AN INTEGRATIVE THEORY OF PREFRONTAL CORTEX FUNCTION Earl K.Miller Center for Learning and Memory.RIKEN-MIT Neuroscience Research Center and Department of Brain and Cognitive Sciences,Massachusetts Institute of Technology. Cambridge,Massachusetts 02139:e-mail:ekm@ai.mit.edu Jonathan D.Cohen Center for the Study of Brain,Mind,and Behavior and Department of Psychology. Princeton University.Princeton.New Jersey 08544:e-mail:jdc@princeton.edu Key Words frontal lobes,cognition,executive control,working memory,attention Abstract The prefrontal cortex has long been suspected to play an important role in cognitive control,in the ability to orchestrate thought and action in accordance with internal goals.Its neural basis,however,has remained a mystery.Here,we propose that cognitive control stems from the active maintenance of patterns of activity in the prefrontal cortex that represent goals and the means to achieve them.They provide bias signals to other brain structures whose net effect is to guide the flow of activity along neural pathways that establish the proper mappings between inputs,internal states,and outputs needed to perform a given task.We review neurophysiological neurobiological,neuroimaging,and computational studies that support this theory and discuss its implications as well as further issues to be addressed. INTRODUCTION One of the fundame tal,pur oseful behavio arises from the distrib ted activity of billions of neurons in the brair Simple behaviors can rely on relatively straightforward interactions between the brain's input and output systems.Animals with fewer than a hundred thousand neurons(in the human brain there are 100 billion or more neurons)can approach food andavoid predators.For animals with a arger brains,behavior is more flex ible.But flexibility carries a cost:Although our elab nsory and moto systems provide detailed information about the external world and make avail able a large repertoire of actions,this introduces greater potential for interference and confusion.The richer information we have about the world and the greater number of options for behavior require appropriate attentional,decision-making and coordinative functions,lest uncertainty prevail.To deal with this multitude of 0147-006X/01/0301-0167514.00 167
P1: FXZ January 12, 2001 14:38 Annual Reviews AR121-07 Annu. Rev. Neurosci. 2001. 24:167–202 Copyright c 2001 by Annual Reviews. All rights reserved AN INTEGRATIVE THEORY OF PREFRONTAL CORTEX FUNCTION Earl K. Miller Center for Learning and Memory, RIKEN-MIT Neuroscience Research Center and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; e-mail: ekm@ai.mit.edu Jonathan D. Cohen Center for the Study of Brain, Mind, and Behavior and Department of Psychology, Princeton University, Princeton, New Jersey 08544; e-mail: jdc@princeton.edu Key Words frontal lobes, cognition, executive control, working memory, attention ■ Abstract The prefrontal cortex has long been suspected to play an important role in cognitive control, in the ability to orchestrate thought and action in accordance with internal goals. Its neural basis, however, has remained a mystery. Here, we propose that cognitive control stems from the active maintenance of patterns of activity in the prefrontal cortex that represent goals and the means to achieve them. They provide bias signals to other brain structures whose net effect is to guide the flow of activity along neural pathways that establish the proper mappings between inputs, internal states, and outputs needed to perform a given task. We review neurophysiological, neurobiological, neuroimaging, and computational studies that support this theory and discuss its implications as well as further issues to be addressed. INTRODUCTION One of the fundamental mysteries of neuroscience is how coordinated, purposeful behavior arises from the distributed activity of billions of neurons in the brain. Simple behaviors can rely on relatively straightforward interactions between the brain’s input and output systems. Animals with fewer than a hundred thousand neurons (in the human brain there are 100 billion or more neurons) can approach food and avoid predators. For animals with larger brains, behavior is more flexible. But flexibility carries a cost: Although our elaborate sensory and motor systems provide detailed information about the external world and make available a large repertoire of actions, this introduces greater potential for interference and confusion. The richer information we have about the world and the greater number of options for behavior require appropriate attentional, decision-making, and coordinative functions, lest uncertainty prevail. To deal with this multitude of 0147-006X/01/0301-0167$14.00 167 Annu. Rev. Neurosci. 2001.24:167-202. Downloaded from arjournals.annualreviews.org by University of California - Los Angeles on 03/27/06. For personal use only
