Human metabolic adaptations and prolonged expensive neurodevelopment: A review

1.	After weaning, human hunter-gatherer juveniles receive substantial (≈3.5-7 MJ day^-1^), extended (≈15 years) and reliable (kin and nonkin food pooling) energy provision.
2.	The childhood (pediatric) and the adult human brain takes a very high share of both basal metabolic rate (BMR) (child: 50-70%; adult: ≈20%) and total energy expenditure (TEE) (child: 30-50%; adult: ≈10%).
3.	The pediatric brain for an extended period (≈4-9 years-of-age) consumes roughly 50% more energy than the adult one, and after this, continues during adolescence, at a high but declining rate. Within the brain, childhood cerebral gray matter has an even higher 1.9 to 2.2-fold increased energy consumption. 
4.	This metabolic expensiveness is due to (i) the high cost of synapse activation (74% of brain energy expenditure in humans), combined with (ii), a prolonged period of exuberance in synapse numbers (up to double the number present in adults). Cognitive development during this period associates with volumetric changes in gray matter (expansion and contraction due to metabolic related size alterations in glial cells and capillary vascularization), and in white matter (expansion due to myelination). 
5.	Amongst mammals, anatomically modern humans show an unique pattern in which very slow musculoskeletal body growth is followed by a marked adolescent size/stature spurt. This pattern of growth contrasts with nonhuman primates that have a sustained fast juvenile growth with only a minor period of puberty acceleration. The existence of slow childhood growth in humans has been shown to date back to 160,000 BP. 
6.	Human children physiologically have a limited capacity to protect the brain from plasma glucose fluctuations and other metabolic disruptions. These can arise in adults, during prolonged strenuous exercise when skeletal muscle depletes plasma glucose, and produces other metabolic disruptions upon the brain (hypoxia, hyperthermia, dehydration and hyperammonemia). These are proportional to muscle mass.
7.	Children show specific adaptations to minimize such metabolic disturbances. (i) Due to slow body growth and resulting small body size, they have limited skeletal muscle mass. (ii) They show other adaptations such as an exercise specific preference for free fatty acid metabolism. (iii) While children are generally more active than adolescents and adults, they avoid physically prolonged intense exertion. 
8.	Childhood has a close relationship to high levels of energy provision and metabolic adaptations that support prolonged synaptic neurodevelopment. 
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Plasma cholesterol levels and brain development in preterm newborns.

BackgroundTo assess whether postnatal plasma cholesterol levels are associated with microstructural and macrostructural regional brain development in preterm newborns.MethodsSixty preterm newborns (born 24-32 weeks gestational age) were assessed using MRI studies soon after birth and again at term-equivalent age. Blood samples were obtained within 7 days of each MRI scan to analyze for plasma cholesterol and lathosterol (a marker of endogenous cholesterol synthesis) levels. Outcomes were assessed at 3 years using the Bayley Scales of Infant Development, Third Edition.ResultsEarly plasma lathosterol levels were associated with increased axial and radial diffusivities and increased volume of the subcortical white matter. Early plasma cholesterol levels were associated with increased volume of the cerebellum. Early plasma lathosterol levels were associated with a 2-point decrease in motor scores at 3 years.ConclusionsHigher early endogenous cholesterol synthesis is associated with worse microstructural measures and larger volumes in the subcortical white matter that may signify regional edema and worse motor outcomes. Higher early cholesterol is associated with improved cerebellar volumes. Further work is needed to better understand how the balance of cholesterol supply and endogenous synthesis impacts preterm brain development, especially if these may be modifiable factors to improve outcomes

