Ian S. Ramsay - US grants

DESCRIPTION (provided by applicant): Patients suffering from schizophrenia and related psychotic illnesses suffer from a varied presentation of hallucinations, delusions, and disorganization. While many of these symptoms are disruptive, it is the cognitive impairments of the illness that are most strongly associated with poor psychosocial functioning. While pharmacological treatments to address cognitive impairments have shown little effect for patients with schizophrenia, cognitive remediation training has been demonstrated to offer cognitive and functional improvements. Previous imaging studies of patients who have undergone cognitive remediation have found increased prefrontal activation associated with cognitive and functional improvements, but it is unclear whether changes in neural connectivity may better characterize and predict changes in cognitive and functional ability. The current proposal will examine schizophrenia patients before and after undergoing a triple blind placebo controlled trial of cognitive remediation. I will first replicate previous findings, demonstrating hat cognitive remediation leads to improvements in prefrontal activation and functional connectivity, but further determine which of these changes best supports changes in cognitive and functional outcome. These analyses will focus on functional activation in a general linear model (GLM) and functional connectivity as measured by independent components analysis (ICA). I will also examine intrinsic connectivity, measured at rest, to determine whether neural plasticity generalizes to instances where task demands are not present. This will allow us to better understand the neural mechanisms and extent of neural plasticity from cognitive remediation. Previous findings have also identified behavioral markers in patients with schizophrenia that predict positive functional change from cognitive remediation. However, it is not yet known whether these markers may also predict neural plasticity. In the second aim of this proposal I will determine whether pre-training cognition, psychosocial functioning, and motivation are predictive of neuro-plastic changes from cognitive remediation. In a second part to this aim, I wil examine the opposite effect, determining whether pre-training neural activation is predictive of behavioral changes in cognitive, functional, or motivational status. Finally, I will use a separate set of data collected from a multi-site placebo-controlled cognitive remediation trial to replicate these results. Findings from this proposal will identify the neural mechanisms that support positive outcomes from cognitive remediation training for schizophrenia.

Project Summary/Abstract Patients suffering from schizophrenia and related disorders experience cognitive disruptions associated with poor functional outcomes. It is therefore critical to achieve the long-term goal of developing efficacious and mechanistically informed treatments to improve cognition in this population. Targeted cognitive training (TCT) has shown promise for improving cognition in patients with schizophrenia, but individual differences in behavioral and neural target engagement limit the efficiency and sustainability of this treatment. TCT enhances prefrontal oscillatory gamma that coincides with improved cognition in patients with schizophrenia. Similar increases in prefrontal gamma and cognitive performance in schizophrenia have been demonstrated using transcranial direct current stimulation (tDCS). The current study will determine whether cognitive enhancement in schizophrenia can be achieved more efficiently by combining tDCS that enhances neural oscillatory rhythms with TCT that harnesses gamma oscillatory plasticity in prefronto-temporal systems. Using an experimental medicine framework, this study will test the central hypothesis that TCT+tDCS will?via the mechanism of increased prefrontal oscillatory gamma?accelerate and sustain the behavioral effects of cognitive training over TCT+Sham. This study will pursue 3 specific aims: 1) Determine whether TCT+tDCS more rapidly improves cognition compared to TCT+Sham; 2) examine the relationship between change in cognition and change in prefrontal oscillatory gamma following TCT+tDCS; and 3) determine whether cognitive and functional benefits following TCT+tDCS are sustained after a 3-month follow-up. An exploratory aim will examine cross-frequency coupling (CFC) between theta and gamma oscillatory signals and determine whether changes in CFC corresponds to improved cognition. To carry out these aims, patients with schizophrenia will be randomized to undergo either 20 hours of TCT+tDCS or TCT+Sham. Participants will be assessed on measures of cognition, symptoms, and functioning at baseline, after 10 hours of training, after 20 of training, and at a 3-month follow- up. To measure changes in oscillatory gamma, participants will undergo task/resting EEG at baseline, after 10 hours, and after 20 hours. The approach is innovative as it investigates the combined effects of a behavioral intervention and neuromodulation, uses an experimental medicine framework to probe neural target engagement, and relies on novel computational and neural analyses. The proposed research is significant because it will establish prefrontal gamma as a treatment target in schizophrenia, and lay the groundwork for personalized treatments that could be deployed in a clinical setting. The outlined proposal will also facilitate the candidate?s training goals: 1) Administration of tDCS; 2) Administration and analysis of EEG; 3) learning computational psychiatry methods. Completion of these goals will establish the candidate as an expert on neuroplasticity-based interventions for serious mental illness, and make them competitive for R01-level funding.