Interindividual variability and age-dependency of motor cortical plasticity induced by paired associative stimulation

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.     

Human motor associative plasticity induced by paired bihemispheric stimulation

Paired associative stimulation (PAS) is an effective non-invasive method to induce human motor plasticity by the repetitive pairing of peripheral nerve stimulation and transcranial magnetic stimulation (TMS) at the primary motor cortex (M1) with a specific time interval. Although the repetitive pairing of two types of afferent stimulation might be a biological basis of neural plasticity and memory, other types of paired stimulation of the human brain have rarely been studied. We hypothesized that the repetitive pairing of TMS and interhemispheric cortico-cortical projection or paired bihemispheric stimulation (PBS), in which the right and left M1 were serially stimulated with a time interval of 15 ms, would produce an associative long-term potentiation (LTP)-like effect. In this study, 23 right-handed healthy volunteers were subjected to a 0.1 Hz repetition of 180 pairings of bihemispheric TMS, and physiological and behavioural measures of the motor system were compared before, immediately after, 20 min after and 40 min after PBS intervention. The amplitude of the motor evoked potential (MEP) induced by the left M1 stimulation and its input–output function increased for up to ∼20 min post-PBS. Fine finger movements were also facilitated by PBS. Spinal excitability measured by the H-reflex was insensitive to PBS, suggesting a cortical mechanism. The associative LTP-like effect induced by PBS was timing dependent, occurring only when the interstimulus interval was 5–25 ms. These findings demonstrate that using PBS in PAS can induce motor cortical plasticity, and this approach might be applicable to the rehabilitation of patients with motor disorders.     

Modulation of rodent cortical motor excitability by somatosensory input

It is assumed that somatosensory input is required for motor learning and recovery from focal brain injury. In rodents and other mammals, corticocortical projections between somatosensory and motor cortices are modified by patterned input. Whether and how motor cortex function is modulated by somatosensory input to support motor learning is largely unknown. Recent human evidence suggests that input changes motor excitability. Using transcranial magnetic stimulation (TMS), this study tested whether motor cortex excitability is affected by patterned somatosensory stimulation in rodents. Motor potentials evoked in gastrocnemius muscles in response to TMS (MEP(TMS)) and to cervical electrical stimulation (MEP(CES)) were recorded bilaterally. Initially, the first negative peak of the MEP(TMS) was identified as a cortical component because it disappeared after decortication in three animals. Subsequently, we studied the effects of 2 h of electrical stimulation of one sciatic nerve on the cortical component of the MEP(TMS), i.e., on motor cortex excitability. After stimulation, its amplitude increased by 117 +/- 45% ( P<0.01) in the stimulated limb. A significantly smaller effect was found in the unstimulated limb ( P<0.02) and no effect was observed in unstimulated control animals. The subcortically evoked MEP(CES) were not affected by stimulation. It is concluded that somatosensory input increases motor excitability in rat. This increase outlasts the stimulation period and is mediated by supraspinal structures, likely motor cortex. Modulation of motor cortex excitability by somatosensory input may play a role in motor learning and recovery from lesion.     

Modification of the human motor cortex by associative stimulation

Manipulation of afferent input is capable of inducing reorganisation of the motor cortex. For example, following 1 h of paired electrical stimulation to the motor point of two hand muscles (associative stimulation) the excitability of the corticospinal projection to the stimulated muscles is increased. Here we investigated the mechanisms responsible for such change using transcranial magnetic stimulation (TMS). Cortical excitability changes were investigated by measuring motor evoked potentials (MEPs), intracortical inhibition (ICI), intracortical facilitation (ICF), and short-interval intracortical facilitation (SICF). Following 1 h of associative stimulation MEP amplitudes in the stimulated muscles significantly increased. Additionally, there was a significant increase in ICF and of SICF at interstimulus intervals in the range of 2.3–3.3 ms. There was no significant change in ICI. These findings confirm previous observations that a 1-h period of associative stimulation can increase the excitability of the cortical projection to stimulated muscles. Additionally, these results suggest that the observed modifications of excitability are due to changes in intracortical excitatory circuits.     

