We studied the effects of low-frequency transcranial magnetic stimulation (TMS) on motor cortex excitability in humans. TMS at 0.1 Hz for 1 hour did not change cortical excitability. Stimulation at 0.9 Hz for 15 minutes (810 pulses), similar to the parameters used to induce long-term depression (LTD) in cortical slice preparations and in vivo animal studies, led to a mean decrease in motor evoked potential (MEP) amplitude of 19.5%. The decrease in cortical excitability lasted for at least 15 minutes after the end of the 0.9 Hz stimulation. The mechanism underlying this decrease in excitability may be similar to LTD. TMS-induced reduction of cortical excitability has potential clinical applications in diseases such as epilepsy and myoclonus. Spread of excitation, which may be a warning sign for seizures, occurred in one subject and was not accompanied by increased MEP amplitude, suggesting that spread of excitation and amplitude changes are different phenomena and also indicating the need for adequate monitoring even with stimulations at low frequencies.

Current models of motor cortical plasticity, developed in studies on experimental animals, emphasize the importance of the conjoint activity of somatosensory afferents and intrinsic motor cortical circuits. The hypothesis that an enduring change in excitability in the cortical output circuitry can be induced in the human motor cortex by a paired-stimulation protocol was tested. Low-frequency median nerve stimulation was paired with transcranial magnetic stimulation (TMS) over the optimal cranial site for stimulating the abductor pollicis brevis muscle (APB). This protocol induced an increase in the amplitudes of the motor evoked potentials (MEPs) in the resting APB as well as a prolongation of the silent period measured in the precontracted APB following TMS; amplitudes of MEPs measured in voluntary contraction remained unchanged. Experiments testing the excitability of spinal motoneurons using F-wave studies and electrical stimulation of the brainstem suggested that the site of the plastic changes was within the motor cortex. The increases in resting amplitudes and silent period duration were conditionally dependent on the timing between the afferent and the magnetic stimulation in that they were present when events elicited by afferent and magnetic stimulation were synchronous at the level of the motor cortex. Plasticity induced by paired stimulation evolved rapidly (within 30 min), was persistent (minimum duration 30–60 min) yet reversible, and was topographically specific. This combination of features and the similarity to properties of induced enduring changes in synaptic efficacy, as elucidated in animal studies, leads us to propose that the induced plasticity may represent a signature of associative long-term potentiation of cortical synapses or closely related neuronal mechanisms in the human cortex.

Classen, Joseph, Joachim Liepert, Steven P. Wise, Mark Hallett, and Leonardo G. Cohen. Rapid plasticity of human cortical movement representation induced by practice. J. Neurophysiol. 79: 1117–1123, 1998. The process of acquiring motor skills through the sustained performance of complex movements is associated with neural plasticity. However, it is unknown whether even simple movements, repeated over a short period of time, are effective in inducing cortical representational changes. Whether the motor cortex can retain specific kinematic aspects of a recently practiced movement is also unknown. We used focal transcranial magnetic stimulation (TMS) of the motor cortex to evoke isolated and directionally consistent thumb movements. Thumb movements then were practiced in a different direction. Subsequently, TMS came to evoke movements in or near the recently practiced direction for several minutes before returning to the original direction. To initiate a change of the TMS-evoked movement direction, 15 or 30 min of continuous training were required in most of the subjects and, on two occasions, as little as 5 or 10 min. Substantially smaller effects followed more direct stimulation of corticofugal axons with transcranial electrical stimulation, pointing to cortex as the site of plasticity. These findings suggest that the training rapidly, and transiently, established a change in the cortical network representing the thumb, which encoded kinematic details of the practiced movement. This phenomenon may be regarded as a short-term memory for movement and be the first step of skill acquisition.

1 Blockade of uptake carriers of γ-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 ≈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 GABA_B 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 GABA_A receptor-mediated inhibition via presynaptic GABA_B 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.

Associative stimulation has been shown to enhance excitability in the human motor cortex (Stefan et al. 2000); however, little is known about the underlying mechanisms. An interventional paired associative stimulation (IPAS) was employed consisting of repetitive application of single afferent electric stimuli, delivered to the right median nerve, paired with single pulse transcranial magnetic stimulation (TMS) over the optimal site for activation of the abductor pollicis brevis muscle (APB) to generate approximately synchronous events in the primary motor cortex. Compared to baseline, motor evoked potentials (MEPs) induced by unconditioned, single TMS pulses increased after IPAS. By contrast, intracortical inhibition, assessed using (i) a suprathreshold test TMS pulse conditioned by a subthreshold TMS pulse delivered 3 ms before the test pulse, and (ii) a suprathreshold test TMS pulse conditioned by afferent median nerve stimulation delivered 25 ms before the TMS pulse, remained unchanged when assessed with appropriately matching test stimulus intensities. The increase of single‐pulse TMS‐evoked MEP amplitudes was blocked when IPAS was performed under the influence of dextromethorphan, an N‐methyl‐d‐aspartate (NMDA) receptor antagonist known to block long‐term potentiation (LTP). Further experiments employing the double‐shock TMS protocol suggested that the afferent pulse, as one component of the IPAS protocol, induced disinhibition of the primary motor cortex at the time when the TMS pulse, as the other component of IPAS, was delivered. Together, these findings support the view that LTP‐like mechanisms may underlie the cortical plasticity induced by IPAS.