Research Article

Dissociable Components of Rule-Guided Behavior Depend on Distinct Medial and Prefrontal Regions

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Science  03 Jul 2009:
Vol. 325, Issue 5936, pp. 52-58
DOI: 10.1126/science.1172377

Abstract

Much of our behavior is guided by rules. Although human prefrontal cortex (PFC) and anterior cingulate cortex (ACC) are implicated in implementing rule-guided behavior, the crucial contributions made by different regions within these areas are not yet specified. In an attempt to bridge human neuropsychology and nonhuman primate neurophysiology, we report the effects of circumscribed lesions to macaque orbitofrontal cortex (OFC), principal sulcus (PS), superior dorsolateral PFC, ventrolateral PFC, or ACC sulcus, on separable cognitive components of a Wisconsin Card Sorting Test (WCST) analog. Only the PS lesions impaired maintenance of abstract rules in working memory; only the OFC lesions impaired rapid reward-based updating of representations of rule value; the ACC sulcus lesions impaired active reference to the value of recent choice-outcomes during rule-based decision-making.

Although there have been recent advances in our understanding of how and where rules are represented in prefrontal cortex (PFC), disparity has emerged between findings from neurophysiology, neuropsychology, and neuroimaging as to the importance of different PFC regions. To address these issues, it is important to make distinctions between different kinds of rule-guided behavior. For instance, some behaviors involve following simple cued rules (e.g., stopping at a red light) wherein the presence of a particular stimulus instructs a fixed behavioral response. Experimental investigations of this category of rule-based behavior often utilize conditional learning tasks, such as arbitrary visuo-motor or visuo-visual mapping where animals acquire and maintain behavioral rules of the form “if A, then B” (with A being an instruction cue and B being the instructed motor response, or stimulus, that should be chosen, respectively). Although single-unit recording studies in macaque monkeys have found that neurons in both the dorsolateral PFC (dlPFC) and ventrolateral PFC (vlPFC) can encode such arbitrary rules (13) (Fig. 1B), human neuroimaging studies have observed activity within the vlPFC associated with the performance of similar tasks (4), and macaque lesion studies have established that the ventral PFC [vlPFC and orbitofrontal cortex (OFC)] is far more important than the dorsal PFC for supporting this kind of rule-based behavior (58).

Fig. 1

Behavioral task, intended lesions, and overall lesion effects. (A) The basic features of the WCST are depicted in this panel: In each trial, a randomly selected sample is displayed alone on the center of the touch screen, and when the sample is touched, three additional choice items immediately appear (one matching in color, one matching in shape, and one not matching in either dimension, with their positions randomly chosen). If the animal’s choice is correct (i.e., the animal selects the choice item that matches according to the currently reinforced rule, which changes unannounced every time the animal attains 85% in 20 consecutive trials), then a reward pellet is delivered, and the correct choice remains on the screen for 1 s to provide visual feedback; if the animal makes an incorrect choice, then no reward is given, and the stimuli are removed and replaced by an error signal (white circle), which is presented on the screen for 1 s instead. (B) From left to right, the extent of the intended lesions of the PS, the ACCs, the OFC, the sdlPFC, and the vlPFC. (C) Group mean postoperative rule changes achieved per daily session, expressed as a percentage of the mean number of preoperative rule changes of each monkey, for each of the following groups: CON (n = 6), PS (n = 4), ACCs (n = 4), OFC (n = 3), sdlPFC (n = 3); error bars, SEM.

Humans and nonhuman primates are also capable of learning to follow abstract rules wherein a rule generalizes to all the possible exemplars (1, 911). For example, neurons throughout dlPFC, vlPFC, and OFC can encode, across a delay period, which of two different abstract rules (“matching” or “nonmatching” in this case) animals should apply to perform a task correctly at the end of the delay (12). Although there is no evidence of any quantitative differences in the proportions of such neurons in these different PFC regions of the macaque, when a human neuroimaging study adopted the same paradigm, activity associated with maintenance of specific rules across delays was observed in vlPFC but not elsewhere within the PFC (13). Another human neuroimaging study has similarly reported the involvement of only the inferior frontal gyral regions of the ventral PFC when rule-specific activation has to be maintained across a delay (14), and lesion studies in macaques have established that the ventral PFC regions, but not the dlPFC or anterior cingulate cortex (ACC), are necessary for acquisition of nonmatching rules (1517). Thus the question arises: What, if any, aspect of rule-guided behavior is the dlPFC necessary to support in its own right?

