Functional localization within the prefrontal cortex: missing the forest for the trees?
Authors: Charles R.E. Wilson, David Gaffan, Philip G.F. Browning, Mark G. Baxter
Journal: Trends in Neurosciences (2010)

Anatomical and functional studies of the prefrontal cortex (PFC) have identified multiple PFC subregions. We argue that the PFC is involved in cognitive functions exceeding the sum of specific functions attributed to its subregions. These can be revealed either by lesions of the whole PFC, or more specifically by selective disconnection of the PFC from certain types of information (for example, visual) allowing the investigation of PFC function in toto. Recent studies in macaque monkeys using the latter approach lead to a second conclusion: that the PFC, as a whole, could be fundamentally specialized for representing events that are extended in time. The representation of temporally complex events might underlie PFC involvement in general intelligence, decision-making, and executive function. Anatomical and functional studies of the prefrontal cortex (PFC) have identified multiple PFC subregions. We argue that the PFC is involved in cognitive functions exceeding the sum of specific functions attributed to its subregions. These can be revealed either by lesions of the whole PFC, or more specifically by selective disconnection of the PFC from certain types of information (for example, visual) allowing the investigation of PFC function in toto. Recent studies in macaque monkeys using the latter approach lead to a second conclusion: that the PFC, as a whole, could be fundamentally specialized for representing events that are extended in time. The representation of temporally complex events might underlie PFC involvement in general intelligence, decision-making, and executive function. The prefrontal cortex (PFC), the anterior portion of the frontal lobes, is thought to be involved in a group of high-level cognitive functions variously described as executive cognitive control [1Miller E.K. Cohen J.D. An integrative theory of prefrontal cortex function.Annu. Rev. Neurosci. 2001; 24: 167-202Crossref PubMed Scopus (8574) Google Scholar, 2O'Reilly R.C. et al.Prefrontal cortex and dynamic categorization tasks: representational organization and neuromodulatory control.Cereb. Cortex. 2002; 12: 246-257Crossref PubMed Scopus (210) Google Scholar], behavioral inhibition [3Aron A.R. et al.Inhibition and the right inferior frontal cortex.Trends Cogn. Sci. 2004; 8: 170-177Abstract Full Text Full Text PDF PubMed Scopus (2323) Google Scholar], or general intelligence [4Duncan J. et al.A neural basis for general intelligence.Science. 2000; 289: 457-460Crossref PubMed Scopus (774) Google Scholar]. Anatomical studies of the PFC have identified multiple subregions within it. This article addresses the question of whether PFC functions should be localized to those subregions, or if the PFC has an overall function in which all regions play a part. We argue that in fact both are true. We show that subregions of PFC can be functionally dissociated. We also present evidence that there is a further overall role of the PFC in processing of temporally complex events, and this is not accounted for by adding together localized subregional functions. The initial argument derives from our own data on the effects of lesions in macaque monkeys, but these ideas are consistent with other methodological approaches to studying PFC function. A number of authoritative reviews of PFC anatomy and connections exist [5Goldman-Rakic P.S. Porrino L.J. The primate mediodorsal (MD) nucleus and its projection to the frontal lobe.J. Comp. Neurol. 1985; 242: 535-560Crossref PubMed Scopus (518) Google Scholar, 6Pandya D.N. Yeterian E.H. Comparison of prefrontal architecture and connections.Philos. Trans. R. Soc. Lond. B Biol. Sci. 1996; 351: 1423-1432Crossref PubMed Scopus (177) Google Scholar, 7Petrides M. Lateral prefrontal cortex: architectonic and functional organization.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2005; 360: 781-795Crossref PubMed Scopus (893) Google Scholar, 8Petrides M. Pandya D.N. Dorsolateral prefrontal cortex: comparative cytoarchitectonic analysis in the human and the macaque brain and corticocortical connection patterns.Eur. J. Neurosci. 