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We synthesized and characterized 15 new derivatives of the highly anticancer-active platinum(II) complex [{cis-Pt(NH 3 ) 2 } 2 (μ-OH)(μ-tetrazolato-N2,N3)] 2+ (5-H-Y) by making substitutions at tetrazole C5. We then evaluated the comprehensive structure-cytotoxicity relationships of a total of 23 derivatives in two murine lymphocytic leukaemia cell lines, sensitive and resistant to cisplatin. We also report the in vivo antitumor efficacy of three ester derivatives, two of which exhibited much higher efficacy than oxaliplatin against mouse homografted Colon-26 colorectal tumor., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Epileptic spikes are associated with rapidly changing brain activation involving the epileptic foci and other brain regions in the "epileptic network". We aim to resolve these activation changes using simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) recordings., Methods: Simultaneous EEG-fMRI recordings from 9 patients with epilepsy were used in the analysis. Our method employed the whole scalp EEG data to generate regressors for the analysis of fMRI data using the general linear model., Results: We were able to resolve, with milliseconds temporal resolution, changes in activation patterns involving suspected epileptic foci and other brain regions in the epileptic network during spike and slow wave. Using summary maps (called SSWAS maps) which show the activation frequency of voxels, we found that suspected epileptic foci tend to be significantly active during this interval. SSWAS maps also enabled the detection of the epileptic foci in 4 of 5 patients where the conventional event-timing-based analysis failed to identify., Conclusion: These findings demonstrated the efficacy of the method and the potential application of SSWAS maps to identify epileptic foci., Significance: The method could help resolve activation changes during epileptic spike and could provide insights into the underlying pathophysiology of these changes., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objectives: To examine the temporal stability and variability of neuronal synchronization among the contralateral primary somatosensory cortex (cSI) and contralateral (cSII) and ipsilateral secondary somatosensory cortex (iSII) in response to median nerve stimulation., Methods: Both the spontaneous magnetoencephalography (MEG) signals as the pre-stimulus condition and somatosensory evoked magnetic-fields (SEF) were recorded in eleven healthy subjects. We calculated a phase-locking value (PLV) between two areas among cSI, cSII, and iSII in five frequency bands (theta: 5-7 Hz, alpha: 8-12 Hz, beta: 15-29 Hz, gamma-1: 30-59 Hz, and gamma-2: 60-90 Hz), and compared the PLV among in pre-stimulus and stimulus conditions., Results: The PLV between cSI and cSII for the theta band activity varied within 2 s from the stimulus onset. On the other hand, the PLV between cSI and iSII for the alpha band did not vary within 2 s., Conclusion: The fluctuation of neuronal synchrony among sensory-related cortices in response to median nerve stimulation depends on the induced frequency band and inter-region., Significance: This study is the first to report the temporal characteristic of stimulus-driven neural synchrony following somatosensory stimulation.

Objective: The recovery function of somatosensory evoked magnetic fields (SEFs) was recorded to investigate excitatory and inhibitory balance in the somatosensory cortex of patients with carpal tunnel syndrome., Methods: SEFs were recorded in patients and controls. Recordings were taken following median nerve stimulation with single and double pulses with interstimulus intervals of 10-200ms. The root mean square for the N20m component following the second stimulation was analyzed. SEFs following stimulation of the first and middle digits were also recorded and the location for the equivalent current dipoles was estimated in three-dimensional planes., Results: Distances on the vertical axis between the equivalent current dipoles for the first and third digits were shorter in patients than in control participants. The root mean square for the N20m recovered earlier in patients compared to controls; this was statistically significant at an interstimulus interval of 10ms. There was no relationship between N20m recovery and the equivalent current dipole location in the primary somatosensory cortex., Conclusions: Carpal tunnel syndrome was associated with functional disinhibition and destruction of the somatotopic organization in the primary somatosensory cortex., Significance: Disinhibitory changes might induce a maladaptation of the central nervous system relating to pain., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: The aim of the study was to investigate the functional differences between N20m and P30m components of somatosensory-evoked magnetic cortical field (SEF) in young and senior subjects., Methods: Twenty-nine healthy subjects, 13 younger (mean age: 21.8years) and 16 senior (63.8 years), participated. Magnetic fields were measured using a 160-channel, whole head MEG. Single- and paired-pulse stimulations of 200 artifact-free MEG signal epochs were averaged separately. We calculated how aging affects recovery function of SEFs., Results: The senior showed a prolonged N20m peak latency compared to the younger, although the P30m peak latency was not significantly different between groups. The N20m ratios at 60 and 80 ms in the senior were significantly increased compared to the ratios in the younger (60 ms: P<0.05, 80 ms: P<0.001). The P30m ratios at inter-stimulus interval (ISI) of 80 and 100 ms showed even disinhibition in the senior than in the younger (P<0.05). The younger also showed a significantly negative correlation between P30m and N20m components' recovery curves (R=0.72, P<0.05)., Conclusion: Aging-related changes that occurred in recovery functioning were the decrease in N20m component suppression and the increase in P30m component recovery, indicating that the N20m and P30m components have different functions in aging-related recovery changes., Significance: Our results show that the N20m ratio at an ISI of 80 ms was significantly increased in the senior group, indicating that the second stimulus-evoked SEF was less inhibited by the initial stimulus at this ISI, suggesting less refractory effect or increased disinhibition., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objectives: We investigated whether incomprehensible high-speed auditory speech stimulation was processed and interacted with visual-word discrimination processing. We hypothesised that an interaction might indicate the capacity of working memory (WM) to perform the temporal processing of auditory verbal information., Methods: We recorded P300 for a visual-word discrimination Oddball paradigm in 14 healthy subjects. Auditory speech and reversed speech stimulation were presented at various speeds as task-irrelevant stimuli during the P300 tasks., Results: The P300 latency was prolonged under forward high-speed speech stimuli (× 2.5 and × 3.5) compared with the standard speed and white noise, but there was no effect of reversed speech stimuli on the P300 latency during the word-discrimination paradigm., Conclusions: We considered that high-speed speech stimulation was processed without conscious comprehension and competed with verbal processing during the visual-word-discrimination task, possibly by interfering with the use of WM., Significance: The present study shows the capacity of the brain to process high-speed verbal stimulation and the interaction with a visual-verbal task., (Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

