Chapter 14 Functional connectivity of the human premotor and motor cortex explored with TMS

Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation (Supplements to Clinical Neurophysiology, Vol. 56) Editors: W. Paulus, F. Tergau, M.A. Nitsche. J.e. Rothwell. U. Ziemann, M. Hallett © 2003 Elsevier Science B.V. All rights reserved

160

Chapter 14

Functional connectivity of the human premotor and motor cortex explored with TMS T. Baumer,

le. Rothwell" and A. Munchau-"

"Neurology Department, Hamburg University, Martinistrasse 52, D-20246 Hamburg (Germany) "Sobell Department of Neurophysiology, Institute of Neurology, Queen Square, London WCIN 3BG (UK)

1. Background The dorsolateral premotor cortex (Broca area F4) is located on the crown of the precentral gyrus anterior to the primary motor cortex, that lies in the anterior bank of the central sulcus (Foerster, 1936; Preuss et aI., 1996). The close proximity of the premotor and the motor cortex and their similar somatotopic organization (Godschalk et al., 1995; Raos et al., 2003) imply that they are also anatomically and functionally interconnected. Anatomical studies in animals have established that apart from direct connections to the spinal cord large areas of the premotor cortex have dense connections to the motor cortex (Dum and Strick, 1991; Morecraft and Van Hoesen, 1993; Stepniewska et al., 1993; Tokuno and Nambu, 2000). A recent human fMRI study suggests that such cortico-cortical organisation between premotor and motor cortex is somatotopically organised also in human subjects (Buccino et al., 2001). In addition to their connections to the motor cortex

* Correspondence to: Dr. A. Miinchau, Neurology Department, Hamburg University, Martinistrasse 52, D-20246 Hamburg, Germany, Tel.: +49 (40) 42803 3770; Fax: +49 (40) 42803 5086; E-mail: muenchautsuke.uni-hamburg.de

different sub-areas of the premotor cortex receive inputs also from the frontal cortex and information on external stimuli via the inferior and superior parietal sulcus (Wise et aI., 1997; Battaglia Mayer et aI., 1998; Rizzolatti et aI., 1998; Marconi et aI., 2001). Apart from its importance for the performance of complex skilled movements (Dum and Strick, 1991; Cisek et aI., 2003) the premotor cortex has therefore been considered to be involved in externally referenced movements, especially visually guided movements (Wise, 1985). It seems to integrate visual response selection and timing adjustments for the responses, i.e. what to do and when to do it (Sakai et al., 2000). A number of studies have looked more closely at the neurophysiology of the premotor-motor circuitry in primates and in human subjects (Ghosh and Porter, 1988; Godschalk et aI., 1995; Ashby et aI., 1999; Tokuno and Nambu, 2000; Civardi et al., 2001; Gerschlager et al., 2001; Miinchau et aI., 2002a). For instance, microstimu1ation of premotor cortex neurons in primates can produce excitatory or inhibitory effects in the motor cortex (Ghosh and Porter, 1988; Tokuno and Nambu, 2000). Stimulation of the premotor cortex results predominantly in short latency inhibition of pyramidal tract neurons that may involve excitatory inputs to superficial inhibitory

161 interneurons in the motor cortex (Tokuno and Nambu, 2(00). The aim of this chapter is to give an overview over neurophysiological, particularly TMS/rTMS studies, that have examined the premotor-motor circuitry in human subjects. We will start with studies on focal electrical stimulation of the premotor and motor area and will then focus on TMS.

2. Subdural electrical stimulation of motor areas To localise the area from which inhibition and facilitation of corticospinal excitability occur Ashby et al. (1999) performed a paired pulse experiment using electrical stimulation applied over an 8 x 8 em grid of subdural electrodes implanted for diagnostic purposes in a young, otherwise healthy epileptic woman. Each of the 64 electrodes had a diameter of 5 mm with a centre-to-centre separation of I cm. After identifying the "hot spot" of the target muscle (i.e. abductor pollicis brevis muscle) they applied sub motor threshold conditioning pulses through adjacent electrodes at different distances between I and 50 ms before suprathreshold electrical test pulses given over the motor "hot spot". They found that when conditioning stimuli were given through a pair of neighbouring electrodes within the hand area of the motor cortex inhibition was obtained at interstimulus intervals (ISIs) of 2 ms and between 30 and 50 ms, and facilitation between 5 and 15 ms. When applying conditioning pulses through more distant electrodes including two that were located anteriorly close to or within the premotor area they showed that facilitation was only induced within a distance of I em from the site where test pulses were given. In contrast, inhibition occurred up to a distance of 1-2 em anterior and anterior-medial of the motor "hot spot". At distances of more than 2 em away from the "hot spot" no changes of the motor evoked potential could be evoked by conditioning pulses. A possible interpretation of these data is that there is a balance of inhibitory and facilitatory inputs, presumably through intracortical intemeurons, close to a given motor "hot spot", whereas projections from more distant sites including the premotor area are

