Brain Stimulation 7 (2014) 836e840
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Effect of Transcranial Static Magnetic Field Stimulation Over the Sensorimotor Cortex on Somatosensory Evoked Potentials in Humans Hikari Kirimoto a, *, Hiroyuki Tamaki a, Takuya Matsumoto a, b, Kazuhiro Sugawara a, Makoto Suzuki c, Mineo Oyama a, Hideaki Onishi a a
Institute for Human Movement and Medical Sciences, Niigata University of Health and Welfare, Niigata 950-1398, Japan Graduate School of Health and Welfare, Niigata University of Health and Welfare, Niigata, Japan c Occupational Therapy Course, School of Allied Health Sciences, Kitasato University, Tokyo, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 July 2014 Received in revised form 20 September 2014 Accepted 23 September 2014 Available online 23 October 2014
Background: The motor cortex in the human brain can be modulated by the application of transcranial static magnetic field stimulation (tSMS) through the scalp. However, the effect of tSMS on the excitability of the primary somatosensory cortex (S1) in humans has never been examined. Objective: This study was performed to investigate the possibility of non-invasive modulation of S1 excitability by the application of tSMS in healthy humans. Methods: tSMS and sham stimulation over the sensorimotor cortex were applied to 10 subjects for periods of 10 and 15 min. Somatosensory evoked potentials (SEPs) following right median nerve stimulation were recorded before and immediately after, 5 min after, and 10 min after tSMS from sites C30 and F3 of the international 10-20 system of electrode placement. In another session, SEPs were recorded from 6 of the 10 subjects every 3 min during 15 min of tSMS. Results: Amplitudes of the N20 component of SEPs at C30 significantly decreased immediately after 10 and 15 min of tSMS by up to 20%, returning to baseline by 10 min after intervention. tSMS applied while recording SEPs every 3 min and sham stimulation had no effect on SEP. Conclusions: tSMS is able to modulate cortical somatosensory processing in humans, and thus might be a useful tool for inducing plasticity in cortical somatosensory processing. Lack of change in the amplitude of SEPs with tSMS implies that use of peripheral nerve stimulation to cause SEPs antagonizes alteration of the function of membrane ion channels during exposure to static magnetic fields. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Transcranial static magnetic field stimulation Somatosensory evoked potentials Non-invasive brain stimulation
Introduction Non-invasive brain stimulation, such as repetitive transcranial magnetic stimulation (rTMS) [1], theta-burst stimulation (TBS) [2], repeated trains of four monophasic TMS pulses (quadripulse
Abbreviations: MEP, motor evoked potential; NdFeB, neodymium, iron, and boron; QPS, quadripulse stimulation; rTMS, repetitive transcranial magnetic stimulation; S1, primary somatosensory cortex; SEP, somatosensory evoked potential; SMF, static magnetic field; TBS, theta-burst stimulation; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation; tSMS, transcranial static magnetic field stimulation. This work was supported in part by a Grant-in-Aid for Scientific Research (C) No. 25350631 from the Japan Society for the Promotion of Science and by a Grantin-Aid for Developed Research (B) from Niigata University of Health and Welfare. * Corresponding author. Tel./fax: þ81 25 257 4737. E-mail address: [email protected] (H. Kirimoto). http://dx.doi.org/10.1016/j.brs.2014.09.016 1935-861X/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved.
stimulation: QPS) [3], and transcranial direct current stimulation (tDCS) [4] has become an increasingly useful technique not only to examine cortical function in healthy subjects, but also to facilitate the treatment of various neurological disorders. Current research by two groups reported that the motor cortex in the human brain can be modulated by application of static magnetic fields (SMFs), unlike time-varying (electromagnetic) fields, through the scalp [5,6]. Initially, Oliviero et al. [5] reported that 10 min of transcranial static magnetic field stimulation (tSMS) using a strongly powered cylindrical neodymium, iron and boron (NdFeB) magnet can reduce the amplitude of motor evoked potentials (MEPs) for a few minutes after the magnet has been removed. In addition, they demonstrated that the polarity of the SMF is not an important factor in this neuromodulation. In line with the results of previous studies at a cellular level and in animals [7,8], they inferred that SMFs applied to the human cortex act primarily at the synapse and alter the
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Figure 1. Experimental setup. For tSMS, a cylindrical neodymium magnet (NdFeB; diameter, 50 mm; height, 30 mm), and for sham stimulation, a non-magnetic stainless steel cylinder of the same size, weight and appearance were centered over position C3 of the international 10-20 system for electrode placement, by using a movable arm type light stand. SEPs were recorded from the C30 (parietal component; 2.5 cm posterior to C3) and F3 areas (frontal component).
