Dry phantom for magnetoencephalography -Configuration, calibration, and contribution.

BACKGROUND: An artificial object that imitates human brain activity is called "phantom" and is used for evaluation of magnetoencephalography (MEG) systems. The accuracy of the phantom itself had not been guaranteed in the previous studies, although role of the phantom is to evaluate the accuracy of MEG measurement. The purposes of this paper are to develop a novel MEG phantom that can be calibrated and to demonstrate the advantages of the calibrated phantoms. NEW METHOD: We proposed and fabricated a practical dry phantom that is composed of 50 isosceles-triangle coils based on Ilmoniemi's model. This phantom was calibrated based on three-dimensional measurement of the current paths in the phantom and on numerical calculations. RESULTS: The calibrated positions of the equivalent current dipoles (ECDs) shifted 0.83mm, on average, from the designed positions. The uncertainties of the calibrated ECDs were also evaluated, by combining the uncertainties which could reasonably be attributed to them. COMPARISON WITH EXISTING METHOD(S): Furthermore, we demonstrated performance of the developed phantom through experimental evaluation of an MEG system. The results of this evaluation differed from those obtained using an uncalibrated phantom. Moreover, the calibrated phantom can provide detailed information regarding the uncertainty of the measurement and also the uncertainty of the phantom itself. CONCLUSIONS: A more appropriate evaluation of MEG measurements can be achieved using a calibrated phantom.

Publication criteria for evoked magnetic fields of the human brain: a proposal.

Magnetoencephalography (MEG) is a record of the magnetic fields produced by the electrical activities of the brain using MEG systems. There are three types of sensors for MEG systems: magnetometer and two types of gradiometer. Among them, two types of gradiometer, axial and planar, have been used worldwide. Unfortunately, the waveforms recorded by the two types of gradiometer are often different from each other. This poses a serious problem in comparing and evaluating the data from the two gradiometers. We consider that the MEG study should be published in a way that allows other workers using different types of gradiometer to evaluate and replicate the results of MEG studies. There have been, however, no publication criteria for reports of studies on stimulus-evoked or event-related magnetic fields in human subjects. In this article, we propose publication criteria for evoked or event-related magnetic fields of the human brain: original waveforms of selected channels covering a region of interest, a root mean-squared (RMS) waveform and a contour map at an appropriate time.

Diversity of neural-hemodynamic relationships associated with differences in cortical processing during bilateral somatosensory activation in rats.

The neural-hemodynamic relationships may vary depending on cortical processing patterns. To investigate how cortical hemodynamics reflects neural activity involving different cortical processing patterns, we delivered electrical stimulation pulses to rat hindpaws, unilaterally or bilaterally, and simultaneously measured electrophysiological (local field potential, LFP < 100 Hz; multiunit activity, MUA>300 Hz) and optical intrinsic signals associated with changes in cerebral blood volume (CBV). Unilateral stimulation evoked neural and optical signals in bilateral primary somatosensory cortices. Ipsilateral optical responses indicating an increased CBV exhibited a peak magnitude of ~30% and mediocaudal shifts relative to contralateral responses. Correlation analyses revealed different scale factors between contralateral and ipsilateral responses in LFP-MUA and LFP-CBV relationships. Bilateral stimulation at varying time intervals evoked hemodynamic responses that were strongly suppressed at 40-ms intervals. This suppression quantitatively reflected suppressed LFP responses to contralateral testing stimulation and not linear summation, with slowly fluctuating LFP responses to ipsilateral conditioning stimulation. Consequently, in the overall responses to bilateral stimulation, CBV-related responses were more linearly correlated with MUA than with LFPs. When extracting high-frequency components (>30 Hz) from LFPs, we found similar scale factors between contralateral and ipsilateral responses in LFP-MUA and LFP-CBV relationships, resulting in significant linear relationships among these components, MUA, and cortical hemodynamics in overall responses to bilateral stimulation. The dependence of LFP-MUA-hemodynamic relationships on cortical processing patterns and the LFP temporal/spectral structure is important for interpreting hemodynamic signals in complex functional paradigms driving diverse cortical processing.

