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Wu Y, Wang C, Qian W, Wang L, Yu L, Zhang M, Yan M. Default mode network-basal ganglia network connectivity predicts the transition to postherpetic neuralgia. IBRO Neurosci Rep 2025; 18:135-141. [PMID: 39896717 PMCID: PMC11783054 DOI: 10.1016/j.ibneur.2025.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/10/2025] [Indexed: 02/04/2025] Open
Abstract
Background Neuroimaging studies have revealed aberrant network functional connectivity in postherpetic neuralgia (PHN) patients. However, there is a lack of knowledge regarding the relationship between the brain network connectivity during the acute period and disease prognosis. Objective The purpose of this study was to detect characteristic network connectivity in the process of herpes zoster (HZ) pain chronification and to identify whether abnormal network connectivity in the acute period can predict the outcome of patients with HZ. Methods In this cross-sectional study, 31 patients with PHN, 33 with recuperation from herpes zoster (RHZ), and 28 with acute herpes zoster (AHZ) were recruited and underwent resting-state functional magnetic resonance imaging (fMRI). We investigated the differences in the connectivity of four resting-state networks (RSN) among the three groups. Receiver operating characteristic (ROC) curve analysis was performed to identify whether abnormal network connectivity in the acute period could predict the outcome of patients with HZ. Results First, we found within-basal ganglia network (BGN) and default mode network (DMN)-BGN connectivity differences, with PHN patients showing increased DMN-BGN connectivity compared to AHZ and RHZ patients, while RHZ patients showing increased within-BGN connectivity compared to AHZ and PHN patients. Moreover, DMN-BGN connectivity was associated with the ID pain score in patients with AHZ. Finally, the DMN-BGN connectivity of AHZ patients could predict the outcome of HZ patients with sensitivity and specificity of 77.8 % and 63.2 %, respectively. Conclusions Our results provide evidence that DMN-BGN connectivity during the acute period confers a risk for the development of chronic pain and can act as a neuroimaging biomarker to predict the outcome of patients with HZ.
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Affiliation(s)
- Ying Wu
- Department of Anesthesiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Chao Wang
- Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Wei Qian
- Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Lieju Wang
- Department of Anesthesiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Lina Yu
- Department of Anesthesiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Minming Zhang
- Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Min Yan
- Department of Anesthesiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
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2
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Mackey S, Aghaeepour N, Gaudilliere B, Kao MC, Kaptan M, Lannon E, Pfyffer D, Weber K. Innovations in acute and chronic pain biomarkers: enhancing diagnosis and personalized therapy. Reg Anesth Pain Med 2025; 50:110-120. [PMID: 39909549 PMCID: PMC11877092 DOI: 10.1136/rapm-2024-106030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 10/17/2024] [Indexed: 02/07/2025]
Abstract
Pain affects millions worldwide, posing significant challenges in diagnosis and treatment. Despite advances in understanding pain mechanisms, there remains a critical need for validated biomarkers to enhance diagnosis, prognostication, and personalized therapy. This review synthesizes recent advancements in identifying and validating acute and chronic pain biomarkers, including imaging, molecular, sensory, and neurophysiological approaches. We emphasize the emergence of composite, multimodal strategies that integrate psychosocial factors to improve the precision and applicability of biomarkers in chronic pain management. Neuroimaging techniques like MRI and positron emission tomography provide insights into structural and functional abnormalities related to pain, while electrophysiological methods like electroencepholography and magnetoencepholography assess dysfunctional processing in the pain neuroaxis. Molecular biomarkers, including cytokines, proteomics, and metabolites, offer diagnostic and prognostic potential, though extensive validation is needed. Integrating these biomarkers with psychosocial factors into clinical practice can revolutionize pain management by enabling personalized treatment strategies, improving patient outcomes, and potentially reducing healthcare costs. Future directions include the development of composite biomarker signatures, advances in artificial intelligence, and biomarker signature integration into clinical decision support systems. Rigorous validation and standardization efforts are also necessary to ensure these biomarkers are clinically useful. Large-scale collaborative research will be vital to driving progress in this field and implementing these biomarkers in clinical practice. This comprehensive review highlights the potential of biomarkers to transform acute and chronic pain management, offering hope for improved diagnosis, treatment personalization, and patient outcomes.
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Affiliation(s)
- Sean Mackey
- Division of Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Nima Aghaeepour
- Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, California, USA
| | - Brice Gaudilliere
- Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, California, USA
| | - Ming-Chih Kao
- Division of Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Merve Kaptan
- Division of Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Edward Lannon
- Division of Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Dario Pfyffer
- Division of Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Kenneth Weber
- Division of Pain Medicine, Stanford University School of Medicine, Stanford, California, USA
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Bautin P, Fortier MA, Sean M, Little G, Martel M, Descoteaux M, Léonard G, Tétreault P. What has brain diffusion magnetic resonance imaging taught us about chronic primary pain: a narrative review. Pain 2025; 166:243-261. [PMID: 39793098 PMCID: PMC11726505 DOI: 10.1097/j.pain.0000000000003345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/12/2024] [Accepted: 06/13/2024] [Indexed: 08/24/2024]
Abstract
ABSTRACT Chronic pain is a pervasive and debilitating condition with increasing implications for public health, affecting millions of individuals worldwide. Despite its high prevalence, the underlying neural mechanisms and pathophysiology remain only partly understood. Since its introduction 35 years ago, brain diffusion magnetic resonance imaging (MRI) has emerged as a powerful tool to investigate changes in white matter microstructure and connectivity associated with chronic pain. This review synthesizes findings from 58 articles that constitute the current research landscape, covering methods and key discoveries. We discuss the evidence supporting the role of altered white matter microstructure and connectivity in chronic primary pain conditions, highlighting the importance of studying multiple chronic pain syndromes to identify common neurobiological pathways. We also explore the prospective clinical utility of diffusion MRI, such as its role in identifying diagnostic, prognostic, and therapeutic biomarkers. Furthermore, we address shortcomings and challenges associated with brain diffusion MRI in chronic primary pain studies, emphasizing the need for the harmonization of data acquisition and analysis methods. We conclude by highlighting emerging approaches and prospective avenues in the field that may provide new insights into the pathophysiology of chronic pain and potential new therapeutic targets. Because of the limited current body of research and unidentified targeted therapeutic strategies, we are forced to conclude that further research is required. However, we believe that brain diffusion MRI presents a promising opportunity for enhancing our understanding of chronic pain and improving clinical outcomes.
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Affiliation(s)
- Paul Bautin
- Department of Anesthesiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Marc-Antoine Fortier
- Department of Anesthesiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Monica Sean
- Department of Anesthesiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Graham Little
- Sherbrooke Connectivity Imaging Lab (SCIL), Computer Science Department, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Marylie Martel
- Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Maxime Descoteaux
- Sherbrooke Connectivity Imaging Lab (SCIL), Computer Science Department, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Guillaume Léonard
- School of Rehabilitation, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
- Research Centre on Aging du Centre intégré universitaire de santé et de services sociaux de l’Estrie—Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Pascal Tétreault
- Department of Anesthesiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC, Canada
- Department of Medical Imaging and Radiation Sciences, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
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Zhang LB, Chen YX, Li ZJ, Geng XY, Zhao XY, Zhang FR, Bi YZ, Lu XJ, Hu L. Advances and challenges in neuroimaging-based pain biomarkers. Cell Rep Med 2024; 5:101784. [PMID: 39383872 PMCID: PMC11513815 DOI: 10.1016/j.xcrm.2024.101784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/24/2024] [Accepted: 09/19/2024] [Indexed: 10/11/2024]
Abstract
Identifying neural biomarkers of pain has long been a central theme in pain neuroscience. Here, we review the state-of-the-art candidates for neural biomarkers of acute and chronic pain. We classify these potential neural biomarkers into five categories based on the nature of their target variables, including neural biomarkers of (1) within-individual perception, (2) between-individual sensitivity, and (3) discriminability for acute pain, as well as (4) assessment and (5) prospective neural biomarkers for chronic pain. For each category, we provide a synthesized review of candidate biomarkers developed using neuroimaging techniques including functional magnetic resonance imaging (fMRI), structural magnetic resonance imaging (sMRI), and electroencephalography (EEG). We also discuss the conceptual and practical challenges in developing neural biomarkers of pain. Addressing these challenges, optimal biomarkers of pain can be developed to deepen our understanding of how the brain represents pain and ultimately help alleviate patients' suffering and improve their well-being.
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Affiliation(s)
- Li-Bo Zhang
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing 100049, China; Neuroscience and Behaviour Laboratory, Italian Institute of Technology, Rome 00161, Italy
| | - Yu-Xin Chen
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhen-Jiang Li
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xin-Yi Geng
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiang-Yue Zhao
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Feng-Rui Zhang
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Yan-Zhi Bi
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xue-Jing Lu
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Li Hu
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing 100049, China.
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5
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Chen Y, Shen P, He Y, Zeng D, Li Y, Zhang Y, Chen M, Liu C. Bibliometric analysis of functional magnetic resonance imaging studies on chronic pain over the past 20 years. Acta Neurochir (Wien) 2024; 166:307. [PMID: 39060813 DOI: 10.1007/s00701-024-06204-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024]
Abstract
PURPOSE The utilization of functional magnetic resonance imaging (fMRI) in studying the mechanisms and treatment of chronic pain has gained significant popularity. However, there is currently a dearth of literature conducting bibliometric analysis on fMRI studies focused on chronic pain. METHODS All the literature included in this study was obtained from the Science Citation Index Expanded of Web of Science Core Collection. We used CiteSpace and VOSviewer to analyze publications, authors, countries or regions, institutions, journals, references and keywords. Additionally, we evaluated the timeline and burst analysis of keywords, as well as the timeline and burst analysis of references. The search was conducted from 2004 to 2023 and completed within a single day on October 4th, 2023. RESULTS A total of 1,327 articles were retrieved. The annual publication shows an overall increasing trend. The United States has the highest number of publications and the main contributing institution is Harvard University. The journal PAIN produces the most articles. In recent years, resting-state fMRI, the prefrontal cortex, nucleus accumbens, thalamus, and migraines have been researched hotspots of fMRI studies on chronic pain. CONCLUSIONS This study provides an in-depth perspective on fMRI for chronic pain research, revealing key points, research hotspots and research trends, which offers valuable ideas for future research activities. It concludes with a summary of advances in clinical practice in this area, pointing out the need for critical evaluation of these findings in the light of guidelines and expert recommendations. It is anticipated that further high-quality research outputs will be generated in the future, which will facilitate the utilization of fMRI in clinical decision-making for chronic pain.
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Affiliation(s)
- Yiming Chen
- Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Peifeng Shen
- Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yanan He
- Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Deyi Zeng
- Department of Radiology, Panyu Health Management Center (Panyu Rehabilitation Hospital), 688 West Yushan Road Shatou Street, Panyu District, Guangzhou, China
| | - Yuanchao Li
- Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuting Zhang
- Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mengtong Chen
- Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chunlong Liu
- Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China.
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6
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Mazza M, Margoni S, Mandracchia G, Donofrio G, Fischetti A, Kotzalidis GD, Marano G, Simonetti A, Janiri D, Moccia L, Marcelli I, Sfratta G, De Berardis D, Ferrara O, Bernardi E, Restaino A, Lisci FM, D'Onofrio AM, Brisi C, Grisoni F, Calderoni C, Ciliberto M, Brugnami A, Rossi S, Spera MC, De Masi V, Marzo EM, Abate F, Boggio G, Anesini MB, Falsini C, Quintano A, Torresi A, Milintenda M, Bartolucci G, Biscosi M, Ruggiero S, Lo Giudice L, Mastroeni G, Benini E, Di Benedetto L, Caso R, Pesaresi F, Traccis F, Onori L, Chisari L, Monacelli L, Acanfora M, Gaetani E, Marturano M, Barbonetti S, Specogna E, Bardi F, De Chiara E, Stella G, Zanzarri A, Tavoletta F, Crupi A, Battisti G, Monti L, Camardese G, Chieffo D, Gasbarrini A, Scambia G, Sani G. This pain drives me crazy: Psychiatric symptoms in women with interstitial cystitis/bladder pain syndrome. World J Psychiatry 2024; 14:954-984. [PMID: 38984334 PMCID: PMC11230088 DOI: 10.5498/wjp.v14.i6.954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/22/2024] [Accepted: 05/07/2024] [Indexed: 06/19/2024] Open
Abstract
BACKGROUND Interstitial cystitis/bladder pain syndrome (IC/BPS) is an at least 6-mo noninfectious bladder inflammation of unknown origin characterized by chronic suprapubic, abdominal, and/or pelvic pain. Although the term cystitis suggests an inflammatory or infectious origin, no definite cause has been identified. It occurs in both sexes, but women are twice as much affected. AIM To systematically review evidence of psychiatric/psychological changes in persons with IC/BPS. METHODS Hypothesizing that particular psychological characteristics could underpin IC/BPS, we investigated in three databases the presence of psychiatric symptoms and/or disorders and/or psychological characteristics in patients with IC/BPS using the following strategy: ("interstitial cystitis" OR "bladder pain syndrome") AND ("mood disorder" OR depressive OR antidepressant OR depression OR depressed OR hyperthymic OR mania OR manic OR rapid cyclasterisk OR dysthymiasterisk OR dysphoriasterisk). RESULTS On September 27, 2023, the PubMed search produced 223 articles, CINAHL 62, and the combined PsycLIT/ PsycARTICLES/PsycINFO/Psychology and Behavioral Sciences Collection search 36. Search on ClinicalTrials.gov produced 14 studies, of which none had available data. Eligible were peer-reviewed articles reporting psychiatric/psychological symptoms in patients with IC/BPS, i.e. 63 articles spanning from 2000 to October 2023. These studies identified depression and anxiety problems in the IC/BPS population, along with sleep problems and the tendency to catastrophizing. CONCLUSION Psychotherapies targeting catastrophizing and life stress emotional awareness and expression reduced perceived pain in women with IC/BPS. Such concepts should be considered when implementing treatments aimed at reducing IC/BPS-related pain.
