Associative plasticity in the human motor cortex is enhanced by concurrently targeting separate muscle representations with excitatory and inhibitory protocols

Abstract

Paired associative stimulation (PAS) induces changes in the excitability of human sensorimotor cortex that outlast the procedure. PAS typically involves repeatedly pairing stimulation of a peripheral nerve that innervates an intrinsic hand muscle with transcranial magnetic stimulation over the representation of that muscle in the primary motor cortex. Depending on the timing of the stimuli (interstimulus interval of 25 or 10 ms), PAS leads to either an increase (PAS25) or a decrease (PAS10) in excitability. Both protocols, however, have been associated with an increase in excitability of nearby muscle representations not specifically targeted by PAS. Based on these spillover effects, we hypothesized that an additive, excitability-enhancing effect of PAS25 applied to one muscle representation may be produced by simultaneously applying PAS25 or PAS10 to a nearby representation. In different experiments prototypical PAS25 targeting the left thumb representation [abductor pollicis brevis (APB)] was combined with either PAS25 or PAS10 applied to the left little finger representation [abductor digiti minimi (ADM)] or, in a control experiment, with PAS10 also targeting the APB. In an additional control experiment PAS10 targeted both representations. The plasticity effects were quantified by measuring the amplitude of motor evoked potentials (MEPs) recorded before and after PAS. As expected, prototypical PAS25 was associated with an increase in MEP amplitude in the APB muscle. This effect was enhanced when PAS also targeted the ADM representation but only when a different interstimulus timing (PAS10) was used. These results suggest that PAS-induced plasticity is modified by concurrently targeting separate motor cortical representations with excitatory and inhibitory protocols.

Keywords: motor cortex; motor evoked potential; paired associative stimulation; plasticity; transcranial magnetic stimulation.

Fig. 1.

Experimental design. Plasticity was induced in the motor cortex with paired associative stimulation (PAS). As shown on left, the technique repeatedly paired transcranial magnetic stimulation (TMS) over right motor cortex with stimulation of the ulnar (UN) and/or median (MN) nerve at the left wrist. PAS-induced effects were investigated by measuring motor evoked potentials (MEPs) and resting motor threshold (rMT) with single-pulse TMS before and after the procedure (top right inset). In different experiments PAS was delivered to 1 nerve or concurrently to both nerves at 1 or 2 interstimulus intervals, as shown in table at bottom right.

Fig. 2.

Mean MEP amplitude in the APB before and after PAS and individual differences in the PAS-induced effects. A: after prototypical PAS (PAS_MN25) mean MEPs increased in the APB. This effect was larger, and reached statistical significance, after PAS that concurrently targeted the median and ulnar nerves with different timings (PAS_MN25+UN10). *P < 0.05. Error bars show SE. B: change in MEP amplitude (relative to baseline) averaged across the 2 post-PAS time points is shown for each participant (circles). Horizontal lines show the mean response for each experiment.

Fig. 3.

Mean MEP amplitude in the ADM before and after PAS and individual differences in the PAS-induced effects. A: after PAS mean MEPs in the ADM showed a pattern of increases similar to those in the APB (Fig. 2A). Overall, MEP amplitudes increased significantly after PAS, and exploratory analysis revealed a significant increase in the PAS_MN25+UN10 condition. Error bars show SE. B: PAS-induced changes in MEP amplitudes in the ADM showed interindividual variability similar to those seen in the APB (Fig. 2B). This variability is even evident in cases where the ADM was not targeted by peripheral nerve stimulation (i.e., PAS_MN25 and PAS_MN25+MN10).