Ventromedial prefrontal cortex activation is associated with memory formation for predictable rewards

During reinforcement learning, dopamine release shifts from the moment of reward consumption to the time point when the reward can be predicted. Previous studies provide consistent evidence that reward-predicting cues enhance long-term memory (LTM) formation of these items via dopaminergic projections to the ventral striatum. However, it is less clear whether memory for items that do not precede a reward but are directly associated with reward consumption is also facilitated. Here, we investigated this question in an fMRI paradigm in which LTM for reward-predicting and neutral cues was compared to LTM for items presented during consumption of reliably predictable as compared to less predictable rewards. We observed activation of the ventral striatum and enhanced memory formation during reward anticipation. During processing of less predictable as compared to reliably predictable rewards, the ventral striatum was activated as well, but items associated with less predictable outcomes were remembered worse than items associated with reliably predictable outcomes. Processing of reliably predictable rewards activated the ventromedial prefrontal cortex (vmPFC), and vmPFC BOLD responses were associated with successful memory formation of these items. Taken together, these findings show that consumption of reliably predictable rewards facilitates LTM formation and is associated with activation of the vmPFC.     

The Roles of Reward,Default, and Executive Control Networks in Set-Shifting Impairments in Schizophrenia

Patients with schizophrenia (SZ) show deficits on tasks of rapid reinforcement learning, like probabilistic reversal learning (PRL), but the neural bases for those impairments are not known. Recent evidence of relatively intact sensitivity to negative outcomes in the ventral striatum (VS) in many SZ patients suggests that PRL deficits may be largely attributable to processes downstream from feedback processing, involving both the activation of executive control task regions and deactivation of default mode network (DMN) components. We analyzed data from 29 chronic SZ patients and 21 matched normal controls (NCs) performing a PRL task in an MRI scanner. Subjects were presented with eight pairs of fractal stimuli, for 50 trials each. For each pair, subjects learned to choose the more frequently-rewarded (better) stimulus. Each time a criterion was reached, the better stimulus became the worse one, and the worse became the better. Responses to feedback events were assessed through whole-brain and regions-of-interest (ROI) analyses in DMN. We also assessed correlations between BOLD signal contrasts and clinical measures in SZs. Relative to NCs, SZ patients showed comparable deactivation of VS in response to negative feedback, but reduced deactivation of DMN components including medial prefrontal cortex (mPFC). The magnitudes of patients'' punishment-evoked deactivations in VS and ventromedial PFC correlated significantly with clinical ratings for avolition/anhedonia. These findings suggest that schizophrenia is associated with a reduced ability to deactivate components of default mode networks, following the presentation of informative feedback and that motivational deficits in SZ relate closely to feedback-evoked activity in reward circuit components. These results also confirm a role for ventrolateral and dorsomedial PFC in the execution of response-set shifts.     

Reward Anticipation in Ventral Striatum and Individual Sensitivity to Reward: A Pilot Study of a Child-Friendly fMRI Task

Reward processing has been implicated in developmental disorders. However, the classic task to probe reward anticipation, the monetary incentive delay task, has an abstract coding of reward and no storyline and may therefore be less appropriate for use with developmental populations. We modified the task to create a version appropriate for use with children. We investigated whether this child-friendly version could elicit ventral striatal activation during reward anticipation in typically developing children and young adolescents (aged 9.5–14.5). In addition, we tested whether our performance-based measure of reward sensitivity was associated with anticipatory activity in ventral striatum. Reward anticipation was related to activity in bilateral ventral striatum. Moreover, we found an association between individual reward sensitivity and activity in ventral striatum. We conclude that this task assesses ventral striatal activity in a child-friendly paradigm. The combination with a performance-based measure of reward sensitivity potentially makes the task a powerful tool for developmental imaging studies of reward processing.     

