Investigating principles of human brain function underlying working memory: What insights from schizophrenia?

Neuroscience 139 (2006) 59 –71

INVESTIGATING PRINCIPLES OF HUMAN BRAIN FUNCTION UNDERLYING WORKING MEMORY: WHAT INSIGHTS FROM SCHIZOPHRENIA? G. D. HONEY* AND P. C. FLETCHER

intrinsic features which contribute substantially to the debilitating nature of the disorder. In addition to these and other experiential disturbances, patients with schizophrenia also show deficits across a broad range of neuropsychological domains. Impairment of cognitive function is increasingly recognized as a core feature of this illness (Green, 1996; Green and Nuechterlein, 1999), and has recently been identified by the ‘Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Initiative’ to comprise primary deficits involving working memory, attention/vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving, speed of processing, and social cognition (Green et al., 2004). Working memory, the ability to maintain and utilize information in short-term memory (Baddeley and Hitch, 1974; Baddeley, 1986), is a process which is central to everyday functioning, and contributes significantly to other areas of cognition. The theoretical concept of working memory was developed in response to limitations of previous models of short-term memory, such as Atkinson and Shiffrin’s ‘Two-Process Model’ (Atkinson and Shiffrin, 1968), to fully account for performance impairments in neuropsychological patients. The working memory model, proposed by Baddeley and Hitch (1974), identified a three component system: the phonological loop (comprising a limited capacity ‘phonological store’ in which verbal information is stored temporarily and maintained by subvocal rehearsal); the ‘visuospatial sketchpad’ (a parallel sub-system to the phonological store, specialized for non-verbal material); and the ‘central executive’, responsible for strategic co-ordination and execution of the slave systems. The original model was updated, to include an ‘episodic buffer,’ which provides an interface between the sub-systems of working memory and long-term memory (Baddeley, 2000). Deficits in working memory have been consistently reported in schizophrenic patients (Weinberger and Cermak, 1973; Park and Holzman, 1992; Fleming et al., 1995; Keefe et al., 1995; Morris et al., 1997; Park and McTigue, 1997; Spindler et al., 1997; Park et al., 1999), and also first-degree asymptomatic relatives (Conklin et al., 2000). There is some evidence of disproportionate memory impairment in the context of other domains of cognitive dysfunction (Saykin et al., 1991, 1994), and prognostic implications of such deficits in psychosocial rehabilitation programs (Green, 1996). Accordingly, deficient working memory is key to a number of contemporary cognitive psychological models of schizophrenic symptoms (Goldman-Rakic, 1990a, 1994; Cohen and Servan-Schreiber, 1992; Weinberger, 1993).

University of Cambridge, Department of Psychiatry, Brain Mapping Unit, Downing Site, Downing Street, Cambridge CB2 3EB, UK

Abstract—Working memory dysfunction is a core component of schizophrenia, which likely contributes substantially to the pervasive and profound cognitive deficits observed in patients with this illness. Developments in functional imaging have facilitated the investigation of the neural basis of these cognitive deficits. A strong tradition within neuropsychology has been that circumscribed lesions provide observations which constrain theoretical models, and generate testable predictions on the basis of observed relationships between structural abnormalities and behavioral dysfunction. In this article, the extent to which the neuropsychological tradition can be applied to neuropsychiatry to advance understanding of the biological basis of working memory is addressed. Empirical studies in schizophrenia research are reviewed in relation to principles of normal brain function sub-serving working memory: the functional role of the lateral prefrontal cortex, physiological response capacity constraints, interregional functional integration, and compensatory adaptations. However, complex heterogeneous psychiatric disorders such as schizophrenia cannot be considered akin to a pure lesion model, and there are considerable methodological challenges in interpreting disruptions of working memory in psychiatric conditions, resulting from clinical, treatment and performance related confounds. The increasing use of psychopharmacological models of disease in healthy human subjects is therefore considered as an attempt to address, or to some extent circumvent these issues. © 2005 Published by Elsevier Ltd on behalf of IBRO. Key words: working memory, schizophrenia, psychiatry, fMRI, functional imaging.

Schizophrenia is a complex psychiatric disorder which encompasses a wide range of behavioral phenomena expressed to varying degrees in symptomatic patients. The ‘positive’ symptoms of the disorder, including hallucinations (primarily in the auditory modality) and delusional ideation, are perhaps the most widely recognized characteristics of the illness, while ‘negative’ symptoms, for example, social withdrawal and flattened affect, are also *Correspondence to: G. D. Honey, University of Cambridge, Department of Psychiatry, Addenbrookes Hospital, Brain Mapping Unit, Box 255, Cambridge CB2 2QQ, UK. Tel: ⫹44-01223-764673; fax: ⫹4401223-764675. E-mail address: [email protected]; URL: http://fs0.psychiatry.cam. ac.uk/gh242/ (G. D. Honey). Abbreviations: fMRI, functional magnetic resonance imaging; NAA, N-acetylaspartate; PCP, phencyclidine; PET, positron emission tomography; TMS, transcranial magnetic stimulation. 0306-4522/06$30.00⫹0.00 © 2005 Published by Elsevier Ltd on behalf of IBRO. doi:10.1016/j.neuroscience.2005.05.036

