Mild to moderate hypoxic insults, attributed to apnea of prematurity, evoke disorders of minimal brain dysfunction with cognitive impairment. Yet, the underlying neuropathology is ill-defined. Our objective is to characterize dopaminergic structure and function in former preterm children who experienced postnatal hypoxic insults. We hypothesize that dopaminergic projections, originating in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) which modulate cognition and motor control, will be structurally and functionally impaired. To establish scientific premise for this proposal, we developed a rodent model emulating apnea of prematurity, which recapitulates many cognitive and behavioral impairments observed in post-hypoxic humans. Structural and neurochemical analyses within key brain regions subserving cognition and motor control revealed 1) reduced levels of extracellular dopamine, 2) increased protein expression of dopamine D-1 receptors, and 3) increased vesicular monoamine transporter within mesotenecephalic pathways. Those studies demonstrated, for the first time, that brief hypoxic insults occurring during the postnatal period impaired structure and function within dopaminergic circuits known to promote wakefulness, attention, locomotor activity and working memory. This proposed study represents the next logical step of our research. To enhance scientific rigor, we will use a cross-sectional two-arm trial design. Our study will enroll 20 former preterm children, now 8-11 years old, in whom we have characterized their postnatal hypoxic exposure continuously during their first eight weeks of life, and 10 healthy control children born at term and closely matched by age/sex/race.
Aim 1 will employ Magnetic Resonance Diffusion Tensor Imaging (DTI) to quantify and compare the structural integrity of dopaminergic circuits originating in the SNpc and VTA between post-hypoxic former preterm children versus healthy control children.
Aim 2 will employ Functional Magnetic Resonance Imaging (fMRI) with simultaneous High-Density Electroencephalography (HD-EEG) to quantify and compare functional activity in cortical brain regions associated with cognitive performance, within those same post-hypoxic former preterm children and healthy control children. Our findings will characterize and quantify the neuropathology attributed to mild to moderate hypoxic insults occurring in the postnatal period. This will inform future studies seeking to develop neuroprotective strategies for at-risk newborns as well as treatments to enhance function within the post-hypoxic infant.

Public Health Relevance

Public Health Relevance Brief episodes of low oxygen resulting from pauses in breathing lead to future cognitive and motor disability for preterm infants, yet the specific brain pathways involved are not well described. This proposal will examine brain structure and function in former preterm children who experienced these episodes of low oxygen, providing information to develop protective strategies and treatments to enhance brain function.

National Institute of Health (NIH)
National Institute of Nursing Research (NINR)
Exploratory/Developmental Grants (R21)
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Nursing and Related Clinical Sciences Study Section (NRCS)
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Hamlet, Michelle R
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Case Western Reserve University
Schools of Nursing
United States
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