Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals

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.

Trial registration: ClinicalTrials.gov NCT00088699.

Conflict of interest statement

CAZ is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the US government but will share a percentage of any royalties that may be received by the government. All other authors have no conflict of interest to disclose, financial or otherwise.

© 2020. The Author(s).

Figures

Fig. 1. Group differences in the effects of ketamine on functional connectivity across four striatal seeds.

Ketamine differentially altered functional connectivity between the groups, as reflected in VS-left dlPFC (a), DC-right vlPFC (b), DCP-pgACC (c), and VRP-left/right OFC (d) coupling. This was identified using group-by-treatment F–tests at a family-wise error (FWE) cluster-corrected threshold level of p < 0.05. Boxplots with individual data points and distributions [75] show that functional connectivity was increased in individuals with treatment-resistant depresssion (TRD) but reduced in healthy volunteers (HVs) post-ketamine relative to placebo (a–d). Resting-state functional magnetic resonance imagining scans (rsfMRI) were acquired 2 days after each infusion. VS ventral striatum; DC dorsal caudate; DCP dorsal caudal putamen; VRP ventral rostral putamen; dlPFC dorsolateral prefrontal cortex; vlPFC ventrolateral prefrontal cortex; pgACC perigenual anterior cingulate cortex; OFC orbitofrontal cortex; L left; R right; FWE family–wise error.

Fig. 2. Ketamine had no effect on functional connectivity (data acquired 2 days post infusion) between the striatum and primary visual cortex (V1).

Individual data points, boxplots, and data distributions are plotted for ventral striatum (VS)-V1 (a), dorsal caudate (DC)-V1 (b), dorsal caudal putamen (DCP)-V1 (c), and ventral rostral putamen (VRP)-V1 (d) functional connectivity post-ketamine and post-placebo for healthy volunteers (HVs) and individuals with treatment-resistant depression (TRD).

Fig. 3. Association between post-ketamine changes in inflammation and functional connectivity.

The relationship between changes in ketamine and peripheral inflammation (measured by C-reactive protein (CRP) 1 day post–infusion) with changes in functional connectivity (measured 2 days post–infusion) between the ventral rostral putamen (VRP) and right orbitofrontal cortex (OFC). Data are plotted separately for healthy volunteers (HVs; p = 0.007) and individuals with treatment-resistant depression (TRD; p = 0.77). Δ ketamine minus placebo.

Fig. 4. Association between post-ketamine changes in anhedonia and functional connectivity.

Relationship between post-ketamine, compared with post-placebo, increases in fronto-striatal functional connectivity and improvements (negative numbers indicate post-ketamine improvements compared with post-placebo) in anhedonia symptoms on the day of the resting-state functional magnetic resonance imaging (rsfMRI) scan (2 days post infusion; a), and 10 days post infusion (b–d) in individuals with treatment-resistant depression (TRD). Shaded area represents estimated 95% confidence interval. SHAPS Snaith–Hamilton Pleasure Scale; DC dorsal caudate; vlPFC ventrolateral prefrontal cortex; DCP dorsal caudal putamen; pgACC perigenual anterior cingulate cortex; VRP ventral rostral putamen; OFC orbitofrontal cortex; Δ ketamine minus placebo.