Prospective memory deficits in subjects with schizophrenia spectrum disorders: a comparison study with schizophrenic subjects, psychometrically defined schizotypal subjects, and healthy controls

Memory impairment is one of the core deficits in schizophrenia. This study explored the memory profiles of schizophrenic and psychometrically defined schizotypal subjects. The study participants included 15 patients with schizophrenia, 41 schizotypal subjects, and 20 healthy controls. All of the participants completed verbal and visual memory, working memory, and prospective memory tasks. The results showed that patients with schizophrenia were impaired in all aspects of memory function, whereas the schizotypal subjects tended to show moderate to large impairment effect sizes in prospective memory. It is suggested that prospective memory be considered a potential endophenotype of schizophrenia.     

Sex differences in prepulse inhibition deficits in chronic schizophrenia

Recent years have seen a dramatic growth in the number of studies using prepulse inhibition (PPI) paradigms to index information processing deficits in schizophrenia. There are, however, robust sex differences in PPI in healthy subjects, with women exhibiting less PPI than men in the absence of any psychopathology. To investigate the role of sex in prepulse modification deficits in the long-term course of schizophrenia, we assessed PPI (response inhibition with the prepulse preceding the pulse by 30-150 ms) and prepulse facilitation (PPF; response facilitation with the prepulse preceding the pulse by 1000 ms) of the acoustic startle response in 42 chronic schizophrenia patients (27 men; all 42 on typical antipsychotics) and 35 controls (15 men). The results revealed that healthy women showed less PPI than healthy men. Men with schizophrenia showed less PPI compared to healthy men, but women with schizophrenia did not differ in PPI from healthy women. Age of illness onset negatively correlated to PPI in male patients. There was no significant effect of sex in PPF, and although patients (regardless of sex) showed less PPF relative to controls, this effect was abolished when the current age was co-varied for. These findings indicate sex differences in PPI deficits in schizophrenia. Future studies of schizophrenia patients need to take sex and age of subjects into account to optimise the investigation of PPI deficits, and their clinical, neural, and pharmacological correlates.     

Effective neuroleptic medication removes prepulse inhibition deficits in schizophrenia patients.

BACKGROUND: The magnitude of the startle eyeblink response is reduced if the startle eliciting stimulus is shortly preceded by another stimulus. There is evidence that schizophrenia patients exhibit impairments in this so-called prepulse inhibition. Our study investigated whether prepulse inhibition is affected by neuroleptic drug treatment as is suggested by animal research. METHODS: Prepulse inhibition was tested in five unmedicated and 20 medicated inpatients with schizophrenia, and 12 normal controls. RESULTS: The unmedicated schizophrenia patients showed a strong impairment of sensorimotor gating as indexed by the absence of prepulse inhibition. By contrast, the medicated patients showed a pronounced prepulse inhibition that did not differ from that of the normal controls. There was a substantial covariation between the rated severity of the positive syndrome and the amount of prepulse inhibition--i.e., the patients whose positive symptoms were rated as more severe showed less prepulse inhibition. CONCLUSIONS: These data suggest that the impaired sensorimotor gating of schizophrenia patients is not a stable vulnerability indicator, but may rather be related to the positive syndrome and may be improved by treatments with neuroleptic medication.     

High glycine levels are associated with prepulse inhibition deficits in chronic schizophrenia patients

Prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating, is decreased in schizophrenia. The validity of a glutamatergic, N-methyl-d-aspartate receptor (NMDAR)-mediated model of PPI disruption is presently equivocal. The NMDAR antagonist ketamine disrupts PPI in rodents, but may increase PPI in healthy volunteers. Glycine (GLY), which acts as an obligatory co-agonist at the NMDAR-GLY site, induces PPI deficits in rats although, consistent with the hypo-NMDAR hypothesis, improves negative and cognitive symptoms in schizophrenia patients. We assessed the hypothesis that GLY serum levels may affect PPI parameters in schizophrenia. Forty-five chronically ill medicated schizophrenia patients and 37 matched healthy comparison subjects were tested for PPI of the eyeblink component of the startle reflex measured by electromyogram recording. Patients' demographic variables, symptom severity scores and GLY, serine and glutamate serum levels were obtained. Patients showed deficient PPI in blocks two and three of the PPI session and differed from controls in terms of change of degree of PPI as a function of the prepulse to eliciting stimulus interval. GLY levels correlated negatively with PPI parameters, such that patients with the highest GLY levels showed decreased PPI (rs=-0.4, p=0.03). These preliminary findings indirectly support previous observations on ketamine effects upon PPI in humans and suggest a dissociation of symptomatology and PPI changes as function of NMDAR modulation in schizophrenia.     

