Cognitive Control Deficits in Schizophrenia:
Mechanisms and Meaning
Tyler A Lesh1, Tara A Niendam1, Michael J Minzenberg1and Cameron S Carter*,1
1Department of Psychiatry, UC Davis Imaging Research Center, Davis School of Medicine, University of California,
Sacramento, CA, USA
Although schizophrenia is an illness that has been historically characterized by the presence of positive symptomatology,
decades of research highlight the importance of cognitive deficits in this disorder. This review proposes that the theoretical
model of cognitive control, which is based on contemporary cognitive neuroscience, provides a unifying theory for the
cognitive and neural abnormalities underlying higher cognitive dysfunction in schizophrenia. To support this model, we outline
converging evidence from multiple modalities (eg, structural and functional neuroimaging, pharmacological data, and animal
models) and samples (eg, clinical high risk, genetic high risk, first episode, and chronic subjects) to emphasize how
dysfunction in cognitive control mechanisms supported by the prefrontal cortex contribute to the pathophysiology of higher
cognitive deficits in schizophrenia. Our model provides a theoretical link between cellular abnormalities (eg, reductions in
dentritic spines, interneuronal dysfunction), functional disturbances in local circuit function (eg, gamma abnormalities), altered
inter-regional cortical connectivity, a range of higher cognitive deficits, and symptom presentation (eg, disorganization) in the
disorder. Finally, we discuss recent advances in the neuropharmacology of cognition and how they can inform a targeted
approach to the development of effective therapies for this disabling aspect of schizophrenia.
Neuropsychopharmacology Reviews (2011) 36, 316–338; doi:10.1038/npp.2010.156; published online 15 September 2010
Keywords: cognitive control; schizophrenia; cognition; disorganization; prefrontal cortex; executive functioning
Cognitive dysfunction represents a core deficit in schizo-
phrenia, and a number of studies (Green, 1996; Green et al,
2000) illustrate how cognitive deficits may strongly
influence the clinical presentation and daily functioning of
people with this illness. Cognitive deficits in schizophrenia
have been associated with disorganization and negative
symptoms (eg, see Cohen et al, 1999; Green et al, 2000;
Kerns and Berenbaum, 2002) as well as with poor functional
outcomes (Green, 1996, 1998; Weinberger and Gallhofer,
1997). Despite these links, cognitive dysfunction shows only
modest improvement with currently available therapies and
the vast majority of patients treated with second-generation
antipsychotic drugs continue to experience significant
cognitive disability (Green, 1998; Harvey and Keefe, 2001;
Weinberger and Gallhofer, 1997). In response to the
increased awareness of the clinical importance of impaired
cognition in schizophrenia, there has been a dramatic
increase in research directed toward understanding the
pathophysiological mechanisms underlying these deficits
as well as developing effective therapies for this aspect of
Previous studies in schizophrenia have utilized standar-
dized neuropsychological batteries to examine various
aspects of cognition in the disorder. Findings reveal that
cognitive deficits are present in schizophrenia regardless of
illness stage, as individuals experiencing their first episode
of schizophrenia show a pattern of deficits on tasks related
to frontal and temporal lobe functioning, including atten-
tion, processing speed, executive functioning, verbal
fluency, verbal memory, and learning (Censits et al, 1997;
Hoff et al, 1992; Mohamed et al, 1999; Riley et al, 2000;
Saykin et al, 1994; Schuepbach et al, 2002; Townsend et al,
2001). Deficits in these domains have been consistently
associated with poor social functioning as well as poor
work/school outcome (Addington and Addington, 1999;
Received 19 March 2010; revised 11 August 2010; accepted 11 August
*Correspondence: Dr CS Carter, Department of Psychiatry, UC Davis
Imaging Research Center, Davis School of Medicine, University of
California, 4701 X Street, Suite E, Sacramento, CA 95817, USA,
Tel: +1 916 734 7783; Fax: +1 916 734 8750,
Neuropsychopharmacology REVIEWS (2011) 36, 316–338
& 2011 Nature Publishing Group All rights reserved 0893-133X/11 $32.00
Addington et al, 1998; Bell and Bryson, 2001; Bilder et al,
2000; Bowen et al, 1994; Brekke et al, 1997; Corrigan and
Toomey, 1995; McGurk and Meltzer, 2000a; Smith et al,
2002; Velligan et al, 2000). Furthermore, impairment in
such cognitive domains has been associated with negative
and disorganization symptoms, including formal thought
disorder (Addington and Addington, 1999, 2000; Bilder
et al, 2000; Breier et al, 1991; Cohen et al, 1999; Dibben et al,
2009; Dickerson et al, 1996; Goldman et al, 1993;
Greenwood et al, 2008; Heslegrave et al, 1997; Kerns and
Berenbaum, 2002; Lenior et al, 2001; MacDonald et al, 2005;
McGurk and Meltzer, 2000a; McGurk et al, 2000b; Moriarty
et al, 2001; Perlstein et al, 2001; Velligan et al, 1997; Yoon
et al, 2008a). Moreover, cognitive improvement in schizo-
phrenia is typically associated with a reduction in negative
symptoms, but not positive symptoms (Censits et al, 1997;
Mohamed et al, 1999; Schuepbach et al, 2002).
Although previous studies have revealed important
information with regard to the impact of impaired cognition
in schizophrenia, the use of standard neuropsychological
measures limits our ability to understand the complexity of
the underlying impairment, as a particular test may engage
numerous cognitive processes (Cho et al, 2005). One
example is the Wechsler Digit SymbolFCoding subtest
(Wechsler, 1997), which shows one of the most reliably
documented impairments in the clinical neuropsychological
literature of schizophrenia (Dickinson et al, 2007). Although
this task is typically categorized as a measure of attention,
accurate and rapid performance requires simple visual
attention, active maintenance of symbol–digit pairings in
working memory, as well as psychomotor speed. Thus,
interpretation of lower performance in a patient population
is difficult, as poor performance may be owing to an
isolated deficit in any one of the component processes
mentioned above and/or a deficit in the fluid integration of
these processes. Consequently, the recruitment of multiple
cognitive processes during a task restricts the ability to
isolate specific neural systems and accurately identify
functional neural markers of risk.
In response to these limitations, research utilizing
cognitive science paradigms that isolate particular cognitive
processes within schizophrenia has increased dramatically
over the past decade. Within the domain of higher cognitive
functions, disturbances have been described in selective
attention (Carter et al, 1992; Cornblatt et al, 1989; Mirsky,
1969; Nuechterlein and Dawson, 1984), working memory
(Carter et al, 1996; Glahn et al, 2000; Gold et al, 1997; Keefe
et al, 1995; Park and Holzman, 1992), episodic memory
(Clare et al, 1993; Ranganath et al, 2008; Saykin et al, 1991;
Schwartz et al, 1992; Tamlyn et al, 1992), language
production (Barch and Berenbaum, 1996a; Docherty et al,
1988, 1996; Harvey, 1983), and comprehension (Condray
et al, 1995; Morice and McNicol, 1985). Although it is
possible that schizophrenia patients have discrete deficits
in multiple cognitive systems, a parsimonious account of
many of these deficits, as suggested by Kraepelin a century
ago (Kraepelin (1919, 1971), ‘The mind in dementia praecox
is like an orchestra without a conductor’), is that they reflect
impaired cognitive control.
This review proposes that the theoretical model of
cognitive control, which is based on contemporary cogni-
tive neuroscience, provides a unifying theory for the
cognitive and neural abnormalities underlying higher
cognitive dysfunction in schizophrenia. In support of this
theory, we summarize the literature on impaired cognition
in schizophrenia as well as in high-risk populations and
discuss the clinical and etiological significance of these
deficits. In doing so, we hope to provide background and
rationale for an integrative cognitive control account of
these seemingly unique and disparate findings. Finally, we
will outline how this model can inform a critical research
agenda that is focused on developing effective therapies to
reduce disability associated with the illness.
A MODEL OF HIGHER COGNITIVE DEFICITS
IN SCHIZOPHRENIA: IMPAIRED COGNITIVE
CONTROL, DISORGANIZATION, AND THE
In order to manage the complex set of demands that come
with day-to-day life, the human brain has developed
mechanisms to coordinate the multitude of incoming
sensory and motor information with higher-level represen-
tations of internal goals or rules to determine appropriate
behavioral responses. The adequate engagement of cogni-
tive control requires the coordination of multiple brain
regions, includingthe dorsolateral
(DLPFC), medial frontal cortex (including the anterior
cingulate cortex), and parietal regions (Botvinick et al, 2001;
Carter et al, 1999; Cohen et al, 2000; Yarkoni et al, 2005).
Owing to its interconnectivity with sensory and motor
regions, the DLPFC is believed to have a central role in the
maintenance of the rules for action as well as response
selection (Asaad et al, 2000; Watanabe, 1990, 1992).
In contrast, medial frontal regions, specifically the anterior
cingulate cortex (ACC), are believed to detect response
conflict as part of a ‘control loop’ and then signal the
DLPFC when control-related activity should be increased to
improve performance (Egner and Hirsch, 2005; Kerns et al,
2005; MacDonald et al, 2000). The activation of parietal
regions provides the DLPFC with the ability to shift
attentional focus and provides information on learned
stimulus–response pairings (Bunge et al, 2002, 2003; Miller
and Cohen, 2001; Posner and Petersen, 1990). When
engaged in tasks requiring cognitive control, functional
neuroimaging studies of healthy individuals have shown
activation of a specific cortical network, including the
DLPFC and anterior cingulate cortex (Brass and von
Cramon, 2002; Braver et al, 2003; Dove et al, 2000; Dreher
et al, 2002; Liston et al, 2006; Sohn et al, 2000; Yeung et al,
2006). When such prefrontal brain regions are damaged,
affected individuals show predictable deficits in context
maintenance and response inhibition (Miller, 2000).