1999; 11: 1011-1036Crossref PubMed Scopus (850) Google Scholar, 9Petrides M. Pandya D.N. Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey.Eur. J. Neurosci. 2002; 16: 291-310Crossref PubMed Scopus (699) Google Scholar, 10Walker A.E. A cytoarchitectural study of the prefrontal area of the macaque monkey.J. Comp. Neurol. 1940; 73: 59-86Crossref Scopus (655) Google Scholar], and therefore we do not reproduce the details here (but see Figure 1 for an illustration of the anatomical regions discussed in this article). We simply make two points about the anatomy of the PFC related to our discussion of its function. First, the PFC is clearly dissociable from surrounding cortical regions. A recent approach to PFC anatomy defines the PFC on the basis of a combination of cortical types, topology and connectivity [11Wise S.P. Forward frontal fields: phylogeny and fundamental function.Trends Neurosci. 2008; 31: 599-608Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar]. Second, the precise localization of divisions within the PFC varies between studies; we would argue that this is because the divisions are much less clear. Indeed, one study refers to an 'alarming disunity' of divisional boundaries in the PFC [12Akert K. Comparative anatomy of frontal cortex and thalamofrontal connections.in: Warren J.M. Akert K. The Frontal Granular cortex and Behavior. McGraw–Hill, 1964: 372-396Google Scholar], and there is notable variation in the placement and naming of cortical areas between studies, whether they are based on cell morphology and cytoarchitecture (Glossary) [8Petrides M. Pandya D.N. Dorsolateral prefrontal cortex: comparative cytoarchitectonic analysis in the human and the macaque brain and corticocortical connection patterns.Eur. J. Neurosci. 1999; 11: 1011-1036Crossref PubMed Scopus (850) Google Scholar, 9Petrides M. Pandya D.N. Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey.Eur. J. Neurosci. 2002; 16: 291-310Crossref PubMed Scopus (699) Google Scholar, 13Brodmann K. Vergleichende Localisationslehre der Grosshirnrinde in Ihren Prinzipien Dargestelt auf Grund des Zellenbaues. Barth, 1909Google Scholar, 14von Bonin G. Bailey P. The Neocortex of Macaca Mulatta. University of Illinois Press, 1947Google Scholar], or on the specific connection patterns of the regions [6Pandya D.N. Yeterian E.H. Comparison of prefrontal architecture and connections.Philos. Trans. R. Soc. Lond. B Biol. Sci. 1996; 351: 1423-1432Crossref PubMed Scopus (177) Google Scholar, 10Walker A.E. A cytoarchitectural study of the prefrontal area of the macaque monkey.J. Comp. Neurol. 1940; 73: 59-86Crossref Scopus (655) Google Scholar, 15Barbas H. Pandya D.N. Architecture and intrinsic connections of the prefrontal cortex in the rhesus monkey.J. Comp. Neurol. 1989; 286: 353-375Crossref PubMed Scopus (756) Google Scholar, 16Carmichael S.T. Price J.L. Connectional networks within the orbital and medial prefrontal cortex of macaque monkeys.J. Comp. Neurol. 1996; 371: 179-207Crossref PubMed Scopus (466) Google Scholar, 17Carmichael S.T. Price J.L. Architectonic subdivision of the orbital and medial prefrontal cortex in the macaque monkey.J. Comp. Neurol. 1994; 346: 366-402Crossref PubMed Scopus (546) Google Scholar, 18Barbas H. Blatt G.J. Topographically specific hippocampal projections target functionally distinct prefrontal areas in the rhesus monkey.Hippocampus. 1995; 5: 511-533Crossref PubMed Scopus (346) Google Scholar, 19Bates J.F. Goldman-Rakic P.S. Prefrontal connections of medial motor areas in the rhesus monkey.J. Comp. Neurol. 1993; 336: 211-228Crossref PubMed Scopus (365) Google Scholar, 20Schmahmann J.D. Pandya D.N. The cerebrocerebellar system.Int. Rev. Neurobiol. 