Behavioral planning in the prefrontal cortex Jun Tanji* and Eiji Hoshi*

Transcription

1 164 Behavioral planning in the prefrontal cortex Jun Tanji* and Eiji Hoshi* Recent studies have presented evidence that the prefrontal cortex plays a crucial role in every aspect of the cognitive processes necessary for behavioral planning: processing and integration of perceived or memorized information, associative learning, reward-based behavioral control, behavioral selection/decision-making and behavioral guidance. We propose that the creation of novel information is the means by which the prefrontal cortex operates to achieve executive control over behavioral planning. The prefrontal cortex is the site of operation of nodal points, where neural circuits integrate currently available or memorized information to generate the information that is necessary to perform an action. The prefrontal cortex also regulates the flow of information through multiple nodes to meet behavioral demands. Addresses *Department of Physiology, Tohoku University School of Medicine, 2 1 Seiryo-cho, Aoba-ku, Sendai, , Japan The Core Research for Evolutional Science and Technology Program, Kawaguchi, , Japan tanjij@mail.cc.tohoku.ac.jp eijih@mail.cc.tohoku.ac.jp Correspondence: Jun Tanji Current Opinion in Neurobiology 2001, 11: /01/$ see front matter 2001 Elsevier Science Ltd. All rights reserved. Abbreviations DLPFC dorsolateral PFC fmri functional magnetic resonance imaging MDL mid-dlpfc OFC orbitofrontal cortex PFC prefrontal cortex Introduction Generating purposeful actions is a cardinal aspect of the cognitive functions of the prefrontal cortex (PFC), and behavioral planning is central to the organization of action. In this review, we introduce and discuss recent reports that are relevant to the issue of behavioral planning in the PFC. Other aspects of prefrontal functions have been discussed extensively in review articles published recently (see e.g. [1 7]). Information processing and integration To plan an action that facilitates adaptation to environmental changes and bodily needs, the PFC must first gather information from broad areas in the cortical and subcortical structures. Physically connected to these structures in the brain (for a recent review, see [8]), the PFC is optimally situated to gather and synthesize information with polysensory, memorized or emotional components. Recent reports provide insight as to how the processes of information retrieval and integration are actually carried out in the PFC. At this stage, the PFC performs four major functions: first, to retrieve sensory information to meet behavioral demands [9,10,11,12 ]; second, to exert executive control of memory retrieval from sites of long-term storage [13 15]; third, to actively maintain either sensory or memory information [16,17,18,19]; and fourth, to integrate or manipulate the retrieved or stored information for subsequent use [20 24]. To achieve these goals, the PFC is dependent on activities in other, connected areas. Chafee and Goldman-Rakic [25 ] have demonstrated how profoundly the interconnections between the prefrontal and posterior parietal cortices influence neuronal activity in each area during performance of an oculomotor delayed-response task. Sawaguchi and Yamane [26 ] studied the properties of positional delay-period activity of PFC neurons during a task in a way that enabled them to assess visuospatial memory independently of sensorimotor-related activity. They found that both discriminative ability and depth of spatial tuning increased during the delay period, suggesting that neuronal activity is characterized by an integrative process of increasing the accuracy of visuospatial memory. Associative learning One of the processes known to occur in the PFC is associative learning [27,28]. A recent functional magnetic resonance imaging (fmri) study [29 ] confirmed findings from positron emission tomography (PET) studies [30] that the ventral PFC was active while human subjects learned a visuomotor conditional task by trial and error. This study is compatible with a new report stating that removal of the ventral PFC in monkeys severely impairs learning of visuomotor conditional tasks [31 ]. Thus, the PFC is involved in associative learning, as well as in performing visuomotor conditional tasks [32,33 ] and cue response association [34]. Inferior prefrontal activation appears to be pronounced when subjects are required to adapt learned stimulus response associations to new circumstances [35 ]. Reward-based behavioral control and the orbitofrontal cortex Behavioral planning is clearly influenced by reward. The orbitofrontal cortex controls voluntary, goal-directed behavior by motivational outcomes [36 ] and emotion [37]. Neurons in the rostral orbitofrontal area (areas 11, 13 and 14) were recently shown to respond to rewards in a manner appropriate for reinforcing behavioral reactions [38,39]. Orbitofrontal neurons responded to instructions reflecting the predicted motivational outcome of behavioral reactions. Neural activation both preceded reinforcement (presumably related to the expectation of reward) and followed dispensation of a liquid reward (probably informing of reward delivery). This reward-related activity changed adaptively when monkeys learned a behavioral task [40 ]. Hikosaka and

