DE102007003565B4 - Device for reducing the synchronization of neuronal brain activity and suitable coil - Google Patents

Device for reducing the synchronization of neuronal brain activity and suitable coil

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Publication number
DE102007003565B4
DE102007003565B4 DE200710003565 DE102007003565A DE102007003565B4 DE 102007003565 B4 DE102007003565 B4 DE 102007003565B4 DE 200710003565 DE200710003565 DE 200710003565 DE 102007003565 A DE102007003565 A DE 102007003565A DE 102007003565 B4 DE102007003565 B4 DE 102007003565B4
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coil
stimulation
coils
means
subpopulations
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DE102007003565A1 (en
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Dr. Dolan Kevin
Milan Majtánik
Prof. Dr. Dr. Tass Peter
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Forschungszentrum Julich GmbH
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Forschungszentrum Julich GmbH
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N2/00Magnetotherapy
    • A61N2/02Magnetotherapy using magnetic fields produced by coils, including single turn loops or electromagnets
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/04Measuring bioelectric signals of the body or parts thereof
    • A61B5/04012Analysis of electro-cardiograms, electro-encephalograms, electro-myograms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/04Measuring bioelectric signals of the body or parts thereof
    • A61B5/0476Electroencephalography
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N2/00Magnetotherapy
    • A61N2/004Magnetotherapy specially adapted for a specific therapy
    • A61N2/006Magnetotherapy specially adapted for a specific therapy for magnetic stimulation of nerve tissue

Abstract

A device for reducing the synchronization of neuronal brain activity, comprising:
A means for stimulating brain regions comprising a quad coil (2) for exciting four subpopulations by means of a magnetic field,
A sensor (3) for measuring a pathological feature, and
- A control unit (4) which is designed such that it controls the four-coil (2) in stochastically reduced multichannel excitation so that it successively stimulates the individual subpopulations successively with pulse trains, the pulse trains are temporally offset by a value T / 4 and T is the middle period of the rhythm to be desynchronized.

Description

  • The invention relates to a device for desynchronization of neuronal brain activity and a suitable coil.
  • In patients with neurological or psychiatric disorders such as Parkinson's disease, essential tremor, dystonia or obsessive-compulsive disorder, neuronal networks are located in circumscribed areas of the brain, e.g. B. of the thalamus and the basal ganglia, pathologically active, for example, exaggerated synchronously. In this case, a large number of neurons synchronously action potentials, that is, the participating neurons fire excessively synchronous. In a healthy patient, the neurons in these brain areas fire qualitatively differently, for example in an uncorrelated way.
  • In Parkinson's disease, the pathologically synchronous activity alters neuronal activity in areas of the cerebral cortex, such as in the primary motor cortex, for example, by impelling it to its rhythm, eventually causing the muscles controlled by these areas to undergo physiological activity, e.g. B. a rhythmic trembling unfold.
  • In patients who can no longer be treated with medication, a deep electrode is implanted on one or both sides, depending on the clinical picture and whether the disease is unilateral or bilateral. Under the skin, a cable leads from the head to the so-called generator, which comprises a control unit with a battery, and is implanted, for example, in the region of the collarbone under the skin. About the depth electrodes is a continuous stimulation with a high-frequency periodic sequence (pulse train with a frequency of> 100 Hz) of individual pulses, z. B. rectangular pulses performed. The aim of this method is to suppress the firing of neurons in the target areas. The mechanism of action on which the standard depth stimulation is based is not yet sufficiently clarified. The results of several studies suggest that standard deep stimulation is like a reversible lesion, i. H. how a reversible tissue deactivation works: The standard deep stimulation suppresses the firing of the neurons in the target areas and / or in associated brain areas.
  • The disadvantage of this form of stimulation is that the energy consumption of the generator is very high, so that the generator including the battery often has to be replaced operationally after about one to three years. Even more disadvantageous is that the high frequency continuous stimulation as unphysiologischer (unnatural) input in the brain, z. As the thalamus or the basal ganglia, in the course of a few years to adapt the affected nerve cell associations can lead. In order to achieve the same stimulation success, then must be stimulated as a result of this adaptation with higher stimulus amplitude. The greater the stimulus amplitude, the greater is the likelihood that side effects such as dysarthria (dysfunctions), dysesthesia (sometimes very painful discomfort), cerebellar ataxia (inability to be safe without help from others), or dysarthria due to irritation of neighboring areas Schizophrenia-like symptoms etc. - comes. These side effects can not be tolerated by the patient. The treatment therefore loses its effectiveness in these cases after a few years.
