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Physiol Rev 88: 37–57, 2008;
doi:10.1152/physrev.00014.2007.
Role of the Lateral Prefrontal Cortex in Executive
Behavioral Control
JUN TANJI AND EIJI HOSHI
Tamagawa University Brain Science Institute, Machida, Tokyo, Japan
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I. Introduction
II. Anatomical Background
A. General trends in the organization of the LPFC: parcelation into dorsal and ventral tiers
B. Inputs to the PFC
C. Connections with cortical motor areas, basal ganglia, and the cerebellum
D. Summary of connections of the LPFC
III. Regional Specialization Within the Lateral Prefrontal Cortex
IV. Working Memory
V. Attention for Action
VI. Response Inhibition
VII. Preparatory Set and Regulation of Cross-Temporal Contingency
VIII. Action Selection and Decision Making
IX. Behavioral Planning Versus Motor Planning
A. Motor planning in the LPFC
B. Task or rule dependency of preparatory activity
C. What is planned in the LPFC?
X. Behavioral Goal Selection
XI. Reward Expectation and Reinforcer-Based Control of Behavior
XII. Temporal Sequencing of Multiple Actions
XIII. Strategic or Conceptual Behavioral Planning
XIV. Conclusions
Tanji J, Hoshi E. Role of the Lateral Prefrontal Cortex in Executive Behavioral Control. Physiol Rev 88: 37–57, 2008;
doi:10.1152/physrev.00014.2007.—The lateral prefrontal cortex is critically involved in broad aspects of executive
behavioral control. Early studies emphasized its role in the short-term retention of information retrieved from
cortical association areas and in the inhibition of prepotent responses. Recent studies of subhuman primates and
humans have revealed the role of this area in more general aspects of behavioral planning. Novel findings of neuronal
activity have specified how neurons in this area take part in selective attention for action and in selecting an intended
action. Furthermore, the involvement of the lateral prefrontal cortex in the implementation of behavioral rules and
in setting multiple behavioral goals has been discovered. Recent studies have begun to reveal neuronal mechanisms
for strategic behavioral planning and for the development of knowledge that enables the planning of macrostructures of event-action sequences at the conceptual level.
I. INTRODUCTION
The prefrontal cortex (PFC) of primates has traditionally been classified into at least three major subdivisions: lateral, medial, and ventral (orbitofrontal). Comprehensive reviews of the structures and functions of the
PFC have appeared in various monographs (e.g., Refs. 75,
188, 259) and review articles (89, 147, 290).
In this review, we concentrate on recent developments in research on the lateral part of the PFC that
includes area 12/47, 45, and 46 ventrally, as well as 8B and
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9 dorsally, according to the cytoarchitectonic classification of Walker (274). Area 8A, which belongs to the
oculomotor control region, is not considered here. The
lateral prefrontal cortex (LPFC) is involved in many aspects of behavior in primates (Table 1). Here, we primarily deal with the issue of integrative action planning,
which is viewed as constituting a core prefrontal function (140).
Toward the end of the 20th century, the primary
research interests concerning the LPFC were the processing of information stored in short-term memory and at-
0031-9333/08 $18.00 Copyright © 2008 the American Physiological Society
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1. Behavioral factors in which the involvement
of the lateral prefrontal cortex is viewed as essential
A. General Trends in the Organization of the
LPFC: Parcelation Into Dorsal and Ventral Tiers
Information processing
Selection and retrieval
Retention and monitoring
Transformation
Manipulation
Synthesis and generation
Attentional and cognitive-set regulation
Integrative action planning
Judgment, inference, and speculation
Language processing
Other aspects of cognitive behavior
When analyzing architectonic organization in the
PFC, Barbas and Pandya (21) found two distinct trends in
gradual changes in laminar characteristics that can be
traced from the limbic periallocortex toward the isocortical areas. Based on cytoarchitectonic and myeloarchitectonic analysis, they observed that one of the architectonic
trends takes a radial basoventral course from the periallocortex in the caudal orbitofrontal region to the adjacent
proisocortex, and then to area 13. The next stage of
advancement in architectonic differentiation begins from
orbital areas 12, 11, and 14, followed by area 10, and the
rostroventral area 46, and finally reaches the caudal part
of ventral areas 46 and 8. The other trend takes a mediodorsal course from the periallocortex, around the rostral portion of the corpus callosum to the proisocortical
areas 24, 25, and 32, and then to the medially situated
isocortical areas 9, 10, and 14. The next stage includes
lateral areas 10 and 9 and rostrodorsal area 46, progressing to the caudal part of dorsal areas 46 and 8. Thus the
dorsal and ventral parts of the LPFC are viewed as having
two distinct origins of architectonic differentiation. By
examining corticocortical connections within the PFC
using tracer techniques, Barbas and Pandya (21) further
found that most interconnections were limited to areas
within the same architectonic trend. Thus the dorsal part
of the LPFC receives inputs largely from areas in the
medial PFC, whereas the ventral LPFC receives afferents
mostly from areas in the orbitofrontal cortex.
Price and co-workers (44, 177) examined corticocortical connections of the orbital and medial PFC and
defined two distinct networks: the orbital network and
the medial network. The orbital network includes most of
the areas on the posterior, central, and lateral orbital
surfaces, whereas the medial prefrontal network includes
all the areas on the medial wall and the related areas on
the orbital surface. Areas within each network are mutually interconnected and have distinct connections with
structures in other parts of the brain. The orbital network
receives ample sensory inputs of multiple modalities, conveying visual, somatosensory, auditory, olfactory, and
gustatory information (46). The medial network is characterized by outputs to the hypothalamus and the periaqueductal gray, which play major roles in autonomic and
somatic (visceromotor) responses to emotional stimuli
(170, 176).
Although the areas defined by the mediodorsal and
basoventral trends (21) may not completely match the
areas belonging to the medial and orbital networks (177),
the existence of two large-scale networks in the PFC
originating from the medial and ventral periallocortex has
been established. The dorsal part of the LPFC (dorsal to
the fundus of the principal sulcus) belongs to the me-
tentional and cognitive-set regulation, which was deeply
influenced by the working memory hypothesis for the
PFC (11, 87). Recent research, however, has revealed the
role of this area in the control of a much broader spectrum of behavior. We discuss the functional role of the
LPFC from the perspective of the executive control of
behavior on the premise that the entire frontal cortex is
primarily devoted to the processing of actions and the
LPFC is located in the central part of the frontal cortex,
playing an important role in regulating aspects of volitional acts by individuals (206).
Here, the term executive control refers to those
mechanisms by which behavioral performance is optimized in situations requiring cognitive processes. We begin by providing an anatomical framework with which to
explore the involvement of the LPFC in various aspects of
executive control. We then discuss regional differences
within the LPFC and their roles in exerting cognitive
control over behavior. Thereafter, we deal with individual
component processes that are essential to achieving executive control of purposeful behavior. We have critically
evaluated the various views on the roles of the individual
components in the face of the many recent reports that
have accumulated on this topic.
II. ANATOMICAL BACKGROUND
We first provide an anatomical framework with
which to consider the role of the LPFC under various
conditions that require subjects to exert adequate control
over behavior. After a brief consideration of heterogeneity within the LPFC based on architectonic differentiation
in the PFC and intrinsic anatomical connectivity, we examine the connections of the LPFC with cortical and
subcortical areas that are relevant in its role in executive
behavioral control. We deal with reports regarding the
PFC of macaque monkeys, in which basic patterns in
the architecture and anatomical connectivity of the PFC
are basically similar to those in humans (200, 201).
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TABLE
LATERAL PREFRONTAL CORTEX AND EXECUTIVE BEHAVIORAL CONTROL
diodorsal network. In contrast, the ventral part of the
LPFC (ventral to the fundus of the principal sulcus) belongs to the orbitoventral (basoventral) network.
