A Neurocomputational Account of How Inflammation Enhances Sensitivity to Punishments Versus Rewards

Neil A Harrison, Valerie Voon, Mara Cercignani, Ella A Cooper, Mathias Pessiglione, Hugo D Critchley, Neil A Harrison, Valerie Voon, Mara Cercignani, Ella A Cooper, Mathias Pessiglione, Hugo D Critchley

Abstract

Background: Inflammation rapidly impairs mood and cognition and, when severe, can appear indistinguishable from major depression. These sickness responses are characterized by an acute reorientation of motivational state; pleasurable activities are avoided, and sensitivity to negative stimuli is enhanced. However, it remains unclear how these rapid shifts in behavior are mediated within the brain.

Methods: Here, we combined computational modeling of choice behavior, experimentally induced inflammation, and functional brain imaging (functional magnetic resonance imaging) to describe these mechanisms. Using a double-blind, randomized crossover study design, 24 healthy volunteers completed a probabilistic instrumental learning task on two separate occasions, one 3 hours after typhoid vaccination and one 3 hours after saline (placebo) injection. Participants learned to select high probability reward (win £1) and avoid high probability punishment (lose £1) stimuli. An action-value learning algorithm was fit to the observed behavior, then used within functional magnetic resonance imaging analyses to identify neural coding of prediction error signals driving motivational learning.

Results: Inflammation acutely biased behavior, enhancing punishment compared with reward sensitivity, through distinct actions on neural representations of reward and punishment prediction errors within the ventral striatum and anterior insula. Consequently, choice options leading to potential rewards were less behaviorally attractive, and those leading to punishments were more aversive.

Conclusions: Our findings demonstrate the neural mediation of a rapid, state-dependent reorientation of reward versus punishment sensitivity during inflammation. This mechanism may aid the adaptive reallocation of metabolic resources during acute sickness but might also account for maladaptive, motivational changes that underpin the association between chronic inflammation and depression.

Keywords: Depression; Imaging; Inflammation; Insula; Reward; Striatum.

Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Experimental task and behavioral responses. (A) Participants chose between stimulus pairs from three conditions: gain (upper images), loss (lower images), and neutral (not shown) associated with the corresponding pairs of outcomes: gain £1/nothing, lose £1/nothing, and look £1/nothing. The two stimuli forming each stimulus pair had reciprocal probabilities (.8/.2 and .2/.8) of receiving the corresponding outcome. For example, in the gain condition, one of the stimulus pairs had an 80% chance of winning £1 and a 20% chance of winning nothing; the other option had a 20% chance of winning £1 and an 80% change of winning nothing. Stimulus pairs were presented randomly, with the high probability win/loss/look stimulus presented on the right on 50% of trials and on the left on 50% of trials. (B) Observed behavioral choices for gain and loss conditions following placebo (blue) or typhoid vaccine induced inflammation (red). The learning curves (moving average) depict trial by trial the percentage of times participants chose the correct stimulus (probability = .8 of winning £1) upper graph and the incorrect stimulus (probability = .8 of losing £1). (C) Modeled behavioral choices for placebo (blue) and inflammation (red). The learning curves represent the probabilities predicted by the computational model. (D) Proportion of the last 50% of trials in which participants chose the correct stimulus for both gain (left) and loss (right) conditions. (E) Modeled behavioral choices for the proportion of the last 50% of trials in which participants chose the correct stimulus. Obs., observed.
Figure 2
Figure 2
Effects of vaccination on model parameters. Behavioral outcomes for model parameters: (A) alpha (learning rate), (B) beta (choice randomness or temperature), (C) R (subjective value), and (D) log likelihood of model fit. Data are represented as solid bars for gain and shaded bars for loss conditions. Higher values represent faster learning, greater choice randomness, reward (and punishment) subjective value, and model fit, respectively. Error bars represent standard error of the mean.
Figure 3
Figure 3
Brain regions correlating with reward and punishment cues and prediction error. Upper rows of both panels denote data from the current study at an uncorrected statistical threshold of p < .001. Lower rows show comparable contrasts from Pessiglione et al. (8). (A) Statistical parametric maps resulting from the main contrasts between stimuli conditions. Go and NoGo refer to stimuli requiring or not requiring a button press to get the optimal outcome. Gain, neutral, and loss correspond to the different pairs of stimuli. Activations are shown on slices comparable with Pessiglione et al. (8) located in the posterior putamen (green), left ventral striatum (blue), and bilateral insula (red). (B) Brain activity correlated with prediction errors (PE) derived from the computational model. Reward prediction errors (positive correlation) are shown across both gain and loss conditions (left and center panels); punishment prediction errors (negative correlation) are found in the loss condition alone (right panel). As above, activations are shown on slices comparable with Pessiglione et al. (8) located in the posterior putamen (green), left ventral striatum (blue), and bilateral insula (red). [Reproduced with permission from Pessiglione et al. (8).]
Figure 4
Figure 4
Effects of inflammation on ventral striatal and insula responses to reward and punishment prediction error (PE). (A) Bottom right panel: right ventral striatal region demonstrating significantly reduced correlation with reward prediction error following inflammation (compared with placebo). Remaining panels illustrate the same contrast (yellow) overlaid on the right ventral striatal region of interest mask (correlation with reward prediction error) from Pessiglione et al. (8) (cyan). (B) Bottom right panel: right insula region demonstrating significantly increased correlation with punishment prediction error following inflammation (compared with placebo). Remaining panels illustrate the same contrast (yellow) overlaid on the right insula region of interest mask (correlation with punishment prediction error) from Pessiglione et al. (8) (cyan). P, placebo; V, vaccine.

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