TMS and drugs

doi:10.1016/j.clinph.2004.03.006

Clinical Neurophysiology

Volume 115, Issue 8, August 2004, Pages 1717-1729

https://doi.org/10.1016/j.clinph.2004.03.006 Get rights and content

Abstract

The application of a single dose of a CNS active drug with a well-defined mode of action on a neurotransmitter or neuromodulator system may be used for testing pharmaco-physiological properties of transcranial magnetic stimulation (TMS) measures of cortical excitability. Conversely, a physiologically well-defined single TMS measure of cortical excitability may be used as a biological marker of acute drug effects at the systems level of the cerebral cortex. An array of defined TMS measures may be used to study the pattern of effects of a drug with unknown or multiple modes of action. Acute drug effects may be rather different from chronic drug effects. These differences can also be studied by TMS measures. Finally, TMS or repetitive TMS by themselves may induce changes in endogenous neurotransmitters or neuromodulators. All these possible interactions are the focus of this in-depth review on TMS and drugs.

Introduction

What are the main topics that come to mind when thinking about transcranial magnetic stimulation (TMS) and drugs? First, drugs with a known mode of action may be used to explore physiological properties of TMS measures of motor excitability. The typical experimental setting is the administration of a single dose of the study drug and to obtain TMS measures before and at one or several time points after drug intake. This application proved to be extremely useful in promoting a better understanding of what is measured with TMS. Second, a single well-defined TMS measure may be used as biological marker of acute drug effects. Typically, this is tested in drug concentration—drug effect relationships. Third, an array of well-defined TMS measures may be used to identify modes of action of a study drug at the systems level of the human motor cortex, if these modes of action are not known or complex. Fourth, chronic drug effects on TMS measures may be different from acute ones. Knowledge about chronic versus acute drug effects is important, if drug effects in the setting of long-term treatment shall be predicted. Fifth, particular anaesthetics may acutely reduce corticospinal excitability. The knowledge, to which extent different anaesthetics are doing this, is very important in the setting of intraoperative monitoring of corticospinal tract integrity. Sixth, TMS and repetitive TMS (RTMS) by themselves may result in changes in the concentration and release of endogenous CNS active substances, such as neurotransmitters and neuromodulators. Knowledge about these effects would be important, if TMS and RTMS are used for therapeutic purposes. This review will present an in-depth survey on all of these topics. It will be limited to research in healthy subjects though because drug effects on TMS measures in patients with CNS disorders may deviate unpredictably from the effects obtained in the intact brain.

Section snippets

Effects of CNS active drugs with a known mode of action on TMS measures of motor excitability

The reviewed studies were always designed to compare TMS measures at one or several time points after drug intake with one baseline measure before drug intake. Some studies added a placebo control in a randomised and blinded parallel or crossover design to minimise experimenter bias. This chapter will review drug effects separately for the different TMS measures of motor cortical and corticospinal excitability.

TMS measures as biological markers of drug effects

A biological marker is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention (Biomarkers Definitions Working Group, 2001). The relation between drug plasma concentration and drug effect may be complex, for instance due to characteristics of the drug related to plasma protein binding, crossing of the blood brain barrier, or kinetics of drug–receptor

Effects of CNS active drugs with incompletely known or multiple modes of action on motor cortical excitability

Many of the TMS measures are by now well defined in terms of their physiological and pharmacological properties (see pt. 2 and Table 1). This knowledge may be used to identify the most prominent actions of CNS active drugs with multiple or incompletely known mechanisms at the systems level of human motor cortex. The available data of this approach are summarised in Table 3.

As a clear example along this avenue, one study tested the effects of the novel anti-epileptic drug topiramate on a broad

Chronic versus acute effects on TMS measures of motor cortical excitability

Chronic drug effects may be fundamentally different from acute ones. There are several processes, which can potentially alter the response of the human brain to a drug, if chronically administered: (1) pharmacokinetic tolerance. This refers to changes in the distribution or metabolism of a drug induced by repeated application. The most common mechanism is an increase in the rate of metabolism; (2) pharmacodynamic tolerance. This refers to adaptive changes within the system affected by the drug.

