Abnormal brain activity during a reward and loss task in opiate-dependent patients receiving methadone maintenance therapy

Abstract

A core feature of human drug dependency is persistence in seeking and using drugs at the expense of other life goals. It has been hypothesized that addiction is associated with overvaluation of drug-related rewards and undervaluation of natural, nondrug-related rewards. Humans additionally tend to persist in using drugs despite adverse consequences. This suggests that the processing of both rewarding and aversive information may be abnormal in addictions. We used fMRI to examine neural responses to reward and loss events in opiate-dependent patients receiving methadone maintenance treatment (MMT, n=30) and healthy controls (n=23) using nondrug-related stimuli. Half of the patients were scanned after/before daily methadone intake (ADM/BDM patient groups). During reward trials, patients as a whole exhibited decreased neural discrimination between rewarding and nonrewarding outcomes in the dorsal caudate. Patients also showed reduced neural discrimination in the ventral striatum with regard to aversive and nonaversive outcomes and failed to encode successful loss avoidance as a reward signal in the ventral striatum. Patients also showed decreased insula activation during the anticipation/decision phase of loss events. ADM patients exhibited increased loss signals in the midbrain/parahippocampal gyrus, possibly related to a disinhibition of dopamine neurons. This study suggests that patients with opiate dependency on MMT exhibit abnormal brain activations to nondrug-related rewarding and loss events. Our findings add support to proposals that treatments for opiate addiction should aim to increase the reward value of nondrug-related rewarding events and highlight the importance of potential abnormalities in aversive information processing.

Figure 1

Experimental task and behavioral results. (a) Experimental task. On each trial, participants select one of two fractal pictures, subsequently, and outcome is displayed. On reward trials, one of the pictures is associated with a 0.7/0.3 probability of delivering ‘win'/‘nothing', whereas the other picture has complementary probabilities. Similarly, on the loss trials, one of the pictures leads to ‘nothing'/‘loss' with probabilities 0.7/0.3, whereas the other picture has complementary probabilities. A neutral condition leads to outcomes ‘no-change'/‘nothing' with probabilities as in the reward and loss trials. t1, duration of the first screen. (b) Behavioral Choice. Proportion (percentage) of the number of times that participants selected the high-rewarding stimulus on reward trials, the high loss avoidance stimulus on the loss trials, and the stimulus more associated with the ‘No-Change' image on the neutral trials. (c) Reaction time in seconds. Error bars denote SEM.

Figure 2

Neural responses during reward trials for the contrast win>no-win at the outcome time of the task. Brain regions active in controls (a) and in patients (b) during reward trials for the contrast win>no-win. (c) Controls exhibited greater activation than patients for the contrast win>no-win in the dorsal caudate (d) Mean value of parameter estimates across voxels within a 10 mm diameter sphere, centered at peak coordinates (−20, 22, 12) of the left dorsal caudate region where patients differed significantly from controls. ADM/BDM, patients scanned after/before the daily methadone intake; DC, dorsal caudate; mPFC, medial prefrontal cortex; S, striatum; VS, ventral striatum. Regions significant at p<0.05 whole brain corrected as described in the methods, overlay on an average structural scan. Error bars denote SEM.

Figure 3

Neural responses during loss trials for the contrast loss avoidance>loss at the outcome time of the task. (a) Controls activated the bilateral ventral striatum for the contrast loss avoidance>loss. (b) In contrast, patients failed to show this activation. (c) Controls exhibited stronger activation than patients for the contrast loss avoidance>loss in the bilateral ventral striatum. (d) Mean value of parameter estimates across voxels within a 10 mm diameter sphere, centered at peak coordinates (−14, 6, −10)/(16, 6, −10) of the left/right ventral striatal regions where patients differed significantly from controls. ADM/BDM, patients scanned after/before the daily methadone intake; VS, ventral striatum. Regions significant at p<0.05 whole brain corrected. Error bars denote SEM.

Figure 4

Neural responses during loss trials for the contrast loss>loss avoidance at the outcome time of the task. (a) Controls activated regions such as the posterior midbrain and the dorsal anterior cingulate for the contrast loss>loss avoidance. (b) Patients displayed a cluster of activation that extended through the midbrain and parahippocampal gyrus for the contras loss>loss avoidance. (c) Patients exhibited stronger activation than controls in the midbrain/parahippocampal gyrus for the contrast loss>loss avoidance. (d) Mean value of parameter estimates across voxels within a 10 mm diameter sphere, centered at peak coordinates (−18,−18, −20)/(16, −18, −20) of the left/right midbrain-parahippocampal gyrus regions where patients differed significantly from controls. (e) Correlation with the methadone daily dose in milligrams for the left midbrain-parahippocampal gyrus of patients. The dependent variable is the mean value of parameter estimates (for the contrast loss>loss avoidance) across voxels within a 10 mm diameter sphere, centered at peak coordinates (−18, −18, −20). ADM/BDM, patients scanned after/before the daily methadone intake; dAC, dorsal anterior cingulate; MB, midbrain; MB/PH, midbrain/parahippocampal gyrus. Regions significant at p<0.05 whole brain corrected. Error bars denote SEM.

Figure 5

Neural responses for the contrast loss>neutral at the decision time of the task. Both controls (a) and patients (b) activated the bilateral insula/inferior frontal gyrus and the dorsal anterior cingulate for the contrast loss>neutral at the decision time of the task. (c) Controls showed stronger neural responses than patients in the left insula/inferior frontal gyrus. (d) Mean value of parameter estimates across voxels within a 10 mm diameter sphere, centered at peak coordinates (−50, 20, −6) of the left insula/inferior frontal gyrus region where patients differed significantly from controls. ADM/BDM, patients scanned after/before the daily methadone intake; IN/IFG, insula/inferior frontal gyrus. Regions significant at p<0.05 whole brain corrected. Error bars denote SEM.