Cerebello-Motor Paired Associative Stimulation and Motor Recovery in Stroke: a Randomized, Sham-Controlled, Double-Blind Pilot Trial.

Cerebellum is a key structure for functional motor recovery after stroke. Enhancing the cerebello-motor pathway by paired associative stimulation (PAS) might improve upper limb function. Here, we conducted a randomized, double-blind, sham-controlled pilot trial investigating the efficacy of a 5-day treatment of cerebello-motor PAS coupled with physiotherapy for promoting upper limb motor function compared to sham stimulation. The secondary objectives were to determine in the active treated group (i) whether improvement of upper limb motor function was associated with changes in corticospinal excitability or changes in functional activity in the primary motor cortex and (ii) whether improvements were correlated to the structural integrity of the input and output pathways. To that purpose, hand dexterity and maximal grip strength were assessed along with TMS recordings and multimodal magnetic resonance imaging, before the first treatment, immediately after the last one and a month later. Twenty-seven patients were analyzed. Cerebello-motor PAS was effective compared to sham in improving hand dexterity (p: 0.04) but not grip strength. This improvement was associated with increased activation in the ipsilesional primary motor cortex (p: 0.04). Moreover, the inter-individual variability in clinical improvement was partly explained by the structural integrity of the afferent (p: 0.06) and efferent pathways (p: 0.02) engaged in this paired associative stimulation (i.e., cortico-spinal and dentato-thalamo-cortical tracts). In conclusion, cerebello-motor-paired associative stimulation combined with physiotherapy might be a promising approach to enhance upper limb motor function after stroke.Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT02284087.

Music Restores Propriospinal Excitation During Stroke Locomotion.

Music-based therapy for rehabilitation induces neuromodulation at the brain level and improves the functional recovery. In line with this, musical rhythmicity improves post-stroke gait. Moreover, an external distractor also helps stroke patients to improve locomotion. We raised the question whether music with irregular tempo (arrhythmic music), and its possible influence on attention would induce neuromodulation and improve the post-stroke gait. We tested music-induced neuromodulation at the level of a propriospinal reflex, known to be particularly involved in the control of stabilized locomotion; after stroke, the reflex is enhanced on the hemiparetic side. The study was conducted in 12 post-stroke patients and 12 controls. Quadriceps EMG was conditioned by electrical stimulation of the common peroneal nerve, which produces a biphasic facilitation on EMG, reflecting the level of activity of the propriospinal reflex between ankle dorsiflexors and quadriceps (CPQ reflex). The CPQ reflex was tested during treadmill locomotion at the preferred speed of each individual, in 3 conditions randomly alternated: without music vs. 2 arrhythmic music tracks, including a pleasant melody and unpleasant aleatory electronic sounds (AES); biomechanical and physiological parameters were also investigated. The CPQ reflex was significantly larger in patients during walking without sound, compared to controls. During walking with music, irrespective of the theme, there was no more difference between groups. In controls, music had no influence on the size of CPQ reflex. In patients, CPQ reflex was significantly larger during walking without sound than when listening to the melody or AES. No significant differences have been revealed concerning the biomechanical and the physiological parameters in both groups. Arrhythmic music listening modulates the spinal excitability during post-stroke walking, restoring the CPQ reflex activity to normality. The plasticity was not accompanied by any clear improvement of gait parameters, but the patients reported to prefer walking with music than without. The role of music as external focus of attention is discussed. This study has shown that music can modulate propriospinal neural network particularly involved in the gait control during the first training session. It is speculated that repetition may help to consolidate plasticity and would contribute to gait recovery after stroke.

Elucidating the Structural and Functional Correlates of Upper-Limb Poststroke Motor Impairment.

Background and Purpose- Many studies have attempted to bring to light the neural correlates of poststroke motor impairment, but few have used multimodal approach to explain it. The aim of this study was to elucidate neural structural and functional correlates of upper limb motor impairment by combining electrophysiological, anatomic, and functional neuroimaging data. Methods- Forty ischemic stroke patients (median [min-max] age: 63 [33-82] years, time poststroke: 3.5 [1.1-58] months) with unilateral upper limb weakness were included. The upper limb motor impairment was defined by a motor composite score. Simple linear analysis followed by multiple linear regression analysis were performed to identify which variables (corticospinal excitability, laterality indices within the primary motor cortex or corticospinal [CST], and corpus callosum tracts integrity) were the best explaining factors of upper limb motor impairment. Results- There was a significant correlation between the resting motor threshold ratio and CST damage (r= -0.50 [95% CI, -0.70 to -0.22]; P<0.001) as well as the motor-evoked potentials amplitude (r= -0.73 [95% CI, -0.85 to -0.54]; P<0.001). Only the resting motor threshold ratio was retained by the multiple regression model and explained half of the variance (49%; P<0.001) of the upper limb motor impairment after stroke. Conclusions- The implementation of quantitative neurophysiological measurements such as the resting motor threshold as a surrogate marker of impairment could be considered in neurorehabilitation trials.

