Primary motor cortical metaplasticity induced by priming over the supplementary motor area

Abstract

Motor cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS) sometimes depends on the prior history of neuronal activity. These effects of preceding stimulation on subsequent rTMS-induced plasticity have been suggested to share a similar mechanism to that of metaplasticity, a homeostatic regulation of synaptic plasticity. To explore metaplasticity in humans, many investigations have used designs in which both priming and conditioning are applied over the primary motor cortex (M1), but the effects of priming stimulation over other motor-related cortical areas have not been well documented. Since the supplementary motor area (SMA) has anatomical and functional cortico-cortical connections with M1, here we studied the homeostatic effects of priming stimulation over the SMA on subsequent rTMS-induced plasticity of M1. For priming and subsequent conditioning, we employed a new rTMS protocol, quadripulse stimulation (QPS), which produces a broad range of motor cortical plasticity depending on the interval of the pulses within a burst. The plastic changes induced by QPS at various intervals were altered by priming stimulation over the SMA, which did not change motor-evoked potential sizes on its own but specifically modulated the excitatory I-wave circuits. The data support the view that the homeostatic changes are mediated via mechanisms of metaplasticity and highlight an important interplay between M1 and SMA regarding homeostatic plasticity in humans.

Figure 1

Timelines of experiments (See Methods.)

Figure 6. Control experiments

A, sham conditioning with real priming did not modify motor cortical excitability. B, the after-effects of QPS-10 ms without priming (open circles) were not different from those of QPS-10 ms with sham priming (grey circles).

Figure 2. QPS-induced plasticity without priming over SMA

A, time courses of MEP amplitude following QPS at various ISIs without priming (mean ±s.e.m.). B, stimulus–response function of QPS-induced plasticity. Normalized amplitudes of MEP measured at 30 min after QPS as a function of the reciprocal of ISI of QPS: mean (±s.e.m.) of baseline. Note that the x-axis is logarithmic. Asterisks denote significant difference from QPS-30 ms (*P < 0.05).

Figure 3. Effects of QPS-5 ms priming over SMA on QPS-induced plasticity

Time courses of MEP amplitude following QPS at various ISIs with (▴) and without (○) QPS-5 ms priming over SMA (mean ±s.e.m.). A, SMA priming did not change subsequent LTP-like plasticity induced by QPS-1.5 ms. B and C, priming reversed MEP sizes induced by QPS-5 ms (B) or QPS-10 ms (C). D, priming enhanced suppression of MEP by QPS-30 ms. E and F, MEP suppression induced by QPS-50 ms (E) and QPS-100 ms (F) were not enhanced, but shortened with SMA priming. Asterisks denote significant difference of MEP sizes with priming from those without priming at each time point (P < 0.05 by post hoc paired t tests).

Figure 4. Effects of QPS-50 ms priming over SMA on QPS-induced plasticity

Time courses of MEP amplitude following QPS at various ISIs with (▾) and without (^) QPS-50 ms priming over SMA (mean ±s.e.m.). A, SMA priming occluded subsequent LTP-like plasticity induced by QPS-5 ms. B, priming did not change plasticity induced by QPS-10 ms. C, priming reversed suppression of MEP by QPS-30 ms. D, MEP suppression induced by QPS-100 ms was not altered with SMA priming. Asterisks denote significant difference of MEP sizes with priming from those without priming at each time point (P < 0.05 by post hoc paired t tests).

Figure 5. Priming-induced shifts in the stimulus–response function

The normalized amplitudes of MEP at 30 min post conditioning as a function of the reciprocal of ISI of QPS with and without priming over SMA (○). A, QPS-5 ms priming (▴). B, QPS-50 ms priming (▾). Note that the x-axis is logarithmic axis. *P < 0.05 by post hoc paired t tests.

Figure 7. Effects of priming over SMA on intracortical circuits of M1

A, SICF was enhanced after QPS-5 ms. SICI, ICF nor LICI were altered by QPS-5 ms priming over SMA alone. B, SICF was suppressed after QPS-50 ms over SMA, whereas others were not altered. Baseline (white bars); post 1 (grey bars), 0–6 min after QPS; post 2 (black bars), 20–26 min after QPS over SMA. *P < 0.05 by post hoc Dunnett's test.

Figure 8. Effects of a conditioning stimulus over SMA on MEP

The test MEPs evoked by the left M1_FDI was conditioned by stimulation of SMA at an ISI of 3 ms (A) or at an ISI of 6 ms (B). Asterisks denote a significant change relative to unconditioned response.