Learning may alter rapidly the output organization of adult motor cortex. It is a long-held hypothesis that modification of synaptic strength along cortical horizontal connections through long-term potentiation (LTP) and long-term depression (LTD) forms one important mechanism for learning-induced cortical plasticity. Strong evidence in favor of this hypothesis was provided for rat primary motor cortex (M1) by showing that motor learning reduced subsequent LTP but increased LTD. Whether a similar relationship exists in humans is unknown. Here, we induced LTP-like and LTD-like plasticity in the intact human M1 by an established paired associative stimulation (PAS) protocol. PAS consisted of 200 pairs of electrical stimulation of the right median nerve, followed by focal transcranial magnetic stimulation of the hand area of the left M1 at an interval equaling the individual N20 latency of the median nerve somatosensory-evoked cortical potential (PAS_N20) or N20-5 msec (PAS_N20-5). PAS_N20induced reproducibly a LTP-like long-lasting (>30 min) increase in motor-evoked potentials from the left M1 to a thumb abductor muscle of the right hand, whereas PAS_N20-5induced a LTD-like decrease. Repeated fastest possible thumb abduction movements resulted in learning, defined by an increase in maximum peak acceleration of the practiced movements, and prevented subsequent PAS_N20-induced LTP-like plasticity but enhanced subsequent PAS_N20-5-induced LTD-like plasticity. The same number of repeated slow thumb abduction movements did not result in learning and had no effects on PAS-induced plasticity. Findings support the view that learning in human M1 occurs through LTP-like mechanisms.

Paired transcranial magnetic stimulation has greatly advanced our understanding of the mechanisms which control excitability in human motor cortex. While it is clear that paired‐pulse excitability depends on the exact interstimulus interval (ISI) between the first (S1) and second stimulus (S2), relatively little is known about the effects of the intensities of S1 and S2, and the effects of manipulating neurotransmission through the GABA_A receptor. When recording the motor evoked potential (MEP) from the resting abductor digiti minimi (ADM) muscle, using a fixed ISI of 1.5 ms, and expressing the interaction between S1 and S2 as MEP_S1+S2/(MEP_S1+ MEP_S2), then a systematic variation of the intensities of S1 and S2 revealed short‐interval intracortical facilitation (SICF) if S1 and S2 were approximately equal to MEP threshold (RMT), or if S1 > RMT and S2 < RMT. In contrast, short‐interval intracortical inhibition (SICI) occurred if S1 < RMT and S2 > RMT. Contraction of the ADM left SICI unchanged but reduced SICF. The GABA_A receptor agonist diazepam increased SICI and reduced SICF in the resting ADM while diazepam had no effect during ADM contraction. Surface EMG and single motor unit recordings revealed that during ADM contraction SICI onset was at the I3‐wave latency of S2, whereas SICF typically ‘jumped up’ by one I‐wave and started with the I2‐wave latency of S2. Findings suggest that SICI is mediated through a low‐threshold GABA_A receptor‐dependent inhibitory pathway and summation of IPSP from S1 and EPSP from S2 at the corticospinal neurone. In contrast, SICF originates through non‐synaptic facilitation at the initial axon segment of interneurones along a high‐threshold excitatory pathway.

Ischemic cerebral stroke is the leading cause of long-term disability among adults in industrialized countries. One fundamental but still not sufficiently solved question is how to improve disability after stroke. Here, evidence will be reviewed on how pharmacological treatment modulates plasticity and learning in the intact human motor cortex. It will be argued that these data may be useful for advancing the concepts of pharmacotherapy for recovery after stroke.

Animal experiments show that motor recovery after focal brain injury is accelerated by the indirect norepinephrine agonist methylphenidate (MPH). The underlying mechanisms are unknown, but an MPH-induced increase in cortical excitability has been advocated. Here, we tested the acute effects of a single oral dose of 40 mg MPH (Ritalin) on motor cortical excitability in eight healthy subjects using focal transcranial magnetic stimulation. MPH increased the slope of the motor evoked potentials (MEP) intensity curve in a hand muscle, reduced short-interval intracortical inhibition, and increased I-wave facilitation. MEP threshold, cortical silent period and measures of spinal and neuromuscular excitability remained unaffected. Findings support the idea that MPH promotes accelerated motor recovery after lesion through facilitation and disinhibition.