Elsevier

NeuroImage

Volume 42, Issue 4, 1 October 2008, Pages 1609-1621
NeuroImage

Striatal sensitivity to reward deliveries and omissions in substance dependent patients

https://doi.org/10.1016/j.neuroimage.2008.06.035Get rights and content

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.

Introduction

The ventral striatum (VS), including nucleus accumbens (NAcc) has been established as a key node in neural circuitry underlying incentive salience or “wanting” of goal-objects (Knutson and Cooper, 2005, McClure et al., 2004b, O'Doherty, 2004). Although there is considerable evidence that the VS is highly responsive to drug associated cues among abusers (Braus et al., 2001, Grusser et al., 2004, London et al., 1999, Myrick et al., 2004, Sinha and Li, 2007), it is not clear how the VS of individuals with substance dependence (SD) responds to cues predictive of nondrug reward. In fact, motivation-based theories of SD etiology make differing predictions as to how individuals with SD might differ from controls in VS recruitment by cues for nondrug reward.

The reward deficiency syndrome (RDS) hypothesis (Blum et al., 2000) posits that individuals prone to addiction have a deficit in recruitment of dopaminergic-(DA) motivational circuitry by nondrug rewards, such that abused drugs are uniquely able to normalize DA levels in the VS to readily motivate drug-taking behavior. The allostatic hypothesis (AH) (Koob et al., 2004), further posits that the neurochemical sequelae of chronic drug use itself also causes mesolimbic incentive neurocircuitry to become under-responsive to stimuli signaling availability of nondrug rewards (Koob and Le Moal, 2005). This pharmacologically induced anhedonia contributes to a generalized dysphoric mood syndrome. Drug use temporarily restores the user's ability to experience pleasure while at the same time progressively-lowering a homeostatic set-point for positive emotion. Notably, alcohol (Schulteis et al., 1995), nicotine (Epping-Jordan et al., 1998), heroin (Kenny et al., 2006), amphetamine (Lin et al., 1999), or cocaine (Markou and Koob, 1991) withdrawal all raise the threshold of electrical current required to elicit mesolimbic self-stimulation in rodents. Accordingly, substance-dependent patients (SDP) might show subnormal activation of the VS by cues signaling availability to respond for nondrug rewards, either by virtue of a premorbid factor or due to chronic drug effects on the VS. A recent study showing reduced VS activation by reward-anticipatory cues in the monetary incentive delay (MID) task among alcoholics (Wrase et al., 2007) supports the RDS hypothesis.

Conversely, an opponent-process theory of SD posits that addiction-prone individuals are characterized by severe trait impulsivity resulting from some combination of overactive mesolimbic reward-approach circuitry and deficient frontocortical punishment–avoidance circuitry (Bechara, 2005, Bickel et al., 2007, Newman and Wallace, 1993). Large-scale twin studies indicate that a heritable, core impulse-control deficiency underlies the comorbidity between SD and other externalizing behavior disorders (Kendler et al., 2003, Kreek et al., 2005, Slutske et al., 1998). Indeed, SDP show impulsive (Bickel and Marsch, 2001) and reward-centric (Bechara et al., 2001) choice behavior in the laboratory. Moreover, individuals with alcohol (Bjork et al., 2004a) and cocaine (Heil et al., 2006) dependence show increased preference for immediately-presented rewards over larger but delayed rewards, and the availability of an immediately-reinforced choice activates VS relative to choices between two delayed rewards (McClure et al., 2004a). Were the opponent-process theory correct, SDP may show increased VS responsiveness to anticipatory cues for potential rewards. Alternatively, since decision-making of SDP is disproportionately influenced by the salience of recent (Yechiam et al., 2005) reward deliveries compared to punishments in laboratory tasks (Lane and Cherek, 2000, Stout et al., 2004), SDP may show increased striatal responsiveness to reward outcome notifications by virtue of trait impulsivity. Recent work showing that reward notification-elicited activation of the VS correlated positively with both psychometric (Forbes et al., 2007) and behavioral (Hariri et al., 2006) measures of impulsivity in healthy adults supports the idea that VS sensitivity to reward notification is a marker for impulsivity.

The incentive salience hypothesis (ISH) (Robinson and Berridge, 2001), on the other hand, attributes compulsive drug use to alterations of striatal circuitry that is normally recruited during associative learning. Drug-associated cues putatively acquire increased incentive-motivational salience irrespective of any changes in the hedonic experience of drug consumption itself. One mechanism for this has been proposed (Redish, 2004) wherein DA release in the VS following administration of abused drugs overrides the attenuation of reward-delivery-elicited DA release that normally occurs once an association between a reward-predictive cue with its subsequent delivery has been formed. This ostensibly causes an “over-learning” of the drug-predictive cue. Although increased incentive salience of drug-predictive cues (per the ISH) could occur in tandem with a general suppression of VS recruitment by nondrug rewards to produce a strong bias toward drug-taking, the ISH itself need not invoke any expectation of altered VS recruitment by nondrug reward-predictive cues. Potentiated VS responsiveness to drug cues alone might sufficiently bias behavior toward drugs. Were subjects with and without SD to show similar recruitment of VS by cues to respond for nondrug rewards, it would suggest that SD results from adaptations in responsiveness to drug cues in particular and not a more general alteration in VS cue responsiveness.

