 |
|||||
|
|||||
|
|||||
|
|||||
|
|||||
The Journal of Neuroscience, June 15, 2003, 23(12):5308-5318
Previous Article | Next Article
Acute Remapping within the Motor System Induced by Low-Frequency Repetitive Transcranial Magnetic Stimulation
Lucy Lee,1 Hartwig R. Siebner,2,3 James B. Rowe,1,4 Vincenzo Rizzo,2,5 John C. Rothwell,2 Richard S. J. Frackowiak,1 andKarl J. Friston1 1Wellcome Department of Imaging Neuroscience and 2Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, WC1N 3BG United Kingdom, 3Department of Neurology, Christian-Albrechts-University, Kiel, D-24105 Germany, 4Department of Neurology, National Hospital for Neurology and Neurosurgery, London, WC1N 3BG United Kingdom, and 5Department of Neuroscience, Psychiatric and Anesthesiological Sciences, University of Messina, Messina, I-98125 Italy
Abstract
Top
Abstract
Introduction
Repetitive transcranial magnetic stimulation (rTMS) of human primary motor cortex (M1) changes cortical excitability at the site of stimulation and at distant sites without affecting simple motor performance. The aim of this study was to explore how rTMS changes regional excitability and how the motor system compensates for these changes. Using functional brain imaging, activation was mapped at rest and during freely selected finger movements after 30 min of 1 Hz rTMS. rTMS increased synaptic activity in the stimulated left M1 and induced widespread changes in activity throughout areas engaged by the task. In particular, movement-related activity in the premotor cortex of the nonstimulated hemisphere increased after 1 Hz rTMS. Analyses of effective connectivity confirmed that the stimulated part of M1 became less responsive to input from premotor and mesial motor areas. Conversely, after rTMS our results were consistent with increased coupling between an inferomedial portion of left M1 and anterior motor areas. These results are important for three reasons. First, they show changes in motor excitability to central inputs from other cortical areas (as opposed to peripheral or exogenous inputs used in previous studies). Second, they suggest that maintenance of task performance may involve activation of premotor areas contralateral to the site of rTMS, similar to that seen in stroke patients. Third, changes in motor activations at the site of rTMS suggest an rTMS-induced remodeling of motor representations during movement. This remapping may provide a neural substrate for acute compensatory plasticity of the motor system in response to focal lesions such as stroke.
Key words: rTMS; functional imaging; plasticity; effective connectivity; motor representation; synaptic efficacy
Introduction
Repetitive transcranial magnetic stimulation (rTMS) causes immediate and lasting changes in cortical excitability at the site of stimulation and at distant sites (Siebner and Rothwell, 2002). The effects of low-frequency (≤1 Hz) rTMS to the sensorimotor hand area on cortical excitability have been investigated with various methods. These studies reveal a complex pattern of interactions among different sets of cortical neurons. rTMS at 1 Hz modulates the excitability of corticospinal projections from the site of stimulation, indexed by reduced amplitude of motor evoked potentials in relaxed hand muscles (Chen et al., 1997
Remote effects of 1 Hz rTMS to primary sensorimotor hand area include decreased corticospinal excitability of the contralateral primary motor cortex (Wassermann et al., 1998
Although 1 Hz rTMS modulates many aspects of motor cortex excitability, no impairment of manual motor control has been demonstrated convincingly during simple motor tasks, e.g., paced fist clench (Pascual Leone et al., 1998
This study used functional imaging and analyses of effective connectivity to investigate neural correlates of three rTMS-related effects on motor cortex activity: (1) changes in neural activity at the site of stimulation and at remote cortical and subcortical sites associated with 30 min subthreshold stimulation; (2) reduced responsiveness of the stimulated site to input from other cortical areas; and (3) the ability of the motor system to compensate for rTMS-induced alterations in cortical excitability. Previous functional imaging experiments using positron emission tomography (PET) (Fox et al., 1997
Materials and Methods
Subjects. Eight healthy, right-handed volunteers (one female) aged between 20 and 68 years (mean age: 37 years), with no history of neurological disorder or head injury, were recruited from the database of volunteers at the Functional Imaging Laboratory, Institute of Neurology, University College London, UK. Written informed consent was obtained from all participants. The study was approved by the joint ethics committee for the National Hospital for Neurology and Neurosurgery and the Institute of Neurology. The administration of radioactivity was covered under the Motor Studies License from the Administration of Radioactive Substances Advisory Committee held at the Functional Imaging Laboratory [RPC528-890 (14364)].Study design. The study had a 2 x 2 factorial design, with two levels per factor: "intervention" (real-rTMS vs sham-rTMS) and "task" (movement vs baseline). Figure 1 illustrates the study design. Real- and sham-rTMS were given on 2 separate days, at least 1 week apart. The order of intervention was counterbalanced across subjects. The effects of rTMS were assessed by consecutive PET measurements of regional cerebral blood flow (rCBF) during the first hour after rTMS. Within each scanning session the baseline and movement tasks were alternated. The order of tasks was kept constant within a subject between sessions but was counterbalanced across subjects.
View larger version (25K):
[in this window]
[in a new window]
Figure 1. Experimental design. Subjects received 1 Hz real- or sham-rTMS on separate days. Changes in regional cerebral blood flow were mapped using PET. Six sequential H2 15O PET scans were acquired at baseline (B) or during the freely selected movement task (M) in alternation during the hour after the end of rTMS. The order of intervention (real-rTMS vs sham-rTMS) and experimental conditions were counterbalanced across subjects.
Repetitive transcranial magnetic stimulation. In each rTMS session, 1800 biphasic stimuli were given over the left primary motor hand area using a MagStim rapid stimulator connected to four booster modules (MagStim Company, Whitland, Wales, UK). All subjects received two 15 min trains of 1 Hz rTMS separated by an intertrain interval of 1 min, delivered outside the PET scanner. Stimulation intensity was set to 90% of resting motor threshold (RMT) of the right, first dorsal interosseus (FDI) muscle. A standard figure-of-eight shaped coil (double 70 mm; coil type P/N 9925, MagStim Company) was used for real-rTMS. For sham-rTMS a specially designed sham coil that induced no magnetic field but provided a comparable acoustic stimulus was used (MagStim Company). The coil was positioned with the handle at 45 o to the sagittal plane. The current flow of the initial rising phase of the biphasic pulse in the TMS coil induced a current flowing from posterior to anterior in the underlying motor cortex.
