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In the central nervous system, the frequency at which reliable synaptic transmission can be maintained varies strongly between different types of synapses. Several pre- and postsynaptic processes must interact to enable high-frequency synaptic transmission. One of the mechanistically most challenging issues arises during repetitive neurotransmitter release, when synaptic vesicles fuse in rapid sequence with the presynaptic plasma membrane within the active zone (AZ), potentially interfering with the structural integrity of the AZ itself. Here we summarize potential mechanisms that help to maintain AZ integrity, including arrangement and mobility of release sites, calcium channel mobility, as well as release site clearance via lateral diffusion of vesicular proteins and via endocytotic membrane retrieval. We discuss how different types of synapses use these strategies to maintain high-frequency synaptic transmission., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Transcranial magnetic stimulation (TMS) of the human primary motor hand area (M1-HAND) can produce multiple descending volleys in fast-conducting corticospinal neurons, especially so-called indirect waves (I-waves) resulting from trans-synaptic excitation. Facilitatory interaction between these I-waves can be studied non-invasively using a paired-pulse paradigm referred to as short-interval intracortical facilitation (SICF)., Objective/hypothesis: We examined whether SICF depends on waveform and current direction of the TMS pulses., Methods: In young healthy volunteers, we applied single- and paired-pulse TMS to M1-HAND. We probed SICF by pairs of monophasic or half-sine pulses at suprathreshold stimulation intensity and inter-stimulus intervals (ISIs) between 1.0 and 5.0 ms. For monophasic paired-pulse stimulation, both pulses had either a posterior-anterior (PA) or anterior-posterior (AP) current direction (AP-AP or PA-PA), whereas current direction was reversed between first and second pulse for half-sine paired-pulse stimulation (PA-AP and AP-PA)., Results: Monophasic AP-AP stimulation resulted in stronger early SICF at 1.4 ms relative to late SICF at 2.8 and 4.4 ms, whereas monophasic PA-PA stimulation produced SICF of comparable size at all three peaks. With half-sine stimulation the third SICF peak was reduced for PA-AP current orientation compared with AP-PA., Conclusion: SICF elicited using monophasic as well as half-sine pulses is affected by current direction at clearly suprathreshold intensities. The impact of current orientation is stronger for monophasic compared with half-sine pulses. The direction-specific effect of paired-pulse TMS on the strength of early versus late SICF shows that different cortical circuits mediate early and late SICF., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Noonan syndrome (NS; OMIM 163950) is a developmental disorder caused by activating mutations in various components of the RAS-MAPK pathway. Recent in vitro studies demonstrated impairment of synaptic plasticity caused by RAS-MAPK pathway hyperactivity. Induction of synaptic plasticity critically depends on the level of attention. We therefore studied the induction of synaptic plasticity in patients with NS and healthy volunteers under different conditions of attention using transcranial magnetic stimulation., Methods: We investigated 10 patients with NS and healthy controls (HC) using paired associative stimulation (PAS) with different attention levels (unspecific, visual and electrical attention control). Changes in motor evoked potential (MEP) amplitudes were assessed immediately after as well as 30 and 60 min after PAS., Results: We demonstrated that MEP amplitudes of healthy controls significantly increased from 1.00 ± 0.17 to 1.74 ± 0.50 mV (p=0.001), which was not seen in patients with Noonan-Syndrome (0.88 ± 0.09 to 1.10 ± 0.48 mV, p=0.148) and there was a significant difference between both groups (p=0.003) when using an unspecific attention control. Under specific electrical attention control, MEP amplitudes decreased significantly in patients with NS, whereas a visual attention focus diminished synaptic plasticity in healthy controls., Conclusion: Our study provides evidence that synaptic plasticity is impaired in patients with NS, which is probably a consequence of constitutive activity of the RAS-MAPK pathway. The induction of synaptic plasticity in these patients critically depends on attention., Significance: This is the first study that indicates reduced synaptic plasticity in patients with a RAS-pathway disorder. Our results may have direct implications for learning and memory strategies in patients with a RAS-pathway disorder., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: Besides its use in epilepsy, lamotrigine (LTG) is also effective as mood stabilizer. The pathophysiology of mood disorders may incorporate a dysfunction of neuronal plasticity and animal experiments suggest that mood stabilizers influence induction of long-term potentiation (LTP) and -depression (LTD), two major forms of synaptic plasticity. However, the exact modes of action of LTG and its impact on neuronal plasticity in humans remain unclear., Methods: Here, we tested the effects of a single oral dose of LTG (300 mg) on motor cortical plasticity induced by paired associative stimulation (PAS(25)), a protocol that typically induces LTP-like plasticity, in 26 young healthy