Abstract: The physiology of the cerebral cortex is organized in hierarchical manner. At the bottom of the cortical organization, sensory and motor areas support specific sensory and motor functions. Progressively higher areas—of later phylogenetic and ontogenetic development—support functions that are progressively more integrative. The prefrontal cortex (PFC) constitutes the highest level of the cortical hierarchy dedicated to the representation and execution of actions. The PFC can be subdivided in three major regions: orbital, medial, and lateral. The orbital and medial regions are involved in emotional behavior. The lateral region, which is maximally developed in the human, provides the cognitive support to the temporal organization of behavior, speech, and reasoning. This function of temporal organization is served by several subordinate functions that are closely intertwined (e.g., temporal integration, working memory, set). Whatever areal specialization can be discerned in the PFC is not so much attributable to the topographical distribution of those functions as to the nature of the cognitive information with which they operate. Much of the prevalent confusion in the PFC literature derives from two common errors. The first is to argue for one particular prefrontal function while opposing or neglecting others that complement it; the second is to localize any of them within a discrete portion of PFC. The functions of the PFC rely closely on its connections with a vast array of other cerebral structures. None of its cognitive functions can be understood if taken out of a broad connectionist context. Any hypothetical modularity of the PFC is functionally meaningless if taken out of wide-ranging networks that extend far beyond the confines of any given prefrontal area. This is the reason why the discussion of the operations of the PFC is here preceded by the placement of the PFC in a cortical connectionist map of cognitive representations. After reviewing the anatomy and connectivity of the PFC, I discuss its highest and most general functions, which are inferred mainly from neuropsychological studies. Then I proceed with a conceptual model of the cognitive organization of the neocortex, which derives from those studies as well as from our knowledge of cortical connectivity. Next, I deal with the dynamics of the PFC in cognitive operations and with current evidence on the functional specificity of its areas. The review concludes with recent insights from physiological research on monkeys into the prefrontal mechanisms of temporal integration. Although the focus here is on the PFC of the primate, it is reasonable to assume that many of the principles discussed below apply also to the PFC of nonprimate species. The PFC is the association cortex of the frontal lobe. In primates, it comprises areas 8–13, 24, 32, 46, and 47 according to the cytoarchitectonic map of Brodmann 1909Brodmann K. Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Barth, Leipzig1909Google Scholar, recently updated for the monkey by Petrides and Pandya (Figure 1). Phylogenetically, it is one of the latest cortices to develop, having attained maximum relative growth in the human brain (Brodmann 1912Brodmann K. Neue Ergebnisse uber die vergleichende histologische Lokalisation der Grosshirnrinde mit besonderer Berucksichtigung des Stirnhirns.Anat. Anz. Suppl. 1912; 41: 157-216Google Scholar, Jerison 1994Jerison H.J. Evolution of the brain.in: Zaidel D.W. Neuropsychology. Academic Press, Inc, San Diego1994Google Scholar), where it constitutes nearly one-third of the neocortex. Furthermore, the PFC undergoes late development in the course of ontogeny. In the human, by myelogenic and synaptogenic criteria, the PFC is clearly late-maturing cortex (Flechsig 1920Flechsig P. Anatomie des Menschlichen Gehirns und Rckenmarks auf Myelogenetischer Grundlage. Thieme, Leipzig1920Google Scholar, Conel 1939Conel J.L. The Postnatal Development of the Human Cerebral Cortex, Volumes 1–6. Harvard University Press, Cambridge, MA1939Google Scholar, Huttenlocher 1990Huttenlocher P.R. Morphometric study of human cerebral cortex development.Neuropsychologia. 