Consistency of Cranial Shape Measures Obtained From Laser Surface and Computed Tomography Imaging.

OBJECTIVE: Children with cranial shape abnormalities are often subjected to radiation from computed tomography (CT) for evaluation and clinical decision making. The STARscanner Laser Data Acquisition System (Orthomerica, Orlando, FL) may be a noninvasive alternate. The purpose of this study is to determine whether the STARscanner provides valid and accurate cranial measurements compared to CT. DESIGN: We performed an institutional review board-approved retrospective review of a prospectively maintained database of patients with metopic suture abnormalities from 2013 to 2016. SETTING: Plastic surgery clinic in an institutional tertiary care center. PATIENTS: Eight patients were included that presented with metopic suture abnormalities, age less than 1 year, and CT and STARscanner imaging within 30 days of one another. MAIN OUTCOME MEASURES: Cranial measurements were collected twice from 3 scan types: STARscanner, CT windowed for soft tissue, and CT windowed for bone. Measurements included: intracranial volume, height, base width, maximum antero-posterior length, maximum medio-lateral width, and oblique diameters. Nested analysis of variance were performed to determine the proportion of error attributable to: between-subject variance, scan type, and rater. RESULTS: Measurements from STARscanner and both CT scans windows were highly consistent, with less than 1% of total error attributable to scan type for all measures. CONCLUSIONS: Cranial shape measurements obtained from STARscanner images are highly consistent with those obtained from CT scans. The STARscanner has added benefits of speed of acquisition, minimal cost, and lack of radiation.

Increased Incidence of Ophthalmologic Findings in Children With Concurrent Isolated Nonsyndromic Metopic Suture Abnormalities and Deformational Cranial Vault Asymmetry.

OBJECTIVE: The purpose of this project was to study the incidence of ophthalmologic findings which are known to be risk factors for amblyopia in children who have coexisting metopic suture abnormalities and deformational plagiocephaly (DP) and brachycephaly (DB). DESIGN: Institutional Review Board-approved retrospective study reviewing records of a consecutive cohort of children under 2 years of age with metopic suture abnormalities and cranial vault asymmetries seen in both the plastic surgery and ophthalmology clinics from 2007 to 2017. SETTING: Institutional tertiary care center with all care in plastic surgery under the senior author and the standard of care accepted in pediatric ophthalmology under one of two ophthalmologists. PATIENTS: After application of exclusion criteria, 76 children diagnosed with metopic suture abnormalities and DP/DB were included in the study. Patients with severe trigonocephaly, other suture involvement, syndromic diagnoses, and primary ocular disorders were excluded. MAIN OUTCOME MEASURES: Describe the incidences of refractive errors (astigmatism, hyperopia, and myopia), anisometropia, strabismus, and amblyopia within the study population. RESULTS: In our patient population, the rates of amblyopia (17.1%) and strabismus (15.8%) are higher than the general pediatric population rates of 1.5% to 1.8% and 2.4% to 3.6%, respectively. Overall, 47.4% had significant refractive error: 28.9% with astigmatism, 15.8% with hyperopia, 5.3% with myopia, and 10.5% with anisometropia. CONCLUSIONS: In our patient population, children with coexisting metopic suture abnormalities and DP or DB had significant risk for amblyopia, strabismus, and refractive errors.

Relationship of a Metopic Ridge and Anterior Cranial Volume Measured by a Noninvasive Laser Shape Digitizer.

Cranial dysmorphology observed in patients with metopic craniosynostosis varies along a spectrum of severity including varying degrees of metopic ridging, bitemporal narrowing, and trigonocephaly. Management has been based upon the subjective clinical impression of presence and severity of trigonocephaly. Severity of cranial dysmorphology does not predict the occurrence or severity of associated abnormal neurodevelopment, as children with mild-to-moderate trigonocephaly may also experience developmental delays. The authors sought to determine the relationship between mild-to-moderate trigonocephaly and anterior cranial volume using a noninvasive laser shape digitizer (STARscanner) in patients with abnormal head shape.An IRB-approved retrospective review of a prospectively maintained database and medical records was performed. Two hundred three patients less than 1 year of age with abnormal head shape were categorized as having a metopic ridge with mild-to-moderate trigonocephaly, metopic ridge without trigonocephaly, or no ridge. Measurements of cranial volume, circumference, and symmetry were calculated by the STARscanner, which quantifies three-dimensional shape of the cranial surface. Measures were analyzed using a series of analyses of variance and post-hoc Tukey honest significant difference.The authors results showed ACV was significantly reduced in patients with mild-to-moderate trigonocephaly compared with those without metopic ridge (P = 0.009), and trended toward significance compared with those with a ridge but without trigonocephaly (P = 0.072). The ratio of anterior-to-posterior cranial volume was significantly reduced in those with mild-to-moderate trigonocephaly compared with those without metopic ridge (P = 0.036).In conclusion, patients with milder anterior cranial deformities demonstrated an association between a metopic ridge with mild-to-moderate trigonocephaly and reduced anterior cranial volume.

