Prefrontal Cortex in Motor Control. In - Wiley Online Library

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Prefrontal cortex in motor control J 0A Q U I N M

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FU STE R

Department of Psychiatry and Brain Research Institute, School of Medicine, University of California, Los Angeles, California

CHAPTER CONTENTS Anatomy Development and comparative anatomy Connections summary Lesion Studies Motility Task performance Discrimination Delay tasks Emotional behavior Summary Electrophysiology Inputs and outputs electrically traced Inhibition from orbital prefrontal cortex Frontal eye fields and oculomotor control Electrical correlates of performance Slow potentials Unit activity Summary Discussion Temporal synthesis of behavior Provisional memory Preparatory set Interference control Summary and Conclusions

THE PREFRONTAL CORTEX is the cortex of the anterior pole of the mammalian brain. By convention it is anatomically defined as that part of the neocortex receiving projection from the mediodorsal nucleus of the thalamus. The available evidence from anatomical, electrophysiological, and neurobehavioral studies indicates that the prefrontal cortex plays not one but several physiological roles. Different areas within it appear engaged in different functions. However, the evidence also suggests that some of these functions are closely interrelated and may be considered constituents of a more general function of prefrontal cortex. That function, in my view, is the temporal organization of complex structures of behavior. The argument can be reasonably made that the organization of elaborate behavior requires three subsidiary functions of prefrontal cortex: the anticipatory preparation of the organism for coming events, the memory of recent

events, and the suppression of interference. Which of these functions is more apparent to the investigator depends on his methodology and the area of prefrontal cortex that he is dealing with. In this chapter we review, from the vantage point of each major methodology, the facts and observations relevant to the role of prefrontal cortex in motor behavior. It should become clear that this role can only be properly understood in the context of a broader function, such as the one indicated, where motor acts are the overt manifestation of an underlying temporal organization also incorporating acts of memory and perception. In any event the readers of this Handbook realize that motor behavior results from the joint operation of many neural components, some of which are principally involved in the cognitive processes that precede, accompany, and succeed voluntary movement. The prefrontal cortex is one of these components. This part of the cerebral mantle can be legitimately conceptualized as the highest level in the hierarchy of neural components taking part in the execution of movement. Thus the motor acts for which the prefrontal cortex appears essential can be characterized as the “least automatic,” in Jacksonian parlance (141, p. 437), and the most dependent on planning and deliberation. ANATOMY

Development and Comparative Anatomy The prefrontal cortex is the most rostral portion of the neocortex. Like the rest of the neopallium, it has phylogenetically evolved between the hippocampus and the piriform lobe, the two ancient structures constituting most of the pallium in nonmammalian vertebrates (8, 85, 194, 270). With phylogenetic development the prefrontal region undergoes more growth than other neocortical regions. It attains maximum expansion in the human brain, where it constitutes over one-fourth of the cortical surface (39). Development is not uniform for all prefrontal areas. The cortex

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THE NERVOUS SYSTEM 11

of the lateral convexity of the frontal lobe, namely that receiving projection from the lateral component of the mediodorsal nucleus, grows more than the cortex of the medial and orbital areas, which is connected to the medial component of the nucleus. Figure 1 shows the medial and lateral aspects of

prefrontal cortex in six different species. The extent of the prefrontal region, as indicated in the figure by shading, conforms to descriptions of mediodorsal nucleus projection, especially those by Akert (2), Hassler (129), Narkiewicz and Brutkowski (266), Pribram et al. (302), Rose and Woolsey (314), and Walker (389-

SQUIRREL MONKEY

p.f.

Pf DS

Pr f

FIG. 1. Prefrontal cortex (shaded area) in 4 primates and 2 carnivores. (Arrangement by brain size is not intended to display a phyletic order.) a.s., Arcuate sulcus; c.s., cingulate sulcus; g. pr., gyrus proreus; i.p.f., inferior precentral fissure; p.f., presylvian fissure; P.s., principal sulcus; pr. f., proreal fissure.

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391). Some portions of the prefrontal boundary coincide with relatively constant furrows, such as the arcuate sulcus, the cingulate sulcus, the inferior precentral fissure, and the presylvian fissure. The comparatively greater development of prefrontal cortex in the course of phylogeny may be related to the increasing importance of the behavioral operations subserved by it. Thus higher primates, with more developed prefrontal cortex, are more proficient than lower primates in performance of certain behavioral tasks, e.g., delayed response and delayed alternation, that are based on the integration of temporally discontinuous information and for which the integrity of prefrontal cortex, particularly its lateral portion, is essential (234,235, 238,376). Ontogenetically the prefrontal region is one of the last to mature, as indicated by its late myelination (66, 94,159). Orbital areas develop earlier than areas of the lateral convexity in both the human and the monkey (284, 285). The late ontogenetic development of prefrontal cortex and the differences in rate of maturation of its parts have some demonstrable functional correlates. Behavioral alterations, such as the deficit in delayed response, that usually result from prefrontal lesion in the adult animal do not occur when the lesion is performed in the young animal (3, 4, 115, 126, 176,

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178). Also orbital prefrontal lesions induce behavioral disorders at an earlier age than lesions of dorsolateral areas (36, 110,111, 114, 115,245). It therefore appears that orbital cortex becomes functionally committed before dorsolateral cortex. In terms of cytoarchitecture, the cortex of the prefrontal region is typical six-layered cortex (1, 2, 13, 15, 32, 83). Its layers are much better defined in primates than in carnivores. The prefrontal cortex of the primate brain is characterized by a well-developed internal granular layer (layer IV) containing small cells of considerable polymorphism (57). The cortex in the outskirts of the prefrontal region is of the transitional type, incorporating features of the granular cortex in the front and the motor or limbic cortex in the back. Figure 2 illustrates cytoarchitectural maps of the frontal cortex of the monkey as described by different investigators. The prefrontal region roughly corresponds to the area designated as FD by von Bonin and Bailey (32), and "area 8" in this chapter corresponds to the area so designated by Brodmann (38).

Connections The most prominent contingent of subcortical afferent fibers comes to prefrontal cortex from the medi-

Brodmann CERC OPITHECUS CAMPBELL1

vonBonin &Bailey "MACAQUE"

MACACA MULATTA

FIG. 2. Cytoarchitectural maps of lateral frontal cortex in cercopithecoid monkeys, including rhesus. Orbital prefrontal cortex, in inferior aspect of hemisphere, is partly visible (with areal demarcations in Brodmann's map). [From Akert (2).]

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odorsal nucleus of the thalamus (2, 170,189,215,233, 314, 388). In addition the prefrontal cortex receives fibers from the nucleus ventralis anterior and the anterior group of intralaminar nuclei (58,155,170,189, 329). All thalamic projections seem to be topologically organized. Thus the medial thalamus, including the magnocellular portion of the mediodorsal nucleus, projects primarily to orbital prefrontal cortex, whereas the lateral thalamus, including the parvocellular portion of the mediodorsal nucleus, projects to dorsolateral prefrontal cortex (2, 170, 302,369, 389,391). Thalamic nuclei, especially medialis dorsalis, probably relay to prefrontal cortex influences from several other structures (216, 267), such as the mesencephalic reticular formation (122), the amygdala (188,189,269),the piriform cortex (296), and the inferior temporal cortex (409).Direct afferents from the brain stem tegmentum (223,309), the hypothalamus (9,147,168,1691, and the amygdala (148,188,223) have also been demonstrated. Furthermore, in cat as well as monkey, the prefrontal cortex has been shown to receive afferent fibers from cingulate cortex and other areas of limbic cortex (23, 149, 157, 287, 315). In summary the prefrontal cortex receives, directly or via the thalamus, inputs from the hypothalamus, the mesencephalon, and the limbic system. Conceivably these inputs convey to prefrontal cortex information related to the internal state and motivations of the organism. A large array of afferent connections links the prefrontal cortex to other neocortical regions (for a detailed discussion see the chapter by Evarts in this Handbook). The areas contributing these afferents are areas that have not been characterized physiologically as primary sensory or motor. Evidence of these connections is more impressive in primates than in carnivores. According to Jones and Powell (157), who have investigated the matter extensively in the rhesus monkey, the prefrontal cortex is the target of three transcortical pathways originating in the primary sensory areas for vision, audition, and somesthesis (154, 156, 199). These pathways converge on the prefrontal region after a series of steps through association cortex. It is reasonable to suppose that these corticocortical afferents convey information of a sensory nature to prefrontal cortex; the convergence of multimodal afferents on prefrontal cortex highlights its associative character. Efferents from prefrontal cortex flow upon the same structures that contribute the cortex’s afferents. Thus the mediodorsal nucleus is a main recipient (11, 64, 190, 239, 242, 267). Other efferents terminate in the ventral and intralaminar nuclei of the thalamus (11, 79, 152, 267, 311). Like the afferents, the efferents are topologically organized. Thus orbital and medial cortical areas project to medial thalamus, and dorsolateral areas project to lateral thalamus (152, 311, 370). The prefrontal cortex also sends projection fibers to hypothalamus, septum, mesencephalon, and pons (11,

