Cognitive Deficits In Schizophrenic Patients Research Articles

Evaluation of cognitive deficits in schizophrenia using event-related potentials and rehabilitation influences using EEG Biofeedback in patients diagnosed with schizophrenia.

Cognitive deficits in schizophrenic patients have a chronic and negative effect on patients' social functioning. Antipsychotic drugs do not sufficiently improve cognitive functions. In this study, an analysis of previous studies on cognitive functions using event-related potentials in schizophrenia patients was conducted on the basis of available publications (Pubmed, Scopus). The studies indicate numerous deviations at various stages of information processing in patients diagnosed with schizophrenia when compared to healthy subjects, and this justifies the need for the development of new methods influencing the bioelectric brain activity in cognitive rehabilitation of these patients. EEG Biofeedback is a method which could be used for rehabilitation of cognitive functions in schizophrenia patients. Despite it being used in practice, the importance of EEG Biofeedback as a rehabilitation influence on cognitive functions in schizophrenia has not been fully ascertained. This paper analyses the results of previous studies on the effect of EEG Biofeedback therapy on cognitive functions as a possible method to be used in the rehabilitation of schizophrenia patients. Currently, the body of research that may prove the value of this method in the rehabilitation of patients with schizophrenia appears to be insufficient, and there is no scientific evidence from randomized studies for the usefulness of EEG Biofeedback in schizophrenia treatment. At the moment, the recommendation of this method in the cognitive rehabilitation of patients is a therapeutic experiment. The researchers, on the basis of an analysis of clinical cases, currently propose that EEG Biofeedback is conducted in patients diagnosed with schizophrenia by experienced practitioners, paying particular attention to strengthening alpha in the right parietal region.

Analysis of the influencing factors for the cognitive deficits in schizophrenic patients with diabetes

Objective To investigate the influencing factors of the cognitive deficits in schizophrenic patients with diabetes. Methods 578 inpatients with schizophrenia and 400 healthy adults were collected.578 schizophrenic patients were divided into schizophrenia group with type 2 diabetes (combined group, n=277) and schizophrenia without type 2 diabetes (single disease group, n=301). The cognitive function of all subjects were examined by the Repeatable Battery for the Assessment of Neuropsychological Status(RBANS). The clinical symptoms of patients with schizophrenia were measured with the Positive and Negative Syndrome Scale(PANSS). Fasting glucose, lipids, hemoglobin A1c (HbA1c) and insulin levels were measured. Results The total score and factor scores of RBANS in the combined group were lower than those in the healthy control group (total score(70.51±14.43) vs (80.04±15.14), immediate memory(62.65±16.81) vs (75.66±17.33), visual span(83.60±20.81) vs (87.61±15.61), verbal function(85.58±14.64) vs (93.88±13.10), attention function(73.66±17.52) vs (87.42±20.37), delayed memory(75.27±17.80) vs (86.27±15.27), all P<0.05). The total score of RBANS, immediate memory and attention function factor were lower in the combined group than that in the single disease group ((70.51±14.43) vs (75.02±15.25), (62.65±16.81) vs (67.37±19.12), (73.66±17.52) vs (84.17±15.22), all P<0.05). Multiple linear stepwise regression analysis showed that education, negative symptoms, positive symptoms, BMI, HbAc1, course of disease and antipsychotic type were the influencing factors of cognitive impairment in schizophrenic patients with diabetes. Conclusion The cognitive impairment of schizophrenic patients with diabetes is more serious and affected by many factors.Targeted early intervention can help reduce cognitive impairment. Key words: Diabetes; Schizophrenia; Cognitive deficits; Influential factors

Are deficits in social cognition differentiating between schizophrenia and affective disorders

Over the last decades, in matters of the assessment of psychopathology and its clinical consequences, there has been an increased interest in neurocognitive function including non-social and social cognition.Classic psychopathology -as represented e.g. by the standardized AMDP system- focuses on pathognomonic signs for the categorization of syndromes [1] and differentiates between disturbances of perception, concentration, memory retention and long-term memory. A recent short screen for cognitive impairment in psychiatry (SCIP) has addressed five domains of cognitive function: verbal learning–immediate, working memory, verbal fluency, verbal learning–delayed and processing speed [2].Using the SCIP in admissions from a defined catchment area in the southwest of Vienna we confirm the presence of cognitive deficits in schizophrenic patients and to a lesser degree in bipolar patients. The deficits were present in all five domains and no discriminatory pathognomonic signs could be found between schizophrenia and bipolar disorder.Recently, possibly selective deficits in social cognition have been described in schizophrenic patients [3]. We review the evidence on the specificity of social impairment to schizophrenia.Disclosure of interestThe authors declare that they have no competing interest.

