Inhibitory Control and Affective Processing in the Prefrontal Cortex: Neuropsychological Studies in the Common Marmoset

A.C. Roberts and J.D. Wallis1

Department of Anatomy, University of Cambridge, Downing Site, Cambridge CB2 3DY, UK


    Abstract
 Top
 Abstract
 Introduction
 The Inhibitory Control Functions...
 Evidence for a Dissociation...
 Inhibitory Control and its...
 Different Types of Associative...
 Summary and Conclusions
 Notes
 References
 
The orbitofrontal cortex has been ascribed a role in the inhibitory control, as well as in the emotional control, of behaviour. While damage to the orbitofrontal cortex in humans and non-human primates can cause inflexibility, impulsiveness and emotional disturbance, the relationship between these effects are unclear. Excitotoxic lesion studies in marmosets comparing the effects of cell loss within specific regions of the prefrontal cortex on performance of a range of behavioural tests reveal that mechanisms of response inhibition are not unique to the orbitofrontal cortex. Instead they are present in distinct cognitive domains for lowerorder as well as higher-order processing throughout the prefrontal cortex. Thus, the lateral prefrontal cortex is involved in the selection and control of action based upon higher-order rules while the orbitofrontal and medial prefrontal cortex may be involved in different but complementary forms of lower-order rule learning, their roles dissociable, as a result of their differential contribution to different types of associative learning.


    Introduction
 Top
 Abstract
 Introduction
 The Inhibitory Control Functions...
 Evidence for a Dissociation...
 Inhibitory Control and its...
 Different Types of Associative...
 Summary and Conclusions
 Notes
 References
 
Over the years two major classes of theory of orbitofrontal function have been proposed, one that stresses the importance of the orbitofrontal cortex in inhibitory control and the other that stresses its importance in the control of emotionality (Mishkin, 1964Go; Fuster, 1989Go, 1998Go; Damasio et al., 1991Go). Evidence for the former comes primarily from experimental lesion studies in monkeys which have shown that damage to the orbitofrontal cortex disrupts performance on those tasks which require inhibition of a pre-potent response tendency. These include (i) an object discrimination reversal task in which a monkey, having learned to respond to one of two simultaneously presented objects in order to obtain reward, is required to inhibit that response, and instead, to begin responding to the other, previously unrewarded object, in order to gain reward (Iversen and Mishkin, 1970Go; Jones and Mishkin, 1972Go); (ii) a go–no go asymmetric discrimination task in which, on any one trial, one of two objects is presented but only a response to one of the objects is rewarded and thus the monkey learns to withhold responding to the unrewarded object (McEnanay and Butter, 1969; Iversen and Mishkin, 1970Go); and (iii) an instrumental response task in which a previously rewarded response is no longer rewarded, leading to extinction of that response (Butter, 1969Go). In all these examples monkeys with orbitofrontal damage appear perseverative, continuing to make responses that are no longer rewarded.

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., 1970Go; Franzen and Myers, 1973Go; Raleigh and Steklis, 1981Go). 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 Kluver–Bucy syndrome, particularly those aspects of the syndrome associated with damage to the amygdala (Weiskrantz, 1956Go). 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, 1868Go), 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, 1985Go). However, like monkeys with orbitofrontal damage, patients with orbitofrontal damage also exhibit signs of behavioural disinhibition, often being described as impulsive (Hornak et al., 1996Go). In an attempt to measure this impulsivity in a laboratory setting Rolls and colleagues tested patients with orbitofrontal damage on the reversal of a go–no go discrimination (Rolls et al., 1994Go). 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, 1970Go), 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, 1964Go; Fuster, 1989Go, 1998Go), 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., 1996Go) [architectonic areas taken from (Petrides and Pandya, 1994Go)]. 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, 1995Go). Moreover, bipolar depression is associated specifically with a reduction in volume within the subgenual cortex, including area 25 (Drevets et al., 1997Go). 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, 1994Go), orbitofrontal cortex includes Walker's area 12 [described as comparable to Brodmann's area 47 (Brodmann, 1909Go)], 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, 1991Go; Preuss, 1995Go). 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.


    The Inhibitory Control Functions of the Prefrontal Cortex: Evidence for a Dissociation between Lower-order and Higher-order Rule Learning
 Top
 Abstract
 Introduction
 The Inhibitory Control Functions...
 Evidence for a Dissociation...
 Inhibitory Control and its...
 Different Types of Associative...
 Summary and Conclusions
 Notes
 References
 
One of the problems with the original hypothesis that the orbitofrontal cortex was specifically involved in the inhibitory control of behaviour was that one of the most commonly described deficits in inhibitory control in humans is that seen in patients, not with orbitofrontal damage, but instead with damage to dorsolateral prefrontal cortex, performing the Wisconsin Card Sort Test (WCST) (Milner, 1964Go). This test requires subjects to learn to sort a pack of cards according to a particular perceptual dimension, i.e. shape, and to switch from sorting the cards from one category to another, i.e. shape to colour. It was claimed that patients with damage to dorsolateral rather than orbital regions of the prefrontal cortex exhibited perseverative responding on the test, continuing to sort the cards, at the time of the switch, according to the previously relevant perceptual dimension (Milner, 1964Go; Eslinger and Damasio, 1985Go; Shallice and Burgess, 1991Go). This was in contrast with the findings in monkeys in which perseverative responding was associated primarily with damage to the orbitofrontal cortex (Mishkin, 1964Go; Fuster, 1989Go). It was this dichotomy between the monkey and human studies that formed the basis of our original investigations into the nature of the inhibitory control functions of the prefrontal cortex (Dias et al., 1996aGo,bGo).

