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INVESTIGATING PRINCIPLES OF HUMAN BRAIN FUNCTIONUNDERLYING WORKING MEMORY: WHAT INSIGHTS FROMSCHIZOPHRENIA?

G. D. HONEY* AND P. C. FLETCHER

University of Cambridge, Department of Psychiatry, Brain Mapping

Unit, Downing Site, Downing Street, Cambridge CB2 3EB, UK

AbstractWorking memory dysfunction is a core component

of schizophrenia, which likely contributes substantially to the

pervasive and profound cognitive deficits observed in pa-

tients with this illness. Developments in functional imaging

have facilitated the investigation of the neural basis of these

cognitive deficits. A strong tradition within neuropsychologyhas 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, inter-

regional functional integration, and compensatory adapta-

tions. However, complex heterogeneous psychiatric disor-

ders such as schizophrenia cannot be considered akin to a

pure lesion model, and there are considerable methodologi-

cal 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 en-compasses a wide range of behavioral phenomena ex-pressed to varying degrees in symptomatic patients. Thepositive symptoms of the disorder, including hallucina-tions (primarily in the auditory modality) and delusionalideation, are perhaps the most widely recognized charac-teristics of the illness, while negative symptoms, for ex-ample, social withdrawal and flattened affect, are also

intrinsic features which contribute substantially to the de-bilitating nature of the disorder. In addition to these andother experiential disturbances, patients with schizophre-nia also show deficits across a broad range of neuropsy-chological domains. Impairment of cognitive function isincreasingly recognized as a core feature of this illness(Green, 1996; Green and Nuechterlein, 1999), and hasrecently been identified by the Measurement and Treat-ment Research to Improve Cognition in Schizophrenia

(MATRICS) Initiative to comprise primary deficits involvingworking memory, attention/vigilance, verbal learning andmemory, visual learning and memory, reasoning and prob-lem solving, speed of processing, and social cognition(Green et al., 2004).

Working memory, the ability to maintain and utilizeinformation in short-term memory (Baddeley and Hitch,1974; Baddeley, 1986), is a process which is central toeveryday functioning, and contributes significantly to otherareas of cognition. The theoretical concept of workingmemory was developed in response to limitations of pre-vious models of short-term memory, such as Atkinson andShiffrins Two-Process Model (Atkinson and Shiffrin,1968), to fully account for performance impairments inneuropsychological patients. The working memory model,proposed by Baddeley and Hitch (1974), identified a threecomponent system: the phonological loop (comprising a lim-ited capacity phonological store in which verbal informationis stored temporarily and maintained by subvocal rehearsal);the visuospatial sketchpad (a parallel sub-system to thephonological store, specialized for non-verbal material); andthe central executive, responsible for strategic co-ordinationand execution of the slave systems. The original model wasupdated, to include an episodic buffer, which provides aninterface between the sub-systems of working memory andlong-term memory (Baddeley, 2000).

Deficits in working memory have been consistently re-

ported in schizophrenic patients (Weinberger and Cermak,1973; Park and Holzman, 1992; Fleming et al., 1995; Keefeet al., 1995; Morris et al., 1997; Park and McTigue, 1997;Spindler et al., 1997; Park et al., 1999), and also first-degreeasymptomatic relatives (Conklin et al., 2000). There is someevidence of disproportionate memory impairment in the con-text of other domains of cognitive dysfunction (Saykin et al.,1991, 1994), and prognostic implications of such deficits inpsychosocial rehabilitation programs (Green, 1996). Accord-ingly, deficient working memory is key to a number ofcontemporary cognitive psychological models of schizo-phrenic symptoms (Goldman-Rakic, 1990a, 1994; Cohenand Servan-Schreiber, 1992; Weinberger, 1993).

*Correspondence to: G. D. Honey, University of Cambridge, Depart-ment of Psychiatry, Addenbrookes Hospital, Brain Mapping Unit, Box255, Cambridge CB2 2QQ, UK. Tel: 44-01223-764673; fax: 44-01223-764675.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 to-mography; TMS, transcranial magnetic stimulation.

Neuroscience 139 (2006) 5971

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 inschizophrenia, the question arises as to whether the infor-mation ascertained from this disorder may provide furtherinsights into normal brain function underlying workingmemory. The precedent for this approach is provided bythe contribution neuropsychological investigations have

made to the development of theoretical models throughoutcognitive psychology. Indeed, the concept of workingmemory and precursive models, have benefited substan-tially from investigations of behavioral impairments in pa-tients following neurological damage, sometimes referredto as natural memory experiments. These studies, typi-cally based on individual case histories, are often particu-larly influential in addressing subtle discriminations, whichmay prove intractable to standard experimental methodol-ogy: for example, observing intact subvocal rehearsal inpatients with anarthria, demonstrating that the subvocal-ization process, necessary to maintain and refresh infor-mation in working memory, does not require explicit artic-

ulation (Baddeley and Wilson, 1985). Similarly, the two-component model of the phonological loop, involving bothsubvocal rehearsal and phonological storage, was sub-stantiated on the basis of observations in patient P.V., whoshowed a specific sensitivity to phonological similarity ef-fects for information presented in the auditory modality.Visually-presented information was insensitive to phono-logical similarity, word length or articulatory suppression.Vallar and Baddeley (1984) interpreted this as an indica-tion of a specific impairment at the level of phonologicalstorage (thereby indicating its process separability), caus-ing the patient to strategically avoid use of the rehearsalmechanism for visual information, whereas the phonolog-ical store has automatic access to auditory information.