B. Inputs to the PFC
1. Visual association cortex (areas TE and TEO)
2. Polymodal area in the dorsal bank of the STS
The polymodal area in the dorsal bank of the STS
(area TPO, temporal polymodal cortex) projects to both
the mediodorsal and orbitoventral networks. In this projection, a rostrocaudal trend has been identified: more
rostral areas (less differentiated areas) of the TPO preferentially project to the less differentiated areas in the
PFC, and the more caudal areas of the TPO (more differentiated areas) project to the more differentiated areas in
the PFC (247).
3. Auditory association cortex (superior
temporal gyrus)
The LPFC across the two networks receives inputs
from the auditory association cortex in the superior temporal gyrus. Topographical connections have been reported: the rostral part of area 46 and area 10 are preferentially interconnected with the rostral belt and parabelt
auditory association cortex, whereas the caudal part of
area 46 and the periarcuate cortex (area 8a) are preferentially linked with the caudal auditory association cortex
(198, 219). The inferior part of the periarcuate cortex
(area 45) is interconnected with both the rostral and
caudal parts of the auditory association cortex (200). In
addition to these connections with the LPFC, the auditory
association cortex and the anterior superior temporal
cortices are heavily interconnected with the medial prefrontal cortices (areas 10, 14, 25, and 32) (16) and orbital
PFC (areas 12 and 13) (46). The dorsal part of the temporal pole, which receives auditory or polymodal inputs
from the superior temporal cortex, projects preferentially
to areas in the mediodorsal networks (e.g., areas 10, 14,
25, and 32) and lateral orbital cortex (area 12) (120).
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4. Perisylvian somatosensory cortex
The ventral rim of the middle part of the principal
sulcus and the medial part of area 12 (both in the
orbitoventral network) are interconnected with the perisylvian somatosensory cortical areas: the second somatosensory area, area 2 of the primary somatosensory area,
granular insular cortex, and PF in the rostral inferior
parietal lobule (19, 48, 205).
5. Inferior parietal lobule
Several distinct areas have been identified in the
inferior parietal lobule. Although the number of areas is
still controversial, a recent report provided evidence that
there are four distinct cytoarchitectonic areas in the convexity of the inferior parietal lobule: area Opt, PG, PFG,
and PF in the caudal to rostral axis (183, 227). The LPFC,
especially area 46, is interconnected with these parietal
areas. There is a general trend in connections between
area 46 and the inferior parietal lobule: dorsal area 46 is
preferentially linked with more caudal areas such as the
area Opt, whereas ventral area 46 is preferentially linked
with more rostral areas such as areas PF and PFG (227).
More specifically, the caudal part of the posterior parietal
cortex is linked with the fundus and banks of the principal
sulcus (4, 47, 199), whereas its rostral part is connected
with the ventral lip of the principal sulcus and area 45 (4,
47, 198).
6. Superior parietal lobule and medial parietal cortex
Only weak outputs from the superior parietal lobule,
if any, reach dorsal area 46 of the PFC (113). Rather, they
primarily reach the dorsal premotor cortex in Brodmann’s
area 6 (199, 201). In contrast, the medial posterior parietal
cortex and the caudal cingulate areas (areas PGm, 29, 30,
23, and 31) are preferentially interconnected with areas in
the mediodorsal network, including the dorsal part of the
LPFC (47, 160, 201).
7. Amygdala, perirhinal cortex, and hypothalamus
The amygdala projects to the less differentiated areas
in both the mediodorsal and orbitoventral networks (2,
15, 45, 202). However, the caudal part of the LPFC, which
is a highly differentiated area, receives few direct inputs
from the amygdala (2, 15, 202). The perirhinal cortex
(areas 35 and 36) is preferentially interconnected with
areas in the orbitoventral network (areas 11, 12, and 13)
(121, 128). The hypothalamus projects to wide areas in the
PFC, including the LPFC (214), although areas in the
medial PFC constitute most of the outputs to the hypothalamus (176).
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Areas TE and TEO and the lower bank of the superior
temporal sulcus (STS) in the inferior temporal cortex,
which are essential for visual object recognition (264),
project preferentially to areas in the orbitoventral network (lateral area 12, ventral area 8, and area 45) (46, 113,
242, 247, 283). The ventral part of the temporal pole,
which receives visual information from the inferior temporal cortex, also projects to areas in the orbitoventral
network (e.g., areas 11 and 13) (120). Areas in the mediodorsal network rarely receive inputs from areas TE
and TEO or the ventral part of the temporal pole (16,
242, 283).
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8. Parahippocampal cortex, entorhinal cortex,
subiculum, and hippocampal formation
The parahippocampal cortex (areas TF/TH) projects
to wide areas across the two networks, with some preference for the mediodorsal network, including the LPFC
(121, 128). The hippocampal formation, subiculum, and
entorhinal cortex preferentially send outputs to the medial frontal cortex (areas 24, 32, 25, and 14) (14, 161). The
LPFC is innervated predominantly by the presubiculum,
but it receives sparser inputs from the hippocampal formation (14, 92).
9. Thalamus
10. Monoaminergic inputs
The PFC receives ample monoaminergic inputs (34):
dopamine, norepinephrine, and serotonin (203, 286). Innervations of dopamine fibers are more prominent in
mediodorsal areas such as areas 9, 8B, and 24. The density
of dopamine terminals decreases in the lateral and orbital
areas (26, 132, 287). Similarly, innervation with norepinephrine is more intense in areas 9, 8B, and 24 (133). In
contrast, overall serotoninergic innervation is more uniform across areas in the PFC (134). The densities of
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C. Connections With Cortical Motor Areas, Basal
Ganglia, and the Cerebellum
1. Motor areas in the frontal cortex
The PFC is interconnected with multiple motor areas
in the frontal cortex (24, 99, 135, 157, 261), which is
believed to play important roles in the cognitive control of
motor behavior. Connections with the lateral premotor
cortex (area 6) differ between the dorsal and ventral parts
of the LPFC. The dorsal part is linked with the dorsal
premotor cortex, medial to the spur of the arcuate sulcus,
whereas the ventral part is linked with the ventral premotor cortex, lateral to the spur (20, 46, 139, 200, 201, 205,
279). In contrast, both dorsal and ventral parts of the
LPFC are linked with the rostral cingulate motor area
(area 24c), presupplementary motor area (area 6), and
supplementary eye field (area 6) (46, 103, 138, 139, 278).
Area 8A, which is involved in eye and head movements, is
also interconnected with both the dorsal and ventral parts
of the LPFC (18, 104, 200, 201).
2. Basal ganglia
Wide areas of the LPFC project to the input stage of
the basal ganglia (caudate and putamen) in a topographic
manner (114, 246). The dorsal part of the LPFC projects
preferentially to the dorsal and central part of the caudate
nucleus, and the ventral part projects to the ventral and
central caudate nucleus (293). A topographic connection
has been reported in projections from the orbital and
medial PFC. The medial PFC preferentially projects to the
ventral striatum (medial caudate nucleus, nucleus accumbens, ventral putamen). In contrast, the orbital PFC
projects to central and lateral parts of the caudate nucleus
and to the ventromedial putamen (64). Because parallel
and looped architectures are suggested to be basic principles of the corticobasal ganglia system (1), it is likely
that there are multiple parallel circuits running through
the PFC and the basal ganglia, with each circuit involved
in distinct aspects of behavioral control. The subthalamic
nucleus, which is another input stage of the basal ganglia
(153, 168), receives inputs only from restricted areas of
the PFC; it was reported that the area 9, but not the area
46, sends its outputs to it (159). Further studies are necessary to reveal more precise profiles of the projection
patterns from the PFC to the subthalamic nucleus.
