Conditioning transcutaneous electrical nerve stimulation induces delayed gating effects on cortical response: A magnetoencephalographic study

www.elsevier.com/locate/ynimg NeuroImage 35 (2007) 1578 – 1585

Conditioning transcutaneous electrical nerve stimulation induces delayed gating effects on cortical response: A magnetoencephalographic study K. Torquati, a,⁎ R. Franciotti, a S. Della Penna, a C. Babiloni, b,c P.M. Rossini, c,d,e G.L. Romani, a and V. Pizzella a Dipartimento di Scienze Cliniche e Bioimmagini and ITAB, Istituto di Tecnologie Avanzate Biomediche, Università “G. D’Annunzio”, Chieti – Italy Dipartimento di Fisiologia Umana e Farmacologia, Università “La Sapienza”, Roma – Italy c IRCCS “S. Giovanni di Dio Fatebenefratelli”, Brescia – Italy d A.Fa.R. CRCCS, Dipartimento di Neuroscienze Ospedale FBF Isola Tiberina, Roma – Italy e Clinica Neurologica, Università “Campus Biomedico”, Roma – Italy a

b

Received 16 October 2006; revised 15 December 2006; accepted 21 December 2006 Available online 22 February 2007 The present study was undertaken to investigate after-effects of 7 Hz non-painful prolonged stimulation of the median nerve on somatosensory-evoked fields (SEFs). The working hypothesis that conditioning peripheral stimulations might produce delayed interfering (“gating”) effects on the response of somatosensory cortex to test stimuli was evaluated. In the control condition, electrical thumb stimulation induced SEFs in ten subjects. In the experimental protocol, a conditioning median nerve stimulation at wrist preceded 6 electrical thumb stimulations. Equivalent current dipoles fitting SEFs modeled responses of contralateral primary area (SI) and bilateral secondary somatosensory areas (SII) following control and experimental conditions. Compared to the control condition, conditioning stimulation induced no amplitude modulation of SI response at the initial stimulusrelated peak (20 ms). In contrast, later response from SI (35 ms) and response from SII were significantly weakened in amplitude. Gradual but fast recovery towards control amplitude levels was observed for the response from SI-P35, while a slightly slower cycle was featured from SII. These findings point to a delayed “gating” effect on the synchronization of somatosensory cortex after peripheral conditioning stimulations. This effect was found to be more lasting in SII area, as a possible reflection of its integrative role in sensory processing. © 2007 Elsevier Inc. All rights reserved. Keywords: Gating; Magnetoencephalography; SEF; Somatosensory cortex

⁎ Corresponding author. Dipartimento di Scienze Cliniche e Bioimmagini, Università Degli Studi Di Chieti “G. D'Annunzio”, Campus Universitario, Via Dei Vestini, 33; 66013 – Chieti, Italy. Fax: +39 0871 3556930. E-mail addresses: [email protected], [email protected] (K. Torquati). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2006.12.047

Introduction Studies on somatosensory-evoked potentials or fields (SEPs or SEFs) have provided electrophysiological evidence of modulation of somatosensory cortical responses due to simultaneous stimulation of two or more skin territories (Jones, 1981; Gandevia et al., 1983; Kang et al., 1985; Kakigi and Jones, 1986; Burke and Gandevia, 1988). The main effect was a reduction in amplitude of SEP and SEF components and was called “gating effect”. Gating effects were generated when the simultaneous electrical stimulations were applied to cutaneous areas served by the same peripheral nerve as well as by different peripheral nerves (Jones and Power, 1984; Kakigi and Jones, 1985; Kakigi et al., 1996). For example, Kakigi and Jones (1986) have reported that SEPs following median nerve stimulation were disrupted by both thumb interference stimulation and little finger interference stimulation. Thus, gating effects were considered as an expression of either spatial occlusion and/or surrounding inhibition of the simultaneous sensory inputs (Hsieh et al., 1995; Biermann et al., 1998; Ishibashi et al., 2000; Torquati et al., 2003). Most of the quoted investigations have focused on the attenuation of cortical surface SEP or SEF components, speculating that it was plausible that gating of a given component indicated interference effects on its cortical generator. Thus, the cortical sites of interaction of the sensory inputs have to be further investigated. Moreover, previous gating studies mainly concerned with the interfering effect between simultaneous stimuli. As an extension, an intriguing issue was to investigate if a stimulation could induce possible reverberating cortical processes that may interfere with subsequent stimulations, possibly leading to a delayed gating effect. The rationale for such a prediction comes from studies addressing the modulation of cortical activity during repetitive electrical nerve stimulation. It

