Trajectories of Early Cortical Development in Healthy and At-Risk Children

Increasing evidence supports the idea that many neurodevelopmental and psychiatric disorders are the result of abnormal brain development, either in the prenatal period or in the first few years of life. Detecting deviations from healthy postnatal developmental trajectories early in life offers an opportunity to identify children who are at increased risk for neurodevelopmental disorders. Use of magnetic resonance imaging (MRI) in a longitudinal study design provides an effective, non-invasive, in vivo method for investigating early stages of brain development in typical and atypical infants. In the first two postnatal years, cortical thickness and surface area have distinct and heterogeneous patterns of development that are exceptionally dynamic. By age 2, cortical thickness has reached an average of 97% of adult values, compared to surface area, which has reached 69%. Cortical thickness and surface area growth in the first postnatal year is significantly related to general cognitive development. Many of the cortical regions that were found to be significant have been shown to be strongly involved in sensorimotor development and language acquisition, two vital foundations for future cognitive functioning. Schizophrenia is highly heritable and studying the offspring of schizophrenia patients provides a powerful tool for assessing the effects of genetic liability on early structural brain development. Infants with a high genetic risk for schizophrenia exhibited significant structural differences at both 1 and 2 years of age when compared to typically developing infants. Results from a qualitative analysis also suggest that infants at high genetic risk for schizophrenia may be experiencing a period of accelerated gray matter growth between birth and 1 year, after which cortical growth appears to arrest in high-risk children between 1 and 2 years of age. Taken together, there is a critical need for a greater understanding of cortical and cognitive development in the first two years of life. As such, this dissertation will have a positive impact because a more complete understanding will lead to more effective early identification strategies and interventions that could attenuate, or even prevent, the progression of neurodevelopmental disorders.Doctor of Philosoph

Neuroimaging auditory verbal hallucinations in schizophrenia patient and healthy populations

BACKGROUND: Auditory verbal hallucinations (AVH) are a cardinal feature of schizophrenia, but they can also appear in otherwise healthy individuals. Imaging studies implicate language networks in the generation of AVH; however, it remains unclear if alterations reflect biologic substrates of AVH, irrespective of diagnostic status, age, or illness-related factors. We applied multimodal imaging to identify AVH-specific pathology, evidenced by overlapping gray or white matter deficits between schizophrenia patients and healthy voice-hearers. METHODS: Diffusion-weighted and T1-weighted magnetic resonance images were acquired in 35 schizophrenia patients with AVH (SCZ-AVH), 32 healthy voice-hearers (H-AVH), and 40 age- and sex-matched controls without AVH. White matter fractional anisotropy (FA) and gray matter thickness (GMT) were computed for each region comprising ICBM-DTI and Desikan-Killiany atlases, respectively. Regions were tested for significant alterations affecting both SCZ-AVH and H-AVH groups, relative to controls. RESULTS: Compared with controls, the SCZ-AVH showed widespread FA and GMT reductions; but no significant differences emerged between H-AVH and control groups. While no overlapping pathology appeared in the overall study groups, younger (<40 years) H-AVH and SCZ-AVH subjects displayed overlapping FA deficits across four regions (p < 0.05): the genu and splenium of the corpus callosum, as well as the anterior limbs of the internal capsule. Analyzing these regions with free-water imaging ascribed overlapping FA abnormalities to tissue-specific anisotropy changes. CONCLUSIONS: We identified white matter pathology associated with the presence of AVH, independent of diagnostic status. However, commonalities were constrained to younger and more homogenous groups, after reducing pathologic variance associated with advancing age and chronicity effects

Cortical thickness and surface area in neonates at high risk for schizophrenia

Schizophrenia is a neurodevelopmental disorder associated with subtle abnormal cortical thickness and cortical surface area. However, it is unclear whether these abnormalities exist in neonates associated with genetic risk for schizophrenia. To this end, this preliminary study was conducted to identify possible abnormalities of cortical thickness and surface area in the high-genetic-risk neonates. Structural magnetic resonance images were acquired from offspring of mothers (N = 21) who had schizophrenia (N = 12) or schizoaffective disorder (N = 9), and also matched healthy neonates of mothers who were free of psychiatric illness (N = 26). Neonatal cortical surfaces were reconstructed and parcellated as regions of interest (ROIs), and cortical thickness for each vertex was computed as the shortest distance between the inner and outer surfaces. Comparisons were made for the average cortical thickness and total surface area in each of 68 cortical ROIs. After false discovery rate (FDR) correction, it was found that the female high-genetic-risk neonates had significantly thinner cortical thickness in the right lateral occipital cortex than the female control neonates. Before FDR correction, the high-genetic-risk neonates had significantly thinner cortex in the left transverse temporal gyrus, left banks of superior temporal sulcus, left lingual gyrus, right paracentral cortex, right posterior cingulate cortex, right temporal pole, and right lateral occipital cortex, compared with the control neonates. Before FDR correction, in comparison with control neonates, male high-risk neonates had significantly thicker cortex in the left frontal pole, left cuneus cortex, and left lateral occipital cortex; while female high-risk neonates had significantly thinner cortex in the bilateral paracentral, bilateral lateral occipital, left transverse temporal, left pars opercularis, right cuneus, and right posterior cingulate cortices. The high-risk neonates also had significantly smaller cortical surface area in the right pars triangularis (before FDR correction), compared with control neonates. This preliminary study provides the first evidence that early development of cortical thickness and surface area might be abnormal in the neonates at genetic risk for schizophrenia

