Paired associative stimulation (PAS) can increase motor cortical excitability, possibly by long-term potentiation (LTP)-like mechanisms. As the capability of the cortex for plasticity decreases with age, we were interested here in testing interindividual variability and age-dependency of the PAS effect. Motor-evoked potentials (MEPs) were recorded from the resting right abductor pollicis brevis muscle before and for 30 min after PAS in 27 healthy subjects (22-71 years of age). PAS consisted of 225 pairs (rate, 0.25 Hz) of right median nerve stimulation followed at an interval equaling the individual N20-latency of the median nerve somatosensory-evoked cortical potential plus 2 ms by transcranial magnetic stimulation of the hand area of left primary motor cortex (PAS(N20+2)). The PAS(N20+2)-induced changes in MEP amplitude (ratio post PAS/pre PAS) were highly variable (1.00 +/- 0.07, range 0.36-1.68). Fourteen subjects showed the expected LTP-like MEP increase (responders) while 13 subjects showed a long-term depression (LTD)-like MEP decrease (non-responders). Responders had a significantly lower resting motor threshold (RMT) and minimum stimulus intensity to elicit MEPs of 1 mV (MEP(1 mV)) than non-responders. RMT and MEP(1 mV) correlated significantly negatively with the PAS(N20+2) effect. The absolute PAS(N20+2) effect size irrespective of its direction decreased with age (r = -0.57, P = 0.002), i.e., LTP-like and LTD-like plasticity were large in young subjects but substantially smaller in elderly subjects. In conclusion, measures of motor cortical excitability (RMT, MEP(1 mV)) and age determine direction and magnitude of PAS effects in individual subjects.

Long-term potentiation (LTP) and long-term depression (LTD) underlie most models of learning and memory, but neural activity would grow or shrink in an uncontrolled manner, if not guarded by stabilizing mechanisms. The Bienenstock-Cooper-Munro (BCM) rule proposes a sliding threshold for LTP/LTD induction: LTP induction becomes more difficult if neural activity was high previously. Here we tested if this form of homeostatic plasticity applies to the human motor cortex (M1) in vivo by examining the interactions between two consecutive sessions of paired associative stimulation (PAS). PAS consisted of repeated pairs of electrical stimulation of the right median nerve followed by transcranial magnetic stimulation of the left M1. The first PAS session employed an interstimulus interval equalling the individual N20-latency of the median nerve somatosensory-evoked cortical potential plus 2 ms, N20-latency minus 5 ms, or a random alternation between these intervals, to induce an LTP-like increase in motor-evoked potential (MEP) amplitudes in the right abductor pollicis brevis muscle (PAS(LTP)), an LTD-like decrease (PAS(LTD)), or no change (PAS(Control)), respectively. The second PAS session 30 min later was always PAS(LTP). It induced an moderate LTP-like effect if conditioned by PAS(Control), which increased if conditioned by PAS(LTD), but decreased if conditioned by PAS(LTP). Effects on MEP amplitude induced by the second PAS session exhibited a negative linear correlation with those in the first PAS session. Because the two PAS sessions activate identical neuronal circuits, we conclude that 'homosynaptic-like' homeostatic mechanisms in accord with the BCM rule contribute to regulating plasticity in human M1.

Electromyographic mirror activity (MA) refers to involuntary activation of the non-active limb during intended strictly unilateral movements of the other limb. MA occurs in the majority of healthy adults but little is known about its neurophysiological foundation. Here we examined in healthy adults the hypothesis that transcallosal interhemispheric inhibition (IHI) between the primary motor cortices determines the extent to which MA occurs. IHI was tested by an established paired transcranial magnetic stimulation protocol [A. Ferbert et al. (1992) J. Physiol. (Lond.), 453, 525-546]. In a first experiment we found that the magnitudes of IHI and MA were inversely correlated. In a second experiment we sought to establish a more causative relation by exploring the changes induced by low-frequency repetitive transcranial magnetic stimulation of primary motor cortex on IHI and MA. These changes were also significantly inversely correlated, i.e. a repetitive transcranial magnetic stimulation-induced increase in IHI was associated with a decrease in MA, and a decrease in IHI was associated with an increase in MA. These results provide strong and consistent evidence that transcallosal inhibitory interhemispheric interaction provides a significant route by which unwanted MA during intended unimanual motor tasks can be controlled.

In the published paper of Müller et al. (2007), there was an error in the last paragraph of results (on page 3465); the P-value was not 0.0047 as printed, but 0.047. We apologize for this error, and reproduce the corrected sentence here.Regression analysis of the data from individual subjects revealed a significant negative linear correlation (r ¼ 0.43, P ¼ 0.047) between the PAS1 and the corrected PAS2 effects.