Interference control and associated brain activity in children with familial high-risk of schizophrenia or bipolar disorder – A Danish register-based study

Background and hypotheses Impaired interference control is a potential prognostic and endophenotypic marker of schizophrenia (SZ) and bipolar disorder (BP). Assessing children with familial high-risk (FHR) of SZ or BP enables characterization of early risk markers and we hypothesize that they express impaired interference control as well as aberrant brain activation compared to population-based control (PBC) children. Study design Using a flanker task, we examined interference control together with functional magnetic resonance imaging (fMRI) in 11-to-12-year-old children with FHR of SZ (FHR-SZ) or FHR of BP (FHR-BP) and population-based control (PBC) children as part of a register-based, prospective cohort-study; The Danish High Risk and Resilience study – VIA 11. Study results We included 85 (44 % female) FHR-SZ, 63 (52 % female) FHR-BP and 98 (50 % female) PBC in the analyses. Interference effects, caused by the spatial visuomotor conflict, showed no differences between groups. Bayesian ANOVA of reaction time (RT) variability, quantified by the coefficient of variation (CVRT), revealed a group effect with similarly higher CVRT in FHR-BP and FHR-SZ compared to PBC (BF10 = 6.82). The fMRI analyses revealed no evidence for between-group differences in task-related brain activation. Post-hoc analyses excluding children with psychiatric illness yielded same results. Conclusion FHR-SZ and FHR-BP at age 11-to-12 show intact ability to resolve a spatial visuo-motor conflict and neural efficacy. The increased variability in RT may reflect difficulties in maintaining sustained attention. Since variability in RT was independent of existing psychiatric illness, it may reflect a potential endophenotypic marker of risk. ### Competing Interest Statement Hartwig R. Siebner has received honoraria as speaker from Sanofi Genzyme, Denmark, Lundbeck AS, Denmark, and Novartis, Denmark, as consultant from Sanofi Genzyme, Denmark, Lophora, Denmark, and Lundbeck AS, Denmark, and as editor-in-chief (Neuroimage Clinical) and senior editor (NeuroImage) from Elsevier Publishers, Amsterdam, The Netherlands. He has received royalties as book editor from Springer Publishers, Stuttgart, Germany and from Gyldendal Publishers, Copenhagen, Denmark. During preparation of the manuscript, Ayna Baladi Nejad changed employment to Novo Nordisk A/S. ### Funding Statement This study was funded by The Lundbeck Foundation Initiative for Integrative Psychiatric Research - iPSYCH (grant number R248-2017-2003) and Innovation Fund Denmark (grant number 6152-00002B). LKJ was funded by The Independent Research Fund (grant number DFF - 6110-00139), Denmark, and KML received funding from Mental Health services - Capital Region of Denmark (no grant number given) as well as the Lundbeck foundation (grant number R322-2019-2311). Hartwig R. Siebner holds a 5-year professorship in precision medicine at the Faculty of Health Sciences and Medicine, University of Copenhagen which is sponsored by the Lundbeck Foundation (grant number R186-2015-2138). The funders had no role in study design, data collection, data analysis, data interpretation, decision to publish or preparation of the manuscript. ### 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: Ethics commmittee/IRB of the National Committee on Health Research Ethics gave ethical approcal for this work (Protocol number: H 16043682) 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 The data that support the findings of this study are not available due to Danish law.