Cortico-cortical stimulation and robot-assisted therapy (CCS and RAT) for upper limb recovery after stroke: study protocol for a randomised controlled trial.

BACKGROUND: Since birth, during the exploration of the environment to interact with objects, we exploit both the motor and sensory components of the upper limb (UL). This ability to integrate sensory and motor information is often compromised following a stroke. However, to date, rehabilitation protocols are focused primarily on recovery of motor function through physical therapies. Therefore, we have planned a clinical trial to investigate the effect on functionality of UL after a sensorimotor transcranial stimulation (real vs sham) in add-on to robot-assisted therapy in the stroke population. METHODS: A randomised double-blind controlled trial design involving 32 patients with a single chronic stroke (onset > 180 days) was planned. Each patient will undergo 15 consecutive sessions (5 days for 3 weeks) of paired associative stimulation (PAS) coupled with UL robot-assisted therapy. PAS stimulation will be administered using a bifocal transcranial magnetic stimulator (TMS) on the posterior-parietal cortex and the primary motor area (real or sham) of the lesioned hemisphere. Clinical, kinematics and neurophysiological changes will be evaluated at the end of protocol and at 1-month follow-up and compared with baseline. The Fugl-Meyer assessment scale will be the primary outcome. Secondly, kinematic variables will be recorded during the box-and-block test and reaching tasks using video analysis and inertial sensors. Single pulse TMS and electroencephalography will be used to investigate the changes in local cortical reactivity and in the interconnected areas. DISCUSSION: The presented trial shall evaluate with a multimodal approach the effects of sensorimotor network stimulation applied before a robot-assisted therapy training on functional recovery of the upper extremity after stroke. The combination of neuromodulation and robot-assisted therapy can promote an increase of cortical plasticity of sensorimotor areas followed by a clinical benefit in the motor function of the upper limb. TRIAL REGISTRATION: ClinicalTrials.gov NCT05478434. Registered on 28 Jul 2022.

Convergent Validity of the Timed Walking Tests with Functional Ambulatory Category in Subacute Stroke.

Determining the walking ability of post-stroke patients is crucial for the design of rehabilitation programs and the correct functional information to give to patients and their caregivers at their return home after a neurorehabilitation program. We aimed to assess the convergent validity of three different walking tests: the Functional Ambulation Category (FAC) test, the 10-m walking test (10MeWT) and the 6-minute walking test (6MWT). Eighty walking participants with stroke (34 F, age 64.54 ± 13.02 years) were classified according to the FAC score. Gait speed evaluation was performed with 10MeWT and 6MWT. The cut-off values for FAC and walking tests were calculated using a receiver-operating characteristic (ROC) curve. Area under the curve (AUC) and Youden's index were used to find the cut-off value. Statistical differences were found in all FAC subgroups with respect to walking speed on short and long distances, and in the Rivermead Mobility Index and Barthel Index. Mid-level precision (AUC > 0.7; p < 0.05) was detected in the walking speed with respect to FAC score (III vs. IV and IV vs. V). The confusion matrix and the accuracy analysis showed that the most sensitive test was the 10MeWT, with cut-off values of 0.59 m/s and 1.02 m/s. Walking speed cut-offs of 0.59 and 1.02 m/s were assessed with the 10MeWT and can be used in FAC classification in patients with subacute stroke between the subgroups able to walk with supervision and independently on uniform and non-uniform surfaces. Moreover, the overlapping walking speed registered with the two tests, the 10MeWT showed a better accuracy to drive FAC classification.

Combining Robot-Assisted Gait Training and Non-Invasive Brain Stimulation in Chronic Stroke Patients: A Systematic Review.

Gait impairment is one of the most common disorders of patients with chronic stroke, which hugely affects the ability to carry out the activities of daily living and the quality of life. Recently, traditional rehabilitation techniques have been associated with non-invasive brain stimulation (NIBS) techniques, which enhance brain plasticity, with the aim of promoting recovery in patients with chronic stroke. NIBS effectiveness in improving gait parameters in patients with chronic stroke has been in several studies evaluated. Robotic devices are emerging as promising tools for the treatment of stroke-related disabilities by performing repetitive, intensive, and task-specific treatments and have been proved to be effective for the enhancement of motor recovery in patients with chronic stroke. To date, several studies have examined the combination of NIBS with robotic-assisted gait training, but the effectiveness of this approach is not yet well established. The main purpose of this systematic review is to clarify whether the combination of NIBS and robot-assisted gait training may improve walking function in patients with chronic stroke. Our systematic review was conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Studies eligible for review were identified through PubMed/MEDLINE, Embase, Scopus, and PEDro from inception to March 15, 2021, and the outcomes considered were gait assessments. Seven studies were included in the qualitative analysis of this systematic review, with a total population of 186 patients with chronic stroke. All studies specified technical characteristics of robotic devices and NIBS used, with high heterogeneity of protocols. Methodological studies have shown a significantly greater improvement in walking capacity recorded with 6MWT. Finally, research studies have highlighted a positive effect on walking recovery by combination of robot-assisted gait training with non-invasive brain stimulation. Furthermore, future studies should identify the best characteristics of the combined therapeutic protocols. Systematic Review Registration: CRD42021244869.