168 MILLER■COHEN possibilities and to curtail confusion,we have evolved mechanisms that coordinate ower-level sensory and motor processes along a common theme,an internal goal This ability for cognitive control no doubt involves neural circuitry that extends over much of the brain,but it is commonly held that the prefrontal cortex(PFC) ymportant that is most elaborated in primates,animals known for thei coordinate a wide range of neural processes:The PFC is a collection of intercon nected neocortical areas that sends and receives projections from virtually all cor tical sensory systems,motor systems,and many subcortical structures(Figure 1). Neurophysiological studies in nonhuman primates have begun to define many of the detailed properties of PFC,and hu neuropsyc ogy and neuroimaging studies have begun to provide a broad view of the task conditions under which it is engaged.However,an understanding of the mechanisms by which the PFC executes control has remained elusive.The aim ofthis article is to describe a theory of PFC function that integrates these diverse findings,and more precisely defines its role in cognitive control. The Role of the PFC in Top-Down Control of Behavior The PFC is not critical for performing simple,automatic behaviors,such as our mechanisms potentiate existing pathw ays or form ne ones "hardwired pathways are advantageous because they allow highly familiar behaviors to be executed quickly and automatically (i.e.without demanding attention).How- ever,these behaviors are inflexible,stereotyped reactions elicited by just the right stimulus.They do not generalize well to novel situations,and they take extensi time and experience to develop.These sorts ofauto omatic behaviors can be though of as relying primarily on"bottom-up"processing;that is,they are determined largely by the nature of the sensory stimuli and well-established neural pathways that connect these with corresponding responses. By contrast,the PFC is important when"top-down"processing is needed:that is when behaviormust be guided by internal statesor intentions.The PFCiscritical in situations when veen sensory inputs,thoughts and actionseithe re weakly established relative to other existing ones or are rapidly chan is when we need to use the "rules of the game,"internal representations of goals and the means to achieve them.Several investigators have argued that this is a cardinal function of the PFC(Cohen Servan-Schreiber 1992 Passingham 1993 Grafman 1994.Wise et al 1996,Miller 1999).Two classic tasks illustrate this point:the Stroop task k and the Wisconsin card sort task(WCST) In the Stroop task(Stroop 1935,MacLeod 1991),subjects either read words or name the color in which they are written.To perform this task,subjects must selectively attend to one attribute.This is especially so when naming the color
P1: FXZ January 12, 2001 14:38 Annual Reviews AR121-07 168 MILLER ¥ COHEN possibilities and to curtail confusion, we have evolved mechanisms that coordinate lower-level sensory and motor processes along a common theme, an internal goal. This ability for cognitive control no doubt involves neural circuitry that extends over much of the brain, but it is commonly held that the prefrontal cortex (PFC) is particularly important. The PFC is the neocortical region that is most elaborated in primates, animals known for their diverse and flexible behavioral repertoire. It is well positioned to coordinate a wide range of neural processes: The PFC is a collection of interconnected neocortical areas that sends and receives projections from virtually all cortical sensory systems, motor systems, and many subcortical structures (Figure 1). Neurophysiological studies in nonhuman primates have begun to define many of the detailed properties of PFC, and human neuropsychology and neuroimaging studies have begun to provide a broad view of the task conditions under which it is engaged. However, an understanding of the mechanisms by which the PFC executes control has remained elusive. The aim of this article is to describe a theory of PFC function that integrates these diverse findings, and more precisely defines its role in cognitive control. The Role of the PFC in Top-Down Control of Behavior The PFC is not critical for performing simple, automatic behaviors, such as our tendency to automatically orient to an unexpected sound or movement. These behaviors can be innate or they can develop gradually with experience as learning mechanisms potentiate existing pathways or form new ones. These “hardwired” pathways are advantageous because they allow highly familiar behaviors to be executed quickly and automatically (i.e. without demanding attention). However, these behaviors are inflexible, stereotyped reactions elicited by just the right stimulus. They do not generalize well to novel situations, and they take extensive time and experience to develop. These sorts of automatic behaviors can be thought of as relying primarily on “bottom-up” processing; that is, they are determined largely by the nature of the sensory stimuli and well-established neural pathways that connect these with corresponding responses. By contrast, the PFC is important when “top-down” processing is needed; that is, when behavior must be guided by internal states or intentions. The PFC is critical in situations when the mappings between sensory inputs, thoughts, and actions either are weakly established relative to other existing ones or are rapidly changing. This is when we need to use the “rules of the game,” internal representations of goals and the means to achieve them. Several investigators have argued that this is a cardinal function of the PFC (Cohen & Servan-Schreiber 1992, Passingham 1993, Grafman 1994, Wise et al 1996, Miller 1999). Two classic tasks illustrate this point: the Stroop task and the Wisconsin card sort task (WCST). In the Stroop task (Stroop 1935, MacLeod 1991), subjects either read words or name the color in which they are written. To perform this task, subjects must selectively attend to one attribute. This is especially so when naming the color Annu. Rev. Neurosci. 