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.

Age-related changes in muscle coordination patterns of stepping responses to recover from loss of balance.

INTRODUCTION: Reactive stepping capacity to recover from a loss of balance declines with aging, which increases the risk of falling. To gain insight into the underlying mechanisms, we investigated whether muscle coordination patterns of reactive stepping differed between healthy young and older individuals. METHODS: We performed a cross-sectional study between 15 healthy young and 14 healthy older adults. They recovered from 200 multidirectional platform translations that evoked reactive stepping responses. We determined spatiotemporal step variables and used muscle synergy analysis to characterize stance- and swing-leg muscle coordination patterns from the start of perturbation until foot landing. RESULTS: We observed delayed step onsets in older individuals, without further spatiotemporal differences. Muscle synergy structure was not different between young and older individuals, but age-related differences were observed in the time-varying synergy activation patterns. In anterior-posterior directions, the older individuals demonstrated significantly enhanced early swing-leg synergy activation consistent with non-stepping behavior. In addition, around step onset they demonstrated increased levels of synergy coactivation (mainly around the ankle) in lateral and anterior directions, which did not appear to hamper foot clearance. CONCLUSION: Although synergy structure was not affected by age, the delayed step onsets and the enhanced early synergy recruitment point at a relative bias towards non-stepping behavior in older adults. They may need more time for accumulating information on the direction of perturbation and making the corresponding sensorimotor transformations before initiating the step. Future work may investigate whether perturbation-based training improves these age-related deficits.

Mild Stroke, Serious Problems: Limitations in Balance and Gait Capacity and the Impact on Fall Rate, and Physical Activity.

BACKGROUND: After mild stroke persistent balance limitations may occur, creating a risk factor for fear of falling, falls, and reduced activity levels. Objective. To investigate whether individuals in the chronic phase after mild stroke show balance and gait limitations, elevated fall risk, reduced balance confidence, and physical activity levels compared to healthy controls. METHODS: An observational case-control study was performed. Main outcomes included the Mini-Balance Evaluation Systems Test (mini-BEST), Timed Up and Go (TUG), 10-m Walking Test (10-MWT), and 6-item version Activity-specific Balance Confidence (6-ABC) scale which were measured in 1 session. Objectively measured daily physical activity was measured for 7 consecutive days. Fall rate in daily life was recorded for 12 months. Individuals after a mild stroke were considered eligible when they: (1) sustained a transient ischemic attack or stroke longer than 6 months ago, resulting in motor and/or sensory loss in the contralesional leg at the time of stroke, (2) showed (near-) complete motor function, that is, ≥24 points on the Fugl-Meyer Assessment-Lower Extremity (range: 0-28). RESULTS: Forty-seven healthy controls and 70 participants after mild stroke were included. Participants with stroke fell more than twice as often as healthy controls, had a 2 point lower median score on the mini-BEST, were 1.7 second slower on TUG, 0.6 km/h slower on the 10-MWT, and had a 12% lower 6-ABC score. Intensity for both total activity (8%) as well as walking activity (6%) was lower in the participants with stroke, while no differences were found in terms of duration. CONCLUSIONS: Individuals in the chronic phase after a mild stroke demonstrate persistent balance limitations and have an increased fall risk. Our results point at an unmet clinical need in this population.

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).

Improvements in spatiotemporal outcomes, but not in recruitment of automatic postural responses, are correlated with improved step quality following perturbation-based balance training in chronic stroke.

Introduction: People with stroke often exhibit balance impairments, even in the chronic phase. Perturbation-based balance training (PBT) is a therapy that has yielded promising results in healthy elderly and several patient populations. Here, we present a threefold approach showing changes in people with chronic stroke after PBT on the level of recruitment of automatic postural responses (APR), step parameters and step quality. In addition, we provide insight into possible correlations across these outcomes and their changes after PBT. Methods: We performed a complementary analysis of a recent PBT study. Participants received a 5-week PBT on the Radboud Fall simulator. During pre- and post-intervention assessments participants were exposed to platform translations in forward and backward directions. We performed electromyography of lower leg muscles to identify changes in APR recruitment. In addition, 3D kinematic data of stepping behavior was collected. We determined pre-post changes in muscle onset, magnitude and modulation of recruitment, step characteristics, and step quality. Subsequently, we determined whether improvements in step or muscle characteristics were correlated with improved step quality. Results: We observed a faster gastrocnemius muscle onset in the stance and stepping leg during backward stepping. During forward stepping we found a trend toward a faster tibialis anterior muscle onset in the stepping leg. We observed no changes in modulation or magnitude of muscle recruitment. Leg angles improved by 2.3° in forward stepping and 2.5° in backward stepping. The improvement in leg angle during forward stepping was accompanied by a -4.1°change in trunk angle, indicating a more upright position. Step length, duration and velocity improved in both directions. Changes in spatiotemporal characteristics were strongly correlated with improvements in leg angle, but no significant correlations were observed of muscle onset or recruitment with leg or trunk angle. Conclusion: PBT leads to a multi-factorial improvement in onset of APR, spatiotemporal characteristics of stepping, and reactive step quality in people with chronic stroke. However, current changes in APR onset were not correlated with improvement in step quality. Therefore, we suggest that, in addition to spatiotemporal outcomes, other characteristics of muscle recruitment or behavioral substitution may induce step quality improvement after PBT.

