Thickness Of Cerebral Cortex Research Articles

Conditional N-WASP knockout in mouse brain implicates actin cytoskeleton regulation in hydrocephalus pathology

Cerebrospinal fluid (CSF) is produced by the choroid plexus and moved by multi-ciliated ependymal cells through the ventricular system of the vertebrate brain. Defects in the ependymal layer functionality are a common cause of hydrocephalus. N-WASP (Neural-Wiskott Aldrich Syndrome Protein) is a brain-enriched regulator of actin cytoskeleton and N-WASP knockout caused embryonic lethality in mice with neural tube and cardiac abnormalities. To shed light on the role of N-WASP in mouse brain development, we generated N-WASP conditional knockout mouse model N-WASPfl/fl; Nestin-Cre (NKO-Nes). NKO-Nes mice were born with Mendelian ratios but exhibited reduced growth characteristics compared to their littermates containing functional N-WASP alleles. Importantly, all NKO-Nes mice developed cranial deformities due to excessive CSF accumulation and did not survive past weaning. Coronal brain sections of these animals revealed dilated lateral ventricles, defects in ciliogenesis, loss of ependymal layer integrity, reduced thickness of cerebral cortex and aqueductal stenosis. Immunostaining for N-cadherin suggests that ependymal integrity in NKO-Nes mice is lost as compared to normal morphology in the wild-type controls. Moreover, scanning electron microscopy and immunofluorescence analyses of coronal brain sections with anti-acetylated tubulin antibodies revealed the absence of cilia in ventricular walls of NKO-Nes mice indicative of ciliogenesis defects. N-WASP deficiency does not lead to altered expression of N-WASP regulatory proteins, Fyn and Cdc42, which have been previously implicated in hydrocephalus pathology. Taken together, our results suggest that N-WASP plays a critical role in normal brain development and implicate actin cytoskeleton regulation as a vulnerable axis frequently deregulated in hydrocephalus.

Regional increase of cerebral cortex thickness in juvenile myoclonic epilepsy

The goal of this study was to characterize cerebral cortex thickness patterns in juvenile myoclonic epilepsy (JME). Surface-based morphometry (SBM) was applied to process brain magnetic resonance images acquired from 24 patients with JME and 40 healthy controls and quantify cerebral cortex thickness. Differences in cortical thickness between patients and controls were determined using generalized linear model (covariates: age and gender). In patients with JME, thickness increase was detected bilaterally within localized regions in the orbitofrontal and mesial frontal cortices. Such thickness patterns coexisted with significant bilateral reduction in thalamic volume. These findings confirm that the underlying mechanisms in JME are related to aberrant corticothalamic structure and indicate that frontal cortex abnormalities are possibly linked to regional increase in cerebral cortical thickness.

청소년의 지능범주별 대뇌피질 변화성 분석 연구

청소년들의 뇌는 급속한 변화를 겪는다. 그동안 신경해부학적 특성과 일반지능(IQ)과의 관련성을 알아보기 위한 연구가 지속적으로 이뤄져 왔으나 대부분 단편적이었다. 본 연구는 단순히 대뇌 피질 두께를 한 번 측정한 것이 아니고, 대뇌 피질 두께의 변화를 추적하여 일반지능과 그 변화 간의 관련성을 추정하였다. 건강한 청소년 75명(M=16세 4개월)을 5단계의 지능범주별로 나눈 뒤 6개월의 간격을 두고 MRI 촬영을 두 번씩 하여 대뇌 피질 두께 변화를 알아냈다. 그 결과 일반지능 범주별로 대뇌 피질 두께 변화에 차이가 크게 나타났다. 일반지능이 120 이상인 세 그룹은 관찰 대상인 11개 뇌 영역의 대뇌 피질 두께가 모두 감소했으나, 그 이하의 두 개 그룹에서는 지능이 낮을수록 늘어나는 영역이 5~8개나 됐다. 이는 일반지능이 낮을수록 대뇌피질의 성숙이 늦어지는 것으로 추정할 수 있다. The brains of adolescents experience rapid changes, which has been studied to prove relatedness between neuroanatomical properties and IQ. But, most previous studies infer the relatedness from purely cross-sectional data. This study not only measured the thickness of the cerebral cortex once, but traced its variability and the relatedness between IQ and this variability, which was presumed to be 75. Healthy adolescents (M=16yr. and 4month) were divided into 5-stage categories based on their intellectual ability and MRI scan was made twice every 6 months to measure the variablity of their cerebral cortex. As a result, a big difference in the variability of the cerebral cortex was shown based on their IQ. Three groups with an IQ of more than 120 showed a decrease in the thickness of the cerebral cortex in 11 brain regions, while two groups with an IQ lower than 120 showed an increase in the cerebral cortex thickness in 5 to 8 regions. It is presumed that the lower the IQ, the slower the maturation of the cerebral cortex.