1990; 28: 517-527Crossref PubMed Scopus (841) Google Scholar, Huttenlocher and Dabholkar 1997Huttenlocher P.R. Dabholkar A.S. Regional differences in synaptogenesis in human cerebral cortex.J. Comp. Neurol. 1997; 387: 167-178Crossref PubMed Scopus (2010) Google Scholar). In the monkey's PFC, myelogenesis also seems to develop late (Gibson 1991Gibson K.R. Myelination and behavioral development a comparative perspective on questions of neoteny, altriciality and intelligence.in: Gibson K.R. Petersen A.C. Brain Maturation and Cognitive Development. Aldine de Gruyter, New York1991Google Scholar). However, the assumption that the synaptic structure of the PFC lags behind that of other neocortical areas has been challenged with morphometric data (Bourgeois et al. 1994Bourgeois J.P. Goldman-Rakic P.S. Rakic P. Synaptogenesis in the prefrontal cortex of rhesus monkeys.Cereb. Cortex. 1994; 4: 78-96Crossref PubMed Scopus (518) Google Scholar). In any case, imaging studies indicate that, in the human, prefrontal areas do not attain full maturity until adolescence (Chugani et al. 1987Chugani H.T. Phelps M.E. Mazziotta J.C. Positron emission tomography study of human brain functional development.Ann. Neurol. 1987; 22: 487-497Crossref PubMed Scopus (1197) Google Scholar, Paus et al. 1999Paus T. Zijdenbos A. Worsley K. Collins D.L. Blumenthal J. Giedd J.N. Rapoport J.L. Evans A.C. Structural maturation of neural pathways in children and adolescents In vivo study.Science. 1999; 283: 1908-1911Crossref PubMed Scopus (1016) Google Scholar, Sowell et al. 1999Sowell E.R. Thompson P.M. Holmes C.J. Jernigan T.L. Toga A.W. In vivo evidence for post-adolescent brain maturation in frontal and striatal regions.Nat. Neurosci. 1999; 2: 859-861Crossref PubMed Scopus (1065) Google Scholar). This conclusion is consistent with the behavioral evidence that these areas are critical for those higher cognitive functions that develop late, such as propositional speech and reasoning. The profuse variety of connections of the PFC is obviously related to the variety of the information it integrates. For detailed accounts of PFC connections in the primate, the reader may wish to consult other reviews (Pandya and Yeterian 1985Pandya D.N. Yeterian E.H. Architecture and connections of cortical association areas.in: Peters A. Jones E.G. Cerebral Cortex, Volume 4. Plenum Press, New York1985Google Scholar, Fuster 1997Fuster J.M. The Prefrontal Cortex-Anatomy Physiology, and Neuropsychology of the Frontal Lobe. Third Edition. Lippincott-Raven, Philadelphia1997Google Scholar, Mesulam 1998Mesulam M.-M. From sensation to cognition.Brain. 1998; 121: 1013-1052Crossref PubMed Scopus (1917) Google Scholar, Barbas 2000Barbas H. Connections underlying the synthesis of cognition, memory, and emotion in primate prefrontal cortices.Brain Res. Bull. 2000; 52: 319-330Crossref PubMed Scopus (511) Google Scholar). Here, I will only consider some of the extrinsic prefrontal connections. The PFC is connected with the brainstem, the thalamus, the basal ganglia, and the limbic system. Much of that connectivity with subcortical structures is reciprocal. Especially well organized topologically are the connections between the PFC and the thalamus. The prefrontal connections with the mediodorsal thalamic nucleus have been used as a criterion for identifying the PFC in a wide variety of species (Fuster 1997Fuster J.M. The Prefrontal Cortex-Anatomy Physiology, and Neuropsychology of the Frontal Lobe. Third Edition. Lippincott-Raven, Philadelphia1997Google Scholar). The functional role of the afferent connections of the PFC can be broadly inferred from the functions of the contributing structures. In the aggregate, the afferent connections from the brainstem, the diencephalon and the limbic system convey to the PFC information about the internal environment, the level of arousal, the drives and motives of the animal, and the visceral concomitants of emotion. Especially relevant for the behavioral integrative functions of the PFC are its afferent connections from the amygdala and the hypothalamus. The amygdala projects to the ventral and medial aspects of the PFC (Porrino et al. 1981Porrino L.J. Crane A.M. Goldman-Rakic P.S. Direct and indirect pathways from the amygdala to the frontal lobe in rhesus monkeys.J. Comp. Neurol. 