Contributions of the prefrontal cortex to the neural basis of human decision making

Transcription

1 Neuroscience and Biobehavioral Reviews 26 (2002) Review Contributions of the prefrontal cortex to the neural basis of human decision making Daniel C. Krawczyk* Department of Psychology, University of California, Los Angeles, 1285 Franz Hall, Box , Los Angeles, CA , USA Received 16 November 2001; revised 29 May 2002; accepted 10 June Abstract The neural basis of decision making has been an elusive concept largely due to the many subprocesses associated with it. Recent efforts involving neuroimaging, neuropsychological studies, and animal work indicate that the prefrontal cortex plays a central role in several of these subprocesses. The frontal lobes are involved in tasks ranging from making binary choices to making multi-attribute decisions that require explicit deliberation and integration of diverse sources of information. In categorizing different aspects of decision making, a division of the prefrontal cortex into three primary regions is proposed. (1) The orbitofrontal and ventromedial areas are most relevant to deciding based on reward values and contribute affective information regarding decision attributes and options. (2) Dorsolateral prefrontal cortex is critical in making decisions that call for the consideration of multiple sources of information, and may recruit separable areas when making well defined versus poorly defined decisions. (3) The anterior and ventral cingulate cortex appear especially relevant in sorting among conflicting options, as well as signaling outcome-relevant information. This topic is broadly relevant to cognitive neuroscience as a discipline, as it generally comprises several aspects of cognition and may involve numerous brain regions depending on the situation. The review concludes with a summary of how these regions may interact in deciding and possible future research directions for the field. q 2002 Elsevier Science Ltd. All rights reserved. Keywords: Orbitofrontal cortex; Dorsolateral prefrontal cortex; Decision making; Reward processing; Reversal learning; Gambling tasks; Binary choice; Frontal lobes; Anterior cingulate Contents 1. Introduction The prefrontal cortex Regions of the OFC DLPFC and surrounding regions The frontopolar and anterior cingulate cortices Critical connecting structures The OFC: reward, emotion, and environmental adaptiveness Decision deficits in patients with OFC damage Reward processing in the OFC Processing regions for reward in non-human primates Reward processing in humans OFC involvement in sensory reward processing Processing abstract rewards Dopaminergic systems and reward processing Deficits in decision making tasks following OFC damage OFC involvement in binary choice tasks OFC involvement in risk and impulsivity Risk and impulsivity in verbal and picture tasks Gambling tasks and the somatic marker hypothesis * Tel.: þ ; fax: þ address: krawczyk@ucla.edu (D.C. Krawczyk) /02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved. PII: S (02)

2 632 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) Evaluating the somatic marker hypothesis Further evidence for OFC involvement in decision making OFC involvement in decisions with known probabilities OFC involvement in maintaining and adjusting to reward history Summary of the OFC in decision making DLPFC: reasoning, comparing, and evaluating Decision processing in DLPFC DLPFC lateralization in processing similarity DLPFC and relational processing relevant to decision making Contributions of the AC to deciding Summary Integration Future directions Acknowledgements References Introduction Decision making is required for behaviors ranging from simple movements to the complex consideration of multiple alternatives and reasoning about distant future consequences. The topic has long been studied in a variety of separate disciplines with an equally broad range of techniques, ranging from investigations of the neuronal correlates of binary choice in non-human primates to complex analyses of group decisions in applied settings. This breadth has resulted in a large gap so that research into the neural basis of decision making has often been limited to the simplest of decision processes and has remained largely disconnected from applications to complex human judgments, while high level decision research has remained heavily descriptive with theories of human decision making rarely making solid connections to neurophysiological underpinnings. Through recent efforts reviewed here, this state of decision research is beginning to change. Investigations over the last decade have begun to view decision making from the perspective of cognitive neuroscience and are closing this longstanding gap between the ends of the decision research spectrum. This review describes studies that have managed to move toward a greater understanding of the neural systems contributing to decision making, while also capturing some of the cognitive complexity and relevance to deciding in everyday life that had previously been strictly the domain of purely descriptive decision research. Viewing complex human decision making in terms of the neural processing that underlies its potentially numerous subprocesses may be a critical next step in the effort to understand human decision making and most critically the mechanisms behind why people decide in the ways they do. This unified approach has the potential to move theories of human decision making towards incorporating the effects that neural system interactions have on reasoning and deciding. This unification may not only better inform theorists about the substrates of traditional findings in decision research, but also lead to integrating normal decision making with the disordered decision processes observed in a variety of patients with brain damage, individuals with mental illnesses, and drug abusers, leading to better characterizations of the behavioral deficits found in disordered populations. From the neural perspective, this paper will argue that the prefrontal cortex is a key brain region in many aspects human decision making. Evidence for this claim includes an extensive neurological history of disordered decision making in patients who have sustained frontal lesions dating back to the now famous case of Phineas Gage. Additionally, many recent neuroimaging studies have investigated decision relevant subprocessing, finding prominent prefrontal activity regularly across a number of studies including those investigating abstract reward processing, guessing, planning, inductive reasoning, and manipulating complex information in working memory. In addition to the prominent role of the prefrontal cortex in deciding, it is further argued that this region may be fractionated according to both separable subprocesses relevant to deciding and the neural connectivity of separable prefrontal regions to other brain areas. This fractionation is not to be taken as an indication that there are autonomous subdivisions of the frontal lobes that carry out functions isolated from the rest of the brain, but rather that different areas of the prefrontal cortex appear to be engaged in separable multi-component neural systems involved in separable cognitive processes. As noted by Fuster [1], the frontal lobes should not be considered to be autonomous in carrying out cognitive processes, but rather they interact with many other brain areas. The goal of this paper is to describe recent advances made in the investigation of neural decision making and present a picture of the neural processing in prefrontal regions that is relevant to complex human decision making. While the scientific study of decision making in the brain is relatively new, several intriguing areas of research have produced results that reveal many clues to its neural architecture.

3 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) Fig. 1. Map of the ventral surface of the human frontal lobe based on cortical maps from Brodmann (1909). Anatomically, there is evidence that different frontal regions contribute uniquely to different decision subprocesses. The orbitofrontal cortex (OFC) appears to be relevant in situations involving incentive gain [3 6], best-guess estimations [7,8], and the emotional experience associated with gains and losses. Studies of the OFC in non-human primates, humans with brain injury, and neuroimaging studies indicate that the region is heavily involved in processing many types of rewards and making rapid changes in behavior to accommodate environmental changes [2]. These abilities implicate the OFC in responding to outcomes in the environment, and adjusting behavior to fit different situations. The dorsolateral prefrontal cortex (DLPFC) tends to be most involved in manipulating decision relevant information on-line, and in conscious deliberation during decisions. Extensive research has implicated DLPFC in working memory [11 13], which is a cognitive requirement for maintaining decision goals, considering options, and integrating the two to predict future outcomes and probabilities of meeting goals. There is also evidence that the DLPFC is involved in deciding under uncertain circumstances that have no objectively correct answer [14 17]. Other important frontal areas include the anterior cingulate (AC), involved in conflict processing [18,19] and outcome relevant processing [66,122] and the frontopolar cortex, which has been implicated in rule-based deciding [123], and self-generated information [124]. 2. The prefrontal cortex Recent analyses of the cytoarchitecture and connectivity of prefrontal areas have provided detailed descriptions of several of the prefrontal systems that appear to be important in processing decision-relevant information. This anatomical overview will serve as a reference point for the remainder of this paper and will be particularly relevant to the discussions of findings from neuroimaging. The content of this section is mostly restricted to prefrontal regions; however, some discussion of other brain areas is necessary, as several of the functional properties of the prefrontal cortex must be understood in terms of the projections to and from its subregions. The frontal lobes are a substantial and easily identified area in the human brain. There is evidence that these lobes have reached their maximal proportional size in humans compared to other organisms [20], thus allowing for a greater complexity of intellectual abilities. The frontal lobes are clearly demarcated by the central sulcus posteriorly (separating them from the parietal lobe), the sylvian fissure inferiorly (separating them from the temporal lobes), and the collosomarginal sulcus caudally (separating cingulate cortex from the corpus collosum) [21]. Within the frontal lobes, three main subdivisions have been identified: the motor cortex (most of the precentral gyrus positioned anterior to the central sulcus and posterior to the premotor sulcus), the premotor cortex (the remaining area of the precentral gyrus, the posterior third of the superior and middle frontal gyri, and the pars opercularis of the inferior frontal gyri), and the prefrontal region (the remaining areas of the frontal lobes) [21]. Further subdivisions have been made based on cell characteristics. These differences were found in both human investigations [22,23] and those of the macaque monkey [22,24 26]. The most notable differentiation within prefrontal cortex for the purposes of this paper is that between OFC and DLPFC, two areas that appear separable both regionally and functionally Regions of the OFC The OFC can be described as the part of the prefrontal region that is located on the roof of the orbit [35] and covers the ventral surface of the frontal lobes [36]. Cytoarchitecture and connectivity provide further differentiation. Fig. 1 shows a brain with Brodmann [22] areas indicated, as these are used in several of the later studies to refer to different portions of OFC. This region may be divided based on the cortical granularity. The rostral areas of OFC closest to Brodmann s area (BA) 10 anteriorly (Fig. 1) is distinctly six layered and granular, with a well defined layer IV [37]. Moving in a caudal direction the cortex becomes dysgranular and finally agranular toward the end anterior to the midbrain, with area IV gradually becoming less distinct [35]. The term ventromedial prefrontal cortex has also been in wide use for many years. While some have maintained that orbitofrontal and ventromedial areas are essentially the same, others have made fine distinctions between these areas [2,40,41]. It is worth clarifying the way these areas will be described in this review, as this issue is important in the debate over the functions of these ventral frontal areas in making decisions. While the term orbitofrontal applies to the majority of the underside of the prefrontal cortex, the ventromedial may be designated as the innermost medial areas of the ventral frontal

4 634 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) Fig. 2. Sample maps of cortical architecture using Brodmann numbers. (A) Lateral view of left hemisphere. B. Medial view of right hemisphere. (Adapted from Brodmann [22].) lobes. This is a useful distinction, as many neuroimaging studies (see Ref. [42] forareview)havefoundrecent evidence that the functions of ventromedial prefrontal cortex may be separable from those of ventrolateral prefrontal cortex (outer regions of the OFC) DLPFC and surrounding regions The DLPFC generally occupies the upper and side regions of the frontal lobes. It is comprised of BA 9 and 46 (Fig. 2). Area 9 occupies the dorsal region of lateral

