Molecular signatures of cortical expansion in the human fetal brain.

The third trimester of human gestation is characterised by rapid increases in brain volume and cortical surface area. A growing catalogue of cells in the prenatal brain has revealed remarkable molecular diversity across cortical areas.1,2 Despite this, little is known about how this translates into the patterns of differential cortical expansion observed in humans during the latter stages of gestation. Here we present a new resource, µBrain, to facilitate knowledge translation between molecular and anatomical descriptions of the prenatal developing brain. Built using generative artificial intelligence, µBrain is a three-dimensional cellular-resolution digital atlas combining publicly-available serial sections of the postmortem human brain at 21 weeks gestation3 with bulk tissue microarray data, sampled across 29 cortical regions and 5 transient tissue zones.4 Using µBrain, we evaluate the molecular signatures of preferentially-expanded cortical regions during human gestation, quantified in utero using magnetic resonance imaging (MRI). We find that differences in the rates of expansion across cortical areas during gestation respect anatomical and evolutionary boundaries between cortical types5 and are founded upon extended periods of upper-layer cortical neuron migration that continue beyond mid-gestation. We identify a set of genes that are upregulated from mid-gestation and highly expressed in rapidly expanding neocortex, which are implicated in genetic disorders with cognitive sequelae. Our findings demonstrate a spatial coupling between areal differences in the timing of neurogenesis and rates of expansion across the neocortical sheet during the prenatal epoch. The µBrain atlas is available from: https://garedaba.github.io/micro-brain/ and provides a new tool to comprehensively map early brain development across domains, model systems and resolution scales.

Cortical remodelling in childhood is associated with genes enriched for neurodevelopmental disorders.

Cortical development during childhood and adolescence has been characterised in recent years using metrics derived from Magnetic Resonance Imaging (MRI). Changes in cortical thickness are greatest in the first two decades of life and recapitulate the genetic organisation of the cortex, highlighting the potential early impact of gene expression on differences in cortical architecture over the lifespan. It is important to further our understanding of the possible neurobiological mechanisms that underlie these changes as cortical thickness may be altered in several common neurodevelopmental and psychiatric disorders. In this study, we combine MRI acquired from a large typically-developing childhood population (n â€‹= â€‹768) with comprehensive human gene expression databases to test the hypothesis that disrupted mechanisms common to neurodevelopmental disorders are encoded by genes expressed early in development and nested within those associated with typical cortical remodelling in childhood. We find that differential rates of thinning across the developing cortex are associated with spatially-varying gradients of gene expression. Genes that are expressed highly in regions of accelerated thinning are expressed predominantly in cortical neurons, involved in synaptic remodelling, and associated with common cognitive and neurodevelopmental disorders. Further, we identify subsets of genes that are highly expressed in the prenatal period and jointly associated with both developmental cortical morphology and neurodevelopmental disorders.

Individual variation in longitudinal postnatal development of the primate brain.

Quantifying individual variation in postnatal brain development can provide insight into cognitive diversity within a population and the aetiology of common neuropsychiatric and neurodevelopmental disorders. Non-invasive studies of the non-human primate can aid understanding of human brain development, facilitating longitudinal analysis during early postnatal development when comparative human populations are difficult to sample. In this study, we perform analysis of a longitudinal MRI dataset of 32 macaques, each with up to five magnetic resonance imaging (MRI) scans acquired between 3 and 36 months of age. Using nonlinear mixed effects model we derive growth trajectories for whole brain, cortical and subcortical grey matter, cerebral white matter and cerebellar volume. We then test the association between individual variation in postnatal tissue volumes and birth weight. We report nonlinear growth models for all tissue compartments, as well as significant variation in total intracranial volume between individuals. We also demonstrate that regional subcortical grey matter varies both in total volume and rate of change between individuals and is associated with differences in birth weight. This supports evidence that birth weight may act as a marker of subsequent brain development and highlights the importance of longitudinal MRI analysis in developmental studies.

Study protocol: families and childhood transitions study (FACTS) - a longitudinal investigation of the role of the family environment in brain development and risk for mental health disorders in community based children.

BACKGROUND: Extant research has demonstrated that parenting behaviour can be a significant contributor to the development of brain structure and mental health during adolescence. Nonetheless, there is limited research examining these relationships during late childhood, and particularly in the critical period of brain development occurring between 8 and 10 years of age. The effects of the family environment on the brain during late childhood may have significant implications for later functioning, and particularly mental health. The Families and Childhood Transitions Study (FACTS) is a multidisciplinary longitudinal cohort study of brain development and mental health, with two waves of data collection currently funded, occurring 18-months apart, when child participants are aged approximately 8- and 10-years old. METHODS/DESIGN: Participants are 163 children (M age [SD] = 8.44 [0.34] years, 76 males) and their mothers (M age [SD] = 40.34 [5.43] years). Of the 163 families who consented to participate, 156 completed a video-recorded and observer-coded dyadic interaction task and 153 completed a child magnetic resonance imaging brain scan at baseline. Families were recruited from lower socioeconomic status (SES) areas to maximise rates of social disadvantage and variation in parenting behaviours. All experimental measures and tasks completed at baseline are repeated at an 18-month follow-up, excluding the observer coded family interaction tasks. The baseline assessment was completed in October 2015, and the 18-month follow up will be completed May 2017. DISCUSSION: This study, by examining the neurobiological and mental health consequences of variations in parenting, has the potential to significantly advance our understanding of child development and risk processes. Recruitment of lower SES families will also allow assessment of resilience factors given the poorer outcomes often associated with this population.

Evidence of a dimensional relationship between schizotypy and schizophrenia: a systematic review.

