Prenatal Cerebral Ischemia Disrupts MRI-Defined Cortical Microstructure Through Disturbances in Neuronal Arborization

Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
Science translational medicine (Impact Factor: 15.84). 01/2013; 5(168):168ra7. DOI: 10.1126/scitranslmed.3004669
Source: PubMed


Children who survive preterm birth exhibit persistent unexplained disturbances in cerebral cortical growth with associated cognitive and learning disabilities. The mechanisms underlying these deficits remain elusive. We used ex vivo diffusion magnetic resonance imaging to demonstrate in a preterm large-animal model that cerebral ischemia impairs cortical growth and the normal maturational decline in cortical fractional anisotropy (FA). Analysis of pyramidal neurons revealed that cortical deficits were associated with impaired expansion of the dendritic arbor and reduced synaptic density. Together, these findings suggest a link between abnormal cortical FA and disturbances of neuronal morphological development. To experimentally investigate this possibility, we measured the orientation distribution of dendritic branches and observed that it corresponds with the theoretically predicted pattern of increased anisotropy within cases that exhibited elevated cortical FA after ischemia. We conclude that cortical growth impairments are associated with diffuse disturbances in the dendritic arbor and synapse formation of cortical neurons, which may underlie the cognitive and learning disabilities in survivors of preterm birth. Further, measurement of cortical FA may be useful for noninvasively detecting neurological disorders affecting cortical development.

Download full-text


Available from: Ev Mcclendon, Oct 01, 2015
30 Reads
  • Source
    • "Furthermore , structural development of the cortex can be detected with the DT model (Neil et al., 1998; McKinstry et al., 2002b), but the model's specificity is limited, because multiple features of the microstructure have similar effects on tensor characteristics (Vos et al., 2011, 2012). For example, the decrease in anisotropy observed over cortical development is thought to results from emerging dendritic arborization (Dean et al., 2013), but the same anisotropy decrease could also result from, for instance a reduction in radial glial fibers (Sizonenko et al., 2007). Most likely, these different changes happen concurrently and therefore it is essential to distinguish these contributions and other microstructural features, not only with postmortem techniques, but also with in vivo methods such as diffusion MRI. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Preterm infants are born during a critical period of brain maturation, in which even subtle events can result in substantial behavioral, motor and cognitive deficits, as well as psychiatric diseases. Recent evidence shows that the main source for these devastating disabilities is not necessarily white matter (WM) damage but could also be disruptions of cortical microstructure. Animal studies showed how moderate hypoxic-ischemic conditions did not result in significant neuronal loss in the developing brain, but did cause significantly impaired dendritic growth and synapse formation alongside a disturbed development of neuronal connectivity as measured using diffusion magnetic resonance imaging (dMRI). When using more advanced acquisition settings such as high-angular resolution diffusion imaging (HARDI), more advanced reconstruction methods can be applied to investigate the cortical microstructure with higher levels of detail. Recent advances in dMRI acquisition and analysis have great potential to contribute to a better understanding of neuronal connectivity impairment in preterm birth. We will review the current understanding of abnormal preterm cortical development, novel approaches in dMRI, and the pitfalls in scanning vulnerable preterm infants.
    Frontiers in Human Neuroscience 01/2015; 8(1066). DOI:10.3389/fnhum.2014.01066 · 2.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Two translational studies-one in humans and one in sheep-suggest that (i) premature birth is associated with delayed maturation of grey matter in the cerebral cortex and (ii) medical care that prohibits impairment of growth in premature neonates may enhance cortical development and reduce neurological disabilities associated with preterm birth.
    Science translational medicine 01/2013; 5(168):168ps2. DOI:10.1126/scitranslmed.3005379 · 15.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypoxic-ischemic and traumatic brain injuries are leading causes of long-term mortality and disability in infants and children. Although several preclinical models using rodents of different ages have been developed, species differences in the timing of key brain maturation events can render comparisons of vulnerability and regenerative capacities difficult to interpret. Traditional models of developmental brain injury have utilized rodents at postnatal day 7-10 as being roughly equivalent to a term human infant, based historically on the measurement of post-mortem brain weights during the 1970's. Here we will examine fundamental brain development processes that occur in both rodents and humans, to delineate a comparable time course of postnatal brain development across species. We consider the timing of neurogenesis, synaptogenesis, gliogenesis, oligodendrocyte maturation and age-dependent behaviors that coincide with developmentally regulated molecular and biochemical changes. In general, while the time scale is considerably different, the sequence of key events in brain maturation is largely consistent between humans and rodents. Further, there are distinct parallels in regional vulnerability as well as functional consequences in response to brain injuries. With a focus on developmental hypoxic-ischemic encephalopathy and traumatic brain injury, this review offers guidelines for researchers when considering the most appropriate rodent age for the developmental stage or process of interest to approximate human brain development.
    Progress in Neurobiology 04/2013; 106-107. DOI:10.1016/j.pneurobio.2013.04.001 · 9.99 Impact Factor
Show more