2 Behavioral planning in the prefrontal cortex Tanji and Hoshi 165 Figure 1 Time courses of neuronal activities in the PFC that express memorized information, currently available sensory information, and forthcoming action, working as conceptualized in the flowchart diagrams shown below. (a) Prefrontal activity during a motor selection task with two behavioral rules. The diagram in the upper panel illustrates the behavioral sequence used in the study (explained in detail in the text). The three squares represent frames in which the cues and targets are displayed. The sample and choice cues are red. When the choice cue turns green, this is the signal for the animal to reach for a target determined according to location-matching or shapematching rules. Traces of PFC neurons showing the time course of three types of activity are indicated in the lower panel. The green trace is a population histogram for delay-related activity, whereas the blue and red traces are histograms representing choice-cue response and reach-targetselective activity, respectively. (b) Schematic diagram showing the basic operation of a neuronal circuit that is processing sample-cue information and choice-cue information, in order to specify motor output directed to each of the three targets to reach in obeisance of the location-matching rule. (c) Diagram of a neuronal circuit processing for the shapematching rule. The three colors in (b) and (c) correspond to activities expressed in the colors used in (a). (a) (b) Neuronal activity Time Sample Delay Choice Sample Sample Choice Target top left Choice (c) GO Target 1 s top right right left Current Opinion in Neurobiology Watanabe [41 ] found orbitofrontal neuronal activity to reflect expectation of reward or nonreward as the response outcome. They further discovered that neurons responded selectively to the expected nature of the reward, reflecting reward preference. Reward-expectancy activity was also found in the lateral frontal cortex (cf. [42,43]), where a variety of cognitive information is abundant. It remains to be seen whether and how motivational information is transmitted from the orbital to the lateral frontal cortex. Furthermore, future study is needed to clarify how reward information is used for behavioral selection or motor decision [44]. A recent neuroimaging study of human subjects [45] demonstrated that the ventral prefrontal cortex responded to both reward level in the context of increasing reward, and penalty level in the context of increasing penalty. These data augmented information obtained from other functional neuroimaging studies. One such study [46 ] revealed that the orbitofrontal cortex is activated when the problem of what to do next is best solved by taking into account the likely reward value of stimuli and responses, rather than their identity or location. The functional responsibility of the orbitofrontal cortex suggested by imaging techniques is in accordance with the somatic marker hypothesis [47,48], which explains impaired decision-making in subjects with orbitofrontal lesions. The orbitofrontal cortex is a part of an integrated neural system connected to a broad network of prefrontal, limbic, sensory and premotor areas [8,49,50]. Among the wealth of possible interactions, the interaction of the orbitofrontal cortex and amygdala recently was found to be crucial for guiding behavior on the basis of expected outcomes [51,52,53]. On the other hand, the orbitofrontal cortex, closely linked to the rhinal cortical region, is likely to be involved in recognition memory or processing of new information. Recent brain imaging studies of human subjects suggest that the rostral orbital region (area 11) is involved in the encoding of new information [54], and the posterior medial orbitofrontal region is involved in the selection of currently relevant memories [55]. Behavioral selection or decision Although active maintenance of information for subsequent use is an important aspect of PFC function, and its

3 166 Cognitive neuroscience operation has been studied extensively in a variety of working memory tasks [56,57], response selection or decision-making is an ultimate goal of purposeful behavior in which the PFC plays a crucial part. A new study of human subjects, using event-related fmri, emphasized the role played by the dorsal PFC in selection of imminent behavior [58 ]. The researchers reported that selection of an item from memory to guide a response, rather than maintenance of memorized information, was a critical factor in activating the dorsal PFC (area 46). They also found that the dorsolateral PFC was activated during a selfinitiated motor task in which decisions were required about the timing of movements [59 ]. Studies of subhuman primates have demonstrated that the decision to initiate or suppress a motor response (during a GO/NO-GO task) is expressed in responses of PFC neurons to visual signals that instruct a forthcoming response [60,61]. It is important to note that the responses selective to