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Given the centrality of working memory dysfunction in schizophrenia, the question arises as to whether the information ascertained from this disorder may provide further insights into normal brain function underlying working memory. The precedent for this approach is provided by the contribution neuropsychological investigations have made to the development of theoretical models throughout cognitive psychology. Indeed, the concept of working memory and precursive models, have benefited substantially from investigations of behavioral impairments in patients following neurological damage, sometimes referred to as ‘natural memory experiments.’ These studies, typically based on individual case histories, are often particularly influential in addressing subtle discriminations, which may prove intractable to standard experimental methodology: for example, observing intact subvocal rehearsal in patients with anarthria, demonstrating that the subvocalization process, necessary to maintain and refresh information in working memory, does not require explicit articulation (Baddeley and Wilson, 1985). Similarly, the twocomponent model of the phonological loop, involving both subvocal rehearsal and phonological storage, was substantiated on the basis of observations in patient P.V., who showed a specific sensitivity to phonological similarity effects for information presented in the auditory modality. Visually-presented information was insensitive to phonological similarity, word length or articulatory suppression. Vallar and Baddeley (1984) interpreted this as an indication of a specific impairment at the level of phonological storage (thereby indicating its process separability), causing the patient to strategically avoid use of the rehearsal mechanism for visual information, whereas the phonological store has automatic access to auditory information. These examples demonstrate how neuropsychology can be critical in developing and constraining theoretical models of cognitive function. This approach can also be extended to incorporate the neurobiological implementation of cognitive processes. This follows the classical tradition inaugurated by Broca’s localization of speech production to the inferior frontal gyrus on the basis of the monosyllabic speech capacity of a patient following a lesion to this region identified postmortem, and similarly Wernicke’s observation that damage to the left posterior temporal cortex produces deficits in speech comprehension. Progressing beyond single dissociations such as these, relating the role of a particular brain region with a specific cognitive process is most compellingly demonstrated by double dissociations, in which the loss of function X and preservation of function Y is observed in patient A, while the reverse pattern is evident in patient B). To what extent can these principles of the neuropsychological approach be applied to neuropsychiatry? Specifically, can the behavioral deficits in working memory observed in patients with schizophrenia inform current models of the neurobiological basis of working memory? The neuropsychological tradition of relating structural lesions to cognitive dysfunction is clearly limited in its application to schizophrenia, since the neuropathology in schizophrenia is diffuse, subtle and variable between pa-

tients and over the course of the illness. However, putative functional pathology associated with schizophrenia may prove revealing in relation to observed cognitive deficits. In this article, the extent to which functional imaging studies of schizophrenia can be considered to have validated biological models of working memory in the normal human brain is reviewed. Implicitly, this asks the question of whether the principles of lesion-based neuropsychology are directly transferable to (dys)functional imaging? The focus on functional neuroimaging is warranted on the basis that this offers an unrivalled technique in cognitive neuroscience to investigate the biological basis of human cognitive function in vivo. For descriptive purposes, this review is organized in terms of principles of brain function which have emerged as important in the biological implementation of working memory. We firstly consider the functional role of the lateral prefrontal cortex: animal studies have clearly demonstrated the involvement of this region in working memory, however, the interpretation of its role in humans, as evidenced by functional neuroimaging is complicated by issues including reverse causality (the influence of behavior on physiological response and vice versa), functional diaschisis (a primary abnormality in a remote brain region), and the limitations of the application of principles used as gold standards in neuropsychology to functional imaging. We further consider the response properties of the prefrontal cortex, and how capacity limitations may explain the relationship between working memory performance, and hypo- or hyper-activity in frontal regions in patients. The prefrontal cortex clearly does not function in isolation, and we review studies which have examined its connectivity with other structures, in both healthy subjects and patients. Finally, we consider how functional deficits in regions including prefrontal cortex may be mitigated by compensatory recruitment of other brain areas, and the implications for behavioral assessments. There are a number of interpretative difficulties in extrapolating from the disease state to the normal brain which are considered, and this is particularly relevant in the case of schizophrenia, in which the uncertain etiology/pathophysiology, and heterogeneity of the clinical profile and its treatment, seriously limit what can be generalized from this disorder to normative brain function subserving working memory. In conclusion, we suggest that an alternative approach involving the use of psychopharmacological models of disease may circumvent some of these issues. Functional neuroimaging in psychiatry as a tool in cognitive neuroscience While there is no implied anatomical localization of the subcomponents of Baddeley’s model of working memory, basic and clinical neuroscience research has increasingly provided support for the dissociation of processes proposed, and has gone some way to formulating a functional topology. Functional neuroimaging, primarily using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) has, with increasing sophistication in experimental design, explored the biolog-

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ical basis of working memory in healthy human subjects (for review, see references (D’Esposito et al., 2000; Owen, 2000; Fletcher and Henson, 2001; Wager and Smith, 2003)). However, a limitation of this approach is that imaging can reveal only the engagement of neural systems which are correlated with cognitive function. As a cognitive process is experimentally manipulated, PET and fMRI provide a remarkable capability to visualize the brain regions which show task-related responsivity. However, while the results of increasingly focused experimental paradigms can be persuasively argued to represent a causal relationship, ultimately this cannot be demonstrated satisfactorily using these techniques in isolation, and must be interpreted in the context of information from other methodological approaches which involve perturbed function, such as behavioral impairments in neuropsychological patients, or noninvasive experimental interventions, such as transcranial magnetic stimulation (TMS). TMS allows experimental manipulation of regional neuronal activity by applying a brief, high-amplitude pulse of current which temporarily interferes with the activity of local neurons. The observation of impaired cognitive performance following local disruption of neural activity in a given region indicates that the functional integrity of a region is necessary for performance of a task. The application of this technique to working memory has been reported by several groups (Mottaghy et al., 2000; Mull and Seyal, 2001; Oliveri et al., 2001; Mottaghy et al., 2002; Nixon et al., 2004). Similarly, the integration of findings from neuroimaging and those of neuropsychological impairment following discrete lesions facilitates identification of regions which are associated with, and necessary for particular functions, respectively (Fiez, 2001). The use of schizophrenia as an in vivo disruption of biological function can be considered in some ways parallel to the TMS and neuropsychological approach, in that behavioral deficits are related to primary physiological disturbances. Indeed, schizophrenia may go beyond the classical lesion model, involving disruptions of inter-regional functional connections, rather than localized regional deficits. Thus schizophrenia offers the opportunity to investigate a systems-level disruption of biological function, and concomitant behavioral impairments may provide some indication of the nature of the processes perturbed by a ‘functional lesion.’ Convergent evidence regarding structure–function relationships may therefore be ascertained from complementary methodologies, incorporating functional imaging in healthy subjects and patients with schizophrenia, TMS and neuropsychological performance in patients with discrete lesions. It is now a decade since the first fMRI studies were reported in patients with schizophrenia (Renshaw et al., 1994; Wenz et al., 1994), and a large number of these have incorporated working memory paradigms (Weinberger et al., 1996; Callicott et al., 1998, 2000, 2003a; Stevens et al., 1998; Honey et al., 1999, 2002a, 2003a; Manoach et al., 1999, 2000, 2001; Barch et al., 2001, 2002, 2003; Egan et al., 2001; Menon et al., 2001; Perlstein et al., 2001, 2003; Wykes et al., 2002; Quintana et al., 2003; Schlosser et al., 2003a,b; Walter et

