Neuroplasticity of Ipsilateral Cortical Motor Representations, Training Effects and Role in Stroke Recovery

This thesis examines the contribution of the ipsilateral hemisphere to motor control with the aim of evaluating the potential of the contralesional hemisphere to contribute to motor recovery after stroke. Predictive algorithms based on neurobiological principles emphasize integrity of the ipsilesional corticospinal tract as the strongest prognostic indicator of good motor recovery. In contrast, extensive lesions placing reliance on alternative contralesional ipsilateral motor pathways are associated with poor recovery. Within the predictive algorithms are elements of motor control that rely on contributions from ipsilateral motor pathways, suggesting that balanced, parallel contralesional contributions can be beneficial. Current therapeutic approaches have focussed on the maladaptive potential of the contralesional hemisphere and sought to inhibit its activity with neuromodulation. Using Transcranial Magnetic Stimulation I seek examples of beneficial plasticity in ipsilateral cortical motor representations of expert performers, who have accumulated vast amounts of deliberate practise training skilled bilateral activation of muscles habitually under ipsilateral control. I demonstrate that ipsilateral cortical motor representations reorganize in response to training to acquisition of skilled motor performance. Features of this reorganization are compatible with evidence suggesting ipsilateral importance in synergy representations, controlled through corticoreticulopropriospinal pathways. I demonstrate that ipsilateral plasticity can associate positively with motor recovery after stroke. Features of plastic change in ipsilateral cortical representations are shown in response to robotic training of chronic stroke patients. These findings have implications for the individualization of motor rehabilitation after stroke, and prompt reappraisal of the approach to therapeutic intervention in the chronic phase of stroke

A Comparative Analysis of Speed Profile Models for Ankle Pointing Movements: Evidence that Lower and Upper Extremity Discrete Movements are Controlled by a Single Invariant Strategy

Little is known about whether our knowledge of how the central nervous system controls the upper extremities (UE), can generalize, and to what extent to the lower limbs. Our continuous efforts to design the ideal adaptive robotic therapy for the lower limbs of stroke patients and children with cerebral palsy highlighted the importance of analyzing and modeling the kinematics of the lower limbs, in general, and those of the ankle joints, in particular. We recruited 15 young healthy adults that performed in total 1,386 visually evoked, visually guided, and target-directed discrete pointing movements with their ankle in dorsal–plantar and inversion–eversion directions. Using a non-linear, least-squares error-minimization procedure, we estimated the parameters for 19 models, which were initially designed to capture the dynamics of upper limb movements of various complexity. We validated our models based on their ability to reconstruct the experimental data. Our results suggest a remarkable similarity between the top-performing models that described the speed profiles of ankle pointing movements and the ones previously found for the UE both during arm reaching and wrist pointing movements. Among the top performers were the support-bounded lognormal and the beta models that have a neurophysiological basis and have been successfully used in upper extremity studies with normal subjects and patients. Our findings suggest that the same model can be applied to different “human” hardware, perhaps revealing a key invariant in human motor control. These findings have a great potential to enhance our rehabilitation efforts in any population with lower extremity deficits by, for example, assessing the level of motor impairment and improvement as well as informing the design of control algorithms for therapeutic ankle robots

A dendritic mechanism for decoding traveling waves: Principles and applications to motor cortex

Traveling waves of neuronal oscillations have been observed in many cortical regions, including the motor and sensory cortex. Such waves are often modulated in a task-dependent fashion although their precise functional role remains a matter of debate. Here we conjecture that the cortex can utilize the direction and wavelength of traveling waves to encode information. We present a novel neural mechanism by which such information may be decoded by the spatial arrangement of receptors within the dendritic receptor field. In particular, we show how the density distributions of excitatory and inhibitory receptors can combine to act as a spatial filter of wave patterns. The proposed dendritic mechanism ensures that the neuron selectively responds to specific wave patterns, thus constituting a neural basis of pattern decoding. We validate this proposal in the descending motor system, where we model the large receptor fields of the pyramidal tract neurons — the principle outputs of the motor cortex — decoding motor commands encoded in the direction of traveling wave patterns in motor cortex. We use an existing model of field oscillations in motor cortex to investigate how the topology of the pyramidal cell receptor field acts to tune the cells responses to specific oscillatory wave patterns, even when those patterns are highly degraded. The model replicates key findings of the descending motor system during simple motor tasks, including variable interspike intervals and weak corticospinal coherence. By additionally showing how the nature of the wave patterns can be controlled by modulating the topology of local intra-cortical connections, we hence propose a novel integrated neuronal model of encoding and decoding motor commands

