A Simulation Toolkit for Testing the Sensitivity and Accuracy of Corticometry Pipelines.

In recent years, the replicability of neuroimaging findings has become an important concern to the research community. Neuroimaging pipelines consist of myriad numerical procedures, which can have a cumulative effect on the accuracy of findings. To address this problem, we propose a method for simulating artificial lesions in the brain in order to estimate the sensitivity and specificity of lesion detection, using different automated corticometry pipelines. We have applied this method to different versions of two widely used neuroimaging pipelines (CIVET and FreeSurfer), in terms of coefficients of variation; sensitivity and specificity of detecting lesions in 4 different regions of interest in the cortex, while introducing variations to the lesion size, the blurring kernel used prior to statistical analyses, and different thickness metrics (in CIVET). These variations are tested in a between-subject design (in two random groups, with and without lesions, using T1-weigted MRIs of 152 individuals from the International Consortium of Brain Mapping (ICBM) dataset) and in a within-subject pre-/post-lesion design [using 21 T1-Weighted MRIs of a single adult individual, scanned in the Infant Brain Imaging Study (IBIS)]. The simulation method is sensitive to partial volume effect and lesion size. Comparisons between pipelines illustrate the ability of this method to uncover differences in sensitivity and specificity of lesion detection. We propose that this method be adopted in the workflow of software development and release.

The BigBrainWarp toolbox for integration of BigBrain 3D histology with multimodal neuroimaging.

Neuroimaging stands to benefit from emerging ultrahigh-resolution 3D histological atlases of the human brain; the first of which is 'BigBrain'. Here, we review recent methodological advances for the integration of BigBrain with multi-modal neuroimaging and introduce a toolbox, 'BigBrainWarp', that combines these developments. The aim of BigBrainWarp is to simplify workflows and support the adoption of best practices. This is accomplished with a simple wrapper function that allows users to easily map data between BigBrain and standard MRI spaces. The function automatically pulls specialised transformation procedures, based on ongoing research from a wide collaborative network of researchers. Additionally, the toolbox improves accessibility of histological information through dissemination of ready-to-use cytoarchitectural features. Finally, we demonstrate the utility of BigBrainWarp with three tutorials and discuss the potential of the toolbox to support multi-scale investigations of brain organisation.

Association of Cannabis Use During Adolescence With Neurodevelopment.

IMPORTANCE: Animal studies have shown that the adolescent brain is sensitive to disruptions in endocannabinoid signaling, resulting in altered neurodevelopment and lasting behavioral effects. However, few studies have investigated ties between cannabis use and adolescent brain development in humans. OBJECTIVE: To examine the degree to which magnetic resonance (MR) imaging-assessed cerebral cortical thickness development is associated with cannabis use in a longitudinal sample of adolescents. DESIGN, SETTING, AND PARTICIPANTS: Data were obtained from the community-based IMAGEN cohort study, conducted across 8 European sites. Baseline data used in the present study were acquired from March 1, 2008, to December 31, 2011, and follow-up data were acquired from January 1, 2013, to December 31, 2016. A total of 799 IMAGEN participants were identified who reported being cannabis naive at study baseline and had behavioral and neuroimaging data available at baseline and 5-year follow-up. Statistical analysis was performed from October 1, 2019, to August 31, 2020. MAIN OUTCOMES AND MEASURES: Cannabis use was assessed at baseline and 5-year follow-up with the European School Survey Project on Alcohol and Other Drugs. Anatomical MR images were acquired with a 3-dimensional T1-weighted magnetization prepared gradient echo sequence. Quality-controlled native MR images were processed through the CIVET pipeline, version 2.1.0. RESULTS: The study evaluated 1598 MR images from 799 participants (450 female participants [56.3%]; mean [SD] age, 14.4 [0.4] years at baseline and 19.0 [0.7] years at follow-up). At 5-year follow-up, cannabis use (from 0 to >40 uses) was negatively associated with thickness in left prefrontal (peak: t785 = -4.87, cluster size = 1558 vertices; P = 1.10 × 10-6, random field theory cluster corrected) and right prefrontal (peak: t785 = -4.27, cluster size = 1551 vertices; P = 2.81 × 10-5, random field theory cluster corrected) cortices. There were no significant associations between lifetime cannabis use at 5-year follow-up and baseline cortical thickness, suggesting that the observed neuroanatomical differences did not precede initiation of cannabis use. Longitudinal analysis revealed that age-related cortical thinning was qualified by cannabis use in a dose-dependent fashion such that greater use, from baseline to follow-up, was associated with increased thinning in left prefrontal (peak: t815.27 = -4.24, cluster size = 3643 vertices; P = 2.28 × 10-8, random field theory cluster corrected) and right prefrontal (peak: t813.30 = -4.71, cluster size = 2675 vertices; P = 3.72 × 10-8, random field theory cluster corrected) cortices. The spatial pattern of cannabis-related thinning was associated with age-related thinning in this sample (r = 0.540; P < .001), and a positron emission tomography-assessed cannabinoid 1 receptor-binding map derived from a separate sample of participants (r = -0.189; P < .001). Analysis revealed that thinning in right prefrontal cortices, from baseline to follow-up, was associated with attentional impulsiveness at follow-up. CONCLUSIONS AND RELEVANCE: Results suggest that cannabis use during adolescence is associated with altered neurodevelopment, particularly in cortices rich in cannabinoid 1 receptors and undergoing the greatest age-related thickness change in middle to late adolescence.

