Striatal sensitivity to reward deliveries and omissions in substance dependent patients

Abstract

Some motivational theories of substance dependence (SD) posit either pathologically increased or decreased ventral striatum (VS) recruitment by cues for nondrug rewards. The incentive-sensitization hypothesis, alternatively, attributes SD to enhanced incentive salience of drug-predictive cues specifically, with no requirement for altered nondrug incentive processing. We assessed whether individuals undergoing inpatient therapy for SD are characterized by altered recruitment of mesolimbic incentive neurocircuitry by cues and deliveries of nondrug rewards. During functional magnetic resonance imaging, substance-dependent patients (SDP) and controls performed a modified monetary incentive delay task featuring: a) anticipatory cues that signaled opportunities to respond to a target to either win money or avoid losing money, b) notifications of wins and losses, and c) unexpected replacement of reward trial outcomes with a demand to repeat the trial. Both anticipatory reward cues and loss cues elicited similar mood responses and VS activation between SDP and controls. However, in SDP (but not controls), reward notifications also activated VS and mesial frontal cortex, and loss notifications activated anterior insula. Finally, substitution of expected outcomes in reward trials with notifications to repeat the trial deactivated the VS in SDP but not in controls. These data do not suggest that SD is characterized by altered recruitment of VS circuitry by cues for nondrug incentives. Rather, SDP may instead have increased limbic system sensitivity to reward and loss delivery, consistent with the role of impulsivity in SD.

Figure 1. Modified monetary incentive delay (MID) task

In each trial, subjects were initially presented with one of four anticipatory cues followed by a fixation crosshair for a jittered duration (1.75-6s), and a target followed by a post-target fixation crosshair for (~2–6s). Subjects were required to respond during target presentation (“hit”) to either win money, avoid losing money, or for no consequence. In single-response trials, subjects then viewed notification of whether the target was hit or not, followed by a jittered (2–6s) intertrial interval with fixation crosshair. In double-response trials (33% of win $0, win 50¢, and win $5 magnitudes), notification of trial outcomes were pseudorandomly replaced with the word “Again!” which notified the subject that he or she must repeat the trial to obtain an outcome. This was followed by: a jittered (2–6s) fixation crosshair, a second presentation of the same incentive cue, a jittered (1.75-6s) post-cue fixation crosshair, target presentation of the same duration, jittered (~2–6s) post-target fixation crosshair, and 2 s outcome notification, where hits on both targets were required for trial success.

Figure 2. Activation by anticipation of rewards and losses

Anticipation of responding for rewards (50¢, $5) contrasted with anticipation of responding for no incentive activated bilateral ventral striatum in controls (a), and SDP (b), with no voxelwise group differences in anticipatory activation. Anticipation of responding to avoid losses ($5) contrasted with anticipation of responding for no incentive activated insula and bilateral dorsal striatum in both controls (c), and SDP (d), with no voxelwise group differences in anticipatory activation. Brain images in this and subsequent figures are right-left reversed per radiological convention, and are derived from a T1-wieghted scan of a representative control subject at the planar Talairach coordinate shown. Color overlays depict uncorrected voxelwise p statistics, where warm colors denote activations and cool colors denote deactivations..

Figure 3. Activation by notification of rewards, losses, and omission of outcomes

Notification of rewards (50¢, $5) contrasted with notification of failure to win reward did not activate mFC and VS in controls (a), but activated both regions in SDP (b). The voxelwise group difference in mFC and VS activation was significant (c; SDP > control activation depicted in warm colors). Notification of losses ($5) contrasted with notification of loss-avoidance did not activate any region above threshold in controls (d), but activated thalamus and anterior insula in SDP (e). The voxelwise group difference in insula activation was significant (corrected p < .05) (f). Replacement of outcome notification with the demand to repeat the trial effort (“Again!”) in reward trials (50¢, $5) contrasted with notification of nonwins in single-response reward trials activated temporal, occipital, and dorsolateral frontal cortex in both controls (g) and SDP (h), with additional suprathreshold deactivation of VS (cool colors) in SDP. The voxelwise group difference (corrected p < .05) in VS deactivation was significant (f; SDP deactivation > control deactivation depicted in cool colors). All coronal inset images are at y = 9.

Figure 4. Anticipation cue-elicited signal change in NAcc VOI

In a VOI drawn in the NAcc bilaterally (Talairach ±10 +10 −4; part a), both controls and SDP showed similar BOLD signal increases anticipating losses (b). Across nonincentive (c) and reward (d,e) trials, a significant magnitude X attempt X time interaction effect (p <.05) indicated magnitude-sensitive anticipatory activation in first attempts (single-response trials plus first attempts in double-response trials), but similar anticipatory responses across magnitudes in the second attempts of double-response trials. Simple effect tests indicated no group difference in signal change at any post-cue timepoint.

Figure 5. Outcome-elicited signal change in VOI

In the NAcc VOI, SDP but not controls showed signal increases in response to notification of low (a) and high (b) rewards in single-response trials. Signal decreases following notification of failure to win reward were similar between groups. In the mFC VOI drawn at the win versus non-win LC maxima of SDP (Tlrc: 0 46 3) (c and d insets), SDP also showed a trend for greater signal increases in response to notification of low (a) and high (b) rewards in single-response trials. In the left insula VOI drawn at the loss versus non-loss LC maxima of SDP (Tlrc: 34 18 2) (e inset), SDP showed greater signal increases following notification of losses (e) with similar response to controls following non-losses. When outcomes were unexpectedly deferred, SDP and controls showed similar signal decreases following “Again!” notification to repeat trials in non-incentive double-response trials (f, left-most plot). However, SDP showed greater deactivation in response to outcome omission in low (center plot) and high (right-most plot) reward double-response trials . Groupwise differences are denoted as * p < .05 and ** p < .10.

Figure 6. Correlations between psychometric measures and signal change in VOI

Excitement and happiness ratings about high reward cues were calculated as the net difference from the subject’s excitement/happiness about the non-incentive cue. In the bilateral NAcc VOI, individual differences in peak anticipatory signal change correlated with net self-reported excitement elicited by the high reward cue in controls (a) but not in SDP (b). Across all subjects, individual differences in NAcc response to notification of low (50¢) rewards correlated with NEO-impulsiveness scores (c), and individual differences in left anterior insula activation by notification of losses correlated with NEO-neuroticism scores (d).