Non-negative data-driven mapping of structural connections with application to the neonatal brain.

Mapping connections in the neonatal brain can provide insight into the crucial early stages of neurodevelopment that shape brain organisation and lay the foundations for cognition and behaviour. Diffusion MRI and tractography provide unique opportunities for such explorations, through estimation of white matter bundles and brain connectivity. Atlas-based tractography protocols, i.e. a priori defined sets of masks and logical operations in a template space, have been commonly used in the adult brain to drive such explorations. However, rapid growth and maturation of the brain during early development make it challenging to ensure correspondence and validity of such atlas-based tractography approaches in the developing brain. An alternative can be provided by data-driven methods, which do not depend on predefined regions of interest. Here, we develop a novel data-driven framework to extract white matter bundles and their associated grey matter networks from neonatal tractography data, based on non-negative matrix factorisation that is inherently suited to the non-negative nature of structural connectivity data. We also develop a non-negative dual regression framework to map group-level components to individual subjects. Using in-silico simulations, we evaluate the accuracy of our approach in extracting connectivity components and compare with an alternative data-driven method, independent component analysis. We apply non-negative matrix factorisation to whole-brain connectivity obtained from publicly available datasets from the Developing Human Connectome Project, yielding grey matter components and their corresponding white matter bundles. We assess the validity and interpretability of these components against traditional tractography results and grey matter networks obtained from resting-state fMRI in the same subjects. We subsequently use them to generate a parcellation of the neonatal cortex using data from 323 new-born babies and we assess the robustness and reproducibility of this connectivity-driven parcellation.

Transient spectral events in resting state MEG predict individual task responses.

Even in response to simple tasks such as hand movement, human brain activity shows remarkable inter-subject variability. Recently, it has been shown that individual spatial variability in fMRI task responses can be predicted from measurements collected at rest; suggesting that the spatial variability is a stable feature, inherent to the individual's brain. However, it is not clear if this is also true for individual variability in the spatio-spectral content of oscillatory brain activity. Here, we show using MEG (N â€‹= â€‹89) that we can predict the spatial and spectral content of an individual's task response using features estimated from the individual's resting MEG data. This works by learning when transient spectral 'bursts' or events in the resting state tend to reoccur in the task responses. We applied our method to motor, working memory and language comprehension tasks. All task conditions were predicted significantly above chance. Finally, we found a systematic relationship between genetic similarity (e.g. unrelated subjects vs. twins) and predictability. Our approach can predict individual differences in brain activity and suggests a link between transient spectral events in task and rest that can be captured at the level of individuals.

An empirical, 21st century evaluation of phrenology.

Phrenology was a nineteenth century endeavour to link personality traits with scalp morphology, which has been both influential and fiercely criticised, not least because of the assumption that scalp morphology can be informative of underlying brain function. Here we test the idea empirically rather than dismissing it out of hand. Whereas nineteenth century phrenologists had access to coarse measurement tools (digital technology referring then to fingers), we were able to re-examine phrenology using 21st century methods and thousands of subjects drawn from the largest neuroimaging study to date. High-quality structural MRI was used to quantify local scalp curvature. The resulting curvature statistics were compared against lifestyle measures acquired from the same cohort of subjects, being careful to match a subset of lifestyle measures to phrenological ideas of brain organisation, in an effort to evoke the character of Victorian times. The results represent the most rigorous evaluation of phrenological claims to date.

Bayesian Optimisation of Large-Scale Biophysical Networks.

The relationship between structure and function in the human brain is well established, but not yet well characterised. Large-scale biophysical models allow us to investigate this relationship, by leveraging structural information (e.g. derived from diffusion tractography) in order to couple dynamical models of local neuronal activity into networks of interacting regions distributed across the cortex. In practice however, these models are difficult to parametrise, and their simulation is often delicate and computationally expensive. This undermines the experimental aspect of scientific modelling, and stands in the way of comparing different parametrisations, network architectures, or models in general, with confidence. Here, we advocate the use of Bayesian optimisation for assessing the capabilities of biophysical network models, given a set of desired properties (e.g. band-specific functional connectivity); and in turn the use of this assessment as a principled basis for incremental modelling and model comparison. We adapt an optimisation method designed to cope with costly, high-dimensional, non-convex problems, and demonstrate its use and effectiveness. Using five parameters controlling key aspects of our model, we find that this method is able to converge to regions of high functional similarity with real MEG data, with very few samples given the number of parameters, without getting stuck in local extrema, and while building and exploiting a map of uncertainty defined smoothly across the parameter space. We compare the results obtained using different methods of structural connectivity estimation from diffusion tractography, and find that one method leads to better simulations.

Resting connectivity predicts task activation in pre-surgical populations.

