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Brain connections, Stroke, Symptoms Predictions and Brain Repair

Periodic Reporting for period 2 - DISCONNECTOME (Brain connections, Stroke, Symptoms Predictions and Brain Repair)

Okres sprawozdawczy: 2021-03-01 do 2022-08-31

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.
Functional lateralisation is a fundamental feature of human brain organisation (Thiebaut de Schotten et al. Physics of Life Rev. 2019; Ioannucci et al. BSAF 2019), and we successfully demonstrated its link with the connections between the two hemispheres of the brain. The more a function is lateralised to one hemisphere of the brain, the less it communicates with the other hemisphere (Karolis et al. Nature Comm. 2019). This result represented the DISCONNECTOME project's first attempt to link the human brain's functional organisation with its connections (WP1). Subsequently, we discovered a method to project directly functional information from the cortex on brain connections (i.e. white matter) . We first applied this method to well known functional networks and revealed part of their white matter circuitry (Alves et al. Comms Bio 2020; Friedrich et al. Neuroimage 2020, Alves et al. in prep, WP1) and build a white matter atlas of the functional networks (Nozais et al. submitted 2022). We also systematically reviewed all the literature associating white matter variation to healthy and pathological behavioural variations (Forkel et al. BSAF 2022) .
Building on this innovative approach, we projected all functions systematically from the cortex to the white matter and built the first atlas of white matter's function (Thiebaut de Schotten et al. Nature Comm. 2020, WP1). We sent a book proposal to Oxford University Press as planned in WP1. We also developed an open-source software that will allow the scientific community to follow our tracks and study the white matter's functional organisation using our methods independently from our team (Nozais et al. Comms Bio 2021, WP1).
In parallel, we refined our brain disconnections measures after a stroke and their link with behaviour. We revealed that the joint disconnection between white matter tracts can lead to profound awareness disorders (i.e. anosognosias, Pacella et al. E-life 2019, Pacella et al. Neuropsychologia 2020; Spatial delusions Alves et al. Annals of Neurology 2021; WP2). We then successfully fractionated the population of stroke patients according to their disconnection profile. Surprisingly, we discovered that the non-random distribution of stroke had influenced how neuroscientists defined the brain's different functions (Thiebaut de Schotten et al. Nature Comm. 2020, WP2). As a consequence, it means that some brain functions thus far remain unknown and unmapped. This discovery led us to start an unexpected new line of investigation (Pacella et al. in prep.) to discover these functions to complete our atlas of the function of white matter (WP1). We also spearheaded the WP3 through the development of a predictive framework for symptoms in stroke made available as an opened web application (http://disconnectomestudio.bcblab.com WP3) and a publication (Talozzi et al. under review 2022).
Due to our work's growing notoriety, the DISCONNECTOME team has been invited to write a commentary on metabolic disconnection (Forkel and Thiebaut de Schotten Brain 2020), displayed on the façade of the CNRS building in Aquitaine and lead to the publication of 14 collaborative papers (+ 12 currently submitted) using its methods. We also organised a special issue on the disconnectome in Brain Structure and Function in order to maximise its impact and visibility (https://bit.ly/3JrrYyN).
The COVID-19 pandemic has considerably hampered our progress regarding the characterisation and the manipulation of brain disconnection recovery (WP4). Specifically, the sanitary situation delayed the delivery of the squirrel monkeys planned for the experimentation. Given that we already recruited the post-docs, we wrote two unplanned literature reviews during the grant's first year. One of these reviews highlights the importance of the squirrel monkeys species for clinical neuroscience (Royo et al. NBR, WP4). The second review highlights how comparative neuroimaging provides insights into the human brain evolutionary history and may help discover neuroprotective mechanisms (Friedrich et al. Neuroimage 2021 WP4). We're now making some quick progress with 2 articles currently in preparation on the Neuroimaging acquisition (Orset et al., in prep.WP4) and behaviour (Royo et al. in prep. WP4) in squirrel monkeys.
For the first time, we have been able to map functions directly onto the white matter. This result led us to the publication of several original articles. However, we plan to prepare a full book illustrating the functional organisation 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 is currently submitted and 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 further extend the predictions to longitudinal symptoms (2week, 6 months 1 year).
The characterisation and manipulation of stroke disconnection recovery are currently 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
Display of our research onto the façade the CNRS-Acquitaine
First comprehensive atlas of the function of the white matter
First comprehensive atlas of the symptoms of the white matter