These examples demonstrate how neuropsychologycan be critical in developing and constraining theoreticalmodels of cognitive function. This approach can also beextended to incorporate the neurobiological implementa-tion of cognitive processes. This follows the classical tra-dition inaugurated by Brocas localization of speech pro-duction to the inferior frontal gyrus on the basis of themonosyllabic speech capacity of a patient following a le-sion to this region identified postmortem, and similarlyWernickes observation that damage to the left posteriortemporal cortex produces deficits in speech comprehen-sion. Progressing beyond single dissociations such asthese, relating the role of a particular brain region with a

specific cognitive process is most compellingly demon-strated by double dissociations, in which the loss of func-tion 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 neuropsy-

chological approach be applied to neuropsychiatry? Spe-cifically, can the behavioral deficits in working memoryobserved in patients with schizophrenia inform currentmodels of the neurobiological basis of working memory?The neuropsychological tradition of relating structural le-sions to cognitive dysfunction is clearly limited in its appli-cation to schizophrenia, since the neuropathology inschizophrenia is diffuse, subtle and variable between pa-

tients and over the course of the illness. However, putativefunctional pathology associated with schizophrenia mayprove revealing in relation to observed cognitive deficits. Inthis article, the extent to which functional imaging studiesof schizophrenia can be considered to have validated bi-ological models of working memory in the normal human

brain is reviewed. Implicitly, this asks the question ofwhether the principles of lesion-based neuropsychologyare directly transferable to (dys)functional imaging? Thefocus on functional neuroimaging is warranted on the basisthat this offers an unrivalled technique in cognitive neuro-science to investigate the biological basis of human cog-nitive function in vivo.

For descriptive purposes, this review is organized interms of principles of brain function which have emergedas important in the biological implementation of workingmemory. We firstly consider the functional role of the lat-eral prefrontal cortex: animal studies have clearly demon-strated the involvement of this region in working memory,

however, the interpretation of its role in humans, as evi-denced by functional neuroimaging is complicated by is-sues including reverse causality (the influence of behavioron physiological response and vice versa), functional di-aschisis (a primary abnormality in a remote brain region),and the limitations of the application of principles used asgold standards in neuropsychology to functional imaging.We further consider the response properties of the prefron-tal cortex, and how capacity limitations may explain therelationship between working memory performance, andhypo- or hyper-activity in frontal regions in patients. Theprefrontal cortex clearly does not function in isolation, andwe review studies which have examined its connectivitywith other structures, in both healthy subjects and patients.

Finally, we consider how functional deficits in regions in-cluding prefrontal cortex may be mitigated by compensa-tory recruitment of other brain areas, and the implicationsfor behavioral assessments. There are a number of inter-pretative difficulties in extrapolating from the disease stateto the normal brain which are considered, and this isparticularly relevant in the case of schizophrenia, in whichthe uncertain etiology/pathophysiology, and heterogeneityof the clinical profile and its treatment, seriously limit whatcan be generalized from this disorder to normative brainfunction subserving working memory. In conclusion, wesuggest that an alternative approach involving the use ofpsychopharmacological models of disease may circum-

vent some of these issues.

Functional neuroimaging in psychiatry as a tool in

cognitive neuroscience

While there is no implied anatomical localization of thesubcomponents of Baddeleys model of working memory,basic and clinical neuroscience research has increasinglyprovided support for the dissociation of processes pro-posed, and has gone some way to formulating a functionaltopology. Functional neuroimaging, primarily usingpositron emission tomography (PET) and functional mag-netic resonance imaging (fMRI) has, with increasingsophistication in experimental design, explored the biolog-

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ical basis of working memory in healthy human subjects(for review, see references (DEsposito et al., 2000; Owen,2000; Fletcher and Henson, 2001; Wager and Smith,2003)).

However, a limitation of this approach is that imagingcan reveal only the engagement of neural systems which

are correlated with cognitive function. As a cognitive pro-cess is experimentally manipulated, PET and fMRI providea remarkable capability to visualize the brain regions whichshow task-related responsivity. However, while the resultsof increasingly focused experimental paradigms can bepersuasively argued to represent a causal relationship,ultimately this cannot be demonstrated satisfactorily usingthese techniques in isolation, and must be interpreted inthe context of information from other methodological ap-proaches which involve perturbed function, such as behav-ioral impairments in neuropsychological patients, or non-invasive experimental interventions, such as transcranialmagnetic stimulation (TMS). TMS allows experimental ma-

nipulation of regional neuronal activity by applying a brief,high-amplitude pulse of current which temporarily inter-feres with the activity of local neurons. The observation ofimpaired cognitive performance following local disruptionof neural activity in a given region indicates that the func-tional integrity of a region is necessary for performance ofa task. The application of this technique to working mem-ory has been reported by several groups (Mottaghy et al.,2000; Mull and Seyal, 2001; Oliveri et al., 2001; Mottaghyet al., 2002; Nixon et al., 2004). Similarly, the integration offindings from neuroimaging and those of neuropsycholog-ical impairment following discrete lesions facilitates identi-fication of regions which are associated with, and neces-sary for particular functions, respectively (Fiez, 2001).

The use of schizophrenia as an in vivo disruption ofbiological function can be considered in some ways paral-lel to the TMS and neuropsychological approach, in thatbehavioral deficits are related to primary physiological dis-turbances. Indeed, schizophrenia may go beyond the clas-sical lesion model, involving disruptions of inter-regionalfunctional connections, rather than localized regional def-icits. Thus schizophrenia offers the opportunity to investi-gate a systems-level disruption of biological function, andconcomitant behavioral impairments may provide someindication of the nature of the processes perturbed by afunctional lesion. Convergent evidence regarding struc-turefunction relationships may therefore be ascertained

from complementary methodologies, incorporating func-tional imaging in healthy subjects and patients with schizo-phrenia, TMS and neuropsychological performance in pa-tients with discrete lesions. It is now a decade since thefirst fMRI studies were reported in patients with schizo-phrenia (Renshaw et al., 1994; Wenz et al., 1994), and alarge number of these have incorporated working memoryparadigms (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 etal., 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

al., 2003; Jacobsen et al., 2004; Kindermann et al., 2004;Mendrek et al., 2004, Thermenos et al., 2005), making areview of this body of literature, and its implications forunderstanding principles of normal brain function associ-ated with working memory, timely.

