WO1999037206A1 - System and method for measuring, estimating and displaying rms current density maps - Google Patents
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- WO1999037206A1 WO1999037206A1 PCT/CA1999/000044 CA9900044W WO9937206A1 WO 1999037206 A1 WO1999037206 A1 WO 1999037206A1 CA 9900044 W CA9900044 W CA 9900044W WO 9937206 A1 WO9937206 A1 WO 9937206A1
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- A—HUMAN NECESSITIES
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- A61B5/242—Detecting biomagnetic fields, e.g. magnetic fields produced by bioelectric currents
- A61B5/245—Detecting biomagnetic fields, e.g. magnetic fields produced by bioelectric currents specially adapted for magnetoencephalographic [MEG] signals
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Definitions
- Magnetoencephalographic (MEG) and Electroencephalographic (EEG) signals may be examined for waveform morphology in independent channels, characterized, for example, by their frequency and amplitude.
- MEG and/or EEG measurements, recorded from a plurality of sites are often represented as topographic distributions of either spontaneous or evoked signals in the form of signal intensity maps about the head.
- MEG and EEG signals synchronously with a stimulus presented to the subject or to a volun- tary motor movement from the subject.
- Signal averaging can improve the signal-to-noise ratio (SNR) of the brain activity underlying a particular sensory or motor event.
- the resulting averaged signal is conventionally known as the event-related potential (ERP) or the event-related field (ERF).
- ERP event-related potential
- ERP event-related field
- the averaged evoked response is most useful for improving the SNR or activity in the primary cerebral cortex, in which the time delay between stimulus and response has low variability.
- the evoked response relating to higher cognitive functions which involve associative cerebral cortex, can be more variable in time delay and duration relative to the driving stimulus.
- signal averaging is less useful for evaluating higher cognitive functions.
- ECD Equivalent Current Dipole
- the ECD can be computed by fitting a simplified model of a current dipole (or multiple dipoles), each characterized by a location, current vector, and magnitude, to the MEG and/or EEG measurements at some selected instant of time, usually in the least squares sense.
- Minimum Norm Current Distribution method a more complex, often under-determined model is fitted to the measurements at some instant of time by a least squares method. Both the ECD and Minimum Norm methods can yield erroneous results (e.g., inaccurate localization and magnitude of cortical generators) when noise is present in the EEG or MEG signal.
- the activity of electrically active organs may also be monitored and imaged using Positron Emission Tomography (PET) and functional magnetic resonance imaging (fMRI).
- PET Positron Emission Tomography
- fMRI functional magnetic resonance imaging
- Neither of these imaging modalities are direct measures of the electrochemical events that comprise neural activity. Instead, they detect local changes in metabolism, metabolic products or blood flow within the brain. These changes are consequent to the energy requirements of the electrochemical events.
- electrochemical events can occur in less than one millisecond, corresponding local changes in metabolism and blood flow are much slower, having time constants of several seconds.
- PET and fMRI lack the time resolution of EEG and MEG, as they are indirect measures of brain activity.
- Lead Field Synthesis departs from previous methods for analyzing bioelectromagnetic measurements. LFS is disclosed by S.E.
- LFS increases the spatial selectivity of an array of MEG sensors by summing the weighted observations. The weights are selected to impart higher spatial selectivity to a specified coordinate in the head. The sum of products of the measured signal and these weights results in a "virtual sensor" that estimates electrical activity as a function of time at the selected location.
- the bioelectromagnetic inverse solution can be improved by constraining the location of source currents to the cortex of the brain, since it is the electrical currents flowing between the dendrites and cell bodies of the neurons that are the primary contributors to the measured magnetic fields and electrical potentials.
- the source current is known to flow in a direction approximately normal to each point on the cortical surface which provides an additional constraint for the inverse solution.
- the coordinates and vectors describing the cortical surface can be extracted from anatomical images of the brain. These images can be obtained, for example, using magnetic resonance imaging (MRI) or computed tomography (CT) scanning of the head.
- MRI magnetic resonance imaging
- CT computed tomography
- certain prior art approaches e.g. , the ECD and Minimum Norm methods discussed above
- a parametric model is used to predict a forward solution for the measurements
- the parameters of the model are adjusted so as to simultaneously minimize the differences between measured and predicted signals at each of the sensors - usually in the least-squares sense.