Neural responses during anticipation of a primary taste reward

The aim of this study was to determine the brain regions involved in anticipation of a primary taste reward and to compare these regions to those responding to the receipt of a taste reward. Using fMRI, we scanned human subjects who were presented with visual cues that signaled subsequent reinforcement with a pleasant sweet taste (1 M glucose), a moderately unpleasant salt taste (0.2 M saline), or a neutral taste. Expectation of a pleasant taste produced activation in dopaminergic midbrain, posterior dorsal amygdala, striatum, and orbitofrontal cortex (OFC). Apart from OFC, these regions were not activated by reward receipt. The findings indicate that when rewards are predictable, brain regions recruited during expectation are, in part, dissociable from areas responding to reward receipt.     

Early Effects of Reward Anticipation Are Modulated by Dopaminergic Stimulation

The abilities to predict future rewards and assess the value of reward delivery are crucial aspects of adaptive behavior. While the mesolimbic system, including dopaminergic midbrain, ventral striatum and prefrontal cortex have long been associated with reward processing, recent studies also indicate a prominent role of early visual brain regions. However, the precise underlying neural mechanisms still remain unclear. To address this issue, we presented participants with visual cues predicting rewards of high and low magnitudes and probability (2×2 factorial design), while neural activity was scanned using magnetoencephalography. Importantly, one group of participants received 150 mg of the dopamine precursor levodopa prior to the experiment, while another group received a placebo. For the placebo group, neural signals of reward probability (but not magnitude) emerged at ∼100 ms after cue presentation at occipital sensors in the event-related magnetic fields. Importantly, these probability signals were absent in the levodopa group indicating a close link. Moreover, levodopa administration reduced oscillatory power in the high (20–30 Hz) and low (13–20 Hz) beta band during both reward anticipation and delivery. Taken together, our findings indicate that visual brain regions are involved in coding prospective reward probability but not magnitude and that these effects are modulated by dopamine.     

Increased Functional Connectivity between Prefrontal Cortex and Reward System in Pathological Gambling

Pathological gambling (PG) shares clinical characteristics with substance-use disorders and is thus discussed as a behavioral addiction. Recent neuroimaging studies on PG report functional changes in prefrontal structures and the mesolimbic reward system. While an imbalance between these structures has been related to addictive behavior, whether their dysfunction in PG is reflected in the interaction between them remains unclear. We addressed this question using functional connectivity resting-state fMRI in male subjects with PG and controls. Seed-based functional connectivity was computed using two regions-of-interest, based on the results of a previous voxel-based morphometry study, located in the prefrontal cortex and the mesolimbic reward system (right middle frontal gyrus and right ventral striatum). PG patients demonstrated increased connectivity from the right middle frontal gyrus to the right striatum as compared to controls, which was also positively correlated with nonplanning aspect of impulsiveness, smoking and craving scores in the PG group. Moreover, PG patients demonstrated decreased connectivity from the right middle frontal gyrus to other prefrontal areas as compared to controls. The right ventral striatum demonstrated increased connectivity to the right superior and middle frontal gyrus and left cerebellum in PG patients as compared to controls. The increased connectivity to the cerebellum was positively correlated with smoking in the PG group. Our results provide further evidence for alterations in functional connectivity in PG with increased connectivity between prefrontal regions and the reward system, similar to connectivity changes reported in substance use disorder.     

Top-down anticipatory control in prefrontal cortex

Summary The prefrontal cortex has been implicated in a wide variety of executive functions, many involving some form of anticipatory attention. Anticipatory attention involves the pre-selection of specific sensory circuits to allow fast and efficient stimulus processing and a subsequently fast and accurate response. It is generally agreed that the prefrontal cortex plays a critical role in anticipatory attention by exerting a facilitatory “top-down” bias on sensory pathways. In this paper we review recent results indicating that synchronized activity in prefrontal cortex, during anticipation of visual stimulus, can predict features of early visual stimulus processing and behavioral response. Although the mechanisms involved in anticipatory attention are still largely unknown, we argue that the synchronized oscillation in prefrontal cortex is a plausible candidate during sustained visual anticipation. We further propose a learning hypothesis that explains how this top-down anticipatory control in prefrontal cortex is learned based on accumulated prior experience by adopting a Temporal Difference learning algorithm.     

