Voluntary motor output is altered by spike-timing-dependent changes in the human corticospinal pathway

Repeated pairs of timed presynaptic and postsynaptic potentials cause lasting changes in efficacy of transmission at many synapses. The corticospinal tract is the major pathway controlling voluntary movement in humans, and corticospinal neurons have monosynaptic connections to motoneurons of many muscles. We hypothesized that corticospinal transmission in humans could be altered by delivering, to the corticospinal-motoneuronal synapses, timed pairs of presynaptic volleys (produced by cortical stimulation) and antidromic postsynaptic volleys (by peripheral nerve stimulation). To test corticospinal transmission, electrical cervicomedullary stimuli evoked motor responses [cervicomedullary motor-evoked potentials (CMEPs)] in biceps brachii before and for 1 h after conditioning with 50 paired cortical and peripheral nerve stimuli. Seven interstimulus intervals (ISIs) of conditioning stimulus pairs were tested on different days. With one ISI (+3 ms; cortical before peripheral nerve stimulation), CMEPs were significantly increased in size by 33 +/- 30% (mean +/- SD; n = 7) from 4 until 32 min after conditioning. With two other ISIs (-13 ms, +22 ms), CMEPs were decreased from approximately 30 until 60 min after conditioning (by 25 +/- 23% and 27 +/- 32%; n = 8). The remaining ISIs produced no changes. In a second study, subjects performed weak bilateral voluntary elbow flexion contractions before and after conditioning of the right elbow flexors. Conditioning ISIs that increased or decreased CMEPs similarly increased or decreased voluntary force and EMG on the right. Thus, depending on their timing, repeated paired stimuli can potentiate or depress corticospinal transmission, and these changes are functionally relevant. We suggest that bidirectional spike-timing-dependent plasticity can be induced at corticospinal-motoneuronal synapses and can influence voluntary motor output.