Macrocerebellum: Significance and Pathogenic Considerations

Macrocerebellum is a rare finding characterized by an abnormally large cerebellum. Only few patients with a syndromal or isolated macrocerebellum have been reported so far. This article aims to categorize the magnetic resonance imaging (MRI) findings, quantitate the macrocerebellum by volumetric analysis, characterize the neurological and dysmorphic features and cognitive outcome, and report the results of genetic analyses in children with macrocerebellum. All MR images were qualitatively evaluated for infratentorial and supratentorial abnormalities. Volumetric analysis was performed. Data about neurological and dysmorphic features, outcome, and genetic analysis were collected from clinical histories and follow-up examinations. Five patients were included. Volumetric analysis in three patients confirmed large cerebellar size compared to age-matched controls. MR evaluation showed that thickening of the cortical gray matter of the cerebellar hemispheres is responsible for the macrocerebellum. Additional infratentorial and supratentorial abnormalities were present in all patients. Muscular hypotonia, as well as impaired motor and cognitive development, was found in all patients, with ocular movement disorders in three of five patients. The five patients differed significantly in terms of dysmorphic features and involvement of extracerebral organs. Submicroscopic chromosomal aberrations were found in two patients. Macrocerebellum is caused by thickening of the cortical gray matter of the cerebellar hemispheres, suggesting that cerebellar granule cells may be involved in its development. Patients with macrocerebellum show highly heterogeneous neuroimaging, clinical, and genetic findings, suggesting that macrocerebellum is not a nosological entity, but instead represents the structural manifestation of a deeper, more basic biological disturbance common to heterogeneous disorder

Volumetric study of brain MRI in a cohort of patients with neurotransmitter disorders

Abstract Purpose Inborn errors of neurotransmitters are rare monogenic diseases. In general, conventional neuroimaging is not useful for diagnosis. Nevertheless, advanced neuroimaging techniques could provide novel diagnosis and prognosis biomarkers. We aim to describe cerebral volumetric findings in a group of Spanish patients with neurotransmitter disorders. Methods Fifteen 3D T1-weighted brain images from the International Working Group on Neurotransmitter related Disorders Spanish cohort were assessed (eight with monoamine and seven with amino acid disorders). Volumes of cortical and subcortical brain structures were obtained for each patient and then compared with those of two healthy individuals matched by sex and age. Results Regardless of the underlying disease, patients showed a smaller total cerebral tissue volume, which was apparently associated with clinical severity. A characteristic volumetric deficit pattern, including the right Heschl gyrus and the bilateral occipital gyrus, was identified. In severe cases, a distinctive pattern comprised the middle and posterior portions of the right cingulate, the left superior motor area and the cerebellum. In succinate semialdehyde dehydrogenase deficiency, volumetric affection seems to worsen over life. Conclusion Despite the heterogeneity and limited size of our cohort, we found novel and relevant data. Total volume deficit appears to be a marker of severity, regardless of the specific neurotransmitter disease and irrespective of the information obtained from conventional neuroimaging. Volumetric assessment of individual brain structures could provide a deeper knowledge about pathophysiology, disease severity and specific clinical traits

Brain magnetic resonance findings in 117 children with autism spectrum disorder under 5 years old.

We examined the potential benefits of neuroimaging measurements across the first 5 years of life in detecting early comorbid or etiological signs of autism spectrum disorder (ASD). In particular, we analyzed the prevalence of neuroradiologic findings in routine magnetic resonance imaging (MRI) scans of a group of 117 ASD children younger than 5 years old. These data were compared to those reported in typically developing (TD) children. MRI findings in children with ASD were analyzed in relation to their cognitive level, severity of autistic symptoms, and the presence of electroencephalogram (EEG) abnormalities. The MRI was rated abnormal in 55% of children with ASD with a significant prevalence in the high-functioning subgroup compared to TD children. We report significant incidental findings of mega cisterna magna, ventricular anomalies and abnormal white matter signal intensity in ASD without significant associations between these MRI findings and EEG features. Based on these results we discuss the role that brain MRI may play in the diagnostic procedure of ASD

Current concepts of polymicrogyria

Polymicrogyria is one of the most common malformations of cortical development. It has been known for many years and its clinical and MRI manifestations are well described. Recent advances in imaging, however, have revealed that polymicrogyria has many different appearances on MR imaging, suggesting that is may be a more heterogeneous malformation than previously suspected. The clinical and imaging heterogeneity of polymicrogyria is explored in this review

