A novel Hebbian stimulation paradigm was employed to examine physiological correlates of motor memory formation in humans. Repetitive pairing of median nerve stimulation with transcranial magnetic stimulation over the contralateral motor cortex (paired associative stimulation, PAS) may decrease human motor cortical excitability at interstimulus intervals of 10 ms (PAS10) or increase excitability at 25 ms (PAS25). The properties of this plasticity have previously been shown to resemble associative timing-dependent long-term depression (LTD) and long-term potentiation (LTP) as established in vitro. Immediately after training a novel dynamic motor task, the capacity of the motor cortex to undergo plasticity in response to PAS25 was abolished. PAS10-induced plasticity remained unchanged. When retested after 6 h, PAS25-induced plasticity recovered to baseline levels. After training, normal PAS25-induced plasticity was observed in the contralateral training-naive motor cortex. Motor training did not reduce the efficacy of PAS25 to enhance cortical excitability when PAS10 was interspersed between the training and application of the PAS25 protocol. This indicated that the mechanism supporting PAS25-induced plasticity had remained intact immediately after training. Behavioral evidence was obtained for continued optimization of force generation at a time when PAS25-induced plasticity was blocked in the training motor cortex. Application of the PAS protocols after motor training did not prevent the consolidation of motor skills evident as performance gains at later retesting. The results are consistent with a concept of temporary suppression of associative cortical plasticity by neuronal mechanisms involved in motor training. Although it remains an open question exactly which element of motor training was responsible for this effect, our findings may link dynamic properties of LTP formation, as established in animal experiments, with human motor memory formation and possibly dynamic motor learning.

Animal experiments suggest that cortical sensory representations may be remodelled as a consequence of changing synaptic efficacy by timing-dependent associative neuronal activity. Here we describe a timing-based associative form of plasticity in human somatosensory cortex. Paired associative stimulation (PAS) was performed by combining repetitive median nerve stimulation with transcranial magnetic stimulation (TMS) over the contralateral postcentral region. PAS increased exclusively the amplitude of the P25 component of the median nerve-evoked somatosensory-evoked potential (MN-SSEP), which is probably generated in the superficial cortical layers of area 3b. SSEP components reflecting neuronal activity in deeper cortical layers (N20 component) or subcortical regions (P14 component) remained constant. PAS-induced enhancement of P25 amplitude displayed topographical specificity both for the recording (MN-SSEP versus tibial nerve-SSEP) and the stimulation (magnetic stimulation targeting somatosensory versus motor cortex) arrangements. Modulation of P25 amplitude was confined to a narrow range of interstimulus intervals (ISIs) between the MN pulse and the TMS pulse, and the sign of the modulation changed with ISIs differing by only 15 ms. The function describing the ISI dependence of PAS effects on somatosensory cortex resembled one previously observed in motor cortex, shifted by approximately 7 ms. The findings suggest a simple model of modulation of excitability in human primary somatosensory cortex, possibly by mechanisms related to the spike-timing-dependent plasticity of neuronal synapses located in upper cortical layers.

Neuronal plasticity is to be kept within operational limits to serve its purpose as a safe memory system that shapes and focuses sensory and motor representations. Temporal and spatial properties of motor cortical plasticity were assessed in patients with writer's cramp using a model of long-term potentiation (LTP) and long-term depression (LTD) of synaptic efficacy. Paired associative stimulation (PAS) combined repetitive electric stimulation of the median or ulnar nerve (MN or UN) with subsequent transcranial magnetic stimulation of the contralateral dominant motor cortex at 21.5 ms (MN-PAS21.5; UN-PAS21.5) or 10 ms (MN-PAS10). Motor-evoked potentials were recorded from abductor pollicis brevis (APB) muscle and abductor digiti minimi (ADM) muscles in 10 patients with writer's cramp and 10 matched healthy control subjects. Following MN-PAS21.5 or UN-PAS21.5 in non-dystonic subjects, motor responses increased if the afferent PAS-component came from a homologous peripheral region and remained stable with a non-homologous input. In contrast, following either MN-PAS21.5 or UN-PAS21.5, both APB- and ADM-amplitudes increased in patients. Compared with controls, this increase started earlier, its magnitude was larger and its duration longer. Following MN-PAS10 in controls, APB-amplitudes decreased, while ADM-amplitudes increased. In writer's cramp, the decrease of APB-amplitudes started earlier and lasted longer. Of note, ADM-amplitudes were decreased, too. LTP-like as well as LTD-like plasticity is abnormal with respect to both gain and spatial organization. These findings may help to develop a pathophysiological model explaining core features of focal dystonia.

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Paired associative stimulation (PAS), which combines repetitive peripheral nerve stimulation with transcranial magnetic stimulation (TMS), may induce neuroplastic changes in somatosensory cortex (S1), possibly by long-term potentiation-like mechanisms. We used multichannel median nerve somatosensory evoked potential (MN-SSEP) recordings and two-point tactile discrimination testing to examine the location and behavioural significance of these changes. When TMS was applied to S1 near-synchronously to an afferent signal containing mechanoreceptive information, MN-SSEP changes (significant at 21-31 ms) could be explained by a change in a tangential source located in Brodmann area 3b, with their timing and polarity suggesting modification of upper cortical layers. PAS-induced MN-SSEP changes between 28 and 32 ms were linearly correlated with changes in tactile discrimination. Conversely, when the near-synchronous afferent signal contained predominantly proprioceptive information, PAS-induced MN-SSEP changes (20-29 ms) were shifted medially, and tactile performance remained stable. With near-synchronous mechanoreceptive stimulation subtle differences in the timing of the two interacting signals tended to influence the direction of tactile performance changes. PAS performed with TMS delivered asynchronously to the afferent pulse did not change MN-SSEPs. Hebbian interaction of mechanoreceptive afferent signals with TMS-evoked activity may modify synaptic efficacy in superficial cortical layers of Brodmann area 3b and is associated with timing-dependent and qualitatively congruent behavioural changes.