Cognitive control deficits in schizophrenia
TA Lesh et al
Early studies of the prefrontal cortex (PFC) structure and
function in non-human primates (Funahashi et al, 1993;
Fuster, 1990; Goldman-Rakic, 1987; Jacobsen, 1936) sug-
gested that the PFC serves as a temporary storage for
incoming information, maintaining it ‘online’ for immedi-
ate use. However, more recent views of the PFC suggest that
its role is much more complex (Braver et al, 2002; Bunge
et al, 2002; D’Esposito and Postle, 2002; Fuster, 2002;
Thompson-Schill et al, 2005). Although a complete discus-
sion of this literature is beyond the scope of this review,
it is important to summarize our current understanding of
the PFC and its role in cognitive control. Given its extensive
interconnections with sensory, motor, and subcortical
regions, the PFC is believed to serve a primary role in
integrating incoming information and providing ‘top-down’
processing to coordinate behavior (Miller, 2000; Miller and
Cohen, 2001). Information processing in the brain is often
competitive as different information is received from
various pathways, leading to a competition for the selection
of a behavioral response. In concordance with early theories
of the PFC as ‘online storage,’ Miller and Cohen (2001)
propose that the PFC actively maintains ‘rules’ online in
order to evaluate incoming information as well as internal
states to guide response selection toward a current goal.
When we are confronted with conflicting behavioral
responses, the PFC provides ‘cognitive control’ by main-
taining the set of rules that are required to be successful in a
new situation and constrains neural information processing
across the brain in accordance with these rules and goals. By
doing so, the PFC biases neural processing in the brain away
from prepotent but incorrect responses and toward the
appropriate response. Figure 1 illustrates this phenomenon
using the Stroop task, in which the ‘high control’ condition
of color naming requires greater engagement of the PFC to
overcome the prepotent response of word reading. In this
way, the PFC is responsible for maintaining goals and rules
and binding them with incoming sensory and motor
information to direct attention to task-relevant information.
This in turn biases information processing and response
selection toward responses that are relevant for the goal at
hand, and facilitates the updating of these rules and goals
based on reward and ongoing experience (Miller and
It is important to note that cognitive control processes
encompass a broad class of mental operations, including
goal or context representation and maintenance, strategic
processes such as attention allocation and stimulus-
response mapping, and performance monitoring (Carter
et al, 1998; Cohen et al, 1990; Miyake and Shah, 1999;
Shallice, 1988). Cognitive control is associated with a wide
range of cognitive processes (Carter et al, 1998; Posner and
Abdullaev, 1996) and is not restricted to a particular
cognitive domain (Banich, 1997; Smith and Jonides, 1999).
Therefore, cognitive control represents the overarching
ability to maintain context for appropriate behavior in a
given situation in the face of interference (such as through
the activation of prepotent response tendencies) and
impaired cognitive control would be expected to lead to a
range of cognitive deficits across a broad range of ‘domains’
of higher cognition. The model of cognitive control deficits
in schizophrenia described in this paper focuses on the
contribution of the DLPFC in maintaining task context and
guiding processing across the brain in a task appropriate
COGNITIVE CONTROL DEFICITS IN
SCHIZOPHRENIA: EVIDENCE FOR A
PREFRONTALLY BASED DISORGANIZATION
Research on the role of the DLPFC has been a topic of
interest to schizophrenia researchers for over three decades,
as early studies of cerebral blood flow showed reductions in
anterior to posterior resting gradients in patients (Ingvar
and Franzen, 1974). Follow-up studies by Weinberger et al
(1986) showed reduced activity in the DLPFC during
the Wisconsin Card Sorting task for both medicated
and unmedicated patients. Since those studies, many
authors have reported decreased prefrontal activation (see
Andreasen et al (1992) and Buchsbaum et al (1996) for early
reviews or Glahn et al (2005) for a more recent review of
activation studies). Such findings are not consistently
reported across the literature (Glahn et al, 2005; Gur and
Gur, 1995; Manoach et al, 1999), and this may be related to
the selection of tasks that do not reliably activate the DLPFC
in healthy controls (Carter et al, 1998; Taylor et al, 1994).
Previous studies in our lab have consistently observed
reduced DLPFC activity during cognitive control tasks in
schizophrenia, which has been associated with impaired
(Barch et al, 2001; Carter et al, 1998; MacDonald
et al, 2005; Perlstein et al, 2001; Snitz et al, 2005; Yoon
et al, 2008a) irrespective of patient medication status
(MacDonald et al, 2005). Interestingly, although DLPFC
activity has been reliably decreased in these studies,
cortex (PFC) during the classic Stroop task, in which the stimulus is
identical but the engagement of control processes is modulated by the
rule. (a) Under low cognitive control demands (ie, word reading), the PFC
is minimally engaged and the response is biased towards the prepotent
word reading response, which is represented by relatively thicker black
vertical arrows. (b) In contrast, under high cognitive control demands (ie,
color naming), the PFC is strongly recruited to bias responding away from
the prepotent response and toward the appropriate response repre-
sented by the large red vertical arrow.
Simplified graphical depiction of the role of the prefrontal
Cognitive control deficits in schizophrenia
TA Lesh et al
posterior regions of VLPFC show normal activation patterns
in patients (Barch et al, 2001; MacDonald et al, 2005;
Perlstein et al, 2001), suggesting a pattern of reduced
DLPFC activation with normal VLPFC functioning in
schizophrenia (Glahn et al, 2005; Wolf et al, 2007). A
meta-analysis of 41 neuroimaging studies of executive
function in schizophrenia revealed similar findings of
reduced activation in patients within bilateral DLPFC,
ACC, and mediodorsal thalamus (Figure 2; Minzenberg
et al, 2009).
Recently, Yoon et al (2008b) utilized fMRI and an
abbreviated version of the AX-Continuous Performance
Task (AX-CPT) to examine the relationship between DLPFC
activation and cognitive and psychosocial functioning in the
early phase of schizophrenia. In the AX-CPT, subjects make
a target response to the probe letter X, only when it follows
the cue letter A. All other stimuli require a non-target
response, including trials in which X is preceded by any
letter other than A (collectively referred to as cue B trials).
Trials with target (AX) cue–probe pairings occur with high
frequency (70%), setting up the tendency to make a target
response to the X probe. The BX condition requires the
highest cognitive control, as subjects must overcome the
tendency to make a target response to X. First episode
schizophrenia participants showed a pattern indicating
poor cognitive control with increased BX relative to AY
errors, which is consistent with previous findings of a
specific deficit in first episode individuals (MacDonald and
Carter, 2003a), and this impairment was associated with
reduced activation of the DLPFC when compared with
normal controls. Using the beta series correlation method
(Rissman et al, 2004), whole-brain functional connectivity
was measured by examining within-subjects correlations
between the time series in the DLPFC seed region and the
rest of the voxels in the brain. In control subjects, DLPFC
activity during this task was correlated with the activation
of a distributed frontoparietal network required to support
optimal task performance. In contrast, first episode patients
showed a significant reduction of DLPFC-related functional
connectivity, as they did not engage the same frontoparietal
network under conditions requiring high cognitive control.
Importantly, the level of DLPFC connectivity was associated
with increased symptoms of disorganization and poorer
psychosocial functioning in the first episode sample.
This pattern of results is strongly consistent with the
notion that impaired PFC function is associated with an
inability to exert top-down control over the task appro-
priate distributed network and suggests a basis for
the association between a PFC-based disorganization
syndrome in schizophrenia and functional impairment in
As noted previously, individuals with schizophrenia show
cognitive impairment in other domains, such as episodic
memory (Aleman et al, 1999). Structural abnormalities in
medial temporal regions found in individuals with schizo-
phrenia (Shenton et al, 2001; Steen et al, 2005), specifically
the hippocampal region (Heckers, 2001), may contribute
to the observed impairment in memory functioning.
However, recent meta-analyses (Ragland et al, 2009;
Ranganath et al, 2008) suggest that episodic memory
impairment in schizophrenia may be, in part, the result of
impaired prefrontal cognitive control mechanisms, which
help to guide encoding and retrieval processes. Specifically,
Ragland et al (2009) examined 18 functional neuroimaging
studies of episodic memory encoding and retrieval in
individuals with schizophrenia and healthy controls.
Results showed decreased activation of prefrontal regions,
including the dorsolateral and ventrolateral prefrontal
cortices, but not medial temporal regions during encoding
and retrieval when compared with healthy controls. When
the participants were provided with an encoding strategy,
decreased activation was still observed in the dorsolateral
prefrontal region, with no difference observed in the
ventrolateral prefrontal region, suggesting that this area
may serve to compensate for continued impairment in
dorsolateral prefrontal functioning. In contrast to expecta-
tion, no reliable findings were found in the hippocampus,
whereas increased activation was observed in the para-
hippocampal gyrus during encoding and retrieval, which
was again interpreted as serving a potential compensatory
role. Taken together, these findings suggest that prefrontal
cognitive control deficits may be related to many aspects
of cognitive impairment
thatare associated with
function studies (reprinted with permission from Minzenberg et al, 2009).
