The Developmental Neurobiology of Brain Connectivity in Schizophrenia

Much work over the past two decades supports the concept that schizophrenia involves a disruption in the orchestration of the multiple neural networks that participate in higher cognitive functions. The connectivity between neural networks arising during normal development is potentially disrupted, leading to the recruitment of either inappropriate regions for task execution, or alternatively, alters the processing requirements in expected regions. For example, studies utilizing both glucose metabolism (FDG-PET), SPECT, and H2O15 PET have demonstrated hypofrontality in the dorslolateral prefrontal cortex (DLPFC) on tasks of executive function. Additionally, studies utilizing diffusion tensor imaging (DTI), which measures the coherence of neuronal fiber tracts, have shown a decrease in the coherence of white matter tracts in schizophrenia. This is presumed to be additional evidence for disrupted connectivity in schizophrenia

Dissecting static and dynamic functional connectivity: Example from the autism spectrum

The ability to measure the intrinsic functional architecture of the brain has grown exponentially over the last 2 decades. Measures of intrinsic connectivity within the brain, typically measured using resting-state functional magnetic resonance imaging (MRI), have evolved from primarily “static” approaches, to include dynamic measures of functional connectivity. Measures of dynamic functional connectivity expand the assumptions to allow brain regions to have temporally different patterns of communication between different regions. That is, connections within the brain can differentially fire between different regions at different times, and these differences can be quantified. Applying approaches that measure the dynamic characteristics of functional brain connectivity have been fruitful in identifying differences during brain development and psychopathology. We provide a brief overview of static and dynamic measures of functional connectivity and illustrate the synergy in applying these approaches to identify both age-related differences in children and differences between typically developing children and children with autistic symptoms

Reduced cortical complexity in children with prader-willi syndrome and its association with cognitive impairment and developmental delay

Background: Prader-Willi Syndrome (PWS) is a complex neurogenetic disorder with symptoms involving not only hypothalamic, but also a global, central nervous system dysfunction. Previously, qualitative studies reported polymicrogyria in adults with PWS. However, there have been no quantitative neuroimaging studies of cortical morphology in PWS and no studies to date in children with PWS. Thus, our aim was to investigate and quantify cortical complexity in children with PWS compared to healthy controls. In addition, we investigated differences between genetic subtypes of PWS and the relationship between cortical complexity and intelligence within the PWS group.Methods: High-resolution structural magnetic resonance images were acquired in 24 children with genetically confirmed PWS (12 carrying a deletion (DEL), 12 with maternal uniparental disomy (mUPD)) and 11 age- and sex-matched typically developing siblings as healthy controls. Local gyrification index (lGI) was obtained using the FreeSurfer software suite.Results: Four large clusters, two in each hemisphere, comprising frontal, parietal and temporal lobes, had lower lGI in children with PWS, compared to healthy controls. Clusters with lower lGI also had significantly lower cortical surface area in children with PWS. No differences in cortical thickness of the clusters were found between the PWS and healthy controls. lGI correlated significantly with cortical surface area, but not with cortical thickness. Within the PWS group, lGI in both hemispheres correlated with Total IQ and Verbal IQ, but not with Performance IQ. Children with mUPD, compared to children with DEL, had two small clusters with lower lGI in the right hemisphere. lGI of these clusters correlated with cortical surface area, but not with cortical thickness or IQ.Conclusions: These results suggest that lower cortical complexity in children with PWS partially underlies cognitive impairment and developmental delay, probably due to alterations in gene networks that play a prominent role in early brain development

What Twin Studies Tell Us About the Heritability of Brain Development, Morphology, and Function: A Review

The development of brain structure and function shows large inter-individual variation. The extent to which this variation is due to genetic or environmental influences has been investigated in twin studies using structural and functional Magnetic Resonance Imaging (MRI). The current review presents an overview of twin studies using MRI in children, adults and elderly, and focuses on cross-sectional and longitudinal designs. The majority of the investigated brain measures are heritable to a large extent (60–80 %), although spatial differences in heritability are observed as well. Cross-sectional studies suggest that heritability estimates slightly increase from childhood to adulthood. Long-term longitudinal studies are better suited to study developmental changes in heritability, but these studies are limited. Results so far suggest that the heritability of change over time is relatively low or absent, but more studies are needed to confirm these findings. Compared to brain structure, twin studies of brain function are scarce, and show much lower heritability estimates (~40 %). The insights from heritability studies aid our understanding of individual differences in brain structure and function. With the recent start of large genetic MRI consortia, the chance of finding genes that explain the heritability of brain morphology increases. Gene identification may provide insight in biological mechanisms involved in brain processes, which in turn will learn us more about healthy and disturbed brain functioning

Beyond Bonferroni revisited: concerns over inflated false positive research findings in the fields of conservation genetics, biology, and medicine