In the paradigms discussed above, an animal knows which abstract rule to apply either because the rule remains constant or because it is instructed by a cue presented at the start of each trial. However, there are many everyday circumstances where we have to decide for ourselves which behavioral rule is most appropriate to follow under the circumstances we find ourselves in (for example, in deciding whether it remains appropriate to behave “in the same way” as others in a social setting). The Wisconsin Card Sorting Test (WCST) (18) has been used extensively in the clinic because it is a relatively simple task to administer and has long been believed to have utility [which has now been verified (19)] in contributing to the diagnosis of patients who are likely to suffer from PFC dysfunction owing to brain disease or damage. In the WCST, subjects first have to discover by trial and error which abstract rule they should follow; then they have to retain that rule in working memory so that they may continue to apply it on subsequent trials. This has to be done up until the point where the subject determines that the rule is no longer valid because it no longer elicits positive feedback; after which point, the subject must determine which alternative rule has become reinforced, and so on. A recent study of ours confirmed that dlPFC neurons in the vicinity of the principal sulcus (PS) in Brodmann’s areas 46 and 9/46 of macaque PFC can maintain representations of uncued rules both within and between trials of a WCST analog (20). As in the human WCST, the rules are not cued at any time in our WCST analog either; rather, macaque monkeys receive “stay” or “switch” cues, by means of positive or negative feedback (Fig. 1A) after each choice, which they can use to determine whether they should either retain the current rule (stay) or change to the other rule (switch) in the next trial. In a recent human neuroimaging study in which participants were either directly told which rule to apply or alternatively were told to switch or stay with their previously chosen rule, greater additional activity was associated with the latter condition in the middle frontal gyrus, including area 46, part of dlPFC (21). Likewise, another study that compared free choice between rules with directly instructed rules, in the context of a working memory task, found greater delay activity in Brodmann’s area 46 in the free-choice condition (22), as has a study in which subjects were able to freely choose which action to perform, or which stimuli to select (23). Thus, we hypothesized that an important factor determining the necessary involvement of the dlPFC in rule-guided decision-making may be the way in which abstract rules are set up. To determine whether the dlPFC is necessary for implementing uncued abstract rules held in working memory, we investigated the effects of lesions to different regions of dlPFC on the WCST analog.

To engage in self-initiated rule-guided decision-making, one needs to be able to adjust behavior flexibly in light of positive or negative feedback. Although neurons throughout swathes of frontal cortex have been observed to have activities related to reward value (24), those in the OFC, in particular, are believed to be most closely implicated in representing the reward value of stimuli or outcomes (25, 26). It has recently been reported that neurons in the OFC might provide a relatively context-free value scale to facilitate comparison of the economic value to the animal of different “goods” (27, 28). Nevertheless, it is clear that OFC lesions do not simply render animals unmotivated by reward or insensitive to the value of reward, as even animals with OFC lesions will work as hard as normal animals to earn food reward and will avoid choosing food items that are in view and on which they have been fed to satiety (29). So what is the specific role played by the OFC? Previous lesion studies in macaques have established that OFC-lesioned animals are impaired on tasks in which animals have to learn about changing stimulus-reward value associations, such as reinforcer devaluation paradigms, wherein the value of the food stuff associated with one object in the pair is subsequently devalued by feeding to satiety (29), and reversal learning paradigms in which the value of food items remain the same but the stimulus-reward reinforcement contingencies are changed (17, 29, 30). Performance on tasks in which there is a consistent relation between stimulus choice and outcomes, such as discrimination learning, is unaffected by OFC lesions (5, 29). The role of the OFC also extends to learning about the changing value of instrumentally learned motor actions; OFC-lesioned animals are impaired in extinction after conditioning to variable interval schedules (30, 31). We included an OFC group in this study to test the hypothesis that the role of the OFC might also extend to learning about the value of rules as is required in the WCST analog, in which maintaining continued successful choices cannot be based either on reference to the reward value of recently chosen stimuli or recently chosen actions, because both the identity and the position of the rewarded stimulus are randomly determined from trial to trial. Like the OFC, the anterior cingulate sulcus cortex (ACCs) has also been implicated in reinforcement-guided decision-making, but in contrast to the OFC, it appears to be more important for making decisions on the basis of action values as opposed to stimulus values (3236). But it is not yet known if the role of the ACCs also extends to learning about the changing value of abstract rules, and so we also included an ACCs-lesioned group in our investigation into the effects of discrete medial frontal and prefrontal cortical lesions on performance of the WCST analog.