Mapping Longitudinal Hemispheric Structural Asymmetries of the Human Cerebral Cortex From Birth to 2 Years of Age

Mapping cortical hemispheric asymmetries in infants would increase our understanding of the origins and developmental trajectories of hemispheric asymmetries. We analyze longitudinal cortical hemispheric asymmetries in 73 healthy subjects at birth, 1, and 2 years of age using surface-based morphometry of magnetic resonance images with a specific focus on the vertex position, sulcal depth, mean curvature, and local surface area. Prominent cortical asymmetries are found around the peri-Sylvian region and superior temporal sulcus (STS) at birth that evolve modestly from birth to 2 years of age. Sexual dimorphisms of cortical asymmetries are present at birth, with males having the larger magnitudes and sizes of the clusters of asymmetries than females that persist from birth to 2 years of age. The left supramarginal gyrus (SMG) is significantly posterior to the right SMG, and the maximum position difference increases from 10.2 mm for males (6.9 mm for females) at birth to 12.0 mm for males (8.4 mm for females) by 2 years of age. The right STS and parieto-occipital sulcus are significantly larger and deeper than those in the left hemisphere, and the left planum temporale is significantly larger and deeper than that in the right hemisphere at all 3 ages. Our results indicate that early hemispheric structural asymmetries are inherent and gender related

Dynamic Development of Regional Cortical Thickness and Surface Area in Early Childhood

Cortical thickness (CT) and surface area (SA) are altered in many neuropsychiatric disorders and are correlated with cognitive functioning. Little is known about how these components of cortical gray matter develop in the first years of life. We studied the longitudinal development of regional CT and SA expansion in healthy infants from birth to 2 years. CT and SA have distinct and heterogeneous patterns of development that are exceptionally dynamic; overall CT increases by an average of 36.1%, while cortical SA increases 114.6%. By age 2, CT is on average 97% of adult values, compared with SA, which is 69%. This suggests that early identification, prevention, and intervention strategies for neuropsychiatric illness need to be targeted to this period of rapid postnatal brain development, and that SA expansion is the principal driving factor in cortical volume after 2 years of age

Loss of Tet1 associated 5-hydroxymethylcytosine is concomitant with aberrant promoter hypermethylation in liver cancer

Aberrant hypermethylation of CpG islands (CGI) in human tumors occurs predominantly at repressed genes in the host tissue, but the preceding events driving this phenomenon are poorly understood. In this study, we temporally tracked epigenetic and transcriptomic perturbations which occur in a mouse model of liver carcinogenesis. Hypermethylated CGI events in the model were predicted by enrichment of the DNA modification 5-hydroxymethylcytosine (5hmC) and the histone H3 modification H3K27me3 at silenced promoters in the host tissue. During cancer progression, CGI underwent hypo-hydroxymethylation prior to hypermethylation, whilst retaining H3K27me3. In livers from mice deficient in Tet1, a tumor suppressor involved in cytosine demethylation, we observed a similar loss of promoter core 5hmC, suggesting that reduced Tet1 activity at CGI may contribute to epigenetic dysregulation observed during hepatocarcinogenesis. Consistent with this possibility, mouse liver tumors exhibited reduced Tet1 protein levels. Similar to humans, DNA methylation changes at CGI in mice did not appear to be direct drivers of hepatocellular carcinoma progression, rather, dynamic changes in H3K27me3 promoter deposition correlated strongly with tumor-specific activation and repression of transcription. Overall, our results suggest that loss of promoter-associated 5hmC in liver tumors licenses reprogramming of DNA methylation at silent CGI during progression

The cortical signature of impaired gesturing: Findings from schizophrenia

Schizophrenia is characterized by deficits in gesturing that is important for nonverbal communication. Research in healthy participants and brain-damaged patients revealed a left-lateralized fronto-parieto-temporal network underlying gesture performance. First evidence from structural imaging studies in schizophrenia corroborates these results. However, as of yet, it is unclear if cortical thickness abnormalities contribute to impairments in gesture performance. We hypothesized that patients with deficits in gesture production show cortical thinning in 12 regions of interest (ROIs) of a gesture network relevant for gesture performance and recognition. Forty patients with schizophrenia and 41 healthy controls performed hand and finger gestures as either imitation or pantomime. Group differences in cortical thickness between patients with deficits, patients without deficits, and controls were explored using a multivariate analysis of covariance. In addition, the relationship between gesture recognition and cortical thickness was investigated. Patients with deficits in gesture production had reduced cortical thickness in eight ROIs, including the pars opercularis of the inferior frontal gyrus, the superior and inferior parietal lobes, and the superior and middle temporal gyri. Gesture recognition correlated with cortical thickness in fewer, but mainly the same, ROIs within the patient sample. In conclusion, our results show that impaired gesture production and recognition in schizophrenia is associated with cortical thinning in distinct areas of the gesture network

Prenatal isolated mild ventriculomegaly is associated with persistent ventricle enlargement at ages 1 and 2

Enlargement of the lateral ventricles is thought to originate from abnormal prenatal brain development and is associated with neurodevelopmental disorders. Fetal isolated mild ventriculomegaly (MVM) is associated with enlargement of lateral ventricle volumes in the neonatal period and developmental delays in early childhood. However, little is known about postnatal brain development in these children