5 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) prefrontal cortex and extends medially to the paracingulate of humans and the cingulate of monkeys [37]. Area 46 is generally located at the anterior end of the middle frontal sulcus. These regions are generally analogous in both humans and monkeys; however, there are slight differences in their boundaries among primates [37]. Further differentiation between these Brodmann areas is based on granularity; with area 9 becoming dysgranular with a poorly developed layer IV dorsally, while area 46 is granular with a well developed layer IV The frontopolar and anterior cingulate cortices The frontopolar prefrontal cortex (FPPFC), BA 10, is a region positioned above the OFC, inferior to area 9, and anterior to area 46 is a junction point between the OFC and DLPFC (Fig. 2). This area appears to act as a boundary between orbitofrontal and dorsolateral regions; however, it is unclear whether it has some unitary functions, or whether it is a heterogeneous cortical area that is comprised of extensions of some parts of these two frontal areas. Another is the AC, which is located medially, visible in a saggital view and overlying the corpus collossum. Finally, the ventrolateral prefrontal cortex occupies BA 11 and is positioned behind the FPPFC Critical connecting structures It is also important to outline the anatomy of the basal ganglia and the amygdala, two additional areas that seem particularly relevant to decision making when rewarding incentives are involved. These areas are closely related to prefrontal regions through connectivity and common function. The basal ganglia are comprised of components that are generally concerned with the control and execution of movement, as well as implicit memory [32] and motor learning. This area is comprised of the globus pallidus, the subthalamic nucleus, and the substantia nigra. These structures contain numerous interconnections and are highly connected with prefrontal regions. Inputs from prefrontal and other regions of cortex initially reach the striatum, which is comprised of the caudate and putamen. These subregions project to the internal and external segments of the globus pallidus, which send fibers to the midbrain tegmentum, thalamus, and substantia nigra. Some of these thalamic inputs are relayed back to prefrontal regions completing a thalamo-cortical loop [33]. Connections from the substantia nigra project back to areas of the striatum and globus pallidus. Five frontal subcortical circuits have been identified, all of which involve the prefrontal cortex and basal ganglia circuitry [33]. Three of these circuits are critically involved in emotional processing, motivation, and higher cognition; thus they appear strongly relevant to high-level decisions. An orbitofrontal subcoritcal circuit is involved in behavioral control, including selection of appropriate social behavior, which may be disrupted if this circuit is damaged. A dorsolateral prefrontal subcortical circuit is responsible for mediating executive functions, which include recall, setshifting, abstraction, and response inhibition. Both of these circuits connect their respective prefrontal regions to areas of the caudate, globus pallidus, substantia nigra, and thalamus. The third circuit of interest is the medial frontal subcortical circuit, which connects the anterior cingulate to the nucleus accumbens and DLPFC. This circuit is involved in regulating motivation and maintaining activity [33]. The amygdala is located subcortically at the anterior end of the temporal lobe. It is densely connected, receiving highly processed visual and auditory information [34] and is involved in the orbitofrontal subcortical and the medial subcortical circuits [33]. The amygdala also has direct projections to the frontal lobes, which relay limbic inputs to these regions. 3. The OFC: reward, emotion, and environmental adaptiveness The OFC and ventromedial prefrontal regions may be viewed as an integration center for emotional content from other areas of the limbic system. They are involved in processing the reward value of environmental stimuli, a function central to decision making, as it may underlie the affective tinting that accompanies decision attributes, as well as the gut feelings that have long been discussed in association with the act of making difficult decisions. Additionally, this area looks to be involved in adapting to rapid changes in reward contingencies and suppressing responses to stimuli that are no longer rewarding. These activities appear critical in deciding under time pressure and accommodating alterations in options. Another general property of the OFC is inhibiting motor responses, another aspect of this area s prominent role in adjusting behavior in accord with environmental contingency changes. Regions of the OFC are densely connected with many regions including the basal ganglia, amygdala, and other prefrontal areas. Both location and connectivity allow these areas to receive perceptual and emotional information, code such information for reward value, and serve as an interface between affective information and the symbolic processing associated with the DLPFC and ventrolateral PFC. These features place the OFC and its connected circuit components in a central position to contribute to the motivational and affective aspects of decision making and perhaps more broadly to mediate the interface between emotion and cognition Decision deficits in patients with OFC damage Patients who have sustained prefrontal damage often

6 636 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) show compelling reasons why the frontal lobes should be considered to be a critical region for deciding effectively. Most cases reviewed in this section include OFC lesions. While lesions to the DLPFC also disrupt cognitive functions important for decision making, accounts of OFC patients most dramatically demonstrate the importance of the frontal lobes in deciding. Such patients often show an intact knowledge of correct actions coupled with choice behavior that violates their knowledge in their day-to-day lives. This striking feature of their profile has inspired much of the experimental work reviewed later in the paper. These cases are representative of many current views about the functions of the frontal lobes as determined by neuropsychological studies. Eslinger and Damasio [44] presented a classic description of a patient with orbitofrontal damage, and the subsequent changes in decision making after the damage. The patient, E.V.R., had a bilateral orbitofrontal meningioma removed leaving orbitofrontal cortical damage. Comparisons of his behavior before and after this incident demonstrate the profound disability that is incurred with such damage and highlights the selective nature of the deficit caused by this type of lesion. Importantly, E.V.R. s behavior counters traditional views of frontal syndromes, which maintain that such damage will impair intellectual faculties revealed by the standard neurological frontal test batteries. E.V.R. had been a successful student, accountant, and husband prior to the surgery; however, he changed dramatically after surgery. He was described as having been a role model to his siblings and had received consistent promotions at work as a comptroller. After the surgery he began to have great difficulties holding a job and was repeatedly fired from jobs due to tardiness and general disorganization. His marital life deteriorated and he went through two divorces. He developed idiosyncratic behaviors such as a refusal to dispose of broken appliances, out of date newspapers, and food containers. Other abnormalities included excessive time spent preparing for work and attending to personal hygiene. He also showed evidence of profoundly impaired decision making. Very soon after the surgery he entered into an unwise business partnership and had to declare bankruptcy. He also took extreme amounts of time to make decisions of minor importance such as choosing a restaurant, or deliberating for hours about small purchases. The authors characterized E.V.R. as taking far too long deliberating; thus we do not see evidence of impulsive or excessive risk taking in his case, another observation that counters many traditional views of decision difficulty in frontal-damaged patients. Importantly, E.V.R. had largely intact knowledge and normal problem solving abilities on laboratory tasks. Intelligence tests revealed that he was well within the normal range. He was also able to reason and decide normally on problems that presented social or ethical dilemmas [45], but despite these abilities, a prominent feature of the disorder was his inability to carry this intact knowledge into action in his day-to-day activities. This dissociation of inappropriate behavior from intact knowledge is also seen in adults with acquired sociopathy due to frontal lobe injury. In these cases frontal lobe damage results in impaired social behavior despite adequate performance on social and moral judgment scales [46]. In a further study of patient E.V.R., Saver et al. [45] suggested that differences between his intact laboratory test performance on social knowledge tasks and the disordered situations in his actual life may be due to the fact in the laboratory that he did not need to decide among the options that he had generated. Interestingly, when pressured to make a choice of action in a laboratory moral reasoning task, E.V.R. was unable to do so effectively. This study indicates that E.V.R. s disorder is largely limited to instances requiring a decision. Other case studies involving frontal lobe dementia patients indicate similar problems consistent with OFC cortical loss. Case studies of several elderly frontal lobe dementia patients indicate that they have difficulties living independently, but may refuse to accept other living arrangements that would improve their situation [47]. Patients needing medications for other health problems chose not to take the medications despite awareness of their symptoms. Such descriptions provide additional evidence of the dissociation of knowledge of appropriate conduct from its real-world implementation. Social behavior deficits may also follow OFC damage. In a report from Rolls et al. [48] one patient had plotted to kill the driver of a car that hit him and had attempted to enlist the help of the police in carrying out this plan. Another patient threatened people around him with karate kicks. Caregiver s ratings of the patient s social inappropriateness were correlated with reversal learning deficits in these patients, suggesting an association between these two deficits. Frontal patients problems often manifest themselves in financial decision making. In a laboratory study, Goel et al. [49] addressed the financial planning deficits of patients with prefrontal damage. These patients were asked to generate a long-term financial plan allowing for buying a house, pay for children s education, and retiring comfortably. Each of these events was to be accomplished during specified points in life. Verbal protocols were taken while the subjects decided what should be done with the finances. The task situation was poorly defined, requiring subjects to spend time structuring the problem before generating solutions. Results showed that patients spent longer on the structuring phase and less time generating solutions than controls. This time allocation was probably not due to the patients fatiguing or running out of time, as they tended to finish the task quickly. The authors concluded that a judgment deficit existed in which the patients generally believed that they had provided acceptable solutions, despite using less solution time and generating fewer viable solutions. Another important aspect of this study that may be