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 stimulus–response or stimulus–reward associations within a particular perceptual dimension, i.e. inhibit responding to object A and instead respond to object B [see (Roberts et al., 1988Go) 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. 1aGo).



View larger version (45K):
[in this window]
[in a new window]
 
Figure 1.  (a) The shape and line exemplars used for various stages of the attentional set-shifting paradigm. In this example the dimension of ‘shape’ is relevant in all discriminations except that requiring an EDS (iv) and reversal (v), and a subsequent IDS II(vi). On any one trial of a compound discrimination, a shape exemplar may be paired with one or other of the line exemplars. Correct and incorrect choices are indicated by + and –, respectively. Grey typeface specifies that ‘shape’ is the relevant dimension, whereas black typeface specifies that ‘line’ is the relevant dimension. (b) Mean number of errors (± SEM) to reach criterion on a visual discrimination that requires maintenance of an attentional set towards the previously relevant dimension, IDS (I); a switch of attentional set from one dimension to another, EDS (I); and reversal of a response between two exemplars within the relevant dimension, REV (I), in monkeys that received excitotoxic lesions of either the lateral prefrontal (Lat) (n = 3) or orbitofrontal (Orb) cortex (n = 3) or a sham operation (C) (n = 3). While the lateral prefrontal lesioned group was impaired on the EDS relative to controls and orbitofrontal lesioned monkeys (*, P < 0.001), the orbitofrontal lesioned group differed significantly from controls and the lateral prefrontal lesioned group on the reversal (**, P < 0.001). (c) Mean number of errors (± SEM) to reach criterion on subsequent visual discriminations that required an IDS [IDS (II)], a second EDS, whereby the dimension that had been relevant earlier on, i.e. prior to EDS (I), had to be re-engaged [EDS (II)] and a second reversal [REV (II)] whereby the previously correct exemplar at EDS (II) became incorrect and vice versa. There were no differences between the groups in performance at any of these stages. (d) Mean number of errors (± SEM) made by sham-operated controls (open bars) (n = 3), lateral prefrontal lesioned marmosets (pale hatched bars) (n = 3) and orbitofrontal lesioned marmosets (dark hatched bars) (n = 3) to reach criterion on a series of compound discriminations in which the same dimension remained relevant across all five discriminations. The improved performance across discriminations (as indicated by the reduction in errors) shown by all three groups, reflects the acquisition of an attentional set towards the relevant perceptual dimension.

 
Two different regions of the prefrontal cortex in a new world monkey, the common marmoset, were compared: the lateral prefrontal region, composed of areas with a well-developed granular layer IV, and the orbitofrontal cortex, containing areas with a far less developed layer IV (Dias et al., 1996bGo). In the first study (Dias et al., 1996aGo) all monkeys were trained prior to surgery to perform a simple and then a series of compound discriminations (composed of two abstract dimensions, blue-filled shapes and white lines). In each of the compound discriminations an exemplar from the same perceptual dimension, e.g. bluefilled shapes, was positively associated with reward across each discrimination [see Fig. 1aGo(ii)]. Following surgery, in which monkeys either received an excitotoxic lesion of the lateral prefrontal cortex or orbitofrontal cortex (illustrated in Fig. 2Go), or a vehicle control procedure, three aspects of discrimination learning were studied: the ability of monkeys firstly, to perform compound discriminations that required them to maintain attentional set towards the previously relevant perceptual dimension, e.g. shapes [Fig. 1aGo(iii)], secondly, to shift their attentional set from one perceptual dimension to another, e.g. shapes to lines [Fig. 1aGo(iv)] and finally to reverse responding between two stimuli or exemplars within the relevant dimension [Fig. 1aGo(v)], e.g. from the previously rewarded line to the previously unrewarded line in Figure 1aGo(iv).



View larger version (58K):
[in this window]
[in a new window]
 
Figure 2.  (a) Schematic diagrams of a series of coronal sections through the frontal lobes illustrating the site of the lesion of the lateral prefrontal (pale hatching), medial prefrontal (dark hatching) and orbitofrontal (intermediate hatching) cortices of representative marmosets. For comparative purposes, all three lesion types are depicted on one brain. The orbitofrontal cortex consists of dysgranular cortex, lateral prefrontal cortex of well-developed granular cortex and medial prefrontal cortex of agranular and dysgranular cortex. (b) Low power photomicrographs of cresyl violet-stained coronal sections through an intermediate level of the frontal pole taken from a representative marmoset from the lateral, medial and orbital lesioned groups. The almost total cell loss in the lateral prefrontal cortex following an excitotoxic lesion of this region is in stark contrast to the dense layering of neurons seen in the same region of an animal that has received either a medial or an orbital lesion. Similarly, the extensive cell loss in the medial prefrontal cortex following an excitotoxic lesion of this cortical region is in marked contrast to the dense layering of neurons seen in the same region of an orbital or lateral lesioned monkey. Finally, the marked cell loss in the orbitofrontal cortex following an excitotoxic lesion of this region of cortex, as indicated by the large reduction in cortical thickness, is in contrast to the dense layering of neurons seen in the orbitofrontal cortex of the other two representative lesions. Arrowheads in each photomicrograph mark the boundaries of each lesion site. lat, lateral prefrontal cortex; orb, orbitofrontal cortex; med, medial prefrontal cortex.

