Verbal Declarative Memory Dysfunction in Schizophrenia: From Clinical Assessment to Genetics and Brain Mechanisms

The recent literature on the neuropsychology of schizophrenia has emphasized memory deficits as a key area of impairment. Abnormalities in the medial temporal lobe, a brain region crucial for long-term memory formation, have also consistently been reported. We conducted a comprehensive review of verbal declarative memory (VDM) in schizophrenia with the aim of systematically addressing the nature of this impairment. We conclude that verbal declarative memory is significantly impaired in schizophrenia and is largely accounted for by deficits in the encoding stage. Subtle impairments in increased rates of forgetting are present, but are mild compared with those in amnestic disorders. Impairment in other cognitive domains studied thus far (e.g., attention), medication effects, or fluctuations in symptoms do not completely account for the deficit. VDM is among the most impaired neurocognitive domains in schizophrenia (along with attention and executive functions). Milder encoding deficits are present in high-risk subjects and non-psychotic relatives of individuals with schizophrenia suggesting that components of the deficit are associated with a genetic vulnerability to the illness, and are independent of the frank psychotic illness. Furthermore, VDM is observed in individuals experiencing their first-psychotic episode and it remains fairly consistent over time. Preliminary imaging studies and other work suggest abnormalities in prefrontal-hippocampal processing networks. Future work should emphasize delineating specific information processing components contributing to the deficit. This would allow imaging studies to determine which brain regions contribute to specific information processing deficits in schizophrenia.     

Behavioral phenotype of individuals with Down syndrome

Evidence is reviewed for a developmentally-emerging behavioral phenotype in individuals with Down syndrome that includes significant delay in nonverbal cognitive development accompanied by additional, specific deficits in speech, language production, and auditory short-term memory in infancy and childhood, but fewer adaptive behavior problems than individuals with other cognitive disabilities. Evidence of dementia emerges for up to half the individuals studied after age 50. Research issues affecting control group selection in establishing phenotypic characteristics are discussed, as well as the possible genetic mechanisms underlying variation in general cognitive delay, specific language impairment, and adult dementia. MRDD Research Reviews 2000;6:84-95. Wiley-Liss, Inc.     

Profile of cognitive deficits and associations with depressive symptoms and intelligence in chronic early‐onset schizophrenia patients

Cognitive deficits in several domains have been demonstrated in early‐onset schizophrenia patients but their profile and relation to depressive symptoms and intelligence need further characterization. The purpose was to characterize the profile of cognitive deficits in chronic, early‐onset schizophrenia patients, assess the potential associations with depressive symptom severity, and examine whether cognitive deficits within several domains reflect intelligence impairments. This study compared attention, visual‐construction, aspects of visual and verbal memory, and executive functions in chronic, early‐onset schizophrenia patients (mean age = 20.7 years) (N = 18) and healthy controls (N = 38). Schizophrenia diagnoses were established at the time of the patients' first clinical presentation during childhood or adolescence and were confirmed five years later. In the chronic phase of early‐onset schizophrenia, significant deficits were observed in all specific cognitive functions. The profile of cognitive deficits was jagged, and visual‐construction, attention, and one aspect of verbal memory (verbal stories recall) were differentially impaired. Deficits of visual recall, visual recognition, and executive functions were accounted for by deficits in intelligence, while this was not the case for deficits of verbal recall of stories or attention. No significant associations were observed between the severity of cognitive deficits and that of depressive symptoms. Chronic, early‐onset schizophrenia is characterized by a broad and jagged profile of cognitive deficits. Deficits of attention and verbal recall of stories appear not to be accounted for by deficits in intelligence, and the severity of cognitive deficits seems independent from that of depressive symptoms     

Oculomotor delayed response abnormalities in young offspring and siblings at risk for schizophrenia

