Deficits in generalized cognitive ability, visual sensorimotor function, and inhibitory control represent discrete domains of neurobehavioral deficit in psychotic disorders.

Psychotic disorders are characterized by impaired cognition, yet some reports indicate specific deficits extend beyond reduced general cognitive ability. This study utilized exploratory and confirmatory factor analytic methods to evaluate the latent structure of a broad neurocognitive battery used in the Bipolar-Schizophrenia Network of Intermediate Phenotypes (B-SNIP) study, which included neuropsychological and neurophysiological measures in psychotic disorder probands and their unaffected first-degree relatives. Findings indicate that the factor structure of data from this set of assessments is more complex than the unitary factor of global cognitive ability underlying the Brief Assessment of Cognition in Schizophrenia (BACS). In addition to assessing generalized cognitive ability, two other factors were identified: visual sensorimotor function and inhibitory behavioral control. This complex cognitive architecture, derived in controls, generalized to patients across the psychosis spectrum and to their unaffected relatives. These findings highlight the need for a more differentiated assessment of neurobehavioral functions in studies designed to test for diagnostically specific biomarkers, endophenotypes for gene discovery and beneficial effects of therapeutics on cognitive function.

Contextualizing the road to recovery: A novel method of assessing outcome trajectories in clinical trials.

In clinical trials, standardized assessment conducted by research staff facilitates identification of treatment benefit. Narrative notes completed by clinicians offer a novel source to characterize and contextualize outcomes. In this study, we examine qualitative analysis of clinical notes as a method to augment quantitative outcome measures and supply meaningful context in clinical trials. Two hundred eighty-four clinical progress notes from 19 participants with schizophrenia or schizoaffective disorder assigned to receive either auditory-targeted cognitive training or treatment as usual were included. Qualitative analysis of weekly progress notes written by clinicians involved in ongoing care of the participants was used to identify overall outcome trajectories and specific changes in program participation, social functioning, and symptom severity. Trajectories were compared with the parent study's 2 primary outcome measures. Qualitative analysis identified personalized and complex trajectories for individual participants. Approximately half the participants improved overall. Most participants displayed improved program participation and social functioning, whereas most participants experienced symptom deterioration. Engagement in targeted cognitive training did not impact change in trajectories. Qualitative trajectories were congruent (e.g., both indicated improvement) with the 2 primary outcome measures for 26-36% of the participants depending on the comparison. Including qualitative analysis of clinician progress notes provides useful context and identifies underlying processes not captured in quantitative data. However, they cannot replace quantitative outcome measurement. Better alignment with clinician- and patient-targeted outcomes may strengthen clinical trials. Qualitative analysis of routinely collected data can benefit research and programmatic decision making in usual care settings. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Gamma oscillations predict pro-cognitive and clinical response to auditory-based cognitive training in schizophrenia.

Cognitive impairments are pervasive and disabling features of schizophrenia. Targeted cognitive training (TCT) is a "bottom-up" cognitive remediation intervention with efficacy for neurocognitive outcomes in schizophrenia, yet individual responses are variable. Gamma oscillatory measures are leading candidate biomarkers in the development of biologically informed pro-cognitive therapeutics. Forty-two schizophrenia patients were recruited from a long-term residential treatment facility. Participants were randomized to receive either 1 h of cognitive training (TCT, n = 21) or computer games (TAU, n = 21). All participants received standard-of-care treatment; the TCT group additionally completed 30 h of cognitive training. The auditory steady-state response paradigm was used to elicit gamma oscillatory power and synchrony during electroencephalogram recordings. Detailed clinical and cognitive assessments were collected at baseline and after completion of the study. Baseline gamma power predicted cognitive gains after a full course of TCT (MCCB, R2 = 0.31). A change in gamma power after 1-h TCT exposure predicted improvement in both positive (SAPS, R2 = 0.40) and negative (SANS, R2 = 0.30) symptoms. These relationships were not observed in the TAU group (MCCB, SAPS, and SANS, all R2 < 0.06). The results indicate that the capacity to support gamma oscillations, as well as the plasticity of the underlying ASSR circuitry after acute exposure to 1 h of TCT, reflect neural mechanisms underlying the efficacy of TCT, and may be used to predict individualized treatment outcomes. These findings suggest that gamma oscillatory biomarkers applied within the context of experimental medicine designs can be used to personalize individual treatment options for pro-cognitive interventions in patients with schizophrenia.

Catechol-O-methyltransferase genotype differentially contributes to the flexibility and stability of cognitive sets in patients with psychotic disorders and their first-degree relatives.

