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1 Human Cortical Physiology Section, National Institute of Neurological Disorders and Stroke, 20892-1428; 2 Biometry and Field Studies Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-9135
Submitted 27 October 2003; accepted in final form 27 December 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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), a form of use-dependent plasticity (Bütefisch et al. 2000; Classen et al. 1998). The operating mechanisms include changes in the balance of excitation and inhibition within the hand motor representation (Bütefisch et al. 2000, 2002; Classen et al. 1998; Sawaki et al. 2001) that are influenced by N-methyl-D-aspartate (NMDA), muscarinic and alpha-adrenergic receptor function as well as GABAergic neurotransmission (Bütefisch et al. 2000, 2002; Sawaki et al. 2001). It has been proposed that the mechanisms underlying this form of plasticity share similarities with those involved in long-term potentiation (LTP) (Bliss and Lomo 1973; Bütefisch et al. 2000; Rioult-Pedotti et al. 1998).
Use-dependent plasticity plays an important role in motor learning and recovery of motor function after brain lesions (Nudo et al. 1996), such as in patients with multiple sclerosis and stroke (Liepert et al. 1998, 2000; Reddy et al. 2000). Enhancing use-dependent plasticity may result in improvements in the ability of the CNS to compensate for the loss of function (Bütefisch et al. 2002; Feeney et al. 1982). Transcranial magnetic stimulation (TMS) is a technique that allows noninvasive focal stimulation of the human brain (Hallett 2000) and that, in particular settings, can enhance cortical reorganization (Ziemann et al. 1998a) and information processing (Boroojerdi et al. 2001; Flitmann et al. 1998). Therefore one possible strategy to enhance use-dependent plasticity could be the synchronous application of TMS to the motor cortex engaged in performing the training motions, a paradigm reminiscent of in vitro experiments in which stimulation of cortical afferents was paired with depolarization of the synaptic target neuron in a specific temporal relationship (Baranyi and Szente 1987; Baranyi et al. 1991).
In the current study, we hypothesized that TMS applied to a thumb motor representation at a time it is engaged in driving a training motion would facilitate encoding of a motor memory for the trained movements.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Six of 11 healthy, right-handed volunteers (4 of them men; mean age: 34.2 yr; range: 23–42 yr) fulfilled the inclusion criteria (see following text) and gave written informed consent and participated in the study under a protocol approved by the Institutional Review Board of the National Institute of Neurological Disorders and Stroke.
Experimental protocol
Subjects, unaware of the experimental purpose of the study, participated in different sessions testing the effects of four different interventions on the ability of training to form an elementary motor memory.
Encoding of a motor memory
Subjects were seated in a chair firmly connected to a frame that kept the head steady and the stimulating coil in a constant position with respect to the head. Head and coil stability were monitored with a three-dimensional laser system as previously described (Bütefisch et al. 2000). Each subject's right forearm was immobilized in a molded armrest with the four long fingers supported and the thumb freely movable. Thumb movements were recorded with a two-dimensional accelerometer mounted on the proximal phalanx of the thumb (Classen et al. 1998). The direction of the thumb movements was calculated from the first-peak acceleration vector.
TMS was delivered from a custom-built magnetoelectric stimulator (Cadwell Laboratories, Kennewick, WA) through a figure-eight–shaped magnetic coil (wing diameter: 7.0 cm). The coil was placed tangentially to the scalp and rotated 45° away from the midline. The current induced in the brain was, therefore directed approximately perpendicular to the central sulcus, which is the optimal condition for activating the corticospinal tract transsynaptically (Kaneko et al. 1996; Werhahn et al. 1994). Stimuli were delivered to the optimal scalp position for eliciting mild isolated thumb movements. In addition to TMS-evoked movement directions, we recorded motor potentials (MEP) evoked by TMS from extensor pollicis brevis (EPB), a hand muscle mediating thumb movements in extension, and from flexor pollicis brevis (FPB), a hand muscle mediating thumb movements in flexion. MEP recorded from the muscle that acted as agonist to the training motions (see following text) is described as MEPagonist, whereas that recorded from the muscle that acted as antagonist to the training movements is described as MEPantagonist. Motor threshold (MT) was defined as the minimum TMS intensity that evoked an MEP of 
50 µV in 5 of 10 trials in the target muscle (Rossini et al. 1994). MT was determined to the nearest 1% of maximum stimulator output in the resting EPB and FPB muscles. MEP amplitudes after the training were expressed relative to MEP amplitudes at baseline.
Initially, we determined the direction of TMS-evoked thumb movements by stimulating the optimal scalp position overlying the contralateral motor cortex (total of 60 stimuli) at 0.1 Hz, a rate that does not affect cortical excitability (Chen et al. 1997). Subjects occasionally realized that the thumb had moved but could not determine its direction. In these trials, the baseline direction was defined as the mean angle of TMS-evoked movements that fell in the predominant direction (Fig. 1).
