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Reduction in amplitude of the subcortical low- and high-frequency somatosensory evoked potentials during voluntary movement: an intracerebral recording study
Clinical Neurophysiology 115 (2004) 104–111 www.elsevier.com/locate/clinph
Reduction in amplitude of the subcortical low- and high-frequency somatosensory evoked potentials during voluntary movement: an intracerebral recording study Angelo Insolaa, Domenica Le Perab,c, Domenico Restucciab, Paolo Mazzoned, Massimiliano Valerianib,e,* a
Neurofisiopatologia, CTO, Rome, Italy Istituto di Neurologia, Universita` Cattolica del Sacro Cuore, L.go A. Gemelli 8, 00168 Rome, Italy c Casa di Cura San Raffaele Pisana, Rome, Italy d Unita` Operativa di Neurochirurgia funzionale e stereotassica, CTO, Rome, Italy e Divisione di Neurologia, Ospedale Pediatrico Bambino Gesu`, IRCCS, Rome, Italy
b
Accepted 5 August 2003
Abstract Objective: To investigate whether the reduction of amplitude of the scalp somatosensory evoked potentials (SEPs) during movement (gating) is due to an attenuation of the afferent volley at subcortical level. Methods: Median nerve SEPs were recorded from 9 patients suffering from Parkinson’s disease, who underwent implant of intracerebral (IC) electrodes in the subthalamic nucleus or in the globus pallidum. SEPs were recorded from Erb’s point ipsilateral to stimulation, from the scalp surface and from the IC leads, at rest and during a voluntary flexo-extension movement of the stimulated wrist. The recorded IC traces were submitted to an off-line filtering by a 300– 1500 bandpass to obtain the high-frequency SEP bursts. Results: IC leads recorded a triphasic component (P1– N1 – P2) from 14 to 22 ms of latency. The amplitudes of the scalp N20, P20 and N30 potentials and of the IC triphasic component were significantly decreased during movement, while the peripheral N9 amplitude remained unchanged. Also the IC bursts, whose frequency was around 1000 Hz, were reduced in amplitude by the voluntary movement. Conclusions: Since the IC triphasic component is probably generated by neurons of the thalamic ventro-postero-lateral nucleus, which receive the somatosensory afferent volley, the P1– N1 amplitude reduction during movement suggests that the gating phenomenon involves also the subcortical structures. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Gating; Somatosensory evoked potential; Thalamus; Deep brain stimulation
1. Introduction The phenomenon of amplitude reduction of the somatosensory evoked potentials (SEPs) during voluntary movement is commonly known as “gating”. Its physiologic meaning is to prevent irrelevant afferent inputs during movement from reaching consciousness. A number of studies in humans have dealt with this topic, and they agree in showing that the gating effect takes place at cortical level, while the subcortical SEP components remain unchanged * Corresponding author. Tel.: þ39-06-3015-4435; fax: þ 39-06-35501909. E-mail address: [email protected] (M. Valeriani).
during movement (Jones, 1981; Cheron and Borenstein, 1987, 1991; Cohen and Starr, 1987; Jones et al., 1989; Reisin et al., 1989; Rossini et al., 1990; Tinazzi et al., 1997; Touge et al., 1997; Valeriani et al., 1998, 1999, 2001a). However, this result does not correspond to what had been found in early experimental studies in animals, which demonstrated a movement-related inhibition of the sensory afferent transmission also in subcortical structures, such as the cuneate nucleus (Ghez and Pisa, 1972), the medial lemniscus (Coulter, 1974) or the thalamus (Shimazu et al., 1965; Tsumoto et al., 1975; Yngling and Skinner, 1977; Chapman et al., 1988). Since the SEP components generated in the subcortical regions are recorded as low-amplitude farfields from the scalp surface, changes of their amplitudes
1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2003.08.003
A. Insola et al. / Clinical Neurophysiology 115 (2004) 104–111
induced by movement may be underestimated. This technical issue can explain the discrepancy between the results obtained from humans, in which surface recording electrodes were used, and from animals, in which SEPs were recorded by intracerebral (IC) leads. The stimulation of the subthalamic nucleus (STN) and of the globus pallidum pars interna (GPi) represent recently introduced techniques for the treatment of Parkinson’s disease (PD) motor symptoms, which are resistant to pharmacological treatment (Benabid et al., 1991; 1996; Limousin-Dowsey et al., 1999; Koller et al., 1999). In these techniques, a stimulating electrode is inserted by a stereotaxic procedure in the STN or in the GPi, and highfrequency stimuli are adjusted at appropriate frequency – intensity levels, in order to reduce the PD motor symptoms without major side effects. During the days immediately following the implant, the stimulator is kept switched off but the IC lead is still accessible, so that the 4 contacts can be connected to the neurophysiological equipment and used as IC recording sites. As far as now, postsynaptic responses have been recorded by using IC leads placed within or near the thalamus (Celesia, 1979; Hashimoto, 1984; Suzuki and Mayanagi, 1984; Tsuji et al., 1984; Albe-Fessard et al., 1986; Katayama and Tsubokawa, 1987; Morioka et al., 1989; Insola et al., 1999; Pinter, 1999). Recent subcortical recordings showed that these slow components are superimposed by a burst of high-frequency (about 1000 Hz) lowamplitude wavelets, lasting from 14 up to 22 ms after the stimulus (Klostermann et al., 1999). High-frequency subcortical SEPs have been suggested to reflect locally restricted near-field activity, coming from the somatosensory relay thalamic nucleus (Klostermann et al., 2002a). Our study aimed at investigating the effect of voluntary movement on both the low- and high-frequency subcortical SEPs, which were recorded by IC electrodes implanted within the STN or within the GPi, in 9 patients suffering from PD.