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.

Quantifying neural and non-neural components of wrist hyper-resistance after stroke: Comparing two instrumented assessment methods.

Patients with poor upper limb motor recovery after stroke are likely to develop increased resistance to passive wrist extension, i.e., wrist hyper-resistance. Quantification of the underlying neural and non-neural elastic components is of clinical interest. This cross-sectional study compared two methods: a commercially available device (NeuroFlexor®) with an experimental EMG-based device (Wristalyzer) in 43 patients with chronic stroke. Spearman's rank correlation coefficients (r) between components, modified Ashworth scale (MAS) and range of passive wrist extension (PRoM) were calculated with 95% confidence intervals. Neural as well as elastic components assessed by both devices were associated (r = 0.61, 95%CI: 0.38-0.77 and r = 0.53, 95%CI: 0.28-0.72, respectively). The neural component assessed by the NeuroFlexor® associated significantly with the elastic components of NeuroFlexor® (r = 0.46, 95%CI: 0.18-0.67) and Wristalyzer (r = 0.36, 95%CI: 0.06-0.59). The neural component assessed by the Wristalyzer was not associated with the elastic components of both devices. Neural and elastic components of both devices associated similarly with the MAS (r = 0.58, 95%CI: 0.34-0.75 vs. 0.49, 95%CI: 0.22-0.69 and r = 0.51, 95%CI: 0.25-0.70 vs. 0.30, 95%CI: 0.00-0.55); elastic components associated with PRoM (r = -0.44, 95%CI: -0.65- -0.16 vs. -0.74, 95%CI: -0.85- -0.57 for NeuroFlexor® and Wristalyzer respectively). Results demonstrate that both methods perform similarly regarding the quantification of neural and elastic wrist hyper-resistance components and have an added value when compared to clinical assessment with the MAS alone. The added value of EMG in the discrimination between neural and non-neural components requires further investigation.

Enhancing visual motion discrimination by desynchronizing bifocal oscillatory activity.

Visual motion discrimination involves reciprocal interactions in the alpha band between the primary visual cortex (V1) and mediotemporal areas (V5/MT). We investigated whether modulating alpha phase synchronization using individualized multisite transcranial alternating current stimulation (tACS) over V5 and V1 regions would improve motion discrimination. We tested 3 groups of healthy subjects with the following conditions: (1) individualized In-Phase V1alpha-V5alpha tACS (0° lag), (2) individualized Anti-Phase V1alpha-V5alpha tACS (180° lag) and (3) sham tACS. Motion discrimination and EEG activity were recorded before, during and after tACS. Performance significantly improved in the Anti-Phase group compared to the In-Phase group 10 and 30 min after stimulation. This result was explained by decreases in bottom-up alpha-V1 gamma-V5 phase-amplitude coupling. One possible explanation of these results is that Anti-Phase V1alpha-V5alpha tACS might impose an optimal phase lag between stimulation sites due to the inherent speed of wave propagation, hereby supporting optimized neuronal communication.

Is Recovery of Somatosensory Impairment Conditional for Upper-Limb Motor Recovery Early After Stroke?

