. Phase I of the proposal involves analysis of fMRI, PET, and ANS data collected during aversive visceral stimulation to examine the hypothesis that there is an increased sympathetic/parasympatheticbalance among IBS patients, particularly males. The central networks involved in ANS responses among IBS patients compared to controls will be delineated, and sex-based differences examined. Phase II continues the candidate's development via study of ANS responses to psychological stress, with the hypothesis that IBS patients will have greater ANS activation. First, changes in sigmoid tone during an experimental stressor will be tested as gut-specific ANS surrogate measure and correlated with skin conductance and heart rate variability. Second, imaging with fMRI will be used to determine the central ANS circuitry involved in emotional responses using the analytic tools of functional and effective connectivity. ANS reflexes in IBS patients will be tested via time course analysis for central and peripheral responses to the Valsalva maneuver during high resolution fMRI to assess for generalized ANS dysfunction. Evaluation of sex differences in ANS reponse will be emphasized, given the striking female predominance in this and many other functional disorders. Relevance: Irritable Bowel Syndrome affects up to 15% of the United States population, making it an important public health issue. The proposed training will provide the candidate with a novel set of skills to use in investigating the potential causes of IBS, and developing new treatment strategies.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT
- Regional neuroplastic brain changes in patients with chronic inflammatory and non-inflammatory visceral painJui Yang Hong
Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, University of California Los Angeles, Los Angeles, California, United States of America Department of Medicine, University of California Los Angeles, Los Angeles, California, United States of America Division of Digestive Diseases, University of California Los Angeles, Los Angeles, California, United States of America Department of Bioengineering, University of California Los Angeles, Los Angeles, California, United States of America
PLoS ONE 9:e84564. 2014..The findings suggest that the mechanisms underlying the observed gray matter changes in UC subjects represent a consequence of peripheral inflammation, while in IBS subjects central mechanisms may play a primary role. ..
- Irritable bowel syndrome in female patients is associated with alterations in structural brain networksJennifer S Labus
Oppenheimer Family Center for Neurobiology of Stress, Pain and Interoception Network PAIN, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA Electronic address
Pain 155:137-49. 2014..Overall, evidence for central alterations in patients with IBS was found in the form of regional GM volume differences and altered global and regional properties of brain volumetric networks. ..
- Sex-related differences of cortical thickness in patients with chronic abdominal painZhiguo Jiang
Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress and Pain and Interoception Network PAIN Repository, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America Human Performance and Engineering Laboratory, Kessler Foundation Research Center, West Orange, New Jersey, United States of America Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, New Jersey, United States of America
PLoS ONE 8:e73932. 2013..We aimed to characterize regional changes in cortical thickness (CT) in a large number of well phenotyped IBS patients, taking into account the role of sex related differences...
- Impaired emotional learning and involvement of the corticotropin-releasing factor signaling system in patients with irritable bowel syndromeJennifer S Labus
Gail and Gerald Oppenheimer Family Center for the Neurobiology of Stress, University of California, Los Angeles, Los Angeles, California Department of Medicine, University of California, Los Angeles, Los Angeles, California Department of Psychiatry, University of California, Los Angeles, Los Angeles, California
Gastroenterology 145:1253-61.e1-3. 2013....
- Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot studyK Tillisch
Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Aliment Pharmacol Ther 35:360-7. 2012..The substance P ⁄ neurokinin-1 receptor system is implicated in the regulation of both pain and anxiety, suggesting a potential therapeutic target in IBS...
- Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomesMatthew G Rees
National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA
J Clin Invest 122:205-17. 2012..In sum, this study utilizes computational, cell biological, and biochemical methods to present a model for interpreting the clinical significance of rare genetic variants in common disease...
- Brain responses to visceral stimuli reflect visceral sensitivity thresholds in patients with irritable bowel syndromeMats B O Larsson
Department of Clinical and Experimental Medicine Gastroenterology, Linkoping University, Linkoping, Sweden
Gastroenterology 142:463-472.e3. 2012..We investigated the brain mechanisms of these perceptual differences...
- Corticotropin-releasing factor receptor 1 antagonist alters regional activation and effective connectivity in an emotional-arousal circuit during expectation of abdominal painCatherine S Hubbard
Center for the Neurobiology of Stress and Departments of Medicine, Physiology, and Psychiatry, University of California, Los Angeles, Los Angeles, California 90095, USA
J Neurosci 31:12491-500. 2011..The unique state anxiety effects observed suggest a potential pathway for therapeutic benefit of CRF(1) receptor antagonism for patients with stress-sensitive disorders...
- Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signalsJ E Below
Department of Human Genetics, University of Chicago, Chicago, IL, USA
Diabetologia 54:2047-55. 2011..We conducted genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) analyses to identify and characterise risk loci for type 2 diabetes in Mexican-Americans from Starr County, TX, USA...
- Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndromeKirsten Tillisch
Center for Neurobiology of Stress, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA
Gastroenterology 140:91-100. 2011..We aimed to identify brain regions consistently activated by supraliminal rectal stimulation in IBS patients and healthy subjects (controls) by performing a quantitative meta-analysis of published studies...
- Calpain-10 is a component of the obesity-related quantitative trait locus Adip1James M Cheverud
Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO, USA
J Lipid Res 51:907-13. 2010..Differences between the LG/J and SM/J Capn10 alleles are the likely source of some of the QTL effects mapped to Adip1 in the LG/J-by-SM/J cross. Capn10 plays an important role in regulating obesity and diabetes in mice...
- Regional gray matter density changes in brains of patients with irritable bowel syndromeDavid A Seminowicz
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada
Gastroenterology 139:48-57.e2. 2010..Several studies have examined structural brain changes associated with chronic pain syndromes, including irritable bowel syndrome (IBS), but study sample sizes have been small and heterogeneous...