Upregulation of cortico-cerebellar functional connectivity after motor learning

Interactions between the cerebellum and primary motor cortex are crucial for the acquisition of new motor skills. Recent neuroimaging studies indicate that learning motor skills is associated with subsequent modulation of resting-state functional connectivity in the cerebellar and cerebral cortices. The neuronal processes underlying the motor-learning-induced plasticity are not well understood. Here, we investigate changes in functional connectivity in source-reconstructed electroencephalography (EEG) following the performance of a single session of a dynamic force task in twenty young adults. Source activity was reconstructed in 112 regions of interest (ROIs) and the functional connectivity between all ROIs was estimated using the imaginary part of coherence. Significant changes in resting-state connectivity were assessed using partial least squares (PLS). We found that subjects adapted their motor performance during the training session and showed improved accuracy but with slower movement times. A number of connections were significantly upregulated after motor training, principally involving connections within the cerebellum and between the cerebellum and motor cortex. Increased connectivity was confined to specific frequency ranges in the mu- and beta-bands. Post hoc analysis of the phase spectra of these cerebellar and cortico-cerebellar connections revealed an increased phase lag between motor cortical and cerebellar activity following motor practice. These findings show a reorganization of intrinsic cortico-cerebellar connectivity related to motor adaptation and demonstrate the potential of EEG connectivity analysis in source space to reveal the neuronal processes that underpin neural plasticity

On mapping epilepsy : magneto- and electroencephalographic characterizations of epileptic activities

Epilepsy is one of the most common neurological disorder, affecting up to 10 individuals per 1000 persons. The disorder have been known for several thousand years, with the first clinical descriptions dating back to ancient times. Nonetheless, characterization of the dynamics underlying epilepsy remains largely unknown. Understanding these patophysiological processes requires unifying both a neurobiological perspective, as well as a technically advanced neuroimaging perspective. The incomplete insight into epilepsy dynamics is reflected by the insufficient treatment options. Approximately 30% of all patients do not respond to anti-epileptic drugs (AEDs) and thus suffers from recurrent seizures despite adequate pharmacological treatments. These pharmacoresistant patients often undergo epilepsy surgery evaluations. Epilepsy surgery aims to resect the part of the brain that generates the epileptic seizure activity (seizure onset zone, SOZ). Nonetheless, up to 50% of all patients relapse after surgery. This can be due to incomplete mapping of both the SOZ and of other structures that might be involved in seizure initiation and propagation. Such cortical and subcortical structures are collectively referred to as the epileptic network. Historically, epilepsy was considered to be either a generalized disorder involving the entire brain, or a highly localized, focal, disorder. The modern technological development of both structural and functional neuroimaging has drastically altered this view. This development has made significant contributions to the now prevailing view that both generalized and focal epilepsies arise from more or less widespread pathological network pathways. Visualization of these pathways play an important role in the presurgical planning. Thus, both improved characterization and understanding of such pathways are pivotal in improvement of epilepsy diagnostics and treatments. It is evident that epilepsy research needs to stand on two legs: Both improved understanding of pathological, neurobiological and neurophysiological process, and improved neuroimaging instrumentation. Epilepsy research do not only span from visualization to understanding of neurophysiological processes, but also from cellular, neuronal, microscopic processes, to dynamical, large-scale network processes. It is well known that neurons involved in epileptic activities exhibit specific, pathological firing patterns. Genetic mutations resulting in neuronal ion channel defects can cause severe, and even lethal, epileptic syndromes in children, clearly illustrating a role for neuron membrane properties in epilepsy. However, cellular processes themselves cannot explain how epileptic seizures can involve, and propagate across, large cortical areas and generate seizure-specific symptomatologies. A strict cellular perspective can neither explain epilepsy-associated pathological interactions between larger distant regions in between seizures. Instead, the dynamical effects of cellular synchronization across both mesoscopic and macroscopic scales also need to be considered. Today, the only means to study such effects in human subjects are by combinations of neuroimaging modalities. However, as all measurement techniques, these exhibit individual limitations that affect the kind of information that can be inferred from these. Thus, once more we reach the conclusion that epilepsy research needs to rest upon both a neurophysiological/neurobiological leg, and a technical/instrumentational leg. In accordance with this necessity of a dual approach to epilepsy, this thesis covers both neurophysiological aspects of epileptic activity development, as well as functional neuroimaging instrumentation development with focus on epileptic activity detection and localization. Part 1 (neurophysiological part) is concerned with the neurophysiological dynamical changes that underlie development of so called interictal epileptiform discharges (IEDs) with special focus on the role of low-frequency oscillations. To this aim, both conventional magnetoencephalography (MEG) and intracranial electroencephalography (iEEG) with neurostimulation is analyzed. Part 2 (instrumentation part) is concerned with development of cutting-edge, novel on-scalp magnetoencephalography (osMEG) within clinical epilepsy evaluations and research with special focus on IEDs. The theses cover both modeling of osMEG characteristics, as well as the first-ever osMEG recording of a temporal lobe epilepsy patient

