Neuropsychological functioning among non-psychotic siblings and parents of schizophrenic patients

Several studies have shown subtle neuropsychological deficits in healthy relatives of schizophrenic patients. However, older relatives and parents have been less frequently assessed than younger adult relatives and siblings. Furthermore, some areas of neuropsychological functioning such as memory and learning have been little studied. Thirty-seven 22-70-year-old non-psychotic parents and siblings of schizophrenic patients were compared to 37 healthy control subjects on a battery of neuropsychological tests (Trail Making, parts A and B, verbal fluency, Wisconsin Card Sorting Test, and four subtests of the Wechsler Memory Scale-Revised: logical memory, design reproduction, verbal paired associates and digit span). Relatives did not differ from control subjects on Wisconsin Card Sorting Test performance and on visual memory, but were significantly impaired on verbal fluency; more subtle deficits were found on Trail Making, part B, digit span and paired associates. A higher proportion of relatives than control subjects showed impairment on verbal fluency and verbal memory. These neuropsychological weaknesseswere present as much in siblings as in parents of schizophrenic patients, and age did not cancel differences between relatives and control subjects. Thus, these subtle deficits seem to be potential phenotypic markers of schizophrenia.     

Verbal working memory impairment in schizophrenia patients and their first-degree relatives: evidence from the digit span task

OBJECTIVE: The evidence for verbal working memory deficits in schizophrenia has been inconsistent. Few studies have evaluated verbal working memory in the first-degree relatives of schizophrenia patients, who likely share the genetic diathesis for schizophrenia but not the potential confounds associated with chronic mental illness. METHOD: The Wechsler Digit Span Task was used to investigate verbal working memory in 52 schizophrenia patients, 56 of their first-degree relatives, and 73 nonpsychiatric comparison subjects. RESULTS: The nonpsychotic relatives showed no impairment on the forward digit span task, a measure of general attention, but did show impairment on the backward digit span task, a measure of verbal working memory. Schizophrenia patients showed impairment on both the forward and backward digit span tasks. CONCLUSIONS: These results indicate that the forward and backward digit span tasks tap different cognitive abilities that are differentially associated with the diathesis for schizophrenia. Working memory deficits associated with schizophrenia appear to be generalized and not limited to the spatial modality.     

Prefrontal cognitive deficits in patients with schizophrenia treated with atypical or conventional antipsychotics.

Forty-three patients with schizophrenia were investigated with a short neurocognitive screening battery focussing on working memory and executive functions. As compared to healthy controls, patients showed impairments in the modified card sorting test, in verbal fluency and all span tasks with exception of digit span forward. Patients who were treated with atypicals showed better performance in the digit ordering test (manipulation task) when compared to a group of patients who received conventional antipsychotics; this difference was not due to disease severity, age or education. Manipulation tasks might be useful for neurocognitive follow-up and intervention studies.     

Memory tests in first-degree adult relatives of schizophrenic patients: a meta-analysis

BACKGROUND: Memory deficits have been clearly demonstrated in schizophrenic patients. However, studies of memory performances in their relatives compared to normal controls provide conflicting results. A meta-analysis was carried out to synthesize all the published data. Unlike previous meta-analyses, which were based on composite scores, we analyzed each memory test separately. This prevents theoretically questionable choices in grouping variables, leads to results with clearer implications for applied research (e.g. the best choice of a test according to its sensitivity) and is more productive in suggesting explanatory hypotheses. METHOD: We initially selected 77 potentially relevant articles, but only 19 met our inclusion criteria. These articles provided data on eight different tasks, from five different memory tests: four tests from the Wechsler Memory Scale (WMS) and the California Verbal Learning Test (CVLT). For each task, we assessed data homogeneity, identified the outliers if any and then estimated effect sizes and tested publication bias using funnel plots. RESULTS: Adult relatives of schizophrenic patients were significantly impaired on most, but not all, tasks. The largest deficits were observed for the verbal paired associates test, the logical stories the digit span forward test and the digit span backward test. We found no significant differences in tasks of delayed recall, when deficits in immediate conditions (reflecting encoding) were taken into account. CONCLUSIONS: Adult relatives of schizophrenic patients have wide but not severe memory impairments. The size of estimated effects suggests that encoding processes are impaired, whereas storage and retrieval processes are relatively unaffected.     

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.     