File-based localization of numerical perturbations in data analysis pipelines.

BACKGROUND: Data analysis pipelines are known to be affected by computational conditions, presumably owing to the creation and propagation of numerical errors. While this process could play a major role in the current reproducibility crisis, the precise causes of such instabilities and the path along which they propagate in pipelines are unclear. METHOD: We present Spot, a tool to identify which processes in a pipeline create numerical differences when executed in different computational conditions. Spot leverages system-call interception through ReproZip to reconstruct and compare provenance graphs without pipeline instrumentation. RESULTS: By applying Spot to the structural pre-processing pipelines of the Human Connectome Project, we found that linear and non-linear registration are the cause of most numerical instabilities in these pipelines, which confirms previous findings.

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/ß-catenin, TGF-ß and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

Influence of Processing Pipeline on Cortical Thickness Measurement.

In recent years, replicability of neuroscientific findings, specifically those concerning correlates of morphological properties of gray matter (GM), have been subject of major scrutiny. Use of different processing pipelines and differences in their estimates of the macroscale GM may play an important role in this context. To address this issue, here, we investigated the cortical thickness estimates of three widely used pipelines. Based on analyses in two independent large-scale cohorts, we report high levels of within-pipeline reliability of the absolute cortical thickness-estimates and comparable spatial patterns of cortical thickness-estimates across all pipelines. Within each individual, absolute regional thickness differed between pipelines, indicating that in-vivo thickness measurements are only a proxy of actual thickness of the cortex, which shall only be compared within the same software package and thickness estimation technique. However, at group level, cortical thickness-estimates correlated strongly between pipelines, in most brain regions. The smallest between-pipeline correlations were observed in para-limbic areas and insula. These regions also demonstrated the highest interindividual variability and the lowest reliability of cortical thickness-estimates within each pipeline, suggesting that structural variations within these regions should be interpreted with caution.

BigBrain 3D atlas of cortical layers: Cortical and laminar thickness gradients diverge in sensory and motor cortices.

Histological atlases of the cerebral cortex, such as those made famous by Brodmann and von Economo, are invaluable for understanding human brain microstructure and its relationship with functional organization in the brain. However, these existing atlases are limited to small numbers of manually annotated samples from a single cerebral hemisphere, measured from 2D histological sections. We present the first whole-brain quantitative 3D laminar atlas of the human cerebral cortex. It was derived from a 3D histological atlas of the human brain at 20-micrometer isotropic resolution (BigBrain), using a convolutional neural network to segment, automatically, the cortical layers in both hemispheres. Our approach overcomes many of the historical challenges with measurement of histological thickness in 2D, and the resultant laminar atlas provides an unprecedented level of precision and detail. We utilized this BigBrain cortical atlas to test whether previously reported thickness gradients, as measured by MRI in sensory and motor processing cortices, were present in a histological atlas of cortical thickness and which cortical layers were contributing to these gradients. Cortical thickness increased across sensory processing hierarchies, primarily driven by layers III, V, and VI. In contrast, motor-frontal cortices showed the opposite pattern, with decreases in total and pyramidal layer thickness from motor to frontal association cortices. These findings illustrate how this laminar atlas will provide a link between single-neuron morphology, mesoscale cortical layering, macroscopic cortical thickness, and, ultimately, functional neuroanatomy.