Regions in which patients with schizophrenia showed co-occurring hypoactivation compared with controls across a full set of executive
Cognitive control deficits in schizophrenia
TA Lesh et al
COGNITION AS A MARKER OF RISK FOR
SCHIZOPHRENIA AND THE RELATIONSHIP
TO COGNITIVE CONTROL
In addition to its role as a predictor of clinical and
psychosocial functioning for those individuals diagnosed
with schizophrenia, impaired cognition may also represent
an endophenotype, or intermediate trait that lies between
an underlying genetic vulnerability and expression of the
clinical phenotype that can be used to identify individuals at
greatest risk for the illness. Unaffected first-degree relatives
of individuals with schizophrenia consistently show deficits
on measures of executive function and processing speed
(Egan et al, 2001a; Faraone et al, 1995; Franke et al, 1993;
Keefe et al, 1994; Kuha et al, 2007), attention (Faraone et al,
1995, 1999; Finkelstein et al, 1997; Mulet et al, 2007), and
verbal memory (Faraone et al, 1995, 1999; Habets et al,
2008). Cannon et al (2000b) showed that frontally mediated
deficits on neuropsychological measures of attention and
working memory were associated with increasing genetic
liability to schizophrenia and were equally impaired in
affected and unaffected monozygotic (MZ) co-twins,
whereas deficits in temporally mediated verbal episodic
memory were significantly more pronounced in the affected
members of discordant MZ pairs. This finding supported
previous work by Harris et al (1996), who showed that a
subset of relatives in multiply affected families showed
deficits on a measure of set shifting and processing speed
when compared with normal controls.
A recent meta-analysis by Snitz et al (2006) showed that
first-degree relatives showed a wide range of effect sizes
across tasks, with the largest effect sizes seen on Trails B,
CPT-X d-prime, and CPT-AX/-IP d-prime and false alarms.
The authors concluded that cognitive deficits, particularly
those involving executive control, working memory, and
inhibition, may be the most likely to yield positive results in
the search for genes conferring risk for schizophrenia.
These data, along with evidence of cognitive dysfunction
early in childhood (Cannon et al, 2000a; Cornblatt et al,
1999; Erlenmeyer-Kimling et al, 2000; Jones et al, 1994;
Niendam et al, 2003; Russell et al, 1997) and impaired
cognition at the onset of the illness, implicate a neurode-
velopmental pathophysiological mechanism that leads to
EVIDENCE FOR COGNITIVE CONTROL
DEFICITS IN GENETIC HIGH-RISK SAMPLES
Given strong evidence of morphometric, functional, and
behavioral dysfunction of the PFC and associated cognitive
control tasks in patients, a body of work has examined
whether cognitive control deficits are associated with a
genetic liability for the disorder. Many studies have
highlighted impairment in frontally mediated executive
functions in both adult (Cannon et al, 2000b; Egan et al,
2001a; Faraone et al, 1995; Finkelstein et al, 1997; Franke
et al, 1993; Keefe et al, 1994) and child genetic high-risk
samples (Cornblatt, 2002; Cosway et al, 2000; Johnstone
et al, 2002; Wolf et al, 2002). More specifically, deficits in
cognitive control have also been shown in first-degree
relatives of individuals with schizophrenia. MacDonald et al
(2003b) used the expectancy version of the AX-CPT task to
show a specific deficit in context processing that was
associated with genetic liability. Specifically, they found that
patients and siblings performed better on AY relative to BX
trials, which implied worse context processing, compared
with controls who performed better on BX relative to AY
trials. A follow-up study utilizing the expectancy variant of
the AX-CPT revealed significantly greater BX errors in
siblings as well as increased activity throughout the
cognitive control network compared with controls (Dela-
walla et al, 2008). Other measures of cognitive control, such
as the Stroop (Filbey et al, 2008) and antisaccade task
(Calkins et al, 2004), have also been shown to be associated
with genetic liability. Becker et al (2008) used fMRI to
evaluate relatives’ performance and neural activity on a
single-trial version of the Stroop task. Although behavioral
performance was similar for relatives and controls, relatives
showed increased activity in right dorsal and ventral PFC
and left parietal cortex, as well as significantly decreased
activity in the left dorsal PFC. In contrast, Thermenos et al
(2004) showed increased activity in the left DLPFC in
relatives compared with controls on the Q3A-INT task,
which is a variant of the AX-CPT, in which subjects
maintained the context of an auditory cue while being
presented with distracting auditory information.
Converging evidence from structural neuroimaging stu-
dies also highlights the association between reduced gray
matter volume and density in the PFC and genetic liability.
Specifically, gray matter volume reductions have been noted
in the DLPFC (Diwadkar et al, 2006) and anterior cingulate
cortex (Job et al, 2003), as well as decreased cortical
thickness in the anterior cingulate (Goghari et al, 2007) in
unaffected first-degree relatives. Cannon et al (2002)
utilized a twin design to show significantly decreased
prefrontal gray matter volume (including DLPFC and polar
PFC) that was associated with increasing genetic risk for
The search for predictors of the development of schizo-
phrenia has revealed a similar set of cognitive, neurofunc-
tional, and structural brain abnormalities in individuals at
genetic high risk. Although few genetic high-risk studies
have employed longitudinal follow-up designs, the devel-
opment of psychosis in adulthood in the offspring of
individuals with schizophrenia has been associated with
impairment in cognitive control as measured by the Stroop
task (Johnstone et al, 2002). In addition, lower gray matter
density in the left inferior temporal gyrus, uncus, and right
cerebellum was found over follow-up in individuals who
subsequently developed schizophrenia (Job et al, 2005).
Increased prefrontal cortical folding has also been asso-
(Harris et al, 2004a,b, 2007), providing evidence that
abnormal development of prefrontal gray matter may
contribute to later illness onset. Functionally, increased
Cognitive control deficits in schizophrenia
TA Lesh et al
parietal activation and reduced anterior cingulate activation
was associated with the later development of schizophrenia
in the Edinburgh High Risk sample (Whalley et al, 2004,
2006). These findings highlight the potential role of genes as
a contributor to structural changes in prefrontal and
parietal regions, which lead to observed deficits in cognitive
control for both affected and unaffected risk groups.
APPLYING PREFRONTAL ENDOPHENOTYPES
TO THE GENETIC STUDY OF SCHIZOPHRENIA
Family, twin, and adoption studies indicate that schizo-
phrenia has a large genetic component, on the order of 65–
85% (Cannon et al, 1998; Cardno et al, 1999; Kendler and
Diehl, 1993; Sullivan et al, 2003). Given that transmission
of the disorder has not been linked to a major gene,
schizophrenia is generally thought to be associated with
multiple genes of small effect, including both common
variants and rare but highly penetrant copy number
variants or CNVs (Karayiorgou and Gogos, 1997). Identi-
fication of the molecular genetic basis of the disorder has
been challenging owing to this polygenic inheritance as well
as to genetic heterogeneity and a non-trivial environmental
component, which is show by incomplete concordance
for schizophrenia in MZ co-twins (Cannon et al, 1998). In
addition, the phenotypic presentation of the disorder is
markedly heterogeneous, with varying expression of core
features of positive, negative, and cognitive symptoms.
Given the phenotypic and genetic complexity of schizo-
phrenia, the utilization of neural and cognitive endophe-
notypes may offer additional power to detect susceptibility
loci by examining traits closer to the mechanism of
abnormal gene action. In addition, the quantitative nature
of these data allows for examination of the trait in
unaffected relatives, as well as offering greater resolution
in mapping genes of small effect. Although the use of
cognitive or neuroimaging endophenotypes has often been
highlighted as a way to facilitate the identification of genes
associated with the pathophysiology of schizophrenia, the
identification of functional variants remains, to date,
somewhat elusive. Therefore, we will discuss current
findings on two potential genetic linkages that have
shown consistent relationships with prefrontally mediated
Two genes, DTNBP1 (ie, dysbindin) and catechol-o-
methyltransferase (COMT), have arguably garnered the
most support as potential contributors to impaired PFC
cognition in schizophrenia (for a review, see Joyce and
Roiser, 2007). Dysbindin codes for a protein that is
expressed within the forebrain glutamatergic neurons and
interacts with proteins involved in vesicular transport and
glutamate release. Using a mouse model, Jentsch et al (2009)
showed that mice carrying a null mutation in the dysbindin
gene showed impairments of spatial working memory in a
gene dose-dependent manner. These data provide support
for a putative mechanism for prefrontal dysfunction
in schizophrenia, suggesting that altered regulation of
glutamatergic circuits in the PFC may play a role in the
cognitive phenotype of the disorder. Generally, the dysbin-
din high-risk haplotype has been associated with cognitive
decline, as measured by a decrease in IQ of 10 points
(Burdick et al, 2007), although the dysbindin genotype only
accounted for 2.2% of the variance in cognitive decline.
Donohoe et al (2007) found lower spatial working memory
performance in patients carrying the dysbindin risk
haplotype, in which the dysbindin haplotype explained
12% of the variation in working memory performance. In
agreement with animal studies mentioned previously
(Jentsch et al, 2009), dysbindin has been associated with
altered activation within the DLPFC during working
memory (Markov et al, 2010). Specifically, the authors
found that healthy subjects who carried the risk allele
showed greater activation in DLPFC compared with non-
carriers. In patients with schizophrenia, the high-risk allele
has been associated with reduced gray matter volume in the
PFC (Donohoe et al, 2010).
COMT is an enzyme involved in synaptic dopamine (DA)
catabolism that has an important role in the PFC, in which
there are relatively fewer DA transporters (Sesack et al,
1998). The majority of studies investigating cognitive
performance and COMT have focused on the val158met
polymorphism (for a recent review, see Tan et al, 2009). In
patients with schizophrenia, loading of the COMT met allele
conferred enhanced cognitive performance on the Wiscon-
sin Card Sorting Test, a measure of executive function, and
a more efficient physiological response in the PFC during an
N-back working memory task (Egan et al, 2001b). Other
complementary studies identified an association between
the val allele and impaired performance on working
memory (Wirgenes et al, 2010; Woodward et al, 2007)
and attention (Bilder et al, 2002). However, others have
either been unable to replicate these findings (Ho et al,
2005; Szoke et al, 2006) or have even found incongruent
results. For example, Neuhaus et al (2009) found that poor
performance on the signal discrimination index of the CPT-
IP was associated with the met variant in a gene dose-
dependent manner. The presence of the val158met genotype
in patients has also been associated with opposite effects in
brain activation compared with controls, such that control
subjects with the homozygous met genotype showed greater
activity on a verbal fluency task in the frontal operculum,
parietal operculum, and middle temporal gyrus than
those with the homozygous val genotype (Prata et al,
2009). These findings were reversed for the patient group,
such that patients with the homozygous met genotype
showed less activity in these regions compared with patients
with the homozygous val genotype. Moreover, a similar
genotype by group interaction was found on behavioral
performance measures, as the loading of the met allele in
patients and the val allele in controls was associated with
better performance. These data have prompted the devel-
opment of an altered efficiency model, which posits that
loading of the met allele in patients, and higher availability
of DA in the PFC, is associated with better performance,
Cognitive control deficits in schizophrenia
TA Lesh et al
whereas loading of the met allele in healthy subjects may
push DA availability and cortical function beyond the
optimal range. Such a discrepancy between healthy controls
and patients was also illustrated in a meta-analysis of COMT
genotype and WCST performance, in which genotype was
associated with perseverative errors in healthy controls but
not in patients with schizophrenia (Barnett et al, 2007).
