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Static magnetic field can transiently alter the human intracortical inhibitory system
Clinical Neurophysiology xxx (2015) xxx–xxx
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Static magnetic field can transiently alter the human intracortical inhibitory system Ippei Nojima a, Satoko Koganemaru b, Hidenao Fukuyama b, Tatsuya Mima b,⇑ a b
Department of Physical Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
a r t i c l e
i n f o
Article history: Accepted 28 January 2015 Available online xxxx Keywords: Static magnetic field Magnetic resonance imaging Transcranial magnetic stimulation Short intracortical inhibition
h i g h l i g h t s Homogeneous and inhomogeneous static magnetic fields suppress the human motor cortex. Short-latency intracortical inhibition was increased after magnetic exposure. The enhancement of the GABAergic system can be used for clinical purposes.
a b s t r a c t Objective: Although recent studies have shown the suppressive effects of static magnetic fields (SMFs) on the human primary motor cortex (M1) possibly due to the deformed neural membrane channels, the effect of the clinical MRI scanner bore has not been studied in the same way. Methods: We tested whether the MRI scanner itself and compact magnet can alter the M1 function using single- and paired-pulse transcranial magnetic stimulation (TMS). Results: We found the transient suppression of the corticospinal pathway in both interventions. In addition, the transient enhancement of the short-latency intracortical inhibition (SICI) was observed immediately after compact magnet stimulation. Conclusions: The present results suggest that not only the inhomogeneous SMFs induced by a compact magnet but also the homogeneous SMF produced by the MRI scanner bore itself can produce the transient cortical functional change. Significance: Static magnetic stimulation can modulate the intracortical inhibitory circuit of M1, which might be useful for clinical purposes. Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Magnetic resonance imaging (MRI), which utilizes static and time-varying magnetic fields, is widely used in neuroscience research, as well as in daily clinical practice. Recent developments of various neuroimaging techniques using MRI enabled us to clarify functional brain activation depicted by BOLD signal change (Ogawa et al., 1990) and microstructural difference via water diffusion (Le Bihan et al., 1986). The biological effects of electromagnetic fields have been extensively assessed for the time-varying magnetic fields (Kangarlu
⇑ Corresponding author at: Department of Brain Pathophysiology, Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan. Tel.: +81 75 751 3602; fax: +81 75 751 3202. E-mail address: [email protected] (T. Mima).
et al., 1999; de Vocht et al., 2006), where eddy currents might cause heating or nerve stimulation. In the case of clinical MRI, biological effects are generally considered harmless for the human body. In addition, static magnetic fields (SMFs) can produce biological effects in several ways (Aldinucci et al., 2003; Chakeres and de Vocht, 2005). The most common mechanism is eddy currents induced by displacements of the head in SMFs, which might cause vertigo or other transient sensations in MRI patients and volunteers (Glover et al., 2007; Mian et al., 2013). Other possible sources are Lorentz’s force, magnetic force, and magnetic torque. However, little is known about the specific biological effects of SMFs on the human cortical neural circuit. Recent studies suggested that local SMFs over the human primary motor cortex (M1) produced by a small high-powered neodymium magnet can modulate the cortical excitability, which can last a few minutes after the removal of the magnet (Oliviero et al.,
http://dx.doi.org/10.1016/j.clinph.2015.01.030 1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Nojima I et al. Static magnetic field can transiently alter the human intracortical inhibitory system. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.01.030
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2011; Silbert et al., 2013). Although the physiologic mechanism of this plastic change is not known, animal experiments indicated the alteration of the ion channel function embedded in the membrane (Rosen, 2003b). It is possible that high-powered SMFs can transiently affect the orientation of the membrane phospholipids due to their diamagnetic anisotropy. However, it has been rarely studied whether homogeneous SMF including the whole head, such as an MRI scanner bore, can modulate the cortical excitability (Schlamann et al., 2010), similar to the compact magnet. This question is particularly important, because functional MRI is widely used in neuroscience research. In addition, to selectively test the human M1 function and to clarify the physiologic effects of SMFs, the paired-pulse transcranial magnetic stimulation (TMS) technique is suitable, which can assess the human intracortical inhibitory circuits mediated by gamma-aminobutyric acid (GABA)-A receptors (Kujirai et al., 1993; Chen, 2004; Ziemann, 2004). Here, we tested the biological effects of SMFs on human M1 and, specifically, the effects of SMFs on the intracortical circuit function. 2. Methods 2.1. Subjects Thirty neurologically healthy subjects (25 males and five females; age, 23.0 ± 2.5 years, mean ± SD) participated in this study. None of the participants had a history of neurological illness by self-report. All volunteers were right handed as determined by Oldfield’s handedness inventory (Oldfield, 1971). The protocol was approved by the Ethics Committee of Kyoto University Graduate School of Medicine (Kyoto, Japan). Written informed consent was obtained from all subjects prior to this study. 