Dopaminergic activity in prefrontal cortex is modulated by the low (Met) and high (Val) activity of the rs4680 Val158Met single nucleotide polymorphism (SNP) in the Catechol-O-Methyltransferase (COMT) gene. While this has been related to working memory maintenance in patients with schizophrenia, the familial pattern, impact across the psychosis spectrum, and the role of this genotype on other aspects of behavior, such as cognitive flexibility, remains unclear. The relationship between COMT Val158Met genotype and both cognitive stability and flexibility were assessed using the Penn Conditional Exclusion Test (PCET) in healthy controls (n = 241), patients with psychotic disorders (n = 542), and their first-degree relatives (n = 613) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Higher rates of perseverative errors (poor flexibility) were associated with the low-activity COMT genotype (Met allele carriers) in probands compared to their first-degree relatives with the same genotype. Probands and first-degree relatives homozygous for the high-activity COMT enzyme (Val/Val) showed elevated rates of regressive errors (poor stability) compared to controls. Conversely, heterozygous relatives had comparable regressive error rates to controls, with probands showing elevated errors in comparison. These findings suggest that impaired suppression of learned response patterns and reduced stability of mental sets may be a familial intermediate cognitive phenotype related to Val COMT allele genotype.

Oscillatory biomarkers of early auditory information processing predict cognitive gains following targeted cognitive training in schizophrenia patients.

Auditory-based targeted cognitive training (TCT) is an effective and well-validated intervention for the treatment of cognitive impairment in schizophrenia patients. Improvements in higher-order cognition, reductions in symptom severity, and increases in psychosocial functioning secondary to TCT are thought to be driven by "bottom-up" enhancement of early auditory information processing (EAIP). Despite strong evidence of efficacy at the group level, there is significant variability in response to TCT, with few well-delineated biomarkers for predicting individual benefit. EEG biomarkers of EAIP are indicators of early-treatment sensitivity that predict full-course TCT outcome; however, further characterization is necessary for biomarker-guided clinical trials. The current study examined baseline and early-treatment sensitivity (i.e., change from baseline after 1 h) in theta band oscillatory activity to deviant stimuli as moderators of full course (30 h) TCT response in treatment-refractory schizophrenia patients randomly assigned to receive either treatment-as-usual (TAU; n = 22) or TAU augmented with TCT (n = 30). Theta evoked power and phase locking at baseline predicted patient improvements in global cognitive function after 30 h of TCT. Decrease in theta activity to deviant stimuli after 1 h of TCT predicted improvements in verbal learning after 30 h. Exploratory analyses using EEG composite scores had high levels of sensitivity and specificity for identifying patients most likely to benefit from TCT. The integrity of baseline neurophysiologic activity associated with EAIP, as well as the sensitivity of the underlying circuity to change, likely reflects an intermediate therapeutic process underlying the effectiveness of TCT that can be used to predict patient response to treatment.

Verbal learning deficits associated with increased anticholinergic burden are attenuated with targeted cognitive training in treatment refractory schizophrenia patients.

Targeted cognitive training (TCT) has been reported to improve verbal learning deficits in patients with schizophrenia (SZ). Despite positive findings, it is not clear whether demographic factors and clinical characteristics contribute to the success of TCT on an individual basis. Medication-associated anticholinergic burden has been shown to impact TCT-associated verbal learning gains in SZ outpatients, but the role of anticholinergic medication burden on TCT gains in treatment refractory SZ patients has not been described. In this study, SZ patients mandated to a locked residential rehabilitation center were randomized to treatment as usual (TAU; n=22) or a course of TAU augmented with TCT (n=24). Anticholinergic medication burden was calculated from medication data at baseline and follow-up using the Anticholinergic Cognitive Burden (ACB) Scale. MATRICS Consensus Cognitive Battery Verbal Learning domain scores were used as the primary outcome variable. The TAU and TCT groups were matched in ACB at baseline and follow-up. While baseline ACB was not associated with verbal learning in either group, increases in ACB over the course of the study were significantly associated with deterioration of verbal learning in the TAU group (r=-0.51, p=0.02). This was not seen in subjects randomized to TCT (r=-0.13, p=0.62). Our results suggest that TCT may blunt anticholinergic medication burden associated reduction in verbal learning in severely disabled SZ inpatients.

Divergence of subjective and performance-based cognitive gains following cognitive training in schizophrenia.