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). At the end of the 30-min training period, TMS-evoked thumb-movement directions were recorded for 30 min (post 1–post 3, see following text) in all conditions. Because testing post 3 in Train+TMS synchronouscontra revealed persistent training effects, a fourth determination was made at 50–60 min after the end of training (Fig. 3B, post 4).
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To describe the effects of the different interventions, we defined a training target zone (TTZ) as a window of ±20° centered on the training direction. The TTZ is shown in Fig. 1B. We measured the increase in the proportion of TMS-evoked movements in the TTZ at the end of training (Fig. 1B). By design, training was in the direction opposite to the baseline direction; hence, the proportion of TMS-evoked movements in the TTZ before training was small. Therefore the end-point measure of this study was the training-induced increase in the proportion of TMS-evoked movements falling in the TTZ as a function of the different interventions. This measure describes the ability of the motor cortex to encode the kinematic details of the practiced movements, an elementary motor memory (Classen et al. 1998). Data analysis was implemented by personnel blind to the type of intervention.
Experimental interventions
Subjects participated in four different sessions separated by 1 day in a randomized, counterbalanced order: training alone (Train alone) (Bütefisch et al. 2002); training with TMS at 0.1 Hz applied synchronous with the training movements in a strict temporal relationship to the motor cortex contralateral (Train+TMS synchronouscontra) and ipsilateral (Train+TMS synchronousipsi) to the training hand; and training combined with TMS at 0.1 Hz applied to the contralateral motor cortex asynchronous to the training movements (Train+TMS asynchronouscontra). TMS was applied at 80% resting motor threshold (MT) because this intensity is effective in modulating cortical plasticity (Ziemann et al. 1998a). TMS at subthreshold intensities used in this study activates corticocortical connections targeting pyramidal tract neurons (Day et al. 1987).
TRAIN ALONE. In this session, subjects performed voluntary thumb movements at 1 Hz in the absence of TMS as previously described (Bütefisch et al. 2000).
TRAIN+TMS SYNCHRONOUSCONTRA. Subjects performed voluntary thumb movements at 1 Hz as in Train alone. A single TMS pulse was applied at 
0.1 Hz to the contralateral motor cortex at 80% resting MT, synchronous with 1 of every 10 voluntary thumb movements, (triggered by the EMG burst in the muscle, acting as training agonist, when it reached a predetermined threshold amplitude level, 10–20% of the maximal amplitude of the EMG burst). In non-human primates, M1 activity associated with performance of a ballistic movement lasts for 250 ms after EMG onset (Crammond and Kalaska 2000). Therefore the TMS pulses in our study were applied to M1 soon after the EMG onset to arrive synchronously with cortical activity in M1 generating the training movements.
TRAIN+TMS SYNCHRONOUSIPSI. Subjects performed voluntary thumb movements at 1 Hz as in Train alone. A single TMS pulse was applied at 0.1 Hz to the ipsilateral motor cortex at 80% MT, synchronous with 1 of every 10 voluntary thumb movements, using a second figure-eight coil connected to a second stimulator (triggered by the EMG burst in the muscle, acting as training agonist, when it reached a predetermined threshold amplitude level, 10–20% of the maximal amplitude of the EMG burst).
TRAIN+TMS ASYNCHRONOUSCONTRA. This intervention was identical to Train+TMS synchronouscontra except that TMS pulses were applied asynchronous in relation to the training movements. Specifically TMS pulses were delivered regularly at 0.1 Hz at random in reference to the movements that occurred at 1 Hz.
Inclusion criteria
Participating subjects fulfilled the following inclusion criteria: ability of TMS to elicit isolated thumb movements in the absence of movements of any other digits, wrist, or arm; consistent (reproducible) direction of TMS-evoked thumb movements in the baseline condition; and posttraining TMS-evoked thumb-movement directions matching the training direction.
Statistical analysis
The proportion of TMS-evoked movements in TTZ before (baseline) and after (post 1) training were compared using Wilcoxon signed-rank test. A distribution-free Friedman rank test compared changes in the proportion of TMS-evoked movements falling in the TTZ after the different interventions calculated for the entire 30-min posttraining period (post 1–post 3). Wilcoxon signed-rank test was used to compare the magnitude of these changes for the entire 30-min posttraining period of each intervention relative to Train alone and to compare the training kinematics of each intervention relative to Train alone.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Training alone or combined with TMS applied to the contralateral M1 either synchronous or asynchronous to the EMG activity of the agonist muscle (Train+TMS synchronouscontra and Train+TMS asynchronouscontra) resulted in a significant increase in the proportion of TMS-evoked thumb movements in the TTZ 0–10 min after completion of the training (post1) in reference to baseline (Wilcoxon signed-rank test: Train alone, P = 0.05; Train+TMS synchronouscontra, P = 0.03; Train+TMS asynchronouscontra, P = 0.05; Fig. 2). TMS applied to the ipsilateral M1 (Train+TMS synchronousipsi) blocked this effect (Wilcoxon signed-rank test: NS; Fig. 2).