The effects of the temporal disruption of language rhythm in Japanese on auditory evoked potentials were investigated in normal subjects. Auditory event-related evoked potentials (AERP) were recorded following syllables using a natural and deviated language rhythm by inserting various (0-400 ms) silent intervals between syllables. The language speed was changed to assess the effect of a deviant rhythm relative to the language speed on AERP in another experiment. The prolonging of intervals did not affect the N100-P150 components until the inserted interval became 400 ms, while the negative component (early negativity, EN), peaking at 250-300 ms, was enhanced when the interval was 100 ms or more. The N100-P150 components following deviated language rhythms did not change during the fast speed but did in the standard and slow speed. We considered that the N100-P150 components were changed by the mixed effects of adaptation and prediction related to the reading speed, and that EN was evoked by deviated language rhythm in a different way from that caused N100-P150 changes, possibly via mismatch detection process between deviant rhythm and intrinsic rehearsed rhythm.

Objective: To establish an objective two-point discrimination test using magnetoencephalography (MEG)., Methods: First, we determined the discrimination threshold (DT) of the two-points. In the first experiment, we applied 0.9DT as standard stimuli, and 0.8DT, 1.1DT and 2DT as deviant stimuli in Conditions 1, 2 and 3, respectively. In the second experiment, we used 2DT and 0.9DT as the standard and deviant stimuli, respectively, in Condition 1. We applied two-stimuli that subjects felt as definitely one point or two-points in Condition 2 and 3, respectively., Results: In the first experiment, the components peaking around 30-70 and 150-250ms following deviant stimuli were significantly larger than those following standard stimuli. Considering the peak latency, these components seem consistent with the magnetic mismatch field (MMF). In the second experiment, the MMF was recorded only in Condition 1. Therefore, it is considered that the MMF was recorded only when subjects automatically discriminate one point from two-points stimuli., Conclusions: This novel method can be used in neurophysiological two-point discrimination tests without the need to rely on the examiners' skills and subjects' reactions., Significance: We confirmed that our new method could be used for the objective examination of two-point spatial discrimination.

Objective: To determine the existence of a pre-attentively evoked somatosensory mismatch negativity component and to investigate the use of that component in objective clinical diagnostics., Methods: First we determined the temporal discrimination threshold (DT) of paired stimuli in each subject, and applied two sequential electrical stimuli to the hand with paired stimulus times of (1) DT-10 ms, (2) DT-30 ms and (3) DT+50 ms. Then, we recorded ERPs using an oddball paradigm, frequent (standard) and rare (deviant). We used two stimuli, DT-30 ms and DT-10 ms, in the first experiment, and DT-30 ms and DT+50 ms, in the second experiment., Results: In each experiment, two specific components, a negative component peaking at approximately 60ms (N60) and a large positive component peaking around 100-200 ms (P150), were identified, mainly following the deviant stimulus, which were considered somatosensory mismatch components. N60 was more remarkably identified in the second experiment and P150 in the first., Conclusions: N60 might be generated during tasks which subjects can clearly discriminate, but P150, which seems to correspond to auditory mismatch negativity, might be generated in tasks which require fine discrimination., Significance: We confirmed that our new method could be used for the objective examination of temporal discrimination.

Objective: To investigate the somatotopic organization of the facial skin area in the secondary somatosensory cortex (SII) in humans., Methods: Somatosensory evoked magnetic fields following air-puff stimulation of 5 body sites, the foot, the lip and 3 points of the facial skin (forehead, cheek and mandibular angle point), were recorded. We focused on activities in SII following stimulation of these 5 sites and compared dipole locations among them., Results: There was a clear somatotopic organization in SII with lip in the most lateral area, foot in the most medial area and face in an intermediate area close to the lip area. However, there was no significant difference of dipole localization in SII among the 3 areas of facial skin, similar to the overlapped somatotopic organization of facial skin areas in the primary somatosensory cortex in our previous study., Conclusions: The facial skin areas are considered to occupy a small area in SII with insufficient spatial separation to differentiate each area of facial skin even using magnetoencephalography which has a high spatial resolution., Significance: This is the first systematic study of the activated regions in SII following stimulation of the facial skin.