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Affiliation(s)
- Marianna Mazza
- Department of Neurosciences, Fondazione Policlinico Universitario A Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Stella Margoni
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Giuseppe Mandracchia
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Guglielmo Donofrio
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Alessia Fischetti
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | | | - Giuseppe Marano
- Department of Neurosciences, Fondazione Policlinico Universitario A Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Alessio Simonetti
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Delfina Janiri
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Lorenzo Moccia
- Department of Neurosciences, Section of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Ilaria Marcelli
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Greta Sfratta
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | | | - Ottavia Ferrara
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Evelina Bernardi
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Antonio Restaino
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | | | | | - Caterina Brisi
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Flavia Grisoni
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Claudia Calderoni
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Michele Ciliberto
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Andrea Brugnami
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Sara Rossi
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Maria Chiara Spera
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Valeria De Masi
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Ester Maria Marzo
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Francesca Abate
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Gianluca Boggio
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | | | - Cecilia Falsini
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Anna Quintano
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Alberto Torresi
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Miriam Milintenda
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Giovanni Bartolucci
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Marco Biscosi
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Sara Ruggiero
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Luca Lo Giudice
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Giulia Mastroeni
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Elisabetta Benini
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Luca Di Benedetto
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Romina Caso
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Francesco Pesaresi
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Francesco Traccis
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Luca Onori
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Luca Chisari
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Leonardo Monacelli
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Mariateresa Acanfora
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Eleonora Gaetani
- Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Monia Marturano
- Division of Gynecologic Oncology, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Sara Barbonetti
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Elettra Specogna
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Francesca Bardi
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Emanuela De Chiara
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Gianmarco Stella
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Andrea Zanzarri
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Flavio Tavoletta
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Arianna Crupi
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Giulia Battisti
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Laura Monti
- UOS Psicologia Clinica, Governo Clinico, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Giovanni Camardese
- Department of Psychiatry, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Daniela Chieffo
- UOS Psicologia Clinica, Governo Clinico, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Antonio Gasbarrini
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome 00168, Italy
| | - Giovanni Scambia
- Department of Woman and Child Health, Catholic University, Rome 00168, Italy
| | - Gabriele Sani
- UOC Psichiatria Clinica e d’Urgenza, Dipartimento di Scienze Dell’Invecchiamento, Neurologiche, Ortopediche e Della Testa-collo, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
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Cao B, Xu Q, Shi Y, Zhao R, Li H, Zheng J, Liu F, Wan Y, Wei B. Pathology of pain and its implications for therapeutic interventions. Signal Transduct Target Ther 2024; 9:155. [PMID: 38851750 PMCID: PMC11162504 DOI: 10.1038/s41392-024-01845-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 04/08/2024] [Accepted: 04/25/2024] [Indexed: 06/10/2024] Open
Abstract
Pain is estimated to affect more than 20% of the global population, imposing incalculable health and economic burdens. Effective pain management is crucial for individuals suffering from pain. However, the current methods for pain assessment and treatment fall short of clinical needs. Benefiting from advances in neuroscience and biotechnology, the neuronal circuits and molecular mechanisms critically involved in pain modulation have been elucidated. These research achievements have incited progress in identifying new diagnostic and therapeutic targets. In this review, we first introduce fundamental knowledge about pain, setting the stage for the subsequent contents. The review next delves into the molecular mechanisms underlying pain disorders, including gene mutation, epigenetic modification, posttranslational modification, inflammasome, signaling pathways and microbiota. To better present a comprehensive view of pain research, two prominent issues, sexual dimorphism and pain comorbidities, are discussed in detail based on current findings. The status quo of pain evaluation and manipulation is summarized. A series of improved and innovative pain management strategies, such as gene therapy, monoclonal antibody, brain-computer interface and microbial intervention, are making strides towards clinical application. We highlight existing limitations and future directions for enhancing the quality of preclinical and clinical research. Efforts to decipher the complexities of pain pathology will be instrumental in translating scientific discoveries into clinical practice, thereby improving pain management from bench to bedside.
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Affiliation(s)
- Bo Cao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Qixuan Xu
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Yajiao Shi
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, Peking University, Beijing, 100191, China
| | - Ruiyang Zhao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Hanghang Li
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Jie Zheng
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, Peking University, Beijing, 100191, China
| | - Fengyu Liu
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, Peking University, Beijing, 100191, China.
| | - You Wan
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, Peking University, Beijing, 100191, China.
| | - Bo Wei
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
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8
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Lackner JM, Clemens JQ, Radziwon C, Danforth TL, Ablove TS, Krasner SS, Vargovich AM, O’Leary PC, Marotto T, Naliboff BD. Cognitive Behavioral Therapy for Chronic Pelvic Pain: What Is It and Does It Work? J Urol 2024; 211:539-550. [PMID: 38228093 PMCID: PMC10939861 DOI: 10.1097/ju.0000000000003847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 01/10/2024] [Indexed: 01/18/2024]
Abstract
PURPOSE Urologic chronic pelvic pain syndrome (UCPPS), which encompasses interstitial cystitis/bladder pain syndrome in women and men and chronic prostatitis/chronic pelvic pain syndrome in men, is a common, often disabling urological disorder that is neither well understood nor satisfactorily treated with medical treatments. The past 25 years have seen the development and validation of a number of behavioral pain treatments, of which cognitive behavioral therapy (CBT) is arguably the most effective. CBT combines strategies of behavior therapy, which teaches patients more effective ways of behaving, and cognitive therapy, which focuses on correcting faulty thinking patterns. As a skills-based treatment, CBT emphasizes "unlearning" maladaptive behaviors and thoughts, and replacing them with more adaptive ones that support symptom self-management. MATERIALS AND METHODS This review describes the rationale, technical procedures, and empirical basis of CBT. RESULTS While evidence supports CBT for treatment-refractory chronic pain disorders, there is limited understanding of why or how CBT might work, for whom it is most beneficial, or the specific UCPPS symptoms (eg, pain, urinary symptoms) it effectively targets. This is the focus of EPPIC (Easing Pelvic Pain Interventions Clinical Research Program), a landmark NIH trial examining the efficacy of low-intensity, home-based CBT for UCPPS relative to a nonspecific comparator featuring self-care recommendations of AUA guidelines. CONCLUSIONS Systematic efforts to increase both the efficiency of CBT and the way it is delivered (eg, home-based treatments) are critical to scaling up CBT, optimizing its therapeutic potential, and reducing the public health burden of UCPPS.
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Affiliation(s)
- Jeffrey M. Lackner
- Division of Behavioral Medicine, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY
| | | | - Christopher Radziwon
- Division of Behavioral Medicine, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY
| | - Teresa L. Danforth
- Department of Urology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo NY
| | - Tova S. Ablove
- Department of Obstetrics and Gynecology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo NY
| | - Susan S. Krasner
- Division of Behavioral Medicine, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY
- Department of Anesthesiology, Jacobs School of Medicine, University at Buffalo, State University of New York, Buffalo NY
| | - Alison M. Vargovich
- Division of Behavioral Medicine, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY
| | - Patricia C. O’Leary
- Division of Behavioral Medicine, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY
| | - Tracy Marotto
- Department of Obstetrics and Gynecology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo NY
| | - Bruce D. Naliboff
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine and Biobehavioral Sciences, UCLA, Los Angeles, CA
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9
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Clemens JQ, Locke K, Landis JR, Kreder K, Rodriguez LV, Yang CC, Tu FF, Harte SE, Schrepf A, Farrar JT, Sutcliffe S, Naliboff BD, Williams DA, Afari N, Spitznagle T, Taple BJ, Lai HH. Validation of a simple body map to measure widespread pain in urologic chronic pelvic pain syndrome: A MAPP Research Network study. Neurourol Urodyn 2024; 43:727-737. [PMID: 38270336 PMCID: PMC10981467 DOI: 10.1002/nau.25400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 01/03/2024] [Accepted: 01/05/2024] [Indexed: 01/26/2024]
Abstract
PURPOSE In patients with urologic chronic pelvic pain syndrome (UCPPS), the presence of widespread pain appears to identify a distinct phenotype, with a different symptom trajectory and potentially different response to treatment than patients with pelvic pain only. MATERIALS AND METHODS A 76-site body map was administered four times, at weekly intervals, to 568 male and female UCPPS participants in the MAPP Network protocol. The 76 sites were classified into 13 regions (1 pelvic region and 12 nonpelvic regions). The degree of widespread pain was scored from 0 to 12 based on the number of reported nonpelvic pain regions. This continuous body map score was regressed over other measures of widespread pain, with UCPPS symptom severity, and with psychosocial variables to measure level of association. These models were repeated using an updated body map score (0-12) that incorporated a threshold of pain ≥ 4 at each site. RESULTS Body map scores showed limited variability over the 4 weekly assessments, indicating that a single baseline assessment was sufficient. The widespread pain score correlated highly with other measures of widespread pain and correlated with worsened UCPPS symptom severity and psychosocial functioning. Incorporating a pain severity threshold ≥4 resulted in only marginal increases in these correlations. CONCLUSIONS These results support the use of this 13-region body map in the baseline clinical assessment of UCPPS patients. It provides reliable data about the presence of widespread pain and does not require measurement of pain severity, making it relatively simple to use for clinical purposes.
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Affiliation(s)
| | - Kenneth Locke
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - J. Richard Landis
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Karl Kreder
- Department of Urology, University of Iowa, Iowa City, IA, USA
| | - Larissa V. Rodriguez
- Departments of Urology and Obstetrics and Gynecology, Weill Cornell Medicine, NY, USA
| | - Claire C. Yang
- Department of Urology, University of Washington, Seattle, WA, USA
| | - Frank F. Tu
- NorthShore University Health System, Pritzker School of Medicine, University of Chicago, IL, USA
| | - Steven E. Harte
- Department of Anesthesiology, University of Michigan, Ann Arbor, MI
| | - Andrew Schrepf
- Department of Anesthesiology, University of Michigan, Ann Arbor, MI
| | - John T. Farrar
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Siobhan Sutcliffe
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Bruce D. Naliboff
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | | | - Niloofar Afari
- VA Center of Excellence for Stress & Mental Health and Department of Psychiatry, University of California, San Diego, CA
| | | | - Bayley J. Taple
- Center for Behavioral Intervention Technologies, Dept. of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - H. Henry Lai
- Division of Urologic Surgery, Departments of Surgery and Anesthesiology, Washington University School of Medicine, St Louis, MO, USA
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10
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Heukamp NJ, Banaschewski T, Bokde AL, Desrivières S, Grigis A, Garavan H, Gowland P, Heinz A, Kandić M, Brühl R, Martinot JL, Paillère Martinot ML, Artiges E, Papadopoulos Orfanos D, Lemaitre H, Löffler M, Poustka L, Hohmann S, Millenet S, Fröhner JH, Smolka MN, Usai K, Vaidya N, Walter H, Whelan R, Schumann G, Flor H, Nees F. Adolescents' pain-related ontogeny shares a neural basis with adults' chronic pain in basothalamo-cortical organization. iScience 2024; 27:108954. [PMID: 38322983 PMCID: PMC10845062 DOI: 10.1016/j.isci.2024.108954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 10/19/2023] [Accepted: 01/15/2024] [Indexed: 02/08/2024] Open
Abstract
During late adolescence, the brain undergoes ontogenic organization altering subcortical-cortical circuitry. This includes regions implicated in pain chronicity, and thus alterations in the adolescent ontogenic organization could predispose to pain chronicity in adulthood - however, evidence is lacking. Using resting-state functional magnetic resonance imaging from a large European longitudinal adolescent cohort and an adult cohort with and without chronic pain, we examined links between painful symptoms and brain connectivity. During late adolescence, thalamo-, caudate-, and red nucleus-cortical connectivity were positively and subthalamo-cortical connectivity negatively associated with painful symptoms. Thalamo-cortical connectivity, but also subthalamo-cortical connectivity, was increased in adults with chronic pain compared to healthy controls. Our results indicate a shared basis in basothalamo-cortical circuitries between adolescent painful symptomatology and adult pain chronicity, with the subthalamic pathway being differentially involved, potentially due to a hyperconnected thalamo-cortical pathway in chronic pain and ontogeny-driven organization. This can inform neuromodulation-based prevention and early intervention.
