The prefrontal

cortex and internally generated

Patricia S. Goldman-Rakic, Yale School

The

neuroanatomical

obtained for

from

guided

and the

isolates

primates

prefrontal

internally

sensory-based

New Haven,

functions,

influence

identifies

and

the specializations

Current

Opinion

in the control

organization

of prefrontal

connections

with motor centers

Pathway tracing studies conducted on non-human primates over the past several years have elucidated a number of pathways from prefrontal association cortex to motor centers. The newest data demonstrate separate cortico-cortical routes between dorsolateral prefrontal regions and premotor areas containing forelimb representations and head/eye representations, respectively. Figure 1 schematizes the following: the tram-cortical connections of the principal sulcus with the rostral supplementary motor area OF Bates and PS Goldman&&c, @ Current

Biology

USA

that on

motor

have output.

from

with premotor

premotor

been

a framework

internally-based

of motor

in Neurobiology

It is becoming widely recognized that a number of prefrontal areas, including the principal sulcus, have a major influence on the initiation, facilitation, and inhibition of movement, by virtue of their integration within multidimensional neural networks comprising the motor system [ 1,2**,3]. Three areas of progress may be noted in recent studies on the anatomical and physiological basis of behavior and the nature of prefrontal involvement. First, the circuitry that links prefrontal cortex directly with mom tor centers is now more precisely known. Second, the physiological analysis of various nodes in this circuitry is proceeding at a rapid pace so as to allow a functional analysis of the specific role played by cortical and subcortical stations in the circuit [2**,3,4]. Third, the role of neurotransmitters traditionally associated with motor systems, e.g. dopamine, is being extended to the domain of cognitive control over motor acts [5,6]. The present review focuses mainly on the advances made in physiological analysis, as the other areas of progress have been recently reviewed [5,6]. To begin, we recapitulate some of the more relevant or recently demonstrated anatomical connections that form the networks underlying motor control.

Somatotopic

the

on

functions

functions

of prefrontal,

Introduction

data

converging

memory-based

circuits, the sensory-based structures

830

are

with prefrontal integrates

Connecticut,

neurophysiological

experimental

understanding

framework

V. Chafee

Julie F. Bates and Matthew

of Medicine,

motor acts

The

externally functions circuits,

and subcortical

acts.

1992, 2:830-835

unpublished data) [7,8-l; the recently described cingulate premotor areas (Rp Dum and PL Strick, this issue, pp 836-839; JF Bates and PS Goldman-Rakic, unpublished data); and the lateral premotor cortex [9]-all areas that contain forelimb representations and, in turn, project to either the primary motor cortex or spinal cord. Also shown are the connections of principal sulcus with the medial (supplementary) [lo] and lateral frontal eyefields (JF Bates and PS Goldman-Rakic: Sot Neurosci Ab str 1988, 14:818) [7]. A possible substrate of the continued segregation of prefrontal motor outputs is found in the projection of the prefrontal cortex to the caudate and putamen, a projection characterized by a patchy or mosaic arrangement of terminals (Fig.1) [ll]. It is well known that corticostriatal fibers terminate on the medium spiny neurons of the neostriatum, which in turn, project upon the substantia nigra or globus pallidus [12,13]. Neuronal activity in the substantia nigra has been related to eye movements [14], while that in the globus pallidus may be selective for limb movements [ 151, We suggest that this mosaic organization may provide the means of maintaining segregation in the cortico-striatal pathways mediating eye and hand movements, by targeting patches projecting to the pallidum and the substantia nigra, respectively. Further anatomical experiments are needed to resolve this issue conclusively. Less known, but also clearly documented, are the prefronto-collicular projections that bring prefrontal neu rons into direct and exclusive contact with the oculomotor system (Fig.1) [16,17]. The principal sulcus targets the intermediate and deep layers of the superior colliculus where eye movement commands are organized. As mentioned above, this prefrontal area also projects to the adjacent frontal eye field and can therefore gain access to the brainstem oculomotor centers indirectly via its connections with the eye field area. It can be concluded that prefrontal cortex is a major component of the cortico-striato-nigro-thalamo-cortical ‘loop’ pathway, numerous prefronto-premotor circuits, and that it has direct cortico-tectal projections, the interruption of any Ltd ISSN 0959-4388