Background: The progression of diabetic nephropathy is closely related to disturbances in glomerular hemodynamics, such as glomerular hypertension and/or hyperperfusion. The aim of this study was to observe and to analyze glomerular hemodynamics in rats with diabetes mellitus (DM) in vivo using confocal laser scan microscopy (CLSM). We also examined the effects of candesartan cilexetil (TCV-116), a selective angiotensin II type 1 receptor blocker (ARB), on glomerular hemodynamics in DM., Methods: Munich-Wistar rats were divided into six groups: (1) four-day control; (2) four-day DM; (3) 28-day control; (4) 28-day DM; (5) DM treated with insulin; (6) DM treated with TCV-116. The kidney-to-body weight ratio, glomerular volume, and proteinuria were estimated. Glomerular hemodynamic changes were observed using CLSM and renal expression of endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) was evaluated by immunofluorescence., Results: The kidney-to-body weight ratio, glomerular volume, the diameters of afferent arterioles (AA) and efferent arterioles (EA), erythrocyte velocities within glomeruli, and volume flow in glomerular capillary loops in four-day DM were significantly higher than in control rats, and increases were even more pronounced in the 28-day DM. TCV-116 treatment ameliorated all these findings and significantly decreased proteinuria, but there was no effect on the blood glucose level. On the other hand, insulin treatment was followed by normalization of all these changes induced in DM. Enhanced renal expression of eNOS in DM was suppressed when treated with either TCV-116 or insulin, while expression of nNOS was unaltered among the four groups., Conclusion: This imaging procedure allowed us to evaluate glomerular microcirculation in vivo, including the diameters of AA and EA, erythrocyte velocity, and volume flow. DM significantly induced glomerular hemodynamic alteration and renal hypertrophy. DM treated with either insulin or ARB ameliorated these changes. This study shows that progress in imaging technology promises to make major contributions to revealing the involvement of hemodynamic changes in glomerular diseases, aiding prognosis and the monitoring of therapeutic effects, as well.

To investigate the representation of facial skin areas in the primary somatosensory cortex (SI), we recorded magnetic fields evoked by air pressure-induced tactile stimulation applied to six points on the face, lower lip and thumb. The thumb area in the SI was located more medial and superior to the lip area, which was consistent with Penfield's homunculus. However, the representations of all skin-covered areas including forehead, cheek, nose and chin in the SI were located between the thumb and lower lip area. There was no significant difference in location among the six facial points. Our results imply that lips occupy a large area of the face representation in the SI, whereas only a small area located between the thumb and lip areas is devoted to skin-covered surfaces. This is the first study showing that the facial skin areas in the human SI are located between the thumb and lower lip areas and close together.

Objective: To elucidate the temporal features of the cognitive process in two-point discrimination (TPD)., Methods: We measured somatosensory event-related potentials (ERPs) in 9 subjects during the TPD task, in which we provided a pair of electrical pulses simultaneously, altering the distance between the electrodes. We analyzed the TPD-related ERPs and investigated the relationship between the potentials and the subjects' judgments., Results: During the TPD task, a negative potential approximately 140 ms after the stimulation (N140) was enhanced as compared to a stimulus counting task. Two late positive components, LPC-1 and LPC-2, whose peak latencies were 300 and 500 ms, respectively, were identified only in the TPD task. The LPC-1 was recorded dominantly in the fronto-central area, while the LPC-2 was detected dominantly in the centro-parietal area. The amplitude of the LPC-2 was significantly modulated by the degree of consistency in the subjects' judgment. On the other hand, these ERP components did not show significant difference between the alternate judgments, i.e. 'one-point' or 'two-point' judgment., Conclusions: Our results suggest that the N140 is related to the attention toward the stimulation. The LPC-1 and LPC-2 are likely to correspond to the processes represented by P3a and P3b, based on their temporal and spatial behavior.

Objective: We investigate the synaptic factor for the recovery function of evoked responses using a repetitive stimulation technique., Methods: Somatosensory evoked cortical magnetic field (SEF) was recorded following stimulation of the median nerve using single to 6-train stimulation in 8 healthy subjects. The SEF responses after each stimulus in the train stimulation were extracted by subtraction of the waveforms., Results: An attenuation of the SEF components was recognized after the second of the stimuli, but there was no significant attenuation with the third or later stimulations. The root mean square (RMS) of the 1M (peak latency at 20 ms after stimulation) and 4M (70 ms) components were smaller than that of the single stimulation during the train stimulation, while the 2M (30 ms) and 3M (45 ms) components were not attenuated, but the 3M was facilitated at the fourth to sixth stimulation., Conclusion: The synaptic factor was not responsible for the attenuation of the SEF components during repetitive stimulation in healthy subjects. The SEF change disclosed a functional difference among the SEF components during the train stimulation, especially among the later components.

Objective: To confirm the somatotopic representation of the ear in the primary somatosensory cortex (SI), we studied the tactile interference effects on somatosensory evoked magnetic fields (SEFs) following stimulation of the ear (Helix, Lobulus and Tragus)., Methods: We applied tactile interference stimulation to the neck or face area continuously and concurrently while a time-locked electrical stimulation was applied to the ear. If the amplitude would be reduced by the interference, this would indicate that the cortical representation for both the time-locked electrical stimulation and the continuous interference stimulation overlapped. A two or 3-source model, Source 1 in the neck area of SI, Source 2 in the face area of SI, and Source 3 in the secondary somatosensory cortex (SII), was found to be the most appropriate by brain electric source analysis (BESA)., Results: Amplitudes of Sources 1 and 2 in most interference conditions were decreased. Source 1 following stimulation of all 3 sites was significantly reduced when the interference was applied to the neck area. Source 2 following stimulation of all 3 sites was significantly reduced when the interference was applied to the face area., Conclusions: These findings showed that the interference effect was found in both the neck and face areas of SI following the ear stimulation., Significance: The representation of the ear in SI might be located in both the neck and face areas.

