Andéol Cadic-Melchior

Healthy aging often entails a decline in cognitive and motor functions, affecting independence and quality of life in older adults. Brain stimulation shows potential to enhance these functions, but studies show variable effects. Previous studies have tried to identify responders and non-responders through correlations between behavioral change and baseline parameters, but results lack generalization to independent cohorts. We propose a method to predict an individual’s likelihood of benefiting from stimulation, based on baseline performance of a sequential motor task. Our results show that individuals with less efficient learning mechanisms benefit from stimulation, while those with optimal learning strategies experience none or even detrimental effects. This differential effect, first identified in a public dataset and replicated here in an independent cohort, was linked to one’s ability to integrate task-relevant information and not age. This study constitutes a further step towards personalized clinical-translational interventions based on brain stimulation.

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 ( P _cluster <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.

Objective. The literature investigating the effects of alpha oscillations on corticospinal excitability is divergent. We believe inconsistency in the findings may arise, among others, from the electroencephalography (EEG) processing for brain-state determination. Here, we provide further insights in the effects of the brain-state on cortical and corticospinal excitability and quantify the impact of different EEG processing. Approach. Corticospinal excitability was measured using motor evoked potential (MEP) peak-to-peak amplitudes elicited with transcranial magnetic stimulation (TMS); cortical responses were studied through TMS-evoked potentials’ TEPs features. A TMS-EEG-electromyography (EMG) dataset of 18 young healthy subjects who received 180 single-pulse (SP) and 180 paired pulses (PP) to determine short-intracortical inhibition (SICI) was investigated. To study the effect of different EEG processing, we compared the brain-state estimation deriving from three published methods. The influence of presence of neural oscillations was also investigated. To evaluate the effect of the brain-state on MEP and TEP features variability, we defined the brain-state based on specific EEG phase and power combinations, only in trials where neural oscillations were present. The relationship between TEPs and MEPs was further evaluated. Main results. The presence of neural oscillations resulted in more consistent results regardless of the EEG processing approach. Nonetheless, the latter still critically affected the outcomes, making conclusive claims complex. With our approach, the MEP amplitude was positively modulated by the alpha power and phase, with stronger responses during the trough phase and high power. Power and phase also affected TEP features. Importantly, similar effects were observed in both TMS conditions. Significance. These findings support the view that the brain state of alpha oscillations is associated with the variability observed in cortical and corticospinal responses to TMS, with a tight correlation between the two. The results further highlight the importance of closed-loop stimulation approaches while underlining that care is needed in designing experiments and choosing the analytical approaches, which should be based on knowledge from offline studies to control for the heterogeneity originating from different EEG processing strategies.

Brain stimulation shows potential at enhancing cognitive and motor functions in humans. However, multiple studies assessing its effects on behavior show heterogeneous results, especially in healthy older subjects. We propose a new method to predict an individual’s likelihood and the magnitude of the benefit from stimulation, based on the baseline performance of a sequential motor task, framed in the context of their age. Our results show a differential effect of stimulation, in which individuals with less efficient learning mechanisms benefit from stimulation, while those possessing optimal learning strategies resent a detrimental effect. Importantly, this differential effect was determined by one’s ability to integrate task-relevant information at the early stages of training, and not the age. This study paves the way towards the personalized application of stimulation to maximize its effects, and constitutes the first steps to implement an individualized translational clinical intervention, based on the state of the neural system. Teaser: Age notwithstanding, brain stimulation is most effective in deficient neural systems, while being detrimental to optimal systems Visual Main finding: Anodal transcranial direct current stimulation (atDCS), applied over the hand representation of the motor cortex concomitant to the training of a sequential motor sequence, has differential effects as a function of the recipient’s ability to integrate task-relevant information at the early stages of training. Stimulation benefits individuals with seemingly less efficient learning mechanisms, enabling the rapid storage of the spatial coordinates of the motor sequence and an accelerated optimization of the accuracy of execution. In contrast, individuals possessing optimal learning mechanisms experience detrimental effects of stimulation, leading to drops in the accuracy of execution.

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.

Objective: 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 TMS-EEG coupling to study cortical reactivity and intracortical GABAergic inhibition, as well as their relationship to residual motor function and recovery longitudinally in a large cohort of stroke patients. Methods: EEG responses evoked by TMS applied to the ipsilesional motor cortex were acquired in 66 stroke patients in the acute (1-week), subacute (3-weeks) and early chronic (3-months) stage. Readouts of cortical reactivity and intracortical inhibition were drawn from TMS-evoked potentials induced by single pulse and paired pulse TMS. Residual function of the upper limb was quantified through a detailed motor evaluation. Results: Most affected patients exhibited larger and simpler brain reactivity patterns. Bayesian statistics revealed a link between abnormally high motor cortical excitability in the acute stage and impairment level, while a decrease of excitability in the following months was related to better motor recovery. The investigation of the intracortical GABAergic inhibitory system using paired pulse TMS revealed the presence of a beneficial disinhibition in the acute stage, followed by a normalization of inhibitory activity. Interpretation: The present results revealed an abnormal motor cortical reactivity in stroke patients, 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 post-stroke is beneficial and promotes neuronal plasticity and recovery.

A key feature of a successful game is its ability to provide the player with an adequate level of challenge. However, the objective of difficulty adaptation in serious games is not only to maintain the player’s motivation by challenging, but also to ensure the completion of training objectives.This paper describes our proposed upper-limb rehabilitation game with tangible robots and investigates the effect of game elements and gameplay on the amount of the performed motion in several planes and percentage of failure by using the data from 33 unimpaired subjects who played 53 games within two consecutive days. In order to provide a more generic adaptation strategy in the future, we discretize the game area to circular zones. We then show the effect of changing these zones during gameplay on the activation of different muscles through EMG data in a pilot study.The study shows that it is possible to increase the challenge level by adding more active agents chasing the player and increasing the speed of these agents. However, only the increase in number of agents significantly increases the users’ motion on both planes. Analysis of player behaviors leads us to suggest that by adapting the behaviour of these active agents in specific zones, it is possible to change the trajectory of the user, and to provide a focus on the activation of specific muscles.