Cerebral Cortex Advance Access originally published online on June 1, 2005
Cerebral Cortex 2006 16(3):376-385; doi:10.1093/cercor/bhi116
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Temporary Occlusion of Associative Motor Cortical Plasticity by Prior Dynamic Motor Training
Human Cortical Physiology and Motor Control Laboratory, Department of Neurology, University of Würzburg, D-97080 Würzburg, Germany
Address correspondence to Dr J. Classen, Human Cortical Physiology and Motor Control Laboratory, University of Würzburg, Josef-Schneider Str. 11, 97080 Würzburg, Germany. Email: Classen_J{at}klinik.uni-wuerzburg.de.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
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.
Key Words: motor learning • motor cortex • transcranial magnetic stimulation • long-term potentiation • human
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Behavioral evidence suggests that motor learning evolves from an initial short-lasting stage into a subsequent functionally different stage (Brashers-Krug et al., 1996
). Neurophysiological and neuroimaging studies are in agreement with a sequential model of human motor memory and have additionally provided evidence placing the primary motor cortex (M1) at the center stage of the early phase of motor learning (Sanes and Donoghue, 2000). During the initial hours after the training of a motor task, perseveration of its dynamic characteristics was evident when subjects performed movements to learn a second, different motor task (Shadmehr and Brashers-Krug, 1997). Furthermore, M1 underwent short-lasting specific representational changes (Karni et al., 1995; Pascual-Leone et al., 1995; Muellbacher et al., 2001) which retained some of the kinematic properties of the trained task (Classen et al., 1998; Bütefisch et al., 2000). These findings provide evidence for a memory in M1 for the trained movements during the early post-training period. While short-term memory for movements exists, learning of a second motor skill is impaired, in relation to the naive acquisition of the first similar skill (Shadmehr and Brashers-Krug, 1997). This phenomenon is known as anterograde interference (Brashers-Krug et al., 1996). Learning of a second motor skill was not impaired, when the second training took place several hours after the first one.
Long-term recall of the first motor skill is disrupted if a conflicting skill is trained during a short time period after the acquisition of the first skill (Brashers-Krug et al., 1996; Shadmehr and Brashers-Krug, 1997). Retention of a motor task, evident at later retesting, is also impaired if subjects are exposed to repetitive high-frequency transcranial magnetic stimulation (rTMS) over M1 immediately after motor training (Muellbacher et al., 2002). In contrast, retention of the skill remained unaffected when the second motor task was practiced, or rTMS was applied, several hours later (however, see Caithness et al., 2004). These observations show that, within a short time window after training, M1 is involved in the consolidation of different motor memories from fragile into more robust forms. The disruption of consolidation of the initial motor skill by behavioral or physiological interventions is known as retrograde interference (Brashers-Krug et al., 1996).
Thus, it appears that short-term motor memory, anterograde interference and retrograde interference all are phenomena that are tied to the initial phase after training a new motor task. However, it remains unknown whether these distinct phenomena may be mapped onto similar physiological mechanisms. To address this question we used a recently established non-invasive Hebbian stimulation protocol, termed paired associative stimulation (PAS), which was shaped after models of associative long-term potentiation (LTP) and long-term depression (LTD) in experimental animals (Stefan et al., 2000; Wolters et al., 2003). PAS consists of pairing repetitively, at near-synchrony, low-frequency median nerve stimulation with transcranial magnetic stimulation (TMS) of the homotopic representation in the primary motor cortex. Following PAS, motor cortical excitability, as probed by the magnitude of TMS-evoked motor potentials, was changed (Stefan et al., 2000, 2002; Wolters et al., 2003). This change was long-lasting, reversible and topographically specific (Stefan et al., 2000; Wolters et al., 2003). The direction of PAS-induced cortical excitability change depended on the exact sequence of events induced in M1 by each of the stimulation modalities (Wolters et al., 2003), similar to the spike-timing dependent plasticity (Dan and Poo, 2004) observed in brain preparations of animals. Both enhancement and depression of excitability were dependent on NMDA-receptor activation (Stefan et al., 2002; Wolters et al., 2003), and depression of excitability additionally depended on activation of L-type voltage-gated Ca2+-channels (Wolters et al., 2003).
Based on our observations that PAS-induced plasticity shares physiological properties with LTP/LTD and that LTP/LTD is a candidate mechanism in motor memory (Rioult-Pedotti et al., 2000; Monfils and Teskey, 2004), we hypothesized that the capacity of the motor cortex to undergo timing-dependent bidirectional plasticity in response to PAS might be modulated by prior motor training, and that induction of PAS-induced plasticity might interfere with retention of motor skill. Preliminary results have been communicated in abstract form (Wycislo and Classen, 2003).
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Subjects
The study was approved by the Ethics committee of the University of Wuerzburg and written informed consent was obtained from all participants. Experiments were performed on 63 healthy volunteers (27 men, 36 women) aged 19 to 34 years (mean 24.4 ± 3.1 years). None had a history of a relevant illness. Sixty of the volunteers were right handed and three were left handed according to the Oldfield handedness inventory (Oldfield, 1971).
Stimulation
Focal transcranial magnetic stimulation (TMS) was performed using a flat figure-eight shaped magnetic coil (diameter of each wing: 70 mm) connected to a Magstim 200 magnetic stimulator (Magstim, Whitland, Dyfed, UK). The coil was held tangentially to the skull with the handle pointing backward and laterally at a 45° angle to the sagittal plane. Electrical mixed nerve stimulation was performed with an electrical stimulator (Digitimer D7AH, Digitimer, Welwyn Garden, Hertfordshire, UK) using a standard stimulation block (cathode proximal) at a stimulation width of 200 µs.
Recording
Electromyographic activity was recorded from the right abductor pollicis brevis (APB) muscle using Ag–AgCl surface electrodes (Fischer Medizintechnik, Nürnberg, Germany). Raw signals were amplified using a 1902 amplifier (Cambridge Electronics Design, Cambridge, UK) and bandpass filtered between 1 Hz and 2 kHz. EMG signals were digitized at 5 kHz by an A/D converter (model 1401 plus, Cambridge Electronics Design, Cambridge, UK) and stored in a laboratory computer for display and later off-line analysis.
Experimental Procedures
Paired Associative Stimulation
Subjects were seated comfortably in an armchair. The optimal position of the magnetic coil for eliciting motor-evoked potentials (MEP) in the resting right APB was assessed over the left motor cortex at a moderately suprathreshold stimulation intensity (usually 
50% of the maximal stimulator output) and marked directly on the scalp with a soft-tip pen. At this optimal site, termed ‘hot spot’, the resting motor threshold was determined as the minimum stimulator intensity needed to produce a response of at least 50 µV in the relaxed APB in at least 5 of 10 consecutive trials (Rossini et al., 1994). This procedure took 15 min to complete.