33,37, 79,152,267,371).Most of these fibers originate in ventral cortex. It is important to note that the prefrontal cortex is the only neocortical region sending projection to the hypothalamus, the septum, and the preoptic region. Several structures of the brain stem receiving prefrontal fibers can be considered part of the limbic system by virtue of their associations (267). Other limbic structures such as the amygdala (211), the hippocampus (267,268), and various parts of limbic cortex (112, 152, 211, 212, 380) also receive prefrontal input. Nauta (267) notes, on the basis of primate findings, that the orbital prefrontal cortex is mainly connected to the amygdala and related subcortical structures, whereas the dorsolateral prefrontal cortex is connected to the hippocampus and parahippocampal cortex. The role of prefrontal efferents to hypothalamus and limbic structures is not yet clear, but these connections suggest that the prefrontal cortex is involved in neural functions that protect the internal milieu. Efferent fibers from prefrontal cortex terminate in neocortical areas of the dorsal and lateral aspects of the cerebral hemisphere. In accord with the principle of reciprocal connectivity, the prefrontal cortex sends efferent fibers to the same areas of neocortex that contribute some of its afferents. Thus it has been shown in the monkey that the cortex around the sulcus principalis projects to I) the inferotemporal cortex (area 21) and the lower bank of the superior temporal sulcus (157, 195,286,287),a cortical region implicated in vision; 2) auditory area 22 and the upper bank of superior temporal sulcus (286, 287); and 3) somatic parietal areas 5 and 7 (237, 286). At variance with the principle of reciprocity is the evidence of profuse efferents from prefrontal cortex to basal ganglia. Most of these efferents terminate in the head of the caudate and the putamen, as shown in the rat (172, 215), the cat (23, 404), the dog (23), the monkey (79, 152, 162, 163,211, 213,267, 392), and the human being (161).Prefrontostriatal connections have been reported to be topologically organized (152, 162, 404). In the monkey, orbital prefrontal cortex projects primarily to ventrolateral caudate, and dorsolateral prefrontal cortex projects to anterodorsal caudate (152). Prefrontal efferents have also been traced to globus pallidus (79, 152, 161, 214), claustrum (79, 211, 265), substantia nigra (23,79,213,214),and red nucleus (23, 213). All these efferent connections implicate the prefrontal cortex in the control of movement. The efferents of area 8 deserve special mention here. Area 8 is a transitional area of prefrontal cortex identified as the so-called frontal eye field because of its apparent involvement in eye movements. Like the rest of prefrontal cortex, this area projects to diencephalic, mesencephalic, limbic, neocortical, and striatal structures (43, 69, 133, 196-198, 287, 288). Projections to pulvinar, striatum, pretectal region, and superior colliculus (196-198) are particularly relevant for ocular motility, as are projections to the premotor region (61,

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149, 286,288). Direct projections to oculomotor nuclei have not been found (10,196). In summary the prefrontal cortex is endowed with a great variety of connections that allow it to integrate information from different sectors of sensorium and from the internal environment. A number of efferent connections can serve a supraordinate function of prefrontal cortex in executing movement (Fig. 3). From the evidence of these connections alone, it is not possible to deduce either the function or the mechanisms, but enough is known about the motor functions of the target structures to allow some inferences of general character. Thus the group of efferent connections to the hypothalamus and other structures of the brain stem related to the limbic system-connections that for the most part originate in orbital prefrontal cortex-clearly indicate a role of this cortical region in emotional behavior. The efferents to striatum, on the other hand, indicate a role of prefrontal cortex in the initiation and regulation of voluntary movement. The efferents from area 8 to premotor cortex, striatum, and pulvinar and tectal structures most probably represent output pathways for the role in eye-movement control that electrophysiological studies attribute to the frontal eye fields. In the ensuing sections of this chapter, I attempt to define more precisely, on the basis of

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other evidence, the participation of prefrontal cortex in motor control that is suggested by its connections. Summary

The prefrontal cortex is that part of the cerebral cortex that receives projection from the mediodorsal nucleus of the thalamus. Phylogenetically it undergoes more growth than other neocortical regions, reaching a maximum of expansion in the human brain. Its lateral and dorsal areas develop later and more extensively than medial and ventral areas. Ontogenetic development follows a similar course: the prefrontal cortex is one of the last cortical regions to mature; in primates, orbital areas mature earlier than dorsolateral areas. Functional correlates of phylogenetic and ontogenetic development have been uncovered by behavioral study. Cytoarchitectonically the cortex of the prefrontal region is typical isocortex. It has six layers, which are better defined in primates than in carnivores. A prominent layer IV (internal granular layer) characterizes the primate's prefrontal cortex. In addition to mediodorsal nucleus, other thalamic nuclei project to prefrontal cortex, especially the nucleus ventralis anterior and intralaminar nuclei. Input

PREFRONTA L

THALAMUS BASAL GANGLIA

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1MIDBRAIN-PONS I FIG.

3. Efferent projections of prefrontal cortex most probably involved in motor control.

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from brain stem and limbic structures can reach prefrontal cortex through thalamus, but direct projections from hypothalamus, mesencephalon, amygdala, and limbic cortex have also been demonstrated. In addition afferents from several neocortical areas implicated in higher sensory functions converge on prefrontal cortex. Thus the prefrontal cortex receives a large variety of afferent inputs and thus can integrate information from the internal as well as the external environment. The prefrontal cortex reciprocates by sending efferent fibers to the same subcortical and cortical structures where its afferents originate. Efferent projections from prefrontal cortex to some of the subcortical structures involved in execution of movement are an exception. Several sets of well-demonstrated efferent connections implicate the prefrontal cortex in motor control: I ) efferents to basal ganglia (striatum, globus pallidus, and substantia nigra); 2) efferents to the tegmentum of the mesencephalon and pons; 3) efferents to the hypothalamus, especially the preoptic area; and 4 ) efferents from area 8 (frontal eye field) to pulvinar, tectum, and premotor cortical region. LESION STUDIES

The surgical ablation method has been extensively used in attempts to elucidate the behavioral functions of prefrontal cortex. This method, however, has certain limitations that make it difficult to interpret the effects of an ablation as simply the result of subtracting the function of the ablated structure from the function of the normal structure. After the lesion, secondary degeneration and functional readjustments in the rest of the brain make such an interpretation hazardous. Nonetheless ablation remains a valuable tool of neurobehavioral research and has provided helpful insights into the neurophysiology of the prefrontal cortex and its role in motor control. The ablation literature is voluminous and of variable reliability. In the following description only a selection of representative contributions is discussed. The selection may be biased and may not include all important works relating to motor control, but I can plead some innocence on the grounds that it is exceedingly difficult to evaluate many published reports. Surgical and behavioral procedures vary widely with investigators and so do the precision and completeness of published reports regarding the extent and effects of ablation. For further discussion and bibliography the reader may consult references 45, 62, 186, 298, 316, 358, and 398.

Motility Ablations of prefrontal cortex generally induce hyperactivity (that is, more spontaneous movement than normally exhibited). Increased aimless locomotion is a common manifestation. Hyperactivity is most con-

sistently reported in monkeys with extensive prefrontal ablation [commonly designated as “frontal animals” (142,167,238,310)], although the phenomenon has not been observed in the squirrel monkey (243, 244). Regarding carnivores the published evidence is contradictory: some studies report hyperactivity (160, 200, 345, 383), and others deny it (48, 209, 400, 401). This discrepancy is possibly due to differences in the amount and location of tissue removed and to differences in quantifying methods. Age is a factor, as it is with respect to performance of delay tasks. Postablation hyperactivity does not seem to occur in young animals as consistently as it occurs in adults (96, 126, 384). Hyperactivity may be suppressed by placing the experimental animal in darkness or by generally diminishing sensory stimulation (118, 137,167,238,283). Moreover stimulation accentuates this condition in proportion to the intensity and variety of the stimuli (99, 118, 137, 238). Consequently hyperactivity has been interpreted as a manifestation of the animal’s tendency to overreact to external stimulation. This hyperreactivity explains the normal distractibility of the frontal animal (121, 177, 185), a symptom also common in the human with prefrontal pathology (91, 226). Thus the experimental animal has difficulty suppressing orienting reactions, especially to novel stimuli (51, 125, 251, 299); in addition, these reactions become more difficult to habituate after the lesion, even though the autonomic manifestations of orienting reaction may be diminished (120, 171, 412). The extinction of discriminant motor responses also becomes more difficult (52, 399). The frontal animal generally seems incapable of inhibiting reactions to irrelevant stimuli, whether or not such stimuli were at one time relevant. For this reason the animal appears distractible and disinhibited in a variety of behavioral settings. Disinhibition is especially evident in the performance of behavioral tasks involving conditioned inhibition, successive discrimination, or reversal (see subsection DISCRIMINATION, p. 1155). In the monkey, lesions of area 8 (the frontal eye field) have been noted to affect ocular motility. Unilateral lesions result in deviations of the eyes and forced circling toward the side that the lesion is on and, concomitantly, visual neglect of stimuli in the opposite side (164, 166, 205, 206, 408). Watson et al. (403) have suggested that such neglect results from disruption of the “intentional” component of orienting reactions. Bilateral lesions have been reported to diminish ocular motility (166, 206) and to impair performance of visual search tasks (203, 204). In the cat the bilateral lesion of eye fields has been reported to elicit a deficit of conditioned anticipatory visual attending (331). These observations, together with electrophysiological studies (see section ELECTROPHYSIOLOGY, p. 1159), point to the importance of area 8 regarding ocular motility of visual attention. To summarize, large lesions of prefrontal cortex

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commonly induce hyperactivity, especially in primates. This symptom is at least partly attributable to disruption of a mechanism normally controlling the reactivity of the animal to extraneous stimuli and thus subserving attention. Lesions of area 8 produce alterations of the ocular motility that normally supports visual attention.

Task Performance After an extensive prefrontal ablation the animal has difficulty performing certain discrimination tasks. The performance of successive discrimination tasks, in which two sensory stimuli are presented at different times and demand different responses (5, 19, 44, 87, 138, 319, 4071, is especially affected. The difficulty is most evident if one of the stimuli demands a given response and the other demands no response at all (go/no go). In this situation the animal makes numerous errors of commission, not only responding to both stimuli but also responding between trials, as if unable to inhibit untimely motor acts (5, 44, 181, 251, 319). Untimely and erroneous response is also evident in the performance of reversal tasks. In these tasks the two stimuli are presented simultaneously and the animal must choose one of them on each trial for a reward, but from time to time the correct (rewarded) stimulus is changed. When that happens the animal must reverse its choice; that is, it must choose the stimulus that was heretofore incorrect and disregard that which was previously correct. The frontal animal has trouble reversing the discrimination habit (127, 333, 372, 377, 401). This difficulty also applies to discrimination between two locations in the testing environment (place reversal) (251, 397, 400). Monkeys with lesions of ventral prefrontal cortex, i.e., the cortex of the lateral inferior convexity (below the sulcus principalis) and the orbital surface, have been reported to exhibit marked deficits in visual (140, 290, 354), auditory (210), tactile (292), and olfactory (366) discrimination tasks. However, little or no evidence of areal specificity has been obtained with respect to sensory modality. The critical factor for discrimination deficit due to lesions of ventral cortex appears to be supramodal and related to the form in which the tasks are administered. Indeed the tasks most critically affected are those that require the inhibition of untimely or inappropriate motor responses, such as successive discrimination, go/no go, and reversal, regardless of the modality of the stimuli. These tasks are generally impaired more by ventral lesions than by lesions of dorsolateral cortex (78, 140, 251, 290, 292, 319). In the dog these and other tasks requiring conditioned inhibition are particularly disrupted by lesions of medial prefrontal cortex (44-46, 70, 71, 361). For this reason medial prefrontal cortex of the dog has been considered the functional homologue of the monkey’s ventral cortex (183, 184). The nature of the supramodal factor accounting for DISCRIMINATION.