Macaque lesion studies. Fourteen macaque monkeys were trained to perform an analog of the human WCST on a touch screen (Fig. 1A) (37). The currently reinforced rule was not directly cued at any time in this WCST analog; rather, animals had to discover for themselves by trial and error which rule was currently reinforced, then they had to maintain performance according to that rule across a series of trials until they attained 85% correct choices in a consecutive series of 20 trials, at which point an unannounced rule change was implemented and the next block of trials, with the other rule now reinforced, commenced. Each daily session comprised 300 trials, and before surgery, the 14 macaques were able to achieve a mean of 10 rule shifts per session with a median preoperative block length (i.e., trials taken to attain criterion on a rule) of 24 trials. The mean preoperative distribution of response types for the first 20 trials after every rule change is shown in Fig. 2. Note that animals rarely selected the stimulus that did not match the sample in either dimension; on average only 2.1% of animals’ preoperative responses were of this type (which we called “nonperseverative” errors). Most of the animals’ errors in the task were “perseverative” errors (defined here as a choice of the nonreinforced rule), and these errors accounted for 91% of the total errors. The dominance of perseverative errors on the very first trial after each unannounced rule change (Fig. 2) confirms that the animals could not predict when the unannounced rule change would occur. Also, the first unexpected instance of an absent reward (i.e., at the end of the first trial after a rule change) was on average insufficient to inform animals that the rule had changed (Fig. 2). Rather, the animals took a few trials to shift their behavior over to that of matching predominantly by the other rule. This failure of animals to change their behavior immediately after failing to receive a reward, the lack of which unambiguously signifies a change in reinforcement schedule, has also been observed in other task-shifting paradigms used with macaques (33). We likewise interpret this as further evidence that, to foraging animals, single outcomes (both negative and positive) are simply pieces of evidence that must be weighed against the recent history of experienced reinforcement to reach a decision as to whether a current behavior (to apply a particular rule in this case) is still optimal.

Fig. 2

Preoperative distribution of response types after rule changes occurred. Proportions of the three types of response (perseverative errors, nonperseverative errors, and correct responses) that were made in each of the first 20 trials of each block in the WCST analog averaged across the performance of all animals in all preoperative sessions.

Experimental groups and general effects of PFC lesions on the WCST analog. On the basis of individuals’ preoperative scores, we divided the animals into three groups of matched abilities, one group (PS group, n = 4, mean preoperative rule shifts per session = 9.8) received bilateral lesions of the PS within the inferior dlPFC; another group (ACCs group, n = 4, mean preoperative rule shifts per session = 10.1) received bilateral lesions of the ACCs within the medial frontal cortex; and the other animals (CON group, n = 6, mean preoperative rule shifts per session = 10) remained unoperated controls. In the second stage of postoperative testing, the unoperated controls were divided into two matched-ability groups: One received bilateral lesions of the superior dlPFC (sdlPFC group, n = 3), whereas the other received bilateral lesions of the OFC (OFC group, n = 3). The intended lesions are depicted in Fig. 1B, and reproductions of the actual lesions, which were as intended, are shown in figs. S1 to S5. None of the lesioned groups were impaired on any of the control tasks [see supporting online material (SOM) text], which included color-matching or shape-matching for an entire session without rule shifts being imposed, confirming that their perceptual, motor, and attentional abilities were intact. However, after the lesions were introduced, the PS, ACCs, and OFC groups were markedly impaired on the WCST analog; they achieved means of only 7.4, 6.7, and 5.5 rule shifts per postoperative session, respectively, compared with means of 10.1 and 11.7 rule shifts per session in the CON and sdlPFC groups at this stage of testing. The number of rule shifts achieved postoperatively is shown (Fig. 1C) as a percentage of the preoperative number attained for each group. As it was clear that the sdlPFC lesion had absolutely no effect on performance on this or any other measure of performance of the WCST analog, for all of the following statistical analyses the sdlPFC group was hereafter considered an operated control group that could be directly compared with the OFC group, as these two groups had experience identical to each other’s. Designed comparisons using the pooled error term confirmed what is shown in Fig. 1C, namely, that both the PS group [t(11) = 2.217, P = 0.024, one-tailed] and the ACCs group [t(11) = 2.459, P = 0.023, one-tailed] were significantly impaired relative to the CON group and that there was no difference in performance between the PS and ACCs groups (t < 1). The OFC group was also significantly impaired [t(4.32) = 4.3, P = 0.006, one-tailed] relative to the sdlPFC group, whose performance did not change postoperatively (t = 0).