7 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) particularly relevant to orbitofrontal-damaged patients is the fact that the frontal-damaged group tended to spend decreasing amounts of time working on the long term future goals. This behavior is consistent with results that suggest that such patients have deficits in foreseeing future long-term consequences [40]. A limitation of the patients of Goel et al. [49] is that many had both dorsolateral and orbitofrontal damage, making it difficult to get a pure sense of how the ventral and medial regions of the frontal lobes operate in the performance of the task. Regardless, much of patients behavior demonstrated a laboratory equivalent of the patients inability to successfully financially plan and allocate resources wisely for future use and indicates that problems may lie in excessive planning without action, much like the characterization of other frontal patients. 4. Reward processing in the OFC Research into the way humans make decisions has often focused on comparisons of risky and conservative behavior [50]. Such work inherently incorporates gains and losses, or rewards and punishments. Many important domains of decision research, including the study of risk taking behavior, the use of mental heuristics, and the framing effect have included precise manipulations of the degrees of potential rewards and punishments; thus reward and punishment have been central in characterizing human decision making. An understanding of how rewards and punishments are processed in the brain is critical in attempting to understand the neural processing associated with human decision making. While many studies have demonstrated impressive differential effects in people s reasoning about choices based on various changes in reward and punishment contingencies, the field of decision research has had difficulty addressing the question of why these effects occur. Perhaps an integration of the findings from neuroscience that involve reward processing will help to elucidate the underpinnings of the dramatic decision biases to which people are prone. This section reviews decision relevant findings in the neuroscience of human reward processing. An important question is whether the physical reception of reward is truly comparable to the attempt to make gains and avoid losses. Recent work [3,4,51] provides an indication that perceived attempts to gain reward do involve the same areas related to processing primary reinforcers. These results suggest that the attempts to maximize gains and avoid losses in making decisions may have similarities at the neural level to the phenomenon of attaining a physical reward Processing regions for reward in non-human primates Attempting to gain rewards and avoid punishments is critical in shaping decisions made though nearly all levels of complexity. Even making minor choices that have little future impact are affected by the desire to at least break even in terms of gain and loss. A brief overview of primate work that has investigated reward processing regions, including the OFC, highlights many of the decision related processing of these areas. This section will broadly review some lesion and cell recording studies investigating reward processing in monkey prefrontal cortex. While the focus is on the pure neural processing of reward, this content is highly related to many of the issues that appear later in this review that deal with the processing of emotional valence in human decision making. Investigators within this research area have made note of the importance of these studies for human decision making and goal-directed action [52,53]. Cell recording and ablation studies have been valuable methods for understanding the functions of the prefrontal cortex. Results of OFC studies indicate their involvement in motivational behavior, affect, and reward processing [34,35, 54]. Monkeys have served as subjects for much of the work as they appear to have prefrontal cortices that are similar to those of humans. These studies provide superior localization to that of many human studies and the monkey results are likely to overlap with similar cortical anatomy found in humans. Several of the patient and neuroimaging studies to be reviewed later show that lesions and imaging activations associated with more complex decision tasks involve similar cortical areas to those identified as relevant for reward processing and learning binary choice tasks in monkey OFC studies. The OFC responds to a range of rewarding stimuli, suggesting that it is a key region involved in the neural processing of reward in general. It is particularly relevant in making rapid adjustments in behavior to accommodate environmental changes. Following OFC damage, animals have been shown to have difficulties with reward related tasks for primary reinforcers. In these tasks a visual representation is linked with a particular reward and learning to associate the two is critical to success. The behavioral consequences of this association are profound when one considers the fact it may be a foundation for much of the complex behavior and motivation of humans. OFC studies in monkeys have demonstrated that this region contains extensive area devoted to the processing of primary reinforcers in the domains of taste and olfaction [34]. Critically, the taste sensitive areas of the region, which comprise the secondary taste cortex, show neural responses when the animal is hungry, but not when it has been fed to satiety. In contrast, the primary taste cortex is not mediated by hunger. This indicates that the orbitofrontal secondary taste cortex may be associated more with processing the reward value of taste than with identifying the taste stimulus [2,34]. Areas in medial OFC contain neurons tuned for both taste and olfaction, suggesting that this may be an area that represents flavor [2]. Additionally, there are face selective neurons here, much like those found in the amygdala, that appear to respond differentially when presented with faces having different expressions. It has been suggested that

8 638 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) these neurons may be involved with representing the positive reward value of certain facial expressions [34], a possible indication that this more abstract form of reward processing overlaps with the processing of more basic sensory rewards. Neurophysiological studies of the macaque monkey OFC demonstrate additional evidence that this region plays an important role in processing reward information. Hikosaka et al. [54] performed a series of experiments in which they administered liquid and food rewards to monkeys after a cue and delay period. They recorded from OFC neurons both during the delay period and during the reward period and found two populations of reward related cells in this region; one that responded to the prereward delay and another that showed differential response to the reward itself. These results indicate that these two cell populations were involved in signaling the presence or absence of rewards, potentially allowing the computation of deviations from expected outcomes. OFC neurons were found to be more sensitive to the presence of reward than to the type of reward given (among three reward types). It is important to note that the delay related neurons responded only when the animal went on to consume the delivered reward, indicating that the level of satiation and motivation for the reward modulates the activity of these reward related neurons. Other work also suggests that reward motivation is present in the reward representations of OFC neurons, but that preference among rewards may also be critical in certain OFC cell populations [53]. The OFC has been shown to be critical in some types of learning, as damage to this region severely disrupts some associative tasks. This area is well suited to participate is associative learning, as it receives visual input, in addition to taste, olfactory, and somatosensory inputs, giving it the essential representations necessary to form stimulus-reward associations. OFC ablation leads to reversal learning deficits [55]. Specifically, the ablated animals perseverate in responding to a formerly rewarded stimulus that is no longer rewarded. Similarly, in a go/no-go task, requiring a decision to respond or to withhold a response, animals with OFC damage tend to respond on the inappropriate (no-go) trials [56]. The OFC is likely to be critical in making behavioral adjustments in response to reward reversals, as its activity may provide a basis for appropriate nonresponding to the no longer rewarded stimulus in intact animals. This property is exemplified in work by Dias et al. [57,58], in which performance of a reward reversal within a pair of stimuli was impaired for monkeys that had received OFC lesions. In addition, dissociations were found with DLPFC lesioned monkeys that were unable to properly focus selective attention, a finding that behaviorally separates these two PFC regions. In considering the unique nature of the OFC capacity to reverse reward association, it is useful to compare it with a similar response from the amygdala. Both structures are involved in aspects of emotional processing [34] and show neural responses to the processing of faces and facial expressions [34,59] and respond to reward and punishment situations [34,2]. Critically, both OFC and amygdala neurons are able to code reward associations and reversals; however, the orbitofrontal neurons appear to have greater plasticity in forming associations [34]. While amygdala neurons that are responsive to rewards tend to require many trials to reverse response after a reward change, OFC neurons appear to code reward reversals very rapidly [34]. These rapid reversals would confer a behavioral advantage to organisms capable of such responses, as this could allow for escape from dangerous or noxious stimuli and improved social abilities due to the learning flexibility that such responses allow. Such abilities may be particularly relevant in facial expression detection in primates, which is critical in social decisions. The OFC reward system can be further understood from investigations of its interactions with the amygdala in processing reward. A study by Baxter et al. [60] demonstrated the importance of such interactions in appropriate associative learning. The task was for the monkey to choose between two objects that were paired with different food rewards. One of the foods was then devalued, leading healthy monkeys to choose the object not associated with this particular food. After learning the associations, the monkeys received unilateral lesions to the amygdala or OFC. Following these lesions, both groups were still competent at choosing the object associated with the nondevalued reward. A second complementary lesion followed so that those monkeys with amygdala lesions received a contralateral orbitofrontal lesion, while those monkeys with orbitofrontal lesions received contralateral amygdala lesions. Following the second lesion, both groups of monkeys were unable to appropriately choose between the objects. This suggests that there are interactions between the amygdala and orbitofrontal cortex that are necessary for appropriate choices to be made. This finding is particularly relevant to much of the work on decisions in gambling tasks by humans with orbitofrontal and amygdala lesions [6,61], which will be covered later in this review Reward processing in humans The brain regions that contribute to the desire to gain incentives may be among some of the most influential in human decision making. Reward processing appears to rely heavily on intact orbital and medial regions of the prefrontal cortex and its connections to other limbic regions. Recent neuroimaging studies have investigated the activation related to receiving rewards in various contexts ranging from sensory to abstract reward representations. Having already discussed some functions of the OFC and amygdala in reward processing in animals, Section reviews evidence of further localization of reward related processing in humans and connects reward processing with human motivation and incentive seeking. Such efforts to understand

9 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) the localization of emotion and reward-based processing in this way reveal that dopaminergic reward circuits and particularly the OFC have subtle and important contributions to this critical component of decision making. There is also evidence that OFC subregions make separable contributions to reward processing OFC involvement in sensory reward processing An important issue in the interpretation of reward related neural evidence in human OFC is how primary reinforcers activate the area and its connected regions. In an fmri study of primary sensory rewards, Francis et al. [62] found separable activations for pleasant touch, taste, and olfaction. These investigators presented pleasant and neutral stimuli in each of these three domains. Neuroimaging results indicated that each of the sensory presentations caused separate regions of activity for pleasant presentations compared to neutral ones. Activations to pleasant touch were found primarily in the somatosensory cortex, as well as the medial and lateral OFC. Further analyses revealed that the orbitofrontal regions, both ipsilateral and contralateral to the area of stimulation, showed considerably more activation for pleasant touch than did the somatosensory cortex. Activations to pleasant taste was localized to bilateral areas of the insular cortex and an area of OFC thought to be the secondary taste cortex [2,34]. Similar OFC activation was also found by Berns et al. [7], after presenting pleasant liquid to subjects in an fmri study. Regions of the amygdala and cingulate gyrus were also active in taste reward. Significant activation for pleasant olfaction included activity in the medial nucleus of the right orbitofrontal cortex. Other regions including the insula and cingulate were also active in response to pleasant smell. Interpretations of these activation sites by Francis et al. [62] indicated that rewarding aspects of these stimuli are associated with separate regions of OFC. Pleasant touch is primarily localized to the right lateral and medial OFC, while taste reward value appears to activate a region slightly medial to the orbitofrontal touch area and left lateralized. The pleasant olfactory region of OFC was more lateral than either touch or taste and was centered in the right hemisphere. Importantly, these results show evidence that each type of sensory reward significantly activates the OFC, but that the areas of activity were asymmetric and did not overlap entirely, indicating that there was not a generalized OFC reward area for sensory stimuli, but rather sensory modality can influence reward activation. Refer to Table 1 for major activation locations to these reward stimuli Processing abstract rewards The locations of brain activity associated with abstract rewards provide evidence that is especially relevant to interpreting the results of decision making studies that involve attempts to gain monetary rewards. In addition to money, abstract rewards such as favorable verbal feedback and social approval are important incentives that are sought after when making decisions. Recent efforts in neuroimaging have discovered key areas involved in the processing of monetary gains and losses. These heavily involve the OFC and associated brain regions thought to play a role in a generalized dopaminergic reward processing system with striatal connections. Evidence also implicates the AC and FPPFC in some aspects of financial decision tasks. Seeking gains and avoiding losses is an essential strategy in making decisions. The brain anatomy related to these basic processes was investigated by Elliott et al. [51] with fmri. Subjects had to select one of two playing cards as being correct and were then informed whether or not they had chosen correctly. A bar was present indicating the cumulative monetary value obtained (Fig. 3 for sample display) and was adjusted either up or down depending on whether the subject had chosen the correct card. Subjects had attempted to develop decision strategies based on card characteristics. The results indicated separate processing regions related to winning and losing. The most consistent activations related to winning monetary rewards were localized to the thalamus, striatum, and subgenual cingulate gyrus. Conversely, hippocampal activity was most associated with monetary loss following a decision. Further analyses revealed that these same areas tended to be most active during streaks of successive wins and losses, respectively. Additional regions, the OFC (Table 1), caudate, and insula, were active for both wins and losses, particularly during streaks of either wins or losses. Elliott et al. suggested that these activations may represent the emotional high associated with gambling, as activation in these areas were correlated with moments during the task that subjects reported to be the most exciting. The activity reported in the striatum, thalamus, and cingulate was interpreted as indicating activation of a basic reward system that would be adaptive in causing an organism to continue to behave in a way to assure attaining further reward, or in this case maintain a strategy that appears profitable. This study provides insight into which areas may be most relevant to processing decision outcome information when money is at stake. In a related study Zalla and colleagues [39] used fmri to investigate activation during wins and losses in a competitive response time task finding somewhat different activations. In this experiment subjects were prompted to make a button press response as quickly as they could. Subjects completed the task under the belief that they were competing against other opponents for the quickest response time and were given either feedback that they had either won or lost after their response or no feedback. Like Elliott et al. [51], these investigators found differing activity to wins and losses. In win trials, significant activation was found in the left amygdala, left inferior frontal gyrus (BA 44), left hippocampus, and right OFC (BA 47) (Table 1). In contrast, loss related activation was found primarily in the right amygdala. These amygdala activations are consistent