Evaluating Children With Metopic Craniosynostosis: The Cephalic Width-Intercoronal Distance Ratio.

OBJECTIVE: To identify an additional objective measure to aid in the evaluation of children with isolated metopic craniosynostosis. DESIGN: This is a retrospective study comparing specific computed tomography scan measurements between surgical and nonsurgical cohorts of children with isolated metopic craniosynostosis. Children were included if they were diagnosed with isolated metopic craniosynostosis and ultimately underwent computed tomography scan imaging as part of their evaluation. The subjects were placed in the surgical or nonsurgical cohorts on the basis of the final treatment recommendation after they completed a full multidisciplinary, multimodality evaluation. Comparisons were made with a control group of unaffected patients from our institutional trauma registry. SETTING: Tertiary academic institution. PATIENTS, PARTICIPANTS: The subjects are patients who had been previously evaluated in our clinic for isolated metopic craniosynostosis and received a computed tomography scan as part of their workup. RESULTS: The average intercoronal distances were significantly different among all three groups (P < .002). The average cephalic width-intercoronal distance ratio for children who received a recommendation for surgery differed significantly from that of both the observation cohort and the control group (P < .001). However, the cephalic width-intercoronal distance ratio did not differ between the observation cohort and the control group (P = .927). CONCLUSIONS: The cephalic width-intercoronal distance ratio may be an additional objective measurement to aid in the clinical evaluation of children with metopic craniosynostosis.

Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice.

BACKGROUND: Differences in cranial morphology arise due to changes in fundamental cell processes like migration, proliferation, differentiation and cell death driven by genetic programs. Signaling between fibroblast growth factors (FGFs) and their receptors (FGFRs) affect these processes during head development and mutations in FGFRs result in congenital diseases including FGFR-related craniosynostosis syndromes. Current research in model organisms focuses primarily on how these mutations change cell function local to sutures under the hypothesis that prematurely closing cranial sutures contribute to skull dysmorphogenesis. Though these studies have provided fundamentally important information contributing to the understanding of craniosynostosis conditions, knowledge of changes in cell function local to the sutures leave change in overall three-dimensional cranial morphology largely unexplained. Here we investigate growth of the skull in two inbred mouse models each carrying one of two gain-of-function mutations in FGFR2 on neighboring amino acids (S252W and P253R) that in humans cause Apert syndrome, one of the most severe FGFR-related craniosynostosis syndromes. We examine late embryonic skull development and suture patency in Fgfr2 Apert syndrome mice between embryonic day 17.5 and birth and quantify the effects of these mutations on 3D skull morphology, suture patency and growth. RESULTS: We show in mice what studies in humans can only infer: specific cranial growth deviations occur prenatally and worsen with time in organisms carrying these FGFR2 mutations. We demonstrate that: 1) distinct skull morphologies of each mutation group are established by E17.5; 2) cranial suture patency patterns differ between mice carrying these mutations and their unaffected littermates; 3) the prenatal skull grows differently in each mutation group; and 4) unique Fgfr2-related cranial morphologies are exacerbated by late embryonic growth patterns. CONCLUSIONS: Our analysis of mutation-driven changes in cranial growth provides a previously missing piece of knowledge necessary for explaining variation in emergent cranial morphologies and may ultimately be helpful in managing human cases carrying these same mutations. This information is critical to the understanding of craniofacial development, disease and evolution and may contribute to the evaluation of incipient therapeutic strategies.

Tissue-specific responses to aberrant FGF signaling in complex head phenotypes.

