Elsevier

Brain Research

Volume 815, Issue 2, 9 January 1999, Pages 192-199
Brain Research

Research report
The effect of benzodiazepines and flumazenil on motor cortical excitability in the human brain

https://doi.org/10.1016/S0006-8993(98)01164-0Get rights and content

Abstract

In the present study, the effects of benzodiazepines (diazepam) were evaluated in terms of cortical excitability changes, as tested with transcranial magnetic simulation (TMS). In particular, analyzed were drug-induced changes regarding two selected parameters of TMS: (1) the cortical excitability threshold and (2) the silent period duration (SP). For this purpose, we evaluated the effects of long-term therapy with diazepam in the patients affected by anxiety disorders and the changes induced by single oral doses of diazepam in both healthy controls and patients. In addition, we tested cortical excitability changes in two `extreme conditions' where a considerable concentration of serum benzodiazepine-like activity was reached, as represented by diazepam overdose and idiopathic recurrent stupor (IRS). In both groups of patients, a significant increment of motor threshold was found, while in the overdose patients, the SP was also increased. The administration of flumazenil in these two conditions was followed by a prompt reversal effect, consisting of a return to normal cortical excitability parameters. The long-term usage of diazepam in patients with anxiety disorders is associated with significantly increased threshold; the increased value of these parameters was temporarily further enhanced by the administration of a single oral dose of diazepam, which, in normal control subjects, is not associated with changes of cortical excitability. The results of this study reveal that different physio-pathological conditions induced by the influence of benzodiazepine and its antagonist are reflected in excitability changes which attest to the involvement and modification of cortical GABAergic activity.

Introduction

The threshold for transcranial magnetic stimulation (TMS) is shown to be a key indicator of motor cortical excitability, able to reveal excitability changes in the patients with neurological disorders 2, 6, 7, 17. This method has been used to assess the effects of antiepileptic drugs (AEDs) and to show that patients with generalized epilepsy have a lower threshold of cortical excitability than healthy subjects, unless treated, in which case they have a higher threshold due to the suppressive action of the AEDs [9]. The effects of a range of AEDs on motor cortical excitability such as carbamazepine, lamotrigine, vigabatrin [28]and sodium valproate have also been documented 8, 23. But there is a lack of a satisfactory number of comparable studies which focus on the action of benzodiazepines on motor cortical excitability, particularly with respect to patients undergoing chronic treatment with benzodiazepines, as well as benzodiazepine overdose or in the case of idiopathic recurrent stupor (IRS), a condition where an endogenous increase of endozepine-4 is implicated 15, 20, 27.

In the present study, we aimed to detect the effects of both increased benzodiazepines and endozepine-4 through the analysis of cortical excitability changes as measured by the use of TMS.

Two parameters were selected: the threshold of motor evoked potentials (MEPs) elicitation and the duration of the cortical silent period (SP).

In addition, during benzodiazepine `excess', as represented by two patients after diazepam overdose and in the patient affected by IRS, we monitored the reversal effect induced by the administration of flumazenil, a non-specific benzodiazepine receptor antagonist.

Section snippets

Subjects and methods

Fifteen patients (eight women and seven men aged between 17 and 45 years) and 10 (age-matched) control subjects participated in the study. The patients were divided into different sub-groups according to the modality of drug assumption. Patients suffering from diabetes, peripheral neuropathies, carpal tunnel syndrome, and radiculopathies were not enrolled in the protocol.

All subjects gave their written informed consent, and the procedures employed in the protocol were performed according to the

Results

The principal finding of our study is represented by the significant increment of cortical excitability threshold found in all patients in the wake of chronic benzodiazepine treatment, overdose and stupor. By contrast, control subjects tested after a single oral dose of diazepam did not show changes of this parameter.

Each group of patients displayed a distinctive pattern of excitability with regard to degrees of threshold and SP changes (Table 1). Means and S.D. of the analyzed parameters are

Discussion

Our study investigating the human motor cortex excitability under the influence of neurotropic drugs shows that the administration of a single oral dose of diazepam in healthy subjects, although inducing subjective changes in the level of vigilance, does not produce modification of the motor excitability threshold. By contrast, it was found that long-term diazepam usage, in the patients with anxiety disorders as well as in diazepam overdose and in the case with stupor, is associated with a

Acknowledgements

We thank Prof. Giorgio Bernardi for his encouraging support, Dr. Paolo Calabresi for his suggestions in discussing the results of this study and Mark Wilson Jones for revising the English.

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