10 640 Table 1 OFC activation sites from neuroimaging studies of human reward processing. Locations given in Talairach coordinates [120] and Brodmann areas [22] where possible Study/method Task Description Orbitofrontal area x y z R/L BA Francis et al. [62]/fMRI Pleasant touch Velvet dowel touch on hand Data from 1 subject, others differed L R Pleasant taste Glucose solution Averaged R L Pleasant scent Vanilla odor Averaged R Elliott et al. [42]/fMRI Guessing for correct outcomes Guessing correct playing card for money Averaged during runs of gains and L 47 losses R 47 Zalla et al. (2000)/fMRI Competition for RT feedback Win or lose feedback to a button Averaged increases for win and decreases R 47 press response for losses Knutson et al. [4]/fMRI Monetary feedback for RT button press Dollar amounts gained or lost based Averaged for gains B 32 on button press responses to cues Averaged for losses B 32 Breiter et al. (2000)/fMRI Viewing a spinner showing monetary prospects and outcomes Wait for and view an outcome on a good, bad, or intermediate spinner O Dougherty et al. (2001)/fMRI Monetary reversal learning task Choose correct patterns to gain or lose money Averaged for good spinner prospects and outcomes Averaged for bad spinner prospects and outcomes R 11/ R 11/ R 11/ L 11/ L 11/47 Averaged for rewards B L B Averaged for punishments R Thut, et al. [65]/PET Go/no-go task Delayed go/no-go task for money Averaged blood flow increase for rewards L 47 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002)

11 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) Fig. 3. Card display used in neuroimaging study by Elliott et al. [51]. The cards are shown along with a reward bar that was adjusted to indicate gains and losses in the task. Reprinted with permission. Copyright 2000 by the Society for Neuroscience. with a study by Bechara et al. [63], in which patients with amygdala damage showed no autonomic arousal to reward and punishment information in a gambling task. In this case the amygdala activity was lateralized depending on the outcome. The results of Elliott et al. [51] and Zalla et al. [39] show a striking lack of overlap in gain and loss activation. Regarding activation for win trials, Elliott et al. found the striatum, thalamus, and subgenual cingulate to be active, whereas Zalla et al. reported activity in ventral frontal and medial temporal regions. The hippocampal difference between these two studies is particularly difficult to interpret. While Zalla et al. found left hippocampal activation for win trials, Elliott et al. found hippocampal regions active primarily in loss situations. The lack of amygdala findings by Elliott and colleagues is another clear difference. It may be that different neural systems or different parts of the same systems were activated for reward and punishment for the two different tasks. Despite the differences, these studies provide converging evidence for a role of the OFC, basal ganglia, and limbic cortex in tasks involving wins and losses (Table 1). The lateralized amygdala response found by Zalla et al. may be related to social pressure that may have accompanied the feeling of competing with another subject. In a related study Knutson et al. [4] provided some converging gain and loss related activity. This fmri experiment investigated the brain activations associated with the anticipation of monetary gains and losses. Subjects received a response cue at varying time intervals and could gain or lose money on certain trials based on a button press response to the cue. Results indicated that the activations associated with gains included the caudate and putamen, the mesial prefrontal cortex (BA 32), the left motor cortex, and the anterior insula. Loss activations included these same areas as well as the thalamus and anterior cingulate (Table 1). This study presents additional evidence of striatal (as reported by Zalla et al. [39]) and insula (as reported by Elliott et al. [51]) involvement for gains and losses. Most prominently the striatal activity may be related to the striatal dopamine system that thought to play a role in forming associations between environmental stimuli and rewards [7, 64]; this system has been shown to connect to frontal regions [3], highlighting a critical neural system involving the frontal lobes in decision making. A methodological limitation prevented imaging of the rostral forebrain, in this case which may have prevented the detection of OFC activity related to the task. The authors suggest that the midbrain activations may be associated with reward related dopaminergic activity similar to that found in studies with monkeys [64]. Breiter et al. [3] used fmri to investigate activations associated with expecting rewards and receiving reward outcomes. On each trial subjects were presented with a circular spinner that had different a monetary values (gain, loss, or zero) written in each wedge. An arrow on the spinner rotated and stopped at one of the positions. The indicated value was then added or subtracted from a running dollar total. Using this procedure, Breiter et al. could track activations associated with an expectancy phase prior to the spin, as well as an outcome phase after the subject became aware of the monetary consequences. Results indicated that the OFC and sublenticular amygdala, were involved in tracking the values in each spinner array. Additionally, amygdalar, hypothalamic, and nucleus accumbens activity increased monotonically along with monetary gain outcomes. There was little difference between activations of the expectancy phase compared to those of the outcome phase; however, there was a hemispheric trend toward right laterality related to gains and left laterality to losses. The authors noted that these activations appeared to overlap with activity related to sensory and drug related reward

12 642 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) processing and that they are indicative of a generalized reward processing circuit. These findings provide additional evidence for dopaminergic activity related to monetary gains and losses, as well as demonstrating a role for of the OFC in monitoring reward outcomes in association with abstract environmental stimuli (Table 1). Evidence of gain loss differences in OFC come from an fmri study of reversal learning by O Doherty et al. [43]. Subjects viewed fractal pattern stimuli that had monetary consequences depending on which of two patterns a subject selected. This allowed the investigators to assess activation related to the choice of a pattern in order to gain money. Trials involved both gains and losses dependent on the choices made. Results indicated that both lateral and medial OFC is involved in monetary gains and losses related to stimulus selection. Additionally, medial OFC was active following monetary gains, while lateral OFC was particularly active in response to monetary losses. Interestingly, the medial regions were depressed in activity following losses, while lateral regions were depressed following gains, thus revealing a dissociation between these OFC areas related to the nature of the monetary outcome and the authors claimed a privileged role of OFC in reward punishment situations over other active brain regions (Table 1). These results fit well with the hypothesis of Elliott et al. [51] that the medial orbitofrontal cortex plays a role in maintaining reward information, while the lateral orbitofrontal regions are involved in inhibiting responses to previous rewards. An investigation that addressed reward motivation in a delayed go/no-go decision task was conducted in humans using PET imaging [65]. In this experiment subjects were trained on several pairs of fractal visual stimuli that would later serve as go and no-go cues for the imaging task. Subjects were to respond with a button press to go visual patterns and withhold a response to no-go patterns. The experimenters manipulated reward motivation by including a condition that involved a reward of money for accurate performance and a second condition of simple feedback with the word OK appearing after correct trials. In each condition a running total of money or OK feedback was displayed at the bottom of the task screen for the duration of the trials. Image subtractions between these two conditions revealed several locations of significant activation for the monetary condition over the OK condition. These sites included the left prefrontal regions (Brodman s area 10 and 44) corresponding to the frontopolar and ventrolateral prefrontal cortex (Table 1); in addition the left lateral OFC, right occipital cortex, left thalamus, and left midbrain were active. The authors suggest that the activity in the prefrontal regions may indicate an abstract reward representation in this area, as these regions have been shown to be related to liquid reward processing in primate studies. This interpretation appears consistent with the sensory reward results of Francis et al. [62], as they had found orbitofrontal fmri activations in response to olfactory reward and medial OFC activations in response to touch rewards. Another possibility is that the prefrontal activity in this study was related in some way to the increase in motivation that is likely to have occurred in the monetary condition. The evidence provided in this study converges with that from neuropsychological work tying the OFC to financial decision making impairments seen in OFC patients. Overall it appears that reward-relevant imaging activation involves a diverse number of brain regions, but that there are relatively consistent similarities and differences between regions involved in gains and those involved in losses. Differences in imaging activation may be dependent on task related differences and perhaps on motivational aspects of behavior. Most of the studies report OFC, insula, and caudate activation in response to either financial gain or loss after decisions [51]. Results also indicate that the striatum is involved in monetary wins. Perhaps this striatal involvement includes dopamine release in response to monetary reward and behavioral success [65]. The role of the amygdala in financial wins and losses appears lateralized under certain conditions [39]; however, this region was not found to be active in the post-decision phase of the other study investigating wins and loss outcomes [51]. It is not readily clear why such a difference existed. Punishment through financial loss appears to be related to lateralized limbic activity in the amygdala and hippocampus. These findings may indicate a neural basis of negative emotional state following loss and is perhaps a neural correlate of postdecisional regret. The OFC emerges as being involved in abstract reward representation of both pleasant sensation and monetary gain. Evidence suggests that the medial orbitofrontal cortex is involved in monitoring and maintaining reward outcome information and gains, while lateral orbitofrontal cortex may to be more related to inhibiting response related information to previously rewarded stimuli, as well as loss processing Dopaminergic systems and reward processing The OFC has key interactions with the basal ganglia in reward related learning. These regions are involved in the striatal dopamine system, a neural circuit related to reward processing. This system includes projections connecting basal ganglia structures to the prefrontal cortex. These include the striatum, globis pallidus externa and substantia nigra, as well as the medial dorsal nucleus of the thalamus [33]. Recent studies have implicated these regions in processing gain and loss information, as well as affective components related to decision outcomes. This section briefly reviews a few key studies that indicate striatal dopaminergic involvement in decision making tasks. Evidence of basal ganglia activity during monetary gains was provided in a study that investigated striatal dopamine release during the performance of a video game [8]. Subjects in this study had to control a video game army tank. Successful performance was rewarded financially for each progress level achieved in the game. The

