Anna Xu1, Bart Larsen1, Alina Henn2, Erica B Baller1,3,4, J Cobb Scott1,5, Vaishnavi Sharma1, Azeez Adebimpe1, Allan I Basbaum6, Gregory Corder1, Robert H Dworkin7, Robert R Edwards8, Clifford J Woolf9,10, Simon B Eickhoff11,12, Claudia R Eickhoff12,13, Theodore D Satterthwaite1. 1. Department of Psychiatry, University of Pennsylvania, Philadelphia. 2. Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen University, Aachen, Germany. 3. Department of Psychiatry, Massachusetts General Hospital, Boston. 4. Department of Psychiatry, Harvard University, Boston, Massachusetts. 5. VISN4 Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA (Veterans Affairs) Medical Center, Philadelphia, Pennsylvania. 6. Department of Anatomy, University of California, San Francisco. 7. Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York. 8. Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 9. FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts. 10. Department of Neurobiology, Harvard Medical School, Boston, Massachusetts. 11. Institute of Systems Neuroscience, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany. 12. Institute of Neuroscience and Medicine, Brain and Behaviour Sections, Research Centre Jülich, Jülich, Germany. 13. Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Abstract
Importance: Functional neuroimaging is a valuable tool for understanding how patients with chronic pain respond to painful stimuli. However, past studies have reported heterogenous results, highlighting opportunities for a quantitative meta-analysis to integrate existing data and delineate consistent associations across studies. Objective: To identify differential brain responses to noxious stimuli in patients with chronic pain using functional magnetic resonance imaging (fMRI) while adhering to current best practices for neuroimaging meta-analyses. Data Sources: All fMRI experiments published from January 1, 1990, to May 28, 2019, were identified in a literature search of PubMed/MEDLINE, EMBASE, Web of Science, Cochrane Library, PsycINFO, and SCOPUS. Study Selection: Experiments comparing brain responses to noxious stimuli in fMRI between patients and controls were selected if they reported whole-brain results, included at least 10 patients and 10 healthy control participants, and used adequate statistical thresholding (voxel-height P < .001 or cluster-corrected P < .05). Two independent reviewers evaluated titles and abstracts returned by the search. In total, 3682 abstracts were screened, and 1129 full-text articles were evaluated. Data Extraction and Synthesis: Thirty-seven experiments from 29 articles met inclusion criteria for meta-analysis. Coordinates reporting significant activation differences between patients with chronic pain and healthy controls were extracted. These data were meta-analyzed using activation likelihood estimation. Data were analyzed from December 2019 to February 2020. Main Outcomes and Measures: A whole-brain meta-analysis evaluated whether reported differences in brain activation in response to noxious stimuli between patients and healthy controls were spatially convergent. Follow-up analyses examined the directionality of any differences. Finally, an exploratory (nonpreregistered) region-of-interest analysis examined differences within the pain network. Results: The 37 experiments from 29 unique articles included a total of 511 patients and 433 controls (944 participants). Whole-brain meta-analyses did not reveal significant differences between patients and controls in brain responses to noxious stimuli at the preregistered statistical threshold. However, exploratory analyses restricted to the pain network revealed aberrant activity in patients. Conclusions and Relevance: In this systematic review and meta-analysis, preregistered, whole-brain analyses did not reveal aberrant fMRI activity in patients with chronic pain. Exploratory analyses suggested that subtle, spatially diffuse differences may exist within the pain network. Future work on chronic pain biomarkers may benefit from focus on this core set of pain-responsive areas.
Importance: Functional neuroimaging is a valuable tool for understanding how patients with chronic pain respond to painful stimuli. However, past studies have reported heterogenous results, highlighting opportunities for a quantitative meta-analysis to integrate existing data and delineate consistent associations across studies. Objective: To identify differential brain responses to noxious stimuli in patients with chronic pain using functional magnetic resonance imaging (fMRI) while adhering to current best practices for neuroimaging meta-analyses. Data Sources: All fMRI experiments published from January 1, 1990, to May 28, 2019, were identified in a literature search of PubMed/MEDLINE, EMBASE, Web of Science, Cochrane Library, PsycINFO, and SCOPUS. Study Selection: Experiments comparing brain responses to noxious stimuli in fMRI between patients and controls were selected if they reported whole-brain results, included at least 10 patients and 10 healthy control participants, and used adequate statistical thresholding (voxel-height P < .001 or cluster-corrected P < .05). Two independent reviewers evaluated titles and abstracts returned by the search. In total, 3682 abstracts were screened, and 1129 full-text articles were evaluated. Data Extraction and Synthesis: Thirty-seven experiments from 29 articles met inclusion criteria for meta-analysis. Coordinates reporting significant activation differences between patients with chronic pain and healthy controls were extracted. These data were meta-analyzed using activation likelihood estimation. Data were analyzed from December 2019 to February 2020. Main Outcomes and Measures: A whole-brain meta-analysis evaluated whether reported differences in brain activation in response to noxious stimuli between patients and healthy controls were spatially convergent. Follow-up analyses examined the directionality of any differences. Finally, an exploratory (nonpreregistered) region-of-interest analysis examined differences within the pain network. Results: The 37 experiments from 29 unique articles included a total of 511 patients and 433 controls (944 participants). Whole-brain meta-analyses did not reveal significant differences between patients and controls in brain responses to noxious stimuli at the preregistered statistical threshold. However, exploratory analyses restricted to the pain network revealed aberrant activity in patients. Conclusions and Relevance: In this systematic review and meta-analysis, preregistered, whole-brain analyses did not reveal aberrant fMRI activity in patients with chronic pain. Exploratory analyses suggested that subtle, spatially diffuse differences may exist within the pain network. Future work on chronic pain biomarkers may benefit from focus on this core set of pain-responsive areas.
Authors: Stefania Ferraro; Benjamin Klugah-Brown; Christopher R Tench; Shuxia Yao; Anna Nigri; Greta Demichelis; Chiara Pinardi; Maria Grazia Bruzzone; Benjamin Becker Journal: Hum Brain Mapp Date: 2021-11-03 Impact factor: 5.038