Introduction 1991 1994 1999 1999 1999 1999 1999 2002 s 2000 2005 1993 1999 2000 2002 2001 2000 2003 2004 1993 2002 2003 2000 2004 2003 2003 2005 1993 2001 2002 2005 2004 2006 2007 2006 2004 2007 2005 2005 2005 2006 s 2007 2007 2000 2005 2005 Methods Subjects Nineteen healthy volunteers between 18 and 35 years were informed about all aspects of the experiments and signed an informed consent. Three subjects chose not to continue the experiment after the first or second session and during off-line EEG analysis four further subjects were dropped out because of their hardly detectable LEP components. Hence, twelve of the subjects (six male, six female; mean age = 26.33 ± 3.17 years) were included in the final analysis. We conformed with the Declaration of Helsinki and the experimental protocol was approved by the Ethics Committee of the University of Göttingen. None of the subjects suffered from chronic pain syndromes, nor took any medication regularly. None had a history of neurological or psychiatric illness. All of them participated in all four sessions, the three TBS and sham stimulations. TBS stimulation 2005 For AMT determination, the coil was placed tangentially to the scalp, with the handle pointing backwards and laterally 45° from mid-line. MEPs of the right abductor digiti minimi muscle (ADM) were recorded by Ag-AgCl-electrodes in a belly tendon-montage before each stimulation. The signals were amplified and filtered (1.59 Hz-1 kHz, sampling rate of 5 kHz), digitalized with a micro 1401 AD converter (Cambridge Electronic Design, Cambridge, UK), recorded by a computer using SIGNAL software (Cambridge Electronic Design, Version 2.13). Complete muscle relaxation was controlled though auditory and visual feedback of EMG activity. AMT was defined as the minimum intensity eliciting a MEP of a superior size when compared to spontaneous moderate muscular activity in at least three of six pulses. 2005 2001 Determination of the primary somatosensory cortex (SI) 1999 2003 1 Fig. 1 MRI black point  Laser stimulation 2003 2003 Psychophysical evaluation We used the verbal analogue score (VAS) to assess the subjective intensity of pain. The subjects were instructed to pay attention to the laser stimuli and to rate the perceived pain verbally (1-warm, 1.1 smallest pain, and 1.9 most intense pain) about 2–3 s after each laser-impulse. The values were individually averaged separately for both hands in each session and conditions. The ears of the subjects were plugged during the measurements to avoid auditory artifacts accompanying laser stimulation. Electrophysiological recordings The EEG was recorded using a 64-channel montage applying 64 ring electrodes (inner diameter: 6 mm, outer diameter: 12 mm) (EasyCap; Falk and Minow GmbH, Münich, Germany). The electrodes were placed in accordance with the extended international 10–20 system. The impedance was kept <5 kΩ. The Fz was used as reference, the ground was placed 2 cm anterior to the tragus of the right ear. Data were collected at a sampling rate of 1,000 Hz with the BrainAmp system (Brain Products GmbH, Munich, Germany) and were analyzed offline. The obtained data were re-referenced to the connected mastoids (TP9-TP10). A 0.5 Hz low-cutoff as well as a 30 Hz high-cutoff filter was used. In addition to automatic artifact detection (200 μV amplitude criterion) all epochs were visually inspected, and those containing eye blinks or muscle movement artifacts were excluded. Baseline correction was performed on the basis of the 100 ms prestimulus interval. The amplitudes of N1 (referring to Fz) and N2–P2 (referring to TP9-TP10) components were measured. Although we recorded data on 64 channels, we assessed LEPs according to the scalp distribution on the analyzed peaks. The N2 is a negative component (referring to TP9-TP10) was peaking around 160–240 ms. The amplitude of the early N1 negative peak which came before N2 on T7 and T8 channels (referring to Fz) was analyzed. The