John H. Gilmore

A Structural MRI Study of Human Brain Development from Birth to 2 Years

Brain development in the first 2 years after birth is extremely dynamic and likely plays an important role in neurodevelopmental disorders, including autism and schizophrenia. Knowledge regarding this period is currently quite limited. We studied structural brain development in healthy subjects from birth to 2. Ninety-eight children received structural MRI scans on a Siemens head-only 3T scanner with magnetization prepared rapid gradient echo T1-weighted, and turbo spin echo, dual-echo (proton density and T2 weighted) sequences: 84 children at 2–4 weeks, 35 at 1 year and 26 at 2 years of age. Tissue segmentation was accomplished using a novel automated approach. Lateral ventricle, caudate, and hippocampal volumes were also determined. Total brain volume increased 101% in the first year, with a 15% increase in the second. The majority of hemispheric growth was accounted for by gray matter, which increased 149% in the first year; hemispheric white matter volume increased by only 11%. Cerebellum volume increased 240% in the first year. Lateral ventricle volume increased 280% in the first year, with a small decrease in the second. The caudate increased 19% and the hippocampus 13% from age 1 to age 2. There was robust growth of the human brain in the first two years of life, driven mainly by gray matter growth. In contrast, white matter growth was much slower. Cerebellum volume also increased substantially in the first year of life. These results suggest the structural underpinnings of cognitive and motor development in early childhood, as well as the potential pathogenesis of neurodevelopmental disorders.

The early stages of schizophrenia: Speculations on pathogenesis, pathophysiology, and therapeutic approaches

Schizophrenia is commonly considered a neurodevelopmental disorder that is associated with significant morbidity; however, unlike other neurodevelopmental disorders, the symptoms of schizophrenia often do not manifest for decades. In most patients, the formal onset of schizophrenia is preceded by prodromal symptoms, including positive symptoms, mood symptoms, cognitive symptoms, and social withdrawal. The proximal events that trigger the formal onset of schizophrenia are not clear but may include developmental biological events and environmental interactions or stressors. Treatment with antipsychotic drugs clearly ameliorates psychotic symptoms, and maintenance therapy may prevent the occurrence of relapse. The use of atypical antipsychotic agents may additionally ameliorate the pathophysiology of schizophrenia and prevent disease progression. Moreover, if treated properly early in the course of illness, many patients can experience a significant remission of their symptoms and are capable of a high level of recovery following the initial episode. Because the clinical deterioration that occurs in schizophrenia may actually begin in the prepsychotic phase, early identification and intervention may favorably alter the course and outcome of schizophrenia.

Evidence on the emergence of the brain's default network from 2-week-old to 2-year-old healthy pediatric subjects

Several lines of evidence have implicated the existence of the brains default network during passive or undirected mental states. Nevertheless, results on the emergence of the default network in very young pediatric subjects are lacking. Using resting functional magnetic resonance imaging in healthy pediatric subjects between 2 weeks and 2 years of age, we describe the temporal evolution of the default network in a critical, previously unstudied, period of early human brain development. Our results demonstrate that a primitive and incomplete default network is present in 2-week-olds, followed by a marked increase in the number of brain regions exhibiting connectivity, and the percent of connection at 1 year of age. By 2 years of age, the default network becomes similar to that observed in adults, including medial prefrontal cortex (MPFC), posterior cingulate cortex/retrosplenial (PCC/Rsp), inferior parietal lobule, lateral temporal cortex, and hippocampus regions. While the anatomical representations of the default network highly depend on age, the PCC/Rsp is consistently observed at in both age groups and is central to the most and strongest connections of the default network, suggesting that PCC/Rsp may serve as the main “hub” of the default network as this region does in adults. In addition, although not as remarkable as the PCC/Rsp, the MPFC also emerges as a potential secondary hub starting from 1 year of age. These findings reveal the temporal development of the default network in the critical period of early brain development and offer new insights into the emergence of brain default network.

Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid and fetal brain.

