Effect of Lifetime Exposure to Depression on Brain Structure and Function in the UK Biobank

Importance Despite several decades of neuroimaging studies reporting brain structural and functional alterations in depression, discrepancies in findings across various studies and limited convergence across several recent meta-analyses have raised questions about the consistency and robustness of the observed brain phenotypes. Objective To investigate the effects of six different operational criteria of lifetime exposure to depression on functional and structural neuroimaging measures. Design, Setting, Participants A cross-sectional study analyzed data from the UK biobank in individuals aged 45 to 80 years enrolled from 2014 to 2018. Six operational depression criteria were defined: Help-seeking for depression, Self-reported Depression, Antidepressant usage, Depression defined by Smith, Hospital International Classification of Disease, 10th Edition (ICD-10), and short-form Composite International Diagnostic Interview. Six increasingly conservative groups of lifetime depression were defined based on the six available depression criteria from meeting only one to more restrictive meeting all six criteria. We tested the effect of these definitions on voxel-wise measures of local functional activity, global connectivity, and gray matter volume. Main Outcomes and Measures Voxel-wise fractional amplitude of low-frequency fluctuations, local connectivity, global connectivity, and gray matter volume. Results We included 20,484 individuals with lifetime depression (12,645 women [61.73%]; mean [SD] age, 63.92 [7.6] years) and 25,462 healthy individuals (11,384 women [44.7%]; mean [SD] age, 65.05 [7.8] years) from the UK biobank. Across all depression definitions, individuals with lifetime depression displayed regionally consistent decreases in local functional activity in sensorimotor regions but not in global connectivity and gray matter volume. Previous hospital ICD10 diagnosis and antidepressant usage resulted in the most pronounced alterations. Conclusions and Relevance Lifetime exposure to depression is associated with robust functional changes with more restrictive criteria revealing more pronounced alterations. Different inclusion criteria for depression may strongly contribute to the substantial variation of imaging findings reported in the literature. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The work was supported by the Chinese scholarship council (Grant No.CSC202006090244), SMHB: Helmholtz Portfolio Theme "Supercomputing and Modeling for the Human Brain" and the European Union's Horizon 2020 research and innovation program "TheVirtualBrain-Cloud"(Grant No.826421). ### 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: 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 The images and phenotypic data that support the current findings are available from UK Biobank. Data would be available from the authors upon reasonable application and with permission of UK Biobank ().