Early alterations in cortical and cerebellar regional brain growth in Down Syndrome: An in vivo fetal and neonatal MRI assessment.

Down Syndrome (DS) is the most frequent genetic cause of intellectual disability with a wide spectrum of neurodevelopmental outcomes. At present, the relationship between structural brain morphology and the spectrum of cognitive phenotypes in DS, is not well understood. This study aimed to quantify the development of the fetal and neonatal brain in DS participants, with and without a congenital cardiac defect compared with a control population using dedicated, optimised and motion-corrected in vivo magnetic resonance imaging (MRI). We detected deviations in development and altered regional brain growth in the fetus with DS from 21 weeks' gestation, when compared to age-matched controls. Reduced cerebellar volume was apparent in the second trimester with significant alteration in cortical growth becoming evident during the third trimester. Developmental abnormalities in the cortex and cerebellum are likely substrates for later neurocognitive impairment, and ongoing studies will allow us to confirm the role of antenatal MRI as an early biomarker for subsequent cognitive ability in DS. In the era of rapidly developing technologies, we believe that the results of this study will assist counselling for prospective parents.

Assessment of oxidative stress in hippocampus, cerebellum and frontal cortex in rat pups exposed to lead (Pb) during specific periods of initial brain development.

Epidemiological studies in children have proved that lead (Pb) exposure causes deficits in neural and cognitive functions. The present study assessed the oxidative stress on postnatal day 30, in the hippocampus, cerebellum and frontal cortex of rat pups exposed to Pb during specific periods of early brain development. Five groups of rat pups were investigated, and 0.2% Pb acetate in drinking was the dosage used. (i) Gestation and lactation (GL) group (n = 9) of rat pups was exposed to Pb during gestation and lactation through their mother, (ii) gestation (G) group (n = 9) of rat pups was exposed to Pb during gestation only, (iii) lactation (L) group (n = 9) of rat pups was exposed to Pb during lactation only, (iv) pre-gestation (PG) group (n = 9) of rat pups was born to mothers who were exposed to Pb for 1 month before conception, and (v) normal control (NC) (n = 9) group of rats pups had no exposure to Pb during gestation and lactation period. From the present study, it is evident that Pb exposure during different periods of early brain development (GL, G, L and PG groups) causes oxidative stress and lactation period (postnatal period) of Pb exposure produces maximum oxidative stress.

Postnatal ultrasound reliability in cerebellar vermis assessment.

BACKGROUND: Cerebellar growth in late gestation is impeded by prematurity which may adversely affect neurocognitive development. Assessment of cerebellar growth should be easily attainable, reliable and reproducible. OBJECTIVE: To assess the reliability of linear sonographic cerebellar vermis measurement. METHOD: Cranial ultrasounds of 110 infants ranging from 24 to 41 weeks' gestation were retrospectively reviewed. Cerebellar vermian height, craniocaudal diameter and superior and inferior vermis widths were independently measured on the first midline sagittal image by three neonatal sonologists of varying experience. Interobserver and intraobserver reliability were calculated using the intraclass correlation coefficient (ICC) (2 way mixed model, SPSS V.15.0). RESULTS: 61 images were technically adequate. Interobserver ICCs (95% CI) were: cerebellar vermian height 0.88 (0.82 to 0.92); craniocaudal diameter 0.91 (0.86 to 0.94); superior vermis width 0.84 (0.77 to 0.89); inferior vermis width 0.92 (0.89 to 0.95). Intraobserver ICCs were similar. CONCLUSION: With adequate images, linear ultrasound measurements of cerebellar vermis are reliable.

Relations between brain volumes, neuropsychological assessment and parental questionnaire in prematurely born children.

The objective of this study is to assess the relationship between brain volumes at term equivalent age and neuropsychological functions at 5 years of age in very low birth weight (VLBW) children, and to compare the results from a neuropsychological assessment and a parental questionnaire at 5 years of age. The study group included a regional cohort of 97 VLBW children and a control group of 161 children born at term. At term equivalent age, brain magnetic resonance imaging (MRI) was performed on the VLBW children, and analysed for total and regional brain volumes. At 5 years of age, a psychologist assessed the neuropsychological performance with NEPSY II, and parents completed the Five to fifteen (FTF) questionnaire on development and behaviour. The results of the control group were used to give the age-specific reference values. No significant associations were found between the brain volumes and the NEPSY II domains. As for the FTF, significant associations were found between a smaller total brain tissue volume and poorer executive functions, between a smaller cerebellar volume and both poorer executive functions and motor skills, and, surprisingly, between a larger volume of brainstem and poorer language functions. Even after adjustment for total brain tissue volume, the two associations between the cerebellar volume and the FTF domains remained borderline significant (P = 0.05). The NEPSY II domains Executive Functioning, Language and Motor Skills were significantly associated with the corresponding FTF domains. In conclusion, altered brain volumes at term equivalent age appear to affect development still at 5 years of age. The FTF seems to be a good instrument when used in combination with other neuropsychological assessment.

Preterm birth and disruptive cerebellar development: assessment of perinatal risk factors.