 
The results of this study are shown in Figure 1bGo. Monkeys with a lesion to either the lateral prefrontal or orbitofrontal cortex were not impaired at learning novel discriminations in which the dimension that had been relevant previously remained relevant, i.e. an intra-dimensional shift. However, whereas lesions of the lateral prefrontal cortex impaired performance on a discrimination which required monkeys to shift their attentional set from one dimension to another and thus learn to respond to an exemplar from the previously irrelevant dimension, i.e. an extradimensional shift, lesions of the orbitofrontal cortex did not. In contrast, the opposite pattern was seen on performance of the discrimination reversal. Monkeys with lesions of the orbitofrontal cortex displayed marked perseverative responding, making many more responses to the previously rewarded exemplar than either controls or monkeys with lesions to the lateral prefrontal cortex. Thus, set-shifting ability was impaired by lateral lesions but not orbital lesions, while reversal learning was impaired by orbital but not lateral lesions, suggesting that a loss of inhibitory control can occur independently at different levels of psychological processing — at the higher-order level of attentional selection (or strategy application) following lesions of lateral prefrontal cortex and at the lower-order level of learning associations between reward and specific stimuli or responses, following lesions of the orbitofrontal cortex. Subsequently, it was demonstrated in an independent study (Dias et al., 1997Go) that firstly, these impairments were restricted to the first occasion on which such shifts in responding were required. Performance on subsequent reversals of stimulus–reward associations or an additional shift of an attentional set [requiring monkeys to switch their responding from the current relevant dimension back to the perceptual dimension that had been relevant initially; Fig. 1aGo(vii)] were unaffected by the lesions (Fig. 1cGo). Secondly, neither lesion disrupted the ability of marmosets to perform compound discriminations per se, or to develop or maintain an attentional set towards one particular perceptual dimension (Fig. 1dGo), highlighting further the specificity of the deficit to one of a disruption of inhibitory control mechanisms.

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.


    Evidence for a Dissociation between Higher-order Strategy Application and Lower-order Rule Learning in a More Naturalistic Setting
 Top
 Abstract
 Introduction
 The Inhibitory Control Functions...
 Evidence for a Dissociation...
 Inhibitory Control and its...
 Different Types of Associative...
 Summary and Conclusions
 Notes
 References
 
Object retrieval requires an animal to inhibit the pre-potent response tendency to reach towards a visible reward and, instead, to make a detour reach around a transparent barrier in order to obtain the reward (Diamond, 1990Go). The test consists of a transparent box which, at any one time, is open on only one side, with the position of the open side (left, right or in front of the animal) varying across trials. The reward is placed deep within the box and the monkey has to learn to obtain the reward by reaching through whichever side of the box is open on that particular trial. Since the pre-potent response tendency of animals is to reach along their line of sight directly towards the reward, all monkeys, when having to make a detour reach, initially make errors on the task, tending to reach directly into the transparent front wall of the box — a response described as ‘barrier reaching’ (Fig. 3aGo). However, monkeys without brain damage learn to inhibit this response and instead to make the necessary detour reach around the transparent front wall and into the open left, or right side, of the box (Fig. 3bGo). Using this test, Diamond demonstrated that there was a critical stage in development before which a human child or infant monkey was unable to inhibit the pre-potent response tendency to reach directly along their line of sight in order to obtain the reward (Diamond, 1990Go). A similar failure was observed in adult rhesus monkeys with damage to the dorsolateral frontal cortex, including Walker's areas 9, 46 and 8 (Walker, 1980), suggesting that this region was critical for the suppression of such pre-potent responses. Since then, reduced activity in the striatal and, to a lesser extent, prefrontal dopamine systems, induced by prolonged MPTP treatment, has also been shown to disrupt object retrieval performance (Taylor et al., 1990Go; Schneider and Roeltgen, 1993Go), as has prolonged treatment with PCP, a glutamatergic agonist which has been shown to reduce dopaminergic activity in the frontal lobes (Jentsch et al., 1997Go). We too have shown that combined damage to both the lateral prefrontal and orbitofrontal cortex in the marmoset impairs acquisition of the object retrieval task, with lesioned monkeys making many more incorrect barrier, as well as non-barrier, reaches before learning to make a detour reach (Dias et al., 1996bGo).



