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.
Keywords
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Article info
Publication history
Published online: February 28, 2015
Identification
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