Brian Knutson

The Reward Circuit: Linking Primate Anatomy and Human Imaging

Although cells in many brain regions respond to reward, the cortical-basal ganglia circuit is at the heart of the reward system. The key structures in this network are the anterior cingulate cortex, the orbital prefrontal cortex, the ventral striatum, the ventral pallidum, and the midbrain dopamine neurons. In addition, other structures, including the dorsal prefrontal cortex, amygdala, hippocampus, thalamus, and lateral habenular nucleus, and specific brainstem structures such as the pedunculopontine nucleus, and the raphe nucleus, are key components in regulating the reward circuit. Connectivity between these areas forms a complex neural network that mediates different aspects of reward processing. Advances in neuroimaging techniques allow better spatial and temporal resolution. These studies now demonstrate that human functional and structural imaging results map increasingly close to primate anatomy.

Dissociation of reward anticipation and outcome with event-related fMRI

Reward processing involves both appetitive and consummatory phases. We sought to examine whether reward anticipation vs outcomes would recruit different regions of ventral forebrain circuitry using event-related fMRI. Nine healthy volunteers participated in a monetary incentive delays task in which they either responded to a cued target for monetary reward, responded to a cued target for no reward, or did not respond to a cued target during scanning. Multiple regression analyses indicated that while anticipation of reward vs non-reward activated foci in the ventral striatum, reward vs non-reward outcomes activated foci in the ventromedial frontal cortex. These findings suggest that reward anticipation and outcomes may differentially recruit distinct regions that lie along the trajectory of ascending dopamine projections.

FMRI Visualization of Brain Activity during a Monetary Incentive Delay Task

Comparative studies have implicated striatal and mesial forebrain circuitry in the generation of autonomic, endocrine, and behavioral responses for incentives. Using blood oxygen level-dependent functional magnetic resonance imaging, we sought to visualize functional activation of these regions in 12 normal volunteers as they anticipated and responded for monetary incentives. Both individual and group analyses of time-series data revealed significant activation of striatal and mesial forebrain structures (including insula, caudate, putamen, and mesial prefrontal cortex) during trials involving both monetary rewards and punishments. In addition to these areas, during trials involving punishment, group analysis revealed activation foci in the anterior cingulate and thalamus. These results corroborate comparative studies which implicate striatal and mesial forebrain circuitry in the elaboration of incentive-driven behavior. This report also introduces a new paradigm for probing the functional integrity of this circuitry in humans.

Distributed Neural Representation of Expected Value

Anticipated reward magnitude and probability comprise dual components of expected value (EV), a cornerstone of economic and psychological theory. However, the neural mechanisms that compute EV have not been characterized. Using event-related functional magnetic resonance imaging, we examined neural activation as subjects anticipated monetary gains and losses that varied in magnitude and probability. Group analyses indicated that, although the subcortical nucleus accumbens (NAcc) activated proportional to anticipated gain magnitude, the cortical mesial prefrontal cortex (MPFC) additionally activated according to anticipated gain probability. Individual difference analyses indicated that, although NAcc activation correlated with self-reported positive arousal, MPFC activation correlated with probability estimates. These findings suggest that mesolimbic brain regions support the computation of EV in an ascending and distributed manner: whereas subcortical regions represent an affective component, cortical regions also represent a probabilistic component, and, furthermore, may integrate the two.

Functional magnetic resonance imaging of reward prediction

Purpose of reviewTechnical and conceptual advances in functional magnetic resonance imaging now allow visualization of real-time changes in oxygenation of deep subcortical regions, leading to rapid advances in scientific characterization of the neural substrates that underlie reward prediction in humans. Recent findingsNeuroimaging research over the past year has focused on determining the necessary neural substrates for reward prediction. SummaryWhile the orbitofrontal cortex has long been implicated in modality-specific reward representation, the ventral striatum (particularly the nucleus accumbens) may play a role in modality-independent representations of predicted reward. On the other hand, the mesial prefrontal cortex appears to play a role in representing reward prediction error and the dorsal caudate in linking reward to behavior. Theoretically, future studies will need to establish the specificity of these responses to reward versus punishment and anticipation versus outcome. Clinically, current findings suggest that patients can predict reward without a prefrontal cortex, but should experience difficulty correcting their behavior when reward predictions are violated.

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.