View larger version (81K):
[in this window]
[in a new window]
 
Figure 3.  Still frames taken from videotapes of the marmoset's behaviour during the performance of the object retrieval task are shown in (a) and (b). In (a) a marmoset can be seen making a ‘barrier’ reach directly into the transparent front wall of the box on a trial in which the opening to the box is on the animal's right hand side. The same side is open in (b) and this time a marmoset is seen performing a successful detour reach around the transparent barrier through the side opening in order to retrieve food reward placed deep within the box. The position of the reward in both examples is marked by the arrow. (c) Performance on the standard version of the object retrieval task showing the total number of barrier and non-barrier reaches until marmosets were able to make a successful reach around the transparent barrier through the side opening on the first attempt of the trial using their preferred hand. (A number of monkeys within the different lesioned and control groups displayed a hand preference whereby they would try to use one particular hand to retrieve the reward regardless of whether the opening of the box was on the right or left side. However, since it was impossible to retrieve the food reward through the right opening using the left hand and vice versa, these monkeys would make a large number of incorrect reaches when they had to use their unpreferred hand. This led to greater variability within groups on the side involving the use of the unpreferred hand and so hand preference was used as an additional factor in the analysis so that the cognitive ability of marmosets to learn the detour reach could be differentiated from any motoric difficulty.) Values are mean number of reaches (± SEM) for marmosets that had received an excitotoxic lesion of the lateral prefrontal ({square}) (n = 3) or orbitofrontal ({bigtriangleup}) (n = 3) cortex or a sham operation ({circ}) (n = 3). The orbital lesioned group made significantly more reaches than either the control (P < 0.01) or lateral lesioned groups (P < 0.01), while the lateral lesioned and control groups did not differ from one another. (d) Performance on the novel variant of the object retrieval task in which all monkeys received extensive overtraining on an opaque version of the box before being presented with the transparent version. The graph shows the total number of barrier and non-barrier reaches made by lateral prefrontal (n = 4) and orbitofrontal (n = 4) lesioned monkeys and sham-operated controls (n = 4) in the session in which they were confronted with the transparent version for the first time. The lateral prefrontal lesioned group made significantly more barrier reaches than either the control group (P < 0.05) or the orbitofrontal lesioned group (P < 0.05). In an independent study, the performance of monkeys with lesions of the medial prefrontal cortex (n = 3) was compared with that of monkeys with either lesions of the lateral prefrontal (n = 3) or orbitofrontal (n = 3) cortex or who had received sham surgery (n = 3) on the standard version of the object retrieval task. Monkeys with lesions of the medial prefrontal cortex made many more non-barrier reaches than controls using the preferred hand (P < 0.05). Unlike lateral prefrontal or orbitofrontal lesioned monkeys, monkeys with lesions of the medial prefrontal cortex were also impaired on their final level of performance on the opaque box (following overtraining), before transfer to the transparent box on the novel variant of the object retrieval task, primarily as a consequence of their awkward reaching (see text for details of awkward reaching).

 
However, the seemingly simple response of reaching directly towards the reward, the very response that needs to be inhibited when learning to make the detour reach, is probably controlled by a number of different response mechanisms which in some cases may arise from different levels within the motor system. For example, reaching directly towards the reward may be a simple Pavlovian approach response or may be an instrumental habit, whereby the presence of the reward simply triggers the habitual reaching response [see (Dickinson, 1994Go) for a detailed discussion of instrumental habits]. In certain circumstances it may also be controlled at a higher-order level whereby monkeys have learned to obtain reward by adopting the strategy of attending to, and directing responses towards, the reward. Indeed, independent evidence that the object retrieval task may depend upon inhibition of a higher-order behavioural strategy has been provided in a recent study by Hauser and colleagues in which ‘paradigmatic’ perseveration has been identified as being responsible, in part, for the poor performance of intact tamarins on the object retrieval task (Hauser, 1999Go). Thus, in order to define more precisely the nature of the contribution of the prefrontal cortex to performance of this task, and to determine whether the lateral prefrontal and orbitofrontal cortex may contribute differentially to performance, we investigated the effects of selective lesions of the orbitofrontal and lateral prefrontal cortex on two different versions of the task. These different versions were designed specifically to examine the possibility that successful performance of the task may require the inhibition of both a higher-order behavioural strategy and a lower-order response tendency to reach directly for the reward, these inhibitory control processes being differentially sensitive to damage to the lateral prefrontal and orbitofrontal cortex in the marmoset, respectively (J.D. Wallis, T.W. Robbins and A.C. Roberts,  submitted for publication).

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., 1996bGo). 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. 3Go 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,dGo. 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. 3cGo, 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. 3dGo, 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. 2dGo) 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., 1996aGo, 1997Go; Wise et al., 1996Go). 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.