Reward Sensitivity Modulates Brain Activity in the Prefrontal Cortex,ACC and Striatum during Task Switching

Current perspectives on cognitive control acknowledge that individual differences in motivational dispositions may modulate cognitive processes in the absence of reward contingencies. This work aimed to study the relationship between individual differences in Behavioral Activation System (BAS) sensitivity and the neural underpinnings involved in processing a switching cue in a task-switching paradigm. BAS sensitivity was hypothesized to modulate brain activity in frontal regions, ACC and the striatum. Twenty-eight healthy participants underwent fMRI while performing a switching task, which elicited activity in fronto-striatal regions during the processing of the switch cue. BAS sensitivity was negatively associated with activity in the lateral prefrontal cortex, anterior cingulate cortex and the ventral striatum. Combined with previous results, our data indicate that BAS sensitivity modulates the neurocognitive processes involved in task switching in a complex manner depending on task demands. Therefore, individual differences in motivational dispositions may influence cognitive processing in the absence of reward contingencies.     

Neural Sensitivity to Absolute and Relative Anticipated Reward in Adolescents

Adolescence is associated with a dramatic increase in risky and impulsive behaviors that have been attributed to developmental differences in neural processing of rewards. In the present study, we sought to identify age differences in anticipation of absolute and relative rewards. To do so, we modified a commonly used monetary incentive delay (MID) task in order to examine brain activity to relative anticipated reward value (neural sensitivity to the value of a reward as a function of other available rewards). This design also made it possible to examine developmental differences in brain activation to absolute anticipated reward magnitude (the degree to which neural activity increases with increasing reward magnitude). While undergoing fMRI, 18 adolescents and 18 adult participants were presented with cues associated with different reward magnitudes. After the cue, participants responded to a target to win money on that trial. Presentation of cues was blocked such that two reward cues associated with $.20, $1.00, or $5.00 were in play on a given block. Thus, the relative value of the $1.00 reward varied depending on whether it was paired with a smaller or larger reward. Reflecting age differences in neural responses to relative anticipated reward (i.e., reference dependent processing), adults, but not adolescents, demonstrated greater activity to a $1 reward when it was the larger of the two available rewards. Adults also demonstrated a more linear increase in ventral striatal activity as a function of increasing absolute reward magnitude compared to adolescents. Additionally, reduced ventral striatal sensitivity to absolute anticipated reward (i.e., the difference in activity to medium versus small rewards) correlated with higher levels of trait Impulsivity. Thus, ventral striatal activity in anticipation of absolute and relative rewards develops with age. Absolute reward processing is also linked to individual differences in Impulsivity.     

Reward-motivated learning: mesolimbic activation precedes memory formation

We examined anticipatory mechanisms of reward-motivated memory formation using event-related FMRI. In a monetary incentive encoding task, cues signaled high- or low-value reward for memorizing an upcoming scene. When tested 24 hr postscan, subjects were significantly more likely to remember scenes that followed cues for high-value rather than low-value reward. A monetary incentive delay task independently localized regions responsive to reward anticipation. In the encoding task, high-reward cues preceding remembered but not forgotten scenes activated the ventral tegmental area, nucleus accumbens, and hippocampus. Across subjects, greater activation in these regions predicted superior memory performance. Within subject, increased correlation between the hippocampus and ventral tegmental area was associated with enhanced long-term memory for the subsequent scene. These findings demonstrate that brain activation preceding stimulus encoding can predict declarative memory formation. The findings are consistent with the hypothesis that reward motivation promotes memory formation via dopamine release in the hippocampus prior to learning.     