1997; 41: 31-60Crossref PubMed Google Scholar]. Furthermore, all regions of the PFC are heavily interconnected across all divisions [21Barbas H. Pandya D.N. Patterns of connections of the prefrontal cortex in the rhesus monkey associated with cortical architecture.in: Levin H.S. Frontal Lobe function and Dysfunction. Oxford University Press, 1991: 35-58Google Scholar]. Thus, anatomical studies reveal a clear cortical regional unit that is the PFC, within which is contained less well-defined subregions. Here, we argue that the functional divisions mirror this pattern. The localization of function in the PFC is neither straightforward nor consistent. To the extent that subregions have different connectional patterns and different physiological properties, it should in theory be possible to ascribe a discrete function to each. It is not yet clear whether this is the case. Early studies, inspired by input patterns, looked for segregation of modalities within PFC, such as separating object and spatial processing in different subregions. Such studies have had only limited success [22Mishkin M. Manning F.J. Non-spatial memory after selective prefrontal lesions in monkeys.Brain Res. 1978; 143: 313-323Crossref PubMed Scopus (268) Google Scholar, 23Mishkin M. Pribram K.H. Analysis of the effects of frontal lesions in monkey. I. Variations of delayed alternation.J. Comp. Physiol. Psychol. 1955; 48: 492-495Crossref PubMed Scopus (72) Google Scholar, 24Bachevalier J. Mishkin M. Visual recognition impairment follows ventromedial but not dorsolateral prefrontal lesions in monkeys.Behav. Brain Res. 1986; 20: 249-261Crossref PubMed Scopus (332) Google Scholar, 25Rao S.C. et al.Integration of what and where in the primate prefrontal cortex.Science. 1997; 276: 821-824Crossref PubMed Scopus (684) Google Scholar], despite suggestions to the contrary [26Wilson F.A. et al.Dissociation of object and spatial processing domains in primate prefrontal cortex.Science. 1993; 260: 1955-1958Crossref PubMed Scopus (1112) Google Scholar], and perhaps the focus is better placed on modality convergence in PFC [27Jones E.G. Powell T.P. An anatomical study of converging sensory pathways within the cerebral cortex of the monkey.Brain. 1970; 93: 793-820Crossref PubMed Scopus (1259) Google Scholar]. A major source of functional evidence has been derived from neuroimaging studies on brain activation in vivo. Multiple neuroimaging investigations have localized specific foci of activity within the PFC that are associated with different task demands or different kinds of information processing [28Hashimoto R. Sakai K.L. Specialization in the left prefrontal cortex for sentence comprehension.Neuron. 2002; 35: 589-597Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 29Badre D. D'Esposito M. Is the rostro-caudal axis of the frontal lobe hierarchical?.Nat. Rev. Neurosci. 2009; 10: 659-669Crossref PubMed Scopus (633) Google Scholar]. A recent model draws on neuroimaging evidence to suggest that there is a hierarchical organization of function from posterior to anterior in the PFC, and that this corresponds to different levels of abstraction [29Badre D. D'Esposito M. Is the rostro-caudal axis of the frontal lobe hierarchical?.Nat. Rev. Neurosci. 2009; 10: 659-669Crossref PubMed Scopus (633) Google Scholar, 30Race E.A. et al.Neural priming in human frontal cortex: multiple forms of learning reduce demands on the prefrontal executive system.J. Cogn. Neurosci. 2009; 21: 1766-1781Crossref PubMed Scopus (93) Google Scholar]. Similarly, different demands on memory processing could be associated with activation of different dorsal/ventral levels within the lateral PFC [7Petrides M. Lateral prefrontal cortex: architectonic and functional organization.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2005; 360: 781-795Crossref PubMed Scopus (893) Google Scholar]. Although it is clear from neuroimaging studies that activations in distinct areas are associated with particular task demands, these data merely reflect correlations between activity and a task. Thus, even though differences in activation could be observed between subregions with high fidelity (for a recent demonstration, see Ref. [31Gilbert S.J. et al.The scale of functional specialization within human prefrontal cortex.J. Neurosci. 2010; 30: 1233-1237Crossref PubMed Scopus (40) Google Scholar]), this might reflect convergence of specific inputs into those subregions [32Logothetis N.K. et al.Neurophysiological investigation of the basis of the fMRI signal.Nature. 