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has been shown that the amplitude of the different components of scalp-recorded SEPs is sensitive to the inter-stimulus interval (ISI) (Rossini et al., 1987; Tomberg et al., 1989; Huttunen and Homberg, 1991; Wikstrom et al., 1996). Specifically, the most characteristic finding is a loss of SEP component amplitude as a function of decreasing time between stimulus presentations. The effect in higher levels of the somatosensory pathway was larger and appeared at longer ISIs. It has been argued that this effect was not a consequence of sensory adaptation or weariness in the receptors afferent pathway (except with very fast stimulus rates, hundred stimuli per second). Rather, it was caused by complex inhibitory mechanisms within the cortex that reduce the excitatory postsynaptic potentials as well as by the complexity and synaptic refractoriness of the networks and relays generating individual peaks. The present study was undertaken to investigate after-effects of 7 Hz non-painful prolonged stimulation of median nerve on human somatosensory-evoked fields (SEFs), to evaluate the working hypothesis that conditioning peripheral stimulations might produce delayed interfering (“gating”) effects on the response of somatosensory cortex to test stimuli. Subjects and methods Subjects and experimental design Recordings were undertaken on ten right-handed healthy subjects (5 males, 5 females), aged between 20 and 42 years (mean 26.9 ± 1.9), none of whom suffered from a peripheral nerve disorder or a systemic disease affecting peripheral nerve function. Subjects were not taking substances or drugs able to interfere with cortical excitability. The general procedure was approved by the local institutional Ethics Committee and conducted with the written informed consent of each volunteer. Electric stimulation of the right thumb was provided using ring electrodes placed at the first and second thumb phalanges. Stimuli were electric rectangular pulses, 200 μs in duration, with a repetition rate of 0.33 Hz and intensity twice above the subjective sensory threshold (mean 11 ± 3 mA). The conditioning train consisted of 280 electrical stimuli, 200 μs in duration, at a frequency of 7 Hz, delivered to the right median nerve at the wrist by means of a pair of non-magnetic 3-cm-spaced Ag/AgCl disk electrodes. The intensity was set at 70% of the subjective resting motor threshold, in order to avoid effects of the afferent input provoked by an induced muscle twitch. At this intensity (8 ± 1 mA) subjects always perceived the stimulus as a tingling, non-painful sensation at the site of stimulation. Preliminarily, control stimulation of the thumb (Ctrl) was performed. Afterward, in the experimental condition, the conditioning stimulation preceded 6 electrical thumb stimulations at the same rate and intensity of the control condition with a lag of 2 s between the train offset and the first stimulation to the thumb. This sequence was repeated 30 times. See Fig. 1 for a schematic description of the experimental condition. In order to check the steadiness of the signal entering the central nervous system, SNAPs (sensory nerve action potentials) were recorded during control and test conditions, using a pair of surface disk Ag/AgCl electrodes with 4-cm inter-electrode distance, placed at the median nerve at the wrist, about 15 cm from the stimulating electrodes. To this aim special acquisition sessions at 4 kHz sampling rate (bandpass 0.002–1000 Hz) were performed.

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Fig. 1. Schematic description of the experimental design: each conditioning stimulation to the median nerve was followed by six electrical stimulations to the thumb. In order to get a larger number of averages and enhance the signal to noise ratio, the stimuli at the thumb were collected and averaged in pairs: first pair (Post 1), second pair (Post 2) and third pair (Post 3).