The prefrontal

cortex

and internally

generated

motor

acts

Bates and Chafee

Goldman-Rakic,

Fig.1. The

principal

connections

with

eas implicated the

arcuate

SMA

sulcus

several

in forelimb premotor

(JF Bates unpublished

data)

portions

CMAr

and

[8*,91; and and

lished data)

in accordance

late

area

and

between

several

the

system,

eyefields

(JF Bates and

striatum

neuronal

IlOl,

and

sulcus and

mosaic

in which

clusters

organiinterdig-

project

to the

substantia

nigra and globus pallidus,

spectively.

Putative

shown

cingulate CMAr, tion.

in

motor

forelimb

light

motor

area,

putative

in dark

premotor

re-

projections

shading;

projections

cingulate

shad-

area. CMAc,

caudal

portion.

motor area, rostra1 por-

PS, principal

mentary

Our understanding of prefrontal cortex involvement in motor control has been greatly enlarged by the findings gained from recordings of individual neurons in a variety of areas in the brains of monkeys performing delayed-response tasks. As these tasks involve the integration of sensory input, mnemonic coding and motor

ocufrontal

[16,171. Connec-

the

itated

ing APA, arcuate

dichotomies

the

PS Coldman-Ra-

the principal reflect

of the striatum

are

Functional

sulcus

of the

eyefields

zation

oculomotor

of which may result in the motor and accompanying cognitive symptoms in such diseases as Parkinson’s disease and Huntington’s disease. It also appears that prefrontal cortex can influence both hand and eye movements independently.

principal

colliculus

tions between the

by

Abstr 1988, 14:818) [71,

supplementary

the superior

cingu-

are also con-

including

kit: Sot Neurosci the

(JF

unpub-

described

components

lomotor

ante-

CMAc with

regions

Strick et a/. 136,371. There nections

[71; rostra1

PS Goldman-Rakic,

motor

ar-

PS Coldman-Ra-

rior

of

direct

movements:

area

and

kit,

Bates

has

premotor

eyefields.

sulcus.

SEF, supple-

SMA, supplementary

area.

output, they provide a powerful approach to the dissection of the relevant circuit components of motor action, and one which has provided insight into how these circuits may be integrated both within and across cortical areas. A current theme in research on this topic is the distinction between sensory-guided and memory-guided [ 41, internally and externally-driven [ 181, and preparatory versus movement-related activity [3] in cortical neurons. These distinctions have arisen to acknowledge a natural division of labor between the cognitive, planning or ‘set’ subfunctions of motor control, on the one hand, from those concerned with the dynamics, metrics or pattern of particular movements, on the other. There is not yet compelling evidence on whether these two classes of operation are equally represented in most or all motor centers as suggested by Alexander and Crutcher [3], or

831

832

Neural

control

whether each area has a distinctive involvement such that only the assembly of areas can accomplish the smooth integration of a proscribed motor plan. Research on this question has been conducted both in manual and ecu lomotor paradigms, as described below.

Analysis of cortical

motor

networks:

forelimb

control Several recent studies have addressed the issue of interactions between or among motor areas that comprise the cortical motor system, by recording from more than one structure in the very same monkey trained to perform manual delayed-response tasks. For example, direct comparisons of neural activity recorded in the prefrontal, dorsomedial and lateral premotor areas reveal distinctly different response profiles in a monkey trained to perform a delayed match-to-sample task [19*]. Prefrontal units in general are more sensitive to sensory cues than premotor units, distinguishing the color of the cue used as the sample stimulus, both during the cue period and the delay period following. Regarding the planning and execution of arm movement, there were units found in all three structures that were selectively and tomtally activated in delay periods before arm movements of a particular direction, indicating that once the decision has been made as to which direction to move in, the motor plan for that movement is shared among the three structures. This tonic activity appears earliest in the prefrontal and dorsomedial areas, but appears to build in the premotor cortex as the time of the response approaches, such that more cells with higher firing rates are found in the premotor cortex overall that predict the direction of the upcoming movement. Phasic responses were also found in all three structures and occurred just before the arm movement, perhaps playing a role in its initiation. Pre-movement responses occurred earliest in the prefrontal cortex, suggesting that under the conditions of the delayed-response task, the motor command to move the arm may originate there. In summary, these data suggest that the sensory processing preceding motor acts is most heavily concentrated in prefrontal regions, and that the motor plan may be initially computed in the prefrontal cortex but becomes increasingly focused in the premotor cortex as the time to act approaches. The trigger to initiate action may originate in the prefrontal cortex, but be transmitted to the premotor cortex, en route to downstream motor structures. A somewhat different perspective is evident in the more comprehensive analysis of unit activity in a different subset of primate motor structures. In a series of studies, Alexander and Crutcher [3] recorded from the supplementary motor cortex, the motor cortex, and the caudate nucleus in the same animals. Their well designed task involved an arm movement, made under visual guidance, which moved a cursor on a video display toward a target. After a delay, the animal was required to reproduce that movement from memory without external cues. In a variation of the task, the direction of cursor movement

