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Neuropsychopharmacology. 2017 Nov;42(12):2434-2445. doi: 10.1038/npp.2017.103. Epub 2017 May 29.

Inflexible Functional Connectivity of the Dorsal Anterior Cingulate Cortex in Adolescent Major Depressive Disorder.

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Division of Child and Adolescent Psychiatry, Department of Psychiatry, University of California, Weill Institute for Neurosciences, San Francisco, CA, USA.
Department of Psychology, Stanford University, Stanford, CA, USA.
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
Max Planck Institute, Human Cognitive and Brain Sciences, Leipzig, Germany.
Department of Radiology, University of California, San Francisco, CA, USA.
The Laureate Institute for Brain Research, Tulsa, OK, USA.
Department of Psychiatry, University of California, San Francisco, CA, USA.
Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Health Care System, San Diego, CA, USA.
Neurosciences Program, Stanford University, Stanford, CA, USA.


Recent evidence suggests that anterior cingulate cortex (ACC) maturation during adolescence contributes to or underlies the development of major depressive disorder (MDD) during this sensitive period. The ACC is a structure that sits at the intersection of several task-positive networks (eg, central executive network, CEN), which are still developing during adolescence. While recent work using seed-based approaches indicate that depressed adolescents show limited task-evoked vs resting-state connectivity (termed 'inflexibility') between the ACC and task-negative networks, no study has used network-based approaches to investigate inflexibility of the ACC in task-positive networks to understand adolescent MDD. Here, we used graph theory to compare flexibility of network-level topology in eight subregions of the ACC (spanning three task-positive networks) in 42 unmedicated adolescents with MDD and 53 well-matched healthy controls. All participants underwent fMRI scanning during resting state and a response inhibition task that robustly engages task-positive networks. Relative to controls, depressed adolescents were characterized by inflexibility in local efficiency of a key ACC node in the CEN: right dorsal anterior cingulate cortex/medial frontal gyrus (R dACC/MFG). Furthermore, individual differences in flexibility of local efficiency of R dACC/MFG significantly predicted inhibition performance, consistent with current literature demonstrating that flexible network organization affords successful cognitive control. Finally, reduced local efficiency of dACC/MFG during the task was significantly associated with an earlier age of depression onset, consistent with prior work suggesting that MDD may alter functional network development. Our results support a neurodevelopmental hypothesis of MDD wherein dysfunctional self-regulation is potentially reflected by altered ACC maturation.

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