membrane ion channels. Different research groups postulated that tSMS reduces corticomotor excitability in association with modulation of the resting motor threshold, as with TMS [6]. This led to the suggestion that the effect of tSMS may be mediated not only by alteration of membrane ion channel function, but also by a reduction in membrane excitability, suggesting a possible role for nonsynaptic (intrinsic) plasticity mechanisms. A number of other non-invasive brain stimulation studies, such as rTMS [9e11], TBS [12,13], QPS [14,15] and tDCS [16e19], revealed that these techniques modulate the excitability of the primary somatosensory cortex (S1). However, the effect of tSMS on the excitability of S1 in humans has never been examined. The advantages of tSMS over other non-invasive brain stimulation methods include its ease of use, absence of an uncomfortable sensation for subjects, lack of the need for high operational skill and expensive devices, and conclusive sham stimulation allowing controlled experiments and randomized controlled clinical trials. Herein, we elucidate whether tSMS modification of the excitability of S1 is important to show that these features may prove tSMS to be a useful tool for modulating cortical somatosensory processing. Therefore, the aim of the present study was to investigate the possibility of non-invasive modulation of S1 excitability by the application of tSMS in healthy humans. Materials and methods Subjects Ten healthy subjects (9 males and 1 female, 21e35 years old) participated in this study. None of them were on medical treatment for any condition. Informed consent was obtained before beginning the experiment, which was conducted according to the Declaration of Helsinki. The experimental procedures were also approved by the Ethics Committee of the Niigata University of Health and Welfare. Based on the Oldfield inventory [20], the handedness scores of all subjects ranged from 0.9 to 1.0 (strongly right-handed).
weight and appearance was used for sham stimulation. The NdFeB magnet and non-magnetic steel cylinder were settled on the scalp by using a movable arm type light stand (C-stand, Avenger, Cassola, Italy). Based on the accepted method for attaching scalp electrodes (silveresilver chloride electrodes; 1.0 cm diameter) for experiments or EEG tests, the NdFeB magnet was centered over position C3 of the international 10-20 system of electrode placement, and thus stimulated both primary motor and somatosensory cortices. Somatosensory evoked potentials (SEPs) following right median nerve stimulation were recorded before and immediately after, 5 min after, and 10 min after tSMS from sites F3 and C30 (2.5 cm posterior to C3) (Fig. 1). A reference electrode was placed on the right earlobe. To study the effect of the duration of tSMS on tSMS-induced effects, we tested the effects of 10 min and 15 min of tSMS. Further, since Oliviero et al. [5] revealed that the effects of tSMS are not polarity-dependent, we selected only south polarity for each session. The duration of sham stimulation was 10 min for half the subjects and 15 min for the remaining half. The use of two investigators allowed double-blinding to be performed as follows. Investigator 1 performed the tSMS that decided whether the real magnet or sham steel cylinder would be used, and placed the appropriate device on the subject’s scalp. Investigator 2 recorded SEPs and analyzed their amplitudes. This investigator was blind to the type of intervention being performed. To avoid carryover effects, all subjects participated in three experimental sessions (10 min and 15 min of tSMS, and 10 min or 15 min of sham stimulation) on separate days that were at least three days
A B
Experimental procedure During the experiment, subjects were seated in a comfortable reclining armchair with a mounted headrest. For tSMS, a cylindrical neodymium magnet (NdFeB; diameter, 50 mm; height, 30 mm) with a maximum energy density of 44 MGOe and a nominal strength of 735 N (75 kg) was used (NeoMag, Ichikawa, Japan). A non-magnetic stainless steel cylinder of the same size,
Figure 2. Experimental procedure. tSMS was applied for periods of 10 and 15 min. The duration of sham stimulation was 10 min in half the subjects and 15 min in the remaining half. SEPs following right median nerve stimulation were recorded before and immediately after, 5 min after, and 10 min after tSMS (A). In another session, SEPs were recorded every 3 min during 15 min of tSMS, and before, immediately, 5 min and 10 min after tSMS (B).