Principles of human brain function involved inworking memory

Functional role of the lateral prefrontal cortex.

Extensive single-unit recording studies in non-human pri-mates demonstrated that cells in and around the principalsulcus in the dorsolateral prefrontal cortex exhibit delay-related activity during delayed match to sample paradigms(Goldman-Rakic, 1987, 1990b). Furthermore, impedinglateral prefrontal activity, either via pharmacological block-ade of dopamine D

1receptors (Sawaguchi and Goldman-

Rakic, 1991, 1994; Williams and Goldman-Rakic, 1995), orneurochemical/surgical lesions (Funahashi et al., 1993) oflocal tissue, impairs working memory. The functional in-

volvement of the homologous region in humans in workingmemory has subsequently been confirmed by a large num-ber of functional imaging studies using both PET and fMRI.However, this indicates that the prefrontal cortex is asso-ciatedwith working memory in humans, but it does not testthe hypothesis that prefrontal activation is a requirementfor working memory. Does psychiatric imaging thereforeconfirm the prediction from animal studies that pathologicalconditions which compromise the integrity of prefrontalfunctioning should be associated with working memoryimpairments?

Goldman-Rakic (1990a, 1999) noted a parallel be-tween the performance deficits of schizophrenic patients

and those of non-human primates following lesion of theprincipal sulcal region of the prefrontal cortex, indicatingthat a pathological functional lesion of the prefrontal cortexin humans may underlie working memory deficits observedin these patients. Early imaging studies in schizophrenia,involving complex cognitive tasks engaging a range ofexecutive processes, typically exhibited a reduced frontalresponse in patients with schizophrenia, termed hypofron-tality (Buchsbaum et al., 1986; Weinberger and Berman,1988; Paulman et al., 1990; Andreasen et al., 1992; Ber-man et al., 1993). More recently, with the growing consen-sus that working memory represents a core deficit inschizophrenia, studies involving tasks designed to morespecifically isolate working memory processes also re-

ported a hypofrontal response (Callicott et al., 1998; Carteret al., 1998; Stevens et al., 1998; Barch et al., 2001, 2002,2003; Perlstein et al., 2003). A possible implication ofthese studies for normal brain function was that the lateralprefrontal cortex, which is consistently activated in healthyvolunteers during working memory tasks, is a necessaryrequirement for working memory processing, and in psy-chiatric conditions in which prefrontal function is disrupted,a failure of working memory is observed. While theseclinical studies largely involved medicated out-patients ex-periencing chronic illness, this is unlikely to represent aneffect 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 12 days of their first contactwith psychiatric services and had not been treated withneuroleptics prior to their involvement in the study.

However, there is an interesting distinction here whichexemplifies the complexities of applying the neuropsycho-logical approach to neuropsychiatry:

Reverse causality. The observation of a cognitivedeficit following a structural lesion to region A which wasabsent prior to the lesion would naturally lead the neuro-psychologist to infer that region A was in some way in-volved in the neural architecture underpinning the psycho-logical function that was lost. Clearly, it would be untenableto imply causality in the opposite direction. However, inevaluating the loss of biological function, as opposed tostructure, causality may indeed operate in either direction.It is possible that a physiological abnormality may lead to acognitive deficit, however it is equally possible that thebehavioral deficit, perhaps mediated indirectly via otherfactors (for example increased distractibility due to perva-

sive psychotic experiences), causes the subject to disen-gage from the task, and thereby fail to recruit task-relatedactivity in associated brain regions (for further discussion,see (Price and Friston, 1999)). Frith et al. (1995) proposedthat the impaired performance of schizophrenic patients onfrontal lobe tasks may result in the use of alternative strat-egies which do not engage prefrontal cortex, and thusresult in hypofrontality. Similarly, Ebmeier et al., suggestedthat The poorer performance of frontal activation tasks bypatients with schizophrenia is probably sufficient explana-tion for the difference from controls, who perform suchtasks 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 rela-tionship between physiological activation and cognitiveperformance is complex. Several studies, which have at-tempted to characterize this further, are considered furtherin Physiological capacity constraints.

Functional diaschisis. Both abnormal prefrontal re-sponse and cognitive impairment could potentially be ex-plained by diaschisis: a primary abnormality in a remotebrain region. Several regions, including the posterior pari-etal cortex and basal ganglia show delay-related activity innon-human primates and similarly, activation in functionalimaging studies in humans. There is certainly evidence ofabnormal activation of these structures in schizophrenia. Itis possible therefore that deficits in either of these could

represent the primary abnormality. Conceivably, this maylead to secondary, downstream effects in other brain re-gions, including the prefrontal cortex. Further investigationof the connectivity between these regions will therefore becritical in interpreting the functional involvement of theprefrontal cortex in working memory impairment.