Individuals with schizophrenia are know to demonstrate cognitive and behavioral difficulties, particularly alterations in executive functions, including working memory. It is unclear whether these deficits reflect trait-related vulnerability to schizophrenia indicators and can be assessed by studying nonpsychotic relatives of patients with schizophrenia. In this study, we used an oculomotor delayed response (ODR) paradigm to examine spatial working memory in 37 "high-risk" child and adolescent offspring and siblings (age range=6-25 years) of patients with schizophrenia or schizoaffective disorder. Compared with 37 age- and sex-matched healthy controls (age range=6-23 years), high-risk subjects showed nonsignificantly greater errors in the ODR task at longer delay intervals. Statistical analyses suggested that performance improved with age in healthy control subjects, whereas it worsened with age in high-risk subjects. In both groups, the ODR errors were generally associated with poorer sustained attention (Continuous Performance Test: visuospatial d prime), somewhat poorer executive function (Wisconsin Card Sorting Test), and elevated Heinrichs-Buchanan neurological soft signs scores. These findings indicate the presence of spatial working memory abnormalities in individuals at risk for schizophrenia. Furthermore, these abnormalities may be progressive in nature. The ODR task is a valuable indicator of prefrontal cortical function and spatial working memory and may be a potentially valuable marker for familial risk of schizophrenia.     

Cognition in schizophrenia: does working memory work?

Recent research suggests that disturbances in social and occupational functioning in individuals with schizophrenia may be more influenced by the severity of cognitive deficits than by the severity of symptoms such as hallucinations and delusions. In this article, I review evidence that one component of cognitive dysfunction in schizophrenia is a deficit in working memory, associated with disturbances in the dopamine system in dorsolateral prefrontal cortex. I suggest that although the cognitive deficits in schizophrenia include working memory dysfunction, because they arise from a disturbance in executive control processes (e.g., the representation and maintenance of context), they extend to a range of cognitive domains. Finally, I discuss the need for further research on the ways in which contextual processing deficits may influence other aspects of this illness, including emotional processing.     

Imagining the future: degraded representations of future rewards and events in schizophrenia

Over the course of life, most people work toward temporally distant rewards such as university degrees or work-related promotions. In contrast, many people with schizophrenia show deficits in behavior oriented toward long-term rewards, although they function adequately when rewards are more immediately present. Moreover, when asked about possible future events, individuals with schizophrenia show foreshortened future time perspectives relative to healthy individuals. Here, we take the view that these deficits are related and can be explained by cognitive deficits. We compared the performance of participants with schizophrenia (n = 39) and healthy participants (n = 25) on tasks measuring reward discounting and future event representations. Consistent with previous research, we found that relative to healthy participants, those with schizophrenia discounted the value of future rewards more steeply. Furthermore, when asked about future events, their responses were biased toward events in the near future, relative to healthy participants' responses. Although discounting and future representations were unrelated in healthy participants, we found significant correlations across the tasks among participants with schizophrenia, as well as correlations with cognitive variables and symptoms. Further analysis showed that statistically controlling working memory eliminated group differences in task performance. Together these results suggest that the motivational deficits characteristic of schizophrenia relate to cognitive deficits affecting the ability to represent and/or evaluate distant outcomes, a finding with important implications for promoting recovery from schizophrenia.     

Context-processing deficits in schizophrenia: converging evidence from three theoretically motivated cognitive tasks

To test the hypothesis that the ability to actively represent and maintain context information in a central function of working memory and that a disturbance in this function contributes to cognitive deficits in schizophrenia, the authors modified 3 tasks--the AX version of the Continuous Performance Test, Stroop, and a lexical disambiguation task--and administered them to patients with schizophrenia as well as to depressed and healthy controls. The results suggest an accentuation of deficits in patients with schizophrenia in context-sensitive conditions and cross-task correlations of performance in these conditions. However, the results do not definitively eliminate the possibility of a generalized deficit. The significance of these findings is discussed with regard to the specificity of deficits in schizophrenia and the hypothesis concerning the neural and cognitive mechanisms that underlie these deficits.     

Context-processing deficits in schizotypal personality disorder

Research suggests that schizotypal personality disorder (SPD) is a part of the spectrum of schizophrenia-related illnesses. This article hypothesizes that a deficit in the representation and maintenance of context is a core cognitive disturbance in schizophrenia and that SPD individuals should demonstrate context-processing deficits. To test this hypothesis, the authors administered 3 versions of their AX-CPT task, designed to assess context processing, to 35 healthy controls and 26 individuals with DSM-IV SPD. They also administered working memory and selective attention tasks. SPD individuals displayed context representation deficits similar to those found in schizophrenia but did not show the same additional deficits in context maintenance. Context processing was strongly associated with working memory and selective attention performance in the SPD individuals.     