predominantly inhibitory. Alternatively, the activation threshold of more distant inhibitory interneurons could be lower than that for facilitatory neurons.

3. TMS studies 3.1. Methodological considerations TMS is an established non-invasive method to chart the functional connectivity of the human motor system, e.g. the corticospinal connection from motor cortex to spinal cord and the transcallosal connection between the two motor cortices (Rothwell et aI., 1991; Ferbert et aI., 1992; Netz et aI., 1995). Several recent TMS/rTMS and combined TMSIEEG or TMS/imaging studies have also explored the connectivity between the motor cortex and non-primary motor areas including the premotor cortex (Praamstra et al., 1999; Civardi et aI., 2001; Gerschlager et aI., 2001; Siebner et al., 2001; Miinchau et al., 2002a, 2oo2b; Oliviero et aI., 2003). Here we focus on TMS and rTMSITMS studies. A principal problem of TMS/rTMS experiments where TMS pulses are applied outside the motor cortex in the premotor area is that the effects of premotor stimulation cannot be determined directly but only indirectly through measurements of motor cortex excitability using single or paired pulse TMS over the motor cortex. An inherent shortcoming of TMS/rTMS is poor spatial accuracy. This is particularly problematic in experiments that aim at identifying differential effects of TMS/rTMS over adjacent brain areas like the motor and premotor cortex. rTMS application over a particular brain area may lead to inadvertent coactivation of adjacent brain areas through physical spread of the stimulus. To avoid such physical spread of TMS pulses from motor to premotor cortex during motor cortex stimulation and vice versa low or very low TMS/rTMS stimulation intensities can be used as was indeed done in the TMS/rTMS studies discussed below. A drawback of low intensity stimulation may, of course, be reduced effectiveness. In addition to physical spread focal rTMS may also lead to physiological spread via synaptic connections.

162 In fact, this is a prerequisite of TMS/rTMS studies on cortico-cortical connectivity. Intensities of TMS or rTMS application to the premotor area are traditionally referenced to the motor cortex threshold for TMS pulses, although it is unknown whether the TMS responsiveness of the premotor cortex is similar to that of the motor cortex. For instance, in animal studies it was shown that the threshold for electrical stimulation was lower in the premotor cortex (Preuss et al., 1996). Moreover, it is conceivable that due to its location at the top of the precentral gyrus the premotor cortex is more "accessible" to external stimulation and has thus lower TMS stimulation thresholds. Conventional coil placement where brain regions other than the motor cortex are stimulated is referenced to the position of the motor "hot spot". However, this does not account for individual variations in the distance between motor areas and the target brain regions and thus leads to variable effective brain stimulation (Herwig et al., 2001). Therefore, to target relevant brain regions accurately neuronavigation systems that guide coil placement on the basis of individual anatomical and functional MRI scans should be used in future studies. These methodological limitations have to be borne in mind when interpreting data of the following experiments. 3.2. TMS study using single conditioning TMS pulses applied over the premotor area

Previously, it was shown that subthreshold conditioning pulses given over the primary motor cortex (M1) can modulate the size of the ipsilateral test MEP depending on the interstimulus intervals (lSI) with conditioning pulses at short intervals (2-5 ms) producing inhibition and those at longer intervals (6-20 ms) producing facilitation (Kujirai et al., 1993). Ferbert and colleagues demonstrated that conditioning pulses applied to Ml contralaterally also lead to an inhibition of the test MEP, presumably via transcalloasal fibres (Ferbert et al., 1992). Recently, Civardi and colleagues studied the effects of conditioning TMS pulse at different positions anterior

