Neuroscience and Psychiatry Unit, University of Manchester and , 1 Wellcome Department of Cognitive Neurology, Institute of Neurology, University College London, London, UK
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Abstract |
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Introduction |
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Anatomy of the OFC |
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However, more recently, Petrides and Pandya have reanalysed and compared the prefrontal, including the orbitofrontal, architecture in monkeys and man (Petrides and Pandya, 1994). They have modified numbering schemes to provide easier interspecies comparison. The most caudal part of the medial OFC is delineated as area 25, extending to area 10 towards the frontal pole. On the lateral surface, area 47/12 is the most caudal region, incorporating the human equivalent of primate area 13. Area 11 extends both medially and laterally on the ventral surface and an analogue of primate area 14 can also be identified on the ventromedial surface of the human cortex. A more detailed discussion of orbitofrontal anatomy can be found elsewhere in this volume.
Connectivity of the OFC
The OFC receives inputs from various regions of the sensory cortex. The lateral region receives inputs from taste areas (Rolls, 1990) while more medial parts receive olfactory inputs (Morecraft et al., 1992
; Rolls and Baylis, 1994
). There are also direct inputs from visual association areas, somatosensory cortex and inferior temporal cortex and temporal pole (Petrides and Pandya, 1988
; Morecraft et al., 1992
; Barbas, 1995
). Direct projections from subcortical structures also reach the OFC, including substantial projections from the amygdala and mediodorsal thalamus (Krettek and Price, 1977
; Ray and Price, 1993
). The OFC, in turn, projects to the inferior temporal and entorhinal cortices, anterior cingulate, hypothalamus, ventral tegmental area and caudate nucleus (Nauta, 1964
; Kemp and Powell, 1970
; Insausti et al., 1987
). This heterogeneous pattern of connectivity suggests that the OFC acts as a convergence zone for afferents from limbic and heteromodal association areas. Such a diversity of connectivity is consistent with either a wide range of functions or a supramodal, integrative role.
Within this general heterogeneity, different regions of the OFC exhibit different patterns of connectivity. The medial subdivision has its strongest connections with the hippocampus and associated areas of the cingulate, retrosplenial and entorhinal cortices, anterior thalamus and septal diagonal band (Pandya et al., 1981; Mesulam et al., 1983
; Vogt and Pandya, 1987
; Morecraft et al., 1992
). The lateral subdivision can be further divided into three sectors, although there are no definite boundaries between these. They are characterized, instead, by a continuous gradient of cytoarchitectonic differentiation (Morecraft et al., 1992
). The most caudal sector is characterized by strong connections with the amygdala, midline thalamus, non-isocortical insula and temporal pole (Mesulam and Mufson, 1982
; Yeterian and Pandya, 1988
; Barbas and De Olmos, 1990
). The most anterior sector has more pronounced connections with the granular insula, association cortex, mediodorsal thalamus, inferior parietal lobule and dorsolateral PFC, involved in higher-order cognition (Goldman-Rakic, 1987
; Fuster, 1997
). This differential pattern of connectivity suggests that different regions of the OFC may be specialized for distinct functional roles; in particular, there is likely to be a functional distinction between medial and lateral subdivisions.
Regions to be Considered from Imaging Studies
The orbitofrontal regions identified in the imaging studies described here include most of the anatomical subdivisions discussed above. In particular, we draw a distinction between the medial OFC, extending from area 25 through the homologue of primate area 14 to the ventromedial part of area 10, and the lateral OFC, extending from area 47/12 through area 11 on the ventral surface to the ventrolateral part of area 10.
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Theories of Orbitofrontal Function |
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It is general agreed that the PFC has a role in generating behaviour that is flexible and adaptive rather than slavishly determined by the current sensory input. Many different terms have been used to characterize the function or nature of this flexible control system, such as planning (Luria, 1966), memory for the future (Ingvar, 1985
), working memory (Goldman-Rakic, 1987
), executive control (Baddeley, 1986
), supervisory attention (Shallice, 1988
) and top-down modulation of bottom-up processes (Frith and Dolan, 1997
). The executive control exerted by the PFC upon behaviour has a number of different aspects including (i) an ability to choose a course of action in novel situations when no obvious course is indicated by the current environment, (ii) an ability to suppress a course of action that is no longer appropriate and (iii) an ability to monitor current, on-going action (Shallice, 1988
). While there is agreement that there are separable aspects to executive control and that these are probably subserved by different regions of the PFC, there is less agreement about how these high-level cognitive components can be related to the distinct regions of the PFC. One view (Goldman-Rakic, 1995
) is that distinct regions are concerned with content, such that the dorsolateral PFC (DLPFC) is involved principally with spatial locations while the ventrolateral PFC (VLPFC) is involved with visual object information. In contrast, Petrides has suggested that the different regions mediate distinct processes, such that the DLPFC is concerned with monitoring actions, while the VLPFC is concerned with active maintenance of information in working memory (Petrides, 1996
). In our opinion the precise function of the various regions of the PFC has yet to be determined. One of the aims in this article is to explore whether data from recent neuroimaging studies suggest a particular role for the OFC as a component of the prefrontal executive system. Our tentative hypothesis is modelled on the suggestion that the DLPFC has a role in sculpting the response space in order to control action (Frith, 2000
). We suggest that the OFC is concerned with sculpting the reward space.
