The Growth and Development of Microvasculature in Human Cerebral Cortex

Norman, Margaret G.; O’Kusky, John R.

doi:10.1097/00005072-198605000-00003

Cited by 99 publications

(67 citation statements)

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“…It is interesting that we observed an increase in blood vessel density and percentage of blood vessel area in gray matter from 16 to 40 wk of gestational age, whereas these measurements in white matter did not increase until close to maturity (36 -40 wk). The description of phases in the development of human cerebral cortical vasculature also supports our finding of an increase in vascularization of cortex with gestational age (14). In addition, two to three times greater cerebral blood flow in term infants compared with preterm infants as measured by positron emission tomography indirectly supports our observation of an increase in cerebral vascularization as a function of gestational age (17).…”

supporting

confidence: 86%

“…Studies on human infants have examined the pattern of vascularization (14), glial ensheathment of cerebral cortical blood vessels (15), and ultrastructure of GM vessels including luminal area (5) and endothelial area (5). However, a systematic study on human premature infants that examines vessel density, percentage of blood vessel area, and measurements of the blood vessel, including mean surface area, length, breadth, perimeter, radius, and shape of the blood vessels in the GM compared with gray and white matter, from early gestational age through term is lacking.…”

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confidence: 99%

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Anatomic Analysis of Blood Vessels in Germinal Matrix, Cerebral Cortex, and White Matter in Developing Infants

2004

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The germinal matrix (GM) located in the thick subependymal cell layer of the thalamostriate groove is a major site of cerebral hemorrhage in premature infants. Comparing the morphology of vasculature among GM, gray and white matter of the brain may help in understanding the pathogenesis of GM hemorrhage and also of periventricular leukomalacia. The objective of the present study was to determine the morphology of blood vessels in the GM, gray matter, and white matter and to examine maturational changes in the morphology of these vessels as a function of gestational age. We measured vessel density, percentage of blood vessel area, mean surface area, length, breadth, perimeter, radius, and shape of blood vessels in coronal sections of the GM, gray matter, and white matter in postmortem human brain samples for 17 fetuses and premature infants of gestational age 16 -40 wk and 2 adults. We performed immunohistochemical staining using anti-laminin primary antibody, confocal microscopy to acquire images, and analysis using Metamorph version 6.1. Vessel density and the percentage of blood vessel area increased as a function of gestational age in the GM, gray matter, and white matter (p Ͻ 0.001 each). The blood vessel density and the percentage of blood vessel area were largest in the GM followed by gray matter and then white matter in all of the gestational age categories (p Ͻ 0.001 for all comparisons). Increased vascularity of the GM compared with gray and white matter may play a role in GM hemorrhage, whereas a relatively low vascularity of white matter may increase the propensity for the occurrence of periventricular leukomalacia in premature infants (Pediatr Germinal matrix hemorrhage (GMH)-intraventricular hemorrhage (IVH) continues to be an important cause of mortality and morbidity in premature infants (1,2). The pathogenesis of IVH is not well understood. However, some theories concerning IVH include venous origin of hemorrhage (3), poorly developed tight junctions (4), greater lumenal areas (5), and low cerebral blood flow (6). Premature infants primarily bleed in the GM and not in gray and white matter, suggesting that there is an intrinsic weakness in the blood vessels of GM compared with blood vessels in other areas of the brain. Thus, this study is based on the premise that maturational changes in the morphology of GM blood vessels and difference in GM vasculature compared with gray and white matter may reveal reasons for the vulnerability of the GM blood vessels to hemorrhage. In addition, development of white matter vasculature may be of importance with respect to the pathogenesis of periventricular leukomalacia (PVL), a white matter disease of premature newborns that is considered to be of hypoxicischemic origin (7).The morphology of GM blood vessels has been studied by a number of investigators in beagle pups (8 -10), rabbits (11), monkey fetuses (12), and premature human infants (5,13). Studies on human infants have examined the pattern of vascularization (14), glial ensheathment of cerebral cortical ...

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confidence: 86%

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confidence: 99%

Anatomic Analysis of Blood Vessels in Germinal Matrix, Cerebral Cortex, and White Matter in Developing Infants

2004

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“…Because these changes are in the opposite direction from those observed during development, the development of autoregulation is most likely not a major factor in the development of hPod. The antiphase contributions of Δα O2 and Δc may also be present, but these effects may be limited because of the gradual development of capillaries (33).…”

Section: Rapid Change Of Hpod From An In-phase To An Antiphase Pattermentioning

confidence: 99%

“…It is well-known that the synaptic architecture of humans rapidly develops during the first one-half of the first year of life and has been thought to form the basis for functional development of the brain under the vast stream of sensory input from the environment (49). However, an anatomical study indicated that capillary formation starts between term and 3 mo postnatal (33). Thus, the development of vascular networks has been thought to proceed in parallel with neural development (50).…”

Section: Rapid Change Of Hpod From An In-phase To An Antiphase Pattermentioning

confidence: 99%

Hemoglobin phase of oxygenation and deoxygenation in early brain development measured using fNIRS

