Abstract
BackgroundTraining of a repetitive synchronised movement of two limb muscles leads to short-term plastic changes in the primary motor cortex, which can be assessed by transcranial magnetic stimulation (TMS) mapping. We used this paradigm to study the effect of memantine, a NDMA antagonist, on short-term motor cortex plasticity in 20 healthy human subjects, and we were especially interested in possible differential effects of different treatment regimens. In a randomised double-blinded cross over study design we therefore administered placebo or memantine either as a single dosage or as an ascending dosage over 8 days. Before and after one hour of motor training, which consisted of a repetitive co-contraction of the abductor pollicis brevis (APB) and the deltoid muscle, we assessed the motor output map of the APB muscle by TMS under the different conditions.ResultsWe found a significant medial shift of the APB motor output map after training in the placebo condition, indicating training-induced short-term plastic changes in the motor cortex. A single dosage of memantine had no significant effect on this training-induced plasticity, whereas memantine administered in an ascending dosage over 8 days was able to block the cortical effect of the motor training. The memantine serum levels after 8 days were markedly higher than the serum levels after a single dosage of memantine, but there was no individual correlation between the shift of the motor output map and the memantine serum level. Besides, repeated administration of a low memantine dosage also led to an effective blockade of training-induced cortical plasticity in spite of serum levels comparable to those reached after single dose administration, suggesting that the repeated administration was more important for the blocking effect than the memantine serum levels.ConclusionWe conclude that the NMDA-antagonist memantine is able to block training-induced motor cortex plasticity when administered over 8 days, but not after administration of a single dose. This differential effect might be mainly due to the prolonged action of memantine at the NMDA receptor. These findings must be considered if clinical studies are designed, which aim at evaluating the potency of memantine to prevent "maladaptive" plasticity, e.g. after limb amputation.
Highlights
Training of a repetitive synchronised movement of two limb muscles leads to short-term plastic changes in the primary motor cortex, which can be assessed by transcranial magnetic stimulation (TMS) mapping
Training effect on mapping parameters and map reproducibility Looking at the placebo sessions of all 15 subjects participating in the placebo-controlled experiments, we found a significant medial shift of the amplitude-weighted centre of gravity (COG) of the motor output map of the abductor pollicis brevis (APB) muscle (y coordinate before training -5.12 ± 0.64 cm mean ± SD, after training -5.02 ± 0.58 cm, paired t-test, p = 0.022) after motor training
This COG shift was accompanied by a significant lowering of the motor threshold (MT before training 37.4 ± 6.0%, after training 36.7 ± 5.5%, p = 0.019)
Summary
Training of a repetitive synchronised movement of two limb muscles leads to short-term plastic changes in the primary motor cortex, which can be assessed by transcranial magnetic stimulation (TMS) mapping. Serial TMS mappings can be used to assess short-term plastic changes of the motor cortex induced by the repetitive performance of a motor task consisting of a synchronised movement of two limb muscles This was demonstrated by a shift of the centre of gravity (COG) of the motor output map derived from a small hand muscle towards the representation of the co-contracted shoulder [9] or leg muscle [10]. This model was used to study the effect of different central acting drugs on short-term motor cortex plasticity: The GABAA agonist lorazepam and the N-methyl-D-aspartate (NMDA)-antagonist amantadine were found to block such cortical plastic changes [11], whereas the indirect dopaminergic and adrenergic agonist amphetamine and the serotonin reuptake inhibitor fluoxetine enhanced training induced cortical plasticity [12,13]. These results support the view that short-term plastic changes in the motor cortex are based on functional changes of synaptic activity, requiring removal of local (presumably GABAA mediated) inhibition, as well as long-term potentiation (LTP)like changes which are mediated through NMDA receptor activation [20,21,22]
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