Mapping heterogeneity in the neuroanatomical correlates of depression

Abstract Major depressive disorder (MDD) affects millions worldwide, yet its neurobiological underpinnings remain elusive. Neuroimaging studies have yielded inconsistent results, hindered by small sample sizes and heterogeneous depression definitions. We sought to address these limitations by leveraging the UK Biobank’s extensive neuroimaging data (n=30,122) to investigate how depression phenotyping depth influences neuroanatomic profiles of MDD. We examined 256 brain structural features, obtained from T1- and diffusion-weighted brain imaging, and nine depression phenotypes, ranging from self-reported symptoms (shallow definitions) to clinical diagnoses (deep). Multivariable logistic regression, machine learning classifiers, and feature transfer approaches were used to explore correlational patterns, predictive accuracy and the transferability of important features across depression definitions. For white matter microstructure, we observed widespread fractional anisotropy decreases and mean diffusivity increases. In contrast, cortical thickness and surface area were less consistently associated across depression definitions, and demonstrated weaker associations. Machine learning classifiers showed varying performance in distinguishing depression cases from controls, with shallow phenotypes achieving similar discriminative performance (AUC=0.807) and slightly higher positive predictive value (PPV=0.655) compared to deep phenotypes (AUC=0.831, PPV=0.456), when sensitivity was standardized at 80%. However, when shallow phenotypes were downsampled to match deep phenotype case/control ratios, performance degraded substantially (AUC=0.690). Together, these results suggest that while core white-matter alterations are shared across phenotyping strategies, shallow phenotypes require approximately twice the sample size of deep phenotypes to achieve comparable classification performance, underscoring the fundamental power-specificity tradeoff in psychiatric neuroimaging research. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by the Tommy Fuss Fund, a foundation established by the Fuss family to promote medical research that furthers our understanding of mental illness and develops more effective means of diagnosing and treating psychopathology. 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 current study has received approval to be conducted by the Mass General Brigham Institutional Review Board (approval number 2022P003366). 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 Footnotes Main manuscript edited for brevity and conciseness; Supplementary Methods and Supplementary Results sections added; Tables 1-3 and Figures 1-3 retained in main manuscript; additional tables and figures moved to supplementary materials. Data Availability The datasets analyzed during the current study are available via the UK Biobank data access process (see http://www.ukbiobank.ac.uk/register-apply/). This research was conducted using the UK Biobank Resource under Application Number 32568.