to Ml in the premotor and prefrontal area on Ml excitability as determined by the size of supratheshold TMS pulse given over the Ml hand area (Civardi et al., 2(01). Two small figure-of-eight coils with an inner diameter of 4 cm were used for the conditioning and the test pulse, respectively. They tested the effects at ISIs of 4, 6 and 8 ms at 13 different positions in a 1 x 1 cm grid anterior to the interauricular line. At an intensity of the conditioning pulse of 90% active motor threshold (AMT) they found inhibitory effects at an lSI of 6 ms which were most pronounced at two distinct positions. One was located 5 em anterior to the "hot spot" and 6 em lateral to the midline (A) and the other in the midline 6 em anterior to the interauricular line (B) corresponding to the premotor cortex and the pre SMA, respectively. At point A inhibition of the test pulse at an lSI of 6 ms was only induced with an intensity of the conditioning pulses of 90% AMT, but not with 80%, and a coil position leading to an anterior-posterior (AP) current flow in the brain, whereas a reverse posterioranterior (PA) current flow produced no significant effects. Facilitation of the test pulse was produced with an intensity of 90% AMT at an lSI of 15 ms and 120% at an lSI of 6 ms, respectively. This implies that there are both inhibitory and facilitatory inputs from the premotor to the motor cortex that can be activated by low intensity stimulation over the premotor area. At higher intensities facilitatory effects prevail which could be due to current spread to the motor cortex with activation of facilitatory motor cortex interneurons. Alternatively, facilitatory premotor interneurons could have higher activation thresholds. 3.2.1. rTMS studies rTMS can influence the excitability of human motor cortex when applied directly over the motor cortex area. MEPs are suppressed after low frequency (1 Hz or less) motor rTMS applied for five minutes or more (Chen et al., 1997; Wassermann et al., 1998; Maeda et al., 2000; Muellbacher et al., 2000). In contrast, an increase of the size of EMG responses occurs if higher frequencies, and higher intensities

163 are used (Pascual-Leone et al., 1994; Wu et al., 2000). Moreover motor cortex rTMS trains also affect intrinsic motor cortex excitability as determined with the Kujirai paired pulse paradigm (Kujirai et al., 1993). Thus, high frequency rTMS decreases intracortical inhibition (ICI) in the stimulated hemisphere (peinemann et al., 2000; Wu et al.. 2(00). Gerschlager et al. (2001) investigated the effect of subthreshold (90% AMT) 1 Hz rTMS applied to the left lateral premotor, left lateral frontal, left anterior parietal cortex and the hand area of the left M1 on net corticospinal excitability as reflected in the MEP size to suprathreshold TMS pulses applied over left MI. They stimulated at different points on a line parallel to the midline, i.e, directly over Ml, 2.5 and 5 em anterior and 2.5 cm posterior to the Ml "hot spot". Five trains of 300 pulses were given in each condition. MEPs were measured before and following application of 900 and 1500 rTMS pulses. MEP amplitudes were significantly reduced after rTMS over the premotor area, but not at any other stimulation site. This effect occurred after 900 pulses and outlasted the rTMS session for at least 15 min. To examine whether this effect was dependent on the effective current flow during rTMS the authors tested two additional coil orientations for premotor rTMS by rotating the coil by 90° and 180° from the customary coil orientation (handle pointing 45° postero-laterally). MEP suppression of similar magnitude was present after premotor rTMS with the coil handle pointing in the antero-medial direction (rotation by 180°) but not in the lateral-medial direction (rotation by 90°). The magnetic stimulus had a biphasic waveform with the first phase of the stimulus inducing a PA current flow in the brain when the coil is held in the customary position. According to recent single pulse studies the more effective stimulation occurs during the second phase of the biphasic pulse which thus induces an AP current (Corthout et al., 2001; Kammer et al., 2001). Apparently, premotor-motor projections mediating MEP depression following biphasic 1 Hz premotor rTMS at 90% AMT can be activated both by AP and PA current flow.