3. Cerebellum
Areas medial to the principal sulcus and medial PFC
(areas in the mediodorsal network) send outputs to the
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The PFC is interconnected with multiple nuclei in the
thalamus, including the ventral nuclei, mediodorsal nucleus, and medial pulvinar nucleus (17, 91, 112, 115). The
ventral anterior nucleus, linked with the PFC, is innervated by the output stage of the basal ganglia (substantia
nigra pars reticulata and the internal segment of the globus pallidus) (107, 292). The ventral lateral nuclei mediate
the projection from the cerebellar nuclei to the PFC (144).
The medial part of the mediodorsal nucleus, predominantly linked with the medial and orbital PFC, receives
inputs from a variety of structures, including the ventral
pallidum, substantia innominata, amygdala, entorhinal
and perirhinal cortices, subiculum, olfactory cortex, hypothalamus, and temporal pole (91, 231). In contrast, the
lateral part of the mediodorsal nucleus, which is preferentially interconnected with the LPFC, is innervated by
the superior colliculus, substantia nigra pars reticulata,
and claustrum (62, 91, 107). Topographical connections
have been shown between the LPFC and the mediodorsal
nucleus: the dorsal and ventral LPFCs tend to be interconnected with the dorsal and ventral mediodorsal nuclei,
respectively (91, 255). The medial pulvinar receives inputs
from the superior colliculus, parahippocampal cortex,
posterior cingulate, and retrosplenial cortex (13, 25).
Taken together, the thalamus mediates pathways to the
PFC from the basal ganglia, cerebellum, and a variety of
limbic structures, including the hippocampus and amygdala.
ceptor subtypes differ markedly across cortical layers (26,
90, 134) and across subclasses of neurons (256, 257),
suggesting that monoamines play important roles in information processing by the PFC (5, 49, 216, 240, 285).
LATERAL PREFRONTAL CORTEX AND EXECUTIVE BEHAVIORAL CONTROL
D. Summary of Connections of the LPFC
We summarized the basic anatomical connectivity of
the LPFC in dealing with multiple inputs and outputs
(Fig. 1). The dorsal and ventral parts of the LPFC can be
viewed as part of two distinct, large-scale networks
within the PFC: the dorsal part is part of a mediodorsal
network originating from the periallocortex in the medial
PFC, and the lateral part is part of an orbitoventral network originating from the periallocortex in the orbital
PFC. The orbitoventral network is characterized by multiple sensory inputs, including visual, auditory, somatosensory, gustatory, and olfactory. This pattern of connections suggests that this network plays a major role in
receiving multiple sensory signals to retrieve and integrate necessary information. In contrast, the mediodorsal
network receives inputs from multimodal areas in the
temporal cortex or auditory areas in the superior temporal gyrus. This suggests that the dorsal network receives
signals that are already processed and are multimodal in
nature. Intensive interconnections within each network
allow the integration of multiple sets of information that
each network receives. Thus the dorsal and ventral parts
of the LPFC seem to process information based on dis-
FIG. 1. Schematic illustration of the cytoarchitecture of the prefrontal cortex and input-output organization of the lateral prefrontal cortex
(LPFC). In the middle column, the middle panel shows the cytoarchitectonic boundaries of the LPFC (according to Walker, Ref. 274). The top and
bottom panels show the cytoarchitectonic boundaries of the medial and orbital prefrontal cortices, respectively (according to Carmichael and Price,
Ref. 44). The medial cortex (top panel) is shown upside down. In the orbital cortex (bottom panel), the midline is along the bottom. Rostral is to
the left in all views. The red and blue arrows indicate the mediodorsal and basoventral trend, respectively, of cytoarchitectonic differentiation,
according to Barbas and Pandya (21). We propose here that the red-colored areas in the medial prefrontal cortex and the dorsal LPFC belong to
the mediodorsal network and the blue-colored areas in the orbital prefrontal cortex and the ventral LPFC belong to the orbitoventral network. In
the left column, trends of inputs to these networks are summarized. Inputs are classified into three categories: areas preferentially projecting to the
mediodorsal network (top), areas preferentially projecting to the orbitoventral network (bottom), and areas commonly projecting to both networks
(middle). Areas chiefly projecting to the orbital or medial prefrontal cortex, but less to the LPFC, are italicized. In the right column, trends of outputs
from the lateral prefrontal cortex to major motor areas are summarized: areas to which the dorsal LPFC preferentially projects (top), areas to which
the ventral LPFC preferentially projects (bottom), and areas to which both parts of the LPFC project (middle). Rs, rostral sulcus; cs, cingulate sulcus;
cc, corpus callosum; as, arcuate sulcus; ps, principal sulcus; mos, medial orbital sulcus; los, lateral orbital sulcus. PF, PFG, PG, PGm, and Opt are
subareas in the parietal cortex (183). SII, secondary somatosensory area; LIP, lateral intraparietal area; CMAr, rostral cingulated motor area;
pre-SMA, pre-supplementary motor area.
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basilar pons (83, 243), the neurons of which send outputs
that connect to neurons in the deep cerebellar nuclei and
granule cells in the cerebellar cortex (108). In contrast,
only a small number of areas (caudal ventral area 46 and
area 45) in the orbitoventral network send less intense
outputs to the pontine nuclei. The ventral and orbital
prefrontal cortices do not send outputs to the pontine
nuclei (83, 243). Using a strain of herpes virus, which is
transported in the retrograde direction across neuronal
synapses, Middleton and Strick (144) identified that dorsal area 46 and area 9, but not ventral area 46 or area 12,
receive substantial inputs from deep cerebellar nuclei.
Thus it appears that areas in the mediodorsal network are
linked with the cerebellum, whereas the cerebellar link is
much weaker in the orbitoventral network.
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III. REGIONAL SPECIALIZATION WITHIN
THE LATERAL PREFRONTAL CORTEX
A major debate regarding the LPFC has been whether
this cortical region should be considered unitary or heterogeneous in function. Lesion studies in which behavioral deficits are examined following an ablation or acute
inhibition or excitation of a restricted area in the PFC
have provided important clues regarding functional specialization within the PFC (54). A consensus has developed that interprets the effects of lesions confined to the
cortex in and around the principal sulcus (dorsal and
ventral area 46) as deficits in behavior that require the
processing of spatial information with a time delay between behavioral events such as between a spatial cue
and a motor act or between successive motor acts in
space (85, 86, 131, 149, 155). In contrast, ablation of the
principal sulcus does not induce deficits in a behavioral
task in which information on object identity must be
handled such as in delayed match- (or non-match-)
to-sample tasks (10, 156, 185). Thus the effects of lesions
applied to the banks of the principal sulcus suggest its key
involvement in processing spatial signals such as the spatial position of a cue and a motor act in space, but not in
processing information on object identity.
Lesions in the ventral part of the LPFC lead to different deficits than those in the banks of the principal
sulcus. Ventral prefrontal lesions cause deficits in behavioral tasks in which information on object identity plays a
key role (156, 185, 277). An important observation is that
animals with lesions in the ventral PFC could not perform
a color-matching task, even if no delay was imposed
(229), and that once the task was relearned, the animals
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could perform the task even with delay. Rushworth and
co-workers (228, 229) suggested that the ventral PFC is
not important for working memory, but may play a role in
selecting attended objects. Bussey et al. (41) showed that
ventral and orbital prefrontal lesions induce deficits in
learning new visuomotor associations and retaining prelearned visuomotor associations. These findings point to
the possibility that the ventral PFC plays an important
role in processing multiple visual items or in associating
visual signals with spatial motor acts (162, 189, 289). In
fact, lesions in this area may also cause some deficits in
spatial tasks (109, 224). Bussey et al. (41) also showed
that prelearned strategies of repeat-stay and change-shift
(repeating the same response when a rewarded cue was
presented repeatedly and altering the response to the
stimulus) were not retained after the lesion. Together
with the perseveration tendency after lesions in the ventral PFC (109, 126), another important function of the
ventral PFC would appear to be the implementation of
behavioral strategies to optimize task performance (41).