Lack of association between prepulse inhibition and antisaccadic deficits in chronic schizophrenia: implications for identification of schizophrenia endophenotypes

Individuals with schizophrenia, compared to healthy individuals, are known to exhibit deficient prepulse inhibition (PPI) of the startle response as well as reduced performance on the antisaccade task. There is evidence for genetic transmission of both PPI and antisaccadic abnormalities in schizophrenia. It has been suggested that PPI and antisaccade measures identify separate endophenotypes, on the basis of a lack of relationship between PPI and antisaccade deficits in patients with schizotypal personality disorder. However, given that patients with schizotypal personality disorder are unlikely to manifest all the abnormalities associated with schizophrenia, it is important to determine that there is no relationship present between these two abnormalities in people affected with schizophrenia. The main objective of this investigation therefore was to establish the lack of the association between PPI and antisaccade deficits in schizophrenia in two independent studies. Study 1 involved 39 patients with schizophrenia and 14 healthy controls and study 2 involved 35 patients with schizophrenia and 22 healthy controls. PPI (uninstructed paradigm) of the acoustically elicited startle (eye blink) was measured electromyographically. Antisaccadic eye movements (standard, non-overlap version) were measured using infrared oculography. Patients displayed reduced PPI and a lower percentage of correct antisaccades relative to healthy controls in both studies. As expected, no relationship occurred between PPI and the percentage of correct antisaccade responses in either group. It is concluded that PPI and antisaccade abnormalities in schizophrenia represent separate endophenotypes, reflecting the functions of different genetic aetiologies and different or only partially overlapping neural systems.     

Cognitive deficits and functional outcome in schizophrenia

Cognitive dysfunction is a core feature of schizophrenia. Deficits are moderate to severe across several domains, including attention, working memory, verbal learning and memory, and executive functions. These deficits pre-date the onset of frank psychosis and are stable throughout the course of the illness in most patients. Over the past decade, the focus on these deficits has increased dramatically with the recognition that they are consistently the best predictor of functional outcomes across outcome domains and patient samples. Recent treatment studies, both pharmacological and behavioral, suggest that cognitive deficits are malleable. Other research calls into question the meaningfulness of cognitive change in schizophrenia. In this article, we review cognitive deficits in schizophrenia and focus on their treatment and relationship to functional outcome.     

Cognitive deficits in recent-onset and chronic schizophrenia

Although cognitive dysfunction is a primary characteristic of schizophrenia, only recently have investigations begun to pinpoint when the dysfunction develops in the individual afflicted by the disorder. Research to date provides evidence for significant cognitive impairments prior to disorder onset. Less is known about the course of cognitive dysfunction from onset to the chronic phase of schizophrenia. Although longitudinal studies are optimal for assessing stability of cognitive deficits, practice effects often confound assessments, and large and representative subject samples have not been followed over long periods of time. We report results of a cross-sectional study of cognitive deficits early and late in the course of schizophrenia carried out at four different geographic locations to increase sample size and generalizability of findings. We examined a broad set of cognitive functions in 41 recent-onset schizophrenia patients and 106 chronic schizophrenia patients. The study included separate groups of 43 matched controls for the recent-onset sample and 105 matched controls for the chronic schizophrenia sample in order to evaluate the effects of cohort (i.e., age) and diagnosis (i.e., schizophrenia) on cognitive functions. All measures of cognitive function showed effects of diagnosis; however, select time-based measures of problem solving and fine motor dexterity exhibited interactions of diagnosis and cohort indicating that these deficits may progress beyond what is expected with normal aging. Also, worse recall of material in episodic memory was associated with greater length of illness. Nevertheless, findings indicate that nearly all cognitive deficits are comparably impaired across recent-onset and chronic schizophrenia.     

