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`Case 6:12—cv—00799—JRG Document 143-1 Filed 04/11/14 Page 1 of 8 Page|D #: 4232
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`EXHIBIT A
`
`EXHIBIT A
`
`

`
`Case 6:12-cv-00799-JRG Document 143-1 Filed 04/11/14 Page 2 of 8 PageID #: 4233
`
`U.S. Patent No. 5,885,215, Dossel et al.,
`“Method of Reconstructing the Spatial
`Current Distribution in a Biological
`Object, and Device for Performing the
`Method” (03/23/99)
`
`U.S. Patent No. 5, 555,190, Derby et al.,
`“Method and Apparatus for Adaptive Line
`Enhancement in Coriolis Mass Flow Meter
`Measurement” (09/10/96)
`
`

`
`Case 6:12-cv-00799-JRG Document 143-1 Filed 04/11/14 Page 3 of 8 PageID #: 4234
`
`United States Patent [19]
`Dossel et al.
`
`US005885215A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,885,215
`Mar. 23, 1999
`
`[54] METHOD OF RECONSTRUCTING THE
`SPATIAL CURRENT DISTRIBUTION IN A
`BIOLOGICAL OBJECT, AND DEVICE FOR
`PERFORMING THE METHOD
`
`[75] Inventors: Olaf Helmut Dossel, Tangstedt; Walter
`Heinrich Kullmann, Hamburg, both of
`Germany
`
`[73] Assignee: U.S. Philips Corporation, New York,
`NY.
`
`[21] Appl. No.: 543,600
`[22]
`Filed:
`Jun. 25, 1990
`[30]
`Foreign Application Priority Data
`
`Jul. 6, 1989 [DE]
`
`Germany ........................... .. 39221504
`
`Int. Cl.6 ...................................................... .. A61B 5/05
`[51]
`[52] US. Cl. ........................................... .. 600/409; 324/248
`[58] Field of Search .............................. .. 128/653 R, 731;
`324/201, 248; 600/407, 409, 544
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6/1983 Ganssen et al. ...................... .. 324/309
`4,390,840
`4/1988 Gevins et al. ........................ .. 128/731
`4,736,751
`4,793,355 12/1988 Crum et al. .... ..
`324/248
`4,862,359
`8/1989 Trivedi et al.
`128/731
`4,913,152
`4/1990 K0 et al. ..... ..
`128/653 R
`4,940,058
`7/1990 Taft et al. ......................... .. 128/653 R
`
`FOREIGN PATENT DOCUMENTS
`
`3725532 2/1989 Germany ....................... .. A61B 5/04
`3735668 5/1989 Germany .
`
`OTHER PUBLICATIONS
`
`B. Jeffs, R. Leahy & M. Singie, “An Evaluation of Methods
`for Nouromanetic Image Reconstruction”, IEEE Transaction
`on Biomedical Engineering, vol. BME—34,—No. 9, Sep.
`1987, pp. 713—723.
`V.O. Dossel & W. Kullmann, “Squids und Bilder Neuronaler
`Strome”, Phys. B1., 44, (1988) NR. 11, pp. 423—425.
`M, Hoke, “Squid—Based Measuring Techniques—A Chal
`lenge For The Functional Diagnostics in Medicine”, The Art
`of Measurement: Metrology in Fundamental & Applied
`Physics, pp. 287—335, 1st Edition: 1988.
`W.J. Dallas, W.E. Smith, H.A. Sclitt, & W. Kullman, “Bio
`electric Current Image Reconstruction From Measurement
`of The Generated Magnetic Fields”, Medical Imaging, SPIE,
`vol. 767, (1987), pp. 1—10.
`S. Ueno et al., “The MEG Topography and The Source
`Model of Abnormal Neural Activities Associated With Brain
`Lesions”, IEEE Transactions on Magnetics, vol. Mag—22,
`No. 5, Sep. 1986, pp. 874—876.
`Primary Examiner—Brian Casler
`Attorney, Agent, or Firm—Jack D. Slobod
`[57]
`ABSTRACT
`
`Amethod of reconstructing the spatial current distribution in
`a biological object, at least one component of the magnetic
`?eld produced by the current sources being measured at a
`number of points outside the object, after Which the current
`distribution at the volume elements situated Within the
`object is reconstructed from the measuring values. In order
`to improve the accuracy of reconstruction, in a representa
`tion containing the morphological structure of the object the
`surfaces are speci?ed on Which the current sources are
`presumably present, the reconstruction being limited to the
`volume elements Which are situated on these surfaces.