Two additional animals were trained preoperatively on our control task for the WCST analog (37), which required color- or shape-matching ability on alternate days but did not require rule changes within a daily session. Both animals were greatly impaired in implementing the rules they had learnt preoperatively after vlPFC lesions. This is consistent with previous studies that have reported that vlPFC-lesioned animals are impaired at both the learning and use of matching and nonmatching rules (16, 3840). The impairment in rule implementation after vlPFC lesions in the WCST analog is unlikely to be attributable largely to impoverished visual input into PFC, because the OFC is also well connected with visual association areas in the temporal lobe (41, 42), and indeed, nonconditional learning tasks, such as concurrent visual discrimination learning, are not impaired by vlPFC lesions (16). It has been proposed that a fundamental role of the PFC is learning about the structure of complex tasks by a model-building approach (43); this gradual learning process allows the conditional or abstract rules that link stimuli with goals and the means to achieve them to be identified. Even after abstract rules have been acquired, the vlPFC may remain necessary to retain these linkages in the face of competing and, in the case of abstract rules, disruptive non–goal-directed learning processes elsewhere, that might otherwise bias animals to respond on the basis of rapidly acquired stimulus-response associations instead (44). The vlPFC has been proposed to be more important for learning and retaining rules based on abstractions as opposed to exemplars (45). This would be consistent with the known patterns of PFC afferents from visual association areas in the temporal lobes. The perirhinal region of the temporal lobe, where object-level representations of exemplars are believed to be represented (46), projects more heavily into OFC than vlPFC (41, 42), whereas vlPFC receives relatively more of its input from the inferotemporal cortex, where representations are more feature-based than object-based (47).

The impairments in the PS, OFC, and ACCs groups in the main experimental task noted above cannot be attributable to impaired rule-switching per se, as none of the groups (see fig. S6) made significantly more perseverative or nonperseverative errors in the trials immediately after rule switches (P > 0.1 for all Group × Stage interactions in two-way analysis of variance for all preoperative versus postoperative comparisons on numbers of perseverative or nonperseverative errors accumulated in the three trials that followed the first trial after each rule changed). Therefore, the underlying natures of the impairments in the PS, OFC, and ACCs groups are explored in detail in the following sections.

The role of the PS in working memory for rule. Having observed the impairment in the PS, ACCs, and OFC groups in adapting to rule shifts, we explored the respective role of these areas in WCST analog performance. In order to test our hypothesis that the PS lesion impairs working memory for uncued abstract rules, it is necessary to show that performance on the WCST analog relies on working memory for rule. To do this, we determined the extent to which animals were able to maintain a rule from one trial to the next in the WCST analog, depending on the interval that elapsed between trials. In these dedicated postoperative rule-memory sessions (see SOM text for details), the WCST analog proceeded as normal, except that from the second block of the day onward, whenever animals again attained the normal criterion level of performance on the current rule, instead of having the rule change at that point, the rule remained the same but the interval before the next trial was either lengthened by 5 s [that this delay length would impede working memory for the rule was informed by a prior preliminary investigation (see SOM text)] or the interval before the next trial remained the same duration as normal (6 s). We recorded the extent to which the animals in different groups applied the currently reinforced rule on the next trial (the rule itself did not change until the animal attained criterion for a second time, i.e., a minimum of 20 trials later). The CON and sdlPFC groups performed at 92.7% and 100% correct, respectively, on the first trial after the normal delay, whereas they performed at only 73.3% and 68.8% correct, respectively, on the first trial after the extended delay. That a relatively short lengthening of the delay between trials can cause such a significant performance decrement in unoperated controls [for CON: t(5) = 3.92, P = 0.01] confirms that between-trial rule remembrance in the WCST analog is mediated by short-term working memory. Next, we assessed how well the PS group performed under the same conditions (Fig. 3A). The performance of the PS group was not significantly different from chance levels of choice between the two matching rules after the 5 s longer interval (t < 1), and the PS group was significantly impaired relative to the CON group at remembering the rule across this slightly longer interval [Group × Delay, F(1,8) = 5.76, P = 0.04]. The ACCs and OFC groups, in comparison, did not perform significantly worse on the trial after the slightly longer interval [ACCs: Group × Delay, F(1,8) = 2.89, P > 0.1; OFC: Group × Delay, F(1,4) = 1.34, P > 0.1]. We conclude that only the PS group had more fragile working memory for the abstract rule. Although previous studies have examined the effect of PFC lesions in the acquisition of extra-dimensional set-shifting abilities in the context of stimulus-reward associative learning toward exemplars (48) or toward categories (49), our study examines the importance of these PFC regions for supporting flexible switching between abstract rules based on short-term memory and outside of the context of associative learning.