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apart. In another session, SEPs were recorded from 6 of the 10 subjects every 3 min during 15 min of tSMS (Fig. 2). SEPs were amplified with bandpass filters set at 1e3000 Hz and 300 responses were averaged (Viking Quest, Nicolet, CA, USA). For this, brief electrical stimulation (0.2 ms) was delivered to the right median nerve at a frequency of 3.3 Hz. The stimulus intensity was fixed at about 1.2 times the motor threshold. Data and statistical analysis
Figure 3. The SEP waveforms recorded from C30 after right median nerve stimulation in a representative subject before and immediately after, 5 min after, and 15 min after tSMS over the sensorimotor cortex for periods of 10 min.
Peak-to-peak amplitudes of the four cortical SEP components (N20, P25, N35, and P45) for C30 and two components (P22 and N30) for F3 were analyzed. The amplitude of each component was measured from the preceding peaks. Amplitudes of SEPs were normalized to those recorded before tSMS. All data are expressed as mean SEM and were statistically analyzed by two-way repeated measures analysis of variance (ANOVA) using the parameters of duration of tSMS (10 min vs. 15 min vs. Sham) and time (before vs.
A
B
Figure 4. Serial changes in SEP amplitudes (N20, P25, N35, P45) from C30 (A) and (P22, N30) from F3 (B) before and immediately after, 5 min after, and 10 min after tSMS for periods of 10 and 15 min and sham stimulation. For the N20 (C30 ) component, post hoc analysis showed a significant difference between sham and 10 min of tSMS immediately after intervention, and sham and 15 min of tSMS immediately after intervention. No significant differences between 10 and 15 min of tSMS were observed. No significant effect of tSMS was observed for other SEP components at both C30 and F3. SEP amplitudes are normalized to those recorded before tDCS (mean SEM). *P < 0.05.
H. Kirimoto et al. / Brain Stimulation 7 (2014) 836e840
Figure 5. Serial changes in SEP amplitudes (N20) from C30 before and immediately after, 5 min after, and 10 min after tSMS for periods of 15 min. No significant main or interactive effects were observed on any of the SEP components when recording SEPs every 3 min (with peripheral nerve stimulation) during and after tSMS. SEP amplitudes are normalized to those recorded before tDCS (mean SEM).
immediately after vs. 10 min after vs. 15 min after tSMS), or one-way repeated measures ANOVA with time (before, during, after). Sphericity of the data was tested by the Mauchly’s test, and GreenhouseeGeisser corrected significance values were used when sphericity was lacking. Post hoc analysis was performed with Bonferroni’s correction for multiple comparisons. A difference was accepted as significant at P < 0.05 for all analyses. Results Figure 3 shows grand averaged waveforms of SEPs recorded before and immediately after, 5 min after, and 10 min after 15 min of tSMS from C30 . Amplitudes of N20 significantly decreased immediately after 10 and 15 min of tSMS, and returned to baseline by 5 min after intervention. The amplitudes of N20 (C30 ) before tSMS in each stimulus condition were comparable: sham, 3.04 0.29 mV; 10 min of tSMS, 3.23 0.2 mV; and 15 min of tSMS, 2.9 0.24 mV, respectively. For the N20 component of SEPs recorded from C30 , two-way repeated measures ANOVA revealed a significant main effect of time (F2,18 ¼ 6.571, P ¼ 0.007) and interaction between duration of tSMS and time (F2.267,20.407 ¼ 3.993, P ¼ 0.032), while no significant main effect of duration of tSMS alone was observed. The amplitude of the N20 component of SEPs was significantly reduced immediately after 10 min of tSMS (83 2.6% of baseline, P ¼ 0.004) and after 15 min of tSMS (80 5.0% of baseline, P ¼ 0.013) compared with sham tSMS. No significant differences in N20 amplitude between 10 min and 15 min of tSMS were observed (P ¼ 0.914). A decrease in N20 amplitude of SEPs was also observed at 5 min after 10 min (88 4.9% of baseline, P ¼ 0.266) and 15 min of tSMS (84 5.0%, P ¼ 0.243), returning to baseline by 10 min after 10 and 15 min of tSMS (92 3.8%, 94 5.0%, respectively), although the decrease was not significant. Other components of SEP amplitudes (P25, N35, P45) were not remarkably affected by tSMS (Fig. 4A). There were also no remarkable effects on the amplitudes of P22 and N30 components of SEPs (Fig. 4B). No significant main or interactive effects were observed on any of the SEP components when recording SEPs every 3 min (with peripheral nerve stimulation) during and after tSMS (Fig. 5). Discussion We confirmed that tSMS over the sensorimotor cortex for 10 and 15 min results in a transient decrease in the excitability of S1, as