Objective: To investigate the effect of conditioning painful stimulation on the early somatosensory magnetic fields (SEF) of test stimulation, in order to clarify the location of the gating effect of pain on tactile response., Methods: We used a conditioning stimulus (CS) and test stimulus (TS) paradigm. The CS was applied at the left index finger followed by the TS at the left median nerve. The interstimulus interval between the CS and TS was varied from 100 to 1000 ms. There were two sessions corresponding to two intensities of the CS, painful CS (PCS) and non-painful CS (NPCS). Early components of SEF recorded 20 (1M) and 30 ms (2M) following the TS and the components obtained 20 (1m) and 30 ms (2m) following the CS were analyzed. Each value was compared between the two sessions., Results: PCS and NPCS attenuated the response of the 2M but not the 1M. The effect of PCS was significantly stronger and lasted longer than that of NPCS. The 1m and 2m components did not differ between PCS and NPCS in terms of amplitude and latency., Conclusions: Our data indicated that the early components of the median nerve SEF were affected by a preceding painful stimulation much more than a non-painful stimulus given on the median nerve, and that the sensory gating effect of a painful stimulation on tactile sensation lasted longer than that of a non-painful stimulation. Furthermore, our findings suggested the existence of a 'touch gate' (effect of pain on tactile sensation) at the level of the thalamus or primary somatosensory cortex (SI)., Significance: The finding suggested that the touch gate might lie in the thalamus or SI.

We investigated the event-related responses following subthreshold and suprathreshold stimulation with facial and non-facial figures using magnetoencephalography (MEG) and EEG recordings to clarify the physiological nature of subconscious perception. Event-related magnetic fields and potentials were recorded from the right hemisphere in eight healthy subjects. Three types of stimulus, i.e., facial image (Face), letters of the alphabet (Letters) and random patterns of dots (Dots), with different presentation periods, subthreshold (16 ms), intermediate (32 ms) and suprathreshold (48 ms) were visually presented in a random order. A psychological discrimination task using the same stimuli was also employed. Clear MEG and EEG responses were recorded for all the stimuli, but the amplitude of the responses was largest for Face and smallest for Dots even in the subthreshold stimulation. The equivalent current dipoles (ECDs) for Face were located around the fusiform gyrus, although the correlation coefficients for ECDs were low under subthreshold and intermediate conditions. The ECDs for Letters and Dots were not estimated with reliable correlation coefficients. The results from the psychological task correlated with the dominancy of face recognition. Face perception was processed differently in the subthreshold condition as well as suprathreshold condition. The subconscious recognition of face might be processed around the fusiform gyrus.

There are two kinds of pain, a sharp pain ascending through Adelta fibers (first pain) and a second burning pain ascending though C fibers (second pain). By using a novel method, the application of a low intensity CO(2) laser beam to a tiny area of skin using a very thin aluminum plate with numerous tiny holes as a spatial filter, we succeeded in selectively stimulating unmyelinated C fibers of the skin in humans, and could record consistent and clear brain responses using electroencephalography (EEG) and magnetoencephalography (MEG). The conduction velocity (CV) of the C fibers of the peripheral nerve and spinal cord, probably spinothalamic tract (STT), is approximately 1-4 m/s, which is significantly slower than that of Adelta (approximately 10-15 m/s) and Abeta fibers (approximately 50-70 m/s). This method should be very useful for clinical application. Following C fiber stimulation, primary and secondary somatosensory cortices (SI and SII) are simultaneously activated in the cerebral hemisphere contralateral to the stimulation, and then, SII in the hemisphere ipsilateral to the stimulation is activated. These early responses are easily detected by MEG. Then, probably limbic systems such as insula and cingulate cortex are activated, and those activities reflected in EEG components. Investigations of the cortical processing in pain perception including both first and second pain should provide a better understanding of pain perception and, therefore, contribute to pain relief in clinical medicine.

We investigated effects of sleep on pain-related somatosensory evoked potentials (SEP) following painful electrical stimulation of the left index finger. The biggest advantage of this method is that signals ascending through both A-beta fibers relating to touch and A-delta fibers relating to pain can be recorded simultaneously. While the subject was awake, non-painful stimulation evoked early- and middle latency components, N20, P30 and N60, at the C4 electrode, and painful stimulation evoked not only early- and middle latency components at the C4 but also later pain-specific components, N130 and P240, at the Cz electrode. During sleep, N20 and P30 did not show a significant change in amplitude, N60 showed a slight but significant amplitude reduction, and N130 and P240 significantly decreased in amplitude or disappeared, as compared with those while awake. Therefore, we speculate on the mechanisms generating each component as follows; (1) N20 and P30 are the primary components generated in SI ascending through A-beta fibers. (2) N60 is the secondary component generated in SI involving cognitive function to some degree. (3) N130-P240 are the pain-specific components ascending through A-delta fibers, and closely related to cognitive function, because they were much affected by consciousness, different from the components ascending through A-beta fibers., (Copyright 2002 Elsevier Science Ireland Ltd and the Japan Neuroscience Society)

Objectives: We investigated the recovery function of the cortical components of somatosensory evoked potentials (SEP) at a very short interstimulus interval (ISI, less than 10 ms) using an integrative computer system in 10 healthy subjects (age, 27-38 years)., Methods: The SEP and nerve action potentials were recorded at P3 with a reference of Fz in the International 10-20 System and the ipsilateral Erb's point, respectively. Double stimulation of the right median nerve with an ISI from 0.5 to 100 ms was performed to analyze the N20 and P30 components at less than 10 ms., Results: The P30 component was recognized following the second stimulation at an ISI of over 1 ms, while N20 was not identified at an ISI of less than 9 ms. There appeared a sub-component of SEP at 1-12 ms ISI, which was not identified following a single stimulation under control conditions., Conclusions: The results indicated that the recovery function of given SEP components was not simply determined by the number of synapses interposed between the stimulus site and the generator source of the response in the central nervous system, but there might be a structural or functional process of low-cut filtering in the primary sensory cortex. We also considered that the final SEP waveform determined by the excitatory and inhibitory balance of the components, which could be changed with ISI, and that the existence of the sub-component might cause the complexity of the recovery curve and large inter-individual difference of the waveform.