Vulnerability of conditional NCAM-deficient mice to develop stress-induced behavioral alterations

Previous studies in rodents showed that chronic stress induces structural and functional alterations in several brain regions, including shrinkage of the hippocampus and the prefrontal cortex, which are accompanied by cognitive and emotional disturbances. Reduced expression of the neural cell adhesion molecule (NCAM) following chronic stress has been proposed to be crucially involved in neuronal retraction and behavioral alterations. Since NCAM gene polymorphisms and altered expression of alternatively spliced NCAM isoforms have been associated with bipolar depression and schizophrenia in humans, we hypothesized that reduced expression of NCAM renders individuals more vulnerable to the deleterious effects of stress on behavior. Here, we specifically questioned whether mice in which the NCAM gene is inactivated in the forebrain by cre-recombinase under the control of the calcium-calmodulin-dependent kinase II promoter (conditional NCAM-deficient mice), display increased vulnerability to stress. We assessed the evolving of depressive-like behaviors and spatial learning and memory impairments following a subchronic stress protocol (2 weeks) that does not result in behavioral dysfunction, nor in altered NCAM expression, in wild-type mice. Indeed, while no behavioral alterations were detected in wild-type littermates after subchronic stress, conditional NCAM-deficient mice showed increased immobility in the tail suspension test and deficits in reversal spatial learning in the water maze. These findings indicate that diminished NCAM expression might be a critical vulnerability factor for the development of behavioral alterations by stress and further support a functional involvement of NCAM in stress-induced cognitive and emotional disturbances.     

Working and long-term memory deficits in schizophrenia: is there a common prefrontal mechanism?

This study tested the hypothesis that dorsolateral prefrontal cortex deficits contribute to both working memory and long-term memory disturbances in schizophrenia. It also examined whether such deficits were more severe for verbal than nonverbal stimuli. Functional magnetic resonance imaging was used to assess cortical activation during performance of verbal and nonverbal versions of a working memory task and both encoding and recognition tasks in 38 individuals with schizophrenia and 48 healthy controls. Performance of both working memory and long-term memory tasks revealed disturbed dorsolateral prefrontal cortex activation in schizophrenia, although medial temporal deficits were also present. Some evidence was found for more severe cognitive and functional deficits with verbal than nonverbal stimuli, although these results were mixed.     

Turner syndrome: a review of genetic and hormonal influences on neuropsychological functioning.

Turner syndrome (TS) is a genetic disorder affecting mainly females that arises from a loss of X chromosome material, most usually one of the two X chromosomes. TS is associated with a number of characteristic physical features such as short stature and absent ovaries as well as a set of common neuropsychological deficits and social and behavioral features. This paper will serve to review the cognitive, social, and psychoeducational abilities of individuals with TS as well as neuroimaging findings. Several putative genetic mechanisms contributing to their particular neurocognitive deficits will also be described including candidate genes. In addition, the available evidence on how hormones affect specific abilities in TS will be reviewed. It will be concluded that the TS neurobehavioral profile arises from an atypical cerebral organization caused by the complex interplay of insufficient expression of certain (unknown) genes on the X chromosome and by abnormal hormonal levels; however, it is still not clear exactly how the specific genes affect broader cognitive abilities. Future research needs to identify the elemental processes that are disturbed in TS and map these both to events in early brain development and subsequent brain function and to specific gene and hormonal contributions.     

Turning it Upside Down: Areas of Preserved Cognitive Function in Schizophrenia

Patients with schizophrenia demonstrate marked impairments on most clinical neuropsychological tests. These findings suggest that patients suffer from a generalized form of cognitive impairment, with little evidence of spared performance documented in several large meta-analytic reviews of the clinical literature. In contrast, we review evidence for relative sparing of aspects of attention, procedural memory, and emotional processing observed in studies that have employed experimental approaches adapted from the cognitive and affective neuroscience literature. These islands of preserved performance suggest that the cognitive deficits in schizophrenia are not as general as they appear to be when assayed with clinical neuropsychological methods. The apparent contradiction in findings across methods may offer important clues about the nature of cognitive impairment in schizophrenia. The documentation of preserved cognitive function in schizophrenia may serve to sharpen hypotheses about the biological mechanisms that are implicated in the illness.     