2001; 412: 150-157Crossref PubMed Scopus (4765) Google Scholar] instead of multiple, functionally-independent units. Lesion studies are advantageous in addressing this problem because they can tell us whether a region is necessary for a particular function. Traditional lesion experiments search for double dissociations – the demonstration that a lesion to area 'A' impairs function one but not function two, whereas a lesion to area 'B' impairs function two but not one. This therefore demonstrates area-specificity and also a level of independence of these regions. Evidence of such dissociations of function within the PFC has been rare [33Gaffan D. Against memory systems.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2002; 357: 1111-1121Crossref PubMed Scopus (113) Google Scholar], with only a few studies, including two clear examples in the 1960 s, having addressed this issue [34Brutkowski, S. et al. (1963) Positive and inhibitory motor conditioned reflexes in monkeys after ablation of orbital or dorso-lateral surface of the frontal cortex. In Central and Peripheral Mechanisms of Motor Functions (Gutman E. and Hník, P., eds), pp. 133–141, Czechoslovak Academy of SciencesGoogle Scholar, 35Butter C.M. Perseveration in extinction and in discrimination reversal tasks following selective frontal ablations in Macaca mulatta.Physiol. Behav. 1969; 4: 163-171Crossref Scopus (319) Google Scholar]. Two recent series of lesion studies in macaque monkeys have clearly identified double dissociations of function within the PFC. The first series [36Baxter M.G. et al.Perseverative interference with object-in-place scene learning in rhesus monkeys with bilateral ablation of ventrolateral prefrontal cortex.Learn. Mem. 2008; 15: 126-132Crossref PubMed Scopus (17) Google Scholar, 37Baxter M.G. et al.Orbital prefrontal cortex is required for object-in-place scene memory but not performance of a strategy implementation task.J. Neurosci. 2007; 27: 11327-11333Crossref PubMed Scopus (35) Google Scholar, 38Baxter M.G. et al.Dorsolateral prefrontal lesions do not impair tests of scene learning and decision-making that require frontal–temporal interaction.Eur. J. Neurosci. 2008; 28: 491-499Crossref PubMed Scopus (32) Google Scholar] demonstrated a range of dissociations and double dissociations within the PFC, for example between ventrolateral and orbital PFC in tests of strategy implementation and reward-based decision making. Another study [39Buckley M.J. et al.Dissociable components of rule-guided behavior depend on distinct medial and prefrontal regions.Science. 2009; 325: 52-58Crossref PubMed Scopus (225) Google Scholar] showed double dissociations between different measures of performance in a monkey version of the Wisconsin card-sorting task. This task is often used as an indicator of PFC dysfunction, and the results of this study help us to understand how and whether this task is a useful diagnostic tool. Studies in patients with PFC damage lend support to these views, demonstrating particular patterns of impairment that coincide with damage to particular subregions of PFC [40Clark L. et al.Differential effects of insular and ventromedial prefrontal cortex lesions on risky decision-making.Brain. 2008; 131: 1311-1322Crossref PubMed Scopus (441) Google Scholar, 41Fellows L.K. Farah M.J. Different underlying impairments in decision-making following ventromedial and dorsolateral frontal lobe damage in humans.Cereb. Cortex. 2005; 15: 58-63Crossref PubMed Scopus (519) Google Scholar]. However, patients usually have PFC damage that is not restricted to a particular subregion, and is often unilateral as well, thus it can often be hard to make definitive conclusions from lesions which have not been experimentally restricted to one specific subregion only. In contrast to studies that suggested specialization of function within the PFC, a number of influential models of PFC function emphasize its 'adaptive coding' properties, in which PFC neurons adapt to the demands of the task at hand, instead of carrying out a predetermined single function. Related models stress the extent to which a network of discrete regions within the PFC is recruited by diverse cognitive demands [1Miller E.K. Cohen J.D. An integrative theory of prefrontal cortex function.Annu. Rev. Neurosci. 2001; 24: 167-202Crossref PubMed Scopus (8574) Google Scholar, 4Duncan J. et al.A neural basis for general intelligence.Science. 2000; 289: 457-460Crossref PubMed Scopus (774) Google Scholar, 42Duncan J. An adaptive coding model of neural function in prefrontal cortex.Nat. Rev. Neurosci. 