Figure 1. Global cerebral blood flow (CBF) is higher at 3 to 11 years of age than in adults. Arterial O₂ content, CBF, cerebral O₂ transport, cerebral metabolic rate of O₂ (CMRO₂), and O₂ extraction fraction in first quantitative cerebral hemodynamic study in children with the nitrous oxide wash‐in technique. Data from nine children were pooled from ages 3 to 11 years. Children at this age have higher CBF, O₂ transport, and CMRO₂, with comparable O₂ extraction fraction as 12 adults undergoing the same technique. Source: Adapted, with permission, from Kennedy C and Sokoloff L, 1957 221.

Figure 2. Cerebral blood flow (CBF) throughout childhood varies by brain region. Regional CBF was measured by SPECT imaging in 42 children ranging in age from 2 days to 19 years. Data are divided into age bins with 5 to 10 children per bin, and the mean and SD are plotted against the average age for each bin. Blood flow in cortical regions increases in infants and reaches adult levels by 1 year and exceeds adult levels from 3 to 12.5 years. CBF in frontal association cortex lags other cortical regions. In thalamus, CBF is already above adult levels in infants. Source: Adapted, with permission, from Chiron C, et al., 1992 96.

Figure 3. Regional cerebral blood flow (CBF) (A) during development (relative to adult levels) paralleled regional developmental increases in cerebral metabolic rate of O₂ (CMRO₂) (B) with little change in O₂ extraction fraction (C). Measurements were made with PET imaging in children with neurosurgical disorders but with normal psychomotor development. Compared with CBF and CMRO₂ values in adults, low values were observed in the frontal association (FA), visual association (VA), and the sensorimotor (SM) areas in the less than 1‐year‐old group (n = 10) and in the FA area in the 1‐ to less than 3‐year‐old group (n = 5). In the 3‐ to less than 8‐year‐old group (n = 7) and in the greater than 8‐year‐old group (9‐17‐years old; n = 8), CBF and CMRO₂ exceeded the corresponding adult levels in all regions (*, P < 0.05 by Mann‐Whitney U‐test), except for the FA area. Consistent with delayed maturation in cortical association cortex, CBF and CMRO₂ values were lower in FA than in primary SM area, and CBF and CMRO₂ in VA cortex were lower than in the primary visual (VC) area (a, P < 0.05 by paired t‐test), except in the ≥8‐year‐old group. P, parietal lobe; T, temporal lobe; Le, lenticulum nuclei; Th, thalamus; Ce, cerebellar hemisphere; BS, brain stem. Source: Adapted, with permission, from Takahashi T, et al., 1999 408, © 1999, American Society of Neuroradiology.

Figure 4. (A) After reaching its peak level in preadolescents, cerebral blood flow (CBF) declines in male adolescents toward levels seen in young male adults. In females, CBF also declines in early adolescence but then increases in specific regions in late adolescence. These regions are denoted by arrows on the MR images; L Inf Parietal, left inferior parietal cortex; R DLPFC, right dorsolateral prefrontal cortex; R insula, right insula cortex; vMPFC, ventromedial prefrontal cortex; R Lat Temporal, right lateral temporal cortex. Source: Reused, with permission, from Satterthwaite TD, et al., 2014 388. © 2014, National Academy of Sciences. Figure 2 from https://www.pnas.org/content/111/23/8643. (B) Structural changes in cerebral cortex during adolescence. Gray matter density (GMD), determined from T1 MRI intensity averaged over the entire brain, increases in adolescence, while gray matter volume (GMV), gray matter mass (GMM = GMD × GMV), and cortical thickness (CT) largely decrease in males and females. Note that the higher CBF per unit mass in females at the end of adolescence is associated with higher GMD and is distributed to a lower gray matter volume and mass in females compared to males, thereby attenuating sex differences in volumetric blood flow to the entire cortical volume. Values are plotted as percentages of the fitted value for males at 8 years of age. Shaded bands correspond to two SE of the fit. Source: Adapted, with permission, from Gennatas ED et al., 156.