  • Therefore, another method was proposed, as described in the DE 102 11 766 A1 "Device for the treatment of patients by brain stimulation, an electronic component and the use of the device and the electronic component in medicine" is described, are applied to demand stimuli in the respective target area, which desynchronize morbidly synchronized neuronal activity. The goal of this method / apparatus is not simply to suppress morbid synchronous firing, as in standard depth stimulation, but to bring it closer to the physiological, uncorrelated firing pattern. On the one hand, this is intended to reduce power consumption and, on the other hand, to prevent adaptation processes of the nervous tissue, which can lead to side effects via an increase in the stimulation amplitude.
  • The German Offenlegungsschrift DE 103 18 071 A1 discloses a method and an apparatus in which a demand-controlled application of stimuli takes place in the respective target area. The aim of these methods and apparatus is not simply to suppress the morbid synchronous firing, but to bring it closer to the physiological, uncorrelated firing pattern. As a result, on the one hand the power consumption is reduced and on the other hand adaptation processes of the nerve tissue which require an increase of the stimulation amplitude are prevented. The main disadvantage of the mentioned stimulation methods is that they require an operative placement of the stimulation electrodes in the brain and that in the case of the standard deep stimulation - due to the power consumption - the generator including the battery often has to be replaced surgically after one to three years. The short time available for calibration during an operation prevents the calculation of frequency-dependent phase resetting maps, which effectively desynchronize the pathological synchronization processes as the main frequency component changes can. The use of these Desynchronostionsverfahren occurs only in the late stages of the disease, which means that here the healing aspect of the stimulation, for example because of the advanced cell degeneration in the target area can not be fully exploited.
  • From the WO 03/85546 A1 There is known a method and a device with which the brain activity can be influenced. The method and the device serve to achieve a predetermined behavioral goal. The device described there employs electromagnetic fields using various algorithms, but it is not possible to derive from these algorithms an explicit therapeutic effect applying the reduction of the synchronization of neuronal activity. Furthermore, this text does not include the therapeutically relevant component of changing coupling topologies nor does it provide an algorithm for reducing the synchronization of neuronal populations.
  • From the WO 03/098268 A1 is a magnetic field stimulation is known, which is used for diagnostic purposes. The WO 03/082405 A1 shows a method for increasing the performance. One method of suppressing brain activity is from the scriptures WO 00/74777 A1 and WO 01/12236 A2 known. The font US Pat. No. 3,082,507 discloses methods for treating psychiatric and developmental diseases, such as stuttering or depression, using various stimulation protocols, e.g. B. single pulse, paired pulse, triple stimulation and low or high frequency repetitive stimulation, which are applied by means of one or more stimulation coils. Two main forms of coils are known, namely the simple O-shape and the shape of an eight 8.
  • The stimulation solenoids known so far can stimulate the brain at most in two directions and thus stimulate a maximum of two target populations or subpopulations.
  • From the Scriptures DE 102 11 766 A1 a device for the treatment of oscillatory brain activity by means of electrical brain stimulation is known. The font US 2004/0143300 A1 describes a non-invasive stimulation of neuronal brain activity using electromagnetic fields.
  • It is the object of the invention to provide a method and a device with which patients can be treated without the need for elaborate, high-risk and cost-intensive brain surgery. Preferably, it is intended to be able to treat patients who have a permanent or transient oscillatory component but are unable to perform surgery, or who have not had the suffering of the patients so far as to be aware of the risks and costs of brain surgery Take, that is, an operation should be superfluous. It should also be possible to treat patients in whom complex and prolonged calibration procedures must be used or in which the main frequency component of the pathological rhythmic activity may vary, such that the physiologically relevant coupling topologies are of physiological relevance through prolonged desynchronization internally or from other brain regions be decoupled, that is, the diseased brain areas are brought to the healthy state. The aim is to create the possibility of frequency-dependent phase resetting maps, with the help of which the pathological synchronization processes with changing main frequency component can be effectively reduced. The term reduced or reduced also includes the complete elimination of the synchronization. It should be possible to treat patients in a previous stage of the disease. It should not only lead to a decoupling of the affected neurons, but it should bring about a physiological change of the neurons, for example, a Reclustern or a dephosphorylation of the ion channels. It should be created a coil with which a stimulation of more than in two directions is possible.