- a single ECD may be described using five free parameters for magnetic measurements - three for position, one describing the tangential dipole-moment vector (radial currents are "silent" in magnetic measurement) and one describing the dipole-moment magnitude.
- SNR signal-to-noise
- the spontaneous signals generated by small functional regions do not provide an adequate SNR ratio (in the case of the brain, this is due to the fact that brain functions are also being carried out in areas which are not of interest). Accordingly, it is necessary to use signal averaging techniques to improve the SNR ratio. For signal averaging techniques to be useful, it is necessary that the regions of interest in, for example, the brain are in precise synchrony with external events resulting in poor vision of associative areas.
- the signals are initially observed; (ii) observed signals are weighted by some coefficient; and (iii) derivation of an additional signal which is an estimate of activity (e.g., brain activity).
- activity e.g., brain activity
- This approach has limited value in evaluating higher cognitive functions due to the rapid fluctuations (liability) of the activity of certain organs (e.g., the brain).
- RMS root mean square
- Synthetic Aperture Magnetometery (SAM) methodology permits tomographic imaging of brain activity and represents a radical departure from the previously described prior art methods for analysing MEG and/or EEG data.
- SAM converts the measured data from, for example when brain activity is being evaluated, an MEG and/or EEG sensor array - 8 -
- the present invention also provides, in the example of evaluating brain activity, a method for displaying the brain activity that differs between two or more states of brain activity. This latter process is referred to herein as Differential Current Density Mapping (DCDM).
- DCDM Differential Current Density Mapping
- individual SAM images are derived from MEG and/or EEG data which has been partitioned into discrete time segments. The time segments correspond to at least two mental states under examination.
- the SAM image derived for each mental state are then combined using DCDM to display the locations and intensities of the brain that differ between the at least two mental states. Since the common mode brain activity is attenuated by the subtraction process, the locations and interactions of the brain activity that differ between any two brain states is readily identified.
- biomagnetic sensors when reference is made to positioning of biomagnetic sensors in a predetermined manner around a target organ, those of skill in the art will appreciate that this means that the sensors are placed in the vicinity of the target organ, usually external to the surface of the body.
- the sensitivity of biomagnetic sensors declines rapidly with distance (inverse cube law for simple magnetometers, inverse 4th power for first-order gradiometers, etc.).
- the fine (i.e., "higher-order") spatial features of the biomagnetic field, necessary for distinguishing different sources also decline with distance. This means that the biomagnetic sensors must be placed as close to the body as is practically feasible.
- biomagetic sensors of a number sufficient to obtain as many different "perspective" measurements as is possible are placed around or in the vicinity of the target organ.
- the common coordinate system encompassing the target organ is related to the position vector and orientation vector of each sensor in the array.
- the magnetic field of the target organ e.g., the brain, as well as other organs
- the features of such a field convey information as to the location and intensity of each of the cortical generators (sources).
- the field should be sampled, spatially, at small enough intervals, surrounding as much of the target organ as possible, to convey information needed for localization and imaging.
- the term "EM signals” is intended to mean the signals generated from ion currents in electrically active organs. Generally, these signals will be bioelectric signals, biomagnetic signals or a combination of these.
- the EM signals can be magnetoencephalogram (MEG) signals, electroencephalogram (EEG) signals or a combination of these.
- the EM signals can be electrocardiogram (ECG) signals, magnetocardio- gram (MCG) signals or a combination of these.
- EMG electrocardiogram
- MCG magnetocardio- gram
- the EMG signals can be electrooculogram (EOG) signals, magnetooculogram (MOG) signals or a combination of these.
- forward solution is intended to mean a computation of the magnetic field or electrical potential response of a mathematically modelled sensor or electrode to a mathematically modeled current distribution within a mathematically modeled conducting volume.
- the method includes repeating Steps (ii) through (vi) over a second time sub-interval within the selected time interval, to produce a second RMS current density image and, the additional step of subtracting the second RMS current density image, voxel by voxel, from the first image to form a third RMS current density image representing the difference source activity in the brain between the first and second time windows.
- This preferred embodiment is typical of DCDM.
- Figure 1 illustrates a multi-channel biomagnetometer system useful to carry out the present method
- Figure 2 illustrates a cross-section of a configuration of a helmet, array of sensors and reference system used in the biomagnetometer system of Figure 1 ;
- Figure 3 is a flowchart representation of the method of one embodiment of the present invention. and, - 12 -
- Figure 4 is a schematic representation of the relationship between the coordinate, vector and sensor systems in the present invention.
