Showing papers by "Trevor W. Robbins published in 2003"

Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans.

Abstract: The precise localization of executive functions such as response inhibition within the prefrontal cortex (PFC), although theoretically crucial, has proven to be controversial and difficult1. Functional neuroimaging has contributed importantly to this debate1,2,3,4,5,6,7, but as human cortical lesions are seldom discrete, the literature still lacks definitive neuropsychological evidence that a specific region is necessary for task performance. We overcame this limitation by using a new observer-independent method to relate the degree of damage within a specific prefrontal region to performance on a stop-signal task that is sensitive to the neurodevelopmental aspects of stopping behavior2 and to attention-deficit/hyperactivity disorder (ADHD) as well as its amelioration by methylphenidate5,8.

Dissociable contributions of the orbitofrontal and infralimbic cortex to pavlovian autoshaping and discrimination reversal learning: further evidence for the functional heterogeneity of the rodent frontal cortex.

Abstract: To examine possible heterogeneity of function within the ventral regions of the rodent frontal cortex, the present study compared the effects of excitotoxic lesions of the orbitofrontal cortex (OFC) and the infralimbic cortex (ILC) on pavlovian autoshaping and discrimination reversal learning. During the pavlovian autoshaping task, in which rats learn to approach a stimulus predictive of reward [conditional stimulus (CS+)], only the OFC group failed to acquire discriminated approach but was unimpaired when preoperatively trained. In the visual discrimination learning and reversal task, rats were initially required to discriminate a stimulus positively associated with reward. There was no effect of either OFC or ILC lesions on discrimination learning. When the stimulus-reward contingencies were reversed, both groups of animals committed more errors, but only the OFC-lesioned animals were unable to suppress the previously rewarded stimulus-reward association, committing more "stimulus perseverative" errors. In contrast, the ILC group showed a pattern of errors that was more attributable to "learning" than perseveration. These findings suggest two types of dissociation between the effects of OFC and ILC lesions: (1) OFC lesions impaired the learning processes implicated in pavlovian autoshaping but not instrumental simultaneous discrimination learning, whereas ILC lesions were unimpaired at autoshaping and their reversal learning deficit did not reflect perseveration, and (2) OFC lesions induced perseverative responding in reversal learning but did not disinhibit responses to pavlovian CS-. In contrast, the ILC lesion had no effect on response inhibitory control in either of these settings. The findings are discussed in the context of dissociable executive functions in ventral sectors of the rat prefrontal cortex.

Cognitive impairments in early Parkinson's disease are accompanied by reductions in activity in frontostriatal neural circuitry.

Abstract: Studies in patients with Parkinson's disease (PD) suggest that the characteristic motor symptoms of the disorder are frequently accompanied by impairments in cognition that are most profound in tasks of executive function. Neuropsychological deficits are not an inevitable consequence of the disease, yet the reasons underlying cognitive heterogeneity in PD are not well understood. To determine the underlying neural correlate of these cognitive deficits, we used event-related functional magnetic resonance imaging (fMRI) to compare groups of cognitively impaired and unimpaired patients, matched on all other clinical measures. fMRI revealed significant signal intensity reductions during a working-memory paradigm in specific striatal and frontal lobe sites in patients with cognitive impairment compared with those patients who were not cognitively unimpaired. These results demonstrate that cognitive deficits in PD are accompanied by neural changes that are related to, but distinct from, those changes that underlie motoric deficits in these patients. Furthermore, they suggest that fMRI may provide a valuable tool for identifying patients who may benefit from targeted therapeutic strategies.

Cognitive enhancing effects of modafinil in healthy volunteers.

Abstract: Rationale. Modafinil, a novel wake-promoting agent, has been shown to have a similar clinical profile to that of conventional stimulants such as methylphenidate. We were therefore interested in assessing whether modafinil, with its unique pharmacological mode of action, might offer similar potential as a cognitive enhancer, without the side effects commonly experienced with amphetamine-like drugs. Objectives. The main aim of this study was to evaluate the cognitive enhancing potential of this novel agent using a comprehensive battery of neuropsychological tests. Methods. Sixty healthy young adult male volunteers received either a single oral dose of placebo, or 100 mg or 200 mg modafinil prior to performing a variety of tasks designed to test memory and attention. A randomised double-blind, between-subjects design was used. Results. Modafinil significantly enhanced performance on tests of digit span, visual pattern recognition memory, spatial planning and stop-signal reaction time. These performance improvements were complemented by a slowing in latency on three tests: delayed matching to sample, a decision-making task and the spatial planning task. Subjects reported feeling more alert, attentive and energetic on drug. The effects were not clearly dose dependent, except for those seen with the stop-signal paradigm. In contrast to previous findings with methylphenidate, there were no significant effects of drug on spatial memory span, spatial working memory, rapid visual information processing or attentional set-shifting. Additionally, no effects on paired associates learning were identified. Conclusions. These data indicate that modafinil selectively improves neuropsychological task performance. This improvement may be attributable to an enhanced ability to inhibit pre-potent responses. This effect appears to reduce impulsive responding, suggesting that modafinil may be of benefit in the treatment of attention deficit hyperactivity disorder.

