Dorsomedial striatal contributions to different forms of risk/reward decision making.

Optimal decision making involving reward uncertainty is integral to adaptive goal-directed behavior. In some instances, these decisions are guided by internal representations of reward history, whereas in other situations, external cues inform a decision maker about how likely certain actions are to yield reward. Different regions of the frontal lobe form distributed networks with striatal and amygdalar regions that facilitate different types of risk/reward decision making. The dorsal medial striatum (DMS) is one key output region of the prefrontal cortex, yet there have been few preclinical studies investigating the involvement of the DMS in different forms of risk/reward decision making. The present study addressed this issue, wherein separate groups of male rats were trained on one of two tasks where they chose between a small/certain or a large/risky reward. In a probabilistic discounting task, reward probabilities changed systematically over blocks of trials (100-6.25% or 6.25-100%), requiring rats to use internal representations of reward history to guide choice. Cue-guided decision-making was assessed with a "Blackjack" task, where different auditory cues indicated the odds associated with the large/risky option (50 or 12.5%). Inactivation of the DMS with GABA agonists impaired adjustments in choice biases during probabilistic discounting, resulting in either increases or decreases in risky choice as the probabilities associated with the large/risky reward decreased or increased over a session. In comparison, DMS inactivation increased risky choices on poor-odds trials on the Blackjack task, which was associated with a reduced impact that non-rewarded choices had on subsequent choices. DMS inactivation also impaired performance of an auditory conditional discrimination. These findings highlight a previously uncharacterized role for the DMS in facilitating flexible action selection during multiple forms of risk/reward decision making.

Differential effects of corticotropin-releasing factor and acute stress on different forms of risk/reward decision-making.

Acute stress and corticotropin-releasing factor (CRF) have been show to perturb cost/benefit decision making involving effort costs. However, previous studies on how stress manipulations affect decisions involving reward uncertainty have yielded variable results. To provide additional insight into this issue, the current study investigated how central CRF infusion and acute restraint stress alter different forms of risk/reward decision-making guided by internal representations of risk/reward contingencies or external informative cues. Male rats were well-trained on one of two tasks that required choice between a small/certain or a large/risky reward. On a probabilistic discounting task, the probability of obtaining the larger reward increased or decreased systematically over blocks of trials (100-6.25%). On a cue-guided Blackjack task, reward probabilities (50% or 12.5%) were signaled by discriminative auditory cues. CRF (1 or 3 µg) was infused intracerebroventricularly (ICV) or one-hour of restraint stress was administered prior to behavioral testing. Neither CRF nor acute stress altered risky choice on probabilistic discounting, but did increase trial omissions in the latter part of the session. Conversely on the Blackjack task, CRF reduced risky choice on good-odds trials (50%), whereas acute stress increased reward sensitivity. CRF but not acute stress also slowed decision latencies across tasks. These data reveal complex and differential manners in which increased CRF activity and acute stress alter distinct forms of risk/reward decision-making, particularly those guided by external cues.

Basolateral amygdala - nucleus accumbens circuitry regulates optimal cue-guided risk/reward decision making.

Maladaptive decision making is a characteristic feature of substance use disorder and pathological gambling. Studies in humans and animals have implicated neural circuits that include the basolateral amygdala (BLA) and nucleus accumbens (NAc) in facilitating risk/reward decision making. However, the preclinical literature has focussed primarily on situations where animals use internally-generated information to adapt to changes in reward likelihood, whereas many real-life situations require the use of external stimuli to facilitate context-appropriate behavior. We recently developed the "Blackjack" task, to measure cued risk/reward decision making requiring rats to chose between Small/Certain and Large/Risky rewards, with auditory cues at the start of each trial explicitly informing that the probability of obtaining a large reward was either good (50%) or poor (12.5%). Here we investigated the contribution of the BLA and its interaction with the NAc in guiding these types of decisions. In well-trained male rats, bilateral inactivation of the BLA induced suboptimal decision making, primarily by reducing risky choice on good-odds trials. In comparison, pharmacological disconnection of the BLA and NAc-shell also induced suboptimal decision making, diverting choice from more preferred option by reducing or increasing risky choice on good vs. poor odds trials respectively. Together, these results suggest that the BLA-NAc circuitry plays a crucial role in integrating information provided by discriminative stimuli. Furthermore, this circuitry may aid in guiding action selection of advantageous options in situations to maximize rewards. Finally, they suggest that perturbations in optimal decision making observed in substance abuse and gambling disorders may be driven in part by dysfunction within this circuitry.