Findings from Lesion and Single-unit Recording Studies in Animals
Lesions of the OFC in animals have pronounced consequences for adaptive behaviour. In monkeys, orbitofrontal lesions result in disruption of feeding and social behaviour (Butter and Snyder, 1972; Baylis and Gaffan, 1991
). It has been argued that these deficits represent impairments in the ability to process reward-related information and particularly in the detection of changes in reinforcement contingencies necessary to make appropriate modifications to ongoing behaviour (Jones and Mishkin, 1972
; Rolls, 1975
, 1990
, 1994
, 1996
). This argument is based on findings that orbitofrontal lesions cause deficits in tasks dependent on reward-related learning, e.g. discrimination reversal learning and extinction (Butter, 1969
; Jones and Mishkin, 1972
; Rolls et al., 1994
). There is also lesion evidence for a distinction between medial and lateral orbitofrontal function. Iversen and Mishkin showed a double dissociation in the effects of medial and lateral lesions on a visual discrimination reversal learning task (Iversen and Mishkin, 1970
). Lesions to the medial OFC impaired the animals' ability to learn to associate a previously non-rewarded stimulus with reward, while lesions to the lateral OFC resulted in a failure to inhibit responding to the previously rewarded stimulus.
Direct single-electrode recording from the OFC of monkeys (Thorpe et al., 1983) demonstrated that the neural response to sensory stimuli depends upon the behavioural and motivational significance of those stimuli. In addition, certain orbitofrontal neurons show activity occurring after a response, suggesting that such neurons code behavioural outcomes of trials. This suggests that the OFC is sensitive to the reinforcement properties, or value, of stimuli and, further, rapidly modulates the nature of this influence in the light of recent experience.
Findings from Lesion Studies in Humans
In humans, like primates, orbitofrontal lesions have been shown to disrupt social and emotional behaviour. Common sequelae of orbitofrontal damage include inappropriate euphoria, lack of affect and social irresponsibility (Bechara et al., 1994; Damasio, 1994
; Rolls et al., 1994
). There are also complex deficits in reasoning, judgement and creativity (Benton, 1968
; Milner, 1982
; Eslinger and Damasio, 1985
; Mesulam, 1986
). Recent neuropsychological studies by Damasio and colleagues, discussed in more detail elsewhere in this volume, found that patients with lesions of the medial OFC manifest impairments in real-life decision making, in the context of otherwise preserved intellectual abilities (Damasio, 1994
). Bechara and co-workers developed a gambling task to model certain key aspects of real life decision-making which is typified by uncertain premises and outcomes, together with the requirement to process both positive and negative reinforcement (Bechara et al., 1994
). These authors found that patients with orbitofrontal lesions were significantly impaired on this gambling paradigm, being overly guided by immediate prospects at the expense of potential long-term consequences. It was noted that even when patients could accurately describe the contingencies governing the task, they failed to actually use this knowledge to guide their behaviour. This apparent dissociation between understanding of the contingencies and an ability to make appropriate behavioural responses has also been reported elsewhere (Rolls, 1996
).
In addition to these behavioural abnormalities resulting from orbitofrontal lesions, Bechara et al. also reported autonomic effects (Bechara et al., 1996). They compared anticipatory skin conductance responses (SCRs) in patients with orbitofrontal lesions and controls performing the gambling paradigm. Both patients and controls generated SCRs in response to reward or punishment. During the gambling task, however, control subjects began to show anticipatory SCRs prior to high-risk response selection as they learned about the contingencies associated with particular response selections. The patient group failed to show this effect; their SCRs were not elevated prior to the execution of a high-risk response. This suggests that signals arising from the OFC are normally involved in generating the autonomic reactions associated with the anticipation of reward and punishment.
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Summary |
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Evidence for StimulusResponseOutcome Association in the Medial OFC |
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Modulation of Cognitive Performance by Feedback
One index of behavioural relevance is provided by feedback about performance. To study its neural concomitants, we used positron emission tomography (PET) in conjunction with a high-level planning task based on the Tower of London (Shallice, 1982). We employed a computerized one-touch version of the task, previously used in studies assessing the neural substrates of planning in normal subjects and patients with depression (Baker et al., 1996
; Elliott et al., 1997b
). The task presents subjects with two arrays of coloured balls and requires them to work out the minimum number of moves required to transform one array into the other according to certain pre-specified rules. The study of performance feedback used a variant of this task with several additional constraints. Firstly, subjects were presented only with the relatively difficult threeto six-move problems and secondly, they were allowed only 10 s to consider a solution after which they had to generate a response. Ten seconds is significantly less than the 1525 s that subjects typically need to solve problems of this level of difficulty and therefore subjects were not given long enough to be certain of their responses. Thirdly, explicit visual feedback was given after each response. This feedback was in fact independent of subjects' responses and was provided according to a pre-specified schedule. In one condition, positive feedback was given to all responses; in another, negative feedback was given to 80% of responses; and in a third, no feedback, condition, the display simply told subjects please wait.
Performance of this planning task was compared with a control condition, which was a guessing task where subjects were required to monitor two identical arrays of coloured balls until they disappeared. This was the signal for subjects to press any one of the six response buttons. They were told that on each trial, three of the buttons were correct and that the correct buttons were assigned randomly on a trial-by-trial basis, such that each trial constituted a 50:50 guess.
There were few differences in regional cerebral blood flow associated with a comparison of the positive and negative feedback conditions (Elliott et al., 1997a). However, there was a significant interaction between task type and the presence of feedback (positive and negative feedback combined and compared with the no feedback condition). In the guessing task, but not the planning task, the presence of feedback was associated with increased rCBF in the ventromedial OFC.
One reason why the medial OFC might be especially concerned with processing feedback in a guessing task (in contrast to a planning task) is that in the guessing task the subject has no rational basis for choosing one response rather than another. Nevertheless a choice must be made. If feedback is available to indicate whether or not one's previous responses were correct, a gambling strategy can be adopted by which responses can be made on the basis of which one seems most likely to be lucky. This feeling of luck is presumably based on the likely reward value of a particular response which is based in turn on the previous sequence of responses and rewards. Thus guessing tasks are likely to induce in subjects the strategy of monitoring the reward values of responses.