Cognitive functioning in adolescents with schizophrenia spectrum disorders

Patients with schizophrenia have deficits in executive function that involve attentional set-shifting and planning ability. It is unclear, however, whether such deficits are stable during the course of the illness or if they fluctuate in response to medication effects or symptom changes. Patients with a DSM-IV diagnosis of schizophrenia (n=28) and healthy control subjects (n=17) were tested on computerised measures of attentional set-shifting and planning at baseline and 9-month follow-up. The measures used were the Intra/Extradimensional Shift test (ID/ED) and the Stockings of Cambridge test (SoC) from the Cambridge Automated Neuropsychological Testing Battery (CANTAB). On both tests, the patients were poorer than controls at baseline; however, there was no evidence of change over the 9-month follow-up. Additionally, there was little evidence of a relationship between executive test performance and medication or length of illness. This study accords with the presence of executive processing deficits in schizophrenia that are stable across time.     

The relationship between IQ, memory, executive function, and processing speed in recent-onset psychosis: 1-year stability and clinical outcome

Studies commonly report poor performance in psychotic patients compared with controls on tasks testing a range of cognitive functions, but, because current IQ is often not matched between these groups, it is difficult to determine whether this represents a generalized deficit or specific abnormalities. Fifty-three first-episode psychosis patients and 53 healthy controls, one-to-one matched for sex, age, and full-scale current IQ, were compared on Wechsler Adult Intelligence Scale (WAIS) subtests representing indices of perceptual organization, verbal comprehension, processing speed, and working memory as well as other tests of executive function and episodic memory. The groups showed an equivalent pattern of performance on all WAIS subtests except digit symbol processing speed, on which the patients were significantly worse. Patients were also worse on measures where performance correlated with digit symbol score, namely working and verbal memory tasks. Standardized residual scores for each subtest were calculated for each patient using the difference between their actual subtest score and a predicted subtest score based on their full-scale IQ and the performance of controls. Scaled scores and residual scores were examined for relationships with clinical measures. Digit symbol-scaled score was significantly correlated with concurrent negative syndrome score at baseline, and digit symbol residual score significantly predicted residual negative symptoms at 1-year follow-up. In summary, our comparison of patients and controls precisely matched for IQ revealed that processing speed was attenuated in recent-onset schizophrenia, contributed significantly to working and episodic memory deficits, and was a prognostic factor for poor outcome at 1 year.     

Cognitive dysfunction in people with convulsive seizures in rural China

One hundred and forty-four people with convulsive seizures (CS) and 144 healthy controls were evaluated for cognitive function, using a battery of neuropsychological tests. People with CS performed significantly worse than the controls on the Mini-Mental State Examination, Hamilton Depression Rating Scale, auditory verbal learning test, digit span test, verbal fluency test, and digit cancellation test. The percentage of patients who had abnormal scores on the Hamilton Depression Rating Scale was higher than that of controls (54.9% vs. 7.6%, p<0.001). Cognitive functional impairment was detected in 65.3% of the patients and 29.2% of the controls (p<0.001). People with CS presented with depressive mood and a wide range of cognitive deficits, particularly deficits in episodic declarative memory, attentional capacity, semantic memory, and mental speed. Years in education were positively associated with the cognitive performance of people with CS (OR=0.655, 95% CI: 0.486-0.882, p=0.005).     

Cognitive dysfunctions in parents of schizophrenic patients parallel the deficits found in patients

Schizophrenia is characterized by a global cognitive impairment, with varying degrees of deficit in all ability domains. Since genetic factors are important in the etiology of schizophrenia we investigated whether parents of schizophrenic patients also show cognitive deficits, particularly on those cognitive ability domains that are most severely affected in patients. Both biological parents of 37 patients with schizophrenia (N=74 subjects) and 28 comparable healthy married control couples (N=56 subjects) were included. A comprehensive and standardized cognitive battery was used including tests measuring verbal memory, executive functioning, language, attention, and psychomotor functioning. Parents of patients differed from control couples on those cognitive constructs that are generally considered to be most impaired in schizophrenic patients, i.e. global verbal memory, bilateral motor skill, continuous performance, and word fluency. In addition, parents differed significantly from control couples on some other cognitive constructs on which patients show a smaller but also significant difference compared to healthy controls, i.e. unilateral motor skill and digit span. Results suggest that the cognitive constructs on which patients show relatively most severe impairment may prove suitable as endophenotypic markers in schizophrenia.     

