I Delvendahl

Two types of exercise-induced neuroplasticity in congenital hemiparesis: a transcranial magnetic stimulation, functional MRI, and magnetoencephalography study

Early unilateral brain lesions can lead to a persistence of ipsilateral corticospinal projections from the contralesional hemisphere, which can enable the contralesional hemisphere to exert motor control over the paretic hand. In contrast to the primary motor representation (M1), the primary somatosensory representation (S1) of the paretic hand always remains in the lesioned hemisphere. Here, we report on differences in exercise‐induced neuroplasticity between individuals with such ipsilateral motor projections (ipsi) and individuals with early unilateral lesions but ‘healthy’ contralateral motor projections (contra).

Occlusion of bidirectional plasticity by preceding low-frequency stimulation in the human motor cortex.

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.

Impaired induction of long‐term potentiation‐like plasticity in patients with high‐functioning autism and Asperger syndrome

Aim  We aimed to investigate the induction of long‐term potentiation (LTP)‐like plasticity by paired associative stimulation (PAS) in patients with high‐functioning autism and Asperger syndrome (HFA/AS).

Transcranial magnetic stimulation with a half-sine wave pulse elicits direction-specific effects in human motor cortex.

BackgroundTranscranial magnetic stimulation (TMS) commonly uses so-called monophasic pulses where the initial rapidly changing current flow is followed by a critically dampened return current. It has been shown that a monophasic TMS pulse preferentially excites different cortical circuits in the human motor hand area (M1-HAND), if the induced tissue current has a posterior-to-anterior (PA) or anterior-to-posterior (AP) direction. Here we tested whether similar direction-specific effects could be elicited in M1-HAND using TMS pulses with a half-sine wave configuration.ResultsIn 10 young participants, we applied half-sine pulses to the right M1-HAND which elicited PA or AP currents with respect to the orientation of the central sulcus.Measurements of the motor evoked potential (MEP) revealed that PA half-sine stimulation resulted in lower resting motor threshold (RMT) than AP stimulation. When stimulus intensity (SI) was gradually increased as percentage of maximal stimulator output, the stimulus–response curve (SRC) of MEP amplitude showed a leftward shift for PA as opposed to AP half-sine stimulation. Further, MEP latencies were approximately 1 ms shorter for PA relative to AP half-sine stimulation across the entire SI range tested. When adjusting SI to the respective RMT of PA and AP stimulation, the direction-specific differences in MEP latencies persisted, while the gain function of MEP amplitudes was comparable for PA and AP stimulation.ConclusionsUsing half-sine pulse configuration, single-pulse TMS elicits consistent direction-specific effects in M1-HAND that are similar to TMS with monophasic pulses. The longer MEP latency for AP half-sine stimulation suggests that PA and AP half-sine stimulation preferentially activates different sets of cortical neurons that are involved in the generation of different corticospinal descending volleys.

The time course of motor cortex plasticity after spaced motor practice

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.

Effects of lamotrigine on human motor cortex plasticity.

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).

The number of full-sine cycles per pulse influences the efficacy of multicycle transcranial magnetic stimulation

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.

Deafferentation of neighbouring motor cortex areas does not further enhance saturated practice-dependent plasticity in healthy adults

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.

Impaired motor cortex plasticity in patients with Noonan syndrome

Objective: Noonan syndrome (NS; OMIM 163950) is a developmental disorder characterized by short stature, congenital heart defects, facial anomalies and variable learning deficits. NS is 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. We therefore intended to find a clue to synaptic plasticity in patients with NS. Methods: We investigated 8 patients with Noonan syndrome and an age and gender matched control group using paired associative stimulation (PAS). Changes in MEP amplitudes were assessed immediately after as well as 30 and 60 minutes after PAS. Results: We demonstrated that MEP amplitudes of healthy controls significantly increased from 1.03±0.18 to 1.81±0.61 mV (p=0.006), which was not seen in patients with Noonan-Syndrome (0.88±0.1 to 1.2±0.49 mV, p=0.103) and that there was a significant difference between both groups 60min after PAS (p=0.044). Conclusions: Our study provides first evidence that synaptic plasticity is impaired in patients with NS which is probably a consequence of constitutive activity of the RAS-MAPK pathway. Significance: This is the first study that indicated impaired synaptic plasticity in patients with a RAS-pathway disorder.

Vorhergehende niederfrequente Stimulation verhindert bidirektionale Plastizität im motorischen Kortex

Hintergrund: Die Wechselwirkungen zwischen neuronale Plastizitat induzierenden Protokollen werden durch die Bienenstock-Cooper-Munroe-(BCM)-Theorie beschrieben, nicht hingegen die im Tierexperiment beschriebene Blockade von Long-Term Potentiation (LTP) und Long-Term Depression (LTD) durch niederfrequente Stimulation. Methoden: Repetitive transkranielle Magnetstimulation (rTMS) mit einer Frequenz von 0,1Hz wurde vor Paired Associative Stimulatioon (PAS) mit den Interstimulusintervallen 25ms und 10ms durchgefuhrt (n=10 fur PAS_25ms, n=8 fur PAS_10ms). Bei den gleichen Probanden wurde zum Vergleich nur PAS angewendet. Ergebnisse: PAS_25ms fuhrte zu einer Vergroserung der Amplituden motorisch evozierter Potentiale (MEP) von 1,10mV zu 1,82mV (p<0,005), PAS_10ms zu einer Verringerung von 1,02mV zu 0,85mV (p=0,07). Bei Konditionierung durch rTMS_0,1Hz fuhrte PAS zu keiner signifikanten Veranderung der MEP Amplituden (PAS_25ms: 1,11mV zu 1,08mV, p=0,86; PAS_10ms: 1,11mV zu 1,20mV, p=0,56). Schlussfolgerungen: 0,1Hz rTMS blockiert die konsekutive Induktion LTP- und LTD- ahnlicher Plastizitat durch PAS im humanen M1. Dieser Mechanismus neuronaler Metaplastizitat geht uber den sliding threshold Mechanismus der BCM-Theorie hinaus.