ABSTRACT Down syndrome (DS) is a leading known cause of intellectual disability and a highly recognized genetic syndrome that involves multiple medical co-morbidities. Hearing deficits in DS are estimated to occur up to rates of 80-90% and are thought to be caused by a combination of structural and functional abnormalities in the external, middle and/or inner ear. This project aims to tackle a timely and significant question regarding the role of hearing loss in DS on auditory function, cognition, language, and structural integrity of brain regions that are important for hearing. Despite the known pervasive nature of hearing deficits in DS, to date, research has yet to identify specific consequences of hearing deficits associated with trisomy 21. Aim 1 will assess hearing status, auditory integrity and maturation using objective measures of auditory processing in subcortical auditory brainstem responses (ABR) and cortical auditory evoked potentials (CAEPs), and functional processing behavioral measures of speech identification and sound localization. The goal is to understand how hearing loss impacts auditory processing and auditory maturation in DS is after compensating for hearing loss. Aim 2 will investigate the associations between hearing/auditory deficits and overall intellectual functioning as well as memory, attention, and executive function, as these cognitive domains have been shown to be influenced in critical ways by hearing status and auditory impairments in non-DS populations. Aim 2 will also examine the associations between hearing and auditory function and receptive and expressive vocabulary, obtained via standardized measures and language samples. Aim 3 will investigate the associations between hearing/auditory deficits and imaging measures of structure and microstructure in brain regions involved in auditory processes, focusing on regional morphometry, relaxometry, and microstructural diffusion measures. We aim to understand whether abnormalities are domain specific within auditory processes, global to all auditory brain regions, or generalized/global to DS brains but not auditory-specific, i.e., related to issues from generic pathophysiology in DS. This work meets the programmatic objectives of INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndrome (INCLUDE) and will advance understanding of the consequences of hearing loss in DS for functional auditory, cognitive and language outcomes and brain integrity. One immediate benefit is that results will inform clinical assessment and intervention of hearing loss catered specifically to the pathophysiology in DS. Longer-term impact is the identification of measures to evaluate effectiveness of future intervention of hearing loss in DS.

PROJECT NARRATIVE Down syndrome (DS) is a leading known cause of intellectual disability and a highly recognized genetic syndrome that involves multiple medical co-morbidities; hearing deficits in DS are estimated to occur at a rate of 80-90% and are thought to be caused by a combination of structural and functional abnormalities in the external and/or inner ear. This project aims to tackle a timely and significant question regarding the role of hearing loss in DS on auditory function, cognition, language, and structural integrity of brain regions that are important for hearing, meeting the programmatic objectives of INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndrome. Results will provided information regarding clinical diagnosis and intervention to facilitate treatment of hearing disorders in individuals with DS, and more long-term impact will be identification of measures that may be used to evaluate effectiveness of pharmaceutical and therapeutic trials.