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

Abstract

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.

Figure 1.. Experimental Design and Methods

Clinical evaluation, gait analysis, and transcranial magnetic stimulation (TMS) with electroencephalogram (EEG) were performed at baseline (T0), after 3 weeks of treatment (T1), and 3 weeks after the end of treatment (T2) (A). The treatment consisted of 3 weeks of daily cerebellar intermittent θ-burst stimulation (CRB-iTBS) or sham iTBS preceding the physiotherapy session. θ-Burst stimulation was applied over the cerebellum contralateral to the hemisphere affected by the stroke in the territory of the middle cerebral artery (B). Cortical activity was evaluated with TMS-EEG over primary motor cortex (M1) and posterior parietal cortex (PPC) of both affected and unaffected hemispheres (C) in terms of oscillatory activity (right upper panel, C) and TMS-evoked potentials (right lower panel, C).

Figure 2.. CONSORT Flow Diagram for Randomization of Patients With Stroke Enrolled in the Study

iTBS indicates intermittent θ-burst stimulation.

Figure 3.. Clinical Scores and Gait Analysis

Berg Balance Scale (BBS), Fugl-Mayer Assessment (FMA), and Barthel Index (BI) mean scores and effectiveness for the cerebellar intermittent θ-burst stimulation (CRB-iTBS) and sham iTBS group at baseline (T0), 3 weeks after treatment (T1), and 3 weeks after the end of the treatment (T2) (A). Patients who underwent CRB-iTBS coupled with physiotherapy showed a significant increase in BBS score after the TBS treatment (T1), which was still significant at T2. B, Step length (vertical lines) and step width (horizontal lines) in the CRB-iTBS and sham iTBS group, before (upper plots) and after (below plots) the 3-week cerebellar TBS treatment. Triangles and circles respectively depict the start and the final point from which the step is measured. Patients who underwent CRB-iTBS coupled with physiotherapy showed a significant reduction of the step width after the TBS treatment. Error bars indicate standard error of the mean. ^aP < .05.

Figure 4.. Cortical Activity

Global mean field power (A) and oscillatory activity (B) evoked from the affected hemisphere–primary motor cortex (M1) and affected hemisphere–posterior parietal cortex (PPC) of the cerebellar intermittent θ-burst stimulation (CRB-iTBS) and sham iTBS group. Light brown and dark brown lines depict the activity evoked before and after the 3-week cerebellar TBS treatment, respectively. Light blue and dark blue lines depict the activity evoked before and after the sham iTBS, respectively. Patients who underwent CRB-iTBS coupled with physiotherapy showed a significant increase of PPC neural activity (A) and θ oscillations (B) after the TBS treatment. C, 3-Dimensional plots of the correlations between step width (x-axis), cortical activity (global mean field power, y-axis) and Berg Balance Scale (BBS, z-axis) in the CRB-iTBS and sham iTBS group. Patients receiving CRB-iTBS with the highest recovery at the BBS (y-axis) were the ones who showed a greater reduction of step width (x-axis) and stronger PPC global mean field power (GMFP) (z-axis). TMS indicates transcranial magnetic stimulation. P1, P2, P3, and P4 indicate the first 4 peaks of the global mean field power waveform. ^aP < .05.