  • The object is achieved by the features mentioned in the independent claims.
  • With the method and the device according to the invention, it is now possible to treat patients without the need for elaborate, high-risk and cost-intensive brain surgery. Preferably, patients may be treated who are underpinned by a permanent or transient oscillatory component, but who can not undergo surgery, or who have not experienced enough patient suffering to take the risks and costs of brain surgery , Patients may also be treated for which complex and prolonged calibration procedures must be used, or where the major frequency component of the pathological rhythmic activity may vary, such that the physiologically relevant coupling topologies of physiological relevance are due to prolonged reduction of synchronization internally or by other brain regions are decoupled, that is, the diseased brain areas are brought to the healthy state. The possibility is created to create frequency-dependent phase resetting maps with which Help the pathological synchronization processes with changing main frequency component can be effectively reduced. It is according to the invention a treatment of patients in an earlier stage of the disease possible. A physiological change of the neurons is brought about, for example a recloning or a dephosphorylation of the inner channels. Brain surgery can be dispensed with and the coil of the invention can be stimulated in more than two directions. For example, a stimulation in four directions is possible. Diseases can be successfully treated that are based on a pathologically synchronous oscillatory component. By way of example, but not limitation, epilepsy, Parkinson's disease, depression, obsessive-compulsive disorder may be mentioned. Tumor patients with synchronous high-amplitude neuronal population near the tumor can be treated.
  • Advantageous developments of the invention are specified in the subclaims.
  • The method features specified in the description are embodied in the device according to the invention by a controller which is designed such that it controls the device for executing the method features. Each specified method step thus also discloses a device having a controller that carries out the method. In this way, disclosed process features are also to be construed as device features.
  • The figures show exemplary embodiments of the device and the coil according to the invention.
  • It shows:
  • 1 : A device according to the invention
  • 2a -E .: coils
  • 3 : Representation of excited subpopulations
  • 4a : Stochastic multi-channel excitation by means of a pair of coils wound in a figure-of-eight form
  • 4b : Stochastic multi-channel excitation with a coil wound in a figure-eight.
  • 5a : Multi-channel excitation, where the randomness of the pulses is reduced by means of a pair of eight coils.
  • 5b : Multi-channel excitation, where the randomness of the pulses is reduced by means of an eight-coil.
  • 6 : Multi-channel excitation, where the randomness of the pulses is reduced by means of a coil in figure-of-eight shape.
  • 7 : Multi-channel excitation, where the randomness of the pulses is reduced by means of a simple coil
  • 8th : Simulation results for the stimulation of a synchronous neuron population by means of a quad coil and stochastic multichannel stimulation.
  • 9 : Temporal evolution of coupling among neurons.
  • The device according to 1 includes a buffer amplifier 1 , to the at least one magnetic coil 2 as well as sensors 3 connected to the detection of physiological measuring signals. The isolation amplifier is still connected to a unit 4 for signal processing and control connected to a stimulator unit 8th is connected to the signal generation. The stimulator unit 8th for the signal generation is available with at least one solenoid coil 2 in connection. At the entrance of the sensors 3 in the isolation amplifier 1 there is a relay 9 or transistor. The relay 9 is controlled by the stimulation unit. The unit 4 is over a line 10 with a telemetry transmitter 11 which is connected to a telemetry receiver 12 communicating, which in this example is outside the device and to which a means of visualizing, processing and storing the data 13 connected. As sensors 3 For example, epicortical electrodes, deep electrodes, brain electrodes or peripheral electrodes can be used. The magnetic coils 2 are attachable to the patient's head.
  • 2a A simple solenoid known in the art.
  • 2 B , c: magnetic double coils, which either correspond to two intersecting circles or which are composed of two substantially elliptical shapes.