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Affiliation(s)
- Nils Jannik Heukamp
- Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany
| | - Tobias Banaschewski
- Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159 Mannheim, Germany
| | - Arun L.W. Bokde
- Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
| | - Sylvane Desrivières
- Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology & Neuroscience, SGDP Centre, King’s College London, London, UK
| | - Antoine Grigis
- NeuroSpin, CEA, Université Paris-Saclay, 91191 Gif-sur-Yvette, France
| | - Hugh Garavan
- Departments of Psychiatry and Psychology, University of Vermont, Burlington, Vermont 05405, USA
| | - Penny Gowland
- Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, UK
| | - Andreas Heinz
- Department of Psychiatry and Psychotherapy CCM, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Mina Kandić
- Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, Germany
| | - Rüdiger Brühl
- Physikalisch-Technische Bundesanstalt (PTB), Braunschweig, Berlin, Germany
| | - Jean-Luc Martinot
- Institut National de la Santé et de la Recherche Médicale, INSERM U A10 "Trajectoires développementales en psychiatrie", Université Paris-Saclay, Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli, Gif-sur-Yvette, France
| | - Marie-Laure Paillère Martinot
- Institut National de la Santé et de la Recherche Médicale, INSERM U A10 "Trajectoires développementales en psychiatrie", Université Paris-Saclay, Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli, Gif-sur-Yvette, France
- AP-HP, Sorbonne Université, Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Paris, France
| | - Eric Artiges
- Institut National de la Santé et de la Recherche Médicale, INSERM U A10 "Trajectoires développementales en psychiatrie", Université Paris-Saclay, Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli, Gif-sur-Yvette, France
- Psychiatry Department, EPS Barthélémy Durand, Etampes, France
| | | | - Herve Lemaitre
- NeuroSpin, CEA, Université Paris-Saclay, 91191 Gif-sur-Yvette, France
- Institut des Maladies Neurodégénératives, UMR 5293, CNRS, CEA, Université de Bordeaux, 33076 Bordeaux, France
| | - Martin Löffler
- Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, Germany
- Clinical Psychology, Department of Experimental Psychology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Integrative Spinal Research Group, Department of Chiropractic Medicine, University Hospital Balgrist, University of Zurich, Zurich, Switzerland
| | - Luise Poustka
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, von-Siebold-Str. 5, 37075 Göttingen, Germany
| | - Sarah Hohmann
- Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159 Mannheim, Germany
| | - Sabina Millenet
- Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159 Mannheim, Germany
| | - Juliane H. Fröhner
- Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany
| | - Michael N. Smolka
- Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany
| | - Katrin Usai
- Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, Germany
| | - Nilakshi Vaidya
- Centre for Population Neuroscience and Stratified Medicine (PONS), Department of Psychiatry and Neuroscience, Charité Universitätsmedizin, Berlin, Germany
| | - Henrik Walter
- Department of Psychiatry and Psychotherapy CCM, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Robert Whelan
- School of Psychology and Global Brain Health Institute, Trinity College Dublin, Berlin, Ireland
| | - Gunter Schumann
- Centre for Population Neuroscience and Stratified Medicine (PONS), Department of Psychiatry and Neuroscience, Charité Universitätsmedizin, Berlin, Germany
- Centre for Population Neuroscience and Precision Medicine (PONS), Institute for Science and Technology of Brain-inspired Intelligence (ISTBI), Fudan University, Shanghai, China
| | - Herta Flor
- Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, Germany
- Department of Psychology, School of Social Sciences, University of Mannheim, 68131 Mannheim, Germany
| | - Frauke Nees
- Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany
- Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159 Mannheim, Germany
- Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, Germany
| | - IMAGEN Consortium
- Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany
- Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159 Mannheim, Germany
- Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
- Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology & Neuroscience, SGDP Centre, King’s College London, London, UK
- NeuroSpin, CEA, Université Paris-Saclay, 91191 Gif-sur-Yvette, France
- Departments of Psychiatry and Psychology, University of Vermont, Burlington, Vermont 05405, USA
- Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, UK
- Department of Psychiatry and Psychotherapy CCM, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, Germany
- Physikalisch-Technische Bundesanstalt (PTB), Braunschweig, Berlin, Germany
- Institut National de la Santé et de la Recherche Médicale, INSERM U A10 "Trajectoires développementales en psychiatrie", Université Paris-Saclay, Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli, Gif-sur-Yvette, France
- AP-HP, Sorbonne Université, Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Paris, France
- Psychiatry Department, EPS Barthélémy Durand, Etampes, France
- Institut des Maladies Neurodégénératives, UMR 5293, CNRS, CEA, Université de Bordeaux, 33076 Bordeaux, France
- Clinical Psychology, Department of Experimental Psychology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Integrative Spinal Research Group, Department of Chiropractic Medicine, University Hospital Balgrist, University of Zurich, Zurich, Switzerland
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, von-Siebold-Str. 5, 37075 Göttingen, Germany
- Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany
- Centre for Population Neuroscience and Stratified Medicine (PONS), Department of Psychiatry and Neuroscience, Charité Universitätsmedizin, Berlin, Germany
- School of Psychology and Global Brain Health Institute, Trinity College Dublin, Berlin, Ireland
- Centre for Population Neuroscience and Precision Medicine (PONS), Institute for Science and Technology of Brain-inspired Intelligence (ISTBI), Fudan University, Shanghai, China
- Department of Psychology, School of Social Sciences, University of Mannheim, 68131 Mannheim, Germany
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11
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Martucci KT, Karshikoff B, Mackey SC. Links between brain neuroimaging and blood inflammatory markers in urological chronic pelvic pain syndrome. Physiol Behav 2023; 271:114358. [PMID: 37769862 PMCID: PMC10599305 DOI: 10.1016/j.physbeh.2023.114358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 09/12/2023] [Accepted: 09/25/2023] [Indexed: 10/02/2023]
Abstract
Urological chronic pelvic pain syndrome (UCPPS) is a debilitating painful condition with unclear etiology. Prior researchers have indicated that compared to healthy controls, patients with UCPPS demonstrated altered brain activity. Researchers have also shown that in UCPPS, several blood inflammatory markers relate to clinical variables of pain, fatigue, and pain widespreadness. However, how altered brain function in patients with UCPPS relates to blood inflammation remains unknown. To extend and connect prior findings of altered brain function and inflammatory factors in UCPPS, we conducted a secondary analysis of data from a cohort of UCPPS patients (N = 29) and healthy controls (N = 31) who provided both neuroimaging and blood data (National Institute of Health MAPP Research Network publicly available dataset). In our present study, we aimed to evaluate relationships between a priori-defined brain neuroimaging markers and inflammatory factors of interest and their relationships to pain-psychological variables. We hypothesized that two brain alterations of interest (i.e., PCC - left hippocampus functional connectivity and PCC - bilateral amygdala functional connectivity) would be correlated with four cytokine markers of interest: interleukin (IL) - 6, tumor necrosis factor-alpha (TNF-a), IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In the UCPPS cohort, we identified a significant PCC - left hippocampus functional connectivity relationship with IL-6 (p = 0.0044). Additionally, in the UCPPS cohort, we identified a PCC - amygdala functional connectivity relationship with GM-CSF which did not meet our model's threshold for statistical significance (p = 0.0665). While these data are preliminary and cross-sectional, our findings suggest connections between brain function and levels of low-grade systemic inflammation in UCPPS. Thus, while further study is needed, our data indicate the potential for advancing the understanding of how brain functional circuits may relate to clinical symptoms and systemic inflammation.
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Affiliation(s)
- Katherine T Martucci
- Human Affect and Pain Neuroscience Laboratory, Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA.
| | - Bianka Karshikoff
- UiS Biopsychology Research Group, Department of Social Studies, Stavanger University, Stavanger, Norway; Department of Clinical Neuroscience, Karolinska Institute, Solna, Sweden
| | - Sean C Mackey
- Stanford Neuroscience and Pain Laboratory, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, CA, USA
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12
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Wang C, Kutch JJ, Labus JS, Yang CC, Harris RE, Mayer EA, Ellingson BM. Reproducible Microstructural Changes in the Brain Associated With the Presence and Severity of Urologic Chronic Pelvic Pain Syndrome (UCPPS): A 3-Year Longitudinal Diffusion Tensor Imaging Study From the MAPP Network. THE JOURNAL OF PAIN 2023; 24:627-642. [PMID: 36435486 PMCID: PMC10676766 DOI: 10.1016/j.jpain.2022.11.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 11/14/2022] [Accepted: 11/16/2022] [Indexed: 11/24/2022]
Abstract
Microstructural alterations have been reported in patients with urologic chronic pelvic pain syndrome (UCPPS). However, it isn't clear whether these alterations are reproducible within 6 months or whether long-term symptom improvement is associated with specific microstructural changes. Using data from the MAPP-II Research Network, the current study performed population-based voxel-wise DTI and probabilistic tractography in a large sample of participants from the multicenter cohort with UCPPS (N = 364) and healthy controls (HCs, N = 61) over 36 months. While fractional anisotropy (FA) differences between UCPPS patients and HCs were observed to be unique at baseline and 6-month follow-up visits, consistent aberrations in mean diffusivity (MD) were observed between UCPPS and HCs at baseline and repeated at 6 months. Additionally, compared to HCs, UCPPS patients showed stronger structural connectivity (SC) between the left postcentral gyrus and the left precuneus, and weaker SC from the left cuneus to the left lateral occipital cortex and the isthmus of the left cingulate cortex at baseline and 6-month. By 36 months, reduced FA and MD aberrations in these same regions were associated with symptom improvement in UCPPS. Together, results suggest changes in white matter microstructure may play a role in the persistent pain symptoms in UCPPS. PERSPECTIVE: This longitudinal study identified reproducible, "disease-associated" patterns in altered mean diffusivity and abnormal microstructural connectivity in UCPPS comparing to HCs over 6 months. These differences were found in regions involved in sensory processing and integration and pain modulation, making it potentially amenable for clinical interventions that target synaptic and/or neuronal reorganization.
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Affiliation(s)
- Chencai Wang
- Department of Radiological Science, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Jason J Kutch
- Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, California
| | - Jennifer S Labus
- Oppenheimer Center for the Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Claire C Yang
- Department of Urology, University of Washington, Seattle, Washington
| | - Richard E Harris
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan
| | - Emeran A Mayer
- Oppenheimer Center for the Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Benjamin M Ellingson
- Department of Radiological Science, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
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13
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Edwards RR, Schreiber KL, Dworkin RH, Turk DC, Baron R, Freeman R, Jensen TS, Latremoliere A, Markman JD, Rice ASC, Rowbotham M, Staud R, Tate S, Woolf CJ, Andrews NA, Carr DB, Colloca L, Cosma-Roman D, Cowan P, Diatchenko L, Farrar J, Gewandter JS, Gilron I, Kerns RD, Marchand S, Niebler G, Patel KV, Simon LS, Tockarshewsky T, Vanhove GF, Vardeh D, Walco GA, Wasan AD, Wesselmann U. Optimizing and Accelerating the Development of Precision Pain Treatments for Chronic Pain: IMMPACT Review and Recommendations. THE JOURNAL OF PAIN 2023; 24:204-225. [PMID: 36198371 PMCID: PMC10868532 DOI: 10.1016/j.jpain.2022.08.010] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 08/01/2022] [Accepted: 08/17/2022] [Indexed: 11/06/2022]
Abstract
Large variability in the individual response to even the most-efficacious pain treatments is observed clinically, which has led to calls for a more personalized, tailored approach to treating patients with pain (ie, "precision pain medicine"). Precision pain medicine, currently an aspirational goal, would consist of empirically based algorithms that determine the optimal treatments, or treatment combinations, for specific patients (ie, targeting the right treatment, in the right dose, to the right patient, at the right time). Answering this question of "what works for whom" will certainly improve the clinical care of patients with pain. It may also support the success of novel drug development in pain, making it easier to identify novel treatments that work for certain patients and more accurately identify the magnitude of the treatment effect for those subgroups. Significant preliminary work has been done in this area, and analgesic trials are beginning to utilize precision pain medicine approaches such as stratified allocation on the basis of prespecified patient phenotypes using assessment methodologies such as quantitative sensory testing. Current major challenges within the field include: 1) identifying optimal measurement approaches to assessing patient characteristics that are most robustly and consistently predictive of inter-patient variation in specific analgesic treatment outcomes, 2) designing clinical trials that can identify treatment-by-phenotype interactions, and 3) selecting the most promising therapeutics to be tested in this way. This review surveys the current state of precision pain medicine, with a focus on drug treatments (which have been most-studied in a precision pain medicine context). It further presents a set of evidence-based recommendations for accelerating the application of precision pain methods in chronic pain research. PERSPECTIVE: Given the considerable variability in treatment outcomes for chronic pain, progress in precision pain treatment is critical for the field. An array of phenotypes and mechanisms contribute to chronic pain; this review summarizes current knowledge regarding which treatments are most effective for patients with specific biopsychosocial characteristics.
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Affiliation(s)
| | | | | | - Dennis C Turk
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington
| | - Ralf Baron
- Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital Schleswig-Holstein, Arnold-Heller-Straße 3, House D, 24105 Kiel, Germany
| | - Roy Freeman
- Harvard Medical School, Boston, Massachusetts
| | | | | | | | | | | | | | | | | | - Nick A Andrews
- Salk Institute for Biological Studies, San Diego, California
| | | | | | | | - Penney Cowan
- American Chronic Pain Association, Rocklin, California
| | - Luda Diatchenko
- Department of Anesthesia and Faculty of Dentistry, McGill University, Montreal, California
| | - John Farrar
- University of Pennsylvania, Philadelphia, Pennsylvania
| | | | | | - Robert D Kerns
- Yale University, Departments of Psychiatry, Neurology, and Psychology, New Haven, Connecticut
| | | | | | - Kushang V Patel
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington
| | | | | | | | | | - Gary A Walco
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington
| | - Ajay D Wasan
- University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ursula Wesselmann
- Department of Anesthesiology/Division of Pain Medicine, Neurology and Psychology, The University of Alabama at Birmingham, Birmingham, Alabama
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14
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Takeuchi N. Pain control based on oscillatory brain activity using transcranial alternating current stimulation: An integrative review. Front Hum Neurosci 2023; 17:941979. [PMID: 36742359 PMCID: PMC9892942 DOI: 10.3389/fnhum.2023.941979] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 01/04/2023] [Indexed: 01/20/2023] Open
Abstract
Developing effective tools and strategies to relieve chronic pain is a high-priority scientific and clinical goal. In particular, the brain regions related to pain processing have been investigated as potential targets to relieve pain by non-invasive brain stimulation (NIBS). In addition to elucidating the relationship between pain and oscillatory brain activity, transcranial alternating current stimulation (tACS), which can non-invasively entrain oscillatory brain activity and modulate oscillatory brain communication, has attracted scientific attention as a possible technique to control pain. This review focuses on the use of tACS to relieve pain through the manipulation of oscillatory brain activity and its potential clinical applications. Several studies have reported that tACS on a single brain reduces pain by normalizing abnormal oscillatory brain activity in patients with chronic pain. Interpersonal tACS approaches based on inter-brain synchrony to manipulate inter-brain communication may result in pain relief via prosocial effects. Pain is encoded by the spatiotemporal neural communication that represents the integration of cognitive, emotional-affective, and sensorimotor aspects of pain. Therefore, future studies should seek to identify the pathological oscillatory brain communication in chronic pain as a therapeutic target for tACS. In conclusion, tACS could be effective for re-establishing oscillatory brain activity and assisting social interaction, and it might help develop novel approaches for pain control.
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15
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Individual treatment expectations predict clinical outcome after lumbar injections against low back pain. Pain 2023; 164:132-141. [PMID: 35543638 DOI: 10.1097/j.pain.0000000000002674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 04/15/2022] [Indexed: 01/09/2023]
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16
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Zhang YN, Xing XX, Chen L, Dong X, Pan HT, Hua XY, Wang K. Modification of the resting-state network involved at different stages of neuropathic pain. Neurosci Lett 2022; 789:136866. [PMID: 36075318 DOI: 10.1016/j.neulet.2022.136866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/20/2022] [Accepted: 09/02/2022] [Indexed: 10/14/2022]
Abstract
Neuropathic pain (NeuP) is shown to be associated with abnormal changes in several specific brain regions. However, the large-scale interactivity of neuronal networks underlying the sensory and emotional abnormalities during NeuP remains unexplored. The present study aimed to explore the alterations in the relevant functional resting-state networks (RSNs) and their intra-networks at the different stages of NeuP based on resting-state functional magnetic resonance imaging (rs-fMRI). A NeuP rat model was established by chronic constriction injury (CCI). Three RSNs were identified to be associated with the NeuP, including the default mode network (DMN), sensorimotor network (SMN), and interoceptive network (IN). The functional connectivity (FC) of the left caudate putamen (CPu) within the DMN and the right piriform cortex within the IN were significantly reduced at the early stage of NeuP, when the maximum allodynia was apparent early, which reflected the suppressed function of the DMN and IN. At 4 weeks post-CCI, when negative emotions were present, the FC of the right insular cortex in the SMN and left visual cortex in the IN were significantly elevated, representing the increased excitability of both SMN and IN. Our study revealed the characteristic functional organization at the network level induced by NeuP and emphasized the role of SMN, DMN, and IN in the pathological mechanisms of NeuP.
