An Examination of Brain Network Organization and the Analgesic Mechanisms of a Non-Pharmacological Treatment in Chronic Centralized Pain

Chronic pain is a global public health challenge, affecting nearly one third of adults worldwide. Current treatments are inadequate, especially since some of the mainstay therapies (e.g. opioids, NSAIDs) are often ineffective and/or associated with significant toxicity. The solution to these problems requires an improved understanding of chronic pain pathology, particularly the role that the brain plays in causing or amplifying pain perception, and how analgesic intervention might target these brain-based mechanisms. This dissertation aims to identify brain network alterations in fibromyalgia (FM), a common and canonical chronic pain condition with presumed CNS pathology, and determine how non-invasive brain stimulation may target aberrant brain network connectivity to promote analgesia. Across a wide range of diverse neurological disorders, hubs (i.e. highly connected brain regions) appear to be disrupted and the character of this disruption can yield insights into the pathophysiology of these disorders. In Chapter 2, we describe the application of a brain network based approach to examine hub topology in FM patients compared to healthy volunteers. We identified significant disruptions in hub rank order in FM patients. In FM, but not controls, the anterior insula was a hub with significantly higher inter-modular connectivity and membership in the rich club (a functional backbone of connectivity formed by highly interconnected hubs). Among FM patients, rich club membership varied with the intensity of clinical pain: the posterior insula, primary somatosensory and motor cortices belonged to the rich club only in FM patients with the highest pain. Further, we found that the eigenvector centrality (a measure of how connected a brain region is to other highly connected regions) of the posterior insula positively correlated with clinical pain, and mediated the relationship between levels of glutamate + glutamine within this structure and the patient’s subjective clinical pain report. Together, these findings demonstrate an altered hub topology in FM and are the first to suggest that disruptions in the excitatory tone within the insula could alter the strength of the insula as a hub and subsequently lead to increased clinical pain. Transcranial direct current stimulation (tDCS) has emerged as an attractive noninvasive treatment for pain, given its ability to target specific cortical regions with relatively few side effects. Motor cortex (M1) tDCS relieves pain in FM, but the analgesic mechanism remains unknown. In Chapter 3, we measured changes in resting state functional connectivity after sham and real M1 tDCS in twelve FM patients and examined if these changes were related to subsequent analgesia. M1 tDCS (compared to sham) reduced pro-nociceptive functional connectivity, specifically between the motor and sensory nuclei of the thalamus and multiple cortical regions, including primary motor and somatosensory areas. Interestingly, decreased connectivity between the thalamus and posterior insula, M1 and somatosensory cortices correlated with reductions in clinical pain after both sham and active treatment. These results suggest that while there may be a placebo response common to both sham and real tDCS, repetitive M1 tDCS causes distinct changes in functional connectivity that last beyond the stimulation period and may produce analgesia by inhibiting pro-nociceptive thalamic connectivity. This research offers new insight into the neurobiology of chronic centralized pain conditions and contributes to the understanding of how non-invasive brain stimulation causes analgesia. This knowledge could lead to more informed stimulation sites and personalized treatment based on network connectivity in each individual patient.PHDNeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/143930/1/chelsmar_1.pd

Outerwear—inner musings: A theoretical framework application for creative scholarship

Scholarship in design, namely clothing and textiles, is based in practice and research. Dire concerns and consequences face academics deciding to undertake creative production as a scholarship track, namely promotion and tenure. With a profession centered on creative practice, efforts to better define and document methodological rigor for creative scholarship must be made, in order to increase knowledge dissemination across the discipline. Studies in information systems design-science theory application indicate various guidelines for undertaking creative practice as design-science (Hevner et al., 2004)

Neurobiologic Features of Fibromyalgia Are Also Present Among Rheumatoid Arthritis Patients

Funding: The study recieved support from Pfizer. The funder had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript. The content is solely the responsibility of the authors. Funding Information Pfizer Aptinyx Cerephex ACKNOWLEDGEMENTS: The authors wish to thank all of the patient volunteers. We also thank Mariella D’Allesandro for supporting recruitment and data collection.Peer reviewedPostprin

Teaching design research through practice: a pilot study for collaborative exploration

As design educators, we experience tension between devoting the precious little time we have in class to educating our students in ways of making (i.e., skills in sewing and patternmaking) and ways of thinking (i.e. design ideation, creativity, etc.)

PR3-ANCA:a promising biomarker in primary sclerosing cholangitis (PSC)