Alternatively this OFC activity may be associated with an implicit requirement to process feedback across trials. During planning, each trial (incorporating problem, response and feedback) is a discrete and meaningful entity. During guessing, by contrast, feedback to a single trial is less meaningful; only when feedback is assimilated across a number of trials can subjects evaluate their performance against chance. Although subjects were told to guess randomly, anecdotal evidence of behaviour in response to chance events predicts that subjects probably monitored performance and chose their responses in the light of previously rewarded responses. Reinforcement in the guessing task was believed by the subjects to be dependent solely on the button chosen, and the relation between the buttons and the outcomes was thought to vary across trials. Thus stimulus reward relations were continually shifting in an unpredictable manner. A putative involvement of the OFC in acquiring and monitoring changing stimulusreinforcement relations is consistent with findings from studies of monkeys (Thorpe et al., 1983) and patients with orbitofrontal lesions as discussed above (Bechara et al., 1994
, 1996
; Damasio, 1994
; Rolls et al., 1994
).
Twoand Four-choice Guessing Task
Having serendipitously established a role for the OFC in a guessing task, we decided to examine more explicitly an orbitofrontal involvement in guessing. Accordingly, we developed a guessing paradigm, based on naturalistic playing card stimuli, for use in functional magnetic resonance imaging (fMRI) (Elliott et al., 1999). In this task subjects were presented with an image depicting the back of a playing card where the task requirement was to predict either the colour (two-choice guess condition) or the suit (four-choice guess condition) of the card. Subjects registered their guesses via a button press and the card then flipped over to show the front of a card, selected at random from a full pack. This image served to provide feedback as to whether the prediction was correct. The guessing task was compared with a control task, where subjects were presented with the image of the front of a playing card and simply had to report either the colour or the suit of the card before it flipped over to the card back. The two tasks were identical in that subjects saw a series of randomly presented playing card faces, alternating with the card back image. However, they differed in whether subjects responded to the card front, reporting what they saw, or the card back, predicting what they would see next. This constituted a factorial design that examined guessing compared with reporting at two levels of contingency (choosing one of two or one of four responses).
Guessing compared with reporting was associated with increased neural response in many regions, including the posterior perceptual regions, subcortical structures and regions of the PFC, and both the dorsolateral and orbitofrontal cortices. There was also a significant modulation of this pattern of activation associated with guessing, by changing the contingencies from 50 to 25% (see Fig. 1). This interaction term was associated with significant focal augmentation of activation in both the medial and lateral OFC (this lateral activation will be discussed further below). The involvement of the medial OFC in this guessing task may again reflect the requirement to monitor the reward value of possible responses. As the number of possible outcomes increases from two to four, this monitoring process becomes more demanding and the activation of the medial OFC increased accordingly.
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Somewhat unexpectedly, we have also observed activity in the OFC in simple matching-to-sample tasks which did not involve any component of guessing. In this study fMRI was used to identify the neural substrates of delayed matching compared with delayed non-matching to sample. In both tasks subjects were initially shown a complex, abstract visual stimulus, then after a delay interval were presented with two stimuli, one of which was the sample stimulus. In delayed matching to sample, the subjects' task was to choose the familiar stimulus; in delayed non-matching, it was to choose the novel stimulus. Two delay intervals were used, 5 and 15 s. When the matching condition was compared with non-matching, a significant neural response was seen in the medial caudate and ventromedial OFC. This differential response occurred for both delay intervals but was slightly, though not significantly, more pronounced at the short delay.
Regions of the OFC have previously been implicated in shortterm memory tasks in humans and animals (Milner et al., 1985; Bachevalier and Mishkin, 1986
; Meunier et al., 1997
). Indeed, Bachevalier and Mishkin argued that the ventromedial prefrontal regions are more implicated in short-term memory tasks than the dorsolateral regions (Bachevalier and Mishkin, 1996). However, the medial OFC activation observed in this task is unlikely to reflect short-term memory processes per se. Both delayed matching and delayed non-matching-to-sample performance are likely to recruit short-term memory processes, but the medial orbitofrontal activation is a differential one, seen for matching but not for non-matching. A crucial difference between matching and non-matching is that for matching, subjects know which stimulus they will be responding to from the point where they see the sample. Thus, an association between a specific stimulus and the forthcoming response can be formed and maintained through the delay interval. For non-matching, the sample stimulus does not specify a forthcoming response and therefore no association is formed. It may therefore be the case that the differential orbitofrontal activation reflects the maintenance of stimulusresponse mappings in the matching-to-sample task. While delayed matching to sample cannot be said to contain the same degree of unpredictability as the guessing tasks discussed above, a version with trial-unique stimuli, as used here, does require subjects to continually update stimulusresponse mappings. A new association between stimulus and forthcoming response must be made on each trial. Therefore, although the situation is not as incompletely specified as in a guessing or gambling task, it shares the requirement to continually update the representation of associations between stimuli and correct responses.
The task can also be seen as one in which subjects have to attend to the familiarity of stimuli and, in the matching-to-sample case, choose the stimulus that feels familiar. There is some evidence for a natural relationship between familiarity and reward (or at least pleasantness). Zajonc has shown that subjects will prefer a familiar stimulus even in circumstances in which they are not aware that it is familiar (Zajonc, 1980). Thus, if familiarity is associated with intrinsic reward, in the delayed-matching-to-sample task the activity in the medial OFC may relate to the need to continuously monitor the reward value of the stimuli.