Neuropsychological impairment in patients with major depressive disorder: the effects of feedback on task performance.

Abstract: Background Recent evidence suggests that an abnormal response to performance feedback may contribute to the wide-ranging neuropsychological deficits typically associated with depressive illness. The present research sought to determine whether the inability of depressed patients to utilize performance feedback advantageously is equally true for accurate and misleading feedback. Method Patients with major depression and matched controls completed: (1) a visual discrimination and reversal task that featured intermittent and misleading negative feedback; and (2) feedback and no-feedback versions of a computerised test of spatial working memory. In the feedback version, negative feedback was accurate, highly informative, and could be used as a mnemonic aid. Results On the Probability Reversal task, depressed patients were impaired in their ability to maintain response set in the face of misleading negative feedback as shown by their increased tendency to switch responding to the 'incorrect' stimulus following negative reinforcement, relative to that of controls. Patients' ability to acquire and reverse the necessary visual discrimination was unimpaired. On the Spatial Working Memory task, depressed patients made significantly more between-search errors than controls on the most difficult trials, but their ability to use negative feedback to facilitate performance remained intact. Conclusions The present results suggest that feedback can have different effects in different contexts. Misleading, negative feedback appears to disrupt the performance of depressed patients, whereas negative but accurate feedback does not. These findings are considered in the context of recent studies on reinforcement systems and their associated neurobiological substrates.

Global 5-HT depletion attenuates the ability of amphetamine to decrease impulsive choice on a delay-discounting task in rats

Abstract: Rationale Psychomotor stimulant drugs such as methylphenidate and amphetamine decrease impulsive behaviour in attention deficit hyperactivity disorder patients by unknown mechanisms. Although most behavioural effects of amphetamine are attributed to the dopaminergic system, some recent evidence suggests a role for serotonin in this paradoxical "calming" effect.

Inhibitory control in rats performing a stop-signal reaction-time task: effects of lesions of the medial striatum and d-amphetamine.

Abstract: The stop-signal task measures the ability to inhibit a response that has already been initiated, that is, the ability to stop. Imaging studies have implicated frontostriatal circuitry in the mediation of this form of response control. The authors report inhibition functions of normal rats and those with medial striatal damage performing the stop-signal task. Excitotoxic lesions of the medial striatum produced significant deficits on task performance, including increased omissions on the go task and flattened inhibition function, possibly as a result of increased reaction-time mean and variability. Medial striatal lesions also significantly slowed stop-signal reaction time. Subsequent treatment with d-amphetamine removed (0.3 mg/kg) or exacerbated (1.0 mg/kg) this deficit.

Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats.

Abstract: The central serotonergic systems are a major target for drugs used to treat neuropsychiatric disorders such as depression and schizophrenia in which disruption of frontal cortex function has been implicated. However, it is not known precisely how serotonin (5-HT) modulates the medial prefrontal cortex (mPFC) to affect cognitive function and behaviour. To investigate the roles of 5-HT1A and 5-HT2A receptors in mPFC on performance of the five-choice serial reaction time task (5CSRT), which assesses visuospatial attention, impulsivity and motivational processes. Following training on the 5CSRT, rats were implanted with bilateral guide cannulae aimed at the mPFC. Rats received intra-mPFC infusions of either 8-OH-DPAT (10, 30 and 100 ng) or M100907 (30, 100 and 300 ng) according to a Latin square design. Both 8-OH-DPAT and M100907 selectively enhanced accuracy of target detection. When the stimulus duration was shortened, infusions of 8-OH-DPAT continued to improve accuracy, whereas M100907 decreased premature responding and omissions, thus partly dissociating the effects of these two compounds. Similar effects were obtained following systemic administration of M100907 and 8-OH-DPAT. The effects of 8-OH-DPAT were blocked by the 5-HT1A antagonist WAY 100635, at a dose that itself had no significant effects on behaviour. These results indicate that modulation of 5-HT function within the mPFC via distinct receptors can enhance performance on the 5CSRT. These findings suggest a mechanism by which serotonergic agents improve cognitive function, which may be relevant to their therapeutic benefit in the treatment of neuropsychiatric disorders.

Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET study

Abstract: We have studied the progression of striatal and extrastriatal post-synaptic dopaminergic changes in a group of 12 patients with Huntington's disease using serial (11)C-raclopride PET, a specific marker of D2 dopamine receptor binding. All patients had two (11)C-raclopride PET scans 29.2 +/- 12.8 months apart, and six of them had a third scan 13.2 +/- 3.9 months later. We found a mean annual 4.8% loss of striatal (11)C-raclopride binding potential (BP) between the first and second scans, and a 5.2% loss between the second and third scans. Statistical Parametric Mapping (SPM) localized significant baseline reductions in (11)C-raclopride BP in both striatal and extrastriatal areas, including amygdala, temporal and frontal cortex in Huntington's disease compared with normal subjects matched for age and sex. When the (11)C-raclopride scans performed 29 months after the baseline scans were considered, SPM revealed further significant striatal, frontal and temporal reductions in (11)C-raclopride BP in Huntington's disease. Cross-sectional Unified Huntington's Disease Rating Scale (UHDRS) scores correlated with (11)C-raclopride binding, but there was no correlation between individual changes in UHDRS motor scores and changes in striatal binding. Performance on all neuropsychological measures deteriorated with time but only the accuracy score of the one-touch Tower of London test correlated significantly with striatal and putamen D2 binding. In summary, serial (11)C-raclopride PET demonstrates a linear progression of striatal loss of D2 receptors in early clinically affected Huntington's disease patients over 3 years. SPM also revealed a progressive loss of temporal and frontal D2 binding. Changes over time in clinical scores and in neuropsychological assessments, except for measures of planning, did not correlate with striatal D2 binding. This probably reflects both contributions from other affected brain structures and high variance in these measures.

Inhibition of subliminally primed responses is mediated by the caudate and thalamus : evidence from functional MRI and Huntington's disease

Abstract: Masked prime tasks have shown that sensory information that has not been consciously perceived can nevertheless trigger the preactivation of a motor response. Automatic inhibitory control processes prevent such response tendencies from interfering with behaviour. The present study investigated the possibility that these inhibitory control processes are mediated by a cortico-striatal-pallidal-thalamic pathway by using a masked prime task with Huntington's disease patients (Experiment 1) and with healthy volunteers in a functional MRI (fMRI) study (Experiment 2). In the masked prime task, clearly visible left- or right-pointing target arrows are preceded by briefly presented and subsequently masked prime arrows. Participants respond quickly with a left or right key-press to each target. Trials are either compatible (prime and target pointing in the same direction) or incompatible (prime and target pointing in different directions). Prior behavioural and electrophysiological results show that automatic inhibition of the initially primed response tendency is reflected in a 'negative compatibility effect' (faster reaction times for incompatible trials than for compatible trials), and is shown to consist of three distinct processes (prime activation, response inhibition and response conflict) occurring within 300 ms. Experiment 1 tested the hypothesis that lesions of the striatum would interrupt automatic inhibitory control by studying early-stage Huntington's disease patients. Findings supported the hypothesis: there was a bimodal distribution for patients, with one-third (choreic) showing disinhibition, manifested as an absent negative compatibility effect, and two-thirds (non-choreic) showing excessive inhibition, manifested as a significantly greater negative compatibility effect than that in controls. Experiment 2 used fMRI and a region of interest (ROI) template-based method to further test the hypothesis that structures of the striatal-pallidal-thalamic pathway mediate one or more of the processes of automatic inhibitory control. Neither prime activation nor response conflict significantly engaged any ROIs, but the response inhibition process led to significant modulation of both the caudate and thalamus. Taken together, these experiments indicate a causal role for the caudate nucleus and thalamus in automatic inhibitory motor control, and the results are consistent with performance of the task requiring both direct and indirect striatal-pallidal-thalamic pathways. The finding that Huntington's disease patients with greater chorea were disinhibited is consistent with the theory that chorea arises from selective degeneration of striatal projections to the lateral globus pallidus, while the exaggerated inhibitory effect for patients with little or no chorea may be due to additional degeneration of projections to the medial globus pallidus.