Active endocytosis and microtubule remodeling restore compressed pyramidal neuron morphology in rat cerebral cortex.

Previous studies have shown that compression alone reduced the thickness of rat cerebral cortex and apical dendritic lengths of pyramidal neurons without apparent cell death. Besides, decompression restored dendritic lengths at different degrees depending on duration of compression. To understand the mechanisms regulating dendritic shortening and lengthening upon compression and decompression, we applied transmission electron microscopy to examine microtubule and membrane structure of pyramidal neurons in rat sensorimotor cortex subjected to compression and decompression. Microtubule densities within apical dendritic trunks decreased significantly and arranged irregularly following compression for a period from 30 min to 24 h. In addition, apical dendritic trunks showed twisted contour. Two reasons are accounted for the decrease of microtubule density within this period. First, microtubule depolymerized and resulted in lower number of microtubules. Second, the twisted membrane widened the diameters of apical dendritic trunks, which also caused a decrease in microtubule density. Interestingly, these compression-induced changes were quickly reversed to control level following decompression, suggesting that these changes were accomplished passively. Furthermore, microtubule densities were restored to control level and the number of endocytotic vesicles significantly increased along the apical dendritic membrane in neurons subjected to 36 h or longer period of compression. However, decompression did not make significant changes on dendrites compressed for 36 h, for they had already shown straight appearance before decompression. These results suggest that active membrane endocytosis and microtubule remodeling occur in this adaptive stage to make the apical dendritic trunks regain their smooth contour and regular microtubule arrangement, similar to that of the normal control neurons.

Abnormal cerebral cortical thinning pattern in adolescent girls with idiopathic scoliosis

Adolescent idiopathic scoliosis (AIS) is a 3-D spinal deformity with uncertain etiology; abnormalities in brain development represent one of the possible explanatory concepts for its pathogenesis. The objective of this study is to investigate the brain maturation by thickness of cerebral cortex among female adolescents with and without idiopathic scoliosis. Fifty AIS patients with a typical right-thoracic curve pattern were compared with 40 age-matched healthy controls. Based on the T1-weighted magnetic resonance images, the thickness of cortical gray-matter was calculated using a well-validated surface measurement method. Focusing on adolescent participants within the age range with the frequent occurrences of AIS cases (i.e., 12 to 17 years), we observed that the cortical thickness declined significantly in almost all cortical lobes in normal subjects (Spearman correlation<-0.4; P ≤ 0.05) except temporal lobe in LH, while in AIS patients this decline was weakly correlated with age (Spearman correlation>-0.4) and largely insignificant (P ≥ 0.05). Quadratic regression results expressed the detailed difference in the age-related cortical changing pattern between the two groups. In addition, focal cortical thickness was significantly different in AIS patients compared with healthy controls in areas involved in motor and vestibular functions as well as object recognition. The findings from this study imply a different thinning pattern of the cerebral cortex during adolescence in patients with AIS; this may be primary (i.e. etiopathogenetic) or secondary (i.e. adaptation) to the development of scoliosis.