    Inhibitory Control and its Relation to Affective Processing
 Top
 Abstract
 Introduction
 The Inhibitory Control Functions...
 Evidence for a Dissociation...
 Inhibitory Control and its...
 Different Types of Associative...
 Summary and Conclusions
 Notes
 References
 
There is limited evidence for functional heterogeneity within the orbitofrontal cortex. While ablation of either the lateral orbitofrontal cortex (Walker's area 12, including the cortex of the inferior prefrontal convexity and the anterolateral region of the orbitofrontal cortex) or the medial orbitofrontal cortex (Walker's areas 11, 13 and 14) disrupts the performance of monkeys on a visual discrimination serial reversal task, the nature of the impairment differs between the two groups (Iversen and Mishkin, 1970Go). A selective increase in the number of perseverative responses made to the previously rewarded object underlies the impairment in monkeys with lesions of the lateral orbitofrontal cortex, consistent with their failure also to inhibit responding to the unrewarded tone in an auditory go–no go task. In contrast, monkeys with lesions of the medial orbitofrontal cortex, while able to reduce their responding to the previously rewarded object as rapidly as controls, make more errors overall at performing reversals, suggestive of a more general impairment in acquiring knowledge about which objects in the environment are associated with reward. Indeed, Gaffan and Murray have shown that ablation of the medial orbitofrontal cortex produces a mild impairment on the acquisition of a series of object discrimination problems (Gaffan and Murray, 1990Go). The same lesion also results in abnormal food preferences, reminiscent of that seen following ablation of the amygdala, whereby lesioned monkeys consistently choose and retain meat, a food unpalatable to controls (Baylis and Gaffan, 1991Go). Again, a deficit in affective processing may underlie such behaviour, reflecting a deficit either in acquiring affective preferences per se or learning to associate particular stimuli in the environment with affective preferences. Similarly, it is damage primarily restricted to the medial orbital and medial prefrontal cortex in humans that is associated with profound changes in social behaviour, including abnormal autonomic responses to social stimuli (Damasio et al., 1990Go) as well as abnormal autonomic responses on a card gambling task (Bechara et al., 1996Go), effects which appear to parallel their aberrant social behaviour. Indeed, the evidence for an involvement of the medial prefrontal cortex in the control of autonomic activity has been well documented in the literature [see (Neafsey, 1990Go) for a comprehensive review].

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 stimulus–reward 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., 1996aGo, 1997Go). 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, 1969Go). 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. 4Go). 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. 4bGo 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.



View larger version (50K):
[in this window]
[in a new window]
 
Figure 4.  (a) Mean number of responses made during extinction of a food-rewarded response by monkeys which had received either an excitotoxic lesion of the medial prefrontal (dark hatched bar) (n = 3), orbitofrontal (pale hatched bar) (n = 3) or lateral prefrontal (striped bar) (n = 2) cortex or a sham-operated control procedure (open bar) (n = 3). For presentation of descriptive statistics the standard error of the differences of the means (SED) was used, as it provides a better estimate of the population variance. The SED is calculated using the formula provided by Cochran and Cox (Cochran and Cox, 1957Go). A one-way ANOVA revealed a main effect of Group [F(3,7) = 5.76, P = 0.026]. Post-hoc analysis using the Newman–Keuls test revealed that the medial prefrontal lesioned group made significantly more responses during extinction than either the control or lateral lesioned group. The orbitofrontal lesioned group did not differ from the control group or the medial prefrontal lesioned group. (b) Mean number of responses over the last five sessions (during which monkeys were displaying stable performance) on the progressive ratio schedule in monkeys which had received either an excitotoxic lesion of the medial prefrontal cortex (dark hatched bar) (n = 3) or a sham-operated control procedure (open bar) (n = 3). The groups did not differ from one another [t(4) = –0.66]. Progressive ratio schedule: monkeys were required to respond to a central square presented on a touch-sensitive computer screen to receive 5 s of reinforcement, making progressively more and more responses to receive reinforcement. At the start of each session, each monkey had to make just one response to receive reinforcement. The response requirements were then incremented to two, three, four and then six responses in order to receive reinforcement. From then on each subsequent reinforcement required an additional three responses. The session either lasted 30 min or was terminated if no response was made in 8 min. A running coefficient of variation of the total number of responses that were made in each of the last five sessions was calculated and performance considered stable if a value of <0.3 was obtained.

 
Finally, when tested on a food preference test, monkeys with a lesion of either the lateral or medial prefrontal cortex showed blunted food preferences in comparison with controls. While the preferences shown by orbitofrontal lesioned monkeys did not differ significantly from controls, their behaviour also did not differ significantly from either the medial or lateral prefrontal lesioned monkeys (Fig. 5Go). Food preference tests examine the ability of monkeys to develop food preferences for a number of novel palatable and unpalatable food items and to learn to associate the sensory properties of each food item, e.g. its colour, texture, shape, with these affective preferences. The monkey's relative preferences for the various foods can then be assessed by measuring their choices when presented with pairs of the food items. In the version used here, all marmosets were presented on three consecutive sessions with a series of choices between pairs of food items taken from a set of four novel foods: popcorn, marzipan, mushroom and lemon. On any one trial, two of the novel food items were paired together and the monkey was given the opportunity to choose just one of them. Their choices were recorded and subsequently their relative preferences for the four novel foods were determined. While lemon was unpalatable for all monkeys, those with a lesion of either the lateral or medial prefrontal cortex showed blunted preferences for the remaining three palatable food items.