Intermittent Cerebellar Theta Burst Stimulation Improves Visuo-motor Learning in Stroke Patients: a Pilot Study.

The cerebellum plays a critical role in promoting learning of new motor tasks, which is an essential function for motor recovery. Repetitive transcranial magnetic stimulation (rTMS) of the cerebellum can be used to enhance learning. In this study, we investigated the effects of cerebellar intermittent theta burst stimulation (c-iTBS), a high-frequency rTMS protocol, on visuo-motor learning in a sample of hemiparetic patients due to recent stroke in the territory of the contralateral middle cerebral artery. Eight stroke patients were enrolled for the purposes of the study in the chronic stage of recovery (i.e., at least 6 months after stroke). In two sessions, Patients were randomly assigned to treatment with real or sham c-iTBS applied over the cerebellar hemisphere ipsilateral to the affected body side. c-iTBS was applied immediately before the learning phase of a visuo-motor adaptation task. Real, but not sham, c-iTBS improved visuo-motor learning as revealed by an increased performance in of the learning phase of the visuo-moto adaptation task. Moreover, we also found that real but not sham c-iTBS induced a sustained improvement in the re-adaptation of the recently learned skill (i.e., when patients were re-tested after 30 min). Taken together, these data point to c-iTBS as a potential novel strategy to promote motor learning in patients with stroke.

Improving visuo-motor learning with cerebellar theta burst stimulation: Behavioral and neurophysiological evidence.

The cerebellum is strongly implicated in learning new motor skills. Theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation, can be used to influence cerebellar activity. Our aim was to explore the potential of cerebellar TBS in modulating visuo-motor adaptation, a form of motor learning, in young healthy subjects. Cerebellar TBS was applied immediately before the learning phase of a visuo-motor adaptation task (VAT), in two different experiments. Firstly, we evaluated the behavioral effects of continuous (cTBS), intermittent (iTBS) or sham TBS on the learning, re-adaptation and de-adaptation phases of VAT. Subsequently, we investigated the changes induced by iTBS or sham TBS on motor cortical activity related to each phase of VAT, as measured by concomitant TMS/EEG recordings. We found that cerebellar TBS induced a robust bidirectional modulation of the VAT performance. More specifically, cerebellar iTBS accelerated visuo-motor adaptation, by speeding up error reduction in response to a novel perturbation. This gain of function was still maintained when the novel acquired motor plan was tested during a subsequent phase of re-adaptation. On the other hand, cerebellar cTBS induced the opposite effect, slowing the rate of error reduction in both learning and re-adaptation phases. Additionally, TMS/EEG recordings showed that cerebellar iTBS induced specific changes of cortical activity in the interconnected motor networks. The improved performance was accompanied by an increase of TMS-evoked cortical activity and a generalized desynchronization of TMS-evoked cortical oscillations. Taken together, our behavioral and neurophysiological findings provide the first-time multimodal evidence of the potential efficacy of cerebellar TBS in improving motor learning, by promoting successful cerebellar-cortical reorganization.

Effect of Cerebellar Stimulation on Gait and Balance Recovery in Patients With Hemiparetic Stroke: A Randomized Clinical Trial.