To investigate the effects of left premotor rTMS on intrinsic left motor cortex excitability, Miinchau et al. (2oo2a) used 1 Hz premotor rTMS at intensities of 70, 80 and 90% AMT and measured motor thresholds, the MEP size, ICI and intracortical facilitation (ICF) using the Kujirai paired pulse paradigm at lSI between 2 and 7, 10 and 15 IDS and the silent period. The coil was always positioned with the handle pointing 45° postero-laterally with the most effective current thus flowing in the AP direction. The rTMS stimulation point over the premotor area was defined as lying 8% of the distance between nasion and inion (typically about 3 em) anterior to the motor cortex hand area "hot spot", i.e. approximately 0.5 em more anterior than the stimulation site chosen by Gerschlager et al. (2001). In control experiments they used identical rTMS trains directly over the motor cortex and 3 em posteriorly of the motor "hot spot". i.e. over the area of the somatosensory cortex. Following premotor rTMS there was a significant increase in intracortical excitability at ISIs of 6 and 7 ms in the paired pulse experiment outlasting the rTMS train by about an hour (Fig. 1). The question arises of whether this effect was caused by effective stimulation of the premotor area under the centre of 18 16

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164 the rTMS coil or in the motor cortex directly because of physical current spread away from the coil. This seems unlikely as after moving the rTMS coil, so that its centre was over the motor hand area, or more posterior, over the sensory cortex, there was no effect on ICIIICF. Since the intensity of rTMS was the same as the intensity of the first pulse in the ICIIICF paradigm (80% AMT), and rTMS over motor cortex had no effect on ICIIICF, we can presume that premotor rTMS was not having a direct effect on the intracortical elements activated in the ICIIICF paradigm. The conclusion is that premotor rTMS was influencing interneurons in the motor cortex through cortico-cortical premotor-motor connections. In addition to specific changes of intracortical excitability and corroborating these findings there was also a shortening of the cortical silent period after premotor rTMS but not after motor or sensory rTMS. In previous studies probing the effect of rTMS on ICIIICF (Ziemann et al., 1998; Siebner et al., 1999; Peinemann et al., 2000; Wu et al., 2000), rTMS was applied over the motor cortex directly, and at a higher intensity and/or frequency than used in the premotor study by Miinchau et al. (2oo2a) (between 90-120% resting motor threshold). It is therefore possible that some of the effects on intracortical inhibition were due to current spread to premotor areas. Assuming that similar to the effects in the motor cortex I Hz rTMS has also overall inhibitory effects in the premotor cortex (Chen et al., 1997; PascualLeone et al., 1998; Wassermann et al., 1998) the results of Gerschlager et al, and Miinchau et al. appear to be somewhat contradictory. Down-regulation of the premotor area by 1 Hz rTMS lead to a reduction of net corticospinal excitability (reduced MEP size) in the former but extra facilitation of intrinsic motor cortex excitability in the latter study. In fact, in contrast to the results of Gerschlager et at (2001), Miinchau et al, (2oo2a) did not find a significant reduction of the MEP amplitudes after 1 Hz premotor rTMS. The most reasonable explanation for this discrepancy is that lower rTMS stimulation intensities used in the study by Miinchau et al, (2oo2a) (80% AMT) induced changes in different sets of interneuronal

projections from the premotor to the motor cortex. Such stimulation may have been sufficient to act on low threshold inhibitory premotor-motor interneurons without activating facilitatory ones. On the other hand, slightly higher intensities in the Gerschlager study (Gerschlager et al., 2001) (90% AMT) may have activated both projections with stronger effects on facilitatory inputs. Alternatively, the slightly more anterior coil placement in the study by Mtinchau et al., could have lead to more anterior effective stimulation. On the basis of the work of Ashby et al. (1999) (see above) it is conceivable that under the experimental conditions used down-regulation of the premotor area closer to the motor cortex (Gerschlager et al., 2001) predominantly affected facilitatory premotor-motor projections resulting in net inhibitory effects in the motor cortex (MEP size reduction) whereas "inhibitory" 1 Hz rTMS at a slightly greater distance from the motor cortex (Munchau et aI., 2oo2a) mainly acted on inhibitory pathways from the premo tor to the motor cortex causing specific extra facilitation (increase of ICF at an lSI of 6 and 7 ms). Finally, which premotor-motor projections are predominantly activated or deactivated by TMS may depend on the direction of the current flow. Deactivation of inhibitory premotor-motor projections by premotor conditioning TMS or 1 Hz rTMS was induced by an effective AP current flow in the studies by Civardi et aI. (2001) and Munchau et al. (2002), whereas a PA current flow did not produce inhibition, at least in the Civardi study (Civardi et al., 2001) (it was not tested in the study by Munchau et al.). In contrast, net inhibitory effects onto the motor cortex, presumably due to deactivation of facilitatory premotor-motor connection, by I Hz premotor rTMS in the study by Gerschlager et al. (2001) could be induced both with an effective AP and PA current flow while only a latero-medial flow did not lead to a change of MEP size. Taken together, in line with studies in primates (Ghosh and Porter, 1988; Tokuno and Nambu, 2000) these data imply a complex neurophysiological interaction between premotor and motor cortex that can be inhibitory or facilitatory.