Semantic verbal fluency deficit as a familial trait marker in schizophrenia

This study examined neurocognitive deficits as familial vulnerability factors to schizophrenia. Twenty-three Chinese schizophrenic patients, 21 of their non-psychotic siblings and 26 healthy volunteers, matched for age, sex and education, were assessed by using a battery of neurocognitive tests including: Wisconsin Card Sorting Test (WCST), semantic verbal fluency, logical memory, digit span, information, comprehension and similarity. The results showed that siblings had significantly less word output in the verbal fluency test as compared to controls. No significant difference was found between siblings and controls for other tests except that a trend difference was noted for the performance on the similarity test and number of categories completed on the WCST. The verbal fluency abnormality can be considered as a familial trait marker for schizophrenia. Relationships between the residual symptoms after an acute psychotic episode and the magnitude of familial risk were examined. More severe residual symptoms of probands at clinical remission could be predicted by their older age of onset and by better verbal fluency performance in their non-psychotic siblings. This tentatively suggests that patients with a milder genetic form of schizophrenic illness may have a more severe environmental contribution to cerebral insult according to the multifactorial/threshold model. The environmental cerebral insult may cause structural abnormalities leading to incomplete remission of clinical symptoms.     

Arithmetic fact retrieval and working memory in schizophrenia.

Despite its importance in every-day life and vocational rehabilitation, arithmetic ability has rarely been investigated in schizophrenic patients. Those few studies reporting arithmetic deficits in schizophrenia, however, administered complex calculation tasks which drew not only on arithmetic abilities, but also on working memory resources known to be impaired in schizophrenia. In the present study, arithmetic abilities and working memory functions were investigated in schizophrenic patients (n=24) and healthy control subjects (n=24). Arithmetic fact retrieval was assessed in single-digit multiplication and corresponding division problems using a result verification task which minimized working memory demands. Problem size and the disparity of the proposed result were manipulated. The storage component of working memory was tested with a digit span forward task and the executive control component with a digit span backward as well as with verbal fluency tasks. Schizophrenic patients performed worse than controls only in the executive tasks. Digit span forward was preserved. In the arithmetic tasks, groups did not differ from each other, and a similar pattern of task manipulations was obtained. Hence, despite the executive control deficit retrieval of arithmetic facts is preserved in schizophrenia. Moreover, the same underlying cognitive processes as in control subjects are involved.     

首发精神分裂症患者神经认知功能的遗传学分析

目的 探索精神分裂症患者及其亲属共同存在的神经认知功能损害,并对22号染色体上儿茶酚氧位甲基转移酶(COMT)基因和脯氨酸脱氢酶(PRODH)基因的5个候选单核苷酸多态性(SNP)位点进行相关的遗传学分析。方法 采用14个神经心理测验(共29项)对235例首发精神分裂症患者(患者组)、322名未患病亲属(亲属组)和133名正常对照(正常对照组)进行有关智力、注意、记忆、言语功能和执行功能等评定,比较各组间的神经认知功能有无差异,并对上述神经认知功能测验与COMT和PRODH基因的5个候选SNP进行定量性状的传递不平衡测试。结果 (1)患者组所有测验的成绩均差于正常对照组,差异有显著性(P<0.01和P<0.05),而亲属组的记忆、注意、言语功能和执行功能界于患者与正常对照之间;(2)PRODH1 195G/A与即刻逻辑记忆测验(P=0.03)、言语流畅性测验的正确数(P=0.03)和连线测验B的犯规数(P=0.01)相关,PRODH1945G/A与数字符号测验(P:0.01)、连线测验A的错误数(P:0.02)、HANOI塔测验的总分(P=0.01)、威斯康星卡片分类测验(WCST)的总错误数(P=0.01)、WCST的非持续错误数(P:0.02)和WCST的总分类数(P=0.02)相关。结论 精神分裂症患者在记忆、注意、言语功能和执行功能等方面存在广泛的神经认知功能损害,这种损害可能是精神分裂症的遗传“内表     

Patients with schizophrenia show deficits of working memory maintenance components in circuit-specific tasks

Working memory (WM) deficits are a neuropsychological core finding in patients with schizophrenia and also supposed to be a potential endophenotype of schizophrenia. Yet, there is a large heterogeneity between different WM tasks which is partly due to the lack of process specificity of the tasks applied. Therefore, we investigated WM functioning in patients with schizophrenia using process- and circuit-specific tasks. Thirty-one patients with schizophrenia and 47 controls were tested with respect to different aspects of verbal and visuospatial working memory using modified Sternberg paradigms in a computer-based behavioural experiment. Total group analysis revealed significant impairment of patients with schizophrenia in each of the tested WM components. Furthermore, we were able to identify subgroups of patients showing different patterns of selective deficits. Patients with schizophrenia exhibit specific and, in part, selective WM deficits with indirect but conclusive evidence of dysfunctions of the underlying neural networks. These deficits are present in tasks requiring only maintenance of verbal or visuospatial information. In contrast to a seemingly global working memory deficit, individual analysis revealed differential patterns of working memory impairments in patients with schizophrenia.     