The site of rTMS stimulation was located at the "motor hot spot," defined functionally as the point of maximum evoked motor response in the relaxed right FDI muscle. The resting motor threshold was defined as the lowest stimulus intensity that elicited at least five twitches in 10 consecutive stimuli given over the motor hot spot. The FDI muscle was used to define the motor threshold because TMS-evoked twitches are clearly visible, and it has a threshold similar to other intrinsic hand muscles. This ensured that the intensity used for rTMS was below movement threshold for all the hand muscles. The use of subthreshold intensity (1) avoided muscle twitches during rTMS that could modulate central processing via sensory afferents and (2) reduced the spread of the stimulation away from the targeted site. An intensity of 90% RMT was chosen because this is above the threshold for activating corticospinal output projections. The latter is usually assessed by measuring active motor threshold (the intensity needed to produce electromyograph activation in precontracting muscles) and is equivalent to
80% RMT. We could therefore be certain that the rTMS pulses produced synaptic activation in at least some of the projection sites of M1.
Motor task. Subjects underwent six sequential H2 15O PET scans on each of the 2 separate days. All scans were acquired during the first hour after 30 min of 1 Hz rTMS to the motor cortex. Normalized rCBF-dependent uptake (referred to hereafter as rCBF) was used as an index of regional synaptic activity during two experimental conditions: baseline (referred to as condition "B") and random selection of finger movements (referred to as condition "M"). Three PET scans were acquired for each of the experimental conditions in an alternating order (B-M-B-M-B-M or M-B-M-B-M-B). Subjects were required to keep their eyes open and fixate a cross on the center of a screen located 0.7 m in front of their face. A pacing tone sounded every 2 sec during both conditions. During the movement task, subjects were required to freely select and execute brisk flexion movements with the index, middle, ring, or little finger of their right hand. They were asked to make a fresh choice on each trial, regardless of previous moves, so as to produce a random sequence. The instructions emphasized that each choice should be independent of previous choices. Subjects were told to actively prepare the forthcoming movement and execute the movement as soon as they heard the pacing tone. To ensure a stable level of task performance, the random selection task started
Subjects responses were made on four buttons, set under their fingertips on a molded wrist splint. All responses were recorded by computer (Apple Macintosh 7300) using COGENT Cognitive Interface Software (Wellcome Department of Imaging Neuroscience, London, UK). The data were subsequently analyzed using Matlab 6.0 (Mathworks, Sherborn, MA) and SPSS 8.0 (SPSS Inc., Chicago, IL).
Behavioral assessment. In addition to the random selection task during scanning, subjects performed two finger-tapping tasks with their right hand after the first, third, and fifth PET scan. These tasks served as additional control conditions to detect potential behavioral effects of rTMS. In the "simple tapping task," subjects tapped their right index finger as many times as possible during a 10 sec interval. In the "sequential tapping task," subjects were asked to repeat an ascending sequence (index, middle, ring, little finger) as quickly as possible for 10 sec. Having familiarized the subjects with the tasks outside the PET scanner, each of the tasks was performed twice in the PET scanner before rTMS on both scanning sessions. This was done to reduce learning effects during sequential PET scans.
From each task, the mean interval between responses and the mean duration of button presses were calculated, as indices of motor performance. These values were entered into a paired-samples t test to look for differences after real-rTMS compared with sham-rTMS. The free selection movement task during scanning was paced; therefore only the mean duration of button presses was considered as a kinematic variable of interest. Simpson's equitability index (Simpson, 1949
PET data acquisition. PET was performed using a CTI ECAT HR+ scanner (CTI, Knoxville, TN) in three-dimensional mode with interdetector collimating septa removed. The axial field of view was 155 mm, providing whole-brain coverage including cerebellum. The subjects lay supine in the scanner. A padded helmet with a chinstrap, fixed to the headrest, reduced head movement. A TV monitor was adjusted to give subjects an unrestricted view of the instructions and fixation point.
Regional cerebral blood flow was assessed using H2 15O. Six to 10 mCi (mean 8.9 mCi) were delivered intravenously over 20 sec to the left arm. Image acquisition began 5 sec before the rising phase of the count curve,
In all subjects, the position of the center of the eight-shaped coil was marked on the skull with a capsule containing cod liver oil. Anatomic structural images were acquired before rTMS stimulation, with the TMS surface markers in place, using a VISION MR scanner at 2 tesla (Siemens, Erlangen, Germany) with a T1 MPRAGE sequence (echo time = 4 msec; repetition time = 9.5 sec; inversion time = 600 msec; resolution 1 x 1 x 1.5 mm; 108 axial slices). This structural image also excluded asymptomatic structural brain abnormalities. In all subjects the cod liver oil capsule marking the motor hot spot was clearly visible, located over the central sulcus. Examples of the TMS coil placement scans for one subject can be seen in Fig. 2.
View larger version (94K):
[in this window]
[in a new window]
Figure 2. Position and orientation of TMS coil (TMS) relative to the central sulcus (CS) shown in one subject. N.B.: Capsules marking the position of the premotor cortex, visible in the sagittal scans, anterior to TMS, are part of a different experiment.
