Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation

Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration

Cortical gamma-synchrony measured with magnetoencephalography is a marker of clinical status and predicts clinical outcome in stroke survivors.

Background: The outcome of stroke survivors is difficult to anticipate. While the extent of the anatomical brain lesion is only poorly correlated with the prognosis, functional measures of cortical synchrony, brain networks and cortical plasticity seem to be good predictors of clinical recovery. In this field, gamma (>30 Hz) cortical synchrony is an ideal marker of brain function, as it plays a crucial role for the integration of information, it is an indirect marker of Glutamate/GABA balance and it directly estimates the reserve of parvalbulin-positive neurons, key players in synaptic plasticity. In this study we measured gamma synchronization driven by external auditory stimulation with magnetoencephalography and tested whether it was predictive of the clinical outcome in stroke survivors undergoing intensive rehabilitation in a tertiary rehabilitation center. Material and methods: Eleven stroke survivors undergoing intensive rehabilitation were prospectively recruited. Gamma synchrony was measured non-invasively within one month from stroke onset with magnetoencephalography, both at rest and during entrainment with external 40 Hz amplitude modulated binaural sounds. Lesion location and volume were quantitatively assessed through a high-resolution anatomical MRI. Barthel index (BI) and Functional Independence Measure (FIM) scales were measured at the beginning and at the end of the admission to the rehabilitation unit. Results: The spatial distribution of cortical gamma synchrony was altered, and the physiological right hemispheric dominance observed in healthy controls was attenuated or lost. Entrained gamma synchronization (but not resting state gamma synchrony) showed a very high correlation with the clinical status at both admission and discharge (both BI and FIM). Neither clinical status nor gamma synchrony showed a correlation with lesion volume. Conclusions: Cortical gamma synchrony related to auditory entrainment can be reliably measured in stroke patients. Gamma synchrony is strongly associated with the clinical outcome of stroke survivors undergoing rehabilitation

Relation Between EEG Measures and Upper Limb Motor Recovery in Stroke Patients: A Scoping Review

Current clinical practice does not leverage electroencephalography (EEG) measurements in stroke patients, despite its potential to contribute to post-stroke recovery predictions. We review the literature on the effectiveness of various quantitative and qualitative EEG-based measures after stroke as a tool to predict upper limb motor outcome, in relation to stroke timeframe and applied experimental tasks. Moreover, we aim to provide guidance on the use of EEG in the assessment of upper limb motor recovery after stroke, suggesting a high potential for some metrics in the appropriate context. We identified relevant papers (N = 16) from databases ScienceDirect, Web of Science and MEDLINE, and assessed their methodological quality with the Joanna Briggs Institute (JBI) Critical Appraisal. We applied the Preferred Reporting Systems for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) Framework. Identified works used EEG to identify properties including event-related activation, spectral power in physiologically relevant bands, symmetry in brain dynamics, functional connectivity, cortico-muscular coherence and rhythmic coordination. EEG was acquired in resting state or in relation to behavioural conditions. Motor outcome was mainly evaluated with the Upper Limb Fugl-Meyer Assessment. Despite great variability in the literature, data suggests that the most promising EEG quantifiers for predicting post-stroke motor outcome are event-related measures. Measures of spectral power in physiologically relevant bands and measures of brain symmetry also show promise. We suggest that EEG measures may improve our understanding of stroke brain dynamics during recovery, and contribute to establishing a functional prognosis and choosing the rehabilitation approach

Rehabilitation and biomarkers of stroke recovery: study protocol for a randomized controlled trial

Background: Stroke is a leading cause of disability. Nonetheless, the care pathway for stroke rehabilitation takes partially into account the needs of chronic patients. This is due in part to the lack of evidence about the mechanisms of recovery after stroke, together with the poor knowledge of related and influencing factors. Here we report on the study protocol \u201cRehabilitation and Biomarkers of Stroke Recovery,\u201d which consists of 7 work-packages and mainly aim to investigate the effects of long-term neurorehabilitation on stroke patients and to define a related profile of (clinical-biological, imaging, neurophysiological, and genetic-molecular) biomarkers of long-term recovery after stroke. The work-package 1 will represent the main part of this protocol and aims to compare the long-term effects of intensive self-rehabilitation vs. usual (rehabilitation) care for stroke. Methods: We planned to include a total of 134 adult subacute stroke patients (no more than 3 months since onset) suffering from multidomain disability as a consequence of first-ever unilateral ischemic stroke. Eligible participants will be randomly assigned to one of the following groups: intensive self-rehabilitation (based on the principles of \u201cGuided Self-Rehabilitation Contract\u201d) vs. usual care (routine practice). Treatment will last 1 year, and patients will be evaluated every 3 months according to their clinical presentation. The following outcomes will be considered in the main work-package: Fugl-Meyer assessment, Cognitive Oxford Screen Barthel Index, structural and functional neuroimaging, cortical excitability, and motor and somatosensory evoked potentials. Discussion: This trial will deal with the effects of an intensive self-management rehabilitation protocol and a related set of biomarkers. It will also investigate the role of training intensity on long-term recovery after stroke. In addition, it will define a set of biomarkers related to post-stroke recovery and neurorehabilitation outcome in order to detect patients with greater potential and define long-term individualized rehabilitation programs. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04323501