Modulation of spike timing by sensory deprivation during induction of cortical map plasticity

Deprivation-induced plasticity of sensory cortical maps involves long-term potentiation (LTP) and depression (LTD) of cortical synapses, but how sensory deprivation triggers LTP and LTD in vivo is unknown. Here we tested whether spike timing-dependent forms of LTP and LTD are involved in this process. We measured spike trains from neurons in layer 4 (L4) and layers 2 and 3 (L2/3) of rat somatosensory cortex before and after acute whisker deprivation, a manipulation that induces whisker map plasticity involving LTD at L4-to-L2/3 (L4-L2/3) synapses. Whisker deprivation caused an immediate reversal of firing order for most L4 and L2/3 neurons and a substantial decorrelation of spike trains, changes known to drive timing-dependent LTD at L4-L2/3 synapses in vitro. In contrast, spike rate changed only modestly. Thus, whisker deprivation is likely to drive map plasticity by spike timing-dependent mechanisms.     

Transcranial magnetic stimulation and the motor learning-associated cortical plasticity

It has been well established that repetitive motor performance and skill learning alter the functional organization of human corticomotoneuronal system. Over the past decade, transcranial magnetic stimulation (TMS) has helped to demonstrate motor practice and learning-related changes in corticomotoneuronal excitability and representational plasticity. It has also provided some insights into the mechanisms underlying such plasticity. TMS-derived indices show that motor practice, skill acquisition and learning are associated with an increase in cortical excitability and a modulation of intracortical inhibition partly related to the amount of GABA-related inhibition. It has been suggested that these changes in excitability might be related to learning and motor memory formation in the motor cortex. However, it has proved difficult to relate different aspects of TMS-derived representational plasticity with specific behavioral outcomes. A better understanding of the relationship between TMS measurements of practice-related cortical plasticity and underlying mechanisms, in the context of associated changes in behavior, will facilitate the development of techniques and protocols that will allow predictable modulation of cortical plasticity in health and disease.     

Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising tool to induce plastic changes that are thought in some cases to reflect N -methyl- d -aspartate-sensitive changes in synaptic efficacy. As in animal experiments, there is some evidence that the sign of rTMS-induced plasticity depends on the prior history of cortical activity, conforming to the Bienenstock–Cooper–Munro (BCM) theory. However, experiments exploring these plastic changes have only examined priming-induced effects on a limited number of rTMS protocols, often using designs in which the priming alone had a larger effect than the principle conditioning protocol. The aim of this study was to introduce a new rTMS protocol that gives a broad range of after-effects from suppression to facilitation and then test how each of these is affected by a priming protocol that on its own has no effect on motor cortical excitability, as indexed by motor-evoked potential (MEP). Repeated trains of four monophasic TMS pulses (quadripulse stimulation: QPS) separated by interstimulus intervals of 1.5–1250 ms produced a range of after-effects that were compatible with changes in synaptic plasticity. Thus, QPS at short intervals facilitated MEPs for more than 75 min, whereas QPS at long intervals suppressed MEPs for more than 75 min. Paired-pulse TMS experiments exploring intracortical inhibition and facilitation after QPS revealed effects on excitatory but not inhibitory circuits of the primary motor cortex. Finally, the effect of priming protocols on QPS-induced plasticity was consistent with a BCM-like model of priming that shifts the crossover point at which synaptic plasticity reverses from depression to potentiation. The broad range of after-effects produced by the new rTMS protocol opens up new possibilities for detailed examination of theories of metaplasticity in humans.     

Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation

Associative stimulation has been shown to enhance excitability in the human motor cortex ( Stefan et al. 2000 ); however, little is known about the underlying mechanisms. An interventional paired associative stimulation (IPAS) was employed consisting of repetitive application of single afferent electric stimuli, delivered to the right median nerve, paired with single pulse transcranial magnetic stimulation (TMS) over the optimal site for activation of the abductor pollicis brevis muscle (APB) to generate approximately synchronous events in the primary motor cortex. Compared to baseline, motor evoked potentials (MEPs) induced by unconditioned, single TMS pulses increased after IPAS. By contrast, intracortical inhibition, assessed using (i) a suprathreshold test TMS pulse conditioned by a subthreshold TMS pulse delivered 3 ms before the test pulse, and (ii) a suprathreshold test TMS pulse conditioned by afferent median nerve stimulation delivered 25 ms before the TMS pulse, remained unchanged when assessed with appropriately matching test stimulus intensities. The increase of single-pulse TMS-evoked MEP amplitudes was blocked when IPAS was performed under the influence of dextromethorphan, an N -methyl- d -aspartate (NMDA) receptor antagonist known to block long-term potentiation (LTP). Further experiments employing the double-shock TMS protocol suggested that the afferent pulse, as one component of the IPAS protocol, induced disinhibition of the primary motor cortex at the time when the TMS pulse, as the other component of IPAS, was delivered. Together, these findings support the view that LTP-like mechanisms may underlie the cortical plasticity induced by IPAS.     

Modulation of human motor cortex excitability by the cholinesterase inhibitor rivastigmine

Acetylcholine exerts strong neuromodulating action at cortical and subcortical neurons and networks. Alterations of cortical excitability, induced by acute and repeated administration of the acetylcholinesterase inhibitor rivastigmine were investigated with transcranial magnetic stimulation in healthy volunteers. It was found that rivastigmine had an overall significant effect on the stimulus-response curve with mean values suggesting an enhancement 1.5 and 3 h after a single loading dose of 3 mg rivastigmine and a reduction after 7 days of daily administration of 3 mg rivastigmine. Motor threshold, intracortical inhibition, intracortical facilitation, cortical silent period, M-wave, F-wave and peripheral silent period remained unaffected either by acute or repeated administration of rivastigmine. Our results demonstrate that effects of acetylcholine on motor cortex excitability in healthy subjects are reflected by alterations of the stimulus-response curve. The differential effect between acute and chronic administration of rivastigmine may reflect dynamic properties of different receptor subtypes.     

Acute exercise enhances the response to paired associative stimulation-induced plasticity in the primary motor cortex

There is evidence that a single session of aerobic exercise can modulate intracortical inhibition. While decreases in inhibition appear to be a necessary precursor to the induction of long-term potentiation (LTP)-like plasticity, it is not known whether aerobic exercise can enhance the response to LTP induction. We investigated whether the addition of a preceding bout of exercise would modulate the response to paired associative stimulation (PAS) of the upper limb. It was hypothesized that exercise would enhance motor cortical (M1) excitability following PAS compared to a session of PAS alone. Ten healthy individuals underwent a control session involving PAS alone and an exercise session where PAS was preceded by 20 min of moderate-intensity stationary biking. PAS involved 180 pairs of stimuli (right median nerve, left M1) delivered at 0.1 Hz to the right abductor pollicis brevis representation. Excitability changes were measured by the area under a stimulus–response curve, and intracortical circuits were probed by testing short-interval intracortical inhibition (SICI), long-interval intracortical inhibition and intracortical facilitation. Two-way ANOVAs were conducted to compare excitability changes between sessions. PAS-induced increases in M1 excitability were enhanced in the exercise session (p < 0.026). In addition, SICI was differentially modulated between the two sessions, with greater decreases in SICI observed immediately after PAS when it was preceded by the exercise session (p < 0.03). Aerobic exercise enhances the effectiveness of PAS and may be a useful adjunct to traditional therapies and interventions that aim to promote neuroplasticity in cortical networks.     