165

The specificity of the extra facilitation only at certain lSI in the study by Mtinchau et al. (2002a) is noteworthy. It has been argued that ICI occurring at lSI between 2 and 6 ms and ICF at longer ISIs (7-20 ms) are caused by separate mechanisms as the threshold of a conditioning pulse to produce inhibition is lower than that to produce facilitation (Kujirai et al., 1993; Ziemann et al., 1996). Also, ICF depends on the orientation of the stimulation coil whereas ICI does not (Ziemann et al., 1996) and ICI and ICF can be modulated independently by drugs acting on the CNS or are altered independently in a number of neurological conditions (Ziemann et al., 1999). Moreover, closer inspection of the results of other studies using the paired pulse paradigm implies that the paired pulse curve reflects the balance of inhibition and facilitation in a number of different classes of interneurons. For instance, intake of haloperidol leads to an increase in ICF at specific lSI (12 and 15), but not at others (10, 20 or 30 ms) in healthy subjects (Ziemann et al., 1997). In patients with Parkinson's disease Ridding et at. (1995a) found a significant decrease in ICI at 2, 4 and 5 ms, but not at 3 or 7 ms. It is therefore probably more appropriate to consider the motor cortex paired pulse curve as a composite of many interneuronal circuits each of which have certain time constants rather than a curve reflecting the activity in one set of inhibitory and another of facilitatory interneurons. These various sets of interneurons may represent modifiable "excitability modules" (Fig. 2) that can be "accessed" and modulated separately. Apparently, there are projections from the premotor to the motor cortex that modulate those "modules" that shape the paired pulse curve at certain intervals (in this case 6 and 7 ms) but not at others. It has to be borne in mind that on the basis of the data discussed above it cannot be decided whether the consequences of premotor rTMS on motor cortex excitability are due to lasting effects on ongoing levels of activity in a connection from premotor to motor cortex (as suggested in Fig. 2) or due to rTMS activation of a connection from premotor to motor cortex which then results in an after effect on the activity of neurons in the motor cortex. Thus, it could

be that following rTMS activity in the premotor area normalizes quickly and that the after effects are caused by altered motor cortex activity only. (A) Q)

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Fig. 2. (A) Schematic drawing of the paired pulse curve with premotor rTMS induced effects. Changes occur at certain lSI (6 and 7 ms) but do not affect the whole "inhibitory" or "facilitatory" part of the curve. The paired pulse curve probably represents a composite of many interneuronal circuits, each of which may correspond to modifiable "excitability modules". These are symbolized by open or filled rectangles. The latter represent those modules that receive premotor inputs. (B) The premotor cortex apparently acts on some modules, e.g. those that determine the level of excitability at an lSI of 6 and 7 ms, but not on others. Under the experimental conditions used in the study by Miinchau et al. (2002) this action is inhibitory. "Inhibitory" 1 Hz rTMS then reduces premotor activity thus "releasing" dependent motor cortex interneuronal modules which leads to extra facilitation in the motor cortex.

166 In a behavioural test of the premotor-motor connection, Strafella and Paus (2000) instructed resting healthy subjects to observe other people during handwriting. During action observation, there was a decrease in the level of ICIIICF in muscles involved in handwriting, similar to what would happen if subjects had voluntarily activated their own muscles (Ridding et al., 1995b). Given the importance of the premotor cortex in selecting movements that are guided by visual cues (Schluter et al., 1998) the authors argued that activation of the premotor cortex during action observation could lead to inhibitory, "shaping" effects on motor cortex excitability, perhaps via the same connections as were tested in the paired pulse TMS/rTMS paradigm described above. What are behavioural consequences of premotor rTMS in healthy subjects or in patients? Schlaghecken et al. (2003) studied the effects of 1 Hz sub-motor threshold rTMS over left motor or premotor cortex on performance in a visually cued choice reaction time task, using a 'masked prime' paradigm in healthy subjects to asses whether rTMS might affect more automatic motor processes. After left motor and left premotor cortex rTMS right but not left hand responses were slower but the modulation of reaction times by subliminal primes was unchanged. One possible explanation for the similarity of behavioural effects after premotor and motor rTMS is that after effects always occurred in the motor cortex, either directly or through activation of a connection from premotor to motor cortex, as pointed out above. Alternatively, as premotor and motor cortex are topographically and functionally closely connected, particularly concerning processing of visuomotor information (Schluter et al., 1998), changes in motor behaviour might ensue whenever activity in either motor or premotor cortex is altered, implying conjoint or parallel rather then sequential processing in these areas. Given the role of the premotor cortex in visuomotor integration the finding that priming effects were not influenced by rTMS is surprising. It might indicate that priming effects are generated at earlier stages of visuo-motor processing, e.g, at the level of the basal ganglia. Indeed, a recent behavioural and

