Pallidal stimulation modifies after-effects of paired associative stimulation on motor cortex excitability in primary generalised dystonia

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Abstract

Objective

To determine the effect of globus pallidus internus (GPi) deep brain stimulation (DBS) on motor cortex plasticity in patients with primary generalised dystonia.

Methods

We studied 10 patients with primary generalised dystonia (5 DYT1+, 5 idiopathic, 5 female, mean age 42) following GPi DBS and 10 healthy subjects. Motor cortex plasticity was assessed using transcranial magnetic stimulation (TMS) paired associative stimulation (PAS) of motor cortex and median nerve, a method which has been shown in healthy subjects to produce LTP-like effects. Thresholds and TMS intensity to produce a resting motor evoked potential (MEP) of 1 mV were determined. Resting MEP amplitude and stimulus response curves were recorded before and after PAS. Patients were recorded ON and OFF DBS in separate sessions.

Results

The mean TMS intensity to produce a resting MEP of 1 mV was 54% of maximum stimulator output when OFF and 52% ON DBS. Fifteen minutes after PAS the resting MEP amplitude increased in patients OFF DBS and in control subjects whereas it decreased in patients ON DBS. Similarly, after PAS, the mean amplitude of the stimulus response curve increased OFF DBS, but this effect was abolished with DBS ON. Furthermore, patients who had the largest clinical response to chronic DBS also had the largest difference in the effect of PAS with DBS ON vs. OFF.

Conclusions

After PAS, patients with primary generalised dystonia showed a similar pattern of increased motor cortex excitability as healthy subjects when GPi DBS was OFF but not with GPi DBS ON. These results suggest that GPi DBS may reduce LTP-like motor cortex plasticity, which could contribute to its mechanism of action in dystonia.

Introduction

Primary dystonia is characterised by involuntary muscle contractions, which result in spasms and abnormal postures (Fahn et al., 1998). The underlying defect is believed to be abnormal basal ganglia modulation of cortical motor pathways, although its detailed pathology is incompletely understood (Berardelli et al., 1998). Studies of patients with focal dystonia have shown reduced excitability of inhibitory connections at cortical (Ridding et al., 1995), brainstem (Berardelli et al., 1985) and spinal (Nakashima et al., 1989) levels but the extent to which these abnormalities cause dystonia is unclear since they are often dissociated from clinical symptoms (Chen et al., 1995, Deuschl et al., 1992). Sensory discrimination (Molloy et al., 2003) and sensorimotor integration (Tinazzi et al., 2003) are also abnormal in patients with focal dystonia. Motor cortex plasticity can be probed using transcranial magnetic stimulation (TMS) with paired associative stimulation (PAS) (Stefan et al., 2000) and repetitive TMS (Huang et al., 2005), and recent studies have demonstrated abnormal plasticity in dystonia patients. Patients with focal hand dystonia show greater increases in motor cortex excitability after conditioning with TMS-PAS than healthy subjects (Quartarone et al., 2003, Weise et al., 2006). Similarly, motor cortex plasticity following repetitive TMS is increased in patients with DYT1 dystonia and sporadic cervical dystonia but reduced in non-manifesting carriers of the DYT1 gene (Edwards et al., 2006). These studies suggest that excessive plasticity within the motor cortex may be one factor that contributes to the occurrence of dystonia. We hypothesise that convergence of abnormal excitability of motor circuits, mis-processing of sensory input and increased cortical synaptic plasticity result in abnormal neural reorganisation and ultimately clinical dystonia.

Chronic deep brain stimulation (DBS) of the globus pallidus internus (GPi) has emerged as an effective treatment for primary generalised dystonia (Coubes et al., 2004, Vidailhet et al., 2005), however, the physiological mechanisms of improvement remain unclear. In dystonia patients, GPi DBS has been shown to progressively reverse spinal and brainstem disinhibition in parallel with clinical improvement suggesting gradual neural reorganisation towards a more normal physiological pattern (Tisch et al., 2006a, Tisch et al., 2006b). Although excessive plasticity has been implicated in dystonia the effect of GPi DBS on these abnormalities is unknown. We therefore examined the effect of GPi DBS on motor cortex plasticity using PAS in patients with dystonia.

Section snippets

Subjects

Ten patients with primary generalised dystonia (5 female, mean age 42 ± 17 years, range 18–64) and 10 healthy participants (6 female, mean age 37 ± 7 years, range 24–52) were enrolled in the study. The patient characteristics are shown in Table 1. Patient 5 underwent unilateral thalamotomy 23 years ago. All patients gave written informed consent. The study was approved by the Joint Research Committee of the National Hospital for Neurology and Neurosurgery and the Institute of Neurology.

Surgical procedures

All patients

Motor thresholds

Although there was slight tendency for AMT, RMT and the 1 mV MEP intensity to be higher with GPi DBS OFF (Fig. 1), this difference was not significant. However, all values were higher than in healthy subjects (p < 0.05 for all comparisons).

Resting MEP amplitudes

Fig. 2A plots the change in the MEP amplitudes evoked before and at three times after the PAS intervention. We first compared the data ON and OFF DBS in the patients. A repeated measures ANOVA with main factors of TIME (pre, 0, 15, 30 min post PAS) and STIM

Discussion

We have shown that PAS produces the same effects as normal on MEP amplitude in patients with primary generalised dystonia when GPi DBS is switched OFF, but that the effect is reversed when stimulation is turned ON. Given that the after-effects of PAS are thought to reflect LTP-like plasticity at motor cortical synapses, this suggests that GPi DBS can modify the plastic response of motor cortical circuits to changes in their input. We argue below that this effect may well contribute to the

Conclusions

The present findings of modification of short-term plasticity by GPi DBS may provide a potential mechanism for the observed neural reorganisation after GPi DBS. Existing evidence suggests that excessive short-term plasticity may be a contributing factor to dystonia. Reversal of LTP-like plasticity might be beneficial by reducing the strength of synaptic connections within aberrantly functioning networks, thereby partially normalising the “excessive plasticity”, gradually resulting in the

Acknowledgments

Dr. Stephen Tisch received support from the Brain Research Trust UK, Medtronic UK, and Action Medical Research, Dr. Patricia Limousin, Professor Marwan Hariz and Mr. Keyoumars Ashkan are supported by the Parkinson's Appeal UK. Mr. L. Zrinzo received educational support from Medtronic UK.

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