A voxel-wise meta-analysis of task-based functional MRI studies on impaired gain and loss processing in adults with addiction

Neural alterations during gain anticipation

All addictions exhibited decreased activation in the PFC (BA 45, inferior frontal gyrus), left striatum and right insula compared to healthy controls (Fig. 2A and Table 2). The striatum and PFC are important components of the reward network. The striatum is crucial for reward experiences and learning,60 and the PFC is crucial for reward-based decision-making61 and higher-level executive functions, including goal representation and action planning.62^,63 Functional interconnections between the PFC and the striatum are responsible for reward detection and regulation.63 Our results were consistent with those of previous reports of reduced PFC and striatal activity in substance detection27 and gambling addiction.22^,24^,58 These results could be validated by the incentive sensitization theory32^,33 and the reward deficiency hypothesis,64^,65 both of which predict attenuated activity in the reward system during anticipation of non-addiction-related gains. According to the incentive sensitization theory, the neural system of a person with addiction attributes higher incentive salience to addiction-related rewards (e.g., drugs) and less incentive salience to non-addiction-related rewards (e.g., monetary gains). As a result, non-addiction-related stimuli used in the experiments may be rendered less salient for people with addiction, leading to reduced activation of the reward network (i.e., PFC and striatum). According to the reward deficiency hypothesis, however, hypoactivity in the reward network is an indicator of a deficient reward system that cannot be adequately activated by rewarding stimuli (i.e., both addiction-related rewards and non-addiction-related rewards). This pattern of activity can also be explained by the reward allostasis model.66^,67 According to this model, sensitivity to non-addiction-related gains is reduced as a compensatory process to maintain the stability of the reward functions. Given the limited capacity of the reward circuits, non-addiction-related rewards may be allocated weaker hedonic effects, and addiction-related stimuli may take up more resources. Consequently, the reward circuits should be less activated for people with addiction during anticipation of non-addiction-related gains.

We also observed reduced activity in the right insula (Fig. 2A and Table 2). The insula is an important brain region for the integration of internal bodily information, necessary for interoceptive awareness and emotional arousal.68 Previous studies have consistently found decreased insular activity in substance dependence69 and gambling addiction,70 indicating a desensitized interoceptive state. In our study, insular hypoactivation may have denoted weaker interoceptive and emotional responses to non-addiction-related gains compared to addiction-related rewards. In addition, the insula is part of the salience network, which is highly responsive to behaviourally relevant stimuli,71 and was consistently upregulated for people with drug addiction during drug-cue exposure.17 It may be that for people with addiction, addiction-related cues are more relevant than other rewarding stimuli. Compatible with the allostasis model, the attenuated activity of the salience network (i.e., insula) in people with addiction during anticipation of non-addiction-related gains likely functioned as a compensation for its hypersensitivity to addiction-related cues.

In contrast, all addictions showed significantly increased activation in the right precuneus, middle temporal gyrus, inferior parietal gyrus and angular gyrus compared to healthy controls (Fig. 2A and Table 2). These regions are important components of the default mode network, which is responsible for self-referential processing and is normally deactivated during cognitive tasks.72^–74 The atypical strengthened activation of the default mode network that we observed in all addictions indicates that the expectation of gains was perhaps associated with the self. It is likely that repeated addictive behaviours in daily life (encompassing the anticipation of the hedonic effects of drugs or monetary wins) are incorporated into self-related memory for people with addiction.75 Therefore, when people with addiction anticipated an imminent reward in the experiments, they were likely prompted by a similar memory of the hedonic sensations. Such an association between gains and self-related memory of hedonic sensations is likely much stronger for people with addiction than for healthy controls,75^,76 leading to a stronger activation of the default mode network for people with addiction. In addition, the precuneus is reported to be crucial for the integration of information from our environment.77 It has been suggested that people with addiction showed heightened exteroceptive awareness toward addiction-related cues.77 This result is consistent with cue-elicited hyperactivation in the precuneus in substance dependence,78^,79 likely indicating that more salience was assigned to rewarding stimuli, such as drugs. Therefore, non-addiction-related rewards may hold a “bottom–up” attentional advantage for people with addiction compared to healthy controls. Because people with addiction show impaired interoceptive awareness (shown by hypoactivation of the insula) and strengthened exteroception (shown by hyperactivation of the precuneus), it is not surprising that they seem to perform less well when it comes to monitoring their internal feelings and refraining from addictive behaviours.

