SQUID magnetoneurography: an old-fashioned yet new tool for noninvasive functional imaging of spinal cords and peripheral nerves.

We are engaged in the development and clinical application of a neural magnetic field measurement system that utilizes biomagnetic measurements to observe the activity of the spinal cord and peripheral nerves. Unlike conventional surface potential measurements, biomagnetic measurements are not affected by the conductivity distribution within the body, making them less influenced by the anatomical structure of body tissues. Consequently, functional testing using biomagnetic measurements can achieve higher spatial resolution compared to surface potential measurements. The neural magnetic field measurement, referred to as magnetoneurography, takes advantage of these benefits to enable functional testing of the spinal cord and peripheral nerves, while maintaining high spatial resolution and noninvasiveness. Our magnetoneurograph system is based on superconducting quantum interference devices (SQUIDs) similar to the conventional biomagnetic measurement systems. Various design considerations have been incorporated into the SQUID sensor array structure and signal processing software to make it suitable for detecting neural signal propagation along spinal cord and peripheral nerve. The technical validation of this system began in 1999 with a 3-channel SQUID system. Over the course of more than 20 years, we have continued technological development through medical-engineering collaboration, and in the latest prototype released in 2020, neural function imaging of the spinal cord and peripheral nerves, which could also be applied for the diagnosis of neurological disorders, has become possible. This paper provides an overview of the technical aspects of the magnetoneurograph system, covering the measurement hardware and software perspectives for providing diagnostic information, and its applications. Additionally, we discuss the integration with a helium recondensing system, which is a key factor in reducing running costs and achieving practicality in hospitals.

Assessing ulnar neuropathy at the elbow using magnetoneurography.

OBJECTIVE: To measure neuromagnetic fields of ulnar neuropathy patients at the elbow after electrical stimulation and evaluate ulnar nerve function at the elbow with high spatial resolution. METHODS: A superconducting quantum interference device magnetometer system recorded neuromagnetic fields of the ulnar nerve at the elbow after electrical stimulation at the wrist in 16 limbs of 16 healthy volunteers and 21 limbs of 20 patients with ulnar neuropathy at the elbow. After artifact removal, neuromagnetic field signals were processed into current distributions, which were superimposed onto X-ray images for visualization. RESULTS: Based on the results in healthy volunteers, conduction velocity of 30 m/s or 50% attenuation in current amplitude was set as the reference value for conduction disturbance. Of the 21 patient limbs, 15 were measurable and lesion sites were detected, whereas 6 limbs were unmeasurable due to weak neuromagnetic field signals. Seven limbs were deemed normal by nerve conduction study, but 5 showed conduction disturbances on magnetoneurography. CONCLUSIONS: Measuring the magnetic field after nerve stimulation enabled visualization of neurophysiological activity in patients with ulnar neuropathy at the elbow and evaluation of conduction disturbances. SIGNIFICANCE: Magnetoneurography may be useful for assessing lesion sites in patients with ulnar neuropathy at the elbow.

Detection of biomagnetic signals from induced pluripotent stem cell-derived cardiomyocytes using deep learning with simulation data.

The detection of spontaneous magnetic signals can be used for the non-invasive electrophysiological evaluation of induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs). We report that deep learning with a dataset that combines magnetic signals estimated using numerical simulation and actual noise data is effective in the detection of weak biomagnetic signals. To verify the feasibility of this method, we measured artificially generated magnetic signals that mimic cellular magnetic fields using a superconducting quantum interference device and attempted peak detection using a long short-term memory network. We correctly detected 80.0% of the peaks and the method achieved superior detection performance compared with conventional methods. Next, we attempted peak detection for magnetic signals measured from mouse iPS-CMs. The number of detected peaks was consistent with the spontaneous beats counted using microscopic observation and the average peak waveform achieved good similarity with the prediction. We also observed the synchronization of peak positions between simultaneously measured field potentials and magnetic signals. Furthermore, the magnetic measurements of cell samples treated with isoproterenol showed potential for the detection of chronotropic effects. These results suggest that the proposed method is effective and has potential application in the safety assessment of regenerative medicine and drug screening.

Detailed magnetoelectric analysis of a nerve impulse propagation along the brachial plexus.

