Elsevier

NeuroImage

Volume 147, 15 February 2017, Pages 233-242
NeuroImage

Heterogeneous increases of regional cerebral blood flow during preterm brain development: Preliminary assessment with pseudo-continuous arterial spin labeled perfusion MRI

https://doi.org/10.1016/j.neuroimage.2016.12.034Get rights and content

Highlights

  • CBF increases heterogeneously across cortical regions in preterm brains.

  • Adjusted pCASL MRI could yield reproducible CBF measures of preterm brains.

  • Global CBF doubles its value during the 3rd trimester.

  • Regional CBF measures were correlated with cortical microstructure.

Abstract

The human brain develops rapidly during 32-45 postmenstrual weeks (PMW), a critical stage characterized by dramatic increases of metabolic demand. The increasing metabolic demand can be inferred through measurements of regional cerebral blood flow (CBF), which might be coupled to regional metabolism in preterm brains. Arterial spin labeled (ASL) perfusion MRI is one of the few viable approaches for imaging regional CBF of preterm brains, but must be optimized for the extremely slow blood velocity unique in preterm brains. In this study, we explored the spatiotemporal CBF distribution in newborns scanned at the age of 32-45PMW using a pseudo-continuous ASL (pCASL) protocol adapted to slow blood flow in neonates. A total of 89 neonates were recruited. PCASL MRI was acquired from 34 normal newborns and phase contrast (PC) images from 19 newborns. Diffusion tensor images (DTI) were acquired from all 89 neonates for measuring cortical fractional anisotropy (FA), which characterizes cortical microstructure. Reproducible CBF measurements were obtained with the adjusted pCASL sequence. Global CBF measurement based on PC MRI was found to double its value in the 3rd trimester. Regional CBF increases were heterogeneous across the brain with a significantly higher rate of CBF increase in the frontal lobe and a lower rate of CBF increase in the occipital lobe. A significant correlation was found between frontal cortical CBF and cortical FA measurements (p<0.01). Increasing CBF values observed in the frontal lobe corresponded to lower FA values, suggesting that dendritic arborization and synaptic formation might be associated with an elevated local CBF. These results offer a preliminary account of heterogeneous regional CBF increases in a vital early developmental period and may shed the light on underlying metabolic support for cortical microstructural changes during the developmental period of 32-45PMW. Preterm effects and limitations of pCASL techniques in newborns need to be carefully considered for interpretation these results.

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.

References (72)

  • R. Pienaar et al.

    A quantitative method for correlating observations of decreased apparent diffusion coefficient with elevated cerebral blood perfusion in newborns presenting cerebral ischemic insults

    Neuroimage

    (2012)
  • A.J. du Plessis

    Cerebral blood flow and metabolism in the developing fetus

    Clin. Perinatol.

    (2009)
  • R.L. Sidman et al.

    Neuronal migration, with special reference to developing human brain: a review

    Brain Res.

    (1973)
  • J.C. Silbereis et al.

    The cellular and molecular landscapes of the developing human central nervous system

    Neuron

    (2016)
  • Z. Wang et al.

    Assessment of functional development in normal infant brain using arterial spin labeled perfusion MRI

    Neuroimage

    (2008)
  • D.C. Alsop et al.

    Recommended implementation of arterial spin‐labeled perfusion MRI for clinical applications: a consensus of the ISMRM perfusion study group and the European consortium for ASL in dementia

    Magn. Reson. Med.

    (2015)
  • D.I. Altman et al.

    Cerebral blood flow requirement for brain viability in newborn infants is lower than in adults

    Ann. Neurol.

    (1988)
  • S. Aslan et al.

    Estimation of labeling efficiency in pseudocontinuous arterial spin labeling

    Magn. Reson. Med.

    (2010)
  • O. Baenziger et al.

    Regional differences of cerebral blood flow in the preterm infant

    Eur. J. Pediatr.

    (1995)
  • C.J. Bakker et al.

    Construction of a protocol for measuring blood flow by two‐dimensional phase‐contrast MRA

    J Magn. Reson. Imaging

    (1999)
  • G. Ball et al.

    Development of cortical microstructure in the preterm human brain

    Proc. Natl. Acad. Sci. U.S.A.

    (2013)
  • K. Borch et al.

    Blood flow distribution in the normal human preterm brain

    Pediatr. Res.

    (1998)
  • J.P. Bourgeois et al.

    Synaptogenesis in visual cortex of normal and preterm monkeys: evidence for intrinsic regulation of synaptic overproduction

    Proc. Natl. Acad. Sci. U.S.A.

    (1989)
  • I. Bystron et al.

    Development of the human cerebral cortex: boulder committee revisited

    Nat. Rev. Neurosci.

    (2008)
  • J.A. Chalela et al.

    Magnetic resonance perfusion imaging in acute ischemic stroke using continuous arterial spin labeling

    Stroke

    (2000)
  • H.T. Chugani et al.

    Maturational changes in cerebral function in infants determined by 18FDG positron emission tomography

    Science

    (1986)
  • J. Conklin et al.

    High-contrast 3D neonate brain imaging with combined T1-and T2-weighted MPRAGE

    Magn. Reson. Med.

    (2008)
  • W. Dai et al.

    Continuous flow-driven inversion for arterial spin labeling using pulsed radio frequency and gradient fields

    Magn. Reson. Med.

    (2008)
  • J.B. De Vis et al.

    Arterial spin-labelling perfusion MRI and outcome in neonates with hypoxic-ischemic encephalopathy

    Eur. Radiol.

    (2015)
  • A.R. delpolyi et al.

    Comparing microstructural and macrostructural development of the cerebral cortex in premature newborns: diffusion tensor imaging versus cortical gyration

    Neuroimage

    (2005)
  • D.S. Dittmer

    Blood and Other Body Fluids

    (1961)
  • Engle, W.A., American Academy of Pediatrics Committee on Fetus and Newborn, 2004. Age terminology during the perintal...
  • A.J. Evans et al.

    Magnetic resonance imaging of blood flow with a phase subtraction technique: in vitro and in vivo validation

    Investig. Radiol.

    (1993)
  • G. Greisen et al.

    Cerebral blood flow, PaCO2 changes, and visual evoked potentials in mechanically ventilated, preterm infants

    Acta Paediatr.

    (1987)
  • P. Herscovitch et al.

    What is the correct value for the brain-blood partition coefficient for water

    J. Cereb. Blood Flow Metab.

    (1985)
  • H. Huang et al.

    Coupling diffusion imaging with histological and gene expression analysis to examine the dynamics of cortical areas across the fetal period of human brain development

    Cereb. Cortex

    (2013)
  • Cited by (0)

    View full text