REVIEWS Box1 Behavioural effects of prefrontal cortex damage ficial carry on a c ave nor d can be the do d m give a burst vity to le the ard and not b y th chang to the cu e with further Card S VTA D to ith is to pr to also help tictyntity-depe Box2A suggested role for the prefrontal cortex in cognitive control d C3):un e(that is,C1.R).But if the ph a patte ues ld ac (CI-R2).By e they depend urrent pattern of PFC activity.A lossc URE REV正WS 2000 Macmillan Magazines LtdBox 1 | Behavioural effects of prefrontal cortex damage Humans with prefrontal damage can seem strikingly normal upon superficial examination. They can carry on a conversation, often have normal IQ scores and can perform familiar routines without difficulty. However, despite their good performance on standard neuropsychological tests of perceptual, memory and motor skills, their ability to organize their lives is profoundly impaired. They are impulsive and irresponsible and consequently can have trouble holding a job, remaining married and so on. Careful testing has revealed that the behaviour of humans and monkeys with prefrontal damage can be described as stimulus-bound. Their behaviour is captured by salient sensory cues that reflexively elicit strongly associated actions. They are unable to override these impulses to engage in behaviours that depend on knowledge of a goal and the means to achieve it, that is, behaviours that are weakly established, complex, changing, or that must be extended over time4,7,10,11,86. For example, consider a classic test of prefrontal impairment, the Wisconsin Card Sorting Task. Subjects are instructed to sort cards according to the shape, colour or number of symbols appearing on them. They start with one rule (for example, colour) and, once that is acquired, the experimenter changes the rule (for example, shape) without telling the subject. Rules are acquired and changed until all the cards have been sorted using all possible rules. Normal people have little difficulty with this task. In contrast, people with prefrontal damage can learn the first rule but then they are unable to escape it: they make a great deal of errors because they lapse back to the earlier rule91. The ability of monkeys with PFC lesions to perform an analogue of this task is also impaired92. Shallice and Burgess described patients with damage to the frontal lobes who are able to execute simple routines in which clear sensory cues could elicit a familiar action (for example,‘buy a loaf of bread’)93. However, they were unable to carry out an errand that involved organizing a series of such routines. They would, for example, enter shops that were irrelevant to the errand. In these cases, the basic elements of behaviour are intact but it seems that they are missing the flexibility to shift between different rules and so override PREPOTENT RESPONSES to persist toward a goal. Here, I suggest that the PFC allows for this flexibility by dynamically establishing task-relevant neural pathways in other brain systems (BOX 2). NATURE REVIEWS | NEUROSCIENCE VOLUME 1 | OCTOBER 2000 | 6 1 REVIEWS Reward information does have a pervasive influence on PFC activity — activity in the lateral PFC and ventro￾medial PFC conveys the identity and size of expected rewards18,28,37–39. A major source of reward-related sig￾nals may be the dopamine-mediated innervation of the PFC from a group of cells situated in the ventral tegmental area(VTA) of the midbrain. VTA neurons have properties that are ideal for pro￾viding a signal that guides acquisition of goal-relevant information. Initially, they give a burst of activity to unpredicted rewards40,41. With experience, they become activated by cues that predict reward and not by the rewards themselves42. These neural responses that have been transferred to the cues also wane with further training, perhaps because they transfer to environmen￾tal cues that are earlier predictors of reward43.VTA neu￾rons are also inhibited when an expected reward is withheld44. This codes the degree to which a reward, or a cue that predicts reward, is surprising. As the aim of the organism is to predict the means to achieve reward, this ‘prediction error’ indicates when the associative learning that underlies this ability should occur45. The resulting dopamine influx into the PFC could affect plasticity through several plausible mechanisms. For example, dopamine could augment NMDA (N￾methyl-D-aspartate) receptor-mediated glutamatergic transmission, which has been directly implicated in plasticity46. Dopamine may also help augment and sustain PFC activity47,48, allowing activity-dependent plasticity mechanisms to work. PREPOTENT RESPONSES Reflexive actions, either innate or well established through a great deal of experience. Box 2 | A suggested role for the prefrontal cortex in cognitive control The figure shows processing units representing cues such as sensory inputs, current motivational state, memories and so on (C1, C2 and C3); units representing two voluntary actions (for example, ‘responses’ R1 and R2); and internal or ‘hidden’ units representing intervening stages of processing. The PFC is shown as being connected to the hidden units because it is interconnected with higher-order ‘association’ and premotor cortices, not with primary sensory or motor cortices. A situation in which the PFC seems particularly important is pictured here: when the same cue (C1) could lead to one or another response (R1 or R2) depending on some other item of information (C2 or C3). For example, if the phone rings (C1) and you are at home (C2), you answer it (that is, C1…R1). But if the phone rings (C1) and you are a guest in someone else’s home (C3), you do not (C1…R2). During learning, reward signals may strengthen the connections between PFC neurons that process the information that leads to reward, resulting in a pattern of activity that reflects the pattern of associations between goal-relevant information that is unique to each situation (that is, the task contingencies). Once established, a subset of the information (for example, C1 and C2) can activate the entire representation (for example, the constellation of PFC ‘units’ shown in red), including information about the appropriate response (for example, R1). Bias signals from the PFC task representations may then select task-relevant neural pathways in other brain systems (for example, C1–R1). A different set of cues (C1 and C3) would activate a different PFC representation (shown in blue) and, consequently, a different pattern of bias signals selects a different set of neural pathways (C1–R2). By providing a bias signal to the intermediate (hidden) units, the PFC favours the pathways in the posterior neocortex and other brain areas that are appropriate for the task. So task-relevant pathways can be dynamically and flexibly established because they depend on the current pattern of PFC activity. A loss of flexibility is a hallmark of PFC damage (BOX 1). Prefrontal cortex R2 R1 C3 C1 C2 © 2000 Macmillan Magazines Ltd