title: A Computational Model of Major Depression: the Role of Glutamate Dysfunction on Cingulo-Frontal Network Dynamics.
abstract: 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.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Ramirez-Mahaluf
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Centre de Recerca Matemàtica, Bellaterra, Spain.
authors.forename: Alexander
authors.initials: A
authors.lastname: Roxin
authors.affiliation: School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Helen S
authors.initials: HS
authors.lastname: Mayberg
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Compte
mesh_terms: D000200:Action Potentials; D058256:Brain Waves / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003198:Computer Simulation; D046690:Deep Brain Stimulation; D003865:Major Depressive Disorder / Q000503:physiopathology* / Q000628:therapy; D018450:Disease Progression; D004644:Emotions / Q000187:drug effects / Q000502:physiology; D005625:Frontal Lobe / Q000187:drug effects / Q000503:physiopathology*; D018698:Glutamic Acid / Q000378:metabolism*; D006179:Gyrus Cinguli / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D008570:Memory, Short-Term / Q000502:physiology; D008959:Models, Neurological; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D009474:Neurons / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use
chemical_list: D018698:Glutamic Acid; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors
keywords: bistability; deep brain stimulation; serotonin; subgenual; theta