13 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) experimenters measured levels of extracellular dopamine during the task using a combination of PET and a labeled neurochemical binding substance. During task performance, scans indicated increases in the level of dopamine release in the ventral striatum. Task performance was correlated with the level of striatal dopamine release, providing neurochemical evidence of a striatal change related to affect and reward. Berns et al. [7] conducted an fmri study of sensory reward by administering pleasant tasting liquid to subjects during scanning. The predictability of the stimulus was varied, and greater medial OFC and nucleus accumbens activity increases were observed during runs of unpredictable taste rewards compared to predictable runs. The authors interpreted this finding to be an indication that dopaminergic reward systems are most active when environmental reward contingencies are uncertain, an interpretation consistent with an OFC role in providing signals relevant to making adaptive choices in a changing environment. Egelman et al. developed a computational model to address the role of dopamine in decision making [67]. In this study a bottom up model was constructed to simulate the effects of dopaminergic modulation on binary decisions. The model included a dopamine parameter that could exert influence on simulated cortical patterns. The model simulated human deliberation time results and human allocations between two choices on a task that involved fluctuating reward functions. In an accompanying behavioral study, subjects had to choose between two possible button presses and received feedback regarding rewards after each selection. Reward magnitudes were dependent on the selections made in previous trials, allowing for reward schedules to be altered. In a computational simulation with lowered dopamine levels, analogous to the deficit of a Parkinson s patient, simulations showed increased deliberation times, as one would expect to find in such patients. Such performance was considered to be consistent with human performance, as administering dopamine treatments to Parkinson s patients is a common way to ameliorate their symptoms. The lowered dopamine parameter was also suggested as a possible mechanism for the decision impairments present in orbitofrontal-damaged patients [61]. Egelman et al. suggested that the dopamine decrease would impair one s ability to make choices, while leaving knowledge structures intact. This interpretation could explain the dissociation often reported between knowledge level and inappropriate behavior in patients as described in an earlier section. Neuroimaging studies have also indicated that dopaminergic activity is important in decision processing. Elliott et al. [51], in their study of wins and losses in response to playing card choices (described in Section 4.2), found activations related to winning monetary reward were localized to the thalamus, striatum of the globus pallidus, and subgenual cingulate gyrus. These areas are all involved in dopaminergic projection systems, suggesting that dopamine may be critical in neural responses to rewards gained from successful decisions. Additionally, Elliott et al. [51] hypothesized that the ventral striatum, a key dopaminergic region, is particularly responsive to the repetitive accumulation of reward. This hypothesis maintains that striatal dopamine levels play a significant role in responses to abstract rewards, and indicates that the repeated involvement of this system in reward related tasks may explain many of the activations described in Section 4.2, as well as implicating a specific neurotransmitter that interacts with orbitofrontal cortical areas in decision making. 5. Deficits in decision making tasks following OFC damage Damage to the OFC has profound effects on human behavior, as described in the earlier section on patient deficits. Such damage may affect emotional states, social abilities, deciding, and reasoning. One of the core deficits of these patients is inability to appreciate and avoid possible negative future consequences of immediate actions. This has been referred to as a blindness to the future [9], which leads to an inability to avoid possible risks that may be incurred after deciding. Devastating results have been described in neurological accounts of the daily life situations of orbitofrontal patients, and recent laboratory studies with such patients indicate that it is possible to replicate such deficits and investigate specific aspects of their judgment difficulties. This section will begin with a review of some basic findings in human decision performance that are closely connected with the work on non-human primates. Those studies set the stage for a review of work that investigates specific decision deficits in OFC patients performing more complex decision tasks OFC involvement in binary choice tasks In considering the impact of OFC damage in human decision making, simpler two choice studies are a useful starting point. This work more closely resembles the nonhuman primate research and seeks to determine whether similar deficits exist in humans with OFC lesions. There is evidence that similar processing probably does occur in the decisions of many primate species, as the results of human lesion studies and electrophysiology show strong similarities to the reward and association reversal results found in animals. The deficits in learning and reward appreciation demonstrated by such studies may have broad implications for the complex behavioral problems of humans with OFC damage, as such an impairment appears to underlie many significant behavioral problems in everyday life. In a study strongly linked to the non-human primate work, Drewe [68] conducted a version of the go/no-go task in frontal patients. Studies with a variety of species had

14 644 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) indicated that damage to the OFC would cause the animal to behave erroneously on no-go trials by performing an action when they ought to withhold responding. Drewe found similar results with human subjects who had either unilateral frontal-damage or unilateral damage to nonfrontal regions of cortex. Frontal-damaged subjects longer to learn the appropriate responses to the two stimuli; they made more errors overall, and made more false positive errors (responding on the no-go trials). Critically, the frontal patients who demonstrated these task deficits were those that had either right or left medial prefrontal damage. Those subjects with dorsolateral lesions were unimpaired relative to the non-frontal brain damaged controls. This study provides evidence of an inability to withhold an action in the face of a stimulus that requires a lack of responding, as well as a dissociation in human prefrontal cortex. The results indicate a medial prefrontal role in preventing impulsivity in decision and action. Evidence of a similar type of impairment was demonstrated in a binary choice task with letter stimuli [10]. Subjects were patients who had either frontal or posterior cortical damage. For each trial a letter appeared briefly on a screen and the subject had to press one of two keys in response to the letter. The subject had practiced half of the letter button associations in an earlier training session and the others were unpracticed. During the task subjects had to press the associated keys in to both practiced and unpracticed letter key pairings. Results indicated that the frontal-damaged group was disproportionately impaired in their hit rate on the letters they had been trained with, demonstrating a difficulty in forming new associations to previously associated keys. This was taken as an indication that the novel decision process was impaired with frontal lobe damage. The authors noted that this effect was probably not due to working memory deficits, as the impaired patients had short term memory capacities that were equivalent to the posterior damaged group. The novel decision deficits reported by these authors may have been mediated by the same ventral cortical regions responsible for the deficits reported by Drewe [68], as the formation of correct associations by frontal patients was slower in both studies. The authors suggested that the performance impairment was probably due to a difficulty in creating new associations between the letter and key, which would be needed to guide the subject s behavior. Again, these results show evidence of an impairment in forming associations that lead to inappropriate behavior. Such a deficit might contribute to the excessive deliberation time in the decision making of orbitofrontal-damaged patients [44]. Rolls et al. [48] investigated learning, reward reversal, and extinction in a two-choice task, and found human analogs of the animal impairments discussed earlier. Subjects were patients with damage primarily to the ventral frontal lobes, a region that would include cortical areas similar to those damaged in monkeys with OFC lesions, as well as a separate patient group who had brain damage not involving the ventral frontal lobes. Subjects in the reversal learning task were instructed to try to gain as many points as possible during the trials and their point total was shown during the task. The task began with a learning phase in which subjects were presented with two fractal pattern images on a computer touch screen. One of the patterns was to be touched in order to gain one point. If the subject failed to touch this pattern and instead touched the other, they would lose a point. All patients were able to reach a criterion of correct responses in succession. At this point a reversal occurred, rendering the previously rewarded stimulus incorrect to touch, while the other pattern now yielded a point gain if it was touched. It was at this phase that the ventral frontal-damaged group showed a deficit. While the non-ventral patients quickly learned the new reward pattern and went on to successfully perform multiple reward reversals with few errors, the ventral-damaged subjects showed great difficulties learning the reversals and continued touching the previously rewarded stimulus for many trials after the contingencies had switched. In a second phase of the study, only the ventral damaged group was unable to achieve extinction of the touching under conditions in which a point could only be gained by not touching either pattern. These results bear considerable similarity to those obtained in reversal learning studies with OFC damaged non-human primates, indicating that similar processing occurs in this region. In a post-experiment interview patient introspections about their performance reveal a dissociation of knowledge and behavior. Patients were asked to describe what had happened in the task, what they had to do to gain points, and what the rewarded patterns had been. All subjects were able to accurately report what stimuli they should have touched, describe the reversal and what ought to have been touched, as well as how to gain points on the extinction phase. The ventral prefrontal patients comments during the task indicated that they knew what they had to do; however, they were unable to prevent themselves from acting inappropriately. For example, one subject in the extinction phase had announced that she would not touch the screen anymore and then began touching again a few trials later. This inability to behaviorally choose the correct action despite intact knowledge of the appropriate strategy appears to be one of the central underlying deficits in decision making of OFC patients. Importantly, Rolls and colleagues note that one of the two non-ventral patients had damage to the DLPFC. Despite this prefrontal damage, they performed like the other brain-damaged controls, demonstrating a dissociation of this region from the ventral portion of prefrontal cortex in humans, similar to those found in other primates [57,58]. This result in a relatively simple task suggests that such patients may be impulsive or impaired in making real-world choices that could have far-reaching negative impact. In each of the preceding studies, OFC patients showed response deficits; however, these deficits were manifested in