Goldman-Rakic (89) proposed that the dorsal and
ventral parts of the LPFC differ primarily with respect to
the information domain, with spatial processes taking
place in the dorsolateral PFC and feature processing taking place in the ventrolateral PFC. This hypothesis, based
on anatomical connectivity exhibiting dorsoventral gradients in afferent and efferent projection patterns (see sect.
II), was initially supported by reports of functional studies
in humans (271, 272) and monkeys (179, 180, 288). However, subsequent functional studies were not necessarily
consistent with this view. Rao et al. (213) examined LPFC
neurons in monkeys during a task that involved processing of both what and where information. Neurons showing either object-tuned (what) or location-tuned (where)
delay activity were distributed widely in both the ventral
and dorsal parts of the LPFC. Furthermore, over half
(52%, 64 of 123) of the PFC neurons with delay activity
showed both what and where tuning, suggesting that their
role in linking object information with spatial information
was needed to guide behavior. In a study by Wilson et al.
(288), 24 of the 31 delay-related neurons in the inferior
convexity reflected visual objects, whereas 6 reflected the
response direction. The existence of response-coding
neurons, along with object-selective neurons in the ventral PFC, is consistent with the conclusions of lesion
studies in that the ventral PFC plays a key role in associating visual information with motor responses. Furthermore, the passive viewing of stimuli presented on a
screen (179, 180) can activate neurons responding to
visual inputs, regardless of their relevance to the control
of actions.
Spatially selective PFC activity is greatly influenced
by behavioral factors such as the sequence of appearance
(8, 22), probability of the direction of forthcoming movements (209), object identity (7, 210, 211), judgment diffi-
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tinct inputs. Additionally, there are extensive interconnections between the two networks (21, 184, 200), allowing the PFC to integrate multiple sets of information on a
large scale.
The LPFC is directly or indirectly connected with
widespread structures in the brain through the orbital and
medial prefrontal cortices: the association cortex, limbic
cortex, and subcortical structures. This organization
places the PFC in a unique position and highlights its
critical role in collecting and integrating diverse sets of
information. On the other hand, the LPFC is interconnected with premotor areas, the basal ganglia, and the
cerebellum. Through these connections, the LPFC can
control broad aspects of motor behavior. Moreover, the
LPFC modulates the flow of information in other areas of
the central nervous system, in conforming to behavioral
requirements, providing a resource for adaptive control of
information flowing through cortical and subcortical
structures (146). The PFC is thus situated at the center of
large-scale information flow in the brain.
LATERAL PREFRONTAL CORTEX AND EXECUTIVE BEHAVIORAL CONTROL
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relatively more direct modality-specific sensory information reaching the areas in the orbitoventral network. The
dichotomy also suggests that the interaction allowed by
the intrinsic connections between the dorsal and ventral
networks allows the dorsal LPFC to execute the monitoring and manipulation of retrieved information, which itself is preferentially represented in the areas of the orbitoventral network.
Hoshi and Tanji (102) compared neuronal activity in
the dorsal and ventral LPFC by designing experiments to
detect neuronal activity reflecting the process of receiving
and retaining two sets of visual information, retrieving
their behavioral meaning, and integrating the two to plan
subsequent actions. Ventral LPFC neurons were preferentially involved in detecting and retaining spatial information contained in visual cues for subsequent use, whereas
dorsal LPFC neurons were predominantly involved in a
more advanced stage of sensorimotor processing, the retrieval of task-relevant information, and the integration of
the two sets of information to construct instructions for
actions to be planned. This observation demonstrating the
progression of information transfer taking place along the
direction from the ventral to dorsal LPFC suggests neuronal mechanisms that could explain the validity of the
aforementioned two-stage hypothesis. Lebedev et al.
(129) showed that neuronal activity reflecting a memorized location (more remote location) tended to be located in the dorsal LPFC, whereas activity reflecting an
attended location (more recent location) was primarily
located in the ventral LPFC. This can be viewed as showing that more processed information is represented dorsally. A recent report demonstrating the preferential role
of the dorsal LPFC in more conceptual aspects of behavioral planning is also consistent with the process-specific
theory (250).
There is sufficient evidence to reveal functional heterogeneity within the LPFC. As long as behavioral tasks
do not require much information processing, neuronal
activity may primarily represent the information received
from sensory signals. However, if the behavioral conditions are demanding, properties that characterize specific
processes that take place in individual portions of the
LPFC are likely to emerge, even if cooperation between
multiple areas belonging to different networks is necessary to allow the functioning of the LPFC at a high level of
operation. From a separate point of view, a caveat against
the process-specific theory is the possibility that some
aspects of specific processes may also rely on domainspecific use of sensory information.
IV. WORKING MEMORY
The term working memory was proposed to refer to
a multicomponent system capable of both storing and
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culty (51), saccade-direction judgment (116), and reward
expectancy (117, 130, 217). Object selectivity of PFC neurons is also affected by such behavioral factors as
go/no-go selection (233–236, 281, 282), category specification (66, 67), object quantity (171), object sequence and
rank order (173, 174), task requirements or behavioral
relevance (100), task rules (284), and an attended dimension of a visual object (shape versus color) (142). These
reports stress the importance of the integrative processing of information within the PFC (189, 226, 229), rather
than the simple reflection or retention of sensory information.
Based on a series of lesion studies in monkeys (193,
195) and on brain imaging studies in humans (181, 196),
Petrides (192, 194) proposed that the dorsal part of the
LPFC was involved in the monitoring and manipulation of
retrieved information in the planning and execution of
behavior. The ventral part of the LPFC, in contrast, was
proposed to be involved in active encoding and retrieval
of specific information held in visual, auditory, and somatosensory association areas, allowing selection, comparison, and decision processes based on such information.
This process-specific model of the functional organization of the LPFC has been influential and essentially
constitutes an antithesis to the domain-specific model,
although some issues remain to be answered. If behavioral monitoring is indeed a critical process that depends
on the integrity of the dorsal LPFC, it is unclear why
lesions in this area cause impairments in simple tests of
spatial delayed response tasks that do not depend on
monitoring (131). It is also unclear whether lesions in the
banks of the principal sulcus, in addition to those in the
more dorsal part of the LPFC, would give rise to deficits
similar to those reported by Petrides (192).
Ninokura et al. (174) recorded neuronal activity
while monkeys received three visual objects presented
successively and reproduce the temporal order of their
appearance by touching them in the presented order.
They found that neuronal activity in the middle part of the
dorsal LPFC, corresponding to the area that Petrides
(194) proposed as a critical area for monitoring, preferentially represented the rank-order of the appearance of
the objects, rather than object identity. Hasegawa et al.
(96) recorded neuronal activity while monkeys performed
a self-ordered task that required them to perform three
steps. They found that neurons in the dorsal LPFC primarily reflected task progress, rather than object identity.
These two studies suggest that the dorsal LPFC is involved in encoding the task phase or task progress, but is
less involved in representing the identity of objects, which
are amply represented in the ventral LPFC. This functional dichotomy is consistent with the pattern of anatomical connectivity, suggesting that the dorsal LPFC preferentially receives processed information, rather than the
43
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Physiol Rev • VOL
sory signals. Attentional control, transformation of mnemonic representations from their encoded state, response
selection, abstraction across trials of stimulus patterns
with which to guide behavioral set, or mediation of the
effects of interference in working memory are among
capacities in which the LPFC is likely to be crucially
involved.