2. Materials and methods 2.1. Patients We recorded SEPs to median nerve stimulation in 9 patients (7 men, 2 women, mean age: 56 ^ 8 years) suffering from PD, whose motor symptoms (tremor, dystonia, rigidity) were not controlled by the pharmacological treatment and presented with serious dyskinesias. All patients gave their informed consent to take part in the study. IC electrodes were placed in the right and left STN in 5 and 1 patients, respectively; in 3 patients the STN nucleus was implanted bilaterally. Besides the lead implant within the STN, the right GPi was also implanted in two patients, while in other two patients a further IC lead was placed within their left GPi; finally, in one patient the GPi was implanted bilaterally. The simultaneous lead implant in both
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STN and GPi was performed in some patients, in order to achieve a better control of the PD symptoms with a higher reduction of drug consumption (Mazzone et al., in press). In all patients, attempts of therapeutic stimulation began 6 days after the implant. 2.2. Surgical procedure The patients underwent a non-telemetric stereotaxic ventriculography, in prone position under general anaesthesia, using the Stereotaxic “3P Maranello” System or the Leksell helmet, and the setting of the target coordinates was made using 2D and 3D “3P Maranello” software (Mazzone, 2001). The surgical procedure was performed in separate instances using a surgical act to reposition the stereotaxic helmet. In order to select the best target for the deep brain stimulation (DBS), extracellular electrophysiological recordings were performed during the operation, under local analgesia, using semi-microelectrodes (FHC, USA). An analysis of the neuromediators’ variations was also possible thanks to a fixed system of dialytic observations, contemporaneous to the neurophysiological recordings (Metalant AB, Sweden—80/13 total probes inserted). DBS multipolar electrodes were implanted: 3387 for GPi and 3389 for STN, Medtronic, Minneapolis, USA. Upon completing the procedure, an X-ray of the cranium in stereotaxic conditions in antero-posterior and latero-lateral was made to verify any discrepancy between the targeted coordinates and the ones actually carried out (recalculation system software 3P Maranello CLS SRL Forli’ Italy). DBS was performed by different types of bipolar or monopolar configurations of leads, and different frequency/intensity combinations were tried out, in order to achieve the best therapeutic effect. Following this analysis, an MRI and/or CT scan check up was performed on the position of the electrodes (Fig. 1) and then, under general anaesthesia, a Soletra double generator or a Kinetra (Medtronic Neurological Division, Minneapolis, USA) was implanted, delivering bipolar stimulation with 1.5 –2.5 V, 60 – 90 ms P.W. and 180 –185 Hz in frequency for the STN and with 2 –3 V, 210 ms P.W. and 185 Hz in frequency for the GPi. Each patient was evaluated acutely and remotely and they currently have a follow-up on an average every 28 months. The clinical outcome was excellent in all patients (Table 1). In particular, when the stimulator was switched on, the motor impairment, evaluated by the Unified Parkinson’s Disease Rating Scale III (UPDRS III), was less (mean value 18.5) than the one obtained by the strongest pharmacological treatment before the implantation (mean value 19.25). Moreover, the implanted patients did not have any dyskinesia due to L -3,4-dihydroxyphenylalanine (L -DOPA). Indeed, although the mean UPDRS III score of our patients was quite low, the severe side effects of the L -DOPA assumption represented the main indication for the DBS.
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Fig. 1. Sagittal MRI pictures showing IC leads implanted in STN (above) and in GPi (below).
2.3. SEP recording technique SEPs were recorded in awake patients no sooner than 5 days after surgery. For SEP recording, the patients lay on a couch in a warm and semidarkened room. The median nerve contralateral to the IC recording electrode was stimulated; stimuli (0.2 ms duration) were delivered by skin electrodes at the wrist, and had an intensity slightly above the motor threshold. The stimulation rate was 1.5 Hz. In all our patients, SEPs were recorded in two different conditions: (i) at rest and (ii) during a voluntary flexion– extension movement of the stimulated wrist (gating condition). Three Table 1 UPDRS III scores Patients
1 2 3 4 5 6 7 8 9
Before surgery (L -DOPA)
After surgery (DBS)
patients were given soluble L -DOPA (125 mg) 20 min before the whole SEP recording, in order to enable them to perform the movement. SEP modifications observed during movements in patients who received L -DOPA did not differ from those in patients who did not need L -DOPA assumption, therefore the two groups will be considered together. Previous studies suggested that the amplitude of the N30 potential can be increased after acute apomorphine (Rossini et al., 1993) or L -DOPA intake (Ulivelli et al., 1999). However, in our 3 patients L -DOPA was given before SEP recording both at rest and during voluntary movement, thus preventing us any comparison between SEP amplitudes before and after L -DOPA administration. In the gating condition, the absence of any modification in amplitude of the peripheral N9 potential, recorded at Erb’s point ipsilateral to the stimulation, ensured that the stimulating electrode contact was not affected by the hand movement. Disk recording electrodes (impedance below 5 kV) were placed at 4 locations: (i) Erb’s point ipsilateral to the stimulated side (Erbi), referred to contralateral Erb’s point (Erbc); (ii) the contralateral parietal position (P3/P4); (iii) the contralateral central position (C3/C4); and (iv) the Fz position. In all patients, SEPs were recorded also from the 4 contacts of the IC leads. The scalp surface electrodes and the IC leads were referred to an electrode placed on the auricular lobe ipsilateral to the stimulation. The ground electrode was at the stimulated arm. The analysis time was 50 ms, with a sampling rate of 10,000 Hz. The amplifier bandpass was 3 –3000 Hz (12 dB roll-off). Two averages of 1000 trials each were obtained for each condition and printed out. 2.4. Subcortical high-frequency SEPs To selectively study the high-frequency responses, a further digital filtering was performed using a bandpass of 300– 1500 Hz (12 dB roll-off). In both rest and gating conditions, the high-frequency bursts were evaluated at the same IC electrode contact where the low-frequency SEPs recorded at rest had shown the highest amplitude. We measured: (i) the onset latency of the burst, (ii) the root mean square amplitude calculated across all the wavelets, and (iii) the mean frequency of the burst. 2.5. Data analyses
Off
On
Off
On
53 75 80 48 60 80 88 73 41
18 8 12 13 9 15 38 42 8
32 31 62 51 58 70 41 63 51
27 4 39 17 7 7 30 11 8
SEP amplitudes and latencies were measured on the average of the two runs obtained for each condition. Amplitudes of the peripheral and scalp potentials were measured from the baseline. The peak-to-peak amplitude of the P1 –N1 potentials (see later) was measured on the IC traces. Latencies were compared by means of Student’s t test. When multiple comparisons were performed, we used the analysis of variance (ANOVA) and, if the statistical significance was reached, the post hoc analysis was performed by means of Student’s t test. The SEP amplitudes
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recorded during gating were normalized as the percentage of the amplitude of the relevant potential recorded at rest. After this normalization, the comparisons were performed by using the ANOVA and the Student’s t test for the post hoc analysis. In statistical analysis, P , 0:05 was considered as significant.
3. Results 3.1. Low- and high-frequency SEPs at rest In the Erbi –Erbc trace, the N9 potential, which represents the peripheral nerve volley, was identified (Figs. 2 and 3). The P14 far-field, which is originated from the medial lemniscus (Garcia-Larrea and Mauguie`re, 1988; Restuccia et al., 1995), was recorded in all scalp traces, and reached its highest amplitude in the Fz trace. The N20 and the P20 potentials, which represent the opposite counterparts of a dipolar source in the primary somatosensory area (Allison et al., 1991; Valeriani et al., 2001b), were measured in the parietal (P3/P4) and in the Fz traces, respectively. Finally, the N30 potential was picked up by the Fz electrode. In the 14– 22 ms latency range, the IC leads in both STN and GPi recorded a triphasic complex, whose amplitude in the STN recording tended to be higher than the one obtained from the GPi (Table 2). Within this complex, an early positivity (P1) at around 14 ms was followed by a negative response (N1), which showed a mean latency of about 18 ms; finally, the P2 potential peaked at around 22.5 ms (Figs. 2 and 3). Since the P1 and N1 potentials showed earlier latencies than the one of the scalp N20 response, which represents the arrival of the thalamo-cortical volley to the primary somatosensory cortex (Allison et al., 1991), only
Fig. 2. SEPs recorded from the scalp (P3 and Fz positions), the right Erb’s point (Erbi) and from an IC electrode in the left STN after right median nerve stimulation. Two averages of 1000 trials each are superimposed. Note the amplitude reduction of the N20, P20 and N30 scalp responses and of the P1 –N1 IC potentials in the gating condition.