Exploring the physiology and function of high-frequency oscillations (HFOs) from the somatosensory cortex.

A brief review of previous studies is presented on high frequency oscillations (HFOs)>300 Hz overlying the cortical response in the somatosensory evoked potential (SEP) or magnetic field (SEF) in humans as well as other mammals. The characteristics of somatosensory HFOs are described about reproducibility and origin (area 3b and 1) of the HFOs, changes during a wake-sleep cycle, effects of stimulus rate or tactile interference, and pharmacological effects. Also, several hypotheses on the neural mechanisms of the HFOs are reconsidered; the early HFO burst is probably generated from action potentials of thalamocortical fibers at the time when they arrive at the area 3b (and 1), since this component is resistant to higher stimulus rate >10 Hz, general anesthesia, or application of glutamatergic receptor antagonist: by contrast, the late HFO burst is sensitive to higher stimulus rate and eliminated after application of glutamatergic receptor antagonist, reflecting activities of a postsynaptic neural network in areas 3b and 1 of the somatosensory cortex. In view of physiological features of the somatosensory HFOs and their pathological or pharmacological changes, possible mechanisms of the late HFO burst genesis are discussed: a fast-spiking interneuron hypothesis, a fast pyramidal cell IPSP hypothesis and a chattering cell hypothesis.

High-frequency transcutaneous electrical nerve stimulation (TENS) differentially modulates sensorimotor cortices: an MEG study.

OBJECTIVE: Transcutaneous electrical nerve stimulation (TENS) affects excitability of the central motor system as well as the somatosensory system. To determine whether TENS has influence on excitability in the sensorimotor cortices of TENS-treated finger muscle, we investigated magnetoencephalogram associated with voluntary, self-paced finger movement before and after TENS. METHODS: High-frequency TENS was applied on the extensor digitorum muscle for 15 min. Subjects underwent alternate middle finger and thumb extension movements before and after the TENS. We recorded movement-related cortical magnetic field (MRCF) associated with TENS-treated middle finger movement and that from untreated thumb movement. RESULTS: The current source for motor field (MF) was located in the pre-central motor cortex and anteriorly-oriented, and that for motor evoked field one (MEF1) was found in the post-central somatosensory cortex and posteriorly-oriented. The amplitude of MF for TENS-treated middle finger movement decreased but unchanged for untreated thumb movement after TENS. The amplitude of MEF1 decreased for either finger movement after TENS. CONCLUSION: High-frequency TENS to the forearm muscle modulates excitability of the limited area of motor cortex but wider area of primary somatosensory cortex. SIGNIFICANCE: High-frequency TENS to the forearm muscle modulates excitability of the primary somatosensory cortex and motor cortex in a different manner.

Impulse propagation along thalamocortical fibers can be detected magnetically outside the human brain.

Orchestrating cortical network activity with synchronous oscillations of neurons across distant regions of the brain underlies information processing in humans (Knight, 2007) and monkeys (Saalmann et al., 2007; Womelsdorf et al., 2007). Frequencies of oscillatory activities depend, to a considerable extent, on the length and conduction velocity of the tracts connecting the neural areas that participate in oscillations (Buzsáki, 2006). However, the impulse propagation along the fiber tracts in the white matter has never been visualized in humans. Here, we show, by recording magnetoencephalogram (MEG) following median nerve stimulation, that a magnetic field component, we labeled "M15," changes dynamically within 1.6-1.8 ms before the onset of magnetic M20 response generated from the primary somatosensory cortex. This new M15 component corresponds to the intracellular depolarizing action current in the thalamocortical fibers propagating with the mean conduction velocity of 29 m/s. The findings challenge the traditional view that MEG is blind to the activity of deep subcortical structures. We argue that the MEG technique holds the promise of providing novel information in impulse transmissions along not only the thalamocortical pathway but also other fiber tracts connecting distant brain areas in humans.

Dynamic movement of N100m current sources in auditory evoked fields: comparison of ipsilateral versus contralateral responses in human auditory cortex.