2.2. SMF exposure for the motor cortex We used two different methods to stimulate the left M1 by SMFs: the MRI scanner bore and the cylindrical neodymium magnet. For inhomogeneous SMFs, we used a cylindrical nickel-plated (Ni–Cu–Ni) NdFeB magnet of 50-mm diameter and 30-mm thickness, with a weight of 442 g (Model N-50; NeoMag, Chiba, Japan). The maximum energy density was 406 kJ/m3 (48–51 MGOe), with a nominal strength of 863 N (88 kg). The surface magnetic flux density was about 5340 G. The distance between the scalp and the M1 was about 20 mm. A nonmagnetic stainless-steel cylinder of the same size was used for sham stimulation as the control group. The magnet and nonmagnet were positioned by using an arm-type light stand (C-stand, Avenger, Cassola, Italy) over the representational area for the right abductor pollicis brevis (APB) muscle identified by TMS and held tangentially against the subject’s head with the north pole oriented toward the subject. It has been reported that the magnetic polarity is irrelevant for neuromodulation (Oliviero et al., 2011). For homogeneous SMFs, we used a 3.0-T MRI scanner bore (Siemens Trio; Siemens Medical Systems, Erlangen, Germany). No imaging was performed, so only SMFs were present. The head was guided to the desired orientation. Padding and wedges were used for comfort and stability. The participants remained stationary on the bed until the end of the intervention, and then slowly withdrawn after MRI exposure. 2.3. TMS measurement TMS was performed with one Magstim 200 magnetic stimulator or two stimulators connected by a Bistim module that allows delivery of two magnetic stimulations through the coil. A single pulse of
TMS was delivered using a flat figure-of-eight magnetic coil at the optimal scalp position to induce a motor response for the right APB. The optimal position was marked on the scalp by a soft-tip pen. The direction of the induced current was from posterior to anterior. The electromyogram (EMG) was recorded from the right APB. The EMG signals were amplified, band-pass-filtered (5– 2000 Hz), and digitized at a rate of 10 kHz using the Map1496 system (Nihon-Santeku Co., Osaka, Japan). During TMS measurement, each subject was seated comfortably in a reclining armchair. The resting motor threshold (rMT) for the right APB muscle was defined as the minimal stimulator output eliciting a motor evoked potential (MEP) of >50 lV in at least five out of 10 consecutive pulses. For the evaluation of the corticospinal excitability, we measured the peak-to-peak MEP amplitudes of the right APB muscle for 10 trials and the averages were taken. The intensity of the test stimulus was adjusted to produce an MEP of 1 mV from the target APB muscle before the intervention (SI 1 mV). We measured short-latency intracortical inhibition and facilitation (SICI and ICF) to evaluate the cortical inhibitory and excitatory neural circuits. Paired-pulse magnetic stimuli were applied over the left M1, with a subthreshold conditioning stimulus (CS) at 80% of the rMT followed by a suprathreshold test stimulus (TS) at SI 1 mV with interstimulus intervals (ISIs) of 3 and 12 ms, respectively (Groppa et al., 2012). The test MEP amplitudes were adjusted to be constant at 1 mV throughout the experiment. The size of the mean conditioned response for SICI and ICF (10 trials each) was expressed as a percentage of the size of the mean test response alone. These techniques allowed us to investigate the different pools of cortical interneurons that modulate the inhibitory and facilitatory neural circuits (Paulus et al., 2008; Badawy et al., 2012). The silent period (SP) was assessed during the isometric contraction of the right APB at 20% of the maximum contraction. For SP recording, the stimulation intensity was adjusted to be 140% of the rMT of the right APB before the intervention. Its duration was taken from the onset of TMS to the return of voluntary EMG activity. 2.4. Experimental procedures Twenty healthy subjects (18 males and two females) participated in the inhomogeneous SMFs intervention using a compact neodymium magnet and nonmagnet as sham stimulation. Subjects were asked to lie on a reclining chair to apply SMFs using the magnet over the left M1. The intervention duration was 20 min. In addition to amplitudes of MEP and rMT, we measured the SICI/ICF and SP for the right APB before, 0, 10, and 30 min after the intervention. Ten other healthy subjects (seven males and three females) participated in the homogeneous SMF intervention using MRI. After measuring the basic TMS parameters (amplitudes of MEP and rMT) before the intervention, subjects were placed at the center of the MRI scanner bore where the most homogeneous magnetic field is achieved for 20 min without performing any task. TMS measurement was performed 0, 10, and 30 min after the MRI exposure (pre, post-0, post-10, and post-30). The TMS measurements took place in a separate room next to the scanner room. 2.5. Statistical analysis Although the present experiment is not designed as a doubleblind study, for MEP measurement, all the data were stored in a computer, and a blinded researcher checked the data without knowing the experimental information. The normal distribution was tested using the Kolmogorov– Smirnov test.
Please cite this article in press as: Nojima I et al. Static magnetic field can transiently alter the human intracortical inhibitory system. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.01.030
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(F3,54 = 3.2, p = 0.021, g2 = 0.163) in the compact magnet intervention. A post hoc t-test revealed a significant suppression (Fig. 1, p = 0.011, g2 = 0.306) of MEP in post-0 of the magnetic intervention compared with the sham intervention. For rMT, two-way repeatedmeasures ANOVA showed no significant effects of Time, but significant effects of Time Group interactions (F3,54 = 3.5, p = 0.022, g2 = 0.162). A post hoc t-test revealed a significant increase (Fig. 1, p = 0.005, g2 = 0.359) of rMT in post-0 of the magnetic intervention compared with sham intervention. For SICI, two-way repeated-measures ANOVA showed no significant effects of Time, but significant effects of Time Group interactions (F3,54 = 2.9, p = 0.046, g2 = 0.161). A post hoc t-test revealed a significant increase (Fig. 2, p = 0.019, g2 = 0.268) of SICI in post-0 of the magnetic intervention compared with sham intervention. On the other hand, two-way repeated-measures ANOVA showed no significant effects of Time and Time Group interactions on ICF and SP. For the MRI bore, the mean MEP amplitudes showed significant effects of Time (F3,27 = 3.2, p = 0.039, g2 = 0.262). The post hoc t-test revealed a significant amplitude decrease in the post-0 compared to the baseline for both interventions (Fig. 3, p = 0.004, g2 = 0.780). For the mean rMT, one-way repeated-measure ANOVA showed no significant effects.
