Intranasal (R)-ketamine modulates depression symptom and neurotransmitters-associated human brain connectivity

Area of Science:

• Neuroscience
• Psychiatry
• Pharmacology

Background:

• Racemic ketamine shows rapid antidepressant effects.
• (R)-ketamine, a specific isomer, may offer sustained efficacy with fewer side effects.
• Neurobiological mechanisms of (R)-ketamine in the human brain remain largely unknown.

Purpose of the Study:

• To investigate the neurobiological mechanisms of intranasal (R)-ketamine using resting-state fMRI.
• To assess changes in long-range functional synchrony and connectivity in the human brain after (R)-ketamine administration.
• To correlate neuroimaging findings with neurotransmitter profiles and clinical depression severity.

Main Methods:

• Resting-state fMRI data acquired from 32 healthy volunteers before and after intranasal (R)-ketamine or placebo.
• Analysis of degree centrality (DC) to assess changes in long-range functional synchrony.
• Functional connectivity (FC) analysis to identify network sources of DC changes.

Main Results:

• (R)-ketamine significantly decreased DC in the supplementary motor area/middle cingulate cortex (SMA/MCC).
• A significant group-by-time interaction confirmed the reduction in DC was specific to (R)-ketamine, not placebo.
• Reduced SMA/MCC synchrony was linked to attenuated FC with dMPFC/dACC and cerebellum, and correlated with neurotransmitter profiles.
• In an MDD cohort, SMA/MCC-dMPFC/dACC FC correlated with depressive symptom severity.

Conclusions:

• Intranasal (R)-ketamine attenuates long-range synchrony in the SMA/MCC, modulating specific human brain networks.
• The observed neuroimaging phenotype is linked to depression-relevant neurotransmitter profiles.
• This study provides evidence for a plausible therapeutic mechanism of (R)-ketamine in treating depression.