Image analysis. All image analysis was performed using Statistical Parametric Mapping software, SPM99 (Wellcome Department of Imaging Neuroscience, University College London, UK; http://www.fil.ion.ucl.ac.uk/spm). For each subject, images were realigned to the first image by rigid body correction for head movements between scans and change of position between sessions (Friston et al., 1995a
The primary analysis used a general linear model that included 12 covariates modeling the task (movement selection vs baseline) separately for each consecutive scan pair, first to third, under each condition of treatment (real-rTMS vs sham-rTMS). The effect of global differences in cerebral blood flow among scans was removed by treating global activity as a confound and scaling to a nominal grand mean of 50 ml/100 gm per minute (Friston et al., 1995b
Predicted changes in effective connectivity within the motor network were assessed using the psychophysiological interaction (PPI) method described by Friston et al. (1997
View larger version (12K):
[in this window]
[in a new window]
Figure 3. Interpretation of PPI analyses. This schematic shows that two mathematically equivalent but biologically complementary hypotheses can be used to motivate the same PPI. In both graphs, x represents activity in an index area subtending the physiological variance in the PPI analysis. Conditions H and L represent some psychological or experimental manipulation. In a during H, a unit increase in activity in area y ( y) is associated with a small increase in activity in area x:
The first PPI was used to test the hypothesis that rTMS alters the responsiveness of the site of stimulation to activity in other motor areas. This hypothesis was motivated by previous work demonstrating that rTMS reduces the sensitivity of primary motor cortex to peripheral and exogenous inputs. The analysis was specified to identify cortical areas with an attenuated influence on the stimulation site after rTMS. The physiological variable here comprised the first eigenvariate of the rCBF signal from a sphere (radius 8 mm) centered on the voxel in primary motor showing the greatest TMS-induced increases (see Table 3). The eigenvector was adjusted to remove subject-specific effects. This ensured that the analysis was sensitive to within-subject variation in activity, and the results do not reflect between-subject differences. A PPI term (a regressor representing the interaction between physiological activity and experimental context) was obtained by multiplying the physiological variable by the TMS-specific effect. Having included the effects of the physiological component (activity in the index region) and the psychological component (real-rTMS vs sham-rTMS) in the same model, SPM was used to test for the PPI (an example of a design matrix is displayed in Fig. 7). The resulting SPM {t} reflects the significance of the PPI. To quantify the effects of rTMS on the motor network identified by the primary analysis, regression slopes were plotted for areas where p < 0.05 (corrected for a 16 mm radius sphere centered on the maxima of the main effect of movement). In this PPI, a significant increase in the regression slope was predicted by a reduction in the response of the index area (the site of rTMS) to putative input from other brain areas (Fig. 3a). This is because the slope represents the ratio of changes in the significant area to changes at the rTMS site. Therefore, positive interactions identify regions where movement-related activity is associated with a smaller response at the site of rTMS after stimulation.
View this table:
[in this window]
[in a new window]
Table 3. Main effect of rTMS
View larger version (38K):
[in this window]
[in a new window]
Figure 7. Changes in effective connectivity (psychophysiological interaction) with the site of rTMS stimulation. Top left panel, Areas showing positive PPI with the site of rCBF increase in left sensorimotor cortex after rTMS. Results are displayed as statistical parametric maps in sagittal, coronal, and transverse projections in stereotactic space. The grayscale areas show all significant voxels at p < 0.001, uncorrected. The black circle shows the location of the region of interest used as the physiological variate in the interaction. The design matrix is displayed alongside the statistical parametric maps. Graphical representations illustrate the psychophysiological interactions between the site of rTMS region of interest (x = -30, y = -26, z = 62) (abscissa) and significant areas. Regression lines between the activity in the two regions have been fitted: sham-rTMS = S (triangles) and real-rTMS = R (diamonds). i, Left dorsal premotor area (x = -14, y = -6, z = 66). Sham-rTMS: r 2 = 0.04, F = 2.01, gradient = 0.01; real-rTMS: r 2 = 0.63, F = 79.40, gradient = 0.80. ii, Proximate left sensorimotor region (x = -38, y = -20, z = 46). Sham-rTMS: r 2 = 0.22, F = 13.19, gradient = 0.36; real-rTMS: r 2 = 0.66 F = 87.37, gradient = 0.81. iii, Left mesial motor area (x = -4, y = 14, z = 34). Sham-rTMS: r 2 = 0.00, F = 2.01, gradient = 0.01; real-rTMS: r 2 = 0.40 F = 30.17, gradient = 0.50.
View this table:
[in this window]
[in a new window]
Table 2. Main effect of movement
The second analysis of effective connectivity was designed to test the hypothesis that after rTMS there are compensatory increases in the influence of components of the motor network involved in the performance of the motor task on nonstimulated regions. Three areas ipsilateral to the site of stimulation were chosen on the basis of the known anatomical connections with the site of stimulation and the areas involved in action preparation and execution: left primary sensorimotor hand area, left dorsal premotor cortex, and left supplementary motor area (SMA). Three separate PPI analyses were performed, one for each area. In each case the physiological variable was the first eigenvariate of the rCBF signal from a region of interest (sphere 8 mm radius) identified by the main effect of movement. The covariate of interest was constructed and tested using SPM as described above. In these three PPI analyses, a significant increase in the regression slope between two areas (a positive interaction) can be interpreted as rTMS-induced increases in movement-related influence of the index area on the regions identified (Fig. 3b).
Results
Subjects did not report any adverse side effects during the course of the study, nor were any motor responses evoked during the 30 min of rTMS. Mean resting motor threshold was 62%, ranging from 46 to 72% of maximum output of the MagStim rapid stimulator.Behavioral data
We did not find a significant effect of 1 Hz rTMS on the rate and duration of finger presses during simple and sequential finger tapping. This is in agreement with previous work investigating the effects of rTMS on simple motor behavior (Wassermann et al., 1996
View this table:
[in this window]
[in a new window]
Table 1. Mean group data (±SD) of kinematic measures (duration of press and interval between presses for the index tapping and sequential tapping tasks, plus duration of press for the free selection task)
For the simple tapping task, there was no effect of rTMS on the duration of button presses or on the interval between button presses. For the sequential tapping task there was no effect of rTMS on duration of button presses or on the interval between presses. For freely selected movements, rTMS had no effect on the randomness of responses measured by Simpson's equitability index or on the duration of button presses. A repeated measures ANOVA used to test for time by condition interactions also failed to detect any significant effect (results not shown).
Imaging data
Conventional analyses were used to investigate the distributed changes in synaptic activity associated with movement, prolonged submotor threshold 1 Hz rTMS, and the interaction between these effects. Analyses of effective connectivity addressed two distinct issues: (1) identification of cortical areas with an influence on the stimulation site that was attenuated by rTMS, and (2) areas that were more sensitive to motor, premotor, and SMA inputs after rTMS has been used to alter the excitability of primary motor cortex.Movement-related activations (main effect of task)
The movement task activated a number of motor areas compatible with freely selected right-hand movements (Fig. 4, Table 2) (reported at p < 0.05 corrected for multiple comparisons). These included the left primary sensorimotor cortex, extending to the left dorsal premotor cortex and left SMA. Additional activations were also seen in the right dorsal premotor cortex, right SMA, right rostral motor cingulate cortex, and left ventral premotor cortex. There were also bilateral activations in the lateral prefrontal cortex and the cerebellum.