fMRI study of patients with Huntington' s disease and healthy subjects using the same 'masked prime' paradigm demonstrated abnormal processing of the subliminal prime stimulus in patients and significant modulation of activity of both the caudate and thalamus during the response inhibition process in healthy subjects (Aron et al., 2003). As various symptoms suggest that premo tor areas are overactive in patients with tic-dominant Gilles de la Tourette syndrome (GTS) (Eidelberg et al., 1997; Peterson et al., 1998; Stem et al., 2000) we studied the effects of 1 Hz motor and premotor rTMS on symptoms in GTS patients. In a single-blinded, placebo-controlled, crossover trial 16 GTS patients received in random sequence 1 Hz motor, premotor (80% AMT) and sham rTMS which each consisted of two 20 min rTMS sessions applied on 2 consecutive days. There was no significant improvement of symptoms after any of the rTMS conditions as assessed with an established rating scale (the MOVES survey) (Munchau et al., 2002b). A possible explanation is that abnormal premotor cortex activity in patients with GTS is compensatory rather than primary. Alternatively, rTMS might have been ineffective to treat symptoms of GTS patients because the rTMS stimulation intensity was too low. Also, as no neuronavigation guidance system was used the negative response may have been caused by inaccurate coil placement. Clearly, further TMS/rTMS studies, preferably combined with neuronavigation systems, are needed to delineate behaviourally relevant effects of premotor rTMS both in healthy subjects and in patients.

4. Future directions The premotor-motor TMS/rTMS studies discussed above show that TMS is a useful method to map the functional connectivity in motor networks. The time course and specificity of premotor-motor interactions as demonstrated in the paired pulse TMS/rTMS paradigms render these an attractive technique not only for studies of premotor-motor connectivity but also plasticity.

167

For instance, we recently examined whether the conditioning effect of premotor 1 Hz rTMS on ipsilateral motor cortex would differ if premotor 1 Hz rTMS was given on 2 consecutive days (Baumer et al., 2003). We hypothesised that two premotor rTMS sessions applied on 2 consecutive days would increase the magnitude and/or duration of excitability changes in the motor cortex compared to the effects of a single rTMS train. Motor cortex excitability was determined at baseline, immediately after, 30, 60, 120 min and 24 h after each premotor rTMS session. Similar to our previous work (Munchau et al., 2oo2a) there was a selective increase of paired pulse facilitation at an lSI of 7 ms after premotor rTMS lasting for less than 30 min on day one. This effect was also present after rTMS on day two and had the same magnitude. However, in contrast to day one it persisted for at least 2 h. These data could indicate that 1 Hz premotor rTMS can lead to cumulative plastic changes of intrinsic motor cortex excitability when repeated within 24 h implying the formation of memory after the first rTMS train lasting for at least 1 day. Such a memory effect may represent the basis of long-term rTMS effects observed in patients after repeated rTMS applications. More work needs to be done to delineate the time course, behavioural correlates and also neuropharmacology of these plastic changes. 5. Conclusions In spite of some methodological shortcomings single and paired pulse TMS and rTMS represent effective, non-invasive tools to study the neurophysiology of premotor-motor connections. TMS studies so far indicate that there are both inhibitory and facilitatory premotor-motor projections, the activation/deactivation of which depends on the TMS intensity, frequency, coil placement and effective current flow. What emerges is a delicate finely tuned motor network consistent with the concept that the premotor area has a "shaping" or "focussing" role in the execution of movements. Acknowledgement A. Miinchau is supported by the Volkswagenstiftung.

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