Fusion of virtual reality and brain-machine interfaces for the assessment and rehabilitation of patients with spinal cord injury

La presente tesis está centrada en la utilización de nuevas tecnologías (Interfaces Cerebro-Máquina y Realidad Virtual). En la primera parte de la tesis se describe la definición y la aplicación de un conjunto de métricas para evaluar el estado funcional de los pacientes con lesión medular en el contexto de un sistema de realidad virtual para la rehabilitación de los miembros superiores. El objetivo de este primer estudio es demostrar que la realidad virtual puede utilizarse, en combinación con sensores inerciales para rehabilitar y evaluar simultáneamente. 15 pacientes con lesión medular llevaron a cabo 3 sesiones con el sistema de realidad virtual Toyra y se aplicó el conjunto definido de métricas a las grabaciones obtenidas con los sensores inerciales. Se encontraron correlaciones entre algunas de las métricas definidas y algunas de las escalas clínicas utilizadas con frecuencia en el contexto de la rehabilitación. En la segunda parte de la tesis se ha combinado una retroalimentación virtual con un estimulador eléctrico funcional (en adelante FES, por sus siglas en inglés Functional Electrical Stimulator), ambos controlados por un Interfaz Cerebro-Máquina (BMI por sus siglas en inglés Brain-Machine Interface), para desarrollar un nuevo tipo de enfoque terapéutico para los pacientes. El sistema ha sido utilizado por 4 pacientes con lesión medular que intentaron mover sus manos. Esta intención desencadenó simultáneamente el FES y la retroalimentación virtual, cerrando la mano de los pacientes y mostrándoles una fuente adicional de retroalimentación para complementar la terapia. Este trabajo es, de acuerdo al estado del arte revisado, el primero que integra BMI, FES y realidad virtual como terapia para pacientes con lesión medular. Se han obtenido resultados clínicos prometedores por 4 pacientes con lesión medular después de realizar 5 sesiones de terapia con el sistema, mostrando buenos niveles de precisión en las diferentes sesiones (79,13% en promedio). En la tercera parte de la tesis se ha definido una nueva métrica para estudiar los cambios de conectividad cerebral en los pacientes con lesión medular, que incluye información de las interacciones neuronales entre diferentes áreas. El objetivo de este estudio ha sido extraer información clínicamente relevante de la actividad del EEG cuando se realizan terapias basadas en BMI

Are There Brain-Based Predictors of the Ability to Learn a New Skill in Healthy Ageing and Can They Help in the Design of Effective Therapy after Stroke?

This thesis aimed at looking for neural correlates of motor adaptation as a model of rehabilitation after brain injury. Healthy adults across the lifespan and stroke patients were tested in a force-field learning paradigm. This thesis focuses on EEG analysis and the complex relationship of brain-derived measures with observed behaviour. To describe each domain in detail, the focus was first on finding group differences between older and younger healthy adults in a similar manner as it was later between stroke patients versus healthy controls. The analyses were finalised by looking for relationships between the EEG and motor performance data in a multiple linear regression approach. As candidate EEG biomarkers of motor adaptation, error related event related potential around movement onset in the frontocentral electrodes was chosen in time domain. In the time-frequency domain, the focus was on movement related beta band spectral perturbation, looking at the electrodes over the primary motor cortex and the frontocentral ROI found significant in the time domain. Finally, functional connectivity was analysed focusing first on electrode over the primary motor cortex contralateral to the movement as a seed region, to narrow down the analysis to bilateral motor cortex connectivity and connectivity between primary motor cortex contralateral to the movement and the frontocentral region identified as important in the time domain analysis. The crucial part of the project was analysing the relationship between the neural and kinematic measures. The most important predictor of summed error in motor adaptation was the connectivity between C3 and C4 electrode at the baseline prestimulus period in motor adaptation condition and pinch asymmetry. Higher prestimulus interhemispheric connectivity was associated with bigger deviation from the optimal trajectory. When looking at summed error dynamic derivative as a dependent variable - performance index - it was the ERP at the central error-related ROI that explained the most variance. It can be concluded that higher baseline interhemispheric connectivity can be a reflection of a maladaptive process, perhaps related to increased interhemispheric inhibition. It is important to also note that the same connectivity at different timepoints in the movement can be of different significance - differences between stroke patients and controls were present in the postmovement period. In conclusion, brain information could be helpful for e.g. stratifying patients into different intensity programs based on their predicted potential to recover. Moreover, brain information could be utilised to apply closed-loop systems modulating the intensity of tasks to reach the optimal brain state that facilitates learning. I believe this work will help incorporating brain-derived measures in informing neurorehabilitation programmes in the future