Although there is evidence for an association with COMT
and prefrontally biased cognition, the effect on risk for
schizophrenia is small and inconsistent based on recent
meta-analyses (Allen et al, 2008; Fan et al, 2005; Munafo
et al, 2005; Okochi et al, 2009).
In addition to COMT and dysbindin, a number of
other candidate genes have been identified by linkage and
targeted association studies, including neuregulin 1 (NRG1),
disrupted in schizophrenia 1, and d-amino-acid oxidase.
NRG1 in particular codes for a trophic factor with a range of
functions that includes the modulation of g-aminobutyric
acid (GABA)-ergic transmission, which is critical for PFC-
mediated cognition and will be described in greater detail
later in the review (Mei and Xiong, 2008).
Although a comprehensive analysis of this literature is
outside the scope of this review (for a review, see Eisenberg
and Berman, 2010), it is important to note that there is
substantial disagreement as to how to interpret the existing
genetic association data (O’Donovan et al, 2009). Some
researchers may place more emphasis on genes with more
modest empirical support but with strong pathophysiolo-
gical relevance to the disorder, whereas others may be more
agnostic to the mechanism of gene action and primarily
concerned with a strong, reliable association. Although the
candidate genes mentioned above all have putatively strong
pathophysiological mechanisms relevant to schizophrenia,
given that they impinge upon prefrontal systems, none of
the genes yet identified remain unchallenged and all await
further study. Moreover, our ability to elucidate the genetic
underpinnings of the disorder may increase as genetic
association studies move towards tasks generated from the
cognitive neuroscience literature that tap specific cognitive
EVIDENCE FOR COGNITIVE CONTROL
DEFICITS IN CLINICAL HIGH RISK
Although most individuals with schizophrenia experience
the onset of clinical symptoms during late adolescence and
early adulthood, deficits in cognition are evident years
before the development of psychotic symptoms, during
childhood and adolescence (Cannon et al, 2000a; Cornblatt
et al, 1999; Erlenmeyer-Kimling et al, 2000; Jones et al, 1994;
Niendam et al, 2003; Russell et al, 1997). These cognitive
deficits are hypothesized to accelerate during the prodromal
period in association with changes in brain functioning that
lead to the development of psychotic symptoms (Feinberg,
1982; McGlashan and Hoffman, 2000). Such neurological
changes may also lead to functional decline in a variety of
domains (Cosway et al, 2000). Therefore, deficits in
cognition in high-risk samples not only serve as markers
of risk, but changes in such deficits over time may
differentiate those individuals who convert to psychosis or
experience functional disability from those who do not.
Impairment in multiple cognitive domains are reported
in clinical high risk (CHR) samples (McGlashan, 2001;
Miller et al, 2002), with the most pronounced deficits
observed on measures of frontal and temporal lobe
functions, including attention, working memory, processing
speed, executive functioning, and verbal learning and
memory (Bartok et al, 2005; Brewer et al, 2005; Eastvold
et al, 2007; Francey et al, 2005; Gschwandtner et al, 2003,
2006; Hambrecht et al, 2002; Hawkins et al, 2004; Keefe
et al, 2006; Lencz et al, 2006; Niendam et al, 2006, 2007;
Pukrop et al, 2007, 2006; Silverstein et al, 2006; Simon et al,
2007; Smith et al, 2006; Wood et al, 2003b). Evidence of
impairment on computerized measures of prefrontal
cognitive functioning in CHR youth when compared with
normal controls has also been reported (Francey et al, 2005;
Gschwandtner et al, 2003, 2006; Hambrecht et al, 2002;
Hawkins et al, 2004; Keefe et al, 2006; Lencz et al, 2006),
although CHR individuals showed better performance than
individuals with first-episode schizophrenia (Hambrecht
et al, 2002; Hawkins et al, 2004; Keefe et al, 2006). Overall,
impairments on measures of prefrontal cognitive function-
ing, including spatial working memory (Wood et al, 2003b),
antisaccade eye movements (Nieman et al, 2007), olfactory
identification (Brewer et al, 2003), and rapid information
processing (Brewer et al, 2005; Lencz et al, 2006), are
associated with conversion to psychosis.
When compared with healthy controls, CHR individuals
also show a variety of structural and functional abnormal-
ities, including reduced gray matter density in frontal,
temporal, and subcortical brain regions (Borgwardt et al,
2007b; Hurlemann et al, 2008; Jung et al, 2009; Phillips et al,
2002; Witthaus et al, 2008; Wood et al, 2005), as well as
reduced N-acetylaspartate (NAA) in frontal regions (Jessen
et al, 2006; Wood et al, 2003a). The frequency of
neurodevelopmentally associated abnormalities was also
higher in CHR samples when compared with healthy
controls (Choi et al, 2008; Takahashi et al, 2008a,b;
Yucel et al, 2003).
Few neuroimaging studies focused on frontal functioning
in CHR samples have been published to date. Morey et al
(2005) examined frontal and striatal functions during a
visual oddball paradigm in CHR, first episode, chronic
schizophrenia, and healthy control samples. Behaviorally,
the CHR individuals’ performance was intermediate bet-
ween the healthy control and first episode samples. In
addition, the CHR group showed significantly smaller
differential activation between task-relevant and task-
irrelevant stimuli in the frontal regions (ACC, inferior
frontal gyrus, middle frontal gyrus) than the control group.
Similarly, CHR individuals have shown intermediate
activation relative to controls and schizophrenia patients
during a working memory task (N-back) in the DLPFC,
inferior frontal, and parietal cortices (Broome et al, 2009).
Cognitive control deficits in schizophrenia
TA Lesh et al
Fusar-Poli et al (2010) replicated this finding of reduced
DLPFC and parietal activation in response to the N-back in
combination with fluorine 18-labeled fluorodopa PET. The
authors revealed that, within the at-risk group, the degree of
abnormality in the PFC (ie, attenuated DLPFC activation)
was associated with the severity of striatal DA dysfunction
(ie, elevated Ki value). This relationship was reversed in the
control group, such that prefrontal activation during
working memory was positively correlated with the level
of striatal DA function. This pattern of results was presented
as evidence of an inverted U relationship compatible with
models of working memory that suggest there is an optimal
level of DA activity associated with maximal efficiency
of working memory performance (Williams and Castner,
2006). Taken together, these studies show that CHR
individuals have difficulty activating the cortical network
that underlies effective cognitive control processes and
provide important evidence supporting the potential role of
abnormalities in this network as a marker of risk for
A recent review of this literature by Wood et al (2008)
noted that impairments in prefrontal cognitive functioning,
and the underlying neurobiological abnormalities, provide
the most likely marker of conversion risk. In CHR samples,
conversion to psychosis was associated with reduced gray
matter density in frontal, temporal, and parietal regions
(Borgwardt et al, 2007a,b, 2008; Fornito et al, 2008; Pantelis
et al, 2003, 2005), although such findings were not
consistent for analyses of the hippocampus (Phillips et al,
2002). Reductions in NAA in the anterior cingulate
cortex (Jessen et al, 2006), thickness of the anterior genu
of the corpus callosum (Walterfang et al, 2008b), and
reduced serotonin receptor density in frontotemporal gray
matter (Hurlemann et al, 2008) were also associated with
conversion. Frontal white matter tracts, specifically the
fronto-occipital fasciculus and left superior longitudinal
fasciculus, were also reduced in size for CHR individuals
who subsequently developed psychosis (Walterfang et al,
2008a). Taken together, these findings suggest that inves-
tigations of frontally mediated cognitive functions through
functional neuroimaging hold the most promise as markers
of risk for clinical, and potentially functional, deterioration
in at-risk samples.
IMPLICATIONS OF HIGHER COGNITIVE
DYSFUNCTION AND THE DEVELOPMENTAL
PATHWAY PRECEDING SCHIZOPHRENIA
As noted above, cognitive deficits are present at the onset of
the psychotic phase of the illness, during the prodromal
phase, and even in those at risk for the illness. Conse-
quently, schizophrenia has been conceptualized as a
neurodevelopmental disorder in which genetic and envir-
onmental etiological factors affect processes related to brain
development that in turn result in the clinical expression
of the disorder during adolescence, itself a time of rapid
brain development. According to the neurodevelopmental
hypothesis of schizophrenia originally proposed by Fein-
berg (1982), abnormal pruning of synaptic connections in
the cortex during adolescence leads to the onset of
psychotic symptoms. In normal development, the pruning
of superfluous synaptic connections during normal brain
development results in increased efficiency and specializa-
tion of cortical and subcortical areas; however, in schizo-
phrenia it is hypothesized that environmental stress and/or
genetic liability could alter the pruning process and cause
an abnormal rate or pattern of synaptic elimination,
resulting in the development of psychotic symptoms.
