Shared Neural Dysregulations Mediate Dysregulated Empathy for Pain across Mental Disorders - a Pre-registered Neuroimaging Meta - Analysis

Importance: Pain empathy represents a fundamental building block of several social functions, which have been demonstrated to be impaired across various mental disorders by accumulating evidence from case-control functional magnetic resonance imaging (fMRI) studies. However, it remains unclear whether the dysregulations are mediated by a shared transdiagnostic neural substrate. Objective: Using coordinate-based, network-level, and behavioral meta-analyses to quantitatively determine transdiagnostic markers of altered pain empathy across mental disorders. Data Sources: A literature search was conducted in PubMed, Web of Science, and Scopus encompassing the period until April 2023. Search terms included pain empathy, functional magnetic resonance imaging, and mental disorders. Study Selection: Case-control neuroimaging studies of pain empathy and peak coordinates and effect sizes reflecting unbiased (whole-brain) pain empathic neural differences between patients and controls in standard stereotactic space were included. Data Extraction and Synthesis: The present pre-registered meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Article screening and data extraction were conducted by three independent reviewers, and data were pooled using the random-effects model. Main Outcome(s) and Measure(s): Robust neural activity differences between patients with mental disorders and healthy controls during pain empathic processing, meta-analytic network level, and behavioral decoding of the identified regions. Results: Patients with mental disorders exhibited increased pain empathic reactivity in the left anterior cingulate gyrus, adjacent medial prefrontal cortex, and right middle temporal gyrus, yet decreased activity in the left cerebellum IV/V and left middle occipital gyrus compared to controls. The hyperactive regions showed strong network-level interactions with the core default mode network (DMN) and were associated with affective and social cognitive domains. Conclusions and Relevance: Pain-empathic alterations across mental disorders are underpinned by excessive empathic reactivity in brain systems involved in empathic distress and social processes. These findings point to a shared therapeutic target to normalize basal social dysfunctions in mental disorders. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Natural Science Foundation of China (Grants No. 82271583, 32250610208), China MOST2030 Brain Project (Grant No. 2022ZD0208500), and a start-up grant from The University of Hong Kong. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data available: Yes How to access data: The data will be uploaded as an Excel file to the Open Science Framework (https://osf.io/axt9k/) When available: With publication Who can access: Anyone