Fig. 3

Effects of different prefrontal lesions on different performance measures in the WCST analog. (A) Response on the first trial after a short unfilled interruption. Group mean postoperative percent correct performance on rare probe trials before which the intertrial interval after a correct response (normally 6 s) was lengthened by 5 s; chance level of choice (between the two matching rules) in this condition would equate to 50% correct. (B) Response after a single correct response. Group mean preoperative levels (light hues) and postoperative levels (dark hues) of correct responses on trials preceded by a single correct response (i.e., trials preceded by more than one correct response were excluded). (C) Response times. Group mean preoperative minus postoperative response times averaged across all trials according to the three different response types (perseverative errors, nonperseverative errors, and correct responses). (D) Response after a single error. Group mean preoperative levels (light hues) and postoperative levels (dark hues) of correct responses on trials after a single error trial that was itself preceded by a correct response. Error bars, SEM.

The role of the OFC in representing the value of rules. If the OFC group were impaired at updating the current value of rules in the WCST analog, then we would predict that once the value of rules was sufficiently established (i.e., after several consecutive correct responses had reinforced the value of the rule) that the OFC group might then be expected to be able to maintain a series of consecutive correct responses on the basis of remembering the rule itself (as the previous analysis showed that the OFC group have no deficit in rule remembrance). However, when the current rule value is not as well established to animals (i.e., after only one or a small number of consecutive correct responses have been made), deficits in the OFC animals’ abilities to choose correctly might be prominent. Thus, we first scored the pre- and postoperative performance of each animal on EC + 1 trials, that is the percent correct on trials that followed a single correct response (C) that was itself preceded by an error (E), and we then scored how well animals could maintain correct responding after varying numbers (n) of consecutive correct responses after the initial errors, which constituted an ECn + 1 analysis (with n ranging from 2 to 10). For both analyses, we included all trials in all blocks excluding the trials immediately after rule changes (responses in the first three trials in each block were not considered in these analyses). The performance of the OFC group on trials after a single reward (EC + 1) was 76.9% preoperatively, but no better than chance postoperatively (Fig. 3B); analyses confirmed that the OFC group was significantly and severely impaired [OFC: Group × Stage, F(1,4) = 16.81, P = 0.01], whereas the numerical trends toward worse postoperative performance on EC + 1 in the PS and ACCs groups did not attain statistical significance [PS: Group × Stage, F(1,8) = 4.18, P > 0.05; ACCs Group × Stage, F(1,8) = 1.66, P > 0.1]. The ECn + 1 data shows that the OFC group was also impaired postoperatively at maintaining a series of correct responses when the value of n in the ECn + 1 was low (Fig. 4E); analyses confirmed a highly significant interaction between Group × Stage × n [F(8,32) = 4.27, P < 0.002] with a significant linear trend component [F(1,4) = 11.74, P = 0.027], showing that the magnitude of the impairment in the OFC group was inversely correlated with increasing values of n. None of the other lesioned groups showed the same pattern of postoperative deficit as the OFC group in the ECn + 1 analysis (Fig. 4); both the PS group [Group × Stage, F(1,8) = 5.34, P = 0.05; Group × Stage × n, F < 1] and the ACCs group [Group × Stage, F(1,8) = 5.31, P = 0.05; Group × Stage × n, F < 1] were more consistently impaired across all values of n in the ECn + 1 analysis, which may be most parsimoniously accounted for as impairments in rule memory (see above) or in reference to the integrated outcome history of recent decisions (see below), respectively, deficits that are not seen in the OFC group. Further, the slope of the curves in Fig. 4E allows us to infer that, after receiving multiple rewards, the rate at which the OFC animals proceed to shift over to making consecutive correct choices according to the new rule is as rapid as controls, which confirms that the OFC group is not insensitive to reward per se, even if their overall sensitivity to initial reward is deficient. Further evidence that the OFC-lesioned animals are not insensitive to reward per se comes from another study (34), which showed that OFC-lesioned animals are not impaired in their responses after receiving a single reward (i.e., n = 1 of ECn + 1) in a task in which animals had to make decisions between specific motor actions, as opposed to between rules.