View larger version (58K):
[in this window]
[in a new window]
Figure 4. Regional activations during freely selected finger movements (main effect of movement). Results are displayed as statistical parametric maps on sagittal, coronal, and transverse projections in stereotactic space. The grayscale areas indicate all significant voxels showing a movement-related activation at p < 0.05 (corrected for multiple comparisons). The X indicates the site of rTMS stimulation.
Changes in rCBF induced by rTMS (main effect of rTMS)
Compared with sham, real-rTMS caused widespread increases and decreases in rCBF throughout the brain (Table 3). There were no significant main effects of time, or time-by-condition interactions (intra-session effects), indicating that rTMS induced sustained changes in rCBF for at least 1 hr.The left primary motor hand area, which was directly targeted by rTMS, showed a sustained increase in rCBF after real-rTMS (averaged over move and baseline conditions) (Fig. 5). rTMS also induced bilateral increases in rCBF in the dorsal premotor cortices (Fig. 5) and cerebellum. Other motor areas showing lasting increases included left caudal SMA, left basal ganglia, and bilateral foci in the inferior parietal lobule. There was also greater activity in the right prefrontal area and bilateral parietal regions.
View larger version (61K):
[in this window]
[in a new window]
Figure 5. Regional increases in rCBF after rTMS to the left motor cortex (main effect of rTMS). Left primary motor and bilateral increases in rCBF displayed on an axial section of averaged anatomical MRI scans. Results are displayed at p < 0.001 uncorrected, masked by main effect of movement, p < 0.001 uncorrected (because these effects are orthogonal this corresponds to p < 0.00001). Parameter estimates showing mean (±SE) activation during the four experimental conditions are also displayed.
There were no decreases in rCBF at or near the site of stimulation (Table 3); however, we found significant decreases in the right cingulate motor cortex and the left ventral premotor area. Additional rCBF decreases were located in frontal operculum, superior temporal gyrus, right cerebellum, and lateral prefrontal cortices.
rTMS-induced changes in task-related activation (movement-by-rTMS interaction)
Increases in task-specific activation (movement vs baseline) after real-rTMS (vs sham-rTMS) were found in two areas. These were left primary sensorimotor cortex (x = -30, y = -24, z = 48; Z score = 3.6; p = 0.028) and right dorsal premotor cortex (x = 30, y = 4, z = 54; Z score = 3.55; p = 0.033). Figure 6 shows the anatomical location of these activations. rTMS caused no task-specific decreases in activation.
View larger version (89K):
[in this window]
[in a new window]
Figure 6. Areas of the brain showing differential movement-related responses after rTMS (interaction between movement and rTMS). Results are displayed on sagittal sections of averaged anatomical MRI scans at p < 0.001 uncorrected, masked by main effect of movement as for Figure 5. Localization of activation and parameter estimates for left sensorimotor site (a) and right premotor site (b).
Changes in effective connectivity between the stimulated area and other motor areas (psychophysiological interactions)
Figure 7 and Table 4a show the results of the first psychophysiological interaction analysis, using the synaptic activity (as indexed by rCBF) from the site of maximal rTMS-induced increase (x = -30, y =-26, z = 62) as the physiological variable. Table 4a lists the coordinates of the maxima of sites shown in Figure 7, with corrected p values. After rTMS, changes in activity in the left premotor (x = -14, y = -6, z = 66) and motor cingulate (x = -4, y = 14, z = 34) cortices were associated with a reduction in the magnitude of the response of the index area (the site of rTMS). A trend toward reduced influence was also found in a region of left sensorimotor cortex (x = -38, y = -20, z = 46). These PPIs are consistent with our prediction that the sensitivity of the stimulation site to input from distal areas is reduced by rTMS.
View this table:
[in this window]
[in a new window]
Table 4. Psychophysiological interactions
Changes in effective connectivity between primary and nonprimary motor areas
Figure 8 and Table 4b—d summarize the results of three psychophysiological interaction analyses looking for changes in coupling among components of the motor system activated during the movement task. When activity in the left sensorimotor hand area (x = -42, y = -26, z = 56) was used as the physiological component, there was a significant increase in the regression slope in the ipsilateral left sensorimotor area (x =-38, y =-20, z = 46) after rTMS (Fig. 8a,b, Table 4b). The PPI analysis based on activity in the left dorsal premotor area (x = -26, y = -14, z = 68) demonstrated that after rTMS, there was increased influence on areas in the left and right primary sensorimotor cortex (Fig. 8c,d, Table 4c). A third analysis used the activity in left SMA (x =-12, y =-4, z = 56) as the physiological variable. It can be seen from Table 4d and Figure 8, e and f, that rTMS increases the influence of left SMA on the left sensorimotor cortex (x = -30, y = -26, z = 54). These results suggest that after rTMS there is a greater degree of movement-related coupling between each index site [left sensorimotor (SM1), dorsal premotor (PMd), and SMA] and activity in a cluster of inferomedial primary motor sites (Fig. 9).
View larger version (30K):
[in this window]
[in a new window]
Figure 8. Changes in effective connectivity (psychophysiological interaction) with the movement-related activations. a, Areas showing positive PPI with left sensorimotor region of interest (x = -42, y = -26, z = 56) during movement-related activity after real-rTMS compared with sham-rTMS, displayed as described for Figure 7. b, Graphical representation illustrating the psychophysiological interactions between left sensorimotor region of interest (abscissa) and a proximate left sensorimotor region (x = -38, y = -20, z = 46). Regressions lines between the activity in the two regions have been fitted: sham-rTMS = S (squares) (r 2 = 0.36, F = 25.68, gradient = 0.37) and real-rTMS = R (diamonds) (r 2 = 0.79, F = 170.87, gradient = 0.71). c, Areas showing positive PPI with left premotor region of interest (x = -26, y = -14, z = 68), as described in Figure 7. d, Graphical representations illustrating the psychophysiological interactions between left premotor region of interest (abscissa) and left sensorimotor region (x = -36, y = -22, z = 44), as described for b. Sham-rTMS: r 2 = 0.06, F = 2.66, gradient = 0.11; real-rTMS: r 2 = 0.43, F = 34.13, gradient = 0.78. e, Areas showing positive PPI with the left SMA region of interest (x = -12, y = -4, z = 56), as described for Figure 7. f, Graphical representation illustrating the psychophysiological interactions between left SMA region of interest (abscissa) and left sensorimotor region (x = -30, y = -26, z = 54), as described for b. Sham-rTMS: r2 = 0.25, F = 15.52, gradient = 0.43; real-rTMS: r2 = 0.61, F = 71.0, gradient = 1.07.