  • 2d : In 2d is a four-coil, which is composed of four individual coils whose centers mark a square.
  • 2e : In 2e a four-coil is shown, which is composed of four individual coils whose centers mark a parallelogram. The angle between the two axes, which run through the centers of the diagonally lying coil parts is preferably 80 °.
  • Fig. 3
  • An exemplary representation of the four excited neural subpopulations ( 24 - 27 ) of a brain substrate ( 22 ) by means of a four-coil ( 21 ). The remaining parts of the brain substrate are not excited ( 28 ). Overall, the quad coil can activate up to four separate subpopulations independently. The dashed lines show the induced magnetic field ( 23 ).
  • Fig. 4a
  • Stochastic multi-channel excitation by means of a four-coil (here a pair of coils wound in a figure-eight shape). The temporal course of the applied stimuli ( 33 ) over the first coil ( 31 ), and the second coil ( 32 ). The orientation ( 34 ) of the current flow in the coils is marked with the positive and negative values + and - of the pulses. The sequence of pulses ( 33 ) is stochastically distributed in time and the pulses ( 33 ) may not overlap.
  • Fig. 4b
  • Stochastic multi-channel excitation by means of a double coil (in this case a coil wound in a figure-eight shape). The temporal course of the applied stimuli ( 42 ) over the coil ( 41 ). The orientation ( 43 ) of the current flow in the coils is marked with the positive and negative values + and - of the pulses. The sequence of pulses ( 42 ) is stochastically distributed in time and the pulses ( 42 ) may not overlap.
  • Fig. 5a
  • Reduced stochastic multi-channel excitation by means of a four-coil (here a pair of coils wound in a figure-eight shape). The temporal course of the applied stimuli ( 53 ) over the first coil ( 51 ), and the second coil ( 52 ). The orientation ( 54 ) of the current flow in the coils is marked with the positive and negative values + and - of the pulses. The sequence of pulses ( 53 ) is ordered in time, ie the sequence of pulses is fixed, z. B. the positive pulse of the first channel follows the positive pulse of the second channel, which in turn follows a negative pulse of the first channel, and so on. The time interval of the individual pulses to each other but has a stochastic characteristic. The pulses ( 53 ) may not overlap.
  • Fig. 5b
  • Reduced stochastic multi-channel excitation by means of a double coil (in this case a coil wound in a figure-eight shape). The temporal course of the applied stimuli ( 62 ) over the coil ( 61 ). The orientation ( 63 ) of the current flow in the coils is marked with the positive and negative values + and - of the pulses. The sequence of pulses ( 62 ) is ordered in time, ie the sequence of pulses is fixed, z. B. the positive pulse of the first channel follows the positive pulse of the second channel, which in turn follows a negative pulse of the first channel, and so on. The time interval of the individual pulses to each other but has a stochastic characteristic. The pulses ( 62 ) may not overlap.
  • Fig. 6
  • A schematic representation of the streams ( 72 ), the magnetic fields ( 73 ) and the induced currents in the brain ( 75 ) during a simple excitation by means of a coil in figure-of-eight form ( 71 ). The maximum of the induced currents has a focal character ( 75 ).
  • Fig. 7
  • A schematic representation of the streams ( 82 ), the magnetic fields ( 83 ) and the induced currents in the brain ( 85 ) during a simple excitation by means of a simple coil ( 81 ). The maximum of the induced currents has an annular character ( 85 ).
  • Fig. 8
  • The firing density, the extent of synchronization and the mean synaptic coupling of a neural network (10 x 10 neurons) before, during and after a stimulation with a reduced stochastic multichannel excitation. The beginning of the stimulation is indicated by the arrow and the stochastic pulse sequences are marked with the black lines in the lower part of the graphs.
  • Fig. 9
  • The temporal evolution of the coupling matrix of the network from the before, during and after a stimulation with a reduced stochastic multichannel excitation. For each point in time, the coupling matrix is represented as a gray value column in the figure. The strength of the coupling is coded with a gray value.