For intervention, a PAS protocol was employed whose principles were described previously (Stefan et al., 2000; Wolters et al., 2003). In brief, single electrical stimuli delivered to the right median nerve at the level of the wrist at 300% of the perceptual threshold were paired repetitively with TMS at 1.3 times resting motor threshold delivered to the hot spot at a fixed interstimulus interval. Ninety pairs were delivered at 0.1 Hz over 15 min. This protocol has been shown to modulate cortical excitability bidirectionally, depending on the sequence of events induced in M1 by the two stimulation modalities (Wolters et al., 2003). During intervention, the TMS pulse followed the median nerve stimulation either at 10 ms (PAS10) or at 25 ms (PAS25). In 80–95% of subjects, PAS10 and PAS25 have been shown previously (Stefan et al., 2000; Wolters et al., 2003) to decrease (PAS10) or increase (PAS25) cortical excitability. PAS10* represented a variation of the PAS10 protocol in that the strength of the magnetic pulse during intervention was lowered to 95% of the resting motor threshold. Unpublished observations from our laboratory suggest that this variation may induce a more pronounced decrease of cortical excitability in a larger proportion of tested subjects.
Complete muscle relaxation was continuously monitored by visual and auditory feedback. Subjects were instructed to maintain attention to the task throughout the entire session. Twenty trials were collected before and immediately after PAS, using a probing stimulus intensity of 1.3 times resting motor threshold and a stimulation rate of 0.1 Hz. Identical stimulus intensities were used before and after intervention.
Dynamic Motor Training
Subjects were asked to perform brisk isometric abductions with their right thumb. The subject's force was recorded by a force transducer (Grass CP122A, Grass Instruments CO, West Warwick, RI) and the force signal was fed back to the subject on a computer screen. The subject's maximum force was established, and a target force window was defined as a range between 30 and 40% (all experiments except experiment 5; see below) of the individual maximum force displayed as two horizontal lines on the computer screen. Because in each experiment the display was scaled to the subject's individual maximum force, the target window had the same geometrical size for all subjects. Each subject had to perform a total of 500 metronome-paced (0.5 Hz) isometric thumb abductions in a series of 10 training blocks that were separated by 30 s and consisted of 50 abductions each.
Experiment 1 (Effect of Dynamic Motor Training on PAS-induced Plasticity)
A total of 32 subjects were scheduled to participate in the main experiment, which consisted of a maximum of four experimental sessions separated by at least 2 days (Fig. 1a).
|
Sessions 1 and 2. All subjects were exposed to PAS10 and PAS25 in different sessions in a counterbalanced order. Subjects were admitted to sessions 3 and 4 if, in the first two sessions, PAS10 had led to a decrease and PAS25 had led to an increase of MEP amplitudes elicited in the APB muscle. Of 32 subjects, 22 of them fulfilled this double criterion. Eleven of these subjects were pseudorandomly assigned to group a, and the other 11 subjects to group b.
Session 3. Subjects underwent motor training as described above. Subsequently, group a was re-exposed to PAS10, whereas group b was re-exposed to PAS25.
Session 4. At least 5 days after session 3, eight subjects belonging to group a were re-exposed to PAS10 and six subjects belonging to group b were re-exposed to PAS25.
Experiment 2 (Duration of Motor-training-induced Blockade of PAS25-induced Plasticity)
Five subjects were scheduled to participate in a maximum of two experimental sessions separated by at least 2 days (Fig. 1b).
Sessions 1. Subjects were exposed to PAS25. Subjects were admitted to session 2 if, in the first session, PAS25 had led to an increase of MEP amplitudes elicited in the APB muscle. All five subjects fulfilled this criterion.
Session 2.
Position of ‘hot spot’, magnitude of resting motor threshold and baseline MEP responses were obtained. Two different stimulation intensities were used [20 TMS pulses at 1.3 times resting motor threshold (SI1.3*RMT) and 20 TMS pulses at 1.15 times resting motor threshold (SI1.15*RMT)] to test the input–output characteristic of the motor cortex at two different points (Devanne et al., 1997). Subsequently, subjects underwent motor training as described above. Thereafter, subjects were exposed to PAS25 and excitability of APB muscle representation was probed (20 TMS pulses at SI1.3*RMT and 20 TMS pulses at SI1.15*RMT). After a delay of 6 h, during which the subjects engaged in their normal daily life activity (reading and attending lectures), subjects were re-exposed to PAS25. To assess the effects of this last PAS25 intervention, a single stimulation intensity (SI1.3*RMT) was utilized to elicit MEP responses before and after PAS.
Experiment 3 (Effect of Dynamic Motor Training on PAS25-induced Plasticity in the Untrained Motor Cortex)
In total, seven subjects were scheduled to participate in a maximum of two sessions (Fig. 1c). The sessions were separated by at least 2 days. This experiment used a design principle similar to experiment 1, except that PAS25 targeted the right, untrained motor cortex. PAS25 was done as in experiment 1. Repetitive TMS over the hot spot for activating the left APB muscle was paired with left median nerve stimulation.
Session 1. PAS25 was tested at baseline. Subjects were admitted to session 2 if PAS25 had an increased MEP size in the left APB. In five of the seven subjects screened for this experiment PAS25 led to an increase of MEP amplitudes.
Session 2. Subjects underwent a motor learning task utilizing their right thumb, as described above. Immediately after completion of the motor training, subjects were re-exposed to PAS25 targeting the right motor cortex.
Experiment 4 (Effect of Prior PAS10 Treatment on Motor-training-induced Blockade of PAS25-induced Plasticity and Motor Skill Consolidation in PAS-treated Motor Cortex)
The purpose of this experiment was to test the following two hypotheses: (i) motor-training induced blockade of PAS25-induced plasticity can be prevented if PAS10 is applied between termination of the motor training and before the PAS25-intervention; and (ii) PAS25-induced plasticity blocks motor skill consolidation if PAS25 is applied within minutes of acquiring the new motor skill. The PAS10* protocol variant was employed instead of the PAS10 protocol used in experiment 1. A total of nine subjects were scheduled to participate in the experiment, which consisted of a maximum of four experimental sessions separated by at least 2 days (Fig. 1d). Data from one subject were excluded from analysis because of an error in the experimental protocol.
Sessions 1 and 2. All subjects were exposed to PAS10* and PAS25 in different sessions in a counterbalanced design. Subjects were admitted to sessions 3 and 4 if in the first two sessions PAS10* had led to a decrease in, and PAS25 had led to an increase in, MEP amplitudes in APB. Seven subjects fulfilled this double criterion.