15 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) tasks that always involved a motor response. It might be argued that the OFC lesions simply cause inappropriate disinhibition of motor responses rather than a true decisional impairment. However, evidence from an electrophysiological study in epileptic patients indicates that OFC is critical in a decision phase, rather than motor output response. Ikeda et al. [69] recorded field potentials from OFC, mesial prefrontal, supplementary motor cortex, and primary motor cortex during a go/no-go task and during a separate movement task. In the go/no-go task, subjects received a tone followed by a short delay. After the delay they received a second tone, which was either high or low signaling a go or no-go response. The go response was to make either a hand or foot movement; the no-go response was to withhold such a movement. In a comparison motor task, subjects made similar hand or foot movements, without the go/no-go instruction. Results showed a slow transient potential (known as Bereitschaftspotential) in supplementary and primary motor areas, but not prefrontal areas, for the movement task. A similar transient potential was found preceding the go/no-go tone in both orbitofrontal and mesial prefrontal areas. An additional transient potential was found in the bilateral mesial prefrontal cortex at the time of the go/ no-go tone in both go and no-go trials. Ikeda et al. [69] concluded that this potential generated at the time of the go/ no-go tone was related to the cognitive decision task component regarding whether to execute or withhold a movement. These results indicate that the OFC is involved in the decision phase of such tasks, prior to the relay of a motor command, while it is the supplementary and primary motor areas that are responsible for the command to begin a movement. While the task demanded a seemingly simple decision in this example, OFC lesions may have important behavioral consequences in decision making and implementation at higher levels as well. These binary choice findings implicate the orbitofrontal cortex as being critically involved in learning associations between stimuli, as well as making decisions about whether to respond or withhold response in humans, as demonstrated in similar animal lesion studies. The deficits in decision at this finer level of precision may underlie some of the more complex behavioral differences seen in humans with orbitofrontal damage, as the inability to withhold response suggests the possibility of a neural basis for impulsive decision making. This possibility is further considered in Section OFC involvement in risk and impulsivity This section reviews work conducted with OFC damaged patients on laboratory tasks that are designed to test behavior that is generalizable to the complex decision making of everyday life. Several of these studies were controlled laboratory attempts to test the decision and risk taking processes that often appear disordered in the everyday lives of these patients. Many of the tasks involve decisions that result in either the addition or subtraction of points or money from a subject s running total. This feature of the experiments makes them relevant to the impairments found in the financial decision making of OFC damaged patients. These studies challenge the notion that OFC patients are risk-seeking in responding, suggesting that their impairments may stem from impulsivity instead Risk and impulsivity in verbal and picture tasks Early studies testing risk taking and impulsive decision making in orbitofrontal-damaged patients were conducted by Miller and Milner [70] and Miller [71] with frontal lobectomy patients. Both studies used a similar procedure in which subjects were shown word or picture clues successively and had to guess the correct answer to the word or object that the clues indicated. Correct guesses yielded point gains, while incorrect guesses resulted in point losses with subjects trying to gain as many points as possible. The points were allocated such that earlier guesses were worth the most if correct, but also resulted in the greatest losses if incorrect. This feature of the task insured that subjects who decide impulsively incur greater risk of being penalized for guessing based on the least information, thus risk taking and impulsivity were coupled in this response type. Subjects received three clues to determine the target word. These were presented either phonetically or semantically. Guesses after the first clue was revealed resulted in a gain, or loss of 50 points, while the second and third clue guesses were valued at 30 and 5 points, respectively. Results indicated that patients with frontal lobe excisions made more first clue guesses than patients with temporal lobe excisions and normal controls. Thus these patients gained fewer points overall and seemed inclined to take risks by choosing to guess early and for the most points. In a related study, Miller [71] used the three-clue procedure with visual materials with frontal and temporal excision patients. Clues in this experiment contained fragments of a target visual image that the subject was to name. If superimposed upon each other, the three clues contained a complete image of the target item. Subjects tried to guess the pictures accurately with or without point risks. Results indicated that frontal-damaged patients made more first clue guesses in the points condition than other subject groups, but did not show this pattern in the condition without points. Importantly, the first clue guessing strategy in the visual task tended to favor point gains, so such guessing was actually a somewhat successful strategy for performing this task in the points condition, but potentially risky. These studies indicated that frontal-damaged patients tend to take risks in order to gain points, regardless of whether such a strategy is profitable. The results are consistent with findings from the binary choice experiments that showed compulsive inappropriate responding by orbitofrontal-damaged patients. A frontal localization limitation of these studies [70,71] is that the damage was

16 646 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) not restricted to any one prefrontal area, though the findings are generally consistent with an OFC role in controlling decision impulsivity, as the majority of the patients with frontal lobectomies had sustained partial or complete excision of the orbitofrontal and medial regions of prefrontal cortex. In a follow-up study, Miller [72] further investigated frontal impulsivity and risk taking with a revised version of the earlier tasks [70,71]. The modified task allowed for a dissociation of risk taking, the intentional guessing on the high point clues, from impulsivity, the act of always guessing on the first clues given regardless of their number or point value. As before the task involved guessing target words and objects, this time based on four clues with successively lower point values (30, 20, 10, or 5 points, respectively). Incorrect guesses resulted in no point change, rather than losses as the previous studies had. In addition to the early clue to late clue decreasing points schedule, a second condition presented four clues initially, which were gradually taken away. Point values were reversed so that a guess after one clue was still worth the most, but now such a guess would occur at the end of the clue sequence rather than the beginning. If the frontal patients were genuinely risk-seeking, their performance on the increasing point clues schedule would show predominantly late guesses, as these would result in gains of the highest magnitude and least information to guess from. By contrast, an impulsive subject ought to make predominantly first clue guesses in both conditions. The investigator also measured patient s assessments of their ability on the tasks and the degree to which impulsivity and risk taking could be dissociated from motor disinhibition. Results indicated that frontal patients are impulsive in performing the task by making guesses after the earliest presentation of clues without regard for the point values or clue number associated with their guess. Additionally, the frontal group was only impulsive in the motor response condition of this task, contrary to the prior studies [70,71]. No patients showed a tendency to be riskseeking in their guessing in this modified study. Overall these studies reveal evidence of impulsive behavior in frontal-damaged patients. It is also difficult to make a solid conclusion about the location of the damage in prefrontal cortex, as some of the impulsive frontal patients had sparing of orbitofrontal regions, while others were fully ablated in this area. Similar to OFC damaged patients everyday life decision impairments, all subjects appeared to have adequate knowledge of their abilities on these tasks. Taken together frontal lobectomy patients seem to be risky largely due to cognitive and motor impulsivity, rather than an intent to seek out risk Gambling tasks and the somatic marker hypothesis An extensive line of studies began in the early 1990s by Damasio and colleagues investigating gambling decisions in patients with medial orbitofrontal damage. This series of studies, like those of Miller et al. [70,71], was targeted at demonstrating real-world decision making deficits of frontal patients in an laboratory setting. The patients had localized damage to a medial region of the ventral frontal lobes [9, 40]. The resulting experiments used a technique known as the gambling task. As in previous studies [48,70,71] the subject s goal was to maximize a number of reward points, or facsimile money in this case, while encountering ways of making large or small gains and being lightly or heavily penalized. Subjects could either take risks or play conservatively. These studies generally capture the realworld financial behavior of orbitofrontal-damaged patients, who characteristically make decisions that have disastrous financial implications [44,47]. The original version of the gambling task was a pure measure of the behavioral differences demonstrated by medial orbitofrontal patients compared to normal controls [61]. The task was intended to simulate real-world financial decision making in these patients by examining their performance during a card game in which the decisions made would determine their degree of financial success. Subjects were given a loan of facsimile money and told that they should try to maximize their profit total as they performed the task. Subjects selected one card at a time from a set of four decks and were stopped after making 100 selections. Two of the card decks were disadvantageous in the long run and two were advantageous. This was accomplished by a preset reward schedule in which disadvantageous decks paid a total of 100$ per selection; however, unpredictably interspersed within the decks were cards that paid the reward, but also required that subjects pay a penalty. The penalties in the disadvantageous decks were varied in terms of their frequency and magnitude, but ultimately selecting 10 cards from either of these decks, resulted in a net loss. Alternatively the advantageous decks paid only 50$ for each selection; however they included penalties that were lower in magnitude, resulting in a net gain over the course of 10 choices made from these decks. Thus choosing from disadvantageous decks was risky and unprofitable overall, while choosing the advantageous decks was conservative and profitable overall. Subjects could not calculate the precise frequencies of rewards and punishments, so they had to rely on developing a general sense of which decks were advantageous or disadvantageous over many trials. Results indicated that medial orbitofrontaldamaged patient s chose more from the disadvantageous decks, while control subjects chose more from the advantageous decks. Thus, medial orbitofrontal damage performed poorly when faced with immediate gains and sporadic losses. Other work suggested that the impairment was not due to misrepresentation of reward or punishment magnitudes, but was instead due to a lack of ability to accurately predict future outcomes [61]. In a subsequent study, physiological responses were measured by taking skin conductance measures related to appropriate and inappropriate decisions in the gambling task [73]. Subjects in this version performed the gambling task