In 2006, Narum published a paper in Conservation Genetics emphasizing that Bonferroni correction for multiple testing can be highly conservative with poor statistical power (high Type II error). He pointed out that other approaches for multiple testing correction can control the false discovery rate (FDR) with a better balance of Type I and Type II errors and suggested that the approach of Benjamini and Yekutieli (BY) 2001 provides the most biologically relevant correction for evaluating the signifcance of population diferentiation in conservation genetics. However, there are crucial diferences between the original Benjamini and Yekutieli procedure and that described by Narum. After carefully reviewing both papers, we found an error due to the incorrect implementation of the BY procedure in Narum (Conserv Genet 7:783–787, 2006) such that the approach does not adequately control FDR. Since the incorrect BY approach has been increasingly used, not only in conservation genetics, but also in medicine and biology, it is important that the error is made known to the scientifc community. In addition, we provide an overview of FDR approaches for multiple testing correction and encourage authors frst and foremost to provide efect sizes for their results; and second, to be transparent in their descriptions of multiple testing correction. Finally, the impact of this error on conservation genetics and other felds will be study-dependent, as it is related to the number of true to false positives for each study

Memory deficits following neonatal critical illness: A common neurodevelopmental pathway

Summary Over the last decade, knowledge has emerged that children growing up after neonatal critical illness, irrespective of underlying diagnosis, are at risk of memory impairment and school problems. Strikingly, these problems are manifest even when intelligence is normal. In this review, we propose a common neurodevelopmental pathway following neonatal critical illness by demonstrating that the survivors of preterm birth, congenital heart disease, and severe respiratory failure, share an increased risk of long-term memory deficits and associated hippocampal alterations. Rather than being a consequence of underlying diagnosis, we suggest that this shared vulnerability is most likely related to common conditions associated with neonatal critical illness. These include hypoxia, neuroinflammation, stress, exposure to anaesthetics, or a complex interplay of these factors at different postconceptional ages. Future work should be aimed at improving early identification of patients at risk and evaluating intervention modalities, such as cognitive or exercise training

Socialization of prosocial behavior: Gender differences in the mediating role of child brain volume

Evidence has been accumulating for the impact of normal variation in caregiving quality on brain morphology in children, but the question remains whether differences in brain volume related to early caregiving translate to behavioral implications. In this longitudinal population-based study (N = 162), moderated mediation was tested for the relation between parental sensitivity and child prosocial behavior via brain volume, in boys and girls. Both maternal and paternal sensitivity were repeatedly observed between 1 and 4 years of age. Brain volume was assessed using magnetic resonance imaging measurements at age 8, and self-reported prosocial behavior of children was assessed at 9 years of age. Parental sensitivity was positively related to child brain volume, and to child prosocial behavior at trend level. Child brain volume was negatively related to child prosocial behavior. A significant gender-by-brain interaction was found, illustrating that daughters of sensitive parents were more prosocial and that less prosocial behavior was reported for girls with a larger total brain volume. Child gender significantly moderated the indirect effect of parental sensitivity on prosocial behavior via total brain volume. A significant indirect pathway was found only in girls. The results warrant replication but indicate the importance of considering gender when studying the behavioral implications of differences in brain volume related to early caregiving experiences

Genetic Burden for Late-Life Neurodegenerative Disease and Its Association With Early-Life Lipids, Brain, Behavior, and Cognition

Background: Genetics play a significant role in the etiology of late-life neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia. Part of the individual differences in risk for these diseases can be traced back decades before the onset of disease symptoms. Previous studies have shown evidence for plausible links of apolipoprotein E (APOE), the most important genetic marker for Alzheimer’s disease, with early-life cognition and neuroimaging markers. We aimed to assess whether genome-wide genetic burden for the aforementioned neurodegenerative diseases plays a role in early-life processes. Methods: We studied children from the Generation R Study, a prospective birth cohort. APOE genotypes and polygenic genetic burdens for Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia were obtained through genome-wide genotyping. Non-verbal intelligence was assessed through cognitive tests at the research center around the age of 6 years, and educational attainment through a national school performance test around the age of 11 years. The Child Behavior Checklist was administered around the age of 10 years, and data from the anxious/depressed, withdrawn/depressed, and the internalizing behavior problems scales were used. Children participated in a neuroimaging study when they were 10 years old, in which structural brain metrics were obtained. Lipid serum profiles, which may be influenced by APOE genotype, were assessed from venal blood obtained around the age of 6 years. The sample size per analysis varied between 1,641 and 3,650 children due to completeness of data. Results: We did not find evidence that APOE genotype or the polygenic scores impact on childhood nonverbal intelligence, educational attainment, internalizing behavior, and global brain structural measures including total brain volume and whole brain fractional anisotropy (all p > 0.05). Carriership of the APOE ε2 allele was associated with lower and APOE ε4 with higher low-density lipoprotein cholesterol concentrations when compared to APOE ε3/ε3 carriers. Conclusion: We found no evidence that genetic burden for late-life neurodegenerative diseases associates with early-life cognition, internalizing behavior, or global brain structure

A prospective population-based study of gestational vitamin D status and brain morphology in preadolescents

Low vitamin D level during pregnancy has been associated with adverse neurodevelopmental outcomes such as autism spectrum disorders (ASD) in children. However, the underlying neurobiological mechanism remains largely unknown. This study investigated the association between gestational 25-hydroxyvitamin D [25(OH)D] concentration and brain morphology in 2597 children at the age of 10 years in the population-based Generation R Study. We studied both 25(OH)D in maternal venous blood in mid-gestation and in umbilical cord blood at delivery, in relation to brain volumetric measures and surface-based cortical metrics including cortical thickness, surface area, and gyrification using linear regression. We found exposure to higher maternal 25(OH)D concentrations in mid-gestation was associated with a larger cerebellar volume in children (b ​= ​0.02, 95%CI 0.001 to 0.04), however this association did not remain after co