Dissociable roles for the ventral and dorsal medial prefrontal cortex in cue-guided risk/reward decision making.

Converging evidence from studies with animals and humans have implicated separate regions of the medial prefrontal cortex (mPFC) corresponding to the anterior cingulate cortex (ACC), in mediating different aspects of reward-related decisions involving uncertainty or risk. However, the dissociable contributions of subregions of the ACC remain unclear, as discrepancies exist between human neuroimaging findings and preclinical rodent studies. To clarify how ventral vs. dorsal regions of the mPFC contribute to risk/reward decision making, the present study assessed the effects of inactivation of different subregions on performance of a "Blackjack task" that measured cue-guided decision making and shares similarities with paradigms used with humans. Male, Long-Evans rats were well-trained to choose between a Small/Certain reward vs a Large/Risky reward delivered with variable probabilities (i.e., good vs. poor-odds, 50% vs. 12.5%). The odds of obtaining the larger reward was signaled by auditory cues at the start of each trial. Inactivation of the ventral, infralimbic region of the mPFC increased risky choice selectively when the odds of winning were poor. By contrast, inactivation of the prelimbic and anterior cingulate regions of the dorsal mPFC led to suboptimal reductions in risky choice on good-odds trials. The effects of prelimbic vs anterior cingulate inactivations were associated with context-dependent alterations in reward vs negative feedback, respectively. These results further clarify the distinct yet complementary manners in which separate ACC regions promote optimal risk/reward decision making and complement neuroimaging findings that activity in human ventral vs dorsal ACC promotes risk aversion or risky choices.

Controlling striatal function via anterior frontal cortex stimulation.

Motivational, cognitive and action goals are processed by distinct, topographically organized, corticostriatal circuits. We aimed to test whether processing in the striatum is under causal control by cortical regions in the human brain by investigating the effects of offline transcranial magnetic stimulation (TMS) over distinct frontal regions associated with motivational, cognitive and action goal processing. Using a three-session counterbalanced within-subject crossover design, continuous theta burst stimulation was applied over the anterior prefrontal cortex (aPFC), dorsolateral prefrontal cortex, or premotor cortex, immediately after which participants (N = 27) performed a paradigm assessing reward anticipation (motivation), task (cognitive) switching, and response (action) switching. Using task-related functional magnetic resonance imaging (fMRI), we assessed the effects of stimulation on processing in distinct regions of the striatum. To account for non-specific effects, each session consisted of a baseline (no-TMS) and a stimulation (post-TMS) fMRI run. Stimulation of the aPFC tended to decrease reward-related processing in the caudate nucleus, while stimulation of the other sites was unsuccessful. A follow-up analysis revealed that aPFC stimulation also decreased processing in the putamen as a function of the interaction between all factors (reward, cognition and action), suggesting stimulation modulated the transfer of motivational information to cortico-striatal circuitry associated with action control.

Differential Contributions of Nucleus Accumbens Subregions to Cue-Guided Risk/Reward Decision Making and Implementation of Conditional Rules.

