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Baseline Functional Connectivity in Resting State Networks Associated with Depression and Remission

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Baseline Functional Connectivity in Resting State Networks Associated with Depression and Remission medRxiv preprint doi: https://doi.org/10.1101/2021.01.27.21250490; this version posted January 29, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . 1 Baseline functional connectivity in resting state networks associated with depression and remission status after 16 weeks of pharmacotherapy: A CAN-BIND Report Authors: Gwen van der Wijk, MA (1), Jacqueline K. Harris, Msc (2,3), Stefanie Hassel, PhD (4,5), Andrew D. Davis, PhD (6,8), Mojdeh Zamyadi, Msc (6), Stephen R. Arnott, PhD (6), Roumen Milev, MD, PhD (9), Raymond W. Lam, MD (10), Benicio N. Frey, MD, PhD (11,12), Geoffrey B. Hall, PhD (13), Daniel J. Müller, MD, PhD (14,15,16,17), Susan Rotzinger, PhD (18,19), Sidney H. Kennedy, MD (14,17,18,20,21), Stephen C. Strother, PhD (6,7), Glenda M. MacQueen, MD, PhD (4,5), Andrea B. Protzner, PhD (1)(5)(22) Affiliations: 1. University of Calgary, Department of Psychology, Calgary, Canada 2. University of Alberta, Department of Computing Science, Edmonton, Canada 3. Alberta Machine Intelligence Institute, Edmonton, Canada 4. University of Calgary, Cumming School of Medicine, Department of Psychiatry, Calgary, Canada 5. Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, Canada 6. Rotman Research Institute, Baycrest Health Sciences, Toronto, Canada 7. University of Toronto, Department of Medical Biophysics, Toronto, Canada 8. Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, Canada 9. Queen’s University, Departments of Psychiatry and Psychology, and Providence Care Hospital, Kingston, Canada 10. University of British Columbia, Department of Psychiatry, Vancouver, Canada 11. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2021.01.27.21250490; this version posted January 29, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . 2 12. Mood Disorders Program and Women’s Health Concerns Clinic, St. Joseph’s Healthcare, Hamilton, Canada 13. Department of Psychology, Neuroscience & Behaviour, McMaster University, and St. Joseph’s Healthcare Hamilton, Hamilton, Canada 14. Department of Psychiatry, University of Toronto, Toronto, Canada 15. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada 16. Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada 17. Institute of Medical Sciences, University of Toronto, Toronto, Canada 18. Centre for Mental Health, University Health Network, Toronto, Canada 19. Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Canada. 20. Centre for Depression and Suicide Studies, Unity Health Toronto, Toronto, Canada 21. Krembil Research Institute, Toronto Western Hospital, Toronto, Canada 22. Hotchkiss Brain Institute, Calgary, Canada Key words: Major depressive disorder, functional connectivity, fMRI, default mode network, salience network, cognitive control network Corresponding author: Gwen van der Wijk Email: [email protected] Phone: +1-403-220-5025 Address: Department of Psychology, University of Calgary, 2500 University Drive NW, T2N 1N4 Calgary, Alberta, CANADA medRxiv preprint doi: https://doi.org/10.1101/2021.01.27.21250490; this version posted January 29, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . 3 Abstract Understanding the neural underpinnings of major depressive disorder (MDD) and its treatment could improve treatment outcomes. While numerous studies have been conducted, findings are variable and large sample replications scarce. We aimed to replicate and extend altered functional connectivity findings in the default mode, salience and cognitive control networks (DMN, SN, and CCN respectively) associated with MDD and pharmacotherapy outcomes in a large, multi-site sample. Resting-state fMRI data were collected from 129 patients and 99 controls through the Canadian Biomarker Integration Network in Depression (CAN-BIND) initiative. Symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). Connectivity was measured as correlations between four seeds (anterior and posterior DMN, SN and CCN) and all other brain voxels across participants. Partial least squares, a multivariate statistical technique, was used to compare connectivity prior to treatment between patients and controls, and between patients reaching remission early (MADRS ≤ 10 within 8 weeks), late (MADRS ≤ 10 within 16 weeks) or not at all. We replicated previous findings of altered connectivity in the DMN, SN and CCN in patients. In addition, baseline connectivity of the anterior/posterior DMN and SN seeds differentiated patients with different treatment outcomes. Weaker connectivity within the anterior DMN and between the anterior DMN and the SN and CCN characterised early remission; stronger connectivity within the SN and weaker connectivity between the SN and the DMN and CCN was related to late remission, of which the weaker SN – anterior DMN connectivity might specifically be associated with remission to dual pharmacotherapy; and connectivity strength between the posterior DMN and cingulate areas distinguished all three groups, with early remitters showing the strongest connections and non-remitters the weakest. The stability of these baseline patient differences was established in the largest single-site subsample of the data. Our replication and extension of altered connectivity within and between the DMN, SN and CCN highlighted previously reported and new differences between patients with MDD and controls, and revealed features that might predict remission prior to pharmacotherapy. Trial registration: ClinicalTrials.gov: NCT01655706. medRxiv preprint doi: https://doi.org/10.1101/2021.01.27.21250490; this version posted January 29, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . 4 Introduction Major depressive disorder (MDD) is a prevalent and debilitating disorder. Although several effective treatments are available, including psychotherapy, pharmacotherapy and neurostimulation therapy, treatment outcomes vary greatly among patients [1, 2]. Many neuroimaging studies have investigated brain changes related to MDD pathology and antidepressant treatment, but while the results are promising, inconsistent findings have led to growing concerns about reproducibility [3]. To improve treatment outcomes for patients with MDD, a robust understanding of the characteristics associated with MDD and antidepressant treatment outcomes is essential. Functional connectivity during rest, as captured by functional magnetic resonance imaging (fMRI) of the brain, has emerged as a potentially informative measure of the neural underpinnings of both the depressive state and its (successful) treatment [4-7]. Based on the more robust findings highlighted in meta-analyses and literature reviews, the three networks that have most consistently been linked to MDD pathology include the default mode network (DMN), the salience network (SN) and the cognitive control network (CCN) [4, 8]. Core regions of the DMN are the posterior cingulate cortex (PCC), precuneus, the bilateral angular gyrus and the medial prefrontal cortex (mPFC; [4]). In MDD, the anterior cingulate cortex (ACC) has also been found to be part of the DMN [9]. This network is generally thought to be related to internal processing in conscious participants ([4], see [10] for a discussion on DMN activity during unconscious states). The core regions of the SN include the bilateral insulae, the amygdalae, the temporal poles and the dorsal anterior cingulate cortex (dACC; [4]). It is involved in emotion processing and bottom-up attentional processes (e.g. monitoring for salient stimuli; [5]). Core CCN regions include the bilateral dorsolateral prefrontal cortex (dlPFC), frontal eye fields (FEF), dorsomedial prefrontal cortex (dmPFC) and the posterior parietal cortex (PPC), which together exert top-down control over cognitive and emotional processes [4]. Disturbed connectivity within and between these networks is thought to lead to the abnormal emotion processing and mood regulation in MDD [5, 11]. Given the frequency with which these networks are highlighted in previous work and their functional relevance to MDD pathology, we focused on these three resting state networks in our study. medRxiv preprint doi: https://doi.org/10.1101/2021.01.27.21250490; this version posted January 29, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is
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