Publications

Abstract

In recent years, brain research has indisputably entered a new epoch, driven by substantial methodological advances and digitally enabled data integration and modelling at multiple scales—from molecules to the whole brain. Major advances are emerging at the intersection of neuroscience with technology and computing. This new science of the brain combines high-quality research, data integration across multiple scales, a new culture of multidisciplinary large-scale collaboration, and translation into applications. As pioneered in Europe’s Human Brain Project (HBP), a systematic approach will be essential for meeting the coming decade’s pressing medical and technological challenges. The aims of this paper are to: develop a concept for the coming decade of digital brain research, discuss this new concept with the research community at large, identify points of convergence, and derive therefrom scientific common goals; provide a scientific framework for the current and future development of EBRAINS, a research infrastructure resulting from the HBP’s work; inform and engage stakeholders, funding organisations and research institutions regarding future digital brain research; identify and address the transformational potential of comprehensive brain models for artificial intelligence, including machine learning and deep learning; outline a collaborative approach that integrates reflection, dialogues, and societal engagement on ethical and societal opportunities and challenges as part of future neuroscience research.

Abstract

Interhemispheric anatomical asymmetries have long been thought to be related to language lateralisation. Previous studies have explored whether asymmetries in the diffusion characteristics of white matter language tracts are consistent with language lateralisation. These studies, typically with smaller cohorts, yielded mixed results. This study investigated whether connectomic analysis of quantitative anisotropy (QA) and shape features of white matter tracts across the whole brain are associated with language lateralisation. We analysed 1040 healthy individuals from the Human Connectome Project database. Hemispheric language dominance for each participant was quantified using a laterality quotient (LQ) derived from fMRI activation in regions of interest (ROIs) associated with a language comprehension task compared against a math task. A linear regression model was used to examine the relationship between structural asymmetry and functional lateralisation. Connectometry revealed that LQs were significantly negatively correlated with QA of corpus callosum tracts, including forceps minor, body, tapetum, and forceps major, indicating that reduced language dominance (more bilateral language representation) is associated with increased QA in these regions. The QA of the left arcuate fasciculus, cingulum, and right cerebellar tracts was positively associated with LQ, suggesting that stronger structural asymmetry in these tracts may identify left language dominance. Language lateralisation was not significantly associated with the shape metrics (including length, span, curl, elongation, diameter, volume, and surface area) of all white matter tracts. These results suggest that diffusion measures of microstructural architecture, and not the geometric features of reconstructed white matter tracts, are associated with lateralisation of language comprehension functions. People with increased dependence on both cerebral hemispheres for language processing may have more developed commissural fibres, which may support more efficient interhemispheric communication.

Abstract

Traditionally, the frontotemporal arcuate fasciculus (AF) is viewed as a single entity in anatomo-clinical models. However, it is unclear if distinct cortical origin and termination patterns within this bundle correspond to specific language functions. We use track-weighted dynamic functional connectivity, a hybrid imaging technique, to study the AF structure and function in two distinct datasets of healthy subjects. Here we show that the AF can be subdivided based on dynamic changes in functional connectivity at the streamline endpoints. An unsupervised parcellation algorithm reveals spatially segregated subunits, which are then functionally quantified through meta-analysis. This approach identifies three distinct clusters within the AF - ventral, middle, and dorsal frontotemporal AF - each linked to different frontal and temporal termination regions and likely involved in various language production and comprehension aspects. Our findings may have relevant implications for the understanding of the functional anatomy of the AF as well as its contribution to linguistic and non-linguistic functions.

Abstract

Stroke is common, and its consequent brain damage can cause various cognitive impairments. Associations between where and how much brain lesion damage a patient has suffered, and the particular impairments that injury has caused (lesion-symptom associations) offer potentially compelling insights into how the brain implements cognition.1 A better understanding of those associations can also fill a gap in current stroke medicine by helping us to predict how individual patients might recover from post-stroke impairments.2 Most recent work in this area employs machine learning models trained with data from stroke patients whose mid-to-long-term outcomes are known.2-4 These machine learning models are tested by predicting new outcomes—typically scores on standardized tests of post-stroke impairment—for patients whose data were not used to train the model. Traditionally, these validation results have been shared in peer-reviewed publications describing the model and its training. But recently, and for the first time in this field (as far as we know), one of these pre-trained models has been made public—The Disconnectome Symptom Discoverer model (DSD) which draws its predictors from structural disconnection information inferred from stroke patients’ brain MRI.5

Here, we test the DSD model on wholly independent data, never seen by the model authors, before they published it. Specifically, we test whether its predictive performance is just as accurate as (i.e. not significantly worse than) that reported in the original (Washington University) dataset, when predicting new patients’ outcomes at a similar time post-stroke (∼1 year post-stroke) and also in another independent sample tested later (5+ years) post-stroke. A failure to generalize the DSD model occurs if it performs significantly better in the Washington data than in our data from patients tested at a similar time point (∼1 year post-stroke). In addition, a significant decrease in predictive performance for the more chronic sample would be evidence that lesion-symptom associations differ at ∼1 year post-stroke and >5 years post-stroke.

