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.

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.

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.

Anatomical and functional correlates of cortical motor threshold of the dominant hand.

BACKGROUND: Resting Motor threshold (rMT) provides information about cortical motor excitability. Interestingly, the influences of the structural or functional variability of the motor system on the rMT inter-individual variability have been poorly investigated. OBJECTIVE/HYPOTHESIS: To investigate relationships between rMT and measures of brain structures and function of the motor system. The hypothesis is that cortical excitability not only depends on the primary motor cortex (M1) but also on the integration of information originating from its vicinity such as premotor (PMd and SMA) and post-central (S1) cortices. METHODS: We measured brain structures, including grey and white matter properties (cortical volume and fiber coherence respectively), and functional interaction (resting-state functional connectivity-FC) in areas contributing to the corticospinal tract axons, i. e, M1, S1, SMA and PMd in the dominant hemisphere of 21 healthy subjects. RESULTS: The rMT was inversely correlated with the FC between PMd and M1 (r = -0.496, 95%CI: -0.764; -0.081; p = 0.02) and the grey matter volume of the dominant hemisphere (r = -0.463, 95%CI: -0.746; -0.039; p = 0.03). The multiple regression analysis model retained the FC between M1 and PMd (coefficient: -25 ± 9) as well as the grey matter volume of the dominant hemisphere (coefficient: -0.15 ± 0.06) explaining 44% of the variance of the rMT (p: 0.005). When adding age and coil-to-cortex distance, two factors known to influence rMT, the model reached a R2 of 75% (p: 0.0001). CONCLUSIONS: These results underline the major role of the PMd and the cortico-cortical connections toward M1 in the excitation of the corticospinal fibers likely through trans-synaptic pathways.