REVIEWS s reflect these learne PEC or a larget to m sin cho on in the brain that ut m d bu be o form This i nble of hat that is th where the t'slocatio he m ding'units in the mo nds of tasks a The re discussed in the next section sory cues,rew sand voluntary actions guided by reward S0 OCTOBER 2000 VOLUME 2000 Macmillan Magazines Ltd Associations, conjunctions and rules GOAL-DIRECTED BEHAVIOUR requires predictions about events, INTERNAL STATES and actions that are likely to achieve a goal. But to make these predictions, we need to form associa￾tions between their internal representations16. A neural ensemble of a task, then, might be composed of neurons whose activity reflects learned associative relationships between these goal-relevant elements, that is, the TASK CON￾TINGENCIES (BOX 2). Prefrontal neurons do have this proper￾ty — they show conjunctive tuning for learned associa￾tions between cues, voluntary actions and rewards. Prefrontal neurons even show tuning for complex, behaviour-guiding rules. So they may help form neuron ensembles that represent the regularities across experi￾ences that describe the principles needed to achieve a par￾ticular goal in a particular situation. For example, the lateral PFC is directly interconnect￾ed with higher-order sensory and motor cortex, and indirectly connected (through the ventromedial PFC) with LIMBIC STRUCTURES that process ‘internal’ information such as reward9–12. The neural activity in the lateral PFC reflects this — many of its neurons show MULTIMODAL RESPONSES17–22. Furthermore, the lateral PFC is critical for normal learning of arbitrary associations between sen￾sory cues, rewards and voluntary actions23–27. 8 46 12 9 46 11 13 45 Posterior parietal cortex Auditory cortex Motor structures Medial temporal structures Inferior temporal cortex Figure 1 | Integrative anatomy of the macaque monkey prefrontal cortex. Numbers refer to sub-regions within prefrontal cotex as defined by Brodmann. Different PFC subregions have unique, but overlapping, patterns of connections with other brain regions. For example, the more posterior and dorsal portions of the lateral PFC are more heavily interconnected with cortical areas that emphasize processing of visuospatial and motor information. Ventral and anterior lateral regions are more heavily interconnected with cortical areas that emphasize information about visual form and stimulus identity. The ventral (orbitofrontal) PFC is more associated with subcortical structures that process ‘internal’ information such as homeostasis. Above and beyond this regional emphasis, however, there is also multimodal convergence. Many PFC areas receive converging inputs from at least two sensory modalities94,95 and there are ample interconnections between different PFC areas (illustrated by the purple lines) that could bring together results from a wide range of brain processes. For simplicity, this figure only shows a subset of PFC areas and a subset of their connections. Areas on the medial surface are not shown or discussed in this review. 60 | OCTOBER 2000 | VOLUME 1 www.nature.com/reviews/neuroscience REVIEWS Many lateral PFC neurons reflect these learned asso￾ciations18,28,29. For example, Watanabe used a set of tasks in which visual and auditory cues signalled, on different trials, whether reward would or would not be deliv￾ered18,28. Most lateral PFC neurons were found to reflect the association between a cue and reward. A given neu￾ron might be activated by a cue, but only when it sig￾nalled ‘reward’. In contrast, another neuron might be activated only by a cue that signalled ‘no reward’. Similarly, we trained monkeys to associate, in different blocks of trials, each of two cue objects with a SACCADE to the right or left29, and found that the activity of 44% of lateral PFC neurons reflected associations between objects and the saccades they instructed (FIG. 2). Other neurons had activity that reflected the cues or the sac￾cades alone, but they were fewer in number. Fuster and colleagues30 have also shown that PFC neurons can reflect learned associations between visual and auditory stimuli. Striking examples of experience-dependent neural plasticity come from Bichot and Schall’s studies of the frontal eye fields, part of Brodmann’s area 8 that is important for voluntary shifts of gaze. Normally, neu￾rons in this area fire selectively to saccade targets appear￾ing in certain visual field locations. However, when mon￾keys were trained to search for a target defined by a particular visual attribute (for example, red), the neu￾rons in the frontal eye fields acquired sensitivity to that attribute31. Bichot and Schall32 trained monkeys to search for a different target every day and found that neurons not only discriminated the current target, but also dis￾tracting stimuli that had been a target on the previous day, relative to stimuli that had been targets even earlier. Monkeys were also more likely to make errors in choos￾ing that distracting stimulus. It was as if the previous day’s experience left an impression in the brain that influenced neural activity and task performance. But monkeys and humans do more than remember simple contingencies. They can discern the regularities across them to extract general principles or rules. This is reflected in PFC activity as well. White and Wise21 found that the activity of up to half of PFC neurons depended on whether the monkey was guiding its behaviour by a spatial rule (a cue’s location indicated where the target would appear) or an associative rule (the identity of the cue indicated the target’s location). Hoshi et al. 33 found that many PFC neurons were modulated by which rule (matching shape or location) the monkey was currently using. We have also observed lateral prefrontal neurons with rule-dependent activity (BOX 3)34,35. These neurons could correspond to the ‘rule-coding’ units in the mod￾els of Dehaene and Changeux13,36. So PFC neurons convey information about the for￾mal demands of tasks, a possible foundation for the complex forms of behaviour of primates. The mecha￾nisms that guide the formation of these representations are discussed in the next section. Reward signals and rule representations If PFC neural ensembles reflect goal-relevant informa￾tion, their construction is probably guided by reward. GOAL-DIRECTED BEHAVIOUR Behaviour directed toward attainment of a future state (for example, obtaining a graduate degree). INTERNAL STATES Brain information not directly related to a sensory input or motor output; for example, homeostatic information such as hunger, thirst or other motivational influences. TASK CONTINGENCIES The logical structure of a given task (for example, if the light is green, cross the street). LIMBIC STRUCTURES A collection of subcortical structures important for processing memory and emotional information. Prominent structures include the hippocampus and amygdala. MULTIMODAL RESPONSES Neural activity elicited by more than one sensory modality. SACCADE A rapid, ballistic eye movement from one point of gaze to another. © 2000 Macmillan Magazines Ltd