Background: Post-stroke depression (PSD) affects up to one-third of stroke survivors, significantly impacting rehabilitation success and quality of life. However, its underlying pathophysiology remains unclear. Methods: We analyzed two independent, prospective ischemic stroke cohorts (PROSCIS-B NCT01363856 and BAPTISe NCT01954797; total N=377) to identify brain regions and networks associated with depressive symptoms post-stroke. Lesion-symptom mapping (LSM) assessed associations between lesion location and depressive symptoms measured via the Center for Epidemiologic Studies Depression Scale (CES-D) up to 12 months post-stroke, while lesion network mapping (LNM) evaluated lesion connectivity with brain networks. We explored correlations between spatial similarity to the LNM-identified network and CES-D scores using linear regression models. Results: LSM revealed no significant associations between lesion location and depressive symptoms. In contrast, LNM showed that lesion connectivity to brain regions?including the frontal pole, middle and inferior frontal gyri, inferior temporal gyrus, supramarginal gyrus, angular gyrus, frontal orbital cortex, and thalamus?correlated with CES-D scores (r=0.12, p=0.02). These regions overlapped with canonical resting-state networks, such as the frontoparietal (Dice coefficient [DC] = 0.28), salience (DC = 0.27), and default-mode networks (DC = 0.20), as well as a previously published depression circuit (DC = 0.43). Conclusions: Lesion location alone was not associated with depressive symptoms post-stroke. However, lesion connectivity analysis revealed associations with brain networks, particularly the frontoparietal, salience, and default-mode networks, suggesting that disruption to these circuits may contribute to the development of PSD up to one-year post-stroke.

ME reports grants from Bayer and fees paid to the Charité from Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Amgen, GSK, Sanofi, Covidien, and Novartis, all outside of the submitted work. CO reports grants from Boehringer Ingelheim and Peak Profiling and honoraria for lectures and/or scientific advice from Boehringer-Ingelheim, Janssen, Limes Klinikgruppe, Neuraxpharm, Oberberg Kliniken and Peak Profiling.

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: AKu and AK are participants in the Berlin Institute of Health-Charité Clinical Scientist Program funded by the Charité-Universitätsmedizin Berlin and the Berlin Institute of Health. ME received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy-EXC-2049-390688087 and Collaborative Research Center ReTune TRR 295- 424778381. ME received additional funding from Bundesministerium für Bildung und Forschung (BMBF; German Ministry for Education and Research) for the Center for Stroke Research Berlin. CO received funding from the German Research Foundation (OT 209/7-3; 14-1, 19-1, 21-1, EXC 2049), the European Commission (IMI2 859366), the German Federal Ministry of Education and Research (KS2017-067), the Berlin Institute of Health (B3010350), and the Wellcome Trust. AHN reports receiving research funding from the Corona Stiftung, the Else Kröner-Fresenius-Stiftung, and the German Center for Cardiovascular Research (DZHK), and was funded by the Berlin Institute of Health-Charité Clinical Scientist Program of the Charité-Universitätsmedizin Berlin and the Berlin Institute of Health.

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All participants provided informed consent. The studies were conducted in accordance to the Declaration of Helsinki and were approved by the local ethics committee in Berlin.

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Data supporting the results of this study is available upon reasonable request from the corresponding author. Code availability: Open source software was used for the pre-processing and analysis of the data, including: Lead-DBS (https://github.com/netstim/leaddbs), FSL 6.0.6.4 (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/) and ANTsPy (https://github.com/ANTsX/ANTsPy). The code used to perform AIC, and cross-validations has been made publicly available at https://osf.io/pgnwh/?view_only=015d9716f84d478eb6e2c5cf7d41fff3.

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