Effects of genetic variations in NRG1 on cognitive domains in patients with schizophrenia and healthy individuals.

The neuregulin 1 (NRG1) gene has been investigated as a candidate susceptibility gene for schizophrenia. A number of studies have also explored the genetic effect of NRG1 on cognitive deficits related to schizophrenia, and thus far generated inconsistent results. The current study aimed to determine whether genetic variations in NRG1 are associated with cognitive domains in schizophrenic patients and healthy individuals. Comprehensive neuropsychological tests composed of six cognitive domains were administered to 135 clinically stable patients with schizophrenia and 119 healthy individuals. On the basis of previous reports of positive association, a total of four single nucleotide polymorphisms were analyzed. In testing the genotype effect on cognitive domains, we used repeated-measure analysis for six cognitive domain scores of each individual as repeated measurements. An association of P-value less than 0.05 with at least one cognitive domain in patients and/or healthy individuals was observed for all of the single nucleotide polymorphisms. After applying the correction for multiple testing, the association remained statistically significant between rs6994992 and general cognitive ability (g) in the patient group and between rs2439272 and the 'working memory' domain in the group of healthy participants. This study suggests the involvement of NRG1 in the susceptibility for developing cognitive deficits in schizophrenic patients. For some cognitive domains, its genetic effect was also significant in generating interindividual variability within the normal functional range.

Distinct phenotypes of new transmembrane-domain neuregulin 1 mutant mice and the rescue effects of valproate on the observed schizophrenia-related cognitive deficits.

Accumulating evidence suggests that neuregulin 1 (NRG1) might be involved in the neurodevelopment, neural plasticity, GABAergic neurotransmission, and pathogenesis of schizophrenia. NRG1 is abundantly expressed in the hippocampus, and emerging studies have begun to reveal the link between NRG1 signaling and cognitive deficits in schizophrenic patients. Because the transmembrane domain of NRG1 is vital for both forward and reverse signaling cascades, new Nrg1-deficient mice that carry a truncation of the transmembrane domain of the Nrg1 gene were characterized and used in this study to test a NRG1 loss-of-function hypothesis for schizophrenia. Both male and female Nrg1 heterozygous mutant mice and their wild-type littermates were used in a series of 4 experiments to characterize the impact of Nrg1 on behavioral phenotypes and to determine the importance of Nrg1 in the regulation of hippocampal neuromorphology and local GABAergic interneurons. First, a comprehensive battery of behavioral tasks indicated that male Nrg1-deficient mice exhibited significant impairments in cognitive functions. Second, pharmacological challenges were conducted and revealed that Nrg1 haploinsufficiency altered GABAergic activity in males. Third, although no genotype-specific neuromorphological alterations were found in the hippocampal CA1 pyramidal neurons, significant reductions in the hippocampal expressions of GAD67 and parvalbumin were revealed in the Nrg1-deficient males. Fourth, chronic treatment with valproate rescued the observed behavioral deficits and hippocampal GAD67 reduction in Nrg1-deficient males. Collectively, these results indicate the potential therapeutic effect of valproate and the importance of Nrg1 in the regulation of cognitive functions and hippocampal GABAergic interneurons, especially in males.

Cigarette Smoking and Cognitive Function in Chinese Male Schizophrenia: A Case-Control study

Schizophrenic patients have higher smoking rates than the general population. Studies show that smoking may be a form of self-medication in an attempt to alleviate cognitive deficits in schizophrenic patients of European background. This study examined the relationships between smoking and cognitive deficits in Chinese schizophrenic patients, which have previously received little systemic study. We recruited 580 male chronic patients meeting DSM-IV criteria for schizophrenia and 175 male control subjects who were matched on age and education. The subjects completed a detailed cigarette smoking questionnaire, the Fagerstrom Test for Nicotine Dependence (FTND), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Patients also were rated on the Positive and Negative Symptom Scale (PANSS), the Simpson and Angus Extrapyramidal Symptom Rating Scale (SAES), and the Abnormal Involuntary Movement Scale (AIMS). All five RBANS subscales except for the Visuospatial/Constructional index showed significantly lower cognitive performance for schizophrenics than normal controls. The schizophrenic smokers scored lower than the schizophrenic non-smokers on the RBANS total score and the Visuospatial/Constructional and Immediate Memory indices. Similarly, the control smokers scored lower than the control non-smokers on the RBANS total score and the Immediate Memory index . Also, the schizophrenic smokers consistently performed the poorest on the cognitive domains of the RBANS. Among the schizophrenic patients, smokers displayed significantly fewer negative symptoms than non-smokers. Using multivariate regression analysis the following variables were independently associated with the RBANS total score: years of education, PANSS negative symptom score, age at schizophrenia onset, and number of hospitalizations. Our results show that smoking is associated with significant cognitive impairment in both schizophrenic patients and normal controls, but the smokers with schizophrenia had a reduced level of negative symptoms, suggesting that the benefits of smoking for those with schizophrenia may be limited to certain aspects of a given clinical phenotype.

