Background/Aims We evaluated the feasibility and long-term efficacy of the combination of cytarabine, idarubicin, and all-trans retinoic acid (ATRA) for treating patients with newly diagnosed acute promyelocytic leukemia (APL). Methods We included 87 patients with newly diagnosed acute myeloid leukemia and a t(15;17) or promyelocytic leukemia/retinoic acid receptor alpha (PML-RARα) mutation. Patients received 12 mg/m2/day idarubicin intravenously for 3 days and 100 mg/m2/day cytarabine for 7 days, plus 45 mg/m2/day ATRA. Clinical outcomes included complete remission (CR), relapse-free survival (RFS), overall survival (OS), and the secondary malignancy incidence during a 20-year follow-up. Results The CR, 10-year RFS, and 10-year OS rates were 89.7%, 94.1%, and 73.8%, respectively, for all patients. The 10-year OS rate was 100% for patients that achieved CR. Subjects were classified according to the white blood cell (WBC) count in peripheral blood at diagnosis (low-risk, WBC < 10,000/mm3; high-risk, WBC ≥ 10,000/mm3). The low-risk group had significantly higher RFS and OS rates than the high-risk group, but the outcomes were not superior to the current standard treatment (arsenic trioxide plus ATRA). Toxicities were similar to those observed with anthracycline plus ATRA, and higher than those observed with arsenic trioxide plus ATRA. The secondary malignancy incidence after APL treatment was 2.7%, among the 75 patients that achieved CR, and 5.0% among the 40 patients that survived more than 5 years after the APL diagnosis. Conclusions Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

Magnetoencephalography (MEG) is a functional neuroimaging technique that noninvasively detects the brain magnetic field from neuronal activations. Conventional MEG measures brain signals using superconducting quantum interference devices (SQUIDs). SQUID-MEG requires a cryogenic environment involving a bulky non-magnetic Dewar flask and the consumption of liquid helium, which restricts the variability of the sensor array and the gap between the cortical sources and sensors. Recently, miniature optically pumped magnetometers (OPMs) have been developed and commercialized. OPMs do not require cryogenic cooling and can be placed within millimeters from the scalp. In the present study, we arranged six OPM sensors on the temporal area to detect auditory-related brain responses in a two-layer magnetically shielded room. We presented the auditory stimuli of 1 kHz pure-tone bursts with 200 ms duration and obtained the M50 and M100 components of auditory-evoked fields. We delivered the periodic stimuli with a 40 Hz repetition rate and observed the gamma-band power changes and inter-trial phase coherence of auditory steady-state responses at 40 Hz. We found that the OPM sensors have a performance comparable to that of conventional SQUID-MEG sensors, and our results suggest the feasibility of using OPM sensors for functional neuroimaging and brain–computer interface applications.

For reliable and long-term operation of superconducting quantum interference devices (SQUIDs), proper protection against mechanical damage and electrostatic discharge is required. In this study, we developed a simple and practical molding method using a polydimethylsiloxane–carbon black composite to protect SQUIDs. By simply dipping SQUIDs into the molding composite precursor, they could be molded reliably with no additional mechanical damage from the molding process itself. Additionally, the molded SQUIDs showed no degradation in the flux–voltage modulation curves for ten thermal cycles between 4.2 K and room temperature. We also compared the electrostatic discharge immune characteristics of bare and molded SQUIDs by applying air discharge voltages in the range of 0.1–4.0 kV. Among the 52 SQUIDs with or without molding, all the molded SQUIDs survived up to 1.2 kV. For higher discharge voltages, the molded SQUIDs have a lower likelihood of damage than the bare SQUIDs. This study also confirmed that neither the molding material nor process increase the flux noise, indicating that the developed molding method can be used reliably for multichannel SQUID systems.

We developed a low-vibrational-noise cooling configuration using continuous liquefaction of evaporated helium gas from a multi-channel SQUID gradiometer system for whole-head magnetoencephalography (MEG) measurements. The initial reduction of the vibration of the cryocooler was done by rigidly mounting the remote motor and cold head chamber on a concrete wall. This significantly reduces transmission of vibrations to the transfer tube, especially compared with mounting them on vertical aluminum frames. In addition, to reduce vibrations from a mechanical SQUID array insert, we completely eliminated it by mounting each SQUID gradiometer separately on the helmet surface within the vacuum space. Thus, vibrations from the boiling liquid helium and transmission from the transfer tube were both greatly reduced. Magnetic field noise of the 150-channel SQUID gradiometer system showed that the vibration-induced interference peaks are comparable in amplitude to those from a conventional MEG system without helium reliquefaction.