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al., 2003; Jacobsen et al., 2004; Kindermann et al., 2004; Mendrek et al., 2004, Thermenos et al., 2005), making a review of this body of literature, and its implications for understanding principles of normal brain function associated with working memory, timely. Principles of human brain function involved in working memory Functional role of the lateral prefrontal cortex. Extensive single-unit recording studies in non-human primates demonstrated that cells in and around the principal sulcus in the dorsolateral prefrontal cortex exhibit delayrelated activity during delayed match to sample paradigms (Goldman-Rakic, 1987, 1990b). Furthermore, impeding lateral prefrontal activity, either via pharmacological blockade of dopamine D1 receptors (Sawaguchi and GoldmanRakic, 1991, 1994; Williams and Goldman-Rakic, 1995), or neurochemical/surgical lesions (Funahashi et al., 1993) of local tissue, impairs working memory. The functional involvement of the homologous region in humans in working memory has subsequently been confirmed by a large number of functional imaging studies using both PET and fMRI. However, this indicates that the prefrontal cortex is associated with working memory in humans, but it does not test the hypothesis that prefrontal activation is a requirement for working memory. Does psychiatric imaging therefore confirm the prediction from animal studies that pathological conditions which compromise the integrity of prefrontal functioning should be associated with working memory impairments? Goldman-Rakic (1990a, 1999) noted a parallel between the performance deficits of schizophrenic patients and those of non-human primates following lesion of the principal sulcal region of the prefrontal cortex, indicating that a pathological functional lesion of the prefrontal cortex in humans may underlie working memory deficits observed in these patients. Early imaging studies in schizophrenia, involving complex cognitive tasks engaging a range of executive processes, typically exhibited a reduced frontal response in patients with schizophrenia, termed ‘hypofrontality’ (Buchsbaum et al., 1986; Weinberger and Berman, 1988; Paulman et al., 1990; Andreasen et al., 1992; Berman et al., 1993). More recently, with the growing consensus that working memory represents a core deficit in schizophrenia, studies involving tasks designed to more specifically isolate working memory processes also reported a hypofrontal response (Callicott et al., 1998; Carter et al., 1998; Stevens et al., 1998; Barch et al., 2001, 2002, 2003; Perlstein et al., 2003). A possible implication of these studies for normal brain function was that the lateral prefrontal cortex, which is consistently activated in healthy volunteers during working memory tasks, is a necessary requirement for working memory processing, and in psychiatric conditions in which prefrontal function is disrupted, a failure of working memory is observed. While these clinical studies largely involved medicated out-patients experiencing chronic illness, this is unlikely to represent an effect of disease chronicity or anti-psychotic treatment, since Barch et al. (2001) observed these effects in patients

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who were scanned within 1–2 days of their first contact with psychiatric services and had not been treated with neuroleptics prior to their involvement in the study. However, there is an interesting distinction here which exemplifies the complexities of applying the neuropsychological approach to neuropsychiatry: Reverse causality. The observation of a cognitive deficit following a structural lesion to region A which was absent prior to the lesion would naturally lead the neuropsychologist to infer that region A was in some way involved in the neural architecture underpinning the psychological function that was lost. Clearly, it would be untenable to imply causality in the opposite direction. However, in evaluating the loss of biological function, as opposed to structure, causality may indeed operate in either direction. It is possible that a physiological abnormality may lead to a cognitive deficit, however it is equally possible that the behavioral deficit, perhaps mediated indirectly via other factors (for example increased distractibility due to pervasive psychotic experiences), causes the subject to disengage from the task, and thereby fail to recruit task-related activity in associated brain regions (for further discussion, see (Price and Friston, 1999)). Frith et al. (1995) proposed that the impaired performance of schizophrenic patients on frontal lobe tasks may result in the use of alternative strategies which do not engage prefrontal cortex, and thus result in hypofrontality. Similarly, Ebmeier et al., suggested that “The poorer performance of ‘frontal’ activation tasks by patients with schizophrenia is probably sufficient explanation for the difference from controls, who perform such tasks well” (Ebmeier et al., 1995). Manoach et al.(1999) suggested that faced with a task which is too difficult, patients may feel overwhelmed and disengage. The relationship between physiological activation and cognitive performance is complex. Several studies, which have attempted to characterize this further, are considered further in ‘Physiological capacity constraints.’ Functional diaschisis. Both abnormal prefrontal response and cognitive impairment could potentially be explained by diaschisis: a primary abnormality in a remote brain region. Several regions, including the posterior parietal cortex and basal ganglia show delay-related activity in non-human primates and similarly, activation in functional imaging studies in humans. There is certainly evidence of abnormal activation of these structures in schizophrenia. It is possible therefore that deficits in either of these could represent the primary abnormality. Conceivably, this may lead to secondary, downstream effects in other brain regions, including the prefrontal cortex. Further investigation of the connectivity between these regions will therefore be critical in interpreting the functional involvement of the prefrontal cortex in working memory impairment. Corroborative evidence that prefrontal dysfunction is critical to working memory impairment is potentially available if it is the case that (i) prefrontal abnormalities are also evident in other psychiatric disorders in which working memory impairment is present, and (ii) pathology did not overlap in other regions except prefrontal cortex. This overlap across disorders would tend to suggest that pre-