Fig. 4

Sustaining rewarded behavior. For each of the five groups, (A) CON, (B) sdlPFC (lesion), (C) PS (lesion), (D) ACCs (lesion), and (E) OFC (lesion), the mean preoperative (light hues) and postoperative (dark hues) performance on trials are depicted depending on how many (n) consecutive correct responses (C) lay between an initial error trial (E) and that trial. For example, “After ECn with n = 3” refers to the mean performance on trials that were preceded by the following sequence of trials: one error and then exactly three correct trials; values are plotted for n = 1 to 7.

We also calculated average response time (i.e., time elapsing between test-item appearance and screen touch) for each animal across the three different kinds of responses: perseverative errors, nonperseverative errors, and correct responses (Fig. 3C). Preoperatively, across all animals, the mean response times were 1231 ms for correct responses, 1689 ms for perseverative errors, and 1951 ms for nonperseverative errors; response times for both error types were significantly slower than correct response times [perseverative versus correct: t(13) = 5.79, P < 0.001; nonperseverative versus correct: t(13) = 6.15, P < 0.001], and nonperseverative error responses were significantly slower than perseverative errors [t(13) = 3.14, P < 0.01]. The response times in the OFC group were on average 287 ms slower for correct responses, 287 ms slower for perseverative errors, and 339 ms slower for nonperseverative responses than the response times recorded by the same animals preoperatively. This slowing of response times in the OFC group was significant and similar across all three response types [Stage × Group, F(1,4) = 8.06, P = 0.047; Stage × Response Type × Group, F < 1]. However, this does not reflect a global lowering of motivation because OFC-lesioned animals’ responses times were unchanged postoperatively [Stage × Group, F < 1; Stage × Response Type × Group, F < 1] in control tasks without conflict between rules (37). In addition, previous studies have observed OFC-lesioned animals to be just as willing as unoperated animals to work for reward in a range of experimental tasks (29, 36, 50). The faster decisions in the CON group compared with the OFC group may be due to their being able to reach decisions more quickly in the presence of a heightened and more reliable bias in rule value, as opposed to any insensitivity to the signal value of reward per se. Consistent with the conclusions of previous studies of OFC lesions (17, 50), our observations of a lack of perseveration after rule changes in the OFC group postoperatively lead us to rule out perseverative tendencies as the explanation for their deficits in adapting to rule shifts (Fig. 1C) and the findings in EC + 1 (Fig. 3B) and ECn + 1 analyses (Fig. 4E). Our observations of slowed response times allow us to rule out a general lack of inhibition in OFC-lesioned macaques.

Rather than OFC being important for rule-value coding per se, as argued here, might there be an alternative explanation that could account for the pattern of data in the OFC group? For instance, it has been argued elsewhere (45) that OFC mediates behavior-guiding rules based on objects and so mediates learning about exemplars, whereas the vlPFC is more important for attaching value to abstractions (48). Thus, it is useful to consider whether the OFC might contribute to higher-order rules in the current study by coding outcomes for specific stimuli in the context of a particular rule in the WCST analog. Unlike in the intradimensional-extradimensional (ID-ED) shift paradigm (48), successful task performance in the WCST analog cannot arise through learning about the relative value of particular exemplars (e.g., “red square”), or indeed about the relative value of particular stimulus features (e.g., the color red) either (49), because the exemplar that is rewarded (and hence any features that are present while reward is given too) changes from trial to trial. Thus, whatever crucial contribution the OFC and vlPFC make toward performance of the WCST task, it cannot be within-block learning about the value of objects or the value of object features. In the SOM, we also argue against the idea that the OFC and vlPFC might contribute to decision-making in the WCST analog by representing the transient value of exemplars or stimulus features, respectively, within the context of an individual trial and within the context of a particular rule (see SOM text, discussion). In ruling out these alternative explanations, we believe that the most parsimonious explanation of the impairment in the OFC group is that these lesioned animals are unable to rapidly update rule-value representations as efficiently as controls and need a greater number of rewards to do so.