To analyze the effects of two interventions on MEP amplitudes and rMT, two-way repeated-measures ANOVA was used with Time (pre and post-0, post-10, and post-30) as a within-subject factor and Group (magnet and sham) as a between-subject factor in the inhomogeneous SMF intervention. One-way repeated-measures ANOVA was used with Time (pre and post-0, post-10, and post30) as a within-subject factor in the homogeneous SMF intervention. The Greenhouse–Geisser method was used to adjust for sphericity if needed. In the case of significant interaction effects, post hoc analyses using the Bonferroni correction for multiple comparisons were applied. The effects were considered significant at p < 0.05.
3. Results To delineate the physiologic mechanism of SMF-induced effects, detailed TMS measurements were performed for the compact magnet and sham interventions. For the mean MEP ratio for the left hand, two-way repeated-measures ANOVA showed no significant effects of Time, but significant effects of Time Group interactions
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Fig. 1. Effect of compact magnet (SMF) and sham (control) on the amplitude of MEP (A) and rMT (B) measured in the right APB muscle. The mean MEP amplitude was significantly decreased, and the mean rMT was significantly increased immediately after both interventions compared to the control condition. The values of these parameters are expressed as a percentage of baselines. ⁄p < 0.05.
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Fig. 2. Effect of compact magnet (SMF) and sham (control) on the SICI (A) and ICF (B) measured in the right APB muscle. The mean SICI was significantly decreased immediately after both interventions compared to the control condition, but not significantly different in ICF. The values of these parameters are expressed as a percentage of baselines. ⁄p < 0.05.
Please cite this article in press as: Nojima I et al. Static magnetic field can transiently alter the human intracortical inhibitory system. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.01.030
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Fig. 3. Effect of MRI exposure on the amplitude of MEP (A) and rMT (B) measured in the right APB muscle. The mean MEP amplitude was significantly decreased, and the mean rMT was significantly increased immediately after interventions. The values of these parameters are expressed as a percentage of baselines. ⁄p < 0.05.
4. Discussion We found that not only the inhomogeneous SMFs induced by a compact magnet but also the homogeneous SMF produced by the MRI scanner bore itself without scanning can alter the human M1 cortical function transiently. Extending the previous studies (Oliviero et al., 2011; Silbert et al., 2013) that reported the suppression of human corticospinal excitability, we found a significant increase of the SICI due to SMFs. We observed the SMF-related increase of cortical inhibitory circuits measured by SICI and SP. SICI is measured in a paired-pulse TMS protocol involving a subthreshold conditioning stimulus followed by a suprathreshold test stimulus with a short interstimulus interval of 1–5 ms (Kujirai et al., 1993; Nakamura et al., 1997; Chen et al., 1998). It is general consensus that SICI occurs at the cortical level and that intracortical inhibitory interneurons play an important role (Ziemann et al., 1996c; Di Lazzaro et al., 2002; Ferreri et al., 2006; Paulus et al., 2008). As SICI can be increased by drugs that enhance GABA-A transmission but is unaffected by drugs that block voltage-gated sodium channels (Ziemann et al., 1996b; Chen et al., 1998), it is likely that SICI provides an index of instantaneous inhibition by fast ionotropic postsynaptic GABA-A receptors that produce an inhibitory postsynaptic potential with a rise time of about 2 ms. By contrast, the duration of SP, which showed the tendency of increase but not a significant effect, is compatible with a long-lasting inhibition mediated by GABA-B receptors (Connors et al., 1988) and can be prolonged by the GABA reuptake inhibitor (Werhahn et al., 1999). Our results suggest that suppression of M1 induced by SMF exposure may be partly related to the modulation of the GABAergic system. There have been a couple of animal studies on the physiologic mechanism of suppressed neural activities under strong SMFs (Rosen and Lubowsky, 1987; Coots et al., 2004). It has been reported that SMFs can interact with membrane ion channels, possibly due to the diamagnetic anisotropic properties of membrane phospholipids (Rosen, 2003b; Miyakoshi, 2005). Previous studies revealed that the activation kinetics of both sodium (Rosen, 2003a; Coots et al., 2004) and calcium channels (Rosen, 1996) are transiently slowed during exposure to SMFs. Reorientation of these molecules during SMF exposure results in deformation of embedded ion channels, thereby altering their activation kinetics (Rosen, 2003b). If the neural effects of SMFs are associated with channel dysfunction in general, we can expect that all neural activities would be suppressed. This hypothesis fits with the M1 excitability measures, such as rMT and MEP amplitudes. Although the basis of rMT is not certain, pharmacological research has suggested that it is modulated by membrane excitability (Ziemann et al., 1996b,a). In addition to the decrease of MEP amplitudes, we found the increase of rMT just after the SMFs in accordance with a previous study (Silbert et al., 2013).
