Reward-based decision-making in mesial temporal lobe epilepsy patients with unilateral hippocampal sclerosis pre- and post-surgery.

BACKGROUND: Correct functioning of the reward processing system is critical for optimizing decision-making as well as preventing the development of addictions and/or neuropsychiatric symptoms such as depression, apathy, and anhedonia. Consequently, patients with mesial temporal lobe epilepsy due to unilateral hippocampal sclerosis (mTLE-UHS) represent an excellent opportunity to study the brain networks involved in this system. OBJECTIVE: The aim of the current study was to evaluate decision-making and the electrophysiological correlates of feedback processing in a sample of mTLE-UHS patients, compared to healthy controls. In addition, we assessed the impact of mesial temporal lobe surgical resection on these processes, as well as general, neuropsychological functioning. METHOD: 17 mTLE-UHS patients and 17 matched healthy controls completed: [1] a computerized version of the Game of Dice Task, [2] a Standard Iowa Gambling Task, and [3] a modified ERP version of a probabilistic gambling task coupled with multichannel electroencephalography. Neuropsychological scores were also obtained both pre- and post-surgery. RESULTS: Behavioral analyses showed a pattern of increased risk for the mTLE-UHS group in decision-making under ambiguity compared to the control group. A decrease in the amplitude of the Feedback Related Negativity (FRN), a weaker effect of valence on delta power, and a general reduction of delta and theta power in the mTLE-UHS group, as compared to the control group, were also found. The beta-gamma activity associated with the delivery of positive reward was similar in both groups. Behavioral performance and electrophysiological measures did not worsen post-surgery. CONCLUSIONS: Patients with mTLE-UHS showed impairments in decision-making under ambiguity, particularly when they had to make decisions based on the outcomes of their choices, but not in decision-making under risk. No group differences were observed in decision-making when feedbacks were random. These results might be explained by the abnormal feedback processing seen in the EEG activity of patients with mTLE-UHS, and by concomitant impairments in working memory, and memory. These impairments may be linked to the disruption of mesial temporal lobe networks. Finally, feedback processing and decision-making under ambiguity were already affected in mTLE-UHS patients pre-surgery and did not show evidence of clear worsening post-surgery.

The interplay between domain-general and domain-specific mechanisms during the time-course of verbal associative learning: An event-related potential study.

Humans continuously learn new information. Here, we examined the temporal brain dynamics of explicit verbal associative learning between unfamiliar items. In the first experiment, 25 adults learned object-pseudoword associations during a 5-day training program allowing us to track the N400 dynamics across learning blocks within and across days. Successful learning was accompanied by an initial frontal N400 that decreased in amplitude across blocks during the first day and shifted to parietal sites during the last training day. In Experiment 2, we replicated our findings with 38 new participants randomly assigned to a consistent learning or an inconsistent learning group. The N400 amplitude modulations that we found, both within and between learning sessions, are taken to reflect the emergence of novel lexical traces even when learning concerns items for which no semantic information is provided. The shift in N400 topography suggests that different N400 neural generators may contribute to specific word learning steps through a balance between domain-general and language-specific mechanisms.

Arcuate fasciculus architecture is associated with individual differences in pre-attentive detection of unpredicted music changes.

The mismatch negativity (MMN) is an event related brain potential (ERP) elicited by unpredicted sounds presented in a sequence of repeated auditory stimuli. The neural sources of the MMN have been previously attributed to a fronto-temporo-parietal network which crucially overlaps with the so-called auditory dorsal stream, involving inferior and middle frontal, inferior parietal, and superior and middle temporal regions. These cortical areas are structurally connected by the arcuate fasciculus (AF), a three-branch pathway supporting the feedback-feedforward loop involved in auditory-motor integration, auditory working memory, storage of acoustic templates, as well as comparison and update of those templates. Here, we characterized the individual differences in the white-matter macrostructural properties of the AF and explored their link to the electrophysiological marker of passive change detection gathered in a melodic multifeature MMN-EEG paradigm in 26 healthy young adults without musical training. Our results show that left fronto-temporal white-matter connectivity plays an important role in the pre-attentive detection of rhythm modulations within a melody. Previous studies have shown that this AF segment is also critical for language processing and learning. This strong coupling between structure and function in auditory change detection might be related to life-time linguistic (and possibly musical) exposure and experiences, as well as to timing processing specialization of the left auditory cortex. To the best of our knowledge, this is the first time in which the relationship between neurophysiological (EEG) and brain white-matter connectivity indexes using DTI-tractography are studied together. Thus, the present results, although still exploratory, add to the existing evidence on the importance of studying the constraints imposed on cognitive functions by the underlying structural connectivity.

