Improvement of immunoassay detection system by using alternating current magnetic susceptibility.

A major goal with this research was to develop a low-cost and highly sensitive immunoassay detection system by using alternating current (AC) magnetic susceptibility. We fabricated an improved prototype of our previously developed immunoassay detection system and evaluated its performance. The prototype continuously moved sample containers by using a magnetically shielded brushless motor, which passes between two anisotropic magneto resistance (AMR) sensors. These sensors detected the magnetic signal in the direction where each sample container passed them. We used the differential signal obtained from each AMR sensor's output to improve the signal-to-noise ratio (SNR) of the magnetic signal measurement. Biotin-conjugated polymer beads with avidin-coated magnetic particles were prepared to examine the calibration curve, which represents the relation between AC magnetic susceptibility change and polymer-bead concentration. For the calibration curve measurement, we, respectively, measured the magnetic signal caused by the magnetic particles by using each AMR sensor installed near the upper or lower part in the lateral position of the passing sample containers. As a result, the SNR of the prototype was 4.5 times better than that of our previous system. Moreover, the data obtained from each AMR sensor installed near the upper part in the lateral position of the passing sample containers exhibited an accurate calibration curve that represented good correlation between AC magnetic susceptibility change and polymer-bead concentration. The conclusion drawn from these findings is that our improved immunoassay detection system will enable a low-cost and highly sensitive immunoassay.

A comparison of two-dimensional techniques for converting magnetocardiogram maps into effective current source distributions.

The aim of this study was to develop a method for converting the pseudo two-dimensional current given by a current-arrow map (CAM) into the physical current. The physical current distribution is obtained by the optimal solution in a least mean square sense with Tikhonov regularization (LMSTR). In the current dipole simulation, the current pattern differences (ΔJ) between the results of the CAM and the LMSTR with several regularization parameters (α = 10(-1)-10(-15)) are calculated. In magnetocardiographic (MCG) analysis, the depth (z(d)) of a reconstruction plane is chosen by using the coordinates of the sinus node, which is estimated from MCG signals at the early p-wave. The ΔJs at p-wave peaks, QRS-complex peaks, and T-wave peaks of MCG signals for healthy subjects are calculated. Furthermore, correlation coefficients and regression lines are also calculated from the current values of the CAM and the LMSTR during p-waves, QRS-complex, and T-waves of MCG signals. In the simulation, the ΔJs (α ≈ 10(-10)) had a minimal value. The ΔJs (α = 10(-10)) at p-wave peaks, QRS-complex peaks, and T-wave peaks of MCG signals for healthy subjects also had minimal value. The correlation coefficients of the current values given by the CAM and the LMSTR (α = 10(-10)) were greater than 0.9. Furthermore, slopes (y) of the regression lines are correlated with the depth (z(d)) (r = -0.93). Consequently, the CAM value can be transformed into the LMSTR current value by multiplying it by the slope (y) obtained from the depth (z(d)). In conclusion, the result given by the CAM can be converted into an effective physical current distribution by using the depth (z(d)).

Identifying patterns of spatial current dispersion that characterise and separate the Brugada syndrome and complete right-bundle branch block.

The aim of the study was to detect patterns of spatial-current distribution in the late QRS and early ST-segments that distinguish Brugada-syndrome cases from complete right-bundle branch block (CRBBB). Magnetocardiograms (MCGs) were recorded from Brugada-syndrome patients (n = 6), CRBBB patients (n = 4) and the members of a control group (n = 33). The current distributions at six time points from Q-onset were estimated by producing current-arrow maps (CAMs). The angle of the current arrow of maximum amplitude at each time point was calculated. In the Brugada cases, the characteristic ST elevation was seen above the upper right chest, and abnormal currents appeared to be present in the right-ventricular outflow tract (RVOT). The angles of the abnormal arrows were -78 degrees +/- 51 degrees at 100 ms and -50 degrees +/- 61 degrees at 110 ms. In the cases of CRBBB, wide S- and R-waves were recorded above the upper right and lower right chest, respectively. The angles of the abnormal arrows for CRBBB were 152 degrees +/- 19 degrees at 100 ms, 159 degrees +/- 20 degrees at 110 ms, and 157 degrees +/- 19 degrees at 120 ms. The findings suggest that an abnormal current from the RVOT to the upper left chest may be a feature of the Brugada syndrome, and that the direction of this current is completely different from that seen in CRBBB.

Predictor of cognitive deterioration in elderly subjects by auditory-evoked magnetic signal using magnetoencephalography.