frontal dysfunction represents the central abnormality in working memory dysfunction. For example, there is some evidence of working memory impairment in patients with unipolar depression (Sweeney et al., 1998; Pelosi et al., 2000), however, few functional imaging studies have investigated the role of the prefrontal cortex during working memory performance in this patient population. Barch et al. (2003) compared patients with major depression to patients with schizophrenia and healthy controls. In contrast to the hypofrontal response in schizophrenia, they did not observe a prefrontal deficit in depressed subjects; however, working memory performance was disrupted in the schizophrenic, but not the depressed patients. A recent study reported by Hugdahl et al. (2004) found that despite similar performance deficits in patients, schizophrenic subjects showed attenuated frontal response during a mental arithmetic task which was not evident in depressed subjects. While this task incorporated a working memory requirement, more process-specific tasks may be required to address the question of whether prefrontal function is disrupted during working memory performance in patients with non-schizophrenic psychiatric conditions, where a behavioral deficit is also evident, and whether there is regionalspecificity of this overlap. While not conclusive, these studies could potentially be informative with regard to whether functional disruption in this region is necessary for working memory performance. Dissociation methodology. The use of double dissociations, which are prevalent in neuropsychological investigations and provide compelling indications of process separability and neuroanatomical localization, does not translate in a straightforward manner to functional imaging data. For example, Bechara et al. (1995) reported that a patient with selective bilateral damage to the amygdala failed to acquire conditioned autonomic responses to visual or auditory stimuli but was able to demonstrate explicit knowledge of the declarative facts about which stimuli were paired to the unconditioned stimulus. The opposite pattern was observed in a patient with selective bilateral damage to the hippocampus. Finally, both conditioning and explicit awareness were found to be disrupted in a patient with bilateral damage to both amygdala and hippocampal formation. This elegant study provides strong evidence for a double dissociation of conditioning and declarative knowledge, and association with the integrity of the amygdala and hippocampus respectively. Could the principles underlying these findings be extended to functional imaging? Process separability would be less convincing on the basis of functional observations, since an alternative explanation of these data could involve a single process which underlies the functional activation of both regions; if this process was engaged to a greater extent in one task, e.g. acquisition of conditioning, and produces both hippocampal activation and deactivation of amygdala, then the apparent double dissociation is misleading. Henson (2005) recently outlined how process separability is identifiable in functional imaging data, if one extends Dunn and Kirsner’s (1988) principle of ‘reversed association.’ The application to functional imaging data

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corresponds to the observation of increased task-related activity in two brain regions, relative to an independent baseline condition, and simultaneously, that the two regions contrast negatively across two task conditions. This particular pattern of activity guards against the possibility that a double dissociation simply represents opposing effects of a shared single process, perhaps mediated via reciprocal connectivity between the two regions. However, while a ‘reversed association’ imbues the observed association between structure and function with a greater degree of process specificity, it does not change in any way the nature of this relationship, i.e. it remains a (processspecific) correlative observation, which is not an indication of whether the pattern of activation is necessary or sufficient. As such, disease-related perturbation of activity observed in regions for which a ‘reverse association’ can be demonstrated remains ambiguous with regard to its implications for normal brain function, as for single and double dissociations. For the reasons outlined above, the interpretation of functional abnormalities, such as hypofrontality in response to working memory tasks in schizophrenia, is confounded by alternative explanations which limit the feasibility of extending these observations to the normal human brain. Brain function, as opposed to structure, has the property of dynamic adaptation, and this causes the functional relationships between regions to be fluid and context-dependent. Physiological abnormalities observed using functional imaging are therefore insufficient to identify regions which are necessary for specific cognitive processes. However, while the application of the principles of classical neuropsychology to modern functional imaging methods may be inappropriate, this is not to suggest that there is no insight to be gained into the normal brain based on the functional deficits identified using neuroimaging in patients with schizophrenia. Neuropsychological and imaging-based investigations are synergistic approaches (Rorden and Karnath, 2004), however, the nature of the insights offered by these two techniques differs considerably. Below, the possible insights from functional imaging are considered further. Physiological capacity constraints. Neuroimaging studies in healthy volunteers have demonstrated that the functional relationship between prefrontal response and cognitive demand is not a simple linear association. Prefrontal activation increases in line with task demands until the capacity limitation of working memory is reached, at which point, activation decreases (Callicott et al., 1999). The relationship between cognitive performance and cortical physiology is therefore best described by an inverted-U function, in contrast to response in other (though not all) brain regions, which plateau as capacity is reached (Callicott et al., 1999). The hypofrontal response observed in patients with schizophrenia, may therefore reflect the normal attenuation of response following overload of working memory capacity, occurring at an abnormally reduced threshold due to pathology. Since patients with schizophrenia have reduced working memory capacity, studying this popula-

