Ghrelin decreases sensitivity to negative feedback and increases prediction-error related caudate activity in humans, a randomized controlled trial

Abstract

The stomach-derived hormone ghrelin plays not only a role in feeding, starvation, and survival, but it has been suggested to also be involved in the stress response, in neuropsychiatric conditions, and in alcohol and drug use disorders. Mechanisms related to reward processing might mediate ghrelin's broader effects on complex behaviors, as indicated by animal studies and mostly correlative human studies. Here, using a within-subject double-blind placebo-controlled design with intravenous ghrelin infusion in healthy volunteers (n = 30), we tested whether ghrelin alters sensitivity to reward and punishment in a reward learning task. Parameters were derived from a computational model of participants' task behavior. The reversal learning task with monetary rewards was performed during functional brain imaging to investigate ghrelin effects on brain signals related to reward prediction errors. Compared to placebo, ghrelin decreased punishment sensitivity (t = -2.448, p = 0.021), while reward sensitivity was unaltered (t = 0.8, p = 0.43). We furthermore found increased prediction-error related activity in the dorsal striatum during ghrelin administration (region of interest analysis: t-values ≥ 4.21, p-values ≤ 0.044). Our results support a role for ghrelin in reward processing that extends beyond food-related rewards. Reduced sensitivity to negative outcomes and increased processing of prediction errors may be beneficial for food foraging when hungry but could also relate to increased risk taking and impulsivity in the broader context of addictive behaviors.

Fig. 1. CONSORT diagram of participant flow.

Consort Consolidated Standards of Reporting Trials. Participants excluded from analyses were excluded for both sessions.

Fig. 2. Probabilistic reversal learning task.

One trial consists of stimulus presentation with a response time window of 1.5 s, feedback of 1 s, and an inter trial interval (ITI) of 1.5–6.5 s. Choosing the currently ‘good’ stimulus leads with a higher probability (80%) to a reward than the other option (20%). After achieving the criterion of 5 correct answers out of the last 6 trials, the chance of a reversal of the probability distribution is 20% for each following trial until the reversal has occurred or the criterion is no longer fulfilled.

Fig. 3. Sensitivity to punishment differs during placebo and ghrelin session.

A Reward sensitivity did not differ between session [t(28) = 0.8, p = 0.43], B Punishment sensitivity was reduced during the ghrelin session [t(28) = −2.448, p = 0.021].

Fig. 4. Increased prediction-error related activation during ghrelin infusion.

Prediction-error related brain responses during placebo (A) and during ghrelin (B). C Higher prediction-error related response in the bilateral caudate during the ghrelin session than during the placebo session. D Average beta parameters from the three caudate clusters containing the significant peaks for visualization purpose. A and B at [−7 28], C at [18 24 −1], all thresholded at p < 0.001, clustersize >20 for display purpose.