Recent development of auditory-evoked magnetoencephalography (A-MEG) made it possible to measure interhemispheric neural conduction time (INCT) of auditory impulses. We estimated INCT with A-MEG and cognitive function with mini-mental state examination (MMSE) in 85 elderly patients with chronic dizziness (CD) and found that INCT was negatively correlated with MMSE scores (p<0.001). In 11 of 85 patients whose MMSE scores were within the normal range, A-MEG and MMSE were repeated for the subsequent 4 years to find longitudinal changes in INCT and cognitive function. The 11 patients were divided into two groups according to the baseline INCT values, such as Group A with normal INCT (n=7) and Group B with abnormally prolonged INCT (n=4). In Group A, INCT and MMSE scores remained within the normal range throughout the 4-year period. In Group B, INCT showed the tendency towards progressive prolongation during the follow-up period, and MMSE scores decreased to abnormally low levels at the third or fourth follow-up year in all the patients. The present results suggest that rapid neural interaction of both cerebral hemispheres is needed to maintain normal cognitive function. Abnormal INCT prolongation in elderly subjects suggests subclinical cortical network dysfunction and may predict the future development of cognitive deterioration.

Classifying cases of fetal Wolff-Parkinson-White syndrome by estimating the accessory pathway from fetal magnetocardiograms.

The paper presents an evaluation of the possibility of using fetal magnetocardiogram (FMCG) signals to estimate and classify the accessory pathway in fetal Wolff-Parkinson-White (WPW) syndrome. The FMCG signals of two fetuses with WPW syndrome (type A) were detected using a 64-channel superconducting quantum-interference device system. An average across the cycles of these signals was taken to obtain clear WPW signals. To determine the direction and position of the accessory pathway in a fetal heart accurately, the accessory pathway and activated pathway at the peak of the QRS complex thus obtained were estimated for each fetus, using a single-dipole model. The phase angle (about 90 degrees) between the equivalent current dipoles (ECDs) was the same for both fetuses. This angle suggested that the accessory pathway is in the left side of the heart, i.e. that the pathway exists in the left ventricle, which indicates type A WPW syndrome. Identification of the position of the accessory pathway in a fetus with WPW syndrome from the angle between the ECD of the accessory pathway and the ECD of the peak in the QRS complex was thus demonstrated.

Visualisation method of spatial interictal discharges in temporal epilepsy patients using magneto-encephalogram.

The aim of the study was to develop a method for investigating how interictal epileptic discharges in temporal epilepsy patients are activated spatially. The activity was measured using magneto-encephalography (MEG). The MEG data were used to produce a current-arrow map that reflected the topographic distribution of the electrical current for each peak epileptic waveform. A large current distribution was obtained that appeared to be contained in the limbic structure, in each temporal lobe. The large current orientation indicated two opposite directions. Furthermore, the decrease in the maximum strength of the current-arrow, depending on the medication (e.g. the decrease from 11 to 6 pT m-1 in the left temporal lobe (contralateral stimuli)), suggested that the discharge distributions could be used to verify the efficacy of medication. Thus the topographical visualisation method could be a new strategy for diagnosis in temporal epilepsy patients.

Detection of atrial-flutter and atrial-fibrillation waveforms by fetal magnetocardiogram.

Two cases of fetal tachycardia are reported: atrial flutter and fibrillation. The waveforms from each case were detected by fetal magnetocardiograms (FMCGs) using a 64-channel superconducting quantum interference device (SQUID) system. Because the magnitude of supraventricular arrhythmia signals is very weak, two subtraction methods were used to detect the fetal MCG waveforms: subtraction of the maternal MCG signal, and subtraction of the fetal ORS complex signal. It was found that atrial-flutter waveforms showed a cyclic pattern and that atrial-fibrillation waveforms showed f-waves with a random atrial rhythm. Fast Fourier transform analysis determined the main frequency of the atrial flutter to be about 7Hz, and the frequency distribution of atrial fibrillation consisted of small, broad peaks. To visualise the current pattern, current-arrow maps, which simplify the observation of pseudo-current patterns in fetal hearts, of the averaged atrial flutter and fibrillation waveforms were produced. The map of the atrial flutter had a circular pattern, indicating a re-entry circuit, and the map of the atrial fibrillation indicated one wavelet, which was produced by a micro-re-entry circuit. It is thus concluded that an FMCG can detect supraventricular arrhythmia, which can be characterised by re-entry circuits, in fetuses.

Detection of cardiac hypertrophy in the fetus by approximation of the current dipole using magnetocardiography.