Figure 5. Mean arterial pressure (MAP), cerebral blood flow (CBF), and cerebrovascular resistance (CVR) during human development. Source: Adapted, with permission, from Chiron C, et al., 1992 96; De Vis JB, et al., 2014 114, 2013 115; Liu P, et al., 2014 290; Ouyang M, et al., 2017 343.

Figure 6. (A) Global cerebral blood flow (CBF), derived from summation of phase‐contrast MRI of internal carotid and vertebral arteries of 14 unsedated neonates studied about 2 to 3 weeks after birth, increased linearly with gestational age determined by postmenstrual weeks (PMW) at a rate of 1.22 mL/min/100 g/ PMW. Source: Adapted, with permission, from Ouyang M, et al., 2017, 343. (B) Global cerebral metabolic rate of O₂ (CMRO₂), derived from MRI measurement of sagittal sinus O₂ saturation and CBF in 10 unsedated neonates, increased linearly with gestational age. Source: Adapted, with permission, from Liu P, et al., 2014 290, © 2014, John Wiley & Sons.

Figure 7. Postnatal increases in cerebral blood flow are coupled to postnatal increases in cerebral metabolic rate of O₂ (CMRO₂) as determined by advance near‐infrared spectroscopy (NIRS) modalities in prematurely born neonates over the first 6 weeks after birth. Noninvasive NIRS‐based optical measures of tissue hemoglobin concentration (A), tissue O₂ saturation (B), cerebral blood volume (C), a cerebral blood flow index (D), and relative CMRO₂ determined with frequency domain NIRS plus diffuse correlation spectroscopy are expressed relative to the group average in human premature neonates born at 25 to 33 weeks PMA brains. The decreases in tissue hemoglobin concentration and tissue oxyhemoglobin saturation without an accompanying decrease in cerebral blood volume are attributed to a postnatal decrease in systemic hematocrit as high‐O₂ affinity fetal hemoglobin‐containing red blood cells are cleared faster than low‐O₂ affinity adult hemoglobin‐containing red blood cells are produced. Lines are linear regressions that were all statistically significant versus age, except for cerebral blood volume. Source: Reused, with permission, from Roche‐Labarbe N, et al., 2010 379.

Figure 8. Cerebral metabolic rate of glucose (CMRGluc) of various brain regions increases during early human development and then overshoots adult levels especially in forebrain regions. Source: Adapted, with permission, from Chugani HT, et al., 1987 100.

Figure 9. Glucose utilization of the human brain by age in males (A) and females (B) and as a % of total body resting metabolic rate (rmr, solid line) and daily energy requirements (der, dashed line), expressed in glucose equivalents, for males (C) and females (D). Glucose utilization of the entire brain was estimated in units of g/day from the PET‐derived glucose consumption for each brain region and the MRI‐derived volume of each brain region at different stages of development. Through 5 years of age, the increase in total brain glucose utilization outpaces the increase in energy requirements for the entire body, whether based on resting caloric demand or including caloric needs for daily activity. The brain glucose utilization, expressed as a percent of rmr (red dots), is out of phase with the body‐weight growth rate (dw/dt, blue dots) in males (E) and females (F), suggesting an evolutionary adaptation to delay body growth so that limited caloric intake can be diverted to the prolonged period brain growth and development in humans. Glucose utilization as a percent of rmr and weight velocities are plotted as SD scores to allow unitless comparison. Source: Adapted, with permission, from Kuzawa CW, et al., 2014 241, © 2014, National Academy of Sciences. Figures 1A‐D and 2A‐B from https://www.pnas.org/content/111/36/13010.

Figure 10. Neurovascular coupling with visual stimulation. (A) Functional MRI BOLD response to visual stimulation (shaded area) in four children at age 4 to 71 months is directionally opposite of the response in adults, with a negative BOLD response occurring in children. Perfusion MRI (not shown) indicated no increase in blood flow in infants, in contrast to a 20% increase in perfusion in adults. Source: Adapted, with permission, from Born AP, et al., 2002 64, © 2002, Elsevier. (B) In response to visual stimulation, the area of significantly activated voxels in visual cortex displays a sharp transition from positive BOLD in neonates to negative BOLD responses beyond 8 weeks of age. Source: Adapted, with permission, from Yamada H, et al., 2000 468, © 2000, Wolters Kluwer.