was inverted relative to the direction of arm movement, such that rightward arm movements moved the cursor to the left and vice versa. The study revealed neurons that were related purely to the direction of the arm movement independent of its effects on the cursor (movement dependent neurons), and neurons that discharged in delays before rightward (or leftward) movements of the cursor, regardless of whether the actual arm movements were to the right or the left (target-dependent neurons). Of particular interest was the fact that both types of units were found in all three structures examined. The onset of the target-dependent activity appeared earlier in the supplementary motor areas than in the motor cortex or putamen, as might be expected if the supplementary area were important for motor preparation. In contrast, the movement-dependent activity occurred earlier in both the supplementary motor area and motor cortex relative to the putamen. Although the Alexander and Crutcher studies rightly stress that multiple levels of motor processing take place concurrently in motor areas at different levels of the neuroaxis, their findings do not rule out a specialized functional contribution of each area. Very likely, tasks with different sensory, mnemonic and more complex motor demands will be necessary to better elucidate and tease these contributions apart.

Oculomotor

paradigms

The use of oculomotor delayed-response paradigms represents another approach for analyzing the relative contributions of prefrontal structures to motor behavior [ 2&24]. In our own studies employing oculomotor tasks [22-241, monkeys were required to Iixate a central cue while target stimuli were briefly presented in one or arother peripheral location in the visual field. At the end of a delay period, the animal was required to indicate a response by moving its eyes to where the target had most recently been presented. Prefrontal neurons in these studies were shown to have ‘memory fields’, that is, an individual prefrontal neuron increased firing when a target in a particular location, and only that location, disappeared from view. The results demonstrate that the same neuron codes the same location trial after trial, and that different neurons code different locations with preference for fields contralateral to the hemisphere in which the neurons were recorded. Thus, transient memory for location appears to be mapped in the prefrontal cortex. Further, in instances where the mnemonic activity of a neuron is not maintained throughout the delay period, the animal generally makes an error. In this instance, the neuronal activity appears to be a way of keeping information ‘in mind’. These and other results provide strong evidence at a cellular level for a role of prefrontal neurons in representational processes, i.e. maintenance of information in the absence of the stimulus that was initially present. However, almost one-quarter of the task-relevant prefrontal neurons recorded in delayed-response tasks are related to the motor response, and about one-fourth of the oculomotor responses are

The prefrontal

Visual

stimulus

Projection

cortex

and internally

generated

motor

acts Goldman-Rakic,

Bates and Chafee

neuron

Post-saccadic

Fig.2. Diagram lationships oculomotor diagram nal

response.

The figure

Information

prefrontal activity IS the

neurons in prefrontal

‘trigger’

movement.