To determine the developmental changes in the myocardial current during fetal life, and to evaluate the clinical usefulness of magnetocardiography for prenatal diagnosis of cardiac hypertrophy or enlargement, we approximated the magnitude of the one-current dipole of the fetal heart using fetal magnetocardiography (fMCG). A total of 95 fetuses with gestational age of 20-40 wk were included in this study. fMCG was recorded with a nine-channel superconducting quantum interference device system in a magnetically shielded room. The magnitude of the dipole (Q) was calculated using an equation based on the fMCG amplitude obtained on the maternal abdomen and the distance between the maternal surface and fetal heart measured ultrasonographically. In uncomplicated pregnancies, the Q value correlated significantly with gestational age, reflecting an increase in the amount of myocardial current, i.e. myocardial mass. Moreover, the Q values in fetuses with cardiomegaly caused by various cardiovascular abnormalities tended to be higher than the normal values. Although there are some limitations of the methodology based on the half-space model, and fetal orientation may influence the magnitude of the dipole, making it smaller, fMCG recorded with a multichannel superconducting quantum interference device system is a clinically useful tool for noninvasive, prenatal, and electrical evaluation of fetal cardiac hypertrophy.

A fetal Wolff-Parkinson-White syndrome diagnosed prenatally by magnetocardiography.

We report a case of fetal Wolff-Parkinson-White (WPW) syndrome diagnosed prenatally by magnetocardiography (MCG). At 32 weeks' gestation, the fetus was diagnosed to have a paroxysmal supraventricular tachycardia by ultrasonography and direct fetal electrocardiogram (ECG). Transplacental fetal therapy by maternal oral administration of propranolol resolved the fetal tachyarrhythmia. Although the wave forms of the fetal MCG at 32 weeks' gestation were normal, the fetal MCG at 35 weeks' gestation showed a short PR interval and a long QRS complex duration with a delta wave, indicating WPW syndrome. The findings of the fetal MCG were confirmed by the postnatal ECG. MCG made the prenatal diagnosis of WPW syndrome possible.

Prenatal diagnosis of QT prolongation by fetal magnetocardiogram--use of QRS and T-wave current-arrow maps.

To determine the T wave of a fetal magnetocardiogram (FMCG), we have evaluated the T/QRS ratio and obtained current-arrow maps that indicate weak currents. We measured FMCG signals for 52 normal fetuses and two abnormal fetuses with prolonged QT waves by using three superconducting quantum interference device (SQUID) systems: a nine-channel system, a 12-channel vector system and a 64-channel system. The T/QRS ratio was calculated for all the normal fetuses from the maximum magnitudes of the QRS complex and the T wave. Current-arrow maps of the QRS complex (R wave) and T wave were obtained by using the 64-channel system, and the phase differences of the total-current vectors were calculated by using the current-arrow maps. The results showed that the T/QRS ratio had a wide variability of 0.35 for the normal fetuses. However, the magnitude of the prolonged T wave was as weak as the detection limit of the SQUID magnetometer. Although the T/QRS ratios for the fetuses with QT prolongation were within the normal range (< 0.35), the weak magnitude of the prolonged T wave could be evaluated. On the other hand, by comparing the current-arrow maps of the R and T waves for the normal fetuses, we found that the maximum-current arrows were indicated as either in the same direction or in opposite directions. These patterns could be identified clearly by the phase differences. Very weak prolonged T waves for the two abnormal fetuses could be determined by using these current-arrow maps and phase differences. Consequently, although the T/QRS ratios of FMCG signals have a wide distribution, we have concluded that the current-arrow map and phase difference can be used to determine the T wave of an FMCG signal.

Impedance magnetocardiogram.

We have developed an impedance magnetocardiogram (IMCG) system to detect the change of magnetic field corresponding to changes in blood volume in the heart. A low magnetic field from the electrical activity of the human heart--the so-called magnetocardiogram (MCG)--can be simultaneously detected by using this system. Because the mechanical and electrical functions in the heart can be monitored by non-invasive and non-contact measurements, it is easy to observe the cardiovascular functions from an accurate sensor position. This system uses a technique to demodulate induced current in a subject. A flux-locked circuit of a superconducting quantum interference device has a wide frequency range (above 1 MHz) because a constant current (40 kHz) is fed through the subject. It is shown for the first time that the system could measure IMCG signals at the same time as MCG signals.

A method for detecting myocardial abnormality by using a current-ratio map calculated from an exercise-induced magnetocardiogram.