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the release of inappropriate motor responses has not yet been determined. Mishkin (251) has characterized it as the “perseveration of central sets,” meaning an abnormal tendency to perseverate in previous behavior, however unproductive it may be at the moment. Thus in a behavioral task, current responses would be proactively disrupted by competing traces of previous trials and experiences. Mishkin sees a major role for basal prefrontal cortex in the inhibition of this form of interference from within the organism. Animals with large lesions of prefrontal cortex are notoriously deficient in the performance of delayed-response and delayed-alternation tasks. The deficit was first observed by Jacobsen (143-145) in the monkey and has since been amply documented in primates (67, 202, 244, 304, 321, 339), the cat (80, 81, 209,230,397,400),the dog (180,185,207,208),and the rat (153, 179, 201,410). Delayed response is a task requiring short-term retention of sensory cues. The following events typically make up a trial: the cue, which is the sight of food being placed under one of two objects; a delay of a few seconds during which the objects are out of reach; the presentation of the objects for choice; and the animal‘s choice. The animal is allowed to retrieve the food if the chosen object is the baited one. Food position is changed at random between trials. Certain versions of the test are administered using automated instruments, where the correct response is signaled at the beginning of a trial by a discrete visual or auditory stimulus, instead of the baiting operation. In delayed alternation the animal is obliged to alternate the site of response, usually between right and left, with a delay between responses. The task is essentially a place-reversal task in which the correct response changes every trial. Frontal monkeys have been reported to fail not only in these two spatial delay tasks, but also in a third task, delayed matching to sample, in which the cue is not spatially defined (108, 351). Here the cue (sample) is a visual stimulus, usually a colored light, always presented in the same location at the start of each trial. After an enforced delay the stimulus is again presented, but now elsewhere and in conjuction with others. Correctly choosing the sample color is then rewarded. The sample is changed at random from one trial to the next. Briefly, all delay tasks that the frontal animal fails to perform correctly consist basically of a succession of motor choices, each dependent on an event that has recently occurred. Both choice and event are part of a repertoire of alternatives with which the animal is familiar. Every correct response requires the perception and retention of the event critical for that trial and, conversely, the rejection of inappropriate alternatives. The appearance and magnitude of a delay-task performance deficit after prefrontal ablation depend on a number of factors, the most important of which are DELAY TASKS.

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related to the conditions under which the task is performed, the spatial aspects of the task, the task‘s temporal aspects, and the location and extent of the ablation. We briefly consider the relevance of these variables. Certain changes in testing conditions can help the frontal monkey overcome the deficit. Some studies show that the impairment of delayed response caused by the lesion may be at least partly compensated by increasing the saliency of the cue or by forcing the animal’s attention to it (29, 93, 241). Similarly, performance has been restored to normality by minimizing the incidence of distractions during the delay period (18, 185, 228). The delay-task deficit can also be overcome to some degree with the help of pharmacological agents that control hyperactivity (256,297,385, 406), a symptom associated with overreaction to extraneous stimuli and distractibility. However, some of the studies purported to demonstrate the beneficial effects of the aforementioned procedures on the frontal animal lack a control (the same procedures in the normal animal). Without that control it is difficult to ascertain the effectiveness of these procedures in restoring capabilities presumably lost in the ablation. In any event all the cited studies point to disorder of attention as an important element of the delayedresponse deficit and also, consequently, to a role of prefrontal cortex in ensuring attention and protecting the animal’s behavioral performance from external interference. These conclusions are supported by the observation that the reversible depression of prefrontal cortex (by cooling) renders delay-task performance more vulnerable to distraction than in normal conditions (106). In the 1950s Mishkin and Pribram (254, 255 303) postulated that the lateral prefrontal cortex of the monkey is essential for processing spatial information, and that the failure of frontal animals to correctly perform delayed-response and delayed-alternation tasks is attributable, above all, to the fact that both these tasks are spatial. To substantiate their hypothesis Mishkin and Pribram tested animals with lateral prefrontal lesions on these and other tasks, some without the spatial factor. The results provided only limited support to their hypothesis (254, 255, 299, 303). However, subsequent studies with other behavioral tests and discrete lesions have definitely established that a portion of lateral cortex, the area of the sulcus principalis, is indeed important for performance requiring use of spatial information (31,63, 113, 116, 119, 250). The cortex most critical for spatial tasks has been localized in a small region of that sulcus, namely the middle third (55,56). By experimentally modifying kinesthetic and somesthetic variables in the delayedresponse task, some evidence has been obtained from monkeys with lateral lesion that the spatial deficit is reducible to a defect in utilization of proprioceptive cues (107, 229, 353). However, other experiments in-

dicate that this interpretation may be too restrictive and instead support a supramodal role of lateral prefrontal cortex in the spatial orientation of the animal (253, 295). In any event the importance of lateral cortex for spatial processing is well documented; however, the spatial factor is clearly insufficient to explain the behavioral deficit of the monkey with lateral lesion. It turns out that lesions of sulcus principalis disrupt spatial tasks only if their trials contain a delay (113, 116). Obviously a temporal factor as well as a spatial factor is essential. Indeed a temporal function seems to transcend the confines of the sulcus principalis, involving most of the lateral prefrontal convexity. The temporal factor was first recognized by Jacobsen (143, 144). It was the basis for his characterization of the delayed-response deficit as a recent-memory deficit. He reasoned that the frontal monkey fails at the task because it is unable to recall the cue after the delay. Indeed the delay seems to determine the failure by imposing a hurdle to memory that the animal with prefrontal lesion cannot negotiate. For the deficit to appear, however, the delay must be of a certain minimum duration (117,240,241, 378). The frontal animal may not err if the delay is brief, but it usually makes many more errors than the normal animal after long delays. Furthermore the relationship between performance and length of delay varies considerably between species (95, 128, 135, 234). Therefore, without taking this variability into consideration, it is difficult to establish interspecies differences in importance of prefrontal cortex for delay-task performance (231,321, 397). The length of the delay is a relevant parameter for testing the validity of Jacobsen’s hypothesis. Inasmuch as recent or short-term memory is a function with a temporal decay, a direct relation between the delay and the magnitude of the delayed-response deficit may substantiate the presumed role of prefrontal cortex in that kind of memory. A parametric study of this relationship cannot be easily conducted with ablation. The application of reversible lesions, allowing the repeated use of the experimental animal as its own normal control, makes the study more feasible. Cooling is one procedure for inducing reversible lesion. By cooling a large portion of the monkey’s prefrontal convexity, a reversible deficit in performance of delay tasks can be induced (20, 104, 106, 334). We observed that this deficit is as pronounced in delayed response as it is in delayed matching to sample, a nonspatial task (20). The observed deficit was delay dependent, that is, it was minimal with brief delay and increased as a function of delay duration (Fig. 4, top). This relationship agrees with the notion that prefrontal lesion interferes with a memory hnction that decays with time. The reaction-time data of our study are also consistent with this notion. Choice reaction times become longer as short-term memory is taxed by

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and cooling provide sufficient evidence for a role of prefrontal cortex in short-term memory, it seems beyond dispute that the interposition of temporal discontinuities between the events of any task makes that task abnormally difficult for the frontal animal to perform (98, 258). This supports a more general concept than the one concerning short-term memory, namely that the prefrontal cortex plays a critical role in the temporal organization of behavior. This was also considered by Jacobsen and his colleagues (143, 146). Experiments such as those by Pribram and collaborators (294,305,306,379),demonstrating that the DELAYED DELAYED frontal animal has difficulty executing motor acts in a RESPONSE MATCH I NG-TO-SAMPLE given time sequence or otherwise organizing tempo-NORMAL r f w rally separate events, lend additional support. Such -"fRON?ZL 20° difficulty can be alleviated by spacing the events of a task (delayed alternation) so as to make temporal organization easier (305,306,379). Finally clinical data further highlight the relevance of the time factor and support the idea of temporal organization. Lesions of prefrontal cortex in humans impair performance of tasks requiring temporally locked categorization of 5OL- - - CHANCE- - - - J- - - CHANCE- - stimuli [that is, tasks in which the categorizing principle changes from one time to another (247, 248)]. The temporal ordering of sequentially presented items r 1.20~ r is also impaired (249). Upon observing that monkeys with orbital lesions failed in delayed-alternation and object-alternation tasks, Mishkin and his colleagues (251,257) concluded that the deficit from ventral lesion was attributable to the reversal factor inherent in these tasks, the same 0 factor that accounts for the failure of orbital-lesion kmonkeys to correctly perform discrimination and re2 w versal tasks (see subsection DISCRIMINATION, p. 1155). n w 0 Thus delayed alternation is disturbed by lesions of 2 0 26 either the dorsolateral convexity (sulcus principalis) H or the orbital area, but for different reasons. In the I first case the trouble is related to the spatial and temporal aspects of the task; in the second case it is related to its reversal feature. This feature challenges the diminished capacity of the orbital animal to with8 14[ stand so-called perseverative interference (251). v, 12 //p To summarize, analysis of the results of selective ablations on performance of behavioral tasks allows P ', , two broadly defined prefrontal areas to be functionally differentiated. In the monkey a dissociation is apparent between dorsolateral cortex (including sulcus principalis) and ventral cortex (including orbital cortex and inferior lateral convexity). The dorsolateral cortex is primarily involved in tasks requiring the integration I# 0'; 4 ; Ik 32 1 4 8 16 32 of temporally discontinuous information. The ventral DELAY IN SECONDS cortex, on the other hand, appears mainly involved in the suppression of interfering tendencies. A similar FIG. 4. Percentage of correct responses, reaction time to sample or cue, reaction time to choice stimuli, and general motor activity as dissociation in the dog's prefrontal cortex can be infunction of delay in delayed matching to sample (left) and delayed ferred. Here the functional homologues of the monresponse (right).Plotted values are for normal cortical temperature and for bilateral cooling of areas indicated at top. [From Bauer and key's dorsolateral and ventral cortex seem to be the Fuster (20). Copyright 1976 by the American Psychological Associ- dorsolateral (proreal) and the medial cortex, respecation. Reprinted by permission.] tively (45, 70, 183). In both primate and carnivore, the longer delay; this effect is more pronounced if the prefrontal cortex is depressed by cold (Fig. 4, third row). Whether or not these interactions between delay