Abstract

Over the past three decades, functional neuroimaging has amassed abundant evidence of the intricate interplay between brain structure and function. However, the potential anatomical and experimental overlap, independence, granularity, and gaps between functions remain poorly understood. Here, we show the latent structure of the current brain-cognition knowledge and its organisation. Our approach utilises the most comprehensive meta-analytic fMRI database (Neurosynth) to compute a three-dimensional embedding space–morphospace capturing the relationship between brain functions as we currently understand them. The space structure enables us to statistically test the relationship between functions expressed as the degree to which the characteristics of each functional map can be anticipated based on its similarities with others–the predictability index. The morphospace can also predict the activation pattern of new, unseen functions and decode thoughts and inner states during movie watching. The framework defined by the morphospace will spur the investigation of novel functions and guide the exploration of the fabric of human cognition.

Abstract

Over the past two decades, the study of resting-state functional magnetic resonance imaging has revealed that functional connectivity within and between networks is linked to cognitive states and pathologies. However, the white matter connections supporting this connectivity remain only partially described. We developed a method to jointly map the white and grey matter contributing to each resting-state network (RSN). Using the Human Connectome Project, we generated an atlas of 30 RSNs. The method also highlighted the overlap between networks, which revealed that most of the brain’s white matter (89%) is shared between multiple RSNs, with 16% shared by at least 7 RSNs. These overlaps, especially the existence of regions shared by numerous networks, suggest that white matter lesions in these areas might strongly impact the communication within networks. We provide an atlas and an open-source software to explore the joint contribution of white and grey matter to RSNs and facilitate the study of the impact of white matter damage to these networks. In a first application of the software with clinical data, we were able to link stroke patients and impacted RSNs, showing that their symptoms aligned well with the estimated functions of the networks.

Abstract

Aberrant anatomical brain connections in attention-deficit/hyperactivity disorder (ADHD) are reported inconsistently across
diffusion weighted imaging (DWI) studies. Based on a pre-registered protocol (Prospero: CRD42021259192), we searched PubMed,
Ovid, and Web of Knowledge until 26/03/2022 to conduct a systematic review of DWI studies. We performed a quality assessment
based on imaging acquisition, preprocessing, and analysis. Using signed differential mapping, we meta-analyzed a subset of the
retrieved studies amenable to quantitative evidence synthesis, i.e., tract-based spatial statistics (TBSS) studies, in individuals of any
age and, separately, in children, adults, and high-quality datasets. Finally, we conducted meta-regressions to test the effect of age,
sex, and medication-naïvety. We included 129 studies (6739 ADHD participants and 6476 controls), of which 25 TBSS studies
provided peak coordinates for case-control differences in fractional anisotropy (FA)(32 datasets) and 18 in mean diffusivity (MD)(23
datasets). The systematic review highlighted white matter alterations (especially reduced FA) in projection, commissural and
association pathways of individuals with ADHD, which were associated with symptom severity and cognitive deficits. The meta-
analysis showed a consistent reduced FA in the splenium and body of the corpus callosum, extending to the cingulum. Lower FA
was related to older age, and case-control differences did not survive in the pediatric meta-analysis. About 68% of studies were of
low quality, mainly due to acquisitions with non-isotropic voxels or lack of motion correction; and the sensitivity analysis in high-
quality datasets yielded no significant results. Findings suggest prominent alterations in posterior interhemispheric connections
subserving cognitive and motor functions affected in ADHD, although these might be influenced by non-optimal acquisition
parameters/preprocessing. Absence of findings in children may be related to the late development of callosal fibers, which may
enhance case-control differences in adulthood. Clinicodemographic and methodological differences were major barriers to
consistency and comparability among studies, and should be addressed in future investigations.

