Ketamine-induced changes in connectivity of functional brain networks in awake female nonhuman primates: a translational functional imaging model.

RATIONALE: There is a significant interest in the NMDA-receptor antagonist ketamine due to its efficacy in treating depressive disorders and its induction of psychotic-like symptoms that make it a useful tool for modeling psychosis. Pharmacological MRI in awake nonhuman primates provides a highly translational model for studying the brain network dynamics involved in producing these drug effects.

OBJECTIVE: The present study evaluated ketamine-induced changes in functional connectivity (FC) in awake rhesus monkeys. The effects of ketamine after pretreatment with the antipsychotic drug risperidone were also examined.

METHODS: Functional MRI scans were conducted in four awake adult female rhesus monkeys during sub-anesthetic i.v. infusions of ketamine (0.345 mg/kg bolus followed by 0.256 mg kg-1  h-1 constant infusion) with and without risperidone pretreatment (0.06 mg/kg). A 10-min window of stable BOLD signal was used to compare FC between baseline and drug conditions. FC was assessed in specific regions of interest using seed-based cross-correlation analysis.

RESULTS: Ketamine infusion induced extensive changes in FC. In particular, FC to the dorsolateral prefrontal cortex (dlPFC) was increased in several cortical and subcortical regions. Pretreatment with risperidone largely attenuated ketamine-induced changes in FC.

CONCLUSIONS: The results are highly consistent with similar human imaging studies showing ketamine-induced changes in FC, as well as a significant attenuation of these changes when ketamine infusion is preceded by pretreatment with risperidone. The extensive increases shown in FC to the dlPFC are consistent with the idea that disinhibition of the dlPFC may be a key driver of the antidepressant and psychotomimetic effects of ketamine.