Hypoxic ischemic (HI) insult damages both white matter and grey matter in infants and causes significant
mortality and morbidity. To investigate the pathological mechanisms of neonatal HI injury and find satisfactory
treatments, animal models of neonatal hypoxic ischemic injury have been established and widely used. In this
project, novel in vivo magnetic resonance imaging on tissue microstructure and neuronal activity will be
developed to examine the progression of HI injury and the effects of therapeutic hypothermia in a neonatal
In aim 1, we will examine the sensitivity of novel diffusion MRI (dMRI) techniques to tissue microstructural
changes caused by HI injury. Preliminary results have shown that the proposed imaging techniques can more
sensitively detect mild brain injuries than conventional dMRI techniques and is less susceptible to confounding
pseudo-normalization of conventional dMRI signals. We will use histology and electron microscopy to
determine the levels of cellular and subcellular structural changes and correlate quantitative measurements
with dMRI signals, and use numerical simulations to understand the relationships between them. The
knowledge will be used to optimize the imaging protocols to detect key structural changes after neonatal HI.
In aim 2, we will examine injury using manganese-enhanced MRI (MEMRI). Previous studies have shown
that the MEMRI contrasts reflect neuronal activity in the brain and can selectively enhance regions with
apoptosis and inflammation after neonatal HI. In this aim, we will examine the sensitivity of MEMRI to loss of
neuronal activity, apoptosis, and inflammation after neonatal HI. With both dMRI and MEMRI, we will be able to
examine a broad range of pathological events after neonatal HI.
Hypothermia is the standard care for newborns with neonatal HI, but its protective mechanisms are not
clearly understood. It has been assumed that hypothermia reduces cell swelling, inflammation, and vasogenic
edema, and may delay the pseudo-normalization process. In aim 3, the techniques developed in the first two
aims will then be applied to characterize HI injury in mice treated with hypothermia to quantitatively
characterize its effects and elucidate its neuroprotective mechanisms.
We expect the project to extend our knowledge on the relationships between pathology and diagnostic
markers in this mouse model, and shed light on the mechanisms of HI injury and therapeutic hypothermia. This
information and techniques developed in this project will be useful to design effective strategies for intervention
and to monitor treatment response in studies using this or similar models.