Effects of Olanzapine and Clozapine on Radial Maze Performance in Naive and MK-801-Treated Mice

Attention, working memory and long-term memory dysfunctions are the most commonly seen cognitive impairments in schizophrenic patients. Conflicting results exist regarding the effects of antipsychotics on cognitive abnormalities. The aim of this study was to investigate the effects of atypical antipsychotic drugs olanzapine (0.4, 0.8 and 1.25 mg/kg, i.p.) and clozapine (0.5 and 1 mg/kg, i.p.) on spatial working memory in naive and MK-801 (0.2 mg/kg, i.p.) treated BALB-c mice in an 8-arm radial arm maze (RAM) task. None of the antipsychotic drugs studied altered number of errors in naive mice, whereas MK-801 significantly increased working memory errors in RAM test. Olanzapine and clozapine potently reversed MK-801 induced increasement of working memory errors. Olanzapine and clozapine prolonged latency of the animals in naive mice. The MK-801-induced enhancement in the speed of mice in performing the RAM task was blocked by olanzapine but not clozapine. Our study shows that atypical antipsychotics olanzapine and clozapine might improve cognitive deficits in schizophrenic patients.

Effects of olanzapine, sertindole and clozapine on learning and memory in the Morris water maze test in naive and MK-801-treated mice

Cognitive dysfunction in schizophrenia is associated with functional disease symptoms. The beneficial effects of second generation antipsychotic drugs on cognitive function in schizophrenic patients are controversial. In this study, we investigated the effects of the second generation antipsychotics olanzapine, sertindole and clozapine on cognitive function in the Morris water maze task in naive or MK-801-treated animals. Male balb-c mice were treated subchronically with olanzapine (1.25, 2.5 and 5mg/kg, i.p.), sertindole (0.63, 1.3, 2.5mg/kg, s.c.) or clozapine (0.5 and 1mg/kg, i.p.), and cognitive deficits were induced by MK-801 (0.2mg/kg, i.p.) administration. Water maze performance was expressed as escape latency to find the hidden platform, the time spent in target quadrant, the mean distance to platform and the swim speed. In naive mice olanzapine impaired water maze performance, whereas sertindole and clozapine had no effect while the MK-801-induced cognitive impairment was reversed by the second generation antipsychotics — olanzapine, sertindole and clozapine at the doses used. These results revealed that while olanzapine had some disturbing effects on cognitive functions in naive animals; olanzapine, sertindole and clozapine might improve cognitive deficits in schizophrenic patients.

Kognitive Leistungen und Adhärenzverhalten bei Patienten mit schizophrenen Psychosen

It is known that many patients with schizophrenia show non-adherence with regard to antipsychotic medication. Furthermore, many studies indicate cognitive deficits in schizophrenic patients. In this review, we compare the results of studies examining the relationship of non-adherence and cognitive performance. Based on a systematic literature review, the impact of cognitive performance on the adherence behaviour of patients with schizophrenia was examined. We found 18 studies analysing the impact of cognitive performance on adherence behaviour. Most studies indicated that patients with stronger cognitive impairments show lower adherence behaviour. Possible causal mechanisms are discussed.