The personality dimension of schizotypy is well established, and schizotypal traits can be taken to represent a proneness toward developing psychosis. Yet, there are competing theories about the latent structure of schizotypy. More specifically, there is controversy over the extent to which this propensity toward psychosis is present only in a small proportion of the population, or whether it is spread dimensionally throughout the general community. On the basis of accumulating research findings the present article argues for a fully dimensional model of schizotypy. It describes recent neurobiological, neuropsychological, social and environmental evidence supporting the idea that schizotypy in healthy populations, and disorders on the schizophrenia spectrum are fundamentally linked. Directions for further research are also considered.

White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study.

OBJECTIVE: Niemann-Pick disease type C (NPC) is a progressive neurovisceral disorder with disrupted intracellular cholesterol metabolism that results in significant alterations to neuronal and axonal structure. Adult patients present with ataxia, gaze palsy, impaired cognition, and neuropsychiatric illness, but the neural substrate has not been well-characterized in vivo. Our aim was to investigate a well-characterized sample of adults with confirmed NPC for gray and white matter abnormalities. METHODS: We utilized a combination of optimized voxel-based morphometry of T1-weighted images and tract-based spatial statistics of diffusion tensor images to examine gray matter volume and white matter structural differences in 6 adult patients with NPC and 18 gender- and age-matched controls. RESULTS: Patients with NPC demonstrated bilateral gray matter reductions in large clusters in bilateral hippocampus, thalamus, superior cerebellum, and insula, in addition to smaller regions of inferoposterior cortex. Patients demonstrated widespread reductions in fractional anisotropy in major white matter tracts. Subsequent analysis of measures of axial and radial diffusivity suggest that these changes are contributed to by both impaired myelination and altered axonal structure. CONCLUSIONS: Findings in gray matter areas are broadly consistent with human and animal studies of selective vulnerability of neuronal populations to the neuropathology of NPC, whereas more widespread white matter changes are consistent with the hypothesis that disrupted myelination and axonal structure predate changes to the neuronal cell body. These findings suggest that volumetric analysis of gray matter and diffusion tensor imaging may be useful modalities for indexing illness stage and monitoring response to emerging treatment.

Characterizing anterior cingulate activation in chronic schizophrenia: a group and single-subject fMRI study.

OBJECTIVE: Functional abnormalities of the dorsal anterior cingulate (dAC) region have been emphasized in schizophrenia, particularly in relation to cognitive deficits. In this study, we sought to further evaluate the notion of dAC hypofunction in chronic schizophrenia patients using a cognitive task specifically designed to activate this region, enabling both group and single-subject level analyses. METHOD: Twelve male schizophrenia patients and 14 male healthy subjects were studied with functional magnetic resonance imaging (fMRI) and the multi-source interference task (MSIT). Patients and healthy subjects were matched for age, gender, education, task performance and gross surface morphology of the AC region. fMRI analyses were conducted at the group and single-subject levels using stringent whole-brain activation thresholds. RESULTS: Multi-source interference task performance was associated with large and significant activation of the dAC and supplementary motor area (SMA) in patients and healthy subjects. Standard comparison of the two groups indicated that the patients were comparable with healthy subjects in their dAC activation, but had a small cluster of greater SMA activation, while single-subject analyses identified minimal differences in the magnitude or spatial dispersion of dAC activation between the groups. CONCLUSION: These findings challenge existing notions of impaired dAC activation in chronic schizophrenia and suggest that the functional pathophysiology of this medial-wall region should be considered beyond straightforward models of hypoactivation.

Deficits in Source Monitoring in Subjects with Auditory Hallucinations May be Due to Differences in Verbal Intelligence and Verbal Memory.

Previous research has proposed that the experience of auditory hallucinations in schizophrenia represents a failure to monitor self-generated verbal mental imagery. However, recent neuropsychological investigations into this matter have provided inconclusive and even contradictory findings with respect to the proposed relationship. This study compared the performance of three groups of adult males, schizophrenic inpatients (hallucinators and nonhallucinators), and normal controls, matched for age, education, and medication, on a source monitoring task. Initial analysis indicated that performance on a Verbal IQ and Verbal Memory test were significantly related to performance on the source monitoring task. Comparisons between groups were made on the basis of state and trait group characteristics with respect to hallucinations. After controlling for the influence of Verbal IQ and Verbal Memory on task performance, no between-group differences were found for overall accuracy in attribution of self-generated items or in the number of self to experimenter misattribution errors. This finding suggests that the inconsistent findings previously noted in this field may be due to a failure to identify and control for these important covariates. The implications of these findings for theoretical models of hallucination are discussed.

Cholecystitis occurring without stones.

A case of acalculous cholecystitis in a 65-year-old man with underlying diabetes mellitus, hypertension, and peripheral arteriosclerosis is presented here. His case remained diagnostically puzzling for some time until symptoms and signs became more severe and very suggestive of acute cholecystitis. The clinical impression was then supported by an abnormal radioisotope biliary scan. The scan has fairly good sensitivity in detecting this condition but may not be totally dependable. Acalculous cholecystitis is an unusual but serious variant of a common disorder in which treatable gallbladder disease may masquerade as a less treatable liver malady. A common denominator among this disorder's many etiologies may be impairment of the gallbladder microcirculation in the presence of one or more conditions that lower the gallbladder's resistance to bacterial invasion. Prompt detection and treatment are desirable to reduce morbidity and mortality. However, early diagnosis is not always possible, because the clinical picture often is unclear, clear, gallstones are absent, and laboratory test results may be normal or equivocal. As in the case reported here, the vague clinical picture may dictate following a patient until the illness reaches an intensity acute enough to permit identification. The greatest aid to earlier diagnosis for the physician faced with circumstances similar to those described here is to think of cholecystitis and then to give strong weight to that clinical suspicion. At times, a recommendation for cholecystectomy may have to be made mainly on clinical judgment.