Background. Spontaneous recovery early after stroke is most evident during a time-sensitive window of heightened neuroplasticity, known as spontaneous neurobiological recovery. It is unknown whether poststroke upper-limb motor and somatosensory impairment both reflect spontaneous neurobiological recovery or if somatosensory impairment and/or recovery influences motor recovery. Methods. Motor (Fugl-Meyer upper-extremity [FM-UE]) and somatosensory impairments (Erasmus modification of the Nottingham Sensory Assessment [EmNSA-UE]) were measured in 215 patients within 3 weeks and at 5, 12, and 26 weeks after a first-ever ischemic stroke. The longitudinal association between FM-UE and EmNSA-UE was examined in patients with motor and somatosensory impairments (FM-UE ≤ 60 and EmNSA-UE ≤ 37) at baseline. Results. A total of 94 patients were included in the longitudinal analysis. EmNSA-UE increased significantly up to 12 weeks poststroke. The longitudinal association between motor and somatosensory impairment disappeared when correcting for progress of time and was not significantly different for patients with severe baseline somatosensory impairment. Patients with a FM-UE score ≥18 at 26 weeks (n = 55) showed a significant positive association between motor and somatosensory impairments, irrespective of progress of time. Conclusions. Progress of time, as a reflection of spontaneous neurobiological recovery, is an important factor that drives recovery of upper-limb motor as well as somatosensory impairments in the first 12 weeks poststroke. Severe somatosensory impairment at baseline does not directly compromise motor recovery. The study rather suggests that spontaneous recovery of somatosensory impairment is a prerequisite for full motor recovery of the upper paretic limb.

Is Resting-State EEG Longitudinally Associated With Recovery of Clinical Neurological Impairments Early Poststroke? A Prospective Cohort Study.

Background. The time course of cortical activation and its relation with clinical measures may elucidate mechanisms underlying spontaneous neurobiological recovery after stroke. Objective. We aimed to investigate (1) the time course of cortical activation as revealed by EEG-based spectral characteristics during awake rest and (2) the development of these spectral characteristics in relation to global neurological and upper-limb motor recovery in the first 6 months poststroke. Methods. Resting-state EEG was measured serially in 41 patients after a first-ever ischemic stroke, within 3 and at 5, 12, and 26 weeks poststroke. We computed the brain symmetry index (BSI) and directional BSI (BSIdir) over different frequency bands (1-25 Hz, delta, theta) and delta/alpha ratio (DAR). The National Institutes of Health Stroke Scale (NIHSS) and Fugl-Meyer motor assessment of the upper extremity (FM-UE) were determined as clinical reflections of spontaneous neurobiological recovery. Longitudinal changes in spectral characteristics and within- and between-subject associations with NIHSS and FM-UE were analyzed with linear mixed models. Results. Spectral characteristics showed a gradual normalization over time, within and beyond 12 weeks poststroke. Significant within- and between-subject associations with NIHSS were found for DAR of the affected hemisphere (DARAH) and BSIdirdelta. BSIdirdelta also demonstrated significant within- and between-subject associations with FM-UE. Conclusions. Changes in spectral characteristics are not restricted to the time window of recovery of clinical neurological impairments. The present study suggests that decreasing DARAH and BSIdirdelta reflect improvement of global neurological impairments, whereas BSIdirdelta was also specifically associated with upper-limb motor recovery early poststroke.

Position-Cortical Coherence as a Marker of Afferent Pathway Integrity Early Poststroke: A Prospective Cohort Study.

Background. Addressing the role of somatosensory impairment, that is, afferent pathway integrity, in poststroke motor recovery may require neurophysiological assessment. Objective. We investigated the longitudinal construct validity of position-cortical coherence (PCC), that is, the agreement between mechanically evoked wrist perturbations and electroencephalography (EEG), as a measure of afferent pathway integrity. Methods. PCC was measured serially in 48 patients after a first-ever ischemic stroke in addition to Fugl-Meyer motor assessment of the upper extremity (FM-UE) and Nottingham Sensory Assessment hand-finger subscores (EmNSA-HF, within 3 and at 5, 12, and 26 weeks poststroke. Changes in PCC over time, represented by percentage presence of PCC (%PCC), mean amplitude of PCC over the affected (Amp-A) and nonaffected hemisphere (Amp-N) and a lateralization index (L-index), were analyzed, as well as their association with FM-UE and EmNSA-HF. Patients were retrospectively categorized based on FM-UE score at baseline and 26 weeks poststroke into high- and low-baseline recoverers and non-recoverers. Results. %PCC increased from baseline to 12 weeks poststroke (ß = 1.6%, CI = 0.32% to 2.86%, P = .01), which was no longer significant after adjusting for EmNSA-HF and FM-UE. A significant positive association was found between %PCC, Amp-A, and EmNSA-HF. Low-baseline recoverers (n = 8) showed longitudinally significantly higher %PCC than high-baseline recoverers (n = 23). Conclusions. We demonstrated the longitudinal construct validity of %PCC and Amp-A as a measure of afferent pathway integrity. A high %PCC in low-baseline recoverers suggests that this measure also contains information on cortical excitability. Use of PCC as an EEG-based measure to address the role of somatosensory integrity to motor recovery poststroke requires further attention.