Data acquisition and analysis During MEG recordings, the subjects were seated inside a magnetically shielded room. Somatosensory-evoked fields (SEFs) were recorded at 1 kHz sampling rate using the whole-head MEG system available at the Institute of Advanced Biomedical Technologies (ITAB), consisting of 165 dc SQUID integrated magnetometers (Pizzella et al., 2001): 153 magnetometers are placed over a whole head helmet surface, with an inter-channel spacing of about 3.2 cm, and 12 are arranged in orthogonal triplets and can be used for the software rejection of background noise. Before and after each stimulation session, the position of the head with respect to the sensor was determined by localizing four coils placed on subject’s head. The locations of the coils and of three anatomical landmarks on the subject’s head were digitized by means of a 3D digitizer (Polhemus, 3Space Fastrak). Since we aimed at studying possible changes over time of somatosensory response following the conditioning train, the 6 stimuli at the thumb were collected and averaged in pairs: first pair (Post 1), second pair (Post 2) and third pair (Post 3). We used pairs of stimuli instead of single ones to get a larger number of averages and enhance the signal to noise ratio. For each of the four stimulation conditions to the thumb (Ctrl, Post 1, Post 2 and Post 3), about 60 artifact-free SEF trials were bandpassed (0.16–250 Hz) and averaged from −100 ms to +300 ms (stimulus onset at 0 time point). As the onset of N20 for all subjects was never earlier than 17 ms poststimulus, the amplitude of SEFs was calculated with respect to a baseline level chosen as the mean value of the interval 10–15 ms period following the stimulus onset. This interval was adopted in order to avoid any possible baseline distortion due to stimulus artifact. In order to convey MEG results on a high resolution anatomical image of subject’s head, magnetic resonance images (MRIs) were obtained by a Siemens Magnetom Vision 1.5 T according to an MPRAGE sequence (256 × 256, FoV 256, TR = 9.7 ms, TE = 4 ms, flip angle 12°, thickness 1 mm). MEG and MRI co-registration was obtained applying 7-mm-diameter spherical oil capsules over the three anatomical landmarks during the structural high-resolution study. Dipole source analysis The dipole source analysis was performed with the BESA– BrainVoyager software using the homogeneous sphere as head model and the equivalent current dipole (ECD) as source model.

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A source configuration with three ECDs modelled responses of contralateral SI, contralateral SII (cSII) and ipsilateral SII (iSII) fitting SEFs in the interval 18–120 ms post-stimulus. The dipoles were determined as follows: firstly, activity in SI at the peak stages of around 20 ms (N20) and 35 ms (P35) was evaluated by calculating dipole position and orientation in the intervals 18– 28 ms and 28–40 ms, respectively; next, cSII and iSII sources were determined in position and orientation by fitting the residual field during the interval 70–120 ms, while the strength of SI source was allowed to change its time evolution to provide the best goodness of fit. For all subjects, this procedure endowed with an explained data variance greater than 90% in the 18–100 ms time window. Statistical analysis For the analysis of the effect of conditioning stimulation on cortical excitability, amplitude and latency of the dipole source activity during the four thumb stimulation conditions were compared across subjects. Values were entered into two-way ANOVA using repeated measures. Mauchley’s test was applied to evaluate the sphericity assumption. The number of degrees of freedom was corrected by means of the Greenhouse–Geisser. For both intensities and latencies of cortical response, within-subject factors were Source (SI, cSII and iSII) and Condition (Ctrl, Post 1, Post 2 and Post 3). A post-hoc analysis using the Duncan test was used for multiple comparisons. The level of statistical significance was set at 5% (P < 0.05). Results The conditioning median nerve stimulation did not cause either significant change in axonal excitability or modifications of the stimulus characteristics, since latency and amplitude of the recorded SNAPs did not differ at any recording time during thumb stimulations. Fig. 2 shows typical SNAPs elicited by the thumb stimulation before (Ctrl) and after (Post 1, Post 2 and Post 3) the conditioning session in a sample subject. No specific behavioural test was carried out, but all subjects reported no significant change in the stimulation perception. Averaged SEFs displayed the classic response waves elicited by the electric stimulation of the thumb. Clear dipolar magnetic fields were obtained from the channels in the hemisphere contralateral to the stimulated side at a latency of less than 50 ms and in both hemispheres at a latency around 80 to 100 ms. The locations of the ECDs fitting SEFs were determined and co-registered with individual MRI images. The ECD for the early responses was located in the posterior bank of the central sulcus corresponding to