Secondary verbal memory: a potential endophenotype of schizophrenia

This study aimed at identifying neuropsychological endophenotypes of schizophrenia which met the criteria of stability and sensitivity. Twenty-six non-schizophrenic first-degree relatives together with their affected family members (all simplex-families) underwent assessment with a comprehensive neuropsychological test battery both at baseline and 13 months follow-up. Follow-up patients were in a state of stable remission. Further, 21 unrelated, demographically balanced, non-vulnerable controls were tested one at a time. A principal components analysis of our test battery resulted in four factors: (1) Vigilance, attention, and psychomotor, (2) secondary verbal memory, (3) immediate and working memory, and (3) abstraction and problem solving. At baseline testing our study revealed a pattern of selective cognitive deficits in the relative group that is less pronounced, yet qualitatively similar, to that found in the patient sample. The most severe deficits displayed both the patients and their relatives in the secondary verbal memory domain. The dysfunctions in secondary verbal memory at baseline testing significantly correlated with negative symptoms only. Secondary verbal memory deficits proved to be relatively independent of age at onset of illness, illness duration, and neuroleptic dosage. Longitudinally, dysfunctions in the patients' secondary verbal memory fluctuated over time and with negative symptoms, and persisted in remitted patients at the same level as in their relatives. In conclusion, the secondary verbal memory met the criteria of relative stability and sensitivity in our sample of simplex-families. Thus, the secondary verbal memory seems to be a potential endophenotypic marker of schizophrenia, even for cases with a hypothetically lower genetic loading.     

Verbal memory in schizophrenia: additional evidence of subtypes having different cognitive deficits

A prior study found a selective deficit in verbal working memory in a subgroup of patients with schizophrenia who performed as well as healthy controls on a screening test of attention and auditory perception [Arch. Gen. Psychiatry 55 (1998) 1093]. Given the importance of defining pathophysiologically distinct subtypes of schizophrenia, the present study aimed to replicate and extend this finding. Patients with schizophrenia who passed the screening test (discriminators or Dsz patients) were compared to those who did not (nondiscriminators, NDsz patients), and healthy controls on a word serial position test (WSPT) and on other tests of verbal and nonverbal cognitive function. Dsz patients performed more poorly than controls on the WSPT and showed serial position effects consistent with a verbal memory deficit. They also showed a deficit in verbal memory but not visual memory on the Wechsler Memory Scale-Revised. In contrast, the NDsz patients showed overall poor performance on both verbal and nonverbal tests, consistent with a generalized deficit. Verbal working memory deficits were not related to education, gender, severity of symptoms, medication status, or hemispheric dominance for perceiving dichotic words. The findings add to growing evidence for the existence of a subgroup of schizophrenia having a specific verbal memory deficit that is not limited to working memory, but extends to learning and recall of verbal material.     

Course of cognitive functioning during the stabilization phase of schizophrenia

The present study aimed at examining the longitudinal course of neuropsychological impairments in schizophrenia patients during the stabilization phase of the illness. Cognitive functioning of 151 schizophrenia patients was assessed at baseline, 9-month, and 15-month follow-up with a comprehensive battery of cognitive tests. Cognitive performance of 40 matched controls was also examined at baseline and follow-up in order to control for effects of repeated testing. We found significant improvements in memory, attention, and global cognitive functioning from baseline to 9-month follow-up. Abstraction was stable at a relatively normal level. Global cognitive functioning remained at 9-month follow-up one standard deviation below normative level. Improvements in patients' cognitive performance between the 9-month and the 15-month follow-up were fewer and less pronounced. The present study implies that schizophrenia is a static encephalopathy with trait and state dependent cognitive components particularly in the attention and memory domain. The statistically and clinically significant cognitive improvements should be ground for clinical optimism.     

Computerized assessment of cognition in schizophrenia: promises and pitfalls of CANTAB.