DEVELOPMENT OF A CEREBELLAR MEAN FIELD MODEL: THE THEORETICAL FRAMEWORK, THE IMPLEMENTATION AND THE FIRST APPLICATION

Brain modeling constantly evolves to improve the accuracy of the simulated brain dynamics with the ambitious aim to build a digital twin of the brain. Specific models tuned on brain regions specific features empower the brain simulations introducing bottom-up physiology properties into data-driven simulators. Despite the cerebellum contains 80 % of the neurons and is deeply involved in a wide range of functions, from sensorimotor to cognitive ones, a specific cerebellar model is still missing. Furthermore, its quasi-crystalline multi-layer circuitry deeply differs from the cerebral cortical one, therefore is hard to imagine a unique general model suitable for the realistic simulation of both cerebellar and cerebral cortex. The present thesis tackles the challenge of developing a specific model for the cerebellum. Specifically, multi-neuron multi-layer mean field (MF) model of the cerebellar network, including Granule Cells, Golgi Cells, Molecular Layer Interneurons, and Purkinje Cells, was implemented, and validated against experimental data and the corresponding spiking neural network microcircuit model. The cerebellar MF model was built using a system of interdependent equations, where the single neuronal populations and topological parameters were captured by neuron-specific inter- dependent Transfer Functions. The model time resolution was optimized using Local Field Potentials recorded experimentally with high-density multielectrode array from acute mouse cerebellar slices. The present MF model satisfactorily captured the average discharge of different microcircuit neuronal populations in response to various input patterns and was able to predict the changes in Purkinje Cells firing patterns occurring in specific behavioral conditions: cortical plasticity mapping, which drives learning in associative tasks, and Molecular Layer Interneurons feed-forward inhibition, which controls Purkinje Cells activity patterns. The cerebellar multi-layer MF model thus provides a computationally efficient tool that will allow to investigate the causal relationship between microscopic neuronal properties and ensemble brain activity in health and pathological conditions. Furthermore, preliminary attempts to simulate a pathological cerebellum were done in the perspective of introducing our multi-layer cerebellar MF model in whole-brain simulators to realize patient-specific treatments, moving ahead towards personalized medicine. Two preliminary works assessed the relevant impact of the cerebellum on whole-brain dynamics and its role in modulating complex responses in causal connected cerebral regions, confirming that a specific model is required to further investigate the cerebellum-on- cerebrum influence. The framework presented in this thesis allows to develop a multi-layer MF model depicting the features of a specific brain region (e.g., cerebellum, basal ganglia), in order to define a general strategy to build up a pool of biology grounded MF models for computationally feasible simulations. Interconnected bottom-up MF models integrated in large-scale simulators would capture specific features of different brain regions, while the applications of a virtual brain would have a substantial impact on the reality ranging from the characterization of neurobiological processes, subject-specific preoperative plans, and development of neuro-prosthetic devices

SLEEPING WHILE AWAKE: A NEUROPHYSIOLOGICAL INVESTIGATION ON SLEEP DURING WAKEFULNESS.