390 – Subjective experience of cognitive deficits in schizophrenic patients treated with antipsychotics: Clinical, neuropsychological and treatment correlates

390 – Subjective experience of cognitive deficits in schizophrenic patients treated with antipsychotics: Clinical, neuropsychological and treatment correlates

Modulating the granularity of category formation by global cortical states

The unsupervised categorization of sensory stimuli is typically attributed to feedforward processing in a hierarchy of cortical areas. This purely sensory-driven view of cortical processing, however, ignores any internal modulation, e.g., by top-down attentional signals or neuromodulator release. To isolate the role of internal signaling on category formation, we consider an unbroken continuum of stimuli without intrinsic category boundaries. We show that a competitive network, shaped by recurrent inhibition and endowed with Hebbian and homeostatic synaptic plasticity, can enforce stimulus categorization. The degree of competition is internally controlled by the neuronal gain and the strength of inhibition. Strong competition leads to the formation of many attracting network states, each being evoked by a distinct subset of stimuli and representing a category. Weak competition allows more neurons to be co-active, resulting in fewer but larger categories. We conclude that the granularity of cortical category formation, i.e., the number and size of emerging categories, is not simply determined by the richness of the stimulus environment, but rather by some global internal signal modulating the network dynamics. The model also explains the salient non-additivity of visual object representation observed in the monkey inferotemporal (IT) cortex. Furthermore, it offers an explanation of a previously observed, demand-dependent modulation of IT activity on a stimulus categorization task and of categorization-related cognitive deficits in schizophrenic patients.

Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antibiotic drug minocycline

Background The N-methyl- d-aspartate (NMDA) receptor antagonist phencyclidine (PCP)-induced cognitive deficits have been used as an animal model for schizophrenia. This study was undertaken to determine whether the antibiotic drug minocycline could improve PCP-induced cognitive deficits in mice. Methods Saline (10 ml/kg/day, s.c., once daily on day 1–5, 8–12) or PCP (10 mg/kg/day, s.c., once daily on day 1–5, 8–12) were administered to mice for 10 days. Subsequently, vehicle (10 ml/kg/day, i.p.) or minocycline (4.0 or 40 mg/kg/day, i.p.) was injected for 14 consecutive days. One day after the final injection, a novel object recognition test was performed. Results PCP-induced cognitive deficits in mice were significantly improved by subsequent subchronic (14 days) administration of minocycline (40 mg/kg), but not minocycline (4.0 mg/kg). Conclusions This study suggests that minocycline could be a potential therapeutic drug for cognitive deficits in schizophrenic patients.

Phencyclidine-Induced Cognitive Deficits in Mice Are Improved by Subsequent Subchronic Administration of the Novel Selective α7 Nicotinic Receptor Agonist SSR180711

Accumulating evidence suggests that alpha7 nicotinic receptor (alpha7 nAChR) agonists could be potential therapeutic drugs for cognitive deficits in schizophrenia. The present study was undertaken to examine the effects of the novel selective alpha7 nAChR agonist SSR180711 on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Saline or PCP (10 mg/kg/day for 10 days) was administered to mice. Subsequently, vehicle, SSR180711 (.3 or 3.0 mg/kg/day), SSR180711 (3.0 mg/kg/day) + the selective alpha7 nAChR antagonist methyllycaconitine (MLA; 3.0 mg/kg/day), or MLA (3.0 mg/kg/day) was administered IP for 2 consecutive weeks. Twenty-four hours after the final administration, a novel object recognition test was performed. The PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of SSR180711 (3.0 mg/kg). The effects of SSR180711 (3.0 mg/kg) were significantly antagonized by co-administration of MLA (3.0 mg/kg). Furthermore, Western blot analysis and immunohistochemistry revealed that levels of alpha7 nAChRs in the frontal cortex and hippocampus of the PCP (10 mg/kg/day for 10 days)-treated mice were significantly lower than those of saline-treated mice. These findings suggest that repeated PCP administration significantly decreased the density of alpha7 nAChRs in the brain and that the alpha7 nAChR agonist SSR180711 could ameliorate cognitive deficits in mice after repeated administration of PCP. Therefore, alpha7 nAChR agonists including SSR180711 are potential therapeutic drugs for treating cognitive deficits in schizophrenic patients.

Reversal of PCP-induced learning and memory deficits in the Morris’ water maze by sertindole and other antipsychotics