To address these hypotheses, we compared substance-dependent patients (SDP) and controls using an enhanced version of the monetary incentive delay (MID) task. The original MID task (Knutson et al., 2001) featured contiguous trials, wherein the anticipatory cues and the trial outcome notifications were closely and time-invariantly yoked, likely compromising independent deconvolution analyses of anticipation and outcome. Adding a jitter in the MID task between each of: cue and target, target and feedback, and between feedback and the cue of the subsequent trial facilitated separable deconvolution of response-anticipatory activation versus reward-notification activation (Dillon et al., 2008). We adopted within- and between-trial jittering to better detect whether the limbic system of SDP might show increased sensitivity to notifications of rewards. In decision-making studies, SDP show increased susceptibility for recent reward deliveries to bias behavioral choice (Lane and Cherek, 2000, Stout et al., 2004, Yechiam et al., 2005). Might this result from an exaggerated VS response to reward notification? Moreover, since SDP are characterized by increased trait neuroticism (Mulder, 2002), where neuroticism is defined by increased affective sensitivity to aversive stimuli (Costa and McCrae, 1992), might SDP show an exaggerated limbic contrast between notification of success versus failure to either win rewards or to avoid losses?

In addition, we wished to stress the motivational system by providing an experience of frustration on some trials. Thus some reward trial outcomes were pseudorandomly omitted and replaced by a notification that the subject would have to repeat the entire trial to possibly obtain its reward. These double-response trials enabled within- and between-subject comparisons of anticipatory activation by informative cues (presented with no specific expectation of frustration) versus the same cues repeated following a dashed expectation of immediate reward. Using this approach, we hoped to determine whether SDP and controls differ in VS recruitment when the instrumental behavior requires greater persistence in the face of frustration. Lack of persistence as a personality trait is one facet of impulsivity (Smith et al., 2007), and has been characteristic of detoxified alcoholics who report more craving (Tavares et al., 2005), and who eventually relapse (Cannon et al., 1997).

Based on preliminary findings consistent with the RDS (Wrase et al., 2007), we hypothesized that SDP (here, detoxified inpatients being treated for alcohol dependence) would show reduced VS recruitment by reward-anticipatory cues of the MID task in this larger sample. Second, we hypothesized that SDP would show increased activation of VS and other limbic neurocircuitry by reward outcomes. Third, because increased negative affect is characteristic of alcoholics (Kessler et al., 1997, Mulder, 2002) and of illicit drug users (Kashdan et al., 2005), we predicted that omission of reward trial notifications with a demand for extra effort would result in increased reward frustration-elicited activation in limbic cortex of SDP (Siegrist et al., 2005).

Section snippets

Subjects

Procedures were approved by the Institutional Review Board of the National Institute on Alcohol Abuse and Alcoholism. All subjects were right-handed. Subjects underwent physical examination and a structured clinical interview for DSM-IV. Exclusion criteria for all subjects were: current use of psychotropic medication, psychosis, craniofacial or soft-sign neurological evidence of fetal alcohol spectrum disorder (FASD), chronic medical conditions (e.g. diabetes), history of significant head

Task behavior and questionnaire responses

In all trial types, SDP responded to targets significantly faster than controls (Fig. S1). Controls (but not SDP) responded more quickly to targets as incentive magnitudes increased. Controls and SDP also responded faster to second targets relative to first/only-response targets, due primarily to faster responses to second targets in nonincentive double-response (“Again!”) trials. Across runs (1–3) of the task, subjects responded more slowly to nonincentive targets.

Due to

Main findings

Although most of these alcoholics also had lifetime histories of comorbid illicit drug use disorders (a severe psychiatric phenotype), their VS recruitment by reward-predictive and loss-predictive cues was substantially similar to that of controls. Self-reported affect elicited by the incentive-linked anticipatory cues was also similar between groups. In both groups, cue-elicited VS hemodynamic responses were sensitive to potential reward magnitude, but not when cues were repeated in

Conclusions

The present paradigm, with its jittered design, provides initial evidence for exaggerated limbic responses to gains, losses, and reward outcome deferrals in treatment-seeking substance-dependent individuals. We posit that these differences reflect a pathophysiological alteration in neurocircuitry related to learning and affect, and likely result from some combination of either premorbid externalizing behavior traits and/or chronic drug-induced neuroadaptations. For example, adults with ADHD

Acknowledgments

This research was sponsored by intramural research funds of the National Institute on Alcohol Abuse and Alcoholism. The authors thank Christopher Geyer, Cinnamon Danube and Swati Murthy for assistance in subject recruitment and data collection. The authors also thank Debbie Hill for classification of the substance-related symptomatology of SDP.

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