Using a computer simulation of the pruning process,
McGlashan and Hoffman (2000) showed how the pruning
of connections above a particular threshold resulted in
cognitive impairment as well as the appearance of
‘hallucinations’ during tasks of speech perception. In their
model, the pruning process can advance at varying levels of
intensity, with the most aggressive pruning leading to the
earliest onset of psychosis and reduced opportunity for later
recovery. Conversely, by decreasing the baseline level of
available connections, it was shown that early brain insult
could reduce the neuronal reserve, in which case a normal
pruning process would be sufficient to cross the threshold
into psychotic symptoms. Therefore, early brain injury in
the form of prenatal insult (eg, Brown and Derkits, 2010;
Cannon et al, 2000c), postnatal environmental stress
(eg, van Winkel et al, 2008), and/or abnormal rates of
synaptic pruning during adolescence could work alone or in
conjunction to push an individual past the threshold into
Empirical evidence has accumulated to support this
notion. In a post-mortem study of individuals with
schizophrenia, Selemon et al (1995) showed abnormally
high neuronal density in the prefrontal and occipital
cortices. A previous hypothesis attributed decreased cortical
gray matter volume to the effects of widespread neuronal
cell death (Weinberger, 1987). However, Selemon and
Goldman-Rakic (1999) associated the increased density of
cells, in the context of reduced volume, with the loss of
neuropil, or interconnections between the neurons, which
could be the result of excessive pruning. Glantz and Lewis
(2000) provided additional support for this hypothesis by
showing decreased dendritic spine density in the layer 3
pyramidal neurons of the DLPFC. Therefore, whereas the
process of synaptic pruning in normal development serves
to increase the efficiency of brain functioning, the observed
deficits in schizophrenia may be related to an overly
aggressive pruning process that reduces neuronal inter-
connection to a detrimental level, leading to the develop-
ment of psychotic symptoms
dysfunction that may become manifest during the prodro-
mal period. Alternatively, an initially depleted neuronal
connectivity, which may be associated with early brain
insult, could lead to symptoms of schizophrenia if
subsequent normal pruning processes decrease that con-
nectivity further, crossing a hypothetical threshold beyond
which the capacity for integrated cognitive and emotional
Cognitive control deficits in schizophrenia
TA Lesh et al
activity is severely compromised. Recently, Reichenberg
et al (2010) used long-term follow-up data to examine
cognitive development between the ages of 7 and 13 in the
Dunedin birth cohort. Examination of cognitive variables
revealed that individuals who later develop schizophrenia
showed deficits in verbal and visual knowledge, compre-
hension and reasoning at age 7, as well as a slowing in the
development of processing speed, working memory, and
visual–spatial reasoning as they progress through puberty.
These findings support an integrated model of aberrant
cognitive development in schizophrenia, incorporating both
a static cognitive deficit that is apparent early in childhood
as well as a developmental lag in cognitive domains
supporting attention and working memory as they grow
THE ROLE OF MICRO- AND MACRO-CIRCUIT
DYSFUNCTION IN IMPAIRED COGNITIVE
CONTROL IN SCHIZOPHRENIA
Given convergent findings from structural and functional
neuroimaging studies, post-mortem data, and genetic
association studies that implicate the PFC as a region
associated with the cognitive deficits that characterize
schizophrenia, a large body of work has led to a search
for pathophysiological mechanisms associated with inter-
neuron connectivity within the PFC (micro-circuits) as well
as regional connectivity (macro-circuits). Sustained firing of
pyramidal neurons within the DLPFC during engagement in
a working memory task has been shown to be crucial
to successful task performance (Goldman-Rakic, 1995;
Wilson et al, 1994). Changes in local circuit function in
the PFC may contribute to failure of this region to recruit
task appropriate networks across the brain and lead to
disorganized brain function and behavior in schizophrenia.
Although such a hypothesis can only be directly tested at
this time in animal models, functional neuroimaging
findings of altered BOLD signal within DLPFC have
generally been the closest proxy. Relevant to this, Logothetis
and others (Logothetis et al, 2001; Murayama et al, 2010;
Niessing et al, 2005) recorded directly from neuronal
populations during fMRI to show that the BOLD signal is
most strongly related to population neuronal activity, as
reflected in field potentials, and specifically to synchronous
neuronal activity in the high-frequency gamma (30–80Hz)
range. This is particularly significant in view of the results
of post-mortem studies in schizophrenia. Reduced GABA
release by the parvalbumin subclass of GABA-ergic inter-
neurons in the PFC and other regions of the brain is
suggested by a range of post-mortem findings reported
across a number of laboratories (for a review, see Gonzalez-
Burgos and Lewis, 2008; Lewis et al, 2005). Other studies,
including those cited above, suggest that there is altered
thalamocortical connectivity, including possibly decreased
neuronal numbers in the thalamus as well as reduced
dendritic spines on pyramidal cells in the thalamic recipient
zones of Brodmann area (BA) 9. Projections from medial
dorsal thalamus to DLPFC are critical for initiating and
maintaining gamma band activity (Jones, 1997), whereas
chandelier cells gate the timing of synchronous activation of
populations of pyramidal neurons by targeting the axon
initial segment of pyramidal cells through membrane
receptors with fast spiking calcium channels. These post-
mortem disturbances would be predicted, in life, to be
associated with impairments in prefrontal gamma activity and
an associated reduction in cognition-related BOLD activity.
Oscillatory activity in the gamma range is readily
recorded from the human EEG and there has been
increasing interest in both normal cognitive neuroscience
and in the study of schizophrenia in recent years.
Oscillatory activity can be evoked or induced (Galambos,
1992). Evoked gamma responses are temporally locked to
stimuli and typically thought to reflect perceptual processes;
induced gamma band responses represent signals indepen-
dent of evoked ones, typically appearing later during a trial
of a task, with a jittered latency across trials, and are
thought to be associated primarily with higher cognitive
processes (for a review, see Tallon-Baudry and Bertrand,
1999a). For example, in studies of visual working memory,
many investigators (Howard et al, 2003; Tallon-Baudry and
Bertrand, 1999a; Tallon-Baudry et al, 1998, 1999b) have
reported induced gamma band responses over frontal leads
during delay periods of working memory tasks. Although
these data are often interpreted as being related to the
maintenance of information in working memory, a
substantial literature in cognitive neuroscience suggests
that the DLPFC maintains context representation during
working memory tasks, in support of task appropriate
responding (Miller and Cohen, 2001) based on items stored
in ventral PFC and posterior areas. This raises the
possibility that alterations in PFC gamma band oscillatory
functions related to forming and maintaining a context
representation might be impaired in schizophrenia and
related to impaired cognitive control. Disturbances in local
micro-circuits in the PFC and an inability to generate
sustained oscillatory activity in this region may form the
basis for disrupted top-down support to task-relevant
circuits across the brain at a macro-circuit level, leading
to impaired task-related cognitive activity and behavioral
disorganization in the illness. Cho et al (2006) reported a
reduction in PFC-related gamma activity in schizophrenia
during cognitive control, a finding that was also related to
impaired task performance and behavioral disorganization
in the patient group. Figure 3 summarizes an integrated
model in which altered local micro-circuit function disrupts
high-frequency oscillations in the PFC, leading to a failure
of top-down support for the recruitment of task appropriate
macro-circuits or distributed networks in the brain,
resulting in impaired task appropriate behavior, clinical
disorganization, and impaired functioning in schizophre-
nia. This model integrates decades of research that has
focused on DLPFC dysfunction in schizophrenia, while
providing detailed links between cellular mechanisms,
altered neurophysiology, and the clinical phenotype of
Cognitive control deficits in schizophrenia
TA Lesh et al
schizophrenia. This specific pathophysiological conceptua-
lization can help guide future genetic studies by providing
specific cognitive and neural endophenotypes. In addition,
this model has the potential of enhancing the identification
and development of novel treatment targets, such as
partial agonists at the a2-subunit of the GABA-A receptor
(Lewis et al, 2008a), as well as aiding the development of
new biomarkers for use in the future for diagnosis and risk
IMPLICATIONS FOR PHARMACOLOGY OF
HIGHER COGNITION IN SCHIZOPHRENIA
Current consensus supports cognitive dysfunction as a
critical treatment target in schizophrenia. The FDA has
recently agreed to consider cognitive dysfunction as a
discrete indication for approval of new pharmacological
agents in schizophrenia (Buchanan et al, 2005). Among the
existing FDA-approved pharmacopoeia, considerable recent
research has addressed the potential of atypical antipsycho-
tic medication for remediation of cognitive dysfunction.
It has been proposed that this advantage may arise
from unique pharmacological actions of the atypical
antipsychotics as these medications elevate catecholamines
and glutamate in the cortex, particularly the PFC (Meltzer
and Huang, 2008; Stip et al, 2005). These effects would likely
be owing to direct antagonism of serotonergic and
adrenergic receptors, which are located on catecholamine
and glutamatergic terminals, and serve to inhibit neuro-
transmitter release. Nonetheless, the clinical literature
addressing effects of atypical antipsychotics on cognition
in schizophrenia is plagued by several important methodo-
logical problems (Goldberg et al, 2007); (Carpenter and
Gold, 2002; Carter, 2005; Harvey and
Montgomery et al, 2004; Weiss et al, 2002), contributing
to considerable heterogeneity in existing findings with
regard to the effects of these medications on cognition. As a
result, there is an emerging consensus that there is no strong
evidence for atypical antipsychotic remediation of cognition
in schizophrenia and there remains a great need to identify
and develop truly novel agents for this indication.
