Abstract

Activity-dependent modulation of cortical synaptic transmission is a fundamental mechanism involved in learning and memory storage. This modulation has been widely studied in in vitro brain slices and in vivo animal models. More recently, transcranial magnetic stimulation has allowed detection of activity-dependent excitability modulation occurring in the intact human primary motor cortex (MI) after execution of different kinds of motor tasks. Both increased and decreased MI excitability have been described after exercise. While increased MI excitability is generally considered direct expression of cortical synaptic plasticity, a controversy still exists as to whether decreased MI excitability reflects fatigue of central nervous system (CNS) structures or cortical neuronal reorganization taking place after exercise. Here, we extend previous findings in order to provide further support for the latter hypothesis. Abduction– adduction movements of the thumb performed for 1 min at 2 Hz frequency rate produce a 55% decrease in MI excitability of mean 30 min duration. Similar decrements in amplitude and duration of motor evoked potentials (MEPs) are not reached if the same task is performed once again during the maximal inhibition phase (10 min post-exercise) produced by a previous activation. Moreover, the same task performed at a lower (1 Hz) frequency rate produces no significant MEP changes but can transiently reverse activity-dependent depression obtained after previous 2 Hz movements. Repeated execution of the same task (2 Hz), each being performed after recovery from a previously induced MEP depression, ceases to produce an MEP decrement, suggesting adaptation in MI excitability modulation. This adaptation is long lasting and task-specific, since a different motor task (1 min circular movement of the thumb) restores activity-dependent modulation. Overall, these findings suggest that the dynamic modulation of MEPs occurring after execution of different kinds of simple motor skills reflects some form of activity-dependent, plastic neuronal reorganization instead of CNS fatigue. Possible anatomo-functional mechanisms involved in this activity-dependent modulation of MI excitability are discussed.

Introduction

Using transcranial magnetic stimulation (TMS) we have previously described a strong and reversible decrease of 30 min duration in the excitability of the primary motor cortex (MI) after 1 min execution of abduction–adduction movements of the thumb at maximal frequency rate (Bonato et al., 1994, 1996; Zanette et al., 1995). We interpreted this decrement, which also occurred after a delay in the ipsilateral non-activated hemisphere (Bonato et al., 1996), as the expression of activity-dependent cortical plasticity, possibly related to some form of motor memory storage. The anatomo-functional structures involved have been suggested to be the intracortical inhibitory GABA-ergic interneurones recruited and potentiated by the axon collaterals of the pyramidal cells activated during execution of the motor task.

Yet the precise meaning of these effects remains to be clarified, since other authors have attributed them to central nervous system fatigue following an effort rather than to plastic cortical changes (Brasil-Neto et al., 1993, 1994; McKay et al., 1995; Liepert et al., 1996). This controversy is supported by experimental evidence that increased MI excitability with concomitant enlargement of cortical motor output maps can occur during learning of complex motor skills (Pascual-Leone et al., 1994, 1995). At first glance, these latter activity-dependent changes in MI excitability may best account for the plastic rearrangements occurring at the neural cortical network level already described during motor learning, such as decreased intracortical GABAergic inhibition and potentiation of cortical pyramidal cells.

Decreased neocortical excitability, which may subserve different kinds of behavioural learning, has also been described (Tsumoto, 1992; Bear and Malenka, 1994; Hess and Donoghue, 1996). Furthermore, it has to be pointed out that while increased MI excitability was generally found for execution of complex motor sequences, decreased MI excitability occurred after repeated performance of simple motor tasks. It is therefore possible that different functional mechanisms may account for these apparently conflicting results in post-exercise MI excitability modulation without being mutually exclusive intrinsic mechanisms (i.e. plastic neuronal reorganization).

In the present study we aimed to collect further evidence in favor of the synaptic plasticity hypothesis accounting for an activity-dependent decrease in MI excitability. In order to do this the same motor task executed in previous studies (repetitive abduction–adduction movements of the thumb) was carried out and, by means of a series of manipulations of the experimental paradigm, data strengthening the hypothesis under discussion have been collected. In particular, we adopted some experimental manipulations which have already been utilised for the investigation of synaptic plasticity in several brain slices and animal studies, such as application and/or exposition of ‘congruent’ and ‘incongruent’ cues to the neural networks under study. Specifically, in our case the congruent and conflicting cues were represented by execution of movements which, albeit involving the same motor district (thumb of the hand), could differ in frequency, total number and directional vector of movements.