Theta rhythm supports hippocampus-dependent integrative encoding in schematic/semantic memory networks.

Integrating new information into existing schematic/semantic structures of knowledge is the basis of learning in our everyday life as it enables structured representation of information and goal-directed behaviour in an ever-changing environment. However, how schematic/semantic mnemonic structures aid the integration of novel elements remains poorly understood. Here, we showed that the ability to integrate novel picture information into learned structures of picture associations that overlapped by the same picture scene (i.e., simple network) or by a conceptually related picture scene (i.e., schematic/semantic network) is hippocampus-dependent, as patients with lesions at the medial temporal lobe (including the hippocampus) were impaired in inferring novel relations between pictures within these memory networks. We also found more persistent and widespread scalp EEG theta oscillations (3-5 Hz) while participants integrated novel pictures into schematic/semantic memory networks than into simple networks. On the other hand, greater neural similarity was observed between EEG patterns elicited by novel and related events within simple networks than between novel and related events within schematic/semantic memory networks. These findings have important implications for our understanding of the neural mechanisms that support the development and organization of structures of knowledge.

Gossip information increases reward-related oscillatory activity.

Previous research has described the process by which the interaction between the firing in midbrain dopamine neurons and the hippocampus results in promoting memory for high-value motivational and rewarding events, both extrinsically and intrinsically driven (i.e. curiosity). Studies on social cognition and gossip have also revealed the activation of similar areas from the reward network. In this study we wanted to assess the electrophysiological correlates of the anticipation and processing of novel information (as an intrinsic cognitive reward) depending on the degree of elicited curiosity and the content of the information. 24 healthy volunteers participated in this EEG experiment. The task consisted of 150 questions and answers divided into three different conditions: trivia-like questions, personal-gossip information about celebrities and personal-neutral information about the same celebrities. Our main results from the ERPs and time-frequency analysis pinpointed main differences for gossip in comparison with personal-neutral and trivia-like conditions. Specifically, we found an increase in beta oscillatory activity in the outcome phase and a decrease of the same frequency band in the expectation phase. Larger amplitudes in P300 component were also found for gossip condition. Finally, gossip answers were the most remembered in a one-week memory test. The arousing value and saliency of gossip information, its rewarding effect evidenced by the increase of beta oscillatory power and the recruitment of areas from the brain reward network in previous fMRI studies, as well as its potential social value have been argued in order to explain its differential processing, encoding and recall.

Electrophysiological correlates of feedback processing in subarachnoid hemorrhage patients.

Patients with subarachnoid hemorrhage (SAH) secondary to anterior communicating artery (AComA) aneurysm rupture often experience deficits in executive functioning and decision-making. Effective decision-making is based on the subjects' ability to adjust their performance based on feedback processing, ascribing either positive or negative value to the actions performed reinforcing the most adaptive behavior in an appropriate temporal framework. A crucial brain structure associated to feedback processing is the medial prefrontal cortex (mPFC), a brain region frequently damaged after AComA aneurysm rupture. In the present study, we recorded electrophysiological responses (event-related potentials (ERPs') and oscillatory activity (time frequency analysis) during a gambling task in a series of 15 SAH patients. Previous studies have identified a feedback related negativity (FRN) component associated with an increase on frontal medial theta power in response to negative feedback or monetary losses, which is thought to reflect the degree of negative prediction error. Our findings show a decreased FRN component in response to negative feedback and a delayed increase of theta oscillatory activity in the SAH patient group when compared to the healthy controls, indicating a reduced sensitivity to negative feedback processing and an effortful signaling of cognitive control and monitoring processes lengthened in time, respectively. These results provide us with novel neurophysiological markers regarding feedback processing and performance monitoring patterns in SAH patients, illustrating a dysfunctional reinforcement learning system probably contributing to the maladaptive day-to-day functioning in these patients.

Brain oscillatory activity of skill and chance gamblers during a slot machine game.