Fig. 3. SEPs recorded from the scalp (P3, C3 and Fz positions), Erb’s point (Erbi) and from an IC electrode in the left GPi after right median nerve stimulation. Two averages of 1000 trials each are superimposed. Note the amplitude reduction of the N20, P20 and N30 scalp responses and of the P1 –N1 IC potentials in the gating condition.
these IC potentials were taken into consideration for further analysis. The subcortical high-frequency bursts were analysed only in the STN traces, since the amplitude of the ones obtained from GPi recordings was too low (Fig. 4). They lasted 13.2 –23.8 ms after the stimulus, and included 6 – 12 wavelet peaks. The mean frequency was 980 Hz. 3.2. Effect of the voluntary movement Movement did not show any significant effect on the latencies of the peripheral N9 potential (t test: P ¼ 0:39), scalp responses (t test: P . 0:05) and of the IC P1 (F ¼ 1:68, P ¼ 0:2 and F ¼ 0:04, P ¼ 0:83 for GPi and STN recordings, respectively) and N1 (F ¼ 0:25, P ¼ 0:62 and F ¼ 0:01, P ¼ 0:91 for GPi and STN recordings, respectively) potentials (Figs. 2 and 3). As shown in Fig. 5, the amplitudes of the peripheral N9 and lemniscal P14 potentials were not affected by movement (t test: P . 0:05). Instead, a significant amplitude reduction in gating condition was observed for the scalp N20, P20 and N30 responses (P , 0:01). Movement considerably reduced the amplitude of the IC P1 –N1 potentials in both GPi (F ¼ 333:05, P , 0:01) and STN (F ¼ 298:44, P , 0:01) recordings (Figs. 2 and 3). The onset latency of high-frequency bursts was not modified by movement (t test: P ¼ 0:12), as well as the burst duration and frequency remained unchanged in gating condition (t test: P ¼ 0:09 and P ¼ 0:23 for bust duration and frequency, respectively). On the contrary, the amplitude of high-frequency SEPs was significantly decreased (0:11 ^ 0:06 and 0:08 ^ 0:06 mV at rest and during the voluntary movement, respectively; t test: P ¼ 0:04) (Fig. 6).
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Table 2 SEP values N9
P14
N20
P20
N30
STN-P1a
Rest Latency (ms) Amplitude (mV)
10.2 ^ 1.4 1.8 ^ 1.1
14.2 ^ 1.6 1 ^ 0.4
19.8 ^ 2.1 1.3 ^ 0.7
20.3 ^ 2.3 0.7 ^ 0.5
27.6 ^ 2.4 1.1 ^ 0.8
14.1 ^ 1.8 2.1 ^ 0.9
18 ^ 2.1 2.6 ^ 0.7
13.9 ^ 1.9 1.5 ^ 0.7
18 ^ 1.7 0.6 ^ 0.4
Gating Latency (ms) Amplitude (mV)
10.1 ^ 1.4 1.9 ^ 1
14.5 ^ 1.9 0.9 ^ 0.2
20.1 ^ 2.2 0.9 6 0.4
20.4 ^ 2.4 0.4 6 0.4b
27.3 ^ 2.8 0.9 6 0.6c
14.1 ^ 1.8 1.4 6 0.6
17.9 ^ 2.1 1.8 6 0.4
15.4 ^ 2 0.9 6 0.5
17.5 ^ 2.3 0.5 6 0.3
a b c
STN-N1a
GPi-P1a
GPi-N1a
Amplitude values in bold are significantly reduced during gating (P , 0:01). Latencies and amplitudes were measured in the IC contact where the highest amplitude was recorded. The potential was identifiable only in 9 out of 15 stimulated median nerves. The potential was identifiable only in 11 out of 15 stimulated median nerves.
4. Discussion Our study shows that voluntary movement affects the amplitude of the low- and high-frequency SEPs recorded by IC electrodes from the STN and the GPi. This result confirms previous findings in animals, according to which the gating phenomenon occurs also at subcortical levels (Shimazu et al., 1965; Ghez and Pisa, 1972; Coulter, 1974; Tsumoto et al., 1975; Yngling and Skinner, 1977; Chapman et al., 1988), and suggests that the amplitude reduction of the cortical potentials during movement is at least partly due to an attenuation of the somatosensory afferent volley within subcortical structures. Since the gating mechanisms rely on the functionality of the whole cortico-subcortical loop involving cortical pre-central areas and subcortical structures, it should be also considered that the IC SEP reduction might be a consequence of a phenomenon occurring at cortical level. Our conclusion was reached by observing the SEP modifications induced by the voluntary movement in our PD patients. We selected this approach based on a previous study which showed that the effect of movement on SEP amplitude is similar in both PD patients and healthy subjects (Cheron et al., 1994).
lemniscal afferents (Klostermann et al., 2002a). Therefore, we can assume that the triphasic potential recorded in the STN and GPi of our patients is probably generated within the thalamus, and that its amplitude is lower in GPi than in STN recordings, since the leads implanted in the GPi are farther from the VPL than those implanted in the STN. It should also be considered that the triphasic IC potential might be generated out of the thalamus. If this were so, the P1 and N1 IC components, which show an earlier latency than the N20 potential, that is the arrival of the somatosensory inputs at the cortex, would be originated below the thalamic nuclei in the lemniscal pathway. Therefore, this possibility does not change our main finding that is the involvement of subcortical SEPs in the gating phenomenon. While several studies investigated the high-frequency SEPs recorded from the scalp electrodes (Curio, 2000; Restuccia et al., 2002a,b), only Klostermann et al. (1999, 2000a,b, 2002a) studied the high-frequency bursts at about 1000 Hz from IC electrodes implanted within the STN. The high-frequency bursts recorded from the thalamus (1000 Hz) and from the scalp surface (600 Hz) have opposite behaviours in the case of double pulse stimulation or
4.1. IC low- and high-frequency SEPs The triphasic potential recorded in our study from both STN and GPi is very similar in shape to the SEP components previously recorded from the ventro-posterolateral (VPL) or ventral intermediate (Vim) nuclei of the thalamus (Tsuji et al., 1984; Suzuki and Mayanagi, 1984; Albe-Fessard et al., 1986; Katayama and Tsubokawa, 1987; Morioka et al., 1989; Insola et al., 1999). While Morioka et al. (1989) suggested that the triphasic component may represent a compound action potential that originated from the junction between the lemniscal pathway and the thalamus, it is more generally agreed that the IC potentials recorded in thalamic nuclei from 14 to 22 ms of latency are postsynaptic events due to the VPL neuron excitation by
Fig. 4. Low- and high-frequency SEPs recorded from STN and GPi. Two averages of 1000 trials each are superimposed. Notice the very low amplitude of the high-frequency bursts in the GPi recording.