Incentive-Elicited Brain Activation in Adolescents: Similarities and Differences from Young Adults

Brain motivational circuitry in human adolescence is poorly characterized. One theory holds that risky behavior in adolescence results in part from a relatively overactive ventral striatal (VS) motivational circuit that readily energizes approach toward salient appetitive cues. However, other evidence fosters a theory that this circuit is developmentally underactive, in which adolescents approach more robust incentives (such as risk taking or drug experimentation) to recruit this circuitry. To help resolve this, we compared brain activation in 12 adolescents (12-17 years of age) and 12 young adults (22-28 years of age) while they anticipated the opportunity to respond to obtain monetary gains as well as to avoid monetary losses. In both age groups, anticipation of potential gain activated portions of the VS, right insula, dorsal thalamus, and dorsal midbrain, where the magnitude of VS activation was sensitive to gain amount. Notification of gain outcomes (in contrast with missed gains) activated the mesial frontal cortex (mFC). Across all subjects, signal increase in the right nucleus accumbens during anticipation of responding for large gains independently correlated with both age and self-rated excitement about the high gain cue. In direct comparison, adolescents evidenced less recruitment of the right VS and right-extended amygdala while anticipating responding for gains (in contrast with anticipation of nongains) compared with young adults. However, brain activation after gain outcomes did not appreciably differ between age groups. These results suggest that adolescents selectively show reduced recruitment of motivational but not consummatory components of reward-directed behavior.

Nucleus accumbens amphetamine microinjections unconditionally elicit 50-kHz ultrasonic vocalizations in rats.

The authors have hypothesized that, in adult rats, 50-kHz ultrasonic vocalizations (USVs) index a state characterized by high arousal and expectations of reward. This study was conducted to investigate whether dopamine agonism of the nucleus accumbens (NAcc) could evoke such an appetitive state, by examining the effects of NAcc amphetamine (AMPH) microinjections on USVs. Intra-NAcc AMPH injections (0.3, 1.0, 3.0, 10.0 microg unilaterally) produced robust, dose-dependent increases in 50-kHz USVs, which could not be accounted for by concomitant increases in locomotor activity (LA). However, AMPH injections into dorsal control caudate putamen sites produced a modest, dose-dependent increase in LA without significant increases in 50-kHz USVs. These findings indicate that NAcc AMPH microinjections selectively evoke 50-kHz USVs in rats, supporting the notion that dopamine elevations in the NAcc may unconditionally elicit a state of reward anticipation.

Ventral striatal hyporesponsiveness during reward anticipation in attention-deficit/hyperactivity disorder.

BACKGROUND Although abnormalities in reward processing have been proposed to underlie attention-deficit/hyperactivity disorder (ADHD), this link has not been tested explicitly with neural probes. METHODS This hypothesis was tested by using fMRI to compare neural activity within the striatum in individuals with ADHD and healthy controls during a reward-anticipation task that has been shown previously to produce reliable increases in ventral striatum activity in healthy adults and healthy adolescents. Eleven adolescents with ADHD (5 off medication and 6 medication-naïve) and 11 healthy controls (ages 12-17 y) were included. Groups were matched for age, gender, and intelligence quotient. RESULTS We found reduced ventral striatal activation in adolescents with ADHD during reward anticipation, relative to healthy controls. Moreover, ventral striatal activation was negatively correlated with parent-rated hyperactive/impulsive symptoms across the entire sample. CONCLUSIONS These findings provide neural evidence that symptoms of ADHD, and impulsivity or hyperactivity in particular, may involve diminished reward anticipation, in addition to commonly observed executive dysfunction.

Dysfunction of reward processing correlates with alcohol craving in detoxified alcoholics

OBJECTIVE Alcohol dependence may be associated with dysfunction of mesolimbic circuitry, such that anticipation of nonalcoholic reward fails to activate the ventral striatum, while alcohol-associated cues continue to activate this region. This may lead alcoholics to crave the pharmacological effects of alcohol to a greater extent than other conventional rewards. The present study investigated neural mechanisms underlying these phenomena. METHODS 16 detoxified male alcoholics and 16 age-matched healthy volunteers participated in two fMRI paradigms. In the first paradigm, alcohol-associated and affectively neutral pictures were presented, whereas in the second paradigm, a monetary incentive delay task (MID) was performed, in which brain activation during anticipation of monetary gain and loss was examined. For both paradigms, we assessed the association of alcohol craving with neural activation to incentive cues. RESULTS Detoxified alcoholics showed reduced activation of the ventral striatum during anticipation of monetary gain relative to healthy controls, despite similar performance. However, alcoholics showed increased ventral striatal activation in response to alcohol-associated cues. Reduced activation in the ventral striatum during expectation of monetary reward, and increased activation during presentation of alcohol cues were correlated with alcohol craving in alcoholics, but not healthy controls. CONCLUSIONS These results suggest that mesolimbic activation in alcoholics is biased towards processing of alcohol cues. This might explain why alcoholics find it particularly difficult to focus on conventional reward cues and engage in alternative rewarding activities.