SI, while the bilateral long-latency responses were estimated to occur in the upper bank of the Sylvian fissure, corresponding to SII. Stable ECD localizations were found in SI and bilaterally in SII cortices. The dipole positions as fitted at the N20 and P35 peak stages showed very small and not significant shifts. No significant difference in individual source localization was found among Ctrl and after-conditioning (Post 1, Post 2 and Post 3) stimulations of the thumb: statistical analysis over coordinates of corresponding sources fitted for different conditions was performed and showed not significant p-values (SI: px > 0.4, py > 0.1, pz > 0.8; SII: px > 0.2, py > 0.7, pz > 0.7). Coordinates of the mean ECD locations (± SE) are provided in Table 1. Fig. 3 shows, for a representative subject, the dipole source waveforms for SI-N20, SI-P35, cSII, and iSII, superimposing the traces for the four thumb stimulation conditions (Ctrl, Post 1, Post 2 and Post 3). It is worth noting that the sources SI-P35, cSII and iSII reveal a modulating effect on their strengths due to the conditioning stimulation, while SI-N20 source does not exhibit any change in strength and latency throughout the experiment. Mean (± SE) peak latencies and dipole strengths across subjects at the four thumb stimulation condition are shown in Table 2. Table 2 also reports the mean values of the source strengths normalized to the control level (Ctrl). The SI-N20 source does not show any significant change in source strength subsequent to the conditioning stimulation, thus it was excluded from further analysis. On the contrary, the responses from SI-P35, cSII and iSII present a strong decrease in ‘Post 1’ with respect to control condition (51% SI-P35 and cSII, 45% iSII), and then a regular improvement across ‘Post 2’ and ‘Post 3’, with cSII and iSII featuring a recovery cycle slower than SI-P35 (Fig. 4). In order to achieve reliable comparison between the different recovery times of all the sources, the slopes of the linear function, f (t) = m ⁎ t + c, fitting the data (R2 = 0.99) were estimated, resulting to the slope for the SI-P35 source (m = 0.20) greater than the one for cSII and iSII sources (m = 0.13). Statistical significance of this observation was provided by following ANOVA analysis. ANOVA analysis for repeated measures on source intensities revealed a significant main effect (p < 0.001) of both Source (SIP35, cSII, iSII) and Condition (Ctrl, Post 1, Post 2 and Post 3), with a significant interaction term (p < 0.001). Post-hoc test on SIP35 showed a fast and progressive recovery of the cortical excitability: a significant amplitude reduction with respect to the Ctrl condition was observed in ‘Post 1’ (p < 0.001) and lasts in ‘Post 2’ (p < 0.01), while in ‘Post 3’ the source strength is no longer significantly smaller than the baseline value. In contrast, the amplitude reduction of SII sources due to the repetitive stimulation was strongly significant in ‘Post 1’ and ‘Post 2’ and still observed in ‘Post 3’ (p < 0.001) (Table 3). As far as latencies are concerned, no significant modifications were found as an effect of the conditioning stimulation. Discussion

Fig. 2. SNAPs for a representative subject recorded during the electrical thumb stimulation before (Ctrl) and after (Post 1, Post 2, Post 3) the conditioning train to the median nerve. Note that SNAPs showed no significant changes in latency, shape and amplitude throughout the experiment.

Conditioning transcutaneous electrical nerve stimulation has been widely used to investigate the after-effects occurring within the central nervous system and cortex in humans in response to an intensive external stimulation. In the eighties, the long-lasting hypoesthesia following prolonged electrical stimulation has been exclusively attributed to post-stimulus axonal hypo-excitability (Ng et al., 1987; Applegate and Burke, 1989; Lundstrom, 1986).

K. Torquati et al. / NeuroImage 35 (2007) 1578–1585 Table 1 Mean fitted source locations in Talairach coordinates (mean ± SE)

Contralateral SI-N20 Contralateral SI-P35 Contralateral SII Ipsilateral SII

x (mm)

y (mm)

z (mm)