Gambling behavior presents a broad variety of individual differences, with a continuum ranging from nongamblers to pathological gamblers. The reward network has been proposed to be critical in gambling behavior, but little is known about the behavioral and neural mechanisms underlying individual differences that depend on gambling preference. The main goals of the present study were to explore brain oscillatory responses to gambling outcomes in regular gamblers and to assess differences between strategic gamblers, nonstrategic gamblers, and nongamblers. In all, 54 healthy volunteers participated in the study. Electroencephalography was recorded while participants were playing a slot machine task that delivered win, near-miss, and full-miss outcomes. Behaviorally, regular gamblers selected a larger percentage of risky bets, especially when they could select the image to play. The time-frequency results showed larger oscillatory theta power increases to near-misses and increased beta power to win outcomes for regular gamblers, as compared to nongamblers. Moreover, theta oscillatory activity after wins was only increased in nonstrategic gamblers, revealing differences between the two groups of gamblers. The present results reveal differences between regular gamblers and nongamblers in both their behavioral and neural responses to gambling outcomes. Moreover, the results suggest that different brain oscillatory mechanisms might underlie the studied gambling profiles, which might have implications for both basic and clinical studies.

Unraveling the Role of the Hippocampus in Reversal Learning.

Research in reversal learning has mainly focused on the functional role of dopamine and striatal structures in driving behavior on the basis of classic reinforcement learning mechanisms. However, recent evidence indicates that, beyond classic reinforcement learning adaptations, individuals may also learn the inherent task structure and anticipate the occurrence of reversals. A candidate structure to support such task representation is the hippocampus, which might create a flexible representation of the environment that can be adaptively applied to goal-directed behavior. To investigate the functional role of the hippocampus in the implementation of anticipatory strategies in reversal learning, we first studied, in 20 healthy individuals (11 women), whether the gray matter anatomy and volume of the hippocampus were related to anticipatory strategies in a reversal learning task. Second, we tested 20 refractory temporal lobe epileptic patients (11 women) with unilateral hippocampal sclerosis, who served as a hippocampal lesion model. Our results indicate that healthy participants were able to learn the task structure and use it to guide their behavior and optimize their performance. Participants' ability to adopt anticipatory strategies correlated with the gray matter volume of the hippocampus. In contrast, hippocampal patients were unable to grasp the higher-order structure of the task with the same success than controls. Present results indicate that the hippocampus is necessary to respond in an appropriately flexible manner to high-order environments, and disruptions in this structure can render behavior habitual and inflexible.SIGNIFICANCE STATEMENT Understanding the neural substrates involved in reversal learning has provoked a great deal of interest in the last years. Studies with nonhuman primates have shown that, through repetition, individuals are able to anticipate the occurrence of reversals and, thus, adjust their behavior accordingly. The present investigation is devoted to know the role of the hippocampus in such strategies. Importantly, our findings evidence that the hippocampus is necessary to anticipate the occurrence of reversals, and disruptions in this structure can render behavior habitual and inflexible.

Auditory Target and Novelty Processing in Patients with Unilateral Hippocampal Sclerosis: A Current-Source Density Study.

The capacity to respond to novel events is crucial for adapting to the constantly changing environment. Here, we recorded 29-channel Event Related Brain Potentials (ERPs) during an active auditory novelty oddball paradigm and used for the first time Current Source Density-transformed Event Related Brain Potentials and associated time-frequency spectra to study target and novelty processing in a group of epileptic patients with unilateral damage of the hippocampus (N = 18) and in healthy matched control participants (N = 18). Importantly, we used Voxel-Based Morphometry to ensure that our group of patients had a focal unilateral damage restricted to the hippocampus and especially its medial part. We found a clear deficit for target processing at the behavioral level. In addition, compared to controls, our group of patients presented (i) a reduction of theta event-related synchronization (ERS) for targets and (ii) a reduction and delayed P3a source accompanied by reduced theta and low-beta ERS and alpha event-related synchronization (ERD) for novel stimuli. These results suggest that the integrity of the hippocampus might be crucial for the functioning of the complex cortico-subcortical network involved in the detection of novel and target stimuli.

Attentional effects on rule extraction and consolidation from speech.