BACKGROUND: The role of fibroblast growth factor and receptor (FGF/FGFR) signaling in bone development is well studied, partly because mutations in FGFRs cause human diseases of achondroplasia and FGFR-related craniosynostosis syndromes including Crouzon syndrome. The FGFR2c C342Y mutation is a frequent cause of Crouzon syndrome, characterized by premature cranial vault suture closure, midfacial deficiency, and neurocranial dysmorphology. Here, using newborn Fgfr2c(C342Y/+) Crouzon syndrome mice, we tested whether the phenotypic effects of this mutation go beyond the skeletal tissues of the skull, altering the development of other non-skeletal head tissues including the brain, the eyes, the nasopharynx, and the inner ears. RESULTS: Quantitative analysis of 3D multimodal imaging (high-resolution micro-computed tomography and magnetic resonance microscopy) revealed local differences in skull morphology and coronal suture patency between Fgfr2c(C342Y/+) mice and unaffected littermates, as well as changes in brain shape but not brain size, significant reductions in nasopharyngeal and eye volumes, and no difference in inner ear volume in Fgfr2c(C342Y/+) mice. CONCLUSIONS: These findings provide an expanded catalogue of clinical phenotypes in Crouzon syndrome caused by aberrant FGF/FGFR signaling and evidence of the broad role for FGF/FGFR signaling in development and evolution of the vertebrate head.

Postnatal brain and skull growth in an Apert syndrome mouse model.

Craniofacial and neural tissues develop in concert throughout prenatal and postnatal growth. FGFR-related craniosynostosis syndromes, such as Apert syndrome (AS), are associated with specific phenotypes involving both the skull and the brain. We analyzed the effects of the FGFR P253R mutation for AS using the Fgfr2(+/P253R) Apert syndrome mouse to evaluate the effects of this mutation on these two tissues over the course of development from day of birth (P0) to postnatal day 2 (P2). Three-dimensional magnetic resonance microscopy and computed tomography images were acquired from Fgfr2(+/P253R) mice and unaffected littermates at P0 (N = 28) and P2 (N = 20).Three-dimensional coordinate data for 23 skull and 15 brain landmarks were statistically compared between groups. Results demonstrate that the Fgfr2(+/P253R) mice show reduced growth in the facial skeleton and the cerebrum, while the height and width of the neurocranium and caudal regions of the brain show increased growth relative to unaffected littermates. This localized correspondence of differential growth patterns in skull and brain point to their continued interaction through development and suggest that both tissues display divergent postnatal growth patterns relative to unaffected littermates. However, the change in the skull-brain relationship from P0 to P2 implies that each tissue affected by the mutation retains a degree of independence, rather than one tissue directing the development of the other.

A volumetric study of basal ganglia structures in individuals with early-treated phenylketonuria.

Whereas the impact of early-treated phenylketonuria (ETPKU) on cortical white matter is well documented, relatively little is known regarding the potential impact of this metabolic disorder on deep gray matter structures such as the basal ganglia. The current study used high-resolution (1mm(3)) magnetic resonance imaging to investigate bilateral basal ganglia structures (i.e., putamen, caudate nucleus, and nucleus accumbens) in a sample of 13 individuals with ETPKU and a demographically-matched sample of 13 neurologically intact individuals without PKU. Consistent with previous research, we found smaller whole brain volumes in the ETPKU group compared with the non-PKU group. Individuals with ETPKU also had significantly larger putamen volumes than non-PKU individuals. In addition, the degree of putamen enlargement was correlated with blood phenylalanine levels and full scale IQ in the ETPKU group. These findings are consistent with the hypothesis that ETPKU-related increases in phenylalanine lead to decreased central dopamine levels thus impacting dopamine-dependent brain regions such as the putamen that play an important role in cognition.

Patterns of differences in brain morphology in humans as compared to extant apes.

Although human evolution is characterized by a vast increase in brain size, it is not clear whether or not certain regions of the brain are enlarged disproportionately in humans, or how this enlargement relates to differences in overall neural morphology. The aim of this study is to determine whether or not there are specific suites of features that distinguish the morphology of the human brain from that of apes. The study sample consists of whole brain, in vivo magnetic resonance images (MRIs) of anatomically modern humans (Homo sapiens sapiens) and five ape species (gibbons, orangutans, gorillas, chimpanzees, bonobos). Twenty-nine 3D landmarks, including surface and internal features of the brain were located on 3D MRI reconstructions of each individual using MEASURE software. Landmark coordinate data were scaled for differences in size and analyzed using Euclidean Distance Matrix Analysis (EDMA) to statistically compare the brains of each non-human ape species to the human sample. Results of analyses show both a pattern of brain morphology that is consistently different between all apes and humans, as well as patterns that differ among species. Further, both the consistent and species-specific patterns include cortical and subcortical features. The pattern that remains consistent across species indicates a morphological reorganization of 1) relationships between cortical and subcortical frontal structures, 2) expansion of the temporal lobe and location of the amygdala, and 3) expansion of the anterior parietal region. Additionally, results demonstrate that, although there is a pattern of morphology that uniquely defines the human brain, there are also patterns that uniquely differentiate human morphology from the morphology of each non-human ape species, indicating that reorganization of neural morphology occurred at the evolutionary divergence of each of these groups.