Several neurotransmitter systems in the brain have
critical roles in supporting the neural networks believed
to be impaired in schizophrenia, including the PFC, and
offer potential treatment targets for cognition. Perhaps, the
most well established are the two primary catecholamine
systems, DA and norepinephrine (NE). The DA hypothesis
of schizophrenia has been an enduring framework for
investigation of the pathophysiology of this illness, and
recent evidence has elaborated the role of this neurotrans-
mitter system (Carlsson and Carlsson, 2006). Seamans and
Yang (2004) outlined an elegant theory of DA modulatory
function in the PFC, such that breadth and salience of
information in working memory is controlled by DA PFC
inputs. This model has relevance to schizophrenia as a
chronic state of hypodopaminergia has been implicated in
the PFC of schizophrenia patients, with decreased tyrosine
hydroxylase binding (Akil et al, 1999) and increased D1
binding, which may represent a compensatory upregulation
in response to a chronic deficit of synaptic DA (Abi-
Dargham et al, 2002). This could contribute to PFC-
dependent cognitive deficits, as research shows that
6-OHDA lesions in the DLPFC disrupt working memory
in monkeys (Brozoski et al, 1979). The D1 receptor appears
critical in delineating PFC DA effects, as microinjection of
D1 antagonists (but not D2 antagonists) into the DLPFC
disrupts working memory-guided saccades (Sawaguchi and
Goldman-Rakic, 1994). In studies of healthy adult humans
as well as patients with schizophrenia, amphetamine
improves working memory (Barch and Carter, 2005), with
associated changes in DLPFC activity measured by fMRI
(Mattay et al, 2000). The D1/D2 agonist pergolide shows
(a) g-aminobutyric acid (GABA)-ergic cellular abnormalities, (b) ‘micro-
circuit’ gamma oscillatory function, (c) regional recruitment of the
prefrontal cortex (PFC) in mediating cognitive control, (d) engagement
of the ‘macro-circuit’, the coordinated activation of frontal and parietal
regions as a neural system, (e) cognitive/behavioral performance on
cognitive control tasks (eg, AX-Continuous Performance Task (AX-CPT)
and Stroop), and (f) disorganization symptoms.
From cells to circumstantiality: a unified model outlining
Cognitive control deficits in schizophrenia
TA Lesh et al
specific benefits for working memory, in contrast to other
cognitive functions (Kimberg and D’Esposito, 2003). D1
receptors also modulate both long-term potentiation and
long-term depression in the rodent PFC, probably through
interactions with NMDA receptors, providing a cellular
mechanism for DA effects on PFC plasticity (Jay, 2003;
Otani et al, 2003). Chronic treatment of monkeys with
typical or atypical antipsychotics (at clinically relevant
doses) also leads to spatial working memory deficits
(Castner et al, 2000), along with D1 receptor downregula-
tion in PFC (Lidow et al, 1997). The potential exacerbation
of pre-existing DA dysfunction could partly explain the lack
of efficacy of existing medications for PFC-dependent
cognition in schizophrenia. D4 receptors have also been
targeted in schizophrenia. However, D4 antagonists do not
appear to have efficacy for the symptoms of schizophrenia,
and enhancements in working and episodic memory have
been observed in animal models after both D4 agonists and
antagonists, suggesting that the role of D4 receptor in
cognition is complex and possibly multiphasic (Gray and
The ascending NE system is also implicated in PFC-
dependent cognition. This relates in part to the observation
that the NE transporter (NET) is largely responsible for the
termination of DA action in the PFC, owing to a paucity of
DA transporter protein (Moron et al, 2002). However, NE
itself strongly modulates PFC neurons and associated
cognitive processes. For instance, a2-receptor agonists
improve working memory performance in monkeys when
administered either systemically or directly into the PFC
(Franowicz and Arnsten, 1998). Clonidine reverses the
working memory deficit induced in rats by PCP (Marrs
et al, 2005). a2-Receptor antagonists can reverse the benefit
of a2-agonists when co-administered, and impair memory
performance when given alone (Li and Mei, 1994). These
effects appear to occur at post-synaptic sites. Guanfacine
also improves spatial working memory in healthy humans
(Jakala et al, 1999). Furthermore, there is considerable
evidence for NE modulation of plasticity-dependent pro-
cesses, such as long-term memory consolidation, via
b-adrenergic receptors in PFC and elsewhere (Tronel et al,
To date, agents that have adequate brain penetration and
direct agonist activity at specific catecholamine receptor
subtypes remain generally unavailable to test this mechan-
ism for remediation of cognition in schizophrenia. How-
ever, a number of catecholamine transporter inhibitors are
in use for other neuropsychiatric indications, particularly
for attention-deficit disorder. Among these, there is
evidence that low-dose amphetamine improves PFC-depen-
dent cognitive function in schizophrenia (Barch and Carter,
2005; Daniel et al, 1991), and more recent evidence that
modafinil improves PFC-dependent cognition in schizo-
phrenia patients (Turner et al, 2004; for a review,
see Minzenberg and Carter, 2008a), which may be a
function of modulation of locus coeruleus neuronal activity
(Minzenberg et al, 2008b). In addition, a small study found
atomoxetine to improve working memory-related PFC
activity in schizophrenia (Friedman et al, 2008), and
inhibition of COMT with tolcapone improves cortical
activity and working memory performance in healthy
adults, dependent on COMT genotype (Apud et al, 2007).
This evidence, while preliminary, suggests that the modula-
tion of catecholamine neuronal activity, and augmentation
of these neurotransmitters in the cortex, may be a safe and
effective therapeutic strategy for cognition in schizophrenia.
More recently, neurons that use GABA as a neurotrans-
mitter have become a major focus for models of pathophy-
siology in schizophrenia (Gonzalez-Burgos and Lewis,
2008). Post-mortem studies have found consistent evidence
of reduced mRNA for the 67-kDa isoform of the enzyme
that synthesizesGABA, glutamic
(GAD-67), as well as reduced mRNA coding for the GABA
membrane transporter (GAT1). These changes are both
observed in the DLPFC in a subpopulation of GABA-ergic
neurons that express the calcium-binding protein parval-
bumin (Gonzalez-Burgos and Lewis, 2008). These fast-
spiking interneurons exert a strong influence on the timing
of cortical pyramidal cell activity as well as subthreshold
membrane potentials in these cells, and are major
determinants of high-frequency cortical oscillations, such
as those in the gamma range (30–80Hz). As described
previously, gamma oscillations are associated with a range
of higher-order cognitive processes, and are consistently
impaired in schizophrenia. Interestingly, a recent study
found that a partial agonist at the a2-subunit of the GABA-A
receptor remediates this oscillatory deficit in schizophrenia
(Lewis et al, 2008a). The predominant medications cur-
rently available that act at the GABA-A receptor are the
benzodiazepines, which lack pharmacological or anatomical
specificity, and probably disrupt the finely tuned temporal
dynamics of GABA-ergic (and thus pyramidal cell) activity.
In contrast, agents that inhibit GAT1 (eg, tiagabine), for
instance, may augment neurotransmission at GABA synap-
ses while largely preserving the temporal pattern of
signaling that is necessary to establish or maintain cortical
oscillations. These remain to be studied for effects on
cognition in schizophrenia.
Glutamate is another neurotransmitter that has been
considered as a potential target for cognitive remediation in
schizophrenia. There is evidence of impaired glutamatergic
function in schizophrenia (Coyle, 2006), including impaired
plasticity processes (Lewis and Gonzalez-Burgos, 2008b),
and the clinical and biological effects of non-competitive
NMDA receptor antagonists (such as ketamine and
phencyclidine) suggest a role in the treatment of cognitive
impairment in schizophrenia. Accordingly, enhancement
of NMDA receptor function has been an emerging line of
research, particularly targeting the glycine modulatory site
on the NMDAR. Although initial small pilot studies
suggested clinical improvement with the administration of
glycine, D-serine and D-alanine, a large multi-center study
found no effects on MATRICS neuropsychological measures
among schizophrenia patients treated with glycine or
Cognitive control deficits in schizophrenia
TA Lesh et al
D-cycloserine (Buchanan et al, 2007). Glycine transporter
inhibitors that have shown promise in pre-clinical studies,
however, have not been tested to date for effects on
cognition in schizophrenia patients. Allosteric potentiators
of AMPA receptor function (AMPAkines) also improve
cognition in animal models; however, a large multi-center
study failed to show cognitive benefits with the AMPAkine
CX-516 added on to existing atypical antipsychotic treat-
ment (Goff et al, 2008). A study of a new agonist at
the metabotropic 2/3 subtype glutamate receptor has
shown promise for symptoms of schizophrenia in a phase
II clinical trial; however, it remains unknown whether
this is accompanied by cognitive improvement (Patil et al,
The central cholinergic system has also been targeted for
cognitive remediation in schizophrenia. Earlier work
focused on acetylcholinesterase inhibition as a mechanism
to enhance synaptic acetylcholine. Although an initial pilot
study showed enhanced PFC activity in schizophrenia
patients on donepezil (Nahas et al, 2003), repeated clinical
trials of AChE inhibitors failed to show improvements
in cognition (Ferreri et al, 2006). More recently, direct
nicotinic receptor agents have been tested, with an
emphasis on the a7-subunit of the nicotinic receptor. A
partial agonist drug with selectivity for the a7-subunit
(DMXB-A) initially showed promise for cognition, with
single-dose benefits on the RBANS summary score (Olincy
et al, 2006); however, a larger phase 2 trial generally failed
to show improvement in the MATRICS neuropsychological
battery (Freedman et al, 2008). It remains unclear whether
this is owing to tachyphylaxis of the nicotinic receptor in
response to sustained exposure to the drug, inadequacy of
the cognitive measures, some aspect of the clinical sample,
or other issues. Muscarinic ACh receptors have been
investigated as well. The antimuscarinic activity of the
antiparkinsonian agents, as well as intrinsic antimuscarinic
activity found in medications such as olanzapine, appears
to exacerbate cognitive dysfunction in schizophrenia
(Minzenberg et al, 2004; Vinogradov et al, 2009). More
specifically, the M1 receptor subtype has been implicated in
schizophrenia post-mortem studies (Crook et al, 2000,
2001), M1 receptor knockout mice exhibit working and
long-term memory deficits (Anagnostaras et al, 2003), and
this receptor strongly modulates cortical gamma oscillatory
activity (Whittington et al, 2000). Although a major
clozapine metabolite (NMDC) appears to be a potent M1
agonist (Sur et al, 2003), there is no available agent yet with
sufficient selectivity for this receptor to provide an adequate
test of M1 agonism in cognitive remediation.