1981; 198: 121-136Crossref PubMed Scopus (376) Google Scholar, Ray and Price 1993Ray J.P. Price J.L. The organization of projections from the mediodorsal nucleus of the thalamus to orbital and medial prefrontal cortex in macaque monkeys.J. Comp. Neurol. 1993; 337: 1-31Crossref PubMed Scopus (317) Google Scholar), and so does the hypothalamus (Kievit and Kuypers 1975Kievit J. Kuypers H.G.J.M. Basal forebrain and hypothalamic connections to frontal and parietal cortex in the rhesus monkey.Science. 1975; 187: 660-662Crossref PubMed Scopus (308) Google Scholar, Jacobson et al. 1978Jacobson S. Butters N. Tovsky N.J. Afferent and efferent subcortical projections of behaviorally defined sectors of prefrontal granular cortex.Brain Res. 1978; 159: 279-296Crossref PubMed Scopus (60) Google Scholar). In all likelihood, these connections carry to the frontal lobe information not only about internal states but about the motivational significance of sensory stimuli. These connections probably play a major role in the representation and enactment of emotional behavior (Le Doux 1993Le Doux J.E. Emotional memory systems in the brain.Behav. Brain Res. 1993; 58: 69-79Crossref PubMed Scopus (618) Google Scholar). The connections of the PFC with the hippocampus are also of major behavioral relevance. All prefrontal regions receive projections from the hippocampus, either directly or indirectly (Rosene and Van Hoesen 1977Rosene D.L. Van Hoesen G.W. Hippocampal efferents reach widespread areas of cerebral cortex and amygdala in the rhesus monkey.Science. 1977; 198: 315-317Crossref PubMed Scopus (514) Google Scholar, Amaral 1987Amaral D.G. Memory anatomical organization of candidate brain regions.in: Volume V: Higher Functions of the Brain, Part 1, F. Plum, ed Handbook of Physiology Nervous System. Amer. Physiol. Soc, Bethesda1987Google Scholar, Barbas and Blatt 1995Barbas H. Blatt G.J. Topographically specific hippocampal projections target functionally distinct prefrontal areas in the rhesus monkey.Hippocampus. 1995; 5: 511-533Crossref PubMed Scopus (323) Google Scholar). The PFC is connected with other cortices of association, but not with primary sensory or motor cortices. Each of the major prefrontal regions—medial, orbital, and lateral—is connected with itself and with the other two (Jacobson and Trojanowski 1977aJacobson S. Trojanowski J.Q. Prefrontal granular cortex of the rhesus monkey. I. Intrahemispheric cortical afferents.Brain Res. 1977; 132 (a): 209-233Crossref PubMed Scopus (163) Google Scholar, Jacobson and Trojanowski 1977bJacobson S. Trojanowski J.Q. Prefrontal granular cortex of the rhesus monkey II. Interhemispheric cortical afferents.Brain Res. 1977; 132 (b): 235-246Crossref PubMed Scopus (48) Google Scholar, Pandya and Yeterian 1985Pandya D.N. Yeterian E.H. Architecture and connections of cortical association areas.in: Peters A. Jones E.G. Cerebral Cortex, Volume 4. Plenum Press, New York1985Google Scholar). Some of the corticocortical connectivity of the PFC is interhemispheric, and almost all of it is reciprocal and topologically organized (Pandya and Yeterian 1985Pandya D.N. Yeterian E.H. Architecture and connections of cortical association areas.in: Peters A. Jones E.G. Cerebral Cortex, Volume 4. Plenum Press, New York1985Google Scholar, Cavada and Goldman-Rakic 1989aCavada C. Goldman-Rakic P.S. Posterior parietal cortex in rhesus monkey I. Parcellation of areas based on distinctive limbic and sensory corticocortical connections.J. Comp. Neurol. 1989; 287 (a): 393-421Crossref PubMed Scopus (595) Google Scholar, Cavada and Goldman-Rakic 1989bCavada C. Goldman-Rakic P.S. Posterior parietal cortex in rhesus monkey II. Evidence for segregated corticocortical networks linking sensory and limbic areas with the frontal lobe.J. Comp. Neurol. 1989; 287 (b): 422-445Crossref PubMed Scopus (847) Google Scholar). In general, connections between association cortices both originate and terminate in upper cortical layers, especially II and III (Jones 1981Jones E.G. Anatomy of cerebral cortex Columnar input-output organization.in: Schmitt F.O. Worden F.G. Adelman G. Dennis S.G. The Organization of the Cerebral Cortex. MIT Press, Cambridge, MA1981Google Scholar, Andersen et al. 1985Andersen R.A. Asanuma C. Cowan W.M. Callosal and prefrontal associational projecting cell populations in area 7A of the macaque monkey A study using retrogradely transported fluorescent dyes.J. Comp. Neurol. 