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determined by a reduction in the amplitude of the N20 component of SEPs at C30 (parietal component). The reduction rate in S1 excitability of up to 20% is in accordance with those described in previous studies that demonstrated a reduction of motor cortex (M1) excitability, as revealed by TMS, by applying tSMS over M1 for 10 [5] or 15 min [6]. Numerous attempts have been made to demonstrate that SMFs can alter central nervous function [7,8,21e26], and that moderateintensity SMFs induce magnetic reorientation of membrane phospholipids by diamagnetic anisotropy effects in cellular and animal studies [27e30]. Of these, the characteristics of greatest interest to tSMS-induced reduction in excitability of the human cortex are that SMFs are not associated with induced electric currents during activation and deactivation or when there is movement within the field [24], and that they alter the activation threshold and velocity of voltage-gated sodium channels [7,24,25,28] and voltage-gated calcium channels [23,24,28]. Slow calcium influx and increased intracellular calcium ion stores caused by impedance of calcium channels are thought to trigger long-term depression [31,32]. Moreover, as indicated by previous studies that showed that tSMS can increase resting motor threshold, the decrease in SEP amplitude in this study may be partly mediated by a reduction in membrane excitability, suggesting a possible role for non-synaptic (intrinsic) plasticity mechanisms. When tSMS is applied in humans, since the cortex is roughly at a depth and distance of 2e3 cm from the NdFeB magnets, it is possible that the strength of the SMFs may not reach the cortex through the scalp and cranial bone. However, Rivadulla et al. [33] demonstrated that the magnetic field strength is in a range between 120 and 200 mT 2e3 cm from the magnet surface, with high reproducibility. The NdFeB magnets that they used in their study were approximately the same as that used in this study. Therefore, it is conceivable that our intervention using a NdFeB magnet (diameter 50 mm, height, 30 mm, and with a maximum energy density of 44 MGOe) produced a magnetic field that is strong enough to reach most cortical targets and to produce biological effects, such as alteration of the function of membrane ion channels [24,28]. We have no definite explanation for why no effects were observed on SEPs recorded during tSMS in our study. Somatosensory afferent information from peripheral nerves generate synaptic potentials at pyramidal cells in the sensory cortex [34]. These synaptic potentials lead to extracellular volume currents that are detected by surface electrodes as SEPs. It seems reasonable to suppose that use of peripheral nerve stimulation to cause SEPs antagonizes diamagnetic ion movements and distortion of ion channels during exposure to static magnetic fields. In addition, our previous tDCS study [35] and that of Antal et al. [36] demonstrated that the corticomotor excitability observed when anodal tDCS is applied to the motor cortex during motor tasks is lower than that observed when anodal tDCS is applied under resting conditions. Further, the inhibitory effect of rTMS at a frequency of 1 Hz is apparently abolished during active contraction of the target muscle [37]. In line with these results, peripheral nerve stimulation performed to elicit SEPs may normalize the excitability of S1 during tSMS, similar to the effect of voluntary movement on M1 excitability. Meanwhile, reduction in SEP amplitude by tSMS was observed only in the early components (N20 at C30 ) of the SEP, while the amplitude of later components of SEPs showed no remarkable changes. N20 at C30 is the earliest localized scalp potential and is believed to be produced by a tangential generator located in Brodman’s area 3b of the somatosensory cortex [38e40]. Meanwhile, there are many views on the generation of later components, such as P25 at C30 from areas 1, 2 [41] and 4 [42], and N30 at F3 from area 4 and/or 6 [2,43,44], although these have not yet been definitively identified. We cannot clearly explain why the later components of SEP amplitude showed no remarkable effect of the application of tSMS, although the magnet
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seemed to cover areas 1, 2, and 4, crossing over the central sulcus. In TMS and tDCS studies, not only S1, but also M1 are considered important targets with proven efficacy in chronic pain treatment [45e48]. Therefore, we plan to investigate the influence of the position of the NdFeB magnet on M1 and S1 in a future study. In conclusion, our results reveal that tSMS over the sensorimotor cortex transiently reduces the excitability of the somatosensory cortex. tSMS is able to modulate cortical somatosensory processing in humans, and thus might be a useful tool for inducing plasticity in cortical sensory processing. The lack of change in the amplitude of SEPs with tSMS implies that use of peripheral nerve stimulation to cause SEPs antagonizes alteration of the function of membrane ion channels during exposure to static magnetic fields. Acknowledgments
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[28]
We would like to thank Dr. Katsuya Ogata for valuable advice about analysis of SEPs.
