Pharmacological control of facilitatory I-wave interaction in the human motor cortex. A paired transcranial magnetic stimulation study

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Abstract

A novel paired transcranial magnetic stimulation (TMS) paradigm with a suprathreshold first and a subthreshold second stimulus was used in healthy volunteers to investigate the acute effects of a single oral dose of various CNS-active drugs on short-interval motor evoked potential (MEP) facilitation. MEPs were recorded from the relaxed abductor digiti muscle. Three peaks of MEP facilitation were consistently observed at interstimulus intervals of 1.1–1.5 ms, 2.3–2.7 ms, and 3.9–4.5 ms. The size of these MEP peaks was transiently suppressed by drugs which enhance gamma-aminobutyric acid (GABA) function in the neocortex (lorazepam, vigabatrin, phenobarbital, ethanol), while the GABA-B receptor agonist baclofen, anti-glutamate drugs (gabapentin, memantine), and sodium channel blockers (carbamazepine, lamotrigine) had no effect. The interstimulus intervals effective for the production of the MEP peaks remained unaffected by all drugs. The MEP peaks are thought to be due to a facilitatory interaction of I-(indirect) waves in the motor cortex. Therefore, the present results indicate that the production of I-waves is primarily controlled by GABA related neuronal circuits. The potential relevance of this non-invasive paired TMS protocol for the investigation of I-waves in patients with neurological disease will be discussed.

Introduction

We reported recently that paired transcranial magnetic stimulation (TMS) can be used as a non-invasive technique to visualize I-(indirect) waves (Tergau et al., 1997; Ziemann et al., 1998). It was demonstrated that the two magnetic stimuli interact in a facilitatory fashion at short interstimulus intervals if a suprathreshold first stimulus and a subthreshold second stimulus were used, rather than a subthreshold conditioning and a suprathreshold test stimulus as in earlier paired TMS protocols (Kujirai et al., 1993; Ziemann et al., 1996c). With the novel protocol, 3 peaks of MEP facilitation were observed at interstimulus intervals of 1.1–1.5 ms, 2.3–2.9 ms, and 4.1–4.4 ms (Tergau et al., 1997; Ziemann et al., 1998). Evidence was presented that these peaks reflect facilitatory I-wave interaction and originate in the motor cortex, most likely at the initial segment of excitatory interneurones and at the cortico-spinal neurones upon which they project.

I-waves were first described by Patton and Amassian (1954)when they recorded cortico-spinal volleys from the pyramidal tract after electrical motor cortex surface stimulation in monkey and cat. They termed the initial potential D-(direct) wave and the multiple following potentials I-waves according to their hypothesis that the D-wave originated from direct, but the I-waves from indirect (transsynaptic) activation of cortico-spinal neurones. Ample evidence in support of this hypothesis was provided in recent years in humans by the intraoperative monitoring of evoked spinal cord potentials (Boyd et al., 1986; Berardelli et al., 1990; Burke et al., 1990; Thompson et al., 1991; Burke et al., 1993; Rothwell et al., 1994; Kaneko et al., 1996; Nakamura et al., 1996; Nakamura et al., 1997). The trans-synaptic mode of I-wave generation through the activation of excitatory motor cortical circuits (for extensive review, see Amassian et al., 1987) offers the opportunity that I-wave recordings may be used to explore the excitability of these circuits.

In the present paired TMS study, we investigated the effect of a single oral dose of various CNS-active drugs on the facilitatory I-wave interaction in the motor cortex of healthy subjects, in order to understand further the physiology of I-waves and their pharmacological control. Our findings will put forward the view that the measurement of I-waves in this novel paired TMS paradigm may become a useful tool for investigating patients with neurological disorders associated with a deficient function of inhibitory circuits in the motor cortex.

Section snippets

Subjects

Eleven healthy volunteers (mean age 30.3±6.3 years, range 23–44 years; two were women, 9 were men) participated in the experiments. All gave their written informed consent. The study was performed according to the Declaration of Helsinki and approved by the ethics committee of the Medical Faculty of the University of Göttingen. Most subjects participated in more than one drug protocol. The minimum interval between testing two different drugs in the same individual was 2 weeks in order to avoid

Results

The principal result is shown for one representative subject in Fig. 1. At baseline, MEPs were facilitated after paired stimulation at ISIs of 1.1–1.5 ms, 2.7–3.1 ms, and at 4.5 ms. Two hours after intake of a single oral dose of 2.5 mg of LZP, these facilitatory MEP peaks were largely suppressed. This effect was reversible and after a delay of 24 h the peaks were back to the baseline level. The average data for LZP from 8 subjects are shown in the left upper diagram of Fig. 2Fig. 3. In Fig. 2,

Pharmacological control of I-waves

The principal finding of the present paired TMS study was a suppressive effect of GABA-enhancing drugs on the magnitude of short-latency MEP facilitation. It is currently thought that the MEP facilitation produced by two magnetic pulses at short interstimulus intervals reflects facilitatory interactions between neuronal circuits in the motor cortex normally responsible for the production of I-waves (Tokimura et al., 1996). Experiments from our group (Tergau et al., 1997; Ziemann et al., 1998)

Acknowledgements

Parts of the present study were presented in abstract form at the 14th meeting of the IFCN in Florence, 24–29 August 1997 (Hildebrandt et al., 1997). We thank Peter Wenig for technical support, and Hoechst Marion Roussel for financial support.

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