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

Racemic (R,S)-ketamine exerts rapid antidepressant effects, and growing evidence suggests its R-isomer may offer sustained efficacy with fewer side effects. However, the neurobiological mechanisms underlying (R)-ketamine's action in the human brain are largely unknown. To address this, we acquired resting-state fMRI data from 32 healthy volunteers 24 ​h before and after intranasal administration of (R)-ketamine (n ​= ​24) or placebo (n ​= ​8). We primarily assessed changes in long-range functional synchrony using degree centrality (DC) and elucidated the sources of these changes with functional connectivity (FC) analysis. (R)-ketamine significantly decreased DC in a key cognitive-motor integration hub: the supplementary motor area/middle cingulate cortex (SMA/MCC, cluster-corrected P ​< ​0.05). Critically, the reduction of DC was absent under the placebo condition, yielding a significant group-by-time interaction (P ​= ​0.01). The reduction in long-range synchrony of the SMA/MCC was primarily driven by attenuated FC with both the dorsal medial prefrontal cortex/dorsal anterior cingulate cortex (dMPFC/dACC) and the cerebellum, and was spatially correlated with serotonin, norepinephrine, and acetylcholine neurotransmitter profiles. More importantly, the clinical relevance of the neuroimaging phenotypes was established in an independent Major Depressive Disorder (MDD) cohort, where FC between the SMA/MCC and dMPFC/dACC significantly correlated with depressive symptom severity (HAMD score, P ​= ​0.019). This study provides novel, system-level evidence that intranasal (R)-ketamine modulates specific human brain networks by attenuating long-range synchrony in the SMA/MCC. The link between the neuroimaging phenotype, depression-relevant neurotransmitter profiles, and clinical symptom severity may offer a plausible therapeutic mechanism of (R)-ketamine.