1985; 232: 443-455Crossref PubMed Scopus (214) Google Scholar). Those connections presumably constitute the structural frame of cognitive networks (Fuster 1995Fuster J.M. Memory in the Cerebral Cortex—An Empirical Approach to Neural Networks in the Human and Nonhuman Primate. MIT Press, Cambridge, MA1995Google Scholar). As the memory networks of posterior cortex acquire associations with action, they extend into PFC to shape the networks of executive memory. What we know about the higher integrative functions of the PFC is inferred mainly from neuropsychological studies in the human. Because of large variations in the location, extent, and clinical manifestations of prefrontal damage, that knowledge is the distillate of a vast literature. In essence, three distinct clusters of symptoms can be observed after lesions of the three major regions of the PFC: orbital or inferior, medial/cingulate, and lateral (Figure 2). Although many reported cases are mixed in terms of cortex affected and clinical picture, the three prefrontal “syndromes” provide insights into the major and most general functions of those regions. Ever since Harlow 1848Harlow J.M. Passage of an iron rod through the head.Boston Med. Surg. J. 1848; 39: 389-393Crossref Google Scholar described the famous case of Phineas Gage, it has been known that lesions of orbital PFC often induce dramatic changes of personality (Damasio et al. 1994Damasio H. Grabowski T. Frank R. Galaburda A.M. Damasio A.R. The return of Phineas Gage Clues about the brain from the skull of a famous patient.Science. 1994; 264: 1102-1105Crossref PubMed Scopus (935) Google Scholar, Fuster 1997Fuster J.M. The Prefrontal Cortex-Anatomy Physiology, and Neuropsychology of the Frontal Lobe. Third Edition. Lippincott-Raven, Philadelphia1997Google Scholar). Subjects with such lesions are impulsive and disinhibited in a host of instinctual behaviors. They are irritable and contentious, with a characteristic tendency to coarse humor and disregard for social and moral principles. Their impulsiveness frequently leads them to reckless high-risk behavior and conflicts with the law. In addition, orbitofrontal patients almost uniformly exhibit a severe disorder of attention. This disorder is characterized by the failure to withstand interference from distraction. Monkeys with orbitofrontal damage show similar difficulties as do people with comparable damage in the control of instinctual impulses and internal or external distraction. The orbitofrontal cortex exerts its functions of inhibitory control via its efferents to the hypothalamus, the basal ganglia, and other neocortical areas, some in the PFC itself. The medial region of the PFC, which includes the most anterior portion of the cingulate gyrus, also appears involved in general motility, attention, and emotion. Lesions of this region commonly lead to loss of spontaneity and difficulty in the initiation of movements and speech (Verfaellie and Heilman 1987Verfaellie M. Heilman K.M. Response preparation and response inhibition after lesions of the medial frontal lobe.Arch. Neurol. 1987; 44: 1265-1271Crossref PubMed Scopus (90) Google Scholar, Cummings 1993Cummings J.L. Frontal-subcortical circuits and human behavior.Arch. Neurol. 1993; 50: 873-880Crossref PubMed Scopus (1892) Google Scholar). Large and bilateral lesions lead to akinetic mutism. Patients with medial/cingulate lesions are commonly apathetic, disinterested in the environment, and unable to concentrate their attention on behavioral or cognitive tasks. Conversely, the neuroimaging of normal subjects by positron emission tomography (PET) or functional magnetic resonance (fMRI) shows marked activations of the anterior cingulate in tasks that demand sustained effort and concentrated attention (Posner et al. 1988Posner M.I. Petersen S.E. Fox P.T. Raichle M.E. Localization of cognitive operations in the human brain.Science. 1988; 24: 1627-1631Crossref Scopus (1018) Google Scholar, Raichle 1994Raichle M.E. Images of the mind Studies with modern imaging techniques.Annu. Rev. Psychol. 