title: Large-Scale Persistent Network Reconfiguration Induced by Ketamine in Anesthetized Monkeys: Relevance to Mood Disorders.
abstract: BACKGROUND
  Ketamine is a highly attractive candidate for developing fast-onset antidepressant agents; however, the relevant brain circuits that underlie sustained, efficacious antidepressant effects remain largely unknown.
  
  
  METHODS
  We used a holistic scheme combining whole-brain resting-state fMRI and graph theoretical analysis to examine the sustained effects on brain networks after administration of a single dose of ketamine and to identify the brain regions and circuits preferentially targeted by ketamine. Topological differences in functional networks of anesthetized macaque monkeys were compared between ketamine (.5 mg/kg) and saline treatment after 18 hours.
  
  
  RESULTS
  We observed persistent global reconfiguration of small-world properties in response to ketamine intake, accompanied by large-scale downregulation of functional connectivity, most prominently in the orbital prefrontal cortex, the subgenual and posterior cingulate cortices, and the nucleus accumbens. Intriguingly, intrinsic connectivity with the medial prefrontal areas in the reward circuits were selectively downregulated. Global and regional regulations of the brain networks precisely opposed the maladaptive alterations in the depressed brain.
  
  
  CONCLUSIONS
  Our results demonstrated that local synaptic plasticity triggered by blockade of N-methyl-D-aspartic acid receptors was capable of translating into prolonged network reconfiguration in the distributed cortico-limbic-striatal circuit, providing mechanistic insight into developing specific loci or circuit-targeted, long-term therapeutics.
authors.affiliation: Key Laboratory of Primate Neurobiology, Institute of Neuroscience, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lv
authors.affiliation: Key Laboratory of Primate Neurobiology, Institute of Neuroscience, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Liqin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Li
authors.affiliation: Key Laboratory of Primate Neurobiology, Institute of Neuroscience, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Primate Neurobiology, Institute of Neuroscience, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhuangming
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Key Laboratory of Primate Neurobiology, Institute of Neuroscience, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Yu
authors.affiliation: Key Laboratory of Primate Neurobiology, Institute of Neuroscience, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qinying
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Primate Neurobiology, Institute of Neuroscience, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Baoyu
authors.initials: B
authors.lastname: Hou
authors.affiliation: Key Laboratory of Primate Neurobiology, Institute of Neuroscience, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Pu
authors.affiliation: Key Laboratory of Primate Neurobiology, Institute of Neuroscience, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hailan
authors.initials: H
authors.lastname: Hu
authors.affiliation: Key Laboratory of Primate Neurobiology, Institute of Neuroscience, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: zheng.wang@ion.ac.cn.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects* / Q000502:physiology*; D001931:Brain Mapping / Q000379:methods; D005260:Female; D007649:Ketamine / Q000008:administration & dosage*; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D008959:Models, Neurological; D019964:Mood Disorders / Q000188:drug therapy / Q000503:physiopathology*; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D007649:Ketamine
keywords: Functional connectivity; Graph theory; Ketamine; Macaque monkey; Mood disorders; Neural network plasticity