Neural basis of implicit motor sequence learning: Modulation of cortical power

Implicit sequence learning describes the acquisition of serially ordered movements and sequentially structured cognitive information, that occurs without awareness. Theta, alpha and beta cortical oscillations are present during implicit motor sequence learning, but their role in this process is unclear. The current study addressed this gap in the literature. A total of 50 healthy adults aged between 19 and 37 years participated in the study. Implicit motor sequence learning was examined using the Serial Reaction Time task where participants unknowingly repeat a sequence of finger movements in response to a visual stimulus. Sequence learning was examined by comparing reaction times and oscillatory power between sequence trials and a set of control trials comprising random stimulus presentations. Electroencephalography was recorded as participants completed the task. Analyses of the behavioral data revealed participants learnt the sequence. Analyses of oscillatory activity, using permutation testing, revealed sequence learning was associated with a decrease in theta band (4–7 Hz) power recorded over frontal and central electrode sites. Sequence learning effects were not observed in the alpha (7–12 Hz) or beta bands (12–20 Hz). Even though alpha and beta power modulations have long been associated with executing a motor response, it seems theta power is a correlate of sequence learning in the manual domain. Theta power modulations on the serial reaction time task may reflect disengagement of attentional resources, either promoting or occurring as a consequence of implicit motor sequence learning     

Sleep-dependent motor memory plasticity in the human brain

Growing evidence indicates a role for sleep in off-line memory processing, specifically in post-training consolidation. In humans, sleep has been shown to trigger overnight learning on a motor-sequence memory task, while equivalent waking periods produce no such improvement. But while the behavioral characteristics of sleep-dependent motor learning become increasingly well characterized, the underlying neural basis remains unknown. Here we present functional magnetic resonance imaging data demonstrating a change in the representation of a motor memory after a night of sleep. Subjects trained on a motor-skill memory and 12 hours later, after either sleep or wake, were retested during functional magnetic resonance imaging. Following sleep relative to wake, regions of increased activation were expressed in the right primary motor cortex, medial prefrontal lobe, hippocampus and left cerebellum; changes that can support faster motor output and more precise mapping of key-press movements. In contrast, signal decreases were identified in parietal cortices, the left insular cortex, temporal pole and fronto-polar region, reflecting a reduced need for conscious spatial monitoring and a decreased emotional task burden. This evidence of an overnight, systems-level change in the representation of a motor memory holds important implications for acquiring real-life skills and in clinical rehabilitation following brain trauma, such as stroke.     

Role of sustained excitability of the leg motor cortex after transcranial magnetic stimulation in associative plasticity

Changes in the strength of corticospinal projections to muscles in the upper and lower limbs are induced in conscious humans after paired associative stimulation (PAS) to the motor cortex. We tested whether an intervention of PAS consisting of 90 low-frequency (0.1-Hz) stimuli to the common peroneal nerve combined with suprathreshold transcranial magnetic stimulation (TMS) produces specific changes to the motor-evoked potentials (MEPs) in lower leg muscles if the afferent volley from peripheral stimulation is timed to arrive at the motor cortex after TMS-induced firing of corticospinal neurons. Unlike PAS in the hand, MEP facilitation in the leg was produced when sensory inputs were estimated to arrive at the motor cortex over a range of 15 to 90 ms after cortical stimulation. We examined whether this broad range of facilitation occurred as a result of prolonged subthreshold excitability of the motor cortex after a single pulse of suprathreshold TMS so that coincident excitation from sensory inputs arriving many milliseconds after TMS can occur. We found that significant facilitation of MEP responses (>200%) occurred when the motor cortex was conditioned with suprathreshold TMS tens of milliseconds earlier. Likewise, it was possible to induce strong MEP facilitation (85% at 60 min) when afferent inputs were directly paired with subthreshold TMS. We argue that in the leg motor cortex, facilitation of MEP responses from PAS occurred over a large range of interstimulus intervals as a result of the paired activation of sensory inputs with sustained, subthreshold activity of cortical neurons that follow a pulse of suprathreshold TMS.     