V. ATTENTION for ACTION
To initiate an action to achieve what is intended,
subjects first search for information to construct the
schema of the action and its goal. Neuronal mechanisms
that mediate perceptual selectivity required in this attentive process have long been known to involve the LPFC
(30, 31, 57). Recent studies have provided evidence that
the PFC is critical for attentional function to code information of specific relevance to current behavior, filtering
out unwanted signals (56, 137, 147). The finding that
cellular activity in the LPFC exhibits strong filtering of
visual signals demonstrates the way in which focused
attention can achieve the selection of behavioral targets
versus non-targets (63). These findings are consistent
with the view that top-down attention that results from
signals emanating from the frontal cortex biases posterior
areas to favor the channel of information relevant to the
intended behavior (145, 191). The role of the LPFC in the
attentional selection of objects, rather than the maintenance of object information, has been reported in eventrelated functional magnetic resonance imaging (fMRI)
studies on human subjects (127, 225). A recent neurophysiological study attempted to examine whether the delay
period activity of PFC neurons after the presentation of a
positional cue signal represented a remembered location
or the target of an attended location (129). In the study,
monkeys attended to a stimulus marking one location
while remembering a different, unmarked location: both
locations served as potential targets of a saccade. Lebedev et al. (129) found that LPFC neurons predominantly
represented attended locations, but not remembered
ones, although the task made intensive demands on shortterm memory. The findings showed that short-term memory functions cannot account for most delay-period activity in the LPFC, pointing to a more general role for the
LPFC than proposed by the maintenance-memory theory
(43, 147, 260, 267), including the top-down control of
selective attention. Numerous studies using event-related
fMRI have reported the participation of multiple cortical
areas in attentional processes, but it has been difficult to
localize various aspects of attentive behavior (165). However, attempts to fractionate attentional control processes
are progressing. In a recent report, for instance, subjects
voluntarily worked out which object was the target in a
stimulus set of two faces and two buildings, and feedback
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manipulating information that plays a central role in complex cognitive activities required for the control of various
aspects of behavior (12). Although the “central executive”
part of this model has remained largely unspecified by
experimental studies until recently, the “short-term storage of information” part of the model has received much
interest in experimental studies. Neurophysiological studies have provided a great deal of evidence that PFC cells
exhibit sustained type of activity throughout the delay
period after the termination of visual (57, 71, 76, 148) or
auditory (28) cue signals. Romo and co-workers (220 –
222) later revealed that the frequency of somatosensory
signals was retained in cellular activity during a period of
short-term storage, in a parametric manner. GoldmanRakic (88, 89) proposed the hypothesis that the PFC
mediates working memory, defined as the short-term storage of information pertinent in the performance of upcoming tasks. The delay-period activity in the PFC was
viewed as essential in keeping memorized information on
line. It was further proposed that the PFC is a collection
of areas with a specialized mnemonic function and that
the multitude of granular prefrontal areas differ from one
another, not in the functions they perform, but rather
more in the nature of the information they process (domain specificity hypothesis, Refs. 87, 89). Although attractive as a theory characterizing the functions of the dorsal
and ventral parts of the LPFC, the working-memory theory of their account and the theory of domain-specific
regional specialization have some problems. The theory
has difficulty in accounting for some of the impairments
observed in monkeys with PFC lesions (80, 154, 187).
Furthermore, the results of ablation studies of the dorsolateral PFC on oculomotor delayed responses (72) have
been inconclusive. Although the data have been interpreted as supporting a spatial working memory hypothesis, postoperative saccades were generally directed close
to the correct direction of saccades to be remembered.
Delay-period activity in the dorsolateral PFC has also
been interpreted in terms of the maintenance-memory
theory (51, 71). However, as revealed by recent studies,
the delay-period activity could be interpreted with nonmemory functions (e.g., selective attention or preparation
of action), as we discuss in subsequent sections in this
review. Evidence arguing against the domain-specific regional specialization theory is accumulating (see sect. III).
Furthermore, brain-imaging studies in humans supported
the memory-maintenance theory at first (53), but subsequently have resulted in questioning the substantial participation of the LPFC in working memory storage (204).
It seems that the capacity of simple storage of information
for a short term may not be of primary importance for the
functional role of the LPFC. Instead, the contribution of
this area to working memory function is more likely to be
in controlling behavior in processes operating at a level
that is abstracted from the processing of individual sen-
LATERAL PREFRONTAL CORTEX AND EXECUTIVE BEHAVIORAL CONTROL
was given once after two consecutive choices (94). With
the use of this experimental design, which sorted out such
behavioral factors as response reversals, stimulus change,
stimulus-response mapping change, and changes in the
dimension of stimulus, it was found that the ventrolateral
PFC was involved in switching attention between stimulus dimensions (extradimensional shifts), whereas the
posterior parietal cortex mediated changes in stimulusresponse mapping.
45
inally applied behavior-guiding principle. By designing a
set of new sorting tests, Delis et al. (55) found that patients with lesions of the PFC also had problems in spontaneously generating sorting categories, using abstract or
explicit cues to guide sorting, identifying rules they had
used to accurately sort, and identifying rules used by the
examiner to sort. With these findings, Delis et al. (55)
uncovered evidence of impairment in the use of behaviorguiding rules and also of deficits that included concept
formation and abstract thinking. We address these behavioral aspects below.
VI. RESPONSE INHIBITION
Physiol Rev • VOL
VII. PREPARATORY SET AND REGULATION
OF CROSS-TEMPORAL CONTINGENCY
Fuster (74) reemphasized the long-standing, traditional concept (110, 152, 207) that the general function of
the LPFC is the temporal organization of behavior. Upon
the initiation of actions, networks involving the PFC are
viewed as providing representations of the schemas of the
behavioral structure and the plan and program outlining
actions. The preparatory set is a prospective function
specifying the occurrence of a forthcoming action with a
proper timing and order. It also regulates temporal relationships between the occurrences of events and actions,
namely, the regulation of cross-temporal contingencies. A
good example of neuronal activity representing crosstemporal contingencies was presented in a study that also
required the cross-modal association of sensory signals
(77). Fukushima et al. (70) found that the delay-period
activity preceding the selection of the forthcoming saccade target shifted when a centrally positioned cue instructed a target shift, indicating that the representation
of temporal contingencies could be updated in accordance with instructions. Furthermore, Genovesio et al.
(82) revealed that two separate groups of neurons in the
PFC represented either previous goals or future goals.
Rainer et al. (212) recorded neuronal activity from
the LPFC while monkeys were performing a paired associate task and showed that activity of PFC neurons reflected not only a given visual signal, but also a visual
object associated with it in the paired association task.
Because similar patterns of activity were reported in the
inferior temporal cortex (158, 169, 237), the interaction
between the PFC and inferior temporal cortex is in no
doubt crucial in retrieving associated visual objects from
long-term memory (61, 93, 95, 269). Furthermore, it is
shown that the interaction between the PFC and the
inferior temporal cortex plays crucial roles in associating
a visual stimulus with an action in a conditional visuomotor task (40) and in strategy implementation in which the
subject could maximize a reward gain by making a choice
of objects in a scheduled manner (79).
These reports indicate that the PFC plays a central
role in forming the cross-temporal contingency of rele-
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A cardinal characteristic of the impairment observed
in “frontal” patients, i.e., the higher rate of perseveration
error, is usually explained as a failure in the inhibition of
the central set or the need for a supervisory system to be
involved in the inhibition of prepotent schemas (248).