Effects of prenatal ethanol exposure on rat brain radial glia and neuroblast migration

Prenatal ethanol exposure (PEE) induces morphologic and functional alterations in the developing central nervous system. The orderly migration of neuroblasts is a key process in the development of a layered structure such as the cerebral cortex (CC). From initial stages of corticogenesis, the transcription factor Pax6 is intensely expressed in neuroepithelial and radial glia cells (RGCs) and is involved in continual regulation of cell surface properties responsible for both cellular identity and radial migration. In the present work, one month before mating, during pregnancy and lactation, a group of female Wistar rats were fed a liquid diet with 5.9% (w/w) ethanol (EtOH), rendering moderate blood EtOH concentrations. Maternal gestational weight progression and fetal CC thickness were measured. CC from E12-P3 rats were examined for expression of vimentin, nestin, S-100b, Pax6 and doublecortin using immunohistochemical assays. RGCs expressing vimentin, nestin, S-100b and Pax6 had abnormal morphologies. The migration distance through the CC and the number of doublecortin-ir neuroblasts in germinative zones were decreased. We found significant morphologic defects on RGCs, a marked delay in neuronal migration, decreased numbers of neuroblasts, and decreased numbers of Pax6-ir cells in the CC as a consequence of exposure to ethanol during development. These observations suggest a sequence of toxic events that contribute to cortical dysplasia in offspring exposed to EtOH during gestation.

Surface-based analysis methods for high-resolution functional magnetic resonance imaging

Functional magnetic resonance imaging (fMRI) has become a popular technique for studies of human brain activity. Typically, fMRI is performed with >3-mm sampling, so that the imaging data can be regarded as two-dimensional samples that average through the 1.5–4-mm thickness of cerebral cortex. The increasing use of higher spatial resolutions, <1.5-mm sampling, complicates the analysis of fMRI, as one must now consider activity variations within the depth of the brain tissue. We present a set of surface-based methods to exploit the use of high-resolution fMRI for depth analysis. These methods utilize white-matter segmentations coupled with deformable-surface algorithms to create a smooth surface representation at the gray-white interface and pial membrane. These surfaces provide vertex positions and normals for depth calculations, enabling averaging schemes that can increase contrast-to-noise ratio, as well as permitting the direct analysis of depth profiles of functional activity in the human brain.

Induction of Perlecan Expression and Neural Cell Proliferation by FGF-2 in the Developing Cerebral Cortex: An In Vivo Study

Fibroblast growth factor has been implicated in cerebral cortical cell proliferation, migration, survival and differentiation. In the nervous system, proteoglycans (PGs) modulate growth factor activities and cell proliferation. Perlecan is a large PG and is expressed during the prenatal stages of brain development. Perlecan can promote fibroblast growth factor-2 (FGF-2) activity. In this study the effects of FGF-2 on neurogenesis and perlecan expression in the cerebral cortex have been studied. FGF-2 and anti-FGF-2 antibody were administered to 1-day-old mouse pups through the cisterna magna. Two days after injection, the pups were harvested and brains were removed for further analysis. We used western blotting and immunohistochemistry in order to analyze perlecan expression and neurogenesis in the cerebral cortex. We showed that the thickness of cerebral cortex, the number of cells produced in the cerebral cortex and perlecan expression are increased in response to injection of FGF-2 and decreased in response to infusion of anti-FGF-2 antibody as compared to controls. In conclusion, the results from this study suggest that FGF-2 increases neural cell production and perlecan expression in the developing cerebral cortex. It is also concluded that FGF-2 is an important factor in the cerebral cortical development, stimulating neuronal precursor proliferation.

