Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data (http://www.brainchart.io/). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
Schizophrenia is a debilitating disorder that typically begins in adolescence and is characterized by perceptual abnormalities, delusions, cognitive and behavioural disturbances and functional impairments. While current treatments can be effective, they are often insufficient to alleviate the full range of symptoms. Schizophrenia is associated with structural brain abnormalities including grey and white matter volume loss and impaired connectivity. Recent findings suggest these abnormalities follow a neuroprogressive course in the earliest stages of the illness, which may be associated with episodes of acute relapse. Neuroinflammation has been proposed as a potential mechanism underlying these brain changes, with evidence of increased density and activation of microglia, immune cells resident in the brain, at various stages of the illness. We review evidence for microglial dysfunction in schizophrenia from both neuroimaging and neuropathological data, with a specific focus on studies examining microglial activation in relation to the pathology of grey and white matter. The studies available indicate that the link between microglial dysfunction and brain change in schizophrenia remains an intriguing hypothesis worthy of further examination. Future studies in schizophrenia should: (i) use multimodal imaging to clarify this association by mapping brain changes longitudinally across illness stages in relation to microglial activation; (ii) clarify the nature of microglial dysfunction with markers specific to activation states and phenotypes; (iii) examine the role of microglia and neurons with reference to their overlapping roles in neuroinflammatory pathways; and (iv) examine the impact of novel immunomodulatory treatments on brain structure in schizophrenia. Linked Articles This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit 10.1111/bph.2016.173.issue-4
The findings suggest that schizophrenia is characterized by an initial, rapid rate of gray matter loss that slows in middle life, followed by the emergence of a deficit in white matter that progressively worsens with age at a constant rate.
Background:The heterogeneity of schizophrenia has defied efforts to derive reproducible and definitive anatomical maps of structural brain changes associated with the disorder. We aimed to map deviations from normative ranges of brain structure for individual patients and evaluate whether the loci of individual deviations recapitulated group-average brain maps of schizophrenia pathology.Methods: For each of 48 white matter tracts and 68 cortical regions, normative percentiles of variation in fractional anisotropy (FA) and cortical thickness (CT) were established using diffusionweighted and structural MRI from healthy adults (n=195). Individuals with schizophrenia (n=322) were classified as either within the normative range for healthy individuals of the same age and sex (5-95% percentiles), infra-normal (<5% percentile) or supra-normal (>95% percentile).Repeating this classification for each tract and region yielded a deviation map for each individual.Results: Compared to the healthy comparison group, the schizophrenia group showed widespread reductions in FA and CT, involving virtually all white matter tracts and cortical regions.Paradoxically, however, no more than 15-20% of patients deviated from the normative range for any single tract or region, whereas 79% of patients showed infra-normal deviations for at least one locus (healthy individuals: 59±2%, p<0.001). Higher polygenic risk for schizophrenia associated with a greater number of regions with infra-normal deviations in CT (r=-0.17, p=0.006). Conclusions: Anatomical loci of schizophrenia-related changes are highly heterogeneous across individuals to the extent that group-consensus pathological maps are not representative of most individual patients. Normative modeling can aid in parsing schizophrenia heterogeneity and guiding personalized interventions.
Brain structure reflects the influence of evolutionary processes that pit the costs of its anatomical wiring against the computational advantages conferred by its complexity. We show that cost-neutral 'mutations' of the human connectome almost inevitably degrade its complexity and disconnect high-strength connections to prefrontal network hubs. Conversely, restoring the peripheral location and strong connectivity of empirically observed hubs confers a wiring cost that the brain appears to minimize. Progressive cost-neutral randomization yields daughter networks that differ substantially from one another and results in a topologically unstable phenomenon consistent with a phase transition in complex systems. The fragility of hubs to disconnection shows a significant association with the acceleration of gray matter loss in schizophrenia. Together with effects on wiring cost, we suggest that fragile prefrontal hub connections and topological volatility act as evolutionary influences on brain networks whose optimal set point may be perturbed in neuropsychiatric disorders.
Mapping gray matter (GM) pathology in Parkinson's disease (PD) with conventional MRI is challenging, and the need for more sensitive brain imaging techniques is essential to facilitate early diagnosis and assessment of disease severity. GM microstructure was assessed with GM-based spatial statistics applied to diffusion kurtosis imaging (DKI) and neurite orientation dispersion imaging (NODDI) in 30 participants with PD and 28 age- and gender-matched controls. These were compared with currently used assessment methods such as diffusion tensor imaging (DTI), voxel-based morphometry (VBM), and surface-based cortical thickness analysis. Linear discriminant analysis (LDA) was also used to test whether subject diagnosis could be predicted based on a linear combination of regional diffusion metrics. Significant differences in GM microstructure were observed in the striatum and the frontal, temporal, limbic, and paralimbic areas in PD patients using DKI and NODDI. Significant correlations between motor deficits and GM microstructure were also noted in these areas. Traditional VBM and surface-based cortical thickness analyses failed to detect any GM differences. LDA indicated that mean kurtosis (MK) and intra cellular volume fraction (ICVF) were the most accurate predictors of diagnostic status. In conclusion, DKI and NODDI can detect cerebral GM abnormalities in PD in a more sensitive manner when compared with conventional methods. Hence, these methods may be useful for the diagnosis of PD and assessment of motor deficits. Hum Brain Mapp 00:000-000, 2017. © 2017 Wiley Periodicals, Inc.
One of the challenges of brain network analysis is to directly compare network organization between subjects, irrespective of the number or strength of connections. In this study, we used minimum spanning tree (MST; a unique, acyclic subnetwork with a fixed number of connections) analysis to characterize the human brain network to create an empirical reference network. Such a reference network could be used as a null model of connections that form the backbone structure of the human brain. We analyzed the MST in three diffusion‐weighted imaging datasets of healthy adults. The MST of the group mean connectivity matrix was used as the empirical null‐model. The MST of individual subjects matched this reference MST for a mean 58%–88% of connections, depending on the analysis pipeline. Hub nodes in the MST matched with previously reported locations of hub regions, including the so‐called rich club nodes (a subset of high‐degree, highly interconnected nodes). Although most brain network studies have focused primarily on cortical connections, cortical–subcortical connections were consistently present in the MST across subjects. Brain network efficiency was higher when these connections were included in the analysis, suggesting that these tracts may be utilized as the major neural communication routes. Finally, we confirmed that MST characteristics index the effects of brain aging. We conclude that the MST provides an elegant and straightforward approach to analyze structural brain networks, and to test network topological features of individual subjects in comparison to empirical null models.
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