The results described above were largely the same for the substance dependence subgroup, but they showed additional increased activation of the right superior occipital gyrus and left middle occipital gyrus (Fig. 2B and Table 2). Previous research in rats found that the ability to predict the timing of imminent rewards elicited the activation of the primary visual cortex, which resides in the occipital lobe.80 This finding suggests that gain anticipation can be reflected in very early visual processing in animals. In humans, drug-related visual cues have been associated with increased brain activation in early visual regions for people with substance dependence.81^–83 It is likely that for people with drug addiction, frequent and large drug doses increased the responsiveness of the primary visual cortex to cues with rewarding properties. Alterations in the early visual areas are likely specific to substance dependence, because human studies have shown that substance use (i.e., ecstasy) is linked to neurotoxic changes in the occipital lobe84 and heightened excitability of the primary visual cortex.85

Neural alterations during loss anticipation

We found that all addictions showed hyperactivation in the striatum and parts of the PFC (Fig. 2C and Table 3). Several studies have observed hyperactivation in the PFC and striatum in substance dependence and gambling addiction during loss anticipation.19^,24^,86 It has been argued that increased reactivity to potential losses is associated with salience improperly attributed to imminent losing events,87 which may lead to loss-chasing, a continued behaviour in an attempt to recover losses.1 It has been shown that impulsive behaviours such as loss-chasing are linked to activity in the ventral PFC and striatum.88^,89 Specifically, researchers have found that heightened PFC activation in smokers is related to increased craving to relieve smoking abstinence.19 Thus, people with addiction may be more aroused by the forthcoming loss than healthy controls and have the impulse to chase the loss. Loss-chasing is particularly central to gambling addiction.87^,90 Thus, the hyperactivities described here may have been driven mainly by the gambling addiction subgroup.

Against this, other researchers have found an opposite trend, which we also observed in the current analysis: decreased striatal activity during loss anticipation in addiction.22^,44^,58^,91 Researchers have suggested that such a hypoactivation is associated with an insensitivity to punishment or loss.91^,92 It has been argued that people with addiction are less sensitive to negative consequences (i.e., losses) and may not be able to activate the brain regions responsible for error tracking and adaptive learning.92 The striatum, along with the PFC, is a critical site for these functions,93^–96 helping people to learn from negative events and adjust their future behaviours.

The conflicting results described above were perhaps caused by the different natures of gambling addiction and substance dependence, the data for which were included in the analysis of all addictions. The impulse to chase losses is a key symptom of problematic gambling.1 In our analysis of all addictions, hyperactivation of the brain regions linked with impulsive behaviours (i.e., PFC and striatum) may have been driven mainly by the gambling addiction subgroup. Indeed, a separate analysis of substance dependence did not find enhanced brain activity, but the hypoactivation pattern in the striatum remained significant. However, given the limited number of studies we found on gambling addiction during loss anticipation, this explanation remains speculative. Future research should gain more insights into gain and loss processing in gambling addiction.

The substance dependence subgroup showed additional hypoactivation in the left middle occipital gyrus and left inferior occipital gyrus (Fig. 2D and Table 3). Similar to the reward allostasis model,66^,67 this pattern can be seen as a compensatory process in which functions of the occipital lobe strive for stability during gain and loss processing. As noted above, the occipital lobe exhibited enhanced activation during gain anticipation for people with drug addiction, possibly indicating increased responsiveness of the primary visual cortex to cues of a rewarding nature (e.g., monetary gains). This change may come at the expense of reactivity to cues of an unrewarding nature (e.g., monetary losses). In other words, it is likely that people with drug addiction allocate few resources to losing events during early visual processing, because the primary visual cortex is more receptive to rewarding stimuli.83 Indeed, the strengthened responsiveness of the visual cortex has been more extensively documented in the literature on gain processing.97 For people with drug addiction to maintain the functional stability of the occipital lobe, loss anticipation should be associated with decreased activation in this region as gain anticipation elicits stronger activation.

