Stroke Recovery-Related Changes in Cortical Reactivity Based on Modulation of Intracortical Inhibition.

BACKGROUND: Cortical excitation/inhibition dynamics have been suggested as a key mechanism occurring after stroke. Their supportive or maladaptive role in the course of recovery is still not completely understood. Here, we used transcranial magnetic stimulation (TMS)-electroencephalography coupling to study cortical reactivity and intracortical GABAergic inhibition, as well as their relationship to residual motor function and recovery longitudinally in patients with stroke. METHODS: Electroencephalography responses evoked by TMS applied to the ipsilesional motor cortex were acquired in patients with stroke with upper limb motor deficit in the acute (1 week), early (3 weeks), and late subacute (3 months) stages. Readouts of cortical reactivity, intracortical inhibition, and complexity of the evoked dynamics were drawn from TMS-evoked potentials induced by single-pulse and paired-pulse TMS (short-interval intracortical inhibition). Residual motor function was quantified through a detailed motor evaluation. RESULTS: From 76 patients enrolled, 66 were included (68.2±13.2 years old, 18 females), with a Fugl-Meyer score of the upper extremity of 46.8±19. The comparison with TMS-evoked potentials of healthy older revealed that most affected patients exhibited larger and simpler brain reactivity patterns (Pcluster<0.05). Bayesian ANCOVA statistical evidence for a link between abnormally high motor cortical excitability and impairment level. A decrease in excitability in the following months was significantly correlated with better motor recovery in the whole cohort and the subgroup of recovering patients. Investigation of the intracortical GABAergic inhibitory system revealed the presence of beneficial disinhibition in the acute stage, followed by a normalization of inhibitory activity. This was supported by significant correlations between motor scores and the contrast of local mean field power and readouts of signal dynamics. CONCLUSIONS: The present results revealed an abnormal motor cortical reactivity in patients with stroke, which was driven by perturbations and longitudinal changes within the intracortical inhibition system. They support the view that disinhibition in the ipsilesional motor cortex during the first-week poststroke is beneficial and promotes neuronal plasticity and recovery.

Differential Impact of Brain Network Efficiency on Poststroke Motor and Attentional Deficits.

BACKGROUND: Most studies on stroke have been designed to examine one deficit in isolation; yet, survivors often have multiple deficits in different domains. While the mechanisms underlying multiple-domain deficits remain poorly understood, network-theoretical methods may open new avenues of understanding. METHODS: Fifty subacute stroke patients (7±3days poststroke) underwent diffusion-weighted magnetic resonance imaging and a battery of clinical tests of motor and cognitive functions. We defined indices of impairment in strength, dexterity, and attention. We also computed imaging-based probabilistic tractography and whole-brain connectomes. To efficiently integrate inputs from different sources, brain networks rely on a rich-club of a few hub nodes. Lesions harm efficiency, particularly when they target the rich-club. Overlaying individual lesion masks onto the tractograms enabled us to split the connectomes into their affected and unaffected parts and associate them to impairment. RESULTS: We computed efficiency of the unaffected connectome and found it was more strongly correlated to impairment in strength, dexterity, and attention than efficiency of the total connectome. The magnitude of the correlation between efficiency and impairment followed the order attention>dexterity ≈ strength (strength: |r|=.03, P=0.02, dexterity: |r|=.30, P=0.05, attention: |r|=.55, P<0.001). Network weights associated with the rich-club were more strongly correlated to efficiency than non-rich-club weights. CONCLUSIONS: Attentional impairment is more sensitive to disruption of coordinated networks between brain regions than motor impairment, which is sensitive to disruption of localized networks. Providing more accurate reflections of actually functioning parts of the network enables the incorporation of information about the impact of brain lesions on connectomics contributing to a better understanding of underlying stroke mechanisms.

Syndrome of the Trephined and Paroxysmal Sympathetic Hyperactivity in a 17-year-old minimally conscious state patient: A Case Report.