Corroborative evidence that prefrontal dysfunction iscritical to working memory impairment is potentially avail-able if it is the case that (i) prefrontal abnormalities are alsoevident in other psychiatric disorders in which workingmemory impairment is present, and (ii) pathology did notoverlap in other regions except prefrontal cortex. Thisoverlap across disorders would tend to suggest that pre-

frontal dysfunction represents the central abnormality inworking memory dysfunction. For example, there is someevidence of working memory impairment in patients withunipolar depression (Sweeney et al., 1998; Pelosi et al.,2000), however, few functional imaging studies have in-vestigated the role of the prefrontal cortex during working

memory performance in this patient population. Barch etal. (2003) compared patients with major depression topatients with schizophrenia and healthy controls. In con-trast to the hypofrontal response in schizophrenia, they didnot observe a prefrontal deficit in depressed subjects;however, working memory performance was disrupted inthe schizophrenic, but not the depressed patients. A recentstudy reported by Hugdahl et al. (2004) found that despitesimilar performance deficits in patients, schizophrenic sub-

jects showed attenuated frontal response during a mentalarithmetic task which was not evident in depressed sub-

jects. While this task incorporated a working memory re-quirement, more process-specific tasks may be required to

address the question of whether prefrontal function is dis-rupted during working memory performance in patientswith non-schizophrenic psychiatric conditions, where a be-havioral deficit is also evident, and whether there is regional-specificity of this overlap. While not conclusive, these stud-ies could potentially be informative with regard to whetherfunctional disruption in this region is necessaryfor workingmemory performance.

Dissociation methodology. The use of double disso-ciations, which are prevalent in neuropsychological inves-tigations and provide compelling indications of processseparability and neuroanatomical localization, does nottranslate in a straightforward manner to functional imagingdata. For example, Bechara et al. (1995) reported that apatient with selective bilateral damage to the amygdalafailed to acquire conditioned autonomic responses to vi-sual or auditory stimuli but was able to demonstrate explicitknowledge of the declarative facts about which stimuliwere paired to the unconditioned stimulus. The oppositepattern was observed in a patient with selective bilateraldamage to the hippocampus. Finally, both conditioningand explicit awareness were found to be disrupted in apatient with bilateral damage to both amygdala and hip-pocampal formation. This elegant study provides strongevidence for a double dissociation of conditioning anddeclarative knowledge, and association with the integrity ofthe amygdala and hippocampus respectively. Could the

principles underlying these findings be extended to func-tional imaging? Process separability would be less con-vincing on the basis of functional observations, since analternative explanation of these data could involve a singleprocess which underlies the functional activation of bothregions; if this process was engaged to a greater extent inone task, e.g. acquisition of conditioning, and producesboth hippocampal activation and deactivation of amygdala,then the apparent double dissociation is misleading.

Henson (2005) recently outlined how process separa-bility is identifiable in functional imaging data, if one ex-tends Dunn and Kirsners (1988) principle of reversedassociation. The application to functional imaging data



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corresponds to the observation of increased task-relatedactivity in two brain regions, relative to an independentbaseline condition, and simultaneously, that the two re-gions contrast negatively across two task conditions. Thisparticular pattern of activity guards against the possibilitythat a double dissociation simply represents opposing ef-

fects of a shared single process, perhaps mediated viareciprocal connectivity between the two regions. However,while a reversed association imbues the observed asso-ciation between structure and function with a greater de-gree of process specificity, it does not change in any waythe nature of this relationship, i.e. it remains a (process-specific) correlative observation, which is not an indicationof whether the pattern of activation is necessary or suffi-cient. As such, disease-related perturbation of activity ob-served in regions for which a reverse association can bedemonstrated remains ambiguous with regard to its impli-cations for normal brain function, as for single and doubledissociations.

For the reasons outlined above, the interpretation offunctional abnormalities, such as hypofrontality in re-sponse to working memory tasks in schizophrenia, is con-founded by alternative explanations which limit the feasi-bility of extending these observations to the normal humanbrain. Brain function, as opposed to structure, has theproperty of dynamic adaptation, and this causes the func-tional relationships between regions to be fluid and con-text-dependent. Physiological abnormalities observed us-ing functional imaging are therefore insufficient to identifyregions which are necessary for specific cognitive pro-cesses. However, while the application of the principles ofclassical neuropsychology to modern functional imaging

methods may be inappropriate, this is not to suggest thatthere is no insight to be gained into the normal brain basedon the functional deficits identified using neuroimaging inpatients with schizophrenia. Neuropsychological and im-aging-based investigations are synergistic approaches(Rorden and Karnath, 2004), however, the nature of theinsights offered by these two techniques differs consider-ably. Below, the possible insights from functional imagingare considered further.

Physiological capacity constraints. Neuroimagingstudies in healthy volunteers have demonstrated that thefunctional relationship between prefrontal response andcognitive demand is not a simple linear association. Pre-

frontal activation increases in line with task demands untilthe capacity limitation of working memory is reached, atwhich point, activation decreases (Callicott et al., 1999). Therelationship between cognitive performance and corticalphysiology is therefore best described by an inverted-U func-tion, in contrast to response in other (though not all) brainregions, which plateau as capacity is reached (Callicott etal., 1999). The hypofrontal response observed in patientswith schizophrenia, may therefore reflect the normal atten-uation of response following overload of working memorycapacity, occurring at an abnormally reduced thresholddue to pathology. Since patients with schizophrenia havereduced working memory capacity, studying this popula-

tion offers the opportunity to dissociate the factors of cog-nitive load and capacity, since capacity will be breached ata lower load threshold in patients compared with healthyvolunteers. This is an important dissociation since incre-ments in working memory load are often not purely quan-titative increases, but may also induce qualitative differ-

ences between levels, such that further processes andadjunctive strategies are engaged as demand increases(Honey et al., 2000). The observation of similar principlesof brain function underlying capacity limitation at low loadin patients, compared with high load in controls wouldtherefore provide robust support for the proposed relation-ship between physiological response and cognitive load,independent of the qualitative variations associated withexperimental task manipulations.