Neural alterations during gain outcome

All addictions exhibited increased activity in the right middle occipital gyrus and right superior occipital gyrus (Fig. 2D and Table 4) compared to healthy controls. A previous study found that the occipital lobe was activated more strongly in response to visually presented pleasant stimuli compared to neutral stimuli.98 It was argued that the visual cortex is responsive to affective information from the stimuli we see. In addition, addictive behaviours have been positively associated with neuroticism and extroversion,99^–102 2 personality traits that are closely linked to affective sensitivity.103 Therefore, it is conceivable that people with addiction are more responsive than healthy controls are to the emotional components of gain outcomes (i.e., pleasantness), even during early visual processing. Our results supported this by showing hyperactivity in the occipital lobe in response to rewarding outcomes.

We observed no significant hyper- or hypoactivation of the PFC or striatum during gain outcome. This was not surprising, because several studies have obtained similar results.21^,51^,104 However, the existing literature also provided a large body of evidence showing altered activity in these regions in addiction. For example, some researchers found reduced activation of the PFC in people with addiction during the delivery of gain outcomes.19^,22^,23^,52^,56 Others found strengthened activation in both the PFC and striatum.46^,48^,53 The discrepancies among the different studies may have been due to methodological factors (including task designs) and participant characteristics (such as addiction severity and abstinence stage). For example, although most studies used the monetary incentive delay task105 or a modified version (i.e., substance-unrelated activity incentive delay tasks), some studies used less common paradigms, including the reward prediction task19 and the probabilistic reversal learning task.23 Participants cannot control the outcomes in paradigms such as the reward prediction task, but they can obtain monetary gains or avoid losses in a monetary incentive delay task.22^,24 It may be that the responses to predetermined outcomes and the responses to rewards that were actively obtained induced different activation patterns in the brain. In addition, the length of abstinence has been negatively associated with brain activity in monetary gain.106 Differences in participants’ abstinence stages or treatment-seeking status were likely other important factors contributing to the conflicting results.

It is also worth mentioning that the absence of elevated striatal activity during gain outcome in our study was inconsistent with the meta-analysis by Luijten and colleagues.27 This was perhaps because our study selection criteria differed from their work in 2 main aspects. First, we included studies comparing gain- or loss-related responses to responses in neutral conditions (i.e., no-win or no-gain) or a baseline, whereas Luijten and colleagues also included gain–loss contrasts. Second, we included data from whole-brain analyses only, whereas they also used data from ROI analyses. As a result, only half of the studies included in our work overlapped with theirs. In addition, because our meta-analysis was conducted more recently, there were more substance dependence data sets (i.e., 21) than in the previous meta-analysis (i.e., 15).

Loss anticipation versus gain anticipation

Previous meta-analyses or reviews did not provide systematic or conclusive findings on loss processing in addiction,27^,107 possibly because some researchers did not include or report on loss-related trials.106^,108^,109 In this study, we compared alterations in brain activity during loss anticipation to gain anticipation in people with addiction.

First, although loss anticipation activated the PFC and striatum, gain anticipation showed no such hyperactivity. This was perhaps because the impulse to chase losses was present only when there was the possibility of losing, leading to enhanced activity in regions associated with impulsivity (i.e., the PFC and striatum). Second, we observed enhanced activation in several posterior parietal areas (e.g., the precuneus and angular gyrus) during anticipation for gains but not losses. The posterior parietal lobe is an important site for spatial awareness and attention.110 It is likely that forthcoming rewards in the environments hold a “bottom–up” attentional advantage for people with addiction, who tend to intentionally seek pleasure through taking drugs or gambling. But such activities were not present when they anticipated a losing outcome. This finding seems to suggest that people with addiction allocate more attentional resources to gains than losses.

