Dawn I. Velligan

Beyond hypofrontality: A quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia

Although there is considerable evidence that patients with schizophrenia fail to activate the dorsolateral prefrontal cortex (DLPFC) to the degree seen in normal comparison subjects when performing working memory or executive tasks, hypofrontality may be coupled with relatively increased activity in other brain regions. However, most imaging studies of working memory in schizophrenia have focused on DLPFC activity. The goal of this work is to review functional neuroimaging studies that contrasted patients with schizophrenia and healthy comparison subjects during a prototypical working memory task, the n‐back paradigm, to highlight areas of hyper‐ and hypoactivation in schizophrenia. We utilize a quantitative meta‐analysis method to review 12 imaging studies where patients with schizophrenia were contrasted with healthy comparison subjects while performing the n‐back paradigm. Although we find clear support for hypofrontality, we also document consistently increased activation in anterior cingulate and left frontal pole regions in patients with schizophrenia compared to that in controls. These data suggest that whereas reduced DLPFC activation is reported consistently in patients with schizophrenia relative to healthy subjects, abnormal activation patterns are not restricted to this region, raising questions as to whether the pathophysiological dysfunction in schizophrenia is specific to the DLPFC and about the relationship between impaired performance and aberrant activation patterns. The complex pattern of hyper‐ and hypoactivation consistently found across studies implies that rather than focusing on DLPFC dysregulation, researchers should consider the entire network of regions involved in a given task when making inferences about the biological mechanisms of schizophrenia. Hum Brain Mapp 25:60–69, 2005.

The functional significance of symptomatology and cognitive function in schizophrenia

The relationships between positive and negative symptomatology, cognitive function, and the ability to perform basic activities of daily living in patients with schizophrenia were examined in two studies. In study 1, 112 medicated patients were assessed utilizing the Brief Psychiatric Rating Scale (positive symptoms), the Negative Symptom Assessment (negative symptoms and cognitive function), and the Functional Needs Assessment (activities of daily living). Study 2 (n = 41), utilized the same measures of symptomatology and added a comprehensive neuropsychological test battery. Regression analyses in both studies determined that symptomatology predicts a relatively small amount of the variance in the ability to perform basic activities of daily living. Cognitive function, whether assessed with the Cognition subscale of the Negative Symptom Assessment or a comprehensive neuropsychological test battery, predicted over 40% of the variance in scores on the Functional Needs Assessment. A path model in which cognition predicted both concurrent symptomatology and activities of daily living and where symptomatology had little direct impact upon activities of daily living fit the data. The importance of addressing cognitive deficits in psychosocial intervention programs is discussed.

The expert consensus guideline series

Abstract Over the past decade, many new epilepsy treatments have been approved in the United States, promising better quality of life for many with epilepsy. However, clinicians must now choose among a growing number of treatment options and possible combinations. Randomized clinical trials (RCTs) form the basis for evidence-based decision making about best treatment options, but they rarely compare active therapies, making decisions difficult. When medical literature is lacking, expert opinion is helpful, but may contain potential biases. The expert consensus method is a new approach for statistically analyzing pooled opinion to minimize biases inherent in other systems of summarizing expert opinion. We used this method to analyze expert opinion on treatment of three epilepsy syndromes (idiopathic generalized epilepsy, symptomatic localization-related epilepsy, and symptomatic generalized epilepsy) and status epilepticus. For all three syndromes, the experts recommended the same general treatment strategy. As a first step, they recommend monotherapy. If this fails, a second monotherapy should be tried. Following this, the experts are split between additional trials of monotherapy and a combination of two therapies. If this fails, most agree the next step should be additional trials of two therapies, with less agreement as to the next best step after this. One exception to these recommendations is that the experts recommend an evaluation for epilepsy surgery after the third failed step for symptomatic localization-related epilepsies. The results of the expert survey were used to develop user-friendly treatment guidelines concerning overall treatment strategies and choice of specific medications for different syndromes and for status epilepticus.