View larger version (12K):
[in this window]
[in a new window]
 
Figure 5.  Mean number of times each food was chosen in rank order of preference across the three sessions of the food preference task in acquisition by monkeys with excitotoxic lesions of the lateral prefrontal ({square}), orbitofrontal ({bigtriangleup}) or medial prefrontal ({diamond}) cortex or who had received a sham operation ({circ}). For presentation of descriptive statistics the SED was used (see Fig. 4Go legend). These data could not be analysed using a repeated-measures ANOVA since the different levels of the preference factor are negatively correlated and linearly dependent, i.e. if a monkey shows a strong preference for one food on the food preference test it must also show a weaker preference for the other foods. Thus, in order to measure an individual marmoset's degree of preference, the standard deviation of each animal's choice scores was examined. The standard deviation was greatest for the scores of those marmosets that displayed very strong, consistent preferences across the four foods, i.e. displayed a very clear first, second, third and fourth choice. A one-way ANOVA revealed a significant difference between the groups [F(3,8) = 4.46, P < 0.05]. Post-hoc analysis using Newman–Keuls failed to reveal which groups were significantly different from one another. If the analysis was restricted using Dunnett's t-test, the medial and lateral lesioned groups (P < 0.05), but not the orbital lesioned group, were found to be significantly different from the control group. Food preference test: the maximum number of times a particular food could have been chosen was 36. Each session was composed of 24 trials in which each of the possible four food items was paired with one of the other three food items an equal number of times. If a monkey failed to choose either of the food items presented on a particular trial within a 1 min period, then the trial was scored a fail.

 
These results demonstrate that both the medial and the lateral prefrontal cortex can contribute to the development of food preferences, as measured by the food preference test. However, careful analysis of the nature of the choices made, and the behaviour of all monkeys while performing the task, could not determine the differential contribution of the lateral and medial prefrontal regions to the development of food preferences. One possibility, based upon the effects of the lateral prefrontal lesion on attentional set-shifting and object retrieval, which is currently being investigated, is that the lateral prefrontal cortex is involved in the learning of a general strategy to aid performance of the task, e.g. to attend to all food items on each trial to ensure that the most preferred food item is chosen. Such a strategy would override any tendency of the monkey to respond to the first palatable food that is seen once the screen goes up at the start of the trial. In contrast, the medial prefrontal cortex may be more involved in the development of the specific food preferences. If so, it would be predicted that lateral lesioned monkeys, who had been trained on the food preference test prior to surgery, would not be impaired at acquiring preferences to a novel set of food items post-surgery since they would have already learned the appropriate strategy. In contrast, monkeys with lesions of the medial prefrontal cortex would be expected to be impaired whenever they were required to acquire a new set of preferences and use the information to guide action.

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, 1991Go). 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, 1991Go) 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, 1981Go) and was shown subsequently to be accounted for fully by the failure of amygdalectomized monkeys to avoid meat (Aggleton and Passingham, 1982Go). 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, 1982Go). 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.


    Different Types of Associative Learning Mechanism within the Orbitofrontal and Medial Prefrontal Cortex?
 Top
 Abstract
 Introduction
 The Inhibitory Control Functions...
 Evidence for a Dissociation...
 Inhibitory Control and its...
 Different Types of Associative...
 Summary and Conclusions
 Notes
 References
 
In discrimination reversal, object retrieval, extinction of a food-rewarded response and the test of food preference the selection of specific responses is required in the presence of competing responses that have been rewarded previously. Successful performance on these tasks is dependent also upon the formation of associations between specific stimuli in the environment, specific actions and the availability of reward, in some cases, the availability of specific rewards. Thus, a variety of different associations may contribute to overall response control, including Pavlovian approach behaviour and instrumental actions including either the formation of stimulus–response habits or goal-directed actions, the latter consisting of at least two forms of learning: the first, learning about the instrumental contingencies between a response and reward (contingency learning), and the second consisting of the acquisition of incentive value by the reward [see (Balleine and Dickinson, 1999Go) for a detailed account of goal-directed instrumental action]. Successful performance of these tasks may well tax these different contributory processes to varying degrees and thus, depending upon the precise processes engaged, deficits will be observed following lesions of either the medial prefrontal or orbitofrontal cortex. Indeed, it is the failure of such associative learning mechanisms to guide action that may well contribute to the decision making difficulties of patients with damage to the ventromedial prefrontal cortex (Bechara et al., 1998Go; Rogers et al., 1999Go). Of relevance to this issue are the recent results by Balleine and Dickinson (Balleine and Dickinson, 1999Go) which suggest that the medial prefrontal region of the rat, which may be homologous to the posterior sector of the medial prefrontal cortex in monkeys (Preuss, 1995Go), plays a role in the learning about the instrumental contingencies between an action and a reward. However, the anatomical selectivity of this effect is as yet unclear since it is not known whether lesions of other regions of the prefrontal cortex would produce similar effects.


    Summary and Conclusions
 Top
 Abstract
 Introduction
 The Inhibitory Control Functions...
 Evidence for a Dissociation...
 Inhibitory Control and its...
 Different Types of Associative...
 Summary and Conclusions
 Notes
 References
 
Neuropsychological studies in marmosets reveal that processes of inhibitory control do not, as originally proposed, reside specifically in the orbitofrontal cortex, but instead may occur throughout the medial, lateral and orbital regions of the prefrontal cortex. Hence, the precise nature of the behavioural disinhibition that is observed following damage to the prefrontal cortex will depend upon the specific psychological functions of the damaged area. The specific impairment induced by lesions of the lateral prefrontal cortex on the higher-order shifting of attention between supra-ordinate features of visual stimuli and on the novel variant of the object retrieval task supports the hypothesis that the lateral prefrontal cortex is involved in the selection and control of action based on higher-order rules or strategies. In contrast, it is proposed that the orbitofrontal and medial prefrontal cortices are essential for controlling actions governed by specific associations formed between stimuli in the environment, responses and the availability of specific reinforcers.