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Fig. 5. The histogram shows the amplitudes, expressed as percentage, of the SEP components recorded on surface (black bars) and from the IC leads (dashed and white bars for STN and GPi recordings, respectively), in the gating condition. The asterisks show the significant differences.
narcosis (Klostermann et al., 2000a,b). Moreover, the IC 1000 Hz bursts show a fixed latency, regardless of the depth of the electrode penetration, thus suggesting that they represent a localised non-propagating thalamic activity (Klostermann et al., 2002a). All these elements seem to suggest that the 1000 Hz SEPs cannot be directly involved in the generation of the 600 Hz bursts obtained from the scalp surface. 4.2. Gating of low- and high-frequency SEPs In our study, the low- and high-frequency thalamic SEPs are reduced in amplitude during voluntary movements. The meaning of this finding may be that the voluntary movement affects in the same way the cell populations generating both the low-frequency SEPs and the 1000 Hz bursts. However, another possibility is that the somatosensory volley may reach the thalamus after having already been attenuated. This last hypothesis is supported by experimental studies in animals, which showed that movement impairs the somatosensory transmission at the level of the dorsal column nuclei or of the medial lemniscus (Ghez and Pisa, 1972; Coulter, 1974).
Fig. 6. Low- and high-frequency SEPs recorded from STN in one patient. Two averages of 1000 trials each are superimposed. Movement causes an evident amplitude reduction of the low-frequency SEP components and the high-frequency bursts.
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The duration and frequency of the thalamic highfrequency SEPs remained unmodified during movement, suggesting that the decreased amplitude of the bursts in gating condition was due to a reduced firing of the same neuronal population, as the one activated at rest. Since the N9 amplitude is not affected by movement, the amplitude decrease of the IC potentials and of the scalp N20, P20 and N30 responses in gating condition cannot be caused by any variation of the peripheral afferent volley, due to a shift of the stimulating electrodes. We found that the amplitudes of both the scalp N20 and P20 potentials are decreased by movement. In previous literature, the N20 amplitude was found to be either reduced (Seyal et al., 1987; Reisin et al., 1989; Huttunene and Ho¨mberg, 1991; Kakigi et al., 1995; Valeriani et al., 1999; Rossini et al., 1999) or unchanged (Cheron and Borenstein, 1987, 1991; Tapia et al., 1987; Cohen and Starr, 1987; Kristeva-Feige et al., 1996; Rossini et al., 1996; Touge et al., 1997). The influence exerted by the movement’s intensity on the gating effect can explain this discrepancy: the larger and the quicker the movement, the deeper the SEP amplitude reduction. Therefore, we may think that in our study the intensity of the voluntary movement was high enough to affect the N20 and P20 amplitudes also. In our patients, the reduction of the N30 amplitude during movement was not surprising since the N30 wave is commonly considered as the main “cortical target” of the gating mechanisms (Cheron and Borenstein, 1987, 1991; Valeriani et al., 1999; Restuccia et al., 2003; Rossi et al., 2002; Abbruzzese and Berardelli, 2003). In a recent article, Klostermann et al. (2002b) showed that the thalamic SEP amplitude does not change during muscle relaxation obtained in anaesthetized patients by means of succinylcholine; conversely, under the same condition, the scalp N20 amplitude is increased. The authors suggest that the gating phenomenon occurs at cortical level since the muscular tone, which represents a weak isometric muscle contraction, has no influence on the amplitude of the thalamic SEP components. Klostermann et al. (2002b) used a bipolar montage to record the IC SEP components, while we referred the IC lead contacts to an earlobe electrode (monopolar derivation). However, this technical difference cannot explain the disagreement between our findings and that of Klostermann et al. (2002b). Indeed, in all our patients we tried also to calculate IC bipolar traces off-line, by referring the uppermost to the deepest IC electrode contact, and found the same result, that is a reduction of the IC SEP amplitude during gating. We should keep in mind that the SEP attenuation during movement is the result of two different processes. Gating is not only due to a competition between the input from the presented stimulus and the afferent proprioceptive feedback caused by movement itself (centripetal gating), but it also involves the centrifugal influence of motor centers on the synapses of the sensory pathways (centrifugal gating), as suggested by the reduction of SEPs when the stimulus precedes the onset of active movement (Cohen and Starr,
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1987). While the SEP gating due to the muscle tone is caused only by a centripetal process, in our experiment, where patients were asked to move their wrist voluntarily, both mechanisms contribute to the decrease of the SEP amplitude. Therefore, our results and those of Klostermann et al. (2000b), taken together, suggest that the centripetal gating occurs within the cerebral cortex, while the centrifugal effect of movement acts also at subcortical level. While the IC high-frequency bursts recorded in our patients were attenuated by the active movement, the 600 Hz bursts obtained from the scalp surface have been reported not to be affected by the isometric muscle contraction (Klostermann et al., 2001). This difference might depend on the different movement task. Indeed, Tanosaki et al. (2002) showed a slight amplitude decrease of the cortical 600 Hz bursts during the voluntary movement of the fingers. However, it is also possible that the different response to movement of the neurones which generate the thalamic and the cortical bursts explains the IC highfrequency SEP decrease during gating, in spite of unmodified cortical high-frequency oscillations.