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Affiliation(s)
- Ya-Nan Zhang
- Acupuncture Anesthesia Clinical Research Institute, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Xiang-Xin Xing
- Department of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai 201203, China
| | - Liu Chen
- Acupuncture Anesthesia Clinical Research Institute, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Xin Dong
- Acupuncture Anesthesia Clinical Research Institute, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Hao-Tian Pan
- Acupuncture Anesthesia Clinical Research Institute, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Xu-Yun Hua
- Department of Traumatology and Orthopedics, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai 201203, China.
| | - Ke Wang
- Acupuncture Anesthesia Clinical Research Institute, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
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17
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Tajerian M, Amrami M, Betancourt JM. Is there hemispheric specialization in the chronic pain brain? Exp Neurol 2022; 355:114137. [PMID: 35671801 PMCID: PMC10723052 DOI: 10.1016/j.expneurol.2022.114137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 05/31/2022] [Accepted: 06/01/2022] [Indexed: 11/25/2022]
Abstract
Organismal bilateral symmetry is associated with near-identical halves of the central nervous system, with certain functions displaying specialization through one brain hemisphere. The processing of pain in the brain as well as brain plasticity in the context of painful injuries have garnered much attention in recent decades. Noninvasive brain imaging studies in pain-free human subjects have identified multiple brain regions that are linked to the sensory and affective components of pain. Longlasting adaptations in brains of chronic pain sufferers have likewise been described, suggesting a mechanism for pain chronification. Invasive molecular and biochemical studies in animal models have expanded on these findings, with added emphasis on the role of specific genes and molecules involved. To date, the extent of hemispheric asymmetry in the context of pain is not well-understood. This topical review evaluates the evidence of hemispheric specialization observed in humans and rodent models of pain and compares it to findings where such asymmetry is absent. Our review shows conflicting information regarding the existence of pain-related asymmetry, and if so, the side to which it can be localized. This could be due to the heterogeneity of pain processing pathways, heterogeneity in study parameters, as well as differences in data reporting. With the advent of progressively sophisticated non-invasive tools that can be used in human subjects, in addition to more precise methods to visualize and control specific brain regions or neuronal ensembles in animal models, we predict that the next few decades will witness a better understanding of the supraspinal control and processing of chronic pain, including the role of each of its hemispheres.
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Affiliation(s)
- Maral Tajerian
- Department of Biology, Queens College, City University of New York, Queens, NY 11367, USA; The Graduate Center, City University of New York, New York, NY 10016, USA.
| | - Michael Amrami
- Department of Biology, Queens College, City University of New York, Queens, NY 11367, USA
| | - John Michael Betancourt
- Neuroscience Graduate Program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10021, USA
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18
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Kmiecik MJ, Tu FF, Silton RL, Dillane KE, Roth GE, Harte SE, Hellman KM. Cortical mechanisms of visual hypersensitivity in women at risk for chronic pelvic pain. Pain 2022; 163:1035-1048. [PMID: 34510138 PMCID: PMC8882209 DOI: 10.1097/j.pain.0000000000002469] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 08/19/2021] [Indexed: 11/25/2022]
Abstract
ABSTRACT Increased sensory sensitivity across non-nociceptive modalities is a common symptom of chronic pain conditions and is associated with chronic pain development. Providing a better understanding of the brain-behavior relationships that underlie multimodal hypersensitivity (MMH) may clarify the role of MMH in the development of chronic pain. We studied sensory hypersensitivity in a cohort of women (n = 147) who had diary confirmation of menstrual status and were enriched with risk factors for chronic pelvic pain, such as dysmenorrhea and increased bladder sensitivity. We administered 2 experimental tasks to evaluate the cross-modal relationship between visual and visceral sensitivity. Visual sensitivity was probed by presenting participants with a periodic pattern-reversal checkerboard stimulus presented across 5 brightness intensities during electroencephalography recording. Self-reported visual unpleasantness ratings for each brightness intensity were simultaneously assessed. Visceral sensitivity was evaluated with an experimental bladder-filling task associated with early clinical symptoms of chronic pelvic pain. Visually evoked cortical activity increased with brightness intensity across the entire scalp, especially at occipital electrode sites. Visual stimulation-induced unpleasantness was associated with provoked bladder pain and evoked primary visual cortex activity. However, the relationship between unpleasantness and cortical activity was moderated by provoked bladder pain. These results demonstrate that activity in the primary visual cortex is not greater in individuals with greater visceral sensitivity. We hypothesize that downstream interpretation or integration of this signal is amplified in individuals with visceral hypersensitivity. Future studies aimed at reducing MMH in chronic pain conditions should prioritize targeting of cortical mechanisms responsible for aberrant downstream sensory integration.
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Affiliation(s)
- Matthew J. Kmiecik
- Department of Ob/Gyn, NorthShore University HealthSystem, Evanston, IL, United States
- Department of Ob/Gyn, Pritzker School of Medicine, University of Chicago, Chicago, IL, United States
| | - Frank F. Tu
- Department of Ob/Gyn, NorthShore University HealthSystem, Evanston, IL, United States
- Department of Ob/Gyn, Pritzker School of Medicine, University of Chicago, Chicago, IL, United States
| | - Rebecca L. Silton
- Department of Psychology, Loyola University Chicago, Chicago, IL, United States
| | - Katlyn E. Dillane
- Department of Ob/Gyn, NorthShore University HealthSystem, Evanston, IL, United States
| | - Genevieve E. Roth
- Department of Ob/Gyn, NorthShore University HealthSystem, Evanston, IL, United States
| | - Steven E. Harte
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI
| | - Kevin M. Hellman
- Department of Ob/Gyn, NorthShore University HealthSystem, Evanston, IL, United States
- Department of Ob/Gyn, Pritzker School of Medicine, University of Chicago, Chicago, IL, United States
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19
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Naliboff BD, Locke K, Schrepf AD, Griffith JW, Moldwin R, Krieger JN, Rodriguez LV, Stephens-Shields AJ, Clemens JQ, Lai HH, Sutcliffe S, Taple BJ, Williams D, Pontari MA, Mullins C, Landis JR. Reliability and Validity of Pain and Urinary Symptom Severity Assessment in Urological Chronic Pelvic Pain: A MAPP Network Analysis. J Urol 2022; 207:1246-1255. [PMID: 35060778 PMCID: PMC10494963 DOI: 10.1097/ju.0000000000002438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2022] [Indexed: 11/25/2022]
Abstract
PURPOSE We assessed the reliability and validity of an efficient severity assessment for pelvic pain and urinary symptoms in urological chronic pelvic pain syndrome, which consists of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS A total of 578 patients were assessed using brief, empirically derived self-report scales for pelvic pain severity (PPS) and urinary symptom severity (USS) 4 times during a 1-month period and baseline clinic visit that included urological, pain and illness-impact measures. Mild, moderate and severe categories on each dimension were examined for measurement stability and construct validity. RESULTS PPS and USS severity categories had adequate reliability and both discriminant validity (differential relationships with specific clinical and self-report measures) and convergent validity (common association with nonurological somatic symptoms). For example, increasing PPS was associated with pelvic tenderness and widespread pelvic pain, whereas USS was associated with urgency during a bladder filling test and increased sensory sensitivity. PPS and USS categories were independently associated with nonurological pain and emotional distress. A descriptive analysis identified higher likelihood characteristics associated with having moderate to severe PPS or USS or both. Lack of sex interactions indicated that the measures are comparable in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. CONCLUSIONS Women and men with urological chronic pelvic pain syndrome can be reliably subgrouped using brief self-report measures of mild, moderate or severe pelvic pain and urinary symptoms. Comparisons with a broad range of clinical variables demonstrate the validity and potential clinical utility of these classifications, including use in clinical trials, health services and biological research.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Chris Mullins
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
| | - J. Richard Landis
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
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20
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López-Solà M, Pujol J, Monfort J, Deus J, Blanco-Hinojo L, Harrison BJ, Wager TD. The neurologic pain signature responds to nonsteroidal anti-inflammatory treatment vs placebo in knee osteoarthritis. Pain Rep 2022; 7:e986. [PMID: 35187380 PMCID: PMC8853614 DOI: 10.1097/pr9.0000000000000986] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 12/02/2021] [Accepted: 12/11/2021] [Indexed: 11/25/2022] Open
Abstract
Supplemental Digital Content is Available in the Text. fMRI-based measures, validated for nociceptive pain, respond to acute osteoarthritis pain, are not sensitive to placebo, and are mild-to-moderately sensitive to naproxen. Introduction: Many drug trials for chronic pain fail because of high placebo response rates in primary endpoints. Neurophysiological measures can help identify pain-linked pathophysiology and treatment mechanisms. They can also help guide early stop/go decisions, particularly if they respond to verum treatment but not placebo. The neurologic pain signature (NPS), an fMRI-based measure that tracks evoked pain in 40 published samples and is insensitive to placebo in healthy adults, provides a potentially useful neurophysiological measure linked to nociceptive pain. Objectives: This study aims to validate the NPS in knee osteoarthritis (OA) patients and test the effects of naproxen on this signature. Methods: In 2 studies (50 patients, 64.6 years, 75% females), we (1) test the NPS and other control signatures related to negative emotion in knee OA pain patients; (2) test the effect of placebo treatments; and (3) test the effect of naproxen, a routinely prescribed nonsteroidal anti-inflammatory drug in OA. Results: The NPS was activated during knee pain in OA (d = 1.51, P < 0.001) and did not respond to placebo (d = 0.12, P = 0.23). A single dose of naproxen reduced NPS responses (vs placebo, NPS d = 0.34, P = 0.03 and pronociceptive NPS component d = 0.38, P = 0.02). Naproxen effects were specific for the NPS and did not appear in other control signatures. Conclusion: This study provides preliminary evidence that fMRI-based measures, validated for nociceptive pain, respond to acute OA pain, do not appear sensitive to placebo, and are mild-to-moderately sensitive to naproxen.
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Affiliation(s)
- Marina López-Solà
- Department of Medicine, School of Medicine and Health Sciences, Serra Hunter Faculty Program, University of Barcelona, Barcelona, Spain
| | - Jesus Pujol
- MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain.,Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM, Barcelona, Spain
| | - Jordi Monfort
- Rheumatology Department, Hospital del Mar, Barcelona, Spain
| | - Joan Deus
- MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain.,Department of Clinical and Health Psychology, Autonomous University of Barcelona, Barcelona, Spain
| | - Laura Blanco-Hinojo
- MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain.,Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM, Barcelona, Spain
| | - Ben J Harrison
- Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne & Melbourne Health, Melbourne, Australia
| | - Tor D Wager
- Department of Psychological and Brain Sciences, Dartmouth College, Dartmouth, MA, USA
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21
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Abstract
Neuroimaging methods can be used to identify biomarkers of acute and chronic pain.
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Affiliation(s)
- Irene Tracey
- Wellcome Centre for Integrative Neuroimaging, Wolfson Building, Nuffield Department Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
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22
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Sheetz T, Clemens JQ, Crescenze I. Neuroanatomy of Bladder Pain. CURRENT BLADDER DYSFUNCTION REPORTS 2021. [DOI: 10.1007/s11884-021-00629-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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23
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Fuentes IM, Jones BM, Brake AD, Pierce AN, Eller OC, Supple RM, Wright DE, Christianson JA. Voluntary wheel running improves outcomes in an early life stress-induced model of urologic chronic pelvic pain syndrome in male mice. Pain 2021; 162:1681-1691. [PMID: 33399417 PMCID: PMC8119308 DOI: 10.1097/j.pain.0000000000002178] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 12/02/2020] [Indexed: 12/13/2022]
Abstract
ABSTRACT Patients with a history of early life stress (ELS) exposure have an increased risk of developing chronic pain and mood disorders later in life. The severity of ELS in patients with urologic chronic pelvic pain syndrome (UCPPS) is directly correlated with symptom severity and increased comorbidity, and is inversely related to likelihood of improvement. Voluntary exercise improves chronic pain symptoms, and our group and others have shown that voluntary wheel running can improve outcomes in stress-induced UCPPS models, suggesting that exercise may negate some of the outcomes associated with ELS. Here, we provide further evidence that voluntary wheel running can attenuate increased perigenital mechanical sensitivity, bladder output, and mast cell degranulation in the bladder and prostate in male mice that underwent neonatal maternal separation (NMS). Sedentary male NMS mice had reduced serum corticosterone, which was not impacted by voluntary wheel running, although stress-related regulatory gene expression in the hypothalamus and hippocampus was significantly increased after exercise. Neurogenesis in the dentate gyrus of the hippocampus was diminished in sedentary NMS mice and significantly increased in both exercised naïve and NMS mice. Sucrose consumption increased in exercised naïve but not NMS mice, and anxiety behaviors measured on an elevated plus maze were increased after exercise. Together these data suggest that voluntary wheel running is sufficient to normalize many of the UCPPS-related outcomes resulting from NMS. Exercise also increased hippocampal neurogenesis and stress-related gene expression within the hypothalamic-pituitary-adrenal axis, further supporting exercise as a nonpharmacological intervention for attenuating outcomes related to ELS exposure.
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Affiliation(s)
- Isabella M. Fuentes
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Brittni M. Jones
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Aaron D. Brake
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Angela N. Pierce
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Olivia C. Eller
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Rachel M. Supple
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Douglas E. Wright
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
- Department of Anesthesiology, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Julie A. Christianson
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
- Department of Anesthesiology, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
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24
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Fitzcharles MA, Cohen SP, Clauw DJ, Littlejohn G, Usui C, Häuser W. Nociplastic pain: towards an understanding of prevalent pain conditions. Lancet 2021; 397:2098-2110. [PMID: 34062144 DOI: 10.1016/s0140-6736(21)00392-5] [Citation(s) in RCA: 522] [Impact Index Per Article: 130.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 08/26/2020] [Accepted: 09/24/2020] [Indexed: 12/26/2022]
Abstract
Nociplastic pain is the semantic term suggested by the international community of pain researchers to describe a third category of pain that is mechanistically distinct from nociceptive pain, which is caused by ongoing inflammation and damage of tissues, and neuropathic pain, which is caused by nerve damage. The mechanisms that underlie this type of pain are not entirely understood, but it is thought that augmented CNS pain and sensory processing and altered pain modulation play prominent roles. The symptoms observed in nociplastic pain include multifocal pain that is more widespread or intense, or both, than would be expected given the amount of identifiable tissue or nerve damage, as well as other CNS-derived symptoms, such as fatigue, sleep, memory, and mood problems. This type of pain can occur in isolation, as often occurs in conditions such as fibromyalgia or tension-type headache, or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain, as might occur in chronic low back pain. It is important to recognise this type of pain, since it will respond to different therapies than nociceptive pain, with a decreased responsiveness to peripherally directed therapies such as anti-inflammatory drugs and opioids, surgery, or injections.
