Patient-specific modeling for guided rehabilitation of stroke patients: the BrainX3 use-case.

BrainX3 is an interactive neuroinformatics platform that has been thoughtfully designed to support neuroscientists and clinicians with the visualization, analysis, and simulation of human neuroimaging, electrophysiological data, and brain models. The platform is intended to facilitate research and clinical use cases, with a focus on personalized medicine diagnostics, prognostics, and intervention decisions. BrainX3 is designed to provide an intuitive user experience and is equipped to handle different data types and 3D visualizations. To enhance patient-based analysis, and in keeping with the principles of personalized medicine, we propose a framework that can assist clinicians in identifying lesions and making patient-specific intervention decisions. To this end, we are developing an AI-based model for lesion identification, along with a mapping of tract information. By leveraging the patient's lesion information, we can gain valuable insights into the structural damage caused by the lesion. Furthermore, constraining whole-brain models with patient-specific disconnection masks can allow for the detection of mesoscale excitatory-inhibitory imbalances that cause disruptions in macroscale network properties. Finally, such information has the potential to guide neuromodulation approaches, assisting in the choice of candidate targets for stimulation techniques such as Transcranial Ultrasound Stimulation (TUS), which modulate E-I balance, potentiating cortical reorganization and the restoration of the dynamics and functionality disrupted due to the lesion.

Redefining stroke rehabilitation: Mobilizing the embodied goal-oriented brain.

Advancements in stroke rehabilitation remain limited and call for a reorientation. Based on recent results, this study proposes a network-centric perspective on stroke, positing that it not only causes localized deficits but also affects the brain's intricate network of networks, transiting it into a pathological state. Translating these system-level insights into interventions requires brain theory, and the Distributed Adaptive Control (DAC) theory offers such a framework. When applied in the rehabilitation gaming system, these principles demonstrate superior results over conventional methods. This impact stems from activating extensive brain networks, particularly the executive control network, focused motor learning, and maintaining excitatory-inhibitory balance, which is essential for neural repair and functional reorganization. The analysis stresses uniting preclinical and clinical research and placing the architecture of the embodied volitional brain at the centre of rehabilitation approaches.

Multiscale effects of excitatory-inhibitory homeostasis in lesioned cortical networks: A computational study.

Stroke-related disruptions in functional connectivity (FC) often spread beyond lesioned areas and, given the localized nature of lesions, it is unclear how the recovery of FC is orchestrated on a global scale. Since recovery is accompanied by long-term changes in excitability, we propose excitatory-inhibitory (E-I) homeostasis as a driving mechanism. We present a large-scale model of the neocortex, with synaptic scaling of local inhibition, showing how E-I homeostasis can drive the post-lesion restoration of FC and linking it to changes in excitability. We show that functional networks could reorganize to recover disrupted modularity and small-worldness, but not network dynamics, suggesting the need to consider forms of plasticity beyond synaptic scaling of inhibition. On average, we observed widespread increases in excitability, with the emergence of complex lesion-dependent patterns related to biomarkers of relevant side effects of stroke, such as epilepsy, depression and chronic pain. In summary, our results show that the effects of E-I homeostasis extend beyond local E-I balance, driving the restoration of global properties of FC, and relating to post-stroke symptomatology. Therefore, we suggest the framework of E-I homeostasis as a relevant theoretical foundation for the study of stroke recovery and for understanding the emergence of meaningful features of FC from local dynamics.

Multi-modal and multi-model interrogation of large-scale functional brain networks.

Existing whole-brain models are generally tailored to the modelling of a particular data modality (e.g., fMRI or MEG/EEG). We propose that despite the differing aspects of neural activity each modality captures, they originate from shared network dynamics. Building on the universal principles of self-organising delay-coupled nonlinear systems, we aim to link distinct features of brain activity - captured across modalities - to the dynamics unfolding on a macroscopic structural connectome. To jointly predict connectivity, spatiotemporal and transient features of distinct signal modalities, we consider two large-scale models - the Stuart Landau and Wilson and Cowan models - which generate short-lived 40 Hz oscillations with varying levels of realism. To this end, we measure features of functional connectivity and metastable oscillatory modes (MOMs) in fMRI and MEG signals - and compare them against simulated data. We show that both models can represent MEG functional connectivity (FC), functional connectivity dynamics (FCD) and generate MOMs to a comparable degree. This is achieved by adjusting the global coupling and mean conduction time delay and, in the WC model, through the inclusion of balance between excitation and inhibition. For both models, the omission of delays dramatically decreased the performance. For fMRI, the SL model performed worse for FCD and MOMs, highlighting the importance of balanced dynamics for the emergence of spatiotemporal and transient patterns of ultra-slow dynamics. Notably, optimal working points varied across modalities and no model was able to achieve a correlation with empirical FC higher than 0.4 across modalities for the same set of parameters. Nonetheless, both displayed the emergence of FC patterns that extended beyond the constraints of the anatomical structure. Finally, we show that both models can generate MOMs with empirical-like properties such as size (number of brain regions engaging in a mode) and duration (continuous time interval during which a mode appears). Our results demonstrate the emergence of static and dynamic properties of neural activity at different timescales from networks of delay-coupled oscillators at 40 Hz. Given the higher dependence of simulated FC on the underlying structural connectivity, we suggest that mesoscale heterogeneities in neural circuitry may be critical for the emergence of parallel cross-modal functional networks and should be accounted for in future modelling endeavours.

Excitatory-Inhibitory Homeostasis and Diaschisis: Tying the Local and Global Scales in the Post-stroke Cortex.

Maintaining a balance between excitatory and inhibitory activity is an essential feature of neural networks of the neocortex. In the face of perturbations in the levels of excitation to cortical neurons, synapses adjust to maintain excitatory-inhibitory (EI) balance. In this review, we summarize research on this EI homeostasis in the neocortex, using stroke as our case study, and in particular the loss of excitation to distant cortical regions after focal lesions. Widespread changes following a localized lesion, a phenomenon known as diaschisis, are not only related to excitability, but also observed with respect to functional connectivity. Here, we highlight the main findings regarding the evolution of excitability and functional cortical networks during the process of post-stroke recovery, and how both are related to functional recovery. We show that cortical reorganization at a global scale can be explained from the perspective of EI homeostasis. Indeed, recovery of functional networks is paralleled by increases in excitability across the cortex. These adaptive changes likely result from plasticity mechanisms such as synaptic scaling and are linked to EI homeostasis, providing a possible target for future therapeutic strategies in the process of rehabilitation. In addition, we address the difficulty of simultaneously studying these multiscale processes by presenting recent advances in large-scale modeling of the human cortex in the contexts of stroke and EI homeostasis, suggesting computational modeling as a powerful tool to tie the meso- and macro-scale processes of recovery in stroke patients.