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
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 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 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, 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. The
‘positive’ symptoms of the disorder, including hallucina-
tions (primarily in the auditory modality) and delusional
ideation, are perhaps the most widely recognized charac-
teristics of the illness, while ‘negative’ symptoms, for ex-
ample, social withdrawal and flattened affect, are also
*Correspondence to: G. D. Honey, University of Cambridge, Depart-
ment of Psychiatry, Addenbrookes Hospital, Brain Mapping Unit, Box
255, Cambridge CB2 2QQ, UK. Tel: ⫹44-01223-764673; fax: ⫹44-
01223-764675.
E-mail address: gh242@cam.ac.uk; 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.
0306-4522/06$30.00⫹0.00 © 2005 Published by Elsevier Ltd on behalf of IBRO.
doi:10.1016/j.neuroscience.2005.05.036
59
intrinsic features which contribute substantially to the de-
bilitating nature of the disorder. In addition to these and
other experiential disturbances, patients with schizophre-
nia also show deficits across a broad range of neuropsy-
chological 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 Treat-
ment 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 prob-
lem 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 pre-
vious 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 lim-
ited 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 re-
ported 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 con-
text of other domains of cognitive dysfunction (Saykin et al.,
1991, 1994), and prognostic implications of such deficits in
psychosocial rehabilitation programs (Green, 1996). Accord-
ingly, deficient working memory is key to a number of
contemporary cognitive psychological models of schizo-
phrenic symptoms (Goldman-Rakic, 1990a, 1994; Cohen
and Servan-Schreiber, 1992; Weinberger, 1993).
60 G. D. Honey and P. C. Fletcher / Neuroscience 139 (2006) 59 –71
Given the centrality of working memory dysfunction in
schizophrenia, the question arises as to whether the infor-
mation 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 substan-
tially from investigations of behavioral impairments in pa-
tients following neurological damage, sometimes referred
to as ‘natural memory experiments.’ These studies, typi-
cally based on individual case histories, are often particu-
larly influential in addressing subtle discriminations, which
may prove intractable to standard experimental methodol-
ogy: for example, observing intact subvocal rehearsal in
patients 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 both
subvocal rehearsal and phonological storage, was sub-
stantiated on the basis of observations in patient P.V., who
showed 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 phonological
storage (thereby indicating its process separability), caus-
ing the patient to strategically avoid use of the rehearsal
mechanism for visual information, whereas the phonolog-
ical 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 implementa-
tion of cognitive processes. This follows the classical tra-
dition inaugurated by Broca’s localization of speech pro-
duction to the inferior frontal gyrus on the basis of the
monosyllabic speech capacity of a patient following a le-
sion to this region identified postmortem, and similarly
Wernicke’s observation that damage to the left posterior
temporal cortex produces deficits in speech comprehen-
sion. Progressing beyond single dissociations such as
these, 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 memory
observed in patients with schizophrenia inform current
models 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 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 bi-
ological 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 neuro-
science to investigate the biological basis of human cog-
nitive 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 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 behavior
on 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 as
gold standards in neuropsychology to functional imaging.
We further consider the response properties of the prefron-
tal 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 in-
cluding prefrontal cortex may be mitigated by compensa-
tory recruitment of other brain areas, and the implications
for behavioral assessments. There are a number of inter-
pretative 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 circum-
vent 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 pro-
posed, and has gone some way to formulating a functional
topology. Functional neuroimaging, primarily using
positron emission tomography (PET) and functional mag-
netic resonance imaging (fMRI) has, with increasing
sophistication in experimental design, explored the biolog-
 G. D. Honey and P. C. Fletcher / Neuroscience 139 (2006) 59 –71
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 pro-
cess 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 ap-
proaches which involve perturbed function, such as behav-
ioral impairments in neuropsychological patients, or non-
invasive experimental interventions, such as transcranial
magnetic 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 of
impaired cognitive performance following local disruption
of neural activity in a given region indicates that the func-
tional integrity of a region is necessary for performance of
a 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; Mottaghy
et al., 2002; Nixon et al., 2004). Similarly, the integration of
findings 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 of
biological function can be considered in some ways paral-
lel to the TMS and neuropsychological approach, in that
behavioral deficits are related to primary physiological dis-
turbances. Indeed, schizophrenia may go beyond the clas-
sical lesion model, involving disruptions of inter-regional
functional connections, rather than localized regional def-
icits. Thus schizophrenia offers the opportunity to investi-
gate 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 struc-
ture–function 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 the
first fMRI studies were reported in patients with schizo-
phrenia (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
61
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 associ-
ated 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 pri-
mates demonstrated that cells in and around the principal
sulcus in the dorsolateral prefrontal cortex exhibit delay-
related activity during delayed match to sample paradigms
(Goldman-Rakic, 1987, 1990b). Furthermore, impeding
lateral prefrontal activity, either via pharmacological block-
ade of dopamine D1 receptors (Sawaguchi and Goldman-
Rakic, 1991, 1994; Williams and Goldman-Rakic, 1995), or
neurochemical/surgical lesions (Funahashi et al., 1993) of
local tissue, impairs working memory. The functional in-
volvement of the homologous region in humans in working
memory 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-
ciated 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 be-
tween 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 ‘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 in
schizophrenia, studies involving tasks designed to more
specifically isolate working memory processes also re-
ported 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 psy-
chiatric conditions in which prefrontal function is disrupted,
a failure of working memory is observed. While these
clinical studies largely involved medicated out-patients ex-
periencing 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
62 G. D. Honey and P. C. Fletcher / Neuroscience 139 (2006) 59 –71
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 neuropsycho-
logical 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 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 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 perva-
sive psychotic experiences), causes the subject to disen-
gage 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 strat-
egies 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 explana-
tion 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 rela-
tionship between physiological activation and cognitive
performance is complex. Several studies, which have at-
tempted to characterize this further, are considered further
in ‘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 remote
brain region. Several regions, including the posterior pari-
etal 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 re-
gions, 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 avail-
able 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 in-
vestigated 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 con-
trast 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 sub-
jects showed attenuated frontal response during a mental
arithmetic 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 patients
with 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 whether
functional disruption in this region is necessary for working
memory performance.