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Affiliation(s)
- Mary-Ann Fitzcharles
- Department of Rheumatology and Alan Edwards Pain Management Unit, McGill University, Montreal, QC, Canada.
| | - Steven P Cohen
- Department of Psychiatry and Behavioral Sciences and Department of Anesthesiology and Critical Care Medicine, Neurology and Physical Medicine and Rehabilitation at Johns Hopkins Hospital, Baltimore, MD, USA; Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Daniel J Clauw
- Departments of Anesthesiology, Medicine, and Psychiatry, Chronic Pain and Fatigue Research Center, the University of Michigan Medical School, Ann Arbor, MI, USA
| | - Geoffrey Littlejohn
- Department of Rheumatology and Department of Medicine, Monash Health and Monash University, Clayton, Melbourne, VIC, Australia
| | - Chie Usui
- Department of Psychiatry, Juntendo University School of Medicine, Tokyo, Japan
| | - Winfried Häuser
- Department Internal Medicine I, Klinikum Saarbrücken, Saarbrücken, Germany; Department of Psychosomatic Medicine and Psychotherapy, Technische Universität München, München, Germany
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25
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Early changes in brain network topology and activation of affective pathways predict persistent pain in the rat. Pain 2021; 162:45-55. [PMID: 32773593 DOI: 10.1097/j.pain.0000000000002010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Adaptations in brain communication are associated with multiple pain disorders and are hypothesized to promote the transition from acute to chronic pain. Despite known increases in brain synaptic activity, it is unknown if and how changes in pathways and networks contribute to persistent pain. A tunable rat model that induces transient or persistent temporomandibular joint pain was used to characterize brain network and subcircuit changes when sensitivity is detected in both transient and persistent pain groups and later when sensitivity is present only for the persistent pain group. Brain activity was measured by F-FDG positron emission tomography imaging and used to construct intersubject correlation networks; network connectivity distributions, diagnostics, and community structure were assessed. Activation of subcircuits was tested by structural equation modeling. Findings reveal differences in the brain networks at day 7 between the persistent and transient pain groups, a time when peripheral sensitivity is detected in both groups, but spontaneous pain occurs only in the persistent pain group. At day 7, increased (P ≤ 0.01) clustering, node strength, network segregation, and activation of prefrontal-limbic pathways are observed only in the group that develops persistent pain. Later, increased clustering and node strength are more pronounced with persistent pain, particularly within the limbic system, and decrease when pain resolves. Pretreatment with intra-articular etanercept to attenuate pain confirms that these adaptations are associated with pain onset. Results suggest that early and sustained brain changes can differentiate persistent and transient pain, implying they could be useful as prognostic biomarkers for persistent pain and in identifying therapeutic targets.
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26
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Ketai LH, Komesu YM, Schrader RM, Rogers RG, Sapien RE, Dodd AB, Mayer AR. Mind-body (hypnotherapy) treatment of women with urgency urinary incontinence: changes in brain attentional networks. Am J Obstet Gynecol 2021; 224:498.e1-498.e10. [PMID: 33122028 PMCID: PMC10739935 DOI: 10.1016/j.ajog.2020.10.041] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 10/02/2020] [Accepted: 10/23/2020] [Indexed: 11/17/2022]
Abstract
BACKGROUND Prior study of patients with urgency urinary incontinence by functional magnetic resonance imaging showed altered function in areas of the brain associated with interoception and salience and with attention. Our randomized controlled trial of hypnotherapy for urgency urinary incontinence demonstrated marked improvement in urgency urinary incontinence symptoms at 2 months. A subsample of these women with urgency urinary incontinence underwent functional magnetic resonance imaging before and after treatment. OBJECTIVE This study aimed to determine if hypnotherapy treatment of urgency urinary incontinence compared with pharmacotherapy was associated with altered brain activation or resting connectivity on functional magnetic resonance imaging. STUDY DESIGN A subsample of women participating in a randomized controlled trial comparing hypnotherapy vs pharmacotherapy for treatment of urgency urinary incontinence was evaluated with functional magnetic resonance imaging. Scans were obtained pretreatment and 8 to 12 weeks after treatment initiation. Brain activation during bladder filling and resting functional connectivity with an empty and partially filled bladder were assessed. Brain regions of interest were derived from those previously showing differences between healthy controls and participants with untreated urgency urinary incontinence in our prior work and included regions in the interoceptive and salience, ventral attentional, and dorsal attentional networks. RESULTS After treatment, participants in both groups demonstrated marked improvement in incontinence episodes (P<.001). Bladder-filling task functional magnetic resonance imaging data from the combined groups (n=64, 30 hypnotherapy, 34 pharmacotherapy) demonstrated decreased activation of the left temporoparietal junction, a component of the ventral attentional network (P<.01) compared with baseline. Resting functional connectivity differed only with the bladder partially filled (n=54). Compared with pharmacotherapy, hypnotherapy participants manifested increased functional connectivity between the anterior cingulate cortex and the left dorsolateral prefrontal cortex, a component of the dorsal attentional network (P<.001). CONCLUSION Successful treatment of urgency urinary incontinence with both pharmacotherapy and hypnotherapy was associated with decreased activation of the ventral (bottom-up) attentional network during bladder filling. This may be attributable to decreased afferent stimuli arising from the bladder in the pharmacotherapy group. In contrast, decreased ventral attentional network activation associated with hypnotherapy may be mediated by the counterbalancing effects of the dorsal (top-down) attentional network.
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Affiliation(s)
- Loren H Ketai
- University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
| | - Yuko M Komesu
- University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Ronald M Schrader
- University of New Mexico Clinical and Translational Science Center, Albuquerque, New Mexico
| | - Rebecca G Rogers
- University of New Mexico Health Sciences Center, Albuquerque, New Mexico; University of Texas Dell Medical School, Austin, TX
| | - Robert E Sapien
- University of New Mexico Health Sciences Center, Albuquerque, New Mexico
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27
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Meier SK, Ray KL, Waller NC, Gendron BC, Aytur SA, Robin DA. Network Analysis of Induced Neural Plasticity Post-Acceptance and Commitment Therapy for Chronic Pain. Brain Sci 2020; 11:E10. [PMID: 33374858 PMCID: PMC7823706 DOI: 10.3390/brainsci11010010] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/05/2020] [Accepted: 12/18/2020] [Indexed: 01/05/2023] Open
Abstract
Chronic musculoskeletal pain is a costly and prevalent condition that affects the lives of over 50 million individuals in the United States. Chronic pain leads to functional brain changes in those suffering from the condition. Not only does the primary pain network transform as the condition changes from acute to persistent pain, a state of hyper-connectivity also exists between the default mode, frontoparietal, and salience networks. Graph theory analysis has recently been used to investigate treatment-driven brain network changes. For example, current research suggests that Acceptance and Commitment Therapy (ACT) may reduce the chronic pain associated hyper-connectivity between the default mode, frontoparietal, and salience networks, as well as within the salience network. This study extended previous work by examining the associations between the three networks above and a meta-analytically derived pain network. Results indicate decreased connectivity within the pain network (including left putamen, right insula, left insula, and right thalamus) in addition to triple network connectivity changes after the four-week Acceptance and Commitment Therapy intervention.
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Affiliation(s)
- Sarah K. Meier
- Department of Communication Sciences and Disorders, University of New Hampshire, Durham, NH 03824, USA; (N.C.W.); (D.A.R.)
| | - Kimberly L. Ray
- Department of Psychology, University of Texas, Austin, TX 78712, USA;
| | - Noah C. Waller
- Department of Communication Sciences and Disorders, University of New Hampshire, Durham, NH 03824, USA; (N.C.W.); (D.A.R.)
| | | | - Semra A. Aytur
- Department of Health Management and Policy, University of New Hampshire, Durham, NH 03824, USA;
| | - Donald A. Robin
- Department of Communication Sciences and Disorders, University of New Hampshire, Durham, NH 03824, USA; (N.C.W.); (D.A.R.)
- Interdisciplinary Program in Neuroscience and Behavior, University of New Hampshire, Durham, NH 03824, USA
- Department of Biological Sciences, University of New Hampshire, Durham, NH 03824, USA
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28
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Tu Y, Cao J, Bi Y, Hu L. Magnetic resonance imaging for chronic pain: diagnosis, manipulation, and biomarkers. SCIENCE CHINA-LIFE SCIENCES 2020; 64:879-896. [PMID: 33247802 DOI: 10.1007/s11427-020-1822-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 09/15/2020] [Indexed: 12/16/2022]
Abstract
Pain is a multidimensional subjective experience with biological, psychological, and social factors. Whereas acute pain can be a warning signal for the body to avoid excessive injury, long-term and ongoing pain may be developed as chronic pain. There are more than 100 million people in China living with chronic pain, which has raised a huge socioeconomic burden. Studying the mechanisms of pain and developing effective analgesia approaches are important for basic and clinical research. Recently, with the development of brain imaging and data analytical approaches, the neural mechanisms of chronic pain have been widely studied. In the first part of this review, we briefly introduced the magnetic resonance imaging and conventional analytical approaches for brain imaging data. Then, we reviewed brain alterations caused by several chronic pain disorders, including localized and widespread primary pain, primary headaches and orofacial pain, musculoskeletal pain, and neuropathic pain, and present meta-analytical results to show brain regions associated with the pathophysiology of chronic pain. Next, we reviewed brain changes induced by pain interventions, such as pharmacotherapy, neuromodulation, and acupuncture. Lastly, we reviewed emerging studies that combined advanced machine learning and neuroimaging techniques to identify diagnostic, prognostic, and predictive biomarkers in chronic pain patients.
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Affiliation(s)
- Yiheng Tu
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, 100101, China.,Department of Psychology, University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Jin Cao
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, 02129, USA
| | - Yanzhi Bi
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, 100101, China.,Department of Psychology, University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Li Hu
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, 100101, China. .,Department of Psychology, University of Chinese Academy of Sciences, Beijing, 100101, China. .,Department of Pain Management, The State Key Clinical Specialty in Pain Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.
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29
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Mawla I, Schrepf A, Ichesco E, Harte SE, Klumpp DJ, Griffith JW, Strachan E, Yang CC, Lai H, Andriole G, Magnotta VA, Kreder K, Clauw DJ, Harris RE, Clemens JQ, Landis JR, Mullins C, Rodriguez LV, Mayer EA, Kutch JJ. Natural bladder filling alters resting brain function at multiple spatial scales: a proof-of-concept MAPP Network Neuroimaging Study. Sci Rep 2020; 10:19901. [PMID: 33199816 PMCID: PMC7669903 DOI: 10.1038/s41598-020-76857-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 10/29/2020] [Indexed: 01/23/2023] Open
Abstract
Neural circuitry regulating urine storage in humans has been largely inferred from fMRI during urodynamic studies driven by catheter infusion of fluid into the bladder. However, urodynamic testing may be confounded by artificially filling the bladder repeatedly at a high rate and examining associated time-locked changes in fMRI signals. Here we describe and test a more ecologically-valid paradigm to study the brain response to bladder filling by (1) filling the bladder naturally with oral water ingestion, (2) examining resting state fMRI (rs-fMRI) which is more natural since it is not linked with a specific stimulus, and (3) relating rs-fMRI measures to self-report (urinary urge) and physiologic measures (voided volume). To establish appropriate controls and analyses for future clinical studies, here we analyze data collected from healthy individuals (N = 62) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Participants orally ingested approximately 350 mL of water, and had a 10 min “fuller bladder” rs-fMRI scan approximately 1 h later. A second 10 min “empty bladder” rs-fMRI scan was conducted immediately following micturition. We examined multiple spatial scales of brain function, including local activity, circuits, and networks. We found changes in brain function distributed across micturition loci (e.g., subregions of the salience, sensorimotor, and default networks) that were significantly related to the stimulus (volume) and response (urinary urge). Based on our results, this paradigm can be applied in the future to study the neurobiological underpinnings of urologic conditions.
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Affiliation(s)
- Ishtiaq Mawla
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.,Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USA
| | - Andrew Schrepf
- Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USA
| | - Eric Ichesco
- Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USA
| | - Steven E Harte
- Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USA
| | - David J Klumpp
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - James W Griffith
- Department of Medical Social Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Eric Strachan
- Department of Psychiatry, University of Washington, Seattle, WA, USA
| | - Claire C Yang
- Department of Urology, University of Washington, Seattle, WA, USA
| | - Henry Lai
- Department of Anesthesiology, Washington University, St. Louis, MO, USA.,Division of Urologic Surgery, Department of Surgery, Washington University, St. Louis, MO, USA
| | - Gerald Andriole
- Division of Urologic Surgery, Department of Surgery, Washington University, St. Louis, MO, USA
| | | | - Karl Kreder
- Department of Urology, University of Iowa, Iowa City, IA, USA
| | - Daniel J Clauw
- Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USA
| | - Richard E Harris
- Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USA
| | | | - J Richard Landis
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Chris Mullins
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Larissa V Rodriguez
- Department of Urology, University of Southern California, Los Angeles, CA, USA
| | - Emeran A Mayer
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA
| | - Jason J Kutch
- Division of Biokinesiology and Physical Therapy, University of Southern California, 1540 E. Alcazar Street, CHP 155, Los Angeles, CA, 90033, USA.