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noted functional dichotomy corresponds to a dichotomy of anatomical connections. In the light of this parallel dichotomy of functional areas and connections, it is reasonable to inquire whether there is a relationship between the behavioral functions of other cerebral structures and those of the part of prefrontal cortex to which they are linked. Rosvold (317, 318, 320), on the basis of his own work and that of others, concluded that there is such a relationship. His argument rested on the analysis of ’the effects of lesions of several brain structures on various behavioral tasks, such as delayed response, delayed alternation, object reversal, visual discrimination, and go/no go. Although the evidence was, and still is, largely fragmentary, he postulated two functional systems of interconnected structures in the monkey, one associated with dorsolateral and the other with orbital cortex. The first, the dorsal system, includes the anterodorsal part of caudate nucleus, the lateral pallidum, the subthalamus, and the hippocampus; the second, the orbital system, includes the vertrolateral part of caudate, the centromedian nucleus, the medial pallidum, and the hypothalamus (320).

siveness seem to have encroached on the limbic cortex behind the prefrontal region. All the lesions seem to have involved medial or orbital prefrontal areas that are anatomically closely connected to the limbic system (see subsection Connections, p. 1151). These studies therefore implicate prefrontal cortex in the control of limbic processes related to hunger and aggressive behavior. This inference is consistent with results of electrical stimulation studies (see section ELECTROPHYSIOLOGY, p. 1159) demonstrating orbitofrontal inhibition of certain autonomic functions. From both lesion and stimulation studies the idea emerged of an orbitofrontal region exerting inhibitory control, through the hypothalamus, over the efferent mechanisms of aggression (100, 165). This view has been supported by evidence that orbital prefrontal lesions can lower the threshold of emotional reactions, particuIarIy rage, elicited by hypothalamic stimulation (325, 326) and, conversely, prefrontal stimulation can inhibit attack behavior (336, 337). The ideas suggested by observations of changes in instinctive behavior have been strengthened by studies of the effects of selective prefrontal lesions on conditioned behavior. Upon review of such studies, Brutkowski (45) proposed “drive inhibition” as the Emotional Behavior essential function of medial prefrontal cortex in carChanges in emotional behavior have long been rec- nivores (or orbital prefrontal cortex in primates); this ognized as common consequences of frontal lobe lesion inhibitory function is mediated by the well-known (24, 90).Early reports concerning the effects of pre- prefrontal efferents to hypothalamus and other limbic frontal ablation on learned behavior refer to changes structures. In the monkey, however, lesions circumscribed to in the affective disposition of the experimental animals (30, 67, 89). Others refer to abnormal voracity and orbital prefrontal cortex do not necessarily entail disaggressiveness (101, 165, 200). However, to this day inhibition of hunger or aggression. Monkeys with such the subject of emotional behavior after prefrontal lesions appear withdrawn and helpless, although caablation remains among the most confusing topics in pable of some emotional expression (173, 175, 307). the lesion literature. The reason is the lack of conven- Fear and flight reactions are more common in them ient methodology for assessing and quantifying emo- than in normal animals (53, 54, 173, 175, 307). Butter tional changes. Our discussion focuses only on those et al. (53, 54) localized the focus for these changes in a small area of posteromedial orbital cortex. The disfindings that appear to be best substantiated. The ablation of the prefrontal (proreal) cortex of crepancy between these observations and those above, the cat reportedly produces an animal that is more which implied a disinhibition of aggression due to submissive, less aggressive, and less successful in com- orbital lesions, is not readily explainable. Two points peting for food than before the operation (280, 281, may be made in attempting to resolve the conflict. 400, 401). Similarly the monkey with total or subtotal First, the aforementioned observations of increased ablation of prefrontal cortex displays varying degrees aggression have been mostly made in carnivores with of indifference toward other animals, increased toler- medial lesions. Second, the functional homology beance of frustration, and withdrawal (67, 73, 97, 146, tween the medial cortex of carnivores and the orbital 261, 263). These symptoms are usually accompanied cortex of primates has not been incontrovertibly esby loss of vocalization and facial expression in addition tablished. Among other things the behavioral effects to hyperactivity (97, 261, 263). After the lesion both of medial lesions in the monkey need to be explored cats and monkeys exhibit blunted emotions and di- further. minished motivation. In spite of the increase in aversion and fear-motiSome large lesions of frontal cortex, however, have vated behavior, the monkey with orbital lesion, acbeen reported to elicit increased appetite in cats (200, cording to one report (53), does not show a facilitation 349), dogs (335), and monkeys (101). Cats (100, 165) of instrumental shock-avoidance behavior. Tanaka and dogs (47, 349) have also been noted to become (368) noted that lesions of medial prefrontal cortex abnormally irascible after the operation. According to elicited a deficit in performance of a shock-avoidance the published accounts of these studies, most of the task; yet the failure to perform the appropriate motor lesions inducing hyperphagia and abnormal aggres- act for avoiding shock was accompanied by signs of

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The well-known deficit of animals with prefrontal agitation and anxiety. These dissociations between emotional behavior and instrumental behavior indi- lesion in performance of delayed response and related cate, at the very least, the inadequacy of avoidance- tasks reflects, above all, a difficulty to integrate temtask performance as a measure of fear (45). Cognitive porally discontinuous information. This deficit is most disorders, rather than emotional disorders, may be the consistently induced by lesions of lateral prefrontal basis for some of the impairments of avoidance-task cortex. The roots of the deficit appear twofold. First, performance that have been observed after prefrontal there is a disorder of attention preventing the animal lesions in primates (368,402),carnivores (12,397,401, from perceiving relevant cues; second, there exists a disorder of short-term memory impeding the retention 413), and rats (363). Lesions of dorsolateral cortex or large lobectomies of relevant information for subsequent action. Large prefrontal lesions generally result in blunted that spare the posterior orbital area do increase aggressiveness in the monkey (41, 174, 246, 338), but in emotions and diminished motivation. Lesions involva peculiar way. Paradoxically the exacerbated attack ing medial or basal cortex have been noted to induce, behavior of the animal is accompanied by a decrease especially in carnivores, behavioral changes suggesting of the emotional expressions that normally go with disinhibition of aggression and hunger drives. In the aggression. The animal vocalizes less and exhibits monkey, orbital lesions are reported to lessen aggresfewer threats and aggressive gestures, yet it attacks sivity and increase aversive behavior. Dorsolateral other monkeys more often than it did before the lesion. lesions have been seen to increase attack behavior and This abnormality has been interpreted as the result of concomitantly decrease expression and communicathe animal’s incapacity to use previously learned pat- tion. This deficit may be secondary to a cognitive terns of avoidance (41). Another interpretation is that impairment. In very general terms, and with due regard for the animal, confused and unable to sort out sensory stimuli, resorts to indiscriminate aggression (246). exceptions, lesion studies indicate that medial and Both interpretations imply that the emotional disor- ventral prefrontal cortex is the source of inhibitory der of the monkey with dorsolateral lesion is secondary influences over motility associated with certain drives, to a cognitive disorder. These views are related to the and over tendencies to execute inappropriate or unnotion that the dorsolateral cortex supports the inte- timely motor acts. Dorsolateral prefrontal cortex, on gration and recognition of communicative signals the other hand, appears to be the substrate for cognitive operations of temporal integration upon which (262). In conclusion, comprehensive ablations of prefrontal certain forms of motor behavior are predicated. cortex in both carnivores and primates induce a decrease of emotional acts and expressions and an apparent loss of motivation. In carnivores, selective le- ELECTROPHYSIOLOGY sions of medial prefrontal cortex elicit a disinhibition of eating and aggressive behavior. This implicates Inputs a n d Outputs Electrically Traced medial cortex in the inhibition of drive, a function Several studies have electrically demonstrated afpresumably exerted through hypothalamus and limbic ferent inputs to prefrontal cortex, corroborating anasystem. In the monkey, orbital prefrontal lesions lead tomical findings. Thus it has been shown, by thalamic to aversion and fear, whereas lesions of the cortex of stimulation and cortical recording, that the prefrontal the prefrontal convexity lead to increased aggressive- cortex receives an exceedingly large proportion of proness. The latter result has been viewed as a conse- jections from the nonspecific thalamic system (151, quence of a perceptual disorder. 271,359, 360). Furthermore sensory evoked-potential studies indicate that the prefrontal cortex is suited for Summary integration of diverse sensory inputs. Walter (393) Lesions of prefrontal cortex tend to induce hyper- showed that electrical responses elicited by visual, motility, especially in monkeys. This phenomenon is auditory, and somatic stimuli can be recorded over partly attributable to excessive reactivity; as a result large frontal areas in humans; considerable overlap of prefrontal lesion, the animal becomes overreactive was observed with regard to sensory modality. In to external stimuli and inordinately distractible. Le- squirrel monkeys, stimuli of three modalities were sions of area 8 adversely affect the motility of the eyes shown to elicit potentials in the prefrontal region, also supporting visual attention. with much intermodality overlap (25,26).The ablation Prefrontal lesions elicit a deficit in performance of of primary sensory areas did not eliminate the evoked discrimination tasks that is largely supramodal and potentials, indicating that sensory inputs to prefrontal dependent on task formalities. Most affected are suc- cortex are at least partly mediated by thalamic pathcessive-discrimination, reversal, and conditioned-in- ways possibly involving the intralaminar nonspecific hibition tasks. The deficit is attributable to the inabil- system (25). However, stimulation of primary sensory ity of the animal to inhibit certain maladaptive re- areas or their vicinities induced potentials in prefronsponse tendencies. In the monkey the deficit results tal cortex even after thalamectomy, indicating that mostly from lesions of ventral prefrontal cortex. corticocortical pathways may also play a part in the