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Effect of Transcranial Static Magnetic Field Stimulation Over the Sensorimotor Cortex on Somatosensory Evoked Potentials in Humans Hikari Kirimoto a, *, Hiroyuki Tamaki a, Takuya Matsumoto a, b, Kazuhiro Sugawara a, Makoto Suzuki c, Mineo Oyama a, Hideaki Onishi a a
Institute for Human Movement and Medical Sciences, Niigata University of Health and Welfare, Niigata 950-1398, Japan Graduate School of Health and Welfare, Niigata University of Health and Welfare, Niigata, Japan c Occupational Therapy Course, School of Allied Health Sciences, Kitasato University, Tokyo, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 July 2014 Received in revised form 20 September 2014 Accepted 23 September 2014 Available online 23 October 2014
Background: The motor cortex in the human brain can be modulated by the application of transcranial static magnetic field stimulation (tSMS) through the scalp. However, the effect of tSMS on the excitability of the primary somatosensory cortex (S1) in humans has never been examined. Objective: This study was performed to investigate the possibility of non-invasive modulation of S1 excitability by the application of tSMS in healthy humans. Methods: tSMS and sham stimulation over the sensorimotor cortex were applied to 10 subjects for periods of 10 and 15 min. Somatosensory evoked potentials (SEPs) following right median nerve stimulation were recorded before and immediately after, 5 min after, and 10 min after tSMS from sites C30 and F3 of the international 10-20 system of electrode placement. In another session, SEPs were recorded from 6 of the 10 subjects every 3 min during 15 min of tSMS. Results: Amplitudes of the N20 component of SEPs at C30 significantly decreased immediately after 10 and 15 min of tSMS by up to 20%, returning to baseline by 10 min after intervention. tSMS applied while recording SEPs every 3 min and sham stimulation had no effect on SEP. Conclusions: tSMS is able to modulate cortical somatosensory processing in humans, and thus might be a useful tool for inducing plasticity in cortical somatosensory processing. Lack of change in the amplitude of SEPs with tSMS implies that use of peripheral nerve stimulation to cause SEPs antagonizes alteration of the function of membrane ion channels during exposure to static magnetic fields. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Transcranial static magnetic field stimulation Somatosensory evoked potentials Non-invasive brain stimulation
Introduction Non-invasive brain stimulation, such as repetitive transcranial magnetic stimulation (rTMS) [1], theta-burst stimulation (TBS) [2], repeated trains of four monophasic TMS pulses (quadripulse
Abbreviations: MEP, motor evoked potential; NdFeB, neodymium, iron, and boron; QPS, quadripulse stimulation; rTMS, repetitive transcranial magnetic stimulation; S1, primary somatosensory cortex; SEP, somatosensory evoked potential; SMF, static magnetic field; TBS, theta-burst stimulation; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation; tSMS, transcranial static magnetic field stimulation. This work was supported in part by a Grant-in-Aid for Scientific Research (C) No. 25350631 from the Japan Society for the Promotion of Science and by a Grantin-Aid for Developed Research (B) from Niigata University of Health and Welfare. * Corresponding author. Tel./fax: þ81 25 257 4737. E-mail address: [email protected] (H. Kirimoto). http://dx.doi.org/10.1016/j.brs.2014.09.016 1935-861X/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved.
stimulation: QPS) [3], and transcranial direct current stimulation (tDCS) [4] has become an increasingly useful technique not only to examine cortical function in healthy subjects, but also to facilitate the treatment of various neurological disorders. Current research by two groups reported that the motor cortex in the human brain can be modulated by application of static magnetic fields (SMFs), unlike time-varying (electromagnetic) fields, through the scalp [5,6]. Initially, Oliviero et al. [5] reported that 10 min of transcranial static magnetic field stimulation (tSMS) using a strongly powered cylindrical neodymium, iron and boron (NdFeB) magnet can reduce the amplitude of motor evoked potentials (MEPs) for a few minutes after the magnet has been removed. In addition, they demonstrated that the polarity of the SMF is not an important factor in this neuromodulation. In line with the results of previous studies at a cellular level and in animals [7,8], they inferred that SMFs applied to the human cortex act primarily at the synapse and alter the
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Figure 1. Experimental setup. For tSMS, a cylindrical neodymium magnet (NdFeB; diameter, 50 mm; height, 30 mm), and for sham stimulation, a non-magnetic stainless steel cylinder of the same size, weight and appearance were centered over position C3 of the international 10-20 system for electrode placement, by using a movable arm type light stand. SEPs were recorded from the C30 (parietal component; 2.5 cm posterior to C3) and F3 areas (frontal component).