OBJECTIVE: To visualize impulse conduction along the brachial plexus through simultaneous electromagnetic measurements. METHODS: Neuromagnetic fields following median nerve stimulation were recorded above the clavicle with a superconducting quantum interference device biomagnetometer system in 7 healthy volunteers. Compound nerve action potentials (CNAPs) were obtained from 12 locations. Pseudocolor maps of equivalent currents reconstructed from magnetic fields and isopotential contour maps were superimposed onto X-ray images. Surface potentials and current waveforms at virtual electrodes along the brachial plexus were compared. RESULTS: In magnetic field analysis, the leading axonal current followed by a trailing backward current traveled rostrally along the brachial plexus. The spatial extent of the longitudinal intra-axonal currents corresponded to the extent of the positive-negative-positive potential field reflecting transmembrane volume currents. The peaks and troughs of the intra-axonal biphasic current waveforms coincided with the zero-crossings of triphasic CNAP waveforms. The amplitudes of CNAPs and current moments were linearly correlated. CONCLUSIONS: Reconstructed neural activity in magnetic field analysis visualizes not only intra-axonal currents, but also transmembrane volume currents, which are in good agreement with the surface potential field. SIGNIFICANCE: Magnetoneurography is a novel non-invasive functional imaging modality for the brachial plexus whose performance can surpass that of electric potential measurement.

Assessing carpal tunnel syndrome with magnetoneurography.

OBJECTIVE: To measure the neuromagnetic fields of carpal tunnel syndrome patients after electrical digital nerve stimulation and evaluate median nerve function with high spatial resolution. METHODS: A superconducting quantum interference device magnetometer system was used to record neuromagnetic fields at the carpal tunnel after electrical stimulation of the middle digital nerve in 10 hands of nine patients with carpal tunnel syndrome. The patients were diagnosed based on symptoms (numbness, tingling, and pain) supported by a positive Phalen or Tinel sign. A novel technique was applied to remove stimulus-induced artifacts, and current distributions were calculated using a spatial filter algorithm and superimposed on X-ray. RESULTS: In 6 of the 10 hands, the amplitude of the inward current waveform attenuated to <70% or the nerve conduction velocity was <40 m/s. The results of conventional nerve conduction studies were normal for two of these six hands. All four hands that could not be diagnosed by magnetoneurography had severe carpal tunnel syndrome superimposed on peripheral neuropathy secondary to comorbidities. CONCLUSIONS: Technical improvements enabled magnetoneurography to noninvasively visualize the electrophysiological nerve activity in carpal tunnel syndrome patients. SIGNIFICANCE: Magnetoneurography may have the potential to contribute to the detailed diagnosis of various peripheral nerve disorders.

Magnetoneurography as a novel functional imaging technique for the ulnar nerve at the elbow.

OBJECTIVE: To visualize the neural activity of the ulnar nerve at the elbow using magnetoneurography (MNG). METHODS: Subjects were asymptomatic volunteers (eight men and one woman; age, 26-53 years) and a male patient with cubital tunnel syndrome (age, 54 years). The ulnar nerve was electrically stimulated at the left wrist and evoked magnetic fields were recorded by a 132-channel biomagnetometer system with a superconducting quantum interference device at the elbow. Evoked potentials were also recorded and their correspondence to the evoked magnetic fields was evaluated in healthy participants. RESULTS: Evoked magnetic fields were successfully recorded by MNG, and computationally reconstructed currents were able to visualize the neural activity of the ulnar nerve at the elbow. In the affected arm of the patient, reconstructed intra-axonal and inflow currents attenuated and decelerated around the elbow. Latencies of reconstructed currents and evoked potentials were correspondent within an error of 0.4 ms in asymptomatic participants. CONCLUSIONS: Neural activity in the ulnar nerve can be visualized by MNG, which may be a novel functional imaging technique for ulnar neuropathy at the elbow, including cubital tunnel syndrome. SIGNIFICANCE: MNG permits visualization of evoked currents in the ulnar nerve at the cubital tunnel.

Assessment of thoracic spinal cord electrophysiological activity through magnetoneurography.

OBJECTIVE: Noninvasive and detailed visualization of electrophysiological activity in the thoracic spinal cord through magnetoneurography. METHODS: In five healthy volunteers, magnetic fields around current flowing in the thoracic spinal cord after alternating unilateral and synchronized bilateral sciatic nerve stimulation were measured using a magnetoneurograph system with superconductive quantum interference device biomagnetometers. The current distribution was obtained from the magnetic data by spatial filtering and visualized by superimposing it on the X-ray image. Conduction velocity was calculated using the peak latency of the current waveforms. RESULTS: A sufficiently high magnetic signal intensity and signal-to-noise ratio were obtained in all participants after synchronized bilateral sciatic nerve stimulation. Leading and trailing components along the spinal canal and inward components flowing into the depolarization site ascended to the upper thoracic spine. Conduction velocity of the inward current in the whole thoracic spine was 42.4 m/s. CONCLUSIONS: Visualization of electrophysiological activity in the thoracic spinal cord was achieved through magnetoneurography and a new method for synchronized bilateral sciatic nerve stimulation. Magnetoneurography is expected to be a useful modality in functional assessment of thoracic myelopathy. SIGNIFICANCE: This is the first report to use magnetoneurography to noninvasively visualize electrophysiological activity in the thoracic spinal cord in detail.