Language Tasks
Sentence Completion
We have also observed activation of the OFC in language-related tasks. One such task is sentence completion (i.e. generating the missing final word in sentences such as: Coming into the room he took off his...). Performance of this task is known to be impaired by frontal lobe damage, especially in the version of the task in which a word that does NOT fit the sentence has to be generated (Burgess and Shallice, 1996). In a recent imaging study, Nathaniel-James and Frith (Frith, 1999) used a sentence completion task in which the level of constraint of the sentences was parametrically varied. Constraint was defined by the probability of the most frequent response listed in the Bloom and Fischler norms (Bloom and Fischler, 1980
). Six levels of constraint, varying from low to high, were used during a PET neuroimaging study (high constraint: He posted the letter without a... ; low constraint, The police had never seen a man so...). An additional factor in this study was whether subjects were told to give an appropriate or an inappropriate word to complete the sentence. The former condition requires response initiation, the latter requires response suppression. Anterior medial orbitofrontal activation was associated with making an appropriate rather than an inappropriate completion. This activation was enhanced in the lower constraint conditions. An open-ended sentence is an incompletely specified situation and the selection of an appropriate completion requires subjects to make associations. A strong mapping between the sentence stimuli and the chosen word ensures a correct outcome. The selection procedure becomes more difficult in less constrained sentences because there are more possible choices that could be associated with a successful outcome. As for the card-based guessing task discussed above, the presence of more possible responses predicts enhanced activation of the medial orbito-frontal region.
In the condition where subjects produced a word that did not fit there was much greater activation in the left DLPFC. This condition is also characterized by the requirement to choose between many possible responses. However, this choice can be made by deliberately selecting a word that breaks semantic and/or syntactic rules. When choosing a word that did fit, particularly in conditions of reduced constraint, more activity was observed in the OFC (see Fig. 2). When choosing a word that fits the subjective experience is of a feeling of rightness' or closure' when a suitable word is found, rather than of some rational consideration of why the word might be correct. Thus the activation of the OFC might be associated with the need to monitor this aspect of possible responses. With the less constrained sentences this need to monitor rightness' in order to choose the best response would be greater.
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Another aspect of language processing, critically dependent on the formation of associations between stimuli and outcomes, is comprehension. Maguire and colleagues performed a PET study of the role of prior knowledge in comprehension and memory (Maguire et al., 1999). There were a number of different cognitive conditions in this study, all involving subjects reading stories. Some of the stories were straightforward and readily comprehensible while others were unusual stories, that were difficult to comprehend without some prior knowledge to provide an explanatory theme. These stories were presented under different conditions, with and without a framework for comprehension provided by prior knowledge. Of the numerous comparisons made in this study, the one associated with activation of the OFC was a covariate analysis with subjective comprehension. After each story presentation, subjects rated their comprehension on a seven-point scale. The more subjectively comprehensible the stories, the greater the blood flow in an anterior region of the medial OFC, almost identical to the region involved in the sentence completion study described above. The unusual stories, in particular, are rather poorly specified and may even require a degree of guesswork to comprehend their meaning. Subjective comprehension, which is also likely to be intrinsically rewarding, depends on making associations between information and flexibly updating these associations in the light of incoming stimulus information.
To comprehend a story we must generate our own version in such a way as to capture the gist intended by the original story-teller. As with the sentence completion task discussed above, our experience of success in comprehension relates largely to a feeling of rightness' rather than any rational analysis of how our version relates to the original. In this experiment it would seem that the greater this feeling of rightness, the greater the activation in the medial OFC.
Summary
The medial OFC activation has been observed in various studies carried out in our laboratory (see Fig. 3). Although very different in some respects, all the studies discussed above shared a common requirement to make associations between stimuli and correct or rewarded responses. Further, these associations had to be updated in a flexible manner. The unifying feature of all the studies was the requirement to select stimuli and/or responses on the basis of their reward value. Subjects had to monitor or hold in mind the reward value of previous stimuli and/or responses, and to contrast the possible reward values of future responses. We suggest, therefore, that the OFC has a function similar to other prefrontal regions in that it is involved in monitoring and in holding things in mind, but that this function is applied specifically to reward values (and related aspects such as familiarity and rightness). However, our experiments also suggest a distinction between the roles of the medial and the lateral OFC. In the next section we shall present evidence that the lateral OFC has a specific role in suppressing responses to previously rewarded stimuli.
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Evidence for an Involvement of the Lateral OFC in Making Choices on the Basis of Response Suppression |
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As discussed above, we used fMRI to study differential responses in delayed matching and delayed non-matching to sample (Elliott and Dolan, 1999). In this study there was a double dissociation between lateral and medial activations. The comparison between matching and non-matching was associated with enhanced activity in medial orbitofrontal activation (see Fig. 4
). However, the reverse comparison, between non-matching and matching, was associated with enhanced activity in a relatively anterior lateral region of the OFC, bilaterally. Both matching and non-matching involve short-term memory processes and the execution of a choice response. The medial activation associated with the matching condition was explained in terms of a need to monitor the familiarity and associated reward value of stimuli. The lateral activation associated with non-matching, however, can be explained in terms of a crucial difference between the tasks at the choice stage. In adult humans, unlike children and animals (Gaffan et al., 1984
; Diamond, 1991
), matching is a more natural process than non-matching; the instinctive response at the choice stage is to the familiar rather than the novel stimulus. Thus, making the choice in non-matching involves inhibiting an instinctively preferred response in order to make a correct one. Inhibition can be seen as a particular feature of making choices, especially in circumstances where an established or salient response may not always be appropriate. Such a role for the lateral OFC is consistent with previous studies implicating the OFC in response inhibition tasks, such as the classic gono go tasks (Jones and Mishkin, 1972
; Kowalska, 1991; Casey et al., 1997
). In particular, the lateral OFC seems to be involved when responses based upon the previous reward value have to be inhibited (Iversen and Mishkin, 1970
).