In humans, the N-methyl-D-aspartate antagonist phencyclidine (PCP) induces behavioral changes that mimic schizophrenia symptoms, including positive and negative symptoms as well as cognitive deficits. In clinic, the cognitive deficits are closely associated with functional outcome. Thus, improvement of cognition may have high impact on patients' daily life. In the present study, three second-generation antipsychotics (sertindole, risperidone, and clozapine) as well as the classical antipsychotic haloperidol were tested for the ability to reverse PCP-induced cognitive deficits in the Morris' water maze. The second-generation antipsychotics reversed the PCP-induced cognitive impairment: sertindole (0.63-2.5 mg/kg, s.c.), risperidone (0.04 mg/kg, s.c.; whereas 0.08 and 0.16 mg/kg were without significant effect), and clozapine (0.63 mg/kg, s.c.; while 1.3 mg/kg was without significant effect). The significant effect of sertindole was observed from day 2 onwards, while clozapine and risperidone only had significant effect at day 3. The classical antipsychotic haloperidol (0.010-0.020 mg/kg, s.c.) was ineffective. No compounds influenced swimming speed at the doses used, indicating that motor function was preserved. These results confirm that repeated PCP administration induces marked cognitive deficits. Further, second-generation antipsychotics like sertindole, clozapine, and risperidone within a certain, often narrow, dose range are able to reverse the impairment and thus might improve cognitive deficits in schizophrenic patients, whereas classical compounds like haloperidol lack this effect. The receptor mechanisms involved in the reversal of PCP's disruptive effect are discussed and likely include a delicate balance between effects on dopamine D(2), 5-HT(2A/6), alpha-adrenergic, muscarinic, and histaminergic H(1) receptors.

Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of tropisetron: Role of α7 nicotinic receptors

We examined the effects of tropisetron, a 5-hydroxytryptamine (5-HT 3) receptor antagonist and α7 nicotinic receptor agonist, on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (2 weeks) administration of tropisetron, but not ondansetron. Effects of tropisetron were significantly antagonized by co-administration of the α7 nicotinic receptor antagonist methyllycaconitine, suggesting the role of α7 nicotinic receptors in the active mechanisms of tropisetron. These findings suggest that tropisetron could be a potential therapeutic drug for cognitive deficits in schizophrenic patients.

Does risperidone act better in schizophrenic patients who have a family or obstetric history?

Purpose: The aim of the study was to assess the effect of treatment with risperidone on psychopathological symptoms and cognitive deficits in schizophrenic patients, in relation to family history, obstetric complications and duration of the illness. Methods: Fifty schizophrenic inpatients (29 males, 21 females), aged 16–50 (mean 28 years), with duration of the illness 1–15 (mean 4 years) who successfully completed a 3-month risperidone treatment were included into the study. Family history of psychiatric illness and the presence of obstetric complications were estimated by a semistructured questionnaire. Schizophrenic symptoms were assessed using the Positive and Negative Symptoms Scale (PANSS). Cognitive abilities were measured by neuropsychological “frontal lobe” tests: Trail Making Test (TMT), part B, Stroop Color Word Interference Test, part B, and Wisconsin Card Sorting Test (WCST). The clinical and neuropsychological evaluation was performed before and after 3 months of risperidone treatment, in doses 2–6 mg (mean 4.2 mg/day). Results: Before treatment, patients with family history had significantly higher intensity of negative symptoms, and obtained worse results on WCST perseverative errors (PE) and correct categories (CC). These measures were also impaired in subjects with obstetric complications. Additionally, in patients with obstetric complications, total and general PANSS psychopathology was higher and the results of Stroop B were worse. After a 3-month treatment with risperidone, no difference between respective groups was observed both in psychopathology and in neuropsychological tests. Patients with obstetric complications had higher degree of improvement on positive and negative symptoms and on TMT-B than the remaining ones. Patients with longer duration of the illness had less improvement on positive symptoms with risperidone treatment. Conclusions: The results of this study show that treatment with risperidone results in better compensation of psychopathological (negative symptoms) and neuropsychological (working memory) deficits in patients who have a family history and/or obstetric complications. This may be due to a favourable effect of risperidone on the prefrontal cortex dysfunction mediating these deficits.

A comparison of the acute effects of zotepine and other antipsychotics on rat cortical dopamine release, in vivo