Vibrotactile technology has been gaining increasing interest for effective human-computer communication in various applications. In addition to psychophysical approaches commonly used to study tactile vibrations, neurocognitive responses to vibrotactile stimuli can provide new insights into mechanisms underlying human vibrotactile perception. In this study, we developed a magnetoencephalography (MEG)-compatible vibrotactile stimulation device based on a polyvinyl chloride (PVC) gel actuator to study neuromagnetic somatosensory responses. A symmetric, double-layered PVC gel structure was applied to minimize the magnetic noise from the actuator. The device was used to generate sinusoidal stimuli at high frequencies to activate mechanoreceptors responsible for high-frequency vibrations greater than 50 Hz, and this device showed very little variability in stimulation onset time from the displacement measurements. We successfully observed vibrotactile-evoked magnetic fields by analyzing whole-head MEG data recorded during the high-frequency vibrotactile stimulation of the fingertips. Prominent peak responses were observed at approximately 56 ms (M50) in the contralateral hemisphere and at approximately 100 ms (M100) in both hemispheres. We identified the activation of contralateral primary somatosensory areas as a source of the vibrotactile M50 response. These results demonstrate the feasibility of using our new device to study vibrotactile perception with neuromagnetic imaging methods.

Background: In recent years, vibrotactile haptic feedback technology has been widely used for user interfaces in the mobile devices. Although functional neuroimaging studies have investigated human brain responses to different types of tactile inputs, the neural mechanisms underlying high-frequency vibrotactile perception are still relatively unknown. Our aim was to investigate neuromagnetic brain responses to high-frequency vibrotactile stimulation, using magnetoencephalography (MEG). Methods: We measured 152-channel whole-head MEG in 30 healthy, right-handed volunteers (aged 20-28 years, 15 females). A total of 300 vibrotactile stimuli were presented at the tip of either the left index finger or the right index finger in two separate sessions. Sinusoidal vibrations at 150 Hz for 200 ms were generated with random inter-stimulus intervals between 1.6 and 2.4 s. Both time-locked analysis and time-frequency analysis were performed to identify peak responses and oscillatory modulations elicited by high-frequency vibrations. The significance of the evoked and induced responses for dominant and non-dominant hand stimulation conditions was statistically tested, respectively. The difference in responses between stimulation conditions was also statistically evaluated. Results: Prominent peak responses were observed at 56 ms (M50) and at 100 ms (M100) for both stimulation conditions. The M50 response revealed clear dipolar field patterns in the contralateral side with significant cortical activations in the contralateral primary sensorimotor area, whereas the M100 response was not as prominent as the M50. Vibrotactile stimulation induced significant suppression of both alpha (8-12 Hz) and beta (20-30 Hz) band activity during the mid-latency period (0.2-0.4 s), primarily in sensorimotor areas contralateral to the stimulation side. In addition, a significant alpha enhancement effect in posterior regions was accompanied with alpha suppressions in sensorimotor regions. The alpha suppression was observed in a broader distribution of cortical areas for the non-dominant hand stimulation. Conclusion: Our data demonstrate that high-frequency tactile vibrations, which is known to primarily activate Pacinian corpuscles, elicit somatosensory M50 and M100 responses in the evoked fields and induce modulations of alpha and beta band oscillations during mid-latency periods. Our study is also consistent with that the primary sensorimotor area is significantly involved in the processing of high-frequency vibrotactile information with contralateral dominance.

Background: When many features and a small number of clinical data exist, previous studies have used a few top-ranked features from the Fisher's discriminant ratio (FDR) for feature selection. However, there are many similarities between selected features. New method: To reduce the redundant features, we applied a technique employing FDR in conjunction with feature correlation. We performed an attention network test on schizophrenic patients and normal subjects with a 152-channel magnetoencephalograph. P300m amplitudes of event-related fields (ERFs) were used as features at the sensor level and P300m amplitudes of ERFs for 500 nodes on the cortex surface were used as features at the source level. Features were ranked using FDR criterion and cross-correlation measure, and then the highest ranked 10 features were selected and an exhaustive search was used to find combination having the maximum accuracy. Results: At the sensor level, we found a single channel of the occipital region that distinguished the two groups with an accuracy of 89.7 %. At source level, we obtained an accuracy of 96.2 % using two features, the left superior frontal region and the left inferior temporal region. Comparison with existing method: At source level, we obtained a higher accuracy than traditional method using only FDR criterion (accuracy = 88.5 %). We used only the P300 m amplitude (not latency) on a single channel and two brain regions at a fairly high rate.

