Department of Anatomy, University of Cambridge, Downing Site, Cambridge CB2 3DY, UK
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Abstract |
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Introduction |
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However, while disinhibition has been the most commonly described deficit in studies of orbitofrontal function in monkeys, changes in monkey social behaviour were reported in some of the earliest studies of frontal lobe function (Butter et al., 1970; Franzen and Myers, 1973
; Raleigh and Steklis, 1981
). Indeed, it was recognized that, in many respects, the profile of abnormal social behaviour seen following frontal lobe damage in monkeys was similar to that seen in the KluverBucy syndrome, particularly those aspects of the syndrome associated with damage to the amygdala (Weiskrantz, 1956
). These behavioural findings, along with anatomical evidence demonstrating the direct reciprocal connections between the frontal lobes, specifically the orbitofrontal cortex, and the amygdala, as well as the indirect connections between these two structures via the mediodorsal thalamus, highlight the close relationship between the orbitofrontal cortex and a structure considered to be central to the expression of a variety of emotional behaviours.
Indeed, the most commonly described behavioural effects in humans with orbitofrontal damage have been the changes in emotional and social behaviour. Phineas Gage, whose social and emotional behaviour changed dramatically following a railroad accident (Harlow, 1868), is perhaps the most well known of these patients but since then, similar social and emotional difficulties have been reported in many other patients with damage to this area of the brain (Eslinger and Damasio, 1985
). However, like monkeys with orbitofrontal damage, patients with orbitofrontal damage also exhibit signs of behavioural disinhibition, often being described as impulsive (Hornak et al., 1996
). In an attempt to measure this impulsivity in a laboratory setting Rolls and colleagues tested patients with orbitofrontal damage on the reversal of a gono go discrimination (Rolls et al., 1994
). Unlike the asymmetric reward versions used previously in experimental studies in monkeys in which only one of the two stimuli were associated with reward (McEnanay and Butter, 1969; Iversen and Mishkin, 1970
), in the study with patients, both stimuli were associated with gaining reward points if the appropriate response was made, namely touching one of the stimuli and refraining from touching the other. In this symmetric reward version patients with orbitofrontal damage learned the initial discrimination task but were impaired on the subsequent reversal. While these patients made a large number of both commission errors (i.e. inappropriate touches) and omission errors (i.e. witholding a touch inappropriately), the greater number of errors were of the commission type, suggesting that these patients had a particular difficulty in witholding responding.
Two major issues arise in the light of these findings. The first is whether the assignment of inhibitory control functions specifically to the orbitofrontal cortex, as originally proposed by Mishkin and Fuster (Mishkin, 1964; Fuster, 1989
, 1998
), is supported by the results of more recent studies. The second issue is the nature of the relationship between behavioural disinhibition and affective disorder. However, before addressing these issues in detail, it is important to acknowledge the fact that those prefrontal patients that display profound social and emotional disturbance very often have damage to both the orbitofrontal and medial prefrontal cortex. Indeed, the regions most commonly associated with these behavioural deficits are areas 14 and the medial sectors of 11 and 13 on the orbital surface, as well as areas 25 and 32, located on the ventral aspects of the medial surface (Bechara et al., 1996
) [architectonic areas taken from (Petrides and Pandya, 1994
)]. In addition, regions within both the medial prefrontal and orbitofrontal cortex have been shown to be specifically activated during depressive episodes in familiar pure depressive disease and induction of sadness in normal subjects (Drevets and Raichle, 1995
). Moreover, bipolar depression is associated specifically with a reduction in volume within the subgenual cortex, including area 25 (Drevets et al., 1997
). Thus, when considering the role of the orbitofrontal cortex in emotional behaviour it may be important to consider it in conjunction with the neighbouring medial prefrontal cortex.