Increased cortical plasticity in the elderly: changes in the somatosensory cortex after paired associative stimulation

A fundamental feature of the human cortex is the capability to express plastic changes that seem to be present even during physiological aging. The paired associative stimulation (PAS) protocol is a paradigm capable of inducing neuroplastic changes, possibly by mechanisms related to spike timing-dependent associative neuronal activity, and represents a suitable tool for investigating age-dependent neuroplastic modulations of the primary somatosensory cortex (S1). To examine age dependency of S1 plasticity, the amplitude changes of median nerve somatosensory evoked potential (SEP) before and after PAS intervention were investigated in young and elderly subjects. The main finding of our study is that low-frequency medial nerve stimulation paired with transcranial magnetic stimulation over the contralateral cortex enhances S1 excitability. Moreover, the S1 long term potentiation–like plasticity changes as a function of aging, with a significant increase of N20–P25 complex in the elderly compared to young subjects. These results are congruent with the hypothesis that some elderly subjects retain a high level of plasticity in specific neuronal circuits. Such plasticity could represent a compensatory mechanism, in terms of functional reserve of somatosensory cortex, used by the aging brain to counterbalance the cortical degeneration associated with aging.     

Modulation of cortical motor networks following primed theta burst transcranial magnetic stimulation

To investigate whether priming stimulation influences the responses of intracortical inhibitory and facilitatory motor circuits to a subsequent plasticity-inducing inhibitory theta burst TMS paradigm. Using standard transcranial magnetic stimulation (TMS) procedures, MEP amplitude, short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF) were assessed at baseline and 5, 20 and 30 min following continuous theta burst stimulation (cTBS), intermittent TBS (iTBS), and iTBS-primed cTBS. SICI was assessed using paired-pulse TMS at inter-stimulus intervals (ISI) of 3 ms (SICI(3)) and the latency corresponding to the latency at which SICF was minimal in each individual. SICF was assessed at ISIs corresponding to Peak 1, Trough 1, Peak 2, and Peak 3 of each individual's SICF curve. When applied alone cTBS inhibited and iTBS facilitated MEP amplitudes. iTBS-primed cTBS resulted in greater MEP inhibition than cTBS alone. There were no changes in SICF and only marginal changes in SICI following any intervention. Synapses mediating MEP generation undergo modification following iTBS-primed cTBS, possibly through mechanisms related to metaplasticity or synaptic depotentiation. A lack of substantial changes in SICI and SICF under all experimental conditions suggests that the tested rTMS paradigms may be non-optimal for inducing robust modulation of the neural elements mediating SICI and SICF across subjects. Priming stimulation may provide an approach which facilitate neuroplastic change within the human motor cortex at least in circuits responsible for MEP generation.     

Correlation between cortical plasticity, motor learning and BDNF genotype in healthy subjects

There is good evidence that synaptic plasticity in human motor cortex is involved in behavioural motor learning; in addition, it is now possible to probe mechanisms of synaptic plasticity using a variety of transcranial brain-stimulation protocols. Interactions between these protocols suggest that they both utilise common mechanisms. The aim of the present experiments was to test how well responsiveness to brain-stimulation protocols and behavioural motor learning correlate with each other in a sample of 21 healthy volunteers. We also examined whether any of these measures were influenced by the presence of a Val66Met polymorphism in the BDNF gene since this is another factor that has been suggested to be able to predict response to tests of synaptic plasticity. In 3 different experimental sessions, volunteers underwent 5-Hz rTMS, intermittent theta-burst stimulation (iTBS) and a motor learning task. Blood samples were collected from each subject for BDNF genotyping. As expected, both 5-Hz rTMS and iTBS significantly facilitated MEPs. Similarly, as expected, kinematic variables of finger movement significantly improved during the motor learning task. Although there was a significant correlation between the effect of iTBS and 5-Hz rTMS, there was no relationship in each subject between the amount of TMS-induced plasticity and the increase in kinematic variables during motor learning. Val66Val and Val66Met carriers did not differ in their response to any of the protocols. The present results emphasise that although some TMS measures of cortical plasticity may correlate with each other, they may not always relate directly to measures of behavioural learning. Similarly, presence of the Val66Met BDNF polymorphism also does not reliably predict responsiveness in small groups of individuals. Individual success in behavioural learning is unlikely to be closely related to any single measure of synaptic plasticity.     