Objectives: We recently developed a new method for the preferential stimulation of Adelta fibers in humans. The aim of the present study was to examine whether this method can serve as an appropriate stimulus in a magnetoencephalographic study., Methods: We recorded somatosensory-evoked magnetic fields (SEFs) following intra-epidermal electrical stimulation applied to the hand and elbow. Superficial parts of the skin were electrically stimulated through a needle electrode whose tip was inserted in the epidermis., Results: In all 13 subjects, the equivalent current dipole was estimated in the secondary somatosensory cortices (SII). In 5 out of 13 subjects, simultaneous activation of the primary somatosensory cortex (SI) in the hemisphere contralateral to the stimulation was identified. The mean peak latencies of magnetic fields corresponding to contralateral SI, SII and ipsilateral SII activation following hand stimulation were 162, 158 and 171 ms, respectively. The respective latency following elbow stimulation was 137, 139 and 157 ms, respectively. Estimated peripheral conduction velocity was 15.6m/s., Conclusions: All the results were consistent with previous findings in pain SEF studies. We concluded that our novel intra-epidermal electrical stimulation is useful for pain SEF studies since it does not need special equipment and is easy to control.

Objectives: We investigated the recovery function of somatosensory evoked magnetic cortical fields (SEFs) to confirm the temporal aspects of the somatosensory process in humans., Methods: SEFs were recorded following median nerve electrical stimulation in 6 healthy subjects. Double stimulation, with interstimulus intervals (ISIs) from 3 to 100 ms, was applied, and the SEF components for the second stimulation were analyzed. In a supplementary experiment, responses to single stimulations of various intensities from the sensory threshold to the motor threshold were studied., Results: The first SEF component (1M) diminished when the ISI was less than 10 ms, while the second component (2M) remained even when the ISI was 3 ms. The two components showed a very similar attenuation with decrease of stimulus intensity. There was no significant difference in dipole location between 1M and 2M in the primary somatosensory cortex (SI)., Conclusions: The results suggested that at least two independent pathways with different recovery functions exist in a similar area in the SI.

Objective: We recorded vocalization-related cortical fields (VRCF) under complete masking of a subject's own voice to identify the auditory component evoked by a subject's own voice in the VRCF complex., Methods: We recorded VRCF during simple vowel (/u/) vocalization in 10 right-handed healthy volunteers under two conditions: (1) no masking (control) and (2) masking of the subject's own voice by weighted-white noise during vocalization. In the second experiment, we recorded auditory evoked magnetic fields (AEF) following stimulation of a speech sound applied by voice-recorder., Results: The onset of VRCF appeared gradually before the vocalization onset, and a clear phase-reversed deflection was identified after the onset of vocalization. The difference waveform obtained by subtracting the VRCF of the masking condition from that of the control showed a deflection (1M) at 81.3+/-20.5 (mean+/-SD) ms after the onset of vocalization, but there was no consistent deflection before the vocalization onset. The AEF following voice sound in the second experiment showed the M100 component at 94.3+/-18.4 ms. The equivalent current dipole of the 1M component for different waveforms was located close in the auditory cortex to that of the M100 for AEF waveforms in each hemisphere., Conclusion: We successfully separated the auditory feedback response from the VRCF complex, using an adequate masking condition during vocalization of a subject's own voice. The masking effect was crucial to the auditory feedback process after the onset of vocalization. The present results suggested that the 1M component was mainly generated from the auditory feedback process by the subject's own voice. The activated auditory area for simple own voice might be similar to that for simple external sound.

Objectives: The effects of the proprioceptive activity of the proximal muscles on somatosensory evoked potentials (SEPs) were investigated, using vibratory stimulation of proximal muscle tendons., Methods: SEPs were recorded following electrical median nerve stimulation at the wrist during vibratory stimulation of tendon of pronator teres, biceps and trapezius muscles and fingers in 8 normal subjects., Results: The cortical SEP components, N20, P25 and N33 recorded from the parietal area, and P20 and N30 recorded from frontal area contralateral to the stimulated side, were markedly attenuated by vibratory stimulation applied to the fingers, but unaffected by vibratory stimulation of the proximal muscles., Conclusion: The proprioceptive afferent, especially group Ia muscle spindle afferent, in the relaxed proximal muscles is not likely to contribute to the gating of SEP following distal nerve stimulation.

Objectives: The after-effect of transcutaneous electrical nerve stimulation (TENS) on pain-related brain responses was investigated using electroencephalography (EEG) and magnetoencephalography (MEG)., Methods: We studied 13 healthy volunteers for the main experiment and 7 for the control experiment. The pain-related evoked cerebral potentials (PREP) at Cz and magnetic cortical fields (PRCF) on both hemispheres following painful electrical finger stimulation were simultaneously recorded before and after TENS on the right forearm of the median nerve territory at 50 Hz for 30 min. PREP and PRCF were similarly recorded without TENS in the control experiment., Results: The PREP components, N150 and P220, were significantly attenuated after TENS, compared to those before TENS (P<0.01, two-way repeated ANOVA). However, there was no consistent change of the PRCF components. Eleven of 13 subjects reported no change of pain sensation after TENS. There was no change of PREP in control experiment without TENS., Conclusions: The results indicated that TENS reduced PREP following painful electrical stimulation, and that the origin of PREP was, at least partially, different from that of PRCF which was not changed after TENS. An after-effect of TENS significantly affected the generation process of PREP, but it was not enough to relieve the subjective painful feeling.