A method for making a current-ratio map to determine the ischaemic area of angina pectoris (AP) patients has been developed. This method uses a current-arrow map calculated using a ORS wave from 64-channel magnetocardiogram (MCG) signals. The current-ratio map can be calculated from the ratio of an exercise-induced current vector to an at-rest current vector. The MCG signals of eight patients with angina pectoris (AP) (six patients with effort AP and two patients with variant AP) and four healthy volunteers were measured before and after a two-step exercise test. The current-ratio maps of the six patients with effort AP showed three distinct patterns: a left-circumflex-artery (LCX) pattern; a right-coronary-artery (RCA) pattern; and a left-anterior-descending (LAD) pattern. The maximum current ratios of these three patterns differed from those of normal patterns. The patterns of two patients with variant AP were similar to normal patterns. Furthermore, a comparison of the current-ratio map before and after percutaneous-transluminal-coronary-angioplasty (PTCA) treatment indicated that the cardiac ischaemia was reduced in all patients. An appropriate criterion to diagnose abnormality in a patient with an ischaemic myocardial area seems to be a maximum current ratio exceeding 0.4 to 0.5. Based on these preliminary results, it is believed that the location of an ischaemic area (the coronary artery part) can be estimated by using the ischaemic current-ratio map pattern.

A method for detecting myocardial abnormality by using a total current-vector calculated from ST-segment deviation of a magnetocardiogram signal.

A simple method to determine the state of ischaemia or fibrosis of myocardial cells has been developed. This method uses the ST wave of 64-channel magnetocardiogram (MCG) signals to calculate three parameters from the current-arrow map of the normal component signal of the MCG. One parameter is a total current vector that is obtained through summation of all current arrows. Another is a variance current vector calculated from the differential vector of two total current vectors at different times. The third is a flatness factor between the magnitude of the total current vector and the variance current vector. The three parameters are independent of the distance between the heart and the gradiometers. We measured the MCG signals of 29 healthy subjects, twenty patients with coronary artery disease (ten with previous myocardial infarction (MI) and ten with angina pectoris (AP)), and eight patients with cardiomyopathy (four with hypertrophic cardiomyopathy (HCM), three with dilated cardiomyopathy (DCM), and one with restrictive cardiomyopathy (RCM)). With our method, none of the healthy subjects tested positive for myocardial abnormalities, while 80% of the MI patients, 50% of the AP patients, and 100% of the cardiomyopathy patients tested positive. Although further testing is needed, we feel this simple technique enables easy diagnosis of myocardial damage.

A case of fetal complete heart block recorded by magnetocardiography, ultrasonography and direct fetal electrocardiography.

Fetal magnetocardiograms (FMCGs) were recorded in a case of fetal complete heart block (CHB) from the 30th to the 37th week of gestation using the multichannel SQUID system (Hitachi, Japan). M-mode ultrasonography and direct fetal electrocardiography using needle electrodes revealed fetal CHB. We identified independent fetal P-waves and QRS complexes in the FMCG recorded in the 32nd week of gestation when the fetal atriums were close to the FMCG sensor. We also recorded FMCG P-waves in the 37th week of gestation when the fetal heart was larger. Fetal heart position and size are important for obtaining a useful FMCG. To establish FMCG as a diagnostic tool of fetal arrhythmia, comparative studies with FECG are needed.

An iso-integral mapping technique using magnetocardiogram, and its possible use for diagnosis of ischemic heart disease.

We have developed an iso-integral mapping technique that uses magneto-cardiogram (MCG) data to obtain a map as projected total current image on the torso from the heart. We have also investigated the applicability of iso-integral mapping to the diagnosis of ischemic heart disease. We simulated and measured the characteristics of two types of iso-integral maps: one using tangential (Bxy) components, and one using the normal component (Bz). Each vector component was measured by two types of superconducting quantum interference device (SQUID) system to determine the tangential and normal components. The tangential component of the magnetic field appeared to be equivalent to the current image in the myocardium projected on the observing plane, and we were able to obtain a projected total current image by integration of the tangential components during the depolarization and repolarization processes. And we found that the iso-integral maps of normal hearts showed similar pattern in both processes; however, those of ischemic hearts showed different patterns.

Magnetocardiographic determination of the developmental changes in PQ, QRS and QT intervals in the foetus.