In addition, when considering the functions of the orbitofrontal cortex it is important to acknowledge that the term orbitofrontal cortex (sometimes described as the ventral prefrontal cortex) has had a number of different definitions over the years. This has primarily arisen due to a conflict between a definition based upon absolute spatial location, i.e. that area of the cortex lying on the ventral surface of the frontal lobes above the orbits, and one that takes into account architectonic differentiation within the prefrontal cortex. If the orbitofrontal cortex is taken as that which lies on the orbital surface, then, using the nomenclature taken from the most recent comparative cytoarchitectonic analysis of the human and macaque prefrontal cortex (Petrides and Pandya, 1994), orbitofrontal cortex includes Walker's area 12 [described as comparable to Brodmann's area 47 (Brodmann, 1909
)], including that area of 12 that lies within the inferior frontal gyrus (commonly referred to as inferior frontal convexity in monkeys) and areas 11, 13 and 14. In contrast, taking into account the cytoarchitectonics of the prefrontal cortex, in particular the presence or absence of a well-developed granular layer IV, Preuss has argued that the orbital domain is non-granular, or certainly dysgranular, and consists primarily of areas 13 and 14, while area 12/47 and 11 are granular in character and should be considered, along with areas 8, 9, 10, 44, 45 and 46 on the dorsal surface, as part of granular prefrontal cortex (Preuss and Goldman-Rakic, 1991
; Preuss, 1995
). For the purposes of this paper, the traditional view of the orbitofrontal cortex, as all the cortex lying along the orbital/ventral surface, will be taken, including areas 11, 13 and 14 and all of area 12/47. However, when reviewing the lesion literature in humans and macaques, particular attention will be paid to the precise locus of damage.
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The Inhibitory Control Functions of the Prefrontal Cortex: Evidence for a Dissociation between Lower-order and Higher-order Rule Learning |
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When comparing the WCST used in the clinic with the classic object discrimination reversal task used in experimental studies in monkeys, it is clear that the two tasks involve very different kinds of psychological processes. In the WCST subjects have to learn to attend to the perceptual dimensions of the stimuli (such as their shape) and to use one of these dimensions to guide responding, and then learn to shift from one dimension to another (i.e. from shape to colour). In contrast, in object discrimination reversals no such shift of an attentional set is required. Instead, monkeys have to reverse stimulusresponse or stimulusreward associations within a particular perceptual dimension, i.e. inhibit responding to object A and instead respond to object B [see (Roberts et al., 1988) for a detailed account]. Therefore, in the WCST subjects have to shift attentional set from one perceptual dimension to another while in discrimination reversals animals switch their responding between one of two visual stimuli within a particular perceptual dimension. Thus our first study set out to investigate the role of the prefrontal cortex in these two types of shift using a computerized test that requires monkeys or humans to learn a series of compound visual discriminations (Fig. 1a
).
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The finding that different types of behavioural disinhibition were associated with damage to at least two different regions of prefrontal cortex ran contrary to the hypothesis that inhibitory control was primarily a function of the orbitofrontal cortex. However, it did provide an explanation for the apparent discrepancy between human and non-human primate studies with respect to the anatomical locus of inhibitory control. Thus the impairment in shifting categories in the WCST associated with damage to the dorsolateral prefrontal, but not the orbitofrontal, cortex in humans is similar to the impairment in shifting an attentional set associated with damage to the lateral prefrontal, but not the orbitofrontal, cortex in marmosets. Moreover, the impairment is independent of the deficit in performing a reversal of a visual discrimination task reported in monkeys with orbitofrontal damage. These findings raise the possibility that the ability to suppress inappropriate pre-potent response tendencies is an intrinsic property of the prefrontal cortex as a whole, with the precise form of the disinhibition being dependent on the nature of the psychological operations performed by any one region. To assess the generality of these findings and determine whether a similar dissociation between lateral prefrontal and orbitofrontal cortex could be found in a more naturalistic setting, we have since investigated the effects of lesions to these two regions of the prefrontal cortex on two different versions of an object retrieval task designed to differentiate higher-order and lower-order rule learning.