  • In the morbid state before stimulation, the neurons fire in common mode and have a very strong coupling with each other. After switching on the stimulation, the couplings between the neurons are reduced. After prolonged stimulation (over 600 cycles in the simulation), stimulation is no longer needed because the network is permanently in the desynchronized state remains and the morbid strong couplings between the neurons were degraded.
  • The magnetic coil 2 can in principle be present in various embodiments. The term "magnetic coil" is intended to include in the content any body which is capable of inducing a magnetic field which is suitable for the establishment of an electric field which leads to the selective activation of the neuron population.
  • According to the invention, the device comprises at least one magnetic coil 2 , But it can also be 2, 3, 4 or more solenoids 2 include.
  • Possible coil forms are, for example:
    • a) a simple solenoid coil (corresponds 2a )
    • b) an arrangement in front of two coils, which are at a small distance from each other, so that they either touch or almost touch. The distance may be for example 1 to 5 mm. This arrangement is referred to below as a double coil. The coils can also touch, provided they are insulated. (Equivalent 2 B and 2c )
    • bb) a coil whose wires are wound in a figure-of-eight shape. This coil shape is referred to as a double coil. (Equivalent 2 B and 2c )
    • c) an arrangement of three coils whose centers preferably form the vertices of a triangle.
    • d) in a particularly preferred embodiment, four coils (= four-coil), corresponding to a pair of coils wound in a figure eight, which are arranged substantially perpendicular, preferably perpendicular to each other. (Equivalent 2d )
    • dd) Four substantially annular coils (= quadruple coil), the centers of which essentially form the vertices of a quadrilateral, preferably of a square (corresponds 2d and 2e ).
  • The coils should have an electrical insulation, or there should be no short circuits. For the purposes of the invention, a four-coil of individual coils and / or eight-shaped coils can be composed.
  • The magnetic coils are examples of means for generating a magnetic field.
  • The spools 2 be over the control 4 supplied with electricity, which allow the construction of magnetic fields of, for example 1.1 to 2.3 Tesla. The optimal magnetic field strengths can be determined by calibration. Basically, any magnetic field strength is suitable, which still has a physiological effect. Exemplary, lower magnetic field strengths are 0.1 Tesla or 0.01 Tesla. The information is not limiting.
  • Preferably, the coils have an inner diameter of 1 cm to 5 cm.
  • The outer diameter can be up to 8 cm, for example.
  • The unit for signal processing and control 4 may comprise means for univariate and / or bivariate and / or multivariate data processing, as described, for example, in "Detection of n: m Phase Locking from Noisy Data: Application to Magnetoencephalography" by P. Tass, et. al. in Physical Review Letters, 81, 3291 (1998). The univariate and / or bivariate and / or multivariate data processing preferably originates from statistical physics and preferably from the area of stochastic phase resettings.
  • According to the invention, the device is equipped with means which detect the signals of the sensors 3 as pathological and in the presence of a pathological pattern on the magnetic coils 2 Give off stimuli that cause the pathological neuronal activity either suppressed short-term or modified so that it is closer to the natural, physiological activity. The pathological activity differs from the healthy activity by a characteristic change of its pattern and / or its amplitude.
  • The means for recognizing the pathological pattern are a computer which receives the measured signals from the sensor 3 processed and compared with data stored in the computer. The computer has a data carrier, which stores data that was determined during a calibration procedure. By way of example, these data can be determined by systematically varying the stimulation parameters in a series of test stimuli and the success of the stimulation via the sensor 3 by means of the control unit 4 is determined. The determination can be performed by uni-, bi-, and multivariate data analysis to characterize the frequency characteristics and the interaction (eg coherence, phase synchronization, directionality and stimulus-response relationship), as for example in PA Tass: "Phase Resetting in Medicine and Biology , Stochastic Modeling and Data Analysis. "Springer Verlag, Berlin 1999 is disclosed.