Injury and disease affect neural processing and increase individual variations in patients when compared with healthy controls. Understanding this increased variability is critical for identifying the anatomical location of eloquent brain areas for pre-surgical planning. Here we show that precise and reliable language maps can be inferred in patient populations from resting scans of idle brain activity. We trained a predictive model on pairs of resting-state and task-evoked data and tested it to predict activation of unseen patients and healthy controls based on their resting-state data alone. A well-validated language task (category fluency) was used in acquiring the task-evoked fMRI data. Although patients showed greater variation in their actual language maps, our models successfully learned variations in both patient and control responses from the individual resting-connectivity features. Importantly, we further demonstrate that a model trained exclusively on the more-homogenous control group can be used to predict task activations in patients. These results are the first to show that resting connectivity robustly predicts individual differences in neural response in cases of pathological variability.

Task-free MRI predicts individual differences in brain activity during task performance.

When asked to perform the same task, different individuals exhibit markedly different patterns of brain activity. This variability is often attributed to volatile factors, such as task strategy or compliance. We propose that individual differences in brain responses are, to a large degree, inherent to the brain and can be predicted from task-independent measurements collected at rest. Using a large set of task conditions, spanning several behavioral domains, we train a simple model that relates task-independent measurements to task activity and evaluate the model by predicting task activation maps for unseen subjects using magnetic resonance imaging. Our model can accurately predict individual differences in brain activity and highlights a coupling between brain connectivity and function that can be captured at the level of individual subjects.

Unmasking Latent Inhibitory Connections in Human Cortex to Reveal Dormant Cortical Memories.

Balance of cortical excitation and inhibition (EI) is thought to be disrupted in several neuropsychiatric conditions, yet it is not clear how it is maintained in the healthy human brain. When EI balance is disturbed during learning and memory in animal models, it can be restabilized via formation of inhibitory replicas of newly formed excitatory connections. Here we assess evidence for such selective inhibitory rebalancing in humans. Using fMRI repetition suppression we measure newly formed cortical associations in the human brain. We show that expression of these associations reduces over time despite persistence in behavior, consistent with inhibitory rebalancing. To test this, we modulated excitation/inhibition balance with transcranial direct current stimulation (tDCS). Using ultra-high-field (7T) MRI and spectroscopy, we show that reducing GABA allows cortical associations to be re-expressed. This suggests that in humans associative memories are stored in balanced excitatory-inhibitory ensembles that lie dormant unless latent inhibitory connections are unmasked.

Dentatorubrothalamic tract localization with postmortem MR diffusion tractography compared to histological 3D reconstruction.

Diffusion-weighted imaging (DWI) tractography is a technique with great potential to characterize the in vivo anatomical position and integrity of white matter tracts. Tractography, however, remains an estimation of white matter tracts, and false-positive and false-negative rates are not available. The goal of the present study was to compare postmortem tractography of the dentatorubrothalamic tract (DRTT) by its 3D histological reconstruction, to estimate the reliability of the tractography algorithm in this specific tract. Recent studies have shown that the cerebellum is involved in cognitive, language and emotional functions besides its role in motor control. However, the exact working mechanism of the cerebellum is still to be elucidated. As the DRTT is the main output tract it is of special interest for the neuroscience and clinical community. A postmortem human brain specimen was scanned on a 7T MRI scanner using a diffusion-weighted steady-state free precession sequence. Tractography was performed with PROBTRACKX. The specimen was subsequently serially sectioned and stained for myelin using a modified Heidenhain-Woelke staining. Image registration permitted the 3D reconstruction of the histological sections and comparison with MRI. The spatial concordance between the two modalities was evaluated using ROC analysis and a similarity index (SI). ROC curves showed a high sensitivity and specificity in general. Highest measures were observed in the superior cerebellar peduncle with an SI of 0.72. Less overlap was found in the decussation of the DRTT at the level of the mesencephalon. The study demonstrates high spatial accuracy of postmortem probabilistic tractography of the DRTT when compared to a 3D histological reconstruction. This gives hopeful prospect for studying structure-function correlations in patients with cerebellar disorders using tractography of the DRTT.

A probabilistic atlas of the cerebellar white matter.

Imaging of the cerebellar cortex, deep cerebellar nuclei and their connectivity are gaining attraction, due to the important role the cerebellum plays in cognition and motor control. Atlases of the cerebellar cortex and nuclei are used to locate regions of interest in clinical and neuroscience studies. However, the white matter that connects these relay stations is of at least similar functional importance. Damage to these cerebellar white matter tracts may lead to serious language, cognitive and emotional disturbances, although the pathophysiological mechanism behind it is still debated. Differences in white matter integrity between patients and controls might shed light on structure-function correlations. A probabilistic parcellation atlas of the cerebellar white matter would help these studies by facilitating automatic segmentation of the cerebellar peduncles, the localization of lesions and the comparison of white matter integrity between patients and controls. In this work a digital three-dimensional probabilistic atlas of the cerebellar white matter is presented, based on high quality 3T, 1.25mm resolution diffusion MRI data from 90 subjects participating in the Human Connectome Project. The white matter tracts were estimated using probabilistic tractography. Results over 90 subjects were symmetrical and trajectories of superior, middle and inferior cerebellar peduncles resembled the anatomy as known from anatomical studies. This atlas will contribute to a better understanding of cerebellar white matter architecture. It may eventually aid in defining structure-function correlations in patients with cerebellar disorders.