BACKGROUND: Cognitive training is effective for improving cognitive performance among people with schizophrenia. An individual's perception of their own cognition is dissociable from performance on objective cognitive tests. Since subjective cognitive benefit may impact engagement, motivation, and satisfaction with time-intensive cognitive interventions, this study aimed to determine whether subjective cognitive difficulties improve in conjunction with cognitive gains following 30 h of cognitive training. METHODS: Patients with schizophrenia or schizoaffective disorder (N = 46) were randomized to treatment as usual (TAU) or TAU augmented with auditory-targeted cognitive training (TCT). All participants completed assessment batteries at baseline and follow-up. As previously reported, the TCT group showed significant improvements in verbal learning and memory and reductions in auditory hallucinations relative to the TAU group. RESULTS: Subjective cognitive difficulties did not significantly improve following TCT, even among TCT participants who showed improvements in cognitive performance (all ps > 0.05). Subjective cognitive difficulties were significantly associated with severity of depressive symptoms and hallucinations (r = 0.48 and r = 0.28, p < 0.001), but not global or specific domains of cognition (all rs < 0.1) at baseline. There were no significant relationships between change in subjective cognitive difficulties and change in cognitive or clinical variables (all ps > 0.05). DISCUSSION: Patients with schizophrenia do not detect change in their cognition following cognitive training, even among those who showed robust gains in cognitive performance. Failure to detect improvement may undermine treatment engagement, motivation, and satisfaction. Translating score improvements on the cognitive exercises into tangible metrics, and providing ongoing, clinician-delivered feedback on performance may facilitate patient ability to detect improvements and improve motivation to engage with cognitive training interventions.

Neurophysiologic measures of target engagement predict response to auditory-based cognitive training in treatment refractory schizophrenia.

Cognitive impairment is a core feature of schizophrenia and a strong predictor of psychosocial disability. Auditory-based targeted cognitive training (TCT) aims to enhance verbal learning and other domains of cognitive functioning through "bottom-up" tuning of the neural systems underlying early auditory information processing (EAIP). Although TCT has demonstrated efficacy at the group level, individual response to TCT varies considerably, with nearly half of patients showing little-to-no benefit. EEG measures of EAIP, mismatch negativity (MMN) and P3a, are sensitive to the neural systems engaged by TCT exercises and might therefore predict clinical outcomes after a full course of treatment. This study aimed to determine whether initial malleability of MMN and P3a to 1-h of auditory-based TCT predicts improvements in verbal learning and clinical symptom reduction following a full (30-h) course of TCT. Treatment refractory patients diagnosed with schizophrenia were randomly assigned to receive treatment-as-usual (TAU; n = 22) or TAU augmented with TCT (n = 23). Results indicated that malleability (i.e., change from baseline after the initial 1-h dose of TCT) of MMN and P3a predicted improvements in verbal learning as well as decreases in the severity of positive symptoms. Examination of MMN and P3a malleability in patients after their first dose of TCT can be used to predict clinical response to a full course of treatment and shows promise for future biomarker-informed treatment assignment.

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 TCT's 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). TCT's 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.

P3 amplitude attenuation secondary to increases in target-to-target interval (TTI) during spatial serial order recall: implications for EEG models of working memory function.

Research suggests that increasing delays in stimulus read-out can trigger declines in serial order recall accuracy due to increases in cognitive demand imposed by the delay; however, the exact neural mechanisms associated with this decline are unclear. Changes in neural resource allocation present as the ideal target and can easily be monitored by examining changes in the amplitude of an ERP component known as the P3. Changes in P3 amplitude secondary to exogenous pacing of stimulus read-out via increased target-to-target intervals (TTIs) during recall could reflect decreased neural resource allocation due to increased cognitive demand. This shift in resource allocation could result in working memory storage decay and the declines in serial order accuracy described by prior research. In order to examine this potential effect, participants were administered a spatial serial order processing task, with the recall series consisting of a series of correct ('match') or incorrect ('non-match' or 'oddball') stimuli. Moreover, the recall series included either a brief (500 ms) or extended (2000 ms) delay between stimuli. Results were significant for the presence of a P3 response to non-match stimuli for both experimental conditions, and attenuation of P3 amplitude secondary to the increase in TTI. These findings suggest that extending the delay between target recognition could increase cognitive demand and trigger a decrease in neural resource allocation that results in a decay of working memory stores.

Sequential processing deficits in schizophrenia: relationship to neuropsychology and genetics.

Utilizing a combination of neuropsychological and cognitive neuroscience approaches may be essential for characterizing cognitive deficits in schizophrenia and eventually assessing cognitive outcomes. This study was designed to compare the stability of select exemplars for these approaches and their correlations in schizophrenia patients with stable treatment and clinical profiles. Reliability estimates for serial order processing were comparable to neuropsychological measures and indicate that experimental serial order processing measures may be less susceptible to practice effects than traditional neuropsychological measures. Correlations were moderate and consistent with a global cognitive factor. Exploratory analyses indicated a potentially critical role of the Met allele of the Catechol-O-methyltransferase (COMT) Val158Met polymorphism in externally paced sequential recall. Experimental measures of serial order processing may reflect frontostriatal dysfunction and be a useful supplement to large neuropsychological batteries.