Human metabolic adaptations and prolonged expensive neurodevelopment: A review

1.	After weaning, human hunter-gatherer juveniles receive substantial (≈3.5-7 MJ day^-1^), extended (≈15 years) and reliable (kin and nonkin food pooling) energy provision.
2.	The childhood (pediatric) and the adult human brain takes a very high share of both basal metabolic rate (BMR) (child: 50-70%; adult: ≈20%) and total energy expenditure (TEE) (child: 30-50%; adult: ≈10%).
3.	The pediatric brain for an extended period (≈4-9 years-of-age) consumes roughly 50% more energy than the adult one, and after this, continues during adolescence, at a high but declining rate. Within the brain, childhood cerebral gray matter has an even higher 1.9 to 2.2-fold increased energy consumption. 
4.	This metabolic expensiveness is due to (i) the high cost of synapse activation (74% of brain energy expenditure in humans), combined with (ii), a prolonged period of exuberance in synapse numbers (up to double the number present in adults). Cognitive development during this period associates with volumetric changes in gray matter (expansion and contraction due to metabolic related size alterations in glial cells and capillary vascularization), and in white matter (expansion due to myelination). 
5.	Amongst mammals, anatomically modern humans show an unique pattern in which very slow musculoskeletal body growth is followed by a marked adolescent size/stature spurt. This pattern of growth contrasts with nonhuman primates that have a sustained fast juvenile growth with only a minor period of puberty acceleration. The existence of slow childhood growth in humans has been shown to date back to 160,000 BP. 
6.	Human children physiologically have a limited capacity to protect the brain from plasma glucose fluctuations and other metabolic disruptions. These can arise in adults, during prolonged strenuous exercise when skeletal muscle depletes plasma glucose, and produces other metabolic disruptions upon the brain (hypoxia, hyperthermia, dehydration and hyperammonemia). These are proportional to muscle mass.
7.	Children show specific adaptations to minimize such metabolic disturbances. (i) Due to slow body growth and resulting small body size, they have limited skeletal muscle mass. (ii) They show other adaptations such as an exercise specific preference for free fatty acid metabolism. (iii) While children are generally more active than adolescents and adults, they avoid physically prolonged intense exertion. 
8.	Childhood has a close relationship to high levels of energy provision and metabolic adaptations that support prolonged synaptic neurodevelopment. 
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Altered white matter microstructure is associated with social cognition and psychotic symptoms in 22q11.2 microdeletion syndrome.

22q11.2 Microdeletion Syndrome (22q11DS) is a highly penetrant genetic mutation associated with a significantly increased risk for psychosis. Aberrant neurodevelopment may lead to inappropriate neural circuit formation and cerebral dysconnectivity in 22q11DS, which may contribute to symptom development. Here we examined: (1) differences between 22q11DS participants and typically developing controls in diffusion tensor imaging (DTI) measures within white matter tracts; (2) whether there is an altered age-related trajectory of white matter pathways in 22q11DS; and (3) relationships between DTI measures, social cognition task performance, and positive symptoms of psychosis in 22q11DS and typically developing controls. Sixty-four direction diffusion weighted imaging data were acquired on 65 participants (36 22q11DS, 29 controls). We examined differences between 22q11DS vs. controls in measures of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), using both a voxel-based and region of interest approach. Social cognition domains assessed were: Theory of Mind and emotion recognition. Positive symptoms were assessed using the Structured Interview for Prodromal Syndromes. Compared to typically developing controls, 22q11DS participants showed significantly lower AD and RD in multiple white matter tracts, with effects of greatest magnitude for AD in the superior longitudinal fasciculus. Additionally, 22q11DS participants failed to show typical age-associated changes in FA and RD in the left inferior longitudinal fasciculus. Higher AD in the left inferior fronto-occipital fasciculus (IFO) and left uncinate fasciculus was associated with better social cognition in 22q11DS and controls. In contrast, greater severity of positive symptoms was associated with lower AD in bilateral regions of the IFO in 22q11DS. White matter microstructure in tracts relevant to social cognition is disrupted in 22q11DS, and may contribute to psychosis risk

Long-term functional outcomes and correlation with regional brain connectivity by MRI diffusion tractography metrics in a near-term rabbit model of intrauterine growth restriction

Background: Intrauterine growth restriction (IUGR) affects 5-10% of all newborns and is associated with increased risk of memory, attention and anxiety problems in late childhood and adolescence. The neurostructural correlates of long-term abnormal neurodevelopment associated with IUGR are unknown. Thus, the aim of this study was to provide a comprehensive description of the long-term functional and neurostructural correlates of abnormal neurodevelopment associated with IUGR in a near-term rabbit model (delivered at 30 days of gestation) and evaluate the development of quantitative imaging biomarkers of abnormal neurodevelopment based on diffusion magnetic resonance imaging (MRI) parameters and connectivity. Methodology: At +70 postnatal days, 10 cases and 11 controls were functionally evaluated with the Open Field Behavioral Test which evaluates anxiety and attention and the Object Recognition Task that evaluates short-term memory and attention. Subsequently, brains were collected, fixed and a high resolution MRI was performed. Differences in diffusion parameters were analyzed by means of voxel-based and connectivity analysis measuring the number of fibers reconstructed within anxiety, attention and short-term memory networks over the total fibers. Principal Findings: The results of the neurobehavioral and cognitive assessment showed a significant higher degree of anxiety, attention and memory problems in cases compared to controls in most of the variables explored. Voxel-based analysis (VBA) revealed significant differences between groups in multiple brain regions mainly in grey matter structures, whereas connectivity analysis demonstrated lower ratios of fibers within the networks in cases, reaching the statistical significance only in the left hemisphere for both networks. Finally, VBA and connectivity results were also correlated with functional outcome. Conclusions: The rabbit model used reproduced long-term functional impairments and their neurostructural correlates of abnormal neurodevelopment associated with IUGR. The description of the pattern of microstructural changes underlying functional defects may help to develop biomarkers based in diffusion MRI and connectivity analysis

