Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation

Abstract

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.

Figure 1. Paired-TMS pulse inhibition (Kujirai et al. 1993) following IPAS; influence of test stimulus efficacy

Before IPAS, test stimulus intensities were adjusted to produce an unconditioned MEP response of approximately 1.0, 1.5 mV or 2.0 mV in the relaxed APB (SI_1mV-PRE, SI_1.5mV-PRE, SI_2mV-PRE). Paired-TMS pulse inhibition was assessed prior to, and following IPAS by conditioning the test pulse by a subthreshold stimulus at 3 ms. Larger test stimulus amplitudes were associated with larger CR3 amplitudes corresponding to a reduction of paired-TMS-pulse inhibition. A, data from a representative subject. Following IPAS, the relative size of the conditioned MEP elicited using a test stimulus intensity = SI_1mV-PRE was larger (i.e. less paired-TMS-pulse inhibition) when compared with the conditioned MEP elicited using a test stimulus intensity = SI_1mV-PRE before IPAS, and similar to the conditioned MEP elicited using a test stimulus intensity = SI_1.5mV-PRE before IPAS. Each record shows the average of 15 trials. B, group data (means ± s.e.m.) from 12 subjects. CR3 (ordinate) is shown as a function of the magnitude of unconditioned test response (abscissa). ○, CR3 as assessed prior to IPAS at different test stimulus intensities producing an unconditioned MEP response of approximately 1.0, 1.5 or 2.0 mV. Following IPAS (▴), mean CR3 and resting amplitude, using SI_1mV-PRE, increased when compared to CR3 or resting amplitude as assessed prior to IPAS. * Significant differences pre vs. post IPAS. For linear regression analysis see Results.

Figure 2. Paired-TMS pulse inhibition (Kujirai et al. 1993) following IPAS; influence of conditioning stimulus intensity and adjustment of test stimulus intensity

A, adjustment of test stimulus intensity. Data from a representative subject. Following IPAS, the relative size of the conditioned MEP elicited using a test stimulus intensity = SI_1mV-PRE was larger (i.e. less paired-TMS-pulse inhibition) when compared with the conditioned MEP elicited using a test stimulus intensity = SI_1mV-PRE before IPAS. When the test stimulus intensity was adjusted to produce a MEP amplitude of approximately 1 mV (SI_1mV-POST), the conditioned MEP matched the size as before IPAS. Each record shows the average of 20 trials. B, influence of conditioning stimulus intensity and adjustment of test stimulus intensity. Data (means ± s.d.) from 6 subjects. CR3 (ordinate) is shown as a function of the intensity of the conditioning stimulus (abscissa). CR3 was assessed before (□) and after (▪ and ░) IPAS. Stimulus intensity was SI_1mV-PRE (□ and ▪), or SI_1mV-POST (░). Following IPAS, mean CR3 increased when using a conditioning stimulus intensity of 70 % of resting motor threshold and a test stimulus intensity of SI_1mV-PRE. With test stimulus set to SI_1mV-POST, CR3 matched that measured prior to IPAS. * Significant differences pre vs. post IPAS.

Figure 3. Short-latency inhibition by afferent input (Tokimura et al. 2000)

Short-latency inhibition before (□) and after (▪ and ░) IPAS. The size of MEPs conditioned by median nerve stimulation was normalized to the size of unconditioned MEPs elicited by magnetic pulses of the same intensity. MEPs were elicited with the test stimulus intensity set to SI_1mV-PRE (□ and ▪), or SI_1mV-POST (░). Data from 6 subjects. Data show means ± s.d.

Figure 4. Effect of dextromethorphan on IPAS induced plasticity

□, before IPAS; ▪, after IPAS. Data of two blocks of experiments, performed in 6 subjects each. Individual data from block 1 (▪) and block 2 (♦), are shown in the innermost part of each panel. Bars show means (± s.d.) of eight experimental sessions each. The ordinate of the right panel was scaled to match the control MEP size with that obtained in the placebo experiments, to facilitate comparison between the experiments. *Significant difference pre vs. post IPAS with placebo.