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Evidence for a Dissociation between Higher-order Strategy Application and Lower-order Rule Learning in a More Naturalistic Setting |
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The standard version of the task that we employed was identical to that described in Dias et al. in which all monkeys received minimal training on an opaque box to familiarize them with the basic demands of the task, i.e. retrieving reward from within a box, before being tested on their ability to learn to retrieve reward from the transparent box (Dias et al., 1996b). However, in the novel variant all monkeys were overtrained on an opaque version of the box which had doors on each side but with only one door being open on any one trial, and thus the monkey had to find which door was open on that particular trial in order to retrieve the reward. As a consequence of this overtraining, the left and right detour reaches became as reinforced as the direct reach. Thus, when monkeys were confronted with the transparent box for the first time, no one reach was more reinforced than another, and thus with no strong response bias towards making a particular reach, i.e. direct reach, it would be predicted that a lesion of the orbitofrontal cortex would not disrupt performance. However, also as a consequence of overtraining on the opaque box, monkeys acquired a strategy of checking each side of the box, once and once only until they found the open door. Thus, when confronted with the transparent box, the monkey must transfer the strategy of checking each side of the opaque box to the transparent box while, at the same time, inhibiting the simpler behavioural strategy of reaching directly for the now visible reward (see Fig. 3
legend for details). Thus, the monkey must resolve a conflict between two strong, competing response strategies: reaching directly for the reward that is now fully visible and checking each side of the box to find the opening. Such a conflict does not arise in the standard version since monkeys have not had the opportunity to learn the strategy of checking the sides of the boxes. Since the lateral prefrontal cortex has been implicated in the control of higher-order behavioural strategies, it might be predicted that overtraining on the opaque box may induce an impairment in monkeys with lesions of this region of the prefrontal cortex in contrast to monkeys with lesions of the orbitofrontal cortex, in which overtraining may be expected to reduce the likelihood of a deficit.
The results of this investigation are illustrated in Figure 3c,d. Lesions of the orbitofrontal but not the lateral prefrontal cortex disrupted the performance of monkeys on the standard version of the task. While the performance of the lateral lesioned group was the same as that of controls, the orbitofrontal lesioned group made many more errors before learning to make a detour reach around the transparent barrier (Fig. 3c
, minimal training). However, as predicted, overtraining on an opaque box completely abolished any impairment upon transfer to the transparent box in the novel variant of the task, with the performance of orbitofrontal lesioned monkeys now being equivalent to that of controls (Fig. 3d
, overtraining). These findings support the hypothesis that the impaired performance of monkeys with orbitofrontal lesions is due to a failure to inhibit a strong response tendency or habit to reach directly towards the reward as a result of a strong reward (or stimulus)response association. Although orbitofrontal lesioned monkeys made more incorrect barrier and non-barrier reaches compared with controls, the finding that they were not impaired in learning to retrieve the reward through the sides of the opaque box during training on the novel variant of the task suggests that the deficit seen in untrained orbitofrontal lesioned monkeys on the transparent box in the standard version of the task must have been a direct consequence of the presence of the visible reward.
The converse was found in the case of monkeys with lesions of the lateral prefrontal cortex, which, unlike orbitofrontal lesioned monkeys, were not impaired on performance of the standard version of the task but for which a deficit did emerge upon transfer to the transparent box following overtraining in an opaque box. Like the orbitofrontal lesioned monkeys, lateral lesioned monkeys were not impaired in learning to retrieve the reward from the opaque box, and following overtraining both lesioned groups acquired the behavioural strategy of checking each side of the box in turn to determine which was the open side. This latter result is consistent with previous findings (Fig. 2d) that neither lesion impaired the ability of marmosets to develop a behavioural strategy to attend to one particular perceptual dimension in order to solve a series of visual discriminations. It also confirms that at the time of transfer to the transparent box monkeys with lesions of the lateral prefrontal cortex, like controls and orbitofrontal lesioned monkeys, had developed a behavioural strategy. However, unlike controls and orbitofrontal lesioned monkeys, they were impaired at inhibiting responding directly to the now visible reward. It could be argued that, since the lateral lesioned monkeys had an intact orbitofrontal cortex which could inhibit inappropriate stimulus response tendencies, such a mechanism could have prevented the lateral lesioned monkeys from responding to the reward. However, given that any one particular response can be governed by a number of different lower-order and higher-order response mechanisms, then even if the lower-order mechanism is being successfully inhibited, this in itself may not preclude that same response being activated by a higher-order control system (Dias et al., 1996a
, 1997
; Wise et al., 1996
). In addition, they confirm our specific proposal that both higher-order and lower-order levels of response selection contribute to performance of the object retrieval task.