However, regarding the significant enhancement of SICI, the transient disturbance of the GABA reuptake mechanism induced by SMFs should be taken into account. Although the sound experimental data in animal models are lacking, it can be speculated that the SMF-induced deformation of membrane channels could also affect GABA transporters (GATs), which modulate phasic and tonic GABA-mediated inhibition and GABA spillover (Conti et al., 2004). Suppression of GATs can cause an increased concentration of ambient GABA at the synapse (Eulenburg and Gomeza, 2010). With higher concentration of GABA molecule in the synaptic cleft due to the dysfunction of the reuptake system, GABA receptor function would be restored immediately after the removal of SMFs. The consequence could result in facilitating the inhibitory circuits by activating GABA-A receptors at postsynaptic sites. For the clinical MRI scanner, however, it has been reported that vertigo and nystagmus can be driven by continuous input from a static homogeneous magnetic field (Mian et al., 2013). One recent study reported that the MRI scanning led to a transient prolongation of the SP and an increase of rMT at 1.5 and 7 T, whereas these effects did not occur during sole exposition to the static MRI field in healthy humans (Schlamann et al., 2010). This observation is inconsistent with the recent studies that showed the modulatory effects of SMFs on human M1 using a compact magnet (Silbert et al., 2013). One possible reason for divergence might be the use of non-focal round large TMS coil in Schlamann’s study. Recent studies, including ours, used a focal TMS coil and found the alteration of M1 function following SMFs associated with the static magnetic fields (Oliviero et al., 2011; Silbert et al., 2013). In sham intervention, one-way repeated-measures ANOVA showed no significant effect. Although we cannot directly compare the MRI bore with the sham intervention for the different experimental settings, the result suggested that the effect of the MRI bore was comparable to the effect of SMF on the human cortex. There are a few possibilities that can explain the effects of SMFs on biological materials. Although the possible effects of Lorentz’s force associated with blood flow have been particularly concerned, SMFs have not been shown to affect other cardiovascular functions (Atkinson et al., 2007). Thus, it is unlikely that the neural effects are mediated by blood flow. Second, as suggested by previous studies (Rosen, 2003b; Oliviero et al., 2011), magnetic force that is caused by a spatially inhomogeneous magnetic field depending on the steepness of the gradient might be relevant for modulating the neural excitability in M1 by affecting the transmembrane channel functions. Although a compact magnet may produce a steep field gradient, our study using an MRI scanner bore showed the possible contribution of magnetic torque within the homogeneous SMFs. The possible effects of homogeneous SMFs have been suggested by previous animal studies (Edelman et al., 1979; Rosen, 1994, 1996, 2003b,a; Coots et al., 2004).
Please cite this article in press as: Nojima I et al. Static magnetic field can transiently alter the human intracortical inhibitory system. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.01.030
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Recent study showed that the magnetic field strength is in a range between 120 and 200 mT 2–3 cm from the magnet surface (Rivadulla et al., 2014). Therefore, it seems that, at least in this range of magnetic fields (0.1–3.0 T), the biological effects of magnetic fields might be similar. Due to the limitation of the time during the experiment, we only tested the SICI with the ISI of 3 ms and the ICF with 12 ms. It is possible that the SICI might be partly contaminated by a short-interval intracortical facilitation (SICF) (Hanajima et al., 2002; Hanajima, 2013; Shirota et al., 2010; Buharin et al., 2014). In addition, ICF parameters, such as stimulus intensity, interval, and/or test MEP sizes (Kujirai et al., 1993; Ortu et al., 2008), have not been systematically investigated. Further studies are necessary to confirm these points. The present study showed that SMFs could potentially be used to transiently influence cortical excitability. Until now, time-varying magnetic fields, for example TMS, are widely used for brain stimulation, which can be applied for rehabilitation or therapy for neuropsychiatric disorders (Lam et al., 2008; Koganemaru et al., 2010; Rossini et al., 2010; Dayan et al., 2013; Schulz et al., 2013). In addition to the possible use of SMFs for suppressive brain stimulation techniques such as low-frequency repetitive TMS or cathodal tDCS, our results suggest that it might be possible to use SMFs to increase SICI. Enhancement of SICI function by SMFs might be a new promising therapeutic tool for neurological disorders associated with GABA dysfunction, such as epilepsy (Meldrum and Rogawski, 2007; White et al., 2007), which was supported by data obtained in animal models (McLean et al., 2003, 2008), and dystonia (Ikoma et al., 1996; Garibotto et al., 2011; Boecker, 2013). However, we should be cautious about the clinical application of brain stimulation methods to modulate the neuroplasticity, because high variability across subjects has been reported (Hamada et al., 2013). Acknowledgments This study was partly supported by Grant-in-Aid for Scientific Research (B) 24300192 (to T.M.) and Grant-in Aid for Young Scientists (B) 25750203 (to I.N.) from the Japan Society for the Promotion of Science. Conflict of interest: None of the authors have potential conflicts of interest to be disclosed. We confirm that we have read the journal’s position on issues involved in ethical publication. References Aldinucci C, Garcia JB, Palmi M, Sgaragli G, Benocci A, Meini A, et al. The effect of strong static magnetic field on lymphocytes. Bioelectromagnetics 2003;24:109–17. Atkinson IC, Renteria L, Burd H, Pliskin NH, Thulborn KR. Safety of human MRI at static fields above the FDA 8 T guideline: sodium imaging at 9.4 T does not affect vital signs or cognitive ability. J Magn Reson Imaging 2007;26:1222–7. Badawy RA, Loetscher T, Macdonell RA, Brodtmann A. Cortical excitability and neurology: insights into the pathophysiology. Funct Neurol 2012;27:131–45. Boecker H. Imaging the role of GABA in movement disorders. Curr Neurol Neurosci Rep 2013;13:385. Buharin VE, Butler AJ, Shinohara M. Motor cortical disinhibition with baroreceptor unloading induced by orthostatic stress. J Neurophysiol 2014;111:2656–64. Chakeres DW, de Vocht F. Static magnetic field effects on human subjects related to magnetic resonance imaging systems. Prog Biophys Mol Biol 2005;87:255–65. Chen R. Interactions between inhibitory and excitatory circuits in the human motor cortex. Exp Brain Res 2004;154:1–10. Chen R, Tam A, Butefisch C, Corwell B, Ziemann U, Rothwell JC, et al. Intracortical inhibition and facilitation in different representations of the human motor cortex. J Neurophysiol 1998;80:2870–81. Connors BW, Malenka RC, Silva LR. Two inhibitory postsynaptic potentials, and GABAA and GABAB receptor-mediated responses in neocortex of rat and cat. J Physiol 1988;406:443–68. Conti F, Minelli A, Melone M. GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications. Brain Res Brain Res Rev 2004;45:196–212.
