Motor cortex stimulation reduces hyperalgesia in an animal model of central pain

Abstract

Electrical stimulation of the primary motor cortex has been used since 1991 to treat chronic neuropathic pain. Since its inception, motor cortex stimulation (MCS) treatment has had varied clinical outcomes. Until this point, there has not been a systematic study of the stimulation parameters that most effectively treat chronic pain, or of the mechanisms by which MCS relieves pain. Here, using a rodent model of central pain, we perform a systematic study of stimulation parameters used for MCS and investigate the mechanisms by which MCS reduces hyperalgesia. Specifically, we study the role of the inhibitory nucleus zona incerta (ZI) in mediating the analgesic effects of MCS. In animals with mechanical and thermal hyperalgesia, we find that stimulation at 50 μA, 50 Hz, and 300 μs square pulses for 30 minutes is sufficient to reverse mechanical and thermal hyperalgesia. We also find that stimulation of the ZI mimics the effects of MCS and that reversible inactivation of ZI blocks the effects of MCS. These findings suggest that the reduction of hyperalgesia may be due to MCS effects on ZI. In an animal model of central pain syndrome, motor cortex stimulation reduces hyperalgesia by activating zona incerta and therefore restoring inhibition in the thalamus.

Figure 1. Continuous Pulse Motor Cortex Stimulation Reduced hyperalgesia

A. Thirty minutes of continuous pulse MCS significantly increased mechanical thresholds in both ipsilateral and contralateral hindpaws (relative to the lesion) after MCS (p < 0.001 Friedman test followed by Dunnett’s post hoc; n=11). Stim. off values taken immediately before stimulation, time=0 marks the time MCS ended). Horizontal dotted lines indicate average mechanical thresholds after spinal surgery (black: hindpaw ipsilateral to the lesion; gray: contralateral). B. Continuous pulse MCS significantly increased latency to withdraw from a radiant heat source in both hindpaws immediately after 30 minutes of stimulation (p < 0.05 Friedman test followed by Dunnett’s post hoc, n=6). C. Continuous theta burst stimulation did not significantly increase mechanical thresholds in either hindpaw of animals with hyperalgesia (n=6). D. Intermittent theta burst stimulation did not significantly increase mechanical thresholds in animals with hyperalgesia (hindpaw ipsilateral to the lesion: p = 0.075, Friedman test; n=6). Asterisk indicates statistically significant difference (p<0.05).

Figure 2. Effect of MCS Parameters on Hyperalgesia

A. The effect of varying stimulation intensity on mechanical withdrawal thresholds. In the hindpaw ipsilateral to the lesion, 25 µA (n=7), 50 µA (n=12) and 75 µA (n=7) stimulation significantly increased mechanical thresholds after the end of MCS (p < 0.001, Kruskal-Wallis followed by Dunn’s post hoc). The contralateral hindpaw showed significantly increased thresholds only after 50 µA stimulation (p = 0.013, Kruskal-Wallis followed by Dunn’s post hoc). B. The effect of varying stimulation frequency on mechanical withdrawal thresholds. Ipsilateral thresholds (ipsilateral to the lesion) were significantly raised when M1 was stimulated at 50 Hz (n=11) and at 75 Hz (n=6) (p < 0.001, Kruskal-Wallis followed by Dunn’s post hoc). Contralateral thresholds were significantly raised when MCS occurred at 50 Hz (p = 0.024, Kruskal-Wallis followed by Dunn’s post hoc). C. The effect of varying stimulation duration on mechanical withdrawal thresholds. Hyperalgesia in the hindpaw ipsilateral to the lesion was significantly reduced after 15 min (n=10), 30 min (n=11), 60 min (n=6), and 90 min (n=10) of continuous pulse MCS while hyperalgesia in the contralateral hindpaw was significantly reduced after only 30 min and 90 min of MCS (p < 0.001 and p = 0.02 respectively, Kruskal-Wallis followed by Dunn’s post hoc). D. Duration of MCS is positively correlated with duration of post effects in both hindpaws (p < 0.001; Spearman’s).

Figure 3. ZI Mediates the Effects of MCS

ZI stimulation significantly increased (A) mechanical thresholds and (B) thermal thresholds bilaterally in animals with hyperalgesia. C. Inactivation of ZI with lidocaine or muscimol occludes the effects of MCS. The infusion of the same volume of saline had no effect on MCS-induced reduction in hyperalgesia (p = 0.01, Friedman test followed by Dunnett’s post hoc). Ipsilateral hindpaw (relative to lesion site) shown for clarity; similar effects were seen in the contralateral hindpaw. D. Representative microdialysis cannula placement in ZI. Arrow indicates small lesion produced by drug infusion, scale bar = 150 µm. E. Schematic representation of ZI and adjacent structures and reconstruction of injection site in three animals. The schematic was adopted from [42] and modified. VP: ventral posterolateral thalamus, ZId: zona incerta, dorsal part; ZIv: zona incerta, ventral part, ic: internal capsule.