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transmission of sensory inputs to prefrontal cortex (25). In the cat, sensory inputs have been electrically traced to the frontal cortex of the anterior sigmoid and orbital gyri (50, 136) but not to the prefrontal cortex itself. However, some convergence of such inputs upon prefrontal cortex is suggested by one study of evoked potentials (264). Single units in the monkey’s prefrontal cortex have been shown to react to sensory stimuli (22, 259, 271, 272,328,365,367).Whereas some cells appear to react to stimuli of only one modality, others exhibit bimodal or trimodal reactivity (22, 271, 328). Units responding to olfactory stimuli have been found in posterior orbital prefrontal cortex (365, 367). Benevento and collaborators (22) have shown interaction of auditory and visual influences on units of more anterior and lateral prefrontal cortex. A few of the efferent connections of prefrontal cortex demonstrated by anatomical studies have been verified by electrical methods. A study in the cat shows that stimulation of prefrontal cortex can modify the discharge of units in the thalamus (particularly mediodorsal nucleus) and hypothalamus (84); the same units are also subject to influences from the amygdala. Other studies in the cat show that prefrontal influences modify the neuroelectrical activity in the caudate nucleus (219, 220), where prefrontal input seems to interact with inputs from substantia nigra and entopeduncular nucleus (220). In the rat an inhibitory pathway has been electrically traced from prefrontal cortex to ventromedial nucleus of the hypothalamus (282). These studies not only confirm some of the efferent connections of prefrontal cortex, but they provide evidence of modulation by prefrontal cortex of cellular elements in subcortical structures regulating movement and emotional behavior.

Inhibition From Orbital Prefrontal Cortex A number of investigations in the cat promote the idea that the orbital prefrontal cortex and the midline thalamic nuclei projecting to it form a system that regulates the electrical activity of large areas of cortex (344). Lesion or cryogenic blockade of the postulated system or any of its parts has been reported to abolish spindle bursts, recruiting, and other forms of synchronous electrocortical activity associated with generalized cortical inhibition (221, 312, 341, 381, 382, 405). Such procedures have also been seen to increase sensory evoked-potential amplitude (342, 343) and to suppress a surface-negative slow potential in the frontal area that is associated with vigilance and expectancy [(340); see subsection SLOW POTENTIALS, p. 11611. In addition the functional blockade of the inferior thalamic peduncle, which connects orbitofrontal cortex with medial thalamus, has been reported to interfere with behavioral performance of a simple alternation task (342). Skinner and Lindsley (344) inter-

pret all these findings as evidence for an orbitothalamic system that inhibits sensory inputs and that is essential for attention. The orbital prefrontal cortex is only a part of the cortical region that has been reported to exert electrographic and behavioral inhibition in both carnivores and primates. More posterior areas, considered and designated by some investigators as orbital cortex, also have inhibitory properties. The stimulation of these areas can induce sleep (6, 65, 158) and inhibition of somatic reflexes (327, 362), the latter via descending projections to the bulbar reticular formation and the pontine tegmentum. Stimulation of posterior orbital loci induces cardiovascular changes, including changes in blood pressure, heart rate, cardiac dynamics, and skin temperature (17, 74, 123, 158, 222, 322). Changes in respiration (17, 158, 346), epinephrine release (88), and plasma cortisol (124) have also been observed. Many of the autonomic effects of stimulation appear to be parasympathetic or the result of inhibition of the sympathetic system (134). In accordance with these findings and findings from studies of visceral afferents to cortex, the posterior orbital area has been viewed as the cortical representation of the vagus (16, 75,86). The autonomic effects of stimulating the area are probably mediated by efferents to the hypothalamus, the amygdala, and other limbic structures connected to ventral prefrontal cortex. To summarize, a large region of basal cortex, including but not limited to orbital prefrontal cortex, seems to be the source of a variety of vegetative and somatic influences of inhibitory character. Judging from the effects of stimulation, motor inhibition is one component of a general inhibitory action on behavior that originates in orbital prefrontal cortex and may be mediated, along with autonomic influences, by the basal ganglia, the hypothalamus, and the limbic system. The disinhibitory effects of orbital lesions on behavior (see section LESION STUDIES, p. 1154) are in accord with this notion.

Frontal Eye Fields and Oculomotor Control The electrical stimulation of points within the transitional cortex of area 8 is known to induce conjugate eye movements in animals of several species. Thus the electrically delimited cortical field from which eye movements can be elicited has been called the frontal eye field. In primates the frontal eye field occupies a relatively well-circumscribed portion of dorsolateral prefrontal cortex practically, though not exactly (313), coinciding with area 8 (2). Two separate eye fields have been identified in the cat, one in the cortex of the presylvian fissure and the other in medial cortex (330). Frontal eye fields have been subdivided into functional sectors in accordance with the direction of eye movements elicited from them by stimulation. This is not the place for discussing the role of

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cortical areas in ocular motility (see the chapter by Robinson in this Handbook), but some properties of the frontal eye fields deserve mention here. It is of special interest that stimuli applied to area 8 may induce not only eye movements but, depending on the parameters of stimulation, may induce eyelid movements, pupillary dilation, rotation of the head, and other phenomena (21, 217, 293, 332, 347, 386, 387). Some of these effects resemble fragments of attentive reactions of the organism. In this regard there has been speculation that the frontal eye fields might be an integral part of a system of neural structures coordinating anticipatory and goal-directed acts. Hess (131) called it a “teleokinetic” system. It is conceivable that the orientation, fixation, centering, and pursuit movements of the eye, all of which are components of behavior in visual attention, are under the control of such a system. In any event the notion that the frontal eye fields are simply a command post for execution of eye movements is not tenable in the light of recent findings, such as those by Bizzi and Schiller (27, 28). These authors have shown two types of cells in the monkey’s eye field; some only fire during voluntary eye saccades and others fire during smooth pursuit or orientation movements of the eyes in a given direction. Practically no cells have been found discharging prior to initiation of eye movement. The cells in the eye fields appear to code position, but the input by which they do so is unclear. That input may be proprioceptive, visual, or both. Some of the cells in area 8 have been noted to have visual receptive fields (259,411). The electrophysiology of the frontal eye fields epitomizes the difficulties and futility of attempting to ascribe either a sensory or motor label to the functions of prefrontal cortex. The idea that area 8 and perhaps the rest of prefrontal cortex perform both sensory and motor functions a t the same time and that these functions are intimately intertwined seems more reasonable. One elaboration of this idea is the “corollary discharge” theory proposed by Teuber (374, 375). According to this theory, as it applies to frontal eye fields, the eye-field cortex integrates afferent information on eye and head position with information related to the anticipated consequences of movement. This integration constitutes a blend of current sensory input and prospective information used by the frontal eye field to modulate both sensory and motor mechanisms, thereby ensuring cohesion in perception as well as movement. The corollary discharge theory has so far received only limited empirical support. At best, electrophysiological data are consistent with it. In any case other interpretations of these data are possible and just as plausible. However, the theory incorporates a concept that has considerable heuristic value for exploring and understanding some aspects of prefrontal cortex function. It is the concept of a neural mechanism anticipating events and preparing the organism for them.

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Electrical Correlates o f Performance Walter and associates (395, 396) found that a sensory stimulus can evoke a slow surface-negative potential over the frontal region of humans if, by experience, that stimulus has become a warning signal for a subsequent stimulus that in turn requires a motor response (Fig. 5). In the original paradigm, the first stimulus (conditional) precedes the second (imperative) by about 1 s. Because of the contingency linking the two stimuli, the frontal potential observed in the interval between them was named the contingent negative variation (CNV). The CNV is of low amplitude (20-40 pV) and must be recorded using direct coupling or with very little filtering of low frequencies. Although fxst discovered in humans, the potential has also been recorded from the monkey in a comparable paradigm (35, 82, 225, 308). The appearance and amplitude of the CNV do not SLOW POTENTIALS.

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FIG. 5. Averaged electrocortical responses to auditory and visual stimuli in the frontal region of man. A-C: responses to click, flicker, and click-flicker pairing before conditioning. D: after conditioning, responses to click (conditional stimulus) followed by flicker (imperative stimulus), terminated by subject pressing a button; note slow negative potential (CNV) during interval between stimuli. [From Walter et al. (396).]

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critically depend on either modality or intensity of the stimuli. The potential can be elicited by pictures or words, provided these are “followed by an event which is expected to involve an action or decision” (236,394). For this reason the CNV has also been called the “expectancy wave” (394). The interval between the stimulus and the ensuing event need not be fixed for the CNV to appear; this interval may be 15 s or longer. Amplitude of CNV and reaction time of the subject have been found to be inversely related (132). A number of questions remain unresolved regarding the CNV and the psychological state or operation that it reflects (for detailed discussions see ref. 76). According to the results of some studies, the CNV, as it appears in Walter’s original paradigm, is comprised of at least two waves with a different cortical source and significance (35,150). One of them is a negative potential that develops in the central area just before a voluntary movement and is largest at the vertex on scalp recording. It has been called the readiness potential [Bereitschaftspotential; (72, 77, 187)]. The other potential is also negative, usually begins earlier, and develops more slowly over a more anterior frontal area after a stimulus requiring a subsequent decision [not necessarily to result in movement (150)l. This second potential (first in time), which appears limited to the prefrontal area, may be considered the CNV proper. As for the neural process generating it, the experimental evidence is, so far, inconclusive. It is unclear whether the phenomenon results from cumulation of excitatory postsynaptic potentials, cell spikes, or dendritic potentials; it may even be generated by an entirely different process. For discussion of the issue, see references 59, 60, 68, 350, 352. The behavioral paradigms in which the CNV has been observed are in some respects similar to the delayed-response paradigms conventionally used in animals. These paradigms generally involve a sensory cue, a delay interval, and a choice contingent on the cue. Stamm and Rosen (355, 357) recorded two slow negative potentials on the prefrontal cortex of monkeys performing a delayed-response task. The first potential appeared in anticipation of the cue on regularly spaced trials. It was identified as the CNV, even though it extended beyond the frontal region. A second potential, circumscribed to prefrontal cortex, was recorded at the end of the cue and the beginning of the delay. On account of its timing, and since its magnitude was related to proficiency of performance, the researchers reasoned that this potential might reflect neural activity related to the formation of short-term memory or the programming of the response. This interpretation was supported by the finding that electrical stimulation of prefrontal cortex disrupted the task when applied precisely at the time of that slow potential, that is, at the end of the cue and the beginning of the delay (356). More generally the functional significance of surface negativity was supported by the finding that delayed-response learning may be facili-