Session 3. Position of ‘hot spot’, magnitude of resting motor threshold, and baseline MEP responses (20 TMS pulses at 1.3 times resting motor threshold) were obtained. Subjects then underwent motor training, as described above. Subsequently, subjects were exposed to PAS10*. Immediately after termination of PAS10* and subsequent probing of cortical excitability (20 TMS pulses), subjects were exposed to PAS25.
Session 4. At least 3 days after session 3, six subjects were retested in the same motor task as in session 3.
Experiment 5 (Efficacy of Motor Training Performed at a Time when PAS25-induced Plasticity was Blocked)
The purpose of this experiment was to test the hypothesis that dynamic motor learning was possible at the same time in experiment 1 that PAS25 was ineffective in inducing enhancement of cortical excitability. Because motor performance had reached an asymptotic phase during motor training in experiments 1 and 2, it is conceivable that additional increments in performance due to continued motor learning would be difficult to detect. Therefore, while the general design of the motor task was retained, the task difficulty was increased by reducing the width of the force window to 5% of the maximal individual force. The lower limit of the force target window was set to 30% and the upper limit to 35% of the individual maximal force. Based on our experience with the first task design, we reasoned that it would be unlikely for motor performance to reach an asymptotic level within 10 blocks of motor training. Five subjects participated in this experiment (Fig. 1e). After completion of the first series of 10 training blocks, subjects performed a second series of 10 blocks of training at the same task. Subjects paused for 20 min after completion of the first series to ensure that the second series was done at a time equivalent to the interval between the end of the training and the beginning of the PAS intervention in experiment 1.
Experiment 6 (Motor Skill Consolidation in PAS-naive Motor Cortex)
Five subjects participated in two sessions (Fig. 1f). In session 1, subjects underwent a motor learning task utilizing their right thumb, as described in experiment 1. In session 2, which took place 7.8 ± 1.8 days after session 1, subjects were retested in the same motor task as in session 1
There was no overlap between subjects participating in experiments 1–6.
Data Analysis
Cortical Excitability
MEP amplitudes were measured peak-to-peak in each individual trial. To assess the effect of PAS-intervention on cortical excitability, for each subject the average of 20 MEP amplitudes after PAS was normalized to the average of 20 MEP amplitudes before PAS. Changes of MEP amplitudes were expressed as a percentage difference from baseline.
Assessment of Dynamic Motor Learning
The number of successful attempts was recorded for each training block. The primary outcome measure of motor learning was the difference between the mean number of hits achieved in the last two training blocks, and the mean number of hits achieved in the first two training blocks. In experiments assessing consolidation, the mean number of hits achieved in the first two training blocks was compared between the first and the second training sessions. Consolidation was assumed if initial performance in the second training session was superior to the initial performance in the first training session. In experiment 1, the percentage increase of MEP amplitudes obtained at 1.3 times the resting motor threshold after training, relative to the mean of baseline MEP size in sessions 1 and 2, served as a secondary outcome measure of motor learning.
Analyses of variance (ANOVA) were employed in factorial and repeated measures (ANOVARM) designs, and post-hoc one- or two-tailed t-tests were employed for statistical analyses as appropriate. Statistical analyses were performed using SPSS (12.0 for Windows, SPSS Inc., Chicago, IL) and statistical functions built in Excel 2002 (Microsoft Corporation, USA). Effects were considered significant if P < 0.05. All data are given as means ± SD.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Effect of dynamic motor training on PAS-induced plasticity (Experiment 1)
Of 32 subjects, 22 fulfilled the double inclusion criteria (decrease of cortical excitability with PAS10 and increase with PAS25). The results of only these 22 subjects are considered here.
Basic Physiological and Behavioral Parameters, Baseline Responsiveness to PAS10 and PAS25
Groups a and b were similar in all baseline physiological and behavioral parameters (Table1).
|
An ANOVARM (2 x 2 x 2) with PAS-type (PAS10, PAS25) and PAS-period (pre-PAS, post-PAS) as within-subject factors and group (a, b) as the between-subjects factor revealed a significant PAS-type x PAS-period interaction (F = 27.63, P < 0.001). None of the main factors and none of the other interactions were significant. At baseline (sessions 1 and 2), the PAS10-induced MEP amplitudes decrease and PAS25-induced MEP amplitudes increase were similar in groups a (PAS10: –22.1 ± 11.5%; PAS25: 41.1 ± 31.8%) and b (PAS10: –23.8 ± 13.0%; PAS25: 43.4 ± 26.1%).
Training Effects on Dynamic Motor Performance and on PAS10- and PAS25- induced Plasticity
During training, the force trajectories gradually became smoother (Fig. 2a) and the number of hits into the force target zone increased (Fig. 2b). The number of hits increased similarly in groups a (from 33.7 ± 5.2 to 38.5 ± 5.8, P = 0.001, paired two-tailed t-test) and b (from 33.3 ± 5.4 to 39.2 ± 4.5; P < 0.001). An ANOVARM (2x2) with training-stage (pre-training, post-training) as the within-subject factor and group (a, b) as the between-subjects factor revealed a significant effect of training-stage (F = 51.63, P < 0.001), while group and training-stage x group were not significant.
|
Following training, resting motor threshold and, therefore, stimulation intensity remained unchanged (data not shown). Training led on average to a moderate, yet interindividually variable increase of MEP amplitudes. The mean magnitude of TMS-evoked MEPs obtained at 1.3 times the resting motor threshold after training, before PAS, was larger when compared with the mean baseline MEP amplitudes obtained in sessions 1 and 2. MEP amplitudes increased similarly in both groups (group a: 27.9 ± 31.8%; group b: 22.3 ± 37.9%). An ANOVARM (2x2) revealed a significant effect of training-stage on MEP amplitudes (F = 5.54, P = 0.029), while group and training-stage x group were not significant.
Immediately after motor training (post-training 1), PAS25 was no longer effective in enhancing MEP amplitudes (MEP amplitudes after PAS25 amounted to 84.5 ± 11.6% of baseline). However, when retested after 8.6 ± 4.3 days (post-training 2), the capacity of PAS25 to induce an enhancement of MEP size was restored (MEP amplitudes after PAS25 amounted to 142.1 ± 44.9% of baseline; n = 6). PAS10 decreased MEP amplitudes in APB to a similar amount as at baseline, both immediately after motor training (–22.7 ± 18.3%) and at the late (–17.2 ± 17.7% of baseline; n = 8) session. Representative data of single subjects are displayed in Figure 3a and group data are displayed in Figure 3b. A one-way factorial [training-stage (pre-training, post-training 1, post-training 2)] ANOVA was performed, separately for each type of PAS-intervention, on baseline-normalized MEP amplitudes. Training-stage was significant for PAS25 (F = 10.71, P < 0.001). Post-hoc testing revealed that baseline-normalized MEP amplitudes obtained at post-training 1 were smaller compared with pre-training (P = 0.001, Scheffé's test) and post-training 2 (P = 0.007), while there was no statistically significant difference between pre-training and post-training 2 (P = 0.996). Training-stage was not significant for PAS10 (F = 0.32, P = 0.733).
|
We considered the possibility that the inefficacy of PAS25 after training could have been related to the (mildly) enhanced cortical excitability following training. Analysis across pre-training sessions 1 and 2 did not reveal a significant correlation between MEP amplitudes before PAS, and PAS25 efficacy (combined results from groups a and b, Pearson's correlation coefficient r = 0.01; P = 0.482). This lack of correlation suggests that small training-induced increases in cortical excitability are unlikely to have caused the loss of PAS25 efficacy.