The nucleus accumbens (NAc) is a key node within corticolimbic circuitry for guiding action selection and cost/benefit decision making in situations involving reward uncertainty. Preclinical studies have typically assessed risk/reward decision making using assays where decisions are guided by internally generated representations of choice-outcome contingencies. Yet, real-life decisions are often influenced by external stimuli that inform about likelihoods of obtaining rewards. How different subregions of the NAc mediate decision making in such situations is unclear. Here, we used a novel assay colloquially termed the "Blackjack" task that models these types of situations. Male Long-Evans rats were trained to choose between one lever that always delivered a one-pellet reward and another that delivered four pellets with different probabilities [either 50% (good-odds) or 12.5% (poor-odds)], which were signaled by one of two auditory cues. Under control conditions, rats selected the large/risky option more often on good-odds versus poor-odds trials. Inactivation of the NAc core caused indiscriminate choice patterns. In contrast, NAc shell inactivation increased risky choice, more prominently on poor-odds trials. Additional experiments revealed that both subregions contribute to auditory conditional discrimination. NAc core or shell inactivation reduced Pavlovian approach elicited by an auditory CS+, yet shell inactivation also increased responding during presentation of a CS-. These data highlight distinct contributions for NAc subregions in decision making and reward seeking guided by discriminative stimuli. The core is crucial for implementation of conditional rules, whereas the shell refines reward seeking by mitigating the allure of larger, unlikely rewards and reducing expression of inappropriate or non-rewarded actions.SIGNIFICANCE STATEMENT Using external cues to guide decision making is crucial for adaptive behavior. Deficits in cue-guided behavior have been associated with neuropsychiatric disorders, such as attention deficit hyperactivity disorder and schizophrenia, which in turn has been linked to aberrant processing in the nucleus accumbens. However, many preclinical studies have often assessed risk/reward decision making in the absence of explicit cues. The current study fills that gap by using a novel task that allows for the assessment of cue-guided risk/reward decision making in rodents. Our findings identified distinct yet complementary roles for the medial versus lateral portions of this nucleus that provide a broader understanding of the differential contributions it makes to decision making and reward seeking guided by discriminative stimuli.

Ventral striatal hyperconnectivity during rewarded interference control in adolescents with ADHD.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is characterized by cognitive deficits (e.g., interference control) and altered reward processing. Cognitive control is influenced by incentive motivation and according to current theoretical models, ADHD is associated with abnormal interactions between incentive motivation and cognitive control. However, the neural mechanisms by which reward modulates cognitive control in individuals with ADHD are unknown. METHOD: We used event-related functional resonance imaging (fMRI) to study neural responses during a rewarded Stroop color-word task in adolescents (14-17 years) with ADHD (n = 25; 19 boys) and healthy controls (n = 33; 22 boys). RESULTS: Adolescents with ADHD showed increased reward signaling within the superior frontal gyrus and ventral striatum (VS) relative to controls. Importantly, functional connectivity analyses revealed a hyperconnectivity between VS and motor control regions in the ADHD group, as a function of reward-cognitive control integration. Connectivity was associated with performance improvement in controls but not in the ADHD group, suggesting inefficient connectivity. CONCLUSION: Adolescents with ADHD show increased neural sensitivity to rewards and its interactions with interference control in VS and motor regions, respectively. The findings support theoretical models of altered reward-cognitive control integration in individuals with ADHD.

Medial Orbitofrontal Cortex Mediates Outcome Retrieval in Partially Observable Task Situations.

Choice between actions often requires the ability to retrieve action consequences in circumstances where they are only partially observable. This capacity has recently been argued to depend on orbitofrontal cortex; however, no direct evidence for this hypothesis has been reported. Here, we examined whether activity in the medial orbitofrontal cortex (mOFC) underlies this critical determinant of decision-making in rats. First, we simulated predictions from this hypothesis for various tests of goal-directed action by removing the assumption that rats could retrieve partially observable outcomes and then tested those predictions experimentally using manipulations of the mOFC. The results closely followed predictions; consistent deficits only emerged when action consequences had to be retrieved. Finally, we put action selection based on observable and unobservable outcomes into conflict and found that whereas intact rats selected actions based on the value of retrieved outcomes, mOFC rats relied solely on the value of observable outcomes.

Reward modulation of cognitive function in adult attention-deficit/hyperactivity disorder: a pilot study on the role of striatal dopamine.

Attention-deficit/hyperactivity disorder (ADHD) is accompanied by impairments in cognitive control, such as task-switching deficits. We investigated whether such problems, and their remediation by medication, reflect abnormal reward motivation and associated striatal dopamine transmission in ADHD. We used functional genetic neuroimaging to assess the effects of dopaminergic medication and reward motivation on task-switching and striatal BOLD signal in 23 adults with ADHD, ON and OFF methylphenidate, and 26 healthy controls. Critically, we took into account interindividual variability in striatal dopamine by exploiting a common genetic polymorphism (3'-UTR VNTR) in the DAT1 gene coding for the dopamine transporter. The results showed a highly significant group by genotype interaction in the striatum. This was because a subgroup of patients with ADHD showed markedly exaggerated effects of reward on the striatal BOLD signal during task-switching when they were OFF their dopaminergic medication. Specifically, patients carrying the 9R allele showed a greater striatal signal than healthy controls carrying this allele, whereas no effect of diagnosis was observed in 10R homozygotes. Aberrant striatal responses were normalized when 9R-carrying patients with ADHD were ON medication. These pilot data indicate an important role for aberrant reward motivation, striatal dopamine and interindividual genetic differences in cognitive processes in adult ADHD.