Figure 11. Neurovascular coupling with tactile stimulation. (A) Functional MRI BOLD responses to 1‐s somatosensory stimulation of the hand in adults (n = 10), infants at term (n = 15), and preterm infants at 34 weeks (n = 10). Positive BOLD responses are smaller and delayed in infants, and the post‐stimulus undershoot is smaller in preterms. Source: Adapted, with permission, from Arichi T, et al., 2012 14. Licensed Under CCBY 3.0 Unported. (B) In six preterm neonates born at 33 to 34 weeks PMA and studied 2.5 weeks after birth, NIRS‐based measurements during 5 s of tactile stimulation show decreased O₂ extraction fraction (OEF) and increased CBF, CMRO₂, and cerebral blood volume (CBV), thereby indicating the presence of functional coupling in premature neonates. Source: Adapted, with permission, from Roche‐Labarbe N, et al. 2014 381, © 2014, Elsevier.

Figure 12. Local cerebral blood flow, measured by laser‐speckle imaging, does not increase in response to hindlimb stimulation in the neonatal mouse brain. (A‐C) Averaged time courses of the change in oxyhemoglobin (Δ[HbO]), deoxyhemoglobin (Δ[HbR]), tissue hemoglobin (Δ[HbT]), and the percent change in laser‐speckle flow (%Δ speckle) in the contralateral hindpaw region of the somatosensory cortex of mice in P7 to P8 (A), P10 to P13 (B), and adult (C) age groups (n = 5, 4, 3, respectively). Source: Adapted, with permission, from Kozberg MG, et al., 2016 236.

Figure 13. Schematic diagram of the major signaling pathways involved in neurovascular coupling. With the initiation of neuronal action, the sequence of events proceeds from left to right, resulting in ascending vasodilation, part of which depends on conduction through endothelial gap junctions. The first step occurs with the increase in CMRO₂ leading to a transient increase in deoxyhemoglobin that results in an increase in red blood cell (RBC) deformability and velocity in capillaries. The second step involves release of the coneurotransmitter ATP acting on astrocyte P2X1 receptors to stimulate mobilization of arachidonic acid (AA) via phospholipase D₂ (PLD₂) and diacylglycerol lipase (DGL). PGE₂ is synthetized by cyclooxygenase‐1 (COX‐1) and released from the astrocyte foot process to induce relaxation of pericytes via EP4 receptors. Relaxation of circumferential pericytes increases capillary diameter in the vicinity of terminal arterioles, thereby increasing RBC flux. In addition to ATP, some interneurons in close proximity to astrocyte foot processes release GABA and VIP that either directly or indirectly act to increase Ca²⁺ in the foot processes adjacent to pericytes and smooth muscle and that act to facilitate rapid vasorelaxation signaling. The third step is the action of neurotransmitters on astrocytes adjacent to vascular smooth muscle of intraparenchymal arterioles. In addition to the effects of ATP on astrocyte P2X1 receptors, glutamate can act on metabotropic glutamate receptor 5 (mGluR5) that is thought to be present on astrocytes of immature brain. Extracellular ATP can be metabolized by ectonucleotidases to adenosine, which in sufficiently high concentration can activate the low‐affinity adenosine A2B receptor. Together, these pathways may facilitate Ca²⁺ wave transmission throughout the astrocyte network leading to mobilization of AA, which can act as a substrate for cytochrome P450 (CYP) epoxygenase to produce epoxyeicosatrienoic acids (EETs). EETs can activate BK_Ca channels on the astrocyte foot process and release sufficient K⁺ into the tight extracellular space between the foot process and smooth muscle to activate Kir channels on smooth muscle, resulting in hyperpolarization and relaxation. Furthermore, ATP can be metabolized by a different ectonucleotidase on astrocytes to ADP, which can lead to activation of heme oxygenase‐2 (HO‐2) expressed in astrocytes of immature brain. HO‐2 generates CO, which in swine can facilitate the opening of BK_Ca channels on smooth muscle and possibly on astrocytes. The intermediate conductance K_Ca channel 3.1 and the TRPV4 channel on astrocytes also play a less well‐defined role in the coupling process. AA can be released as a coneurotransmitter and serve as an agonist on TRPV4 channels that signal the release of ATP into the extracellular space where they can act on adjacent astrocyte processes to produce a Ca²⁺ response. This slow spread of Ca²⁺ waves in surrounding astrocytes presumably augments vasorelaxation signaling converging on smooth muscle. In addition to astrocyte‐mediated vasodilation, neurons can exert direct effects on smooth muscle, including release of PGE₂ generated by COX‐2 in select neurons and release of NO by neuronal NO synthase (NOS) mediated by NMDA receptors. The NO can stimulate guanylyl cyclase and increase vasorelaxant cGMP in smooth muscle. NO can also inhibit CYP ω‐hydroxylase activity and the generation of 20‐HETE that normally inhibits BK_Ca channels. Some GABAergic interneurons have processes in close proximity to arterioles and capillaries and are thought to induce relaxation via an NO‐dependent mechanism. The fourth step is dilation of pial arterioles to maintain the perfusion pressure for the penetrating arterioles serving the activated and nonactivated regions. This dilation involves some of the same mechanisms mediating penetrating arteriolar dilation, including NO generated by neuronal NOS and CO generated by HO‐2 in astrocytes in the glia limitans. One difference is that the astrocyte‐derived adenosine acts directly on pial arteriole smooth muscle A2A receptors to produce dilation.

