Jennifer S. Labus, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Although there is a rapidly expanding technology for assessing central and autonomic nervous system activity in irritable bowel syndrome (IBS) using techniques such as fMRI and modulation of the startle reflex, large and complex data sets are generated that render conventional statistical approaches of limited applicability and have increased the need for more sophisticated analytic strategies. Research scientists trained in both the substantive knowledge in the field as well as the application and development of state-of-the-art and emerging statistical techniques for data analysis are essential to successful advancements in the science of functional gastrointestinal (GI) disorders. Currently, few functional GI disorder researchers have this dual training. The goal of this Mentored Clinical Scientist Award is to develop a research program applying state of the art analysis and design techniques to functional brain imaging and psychophysiological studies in functional GI disorders. An emerging biopsychosocial disease model for IBS posits underlying alterations in central nervous system mechanisms involved in stress and fear. The primary aim of the research is to improve understanding of central processes in functional GI disorders through better statistical analysis and network modeling with particular attention toward fMRI and experimental psychophysiological studies (including startle paradigms and evoked-response potentials). The research focus is on the application of neural network modeling approaches to complex data sets obtained with different brain imaging techniques, and to relate these results to simultaneously obtained psychological, behavioral, autonomic measures. The training plan involves the acquisition, development and application of novel quantitative methods such as effective connectivity modeling and mixed-effects modeling for fMRI and psychophysiological data and includes coursework and mentored training in neuroscience, neurobiology of brain-gut interactions, advanced biostatistics, neuroengineering, and clinical research in IBS. The proposed research plan which includes new analyses of extensive existing and ongoing study databases,and two new neuropsychophysiological studies will provide the candidate an opportunity to investigate the neuroanatomical and pathophysiologic substrates of the cognitive, behavioral, affective and physiologic alterations observed in health and disease with major implications for IBS and related functional disorders. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Vulvodynia (VD) is a chronic pain disorder affecting up to 15% of women and resulting in substantial impairment in health-related quality-of-life. The treatment of the disorder is hampered by a lack of knowledge regarding its neurobiological basis. The proposed study is based on the general hypothesis that like other persistent pain conditions, VD clinical phenotypes are composed of multiple biological endophenotypes, and that meaningful subgroups can be identified. In the current proposal, we plan to extensively phenotype a large sample of VD patients using functional and structural brain imaging together with genetic, physiological, and biological parameters. We hypothesize that central mechanisms (including alterations in the processing/modulation of interoceptive signals from the external genitals) are important determinants of the clinical presentation, and that differences in these brain signatures could play an important role in treatment responsiveness. Such phenotyping has considerable implications for future drug development. We propose to test this hypothesis by accomplishing three specific aims. Aim 1 will characterize alterations in multimodal structural brain and connectivity indices in VD. This will be accomplished by applying complex network analysis and machine learning algorithms to compare resting state [RS] functional and structural (grey and white matter) brain imaging in VD patients to 200 age-matched female healthy controls (HC), 200 patients with irritable bowel syndrome (IBS) and 100 patients with interstitial cystitis/painful bladder syndrome which are available from a large brain scan repository at UCLA. Aim 2 will characterize the connectivity indices in VD and identify the association between structural (grey and white matter) and RS alterations with clinical, behavioral and genetic parameters. This will be accomplished by associating structural and RS functional abnormalities identified in Aim 1 with relevant parameters including: clinical (symptom severity, disease duration, co-morbid pain or psychiatric diagnosis), behavioral (pressure pain thresholds), and biological (candidate gene polymorphisms belonging to clusters of genes related to hypothalamic-pituitary-adrenal [HPA] axis function, pain, inflammatory, catecholamine, and serotonin signaling systems). Aim 3 will identify VD patient subgroups based on endophenotype clusters by applying advanced mathematical classification techniques to brain, biological, behavioral and clinical endophenotypes. This will be accomplished by combining imaging and other phenotyping data using unsupervised machine learning algorithms and will yield distinct mechanistic subgroups of VD.