Duration of Motor-training-induced Blockade of PAS25-induced Plasticity (Experiment 2)
This experiment served to determine the duration of motor-learning-induced blockade of PAS25-induced plasticity. At the first session, PAS25 led to an increase of MEP amplitudes in APB muscle (20.4 ± 6.0%; P = 0.004, paired one-sided t-test). Training to optimize isometric force production (second session) led to an increase in the number of hits into the force target window (from 35.3 ± 4.0 to 42.9 ± 3.6; P = 0.003, paired one-sided t-test), similar to that in experiment 1.
Immediately after motor training (post-training 1), PAS25 was no longer effective in enhancing MEP amplitudes, similarly to experiment 1. There was no difference between the baseline-normalized MEP amplitudes after PAS25 when different stimulation intensities were used (SI1.3*RMT, MEP-amplitude pre-PAS: 1.12 ± 0.34 mV, post-PAS: 1.02 ± 0.33 mV or 91.5 ± 14.9% of baseline; SI1.15*RMT: MEP-amplitude pre-PAS: 0.56 ± 0.26 mV, post-PAS: 0.51 ± 0.17 mV or 91.2 ± 16.5% of baseline; P = 0.228). This observation suggests that the failure of PAS25 to induce an enhancement of motor cortical excitability after motor training did not arise as a consequence of a differential modulation of the input–output characteristic of the motor cortex.
After a delay of 6 h, the capacity of PAS25 to induce an enhancement of MEP size was restored (MEP amplitudes increase after PAS25 amounted to 17.5 ± 10.2% of baseline; P = 0.012, paired one-sided t-test). An ANOVARM revealed a significant effect of training-stage (pre-training, post-training 1, post-training 2) (F = 16.94, P = 0.001). Post-hoc testing revealed that baseline-normalized MEP amplitudes obtained at post-training 1 were smaller compared with pre-training (P = 0.003, paired one-sided t-test) and post-training 2 (P = 0.009), while there was no statistically significant difference between pre-training and post-training 2 (P = 0.280, data not illustrated).
Effect of Dynamic Motor Training on PAS25-induced Plasticity in the Untrained Motor Cortex (Experiment 3)
This experiment served to test the hemispheric specificity of the blockade of PAS25-induced plasticity following training observed in experiment 1. In five of the seven subjects screened for this experiment PAS25 targeting the right motor cortex led to an increase of MEP amplitudes in left APB muscle (29.8 ± 14.0%). Training to optimize isometric force production engaging the right thumb led to an increase in the number of hits into the force target window (from 37.5 ± 2.9 to 44.1 ± 1.7; P = 0.006, paired one-sided t-test), similar to that in experiment 1. After motor training, PAS25 targeting the right motor cortex led to an increase of MEP amplitudes in left APB muscle (49.6 ± 39.2%). Therefore, motor training activating the left motor cortex did not abolish the efficacy of PAS25 to induce an enhancement of cortical excitability in the right motor cortex. Representative data from a single subject are displayed in Figure 4a, group data in Figure 4b. An ANOVARM (2 x 2) with training-stage (pre-training, post-training) and PAS-period (pre-PAS, post-PAS) as within-subject factors revealed a significant effect of PAS-period (F = 15.89, P = 0.016), while training-stage and training-stage x PAS-period were not significant.
|
Effect of Prior PAS10 Treatment on Motor-training-induced Blockade of PAS25-induced Plasticity (Experiment 4)
In seven of the eight subjects screened for this experiment PAS25 led to an increase of MEP amplitudes (27.7 ± 6.7%) and PAS10* led to a decrease of MEP amplitudes (–33.7 ± 17.8%). Training to optimize isometric force production led to an increase in the number of hits into the force target window (from 32.8 ± 3.1 to 40.3 ± 2.8; P < 0.001), similar to that in experiments 1 and 2. Baseline MEP amplitudes, obtained immediately before PAS, increased by 14.2 ± 7.1% compared with baseline MEP amplitudes before motor training (P = 0.011, two-sided paired t-test). In contrast to experiment 1, motor training did not abolish the efficacy of PAS25 to enhance cortical excitability when PAS10* was applied between termination of the training and application of the PAS25 protocol. Representative data from a single subject are displayed in Figure 5a, group data in Figure 5b. Following motor training, PAS10* led to a decrease of MEP amplitudes of –27.7 ± 9.6% (P = 0.001, two-sided paired t-test). PAS25, applied after PAS10*, induced an enhancement of MEP amplitudes of 73.1 ± 36.3% (P = 0.023), relative to the baseline MEP size obtained after PAS10*, or of 27.3 ± 38.7% relative to MEP size before PAS10*. PAS25-induced increase of MEP amplitudes post-training (relative to MEP size before PAS10*) was similar to the PAS25-induced increase of MEP amplitudes pre-training (two-sided paired t-test, P = 0.982). This result suggests that motor-training induced blockade of PAS25-induced plasticity can be prevented by applying PAS10* before PAS25.
|
Effect of Motor Training Performed at a Time when PAS25-induced Plasticity was Blocked (Experiment 5)
To examine the relationship between PAS25-induced plasticity and motor learning we tested whether motor learning was possible at a time when PAS25-induced plasticity was blocked in experiment 1. Over the first training period, which comprised a total of 500 single isometric thumb abductions (cf. Fig. 1), the number of hits into the force target window increased (from 19.1 ± 4.5 to 24.2 ± 3.5; P = 0.017, one-sided paired t-test). As expected, the number of hits was substantially smaller than in experiments 1 and 2, due to the greater challenge on force control. Performing a second series of training, which began 20 min after completion of the first, led to a further increase of the number of hits into the target window (24.6 ± 3.9 to 30.8 ± 4.8, P < 0.001; Fig. 6). The magnitude of increase was similar in the two training periods (P = 0.209). This indicated that motor learning was possible at a time when PAS25-induced plasticity was blocked.
|
Motor Skill Consolidation in PAS-naive and PAS-treated Motor Cortex (Experiments 4 and 6)
In experiment 6, five subjects were retested at the same motor task 7.8 ± 1.8 days after the first motor training session. The initial motor performance in the second session was superior to the initial motor performance observed in the first motor training session. The initial number of hits increased from 33.3 ± 3.1 in the first motor training session to 39.3 ± 2.7 in the second session (P = 0.005; paired two-tailed t-test). Therefore, in the absence of PAS-intervention over the learning motor cortex, some of the motor skill acquired in the first motor training session could be retained and recalled at the later session.