View larger version (33K):
[in this window]
[in a new window]
Figure 9. Three-dimensional representation of the relative positions of the primary motor cortex sites identified in the three PPI analyses shown in Figure 8a—f. The solid circle, square, and triangle symbols represent the regions of interest (the maxima of the main effect of movement) from which activity was used to create the PPI (see Materials and Methods). The open circle, square, and triangle symbols indicate the relative position of the sites in primary motor cortex that are more strongly influenced by activity in SM1, PMd, and SMA, respectively, after rTMS. The solid diamond indicates the position of the SM1 site seen in the movement-by-rTMS interaction (Fig. 6). X marks the site of stimulation with 1 Hz rTMS.
Discussion
The findings of this study are discussed in two sections: (1) the neural correlates of reduced cortical excitability after 1 Hz rTMS and (2) mechanisms by which the brain maintains functional integrity in the context of altered cortical excitability.Neural correlates of reduced cortical excitability
We found widespread changes in rCBF within the motor system after a period of subthreshold rTMS, including increased rCBF at the site of stimulation, that were stable for up to 1 hr after the end of stimulation. These data extend previous H215O PET studies that had described increases in neuronal activity in motor areas during rTMS of the motor cortex (Fox et al., 1997There are two mechanisms by which rTMS can decrease cortical and corticospinal excitability (Chen et al., 1997
In this study, the site of increased rCBF at the site of stimulation with rTMS was 13 mm superior and medial to the maximal activation of the left sensorimotor cortex during freely selected movement. This may be because the site of stimulation with rTMS was located by generating twitches in the FDI muscle, whereas the movement task used the full range of finger flexors and extensors. Also, the activation during movement may represent a conflation of sensory and motor effects, as compared with the purely motor site stimulated with rTMS.
Maintenance of functional integrity during modulation of cortical excitability
The right dorsal premotor cortex (contralateral to the site of stimulation) showed increased activation during freely selected finger movements of the right hand (Fig. 6). This reinforcement of movement-related activation in the contralateral premotor cortex has interesting parallels with a TMS study published recently by Johansen-Berg et al. (2002The second set of PPI analyses demonstrates that after rTMS activity in caudal SMA, dorsal premotor and primary motor cortices became more tightly coupled with a distinct sensorimotor cluster in the primary hand area. This cluster was close to the area in left primary sensorimotor cortex seen in the movement-by-rTMS interaction (Fig. 9). It is worth noting that these sites were located inferior to the sensorimotor site that showed maximal activation during movement. This does not imply that 1 Hz rTMS remodels motor representations per se, but having rendered a superficial part of primary motor cortex less sensitive to inputs from premotor and mesial motor areas (Fig. 7), other regions within the primary sensorimotor cortex may become more responsive during movement. The intensity chosen for rTMS modulates more superficial portions of the primary sensorimotor cortex because the strength of stimulation attenuates with increasing vertical distance from the plane of the coil. Regions of primary sensorimotor cortex deep in the central sulcus would be less affected by rTMS and therefore capable of responding to input from premotor cortex and SMA during movement. Such operational remapping of motor representations would explain how the motor system compensates for rTMS-induced reductions in cortical excitability.
For this explanation to be plausible there are three requirements. First, the adult motor cortex should contain multiple motor representations and be capable of plastic changes. Second, such changes should occur at time scales similar to those seen in this experiment i.e., within 1 hr. Third, rTMS parameters should be comparable with stimulation protocols that modulate neuronal systems involved in motor cortical plasticity in animals.
Recent work with fMRI has confirmed early PET findings (Colebatch et al., 1991
Work in rat motor cortex confirms that within hours of motor nerve lesion (Donoghue et al., 1990
The basis for cortical reorganization is thought to involve changes in cortical synaptic efficacy, through mechanisms such as long-term potentiation and long-term depression (Buonomano and Merzenich, 1998
This study adds to the body of evidence that low-intensity rTMS to the primary motor hand area induces long-lasting changes in neural activity in local and remote brain regions. However, the motor system is able to fully compensate for this by increasing activity in the contralateral premotor cortex, similar to that seen in stroke (Johansen-Berg et al., 2002
Footnotes
Received Jan. 24, 2003; revised Mar. 20, 2003; accepted Mar. 24, 2003.This work was supported by the Wellcome Trust (L.L., J.B.R., R.S.J.F., K.J.F.), the Medical Research Council (J.C.R.), Deutsche Forschungsgemeinschaft (Grant SI 738/1-1) (H.R.S.), and the European Commission Improving Human Potential program (contract number HPRI-CT-1999-00025) (V.R.).
Correspondence should be addressed to Dr. Lucy Lee, Wellcome Department of Imaging Neuroscience, 12 Queen Square, London, WC1N 3BG UK. E-mail: llee{at}fil.ion.ucl.ac.uk.
Copyright © 2003 Society for Neuroscience 0270-6474/03/235308-11$15.00/0
References
Abbott LF, Varela JA, Sen K, Nelson SB (1997) Synaptic depression and cortical gain control. Science 275: 220–224.
Ackermann RF, Finch DM, Babb TL, Engel J Jr (1984) Increased glucose metabolism during long-duration recurrent inhibition of hippocampal pyramidal cells. J Neurosci 4: 251–264.[Abstract]
Bohning DE, Shastri A, McGavin L, McConnell KA, Nahas Z, Lorberbaum JP, Roberts DR, George MS (2000) Motor cortex brain activity induced by 1-Hz transcranial magnetic stimulation is similar in location and level to that for volitional movement. Invest Radiol 35: 676–683.[Web of Science][Medline]
Buonomano DV, Merzenich MM (1998) Cortical plasticity: from synapses to maps. Annu Rev Neurosci 21: 149–186.[Web of Science][Medline]
Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM, Hallett M, Cohen LG (1997) Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 48: 1398–1403.
[Abstract/Free Full Text] Cohen LG, Bandinelli S, Topka HR, Fuhr P, Roth BJ, Hallett M (1991) Topographic maps of human motor cortex in normal and pathological conditions: mirror movements, amputations and spinal cord injuries. Electroencephalogr Clin Neurophysiol [Suppl] 4336–4350.