We reasoned that if the plasticity hypothesis is correct, bidirectional changes in MI excitability could be assessed, in line with what has been found for neural synaptic transmission in brain slices and animal studies.

Materials and Methods

Experiment 1: Effects on MI Excitability of Movements Performed at Different Frequency Rates

Two groups of subjects performed abduction–adduction movements of the right thumb of 1 min duration. Movement rate was controlled by audio–video cues provided by a metronome. All subjects were right-handed and naïve to the motor task. The rate of movement was 2 Hz for one group (n = 5, mean age 24 years) and 1 Hz for the second group (n = 5, mean age 26 years), the former frequency being chosen because of its approximation to the maximal rate spontaneously adopted by subjects in previous studies (Bonato et al., 1994, 1996; Zanette et al., 1995). All subjects gave their informed consent to the study, which was approved by the local ethics committee.

Motor evoked potentials (MEPs) induced by TMS were first collected from subjects at rest. Three sets of eight stimuli with an inter-stimulus interval of 5 s were delivered with a Novametrix 200 magnetic stimulator using a circular coil (9 cm diameter) centered at the vertex and oriented tangentially to the scalp in an antero-posterior direction. We decided to use a circular rather than the more focal figure-of-eight coil so that the present data would conform with those derived from our previous studies, where the same shaped coil was used. In any case, despite some greater inter-subject variability in post-exercise MEP amplitude depression obtained using the more focal coil, no other substantial differences have been found for MEP amplitude after exercise between the two kinds of stimulation (Bonato et al., 1994; Zanette et al., 1995). The current in the coil flowed anticlockwise, thus producing a preferential stimulation of the left hemisphere. Recordings were made with surface electrodes overlying the belly of the right thenar eminence muscles using a 50–5000 Hz band-pass filter (sampling rate for digitizing EMG, 10 kHz). Magnetic stimuli were delivered at an intensity 20% higher than the MEP threshold, defined, in line with international standards, as the lowest stimulus intensity capable of eliciting at least three MEPs of >50 μV out of five consecutive trials in full relaxation (Rossini et al., 1994, 1999).

MEPs were then recorded after the execution of the motor task 1, 3 and 5 min post-exercise and then at 5 min intervals until MEP amplitudes returned to pre-exercise values.

Experiment 2: Effects on MI Excitability of Movements Performed Sequentially with ‘Congruent’ and ‘Incongruent’ Frequency Rates

Two other groups of subjects were studied. Ten minutes after a previous bout of movements performed at the 2 Hz rate, subjects in the first group (n = 7, mean age 27 years) were requested to perform the same task a second time and MEPs were collected until recovery to pre-exercise values. In the other group of subjects (n = 7, mean age 25 years) MEPs were measured after 1 Hz movements performed during the maximal inhibition phase produced by two previous bouts of 2 Hz movements (20 min post-exercise).

Experiment 3: Effects on MI Excitability of Repetitive Bouts of Movements

We also tested whether a reduction in post-exercise MEP depression could occur over time, given that in some cases we occasionally observed that the magnitude of the effect tended to decrease with repeated testing. In five naïve subjects (mean age 25 years) MI excitability was evaluated after four bouts of 2 Hz movements. Each bout was performed after the amplitude of MEPs, previously decreased by exercise, had returned to pre-exercise values. Three of the five subjects were requested to perform the 2 Hz motor task for 30 min per day for 1 week and were tested 2 months later. These three experiments are presented in Table 1.

Statistical Analysis

Peak-to-peak MEP amplitudes were analyzed by a Friedman’s distribution-free analysis of variance for matched measures. Pairwise comparisons were performed with the non-parametric Wilcoxon test, using Tukey’s correction for multiple comparison. In the last experiment, where subjects were requested to perform four bouts of 2 Hz movements, statistical analysis of MEP amplitudes was performed using the paired t-test for each subject and the significance threshold was set at P ≤ 0.05.

Results

Figure 1 shows that 1 min execution of 2 Hz movements produces a decrease in the excitability of MI.