Do specific neurocognitive deficits predict specific domains of community function in schizophrenia

We examined whether specific neurocognitive deficits predicted specific domains of community outcome in 40 schizophrenic patients. Neuropsychological assessments were conducted before hospital discharge, and measures of functional outcome were obtained 1 to 3.5 years later. A priori hypotheses were generated based upon a recent review by Green (Green MF [1996] What are the functional consequences of neurocognitive deficits in schizophrenia? American Journal of Psychiatry, 153(3):321-330). As hypothesized, verbal memory predicted all measures of community outcome, vigilance predicted social outcomes, and executive functioning predicted work and activities of daily living (ADLs). However, in addition to the predicted relationships, many other associations were found between neuropsychological test scores and adaptive function. Furthermore, both cognitive and functional measures were intercorrelated. If deficits in adaptive functioning are neurocognitively multi-determined, utilizing compensatory strategies to bypass multiple areas of cognitive impairment may be more efficient than cognitive remediation in improving community outcomes.

The neurocognitive signature of psychotic bipolar disorder.

BACKGROUND Psychotic bipolar disorder may represent a neurobiologically distinct subgroup of bipolar affective illness. We sought to ascertain the profile of cognitive impairment in patients with bipolar disorder and to determine whether a distinct profile of cognitive deficits characterizes bipolar patients with a history of psychosis. METHODS Sixty-nine outpatients with bipolar I disorder (34 with a history of psychotic symptoms and 35 with no history of psychosis) and 35 healthy comparison subjects underwent a comprehensive neurocognitive battery. All three groups were demographically matched. RESULTS Despite preserved general intellectual function, bipolar I patients overall showed moderate impairments on tests of episodic memory and specific executive measures (average effect size = .58), and moderate to severe deficits on attentional and processing speed tasks (average effect size = .82). Bipolar I patients with a history of psychosis were impaired on measures of executive functioning and spatial working memory compared with bipolar patients without history of psychosis. CONCLUSIONS Psychotic bipolar disorder was associated with differential impairment on tasks requiring frontal/executive processing, suggesting that psychotic symptoms may have neural correlates that are at least partially independent of those associated with bipolar I disorder more generally. However, deficits in attention, psychomotor speed, and memory appear to be part of the broader disease phenotype in patients with bipolar disorder.

Does cognitive function improve with quetiapine in comparison to haloperidol

Recent evidence suggests that schizophrenia patients taking atypical antipsychotic medications may perform better on some tests of cognitive function than those treated with older antipsychotics. The current study compared the effects of quetiapine and haloperidol on measures of executive function, memory and attention. Subjects were 58 stable outpatients with schizophrenia (DSM III-R) who received a battery of cognitive tests as part of a randomized, double-blind, multi-site clinical efficacy study conducted by AstraZeneca Pharmaceuticals. Cognitive assessments were conducted prior to randomization when patients were receiving < or =30 mg haloperidol or equivalent (mean: 9.2mg/day haloperidol equivalents), and again after 24 weeks of fixed-dose treatment with either quetiapine 600 or 300 mg/day or haloperidol 12 mg/day. Analyses of covariance with planned comparisons were used to compare scores on cognitive measures at the end of 24 weeks by treatment group with baseline cognitive function scores used as covariates. Patients receiving quetiapine 600 mg/day improved to a greater extent than patients receiving haloperidol on overall cognitive function (p<0.02). Specific differences were found for executive function (Verbal Fluency Test, p<0.04), attention (Stroop Color Word Test, p<.03) and verbal memory (Paragraph Recall Test, p<0.02). Treatment group differences were not solely due to benztropine use, medication side effects, or changes in symptomatology. Treatment with quetiapine at higher doses (600 mg/day) relative to haloperidol appears to have a positive impact on important domains of cognitive performance that have been found to predict role function and community outcomes in patients with schizophrenia.