Using marmoset monkeys, Dias et al. (58) found that
damage to the LPFC caused a loss of inhibitory control in
attentional selection (failure of extra-dimensional shift),
whereas lesions in the orbitofrontal cortex led to a loss of
inhibitory control in affective processing (failure of intradimensional shift). In human subjects, damage to the
LPFC is associated with impairment on the Wisconsin
Card Sort Test (WCST) (151, 186). With the use of eventrelated fMRI, a transient activation focused in the LPFC
was found in humans (33, 52, 124, 230, 258) and monkeys
(166) during cognitive set shifting in the WCST. Miyashita
and colleagues (125) further found that the active area
during set shifting coincided with an area that was active
during the performance of a go/no-go response, suggesting that the ventral LPFC (right hemisphere in humans) is
commonly involved in the inhibition of different targets
such as the go response during the performance of a
go/no-go task and the cognitive set during the performance of the WCST. In a later study, however, a different
area was found to be active when the WCST task was
modified to temporally isolate the inhibitory processes of
the cognitive set (123). Under such conditions, the dorsal
LPFC (left middle frontal gyrus near the superior frontal
sulcus) was activated. These findings indicate the presence of multiple inhibitory mechanisms in the LPFC. Indeed, when the WCST was modified to reveal the inhibition of prolonged proactive interference from a previous
set, the participation of the anterior part of the LPFC was
detected (122). A recent proposal that the right inferior
frontal cortex of humans could be a focal structure to
exert inhibitory control (6) awaits further confirmation.
Failure on the WCST or related tests may not necessarily mean the presence of perseverative response selection or the lack of inhibition of the prepotent cognitive
set. Poor performance on the WCST could also be explained as the failure to reject prevailing behavioral rules,
or alternatively, as the inability to think beyond the orig-
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JUN TANJI AND EIJI HOSHI
vant events and actions in accordance with the current
behavioral context. Depending on task demands, the PFC
neurons can encode and represent a wide variety of signals across sensory and motor domains in a retrospective
or prospective manner (cf. adaptive coding model by
Duncan, Ref. 59).
VIII. ACTION SELECTION
AND DECISION MAKING
Physiol Rev • VOL
IX. BEHAVIORAL PLANNING VERSUS
MOTOR PLANNING
A. Motor Planning in the LPFC
The concept that a substantial proportion of prefrontal neurons takes part in the preparation of movement has
received support from studies examining neuronal activity in the LPFC (27, 215, 233, 241). In a subsequent study,
Funahashi et al. (73) recorded LPFC neurons in monkeys
required to make saccades toward a remembered target
and also toward a direction opposite to the remembered
target. They found that 30 neurons coded the location of
the visual stimulus memorized, whereas 13 neurons
coded the direction of the impending saccade. Based on
these data, they concluded that the cue location is represented more than saccade direction. However, in a study
examining the LPFC of monkeys performing a manual
response in a task condition requiring visuomotor memory (209), more neurons were found to specify the direction of forthcoming arm motion than those to code the
memorized visual information. For these motion-coupled
cells, the slope of acceleration of their firing during the
delay period was proportional to the degree of probability
with which the monkey could predict the direction of the
forthcoming manual response. In later studies, Takeda
and Funahashi (262, 263) found that neuronal activity in
the PFC signaling memorized sensory signals was replaced with the activity signaling the direction of forthcoming saccade, during a delay period. Thus, until recently, it had been thought generally that neurons in the
LPFC play a considerable role in preparing or planning an
intended movement.
B. Task or Rule Dependency
of Preparatory Activity
A separate group of experiments casts some doubt
on the notion that the LPFC codes for a planned move-
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Although the involvement of the LPFC in the selection of action has long been inferred from studies in
humans (e.g., Ref. 68) and monkeys (97, 106), it has been
controversial whether the cortical activity during the behavioral action selection process, often involving working
memory tasks, reflected the maintenance of memorized
information or the selection of manual, verbal, or oculomotor responses. Rowe et al. (226) used fMRI to study
prefrontal activity in a behavioral condition that distinguished the maintenance of spatial items from the selection of an item from memory to guide a response. They
revealed that selection, but not maintenance, was associated with activation of area 46. The LPFC was also found
to be active during a self-initiation task in which a timing
selection was required (111).
Action selection takes time to form when no instruction for action specifies a target or no associative learning
has been established to prompt the selection of an action.
One example of such behavioral conditions is a case of
double-rule decision making in which the selection of a
target should be made in accordance with two rules imposed simultaneously. Hoshi et al. (101) trained monkeys
to select a reach target in accordance with two concurrent rules. Initially, a sample cue (triangle or circle) appeared at one of three possible locations (top, right, or
left) on a touch screen. After a delay period, one of two
choice cues appeared. In the first, either three circles or
three triangles occupying the three locations solicited the
monkeys to select a target by matching the locations of
the sample-choice cues (location-match rule). In the second, a circle and a triangle at two of the three possible
locations required the monkeys to select a target by
matching the shapes of the sample-choice cues (shapematch rule). Thus neither the sample nor choice cues
themselves instructed the target to be selected; the information specifying the target to be selected had to be
generated internally. Under both behavioral rules, it was
found that the information for target selection emerged
promptly in neuronal activity in the LPFC within 300 ms
after the appearance of the choice cue. This finding, along
with the effects of transient inactivation of the LPFC by
local application of GABA agonist (101), suggests that the
necessary information was generated, at least in part, in
the LPFC or in a neuronal circuit involving the LPFC,
providing a case for the generation of information for
decision making (266).
Another example of a behavioral condition requiring
problem resolution is related to decisions for the selection of actions under uncertainty. Using fMRI, Huettel
et al. (105) found activity focused in the LPFC, as well as
in the intraparietal sulcus, when subjects were engaged in
a task in which uncertainty developed over short time
scales as information was accumulated toward a decision.
This finding is in contrast to a report that the activation of
the frontomedial cortex reflected the degree of uncertainty for predictions induced in a long-term stimulusresponse adaptation process (273).
LATERAL PREFRONTAL CORTEX AND EXECUTIVE BEHAVIORAL CONTROL
C. What is Planned in the LPFC?
These reports raise a more fundamental question of
whether movements themselves are planned or prepared
in the LPFC. An alternative hypothesis is that behavioral
factors not directly relevant to the selection of movements (or motor parameters) could be the primary components processed in the PFC, and this area may not be
much concerned with the specification of how motor
effectors would operate. To resolve this issue, monkeys
were trained to move a cursor on a video monitor by
operating two manipulanda with either hand (164). Supination or pronation of the manipulandum with the right or
left hand was linked to the movements of the cursor in
Physiol Rev • VOL
four directions (up, down, right, left). The directions of
cursor motion were assigned to each of four different
hand movements in three different ways. For the great
majority of neurons, activity in the preparatory period
reflected movement of the cursor (or the location of the
cursor) on the monitor screen, but not the movement to
be performed (use of the right/left hand or the direction of
the movement). Thus PFC neurons primarily represented
the movement of an object that will occur as a consequence of an intended limb movement, but not the movement per se. This finding raises the possibility that the
planning of motor behavior in the PFC is generally executed in terms of the end result of a target object occurring as an outcome of a planned action, but not in terms
of an intended movement. Averbeck et al. (8) recorded
the activity of small ensembles of neurons in the LPFC
while monkeys copied geometrical shapes shown on a
screen. Monkeys drew the shapes as sequences of movement segments, and these segments were associated with
distinct patterns of neuronal ensemble activity. Averbeck
et al. (8) concluded that the neuronal ensemble activity
observed during the time preceding the actual drawing
reflected distinct segments of movements. However, it is
also possible that the neuronal activity reflected the trajectories of the segments of the geometric figure planned
to be drawn, rather than segments of limb movements,
because these two behavioral factors were not dissociated in the experiment. The results may have indicated
the representation of segments of shapes that were
planned to appear as the outcome of the intended copying
action.