High resolution whole brain diffusion imaging at 7T for the Human Connectome Project.

Mapping structural connectivity in healthy adults for the Human Connectome Project (HCP) benefits from high quality, high resolution, multiband (MB)-accelerated whole brain diffusion MRI (dMRI). Acquiring such data at ultrahigh fields (7T and above) can improve intrinsic signal-to-noise ratio (SNR), but suffers from shorter T2 and T2(⁎) relaxation times, increased B1(+) inhomogeneity (resulting in signal loss in cerebellar and temporal lobe regions), and increased power deposition (i.e. specific absorption rate (SAR)), thereby limiting our ability to reduce the repetition time (TR). Here, we present recent developments and optimizations in 7T image acquisitions for the HCP that allow us to efficiently obtain high quality, high resolution whole brain in-vivo dMRI data at 7T. These data show spatial details typically seen only in ex-vivo studies and complement already very high quality 3T HCP data in the same subjects. The advances are the result of intensive pilot studies aimed at mitigating the limitations of dMRI at 7T. The data quality and methods described here are representative of the datasets that will be made freely available to the community in 2015.

Differential structural and resting state connectivity between insular subdivisions and other pain-related brain regions.

Functional neuroimaging studies suggest that the anterior, mid, and posterior division of the insula subserve different functions in the perception of pain. The anterior insula (AI) has predominantly been associated with cognitive-affective aspects of pain, while the mid and posterior divisions have been implicated in sensory-discriminative processing. We examined whether this functional segregation is paralleled by differences in (1) structural and (2) resting state connectivity and (3) in correlations with pain-relevant psychological traits. Analyses were restricted to the 3 insular subdivisions and other pain-related brain regions. Both type of analyses revealed largely overlapping results. The AI division was predominantly connected to the ventrolateral prefrontal cortex (structural and resting state connectivity) and orbitofrontal cortex (structural connectivity). In contrast, the posterior insula showed strong connections to the primary somatosensory cortex (SI; structural connectivity) and secondary somatosensory cortex (SII; structural and resting state connectivity). The mid insula displayed a hybrid connectivity pattern with strong connections with the ventrolateral prefrontal cortex, SII (structural and resting state connectivity) and SI (structural connectivity). Moreover, resting state connectivity revealed strong connectivity of all 3 subdivisions with the thalamus. On the behavioural level, AI structural connectivity was related to the individual degree of pain vigilance and awareness that showed a positive correlation with AI-amygdala connectivity and a negative correlation with AI-rostral anterior cingulate cortex connectivity. In sum, our findings show a differential structural and resting state connectivity for the anterior, mid, and posterior insula with other pain-relevant brain regions, which might at least partly explain their different functional profiles in pain processing.

Effects of image reconstruction on fiber orientation mapping from multichannel diffusion MRI: reducing the noise floor using SENSE.

PURPOSE: To examine the effects of the reconstruction algorithm of magnitude images from multichannel diffusion MRI on fiber orientation estimation. THEORY AND METHODS: It is well established that the method used to combine signals from different coil elements in multichannel MRI can have an impact on the properties of the reconstructed magnitude image. Using a root-sum-of-squares approach results in a magnitude signal that follows an effective noncentral-χ distribution. As a result, the noise floor, the minimum measurable in the absence of any true signal, is elevated. This is particularly relevant for diffusion-weighted MRI, where the signal attenuation is of interest. RESULTS: In this study, we illustrate problems that such image reconstruction characteristics may cause in the estimation of fiber orientations, both for model-based and model-free approaches, when modern 32-channel coils are used. We further propose an alternative image reconstruction method that is based on sensitivity encoding (SENSE) and preserves the Rician nature of the single-channel, magnitude MR signal. We show that for the same k-space data, root-sum-of-squares can cause excessive overfitting and reduced precision in orientation estimation compared with the SENSE-based approach. CONCLUSION: These results highlight the importance of choosing the appropriate image reconstruction method for tractography studies that use multichannel receiver coils for diffusion MRI acquisition.

Social network size affects neural circuits in macaques.