We recorded auditory evoked magnetic fields (AEFs) to monaural 400Hz tone bursts and investigated spatio-temporal features of the N100m current sources in the both hemispheres during the time before the N100m reaches at the peak strength and 5ms after the peak. A hemispheric asymmetry was evaluated as the asymmetry index based on the ratio of N100m peak dipole strength between right and left hemispheres for either ear stimulation. The results of asymmetry indices showed right-hemispheric dominance for left ear stimulation but no hemispheric dominance for right ear stimulation. The current sources for N100m in both hemispheres in response to monaural 400Hz stimulation moved toward anterolateral direction along the long axis of the Heschl gyri during the time before it reaches the peak strength; the ipsilateral N100m sources were located slightly posterior to the contralateral N100m ones. The onset and peak latencies of the right hemispheric N100m in response to right ear stimulation are shorter than those of the left hemispheric N100m to left ear stimulation. The traveling distance of the right hemispheric N100m sources following right ear stimulation was longer than that for the left hemispheric ones following left ear stimulation. These results suggest the right-dominant hemispheric asymmetry in pure tone processing.

High-frequency oscillations change in parallel with short-interval intracortical inhibition after theta burst magnetic stimulation.

OBJECTIVE: Theta burst transcranial magnetic stimulation (TBS) causes changes in motor cortical excitability. In the present study, somatosensory-evoked potentials (SEPs) and high-frequency oscillations (HFOs) were recorded before and after TBS over the motor cortex to examine how TBS influenced the somatosensory cortex. METHODS: SEPs following electric median nerve stimulation were recorded, and amplitudes for the P14, N20, P25, and N33 components were measured and analyzed. HFOs were separated by 400-800 Hz band-pass filtering, and root-mean-square amplitudes were calculated from onset to offset. SEPs and HFOs were measured before and after application of either intermittent or continuous TBS (iTBS/cTBS; 600 total pulses at 80% active motor threshold) over the motor cortex. Motor-evoked potentials (MEPs) and short-interval intracortical inhibition (SICI) of the first dorsal interosseous muscle were examined before and after TBS. RESULTS: MEPs, SICI, and HFO amplitudes were increased and decreased significantly after iTBS and cTBS, respectively. Wide-band SEPs did not change significantly after TBS. CONCLUSIONS: TBS changed the cortical excitability of the sensorimotor cortices. Changes in HFOs after TBS were parallel to those in SICI. SIGNIFICANCE: The mechanisms of changes in HFOs after TBS may be the same as those in SICI.

Changes in somatosensory-evoked potentials and high-frequency oscillations after paired-associative stimulation.

Paired-associative stimulation (PAS), combining electrical median nerve stimulation with transcranial magnetic stimulation (TMS) with a variable delay, causes long-term potentiation or depression (LTP/LTD)-like cortical plasticity. In the present study, we examined how PAS over the motor cortex affected a distant site, the somatosensory cortex. Furthermore, the influences of PAS on high-frequency oscillations (HFOs) were investigated to clarify the origin of HFOs. Interstimulus intervals between median nerve stimulation and TMS were 25 ms (PAS(25)) and 10 ms (PAS(10)). PAS was performed over the motor and somatosensory cortices. SEPs following median nerve stimulation were recorded before and after PAS. HFOs were isolated by 400-800 Hz band-pass filtering. PAS(25) over the motor cortex increased the N20-P25 and P25-N33 amplitudes and the HFOs significantly. The enhancement of the P25-N33 amplitude and the late HFOs lasted more than 60 min. After PAS(10) over the motor cortex, the N20-P25 and P25-N33 amplitudes decreased for 40 min, and the HFOs decreased for 60 min. Frontal SEPs were not affected after PAS over the motor cortex. PAS(25/10) over the somatosensory cortex did not affect SEPs and HFOs. PAS(25/10) over the motor cortex caused the LTP/LTD-like phenomena in a distant site, the somatosensory cortex. The PAS paradigms over the motor cortex can modify both the neural generators of SEPs and HFOs. HFOs may reflect the activation of GABAergic inhibitory interneurons regulating pyramidal neurons in the somatosensory cortex.

Co-activation of the secondary somatosensory and auditory cortices facilitates frequency discrimination of vibrotactile stimuli.