The role of the central histaminergic (HA) neurotrans-
mitter system in systems neuroscience and cognition has
been elaborated recently. The major focus has been on the
recently discovered H3 receptor, which acts as both an
autoreceptor on histaminergic terminals, but importantly
also as an inhibitory heteroreceptor on the terminals
(Esbenshade et al, 2006). These include catecholamines,
and cholinergic and serotonin neurons. The central HA
system serves an information-processing role quite similar
to that of the cholinergic system, directly modulating
various forms of attention and memory. Non-selective
antihistamine medications that penetrate the brain are well
known to impair a range of cognitive processes, and
antagonism of the H3 terminal autoreceptor could improve
cognition in part by enhancing synaptic HA. In addition,
however, the indirect effects of HA antagonism (or H3 gene
knockout) at the H3 terminal heteroreceptor serve to
amplify catecholamine and cholinergic modulatory effects
on cortical function. This includes PFC function subserving
working and long-term memory, attention, and executive
functions (Esbenshade et al, 2006). Although it remains
unknown whether there is any underlying disturbance in
the HA system in schizophrenia, these HA modulatory
effects on other transmitter systems and cortical function
suggest a very novel target with a potentially excellent cost–
benefit profile in clinical terms. Accordingly, several
pharmaceutical firms have H3 antagonists in development
for cognition in schizophrenia.
Finally, the endocannibinoid system has been implicated
in schizophrenia, and may serve as a highly novel treatment
target for both cognitive and clinical symptomatology.
Epidemiological studies indicate a strong association of
high levels of cannabis use and psychosis (Henquet et al,
2008), and acute intoxication can produce symptoms
(D’Souza et al, 2004). There is also evidence of alterations
in this system in schizophrenia, such as increased binding
at the CB1 receptor, the primary cannabinoid receptor in
the brain (Dean et al, 2001; Newell et al, 2006; Zavitsanou
et al, 2004), and increased CSF levels of anandamide,
the primary endogenous ligand in the brain (Giuffrida et al,
2004; Leweke et al, 1999), in schizophrenia patients.
Variation in the CNR1 gene (which codes for the CB1
receptor) is associated with both risk for schizophrenia
(Ujike et al, 2002) and variation in clinical response to
atypical antipsychotics (Hamdani et al, 2008). CB1 recep-
tors function primarily to mediate retrograde signals from
post-synaptic to pre-synaptic neurons and, via this mechan-
ism, influence a range of plasticity processes (Heifets and
Castillo, 2009; Lovinger, 2008). The cell types regulated by
CB1 receptors include DA, glutamate, and GABA. In animal
models of cognition, CB1-active agents modify various
forms of memory, with antagonists remediating the adverse
effects of endogenous or exogenous CB1 agonists to
normalize cognition (Egerton et al, 2006). This suggests
that CB1 antagonists may remediate the cognitive deficits
inherent to schizophrenia, the adverse effects of cannabis
use on cognition and clinical state, or even modify a major
risk factor for the onset of this illness. Rimonabant is a CB1
antagonist that was initially tested to treat cardiovascular
risk factors associated with obesity, but was withdrawn
owing to safety concerns. However, this class of agents
remains of interest for various clinical indications in
medicine, and a test of their potential for cognitive and
clinical remediation in schizophrenia is warranted.
Cognitive control deficits in schizophrenia
TA Lesh et al
PFC-BASED COGNITIVE CONTROL AS A
TREATMENT TARGET IN SCHIZOPHRENIA
As observed above, there are varied effects of pharmaco-
logical intervention on PFC function and the range of
cognitive processes supported by the PFC. This hetero-
geneity may arise from the diverse roles of different
neurotransmitter systems in the support of these processes,
and from numerous methodological factors in the existing
empirical literature in both animal models and in clinical
trials. Nonetheless, the construct of cognitive control may
offer an integrative framework to specify a novel target for
This warrants the consideration of pharmacology studies
that use explicit cognitive control measures. This is a small
literature to date and the majority of studies focused
on catecholamine systems. Single-dose d-amphetamine
(d-AMP) 0.25mg/kg orally has been found to enhance
speed on a classic Stroop task, both in healthy subjects and
in stable schizophrenia patients (Barch and Carter, 2005),
and improved accuracy in healthy subjects on the conflict
condition of the Eriksen Flanker task (Servan-Schreiber
et al, 1998). A study of healthy subjects using a lateralized
version of the classic Stroop found bromocriptine to
modestly improve conflict-related RT, whereas pergolide
(a mixed D1/D2 agonist) was ineffective (Roesch-Ely et al,
2005). These findings suggest that D2 receptors may
mediate the major effect of DA on control processes,
possibly by modulating the rate or pattern of DA cell firing
via the cell-body D2 autoreceptor. Using the AX-CPT task, a
4-week double-blind course of treatment of schizotypal
personality disorder subjects with guanfacine, a specific a-2
adrenergic agonist, was associated with improved perfor-
mance, as BX errors were significantly reduced and AY
errors were more modestly increased, a pattern approaching
that of healthy subjects (McClure et al, 2007). In contrast, a
parenteral dose of d-AMP administered to rats (0.5mg/kg
subcutaneously) led to increased BX errors (but not AY
errors) on an AX-CPT analog task (Maes et al, 2001). This
may occur at higher AMP doses that push subjects to the
descending limb of an inverted-U curve relating cognition
to neurotransmission. Studies using electrophysiology
during Flanker performance by healthy subjects have found
haloperidol to attenuate both performance and the error-
related negativity (ERN) (Zirnheld et al, 2004), whereas
yohimbine augmented both the performance and the ERN
(Riba et al, 2005). As an a-2 antagonist, yohimbine
may have exerted its major effect either at the cell body,
to increase action potential activity (potentially in a task-
related manner), and/or to augment NE release by
inhibiting the terminal autoreceptor. The effect of mod-
afinil, a mixed DAT/NET inhibitor, on neural activity
measured by fMRI during cognitive control performance
suggests that modulation of LC cell-body activity may
be a strong determinant of PFC-based control processes
(Minzenberg et al, 2008b). The role of DA in performance
monitoring, specifically in modulating the ERN (Holroyd
and Coles, 2002) is proposed to arise from the reward
prediction error. This is observed in reinforcement learning
paradigms and mediated by a transient decrease in
midbrain DA cell firing in response to errors or negative
feedback (Schultz et al, 1997), disinhibiting pyramidal cells
in the ACC as one result. Although this model remains to be
adequately tested, it does provide a useful heuristic to guide
The role of other neurotransmitter systems in modulating
cognitive control processes has been much less well studied.
A few studies have found that decreased serotonin activity
during Stroop performance (achieved by orally induced
transient depletion of tryoptophan, a precursor to seroto-
nin) is associated with increased neural activity in ACC and
DLPFC (Horacek et al, 2005) and improved performance
(Scholes et al, 2007). Given the opponent interactions
between DA and serotonin (Daw et al, 2002), probably
mediated primarily via inhibitory serotonin (5-HT2)
receptors on DA neurons, an advantageous feature of
candidate pro-control agents for schizophrenia may com-
bine pro-catecholamine and serotonin antagonist activity,
analogous to the combination of DA antagonist and
serotonin antagonist activity for the symptomatology
of schizophrenia. Another important consideration arising
from this relatively small but provocative literature is that
agents that alter the firing patterns of monoamine cells may
have a unique potential, compared with direct post-synaptic
and their effects on the distributed cortical–subcortical
networks that support complex cognitive processes. The
potential of other neurotransmitter systems as targets to
enhance cognitive control processes awaits further basic
science research, both in animal models and in humans.
ALTERNATIVE MODELS FOR HIGHER
COGNITIVE DEFICITS IN SCHIZOPHRENIA
Although the cognitive control model we propose here seeks
to unify a number of discrete findings of deficits within the
domain of higher cognitive dysfunction in schizophrenia,
several alternative views have been articulated. One such
view is that the range of cognitive deficits noted in
schizophrenia, in fact, represents multiple distinct impair-
ments that are each linked to individual neural systems that
together produce the syndrome. In this ‘multiple endophe-
notype’ view, cognitive control processes would simply
represent one of the many discrete deficits that compose
schizophrenia. This view is reinforced by findings that
particular morphometric features (eg, hippocampal size)
and cognitive performance (eg, verbal declarative memory)
may be associated with increasing genetic liability to the
disorder (for a review, see Cannon and Keller, 2006; van Erp
et al, 2004). As mentioned previously, other candidate
cognitive endophenotypes have been proposed and inves-
tigated, including early sensory processing (eg, mismatch
negativity, prepulse inhibition), executive dysfunction,
and language dysfunction (Bertisch et al, 2010; Braff and
Light, 2005; Calkins et al, 2004; Freedman et al, 2003;
Cognitive control deficits in schizophrenia
TA Lesh et al
Glahn et al, 2003; Gottesman and Gould, 2003; Hasenkamp
et al, 2010; Winterer et al, 2003). The ‘multiple endophe-
notype’ approach has developed and maintained strength
owing to the idea that each specific cognitive endopheno-
type may be more tightly linked to a particular functional
gene that may be causal for schizophrenia. However, this
drive toward cognitive and genetic specificity may have
narrowed our focus too sharply and led the field away from
a broader, more integrative perspective. Just as some
medical illnesses can manifest with a variety of disparate
physical symptoms (eg, systemic lupus erythematosis), a
piecemeal approach to cognition in schizophrenia may
obscure the fact that the failure of a singular overarching
cognitive domain could yield a substantial proportion of
the varied pattern of cognitive deficits that are observed in
the disorder. Future investigations should systematically
investigate the interplay between diverse cognitive systems
to address the question as to whether impairment in one
overarching domain, such as cognitive control, is the most
parsimonious explanation for the array of higher cognitive
deficits that are observed in the disorder.