Incidental learning plays a crucial role in the initial phases of language acquisition. However the knowledge derived from implicit learning, which is based on prediction-based mechanisms, may become explicit. The role that attention plays in the formation of implicit and explicit knowledge of the learned material is unclear. In the present study, we investigated the role that attention plays in the acquisition of non-adjacent rule learning from speech. In addition, we also tested whether the amount of attention during learning changes the representation of the learned material after a 24h delay containing sleep. For that, we developed an experiment run on two consecutive days consisting on the exposure to an artificial language that contained non-adjacent dependencies (rules) between words whereas different conditions were established to manipulate the amount of attention given to the rules (target and non-target conditions). Furthermore, we used both indirect and direct measures of learning that are more sensitive to implicit and explicit knowledge, respectively. Whereas the indirect measures indicated that learning of the rules occurred regardless of attention, more explicit judgments after learning showed differences in the type of learning reached under the two attention conditions. 24 hours later, indirect measures showed no further improvements during additional language exposure and explicit judgments indicated that only the information more robustly learned in the previous day, was consolidated.

The right inferior frontal cortex in response inhibition: A tDCS-ERP co-registration study.

In any given common situation, when an individual controls him/herself or obeys and stops a current action when asked to do, it is because the brain executes an inhibitory process. This ability is essential for adaptive behaviour, and it is also a requirement for accurate performance in daily life. It has been suggested that there are two main inhibitory functions related to behaviour, as inhibition is observed to affect behaviour at different time intervals. Proactive inhibition permits the subject to control his behavioural response over time by creating a response tendency, while reactive inhibition is considered to be a process that usually inhibits an already initiated response. In this context, it has been established that inhibitory function is implemented by specific fronto-basal-ganglia circuits. In the present study, we investigated the role of the right inferior frontal cortex (rIFC) in response inhibition by combining into a single task the Go-NoGo task and the Stop-Signal task. Concurrently, we applied transcranial direct current stimulation (tDCS) over the IFC and recorded electroencephalography (EEG). Thus, we obtained online EEG measurements of the tDCS-induced modifications in the IFC together with the participant's performance in a response inhibition task. We found that applying bilateral tDCS on the IFC (right anodal/left cathodal) significantly increased proactive inhibition, although the behavioural parameters indicative of reactive inhibition were unaffected by the stimulation. Finally, the inhibitory-P3 component reflected a similar modulation under both inhibitory conditions induced by the stimulation. Our data indicates that an online tDCS-ERP approach is achievable, but that a tDCS bilateral montage may not be the most efficient one for modulating the rIFC.

Individual differences in error tolerance in humans: Neurophysiological evidences.

When interacting in error-prone environments, humans display different tolerances to changing their decisions when faced with erroneous feedback information. Here, we investigated whether these individual differences in error tolerance (ET) were reflected in neurophysiological mechanisms indexing specific motivational states related to feedback monitoring. To explore differences in ET, we examined the performance of 80 participants in a probabilistic reversal-learning task. We then compared event-related brain responses (ERPs) of two extreme groups of participants (High ET and Low ET), which showed radical differences in their propensity to maintain newly learned rules after receiving spurious negative feedback. We observed that High ET participants showed reduced anticipatory activity prior to the presentation of incoming feedback, informing them of the correctness of their performance. This was evidenced by measuring the amplitude of the stimulus-preceding negativity (SPN), an ERP component indexing attention and motivational engagement of incoming informative feedback. Postfeedback processing ERP components (the so-called Feedback-Related Negativity and the P300) also showed reduced amplitude in this group (High ET). The general decreased responsiveness of the High ET group to external feedback suggests a higher proneness to favor internal(rule)-based strategies, reducing attention to external cues and the consequent impact of negative evaluations on decision making. We believe that the present findings support the existence of specific cognitive and motivational processes underlying individual differences on error-tolerance among humans, contributing to the ongoing research focused on understanding the mental processes behind human fallibility in error-prone scenarios.

Human oscillatory activity in near-miss events.

Near-miss events are situations in which an action yields a negative result but is very close to being successful. They are known to influence behavior, especially in gambling scenarios. Previous neuroimaging studies have described an 'anomalous' activity of brain reward areas following these events. The goal of the present research was to study electrophysiological correlates of near-misses in the expectation and outcome phases. Electroencephalography was recorded while participants were playing a simplified version of a slot machine. Four possible outcomes (gain, near-miss, loss and no-information) were presented in a pseudorandom order to ensure fixed proportions. Results from the time-frequency analysis for the theta (4-8 Hz), alpha (9-13 Hz), low beta (15-22 Hz) and beta-gamma (25-35 Hz) frequency-bands presented larger power increases for wins and near-misses compared with losses. In the anticipation phase, power changes were lower than in the resolution phase. The current results are in agreement with previous studies showing that near-miss events recruit brain areas of the reward network. Likewise, the oscillatory activity in near-misses is very similar to the one elicited in the gain condition. In addition, present findings suggest that oscillatory activity in the expectation phase does not play a crucial role in near-miss events.