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Static magnetic field can transiently alter the human intracortical inhibitory system Ippei Nojima a, Satoko Koganemaru b, Hidenao Fukuyama b, Tatsuya Mima b,⇑ a b
Department of Physical Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
a r t i c l e
i n f o
Article history: Accepted 28 January 2015 Available online xxxx Keywords: Static magnetic field Magnetic resonance imaging Transcranial magnetic stimulation Short intracortical inhibition
h i g h l i g h t s Homogeneous and inhomogeneous static magnetic fields suppress the human motor cortex. Short-latency intracortical inhibition was increased after magnetic exposure. The enhancement of the GABAergic system can be used for clinical purposes.
a b s t r a c t Objective: Although recent studies have shown the suppressive effects of static magnetic fields (SMFs) on the human primary motor cortex (M1) possibly due to the deformed neural membrane channels, the effect of the clinical MRI scanner bore has not been studied in the same way. Methods: We tested whether the MRI scanner itself and compact magnet can alter the M1 function using single- and paired-pulse transcranial magnetic stimulation (TMS). Results: We found the transient suppression of the corticospinal pathway in both interventions. In addition, the transient enhancement of the short-latency intracortical inhibition (SICI) was observed immediately after compact magnet stimulation. Conclusions: The present results suggest that not only the inhomogeneous SMFs induced by a compact magnet but also the homogeneous SMF produced by the MRI scanner bore itself can produce the transient cortical functional change. Significance: Static magnetic stimulation can modulate the intracortical inhibitory circuit of M1, which might be useful for clinical purposes. Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Magnetic resonance imaging (MRI), which utilizes static and time-varying magnetic fields, is widely used in neuroscience research, as well as in daily clinical practice. Recent developments of various neuroimaging techniques using MRI enabled us to clarify functional brain activation depicted by BOLD signal change (Ogawa et al., 1990) and microstructural difference via water diffusion (Le Bihan et al., 1986). The biological effects of electromagnetic fields have been extensively assessed for the time-varying magnetic fields (Kangarlu
⇑ Corresponding author at: Department of Brain Pathophysiology, Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan. Tel.: +81 75 751 3602; fax: +81 75 751 3202. E-mail address: [email protected] (T. Mima).
et al., 1999; de Vocht et al., 2006), where eddy currents might cause heating or nerve stimulation. In the case of clinical MRI, biological effects are generally considered harmless for the human body. In addition, static magnetic fields (SMFs) can produce biological effects in several ways (Aldinucci et al., 2003; Chakeres and de Vocht, 2005). The most common mechanism is eddy currents induced by displacements of the head in SMFs, which might cause vertigo or other transient sensations in MRI patients and volunteers (Glover et al., 2007; Mian et al., 2013). Other possible sources are Lorentz’s force, magnetic force, and magnetic torque. However, little is known about the specific biological effects of SMFs on the human cortical neural circuit. Recent studies suggested that local SMFs over the human primary motor cortex (M1) produced by a small high-powered neodymium magnet can modulate the cortical excitability, which can last a few minutes after the removal of the magnet (Oliviero et al.,
http://dx.doi.org/10.1016/j.clinph.2015.01.030 1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Nojima I et al. Static magnetic field can transiently alter the human intracortical inhibitory system. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.01.030
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2011; Silbert et al., 2013). Although the physiologic mechanism of this plastic change is not known, animal experiments indicated the alteration of the ion channel function embedded in the membrane (Rosen, 2003b). It is possible that high-powered SMFs can transiently affect the orientation of the membrane phospholipids due to their diamagnetic anisotropy. However, it has been rarely studied whether homogeneous SMF including the whole head, such as an MRI scanner bore, can modulate the cortical excitability (Schlamann et al., 2010), similar to the compact magnet. This question is particularly important, because functional MRI is widely used in neuroscience research. In addition, to selectively test the human M1 function and to clarify the physiologic effects of SMFs, the paired-pulse transcranial magnetic stimulation (TMS) technique is suitable, which can assess the human intracortical inhibitory circuits mediated by gamma-aminobutyric acid (GABA)-A receptors (Kujirai et al., 1993; Chen, 2004; Ziemann, 2004). Here, we tested the biological effects of SMFs on human M1 and, specifically, the effects of SMFs on the intracortical circuit function. 2. Methods 2.1. Subjects Thirty neurologically healthy subjects (25 males and five females; age, 23.0 ± 2.5 years, mean ± SD) participated in this study. None of the participants had a history of neurological illness by self-report. All volunteers were right handed as determined by Oldfield’s handedness inventory (Oldfield, 1971). The protocol was approved by the Ethics Committee of Kyoto University Graduate School of Medicine (Kyoto, Japan). Written informed consent was obtained from all subjects prior to this study. 