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A study looking more explicitly at response inhibition was a PET study using a variant of the Posner covert orienting task (Posner et al., 1980) in which subjects are cued to orient spatial attention to a particular location prior to a response. Nobre et al. used a version of the task where cues were either spatial, directing subjects to a particular side of the screen, or temporal, indicating whether the target would appear 300 or 1500 ms after the cue (Nobre et al., 1999). Subjects performed both the temporal and spatial tasks under two conditions: either with all cues valid or with 40% of the cues invalid (i.e. predicting the wrong location or interval). The presence of invalid cues in both the spatial and the temporal tasks was associated with activation of the lateral OFC bilaterally, with a relatively anterior focus, close to that seen in delayed non-matching to sample. This activation can be readily interpreted in terms of the requirement to inhibit a prepared motor sequence that the cue has (mis)led subjects to believe is correct. In this study, the invalid cues can also be seen as creating a situation of high unpredictability and the orbito-frontal activation is therefore also consistent with a wider role for this region in dealing with uncertainty.
Modulation of Hypothesis Testing by the Requirement to Make a Choice
A clear indication of a role for the lateral OFC in the expression of behavioural choice comes from a PET study of how the requirement to make a choice modulates cognitive performance (Elliott and Dolan, 1998). The paradigm used in this study was a visuospatial hypothesis-testing task under two conditions: with and without the requirement to make a choice. In the task, subjects were presented with a series of pairs of 6 x 6 checker-boards where the distribution of black and white squares was randomly arranged. Subjects were told that on each trial one of the two checkerboards was correct based upon a visuospatial rule. Their task was to try and work out this rule by hypothesis generation and testing across a number of trials (ten in each scanning block). In reality there was no rule, which obviated the possibility of subjects hitting on the right rule early on in the task and thereafter ceasing to generate and test hypotheses. In the choice condition, subjects had to select which of each pair of stimuli they thought was correct on the basis of their current hypothesis, and were told whether the choice made was correct. In the no choice condition, subjects were told which of the two stimuli was correct and were simply required to respond to this specified stimulus. In both cases, subjects obtained the same amount of information on each trial; namely, a knowledge of which of the two patterns was right such that their current hypothesis was either supported or disconfirmed. The only difference was that in the choice condition, their response represented commitment to a current hypothesis. A simple guessing control task was used where identical pairs of checkerboards were used as a signal for subjects to press either one of the response buttons (choice condition) or a specified button (no choice condition).
The comparison between the hypothesis-testing and guessing tasks was associated with the activation of a number of cortical and subcortical regions. There was no activation of the medial OFC, which may reflect that both tasks involve incompletely specified situations where stimulusoutcome associations are made and updated. However, the comparison between the choice and the no choice conditions was associated with activation of an anterior region of the lateral OFC bilaterally, as well as the ventral anterior cingulate. This is a clear demonstration that the lateral OFC is involved in the expression of behavioural choice in a situation where the outcome is uncertain. In the choice condition of both tasks subjects must select a response in a situation of extreme uncertainty. Because both tasks are insoluble there is a particular emphasis on rejecting previous hypotheses and thus a frequent need to suppress a previously rewarded response. This, we argue, is further evidence that the lateral OFC has a special role in suppressing previously rewarded responses.
Twoand Four-choice Guessing
Lateral orbitofrontal activation was also seen in the fMRI study of two-choice compared with four-choice guessing (Elliott et al., 1999), described above. Guessing was associated with significant neural response in the lateral as well as the medial OFC, and this activity was also enhanced when the number of possible choices increased from two to four. Thus in this study, where the experimental but not the control task involved flexibly associating stimuli with outcomes and making a choice in the face of uncertainty, there was co-activation of both the medial and lateral OFC.
Another feature of these guessing tasks is that subjects will deliberately withhold previously rewarded responses from time to time because they know, due to the insoluble nature of such tasks, that their luck must change. This is the gamblers fallacy that leads us to believe that, if there have been five heads in a row, then the next toss is more likely to produce a tail. However, on this hypothesis we might also have expected to see activation of the lateral OFC in the guessing condition of the experiment described in Modulation of Cognitive Performance by Feedback. This difference may arise because the planning task used in this experiment was soluble and therefore there was less emphasis on the need to reject hypotheses and suppress previously rewarded responses.
Response to Unstable Situations in a Reward Paradigm
A relatively posterior region of the lateral OFC was activated in a recent fMRI study of financial reward and punishment. We used a two-choice guessing task where subjects had to guess which of two playing cards was correct (a red card or a black card). The sequence of correct and incorrect choices had been predetermined. A bar at the side of the screen displayed the cumulative score across trials and this score had direct financial implications for subjects. Every time the subjects guessed correctly, the bar went up by a £1 increment; every time they were incorrect the bar went down by £1. The height of the bar, the rate of change of height and the interaction between the two were used to model the haemodynamic response. Orbitofrontal response was seen under a particular set of circumstances in the experiment, namely when the reward bar was either at a high level and rising quickly or at a low level and falling quickly. Subjectively, these were circumstances that were least stable, where subjects felt that their luck must be about to change. The orbitofrontal focus in these circumstances was accompanied by a response in the insula cortex and may represent the excitement associated with increased instability. The requirement to make choices between two responses was constant throughout this experiment but the subjective context in which these choices were made varied. Several studies suggesta role for the insula in processing emotionally relevant contexts (Casey et al., 1995; Augustine, 1996
), and the adjacent posterior lateral OFC may play a similar role. Thus the region may be implicated in a specific aspect of choice behaviour in uncertain situations, subsuming the emotional response to such choices. This experiment provides direct evidence of a link between the feeling that luck is going to change and activation in the lateral OFC. This is the point in a guessing task when the subject must deliberately override response selection of the basis of previous rewards and try a new strategy.
Response to Angry Faces
Another study emphasizing the inhibitory role of the OFC was that of Blair et al., who used PET to assess neural responses to facial expressions of sadness and anger (Blair et al., 1999). Subjects were shown photographs of faces with sad, angry or neutral expressions and were required to make a behavioural response indicating whether the face was male or female. Activation of a region of the right lateral OFC (BA 47) was associated with responses to angry but not to sad or neutral faces (see Fig. 5
). This orbitofrontal activation was correlated with the intensity of the angry expression and was close to that seen in the studies involving response inhibition: delayed non-matching to sample and the invalid cue task. This is consistent with the argument that angry expressions in others are a signal to us that our current behaviour is socially unsuitable or unacceptable. The anger of others should thus serve as a cue to cease the current behaviour. We propose that the orbitofrontal response to angry expressions may reflect this inhibitory effect.