Deficits have also been reported on perceptual tasks in
thresholds, perceptual context effects and sensory gating,
such as mismatch negativity, p50 suppression, and pre-
pulse inhibition. There should be little doubt that percep-
tion is altered in schizophrenia given the prominence of
hallucinatory behavior in the symptomatology of the illness.
However, the relationship between performance on percep-
tual tasks and higher cognitive deficits in schizophrenia is
unknown, as indeed is the relationship between different
perceptual tasks themselves. Some of the tasks involving
perceptual discrimination would be conceptualized by
cognitive neuroscientists as perceptual decision-making
tasks (Heekeren et al, 2004; Wendelken et al, 2009) and
these have been shown to engage a distributed brain
circuitry that includes the PFC, which is strongly engaged
when subjects are pushed to their limit of perceptual
discrimination. Others, such as mismatch paradigms,
typically include a distractor task that involves reading or
watching a movie. Functional imaging studies of these
paradigms show that they also engage frontal networks
(Molholm et al, 2005). Interestingly, in a study of perceptual
organization, Silverstein et al (1996) showed a full recovery
in performance to the normal range in patients simply by
removing several conditions of the task to reduce strategy-
shifting demands, suggesting a role for altered cognitive
control processes in these deficits. Other work showing
intact subliminal priming in the context of lowered back-
ward masking performance also suggests that low-level
visual processes may be preserved, while top-down atten-
tional and control mechanisms may be associated with
impaired performance (Del Cul et al, 2006). Finally,
psychophysical tasks involving staircasing methods for
threshold discrimination are highly sensitive to attention
lapses and, whereas some studies have controlled for this
(Dakin et al, 2005), many such studies in schizophrenia
have not. Hence, it is unclear as to what degree impaired
performance on some tasks involving perceptual thresholds
and discrimination might also reflect a generalized perfor-
Finally, it could be hypothesized that altered perceptual
processing could result in higher cognitive deficits related
to attention, executive functions, memory, and language
processing in schizophrenia in a bottom-up manner. This is
unlikely, however, because many studies have shown that
stimuli such as words or images are processed quite
normally in schizophrenia, fully to the semantic level,
where they elicit normal or even increased priming effects.
The opposite pattern, reduced priming, is seen when
patients are required to rely on strategic processing (Barch
et al, 1996b; Kerns and Berenbaum, 2002; Kreher et al,
2009). Using a degraded stimulus version of the AX CPT,
Barch et al (1997) showed that, unlike the pattern typically
seen in schizophrenia, healthy subjects working with
degraded perceptual input show a general increase in error
rates (generalized deficit pattern) and did not change
the level of DLPFC activation during fMRI rather than the
selective increase in BX errors and decrease in PFC
activation that characterizes patients with schizophrenia.
Understanding the relationship between deficits on the
performance of tasks engaging higher cognitive functions
such as attention, executive functions, memory and
language process, which can readily be accounted for by
the prefrontally mediated cognitive control model, and
performance on measures of different aspects of perceptual
processing would bring increased coherence to our under-
standing of the mechanisms of impaired brain function and
behavior in schizophrenia, and should be an increased focus
of future research.
A large body of evidence has accumulated implicating
higher cognitive dysfunction as a core feature of schizo-
phrenia that is associated with clinical features of the
disorder (eg, disorganization, negative symptoms) and
functional outcome. In addition, higher cognitive deficits
are present in childhood, in various risk states (eg, genetic
high risk, CHR), at the onset of the illness, and stably persist
throughout the course of the disorder. Given the pervasive
nature of these deficits, a great deal of effort has been put
forth to characterize cognitive impairment and use these
data to inform our understanding of the pathophysiology of
schizophrenia as well as identify treatment targets. There
has also been some progress using these methods to identify
functional susceptibility genes.
In this review, we have described a model of impaired
cognitive control that seeks to account for a notable
proportion of higher cognitive deficits that have been
discussed in the schizophrenia literature. Cognitive control
regulates a wide array of cognitive systems (Carter et al,
1998; Posner and Abdullaev, 1996) and is not restricted to a
particular cognitive domain (Banich, 1997; Smith and
Cognitive control deficits in schizophrenia
TA Lesh et al
Jonides, 1999). For example, in addition to accounting for
deficits in attention and working memory, the cognitive
control model posits that episodic memory deficits may be
driven primarily by frontally mediated encoding and
retrieval failures rather than a hippocampally mediated
inability to learn (Ragland et al, 2009). In addition, we
outlined data that might indicate the pathophysiological
basis of impaired cognitive control, starting at the ‘micro-
circuit’ cellular level where functional alterations of the
chandelier subtype of GABA-ergic interneurons in the
DLPFC may result in reduced neuronal synchrony followed
by subsequent prefrontal cortical dysfunction (for a review
see, Lewis et al, 2005) and associated BOLD response
reductions. Dysfunctional prefrontal recruitment of task
appropriate networks during cognitive control represents
‘macro-circuit’ systems-level abnormalities that in turn lead
to the impaired cognitive performance and behavioral
Although we are focusing on a model of prefrontally
based cognitive deficits, it is important to note that we are
in no way implying that only the PFC is impaired in
schizophrenia. Abnormalities in post-mortem tissue as well
as morphometric and functional imaging changes have been
reported in a wide range of brain regions, including
the hippocampus, thalamus, superior temporal gyrus, and
visual cortex (Benes et al, 2001; Dorph-Petersen et al, 2007;
Ellison-Wright et al, 2008; Glahn et al, 2008; Honea et al,
2005; Wright et al, 2000). By formulating this model based
on the evidence presented above, we propose that altered
PFC function is likely to be a central driver in impaired
cognition in schizophrenia and that a detailed under-
standing of the nature of impaired function in this neural
system can inform our understanding not only of cognitive
deficits in schizophrenia but also key targets for interven-
tion. Importantly, our model, which attempts to link
impaired local circuit dysfunction in the DLPFC to impaired
distributed network dysfunction and a broad range of
cognitive and functional impairments, has implications far
beyond the simple notion that the DLPFC is affected in
schizophrenia. The developmental, cellular, and molecular
processes underlying local circuit function in the DLPFC
should and are receiving a great deal of attention in research
that seeks to understand pathophysiology and treatment
targets. Cognitive neuroscience tasks implemented in
imaging and cognitive EEG are providing a new generation
of phenotypic measures that can help clarify the boundaries
and overlap between schizophrenia and other serious
mental disorders as well as to understand the functional
significance of schizophrenia-related genetic variation.
Furthermore, an understanding of the role of cognitive
control can inform the development of cognitive training
technologies, which to date are the only viable treatment
approaches to impaired cognition in schizophrenia.
To this end, cognition is an important emerging
treatment target in schizophrenia. The role of neurotrans-
mitter systems in modulating prefrontal cortical function
has become increasingly well understood and these systems
have been identified as important treatment targets.
Accordingly, there is preliminary evidence that catechola-
mine and other agents improve PFC function and cognition,
including in schizophrenia patients. Although there have
been variable outcomes among recent clinical trials of novel
agents that act on catecholamine, glutamate, and choliner-
gic systems, these studies are complex and must overcome
methodological challenges. Nonetheless, monoamine and
amino-acid transmitter systems remain promising targets.
FUTURE RESEARCH DIRECTIONS
Although we have accumulated a large body of knowledge
with regard to the course of the disorder after onset and
factors influencing outcome, one of the most rapidly
expanding areas of research is investigating how to
accurately identify those individuals who will go on to
develop schizophrenia. This area of research is particularly
important as these findings promote early intervention,
which has the potential to alter the trajectory of the illness
for those at highest risk and reduce the burden on
individuals, their families, and the health-care system.
As discussed previously, there is evidence of cognitive
deficits before the onset of the illness; however, there is
limited knowledge as to when cognitive dysfunction
emerges and how these deficits progress throughout child-
hood and adolescence. In addition, it remains unclear
whether deficits at the population level in pre-adolescent
samples are uniform across the sample or whether they
reflect a subgroup with developmental pathology. These
types of questions require prospective, most likely multi-
center, studies that examine at-risk individuals in youth and
continue through years after the disorder may manifest.
Although the majority of current studies of at-risk youth
measure clinical factors associated with transition to
psychosis, future studies would benefit from examining
cognitive predictors of conversion as well.
Treatment research may benefit substantially from the
use of measures and methods that are linked to the function
of neural systems, including behavioral and imaging
measures from cognitive neuroscience, which might not
have traditionally been included in the treatment develop-
ment process. Such methods offer unique advantages for
translational research, as many cognitive processes and
their associated neural systems are preserved across species.
Substantial interest in optimizing research in this way has
led to recent initiatives such as CNTRICS (Carter and Barch,
2007; Carter et al, 2008; www.cntrics.ucdavis.edu). However,
it is challenging to optimize the measurement properties
of these sorts of tools and substantial work remains to
be carried out before valid reliable imaging biomarkers will
be developed and optimized for the purpose of enhancing
Finally, ongoing research into pharmacotherapy for
impaired cognition in schizophrenia will also need to
address patient heterogeneity by developing tailored treat-
ment based on phenotypic (eg, cognitive symptoms,
Cognitive control deficits in schizophrenia
TA Lesh et al
disorganization) and possibly genotypic variability. Such a
personalized approach may allow us to get greater traction
on the elusive problem of developing a successful treatment
for the cognitive deficits that form a functional ‘glass
ceiling’ for many people with schizophrenia.
Drs Lesh, Niendam, and Minzenberg have no disclosures to
report. Dr Carter has served as a consultant for Pfizer, Lilly,
Merck, and Servier, and receives research funding from
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