Prenatal exposure to infection appears to increase the risk of schizophrenia and other neurodevelopmental disorders. We have hypothesized that cytokines, generated in response to maternal infection, play a key mechanistic role in this association. E16 timed pregnancy rats were injected i.p. with Escherichia coli lipopolysaccharide (LPS) to model prenatal exposure to infection. Placenta, amniotic fluid and fetal brains were collected 2 and 8h after LPS exposure. There was a significant treatment effect of low-dose (0.5mg/kg) LPS on placenta cytokine levels, with significant increases of interleukin (IL)-1beta (P<0.0001), IL-6 (P<0.0001), and tumor necrosis factor-alpha (TNF-alpha) (P=0.0001) over the 2 and 8h time course. In amniotic fluid, there was a significant effect of treatment on IL-6 levels (P=0.0006). Two hours after maternal administration of high-dose (2.5mg/kg) LPS, there were significant elevations of placenta IL-6 (P<0.0001), TNF-alpha (P<0.0001), a significant increase of TNF-alpha in amniotic fluid (P=0.008), and a small but significant decrease in TNF-alpha (P=0.035) in fetal brain. Maternal exposure to infection alters pro-inflammatory cytokine levels in the fetal environment, which may have a significant impact on the developing brain.

Regional Gray Matter Growth, Sexual Dimorphism, and Cerebral Asymmetry in the Neonatal Brain

Although there has been recent interest in the study of childhood and adolescent brain development, very little is known about normal brain development in the first few months of life. In older children, there are regional differences in cortical gray matter development, whereas cortical gray and white matter growth after birth has not been studied to a great extent. The adult human brain is also characterized by cerebral asymmetries and sexual dimorphisms, although very little is known about how these asymmetries and dimorphisms develop. We used magnetic resonance imaging and an automatic segmentation methodology to study brain structure in 74 neonates in the first few weeks after birth. We found robust cortical gray matter growth compared with white matter growth, with occipital regions growing much faster than prefrontal regions. Sexual dimorphism is present at birth, with males having larger total brain cortical gray and white matter volumes than females. In contrast to adults and older children, the left hemisphere is larger than the right hemisphere, and the normal pattern of fronto-occipital asymmetry described in older children and adults is not present. Regional differences in cortical gray matter growth are likely related to differential maturation of sensory and motor systems compared with prefrontal executive function after birth. These findings also indicate that whereas some adult patterns of sexual dimorphism and cerebral asymmetries are present at birth, others develop after birth.

Automatic segmentation of MR images of the developing newborn brain

This paper describes an automatic tissue segmentation method for newborn brains from magnetic resonance images (MRI). The analysis and study of newborn brain MRI is of great interest due to its potential for studying early growth patterns and morphological changes in neurodevelopmental disorders. Automatic segmentation of newborn MRI is a challenging task mainly due to the low intensity contrast and the growth process of the white matter tissue. Newborn white matter tissue undergoes a rapid myelination process, where the nerves are covered in myelin sheathes. It is necessary to identify the white matter tissue as myelinated or non-myelinated regions. The degree of myelination is a fractional voxel property that represents regional changes of white matter as a function of age. Our method makes use of a registered probabilistic brain atlas. The method first uses robust graph clustering and parameter estimation to find the initial intensity distributions. The distribution estimates are then used together with the spatial priors to perform bias correction. Finally, the method refines the segmentation using training sample pruning and non-parametric kernel density estimation. Our results demonstrate that the method is able to segment the brain tissue and identify myelinated and non-myelinated white matter regions.

Apoptotic mechanisms and the synaptic pathology of schizophrenia

The cortical neuropathology of schizophrenia includes neuronal atrophy, decreased neuropil, and alterations in neuronal density. Taken together with evidence of decreased synaptic markers and dendritic spines, the data suggest that synaptic circuitry is altered. Recent neuroimaging studies also indicate that a progressive loss of cortical gray matter occurs early in the course of schizophrenia. Although the mechanisms underlying these deficits are largely unknown, recent postmortem data implicate a role for altered neuronal apoptosis. Apoptosis, a form of programmed cell death, is regulated by a complex cascade of pro- and anti-apoptotic proteins. Apoptotic activation can lead to rapid neuronal death. However, emerging data also indicate that sub-lethal apoptotic activity can lead to a limited form of apoptosis in terminal neurites and individual synapses to cause synaptic elimination without cell death. For example, in Alzheimers disease, a localized apoptotic mechanism is thought to contribute to early neurite and synapse loss leading to the initial cognitive decline. Recent studies indicate that apoptotic regulatory proteins and DNA fragmentation patterns are altered in several cortical regions in schizophrenia. This paper will review converging lines of data that implicate synaptic deficits in the pathophysiology of schizophrenia and propose an underlying role for apoptotic dysregulation.

