We have examined whether ventral forebrain dopamine projection areas were activated prior to motor behavior, during anticipation of reward and punishment. During the anticipation interval, subjects saw a cue indicating that they could either win money or not, waited a variable delay, and then pressed a button in response presentation of a target. If subjects responded before the target following the reward cue disappeared, they won $5.00, $1.00, or $.20 whereas their response to the neutral target did not affect their total. During the active avoidance portion of the task, subjects responded to targets that followed either a punishment cue or a neutral cue. If they failed to respond before the disappearance of the target following the punishment cue, they lost $5.00, $1.00, or $.20 whereas their response to the neutral target again did not affect their total. T2*-weighted gradient echoplanar MR volumes depicting blood oxygenation level dependent (BOLD)-contrast were acquired using a 3.0 Tesla GE System. After correcting for in-plane motion, individual voxel activations were correlated with an ideal waveform corresponding to the expected activation time course using the AFNI software package. The ideal waveform consisted of a waveform representing the task that was convolved with the brain hemodynamic response function. Anticipation of reward activated striatal areas (caudate, putamen) and mesial forebrain areas (anterior cingulate, mesial prefrontal cortex, and thalamic regions). Anticipation of punishment also activated these regions relative to anticipation of no monetary outcome. However, anticipation of reward but not punishment produced activation in the nucleus accumbens. Magnitude of nucleus accumbens activation predicted the amount of positive emotion subjects reported feeling when the cues signaling monetary reward. We also separately examined reward anticipation and outcomes with event-related fMRI. This study confirmed that the nucleus accumbens is recruited by anticipation of monetary reward. We have also developed a series of fMRI tasks which allow us to examine brain BOLD response during a risk taking task in which financial reward is determined by how much risk an individual is willing to endure. This task shows robust BOLD activation in the cognitive division of the anterior cingulate cortex, and that this activation is less pronounced among adolescents. This may represent a brain correlate of the developmental tendency of adolescents to engage in risky behavior. Similarly we have found less activation among alcoholic subjects compared to controls. Using the an advanced version of the motivational task described above which allows us to more clearly separate individual events during a sequence of motivated behavior, we have recently shown that alcoholics are more sensitive to the notification of both rewarding or punishing outcomes than non-alcoholic controls. This increased sensitivity to outcome is present in both the ventral striatum and the anterior insular cortex and may relate to differences in impulsivity that characterize substance-abusing individuals. In addition, it is possible that this increase sensitivity to outcome maybe equivalent to a greater magnitude of prediction error among alcoholics. Prediction error is a major component of models of human, animal and machine learning. Prediction error has been shown to correspond to the activity of midbrain dopamine neurons and BOLD activation in the nucleus accumbens. In addition, we have used fMRI with an incentive task to determine whether externalizing symptomatology in adolescence is correlated with an enhanced Ventral Striatal recruitment by cues for rewards, or by deliveries of rewards among adolescents with or without externalizing. Cues to respond for rewards activated the NAcc (relative to cues for no incentive), in both subject groups similarly, with greatest NAcc recruitment by cues for the largest reward. Loss-anticipatory NAcc signal increase was detected in a volume-of-interest analysis but this increase occurred only in trials when subjects hit the target. Relative to controls, adolescents with externalizing disorders showed significantly elevated NAcc activation by a linear contrast between reward notification versus notification of failure to win reward. Externalizing behavior, whether assessed dimensionally with a questionnaire, or in the form of a diagnostic categorization, is associated with an exaggerated limbic response to outcomes of reward-directed behavior. This could be a neurobiological signature of the behavioral sensitivity to laboratory reward delivery that is characteristic of children with externalizing symptomatology. The we have continue to study the effects of intravenously on brain activation measured by fMRI. Intravenously administered ethanol is associated with a significant increase in BOLD signal in the ventral forebrain, including extended amygdala nucleus accumbens and ventral striatum. We are also beginning to explore how administration of alcohol affects risky decision-making in the brain. We have recently begun a study to examine a very simple executive brain function among alcoholics. Results from other functional imaging labs have suggested that alcoholics show greater activation than non-alcoholics in circuits involving frontal lobes when engaged in executive-type tasks. We compared brain activations of alcohol dependent patients and healthy non-alcoholics while they performed two simple judgment tasks designed to activate frontal circuits involved in a basic form of decision making. Participants completed one judgment task that required an emotional judgment and one task that did not. This study showed that alcoholics have greater brain activation while performing executive tasks suggesting that the brains of alcoholics are less efficient than those of controls.
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