Importance: Gait and balance impairment is associated with poorer functional recovery after stroke. The cerebellum is known to be strongly implicated in the functional reorganization of motor networks in patients with stroke, especially for gait and balance functions. Objective: To determine whether cerebellar intermittent θ-burst stimulation (CRB-iTBS) can improve balance and gait functions in patients with hemiparesis due to stroke. Design, Setting, Participants: This randomized, double-blind, sham-controlled phase IIa trial investigated efficacy and safety of a 3-week treatment of CRB-iTBS coupled with physiotherapy in promoting gait and balance recovery in patients with stroke. Thirty-six patients with consecutive ischemic chronic stroke in the territory of the contralateral middle cerebral artery with hemiparesis were recruited from a neuro-rehabilitation hospital. Participants were screened and enrolled from March 2013 to June 2017. Intention-to-treat analysis was performed. Interventions: Patients were randomly assigned to treatment with CRB-iTBS or sham iTBS applied over the cerebellar hemisphere ipsilateral to the affected body side immediately before physiotherapy daily during 3 weeks. Main Outcomes and Measures: The primary outcome was the between-group difference in change from baseline in the Berg Balance Scale. Secondary exploratory measures included the between-group difference in change from baseline in Fugl-Meyer Assessment scale, Barthel Index, and locomotion assessment with gait analysis and cortical activity measured by transcranial magnetic stimulation in combination with electroencephalogram. Results: A total of 34 patients (mean [SD] age, 64 [11.3] years; 13 women [38.2%]) completed the study. Patients treated with CRB-iTBS, but not with sham iTBS, showed an improvement of gait and balance functions, as revealed by a pronounced increase in the mean (SE) Berg Balance Scale score (baseline: 34.5 [3.4]; 3 weeks after treatment: 43.4 [2.6]; 3 weeks after the end of treatment: 47.5 [1.8]; P < .001). No overall treatment-associated differences were noted in the Fugl-Meyer Assessment (mean [SE], baseline: 163.8 [6.8]; 3 weeks after treatment: 171.1 [7.2]; 3 weeks after the end of treatment: 173.5 [6.9]; P > .05) and Barthel Index scores (mean [SE], baseline: 71.1 [4.92]; 3 weeks after treatment: 88.8 [2.1]; 3 weeks after the end of treatment: 92.2 [2.4]; P > .05). Patients treated with CRB-iTBS, but not sham iTBS, showed a reduction of step width at the gait analysis (mean [SE], baseline: 16.8 [4.8] cm; 3 weeks after treatment: 14.3 [6.2] cm; P < .05) and an increase of neural activity over the posterior parietal cortex. Conclusions and Relevance: Cerebellar intermittent θ-burst stimulation promotes gait and balance recovery in patients with stroke by acting on cerebello-cortical plasticity. These results are important to increase the level of independent walking and reduce the risk of falling. Trial Registration: ClinicalTrials.gov Identifier: NCT03456362.

Osteopathic Manipulative Therapy Potentiates Motor Cortical Plasticity.

CONTEXT: Osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) is effective in managing pain caused by a variety of clinical conditions. Nevertheless, the physiologic mechanisms at the basis of the clinical improvement are poorly understood. OBJECTIVE: To investigate the effects of OMTh, muscle stretching, and soft touch interventions on motor cortical excitability through a rapid-rate paired associative stimulation (PAS) protocol. METHODS: In this crossover study, participants underwent OMTh, muscle stretching, and soft touch interventions. A rapid-rate PAS transcranial magnetic stimulation protocol was performed immediately after each intervention session, which consisted of 600 pairs of stimuli continuously delivered to the left primary motor cortex and to the right median nerve at a rate of 5 Hz for 2 minutes. The interstimulus intervals between the peripheral stimulus and the transcranial magnetic stimulation was set at 25 milliseconds. Before and after rapid-rate PAS (immediately after and 15 minutes after), changes in the amplitude of the motor evoked potentials were measured in the right abductor pollicis brevis and the right first dorsal interosseous. RESULTS: Of the potential 15 participants initially recruited, 12 fit the inclusion criteria. Two of the 12 participants were excluded from the final analysis because of excessive artifact movements. Rapid-rate PAS induced a more pronounced, longer-lasting increase in cortical excitability in the abductor pollicis brevis muscle in patients 15 minutes after the OMTh intervention than after the muscle stretching or sham interventions (P=.016). CONCLUSION: Results of the current study provide support for the effects of OMTh on cortical plasticity.

Dynamic reorganization of TMS-evoked activity in subcortical stroke patients.

Since early days after stroke, the brain undergoes a complex reorganization to allow compensatory mechanisms that promote functional recovery. However, these mechanisms are still poorly understood and there is urgent need to identify neurophysiological markers of functional recovery after stroke. Here we aimed to track longitudinally the time-course of cortical reorganization by measuring for the first time EEG cortical activity evoked by TMS pulses in patients with subcortical stroke. Thirteen patients in the sub-acute phase of ischemic subcortical stroke with motor symptoms completed the longitudinal study, being evaluated within 20 days and after 40, 60 and 180 days after stroke onset. For each time-point, EEG cortical activity evoked by single TMS pulses was assessed over the motor and parietal cortex of the affected and unaffected hemisphere. We evaluated global TMS-evoked activity and TMS-evoked oscillations in different frequency bands. These measurements were paralleled with clinical and behavioral assessment. We found that motor cortical activity measured by TMS-EEG varied across time in the affected hemisphere. An increase of TMS-evoked activity was evident at 40 days after stroke onset. Moreover, stroke patients showed a significant increase in TMS-evoked alpha oscillations, as highlighted performing analysis in the time-frequency domain. Notably, these changes indicated that crucial mechanisms of cortical reorganization occur in this short-time window. These changes coincided with the clinical improvement. TMS-evoked alpha oscillatory activity recorded at baseline was associated to better functional recovery at 40 and 60 days' follow-up evaluations, suggesting that the power of the alpha rhythm can be considered a good predictor of motor recovery. This study demonstrates that cortical activity increases dynamically in the early phases of recovery after stroke in the affected hemisphere. These findings point to TMS-evoked alpha oscillatory activity as a potential neurophysiological markers of stroke recovery and could be helpful to determine the temporal window in which neuromodulation should be potentially able to drive neuroplasticity in an effective functional direction.