Intracranial volume and whole brain volume in infants with unicoronal craniosynostosis.

OBJECTIVE: Craniosynostosis has been hypothesized to result in alterations of the brain and cerebral blood flow due to reduced intracranial volume, potentially leading to cognitive deficits. In this study we test the hypothesis that intracranial volume and whole brain volume in infants with unilateral coronal synostosis differs from those in unaffected infants. DESIGN: Our study sample consists of magnetic resonance images acquired from 7- to 72-week-old infants with right unilateral coronal synostosis prior to surgery (n  =  10) and age-matched unaffected infants (n  =  10). We used Analyze 9.0 software to collect three cranial volume measurements. We used nonparametric tests to determine whether the three measures differ between the two groups. Correlations were calculated between age and the three volume measures in each group to determine whether the growth trajectory of the measurements differ between children with right unicoronal synostosis and unaffected infants. RESULTS: Our results show that the three volume measurements are not reduced in infants with right unicoronal synostosis relative to unaffected children. Correlation analyses between age and various volume measures show similar correlations in infants with right unicoronal synostosis compared with unaffected children. CONCLUSIONS: Our results show that the relationship between brain size and intracranial size in infants with right unicoronal synostosis is similar to that in unaffected children, suggesting that reduced intracranial volume is not responsible for alterations of the brain in craniosynostosis.

Beyond the closed suture in apert syndrome mouse models: evidence of primary effects of FGFR2 signaling on facial shape at birth.

Apert syndrome is a congenital disorder caused mainly by two neighboring mutations on fibroblast growth factor receptor 2 (FGFR2). Premature closure of the coronal suture is commonly considered the identifying and primary defect triggering or preceding the additional cranial malformations of Apert phenotype. Here we use two transgenic mouse models of Apert syndrome, Fgfr2(+/S252W) and Fgfr2(+/P253R), to explore variation in cranial phenotypes in newborn (P0) mice. Results show that the facial skeleton is the most affected region of the cranium. Coronal suture patency shows marked variation that is not strongly correlated with skull dysmorphology. The craniofacial effects of the FGFR2 mutations are similar, but Fgfr2(+/S252W) mutant mice display significantly more severe dysmorphology localized to the posterior palate. Our results demonstrate that coronal suture closure is neither the primary nor the sole locus of skull dysmorphology in these mouse models for Apert syndrome, but that the face is also primarily affected.

Brain phenotypes in two FGFR2 mouse models for Apert syndrome.

Apert syndrome (AS) is one of at least nine disorders considered members of the fibroblast growth factor receptor (FGFR) -1, -2, and -3-related craniosynostosis syndromes. Nearly 100% of individuals diagnosed with AS carry one of two neighboring mutations on Fgfr2. The cranial phenotype associated with these two mutations includes coronal suture synostosis, either unilateral (unicoronal synostosis) or bilateral (bicoronal synostosis). Brain dysmorphology associated with AS is thought to be secondary to cranial vault or base alterations, but the variation in brain phenotypes within Apert syndrome is unexplained. Here, we present novel three-dimensional data on brain phenotypes of inbred mice at postnatal day 0 each carrying one of the two Fgfr2 mutations associated with AS. Our data suggest that the brain is primarily affected, rather than secondarily responding to skull dysmorphogenesis. Our hypothesis is that the skull and brain are both primarily affected in craniosynostosis and that shared phenogenetic developmental processes affect both tissues in craniosynostosis of Apert syndrome.

Structural abnormalities in gyri of the prefrontal cortex in individuals with schizophrenia and their unaffected siblings.

BACKGROUND: The relatives of individuals with schizophrenia exhibit deficits of overall frontal lobe volume, consistent with a genetic contribution to these deficits. AIMS: To quantify the structure of gyral-defined subregions of prefrontal cortex in individuals with schizophrenia and their siblings. METHOD: Grey matter volume, cortical thickness, and surface area of the superior, middle and inferior frontal gyri were measured in participants with schizophrenia and their unaffected (non-psychotic) siblings (n = 26 pairs), and controls and their siblings (n = 40 pairs). RESULTS: Grey matter volume was reduced in the middle and inferior frontal gyri of individuals with schizophrenia, relative to controls. However, only inferior frontal gyrus volume was also reduced in the unaffected siblings of those with schizophrenia, yielding a volume intermediate between their affected siblings and controls. CONCLUSIONS: The structure of subregions of the prefrontal cortex may be differentially influenced by genetic factors in schizophrenia, with inferior frontal gyrus volume being most related to familial risk.