Noninvasive measurement of sensory action currents in the cervical cord by magnetospinography.

OBJECTIVE: To obtain magnetic recordings of electrical activities in the cervical cord and visualize sensory action currents of the dorsal column, intervertebral foramen, and dorsal horn. METHODS: Neuromagnetic fields were measured at the neck surface upon median nerve stimulation at the wrist using a magnetospinography system with high-sensitivity superconducting quantum interference device sensors. Somatosensory evoked potentials (SEPs) were also recorded. Evoked electrical currents were reconstructed by recursive null-steering beamformer and superimposed on cervical X-ray images. RESULTS: Estimated electrical currents perpendicular to the cervical cord ascended sequentially. Their peak latency at C5 and N11 peak latency of SEP were well-correlated in all 16 participants (r = 0.94, p < 0.0001). Trailing axonal currents in the intervertebral foramens were estimated in 10 participants. Estimated dorsal-ventral electrical currents were obtained within the spinal canal at C5. Current density peak latency significantly correlated with cervical N13-P13 peak latency of SEPs in 13 participants (r = 0.97, p < 0.0001). CONCLUSIONS: Magnetospinography shows excellent spatial and temporal resolution after median nerve stimulation and can identify the spinal root entry level, calculate the dorsal column conduction velocity, and analyze segmental dorsal horn activity. SIGNIFICANCE: This approach is useful for functional electrophysiological diagnosis of somatosensory pathways.

Visualization of electrical activity in the cervical spinal cord and nerve roots after ulnar nerve stimulation using magnetospinography.

OBJECTIVE: To establish a method for magnetospinography (MSG) measurement after ulnar nerve stimulation and to clarify its characteristics. METHODS: Using a 132-channel magnetoneurography system with a superconducting quantum interference device, cervical MSG measurements were obtained for 10 healthy volunteers after stimulation of the ulnar nerve at the elbow and the wrist, and neural current distribution was calculated and superimposed on the cervical X-ray images. RESULTS: Neuromagnetic signals were obtained in all participants after applying the stimulus artifact removal algorithm. The measured magnetic field intensity after elbow stimulation was about twice that after wrist stimulation. Calculated neural currents flowed into the intervertebral foramina at C6/7 to T1/2 and propagated cranially along the spinal canal. The conduction velocity from the peak latency of inward currents at C5-C7 was 73.4 ± 19.6 m/s. CONCLUSIONS: We successfully obtained MSG measurements after ulnar nerve stimulation. The neural currents flowed into the spinal canal from more caudal segments after ulnar nerve stimulation compared with median nerve stimulation, and these MSG measurements were effective in examining the spinal tracts at C5/6/7. SIGNIFICANCE: This is the first report on the use of MSG to visualize electrical activity in the cervical spinal cord and nerve root after ulnar nerve stimulation.

Evaluation of neural activity by magnetospinography with 3D sensors.

OBJECTIVE: Magnetospinography (MSG) has been developed for clinical application and is expected to be a novel neurophysiological examination. Here, we used an MSG system with sensors positioned in three orthogonal directions to record lumbar canal evoked magnetic fields (LCEFs) in response to peripheral nerve stimulation and to evaluate methods for localizing spinal cord lesions. METHODS: LCEFs from the lumbar area of seven rabbits were recorded by the MSG system in response to electrical stimulation of a sciatic nerve. LCEFs and lumbar canal evoked potentials (LCEPs) were measured before and after spinal cord compression induced by a balloon catheter. The lesion positions were estimated using LCEPs and computationally reconstructed currents corresponding to the depolarization site. RESULTS: LCEFs were recorded in all rabbits and neural activity in the lumbar spinal cord could be visualized in the form of a magnetic contour map and reconstructed current map. The position of the spinal cord lesion could be estimated by the LCEPs and reconstructed currents at the depolarization site. CONCLUSIONS: MSG can visualize neural activity in the spinal cord and localize the lesion site. SIGNIFICANCE: MSG enables noninvasive assessment of neural activity in the spinal canal using currents at depolarization sites reconstructed from LCEFs.

Visualization of electrophysiological activity at the carpal tunnel area using magnetoneurography.