Objective: Identification of a detailed topography of the receptive area for each of the thoracic dermatomes in humans using somatosensory evoked magnetic fields (SEF)., Methods: We analyzed the location of the equivalent current dipole (ECD) of SEF following electrical stimulation of the skin at Th4, Th6, Th8, Th10 and Th12 dermatomes in 14 normal subjects., Results: Three deflections, M18, M25 and M40, were obtained within 60 ms of stimulation of Th6, Th8 and Th10 dermatomes. No consistent deflection could be identified following Th4 and Th12 dermatomal stimulation, probably due to a poor signal-to-noise ratio and difficulty in fixing the stimulation electrodes. M18 was absent or small in amplitude. The latency of M25 ranged from short to long in the order Th6, Th8 and Th10 (P<0.05). ECDs of all components for each site stimulation were located in the truncal area of the primary somatosensory cortex. Although the locations of the ECDs tend to be arranged from lateral to medial in the sequence Th6, Th8 and Th10, the difference was not significant., Conclusion: The representation area of the trunk is small, and the receptive areas for the stimulation of Th6, Th8 and Th10 dermatomes are considered to be very close or to overlap.

Objective: We recorded vocalization related cortical potentials (VRCP) with complete masking of one's own voice, and separated the feedback auditory potentials following vocalization from the VRCP complex., Methods: We used 9 right-handed healthy subjects. We recorded VRCP during simple vowel vocalizing under two conditions, (1) without masking (control); (2) with masking. Electroencephalography (EEG) was recorded from seven areas, Fz, Cz, Pz, C3, C4, T3 and T4, of the International 10-20 system. The trigger point was the onset of vocalized sound recorded through a microphone., Results: In both control and masking conditions, similar negative potentials prior to the vocalization were observed. However, the amplitude just after the onset of vocalization was significantly smaller in the masking than the control condition. The difference waveform, obtained by subtracting the waveforms in the masking from those in the control condition, showed a simple negative peak after the vocalization onset., Conclusions: We considered that the difference waveform indicated the auditory evoked potentials following own voice in the auditory feedback process. Since there was no difference of the negative potentials before vocalization between the two conditions, we speculated that the masking effect on auditory feedback following vocalization was crucial, while its effect on the preparatory process of simple vocalization might be minimal.

Objectives: We investigated changes in the cortical silent period (CSP) following transcranial magnetic cortical stimulation (TCMS) during a standard paradigm which was designed to evoke contingent negative variation (CNV) in ten normal subjects., Methods: We recorded the motor evoked potentials (MEP) and CSP during the inter-stimulus interval (ISI) of a CNV paradigm in ten normal subjects. The CNV paradigm consisted of a visual warning stimulus (S1) followed by a visual response stimulus (S2). The CSP following TCMS on the hand motor area was recorded from mildly contracted first dorsal interosseous muscles., Results: The CSP was significantly shortened during the ISI (P < 0.01, t test) with a highly significant correlation with the TCMS timing during the ISI (P < 0.02, Spearman's correlation coefficient), while the MEP amplitude and latency were unchanged., Conclusions: The results suggested that shortening of the CSP was associated with neural processes related to preparation for voluntary movement during the paradigm.

The somatosensory evoked magnetic fields (SEFs) and evoked potentials (SEPs) following passive toe movement were studied in 10 normal subjects. Five main components were identified in SEFs recorded around the vertex around the foot area of the primary sensory cortex (SI). The first and second components, 1M and 2M, were identified at approximately 35 and 46 ms. Equivalent current dipoles (ECDs) of both 1M and 2M were estimated around SI in the hemisphere contralateral to the movement toe, and were probably generated in area 3a or area 2, which mainly receive inputs ascending through muscle and joint afferents. The large inter-individual difference of 1M and 2M in terms of ECD orientation was probably due to a large anatomical variance of the foot area of SI. The third and fourth components, 3M and 4M, were identified at approximately 62 ms and 87 ms, respectively. They appeared to be a single large long-duration component with two peaks. Since the 3M and 4M components were significantly larger than the 1M and 2M components in amplitude and their ECD location was significantly superior to that of 1M and 2M, we suspected that they were generated in different sites from those of 1M and 2M, probably area 3b or area 4. Four components, 1E, 2E, 3E and 4E, were identified in SEPs, which appeared to correspond to 1M, 2M, 3M and 4M, respectively. The variation observed in the scalp distribution of the primary component, 1E, could be accounted for by the variation of the orientation of ECD of the 1M component. There was a large difference in the waveform of the long-latency component (longer than 100 ms) between SEFs and SEPs. The 5E of SEPs was a large amplitude component, but the 5M of SEFs was small or absent. We speculate that this long-latency component was generated by multiple generators.

To elucidate the effects of the decision to move on the pyramidal tract in humans, we examined the changes in the motor evoked potentials (MEP) of the forearm muscles following transcranial magnetic cortical stimulation (TMS) of the hand area during a go/no-go hand-movement task in 10 normal subjects. The subjects performed an extension of the right wrist according to the go, no-go and control signals, one of which was randomly presented on a TV. A single TMS was applied to the primary hand motor area in the left hemisphere 0-300 ms after each signal. The MEPs recorded from the wrist extensor and flexor muscles changed in amplitude after both go and no-go signals. In comparison with the control, the MEPs were significantly facilitated in the agonistic muscles (wrist extensor muscles) and attenuated in the antagonistic muscles (wrist flexor muscles), at the latencies of 100-200 ms after the go signal (P < 0.02). In contrast, the MEPs of both the extensor and flexor muscles were significantly attenuated during the period of 100-200 ms after the no-go signal (P < 0.001). We speculate that there is strong inhibition on the pyramidal tract after the no-go signal and that the inhibitory effect is non-specific to the target muscles. This inhibition differs from the reciprocal inhibition of the MEP observed in antagonistic muscles after the go signal, and it is probably related to the movement decision originating in the prefrontal cortex.