An immediate decrease in MEPs (30% compared with baseline) occurs 1 min post-exercise (P < 0.01) and reaches mean maximal values of ~55% between 5 and 15 min post-exercise (P < 0.01). Subsequently, MEPs gradually recover to pre-exercise values, remaining significantly reduced up to 30 min (P < 0.01). These findings are in keeping with previous evidence obtained with a similar, self-generated rate of movement (Bonato et al., 1994, 1996; Zanette et al., 1995).

When a different group of subjects was tested for the same task performed at a lower (1 Hz) frequency rate, MEPs show a slight decrease of ~15% without reaching statistical significance (P > 0.05) up to 15 min post-exercise, i.e. in the post-exercise time period when the 2 Hz movements produced the maximal decrement in MEPs.

Figure 2A shows that when a second 2 Hz activation is performed during the maximal MEP inhibition phase, 10 min after a bout of 2 Hz movements, the amount as well as the time course of post-exercise MEP decrease is not affected when compared with that obtained after a single 2 Hz activation.

Conversely, MEPs depressed by two bouts of 2 Hz movements increase dramatically after the execution of 1 Hz movements (Fig. 2B). Shortly (1 min) after the end of the 1 Hz motor task MEPs immediately increase, with complete recovery to pre-exercise value within 3–5 min. Thereafter, a rebound decrease in MEPs occurs with recovery at 42 min from the first 2 Hz activation.

Repeated performance of the 2 Hz motor task leads to a reduction in the amount of MEP depression.

Figure 3A shows that a decrease in MEPs occurred in all five subjects following execution of the first motor task, with time of recovery ranging from ~25 (subjects a, b and e) to ~35–40 min (subjects c and d). With repeated training the amount of decrease becomes progressively less substantial. Subject a presents no significant decrease in MEPs after the second bout of 2 Hz movements, while such a condition is reached after the third and fourth bouts for subjects d and c, respectively. A decrease in MEPs (P < 0.05) of only brief duration (3 min) was recorded in subjects b and e after the fourth bout of the 2 Hz motor task. The mean duration of MEP depression for all five subjects (Fig. 3B) was on average 30 min after bout 1, decreasing to 12 min after the second bout and to 2.6 and 1.2 min after the third and fourth bouts, respectively.

The activity-dependent decrease in post-exercise MEP depression is long lasting (Fig. 4A). When the three previously responsive subjects (subjects c, d and e of Fig. 3A) were tested for 2 Hz movements 2 months after the week of training (solid vertical line), no significant decrease in post-exercise MEP amplitudes was found up to 15 min (P > 0.05). Nevertheless, MEP decrease could be temporarily restored after the execution of a different motor task. In fact, if the same subjects performed 1 min rotatory movements of the thumb after adaptation to 2 Hz abduction–adduction movements had been reached (dashed vertical line, Fig. 4A), a resumption of MEP depression ensued and remained significant (P < 0.05) up to 10 min after the end of rotation. The same was also observed in another subject following a different protocol (Fig. 4B). Subject a of Figure 3A was tested for rotatory movement after the fourth bout of abduction–adduction movements. Again, a depression of MEPs of 10 min duration (P < 0.01) occurred after rotation.

Discussion

The present findings seem to confirm that the post-exercise depression in MI excitability is the result of an activity-dependent modulation in cortical synaptic transmission, perhaps related to some form of synaptic memory storage along the relevant neural pathways. A modulation of spinal excitability in determining the decrease in MEP amplitude after exercise may also be involved. In any case, extensive data suggest that activity-dependent changes in cortico-spinal excitability produced by sustained motor activity are due to modulations in the level of excitability of supraspinal, mainly cortical, structures (Brasil-Neto et al., 1993, 1994; Bonato et al., 1994, 1996; McKay et al., 1995; Zanette et al., 1995; Liepert et al., 1996). Spinal excitability, albeit reduced, was found after exercise (Mckay et al., 1995; Liepert et al., 1996), with the reduction not exceeding 1–3 min, thereby not accounting for the prolonged decrease in MEP amplitude, ranging from 20 to 40 min.

This activity-dependent decrement in MEP amplitude is likely to be involved in some form of motor memory storage. The most convincing evidence in support of this view is the occurrence of a long lasting reduction in the amount of post-exercise MEP decrease with repeated training of subjects. This finding suggests adaptation, which is considered to be a form of implicit memory taking place within a time scale ranging from a few milliseconds to minutes (Fairhall et al., 2001).