  • The device according to the invention comprises means for establishing frequency-dependent phase resetting maps (fPRK). In the morbid state, the neurons fire very synchronously. If you measure the activity of this neural population, z. B. with the derivation of a local field potential, in the measured signals strong oscillatory Components corresponding to the synchronous firing of the neurons can be detected. In practice, it is often observed that the frequency of the oscillatory activity is subject to frequent fluctuations. It can therefore not be assumed that during the oscillations in different frequencies the responses of the neurons to a stimulation remain constant. Therefore, one would not expect that the vulnerable phase, in which pacing the network leads to its desynchronization, is identical for all frequencies. The purpose of the frequency-dependent phase resetting maps is to determine the vulnerable phase as a function of the instantaneous frequency of the oscillatory activity of the diseased area. This makes it possible to perform stimulation in the vulnerable phase even for non-stationary oscillatory processes. Since the determination of the fPRK requires complex measurements, these can only be determined with the non-invasive stimulation method, magnetic field stimulation. Thus, the device according to the invention has a significant advantage over the devices (the PT double pulse and soft-phase resetting.)
  • For the determination of the fPRK a long sequence of single stimuli with constant parameters at different times is applied. In the data analysis, for each stimulus, its initial phase and the instantaneous frequency of the oscillation are determined, e.g. B. by Hilbert transformation and filtering, and the course of the phase during and after the stimulus application (the calculation period). Then, for each instantaneous frequency of the oscillation, a phase resetting curve is constructed for each time t in the entire calculation period. A phase resetting curve assigns the phase at time t to each value of the initial phase at time t after stimulation. In the next step, the number of turns of the phase resetting curves is determined for each time t. The number of turns indicates how often the phase after stimulation passes through the value range between 0 and 2 PI at time t, while the initial phase passes through this range of values once. This is equivalent to the mean gradient of the phase resetting curve. The determination of the vulnerable phase is now carried out with the determination of the change in the number of turns from 1 to 0. The vulnerable phase is now in the range of the maximum absolute gradient of the last phase resetting curve with the number of turns 1. If for some instantaneous frequencies this transition between 1 and 0 is not found, the stimulus application is repeated with a higher stimulation amplitude.
  • The PRPRs are then stored in the device. During single-stimulus stimulation, the device calculates the phase and the instantaneous frequency and selects the optimal combination of parameters from the fPRK.
  • The device according to the invention therefore comprises a computer which contains a data carrier which carries the data of the clinical picture, compares with the measured data and, in the case of the occurrence of pathological activity, a stimulus signal to the magnetic coil 2 gives off, so that a stimulation of the brain tissue takes place. The data stored in the data carrier of the clinical picture can be either person-specific, determined by calibration optimal stimulation parameters or a data pattern, which has been determined from a patient collective and typically occurring optimal stimulation parameters. The computer recognizes the pathological pattern and / or the pathological amplitude.
  • The stimulus species used for the treatment of the pathological findings are known to the person skilled in the art. For example, longer periodic sequences of single stimuli or more complex stimulus sequences may be used. Examples of these complex stimuli are on the one hand a stochastic multi-channel excitation. During stochastic multichannel stimulation, pulses or pulse trains across different coils and in different directions are not temporally superimposed and randomized at the time of onset. The amplitude and frequency of the individual pulses in pulse trains can vary randomly (noise processes / random processes), the intensity of the variations being adapted to the pathological feature. Excitation via a channel is understood as influencing the neuronal activity of a subpopulation in the brain. Multi-channel stimulation affects the activity of several subpopulations. The excited subpopulations can overlap. A stimulation channel is the stimulation of a subpopulation by means of the magnetic field. The stochastic multichannel stimulus causes the stimulated subpopulations to display temporally independent fire behavior that translates into uncorrelated firing of the individual populations. Surprisingly, one obtains a significantly reduced synchronization, even if the extent of the stochastic variation of the time intervals between the pulses in different channels is significantly reduced. In principle, it can be achieved by changing the current direction in the coil that different subpopulations are excited. This means that two subpopulations can be excited with a simple coil. This also applies to two coils or an eight-shaped coil. When using two simple coils or an eight-shaped coil, in addition, the focusing of the resulting electric field can be improved. The use of three coils allows the excitation of 6 different Subpopulations. When 4 individual coils are used, arranged to substantially overlap at one point, even 12 different subpopulations can be excited by changing the combination of coils or the direction of current flow. A four-coil coil composed of two 8-row coils makes it possible to excite 4 subpopulations. Since the excitation of the neurons in the target population depends on the angle of the axons to the electric field, up to 4 subpopulations can be selectively excited with the double coil. The individual subpopulations differ from each other by the angle they form with the induced electric field.