Integrating working memory capacity and context-processing views of cognitive control

Individuals low in working memory capacity (WMC) exhibit impaired performance on a variety of cognitive control tasks. The executive-attention theory of WMC (Engle & Kane, 2004) accounts for these findings as failures of goal maintenance and response conflict resolution. Similarly, the context-processing view (Braver et al., 2001) provides an explanation of cognitive control deficits observed in schizophrenia patients and older adults that is based on the ability to maintain context information. Instead of maintenance deficits, the inhibition view (Hasher, Lustig, & Zacks, 2007) states that older adults and individuals low in WMC primarily have an impairment in the ability to inhibit information. In the current experiment, we explored the relationships among these theories. Individuals differing in performance on complex span measures of WMC performed the AX-Continuous Performance Test to measure context-processing performance. High-WMC individuals were predicted to maintain the context afforded by the cue, whereas low-WMC individuals were predicted to fail to maintain the context information. Low-WMC individuals made more errors on AX and BX trials and were slower to respond correctly on AX, BX, and BY trials. The overall pattern of results is most consistent with both the executive-attention and context-processing theories of cognitive control.     

Temporal discounting of rewards in patients with bipolar disorder and schizophrenia

Patients with bipolar disorder (BD) and schizophrenia (SZ) often show decision-making deficits in everyday circumstances. A failure to appropriately weigh immediate versus future consequences of choices may contribute to these deficits. We used the delay discounting task in individuals with BD or SZ to investigate their temporal decision making. Twenty-two individuals with BD, 21 individuals with SZ, and 30 healthy individuals completed the delay discounting task along with neuropsychological measures of working memory and cognitive function. Both BD and SZ groups discounted delayed rewards more steeply than did the healthy group even after controlling for current substance use, age, gender, and employment. Hierarchical multiple regression analyses showed that discounting rate was associated with both diagnostic group and working memory or intelligence scores. In each group, working memory or intelligence scores negatively correlated with discounting rate. The results suggest that (a) both BD and SZ groups value smaller, immediate rewards more than larger, delayed rewards compared with the healthy group and (b) working memory or intelligence is related to temporal decision making in individuals with BD or SZ as well as in healthy individuals.     

Validating age-related functional imaging changes in verbal working memory with acute stroke

Functional imaging studies consistently find that older adults recruit bilateral brain regions in cognitive tasks that are strongly lateralized in younger adults, a characterization known as the Hemispheric Asymmetry Reduction in Older Adults model. While functional imaging displays what brain areas are active during tasks, it cannot demonstrate what brain regions are necessary for task performance. We used behavioral data from acute stroke patients to test the hypothesis that older adults need both hemispheres for a verbal working memory task that is predominantly left-lateralized in younger adults. Right-handed younger (age ? 50, n = 7) and older adults (age > 50, n =21) with acute unilateral stroke, as well as younger (n =6) and older (n =13) transient ischemic attack (TIA) patients, performed a self-paced verbal item-recognition task. Older patients with stroke to either hemisphere had a higher frequency of deficits in the verbal working memory task compared to older TIA patients. Additionally, the deficits in older stroke patients were mainly in retrieval time while the deficits in younger stroke patients were mainly in accuracy. These data suggest that bihemispheric activity is necessary for older adults to successfully perform a verbal working memory task.     

COMT val158Met and executive control: a test of the benefit of specific deficits to translational research

The role of catechol-O-methyltransferase (COMT) val158met in prefrontal cortical deficits associated with the liability to schizophrenia remains controversial. This study evaluated 464 healthy adult participants using three measures of executive functions in working memory: a 3-back version of the N-back continuous performance task (CPT) and two variants of the AX-CPT. The interpretability of N-back performance was confounded by possible generalized deficits, whereas the AX variants included internal controls for uncovering specific deficits. There was no relationship between the COMT genotype and N-back performance, whereas val/val individuals had a specific deficit on a dot-pattern version of the AX-CPT. In this case, a specific executive function known as context processing appeared to be compromised. These data suggest that the interpretability gained by including task manipulations to uncover specific deficits can enhance associations between cognitive and genetic levels of analysis.     

