Effects of Short-Term Repetitive Transcranial Magnetic Stimulation on P300 Latency in an Auditory Odd-Ball Task

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1 28 INTERNATIONNAL JOURNAL OF APPLIED BIOMEDICAL ENGINEERING VOL.5, NO Effects of Short-Term Repetitive Transcranial Magnetic Stimulation on P300 Latency in an Auditory Odd-Ball Task Tetsuya Torii 1, Aya Sato 1, Yukiko Nakahara 1, Masakuni Iwahashi 2, Yuji Itoh 1, and Keiji Iramina 3, ABSTRACT The present study analyzed the effects of repetitive transcranial magnetic stimulation (rtms) on brain activity. The latency of the P300 component of the event-related potential (ERP) was used to evaluate the effects of low-frequency and short-term rtms over areas thought to be related to the generation of the P300, including the supramarginal gyrus (SMG) and dorsolateral prefrontal cortex (DLPFC). A flat figure-eight coil was used to stimulate left and right SMG and DLPFC, applying magnetic stimulation at an intensity that was 80% of the subjectś motor threshold. A total of 100 magnetic pulses were applied in rtms, with stimulation frequencies of 1.0 and 0.5 Hz. ERPs were measured while subjects completed the odd-ball task pre- and post-rtms. We found that rtms over the left SMG decreased P300 latency at 1.0 Hz rtms. Compared with the latency of pre-rtms, the latency differed by approximately 20 ms at Cz. In contrast, P300 latency increased at 0.5 Hz rtms. Compared with the latency of pre-rtms, the latency time difference was approximately 20 ms at Cz. However, 1.0 Hz rtms over left DLPFC caused an increase in P300 latency. Following rtms, latency differed by approximately 25 ms at Cz. In contrast, P300 latency was unchanged following 0.5 Hz rtms. rtms applied to the right SMG and DLPFC caused no significant differences between pre- and post-rtms, regardless of the stimulation frequency. The results demonstrated that P300 latency varied according to the frequency of rtms. These findings suggest that the effects of rtms are frequency-dependent and hemisphere-dependent. 1. INTRODUCTION Transcranial magnetic stimulation (TMS) is a neurodiagnostic tool that was first developed in 1985 [1], [2]. TMS has been used to map the function of different cortical areas [3], [4]. Repetitive transcranial magnetic stimulation (rtms) has been used in studies of the human brain [5], and to treat certain brain diseases and neurological disorders [6], [7]. Stimulating the dorsolateral prefrontal cortex (DLPFC) using TMS or rtms has been reported to provide an effective treatment for depression [8]. A brief high-current pulse produced in a wire coil (a magnetic coil) produces magnetic stimulation. In TMS or rtms, a coil placed on the scalp produces an eddy current in the brain [9], [10]. In addition, TMS and rtms are noninvasive methods for directly stimulating brain areas. Although electroconvulsive therapy (ECT) can also be used for brain stimulation, it is affected by the high impedance of the skull, skin and hair. In contrast, TMS and rtms are not affected by impedance. Magnetic fields can induce an electric current in the cortex by non-infestation. The induced electric current is required to alter neuronal activity [11]. Because of these advantages, TMS and rtms have attracted much recent research attention. Most studies of the effects of TMS and rtms have focused on the motor evoked potential (MEP) or event-related potential (ERP) [12]-[20]. The MEP has been used to evaluate the effects of TMS and rtms. While MEPs can only be used to assess the effects of magnetic stimulation to motor areas, other ERPs can be used to assess the effects of TMS and rtms to sensory areas. The P300 component of ERPs has also been used to evaluate the effects of TMS and rtms. A recent study revealed that P300 latency was delayed when TMS was applied to the left supramarginal gyrus (SMG) at 200 or 250 ms after odd-ball auditory stimulation [21]. This magnetic stimulation point (SMG) is thought to constitute the source of generation of the P300 [22]. In contrast, one study found that low-frequency rtms in the right DLPFC produced no significant change in the P300 component before and after magnetic stimulation [23]. Manuscript received on August 14, 2012 ; revised on October 17, The authors are with the Department of Medical Engineering, Gakuen University, Japan, torii@junshin-u.ac.jp 2 The author is with the Course of Information Technology, Tokai University, Japan 3 The author is with the Graduate School of Systems Life Sciences, Kyushu University, Japan However, little is known about the effects of P300 latency following low-frequency and short-term magnetic stimulation (e.g., 100 magnetic pulses at 1.0 or 0.5 Hz) using rtms. Thus, in the present study, we analyzed the effects of rtms (at 1.0 and 0.5 Hz) in the left-right SMG and DLPFC.