2001; 2: 820-829Crossref PubMed Scopus (648) Google Scholar, 43Duncan J. Owen A.M. Common regions of the human frontal lobe recruited by diverse cognitive demands.Trends Neurosci. 2000; 23: 475-483Abstract Full Text Full Text PDF PubMed Scopus (1910) Google Scholar], suggesting equipotentiality of function throughout the PFC. Combined with the relative lack of double dissociations in the PFC, these observations have led to the proposal that the function of the PFC is unique and integrative [33Gaffan D. Against memory systems.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2002; 357: 1111-1121Crossref PubMed Scopus (113) Google Scholar], and that it does not have subregions with specialized functions in the way that other areas of the cortex do. Here we summarize studies that support two opposing views: equipotentiality of function within the PFC versus a strict localization of function within the PFC, and we propose an argument that can account for both views. We accept evidence of localization, but we also argue for a global function of the PFC over and above those localized functions. This is not an argument for general equipotentiality – the differences between regions have been made clear by the recent lesion studies [36Baxter M.G. et al.Perseverative interference with object-in-place scene learning in rhesus monkeys with bilateral ablation of ventrolateral prefrontal cortex.Learn. Mem. 2008; 15: 126-132Crossref PubMed Scopus (17) Google Scholar, 37Baxter M.G. et al.Orbital prefrontal cortex is required for object-in-place scene memory but not performance of a strategy implementation task.J. Neurosci. 2007; 27: 11327-11333Crossref PubMed Scopus (35) Google Scholar, 38Baxter M.G. et al.Dorsolateral prefrontal lesions do not impair tests of scene learning and decision-making that require frontal–temporal interaction.Eur. J. Neurosci. 2008; 28: 491-499Crossref PubMed Scopus (32) Google Scholar, 39Buckley M.J. et al.Dissociable components of rule-guided behavior depend on distinct medial and prefrontal regions.Science. 2009; 325: 52-58Crossref PubMed Scopus (225) Google Scholar]. Instead, it is an argument for a specific higher order PFC function, above and beyond the localized functions. This function is not subregion-specific, and so is only revealed by studies focusing on the whole of the PFC. This idea of a system having different orders of functions is not uncommon. To take a trivial example, subregions of a car engine, such as the spark plugs, have localized functions, such as igniting fuel. But only when the engine is considered as a whole does it become clear that its higher-order function is to make the car move. However, we present evidence below that, unlike a car engine, the PFC is more than the sum of its parts – so that adding up the functions of its subregions doesn't equate to the function of the whole. We believe this to be because the PFC is a complex and plastic system (properties discussed later on). Thus, our argument is that it is important to see the entire forest, no matter how visible the individual trees might be. Evidence derived from lesion studies in macaque monkeys [44Parker A. Gaffan D. Memory after frontal/temporal disconnection in monkeys: conditional and non-conditional tasks, unilateral and bilateral frontal lesions.Neuropsychologia. 1998; 36: 259-271Crossref PubMed Scopus (106) Google Scholar] provides one example to demonstrate that the PFC is doing something over and above the sum of the functions of its subregions. Monkeys with lesions of either the dorsal or ventral half of the PFC and premotor cortex were unimpaired on a test of object–reward association learning in which they learn to associate food reward with one of two stimuli [44Parker A. Gaffan D. Memory after frontal/temporal disconnection in monkeys: conditional and non-conditional tasks, unilateral and bilateral frontal lesions.Neuropsychologia. 1998; 36: 259-271Crossref PubMed Scopus (106) Google Scholar]. By contrast, monkeys with bilateral lesions that included the entire PFC and premotor cortex were incapable of object–reward association learning [44Parker A. Gaffan D. Memory after frontal/temporal disconnection in monkeys: conditional and non-conditional tasks, unilateral and bilateral frontal lesions.Neuropsychologia. 