Dopaminergic hypofunctions and prepulse inhibition deficits in mice lacking midkine

Midkine is a 13-kDa retinoic acid-induced heparin-binding growth factor involved in various biological phenomena such as cell migration, neurogenesis, and tissue repair. We previously demonstrated that midkine-deficient (Mdk(−/−)) mice exhibited a delayed hippocampal development with impaired working memory and increased anxiety only at the age of 4 weeks. To assess whether midkine gene could play important roles in development and maintenance of central nervous system, we investigated biochemical and behavioral parameters in dopamine and glutamate neurotransmission of Mdk(−/−) mice. The Mdk(−/−) mice exhibited a hypodopaminergic state (i.e., decreased levels of dopamine and its receptors in the striatum) with no alterations of glutamatergic system (i.e., normal level of glutamate, glutamine, glycine, d-serine, l-serine, and NMDA receptors in the frontal cortex and hippocampus). We also found prepulse inhibition deficits reversed by clozapine and haloperidol in the Mdk(−/−) mice. Our results suggested that midkine deficiency may be related to neurochemical and behavioral dysfunctions in dopaminergic system.     

Impact of prepulse characteristics on the detection of sensorimotor gating deficits in schizophrenia

Schizophrenia patients have prominent deficits in information processing that can be detected by measures of prepulse inhibition (PPI) of the startle response. Deficient PPI in schizophrenia is thought to reflect a failure of brain-based information 'protective' mechanisms that normally inhibit responsivity for 30-500ms after a weak prepulse stimulus. The relationship between specific prepulse stimulus characteristics and PPI deficits in this study was examined in 31 schizophrenia patients and 34 normal comparison subjects. Schizophrenia patients had overall deficits in PPI across four conditions where the prepulse was either discrete (abrupt) or continuous (sustained) and consisted of either white noise or a pure tone. On inspection and analysis of the data, it appears that the white noise conditions, rather than tone conditions, account for the group differences. Thus, the discrete white noise prepulse was most effective in eliciting PPI deficits, resulting in a large effect size between groups (d=0.85; P<0.01). Deficits in information-protective mechanisms in schizophrenia may be differentially sensitive to specific stimulus characteristics; this observation may be relevant both to the neurobiology of information processing deficits in schizophrenia and to the methodologies for studying these deficits experimentally.     

Cognitive deficits in the families of patients with schizophrenia

PURPOSE OF REVIEW: Studies of first-degree relatives of patients with schizophrenia over the past 25 years have reported a number of cognitive deficits, primarily in the domains of memory and executive function. Nevertheless, due to a number of methodological issues, such as including different types of relatives and not controlling for possible psychopathology, it is not yet clear that these findings can fully support a conclusion of heritability of cognitive dysfunction associated with a schizophrenia genotype. RECENT FINDINGS: Several recent meta-analyses have shown that the most consistent deficit shown by relatives is impaired performance on 'maintenance plus' frontal-lobe tasks requiring increased effort and higher central executive processing. Studies of multiplex families (multiple diagnoses in one family) also report that family members tend to have more difficulty on executive function tasks. Another interesting trend is research on subgroups of patients and relatives displaying distinct cognitive syndromes, particularly a subgroup with a generalized cognitive deficit. SUMMARY: As methodological designs improve, this field of study holds promise not only for understanding the neurobiological mechanisms of schizophrenia and the associated cognitive deficits, but also for possibly describing endophenotypes that may lead to identifying at-risk patients and relatives.     

Impaired prepulse inhibition and prepulse-elicited reactivity but intact reflex circuit excitability in unmedicated schizophrenia patients: a comparison with healthy subjects and medicated schizophrenia patients

Deficient sensorimotor gating as indexed by prepulse inhibition (PPI) of the startle response has been reported repeatedly in patients suffering from schizophrenia. According to the widely accepted "protective hypothesis," PPI reflects the protection of ongoing information processing against interference by other stimuli. Alternatively, it has been proposed that PPI might be regulated by startle reflex circuit excitability. In the present study, we evaluated these 2 conceptually divergent approaches underlying the regulation of PPI. To this end, we assessed sensorimotor gating as indexed by PPI, the reactivity to the prepulse-alone stimulus indexed as prepulse-elicited reactivity (PPER), and acoustic blink reflex excitability in terms of paired pulse suppression (PPS) within a single recording session in 13 unmedicated and 24 medicated (11 first break) schizophrenia patients in comparison to 43 healthy control subjects. The results showed that PPI was significantly reduced in unmedicated, but not in medicated schizophrenia patients. Furthermore, unmedicated patients could be distinguished from the medicated patients and control subjects in terms of PPER. In contrast to PPI, PPS did not differ between patients and control subjects. These findings are in line with the "protective hypothesis" of PPI and indicate that reduced sensorimotor gating in schizophrenia patients might be based on a reduced perception and/or processing of the prepulse stimulus. The extent to which PPER may or may not be causally associated with sensorimotor gating in schizophrenia has to be further investigated in human and animal studies.     

