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Monte-Carlo diffusion simulations are a powerful tool for validating tissue microstructure models by generating synthetic diffusion-weighted magnetic resonance images (DW-MRI) in controlled environments. This is fundamental for understanding the link between micrometre-scale tissue properties and DW-MRI signals measured at the millimetre-scale, optimising acquisition protocols to target microstructure properties of interest, and exploring the robustness and accuracy of estimation methods. However, accurate simulations require substrates that reflect the main microstructural features of the studied tissue. To address this challenge, we introduce a novel computational workflow, CACTUS (Computational Axonal Configurator for Tailored and Ultradense Substrates), for generating synthetic white matter substrates. Our approach allows constructing substrates with higher packing density than existing methods, up to 95 % intra-axonal volume fraction, and larger voxel sizes of up to (500um) 3 with rich fibre complexity. CACTUS generates bundles with angular dispersion, bundle crossings, and variations along the fibres of their inner and outer radii and g-ratio. We achieve this by introducing a novel global cost function and a fibre radial growth approach that allows substrates to match predefined targeted characteristics and mirror those reported in histological studies. CACTUS improves the development of complex synthetic substrates, paving the way for future applications in microstructure imaging., Comment: 21 pages, 7 figures

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

Microstructure imaging with diffusion MRI (dMRI) is usually based on fitting models to the data using voxelwise nonlinear procedures that (i) are time consuming and (ii) need long acquisitions. Recently, we introduced the AMICO framework to accelerate the fit; here, we propose an extension to enable faster acquisitions, too. Our formulation allows exploiting information from neighboring voxels that is not accessible with existing approaches.

State-of-the-art microstructure imaging methods usually fit biophysical models to the diffusion MRI data on a voxel-by-voxel basis using non-linear procedures that require both long acquisitions and processing time. We recently introduced AMICO, a framework to reformulate these techniques as efficient linear problems and enable faster reconstructions. Here, we propose an extension that enables robust reconstructions from a reduced number of diffusion measurements, thus leading to faster acquisitions, too. Our novel formulation estimates simultaneously the microstructure configuration in all voxels as a global optimization problem, exploiting information from neighboring voxels that cannot be taken into account with existing techniques.

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega -analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related het-erogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega -analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random - effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).