Il sonno e la veglia vengono comunemente considerati come due stati distinti. L\u2019alternanza tra essi, la cui presenza \ue8 stata dimostrata in ogni specie animale studiata fino ad oggi, sembra essere una delle caratteristiche che definisce la nostra vita. Allo stesso tempo, per\uf2, le scoperte portate alla luce negli ultimi decenni hanno offuscato i confini tra questi due stati. I meccanismi del sonno hanno sempre affascinato i neurofisiologi, che infatti, nell\u2019ultimo secolo, li hanno caratterizzati in dettaglio: ora sappiamo che all\u2019attivit\ue0 del sonno sottost\ue0 una specifica attivit\ue0 neuronale chiamata slow oscillation. La slow oscillation, che \ue8 costituita da (ancora una volta) un\u2019alternanza tra periodi di attivit\ue0 e periodi di iperpolarizzazione e silenzio neuronale (OFF-periods), \ue8 la modalit\ue0 base di attivazione del cervello dormiente. Questa alternanza \ue8 dovuta alla tendenza dei neuroni surante lo stato di sonno, di passare ad un periodo silente dopo un\u2019attivazione iniziale, una tendenza a cui viene dato il nome di bistabilit\ue0 neuronale. Molti studi hanno dimostrato come la bistabilit\ue0 neuronale tipica del sonno ed i relativi OFF-periods, possano accadere anche durante la veglia in particolari condizioni patologiche, nelle transizioni del sonno e durante le deprivazioni di sonno. Per questo motivo, se accettassimo che la bistabilit\ue0 neuronale e gli OFF-periods rappresentino una caratteristica fondamentale del sonno, allora dovremmo ammettere che stiamo assistendo ad un cambio di paradigma: da una prospettiva neurofisiologica il sonno pu\uf2 intrudere nella veglia. In questa tesi ho analizzato i nuovi -fluidi- confini tra sonno e veglia e le possibili implicazioni di questi nel problema della persistenza personale attraverso il tempo. Inoltre, ho studiato le implicazioni cliniche dell\u2019intrusione di sonno nella veglia in pazienti con lesioni cerebrali focali di natura ischemica. In particolare, i miei obiettivi sono stati: 1) Dimostrare come la bistabilit\ue0 neuronale possa essere responsabile della perdita di funzione nei pazienti affetti da ischemia cerebrale e come questo potrebbe avere implicazioni nello studio della patofisiologia dell\u2019ischemia cerebrale e nella sua terapia; 2) Stabilire le basi per un modello di sonno locale presente nella vita di tutti i giorni: la sensazione di sonnolenza. Infatti, essa potrebbe riflettere la presenza di porzioni di corteccia in stato di sonno, ma durante lo stato di veglia; 3) Difendere il criterio biologico di identit\ue0, che troverebbe nell\u2019attivit\ue0 cerebrale la continuit\ue0 necessaria al mantenimento della nostra identit\ue0 nel tempo.Sleep and wakefulness are considered two mutually exclusive states. The alternation between those two states seems to be a defining characteristic of our life, a ubiquitous phenomenon demonstrated in every animal species investigated so far. However, during the last decade, advances in neurophysiology have blurred the boundaries between those states. The mechanisms of sleep have always intrigued neurophysiologists and great advances have been made over the last century in understanding them: we now know that the defining characteristic underlying sleep activity is a specific pattern of neuronal activity, namely the slow oscillation. The slow oscillation, which is characterized by the periodic alternation between periods of activity (ON-periods) and periods of hyperpolarization and neuronal silence (OFF-periods) is the default mode of activity of the sleeping cortex. This alternation is due to the tendency of neurons to fall into a silent period after an initial activation; such tendency is known as \u201cbistability\u201d. There is accumulating evidence that sleep-like bistability, and the ensuing OFF-periods, may occur locally in the awake human brain in some pathological conditions, in sleep transition, as well as after sleep deprivation. Therefore, to the extent that bistability and OFF periods represents the basic neuronal features of sleep, a paradigm shift is in place: from a neurophysiological perspective sleep can intrude into wakefulness. In this thesis, I explore the fluid boundaries between sleep and wakefulness and investigate their possible implications on the problem of personal persistence over time. Moreover, I study the clinical implications of the intrusion of sleep into wakefulness in patients with focal brain injury due to stroke. Specifically, I aim to: 1) show how the sleep-like bistability can be responsible for the loss of function in stroke patients. This may have implications for understanding the pathophysiology of stroke and helping to foster recovery; 2) establish the basis for a model of local sleep that might be present in the everyday life, id est the sensation of sleepiness. Indeed, sleepiness could reflect islands of sleep during wakefulness; 3) advocate the biological criterion of identity, in which the continuity necessary for maintaining ourselves over time could be represented by never resting activity in the brain

L’étude de la contribution des mécanismes dépendants de la répétition aux processus de consolidation des mémoires motrices dans le cortex moteur primaire et de la manifestation électrophysiologique du traitement des récompenses monétaires au-dessus des aires cérébrales motrices