Functional disconnection of the medial prefrontal cortex and subthalamic nucleus in attentional performance: evidence for corticosubthalamic interaction.

Abstract: The present study used a disconnection procedure to test whether the medial prefrontal cortex (mPFC) and the subthalamic nucleus (STN) were functional components in a common neural system that controlled continuous performance in a test of sustained and divided visual attention. Animals with disconnected lesions of the mPFC and STN in contralateral hemispheres were severely impaired in several aspects of performance, including discriminative accuracy, increased perseveration, and slowed response latencies during postoperative testing. These deficits persisted throughout the entire experimental test period. Increasing the stimulus duration alleviated the accuracy deficit but failed to improve speed of responding or reduce perseverative responses. These deficits were in marked contrast to animals with combined mPFC and STN lesions made on the ipsilateral side, which produced behavior not different from that of sham controls. Rats with unilateral lesions of either structure alone were also impaired in terms of accuracy and perseveration. These data suggest that some of the deficits observed after bilateral STN lesions (attention and perseveration) may be attributable to a disrupted corticosubthalamic projection. This study provides direct evidence that performance in tasks that require optimal attentional and executive control relies on a corticosubthalamic interaction within the neural circuitry of the basal ganglia.

Double dissociation of serotonergic and dopaminergic mechanisms on attentional performance using a rodent five-choice reaction time task

Abstract: Rationale. Converging evidence suggests that dopaminergic and serotonergic mechanisms affect distinct aspects of cognitive performance. Experiments using the rodent five-choice reaction time task have established a critical role for dopaminergic mechanisms in the rat medial prefrontal cortex (mPFC), but have yielded only incomplete evidence regarding the specific functions of serotonin receptors. Objectives. To contrast the effects of systemic or intra-mPFC administration of dopamine or serotonin agents on performance of the five-choice reaction time task. Methods. Two groups of rats trained on the five-choice reaction time task received systemic administration of either the dopamine D1 receptor partial agonist SKF 38393 (0, 1, 3 or 10 mg/kg IP) or the serotonin 5-HT2A/C receptor antagonist ketanserin (0, 0.3, 0.6 or 1 mg/kg SC) prior to testing; a further group was implanted with chronic guide cannulae and received ketanserin (0, 0.025, 0.1 or 0.4 µg/side) infused into the mPFC prior to testing. Results. SKF 38393 affected aspects of accuracy and vigour of responding, while regardless of the route of administration ketanserin reduced premature responding without any effect on choice accuracy. Conclusions. Together with our previous findings of increased choice accuracy following intra-mPFC SKF 38393 (Granon et al. 2000), the present results support the notion that the functions of dopamine and serotonin receptors in the mPFC relate to two distinct domains of executive control. Dopamine D1 receptors are critical to optimise response selection in skilled non-automatic tasks, while serotonin 5-HT2A receptors regulate the execution of primed responses.

Role of the anterior cingulate cortex in the control over behavior by Pavlovian conditioned stimuli in rats.

Abstract: To investigate the contribution of the anterior cingulate cortex (ACC) to stimulus-reward learning, rats with lesions of peri- and postgenual ACC were tested on a variety of Pavlovian conditioning tasks. Lesioned rats learned to approach a food alcove during a stimulus predicting food, and responded normally for conditioned reinforcement. They also exhibited normal conditioned freezing and Pavlovian-instrumental transfer, yet were impaired at autoshaping. To resolve this apparent discrepancy, a further task was developed in which approach to the food alcove was under the control of 2 stimuli, only 1 of which was followed by reward. Lesioned rats were impaired, approaching during both stimuli. It is suggested that the ACC is not critical for stimulus-reward learning per se, but is required to discriminate multiple stimuli on the basis of their association with reward.

