Inhibition versus facilitation of contralesional motor cortices in stroke: Deriving a model to tailor brain stimulation

Abstract

Objective: The standard approach to brain stimulation in stroke is based on the premise that ipsilesional M1 (iM1) is important for motor function of the paretic upper limb, while contralesional cortices compete with iM1. Therefore, the approach typically advocates facilitating iM1 and/or inhibiting contralesional M1 (cM1). But, this approach fails to elicit much improvement in severely affected patients, who on account of extensive damage to ipsilesional pathways, cannot rely on iM1. These patients are believed to instead rely on the undamaged cortices, especially the contralesional dorsal premotor cortex (cPMd), for support of function of the paretic limb. Here, we tested for the first time whether facilitation of cPMd could improve paretic limb function in severely affected patients, and if a cut-off could be identified to separate responders to cPMd from responders to the standard approach to stimulation.

Methods: In a randomized, sham-controlled crossover study, fifteen patients received the standard approach of stimulation involving inhibition of cM1 and a new approach involving facilitation of cPMd using repetitive transcranial magnetic stimulation (rTMS). Patients also received rTMS to control areas. At baseline, impairment [Upper Extremity Fugl-Meyer (UEFMPROXIMAL, max=36)] and damage to pathways [fractional anisotropy (FA)] was measured. We measured changes in time to perform proximal paretic limb reaching, and neurophysiology using TMS.

Results: Facilitation of cPMd generated more improvement in severely affected patients, who had experienced greater damage and impairment than a cut-off value of FA (0.5) and UEFMPROXIMAL (26-28). The standard approach instead generated more improvement in mildly affected patients. Responders to cPMd showed alleviation of interhemispheric competition imposed on iM1, while responders to the standard approach showed gains in ipsilesional excitability in association with improvement.

Conclusions: A preliminary cut-off level of severity separated responders for standard approach vs. facilitation of cPMd.

Significance: Cut-offs identified here could help select candidates for tailored stimulation in future studies so patients in all ranges of severity could potentially achieve maximum benefit in function of the paretic upper limb.

Keywords: Diffusion tensor imaging; Motor cortex; Neuronal plasticity; Premotor cortex; Rehabilitation; Stroke; Transcranial magnetic stimulation.

Conflict of interest statement

Conflict of interest

Andre G. Machado has the following conflict of interests to disclose: being a consultant of functional neuromodulation at St Jude; having distribution rights at Enspire, ATI, and Cardionomics; having fellowship support from Medtronic. Unrelated to present work, Adriana B. Conforto has the following conflict of interests to disclose: as a consultant at BMS/Pfizer and Bayer. Other authors have no conflict of interests to disclose.

Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1

Study design. Abbreviations: RT, reaching time; UEFM, Upper Extremity Fugl-Meyer; TMS, transcranial magnetic stimulation; DTI, diffusion tensor imaging; cM1, contralesional primary motor cortex; cPMd, contralesional dorsal premotor cortex; iPMd, ipsilesional dorsal premotor cortex; iM1, ipsilesional primary motor cortex. Note: To facilitate iM1, we used a standard approach that involved inhibition of cM1 using 1Hz rTMS.

Fig. 2

Outcomes and Neurophysiology. Abbreviations: MEP, motor evoked potential; EMG, electromyography; AMT, active motor threshold; iSP, ipsilateral silent period. (A) Outcomes are recorded as time to perform proximal reaching at the paretic upper limb, or reaching time (B) Neurophysiology is studied as changes in corticospinal output and interhemispheric inhibition imposed on iM1 from contralesional motor cortices. Corticospinal output is computed as percent change in amplitude of (normalized) MEPs from pre- to post-rTMS, while patients maintained 20%–50% maximum volitional contraction of the contralateral (paretic) target muscle (top panel). Interhemispheric inhibition is calculated as percent change in iSP relative to mean prestimulus EMG from pre- to post-rTMS, while patients maintained 50% maximum volitional contraction of the ipsilateral (paretic) target muscle (bottom panel).

Fig. 3

Main experiment — Outcomes. Abbreviations: RT, reaching time; MEP, motor evoked potential; cPMd, contralesional dorsal premotor cortex; FA, fractional anisotropy; UEFM, Upper Extremity Fugl-Meyer. Change in RT performance (ms or %) vs (A) Baseline impairment (UEFMPROXIMAL), (B) Baseline damage (mean FA) and (C) Baseline damage (presence or absence of MEP) with standard approach and cPMd facilitation. At severe UEFMPROXIMAL and mean FA values, standard approach elicited little to no improvement in RT performance, whereas cPMd facilitation elicited significant improvement. Cut-off values of UEFMPROXIMAL and mean FA (23 and 0.46 respectively) are indicated by an ‘x’. Although patients with severe physiologic damage (MEPABSENT) seemed to respond more to cPMd facilitation, and patients with less damage (MEPABSENT) to standard approach, findings were not significant. (D) Decision tree stratifying responders for standard approach vs cPMd facilitation technique.

Fig 4

Sub-experiment. Abbreviations: RT, reaching time; iSP, ipsilateral silent period; cM1, contralesional primary motor cortex; cPMd, contralesional dorsal premotor cortex. (A) cPMd but not cM1 facilitation tended to show more improvements in RT performance in severely affected patients, and tended to show greater reduction in iSP (B).

Fig. 5

Main experiment — Neurophysiology. Abbreviations: MEP, motor evoked potential; RT, reaching time; iSP, ipsilateral silent period; cPMd, contralesional dorsal premotor cortex; AMT, active motor threshold; UEFM, Upper Extremity Fugl-Meyer. (A) Percent change in MEP vs Baseline damage (AMT) with standard approach. Patients with mild physiologic damage (lower AMT) showed notable increases in paretic MEPs. Paretic MEPs are shown for a patient with lower AMT and for a patient with higher AMT at pre- and post-stimulation. (B) Percent change in MEP vs change in RT performance (ms) with standard approach. Increase in paretic MEPs were associated with improvements in RT performance. (C) Percent change in iSP vs Baseline impairment (UEFMPROXIMAL) following cPMd facilitation. Severely impaired patients (lower UEFMPROXIMAL) showed greater reduction in iSP. Average iSPs are shown for a mildly impaired patient and a severely impaired patient at pre- and post-stimulation. (D) Percent change in iSP vs change in RT performance following cPMd facilitation (ms). Reduction in iSPs were associated with improvements in RT performance. Note: Patient 1 (UEFMPROXIMAL =7) showed substantial reduction in iSPs. When we repeated the analysis without this individual, reduction in iSPs were still associated with improvements in RT performance.

Fig. 6

Control experiment. Abbreviations: RT, reaching time; MEP, motor evoked potential; iPMd, ipsilesional dorsal premotor cortex; cM1, contralesional primary motor cortex; cPMd, contralesional dorsal premotor cortex; FA, fractional anisotropy; UEFM, Upper Extremity Fugl-Meyer. Change in RT performance (ms or %) vs (A) Baseline impairment (UEFMPROXIMAL), (B) Baseline damage (mean FA) and (C) Baseline damage (presence or absence of MEP) with standard approach and cPMd facilitation. At severe UEFMPROXIMAL and mean FA values, both standard approach and iPMd facilitation elicited little to no improvement in RT performance. Improvements in RT performance with iPMd facilitation were smaller than improvements in RT performance with standard approach in patients with less physiologic damage (MEPPRESENT), and were not any better in patients with more damage (MEPABSENT).