17 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) while researchers recorded skin conductance responses (SCRs), a measure of autonomic arousal. Recordings were taken after the obtaining of rewards alone, rewards along with penalties, and prior to the selection of a card. Results indicated that both medial orbitofrontal patients and normal controls generated post-selection SCRs both to reward cards and to those indicating reward and penalty. Control subjects also began to show SCR activity prior to selecting from a disadvantageous deck as they became familiar with the outcomes, while medial OFC patients showed no such SCR activity at any time during the course of the experiment. This finding was interpreted as an evidence that a physiological marker, indicated by the anticipatory SCR, may serve a critical function in making decisions that involve risk. The authors raised the possibility that the medial OFC is critical in linking outcome knowledge to biological responses from the body, and in addition may relay biological signals regarding outcomes through other connected structures such as the amygdala and hippocampus, leading to an emotional reaction associated with certain decision options. A further investigation of the gambling task indicated that there is a typical timecourse for learning the appropriate strategies and that it is disrupted in medial OFC damaged patients [74]. Skin conductance measures were again recorded. During this administration of the task, subjects had to report their knowledge about the decks after the first 20 trials and every 10 trials after that. Typically subjects preferred cards from the disadvantageous decks for the first several trials prior to encountering a penalty. During this time, labeled the prepunishment phase, subjects showed no anticipatory SCR activity. After encountering penalties from the disadvantageous decks, the normal subjects began to show anticipatory SCRs, while the patients did not. At the time of the first questioning, 20 trials into the task, no subject knew what the appropriate decision strategy was. This period was labeled prehunch. Half-way through the task, normal subjects verbalized a hunch that the disadvantageous decks were riskier than the others and continued to show anticipatory SCR activity when considering a choice from these decks. In contrast, the patient group did not express a hunch at this time and failed to show anticipatory SCRs. This period of the task was labeled the hunch period. Just over three quarters of the way through the task, most of the normal controls were able to report why the disadvantageous decks were poor choices, while the advantageous decks were sensible choices; this period was labeled conceptual. All controls continued to show anticipatory SCR activity to the disadvantageous decks and continued to choose predominantly from the advantageous decks. Interestingly, even those control subjects who did not reach the conceptual phase continued to choose advantageously. Meanwhile half of the medial OFC patients reached the conceptual knowledge period and could accurately describe the advantages of profitable decks and the disadvantages of the risky ones; however, they continued to choose regularly from the disadvantageous decks, while showing no anticipatory SCRs. This study again demonstrated the dissociation of knowledge and behavior in OFC damaged patients, even indicating a double dissociation in some subjects. In addition to the gambling task, Damasio et al. [75] have tested the autonomic activation responses of medial OFC damaged patients. Subjects in the task viewed sets of socially relevant pictures while SCR s were recorded. Subjects were medial OFC damaged patients, non-orbitofrontal brain damaged controls, and normal controls. Subjects viewed target slides depicting nudes, mutilation scenes, and disasters, all intended to elicit SCRs, as well as neutral stimuli lacking social significance. In an active condition, subjects were to give a verbal description of the scene, or a subjective impression, while in a passive condition no responses were required. Results indicated abnormal SCRs from the medial OFC patients for the passive condition only. In the active condition these patients showed appropriate SCR activity, suggesting that there may be an insensitivity to social implications if pictures do not undergo a threshold degree of processing. In a later study [63] this hypothesis was suggested as being a possible basis for the slightly lower SCR activity of medial OFC patients compared to control subjects during gambling task performance. Interestingly, one of the verbal reports from a medial OFC patient indicated that the subject suspected that they should have had certain feelings toward some of the target slides; however those feelings were absent. In terms of the overt and covert forms of processing referred by Bechara et al. [74] the fact that the SCR activity was abnormal in the passive condition would correspond to the lack of a covert somatic state dependent on intact medial OFC, while the normal SCR present in the active condition could be due to the conscious processing necessary to respond verbally to the emotionally charged pictures. The Somatic Marker Hypothesis of Damasio and colleagues [9,81] was aimed specifically at explaining the behavior of patients who had sustained damage to their medial OFC and serves as an explanation of the results of the gambling task and variations upon it. Such patients include E.V.R., who had relatively intact intellectual capacities, yet displayed disastrous decision deficits. The term somatic refers to states of the organism, including diffuse neural activation patterns that occur when associations are learned between stimuli and outcomes. It is claimed that ventromedial regions of the prefrontal cortex reactivate these previously associated states of the body. There are two ways that the reinstatement may occur. One is via the body loop, a process wherein the original associated somatic signals from the body are activated, sending somatic state information to the somatosensory cortex. The other is via the as if body loop, a process in which the original somatic information is not reexperienced, but simply sent to the somatosensory cortex. These loops are claimed to operate either overtly or covertly and their

18 648 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) resulting somatosensory activations serve as markers that positively or negatively bias the options that evoked them. In terms of the proposed neural activity, the ventromedial prefrontal cortex stores the temporal associations formed in prior events, and sensory experience of a similar event causes reinstatement of the association in ventromedial prefrontal cortex. This area then activates somatic effectors in the amygdala, hypothalamus, and midbrain nuclei. These regions in turn may cause somatic changes in regions such as the vascular bed, viscera, and endocrine system [76]. The outcome of this process is that one or more potential options in a decision are marked, either overtly or covertly, in terms of their valence. The marking will serve as a bias towards or away from a given option; however, this bias does not eliminate cost-benefit analysis, presumably involving DLPFC. The end result is that possible decision options are affectively tagged, based on their potential outcomes, allowing for quicker and more efficient deliberation and resolution in deciding among options. In cases of ventromedial prefrontal damage, these affective biases would be eliminated, leaving the decision maker to ponder costs and benefits exclusively. Such an impairment could explain the excessive deliberation times evident in real-world decisions of patients. A second decision making process alluded to by Bechara et al. [74] is that of overt reasoning using explicit memory, and stands as an alternative to the bias of somatic markers. In this case reasoning using declarative memories of the consequences of the disadvantageous decks and making guesses about the probabilities of reward and penalty. Such overt processes would be demonstrated by reports from the conceptual knowledge period of the gambling task. Bechara et al. [74] noted that the somatic markers may serve as a valuable source of information and feedback during overt thinking processes, as the somatic activities occurred prior to conscious memory and reasoning. Evidence suggests that many of these overt processes may be mediated by the DLPFC [11,17,77] and are separable from the medial OFC contributions to the task [78]. Critically, this work suggests that intact medial OFC is essential for representing and relaying these signals to the higher processing regions. This could explain why patients were slower to reach the conceptual knowledge period and unable to decide advantageously even after gaining explicit knowledge of the deck characteristics Evaluating the somatic marker hypothesis The somatic marker hypothesis can explain many of the empirical findings described thus far in this paper. The series of experiments by Bechara and colleagues [61,63,73, 74] demonstrated that OFC damaged patients were impaired on a gambling task requiring decisions for rewards under uncertain conditions. Additionally, Damasio et al. [75] indicated that such patients failed to show normal autonomic arousal in response to pictures with emotional content. Moreover, in the work on binary choice decisions in frontal patients, a lack of somatic state associations would be consistent with their inability to learn contingency reversals as seen in the go/no-go study of Drewe [68]. In such cases a go response could be repeated after a reversal cue, due to a lack of somatic marking alerting the subject that this choice had become disadvantageous. When interpreting results in terms of somatic markers, caution must be exercised. One reason is that the localization within OFC is claimed to be fine grained, as ventromedial prefrontal regions specifically have been hypothesized as responsible for the somatic marker deficit. Specifically, Bechara et al. [79] have claimed that the key damage site is in a medial portion of the ventral frontal lobes, and that this does not include the other OFC regions. This hypothesis was based on Bechara and colleagues characterization of the patients from the Rolls et al. [48] study, as having motor disinhibition. Critically, these authors claim that the patients in the Rolls et al. study had damage to regions more lateral than their gambling task patients and that the patients investigated by Rolls et al. had additional OFC damage that was lacking in their patient group. Such regional specificity in the OFC would indicate that many ventral orbitofrontal patients would not have somatic marker deficit. Lesions from the other studies [70 72] were not assessed for ventromedial OFC damage specifically, so it is not clear whether such patients would fall into the group that would possibly have a somatic marker deficit. Another reason for caution regarding the interpretation of other OFC studies involving a somatic marker deficit is one of parsimony. As reversal learning deficits are common in animals and humans with OFC damage [48,55 58], implicating somatic marker activity may be overly elaborate in explaining the results. It may be that the lack of forming appropriate stimulus-response associations, an OFC function at a simpler level [2,48], without reinvoking somatic states, is sufficient to explain these reversal learning difficulties. Additionally, Damasio [9] claimed that the patients involved in the gambling task studies lacked deficits in association learning tasks. In a prominent criticism of the somatic marker hypothesis. Rolls [34,41] has argued that it is essentially a modified version of the James Lange theory of emotion, which claims that the emotion itself precedes the interpretation of its meaning. This proposition, that emotion precedes subjective feeling, has received extensive criticism over the last century. Rolls [34] defines emotions broadly as responses that occur as result of either rewards or punishments, noting that there are few exceptions to this general principle. The hypothesis that a bodily signal is sent to somatosensory cortex causing emotional biasing is incompatible with this definition. In the case of decision making, a reward punishment reaction theory of emotion, such as that of Rolls, would instead implicate the OFC and amygdala directly in the experience of emotion as a reaction to stimuli, and place these components in connection with the

19 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) basal ganglia for invoking a response. Such a theory is well supported by evidence that reward and punishment related processing are key functions of the OFC and amygdala [2, 34]. Additionally, the work of Koeppe et al. [8] and that of Elliott et al. [51] are compatible with a striatal dopaminergic role in reward response. The somatic marker hypothesis is also criticized as being inefficient [2]. Somatic markers would seem to require great amounts of interpretation by the brain in order to decipher potentially massive amounts of somatic input. It is not fully clear that a simpler association deficit in orbitofrontal cortex would not yield the same result as a lack of somatic markers might, while requiring many fewer inputs and providing greater parsimony of processing. Such an interpretation was recently proposed by Rolls [2] to account for the gambling task results of Bechara and colleagues. The hypothesis is that OFC damage impairs learning contingency reversals, as demonstrated previously [48]. In the case of the gambling tasks, choices from the bad decks that yield immediate high rewards, or immediate low punishments, would be the initial preference of the OFC patients and in subsequent trials these patients would be unable to alter this behavior due to the lack of association between the bad decks and long term punishments, just as the reversal learning patients could not alter their choices despite a change of reward contingency. This assessment would be countered by Bechara and colleagues claim that the patients of Rolls et al. [48] had orbital and lateral OFC damage not critical to the gambling task. Rolls and Bechara et al. disagree with regard to the impairment shown by Rolls and colleagues [48] patients. While Rolls et al. described the reversal learning deficit as potentially explanatory for a range of complex behavior impaired in OFC patients, Bechara et al. refer to these patients deficit as motor disinhibition [79]. The cell recording results of Ikeda et al. [69] would not support this claim; however, the term motor disinhibition may be too broad to disambiguate based on such specific results. One aspect of Rolls position that remains unclear is what the lack of anticipatory autonomic activity prior to bad deck selections indicates. As suggested by Rolls [34], further research might also be useful in determining whether patients with somatosensory cortical damage do indeed show deficits in the gambling task, thus testing the body loop and as if body loop aspects of the theory. This is certainly one of the few ways of truly testing the somatic marker hypothesis, as it has been described as having so many channels of input for bodily response information. A controversial point of the somatic marker hypothesis is that it maintains that there are numerous possible avenues for the brain to receive bodily feedback so there almost always appears to be a way to explain any result that seems contradictory by invoking another somatic transfer channel. A recent study [121] tested whether spinal cord injured subjects would show a deficit on the Bechara et al. gambling task [61] due to their reduced degree of peripheral feedback. These subjects performed the same on that task as normal controls. This result weakens the somatic marker hypothesis limiting it to utilizing bodily feedback from the cranial nerves and blood hormonal levels; however, even if these could be shown to play no part in ventromedial OFC associative learning, there would still be the as if body loop which is claimed to act covertly in the brain, essentially bypassing the bodily signal. 6. Further evidence for OFC involvement in decision making The medial OFC and amygdala are closely related but evidence suggests that they have separable functions in risky decisions. Bechara et al. [63] assessed the differential behavioral effects of OFC and amygdala damage using their gambling task [61]. The medial OFC patient results replicated previous studies [61,73,74], showing that such patients are unable to decide advantageously and fail to show differential skin conductance activity in anticipation of risky choices. The results of the amygdala-damaged patients were similar showing impaired decision making by choosing predominantly from the disadvantageous decks and failing to generate anticipatory SCRs to risky choices. The underlying processing deficits between OFC and amygdala damaged patients were probably not the same in this case, despite the close connection of these regions; both anatomically and functionally. The difference is indicated by additional research on SCRs that demonstrated that patients with amygdala damage failed to show normal SCRs to facsimile money, despite their normal SCRs in response to a loud tone, while medial OFC patients were able to show normal reaction SCRs to both facsimile money and tones. While the medial OFC patients will choose disadvantageously, probably due to an associative learning deficit of some type, the amygdala-damaged patient s decision deficit apparently involves a complete insensitivity to the typical emotional responses associated with gains and losses [63]. A related fmri study that dealt with the neural correlates of reactivity to decisions [80] indicated that BA10, the frontopolar prefrontal cortex, as well as OFC regions are especially relevant to sympathetic arousal responses. This study investigated activity related to sympathetic arousal and activity related to winning and losing points. The task was the same as that employed by Elliott et al. [51], in which subjects made a card choice and were allocated money on a bar (Fig. 3). Imaging results indicated that increase in sympathetic arousal, as measured by the SCR, were correlated with regional brain activity in areas including the right lateral OFC, the anterior insula, left lingual gyrus, right fusiform gyrus, and left cerebellum. Less stringent analyses revealed activity in bilateral areas of the medial OFC and the right inferior parietal lobule. The activity in both medial and lateral OFC provide converging evidence that the sympathetic arousal patterns detected by SCRs