X. BEHAVIORAL GOAL SELECTION
One of the cardinal problems characterizing frontal
lobe patients is the neglect of behavioral goals (60, 141).
During the performance of a variety of behavioral tasks
that require such cognitive control as multistep tasks or
concurrent execution of dual tasks, frontal patients often
fail to achieve the behavioral goal, although they understand the requirements of the behavioral task (151, 175,
190). With the use of a Tower of Hanoi task (84) or a
variant (65), the PFC has been implicated in resolving
goal-subgoal conflicts. Clinical studies and reports on
human subjects prompted an attempt to look for the
representation of behavioral goal information in the PFC
in experimental studies. Saito et al. (232) constructed a
spatial maze task to induce monkeys to determine multiple behavioral goals to be attained in a temporal sequence. Monkeys were trained to move a cursor on the
screen from a start position to a goal position in a maze by
tracking a path with three steps of moves that were
temporally separated. During a preparatory delay period
after receiving an instruction signal, they were also re-
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ment, thus participating in the specification of motor
variables constituting the intended movement (e.g.,
choice of body part or parameters such as direction,
amplitude, or speed of forthcoming movement). Hoshi
et al. (100) examined neuronal activity while monkeys
were preparing and executing reaching movements to
objects that appeared on a video screen. They found that
36% of LPFC neurons that were active during the preparation and execution of arm reaching differed depending
on whether the object to reach was circular or triangular.
Furthermore, the neuronal activity preceding arm-reach
movements differed greatly depending on whether the
monkeys were performing the motor task to match the
shape of a response object with a sample object or to
match the location of the response object with the sample
object. The former finding raised the possibility that neuronal activity signified the objective of the action (i.e., to
capture a circle or a triangle). The latter finding may be
interpreted as the expression of the task rule: achievement of a motor task in conforming to a task rule (i.e.,
shape-match or location-match rule). Alternatively, the
findings suggest the possibility that neuronal activity related to the preparation or execution of motor acts is
strongly modulated by behavioral objectives or behavioral rules. White and Wise (284) designed experiments to
test more explicitly whether the rule of the behavioral
task is represented in neuronal activity. By presenting
instructional cue signals, they required monkeys to perform arm reaching in accordance with two behavioral
rules: matching to a sample rule or a spatial match rule.
They found that movement-related activity of LPFC neurons, as well as activity responding to visual signals or
during the delay period, was profoundly modulated by the
rule. The rule dependency of activity during the preparation or planning of motor responses was also reported in
a study incorporating behavioral rules of either match or
non-match to sample objects (275). In human subjects,
neural substrates for behavioral rules have been reported
in a number of studies (32, 35–38, 182, 238, 239).
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JUN TANJI AND EIJI HOSHI
XI. REWARD EXPECTATION
AND REINFORCER-BASED
CONTROL OF BEHAVIOR
Although the orbitofrontal cortex is the primary site
representing primary reinforcers, for learning and reversing associations of audiovisual information to the primary
reinforcers, and for controlling behavior based on reinforcers (218, 268), neurons in the LPFC also encode reinforcers (3, 172, 178, 223). Watanabe (280) found that the
activity of LPFC neurons during a delay period reflected
not only the expectancy of a reward or no reward, but
also the nature of the reward. Neuronal activity reflected
the object to be obtained as a reward and also reflected
the preference for the expected reward. Furthermore,
LPFC neurons reflected the discrepancy between the expectancy of a specific reward and the reward actually
obtained. Thus neuronal activity in this area is likely
related to the expectancy of the nature and preference of
an anticipated reward or its magnitude (130). An alternative interpretation of the neuronal activity could be the
Physiol Rev • VOL
alteration of attentive processes selectively connected to
aspects of reward expectation or alteration of the general
attentive state in preparing for the outcome of the behavioral action. Similar reward expectancy-related activity
has been recorded in the orbitofrontal cortex (98).
Wallis and Miller (276) directly compared neuronal
activity in the orbital and dorsolateral PFCs while monkeys were performing a reward preference task to choose
between pictures associated with different amounts of
reward. The neuronal activity in both areas reflected the
reward amount, although reward selectivity arose more
rapidly in the orbitofrontal cortex than in the LPFC. However, LPFC neurons encoded both the reward amount
and the monkeys’ forthcoming response, whereas orbitofrontal neurons more often encoded the reward amount
alone. These findings were consistent with the hypothesis
that the orbitofrontal cortex primarily encodes the reward per se, whereas the LPFC uses this information to
control behavior. Matsumoto et al. (143) also recorded
neuronal activity from the medial frontal cortex and LPFC
while monkeys performed a differentially cued, delayed
go/no-go task in which two visual cues, two responses (go
or no-go), and two reward conditions (reward ⫹ and ⫺)
were combined in eight different combinations. The cue
responses were strongly modulated depending on
whether they were associated with reward or no reward
at the completion of the task. Furthermore, neuronal
activity selective to either go or no-go responses was also
modulated depending on whether the motor response
would give rise to a reward or no reward. The latter
neuronal activity appeared earlier in the medial frontal
cortex than in the LPFC. These findings indicate the apparent involvement of both prefrontal areas in rewardbased response selection or reward prediction (cf.,
Ref. 270).
Because both appetitive and aversive behavioral outcomes can reinforce animals’ responses, it is of interest to
know whether information for the opposing reinforcers is
processed in the LPFC. Kobayashi et al. (118) examined
neuronal activity while monkeys performed a delayed
saccade task in which a correct motor response led to
three different outcomes: delivery of a liquid reward,
avoidance of an air puff, or feedback with sound only.
They found that aversive avoidance had clear effects on
some prefrontal activity, although the effects of rewards
were more common. Their results demonstrated that information about positive and negative reinforcers is processed differentially in the LPFC.
XII. TEMPORAL SEQUENCING
OF MULTIPLE ACTIONS
Many purposeful behaviors are composed of sequences of actions, and the brain must gather information
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quired to plan a path to take with the three motion steps
while waiting at the start position for the first go signal to
initiate the first step. Saito et al. (232) found that neuronal
activity in the LPFC during the delay period first began to
represent the final goal to be reached. Subsequently, during the later part of the delay period, the final goal representation was gradually substituted with the representation of an immediate goal that was planned to be reached
(the first of the three goal positions to be acquired, in
order). The second goal representation appeared after
completion of the first step. This exhibits the way in
which neurons in the LPFC take part in governing goaloriented sequential behavior by temporally arranging representations for a goal and subgoals.
The term behavioral goal is sometimes used simply
to refer to reward acquisition. Apparently, animal behavior is often oriented to obtain rewards. The potency of
reward expectation, internal drive to acquire a reward, or
reward reception in influencing neuronal activity everywhere in the brain has been described in the literature
(e.g., Refs. 244, 245). Prefrontal neurons certainly reflect
reward relevance or reward expectation, as we describe
below. However, it is important to differentiate simple
reward-seeking behavior, which is ubiquitous among animals, including unicellular creatures such as amoebae,
from the kind of behavior requiring the regulation of
temporal structures of action based on current and remembered information. We suggest the use of the term
behavioral goal to refer to the latter category, but not to
everything related to reward acquisition, at least when
considering the involvement of the PFC in executive behavioral control.