Furthermore, we observed hypoactivity in the PFC and striatum during both gain and loss anticipation. This was inconsistent with the previous literature, which found robust ventral striatal activities in expectation of both positive and negative outcomes.111^–113 Diminished activity in the reward circuits may indicate impaired reward value updating and adaptive learning.93^,95^,114 People with addiction may have difficulty updating the subjective reward value of the substance and consequently require more of the substance to obtain pleasurable effects. This is likely one of the reasons why people with addiction tend to increase drug dosage or administration frequencies over time.115 Although we interpreted the hypoactivity during gain anticipation as a result of sensitization processes, we proposed that the striatal hypoactivation during loss anticipation was due to insensitivity to losses in people with addiction. Alternatively, we offer a parsimonious explanation for these results altogether by applying the reward allostasis model again.66^,67 According to this model, the attenuation of the PFC and striatum is likely a compensatory process for people with addiction to maintain the stability of the reward function. That is, people with addiction allocate more resources from the reward network to addiction-related cues at the expense of its reactivity to non-addiction-related gains and losses. By the same token, in areas involved in early visual processing (i.e., the occipital lobe), activity was strengthened during gain anticipation but attenuated during loss anticipation for people with drug addiction. It is possible that the reduced reactivity of the occipital lobe to anticipatory losses was a compensatory process to reach functional stability of the primary visual cortex.

Conditioning perspective

It is worth noting that some of our findings can be explained by the conditioning literature. The experimental tasks used in the included studies (especially monetary incentive delay tasks) encompassed components of both classical conditioning and operant conditioning.116 Specifically, a cue that predicted a potential gain or loss can be seen as a conditioned stimulus, while a delivered outcome can be considered an unconditioned stimulus, forming classical conditioning.29 Participants’ action during the anticipation phase can then be considered a conditioned response, because it was preceded or triggered by a cue. In the meantime, because the specific value of an outcome (i.e., win $1 or win $0) was contingent on participants’ actions, the response–outcome association formed an operant conditioning in which the outcome could also reinforce participants to adapt their actions to maximize gains and minimize losses. Therefore, it is reasonable to expect brain activity in regions related to both types of conditioning during these gain and loss processing tasks. Indeed, we found lower activation of the striatum during the anticipation phase in people with addiction compared to healthy controls. Previous research has found that the striatum is crucial in human classical and operant conditioning.117^,118 Hypoactivity in this region may indicate impaired associative learning,119 especially punishment-based (e.g., monetary loss) learning,120 in people with addiction. As pointed out earlier, the components of classical and operant conditioning are intricately entangled in gain and loss processing paradigms: the cue-outcome association forms a classical conditioning, and the response-outcome association forms an operant conditioning. Moreover, because we contrasted gain and loss responses against a neutral condition or baseline, the effect of conditioning may have been weakened in the extracted data. Consequently, the majority of our findings may not be entirely interpretable under the conditioning framework. Future research can aim at gaining further insights into conditioning in people with addiction by applying established conditioning paradigms.

Limitations

There were some limitations in this study. First, the number of included studies on gambling addiction was very small. Because of relatively stringent inclusion criteria, we identified and included only 5 studies on gambling addiction. Thus, we were unable to investigate unique alterations in the brain for people with gambling addiction from the perspective of a meta-analysis. Such a limitation kept us from making conclusive statements about some of the brain activation patterns we observed. For example, was the hyperactivity in the PFC and striatum during loss anticipation indeed driven by the gambling addiction subgroup? Is there any increased activation in the occipital lobe for people with gambling addiction during gain anticipation? Second, only a few studies included in our meta-analysis reported clinical information about the participants (i.e., mean duration of substance use and age of onset of use). As a result, we were unable to conduct regression analysis, which could have revealed if there were any moderating effects of clinical traits on the neural abnormalities. Future research should gain more insight into the altered brain mechanisms in gambling addiction and emphasize the clinical attributes of the patients. Third, some included studies24^,47^,50^,51 controlled for potential confounding variables in their analyses and reported adjusted effect sizes for the peak coordinates (e.g., t values), but the majority of studies did not control for variables of no interest and reported unadjusted statistics. This inconsistency in controlling for confounders and reporting related effect sizes may have had some influence on our findings, but we infer that the effect(s) should be relatively minor because almost all included studies discounted the possibility of potential confounders driving the results by, for instance, matching the participants in advance or conducting correlational analyses between the findings and confounders post hoc. Finally, we included only studies in adults with addiction in our analyses. This was because non-adults, especially adolescents, undergo significant structural and functional changes in reward-related brain regions that are not fully developed until their mid-20s.121 It is not yet clear how these changes may influence adolescents’ susceptibility to addictive behaviours.122 Moreover, although many adolescents try drugs, only a small group of them transition to substance dependence.123 On these grounds, we investigated only adults with addiction.