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30
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Tinnermann A, Büchel C, Cohen-Adad J. Cortico-spinal imaging to study pain. Neuroimage 2020; 224:117439. [PMID: 33039624 DOI: 10.1016/j.neuroimage.2020.117439] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 09/21/2020] [Accepted: 10/01/2020] [Indexed: 12/15/2022] Open
Abstract
Functional magnetic resonance imaging of the brain has helped to reveal mechanisms of pain perception in health and disease. Recently, imaging approaches have been developed that allow recording neural activity simultaneously in the brain and in the spinal cord. These approaches offer the possibility to examine pain perception in the entire central pain system and in addition, to investigate cortico-spinal interactions during pain processing. Although cortico-spinal imaging is a promising technique, it bears challenges concerning data acquisition and data analysis strategies. In this review, we discuss studies that applied simultaneous imaging of the brain and spinal cord to explore central pain processing. Furthermore, we describe different MR-related acquisition techniques, summarize advantages and disadvantages of approaches that have been implemented so far and present software that has been specifically developed for the analysis of spinal fMRI data to address challenges of spinal data analysis.
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Affiliation(s)
- Alexandra Tinnermann
- Department for Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Max Planck School of Cognition, Leipzig, Germany.
| | - Christian Büchel
- Department for Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Max Planck School of Cognition, Leipzig, Germany
| | - Julien Cohen-Adad
- NeuroPoly Lab, Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, Quebec, Canada; Functional Neuroimaging Unit, CRIUGM, Université de Montréal, Montreal, Quebec, Canada.
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31
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Čeko M, Frangos E, Gracely J, Richards E, Wang B, Schweinhardt P, Catherine Bushnell M. Default mode network changes in fibromyalgia patients are largely dependent on current clinical pain. Neuroimage 2020; 216:116877. [PMID: 32344063 DOI: 10.1016/j.neuroimage.2020.116877] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 04/20/2020] [Accepted: 04/22/2020] [Indexed: 01/15/2023] Open
Abstract
Differences in fMRI resting-state connectivity of the default mode network (DMN) seen in chronic pain patients are often interpreted as brain reorganization due to the chronic pain condition. Nevertheless, patients' pain at the time of fMRI might influence the DMN because pain, like cognitive stimuli, engages attentional mechanisms and cognitive engagement is known to alter DMN activity. Here, we aimed to dissociate the influence of chronic pain condition (trait) from the influence of current pain experience (state) on DMN connectivity in patients with fibromyalgia (FM). We performed resting-state fMRI scans to test DMN connectivity in FM patients and matched healthy controls in two separate cohorts: (1) in a cohort not experiencing pain during scanning (27 FM patients and 27 controls), (2) in a cohort with current clinical pain during scanning (16 FM patients and 16 controls). In FM patients without pain during scanning, the connectivity of the DMN did not differ significantly from controls. By contrast, FM patients with current clinical pain during the scan had significantly increased DMN connectivity to bilateral anterior insula (INS) similar to previous studies. Regression analysis showed a positive relationship between DMN-midINS connectivity and current pain. We therefore suggest that transient DMN disruptions due to current clinical pain during scanning (current pain state) may be a substantial contributor to DMN connectivity disruptions observed in chronic pain patients.
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Affiliation(s)
- Marta Čeko
- Institute of Cognitive Science, University of Colorado, Boulder, CO, USA.
| | - Eleni Frangos
- National Center for Complementary and Integrative Health (NCCIH), National Institutes of Health, Bethesda, MD, USA
| | - John Gracely
- National Center for Complementary and Integrative Health (NCCIH), National Institutes of Health, Bethesda, MD, USA
| | - Emily Richards
- National Center for Complementary and Integrative Health (NCCIH), National Institutes of Health, Bethesda, MD, USA
| | - Binquan Wang
- National Center for Complementary and Integrative Health (NCCIH), National Institutes of Health, Bethesda, MD, USA
| | - Petra Schweinhardt
- The Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada; Department of Chiropractic Medicine, Balgrist University Hospital and University of Zurich, Zurich, Switzerland
| | - M Catherine Bushnell
- National Center for Complementary and Integrative Health (NCCIH), National Institutes of Health, Bethesda, MD, USA
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32
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Davis KD, Aghaeepour N, Ahn AH, Angst MS, Borsook D, Brenton A, Burczynski ME, Crean C, Edwards R, Gaudilliere B, Hergenroeder GW, Iadarola MJ, Iyengar S, Jiang Y, Kong JT, Mackey S, Saab CY, Sang CN, Scholz J, Segerdahl M, Tracey I, Veasley C, Wang J, Wager TD, Wasan AD, Pelleymounter MA. Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities. Nat Rev Neurol 2020; 16:381-400. [PMID: 32541893 PMCID: PMC7326705 DOI: 10.1038/s41582-020-0362-2] [Citation(s) in RCA: 245] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2020] [Indexed: 02/06/2023]
Abstract
Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.
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Affiliation(s)
- Karen D Davis
- Department of Surgery and Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
- Division of Brain, Imaging and Behaviour, Krembil Brain Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
| | - Nima Aghaeepour
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Martin S Angst
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - David Borsook
- Center for Pain and the Brain, Harvard Medical School, Boston, MA, USA
| | | | | | | | - Robert Edwards
- Pain Management Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Brice Gaudilliere
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Georgene W Hergenroeder
- The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Michael J Iadarola
- Department of Perioperative Medicine, Clinical Center, NIH, Rockville, MD, USA
| | - Smriti Iyengar
- Division of Translational Research, National Institute of Neurological Disorders and Stroke, NIH, Rockville, MD, USA
| | - Yunyun Jiang
- The Biostatistics Center, Milken Institute School of Public Health, The George Washington University, Washington, DC, USA
| | - Jiang-Ti Kong
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Sean Mackey
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Carl Y Saab
- Department of Neuroscience and Department of Neurosurgery, Carney Institute for Brain Science, Brown University, Providence, RI, USA
| | - Christine N Sang
- Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Joachim Scholz
- Neurocognitive Disorders, Pain and New Indications, Biogen, Cambridge, MA, USA
| | | | - Irene Tracey
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | | | - Jing Wang
- Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU School of Medicine, New York, NY, USA
| | - Tor D Wager
- Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, USA
| | - Ajay D Wasan
- Anesthesiology and Perioperative Medicine and Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mary Ann Pelleymounter
- Division of Translational Research, National Institute of Neurological Disorders and Stroke, NIH, Rockville, MD, USA
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33
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Clemens JQ, Kutch JJ, Mayer EA, Naliboff BD, Rodriguez LV, Klumpp DJ, Schaeffer AJ, Kreder KJ, Clauw DJ, Harte SE, Schrepf AD, Williams DA, Andriole GL, Lai HH, Buchwald D, Lucia MS, van Bokhoven A, Mackey S, Moldwin RM, Pontari MA, Stephens-Shields AJ, Mullins C, Landis JR. The Multidisciplinary Approach to The Study of Chronic Pelvic Pain (MAPP) Research Network*: Design and implementation of the Symptom Patterns Study (SPS). Neurourol Urodyn 2020; 39:1803-1814. [PMID: 32578257 DOI: 10.1002/nau.24423] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 05/29/2020] [Indexed: 11/07/2022]
Abstract
AIMS The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network initiated a second observational cohort study-the Symptom Patterns Study (SPS)-to further investigate the underlying pathophysiology of Urologic Chronic Pelvic Pain Syndrome (UCPPS) and to discover factors associated with longitudinal symptom changes and responses to treatments. METHODS This multisite cohort study of males and females with UCPPS features a run-in period of four weekly web-based symptom assessments before a baseline visit, followed by quarterly assessments up to 36 months. Controls were also recruited and assessed at baseline and 6 months. Extensive clinical data assessing urological symptoms, nonurological pain, chronic overlapping pain syndromes, and psychosocial factors were collected. Diverse biospecimens for biomarker and microbiome studies, quantitative sensory testing (QST) data under multiple stimuli, and structural and functional neuroimaging scans were obtained under a standardized protocol. RESULTS Recruitment was initiated (July 2015) and completed (February 2019) at six discovery sites. A total of 620 males and females with UCPPS and 73 Controls were enrolled, including 83 UCPPS participants who re-enrolled from the first MAPP Network cohort study (2009-2012). Baseline neuroimaging scans, QST measures, and biospecimens were obtained on 578 UCPPS participants. The longitudinal follow-up of the cohort is ongoing. CONCLUSIONS This comprehensive characterization of a large UCPPS cohort with extended follow-up greatly expands upon earlier MAPP Network studies and provides unprecedented opportunities to increase our understanding of UCPPS pathophysiology, factors associated with symptom change, clinically relevant patient phenotypes, and novel targets for future interventions.
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Affiliation(s)
| | - Jason J Kutch
- Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, California
| | - Emeran A Mayer
- Department of Medicine, David Geffen School of Medicine at The University of California, Los Angeles, California
| | - Bruce D Naliboff
- Department of Medicine, David Geffen School of Medicine at The University of California, Los Angeles, California
| | - Larissa V Rodriguez
- Departments of Urology & Obstetrics and Gynecology, University of Southern California, Los Angeles, California
| | - David J Klumpp
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Anthony J Schaeffer
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Karl J Kreder
- Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, Iowa
| | - Daniel J Clauw
- Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, Michigan
| | - Steven E Harte
- Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, Michigan
| | - Andrew D Schrepf
- Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, Michigan
| | - David A Williams
- Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, Michigan
| | - Gerald L Andriole
- Department of Surgery, Division of Urologic Surgery, Washington University School of Medicine, St Louis, Missouri
| | - H Henry Lai
- Department of Surgery, Division of Urologic Surgery, Washington University School of Medicine, St Louis, Missouri
| | - Dedra Buchwald
- Department of Epidemiology and Medicine, Washington State University Institute for Research and Education to Advance Community Health, Seattle, Washington
| | - M Scott Lucia
- Department of Pathology, University of Colorado Denver, Aurora, Colorado
| | - Adrie van Bokhoven
- Department of Pathology, University of Colorado Denver, Aurora, Colorado
| | - Sean Mackey
- Department of Anesthesiology, Perioperative, and Pain Medicine, Division of Pain Medicines, Stanford University School of Medicine, Stanford, California
| | - Robert M Moldwin
- Department of Urology, Hofstra University School of Medicine, The Arthur Smith Institute for Urology, New Hyde Park, New York
| | - Michel A Pontari
- Department of Urology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Alisa J Stephens-Shields
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Chris Mullins
- Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - J Richard Landis
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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34
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Yang CC, Clemens JQ. Lower Urinary Tract Symptoms: Advances in Women's Urologic Health From MAPP and LURN. Urology 2020; 150:223-226. [PMID: 32330529 DOI: 10.1016/j.urology.2020.04.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 04/05/2020] [Indexed: 10/24/2022]
Affiliation(s)
- Claire C Yang
- Department of Urology, University of Washington, Seattle, WA.
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35
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Urologic chronic pelvic pain syndrome: insights from the MAPP Research Network. Nat Rev Urol 2020; 16:187-200. [PMID: 30560936 DOI: 10.1038/s41585-018-0135-5] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Urologic chronic pelvic pain syndrome (UCPPS), which encompasses interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, is characterized by chronic pain in the pelvic region or genitalia that is often accompanied by urinary frequency and urgency. Despite considerable research, no definite aetiological risk factors or effective treatments have been identified. The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network uses a novel integrated strategy to characterize UCPPS as a systemic disorder that potentially involves multiple aetiologies. The first phase, MAPP I, included >1,000 participants who completed an intensive baseline assessment followed by a 12-month observational follow-up period. MAPP I studies showed that UCPPS pain and urinary symptoms co-vary, with only moderate correlation, and should be evaluated separately and that symptom flares are common and can differ considerably in intensity, duration and influence on quality of life. Longitudinal clinical changes in UCPPS correlated with structural and functional brain changes, and many patients experienced global multisensory hypersensitivity. Additionally, UCPPS symptom profiles were distinguishable by biological correlates, such as immune factors. These findings indicate that patients with UCPPS have objective phenotypic abnormalities and distinct biological characteristics, providing a new foundation for the study and clinical management of UCPPS.
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36
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Farrell AT, Panepinto J, Carroll CP, Darbari DS, Desai AA, King AA, Adams RJ, Barber TD, Brandow AM, DeBaun MR, Donahue MJ, Gupta K, Hankins JS, Kameka M, Kirkham FJ, Luksenburg H, Miller S, Oneal PA, Rees DC, Setse R, Sheehan VA, Strouse J, Stucky CL, Werner EM, Wood JC, Zempsky WT. End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain. Blood Adv 2019; 3:3982-4001. [PMID: 31809538 PMCID: PMC6963237 DOI: 10.1182/bloodadvances.2019000882] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 09/26/2019] [Indexed: 12/12/2022] Open
Abstract
To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points.
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Affiliation(s)
| | - Julie Panepinto
- Pediatric Hematology, Medical College of Wisconsin/Children's Wisconsin, Milwaukee, WI
| | - C Patrick Carroll
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD
| | | | - Ankit A Desai
- Krannert Institute of Cardiology, Indiana University, Bloomington, IN
| | - Allison A King
- Division of Hematology and Oncology in Pediatrics and Medicine, Washington University School of Medicine, St. Louis, MO
| | - Robert J Adams
- Department of Neurology, Medical University of South Carolina, Charleston, SC
| | | | - Amanda M Brandow
- Pediatric Hematology, Medical College of Wisconsin/Children's Wisconsin, Milwaukee, WI
| | - Michael R DeBaun
- Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease, Vanderbilt University Medical Center, Nashville, TN
| | - Manus J Donahue
- Department of Radiology and Radiological Sciences
- Department of Neurology, and
- Department of Psychiatry, School of Medicine, Vanderbilt University, Nashville, TN
| | - Kalpna Gupta
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Medical School, University of Minnesota, Minneapolis, MN
| | - Jane S Hankins
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN
| | - Michelle Kameka
- Nicole Wertheim College of Nursing and Health Sciences, Florida International University, Miami, FL
| | - Fenella J Kirkham
- Developmental Neurosciences Unit and
- Biomedical Research Unit, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Harvey Luksenburg
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | | | | | - David C Rees
- Department of Haematological Medicine, King's College Hospital, London, United Kingdom
- School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom
| | | | - Vivien A Sheehan
- Division of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
| | - John Strouse
- Division of Hematology, Department of Medicine, and
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Duke University School of Medicine, Durham, NC
| | - Cheryl L Stucky
- Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI
| | - Ellen M Werner
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - John C Wood
- Children's Hospital Los Angeles, Los Angeles, CA; and
| | - William T Zempsky
- Department of Pediatrics, Connecticut Children's/School of Medicine, University of Connecticut, Hartford, CT
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Zheng W, Woo CW, Yao Z, Goldstein P, Atlas LY, Roy M, Schmidt L, Krishnan A, Jepma M, Hu B, Wager TD. Pain-Evoked Reorganization in Functional Brain Networks. Cereb Cortex 2019; 30:2804-2822. [PMID: 31813959 DOI: 10.1093/cercor/bhz276] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/21/2019] [Accepted: 10/27/2019] [Indexed: 12/18/2022] Open
Abstract
Recent studies indicate that a significant reorganization of cerebral networks may occur in patients with chronic pain, but how immediate pain experience influences the organization of large-scale functional networks is not yet well characterized. To investigate this question, we used functional magnetic resonance imaging in 106 participants experiencing both noxious and innocuous heat. Painful stimulation caused network-level reorganization of cerebral connectivity that differed substantially from organization during innocuous stimulation and standard resting-state networks. Noxious stimuli increased somatosensory network connectivity with (a) frontoparietal networks involved in context representation, (b) "ventral attention network" regions involved in motivated action selection, and (c) basal ganglia and brainstem regions. This resulted in reduced "small-worldness," modularity (fewer networks), and global network efficiency and in the emergence of an integrated "pain supersystem" (PS) whose activity predicted individual differences in pain sensitivity across 5 participant cohorts. Network hubs were reorganized ("hub disruption") so that more hubs were localized in PS, and there was a shift from "connector" hubs linking disparate networks to "provincial" hubs connecting regions within PS. Our findings suggest that pain reorganizes the network structure of large-scale brain systems. These changes may prioritize responses to painful events and provide nociceptive systems privileged access to central control of cognition and action during pain.