Redundancy Among Parameters Describing the Input-Output Relation of Motor Evoked Potentials in Healthy Subjects and Stroke Patients.

Background: Transcranial magnetic stimulation (TMS) is widely used to probe corticospinal excitability through Motor Evoked Potential (MEP) amplitude measurements. The input-output (I/O) curve is a sigmoid-shaped relation between the MEP amplitude at incremented TMS intensities. The aim of this study was to examine the relationships between seven parameters derived from the sigmoid function. Methods: Principal Component Analysis and Spearman's rank correlation matrices were used to determine if the seven I/O curve parameters capture similar or, conversely, different aspects of the corticospinal excitability in 24 healthy subjects and 40 stroke survivors with a hand motor impairment. Results: Maximum amplitude (MEPmax), peak slope, area under the I/O curve (AUC), and MEP amplitude recorded at 140% of the resting motor threshold showed strong linear relationships with each other (ρ > 0.72, p < 0.001). Results were found to be similar in healthy subjects and in both hemispheres of stroke patients. Our results did not support an added benefit of sampling entire I/O curves in both healthy subjects and stroke patients, with the exception of S50, the stimulus intensity needed to obtain half of MEPmax amplitude. Conclusions: This demonstrates that MEP elicited at a single stimulus intensity allows to capture the same characteristics of the corticospinal excitability as measured by the AUC, MEPmax and the peak slope, which may be of interest in both clinical and research settings. However, it is still necessary to plot I/O curves if an effect or a difference is expected at S50.

Closed-Loop Control of the Centre of Pressure in Post-Stroke Patients With Balance Impairments.

When a lightly touched surface is moved according to a closed-loop control law, it has been shown in young adults that the centre of pressure (CoP) can be displaced in a controllable way without the conscious cooperation of participants. In this closed-loop paradigm, the surface velocity was continuously adjusted according to the CoP position. Since the closed-loop control of the CoP does not require the participant's voluntary cooperation, it could be of interest for the development of innovative biofeedback devices in balance rehabilitation. Before anticipating the implementation of this closed-loop control paradigm with patients, it is necessary to establish its effects on people suffering from balance impairments. The aim of this paper was to assess the effects of this CoP closed-loop control in post-stroke (PS) patients and aged-matched healthy controls. Efficacy of the closed-loop control for driving the patients' CoP was assessed using the saturation time and two scores computing the error between the predefined and the current CoP trajectories. 68% and 83% of the trials were considered as successful in patients and controls, respectively. The global tracking error of the closed-loop score was similar between the two groups. However, when examining the real CoP displacement from the starting position to the desired one, PS patients responded to the closed-loop control to a lesser extent than controls. These results, obtained in the same conditions for healthy and PS individuals could be improved by tuning the closed-loop parameters according to individual characteristics. This paper paves the road towards the development of involuntary/automatic biofeedback techniques in more ecological conditions.

Comparison of spatial normalization strategies of diffusion MRI data for studying motor outcome in subacute-chronic and acute stroke.

A common means of studying motor recovery in stroke patients is to extract Diffusion Tensor Imaging (DTI) parameters from the corticospinal tract (CST) and correlate them with clinical outcome scores. To that purpose, conducting group-level analyses through spatial normalization has become a popular approach. However, the reliability of such analyses depends on the accuracy of the particular registration strategy employed. To date, most studies have employed scalar-based registration using either high-resolution T1 images or Fractional Anisotropy (FA) maps to warp diffusion data to a common space. However, more powerful registration algorithms exist for aligning major white matter structures, such as Fiber Orientation Distribution (FOD)-based registration. Regardless of the strategy chosen, automatic normalization algorithms are prone to distortions caused by stroke lesions. While lesion masking is a common means to lessen such distortions, the extent of its effect on tract-related DTI parameters and their correlation with motor outcome has yet to be determined. Here, we aimed to address these concerns by first investigating the effect of common T1 and FA-based registration as well as novel FOD-based registration algorithms with and without lesion masking on lesion load and DTI parameter extraction of the CST in datasets typically acquired for subacute-chronic and acute stroke patients. Second, we studied how differences in these procedures influenced correlation strength between CST damage (through DTI parameters) and motor outcome. Our results showed that, for high-quality subacute-chronic stroke data, FOD-based registration captured significantly higher lesion loads and significantly larger FA asymmetries in the CST. This was also associated with significantly stronger correlations in motor outcome with respect to T1 or FA-based registration methods. For acute data acquired in a clinical setting, there were few observed differences, suggesting that commonly employed FA-based registration is appropriate for group-level analyses.

Cerebello-Cortical Differences in Effective Connectivity of the Dominant and Non-dominant Hand during a Visuomotor Paradigm of Grip Force Control.

