Levin et al. Neuropsychology of risky gains/losses research on the approach–avoidance conﬂict evolved into studies of risky decision-making where the shift was to a more microscopic analysis of neural systems. Neuroimaging data have been used to gain new insights con- cerning risky decision-making. In particular, fMRI studies use changes in blood ﬂow that accompany neural activity in different parts of the brain to associate these areas to particular behav- iors. For instance, in a recent meta-analysis of fMRI studies of risky decision-making using young, healthy adults, Mohr et al. (2010) found evidence common to all studies that risk process- ing is associated with activation of speciﬁc emotional systems in the brain such as the anterior insula, especially when potential losses are involved. The dorsolateral prefrontal cortex and pari- etal cortex are also activated when making decisions involving risk. Using fMRI in conjunction with a paradigm in which indi- viduals decided whether to accept or reject gambles offering a 50/50 chance of gaining or losing varying amounts of money, Tom et al. (2007) found that activity in the ventral striatum and the VMPFC increased as potential gains increased but decreased as potential losses increased. Also, in the anterior insula, activity was found more strongly associated with the anticipation of losses than with anticipation of gains (Knutson et al., 2007). Earlier research showed increased arousal following losses than following gains (Bechara et al., 1999). Such results motivated us to classify study results based on whether activation was measured before, during, or after a decision was made. In order to get a more complete picture, we conducted a focused literature search. Using the keywords “fMRI,” “gains,” “losses,” “risk,” and “uncertainty,” Table 1 summarizes the results of a num- ber of fMRI studies in terms of which areas of the brain were studied and at what point in time, and whether the study pro- vided support for distinct mechanisms involved in risky decision- making for gains and losses. While the results are “mixed,” a pattern emerges when the studies are separated based on whether brain activation was measured before, during, or after a risky choice was made. Most noteworthy, while different regions were the focus of different studies, in 14 studies in which activation was assessed prior to a choice (i.e., anticipation), support for separate mech- anisms was found in eight studies, four studies did not support separate structures, and two studies did not make claims about separate structures because they focused on a speciﬁc region only. For example, studies by Kuhnen and Knutson (2005) and Knut- son et al. (2008b) each found that the nucleus accumbens was activated in anticipation of a risky gain, whereas the insula was activated in anticipation of a risky loss. We think these results are particularly compelling because they suggest that different parts of the brain drive risky decision-making in anticipation of uncertain gains versus uncertain losses. Whereas activation during or after a risky choice can inﬂuence subsequent risky choices, activation prior to a choice is unique in its potential to inﬂuence the current choice. Beside the dissociation at the pre-decision stage, recent evi- dence suggests that experienced gains and losses might also activate different regions, which then affect subsequent decisions mak- ing. In a recent study using the cups task, we found that at the feedback stage, experienced reward was associated with strong acti- vation in the VMPFC and the ventral striatum, and the stronger reward-related responses in the VMPFC were positively associated with risk-taking (Xue et al., 2009). In a follow up study, we explic- itly examined how neural and behavioral responses to gains and losses were associated with subsequent decisions. We developed a modiﬁed version of the cups task in which a single array of cups was presented on a given trial where one coin would be lost for all but one randomly selected cup, but multiple coins would be won if the other cup was drawn (Xue et al., 2011). The decision-maker indicated whether to take or not take the gamble. In one analysis, we focused on how an experienced gain versus an experienced loss could modulate subsequent risky decision-making, both behav- iorally and neurally. We found that subjects took more risk after losing a gamble than after winning a gamble. At the neural level, we again found that at the feedback stage, win was associated with stronger activation than loss in the anterior cingulate cor- tex, the posterior cingulate cortex, the ventral striatum, and the insula. More importantly, decisions after loss were associated with stronger activation in the frontoparietal network, which was posi- tively correlated with individuals’ increased tendency to take more risk. These results thus suggest that experienced gains and losses not only involve different brain regions, but also trigger differential neural responses and behaviors in subsequent decisions. Despite this suggested anatomical separation, the fact remains that the same structure, for example, the insula, has sometimes been implicated in the processing of both painful and pleasurable stimuli (e.g., Craig, 2009). Indeed, when compared to a base- line of activation following trials on which the decision-maker decided not to take the gamble, both experienced gains and losses elicited strong insular activation, which then modulated subse- quent decision-making (Xue et al., 2010). This calls for caution when making absolute determination about the anatomical sepa- ration of these pleasure (gain)–loss (pain) systems. In particular, a proper baseline should be included in this analysis since the same regions might show opposite modulation by gains and losses (Tom et al., 2007). Thus, the stronger activation for gains or losses in some regions might not necessarily reﬂect distinct neural struc- tures for gains and losses. Another reason for these difﬁculties in establishing absolute anatomical separations is that cellular physi- ological evidence of neurons responding to positive versus negative valence stimuli, at least within the amygdala, indicates separation, while anatomical evidence is highly inter-mixed (e.g., Paton et al., 2006). This explains why the neural systems for risky gains versus losses can be functionally separate, but ﬁnding clear-cut separa- tion viewed at the global anatomical level is more difﬁcult, given the proximity and overlap of these two systems. Next, we turn to lesion studies which are smaller in number in terms of addressing this issue but which should align with the “anticipatory” fMRI studies because, of course, pre-existing brain damage would likewise serve to inﬂuence revealed choices. While neuroimaging studies argue whether a particular brain region is involved in a particular function, lesion studies test whether that brain region is necessary for that function, and thus form more direct tests of the model in Figure 1 and our earlier reference to anatomically separate neural substrates. The logic here is that if a particular function is impaired in individuals with a local- ized lesion, then the affected neural region must play a crucial role in executing that function. Lesion studies seem to reveal little Frontiers in Neuroscience | Decision Neuroscience February 2012 | Volume 6 | Article 15 | 4