2 T. Torii, A. Sato, Y. Nakahara, M. Iwahashi, Y. Itoh and K. Iramina 29 pling frequency was 1,000 Hz and the synchronized sum was 20 times. Recorded data were processed using a band-pass digital filter from 0.5 Hz to 50 Hz Repetitive transcranial magnetic stimulation (rtms) Fig.1:: Auditory odd-ball task. Fig.2:: The paradigm involved the auditory odd-ball task, conducted before and shortly after repetitive magnetic stimulation (rtms). In this study, the Super Rapid Stimulator (Magstim Co. Ltd.) was used as the magnetic stimulator device, with a flat figure-eight coil (70 mm diameter). rtms was conducted with 1.0 Hz and 0.5 Hz stimulation. We used four stimulation points, including left SMG, right SMG, left DLPFC and right DLPFC. rtms was conducted using 100 magnetic pulses, each with a width of 2 ms. The strength of magnetic stimulation was set at 80% of subjects motor threshold (MT). The subjects individual MT was the point at which MEPs of more than 50 µv peakto-peak amplitude were produced in at least six of 10 successive trials. 2. MATERIALS AND METHODS 2. 1 Measurements In the current study, STIM2 (Neuro Scan Ltd.) was used to produce sound stimuli and trigger signals. The sound stimuli were used in the auditory odd-ball task, and the trigger signals were used for the initiation of electroencephalography (EEG). EEG was recorded using a personal computer. Subjects were instructed to click a computer mouse button when the target sounds in the auditory odd-ball task were presented. Reaction times (RTs) were measured using STIM Auditory odd-ball task Fig. 1 illustrates the auditory odd-ball task in this study. The auditory odd-ball task consisted of 1 khz and 2 khz sound stimuli. The standard auditory stimulus was a 1 khz sound (non-target). The deviant auditory stimulus was a 2 khz sound (target). The standard stimulus was presented in 80% of trials. The deviant stimulus was presented in 20% of trials. The auditory stimuli were randomly presented, consisting of a burst wave with a duration of 50 ms. The interval of the stimulation sounds was 2.5 seconds, and the sound pressure was 60 db. Stimulus sounds were presented to the subject through earphones Electroencephalography (EEG) EEG data were recorded in an electrically shielded room. EEG data were measured at the Fz, Cz and Pz electrodes according to the international system, and each polar contact impedance was set at less than 5 kilo ohms. Each EEG recording period lasted 1.0 second, and recording began with the standing edge of the stimulation sound. The sam- Fig.3:: Event-related potentials (ERPs) at Fz before and after 1.0 and 0.5 Hz stimulation of the left supramarginal gyrus (SMG). The black line represents the ERP before the magnetic stimulation, and the gray line represents an ERP after magnetic stimulation Experimental procedure Fig. 2 shows the experimental paradigm, divided into three phases. In this paradigm, an auditory oddball task was conducted prior to magnetic stimulation as a control condition. rtms was then applied to the left SMG, right SMG, left DLPFC or right DLPFC. The auditory odd-ball task was then conducted again immediately following rtms, to evaluate the effects of magnetic stimulation. In this study, we enrolled 13 healthy (six female and seven male) right-handed volunteers as subjects. Subjects ages ranged from years of age. Subjects were instructed to relax and remain seated during testing.