- Synthetic Aperture Magnetometery (SAM) methodology generally resembles techniques previously employed for forming synthetic aperture antenna arrays, as used in radio.
- SAM Synthetic Aperture Magnetometery
- an array of antennas can be combined into a much more directional antenna than any of its individual elements taken alone.
- MEG magnetometery and magnetoencephalographic
- EEG electroencephalographic
- the spatial selectivity of the sensor array to source activity can be much greater than that of the individual sensors.
- the results of the method of the present invention displays an estimate of the source activity in the form of images of the intensity versus location of the brain's electrical activity, as known to those of skill in the art as being encompassed by "Functional Neuroimaging” .
- an image of each activity state can be produced.
- the images are then subtracted from each other to remove the common-mode brain activity.
- the result of this method reveals images of the brain activity representative of the selected cognitive state.
- the MEG of a subject might be measured while reading a story containing additional unreadable words, presented one word at a time or tachistoscopically.
- Two SAM images can then be created from the measurements of the brain activity: one image illus- trating brain activity during perception of the words of the story; and the second illustrating brain activity during perception of the unreadable words.
- a third "difference image" is derived for which the activity common to both states or the "common-mode" brain activity is removed.
- a difference image By repre- senting the brain activity by a difference image, one can then localize where in the brain reading activity takes place.
- the SAM method which permits tomographic imaging of brain activity, represents a radical departure from the conventional previously described prior art methods for analysing MEG and/or EEG signals.
- SAM converts the data measurements of the sensor array over a user selected time window rather than at a single instant in time, into an estimate of the RMS source current density at any designated location in the brain.
- System 100 uses SQUID (acronym for "superconducting quantum interference devices”) detectors and superconducting gradiometer coils for obtaining the highest sensitivity.
- System 100 comprises a dewar 104 which is supported by a gantry 108, the dewar having a head-shaped helmet 116 at is lower end, and a patient support - 15 -
- Dewar 104 further includes an array 112 of magnetic sensors about helmet 116 and a magnetic reference sensor system 124 above helmet 116.
- Array 112 of magnetic sensors may comprises gradio- meter sensors, magnetometer sensors, MEG sensors and the like.
- the SQUIDs (not illustrated) associated with array 112 of magnetic sensors and reference sensor system 124 are located above reference sensor system 124 within dewar 104 which is filled with a cryogen (for example, liquid helium for low temperature superconductor or liquid nitrogen for high temperature superconductors) in operation, or may be refrigerated by mechanical means.
- a cryogen for example, liquid helium for low temperature superconductor or liquid nitrogen for high temperature superconductors
- gantry 108 is designed to minimize vibrations and to have a relatively high characteristic frequency, preferably outside the range of frequencies characteristic of brain signals.
- gantry 108 and dewar 104 with its array 112 of magnetic sensors and reference sensor system 124, can be designed with different characteristics for different sensor array and biomagnetic sources.
- a different gantry and dewar that are arranged to bring the sensors proximal to the chest wall typically would be used.
- the design of such a system is not particularly limited and various tech- niques and design will occur to those of skill in the art.
- a set of outputs 118 from the SQUIDs associated with array 112 of magnetic sensors and reference sensor system 124 are - 16 -
- System Electronics 140 comprises a plurality of SQUID controllers and analog to digital (A/D) conversion means, to convert signals 136 to digital values of the magnetic fields and gradients measured by array 112 of magnetic sensors and reference sensor system 124, and a plurality of digital signal processors (DSPs) to perform desired processing of these digital values.
- DSPs digital signal processors
- the resulting signals are transmitted to an Acquisition computer 144 via a suitable communications link, such as a SCSI interface and, thereafter, to a Processing computer 148 via another communications link, such as an Ethernet interface.
- Acquisition computer 144 and Processing computer 148 are different computer systems, but in some circumstances they may be combined in a single computer system.