The suggestion that hypofrontality may reflect reducedcognitive capacity, with normal (or increased) frontal re-sponse occurring within performance capacity was firstproposed by Fletcher et al. (1998) employing a word-recall

task: they observed that patients showed normal frontalactivation when the cognitive demands of the task werelow, but failed to show the increased prefrontal activationto increased word list length observed in controls. As theynoted, since list length was also associated with time, thisfinding may relate to a failure to engage long-term memoryprocesses or the maintenance of information in workingmemory. The latter interpretation was supported by sub-sequent studies involving more specific working memorytasks. Using the Sternberg item recognition task (Stern-berg, 1966) Manoach et al. (1999, 2000) reported in-creased frontal activation in patients performing a taskwhich was within capacity, but for which behavioral indicesdemonstrated that patients found the task more difficultthan controls. Interestingly, a negative correlation was ob-served between error rate and prefrontal activation in thepatients, suggesting that activation increases with de-mand, until cognitive capacity is exceeded. As they noted,this leads to the intriguing speculation that further in-creases in load may have resulted in a hypofrontal re-sponse in the patients, whereas this increase may haveremained within the performance capacity of the controls,and therefore resulted in increased activation in line withdemand, thus reversing the between-group comparisonobserved at lower cognitive loads. In accordance with this,Perlstein et al. (2001) found that hypofrontality was ob-served in the patient group only at the highest load, the

only level which differentiated groups on behavioral per-formance. The hypofrontal response variably reported inschizophrenia is thus not a static phenomenon, but dynam-ically related to task requirements and subjects capacityrange to perform the task. Callicott et al. (2000) recruitedpatients based on prior screening of minimal proficiency(90% accuracy on the n-back task) and demonstrated ahyperfrontal response to working memory demands asobserved by Manoach et al. (1999, 2000). They also con-firmed the correlation between accuracy and prefrontalresponse, and additionally showed that while this wasobserved for both dorsolateral and ventrolateral prefrontalcortex in controls, the pattern was reversed, specifically in



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the dorsolateral region. Furthermore, this association be-tween behavior and physiology was predicted by reducedN-acetylaspartate (NAA) concentrations in dorsolateralprefrontal cortex: neuronal pathology (reduced NAA) wasassociated 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 ac-count for all discrepancies in the literature (see Method-ological challenges for further methodological challenges;for review of other relevant technical issues in assessingprefrontal function in schizophrenia, see Manoach (2003)).However, the proposed relationship between increasingprefrontal activation in response to increased cognitiveload, and the disruption of prefrontal function once cogni-tive capacity is reached, is strengthened by the observa-tion from schizophrenia studies, where the interpretationappears to hold, despite the fact that cognitive capacity isreduced, and therefore capacity limitations are reached at

lower thresholds. Psychiatric studies therefore serve totest the hypothesized relationship between performanceand physiology over a broader dose-response curve ofcognitive ability. The contribution of studies in schizophre-nia has therefore been to provide convergent evidence,critical to the development of a robust theory of workingmemory.

Functional connectivity. The prefrontal cortex clearlyplays a critical role in working memory, however a morecomplete description of its neurobiological basis requiresconsideration of a complex integration of informationacross a large scale neurocognitive network to supportcognitive function. Physiological connectivity is inferred

from neuroimaging data on the basis of the correlationobserved between time-series from two distinct brain re-gions. This correlation may indicate a direct inter-regionalcausal relationship, or alternatively may be mediated byadditional regions. In order to evaluate a quantitative as-sessment of the functional relationship between multiplebrain regions, multivariate methods such as path analysisand structural equation modeling (McIntosh et al., 1994;Buchel and Friston, 1997; Bullmore et al., 2000) are in-creasingly applied to imaging data in order to test hypoth-esis-driven models of integrative function within anatomi-cal constraints. These techniques have been termed func-tional and effective connectivity respectively (Friston et

al., 1997).Theoretical models of schizophrenia increasingly iden-

tify functional dysconnectivity as a primary pathophysio-logical mechanism (Weinberger, 1993; Friston and Frith,1995; Bullmore et al., 1997). Accordingly, a number ofstudies have reported functional abnormalities involvingthe afferent and efferent projections of the prefrontal cortex(Fletcher et al., 1999; Bunney and Bunney, 2000; Meyer-Lindenberg 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 disorderof functional connectivity may therefore provide an appro-priate test of connectionist models of the components of

working memory, involving a functional lesion, comparedwith discrete structural lesions typically the focus of neu-ropsychology.

Both functional (Li et al., 2004) and effective (Honey etal., 2002c) connectivity analyses of working memory havebeen reported in healthy volunteers. Honey et al. (2002c)

reported that increasing working memory load was asso-ciated with increased connectivity between frontal and pa-rietal regions, and also increased inter-hemispheric com-munication between dorsolateral frontal regions. The pro-posed dysconnectivity and associated failure of workingmemory performance in schizophrenia provides an idealopportunity to test the hypothesis of whether the strengthof fronto-frontal and fronto-parietal connections is indeedrequired to meet increasing working memory demands. Insupport of this, Meyer-Lindenberg et al. (2001) found thatwhile a pattern of connectivity involving lateral prefrontal,cingulate and parietal regions was observed in controls, apattern incorporating inferotemporal, parahippocampal

and cerebellar connectivity was observed for the patientgroup. Similarly, Kim et al. (2003) found that prefrontalactivation correlated significantly with bilateral parietal re-gions in controls, but not in patients. Schlosser et al.(2003a) compared patients treated with either typical oratypical anti-psychotics and healthy volunteers. Theyfound that both patient groups showed reduced inter-hemi-spheric communication between dorsolateral frontal re-gions, and that this was most severe in the typically-treatedgroup, and replicated these findings in drug-free patients(Schlosser et al., 2003b). Taken together, these studiesprovide convergent evidence that fronto-parietal and inter-hemispheric frontal connectivity is central to working mem-

ory function. These studies also reported impaired workingmemory performance in patients; it will be important forfuture studies to determine whether increased functionalconnectivity is observed at working memory loads withinthe performance capacity of the patients.