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Inhibitory Control and its Relation to Affective Processing |
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These findings have been interpreted as suggesting that both the orbital and medial regions of the prefrontal cortex contribute to affective behaviour, but while the lateral orbitofrontal cortex is involved generally in the inhibitory control of such behaviour, the medial orbital and medial prefrontal cortex are involved particularly in that aspect of behaviour that is governed by knowledge of specific stimulusreward relationships. Clearly, such a view is in contrast to our working hypothesis that inhibitory control may be a general process operating across all regions of the prefrontal cortex (Dias et al., 1996a, 1997
). However, to address the latter hypothesis it is necessary to examine the effects of lesions restricted to different areas within the orbital and medial prefrontal cortex on a range of different types of inhibitory control task. The only such study to have been performed in monkeys compared the effects of lesions to the posteromedial, anteromedial and lateral orbitofrontal cortex on a discrimination reversal task and extinction of a foodrewarded instrumental response (Butter, 1969
). While precise details of the lesions are lacking, making it difficult to localize the observed behavioural effects to specific areas within the orbital and medial prefrontal cortex, the results did suggest that under certain circumstances perseverative responding following extinction of a bar-pressing response may be dissociable from a perseverative deficit on a discrimination reversal task.
Consequently, in order to clarify the nature of the relationship between inhibitory control and affective processing within the orbital and medial prefrontal cortex we compared the effects of lesions of the medial prefrontal cortex of the marmoset with those seen following damage to the orbitofrontal cortex as well as the lateral prefrontal cortex on two different tests requiring inhibitory control object retrieval and extinction of a foodrewarded response along with a test of food preference. To control for changes in performance as a result of altered motivation, the number of responses marmosets were prepared to make for a single reward was examined using a progressive ratio schedule.
Lesions of the medial prefrontal cortex did disrupt the performance of monkeys on the standard version of the object retrieval task but, unlike the deficits seen following lesions of the orbitofrontal and lateral prefrontal cortex, the deficit was not restricted to performance on the transparent box. Monkeys with lesions of the medial prefrontal cortex not only made more errors than controls on the standard version of the task but also their performance was impaired during overtraining on the opaque box in the novel variant of the task, e.g. they tended to make awkward reaches through the doors, i.e. using two hands, one to open the door and the other to retrieve the food reward a response never seen in sham-operated controls, or lateral prefrontal or orbitofrontal lesioned monkeys. However, it could not be determined whether this was a problem in motor control or a strategy adopted by the medial prefrontal lesioned monkeys in order to actually see the reward within the opaque box before retrieving it. While for two of the medial prefrontal lesioned monkeys the awkward reaching was seen when attempting to retrieve the reward from either side of the box, for the other two monkeys it was only observed when attempting to retrieve the reward from one side only. Monkeys with lesions of the medial prefrontal cortex also made by far the greatest number of responses during extinction of a food-rewarded response. Having been trained to respond to a central coloured square presented on a touch-sensitive computer screen in order to gain a reward, all monkeys were placed under extinction in which, after the first 20 responses, all subsequent responses were unrewarded. While monkeys with lateral prefrontal or orbitofrontal cortex lesions responded at a level similar to controls during extinction, the medial prefrontal lesioned monkeys made significantly more responses (Fig. 4). However, although the medial prefrontal lesioned monkeys were significantly different from both controls and lateral lesioned monkeys, their performance did not differ significantly from the orbital lesioned monkeys. In order to determine whether the prolonged responding during extinction by monkeys with medial prefrontal lesions could be the result of a general alteration in motivation, their performance was compared with controls on a progressive ratio schedule which determines the maximum number of responses an animal is prepared to make in order to obtain a reward (see Fig. 4b
for details of experimental design). Since the level of responding reached by monkeys with medial prefrontal lesions did not differ to that of controls, it is unlikely that a change in motivation was responsible for the lesioned monkeys' altered performance during extinction.