EEG During Motor Tasks in Stroke: The Effects of Remote Ischemic Conditioning and Fatigue on Brain Activity

This dissertation aimed to use electroencephalography (EEG) to identify the effects of fatigue and remote ischemic conditioning on brain activity. Lesions due to stroke directly or indirectly affect regions of the brain and the descending corticospinal pathways. Cortical reorganization and alternate descending neural pathways are used during recovery from stroke as compensation mechanisms for motor deficits. These mechanisms exacerbate the deficits by worsening the ability to terminate muscle activity, individuate muscles for fine motor control and minimize abnormal muscle synergy and coactivation patterns to conserve resources during movement. Even though imaging and muscle activation studies have documented the existence and impact of cortical reorganization and the use of alternate descending pathways, temporal changes in cortical activation during long motor tasks are not well understood. We expect that potential changes in cerebrovascular function and physiology of brain metabolism after stroke might impact the ability of the brain to produce extended activity. We used EEG for its high temporal resolution compared to other imaging modalities to document temporal changes in brain activity when people with stroke performed various motor tasks. We first documented the changes in activation during and at the end of a simple cued finger tap task between people with stroke and controls. We then pushed the neuromuscular system to its limits using a fatiguing contraction of the wrist to visualize changes in brain activation patterns after extended muscle contraction. Lastly, we tested a neurorehabilitation therapy protocol, remote ischemic conditioning (RIC), that has shown functional improvements in people with stroke to determine if cortical activation is changed during a complex, multijoint visuomotor task. The results show that cortical activation in people with stroke is divergent from controls. People with stroke continue brain activation at the end of a simple task but cannot increase activation at the end of a fatiguing task. RIC, however, increases activation during a multijoint elbow/shoulder task. This research has improved our understanding of brain activation during a simple task and in response to fatigue in people with stroke. The knowledge of cortical changes due to RIC demonstrates the therapy’s ability to “prime” the brain for neurorehabilitation, which might lead to better therapeutic outcomes post-rehabilitation in people with stroke

Brain computer interface based neurorehabilitation technique using a commercially available EEG headset

Neurorehabilitation has recently been augmented with the use of virtual reality and rehabilitation robotics. In many systems, some known volitional control must exist in order to synchronize the user intended movement with the therapeutic virtual or robotic movement. Brain Computer Interface (BCI) aims to open up a new rehabilitation option for clinical population having no residual movement due to disease or injury to the central or peripheral nervous system. Brain activity contains a wide variety of electrical signals which can be acquired using many invasive and non-invasive acquisition techniques and holds the potential to be used as an input to BCI. Electroencephalogram (EEG) is a non-invasive method of acquiring brain activity which then, with further processing and classification, can be used to predict various brain states such as an intended motor movement. EEG provides the temporal resolution required to obtain significant result which may not be provided by many other non-invasive techniques. Here, EEG is recorded using a commercially available EEG headset provided by Emotiv Inc. Data is collected and processed using BCI2000 software, and the difference in the Mu-rhythm due to Event Related Synchronization (ERS) and Desynchronization (ERD) is used to distinguish an intended motor movement and resting brain state, without the need for physical movement. The idea is to combine this user intent/free will with an assistive robot to achieve the user initiated, repetitive motor movements required to bring therapeutic changes in the targeted subject group, as per Hebbian type learning

Continuous theta burst stimulation increases contralateral mu and beta rhythms with arm elevation:implications for neurorehabilitation

The study of the physiological effects underlying brain response to transcranial magnetic stimulation is important to understand its impact on neurorehabilitation. We aim to analyze the impact of a transcranial magnetic stimulation protocol, the continuous theta burst (cTBS), on human neurophysiology, particularly on contralateral motor rhythms. cTBS was applied in 20 subjects over the primary motor cortex. We recorded brain electrical activity pre- and post-cTBS with electroencephalography both at rest and while performing motor tasks, to evaluate changes in brain oscillatory patterns such as mu and beta rhythms. Moreover, we measured motor-evoked potentials before and after cTBS to assess its impact on brain's excitability. On the hemisphere contralateral to the protocol, we did observe a significant increase in mu (p = 0.027) and beta (p = 0.006) rhythms from pre- to post-cTBS, at the beginning of arm elevation. The topology of action planning and motor execution suggests that cTBS produced an inhibitory effect that propagated to the contralateral hemisphere, thereby precluding the expected/desired excitation for therapy purposes. This novel approach provides support for the notion that this protocol induces inhibitory changes in contralateral motor rhythms, by decreasing desynchronization, contradicting the ipsilateral inhibition vs. contralateral disinhibition hypothesis. Our results have implications for personalized cTBS usage as a rehabilitation intervention, suggesting that an unexpected propagation of inhibition can occur