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Longevity of the encoded motor memory
The longevity of changes in TMS-evoked movement directions differed according to the intervention [Friedman rank test (post 1–post 3 pooled): P < 0.001; Fig. 3]. The changes lasted longer in Train+TMS synchronouscontra (Fig. 3B) than in Train alone [Fig. 3A; Wilcoxon signed-rank test (post 1–post 3 pooled data): P < 0.001], which was similar to Train+TMS asynchronouscontra [Fig. 3C; Wilcoxon signed-rank test (post 1–post 3: NS)].
Changes in TMS-evoked movement directions lasted for 20 min in Train alone (Fig. 3A) and Train+TMS asynchronouscontra (Fig. 3C). Train+TMS synchronouscontra led to a substantial enhancement of the effect to >60 min (Fig. 3B). Consistent with the kinematic data, the differential regulation of MEP training agonist and MEP training antagonist amplitudes in Train alone and Train+TMS synchronouscontra was present for 30 min (Fig. 3, A and B). Data from a representative subject are shown in Fig. 4.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Motor training leads to encoding motor memories in the CNS (Shadmehr and Brashers-Krug 1997). Under our experimental conditions, training leaves a memory trace in the primary motor cortex that reflects the kinematic details of the practiced movements (Classen et al. 1998). Here, we investigated if it is possible to enhance this plastic process by synchronous stimulation to the motor cortex engaged in the training motions, a proposal consistent with the Hebbian principle that potentiation of synaptic efficacy (LTP) occurs when its pre- and postsynaptic elements are simultaneously active (Hebb 1949). When inputs converge onto a target neural structure in temporal synchrony, they can enhance cortical plasticity (Baranyi and Feher 1981; Baranyi and Szente 1987; Iriki et al. 1989). With these considerations in mind, we hypothesized that application of TMS, a technique that stimulates preferentially intracortical connections targeting pyramidal tract neurons (Rothwell 1997) at a time when the motor cortex is engaged in generating a training motion, should lead to an enhancement in this form of plasticity. Previous work demonstrated that TMS can increase the excitability of the primary motor cortex (Pascual-Leone et al. 1994b), enhance deafferentation-induced plasticity in humans (Ziemann et al. 1998), and induce LTP- and LTD-like changes in slice preparations of cortical tissue (Wang et al. 1996).
Subjects participated in four different sessions testing the effects of motor training alone and motor training accompanied by TMS applied in synchrony and out of synchrony with the training motions. Preceding training, measures of corticomotoneuronal excitability, including motor thresholds (Mavroudakis et al. 1994), movement thresholds, and MEP amplitudes (Amassian et al. 1987; Ridding and Rothwell 1997) in two muscle groups controlling thumb movements, were similar across conditions. Additionally, monitoring of motor training kinematics revealed that the magnitude of the first-peak acceleration of training movements, the dispersion of training movement directions, and the angular difference between mean baseline and training angles did not differ significantly across conditions. The mean peak acceleration of training motions in Train+TMS synchronouscontra was slightly larger than in Train alone, similar to Train+TMS asynchronouscontra (Table 2). It is possible that subthreshold TMS application in combination with training led to larger movement amplitudes. If present, this effect was very small because TMS was applied in only 1 of 10 trials, and in those trials, it did not evoke muscle twitches. More importantly, prolongation of learning occurred in the Train+TMS synchronouscontra but not in Train+TMS asynchronouscontra despite comparable acceleration levels. Overall, these results document comparable baseline motor cortical excitability levels preceding training and comparable motor training kinematics across the four interventions.
First, we evaluated the effects of the different interventions on the formation of a motor memory. TMS applied to the motor cortex involved in the training task enhanced this form of plasticity, whereas TMS applied to the motor cortex ipsilateral to the training hand reduced it. This latter finding is consistent with interhemispheric competition models of cortical sensory processing (Mesulam 1999). Each hand motor representation exerts inhibitory influences on the homonymous representation in the opposite hemisphere (Di Lazzaro et al. 1999; Ferbert et al. 1992; Gerloff et al. 1998; Murase et al. 2004; Werhahn et al. 2002). It has been proposed that balanced interhemispheric interactions are required for the generation of proper voluntary movements (Ferbert et al. 1992). It is then possible that stimulation of the motor cortex ipsilateral to the training hand resulted in enhanced inhibitory drive exerted over the hand motor representation engaged in the training task, leading to the observed attenuation of the training effects (see Fig. 3D), a finding reminiscent of the reported reduction in deafferentation-induced plasticity in one hemisphere by application of TMS to the other hemisphere (Ziemann et al. 1998a). This proposal is consistent with the reported modulation of corticomotor excitability (Schambra et al. 2003) and intracortical inhibitory circuits in one hemisphere by stimulation of homologous motor areas of the opposite hemisphere (Daskalakis et al. 2002; Schnitzler et al. 1996). Additionally, Train+TMS synchronousipsi resulted in cancellation of training effects on encoding of this memory trace, consistent with a similar decrease in MEP amplitudes in agonist and antagonist muscles. It is of note that this form of plasticity relies on differential changes in excitability in agonist and antagonist muscles (Bütefisch et al. 2000) that were cancelled by application of ipsilateral TMS.