Compensatory adaptation. Functional reorganizationfollowing a structural lesion resulting from a cerebrovascu-lar infarction is commonly observed in cerebral ischemicpatients. In functional disorders such as schizophrenia,there is some evidence that similar compensatory adapta-tions may also occur in response to compromised functionin a given brain region. The observations of alternativepatterns of activity in patients, in the context of intact

behavioral performance, have been reported by severalgroups. This may be an indication of the greater sensitivity offunctional imaging to neurocognitive dysfunction in compari-son to routine neuropsychological assessments, wherebygross measures, such as task accuracy and reaction timemay present as unimpaired, but conceal more subtle phys-iological abnormalities, leading to physiological compen-sation in other brain regions, or cognitive compensation,such as adapting alternative strategies. In relation to nor-mal brain function, such observations could potentiallyprovide information that the functional recruitment of par-ticular brain regions may not be necessary for workingmemory, and can be replaced or at least supplemented,



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without loss of function. Additionally, aberrant activity atlower performance requirements may provide insight intothe cause of behavioral disruption as task demands in-crease.

Manoach et al. (2000) found that patients with schizo-phrenia showed increased activation of basal ganglia and

thalamus during performance of a working memory task,which was not observed in controls. This observation wasindependent of whether or not performance was equatedacross groups (by comparing high load in controls and lowload in patients). The authors suggest that studies in pa-tients with Parkinsons disease indicate that fronto-striatalcircuitry is critical in supporting working memory function(Owen, 1997) and subcortical activation is frequently ob-served under conditions involving increasing workingmemory load (Barch et al., 1997; Goldberg et al., 1998;Callicott et al., 1999; Rypma et al., 1999). They thereforespeculate that the activation of basal ganglia and thalamusin the patient group may reflect a failure to automate

aspects of task performance, and tune patterns of activityto optimize performance. Increased recruitment of thebasal ganglia is compatible with the findings of Schlosseret al. (2003a), who reported that patients treated witheither typical or atypical anti-psychotics showed increasedconnectivity between thalamus and prefrontal cortex. Theimplication of these studies is that basal ganglia projec-tions to frontal cortex via the thalamus are involved in thenormal circuitry of the early phases underlying workingmemory, and that other regions, such as prefrontal andparietal cortices, supplant subcortical activity as perfor-mance improves. These predictions were subsequentlysupported in a recent study demonstrating that increasingpractice 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-striatalcircuitry and the formation of arbitrary visuomotor associ-ations and abstract rules (Murray et al., 2000), the authorssuggest that the attenuation of fronto-striatal recruitmentmay 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 schizo-phrenia may therefore reflect a compensatory response tomaintain task requirements during performance. This ab-errant activation of basal ganglia may also lead to ineffi-cient recruitment of the frontal cortex: Callicott et al.

(2003b) found that in patients with performance levelssimilar to low-performing controls, a predominantly hyper-frontal response was observed, but regions of hypofrontal-ity were also evident. Studies of working memory in pa-tients with schizophrenia have therefore provided an indi-cation of the transition from inefficient, novice taskperformance to automation and expertise, characterizedby a development from subcortical to cortical mediation offunction.

Methodological challenges

Observations based on physiological abnormalities asso-ciated with working memory deficits in schizophrenia have

certainly provided useful information which allow hypothe-ses regarding specialization and integration of function tobe tested in vivo by observing the effects of physiologicalabnormalities in the brain. However, one should be cau-tious in extrapolating from the disease state to the normalbrain, and indeed this is particularly the case for

schizophrenia.

Schizophrenia is a disorder of unknown etiology/

pathophysiology. Schizophrenia cannot be consideredas a pure lesion model. In contrast to the discrete localizedstructural lesions explored in neuropsychological investi-gations, gross structural abnormalities are not typical ofschizophrenia. Any observed relationship between a cog-nitive deficit and presumed neurophysiological functionalabnormality must be considered tentatively since thepathophysiological basis of schizophrenia remains unde-termined. Schizophrenia is therefore a complex illness withno known etiology, no biological markers, treatment whichis ineffective or only partially effective in a large number ofcases, and its expression varies widely across individuals.These are critical questions which must be addressedbefore one can confidently draw conclusions from an ob-served abnormality in schizophrenia in relation to normalhuman brain function (Honey et al., 2002b).

Heterogeneity of schizophrenia. Schizophrenia in-corporates heterogeneous psychotic phenomena, none ofwhich are pathognomonic of the illness. Patients differwidely along numerous parameters, including clinical pre-sentation, prognosis, insight, cognitive dysfunction, neuro-logical impairment, institutionalization, susceptibility topharmacological side-effects and demographic history. Ac-

cordingly, clinicians confront each individual case with avariety of principal and concomitant management options,which will often vary over the course of an individualsprogression through the illness, and particularly betweenpatients. Given this complex scenario of heterogeneity ofboth illness characterization and treatment, researchefforts are forced to confront numerous confounds andmyriad possible confound interactions. Consequently, re-search which groups subjects simply on the basis of diag-nostic categories may be misleading, incorporating sub-

jects which may have few, if any symptoms in common.However, in order to examine the neurobiological basis ofworking memory dysfunction, a case-control design hastypically been adopted, involving the comparison of patient

groups with healthy volunteers. Given the heterogeneity ofpsychiatric disorders, and variability over the course of theillness, this design may not be optimal:

If a diverse group of disorders is pooled together instudies of biological correlates, important findings may belost because fundamental differences have been averagedout. Only a broad spread of variance is left behind as a clueto suggest the possible heterogeneity of schizophrenia.This variance is perhaps one of the most consistent ob-servations in research on schizophrenia (Andreasen,1987).