We studied somatosensory evoked magnetic fields (SEFs) following stimulation of bilateral posterior tibial nerves ('bilateral' waveform) in normal subjects to determine the inter- and intra-hemispheric interference effects caused by activation of sensory areas in bilateral hemispheres. Activated areas in the primary and second sensory cortices (SI and SII) in each hemisphere following bilateral stimulation were clearly identified by estimation of the double best-fitted equivalent current dipoles (ECD) using the spherical head model, and the large inter-individual differences were identified. SEFs following the right posterior tibial nerve stimulation and those following the left stimulation were summated ('summated' waveform). The 'difference' waveform was induced by a subtraction of 'bilateral' waveforms from the 'summated' waveform. Short-latency deflections showed no consistent changes between the 'summated' and 'bilateral' waveforms, but the long-latency deflection, the N100m-P100m, in the 'bilateral' waveform was significantly (P < 0.02) reduced in amplitude as compared with the 'summated' waveform. The differences were clearly identified in the 'difference' waveform, in which the main deflections, U100m-D100m, were found. The ECDs of the short-latency deflections were located in SI contralateral to the stimulated nerve, but the ECDs of the N100m-P100m were located in bilateral SII which are considered to receive ascending signals from the body bilaterally. Therefore, some inhibitory interactions might take place in SII by receiving inputs from the body bilaterally.

Somatosensory evoked magnetic fields (SEFs) following painful electrical stimulation of the sural nerve were examined in 6 normal subjects. Equivalent current dipoles (ECDs) of the deflections shorter than 100 ms in latency were located in the foot area of the primary sensory cortex (SI) in the contralateral hemisphere following both weak and painful stimulations. Two main deflections, N150m-P150m and N250m-P250m, were independently identified only following painful stimulation. ECDs of the N150m-P150m were considered to be located in bilateral second sensory cortices (SII). ECDs of the N250m-P250m were identified in multiple areas including bilateral cingulate cortices and SII. These findings were consistent with the pain-related SEFs following upper limb stimulation. Therefore, we considered that bilateral SII and the cingulate cortices were activated by the painful stimulation and that pain-specific brain activities in those areas did not depend on the stimulation site.

We investigated the olfactory evoked magnetic fields (OEFs) in 14 normal subjects. Pulses of odorant air containing amyl acetate or phenethyl alcohol, and odorless air were administered to the subject through a nasal tube. A clear and consistent OEF component, 1M, was identified in all subjects, and a second component, 2M, was detected in seven subjects, but no consistent component was identified in response to the odorless air. The peak latencies of the 1M and 2M components were approximately 320 and 630 ms, respectively. The waveforms produced by the odorless air were subtracted from the waveforms produced by the odorant air to obtain the 'subtraction' waveform, which indicated the 1M and 2M component more clearly. Their equivalent current dipoles (ECDs) were estimated in the regions around the Sylvian fissure symmetrically in both hemispheres. Therefore, these areas are proposed to be involved in olfactory perception in humans.

The topography of somatosensory evoked magnetic fields (SEFs) following stimulation of the upper and lower lips was investigated in 6 normal subjects. When the lateral side of the upper lip was stimulated, P20m and its counterpart, N20m, were identified in the hemisphere contralateral to the stimulated side. The equivalent current dipoles (ECDs) of N20m-P20m were considered to be located in lip area of the primary sensory cortex (SI). Middle latency deflections (N40m-P40m, N60m-P60m, and N80m-P80m) were identified in bilateral hemispheres. Their ECDs were located in the SI in both hemispheres. Long latency deflections (P110m-N110m) were recognized in both hemispheres, and their ECDs were located inferior to the SI, in an area considered to be the secondary sensory cortex (SII). When the midline of the lip was stimulated, similar short and middle latency deflections was also identified, but SII deflections (P110m-N110m) were decreased in amplitude. When the lower lip was stimulated, the ECDs of short and middle latency deflections were located at a site in the SI inferior to or near those elicited by upper lip stimulation. The ECDs of P110m-N110m were located in an area of the SII similar to that upon stimulation of the upper lip, but their orientations were different.

We examined the motor evoked potentials (MEP) of the forearm muscles following transcranial magnetic stimulation after the Go/No-go reaction-time hands movement in ten normal subjects. Facilitation of MEP of the agonistic muscles and suppression of MEP of the antagonistic muscles were recognized during the 'Go' session, while the MEPs of both muscles were markedly suppressed in the 'No-go' session. We considered that this MEP changes reflected the inhibition on the pyramidal tract during the 'No-go' session.

Somatosensory evoked magnetic fields (SEFs) following stimulation of the median nerves bilaterally ('bilateral' waveform) were examined in normal subjects to determine the interference effects of activation of sensory areas in bilateral hemispheres. SEFs following right median nerve stimulation and those following left median nerve stimulation were summated ('summated' waveform). A 'difference' waveform was induced by subtraction of the 'bilateral' waveform from 'summated' waveform. Short-latency deflections showed no consistent differences between the 'summated' and 'bilateral' waveforms, but the middle-latency deflection. N60m-P60m, in the 'bilateral' waveform was significantly (P < 0.01) smaller than that in the 'summated' waveform. The long-latency deflection, the N90m-P90m, in the 'bilateral' waveform was markedly (P < 0.001) reduced in amplitude as compared with the 'summated' waveform. The differences were clearly identified in the 'difference' waveform, in which the main deflections, U90m-D90m, were found in all subjects. Equivalent current dipoles (ECDs) of the short- and middle-latency deflections were located in the primary sensory cortex (SI) contralateral to the stimulated nerve, but ECDs of the N90m-P90m and U90m-D90m were located in bilateral second sensory cortices (SII) which are considered to receive ascending signals from bilateral sides of the body.