Improvement of brain segmentation accuracy by optimizing non-uniformity correction using N3

Smoothly varying and multiplicative intensity variations within MR images that are artifactual, can reduce the accuracy of automated brain segmentation. Fortunately, these can be corrected. Among existing correction approaches, the nonparametric non-uniformity intensity normalization method N3 (Sled, J.G., Zijdenbos, A.P., Evans, A.C., 1998. Nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans. Med. Imag. 17, 87–97.) is one of the most frequently used. However, at least one recent study (Boyes, R.G., Gunter, J.L., Frost, C., Janke, A.L., Yeatman, T., Hill, D.L.G., Bernstein, M.A., Thompson, P.M., Weiner, M.W., Schuff, N., Alexander, G.E., Killiany, R.J., DeCarli, C., Jack, C.R., Fox, N.C., 2008. Intensity non-uniformity correction using N3 on 3-T scanners with multichannel phased array coils. NeuroImage 39, 1752–1762.) suggests that its performance on 3 T scanners with multichannel phased-array receiver coils can be improved by optimizing a parameter that controls the smoothness of the estimated bias field. The present study not only confirms this finding, but additionally demonstrates the benefit of reducing the relevant parameter values to 30–50 mm (default value is 200 mm), on white matter surface estimation as well as the measurement of cortical and subcortical structures using FreeSurfer (Martinos Imaging Centre, Boston, MA). This finding can help enhance precision in studies where estimation of cerebral cortex thickness is critical for making inferences.

Prenatal Ethanol Exposure Reduces the Expression of the Transcriptional Factor Pax6 in the Developing Rat Brain

Prenatal ethanol exposure (PEE) induces functional and structural disorders in the developing central nervous system (CNS). The relationship between radial glial cells (RGCs) and migrating neuroblasts is crucial for the establishment of normal CNS laminated structures. Pax6, a transcription factor involved in mammalian neuronal developmental processes, could be affected by PEE, as it is already known to occur in amphibians. From gestational day 10 to 18 (G10-G18), pregnant Wistar rats were subjected to an intraperitoneal injection of a daily ethanol (EtOH) 3.5 g/kg dose. Control pregnant rats received equivalent volumes of saline solution. Fetal weights and cerebral cortex thickness were significantly lower in G18 PEE than in control fetuses, and neural tube defects were found in the G18 PEE fetuses. Cortical expression of vimentin (an RGC cytoskeletal marker), S-100b protein (a neurotrophic factor and cytosolic marker of RGCs during embryonic development), and 68 kDa neurofilaments (a neuronal cytoskeletal marker) were also decreased in G18 PEE fetuses. At G14, a reduction in Pax6 cortical expression was found. Our results suggest that PEE reduces Pax6 expression in undifferentiated mammalian CNS cells. This could be one of the factors that induce RGCs and neuronal alterations at end-gestation. These alterations could be involved in the pathophysiology of neurodevelopmental disorders observed in the children affected by the fetal alcohol syndrome.

SEGMENTATION-FREE MEASURING OF CORTICAL THICKNESS FROM MRI.

Estimating the thickness of cerebral cortex is one of the most essential measurements performed in MR brain imaging. In this work we present a new approach to measure the cortical thickness which is based on minimizing line integrals over the probability map of the gray matter in the MRI volume. Previous methods often perform a pre-segmentation of the gray matter before measuring the thickness. Considering the noise and the partial volume effects, there are underlying class probabilities allocated to each voxel that this hard classification ignores, a result of which is a loss of important available information. Following the introduction of the proposed framework, the performance of our method is demonstrated on both artificial volumes and real MRI data for normal and Alzheimer affected subjects.

Thickness of cerebral cortex measured using anatomical mesoscopic imaging and magnetic resonance imaging