The

of neuro-

in anatomically

the execution

in an

task.

the pattern

Immediately

re-

to events

delayed-response

activity

tional

respect

illustrates

structures after

of structure-function

with

connected

before

and

just

of a memory-guided suggests is held and that

that ‘on

direcline’ by

presaccadic

neurons

ultimately

for a memory-driven

See text for further

eye

explana-

tlons.

pre-saccadic [ 241. The pre-saccadic responses, like delayperiod and cue-period activity, are directionally specific, favoring contralateral visual targets. The larger fraction of response-related responses occur as a post-saccadic response, i.e. possibly serving as a signal that the response has been executed. About 2OPiOO ms elapsed between the peak of presaccadic activation and the peak of the postsaccadic responses in the population of neurons studied by M Chafee, S Funahashi and PS GOkhndn-R&c (Sot Neurosci Abstr 1989, 15:786). Similar enhanced activity during the delay period has now been observed in a number of other structures, including the posterior parietal cortex (M Chafee et al., unpublished data) [25,26], the basal ganglia [14,27], the premotor [ 3,26,28] and motor [ 291 cortices. Each of these areas is connected with the dorsolateral prefrontal centers, directly or indirectly, where the neurons described above have been found [3@32]. Some of these projections, in particular those with premotor structures, are illustrated in Fig.1.

Figure 2 summarizes the physiological data available with respect to oculomotor performance in the structures that compose the prefronto-striato-thalamo-cortical loop circuitry reviewed above. A diagram of a typical record of prefrontal neuronal activity recorded during a delayed-response trial is shown at the top of the figure. The neuron shows a phasic response to the onset of a target stimulus presented in the upper right visual field. When the target disappears, neuronal activation in a tonic mode continues throughout the delay. At the end of the delay, another phasic response in the prefrontal cortex heralds the initiation of a motor response. At approximately the same time, an excitatory burst can be recorded in the basal ganglia [ 3,333. Neuronal activity in the substantia nigra is simultaneously depressed for about 100 ms by activation of the striatonigral projections [14]. Finally, a contralatem1 eye movement follows the initial pre-saccadic burst in concert with phasic responses in the superior colliculus and thalamus [ 341. A speculative part of Fig.2 is the suggestion that the disinhibition of thalamic activity results in a feedback excitation of the layer V neuron

833

834

Neural

control

that is recorded in the prefrontal cortex an average of 130ms following the execution of the oculomotor response [ 241.

7.

BAR&!

H, MESUIAM M-M: Cortical Afferent Input to the Principalis Region of the Rhesus Monkey. Neuroscience 1985, 5:61%637.

8. .

Conclusion The studies reviewed establish a framework for analysis of complex tinctions carried out by cortical networks. From the foregoing review, it seems clear that there are at least two basic types of response-related neuronal activity patterns-ne that is tied to the organization of the movements themselves, and one that is tied to the target direction or goal of a movement and referenced to the direction of the stimulus. The latter falls into the category of a mental representation and it is reasonable to assume that its maintenance in the guidance of responses requires the participation of the prefrontal cortex. According to this view, directional information is held temporarily in prefrontal memory circuits, and transmitted to premotor areas where it is recoded as directional delay period activity. Lesions of the prefrontal cortex impair the guidance of behavior in the absence of external cues [35], and future experiments can test whether the preparatoty directional delay-period activation of premotor and subcortical structures depends upon the integrity of prefrontal cortex.

MCGUIRE PK, BATESJF, GOLDMAN-RAKIC PS: Interhemispheric Integration: II. Symmetry and Convergence of the Corticostriatal Projections of the Left and Right Principal Sulcus (F’S) and the Left and the Right Supplementary Motor Area (SMA) of the Rhesus Monkey. Cerebr Cortex 1991, 1:408-417. Projections from the right and left principal sulcus were found to overlap precisely in topographically specific territories of the striatum, on the basis of double-label studies in which topographically matched regions of the principal sulcus were injected differentially in each hemisphere. The same form of convergence was found for projections from the supplementary motor area fo the striatum. 9.

BARBAS H, PANDYA DN: Architecture and Frontal Cortical Connections of the Premotor Cortex (Area 6) in the Rhesus Monkey. J Comp Neurol 1987, 256:211-228.

10.

HUERTA

11.

SELEMON LD,

12.

SMITH Y,

MF, BAASJH: Supplementary Eye field as Defined by Intracortical Microstimulation: Connections in Macaques. J Comp Neural 1990, 293:29+330. GOLDMAN-RAKIC PS: Longitudinal Topography and Interdigitation of Corticostriatal Projections in the Rhesus Monkey. J Neuraui 1985, 5~776794.

Nucleus sciureus).

PARENT A: Differential Connections of Caudate and Putamen in the Squirrel Monkey (Sairniri Neuroscience 1986, 18:347-371.

