Infants born prematurely are predisposed to hypoxic-ischemic (HI) injury such as periventricular leukomalacia (PVL), resulting in developmental disturbances to the thalamus, white matter, and cerebral cortex. As a consequence, survivors of PVL frequently demonstrate visual impairments to varying degrees. Because the thalamus is critical to visual processing, visual dysfunctions may be more severe if the thalamus is affected as a consequence of the HI insult. Yet, the effects of PVL on the developing thalamo-cortical network are unclear. In particular, it is currently not known how aberrant thalamo-cortical connectivity or altered volume of thalamic nuclei contribute to the deficits in visual processing that are commonly observed in individuals with PVL. To this end, the overall goal of the current study is to address the hypothesis that visual perceptual processing deficits may be more severe in individuals with PVL who have decreased volume of visual thalamic nuclei, distinct changes in myelination of thalamo-cortical networks, or atypical thalamo-cortical connectivity. We have developed a cutting-edge multimodal MRI approach consisting of morphometric analysis of individual thalamic nuclei, diffusion kurtosis imaging (DKI), high angular resolution diffusion imaging (HARDI), myelin water fraction maps, and network connectivity analyses that will be used in conjunction with a battery of tests of visual perceptual functions to determine the link between thalamic neuronal loss, thalamo-cortical connectivity, and visual perceptual processing abilities. A total of 36 individuals with PVL will be recruited, along with a cohort of 36 typically-developing controls. A rigorous statistical plan will use multiple levels of analysis to investigate the differences in behavioral and neuroimaging variables between individuals with PVL and controls, as well as the correlation between outcome measures. A series of regression analyses will evaluate the associations of neuroimaging variables with PVL and functional vision. Models will also consider the effects of age and gender on neuroimaging and behavioral outcomes. The unique combination of neuroimaging modalities utilized in this proposed study will provide complementary insight regarding the complex interplay between preterm HI damage in PVL and the resulting changes in thalamic development, and ultimately relate these findings to visual perceptual deficits. This study will contribute to our understanding of the impact of PVL on the establishment and myelination of the thalamo-cortical networks involved with visual perceptual processes, providing evidence-based biomarkers that can be used to evaluate future therapeutic approaches.

Public Health Relevance

The brain damage incurred by individuals with periventricular leukomalacia (PVL) often leads to visual processing impairments, which may be more severe when the thalamus or thalamo-cortical connections are affected. The studies outlined in this proposal will use a multimodal neuroimaging approach to characterize the morphometry of thalamic nuclei and integrity of visual thalamo-cortical networks to determine how they contribute to the observed visual dysfunctions in individuals with PVL. The results from these studies will advance our understanding of the impact early white matter injury has on the visual thalamo-cortical networks and functional vision in persons with PVL, ultimately providing a set of neuroimaging and behavioral targets that may be used to develop effective habilitation strategies for these individuals in the future.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Flanders, Martha C
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Massachusetts Eye and Ear Infirmary
United States
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