Dissociation methodology. The use of double disso-
ciations, which are prevalent in neuropsychological inves-
tigations 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 vi-
sual 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 hip-
pocampal 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 func-
tional imaging? Process separability would be less con-
vincing 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 separa-
bility is identifiable in functional imaging data, if one ex-
tends Dunn and Kirsner’s (1988) principle of ‘reversed
association.’ The application to functional imaging data
 G. D. Honey and P. C. Fletcher / Neuroscience 139 (2006) 59 –71
corresponds to the observation of increased task-related
activity in two brain regions, relative to an independent
baseline condition, and simultaneously, that the two re-
gions contrast negatively across two task conditions. This
particular pattern of activity guards against the possibility
that a double dissociation simply represents opposing ef-
fects of a shared single process, perhaps mediated via
reciprocal 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 way
the nature of this relationship, i.e. it remains a (process-
specific) correlative observation, which is not an indication
of 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 be
demonstrated remains ambiguous with regard to its impli-
cations for normal brain function, as for single and double
dissociations.
For the reasons outlined above, the interpretation of
functional 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 human
brain. Brain function, as opposed to structure, has the
property 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 identify
regions which are necessary for specific cognitive pro-
cesses. 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 im-
aging-based investigations are synergistic approaches
(Rorden and Karnath, 2004), however, the nature of the
insights offered by these two techniques differs consider-
ably. 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. Pre-
frontal 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 func-
tion, 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 atten-
uation 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-
63
tion offers the opportunity to dissociate the factors of cog-
nitive 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 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 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 relation-
ship 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 re-
sponse 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 sub-
sequent studies involving more specific working memory
tasks. Using the Sternberg item recognition task (Stern-
berg, 1966) Manoach et al. (1999, 2000) reported in-
creased 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 ob-
served between error rate and prefrontal activation in the
patients, 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 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 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 in
schizophrenia is thus not a static phenomenon, but dynam-
ically 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 con-
firmed 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
64 G. D. Honey and P. C. Fletcher / Neuroscience 139 (2006) 59 –71
the dorsolateral region. Furthermore, this association be-
tween 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 ac-
count for all discrepancies in the literature (see ‘Method-
ological 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 cogni-
tive capacity is reached, is strengthened by the observa-
tion 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 schizophre-
nia 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 re-
gions. This correlation may indicate a direct inter-regional
causal relationship, or alternatively may be mediated by
additional regions. In order to evaluate a quantitative as-
sessment 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 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 of
studies have reported functional abnormalities involving
the 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 disorder
of functional connectivity may therefore provide an appro-
priate test of connectionist models of the components of
working memory, involving a ‘functional lesion,’ compared
with discrete structural lesions typically the focus of neu-
ropsychology.
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 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 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 re-
gions 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-hemi-
spheric communication between dorsolateral frontal re-
gions, 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 inter-
hemispheric frontal connectivity is central to working mem-
ory 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 cerebrovascu-
lar infarction is commonly observed in cerebral ischemic
patients. In functional disorders such as schizophrenia,
there is some evidence that similar compensatory adapta-
tions 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 compari-
son to routine neuropsychological assessments, whereby
gross measures, such as task accuracy and reaction time
may 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 potentially
provide information that the functional recruitment of par-
ticular brain regions may not be necessary for working
memory, and can be replaced or at least supplemented,
 G. D. Honey and P. C. Fletcher / Neuroscience 139 (2006) 59 –71
without loss of function. Additionally, aberrant activity at
lower performance requirements may provide insight into
the 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 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 pa-
tients with Parkinson’s disease indicate that fronto-striatal
circuitry is critical in supporting working memory function
(Owen, 1997) and subcortical activation is frequently ob-
served 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 projec-
tions 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 perfor-
mance 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 associ-
ations 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 schizo-
phrenia may therefore reflect a compensatory response to
maintain 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 levels
similar 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 task
performance to automation and expertise, characterized
by a development from subcortical to cortical mediation of
function.