Infant Brain Atlases from Neonates to 1- and 2-Year-Olds

Background Studies for infants are usually hindered by the insufficient image contrast, especially for neonates. Prior knowledge, in the form of atlas, can provide additional guidance for the data processing such as spatial normalization, label propagation, and tissue segmentation. Although it is highly desired, there is currently no such infant atlas which caters for all these applications. The reason may be largely due to the dramatic early brain development, image processing difficulties, and the need of a large sample size. Methodology To this end, after several years of subject recruitment and data acquisition, we have collected a unique longitudinal dataset, involving 95 normal infants (56 males and 39 females) with MRI scanned at 3 ages, i.e., neonate, 1-year-old, and 2-year-old. State-of-the-art MR image segmentation and registration techniques were employed, to construct which include the templates (grayscale average images), tissue probability maps (TPMs), and brain parcellation maps (i.e., meaningful anatomical regions of interest) for each age group. In addition, the longitudinal correspondences between age-specific atlases were also obtained. Experiments of typical infant applications validated that the proposed atlas outperformed other atlases and is hence very useful for infant-related studies. Conclusions We expect that the proposed infant 0–1–2 brain atlases would be significantly conducive to structural and functional studies of the infant brains. These atlases are publicly available in our website, http://bric.unc.edu/ideagroup/free-softwares/.

Temporal and Spatial Development of Axonal Maturation and Myelination of White Matter in the Developing Brain

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) has been widely used to investigate the development of white matter (WM). However, information about this development in healthy children younger than 2 years of age is lacking, and most previous studies have only measured fractional anisotropy (FA). This study used FA and radial and axonal diffusivities in children younger than 2 years of age, aiming to determine the temporal and spatial development of axonal maturation and myelination of WM in healthy children. MATERIALS AND METHODS: A total of 60 healthy pediatric subjects were imaged by using a 3T MR imaging scanner. They were divided into 3 groups: 20 at 3 weeks, 20 at 1 year of age, and 20 at 2 years of age. All subjects were imaged asleep without sedation. FA and axial and radial diffusivities were obtained. Eight regions of interest were defined, including both central and peripheral WM for measuring diffusion parameters. RESULTS: A significant elevation in FA (P < .0001) and a reduction in axial and radial diffusivities (P < .0001) were observed from 22 days to 1 year of age, whereas only radial diffusivity showed significant changes (P = .0014) from 1 to 2 years of age. The region-of-interest analysis revealed that FA alone may not depict the underlying biologic underpinnings of WM development, whereas directional diffusivities provide more insights into the development of WM. Finally, the spatial development of WM begins from the central to the peripheral WM and from the occipital to the frontal lobes. CONCLUSIONS: With both FA and directional diffusivities, our results demonstrate the temporal and spatial development of WM in healthy children younger than 2 years of age.

Longitudinal Development of Cortical and Subcortical Gray Matter from Birth to 2 Years

Very little is known about cortical development in the first years of life, a time of rapid cognitive development and risk for neurodevelopmental disorders. We studied regional cortical and subcortical gray matter volume growth in a group of 72 children who underwent magnetic resonance scanning after birth and at ages 1 and 2 years using a novel longitudinal registration/parcellation approach. Overall, cortical gray matter volumes increased substantially (106%) in the first year of life and less so in the second year (18%). We found marked regional differences in developmental rates, with primary motor and sensory cortices growing slower in the first year of life with association cortices growing more rapidly. In the second year of life, primary sensory regions continued to grow more slowly, while frontal and parietal regions developed relatively more quickly. The hippocampus grew less than other subcortical structures such as the amygdala and thalamus in the first year of life. It is likely that these patterns of regional gray matter growth reflect maturation and development of underlying function, as they are consistent with cognitive and functional development in the first years of life.