To test whether application of PAS over the training motor cortex would disrupt the retention of the acquired motor skill, six of the seven subjects participating in experiment 4 (motor training followed by combined application of PAS10* plus PAS25) were retested at the same motor task in a separate session performed 7.5 ± 4.4 days after completion of the first motor learning task. The initial motor performance in the second motor learning session was superior to that in the first motor learning session. The initial number of hits increased from 31.2 ± 2.6 in the first session to 36.2 ± 3.1 in the second session (P = 0.032; paired one-tailed t-test). Thus, the combined application of PAS10* plus PAS25 after motor training did not disrupt the ability of the subjects to retain some of the motor skill. Performance improvement at retesting was similar in PAS-naive (3.5 ± 1.8) and PAS10* plus PAS25-treated (5.0 ± 5.2, P = 0.597, two-sided t-test) motor cortex. Therefore, PAS25 (whose effect on cortical excitability was made possible by prior application of PAS10*) did not disrupt consolidation of the acquired motor skill.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The present study has shown that training to improve force control temporarily interfered with the efficacy of an external Hebbian associative stimulation protocol. Induction of associative plasticity early after training did not prevent the consolidation of motor skills.
Mechanism of Occlusion of PAS25-induced Plasticity by Prior Dynamic Motor Training
PAS-induced timing-dependent plasticity of motor cortex excitability shares many physiological and pharmacological properties with LTP and LTD (Stefan et al., 2000, 2002; Wolters et al., 2003). In particular, the fact that the sign of excitability changes is determined by the sequence of near-synchronous events induced by the two stimulation modalities in the motor cortex (Wolters et al., 2003) parallels the spike-timing-dependent rule governing induction of Hebbian LTP and LTD in animal experiments (Dan and Poo, 2004). While the physiological properties of PAS-induced plasticity are consistent with a synaptic origin, changes of intrinsic neuronal excitability (Daoudal and Debanne, 2003; Zhang and Linden, 2003; Li et al., 2004) may represent pre- or postsynaptic mechanisms involved synergistically in generating motor plasticity by associative stimulation. The results of the present study show that motor training has interfered with the ability of the cortex to undergo timing-dependent plasticity in response to a Hebbian induction protocol. The specificity of our findings is demonstrated by the fact that PAS-induced plasticity in the ipsilateral, untrained motor cortex was unaffected by motor training (Fig. 4) and by the observation that PAS-induced plasticity could readily be reinduced in the trained motor cortex after 6 h (experiment 2) or several days (Fig. 3) had elapsed. The latter observation also testifies to the reproducibility of the excitability changes induced by the PAS protocol.
Conceivably, motor training could have temporarily erased the capacity of M1 to express plasticity in response to PAS25. However, PAS25 efficacy was reinstalled after PAS10* had induced a decrease of motor cortical excitability (Fig. 5). This finding is explained more easily if we assume that motor training had led to a temporary saturation of timing-dependent associative plasticity, while the capacity of M1 to express PAS25-induced plasticity had, in principle, remained intact.
Our observations are similar to findings in rats, obtained in vitro (Rioult-Pedotti et al., 2000) and in vivo (Monfils et al., 2004; Hodgson et al., 2005), that relate motor cortical LTP formation to motor learning. These studies showed that after rats had been trained in a highly demanding novel motor task, the magnitude of LTP inducible in the motor cortex was profoundly reduced when tested several hours after the end of the training (Rioult-Pedotti et al., 2000; Monfils et al., 2004; Hodgson et al., 2005). In one study, a normal amount of LTP was induced later, after a plateau of performance had been reached (Monfils et al., 2004). These studies also demonstrated that the reduction of LTP was accompanied by a comparable increase in LTD (Rioult-Pedotti et al., 2000; Monfils and Teskey, 2004). Based on their finding of a fixed synaptic modification range, Rioult-Pedotti et al. (2000) and Montfils et al. (2004) promoted the hypothesis that LTP may underlie the initial mnemonic representation of the new motor skill in the motor cortex, assuming that LTP induced by the induction protocol may be equivalent to endogenous LTP.
PAS10-induced plasticity remained unchanged in our study, consistent with recent observations in animals that skilled motor learning does not enhance LTD in animals (Cohen and Castro-Alamancos, 2005). On the other hand, in vivo studies of LTD in animals (Froc et al., 2000) suggest that a maximal depression of MEP amplitudes would have emerged only after multiple or more intense applications of the PAS10 protocol. Therefore, it is possible that an enhanced capacity of M1 to express PAS10-induced plasticity may have been missed, and that the modification range of cortical excitability has, in fact, remained stable. Animal studies suggest that LTP is induced principally during the process of skill acquisition and may not be generated by a repetition of movements that is not associated with improvements of the experimental target variable (Monfils and Teskey, 2004). The behavioral intervention employed in the present study had several components, including repetition of movements, intention to improve performance, attention to the task, and finally actual achievement of superior task performance as the result of motor training. Because the experimental protocol was not designed to distinguish between these different aspects, it remains an open question to which aspect of the task-training-induced blockade of PAS25-induced plasticity was related. It is conceivable that blockade of PAS25-induced plasticity was more related to the repetition of movements, to the attended performance of repetitive movements or to the intention to improve performance rather than to the later performance increment itself. Indeed, findings obtained in experiment 5 argue against complete identity between mechanisms underlying the encoding of a new motor skill and PAS-induced plasticity. Subjects continued to improve their performance even at a time when in experiment 1 no PAS25-induced plasticity could be elicited (Fig. 6). If the mechanism underlying the mnemonic representation of the new skill was fully identical with PAS25-induced associative plasticity then no further improvement of motor performance should be expected.