`
`2 Claims, 2 Drawing Sheets
`
`

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`Case 6:12-cv-00799-JRG Document 143-1 Filed 04/11/14 Page 4 of 8 PageID #: 4235
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`U.S. Patent
`
`Mar. 23, 1999
`
`Sheet 1 of2
`
`5,885,215
`
`

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`Case 6:12-cv-00799-JRG Document 143-1 Filed 04/11/14 Page 5 of 8 PageID #: 4236
`Case 6:12—cv—OO799—JRG Document 143-1 Filed 04/11/14 Page 5 of 8 Page|D #: 4236
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`U.S. Patent
`
`Mar. 23, 1999
`
`Sheet 2 of2
`
`5,885,215
`
`

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`Case 6:12-cv-00799-JRG Document 143-1 Filed 04/11/14 Page 6 of 8 PageID #: 4237
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`5,885,215
`
`1
`METHOD OF RECONSTRUCTING THE
`SPATIAL CURRENT DISTRIBUTION IN A
`BIOLOGICAL OBJECT, AND DEVICE FOR
`PERFORMING THE METHOD
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`The invention relates to a method of reconstructing the
`spatial current distribution in a biological object, at least one
`component of the magnetic ?eld produced by the current
`sources being measured at a number of points outside the
`object, after Which the current distribution at the volume
`elements situated Within the object is reconstructed on the
`basis of the measuring values, and also relates to a device for
`performing the method.
`A method and a device of this kind are knoWn from the
`publication “SQUIDs und Bilder neuronaler Strome” by
`O.Dossel and W. Kullmann (Phys. B1. 44 (1988) No. 11, pp.
`423—425).
`2. Description of the Prior Art
`Therein, for the reconstruction, the magnitude and direc
`tion of the current densities in the individual volume ele
`ments constituting the three-dimensional object region must
`be calculated from the magnetic ?elds measured outside the
`object region to be examined. It can be demonstrated that
`this so-called inverse three-dimensional problem cannot be
`unambiguously solved. The knoWn method, therefore, uses
`reconstruction algorithms Which enable an approximative
`calculation of the current distribution. The distribution thus
`determined, hoWever, deviates from the actual distribution.
`It is to be noted that from the publication by J. W. H. Meijs
`et al. “The EEG and MEG, using a model of eccentric
`spheres to describe the head”, IEEE Trans. Biomed. Eng.,
`Vol. BME-34, pp. 913—920, 1987, it is already knoWn to
`derive information regarding the individual head or brain
`geometry from magnetic resonance tomogram or computer
`tomograms, thus enabling more accurate determination of
`the position of a single current dipole. This knoWn method
`aims to determine, using the values of the magnetic ?ux
`density measured at different measuring points, the position
`of a single tangential, point shaped current dipole in a
`volume conductor, i.e. so that the measured magnetic ?eld
`corresponds as Well as possible to the magnetic ?eld Which
`Would be measured if the current dipole Were present at the
`relevant area. This approach utilises magnetic resonance
`tomograms or computer tomograms Which represent the
`morphology of the head and in Which areas of similar
`electrical conductivity are marked so as to enable more
`accurate modelling of the volume currents in the brain.
`It is an object of the present invention to provide a method
`of the kind set forth so that such deviations are reduced. This
`object is achieved in accordance With the invention in that in
`a representation Which contains the morphological structure
`of the object the surfaces on Which the current sources are
`presumably present are speci?ed, the reconstruction being
`limited to the volume elements Which are situated on the
`surfaces.
`The invention is based on the recognition of the fact that
`for many brain activities it is knoWn that the neuronal
`current sources are situated on given surfaces. For example,
`tumors can initiate epileptic attacks because of their space
`requirements. The interior of the tumor is electrically
`inactive, the epileptical focus (current source) is situated
`someWhere on the periphery of the tumor. For some forms
`of focal epilepsy Which cannot be traced to a tumor, a
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`morphologically modi?ed region occurs; the focus pursued
`is very probably present on the periphery thereof. Finally, it
`is knoWn that evoked ?elds Which can be measured on the
`head after a stimulation of the sense organs originate from
`a spatially de?nable Zone of the folded cerebral cortex.
`Consequently, the reconstruction of the current source
`density takes place only for the speci?ed (tWo dimensional)
`surfaces and not for a three dimensional region Within the
`object to be examined. Consequently, the tWo dimensional
`inverse problem occurs Which can in principle be unam
`biguously solved. Therefore, the reconstruction in practice is
`in?uenced merely by the fact that the measurement of the
`magnetic ?eld is performed at a ?nite number of points and
`that measurement thus takes place With a ?nite accuracy.
`A device for performing the method in accordance With
`the invention is characteriZed in that it comprises a measur
`ing device for determining the magnetic ?ux density outside
`the object, a memory for storing the measuring values thus
`obtained, a unit for determining the volume elements Which
`are situated on surfaces to be speci?ed, and a reconstruction
`unit for determining the current distribution the volume
`elements from the values stored.
