Biology subjects

Vertes, P. E.

Publications and source records attributed to Vertes, P. E..

25 records · Page 2Linked to original sources

bioRxiv2019

Transcriptomic and Cellular Decoding of Regional Brain Vulnerability to Neurodevelopmental Disorders

Neurodevelopmental disorders are highly heritable and associated with spatially-selective disruptions of brain anatomy. The logic that translates genetic risks into spatially patterned brain vulnerabilities remains unclear but is a fundamental question in disease pathogenesis. Here, we approach this question by integrating (i) in vivo neuroimaging data from patient subgroups with known causal genomic copy number variations (CNVs), and (ii) bulk and single-cell gene expression data from healthy cortex. First, for each of six different CNV disorders, we show that spatial patterns of cortical anatomy change in youth are correlated with spatial patterns of expression for CNV region genes in bulk cortical tissue from typically-developing adults. Next, by transforming normative bulk-tissue cortical expression data into cell-type expression maps, we further link each disorders anatomical change map to specific cell classes and specific CNV-region genes that these cells express. Finally, we establish convergent validity of this "transcriptional vulnerability model" by inter-relating patient neuroimaging data with measures of altered gene expression in both brain and blood-derived patient tissue. Our work clarifies general biological principles that govern the mapping of genetic risks onto regional brain disruption in neurodevelopmental disorders. We present new methods that can harness these principles to screen for potential cellular and molecular determinants of disease from readily available patient neuroimaging data.

neuroscience↗

bioRxiv2018

Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia related genes

Schizophrenia has been conceived as a disorder of brain connectivity but it is unclear how this network phenotype is related to the emerging genetics. We used morphometric similarity analysis of magnetic resonance imaging (MRI) data as a marker of inter-areal cortical connectivity in three prior case-control studies of psychosis: in total, N=185 cases and N=227 controls. Psychosis was associated with globally reduced morphometric similarity (MS) in all 3 studies. There was also a replicable pattern of case-control differences in regional MS which was significantly reduced in patients in frontal and temporal cortical areas, but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case-control differences in MS was spatially correlated with cortical expression of a weighted combination of genes enriched for neu-robiologically relevant ontology terms and pathways. In addition, genes that were normally over-expressed in cortical areas with reduced MS were significantly up-regulated in a prior post mortem study of schizophrenia. We propose that this combination of neuroimaging and transcriptional data provides new insight into how previously implicated genes and proteins, as well as a number of unreported proteins in their vicinity on the protein interaction network, may interact to drive structural brain network changes in schizophrenia.

neuroscience↗

bioRxiv2018

Schizotypy-related magnetization of cortex in healthy adolescence is co-located with expression of schizophrenia risk genes

BackgroundGenetic risk is thought to drive clinical variation on a spectrum of schizophrenia-like traits but the underlying changes in brain structure that mechanistically link genomic variation to schizotypal experience and behaviour are unclear. MethodsWe assessed schizotypy using a self-reported questionnaire, and measured magnetization transfer (MT), as a putative micro-structural MRI marker of intra-cortical myelination, in 68 brain regions, in 248 healthy young people (aged 14-25 years). We used normative adult brain gene expression data, and partial least squares (PLS) analysis, to find the weighted gene expression pattern that was most co-located with the cortical map of schizotypy-related magnetization (SRM). ResultsMagnetization was significantly correlated with schizotypy in bilateral posterior cingulate cortex and precuneus (and for disorganized schizotypy also in medial prefrontal cortex; all FDR-corrected P < 0.05), which are regions of the default mode network specialized for social and memory functions. The genes most positively weighted on the whole genome expression map co-located with SRM were enriched for genes that were significantly down-regulated in two prior case-control histological studies of brain gene expression in schizophrenia. Conversely, the most negatively weighted genes were enriched for genes that were transcriptionally up-regulated in schizophrenia. Positively weighted (down-regulated) genes were enriched for neuronal, specifically inter-neuronal, affiliations and coded a network of proteins comprising a few highly interactive "hubs" such as parvalbumin and calmodulin. ConclusionsMicrostructural MRI maps of intracortical magnetization can be linked to both the behavioural traits of schizotypy and to prior histological data on dysregulated gene expression in schizophrenia.

neuroscience↗

bioRxiv2018

Waves of maturation and senescence in micro-structural MRI markers of human cortical myelination over the lifespan