Task-Set Switching Deficits in Early-Stage Huntington's Disease: Implications for Basal Ganglia Function

Abstract: Executive functions are likely mediated by interconnected circuits including frontal lobe and basal ganglia structures. We assessed the executive function of task switching in patients with early-stage Huntington's disease (HD), a neurodegenerative disease affecting the basal ganglia. In two experiments, the HD patients had greater difficulty when switching than when repeating a task than matched controls, and this was true even when scaling for the overall slowing of the patients. In the first experiment, HD patients had a switching deficit even in a "pure" condition where they had to switch, predictably, and with substantial preparation time, between stimuli having only one possible response, indicating a switching deficit different from that for patients with Parkinson's disease or frontal lobe trauma, and possibly relating to inadequate activation of stimulus-response links or "response set." In the more elaborate second experiment, we could not account for the switching deficit of the patients in terms of inadequate preparation in advance of a switch, deficient suppression of task-set processing from the preswitch trial, or impaired suppression of interference due to the presence of a competing task set. Instead, we found that part of the switching deficit was due to elevated reaction time and errors on switch trials for a repeated response (same button press as on preswitch trial) relative to an alternated response (different button press from preswitch trial). We argue that this elevated "repetition effect" for the HD patients is due to excessive inhibition of the just-performed response in advance of a switch. Alterations in the "response-setting" process alone (Experiment 1) and both the response-setting and "response inhibition" process (Experiment 2) probably arise from striatal pathology in HD, thus accounting for the task-switching deficits and showing how basal ganglia implemented response processes may underpin executive function.

Individual differences in prefrontal cortical activation on the Tower of London planning task: implication for effortful processing.

Abstract: Solving challenginxg ('effortful') problems is known to involve the dorsal and dorsolateral prefrontal cortex in normal volunteers, although there is considerable individual variation. In this functional magnetic resonance imaging study, we show that healthy subjects with different levels of performance in the Tower of London planning task exhibit different patterns of brain activation. All subjects exhibited significant bilateral activation in the dorsolateral prefrontal cortex, the anterior and posterior cingulate areas and the parietal cortex. However, 'standard performers' (performance 70% correct) differed in the patterns of activation exhibited. Superior performers showed a significantly more spatially extended activation in the left dorsolateral prefrontal cortex than did standard performers, whereas the latter group tended to show increased activation of the anterior cingulate region.

Relative lack of cognitive effects of methylphenidate in elderly male volunteers

Abstract: Rationale Methylphenidate, a dopaminergic and noradrenergic reuptake inhibitor, has been shown in young, healthy adult volunteers to produce pronounced effects on working memory and sustained attention. We were interested in assessing whether similar improvements could be conferred upon elderly volunteers in order to gain a more complete understanding of the effects of age on monoaminergic manipulations of working memory and attention, as well as to explore the potential for pharmacological intervention in attention and executive dysfunction disorders in this age group.

Dopamine and cognition.

Abstract: © 2003 Lippincott Williams & Wilkins 1350-7540 Editorial review The mapping of the central dopamine pathways into mesostriatal, mesolimbic and mesocortical systems, the cloning of the main dopamine receptors and the identification and characterization of their cell signalling pathways, have all raised important questions about the functions of this important neuromodulatory neurotransmitter [1]. The involvement of dopamine in Parkinson’s disease has focused attention on the apparent motor functions of this neurotransmitter in regulating the output of the striatum, but discoveries that fluctuations in mesolimbic dopamine subserve the reinforcing effects of many drugs of abuse, especially the psychomotor stimulants amphetamine and cocaine, also indicate parallel roles for dopamine in motivational as well as motor, functions. More recently, electrophysiological studies of single units in monkeys exhibiting burst firing patterns in certain conditioning contexts [2] have implicated these same dopamine neurons in error prediction for reinforcement learning. However, burgeoning evidence of a role for dopamine in aspects of frontal lobe function, such as working memory, suggests an even closer and more direct relationship to cognition. A now classic study by the late Patricia Goldman-Rakic and colleagues [3] indicated that dopamine depletion from the sulcus principalis of the monkey prefrontal cortex specifically impaired spatial working memory, as measured in the delayed response task. Moreover, these deficits were remediated by drugs such as L-dopa and apomorphine, thus opening up a new era of potential therapeutic approaches in treating the cognitive deficits in such neurological and neuropsychiatric disorders as Parkinson’s disease, attention deficit hyperactivity disorder, schizophrenia and phenylketonuria.

