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Neuropsychopharmacology. 2016 Nov;41(12):2951-2960. doi: 10.1038/npp.2016.76. Epub 2016 May 26.

Large-Scale Hypoconnectivity Between Resting-State Functional Networks in Unmedicated Adolescent Major Depressive Disorder.

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Neurosciences Program and Department of Psychology, Stanford University, Stanford, CA, USA.
Department of Psychiatry, Division of Child and Adolescent Psychiatry, University of California San Francisco, San Francisco, CA, USA.
Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
Institute of Interdisciplinary Studies, Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, The Netherlands.
Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden.
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Department of Psychiatry, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
Neuroscience Program, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
Laureate Institute for Brain Research, Tulsa, OK, USA.
Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Health Care System, San Diego, CA, USA.


Major depressive disorder (MDD) often emerges during adolescence, a critical period of brain development. Recent resting-state fMRI studies of adults suggest that MDD is associated with abnormalities within and between resting-state networks (RSNs). Here we tested whether adolescent MDD is characterized by abnormalities in interactions among RSNs. Participants were 55 unmedicated adolescents diagnosed with MDD and 56 matched healthy controls. Functional connectivity was mapped using resting-state fMRI. We used the network-based statistic (NBS) to compare large-scale connectivity between groups and also compared the groups on graph metrics. We further assessed whether group differences identified using nodes defined from functionally defined RSNs were also evident when using anatomically defined nodes. In addition, we examined relations between network abnormalities and depression severity and duration. Finally, we compared intranetwork connectivity between groups and assessed the replication of previously reported MDD-related abnormalities in connectivity. The NBS indicated that, compared with controls, depressed adolescents exhibited reduced connectivity (p<0.024, corrected) between a specific set of RSNs, including components of the attention, central executive, salience, and default mode networks. The NBS did not identify group differences in network connectivity when using anatomically defined nodes. Longer duration of depression was significantly correlated with reduced connectivity in this set of network interactions (p=0.020, corrected), specifically with reduced connectivity between components of the dorsal attention network. The dorsal attention network was also characterized by reduced intranetwork connectivity in the MDD group. Finally, we replicated previously reported abnormal connectivity in individuals with MDD. In summary, adolescents with MDD show hypoconnectivity between large-scale brain networks compared with healthy controls. Given that connectivity among these networks typically increases during adolescent neurodevelopment, these results suggest that adolescent depression is associated with abnormalities in neural systems that are still developing during this critical period.

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