`
`IN THE DRAWING
`
`The invention Will be described in detail hereinafter With
`reference to the draWing. Therein:
`FIG. 1 shoWs a device for measuring the magnetic ?elds,
`FIG. 2 shoWs a circuit diagram of a unit for processing the
`signals measured.
`
`DESCRIPTION OF THE PREFERRED
`EMBODIMENT
`
`The reference numeral 1 in FIG. 1 denotes the skull of a
`patient and the reference numeral 2 denotes, by Way of
`dash-dotted lines, the brain therein. The reference numeral 3
`denotes the surface of a structure inside the brain Which
`morphologically deviates from its environment, for example
`a tumor. It is also assumed that an impressed current, caused
`by electrochemical transformation processes, ?oWs at the
`interface betWeen the tumor and the healthy tissue, i.e. on its
`surface, the current being represented by a heavy arroW. Due
`to this impressed current, volume currents ?oW (dotted
`lines). These volume currents Would not cause a magnetic
`?eld outside the skull should it be possible to consider the
`head to be an exactly spherical conductor.
`Therefore, the radial component of the magnetic ?eld
`measured outside the skull depends mainly on the impressed
`current, that is to say on the tangential component thereof.
`The current density of the tangential components of the
`impressed currents is to be determined as a function of
`location by measurement of the radial component of the
`magnetic ?eld at a plurality of points outside the skull. More
`than one impressed current can thus also be localiZed and the
`current dipole need not necessarily be point-shaped.
`For measurement of the radial component of the magnetic
`?ux density there is provided, accommodated Within a
`helium cryostat 4 arranged over the skull of the patient, a
`measuring system Which comprises a plurality of measuring
`channels, each of Which comprises a superconducting gra
`diometer (5a .
`.
`. 5c) Which couples the magnetic ?ux density
`produced by the impressed current into a respective SQUID
`(6a .
`.
`. 6c). Measuring systems of this kind are knoWn
`(DE-OS 37 35 668).
`The present embodiment involves a measuring system
`comprising only three measuring channels, so that the mag
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`5,885,215
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`3
`netic ?ux density can be determined at three measuring
`points only. In practice, however, the magnetic ?eld should
`be measured at more than three measuring points, for
`example at 19 or even more points. Therefore, a measuring
`system comprising a larger number of channels is required.
`HoWever, for the measurement of evoked ?elds Which can
`be measured after stimulation of the sense organs, use can
`also be made of a measuring system comprising only one
`measuring channel if such a measuring system is succes
`sively moved to a series of de?ned positions With respect to
`the skull. In each of these positions the variation in time of
`the magnetic ?eld is then measured, the reference instant
`alWays being the instant at Which stimulation takes place.
`Suitable measuring methods for the simultaneous or con
`secutive measurement of the magnetic ?eld at different
`points are described in the article by M. Hoke “SQUID
`Based Measuring Techniques” in “The art of Measure
`mento” Ed. by B. Kramer, VCH Verlagsgesellschaft mbH,
`Weinheim, 1988.
`The analog measuring signals supplied by the individual
`measuring channels and representing the variation in time of
`the radial component of the magnetic ?ux density are
`applied to an analog-to-digital converter device 7 in Which
`they are converted into a respective series of digital data
`Words (FIG. 2). These data Words are stored in a memory 8,
`after multiple repetition of the measurement and formation
`of the mean value Which may be necessary for the measure
`ment of the comparatively Weak evoked ?elds in order to
`improve the signal-to-noise ratio (the control unit required
`for controlling the measuring channels and the units 7 and 8
`has been omitted in FIG. 2 for the sake of simplicity). At the
`end of the measurement, the memory thus contains a set of
`digital values Which represent the variation in time of the
`radial component B of the magnetic ?ux density for each
`measuring point Pk (Where k=1 .
`.
`. m) and m is the number
`of measuring points).
`Before or after the measurement of the magnetic ?eld the
`morphological structure of the skull or the brain is deter
`mined. This can be realiZed by Way of an X-ray computer
`tomography device Which forms computer tomograms of
`equidistant parallel slices through the skull of the patient as
`denoted by a set of parallel broken lines 9 in FIG. 1. The
`morphology can instead be determined by Way of a magnetic
`resonance examination, in Which case several (tWo
`dimensional) magnetic resonance tomograms of parallel
`slice can again be formed; hoWever, a three-dimensional
`imaging method can alternatively be used from the start. The
`morphology, hoWever, can also be determined in a different
`Way, for example using the so-called X-ray tomosynthesis.