The contribution of the auditory cortex to tactile information processing was studied by measuring somatosensory evoked magnetic fields (SEFs). Three kinds of vibrotactile stimuli with frequencies of 180, 280 and 380 Hz were randomly delivered on the right index finger with a probability of 40, 20 and 40%, respectively. Twenty normal subjects participated in four kinds of tasks: a control condition to ignore these stimuli, a simple task to discriminate the 280-Hz stimulus from the other two stimuli (discrimination task for the vibrotactile stimuli, Ts task), a feedback task modified from the Ts task by adding acoustic feedback of the vibratory frequency at 1300 ms poststimulus (tactile discrimination with auditory clues, TA), and an easy version of the TA task (TA-easy) to discriminate the 280-Hz stimulus (20% target) from the 180- or 380-Hz stimuli (80% nontarget). The Ts and TA tasks required accurate perception of the vibrotactile frequencies to discriminate among the three kinds of stimuli. Under such a task demand, the post hoc auditory feedback in the TA task was expected to induce acoustic imagery for the tactile sensation. The SEFs for the nontarget stimuli were analyzed. A middle-latency component (M150/200) was specifically evoked by the three discrimination tasks. In the Ts and TA-easy tasks, the M150/200 source indicated inferior parietal cortical activities (SII area). In the TA task, 11 subjects showed activity in both the SII area and the superior temporal auditory region and increased accuracy of discrimination compared with the Ts task, in contrast with other subjects who showed activity only in the SII area and small changes in task accuracy between the Ts and TA tasks. Asynchronous auditory feedback for the vibrotactile sensation induced the auditory cortex activity in the SEFs in relation to the progress in tactile discrimination, which suggested an induction of acoustic imagery to complement the tactile information processing.

Human tonotopic maps and their rapid task-related changes studied by magnetic source imaging.

A brief review of previous studies is presented on tonotopic organization of primary auditory cortex (AI) in humans. Based on the place theory for pitch perception, in which place information from the cochlea is used to derive pitch, a well-organized layout of tonotopic map is likely in human AI. The conventional view of tonotopy in human AI is a layout inwhich the medial-to-lateral portion of Heschl's gyrus represents high-to-low frequency tones. However, we have shown that the equivalent current dipole (ECD) in auditory evoked magnetic fields in the rising phase of N100m response dynamically moves along the long axis of Heschl's gyrus. Based on analyses of the current sources for high-pitched and low-pitched tones in the right and left hemispheres, we propose an alternative tonotopic map in human AI. In the right AI, isofrequency bands for each tone frequency are parallell to the first transverse sulcus; on the other hand, the layout for tonotopy in the left AI seems poorly organized. The validity of single dipole modelling in the calculation of a moving source and the discrepancy as to tonotopic maps in the results between auditory evoked fields or intracerebral recordings and neuroimaging studies also are discussed. The difference in the layout of isofrequency bands between the right and left auditory cortices may reflect distinct functional roles in auditory information processing such as pitch versus phonetic analysis.

Interferon-gamma down-regulates expression of the 230-kDa bullous pemphigoid antigen gene (BPAG1) in epidermal keratinocytes via novel chimeric sequences of ISRE and GAS.

The 230-kDa bullous pemphigoid antigen (BPAG1) is an integral component of hemidesmosomes. We have previously reported that interferon-gamma (IFNgamma) inhibits the transcription of the BPAG1 gene (1). Here we investigated the target sequences of IFNgamma-signal transduction pathway in the BPAG1 promoter in epidermal keratinocytes. Transient transfections with 5'-deletion constructs of BPAG1 promoter-luciferase reporter gene plasmids in cultured normal human epidermal keratinocytes (NHEK) allowed us to narrow the DNA region containing IFNgamma inhibitory element (IGIE) to between -1 and -89, upstream from the transcription initiation site (+1). Homology search in this region identified a chimeric sequence, consisting of IFN-stimulated responsive element (ISRE) with a partial 7-bp sequence of IFNgamma activation site (GAS), as identified in the guanylate-binding protein (GBP) gene, inserted at its center. Functional analysis of IGIE, inserted in front of the heterologous thymidine kinase promoter, indicated that IGIE acts as a down-regulatory element of the promoter through IFNgamma-dependent signal pathway. Transient transfection studies with BPAG1 promoter-reporter gene constructs containing mutated IGIE (with TT to GG transversions in the region of 5'ISRE, GAS, and 3'ISRE) demonstrated that disruption of the ISRE sequences, but not GAS, markedly suppressed the BPAG1 basal promoter activity and resulted in attenuated IFNgamma response in keratinocytes. Our findings provide novel insight into the mechanism of IFNgamma regulation in keratinocyte differentiation and proliferation.