Figure 14. Developmental increases in nitric oxide synthase (NOS) activity in sheep. (A) NOS catalytic activity, measured in fresh cortical samples, increased fourfold between 0.48 and 0.92 gestation in fetal sheep. CBF (B) and CMRO₂ (C) increase threefold between 0.63 and 0.92 gestation, and inhibition of NOS activity with nitro‐L‐arginine methyl ester (L‐NAME) decreases CBF in unanesthetized fetal sheep at both gestational ages without reducing CMRO₂. These results imply that NO is tonically generated in quantities sufficient to induce vasodilation by midgestation in fetal sheep. Source: Modified, with permission, from Northington FJ, et al., 1997 335.

Figure 15. Angiogenesis across cerebral cortical layers. In cerebral cortex of PND1 rabbits, capillary density and CBF are lower in deeper layers and increase during postnatal development. Cytochrome oxidase activity also increases in all cortical layers during development, but in relative terms, its spatial gradient is less than the spatial gradient of capillary density. This comparison suggests that increases in capillary density lag the increases in the mitochondrial capacity for energy metabolism. Source: Adapted, with permission, from Tuor UI, et al., 1994 417.

Figure 16. Pressure‐diameter relationship of human infant middle cerebral artery at 37 week gestation. The artery was subjected to changes in transmural pressure in random steps between 30 and 80 mmHg in physiologic salt solution (PSS). With increased transmural pressure, arterial diameter decreased (open circles), indicative of increased myogenic tone. In the presence of PSS containing 127 mmol/liter of KCl to induce depolarization and a maximum contractile state (closed circles), diameter increased slightly with increasing transmural pressure. In the presence of Ca²⁺‐free PSS containing 2 mmol/liter EGTA (triangles), the diameter increased passively at each pressure value. The difference between the passive and active curves indicates that the human middle cerebral artery is capable of generating a considerable myogenic response at this developmental age. Source: Adapted, with permission, from Bevan RD, et al., 1998 58, © 1998, Springer Nature.

Figure 17. Relationship of cerebral blood flow to cerebral perfusion pressure at different stages of human development. These idealized autoregulation curves are based on the limited number of studies of autoregulation in early human development and of studies of autoregulation in immature animals with extrapolation of the stage of brain maturation of the particular species to human development.