Reward representations and reward-related learning in the human brain: insights from neuroimaging

This review outlines recent findings from human neuroimaging concerning the role of a highly interconnected network of brain areas including orbital and medial prefrontal cortex, amygdala, striatum and dopaminergic mid-brain in reward processing. Distinct reward-related functions can be attributed to different components of this network. Orbitofrontal cortex is involved in coding stimulus reward value and in concert with the amygdala and ventral striatum is implicated in representing predicted future reward. Such representations can be used to guide action selection for reward, a process that depends, at least in part, on orbital and medial prefrontal cortex as well as dorsal striatum.     

Modulation of caudate activity by action contingency

Research has increasingly implicated the striatum in the processing of reward-related information in both animals and humans. However, it is unclear whether human striatal activation is driven solely by the hedonic properties of rewards or whether such activation is reliant on other factors, such as anticipation of upcoming reward or performance of an action to earn a reward. We used event-related functional magnetic resonance imaging to investigate hemodynamic responses to monetary rewards and punishments in three experiments that made use of an oddball paradigm. We presented reward and punishment displays randomly in time, following an anticipatory cue, or following a button press response. Robust and differential activation of the caudate nucleus occurred only when a perception of contingency existed between the button press response and the outcome. This finding suggests that the caudate is involved in reinforcement of action potentially leading to reward, rather than in processing reward per se.     

Altered Resting-State Functional Connectivity of the Frontal-Striatal Reward System in Social Anxiety Disorder

We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.     

Feature-based anticipation of cues that predict reward in monkey caudate nucleus

A subset of caudate neurons fires before cues that instruct the monkey what he should do. To test the hypothesis that the anticipatory activity of such neurons depends on the context of stimulus-reward mapping, we examined their activity while the monkeys performed a memory-guided saccade task in which either the position or the color of a cue indicated presence or absence of reward. Some neurons showed anticipatory activity only when a particular position was associated with reward, while others fired selectively for color-reward associations. The functional segregation suggests that caudate neurons participate in feature-based anticipation of visual information that predicts reward. This neuronal code influences the general activity level in response to visual features without improving the quality of visual discrimination.     

Neural Correlates of Advantageous and Disadvantageous Inequity in Sharing Decisions

Humans have a strong preference for fair distributions of resources. Neuroimaging studies have shown that being treated unfairly coincides with activation in brain regions involved in signaling conflict and negative affect. Less is known about neural responses involved in violating a fairness norm ourselves. Here, we investigated the neural patterns associated with inequity, where participants were asked to choose between an equal split of money and an unequal split that could either maximize their own (advantageous inequity) or another person’s (disadvantageous inequity) earnings. Choosing to divide money unequally, irrespective who benefited from the unequal distribution, was associated with activity in the dorsal anterior cingulate cortex, anterior insula and the dorsolateral prefrontal cortex. Inequity choices that maximized another person’s profits were further associated with activity in the ventral striatum and ventromedial prefrontal cortex. Taken together, our findings show evidence of a common neural pattern associated with both advantageous and disadvantageous inequity in sharing decisions and additional recruitment of neural circuitry previously linked to the computation of subjective value and reward when violating a fairness norm at the benefit of someone else.     

Medial-frontal cortex hypometabolism in chronic phencyclidine exposed rats assessed by high resolution magic angle spin 11.7 T proton magnetic resonance spectroscopy

BackgroundProton magnetic resonance spectroscopy (¹H-MRS) clinical studies of patients with schizophrenia document prefrontal N-acetylaspartate (NAA) reductions, suggesting an effect of the disease or of antipsychotic medications. We studied in the rat the effect of prolonged exposure to a low-dose of the NMDA glutamate receptor antagonist phencyclidine (PCP) on levels of NAA, glutamate and glutamine in several brain regions where metabolite reductions have been reported in chronically medicated patients with schizophrenia.MethodsTwo groups of ten rats each were treated with PCP (2.58 mg/kg/day) or vehicle and were sacrificed after 1 month treatment. Concentrations of neurochemicals were determined with high resolution magic angle (HR-MAS) ¹H-MRS at 11.7 T in ex vivo punch biopsies from the medial frontal and cingulate cortex, striatum, nucleus accumbens, amygdala and ventral hippocampus.ResultsPCP treatment reduced NAA, glutamate, glycine, aspartate, creatine, lactate and GABA in medial frontal cortex. In the nucleus accumbens, PCP reduced levels of NAA, aspartate and glycine; similarly aspartate and glycine were reduced in the striatum. Finally the amygdala and hippocampus had elevations in glutamine and choline, respectively.ConclusionsLow-dose PCP in rats models prefrontal NAA and glutamate reductions documented in chronically-ill schizophrenia patients. Chronic glutamate NMDA receptor blockade in rats replicates an endophenotype in schizophrenia and may contribute to the prefrontal hypometabolic state in schizophrenia.     