Watanabe

Shitara

Aoki

et al. 2017

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

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A crucial issue in neonatal medicine is the impact of preterm birth on the developmental trajectory of the brain. Although a growing number of studies have shown alterations in the structure and function of the brain in preterm-born infants, we propose a method to detect subtle differences in neurovascular and metabolic functions in neonates and infants. Functional near-infrared spectroscopy (fNIRS) was used to obtain time-averaged phase differences between spontaneous low-frequency (less than 0.1 Hz) oscillatory changes in oxygenated hemoglobin (oxy-Hb) and those in deoxygenated hemoglobin (deoxy-Hb). This phase difference was referred to as hemoglobin phase of oxygenation and deoxygenation (hPod) in the cerebral tissue of sleeping neonates and infants. We examined hPod in term, late preterm, and early preterm infants with no evidence of clinical issues and found that all groups of infants showed developmental changes in the values of hPod from an inphase to an antiphase pattern. Comparison of hPod among the groups revealed that developmental changes in hPod in early preterm infants precede those in late preterm and term infants at term equivalent age but then, progress at a slower pace. This study suggests that hPod measured using fNIRS is sensitive to the developmental stage of the integration of circular, neurovascular, and metabolic functions in the brains of neonates and infants.irth is a drastic event for the developing brain, because this is when the oxygen supply switches from the fetal-placental circulation to an autonomous system. In addition, the extrauterine environment begins to provide the neonate with a tremendous flow of stimuli. Earlier exposure to the extrauterine environment is thought to influence the developmental trajectory of the brain. It has long been known that preterm birth affects brain development and is associated with a higher rate of neurodevelopmental impairment (1). A growing number of MRI studies have shown that preterm-born neonates and infants have brain structures with aberrant volumes, morphologies, and networks at term equivalent (2, 3) and school age (4, 5). Studies of resting-state fMRI have also shown that the functional connectivity of the cortex is different in term and preterm infants (6). However, it is a matter of controversy whether neonatal MRI of the brain can predict long-term adverse outcomes, such as minor neurological dysfunction (7,8). Given the fact that preterm birth before 37 wk of gestation accounts for more than 10% of all live births (9), we need a practical and safe method to detect the status of brain development in newborns.The development of the brain involves underlying hemodynamic and metabolic changes (10). Near-infrared spectroscopy (NIRS) has been used to measure cerebral blood concentrations of oxygenated Hb (oxy-Hb) and deoxygenated Hb (deoxy-Hb) at the bedside and estimate cerebral blood volume, oxygen saturation (SO 2 ), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO 2 ) in neonates (11,12). Previous studies in pr...

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“…For example, astrocytes do not mature in rats until approximately P21 and do not reach adult density levels in the cortex until P50 (38,39). Prostanoids are not synthesized at adult levels until P21 in the rat brain (40), and the vasculature itself is also still undergoing substantial angiogenesis and vascular pruning/remodeling postnatally (41). Cortical vasculature may only begin to take on defined arterial and venous characteristics at around P10 (42), and intravascular upstream signaling mechanisms are not well established in the newborn brain (43,44).…”

Section: Consequences For Interpretation Of Functional Imaging Studiesmentioning

confidence: 99%

Resolving the transition from negative to positive blood oxygen level-dependent responses in the developing brain

Kozberg

Chen

DeLeo

et al. 2013

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

106

137

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The adult brain exhibits a local increase in cortical blood flow in response to external stimulus. However, broadly varying hemodynamic responses in the brains of newborn and young infants have been reported. Particular controversy exists over whether the "true" neonatal response to stimulation consists of a decrease or an increase in local deoxyhemoglobin, corresponding to a positive (adult-like) or negative blood oxygen level-dependent (BOLD) signal in functional magnetic resonance imaging (fMRI), respectively. A major difficulty with previous studies has been the variability in human subjects and measurement paradigms. Here, we present a systematic study in neonatal rats that charts the evolution of the cortical blood flow response during postnatal development using exposed-cortex multispectral optical imaging. We demonstrate that postnatal-day-12-13 rats (equivalent to human newborns) exhibit an "inverted" hemodynamic response (increasing deoxyhemoglobin, negative BOLD) with early signs of oxygen consumption followed by delayed, active constriction of pial arteries. We observed that the hemodynamic response then matures via development of an initial hyperemic (positive BOLD) phase that eventually masks oxygen consumption and balances vasoconstriction toward adulthood. We also observed that neonatal responses are particularly susceptible to stimulus-evoked systemic blood pressure increases, leading to cortical hyperemia that resembles adult positive BOLD responses. We propose that this confound may account for much of the variability in prior studies of neonatal cortical hemodynamics. Our results suggest that functional magnetic resonance imaging studies of infant and child development may be profoundly influenced by the maturing neurovascular and autoregulatory systems of the neonatal brain.

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The Growth and Development of Microvasculature in Human Cerebral Cortex

Cited by 99 publications

References 0 publications

Anatomic Analysis of Blood Vessels in Germinal Matrix, Cerebral Cortex, and White Matter in Developing Infants

Anatomic Analysis of Blood Vessels in Germinal Matrix, Cerebral Cortex, and White Matter in Developing Infants

Hemoglobin phase of oxygenation and deoxygenation in early brain development measured using fNIRS

Resolving the transition from negative to positive blood oxygen level-dependent responses in the developing brain

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