Brain structural and functional abnormalities in the executive function network in children with developmental language disorder - Summary Developmental Language Disorder (DLD) is a neurodevelopmental condition that emerges in early childhood and persists throughout adulthood. It is one of the most common neurodevelopmental disorders with an estimated prevalence of 7-8% which is nearly seven times more common than autism spectrum disorder. While people with DLD have significant difficulty learning, understanding and using spoken language, they also show impairments in other higher-order cognitive domains such as executive function, including working memory, which typically persist into adulthood. It is therefore critical to understand the brain mechanisms underlying DLD and how they relate to language and other cognitive impairments, as this could guide the development of novel more-targeted interventions and improve outcomes. Until now, most research on DLD has been largely based on behavioral tasks and cognitive assessments. While these previous studies have significantly advanced the field, the neural bases of DLD remain largely unknown and there is currently no biologically validated model that can explain the large range of cognitive deficits and their inter-connections reported in this population. In the relatively few neuroimaging studies that exist, the focus has mostly been on investigating the language brain system as the major origin of this disorder, while ignoring the role of the other brain systems. In our pilot analyses, we found that children with DLD show brain structural and functional brain abnormalities in regions typically supporting working memory, with them being associated with greater language impairments. We suggest that such alterations may be related to atypical development with a lack of synaptic pruning in these regions as revealed by thicker cortex and stronger brain functional connectivity with development, which led to greater language deficits, in comparison to their typically developing peers. In this context, the aim of this application is to provide, for the first time, a comprehensive view of DLD-related brain in-vivo structural, functional, neurochemical and myelination properties in the working memory network to accurately map the neural mechanisms underlying DLD and their relationship to language impairment, during childhood. To achieve this, we will use advanced and cutting-edge multi-modal MRI methods in 90 children with DLD and 90 matched typically developing children, aged 6-12 years. We will first identify atypical patterns in brain structure (cortical thickness, subcortical volume and myelin; in Aim 1), brain functional activation and connectivity (using a working memory task and resting-state functional MRI; in Aim 2) and GABA (using Magnetic Resonance Spectroscopy; in Aim 3) in key regions supporting language and working memory, in DLD. Lastly, Aim 4 will provide an integrative view of these brain features and their role to predict language impairment by conducting moderation and mediation analyses. By mapping the brain mechanisms underlying this disorder, this work has the potential to elucidate the origins of behavioral deficits in DLD and also provide guidance for the design of future therapeutic interventions.