The role of the ACC in rule-based decision-making. One previous proposal regarding the role of the ACC was that it might be important for error detection and the enabling of subsequent error correction [see (51) for a review]. Here, we found that ACCs lesions had no effect on the performance on trials that followed immediately after errors. Indeed, none of the lesioned groups showed any postoperative change in performance on trials that followed single errors that were themselves preceded by a correct response (Group × Stage: F < 1 for all groups) (Fig. 3D). In all groups, the effect of a single error in this task was the same, that is, to “reset” the animals’ performance on the next trial back close to chance level of selection between the two rules. Previous studies have also refuted the hypothesis that the ACC is important only for error detection and correction because ACC lesions have been observed to impair reward-guided action selection (52). Another influential hypothesis regarding the role of the ACC is that this brain region is important for conflict monitoring (53). However, a recent macaque lesion study of our own showed that ACCs lesions leave intact animals’ abilities to detect and respond to different levels of conflict (54). Thus, we interpret the deficits in the ACCs group in the present experiment as deficits in response selection and decision-making, a notion explored in more detail below.

First, we found that the ACCs group were impaired across all values of n in our ECn + 1 analysis of the WCST analog performance data [Group × Stage, F(1,8) = 5.31, P = 0.05; Group × Stage × n, F < 1], which indicated that they are impaired relative to controls at maintaining extended sequences of correct choices between abstract rules. This kind of ECn + 1 analysis was recently used elsewhere to show that ACCs lesions produced a similar pattern of impairment in a reinforcement-guided decision-making task that necessitated making decisions between motor responses (33); however, another study showed that ACCs lesions do not impair reinforcement-guided decision-making in a task where the choices were between stimuli (36). These differences indicate that the OFC and ACCs are more important for reward-based decision-making between stimuli and actions, respectively (34, 35), but this dichotomy alone does not provide an account of why the ACCs group is impaired on the WCST analog. The reason for the impairment in the ACCs group on the WCST analog might be related instead to another difference between the ACC and the OFC, namely, that the ACC may be more important than the OFC for representing more highly integrated and “context-dependent” representations of choice-outcome values (55). Whereas ACC representations of choice-outcome values may be more dependent on the recent history of the monkey’s responses and rewards and the context of changing environmental constraints, the OFC may represent indices of value in a relatively less integrated and more context-independent manner. For example, OFC neurons in macaques are reported to represent goods on a common value-scale independent of what other goods are available (28), and OFC neurons in rats appear to represent the costs of a choice independent from the magnitude of the reward (56). Integrated choice outcomes reflect costs as well as benefits, and both may vary depending on the environment context; ACC lesions have been observed to impair animals’ cost-benefit decision-making in rodents (57), and human neuroimaging studies have implicated the ACC in representing estimates of environmental volatility (58), a statistic that animals make reference to when determining the degree to which recent outcomes should be allowed to influence subsequent choices. Thus, the ACC has been proposed to be involved in context-driven estimations of the uncertainty of obtaining reward (55, 59). The impairments in the ECn + 1 analysis in the current study may also reflect animals’ being uncertain about the value of repeating previously successful choices; this may be attributable to deficits in postoutcome updating of, or predecision referral to, representations of the extent to which recent outcomes should influence future decisions.

Second, unlike the OFC-lesioned animals who were reported to respond slower postoperatively in the preceding section, the response times in the PS group were unchanged postoperatively (F < 1 for all interactions involving Stage and Group with Rule and/or Response-type factors), whereas those of the ACCs group were significantly faster [Stage × Group, F(1,8) = 20.58, P < 0.01] for both perseverative errors [F(1,8) = 11.21, P = 0.01] and nonperseverative error responses [F(1,8) = 28.05, P < 0.01], but were unchanged for correct responses [F(1,8) = 2.72, P > 0.1] (Fig. 3C). That this might reflect general disinhibition in the ACCs can be ruled out because the response times of the ACCs group were unchanged in our control tasks described in (37) (Stage × Group, F < 1; Stage × Response type × Group, F < 1). In addition, we have previously reported data confirming that ACCs-lesioned animals do not exhibit selective disinhibition under conditions of high cognitive load (54); in this study, the difference in response time between conditions of high and low cognitive load was observed to be no different in ACCs compared with unoperated controls. Rather, this selective quickening of response times in erroneous trials in the ACCs group is further consistent with the idea that errors are commissioned in this group when the animals fail to complete the normal processes of response selection, as outlined above, when cognitively challenged.

