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Cerebral Blood Flow Patterns in Term and Premature Neonates measured at Term-Equivalent-Age: a PCASL study1Department of Neuroscience, Imaging and Clinical Sciences, University G. D'Annunzio of Chieti Pescara, Chieti, Italy, 2Department of Radiology, SS. Annunziata University Hospital, Chieti, Italy
Synopsis
During the perinatal period the brain undergoes extensive development, including increasing brain perfusion and metabolism. More rapidly modifying brain areas may be more sensitive to insults and transient hypoxic states. We performed PCASL on 115 infants at term equivalent age (TEA) with variable gestational age at birth. Insular-subcortical and somato-motor regions exhibited high grey matter CBF(GM) in both term and preterm newborns. However, premature neonates showed a redistribution of perfusion compared to term infants, with somato-motor regions showing even higher CBFGM. These results suggest that insular-subcortical and somato-motor regions may reflect brain health and development at TEA.
Introduction
The third trimester of gestation and the first months of life are critical periods for brain development1,2. Premature birth can be associated with poor neurodevelopmental outcome even without evident radiological alterations3. Indeed, rapidly developing brain areas with a higher need for oxygen may be more sensitive to perinatal suffering and transient hypoxic states. Cerebral blood flow (CBF) tends to be coupled to brain oxygen consumption4. Hence, regions with high CBF may be the focus of perinatal investigation to probe brain health and infer long-term neurodevelopmental outcome5.Here we report a pseudo-continuous arterial spin labelling (PCASL) study, performed at term-equivalent age (TEA), to evaluate CBF patterns in term and preterm infants with variable gestational age at birth (GAB).
Methods
After ethical committee approval, preterm infants were recruited from the Neonatology Unit of the University Hospital of Chieti based on the following inclusion criteria: absent neurological abnormalities (e.g. stroke, germinal matrix hemorrhage with grade >2) or congenital infection. Infants at term were selected from a group of neonates without asphyxia. The selection resulted in a group of 115 infants (67 males) between 25 and 40 weeks of GAB (mean = 34 weeks, SD = 4.7 weeks), 45 were born at term (>37 weeks of GAB) .MRI was performed at TEA with a 3T scanner using a 32-channel head array coil (Ingenia Cx, Philips, Best, the Netherlands). Patients were fed and then sedated with 0.05 mg of oral Midazolam/kg6. pCASL was performed acquiring 4 paired tag-control volumes with a multi-shot 3D GRaSE readout (t=1.8s, PLD=2s, TE=14ms, TR=4.4s, res.=2.5×2.5x7mm3 , FOV=200×200x91mm3) and background suppression. 2 images were acquired without background suppression to measure M0. The imaging-labeling planes gap ranged from 10mm to 20mm. An axial T2-w volume was acquired for segmentation and coregistration purposes (res.=0.4×0.4x3.5mm3 , FOV=204×204x98mm3).
CBF was obtained by averaging the 4 tag-control difference images, using voxelwise M0 normalization and applying the single-compartment kinetic model with a brain/blood partition coefficient of λ=0.9ml/g, labelling efficiency α=0.85, labelling efficiency reduction due to background suppression αINV=0.88 and T1blood=1.67s7. T2-w images were segmented using dHCP pipeline8 and registered to the UNC Infant Atlas9,10. Original T2-w images, their tissue segmentations and the UNC Atlas were transformed into the PCASL space. Grey Matter CBF(GM) was extracted from the 90 regions of interest (ROIs).
Due to T1blood variability caused by significant differences in hemoglobin concentration within the population, to evaluate modifications of the CBFGM pattern across subjects we normalized the CBF maps through z-scoring. The normalized (n)CBFGM for each ROI represented the distance, in units of standard deviation, from the subject global CBFGM. A hierarchical clustering11 of ROIs (ward metric, preceded by spatial principal component analysis retaining 95% of the variance) was performed on nCBFGM to reduce the number of regions and increase the study power and interpretability. The effect of prematurity on nCBFGM was also evaluated.
Results
Figure 1 shows a CBF map and the UNC Infant Atlas registered to the T2-w image as well as the tissue segmentation of the T2-w image of the same subject.Figure 2 shows the group average CBFGM in the 90 ROIs. Regions of higher perfusion (above 16 ml/100g/min) such as subcortical and somato-motor regions and lower perfusion (~8 ml/100g/min) such as ventral-frontotemporal regions are visible.
Figure 3 reports the hierarchical clustering outcome. 5 main clusters were identified retaining more than 70% of the data variance. The 5 clusters were named: ventral-frontotemporal, medial-occipitotemporal, fronto-parietal, insular-subcortical and somato-motor clusters. Ventral-frontotemporal and fronto-parietal clusters had a nCBFGM below 0 (t=-23.1, df=114, p~0; t=-12.7, df=114, p~0) and insular-subcortical and somato-motor clusters had a nCBF above 0 (cluster 1: t=21.1, df=114, p~0; t=15, df=114, p~0).
Figure 4 reports t-score maps (p<0.05, uncorrected) evaluating the difference in nCBFGM between premature and term infants. Significant (Bonferroni corrected) differences were obtained for somato-motor ROIs, with higher relative perfusion, and for left temporal pole and orbitofrontal regions, with lower relative perfusion in premature neonates.
Figure 5 reports the boxplots comparing premature and term infants in the 5 clusters identified. nCBFGM was higher in premature neonates in the somato-motor cluster (t=3.3, df=113, p=1.4∙10-3) and lower in the ventral-frontotemporal (t=-3.0, df=113, p=2.8∙10-3) and fronto-parietal (t=-3.4, df=113, p=7.8∙10-4) clusters.
Discussion and Conclusion
A data-driven clustering of ROIs, using nCBFGM, identified 5 main clusters, two with lower perfusion (ventral-frontotemporal and fronto-parietal clusters), one with intermediate perfusion (medial-occipitotemporal cluster), and two with higher perfusion (insular-subcortical and somato-motor clusters), Premature infants had a redistribution of CBF compared to term infants, with higher nCBFGM in the somato-motor cluster and lower nCBFGM in ventral-frontotemporal and fronto-parietal clusters. The high perfusion in the somato-motor regions in premature neonates might be associated with the longer extrauterine exposure.We suggest that insular-subcortical and somato-motor regions should be a focus of investigation after perinatal suffering for assessing brain health and predicting neurodevelopmental outcome at TEA. Moreover, accurate evaluation of T1blood and labelling efficiency would allow the cross-sectional results to be reinterpreted in absolute CBF units rather than being limited to consideration of the spatial distribution of CBF.
Acknowledgements
This work was partially conducted under the framework of the Departments of Excellence 2018–2022 initiative of the Italian Ministry of Education, University and Research for the Department of Neuroscience, Imaging and Clinical Sciences (DNISC) of the University of Chieti-Pescara, Italy.References
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