Magnetic resonance imaging method opened up the possibility for in vivo examination of the anatomy of human brain. For this reason it is interesting and relevant to compare the knowledge accumulated over a number of years during the examination of the composition of dead brain to that obtained from magnetic resonance images. The aim of this study was to determine and compare the thickness of cerebral cortex in human of different age and sex, measured in different sites of the hemispheres when applying anatomical mesoscopic imaging and magnetic resonance imaging. The thickness of cerebral cortex was measured in symmetrical Brodmann's areas of both hemispheres. The anatomical mesoscopic imaging technique was used for the examination of 2x2-cm cortex samples obtained during autopsy and fixed for 4 weeks in 10% paraformaldehyde. In these samples, cortex thickness was measured in sections perpendicular to the convolution, using an operative microscope, in a mesoscopic image at x16 magnification and with an accuracy of 0.01 mm. Using cerebral magnetic resonance imaging, the thickness of cerebral cortex in live subjects was measured on T1-weighted images of patients examined at the Clinic of Radiology, Kaunas University of Medicine Hospital. The measured cortical field image was magnified to the smallest element of digital image - the pixel - and measured with an accuracy of 0.01 mm. Each of the two techniques was applied for the examination of 20 men and women who were divided into age groups of 20-60 years (n=10) and older than 60 years (n=10). Both examination methods yielded a statistically significant difference in the thickness of cerebral cortex between Brodmann's areas 1, 4, and 19. No significant difference in cortex thickness was found between different age and sex groups; however, the findings showed that the difference in cortex thickness between the different age male groups was 4.6% and female - 1.6%. No significant difference using different techniques was found, but the cortex thickness in the fixed samples was reduced by 0.5 cm on average.

Reliability of MRI-derived measurements of human cerebral cortical thickness: The effects of field strength, scanner upgrade and manufacturer

In vivo MRI-derived measurements of human cerebral cortex thickness are providing novel insights into normal and abnormal neuroanatomy, but little is known about their reliability. We investigated how the reliability of cortical thickness measurements is affected by MRI instrument-related factors, including scanner field strength, manufacturer, upgrade and pulse sequence. Several data processing factors were also studied. Two test–retest data sets were analyzed: 1) 15 healthy older subjects scanned four times at 2-week intervals on three scanners; 2) 5 subjects scanned before and after a major scanner upgrade. Within-scanner variability of global cortical thickness measurements was <0.03 mm, and the point-wise standard deviation of measurement error was approximately 0.12 mm. Variability was 0.15 mm and 0.17 mm in average, respectively, for cross-scanner (Siemens/GE) and cross-field strength (1.5 T/3 T) comparisons. Scanner upgrade did not increase variability nor introduce bias. Measurements across field strength, however, were slightly biased (thicker at 3 T). The number of (single vs. multiple averaged) acquisitions had a negligible effect on reliability, but the use of a different pulse sequence had a larger impact, as did different parameters employed in data processing. Sample size estimates indicate that regional cortical thickness difference of 0.2 mm between two different groups could be identified with as few as 7 subjects per group, and a difference of 0.1 mm could be detected with 26 subjects per group. These results demonstrate that MRI-derived cortical thickness measures are highly reliable when MRI instrument and data processing factors are controlled but that it is important to consider these factors in the design of multi-site or longitudinal studies, such as clinical drug trials.

Cerebral cortex thickness in 15-year-old adolescents with low birth weight measured by an automated MRI-based method

Infants with low birth weight are at increased risk of perinatal brain injury. Disruption of normal cortical development may have consequences for later motor, behavioural and cognitive development. The aim of this study was to measure cerebral cortical thickness, area and volume with an automated MRI technique in 15-year-old adolescents who had low birth weight. Cerebral MRI for morphometric analysis was performed on 50 very low birth weight (VLBW, birth weight </=1500 g), 49 term small for gestational age births (SGA, birth weight <10th percentile at term) and 58 control adolescents. A novel method of cortical surface models yielded measurements of cortical thickness and area for each subject's entire brain and computed cross-subject statistics based on cortical anatomy. The cortical surface models demonstrated regional thinning of the parietal, temporal and occipital lobes in the VLBW group, whereas regional thickening was demonstrated in the frontal and occipital lobes. The areas of change were greatest in those with the shortest gestational age at birth and lowest birth weight. Cortical surface area and cortical volume were lower in the VLBW than in the Control group. Within the VLBW group, there was an association between surface area and estimation of the intelligence quotient IQ (IQ(est)) and between cortical volume and IQ(est). Furthermore, cortical grey matter as a proportion of brain volume was significantly lower in the VLBW, but not in the SGA group compared with Controls. This observed reorganization of the developing brain offers a unique opportunity to investigate any relationship between changes in cortical anatomy and cognitive and social impairments, and the increase in psychiatric disorders that have been found in VLBW children and adolescents.

