The largest portion of the SBEI efforts has involved fMRI studies of motivation. These involve examination of how the brain responds during the anticipation of working to gain reward or to avoid punishment as well as examination of how the brain responds to notification of the results of an attempt to gain reward or avoid punishment. We have used different versions of a monetary incentive delay (MID) task to study motivation. Studies from many labs have shown that MID type tasks reliably activate the ventral striatum (VS) in response to cues that signal an imminent opportunity to respond for rewards. The brain response is proportional to the amount of money at stake. Conversely, the VS is not as robustly recruited by cues for reward deliveries that require no behavioral response. In addition, the VS as well as ventral mesofrontal cortex (mFC) are activated by notification of reward, typically when contrasted with notification that there will be no reward. Thus, the MID task can provide measurements of an individuals sensitivity to anticipation of working for reward as well as sensitivity to notification that the reward has been won or lost. An individuals sensitivity to reward plays a major role in each of the two competing hypotheses about how alterations in brain function motivation lead to the acquisition and maintenance of alcoholism. One of these ideas, the reward deficiency syndrome (RDS) hypothesis, suggests that individuals predisposed to alcoholism (or substance use disorders in general) have a dysfunctional reward circuit which nondrug rewards fail to activate but which can be activated by the more powerful effect provided by addictive substances. In contrast, the competing idea, which we can call the impulsivity hypothesis, suggests that at risk individuals (as well as those currently addicted) have an increased VS response to gaining rewards (1). As discussed above aberrant sensitivity of incentive neurocircuitry to nondrug rewards has been suggested as either a risk factor for or consequence of drug addiction. Using functional magnetic resonance imaging, we tested whether alcohol-dependent patients (ADP: n = 29) showed altered recruitment of ventral striatal (VS) incentive neurocircuitry compared to controls (n = 23) by: (1) cues to respond for monetary rewards, (2) post-response anticipation of rewards, or (3) delivery of rewards. We found no significant group differences in voxelwise activation by task contrasts, or in signal change extracted from VS. Both ADP and controls showed significant VS and other limbic recruitment by pre-response reward anticipation. In addition, controls also showed VS recruitment by post-response reward-anticipation, and ADP had appreciable subthreshold VS activation. Both groups also showed similar mesolimbic responses to reward deliveries. These findings indicate that incentive-motivational processing of nondrug rewards is substantially maintained in recovering alcoholics, and that reward-elicited VS recruitment correlates more with individual differences in trait impulsivity irrespective of addiction (2). Maturational differences in brain responsiveness to rewards have been implicated in the increased rates of injury and death in adolescents from behavior-related intoxication or other externalizing behaviors, and may be concentrated in a subset of adolescents who are at psychosocial or neurobiological risk. To examine whether individual differences in psychosocial and behavioral symptomatology relate to activation of motivational neurocircuitry, we scanned 26 psychiatrically-healthy adolescents as they performed a MID task. Overall Problem Density on the Drug Use Screening Inventory (DUSI-OPD) correlated positively with activation of ventral mesofrontal cortex (mFC) during anticipation of responding for rewards (versus responding for no incentive). In addition, DUSI-OPD also correlated positively with right ventral striatum recruitment during anticipation of responding to win rewards (versus responding for no incentive or to avoid losses of identical magnitudes) (3). Considered in their entirety we believe our recent work on imaging of motivation as related to the risk for alcoholism supports two conclusions: 1. The RDS hypothesis is less strongly supported than an alternative model involving greater sensitivity to reward receipt among alcoholics and individuals at risk for alcoholism. 2. This greater sensitivity does not directly map onto alcoholism as a diagnosis but rather is related to a set of personality traits comprising impulsiveness, sensation seeking and uninhibited externalizing behavior. It is possible that later in the course of alcoholism a kind of motivational blunting like that postulated in the RDS does develop. We have continued to study the effects of intravenously administered alcohol 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. It appears that alcohol specifically increases striatal activation during anticipation of responding for reward but blunts response to notification of the outcome of the motivated response. This is consistent with alcohol's ability to increase approach behavior while decreasing judgment and other higher cognitive functions (4). We have also examined BOLD response to alcohol in the VS of heavy and social drinkers. Heavy drinkers have a significantly blunted response in VS suggesting tolerance. Heavy alcohol consumption during young adulthood is a risk factor for the development of serious alcohol use disorders. Research has shown that individual differences in subjective responses to alcohol may affect individuals'vulnerability to developing alcoholism. Studies comparing the subjective and objective response to alcohol between light and heavy drinkers (HDs), however, have yielded inconsistent results, and neural responses to alcohol in these groups have not been characterized. We performed a double-blind, placebo-controlled, randomized crossover alcohol challenge study comparing functional magnetic resonance imaging and subjective response to intravenously administered 6% v/v ethanol to a target blood alcohol concentration of 0.08% or placebo between HDs and social drinkers (SDs). During the imaging, we presented emotional cues in order to measure how emotion modulated the effects of alcohol on the brain's reward circuitry. We found that, at equivalent blood alcohol concentrations, HDs reported lower subjective alcohol effects than SDs. Alcohol significantly activated the nucleus accumbens in SDs, but not in HDs. Self-reported ratings of intoxication correlated with striatal activation, suggesting that activation may reflect subjective experience of intoxication. Fearful faces significantly activated the amygdala in the SDs only, and this activation was attenuated by alcohol. This study shows that HDs not only experience reduced subjective effects of alcohol, but also demonstrate a blunted response to alcohol in the brain's reward system. Our findings indicate that reduced subjective and neural response to alcohol in HDs may be suggestive of either the development of tolerance to alcohol, or of pre-existing decreased sensitivity to alcohol's effects(5).
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