2001.24:167-202. Downloaded from arjournals.annualreviews.org by University of California - Los Angeles on 03/27/06. For personal use only
PREFRONTAL FUNCTION 169 .29al9 Sensory cortex Mid-dorsal area9 Dorsal Motor Dorsolatera Ventral structures area 46 Area ventrolateral (FEF) areas 12,45 Auditory Superior temporal gyrus Orbital and medial aeas10.11. Multimodal Basal 13.14 Ganglia Rostral superior 0a0装Nmmam temporal sulcus Thalamus Medial tempor lobe Figure 1 Schematic diagram of some of the extrinsic and intrinsic connections of the prefrontal cortex.The partial convergence of inputs from many brain systems and internal connections ofthe prefrontal cortex(PFC)may allow it to play a central role in the synthesis of diverse information needed for complex behavior.Most connections are reciprocal,the exceptions are indicated by arrows.The frontal eye field (FEF)has variously been considered either adjacent to,or part of,the PFC.Here,we compromise by depicting it as adjacent to, yet touching,the PFC
P1: FXZ January 12, 2001 14:38 Annual Reviews AR121-07 PREFRONTAL FUNCTION 169 Figure 1 Schematic diagram of some of the extrinsic and intrinsic connections of the prefrontal cortex. The partial convergence of inputs from many brain systems and internal connections of the prefrontal cortex (PFC) may allow it to play a central role in the synthesis of diverse information needed for complex behavior. Most connections are reciprocal; the exceptions are indicated by arrows. The frontal eye field (FEF) has variously been considered either adjacent to, or part of, the PFC. Here, we compromise by depicting it as adjacent to, yet touching, the PFC. Annu. Rev. Neurosci. 2001.24:167-202. Downloaded from arjournals.annualreviews.org by University of California - Los Angeles on 03/27/06. For personal use only
170 MILLER■COHEN ofa conict stimulus (the word GREEN displayed n red),because there is a strong prepotent tendency to read the word("green").which competes with the response to the color("red").This illustrates one of the most fundamental aspects of cognitive control and goal-directed behavior:the ability to select a weaker task-relevant response(or source of information)in the face of competition from ,but task-irrelevantone.Patients with frontal h this task (eg.Perrett 19,CohenServan-Schreiber Vendrell et al 1995),especially when the instructions vary frequently(Dunbar& Sussman 1995,Cohenetal 1999),which suggests that they have difficulty adhering to the goal of the task or its rules in the face of a competing stronger (ie.more salient or habitual)response. Similar findir ng s are evident in the WCST.Subjects are instructed to sort card according to the shape,color,or number of symbols appearing on them and the sorting rule varies periodically.Thus,any given card can be associated with several possible actions,no single stimulus-response mapping will work,and the correct one changes and is dictated by whichever rule is currently in effect.Humans with PEC dar nage show stere ch di culty but ar unable to adapt their beh Mner 1)Monkeys with PFClesonsrrd n analog of this task(Dias et al 1996b,1997)and in others when they must switch between different rules(Rossi et al 1999). The Stroop task and WCST are variously described as tapping the cognitive functions of either selective atte or rule-bas workin ed or goal-directed behavio we functions depend on the representation of goals and rules in the form of patterns of activity in the PFC,which configure processing in other parts of the brain in accordance with current task demands.These top-down signals favor weak(but task-relevant)stimulus-response mappings when they are in competition with more habitual,strongero he Stroop task),especially whe needed (such as in the WCST).We believe that this can account for the wide range of other tasks found to be sensitive to PFC damage,such as A-not-B(Piaget 1954. Diamond Goldman-Rakic 1989),Tower of London(Shallice 1982,1988;Owen et al 1990).and others (Duncan 1986.Duncan et al 1996).Stuss Benson 1986). We build on the fundamental principle that processing in the brain is compet itive:Different carrying different source s of inf ormation,compete for expression in behavior,and the winners are those with the strongest sources ofsup port.Desimone Duncan(1995)have proposed a model that clearly articulates such a view with regard to visual attention.These authors assume that visual corti- cal neurons processing different aspects ofa scene compete witheachother viamu- tually inhibi inter action The neur ns that"win active reach higher levels hey share inhibitory interactions.Voluntary shifts of attention result from the influence of excitatory top-down signals representing the to-be-attended features of the scene.These bias the competition among neurons representing the scene,increasing the activity of