− 50 ± 3 − 45 ± 3 − 49 ± 2 50 ± 3

− 24 ± 3 − 22 ± 3 − 19 ± 2 − 17 ± 2

44 ± 3 46 ± 3 18 ± 3 20 ± 3

The only exception was an animal study supporting an alternative explanation: the responsiveness of cuneate neurons (i.e., secondorder cutaneous afferents) to mechanical stimulation of cat footpad underwent a pronounced and prolonged depression that could not be accounted for by changes in responsiveness of the primary afferents (O'Mara et al., 1988). Later, Macefield and Burke (1991) have reported that prolonged high-frequency stimulation produced a long-lasting reduction in amplitude of the primary cortical potential that was independent of peripheral changes. In the present study, a non-painful 7 Hz conditioning electrical stimulation at the median nerve significantly and transiently attenuated the subsequent cortical responses at SI and SII, as revealed by the dipole source strength estimated from surface SEFs. A number of reasons suggested the choice of the rate and the intensity of the conditioning stimulation, in order to avoid post train changes in nerve excitability. Firstly, a 7 Hz rate may not cause a failure of impulse conduction in the distal axon, at branch points, at the neuromuscular junction or along the muscle fiber. Secondly, it would prevent the decrease in nerve excitability due to the phenomenon termed H1 by Bergmans (1970) and attributable to slow K+ conductance, as for human nerves the recovery cycle following a single impulse or brief trains is complete in 100– 150 ms (Bergmans, 1970; Taylor et al., 1992). Finally, the intensity of repetitive stimulation was below resting motor threshold in order to avoid evoking muscle twitches that could modify central processing through changed afferent input. Moreover, a submaximal stimulation was adopted, since an 8 Hz supra-maximal stimulation for 10 min was recently found producing a prolonged depression in the excitability of both cutaneous afferents and motor axons, with gradual recovery to control levels over 15–20 min (Kiernan et al., 2004). Actually, in the present study, no significant difference in the nerve fibers synchronous firing triggered by the stimulus (i.e. SNAPs) was found throughout the experiment. Thus, the observed reduction of post-train cortical response should not be peripheral in origin as it was not due to a reduced amount of sensory inputs flowing towards the central nervous system.

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Mauguiere et al., 1999; Legatt and Kader, 2000; Balzamo et al., 2004). The N20 component is believed to represent the activation of pyramidal cells in layer 4, the input layer of the cortex that receives direct thalamo-cortical projections (Desmedt and Cheron, 1980; Rossini et al., 1987; Allison et al., 1991). Conversely, the P35 component should reflect the depolarization of the superficial portion of apical dendrites located in cortical layers 2/3 (Rossini et al., 1987; Vaughan and Arezzo, 1988; Allison et al., 1991; Nicholson Peterson et al., 1995). Therefore, given the serial nature of information transmission from layer 4 to layer 2/3, both SI-N20 and SI-P35 source amplitudes would have been similarly affected by possible changes in thalamo-cortical activity. Our results showing no changes for SI-N20 source imply that thalamo-cortical pathways mediating this ‘early’ response do not account for the cortical excitability changes demonstrated after prolonged conditioning stimulation of median nerve. Hence, although a contribution of sub-cortical circuitry to the suppression of the sensory cortex activity cannot be completely excluded, the post-conditioning effect is presumed to take mainly place at a cortical level. Although in the present study no significant difference was found between SI-N20 and SI-P35 locations, possibly due to the limited number of examined subjects, other MEG studies investigating a larger number of hemispheres provided evidence that the source localization of the SEF component peaking around 30–35 ms (M30) is compatible with a more anterior and medial source with respect to SI-N20, possibly corresponding to the anterior wall of the central sulcus, with a consistent contribution of the primary motor area (Kawamura et al., 1996; Huang et al., 2000; Tecchio et al., 1997; Zappasodi et al., 2006). This is supported

Cortical origin of train-induced excitability changes A reduction of the excitability of the thalamo-cortical projection could be responsible for the amplitude reduction (‘gating’) of somatosensory cortical responses evoked by thumb stimulations after conditioning stimuli of median nerve of the same side. If this were the case, a given input would discharge fewer pyramidal cells because they would be further away from their threshold level. Nevertheless, the observed different effect on SI-N20 and SI-P35 source strengths has to be taken into account. Both the N20 and the P35 components are now widely accepted to be mainly generated in the posterior bank of the central sulcus, corresponding to Brodmann area 3b, although some evidence would suggest a minor contribution of motor cortex to the production of P35 (Allison et al., 1991, 1996; Kristeva-Feige et al., 1995; Urbano et al., 1997;

Fig. 3. Example traces from one subject. Source waveforms obtained before (Ctrl) and after (Post 1, Post 2, Post 3) intervention with the conditioning stimulation are shown for SI-N20, SI-P35, cSII and iSII. A clear modulation is appreciable for the last three sources, but not for SI-N20.

