Single session cross-frequency bifocal tACS modulates visual motion network activity in young healthy population and stroke patients.

BACKGROUND: Phase synchronization over long distances underlies inter-areal communication and importantly, modulates the flow of information processing to adjust to cognitive demands. OBJECTIVE: This study investigates the impact of single-session, cross-frequency (Alpha-Gamma) bifocal transcranial alternating current stimulation (cf-tACS) to the cortical visual motion network on inter-areal coupling between the primary visual cortex (V1) and the medio-temporal area (MT) and on motion direction discrimination. METHODS: Based on the well-established phase-amplitude coupling (PAC) mechanism driving information processing in the visual system, we designed a novel directionally tuned cf-tACS protocol. Directionality of information flow was inferred from the area receiving low-frequency tACS (e.g., V1) projecting onto the area receiving high-frequency tACS (e.g., MT), in this case, promoting bottom-up information flow (Forward-tACS). The control condition promoted the opposite top-down connection (from MT to V1, called Backward-tACS), both compared to a Sham-tACS condition. Task performance and EEG activity were recorded from 45 young healthy subjects. An additional cohort of 16 stroke patients with occipital lesions and impairing visual processing was measured to assess the influence of a V1 lesion on the modulation of V1-MT coupling. RESULTS: The results indicate that Forward cf-tACS successfully modulated bottom-up PAC (V1 α-phase-MT É£-amplitude) in both cohorts, while producing opposite effects on the reverse MT-to-V1 connection. Backward-tACS did not change V1-MT PAC in either direction in healthy participants but induced a slight decrease in bottom-up PAC in stroke patients. However, these changes in inter-areal coupling did not translate into cf-tACS-specific behavioural improvements. CONCLUSIONS: Single session cf-tACS can alter inter-areal coupling in intact and lesioned brains but is probably not enough to induce longer-lasting behavioural effects in these cohorts. This might suggest that a longer daily visual training protocol paired with tACS is needed to unveil the relationship between externally applied oscillatory activity and behaviourally relevant brain processing.

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.

Noninvasive theta-burst stimulation of the human striatum enhances striatal activity and motor skill learning.

The stimulation of deep brain structures has thus far only been possible with invasive methods. Transcranial electrical temporal interference stimulation (tTIS) is a novel, noninvasive technology that might overcome this limitation. The initial proof-of-concept was obtained through modeling, physics experiments and rodent models. Here we show successful noninvasive neuromodulation of the striatum via tTIS in humans using computational modeling, functional magnetic resonance imaging studies and behavioral evaluations. Theta-burst patterned striatal tTIS increased activity in the striatum and associated motor network. Furthermore, striatal tTIS enhanced motor performance, especially in healthy older participants as they have lower natural learning skills than younger subjects. These findings place tTIS as an exciting new method to target deep brain structures in humans noninvasively, thus enhancing our understanding of their functional role. Moreover, our results lay the groundwork for innovative, noninvasive treatment strategies for brain disorders in which deep striatal structures play key pathophysiological roles.

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.