Cortical thickness analysis examined through power analysis and a population simulation

We have previously developed a procedure for measuring the thickness of cerebral cortex over the whole brain using 3-D MRI data and a fully automated surface-extraction (ASP) algorithm. This paper examines the precision of this algorithm, its optimal performance parameters, and the sensitivity of the method to subtle, focal changes in cortical thickness. The precision of cortical thickness measurements was studied using a simulated population study and single subject reproducibility metrics. Cortical thickness was shown to be a reliable method, reaching a sensitivity (probability of a true-positive) of 0.93. Six different cortical thickness metrics were compared. The simplest and most precise method measures the distance between corresponding vertices from the white matter to the gray matter surface. Given two groups of 25 subjects, a 0.6-mm (15%) change in thickness can be recovered after blurring with a 3-D Gaussian kernel (full-width half max = 30 mm). Smoothing across the 2-D surface manifold also improves precision; in this experiment, the optimal kernel size was 30 mm.

Focal thinning of the cerebral cortex in multiple sclerosis.

Brain atrophy as determined by quantitative MRI can be used to characterize disease progression in multiple sclerosis. Many studies have addressed white matter (WM) alterations leading to atrophy, while changes of the cerebral cortex have been studied to a lesser extent. In vivo, the cerebral cortex has been difficult to study due to its complex structure and regional variability. Measurement of cerebral cortex thickness at different disease stages may provide new insights into grey matter (GM) pathology. In the present investigation, we evaluated in vivo cortical thickness and its relationship to disability, disease duration, WM T2 hyper-intense and T1 hypo-intense lesion volumes. High-resolution MRI brain scans were obtained in 20 patients with clinically definite multiple sclerosis and 15 age-matched normal subjects. A novel method of automated surface reconstruction yielded measurements of the cortical thickness for each subject's entire brain and computed cross-subject statistics based on the cortical anatomy. Statistical thickness difference maps were generated by performing t-tests between patient and control groups and individual thickness measures were submitted to analyses of variance to investigate the relationship between cortical thickness and clinical variables. The mean overall thickness of the cortical ribbon was reduced in multiple sclerosis patients compared with controls [2.30 mm (SD 0.14) versus 2.48 mm (SD 0.11)], showing a significant main effect of group (controls versus patients). In patients, we found significant main effects for disability, disease duration, T2 and T1 lesion volumes. The visualization of statistical difference maps of the cortical GM thickness on inflated brains across the cortical surface revealed a distinct distribution of significant focal thinning of the cerebral cortex in addition to the diffuse cortical atrophy. Focal cortical thinning in frontal [2.37 mm (SD 0.17) versus 2.73 mm (SD 0.25)] and in temporal [2.65 mm (SD 0.15) versus 2.95 mm (SD 0.11)] brain regions was observed, even early in the course of the disease or in patients with mild disability. Patients with longstanding disease or severe disability, however, presented additionally with focal thinning of the motor cortex area [2.35 mm (SD 0.19) versus 2.74 mm (SD 0.15)]. We conclude that in vivo measurement of cortical thickness is feasible in patients suffering from multiple sclerosis. The data provide new insight into the cortical pathology in multiple sclerosis patients, revealing focal cortical thinning beside an overall reduction of the cortical thickness with disease progression.

A genetic mouse model carrying the nonfunctional xeroderma pigmentosum group G gene.