Effects of anaesthetics and analgesics on motor cortical excitability

MEP recordings are increasingly employed to monitor corticospinal tract integrity during surgery of brainstem and spinal cord. In the intraoperative setting, transcranial electrical stimulation (TES) is more often used than TMS because it is less bulky and the electrodes can remain on the scalp once they have been fixed there so that continuous access to the patient's head is no longer necessary. It appeared that the sensitivity of TES and TMS to detect changes in motor excitability induced by

TMS/RTMS induced changes in endogenous neurotransmitters and neuromodulators

Endogenous neurotransmitters such as GABA and glutamate, and neuromodulators (DA, NE, 5-HT, ACh) play a fundamental role in the regulation of the neuronal activity in the cerebral cortex (for review, (McCormick et al., 1993, Hasselmo, 1995)). The basis of many neurological and psychiatric disorders is thought to lie in abnormal neuronal network activity as a consequence of altered neurotransmitter or neuromodulator systems. For instance, DA is implicated in the control of fundamental processes

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Invited reviewTMS and drugs

Abstract

Introduction

Section snippets

Effects of CNS active drugs with a known mode of action on TMS measures of motor excitability

TMS measures as biological markers of drug effects

Effects of CNS active drugs with incompletely known or multiple modes of action on motor cortical excitability

Chronic versus acute effects on TMS measures of motor cortical excitability

Effects of anaesthetics and analgesics on motor cortical excitability

TMS/RTMS induced changes in endogenous neurotransmitters and neuromodulators

Eur J Pharmacol

Clin Neurophysiol

Brain Res Brain Res Rev

Trends Neurosci

J Neurol Sci

Epilepsy Res

Clin Neurophysiol

Clin Neurophysiol

Electroencephalogr Clin Neurophysiol

Behav Brain Res

Neurosci Lett

Clin Neurophysiol

J Neurol Sci

Br, J Anaesth

Neuropharmacology

Clin Neurophysiol

Neurosci Lett

Neurosci Lett

Br J Anaesth

Clin Neurophysiol

Electroencephalogr Clin Neurophysiol

Electroencephalogr Clin Neurophysiol

Electroencephalogr Clin Neurophysiol

Neurosci Lett

Neurosci Lett

Brain Res

Electroencephalogr Clin Neurophysiol

Neurosci Lett

Neurosci Lett

Neurosci Lett

Br J Anaesth

Neurosci Lett

Electroencephalogr Clin Neurophysiol

Neurosci Lett

Neuropsychologia

Physiological basis of motor effects of a transient stimulus to cerebral cortex

Neurosurgery

Magnetic stimulation of the brain in animal depression models responsive to ECS

J Ect

Vigabatrin. Chemistry, absorption, distribution and elimination

Transcranial magnetic stimulation induces alterations in brain monoamines

J Neural Transm

Biomarkers and surrogate endpoints: preferred definitions and conceptual framework

Clin Pharmacol Ther

Latent addition in motor and sensory fibres of human peripheral nerve

J Physiol

Direct comparison of corticospinal volleys in human subjects to transcranial magnetic and electrical stimulation

J Physiol (Lond)

The effects of a volatile anaesthetic on the excitability of human corticospinal axons

Brain

Isoflurane-induced attenuation of motor evoked potentials caused by electrical motor cortex stimulation during surgery

J Neurosurg

Magnetic brain stimulation: the silent period after the motor evoked potential

Neurology

Interactions between inhibitory and excitatory circuits in the human motor cortex

Exp Brain Res

Effects of phenytoin on cortical excitability in humans

Neurology

The motor syndrome associated with exaggerated inhibition within the primary motor cortex of patients with hemiparetic stroke

Brain

Two inhibitory postsynaptic potentials, and GABAA and GABAB receptor- mediated responses in neocortex of rat and cat

J Physiol (Lond)

Effect of antipsychotics on cortical inhibition using transcranial magnetic stimulation

Psychopharmacology (Berl)

Invited review
TMS and drugs