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Blunted food preferences, on a task similar to that used in the present study, have been observed in rhesus monkeys following ablation of the ventromedial prefrontal cortex (including areas 11, 13 and 14) (Baylis and Gaffan, 1991). In contrast, monkeys with lesions of the orbitofrontal cortex in the present study did not differ from controls in their ability to develop preferences, although there may have been a slight trend for an impairment. This may reflect differences between the extent of the lesions in the two studies, but may also reflect differences in the food preference test used in the two studies. In Baylis and Gaffan's study (Baylis and Gaffan, 1991
) the most marked behavioural difference between lesioned and controls monkeys was the lesioned monkeys' choice of meat, a food that normal unoperated monkeys consistently avoid. The same abnormal response to meat has also been observed in monkeys that have received amygdalectomies (Aggleton and Passingham, 1981
) and was shown subsequently to be accounted for fully by the failure of amygdalectomized monkeys to avoid meat (Aggleton and Passingham, 1982
). Since it has been reported that normal unoperated rhesus monkeys will readily accept meat once they have eaten foods that have been adulterated with meat, Aggleton and Passingham proposed that the deficit in food preference following amygdalectomy was more likely a consequence of reduced neophobia rather than an impairment in the expression of relative food preferences (Aggleton and Passingham, 1982
). Thus, the blunted food preferences displayed by rhesus monkeys following ventromedial prefrontal ablation may also be the result of reduced neophobia. However, in the present study none of the novel foods used in the test elicited a neophobic reaction and therefore any blunting of preferences cannot be the result of a reduction in neophobia. The one unpalatable food item, i.e. lemon, was only avoided after having been selected and tasted. Consequently, the blunted food preferences between the three palatable foods observed were more likely to be the result of a failure to acquire relative reward preferences or to use such information to guide choice behaviour.
In summary, while the behavioural effects of lesions of the medial prefrontal cortex could be dissociated from those seen following lesions of the lateral prefrontal cortex on both versions of the object retrieval task and extinction of a food-rewarded response, they were less clearly dissociable from the effects of lesions of the orbitofrontal cortex. Many of the differences observed tended to be quantitative, rather than qualitative, in nature. Thus, lesions of the medial prefrontal cortex induced significantly prolonged responding during extinction of a foodrewarded response and significantly blunted food preferences. In contrast, while monkeys with lesions of the orbitofrontal cortex showed a trend towards both prolonged responding during extinction and blunted food preferences, these effects did not reach statistical significance as they were not consistently observed in all monkeys and were far less marked than those seen following medial prefrontal lesions. The converse was the case for performance on the object retrieval task. While monkeys with lesions of the orbitofrontal cortex showed a severe behavioural impairment on the standard version of the task, the deficit seen in monkeys with lesions of the medial prefrontal cortex was much less severe. However, while the deficit following orbitofrontal lesions was specific to acquiring the detour reach around the transparent box in the standard version of the object retrieval task and therefore was dependent upon the reward being visible, the deficit following lesions of the medial prefrontal cortex was relatively non-specific, since these lesioned monkeys also showed impaired performance during overtraining on the opaque box in the novel variant of the object retrieval task. Thus, the deficit following a lesion of the medial prefrontal cortex on the object retrieval task was less likely the result of a failure of inhibitory control.
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Different Types of Associative Learning Mechanism within the Orbitofrontal and Medial Prefrontal Cortex? |
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Summary and Conclusions |
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Notes |
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Address correspondence to A.C. Roberts, Department of Anatomy, University of Cambridge, Downing Site, Cambridge CB2 3DY, UK. Email: acr4{at}cus.cam.ac.uk.
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Footnotes |
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References |
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