1994; 45: 333-356Crossref PubMed Scopus (110) Google Scholar). Such evidence led to the formulation of an “anterior attentional system” (Posner and Petersen 1990Posner M.I. Petersen S.E. The attention system of the human brain.Annu. Rev. Neurosci. 1990; 13: 25-42Crossref PubMed Scopus (5386) Google Scholar), of which the anterior cingulate region would be an essential part (further discussion below). Lesions of the lateral region induce the most characteristic cognitive deficits from frontal lobe injury. In humans with large lateral prefrontal damage, the most common disorder is the inability to formulate and to carry out plans and sequences of actions. Luria 1966Luria A.R. Higher Cortical Functions in Man. Basic Books, New York1966Google Scholar was the first to investigate and describe this disorder in a large number of patients. The deficit in planning, which extends to the representation and construction of sequences of spoken and written language (Luria 1970Luria A.R. Traumatic Aphasia. Mouton, The Hague1970Crossref Google Scholar), is now widely recognized as a constant manifestation of large lateral PFC damage. It has two major aspects: one is the difficulty to consciously represent sequences of speech or behavior, especially if they are novel or complex; the other is the difficulty to initiate them and to execute them in orderly manner. These difficulties constitute what has been termed the dysexecutive syndrome (Baddeley 1986Baddeley A. Working Memory. Clarendon Press, Oxford1986Google Scholar), which is usually accompanied by a severe attention disorder that Shallice 1988Shallice T. From Neuropsychology to Mental Structure. Cambridge University Press, New York1988Crossref Google Scholar characterizes as a loss of “supervisory attentional control.” In sum, from the neuropsychological evidence, it can be concluded that the lateral PFC plays a crucial role in the organization and execution of behavior, speech, and reasoning. The cortex of the human appears divided by the Rolandic fissure into two major parts, each dedicated to a separate broad category of functions: the cortex of the occipital, temporal, and parietal lobes, dedicated to “sensory” functions; and the cortex of the frontal lobe, dedicated to “motor” functions. This dichotomy of cortices seems to represent the evolutionary expansion into the telencephalon of the dichotomy of structures that spans the entire length of the nerve axis from the spinal cord upwards: a posterior sensory moiety and an anterior motor one. On the basis of a large body of anatomical, electrophysiological, and neuropsychological evidence reviewed elsewhere (Fuster 1995Fuster J.M. Memory in the Cerebral Cortex—An Empirical Approach to Neural Networks in the Human and Nonhuman Primate. MIT Press, Cambridge, MA1995Google Scholar), it is reasonable to treat the cortex behind the Rolandic fissure as the substrate for perceptual memory, and the frontal cortex for executive memory (Figure 3). According to this view, neuronal networks of perceptual memory are formed in postrolandic cortex and organized hierarchically over a base layer of primary sensory cortices (phyletic sensory memory). Progressively higher areas accommodate progressively more general categories of memory, including episodic and semantic memory—which together constitute declarative memory. That upward expansion of perceptual memory networks occurs along well-identified paths of corticocortical connection. Although the general categories of both memory and knowledge are hierarchically organized, individual items of memory or knowledge are to some degree heterarchical. Autobiographical memory contains both semantic and sensory components intermixed. Thus, the memory of an episode in one's life is probably represented by a cortical network that spans several levels of the perceptual hierarchy. The counterpart of the perceptual memory hierarchy in posterior cortex is an executive memory hierarchy in frontal cortex. Motor networks grow toward cortex of association (PFC) on a base of primary motor cortex (phyletic motor memory). At the lower level of that hierarchy, movements are defined mainly by the action of muscles or muscle groups. At higher