The same adaptational effect, its reversibility for execution of different patterns of motor activation (opposition versus rotation of the thumb) and the reversal effect produced by performing the same motor task at an ‘incongruent’ frequency rate (1 versus 2 Hz opposition movements of the thumb) makes the fatigue hypothesis unlikely when compared with the plasticity one.

It has previously been proposed that the post-exercise decrease in MI excitability may reflect optimization for skilled motor performance (Zanette et al., 1995; Bonato et al., 1996). Here, this concept is further extended to suggest that the decrease may be part of an on-going mechanism of optimization for motor working memory and that such an optimization is reached when adaptation is established. In this perspective, the decrease in MEP amplitude occurring after exercise may correspond to some form of information acquisition, i.e. learning itself, related to motor performance, whereas adaptation, which is task-specific, may be the sign that learning has taken place.

The hypothesis that motor learning can take place through reduced MI excitability with concomitant shrinking of cortical motor output maps (Zanette et al., 1995; Bonato et al., 1996) may somehow be out of alignment with results reported by others. In fact, there is also evidence that increased MI excitability with enlargement of cortical motor output maps occurs during the whole learning phase for motor skills until stabilized values of cortical excitability have been reached up to complete acquisition of motor performance (Pascual-Leone et al., 1994, 1995). It may be, however, that such discrepancies are only apparent, with the underlying contradiction deriving from the different kinds of motor tasks utilized in the experimental paradigms. In fact, while here a simple motor task is used which probably does not require any explicit learning, being part of an everyday motor pattern (i.e. index finger–thumb prehension), the tasks utilized by other authors have involved complex motor sequences which need a strong attentional drive and an active phase of explicit learning with involvement of the primary sensory cortex (Sakamoto et al., 1989; Pavlides et al., 1993; Asanuma and Pavlides, 1997) and the supplementary motor area (Grafton et al., 1992) in addition to MI.

The parameters encoded by the kind of motor memory storage we have hypothesized to take place after exercise remain to be evaluated. Nevertheless, a recent study (Classen et al., 1998) may provide some important clues about this issue. This study showed that repeated performance of thumb movements can trigger cortical plasticity encoding kinematic parameters of the practised movement of 20–30 min duration. Specifically, the direction of TMS-evoked thumb movements changes after training towards the direction of the trained movement while that recorded before training is largely inhibited. Further studies with concomitant recordings of MEPs derived from agonist and antagonist muscles involved in the execution of the motor task may reveal whether an opposite pattern also occurs for post-exercise MI excitability modulation, as it does for the movement-related directional vector. Indeed, the occurrence of such modulation of the post-training direction of TMS-evoked thumb movements is related to the amount of training, thus suggesting that a sort of threshold for inducing cortical rearrangements could exist, as proposed in the present study. It is therefore possible that the 1 Hz activation can also promote a MEP decrease by extending the training period beyond 1 min duration, as was done in the present experiment.

Classen et al. claim that the most important parameters encoded during training are the initial direction of force or movement. This may be in keeping with the present results. The task specificity of the adaptation effect, i.e. the temporary resumption of MEP depression for rotatory movements in subjects who were previously ‘adapted’ for the abduction– adduction motor task, stresses the importance of the vector of movement direction in modulating cortical rearrangements. On the other hand, the reversal effect caused by 1 Hz abduction– adduction movements onto depressed MI excitability resulting from previous 2 Hz activations suggests that the amount of force, possibly in association with velocity, acceleration and number of thumb movements, could also play a role in modulating cortical plasticity.

Possible Anatomo-functional Mechanisms

A large body of evidence stresses the pivotal role of intracortical GABAergic interneurones in regulating plasticity of the sensorimotor cortex (Jacobs and Donoghue, 1991; Jones, 1993). In line with this view it is conceivable that potentiation of intracortical inhibitory GABAergic neurons, driven by the long horizontal axon collaterals of cortical pyramidal cells involved in motor control, is a likely anatomo-functional substrate for the production of post-exercise depression of MEPs (Bonato et al., 1994, 1996; Zanette et al., 1995). Recent TMS studies utilizing drugs interfering with GABA activity (Butefisch et al., 1998, 2000) suggest that the change in post-training TMS-induced thumb movement direction (Classen et al., 1998) is strikingly related to regulation of intracortical GABAergic interneuronal activity.