2.2. SMF exposure for the motor cortex We used two different methods to stimulate the left M1 by SMFs: the MRI scanner bore and the cylindrical neodymium magnet. For inhomogeneous SMFs, we used a cylindrical nickel-plated (Ni–Cu–Ni) NdFeB magnet of 50-mm diameter and 30-mm thickness, with a weight of 442 g (Model N-50; NeoMag, Chiba, Japan). The maximum energy density was 406 kJ/m3 (48–51 MGOe), with a nominal strength of 863 N (88 kg). The surface magnetic flux density was about 5340 G. The distance between the scalp and the M1 was about 20 mm. A nonmagnetic stainless-steel cylinder of the same size was used for sham stimulation as the control group. The magnet and nonmagnet were positioned by using an arm-type light stand (C-stand, Avenger, Cassola, Italy) over the representational area for the right abductor pollicis brevis (APB) muscle identified by TMS and held tangentially against the subject’s head with the north pole oriented toward the subject. It has been reported that the magnetic polarity is irrelevant for neuromodulation (Oliviero et al., 2011). For homogeneous SMFs, we used a 3.0-T MRI scanner bore (Siemens Trio; Siemens Medical Systems, Erlangen, Germany). No imaging was performed, so only SMFs were present. The head was guided to the desired orientation. Padding and wedges were used for comfort and stability. The participants remained stationary on the bed until the end of the intervention, and then slowly withdrawn after MRI exposure. 2.3. TMS measurement TMS was performed with one Magstim 200 magnetic stimulator or two stimulators connected by a Bistim module that allows delivery of two magnetic stimulations through the coil. A single pulse of
TMS was delivered using a flat figure-of-eight magnetic coil at the optimal scalp position to induce a motor response for the right APB. The optimal position was marked on the scalp by a soft-tip pen. The direction of the induced current was from posterior to anterior. The electromyogram (EMG) was recorded from the right APB. The EMG signals were amplified, band-pass-filtered (5– 2000 Hz), and digitized at a rate of 10 kHz using the Map1496 system (Nihon-Santeku Co., Osaka, Japan). During TMS measurement, each subject was seated comfortably in a reclining armchair. The resting motor threshold (rMT) for the right APB muscle was defined as the minimal stimulator output eliciting a motor evoked potential (MEP) of >50 lV in at least five out of 10 consecutive pulses. For the evaluation of the corticospinal excitability, we measured the peak-to-peak MEP amplitudes of the right APB muscle for 10 trials and the averages were taken. The intensity of the test stimulus was adjusted to produce an MEP of 1 mV from the target APB muscle before the intervention (SI 1 mV). We measured short-latency intracortical inhibition and facilitation (SICI and ICF) to evaluate the cortical inhibitory and excitatory neural circuits. Paired-pulse magnetic stimuli were applied over the left M1, with a subthreshold conditioning stimulus (CS) at 80% of the rMT followed by a suprathreshold test stimulus (TS) at SI 1 mV with interstimulus intervals (ISIs) of 3 and 12 ms, respectively (Groppa et al., 2012). The test MEP amplitudes were adjusted to be constant at 1 mV throughout the experiment. The size of the mean conditioned response for SICI and ICF (10 trials each) was expressed as a percentage of the size of the mean test response alone. These techniques allowed us to investigate the different pools of cortical interneurons that modulate the inhibitory and facilitatory neural circuits (Paulus et al., 2008; Badawy et al., 2012). The silent period (SP) was assessed during the isometric contraction of the right APB at 20% of the maximum contraction. For SP recording, the stimulation intensity was adjusted to be 140% of the rMT of the right APB before the intervention. Its duration was taken from the onset of TMS to the return of voluntary EMG activity. 2.4. Experimental procedures Twenty healthy subjects (18 males and two females) participated in the inhomogeneous SMFs intervention using a compact neodymium magnet and nonmagnet as sham stimulation. Subjects were asked to lie on a reclining chair to apply SMFs using the magnet over the left M1. The intervention duration was 20 min. In addition to amplitudes of MEP and rMT, we measured the SICI/ICF and SP for the right APB before, 0, 10, and 30 min after the intervention. Ten other healthy subjects (seven males and three females) participated in the homogeneous SMF intervention using MRI. After measuring the basic TMS parameters (amplitudes of MEP and rMT) before the intervention, subjects were placed at the center of the MRI scanner bore where the most homogeneous magnetic field is achieved for 20 min without performing any task. TMS measurement was performed 0, 10, and 30 min after the MRI exposure (pre, post-0, post-10, and post-30). The TMS measurements took place in a separate room next to the scanner room. 2.5. Statistical analysis Although the present experiment is not designed as a doubleblind study, for MEP measurement, all the data were stored in a computer, and a blinded researcher checked the data without knowing the experimental information. The normal distribution was tested using the Kolmogorov– Smirnov test.
Please cite this article in press as: Nojima I et al. Static magnetic field can transiently alter the human intracortical inhibitory system. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.01.030
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(F3,54 = 3.2, p = 0.021, g2 = 0.163) in the compact magnet intervention. A post hoc t-test revealed a significant suppression (Fig. 1, p = 0.011, g2 = 0.306) of MEP in post-0 of the magnetic intervention compared with the sham intervention. For rMT, two-way repeatedmeasures ANOVA showed no significant effects of Time, but significant effects of Time Group interactions (F3,54 = 3.5, p = 0.022, g2 = 0.162). A post hoc t-test revealed a significant increase (Fig. 1, p = 0.005, g2 = 0.359) of rMT in post-0 of the magnetic intervention compared with sham intervention. For SICI, two-way repeated-measures ANOVA showed no significant effects of Time, but significant effects of Time Group interactions (F3,54 = 2.9, p = 0.046, g2 = 0.161). A post hoc t-test revealed a significant increase (Fig. 2, p = 0.019, g2 = 0.268) of SICI in post-0 of the magnetic intervention compared with sham intervention. On the other hand, two-way repeated-measures ANOVA showed no significant effects of Time and Time Group interactions on ICF and SP. For the MRI bore, the mean MEP amplitudes showed significant effects of Time (F3,27 = 3.2, p = 0.039, g2 = 0.262). The post hoc t-test revealed a significant amplitude decrease in the post-0 compared to the baseline for both interventions (Fig. 3, p = 0.004, g2 = 0.780). For the mean rMT, one-way repeated-measure ANOVA showed no significant effects.