`As has already been explained, on the basis of the
`morphology of the skull it can in many cases be indicated
`from Which surfaces of the brain the electrical activities
`thereof originate. This holds good for evoked currents Which
`occur due to stimulation of the sense organs as Well as for
`currents Which occur spontaneously, for example in the case
`of an epileptical attack. These surfaces are speci?ed by
`means of a unit 10, for example an interactive display Which
`is used by the operator in order to mark the surfaces on
`Which the centers of electrical activity are presumably
`situated. To this end, the slice images are successively
`displayed on the unit 10 and the relevant surfaces are
`suitably marked by the user, for example by means of a
`so-called light pencil. HoWever, it is alternatively possible to
`determine the surfaces in an automatic unit 10 by means of
`a suitable contour searching algorithm Which automatically
`determines the position of, for example a tumor. The unit 10
`thus supplies the coordinates of the volume elements
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`(voxels) Vi Which are situated on the desired surface Which
`is denoted by the reference numeral 3 in the present case.
`These coordinates are suitably adapted to those of the
`magnetic ?eld measuring system, for example by providing
`reference markers on the skull 1.
`A reconstruction unit 11 reconstructs the density of the
`impressed current at the individual voxels Vi (1 .
`.
`. i .
`.
`. s,
`Where s is the number of voxels on the marked surface) from
`the measuring values of the magnetic ?ux density at the
`various pixels at each time the same instant. KnoWn algo
`rithms can be used for this purpose.
`The relationship betWeen the measuring values of the
`magnetic ?ux density B at the measuring points Pk and the
`current density J at the voxels Vi can be described in matrix
`form by a Way of the Biot-Savart equation: B=A*j+n.
`Therein, B is a column matrix of the type (m, 1), i.e. a
`matrix comprising one column consisting of m elements
`Which describe the magnetic ?ux density at the m measuring
`points at the selected instant. n is a matrix of the same type
`Which represents the noise components of the magnetic ?ux
`density at the individual measuring points. j is also a column
`matrix comprising 2s elements, each of Which represents the
`tWo (mutually perpendicular) tangential components of the
`current density at the s voxels on the marked surface 3.
`A is the Biot-Savart matrix of the type (m, 2s) Whose
`matrix elements are de?ned by the geometrical relationships
`betWeen the measuring points and the voxels; the matrix
`elements are thus unambiguously de?ned by the geometrical
`position of the associated measuring points and voxels.
`For the above matrix equations to be solved unambigu
`ously it is necessary that the matrix A has the rank n and that
`n=2s. In this case the desired matrix can be determined for
`j directly by inverting the matrix A. In the other cases, and
`also in the described case, an optimum estimate of the
`current density matrix j can be made by means of the
`so-called Moore-Penrose pseudo inverse functions. This
`method and its use for the reconstruction of the current
`density distribution is knoWn inter alia from the article by
`Dallas et al “Bioelectric current image reconstruction from
`measurement of the generated magnetic ?elds” in “Medical
`Imaging”, R. H. Schneider, S. J. DWyer III. Editors, Proc.
`SPIE 767, pp. 2—10, 1987. Because the reconstruction is
`limited to the surfaces of volume elements Vi speci?ed by
`the unit 10 in the present case, this reconstruction is sub
`stantially more adequate than in the applications described
`in the cited publication Where the current density distribu
`tion is reconstructed at all voxels on the basis of an estimate.
`The result of the reconstruction process, therefore is the
`current density j or its mutually perpendicular tangential
`components at the voxels speci?ed via the unit 10. This
`distribution can be displayed on a suitable display apparatus
`12; in order to facilitate orientation, a tomogram Which
`alloWs for recognition of the morphological structures on
`Which the currents determined How can be superposed on
`the image.
`What is claimed is:
`1. A device for reconstructing spatial current distributions
`in a biological object Within Which object volume elements
`exhibit current distributions produced by current sources in
`said object, it being presumed that said current sources are
`present on surfaces inside of the morphological structure of
`the object, said device comprising:
`means for specifying a representation Which contains the
`morphological structure of said object at said surfaces
`on Which the current sources are presumed present;
`means for measuring at a plurality of points outside the
`object the values of at least one component of the
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`5,885,215
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`5
`magnetic ?elds produced by respective ones of said
`current sources Within the object manifesting said sur
`faces; and
`means for reconstructing the current distribution of the
`volume elements Which are situated on said surfaces on
`the basis of said measured values.
`2. A device for reconstructing the spatial current distri
`bution in a biological object having a morphological struc
`ture Within Which object volume elements exhibit current
`distributions produced by current sources in said object, it
`being presumed that said current sources are present on
`speci?ed surfaces inside of the morphological structure of
`the object, said device comprising:
`
`10
`
`6
`measuring means for determining values of magnetic ?uX
`density produced by said presumed current sources
`outside said object;
`memory means for storing said determined ?uX density
`values;
`means for determining the volume location of the ele
`ments Which are on speci?ed surfaces inside said
`object; and
`reconstruction means for determining the current distri
`butions at said determined volume elements from said
`stored values.