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Shimazu H, Yanagisawa N, Garoutte B. Cortico-pyramidal influences of thalamic somatosensory transmission in the cat. J Physiol 1965;15: 1011. Suzuki I, Mayanagi Y. Intracranial recording of short latency somatosensory evoked potentials in man: identification of origin of each component. Electroenceph clin Neurophysiol 1984;59:286–96. Tanosaki M, Kimura T, Takino R, Iguchi Y, Suzuki A, Kurobe Y, et al. Movement interference attenuates somatosensory high-frequency oscillations: contribution of local axon collaterals of 3b pyramidal neurons. Clin Neurophysiol 2002;113:993 –1000. Tapia MC, Cohen LG, Starr A. Selectivity of attenuation (i.e., gating) of somatosensory potentials during voluntary movement in humans. Electroenceph clin Neurophysiol 1987;68:226–30. Tinazzi M, Zanette G, La Porta F, Polo A, Volpato D, Fiaschi A, et al. Selective gating of lower limb somatosensory evoked potentials (SEPs) during passive and active foot movements. Electroenceph clin Neurophysiol 1997;104:312 –21. Touge T, Takeuchi H, Sasaki I, Deguchi K, Ichihara N. Enhanced amplitude reduction of somatosensory evoked potentials by voluntary movement in the elderly. Electroenceph clin Neurophysiol 1997;104: 108– 14. Tsuji S, Shibasaki H, Kato M, Kuroiwa Y, Shima F. Subcortical, thalamic and cortical somatosensory evoked potentials to median nerve stimulation. Electroenceph clin Neurophysiol 1984;59:465–76. Tsumoto T, Nakamura S, Iwama K. Pyramidal tract control over cutaneous and kinesthetic sensory transmission in the cat thalamus. Exp Brain Res 1975;22:281–94. Ulivelli M, Rossi S, Pasqualetti P, Rossini PM, Ghiglieri O, Passero S, et al. Time course of frontal somatosensory evoked potentials. Relation to L DOPA plasma levels and motor performance in PD. Neurology 1999; 53:1451–7. Valeriani M, Restuccia D, Di Lazzaro V, Barba C, Le Pera D, Tonali P. Dissociation induced by voluntary movement between two different components of the centro-parietal P40 SEP to tibial nerve stimulation. Electroenceph clin Neurophysiol 1998;108:190–8. Valeriani M, Restuccia D, Di Lazzaro V, Le Pera D, Tonali P. Effect of movement on dipolar source activities of somatosensory evoked potentials. Muscle Nerve 1999;22:1510– 9. Valeriani M, Insola A, Restuccia D, Le Pera D, Mazzone P, Altibrandi MG, et al. Source generators of the early somatosensory evoked potentials to tibial nerve stimulation: an intracerebral and scalp recording study. Clin Neurophysiol 2001a;112:1999–2006. Valeriani M, Le Pera D, Tonali P. Characterizing somatosensory evoked potential sources with dipole models: advantages and limitations. Muscle Nerve 2001b;24:325 –39. Yngling CD, Skinner JE. Gating of thalamic input to cerebral cortex by nucleus reticularis thalami. In: Desmedt JE, editor. Attention, voluntary contraction and event-related cerebral potentials. Progress in clinical neurophysiology, vol. 1. Basel/London: S. Karger; 1977. p. 70–96.
Reduction in amplitude of the subcortical low- and high-frequency somatosensory evoked potentials during voluntary movement: an intracerebral recording study Angelo Insolaa, Domenica Le Perab,c, Domenico Restucciab, Paolo Mazzoned, Massimiliano Valerianib,e,* a
Neurofisiopatologia, CTO, Rome, Italy Istituto di Neurologia, Universita` Cattolica del Sacro Cuore, L.go A. Gemelli 8, 00168 Rome, Italy c Casa di Cura San Raffaele Pisana, Rome, Italy d Unita` Operativa di Neurochirurgia funzionale e stereotassica, CTO, Rome, Italy e Divisione di Neurologia, Ospedale Pediatrico Bambino Gesu`, IRCCS, Rome, Italy
b
Accepted 5 August 2003
Abstract Objective: To investigate whether the reduction of amplitude of the scalp somatosensory evoked potentials (SEPs) during movement (gating) is due to an attenuation of the afferent volley at subcortical level. Methods: Median nerve SEPs were recorded from 9 patients suffering from Parkinson’s disease, who underwent implant of intracerebral (IC) electrodes in the subthalamic nucleus or in the globus pallidum. SEPs were recorded from Erb’s point ipsilateral to stimulation, from the scalp surface and from the IC leads, at rest and during a voluntary flexo-extension movement of the stimulated wrist. The recorded IC traces were submitted to an off-line filtering by a 300– 1500 bandpass to obtain the high-frequency SEP bursts. Results: IC leads recorded a triphasic component (P1– N1 – P2) from 14 to 22 ms of latency. The amplitudes of the scalp N20, P20 and N30 potentials and of the IC triphasic component were significantly decreased during movement, while the peripheral N9 amplitude remained unchanged. Also the IC bursts, whose frequency was around 1000 Hz, were reduced in amplitude by the voluntary movement. Conclusions: Since the IC triphasic component is probably generated by neurons of the thalamic ventro-postero-lateral nucleus, which receive the somatosensory afferent volley, the P1– N1 amplitude reduction during movement suggests that the gating phenomenon involves also the subcortical structures. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Gating; Somatosensory evoked potential; Thalamus; Deep brain stimulation
1. Introduction The phenomenon of amplitude reduction of the somatosensory evoked potentials (SEPs) during voluntary movement is commonly known as “gating”. Its physiologic meaning is to prevent irrelevant afferent inputs during movement from reaching consciousness. A number of studies in humans have dealt with this topic, and they agree in showing that the gating effect takes place at cortical level, while the subcortical SEP components remain unchanged * Corresponding author. Tel.: þ39-06-3015-4435; fax: þ 39-06-35501909. E-mail address: [email protected] (M. Valeriani).
during movement (Jones, 1981; Cheron and Borenstein, 1987, 1991; Cohen and Starr, 1987; Jones et al., 1989; Reisin et al., 1989; Rossini et al., 1990; Tinazzi et al., 1997; Touge et al., 1997; Valeriani et al., 1998, 1999, 2001a). However, this result does not correspond to what had been found in early experimental studies in animals, which demonstrated a movement-related inhibition of the sensory afferent transmission also in subcortical structures, such as the cuneate nucleus (Ghez and Pisa, 1972), the medial lemniscus (Coulter, 1974) or the thalamus (Shimazu et al., 1965; Tsumoto et al., 1975; Yngling and Skinner, 1977; Chapman et al., 1988). Since the SEP components generated in the subcortical regions are recorded as low-amplitude farfields from the scalp surface, changes of their amplitudes
1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2003.08.003
A. Insola et al. / Clinical Neurophysiology 115 (2004) 104–111
induced by movement may be underestimated. This technical issue can explain the discrepancy between the results obtained from humans, in which surface recording electrodes were used, and from animals, in which SEPs were recorded by intracerebral (IC) leads. The stimulation of the subthalamic nucleus (STN) and of the globus pallidum pars interna (GPi) represent recently introduced techniques for the treatment of Parkinson’s disease (PD) motor symptoms, which are resistant to pharmacological treatment (Benabid et al., 1991; 1996; Limousin-Dowsey et al., 1999; Koller et al., 1999). In these techniques, a stimulating electrode is inserted by a stereotaxic procedure in the STN or in the GPi, and highfrequency stimuli are adjusted at appropriate frequency – intensity levels, in order to reduce the PD motor symptoms without major side effects. During the days immediately following the implant, the stimulator is kept switched off but the IC lead is still accessible, so that the 4 contacts can be connected to the neurophysiological equipment and used as IC recording sites. As far as now, postsynaptic responses have been recorded by using IC leads placed within or near the thalamus (Celesia, 1979; Hashimoto, 1984; Suzuki and Mayanagi, 1984; Tsuji et al., 1984; Albe-Fessard et al., 1986; Katayama and Tsubokawa, 1987; Morioka et al., 1989; Insola et al., 1999; Pinter, 1999). Recent subcortical recordings showed that these slow components are superimposed by a burst of high-frequency (about 1000 Hz) lowamplitude wavelets, lasting from 14 up to 22 ms after the stimulus (Klostermann et al., 1999). High-frequency subcortical SEPs have been suggested to reflect locally restricted near-field activity, coming from the somatosensory relay thalamic nucleus (Klostermann et al., 2002a). Our study aimed at investigating the effect of voluntary movement on both the low- and high-frequency subcortical SEPs, which were recorded by IC electrodes implanted within the STN or within the GPi, in 9 patients suffering from PD.