behavioral decisions appeared immediately following the presentation of visual signals, long before the execution of GO or NO-GO responses that were initiated with a trigger signal. The neuronal activity that appeared in the PFC also was closely related to the selection of saccade targets [62,63]. In an oculomotor delayed-matching-tosample task, the saccade-direction-selective activity appeared as early as ms after the appearance of a matching cue. Selectivity was not limited to the location of a future target of choice in a study that required subjects to choose arm movements determined by the combination of a sample cue and a matching cue [64 ]. Decision-related activity was selective, depending on whether the subject decided to reach for a triangle or circle (reach-object selectivity), and whether the target-reach action was selected on the basis of a shape-matching or a location-matching rule (task-selective activity). Behavioral guidance By making appropriate behavioral decisions, the PFC serves to guide behavior in accordance with environmental requirements perceived by individuals. Fuster [1,65] proposed that a crucial role played by the PFC is the mediation of cross-temporal contingencies between perceived information and the behavioral responses that come later. A good way to study cross-temporal contingencies is to use an experimental paradigm incorporating delay between sensory instructions and behavioral responses [57]. A recent report by Fuster et al. [66 ] is a typical example; the authors demonstrated that PFC neurons were involved in mediating cross-temporal association of auditory information and motor responses that were selective to visual information (colors). In our research [64,67], we have demonstrated how neurons in the lateral PFC take part in guiding motor behavior to obey two rules. Monkeys were trained to reach for a target based on the integration of memorized and current sensory information. The time course of the behavioral sequence is illustrated in Figure 1. Initially, a sample cue (triangle or filled circle) appeared at one of three locations (top, left or right). After a delay period, one of two types of choice cue appeared. The first type solicited the monkeys to reach for a target by matching the location (Figure 1b); the second type by matching the shape (Figure 1c). The choice cue for location-matching comprised either three circles or three triangles, and the choice cue for shape-matching comprised a circle and a triangle. When the color of the choice cue changed (GO signal), the monkeys reached to the correct reach target. We found cue-, delay-, choice- and movement-related neuronal activity. Most interesting were the time courses of three types of neuronal activity observed around the occurrence of the choice cue. The first type of activity, carrying information about the sample cue (Figure 1, green trace), built up gradually toward the choice-cue onset, and subsided afterwards. The second type was an immediate and transient response to the choice cue (blue trace). The third type of activity, reflecting the target to be reached (red trace), emerges promptly (300 ms) after the choice-cue onset, replacing sample- and choice-cue-related activity. In view of the rapid development of target-specifying neuronal activity, it seems inevitable that the neuronal circuit that determined the activity was pre-wired. We suggest that the wiring is constructed as illustrated in Figures 1b and c, where sample-cue and choice-cue information are connected appropriately to produce the information for the target of the forthcoming reach. A separate issue in the general concept of behavioral guidance is the possible involvement of the mid-dorsolateral PFC (MDL) in the executive process of monitoring information in the working memory, keeping track of multiple behavioral events such as selection of items [68,69] (however, see [70]). A recent study [71 ] found that, after lesion of mid-dorsal regions including dorsal areas 46 and 9, task performance was impaired if the number of items that had to be monitored was increased, whereas increasing the delay period had no effect. Future studies should focus on clarifying what kind of cellular activity would support this monitoring function, and to what extent the procedure for behavioral monitoring, as opposed to maintenance of information per se, is represented in this region of the PFC. Two new fmri studies suggest that the PFC in human subjects performs different aspects of behavioral guidance. One study [72 ] proposed that the lateral anterior PFC is engaged in processing plans in an unpredictable (i.e. random) behavioral mode, whereas the medial anterior PFC is more active in the predictable mode. The other study compared activity foci during performance of single tasks and of dual tasks that included two components of the single tasks [73 ]. The best explanation of which areas were activated during completion of dual tasks was that activation is summed during the two component tasks. The experimental findings did not support the view that surplus areas are dedicated to a generic executive system responsible for the completion of dual tasks.