The somatic marker hypothesis proposes that the cortical representation of visceral signals is a crucial component of emotional processing. No previous study has investigated the information flow among brain regions that process visceral information during emotional perception. In this magnetoencephalography study of 32 healthy subjects of either sex, heartbeat-evoked responses (HERs), which reflect the cortical processing of heartbeats, were modulated by the perception of a sad face. The modulation effect was localized to the prefrontal cortices, the globus pallidus, and an interoceptive network including the right anterior insula (RAI) and dorsal anterior cingulate cortex (RdACC). Importantly, our Granger causality analysis provides the first evidence for the increased flow of heartbeat information from the RAI to the RdACC during sad face perception. Moreover, using a surrogate R-peak analysis, we have shown that this HER modulation effect was time-locked to heartbeats. These findings advance the understanding of brain-body interactions during emotional processing.

Thermoreception is an important cutaneous sense, which plays a role in the maintenance of our body temperature and in the detection of potential noxious heat stimulation. In this study, we investigated event‐related fields (ERFs) and neural oscillatory activities, which were modulated by warmth stimulation. We developed a warmth stimulator that could elicit a warmth sensation, without pain or tactile sensation, by using a deep‐penetrating 980‐nm diode laser. The index finger of each participant (n = 24) was irradiated with the laser warmth stimulus, and the cortical responses were measured using magnetoencephalography (MEG). The ERFs and oscillatory responses had late latencies (∼1.3 s and 1.0–1.5 s for ERFs and oscillatory responses, respectively), which could be explained by a slow conduction velocity of warmth‐specific C‐fibers. Cortical sources of warmth‐related ERFs were seen in the bilateral primary and secondary somatosensory cortices (SI and SII), posterior part of the anterior cingulate cortex (pACC), ipsilateral primary motor, and premotor cortex. Thus, we suggested that SI, SII, and pACC play a role in processing the warmth sensation. Time–frequency analysis demonstrated the suppression of the alpha (8–13 Hz) and beta (18–23 Hz) band power in the bilateral sensorimotor cortex. We proposed that the suppressions in alpha and beta band power are involved in the automatic response to the input of warmth stimulation and sensorimotor interactions. The delta band power (1–4 Hz) increased in the frontal, temporal, and cingulate cortices. The power changes in delta band might be related with the attentional processes during the warmth stimulation.

Recently, neurophysiological findings about social interaction have been investigated widely, and hardware has been developed that can measure multiple subjects' brain activities simultaneously. These hyperscanning studies have enabled us to discover new and important evidences of interbrain interactions. Yet, very little is known about verbal interaction without any visual input. Therefore, we conducted a new hyperscanning study based on verbal, interbrain turn‐taking interaction using simultaneous EEG/MEG, which measures rapidly changing brain activities. To establish turn‐taking verbal interactions between a pair of subjects, we set up two EEG/MEG systems (19 and 146 channels of EEG and MEG, respectively) located ∼100 miles apart. Subjects engaged in verbal communication via condenser microphones and magnetic‐compatible earphones, and a network time protocol synchronized the two systems. Ten subjects participated in this experiment and performed verbal interaction and noninteraction tasks separately. We found significant oscillations in EEG alpha and MEG alpha/gamma bands in several brain regions for all subjects. Furthermore, we estimated phase synchronization between two brains using the weighted phase lag index and found statistically significant synchronization in EEG and MEG data. Our novel paradigm and neurophysiological findings may foster a basic understanding of the functional mechanisms involved in human social interactions. Hum Brain Mapp 39:171–188, 2018 . © 2017 Wiley Periodicals, Inc.

In this article, we briefly introduce our developmental history and main technical focuses for commercializing magnetoencephalography (MEG) technology.MEG is a cutting-edge