Seminal human brain histology work has demonstrated developmental waves of myelination. Here, using a micro-structural magnetic resonance imaging (MRI) marker linked to myelin, we studied fine-grained age differences to deduce waves of growth, stability, and decline of cortical myelination over the life-cycle. In 484 participants, aged 8-85 years, we fitted smooth growth curves to T1- to T2-weighted ratio in each of 360 regions from one of 7 cytoarchitectonic classes. From the first derivatives of these generally inverted-U trajectories, we defined three milestones: the age at peak growth; the age at onset of a stable plateau; and the age at the onset of decline. Age at peak growth had a bimodal distribution comprising an early (pre-pubertal) wave of primary sensory and motor cortices and a later (post-pubertal) wave of association, insular and limbic cortices. Most regions reached stability in the 30s but there was a second wave reaching stability in the 50s. Age at onset of decline was also bimodal: in some right hemisphere regions, the curve declined from the 60s, but in other left hemisphere regions, there was no significant decline from the stable plateau. These results are consistent with regionally heterogeneous waves of intracortical myelinogenesis and age-related demyelination.

neuroscience↗

bioRxiv2017

Low dimensional morphospace of topological motifs in human fMRI brain networks

We present a low-dimensional morphospace of fMRI brain networks, where axes are defined in a data-driven manner based on the network motifs. The morphospace allows us to identify the key variations in healthy fMRI networks in terms of their underlying motifs and we observe that two principal components (PCs) can account for 97% of the motif variability. The first PC corresponds to the small-world axis and correlates strongly with the networks global efficiency. There is also some evidence that PC1 correlates with the average length of the 5% of longest edges in the network. Hence this axis represents the trade-off between the cost of long distance edges and their topological benefits. The second PC correlates with the networks assortativity. Finally, we show that the economical clustering generative model proposed by Vertes et al. can approximately reproduce the motif PC space of the real fMRI brain networks, in contrast to other generative models. Overall, the motif morphospace provides a powerful way to visualise the relationships between network properties and to study the driving forces behind the topology of fMRI brain networks.

neuroscience↗

bioRxiv2017

Morphometric Similarity Networks Detect Microscale Cortical Organisation And Predict Inter-Individual Cognitive Variation

Macroscopic cortical networks are important for cognitive function, but it remains challenging to construct anatomically plausible individual structural connectomes from human neuroimaging. We introduce a new technique for cortical network mapping, based on inter-regional similarity of multiple morphometric parameters measured using multimodal MRI. In three cohorts (two human, one macaque), we find that the resulting morphometric similarity networks (MSNs) have a complex topological organisation comprising modules and high-degree hubs. Human MSN modules recapitulate known cortical cytoarchitectonic divisions, and greater inter-regional morphometric similarity was associated with stronger inter-regional co-expression of genes enriched for neuronal terms. Comparing macaque MSNs to tract-tracing data confirmed that morphometric similarity was related to axonal connectivity. Finally, variation in the degree of human MSN nodes accounted for about 40% of between-subject variability in IQ. Morphometric similarity mapping provides a novel, robust and biologically plausible approach to understanding how human cortical networks underpin individual differences in psychological functions.

neuroscience↗

bioRxiv2017

Adolescent Tuning Of Association Cortex In Human Structural Brain Networks

Motivated by prior data on local cortical shrinkage and intracortical myelination, we predicted age-related changes in topological organisation of cortical structural networks during adolescence. We estimated structural correlation from magnetic resonance imaging measures of cortical thickness at 308 regions in a sample of N=297 healthy participants, aged 14-24 years. We used a novel sliding-window analysis to measure age-related changes in network attributes globally, locally and in the context of several community partitions of the network. We found that the strength of structural correlation generally decreased as a function of age. Association cortical regions demonstrated a sharp decrease in nodal degree (hubness) from 14 years, reaching a minimum at approximately 19 years, and then levelling off or even slightly increasing until 24 years. Greater and more prolonged age-related changes in degree of cortical regions within the brain network were associated with faster rates of adolescent cortical myelination and shrinkage. The brain regions that demonstrated the greatest age-related changes were concentrated within prefrontal modules. We conclude that human adolescence is associated with biologically plausible changes in structural imaging markers of brain network organization, consistent with the concept of tuning or consolidating anatomical connectivity between frontal cortex and the rest of the connectome.

neuroscience↗