tated if trials are presented during spontaneous surface-negative potentials in prefrontal cortex (324). UNIT ACTIVITY. The prefrontal cortex has been explored with microelectrodes during performance of behavioral tasks for which, as lesion studies show, the integrity of this cortex is important. This work is partially based on the expectation that changes in neuron activity, by their timing and course, provide insight into the aspects of performance in which prefrontal neurons are involved. Thus single-unit discharge has been extensively investigated in prefrontal cortex of monkeys performing delayed-response and delayed-alternation tasks. Delayed-response trials, as noted before, consist of the presentation of a visual cue, a period of enforced delay, and a motor response dependent on some characteristic of the cue. For correct performance the animal must retain information on the cue through the delay. As a result of single-unit study, clear-cut temporal correlations have been demonstrated between prefrontal cell discharge and the main events of the delayed-response trial (102, 103, 192, 273, 276). Such correlations led this author to classify cells of prefrontal cortex into several types [Fig. 6; (102)]. A large number of units show an increase of spike dis-

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FIG. 6. Unit discharge patterns in prefrontal cortex during delayed-response trial. Heavy line marks deviations from intertrial baseline fming, activation emphasized by shading. Arrows at bottom mark movements of opaque screen interposed between animal and test objects. During cue phase, food is placed under 1 of 2 identical objects; during delay phase (about 18 s), screen is down (as between trials); at end of delay, screen is raised, exposing objects for choice. [From Fuster (102).]

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charge when the cue is presented. The two cues commonly used in delayed response (right, left) and in delayed matching (red, green) elicit different reactions in some units (103, 273, 276). Many units are also activated by auditory and visual stimuli that precede or accompany the presentation of the specific cue for a given trial (102, 103, 109). Therefore prefrontal cells appear to react to two kinds of input: 1 ) sensory information that is constant from trial to trial and that may be used by the animal for directing attention to the cue and 2) trial-specific sensory information contained in the cue itself, on which correct performance above the level of chance depends (103). I interpreted some unit reactions to cue presentation as evidence for a role of prefrontal cells in sensorial attention (102). Other observations subsequently supported this view. Thus Suzuki and Azuma (364) found that units around the sulcus principalis increased firing during fixation on a light spot that determined the animal’s behavior by subtle changes in brightness. In another visuomotor task, with trials presented at regular intervals, some units accelerated firing in anticipation of the stimulus initiating each trial (323). These attention-related changes of principalis units, unlike those of units in the frontal eye field, do not seem related to the oculomotor components of visual attention, since no systematic correlations have been observed between the activity of the units and eye movements (102, 323). Firing changes of principalis units, however, may greatly depend on whether or not the stimulus has behavioral significance. Units in two of the studies mentioned (323, 364) were not activated unless the visual stimulus called for a particular manual response. Kubota et al. (192) have described a category of units, which they call “visuokinetic.” It is characterized not only by reactions to visual stimuli but by increased firing prior to a conditioned motor response of the hand. When a delay of a few seconds is interposed between a given cue and the appropriate response, the activity of many prefrontal units is seen to persist at a high level throughout that delay (Fig. 6, type C). FurtherCUE

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more some units that are inhibited during the cues are now activated to a higher level than between trials (Fig. 6, type D). Nearly one-half of all prefrontal units investigated by Fuster and Alexander (102, 103, 105) in delayed response fired more during the delay than between trials, and only a small proportion (under 8%) fired less. Discharge was often highest at the beginning of the delay. In some units sustained activation extended throughout delays of 1 min or longer; their firing returned to normal as soon as the trial ended (Fig. 7). The cues for delayed response failed to elicit delay activation in prefrontal units of untrained animals. In trained animals, units exhibiting delay activation in ordinary trials failed to do so in dry runs, where the cue was deleted but other stimuli normally preceding it were preserved. Delay activation could be attenuated by distractions and was related to proficiency of performance. All these observations indicate that elevated discharge during the delay is largely determined by the relation of contingency between temporally separate events. This relation is established by learning. The phenomenon of delay activation is not easily attributable to nonspecific factors such as arousal or motivation; these factors should be as influential during cue and response periods as in the interim, yet some units are only activated in the interim (e.g., unit in Fig. 7). The most critical factor for sustained activation between the cue and the response is the presence of mutual contingencies between the two. The relationship between the sustained activation of a large proportion of prefrontal cells and some of the task-related slow potentials discussed in the previous section should now be apparent. These cells may in fact be the source of the CNV or OK of its component waves. What is the functional significance of unit activity during the delay? One possibility is that it reflects participation of prefrontal cells in the mnemonic process of retaining the cue. Fuster and Alexander (102, 103,105) have argued in favor of this possibility, basing arguments largely on the characteristics of delay firing and the factors that modify it. Also supporting this

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7. Spike activity of single unit (type D) in prefrontal cortex during 5 delayed-response trials. Spikes are represented by vertical lines. Cue phase is marked by horizontal bar and end of delay by arrow. Observe prolonged activation of firing during delay; fuing returns to normal with animal’s response in trials longer than 30 s (top 3 trials) and 1 min (bottom 2 trials). [From Fuster and Alexander (105). Copyright 1971 by the American Association for the Advancement of Science.] FIG.

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notion is the evidence that a number of units exhibit different firing rates during the delay, depending on the specific cue for the trial (103,273,276-278). Indeed units with this kind of differential activity appear to code a feature of the cue after the cue is no longer present. Another possibility is that unit discharge during the delay reflects the participation of prefrontal cells in setting up the motor system for the forthcoming response. This possibility has been explored in delayed response as well as delayed alternation, the latter a task in which no exteroceptive trial-specific cue is given and in which each choice of response is contingent on the direction of the previous response. In both tasks (192, 193, 273-276), as well as in a timing task (279),prefrontal units have been seen to increase firing in anticipation of motor response, e.g., lever pressing; the increase in firing has been reported to precede movement by some 200 ms or more, even up to several seconds in some units. In addition units have been noted to display differential rates depending on the direction of the impending response (273-276). A delayed-alternation study of prefrontal units in the cat has revealed units that discharge prior to movement in a differential manner (232).Niki (274,275) observed that differential firing depends not only on the absolute location of the monkey’s instrumental response but also on the relative location of the two alternative responses with respect to each other. Of course the two mentioned possibilities are not mutually exclusive, for there may be some prefrontal cells involved in short-term memory and others involved in motor setting. Niki and Watanabe (277,278) have provided support to this hypothesis. During unit recording, they tested the experimental animals on two different tasks: a spatial delayed-response task, in which cue and response occur in the same location, and a conditional position discrimination, in which cue in one place demands later response in another. Two types of units were found: for some, delay discharge depended on cue location; for others, it depended on response location. The anatomical distribution of different types of cells in prefrontal cortex has not been elucidated. Some areas still need to be explored, particularly in orbital and medial prefrontal cortex. This is important for correlating unit data with lesion data. However, I (102) have observed clusters of units of similar type in small parcels of dorsolateral and dorsomedial prefrontal cortex in the monkey. The precise configuration and dimensions of the clusters are still undetermined. A columnar distribution of units of similar features, as found in parietal cortex (260), has not been found in prefrontal cortex, although there are anatomical indications of translaminar organization within it (34,112). To conclude, a good case can be made on the basis of unit data for involvement of prefrontal neurons in sensorial attention, short-term memory, and motor set (the preparation of the motor apparatus for a given

motor act or class of acts). There is evidence that some neurons participate in more than one of these processes. This evidence and the close coexistence of cells of different types-some attuned to sensory information and some to motor response-point to the eminently integrative character of the parts of prefrontal cortex explored heretofore with microelectrodes in behaving animals. Furthermore the protracted activation of prefrontal units between temporally separate but mutually contingent events points to the probable involvement of prefrontal cortex in temporal integration. How the neurons of prefrontal cortex perform their integrative function and how the motor system is modulated by them is not yet clear. Conceivably the neural apparatus for some of the operations of attention and short-term memory makes use of the profuse array of reciprocal connections linking prefrontal cortex to several areas of associative neocortex as well as to the hippocampus and limbic cortex. On the other hand, a role of prefrontal cortex in motor set and in the organization of movement would most likely be carried out primarily through descending efferent connections to the basal ganglia (especially the striatum), the hypothalamic region, the midbrain, and the pons. It is probably by way of these efferent connections that the prefrontal cortex exerts its influence on the motor system and determines the timing and configuration of the individual motor act within a behavioral structure such as that exemplified by a trial in a delay task. That motor act, however, must be considered the product of a series of complex integrations in a temporal order of sensory, cognitive, and motor processes with a unifying behavioral goal. The prefrontal cortex appears essential for such integrations.