A simultaneous modulation of reactive and proactive inhibition processes by anodal tDCS on the right inferior frontal cortex.

Proactive and reactive inhibitory processes are a fundamental part of executive functions, allowing a person to stop inappropriate responses when necessary and to adjust performance in in a long term in accordance to the goals of a task. In the current study, we manipulate, in a single task, both reactive and proactive inhibition mechanisms, and we investigate the within-subjects effect of increasing, by means of anodal transcranial direct current stimulation (tDCS), the involvement of the right inferior frontal cortex (rIFC). Our results show a simultaneous enhancement of these two cognitive mechanisms when modulating the neural activity of rIFC. Thus, the application of anodal tDCS increased reaction times on Go trials, indicating a possible increase in proactive inhibition. Concurrently, the stop-signal reaction time, as a covert index of the inhibitory process, was reduced, demonstrating an improvement in reactive inhibition. In summary, the current pattern of results validates the engagement of the rIFC in these two forms of inhibitory processes, proactive and reactive inhibition and it provides evidence that both processes can operate concurrently in the brain.

Electrophysiological correlates of anticipating improbable but desired events.

Psychological studies have emphasized that motivation is regulated by the anticipation of the emotional impact from the possible occurrence of unexpected rewarding events. Here, we scrutinized the existence of a corresponding neural signal by means of event-related potentials (ERPs) and computational modeling. In the first experiment, we designed a task that manipulated the probability of gaining a monetary reward and measured ERPs during anticipation and at reward delivery. A sustained frontocentral neural activity (i.e., the stimulus preceding negativity, SPN) was evidenced during the anticipation period. Critically, the SPN was found to increase in amplitude as the reward became more unexpected. Changes in the SPN were found to be predictive of individual differences in risk seeking, suggesting that a greater risk attitude involved a greater motivational state for receiving an improbable reward. In the second experiment, SPN results associated with unexpected monetary gains were replicated in a condition in which participants avoided monetary losses and the occurrence of unexpected rewards was also associated with an increase in the amount of self-reported pleasure. These findings support the existence of a neural ERP signature that encodes the process of tuning our motivation to the possibility of receiving a desirable but improbable rewarding outcome.

Neurophysiological differences in reward processing in anhedonics.

Anhedonia is characterized by a reduced capacity to experience pleasure in response to rewarding stimuli and has been considered a possible candidate endophenotype in depression and schizophrenia. However, it is still not well understood whether these reward deficits are confined to anticipatory and/or to consummatory experiences of pleasure. In the present study, we recorded electrophysiological responses (event-related brain potentials [ERPs] and oscillatory activity) to monetary gains and losses in extreme groups of anhedonic and nonanhedonic participants. The anhedonic participants showed reduced motivation to incur risky decisions, especially after monetary rewards. These sequential behavioral effects were correlated with an increased sensitivity to punishment, which psychometrically characterized the anhedonic group. In contrast, both electrophysiological measures associated with the impacts of monetary losses and gains--the feedback-related negativity (FRN) and the beta-gamma oscillatory component--clearly revealed preserved consummatory responses in anhedonic participants. However, anhedonics showed a drastic increase in frontal medial theta power after receiving the maximum monetary gain. This increase in theta oscillatory activity could be associated with an increase in conflict and cognitive control for unexpected large positive rewards, thus indexing the violation of default negative expectations built up across the task in anhedonic participants. Thus, the present results showed that participants with elevated scores on Chapman's Physical Anhedonia Scale were more sensitive to possible punishments, showed deficits in the correct integration of response outcomes in their actions, and evidenced deficits in sustaining positive expectations of future rewards. This overall pattern suggests an effect of anhedonia in the motivational aspects of approach behavior rather than in consummatory processes.

Updating fearful memories with extinction training during reconsolidation: a human study using auditory aversive stimuli.