13.

&LEMON

14.

HIKOSAKA

15.

HAMADA I, DEL~NC MR, MANO N: Activity of Identified Wrist-Related PalIidal Neurons During Step and Ramp Wrist Movements in the Monkey. J Neurophysiol 1990, 64:1892Z1906

16.

GOLDMANPS, NAUTA WJH: Autoradiographic Demonstration of a Projection from the Prefrontal Association Cortex to the Superior CoIliculus in the Monkey. Brain Res 1976, 116:145-149.

GOLDMAN-RAKIC PS: Topography of Cognition: Parallel Distributed Networks in Primate Association Cortex. Annu Rev Neurosci 1988, 11:137-156.

17.

FRJES

KAL&SKA JF, CRAMMOND DJ: Cerebral Cortical Mechanisms of 2. .. Reaching Movements. Science 1992, 255:1517-1523. The premotor cortex, an area with which the prefrontal cortex is intimately connected, is identified as a structure containing neurons firing before arm movements. Both dynamic (muscle) and kinematic (trajec~ tory) parameters of the movement are represented. Access to these neurons enables the prefrontal cortex to directly Wluence forelimb motor control. Differences at the population level between connected motor structllres are described. Motor-planning responses are concentrated in premotor cortex, pre-movement cells more closely linked to muscle activation are concentrated in primary motor cortex.

18.

KURATA

References

and recommended

Papers of particular interest, published view, have been highlighted as: . of special interest .. of outstanding interest 1.

reading

within the annual period of re-

3.

ALEXANDER

GE, CRUTCHER MD: Neural Representations of the Target (Goal) of VisuaIly Guided Arm Movements in Three Motor Areas of the Monkey. J Neuropbysioi 1990, 64:164-178.

4.

GOLDMAWRAKIC PS, FUNAHASHI S, BRUCE CJ: Neocortical ory Circuits. Q J Quunt Biol 1990, 55:1025-1038.

5.

GOLDMAWRAIUCPS, WIDOWMS, SMILEY JF, WILLIAMS SM: The Anatomy of Dopamine in Monkey and Human Prefrontal Cortex. J Neural Transm Suppl 1992, 36:163-179.

6.

Go~~~AN-RAKIc PS: Dopamine-Mediated Prefrontal Cortex. The Neurosciences

Intermingling in the Rhesus

0, WURTZ RH: Visual and Oculomotor Functions of Monkey Substantia Nigra Pars Reticulata. III. MemoryContingent Visual and Saccade Responses. J Neuropbysiol 1983, 49:1268-1284.

W: Cortical Projections to the Superior Collicu111s in the Macaque Monkey: a Retrograde Study Using Horseradish Peroxidase. J Comp Neural 1984, 230~5576. K, WISE SP: Premotor and Supplementary Motor Cortex in Rhesus Monkeys: Neuronal Activity During Externallyand Internally-Instructed Motor Tasks. EaP Brain Res 1988, 72:237-248.

DI PELLIGRINOGD, WISE SP: A Neurophysiological Comparison of Three Distinct Regions in the Primate Frontal Lobe. Brain 1991, 114:951-978. Monkeys were trained fo choose and press a left or right touch-pad depending on whether its LED matched the color of an earlier sample stimulus. Prefrontal and premotor unit responses were recorded and compared. Differences that were found between populations included the restriction of color-selective delay neurons to the prefrontal cortex and a greater concentration of tonic, direction-selective motor planning units in the premotor cortex. 19. .

20.

BOCH RA, GOLDBERG ME:

21.

JOSEPH JP, BARONE P:

Mem-

Participation of Prefrontal Neurons in the Preparation of Visually Guided Eye Movements in the Rhesus Monkey. J Neuropbysiol 1989, 61:10641084.

layed Oculomotor 67~460-468. 22.

Mechanisms of the 1992, 4:14+159.

LD, GOLDMAN~RAKIC PS: Topographic of Striatonigral and StriatopaUidal Neurons Monkey. J Comp Neural 1990, 297~359376.

