Computational Model of Neurocognitive Impairment in Multiple Sclerosis

Project Summary/Abstract. The goal of this project is to provide a long overdue psychometrically valid and biologically informed update of cognitive status in relapsing remitting and progressive multiple sclerosis (MS). The existing framework used to characterize cognition in MS assumes slowing of cognitive processing speed (COG SPD) is the primary cognitive disability and slowing causes impairments in other cognitive domains (e.g., memory). This framework has never been prospectively tested, does not incorporate the past two decades of advances in disease management, including treatment discoveries that slow disease progression alongside improved diagnostic sensitivity leading to ascertainment of milder cases and has not been updated in over 30 years. The speed- centric framework depends on invalid polyfactorial psychometric COG SPD assessment tools. There is no way to know if low scores indicate impaired COG SPD or impairments in other cognitive domains. Cognitive psychology and computational modeling offer strong frameworks to investigate a psychometrically valid, theoretically derived, and empirically testable model of the time-course of cognitive processing in MS. Specifically, the diffusion model (DM) is an empirically validated mathematical method that extracts 'less contaminated' dissociable components of cognitive processing. Components include rate of information accumulation (COG SPD), criteria necessary to make a cognitive decision, and stimulus encoding/motor response execution. Our preliminary psychometrically valid computational modeling research strongly supports a revised cognitive profile in MS that is likely a result of the clinical advances in disease treatment and diagnosis. In aim 1, we translate and integrate cognitive psychology and computational modelling with confirmatory factor analysis to reappraise and prospectively test the longstanding speed-centric model of MS cognition and determine whether there are domain general vs. domain specific changes in DM cognitive processes across MS phenotypes. We test the specific hypothesis that MS cognitive impairment is primarily due to changes in stimulus encoding/motor response execution with larger differences in the progressive compared to relapsing remitting disease course. We also test the hypothesis that COG SPD is impacted in more advanced progressive disease where neurodegeneration is more prominent. In aim 2, we investigate the predictive value of DM components of cognitive processing and use structural equation modeling to evaluate relationships between DM cognitive processes and brain pathology (T2 lesion and normalized brain volumes) along with patient reported outcomes (PRO: psychological/psychiatric and cognitive symptoms) and performance in other cognitive domains (derived from extensive neuropsychological battery). This will lead to a comprehensive scientific understanding of the dynamic interplay across what cognitive domains are impaired in present-day MS, at what stages of disease and pathology, and moderating effects of PROs that will allow us to closely monitor and develop treatments that specifically target those domains and/or moderating variables.