- Acquisition computer 144 and Processing computer 148 can be any suitable computer systems with graphical workstation capabilities such as, for example, a suitably equipped UNIX-based workstation or a member of the Macintosh family of microcomputers manufactured by Apple. Acquisition computer 144 performs several tasks, including tuning of SQUIDs, data collection and storage and control of optional peripheral components, such as stimulus and EEG systems. Process- ing computer 148 performs off-line data processing of stored data and display of real time or stored data, and the results of analysis of the data. As will be apparent to those of skill in the art, processing - 17 -
- computer 148 may also combine data from the biomagnetometer with other data, such as MRI or CAT scans, to produce graphical displays which can be interpreted in a more intuitive manner.
- EEG or other data of interest may be collected simultaneously with the measurements made by array 112 of magnetic sensors and reference sensor system 124 and, for example, system electronics 140 may include 64 additional channels to which such inputs may be applied.
- FIG. 2 illustrates helmet 116, array 112 of magnetic sensors, reference sensor system 124 and a portion of dewar 104 in more detail.
- helmet 116 is formed of two spaced and generally parallel walls 149, 150.
- a series of individual sensor gradiometers 152 which make up array 112 of magnetic sensors, is disposed in a liquid helium bath adjacent parallel walls 149,150.
- Wall 149 is shaped to receive a human head.
- Helmet 116 is shaped such that each sensor 152 is located in close proximity to the surface of the human head received therein.
- Helmet 116 is used in combination with some means of determining the head position and head frame coordinate system, relative to the sensor array. For example, a number (e.g., three) of tiny coils, also known in the art as “head coils", are affixed to a respective number of fiduciary points on the head (for example, the nasion
- NAS left pre-auricular
- LPA left pre-auricular
- RPA right pre-auricular
- the head coils are simultaneously energized with small AC currents, each at a different frequency, generated by digital-to-analog converters in System Electronics 140.
- the MEG and reference sensors are used to measure the AC magnetic fields emitted by the coils.
- a precise inverse solution for the positions of each of the head coils, relative to the sensor array coordinates, can then be calculated.
- a further head coil i.e., a fourth if three head coils are used originally
- FIG. 3 a flowchart representing the method of the present invention is indicated generally at 10.
- the first step in the method is to obtain EM signals from the organ under observation (block 14).
- data representing the electrical activity of the organ are measured by either biomagnetic sensors (e.g.
- the sensors may also include a means of detecting ambient biomagnetic and bioelectrical signals such as reference sensors, and a means of measuring the coordinates of the head relative to the sensors known as head localization (e.g. , when the - 19 -
- target organ is the brain.
- data is measured simultaneously by the plurality of sensors in the array of sensors, optionally in combination with reference sensors.
- data is measured at discrete and regular time intervals determined by the measurement sample frequency.
- the SAM method can be applied to any set of time samples such as for multiple intervals of time. The time interval is generally dictated by the conditions of the test and the operator, and should be of a sufficient length to enable to adequately measure at least one state of the target organ.
- the conditions of the test may include "Object-Naming" language paradigm.
- Object-Naming a prescribed number of images (e.g., 120) of objects are presented to the subject, one image at a time. The subject is instructed to state the name of each object, as soon as it presented.
- the "active-state covariance" is computed (as described in detail hereinbelow) from the MEG data for a prescribed time interval (e.g., one second) prior to vocalization.
- control-state covariance For each image of object presented to the subject, the "control-state" covariance is computed (as described in detail hereinbelow) from the MEG data for a prescribed time interval (e.g., one second) after vocalization is complete.
- the data may therefore be divided in any logical manner to distinguish intervals of brain activity, including multiple intervals for a common state of brain activity.
- the present inventor has employed a CTF Systems, Inc.TM 143-channel whole cortex MEG system; a Hewlett- Packard model C-100 UNIX workstation was employed as a host computer for data measurement.
- CTF Systems, Inc.TM 143-channel whole cortex MEG system a Hewlett- Packard model C-100 UNIX workstation was employed as a host computer for data measurement.
- other MEG and computing systems may be employed with similar success.
- the position of each sensor in the array of sensors is determined relative to the organ under observation.
- both the sensors and the organ positions are referenced to a common coordinate system.
- the organ under examination is a human brain.
- the coordinate system is established in a "head frame" .
- the head frame is a coordinate system based upon three fiducial marks on the head (as referred to above). These are: the nasion (NAS; i.e.