3 30 INTERNATIONNAL JOURNAL OF APPLIED BIOMEDICAL ENGINEERING Fig.4:: ERPs at the Fz before and after 1.0 and 0.5 Hz stimulation of the right SMG. The black line represents an ERP before the magnetic stimulation, and the gray line represents an ERP after the magnetic stimulation. Fig.5:: ERPs at Fz before and after 1.0 and 0.5 Hz stimulation of the left dorsolateral prefrontal cortex (DLPFC). The black line represents an ERP before the magnetic stimulation, and the gray line represents an ERP after magnetic stimulation. 3. RESULTS Fig. 3 shows ERPs at the Fz electrode before and after magnetic stimulation of the left SMG, which was found to shorten P300 latency with 1.0 Hz rtms, and delay P300 latency with 0.5 Hz rtms. Compared with the control condition, immediately following 1.0 Hz magnetic stimulation, P300 latencies were shortened by 25.6 ms at the Fz electrode, 20.6 ms at the Cz electrode and 33.6 ms at the Pz electrode. Compared with the control condition, immediately following 0.5 Hz stimulation, P300 latencies were delayed by 25.3 ms at the Fz electrode, 17.3 ms at the Cz electrode and 23.4 ms at the Pz electrode. Fig. 4 shows ERPs at the Fz electrode before and after magnetic stimulation of the right SMG, which did not affect P300 latencies with 1.0 and 0.5 Hz rtms. Compared with the control condition, immediately after 1.0 Hz magnetic stimulation, P300 la- VOL.5, NO Fig.6:: ERPs at Fz before and after 1.0 and 0.5 Hz stimulation of the right DLPFC. The black line represents an ERP before magnetic stimulation, and the gray line represents an ERP after magnetic stimulation. tencies were little altered by 0.9 ms at the Fz electrode, 4.8 ms at the Cz electrode and 6.0 ms at the Pz electrode. Compared with the control condition, immediately after 0.5 Hz, magnetic stimulation, P300 latencies were little altered by 1.7 ms at the Fz electrode, 1.2 ms at the Cz electrode and 0.1 ms at the Pz electrode. Fig. 5 shows ERPs at the Fz electrode before and after magnetic stimulation of the left DLPFC. DLPFC stimulation delayed P300 latency with 1.0 Hz rtms and did not change P300 latency with 0.5 Hz rtms. Compared with the control condition, immediately after 1.0 Hz magnetic stimulation, P300 latencies were delayed by 17.7 ms at the Fz electrode, 27.2 ms at the Cz electrode and 25.8 ms at the Pz electrode. Compared with the control condition, immediately after magnetic stimulation with 0.5 Hz, P300 latencies were little altered by 6.7 ms at the Fz electrode, 1.7 ms at the Cz electrode and 7.9 ms at the Pz electrode. Fig. 6 shows ERPs at the Fz electrode before and after magnetic stimulation of the right DLPFC, which did not change P300 latencies at 1.0 and 0.5 Hz rtms. Compared with the control condition, immediately after 1.0 Hz magnetic stimulation, P300 latencies were little altered by 4.6 ms at the Fz electrode, 3.9 ms at the Cz electrode and 0.2 ms at the Pz electrode. Compared with the control condition, immediately after 0.5 Hz magnetic stimulation, P300 latencies were little altered by 6.8 ms at the Fz electrode, 5.5 ms at the Cz electrode and 4.7 ms at the Pz electrode. Paired t-tests were used to examine significant differences in P300 latencies between before and after rtms. Fig. 7 shows P300 latencies and the ratio of P300 latency before (control condition) and after magnetic stimulation of the left SMG with (a) 1.0 and (b) 0.5 Hz rtms. With 1.0 Hz rtms, the significant difference before and after rtms was observed (Fz: p 0.001, Cz: p 0.001, Pz: p 0.001).

4 T. Torii, A. Sato, Y. Nakahara, M. Iwahashi, Y. Itoh and K. Iramina 31 (a) 1.0 Hz rtms (a) 1.0 Hz rtms (b) 0.5 Hz rtms Fig.7:: P300 latencies and difference in normalized P300 latencies to each pre-rtms over the left SMG at (a) 1.0 Hz and (b) 0.5 Hz. In the difference in normalized P300 latency, the positive bar indicates the shortened state and negative bar indicates the delayed state. (b) 0.5 Hz rtms Fig.8:: P300 latencies and difference in normalized P300 latencies difference to each pre-rtms over the right SMG at (a) 1.0 Hz and (b) 0.5 Hz. In the difference in normalized P300 latency, the positive bar indicates the shortened state and the negative bar indicates the delayed state.

5 32 INTERNATIONNAL JOURNAL OF APPLIED BIOMEDICAL ENGINEERING VOL.5, NO (a) 1.0 Hz rtms (a) 1.0 Hz rtms (b) 0.5 Hz rtms Fig.9:: P300 latencies and difference in normalized P300 latencies to each pre-rtms over the left DLPFC at (a) 1.0 Hz and (b) 0.5 Hz. In the difference in normalized P300 latency, the positive bar indicates the shortened state and the negative bar indicates the delayed state. (b) 0.5 Hz rtms Fig.10:: P300 latencies and difference in normalized P300 latencies to each pre-rtms over the right DLPFC at (a) 1.0 Hz and (b) 0.5 Hz. In the difference in normalized P300 latency, the positive bar indicates the shortened state and the negative bar indicates the delayed state.

