Efficacy of Personalizing Cognitive Remediation for Schizophrenia by Targeting Impairments in Early Auditory Processing

Schizophrenia is associated with cognitive deficits that negatively impact daily functioning. Interventions that improve cognitive functioning in schizophrenia are critical to limit long-term disability. Cognitive remediation (CR) for schizophrenia has low moderate effect sizes on cognitive and functional outcomes, but therapeutic responses to CR are heterogeneous. Prospective identification of treatment-responsive individuals and individualized treatment approaches remains an unmet challenge. Our preliminary studies using personalized CR approaches for schizophrenia indicate that baseline early auditory processing (EAP), which is impaired in about half of people with schizophrenia, is a good neurobehavioral marker for informing treatment strategy. We found that people with baseline impaired EAP improve significantly more on cognitive outcomes when CR includes EAP training, and this facilitates larger functional gain. However, there is no added benefit to giving this training to people with baseline intact EAP. Subgroup specificity of therapeutic mechanism is suggested by the positive association of auditory processing gain with cognitive improvement among EAP impaired versus the negative or non-significant association among those who are EAP intact. These findings support the importance of addressing basic auditory processing deficits when attempting to remediate higher order auditory impairments such as verbal learning. In addition, they highlight the need for routine assessment of EAP in CR participants, so treatment can be personalized. Pilot data from an ongoing center grant project indicates that clinicians are able to assess EAP status and use it to personalize treatment to either include or exclude EAP training. Thus it is feasible to implement this kind of personalized CR in public clinic settings. The proposed study uses a treatment controlled randomized design, first stratifying subjects by EAP status and then randomizing to EAP enhanced CR, regular CR, or treatment as usual. The study will be conducted in community clinics using the infrastructure of the ongoing center grant CR project. Cognition will be the primary outcome with functional capacity the secondary outcome. Mobile EEG administered to CR participants will examine neurophysiologic markers of need for and response to EAP training. Mediation analysis will examine whether gains in cognition mediate the relationship between gains in EAP and functional outcome. This will inform our understanding of EAP as the therapeutic change mechanism for about half of CR participants and confirm that EAP training need not be given to those CR participants with baseline intact EAP. The goal of this study is to enhance CR outcomes in schizophrenia spectrum disorders by identifying a scalable approach to optimizing and personalizing treatment. By facilitating a better understanding of EAP as a neurobehavioral marker, early auditory processing as mechanism of change, and the essential CR treatment targets for EAP impaired CR participants, the proposed 4-year study will inform improved clinical decision- making and guide clinical judgment about how to best provide cognitive training.