2. Materials and methods 2.1. Patients We recorded SEPs to median nerve stimulation in 9 patients (7 men, 2 women, mean age: 56 ^ 8 years) suffering from PD, whose motor symptoms (tremor, dystonia, rigidity) were not controlled by the pharmacological treatment and presented with serious dyskinesias. All patients gave their informed consent to take part in the study. IC electrodes were placed in the right and left STN in 5 and 1 patients, respectively; in 3 patients the STN nucleus was implanted bilaterally. Besides the lead implant within the STN, the right GPi was also implanted in two patients, while in other two patients a further IC lead was placed within their left GPi; finally, in one patient the GPi was implanted bilaterally. The simultaneous lead implant in both
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STN and GPi was performed in some patients, in order to achieve a better control of the PD symptoms with a higher reduction of drug consumption (Mazzone et al., in press). In all patients, attempts of therapeutic stimulation began 6 days after the implant. 2.2. Surgical procedure The patients underwent a non-telemetric stereotaxic ventriculography, in prone position under general anaesthesia, using the Stereotaxic “3P Maranello” System or the Leksell helmet, and the setting of the target coordinates was made using 2D and 3D “3P Maranello” software (Mazzone, 2001). The surgical procedure was performed in separate instances using a surgical act to reposition the stereotaxic helmet. In order to select the best target for the deep brain stimulation (DBS), extracellular electrophysiological recordings were performed during the operation, under local analgesia, using semi-microelectrodes (FHC, USA). An analysis of the neuromediators’ variations was also possible thanks to a fixed system of dialytic observations, contemporaneous to the neurophysiological recordings (Metalant AB, Sweden—80/13 total probes inserted). DBS multipolar electrodes were implanted: 3387 for GPi and 3389 for STN, Medtronic, Minneapolis, USA. Upon completing the procedure, an X-ray of the cranium in stereotaxic conditions in antero-posterior and latero-lateral was made to verify any discrepancy between the targeted coordinates and the ones actually carried out (recalculation system software 3P Maranello CLS SRL Forli’ Italy). DBS was performed by different types of bipolar or monopolar configurations of leads, and different frequency/intensity combinations were tried out, in order to achieve the best therapeutic effect. Following this analysis, an MRI and/or CT scan check up was performed on the position of the electrodes (Fig. 1) and then, under general anaesthesia, a Soletra double generator or a Kinetra (Medtronic Neurological Division, Minneapolis, USA) was implanted, delivering bipolar stimulation with 1.5 –2.5 V, 60 – 90 ms P.W. and 180 –185 Hz in frequency for the STN and with 2 –3 V, 210 ms P.W. and 185 Hz in frequency for the GPi. Each patient was evaluated acutely and remotely and they currently have a follow-up on an average every 28 months. The clinical outcome was excellent in all patients (Table 1). In particular, when the stimulator was switched on, the motor impairment, evaluated by the Unified Parkinson’s Disease Rating Scale III (UPDRS III), was less (mean value 18.5) than the one obtained by the strongest pharmacological treatment before the implantation (mean value 19.25). Moreover, the implanted patients did not have any dyskinesia due to L -3,4-dihydroxyphenylalanine (L -DOPA). Indeed, although the mean UPDRS III score of our patients was quite low, the severe side effects of the L -DOPA assumption represented the main indication for the DBS.
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Fig. 1. Sagittal MRI pictures showing IC leads implanted in STN (above) and in GPi (below).
2.3. SEP recording technique SEPs were recorded in awake patients no sooner than 5 days after surgery. For SEP recording, the patients lay on a couch in a warm and semidarkened room. The median nerve contralateral to the IC recording electrode was stimulated; stimuli (0.2 ms duration) were delivered by skin electrodes at the wrist, and had an intensity slightly above the motor threshold. The stimulation rate was 1.5 Hz. In all our patients, SEPs were recorded in two different conditions: (i) at rest and (ii) during a voluntary flexion– extension movement of the stimulated wrist (gating condition). Three Table 1 UPDRS III scores Patients
1 2 3 4 5 6 7 8 9
Before surgery (L -DOPA)
After surgery (DBS)
patients were given soluble L -DOPA (125 mg) 20 min before the whole SEP recording, in order to enable them to perform the movement. SEP modifications observed during movements in patients who received L -DOPA did not differ from those in patients who did not need L -DOPA assumption, therefore the two groups will be considered together. Previous studies suggested that the amplitude of the N30 potential can be increased after acute apomorphine (Rossini et al., 1993) or L -DOPA intake (Ulivelli et al., 1999). However, in our 3 patients L -DOPA was given before SEP recording both at rest and during voluntary movement, thus preventing us any comparison between SEP amplitudes before and after L -DOPA administration. In the gating condition, the absence of any modification in amplitude of the peripheral N9 potential, recorded at Erb’s point ipsilateral to the stimulation, ensured that the stimulating electrode contact was not affected by the hand movement. Disk recording electrodes (impedance below 5 kV) were placed at 4 locations: (i) Erb’s point ipsilateral to the stimulated side (Erbi), referred to contralateral Erb’s point (Erbc); (ii) the contralateral parietal position (P3/P4); (iii) the contralateral central position (C3/C4); and (iv) the Fz position. In all patients, SEPs were recorded also from the 4 contacts of the IC leads. The scalp surface electrodes and the IC leads were referred to an electrode placed on the auricular lobe ipsilateral to the stimulation. The ground electrode was at the stimulated arm. The analysis time was 50 ms, with a sampling rate of 10,000 Hz. The amplifier bandpass was 3 –3000 Hz (12 dB roll-off). Two averages of 1000 trials each were obtained for each condition and printed out. 2.4. Subcortical high-frequency SEPs To selectively study the high-frequency responses, a further digital filtering was performed using a bandpass of 300– 1500 Hz (12 dB roll-off). In both rest and gating conditions, the high-frequency bursts were evaluated at the same IC electrode contact where the low-frequency SEPs recorded at rest had shown the highest amplitude. We measured: (i) the onset latency of the burst, (ii) the root mean square amplitude calculated across all the wavelets, and (iii) the mean frequency of the burst. 2.5. Data analyses
Off
On
Off
On
53 75 80 48 60 80 88 73 41
18 8 12 13 9 15 38 42 8
32 31 62 51 58 70 41 63 51
27 4 39 17 7 7 30 11 8
SEP amplitudes and latencies were measured on the average of the two runs obtained for each condition. Amplitudes of the peripheral and scalp potentials were measured from the baseline. The peak-to-peak amplitude of the P1 –N1 potentials (see later) was measured on the IC traces. Latencies were compared by means of Student’s t test. When multiple comparisons were performed, we used the analysis of variance (ANOVA) and, if the statistical significance was reached, the post hoc analysis was performed by means of Student’s t test. The SEP amplitudes
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recorded during gating were normalized as the percentage of the amplitude of the relevant potential recorded at rest. After this normalization, the comparisons were performed by using the ANOVA and the Student’s t test for the post hoc analysis. In statistical analysis, P , 0:05 was considered as significant.