Purpose: Syndrome of the Trephined (SoT) is one of the most unknown complications of the Decompressive Craniectomy (DC) after Traumatic Brain Injury (TBI). A combination of neurological clinical criteria and radiological signs after DC is necessary to make its diagnosis. In our case, as the patient was in a minimally conscious state (MCS), it was impossible to clinically assess any neurological deterioration according to the criteria found in the literature. There is no description of clinical diagnostic criteria suitable for patients with MCS apart from the visible 'Skin Flap.'Method: A 17-year-old patient sustained a severe TBI. Two months after the TBI and a DC he exhibited an MCS with a Glasgow Coma Scale (GCS) of 7 and a Wessex Head Injury Matrix (WHIM) of 5. He presented several paroxysmal sympathetic hyperactivity (PSH) episodes a day and developed a sinking skin flap. A cranioplasty was performed. Then, we noticed the gradual disappearance of PSH episodes plus an improvement of the CRS and the WHIM. Results: The evolution of the WHIM data revealed a statistically significant difference (p 0.0047). Conclusion: Further studies should be conducted to assess whether the WHIM and the frequency of PSH episodes may be part of the diagnostic criteria for SoT in MCS patients.

[Complex regional pain syndrome]. / Syndrome douloureux régional complexe.

The Complex Regional Pain Syndrome (previously algodystrophy) is a rare affliction that usually affects a distal extremity (hand, foot). It occurs most frequently within weeks following a traumatic injury or stroke. It is a syndromic entity whose diagnosis is based on precise criteria, known as the Budapest criteria, excluding any disease that better explains the symptoms. The treatment must be given early. Functional restoration (physiotherapy, occupational therapy) is at the heart of the treatment, along with psychoeducation. Inappropriate disuse and avoidance, often encountered, must be combated. Bisphosphonates or steroids are first-line drugs at early stages. The evolution is often long, but the prognosis is favorable in about 75 % of cases (≤ 1 year).

Le syndrome douloureux régional complexe (anciennement algodystrophie) est une affection rare qui touche préférentiellement une extrémité (main, pied). Il se développe le plus souvent dans les semaines qui suivent un traumatisme ou un accident vasculaire cérébral. Il s'agit d'une entité syndromique dont le diagnostic repose sur des critères précis, dits de Budapest, excluant toute atteinte expliquant mieux les symptômes. Le traitement doit être précoce. La restauration fonctionnelle en est le cœur (physiothérapie, ergothérapie), associée à une psychoéducation. L'immobilisation inappropriée et l'évitement, souvent rencontrés, doivent être combattus. Bisphosphonates ou corticoïdes sont les médicaments de premier choix des formes précoces. L'évolution est souvent longue, mais le pronostic favorable dans environ 75 % des cas (≤ 1 an).

Novel personalized treatment strategy for patients with chronic stroke with severe upper-extremity impairment: The first patient of the AVANCER trial.

BACKGROUND: Around 25% of patients who have had a stroke suffer from severe upper-limb impairment and lack effective rehabilitation strategies. The AVANCER proof-of-concept clinical trial (NCT04448483) tackles this issue through an intensive and personalized-dosage cumulative intervention that combines multiple non-invasive neurotechnologies. METHODS: The therapy consists of two sequential interventions, lasting until the patient shows no further motor improvement, for a minimum of 11 sessions each. The first phase involves a brain-computer interface governing an exoskeleton and multi-channel functional electrical stimulation enabling full upper-limb movements. The second phase adds anodal transcranial direct current stimulation of the motor cortex of the lesioned hemisphere. Clinical, electrophysiological, and neuroimaging examinations are performed before, between, and after the two interventions (T0, T1, and T2). This case report presents the results from the first patient of the study. FINDINGS: The primary outcome (i.e., 4-point improvement in the Fugl-Meyer assessment of the upper extremity) was met in the first patient, with an increase from 6 to 11 points between T0 and T2. This improvement was paralleled by changes in motor-network structure and function. Resting-state and transcranial magnetic stimulation-evoked electroencephalography revealed brain functional changes, and magnetic resonance imaging (MRI) measures detected structural and task-related functional changes. CONCLUSIONS: These first results are promising, pointing to feasibility, safety, and potential efficacy of this personalized approach acting synergistically on the nervous and musculoskeletal systems. Integrating multi-modal data may provide valuable insights into underlying mechanisms driving the improvements and providing predictive information regarding treatment response and outcomes. FUNDING: This work was funded by the Wyss-Center for Bio and Neuro Engineering (WCP-030), the Defitech Foundation, PHRT-#2017-205, ERA-NET-NEURON (Discover), and SNSF (320030L_197899, NiBS-iCog).

The effect of gamified robot-enhanced training on motor performance in chronic stroke survivors.