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Table 2 Mean source values Peak latency (ms)

Ctrl Post 1 Post 2 Post 3

Dipole strength (nA m)

Normalized dipole strength (%)

SI-N20

SI-P35

cSII

iSII

SI-N20

SI-P35

cSII

iSII

SI-N20

SI-P35

cSII

iSII

22 ± 2 22 ± 2 22 ± 2 22 ± 2

38 ± 2 38 ± 2 39 ± 2 38 ± 2

77 ± 7 78 ± 6 78 ± 6 77 ± 6

89 ± 3 90 ± 3 90 ± 4 88 ± 3

22 ± 3 22 ± 3 22 ± 3 21 ± 3

29 ± 2 13 ± 2 19 ± 2 25 ± 2

115 ± 9 57 ± 8 73 ± 9 87 ± 9

81 ± 9 44 ± 7 53 ± 8 64 ± 8

100 102 ± 3 101 ± 9 98 ± 7

100 49 ± 7 68 ± 7 89 ± 7

100 49 ± 5 60 ± 6 74 ± 5

100 54 ± 4 66 ± 6 81 ± 6

Mean peak latencies and mean strength (±SE) of the source responses across all subjects at the four thumb stimulation conditions. Normalized dipole strengths are also reported.

by sensory gating MEG studies in healthy humans showing a selective suppression of the M30 strength during voluntary movement execution, due to either centrifugal (due to interfering influences of motor cortex) or centripetal (due to sensory inputs associated to the movement) gating mechanisms or both (Rossi et al., 2002; Tecchio et al., 2006). Such competing mechanisms were assumed also to be responsible for the delayed gating effect observed on the pre-central cortical SEP amplitudes persisting beyond the cessation of a repetitive movement (Murphy et al., 2003). In this perspective, our findings could point to a delayed gating cortical effect arguing in favour of a centripetal mechanism. Several studies have focused on the interaction of sensory inputs and the observed occlusive effect was thought to be greatest when the two inputs converged simultaneously onto the target neurons. However, Burke et al. (1982) have found that the sural SEP was most suppressed when the volleys were timed so that a tibial conditioning input reached the cerebral cortex a few milliseconds earlier. Moreover, Yamada et al. (1992) have explored the recovery function of tibial nerve SEPs conditioned by preceding peroneal nerve stimulation. The results have been interpreted as due to a general suppression of all peaks of SEPs for inter-stimulus intervals greater than 2 ms. They suggested that inhibitory synapses activated by peroneal nerve stimulation could convey inputs to the majority of synapses that mediate the tibial SEP. In the present experiment, as the thumb stimulation involved the sensory components of the median nerve, conditioning and test inputs strongly interacted, affecting the same synaptic connections. It is to be expected that the somatosensory cortex synchronization, as induced by intensive repetitive median nerve stimulation, may produce a reverberation interfering with succeeding responses to thumb stimulation. As the excitability of the sensory cortex is a function of cells excitability, synaptic strength and balance between excitatory cells and inhibitory cells, some speculations about the neurophysiological mechanisms responsible for the observed effect can be put forward.

A transient decrease in the efficacy of excitatory synapses, i.e. the long-term depression (LTD), could be responsible for the observed inhibition. In this case, synapses would be made less efficient by the conditioning train so that the synaptic excitation provoked by a given input is reduced. A study on SI cortical slices taken from rat barrel cortex has shown that LTD was induced at vertical inputs to layer 2/3 pyramidal cells, while layer 4 neurons did not express synaptic plasticity (Feldman, 2000). Thus, our finding of different modulation on SI-N20 and SI-P35 source strengths provides support for the LTD hypothesis. Moreover, this supposition would be consistent with previous finding from rTMS studies: LTD has been often considered responsible for the suppression of excitability induced by rTMS (Chen et al., 1997), which was observed from milliseconds (Berardelli et al., 1998) to minutes (Pascual-Leone et al., 1994) depending on stimulus intensity, inter-train interval and duration of the rTMS. Although low- and high-frequency rTMS were found to have opposite effects on motor cortical excitability, they were both found to produce interference with the normal sensory function. Oliviero et al. (2005) have described that highfrequency rTMS of the sensorimotor cortex caused a significant increase in the temperature perception thresholds (cold and warm sensation) lasting a few minutes after the end of the stimulation. Similarly, Satow et al. (2003) have reported increased tactile threshold for a short time after low-frequency rTMS over the sensorimotor cortex. The suggested account was that a perfect balance between excitation and inhibition is needed within the sensory cortex to have a normal function and, whatever a significant change of this balance, the function can only worsen. Since the response from cortical neurons is determined by the activation of both intracortical inhibitory and excitatory circuits by the peripheral stimulation, an alternative or concurrent effect would be the change of intrinsic neuronal excitability, specifically an alteration on the relative balance between inhibitory and facilitatory intracortical systems. Different effects on primary and secondary somatosensory cortex The profiles of dipole strength in the period immediately after the conditioning stimulation (Fig. 4) provide an estimate of the recovery time of normal cortical excitability. The different Table 3 Results of post-hoc analysis: significant p-values