This point is supported by the observation by Manoachet al. (2000) examining individual responses to a working



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memory task: they found that increased spatial heteroge-neity of response in dorsolateral prefrontal cortex wasevident in patients with schizophrenia compared with con-trols. The source of this heterogeneity is unknown, how-ever, as the authors point out, this observation raises thepossibility that group-averaging may underestimate frontal

response to working memory tasks in schizophrenia. Whilethis could not explain a hyperfrontal response, it may pro-vide an explanation for hypofrontality, as frequently re-ported. Strauss et al. (1974) suggested that, Group com-parison studies, using summarizing statistics, the normalscience in schizophrenia research, may at times be mis-leading if not inappropriate. Such group summary data arecrucial to PET studies and almost ubiquitously used infMRI studies of working memory. Shallice et al. (1991)suggested: inferences about the impaired functioning ofparticular regions of the brain in schizophrenics on thebasis of the performance of groups of patients on individualneuropsychological tests should only be made tentatively.

The implication of the heterogeneity of prefrontal re-sponse to working memory tasks in schizophrenia is thatthe expression of certain symptoms may be of particularrelevance to working memory dysfunction, and that this willpotentially impact on the cortical response to workingmemory demands. Accordingly, McGrath et al. (2001)found that working memory impairment corresponded withthe severity of negative symptoms and thought disorder;Menon et al. (2001) found that negative symptoms andthought disorder were inversely correlated with activationin the frontal operculum and right dorsolateral prefrontalcortex respectively. Honey et al. (2003a) found that apositive sub-syndrome was associated with a reduced

fronto-temporal response to working memory, and nega-tive symptoms were associated with increased response inmedial and lateral premotor regions. Further investiga-tions of associations between psychiatric symptoms,cognitive performance and physiological response mayyield important information about the implications ofworking memory (dys)function, which would inaccessi-ble by other means, and may serve to inform currentmodels of working memory.

Treatment-related confounds. Patients with schizo-phrenia are treated with a variety of anti-psychotics. Themechanism of action of these therapeutic agents is cur-rently unknown. To a varying degree, all anti-psychotic

medications have a considerable influence on the dopami-nergic system (Strange, 2001; Kapur and Mamo, 2003),which is critically involved in working memory performance(Sawaguchi and Goldman-Rakic, 1991, 1994; Williamsand Goldman-Rakic, 1995). There is some evidence thatatypical anti-psychotics (newer compounds which tend tohave reduced propensity to cause parkinsonian symptomsin humans and animal models as observed with typicalanti-psychotics (Kerwin, 1994)) have some improvement inworking memory and executive function (Green et al.,1997; Meltzer and McGurk, 1999; Harvey et al., 2003).However, the impact of anti-psychotics on the cerebralresponse to working memory has frequently been over-

looked in interpreting cortical responses in schizophrenicpatients. Honey et al. (1999) investigated the effect of theatypical antipsychotic, risperidone, on prefrontal function.

Atypical antipsychotics were predicted to enhance prefron-tal function during performance of a working memory task,hypothetically via increased dopaminergic drive to the pre-

frontal cortex. This was predicted on the basis that patientswith schizophrenia perform poorly on tests of workingmemory, and typically exhibit a hypofrontal response tosuch tasks (see Functional role of the lateral prefrontalcortex), which can be reversed by administration of dopa-mine agonists (Daniel et al., 1989). Furthermore, atypicalantipsychotics have been shown to increase prefrontaldopaminergic activity in animal models (Hertel et al.,1996). The substitution of typical antipsychotics for risperi-done was associated with increased activation of prefron-tal cortex, compared with patients maintained on typicalantipsychotics (Honey et al., 1999). There is also evidencethat anti-psychotic treatment affects the functional connec-

tions of the prefrontal cortex (Stephan et al., 2001; Nahaset al., 2003). The interpretation of physiological deficitsobserved during the performance of working memory tasksin patients with schizophrenia is therefore complicated bythe effects of both the illness and its treatment. It is pos-sible to circumvent this issue by studying patients nave todrug exposure, or following a drug-washout period. Suchstudies (Barch et al., 2001; Stephan et al., 2001; Schlosseret al., 2003b), which are particularly difficult to perform andrelatively infrequently reported, therefore carry consider-able influence, as highlighted elsewhere in this review.

Psychopharmacological models

Overview. Exposure to psychedelic substances innon-psychotic individuals produces profound perceptual,sensorimotor and cognitive disturbances. These effectsvary considerably across drug categories, such as psy-chomotor stimulants (e.g. cocaine and amphetamine), psy-chotomimetic indoleamines (e.g. lysergic acid diethylam-ide (LSD)) and dissociative anesthetics (e.g. phencyclidine(PCP) and ketamine). The experiences produced by someof these compounds bear impressive similarity [to] . . .certain primary symptoms of the schizophrenic process(Luby et al., 1959). The use of psychotomimetic com-pounds to induce a transitory state of psychopathology inhealthy controls has therefore increasingly been employedas a human in vivo model of psychosis, to reproduce the

features of schizophrenia in healthy subjects. In accor-dance with the view that working memory dysfunction is akey aspect of schizophrenia, these compounds also per-turb working memory performance, and thereby provide anopportunity to explore neurotransmitter mechanisms in-volved in working memory disruption. Combining psycho-pharmacological models of disease with functional imagingtherefore provides a powerful approach to exploring thebiological basis of working memory (dys)function.

