Cerebellar modulation of human associative plasticity

Abstract

Paired associative stimulation (PAS) is a method commonly used in human studies of motor cortex synaptic plasticity. It involves repeated pairs of electrical stimuli to the median nerve and transcranial magnetic stimulation (TMS) of the motor cortex. If the interval between peripheral and TMS stimulation is around 21–25 ms, corticospinal excitability is increased for the following 30–60 min via a long term potentiation (LTP)-like effect within the primary motor cortex. Previous work has shown that PAS depends on the present and previous levels of activity in cortex, and that it can be modified by motor learning or attention. Here we show that simultaneous transcranial direct current stimulation (TDCS; 2 mA) over the cerebellum can abolish the PAS effect entirely. Surprisingly, the effect is seen when the PAS interval is 25 ms but not when it is 21.5 ms. There are two implications from this work. First, the cerebellum influences PAS effects in motor cortex; second, LTP-like effects of PAS have at least two different mechanisms. The results are relevant for interpretation of pathological changes that have been reported in response to PAS in people with movement disorders and to changes in healthy individuals following exercise or other interventions.

Figure 1. Modulation of PAS25 by cerebellar DC

A, mean (±SEM) amplitudes of MEPs before (baseline), immediately after (T0), and after 30 min (T30) of PAS25 with cerebellar DC (sham-PAS25, white circles; anodal-PAS25, black circles; cathodal-PAS25, grey circles). Asterisks indicate significant difference from baseline MEP sizes (P < 0.05 with Bonferroni's multiple correction). B, grand average of normalized MEPs at T0 and T30 to baseline in each session. Asterisks indicate significant difference from sham-PAS25 (P < 0.05 with Bonferroni's multiple correction).

Figure 2. Motor thresholds, recruitment curves, and short afferent inhibition

A, RMT and AMT before and after each intervention. RMT, circles; AMT, triangles. White, sham-PAS25; black, anodal-PAS25; grey, cathodal-PAS25. No significant effect of TIME in each condition was found. B, the recruitment curve before and after intervention (left, sham-PAS25; middle, anodal-PAS25; right, cathodal-PAS25). After sham-PAS25, there were strong trend for the effects of TIME (F (2, 22) = 2.923, P = 0.075) indicating time-dependent increase of slope of the recruitment curve. Post hoc analysis with Bonferroni's correction showed strong trend for the increase in the slope after T30 (P = 0.077). C and D, SAI changes in each condition (C for ISI at 20 ms; D for ISI at 25 ms). No significant effects of TIME in each condition were found.

Figure 3. Modulation of PAS25 and PAS21.5 by anodal cDC

LTP-like plasticity of PAS25 was blocked, whereas that of PAS21.5 was unaltered. Asterisks, P < 0.05 with paired t tests.