Figure 18. (A) The distribution of the cerebral oximetry index (COx) across binned mean arterial blood pressure (ABP) in children undergoing cardiopulmonary bypass (CPB). Assuming a constant CMRO₂ during the sampling period, a low COx indicates a low correlation of tissue HbO₂ with variations in ABP (good CBF autoregulation), and a high COx indicates a high correlation of tissue HbO₂ with variations in ABP (poor CBF autoregulation). A COx value of 0.4 (horizontal dashed line) is assumed to correspond to the lower limit of autoregulation (LLA) threshold. (B) The distribution of percent of total monitoring time at each ABP before, during, and after CPB. (A, B) Source: Adapted, with permission, from Brady K, et al., 2010 66. (C) The percentage of time spent below an ABP of 40 mmHg was greater during CPB than before or after CPB. (D) The average individual LLA with COx less than 0.4 for 42 pediatric patients was 42 ± 7 mmHg compared with 55 ± 14 mmHg for 37 adults patients undergoing cardiopulmonary bypass (±SD; P < 0.0001 between age groups).

Figure 19. Phase‐angle relationship of the response of ICP to quasi‐sinusoidal variations in arterial blood pressure (ABP) induced by frequency modulation of positive end‐expiratory pressure in two‐week‐old piglets. When ABP was above the lower limit of autoregulation (LLA, open circles), the phase angle decreased when the ABP frequency increased from 1 to 6 cycles per minute (CPM). Assuming that ICP is related to cerebral blood volume, which is related to cerebral vasodilation and vasoconstriction responses, dynamic autoregulation is ineffective at periodicities less than 10 s. When ABP is below the LLA (closed circles), the phase angle is already reduced at low frequencies, confirming that frequency analysis at low ABP frequencies can be used to assess autoregulation. Source: Adapted, with permission, from Fraser CD, 2013 144, © 2013, The American Physiological Society.

Figure 20. Noradrenergic constriction is enhanced in human preterm cerebral arteries. (A) Catecholamine histofluorescence of perivascular nerves is prominent in proximal middle cerebral artery at gestational age 38 weeks (a) and term (b) and in basilar artery at gestational age 32 weeks (c), 5 weeks (d), and 38 weeks (e). (B) Catecholamine histofluorescence in perivascular nerves is also prominent at gestational age of 24 weeks in distal middle cerebral artery (a) and a branch of basilar artery (b). (C) The response of middle cerebral artery from infant of 24 weeks of gestation to norepinephrine before (left) and after (right) endothelium inactivation, which attenuated the relaxation to acetylcholine while preserving norepinephrine‐induced contraction. Source: Adapted, with permission, from Bevan R, et al. 1998 56, © 1998, Springer Nature. Comparison of the dose to produce constriction in 50% of cerebral arteries (ED₅₀) (D) and normalized tension generated in response to norepinephrine (E) and electrical field stimulation (F) of cerebral arteries studied within 2 days of autopsy in eight neonates at 23 to 38 weeks PMA and 21 adults (mean ± SE). Comparison of the mean number of catecholaminergic nerve fibers per millimeter length of cerebral arteries in 2 neonates and 15 adults (G). Source: Adapted, with permission, from Bevan R, et al., 1998 56.

Figure 21. Developmental changes in norepinephrine‐induced constriction of pial arteries. (A) When applied through a closed cranial window, norepinephrine produced dose‐dependent constriction in anesthetized fetal sheep and newborn lambs but not in adult sheep. The effect was most pronounced in fetuses less than 121 days gestation (<0.8 full term). (B) Electrical stimulation of the superior cervical sympathetic ganglion produced constriction of pial arteries that was blocked by the α‐adrenergic antagonist prazosin. Source: Adapted, with permission, from Wagerle LC, et al., 1990 442, © 1990, The American Physiological Society.

Figure 22. Developmental changes in blood‐brain barrier permeability in sheep. The influx transfer constant (Ki) for radiolabeled aminoisobutyric acid shows a progressive decrease from 60% of gestation in fetal sheep through adulthood in various brain regions. However, even at 60% of gestation, the transfer constant is not considered high and indicates that significant diffusion restriction is present for this metabolically inert small molecule. Source: Modified, with permission, from Stonestreet BS, et al., 1996 402, © 1996, The American Physiological Society.