    Notes
 Top
 Abstract
 Introduction
 The Inhibitory Control Functions...
 Evidence for a Dissociation...
 Inhibitory Control and its...
 Different Types of Associative...
 Summary and Conclusions
 Notes
 References
 
This work was supported by a Programme Grant from the Wellcome Trust (T.W. Robbins, B.J. Everitt, A.C.R., B.J. Sahakian) and a Royal Society University Research Fellowship grant to A.C.R. J.D.W. received a Wellcome prize studentship from the Wellcome Trust. We thank Dr R.M. Ridley for supplying the marmosets, Ms C. Morrison and Ms H. Sweet for preparation of histological material, Mr J. Bashford for photographic assistance, and Mr A. Newman and Mr I. Bolton for preparation of the figures. This is a publication within the MRC Cooperative on Brain, Behaviour and Neuropsychiatry.

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.


    Footnotes
 
1 Current address: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA Back


    References
 Top
 Abstract
 Introduction
 The Inhibitory Control Functions...
 Evidence for a Dissociation...
 Inhibitory Control and its...
 Different Types of Associative...
 Summary and Conclusions
 Notes
 References
 
Aggleton JP, Passingham RE (1981) The syndrome produced by lesions of the amygdala in monkeys. J Comp Physiol Psychol 95:961–977.[ISI][Medline]

Aggleton JP, Passingham RE (1982) An assessment of the reinforcing properties of foods after amygdaloid lesions in rhesus monkeys. J Comp Physiol Psychol 96:71–77.[ISI][Medline]

Balleine BW, Dickinson A (1999) Goal-directed instrumental action: contingency and incentive learning and their cortical substrates. Neuropharmacology 37:407–419.[ISI]

Baylis LL, Gaffan D (1991) Amygdalectomy and ventromedial prefrontal ablation produce similar deficits in food choice and in simple object discrimination learning for an unseen reward. Exp Brain Res 86: 617–622.[ISI][Medline]

Bechara A, Tranel D, Damasio H, Damasio AR (1996) Failure to respond autonomically to anticipated future outcomes following damage to prefrontal cortex. Cereb Cortex 6:215–225.[Abstract]

Bechara A, Damasio H, Tranel D, Anderson SW (1998) Dissociation of working memory from decision making within human prefrontal cortex. J Neurosci 18:428–437.[Abstract/Free Full Text]

Brodmann K (1909) Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien daregstellt auf Grund des Zellenbaues. Leipzig: Barth.

Butter CM (1969) Perseveration in extinction and in discrimination reversal tasks following selective frontal ablations in Macaca mulatta. Physiol Behav 4:163–171.[ISI]

Butter CM, Snyder DR, McDonald JA (1970) Effects of orbital frontal lesions on aversive and aggressive behaviors in rhesus monkeys. J Comp Physiol Psychol 72:132–144.[ISI][Medline]

Cochran, WG, Cox, GM (1957) Experimental Designs, 2nd edn. New York: John Wiley.

Damasio AR, Tranel D, Damasio H (1990) Individuals with sociopathic behavior caused by frontal damage fail to respond autonomically to social stimuli. Behav Brain Res 41:81–85.[ISI][Medline]

Damasio AR, Tranel D, Damasio HC (1991) Somatic markers and the guidance of behavior: theory and preliminary testing. In: Frontal lobe function and dysfunction (Levin HS, Eisenberg HM, Benton AL, eds), pp. 217–229. New York: Oxford University Press.

Diamond A (1990) Developmental time course in human infants and infant monkeys, and the neural bases of inhibitory control in reaching. Ann NY Acad Sci 608:637–676.[ISI][Medline]

Dias R, Robbins TW, Roberts AC (1996a) Dissociation in prefrontal cortex of affective and attentional shifts. Nature 380:69–72.[ISI][Medline]

Dias R, Robbins TW, Roberts AC (1996b) Primate analogue of the wisconsin card sort test: effects of excitotoxic lesions of the prefrontal cortex in the marmoset. Behav Neurosci 110:872–886.[ISI][Medline]

Dias R, Robbins TW, Roberts AC (1997) Dissociable forms of inhibitory control within prefrontal cortex with an analog of the wisconsin card sort test: restriction to novel situations and independence from ‘on-line’ processing. J Neurosci 17:9285–9297.[Abstract/Free Full Text]

Dickinson A (1994) Instrumental conditioning. In: Animal Learning and Cognition (Mackintosh NJ, ed), pp 45–79. Academic Press.

Drevets WC, Raichle ME (1995) Positron emission tomographic imaging studies of human emotional disorders. In: The cognitive neurosciences (Gazzaniga MS, ed.), pp. 1153–1164. Cambridge, MA: MIT Press.