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tion offers the opportunity to dissociate the factors of cognitive load and capacity, since capacity will be breached at a lower load threshold in patients compared with healthy volunteers. This is an important dissociation since increments in working memory load are often not purely quantitative increases, but may also induce qualitative differences between levels, such that further processes and adjunctive strategies are engaged as demand increases (Honey et al., 2000). The observation of similar principles of brain function underlying capacity limitation at low load in patients, compared with high load in controls would therefore provide robust support for the proposed relationship between physiological response and cognitive load, independent of the qualitative variations associated with experimental task manipulations. The suggestion that hypofrontality may reflect reduced cognitive capacity, with normal (or increased) frontal response occurring within performance capacity was first proposed by Fletcher et al. (1998) employing a word-recall task: they observed that patients showed normal frontal activation when the cognitive demands of the task were low, but failed to show the increased prefrontal activation to increased word list length observed in controls. As they noted, since list length was also associated with time, this finding may relate to a failure to engage long-term memory processes or the maintenance of information in working memory. The latter interpretation was supported by subsequent studies involving more specific working memory tasks. Using the Sternberg item recognition task (Sternberg, 1966) Manoach et al. (1999, 2000) reported increased frontal activation in patients performing a task which was within capacity, but for which behavioral indices demonstrated that patients found the task more difficult than controls. Interestingly, a negative correlation was observed between error rate and prefrontal activation in the patients, suggesting that activation increases with demand, until cognitive capacity is exceeded. As they noted, this leads to the intriguing speculation that further increases in load may have resulted in a hypofrontal response in the patients, whereas this increase may have remained within the performance capacity of the controls, and therefore resulted in increased activation in line with demand, thus reversing the between-group comparison observed at lower cognitive loads. In accordance with this, Perlstein et al. (2001) found that hypofrontality was observed in the patient group only at the highest load, the only level which differentiated groups on behavioral performance. The hypofrontal response variably reported in schizophrenia is thus not a static phenomenon, but dynamically related to task requirements and subjects’ capacity range to perform the task. Callicott et al. (2000) recruited patients based on prior screening of minimal proficiency (⬎90% accuracy on the n-back task) and demonstrated a hyperfrontal response to working memory demands as observed by Manoach et al. (1999, 2000). They also confirmed the correlation between accuracy and prefrontal response, and additionally showed that while this was observed for both dorsolateral and ventrolateral prefrontal cortex in controls, the pattern was reversed, specifically in

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the dorsolateral region. Furthermore, this association between behavior and physiology was predicted by reduced N-acetylaspartate (NAA) concentrations in dorsolateral prefrontal cortex: neuronal pathology (reduced NAA) was associated with inefficient dorsolateral activation. The relationship between cognitive performance and physiological response is clearly a complex association; the above summary is not conclusive, and does not account for all discrepancies in the literature (see ‘Methodological challenges’ for further methodological challenges; for review of other relevant technical issues in assessing prefrontal function in schizophrenia, see Manoach (2003)). However, the proposed relationship between increasing prefrontal activation in response to increased cognitive load, and the disruption of prefrontal function once cognitive capacity is reached, is strengthened by the observation from schizophrenia studies, where the interpretation appears to hold, despite the fact that cognitive capacity is reduced, and therefore capacity limitations are reached at lower thresholds. Psychiatric studies therefore serve to test the hypothesized relationship between performance and physiology over a broader ‘dose-response curve’ of cognitive ability. The contribution of studies in schizophrenia has therefore been to provide convergent evidence, critical to the development of a robust theory of working memory. Functional connectivity. The prefrontal cortex clearly plays a critical role in working memory, however a more complete description of its neurobiological basis requires consideration of a complex integration of information across a large scale neurocognitive network to support cognitive function. Physiological connectivity is inferred from neuroimaging data on the basis of the correlation observed between time-series from two distinct brain regions. This correlation may indicate a direct inter-regional causal relationship, or alternatively may be mediated by additional regions. In order to evaluate a quantitative assessment of the functional relationship between multiple brain regions, multivariate methods such as path analysis and structural equation modeling (McIntosh et al., 1994; Buchel and Friston, 1997; Bullmore et al., 2000) are increasingly applied to imaging data in order to test hypothesis-driven models of integrative function within anatomical constraints. These techniques have been termed ‘functional’ and ‘effective’ connectivity respectively (Friston et al., 1997). Theoretical models of schizophrenia increasingly identify functional dysconnectivity as a primary pathophysiological mechanism (Weinberger, 1993; Friston and Frith, 1995; Bullmore et al., 1997). Accordingly, a number of studies have reported functional abnormalities involving the afferent and efferent projections of the prefrontal cortex (Fletcher et al., 1999; Bunney and Bunney, 2000; MeyerLindenberg et al., 2001; Stephan et al., 2001; Ford et al., 2002; Lawrie et al., 2002; Kim et al., 2003; Schlosser et al., 2003a; Winterer et al., 2003). Schizophrenia, as a disorder of functional connectivity may therefore provide an appropriate test of connectionist models of the components of

