Ketamine attenuates habenula activity in response to aversive outcomes during Pavlovian learning

A single sub-anesthetic dose of ketamine reduces activity in the lateral habenula, a small midbrain structure involved in aversive learning, when healthy volunteers expect or experience unpleasant stimuli a day later. In a randomized trial with 70 adults, those who received ketamine showed attenuated habenula responses during an aversive Pavlovian conditioning task measured with 7-Tesla functional neuroimaging. Preliminary evidence suggests that reduced habenula activity during aversive learning may weaken the emotional impact of negative memories. These results support preclinical models of how ketamine may rapidly relieve depression by acting on the human habenula.

Study at a glance

Abstract

Abstract Ketamine is an NMDA receptor antagonist with rapid-antidepressant properties when administered at a sub-anesthetic dose. Preclinical models indicate that a direct injection of ketamine into lateral habenula (Hb), a small midbrain structure with an evolutionarily preserved role in aversive learning across mammals, can rapidly relieve depression-like behavior. However, there is limited evidence to explain how ketamine acts on the function of the human habenula. In a translational computational neuroscience study, 70 healthy adult volunteers were randomised in a 1:1 ratio to receive ketamine or placebo (NaCl 0.9%). We used an aversive Pavlovian conditioning paradigm combined with 7-Tesla functional neuroimaging to show that ketamine attenuates habenula response during aversive stimuli expectations and outcomes 24 hours post-infusion. We further present preliminary evidence suggesting that when aversive learning occurs after ketamine infusion, reduced habenula activity during the learning process may lead to downstream effects that diminish the aversive impact of negative affective memories. These findings provide translational support for preclinical models of ketamine’s mechanisms in humans.