3. Results 3.1. Low- and high-frequency SEPs at rest In the Erbi –Erbc trace, the N9 potential, which represents the peripheral nerve volley, was identified (Figs. 2 and 3). The P14 far-field, which is originated from the medial lemniscus (Garcia-Larrea and Mauguie`re, 1988; Restuccia et al., 1995), was recorded in all scalp traces, and reached its highest amplitude in the Fz trace. The N20 and the P20 potentials, which represent the opposite counterparts of a dipolar source in the primary somatosensory area (Allison et al., 1991; Valeriani et al., 2001b), were measured in the parietal (P3/P4) and in the Fz traces, respectively. Finally, the N30 potential was picked up by the Fz electrode. In the 14– 22 ms latency range, the IC leads in both STN and GPi recorded a triphasic complex, whose amplitude in the STN recording tended to be higher than the one obtained from the GPi (Table 2). Within this complex, an early positivity (P1) at around 14 ms was followed by a negative response (N1), which showed a mean latency of about 18 ms; finally, the P2 potential peaked at around 22.5 ms (Figs. 2 and 3). Since the P1 and N1 potentials showed earlier latencies than the one of the scalp N20 response, which represents the arrival of the thalamo-cortical volley to the primary somatosensory cortex (Allison et al., 1991), only
Fig. 2. SEPs recorded from the scalp (P3 and Fz positions), the right Erb’s point (Erbi) and from an IC electrode in the left STN after right median nerve stimulation. Two averages of 1000 trials each are superimposed. Note the amplitude reduction of the N20, P20 and N30 scalp responses and of the P1 –N1 IC potentials in the gating condition.
Fig. 3. SEPs recorded from the scalp (P3, C3 and Fz positions), Erb’s point (Erbi) and from an IC electrode in the left GPi after right median nerve stimulation. Two averages of 1000 trials each are superimposed. Note the amplitude reduction of the N20, P20 and N30 scalp responses and of the P1 –N1 IC potentials in the gating condition.
these IC potentials were taken into consideration for further analysis. The subcortical high-frequency bursts were analysed only in the STN traces, since the amplitude of the ones obtained from GPi recordings was too low (Fig. 4). They lasted 13.2 –23.8 ms after the stimulus, and included 6 – 12 wavelet peaks. The mean frequency was 980 Hz. 3.2. Effect of the voluntary movement Movement did not show any significant effect on the latencies of the peripheral N9 potential (t test: P ¼ 0:39), scalp responses (t test: P . 0:05) and of the IC P1 (F ¼ 1:68, P ¼ 0:2 and F ¼ 0:04, P ¼ 0:83 for GPi and STN recordings, respectively) and N1 (F ¼ 0:25, P ¼ 0:62 and F ¼ 0:01, P ¼ 0:91 for GPi and STN recordings, respectively) potentials (Figs. 2 and 3). As shown in Fig. 5, the amplitudes of the peripheral N9 and lemniscal P14 potentials were not affected by movement (t test: P . 0:05). Instead, a significant amplitude reduction in gating condition was observed for the scalp N20, P20 and N30 responses (P , 0:01). Movement considerably reduced the amplitude of the IC P1 –N1 potentials in both GPi (F ¼ 333:05, P , 0:01) and STN (F ¼ 298:44, P , 0:01) recordings (Figs. 2 and 3). The onset latency of high-frequency bursts was not modified by movement (t test: P ¼ 0:12), as well as the burst duration and frequency remained unchanged in gating condition (t test: P ¼ 0:09 and P ¼ 0:23 for bust duration and frequency, respectively). On the contrary, the amplitude of high-frequency SEPs was significantly decreased (0:11 ^ 0:06 and 0:08 ^ 0:06 mV at rest and during the voluntary movement, respectively; t test: P ¼ 0:04) (Fig. 6).
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Table 2 SEP values N9
P14
N20
P20
N30
STN-P1a
Rest Latency (ms) Amplitude (mV)
10.2 ^ 1.4 1.8 ^ 1.1
14.2 ^ 1.6 1 ^ 0.4
19.8 ^ 2.1 1.3 ^ 0.7
20.3 ^ 2.3 0.7 ^ 0.5
27.6 ^ 2.4 1.1 ^ 0.8
14.1 ^ 1.8 2.1 ^ 0.9
18 ^ 2.1 2.6 ^ 0.7
13.9 ^ 1.9 1.5 ^ 0.7
18 ^ 1.7 0.6 ^ 0.4
Gating Latency (ms) Amplitude (mV)
10.1 ^ 1.4 1.9 ^ 1
14.5 ^ 1.9 0.9 ^ 0.2
20.1 ^ 2.2 0.9 6 0.4
20.4 ^ 2.4 0.4 6 0.4b
27.3 ^ 2.8 0.9 6 0.6c
14.1 ^ 1.8 1.4 6 0.6
17.9 ^ 2.1 1.8 6 0.4
15.4 ^ 2 0.9 6 0.5
17.5 ^ 2.3 0.5 6 0.3
a b c
STN-N1a
GPi-P1a
GPi-N1a
Amplitude values in bold are significantly reduced during gating (P , 0:01). Latencies and amplitudes were measured in the IC contact where the highest amplitude was recorded. The potential was identifiable only in 9 out of 15 stimulated median nerves. The potential was identifiable only in 11 out of 15 stimulated median nerves.
4. Discussion Our study shows that voluntary movement affects the amplitude of the low- and high-frequency SEPs recorded by IC electrodes from the STN and the GPi. This result confirms previous findings in animals, according to which the gating phenomenon occurs also at subcortical levels (Shimazu et al., 1965; Ghez and Pisa, 1972; Coulter, 1974; Tsumoto et al., 1975; Yngling and Skinner, 1977; Chapman et al., 1988), and suggests that the amplitude reduction of the cortical potentials during movement is at least partly due to an attenuation of the somatosensory afferent volley within subcortical structures. Since the gating mechanisms rely on the functionality of the whole cortico-subcortical loop involving cortical pre-central areas and subcortical structures, it should be also considered that the IC SEP reduction might be a consequence of a phenomenon occurring at cortical level. Our conclusion was reached by observing the SEP modifications induced by the voluntary movement in our PD patients. We selected this approach based on a previous study which showed that the effect of movement on SEP amplitude is similar in both PD patients and healthy subjects (Cheron et al., 1994).
