Late Cortical Disinhibition in Human Motor Cortex: A Triple-Pulse Transcranial Magnetic Stimulation Study

1. Blockade of uptake carriers of gamma-aminobutyric acid (GABA) has been shown to modulate inhibition in cortical slices of experimental animals, although little is known about this mechanism in vivo and, in particular, in humans. 2. The effects of blockade of GABA uptake were studied using transcranial magnetic stimulation (TMS) in humans. In eight healthy volunteers several measures of cortical excitation and inhibition were obtained before and approximately 2 h after ingestion of 5-15 mg of tiagabine (TGB). 3. After TGB ingestion, the duration of the TMS-induced silent period observable in the electromyogram of the voluntarily contracted target muscle was prolonged. Similarly, paired-pulse inhibition of the motor-evoked potential (MEP), as tested by delivering two magnetic shocks of equal suprathreshold intensities at 160 ms interstimulus interval (ISI), was more pronounced. In apparent contradistinction, paired-pulse inhibition of the MEPs produced by a subthreshold conditioning stimulus delivered 3 ms prior to a suprathreshold stimulus was reduced. Paired-pulse facilitation elicited by the same double-shock protocol at an ISI of 10 ms was increased. 4. The prolongation of the GABAB receptor-mediated component of the inhibitory postsynaptic potential observed with TGB in in vitro studies probably underlies the increase in cortical silent period duration. The reduction of the paired-pulse inhibition at 3 ms, in turn, probably reflects inhibition of GABAA receptor-mediated inhibition via presynaptic GABAB receptors. 5. These data provide in vivo evidence of differential modulation of cortical inhibition by blockade of GABA uptake. Presynaptic GABA autoreceptors may be involved in modulating cortical inhibition in the human motor cortex.

Transcranial magnetic stimulation (TMS) was initially used to evaluate the integrity of the corticospinal tract in humans non-invasively. Since these early studies, the development of paired-pulse and repetitive TMS protocols allowed investigators to explore inhibitory and excitatory interactions of various motor and non-motor cortical regions within and across cerebral hemispheres. These applications have provided insight into the intracortical physiological processes underlying the functional role of different brain regions in various cognitive processes, motor control in health and disease and neuroplastic changes during recovery of function after brain lesions. Used in combination with neuroimaging tools, TMS provides valuable information on functional connectivity between different brain regions, and on the relationship between physiological processes and the anatomical configuration of specific brain areas and connected pathways. More recently, there has been increasing interest in the extent to which these physiological processes are modulated depending on the behavioural setting. The purpose of this paper is (a) to present an up-to-date review of the available electrophysiological data and the impact on our understanding of human motor behaviour and (b) to discuss some of the gaps in our present knowledge as well as future directions of research in a format accessible to new students and/or investigators. Finally, areas of uncertainty and limitations in the interpretation of TMS studies are discussed in some detail.

While GABA(B) receptors are thought to have an important role in mediating long interval intracortical inhibition (LICI) in the human motor cortex, the effect of a selective GABA(B) receptor agonist on this measure has not been directly tested. Nine healthy volunteers ingested either 50 mg baclofen (BAC) or placebo (PBO) in a randomized, double blind crossover design, with the second session one week later. We used transcranial magnetic stimulation to assess motor threshold, motor evoked potential (MEP) amplitude, cortical silent period (CSP) duration, short interval intracortical inhibition (SICI) and LICI before and 90 min following drug intake. There was no specific effect of drug on motor threshold, MEP amplitude or CSP duration. BAC resulted in a significant increase in LICI (P=0.002) and a significant decrease in SICI (P=0.046) while PBO had no effect. Our findings demonstrate that the enhanced GABA(B) receptor activation results in differential effects on these two measures of intracortical inhibition in the human motor cortex. The increase in LICI is likely to be a result of increased GABA(B) receptor mediated inhibitory post-synaptic potentials, while the reduction in SICI may relate to the activation of pre-synaptic GABA(B) receptors reducing GABA release.