The effects of early-treated phenylketonuria on volumetric measures of the cerebellum.

Past murine studies of phenylketonuria (PKU) have documented significant effects on cerebellum at both the gross and cellular levels. The profile of neurocognitive and motor difficulties associated with early-treated PKU (ETPKU) is also consistent with potential cerebellar involvement. Previous neuroanatomical studies of cerebellum in patients with PKU, however, have yielded mixed results. The objective of the present study was to further examine potential differences in cerebellar morphometry between individuals with and without ETPKU. To this end, we analyzed high resolution T1-weighted MR images from a sample of 20 individuals with ETPKU and an age-matched comparison group of 20 healthy individuals without PKU. Measurements of whole brain volume, whole cerebellum volume, cerebellar gray matter volume, and cerebellar white matter volume were collected by means of semiautomatic volumetric analysis. Data analysis revealed no significant group differences in whole brain volume, whole cerebellar volume, or cerebellar white matter volume. A significant reduction in cerebellar gray matter volume, however, was observed for the ETPKU group compared to the non-PKU comparison group. These findings expand on previous animal work suggesting that cerebellar gray matter is impacted by PKU. It is also consistent with the hypothesis that the cognitive difficulties experienced by individuals with ETPKU may be related to disruptions in gray matter. Additional studies are needed to fully elucidate the timing and extent of the impact of ETPKU on cerebellum and the associated neurocognitive consequences.

Brain morphology in nonsyndromic unicoronal craniosynostosis.

Studies of isolated craniosynostosis have shown biomechanical and biochemical influences on the craniofacial phenotype, resulting from both genetic and epigenetic factors. Much less attention has been directed toward the morphology of the brain, despite the interactive nature of the developing skull and developing brain. The aim of this study is to define the morphology of the brain in nonsyndromic unilateral coronal synostosis (UCS) in order to form more complete hypotheses about the cause of craniosynostosis. Landmark coordinate data were collected from 3D magnetic resonance image reconstructions of the brain in a sample of UCS patients and an age-matched morphologically normal cohort. These data were analyzed using Euclidean distance matrix analysis. The results of our study demonstrate that despite the basic similarity of overall shape of the brain and skull in UCS, the effects of craniosynostosis on the brain are not localized to structures immediately adjacent to the fused suture or to the endocranial surface of the skull. Rather, alterations are observed throughout the volume of the brain, with subcortical structures altered in conjunction with cortical changes. These results indicate that the morphological correlates are different for brain and skull and suggest that there is a large degree of independence in the developmental trajectories of the brain and skull.

Facial structure analysis separates autism spectrum disorders into meaningful clinical subgroups.

Varied cluster analysis were applied to facial surface measurements from 62 prepubertal boys with essential autism to determine whether facial morphology constitutes viable biomarker for delineation of discrete Autism Spectrum Disorders (ASD) subgroups. Earlier study indicated utility of facial morphology for autism subgrouping (Aldridge et al. in Mol Autism 2(1):15, 2011). Geodesic distances between standardized facial landmarks were measured from three-dimensional stereo-photogrammetric images. Subjects were evaluated for autism-related symptoms, neurologic, cognitive, familial, and phenotypic variants. The most compact cluster is clinically characterized by severe ASD, significant cognitive impairment and language regression. This verifies utility of facially-based ASD subtypes and validates Aldridge et al.'s severe ASD subgroup, notwithstanding different techniques. It suggests that language regression may define a unique ASD subgroup with potential etiologic differences.

Size of the anterior fontanelle: three-dimensional measurement of a key trait in human evolution.

The anterior fontanelle (AF) is an integral element of the developing human infant craniofacial system. Consideration of the AF is crucial for assessing craniofacial growth, as altered development of this feature may indicate abnormal growth. Moreover, prolonged patency of the AF may represent a derived hominin feature. The AF is regarded as essential for fetal head molding during birth in humans, with deformation of the head during birth often necessary for successful delivery. However, the function of a patent AF among fossil hominins is unclear. Because the AF represents an important structure in both a clinical and evolutionary context, techniques for estimating the size of the AF must be accurate and reproducible. Therefore, we have developed a novel method for assessing surface area of the AF with the goal of creating a more accurate measure of this feature. In this study, we test the accuracy and repeatability of a novel three-dimensional (3D) method for assessing the size of the AF in human infants and compare the results obtained for surface area of the AF using the conventional and 3D methods.