working memory, involving a ‘functional lesion,’ compared with discrete structural lesions typically the focus of neuropsychology. Both functional (Li et al., 2004) and effective (Honey et al., 2002c) connectivity analyses of working memory have been reported in healthy volunteers. Honey et al. (2002c) reported that increasing working memory load was associated with increased connectivity between frontal and parietal regions, and also increased inter-hemispheric communication between dorsolateral frontal regions. The proposed dysconnectivity and associated failure of working memory performance in schizophrenia provides an ideal opportunity to test the hypothesis of whether the strength of fronto-frontal and fronto-parietal connections is indeed required to meet increasing working memory demands. In support of this, Meyer-Lindenberg et al. (2001) found that while a pattern of connectivity involving lateral prefrontal, cingulate and parietal regions was observed in controls, a pattern incorporating inferotemporal, parahippocampal and cerebellar connectivity was observed for the patient group. Similarly, Kim et al. (2003) found that prefrontal activation correlated significantly with bilateral parietal regions in controls, but not in patients. Schlosser et al. (2003a) compared patients treated with either typical or atypical anti-psychotics and healthy volunteers. They found that both patient groups showed reduced inter-hemispheric communication between dorsolateral frontal regions, and that this was most severe in the typically-treated group, and replicated these findings in drug-free patients (Schlosser et al., 2003b). Taken together, these studies provide convergent evidence that fronto-parietal and interhemispheric frontal connectivity is central to working memory function. These studies also reported impaired working memory performance in patients; it will be important for future studies to determine whether increased functional connectivity is observed at working memory loads within the performance capacity of the patients. Compensatory adaptation. Functional reorganization following a structural lesion resulting from a cerebrovascular infarction is commonly observed in cerebral ischemic patients. In functional disorders such as schizophrenia, there is some evidence that similar compensatory adaptations may also occur in response to compromised function in a given brain region. The observations of alternative patterns of activity in patients, in the context of intact behavioral performance, have been reported by several groups. This may be an indication of the greater sensitivity of functional imaging to neurocognitive dysfunction in comparison to routine neuropsychological assessments, whereby gross measures, such as task accuracy and reaction time may present as unimpaired, but conceal more subtle physiological abnormalities, leading to physiological compensation in other brain regions, or cognitive compensation, such as adapting alternative strategies. In relation to normal brain function, such observations could potentially provide information that the functional recruitment of particular brain regions may not be necessary for working memory, and can be replaced or at least supplemented,

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without loss of function. Additionally, aberrant activity at lower performance requirements may provide insight into the cause of behavioral disruption as task demands increase. Manoach et al. (2000) found that patients with schizophrenia showed increased activation of basal ganglia and thalamus during performance of a working memory task, which was not observed in controls. This observation was independent of whether or not performance was equated across groups (by comparing high load in controls and low load in patients). The authors suggest that studies in patients with Parkinson’s disease indicate that fronto-striatal circuitry is critical in supporting working memory function (Owen, 1997) and subcortical activation is frequently observed under conditions involving increasing working memory load (Barch et al., 1997; Goldberg et al., 1998; Callicott et al., 1999; Rypma et al., 1999). They therefore speculate that the activation of basal ganglia and thalamus in the patient group may reflect a failure to automate aspects of task performance, and ‘tune’ patterns of activity to optimize performance. Increased recruitment of the basal ganglia is compatible with the findings of Schlosser et al. (2003a), who reported that patients treated with either typical or atypical anti-psychotics showed increased connectivity between thalamus and prefrontal cortex. The implication of these studies is that basal ganglia projections to frontal cortex via the thalamus are involved in the normal circuitry of the early phases underlying working memory, and that other regions, such as prefrontal and parietal cortices, supplant subcortical activity as performance improves. These predictions were subsequently supported in a recent study demonstrating that increasing practice on a working memory task in healthy volunteers was associated with diminishing activation of putamen, thalamus and anterior frontal gyrus (Landau et al., 2004). On the basis of prior associations between fronto-striatal circuitry and the formation of arbitrary visuomotor associations and abstract rules (Murray et al., 2000), the authors suggest that the attenuation of fronto-striatal recruitment may reflect subjects’ reducing need to focus on task rules, as subjects became more practiced (Landau et al., 2004). The persistence of such activation in patients with schizophrenia may therefore reflect a compensatory response to maintain task requirements during performance. This aberrant activation of basal ganglia may also lead to inefficient recruitment of the frontal cortex: Callicott et al. (2003b) found that in patients with performance levels similar to low-performing controls, a predominantly hyperfrontal response was observed, but regions of hypofrontality were also evident. Studies of working memory in patients with schizophrenia have therefore provided an indication of the transition from inefficient, novice task performance to automation and expertise, characterized by a development from subcortical to cortical mediation of function. Methodological challenges Observations based on physiological abnormalities associated with working memory deficits in schizophrenia have

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certainly provided useful information which allow hypotheses regarding specialization and integration of function to be tested in vivo by observing the effects of physiological abnormalities in the brain. However, one should be cautious in extrapolating from the disease state to the normal brain, and indeed this is particularly the case for schizophrenia. Schizophrenia is a disorder of unknown etiology/ pathophysiology. Schizophrenia cannot be considered as a pure lesion model. In contrast to the discrete localized structural lesions explored in neuropsychological investigations, gross structural abnormalities are not typical of schizophrenia. Any observed relationship between a cognitive deficit and presumed neurophysiological functional abnormality must be considered tentatively since the pathophysiological basis of schizophrenia remains undetermined. Schizophrenia is therefore a complex illness with no known etiology, no biological markers, treatment which is ineffective or only partially effective in a large number of cases, and its expression varies widely across individuals. These are critical questions which must be addressed before one can confidently draw conclusions from an observed abnormality in schizophrenia in relation to normal human brain function (Honey et al., 2002b). Heterogeneity of schizophrenia. Schizophrenia incorporates heterogeneous psychotic phenomena, none of which are pathognomonic of the illness. Patients differ widely along numerous parameters, including clinical presentation, prognosis, insight, cognitive dysfunction, neurological impairment, institutionalization, susceptibility to pharmacological side-effects and demographic history. Accordingly, clinicians confront each individual case with a variety of principal and concomitant management options, which will often vary over the course of an individual’s progression through the illness, and particularly between patients. Given this complex scenario of heterogeneity of both illness characterization and treatment, research efforts are forced to confront numerous confounds and myriad possible confound interactions. Consequently, research which groups subjects simply on the basis of diagnostic categories may be misleading, incorporating subjects which may have few, if any symptoms in common. However, in order to examine the neurobiological basis of working memory dysfunction, a case-control design has typically been adopted, involving the comparison of patient groups with healthy volunteers. Given the heterogeneity of psychiatric disorders, and variability over the course of the illness, this design may not be optimal: “If a diverse group of disorders is pooled together in studies of biological correlates, important findings may be lost because fundamental differences have been averaged out. Only a broad spread of variance is left behind as a clue to suggest the possible heterogeneity of schizophrenia. This variance is perhaps one of the most consistent observations in research on schizophrenia” (Andreasen, 1987). This point is supported by the observation by Manoach et al. (2000) examining individual responses to a working