Neuropsychological profiles of six children with anoxic brain injury

Anoxic brain injury (ABI) often results in severe memory impairment and other cognitive and behavioral deficits, although limited information is available regarding pediatric cases. This study reported the neuropsychological outcomes in six children and adolescents who sustained ABI. Profiles were compared by mechanism of injury (ischemic vs. hypoxemic) and three cases were evaluated more than once. Severe intellectual, attention, memory, and behavioral impairments were observed in all six cases although academic achievement, internalizing behavioral problems, and visuospatial deficits were in general less severe than other cognitive and behavioral deficits. The longitudinal case studies varied but showed steady increases in memory and intellectual performance in the younger children with strongest improvement in nonverbal abilities and little change in parent-reported behavior. This study raises several possible hypotheses about specific cognitive and behavioral outcomes observed in pediatric ABI.     

Integrating working memory capacity and context-processing views of cognitive control

Individuals low in working memory capacity (WMC) exhibit impaired performance on a variety of cognitive control tasks. The executive-attention theory of WMC (Engle & Kane, [2004[) accounts for these findings as failures of goal maintenance and response conflict resolution. Similarly, the context-processing view (Braver et al., [2001]) provides an explanation of cognitive control deficits observed in schizophrenia patients and older adults that is based on the ability to maintain context information. Instead of maintenance deficits, the inhibition view (Hasher, Lustig, & Zacks, [2007]) states that older adults and individuals low in WMC primarily have an impairment in the ability to inhibit information. In the current experiment, we explored the relationships among these theories. Individuals differing in performance on complex span measures of WMC performed the AX-Continuous Performance Test to measure context-processing performance. High-WMC individuals were predicted to maintain the context afforded by the cue, whereas low-WMC individuals were predicted to fail to maintain the context information. Low-WMC individuals made more errors on AX and BX trials and were slower to respond correctly on AX, BX, and BY trials. The overall pattern of results is most consistent with both the executive-attention and context-processing theories of cognitive control.     

Emotion-cognition interaction in people at familial high risk for schizophrenia: the impact of sex differences

Cognitive deficits are fundamental to schizophrenia, and research suggests that negative emotion abnormally interferes with certain cognitive processes in those with the illness. To a lesser extent, cognitive impairment is found in persons at risk for schizophrenia, but there is limited research on the impact of emotion on cognitive processing in at-risk groups. It is unknown whether interference of negative emotion precedes illness and contributes to vulnerability for the disorder. We studied the extent to which negative emotional information interferes with working memory in 21 adolescent and young adult first-degree relatives of people with schizophrenia and 22 community controls. Groups were comparable in age, sex, education, ethnicity, and socioeconomic status. Primary measures were n-back tasks varying in cognitive load (1-back, 2-back, 3-back) with emotional faces (neutral, happy, fearful) as stimuli. The control group's response times (RTs) and the women's RTs, regardless of group, differed depending on the emotion condition. In contrast, the RTs of the relatives and of the men, regardless of group, did not differ by emotion. This study is the first to examine emotion-cognition interactions in relatives of individuals with schizophrenia. Reduced efficiency in processing emotional information may contribute to a greater vulnerability for schizophrenia that may be heightened in men. Additional research with larger samples of men and women is needed to test these preliminary findings.     

What Do We Know About Neuropsychological Aspects Of Schizophrenia?

Application of a neuropsychological perspective to the study of schizophrenia has established a number of important facts about this disorder. Some of the key findings from the existing literature are that, while neurocognitive impairment is present in most, if not all, persons with schizophrenia, there is both substantial interpatient heterogeneity and remarkable within-patient stability of cognitive function over the long-term course of the illness. Such findings have contributed to the firm establishment of neurobiologic models of schizophrenia, and thereby help to reduce the social stigma that was sometimes associated with purely psychogenic models popular during parts of the 20th century. Neuropsychological studies in recent decades have established the primacy of cognitive functions over psychopathologic symptoms as determinants of functional capacity and independence in everyday functioning. Although the cognitive benefits of both conventional and even second generation antipsychotic medications appear marginal at best, recognition of the primacy of cognitive deficits as determinants of functional disability in schizophrenia has catalyzed recent efforts to develop targeted treatments for the cognitive deficits of this disorder. Despite these accomplishments, however, some issues remain to be resolved. Efforts to firmly establish the specific neurocognitive/neuropathologic systems responsible for schizophrenia remain elusive, as do efforts to definitively demonstrate the specific cognitive deficits underlying specific forms of functional impairment. Further progress may be fostered by recent initiatives to integrate neuropsychological studies with experimental neuroscience, perhaps leading to measures of deficits in cognitive processes more clearly associated with specific, identifiable brain systems.