Deep brain stimulation of the lateral cerebellar nucleus produces frequency-specific alterations in motor evoked potentials in the rat in vivo

Abstract

The cerebral cortex is tightly and reciprocally linked to the cerebellum and the ascending dentato-thalalmo-cortical pathway influences widespread cortical regions. Using a rodent model of middle cerebral artery stroke, we showed previously that chronic, 20 Hz stimulation of the contralateral lateral cerebellar nucleus (LCN) improved motor recovery, while 50 Hz stimulation did not. Using motor evoked potentials (MEP) elicited by intracortical microstimulation, we now show the effect of LCN stimulation on motor cortex excitability as a function of pulse frequency in propofol-anesthetized rats. MEPs were recorded serially, at 15-s intervals, with cerebellar stimulation delivered in 10-min blocks at rates of 20, 30, 40, 50 or 100 Hz. Stimulation at 20, 30, 40 or 50 Hz enhanced the average MEP response across the block, with the maximal overall increase observed during 30 Hz stimulation. However, the effect varied as a function of both repeated trials within the block and LCN stimulation frequency, such that 40 Hz and 50 Hz stimulation showed a reduced effect over time. Stimulation at 100 Hz produced a transient increase in MEP amplitude in some animals; however the overall effect across the block was a trend towards reduced cortical excitability. These results suggest that direct stimulation of the LCN can yield frequency-dependent changes in cortical excitability and may provide a therapeutic approach to modulating cortical activity for the treatment of strokes or other focal cortical lesions, movement disorders and epilepsy.

Figure 1

A. Stimulation and recording set-up. MEPs recorded from the hamstring muscle in response to intracortical microstimulation of the contralateral motor cortex before (upper right) and during (lower) stimulation of the LCN. Each raw EMG tracing presents a 200ms segment, comprised of a 50ms baseline followed by a 150ms response window, with intracortical stimulation denoted by the arrow. B. Coronal cut of the rat's cerebellum stained for H&E. The arrow points to the artifact of the location of the tip of the electrode at the topography of the LCN.

Figure 2

Time series plot for a single experimental animal depicting changes in the RMS ratio of the individual MEP responses (dots) across the 100 minute experimental window. The animal underwent cerebellar stimulation at both 20 (3 blocks) and 50 Hz (2 blocks) as shown in the horizontal box at the top of the figure. A three-point moving average is overlaid on the data to highlight changes in the MEP as a function of stimulation status and frequency.

Figure 3

LEFT: The effect of LCN stimulation on mean MEP amplitude across the 10-minute recording window is frequency dependent, with maximal increase observed at 30 Hz. RIGHT: The persistence of the LCN stimulation effect across the 10-minute recording window is frequency dependent. The mean response is shown as a function of time for each of the five frequency levels, with the initial 10 minutes of data representing the “off” condition, followed by the 10 minute “on” block. With the exception of 100 Hz, all frequency groups show an initial increase in response magnitude at the start of LCN stimulation. At 50 Hz however, the effect is transient, with the response approximating baseline levels by the end of the 10 minute block. A similar pattern is seen for stimulation at 40 Hz, though the decrement is less dramatic. The enhancement is sustained at both 20 and 30 Hz, while there appears to be a negative effect of 100 Hz stimulation on cortical excitability over time.