Abstract
Ketamine improves motivation-related symptoms in depression but simultaneously elicits similar symptoms in healthy individuals, suggesting that it might have different effects in health and disease. This study examined whether ketamine affects the brain’s fronto-striatal system, which is known to drive motivational behavior. The study also assessed whether inflammatory mechanisms—which are known to influence neural and behavioral motivational processes—might underlie some of these changes. These questions were explored in the context of a double-blind, placebo-controlled, crossover trial of ketamine in 33 individuals with treatment-resistant major depressive disorder (TRD) and 25 healthy volunteers (HVs). Resting-state functional magnetic resonance imaging (rsfMRI) was acquired 2 days post-ketamine (final sample: TRD n = 27, HV n = 19) and post-placebo (final sample: TRD n = 25, HV n = 18) infusions and was used to probe fronto-striatal circuitry with striatal seed-based functional connectivity. Ketamine increased fronto-striatal functional connectivity in TRD participants toward levels observed in HVs while shifting the connectivity profile in HVs toward a state similar to TRD participants under placebo. Preliminary findings suggest that these effects were largely observed in the absence of inflammatory (C-reactive protein) changes and were associated with both acute and sustained improvements in symptoms in the TRD group. Ketamine thus normalized fronto-striatal connectivity in TRD participants but disrupted it in HVs independently of inflammatory processes. These findings highlight the potential importance of reward circuitry in ketamine’s mechanism of action, which may be particularly relevant for understanding ketamine-induced shifts in motivational symptoms.
Highlights
Altered function has been observed in the ventral striatum (VS), orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (PFC), and perigenual anterior cingulate cortex [16,17,18,19,20,21]. Complementing and extending these findings, studies investigating resting-state functional magnetic resonance imaging (fMRI)—which is thought to reflect the intrinsic functional organization of neural circuits—reported that depression is associated with altered functional connectivity between striatal and prefrontal regions [22,23,24,25,26,27,28]
The hypothesis was that ketamine would increase functional connectivity within the fronto-striatal circuitry of treatment-resistant major depressive disorder (TRD) participants but decrease it in healthy volunteers (HVs), and that these effects would be associated with ketamineinduced changes in inflammatory response
A negative association was observed between ΔCRP and ventral rostral putamen (VRP)-right OFC ΔFC in HVs (r = −0.64, p = 0.007; Fig. 3), such that increased C-reactive protein (CRP) levels post-ketamine correlated with decreased VRP-right OFC functional connectivity
Summary
Altered function has been observed in the ventral striatum (VS), orbitofrontal cortex (OFC), dorsolateral PFC (dlPFC), and perigenual anterior cingulate cortex (pgACC) [16,17,18,19,20,21] Complementing and extending these findings, studies investigating resting-state fMRI (rsfMRI)—which is thought to reflect the intrinsic functional organization of neural circuits—reported that depression is associated with altered functional connectivity between striatal and prefrontal regions [22,23,24,25,26,27,28]. Ketamine may affect dopaminergic function through glutamatergic downstream effects [45, 46] and may influence inflammatory processes [47, 48] These studies lend credence to the hypothesis that fronto-striatal circuitry is important in ketamine’s mechanism of action, this has never been directly tested. The hypothesis was that ketamine would increase functional connectivity within the fronto-striatal circuitry of TRD participants but decrease it in HVs, and that these effects would be associated with ketamineinduced changes in inflammatory response
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