Summary and conclusions. This lesion study has shown that macaque PS, OFC, ACC, and vlPFC (but not sdlPFC) all play indispensable, but different, roles in rule-guided behavior. Our data confirm that implementing previously acquired abstract rules is crucially dependent on the vlPFC region, and we propose that the vlPFC may support abstract rule implementation by biasing behavior toward such acquired rules and away from the influence of competing concrete stimulus-reward associations mediated by other areas. Our study also showed that among all the areas we targeted, only the PS region was necessary to support working memory for abstract rules. We propose that this region of dlPFC is important when subjects have to select an abstract rule themselves and then actively maintain a representation of the chosen rule in working memory in order to bias behavior away from other competing rules. This finding extends the known range of functions crucially supported by the PS beyond spatial working memory [see SOM text, discussion, and (54)]. Our OFC lesion was the only target lesion that impaired animals’ responses after single rewards, and we argue that the pattern of data after OFC lesions supports the hypothesis that the role of the OFC extends to representing the value of rules and that the OFC is necessary to rapidly update rule value on the basis of reinforcement. The pattern of deficits after ACCs lesions was consistent with a deficit in response selection and reference to integrated representations of the outcome of rule selection, which extends the known role of the ACCs to rule-based decision-making. In contrast to these lesion effects, the sdlPFC lesion was unique in the areas we investigated in that it was the only region that proved not to be crucially involved in any aspect of the WCST analog. The role of the sdlPFC deserves further investigation, as lesions to this region in macaques, to date, have only been shown to impair working-memory tasks that involve monitoring externally or self-ordered choices (60) (see SOM text, discussion). Nevertheless, our results indicate that in tasks requiring cognitive flexibility to adapt to the rule changes, there is a functional dissociation even in the dlPFC.

These dissociations and double-dissociations refute the idea that there may be no real specialization of function within the PFC (61). One PFC region that we did not target in the current study is the frontopolar cortex (FPC). The FPC has not yet been targeted selectively by nonhuman primate lesion studies, but human neuropsychological patient-testing studies have reported that patients with lesions that include the FPC region are associated with greater incidence of rule-breaking behaviors and deficits in the prospective memory component of multitasking (62). Although human patient neuropsychology is limited because lesions are not circumscribed to cytoarchitectural regions of interest, such studies do provide some evidence of fractionalization of function within the human PFC (62); indeed, with regard to abstract rules, patients whose lesions are more rostrally located are reported to be more impaired in higher-order abstract rules (63). The precise role of the FPC remains to be verified, but it has been suggested that the FPC may lie at the top of a processing hierarchy of rule-guided behavior, possibly important for implementing the most complex (higher-order) rules or for selecting between multiple nested abstract rules in branching or multitasking paradigms (6466). Here, in a species capable of flexible switching between abstract rules, we used the animal lesion approach where highly circumscribed lesions can be placed within anatomical regions of interest to demonstrate how a range of different PFC and medial frontal regions contribute in different ways to separable cognitive processes involved in rule-guided behavior. Our task is the closest nonhuman primate analog to date of the human WCST, which has been used extensively in the clinic because of its efficacy in diagnosing frontal lobe dysfunction (19), and this study offers a bridge between neurophysiological investigations of the mechanisms of rule-guided behavior in nonhuman primates and human neuropsychological and clinical studies.

Supporting Online Material

www.sciencemag.org/cgi/content/full/325/5936/52/DC1

Materials and Methods

SOM Text

Figs. S1 to S6

References

  • * These authors contributed equally to this work.

References and Notes

  1. Materials and methods are available as supporting material on Science Online.
  2. This research was jointly supported by a Royal Society University Research Fellowship (M.J.B.), a U.K. Medical Research Council (MRC) project grant (M.J.B.), a grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (K.T.), and an MRC program grant held by D. Gaffan, whom we thank for encouragement and support. We also wish to thank M. G. Baxter for assistance with anesthesia, and G. J. Daubney, K. Rockland, N. Ichinohe, H. Mashiko, and Y. Abe for assistance in preparing tissues for histology.
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