Direct demonstration of the effect of lorazepam on the excitability of the human motor cortex

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Abstract

Objectives: The present study explored the effects of lorazepam, a benzodiazepine with agonist action at the GABAA receptor, on human motor cortex excitability as tested using transcranial magnetic stimulation.

Methods: We recorded directly the descending volley evoked by single and paired transcranial magnetic stimulation from the spinal cord of a conscious subject with a cervical epidural electrode before and after a single oral dose of lorazepam. We evaluated the effects of lorazepam on the descending volleys evoked by a single magnetic stimulation and paired cortical stimulation using the intracortical inhibition paradigm (subthreshold conditioning stimulus) and the short latency intracortical facilitation paradigm (suprathreshold conditioning stimulus).

Results: Using a single magnetic stimulus lorazepam decreased the amplitude of the later I waves in the descending volley; this was accompanied by a decrease in the amplitude of the evoked EMG response. Using the intracortical inhibition paradigm lorazepam increased the amount of corticocortical inhibition, particularly at 4 and 5 ms interstimulus intervals. There was no effect on the amount of facilitation observed in the short latency intracortical facilitation paradigm.

Conclusions: The present findings provide direct evidence that lorazepam increases the excitability of inhibitory circuits in the human motor cortex.

Introduction

Benzodiazepines bind to specific sites on the GABAA receptor where they enhance chloride channel mediated hyperpolarization of the cell membrane. GABA is the principal inhibitory transmitter in the brain. GABA neurons are particularly prominent in the cortex, where they are local circuit interneurons with a key role as inhibitory constraints over pyramidal cells. The facilitation of GABA action by benzodiazepines should have detectable effects on neurophysiological measures of cortical excitability.

It is possible to test the excitability of the motor areas of cortex non-invasively with transcranial magnetic stimulation. Transcranial magnetic stimulation oriented to induce a posterior-anterior current flow over the lateral part of the motor strip preferentially produces transsynaptic activation of the corticospinal projection to hand muscles. Thus, the amplitude and threshold of the evoked EMG responses depend on the excitability of intrinsic corticocortical connections. They can therefore be used as an indirect measure of motor cortical excitability. Paired magnetic stimulation of the motor cortex can also be used to study intracortical excitatory and inhibitory circuits. Again, the excitability of corticocortical inhibitory and excitatory circuits is reflected in the behaviour of EMG responses elicited in small hand muscles.

There have been several recent reports on the effect of benzodiazepines on the responses to TMS. Schonle et al. (1989) gave normal subjects a 30 min infusion of the short acting compound midazolam. They found that the amplitude of responses evoked by a suprathreshold stimulus fell gradually over the period of infusion. They thought that this was due to enhanced inhibition in GABAergic cortical interneurones that decreased the excitability of pyramidal cells and reduced the number of neurones available for generation of descending pyramidal tract activity. A similar conclusion was reached recently by Palmieri et al. (1999) who found that an extra single oral dose of diazepam in patients with anxiety disorders increased relaxed threshold and lengthened the cortical silent period.

Ziemann et al., 1996, Ziemann et al., 1998a performed more complex studies in which they gave healthy subjects a single oral dose of lorazepam and measured the response to both single and paired stimuli 2 h later. There was no change in the active or relaxed threshold and, in contrast to the work of Schonle et al. (1989), no significant decrease in the amplitude of responses evoked by a suprathreshold stimulus. However, since there was a tendency for responses to be smaller after lorazepam in both of Ziemann's studies, this apparent difference in results may not be important. Using paired pulse stimulation in the Kujirai paradigm (Kujirai et al., 1993) there was a small increase in the amount of corticocortical inhibition at an interstimulus interval of 4 ms, and a more obvious reduction in facilitation at 10–20 ms. In the Tokimura/Ziemann I wave facilitation paradigm (Tokimura et al., 1996, Ziemann et al., 1998b), there was less facilitation in presumed I wave circuitry. Again, the implication from these results was that lorazepam had increased the excitability of inhibitory circuits in the cerebral motor cortex.

This previous work has, by necessity, had to rely on EMG measures as an indirect indicator of excitability in motor cortex circuits. However, we have recently had the rare opportunity to record the descending volley evoked by TMS from the spinal cord of a conscious subject before and after a single oral dose of lorazepam. This provides a direct measure of the output of the cortex after TMS that can be compared with the EMG data. Although the number of observations is limited, and the results come from only a single individual, we think that they will be of some interest because they generally confirm previous indirect conclusions about the effect of benzodiazepines on motor cortical excitability.

Section snippets

Methods

Corticospinal volleys evoked by transcranial electrical stimulation of the motor cortex were recorded from the high cervical cord in one subject aged 68 years with no abnormality of the central nervous system. The subject had a spinal cord stimulator implanted for treatment of intractable low back pain. The electrode (model Quad 3487A Medtronic, Minneapolis, MN) was positioned percutaneously in the epidural space at the C6–C7 level, and recordings of descending activity were made 2–3 days after

Electrical anodal stimulation

Electrical (anodal) stimulation of the motor cortex evoked a single negative wave. It had a latency of 2.7 ms.

Single pulse magnetic stimulation

Lorazepam had no discernible effect on the active and resting motor threshold; AMT was 35% of maximum stimulator output both in baseline conditions and after lorazepam and RMT was 41% in baseline conditions and 42% after lorazepam. In order to compare the present results with previous data, we gave stimuli at two different intensities: during contraction at active motor threshold (AMT)

Discussion

The present results are a direct confirmation in a single rare case of many of the conclusions that had previously been reached using indirect arguments in the studies of Schonle et al. (1989) and Ziemann et al., 1996, Ziemann et al., 1998a, Ziemann et al., 1998b. They provide further evidence that lorazepam affects the excitability of the corticospinal system, at least as tested by transcranial magnetic stimulation over the motor cortex in conscious humans.

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