Landmarking the brain for geometric morphometric analysis: an error study.

Neuroanatomic phenotypes are often assessed using volumetric analysis. Although powerful and versatile, this approach is limited in that it is unable to quantify changes in shape, to describe how regions are interrelated, or to determine whether changes in size are global or local. Statistical shape analysis using coordinate data from biologically relevant landmarks is the preferred method for testing these aspects of phenotype. To date, approximately fifty landmarks have been used to study brain shape. Of the studies that have used landmark-based statistical shape analysis of the brain, most have not published protocols for landmark identification or the results of reliability studies on these landmarks. The primary aims of this study were two-fold: (1) to collaboratively develop detailed data collection protocols for a set of brain landmarks, and (2) to complete an intra- and inter-observer validation study of the set of landmarks. Detailed protocols were developed for 29 cortical and subcortical landmarks using a sample of 10 boys aged 12 years old. Average intra-observer error for the final set of landmarks was 1.9 mm with a range of 0.72 mm-5.6 mm. Average inter-observer error was 1.1 mm with a range of 0.40 mm-3.4 mm. This study successfully establishes landmark protocols with a minimal level of error that can be used by other researchers in the assessment of neuroanatomic phenotypes.

Distinct abnormalities of the primate prefrontal cortex caused by ionizing radiation in early or midgestation.

Prenatal exposure of the brain to environmental insult causes different neurological symptoms and behavioral outcomes depending on the time of exposure. To examine the cellular bases for these differences, we exposed rhesus macaque fetuses to x-rays during early gestation (embryonic day [E]30-E42), i.e., before the onset of corticogenesis, or in midgestation (E70-E81), when superficial cortical layers are generated. Animals were delivered at term (~E165), and the size and cellular composition of prefrontal association cortex (area 46) examined in adults using magnetic resonance imaging (MRI) and stereologic analysis. Both early and midgestational radiation exposure diminished the surface area and volume of area 46. However, early exposure spared cortical thickness and did not alter laminar composition, and due to higher cell density, neuron number was within the normal range. In contrast, exposure to x-rays at midgestation reduced cortical thickness, mainly due to elimination of neurons destined for the superficial layers. A cell-sparse gap, observed within layer III, was not filled by the later-generated neurons destined for layer II, indicating that there is no subsequent replacement of the lost neurons. The distinct areal and laminar pathology consequent to temporally segregated irradiation is consistent with basic postulates of the radial unit hypothesis of cortical development. In addition, we show that an environmental disturbance inflicted in early gestation can induce subtle cytoarchitectonic alterations without loss of neurons, such as those observed in schizophrenia, whereas midgestational exposure causes selective elimination of neurons and cortical thinning as observed in some forms of mental retardation and fetal alcohol syndrome.

A longitudinal analysis of regional brain volumes in macaques exposed to X-irradiation in early gestation.

BACKGROUND: Early gestation represents a period of vulnerability to environmental insult that has been associated with adult psychiatric disease. However, little is known about how prenatal perturbation translates into adult brain dysfunction. Here, we use a longitudinal study design to examine the effects of disruption of early gestational neurogenesis on brain volume in the non-human primate. METHODS AND PRINCIPAL FINDINGS: Five Rhesus macaques were exposed to x-irradiation in early gestation (E30-E41), and four control monkeys were sham-irradiated at comparable ages. Whole brain magnetic resonance imaging was performed at 6 months, 12 months, and 3 and 5 years of age. Volumes of whole cerebrum, cortical gray matter, caudate, putamen, and thalamus were estimated using semi-automated segmentation methods and high dimensional brain mapping. Volume reductions spanning all ages were observed in irradiated monkeys in the putamen (15-24%, p = 0.01) and in cortical gray matter (6-15%, p = 0.01). Upon covarying for whole cerebral volume, group differences were reduced to trend levels (putamen: p = 0.07; cortical gray matter: p = 0.08). No group-by-age effects were significant. CONCLUSIONS: Due to the small number of observations, the conclusions drawn from this study must be viewed as tentative. Early gestational irradiation may result in non-uniform reduction of gray matter, mainly affecting the putamen and cerebral cortex. This may be relevant to understanding how early prenatal environmental insult could lead to brain morphological differences in neurodevelopmental diseases.