Adapting Social Neuroscience Measures for Schizophrenia Clinical Trials,Part 3: Fathoming External Validity

It is unknown whether measures adapted from social neuroscience linked to specific neural systems will demonstrate relationships to external variables. Four paradigms adapted from social neuroscience were administered to 173 clinically stable outpatients with schizophrenia to determine their relationships to functionally meaningful variables and to investigate their incremental validity beyond standard measures of social and nonsocial cognition. The 4 paradigms included 2 that assess perception of nonverbal social and action cues (basic biological motion and emotion in biological motion) and 2 that involve higher level inferences about self and others’ mental states (self- referential memory and empathic accuracy). Overall, social neuroscience paradigms showed significant relationships to functional capacity but weak relationships to community functioning; the paradigms also showed weak correlations to clinical symptoms. Evidence for incremental validity beyond standard measures of social and nonsocial cognition was mixed with additional predictive power shown for functional capacity but not community functioning. Of the newly adapted paradigms, the empathic accuracy task had the broadest external validity. These results underscore the difficulty of translating developments from neuroscience into clinically useful tasks with functional significance.Key words: schizophrenia, social cognition, social neuroscience, functional outcome     

Adapting Social Neuroscience Measures for Schizophrenia Clinical Trials,Part 2: Trolling the Depths of Psychometric Properties

The psychometric properties of 4 paradigms adapted from the social neuroscience literature were evaluated to determine their suitability for use in clinical trials of schizophrenia. This 2-site study (University of California, Los Angeles and University of North Carolina) included 173 clinically stable schizophrenia outpatients and 88 healthy controls. The social cognition battery was administered twice to the schizophrenia group (baseline, 4-week retest) and once to the control group. The 4 paradigms included 2 that assess perception of nonverbal social and action cues (basic biological motion and emotion in biological motion) and 2 that involve higher level inferences about self and others’ mental states (self-referential memory and empathic accuracy). Each paradigm was evaluated on (1) patient vs healthy control group differences, (2) test-retest reliability, (3) utility as a repeated measure, and (4) tolerability. Of the 4 paradigms, empathic accuracy demonstrated the strongest characteristics, including large between-group differences, adequate test-retest reliability (.72), negligible practice effects, and good tolerability ratings. The other paradigms showed weaker psychometric characteristics in their current forms. These findings highlight challenges in adapting social neuroscience paradigms for use in clinical trials.Key words: social neuroscience, schizophrenia, psychometrics     

Adapting Social Neuroscience Measures for Schizophrenia Clinical Trials,Part 1: Ferrying Paradigms Across Perilous Waters

Social cognitive impairment is prominent in schizophrenia, and it is closely related to functional outcome. Partly for these reasons, it has rapidly become a target for both training and psychopharmacological interventions. However, there is a paucity of reliable and valid social cognitive endpoints that can be used to evaluate treatment response in clinical trials. Also, clinical studies in schizophrenia have benefited rather little from the surge of activity and knowledge in nonclinical social neuroscience. The National Institute of Mental Health-sponsored study, “Social Cognition and Functioning in Schizophrenia” (SCAF), attempted to address this translational challenge by selecting paradigms from social neuroscience that could be adapted for use in schizophrenia. The project also evaluated the psychometric properties and external validity of the tasks to determine their suitability for multisite clinical trials. This first article in the theme section presents the goals, conceptual background, and rationale for the SCAF project.Key words: social neuroscience, social cognition, schizophrenia, clinical trials     

A Multisite,Randomized Controlled Clinical Trial of Computerized Cognitive Remediation Therapy for Schizophrenia

The effectiveness of cognitive remediation therapy (CRT) for the neuropsychological deficits seen in schizophrenia is supported by meta-analysis. However, a recent methodologically rigorous trial had negative findings. In this study, 130 chronic schizophrenic patients were randomly assigned to computerized CRT, an active computerized control condition (CC) or treatment as usual (TAU). Primary outcome measures were 2 ecologically valid batteries of executive function and memory, rated under blind conditions; other executive and memory tests and a measure of overall cognitive function were also employed. Carer ratings of executive and memory failures in daily life were obtained before and after treatment. Computerized CRT was found to produce improvement on the training tasks, but this did not transfer to gains on the primary outcome measures and most other neuropsychological tests in comparison to either CC or TAU conditions. Nor did the intervention result in benefits on carer ratings of daily life cognitive failures. According to this study, computerized CRT is not effective in schizophrenia. The use of both active and passive CCs suggests that nature of the control group is not an important factor influencing results.Key words: schizophrenia, cognition, neuropsychology, cognitive remediation     

Hierarchical Pathways from Sensory Processing to Cognitive,Clinical, and Functional Impairments in Schizophrenia

Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, “bottom-up” effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions.     