精神分裂症患者认知功能损害与氧化应激关系的初步研究

目的：探讨精神分裂症患者认知功能缺损与氧化应激的关系。方法：对39例精神分裂症患者（患者组），36名健康对照者（对照组）进行神经心理测验和氧化应激指标的检测.结果：（1）在神经心理测验中，患者组与对照组在总测验数、总错误数、持续错误数、语言流畅、领悟、相似和联想学习的差异有非常显著性（P＜0．01），数字广度的差异有显著性（P＜0．05）；（2）患者组后的一氧化氮（NO）浓度与WCST的总错误数呈显著正相关，与相似测验呈显著性负相关，超氧化物歧化酶（SOD）活性与相似性测验、数字广度测验呈显著性负相关（r分别为0．409，－0．404，－0．432，－0．420，P＜0．05）。结论：（1）精神分裂症认知功能缺损的生物学基础可能与氧化应激有关；（2）SOD和NO可能是与认知功能密切相关的氧化应激指标。     

Cognitive deficits and social functioning in schizophrenia: a clinical perspective

Impaired social functioning is one of the diagnostic features of schizophrenia. Cognitive functioning is also often impaired in several domains. Meta-analysis has shown a predictive value of cognition for a variety of domains related to social functioning (Green, Kern, Braff, & Mintz, 2000). The significance of these findings for clinical practice has remained largely uninvestigated, however, and is therefore taken up here. We investigated verbal memory, attention and executive functioning in 52 schizophrenia patients. Social functioning was assessed for different types of social roles. The percentages of cognitive and social impairments in our group were assessed according to clinical principles, normally used to judge an individual patient. A possible predictive relationship between cognition and social functioning was studied on the basis of these clinical criteria. A large proportion of patients showed impairments in both cognitive functioning and social functioning. However, the clinical method resulted in a successful prediction of social functioning in only 21-69% of the cases. Social functioning and cognitive functioning were impaired in a large proportion of patients, but were largely independent from each other. Since relationships between cognition and social functioning are weak, assessment procedures are inconsistent and possibly not optimally adjusted to the psychiatric population, the clinical relevance of cognitive testing in order to predict social functioning is as yet questionable.     

Anomalous self-experiences are related to general cognition deficits in schizophrenia

European Archives of Psychiatry and Clinical Neuroscience - Anomalous self-experiences (ASEs) are prevalent in schizophrenia, but its underpinnings are not completely understood. Given the likely...     

Cognitive deficits in schizophrenia: an updated metanalysis of the scientific evidence

ABSTRACT: BACKGROUND: This is an update of a previous meta-analysis published in 2005. METHODS: It includes the data published up to march 2010 for a total of 247 papers and 18,300 cases. Cognitive deficits are examined in 5 different domains: Memory functioning (128 studies), Global cognitive functioning (131 studies), Language (70 studies), Executive function (67 studies), Attention (76 studies). Only controlled studies were included: patients vs. normal subjects. RESULTS: Results evidence that in all domains and in all different analyses performed within each domain, patients show a significant reduction of cognitive efficiency with respect to normal subjects. The between studies heterogeneity is very high in almost all domains. There are various sources of this heterogeneity (age, sex, sample size, type of patients, and type of measurement) which contribute to the high degree of not-overlapping information offered by the single studies. CONCLUSIONS: Our results, based on the current scientific evidence, confirm the previous findings that there is a generalized impairment of various cognitive functions in patients with schizophrenia when compared to normal cases. The modalities with which these results are obtained have not changed over the years and the more recent studies do not modify the high heterogeneity previously found between the studies. This reduces the methodological quality of the results. In order to improve the methodological quality of the studies performed in the field of cognitive deficits of patients with schizophrenia, various factors should be taken into account and better managed in designing future studies.     

Cognitive inhibition and thought disorder in schizophrenia

In schizophrenia, inhibitory control is reported to be disturbed and has been associated with formal thought disorder (TD). The negative priming task (NP) is used as a measure for inhibition; however, controversial results are found in the literature. The aim of this study was to evaluate cognitive inhibition in schizophrenia and TD. Additionally, the influence of the course of disease and of medication were evaluated. The NP was used to compare TD patients (n = 17) with non-TD (n = 19) and healthy controls (n = 21). Results showed similar performance among TD and non-TD patients, and controls. No influence of the course of disease or medication was found. Our results are in line with recent studies, where patients, irrespective of TD, show normal performance in the NP.     