BACKGROUND AND AIMS:The only recognized biomarker for primary sclerosing cholangitis (PSC) is atypical anti-neutrophil cytoplasmic antibodies (aANCA), which, in addition to having low sensitivity and specificity, is an indirect immunofluorescence (IIF) test lacking the advantages of high throughput and objectivity. Recent reports have shown that antibodies to proteinase-3 (PR3-ANCA) might add diagnostic value in inflammatory bowel disease (IBD), specifically in ulcerative colitis (UC). As PSC is associated with IBD, the objective of this study was to evaluate the frequency and clinical significance of PR3-ANCA in a large cohort of patients. METHODS:A total of 244 PSC and 254 control [autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), hepatitis C viral infection (HCV), hepatitis B viral infection (HBV), and healthy controls] sera and their clinical correlations were retrospectively analyzed for PR3-ANCA determined by ELISA and a new chemiluminescence immunoassay (CIA). Testing was also performed for aANCA by IIF. RESULTS:When measured by CIA, PR3-ANCA was detected in 38.5% (94/244) of PSC patients compared to 10.6% (27/254) controls (p<0.0001). By ELISA, PR3-ANCA was detected in 23.4% (57/244) of PSC patients compared to 2.7% (6/254) controls (p<0.0001). PR3-ANCA in PSC patients was not associated with the presence or type of underlying IBD, and, in fact, it was more frequent in Crohn's disease (CD) patients with PSC than previously reported in CD alone. PR3-ANCA in PSC measured by CIA correlated with higher liver enzymes. CONCLUSION:PR3-ANCA is detected in a significant proportion of PSC patients compared to other liver diseases including PBC and AIH. PR3-ANCA is associated with higher liver enzyme levels in PSC, and is not solely related to underlying IBD

Top down or bottom up? An observational investigation of improvement in fibromyalgia symptoms following hip and knee replacement

Objectives: Many patients with osteoarthritis have comorbid symptoms of FM, but it is unknown how these symptoms respond to surgical procedures that address nociceptive input in the periphery, such as total joint replacement. Here we explore differences in clinical characteristics between patients whose FM symptoms do and do not improve following total hip or knee replacement. Methods: Participants were 150 patients undergoing knee or hip replacement who had a minimum FM survey score of 4 or greater prior to surgery. The top tertile of patients experiencing the most improvement in FM symptoms at month 6 were categorized as ‘Improve’ (n = 48) while the bottom two tertiles were categorized as ‘Worsen/Same’ (n = 102). Baseline symptom characteristics were compared between groups, as well as improvement in overall pain severity, surgical pain severity and physical function at 6 months. Results: The Worsen/Same group had higher levels of fatigue, depression and surgical site pain at baseline (all P &lt; 0.05). Additionally, they improved less on overall pain severity and physical functioning 6 months after surgery (both P &lt; 0.05). Conclusion: Most patients derive significant benefit in improvement of comorbid FM symptoms following total joint replacement, but a substantial proportion do not. Understanding the neurobiological basis for these different trajectories may help inform clinical judgment and improve patient care

Development of the Advancing the Patient Experience in COPD Registry:A Modified Delphi Study

Background: Chronic obstructive pulmonary disease (COPD) is commonly managed by family physicians, but little is known about specifics of management and how this may be improved. The Advancing the Patient Experience in COPD (APEX COPD) registry will be the first U.S. primary care, health system-based registry following patients diagnosed with COPD longitudinally, using a standardized set of variables to investigate how patients are managed in real life and assess outcomes of various management strategies.Objective: Gaining expert consensus on a standardized list of variables to capture in the APEX COPD registry.Methods: A modified, Delphi process was used to reach consensus on which data to collect in the registry from electronic health records (EHRs), patient-reported information (PRI) and patient-reported outcomes (PRO), and by physicians during subsequent office visits. The Delphi panel comprised 14 primary care and specialty COPD experts from the United States and internationally. The process consisted of 3 iterative rounds. Responses were collected electronically.Results: Of the initial 195 variables considered, consensus was reached to include up to 115 EHR variables, 34 PRI/PRO variables and 5 office-visit variables in the APEX COPD registry. These should include information on symptom burden, diagnosis, COPD exacerbations, lung function, quality of life, comorbidities, smoking status/history, treatment specifics (including side effects), inhaler management, and patient education/self-management.Conclusion: COPD experts agreed upon the core variables to collect from EHR data and from patients to populate the APEX COPD registry. Data will eventually be integrated, standardized and stored in the APEX COPD database and used for approved COPD-related research.</p

Development of the Advancing the Patient Experience (APEX) in COPD Registry : A Modified Delphi Study

Funding statement: APEX COPD is conducted by Optimum Patient Care (OPC) Global Limited, and co-funded by OPC Global and Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors received no direct compensation related to the development of the manuscript. Writing, editorial support, and/or formatting assistance was provided by Ms. Audrey Ang of the Observational and Pragmatic Research Institute, Singapore, and Dr. Lisa Buttle of Medscript Ltd, Ireland, which was funded by BIPI. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Acknowledgments The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). We thank Dr. Alvaro Aranda (Hospital Auxilio Mutuo, San Juan, Puerto Rico) for his scientific and clinical contributions during the drafting of this manuscript. We also thank Ms. Audrey Ang for editorial assistance, Ms. Bronte Sawyer for project coordination, and Dr. Lisa Buttle for assistance with drafting the article. Dr. Ruth B. Murray is acknowledged for her substantial contribution to the interpretation, summarization and presentation of data in this article and significant intellectual input to the manuscript. She has provided her final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Ruth B. Murray is the founder and director of Medscript Ltd., a company that provided writing and editorial support for APEX COPD publications.Peer reviewedPostprin

A multi-modal MRI study of the central response to inflammation in rheumatoid arthritis

Special thanks to the patient community who participated in this research effort. Thanks to Mariella D’Allesandro for efforts towards recruitment.Peer reviewedPublisher PD

Variation in Demographic and Clinical Characteristics of COPD Patients Managed in U.S. Primary Care : Data from a Real-Life COPD Registry

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