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memory task: they found that increased spatial heterogeneity of response in dorsolateral prefrontal cortex was evident in patients with schizophrenia compared with controls. The source of this heterogeneity is unknown, however, as the authors point out, this observation raises the possibility that group-averaging may underestimate frontal response to working memory tasks in schizophrenia. While this could not explain a hyperfrontal response, it may provide an explanation for hypofrontality, as frequently reported. Strauss et al. (1974) suggested that, “Group comparison studies, using summarizing statistics, the ‘normal science’ in schizophrenia research, may at times be misleading if not inappropriate.” Such group summary data are crucial to PET studies and almost ubiquitously used in fMRI studies of working memory. Shallice et al. (1991) suggested: “inferences about the impaired functioning of particular regions of the brain in schizophrenics on the basis of the performance of groups of patients on individual neuropsychological tests should only be made tentatively.” The implication of the heterogeneity of prefrontal response to working memory tasks in schizophrenia is that the expression of certain symptoms may be of particular relevance to working memory dysfunction, and that this will potentially impact on the cortical response to working memory demands. Accordingly, McGrath et al. (2001) found that working memory impairment corresponded with the severity of negative symptoms and thought disorder; Menon et al. (2001) found that negative symptoms and thought disorder were inversely correlated with activation in the frontal operculum and right dorsolateral prefrontal cortex respectively. Honey et al. (2003a) found that a positive sub-syndrome was associated with a reduced fronto-temporal response to working memory, and negative symptoms were associated with increased response in medial and lateral premotor regions. Further investigations of associations between psychiatric symptoms, cognitive performance and physiological response may yield important information about the implications of working memory (dys)function, which would inaccessible by other means, and may serve to inform current models of working memory. Treatment-related confounds. Patients with schizophrenia are treated with a variety of anti-psychotics. The mechanism of action of these therapeutic agents is currently unknown. To a varying degree, all anti-psychotic medications have a considerable influence on the dopaminergic system (Strange, 2001; Kapur and Mamo, 2003), which is critically involved in working memory performance (Sawaguchi and Goldman-Rakic, 1991, 1994; Williams and Goldman-Rakic, 1995). There is some evidence that atypical anti-psychotics (newer compounds which tend to have reduced propensity to cause parkinsonian symptoms in humans and animal models as observed with typical anti-psychotics (Kerwin, 1994)) have some improvement in working memory and executive function (Green et al., 1997; Meltzer and McGurk, 1999; Harvey et al., 2003). However, the impact of anti-psychotics on the cerebral response to working memory has frequently been over-

looked in interpreting cortical responses in schizophrenic patients. Honey et al. (1999) investigated the effect of the atypical antipsychotic, risperidone, on prefrontal function. Atypical antipsychotics were predicted to enhance prefrontal function during performance of a working memory task, hypothetically via increased dopaminergic drive to the prefrontal cortex. This was predicted on the basis that patients with schizophrenia perform poorly on tests of working memory, and typically exhibit a hypofrontal response to such tasks (see Functional role of the lateral prefrontal cortex), which can be reversed by administration of dopamine agonists (Daniel et al., 1989). Furthermore, atypical antipsychotics have been shown to increase prefrontal dopaminergic activity in animal models (Hertel et al., 1996). The substitution of typical antipsychotics for risperidone was associated with increased activation of prefrontal cortex, compared with patients maintained on typical antipsychotics (Honey et al., 1999). There is also evidence that anti-psychotic treatment affects the functional connections of the prefrontal cortex (Stephan et al., 2001; Nahas et al., 2003). The interpretation of physiological deficits observed during the performance of working memory tasks in patients with schizophrenia is therefore complicated by the effects of both the illness and its treatment. It is possible to circumvent this issue by studying patients naïve to drug exposure, or following a drug-washout period. Such studies (Barch et al., 2001; Stephan et al., 2001; Schlosser et al., 2003b), which are particularly difficult to perform and relatively infrequently reported, therefore carry considerable influence, as highlighted elsewhere in this review. Psychopharmacological models Overview. Exposure to psychedelic substances in non-psychotic individuals produces profound perceptual, sensorimotor and cognitive disturbances. These effects vary considerably across drug categories, such as psychomotor stimulants (e.g. cocaine and amphetamine), psychotomimetic indoleamines (e.g. lysergic acid diethylamide (LSD)) and dissociative anesthetics (e.g. phencyclidine (PCP) and ketamine). The experiences produced by some of these compounds bear “impressive similarity [to] . . . certain primary symptoms of the schizophrenic process” (Luby et al., 1959). The use of psychotomimetic compounds to induce a transitory state of psychopathology in healthy controls has therefore increasingly been employed as a human in vivo model of psychosis, to reproduce the features of schizophrenia in healthy subjects. In accordance with the view that working memory dysfunction is a key aspect of schizophrenia, these compounds also perturb working memory performance, and thereby provide an opportunity to explore neurotransmitter mechanisms involved in working memory disruption. Combining psychopharmacological models of disease with functional imaging therefore provides a powerful approach to exploring the biological basis of working memory (dys)function. While this approach introduces additional considerations, such as the effect of the drug on the dependent imaging measure, e.g. the blood oxygenation level dependent (BOLD) contrast (Honey and Bullmore, 2004; Shah

