Mechanisms of deafferentation-induced plasticity in human motor cortex

Abstract

Deafferentation induces rapid plastic changes in the cerebral cortex, probably via unmasking of pre-existent connections. Several mechanisms may contribute, such as changes in neuronal membrane excitability, removal of local inhibition, or various forms of short- or long-term synaptic plasticity. To understand further the mechanisms involved in cortical plasticity, we tested the effects of CNS-active drugs in a plasticity model, in which forearm ischemic nerve block (INB) was combined with low-frequency repetitive transcranial magnetic stimulation (rTMS) of the deafferented human motor cortex. rTMS was used to upregulate the plastic changes caused by INB. We studied six healthy subjects. In two control sessions without drug application, INB plus rTMS increased the motor-evoked potential (MEP) size and decreased intracortical inhibition (ICI) measured with single- and paired-pulse TMS in the biceps brachii muscle proximal to INB. A single oral dose of the benzodiazepine lorazepam (2 mg) or the voltage-gated Na+ and Ca2+ channel blocker lamotrigine (300 mg) abolished these changes. The NMDA receptor blocker dextromethorphan (150 mg) suppressed the reduction in ICI but not the increase in MEP size. With sleep deprivation, used to eliminate sedation as a major factor of these drug effects, INB plus rTMS induced changes similar to that seen in the control sessions. The findings suggest that (1) the INB plus rTMS-induced increase in MEP size involves rapid removal of GABA-related cortical inhibition and short-term changes in synaptic efficacy dependent on Na+ or Ca2+ channels and that (2) the long-lasting (>60 min) reduction in ICI is related to long-term potentiation-like mechanisms given its duration and the involvement of NMDA receptor activation.

Fig. 1.

Effect of intervention on the changes in MT induced by ischemic forearm deafferentation and repetitive transcranial magnetic stimulation of the motor cortex contralateral to the side of ischemic nerve block. Changes in MT measured late into ischemia (circles) and 20 min (squares) and 60 min (triangles) after the end of ischemia are shown as differences from measurements obtained before the start of ischemia. These differences are given as a percentage of the maximal stimulator output (y-axis). Data are mean values of six subjects; error bars indicate SEM. Interventions are indicated (x-axis).

Fig. 2.

Effect of intervention on the increase in MEP amplitude induced by ischemic forearm deafferentation and repetitive transcranial magnetic stimulation of the motor cortex contralateral to the side of ischemic nerve block. Changes in MEP size measured late into ischemia (circles) and 20 min (squares) and 60 min (triangles) after the end of ischemia are given as differences (Δ mV) from the values obtained before ischemic nerve block, which were assigned a value of 0 (y-axis). Other conventions and arrangements are described in Figure 1. Note that LZP and LTG led to suppression of the ischemia plus transcranial magnetic stimulation-induced increase in MEP size. *p < 0.05; **p < 0.01.

Fig. 3.

Effect of intervention on the decrease in ICI induced by ischemic forearm deafferentation and repetitive transcranial magnetic stimulation of the motor cortex contralateral to the side of ischemic nerve block. ICI values measured late into ischemia (circles) and 20 min (squares) and 60 min (triangles) after the end of ischemia are given as differences from the values obtained before ischemic nerve block. Because ICI values are percentages of conditioned to control motor-evoked potential amplitudes, the changes in ICI are expressed in Δ% (y-axis). Differences >0 indicate a decrease in ICI. Other conventions and arrangements are described in Figures 1 and 2. Note that DM, LZP, and LTG led to significant suppression of the ischemia plus transcranial magnetic stimulation-induced decrease in intracortical inhibition. *p < 0.05.

Fig. 4.

EMG recordings from the biceps brachii muscle of one subject, illustrating the effects of intervention on the increase in MEP size (A) and on the decrease in intracortical inhibition (B) induced by ischemic forearm deafferentation and repetitive transcranial magnetic stimulation of the motor cortex contralateral to ischemic nerve block.A, MEPs obtained before ischemic nerve block (gray lines) and late into ischemia (black lines) are superimposed. The numbers (in mV) refer to the deafferentation-induced change in MEP size.B, Control MEPs produced by the test stimulus alone (gray lines) and MEPs elicited by paired stimulation at an interstimulus interval of 2 msec (black lines) are superimposed. For each intervention, thetop and bottom traces refer to MEPs obtained before and late into forearm ischemia, respectively. Thepercentages indicate the amount of intracortical inhibition and the difference (Dif) in intracortical inhibition before and late into ischemia. All MEPs are averages of eight single trials. Calibration bars: A, 20 msec, 0.5 mV; B, 20 msec, 0.25 mV. Note that LTG and LZP led to virtually complete abolition of the deafferentation-induced increase in MEP size in this subject. Furthermore, both of these drugs and DM had a suppressive effect on the deafferentation-induced decrease in intracortical inhibition.