Intracortical GABAergic neural transmission may not be the only way exercise produces a decrease in MEP amplitude. Cholinergic neural transmission may be involved as well.

Cholinergic innervation of the cerebral cortex mainly comes from Meynert’s nucleus and the brainstem reticular formation. These neural structures are involved in the modulation of a variety of physiological functions, among which are the control of cortical synaptic plasticity dynamics and, consequently, of the mechanisms devoted to learning, adaptation and memory storage (Singer and Rauschecker, 1982; Bakin and Weinberger, 1996; Munk et al., 1996; Miranda and Bermùdez-Rattoni, 1999). From the electrophysiological point of view, such cortical secretion of acetylcholine (ACh) produces strong desynchronization of the EEG, probably by depolarization (i.e. excitation) of thalamo-cortical GABAergic interneurones (Jefferys et al., 1996; Traub et al., 1996a,b; Whittington et al., 1996), which, in fact, receive abundant subcortical cholinergic innervation (De Lima and Singer, 1986; Kawaguchi, 1997; Xiang et al., 1998).

The entity and time course of cortical and hippocampal cholinergic secretion nicely fits with the present findings. In fact, it has been demonstrated that a variety of stimuli can induce an ~50–60% increase in ACh concentration of 20–40 min (mean 30 min) duration (Inglis and Fibiger, 1995; Acquas et al., 1996; Aloisi et al., 1997; Giovannini et al., 1998; Ceccarelli et al., 1999), i.e. the same values we have obtained for the post-exercise MEP decrease. Furthermore, neural reticular activation (Bell et al., 1964; Sheibel and Sheibel, 1965) and ACh secretion (Acquas et al., 1996; Aloisi et al., 1997; Giovannini et al., 1998; Miranda et al., 2000) progressively decrease with stimulus repetition, a phenomenon resembling the adaptation in MEP amplitude decrease for repeated performance of the same motor task; indeed, this kind of habituation is rapidly erased (and excitability restored to the pre-stimulus levels) with the introduction of a different pattern of electrical stimulation or exposure to an unfamiliar environment. Of note, a very recent study performed in humans (Sawaki et al., 2002) has demonstrated that cholinergic transmission is strongly involved in promoting post-training changes in TMS-induced thumb movements.

Table 1

Schematic recapitulation of the experimental protocol

Experiment Motor task 
 II III IV VI VII 
aInter-bout interval = 10 min. 
bEach motor task performed after MEPs have recovered from previous activation. 
2 Hz opp.       
 1 Hz opp.       
IIa 2 Hz opp. 2 Hz opp.      
 2 Hz opp. 2 Hz opp. 1 Hz opp.     
IIIb 2 Hz opp. 2 Hz opp. 2 Hz opp. 2 Hz opp.    
 2 Hz opp. 2 Hz opp. 2 Hz opp. 2 Hz opp. Rotation   
 2 Hz opp. 2 Hz opp. 2 Hz opp. 2 Hz opp. Home training 2 Hz opp. Rotation 
Experiment Motor task 
 II III IV VI VII 
aInter-bout interval = 10 min. 
bEach motor task performed after MEPs have recovered from previous activation. 
2 Hz opp.       
 1 Hz opp.       
IIa 2 Hz opp. 2 Hz opp.      
 2 Hz opp. 2 Hz opp. 1 Hz opp.     
IIIb 2 Hz opp. 2 Hz opp. 2 Hz opp. 2 Hz opp.    
 2 Hz opp. 2 Hz opp. 2 Hz opp. 2 Hz opp. Rotation   
 2 Hz opp. 2 Hz opp. 2 Hz opp. 2 Hz opp. Home training 2 Hz opp. Rotation 
Figure 1.

The graph illustrates the mean ± SE (five subjects) of MEP amplitudes at different times before and after the execution of abduction–adduction movements of the thumb of 1 min duration. The arrow indicates execution of the exercise. Each value is the average of MEP percentage differences compared with a baseline value, taken as 100%, obtained from the mean of the three pre-exercise trials. When movements were performed at 2 Hz frequency rate (♦) an immediate decrease in MEPs (30% compared with basal values) occurs at 1 min post-exercise (P < 0.01). The decrease reaches mean maximal values of ~55% between 5 and 15 min post-exercise (P < 0.01) and recovers within 35 min. When another five subjects were tested for the same task performed at a lower (1 Hz) frequency rate (•), no significant modifications in post-exercise MEP amplitudes were found up to 15 min (P > 0.05). Baseline values are equated between the two groups of subjects.