membrane ion channels. Different research groups postulated that tSMS reduces corticomotor excitability in association with modulation of the resting motor threshold, as with TMS [6]. This led to the suggestion that the effect of tSMS may be mediated not only by alteration of membrane ion channel function, but also by a reduction in membrane excitability, suggesting a possible role for nonsynaptic (intrinsic) plasticity mechanisms. A number of other non-invasive brain stimulation studies, such as rTMS [9e11], TBS [12,13], QPS [14,15] and tDCS [16e19], revealed that these techniques modulate the excitability of the primary somatosensory cortex (S1). However, the effect of tSMS on the excitability of S1 in humans has never been examined. The advantages of tSMS over other non-invasive brain stimulation methods include its ease of use, absence of an uncomfortable sensation for subjects, lack of the need for high operational skill and expensive devices, and conclusive sham stimulation allowing controlled experiments and randomized controlled clinical trials. Herein, we elucidate whether tSMS modification of the excitability of S1 is important to show that these features may prove tSMS to be a useful tool for modulating cortical somatosensory processing. Therefore, the aim of the present study was to investigate the possibility of non-invasive modulation of S1 excitability by the application of tSMS in healthy humans. Materials and methods Subjects Ten healthy subjects (9 males and 1 female, 21e35 years old) participated in this study. None of them were on medical treatment for any condition. Informed consent was obtained before beginning the experiment, which was conducted according to the Declaration of Helsinki. The experimental procedures were also approved by the Ethics Committee of the Niigata University of Health and Welfare. Based on the Oldfield inventory [20], the handedness scores of all subjects ranged from 0.9 to 1.0 (strongly right-handed).
weight and appearance was used for sham stimulation. The NdFeB magnet and non-magnetic steel cylinder were settled on the scalp by using a movable arm type light stand (C-stand, Avenger, Cassola, Italy). Based on the accepted method for attaching scalp electrodes (silveresilver chloride electrodes; 1.0 cm diameter) for experiments or EEG tests, the NdFeB magnet was centered over position C3 of the international 10-20 system of electrode placement, and thus stimulated both primary motor and somatosensory cortices. Somatosensory evoked potentials (SEPs) following right median nerve stimulation were recorded before and immediately after, 5 min after, and 10 min after tSMS from sites F3 and C30 (2.5 cm posterior to C3) (Fig. 1). A reference electrode was placed on the right earlobe. To study the effect of the duration of tSMS on tSMS-induced effects, we tested the effects of 10 min and 15 min of tSMS. Further, since Oliviero et al. [5] revealed that the effects of tSMS are not polarity-dependent, we selected only south polarity for each session. The duration of sham stimulation was 10 min for half the subjects and 15 min for the remaining half. The use of two investigators allowed double-blinding to be performed as follows. Investigator 1 performed the tSMS that decided whether the real magnet or sham steel cylinder would be used, and placed the appropriate device on the subject’s scalp. Investigator 2 recorded SEPs and analyzed their amplitudes. This investigator was blind to the type of intervention being performed. To avoid carryover effects, all subjects participated in three experimental sessions (10 min and 15 min of tSMS, and 10 min or 15 min of sham stimulation) on separate days that were at least three days
A B
Experimental procedure During the experiment, subjects were seated in a comfortable reclining armchair with a mounted headrest. For tSMS, a cylindrical neodymium magnet (NdFeB; diameter, 50 mm; height, 30 mm) with a maximum energy density of 44 MGOe and a nominal strength of 735 N (75 kg) was used (NeoMag, Ichikawa, Japan). A non-magnetic stainless steel cylinder of the same size,
Figure 2. Experimental procedure. tSMS was applied for periods of 10 and 15 min. The duration of sham stimulation was 10 min in half the subjects and 15 min in the remaining half. SEPs following right median nerve stimulation were recorded before and immediately after, 5 min after, and 10 min after tSMS (A). In another session, SEPs were recorded every 3 min during 15 min of tSMS, and before, immediately, 5 min and 10 min after tSMS (B).