Brain development in fetal ventriculomegaly

Introduction Fetal ventriculomegaly is the most common detectable central nervous system abnormality affecting 1% of fetuses and is associated with abnormal neurodevelopment in childhood. Neurodevelopmental outcome is partially predictable by the 2D size of the ventricles in the absence of other abnormalities while the aetiology of the dilatation remains unknown. The main aim of this study was to investigate brain development in the presence of isolated ventriculomegaly during fetal and neonatal life. Methods Fetal brain MRI (1.5T) was performed in 60 normal fetuses and 65 with isolated ventriculomegaly from 22-38 gestational weeks. Volumetric analysis of the ventricles and supratentorial brain structures was performed on 3D reconstructed datasets while cortical maturation was assessed using a detailed cortical scoring system. The metabolic profile of the fetal brain was assessed using magnetic resonance spectroscopy. During neonatal life, volumetric analysis of ventricular and supratentorial brain tissue was performed while white matter microstructure was assessed using Diffusion Tensor Imaging. The neurodevelopmental outcome of these children was evaluated at 1 and 2 years of age. Results Fetuses with isolated ventriculomegaly had significantly increased cortical volumes when compared to controls while cortical maturation of the calcarine sulcus and parieto-occipital fissure was delayed. NAA:Cho, MI:Cho and MI:Cr ratios were lower whilst Cho:Cr ratios were higher in fetuses with ventriculomegaly. Neonates with prenatally diagnosed ventriculomegaly had increased ventricular and supratentorial brain tissue volumes and reduced FA values in the splenium of the corpus callosum, sagittal striatum and corona radiata. At year 2 of age, only 37.5% of the children assessed had a normal neurodevelopment. Conclusions The presence of relative cortical overgrowth, delayed cortical maturation and aberrant white matter development in fetuses with ventriculomegaly may represent the neurobiological substrate for cognitive, language and behavioural deficits in these children

Characterization of Normal Development and Injury in the Premature Baboon Brain

Nearly 13% of infants born in the United States each year are preterm - that is, born before 37 weeks gestation. Although improvements in clinical care have contributed to survival rates that now exceed 85%, premature infants are at high risk for motor, sensory, cognitive and behavioral disabilities. In order to develop therapeutic interventions to prevent these adverse neurodevelopmental outcomes, we must first understand the nature of cerebral injury associated with premature birth and the mechanisms by which it leads to altered brain development. A baboon: Papio papio) model of preterm birth was used to evaluate cerebral development from 90 days of gestation: dg) to term: ∼ 185 dg). Conventional magnetic resonance imaging: MRI) and diffusion tensor imaging: DTI) was obtained on fixed brains. In addition, histopathology was obtained. Analysis of this model led to the following conclusions.: 1) MRI/DTI findings during brain maturation closely paralleled those from live premature infants, indicating that the preterm baboon is a good model of human development.: 2) Both qualitative MRI scoring and quantitative analysis of DTI parameters correlated with pathologic abnormalities in cerebral white matter. In particular, reduced oligodendrocyte number was associated with increased radial diffusivity and decreased diffusion anisotropy, while astrocytosis corresponded to increased apparent diffusion coefficient.: 3) The birth weight of control animals correlated strongly with cerebral development as measured with MRI/DTI, with lower weight corresponding to less mature brain. Since birth weight may be an indicator of the quality of the intrauterine environment, it may better predict cerebral growth and maturation than gestational age.: 4) Clinical therapies differentially affect cerebral development and provide opportunities for neuroprotection. Positive pressure and high frequency ventilation were associated with more cerebral injury: as measured using both histology and MRI/DTI) than nasal continuous positive airway pressure.: 5) High-dose erythropoietin, a novel neuroprotective agent, had no adverse effects on cerebral development and may increase the potential for cerebral repair by inducing proliferation of cells in the subventricular zone

Human neuromaturation, juvenile extreme energy liability, and adult cognition/cooperation

Human childhood and adolescence is the period in which adult cognitive competences (including those that create the unique cooperativeness of humans) are acquired. It is also a period when neural development puts a juvenile’s survival at risk due to the high vulnerability of their brain to energy shortage. The brain of a 4 year-old human uses ≈50% of its total energy expenditure (TEE) (cf. adult ≈12%). This brain expensiveness is due to (1) the brain making up ≈6% of a 4 year-old body compared to 2% in an adult, and (2) increased energy metabolism that is ≈100% greater in the gray matter of a child than in an adult (a result of the extra costs of synaptic neuromaturation). The high absolute number of neurons in the human brain requires as part of learning a prolonged neurodevelopment. This refines inter- and intraarea neural networks so they become structured with economical “small world” connectivity attributes (such as hub organization and high cross-brain differentiation/integration). Once acquired, this connectivity enables highly complex adult cognitive capacities. Humans evolved as hunter-gatherers. Contemporary hunter-gatherers (and it is also likely Middle Paleolithic ones) pool high energy foods in an egalitarian manner that reliably supported mothers and juveniles with high energy intake. This type of sharing unique to humans protects against energy shortage happening to the immature brain. This cooperation that protects neuromaturation arises from adults having the capacity to communicate and evaluate social reputation, cognitive skills that exist as a result of extended neuromaturation. Human biology is therefore characterized by a presently overlooked bioenergetic-cognition loop (called here the “HEBE ring”) by which extended neuromaturation creates the cooperative abilities in adults that support juveniles through the potentially vulnerable period of the neurodevelopment needed to become such adults

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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