Modulation of Cortical Motor Evoked Potential After Stroke During Electrical Stimulation of the Lateral Cerebellar Nucleus

Abstract

Background: Deep brain stimulation (DBS) targeting the dentato-thalamo-cortical (DTC) pathway at its origin in the lateral cerebellar nucleus (LCN) has been shown to enhance motor recovery in a rodent model of cortical ischemia. LCN DBS also yielded frequency-specific changes in motor cortex excitability in the normal brain, indexed by motor evoked potential (MEP) amplitude.

Objective: To investigate the effect of cortical stroke on cortical motor excitability in a rodent ischemia model and to measure the effects of LCN DBS on post-ischemia excitability as a function of stimulation parameters.

Methods: Adult Sprague-Dawley rats were divided into two groups: naïve and stroke, with cortical ischemia induced through multiple, unilateral endothelin-1 injections. All animals were implanted with a bipolar electrode in the LCN opposite the affected hemisphere. MEPs were elicited from the affected hemisphere using intracortical microstimulation (ICMS) techniques. Multiple LCN DBS parameters were examined, including isochronal stimulation at 20, 30, 50, and 100 Hz as well as a novel burst stimulation pattern.

Results: ICMS-evoked MEPs were reduced in stroke (n = 10) relative to naïve (n = 12) animals. However, both groups showed frequency-dependent augmentation of cortical excitability in response to LCN DBS. In the naïve group, LCN DBS increased MEPs by 22-58%, while in the stroke group, MEPs were enhanced by 9-41% compared to OFF-DBS conditions.

Conclusions: Activation of the DTC pathway increases cortical excitability in both naïve and post-stroke animals. These effects may underlie, at least partially, functional reorganization and therapeutic benefits associated with chronic LCN DBS in post-stroke animals.

Keywords: Deep brain stimulation; Dentato-thalamo-cortical pathway; Lateral cerebellar nucleus; Motor evoked potential; Stroke.

Conflict of interest statement

DISCLOSURES Drs. Machado and Baker have potential financial conflict of interest with the research related to intellectual property and ownership rights in IntElect Medical, ATI and Cardionomics. The Cleveland Clinic Conflict of Interest committee has approved a plan for managing the conflict of interest in the conduct of this research. The authors have adhered to the management plan in the conduct and reporting of research findings.

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1. Experimental setup

(A) The LCN, represented in green, is the target of DBS. The bipolar electrode is shown superimposed on a coronal view of the rat atlas (AP= −11 mm). (B) LCN and ICMS stimulation and MEP recording set-up. MEPs recorded from the biceps brachii muscle in response to ICMS of the contralateral motor cortex during OFF-DBS (first row) and during ON-DBS (second row) of the LCN. Both ICMS artifacts and LCN DBS artifacts are noticeable. (C) Diagrammatic representation of the time course of the experiments. Each ON-DBS stimulation condition was tested in a 10 min block. The order of ON-DBS settings was tested pseudo-randomly but there was always an OFF-DBS condition block in between ON-DBS blocks. (D) A typical lesion volume induced by endothelin-1 intracortical injections in relation to bregma [22].

Figure 2. OFF-DBS MEPs

Motor evoked potential characteristics in the naïve and stroke group in the absence of LCN DBS. (A) The mean (± SEM) amplitude of the MEP response differed significantly between the naïve and stroke groups during the initial baseline (time 0), OFF DBS block. (B) The mean (± SEM) response during sequential OFF-DBS blocks increased as a function of experimental duration for both the naïve and stroke group animals. (C) The percent change in mean MEP response relative to the baseline epoch increased linearly for both groups, however (D) this increase, expressed as the ratio of the median response of each group per epoch, did not differ significantly between groups. (E) Despite the overall increase in mean MEP amplitude across sequential OFF blocks, changes in MEP amplitude (mean ± SD of the average MEPs over the animals per each trial) across the 40 ICMS trials within each of the ten OFF-DBS blocks were limited and not significant.

Figure 3. The effects of LCN DBS on MEPs

(A) Time drift compensated MEP amplitudes under different LCN stimulation conditions including OFF DBS for both naïve and stroke group animals. LCN DBS tended to increase MEP amplitude regardless of stimulus parameters; however, the magnitude of the effect varied both between the two groups and across the parameter sets. * p