Pexa-Vec (pexastimogene devacirpvec; JX-594) has emerged as an attractive tool in oncolytic virotherapy. Pexa-Vec demonstrates oncolytic and immunotherapeutic mechanisms of action. But the determinants of resistance to Pexa-Vec are mostly unknown. We treated hemoatologic malignant cells with Pexa-Vec and examined the gene-expression pattern of sensitive and resistant cells. Human myeloid malignant cell lines (RPMI-8226, IM-9, K562, THP-1) and lymphoid cancer cell lines (MOLT4, CCRF-CEM, Ramos, U937) were treated with Pexa-Vec. Pexa-Vec was cytotoxic on myeloid cell lines in a dose-dependent manner, and fluorescent imaging and qPCR revealed that Pexa-Vec expression was low in RAMOS than IM-9 after 24 hrs and 48 hrs of infection. Gene expression profiles between two groups were analyzed by microarray. Genes with at least 2-fold increase or decrease in their expression were identified. A total of 660 genes were up-regulated and 776 genes were down-regulated in lymphoid cancer cell lines. The up- and down-regulated genes were categorized into 319 functional gene clusters. We identified the top 10 up-regulated genes in lymphoid cells. Among them three human genes (LEF1, STAMBPL1, and SLFN11) strongly correlated with viral replication. Up-regulation of PVRIG, LPP, CECR1, Arhgef6, IRX3, IGFBP2, CD1d were related to resistant to Pexa-Vec. In conclusion, lymphoid malignant cells are resistant to Pexa-Vec and displayed up-regulated genes associated with resistance to oncolytic viral therapy. These data provide potential targets to overcome resistance, and suggest that molecular assays may be useful in selecting patients for further clinical trials with Pexa-Vec.

Magnetoencephalography (MEG) based on superconducting quantum interference devices enables the measurement of very weak magnetic fields (10-1000 fT) generated from the human or animal brain. In this article, we introduce a small MEG system that we developed specifically for use with rats. Our system has the following characteristics: (1) variable distance between the pick-up coil and outer Dewar bottom (∼5 mm), (2) small pick-up coil (4 mm) for high spatial resolution, (3) good field sensitivity (45∼ 80fT/cm/Hz), (4) the sensor interval satisfies the Nyquist spatial sampling theorem, and (5) small source localization error for the region to be investigated. To reduce source localization error, it is necessary to establish an optimal sensor layout. To this end, we simulated confidence volumes at each point on a grid on the surface of a virtual rat head. In this simulation, we used locally fitted spheres as model rat heads. This enabled us to consider more realistic volume currents. We constrained the model such that the dipoles could have only four possible orientations: the x- and y-axes from the original coordinates, and two tangentially layered dipoles (local x- and y-axes) in the locally fitted spheres. We considered the confidence volumes according to the sensor layout and dipole orientation and positions. We then conducted a preliminary test with a 4-channel MEG system prior to manufacturing the multi-channel system. Using the 4-channel MEG system, we measured rat magnetocardiograms. We obtained well defined P-, QRS-, and T-waves in rats with a maximum value of 15 pT/cm. Finally, we measured auditory evoked fields and steady state auditory evoked fields with maximum values 400 fT/cm and 250 fT/cm, respectively.

Computation of headmodel and sourcemodel from the subject's MRI scan is an essential step for source localization of magnetoencephalography (MEG) (or EEG) sensor signals. In the absence of a real MRI scan, pseudo MRI (i.e., associated headmodel and sourcemodel) is often approximated from an available standard MRI template or pool of MRI scans considering the subject's digitized head surface. In the present study, we approximated two types of pseudo MRI (i.e., associated headmodel and sourcemodel) using an available pool of MRI scans with the focus on MEG source imaging. The first was the first rank pseudo MRI; that is, the MRI scan in the dataset having the lowest objective registration error (ORE) after being registered (rigid body transformation with isotropic scaling) to the subject's digitized head surface. The second was the averaged rank pseudo MRI that is generated by averaging of headmodels and sourcemodels from multiple MRI scans respectively, after being registered to the subject's digitized head surface. Subject level analysis showed that the mean upper bound of source location error for the approximated sourcemodel in reference to the real one was 10 ± 3 mm for the averaged rank pseudo MRI, which was significantly lower than the first rank pseudo MRI approach. Functional group source response in the brain to visual stimulation in the form of event-related power (ERP) at the time latency of peak amplitude showed noticeably identical source distribution for first rank pseudo MRI, averaged rank pseudo MRI, and real MRI. The source localization error for functional peak response was significantly lower for averaged rank pseudo MRI compared to first rank pseudo MRI. We conclude that it is feasible to use approximated pseudo MRI, particularly the averaged rank pseudo MRI, as a substitute for real MRI without losing the generality of the functional group source response.