Figure 23. Developmental changes in tight junction protein organization. Immunostaining of occludin and claudin‐5 shows endothelial cytoplasmic staining with some linear cell membrane assembly of occludin present at 12 weeks PMA in human fetal telencephalon (A, B). By 14 weeks, linear beaded staining of occludin and claudin‐5 becomes evident in the cell membrane (C, D). At 18 weeks, a more mature appearance of nearly linear immunostaining of occludin and claudin‐5 occurs. Source: Adapted, with permission, from Virgintino et al. 434.

Figure 24. Endothelial vasodilator function is depressed in fetal sheep carotid arteries. Postnatal maturation is associated with a moderately increased abundance of endothelial nitric oxide synthase (eNOS). However, when normalized by the luminal surface area or by eNOS concentration, the amount of NO generated in response to the calcium ionophore A23187 or to endothelial shear stress is greater in adult than in fetal arteries. In contrast, NO generation by ADP is not significantly different. Thus, eNOS coupling mechanisms are not fully mature in fetal sheep arteries, and maturation may depend on the nature of the stimulus. Mean ± SE, n = 6‐8. Source: Adapted, with permission, from White CR, et al., 2005 451, © 2005, The American Physiological Society.

Figure 25. Role of CO in immature neurovascular unit in glia limitans. Neurotransmitter glutamate binds to astrocyte ionotropic and metabotropic glutamate (GLU) receptors (iGLUR and mGLUR) expressed on immature astrocytes, elevating [Ca²⁺]_i that increases heme oxygenase‐2 (HO‐2 activity) and generates CO. The CO diffuses to pial artery vascular smooth muscle where it binds to a heme element that increases Ca²⁺ spark‐to‐BK_Ca channel coupling, thereby elevating BK_Ca channel activity. In addition, CO increases Ca²⁺ spark frequency, further increasing BK_Ca channel activity. The resulting smooth muscle cell hyperpolarization produces vasodilation. Furthermore, endothelial‐derived NO and PGI₂ provide a minimal amount of guanylyl cyclase (GC) and cGMP and/or activation of PGI₂ receptors (IP), adenylyl cyclase (AC), and cAMP. The resulting protein kinase G (PKG) activity may phosphorylate sarcoplasmic reticulum RyRs, increasing Ca²⁺ spark frequency and/or the BK_Ca channel. In the intact vasculature, NO and PGI₂ can activate smooth muscle cell GC and AC directly, if a stimulus is sufficient at the endothelial cell. In addition to glutamate, neurons can release ATP from neurotransmitter vesicles, the ATP can be degraded to ADP by an astrocyte endonucleotidase, and the ADP can act on astrocyte P2Y1 receptors to also activate HO‐2 (not shown). IP₃, inositol 1,4,5‐trisphosphate. Source: Adapted, with permission, from Leffler CW, et al., 2011 276, © 2011, The American Physiological Society.

Figure 26. Schematic diagram of endothelial‐derived factors in dilation of pial arterioles to hypercapnia. Acidosis is thought to activate cystathionine γ‐lyase (CSE) and generate H₂S, which activates K_ATP channels and induces hyperpolarization and consequent inhibition of VDCC, voltage‐dependent Ca²⁺ channels (VDCC). H₂S also promotes Ca²⁺ sparks and activation of BK_Ca channels (not shown), which also play a role in hypercapnic dilation. In addition, acidosis is thought to stimulate arachidonic acid (AA) release and cyclooxygenase (COX) activity and generate PGI₂, which then acts on the smooth muscle prostacyclin receptor (IP) to stimulate adenylyl cyclase (AC). Source: Adapted, with permission, from Leffler CW, et al., 2011 274, © 2011, The American Physiological Society.