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.

Cortical surface area variations within the dorsolateral prefrontal cortex are better predictors of future cognitive performance than fluid ability and working memory.

BACKGROUND: Are cognitive and biological variables useful for predicting future behavioral outcomes? METHOD: In two independent groups, we measured a set of cognitive (fluid and crystallized intelligence, working memory, and attention control) and biological (cortical thickness and cortical surface area) variables on two occasions separated by six months, to predict behavioral outcomes of interest (performance on an adaptive version of the n-back task) measured twelve and eighteen months later. We followed three stages: discovery, validation, and generalization. In the discovery stage, cognitive/biological variables and the behavioral outcome of interest were assessed in a group of individuals (in-sample). In the validation stage, the cognitive and biological variables were related with a parallel version of the behavioral outcome assessed several months later. In the generalization stage, the validation findings were tested in an independent group of individuals (out-of-sample). RESULTS: The key finding revealed that cortical surface area variations within the right dorsolateral prefrontal cortex predict the behavioral outcome of interest in both groups, whereas the cognitive variables failed to show reliable predictive validity. CONCLUSIONS: Individual differences in biological variables might predict future behavioral outcomes better than cognitive variables concurrently correlated with these behavioral outcomes.

Gray matter responsiveness to adaptive working memory training: a surface-based morphometry study.

Here we analyze gray matter indices before and after completing a challenging adaptive cognitive training program based on the n-back task. The considered gray matter indices were cortical thickness (CT) and cortical surface area (CSA). Twenty-eight young women (age range 17-22 years) completed 24 training sessions over the course of 3 months (12 weeks, 24 sessions), showing expected performance improvements. CT and CSA values for the training group were compared with those of a matched control group. Statistical analyses were computed using a ROI framework defined by brain areas distinguished by their genetic underpinning. The interaction between group and time was analyzed. Middle temporal, ventral frontal, inferior parietal cortices, and pars opercularis were the regions where the training group showed conservation of gray matter with respect to the control group. These regions support working memory, resistance to interference, and inhibition. Furthermore, an interaction with baseline intelligence differences showed that the expected decreasing trend at the biological level for individuals showing relatively low intelligence levels at baseline was attenuated by the completed training.

Partial Correlation-Based Retinotopically Organized Resting-State Functional Connectivity Within and Between Areas of the Visual Cortex Reflects More Than Cortical Distance.

Numerous studies have demonstrated functional magnetic resonance imaging (fMRI)-based resting-state functional connectivity (RSFC) between cortical areas. Recent evidence suggests that synchronous fluctuations in blood oxygenation level-dependent fMRI reflect functional organization at a scale finer than that of visual areas. In this study, we investigated whether RSFCs within and between lower visual areas are retinotopically organized and whether retinotopically organized RSFC merely reflects cortical distance. Subjects underwent retinotopic mapping and separately resting-state fMRI. Visual areas V1, V2, and V3, were subdivided into regions of interest (ROIs) according to quadrants and visual field eccentricity. Functional connectivity (FC) was computed based on Pearson's linear correlation (correlation), and Pearson's linear partial correlation (correlation between two time courses after the time courses from all other regions in the network are regressed out). Within a quadrant, within visual areas, all correlation and nearly all partial correlation FC measures showed statistical significance. Consistently in V1, V2, and to a lesser extent in V3, correlation decreased with increasing eccentricity separation. Consistent with previously reported monkey anatomical connectivity, correlation/partial correlation values between regions from adjacent areas (V1-V2 and V2-V3) were higher than those between nonadjacent areas (V1-V3). Within a quadrant, partial correlation showed consistent significance between regions from two different areas with the same or adjacent eccentricities. Pairs of ROIs with similar eccentricity showed higher correlation/partial correlation than pairs distant in eccentricity. Between dorsal and ventral quadrants, partial correlation between common and adjacent eccentricity regions within a visual area showed statistical significance; this extended to more distant eccentricity regions in V1. Within and between quadrants, correlation decreased approximately linearly with increasing distances separating the tested ROIs. Partial correlation showed a more complex dependence on cortical distance: it decreased exponentially with increasing distance within a quadrant, but was best fit by a quadratic function between quadrants. We conclude that RSFCs within and between lower visual areas are retinotopically organized. Correlation-based FC is nonselectively high across lower visual areas, even between regions that do not share direct anatomical connections. The mechanisms likely involve network effects caused by the dense anatomical connectivity within this network and projections from higher visual areas. FC based on partial correlation, which minimizes network effects, follows expectations based on direct anatomical connections in the monkey visual cortex better than correlation. Last, partial correlation-based retinotopically organized RSFC reflects more than cortical distance effects.

