Importance Neurophysiological measures of early auditory information processing (EAP) are used as endophenotypes in genomic studies and biomarkers in clinical intervention studies. Research in schizophrenia has established correlations among measures of EAP, cognition, clinical symptoms, and functional outcome. Clarifying these relationships by determining the pathways through which deficits in EAP affect functioning would suggest when and where to therapeutically intervene. Objective We sought to characterize the pathways from EAP to outcome and to estimate the extent to which enhancement of basic information processing might improve both cognition and psychosocial functioning in schizophrenia. Design Cross-sectional data were analyzed using structural equation modeling to examine the associations between EAP, cognition, negative symptoms, and functional outcome. Setting Participants were recruited from the community at five geographically distributed laboratories as part of the Consortium on the Genetics of Schizophrenia-2 (COGS-2). Participants This well-characterized cohort of schizophrenia patients (N = 1,415) underwent EAP and cognitive testing as well as thorough clinical and functional assessment. Main Outcome and Measures EAP was measured by mismatch negativity, P3a, and reorienting negativity. Cognition was measured by the Letter Number Span test and scales from the California Verbal Learning Test - Second Edition, the Wechsler Memory Scale Third Edition, and the Penn Computerized Neurocognitive Battery. Negative symptoms were measured by the Scale for the Assessment of Negative Symptoms. Functional outcome was measured by the Role Functioning Scale. Results EAP had a direct effect on cognition (β = 0.37, p < .001), cognition had a direct effect on negative symptoms (β = −0.16, p < .001), and both cognition (β = 0.26, p < .001) and experiential negative symptoms (β = −0.75, p < .001) had direct effects on functional outcome. Overall, EAP had a fully mediated effect on functional outcome, engaging general rather than modality-specific cognition, with separate pathways that either involved or bypassed negative symptoms. Conclusions and Relevance The data support a model where EAP deficits lead to poor functional outcome via impaired cognition and increased negative symptoms. Results can be used to help guide mechanistically informed, personalized treatments, and support the strategy of using EAP measures as surrogate endpoints in early stage pro-cognitive intervention studies.
Computerized cognitive training is gaining empirical support for use in the treatment of schizophrenia (SZ). Although cognitive training is efficacious for SZ at a group level when delivered in sufficiently intensive doses (eg, 30-50 h), there is variability in individual patient response. The identification of biomarkers sensitive to the neural systems engaged by cognitive training interventions early in the course of treatment could facilitate personalized assignment to treatment. This proof-of-concept study was conducted to determine whether mismatch negativity (MMN), an event-related potential index of auditory sensory discrimination associated with cognitive and psychosocial functioning, would predict gains in auditory perceptual learning and exhibit malleability after initial exposure to the early stages of auditory cognitive training in SZ. MMN was assessed in N=28 SZ patients immediately before and after completing 1 h of a speeded time-order judgment task of two successive frequency-modulated sweeps (Posit Science 'Sound Sweeps' exercise). All SZ patients exhibited the expected improvements in auditory perceptual learning over the 1 h training period (p<0.001), consistent with previous results. Larger MMN amplitudes recorded both before and after the training exercises were associated with greater gains in auditory perceptual learning (r=-0.5 and r=-0.67, respectively, p's<0.01). Significant pretraining vs posttraining MMN amplitude reduction was also observed (p<0.02). MMN is a sensitive index of the neural systems engaged in a single session of auditory cognitive training in SZ. These findings encourage future trials of MMN as a biomarker for individual assignment, prediction, and/or monitoring of patient response to procognitive interventions, including auditory cognitive training in SZ.
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