Neural mechanisms of the ultrafast activities.

A brief review of previous studies is presented on ultra-fast activities > 300 Hz (high frequency oscillations, HFOs) overlying the cortical response in the somatosensory evoked potential (SEP) or magnetic field (SEF). The characteristics of somatosensory HFOs are described in terms of reproducibility and origin (area 3b and 1) of the HFOs, changes during a wake-sleep cycle, effects of higher stimulus rate or tactile interference, etc. Also, several hypotheses on the neural mechanisms of the HFOs are introduced; the early HFO burst is probably generated from action potentials of thalamocortical fibers at the time when they arrive at the area 3b (and 1), since this component is resistant to higher stimulus rate > 10Hz or general anesthesia: by contrast, the late HFO burst is sensitive to higher stimulus rate, reflecting activities of a postsynaptic neural network in the somatosensory cortices, area 3b and 1. As to possible mechanisms of the late HFO burst genesis, an interneuron hypothesis, a fast inhibitory postsynaptic potential (IPSP) hypothesis of the pyramidal cell and a chattering cell hypothesis will be discussed on the basis of physiological and pathological features of the somatosensory HFOs.

Keratinocyte-specific modulation of type VII collagen gene expression by pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1beta).

Previous studies have shown that pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta up-regulate type VII collagen gene (COL7A1) expression in cultured dermal fibroblasts. The present study was designed to investigate the effects of TNF-alpha and IL-1beta on COL7A1 expression in epidermal keratinocytes. We demonstrated that both TNF-alpha and IL-1beta reduced COL7A1 expression in epidermal keratinocytes in an additive manner, whereas they increased COL7A1 expression in dermal fibroblasts. Thus, regulation of COL7A1 by pro-inflammatory cytokines is cell type specific. In particular, the inhibitory effects of TNF-alpha and IL-1beta occurred, at least in part, at the transcriptional level. Finally, we demonstrated that TNF-alpha and IL-1beta enhanced the TGF-beta-mediated up-regulation of COL7A1 expression in HaCaT keratinocytes, suggesting that the combination of TGF-beta and TNF-alpha or IL-1beta induces a signaling pathway that is completely different from that induced by either pro-inflammatory cytokine alone.

Attention induces reciprocal activity in the human somatosensory cortex enhancing relevant- and suppressing irrelevant inputs from fingers.

OBJECTIVE: We studied whether attention regulates information processing in the human primary somatosensory cortex (SI) by selective enhancement of relevant- and suppression of irrelevant information. METHODS: Under successive and simultaneous electric stimuli to both the right index and middle fingers, tactile stimuli were randomly (20%) presented on one of the two fingers in separate two runs exchanging the finger. Subjects were requested to discriminate the tactile stimuli in an attention task to induce attention to one finger and to ignore the stimuli in a control task to avoid such an attention focus. Somatosensory evoked magnetic fields were measured only for the two-finger electric stimulation and an early component (M50) was analyzed. RESULTS: In spite of the two-finger simultaneous stimulation, attention to either the index or middle finger lowered or heightened the M50-sourse location, respectively. The attention task did not increase the M50 amplitude. CONCLUSIONS: Attention to a finger enhanced selectively the representation of the finger in the SI cortex. However, this SI activity did not increase the M50 amplitude, suggesting that the attention suppressed another finger region receiving the unattended inputs. SIGNIFICANCE: Attention regulates the SI activity by selectively enhancing the task-relevant information and by filtering out other noise inputs.

