NEurological MEchanismS of Injury, and Sleep-like cellular dynamics

Informazioni relative al progetto

NEMESIS

ID dell’accordo di sovvenzione: 101071900

DOI

10.3030/101071900

Data della firma CE 28 Febbraio 2023

Data di avvio 1 Ottobre 2023

Data di completamento 30 Settembre 2029

Finanziato da

• European Research Council (ERC)

Costo totale

€ 9 927 253,75

Contributo UE

€ 9 927 253,75

Coordinato da

UNIVERSITA DEGLI STUDI DI PADOVA
Italy

Periodic Reporting for period 1 - NEMESIS (NEurological MEchanismS of Injury, and Sleep-like cellular dynamics)

Periodo di rendicontazione: 2023-10-01 al 2025-03-31

Sintesi del contesto e degli obiettivi generali del progetto

Focal brain disorders, such as stroke, head injuries, and epilepsy, are major causes of disability,
robbing people of their ability to work and costing Europe a staggering 500 billion euros
annually. Presently, doctors target these disorders by pinpointing the specific trouble spot in
the brain.
Yet, emerging evidence reveals a more complex picture. Many brain disorders don't originate
solely in one place; they impact large portions of the entire brain network. Our research
indicates that substantial portions of the brain may remain dormant, essentially "asleep," even
during wakefulness. Moreover, these network abnormalities appear to be linked to patients'
deficits and could be rectified to improve their condition. Nonetheless, substantial challenges
persist. We lack a comprehensive understanding of how these brain networks function, their
impact on behavior, and the precise locations to stimulate for therapeutic benefit.
Enter NEMESIS. Translated from Ancient Greek as "give what is due," NEMESIS aims to
revive injured brains by using stimulation to awaken dormant brain circuits. Our approach
spans different levels of study, from the entire brain down to intricate circuits. We employ
various tools such as brain scans, EEG, optical neural recordings, and brain stimulation to
investigate whether these disconnected networks resemble a slumbering part of the brain with
impaired communication.
Subsequently, we will construct computer models that elucidate the connections between
brain structure and function. These models will facilitate predictions about the consequences
of brain injuries and guide us in stimulating the brain effectively to promote healing.
Finally, we will utilize these personalized computer models of injured brains to conduct
clinical trials involving non-invasive brain stimulation coupled with targeted training to aid
individuals in their recovery journey. In essence, this project seeks to restore what the brain
has lost and assist people in recuperating from debilitating conditions like stroke, epilepsy, and
degenerative disorders.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

Over the reporting period, the team has made substantial progress across several research lines focused on stroke and brain lesion modelling. Using diffusion MRI data, we demonstrated that stroke lesions induce progressive alterations in structural connectivity, which worsen during recovery, providing critical input for upcoming modelling efforts. A preliminary analysis linked memory performance to EEG and eye movement markers in healthy individuals, setting the stage for translation to patient populations. We also developed a workflow to extract electrophysiological features, such as slow-wave activity, from stroke patients, and advanced our analysis of TMS-EEG responses to understand local and global network reactivity, which will inform ongoing clinical protocols. Behavioural analyses highlighted that motor recovery is tightly linked to initial lesion severity. In parallel, we developed generative whole-brain models that simulate resting-state dynamics based on individual lesion maps. These models successfully predicted functional connectivity patterns and behavioural outcomes, outperforming traditional approaches and providing a mechanistic framework for understanding stroke-induced network reorganization. Furthermore, work on rodent models combined high-resolution imaging, local field potentials, and novel lesion techniques (e.g. thermocoagulation, TBI) to explore common mechanisms of perilesional vulnerability and pathological activity propagation.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

This project decisively goes beyond correlational approaches by introducing generative, patient-specific whole-brain models capable of mechanistically linking structural lesions to emergent pathological dynamics and clinical outcomes. Notably, we introduced novel perturbative metrics, perturbability and perturbability recovery, that provide stronger predictive power for behavioural impairment and recovery than standard connectivity measures. We further demonstrated that network dysconnection (i.e. maladaptive connectivity changes) plays a more critical role than mere disconnection in shaping post-stroke symptoms. At the frontier of consciousness research, our work revealed that violations of the Fluctuation-Dissipation Theorem (FDT), derived from whole-brain simulations, closely track consciousness levels across brain states, aligning with empirical PCI measurements and suggesting a new, non-invasive biomarker for assessing unresponsiveness. The integration of electrophysiology, fMRI, and structural imaging in animal models allowed us to bridge local mechanisms, such as cortical bistability and perilesional slow-wave activity, with whole-brain dynamics. This approach opens the door to cross-species insights and in silico personalized interventions, marking a step change in our ability to simulate, predict, and eventually treat brain dysfunction in stroke and other lesion models.