Recently, an increasing number of studies have employed multivariate pattern analysis (MVPA) rather than univariate analysis for the dynamic pattern decoding of event-related responses recorded with a MEG/EEG sensor. The use of the MVPA approach for source-reconstructed MEG/EEG data is uncommon. For these data, we need to consider the source orientation information and the signal leakage among brain regions. In the present study, we evaluate the perspective of the MVPA approach in the context of source orientation information and signal leakage in source-reconstructed MEG data. We perform face vs. tool object category decoding (FvsT-OCD) of event-related responses from single or multiple voxels from a brain region using a univariate analysis approach and/or the MVPA approach. We also propose and perform symmetric signal leakage correction of source reconstructed data using an independent component analysis-based approach. FvsT-OCD using single voxel information shows higher sensitivity for the MVPA approach than univariate analysis, as the MVPA approach efficiently utilizes information on all three dipole orientations and is less affected by inter-subject variability. The MVPA approach shows higher sensitivity for FvsT-OCD when considering information from multiple voxels than for a single voxel in a brain region. This finding suggests that the MVPA approach captures the latent multivoxel distributed pattern. However, the results may be partly or entirely attributable to signal leakage between brain regions, as the sensitivity is substantially reduced after signal leakage correction. A consideration of signal leakage is therefore essential during the evaluation of MVPA outcomes.

The somatic marker hypothesis proposes that the cortical representation of visceral signals is a crucial component of emotion processing. No previous study has investigated the causal relationships among brain regions that process visceral information during emotional perception. In this magnetoencephalography study of 32 healthy subjects, heartbeat-evoked potentials (HEPs), which reflect the cortical processing of heartbeats, were modulated by the perception of a sad face. The modulation effect was localized to the prefrontal cortices, the globus pallidus, and an interoceptive network including the right anterior insula (RAI) and anterior cingulate cortex (RACC). Importantly, our Granger causality analysis provides the first evidence for increased causal flow of heartbeat information from the RAI to the RACC during sad face perception. Moreover, this HEP modulation effect was neither an artefact nor an effect of visual-evoked potentials. These findings provide important progress in the understanding of brain-body interactions during emotion processing.

Background: We conducted the study to examine accuracy of the magnetoencephalography (MEG) spike source localization in presurgical evaluation of patients with medically refractory focal epilepsy.Methods: Ten consecutive patients with refractory focal epilepsy who were candidates for two-stagesurgery with long-term intracranial electroencephalography (ICEEG) monitoring were enrolled. Interictal MEG recordings with simultaneous scalp EEG were obtained within 7 days before the ICEEG electrode implantation. The location of each MEG spike source was quantitatively compared with ICEEG spike foci (focal area of interictal spikes) and ICEEG ictal foci (earliest cortical origin of seizures). Gyral-width concordance and sublobar concordance were also determined for all MEG spike sources. Gyral-width concordance was defined by distance of 15 mm or less between MEG spike sources and ICEEG spike foci or ICEEG ictal foci.Results: Visual analyses of the MEG traces of all 10 patients revealed 292 spikes (29.2 +/- 24.0 per patient). Spike yield of the MEG was similar to the simultaneously recorded scalp EEG. MEG spike sources were closely located with ICEEG spike foci (distance: 9.3 +/- 10.8 mm). Clustered MEG spike sources were even closer to ICEEG spike foci (distance: 7.3 +/- 6.4 mm). MEG spike sources, even clustered ones, were less concordant with ICEEG ictal foci and had significant longer distance from ICEEG ictal foci (distance: 21.5 perpendicular to 15.6 mm for all sources, 19.7 perpendicular to 13.7 mm for clustered sources). Gyral-width concordance rate and sublobar concordance rate were also higher with ICEEG interictal spike foci than with ICEEG ictal foci. On the other hand, 53.4% of interictal spike foci from ICEEG were not detected by interictal MEG recordings.Conclusions: MEG spike sources, especially clustered ones, from interictal recording could localize the irritative zone of ICEEG with a high accuracy. However, MEG spike sources have relatively poor correlation with seizure onset zone and lower sensitivity in identifying all irritative zones of ICEEG. This limitation should be considered in the interpretation of MEG results. (C) 2016 Published by Elsevier B.V.

Phase-amplitude coupling (PAC) plays an important role in neural communication and computation. Interestingly, recent studies have indicated the presence of ubiquitous PAC phenomenon even during the resting state. Despite the importance of PAC phenomenon, estimation of significant physiological PAC is challenging because of the lack of appropriate surrogate measures to control false positives caused by non-physiological PAC. Therefore, in the present study, we evaluated PAC phenomenon during resting-state magnetoencephalography (MEG) signal and considered various surrogate measures and computational approaches widely used in the literature in addition to proposing new ones. We evaluated PAC phenomenon over the entire length of the MEG signal and for multiple shorter time segments. The results indicate that the extent of PAC phenomenon mainly depends on the surrogate measures and PAC computational methods used, as well as the evaluation approach. After a careful and critical evaluation, we found that resting-state MEG signals failed to exhibit ubiquitous PAC phenomenon, contrary to what has been suggested previously.