Colebatch JG, Deiber MP, Passingham RE, Friston KJ, Frackowiak RS (1991) Regional cerebral blood flow during voluntary arm and hand movements in human subjects. J Neurophysiol 65: 1392–1401.
[Abstract/Free Full Text] Donoghue JP, Suner S, Sanes JN (1990) Dynamic organization of primary motor cortex output to target muscles in adult rats. II. Rapid reorganization following motor nerve lesions. Exp Brain Res 79: 492–503.[Web of Science][Medline]
Duffau H (2001) Acute functional reorganisation of the human motor cortex during resection of central lesions: a study using intraoperative brain mapping. J Neurol Neurosurg Psychiatry 70: 506–513.
[Abstract/Free Full Text] Enomoto H, Ugawa Y, Hanajima R, Yuasa K, Mochizuki H, Terao Y, Shiio Y, Furubayashi T, Iwata NK, Kanazawa I (2001) Decreased sensory cortical excitability after 1 Hz rTMS over the ipsilateral primary motor cortex. Clin Neurophysiol 112: 2154–2158.[Medline]
Fierro B, Piazza A, Brighina F, La Bua V, Buffa D, Oliveri M (2001) Modulation of intracortical inhibition induced by low- and high-frequency repetitive transcranial magnetic stimulation. Exp Brain Res 138: 452–457.[Web of Science][Medline]
Fitzgerald PB, Brown TL, Daskalakis ZJ, Chen R, Kulkarni J (2002) Intensity-dependent effects of 1 Hz rTMS on human corticospinal excitability. Clin Neurophysiol 113: 1136–1141.[Web of Science][Medline]
Fox P, Ingham R, George MS, Mayberg H, Ingham J, Roby J, Martin C, Jerabek P (1997) Imaging human intra-cerebral connectivity by PET during TMS. NeuroReport 8: 2787–2791.[Web of Science][Medline]
Friston KJ, Ashburner J, Poline JB, Frith CD, Heather JD, Frackowiak RSJ (1995a) Spatial registration and normalization of images. Hum Brain Mapp 2: 165–189.
Friston KJ, Holmes AP, Worsley KJ, Poline JP, Frith CD, Frackowiak RSJ (1995b) Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 2: 189–210.
Friston KJ, Buechel C, Fink GR, Morris J, Rolls E, Dolan RJ (1997) Psychophysiological and modulatory interactions in neuroimaging. NeuroImage 6: 218–229.[Web of Science][Medline]
Gerschlager W, Siebner HR, Rothwell JC (2001) Decreased corticospinal excitability after subthreshold 1 Hz rTMS over lateral premotor cortex. Neurology 57: 449–455.
[Abstract/Free Full Text] Grafton ST, Woods RP, Mazziotta JC, Phelps ME (1991) Somatotopic mapping of the primary motor cortex in humans: activation studies with cerebral blood flow and positron emission tomography. J Neurophysiol 66: 735–743.
[Abstract/Free Full Text] Grafton ST, Woods RP, Mazziotta JC (1993) Within-arm somatotopy in human motor areas determined by positron emission tomography imaging of cerebral blood flow. Exp Brain Res 95: 172–176.[Web of Science][Medline]
Hess G, Donoghue JP (1996) Long-term depression of horizontal connections in rat motor cortex. Eur J Neurosci 8: 658–665.[Web of Science][Medline]
Indovina I, Sanes JN (2001) On somatotopic representation centers for finger movements in human primary motor cortex and supplementary motor area. NeuroImage 13: 1027–1034.[Web of Science][Medline]
Johansen-Berg H, Rushworth MF, Bogdanovic MD, Kischka U, Wimalaratna S, Matthews PM (2002) The role of ipsilateral premotor cortex in hand movement after stroke. Proc Natl Acad Sci USA 99: 14518–14523.
[Abstract/Free Full Text] Karni A, Meyer G, Rey-Hipolito C, Jezzard P, Adams MM, Turner R, Ungerleider LG (1998) The acquisition of skilled motor performance: fast and slow experience-driven changes in primary motor cortex. Proc Natl Acad Sci USA 95: 861–868.
[Abstract/Free Full Text] Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD (1993) Corticocortical inhibition in human motor cortex. J Physiol (Lond) 471: 501–519.
[Abstract/Free Full Text] Liepert J, Bauder H, Wolfgang HR, Miltner WH, Taub E, Weiller C (2000) Treatment-induced cortical reorganization after stroke in humans. Stroke 31: 1210–1216.
[Abstract/Free Full Text] Maeda F, Keenan JP, Tormos JM, Topka H, Pascual Leone A (2000) Modulation of corticospinal excitability by repetitive transcranial magnetic stimulation. Clin Neurophysiol 111: 800–805.[Web of Science][Medline]
Muellbacher W, Ziemann U, Boroojerdi B, Hallett M (2000) Effects of low-frequency transcranial magnetic stimulation on motor excitability and basic motor behavior. Clin Neurophysiol 111: 1002–1007.[Web of Science][Medline]
Munchau A, Bloem BR, Irlbacher K, Trimble MR, Rothwell JC (2002) Functional connectivity of human premotor and motor cortex explored with repetitive transcranial magnetic stimulation. J Neurosci 22: 554–561.
[Abstract/Free Full Text] Nudo RJ, Masterton RB (1986) Stimulation-induced [14C]2-deoxyglucose labeling of synaptic activity in the central auditory system. J Comp Neurol 245: 553–565.[Web of Science][Medline]
Nudo RJ, Jenkins WM, Merzenich MM (1990) Repetitive microstimulation alters the cortical representation of movements in adult rats. Somatosens Mot Res 7: 463–483.[Web of Science][Medline]
Pascual Leone A, Tormos JM, Keenan J, Tarazona F, Canete C, Catala MD (1998) Study and modulation of human cortical excitability with transcranial magnetic stimulation. J Clin Neurophysiol 15: 333–343.[Web of Science][Medline]
Rao SM, Binder JR, Hammeke TA, Bandettini PA, Bobholz JA, Frost JA, Myklebust BM, Jacobson RD, Hyde JS (1995) Somatotopic mapping of the human primary motor cortex with functional magnetic resonance imaging. Neurology 45: 919–924.