Drevets WC, Price JL, Simpson JR, Todd RD, Reich T, Vannier M, Raichle ME (1997) Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386:824–827.[ISI][Medline]

Eslinger PJ Damasio AR (1985) Severe disturbance of higher cognition after bilateral frontal lobe ablation: patient EVR. Neurology 35: 1731–1741.[Abstract]

Franzen EA, Myers RE (1973) Neural control of social behavior: prefrontal and anterior temporal cortex. Neuropsychologia 11:141–157.[ISI][Medline]

Fuster JM (1989) The prefrontal cortex: anatomy, physiology and neuropsychology of the frontal lobe, 2nd edn. New York: Raven Press.

Fuster JM (1998) The prefrontal cortex, 3rd edn. New York: Raven Press.

Gaffan D, Murray EA (1990) Amygdalar interaction with the mediodorsal nucleus of the thalamus and the ventromedial prefrontal cortex in stimulus–reward associative learning in the monkey. J Neurosci 10:3479–3493.[Abstract]

Harlow JM (1868) Recovery from the passage of an iron bar through the head. Publ Mass Med Soc 2:327–347.

Hauser M (1999) Perseveration, inhibition and the prefrontal cortex: a new look. Curr Opin Neurobiol 9:214–222.[ISI][Medline]

Hornak J, Rolls ET, Wade D (1996) Face and voice expression identification in patients with emotional and behavioural changes following ventral frontal lobe damage. Neuropsychologia 34:247–261.[ISI][Medline]

Iversen SD, Mishkin M (1970) Perseverative interference in monkeys following selective lesions of the inferior prefrontal convexity. Exp Brain Res 11:376–386.[ISI][Medline]

Jentsch JD, Redmond DE, Elsworth JD, Taylor JR, Youngren, KD, Roth, RH (1997) Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. Science 277:953–955.[Abstract/Free Full Text]

Jones B, Mishkin M (1972) Limbic lesions and the problem of stimulus–reinforcement associations. Exp Neurol 36:362–377.[ISI][Medline]

McEnaney KW, Butter CM (1969) Perseveration of responding and nonresponding in monkeys with orbital frontal ablations. J Comp Physiol Psychol 68:558–561.[ISI][Medline]

Milner B (1964) Some effects of frontal lobectomy in man. In: The frontal granular cortex and behavior (Warren JM, Akert K, eds), pp. 313–334. New York: McGraw-Hill.

Mishkin M (1964) Perseveration of central sets after frontal lesions in man. In: The frontal granular cortex and behavior (Warren JM, Akert K, eds), pp. 219–294. New York: McGraw-Hill.

Neafsey EJ (1990) Prefrontal cortical control of the autonomic nervous system: anatomical and physiological observations. Prog Brain Res 85:147–165.[Medline]

Petrides M, Pandya DN (1994) Comparative architectonic analysis of the human and the macaque frontal cortex. Handbook Neuropsychol 9:17–58.

Preuss TM (1995) Do rats have prefrontal cortex? The Rose–Woolsey– Akert program reconsidered. J Cogn Neurosci 7:1–24.[ISI]

Preuss TM, Goldman-Rakic PS (1991) Myeloand cytoarchitecture of the granular frontal cortex and surrounding regions in the strepsirhine primate Galago and the anthropoid primate Macaca. J Comp Neurol 310:429–474.[ISI][Medline]

Raleigh MJ, Steklis, D (1981) Effects of orbitofrontal and temporal neocortical lesions on the affiliative behavior of vervet monkeys. Exp Neurol 73:378–389.[ISI][Medline]

Roberts AC, Robbins TW, Everitt BJ (1988) The effects of intradimensional and extradimensional shifts on visual discrimination learning in humans and non-human primates. Q J Exp Psychol B 40:321–341.[ISI][Medline]

Rogers RD, Everitt BJ, Baldacchino A, Blackmore AJ, Swainson R, London M, Deakin JWF, Sahakian BJ, Robbins TW (1999) Dissociating 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 20:322–329.[ISI][Medline]

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 57:1518–1524.[Abstract]

Schneider JS, Roeltgen DP (1993) Delayed matching-to-sample, object retrieval, and discrimination reversal deficits in chronic low dose MPTP-treated monkeys. Brain Res 615:351–354.[ISI][Medline]

Shallice T, Burgess PW (1991) Deficits in strategy application following frontal lobe damage in man. Brain 114:727–741.[Abstract]

Taylor JR, Elsworth JD, Roth RH, Sladek JRJ, Redmond DEJ (1990) Cognitive and motor deficits in the acquisition of an object retrieval/detour task in MPTP-treated monkeys. Brain 113:617–637.[Abstract]

Walker C (1940) A cytoarchitectural study of the prefrontal area of the macaque monkey. J Comp Neurol 98:59–86.

Weiskrantz L (1956) Behavioural changes associated with ablation of the amygdaloid complex in monkeys. J Comp Physiol Psychol 49: 381–391.[ISI]

Wise SP, Murray EA, Gerfen CR (1996) The frontal cortex-basal ganglia system in primates. Crit Rev Neurobiol 10:317–356.[ISI][Medline]