Learning to fear danger in the environment is essential to survival, but dysregulation of the fear system is at the core of many anxiety disorders. As a consequence, a great interest has emerged in developing strategies for suppressing fear memories in maladaptive cases. Recent research has focused in the process of reconsolidation where memories become labile after being retrieved. In a behavioral manipulation, Schiller et al., (2010) reported that extinction training, administrated during memory reconsolidation, could erase fear responses. The implications of this study are crucial for the possible treatment of anxiety disorders without the administration of drugs. However, attempts to replicate this effect by other groups have been so far unsuccessful. We sought out to reproduce Schiller et al., (2010) findings in a different fear conditioning paradigm based on auditory aversive stimuli instead of electric shock. Following a within-subject design, participants were conditioned to two different sounds and skin conductance response (SCR) was recorded as a measure of fear. Our results demonstrated that only the conditioned stimulus that was reminded 10 minutes before extinction training did not reinstate a fear response after a reminder trial consisting of the presentation of the unconditioned stimuli. For the first time, we replicated Schiller et al., (2010) behavioral manipulation and extended it to an auditory fear conditioning paradigm.

On the number of trials needed for a stable feedback-related negativity.

Feedback-related negativity is an event-related brain potential elicited by negative feedback. Its properties make it a valuable tool for the assessment of cognitive-affective processes that are involved in feedback and reward processing. The present study sought to determine the minimum number of trials that are required to obtain a reliable FRN component using a simple gambling paradigm. Three independent groups of young participants and one group of old participants were used. In the experimental conditions with healthy young controls, 20 trials were sufficient to measure the optimal FRN amplitude. In older participants, 50 trials were needed to obtain a reliable FRN. Whereas 20 trials would be enough to ensure a reliable FRN component in studies with nonclinical samples, the number of trials needed in clinical and cognitively impaired populations has to be determined based on the signal-to-noise ratios and the characteristics of the signals recorded.

Neurophysiological markers of novelty processing are modulated by COMT and DRD4 genotypes.

Humans are faced with the dilemma to maintain a stable cognitive set on the one hand and to be able to redirect and switch attention to novel stimuli of potential importance. The dopaminergic system has been implicated in the balance between these two antagonistic constraints and in particular in novelty processing. Here we studied the impact of two polymorphisms affecting dopaminergic functioning (COMT Val108/158Met and DRD4 SNP -521) on neurophysiological correlates of novelty processing. Recording event-related potentials (ERPs) and oscillatory activity in a modified oddball task that featured infrequent but task-irrelevant novel sounds in addition to frequent standard and rare target tones, we examined participants homozygous for the Met or Val variant of COMT as well as homozygous for the C or T variant of DRD4. We found effects mainly on the P3a component to novel stimuli. A greater P3a amplitude was found for the COMT-ValVal group relative to MetMet. There was a tendency for DRD4-TT participants to show greater P3a amplitude and shorter P3a latency. Finally, DRD4-TT and COMT-ValVal participants showed the greatest increase of theta-power to novel stimuli. By contrast, the P3b component to target stimuli showed little influence of the studied polymorphism. Individual differences in dopaminergic genes explain part of the interindividual variance in the neural correlates of novelty but not target processing.

The effects of COMT (Val108/158Met) and DRD4 (SNP -521) dopamine genotypes on brain activations related to valence and magnitude of rewards.

People's sensitivity to reinforcing stimuli such as monetary gains and losses shows a wide interindividual variation that might in part be determined by genetic differences. Because of the established role of the dopaminergic system in the neural encoding of rewards and negative events, we investigated young healthy volunteers being homozygous for either the Valine or Methionine variant of the catechol-O-methyltransferase (COMT) codon 158 polymorphism as well as homozygous for the C or T variant of the SNP -521 polymorphism of the dopamine D4 receptor. Participants took part in a gambling paradigm featuring unexpectedly high monetary gains and losses in addition to standard gains/losses of expected magnitude while undergoing functional magnetic resonance imaging at 3 T. Valence-related brain activations were seen in the ventral striatum, the anterior cingulate cortex, and the inferior parietal cortex. These activations were modulated by the COMT polymorphism with greater effects for valine/valine participants but not by the D4 receptor polymorphism. By contrast, magnitude-related effects in the anterior insula and the cingulate cortex were modulated by the D4 receptor polymorphism with larger responses for the CC variant. These findings emphasize the differential contribution of genetic variants in the dopaminergic system to various aspects of reward processing.