levels, in premotor cortex, executive networks represent acts and programs of movement defined by goal and trajectory. Networks in some premotor areas represent elementary linguistic structures (notably “Broca's area,” area 45). From the neuropsychological research briefly reviewed in the previous section, the lateral PFC appears to harbor networks representing schemas, plans, and concepts of action. In sum, the neuroanatomy and neuropsychology of the frontal lobe strongly suggest the upward hierarchical layering of executive memory, from the innate representation of elementary movement in motor cortex to the representation of sequential action in the PFC. That upward layering appears to take place in several interrelated domains of action (e.g., skeletal, linguistic), each containing executive representations of varying degrees of specificity and abstraction. As in posterior cortex, however, the organization of representations in frontal cortex does not appear strictly hierarchical, at least inasmuch as hierarchical representation implies serial processing from the top down. In the execution of complex actions, the activations of prefrontal, premotor, and motor networks do not always follow a strict temporal sequence (Kalaska et al. 1998Kalaska J.F. Sergio L.E. Cisek P. Cortical control of whole-arm motor tasks.Novartis Foundation Symp. 1998; 218: 176-190PubMed Google Scholar). Even at the lowest cortical level (motor cortex), actions seem to be represented, to a degree, in terms of direction of movement (Georgopoulos et al. 1982Georgopoulos A.P. Kalaska J.F. Caminiti R. Massey J.T. On the relations between the direction of two-dimensional arm movements and cell discharge in primate motor cortex.J. Neurosci. 1982; 2: 1527-1537Crossref PubMed Google Scholar). Thus, it is reasonable to suppose that executive networks, like perceptual networks, are to some degree heterarchical. Imaging studies show that lateral prefrontal and premotor areas are activated at the beginning of the learning of a motor sequence; with practice and repetition, however, that activation subsides, while that of subcortical structures, notably the basal ganglia, increases (Grafton et al. 1992Grafton S.T. Mazziotta J.C. Presty S. Friston K.J. Frackowiak R.S.J. Phelps M.E. Functional anatomy of human procedural learning determined with regional cerebral blood flow and PET.J. Neurosci. 1992; 12: 2542-2548PubMed Google Scholar, Jenkins et al. 1994Jenkins I.H. Brooks D.J. Nixon P.D. Frackowiak R.S.J. Passingham R.E. Motor sequence learning A study with positron emission tomography.J. Neurosci. 1994; 14: 3775-3790PubMed Google Scholar, Iacoboni et al. 1996Iacoboni M. Woods R.P. Mazziotta J.C. Brain-behavior relationships Evidence from practice effects in spatial stimulus-response compatibility.J. Neurophysiol. 1996; 76: 321-331PubMed Google Scholar, Petersen et al. 1998Petersen S.E. van Mier H. Fiez J.A. Raichle M.E. The effects of practice on the functional anatomy of task performance.Proc. Natl. Acad. Sci. USA. 1998; 95: 853-860Crossref PubMed Scopus (414) Google Scholar). Thus, as sequences become overlearned and automatic, their representation seems to “migrate” to lower executive stages. The same imaging studies also show that, even after repetition and automation of their performance, sequences retain a degree of representation in lateral PFC. Whereas the automatic aspects of motor behavior may have been relegated to lower structures, the more abstract and schematic representations of sequential action, as well as the general rules and contingencies of motor tasks, appear to remain represented in prefrontal networks. The theoretical scheme of memory representations just outlined may be considered a static cognitive map. It represents long-term memory after consolidation. Also, however, it is a changing and dynamic map, because the cortical networks of perceptual and executive memory constitute the anatomical substrate for all cognitive functions (e.g., perception, attention, reasoning, language). Cognitive functions activate those representational networks, which by their activation become operational. One of the cognitive operations is the acquisition of new memory, which cannot take place without the