Task-specific training constitutes a core element for evidence-based rehabilitation strategies targeted at improving upper extremity activity after stroke. Its combination with additional treatment strategies and neurotechnology-based solutions could further improve patients' outcomes. Here, we studied the effect of gamified robot-assisted upper limb motor training on motor performance, skill learning, and transfer with respect to a non-gamified control condition with a group of chronic stroke survivors. The results suggest that a gamified training strategy results in more controlled motor performance during the training phase, which is characterized by a higher accuracy (lower deviance), higher smoothness (lower jerk), but slower speed. The responder analyses indicated that mildly impaired patients benefited most from the gamification approach. In conclusion, gamified robot-assisted motor training, which is personalized to the individual capabilities of a patient, constitutes a promising investigational strategy for further improving motor performance after a stroke.

A Novel Patient-Tailored, Cumulative Neurotechnology-Based Therapy for Upper-Limb Rehabilitation in Severely Impaired Chronic Stroke Patients: The AVANCER Study Protocol.

Effective, patient-tailored rehabilitation to restore upper-limb motor function in severely impaired stroke patients is still missing. If suitably combined and administered in a personalized fashion, neurotechnologies offer a large potential to assist rehabilitative therapies to enhance individual treatment effects. AVANCER (clinicaltrials.gov NCT04448483) is a two-center proof-of-concept trial with an individual based cumulative longitudinal intervention design aiming at reducing upper-limb motor impairment in severely affected stroke patients with the help of multiple neurotechnologies. AVANCER will determine feasibility, safety, and effectivity of this innovative intervention. Thirty chronic stroke patients with a Fugl-Meyer assessment of the upper limb (FM-UE) <20 will be recruited at two centers. All patients will undergo the cumulative personalized intervention within two phases: the first uses an EEG-based brain-computer interface to trigger a variety of patient-tailored movements supported by multi-channel functional electrical stimulation in combination with a hand exoskeleton. This phase will be continued until patients do not improve anymore according to a quantitative threshold based on the FM-UE. The second interventional phase will add non-invasive brain stimulation by means of anodal transcranial direct current stimulation to the motor cortex to the initial approach. Each phase will last for a minimum of 11 sessions. Clinical and multimodal assessments are longitudinally acquired, before the first interventional phase, at the switch to the second interventional phase and at the end of the second interventional phase. The primary outcome measure is the 66-point FM-UE, a significant improvement of at least four points is hypothesized and considered clinically relevant. Several clinical and system neuroscience secondary outcome measures are additionally evaluated. AVANCER aims to provide evidence for a safe, effective, personalized, adjuvant treatment for patients with severe upper-extremity impairment for whom to date there is no efficient treatment available.

Toward individualized medicine in stroke-The TiMeS project: Protocol of longitudinal, multi-modal, multi-domain study in stroke.

Despite recent improvements, complete motor recovery occurs in <15% of stroke patients. To improve the therapeutic outcomes, there is a strong need to tailor treatments to each individual patient. However, there is a lack of knowledge concerning the precise neuronal mechanisms underlying the degree and course of motor recovery and its individual differences, especially in the view of brain network properties despite the fact that it became more and more clear that stroke is a network disorder. The TiMeS project is a longitudinal exploratory study aiming at characterizing stroke phenotypes of a large, representative stroke cohort through an extensive, multi-modal and multi-domain evaluation. The ultimate goal of the study is to identify prognostic biomarkers allowing to predict the individual degree and course of motor recovery and its underlying neuronal mechanisms paving the way for novel interventions and treatment stratification for the individual patients. A total of up to 100 patients will be assessed at 4 timepoints over the first year after the stroke: during the first (T1) and third (T2) week, then three (T3) and twelve (T4) months after stroke onset. To assess underlying mechanisms of recovery with a focus on network analyses and brain connectivity, we will apply synergistic state-of-the-art systems neuroscience methods including functional, diffusion, and structural magnetic resonance imaging (MRI), and electrophysiological evaluation based on transcranial magnetic stimulation (TMS) coupled with electroencephalography (EEG) and electromyography (EMG). In addition, an extensive, multi-domain neuropsychological evaluation will be performed at each timepoint, covering all sensorimotor and cognitive domains. This project will significantly add to the understanding of underlying mechanisms of motor recovery with a strong focus on the interactions between the motor and other cognitive domains and multimodal network analyses. The population-based, multi-dimensional dataset will serve as a basis to develop biomarkers to predict outcome and promote personalized stratification toward individually tailored treatment concepts using neuro-technologies, thus paving the way toward personalized precision medicine approaches in stroke rehabilitation.