- LPA and RPA right and left pre- auricular points
- the Y-axis is defined by the line connecting the two pre- auricular points;
- the X-axis is defined as the line connecting the nasion with the Y-axis that is perpendicular to the Y-axis (i.e., not necessarily at the midpoint of the two pre-auricular points); and - 21 -
- the Z-axis is defined as perpendicular to the XY-plane, at its origin.
- the origin of this head frame is at the intersection of the three principal axes.
- Having a common frame of reference for the brain and the sensors is important, as the signals detected by MEG or EEG sensors depend upon the relative positions and vectors of (i) the sensors, (ii) the source generators, and (iii) the intervening conducting medium (e.g. , brain, skull, scalp, etc.).
- the intervening conducting medium e.g. , brain, skull, scalp, etc.
- a plurality of sensors 152a through 152n are positioned in a predetermined manner about the head. As discussed above with reference to Figures 1 and 2, the plurality of sensors are fixed in a helmet worn by a subject such that the geometric relationship and orientation of each sensor 152 is known.
- a coordinate system is shown in Figure 4, as indicated by the X, Y and Z axes, and an origin is selected as appropriate proximal a region desired for measurement. As will be understood by those of skill in the art, the coordinate system does not have to be cartesian in nature but may be any other system suitable to the particular application.
- 152a... n can be located by a vector r ; relative to the origin.
- the vector describing the orientation of each sensor is denoted n,..
- an intervoxel spacing is selected and a grid of voxels is formed within the ROI referenced to the coordinate system (block 22).
- any voxel position can be located by a vector r 0 having both a magnitude and direction from the origin of the coordinate system. Accordingly, the current vector at r 0 is u 0 .
- This step corresponds to block 26 in Figure 3.
- the current vector at each voxel is best determined using anatomical constraints. For example, source current due to cortical activity in the brain is known to flow in a direction normal to the local cortical surface, at each point on that surface.
- This vector data could be obtained from an anatomical image, such as a magnetic resonance image (MRI) or computed tomography (CT) of the head. This is provided that the image is translated into the common coordinate system determined for application the SAM method.
- the current vector may be estimated by searching in u for a maximum in current density at each voxel as would be apparent to those of skill in the art.
- the forward solution per unit source current is computed for the potential data measured by the bioelectric sensors and/or the magnetic field data measured by the biomagnetic sensors.
- the data measured by each sensor in the array of sensors at time sample k, neglecting sensor noise, is given by: - 23 -
- Equation 1 is a general expression which represents forward solutions but is not readily solved.
- the Green's function should account for factors such as: the size and extent of the current density; the conductive medium and boundaries within which the currents flow; and, the geometry and positions of the sensors.
- the current dipole model generally simplifies the need for knowing the current density everywhere in space, J(r), to simply assuming it is zero everywhere except for a single point in space.
- J(r) the current density everywhere in space
- the various previously-mentioned forward solution models make use of bounded homogeneously conducting spaces, which may have multiple compart- ments. Furthermore, they are a simplification of the actual medium which consists of various organs of the body and various tissue structures.
- the operator optionally filters the measured bioelectric and/or biomagnetic data into selected frequency bands of interest.
- the collected data can be divided into distinct frequency bands, using a second-order digital bandpass filter.
- the operator selects at least one time window within the predetermined time interval within which the data is to be analyzed (block 38) and for which an image is to be constructed.
- the optionally filtered and time segmented data is employed to compute the covariance of the measured data.
- Each element of the covariance matrix is given by:
- the covariance matrix will be MxM in size.
- the covariance may be computed as a time integral over any time window or multiple time windows in the time interval. Covariance, for which the mean signal is removed is preferred, instead of the correlation matrix R, as real measurements may contain a DC offset which originates in the sensors and are therefore not part of the electrophy siological measurements .
- the results of blocks 30 and 42 are then combine to compute the Voxel RMS current density estimate.
- r 0 is the selected three dimensional coordinate
- u 0 is the unit current vector at r 0 as previously described with respect to Figure 4.
- C is the covariance matrix of the measurements
- S is the uncorrelated sensor noise variance of all the measurements
- ⁇ is a regulariz- ation parameter which is selected to control the trade off between noise and spatial selectivity of the current density estimate.
- the superscript "T” refers to the matrix transpose. Matrix and vector variables are designated by bold letters.
- the vector u 0 specifying the direction of the current can be selected by using the vector normal to that point on the surface of the cerebral cortex, for example, extracted from a segmented MRI or CT image of the subject's brain.