20 650 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) involve this region. These results, like those of Bechara et al. [61], suggest a degree of regional specialization between lateral and medial areas. In this case the activity was more highly significant in the lateral OFC, a differentiation difficult to detect in patient lesion studies. Further analyses indicated that generation of the SCR is related to activity in the cerebellum, visual cortices, and left medial prefrontal cortex. Other activations likely to be related to the representation of the SCR were found in the right medial prefrontal cortex. Other evidence [76] supports these conclusions, as damage to a region medial to the right OFC appeared to disrupt the generation of SCRs in patients. The authors concluded that the SCR response appears to be localized to area 10, the frontopolar prefrontal cortex, and may include additional areas of medial OFC inaccessible to this imaging study due to artifacts. Additionally, they concluded that regions of medial prefrontal and OFC are probably a linking point for cognitive and emotional aspects of a decision task, a conclusion relevant to the somatic marker hypothesis discussed earlier. An additional study by Bechara et al. [79] employing the gambling task supports to the hypothesis that patients impairments in this task indicate a generalized inability to appropriately act in ways that will yield positive future consequences, rather than a specific loss or gain related deficit. Bechara et al. [79] sought to determine whether variations in the original gambling task [61] would affect the performance of patients with medial OFC damage. In a novel variant of the original task, the experimenters adjusted the card outcomes such that there were now two decks that yielded high immediate monetary losses, but higher monetary gains in the long term. Thus these decks were advantageous to choose from and would result in gaining money, despite the frequent and high losses. Meanwhile the other two decks were altered such that they resulted in small losses, but in the long term would yield small enough gains that they were disadvantageous overall, resulting in a net monetary loss over the long term. Results showed that normal control subjects chose overall from the advantageous decks, suffering the higher losses, but coming out ahead eventually based on the large gains. In contrast, patients with OFC damage tended to select from the disadvantageous decks, opting to receive the lesser immediate losses and ultimately losing money overall due to the excessively small payouts from those decks. This indicates that the patients decision impairments are not due to the specific magnitudes of reward and punishment present in the original gambling task. Attempts to correct for the disadvantageous behavior of medial orbitofrontal patients involved further modification of the gambling task. Bechara et al. [79] altered the long term progression of reward and punishment in both the original [61] version and the modified [79] version. These altered versions operated such that in the advantageous decks the difference between wins and losses increased in the positive direction, yielding higher overall gains if these decks were consistently selected. In contrast, the difference between win and loss values in the disadvantageous decks increased in the negative direction, resulting in even higher overall financial losses if these decks were consistently chosen from. These modifications were made to determine whether orbitofrontal-damaged patients could be influenced to choose advantageously if the two outcome progressions more strongly led them to favor the advantageous decks. Results of these new versions replicated the previous studies, in which normal controls choose from the advantageous decks, while orbitofrontal patients continued to choose from the disadvantageous decks. Additionally, the experimenters measured SCR activity during the modified versions, and such activity was equivalent to that of normal subjects under conditions of extreme gain and extreme loss. This finding suggests that these patients have no greater sensitivity to gains or losses than do normal subjects. The work of Bechara and colleagues [61,63,73,74] provide considerable support for the hypothesis that OFC patients have an inability to employ and profit from a conservative long term gain strategy. These patients continued to make choices that yielded immediate gains and long term losses even under conditions in which they were conceptually aware of the fact that choosing from the risky decks was not to their advantage. These results are similar to the earlier reversal learning findings of Rolls et al. [48], in which the disadvantageous behavior of OFC patients continued despite verbal statements of some patients that they had conceptual knowledge of the appropriate choice. Such findings generally indicate OFC involvement in making the connection between conceptual knowledge and carrying out the appropriate plan; however, the precise lesion sites may vary between the patients in these two studies [79]. Bechara et al. have also shown evidence for the influence of emotional connections in the OFC on deciding OFC involvement in decisions with known probabilities Recent studies have begun to show evidence of differential behavior following OFC damage even in gambling situations when probabilities are explicitly known. Rogers et al. [6] tested several classifications of subjects, including OFC patients on a decision making task in which rewards and probabilities were available to the subjects. OFC patients were compared to other prefrontal patients whose damage was restricted to the dorsolateral and dorsomedial regions, allowing these frontal areas to be dissociated. The task was presented on a computer with a touch screen showing 10 colored boxes and subjects were to locate a token hidden in one of the boxes. On each trial some proportion of the boxes were red and the others blue with subjects choosing which color box they felt contained the token. Points could be added to or subtracted from a running total, based on subject s decision performance (see Fig. 4 for an example screen from the experiment). Subjects were

21 D.C. Krawczyk / Neuroscience and Biobehavioral Reviews 26 (2002) Fig. 4. Example display from Rogers et al. [6]. The screen shows a ratio favoring red boxes (light gray in figure) with the choice red having been made below. The current bet value was included in the middle box, along with the current point total. Reprinted with permission (see Acknowledgements). then given an opportunity to place a point bet on their choice. A succession of five possible bets was shown to the subjects and during each time window the subject was able to select the bet by touching a bet box on the screen. The bet presentation order allowed the experimenters to assess risk taking and impulsivity, as had been done previously by Miller [72]. Following each bet, the subject was informed whether they had won or lost and the value of the bet was either added to or subtracted from the subject s point total from the beginning of the trial. The OFC patients took longer to decide on color of box and were more likely to choose the less probable of the two options than dorsolateral patients and controls. These patients acted conservatively, tending to place bets of lower value than the control groups. OFC patients that completed the task multiple times improved by choosing the more likely of the two colors more often, suggesting that such patients are particularly impaired when they must decide under novel conditions, a finding congruent with those of Godefroy et al. [10] in their binary choice task. Rogers et al. [6] provided evidence that OFC damage leads to disadvantageous choices even under circumstances where the probabilities of success are explicitly available. This study demonstrated support for the conclusion of Miller [72] that frontal-damaged patients were not riskseeking when given the opportunity to place high bets on their choices and in fact appear to be more conservative in placing bets. Rogers et al. [6] failed to find impulsive responses by either the orbitofrontal or dorsolateral patient group, despite the fact that a motor response was required for the placing of bets. This result is surprising because Miller [72] had found evidence of impulsive responding in frontal lobectomized patients on a task requiring a motor response. These contradictory findings may indicate that impulsivity does not necessarily follow frontal damage. Other evidence from Rogers et al. [6] indicated that the decision making of drug abusers shows similarity to that of OFC patients. In addition to frontal patients, Rogers and colleagues had studied the effects of dopaminergic and serotonergic changes on decision performance. Chronic amphetamine abusers were tested, as such abuse is considered to lower the concentrations of dopamine in the striatum and levels of 5-hydroxytryptamine (5-HT) in the OFC. Results indicated that amphetamine abusers, like OFC patients, tended to deliberate longer and select the least probable color more often than controls. There were no differences in bet magnitudes chosen by any of the groups indicating that no group was overly impulsive, or inclined to risk exceptional point amounts on any given bet. Bechara and colleagues [82] have linked stages of decision making to dopaminergic and serotinergic functions. These authors associated the early, covert decision-bias phase of their gambling task with dopaminergic function, as a dopaminergic antagonist disrupted subjects making early advantageous choices, while serotonergic drug manipulations indicated a late, overt knowledge association, as subjects given a serotoneric agonist improved their choices in the late phase of the task. These results, along with those of Rogers et al. suggest that drug abusers may decide in similar ways to subjects with OFC damage. Other evidence rules out the involvement of frontostriatal circuitry in the decision deficits on the Rogers et al. [6] decision task. Watkins et al. [85] tested a patient group with Huntington s disease who were believed to have disruptions of the fronto-striatal circuits. These patients showed reduced decision latency; however, their choice of the higher probability box color was intact. This result may serve as an indication that the OFC specifically is critical in choosing the correct probability, and that connections to the basal ganglia may be less important in disrupting performance. The longer decision latency is consistent with the fact that these circuits appear to be involved in performing actions efficiently [11]. This result is consistent with claims by O Doherty et al. [43] that the OFC is critical in monetary gain and loss performance. A PET imaging study of this explicit gambling task [38] also indicated OFC involvement, along with the FPPFC and limbic association areas. The task was a variant of the two choice point reward task discussed previously [6]. Like the version run with patients (Fig. 4), subjects chose between red or blue boxes in order to gain points for finding a token located in one of the boxes. Unlike the patient version, this PET task included single predetermined bets that were associated with each color choice and set up so that varying proportions of six colored boxes were either red or blue. Subjects were told that each box had an equal probability of containing the token. Higher bet values was always linked to the less probable color, allowing for a tradeoff in which subjects could opt to choose conservatively by taking the