Heterogeneous increases of regional cerebral blood flow during preterm brain development: Preliminary assessment with pseudo-continuous arterial spin labeled perfusion MRI
Introduction
During the 3rd trimester, dramatic cellular and molecular processes, including cell proliferation, migration (Jacobson, 1991; Rabinowicz, 1986), synapse formation, dendritic arborization (Bystron et al., 2008, Huttenlocher and Dabholkar, 1997) and myelination (Yakovlev and Lecours, 1967), take place in the cerebral cortex. Both glucose and oxygen, essential substrates for maintaining cellular and molecular processes during brain development, are delivered through cerebral blood flow (CBF). Rapid brain maturation requires both increases in whole brain CBF and localized increases as brain function begins to differentiate (see Silbereis et al., 2016 for review). Quantifying both global and regional CBF thus provide critical information about brain physiology and functional development. Furthermore, cortical microstructural architecture is also dramatically reshaped during 32-45 postmenstrual weeks (PMW) (Bystron et al., 2008, Kostovic and Jovanov-Milosevic, 2006, Rakic, 1972, Rakic, 1995, Sidman and Rakic, 1973). However, how these regional microstructural changes relate to regional CBF changes has yet to be elucidated.
Arterial spin labeled (ASL) (Detre and Alsop, 1999) perfusion magnetic resonance imaging (MRI) provides a noninvasive approach for quantifying regional CBF without exposure to ionizing radiation or the administration of exogenous contrast agents, and hence is especially suitable for regional CBF measurements of infants and young children. ASL has become a reliable tool to study regional CBF in the brains of infants (e.g. Wang et al., 2008), children (e.g. Jain et al., 2012; Wang et al., 2003), adolescents (e.g. Satterthwaite et al., 2014) and adults (e.g. Chalela et al., 2000). ASL has also been applied to study regional CBF in neonate brains in normal (De Vis et al., 2013, Miranda et al., 2006) and pathological conditions (e.g. congenital heart disease, cardiac arrest or hypoxic-ischemic encephalopathy) (Licht et al., 2004, De Vis et al., 2015, De Vis et al., 2014, Massaro et al., 2013, Nagaraj et al., 2015, Pienaar et al., 2012, Varela et al., 2014, Wintermark et al., 2011). In these studies, regional CBF measures in both frontal and occipital cortex were significant higher in healthy neonates at 40-43PMW than those at 30-33PMW (De Vis et al., 2013). In contrast to research on regional CBF in relatively older children or adults, the major challenge unique in neonate brains is the extremely slow blood velocity (Wu et al., 2010). To date, there has been no standardized ASL protocol established for neonate brains, and optimization of ASL perfusion MRI protocol is needed. Moreover, successful measurement of the spatiotemporal dynamics of regional CBF during the critical developmental period of 32-45PMW would provide new insights into metabolic demand of underlying differentiated cellular activities. The associated brain microstructural changes can be inferred by the metric measurements with diffusion tensor imaging (DTI) (Basser et al., 1994). As an alternative to ASL, phase contrast (PC) MRI has been used to quantify global CBF (Bakker et al., 1999) of children and adolescents in a number of studies (e.g. Aslan et al., 2010; Jain et al., 2012). However, PC MRI slice locations have yet to be optimized to adapt to the complex anatomy of arteries at the neck region of neonate brains (Liu et al., 2014).
In this study, we explored the spatiotemporal dynamics of regional CBF during 32-45PMW using pseudo-continuous ASL (pCASL) (Alsop et al., 2015, Dai et al., 2008). We measured global CBF with PC MRI to reveal the extent of global CBF increase during the age of 33-42PMW. Using fractional anisotropy (FA) derived from DTI as a means of quantifying changes in regional cortical microstructure of the preterm brains (McKinstry et al., 2002, delpolyi et al., 2005, Ball et al., 2013, Yu et al., 2016), we also explored the relationship between regional CBF and cortical microstructure. A pCASL protocol was adjusted to be adapted to the slow cerebral blood velocity seen in the neonates, and pCASL, PC MRI and DTI were acquired from part (for pCASL and PC MRI) and the entire (for DTI) cohort of 89 neonates, respectively. Without additional description, the age defined in postmenstrual week according to Engle's policy statement (Engle et al., 2004) was used.
Section snippets
Neonate subjects
This study was approved by the local Institutional Review Board (IRB) of The University of Texas Southwestern Medical Center. 89 normal neonates were recruited from Parkland Memorial Hospital, Dallas, TX, USA, for research of normal prenatal and perinatal human brain development. These infants were selected through rigorous screening procedures by a board-certified neonatologist (LC). Exclusion criteria included the maternal drug or alcohol abuse during pregnancy; grade III-IV intraventricular
Age-dependent increase of global CBF for neonates
Fig. 4 shows the age-dependent increase of global CBF derived from PC MRI of 14 infants aged 33 to 42PMW. Global CBF increases significantly (r=0.65, p=0.01) with postmenstrual age. Specifically, the global CBF increases from 8.4 ml/100 g/min at 33PMW to 21.6 ml/100 g/min at 42PMW with an increase rate of 1.22 ml/100 g/min per PMW. Note that the value of global CBF at 42PWM almost doubles the value of global CBF at 33PMW. After removing the effects of postnatal age, global CBF still shows significant
Discussion
Heterogeneous increases of regional cortical CBF were demonstrated using pCASL data of neonate brains in the age range of 32-45PMW. Frontal CBF increases faster than occipital CBF (Fig. 5). In parallel to regionally heterogeneous CBF increases, global CBF increases were also demonstrated using PC MRI during this period. Specifically, the measured global CBF value at 42PMW almost doubles the global CBF value at 33PMW (Fig. 4), suggesting dramatic increase of whole brain metabolic needs during
Conclusion
In summary, the present study revealed spatiotemporally heterogeneous increases of cortical regional CBF in preterm brains scanned with pCASL MRI during 32-45PMW, a period of rapid brain development. Dramatic global CBF increases were found with PC MRI in parallel with heterogeneous regional CBF increases based on pCASL MRI. In addition, significant correlations between cortical CBF and cortical FA measurements in the frontal cortex suggest an association between active cellular processes
Funding and disclosure
This study was supported by NIH (Grant nos. R01 MH092535, U54 HD086984, P41 EB015893, R01 MH084021, and R21 NS085634). The authors report no biomedical financial interests or potential conflicts of interest.
Acknowledgements
The authors are grateful to Neonatal-Perinatal Division in University of Texas at Southwestern Medical Center and MRI technologists in Radiology Department from Children's Medical Center of Dallas for their support and assistance, and also the parents of the scanned neonates for their essential involvement in this study.
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