Andrew Bismark

Neurophysiological Characterization of Attentional Performance Dysfunction in Schizophrenia Patients in a Reverse-Translated Task

Attentional dysfunction in schizophrenia (SZ) contributes to the functional deficits ubiquitous to the disorder. Identifying the neural substrates of translational measures of attentional dysfunction would prove invaluable for developing therapeutics. Attentional performance is typically assessed via continuous performance tasks (CPTs), though many place additional cognitive demands with little cross-species test-relevance. Herein, event-related potentials (ERPs) were used to investigate the neurophysiological correlates of attention and response inhibition of SZ and healthy participants, whereas they performed the cross-species-translated five-choice CPT (5C-CPT). Chronically ill, medicated SZ patients and matched controls (n=25 SZ and 26 controls) were tested in the 5C-CPT, in conjunction with ERP and source localization assessments. The ERPs generated in response to correctly identified target and non-target trials revealed three peaks for analysis, corresponding to sensory registration (P1), response selection (N2), and response action (P3). Behavioral responses revealed that SZ patients exhibited impaired attention driven by impaired and slower target detection, and poorer cognitive control. ERPs revealed decreased N2 amplitudes reflecting poorer response selection for both target and non-target trials, plus reduced non-target P3s in SZ patients, the latter accounting for 37% of variance in negative symptoms. Source analyses revealed that the brain regions of significant differences localized to the left dorsolateral prefrontal cortex during response selection and the posterior cingulate cortex for cognitive processes. SZ patients exhibited impaired attention and cognitive control, characterized by less robust frontal and parietal ERP distributions across the response selection and cognitive response time windows, providing neurophysiological characterization of attentional dysfunction in SZ using the reverse-translated 5C-CPT.

Evidence of systematic attenuation in the measurement of cognitive deficits in schizophrenia.

Cognitive tasks that are too hard or too easy produce imprecise measurements of ability, which, in turn, attenuates group differences and can lead to inaccurate conclusions in clinical research. We aimed to illustrate this problem using a popular experimental measure of working memory—the N-back task—and to suggest corrective strategies for measuring working memory and other cognitive deficits in schizophrenia. Samples of undergraduates (n = 42), community controls (n = 25), outpatients with schizophrenia (n = 33), and inpatients with schizophrenia (n = 17) completed the N-back. Predictors of task difficulty—including load, number of word syllables, and presentation time—were experimentally manipulated. Using a methodology that combined techniques from signal detection theory and item response theory, we examined predictors of difficulty and precision on the N-back task. Load and item type were the 2 strongest predictors of difficulty. Measurement precision was associated with ability, and ability varied by group; as a result, patients were measured more precisely than controls. Although difficulty was well matched to the ability levels of impaired examinees, most task conditions were too easy for nonimpaired participants. In a simulation study, N-back tasks primarily consisting of 1- and 2-back load conditions were unreliable, and attenuated effect size (Cohen’s d) by as much as 50%. The results suggest that N-back tasks, as commonly designed, may underestimate patients’ cognitive deficits as a result of nonoptimized measurement properties. Overall, this cautionary study provides a template for identifying and correcting measurement problems in clinical studies of abnormal cognition.

Reverse translated and gold standard continuous performance tests predict global cognitive performance in schizophrenia

Attentional dysfunction contributes to functional impairments in schizophrenia (SZ). Sustained attention is typically assessed via continuous performance tasks (CPTs), though many CPTs have limited cross-species translational validity and place demands on additional cognitive domains. A reverse-translated 5-Choice Continuous Performance Task (5C-CPT) for human testing—originally developed for use in rodents—was designed to minimize demands on perceptual, visual learning, processing speed, or working memory functions. To-date, no studies have validated the 5C-CPT against gold standard attentional measures nor evaluated how 5C-CPT scores relate to cognition in SZ. Here we examined the relationship between the 5C-CPT and the CPT-Identical Pairs (CPT-IP), an established and psychometrically robust measure of vigilance from the MATRICS Consensus Cognitive Battery (MCCB) in a sample of SZ patients (n = 35). Relationships to global and individual subdomains of cognition were also assessed. 5C-CPT and CPT-IP measures of performance (d-prime) were strongly correlated (r = 0.60). In a regression model, the 5C-CPT and CPT-IP collectively accounted for 54% of the total variance in MCCB total scores, and 27.6% of overall cognitive variance was shared between the 5C-CPT and CPT-IP. These results indicate that the reverse translated 5C-CPT and the gold standard CPT-IP index a common attentional construct that also significantly overlaps with variance in general cognitive performance. The use of simple, cross-species validated behavioral indices of attentional/cognitive functioning such as the 5C-CPT could accelerate the development of novel generalized pro-cognitive therapeutics for SZ and related neuropsychiatric disorders.

Targeted cognitive training improves auditory and verbal outcomes among treatment refractory schizophrenia patients mandated to residential care

Computerized targeted cognitive training (TCT) of auditory processing has been shown to improve verbal learning in several clinical trials of schizophrenia outpatients. Less is known, however, about the effectiveness of this promising intervention in more chronic, treatment-refractory patients who are treated in non-academic settings. This study aimed to determine whether TCT improves auditory processing, verbal learning, and clinical symptoms in SZ patients mandated to receive care at a locked residential rehabilitation center. Secondarily, potential factors that moderate TCTs effectiveness including age, symptom severity, antipsychotic medication load, and duration of illness were examined. Schizophrenia patients were randomized to treatment as usual (TAU; n = 22) or TAU augmented with TCT (TAU + TCT; n = 24). Outcomes included a measure of auditory perception (Word-In-Noise test, WIN), verbal learning domain scores from the MATRICS Consensus Cognitive Battery (MCCB), and clinical symptoms (Scale for the Assessment of Positive Symptoms, SAPS; Scale for the Assessment of Negative Symptoms, SANS). TCT produced significant improvements in auditory perception (d = 0.67) and verbal learning (d = 0.65); exploratory analyses revealed a statistically significant reduction in auditory hallucinations (d = -0.64). TCTs effects were only weakly, and mostly non-significantly, moderated by age, clinical symptoms, medication, and illness duration. These findings indicate that even highly symptomatic, functionally disabled patients with chronic illness benefit from this emerging treatment. Ongoing studies will examine the predictive utility of neurophysiological biomarkers and other characteristics assessed at baseline.