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apart. In another session, SEPs were recorded from 6 of the 10 subjects every 3 min during 15 min of tSMS (Fig. 2). SEPs were amplified with bandpass filters set at 1e3000 Hz and 300 responses were averaged (Viking Quest, Nicolet, CA, USA). For this, brief electrical stimulation (0.2 ms) was delivered to the right median nerve at a frequency of 3.3 Hz. The stimulus intensity was fixed at about 1.2 times the motor threshold. Data and statistical analysis
Figure 3. The SEP waveforms recorded from C30 after right median nerve stimulation in a representative subject before and immediately after, 5 min after, and 15 min after tSMS over the sensorimotor cortex for periods of 10 min.
Peak-to-peak amplitudes of the four cortical SEP components (N20, P25, N35, and P45) for C30 and two components (P22 and N30) for F3 were analyzed. The amplitude of each component was measured from the preceding peaks. Amplitudes of SEPs were normalized to those recorded before tSMS. All data are expressed as mean SEM and were statistically analyzed by two-way repeated measures analysis of variance (ANOVA) using the parameters of duration of tSMS (10 min vs. 15 min vs. Sham) and time (before vs.
A
B
Figure 4. Serial changes in SEP amplitudes (N20, P25, N35, P45) from C30 (A) and (P22, N30) from F3 (B) before and immediately after, 5 min after, and 10 min after tSMS for periods of 10 and 15 min and sham stimulation. For the N20 (C30 ) component, post hoc analysis showed a significant difference between sham and 10 min of tSMS immediately after intervention, and sham and 15 min of tSMS immediately after intervention. No significant differences between 10 and 15 min of tSMS were observed. No significant effect of tSMS was observed for other SEP components at both C30 and F3. SEP amplitudes are normalized to those recorded before tDCS (mean SEM). *P < 0.05.
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Figure 5. Serial changes in SEP amplitudes (N20) from C30 before and immediately after, 5 min after, and 10 min after tSMS for periods of 15 min. No significant main or interactive effects were observed on any of the SEP components when recording SEPs every 3 min (with peripheral nerve stimulation) during and after tSMS. SEP amplitudes are normalized to those recorded before tDCS (mean SEM).
immediately after vs. 10 min after vs. 15 min after tSMS), or one-way repeated measures ANOVA with time (before, during, after). Sphericity of the data was tested by the Mauchly’s test, and GreenhouseeGeisser corrected significance values were used when sphericity was lacking. Post hoc analysis was performed with Bonferroni’s correction for multiple comparisons. A difference was accepted as significant at P < 0.05 for all analyses. Results Figure 3 shows grand averaged waveforms of SEPs recorded before and immediately after, 5 min after, and 10 min after 15 min of tSMS from C30 . Amplitudes of N20 significantly decreased immediately after 10 and 15 min of tSMS, and returned to baseline by 5 min after intervention. The amplitudes of N20 (C30 ) before tSMS in each stimulus condition were comparable: sham, 3.04 0.29 mV; 10 min of tSMS, 3.23 0.2 mV; and 15 min of tSMS, 2.9 0.24 mV, respectively. For the N20 component of SEPs recorded from C30 , two-way repeated measures ANOVA revealed a significant main effect of time (F2,18 ¼ 6.571, P ¼ 0.007) and interaction between duration of tSMS and time (F2.267,20.407 ¼ 3.993, P ¼ 0.032), while no significant main effect of duration of tSMS alone was observed. The amplitude of the N20 component of SEPs was significantly reduced immediately after 10 min of tSMS (83 2.6% of baseline, P ¼ 0.004) and after 15 min of tSMS (80 5.0% of baseline, P ¼ 0.013) compared with sham tSMS. No significant differences in N20 amplitude between 10 min and 15 min of tSMS were observed (P ¼ 0.914). A decrease in N20 amplitude of SEPs was also observed at 5 min after 10 min (88 4.9% of baseline, P ¼ 0.266) and 15 min of tSMS (84 5.0%, P ¼ 0.243), returning to baseline by 10 min after 10 and 15 min of tSMS (92 3.8%, 94 5.0%, respectively), although the decrease was not significant. Other components of SEP amplitudes (P25, N35, P45) were not remarkably affected by tSMS (Fig. 4A). There were also no remarkable effects on the amplitudes of P22 and N30 components of SEPs (Fig. 4B). No significant main or interactive effects were observed on any of the SEP components when recording SEPs every 3 min (with peripheral nerve stimulation) during and after tSMS (Fig. 5). Discussion We confirmed that tSMS over the sensorimotor cortex for 10 and 15 min results in a transient decrease in the excitability of S1, as
