Brain connections, Stroke, Symptoms Predictions and Brain Repair

Informations projet

DISCONNECTOME

N° de convention de subvention: 818521

DOI

10.3030/818521

Projet clôturé

Date de signature de la CE 30 Avril 2019

Date de début 1 Septembre 2019

Date de fin 28 Février 2026

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 999 201,00

Contribution de l’UE

€ 1 999 201,00

Coordonné par

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France

Periodic Reporting for period 4 - DISCONNECTOME (Brain connections, Stroke, Symptoms Predictions and Brain Repair)

Période du rapport: 2024-03-01 au 2025-02-28

Résumé du contexte et des objectifs généraux du projet

Every year a stroke to the brain will impair approximately 2 million Europeans. Notwithstanding recent progress, many of these individuals will have persistent cognitive deficits, impacting their personality, degrading their quality of life, and preventing their return to work. Early identification of anatomical predictors of brain recovery may significantly reduce the disease burden on patients, their families and wider society, while also leading to the discovery of new targets for treatments.
Brain lesions do not just disable but also disconnect brain areas, which once deprived of their input or output, can no longer subserve behaviour and cognition. I have pioneered the development of imaging techniques that allow for the exploration of the relationship between brain disconnection and neuropsychological syndromes. With these tools, I aim to demonstrate that the structural organisation of the human brain's connections is the common denominator supporting functional specialisation and, when damaged, neuropsychological disorders.
Building on my expertise, I plan to (WP1) establish a comprehensive atlas of the function of white matter for the entire human brain, (WP2) fractionate the stroke population according to disconnection profiles, (WP3) predict neuropsychological symptoms based on disconnection profiles, and (WP4) characterise and manipulate the fine biology involved in the disconnection recovery.
In so doing, this project will introduce a paradigm shift in the relationship between brain structure, function, and behavioural/cognitive disorders. I will deliver a comprehensive biological model of the neurocircuitry that supports neuropsychological syndromes, which will gather the modular organisation of primary idiotypic functions with the integrative organisation of highly associative levels of functions. In the long term, this project will allow me to determine if measures of brain ‘connectivity’ can be translated into advanced standard procedures that provide personalised medicine, that focuses on rehabilitation and improves the prediction of symptom recovery while providing new targets for pharmacological treatments.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The Disconnectome project represents a pioneering endeavor within neuroscience, focusing on elucidating the pivotal role of white matter connections in brain functionality and pathology. This initiative posits that integration and disintegration mechanisms of brain functions are central to understanding the brain's operational architecture. This groundbreaking model was published and featured on the cover of Science. Functional lateralization is a cornerstone of human brain organization, extensively documented in the literature. The project made significant strides in correlating this lateralization with interhemispheric brain connections, uncovering that a function's lateralization inversely affects its communication across hemispheres. This discovery marked the project's inaugural venture into associating the functional organization of the human brain with its structural connectivity, designated as Work Package 1 (WP1). Progressing further, the project innovated a methodology for directly projecting functional information from the cortex onto white matter connections. Initially applied to established functional networks, this approach unveiled aspects of their white matter circuitry, culminating in creating a white matter atlas delineating these functional networks. A comprehensive review of literature correlating white matter variations with behavioral variations across healthy and pathological spectrums further solidified this approach. Building on these methodologies, the team systematically projected cortical functions to white matter, assembling the inaugural atlas detailing the function of white matter. The acceptance of a book proposal by Oxford University Press underscored this work's significance. Additionally, we developed open-source software to facilitate the independent examination of white matter's functional organization by the broader scientific community, furthering the project's impact (i.e.: the functionnectome). Concurrently, the project refined measures of brain disconnection and their behavioral implications post-stroke, uncovering that simultaneous disconnections in white matter tracts could precipitate severe awareness disorders. A novel analysis partitioned stroke patients based on their disconnection profiles, revealing the non-random distribution of strokes and its influence on neuroscientists' historical definition of brain functions. This revelation unearthed a potential myriad of hitherto unidentified and unmapped brain functions, spurring a new investigative direction to complete the white matter function atlas (WP1). The project also led Work Package 3 (WP3), launching the Disconnectome Symptoms Discoverer, a predictive web application for stroke symptoms, available publicly (http://disconnectomestudio.bcblab.com WP3) and documented in a publication. This initiative has garnered attention within the brain research community, with its findings being independently replicated, attesting to its validity. The DISCONNECTOME team's increasing prominence facilitated an invitation to author a commentary on metabolic disconnection (Forkel and Thiebaut de Schotten, Brain, 2020), with the project's influence extending to its methods being utilized in numerous collaborative papers and its recognition on the CNRS building in Aquitaine. A special issue dedicated to the disconnectome was organized to augment its impact and visibility in the journal, Brain Structure and Function (https://bit.ly/3JrrYyN). The COVID-19 pandemic posed significant challenges to the project, notably affecting the progression of work aimed at characterizing and manipulating brain disconnection recovery (WP4). The pandemic-induced delays in delivering squirrel monkeys for experimentation prompted the recruitment of post-docs to author two unplanned literature reviews during the grant's inaugural year, emphasizing the squirrel monkey's clinical neuroscience significance and the insights comparative neuroimaging offers into the evolutionary history of the human brain and potential neuroprotective mechanisms. Despite these challenges, the team successfully published and made accessible the first high-resolution dataset of brain connections in a squirrel monkey colony, marking a significant achievement in the project's endeavors.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

We have been able to map functions directly onto the white matter for the first time. This result led us to the publication of several original articles. However, we plan to prepare a full book illustrating the functional organization of the white matter. The production of this book will mark the achievement of WP1.
We fractionated the population of stroke patients and, by doing so, completed WP2 of the project.
WP3 aims at predicting symptoms in stroke based on their pattern of disconnections. This work has been published and made available as an interactive website for 1 year after the stroke symptom predictions based on brain disconnection is already available (http://disconnectomestudio.bcblab.com). We plan to extend the predictions to longitudinal symptoms (2week, 6 months 1 year).
The characterization and manipulation of stroke disconnection recovery are ongoing and should also lead to fundamental discoveries regarding brain mechanisms and potential new opportunities for brain repair.

Connectional anatomy of the default mode network

Anatomy & Function of the squirrel monkey

The structure of brain lateralisation

First comprehensive atlas of the function of the white matter

First comprehensive atlas of the symptoms of the white matter