Stimulation-induced changes in lower limb corticomotor excitability during treadmill walking in humans

Abstract

Magnetic stimulation of human primary motor cortex (M1) paired with electrical stimulation of a peripheral motor nerve has been used to produce a lasting modulation of corticomotor (CM) excitability. This 'paired associative stimulation' (PAS) protocol has been used to induce bidirectional changes in excitability in upper limb CM pathways. The present study tested the hypothesis that temporally dependent PAS applied to the common peroneal nerve during the swing phase of walking would induce bidirectional changes in CM excitability consistent with the Hebbian principle of activity-dependent plasticity. Fourteen subjects with no known neurological disorder participated in two data collection sessions each. PAS was delivered as a single block of 120 pairs of stimuli delivered in a 10 min period during treadmill walking at 4.0 km h(-1). Changes in CM excitability were assessed by examining the size of motor potentials evoked by transcranial magnetic stimulation prior to and following PAS. Tibialis anterior motor-evoked potentials amplitude increased to 121% over baseline when the magnetic stimulus was delivered over M1 after the estimated arrival time of the afferent volley in sensorimotor cortex and decreased to 83% of baseline when the magnetic stimulus was delivered prior to the estimated afferent volley arrival. This extent of modulation was undiminished following a further 10 min period of walking without stimulation. The temporal nature of the bidirectional effects following PAS, their rapid evolution and subsequent persistence supported the study's hypothesis and were similar to the effects described by others in quiescent muscles of the upper limb.

Figure 1. Schematics of experimental protocols

The main experimental sessions are illustrated in A, where in the first session, odd-numbered subjects received PAS_inhib and even-numbered subjects received PAS_fac. In the second session odd-numbered subjects received PAS_fac and even-numbered subjects received PAS_inhib. Time points when Pre, Post₀ and Post₁₀ measures were made during the 20 min period of treadmill walking are illustrated in B. Similarly, the time points when measures were made during the 50 min period of walking for the control experiments are illustrated in C. After Pre measures were made, control sessions always began with a 10 min period of walking without stimulation, followed immediately by a 10 min period of PN stimulation only for even-numbered subjects and TMS only for odd-numbered subjects. The type of stimulation was reversed for the third 10 min period. During the fourth and fifth 10 min periods, PAS was applied in the same manner as the main experiment. In the first control session even-numbered subjects received PAS_fac and odd-numbered subjects received PAS_inhib. In the second control session even-numbered subjects received PAS_inhib and odd-numbered subjects received PAS_fac.

Figure 2. Sample EMG recorded simultaneously from the right TA and the left Sol during late swing and late stance, respectively

Four seconds of EMG from Subject V showing bursts in right TA (top trace) and left Sol (middle trace) during treadmill walking at 4.0 km h⁻¹. The bottom trace indicates when the TMS trigger occurred during late swing and late stance, respectively. Simultaneous MEPs (including the post-MEP silent period) can be distinguished in each trace at the time of the trigger. These MEPs are illustrated on a larger scale in the boxes below. Left box, TA MEP; right box, Sol MEP. The TA MEP is typically triphasic and the Sol MEP is typically polyphasic.

Figure 3. Individual and group means of MEP amplitude showing facilitation following PAS_fac and inhibition following PAS_inhib

Individual responses for fourteen subjects in stimulated TA CM pathways following PAS_fac (A) and PAS_inhib (B) showing persistent modulation in group means illustrated by the thick continuous line. All values are expressed as a percentage of Pre.

Figure 4. A comparison of TA MEP amplitude for individual subjects following PAS_fac in stimulated and non-stimulated TA CM pathways

Means for individual subjects are illustrated in stimulated limb and non-stimulated limb TA CM pathways. Stimulated (Stim) and non-stimulated (Non-Stim) values are subject's means of responses recorded immediately after a 10 min period of stimulation (Post₀) and at the end of a further 10 min of walking without stimulation (Post₁₀). The group means are illustrated by the thick continuous line. The horizontal thin dashed line represents Pre values. Values for four subjects (I, III, IV, VIII) that are highlighted with thick dashed lines and large symbols revealed inhibition in non-stimulated TA CM pathways.

Figure 5. Group means of MEP amplitude and MEP area reveal a persistent effect of PAS_fac in stimulated TA pathways but no effect in non-stimulated TA pathways

The comparison of mean MEP size (A, amplitude; B, rectified area) during late swing recorded from stimulated TA pathways and during late swing recorded from non-stimulated TA pathways (contralateral). MEP size is expressed as a percentage of pre-intervention (Pre). Open bars represent the means of Post₀, and filled bars represent the means of Post₁₀ responses. The horizontal dashed line represents the Pre mean. Non-bracketed stars indicate the significance of the difference of the means from 100% (one-tailed t tests). Bracketed stars indicate the significance of the difference between Stim and Non-Stim means (2-way repeated measures ANOVA). *P < 0.05; **P < 0.01; ***P < 0.001. Error bars represent 1 s.e.m.

Figure 6. Group means of MEP amplitude and MEP area reveal a persistent effect of PAS_inhib in stimulated TA pathways but no effect in non-stimulated TA pathways

The comparison of mean MEP size (A, amplitude; B, rectified area) during late swing recorded from stimulated (Stim) TA pathways and during late swing recorded from non-stimulated (Non-Stim) TA pathways (contralateral). MEP size is expressed as a percentage of pre-intervention (Pre). Open bars represent the means of Post₀, and filled bars represent the means of Post₁₀ responses. The horizontal dashed line represents the Pre mean. Stars indicate the significance of the difference of the means from 100% (one-tailed t tests). *P < 0.05; **P < 0.01; ***P < 0.001, d.f. 13. Error bars represent 1 s.e.m.

Figure 7. Subjects who revealed robust facilitation in response to PAS_fac also revealed robust inhibition in response to PAS_inhib

A comparison of the effects of PAS_fac and PAS_inhib in each subject. A, averaged Post₀ and Post₁₀ values of individual subject's means. The thick line represents the group mean. B, a scatter plot of means from subjects I, V, VI, VIII, IX, XI and XIII with fac-inhib differences of > 40 revealing that although greater facilitation was associated with less inhibition, subjects who demonstrated robust facilitation in one session also demonstrated robust inhibition in the other session (P = 0.005).

Figure 8. Only the group mean of MEP area recorded from Sol in the stimulated limb during late stance following PAS_fac of TA pathways differed from unity

The comparison of mean MEP size (A, amplitude; B, rectified area) during late stance recorded from the Sol ipsilateral to the stimulated TA pathways (‘Stim’) and during late stance recorded from the Sol ipsilateral to the non-stimulated TA pathways (‘Non-Stim’). MEP size expressed as a percentage of pre-intervention (Pre). Open bars represent the means of Post₀, and filled bars represent the means of Post₁₀ responses. The horizontal dashed line represents the Pre mean. The star indicates that the mean differed from 100% (one-tailed t test), P < 0.05. Error bars represent 1 s.e.m.

Figure 9. Control conditions during walking did not significantly modulate MEP size

▪, the means of the four control subjects (VI, VII, IX, XIII) during the session that culminated in PAS_fac. •, the means of the four control subjects during the session that culminated in PAS_inhib. Filled symbols represent means expressed as a percentage of Pre_walk. Open symbols represent means expressed as a percentage of either Post_TMS or Post_PN. Stars indicate that means of unsigned changes in MEP amplitude following PAS_fac and PAS_inhib that were grouped for statistical analysis differed from 100% (see text for details). Error bars are 1 s.e.m.