On the other hand, we found that stimulation of the motor cortex engaged in the training task enhanced the training effects if applied in synchrony with the training motions. Intracortical microstimulation (ICMS) alone results in cortical reorganization in the somatosensory and motor cortices in the rat (Nudo et al. 1990; Recanzone et al. 1992; Spengler and Dinse 1994). In humans, TMS increases motor cortical excitability (Pascual-Leone et al. 1994b) and can also facilitate functions mediated by the stimulated cortical areas (Boroojerdi et al. 2001; Flitmann et al. 1998). Interestingly, the facilitatory influence of TMS on training effects was observed in our study when stimulation was applied in synchrony with the training motions. The mechanisms underlying this effect remain to be determined. However, it is conceivable that LTP-like processes, known to operate in the motor cortex in vivo (Rioult-Pedotti et al. 1998) and thought to influence this particular form of plasticity (Bütefisch et al. 2000), could be enhanced by such Hebbian paradigm as also proposed when synchronized tactile-stimulation strategies were applied in the somatosensory system (Dinse et al. 2003). The duration of this elementary motor memory (>60 min when training was combined with synchronous stimulation but only 20 min when TMS application was asynchronous to the training motions) is consistent with this hypothesis.
Therefore we demonstrate for the first time that it is possible to enhance the effects of motor training and the duration of this memory trace by noninvasive cortical stimulation. This form of memory encoding may underlie the beneficial effect of preperformance practice (for example, in athletics or musical performance), and it may be a requirement for purposeful skill acquisition in intact humans and in the rehabilitation of persons with brain damage (Bütefisch et al. 1995). The results raise the exciting possibility that cortical stimulation combined with rehabilitative treatment could lead to more prominent behavioral gains than rehabilitative treatment alone in patients with cortical lesions like stroke.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Present address and address for reprint requests and other correspondence: C. Bütefisch, Neurological Therapeutic Center, Institut at the Heinrich-Heine University, Hohensandweg 37, 40591 Düsseldorf, Germany (E-mail: cathrin.buetefisch{at}uni-duesseldorf.de or cohen{at}ninds.nih.gov).
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 M.-H. Monfils, E. J. Plautz, and J. A. Kleim In Search of the Motor Engram: Motor Map Plasticity as a Mechanism for Encoding Motor Experience Neuroscientist, October 1, 2005; 11(5): 471 - 483. [Abstract] [PDF]
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 N S Ward Mechanisms underlying recovery of motor function after stroke Postgrad. Med. J., August 1, 2005; 81(958): 510 - 514. [Abstract] [Full Text] [PDF]
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F. Hummel and L. G. Cohen Improvement of Motor Function with Noninvasive Cortical Stimulation in a Patient with Chronic Stroke Neurorehabil Neural Repair, March 1, 2005; 19(1): 14 - 19. [Abstract] [PDF]
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 F. Hummel, P. Celnik, P. Giraux, A. Floel, W.-H. Wu, C. Gerloff, and L. G. Cohen Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke Brain, March 1, 2005; 128(3): 490 - 499. [Abstract] [Full Text] [PDF]
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A. Kaelin-Lang, L. Sawaki, and L. G. Cohen Role of Voluntary Drive in Encoding an Elementary Motor Memory J Neurophysiol, February 1, 2005; 93(2): 1099 - 1103. [Abstract] [Full Text] [PDF]
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 N. S. Ward and L. G. Cohen Mechanisms Underlying Recovery of Motor Function After Stroke Arch Neurol, December 1, 2004; 61(12): 1844 - 1848. [Abstract] [Full Text] [PDF]
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 J. J. Shih and L. G. Cohen Cortical reorganization in the human brain: How the old dog learns depends on the trick Neurology, November 23, 2004; 63(10): 1772 - 1773. [Full Text] [PDF]
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) and antagonist (
) muscles (left y axis) after Train alone (A), Train+TMS synchronouscontra (B), Train+TMS asynchronouscontra (C), and Train+TMS synchronousipsi (D). Note that changes in the proportion of TMS-evoked movement in the TTZ lasted for 