Prefrontal Unit Activity During a DeTask in the Monkey. Exp Bruin Res 1987,

FUNAHA~HI S, BRUCE CJ, GOLDMAN-RAKIC

PS: Mnemonic

ing of Visual Space in the Primate DorsolateraI Conex. J Neuropbysiol 1989, 61:331-349.

CodPrefrontal

The prefrontal

cortex

and internally

CJ, GOLDMAN-WCPS: VisuospatiaI Coding in Primate Prefrontal Neurons Revealed by Oculomotor Paradigms. J Neuropbysiol 1990, 63:814-831.

generated

motor

acts Goldman-Rakic,

Bates and Chafee

23.

FUNAHASHI S, BRUCE

31.

24.

FUNAHASHIS, BRUCECJ, GOLDMAN-RAKIcPS: NeuronaI Activity Related to Saccadic Eye Movements in the Monkey’s Dorsolateral Prefrontal Cortex. J Neurop@siol 1991, 65:1464-1483.

CAVADAC, GOLDMAN~RAK~C PS: Posterior ParietaI Cortex in Rhesus Monkey: I. ParceIIation of Areas Based on Distinctive Limbic and Sensory Corticocortical Connections. J Comp New-01 1989, 287:393421.

32.

CAVADAC, GOU)MAN-RAKIc PS: Posterior ParietaI Cortex in Rhesus Monkey: II. Evidence for Segregated CorticocorticaI Networks Linking Sensory and Lhnbic Areas with the Frontal Lobe. J Comp Neural 1989, 287:422445.

33.

HIKOSAKA0, SAKAMOTOM: CeII Activity in Monkey Caudate Nucleus Preceding Saccadic Eye Movements. Exp Bruin Res 1986, 63:65?662.

34.

CHEVALIER G, DENLMJ JM: Disinhibition as a Basic Process in the Expression of StriataI Functions. Trends Neurosci 1990, 13:277-280.

25.

26.

27. 28.

29.

30.

GNADT JW, ANDERSEN RA: Memory Related Motor Planning Activity in Posterior ParietaI Cortex of Macaque. Exp Rruin Res 1988, 70:216220. TANJIJ, TANUCUCHIK, SAGA T: Supplementary Motor Area: Neuronal Response to Motor Instructions. J Neurophysiol 1980, 43:6&68. BROTCHIE P, LWSEK R, HORNE MK: Motor Function Monkey Globus PaUidus. Bruin 1991, 114:1685-1702.

of the

TANJI J, KLIRATAK: Contrasting NeuronaI Activity in Supplementary and PrecentraI Motor Cortex of Monkeys. I. Responses to Instruction Determining Motor Responses to Forthcoming Signals of Different ModaIities. J Neurophysiol 1985, 53:12’+141. GEORGOPO~JLOSAP, CR~JTCHERMD, SCHWARTZAB: Cognitive Spatial Motor Processes. 3. Motor Cortical Prediction of Movement Direction During an Instructed Delay Period. Exp Bruin Res 1989, 75:183-194. SELEMONLD, GOU>MAN-RAKIcPS: Common Cortical and Subcortical Target Areas of the Dorsolateral Prefrontal and Posterior ParietaI Cortices in the Rhesus Monkey: Evidence for a Distributed Neural Network Subserving SpatiaIIy Guided Behavior. J Neurosci 1988, 8:4049-W&.

35.

GOLDMAN-WC PS: Circuitry of Primate Prefrontal Cortex and Regulation of Behavior by Representational Memory. In Handbook of Physiology. The Nervous System. Higher Functions of the Brain. Edited by Plum F. Bethesda: American Physiology Association; 1987, V: 373-417.

36.

MUAKKA.SSA KF, STRJCK PL: Frontal Lobe Inputs to Primate Motor Cortex: Evidence for Four SomatotopicaIIy Organized ‘Premotor’ Areas. Brain Res 1979, 177~176182.

37.

HIJTCHINSKD, MARTINOAM, STRUCKPL: CorticospinaI Projections from the Medial WaII of the Hemisphere. EXp Bruin Res 1988, 71~667-672.

PS Goldman-Rakic, JF Bates and MV Chafe, Section of Neurobiology, Yale University School of Medicine, 333 Cedar Street, SHM C303, New Haven, Connecticut 06510, USA

835