lemniscal afferents (Klostermann et al., 2002a). Therefore, we can assume that the triphasic potential recorded in the STN and GPi of our patients is probably generated within the thalamus, and that its amplitude is lower in GPi than in STN recordings, since the leads implanted in the GPi are farther from the VPL than those implanted in the STN. It should also be considered that the triphasic IC potential might be generated out of the thalamus. If this were so, the P1 and N1 IC components, which show an earlier latency than the N20 potential, that is the arrival of the somatosensory inputs at the cortex, would be originated below the thalamic nuclei in the lemniscal pathway. Therefore, this possibility does not change our main finding that is the involvement of subcortical SEPs in the gating phenomenon. While several studies investigated the high-frequency SEPs recorded from the scalp electrodes (Curio, 2000; Restuccia et al., 2002a,b), only Klostermann et al. (1999, 2000a,b, 2002a) studied the high-frequency bursts at about 1000 Hz from IC electrodes implanted within the STN. The high-frequency bursts recorded from the thalamus (1000 Hz) and from the scalp surface (600 Hz) have opposite behaviours in the case of double pulse stimulation or
4.1. IC low- and high-frequency SEPs The triphasic potential recorded in our study from both STN and GPi is very similar in shape to the SEP components previously recorded from the ventro-posterolateral (VPL) or ventral intermediate (Vim) nuclei of the thalamus (Tsuji et al., 1984; Suzuki and Mayanagi, 1984; Albe-Fessard et al., 1986; Katayama and Tsubokawa, 1987; Morioka et al., 1989; Insola et al., 1999). While Morioka et al. (1989) suggested that the triphasic component may represent a compound action potential that originated from the junction between the lemniscal pathway and the thalamus, it is more generally agreed that the IC potentials recorded in thalamic nuclei from 14 to 22 ms of latency are postsynaptic events due to the VPL neuron excitation by
Fig. 4. Low- and high-frequency SEPs recorded from STN and GPi. Two averages of 1000 trials each are superimposed. Notice the very low amplitude of the high-frequency bursts in the GPi recording.
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Fig. 5. The histogram shows the amplitudes, expressed as percentage, of the SEP components recorded on surface (black bars) and from the IC leads (dashed and white bars for STN and GPi recordings, respectively), in the gating condition. The asterisks show the significant differences.
narcosis (Klostermann et al., 2000a,b). Moreover, the IC 1000 Hz bursts show a fixed latency, regardless of the depth of the electrode penetration, thus suggesting that they represent a localised non-propagating thalamic activity (Klostermann et al., 2002a). All these elements seem to suggest that the 1000 Hz SEPs cannot be directly involved in the generation of the 600 Hz bursts obtained from the scalp surface. 4.2. Gating of low- and high-frequency SEPs In our study, the low- and high-frequency thalamic SEPs are reduced in amplitude during voluntary movements. The meaning of this finding may be that the voluntary movement affects in the same way the cell populations generating both the low-frequency SEPs and the 1000 Hz bursts. However, another possibility is that the somatosensory volley may reach the thalamus after having already been attenuated. This last hypothesis is supported by experimental studies in animals, which showed that movement impairs the somatosensory transmission at the level of the dorsal column nuclei or of the medial lemniscus (Ghez and Pisa, 1972; Coulter, 1974).
Fig. 6. Low- and high-frequency SEPs recorded from STN in one patient. Two averages of 1000 trials each are superimposed. Movement causes an evident amplitude reduction of the low-frequency SEP components and the high-frequency bursts.
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The duration and frequency of the thalamic highfrequency SEPs remained unmodified during movement, suggesting that the decreased amplitude of the bursts in gating condition was due to a reduced firing of the same neuronal population, as the one activated at rest. Since the N9 amplitude is not affected by movement, the amplitude decrease of the IC potentials and of the scalp N20, P20 and N30 responses in gating condition cannot be caused by any variation of the peripheral afferent volley, due to a shift of the stimulating electrodes. We found that the amplitudes of both the scalp N20 and P20 potentials are decreased by movement. In previous literature, the N20 amplitude was found to be either reduced (Seyal et al., 1987; Reisin et al., 1989; Huttunene and Ho¨mberg, 1991; Kakigi et al., 1995; Valeriani et al., 1999; Rossini et al., 1999) or unchanged (Cheron and Borenstein, 1987, 1991; Tapia et al., 1987; Cohen and Starr, 1987; Kristeva-Feige et al., 1996; Rossini et al., 1996; Touge et al., 1997). The influence exerted by the movement’s intensity on the gating effect can explain this discrepancy: the larger and the quicker the movement, the deeper the SEP amplitude reduction. Therefore, we may think that in our study the intensity of the voluntary movement was high enough to affect the N20 and P20 amplitudes also. In our patients, the reduction of the N30 amplitude during movement was not surprising since the N30 wave is commonly considered as the main “cortical target” of the gating mechanisms (Cheron and Borenstein, 1987, 1991; Valeriani et al., 1999; Restuccia et al., 2003; Rossi et al., 2002; Abbruzzese and Berardelli, 2003). In a recent article, Klostermann et al. (2002b) showed that the thalamic SEP amplitude does not change during muscle relaxation obtained in anaesthetized patients by means of succinylcholine; conversely, under the same condition, the scalp N20 amplitude is increased. The authors suggest that the gating phenomenon occurs at cortical level since the muscular tone, which represents a weak isometric muscle contraction, has no influence on the amplitude of the thalamic SEP components. Klostermann et al. (2002b) used a bipolar montage to record the IC SEP components, while we referred the IC lead contacts to an earlobe electrode (monopolar derivation). However, this technical difference cannot explain the disagreement between our findings and that of Klostermann et al. (2002b). Indeed, in all our patients we tried also to calculate IC bipolar traces off-line, by referring the uppermost to the deepest IC electrode contact, and found the same result, that is a reduction of the IC SEP amplitude during gating. We should keep in mind that the SEP attenuation during movement is the result of two different processes. Gating is not only due to a competition between the input from the presented stimulus and the afferent proprioceptive feedback caused by movement itself (centripetal gating), but it also involves the centrifugal influence of motor centers on the synapses of the sensory pathways (centrifugal gating), as suggested by the reduction of SEPs when the stimulus precedes the onset of active movement (Cohen and Starr,
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1987). While the SEP gating due to the muscle tone is caused only by a centripetal process, in our experiment, where patients were asked to move their wrist voluntarily, both mechanisms contribute to the decrease of the SEP amplitude. Therefore, our results and those of Klostermann et al. (2000b), taken together, suggest that the centripetal gating occurs within the cerebral cortex, while the centrifugal effect of movement acts also at subcortical level. While the IC high-frequency bursts recorded in our patients were attenuated by the active movement, the 600 Hz bursts obtained from the scalp surface have been reported not to be affected by the isometric muscle contraction (Klostermann et al., 2001). This difference might depend on the different movement task. Indeed, Tanosaki et al. (2002) showed a slight amplitude decrease of the cortical 600 Hz bursts during the voluntary movement of the fingers. However, it is also possible that the different response to movement of the neurones which generate the thalamic and the cortical bursts explains the IC highfrequency SEP decrease during gating, in spite of unmodified cortical high-frequency oscillations.
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