Prefrontal cortical engagement and clinical effects of non-invasive direct current stimulation for cognitive control impairments in schizophrenia

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 DESCRIPTION (provided by applicant): Cognitive deficits are a strong predictor of functional outcome in schizophrenia, yet poorly remediated by current treatments. Disturbances in dorsolateral prefrontal cortex (DLPFC) function underlie core impairments such as in cognitive control and thus represent a critical target for novel therapeutics. Initial studies indicate transcranial direct-current stimulation (tDCS) may be effective in reducing symptoms due to DLPFC dysfunction. While tDCS potentially represents an exciting, novel therapeutic advance, a number of basic questions should be addressed prior to conducting larger-scale clinical trials, including: verifying therapeutic target engagement, optimizing treatment parameters, and evaluating for meaningful clinical effects. Recent studies employing tDCS to enhance prefrontal cortical function in schizophrenia applied stimulating electrodes over the left frontal scalp regio, putatively targeting the left DLPFC. However, explicit confirmation of such target engagement is lacking. Further, EEG studies have demonstrated close links of frontal cortical gamma oscillations to cognitive control processes but modulation of this critical physiologic process has not been investigated. Accordingly, the primary R61 aim (R61-Aim 1) will employ multimodal imaging to explicitly test for the assumed DLPFC engagement (fMRI) and modulation of frontal gamma activity (EEG) by tDCS. The R61-Aim 2 will investigate the optimization of tDCS application parameters. Analogous to dose-finding investigations in drug studies, we will conduct a parametric investigation of optimal current strengths. Also, while there is extensive evidence for tolerability of single session tDCS, confirmation of feasibility of multi- session optimized protocols in schizophrenia is lacking and so will be explicitly evaluated (R61-Aim 3). The R33 phase will be predicated on initial demonstration of target engagement, namely, tDCS modulation of DLPFC BOLD and frontal gamma oscillatory activity (R61-Aim 1). With such demonstration and equipped with an optimized tDCS protocol (R61-Aim 2) that has been verified to be well-tolerated (R61-Aim 3), the R33 phase would then seek to demonstrate clinical effect, namely, the modulation of cognitive control probed by a cued stimulus-response reversal paradigm (R33-Aim 1). We will also evaluate clinical and functional outcome employing relevant assessment tools (BPRS/SANS/SAPS and SLOF/SFS/UPSA-B, respectively) (R33-Aim 2). Finally, we will investigate whether any observed improvements in cognitive control and functional outcome are mediated by DLPFC and frontal gamma oscillation engagement (R33-Aim 3). In summary, a successful outcome of this study would provide tDCS the sound mechanistic, methodologic and clinical-relevance basis for more definitive testing in large-scale clinical trials as a highly innovative therapeutic intervention for cognitive impairments in schizophrenia.