How does human brain structure mature during adolescence? We used MRI to measure cortical thickness and intracortical myelination in 297 population volunteers aged 14-24 y old. We found and replicated that association cortical areas were thicker and less myelinated than primary cortical areas at 14 y. However, association cortex had faster rates of shrinkage and myelination over the course of adolescence. Age-related increases in cortical myelination were maximized approximately at the internal layer of projection neurons. Adolescent cortical myelination and shrinkage were coupled and specifically associated with a dorsoventrally patterned gene expression profile enriched for synaptic, oligodendroglial-and schizophrenia-related genes. Topologically efficient and biologically expensive hubs of the brain anatomical network had greater rates of shrinkage/myelination and were associated with overexpression of the same transcriptional profile as cortical consolidation. We conclude that normative human brain maturation involves a genetically patterned process of consolidating anatomical network hubs. We argue that developmental variation of this consolidation process may be relevant both to normal cognitive and behavioral changes and the high incidence of schizophrenia during human brain adolescence. A dolescence is associated with major behavioral, social, and sexual changes as well as increased risk for many psychiatric disorders (1). However, human brain maturation during adolescence is not yet so well understood. Historically, pioneering studies used histological techniques to show that distinct areas of cortex were differentially myelinated in postmortem examination of perinatal tissue, suggesting "myelinogenesis" as an important process in human brain development (2, 3). MRI can measure human brain development more comprehensively and over a wider age range than is possible for postmortem anatomists. The thickness of human cortex can be reliably and replicably measured by MRI (4), and longitudinal studies have shown that cortical thickness (CT; millimeters) monotonically shrinks over the course of postnatal development, with variable shrinkage rates estimated for different age ranges (5-11; review in ref. 12). CT typically shrinks from about 3.5 mm at age 13 y old (9) to about 2.2 mm at age 75 y old (10, 11). Rates of cortical shrinkage are faster during adolescence (approximately −0.05 mm/y) than in later adulthood or earlier childhood (9).What does this MRI phenomenon of cortical shrinkage represent at a cellular level? There are broadly two tenable models: pruning and myelination. Basic physical principles of MRI predict that shorter longitudinal (T1) relaxation times reflect either a reduction in the fraction of "watery" cytoplasmic material, like cell bodies, synapses, or extracellular fluid, or an increase in the fraction of "fatty" myelinated material, like axons. Pruning models propose that cortical shrinkage in adolescence represents loss or remodeling of synapses, dendrites, or cell bodies (13). Myelin...

Human functional magnetic resonance imaging (fMRI) brain networks have a complex topology comprising integrative components, e.g. long-distance inter-modular edges, that are theoretically associated with higher biological cost. Here, we estimated intra-modular degree, inter-modular degree and connection distance for each of 285 cortical nodes in multi-echo fMRI data from 38 healthy adults. We used the multivariate technique of partial least squares (PLS) to reduce the dimensionality of the relationships between these three nodal network parameters and prior microarray data on regional expression of 20 737 genes. The first PLS component defined a transcriptional profile associated with high intra-modular degree and short connection distance, whereas the second PLS component was associated with high inter-modular degree and long connection distance. Nodes in superior and lateral cortex with high inter-modular degree and long connection distance had local transcriptional profiles enriched for oxidative metabolism and mitochondria, and for genes specific to supragranular layers of human cortex. In contrast, primary and secondary sensory cortical nodes in posterior cortex with high intra-modular degree and short connection distance had transcriptional profiles enriched for RNA translation and nuclear components. We conclude that, as predicted, topologically integrative hubs, mediating long-distance connections between modules, are more costly in terms of mitochondrial glucose metabolism.This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’.

Depigmentation of the substantia nigra is a conspicuous pathological feature of Parkinson's disease and related to a loss of neuromelanin. Similar to melanin, neuromelanin has paramagnetic properties resulting in signal increase on specific T1-weighted magnetic resonance imaging. The aim of this study was to assess signal changes in the substantia nigra in patients with Parkinson's disease using an optimized neuromelanin-sensitive T1 scan. Ten patients with Parkinson's disease and 12 matched controls underwent high-resolution T1-weighted magnetic resonance imaging with magnetization transfer effect at 3T. The size and signal intensity of the substantia nigra pars compacta were determined as the number of pixels with signal intensity higher than background signal intensity+3 standard deviations and regional contrast ratio. Patients were subclassified as early stage (n=6) and late stage (n=4) using the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr Parkinson's disease staging scale. The T1 hyperintense area in the substantia nigra was substantially smaller in patients compared with controls (-60%, P<.01), and contrast was reduced (-3%, P<.05). Size reduction was even more pronounced in more advanced disease (-78%) than in early-stage disease (-47%). We present preliminary findings using a modified T1-weighted magnetic resonance imaging technique showing stage-dependent substantia nigra signal reduction in Parkinson's disease as a putative marker of neuromelanin loss. Our data suggest that reduction in the size of neuromelanin-rich substantia nigra correlates well with postmortem observations of dopaminergic neuron loss. Further validation of our results could potentially lead to development of a new biomarker of disease progression in Parkinson's disease.

Prion-like, trans-neuronal spread of tau pathology in humans is controversial. By evaluating tau burden and functional connectivity in living patients, Cope et al. demonstrate relationships consistent with this in Alzheimer's disease but not progressive supranuclear palsy. Tau distribution in the latter is better explained by metabolic demand and trophic support.

BackgroundDopaminergic drugs remain the mainstay of Parkinson’s disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm.MethodsThis pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging.ResultsPatients with Parkinson’s disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity.ConclusionsThis study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson’s disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson’s disease.