OBJECTIVE: To establish a noninvasive method to measure the neuromagnetic fields of the median nerve at the carpal tunnel after electrical digital nerve stimulation and evaluate peripheral nerve function. METHODS: Using a vector-type biomagnetometer system with a superconducting quantum interference device, neuromagnetic fields at the carpal tunnel were recorded after electrical stimulation of the index or middle digital nerve in five healthy volunteers. A novel technique for removing stimulus-induced artifacts was applied, and current distributions were calculated using a spatial filter algorithm and superimposed on X-ray. RESULTS: A neuromagnetic field propagating from the palm to the carpal tunnel was observed in all participants. Current distributions estimated from the magnetic fields had five components: leading and trailing components parallel to the conduction pathway, outward current preceding the leading component, inward currents between the leading and trailing components, and outward current following the trailing component. The conduction velocity and peak latency of the inward current agreed well with those of sensory nerve action potentials. CONCLUSION: Removing stimulus-induced artifacts enabled magnetoneurography to noninvasively visualize with high spatial resolution the electrophysiological neural activity from the palm to the carpal tunnel. SIGNIFICANCE: This is the first report of using magnetoneurography to visualize electrophysiological nerve activity at the palm and carpal tunnel.

Novel functional imaging technique for the brachial plexus based on magnetoneurography.

OBJECTIVE: To visualize neural activity in the brachial plexus using magnetoneurography (MNG). METHODS: Using a 124- or 132-channel biomagnetometer system with a superconducting quantum interference device, neuromagnetic fields above the clavicle and neck region were recorded in response to electrical stimulation of the median and ulnar nerves in five asymptomatic volunteers (four men and one woman; age, 27-45 years old). Equivalent currents were computationally reconstructed from neuromagnetic fields and visualized as pseudocolor maps. Reconstructed currents at the depolarization site and compound nerve action potentials (CNAPs) at Erb's point were compared. RESULTS: Neuromagnetic fields were recorded in all subjects. The reconstructed equivalent currents propagated into the vertebral foramina, and the main inflow levels differed between the median nerve (C5/C6-C7/T1 vertebral foramen) and the ulnar nerve (C7/T1-T1/T2). The inward current peaks at the depolarization site and CNAPs showed high linear correlation. CONCLUSIONS: MNG visualizes neural activity in the brachial plexus and can differentiate the conduction pathways after median and ulnar nerve stimulations. In addition, it can visualize not only the leading and trailing components of intra-axonal currents, but also inward currents at the depolarization site. SIGNIFICANCE: MNG is a novel and promising functional imaging modality for the brachial plexus.

Visualization of the electrical activity of the cauda equina using a magnetospinography system in healthy subjects.

OBJECTIVE: To establish a method to measure cauda equina action fields (CEAFs) and visualize the electrical activities of the cauda equina in a broadly aged group of healthy adults. METHODS: Using a 124-channel magnetospinography (MSG) system with superconducting interference devices, the CEAFs of 43 healthy volunteers (22-64 years of age) were measured after stimulation of the peroneal nerve at the knee. Reconstructed currents were obtained from the CEAFs and superimposed on the X-ray image. Conduction velocities were also calculated from the waveform of the reconstructed currents. RESULTS: The reconstructed currents were successfully visualized. They flowed into the L5/S1 foramen about 8.25-8.95 ms after the stimulation and propagated cranially along the spinal canal. In 32 subjects (74%), the conduction velocities of the reconstructed currents in the cauda equina could be calculated from the peak latency at the L2-L5 level. CONCLUSIONS: MSG visualized the electrical activity of the cauda equina after peroneal nerve stimulation in healthy adults. In addition, the conduction velocities of the reconstructed currents in the cauda equina could be calculated, despite previously being difficult to measure. SIGNIFICANCE: MSG has the potential to be a novel and noninvasive functional examination for lumbar spinal disease.

Magnetocardiography Using a Magnetoresistive Sensor Array.

In previous magnetocardiography studies, magnetocardiograms (MCGs) have been obtained using superconducting quantum interference device (SQUID) systems. SQUID is the most sensitive instrument for measuring low-frequency magnetic fields, but it requires liquid helium for cooling, so operating costs are high. In contrast, magnetoresistive (MR) magnetometers function by detecting the change in resistance, caused by an external magnetic field, and have much lower costs. This study was aimed to evaluate feasibility of the MR sensor array for acquiring MCGs.We used an MR sensor array, which was developed for measuring magnetic fields in the picotesla range, with a reduced noise level (TDK Corporation, Tokyo, Japan). A 30-channel MR sensor array was placed in a magnetically shielded room, and the cardiac magnetic field over the anterior chest walls of five healthy subjects was recorded.For all five subjects, MCGs were successfully recorded using the MR sensor array. The cardiac magnetic field corresponding to P, QRS, and T waves on an electrocardiogram (ECG) was detectable by signals averaging 272 ± 27.5 beats.An MR sensor array can be used to measure cardiac magnetic fields. Our results will contribute to the development of low-cost devices for recording MCGs, which will help develop non-invasive diagnostics in cardiovascular medicine.