Executive-frontal lobe cognitive dysfunction in schizophrenia: A symptom subtype analysis

Impairment of executive-frontal lobe functioning, affecting the planning, initiation and regulation of goal-directed behavior, is a common cognitive deficit in schizophrenia. However, it is unclear if deficits in these frontal-lobe-mediated abilities are differentially expressed across clinical subgroups. We analyzed executive-frontal abilities in relation to symptom expression in 53 hospitalized schizophrenic patients. Patients were assigned to one of three subgroups based on rank order analysis of Brief Psychiatric Rating Scale factors: Withdrawal-Retardation, Reality Distortion and Conceptual Disorganization. Executive-frontal tests included Visual Search, Verbal Fluency, Verbal Series Attention, Trail Making - Part B, Symbol Digit, Hopkins Verbal Learning, Digit Span, Wisconsin Card Sorting, Stroop Color-Word and Attentional Capacity. The schizophrenia group showed significant deficits relative to healthy control subjects (n = 20) on all tests. Exploratory factor analysis of test scores revealed three factors: (i) Verbal Processing/Memory; (ii) Cognitive Flexibility/Attention; and (iii) Psychomotor Speed/Visual Scanning. The three symptom subgroups were differentially impaired on executive-frontal abilities: Withdrawal-Retardation on psychomotor speed, verbal fluency, working memory, visual search and cognitive flexibility; Conceptual Disorganization on attention; Reality Distortion on verbal memory. The results have implications for syndrome definition, pharmacological intervention and prediction of outcome in schizophrenia.

Executive function in schizophrenia.

Many domains of executive function are impaired in patients with schizophrenia including forward planning, concept formation, initiation, self-monitoring, and the ability to direct attention and memory. These impairments are noticeable against a background of generalized cognitive deficits, and many affect 40% to 95% of individuals with this disorder. Specific executive deficits appear to be related to specific symptom clusters and are linked to structural and functional brain abnormalities. Executive impairment predicts multiple domains of functional outcome in schizophrenia patients. Atypical antipsychotic agents and cognitive rehabilitation may be promising new approaches for the treatment of cognitive and functional impairment in schizophrenia.

Predicting quality of life from symptomatology in schizophrenia at exacerbation and stabilization

There has been little research investigating how symptoms of schizophrenia and changes in symptomatology across the course of the illness relate to measures of quality of life in patients. We examined this issue in 45 patients assessed at hospital admission for illness exacerbation, at stabilization (prior to discharge) and at follow-up (5-9 months post-discharge). Symptom ratings at each time period consisted of the Brief Psychiatric Rating Scale (BPRS) and the Negative Symptom Assessment (NSA). The Heinrichs-Carpenter Quality of Life Scale (QLS) was administered upon admission to the hospital (assessing the 3 months prior to admission) and again at follow-up. Correlational analyses revealed relationships of both positive and negative symptoms with quality of life. These relationships are particularly strong at stabilization. Stepwise regression analyses revealed changes in the NSA motivation component to be most important in predicting quality of life for the patients at follow-up. BPRS psychosis and paranoia components are important predictors of quality of life at stabilization (but not during acute exacerbation). These results are important in terms of understanding the impact of changes in symptomatology on the quality of life for patients with schizophrenia as well as in targeting specific symptom clusters for treatment to maximize quality of life post-hospitalization.

Frontal Systems Behavior Scale in schizophrenia: relationships with psychiatric symptomatology, cognition and adaptive function.

Schizophrenia patients often exhibit impairments in executive functioning on formal testing and exhibit behaviors consistent with executive/frontal impairment in daily life. The Frontal Systems Behavior Scale (FrSBe) assesses behaviors associated with frontal lobe damage including executive dysfunction, apathy and disinhibition. We examined the reliability and validity of the FrSBe in 131 schizophrenia outpatients. Subjects were rated on the FrSBe and received symptom, cognitive and functional assessments. Statistical tests were corrected for multiple comparisons. The FrSBe was found to have good internal consistency and test-retest reliability. All three dimensions of the FrSBe (i.e. executive dysfunction, apathy and disinhibition) were significantly correlated with poor adaptive functioning as measured by the Social and Occupational Functioning Scale and the Functional Needs Assessment. In addition, differential relationships were found for apathy and disinhibition with symptoms as rated from the Brief Psychiatric Rating Scale and with cognitive variables including Trails B and verbal fluency scores. A multivariate analysis of variance examined differences on the FrSBe between patients and a group of 51 education-matched controls. Patients had significantly greater impairment on the FrSBe than controls. These differences were found for all FrSBe subscales. Results support the use of the FrSBe to characterize goal-directed behavior in schizophrenia patients.