OBJECTIVE: Abnormal cerebellar development was recently recognized to be related to prematurity. Aim of the present study was to evaluate preterm birth and possible peri- and postnatal risk factors associated with this type of brain injury. PATIENTS AND METHODS: We report on a series of 35 very low birth weight infants (birth weight 986+/-257g S.D.) born between 24 and 32 weeks of gestation (27.0+/-1.8 weeks of gestation S.D.) sustaining disruption of cerebellar development after preterm birth. Perinatal medical records of study patients were compared to 41 preterm control infants (birth weight 900+/-358g S.D., gestational age 26.3+/-2.1 weeks S.D.) with normal cerebellar development on MRI scan. RESULTS: A severely compromised postnatal condition with consecutive intubation and catecholamine support was found to be significant risk factor. Additional supratentorial hemorrhagic brain injury followed by posthemorrhagic hydrocephalus, neurosurgical interventions and hemosiderin deposits on the cerebellar surface were significantly related to disruptive cerebellar development. No other differences in perinatal factors were found between the groups. CONCLUSION: Premature birth between 24 and 32 gestational weeks associated with poor postnatal conditions and complicated supratentorial hemorrhagic brain lesions represents a high-risk situation for disruption of cerebellar development.

Heterogeneous conductance levels of native AMPA receptors.

The single-channel properties of AMPA receptors can affect information processing in neurons by influencing the amplitude and kinetics of synaptic currents, yet little is known about the unitary properties of native AMPA receptors in situ. Using whole-cell and outside-out patch-clamp recordings from granule cells in acute cerebellar slices, we found that migrating granule cells begin to express AMPA receptors before they arrive in the internal granule cell layer and receive synaptic input. At saturating agonist concentrations, the open probability of channels in outside-out patches from migrating cells was very high, allowing us to identify patches that contained only one or two active channels. Analysis of the single-channel activity in these patches showed that individual AMPA receptors exhibit as many as four distinguishable conductance levels. The conductance levels observed varied substantially for different channels, although on average the values fell within the range of unitary conductances estimated previously for synaptic AMPA receptors. In contrast to patches from migrating granule cells, we rarely observed directly resolvable single-channel currents in patches excised from the somata of granule cells in the internal granular layer, even though these cells gave large AMPA receptor whole-cell currents. We did, however, detect AMPA receptors with apparent unitary conductances of <1 pS in patches from both migrating and mature granule cells. Our results suggest that granule cells express a heterogeneous population of AMPA receptors, a subset of which are segregated to postsynaptic sites after synaptogenesis.

MRI assessment of myelination of motor and sensory pathways in the brain of preterm and term-born infants.

A study was performed in 48 neurologically normal preterm and term-born infants, with a postconceptional age at MRI varying between 30 2/7 and 46 weeks and a mean age of 34 2/7 weeks. The purpose of the study was to determine the normal progress of myelination on MRI in that age range. T1- and T2-weighted images of the brain were assessed for changes in signal intensity of white matter relative to gray matter. Multiple sites in the brainstem, cerebellum and cerebral hemispheres were assessed separately. The findings were correlated with the ages of the infants. As judged from relative signal intensities, myelin was present at the post-conceptional age of 30-34 weeks in the following structures: tegmentum pontis (in particular medial lemniscus), superior and inferior colliculi, decussation of the superior cerebellar peduncles, crura cerebri, ventrolateral thalamus, lateral globus pallidus, dorsolateral putamen, dentate nucleus, middle and superior cerebellar peduncles, vermis cerebelli, cortex bordering the central sulcus and hippocampus. Little progress in myelination was noticed up to the post-conceptional age of 46 weeks. Between 34 and 46 weeks, myelin appeared in the lateral part of the posterior limb of the internal capsule and in the central part of the corona radiata and became more prominently visible in the cortex bordering the central sulcus.

Development and aging of brain midline structures: assessment with MR imaging.

The development and aging of four brain midline structures--the pituitary gland, pons, cerebellar vermis, and corpus callosum--were studied. The dimensions and area of these structures were measured by means of midsagittal magnetic resonance imaging. The study group consisted of 94 patients newborn to 15 years old and 49 patients and seven volunteers 16-60 years old. Except for growth spurts in the 1st year and in the 10-15-year age range, the pituitary gland showed linear growth. The pons, cerebellar vermis, and corpus callosum all showed exponential growth. The cerebellar vermis showed the sharpest 1st-year growth spurt, followed by the corpus callosum and the pons. The pituitary gland showed a decrease in size in the 51-60-year age range. The corpus callosum also showed a tendency to diminish in size but to a lesser degree. There were no statistically significant declines in the size of either the pons or the cerebellar vermis in the 51-60-year age range.

Assessment of chemically-induced alterations in brain development using assays of neuron- and glia-localized proteins.

Chemical-induced injury of the developing central nervous system (CNS) is often manifested by alterations in the cellular ontogeny of specific neuroanatomical regions. Within the affected area, critical developmental processes encompassing a variety of neuronal and glial cell types may be transiently or permanently altered. Because the cellular heterogeneity of the developing CNS is expressed by unique neuronal and glial proteins, we proposed that radioimmunoassays of these proteins can be used to define normal and chemically- altered patterns of CNS development. We are testing this hypothesis by administering prototype neurotoxicants to the developing rat and then assessing the effects of these agents on previously characterized neuronal and glial proteins. Using this approach, we have characterized several features associated with perinatal chemical exposure: (1) region-dependent patterns of altered brain development are revealed by changes in the amounts of specific neuronal and glial proteins; (2) chemical-induced changes in neuronal and glial proteins depend on the time of exposure and nature of the insult; and (3) significant changes in neuron- and glial-localized proteins can be observed in the absence of cytopathology or decreases in brain weight. Data obtained from studies of toxicant-induced injury of the CNS will be presented as models for the use of neuron- and glial-localized proteins as biochemical indicators of altered brain development.