adults in a placebo-controlled, randomized, double-blind crossover design. We stratified analysis of the LTG effects according to the individual PAS(25) response in the placebo session (14 LTP-responders vs. 12 LTD-responders). Plasticity was indexed by motor evoked potential (MEP) amplitudes recorded before and for 60 min after PAS(25)., Results: LTG resulted in a significant reduction of the LTP-like MEP increase in the LTP-responders and a reduction of the LTD-like MEP decrease in the LTD-responders, with the majority of LTD-responders even showing an MEP increase., Conclusions: In summary, LTG differentially modulated cortical plasticity induced by non-invasive brain stimulation in human subjects depending on their individual intrinsic propensity for expressing LTP-like or LTD-like plasticity., Significance: Findings contribute to our understanding of the anticonvulsant and antidepressant clinical effects of LTG, which have been suggested to occur, at least in part, through downregulation of LTP (epilepsy) and LTD (depressive disorders)., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Neuronal plasticity is the physiological correlate of learning and memory. In animal experiments, synaptic (i.e. long-term potentiation (LTP) and depression (LTD)) and intrinsic plasticity are distinguished. In human motor cortex, cortical plasticity can be demonstrated using transcranial magnetic stimulation (TMS). Changes in motor-evoked potential (MEP) amplitudes most likely represent synaptic plasticity and are thus termed LTP-like and LTD-like plasticity., Objective/hypothesis: We investigated the role of changes of motor threshold and their relation to changes of MEP amplitudes., Methods: We induced plasticity by paired associative stimulation (PAS) with 25 ms or 10 ms inter-stimulus interval or by motor practice (MP) in 64 healthy subjects aged 18-31 years (median 24.0)., Results: We observed changes of MEP amplitudes and motor threshold after PAS[25], PAS[10] and MP. In all three protocols, long-term individual changes in MEP amplitude were inversely correlated to changes in motor threshold (PAS[25]: P = .003, n = 36; PAS[10]: P = .038, n = 19; MP: P = .041, n = 19)., Conclusion: We conclude that changes of MEP amplitudes and MT represent two indices of motor cortex plasticity. Whereas increases and decreases in MEP amplitude are assumed to represent LTP-like or LTD-like synaptic plasticity of motor cortex output neurons, changes of MT may be considered as a correlate of intrinsic plasticity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Previous studies have shown that the efficacy of transcranial magnetic stimulation (TMS) to excite corticospinal neurons depends on pulse waveform., Objective/hypotheses: In this study, we examined whether the effectiveness of polyphasic TMS can be increased by using a pulse profile that consists of multiple sine cycles., Methods: In eight subjects, single-pulse TMS was applied to the left primary motor hand area through a round coil attached to a stimulator device that generated polyphasic pulses consisting of one to six full-sine cycles with a cycle length of 86 μs. In different blocks, we varied the number of sine cycles per pulse and recorded the motor-evoked potential (MEP) from the right first dorsal interosseus muscle. For each stimulus type, we determined resting motor threshold (RMT), stimulus-response curve (SRC), and mean MEP amplitude evoked at maximal stimulator output to assess the efficacy of stimulation., Results: Multicycle pulses were more effective than a single full-sine cycle in exciting corticospinal neurons. TMS with multicycle pulses resulted in lower RMT, larger MEP amplitudes at maximal stimulator output and a steeper slope of the SRC relative to a TMS pulse consisting of a single-sine cycle. The increase in efficacy was already evident when two full-sine cycles were used and did not increase further by adding more cycles to the TMS pulse., Conclusions: Increasing the number of full-sine cycles per pulse can improve the efficacy of TMS to excite corticospinal neurons, but there is no simple linear relationship between the number of cycles and TMS efficacy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Motor learning takes place in several phases. Animal experiments suggest that synaptic plasticity plays an important role in acquisition of motor skills, whereas retention of motor performance is most likely achieved by other mechanisms., Objective/hypothesis: This study compared two spacing approaches and investigated the time course of synaptic plasticity after spaced motor practice (MP)., Methods: Twenty subjects performed a ballistic thumb flexion task in sessions of 6 × 10 minutes or 12 × 5 minutes. We measured peak acceleration of the target movement throughout the experiment and cortical excitability more than 60 minutes after MP via transcranial magnetic stimulation (TMS). After a retention period, both parameters were re-evaluated., Results: Mean peak acceleration of the target movement significantly increased (6 × 10 minutes: 21.61 m/s(2) versus 30.80 m/s(2), P = .002; 12 × 5 minutes: 18.52 m/s(2) versus 29.65 m/s(2), P = .01). In both training groups, motor evoked potential (MEP) amplitudes of the trained muscle continuously increased after MP (6 × 10 min: 0.93 mV versus 1.57 mV, P = .19; 12 × 5 min: 0.90 mV versus 1.76 mV, P = .004). After the retention period, motor performance was still significantly