Isolation rearing of mice induces deficits in prepulse inhibition of the startle response

Male 129T2 and C57BL/6J mice were housed either in groups of three (socials) or singly (isolates) at weaning. Six and seven weeks later, prepulse inhibition (PPI), startle reactivity, and locomotor activity (LMA) were measured. Isolation-reared mice of both strains exhibited PPI deficits compared to socially reared controls in at least one of the two PPI test sessions. Isolation rearing had no effect on startle reactivity or habituation and only 129T2 isolates exhibited increased LMA. Isolation rearing induced locomotor hyperactivity and PPI deficits in mice and may be an effective developmental manipulation to use in combination with studies of genetically altered mice.     

Deficits in prepulse inhibition and habituation in never-medicated, first-episode schizophrenia.

BACKGROUND: Prepulse inhibition (PPI) is the normal suppression of the startle reflex when an intense startling stimulus is preceded by a barely detectable prepulse. Habituation of the acoustic startle reflex is decrement in response when the same stimulus is presented repeatedly. These factors have been proposed as neurophysiologic measures of sensorimotor gating or filtering and discussed as trait-linked markers for information-processing deficits in schizophrenia-spectrum disorders. The aim of this study was to examine whether first-episode schizophrenia patients also exhibit deficits in PPI and habituation. METHODS: Never-medicated male schizophrenic and schizophreniform patients in their first psychotic episode (n=24) were compared with age-matched healthy men (n=21) in an acoustic startle paradigm assessing PPI (30-, 60-, 120-, 240-, and 2000-msec interstimulus intervals) and habituation. RESULTS: Compared with control subjects, first-episode patients exhibited significant deficits in both PPI in the 60-msec prepulse condition and startle habituation. Patients also exhibited less facilitation in the 2000-msec prepulse condition. CONCLUSIONS: In combination with other studies, these findings indicate that PPI and habituation may be sensitive intermediate phenotypic markers for information-processing deficits in schizophrenic patients.     

Medication status affects the relationship of symptoms to prepulse inhibition of acoustic startle in schizophrenia

Inhibition of the acoustic startle response by a smaller preliminary nonstartling stimulus is termed prepulse inhibition (PPI). Schizophrenia patients have impairments in PPI that may not fully normalize even when they are clinically stable on medication, particularly typical antipsychotics. There is evidence that more severe symptoms are associated with more severe PPI abnormalities, but the effect of antipsychotics on this relationship is not clear. Seventy-three male schizophrenia patients underwent acoustic startle and PPI testing. Symptom ratings were performed using the Brief Psychiatric Rating Scale (BPRS) and its subscales. Fifty-two subjects were treated with antipsychotic medication at time of testing; 21 were unmedicated. For all subjects, PPI was negatively correlated with the BPRS psychological discomfort subscale but not with BPRS total symptoms, BPRS positive symptoms or BPRS negative symptoms. For medicated subjects analyzed separately, there were no correlations with BPRS total scores or any subscales. For the unmedicated subjects analyzed separately, there were significant correlations of lower PPI with greater severity of BPRS total symptoms, positive symptoms and the psychological discomfort subscale. These data indicate that more severe symptoms are associated with lower PPI, but that medication status is an important factor in the relationship between symptom severity and sensorimotor gating.     

Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis

BACKGROUND: Schizophrenia is characterized by a generalized cognitive impairment with pronounced deficits in the domains of verbal memory, executive functioning and attention. AIM: To investigate whether cognitive deficits found in patients with schizophrenia are also found in non-affected relatives. METHOD: A meta-analytic review of the published literature on cognitive performance between relatives of schizophrenic patients and healthy controls. RESULTS: The meta-analyses yielded nine weighted effect sizes from 37 studies comprising 1639 relatives of schizophrenia patients and 1380 control subjects. The largest differences were found on verbal memory recall (d=0.54, 95% CI=0.43-0.66) and executive functioning (d=0.51, 0.36-0.67). Attentional functioning showed smaller effect sizes (d=0.28, 0.06-0.50). These effect sizes are in the moderate range. CONCLUSION: Cognitive deficits found in patients with schizophrenia are also found in non-affected relatives. This finding is consistent with the idea that certain cognitive deficiencies in relatives are caused by familial predisposition to schizophrenia and that these deficiencies might be putative endophenotypes for schizophrenia. However, our results do not address genetic causes directly. Further work is needed to determine whether certain cognitive traits are familial and whether there is co-inheritance of these traits with schizophrenia within families.