Reproducibility of neuroimaging analyses across operating systems.

Neuroimaging pipelines are known to generate different results depending on the computing platform where they are compiled and executed. We quantify these differences for brain tissue classification, fMRI analysis, and cortical thickness (CT) extraction, using three of the main neuroimaging packages (FSL, Freesurfer and CIVET) and different versions of GNU/Linux. We also identify some causes of these differences using library and system call interception. We find that these packages use mathematical functions based on single-precision floating-point arithmetic whose implementations in operating systems continue to evolve. While these differences have little or no impact on simple analysis pipelines such as brain extraction and cortical tissue classification, their accumulation creates important differences in longer pipelines such as subcortical tissue classification, fMRI analysis, and cortical thickness extraction. With FSL, most Dice coefficients between subcortical classifications obtained on different operating systems remain above 0.9, but values as low as 0.59 are observed. Independent component analyses (ICA) of fMRI data differ between operating systems in one third of the tested subjects, due to differences in motion correction. With Freesurfer and CIVET, in some brain regions we find an effect of build or operating system on cortical thickness. A first step to correct these reproducibility issues would be to use more precise representations of floating-point numbers in the critical sections of the pipelines. The numerical stability of pipelines should also be reviewed.

BigBrain: an ultrahigh-resolution 3D human brain model.

Reference brains are indispensable tools in human brain mapping, enabling integration of multimodal data into an anatomically realistic standard space. Available reference brains, however, are restricted to the macroscopic scale and do not provide information on the functionally important microscopic dimension. We created an ultrahigh-resolution three-dimensional (3D) model of a human brain at nearly cellular resolution of 20 micrometers, based on the reconstruction of 7404 histological sections. "BigBrain" is a free, publicly available tool that provides considerable neuroanatomical insight into the human brain, thereby allowing the extraction of microscopic data for modeling and simulation. BigBrain enables testing of hypotheses on optimal path lengths between interconnected cortical regions or on spatial organization of genetic patterning, redefining the traditional neuroanatomy maps such as those of Brodmann and von Economo.

Evaluation and calibration of functional network modeling methods based on known anatomical connections.

Recent studies have identified large scale brain networks based on the spatio-temporal structure of spontaneous fluctuations in resting-state fMRI data. It is expected that functional connectivity based on resting-state data is reflective of - but not identical to - the underlying anatomical connectivity. However, which functional connectivity analysis methods reliably predict the network structure remains unclear. Here we tested and compared network connectivity analysis methods by applying them to fMRI resting-state time-series obtained from the human visual cortex. The methods evaluated here are those previously tested against simulated data in Smith et al. (Neuroimage, 2011). To this end, we defined regions within retinotopic visual areas V1, V2, and V3 according to their eccentricity in the visual field, delineating central, intermediate, and peripheral eccentricity regions of interest (ROIs). These ROIs served as nodes in the models we study. We based our evaluation on the "ground-truth", thoroughly studied retinotopically-organized anatomical connectivity in the monkey visual cortex. For each evaluated method, we computed the fractional rate of detecting connections known to exist ("c-sensitivity"), while using a threshold of the 95th percentile of the distribution of interaction magnitudes of those connections not expected to exist. Under optimal conditions - including session duration of 68min, a relatively small network consisting of 9 nodes and artifact-free regression of the global effect - each of the top methods predicted the expected connections with 67-85% c-sensitivity. Correlation methods, including Correlation (Corr; 85%), Regularized Inverse Covariance (ICOV; 84%) and Partial Correlation (PCorr; 81%) performed best, followed by Patel's Kappa (80%), Bayesian Network method PC (BayesNet; 77%), General Synchronization measures (67-77%), and Coherence (CohB; 74%). With decreased session duration, these top methods saw decreases in c-sensitivities, achieving 59-76% for 17min sessions. With a short resting-state fMRI scan of 8.5min, none of the methods predicted the real network well, with Corr (65%) performing best. With increased complexity of the network from 9 to 36 nodes, multivariate methods including PCorr and BayesNet saw a decrease in performance. Artifact-free regression of the global effect increased the c-sensitivity of the top-performing methods. In an overall evaluation across all tests we performed, correlation methods (Corr, ICOV, and PCorr), Patel's Kappa, and BayesNet method PC set themselves somewhat above all other methods. We propose that data-based calibration based on known anatomical connections be integrated into future network studies, in order to maximize sensitivity and reduce false positives.

