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.

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).

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.

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.

Disconnectomics of the Rich Club Impacts Motor Recovery After Stroke.

BACKGROUND AND PURPOSE: Structural brain networks possess a few hubs, which are not only highly connected to the rest of the brain but are also highly connected to each other. These hubs, which form a rich-club, play a central role in global brain organization. To investigate whether the concept of rich-club sheds new light on poststroke recovery, we applied a novel network-theoretical quantification of lesions to patients with stroke and compared the outcomes with what lesion size alone would indicate. METHODS: Whole-brain structural networks of 73 patients with ischemic stroke were reconstructed using diffusion-weighted imaging data. Disconnectomes, a new type of network analyses, were constructed using only those fibers that pass through the lesion. Fugl-Meyer upper extremity scores and their changes were used to determine whether the patients show natural recovery or not. RESULTS: Cluster analysis revealed 3 patient clusters: small-lesion-good-recovery, midsized-lesion-poor-recovery (MLPR), and large-lesion-poor-recovery (LLPR). The small-lesion-good-recovery consisted of subjects whose lesions were small, and whose prospects for recovery were relatively good. To explain the nondifference in recovery between the MLPR and LLPR clusters despite the difference (LLPR>MLPR) in lesion volume, we defined the [Formula: see text] metric to be the sum of the entries in the disconnectome and, more importantly, the [Formula: see text] to be the sum of all entries in the disconnectome corresponding to edges with at least one node in the rich-club. Unlike lesion volume and corticospinal tract damage (MLPRLLPR) or showed no difference for [Formula: see text]. CONCLUSIONS: Smaller lesions that focus on the rich-club can be just as devastating as much larger lesions that do not focus on the rich-club, pointing to the role of the rich-club as a backbone for functional communication within brain networks and for recovery from stroke.