Abstract

A large amount of variability exists across human brains; revealed initially on a small scale by postmortem studies and,
more recently, on a larger scale with the advent of neuroimaging. Here we compared structural variability between human
and macaque monkey brains using grey and white matter magnetic resonance imaging measures. The monkey brain was
overall structurally as variable as the human brain, but variability had a distinct distribution pattern, with some key areas
showing high variability. We also report the first evidence of a relationship between anatomical variability and evolutionary
expansion in the primate brain. This suggests a relationship between variability and stability, where areas of low variability
may have evolved less recently and have more stability, while areas of high variability may have evolved more recently and
be less similar across individuals. We showed specific differences between the species in key areas, including the amount of
hemispheric asymmetry in variability, which was left-lateralized in the human brain across several phylogenetically recent
regions. This suggests that cerebral variability may be another useful measure for comparison between species and may add
another dimension to our understanding of evolutionary mechanisms.

Abstract

Patients with stroke offer a unique window into understanding human brain function. Mapping stroke lesions poses several challenges due to the complexity of the lesion anatomy and the mechanisms causing local and remote disruption on brain networks. In this prospective longitudinal study, we compare standard and advanced approaches to white matter lesion mapping applied to acute stroke patients with aphasia. Eighteen patients with acute left hemisphere stroke were recruited and scanned within two weeks from symptom onset. Aphasia assessment was performed at baseline and six-month follow-up. Structural and diffusion MRI contrasts indicated an area of maximum overlap in the anterior external/extreme capsule with diffusion images showing a larger overlap extending into posterior perisylvian regions. Anatomical predictors of recovery included damage to ipsilesional tracts (as shown by both structural and diffusion images) and contralesional tracts (as shown by diffusion images only). These findings indicate converging results from structural and diffusion lesion mapping methods but also clear differences between the two approaches in their ability to identify predictors of recovery outside the lesioned regions.

Abstract

Structural imaging based on computerized tomography (CT) and magnetic resonance imaging (MRI) has progressively replaced traditional post‐mortem studies in the process of identifying the neuroanatomical basis of language. In the clinical setting, the information provided by structural imaging has been used to confirm the exact diagnosis and formulate an individualized treatment plan. In the research arena, neuroimaging has permitted to understand neuroanatomy at the individual and group level. The possibility to obtain quantitative measures of lesions has improved correlation analyses between severity of symptoms, lesion load, and lesion location. More recently, the development of structural imaging based on diffusion MRI has provided valid solutions to two major limitations of more conventional imaging. In stroke patients, diffusion can visualize early changes due to a stroke that are otherwise not detectable with more conventional structural imaging, with important implications for the clinical management of acute stroke patients. Beyond the sensitivity to early changes, diffusion imaging tractography presents the possibility of visualizing the trajectories of individual white matter pathways connecting distant regions. A pathway analysis based on tractography is offering a new perspective in neurolinguistics. First, it permits to formulate new anatomical models of language function in the healthy brain and allows to directly test these models in the human population without any reliance on animal models. Second, by defining the exact location of the damage to specific white matter connections we can understand the contribution of different mechanisms to the emergence of language deficits (e.g., cortical versus disconnection mechanisms). Finally, a better understanding of the anatomical variability of different language networks is helping to identify new anatomical predictors of language recovery. In this chapter we will focus on the principles of structural MRI and, in particular, diffusion imaging and tractography and present examples of how these methods have informed our understanding of variance in language performances in the healthy brain and language deficits in patient populations.

Abstract

Insight in the developmental trajectory of the neuroanatomical reading correlates is important to understand related cognitive processes and disorders. In adults, a dual pathway model has been suggested encompassing a dorsal phonological and a ventral orthographic white matter system. This dichotomy seems not present in pre-readers, and the specific role of ventral white matter in reading remains unclear. Therefore, the present longitudinal study investigated the relation between ventral white matter and cognitive processes underlying reading in children with a broad range of reading skills (n = 61). Ventral pathways of the reading network were manually traced using diffusion tractography: the inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF) and uncinate fasciculus (UF). Pathways were examined pre-reading (5–6 years) and after two years of reading acquisition (7–8 years). Dimension reduction for the cognitive measures resulted in one component for pre-reading cognitive measures and a separate phonological and orthographic component for the early reading measures. Regression analyses revealed a relation between the pre-reading cognitive component and bilateral IFOF and left ILF. Interestingly, exclusively the left IFOF was related to the orthographic component, whereas none of the pathways was related to the phonological component. Hence, the left IFOF seems to serve as the lexical reading route, already in the earliest reading stages.