[Abstract/Free Full Text] Romero JR, Anschel D, Sparing R, Gangitano M, Pascual Leone A (2002) Subthreshold low frequency repetitive transcranial magnetic stimulation selectively decreases facilitation in the motor cortex. Clin Neurophysiol 113: 101–107.[Web of Science][Medline]
Rossi S, Pasqualetti P, Rossini PM, Feige B, Ulivelli M, Glocker FX, Battistini N, Lucking CH, Kristeva Feige R (2000) Effects of repetitive transcranial magnetic stimulation on movement-related cortical activity in humans. Cereb Cortex 10: 802–808.
[Abstract/Free Full Text] Sanes JN, Donoghue JP (2000) Plasticity and primary motor cortex. Annu Rev Neurosci 23: 393–415.[Web of Science][Medline]
Sanes JN, Donoghue JP, Thangaraj V, Edelman RR, Warach S (1995) Shared neural substrates controlling hand movements in human motor cortex. Science 268: 1775–1777.
[Abstract/Free Full Text] Seitz RJ, Hoflich P, Binkofski F, Tellmann L, Herzog H, Freund HJ (1998) Role of the premotor cortex in recovery from middle cerebral artery infarction. Arch Neurol 55: 1081–1088.
[Abstract/Free Full Text] Siebner HR, Rothwell J (2002) Transcranial magnetic stimulation: new insights into representational cortical plasticity. Exp Brain Res 148: 1–16.[Medline]
Siebner HR, Peller M, Willoch F, Minoshima S, Boecker H, Auer C, Drzezga A, Conrad B, Bartenstein P (2000) Lasting cortical activation after repetitive TMS of the motor cortex: a glucose metabolic study. Neurology 54: 956–963.
[Abstract/Free Full Text] Siebner HR, Takano B, Peinemann A, Schwaiger M, Conrad B, Drzezga A (2001) Continuous transcranial magnetic stimulation during positron emission tomography: a suitable tool for imaging regional excitability of the human cortex. NeuroImage 14: 883–890.[Web of Science][Medline]
Simpson EH (1949) Measurement of diversity. Nature 163: 688.
Strafella AP, Paus T, Barrett J, Dagher A (2001) Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J Neurosci 21:RC157(1–4).
[Free Full Text] Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of a human brain. Stuttgart: Thieme.
Terao Y, Ugawa Y (2002) Basic mechanisms of TMS. J Clin Neurophysiol 19: 322–343.[Web of Science][Medline]
Touge T, Gerschlager W, Brown P, Rothwell JC (2001) Are the after-effects of low-frequency rTMS on motor cortex excitability due to changes in the efficacy of cortical synapses? Clin Neurophysiol 112: 2138–2145.[Web of Science][Medline]
Tsuji T, Rothwell JC (2002) Long lasting effects of rTMS and associated peripheral sensory input on MEPs, SEPs and transcortical reflex excitability in humans. J Physiol (Lond) 540: 367–376.
[Abstract/Free Full Text] Wassermann EM, Grafman J, Berry C, Hollnagel C, Wild K, Clark K, Hallett M (1996) Use and safety of a new repetitive transcranial magnetic stimulator. Electroencephalogr Clin Neurophysiol 101: 412–417.[Medline]
Wassermann EM, Wedegaertner FR, Ziemann U, George MS, Chen R (1998) Crossed reduction of human motor cortex excitability by 1-Hz transcranial magnetic stimulation. Neurosci Lett 250: 141–144.[Web of Science][Medline]
Weiller C, Chollet F, Friston KJ, Wise RJ, Frackowiak RSJ (1992) Functional reorganization of the brain in recovery from striatocapsular infarction in man. Ann Neurol 31: 463–472.[Web of Science][Medline]
Ziemann U, Wittenberg GF, Cohen LG (2002) Stimulation-induced within-representation and across-representation plasticity in human motor cortex. J Neurosci 22: 5563–5571.
[Abstract/Free Full Text]
This article has been cited by other articles:
X. Wang, M. Gerken, M. Dennis, R. Mooney, J. Kane, S. Khuder, H. Xie, W. Bauer, A. V. Apkarian, and J. Wall
Profiles of Precentral and Postcentral Cortical Mean Thicknesses in Individual Subjects over Acute and Subacute Time-Scales
Cereb Cortex, October 13, 2009; (2009) bhp226v1.
[Abstract] [Full Text] [PDF]
D. A. Nowak, C. Grefkes, M. Ameli, and G. R. Fink
Interhemispheric Competition After Stroke: Brain Stimulation to Enhance Recovery of Function of the Affected Hand
Neurorehabil Neural Repair, September 1, 2009; 23(7): 641 - 656.
[Abstract] [PDF]
S. Kloppel, B. Draganski, H. R. Siebner, S. J. Tabrizi, C. Weiller, and R. S. J. Frackowiak
Functional compensation of motor function in pre-symptomatic Huntington's disease
Brain, June 1, 2009; 132(6): 1624 - 1632.
[Abstract] [Full Text] [PDF]
M. A. Lambon Ralph, G. Pobric, and E. Jefferies
Conceptual Knowledge Is Underpinned by the Temporal Pole Bilaterally: Convergent Evidence from rTMS
Cereb Cortex, April 1, 2009; 19(4): 832 - 838.
[Abstract] [Full Text] [PDF]
B.F.L. van Nuenen, M. M. Weiss, B. R. Bloem, K. Reetz, T. van Eimeren, K. Lohmann, J. Hagenah, P. P. Pramstaller, F. Binkofski, C. Klein, et al.
Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype
Neurology, March 24, 2009; 72(12): 1041 - 1047.
[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]
M. A. Perez, S. Tanaka, S. P. Wise, D. T. Willingham, and L. G. Cohen
Time-Specific Contribution of the Supplementary Motor Area to Intermanual Transfer of Procedural Knowledge
J. Neurosci., September 24, 2008; 28(39): 9664 - 9669.
[Abstract] [Full Text] [PDF]
V. Di Lazzaro, F. Pilato, M. Dileone, P. Profice, A. Oliviero, P. Mazzone, A. Insola, F. Ranieri, P. A. Tonali, and J. C. Rothwell
Low-frequency repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex
J. Physiol., September 15, 2008; 586(18): 4481 - 4487.
[Abstract] [Full Text] [PDF]
A. Hiscock, S. Miller, J. Rothwell, R. C. Tallis, and V. M. Pomeroy
Informing Dose-Finding Studies of Repetitive Transcranial Magnetic Stimulation to Enhance Motor Function: A Qualitative Systematic Review
Neurorehabil Neural Repair, June 1, 2008; 22(3): 228 - 249.