P2 positive component after N2 was peaking around 300–360 ms. The N2 component is largest over the lateral temporal and fronto-central areas on electrodes Fz, Cz, CPz, F1–F4, FC1–FC6, C1–C6, T7, T8, and CP1–CP6. In contrast, the P2 peak has its maximum amplitude over the vertex on electrodes FCz, Cz, CPz, Pz, F1–F4, FC1–FC4, C1–C4, CP1–CP4, and P1–P4. For the analysis of LEPs according to regional distribution, we defined three distinct areas with pooling the data: central (with all the mid-line electrodes such as Fz, FCz, Cz, CPz, and Pz), left (F3, FC3, C3, CP3, P3, FC5, C5, CP5, and T7) and right (electrodes according to the left side) instead of separate electrodes. Experimental design 2003 The experimental sessions were separated from each other by at least 5 days. The subjects were blinded as to the type of magnetic stimulation. The order of the sessions was randomized across subjects. Data analysis t P Results Psychophysics 2 2 2 2 F P F P F P F P F P F P 2 Fig. 2 left right  Electrophysiology 3 4 Fig. 3 solid line intermittent line  Fig. 4 right central left right solid line intermittent line  The N1 component F P F P F P F P F P F P 3 The N2 component F P F P F P 5 F P F P F P 5 F P t 1 t Fig. 5 left right central left right stars mark t P  Table 1 Post hoc analysis of the N2 component   cTBS iTBS imTBS sham Before versus after Before versus after Before versus after Before versus after Central P 0.0033 0.0002 0.0021 0.3942 t −3.730 −5.499 −4.005 −0.887 Left P 0.0054 0.0004 0.0031 0.5921 t −3.451 −5.041 −3.775 −0.552 Right P 0.0394 0.0085 0.0039 0.8118 t −2.337 −3.196 −3.645 0.244 t P The P2 component F P F P F P F P F P F P 2 Table 2 The mean amplitudes of the LEP components Peak  cTBS iTBS imTBS sham Before After Before After Before After Before After Left hand N1 T7 −4.42 ± 2.75 −4.60 ± 3.13 −4.68 ± 2.52 −3.71 ± 2.65 −3.33 ± 3.22 −3.50 ± 3.15 −4.98 ± 2.70 −5.20 ± 3.08 T8 −6.13 ± 2.17 −4.78 ± 3.60 −6.73 ± 3.44 −5.13 ± 2.89  −4.99 ± 4.27 −4.64 ± 3.62 −6.56 ± 3.47 −6.33 ± 3.11 N2 Central −9.77 ± 5.48 −7.92 ± 4.91 −10.29 ± 5.01 −8.88 ± 3.98 −9.04 ± 5.43 −7.25 ± 5.52 −10.02 ± 4.43 −8.11 ± 6.16 Left −7.13 ± 3.60 −6.05 ± 3.44 −7.44 ± 3.49 −6.69 ± 2.91 −6.81 ± 3.69 −5.55 ± 3.88 −7.13 ± 3.55 −5.98 ± 4.28 Right −6.70 ± 3.05 −4.59 ± 3.25 −6.42 ± 3.54 −5.41 ± 2.56 −5.88 ± 3.05 −4.70 ± 3.19 −6.11 ± 3.24 −4.82 ± 3.85 P2 Central 14.79 ± 8.02 11.74 ± 7.03 14.86 ± 7.69 12.43 ± 7.00 13.19 ± 7.74 11.26 ± 8.23 13.83 ± 6.75 12.03 ± 6.31 Left 8.40 ± 3.89 7.18 ± 3.66 9.19 ± 4.74  7.74 ± 3.59 7.36 ± 4.80 6.63 ± 5.16 7.90 ± 3.64 6.84 ± 3.67 Right 8.80 ± 3.80 6.78 ± 3.03 8.68 ± 4.65 7.59 ± 3.68 7.91 ± 3.70 6.90 ± 3.98 8.28 ± 4.27 7.76 ± 4.17 Right hand N1 T7 −8.18 ± 4.79 −5.98 ± 3.39 −6.38 ± 4.67 −5.12 ± 3.62 −7.34 ± 4.70 −5.88 ± 3.73 −7.43 ± 3.30 −6.38 ± 3.21 T8 −4.92 ± 4.43 −3.96 ± 3.24 −3.25 ± 3.29 −2.98 ± 2.35 −4.56 ± 4.61 −3.03 ± 2.39 −4.37 ± 3.53 −4.15 ± 2.62 N2 Central −10.11 ± 3.83 −7.44 ± 4.52 −11.05 ± 4.87 −6.69 ± 4.23 −9.99 ± 5.06 −6.40 ± 4.27 −9.57 3.97 −8.94 ± 5.40 Left −7.74 ± 2.70 −5.67 ± 2.77 −8.62 ± 3.65 −5.71 ± 3.43 −7.77 ± 3.80 −5.09 ± 2.64 −6.79 ± 3.29 −6.42 ± 3.78 Right −6.58 ± 3.37 − 5.12 ± 3.34 −6.76 ± 3.00 −4.80 ± 3.26 −6.52 ± 3.59 −4.24 ± 2.72 −5.82 ± 2.74 −6.00 ± 3.99  P2 Central 14.30 ± 6.56 11.62 ± 5.93 14.52 ± 7.14 10.90 ± 5.49 14.04 ± 7.79 10.74 ± 7.13 11.37 ± 6.38 10.75 ± 5.73 Left 8.47 ± 3.87 6.95 ± 3.03 8.90 ± 4.14 7.00 ± 2.91 8.65 ± 4.79 6.64 ± 3.37 6.21 ± 3.45 6.62 ± 3.22 Right 8.52 ± 3.83 6.73 ± 2.75 8.29 ± 4.17 6.41 ± 3.32 8.75 ± 4.29 6.90 ± 3.76 6.84 ± 4.44 6.67 ± 4.04 The mean amplitudes of the LEP components before and after stimulation in all four conditions. (mean ± standard deviation) Discussion 2005 2006 2007 2007 2007 2007 2005 2006 2007 2007 2007 2007 2003 1997 2003 2003 2004 2000 2004 2000 2003 1997 2000 2004a 1997 2006 2003 2005 2000 2004 2 2005 2004 1999 2007 2000 2001 2000 2001 2000 1999 2005 1986 2004b 2004a 2006 2004 2006 2007 2007 2004 2005 2007 2007 2004 2005