Our findings can perhaps be explained best when certain dynamic properties of LTP are considered. The term ‘metaplasticity’ has been introduced to describe changes in the ability of synapses to undergo LTP and LTD that are dependent on prior activity (Abraham and Bear, 1996). For instance, LTP formation was significantly enhanced in rat visual cortex after extended light deprivation (Kirkwood et al., 1996). LTP formation reverted to baseline level after a 2 day exposure to light (Kirkwood et al., 1996). In this example, the decrease of neuronal activity by light deprivation was associated with an enhancement of the capacity to express LTP in response to an induction protocol. This ‘metaplasticity’ principle has also been found in numerous in vitro and in vivo studies in which two electrical induction treatments have been applied successively (Colino et al., 1992; Huang et al., 1992; Staubli and Chun, 1996a,b; Holland and Wagner, 1998; Volgushev et al., 1999; Wang and Wagner, 1999; Abraham et al., 2001; for review see Abraham and Tate, 1997). Importantly, while metaplasticity effects have typically been specific to the activated synapses, in vitro (Holland and Wagner, 1998; Wang and Wagner, 1999) as well as in vivo (Abraham et al., 2001) experiments show that the change occurs for all excitatory synapses terminating on the affected neurons, regardless of which inputs are overactive or quiescent, i.e. it occurs not only homosynaptically but also heterosynaptically. Considering these properties of LTP, we speculate that endogenous LTP induced by dynamic motor training has interfered with formation of associative LTP-like phenomena induced by the PAS protocol. Synapses targeted by PAS could represent a subset of synapses encoding the new motor skill, indicating that not all of these synapses are accessible to PAS. Alternatively, synapses modifiable by PAS could be distinct from motor-skill-encoding synapses. In this way, heterosynaptic blockade of LTP formation (on PAS-modifiable synapses) would be present before motor-skill-encoding synapses had reached their maximum efficacy. Importantly, this latter hypothesis would be entirely consistent with a view that the mnemonic representation of the new motor skill is not directly related to changes of susceptibility of motor cortical synapses toward external modification.On the other hand, our findings support other indirect evidence (Bütefisch et al., 2000; Donchin et al., 2002) suggesting that LTP is involved in early human motor memory.
Relationship to Previous Studies in Humans
Our findings agree with recent human studies demonstrating that motor cortical plasticity depends on the activation history of M1 (Iyer et al., 2003; Siebner et al., 2004; Ziemann et al., 2004). In one study, a protocol similar to PAS25 failed to induce an increase of cortical excitability after training repetitive ballistic thumb abductions at a subject's maximal speed (Ziemann et al., 2004). Instead, a pronounced decrease was induced. Because the current study used a dynamic isometric task involving submaximal muscular activation, the present results suggest that ballistic and dynamic motor tasks share similar physiological mechanisms. In the study of Ziemann et al. (2004) the MEP-amplitude-enhancing PAS protocol employed an interval between median nerve and TMS pulse that differed by only 5 ms from the MEP-amplitude-decreasing interval. Maximal acceleration training led to substantial increases of cortical excitability (Ziemann et al., 2004). As a consequence of this, it is important to consider the possibility that the timing of the postsynaptic action potential induced transsynaptically by TMS in cortical neurons may have been advanced by a few milliseconds. Even if the postsynaptic action potential was advanced by only a small amount of time this could be sufficient to reverse the temporal sequence of events induced by afferent stimulation and TMS. The spike-timing dependent plasticity rule (Dan and Poo, 2004) predicts that this reversal of temporal sequence alone would alter the sign of the induced synaptic changes (from enhancement to depression). This consideration challenges the interpretation of the profound post-training MEP depression induced by the previously enhancing PAS protocol put forward by Ziemann and colleagues (Ziemann et al., 2004). In our study both PAS protocols differed by 15 ms. Therefore, the possibility that a training-induced change in the efficacy of PAS25 protocol was due to shifts in the timing of the activation of postsynaptic neurons appears highly unlikely.
Our data concur with the principal results of two other recent studies (Iyer et al., 2003; Siebner et al., 2004) demonstrating that the effect of a stimulation treatment may be influenced by pretreatment with a different stimulation protocol. A priming session utilizing high-frequency rTMS at 6 Hz (Iyer et al., 2003) or anodal transcranial direct current stimulation (Siebner et al., 2004) augmented the MEP-amplitude suppressing effect of subsequently applied 1 Hz repetitive TMS. When cathodal direct current stimulation was employed as pretreatment the depressing effect of 1 Hz stimulation was reversed into a large facilitating effect (Siebner et al., 2004). Together, these studies reveal remarkable similarities between observations in animal preparations and findings at the systems level of human physiology.
Implication for Mechanisms of Anterograde and Retrograde Interference
Because responsiveness toward the PAS25 protocol was restored after 6 h, the present study indicates for the first time that occlusion of associative plasticity by dynamic motor training is only temporary. Although the minimum time interval for restoration of PAS25-induced plasticity was not explored here, our observation offers an explanation for the phenomenon of anterograde interference (Shadmehr and Brashers-Krug, 1997). As noted above, the acquisition of a novel motor skill was found to be impaired for a limited period of time after the training of a first motor skill (Shadmehr and Brashers-Krug, 1997). We suggest that the temporary failure of PAS25 to induce plasticity in the motor cortex may be a physiological signature of this phenomenon. In this way, two properties of motor skill acquisition, formation of a short-term memory and blockade of subsequent acquisition of competing memories (anterograde interference) may be mapped onto a single physiological mechanism in M1, one that is similar to LTP of neuronal synapses.
In hippocampus-dependent memory systems LTP induction after learning may produce retrograde amnesia (Brun et al., 2001; McNaughton et al., 1986), possibly by ‘overwriting’ the synaptic weights underlying memories formed by the previous learning experiences. Disruption of consolidation of a motor memory by a second motor training (Shadmehr and Brashers-Krug, 1997) or by rTMS (Baraduc et al., 2004; Muellbacher et al., 2002) performed within a few hours after the first training may depend on a similar mechanism. In our study, application of a PAS10*/PAS25 protocol immediately after motor training did not diminish performance gains at later retesting, when compared with performance gains in a PAS-naive motor cortex. This finding indicates that disruption of consolidation of motor memories, or retrograde interference, may not operate through the interference with LTP-like mechanisms, or may require a more complete saturation of LTP-like plasticity than achievable by PAS. The latter possibility is strongly favored by findings in the hippocampus (Barnes et al., 1994). Alternatively, but less likely, consolidation of dynamic motor skills may not involve M1 (Baraduc et al., 2004) and hence may be resistant to LTP-induction in M1. On a different view, our observation suggests that motor consolidation of a dynamic motor skill does not depend on inactivation of competing associative plasticity induced in the same motor representation.
|
Acknowledgments |
|---|
The technical assistance of Martin Luboschik is gratefully acknowledged. We acknowledge support by Hertie-Foundation, Germany and Dystonia Medical Research Foundation, USA.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abraham WC, Bear MF (1996) Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci 19:126–130.[CrossRef][Web of Science][Medline]
Abraham WC, Tate WP (1997) Metaplasticity: a new vista across the field of synaptic plasticity. Prog Neurobiol 52:303–323.[CrossRef][Web of Science][Medline]
Abraham WC, Mason-Parker SE, Bear MF, Webb S, Tate WP (2001) Heterosynaptic metaplasticity in the hippocampus in vivo: a BCM-like modifiable threshold for LTP. Proc Natl Acad Sci USA 98:10924–10929.