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The other task discussed above where lateral orbitofrontal activation occurred in the same comparison as more medial activation was the sentence completion study of Nathanial-James and Frith. Again, the comparison between this task and its control involves not only making associations but also expressing responses in terms of a choice between alternatives. When the sentences were to be completed with appropriate words, and particularly, at a lower level of constraint, bilateral area 11 was activated, in regions extremely close to the lateral foci in the two choice guessing task of Elliott et al. (Elliott et al., 1999). As in the card-playing task, the appropriate completion task requires subjects to select a response from a finite range of alternatives. Increasing the number of possible alternatives by lowering the level of constraint may place greater demands on the choice-making function subsumed by the lateral OFC.
We have suggested that finding a word that fits in this sentence completion task involves monitoring the possible responses for how right they feel and that this is associated with activity in the medial OFC. However, it is also necessary to reject words have high local associations but do not fit the sentence as a whole. For example, pepper would be an incorrect completion to the sentence, the sea water tasted of salt and.... It is possible that the activity in the lateral OFC seen in this study reflects suppression of these local associations (albeit, we admit, very forced).
Summary
Evidence from the experiments reviewed in this section suggests that the lateral OFC is particularly likely to be activated when the tendency to select previously rewarded responses has to be overridden (see Fig. 6).
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Conclusions |
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A putative role for the OFC in coping with novel and uncertain situations does not distinguish it from other regions of the PFC. There is ample evidence that the prefrontal system has an executive function of this kind. However, we consider that the evidence we have presented here suggests that we can start to delineate a specific role for the OFC within the prefrontal executive system.
The Specific Role of the OFC
We have suggested that the OFC has a specific role in using the reward value associated with stimuli and responses in order to select actions. As a result, activity is seen in the OFC when tasks are performed that require monitoring of reward values and the holding in mind of reward values of past and future stimuli and responses. We suggest that the irrational sense of the rightness of a stimulus (which may relate to familiarity) is also associated with reward value. We derive these suggestions from the observation that the OFC is activated in tasks where the major determinant of the correct response is reward value or familiarity rather than sensory properties of the stimuli or motor properties of the response. Guessing tasks typify this situation. Our findings of a medial orbitofrontal involvement in simple guessing tasks is compatible with the findings of lesions studies that orbitofrontal damage impairs performance of gambling tasks (Bechara, 1994, 1996; Damasio, 1994; Rogers et al., 1999
). Finally we discussed two language tasks: sentence completion and comprehension of unusual stories, associated with anterior orbitofrontal activation. We suggest that performance of these language tasks depends upon monitoring possible responses on the basis of a feeling of rightness or familiarity rather than a rational analysis of syntactic or semantic features. Our formulation is consistent with Roll's suggestion that a key function of the OFC is rapid stimulusreinforcement learning and reversal (Rolls, 1996
). A flexible, rather than a hard-wired, system of this kind would require the monitoring and holding in mind of currently relevant reward values.
Specific Roles for the Medial and Lateral OFC
We suggest that, while the OFC in general is concerned with monitoring reward values, the lateral OFC is especially likely to be activated when a response previously associated with reward has to be suppressed. Response suppression is clearly involved in tasks such as delayed non-matching to sample and when responding to invalid cues in covert orienting tasks. We suggest that response suppression of this kind is also involved in gambling tasks, as when subjects decide that a response previously perceived as being lucky will probably cease to be so. This region is also responsive to angry facial expressions, which in social contexts may be an important signal to inhibit the current choice of behaviour. This anterior region corresponds to the isocortical section of the lateral OFC, the most significant connections of which include those to the dorsolateral PFC, a structure that has also been implicated in inhibitory processes (Fuster, 1997).
A more posterior and caudal region of the lateral OFC appears to be involved in the excitement engendered in making risky choices. This is the region that has strongest connections with the amygdala, insula and temporal pole structures which are involved in emotional experience and expression (Aggleton, 1992; Augustine, 1996
; Fink et al., 1996
). The making of risky choices may also elicit activity in this region since, when selecting risky responses, we allow knowledge that this choice may lead to an enhanced reward to override a wish to avoid such responses because they have previously been punished.
Contrast with the Role of Other Prefrontal Regions
In this article we have described a number of imaging studies in which activation has been seen in the OFC. On the basis of the nature of the tasks used in these studies we have suggested that the OFC has a specific role in monitoring the reward values of stimuli and responses so that reward value can be used to choose appropriate actions in a flexible and purposeful manner, particularly in situations of novelty and uncertainty. Although our account is somewhat speculative, it has the advantage of specifying a role for the OFC which accords with the idea that the PFC in general has an executive function while its various regions are concerned with different contextual aspects of executive control.
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Address correspondence to Chris Frith, 12 Queen Square, London WC1N 3BG, UK.
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Augustine JR (1996) Circuitry and functional-aspects of the insular lobe in primates including humans. Brain Res Rev 22:229244.[ISI][Medline]
Bachevalier J, Mishkin M (1986) Visual recognition impairment following ventromedial but not dorsolateral prefrontal lesions in monkeys. Behav Brain Res 20:249261.[ISI][Medline]
Baddeley A (1986) Working memory. Oxford: Clarendon Press.
Baker SC, Rogers RD, Owen AM, Frith CD, Dolan RJ, Frackowiak RSJ, Robbins TW (1996) Neural systems engaged by planning: a PET study of the Tower of London task. Neuropsychologia 6:515526.