To analyze the effects of two interventions on MEP amplitudes and rMT, two-way repeated-measures ANOVA was used with Time (pre and post-0, post-10, and post-30) as a within-subject factor and Group (magnet and sham) as a between-subject factor in the inhomogeneous SMF intervention. One-way repeated-measures ANOVA was used with Time (pre and post-0, post-10, and post30) as a within-subject factor in the homogeneous SMF intervention. The Greenhouse–Geisser method was used to adjust for sphericity if needed. In the case of significant interaction effects, post hoc analyses using the Bonferroni correction for multiple comparisons were applied. The effects were considered significant at p < 0.05.
3. Results To delineate the physiologic mechanism of SMF-induced effects, detailed TMS measurements were performed for the compact magnet and sham interventions. For the mean MEP ratio for the left hand, two-way repeated-measures ANOVA showed no significant effects of Time, but significant effects of Time Group interactions
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Fig. 1. Effect of compact magnet (SMF) and sham (control) on the amplitude of MEP (A) and rMT (B) measured in the right APB muscle. The mean MEP amplitude was significantly decreased, and the mean rMT was significantly increased immediately after both interventions compared to the control condition. The values of these parameters are expressed as a percentage of baselines. ⁄p < 0.05.
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Fig. 2. Effect of compact magnet (SMF) and sham (control) on the SICI (A) and ICF (B) measured in the right APB muscle. The mean SICI was significantly decreased immediately after both interventions compared to the control condition, but not significantly different in ICF. The values of these parameters are expressed as a percentage of baselines. ⁄p < 0.05.
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Fig. 3. Effect of MRI exposure on the amplitude of MEP (A) and rMT (B) measured in the right APB muscle. The mean MEP amplitude was significantly decreased, and the mean rMT was significantly increased immediately after interventions. The values of these parameters are expressed as a percentage of baselines. ⁄p < 0.05.
4. Discussion We found that not only the inhomogeneous SMFs induced by a compact magnet but also the homogeneous SMF produced by the MRI scanner bore itself without scanning can alter the human M1 cortical function transiently. Extending the previous studies (Oliviero et al., 2011; Silbert et al., 2013) that reported the suppression of human corticospinal excitability, we found a significant increase of the SICI due to SMFs. We observed the SMF-related increase of cortical inhibitory circuits measured by SICI and SP. SICI is measured in a paired-pulse TMS protocol involving a subthreshold conditioning stimulus followed by a suprathreshold test stimulus with a short interstimulus interval of 1–5 ms (Kujirai et al., 1993; Nakamura et al., 1997; Chen et al., 1998). It is general consensus that SICI occurs at the cortical level and that intracortical inhibitory interneurons play an important role (Ziemann et al., 1996c; Di Lazzaro et al., 2002; Ferreri et al., 2006; Paulus et al., 2008). As SICI can be increased by drugs that enhance GABA-A transmission but is unaffected by drugs that block voltage-gated sodium channels (Ziemann et al., 1996b; Chen et al., 1998), it is likely that SICI provides an index of instantaneous inhibition by fast ionotropic postsynaptic GABA-A receptors that produce an inhibitory postsynaptic potential with a rise time of about 2 ms. By contrast, the duration of SP, which showed the tendency of increase but not a significant effect, is compatible with a long-lasting inhibition mediated by GABA-B receptors (Connors et al., 1988) and can be prolonged by the GABA reuptake inhibitor (Werhahn et al., 1999). Our results suggest that suppression of M1 induced by SMF exposure may be partly related to the modulation of the GABAergic system. There have been a couple of animal studies on the physiologic mechanism of suppressed neural activities under strong SMFs (Rosen and Lubowsky, 1987; Coots et al., 2004). It has been reported that SMFs can interact with membrane ion channels, possibly due to the diamagnetic anisotropic properties of membrane phospholipids (Rosen, 2003b; Miyakoshi, 2005). Previous studies revealed that the activation kinetics of both sodium (Rosen, 2003a; Coots et al., 2004) and calcium channels (Rosen, 1996) are transiently slowed during exposure to SMFs. Reorientation of these molecules during SMF exposure results in deformation of embedded ion channels, thereby altering their activation kinetics (Rosen, 2003b). If the neural effects of SMFs are associated with channel dysfunction in general, we can expect that all neural activities would be suppressed. This hypothesis fits with the M1 excitability measures, such as rMT and MEP amplitudes. Although the basis of rMT is not certain, pharmacological research has suggested that it is modulated by membrane excitability (Ziemann et al., 1996b,a). In addition to the decrease of MEP amplitudes, we found the increase of rMT just after the SMFs in accordance with a previous study (Silbert et al., 2013).