Baraduc P, Lang N, Rothwell JC, Wolpert DM (2004) Consolidation of dynamic motor learning is not disrupted by rTMS of primary motor cortex. Curr Biol 14:252–256.[CrossRef][Web of Science][Medline]
Barnes CA, Jung MW, McNaughton BL, Korol DL, Andreasson K, Worley PF (1994) LTP saturation and spatial learning disruption: effects of task variables and saturation levels. J Neurosci 14:5793–806.[Abstract]
Brashers-Krug T, Shadmehr R, Bizzi E (1996) Consolidation in human motor memory. Nature 382:252–5.[CrossRef][Medline]
Brun VH, Ytterbo K, Morris RG, Moser MB, Moser EI (2001) Retrograde amnesia for spatial memory induced by NMDA receptor-mediated long-term potentiation. J Neurosci 21:356–62.
Bütefisch CM, Davis BC, Wise SP, Sawaki L, Kopylev L, Classen J, Cohen LG. (2000) Mechanisms of use-dependent plasticity in the human motor cortex. Proc Natl Acad Sci USA 97:3661–3665.
Caithness G, Osu R, Bays P, Chase H, Klassen J, Kawato M, et al. (2004) Failure to consolidate the consolidation theory of learning for sensorimotor adaptation tasks. J Neurosci 24:8662–8671.
Classen J, Liepert A, Wise SP, Hallett M, Cohen LG (1998) Rapid plasticity of human cortical movement representation induced by practice. J Neurophysiol 79:1117–1123.
Cohen JD, Castro-Alamancos MA (2005) Skilled motor learning does not enhance long-term depression in the motor cortex in vivo. J Neurophysiol 93:1486–1497.
Colino A, Huang YY, Malenka RC (1992) Characterization of the integration time for the stabilization of long-term potentiation in area CA1 of the hippocampus. J Neurosci 12:180–187.[Abstract]
Dan Y, Poo MM (2004) Spike timing-dependent plasticity of neural circuits. Neuron 44:23–30.[CrossRef][Web of Science][Medline]
Daoudal G, Debanne D (2003) Long-term plasticity of intrinsic excitability: learning rules and mechanisms. Learn Mem 10:456–465.
Devanne H, Lavoie BA, Capaday C. (1997) Input–output properties and gain changes in the human corticospinal pathway. Exp Brain Res 114:329–338.[CrossRef][Web of Science][Medline]
Donchin O, Sawaki L, Madupu G, Cohen LG, Shadmehr R (2002) Mechanisms influencing acquisition and recall of motor memories. J Neurophysiol 88:2114–2123.
Froc DJ, Chapman CA, Trepel C, Racine RJ (2000) Long-term depression and depotentiation in the sensorimotor cortex of the freely moving rat. J Neurosci 20:438–445.
Hodgson RA, Ji Z, Standish S, Boyd-Hodgson TE, Henderson AK, Racine RJ (2005) Training-induced and electrically induced potentiation in the neocortex. Neurobiol Learn Mem 83:22–32.[CrossRef][Web of Science][Medline]
Holland LL, Wagner JJ (1998) Primed facilitation of homosynaptic long-term depression and depotentiation in rat hippocampus. J Neurosci 18:887–894.
Huang YY, Colino A, Selig DK, Malenka RC (1992) The influence of prior synaptic activity on the induction of long-term potentiation. Science 255:730–733.
Iyer MB, Schleper N, Wassermann EM (2003) Priming stimulation enhances the depressant effect of low-frequency repetitive transcranial magnetic stimulation. J Neurosci 23:10867–10872.
Karni A, Meyer G, Jezzard P, Adams MM, Turner R, Ungerleider LG (1995) Functional MRI evidence for adult motor cortex plasticity during motor skill learning. Nature 377:155–158.[CrossRef][Medline]
Kirkwood A, Rioult MC, Bear MF (1996) Experience-dependent modification of synaptic plasticity in visual cortex. Nature 381:526–528.[CrossRef][Medline]
Li C, Lu J, Wu C, Duan S, Poo M (2004) Bidirectional modification of presynaptic neuronal excitability accompanying spike timing-dependent synaptic plasticity. Neuron 41:257–268.[CrossRef][Web of Science][Medline]
McNaughton BL, Barnes CA, Rao G, Baldwin J, Rasmussen M (1986) Long-term enhancement of hippocampal synaptic transmission and the acquisition of spatial information. J Neurosci 6:563–571.[Abstract]
Monfils MH, Teskey GC (2004) Skilled-learning-induced potentiation in rat sensorimotor cortex: a transient form of behavioural long-term potentiation. Neuroscience 125:329–336.[CrossRef][Web of Science][Medline]
Monfils MH, VandenBerg PM, Kleim JA, Teskey GC (2004) Long-term potentiation induces expanded movement representations and dendritic hypertrophy in layer V of rat sensorimotor neocortex. Cereb Cortex 14:586–593.
Muellbacher W, Ziemann U, Boroojerdi B, Cohen L, Hallett M (2001) Role of the human motor cortex in rapid motor learning. Exp Brain Res 136:431–438.[CrossRef][Web of Science][Medline]
Muellbacher W, Ziemann U, Wissel J, Dang N, Kofler M, Facchini S, et al. (2002) Early consolidation in human primary motor cortex. Nature 415:640–644.[CrossRef][Medline]
Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113.[CrossRef][Web of Science][Medline]
Pascual-Leone A, Nguyet D, Cohen LG, Brasil-Neto JP, Cammarota A, Hallett M (1995) Modulation of muscle responses evoked by transcranial magnetic stimulation during the acquisition of new fine motor skills. J Neurophysiol 74:1037–1045.
Rioult-Pedotti MS, Friedman D, Donoghue JP (2000) Learning-induced LTP in neocortex. Science 290:533–536.
Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ, et al. (1994) Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalogr Clin Neurophysiol 91:79–92.[CrossRef][Web of Science][Medline]
Sanes JN, Donoghue JP (2000) Plasticity and primary motor cortex. Annu Rev Neurosci 23:393–415.[CrossRef][Web of Science][Medline]
Shadmehr R, Brashers-Krug T (1997) Functional stages in the formation of human long-term motor memory. J Neurosci 17:409–419.
Siebner HR, Lang N, Rizzo V, Nitsche MA, Paulus W, Lemon RN, et al. (2004) Preconditioning of low-frequency repetitive transcranial magnetic stimulation with transcranial direct current stimulation: evidence for homeostatic plasticity in the human motor cortex. J Neurosci 24:3379–3385.
Staubli U, Chun D (1996a) Factors regulating the reversibility of long-term potentiation. J Neurosci 16:853–860.