LATERAL PREFRONTAL CORTEX AND EXECUTIVE BEHAVIORAL CONTROL
movements (e.g., tracking targets at the top, right, and left
versus top, left, and right). In more recent reports (173,
174), the involvement of the LPFC in the temporal organization of sequential actions was studied in a behavioral
condition that eliminated the confounding factor of spatial trajectory. Monkeys were trained to plan a sequential
capture of three objects that would appear at unpredictable locations on the screen (e.g., capture a circle, a cross,
and a square in that order). During the stage when the
monkeys gathered information about a sequence of threeobject captures, neuronal activity representing the rank
order of each object (e.g., yellow circle appearing first or
red cross appearing second) was detectable. During planning, LPFC neurons also represented the temporal order
of objects that were planned to be captured, regardless of
their spatial position. Fujii and Graybiel found that neuronal activity of the LPFC was preferentially active in the
first and last parts of sequential saccadic eye movements
FIG. 2. Activity of PF cells selective for a category of sequences during planning and their recording sites in the prefrontal cortex. A: Raster
displays and peri-event histograms illustrating the cellular activity selective for the “paired” category. The discharges are aligned on the appearance
of the GO signal for the first of memorized movements. B: Activity selective for the “alternate” category. C: “Four-repeat” category selective activity.
D, Top: recording sites of category-selective cells plotted on the surface maps of the prefrontal cortex of two monkeys. The size of the circle is
proportional to the number of selective cells at each site. Bottom: a cortical surface map showing the surveyed area. PS, principal sulcus; ARC,
arcuate sulcus.[From Shima et al. (250).]
Physiol Rev • VOL
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concerning the sequence required before planning to execute that particular sequence. Neuronal activity reflecting sequence-specific information, reported in many areas
in the frontal cortex (136, 163, 167, 208, 251), is viewed as
constituting the neural elements necessary to construct
the temporal structure of sequences (265). In the LPFC,
Barone and Joseph (22) were the first to describe neuronal activity that was selective to the sequence of a visuospatial eye-hand task (reaching to three spatial targets
located at the top, right, and left of a panel). During an
instruction period, they described neuronal activity specific to the sequence of the three spatial targets to be
captured. They also reported sequence selectivity of cells
that appeared during the performance of sequential eyehand movements. The performance of each sequence also
required eye-hand movements with specific trajectories in
space. Thus the selectivity of neuronal activity may have
meant selectivity for the spatial trajectory of tracking
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50
JUN TANJI AND EIJI HOSHI
XIII. STRATEGIC or CONCEPTUAL
BEHAVIORAL PLANNING
To achieve internal goals, behavioral planning often
requires the ability to coordinate thoughts and actions at
cognitive levels that go beyond the association of sensory
information with action or the expectation of reward
relevance. In complex behavioral tasks, patients with prefrontal damage use poor strategies, exhibit behavioral
incoherence (249), and are impaired in organizing strategies to improve task performance (182). The involvement
of the LPFC in encoding strategies has been substantiated
by an event-related fMRI study (29) using a behavioral
task that required strategic chunking of spatial sequences
to remember. The organization of memory contents (spatial structures) into higher-level chunks was associated
with increased prefrontal activity, even when the memory
demand itself was decreased. In subhuman primates, the
involvement of the PFC in the strategic organization of
spatial-sequencing (50) or object-retrieval tasks (78) has
been proposed. At the single-neuron level, Barraclough
et al. (23) studied LPFC activity while monkeys were
engaged in a mixed-strategy game against a computer
opponent. Signals related to the conjunction of the animal’s previous decision and its outcome were processed
differently in the PFC according to the type of decisions
made by the animal, suggesting a role for the LPFC in
optimizing decision-making strategies. Subsequently,
Genovesio et al. (81) analyzed neuronal activity using a
behavioral task in which monkeys learned to map visual
symbols to saccade responses by trial and error. During
Physiol Rev • VOL
learning, monkeys used two response strategies. According to the repeat-stay strategy, if a symbol repeats from a
previous successful trial, the monkeys should stay with
their most recent response choice. According to the
change-shift strategy, the monkeys should shift to a different choice if the symbol changes. Many LPFC neurons
exhibited activity selective for the strategy used, implying
their contribution to the implementation of abstract response strategies.
A separate issue is behavioral planning based on the
development of a generalized concept of a set of behavioral activities encompassing multiple events and actions.
Behavioral planning in daily life often starts with the
formulation of a general plan to achieve the aim of what
is intended, followed by the determination of individual
details involved in that general plan. An aspect of behavioral problems for patients with frontal cortex lesions is
the failure to achieve an objective of goal-oriented behavior by performing a series of simple actions (39). Patients
with frontal cortex lesion were also impaired in arranging
a set of open-ended, simple tasks in an appropriate temporal order to achieve a behavioral goal (249). More recently, clinical reports have suggested that patients with
prefrontal lesions are impaired in analyzing clusters of
action sequences (294) or in formulating action plans that
accord with managerial knowledge (253, 254). To investigate the involvement of the LPFC in formulating macrolevel plans that cover multiple actions, an experimental
model was recently introduced to analyze neuronal activity in the LPFC during the formulation of a plan at the
conceptual level, including categories of planned behavior (250). If subjects are required to remember a large
number of complex motor sequences and plan to execute
each of them individually, categorization of the sequences
according to the specific temporal structure inherent in
FIG. 3. Diagram summarizing the flow of information requiring the
executive function of the prefrontal cortex.
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and suggested that these types of activity reflect the action sequence boundaries (69).
These findings are compatible with those of clinical
studies that report disturbances in the temporal ordering
of events (150, 197, 252) and with those of brain imaging
studies (42, 196), which report activity in the LPFC during
behavioral tasks that require the temporal structuring of
visual information. In a recent study (9), monkeys were
trained to produce a series of eye movements according
to a sequence that changed unpredictably from one block
of trials to the next. Ensemble neuronal activity in the
LPFC predicted the sequence in a manner that changed
gradually from the sequence that had been correct in the
previous block to the sequence that was correct in the
current block. Based on this dynamic property of neurons
to action sequences, Averbeck et al. (9) proposed prefrontal involvement in representing subjective knowledge of
the correct action sequence. Finally, in a very recent
report, information on the behavioral sequence was represented at a higher order of abstraction: the categorization of behavioral sequences (250). This is described
below.
LATERAL PREFRONTAL CORTEX AND EXECUTIVE BEHAVIORAL CONTROL
XIV. CONCLUSIONS
The LPFC is involved in broad aspects of executive
behavioral control based on anatomical connectivity that
enables communication with cortical association areas
and subcortical areas (Fig. 3). Executive functioning that
takes place in this area can be fractionated into component processes for the purposeful integration of behavior.
Here, we critically assessed research reports on the involvement of the LPFC in each component.
Within the LPFC, regions are differentiated primarily
according to the functional operations that they perform.
The ventrolateral part is involved in first-order executive
processes such as active retrieval and selection of information, whereas the dorsolateral part is more involved in
higher-order executive components of behavioral planning, including monitoring, manipulation, and integration
of multiple pieces of information.
The LPFC takes part in various aspects of executive
behavioral control, including attention for action, retrieval and manipulation of relevant information, response suppression, behavioral planning of temporal
structures of actions and events, behavioral-rule implementation, action selection and decision making, behavioral goal selection, reinforcer-based behavioral decisions, and strategic or conceptual behavioral planning.
Recent developments in research on this topic increasingly stress the importance of the LPFC in providing novel
information to cope with requirements imposed by enviPhysiol Rev • VOL
ronmental alterations or in formulating concepts that enable subjects to effectively deal with complex behavioral
demands.
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence: J.
Tanji, Tamagawa University Brain Science Institute, TamagawaGakuen 6-1-1, Machida, Tokyo 194-8610, Japan (e-mail: tanji@lab.
tamagawa.ac.jp).
GRANTS
This work was supported by the 21st Century Center of
Excellence Program from the Japan Society for the Promotion
of Science; a Grant-in-Aid for Scientific Research on Priority
Areas, Integrative Brain Research, from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT;
18019032 and 16067101); and a Grant-in-Aid for Young Scientists
(A) from MEXT (18680035).
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