Fig. 4. Mean source intensities at control (Ctrl) and after-conditioning (Post 1, Post 2, Post 3) stimulations across subjects. Data are normalized to the control level values. Standard error bars are shown.

SI-N20 SI-P35 cSII iSII

Ctrl vs. Post 1

Ctrl vs. Post 2

Ctrl vs. Post 3

ns <0.001 <0.001 <0.001

ns 0.01 <0.001 <0.001

ns ns <0.001 0.001

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modulation observed for SI and SII strengthens the hypothesis that the cortex was the anatomical substrate where the excitability changes occurred, since a sub-cortical inhibitory mechanism would have similarly affected the responses from these cortical areas which are known to belong to a serial hierarchical network (Hari et al., 1993; Mauguiere et al., 1997; Forss et al., 1999). The different behaviours of SI and SII suggest a change in the distribution of excitability: the timing of gating effect differs, with the inhibition of the higher level cortical area lasting for a longer period. The longer sensitivity of SII to the conditioning stimulation may reflect a long-term ‘habituation’ (Tomberg et al., 1989), in accordance with previous findings of a gradual decrease of longlatency SEPs with advancing position of the stimulus in a stimulus train (Angel et al., 1985) and a longer recovery period of SII if compared to SI (Wegner et al., 2000; Inoue et al., 2002). Provided that the recovery profile may reflect some aspect of memory trace in the sensory cortex, the lifetime of somatic sensory memory in SII seems to be longer than that in SI, consistent with the different role of the two cortical areas in processing somatosensory inputs. SI, as the primary projection area, is known to process rudimentary somatosensory information, encoding type and intensity of sensory inputs and producing temporarily and spatially accurate information about the stimulus characteristics. Conversely, neurons in SII have larger receptive fields (Sinclair and Burton, 1993) and processing of the somatosensory stimulus is increasingly elaborated by the integration of information from a larger number of areas. Recently, Hamada et .al. (2002) have shown that the time constant of the recovery cycle (defined as the ratio of the cortical activity in the test condition to that in the control condition for different ISIs) is of longer duration in SII than that in SI, consistent with the need to integrate information arriving from a wider external space and probably concerning other non-physical stimulus properties; i.e. those having to do with attention – and at differing latencies. Moreover, as anticipated, it is widely accepted that SII is devoted to serve a higher level of cognitive function in somatosensory information processing, such as attention (Mima et al., 1998; Burton et al., 1999), learning (Diamond et al., 2002), memory (Ridley and Ettlinger, 1976; Diamond et al., 2002), sensorimotor integration and emotional coding of nociceptive and non-nociceptive sensory inputs. Performing these higher-order functions requires the integration of considerably more information than that required to simply detect a sensory stimulus. It seems plausible that SII would require a longer lifetime of sensory memory to overlook a prolonged afferent barrage to the central nervous system which may involve attentional, emotional and learning aspects. Conclusion This study indicates that a sustained period of non-painful peripheral electrical stimulation temporarily and reversibly decreases the amplitude of cortical responses of somatosensory pathways, most likely by producing a sustained gating effect in the cortex. Such a delayed ‘gating’ lasted more in SII than in SI, as a possible reflection of the integrative role of the former. At this stage of research, we are unable to offer a conclusive physiological interpretation of the mechanisms underlying the modulation effect over cortical excitability. In the future, it would be important to complement results from MEG experiments with other physiological (i.e. transcranial magnetic stimulation following the pioneering studies of Mariorenzi et al., 1991; Kasai et al., 1992; Stefan et al., 2000; Enomoto et al., 2001; Di Lazzaro et al., 2002) and behavioural

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