Staubli U, Chun D (1996b) Proactive and retrograde effects on LTP produced by theta pulse stimulation: mechanisms and characteristics of LTP reversal in vitro. Learn Mem 3:96–105.
Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J (2000) Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 123:572–584.
Stefan K, Kunesch E, Benecke R, Cohen LG, Classen J (2002) Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation. J Physiol 543:699–708.
Volgushev M, Mittmann T, Chistiakova M, Balaban P, Eysel UT (1999) Interaction between intracellular tetanization and pairing-induced long-term synaptic plasticity in the rat visual cortex. Neuroscience 93:1227–1232.[CrossRef][Web of Science][Medline]
Wang H, Wagner JJ (1999) Priming-induced shift in synaptic plasticity in the rat hippocampus. J Neurophysiol 82:2024–2028.
Wolters A, Sandbrink F, Schlottmann A, Kunesch E, Stefan K, Cohen LG, et al. (2003) A temporally asymmetric Hebbian rule governing plasticity in the human motor cortex. J Neurophysiol 89:2339–2345.
Wycislo M, Classen J (2003) Involvement of long-term potentiation-like plasticity in human motor learning: a TMS study. In: 29th Göttingen Neurobiology Conference, 5th Meeting of the German Neuroscience Society, 2nd International Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation Symposium Göttingen (Elsner N, Zimmermann H, eds), pp. 1170–1171. Göttingen: Thieme.
Zhang W, Linden DJ (2003) The other side of the engram: experience-driven changes in neuronal intrinsic excitability. Nat Rev Neurosci 4:885–900.[CrossRef][Web of Science][Medline]
Ziemann U, Iliac TV, Pauli C, Meintzschel F, Ruge D (2004) Learning modifies subsequent induction of long-term potentiation-like and long-term depression-like plasticity in human motor cortex. J Neurosci 24:1666–1672.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Rothkegel, M. Sommer, T. Rammsayer, C. Trenkwalder, and W. Paulus Training Effects Outweigh Effects of Single-Session Conventional rTMS and Theta Burst Stimulation in PD Patients Neurorehabil Neural Repair, May 1, 2009; 23(4): 373 - 381. [Abstract] [PDF]
|
|
|
|
 |
|
 P. Jung and U. Ziemann Homeostatic and Nonhomeostatic Modulation of Learning in Human Motor Cortex J. Neurosci., April 29, 2009; 29(17): 5597 - 5604. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Avanzino, M. Bove, A. Tacchino, C. Trompetto, C. Ogliastro, and G. Abbruzzese Interaction Between Finger Opposition Movements and Aftereffects of 1Hz-rTMS on Ipsilateral Motor Cortex J Neurophysiol, March 1, 2009; 101(3): 1690 - 1694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hortobagyi, S. P. Richardson, M. Lomarev, E. Shamim, S. Meunier, H. Russman, N. Dang, and M. Hallett Chronic low-frequency rTMS of primary motor cortex diminishes exercise training-induced gains in maximal voluntary force in humans J Appl Physiol, February 1, 2009; 106(2): 403 - 411. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Iezzi, A. Conte, A. Suppa, R. Agostino, L. Dinapoli, A. Scontrini, and A. Berardelli Phasic Voluntary Movements Reverse the Aftereffects of Subsequent Theta-Burst Stimulation in Humans J Neurophysiol, October 1, 2008; 100(4): 2070 - 2076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. V. Sale, M. C. Ridding, and M. A. Nordstrom Cortisol Inhibits Neuroplasticity Induction in Human Motor Cortex J. Neurosci., August 13, 2008; 28(33): 8285 - 8293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-Z. Huang, J. C. Rothwell, M. J. Edwards, and R.-S. Chen Effect of Physiological Activity on an NMDA-Dependent Form of Cortical Plasticity in Human Cereb Cortex, March 1, 2008; 18(3): 563 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Rosenkranz, K. Butler, A. Williamon, C. Cordivari, A. J. Lees, and J. C. Rothwell Sensorimotor reorganization by proprioceptive training in musician's dystonia and writer's cramp Neurology, January 22, 2008; 70(4): 304 - 315. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Reis, O. B. Swayne, Y. Vandermeeren, M. Camus, M. A. Dimyan, M. Harris-Love, M. A. Perez, P. Ragert, J. C. Rothwell, and L. G. Cohen Contribution of transcranial magnetic stimulation to the understanding of cortical mechanisms involved in motor control J. Physiol., January 15, 2008; 586(2): 325 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-F. Kuo, J. Grosch, F. Fregni, W. Paulus, and M. A. Nitsche Focusing Effect of Acetylcholine on Neuroplasticity in the Human Motor Cortex J. Neurosci., December 26, 2007; 27(52): 14442 - 14447. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Krutky and E. J. Perreault Motor Cortical Measures of Use-Dependent Plasticity Are Graded From Distal to Proximal in the Human Upper Limb J Neurophysiol, December 1, 2007; 98(6): 3230 - 3241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Rosenkranz, A. Kacar, and J. C. Rothwell Differential Modulation of Motor Cortical Plasticity and Excitability in Early and Late Phases of Human Motor Learning J. Neurosci., October 31, 2007; 27(44): 12058 - 12066. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Rosenkranz, A. Williamon, and J. C. Rothwell Motorcortical Excitability and Synaptic Plasticity Is Enhanced in Professional Musicians J. Neurosci., May 9, 2007; 27(19): 5200 - 5206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Nitsche, A. Roth, M.-F. Kuo, A. K. Fischer, D. Liebetanz, N. Lang, F. Tergau, and W. Paulus Timing-Dependent Modulation of Associative Plasticity by General Network Excitability in the Human Motor Cortex J. Neurosci., April 4, 2007; 27(14): 3807 - 3812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Mrachacz-Kersting, M. Fong, B. A. Murphy, and T. Sinkjaer Changes in Excitability of the Cortical Projections to the Human Tibialis Anterior After Paired Associative Stimulation J Neurophysiol, March 1, 2007; 97(3): 1951 - 1958. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Matsuzaka, N. Picard, and P. L. Strick Skill Representation in the Primary Motor Cortex After Long-Term Practice J Neurophysiol, February 1, 2007; 97(2): 1819 - 1832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Weise, A. Schramm, K. Stefan, A. Wolters, K. Reiners, M. Naumann, and J. Classen The two sides of associative plasticity in writer's cramp Brain, October 1, 2006; 129(10): 2709 - 2721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Cooke and T. V. P. Bliss Plasticity in the human central nervous system Brain, July 1, 2006; 129(7): 1659 - 1673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Ziemann, F. Meintzschel, A. Korchounov, and T. V. Ilic Pharmacological Modulation of Plasticity in the Human Motor Cortex Neurorehabil Neural Repair, June 1, 2006; 20(2): 243 - 251. [Abstract] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||