By means of somatosensory evoked brain potentials following painful CO2 laser stimulation (pain SEPs) and a pain visual analogue scale (VAS), we investigated changes in pain perception caused by noxious cooling of the skin in normal subjects. Pain SEPs were recorded from scalp electrodes following laser stimulation applied to the leg under various conditions as follows: (1) control (without any interference); (2) 46 degrees C foot (dipping the foot ipsilateral to the stimulated leg in hot water at 46 degrees C); (3) 0 degrees C foot (dipping the foot ipsilateral to the stimulated leg in ice water at 0 degrees C); and (4) 0 degrees C hand (dipping the hand contralateral to the stimulated leg in ice water at 0 degrees C). Marked decreases in amplitude of pain SEPs and VAS were observed under all conditions as compared with the control (P < 0.001); the degree of pain relief was significantly correlated with changes in pain SEPs. These changes were greatest in the '0 degrees C hand' condition, followed in decreasing order by '0 degrees C foot' and '46 degrees C foot', and there was a significant difference between '0 degrees C hand' and the '46 degrees C foot' condition. We considered that the decrease in pain is due to the diffuse noxious inhibitory control (DNIC). The reason why the degree of pain relief in '0 degrees C foot' condition was less than that in '0 degrees C hand' condition is unclear, but some particular spatial summation of two kinds of nociceptive impulses mediated by the same pathway might take place.

Somatosensory evoked magnetic fields (SEFs) following painful electrical stimulation of the finger were investigated in 5 normal subjects. Equivalent current dipoles (ECDs) of deflections shorter than 100 msec in latency were located in the primary sensory cortex (SI) in the hemisphere contralateral to the stimulated finger following either non-painful or painful stimulation. Two main deflections, N100m-P100m and N250m-P250m, were independently identified following painful stimulation, although they were not found in SEFs following non-painful weak stimulation. ECDs of the N100m-P100m were considered to be located in the bilateral second sensory cortices (SII). ECDs of the N250m-P250m were identified in the bilateral cingulate cortices and SII, but the intersubject difference was large. Therefore, we considered that contralateral SI and bilateral SII were initially activated by painful noxious stimulation, and then multiple areas including bilateral SII and cingulate cortices were activated. In EEG recordings (evoked potentials), no potential corresponding to N100m-P100m was found, probably because it was difficult to record activation in SII by EEG recordings. The P250 potential which corresponded to the N250m-P250m was clearly identified, probably because activation of multiple areas generated large long-duration EEG potentials which were maximal around the vertex, unlike MEG recordings.

The topography of somatosensory evoked magnetic fields (SEFs) following stimulation of the right and left posterior tibial nerves was investigated in 5 normal subjects (10 nerves). The main deflections N37m-P45m-N60m-P75m and their counterparts P37m-N45m-P60m-N75m were identified in the hemisphere contralateral to the stimulated nerve. Their equivalent current dipoles (ECDs) were located in the foot area of the primary sensory cortex (SI), probably in area 3b. Restricted minor deflections, P40m-N40m and N50m-P50m, were considered to be generated in area 1 in SI. As the generator sources of P37m-N37m, P40m-N40m and N45m-P45m were temporarily changed and interfered with each other, the direction of ECDs appeared to be rotated with the passage of time. Small middle-latency deflections, N100m-P100m, were clearly identified in 2 subjects. ECDs of these deflections were found in the second sensory cortex (SII), in both hemispheres, although they were clearer in the hemisphere contralateral to the stimulated nerve. In conclusion, short- and middle-latency SEFs are mainly generated in area 3b in SI contralateral to the stimulated nerve, and responses generated in area 1 of SI and SII affect the SEFs to some degree, but interindividual differences are large compared with SEFs evoked by upper limb stimulation.

The "gating" effects caused by active finger movements on somatosensory evoked magnetic fields (SEFs) following stimulation of the median nerve were examined in normal subjects. The effects of the interfering stimulus were best demonstrated by subtracting the "interference" wave forms from the "control" wave forms to derive the "difference" wave form. The short-latency cortical deflections, N20m-P20m, P30m-N30m and P25m-N35m were significantly attenuated with no latency changes. In contrast, the following middle-latency deflections, the N40m-P40m and the P60m-N60m were clearly changed in terms of latency and duration by the interference. The D30m-U30m and the U60m-D60m in the "difference" wave form were derived from these interference changes. It is considered that the gating effects on all deflections took place in the hemisphere contralateral to the stimulated median nerve, because all of the equivalent current dipoles (ECDs) of the short- and the middle-latency deflections in the "control", "interference" and "difference" wave forms were located there. The gating effects on the short-latency deflections were suggested to be due to the interactions between the neurons in areas 1 and 3b, which were activated by sensory inputs from cutaneous mechanoreceptors, and the neurons in area 3a which were activated by sensory inputs from the muscle spindles. The gating effects on the middle-latency deflections may mainly be due to the excitations of neurons in area 4 caused by either continuous movement-related activities or by sensory inputs spreading from the sensory cortex.