Cognitive and motor dysfunction in Parkinson's disease. Clinical, performance, and computed tomographic correlations

The neuropathologic and pathophysiological relationship of specific to more generalized cognitive dysfunction in Parkinson's disease (PD) remains incompletely understood. This issue was examined in a study of 39 patients with PD, utilizing standardized clinical measures, computerized neuropsychological tests, and quantitative computed tomography. Disorders of visuospatial discrimination and perceptual-motor function closely paralleled motor scores, suggesting a common neuropathologic basis. Caudate nuclear and mesocortical dopamine depletion play a role in this context. More generalized cognitive dysfunction occurred in older patients with a somewhat longer disease duration, more advanced parkinsonism, and computed tomographic evidence of subcortical and frontal cortical atrophy but without significant cerebral atrophy when compared with age-matched controls. Further prospective clinicopathologic studies will be required to clarify the relative contribution of the primary dopaminergic dysfunction, age-related changes, Alzheimer-type pathologic condition, and other coexisting neurotransmitter deficits to the dementia seen in PD.     

Detection and staging of dementia in Alzheimer's disease. Use of the neuropsychological measures developed for the Consortium to Establish a Registry for Alzheimer's Disease.

Our earlier studies using the Consortium to Establish a Registry of Alzheimer's Disease neuropsychological battery showed that delayed recall was a highly sensitive indicator of early Alzheimer's disease. None of the learning and memory measures in the battery were found to be useful in staging the severity of this form of dementia. This study explores the nonmemory functions (fluency, naming, and praxis) of the Consortium to Establish a Registry of Alzheimer's Disease battery and asks whether performance on any of these measures adds to the detection of early Alzheimer's disease or is sensitive to the later progression of the illness. We stratified patients with this disease according to severity (mild, moderate, severe), and compared them with age-, education-, and gender-matched control subjects (group N = 49 each). Multivariate procedures and cutting scores were used to determine the efficacy of the various measures in distinguishing between the cases and control subjects. Impairment of delayed recall was again found to be the best discriminator for detecting mild cases of Alzheimer's disease. Confrontation naming was the only nonmemory factor that assisted in this discrimination. For staging the illness, a combination of measures including fluency, praxis, and recognition memory best differentiated cases with mild dementia from those with either moderate or severe stages of disease. Measures of delayed recall quickly "bottomed out" in the patients with Alzheimer's disease and proved of little value in staging the disorder.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Cognitive Neuroscience of Psychopathy and Implications for Judgments of Responsibility

Psychopathy is a developmental disorder associated with specific forms of emotional dysfunction and an increased risk for both frustration-based reactive aggression and goal-directed instrumental antisocial behavior. While the full behavioral manifestation of the disorder is under considerable social influence, the basis of this disorder appears to be genetic. At the neural level, individuals with psychopathy show atypical responding within the amygdala and ventromedial prefrontal cortex (vmPFC). Moreover, the roles of the amygdala in stimulus-reinforcement learning and responding to emotional expressions and vmPFC in the representation of reinforcement expectancies are compromised. The implications of these functional impairments for responsibility are discussed.     

Reliability and validity of the Danish version of the Calgary Depression Scale for Schizophrenia

Depressive symptoms within the range of schizophrenic syndromes constitute a major diagnostic and therapeutic problem. Earlier research has indicated that available depression scales are not adequate when examining mood disturbances in patients with schizophrenia. We have made an attempt to estimate the reliability and validity of the Danish version of the Calgary Depression Scale for Schizophrenia. The external validity has been analysed in relation to the Major Depression Inventory (MDI). The internal validity has been analysed by using Loevinger's coefficient of homogeneity as the primary statistic. For the inter-observer reliability the intra-class coefficients have been calculated. It was shown that a subscale of the Calgary scale has sufficient reliability and validity.