It has been suggested that variation in brain structure correlates with the sizes of individuals' social networks. Whether variation in social network size causes variation in brain structure, however, is unknown. To address this question, we neuroimaged 23 monkeys that had been living in social groups set to different sizes. Subject comparison revealed that living in larger groups caused increases in gray matter in mid-superior temporal sulcus and rostral prefrontal cortex and increased coupling of activity in frontal and temporal cortex. Social network size, therefore, contributes to changes both in brain structure and function. The changes have potential implications for an animal's success in a social context; gray matter differences in similar areas were also correlated with each animal's dominance within its social network.

Network analysis detects changes in the contralesional hemisphere following stroke.

Changes in brain structure occur in remote regions following focal damage such as stroke. Such changes could disrupt processing of information across widely distributed brain networks. We used diffusion MRI tractography to assess connectivity between brain regions in 9 chronic stroke patients and 18 age-matched controls. We applied complex network analysis to calculate 'communicability', a measure of the ease with which information can travel across a network. Clustering individuals based on communicability separated patient and control groups, not only in the lesioned hemisphere but also in the contralesional hemisphere, despite the absence of gross structural pathology in the latter. In our highly selected patient group, lesions were localised to the left basal ganglia/internal capsule. We found reduced communicability in patients in regions surrounding the lesions in the affected hemisphere. In addition, communicability was reduced in homologous locations in the contralesional hemisphere for a subset of these regions. We interpret this as evidence for secondary degeneration of fibre pathways which occurs in remote regions interconnected, directly or indirectly, with the area of primary damage. We also identified regions with increased communicability in patients that could represent adaptive, plastic changes post-stroke. Network analysis provides new and powerful tools for understanding subtle changes in interactions across widely distributed brain networks following stroke.

Multiple-subjects connectivity-based parcellation using hierarchical Dirichlet process mixture models.

We propose a hierarchical infinite mixture model approach to address two issues in connectivity-based parcellations: (i) choosing the number of clusters, and (ii) combining data from different subjects. In a Bayesian setting, we model voxel-wise anatomical connectivity profiles as an infinite mixture of multivariate Gaussian distributions, with a Dirichlet process prior on the cluster parameters. This type of prior allows us to conveniently model the number of clusters and estimate its posterior distribution directly from the data. An important benefit of using Bayesian modelling is the extension to multiple subjects clustering via a hierarchical mixture of Dirichlet processes. Data from different subjects are used to infer on class parameters and the number of classes at individual and group level. Such a method accounts for inter-subject variability, while still benefiting from combining different subjects data to yield more robust estimates of the individual clusterings.

Accurate anisotropic fast marching for diffusion-based geodesic tractography.

Using geodesics for inferring white matter fibre tracts from diffusion-weighted MR data is an attractive method for at least two reasons: (i) the method optimises a global criterion, and hence is less sensitive to local perturbations such as noise or partial volume effects, and (ii) the method is fast, allowing to infer on a large number of connexions in a reasonable computational time. Here, we propose an improved fast marching algorithm to infer on geodesic paths. Specifically, this procedure is designed to achieve accurate front propagation in an anisotropic elliptic medium, such as DTI data. We evaluate the numerical performance of this approach on simulated datasets, as well as its robustness to local perturbation induced by fiber crossing. On real data, we demonstrate the feasibility of extracting geodesics to connect an extended set of brain regions.

A Bayesian framework for global tractography.

We readdress the diffusion tractography problem in a global and probabilistic manner. Instead of tracking through local orientations, we parameterise the connexions between brain regions at a global level, and then infer on global and local parameters simultaneously in a Bayesian framework. This approach offers a number of important benefits. The global nature of the tractography reduces sensitivity to local noise and modelling errors. By constraining tractography to ensure a connexion is found, and then inferring on the exact location of the connexion, we increase the robustness of connectivity-based parcellations, allowing parcellations of connexions that were previously invisible to tractography. The Bayesian framework allows a direct comparison of the evidence for connecting and non-connecting models, to test whether the connexion is supported by the data. Crucially, by explicit parameterisation of the connexion between brain regions, we infer on a parameter that is shared with models of functional connectivity. This model is a first step toward the joint inference on functional and anatomical connectivity.

Probabilistic diffusion tractography with multiple fibre orientations: What can we gain?

We present a direct extension of probabilistic diffusion tractography to the case of multiple fibre orientations. Using automatic relevance determination, we are able to perform online selection of the number of fibre orientations supported by the data at each voxel, simplifying the problem of tracking in a multi-orientation field. We then apply the identical probabilistic algorithm to tractography in the multi- and single-fibre cases in a number of example systems which have previously been tracked successfully or unsuccessfully with single-fibre tractography. We show that multi-fibre tractography offers significant advantages in sensitivity when tracking non-dominant fibre populations, but does not dramatically change tractography results for the dominant pathways.