6 T. Torii, A. Sato, Y. Nakahara, M. Iwahashi, Y. Itoh and K. Iramina 33 (a) Left SMG (a) Left DLPFC (b) Right SMG Fig.11:: Reaction time and difference in normalized reaction time difference for each pre-rtms over (a) the left SMG and (b) right SMG at target sounds. For the difference in normalized reaction time, the positive bar indicates shortened latency, and the negative bar indicates delayed latency. (b) Right DLPFC Fig.12:: Reaction time and difference in normalized reaction time to each pre-rtms over (a) the left DLPFC and (b) right DLPFC at target sounds. For the difference in normalized reaction time, the positive bar indicates shortened latency and the negative bar indicates delayed latency.

7 34 INTERNATIONNAL JOURNAL OF APPLIED BIOMEDICAL ENGINEERING VOL.5, NO The results revealed a significant difference before and after 0.5 Hz rtms (Fz: p<0.001, Cz: p<0.001, Pz: p<0.01). Fig. 8 shows P300 latencies and the ratio of P300 latency before (control condition) and after magnetic stimulation to the right SMG with (a) 1.0 and (b) 0.5 Hz. Significant differences were not observed before and after magnetic stimulation of this area. Fig. 9 shows P300 latencies and the ratio of P300 latency before (control condition) and after magnetic stimulation of the left DLPFC with (a) 1.0 and (b) 0.5 Hz. The results revealed a significant difference before and after 1.0 Hz rtms (Fz: p<0.01, Cz: p<0.01, Pz: p<0.01). With 0.5 Hz rtms, significant differences were not observed before and after left DLPFC stimulation. Fig. 10 shows P300 latencies and the ratio of P300 latency before (control condition) and after magnetic stimulation of the right DLPFC with (a) 1.0 and (b) 0.5 Hz. Significant differences were not observed before and after magnetic stimulation in this area. Fig. 11 and Fig. 12 show RTs before and after magnetic stimulation of the left SMG, right SMG, left DLPFC and right DLPFC, and the normalization of the ratio of reaction time in the control condition. Significant differences were not observed before and after magnetic stimulation. 4. DISCUSSION Previous studies have reported that low-frequency rtms decreases cortical excitability, while highfrequency rtms increases excitability [24]-[26]. As such, we predicted that low-frequency rtms would delay P300 latencies. This hypothesis was confirmed by the observed effects of 1.0 Hz rtms over the left DLPFC and 0.5 Hz rtms over the left SMG. These results indicate that 1.0 Hz rtms over the left DLPFC and 0.5 Hz rtms over the left SMG inhibit cerebral cortex activity. However, P300 latency was not delayed following 1.0 Hz rtms in the left SMG, 0.5 Hz rtms in the left DLPFC, or rtms of either frequency in the right SMG or DLPFC. P300 latency exhibited a particularly strong decrease following 1.0 Hz rtms over the left SMG. This result suggests that 1.0 Hz rtms over the left SMG excites the cerebral cortex. Previous studies have suggested that neuronal excitation can be induced by rtms [27], [28]. Thus, the current results suggest that neuronal excitation elicited by rtms increased the activity of inhibitory synapses. This indicates that excited neurons were inhibited, transitioning to a suppressed or resting state. This inhibition also resulted from low-frequency magnetic stimulation, including 1.0 Hz rtms of the left DLPFC and 0.5 Hz rtms of the left SMG. The present results thus suggest that activated neurons in the left DLPFC (0.5 Hz rtms), right SMG and DLPFC (1.0 or 0.5 Hz rtms) were inhibited by inhibitory synapses. Following this inhibition, excited neurons returned to the resting state. This may explain why P300 latencies were not affected by these types of stimulation. In other words, it is thought that the left DLPFC (0.5 Hz rtms) and right SMG and DLPFC (1.0 and 0.5 Hz rtms) were affected by magnetic stimulation even when P300 latency was unaltered. However, if neurons were exposed to high-frequency magnetic stimulation, even at inhibitory synapses, the transition from a strongly excited state to the resting or inhibited state may be difficult. In the current study, 1.0 Hz rtms over the left SMG was found to induce a sustained state of excitation. This was caused by low-frequency magnetic stimulation of 1.0 Hz. In addition, the SMG and DLPFC have been shown to be involved in generating the P300 [22]. However, the P300 latency of right SMG and DLPFC has been little altered compared with the left SMG and DLPFC. These results suggest that the left SMG was most susceptible to magnetic stimulation and most tributary to generation of P300, compared with other areas. These results are consistent with other frequency-dependent effects reported in the left but not the right DLPFC [29], indicating that low-frequency rtms applied to the right DLPFC produced no significant changes [23]. In this study, 1.0 Hz magnetic stimulation of the left SMG induced excitation, while inhibition was induced by 1.0 Hz magnetic stimulation of the left DLPFC and 0.5 Hz magnetic stimulation of the left SMG. In addition, the resting state was induced by 0.5 Hz magnetic stimulation of the left DLPPFC and 1.0 or 0.5 Hz magnetic stimulation of the right SMG and DLPFC. Taken together, the current results demonstrate that 1.0 and 0.5 Hz rtms over the left SMG and DLPFC results in different effects on P300 latencies. 