prior or concomitant retrieval of old memory. New memories consist invariably of the update and expansion of old ones, which new experience activates by associative recognition and recall. The same can be said for their hypothetical supporting networks. Many neuroimaging studies deal with the putative role of the PFC in the formation and recall of long-term memory (Tulving et al. 1994Tulving E. Kapur S. Craik F.I.M. Moscovitch M. Houle S. Hemispheric encoding/retrieval asymmetry in episodic memory Positron emission tomography findings.Proc. Natl. Acad. Sci. USA. 1994; 91: 2016-2020Crossref PubMed Scopus (1280) Google Scholar, Kapur et al. 1995Kapur S. Craik F.I.M. Jones C. Brown G.M. Houle S. Tulving E. Functional role of the prefrontal cortex in retrieval of memories a PET study.NeuroReport. 1995; 6: 1880-1884Crossref PubMed Scopus (303) Google Scholar, Buckner et al. 1995Buckner R.L. Petersen S.E. Ojemann J.G. Miezin F.M. Squire L.R. Raichle M.E. Functional anatomical studies of explicit and implicit memory retrieval tasks.J. Neurosci. 1995; 15: 12-29PubMed Google Scholar, Fletcher et al. 1998aFletcher P.C. Shallice T. Dolan R.J. The functional roles of prefrontal cortex in episodic memory. I.Encoding Brain. 1998; 121 (a): 1239-1248Crossref PubMed Scopus (269) Google Scholar, Fletcher et al. 1998bFletcher P.C. Shallice T. Frith C.D. Frackowiak R.S.J. Dolan R.J. The functional roles of prefrontal cortex in episodic memory. II.Retrieval Brain. 1998; 121 (b): 1249-1256PubMed Google Scholar). In these studies, the experimental subject is typically asked to remember sensory material for subsequent recall. There may be the additional requirement of mentally organizing or categorizing the material. Functional imaging methods are then utilized to determine levels of cortical activity—in terms of blood flow—during performance of those cognitive operations. A common procedure is to compare—by subtraction—the activity of a given area under one condition with the activity of the same area under another. Two relatively consistent observations have been made: (1) encoding new memory activates the left more than the right PFC; (2) conversely, retrieving stored memory activates the right more than the left PFC. These asymmetric encoding/retrieval activations of PFC cooccur with activations of other cortical areas. The greater left PFC activation in encoding may reflect the greater demands of this operation on semantic (verbal) memory (Gabrieli et al. 1998Gabrieli J.D.E. Poldrack R.A. Desmond J.E. The role of left prefrontal cortex in language and memory.Proc. Natl. Acad. Sci. USA. 1998; 95: 906-913Crossref PubMed Scopus (692) Google Scholar)—which is represented mainly in the left hemisphere. Probably because of it, that activation is enhanced by semantically organizing the material encoded (Fletcher et al. 1998aFletcher P.C. Shallice T. Dolan R.J. The functional roles of prefrontal cortex in episodic memory. I.Encoding Brain. 1998; 121 (a): 1239-1248Crossref PubMed Scopus (269) Google Scholar). The right PFC activation in retrieval, on the other hand, seems attributable to the internal monitoring of retrieved material with respect to a preestablished semantic organization (Fletcher et al. 1998bFletcher P.C. Shallice T. Frith C.D. Frackowiak R.S.J. Dolan R.J. The functional roles of prefrontal cortex in episodic memory. II.Retrieval Brain. 1998; 121 (b): 1249-1256PubMed Google Scholar). In summary, it is not altogether clear that the asymmetric activations of the two prefrontal cortices in encoding and retrieval are attributable to their differential involvement in these two cognitive operations. The apparent functional dissociation of right and left PFC may be a product of the subtractive method if the material utilized to test the two operations carries a different semantic load. In any case, both the encoding and the retrieval of imaging studies are typically performed in the context of a task that requires the integration of sensory cues with cognitive actions across time. Thus, in both encoding and retrieval tasks, the executive memory networks of lateral PFC may be activated inasmuch as the tasks consist of temporally integrative acts based on internal or external contingencies. Cort