Summary Several of the anatomically demonstrated connections of prefrontal cortex to cortical and subcortical structures have been confirmed by electrophysiological methods. Such methods have also provided evidence of multiple inputs of sensory origin (with a degree of cross-modality convergence) on prefrontal areas and units. Prefrontal influences have been shown to modulate the activity of diencephalic and striatal units. Electrophysiological studies have identified two functionally distinct (architectonically transitional) areas in outskirts of prefrontal cortex. One in the orbital cortex gives rise to inhibitory influences over sensory and motor systems. It is part of a large basal area, including limbic cortex, that seems to be the source of inhibition over a variety of somatic and autonomic functions. The other area roughly coincides with Brodmann’s area 8 and is evidently involved in the control of eye movements. Slow surface-negative potentials can be recorded from prefrontal cortex in the interval between tem-

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porally separate events that by conditioning have been In my view though, it should be modified to account tied to one another in a relationship of reciprocal for the critical importance of the temporal factor, for contingency. Insofar as a motor act in a behavioral it is usually in the context of a temporally extended task is preceded and determined by stimuli thus re- behavioral structure that the frontal animal fails to lated, a slow prefrontal potential occurs between the act appropriately, i.e., in accord with the goal. As a consequence the structure loses its unity, becomes stimuli and before the motor act. Cells in prefrontal cortex show characteristic firing fragmented, and the goal is not attained. This is epitchanges in relation to performance of delay tasks. In omized by impaired performance of delay tasks, where a delayed-response trial, firing changes can be ob- the extended structure and the goal are prescribed by served concomitantly with presentation of the cue and the experimenter. The deficit can be best understood with execution of the subsequent response, suggesting as a failure to integrate temporally discontiguous items involvement of prefrontal cells in both sensorial atten- of information; this suggests that the function of pretion and motor action. Many cells show sustained frontal cortex is primarily one of temporal synthesis. activation during the delay interposed between cue The more general concept of a critical role of prefronand response. This activation is dependent on the tal cortex in the temporal organization of behavior has contingency that relates the two. In some cells dis- been expressed by other authors in the past, most of charge during the delay appears related to retention them basing their arguments on the difficulties that of the cue; in others it seems related to preparation frontal animals have in sequencing behavior (92, 143, for motor response. Cellular activity that occurs in 299, 306, 379). This concept is also in accord with the anticipation of motor response and that is differen- difficulties in temporal ordering and categorizing extially related to direction of response has also been perienced by patients with frontal damage (226, 247, demonstrated in delayed alternation. In general terms 248). For a more extensive discussion of the concept the discharge of a very substantial proportion of pre- and pertinent clinical literature, see reference 103a. frontal units during the delay of delay-task trials imTo better understand the synthetic function of preplicates neuronal populations of prefrontal cortex in frontal cortex that I am proposing, it is useful to temporal integration. This incorporates both the re- conceptualize all behavior as a hierarchical order of tention of critical information and the preparation of temporally structured units. The reflex act or some the organism for behaviorally consequent motor ac- form of cybernetic interaction with the environment may be considered the most elementary unit. Succestions. sive units with a limited and immediate goal make up larger units with a longer term goal; these in turn form DISCUSSION still larger and longer units, and so on. Thus a pyraWhat role does the prefrontal cortex play in the midal hierarchy of behavioral structures of increasing control of movement? How is the role played? Al- duration and complexity may be deemed to reflect a though the evidence we have reviewed is not sufficient corresponding hierarchy of goals. The prefrontal corto answer these two questions definitively, important tex is needed for formation of the higher structures in clues with regard to the first question can be found in that hierarchy, but only inasmuch as they require the lesion studies and, with regard to the second question, integration of temporally discontinuous information. in anatomy and electrophysiology. I now briefly out- Excluded therefore from this category are behavioral line a conceptual scheme largely based on these clues sequences, however long, in which one act leads to the next and none depends on a previous and distant event and attempt to solidify a few conclusions. in the series. Elaborate behavioral structures may be high in a hierarchy of motor programs (42), but what Temporal Synthesis of Behavior puts them under the purview of prefrontal cortex is One conclusion we can draw with confidence from not so much the complexity or even duration of motor lesion studies is that depriving an animal of pre frontal action but the fact that movement is contingent on cortex does not disable it to perform any motor act the integration of temporally distant elements of the that the normal animal can perform. As we have seen, structure. however, the animal without prefrontal cortex often Evidently prefrontal ablations elicit different behavfails to execute the right act at the right time, or it ioral deficits depending on the amount and parcel of fails to refrain from executing inappropriate acts. The cortex extirpated. Yet most, if not all, of the wellanimal has been rendered incapable of fully adjusting documented deficits in discrimination and delay tasks its motility to the circumstances. Pribram (300) ac- appear to reflect the impairment of one or another cordingly proposed that the prefrontal cortex is infunction or a combination of functions essential for volved in what he calls context-dependent behavior, temporal integration. In very extensive lesions the by analogy with certain computer operations. The idea deficit appears largely the result of diminished motiis plausible and has received some support from data vation or impairment of the complex processes of obtained when frontal animals were tested on perform- attention. In both animals and humans (91, 130, 226), ance of spatial tasks in varying contexts (7, 40,305). large prefrontal damage can induce severe disorders of

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motivation and attention. For subjects that have susSome of the patterns of sustained activation extained such damage, temporal integration is difficult hibited by units of prefrontal cortex during delay because of a lack of drive to formulate any complex between cue and motor response may represent neubehavioral structure or to attend to the critical cues ronal participation in the process of provisional memon the way to its goal. On the other hand, the analysis ory. The relations of such patterns to cue and performof effects of restricted prefrontal lesions, which has ance favor this possibility (102,277,278). Furthermore been widely carried out in the monkey and to a lesser some of those unit activations tend to decrease in the extent in carnivores, leads us to conclude that at least course of delay, thus suggesting the temporal course three fundamental functions of prefrontal cortex, with of a decaying memory function (103). In any event it somewhat different topographic representation, make seems unlikely that the neuronal populations of pretemporal integration possible. The first is a retrospec- frontal cortex act by themselves as the depositories of tive function of provisional memory; the second, a memory, even only for the short term. Rather they prospective function of anticipatory set; and the third, more likely participate in a mnemonic mechanism also a function that can best be characterized as the capac- involving neuronal populations elsewhere in the brain. ity to suppress interference. Motivation is essential for The prefrontal cortex may play its memory role priall the functions, and each incorporates a particular marily by interacting with other cortical areas. Deform or aspect of attention. They are briefly discussed pending on the sensory modality of the information to be retained, connective loops between prefrontal corbelow. tex and other association areas of parietal, temporal, PROVISIONAL MEMORY. The rationale for postulating and occipital cortex may be brought into play. The a memory function of prefrontal cortex lies almost rich array of reciprocal corticocortical connections of exclusively in the deficits of delayed-response and prefrontal cortex with those other areas (see subsecdelayed-matching performances resulting from lesions tion Connections, p. 1151) would provide the substrate of lateral cortex. Reversible lesion in the monkey was for the interactions. Also involved in memory function particularly revealing since it helped outline the tem- may be the connections between prefrontal cortex and poral characteristics of the function impaired. Jacob- hippocampus. It is attractive to speculate that these sen’s memory hypothesis (143, 144) is still viable and, connections are brought into play when and if a new not surprisingly, has been endorsed in one way or content of provisional memory is deposited and conother by many authors, including some of his most solidated in permanent storage, thus transcending the severe critics (113, 119, 139, 182,252,301).It obviously temporal context of the particular behavioral structure needs qualification, though. As we have seen, the that it originally served. memory deficit from prefrontal injury is not only Insofar as the motor constituents of a behavioral attributable in part to defective attention but also to structure depend on previous constituents of the structhe impairment of a very special form of mnemonic ture, their execution may be assumed to depend on retention. It is not the form of memory needed for the provisional memory function of prefrontal cortex. establishing new associations between stimuli or for Those previous constituents may be either critical learning new discriminations. Rather it is a form of sensory cues or information related to previous motor memory for which context is of the essence. It is not acts. The farther removed a motor act is from its short-term memory per se, though often referred to markers and precursors, the more its execution rethis way, but rather memory for the short term. Also quires the mnemonic function of prefrontal cortex. If it has been variously characterized as recent, transient, that function fails, as it does after prefrontal lesion, or operant memory. I prefer to call it provisional the structure dissolves and the motor act, if it occurs memory because this designation more aptly connotes at all, is likely to miss the objective or an indispensable its time-bracketed usefulness and context. Both time- step toward it. liness and term, its most essential features, are limited by the purpose or goal of the behavioral structure that PREPARATORY SET. Lesion studies as well as electrophysiological studies suggest an anticipatory function it serves. It is not yet clear whether the provisional memory of prefrontal cortex. Again much of the evidence defunction of prefrontal cortex is supramodal or specific rives from work in the monkey and relates to the for information of a given sensory modality (e.g., pro- involvement of prefrontal cortex in the organization of prioceptive memory). Our data indicate that it applies behavior. In the first place, lesion studies (204, 205, to spatial as well as nonspatial information (20, 106). 331) and electrophysiology (21, 347, 387) implicate a A study of prefront.al lesions in the human indicates portion of this cortex, the frontal eye field, in the that their detrimental effect on short-term memory is execution of orienting movements of the eyes (and supramodal (218). However, it is possible that separate head) that are an integral part of visual attention. The memory functions for different modalities have differ- teleological significance of this motility is clear: it ent representation within lateral prefrontal cortex. prepares the visual apparatus for anticipated input. Two studies in the monkey show that spatial and Then we have the evidence that single cells in more nonspatial memory tasks can be disrupted by different rostral areas of lateral prefrontal cortex participate in selective lesions of the prefrontal convexity (252,291). more central aspects of visual attending, less related

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to eye movement (102,323,364). Also the preparation for skeletal movement in the context of a behavioral task is accompanied by slow surface-negative potentials (such as the CNV and the “readiness potential”) over the frontal region (76,82, 150,308,395). Furthermore in both delayed response and delayed alternation, patterns of cell discharge have been observed that precede motor acts and that are related to them (193, 274, 275, 278). These patterns implicate prefrontal neuron participation in preparation for and perhaps initiation of movement. The anticipatory function I am postulating may be viewed as temporally symmetrical to and complementary of provisional memory. It consists in the presetting of sensory and motor apparatus for anticipated events in a behavioral structure. Although essentially a prospective function, it is rooted in the past. First of all it is from experience that the organism forms the schema for action. The idea of a schema is similar to that of presynthesis but does not have the restrictive connotation of a linguistic construct that Luria and Homskaya (226,227)gave it. Anticipation derives from that schema and from experience with some of the elements of the behavioral structure (see the chapter by Arbib in this Handbook). This way the organism is able to prepare for a range of contingencies, and I hypothesize that this is done under the agency of prefrontal cortex. Sensory organs are adjusted so that relevant information is best received and sensory systems modulated ahead of reception and movement. The motor system is set for impending movement. The function of the frontal eye field, which is implicated in visual attention and, at the same time, is a possible source of corollary discharge in preparation for motion (373, 374), may be conceived as a microcosm of the anticipatory function of prefrontal cortex in the formation of behavioral structures. We can only speculate about the mechanism involved in setting up sensory and motor systems. However, the connectivity of prefrontal cortex suggests certain pathways and structures most probably involved in the process. First in importance appears to be the efferent output to basal ganglia. Although these subcortical formations are well known to be involved in the control of skeletal movement, their possible role in perception cannot be ignored. At the very least they probably help coordinate the anticipatory ocular motility serving visual perception. Their afferents from prefrontal cortex, the eye field in particular, may be used in the process. In addition the basal ganglia, together with prefrontal cortex, may participate in certain forms of cognitive integration prior to movement. Buchwald and his colleagues (49) propose that the basal ganglia are critically involved in what they call “cognitive set.” More specifically they speculate that the striatum is important for the transfer of information across time, so that consequent movements can be executed. Changes in neuronal activity of basal ganglia during the transfer (delay) period of a delay task are in accord with this notion (348).