Barbas H (1995) Anatomic basis of cognitiveemotional interactions in the primate prefrontal cortex. Neurosci Biobehav Rev 19:499510.[ISI][Medline]
Barbas H, De Olmos J (1990) Projections from the amygdala to basoventral and mediodorsal prefrontal regions in the rhesus monkey. J Comp Neurol 300:549571.[ISI][Medline]
Baylis LL, Gaffan D (1991) Responses of neurons in the primate taste cortex to glutamate. Exp Brain Res 86:617622.[ISI][Medline]
Bechara A, Damasio AR, Damasio H, Anderson SW (1994) Insensitivity to future consequences following damage to human prefrontal cortex. Cognition 50:715.[ISI][Medline]
Bechara A, Tranel D, Damasio H, Damasio AR (1996) Failure to respond autonomically to anticipated future outcomes following damage to the prefrontal cortex. Cereb Cortex 6:215225.[Abstract]
Benton AL (1968) Differential behavioral effects in frontallobe disease. Neuropsychologia 6:5360.[ISI]
Blair RJR, Morris JS, Frith CD, Perret DI, Dolan RJ (1999) Dissociable neural responses to facial expressions of sadness and anger. Brain 122:883893.
Bloom PA, Fischler I (1980) Completion norms for 329 sentence contexts. Memory Cogn 8:631642.
Brodmann K (1909) Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipen dargestellt auf Grand des Zellenbaues. Leipzig: Barth.
Burgess PW, Shallice T (1996) Response suppression, initiation and strategy use following frontal lobe lesions. Neuropsychologia 34: 263273.[ISI][Medline]
Butter CM (1969) Perseveration in extinction and in discrimination reversal tasks following selective frontal ablations in Macaca mulatta. Physiol Behav 4:163171.[ISI]
Butter CM, Snyder DR (1972) Alterations in aversive and aggressive behaviors following orbitofrontal lesions in rhesus monkeys. Acta Neurobiol Exp 32:525565.[Medline]
Casey BJ, Trainor RJ, Orendi JL, Schubert AB, Nystrom LE, Giedd JN, Castellanos X, Haxby JV, Noll DC, Cohen JD, Forman SD, Dahl RE, Rapoport JL (1997) A developmental functional MRI study of pre-frontal activation during performance of a gono go task. J Cogn Neurosci 9:835847.[Abstract]
Casey KL, Minoshima S, Morrow TJ, Koeppe RA, Frey KA (1995) Imaging the brain in pain potentials, limitations, and implications. Adv Pain Res Ther 22:201211.[ISI]
Damasio AR (1994) Descartes' error. New York: Putnam.
Diamond A (1991) Guidelines for the study of brainbehaviour relationships during development. In: Frontal lobe function and dysfunction (Levin HS, Eisenberg HM, Benton AL, eds), pp. 339380. Oxford: Oxford University Press.
Elliott R, Dolan RJ (1998) Activation of different anterior cingulate foci in association with hypothesis testing and response selection. Neuroimage 8:1729.[ISI][Medline]
Elliott R, Dolan RJ (1999) Differential neural responses during performance of matching and nonmatching to sample tasks at two delay intervals. J Neurosci 19:50665073.
Elliott R, Frith CD, Dolan RJ (1997a) Differential neural response to positive and negative feedback in planning and guessing tasks. Neuropsychologia 35:13951404.[ISI][Medline]
Elliott R, Sahakian BJ, Michael A, Paykel ES, Dolan RJ (1997b) Neural response to feedback on planning and guessing tasks in patients with unipolar depression. Psychol Med 28:559571.[ISI]
Elliott R, Rees GE, Dolan RJ (1999) Ventromedial prefrontal cortex mediates guessing. Neuropsychologia. 37:403411.[ISI][Medline]
Eslinger PJ, Damasio AR (1985) Severe disturbance of higher cognition after bilateral frontal lobe ablation: patient EVR. Neurology 35: 17311741.[Abstract]
Fink GR, Markowitsch HJ, Reinkemeier M, Bruckbauer T, Kessler J, Heiss WD (1996) Cerebral representation of one's own past: neural networks involved in autobiographical memory. J Neurosci 16: 42754282.
Frith CD (2000) The role of dorsolateral prefrontal cortex in the selection of action, as revealed by functional imaging. In: Control of cognitive processes: attention and performance XVIII (Monsell S, Driver J, eds). Cambridge, MA: MIT Press.
Frith CD, Dolan RJ (1997) Brain mechanisms associated with top-down processes in perception. Phil Trans R Soc Lond B 352:12211230.[ISI][Medline]
Fuster JM (1997) The prefrontal cortex. Anatomy, physiology and neuropsychology of the frontal lobe, 3rd edn. New York: Raven.
Gaffan D, Gaffan EA, Harrison S (1984) Effects of fornix transection on spontaneous and trained non-matching by monkeys. Q J Exp Psychol 36b:285303.[ISI]
Goldman-Rakic PS (1987) Circuitry of primate prefrontal cortex and regulation of behavior by representational memory. In: Handbook of physiology, Vol. 5, pt I (Mountcastle VB, Plum F, eds), pp. 373417. Bethesda, MD: American Physiological Society.
Goldman-Rakic PS (1995) Architecture of the prefrontal cortex and the central executive. Ann NY Acad Sci 769:7183.[ISI][Medline]
Insausti R, Amaral DG, Cowan WM (1987) The entorhinal cortex of the monkey: II. Cortical afferents. J Comp Neurol 264:356395.[ISI][Medline]
Ingvar DH (1985) Memory of the future. An essay on the temporal organisation of conscious awareness. Hum Neurobiol 4:127136.[Medline]
Iversen S, Mishkin M (1970) Perseverative interference in monkey following selective lesions of the inferior prefrontal convexity. Exp Brain Res 11:376386.[ISI][Medline]
Jones B, Mishkin M (1972) Limbic lesions and the problem of stimulus-reinforcement associations. Exp Neurol 36:362377.[ISI][Medline]
Kemp JM, Powell TPS (1970) The cortico-striate projections in the monkey. Brain 93:525546.[ISI][Medline]
Kowalska DM, Bachevalier J, Mishkin M (1991) The role of the inferior prefrontal convexity in performance of delayed nonmatching to sample. Neuropsychologia 29:583600.[ISI][Medline]
Krettek JE, Price JL (1977) The cortical projections of the mediodorsal nucleus and adjacent thalamic nuclei in the rat. J Comp Neurol 171: 157192.[ISI][Medline]
Luria AR (1966) Higher cortical functions in man. New York: Basic Books.