P1: FXZ January 12, 2001 14:38 Annual Reviews AR121-07 170 MILLER ¥ COHEN of a conflict stimulus (e.g. the word GREEN displayed in red), because there is a strong prepotent tendency to read the word (“green”), which competes with the response to the color (“red”). This illustrates one of the most fundamental aspects of cognitive control and goal-directed behavior: the ability to select a weaker, task-relevant response (or source of information) in the face of competition from an otherwise stronger, but task-irrelevant one. Patients with frontal impairment have difficulty with this task (e.g. Perrett 1974, Cohen & Servan-Schreiber 1992, Vendrell et al 1995), especially when the instructions vary frequently (Dunbar & Sussman 1995, Cohen et al 1999), which suggests that they have difficulty adhering to the goal of the task or its rules in the face of a competing stronger (i.e. more salient or habitual) response. Similar findings are evident in the WCST. Subjects are instructed to sort cards according to the shape, color, or number of symbols appearing on them and the sorting rule varies periodically. Thus, any given card can be associated with several possible actions, no single stimulus-response mapping will work, and the correct one changes and is dictated by whichever rule is currently in effect. Humans with PFC damage show stereotyped deficits in the WCST. They are able to acquire the initial mapping without much difficulty but are unable to adapt their behavior when the rule varies (Milner 1963). Monkeys with PFC lesions are impaired in an analog of this task (Dias et al 1996b, 1997) and in others when they must switch between different rules (Rossi et al 1999). The Stroop task and WCST are variously described as tapping the cognitive functions of either selective attention, behavioral inhibition, working memory, or rule-based or goal-directed behavior. In this article, we argue that all these functions depend on the representation of goals and rules in the form of patterns of activity in the PFC, which configure processing in other parts of the brain in accordance with current task demands. These top-down signals favor weak (but task-relevant) stimulus-response mappings when they are in competition with more habitual, stronger ones (such as in the Stroop task), especially when flexibility is needed (such as in the WCST). We believe that this can account for the wide range of other tasks found to be sensitive to PFC damage, such as A-not-B (Piaget 1954, Diamond & Goldman-Rakic 1989), Tower of London (Shallice 1982, 1988; Owen et al 1990), and others (Duncan 1986, Duncan et al 1996), Stuss & Benson 1986). We build on the fundamental principle that processing in the brain is competitive: Different pathways, carrying different sources of information, compete for expression in behavior, and the winners are those with the strongest sources of support. Desimone & Duncan (1995) have proposed a model that clearly articulates such a view with regard to visual attention. These authors assume that visual cortical neurons processing different aspects of a scene compete with each other via mutually inhibitory interactions. The neurons that “win” the competition and remain active reach higher levels of activity than those with which they share inhibitory interactions. Voluntary shifts of attention result from the influence of excitatory top-down signals representing the to-be-attended features of the scene. These bias the competition among neurons representing the scene, increasing the activity of Annu. Rev. Neurosci. 2001.24:167-202. Downloaded from arjournals.annualreviews.org by University of California - Los Angeles on 03/27/06. For personal use only
PREFRONTAL FUNCTION 171 neurons representing the to-be-attended features and,by virtue of mutual inhi bition,suppressing activity of neurons processing other features.Desimone Duncan suggest that the PFC is an important source of such top-down biasing. However,they left unspecified the mechanisms by which this occurs.That is the focus of thisarticle. We begin by outlining a theory that extends the notion of biased competition and proposes that it provides a fundamental mechanism by which the PFC exerts control over a wide range ofprocesses in the service of goal-directed behavior.We describe the minimal set of functional properties that such a system must exhibit if it can serve as a mechanism of cognitive control.We then review the existing literature that provides suppor sion of recent computational modeling efforts that illustrate how a system with these properties can support elementary forms of control.Finally,we consider unresolved issues that provide a challenge for future empirical and theoretical research. Overview of the Theory We assume that the PFC serves a specific