PROJECT SUMMARY Vulvodynia is a chronic pain disorder affecting up to 15% of women and resulting in substantial impairment in health related quality of life. Provoked Vestibulodynia (PVD), a form of localized provoked vulvodynia (formerly called vulvar vestibulitis syndrome) consists of severe pain upon vaginal penetration and objective findings of vulvar burning pain when touching the vulvar vestibule with a cotton swab in the absence of detectable infectious, neurological or immunological explanation The treatment of the disorder is hampered by a lack of knowledge regarding the biological mechanism underlying symptoms. The human vaginal microbiota play a key role in preventing a number of urogenital diseases. Research on the association between altered composition of the vaginal microbiome in vulvodynia is sparse, but provides tentative support for the involvement of microbiota. Discovering an association between microbiome and PVD has great implications for personalized prevention, practical, targeted diagnostic testing, and personalized therapy for girls and women with PVD. Research indicates brain regions involved in the processing/modulation of signals from the external genitals are altered in vulvodynia subjects and that these alterations correlate with subjective reports of pain and vaginal muscle tenderness. There is growing preclinical and emerging clinical evidence that the microbiota and their metabolites may play a significant role in the modulation of brain activity and central signaling systems, and a potential role in the etiology and pathophysiology of pain and psychiatric disorders. In the current proposal, we will assess the vaginal microbiota and plasma and vaginal metabolites of 50 female healthy controls and 50 PVD subjects. The PVD subjects will have also been enrolled in our extensive phenotyping study (Labus/Rapkin R01 HD076756) where we use brain imaging to assess the structure and function of the brain along with clinical, genetic, physiological, and biological parameters. This study will test the hypotheses that 1) Microbiota composition and/or metabolite profiles discriminate PVD patients from HCs as well as within PVD subjects, 2) Microbiota composition and/or metabolite profiles are correlated with PVD symptom severity, pressure pain sensitivity, perceived stress and trauma history, and 3) Microbiota composition and/or metabolite profiles are correlated with brain regions altered in PVD, suggesting a possible interaction between the microbiota and the brain structure/function.

ABSTRACT Irritable bowel syndrome (IBS) is a highly prevalent intestinal disorder characterized by chronically recurring abdominal pain and altered bowel habit. Despite extensive research efforts over the past few decades, there is no general consensus about the pathophysiology, the role of SABV in pathophysiology, nor are there been any reliable biomarkers for guiding treatment decisions. This lack of progress is reflected in the continued excessive direct and indirect health care costs generated by these conditions, largely due to unnecessary diagnostic procedures and lack of effective therapies. Increasing evidence supports a role of dysregulations within the brain-gut microbiome (BGM) axis in IBS. Therefore, the overall goal of this proposal is to determine the sex-specific role of distinct brainstem nuclei and their bidirectional interactions with several brain networks, of the gut, and of gut microbial metabolites and female sex hormones in symptom generation in IBS. To address this goal we will first characterize sex-specific functional and structural changes in the brain and brainstem using multimodal MRI (structural, DTI, functional MRI) in IBS patients and healthy control subjects (HCs). We will use machine learning and neural network approaches to identify a CNS signature from the imaging data for IBS by leveraging both the newly enrolled IBS subjects and our large existing database of functional and structural MRI scans in IBS and HCs. We will identify sex differences in cross sectional associations between functional and structural imaging measurements, gut microbial measures (RNA sequencing, shotgun metagenomics, metabolomics) and behavioral characteristics of IBS patients, with an emphasis on estrogen and tryptophan metabolites and short chain fatty acids. The information garnered from this study is expected to identify biologically based male and female patient subgroups, to reveal novel insights into the involvement of BGM interactions in IBS pathophysiology, in particular about the involvement of the brainstem and gut microbial metabolites, and to aid in the development of more effective treatment strategies in IBS.