Maguire EA, Frith CD, Morris RGM (1999) The functional neuroanatomy of comprehension and memory: the importance of prior knowledge. Brain 122:18391850.
Mesulam MM (1986) Frontal cortex and behavior. Ann Neurol 19: 320325.[ISI][Medline]
Mesulam M-M, Mufson EJ (1982) Insula of the old world monkey: I. Architectonics in the insulo-orbitotemporal component of the paralimbic brain. J Comp Neurol 212:122.[ISI][Medline]
Mesulam MM, Mufson EJ, Levey AI, Wainer BH (1983) Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J Comp Neurol 214:170197.[ISI][Medline]
Meunier M, Bachevalier J, Mishkin M (1997) Effects of orbital frontal and anterior cingulate lesions on object and spatial memory in rhesus monkeys. Neuropsychologia 35:9991016.[ISI][Medline]
Milner B (1982) Some cognitive effects of frontal-lobe lesions in man, Phil Trans R Soc Lond B 298:211226.[ISI][Medline]
Milner B, Petrides M, Smith ML (1985) Frontal lobes and the temporal organisation of memory. Hum Neurobiol 4:137142.[ISI][Medline]
Morecraft RJ, Geula C, Mesulam M-M (1992) Cytoarchitecture and neural afferents of orbitofrontal cortex in the brain of the monkey. J Comp Neurol 323:341358.[ISI][Medline]
Nauta WJH (1964) Some efferent connections of the prefrontal cortex in the monkey. In: The frontal granular cortex and behavior (Warren JM, Akert K, eds), pp. 397407. New York: McGraw-Hill.
Nobre AC, Coull JT, Frith CD, Mesulam M-M (1999) Orbitofrontal cortex is activated during breaches of expectation in tasks of visual attention. Nature Neurosci 2:1112.[ISI][Medline]
Pandya DN, Van Hoesen GW, Mesulam MM (1981) Efferent connections of the cingulate gyrus in the rhesus monkey. Exp Brain Res 42: 319330.[ISI][Medline]
Petrides M (1996) Specialized systems for the processing of mnemonic information within the primate frontal cortex. Phil Trans R Soc Lond B 351:14551462.[ISI][Medline]
Petrides M, Pandya DN (1988) Association fiber pathways to the frontal cortex from the superior temporal region in the rhesus monkey. J Comp Neurol 273:5266.[ISI][Medline]
Petrides M, Pandya DN (1994)Comparative architechtonic analysis of the human and macaque frontal cortex. In: Handbook of neuropsychology, Vol. 9 (Boller F, Grafman J, eds), pp. 1758. Amsterdam: Elsevier Science BV.
Posner MI (1980) Orienting of attention. Q J Exp Psychol 32:325.[ISI][Medline]
Ray JP, Price JL (1993) The organization of the projections from the mediodorsal nucleus of the thalamus to orbital and medial prefrontal cortex in the monkey.
Rogers RD, Everitt BJ, Baldacchino A, Blackshaw AJ, Swainson R, Wynne K, Baker NB, Hunter J, Carthy T, Booker E, London M, Deakin JFW, Sahakian BJ, Robbins TW (1999) Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: evidence for monoaminergic mechanisms. Neuropsychopharmacology 20:322339.[ISI][Medline]
Rolls ET (1975) The brain and reward. Oxford: Pergamon.
Rolls ET (1990) A theory of emotion, and its application to understanding the neural basis of emotion. Cogn Emot 4:161190.[ISI]
Rolls ET (1994) Brain mechanisms for invariant visual recognition and learning. Behav Proc 33:113138.[ISI]
Rolls ET (1996) The orbitofrontal cortex. Phil Trans R Soc Lond B 351: 14331444.[ISI][Medline]
Rolls ET, Baylis LL (1994) Gustatory, olfactory and visual convergence within the primate orbitofrontal cortex. J Neurosci 14:54375452.[Abstract]
Rolls ET, Hornak J, Wade D, McGrath J (1994) Emotion related learning in patients with social and emotional changes associated with frontal lobe damage. J Neurol Neurosurg Psychiat 57:15181524.[Abstract]
Shallice T (1982) Specific impairments in planning. Phil Trans R Soc Lond B 298:199209.[ISI][Medline]
Shallice T (1988) From neuropsychology to mental structure. Cambridge: Cambridge University Press.
Talairach J, Tournoux P (1988) A co-planar stereotactic atlas of the human brain. Stuttgart: Thieme.
Thorpe SJ, Rolls ET, Maddison S (1983) The orbitofrontal cortex: neuronal activity in the behaving monkey. Exp Brain Res 49:93115.[ISI][Medline]
Vogt BA, Pandya DN (1987) Cingulate cortex of the rhesus monkey: II. Cortical afferents. J Comp Neurol 262:271289.[ISI][Medline]
Walker AE (1940) A cytoarchitectural study of the prefrontal area of the macaque monkey. J Comp Neurol 73:5986.
Yeterian EH, Pandya DN (1988) Corticothalamic connections of paralimbic regions in the rhesus monkey. J Comp Neurol 269:130146.[ISI][Medline]
Zajonc RB (1980) Feeling and thinking: preferences need no inferences. Am J Psychol 35:151175.