Disorders of brain and mind

Abstract: Introduction D. F. Benson Part I. Basal Ganglia and Neuropsychiatry: 1. The neuropsychology of basal ganglia disorders: an integrative cognitive and comparative approach T. W. Robbins, A. M. Owen and B. J. Sahakian 2. The behavioural pharmacology of brain dopamine systems: implications for the cognitive pharmacotherapy of schizophrenia E. Joyce and S. Hutton Part II. Frontal Lobes and Neuropsychiatry: 3. The neuropsychology of the frontal lobes S. E. McPherson and J. L. Cummings 4. Frontal lobe structural abnormalities in schizophrenia: evidence from neuroimaging B. Toone Part III. Memory and its Disorders: 5. Neuropsychology of memory and amnesia A. R. Mayes 6. Clinical and neuropsychological studies of patients with amnesic disorders M. D. Kopelman Part IV. Brain Disease and Mental Illness: 7. Psychiatric manifestations of demonstrable brain disease M. A. Ron 8. Structural brain imaging in the psychoses S. Lewis Part V. Epilepsy: Biology and Behaviour: 9. Behaviour in chronic experimental epilepsies J. G. R. Jefferys and J. Mellanby 10. A neurobiological perspective of the behaviour disorders of epilepsy M. R. Trimble Part VI. Perspectives on Neurodevelopment: The Case of Schizophrenia: 11. Early disorders and later schizophrenia: a developmental neuropsychiatric perspective E. Taylor 12. Neurodevelopmental disturbances in the aetiology of schizophrenia J. M. Hollister and T. D. Cannon Part VII. Imaging Brain and Mind: 13. Magnetic resonance spectroscopy in neuropsychiatry M. Maier 14. The hallucination: a disorder of brain and mind A. S. David and G. Busatto.

Cognition in schizophrenia: from basic science to clinical treatment.

Abstract: Interest in cognition in schizophrenia has skyrocketed in the past decade, as evidenced by this special issue. This issue is partially based on presentations made at the 5th Biennial Mount Sinai Conference on Cognition in Schizophrenia, in April 2001 in Whistler, B.C., Canada. The first Mount Sinai Meeting in 1993 had 27 attendees and the one in Whistler (from which this issue originated) had 298. The latest meeting, in Colorado Springs in 2003, had 315 attendees. The number of publications on the topic has increased as well, with some journal editors noting that the majority of papers on schizophrenia submitted to their journals are focused on cognitive functioning. The number of papers on cognition in schizophrenia published and presented at major meetings has increased as much as 5-fold in the past 15 years. Further, the NIH has recently acknowledged (Hyman and Fenton 2003) that treatment of cognitive impairment with pharmacological means is an important intervention target, as evidenced by several recent initiatives that are aimed at the treatment of cognitive impairment in schizophrenia through various means. This increase in interest can be traced to two emerging trends. The first is the increased understanding of the functional importance of cognitive impairments in schizophrenia, where it is now widely accepted, in the scientific if not the clinical community, that cognitive impairments are the primary determinant of functional deficits in schizophrenia (e.g. Green 1996; Harvey et al. 1998; Green et al. 2000). Since functional limitations in the illness are responsible for much of the disability that occurs, this is an important revelation and one that has moved the study of cognition in schizophrenia outside the realm of an academic exercise. The second important trend in the field is the increased interest in the neurobiology and treatment of cognitive impairment in schizophrenia. If cognitive deficits are the determinants of functional limitations, it seems logical that treatment of cognitive deficits would lead, all other things equal, to functional improvements. Treatments can be either behavioral in nature or pharmacologically based. Rational pharmacology will progress the most rapidly with the understanding of biological substrates of cognitive impairments. This Special Issue is multifaceted in its topics. They arise from three different sources, including presentations made at the Mount Sinai conference in 2001, articles spontaneously submitted to the journal that addressed the neural bases of cognitive impairments in schizophrenia, and articles that address basic science topics that are relevant to cognitive impairments similar to those seen in schizophrenia. There are three different sections in this issue. The sections include studies of NMDA receptor manipulations, pharmacological manipulation of prepulse inhibition and latent inhibition, and treatment of cognitive impairments in schizophrenia, with a final article describing the US National Institute of Health’s large-scale project on Measurement and Treatment Research Involving Cognition in Schizophrenia (MATRICS). This project itself arises from the increased recognition of the fact that treating cognition in schizophrenia may be the path to improvement in functional outcome in the illness. While mice are not men and a widely useful animal model of schizophrenia in general has proven difficult to develop, we believe that the usefulness of animal models P. D. Harvey ()) Department of Psychiatry, Mt. Sinai School of Medicine, Box 1229, New York, NY 10029, USA e-mail: pdharvey@compuserve.com