1998; 36: 259-271Crossref PubMed Scopus (106) Google Scholar]. The impairment is striking because this is an extremely simple learning task that both control monkeys and those with subtotal lesions find trivial [44Parker A. Gaffan D. Memory after frontal/temporal disconnection in monkeys: conditional and non-conditional tasks, unilateral and bilateral frontal lesions.Neuropsychologia. 1998; 36: 259-271Crossref PubMed Scopus (106) Google Scholar]. It suggests that monkeys lacking the entire PFC are incapable of learning about a single object, a much more severe memory deficit than one might expect to see on the basis of the data on the role of the PFC's subregions in memory. A similar finding is evident from studies utilizing other behavioral tasks in monkeys [45Gaffan D. Scene-specific memory for objects: a model of episodic memory impairment in monkeys with fornix transection.J. Cogn. Neurosci. 1994; 6: 305-320Crossref PubMed Scopus (340) Google Scholar] where the PFC lesions do not extend into the premotor cortex (e.g. Refs [36Baxter M.G. et al.Perseverative interference with object-in-place scene learning in rhesus monkeys with bilateral ablation of ventrolateral prefrontal cortex.Learn. Mem. 2008; 15: 126-132Crossref PubMed Scopus (17) Google Scholar, 37Baxter M.G. et al.Orbital prefrontal cortex is required for object-in-place scene memory but not performance of a strategy implementation task.J. Neurosci. 2007; 27: 11327-11333Crossref PubMed Scopus (35) Google Scholar, 38Baxter M.G. et al.Dorsolateral prefrontal lesions do not impair tests of scene learning and decision-making that require frontal–temporal interaction.Eur. J. Neurosci. 2008; 28: 491-499Crossref PubMed Scopus (32) Google Scholar, 39Buckley M.J. et al.Dissociable components of rule-guided behavior depend on distinct medial and prefrontal regions.Science. 2009; 325: 52-58Crossref PubMed Scopus (225) Google Scholar, 46Browning P.G. et al.The role of prefrontal cortex in object-in-place learning in monkeys.Eur. J. Neurosci. 2005; 22: 3281-3291Crossref PubMed Scopus (67) Google Scholar]). The object-in-place scene-learning task is a test of episodic memory in the monkey [45Gaffan D. Scene-specific memory for objects: a model of episodic memory impairment in monkeys with fornix transection.J. Cogn. Neurosci. 1994; 6: 305-320Crossref PubMed Scopus (340) Google Scholar] (Figure 2a) . This task is performed at chance levels by monkeys with bilateral lesions of the whole of the PFC [46Browning P.G. et al.The role of prefrontal cortex in object-in-place learning in monkeys.Eur. J. Neurosci. 2005; 22: 3281-3291Crossref PubMed Scopus (67) Google Scholar]. Thus, like object–reward association learning, monkeys with bilateral lesions of the PFC are incapable of learning new object-in-place scene problems. However, even though lesions of subregions of the PFC – for example, orbital or ventrolateral – can reliably impair scene-learning [36Baxter M.G. et al.Perseverative interference with object-in-place scene learning in rhesus monkeys with bilateral ablation of ventrolateral prefrontal cortex.Learn. Mem. 2008; 15: 126-132Crossref PubMed Scopus (17) Google Scholar, 37Baxter M.G. et al.Orbital prefrontal cortex is required for object-in-place scene memory but not performance of a strategy implementation task.J. Neurosci. 2007; 27: 11327-11333Crossref PubMed Scopus (35) Google Scholar], the impairments that occur after subregional lesions are a long way short of the magnitude of those that follow bilateral ablation of the entire PFC (Figure 2). Furthermore, in a test of strategy implementation, only bilateral ventrolateral PFC lesions produce a reliable impairment, but this is much smaller in magnitude than that which follows functional disconnection between the PFC and inferotemporal (IT) cortex (see below) [36Baxter M.G. et al.Perseverative interference with object-in-place scene learning in rhesus monkeys with bilateral ablation of ventrolateral prefrontal cortex.Learn. Mem. 2008; 15: 126-132Crossref PubMed Scopus (17) Google Scholar, 37Baxter M.G. et al.Orbital prefrontal cortex is required for object-in-place scene memory but not performance of a strategy implementation task.J. Neurosci. 