Signatures of Value Comparison in Ventral Striatum Neurons

The ventral striatum (VS), like its cortical afferents, is closely associated with processing of rewards, but the relative contributions of striatal and cortical reward systems remains unclear. Most theories posit distinct roles for these structures, despite their similarities. We compared responses of VS neurons to those of ventromedial prefrontal cortex (vmPFC) Area 14 neurons, recorded in a risky choice task. Five major response patterns observed in vmPFC were also observed in VS: (1) offer value encoding, (2) value difference encoding, (3) preferential encoding of chosen relative to unchosen value, (4) a correlation between residual variance in responses and choices, and (5) prominent encoding of outcomes. We did observe some differences as well; in particular, preferential encoding of the chosen option was stronger and started earlier in VS than in vmPFC. Nonetheless, the close match between vmPFC and VS suggests that cortex and its striatal targets make overlapping contributions to economic choice.     

Attentional bias to food images associated with elevated weight and future weight gain: an fMRI study

Behavioral studies reveal that obese vs. lean individuals show attentional bias to food stimuli. Yet research has not investigated this relation using objective brain imaging or tested whether attentional bias to food stimuli predicts future weight gain, which are important aims given the prominence of food cues in the environment. We used functional magnetic resonance imaging (fMRI) to examine attentional bias in 35 adolescent girls ranging from lean to obese using an attention network task involving food and neutral stimuli. BMI correlated positively with speed of behavioral response to both appetizing food stimuli and unappetizing food stimuli, but not to neutral stimuli. BMI correlated positively with activation in brain regions related to attention and food reward, including the anterior insula/frontal operculum, lateral orbitofrontal cortex (OFC), ventrolateral prefrontal cortex (vlPFC), and superior parietal lobe, during initial orientation to food cues. BMI also correlated with greater activation in the anterior insula/frontal operculum during reallocation of attention to appetizing food images and with weaker activation in the medial OFC and ventral pallidum during reallocation of attention to unappetizing food images. Greater lateral OFC activation during initial orientation to appetizing food cues predicted future increases in BMI. Results indicate that overweight is related to greater attentional bias to food cues and that youth who show elevated reward circuitry responsivity during food cue exposure are at increased risk for weight gain.     

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic,Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [¹¹C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis.     

Identifying the neural circuitry of alcohol craving and relapse vulnerability

With no further intervention, relapse rates in detoxified alcoholics are high and usually exceed 80% of all detoxified patients. It has been suggested that stress and exposure to priming doses of alcohol and to alcohol-associated stimuli (cues) contribute to the relapse risk after detoxification. This article focuses on neuronal correlates of cue responses in detoxified alcoholics. Current brain imaging studies indicate that dysfunction of dopaminergic, glutamatergic and opioidergic neurotransmission in the brain reward system (ventral striatum including the nucleus accumbens) can be associated with alcohol craving and functional brain activation in neuronal systems that process attentional relevant stimuli, reward expectancy and experience. Increased functional brain activation elicited by such alcohol-associated cues predicted an increased relapse risk, whereas high brain activity elicited by affectively positive stimuli may represent a protective factor and was correlated with a decreased prospective relapse risk. These findings are discussed with respect to psychotherapeutic and pharmacological treatment options.