- the results of Equation 3 is the SAM solution for the RMS current density for a voxel located at r 0 and having a current (unit) vector direction u 0 .
- Equation 3 The direct conversion of MEG and/or EEG measurements, over some designated time period, into RMS currents by Equation 3 can be - 27 -
- the quantity in the square brackets is conventionally referred to as the "Gram-Schmidt matrix" , appearing frequently in the linear algebra of inverse problems. It is normally computed using an a priori model of all possible sources.
- the covariance of the measurement can be seen here to be equivalent to a Gram-Schmidt matrix that has been weighted by the mean square current density that originally gave rise to the measurement.
- use of the covariance obviates the need of having an a priori model of the sources to perform inverse calculations.
- spontaneous brain signals are collected, without signal averaging.
- the correlation or covariance matrix is computed from the signals over some time interval or intervals selected from some or all of the measured signals.
- signals from the array may be averaged synchronously to a stimulus presented to a subject, or be triggered by an external event such as a subject pressing a switch.
- the stimulus may be either visual, auditory, or somatosensory.
- the voxels estimating the RMS current density are then displayed, for example on a monitor, as a first image or a second image.
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- Veterinary Medicine (AREA)
- Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)
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Abstract
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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EP99900857A EP1049402B1 (en) | 1998-01-23 | 1999-01-20 | Method for measuring, estimating and displaying rms current density maps |
DE69900494T DE69900494D1 (en) | 1998-01-23 | 1999-01-20 | METHOD FOR MEASURING, DETERMINING AND DISPLAYING EFFECTIVE VALUES OF THE CURRENT DENSITY DISTRIBUTION |
AU20436/99A AU2043699A (en) | 1998-01-23 | 1999-01-20 | System and method for measuring, estimating and displaying rms current density maps |
AT99900857T ATE209465T1 (en) | 1998-01-23 | 1999-01-20 | METHOD FOR MEASUREMENT, DETERMINATION AND DISPLAY OF RMS VALUES OF CURRENT DENSITY DISTRIBUTION |
US09/600,730 US6370414B1 (en) | 1998-01-23 | 1999-01-20 | System and method for measuring, estimating and displaying RMS current density maps |
JP2000528204A JP2002500909A (en) | 1998-01-23 | 1999-01-20 | Apparatus and method for measuring, estimating, and displaying RMS current density maps |
CA002319227A CA2319227C (en) | 1998-01-23 | 1999-01-20 | System and method for measuring, estimating and displaying rms current density maps |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US7234098P | 1998-01-23 | 1998-01-23 | |
US60/072,340 | 1998-01-23 |
Publications (1)
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WO1999037206A1 true WO1999037206A1 (en) | 1999-07-29 |
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Family Applications (1)
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PCT/CA1999/000044 WO1999037206A1 (en) | 1998-01-23 | 1999-01-20 | System and method for measuring, estimating and displaying rms current density maps |
Country Status (8)
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US (1) | US6370414B1 (en) |
EP (1) | EP1049402B1 (en) |
JP (1) | JP2002500909A (en) |
AT (1) | ATE209465T1 (en) |
AU (1) | AU2043699A (en) |
CA (1) | CA2319227C (en) |
DE (1) | DE69900494D1 (en) |
WO (1) | WO1999037206A1 (en) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US7123952B2 (en) | 2000-07-18 | 2006-10-17 | Japan Science And Technology Corporation | Cardiac magnetic field diagnozer for atrial flutter and atrial fibrillation and method for identifying electric turning path of atrial flutter and atrial fibrillation |
US11766204B2 (en) | 2017-05-12 | 2023-09-26 | The Korea Research Institute of Standards and Science (“KRISS”) | Multi-sensor magneto-monitoring-imaging system |
Also Published As
Publication number | Publication date |
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CA2319227C (en) | 2003-09-30 |
EP1049402B1 (en) | 2001-11-28 |
AU2043699A (en) | 1999-08-09 |
DE69900494D1 (en) | 2002-01-10 |
US6370414B1 (en) | 2002-04-09 |
EP1049402A1 (en) | 2000-11-08 |
JP2002500909A (en) | 2002-01-15 |
ATE209465T1 (en) | 2001-12-15 |
CA2319227A1 (en) | 1999-07-29 |
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