Levin et al. Table 1 | Continued Authors and Focal topic year Time of measurement Conditions Active regions identiﬁed Inferior operculum Insula Midbrain Middle temporal gyrus Neuropsychology of risky gains/losses Sample size Result This table is sorted by time of measurement (before, during, or after decision-making) and by result (supportive of separate structures or not). In each category, the table is sorted ﬁrst in chronological order, then in alphabetical order. dissociation between the domains of gains and losses within the prefrontal cortex region, but such dissociations are more likely to be revealed when one considers two other neural systems, the insula and amygdala, which feed information into the prefrontal cortex. Indeed, within the prefrontal cortex, patients with dam- age to the VMPFC show deﬁcits for both risky gains and risky losses (Weller et al., 2007). Compared to healthy controls, VMPFC patients showed increased levels of risk-taking and decreased sen- sitivity to EV differences in both gain and loss domains. In contrast, amygdala patients showed impaired decision-making and exag- gerated levels of risk-taking to achieve gains. However, in the loss domain amygdala damage was not associated with signiﬁcantly increased risk-taking or decreased EV sensitivity. Given the abun- dance of literature suggesting that the amygdala is involved with avoidance of punishment, this ﬁnding suggests that other struc- tures may act in concert with the amygdala to produce a signal that engages the VMPFC. When patients with insula damage were com- pared to controls, a different pattern emerged (Weller et al., 2009). Consistent with research suggesting that the insula is important for risk processing (Preuschoff et al., 2008), insula lesion patients like VMPFC and amygdala patients showed decreased sensitiv- ity to EV differences between choice options for both risky gains and risky losses. However, these individuals showed lower levels of risk-taking compared to healthy controls, especially on gain trials. Thus the insula, with connections to the amygdala, ventral striatum, and the VMPFC, may serve the purpose of providing a “gate” to determine the effectiveness of excitatory and inhibitory motivational circuits, signaling approach or danger. Subsequently, insula damage may result in a blunted response toward risk, and would lead to insensitivity to changes in environmental contin- gencies signaling the approach or avoidance of a risk, regardless of domain. Because the amygdala and insula have long been implicated in the processing of negative emotions, evoked from stimuli that are particularly aversive and perhaps even a threat to survival (e.g., LeDoux, 2000; Paulus and Stein, 2006; Phelps, 2006), we argue that these emotional reactions may be processed by multiple neural structures and are thus more difﬁcult to disrupt as a result of a focal lesion to the amygdala or the insula alone3. Speciﬁcally, a person with a damaged amygdala but an intact insula can still 3It should be noted that redundancy has also been found in learning and mem- ory systems, which allow learning to occur in multiple parallel memory systems; see Pinker and Ullman (2002) for an example of how multiple memory systems support the generation of verb past-tense. make reasoned decisions in the domain of losses even when they cannot in the domain of gains. While a separation in processing gains and losses is achieved at the level of the amygdala versus insular cortex, the two neural systems may come closely together (and become more difﬁcult to dissociate) by the time information reaches the prefrontal cortex, which responds similarly to risky gains and risky losses. Nevertheless, when considering the evi- dence from both insula and amygdala lesions, support for separate processes for risky decision-making in the gain and loss domains seems to emerge. Consistent with our model, the insula, in addi- tion to its general role in processing risk, serves to especially aid in recruitment of the VMPFC to guide risky decisions in the more emotion-laden loss domain. SUMMARY AND CONCLUSION Taken individually, each of the neuroimaging and lesion studies reviewed here has its limitations. Lesion studies are limited to the small sample of available participants who meet the criteria of damage to a targeted area. Furthermore, some of those included may have collateral damage to other adjacent areas. fMRI stud- ies also typically have small sample size due to ﬁnancial and time constraints. Furthermore, the complexity and length of tasks that can be conducted in a scanner are limited. Also, because differ- ent studies focus on different areas (see Table 1), comparisons, and integration of ﬁndings can be difﬁcult. Finally, for present purposes, the tasks used in the different studies differed in their ability to separate the gain and loss domains. Nevertheless, we believe that we can provide a meaningful sum- mary of the ﬁndings reviewed here. Behavioral studies suggest differences in decision-making for risky gains and risky losses. A study comparing different age groups suggests different develop- mental trajectories for risk-taking in the gain and loss domains. Neuroimaging studies are sometimes inconclusive in mapping brain systems to differential reactions to risky gains and losses. For example, while there is evidence that a system such as the VMPFC or the striatum is involved in both risky gains and losses, different parts of the system may be differentially sensitive to gains and losses (Xue et al., 2009). In such cases, the more general hypothesis of separate processes underlying risk-taking for gains and losses is still supported. With regard to the stricter hypothesis of separate structures, a breakdown of fMRI studies in Table 1 shows the strongest evidence for this hypothesis when recordings capture pre-decisional or anticipatory processes. We believe that the lesion studies provide the most direct evidence implicating separate structures. www.frontiersin.org February 2012 | Volume 6 | Article 15 | 9