Media Violence Effects on Brain Development: What Neuroimaging Has Revealed and What Lies Ahead

Substantial research has indicated that media violence induces both short- and long-term increases in aggressive thoughts, feelings, and behaviors. Recently, neuroimaging techniques have begun to identify the mechanisms driving these changes. An important avenue that these neuroimaging tools can address is how exposure to media violence in childhood affects brain development, which can have lifelong behavioral consequences. This review highlights neuroimaging research examining how media violence exposure affects the pediatric brain. While such research is limited, evidence suggests that prefrontal mechanisms for controlling emotion and behavior are altered by exposure to violent media. Therefore, long-term increases in aggression and decreases in inhibitory control due to excessive media violence exposure may result from impaired development of prefrontal regions. However, additional neuroimaging research is necessary to establish whether and how exposure to media violence specifically shapes subsequent neural maturation. To optimize the use of neuroimaging in this inquiry, imaging studies should not stand on their own, but instead must be integrated with more traditional research paradigms to establish a more complete picture of effects. Future research must employ more longitudinal approaches to better characterize long-term effects that high exposure to violent screen media may have on brain development, particularly prefrontal and limbic brain regions

Later-life structural and functional consequences of youth exposure to repeated head impacts

Youth football players ages 8-12 may incur hundreds of repeated head impacts (RHI) each season. Evidence suggests concussive brain injury during childhood may disrupt normal developmental processes resulting in long-term impairments. However, little research has investigated the long-term effects of incurring RHI during critical periods of neurodevelopment. Rapid myelination and cerebral blood flow rates, peaks in regional cortical thickness and volumes of specific structures, refinement of regional connectivity, and other neurodevelopmental changes occurring in the brain from ages 10-12 could create a window of vulnerability to RHI. The objective of this research was to determine the relationship between exposure to RHI prior to age 12, during a critical period of neurodevelopment, and later-life brain structure and function. Former National Football League (NFL) players ages 40-65 were divided into two groups based on their age of first exposure (AFE) to RHI through tackle football: AFE <12 and AFE ≥12. In the first study, we observed significantly lower scores on objective tests of executive functioning, memory, and estimated verbal IQ in those who began playing football prior to age 12 compared to those who began playing at age 12 or older. Next, we used diffusion tensor imaging (DTI) to examine the structural integrity of the corpus callosum (CC) and observed that the AFE <12 group had significantly lower fractional anisotropy (FA) as well as a greater decline in FA with age in anterior CC regions than the AFE ≥12 group. Lastly, we used advanced DTI tractography techniques to examine seven CC regions. Significant differences between AFE groups in associations between CC diffusion measures and cognition, mood, and behavior were found. The results of this research suggest that incurring RHI through tackle football during a critical neurodevelopmental period prior to age 12 may result in later-life structural and functional consequences, including cognitive, mood, and behavioral impairments; alterations in white matter structure; and greater vulnerability of white matter to the normal aging process. If replicated with longitudinal designs, larger samples, and athletes whose highest level of play was youth, high school, or college, these findings may have implications for safety recommendations for youth sports

TEST-RETEST RELIABILITY OF FRACTIONAL ANISOTROPY IN 5-YEAR-OLDS

Diffusion tensor imaging (DTI) has provided great insights to the microstructural features of developing brain and has been shown to be reliable in infants. However, the repeatability of the DTI scalars for older pediatric age groups has not been thoroughly addressed. In this study, DTI scans of 5-year-olds were used to investigate the test-retest reliability of three different measurements with both voxel-wise and region of interest (ROI) analysis. Out of 96 diffusion encoding directions, divided into three parts, 20 unique diffusion encoding directions were chosen per measurement from 48 subjects. Tract based spatial analysis (TBSS) was used to extract fractional anisotropy (FA) values from those images and using the FA values the repeatability of the measurements was assessed by intraclass correlation coefficient (ICC) and standard error of measurement (SEM). Overall, FA values had high repeatability both in voxel-based analysis (ICC>0.73) and ROI analysis (for non-skeletonized ROI type 88% of the ROI labels: ICC>0.75, for skeletonized ROI type 87% of the ROI labels: ICC>0.75). Using a skeleton in the ROI analysis did not contribute to the repeatability and the volume size was found to be a contributing factor for repeatability. Interscanner reliability as well as reliability measured by using different atlases are yet to be investigated in 5-year-old data