In order to determine developmental changes in atrioventricular (PQ), ventricular depolarizing (QRS) and QT intervals of the foetal heart, we recorded foetal magnetocardiographic waveforms using a superconducting quantum interference device system in a magnetically shielded room in 150 uncomplicated foetuses of gestational age >20 wk. Recording of the QRS waveform was successful in 128 (85%) of the subjects, based on unaveraged tracings. After signal averaging of the data from these 128 cases, P waves were recognized in 102 (68%) subjects and T waves in 64 (43%). The QRS interval, ranging from 32-74 ms, showed a positive linear correlation with the gestational age, which probably reflects an increase in the number and size of myocardial cells. The PQ interval showed low correlation with the gestational age, and was rather constant, with an average value of 100 ms. The QT interval ranged from 180-302 ms, and tended to be slightly shorter during early gestation. Although the success rate of measuring the PQ and QT intervals was unsatisfactory for this methodology to prevail in a clinical setting, these values provide the basis for in utero non-invasive investigation of foetal cardiac activity by magnetocardiography.

Visualization of regional myocardial depolarization by tangential component mapping on magnetocardiogram in children.

BACKGROUND: Tangential components to the body surface on magnetocardiography theoretically reflect regional myocardial current sources just below the gradiometer. The usefulness of tangential component mapping on magnetocardiography in determination of regional myocardial abnormalities has not been investigated in children. METHODS: Twenty-six children with ventricular hypertrophy, including a child with a left ventricular diverticulum (aged 7 to 15), and age matched 22 healthy children (aged 7 to 15) were studied. Tangential components on magnetocardiography were measured using a newly-developed super-conducting quantum interference device system housed in a magnetically shielded room. Isomagnetic maps and current vector maps were constructed from the data obtained. RESULTS: The peak magnetic fields and current dipoles were demonstrated to be located at the interventricular septum initially, and then were shifted to the anterior and inferior walls of the left ventricle and to the right ventricular outflow tract, successively. In patients with right ventricular hypertrophy whose systolic right ventricular pressure was over 60 mmHg, the peak magnetic fields were located in the right half with rightward directed current vectors throughout ventricular depolarization. In patients with left ventricular hypertrophy, the maximal magnetic fields during depolarization were shifted to the hypertrophic site, showing significantly stronger forces than those in healthy children (35.5+/-11.7 pT vs 26.5+/-11.9 pT, p < 0.01). In a patient with left ventricular diverticulum, two discrete depolarizing current dipoles were visualized. The mean time required in measuring MCGs among all subjects was 10 minutes. CONCLUSION: The time course as well as the location of the regional electrical activities of the myocardium in children can be visualized, in a short time, as a two-dimensional projection to the frontal plane by tangential component mapping on magnetocardiography.

Prenatal diagnosis of long QT syndrome using fetal magnetocardiography.

We describe the detection of congenital long QT syndrome in a fetus at 37 weeks' gestation using magnetocardiography (MCG). The prenatal diagnosis was confirmed by standard electrocardiography (ECG) performed after birth. This is the first case report of fetal long QT syndrome detected by MCG. Fetal MCG may be useful in the prenatal diagnosis of congenital cardiac disease with abnormal ECG findings.

Sensitivity of foetal magnetocardiograms versus gestation week.

Foetal magnetocardiograms (FMCGs) were measured using a nine-channel SQUID system equipped with first-order gradiometers (60 mm baseline, 20 mm diameter). The system was installed in a magnetically shielded room in a hospital. The white noise level was less than 10 fT/square root of Hz, and FMCGs above 1 pT were detected. These results and the depth to the foetal heart were used to estimate the current dipole. The relationship between the current dipole (Q) and the gestation week (G) was calculated and the average performance was determined as Q = 18G - 295. By using the estimated foetal current dipole, the measurement limit (average value) between depth and gestation weeks was determined. When the depth from the pickup coil to the foetal heart is 50, 60, 70 and 80 mm, the first detectable gestation weeks of FMCGs above 1 pT measured by a first-order gradiometer with 60 mm baseline were determined at 21, 23, 26, and 30 weeks respectively, and the detectable gestation weeks in the case of a 30 mm baseline were determined at 22, 26, 30 and 36 weeks respectively.

Reconstruction of two-dimensional current distribution from tangential MCG measurement.

We describe a two-dimensional reconstruction method for tangential magnetocardiograms (MCGs). This method is based on two-dimensional Fourier analysis, and we used a new type of window function for tangential MCG to solve the problem of the small number of measurement points. By using this method, cardiac activity can be estimated as a two-dimensional current distribution. To determine the effectiveness of this method, we measured tangential MCGs of normal subjects, and compared the estimated current distribution with the actual cardiac muscle activity. Using this method, we were able to clearly show cardiac activity.