2007; 27: 11327-11333Crossref PubMed Scopus (35) Google Scholar, 38Baxter M.G. et al.Dorsolateral prefrontal lesions do not impair tests of scene learning and decision-making that require frontal–temporal interaction.Eur. J. Neurosci. 2008; 28: 491-499Crossref PubMed Scopus (32) Google Scholar, 44Parker A. Gaffan D. Memory after frontal/temporal disconnection in monkeys: conditional and non-conditional tasks, unilateral and bilateral frontal lesions.Neuropsychologia. 1998; 36: 259-271Crossref PubMed Scopus (106) Google Scholar]. For the purposes of the current argument, the details of these tasks are less important than the emerging pattern: across a range of tasks, functional correlates of the whole of the PFC have been demonstrated, and these are not accounted for by what we know about its subregions. A number of studies utilizing neuroimaging techniques in human subjects are consistent with this idea. For example, a meta-analysis has shown consistent recruitment of the same network of regions in the PFC across a range of cognitive demands [43Duncan J. Owen A.M. Common regions of the human frontal lobe recruited by diverse cognitive demands.Trends Neurosci. 2000; 23: 475-483Abstract Full Text Full Text PDF PubMed Scopus (1910) Google Scholar]. The authors argue that this supports specialization of function within the PFC, but of an unexpected nature, namely 'a specific frontal-lobe network that is consistently recruited for solution of diverse cognitive problems' [43Duncan J. Owen A.M. Common regions of the human frontal lobe recruited by diverse cognitive demands.Trends Neurosci. 2000; 23: 475-483Abstract Full Text Full Text PDF PubMed Scopus (1910) Google Scholar]. The idea that large and different regions of the PFC are recruited by any task at hand supports our argument that the function of the PFC as a whole exceeds the sum of the functions of its subcomponents. The resulting question is: what is this higher-order function? Studying the functions of the PFC as an integrated unit is difficult because of its size and diverse anatomical inputs and outputs. Bilateral lesions of the PFC are problematic in that they produce a severe generalized disruption of behavior; as we have seen, monkeys with bilateral PFC lesions are incapable of learning single discrimination problems (usually a trivial task for monkeys) over a thousand training trials [44Parker A. Gaffan D. Memory after frontal/temporal disconnection in monkeys: conditional and non-conditional tasks, unilateral and bilateral frontal lesions.Neuropsychologia. 1998; 36: 259-271Crossref PubMed Scopus (106) Google Scholar]. Of course, this indicates the fundamental importance of the PFC in generating organized behavior, but it does not shed any light on how the PFC acts on particular kinds of information. One way to address this problem is with selective disconnections of the PFC from particular sensory inputs using crossed unilateral lesions. This technique makes it possible to study the effects of disruption of PFC function as a whole without producing a generalized disruption of behavior [47Ettlinger G. Visual discrimination following successive temporal ablations in monkeys.Brain. 1959; 82: 232-250Crossref PubMed Scopus (25) Google Scholar]. For example, the inferotemporal cortex (IT, Figure 1) is a region known to represent visual object identities. In the disconnection procedure, a monkey might receive a unilateral lesion of the IT in one hemisphere and PFC in the other hemisphere. Because the connections between these structures are predominantly in the same hemisphere [27Jones E.G. Powell T.P. An anatomical study of converging sensory pathways within the cerebral cortex of the monkey.Brain. 1970; 93: 793-820Crossref PubMed Scopus (1259) Google Scholar, 48Kuypers H.G. et al.Occipitotemporal corticocortical connections in the rhesus monkey.Exp. Neurol. 1965; 11: 245-262Crossref PubMed Scopus (315) Google Scholar], this has the effect of disconnecting them from each other, while leaving the animal with functional areas of both PFC and IT. The intact IT in one hemisphere is capable of carrying out visual functions that do not depend on interaction with the PFC, and the intact PFC in the opposite hemisphere is capable of carrying out tasks tha