[Abstract] [PDF]
S. Bestmann, O. Swayne, F. Blankenburg, C. C. Ruff, P. Haggard, N. Weiskopf, O. Josephs, J. Driver, J. C. Rothwell, and N. S. Ward
Dorsal Premotor Cortex Exerts State-Dependent Causal Influences on Activity in Contralateral Primary Motor and Dorsal Premotor Cortex
Cereb Cortex, June 1, 2008; 18(6): 1281 - 1291.
[Abstract] [Full Text] [PDF]
R. P. Lesser, H. W. Lee, W. R. S. Webber, B. Prince, N. E. Crone, and D. L. Miglioretti
Short-term variations in response distribution to cortical stimulation
Brain, June 1, 2008; 131(6): 1528 - 1539.
[Abstract] [Full Text] [PDF]
A. Hadipour-Niktarash, C. K. Lee, J. E. Desmond, and R. Shadmehr
Impairment of Retention But Not Acquisition of a Visuomotor Skill Through Time-Dependent Disruption of Primary Motor Cortex
J. Neurosci., December 5, 2007; 27(49): 13413 - 13419.
[Abstract] [Full Text] [PDF]
V. M. Pomeroy, G. Cloud, R. C. Tallis, C. Donaldson, V. Nayak, and S. Miller
Transcranial Magnetic Stimulation and Muscle Contraction to Enhance Stroke Recovery: A Randomized Proof-of-Principle and Feasibility Investigation
Neurorehabil Neural Repair, December 1, 2007; 21(6): 509 - 517.
[Abstract] [PDF]
G. Koch, M. Fernandez Del Olmo, B. Cheeran, D. Ruge, S. Schippling, C. Caltagirone, and J. C. Rothwell
Focal Stimulation of the Posterior Parietal Cortex Increases the Excitability of the Ipsilateral Motor Cortex
J. Neurosci., June 20, 2007; 27(25): 6815 - 6822.
[Abstract] [Full Text] [PDF]
P. C.J. Taylor, A. C. Nobre, and M. F.S. Rushworth
FEF TMS Affects Visual Cortical Activity
Cereb Cortex, February 1, 2007; 17(2): 391 - 399.
[Abstract] [Full Text] [PDF]
A. G. Richardson, S. A. Overduin, A. Valero-Cabre, C. Padoa-Schioppa, A. Pascual-Leone, E. Bizzi, and D. Z. Press
Disruption of Primary Motor Cortex before Learning Impairs Memory of Movement Dynamics
J. Neurosci., November 29, 2006; 26(48): 12466 - 12470.
[Abstract] [Full Text] [PDF]
E. Rounis, K. E. Stephan, L. Lee, H. R. Siebner, A. Pesenti, K. J. Friston, J. C. Rothwell, and R. S. J. Frackowiak
Acute changes in frontoparietal activity after repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex in a cued reaction time task.
J. Neurosci., September 20, 2006; 26(38): 9629 - 9638.
[Abstract] [Full Text] [PDF]
Y. Ueki, T. Mima, K. Nakamura, T. Oga, H. Shibasaki, T. Nagamine, and H. Fukuyama
Transient Functional Suppression and Facilitation of Japanese Ideogram Writing Induced by Repetitive Transcranial Magnetic Stimulation of Posterior Inferior Temporal Cortex.
J. Neurosci., August 15, 2006; 26(33): 8523 - 8530.
[Abstract] [Full Text] [PDF]
N. S. Ward, J. M. Newton, O. B. C. Swayne, L. Lee, A. J. Thompson, R. J. Greenwood, J. C. Rothwell, and R. S. J. Frackowiak
Motor system activation after subcortical stroke depends on corticospinal system integrity
Brain, March 1, 2006; 129(3): 809 - 819.
[Abstract] [Full Text] [PDF]
N. Takeuchi, T. Chuma, Y. Matsuo, I. Watanabe, and K. Ikoma
Repetitive Transcranial Magnetic Stimulation of Contralesional Primary Motor Cortex Improves Hand Function After Stroke
Stroke, December 1, 2005; 36(12): 2681 - 2686.
[Abstract] [Full Text] [PDF]
B. Pirotte, C. Neugroschl, T. Metens, D. Wikler, V. Denolin, P. Voordecker, A. Joffroy, N. Massager, J. Brotchi, M. Levivier, et al.
Comparison of Functional MR Imaging Guidance to Electrical Cortical Mapping for Targeting Selective Motor Cortex Areas in Neuropathic Pain: A Study Based on Intraoperative Stereotactic Navigation
AJNR Am. J. Neuroradiol., October 1, 2005; 26(9): 2256 - 2266.
[Abstract] [Full Text] [PDF]
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]
S. C. Cramer, R. R. Benson, D. M. Himes, V. C. Burra, J. S. Janowsky, M. E. Weinand, J. A. Brown, and H. L. Lutsep
Use of Functional MRI to Guide Decisions in a Clinical Stroke Trial
Stroke, May 1, 2005; 36(5): e50 - e52.
[Abstract] [Full Text] [PDF]
K. Matsunaga, A. Maruyama, T. Fujiwara, R. Nakanishi, S. Tsuji, and J. C. Rothwell
Increased corticospinal excitability after 5 Hz rTMS over the human supplementary motor area
J. Physiol., January 1, 2005; 562(1): 295 - 306.
[Abstract] [Full Text] [PDF]
H. L. Roth, S. E. Nadeau, and W. J. Triggs
Effect of repetitive transcranial magnetic stimulation on rate of memory acquisition
Neurology, October 26, 2004; 63(8): 1530 - 1531.
[Abstract] [Full Text] [PDF]
This Article Abstract 
Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager 
Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (105) Citing Articles via Google Scholar Google Scholar Articles by Lee, L. Articles by Friston, K. J. Search for Related Content PubMed PubMed Citation Articles by Lee, L. Articles by Friston, K. J. Pubmed/NCBI databases
Medline Plus Health Information Electromagnetic Fields
|
|
|
|
 |
|