function in cognitive control:the active maintenance of patterns of activity that represent goals and the means to achieve them.They provide bias signals throughout much of the rest of the brain,affecting oyisual processes but also other sensory modalities.as well as systems responsible for r exe on,memory retrieva The aggregate effect of these bias signals is to guide the flow of neural activity along pathways that establish the proper mappings between inputs,internal states, and outputs needed to perform a given task.This is especially important whenever stimuli are ambiguous (ie they activate more than one input representation) or when multiple responses are possible and the task-appropriate resp compete w biases-which resolves competition,guides activity along appropriate pathways and establishes the mappings needed to perform the task-can be viewed as the neural implementation of attentional templates,rules,or goals,depending on the target of their biasing influence To heln understand how this Figure 2 They can be thought of as neural representations of sensory events.internal states (e.g.stored memories,emotions,etc),or combinations of these.Also shown are units corresponding to the motor circuits mediating two responses(RI and R2). pro cessing pathy e and response units We have set up the type of situ ation thought to be important.Namely,one cue(C1)can lead to either of two responses (RI or R2)depending on the situation(C2 or C3),and appropriate behavior de- pends on establishing the correct mapping from CI to RI or R2.For example imagine you are standing at the corner of a street(cue C1).Your natural reaction is to look left before crossing(R1),and this is the correct thing to do in most
P1: FXZ January 12, 2001 14:38 Annual Reviews AR121-07 PREFRONTAL FUNCTION 171 neurons representing the to-be-attended features and, by virtue of mutual inhibition, suppressing activity of neurons processing other features. Desimone & Duncan suggest that the PFC is an important source of such top-down biasing. However, they left unspecified the mechanisms by which this occurs. That is the focus of this article. We begin by outlining a theory that extends the notion of biased competition and proposes that it provides a fundamental mechanism by which the PFC exerts control over a wide range of processes in the service of goal-directed behavior. We describe the minimal set of functional properties that such a system must exhibit if it can serve as a mechanism of cognitive control. We then review the existing literature that provides support for this set of properties, followed by a discussion of recent computational modeling efforts that illustrate how a system with these properties can support elementary forms of control. Finally, we consider unresolved issues that provide a challenge for future empirical and theoretical research. Overview of the Theory We assume that the PFC serves a specific function in cognitive control: the active maintenance of patterns of activity that represent goals and the means to achieve them. They provide bias signals throughout much of the rest of the brain, affecting not only visual processes but also other sensory modalities, as well as systems responsible for response execution, memory retrieval, emotional evaluation, etc. The aggregate effect of these bias signals is to guide the flow of neural activity along pathways that establish the proper mappings between inputs, internal states, and outputs needed to perform a given task. This is especially important whenever stimuli are ambiguous (i.e. they activate more than one input representation), or when multiple responses are possible and the task-appropriate response must compete with stronger alternatives. From this perspective, the constellation of PFC biases—which resolves competition, guides activity along appropriate pathways, and establishes the mappings needed to perform the task—can be viewed as the neural implementation of attentional templates, rules, or goals, depending on the target of their biasing influence. To help understand how this might work, consider the schematic shown in Figure 2. Processing units are shown that correspond to cues (C1, C2, C3). They can be thought of as neural representations of sensory events, internal states (e.g. stored memories, emotions, etc), or combinations of these. Also shown are units corresponding to the motor circuits mediating two responses (R1 and R2), as well as intervening or “hidden” units that define processing pathways between cue and response units. We have set up the type of situation for which the PFC is thought to be important. Namely, one cue (C1) can lead to either of two responses (R1 or R2) depending on the situation (C2 or C3), and appropriate behavior depends on establishing the correct mapping from C1 to R1 or R2. For example, imagine you are standing at the corner of a street (cue C1). Your natural reaction is to look left before crossing (R1), and this is the correct thing to do in most Annu. Rev. Neurosci. 2001.24:167-202. Downloaded from arjournals.annualreviews.org by University of California - Los Angeles on 03/27/06. For personal use only