Structural and functional differences are known to exist within the cortical sensorimotor networks with respect to the dominant vs. non-dominant hand. Similarly, the cerebellum, a key structure in the sensorimotor network with its cerebello-cortical connections, has been reported to respond differently when using the dominant vs. non-dominant hand. Several groups have already investigated causal interactions during diverse motor paradigms using effective connectivity but few have studied the larger visuomotor network, including key structures such as the parietal cortex and the cerebellum, with both hands. Moreover, the effect of force level on such interactions is still unclear. We therefore sought to determine the hemispheric asymmetries in the cerebello-cortical sensorimotor network in right-handers at two force levels (5% and 10% maximum voluntary contraction) for both hands. Cerebello-cortical modulations were investigated in 28 healthy, right-handed volunteers by determining the effective connectivity during a visuomotor task at two force levels under fMRI. A network was built consisting of the left and right primary motor (M1), ventral premotor (PMv) and posterior parietal cortices (PPC), in addition to the supplementary motor area (SMA), and the ipsilateral cerebellum (Cer) to the hand performing the motor task. Task performance (precision of isometric grip force tracking) did not differ between hands, nor did task-related activations in the sensorimotor areas apart from the contralateral primary motor cortex. However, during visuomotor control of the non-dominant hand, connectivity analysis revealed causal modulations between (i) the ipsilateral cerebellum and SMA, and (ii) the ipsilatearl cerebellum and contralateral PPC, which was not the case when using the dominant hand. These cerebello-cortical modulations for the non-dominant hand were more present at the higher of the two force levels. We conclude that precision force generation executed with the non-dominant hand, compared to the dominant hand, may require enhanced cerebello-cortical interaction to ensure equivalent left-right task performance.

Do Motor Imagery Performances Depend on the Side of the Lesion at the Acute Stage of Stroke?

Motor imagery has been considered a substitute for overt motor execution to study post-stroke motor recovery. However, motor imagery abilities at the acute stage (<3 weeks) are poorly known. The aim of this study was to compare explicit and implicit motor imagery abilities in stroke patients and healthy subjects, correlate them with motor function, and investigate the role of right or left hemisphere lesions on performance. Twenty-four stroke patients at the acute stage and 24 age- and gender-matched healthy volunteers performed implicit (Hand Laterality Judgment Task) and explicit (number of imagined/executed hand movements) motor imagery tasks and a clinical motor assessment. Differences between healthy subjects and patients as well as the impact of lesion side on motor imagery were studied using ANOVA. We analyzed the relationship between motor executed and imagined movements (temporal congruence) using Pearson correlations. Our study shows that for implicit imagery, stroke patients had slower reaction times [RTs, t(46) = 1.7, p = 0.02] and higher error rates for the affected hand [t(46) = 3.7, p < 0.01] yet shared similar characteristics [angle effect: F(1,46) = 30.8, p ≤ 0.0001] with respect to healthy subjects. For the unaffected hand, right-sided stroke patients had a higher error rate and similar RTs whereas left sided stroke had higher RTs but similar error rate than healthy subjects. For explicit imagery, patients exhibited bilateral deficits compared to healthy subjects in the executed and imagined condition (p < 0.0001). Patients and healthy subjects exhibited a temporal congruence between executed and imagined movements (p ≤ 0.04) except for right-sided strokes who had no correlation for both hands. When using motor imagery as a tool for upper limb rehabilitation early after stroke, caution must be taken related to the side of the lesion.

Complex muscle vibration patterns to induce gait-like lower-limb movements: proof of concept.

Muscle vibrations can induce motor responses and illusions of complex movements. However, inducing gait-like cyclical movements and illusions requires the application of multiple fast alternating vibrations to lower-limb muscles. The objectives were (1) to test the feasibility of delivering complex vibrations in a time-organized manner and (2) to illustrate the possibility of inducing alternate gait-in-place-like movements using these vibrations. Patterns of vibration, produced by 12 vibrators applied bilaterally on the flexor and extensor muscle groups of the lower limbs, were based on normal gait kinematics. We tested 1 s and 2 s cycle patterns of vibration. Vibrator responses were assessed using auto- and crosscorrelations and frequency analyses based on accelerometry measurements, and compared between patterns. High auto- (>0.8) and crosscorrelation (>0.6) coefficients demonstrated a good response by the vibrators to the control signal. Vibrations induced cyclical, low-amplitude stepping-in-place movements that mimicked alternate walking movements with both legs, with 1 s and 2 s cycle durations, in one nondisabled participant and one participant with American Spinal Injury Association Impairment Scale B spinal cord injury standing, relaxed, with body-weight support. Electromechanical vibrators can deliver complex cyclical vibrations and trigger gait-like lower-limb movements. These results warrant the application of these vibration patterns on individuals with sensorimotor impairments to test their potential in gait rehabilitation.