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

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Abstract

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.

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The mismatch negativity (MMN) in basic research of central auditory processing: a review.

R Näätänen, P Paavilainen, T Rinne … (2007)

In the present article, the basic research using the mismatch negativity (MMN) and analogous results obtained by using the magnetoencephalography (MEG) and other brain-imaging technologies is reviewed. This response is elicited by any discriminable change in auditory stimulation but recent studies extended the notion of the MMN even to higher-order cognitive processes such as those involving grammar and semantic meaning. Moreover, MMN data also show the presence of automatic intelligent processes such as stimulus anticipation at the level of auditory cortex. In addition, the MMN enables one to establish the brain processes underlying the initiation of attention switch to, conscious perception of, sound change in an unattended stimulus stream.

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The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity.

Keith Nuechterlein, Michael Green, Robert Kern … (2008)

The lack of an accepted standard for measuring cognitive change in schizophrenia has been a major obstacle to regulatory approval of cognition-enhancing treatments. A primary mandate of the National Institute of Mental Health's Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was to develop a consensus cognitive battery for clinical trials of cognition-enhancing treatments for schizophrenia through a broadly based scientific evaluation of measures. The MATRICS Neurocognition Committee evaluated more than 90 tests in seven cognitive domains to identify the 36 most promising measures. A separate expert panel evaluated the degree to which each test met specific selection criteria. Twenty tests were selected as a beta battery. The beta battery was administered to 176 individuals with schizophrenia and readministered to 167 of them 4 weeks later so that the 20 tests could be compared directly. The expert panel ratings are presented for the initially selected 36 tests. For the beta battery tests, data on test-retest reliability, practice effects, relationships to functional status, practicality, and tolerability are presented. Based on these data, 10 tests were selected to represent seven cognitive domains in the MATRICS Consensus Cognitive Battery. The structured consensus method was a feasible and fair mechanism for choosing candidate tests, and direct comparison of beta battery tests in a common sample allowed selection of a final consensus battery. The MATRICS Consensus Cognitive Battery is expected to be the standard tool for assessing cognitive change in clinical trials of cognition-enhancing drugs for schizophrenia. It may also aid evaluation of cognitive remediation strategies.

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A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes.

Til Wykes, Vyv Huddy, Caroline Cellard … (2011)

Cognitive remediation therapy for schizophrenia was developed to treat cognitive problems that affect functioning, but the treatment effects may depend on the type of trial methodology adopted. The present meta-analysis will determine the effects of treatment and whether study method or potential moderators influence the estimates. Electronic databases were searched up to June 2009 using variants of the key words "cognitive," "training," "remediation," "clinical trial," and "schizophrenia." Key researchers were contacted to ensure that all studies meeting the criteria were included. This produced 109 reports of 40 studies in which ≥70% of participants had a diagnosis of schizophrenia, all of whom received standard care. There was a comparison group and allocation procedure in these studies. Data were available to calculate effect sizes on cognition and/or functioning. Data were independently extracted by two reviewers with excellent reliability. Methodological moderators were extracted through the Clinical Trials Assessment Measure and verified by authors in 94% of cases. The meta-analysis (2,104 participants) yielded durable effects on global cognition and functioning. The symptom effect was small and disappeared at follow-up assessment. No treatment element (remediation approach, duration, computer use, etc.) was associated with cognitive outcome. Cognitive remediation therapy was more effective when patients were clinically stable. Significantly stronger effects on functioning were found when cognitive remediation therapy was provided together with other psychiatric rehabilitation, and a much larger effect was present when a strategic approach was adopted together with adjunctive rehabilitation. Despite variability in methodological rigor, this did not moderate any of the therapy effects, and even in the most rigorous studies there were similar small-to-moderate effects. Cognitive remediation benefits people with schizophrenia, and when combined with psychiatric rehabilitation, this benefit generalizes to functioning, relative to rehabilitation alone. These benefits cannot be attributed to poor study methods.