Journal
CEREBRAL CORTEX
Volume 27, Issue 1, Pages 660-679Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhv249
Keywords
bistability; deep brain stimulation; theta; serotonin; subgenual
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Funding
- Ministry of Economy and Competitiveness of Spain
- European Regional Development Fund [BFU2009-09537, BFU2012-34838]
- NIMH [1RO1MH073719, P50 MH077083]
- Dana Foundation
- Woodruff Fund
- Stanley Medical Research Institute
- Hope for Depression Research Foundation
- Spanish Ministry of Economy and Competitiveness (FPI program)
- NATIONAL INSTITUTE OF MENTAL HEALTH [P50MH077083, R01MH073719] Funding Source: NIH RePORTER
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Major depression disease (MDD) is associated with the dysfunction of multinode brain networks. However, converging evidence implicates the reciprocal interaction between midline limbic regions (typified by the ventral anterior cingulate cortex, vACC) and the dorso-lateral prefrontal cortex (dlPFC), reflecting interactions between emotions and cognition. Furthermore, growing evidence suggests a role for abnormal glutamate metabolism in the vACC, while serotonergic treatments (selective serotonin reuptake inhibitor, SSRI) effective for many patients implicate the serotonin system. Currently, no mechanistic framework describes how network dynamics, glutamate, and serotonin interact to explain MDD symptoms and treatments. Here, we built a biophysical computational model of 2 areas (vACC and dlPFC) that can switch between emotional and cognitive processing. MDD networks were simulated by slowing glutamate decay in vACC and demonstrated sustained vACC activation. This hyperactivity was not suppressed by concurrent dlPFC activation and interfered with expected dlPFC responses to cognitive signals, mimicking cognitive dysfunction seen in MDD. Simulation of clinical treatments (SSRI or deep brain stimulation) counteracted this aberrant vACC activity. Theta and beta/gamma oscillations correlated with network function, representing markers of switch-like operation in the network. The model shows how glutamate dysregulation can cause aberrant brain dynamics, respond to treatments, and be reflected in EEG rhythms as biomarkers of MDD.
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