A genetic mouse model with a disrupted XPG allele was generated by insertion of neo cassette sequences into exon 3 of the XPG gene by using embryonic stem (ES) cell techniques. The xpg-deficient mice showed distinct developmental characteristics. Their body was marked smaller than that in wild-type littermates since the postnatal day 6, and this postnatal growth failure became more severe with developmental proceeding. Their life span was very short, all of the mutants died by postnatal day 23 after showing great weakness and emaciation. In addition, the mutant homozygous mice also showed some progressive neurological signs, like the lower level of activity and a progressive ataxia. Further examination indicated there was developmental retardation of the brain in the mutant mice. Their brain weight, and thickness of cerebral cortex and cerebellar cortex were significant different from the controls. These characteristics, like small size brain, brain developmental retardation and progressive neurological dysfunctions in the homozygotes were similar to the typical clinical phenotype of the XPG patients and Cockayne syndrome, we believe that the xpgdeficient mice will be an animal model for studying the function of the XP-G protein in nucleotide-excision repair and mechanisms related to the clinic symptoms of XP-G and Cockayne syndrome in humans.

Study on the Nootropic Mechanism of (-)Clausenamide - Influence on the Formation of Synapses in Mouse Brain

The effects of (-)clausenamide (claus) on brain development were studied. Sixty kunming strain weaning mice were divided into 4 groups. One group was served as control administered with normal saline, the other 3 groups were treated with (-)claus 5, 10 and 20mg kg−1 respectively by gavage once a day for 4 weeks. Results showed that (-)claus at dosage of 5 and 10 mg kg−1 facilitated learning and memory acquisition in step down and step through tests and increased thickness of cerebral cortex and synapse density significantly in the dentate cells over pyramidel cells in hippocampal region using quantitative technique of synapses analysis. These data provided the morphological basis of the nootropic effect of (-)claus.

Short communication: Effects of prenatal treatment with tritiated water on the developing brain in mouse

Pregnant mice were injected intraperitoneally with various doses of tritiated water on embryonic day 13. The litters received total cumulative absorbed beta -irradiation to a dose of 0, 0.1, 0.2, 0.4 or 0.8 Gy. We found that 0.4 Gy beta -irradiation caused a significant reduction in brain weight but not in body weight among 8-week-old mice. The highest dose (0.8 Gy) inhibited both body and brain development. A quantitative study showed that a significant reduction in cerebral pyramidal cells was present in the groups exposed to 0.2 Gy. In tritiated watertreated groups, the pyramidal cells reduced in a dose-dependent manner, with reductions ranging from 3 to 12%. The thickness of cerebral cortex was significantly reduced in the groups exposed to 0.4 Gy. Numerical density of pyramidal cells was the most sensitive indicator of developmental disturbance of cerebral cortex manifested postnatally. No significant difference in the numerical density of Purkinje cells was found between the irradiated and control groups. These results demonstrated that the time at which the insult occurred was an important factor determining the resulting abnormalities.

Effect of In Utero Irradiation on the Postnatal Development, Behavior, and Brain Structure of Rats: Dose Fractionation with a 6-h Interval

Based on previous studies showing that exposure of the rat fetus to ionizing radiation produces dose-dependent (0.25-1.25 Gy) changes in postnatal development of behavior and decreases in the thickness of the cerebral cortex, we examined the extent to which dose fractionation would reduce expression of damage. Pregnant rats were exposed to single doses of 0.5 or 1.0 Gy, or to two doses of 0.5 Gy 6 h apart on day 15 of gestation. Offspring were subjected to four behavioral tests on postnatal days 7-28; the rats were then sacrificed and their brains removed and processed for histology. For all end points, the fractionated dose produced an effect that was intermediate between that of the 0.5- and 1.0-Gy doses and which, by interpolation, could be expressed as equivalent to a single dose between 0.5 and 1.0 Gy. The equivalent single dose was not significantly different from the 1.0-Gy dose for negative geotaxis (0.54 Gy), reflex suspension (0.80 Gy), and continuous corridor (0.85 Gy). For sine of the angle of the advance of hind feet (0.58 Gy), width of stride (0.69 Gy), length of stride (0.75 Gy), body weight (0.73 Gy), and cerebral cortex thickness (0.69 Gy), the fractionated dose produced effects significantly different (P < 0.05) from the 1.0-Gy dose. Overall, exposure of fetal rats to two doses of 0.5 Gy separated by 6 h produced effects equivalent to a single dose of 0.70 Gy, as measured by postnatal behavioral tests and morphological assessment of brain structure.