Functional connectivity between forearm and digits representations in human somatosensory area 3b.

OBJECTIVE: We compared the effects of tactile interference to the forearm on magnetic responses evoked by electric stimulation of the little finger (D5) and the thumb (D1). METHODS: Electric stimulation was delivered to D5 or D1 individually. In each stimulus session, magnetic recordings were conducted with or without concurrent tactile interference to the radial side of the anterior forearm. RESULTS: With forearm interference, the amplitude of the primary response (N20m) following D5 stimulation was reduced to 90.7% of the control value without interference, while that following D1 stimulation was not affected (100.7%). CONCLUSIONS: In human somatosensory area 3b, the representation of the forearm is immediately adjacent to that of the D5, and distant from that of the D1. Thus, the result suggests that the tactile interference effect on N20m depends on the cortical distance between electrically and mechanically activated 3b areas. SIGNIFICANCE: Intrinsic synaptic connections between the 3b hand representation and its surroundings have been hypothesized as a neural basis for plastic changes of the human brain, such as a phantom hand phenomenon. The present finding implies that these connections may play some physiological roles even in normal adult humans.

Rapid change of tonotopic maps in the human auditory cortex during pitch discrimination.

OBJECTIVE: To study early cognitive processes and hemispheric differences in the primary auditory cortex during selective attention. METHODS: We measured auditory evoked magnetic fields (AEFs) to 400 and 4000 Hz tone pips that were randomly presented at the right or left ear. Subjects paid attention to target stimuli during pitch (high or low) or laterality (left or right) discrimination tasks. In the control session, 400 or 4000 Hz tone alone was presented at the left or right ear. We calculated the location and strength of N100m dipole for 400 and 4000 Hz tones, based on the AEFs obtained from the hemisphere contralateral to the stimulated ear. RESULTS: N100m amplitude increased in both hemispheres in pitch or laterality discriminating conditions. N100m latency also shortened during selective attention. The N100m dipole distance between 400 and 4000 Hz tones was enlarged, especially in the right auditory cortex during pitch discrimination task, but was unchanged during the laterality discrimination task. CONCLUSIONS: We conclude that these dynamic changes in the N100m dipole reflect short-term plastic changes in the primary auditory cortex, supporting early selection models. SIGNIFICANCE: This work is the first to disclose short-term plastic changes during pitch discrimination in the human auditory cortex based on the analysis of magnetoencephalography.

Disinhibition of the somatosensory cortex in cervical dystonia-decreased amplitudes of high-frequency oscillations.

OBJECTIVE: To determine whether patients with cervical dystonia have electrophysiological signs of disinhibition in the somatosensory cortex by recording high-frequency oscillations (HFOs) in somatosensory evoked potentials (SEPs). METHODS: HFOs were recorded in 13 patients and 10 age-matched control subjects, and the data were analyzed statistically by paired comparison and by Pearson's correlation. RESULTS: In patients with cervical dystonia, the early part of HFOs showed a significant decrease in amplitude, and the amplitude ratios of both early and late parts of HFOs/N20 potential were also significantly decreased. The amplitudes of HFOs and N20 potential were linearly correlated in the control subjects but not in dystonia patients. CONCLUSIONS: Patients with cervical dystonia may suffer from a disturbance of inhibition in the sensory cortex. This disturbance is reflected by decreased HFO amplitude, representing decreased activities of inhibitory interneurons in area 3b.

Serial N20m dipoles in somatosensory evoked magnetic fields move along the distal-proximal representation of the digit area 3b of the human cortex.

We studied the relationship between the distal-proximal representation of the digit in area 3b and moving dipoles of the primary magnetic response (N20m). By the use of ring electrodes, a distal or proximal portion of the middle finger was stimulated to elicit N20m. The dipole locations were sequentially analyzed around the N20m peak. The dipole locations did not differ between distal and proximal stimulation before the N20m peak. After 0.4 ms post-N20m peak, however, the dipoles following proximal stimulation substantially and progressively shifted laterally to those following distal stimulation. The result suggests that the N20m dipole moves from the distal representation toward the proximal representation of the digits in area 3b.