Central and Peripheral Autonomic Responses in Irritable Bowel Syndrome

Summary

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

Top Publications

  1. pmc Regional neuroplastic brain changes in patients with chronic inflammatory and non-inflammatory visceral pain
    Jui 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
  2. pmc Irritable bowel syndrome in female patients is associated with alterations in structural brain networks
    Jennifer 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
  3. pmc Sex-related differences of cortical thickness in patients with chronic abdominal pain
    Zhiguo 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
  4. pmc Impaired emotional learning and involvement of the corticotropin-releasing factor signaling system in patients with irritable bowel syndrome
    Jennifer 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
  5. pmc Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study
    K Tillisch
    Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
    Aliment Pharmacol Ther 35:360-7. 2012
  6. pmc Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes
    Matthew G Rees
    National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA
    J Clin Invest 122:205-17. 2012
  7. pmc Brain responses to visceral stimuli reflect visceral sensitivity thresholds in patients with irritable bowel syndrome
    Mats B O Larsson
    Department of Clinical and Experimental Medicine Gastroenterology, Linkoping University, Linkoping, Sweden
    Gastroenterology 142:463-472.e3. 2012
  8. pmc Corticotropin-releasing factor receptor 1 antagonist alters regional activation and effective connectivity in an emotional-arousal circuit during expectation of abdominal pain
    Catherine 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
  9. pmc 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 signals
    J E Below
    Department of Human Genetics, University of Chicago, Chicago, IL, USA
    Diabetologia 54:2047-55. 2011
  10. pmc Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome
    Kirsten 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

Scientific Experts

  • James Cheverud
  • K Tillisch
  • Jennifer S Labus
  • Emeran A Mayer
  • Jui Yang Hong
  • Zhiguo Jiang
  • Cody Ashe-McNalley
  • Yonggang Shi
  • Arpana Gupta
  • Jean Stains
  • Catherine S Hubbard
  • Bruce D Naliboff
  • Alen Zamanyan
  • Ivo D Dinov
  • Bahar Ebrat
  • Arthur W Toga
  • Jennifer Labus
  • Mats B O Larsson
  • Matthew G Rees
  • George E Dukes
  • Joshua Bueller
  • Dennis L Kelleher
  • J E Below
  • David A Seminowicz
  • Suzanne R Smith
  • Sam Hobel
  • Ivo Dinov
  • Shantanu Joshi
  • Nuwanthi Heendeniya
  • Boris A Gutman
  • Paul M Thompson
  • Michelle Chen
  • Michael Fanselow
  • Nicola L Beer
  • Ilana Blech
  • Jennifer E Below
  • Leslie G Biesecker
  • Mario A Morken
  • Maria Engström
  • A D Craig
  • Amy J Swift
  • Magnus Ström
  • Bruce Naliboff
  • Susanna A Walter
  • Clesson Turner
  • David Ng
  • Sarah Ruppert
  • Francis S Collins
  • Mark I McCarthy
  • James C Mullikin
  • Anna L Gloyn
  • Peter Lundberg
  • P M McKeigue
  • G I Bell
  • E J Parra
  • J V Morrison
  • Brandall Suyenobu
  • D M Hallman
  • A Konkashbaev
  • D L Nicolae
  • N J Cox
  • A Pluzhnikov
  • M Cruz
  • C L Hanis
  • S C Elbein
  • E R Gamazon
  • M Catherine Bushnell
  • Joshua A Bueller

Detail Information

Publications14

  1. pmc Regional neuroplastic brain changes in patients with chronic inflammatory and non-inflammatory visceral pain
    Jui 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. ..
  2. pmc Irritable bowel syndrome in female patients is associated with alterations in structural brain networks
    Jennifer 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. ..
  3. pmc Sex-related differences of cortical thickness in patients with chronic abdominal pain
    Zhiguo 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...
  4. pmc Impaired emotional learning and involvement of the corticotropin-releasing factor signaling system in patients with irritable bowel syndrome
    Jennifer 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
    ....
  5. pmc Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study
    K 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...
  6. pmc Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes
    Matthew 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...
  7. pmc Brain responses to visceral stimuli reflect visceral sensitivity thresholds in patients with irritable bowel syndrome
    Mats 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...
  8. pmc Corticotropin-releasing factor receptor 1 antagonist alters regional activation and effective connectivity in an emotional-arousal circuit during expectation of abdominal pain
    Catherine 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...
  9. pmc 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 signals
    J 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...
  10. pmc Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome
    Kirsten 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...
  11. pmc Calpain-10 is a component of the obesity-related quantitative trait locus Adip1
    James 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...
  12. pmc Regional gray matter density changes in brains of patients with irritable bowel syndrome
    David 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...