Methodological challenges
Observations based on physiological abnormalities asso-
ciated with working memory deficits in schizophrenia have
65
certainly provided useful information which allow hypothe-
ses 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 cau-
tious 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 investi-
gations, gross structural abnormalities are not typical of
schizophrenia. Any observed relationship between a cog-
nitive deficit and presumed neurophysiological functional
abnormality must be considered tentatively since the
pathophysiological basis of schizophrenia remains unde-
termined. 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 ob-
served abnormality in schizophrenia in relation to normal
human brain function (Honey et al., 2002b).
Heterogeneity of schizophrenia. Schizophrenia in-
corporates heterogeneous psychotic phenomena, none of
which are pathognomonic of the illness. Patients differ
widely along numerous parameters, including clinical pre-
sentation, prognosis, insight, cognitive dysfunction, neuro-
logical impairment, institutionalization, susceptibility to
pharmacological side-effects and demographic history. Ac-
cordingly, 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, 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 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 ob-
servations in research on schizophrenia” (Andreasen,
1987).
This point is supported by the observation by Manoach
et al. (2000) examining individual responses to a working
66 G. D. Honey and P. C. Fletcher / Neuroscience 139 (2006) 59 –71
memory task: they found that increased spatial heteroge-
neity of response in dorsolateral prefrontal cortex was
evident 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 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 pro-
vide an explanation for hypofrontality, as frequently re-
ported. Strauss et al. (1974) suggested that, “Group com-
parison studies, using summarizing statistics, the ‘normal
science’ in schizophrenia research, may at times be mis-
leading 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 re-
sponse 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 nega-
tive symptoms were associated with increased response in
medial and lateral premotor regions. Further investiga-
tions of associations between psychiatric symptoms,
cognitive performance and physiological response may
yield important information about the implications of
working memory (dys)function, which would inaccessi-
ble by other means, and may serve to inform current
models of working memory.
Treatment-related confounds. Patients with schizo-
phrenia are treated with a variety of anti-psychotics. The
mechanism 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; 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 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 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 dopa-
mine 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 risperi-
done was associated with increased activation of prefron-
tal cortex, compared with patients maintained on typical
antipsychotics (Honey et al., 1999). There is also evidence
that anti-psychotic treatment affects the functional connec-
tions 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 pos-
sible 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 consider-
able 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 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 some
of 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 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 accor-
dance with the view that working memory dysfunction is a
key aspect of schizophrenia, these compounds also per-
turb working memory performance, and thereby provide an
opportunity to explore neurotransmitter mechanisms in-
volved in working memory disruption. Combining psycho-
pharmacological 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 consider-
ations, such as the effect of the drug on the dependent
imaging measure, e.g. the blood oxygenation level depen-
dent (BOLD) contrast (Honey and Bullmore, 2004; Shah
 G. D. Honey and P. C. Fletcher / Neuroscience 139 (2006) 59 –71
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 the
interpretative 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 beyond
cognitive capacity constraints. Furthermore, subjects
serve 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 the
threshold at which psychotic phenomenon are observed,
thus facilitating a dissociation of these effects. For exam-
ple, the presence of a hallucination may be sufficiently
attentionally distracting to indirectly impair working mem-
ory 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 inter-
pretation of the psychopharmacological manipulation.
Before this approach can serve to clarify observations
made on the basis of performance of schizophrenic pa-
tients, the validity of psychopharmacological models re-
mains to be fully explored and validated at the cognitive
and physiological level. However, psychopharmacological
modulation of working memory has already proved a valu-
able 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 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 positive
symptoms of schizophrenia is highly correlated with their
affinity for post-synaptic dopamine (D2) 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 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, pre-
viously observed using electrophysiological recordings of
single unit activity recorded from prefrontal neurons in non-
human primates (Williams and Goldman-Rakic, 1995). Mat-
tay et al. (2000) found that dextroamphetamine improved
working 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
67
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 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/val
genotype showed improved working memory performance
and reduced prefrontal activity under amphetamine com-
pared 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 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 also
produces disruption of cognitive function similar to that
observed in schizophrenia, including impairments in work-
ing 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 mem-
ory 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 pro-
cesses (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 manipu-
lation and maintenance processes, envisaged as separate
component processes within current theoretical models of
working 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
68 G. D. Honey and P. C. Fletcher / Neuroscience 139 (2006) 59 –71
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 pro-
viding convergent evidence for observations made in
healthy volunteers. This is a modest, though important
contribution. As our understanding increases of the neuro-
biological mechanisms which give rise to the cognitive
deficits in schizophrenia, or the sub-syndromes which
comprise it, we may see this information serving to gener-
ate testable hypotheses regarding normal brain function
underlying working memory. Alternative approaches which
index psychosis indirectly may provide an effective solu-
tion 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 ex-
plored in this review, the use of psychopharmacological
models 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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