While this approach introduces additional consider-ations, such as the effect of the drug on the dependentimaging measure, e.g. the blood oxygenation level depen-dent (BOLD) contrast (Honey and Bullmore, 2004; Shah



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and Marsden, 2004), the primary advantage of this tech-nique is that specific neurotransmitters can be experimen-tally augmented/inhibited in order to test hypotheses re-garding their involvement in working memory and schizo-phrenia. This approach circumvents many of theinterpretative problems outlined earlier, associated with

observing cognitive deficits in patients with schizophrenia,by avoiding confounding factors such as chronicity of ill-ness/treatment. In contrast to the static performance defi-cits in patient groups, dose administration can be gradu-ated to establish a dose-response curve, up to and beyondcognitive capacity constraints. Furthermore, subjectsserve as their own controls in double-blind, placebo-con-trolled, repeated measures designs, to some extent miti-gating issues of group heterogeneity associated with be-tween-group comparisons. The use of low-dose adminis-tration also offers the possibility of observing cognitive/physiological effects of the drug which are below thethreshold at which psychotic phenomenon are observed,

thus facilitating a dissociation of these effects. For exam-ple, the presence of a hallucination may be sufficientlyattentionally distracting to indirectly impair working mem-ory performance, despite no specific effect on workingmemory processing per se. Eliciting cognitive disturbancesat levels of drug exposure below that at which psychoticsymptoms are evident thereby allows a more direct inter-pretation of the psychopharmacological manipulation.

Before this approach can serve to clarify observationsmade on the basis of performance of schizophrenic pa-tients, the validity of psychopharmacological models re-mains to be fully explored and validated at the cognitiveand physiological level. However, psychopharmacological

modulation of working memory has already proved a valu-able research tool in increasing understanding of how thenormal brain implements working memory processes, andalso in validating current models of working memory.

Dopamine. The dominant hypothesis of the patho-physiology of schizophrenia has centered around a distur-bance of dopaminergic neurotransmission. The most com-pelling evidence for this is based on two observations: (i)the efficacy of anti-psychotic drugs in treating positivesymptoms of schizophrenia is highly correlated with theiraffinity for post-synaptic dopamine (D

2) receptors (Carls-

son and Lindqvist, 1963; Matthysse, 1973; Creese et al.,1976; Seeman et al., 1976), and (ii) psychostimulants

which serve to increase dopaminergic transmission causepsychotic symptoms.

Amphetamine, which increases dopamine release andblocks re-uptake has been used in humans to demonstratethe inverted-U-shaped association between dopaminergictone and prefrontal response to working memory tasks, pre-viously observed using electrophysiological recordings ofsingle unit activity recorded from prefrontal neurons in non-human primates (Williams and Goldman-Rakic, 1995). Mat-tay et al. (2000) found that dextroamphetamine improvedworking memory performance only in subjects with low ca-pacity prior to drug; subjects with high capacity showed per-formance impairment and a greater increase in prefrontal

activation. This study demonstrates that dopamine optimizesefficiency of prefrontal activity in low-capacity individuals, andreduces efficiency in high-capacity individuals, by increasingdopamine beyond optimum levels. Mattay et al.(2003) alsodemonstrated that working memory performance under am-phetamine is influenced by a common polymorphism

[val(158)-met] in the catechol O-methyltransferase (COMT)gene, important for metabolism of synaptically released do-pamine in the prefrontal cortex: individuals with the val/valgenotype showed improved working memory performanceand reduced prefrontal activity under amphetamine com-pared with placebo, whereas performance was disrupted byamphetamine in individuals with the met/met genotype, andincreased prefrontal activity was observed (Mattay et al.,2003).

Glutamate. The proposed involvement of glutamatein schizophrenia developed from the observation that dis-sociative anesthetics such as PCP and ketamine repro-duce both positive and negative symptoms of psychosis in

healthy volunteers (Krystal et al., 1994), as well as exac-erbating 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 compre-hensive model of psychosis than amphetamine, which elic-its only the positive symptoms of psychosis. Ketamine alsoproduces disruption of cognitive function similar to thatobserved in schizophrenia, including impairments in work-ing memory (Adler et al., 1998; Honey et al., 2003c, 2004).Honey et al. (2003b) demonstrated that impairment ofworking memory results specifically from a disruption ofmanipulating the contents of working memory, whereasthe requirement to simply maintain items online was not

affected. This dichotomy serves to support the theoreticaldissociation between rehearsal processes required tomaintain information in storage, and executive processessuch as updating, manipulating and monitoring. In thisstudy, analogous measures of visuo-spatial working mem-ory were not measurably impaired, tentatively providingsome indication of domain-specificity (Honey et al.,2003b). This pattern of findings provided some support forthe proposed anatomical dissociation of function betweenthe dorsolateral region of the prefrontal cortex, typicallyengaged in association with the executive component ofworking memory tasks, compared with the associationbetween the ventrolateral region and maintenance pro-cesses (DEsposito et al., 1999; Fletcher and Henson,2001). In a subsequent study, it was further shown thatketamine augments fronto-parietal activation in responseto manipulation compared with maintenance processes(Honey et al., 2004). These findings suggest that manipu-lation and maintenance processes, envisaged as separatecomponent processes within current theoretical models ofworking memory, are both anatomically and pharmacolog-ically dissociable.

CONCLUSIONS

The extrapolation of observations from studies in schizo-phrenia to contribute to understanding of the processes



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underlying working memory in the normal brain must bemade with some caution, and with appropriate caveatsgiven the blurred taxonomic boundaries of the illness, andvariability of the effects of the disease and its treatment onbrain function. To date, this contribution is limited to pro-viding convergent evidence for observations made in

healthy volunteers. This is a modest, though importantcontribution. As our understanding increases of the neuro-biological mechanisms which give rise to the cognitivedeficits in schizophrenia, or the sub-syndromes whichcomprise it, we may see this information serving to gener-ate testable hypotheses regarding normal brain functionunderlying working memory. Alternative approaches whichindex psychosis indirectly may provide an effective solu-tion to some of these issues. These approaches includethe study of susceptible populations, such as non-affectedfamilial relatives of psychotic patients, or as we have ex-plored in this review, the use of psychopharmacologicalmodels of the illness. The application of these techniques

is likely to facilitate greater understanding of both schizo-phrenia and the biological basis of working memory (dys)function.

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