Rapid-rate paired associative stimulation of the median nerve and motor cortex can produce long-lasting changes in motor cortical excitability in humans

Repetitive transcranial magnetic stimulation (rTMS) or repetitive electrical peripheral nerve stimulation (rENS) can induce changes in the excitability of the human motor cortex (M1) that is often short-lasting and variable, and occurs only after prolonged periods of stimulation. In 10 healthy volunteers, we used a new repetitive paired associative stimulation (rPAS) protocol to facilitate and prolong the effects of rENS and rTMS on cortical excitability. Sub-motor threshold 5 Hz rENS of the right median nerve was synchronized with submotor threshold 5 Hz rTMS of the left M1 at a constant interval for 2 min. The interstimulus interval (ISI) between the peripheral stimulus and the transcranial stimulation was set at 10 ms (5 Hz rPAS_10ms) or 25 ms (5 Hz rPAS_25ms). TMS was given over the hot spot of the right abductor pollicis brevis (APB) muscle. Before and after rPAS, we measured the amplitude of the unconditioned motor evoked potential (MEP), intracortical inhibition (ICI) and facilitation (ICF), short- and long-latency afferent inhibition (SAI and LAI) in the conditioned M1. The 5 Hz rPAS_25ms protocol but not the 5 Hz rPAS10_ms protocol caused a somatotopically specific increase in mean MEP amplitudes in the relaxed APB muscle. The 5 Hz rPAS_25ms protocol also led to a loss of SAI, but there was no correlation between individual changes in SAI and corticospinal excitability. These after-effects were still present 6 h after 5 Hz rPAS_25ms. There was no consistent effect on ICI, ICF and LAI. The 5 Hz rENS and 5 Hz rTMS protocols failed to induce any change in corticospinal excitability when given alone. These findings show that 2 min of 5 Hz rPAS_25ms produce a long-lasting and somatotopically specific increase in corticospinal excitability, presumably by sensorimotor disinhibition.     

Short-term cortical plasticity induced by conditioning pain modulation

To investigate the effects of homotopic and heterotopic conditioning pain modulation (CPM) on short-term cortical plasticity. Glutamate (tonic pain) or isotonic saline (sham) was injected in the upper trapezius (homotopic) and in the thenar (heterotopic) muscles. Intramuscular electrical stimulation was applied to the trapezius at pain threshold intensities, and somatosensory evoked potentials were recorded with 128 channel EEG. Pain ratings were obtained during glutamate and sham pain injection. Short-term cortical plasticity to electrical stimulation was investigated before, during, and after homotopic and heterotopic CPM versus control. Peak latencies at N100, P200, and P300 were extracted and the location/strength of corresponding dipole current sources and multiple dipoles were estimated. Homotopic CPM caused hypoalgesia (P = 0.032, 30.6% compared to baseline) to electrical stimulation. No cortical changes were found for homotopic CPM. A positive correlation at P200 between electrical pain threshold after tonic pain and the z coordinate after tonic pain (P = 0.032) was found for homotopic CPM. For heterotopic CPM, no significant hypoalgesia was found and a dipole shift of the P300 z coordinate (P = 0.001) was found between glutamate versus sham pain (P = 0.009). This generator was located in the cingulate. A positive correlation at P300 between pain ratings to glutamate injection and the x coordinate during tonic pain (P = 0.016) was found for heterotopic CPM. Heterotopic CPM caused short-term cortical plasticity within the cingulate that was correlated to subjective pain ratings. The degree of long-term depressive effect to homotopic CPM was correlated to the change in location of the P200 dipole.     

Suppression of LTP-like plasticity in human motor cortex by the GABAB receptor agonist baclofen

Previous experiments in slice preparations revealed that pharmacological activation of GABA_B receptors down- or up-regulates long-term potentiation (LTP), depending on whether increase of GABA_B receptor mediated inhibitory postsynaptic potentials or decrease of presynaptic auto-inhibition of GABA_A receptor mediated inhibition predominates. The effects of GABA_B receptor activation on LTP in humans in vivo are unknown. Here we show, by using transcranial magnetic stimulation, that the GABA_B receptor agonist baclofen decreases paired associative stimulation induced LTP-like plasticity in human motor cortex. This suggests that increased GABA_B mediated inhibitory postsynaptic potentials drive this effect, and that baclofen may have a negative impact on LTP-dependent behavioural processes such as motor learning.