Chronic electrical stimulation of the contralesional lateral cerebellar nucleus enhances recovery of motor function after cerebral ischemia in rats

Abstract

Novel neurorehabilitative strategies are needed to improve motor outcomes following stroke. Based on the disynaptic excitatory projections of the dentatothalamocortical pathway to the motor cortex as well as to anterior and posterior cortical areas, we hypothesize that chronic electrical stimulation of the contralesional dentate (lateral cerebellar) nucleus output can enhance motor recovery after ischemia via augmentation of perilesional cortical excitability. Seventy-five Wistar rats were pre-trained in the Montoya staircase task and subsequently underwent left cerebral ischemia with the 3-vessel occlusion model. All survivors underwent stereotactic right lateral cerebellar nucleus (LCN) implantation of bipolar electrodes. Rats were then randomized to 4 groups: LCN stimulation at 10 pps, 20 pps, 50 pps or sham stimulation, which was delivered for a period of 6 weeks. Performance on the Montoya staircase task was re-assessed over the last 4 weeks of the stimulation period. On the right (contralesional) side, motor performance of the groups undergoing sham, 10 pps, 20 pps and 50 pps stimulation was, respectively, 2.5+/-2.7; 2.1+/-2.5; 6.0+/-3.9 (p<0.01) and 4.5+/-3.5 pellets. There was no difference on the left (ipsilesional) side motor performance among the sham or stimulation groups, varying from 15.9+/-6.7 to 17.2+/-2.1 pellets. We conclude that contralesional chronic electrical stimulation of the lateral cerebellar nucleus at 20 pps but not at 10 or 50 pps improves motor recovery in rats following ischemic strokes. This effect is likely to be mediated by increased perilesional cortical excitability via chronic activation of the dentatothalamocortical pathway.

Conflict of interest statement

Conflicts of Interest: Andre Machado has a significant conflict of interest related to this research with IntElect Medical due inventorship shares (stockholder), as a consultant and as a member of the scientific advisory board. Andre Machado is employed by the Cleveland Clinic. IntElect Medical is a spin-off company of the Cleveland Clinic.

Kenneth Baker has a conflict of interest with IntElect Medical due to inventorship shares. Dr. Baker is employed by the Cleveland Clinic. IntElect Medical is a spin-off company of the Cleveland Clinic.

Daniel Schuster has no conflicts with this research other than his employment at the Cleveland Clinic. Daniel Schuster is employed by the Cleveland Clinic. IntElect Medical is a spin-off company of the Cleveland Clinic.

Robert Butler has no conflicts with this research other than his employment at the Cleveland Clinic. Daniel Schuster is employed by the Cleveland Clinic. IntElect Medical is a spin-off company of the Cleveland Clinic.

Ali Rezai has significant conflict of interest related to this research with IntElect Medical. He has inventorship shares (stockholder). He was until 2008 the chairman of the scientific advisory board, a member of the IntElect Medical board and a consultant to the company. He no longer serves in these capacities. Dr. Rezai is employed by the Cleveland Clinic. IntElect Medical is a spin-off company of the Cleveland Clinic.

Figures

Figure 1

a) Diagrammatic representation of a coronal slice of the cerebellum at bregma = −11.0 mm (Paxinos and Watson, 1998) showing the indented target for implantation of the electrode in the lateral cerebellar nucleus (arrow). b) coronal Pearls/DAB stained section of the cerebellum showing the artifact from the trajectory and the location corresponding to the tip of the implanted electrode (arrow), where there electrolytic lesion was created.

Figure 2

Diagrammatic representation of the typical stroke. The cortex anterior to the bregma was predominantly affected, with relative sparing of the areas posterior to the bregma. Limited injury to the anterior part of the somatossensory cortex was observed, mostly anterior to segments 2 mm posterior to the bregma. The subcortical white matter was affected proportionately to the cortex but with near complete sparing of the basal ganglia and complete sparing of the thalamus).

Figure 3

The box plot represents the data from the last week of post-stroke assessment in the Montoya staircase task for all groups: sham stimulation. 10pps, 20 pps and 50 pps stimulation. For reference, the performance of the last week of pre-stroke training in the Montoya task is also shown on the left. The top and bottom of the box represent, respectively, the second and third quartiles. Inside each box, the median (second quartile) is represented. A marked suppression in motor performance was observed across all groups after strokes and was maintained throughout the observation period. Although a trend for improvement could be observed in the 50 pps group, only stimulation at 20 pps resulted in a significant difference in motor outcomes compared to sham stimulation.

Figure 4

Time course of the average right sided motor training (pre-stroke). All animals included. Each column of data in the graph represents a session in the Montoya staircase (2 sessions per day). Each dot represents data derived from the first cohort. Each circle represents data from the second cohort of animals. Circles with a dot in the center indicate data overlapping from animals from more than one cohort. The learning curve of the motor outcome task is steep during the first 10 days and then approximates a plateau near an average of 16 pellets per side. Only animals consuming at least 13 pellets per side continued in the study.

Figure 5

Time course of right sided motor recovery of rats undergoing chronic 20 pps stimulation. This is the only stimulation group that presented with motor outcomes significantly improved in relation to sham stimulation. There is an ascending slope of motor performance up to 15 days into the post-stroke Montoya assessment period, followed by a plateau in motor performance. This corresponds to the end of the third week of assessments (5 assessment days per week).