enhanced, whereas MEP amplitudes were no longer significantly increased., Conclusions: These findings do not provide evidence that in small scale motor learning the duration of practice and rest influences behavioral improvement or induction of cortical plasticity. Our study demonstrates that cortical plasticity after MP displays a dynamical time course that might be caused by different mechanisms., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Low-frequency stimulation, which does not induce long-term potentiation (LTP) or long-term potentiation (LTD) by itself, suppresses consecutive LTP or LTD induction in vitro. We tested whether a similar interaction occurs in the human motor cortex., Methods: LTP- or LTD-like plasticity was induced using paired associative stimulation (PAS) with 25 and 10 ms interstimulus interval and conditioned by suprathreshold repetitive transcranial magnetic stimulation (rTMS) at a frequency of 0.1Hz., Results: RTMS completely abolished the significant increase of motor-evoked potential (MEP) amplitudes after PAS(25 ms) (PAS(25 ms) only: 1.05+/-0.14 to 1.76+/-0.66 mV, p=0.001; rTMS+PAS(25 ms): 1.08+/-0.18 to 1.02+/-0.44 mV, n.s.) and also abolished the significant decrease of MEP amplitudes after PAS(10 ms) (PAS(10 ms) only: 1.00+/-0.14 to 0.73+/-0.32 mV; rTMS+PAS(10 ms): 1.15+/-0.35 to 1.25+/-0.43 mV, p=0.006). RTMS alone did not significantly alter MEP amplitudes but increased SICI and LICI., Conclusions: Low frequency stimulation increases intracortical inhibition and occludes LTP- and LTD-like plasticity in the human motor cortex., Significance: This finding supports the concept that metaplasticity in the human motor cortex follows similar rules as metaplasticity in in vitro experiments., (2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: One major attribute of transcranial magnetic stimulation (TMS) is the variability of motor-evoked potential (MEP) amplitudes, to which variations of coil positioning may contribute. Navigated TMS allows the investigator to retrieve a stimulation site with an accuracy of 2.5 mm and to retain coil position with low spatial divergence during stimulation., Objective: The purpose of this study was to investigate whether increased spatial constancy of the coil using a navigational system decreases the variability of MEP amplitudes and increases their reproducibility between different points in time of investigation., Methods: We investigated eight healthy subjects (mean age 23.8 +/- 1.2 years, range 22-25, four women, four men) at three different points in time with and without an optically tracked frameless navigational device, respectively. Input-output curves, motor threshold, and MEP amplitudes were recorded. We calculated the coefficient of variation as statistical parameter of variability. Reproducibility between different sessions was assessed via the MEP amplitude., Results: The coefficient of variance of MEP amplitudes did not show a distinct difference between navigated and non-navigated TMS in input-output curves. MEP amplitudes, indicating reproducibility, did not significantly differ between sessions with and without navigated TMS, either., Conclusions: Our results do not support the hypothesis that increased spatial constancy using a navigational system improves variability and reproducibility of MEP amplitudes. Variability of MEPs might mainly be due to not influenceable neurophysiologic factors such as undulant cortical excitability and spinal desynchronization., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: To assess effects of deafferentation of the arm representation of primary motor cortex (M1) on practice-dependent plasticity in healthy adults., Methods: Twelve healthy, right-handed adults (18-48 years, median 20.2 years) performed two consecutive experiments (exp. 1 and exp. 2). Exp. 1 consisted of a motor practice (MP) of repeated ballistic flexion movements of the left thumb. This was followed by exp. 2 consisting of selective anaesthesia of the upper brachial plexus (SPA) to disinhibit the training M1 and a second period of the same MP. Peak acceleration of the trained thumb movement and the motor evoked potential (MEP) amplitude in the flexor pollicis brevis muscle elicited by single-pulse transcranial magnetic stimulation of the training M1 were studied before and after exp. 1 and after exp. 2., Results: After exp. 1 all subjects demonstrated an increase of peak acceleration (baseline: 19.23+/-3.81ms(-2); after exp. 1: 43.28+/-17.63ms(-2), p=0.008) and MEP amplitude (from 0.46+/-0.23mV to 1.26+/-0.77mV, p=0.03). There was no additional increase of these measures after exp. 2 (44.37+/-19.56ms(-2), p=0.78, 1.69+/-1.21mV (p=0.07))., Conclusions: Training of ballistic thumb movements leads to behavioural improvement as well as to an increased excitability of the corresponding M1 representation. These effects do not increase further during deafferentation of the training M1. In contrast to stroke patients [Muellbacher W, Richards C, Ziemann U, Wittenberg G, Weltz D, Boroojerdi B, et al. Improving hand function in chronic stroke. Arch Neurol 2002;59:1278-82], practice-dependent plasticity in healthy subjects cannot be enhanced by deafferentation of neighbouring motor cortex areas., Significance: Healthy subjects, in contrast to patients with central motor lesions, are capable of saturating practice-dependent plasticity to a level that cannot be further enhanced by experimental manipulation.