  • As a result of the stimuli applied, the pathological activity is typically briefly suppressed in the case of using longer periodic sequences of individual stimuli and, in the case of the more complex stimulus sequences, is typically brought close to or completely aligned with the natural, non-pathological activity.
  • By way of example, the following types of irritation can be cited:
  • Longer periodic sequence of single stimuli:
  • During such a sequence, a short single stimulus (one turn on and off of the stimulation) is repeatedly applied. Preferably, the individual stimuli are applied in the vulnerable phase of the oscillations
  • Complex stimulus sequence:
  • A complex sequence of stimuli refers to a set of on and off processes of the simulation unit which are distributed only over several stimulation channels and are variable in number and parameters (such as duration, amplitude, shape).
  • pulse train:
  • A pulse train refers to a set of on and off processes of the simulation unit which are distributed only over one stimulation channel and are variable in number and parameters.
  • The device according to the invention is preferably designed as it is in the case where the sensor 3 after the irritation detects a loss of pathological activity, the stimulation is interrupted. For this purpose, the computer determines whether the pathologically increased amplitude or the pathologically increased pronounced pattern is present. This is done by means of the data analysis realized by the electronics. Once these pathological features are detected again, the next stimulation begins in the same way. The stimulation is switched on and off either by a control unit or by two control units communicating with each other, which in 1 as a control unit 4 are summarized.
  • The control unit 4 For example, it may include a chip or other electronic device with comparable computing power.
  • The control unit 4 controls the solenoid 2 preferably in the following manner. About the stimulator unit 8th then targeted stimuli on the magnetic coils 2 passed on to the target region in the brain.
  • Furthermore, the device according to the invention is preferably provided with means for visualization and processing of the signals as well as for data backup 13 via the telemetry receiver 12 in connection. The unit can 13 have the data analysis methods mentioned below.
  • Furthermore, the device according to the invention via the telemetry receiver 12 with an additional reference database in connection for example to accelerate a calibration process.
  • The 2a -E show by way of example magnetic coils which are suitable for magnetic stimulation. These are:
  • 2a A simple solenoid known in the art.
  • 2 B , c: magnetic double coils, which either correspond to two intersecting circles or which are composed of two substantially elliptical shapes.
  • 2d : In 2d is a four-coil, which is composed of four individual coils whose centers mark a square.
  • 2e : In 2e a four-coil is shown, which is composed of four individual coils whose centers mark a parallelogram. The angle between the two axes, which run through the centers of the diagonally lying coil parts is preferably 80 °.
  • The spools 2 B . 2c . 2d and 2e are particularly effective. With them, a penetration depth of the magnetic field in the cortex up to 2 cm can be effected.
  • The spools 2d and 2e are particularly effective in reducing synchronicity and in sharing a synchronous one Neuron population in two or more subcorrelated subpopulations.
  • In the following, the invention will be described in its general form.
  • According to the invention with the magnetic coils 2 Magnetic fields induce which generate electrical fields in the brain and thus cause the intracortical currents to apply stimulus patterns in the target areas of the brain.
  • The respective magnetic field is perpendicular to the current direction.
  • Will be a simple solenoid 2 after the example 2a ), it induces a simple magnetic field which causes a circular electrical gradient in the brain tissue that can be used for stimulus application.
  • In the embodiment of the examples 2 B ) and 2c ) forms a very good focus of the magnetic fields below the point of the coils where they come closest, so that a very good stimulation is effected. The current direction in the area of the maximum spatial approach of the coils must have the same direction, so that the currents and thus the magnetic field do not cancel each other or reduce Depending on the direction of current flow, the magnetic field has an orientation in one of two opposite directions.
  • In the embodiments of the example 2d ) and 2e ) training of current flow in a brain in four directions is possible. In each case two opposite directions are generated by two double coils, which preferably form the diagonal vertices of a quadrangle. The formed by this coil shape temporally not overlapping trained electric fields preferably include an angle of 90 °. This can cause a special decoupling of the neural activity. In a less preferred embodiment, the arrangement of the coils differs from that of an ideal symmetry and / or overlaps of the coils, so that an angle can be formed between the two electric fields which is different from 90 °. The angle can reach 75 °, for example. However, the best healing and treatment successes are achieved when an angle of 90 ° is formed. Good results are also achieved with a deviation of 90 ° ± 5 °.
