Thursday, April 25, 2024
4/25/2024
Project Summary The goal of our research program is to identify specific, low-level “building blocks” of cognition that are impaired in people with schizophrenia (PSZ), are linked with neurobiology, and can explain deficits in a higher- level cognitive function. Our prior research has led to the hyperfocusing hypothesis, which proposes that many aspects of cognitive impairment in PSZ can be traced to overly narrow and intense focusing of processing resources on a subset of available inputs, and an inability to distribute resources among multiple sources of information. Hyperfocusing can explain reduced working memory capacity and impaired performance in a variety of attention tasks, and measures of hyperfocusing are strongly correlated with measures of broad cognitive function (e.g., IQ). We have developed a working model of the underlying neurobiology, which predicts that hyperfocusing will lead to exaggerated competitive inhibition and increased repulsion between similar neural representations, and we have obtained preliminary evidence showing that PSZ exhibit the predicted increase in repulsion between representations. If hyperfocusing can be established as a significant mechanism underlying cognitive dysfunction in PSZ, this will set the stage for (a) the near-term development of cognitive training treatments that are designed to counteract hyperfocusing, and (b) the medium-term development of biotherapies that target the neurobiology underlying hyperfocusing. However, additional research is necessary before moving to treatment development. In Aim 1, we will use several new behavioral paradigms to extend the scope of the hyperfocusing hypothesis. In each of these tasks, the hyperfocusing hypothesis predicts that PSZ will exhibit supranormal attention effects, which cannot easily be explained by generalized deficits. In Aim 2, we will use state-of-the-art multivariate fMRI and EEG-based methods to provide more direct evidence of narrower but more intense neural activity in PSZ. These methods will make it possible to go beyond measuring simple activity levels and assess the neural representations formed by PSZ and control subjects. In Aim 3, we will use newly developed fMRI and ERP methods to test the hypothesis that hyperfocusing leads to increased attention-driven competitive inhibition in PSZ. Each of the experiments for Aims 1-3 will involve medium sample sizes (40 PSZ and 40 controls). For Aim 4, each participant across the 5-year project period will also be tested in a set of 7 core tasks that are hypothesized to reflect either hyperfocusing or cognitive control, along with measures of broad cognitive function and functional outcome/capacity. This will provide data from 200+ subjects that will allow us to test the hypothesis that hyperfocusing and cognitive control are separate factors that explain unique variance in cognitive ability and functional outcome/capacity. Together, these 4 aims will provide a rigorous test of the proposal that hyperfocusing is a key contributor to cognitive dysfunction in schizophrenia and can provide a target for near- and medium-term treatment development efforts.
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