Response inhibition during cue reactivity in problem gamblers: an fMRI study.

Disinhibition over drug use, enhanced salience of drug use and decreased salience of natural reinforcers are thought to play an important role substance dependence. Whether this is also true for pathological gambling is unclear. To understand the effects of affective stimuli on response inhibition in problem gamblers (PRGs), we designed an affective Go/Nogo to examine the interaction between response inhibition and salience attribution in 16 PRGs and 15 healthy controls (HCs).Four affective blocks were presented with Go trials containing neutral, gamble, positive or negative affective pictures. The No-Go trials in these blocks contained neutral pictures. Outcomes of interest included percentage of impulsive errors and mean reaction times in the different blocks. Brain activity related to No-Go trials was assessed to measure response inhibition in the various affective conditions and brain activity related to Go trials was assessed to measure salience attribution.PRGs made fewer errors during gamble and positive trials than HCs, but were slower during all trials types. Compared to HCs, PRGs activated the dorsolateral prefrontal cortex, anterior cingulate and ventral striatum to a greater extent while viewing gamble pictures. The dorsal lateral and inferior frontal cortex were more activated in PRGs than in HCs while viewing positive and negative pictures. During neutral inhibition, PRGs were slower but similar in accuracy to HCs, and showed more dorsolateral prefrontal and anterior cingulate cortex activity. In contrast, during gamble and positive pictures PRGs performed better than HCs, and showed lower activation of the dorsolateral and anterior cingulate cortex.This study shows that gambling-related stimuli are more salient for PRGs than for HCs. PRGs seem to rely on compensatory brain activity to achieve similar performance during neutral response inhibition. A gambling-related or positive context appears to facilitate response inhibition as indicated by lower brain activity and fewer behavioural errors in PRGs.

Striatal Dopamine and the Interface between Motivation and Cognition.

Brain dopamine has long been known to be implicated in the domains of appetitive motivation and cognition. Recent work indicates that dopamine also plays a role in the interaction between appetitive motivation and cognition. Here we review this work. Animal work has revealed an arrangement of spiraling connections between the midbrain and the striatum that subserves a mechanism by which dopamine can direct information flow from ventromedial to more dorsal regions in the striatum. In line with current knowledge about dopamine's effects on cognition, we hypothesize that these striato-nigro-striatal connections provide the basis for functionally specific effects of appetitive motivation on cognition. One implication of this hypothesis is that appetitive motivation can induce cognitive improvement or impairment depending on task demands.

Human cognitive flexibility depends on dopamine D2 receptor signaling.

RATIONALE: Accumulating evidence indicates that the cognitive effects of dopamine depend on the subtype of dopamine receptor that is activated. In particular, recent work with animals as well as current theorizing has suggested that cognitive flexibility depends on dopamine D2 receptor signaling. However, there is no evidence for similar mechanisms in humans. OBJECTIVES: We aim to demonstrate that optimal dopamine D2 receptor signaling is critical for human cognitive flexibility. METHODS: To this end, a pharmacological pretreatment design was employed. This enabled us to investigate whether effects of the dopamine receptor agonist bromocriptine on task-set switching were abolished by pretreatment with the D2 receptor antagonist sulpiride. To account for individual (genetic) differences in baseline levels of dopamine, we made use of a common variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region of the dopamine transporter gene, DAT1. RESULTS: Bromocriptine improved cognitive flexibility relative to placebo, but only in subjects with genetically determined low levels of dopamine (n = 27). This beneficial effect of bromocriptine on cognitive flexibility was blocked by pretreatment with the selective dopamine D2 receptor antagonist sulpiride (n = 14). CONCLUSIONS: These results provide strong evidence in favor of the hypothesis that human cognitive flexibility implicates dopamine D2 receptor signaling.