The effect of cerebellar transcranial direct current stimulation to improve standing balance performance early post-stroke, study protocol of a randomized controlled trial.

RATIONALE: Restoration of adequate standing balance after stroke is of major importance for functional recovery. POstural feedback ThErapy combined with Non-invasive TranscranIAL direct current stimulation (tDCS) in patients with stroke (POTENTIAL) aims to establish if cerebellar tDCS has added value in improving standing balance performance early post-stroke. METHODS: Forty-six patients with a first-ever ischemic stroke will be enrolled in this double-blind controlled trial within five weeks post-stroke. All patients will receive 15 sessions of virtual reality-based postural feedback training (VR-PFT) in addition to usual care. VR-PFT will be given five days per week for 1 h, starting within five weeks post-stroke. During VR-PFT, 23 patients will receive 25 min of cerebellar anodal tDCS (cb_tDCS), and 23 patients will receive sham stimulation. STUDY OUTCOME: Clinical, posturographic, and neurophysiological measurements will be performed at baseline, directly post-intervention, two weeks post-intervention and at 15 weeks post-stroke. The primary outcome measure will be the Berg Balance Scale (BBS) for which a clinical meaningful difference of six points needs to be established between the intervention and control group at 15 weeks post-stroke. DISCUSSION: POTENTIAL will be the first proof-of-concept randomized controlled trial to assess the effects of VR-PFT combined with cerebellar tDCS in terms of standing balance performance in patients early post-stroke. Due to the combined clinical, posturographical and neurophysiological measurements, this trial may give more insights in underlying post-stroke recovery processes and whether these can be influenced by tDCS.

Short-Term Effects of Cerebellar tDCS on Standing Balance Performance in Patients with Chronic Stroke and Healthy Age-Matched Elderly.

Transcranial direct current stimulation (tDCS) may serve as an adjunct approach in stroke rehabilitation. The cerebellum could be a target during standing balance training due to its role in motor adaptation. We tested whether cerebellar tDCS can lead to short-term effects on standing balance performance in patients with chronic stroke. Fifteen patients with a chronic stroke were stimulated with anodal stimulation on the contra-lesional cerebellar hemisphere, ipsi-lesional cerebellar hemisphere, or sham stimulation, for 20 min with 1.5 mA in three sessions in randomized order. Ten healthy controls participated in two sessions with cerebellar stimulation ipsi-lateral to their dominant leg or sham stimulation. During stimulation, subjects performed a medio-lateral postural tracking task on a force platform. Standing balance performance was measured directly before and after each training session in several standing positions. Outcomes were center of pressure (CoP) amplitude and its standard deviation, and velocity and its standard deviation and range, subsequently combined into a CoP composite score (comp-score) as a qualitative outcome parameter. In the patient group, a decrease in comp-score in the tandem position was found after contra-lesional tDCS: ß = - 0.25, CI = - 0.48 to - 0.03, p = 0.03. No significant differences in demographics and clinical characteristics were found between patients who responded (N = 10) and patients who did not respond (N = 5) to the stimulation. Contra-lesional cerebellar tDCS shows promise for improving standing balance performance. Exploration of optimal timing, dose, and the relation between qualitative parameters and clinical improvements are needed to establish whether tDCS can augment standing balance performance after stroke.

Poor motor function is associated with reduced sensory processing after stroke.

The possibility to regain motor function after stroke depends on the intactness of motor and sensory pathways. In this study, we evaluated afferent sensory pathway information transfer and processing after stroke with the coherence between cortical activity and a position perturbation (position-cortical coherence, PCC). Eleven subacute stroke survivors participated in this study. Subjects performed a motor task with the affected and non-affected arm while continuous wrist position perturbations were applied. Cortical activity was measured using EEG. PCC was calculated between position perturbation and EEG at the contralateral and ipsilateral sensorimotor area. The presence of PCC was quantified as the number of frequencies where PCC is larger than zero across the sensorimotor area. All subjects showed significant contralateral PCC in affected and non-affected wrist tasks. Subjects with poor motor function had a reduced presence of contralateral PCC compared with subjects with good motor function in the affected wrist tasks. Amplitude of significant PCC did not differ between subjects with good and poor motor function. Our results show that poor motor function is associated with reduced sensory pathway information transfer and processing in subacute stroke subjects. Position-cortical coherence may provide additional insight into mechanisms of recovery of motor function after stroke.