Beamspace dual signal space projection (bDSSP): a method for selective detection of deep sources in MEG measurements.

OBJECTIVE: Magnetoencephalography (MEG) has a well-recognized weakness at detecting deeper brain activities. This paper proposes a novel algorithm for selective detection of deep sources by suppressing interference signals from superficial sources in MEG measurements. APPROACH: The proposed algorithm combines the beamspace preprocessing method with the dual signal space projection (DSSP) interference suppression method. A prerequisite of the proposed algorithm is prior knowledge of the location of the deep sources. The proposed algorithm first derives the basis vectors that span a local region just covering the locations of the deep sources. It then estimates the time-domain signal subspace of the superficial sources by using the projector composed of these basis vectors. Signals from the deep sources are extracted by projecting the row space of the data matrix onto the direction orthogonal to the signal subspace of the superficial sources. MAIN RESULTS: Compared with the previously proposed beamspace signal space separation (SSS) method, the proposed algorithm is capable of suppressing much stronger interference from superficial sources. This capability is demonstrated in our computer simulation as well as experiments using phantom data. SIGNIFICANCE: The proposed bDSSP algorithm can be a powerful tool in studies of physiological functions of midbrain and deep brain structures.

Magnetospinography visualizes electrophysiological activity in the cervical spinal cord.

Diagnosis of nervous system disease is greatly aided by functional assessments and imaging techniques that localize neural activity abnormalities. Electrophysiological methods are helpful but often insufficient to locate neural lesions precisely. One proposed noninvasive alternative is magnetoneurography (MNG); we have developed MNG of the spinal cord (magnetospinography, MSG). Using a 120-channel superconducting quantum interference device biomagnetometer system in a magnetically shielded room, cervical spinal cord evoked magnetic fields (SCEFs) were recorded after stimulation of the lower thoracic cord in healthy subjects and a patient with cervical spondylotic myelopathy and after median nerve stimulation in healthy subjects. Electrophysiological activities in the spinal cord were reconstructed from SCEFs and visualized by a spatial filter, a recursive null-steering beamformer. Here, we show for the first time that MSG with high spatial and temporal resolution can be used to map electrophysiological activities in the cervical spinal cord and spinal nerve.

Dual signal subspace projection (DSSP): a novel algorithm for removing large interference in biomagnetic measurements.

OBJECTIVE: In functional electrophysiological imaging, signals are often contaminated by interference that can be of considerable magnitude compared to the signals of interest. This paper proposes a novel algorithm for removing such interferences that does not require separate noise measurements. APPROACH: The algorithm is based on a dual definition of the signal subspace in the spatial- and time-domains. Since the algorithm makes use of this duality, it is named the dual signal subspace projection (DSSP). The DSSP algorithm first projects the columns of the measured data matrix onto the inside and outside of the spatial-domain signal subspace, creating a set of two preprocessed data matrices. The intersection of the row spans of these two matrices is estimated as the time-domain interference subspace. The original data matrix is projected onto the subspace that is orthogonal to this interference subspace. MAIN RESULTS: The DSSP algorithm is validated by using the computer simulation, and using two sets of real biomagnetic data: spinal cord evoked field data measured from a healthy volunteer and magnetoencephalography data from a patient with a vagus nerve stimulator. SIGNIFICANCE: The proposed DSSP algorithm is effective for removing overlapped interference in a wide variety of biomagnetic measurements.

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.

Fst-Filter: A flexible spatio-temporal filter for biomedical multichannel data denoising.

In this paper, we present the noise reduction method for a multichannel measurement system where the true underlying signal is spatially low-rank and contaminated by spatially correlated noise. Our proposed formulation applies generalized singular value decomposition (GSVD) with signal recovery approach to extend the conventional subspace-based methods for performing the spatio-temporal filtering. Without necessarily requiring the noise covariance data in advance, the implemented optimization scheme allows users to choose the denoising function, F(·) flexibly satisfying for different temporal noise characteristics from a variety of existing efficient temporal filters. An effectiveness of proposed method is demonstrated by yielding the better accuracy for the brain source estimation on simulated magnetoencephalography (MEG) experiments than some traditional methods, e.g., principal component analysis (PCA), robust principal component analysis (RPCA) and multivariate wavelet denoising (MWD).