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Affiliation(s)
- Weihao Zheng
- School of Information Science and Engineering, Lanzhou University, Lanzhou, 730000, P. R. China.,Key Laboratory for Biomedical Engineering of Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, 310027, P. R. China
| | - Choong-Wan Woo
- Center for Neuroscience Imaging Research, Institute for Basic Science, Suwon 16419, Republic of Korea.,Department of Biomedical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Zhijun Yao
- School of Information Science and Engineering, Lanzhou University, Lanzhou, 730000, P. R. China
| | - Pavel Goldstein
- Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309, USA.,Institute of Cognitive Science, University of Colorado, Boulder, CO 80309, USA.,The School of Public Health, University of Haifa, Haifa, 3498838, Israel
| | - Lauren Y Atlas
- National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, MD 20892, USA.,National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.,National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA
| | - Mathieu Roy
- Department of Psychology, McGill University, Montréal, Quebec H3A 0G4, Canada
| | - Liane Schmidt
- Control-Interoception-Attention (CIA) team, Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne University / CNRS / INSERM, 75013 Paris, France
| | - Anjali Krishnan
- Department of Psychology, Brooklyn College of the City University of New York, Brooklyn, NY 11210, USA
| | - Marieke Jepma
- Department of Psychology, University of Amsterdam, Amsterdam, 1018 WS, The Netherlands
| | - Bin Hu
- School of Information Science and Engineering, Lanzhou University, Lanzhou, 730000, P. R. China
| | - Tor D Wager
- Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309, USA.,Institute of Cognitive Science, University of Colorado, Boulder, CO 80309, USA.,Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH 03755, USA
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Abstract
Abstract
Purpose of Review
Centralized pain syndromes (CPS), including chronic pelvic pain (CPP) syndrome, are significant public health problems with prevalence more than diabetes, cancer, or cardiovascular disease. A variety of pathologies are linked with CPP syndrome; however, pain often continues without the presence of pathology, or when an underlying pelvic disease is found, the extent and severity of pain are disproportionate. Although this is not a systematic review, we performed a detailed literature search to identify relevant papers and to provide the available evidence for central changes in association with CPP syndrome.
Recent Findings
Recent advances in brain imaging techniques have provided more accurate data on gray matter volume, functional connectivity, and metabolite levels in the pain-relevant areas of the brain. The present evidence shows that like other chronic pain conditions, the CPP syndrome is associated with central nervous system (CNS) alterations. In particular, these include changes in brain structure, in the activity of both the hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous system, and in the behavioral and central response to noxious stimulation.
Summary
A growing body of evidence, mostly from neuroimaging, suggests that for many patients with CPP, the pain may be associated to changes in both structure and function of the CNS. The treatment of pain symptoms, even without the presence of identifiable pathology, may prevent the development or at least minimize the progression of long-term central changes. These findings support the use of new therapeutic strategies targeting the CNS for controlling of pain in CPP conditions.
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Schrepf A, Naliboff B, Williams DA, Stephens-Shields AJ, Landis JR, Gupta A, Mayer E, Rodriguez LV, Lai H, Luo Y, Bradley C, Kreder K, Lutgendorf SK. Adverse Childhood Experiences and Symptoms of Urologic Chronic Pelvic Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Study. Ann Behav Med 2019; 52:865-877. [PMID: 30212850 DOI: 10.1093/abm/kax060] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background Adverse Childhood Experiences (ACEs) such as sexual and physical violence, serious illness, and bereavement have been linked to number of chronic pain conditions in adulthood, and specifically to urologic chronic pelvic pain syndrome (UCPPS). Purpose We sought to characterize the prevalence of ACEs in UCPPS using a large well-characterized cohort in comparison with a group of healthy controls. We also sought to determine the association of ACE severity with psychological factors known to impact pain and to determine whether ACEs are associated with patterns of improvement or worsening of symptom over a year of naturalistic observation. Methods For longitudinal analyses we used functional clusters identifying broad classes of (a) improved, (b) worsened, and (c) stable groups for genitourinary pain and urinary symptoms. We employed a mediation/path analysis framework to determine whether ACEs influenced 1 year outcomes directly, or indirectly through worse perceptions of physical well-being. Results ACE severity was elevated in UCPPS (n = 421) participants compared with healthy controls (n = 414; p < .001), and was most strongly associated with factors associated with complex chronic pain, including more diffuse pain, comorbid functional symptoms/syndromes, and worse perceived physical well-being (all p < .001). Finally, worse physical well-being mediated the relationship between ACE severity and less likelihood of painful symptom improvement (OR = .871, p = .007)) and a greater likelihood of painful symptom worsening (OR = 1.249, p = .003) at 1 year. Conclusions These results confirm the association between ACEs and UCPPS symptoms, and suggest potential targets for therapeutic interventions in UCPPS. Clinical Trial registration NCT01098279.
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Affiliation(s)
- Andrew Schrepf
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
| | - Bruce Naliboff
- Department of Medicine, University of California, Los Angeles, CA, USA.,Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA
| | - David A Williams
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
| | - Alisa J Stephens-Shields
- Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - J Richard Landis
- Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Arpana Gupta
- Oppenheimer Center for Neurobiology of Stress, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | - Emeran Mayer
- Oppenheimer Center for Neurobiology of Stress, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | - Larissa V Rodriguez
- Department of Urology, University of Southern California, Los Angeles, CA, USA
| | - Henry Lai
- Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.,Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Yi Luo
- Department of Urology, University of Iowa, Iowa City, IA, USA
| | - Catherine Bradley
- Department of Urology, University of Iowa, Iowa City, IA, USA.,Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, USA
| | - Karl Kreder
- Department of Urology, University of Iowa, Iowa City, IA, USA
| | - Susan K Lutgendorf
- Department of Psychological and Brain Sciences and Urology, University of Iowa, Iowa City, IA, USA
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Weber Ii KA, Wager TD, Mackey S, Elliott JM, Liu WC, Sparks CL. Evidence for decreased Neurologic Pain Signature activation following thoracic spinal manipulation in healthy volunteers and participants with neck pain. NEUROIMAGE-CLINICAL 2019; 24:102042. [PMID: 31670070 PMCID: PMC6831903 DOI: 10.1016/j.nicl.2019.102042] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 09/18/2019] [Accepted: 10/17/2019] [Indexed: 12/19/2022]
Abstract
The use of brain-based models of pain were explored in two clinical studies. Neurologic pain signature activation decreased following spinal manipulation. Spinal manipulation altered the processing of pain-related brain activity. We provide evidence for a centrally mediated therapeutic action of spinal manipulation. Brain-based models have potential as objective clinical biomarkers of pain. Background Context Spinal manipulation (SM) is a common treatment for neck and back pain, theorized to mechanically affect the spine leading to therapeutic mechanical changes. The link between specific mechanical effects and clinical improvement is not well supported. SM's therapeutic action may instead be partially mediated within the central nervous system. Purpose To introduce brain-based models of pain for spinal pain and manual therapy research, characterize the distributed central mechanisms of SM, and advance the preliminary validation of brain-based models as potential clinical biomarkers of pain. Study Design Secondary analysis of two functional magnetic resonance imaging studies investigating the effect of thoracic SM on pain-related brain activity: A non-controlled, non-blinded study in healthy volunteers (Study 1, n = 10, 5 females, and mean age = 31.2 ± 10.0 years) and a randomized controlled study in participants with acute to subacute neck pain (Study 2, n = 24, 16 females, mean age = 38.0 ± 15.1 years). Methods Functional magnetic resonance imaging was performed during noxious mechanical stimulation of the right index finger cuticle pre- and post-intervention. The effect of SM on pain-related activity was studied within brain regions defined by the Neurologic Pain Signature (NPS) that are predictive of physical pain. Results In Study 1, evoked mechanical pain (p < 0.001) and NPS activation (p = 0.010) decreased following SM, and the changes in evoked pain and NPS activation were correlated (rRM2 = 0.418, p = 0.016). Activation within the NPS subregions of the dorsal anterior cingulate cortex (dACC, p = 0.012) and right secondary somatosensory cortex/operculum (rS2_Op, p = 0.045) also decreased following SM, and evoked pain was correlated with dACC activity (rRM2 = 0.477, p = 0.019). In Study 2, neck pain (p = 0.046) and NPS (p = 0.033) activation decreased following verum but not sham SM. Associations between evoked pain, neck pain, and NPS activation, were not significant and less clear, possibly due to inadequate power, methodological limitations, or other confounding factors. Conclusions The findings provide preliminary evidence that SM may alter the processing of pain-related brain activity within specific pain-related brain regions and support the use of brain-based models as clinical biomarkers of pain.
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Affiliation(s)
- Kenneth A Weber Ii
- Systems Neuroscience and Pain Lab, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, CA, United States.
| | - Tor D Wager
- Psychology and Neuroscience, Center for Neuroscience, Institute of Cognitive Science, University of Colorado Boulder, Boulder, CO, United States
| | - Sean Mackey
- Systems Neuroscience and Pain Lab, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, CA, United States
| | - James M Elliott
- Northern Sydney Local Health District, The Kolling Research Institute and The Faculty of Health Sciences, The University of Sydney, St. Leonards, NSW, Australia
| | - Wen-Ching Liu
- Center for Collaborative Brain Research, Department of Radiology, OSF HealthCare Saint Francis Medical Center, Peoria, IL, United States
| | - Cheryl L Sparks
- Center of Expertise, Rehabilitation and Occupational Health, OSF HealthCare, Peoria, IL, United States; School of Physical Therapy, South College, Knoxville, TN, United States
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Neuroimaging of Pain: Human Evidence and Clinical Relevance of Central Nervous System Processes and Modulation. Anesthesiology 2019; 128:1241-1254. [PMID: 29494401 DOI: 10.1097/aln.0000000000002137] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Neuroimaging research has demonstrated definitive involvement of the central nervous system in the development, maintenance, and experience of chronic pain. Structural and functional neuroimaging has helped elucidate central nervous system contributors to chronic pain in humans. Neuroimaging of pain has provided a tool for increasing our understanding of how pharmacologic and psychologic therapies improve chronic pain. To date, findings from neuroimaging pain research have benefitted clinical practice by providing clinicians with an educational framework to discuss the biopsychosocial nature of pain with patients. Future advances in neuroimaging-based therapeutics (e.g., transcranial magnetic stimulation, real-time functional magnetic resonance imaging neurofeedback) may provide additional benefits for clinical practice. In the future, with standardization and validation, brain imaging could provide objective biomarkers of chronic pain, and guide treatment for personalized pain management. Similarly, brain-based biomarkers may provide an additional predictor of perioperative prognoses.
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Neuroimaging-based pain biomarkers: definitions, clinical and research applications, and evaluation frameworks to achieve personalized pain medicine. Pain Rep 2019; 4:e762. [PMID: 31579854 PMCID: PMC6727999 DOI: 10.1097/pr9.0000000000000762] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 04/28/2019] [Accepted: 05/15/2019] [Indexed: 12/22/2022] Open
Abstract
One of the key ambitions of neuroimaging-based pain biomarker research is to augment patient and clinician reporting of clinically relevant phenomena with neural measures for prediction, prognosis, and detection of pain. Despite years of productive research on the neuroimaging of pain, such applications have seen little advancement. However, recent developments in identifying brain-based biomarkers of pain through advances in technology and multivariate pattern analysis provide some optimism. Here, we (1) define and review the different types of potential neuroimaging-based biomarkers, their clinical and research applications, and their limitations and (2) describe frameworks for evaluation of pain biomarkers used in other fields (eg, genetics, cancer, cardiovascular disease, immune system disorders, and rare diseases) to achieve broad clinical and research utility and minimize the risks of misapplication of this emerging technology. To conclude, we discuss future directions for neuroimaging-based biomarker research to achieve the goal of personalized pain medicine.
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Wang WE, Roy A, Misra G, Ho RLM, Ribeiro-Dasilva MC, Fillingim RB, Coombes SA. Altered neural oscillations within and between sensorimotor cortex and parietal cortex in chronic jaw pain. NEUROIMAGE-CLINICAL 2019; 24:101964. [PMID: 31412309 PMCID: PMC6704052 DOI: 10.1016/j.nicl.2019.101964] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/02/2019] [Accepted: 07/28/2019] [Indexed: 12/22/2022]
Abstract
Pain perception is associated with priming of the motor system and the orienting of attention in healthy adults. These processes correspond with decreases in alpha and beta power in the sensorimotor and parietal cortices. The goal of the present study was to determine whether these findings extend to individuals with chronic pain. Individuals with chronic jaw pain and pain-free controls anticipated and experienced a low pain or a moderate pain-eliciting heat stimulus. Although stimuli were calibrated for each subject, stimulus temperature was not different between groups. High-density EEG data were collected during the anticipation and heat stimulation periods and were analyzed using independent component analyses, EEG source localization, and measure projection analyses. Direct directed transfer function was also estimated to identify frequency specific effective connectivity between regions. Between group differences were most evident during the heat stimulation period. We report three novel findings. First, the chronic jaw pain group had a relative increase in alpha and beta power and a relative decrease in theta and gamma power in sensorimotor cortex. Second, the chronic jaw pain group had a relative increase in power in the alpha and beta bands in parietal cortex. Third, the chronic jaw pain group had less connectivity strength in the beta and gamma bands between sensorimotor cortex and parietal cortex. Our findings show that the effect of chronic pain attenuates rather than magnifies neural responses to heat stimuli. We interpret these findings in the context of system-level changes in intrinsic sensorimotor and attentional circuits in chronic pain.