4 Behavioral planning in the prefrontal cortex Tanji and Hoshi 167 Figure 2 Diagrams showing principles of operation of information processing at a nodal point in the PFC, or through a cascade of nodes that processes information successively to achieve a behavioral goal. (a) Delayed-matching-to-sample task: the fundamental operation. Memorized information about a sample cue, and sensory information signaling the content of a choice cue, are fed into a node of a prewired neuronal circuit in the PFC that integrates, processes, and generates the output information that determines a required action. (b) The diagram illustrates the general principle of operation at a nodal point. Two information sets are fed into a node where a neural circuit, constructed in accordance with an implementing rule, creates a novel set of information useful to achieve the goal of a behavioral task. (c) A cascade of operation at individual nodes can accomplish a complex behavioral task. As an example, processes while performing the Wisconsin card-sorting test are broken down into steps of unitary action. When performing this test, subjects are presented with a target card and four reference cards that may or may not be matched to the target card with respect to various stimulus dimensions such as color, form or number of objects. Only one of these dimensions is relevant in determining the correct match, and subjects must identify the matching card, learning by trial and error which is the relevant dimension to which they must attend. At each node, different sets of information are integrated to produce a set of task-specific information which, in turn, is fed into the next node. For simplicity, only the flow of information along a straightforward path is drawn, leaving out branching or feed-forward/feed-back pathways. Governing such flow of information is an important part of the operation of the PFC. (a) (c) Sample cue Choice cue Attend to shape Start Action target circle Now color blue (b) Available information set A Again shape Available information set B triangle Stop attending to color Three red circles Right Two yellow triangles Wrong two Right Four red stars Again number four Right Novel information set C Stop attending to shape Now number Three blue circles Again number implementing rule Free 2-choice One blue triangle Wrong Not shape Two green circles three Current Opinion in Neurobiology Generation of novel information We propose, on the basis of observations described in the preceding section, a basic description of how the PFC operates: as a network generating novel information out of available sets of information. In the case of a typical delayed-matching-to-sample task, an essential procedure is to combine sample-cue information stored in short-term memory with choice-cue information at a nodal point (Figure 2a). At the nodal point, a neural circuit is wired to generate new information that specifies an action satisfying the requirement given in individual behavioral tasks. This operation can be generalized, as in Figure 2b, where two sets of available information are fed into a nodal point that then generates novel information conforming to behavioral requirements. The input and output information in the diagram covers a broad spectrum: perceived sensory inputs, short- or long-term memory, action and behavioral goals, rewards, emotions or rules. The neural circuit at the nodal point may be structured in accordance with an implementing rule specified by a behavioral task. The structuring of the neural circuit would correspond to behavioral learning as dictated by the PFC. If the behavioral task included more than one rule, multiple nodal points would be required to meet behavioral demand. Thus, a dual-rule task of location and shape matching is likely to require separate nodal points wired as shown in Figure 1b,c. In the diagrams shown in Figure 2a,b, single nodal points account for an operation of a behavioral task. For behavioral tasks requiring more complex organization, however, we need a cascade of multiple nodes that individually generate a variety of information. By using the example of the Wisconsin card-sorting task, we here attempt to visualize how a cascade of nodes operates to generate the information necessary to follow successive steps in achieving the task (Figure 2c). The diagram indicates how a complex behavioral task can be broken down into steps of operations involving unitary nodes in which a set of information is integrated to create purposeful, step-specific information. In the diagram, for the purpose of simplicity, the flow of information along a straightforward path is drawn. During actual performance of behavioral tasks, information flows through multiple nodes along complexly structured routes, including branching or feed-forward/feed-back