OBJECTIVE: Over the last decade, the Cambridge Neuropsychological Test Automated Battery (CANTAB), which comprises visuo-spatial tasks, has been utilized in cognitive studies of schizophrenia. A clear approach concerning the usage of CANTAB for the appraisal of neurocognitive dysfunction in schizophrenia is currently lacking. METHOD: In this paper, we have first reviewed the overall applications of CANTAB and then evaluated methodological strengths and weaknesses of CANTAB as a neurocognitive battery for schizophrenia. We carried out a systematic search and assessment of studies where CANTAB was utilized to measure cognitive function in schizophrenia. We have also attempted to quantify the available data and perform a meta-analysis, but this approach turned out to be still premature. RESULTS: CANTAB has enabled researchers to highlight significant deficits affecting broad cognitive domains in schizophrenia, such as working memory, decision-making, attention, executive functions and visual memory. So far, the most consistent deficit observed with CANTAB testing has been attentional set-shifting, suggestive of fronto-striatal dysfunctions. In addition, preliminary evidence points towards the potential use of CANTAB to identify cognitive predictors of psychosocial functioning, to describe the relationships between symptoms and cognition, and to measure the impact of pharmacological agents on cognitive functioning. CONCLUSION: CANTAB has been used successfully to highlight the range of visuo-spatial cognitive deficits in schizophrenia, producing similar results to those obtained with some traditional neuropsychological tests. Further studies validating the use of CANTAB following the standard set by Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) are warranted.     

Durability of cognitive remediation training in schizophrenia: performance on two memory tasks at 6-month and 12-month follow-up

Patients with schizophrenia have consistently been found to exhibit cognitive deficits, particularly in memory, which have been suggested to mediate functional outcomes. Several recent reviews of cognitive retraining have concluded that these deficits respond to training, although the sustainability of cognitive improvement following completion of training has not been adequately evaluated. Most studies had small samples and very short follow-up periods. As part of a larger study, we examined performance on two memory tasks in two groups of participants: those who received computerized cognitive remediation training in addition to work therapy (n=45), vs. those who only received work therapy (n=49). Computerized cognitive remediation included hierarchical training on a computerized digit span task and a computerized words serial position task. Assessments using the same computerized tasks were made at three time points: baseline, end of active intervention, and 6-month follow-up. Compared to the active control condition (work therapy only), the group receiving computerized cognitive remediation in addition to work therapy showed significantly greater improvements on the trained digit span task following training. These improvements were maintained at the 6-month follow-up. There were no significant group differences on the word serial position task at any time point. Results indicate that computerized training can lead to sustained improvements on some, but not all, training tasks.     

Executive functioning and theory of mind in euthymic bipolar disorder

Objectives:  To examine the nature of executive deficits in euthymic patients with bipolar disorder (BD).
Methods:  Fifteen euthymic BD patients and 13 controls were administered a battery of executive tasks including verbal fluency, Stroop, Theory of Mind (ToM) tests and selected subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Self-report and clinician ratings of mood and social and occupational functioning were also obtained.
Results:  There were no significant differences between BD patients and controls on the primary measures of the following executive tasks: verbal fluency, attentional set-shifting, problem solving or planning. On secondary measures of speed, BD patients were slower to complete the first trial of the Stroop task (p = 0.001). Patients with BD committed more errors across all secondary measures. Patients performed poorly when compared with controls on tests of verbal ToM (p = 0.02), and although they performed non-verbal ToM tasks at a level comparable to controls (p = 0.60), they were slower to initiate a response (p = 0.006). ToM was not significantly correlated with any measure of social and occupational functioning; however it correlated with the achievement scores of the CANTAB Stockings of Cambridge task (Pearson's r  = 0.68, p < 0.01).
Conclusions:  Deficits found in euthymic bipolar patients suggest fronto-subcortical pathway dysfunction. This is consistent with other neuropsychological and neuroimaging research that points to a trait deficit in BD. Further investigation is necessary perhaps using more real-world tests.     

Comparison of the neuropsychological deficits associated with early and advanced Huntington's disease.

Patients with "recently" diagnosed Huntington's Disease (RHD) were compared on a neuropsychological test battery to patients who have had the disease three to 15 years (AHD) and to intact controls. While the patients with HD showed general nonfocal deficits on the Wechsler Adult Intelligence Scale, the Wechsler Memory Scale, and tests of short-term memory and verbal fluency, the patients with RHD had focal deficits that stressed their memory deficits. The patients with RHD had IQs within the normal range, but their memory quotients, their performance on short-term memory tests, and their ability to search and retrieve from long-term memory were severely imparied. These results suggest that the cognitive deficits of patients with HD do not develop uniformally; memory disorders are early focal signs that precede the patients' more widespread intellectual deterioration.