Abstract : The present thesis seeks to provide insights into the contribution of the two major learning mechanisms driving motor memory consolidation in the primary motor cortex (M1): repetition-dependent and reward-based learning mechanisms. However, because evidence remains scarce on this last learning mechanism, the study of the neural manifestation of reward processing in motor areas was investigated. More specifically, the first scientific contribution presented in this thesis sought to address the contribution of repetition-dependent mechanisms to motor memory consolidation in M1. As such, the first project used single-pulse transcranial magnetic stimulation (TMS) to interfere with M1 activity as participants executed newly learned motor behaviors during a performance asymptote. Results revealed that motor memory formation in M1 was initiated when behaviors were repeating, suggesting that repetition-dependent mechanisms contributed to retention in M1. The second scientific contribution sought to use scalp electroencephalography (EEG) recordings to investigate the electrophysiological manifestations of reward processing over cortical motor areas. Overall, results revealed that increases in beta-band power (20-30 Hz) over contralateral motor electrodes are modulated by reward processing. Although these results did not allow specifically addressing the contribution of reward-based learning mechanisms to consolidation in M1, they nonetheless provide the plausible neural substrates involved in this learning mechanism. The discussion first sought to integrate these two projects and second to provide an overview of the future perspectives that the two projects have led to. Overall, the proposed research projects mainly revolve around the demonstration of the associations– even maybe causality – between motor memory consolidation in M1, reward processing, beta-band power and dopaminergic activity. Throughout the discussion, working hypotheses as well as the methodological means to test them – ranging from non-invasive brain stimulation to electroencephalography recordings and even to the study of interindividual variations in the expression of dopamine-related genes – are outlined.Le présent mémoire cherche à fournir un aperçu des mécanismes neurophysiologiques qui sous-tendent les deux mécanismes principaux d’apprentissage impliqués dans la consolidation des mémoires motrices dans le cortex moteur primaire (M1). Bien que le modèle cellulaire le plus accepté pour la formation des mémoires motrices soit la potentialisation à long-terme (long-term potentiation, en anglais), la littérature suggère que les mécanismes d’apprentissage qui initient le stockage synaptique des mémoires motrices dépendent de la plasticité Hebienne (i.e., répétitions dans les mouvements) et des récompenses vécues pendant l’acquisition d’une nouvelle habileté motrice. La première contribution scientifique du présent mémoire aborde la contribution des mécanismes Hebbiens d’apprentissage à la consolidation des mémoires motrices dans le M1. Dans ce premier projet, la stimulation magnétique transcrânienne (SMT) a été utilisée pour interférer avec l’activité neuronale du M1 lorsque les participants acquéraient et exécutaient de nouveaux comportements moteurs pendant l’atteinte d’un plateau de performance (i.e., répétitions dans les mouvements). Les résultats démontrent que la formation des mémoires motrices dans le M1 est initiée lorsque les comportements moteurs sont de plus en plus répétés, ce qui suggère que le stockage synaptique des mémoires motrices dans M1 est dépendant de la répétition des comportements pendant l’acquisition. Le deuxième projet scientifique a cherché à mettre en lumière la contribution des régions motrices au traitement des récompenses dans un contexte moteur en utilisant l’enregistrement d’activités électroencéphalographiques. Entre autres, suite à l’octroi d’une récompense, les résultats démontrent une augmentation de la puissance spectrale dans la bande de fréquences bêta (20-30 Hz) des électrodes motrices contralatérales à la main utilisée pendant la tâche motrice. Dans l’ensemble, bien que ce deuxième projet ne puisse statuer sur la contribution spécifique du M1 dans la consolidation des mémoires motrices sur la base des récompenses vécues pendant l’acquisition, les résultats qui en émergent pourraient être un reflet des substrats neuronaux impliqués dans ce mécanisme d’apprentissage. Dans un premier temps, la discussion intègre ces deux contributions et, dans un deuxième temps, donne un aperçu des perspectives futures de recherche qui émanent de ces deux contributions scientifiques. Globalement, les hypothèses de recherche suggérées se concentrent principalement autour de la démonstration d’une association ou d’un lien causal entre la formation des mémoires motrices dans le M1, le traitement de récompenses, les réponses spectrales en bêta ainsi que l’activité dopaminergique. Au travers de la discussion, les hypothèses spécifiques ainsi que les moyens méthodologiques pour les tester – qui vont des techniques de stimulation cérébrale non invasives à l’enregistrement d’activité électroencéphalographique et même jusqu’à l’étude des variations génétiques interindividuelles dans l’expression des gènes régulant l’activité dopaminergique – sont décrits