5 168 Cognitive neuroscience pathways. To deal with this complexity, additional elements that govern and supervise the flow of information are necessary, and they are viewed as residing in the PFC. The discovery of activation of inferior prefrontal cortex during attentional shifting from one category of stimulus attributes to another [74] provides evidence for this view. Further advances in the level of complexity of the behavioral task would require participation of a different part of the PFC. It has been reported that bilateral fronto-polar prefrontal cortex is activated when subjects have to keep in mind the main goal of a behavioral task while performing concurrent subgoals [75]. Concluding remarks The PFC is the site of convergence of information from broad areas across the brain. Managing the vast expanse of cortical structures endowed as a result of phylogenetic development, the PFC accommodates an enormous number of neural circuits that integrate information contained in afferent inputs, producing novel information necessary for, or meaningful to, individuals. Thus, creation of new information is the salient function of the PFC. Operation of information-integrating circuits that output information at a single node accounts for neural control of simple behavioral tasks. More complex aspects of behavior, including long-range behavioral planning, require the structuring of a large number of operating nodes, each designed for a unique purpose. Acknowledgements We thank M Kurama and Y Takahashi for technical assistance. This work was supported by the Ministry of Education, Science, and Culture of Japan, by the Japan Science and Technology Corporation (J Tanji), and by the Japan Society for the Promotion of Science (E Hoshi). 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7 170 Cognitive neuroscience 60. Sakagami M, Niki H: Encoding of behavioral significance of visual stimuli by primate prefrontal neurons: relation to relevant task conditions. Exp Brain Res 1994, 97: Sakagami M, Tsutsui K: The hierarchical organization of decision making in the primate prefrontal cortex. Neurosci Res 1999, 34: Hasegawa R, Sawaguchi T, Kubota K: Monkey prefrontal neuronal activity coding the forthcoming saccade in an oculomotor delayed matching-to-sample task. J Neurophysiol 1998, 79: Hasegawa RP, Matsumoto M, Mikami A: Search target selection in monkey prefrontal cortex. J Neurophysiol 2000, 84: Hoshi E, Shima K, Tanji J: Neuronal activity in the primate prefrontal cortex in the process of motor selection based on two behavioral rules. J Neurophysiol 2000, 83: This paper reports neuronal activity in the PFC when monkeys are performing a task requiring them to select a reach-target following two behavioral rules concurrently, a shape- and a location-matching rule. Three types of neuronal activity are found after the appearance of a choice cue (i.e. when they are sorting out a target): first, activity conveying information of sample cues; second, activity selective for the configuration of choice cues; and third, activity reflecting the information of correct targets. The temporal profile of the activity found in each type indicates how efficiently selection is processed in the PFC by integrating multiple sets of information. 65. Fuster JM: The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of The Frontal Lobe, 3rd Edn. Philadelphia: Lippincott Raven; Fuster JM, Bodner M, Kroger JK: Cross-modal and cross-temporal association in neurons of frontal cortex. Nature 2000, 405: In this paper, the authors demonstrate that single neurons in the PFC respond selectively to initial tones and also to the subsequent matching colors according to the task rule, suggesting that the PFC is a part of networks that integrate multimodal information to mediate cross-temporal contingencies. 67. Hoshi E, Shima K, Tanji J: Task-dependent selectivity of movementrelated neuronal activity in the primate prefrontal cortex. J Neurophysiol 1998, 80: Petrides M: Impairments on nonspatial self-ordered and externally ordered working memory tasks after lesions of the mid-dorsal part of the lateral frontal cortex in the monkey. J Neurosci 1995, 15: Petrides M: Monitoring of selections of visual stimuli and the primate frontal cortex. Proc R Soc Lond B Biol Sci 1991, 246: Levy R, Goldman-Rakic PS: Association of storage and processing functions in the dorsolateral prefrontal cortex of the nonhuman primate. J Neurosci 1999, 19: Petrides M: Dissociable roles of mid-dorsolateral prefrontal and anterior inferotemporal cortex in visual working memory. J Neurosci 2000, 20: This is a demonstration that performance of a self-ordered task by monkeys with lesions in the MDL deteriorates when the number of items to be individually selected increases, suggesting that the MDL participates in the executive process of monitoring memorized items. 72. Koechlin E, Corrado G, Pietrini P, Grafman J: Dissociating the role of the medial and lateral anterior prefrontal cortex in human planning. Proc Natl Acad Sci USA 2000, 97: This describes an fmri study demonstrating that the lateral anterior prefrontal cortex (BA 10/46) is engaged in processing plans in a random manner and that the medial anterior prefrontal cortex (BA 32/10) is involved in processing plans in a predictive mode. The results suggest that the function of the PFC may be divided by the mode of task plans. 73. Adcock RA, Constable RT, Gore JC, Goldman-Rakic PS: Functional neuroanatomy of executive processes involved in dual-task performance. Proc Natl Acad Sci USA 2000, 97: This describes an fmri study comparing activity foci during single-task and dual-task performance, reporting that areas activated by dual-task performance are approximately the summation of areas activated by each single task. The authors conclude that the executive process enabling dual task performance is mediated by interactions between distinct systems engaged in component tasks. 74. Konishi S, Nakajima K, Uchida I, Kameyama M, Nakagara K, Miyashita Y: Transient activation of inferior prefrontal cortex during cognitive set shifting. Nat Neurosci 1998, 1: Koechlin E, Basso G, Pietrini P, Panzer S, Grafman J: The role of the anterior prefrontal cortex in human cognition. Nature 1999, 399: