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Schizophrenia Bulletin Advance Access originally published online on August 17, 2005
Schizophrenia Bulletin 2005 31(4):854-864; doi:10.1093/schbul/sbi044
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© The Author 2005. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org.

Synthesizing Schizophrenia: A Bottom-Up, Symptomatic Approach

Trevor W Robbins
Department of Experimental Psychology, University of Cambridge, Downing St., Cambridge CB2 3EB, UK


   Abstract
Top
 Abstract
Introduction
 The MATRICS Neuropsychological...
 Working Memory Deficits in...
 Attentional Deficits in...
 CANTAB: Its Utility for...
 Toward a MATRICS Preclinical...
 References
 
The cognitive deficits in schizophrenia are discussed in terms of the other symptoms of the disorder, as well as according to a translational approach that involves using similar or analogous tests for humans and experimental animals. This approach, it is argued, will enable the testing of novel drugs and the development of adequate etiological models of schizophrenia.

Keywords: cognition / memory / attention / prefrontal cortex / psychosis / dopamine


   Introduction
Top
 Abstract
 Introduction
The MATRICS Neuropsychological...
 Working Memory Deficits in...
 Attentional Deficits in...
 CANTAB: Its Utility for...
 Toward a MATRICS Preclinical...
 References
 
Schizophrenia is one of a large number of neuropsychiatric or neurological disorders with cognitive deficits as a major component. Current neuropsychological analysis suggests that there is no particular cognitive deficit that is characteristic of or unique for schizophrenia, although it is possible that certain subtle impairments may yet be shown to have this status. It is possible that the psychotic symptoms of schizophrenia might themselves eventually be explained in terms of a specific form of cognitive impairment, as has been argued by Frith.1 Relating such cognitive impairments to conventional effects of brain damage such as frontal lobe lesions is difficult: a new type of neuropsychological analysis will be required that can be related to the pathological features of the disorder, for example, in terms of developmental dysplasias, disconnection syndromes, or regulation of subcortical dopamine activity, quite possibly in combination. The problems facing the field are depicted in figure 1. We need first to match a well-defined neurobehavioral endophenotype for schizophrenia to etiological models of the disorder that are validated by the appropriate behavioral and cognitive features of the disorder in paradigms exhibiting plausible functional homology from animals to humans; and then we must use the model to discover effective new, probably pharmaceutical, therapies.



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  		Fig. 1. Preclinical Models in Schizophrenia—The Nature of the Problem.

 
Currently, it appears that schizophrenia has a profile of cognitive deficits that may be quite heterogeneous but includes impairments customarily related to malfunctions of the medial temporal and frontal lobes (including the anterior cingulate cortex) and their connections with the basal ganglia. Other works have chosen to emphasize the lateralization of impairment, for example, to left hemisphere (predominantly language) functions, but the recent Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) analysis has not tended to support this analysis.2 In translational terms, this suggests that one should focus on particular paradigms for assessing specific symptoms of cognitive deficit such as working memory or attentional gating functions, but one should not then lose sight of the overall profile of impairment. This strategy simplifies the search for simple models that might be reduced to the effects of a lesion to a particular brain region or treatment with a particular drug (e.g., ketamine). Such symptomatic models will be successful at simulating some of the cognitive deficits and would therefore be useful in the evaluation of candidate therapeutic drug effects and in the assessment of etiological models. The latter are methods for understanding the origins and subsequent progress of the disorder at the level of the underlying molecular and cellular mechanisms. While there has been marked progress in identifying the genetic contributions to schizophrenia and also in identifying environmental risk factors, leading, for example, to the so-called neurodevelopmental hypothesis, it has proven difficult so far to implement an animal model incorporating all of these factors.3 Clearly, where etiological factors are quite well understood, as in the case of Alzheimer's disease, it is feasible to model the pathology itself and observe the consequences for cognition. However, for many neuropsychiatric disorders such as schizophrenia, the etiological factors are not at all well understood, so the modeling of the most important aspects of the cognitive profile is all that can be readily achieved. The main factors so far considered have used the rat and include several attempts to capture the main developmental features of the disorder, such as the use of neonatal lesions, for example, of the hippocampus; disruptions of neurogenesis, for example, following treatment with methylazoxymethanol or X-irradiation; early stress (e.g., maternal deprivation or rearing in isolation during adolescence); and generally in adulthood, pharmacological models (amphetamine, phencyclidine, and hallucinogens such as psilocybin [see table 1]). It is, of course, possible that combinations of subsets of these treatments may be necessary to achieve the most convincing synthesis of the disorder.


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  		Table 1. Building Models of Schizophrenia

 
Typically, these animal models have also been used to simulate behavioral changes that may be relevant to the psychotic symptoms of schizophrenia, which, despite the apparent independence from the cognitive deficits, may nevertheless be expected to arise in part from similar etiological factors and related pathology. Thus, it is interesting to consider that analogues of positive symptoms (hallucinations, delusions), as well as negative symptoms such as social withdrawal and "stereotypy," the tendency to repeat behavior with no apparent purpose, are all features of the models described above (table 2). For example, apparent hallucinations are caused by chronic amphetamine treatment in monkeys.4 Paranoid delusions are perhaps akin to the effects of amphetamine to exaggerate the salience of negative conditioned stimuli.5 This is consistent with Kapur's hypothesis regarding the relationship between such behavioral effects in animals, generally involving an amplification of the effects of environmental stimuli, and delusional behavior in schizophrenia.6 Social withdrawal, as exemplified by reduced contact with unfamiliar partners in an open field setting, is produced by chronic amphetamine treatment but may be modified by social hierarchy.7 Finally, several authors have noted that the stereotypy occurring in some schizophrenic patients8–9 might potentially be similar to the more complex forms of perseverative behavior produced, for example, by higher doses of amphetamine in experimental animal such as rats10 or monkeys.11


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  		Table 2. Behavioral Paradigms for Measuring Psychotic Dysfunction Relevant to Schizophrenia in Animals and Humans

 

   The MATRICS Neuropsychological Meta-analysis
Top
 Abstract
 Introduction
 The MATRICS Neuropsychological...
Working Memory Deficits in...
 Attentional Deficits in...
 CANTAB: Its Utility for...
 Toward a MATRICS Preclinical...
 References
 
Of the 7 areas of cognitive deficit identified,2 at least 5 (speed of processing, attention/vigilance, working memory, visual learning and memory, reasoning and problem solving) are probably amenable to examination in animal models, and it may also be possible to investigate social cognition, for example, in nonhuman primates. Only verbal learning and memory, for obvious reasons, are not translatable end points for animal research; however, it seems rather dubious that the principles governing verbal learning and memory will be so different from those for visual learning and memory. I now survey some of the main domains that have yielded most effectively to further exploration via animal models.


   Working Memory Deficits in Schizophrenia
Top
 Abstract
 Introduction
 The MATRICS Neuropsychological...
 Working Memory Deficits in...
Attentional Deficits in...
 CANTAB: Its Utility for...
 Toward a MATRICS Preclinical...
 References
 
Thanks to the work of the late Patricia Goldman-Rakic, a now classical test of spatial working memory based on the delayed-response task in nonhuman primates has had enormous impact, not only for the elucidation of prefrontal cortex (PFC) function but also in its application to human psychopathology, especially schizophrenia. A landmark paper has shown that depletion of dopamine in the sulcus principalis of the PFC of monkeys produced deficits on this test almost as great as those produced by ablation of the entire region.12 Moreover, these deficits were subsequently shown to be reversible by dopaminergic agents, providing some of the first proof of principle that cognitive deficits could be remediated by pharmacological treatment. Subsequent work using a combination of single-unit electrophysiology, microiontophoresis, and behavioral measures has expanded these initial observations considerably to demonstrate the primary involvement of D1 receptor mechanisms.13 These striking advances in our understanding of the prefrontal cortex came at a most opportune time for burgeoning investigations of the neurobiology of schizophrenia, when, for example, the concept of hypofrontality was coming to the fore, as a consequence of advances in brain imaging.14

A particularly effective example of the utility of the working memory model has been provided by a study of the effects of repeated systemic administration of a typical neuroleptic drug (haloperidol) on performance in the delayed-response task in rhesus monkeys—which were shown to produce massive impairments in performance, hypothetically via a substantial down-regulation of cortical D1 receptors.15 These data are significant in themselves in demonstrating cognitive sequelae of long-term neuroleptic treatment, as this is virtually impossible to show definitively in human studies alone. The improvements in working memory performance produced by treatment with a selective D1 agent, also shown by these authors, provide perhaps the best rationale for D1 receptor treatment for cognitive deficits in schizophrenia.

The application of working memory procedures to other experimental animals, for example, rats and mice, has shown some strong commonalties with nonhuman primates. Thus, the delayed alternation procedure has some similar requirements to the delayed-response task and has been used to demonstrate an "inverted U–shaped" function relating performance to the level of D1 receptor stimulation, with high as well as low levels of D1 receptor activity being detrimental to performance.16 Using a subtly different radial 8-arm maze procedure, Floresco and others have elegantly shown how D1 receptor stimulation interacts with endogenous levels of extracellular dopamine (DA) at different delays to produce both improvements and deficits in working memory performance.17–19

As well as proving to be a theoretically significant development for our understanding of PFC function, the working memory model has been significant for exploring the nature of cognitive impairment in schizophrenia itself. Initially, Park and Holzman introduced the concept of working memory to the analysis of cognitive impairments in schizophrenia by using a delayed saccade paradigm.20 Subsequent investigators have employed a variety of procedures to investigate working memory in schizophrenia, with the n-back verbal memory procedures being particularly popular.

A challenge to optimizing the translation of the working memory paradigm as used in experimental animals to schizophrenia lies partly in the precise theoretical notion of working memory employed. Whereas the term in research using experimental animals generally refers to the maintenance of a trace for a short period beyond its sensory impact (the usual definition favored by behavioral electrophysiologists) or to the use of information on recent trials of a task (usually the last trial) for guiding performance on the current trial, this is not the classical formulation of cognitive psychologists such as Baddeley.21 In his theory, working memory comprises the coordinated use of at least 2 satellite short-term memory systems, 1 of which is articulatory (i.e., subvocal verbal) in nature, and the other of which is a visuospatial "sketch pad." The coordination is achieved by a "central executive" that serves to select appropriate responses, generate strategy, and manipulate the contents of the satellite memory stores. While the operation of the "central executive" is often controversially equated with the functioning of the frontal cortex, it is not synonymous with it.

These theoretical challenges have led to a number of other attempts to analyze working memory function in animals that include the invention of a novel form of working memory procedure that introduces a more explicit element of strategic planning. Such procedures embody the central tenet of the cognitive theory, that working memory requires the manipulation of information in short-term store when solving current tasks or problems. The key example of this approach is that of "self-ordered memory" where the subjects themselves are required to determine the most efficient method of sampling and retrieving information—and equivalent procedures have been implemented effectively in both nonhuman primates and human subjects.22 It is this class of procedures that has been employed in the Cambridge Neuropsychological Test Automated Battery (CANTAB) to be described below.


   Attentional Deficits in Schizophrenia
Top
 Abstract
 Introduction
 The MATRICS Neuropsychological...
 Working Memory Deficits in...
 Attentional Deficits in...
CANTAB: Its Utility for...
 Toward a MATRICS Preclinical...
 References
 
Considerable evidence suggests that attentional dysfunction contributes prominently to the profile of cognitive deficit associated with schizophrenia. However, while individuals with schizophrenia are often characterized as hyperdistractible or lacking an attentional "filter," this has led to the postulation of several forms of attentional deficit (see table 3), including fundamental "sensorimotor" gating processes that are engaged during pre-pulse inhibition23 and impairments in "latent inhibition"24 or "covert orienting,"25 as well as executive forms of attention such as the shifting functions engaged by the Wisconsin Card Sorting Test or by the sustained attentional demands of the Continuous Performance Test. Remarkably, each of the forms of attention can be studied in experimental animals, and all have been shown to recruit quite specific, although sometimes overlapping, neural networks. Each of these aspects of attentional function may be impaired in schizophrenia because of the wide-ranging nature of its neuropathology, and so their comparison is of especial importance (for a detailed review, see 26).


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  		Table 3. Behavioral Paradigms for Measuring Attentional Dysfunction Relevant to Schizophrenia in Animals and Humans

 
In this account, I will focus on an analogue of a human test of sustained attention, the 5-choice serial reaction time task (5CSRTT), which has now been employed in monkeys and mice as well as rats. This test has analogies to the Continuous Performance Test of Rosvold and Mirsky and is more directly related to Leonard's Serial Reaction Time Test (see 26). The 5CSRTT is one of the tests embedded in the CANTAB to be discussed further below; it is one of the main tests from that battery that makes direct contact with work in rodents.

5-Choice Serial Reaction Time Task
This task is implemented in animals trained to detect brief visual target stimuli and to resist responding at inappropriate times; it thus engages executive cognitive processes of selection and inhibition. These processes appear to be mediated in part by different subregions of the rat prefrontal cortex. For example, damage to the dorsal prelimbic cortex particularly impairs accuracy, whereas damage to the infralimbic cortex increases premature responses (which can be described as "impulsive"), and damage to the orbitofrontal cortex (OFC) causes perseveration.27 Recently, it has been shown that selective N-methyl-D-aspartate receptor antagonists can produce similar deficits, presumably arising from their effect in the rat PFC.28 The basic paradigm can be manipulated in various ways to alter the attentional demands on the animal, for example, by making the stimuli occur unpredictably in time, as well as space, or by shortening the duration of the target stimuli.

Such behavioral manipulations have enabled us to show considerable dissociation in the way in which performance is affected following relatively selective manipulation of the ascending neuromodulatory transmitter systems, such as noradrenaline, serotonin (5-HT), dopamine, and acetylcholine (ACh).29 More recently, we have focused investigations on the role of these systems within the prefrontal cortex and related structures, using a range of techniques including in vivo dialysis (to sample fluxes in these neurotransmitters and their metabolites as the rat performs the task), selective neurotoxic lesions, and focal infusion of drugs with selective neuropharmacological actions.

The studies with microdialysis of PFC neurotransmitter fluxes show that acetylcholine and dopamine are particularly engaged by the task, whereas the noradrenergic system is active when contingencies are altered.30 Although the mesofrontal 5-HT system appears "silent" during performance of the task, individual levels of 5-HT are significantly correlated with the performance of premature, "impulsive" responses31—thus, it appears that levels of 5-HT activity may reflect a "trait" factor related to impulsivity.

These neurochemical observations are generally consistent with neuropharmacological and psychopharmacological studies, using, for example, microinfusions of agents directly into the rat medial (m-)PFC. For example, basal forebrain cholinergic lesions, which produce profound depletion of acetylcholine in the mPFC, lead to impaired accuracy on the 5CSRTT, often exacerbated under certain conditions, together with other evidence of disinhibitory deficits such as increased premature and perseverative responding. The impairments can be exacerbated by treatment with antimuscarinic agents such as scopolamine and remediated by pro-cholinergic drugs such as anticholinesterases and nicotine, as well as by the implantation of cholinergically enriched regions of embryonic basal forebrain into regions of the rat cerebral cortex depleted of acetylcholine such as the parietal cortex and PFC (see 26). These findings were useful in predicting the attentional-enhancing action of pro-cholinergic drugs found for patients with dementia of the Alzheimer's type performing a human analogue of the 5CSRTT.32

In comparison, infusion of selective dopamine receptor agents directly into the mPFC can improve accuracy, at least in relatively poorly performing rats. By contrast, the D1 receptor antagonist SCH-23390 only impairs accuracy in rats with relatively high levels of performance (>80% correct).33 Intra-PFC infusion of the D2 receptor antagonist sulpiride had no effects. These data suggest that the mesofrontal DA system is recruited under certain circumstances to optimize performance; in those rats with inferior performance, this system presumably has not been engaged and so is susceptible to cognitive enhancement produced by dopamine D1 receptor agonists. The data may conform to the well-known "inverted U–shaped" function that relates cognitive performance to optimal levels of arousal (or in this case D1 receptor stimulation).16 The lack of effect of DA D2 receptors is of interest, as a recent study by Passetti et al. has indicated that systemic treatment with the D2 receptor antagonist sulpiride improves accuracy significantly in rats with excitotoxic lesions of the PFC, possibly reflecting a striatal action of this drug that antagonizes a possible, up-regulation of striatal DA function caused by the lesion that contributes to the lesion-induced disruption of performance.89 Extensions of this work have shown that the locus of this effect is in the nucleus accumbens, as infusions of sulpiride there, but not in the dorsal striatum, ameliorate the impairments in accuracy caused by prefrontal lesions (Pezze M, Dalley JW, Robbins TW, unpublished observations).

Granon et al. showed that manipulations of DA receptor function in the PFC itself had little, if any, effect on other parameters of performance such as impulsive or perseverative responding.33 This is especially interesting given the effects of 5-HT receptor agents—for example, the 5-HT2A/2C receptor antagonist ketanserin has no effect on accuracy but selectively reduces premature, "impulsive" responses,34 suggesting some specific actions of the DA and 5-HT systems on different aspects of performance controlled by the PFC. These effects of ketanserin can be reproduced by the more selective 5-HT2A receptor antagonist M100907, under certain circumstances.35 However, in other situations this drug can also significantly improve accuracy, even in high-performing rats, possibly via some interaction with the DA or ACh system. These data indicate that interactions among the ascending neurotransmitter systems also have to be taken into account when predicting their impact on performance. The data with M100907 are of importance when considering the possible role of the 5-HT2A receptor in mediating some of the effects of the "atypical" neuroleptic drugs such as clozapine on cognition in schizophrenia.

The 5CSRTT has proven useful in analyzing the role of various neurotransmitters in the rat PFC. However, as well as the human analogue, there also exist versions of the task for rhesus monkeys,36 marmosets,37 and mice38 that will hopefully lead to an effective "vertical integration" of data across species. As mentioned above, the 5CSRTT has been used in human studies of patients with Alzheimer's disease. However, it is likely that a more stringent test is required to reveal deficits in schizophrenic patients. One such demanding test of sustained attention from the CANTAB is Rapid Visual Information Processing, which also has a working memory component (see 39). In this sense it is analogous to some of the elaborations of the Continuous Performance Test employed by Cohen and colleagues.40


   CANTAB: Its Utility for Characterizing the Cognitive Deficits in Schizophrenia and Their Neural Basis
Top
 Abstract
 Introduction
 The MATRICS Neuropsychological...
 Working Memory Deficits in...
 Attentional Deficits in...
 CANTAB: Its Utility for...
Toward a MATRICS Preclinical...
 References
 
The original concept of CANTAB was to define some tests sensitive to frontal and temporal lobe dysfunction that could be performed by monkeys as well as humans. This comparison cannot always be done directly. For example, the CANTAB test of planning, based on the so-called Tower of London, could not easily be implemented with monkeys. However, spatial planning recruits basic working memory functions that can be assessed by tests of spatial working memory inspired by, or deriving from, the animal literature. As performance on the Tower of London test is correlated with spatial working memory performance in humans, this thus helps to link the findings from animal studies of working memory to higher aspects of human cognition.

CANTAB Tests of Spatial Working Memory
CANTAB has several related tests of spatial working memory. One test assesses short-term spatial memory capacity based on the Corsi span task. Another requires subjects to retrieve spatial information from a list of stored items ("spatial recognition memory"). The most elaborate test is that of self-ordered spatial working memory, based on the self-ordered working memory22 paradigm described above. This test has been extensively validated as being sensitive to damage to the PFC (e.g., 41) and also shows activations in the dorsolateral and ventrolateral PFC in functional imaging paradigms.42 By comparison, the test of spatial span only activates the ventrolateral PFC, presumably because it has no strategic requirements. Subsidiary analyses of performance on the spatial working memory task make it clear that frontal patients, in contrast to patients with temporal lobe lesions and patients with Parkinson's disease, who also perform poorly on the test exhibit impairments in a measure of strategic performance, as distinct from short-term memory capacity per se.43

The test of self-ordered spatial working memory in particular has considerable relevance in schizophrenia. Pantelis et al. show huge deficits in chronic schizophrenia, arising mainly from impaired use of strategy and therefore similar to those of frontal patients.44 More recently, this group has shown that there are significant correlations of performance on this test with tardive dyskinesia and negative symptoms.45 Of even greater significance is evidence not only for considerable impairments in first-episode schizophrenia46 but also in patients at risk for first-episode schizophrenia.47 Thus, performance on this self-ordered spatial working memory task has potential utility as a biomarker for premorbid schizophrenia.

CANTAB Analogue of the Wisconsin Card Sorting Test: The Intradimensional/Extradimensional Shift Test
Sometimes, tests or findings in the clinic can shape the direction of the animal research. A case in point is a test of cognitive flexibility called the Wisconsin Card Sorting Test (WCST), which is often used in the assessment of patients with frontal lobe damage.48 Still more pertinently, the WCST has been shown to be an excellent challenge test for schizophrenia in a functional imaging context14 and has had a prominent role in the development of the "hypofrontality" concept in schizophrenia.

The WCST has been reconfigured in CANTAB to produce a simpler suite of tasks that reflect the building blocks of this complex cognitive test for humans. In short, 2 perceptual dimensions (e.g., shape and color) are defined, and stimuli comprise the compound stimulus that is formed by combining exemplars of the 2 dimensions. The subject is then trained to discriminate the dimensions on the basis of trial-and-error feedback and learn which exemplar is correct. This discrimination may be reversed so that the alternative stimulus is correct and the formerly correct stimulus is wrong. When the subject has learned to discriminate and reverse this discrimination, new exemplars are introduced with the same dimension remaining relevant. This is called an "intradimensional (ID) shift" and requires the establishment of an attentional set, through "learning-to-learn." Eventually, once the subject has learned to form an overall set in this way, new exemplars are again introduced, and the subject is required to shift attention to the alternative dimension. This is called an "extradimensional (ED) shift" and is a core element of the WCST.49

This test suite has been employed in studies of marmoset monkeys with fiber-sparing lesions of the lateral PFC or OFC.50 Strikingly, whereas reversal learning was impaired by lesions to the OFC, ED shifting was deficient following lesions to the lateral prefrontal cortex, thus demonstrating an informative "double dissociation" of the roles of these 2 PFC regions in these different forms of shifting behavior. Understanding the basic functions of these 2 PFC regions is a necessary prerequisite of understanding their contribution to cognitive deficits in neuropsychiatric disorders and also to interpreting the effects of selective neurotransmitter manipulations on these aspects of cognitive performance.

Selective manipulations of the mesofrontal dopamine system, using the neurotoxin 6-hydroxydopamine (6-OHDA), led to intriguing findings in marmosets. Surprisingly, profound DA depletion in well-trained monkeys led to enhanced set shifting at the ED shift stage—a result actually opposite to that of lateral PFC lesions.51 Further experiments showed that marmosets with PFC DA depletion exhibited 2 major forms of deficit: first, they were unable to maintain a set when presented with different exemplars of the same 2 stimulus dimensions and transfer responding according to the already established set. Normal monkeys rapidly learn to focus responding on the dimension that has already been made relevant by reinforcement. Second, lesioned animals showed greater disruption than normal marmosets when the background, irrelevant stimuli were changed but the previously reinforced stimuli were still present.52 This is reminiscent of hyperdistractibility. Both deficits can be related to problems exhibited by patients with schizophrenia performing a similar task.53 Thus, chronic schizophrenic patients, as well as having problems with ED shifting, are also impaired in ID shifting, indicative of possible problems in set maintenance or even abstracting ability.46, 54

The results are even more dramatic considered in comparison to the effects of dopamine depletion within the caudate nucleus, which produced reduced distractibility.52 One issue that still has to be resolved, however, is whether the effects of 6-OHDA lesions of the marmoset PFC might also be attributed to noradrenaline depletion, as there is in fact a partial loss of this neurotransmitter, even following pharmacological protection by pre-treatment. Nevertheless, there is evidence from the rat that performance on an analogous ED shift is impaired by selective cortical noradrenergic depletion,55 and so it seems unlikely that prefrontal noradrenaline depletion is responsible for this very different pattern of effects in the marmoset. If it can be assumed that the effects on set maintenance and distractibility are indeed due to prefrontal DA loss, then this, as well as the effects of D1 agonists on attention in rats,33, 56 would be consistent with a theoretical position advocated by Durstewitz et al. that prefrontal dopamine normally serves to protect the stability of attentional set.57 As mentioned above, the ID/ED task has been shown to have utility in studies of chronic schizophrenia. Interestingly, the test was not of especial sensitivity in first-episode cases, compared, for example, with tests of visuospatial paired associates or verbal learning or spatial working memory. However, on repeated testing, performance on this test showed decline compared to performance on some of these other tasks;58 it is not yet clear whether this is an effect of chronic medication (the D2 receptor antagonist sulpiride produces minor deficits in the performance of the ED shift in normal human volunteers).59 However, those subjects exhibiting the greatest decline in performance on the ID/ED test tended to be those with the longest period of untreated psychosis, suggesting that other factors may be operating.58 This includes the possibility that schizophrenic patients exhibit progressive decline in some aspects of cognition as an integral part of the disease process. Such results make it necessary to consider including a range of tests sensitive to fronto-executive impairment in any battery for assessing cognitive deficits in schizophrenia. It is of interest that performance on the ID/ED test was one of the most sensitive tests for detecting the beneficial effects of the atypical stimulant drug modafinil in a group of chronic schizophrenic patients in a recent study.60

Reversal Learning and Decision-Making Cognition: Effects of Serotoninergic Manipulations
It is evident that the effects of prefrontal 6-OHDA in marmosets on the ID/ED test described above could not have been produced by serotonin depletion, as the indoleamine was completely protected by appropriate pharmacological pre-treatment. This is important, as the selective prefrontal depletion of 5-HT by intracerebral infusion of 5,7 dihydroxytryptamine does not affect ED shifting but does severely impair reversal learning,61 a form of cognitive flexibility dependent on the orbitofrontal cortex in monkeys,50 rats,62 and humans.63–64 Moreover, there is evidence in humans that transient depletion of central 5-HT produces similarly selective impairments in reversal learning rather than ID or ED shifting.65–66 What is the significance of these effects on reversal learning, in theoretical as well as clinical terms? It is certainly of interest that prefrontal 5-HT and catecholamine depletion have completely contrasting effects, possibly due to their differential effects on the (dorso-)lateral PFC and OFC. Perhaps this reflects a hierarchical mode of organization, with the more basic stimulus–reward learning processes dependent on the OFC, possibly consonant with its connectivity with the limbic system and consequent involvement in emotional processing and the "higher-order" shifting of attention from one entire dimension or category of responding (e.g., color) to another (e.g., shape). The differential involvement of prefrontal 5-HT in reversal learning and the catecholamines in attentional set shifting may represent the relatively more recent evolutionary development of the dorsolateral prefrontal and the catecholaminergic (especially noradrenergic) systems. In clinical terms, it may be that the effects of 5-HT loss in impairing reversal learning are most relevant to obsessive-compulsive disorder, especially as (i) this disorder has been linked with abnormalities of orbitofrontal processing, (ii) the most common mode of pharmaceutical treatment is with selective serotonin reuptake inhibitors, and (iii) the behavioral deficit found on reversal learning is perseverative in nature, with marmosets with serotonin depletion continuing to respond to the formerly reinforced stimulus (rather than, for example, having difficulty learning the new stimulus–reward association). However, we have also shown that schizophrenic patients may have difficulties with reversal,67 and it may provide good measures for possible effects of neuroleptic medication affecting 5-HT transmission. Reversal learning is also a basic "building block" of more complex forms of cognition, including, for example, decision making in the Iowa gambling task of Bechara et al.,68 the performance of which is drastically impaired following lesions that include the OFC in humans. Performance is also deficient on analogous tasks such as the Cambridge Gamble task in patients with such disorders as mania and schizophrenia.69–71

CANTAB Tests of Visual Learning and Memory
In both structural and functional terms, schizophrenia is associated with medial temporal lobe impairment, particularly the hippocampus. Thus, it is perhaps unsurprising that schizophrenic patients exhibit marked impairments in memory functioning associated with the hippocampus and its interactions with other structures including the prefrontal cortex. Although verbal memory deficits are evident, there are also impairments in visual recognition memory and in visuospatial paired associates learning (PAL) that can be as profound as those in early Alzheimer's disease.46 The PAL test has recently been found to be sensitive in detecting early Alzheimer's disease from a memory clinic sample72 and is known to be sensitive to neurosurgical lesions of either the frontal or temporal lobes.73 Consequently, it is of considerable interest that a recent neuropsychological study of first-episode schizophrenia has shown that the PAL test successfully differentiates different subgroups of patients.74

The neuropsychological precursors of the PAL test derive from a test of object-location memory ("toys on the tray") employed by Smith and Milner to demonstrate spatial memory problems in patients with right hippocampal lesions.75 It was also, however, associated with a test of object-location memory employed by Parkinson et al. to show impairments following large hippocampal lesions in monkeys.76 The main difference is that the latter was a form of matching-to-spatial position task. In comparison, PAL requires the learning of a list of such object-location associations. This feature is implemented in a version of the PAL test that has been used extensively by Taffe, Weed, and colleagues in a number of psychopharmacological studies, including the effects of ketamine.77

The CANTAB tests of visual recognition memory, including a delayed matching-to-sample test, are clearly inspired by the tests employed originally by Delacour and Mishkin to map the neural substrates of recognition memory.78 More recently, the role of the hippocampus in recognition memory has become much more controversial, and the perirhinal cortex has been shown to play a more direct role.79 Understanding the contributions of these different components of the temporal lobe in both animals and humans may well prove significant in the further analysis of cognitive impairments involving memory in schizophrenia, especially in terms of their interactions with other areas such as the prefrontal cortex.


   Toward a MATRICS Preclinical Battery
Top
 Abstract
 Introduction
 The MATRICS Neuropsychological...
 Working Memory Deficits in...
 Attentional Deficits in...
 CANTAB: Its Utility for...
 Toward a MATRICS Preclinical...
References
 
The cognitive impairments in schizophrenia surveyed above can clearly be modeled by analogous, sometimes near-identical tests in animals that require similar neural substrates. The obvious presumption is that successful performance on these tests also requires similar cognitive processes, although probably at a much more primitive level than in human subjects. Nevertheless, the possibility that one is tapping into the building blocks of cognitive function makes it plausible to employ these tests to assess new drugs that may be useful in the treatment of cognitive deficits in schizophrenia. Many of the CANTAB tests were based on those already used for testing nonhuman primates: some of them (e.g., ID/ED and PAL tests)77, 80 have been devised for the testing of nonhuman primates, such as marmosets or rhesus monkeys. Furthermore, some have rodent analogues, for example, not only the 5CSRTT but also the ID/ED test paradigm.81 Rodent tests of working memory based on delayed alternation, or the combined attention and memory test,56 are related to the CANTAB self-ordered spatial working memory test. Recognition memory tests are being widely employed in rodents for assessing drug effects and defining the neural substrates of memory. In terms of tests of hippocampal memory, there are of course established paradigms available in the form of the Morris water maze for assessing both long-term spatial "reference" memory and working as well as contextual fear memory. However, it may prove to be more difficult to employ these for translational purposes because of the obvious difficulties in extrapolating results to human subjects. Nevertheless, it is clear that there are many convenient points of contact between animal and human tests of cognition that will allow such extrapolation. It should also not be overlooked that many useful measures can derive from parallel studies of animal behavior. One well-known and successful example of unconditioned behavior that has been studied in animals and humans is pre-pulse inhibition.23 Other useful comparators may derive from applying animal associative learning theory to humans.82 A future target should include the development of indexes of social cognition, although there is much to do in firmly establishing such tests reliably for humans. One obvious area for possible exploitation is that of emotional facial expression; others may depend on subtle measures of social interaction. Overall, it is clear that there already exists a battery of tests that could be employed in both monkeys and rats to assess the possible cognition-enhancing effects of new compounds and the validity of future etiological models of schizophrenia. In general, however, it is argued that despite the availability of the MATRICS battery, it will continue to be productive to analyze the nature of the cognitive impairments in schizophrenia while taking into account contemporary advances in animal behavioral neuroscience.


  Footnotes
 
To whom correspondence should be addressed; tel: 44-1223-333551, fax: 44-1223-333564, e-mail: twr2{at}cam.ac.uk.


   Acknowledgments
 
This research was supported by the Wellcome Trust and completed within the Medical Research Council Behavioural and Clinical Neuroscience Centre. N. Allanson is thanked for manuscript preparation.


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 The MATRICS Neuropsychological...
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