The acute effects of systemic administration of the antipsychotic drug, zotepine, on extracellular dopamine (DA) in the frontal cortex of freely-moving rats were studied using in vivo microdialysis and compared with the actions of clozapine, olanzapine and haloperidol. Treatment with zotepine (1.0 mg/kg, i.p.) resulted in a prolonged elevation of cortical DA levels for up to 180 min post-drug. A maximal rise of +333% was observed at 120 min post-zotepine treatment. Clozapine (10.0 mg/kg, i.p.) also evoked a rise in extracellular DA which was similar in duration (200 min) to that resulting from treatment with zotepine. A maximal rise of +223% was observed at 100 min post-clozapine treatment. Olanzapine (1.0 mg/kg, i.p.) resulted in an immediate increase in DA levels which was maximal 40 min post-treatment (+280%) with levels returning to pre-injection values by 100 min after dosing. In contrast, haloperidol (0.1 mg/kg, i.p.) had no measurable influence on cortical DA levels. Local perfusion with the NA uptake inhibitor, nisoxetine (10 microM), resulted in an increase in cortical DA levels which was maximal at 100 min post-onset of perfusion (+257% above baseline). Administration of zotepine (1.0 mg/kg, i.p.) during nisoxetine perfusion elevated DA levels to a maximum of +301% above baseline, 60 min post-zotepine. These results show that acute administration of each of three drugs with an atypical antipsychotic profile causes an elevation of cortical DA in freely-moving rats at doses relevant to those derived from animal models which predict antipsychotic activity. As a dysfunction in cortical DA is thought to be involved in both the negative symptoms of schizophrenia and cognitive deficits in schizophrenic patients, it is possible that zotepine's ability to elevate cortical DA levels may underlie its effectiveness in successfully treating these components of schizophrenia. Furthermore, the ability of zotepine to elevate cortical DA is more likely to derive from its inhibition of the NA transporter rather than DA receptor blockade in this region.

Cognitive deficit measures in schizophrenia: factor structure and clinical correlates.

The authors aimed to delineate the "common denominators" across a representative number of cognitive measures by administering such measures to a large number of schizophrenic subjects. The authors also aimed to study the consistency of the subjects' performance over a 1-year period and to look into the relationship between cognitive task performance and clinical status. One hundred fifty-seven schizophrenic subjects with a DSM-III-R diagnosis of schizophrenia were assessed under standardized testing conditions on the dichotic listening and shadowing task, the span of apprehension task, the simple reaction time tasks, the critical stimulus duration, and the interstimulus interval in which they would become free from the masking effect. The clinical status of the subjects was assessed during index assessment, and 97 subjects were reassessed at the end of 1 year. Forty-seven subjects were randomly selected for reassessment on the cognitive tasks administered 1 year earlier. The subjects' performance was compared to that of 56 nonschizophrenic patients with nasopharyngeal carcinoma who had undergone radiation therapy. The cognitive task scores were factor analyzed, giving five distinct factors made up of the span of apprehension accuracy scores, simple reaction time scores, shadowing accuracy scores, span of apprehension error scores, and susceptibility to interference scores. At index assessment, the subjects' shadowing accuracy and reaction time were significantly related to their quality of life, social adjustment, and positive symptoms. The subjects' span of apprehension scores were related to their negative symptoms, measured in terms of work and daily life functions. The initial relationship between the subjects' cognitive test scores and their outcome status remained consistent at follow-up. The documented cognitive deficits in schizophrenic patients probably reflect a more enduring trait-like status with correlations with outcome status. These results also indicate that the cognitive measures may be simplified in complexity without a corresponding reduction in their clinical significance.

Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients.

Psychiatric researchers need specific animal models to better understand the neurobiology of schizophrenia. Prepulse inhibition (PPI), the reduction in startle produced by a prepulse stimulus, is diminished in schizophrenic patients. Theoretically, deficient PPI in schizophrenic patients reflects a loss of sensorimotor gating that may lead to sensory flooding and cognitive fragmentation. In rats, PPI is disrupted by systemic administration of dopamine agonists or by manipulations of neural circuitry linking the limbic cortex, striatum, pallidum, and pontine reticular formation. This loss of PPI in rats may be a useful model for studying the neurobiology of impaired sensorimotor gating in schizophrenic patients. We assessed the face, predictive, and construct validity of this animal model. Face validity was supported: stimulus manipulations produced parallel changes in PPI in humans and rats, and the dopamine agonist apomorphine disrupted PPI in rats, mimicking PPI deficits in schizophrenics. Predictive validity was supported: the ability of antipsychotics to restore PPI in apomorphine-treated rats correlated with clinical antipsychotic potency (rs = .991) and D2-receptor affinity (rs = .893). Antipsychotics that restore PPI in apomorphine-treated rats include "typical" antipsychotics and the "atypical" antipsychotic clozapine. Construct validity was supported: PPI was disrupted in rats when dopamine was infused into the nucleus accumbens; this effect was blocked by haloperidol. The loss of PPI in dopamine-activated rats may be a valid animal model of sensorimotor gating deficits in schizophrenic patients. This model may help us understand the neurobiology of cognitive deficits in schizophrenic patients.