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Although the role of prefrontal cortex in motor set is probably mediated primarily by the basal ganglia, direct prefrontal efferents to the motor centers of the brain stem may also be involved. As can be inferred from its connections, the prefrontal cortex has access to the mechanisms of motor integration at multiple levels: the basal ganglia and, through them, lateral thalamus and motor cortex, as well as the lower centers of the diencephalic, mesencephalic, and pontine tegmentum. Thus having critically participated in the choice of a specific movement or category of movement-in functional cooperation with other cortical areas-the prefrontal cortex can put a given sector of the motor system, at all levels, in a state of readiness such that the movement is executed with speed and purpose within the context of the overall structure of behavior. For further discussion on the tuning and priming that the state of readiness entails at one level, namely the motor cortex, the reader is referred to the chapters by Evarts and by Wiesendanger in this Handbook. If the prefrontal cortex has the role that we suppose in determining set, choice, and timeliness of movement (see the next section), it is also reasonable to suppose that it has a decisive role in the initiation of at least some motor acts. Still, the evidence in this regard is inconclusive. The demonstration that prefrontal units initiate discharge some tens or hundreds of milliseconds before muscular contraction does not confirm the idea (191,193). The large variability of such latencies, and the fact that this variability widely overlaps that observed by study of units in other structures (including motor cortex and caudate nucleus) make the argument difficult. Nevertheless, even if within certain behavioral structures a command to move originates in prefrontal cortex, that command should be considered the product of multiple interactions of prefrontal cortex with other cerebral components, cortical and subcortical. Thus the quest for a prefrontal executive is pointless. Only by reasoning this way do we avoid an infinite regress of ever higher executives or the implausible notion of prefrontal cortex in a pontifical position. INTERFERENCE CONTROL. A variety of extraneous influences can disrupt the orderly synthesis and execution of a behavioral structure. The longer the structure, the more vulnerable it generally is to interference. As we have seen, the integrity of prefrontal cortex is essential for protection against interference from both inside and outside the organism. We can conclude that this is one of the important functions of prefrontal cortex in the organization of behavior. The available evidence indicates that this function is based primarily in ventral and medial areas. In the exercise of temporally extended, goal-directed behavior, the organism has to contend with environmental stimuli that are unrelated to current behavior and that may draw attention away from it. The frontal animal is abnormally distracted by such stimuli, and

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when these are not controlled, the animal shows poor task performance and reactive hyperactivity (99, 118, 137, 167). Another source of interference is the presence of stimuli that are similar, but not equivalent, to certain sensory elements of the behavioral structure in progress. The extraneous stimuli compete with these elements and can distort the structure of behavior and prevent attainment of the goal. Extraneous stimuli can interfere at any time in structure formation, often during the intervals that separate critical substructures. Thus a delayed-response trial is notably vulnerable to interference during the delay (18, 106, 185, 228). In short the animal deprived of prefrontal cortex is inordinately susceptible to all forms of external interference because it lacks the normal capacity to suppress them. The animal with prefrontal lesion is also ill equipped to suppress internal interference, especially if the lesion involves medial or orbital cortex. Among the internal sources of interference are mnemonic traces that, by virtue of their associations with parts of the ongoing structure, can contaminate or divert it. Old motor habits and response tendencies may also play a disruptive role. In the absence of defense against these kinds of interference, performance is impaired, especially reversal tasks, spatial and object alternation, and successive discrimination. It is on the basis of deficits in such tasks that Mishkin (251) devised the notion of a role of prefrontal cortex in protecting behavior from what he called “perseveration of central sets.” Unfortunately this terminology contains ambiguities. “Central set” has not been precisely defined, and the term “perseveration” connotes stereotypies of behavior hardly peculiar to the prefrontal syndrome. However, the concept of a prefrontal mechanism for controlling a tendency to perform untimely acts is an exceedingly useful one and helps explain a variety of abnormalities of motor performance in both animals and humans with injured prefrontal cortex. Finally, purposeful behavior must be protected from instinctual impulses, and some suppression of such impulses is also necessary for communal life and survival of the animal. In the presence of a guiding goal, the animal must forego acting on impulses competing with that goal. whether the behavior to attain the goal is inborn or hcquired. The animal also has to refrain from excesses that can elicit conflict with other animals. The animal with basal or medial prefrontal lesion might be unable to do either. Uncontrolled alimentary, aggressive, or flight impulses account for some abnormal emotional behavior. The same impulses, demanding immediate gratification, can short circuit the route toward the goal of a temporally extended configuration of behavior. Such evidence led Brutkowski (44,45) to postulate inhibition of drive as a basic function of prefrontal cortex. To conclude, the restraint from untimely action and excessive emotional behavior can be ascribed to ventromedial prefrontal cortex and the subcortical struc-

tures connected to it, which constitute what Rosvold (317, 320) called the “orbital system.” The prefrontal inhibition of untimely acts is probably effected by outflow to striatum, whereas that of emotional behavior is probably effected by outflow to the hypothalamus, the subthalamus (notably substantia nigra), and portions of the brain stem associated with the limbic system (267). We should keep in mind that some of those same diencephalic and limbic regions almost certainly form the substrate giving rise to the motivational force behind the formation of any behavioral structure. These regions also provide the prefrontal cortex with information on the state of the internal milieu. Therefore it is a reasonable possibility that, in the making of a behavioral structure, a vital two-way traffic of information travels along the pathways of the prefrontodiencephalic axis at the base of the brain; ascending impulses initiate and maintain the behavioral structure, descending impulses check interfering drives and untimely acts, and ascending feedback signals inform prefrontal cortex that the synthesis has been completed and its goal has been attained. SUMMARY AND CONCLUSIONS

The prefrontal cortex is one of the latest neocortical regions to develop, both phylogenetically and ontogenetically. It reaches maximum growth in the human brain. Its myelination is not complete until long after birth. In primates it is typical six-layered isocortex with a prominent internal granular layer. The prefrontal cortex is connected in reciprocal fashion to thalamus, limbic structures, hypothalamus, and tegmental formations of the brain stem. Profuse reciprocal connections also link it to other regions of associative neocortex. Unidirectional fiber connections flow from prefrontal cortex to the basal ganglia, particularly the striatum. Lesions of prefrontal cortex result in changes of general motility and emotional behavior, as well as demonstrable deficits in performance of structured behavioral tasks. These effects are manifestations of underlying disorders in interrelated processes of attention, short-term memory, and suppression of interference. The character of a lesion-induced disorder depends to some degree on the location and magnitude of the lesion. A common symptom of such a disorder, not easily ascribable to any particular prefrontal locus, is motor hyperactivity; this is largely due to excessive reactivity to stimuli and is therefore related to abnormal distractibility, which is another common symptom. Total ablations of prefrontal cortex generally induce an apparent loss of motivation and a dulling of all emotional behavior. Lesions circumscribed to medial or ventral prefrontal cortex disinhibit certain forms of emotional behavior and untimely motor tendencies in the context of behavioral tasks. Lesions of dorsolateral prefrontal cortex, on the other hand, cause certain cognitive disorders resulting in defective

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performance of delay tasks. The characteristic deficit integration of temporally discontinuous information, in delayed response portends a fundamental disorder the dorsolateral prefrontal cortex is indispensable for in temporal integration attributable to at least two their orderly execution. This cortex is the substrate factors: defective attention and defective memory for for cognitive operations of provisional memory and preparatory set that allow the appropriate choice, the short term (provisional memory). Electrophysiological studies substantiate the con- timing, and execution of motor action. On the other nections of prefrontal cortex and reveal the functional hand, the cortex of medial and ventral areas appears identity of two prefrontal districts: a portion of baso- indispensable for the protection of purposive behavior medial cortex that is a source of inhibition over so- from competing drives and from the tendency to exematic and vegetative systems, and the frontal eye field cute untimely acts. The available evidence also indi(almost coinciding with Brodmann’s cytoarchitectonic cates that the preparatory set for movement and the area a), which is implicated in oculomotor control and prevention of untimely acts are primarily mediated by visual attention. Certain neuroelectrical phenomena efferents from prefrontal cortex to basal ganglia. The during behavioral performance reflect the involvement control of competing drives and emotional behavior, of prefrontal cortex in temporal integration. Among on the other hand, is probably accomplished by way these phenomena are slow surface-negative potentials of prefrontal efferents to the limbic system and the and prolonged unit activations between temporally diencephalon. separate and mutually contingent events. By appropriately manipulating behavioral variables, it has been This chapter was written during tenure of a Research Scientist shown that some prefrontal units fire in relation to the Award from the National Institute of Mental Health. My research memorization of a critical event, whereas others fire on the prefrontal cortex of primates has been supported by grants in relation to the preparation for a consequent motor from the National Science Foundation. I am gratefully indebted to Drs. Donald B. Lindsley, James T. Marsh, Mortimer Mishkin, Walle act. J. H. Nauta, Karl H. Pribram, and John M. Warren for their In conclusion the experimental evidence obtained valuable comments. Special thanks are due to Mrs. Pat L. Walter of thus far indicates that the prefrontal cortex is essential the UCLA Brain Information Service for help in the literature for the temporal organization of complex behavior. To search and to Ms. Jill Penkhus for the brain drawings of the first the extent that motor acts are dependent on the figure. REFERENCES

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