Quantitative Ultrasound Imaging of the Neonatal Brain

Abstract Brain injuries affect millions of infants each year and may cause irreversible cell death. Visualizing cell death in their brains is challenging. There is a need for non-invasive and easy-to-implement bedside imaging methods which can be performed safely, and repeatedly and have the ability to detect cell death in the brain. Cell death in infant brains can occur after hypoxia/ischemia, stroke, trauma, or exposure to sedative/anesthetic or antiseizure medications and presents in different forms (necrosis, apoptosis, autophagy). Structural features of cell death modify the acoustic scattering properties of tissue, therefore reflecting ultrasound differently from viable cells. Quantitative ultrasound (QUS) has been used to detect the unique scattering properties of apoptotic cells in cancer and necrotic cells in cultures. Low cost, portability, lack of need for contrast agents, and rapid image acquisition and processing make QUS appealing for the in vivo detection of cell death in infants. Our group has applied these techniques to study cell death in the brains of newborn non-human primates (NHPs) exposed to sevoflurane anesthesia. Within the thalamus, a region that undergoes apoptosis after prolonged sevoflurane administration in infancy, we detected changes in the “effective scatterer size” (ESS) and confirmed histologically that apoptosis was present in this brain region. Notably, a strong correlation between changes in ESS and the severity of histologically detected apoptosis was confirmed. Furthermore, we performed pilot studies in four typically developing human neonates, whose fontanels are excellent sonographic windows, and produced high-quality ultrasound brain images and QUS measurements with consistent values. Here we want to apply knowledge gained from the NHP work and develop QUS technology that will enable capturing cell death in neonatal human brains. First, we will optimize QUS acquisition and analysis of echo data in typically developing human neonatal brains and obtain normative data for key QUS features in selected brain regions in the basal ganglia. These regions are the caudate nucleus (CN), globus pallidus (GP), putamen (Put), and thalamus (Th). Then, we will apply QUS in neonates with brain injury caused by perinatal asphyxia. In these brains, hypoxic/ischemic cell death can occur in the CN, GP, Put, and Th, and is accompanied by diffusion restriction on magnetic resonance imaging (MRI). We expect that QUS features obtained from the CN, GP, Put, and Th in neonates with perinatal asphyxia, who demonstrate diffusion restriction and altered apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps in the basal ganglia on MRIs, will differ from those in typically developing human neonates. The translational significance of this research is immense. QUS may enable the study of when and where cell death occurs in infants’ brains and follow its time evolution. It may provide invaluable means of neuromonitoring in neurocritical care, help address fundamental research questions and assist in optimizing clinical treatments.