Are Brain Responses to Emotion a Reliable Endophenotype of Schizophrenia? An Image-based fMRI Meta-analysis

Background Impaired emotion processing constitutes a key dimension of schizophrenia and a possible endophenotype of this illness. Empirical studies consistently report poorer emotion recognition performance in patients with schizophrenia as well as in individuals at enhanced risk of schizophrenia (“at risk”). fMRI studies also report consistent patterns of abnormal brain activation in response to emotional stimuli in patients, in particular decreased amygdala activation. In contrast, brain-level abnormalities in at-risk individuals are more elusive. We address this gap using an image-based meta-analysis of the fMRI literature. Methods fMRI studies investigating brain responses to negative emotional stimuli and reporting a comparison between at-risk individuals and healthy controls were identified. Frequentist and Bayesian voxel-wise meta-analyses were performed separately, by implementing a random effect model with unthresholded group-level T-maps from individual studies as input. Results Seventeen studies with a cumulative total of 677 at-risk individuals and 805 healthy controls were included. Frequentist analyses did not reveal significant differences between at-risk individuals and healthy controls. Similar results were observed with Bayesian analyses, which provided strong evidence for the absence of meaningful brain activation differences across the entire brain. Region of interest analyses specifically focusing on the amygdala confirmed the lack of group differences in this region. Conclusions These results suggest that brain activation patterns in response to emotional stimuli are unlikely to constitute a reliable endophenotype of schizophrenia. We suggest that future studies rather focus on impaired functional connectivity as an alternative and promising endophenotype. ### Competing Interest Statement GB has received lecture fees from Lundbeck. EF has received consultancy fees from JBristol Myers Squibb, Janssen- Cilag, Lilly, Lundbeck, Otsuka, Recordatti, Sanofi; and has lectured for Abbvie, AstraZeneca, Bristol Myers Squibb, Janssen- Cilag, Lundbeck, Otsuka, MSD, Sanofi. AM-L has received grants from the Federal Ministry of Education and Research, the German Research Foundation, the Seventh Framework Programme of the European Union and the Ministry of Science, Research and the Arts of the State of Baden Wurttemberg. All other authors report no biomedical financial interest or potential conflicts of interest. ### Funding Statement AF was supported by the Fondation Pierre Deniker. EF was supported by the Fondation de France. GS was supported by the Agence Nationale de la Recherche [grant number ANR-19-CE37-0012-01] and the Fondation NRJ-Institut de France. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study is a meta-analytical work and only uses second-level results from published individual studies which obtained approval from Ethics Committees (no individual data was used but only results from group comparisons which were obtained from authors upon request) 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Unthresholded whole-brain maps of within- and between-group meta-analyses are available on NeuroVault at