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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

Chronic psychotic disorders, including schizophrenia (SZ), are highly heterogeneous at many levels of analysis, from genetics to clinical presentation and treatment sensitivity. This heterogeneity reflects both a divergence of shared biological pathways moving from over a hundred “risk genes” to many different clinical phenotypes, and the convergence of distinct biological pathways to a shared “phenocopies” of chronic psychosis. Successful strategies for developing “next generation” interventions in SZ – including “pro-cognitive” medications, cognitive remediation, neurostimulation and combinations thereof – will address these pathways to clinical heterogeneity by using biological signals, or “biomarkers” that characterize treatment-sensitive subpopulations. Identifying and detecting these meaningful signals in the complex biology of SZ is a vexing scientific challenge. We propose that rational starting points are neurophysiological measures of early auditory information processing (EAIP), based on their functional importance as strong mediators of both cognition and function in SZ, their plasticity in response to both pharmacologic and non-pharmacologic therapeutic “challenge”, and their experimental characteristics as highly quantitative, robust and reliable measures of brain activity. Here we describe some of our current approaches to developing neurophysiological biomarkers for “next generation” therapeutic sensitivity in SZ, and some potentially novel experimental strategies that we envision on the near horizon.

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.