5. CONCLUSION The present study analyzed the effects of rtms on regional brain activity. The P300 latency of ERPs was used to evaluate the effects of low-frequency and short-term rtms by stimulating bilateral SMG and DLPFC. The results revealed different effects on P300 latencies following 1.0 and 0.5 Hz rtms over the left SMG and DLPFC. These findings indicate that the effects of rtms over the left SMG and DLPFC were frequency-dependent. The results also demonstrated that rtms over the right SMG and DLPFC had no significant effects on P300 latencies and were therefore not frequency-dependent. There were also no differences in RTs, regardless of the stimulation frequency or the hemisphere stimulated. References [1] A. T. Barker, I. L. Freeston, R. Jalinous, P. A. Merton, and H. B. Morton, Magnetic stimulation of the human brain., J. Physiol, vol. 369, p. 3, July [2] A. T. Barker, R. Jalinous, and I. L. Freeston, Non-invasive magnetic stimulation of human motor cortex., Lancet, vol. 1, pp , May [3] T. Paus, R. Jech, C. J. Thompson, R. Comeau, T.

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9 36 INTERNATIONNAL JOURNAL OF APPLIED BIOMEDICAL ENGINEERING VOL.5, NO M. Manfredi, Facilitation of muscle evoked responses after repetitive cortical stimulation in man., Exp Brain Res, vol. 122, pp , [27] Y. Mano, Y. Morita, R. Tamura, S. Morimoto, T. Takayanagi and R. F. Mayer, The site of action of magnetic stimulation of human motor cortex in a patient with motor neuron disease., J Electromyography Kinesiology, vol. 3, pp , [28] Y. Mano, T. Nakamurro, K. Ikoma, T. Takayanagi and R. F. Mayer, A clinicophysiologic study of central and peripheral motor conduction in hereditary demyelinating motor and sensory neuropathy., Electromyogr. Clin. Neurophysiol., vol. 33, pp , [29] D. Knoch, P. Brugger and M. Regard, Suppressing versus releasing a habit: Frequencydependent effects of prefrontal transcranial magnetic stimulation., Cerebral Cortex, vol. 15, pp , Y. Nakahara received her Ph.D degree in Engineering from Kyushu University, Japan, in From 1997 to 2011, she worked at the Faculty of Engineering, Tohwa University. She has been a professor of the Faculty of Engineering in Tohwa University. In 2011, she moved to Junshin Gakuen University as an associate professor of Faculty of Health Sciences. M. Iwahashi received his Ph.D degree in Engineering from Kyushu University, Japan, in From 1980 to 2011, he worked at the Faculty of Engineering, Tohwa University. In 2011, he moved to Junshin Gakuen University, and he has been a professor of Faculty of Health Sciences in Junshin Gakuen University. In 2012, he moved to Tokai University as a project professor of School of Industrial Engineering. T. Torii completed his Ph.D program without a Ph.D. degree in the Graduate School of Life Science and Systems Engineering from Kyushu Institute of Technology, Japan, in From 1996 to 2011, he worked at the Faculty of Engineering, Tohwa University. He has been a lecturer of the Faculty of Engineering in Tohwa University. In 2011, he moved to Junshin Gakuen University as a lecturer of Faculty of Health Sciences. A. Sato received her masters degree in Engineering from Kurume Institute of Technology, Japan, in From 2004 to 2011, she worked at the Faculty of Engineering, Tohwa University. She has been a project lecturer of the Faculty of Engineering in Tohwa University. In 2011, she moved to Junshin Gakuen University as a research associate of Faculty of Health Sciences. Y. Ito received his M.D. degree in Medicine from Kurume University, Japan, in In 2011, he moved to Junshin Gakuen University as a project professor of Faculty of Health Sciences. K. Iramina received his Ph.D degree in Engineering from Kyushu University, Japan, in From 1991 to 1995, he worked at the Department of Electronics, Kyushu University. In 1996, he moved to the University of Tokyo, Japan and he has been an associate professor of Institute of Biomedical Engineering, the University of Tokyo. In 2005, he moved Kyushu University as a professor of Graduate School of Information Science an Electrical Engineering. He has been also a professor of Graduate School of Systems Life Sciences in Kyushu University.