Batten disease, which has no treatment, is a devastating neurological disorder characterized by severe seizures, loss of vision, language disabilities, and dementia. The absence of objective neurologic biomarkers of disease progression is one reason why there has been limited progress in developing effective therapies for Batten and other genetic neurological disorders. This application will advance a radically new approach to track functional and structural changes in progressive neurologic disorders by using functional ultrasound (fUS) and shear wave elastography (SWE). The structural and functional ultrasound imaging data acquired across the brain will provide a critical link between single-cell properties afforded by optical imaging and large-scale functional organization afforded by functional magnetic resonance imaging (fMRI). Together, these multi-modal and multi-scale data will complement the current electroencephalography (EEG)-based neuromarkers of Batten disease and provide a more detailed and comprehensive view of brain structural and functional changes during disease progression. Using a Batten disease mouse model, we will measure fUS sensitivity to changes in the functional connectivity between cortical and subcortical brain structures in response to various sensory stimuli. We will conduct histological analysis to confirm the validity of the activation maps. To determine how mechanical properties of the brain change during disease progression and with different stimuli, we will perform studies using a preclinical SWE system to assess structural and mechanical changes in Batten disease mouse models. In this phase of the project, we will develop advanced elastography techniques to visualize changes in brain morphology. This exciting project brings together two experienced researchers, Dr. Marvin Doyley, an expert in ultrasound and elastography imaging, and Dr. Kuan Hong Wang, an expert in neurobiology and genetic models of brain disorders, to establish imaging biomarkers for studying progressive neurological disorders such as Batten disease. This project will demonstrate that it is feasible to use emerging ultrasound imaging techniques to understand the pathological changes in progressive neurologic disorders and facilitate testing and translation of different therapeutic interventions.