Mechanisms of use-dependent plasticity in the human motor cortex

Abstract

Practicing movements results in improvement in performance and in plasticity of the motor cortex. To identify the underlying mechanisms, we studied use-dependent plasticity in human subjects premedicated with drugs that influence synaptic plasticity. Use-dependent plasticity was reduced substantially by dextromethorphan (an N-methyl-d-aspartate receptor blocker) and by lorazepam [a gamma-aminobutyric acid (GABA) type A receptor-positive allosteric modulator]. These results identify N-methyl-d-aspartate receptor activation and GABAergic inhibition as mechanisms operating in use-dependent plasticity in intact human motor cortex and point to similarities in the mechanisms underlying this form of plasticity and long-term potentiation.

Figure 1

(a) Acceleration signals were recorded in the horizontal (extension and flexion) and vertical (abduction and adduction) axes of thumb movements. The direction of TMS-evoked or voluntary movement was derived from the first-peak acceleration in the two major axes of the movement. (b) Schematic diagram of the directional change of first-peak-acceleration vector of movements evoked by TMS after 30 min of training. At baseline, TMS evoked predominantly extension and abduction thumb movements. Therefore, training consisted of repetitive, stereotyped, brisk thumb movements in a flexion and adduction direction. Posttraining, the direction of TMS-evoked thumb movements changed from the baseline direction to the trained direction. (c) Circular frequency histogram from one representative subject. Baseline TMS-induced movement directions are predominantly a combination of extension and abduction. The open arrow indicates the mean training direction at the center of the training target zone (TTZ). The scale shows the number of TMS-evoked movements that fall in each 10° bin (see Methods). TMS-induced movement directions after training fell largely within the TTZ, close to a 180° change from the baseline direction. Circular frequency histograms in the following figures are constructed in the same way.

Figure 2

Drug effects on directional distribution of TMS-evoked movements in a single subject. Directions of TMS-evoked movements are shown in pairs of circular histograms, baseline (Upper) and posttraining (Lower). Frequencies are plotted on the same scale. Directions are grouped in bins of 10°. Mean training angle (arrow) and TTZ for all conditions are shown in a. In the control (a) and LG (b) condition, TMS-evoked movements at baseline were mainly in the extension/abduction (ext./abd.) direction (Inset). Posttraining, the majority of TMS-evoked movements occurred in TTZ, in the flexion/adduction (flex./add.) direction. LZ (c) and DM (d) blocked the training effect. TMS-evoked movements remained in the ext./abd. direction after training.

Figure 3

Drug effects on TMS-evoked movements in TTZ in five subjects. (a) Control condition. Proportion of TMS-evoked movements that occurred in TTZ at baseline and 0–10, 10–20, and 20–30 min after the training was completed (mean ± SE). Compared with baseline, the number of movements that occurred in TTZ increased significantly after training (0–10 min) and remained high for at least 30 min. (b) Posttraining (0–10 min) condition. Increase in the proportion of movements falling in the TTZ in the control and drug conditions (mean ± SE). LZ and DM blocked the increase in proportions seen in the control condition. *, P < 0.025.

Figure 4

Drug effects on MEP amplitudes in five subjects. (a) Amplitudes for MEP_baseline (□) and MEP_training (●) at baseline (pre) and posttraining p1 (0–10 min), p2 (10–20 min), and p3 (20–30 min). For the LZ condition, only p1 and p2 are shown, because one subject did not complete p3. At baseline, MEP_baseline amplitude exceeded that of MEP_training in all conditions. (b) MEP_training/MEP_baseline amplitude ratios (mean ± SE) at baseline (pre) and posttraining (p1, p2, and p3). In the control and LG conditions, training resulted in MEP_training/MEP_baseline amplitude ratios (♦) >1. By contrast, LZ and DM blocked these training-induced changes, resulting in MEP_training/MEP_baseline amplitude ratios <1.