Figure 1.

The graph illustrates the mean ± SE (five subjects) of MEP amplitudes at different times before and after the execution of abduction–adduction movements of the thumb of 1 min duration. The arrow indicates execution of the exercise. Each value is the average of MEP percentage differences compared with a baseline value, taken as 100%, obtained from the mean of the three pre-exercise trials. When movements were performed at 2 Hz frequency rate (♦) an immediate decrease in MEPs (30% compared with basal values) occurs at 1 min post-exercise (P < 0.01). The decrease reaches mean maximal values of ~55% between 5 and 15 min post-exercise (P < 0.01) and recovers within 35 min. When another five subjects were tested for the same task performed at a lower (1 Hz) frequency rate (•), no significant modifications in post-exercise MEP amplitudes were found up to 15 min (P > 0.05). Baseline values are equated between the two groups of subjects.

Figure 2.

(A) The execution of a second bout of 2 Hz movements, 10 min after the first, does not modify the amount and time course of post-exercise MEP decrease, remaining ~55–60% compared with basal values (P < 0.01) up to 20 min post-exercise, with recovery within 35 min from the end of the first bout of exercise. (B) When a low frequency (1 Hz) exercise motor task (dashed arrow), which by itself does not produce significant modulation in MI excitability, is performed after two previous maximal activations, a transient recovery of MEPs occurs. At 23 min post-exercise (1 min after the end of the 1 Hz motor task) MEPs immediately increased, from an ~55–60% depression at 21 min (P < 0.01) to a decrease of only 25% (P < 0.05). MEPs completely recovered (P > 0.05) at 25–27 min (3–5 min after the end of the 1 Hz activation). A rebound decrease in MEPs (40% compared to basal values) occurred at 32–37 min (P <0.05) with recovery at 42 min (P > 0.05).

Figure 2.

(A) The execution of a second bout of 2 Hz movements, 10 min after the first, does not modify the amount and time course of post-exercise MEP decrease, remaining ~55–60% compared with basal values (P < 0.01) up to 20 min post-exercise, with recovery within 35 min from the end of the first bout of exercise. (B) When a low frequency (1 Hz) exercise motor task (dashed arrow), which by itself does not produce significant modulation in MI excitability, is performed after two previous maximal activations, a transient recovery of MEPs occurs. At 23 min post-exercise (1 min after the end of the 1 Hz motor task) MEPs immediately increased, from an ~55–60% depression at 21 min (P < 0.01) to a decrease of only 25% (P < 0.05). MEPs completely recovered (P > 0.05) at 25–27 min (3–5 min after the end of the 1 Hz activation). A rebound decrease in MEPs (40% compared to basal values) occurred at 32–37 min (P <0.05) with recovery at 42 min (P > 0.05).

Figure 3.

(A) The subjects (a–e) were requested to perform four bouts of 2 Hz movements, each performed after the amplitudes of MEPs had recovered to pre-exercise values. After the first, a decrease in MEPs occurs in all subjects, with recovery time ranging from 25 (subjects a, b and e) to 35–40 min (subjects c and d). As shown in panels a–e, adaptation of the post-exercise MEP decrease occurs at various times in the different subjects. (B) Mean duration of MEP decrease after bouts 1, 2, 3 and 4.

Figure 3.

(A) The subjects (a–e) were requested to perform four bouts of 2 Hz movements, each performed after the amplitudes of MEPs had recovered to pre-exercise values. After the first, a decrease in MEPs occurs in all subjects, with recovery time ranging from 25 (subjects a, b and e) to 35–40 min (subjects c and d). As shown in panels a–e, adaptation of the post-exercise MEP decrease occurs at various times in the different subjects. (B) Mean duration of MEP decrease after bouts 1, 2, 3 and 4.

The authors are very grateful to Prof. Giovanni Berlucchi for his encouragement, support and usefull discussions and suggestions on the manuscript.

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