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determined by a reduction in the amplitude of the N20 component of SEPs at C30 (parietal component). The reduction rate in S1 excitability of up to 20% is in accordance with those described in previous studies that demonstrated a reduction of motor cortex (M1) excitability, as revealed by TMS, by applying tSMS over M1 for 10 [5] or 15 min [6]. Numerous attempts have been made to demonstrate that SMFs can alter central nervous function [7,8,21e26], and that moderateintensity SMFs induce magnetic reorientation of membrane phospholipids by diamagnetic anisotropy effects in cellular and animal studies [27e30]. Of these, the characteristics of greatest interest to tSMS-induced reduction in excitability of the human cortex are that SMFs are not associated with induced electric currents during activation and deactivation or when there is movement within the field [24], and that they alter the activation threshold and velocity of voltage-gated sodium channels [7,24,25,28] and voltage-gated calcium channels [23,24,28]. Slow calcium influx and increased intracellular calcium ion stores caused by impedance of calcium channels are thought to trigger long-term depression [31,32]. Moreover, as indicated by previous studies that showed that tSMS can increase resting motor threshold, the decrease in SEP amplitude in this study may be partly mediated by a reduction in membrane excitability, suggesting a possible role for non-synaptic (intrinsic) plasticity mechanisms. When tSMS is applied in humans, since the cortex is roughly at a depth and distance of 2e3 cm from the NdFeB magnets, it is possible that the strength of the SMFs may not reach the cortex through the scalp and cranial bone. However, Rivadulla et al. [33] demonstrated that the magnetic field strength is in a range between 120 and 200 mT 2e3 cm from the magnet surface, with high reproducibility. The NdFeB magnets that they used in their study were approximately the same as that used in this study. Therefore, it is conceivable that our intervention using a NdFeB magnet (diameter 50 mm, height, 30 mm, and with a maximum energy density of 44 MGOe) produced a magnetic field that is strong enough to reach most cortical targets and to produce biological effects, such as alteration of the function of membrane ion channels [24,28]. We have no definite explanation for why no effects were observed on SEPs recorded during tSMS in our study. Somatosensory afferent information from peripheral nerves generate synaptic potentials at pyramidal cells in the sensory cortex [34]. These synaptic potentials lead to extracellular volume currents that are detected by surface electrodes as SEPs. It seems reasonable to suppose that use of peripheral nerve stimulation to cause SEPs antagonizes diamagnetic ion movements and distortion of ion channels during exposure to static magnetic fields. In addition, our previous tDCS study [35] and that of Antal et al. [36] demonstrated that the corticomotor excitability observed when anodal tDCS is applied to the motor cortex during motor tasks is lower than that observed when anodal tDCS is applied under resting conditions. Further, the inhibitory effect of rTMS at a frequency of 1 Hz is apparently abolished during active contraction of the target muscle [37]. In line with these results, peripheral nerve stimulation performed to elicit SEPs may normalize the excitability of S1 during tSMS, similar to the effect of voluntary movement on M1 excitability. Meanwhile, reduction in SEP amplitude by tSMS was observed only in the early components (N20 at C30 ) of the SEP, while the amplitude of later components of SEPs showed no remarkable changes. N20 at C30 is the earliest localized scalp potential and is believed to be produced by a tangential generator located in Brodman’s area 3b of the somatosensory cortex [38e40]. Meanwhile, there are many views on the generation of later components, such as P25 at C30 from areas 1, 2 [41] and 4 [42], and N30 at F3 from area 4 and/or 6 [2,43,44], although these have not yet been definitively identified. We cannot clearly explain why the later components of SEP amplitude showed no remarkable effect of the application of tSMS, although the magnet
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seemed to cover areas 1, 2, and 4, crossing over the central sulcus. In TMS and tDCS studies, not only S1, but also M1 are considered important targets with proven efficacy in chronic pain treatment [45e48]. Therefore, we plan to investigate the influence of the position of the NdFeB magnet on M1 and S1 in a future study. In conclusion, our results reveal that tSMS over the sensorimotor cortex transiently reduces the excitability of the somatosensory cortex. tSMS is able to modulate cortical somatosensory processing in humans, and thus might be a useful tool for inducing plasticity in cortical sensory processing. The lack of change in the amplitude of SEPs with tSMS implies that use of peripheral nerve stimulation to cause SEPs antagonizes alteration of the function of membrane ion channels during exposure to static magnetic fields. Acknowledgments
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[28]
We would like to thank Dr. Katsuya Ogata for valuable advice about analysis of SEPs.
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