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Affiliation(s)
- Wei-En Wang
- Laboratory for Rehabilitation Neuroscience, Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, United States of America
| | - Arnab Roy
- Laboratory for Rehabilitation Neuroscience, Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, United States of America
| | | | - Rachel L M Ho
- Laboratory for Rehabilitation Neuroscience, Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, United States of America
| | | | - Roger B Fillingim
- Department of Community Dentistry and Behavioral Science, University of Florida, Gainesville, FL, United States of America
| | - Stephen A Coombes
- Laboratory for Rehabilitation Neuroscience, Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, United States of America.
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van der Miesen MM, Lindquist MA, Wager TD. Neuroimaging-based biomarkers for pain: state of the field and current directions. Pain Rep 2019; 4:e751. [PMID: 31579847 PMCID: PMC6727991 DOI: 10.1097/pr9.0000000000000751] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 03/20/2019] [Accepted: 04/07/2019] [Indexed: 12/15/2022] Open
Abstract
Chronic pain is an endemic problem involving both peripheral and brain pathophysiology. Although biomarkers have revolutionized many areas of medicine, biomarkers for pain have remained controversial and relatively underdeveloped. With the realization that biomarkers can reveal pain-causing mechanisms of disease in brain circuits and in the periphery, this situation is poised to change. In particular, brain pathophysiology may be diagnosable with human brain imaging, particularly when imaging is combined with machine learning techniques designed to identify predictive measures embedded in complex data sets. In this review, we explicate the need for brain-based biomarkers for pain, some of their potential uses, and some of the most popular machine learning approaches that have been brought to bear. Then, we evaluate the current state of pain biomarkers developed with several commonly used methods, including structural magnetic resonance imaging, functional magnetic resonance imaging and electroencephalography. The field is in the early stages of biomarker development, but these complementary methodologies have already produced some encouraging predictive models that must be tested more extensively across laboratories and clinical populations.
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Affiliation(s)
- Maite M. van der Miesen
- Institute for Interdisciplinary Studies, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Tor D. Wager
- Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA
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Gupta A, Bhatt RR, Naliboff BD, Kutch JJ, Labus JS, Vora PP, Alaverdyan M, Schrepf A, Lutgendorf S, Mayer EA. Impact of early adverse life events and sex on functional brain networks in patients with urological chronic pelvic pain syndrome (UCPPS): A MAPP Research Network study. PLoS One 2019; 14:e0217610. [PMID: 31220089 PMCID: PMC6586272 DOI: 10.1371/journal.pone.0217610] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 05/16/2019] [Indexed: 12/11/2022] Open
Abstract
Pain is a highly complex and individualized experience with biopsychosocial components. Neuroimaging research has shown evidence of the involvement of the central nervous system in the development and maintenance of chronic pain conditions, including urological chronic pelvic pain syndrome (UCPPS). Furthermore, a history of early adverse life events (EALs) has been shown to adversely impact symptoms throughout childhood and into adulthood. However, to date, the role of EAL's in the central processes of chronic pain have not been adequately investigated. We studied 85 patients (56 females) with UCPPS along with 86 healthy controls (HCs) who had resting-state magnetic resonance imaging scans (59 females), and data on EALs as a part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network Study. We used graph theory methods in order to investigate the impact of EALs on measures of centrality, which characterize information flow, communication, influence, and integration in a priori selected regions of interest. Patients with UCPPS exhibited lower centrality in the right anterior insula compared to HCs, a key node in the salience network. Males with UCPPS exhibited lower centrality in the right anterior insula compared the HC males. Females with UCPPS exhibited greater centrality in the right caudate nucleus and left angular gyrus compared to HC females. Males with UCPPS exhibited lower centrality in the left posterior cingulate, angular gyrus, middle temporal gyrus, and superior temporal sulcus, but greater centrality in the precuneus and anterior mid-cingulate cortex (aMCC) compared to females with UCPPS. Higher reports of EALs was associated with greater centrality in the left precuneus and left aMCC in females with UCPPS. This study provides evidence for disease and sex-related alterations in the default mode, salience, and basal ganglia networks in patients with UCPPS, which are moderated by EALs, and associated with clinical symptoms and quality of life (QoL).
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Affiliation(s)
- Arpana Gupta
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, United States of America
- David Geffen School of Medicine, UCLA, Los Angeles, CA, United States of America
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, United States of America
| | - Ravi R. Bhatt
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, United States of America
- David Geffen School of Medicine, UCLA, Los Angeles, CA, United States of America
| | - Bruce D. Naliboff
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, United States of America
- David Geffen School of Medicine, UCLA, Los Angeles, CA, United States of America
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, United States of America
| | - Jason J. Kutch
- USC Division of Biokinesiology and Physical Therapy, Los Angeles, CA, United States of America
| | - Jennifer S. Labus
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, United States of America
- David Geffen School of Medicine, UCLA, Los Angeles, CA, United States of America
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, United States of America
| | - Priten P. Vora
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, United States of America
- David Geffen School of Medicine, UCLA, Los Angeles, CA, United States of America
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, United States of America
| | - Mher Alaverdyan
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, United States of America
| | - Andrew Schrepf
- Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, United States of America
- Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States of America
| | - Susan Lutgendorf
- Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA, United States of America
- Department of Urology, University of Iowa, Iowa City, IA, United States of America
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States of America
| | - Emeran A. Mayer
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, United States of America
- David Geffen School of Medicine, UCLA, Los Angeles, CA, United States of America
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, United States of America
- Ahmanson-Lovelace Brain Mapping Center, UCLA, Los Angeles, CA, United States of America
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Pfannmöller J, Lotze M. Review on biomarkers in the resting-state networks of chronic pain patients. Brain Cogn 2019; 131:4-9. [DOI: 10.1016/j.bandc.2018.06.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 06/12/2018] [Accepted: 06/12/2018] [Indexed: 01/09/2023]
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Abstract
Changes in brain function in chronic pain have been studied using paradigms that deliver acute pain-eliciting stimuli or assess the brain at rest. Although motor disability accompanies many chronic pain conditions, few studies have directly assessed brain activity during motor function in individuals with chronic pain. Using chronic jaw pain as a model, we assessed brain activity during a precisely controlled grip force task and during a precisely controlled pain-eliciting stimulus on the forearm. We used multivariate analyses to identify regions across the brain whose activity together best separated the groups. We report 2 novel findings. First, although the parameters of grip force production were similar between the groups, the functional activity in regions including the prefrontal cortex, insula, and thalamus best separated the groups. Second, although stimulus intensity and pain perception were similar between the groups, functional activity in brain regions including the dorsal lateral prefrontal cortex, rostral ventral premotor cortex, and inferior parietal lobule best separated the groups. Our observations suggest that chronic jaw pain is associated with changes in how the brain processes motor and pain-related information even when the effector producing the force or experiencing the pain-eliciting stimulus is distant from the jaw. We also demonstrate that motor tasks and multivariate analyses offer alternative approaches for studying brain function in chronic jaw pain.
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Martucci KT, Weber KA, Mackey SC. Altered Cervical Spinal Cord Resting-State Activity in Fibromyalgia. Arthritis Rheumatol 2019; 71:441-450. [PMID: 30281205 DOI: 10.1002/art.40746] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 09/27/2018] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Altered afferent input and central neural modulation are thought to contribute to fibromyalgia symptoms, and these processes converge within the spinal cord. We undertook this study to investigate the hypothesis that, using resting-state functional magnetic resonance imaging (rs-fMRI) of the cervical spinal cord, we would observe altered frequency-dependent activity in fibromyalgia. METHODS Cervical spinal cord rs-fMRI was conducted in fibromyalgia patients (n = 16) and healthy controls (n = 17). We analyzed the amplitude of low-frequency fluctuations (ALFF), a measure of low-frequency oscillatory power, for frequencies of 0.01-0.198 Hz and frequency sub-bands to determine regional and frequency-specific alterations in fibromyalgia. Functional connectivity and graph metrics were also analyzed. RESULTS As compared to healthy controls (n = 14), greater ventral and lesser dorsal mean ALFF of the cervical spinal cord was observed in fibromyalgia patients ( n = 15) (uncorrected P < 0.05) for frequencies of 0.01-0.198 Hz and all sub-bands. Additionally, lesser mean ALFF within the right dorsal quadrant (corrected P < 0.05) for frequencies of 0.01-0.198 Hz and sub-band frequencies of 0.073-0.198 Hz was observed in fibromyalgia. Regional mean ALFF was not correlated with pain; however, regional lesser mean ALFF was correlated with fatigue in patients (r = 0.763, P = 0.001). Functional connectivity and graph metrics were similar between groups. CONCLUSION Our results indicate unbalanced activity between the ventral and dorsal cervical spinal cord in fibromyalgia. Increased ventral neural processes and decreased dorsal neural processes may reflect the presence of central sensitization and contribute to fatigue and other bodily symptoms in fibromyalgia.
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Affiliation(s)
- Katherine T Martucci
- Stanford University, Stanford, California, and Duke University, Durham, North Carolina
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Eller-Smith OC, Nicol AL, Christianson JA. Potential Mechanisms Underlying Centralized Pain and Emerging Therapeutic Interventions. Front Cell Neurosci 2018; 12:35. [PMID: 29487504 PMCID: PMC5816755 DOI: 10.3389/fncel.2018.00035] [Citation(s) in RCA: 142] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 01/30/2018] [Indexed: 12/11/2022] Open
Abstract
Centralized pain syndromes are associated with changes within the central nervous system that amplify peripheral input and/or generate the perception of pain in the absence of a noxious stimulus. Examples of idiopathic functional disorders that are often categorized as centralized pain syndromes include fibromyalgia, chronic pelvic pain syndromes, migraine, and temporomandibular disorder. Patients often suffer from widespread pain, associated with more than one specific syndrome, and report fatigue, mood and sleep disturbances, and poor quality of life. The high degree of symptom comorbidity and a lack of definitive underlying etiology make these syndromes notoriously difficult to treat. The main purpose of this review article is to discuss potential mechanisms of centrally-driven pain amplification and how they may contribute to increased comorbidity, poorer pain outcomes, and decreased quality of life in patients diagnosed with centralized pain syndromes, as well as discuss emerging non-pharmacological therapies that improve symptomology associated with these syndromes. Abnormal regulation and output of the hypothalamic-pituitary-adrenal (HPA) axis is commonly associated with centralized pain disorders. The HPA axis is the primary stress response system and its activation results in downstream production of cortisol and a dampening of the immune response. Patients with centralized pain syndromes often present with hyper- or hypocortisolism and evidence of altered downstream signaling from the HPA axis including increased Mast cell (MC) infiltration and activation, which can lead to sensitization of nearby nociceptive afferents. Increased peripheral input via nociceptor activation can lead to “hyperalgesic priming” and/or “wind-up” and eventually to central sensitization through long term potentiation in the central nervous system. Other evidence of central modifications has been observed through brain imaging studies of functional connectivity and magnetic resonance spectroscopy and are shown to contribute to the widespreadness of pain and poor mood in patients with fibromyalgia and chronic urological pain. Non-pharmacological therapeutics, including exercise and cognitive behavioral therapy (CBT), have shown great promise in treating symptoms of centralized pain.
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Affiliation(s)
- Olivia C Eller-Smith
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Andrea L Nicol
- Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Julie A Christianson
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, United States
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Harper DE, Ichesco E, Schrepf A, Halvorson M, Puiu T, Clauw DJ, Harris RE, Harte SE. Relationships between brain metabolite levels, functional connectivity, and negative mood in urologic chronic pelvic pain syndrome patients compared to controls: A MAPP research network study. NEUROIMAGE-CLINICAL 2017; 17:570-578. [PMID: 29201643 PMCID: PMC5702874 DOI: 10.1016/j.nicl.2017.11.014] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 11/06/2017] [Accepted: 11/14/2017] [Indexed: 02/01/2023]
Abstract
Until recently, the predominant pathology of chronic pelvic pain conditions was thought to reside in the peripheral tissues. However, mounting evidence from neuroimaging studies suggests an important role of the central nervous system in the pathogenesis of these conditions. In the present cross-sectional study, proton magnetic resonance spectroscopy (1H-MRS) of the brain was conducted in female patients with urologic chronic pelvic pain syndrome (UCPPS) to determine if they exhibit abnormal concentrations of brain metabolites (e.g. those indicative of heightened excitatory tone) in regions involved in the processing and modulation of pain, including the anterior cingulate cortex (ACC) and the anterior and posterior insular cortices. Compared to a group of age-matched healthy subjects, there were significantly higher levels of choline (p = 0.006, uncorrected) in the ACC of UCPPS patients. ACC choline levels were therefore compared with the region's resting functional connectivity to the rest of the brain. Higher choline was associated with greater ACC-to-limbic system connectivity in UCPPS patients, contrasted with lower connectivity in controls (i.e. an interaction). In patients, ACC choline levels were also positively correlated with negative mood. ACC γ-aminobutyric acid (GABA) levels were lower in UCPPS patients compared with controls (p = 0.02, uncorrected), but this did not meet statistical correction for the 4 separate regional comparisons of metabolites. These results are the first to uncover abnormal GABA and choline levels in the brain of UCPPS patients compared to controls. Low GABA levels have been identified in other pain syndromes and might contribute to CNS hyper-excitability in these conditions. The relationships between increased ACC choline levels, ACC-to-limbic connectivity, and negative mood in UCPPS patients suggest that this metabolite could be related to the affective symptomatology of this syndrome.
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Affiliation(s)
- Daniel E Harper
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
| | - Eric Ichesco
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
| | - Andrew Schrepf
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
| | - Megan Halvorson
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
| | - Tudor Puiu
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
| | - Daniel J Clauw
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
| | - Richard E Harris
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
| | - Steven E Harte
- Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
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