Rafael Romero-Garcia
Profile Url: rafael-romero-garcia589
Researcher at University of Cambridge
0
0
0
Biological Psychiatry, 2019-12-13
Video Abstract (AI generated)
Paper
Preprint
Biological Psychiatry
Background Genetic 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. Methods We 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). Results Magnetization 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. Conclusions Microstructural 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.
0
0
0
Video Abstract (AI generated)
Paper
Preprint
Adolescent changes in human brain function are not entirely understood. Here we used multi-echo functional magnetic resonance imaging (fMRI) to measure developmental change in functional connectivity (FC) of resting-state oscillations between pairs of 330 cortical regions and 16 subcortical regions in N=298 healthy adolescents. Participants were aged 14-26 years and were scanned on two or more occasions at least 6 months apart. We found two distinct modes of age-related change in FC: "conservative'' and "disruptive''. Conservative development was characteristic of primary cortex, which was strongly connected at 14 years and became even more connected in the period 14-26 years. Disruptive development was characteristic of association cortex, hippocampus and amygdala, which were not strongly connected at 14 years but became more strongly connected during adolescence. We defined the maturational index (MI) as the signed coefficient of the linear relationship between baseline FC (at 14 years, FC14) and adolescent change in FC (ΔFC14-26). Disruptive systems (with negative MI) were functionally specialised for social cognition and autobiographical memory and were significantly co-located with prior maps of aerobic glycolysis (AG), AG-related gene expression, post-natal expansion of cortical surface area, and adolescent shrinkage of cortical depth. We conclude that human brain organization is disrupted during adolescence by the emergence of strong functional connectivity of subcortical nuclei and association cortical areas, representing metabolically expensive re-modelling of synaptic connectivity between brain regions that were not strongly connected in childhood. We suggest that this re-modelling process may support emergence of social skills and self-awareness during healthy human adolescence.
0
0
0
Video Abstract (AI generated)
Paper
Preprint
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 disorder’s 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.
0
0
0
Cerebral Cortex, 2018-12-27
Video Abstract (AI generated)
Paper
Preprint
Cerebral Cortex
Seminal human brain histology work has demonstrated developmental waves of myelination. Here, using a micro-structural magnetic resonance imaging (MRI) marker sensitive 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. Network analysis of the micro-structural connectome revealed that late developing (second wave) regions had significantly higher degree and other measures of centrality. These results are consistent with regionally heterogeneous waves of intracortical myelinogenesis and age-related demyelination, which may be relevant to the onset of neuropsychiatric disorders, and dementia, and the staged acquisition and decline of motor and cognitive skills over the course of the life-cycle.