However, regarding the significant enhancement of SICI, the transient disturbance of the GABA reuptake mechanism induced by SMFs should be taken into account. Although the sound experimental data in animal models are lacking, it can be speculated that the SMF-induced deformation of membrane channels could also affect GABA transporters (GATs), which modulate phasic and tonic GABA-mediated inhibition and GABA spillover (Conti et al., 2004). Suppression of GATs can cause an increased concentration of ambient GABA at the synapse (Eulenburg and Gomeza, 2010). With higher concentration of GABA molecule in the synaptic cleft due to the dysfunction of the reuptake system, GABA receptor function would be restored immediately after the removal of SMFs. The consequence could result in facilitating the inhibitory circuits by activating GABA-A receptors at postsynaptic sites. For the clinical MRI scanner, however, it has been reported that vertigo and nystagmus can be driven by continuous input from a static homogeneous magnetic field (Mian et al., 2013). One recent study reported that the MRI scanning led to a transient prolongation of the SP and an increase of rMT at 1.5 and 7 T, whereas these effects did not occur during sole exposition to the static MRI field in healthy humans (Schlamann et al., 2010). This observation is inconsistent with the recent studies that showed the modulatory effects of SMFs on human M1 using a compact magnet (Silbert et al., 2013). One possible reason for divergence might be the use of non-focal round large TMS coil in Schlamann’s study. Recent studies, including ours, used a focal TMS coil and found the alteration of M1 function following SMFs associated with the static magnetic fields (Oliviero et al., 2011; Silbert et al., 2013). In sham intervention, one-way repeated-measures ANOVA showed no significant effect. Although we cannot directly compare the MRI bore with the sham intervention for the different experimental settings, the result suggested that the effect of the MRI bore was comparable to the effect of SMF on the human cortex. There are a few possibilities that can explain the effects of SMFs on biological materials. Although the possible effects of Lorentz’s force associated with blood flow have been particularly concerned, SMFs have not been shown to affect other cardiovascular functions (Atkinson et al., 2007). Thus, it is unlikely that the neural effects are mediated by blood flow. Second, as suggested by previous studies (Rosen, 2003b; Oliviero et al., 2011), magnetic force that is caused by a spatially inhomogeneous magnetic field depending on the steepness of the gradient might be relevant for modulating the neural excitability in M1 by affecting the transmembrane channel functions. Although a compact magnet may produce a steep field gradient, our study using an MRI scanner bore showed the possible contribution of magnetic torque within the homogeneous SMFs. The possible effects of homogeneous SMFs have been suggested by previous animal studies (Edelman et al., 1979; Rosen, 1994, 1996, 2003b,a; Coots et al., 2004).
Please cite this article in press as: Nojima I et al. Static magnetic field can transiently alter the human intracortical inhibitory system. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.01.030
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Recent study showed that the magnetic field strength is in a range between 120 and 200 mT 2–3 cm from the magnet surface (Rivadulla et al., 2014). Therefore, it seems that, at least in this range of magnetic fields (0.1–3.0 T), the biological effects of magnetic fields might be similar. Due to the limitation of the time during the experiment, we only tested the SICI with the ISI of 3 ms and the ICF with 12 ms. It is possible that the SICI might be partly contaminated by a short-interval intracortical facilitation (SICF) (Hanajima et al., 2002; Hanajima, 2013; Shirota et al., 2010; Buharin et al., 2014). In addition, ICF parameters, such as stimulus intensity, interval, and/or test MEP sizes (Kujirai et al., 1993; Ortu et al., 2008), have not been systematically investigated. Further studies are necessary to confirm these points. The present study showed that SMFs could potentially be used to transiently influence cortical excitability. Until now, time-varying magnetic fields, for example TMS, are widely used for brain stimulation, which can be applied for rehabilitation or therapy for neuropsychiatric disorders (Lam et al., 2008; Koganemaru et al., 2010; Rossini et al., 2010; Dayan et al., 2013; Schulz et al., 2013). In addition to the possible use of SMFs for suppressive brain stimulation techniques such as low-frequency repetitive TMS or cathodal tDCS, our results suggest that it might be possible to use SMFs to increase SICI. Enhancement of SICI function by SMFs might be a new promising therapeutic tool for neurological disorders associated with GABA dysfunction, such as epilepsy (Meldrum and Rogawski, 2007; White et al., 2007), which was supported by data obtained in animal models (McLean et al., 2003, 2008), and dystonia (Ikoma et al., 1996; Garibotto et al., 2011; Boecker, 2013). However, we should be cautious about the clinical application of brain stimulation methods to modulate the neuroplasticity, because high variability across subjects has been reported (Hamada et al., 2013). Acknowledgments This study was partly supported by Grant-in-Aid for Scientific Research (B) 24300192 (to T.M.) and Grant-in Aid for Young Scientists (B) 25750203 (to I.N.) from the Japan Society for the Promotion of Science. Conflict of interest: None of the authors have potential conflicts of interest to be disclosed. We confirm that we have read the journal’s position on issues involved in ethical publication. References Aldinucci C, Garcia JB, Palmi M, Sgaragli G, Benocci A, Meini A, et al. The effect of strong static magnetic field on lymphocytes. Bioelectromagnetics 2003;24:109–17. Atkinson IC, Renteria L, Burd H, Pliskin NH, Thulborn KR. Safety of human MRI at static fields above the FDA 8 T guideline: sodium imaging at 9.4 T does not affect vital signs or cognitive ability. J Magn Reson Imaging 2007;26:1222–7. Badawy RA, Loetscher T, Macdonell RA, Brodtmann A. Cortical excitability and neurology: insights into the pathophysiology. Funct Neurol 2012;27:131–45. Boecker H. Imaging the role of GABA in movement disorders. Curr Neurol Neurosci Rep 2013;13:385. Buharin VE, Butler AJ, Shinohara M. Motor cortical disinhibition with baroreceptor unloading induced by orthostatic stress. J Neurophysiol 2014;111:2656–64. Chakeres DW, de Vocht F. Static magnetic field effects on human subjects related to magnetic resonance imaging systems. Prog Biophys Mol Biol 2005;87:255–65. Chen R. Interactions between inhibitory and excitatory circuits in the human motor cortex. Exp Brain Res 2004;154:1–10. Chen R, Tam A, Butefisch C, Corwell B, Ziemann U, Rothwell JC, et al. Intracortical inhibition and facilitation in different representations of the human motor cortex. J Neurophysiol 1998;80:2870–81. Connors BW, Malenka RC, Silva LR. Two inhibitory postsynaptic potentials, and GABAA and GABAB receptor-mediated responses in neocortex of rat and cat. J Physiol 1988;406:443–68. Conti F, Minelli A, Melone M. GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications. Brain Res Brain Res Rev 2004;45:196–212.
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Please cite this article in press as: Nojima I et al. Static magnetic field can transiently alter the human intracortical inhibitory system. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.01.030