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and Marsden, 2004), the primary advantage of this technique is that specific neurotransmitters can be experimentally augmented/inhibited in order to test hypotheses regarding their involvement in working memory and schizophrenia. This approach circumvents many of the interpretative problems outlined earlier, associated with observing cognitive deficits in patients with schizophrenia, by avoiding confounding factors such as chronicity of illness/treatment. In contrast to the static performance deficits in patient groups, dose administration can be graduated to establish a dose-response curve, up to and beyond cognitive capacity constraints. Furthermore, subjects serve as their own controls in double-blind, placebo-controlled, repeated measures designs, to some extent mitigating issues of group heterogeneity associated with between-group comparisons. The use of low-dose administration also offers the possibility of observing cognitive/ physiological effects of the drug which are below the threshold at which psychotic phenomenon are observed, thus facilitating a dissociation of these effects. For example, the presence of a hallucination may be sufficiently attentionally distracting to indirectly impair working memory performance, despite no specific effect on working memory processing per se. Eliciting cognitive disturbances at levels of drug exposure below that at which psychotic symptoms are evident thereby allows a more direct interpretation of the psychopharmacological manipulation. Before this approach can serve to clarify observations made on the basis of performance of schizophrenic patients, the validity of psychopharmacological models remains to be fully explored and validated at the cognitive and physiological level. However, psychopharmacological modulation of working memory has already proved a valuable research tool in increasing understanding of how the normal brain implements working memory processes, and also in validating current models of working memory. Dopamine. The dominant hypothesis of the pathophysiology of schizophrenia has centered around a disturbance of dopaminergic neurotransmission. The most compelling evidence for this is based on two observations: (i) the efficacy of anti-psychotic drugs in treating positive symptoms of schizophrenia is highly correlated with their affinity for post-synaptic dopamine (D2) receptors (Carlsson and Lindqvist, 1963; Matthysse, 1973; Creese et al., 1976; Seeman et al., 1976), and (ii) psychostimulants which serve to increase dopaminergic transmission cause psychotic symptoms. Amphetamine, which increases dopamine release and blocks re-uptake has been used in humans to demonstrate the inverted-U-shaped association between dopaminergic tone and prefrontal response to working memory tasks, previously observed using electrophysiological recordings of single unit activity recorded from prefrontal neurons in nonhuman primates (Williams and Goldman-Rakic, 1995). Mattay et al. (2000) found that dextroamphetamine improved working memory performance only in subjects with low capacity prior to drug; subjects with high capacity showed performance impairment and a greater increase in prefrontal

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activation. This study demonstrates that dopamine optimizes efficiency of prefrontal activity in low-capacity individuals, and reduces efficiency in high-capacity individuals, by increasing dopamine beyond optimum levels. Mattay et al.(2003) also demonstrated that working memory performance under amphetamine is influenced by a common polymorphism [val(158)-met] in the catechol O-methyltransferase (COMT) gene, important for metabolism of synaptically released dopamine in the prefrontal cortex: individuals with the val/val genotype showed improved working memory performance and reduced prefrontal activity under amphetamine compared with placebo, whereas performance was disrupted by amphetamine in individuals with the met/met genotype, and increased prefrontal activity was observed (Mattay et al., 2003). Glutamate. The proposed involvement of glutamate in schizophrenia developed from the observation that dissociative anesthetics such as PCP and ketamine reproduce both positive and negative symptoms of psychosis in healthy volunteers (Krystal et al., 1994), as well as exacerbating existing symptoms in patients (Lahti et al., 1995), linked to its affinity to the NMDA receptor (Javitt and Zukin, 1991). Ketamine may therefore provide a more comprehensive model of psychosis than amphetamine, which elicits only the positive symptoms of psychosis. Ketamine also produces disruption of cognitive function similar to that observed in schizophrenia, including impairments in working memory (Adler et al., 1998; Honey et al., 2003c, 2004). Honey et al. (2003b) demonstrated that impairment of working memory results specifically from a disruption of manipulating the contents of working memory, whereas the requirement to simply maintain items online was not affected. This dichotomy serves to support the theoretical dissociation between rehearsal processes required to maintain information in storage, and executive processes such as updating, manipulating and monitoring. In this study, analogous measures of visuo-spatial working memory were not measurably impaired, tentatively providing some indication of domain-specificity (Honey et al., 2003b). This pattern of findings provided some support for the proposed anatomical dissociation of function between the dorsolateral region of the prefrontal cortex, typically engaged in association with the executive component of working memory tasks, compared with the association between the ventrolateral region and maintenance processes (D’Esposito et al., 1999; Fletcher and Henson, 2001). In a subsequent study, it was further shown that ketamine augments fronto-parietal activation in response to manipulation compared with maintenance processes (Honey et al., 2004). These findings suggest that manipulation and maintenance processes, envisaged as separate component processes within current theoretical models of working memory, are both anatomically and pharmacologically dissociable.

CONCLUSIONS The extrapolation of observations from studies in schizophrenia to contribute to understanding of the processes

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underlying working memory in the normal brain must be made with some caution, and with appropriate caveats given the blurred taxonomic boundaries of the illness, and variability of the effects of the disease and its treatment on brain function. To date, this contribution is limited to providing convergent evidence for observations made in healthy volunteers. This is a modest, though important contribution. As our understanding increases of the neurobiological mechanisms which give rise to the cognitive deficits in schizophrenia, or the sub-syndromes which comprise it, we may see this information serving to generate testable hypotheses regarding normal brain function underlying working memory. Alternative approaches which index psychosis indirectly may provide an effective solution to some of these issues. These approaches include the study of susceptible populations, such as non-affected familial relatives of psychotic patients, or as we have explored in this review, the use of psychopharmacological models of the illness. The application of these techniques is likely to facilitate greater understanding of both schizophrenia and the biological basis of working memory (dys) function.

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(Accepted 27 May 2005) (Available online 15 December 2005)