Implicit memory for novel associations between pictures: effects of stimulus unitization and aging.

Studies of implicit memory for novel associations have focused primarily on verbal materials and have highlighted the contribution of conceptually unitized representations to such priming. Using pictorial stimuli in a perceptual identification task, we examined whether new association priming can occur at a purely perceptual level. By manipulating the spatial contiguity of stimuli, we also evaluated whether such priming requires the creation of perceptually unitized representations. Finally, we examined the status of such priming in aging. In Experiment 1, we found that spatial contiguity of stimuli is not necessary for novel pictorial association priming to emerge, although such contiguity does enhance the magnitude of associative priming. In Experiment 2, we found that new association priming is age invariant, regardless of spatial contiguity. In Experiment 3, we provide additional evidence that pictorial association priming is perceptually based. These findings expand the scope and delineate the conditions of novel association priming and inform theories about the nature of implicit memory for new associations.

Mechanisms of cross-modal plasticity in early-blind subjects.

A variety of studies have demonstrated enhanced blood oxygenation level dependent responses to auditory and tactile stimuli within occipital cortex as a result of early blindness. However, little is known about the organizational principles that drive this cross-modal plasticity. We compared BOLD responses to a wide variety of auditory and tactile tasks (vs. rest) in early-blind and sighted subjects. As expected, cross-modal responses were larger in blind than in sighted subjects in occipital cortex for all tasks (cross-modal plasticity). Within both blind and sighted subject groups, we found patterns of cross-modal activity that were remarkably similar across tasks: a large proportion of cross-modal responses within occipital cortex are neither task nor stimulus specific. We next examined the mechanisms underlying enhanced BOLD responses within early-blind subjects. We found that the enhancement of cross-modal responses due to early blindness was best described as an additive shift, suggesting that cross-modal plasticity within blind subjects does not originate from either a scaling or unmasking of cross-modal responsivities found in sighted subjects.

Visual Motion Area MT+/V5 Responds to Auditory Motion in Human Sight-Recovery Subjects.

Using functional magnetic resonance imaging, we found that cortical visual motion area MT+/V5 responded to auditory motion in two rare subjects who had been blind since early childhood and whose vision was partially recovered in adulthood. Visually normal control subjects did not show similar auditory responses. These auditory responses in MT+ were specific to motion compared with other complex auditory stimuli including frequency sweeps and speech. Thus, MT+ developed motion-specific responses to nonvisual input, suggesting that cross-modal plasticity can be influenced by the normal functional specialization of a cortical region. Regarding sight recovery after early blindness, our results further demonstrate that cross-modal responses coexist with regained visual responses within the visual cortex.

Integration of one- and two-dimensional motion signals in infants: evidence from the barber-pole illusion.

Several previous studies in adults have investigated how one- and two-dimensional moving features are integrated into a coherent global motion percept by studying the "barber-pole illusion"; when a one-dimensional moving grating is presented within a rectangular aperture, the two-dimensional line terminators at the edges of the aperture bias the perceived direction of motion toward the longer axis of the aperture. In the current study, we used barber-pole stimuli to investigate the development of motion mechanisms that integrate one- and two-dimensional motion signals. Using a directional eye movement technique, we measured responses to obliquely moving gratings presented within horizontally vs. vertically oriented apertures, in infants (ages 2-5 months) and adults. For all ages, we found that horizontal eye movements were significantly stronger when gratings were presented within horizontal than within vertical apertures, as predicted by the barber-pole illusion. Additionally, we devised a way to infer the "effective shift" in eye movement direction produced by the barber-pole illusion. Using a simple motion integration model, effective shift values were then used to calculate the relative weightings of one- and two-dimensional motion signals to direction coding. The results show that by 2 months of age, infants integrate one- and two-dimensional motion signals, and that the relative weighting of one- and two-dimensional signals remains roughly constant from 2 months of age into adulthood.