Figure 27. Developmental changes in the cerebrovascular response to hypoxia in unanesthetized sheep. (A) Over a wide range of arterial O₂ content, cerebral blood flow (CBF) increases from 0.6 gestation to 0.9 gestation in fetal sheep, remains elevated after birth, and then decreases in adults. (B) At 0.6 gestation, the increase in CBF is inadequate to maintain cerebral O₂ transport, whereas the O₂ transport is maintained later in development during hypoxia. (C) O₂ extraction fraction, which is the ratio of CMRO₂ to O₂ transport, is also maintained during hypoxia later in development, although the level is highest in adults and lowest at 0.6 gestation. The levels of O₂ extraction fraction differed among groups despite normalization with the different levels of CMRO₂ (indicated as μmol O₂/min/100 g). (D‐F) Fetal sheep at 0.9 gestation and neonatal lambs underwent a partial exchange transfusion with adult sheep blood having a P₅₀ (PO₂ at 50% oxyhemoglobin saturation) of 44 Torr to increase the P₅₀ from 17 to 32 Torr in fetal sheep and from 26 to 37 Torr in neonatal lambs. Compared to the pretransfusion responses to hypoxia, the CBF and O₂ transport responses were reduced, and the O₂ extraction fraction was elevated to levels closer to those seen in adult sheep. Source: Adapted, with permission, from Koehler RC, et al., 1986 228, 1984 230; Gleason CA, et al., 1990 161; Rosenberg AA, et al., 1986 382.

Figure 28. (A) Example of real‐time monitoring of pressure‐reactivity index (PRx) for 72 h in a child after TBI. Top trace shows arterial blood pressure (ABP, black) and CPP (gray), second trace shows ICP, and third trace shows PRx. Bottom chart shows the PRx within 5 mmHg CPP bins averaged over 72 h for this single patient. An optimal CPP of 57.5 mmHg could be identified wherein PRx had a minimal value. (B) The average PRx for 36 children after TBI displays a U‐shaped curve. (C) The optimal CPP (CPP_opt) in 34 TBI patients correlated with the patient's age. Source: Adapted, with permission, from Lewis PM, et al., 2015 278, © 2015, Wolters Kluwer.

Figure 29. Schematic diagram of potential mechanisms of impaired cerebrovascular regulation after hypoxia‐ischemia, stroke, and fluid percussion injury in piglets. Endothelin‐1 (ET‐1) and vasopressin have been implicated in the release of the endogenous opioid nociception/orphanin FQ (NOC/oFQ) that can result in the generation of superoxide through a PKC signaling in concert with activation of cyclooxygenase (COX). Acting through protein tyrosine kinase (PKT) and ERK/MAPK signaling, superoxide generation results in impaired K⁺ channel function. Focal stroke stimulates endogenous tissue plasminogen activator (tPA) that is known to augment activation of NMDA receptors. This pathway can result in increased ET‐1 and activation of ERK/MAPK. It also produces an inflammatory response leading to increased interleukin‐6 and impaired function of K⁺ channels. Inhaled nitric oxide can block the increase in ET‐1 and preserve autoregulation. Source: Adapted, with permission, from Pastor P, et al., 2019 361; Armstead, WM, 2005 34.

Figure 30. Synthesis of the relative time course of developmental regulation of the cerebral circulation and energy metabolism. Blood‐brain barrier (BBB) function, CMRO₂, CMRGluc, cerebral O₂ transport, CBF reactivity to CO₂, and neurovascular coupling are normalized relative to an adult value of 1. Autoregulation is displayed in terms of the upper (ULA) and lower (LLA) limits of autoregulation (mmHg) below and above which CBF is pressure passive. All lines are based on human data or, in the cases where human data are not available, on animal data. Interpolation was used in cases where no data are available for a particular developmental stage. Note that energy metabolism and O₂ transport overshoot adult values between the infant and adolescent stages, whereas CO₂ reactivity does not. Also, O₂ transport has a postnatal dip, attributable to transient anemia and the decrease in hemoglobin O₂ affinity as fetal hemoglobin is replaced with adult hemoglobin. Neurovascular coupling is thought to have a transient increase near term and then decrease during the period of elevated CMRGluc. The range of autoregulation between the ULA and LLA progressively expands during development.