  • In principle, other coil shapes are possible.
  • With the electric fields generated by the magnetic coils or their temporal sequence and orientation, it is possible to generate stimuli in defined brain regions which cause desynchronization and even healing of the diseased regions. It is also possible to apply electric electromagnetic stimulation patterns with the electrical fields that form a specific time sequence and spatial extent and / or spatial orientation.
  • Various stimulus patterns can be applied.
  • Possible stimuli are individual pulses which have a duration in the sub-millisecond range of, for example, 200-500 μs.
  • With these single pulses, a low-frequency stimulation of a frequency of less than one Hz can be made. It is also possible to apply high-frequency stimulus sequences of a frequency of more than one Hz to, for example, 200 Hz.
  • With the method and the device according to the invention, a desynchronisation of neuronal activity is achieved technically differently than with the devices which make use of stimulating electrodes. Instead of placing a stimulation electrode in the morbidly synchronous nerve cell structure, a magnetic coil is positioned over the area so that the maximum of the electrical gradient induced by the magnetic coil in the brain is in the target population. (= Induction of electric fields in the brain) can be done with different stimulation methods. These can be chosen depending on the disease: single stimulus, compound stimuli, stochastic and deterministic multichannel stimulation. The device is not intended for a particular stimulation technique, but may vary the algorithms for reducing the synchronization as needed. An essential part of the functioning of the device is the changing of the coupling topologies within or between neuronal populations. The change in coupling epitopes is essentially due to an uncorrelated activity in the brain tissue and results in a minimization of stimulation after reaching the treatment goal, that is, no more post-healing stimulation is needed.
  • Example: Reduction of the synchronization by means of the stochastic multichannel excitation:
  • For example, by means of a double coil 2d used the stimulation by means of coordinated reset, as an example, the following stimuli can be delivered via two stimulation coils: About each coil, a set of pulse trains is applied, the Stimulation phases must not overlap and two of the pulse trains are applied by means of the same coil, only with reverse polarity.
  • In 8th For example, the stochastic multi-channel excitation is shown. In the morbid state before the stimulation, the neurons fire in common mode and have a very strong coupling with each other. This can be seen in the high fire density and the high degree of synchronization. After switching on the stimulation by means of the stochastic multichannel excitation (4), the synchronous activity in the network is significantly reduced. In addition, as a result of continuous desynchronization, the couplings between the neurons are reduced. This leads to a weakening of the synchronization tendency in the network and a reduction in the frequency of the stimulation application. After prolonged stimulation (over 600 cycles in the simulation), stimulation is no longer needed because the network remains permanently in the desynchronized state, ie the network is healed. A four-coil with α = 90 ° ( 2d ) used. The stimulation of the four subpopulations happens randomly or randomized with a randomization factor RF = K + S · epsilon with (K = T / 4, S = 0.2) ie the individual subpopulations are separated by a distance of A = T / 4 + S Epsilon is excited, where Epsilon is a normally distributed random process with the expected value 0 and the variance is equal to 1, and T is the period of the rhythm to be desynchronized. After a pulse train with duration D is switched on at time t 1 , the turn-on point t 2 of the next pulse train t 2 = t 1 + T / 4 + S · epsilon is calculated. If the turn-on time t 2 is less than (t 1 + D), ie the pulse trains would overlap, additional factors (T / 8 + S · epsilon) are added until t 2 is greater than (t 1 + D). The individual subpopulations are successively stimulated one after the other. During the stochastic multichannel excitation the pathological synchronization is clearly suppressed ( 8a , b), that is, the firing of the neuronal population shows a significantly reduced amplitude ( 8a ) and also a reduction of synchronization indices ( 8b ) If the stochastic multichannel stimulation is applied over a longer period of time, it leads to a recovery / coupling reduction of the target area ( 8th . 9 ), where the decoupling has a much slower dynamics than the synchronization behavior. The healthy target area no longer needs stimulation.
  • In an alternative embodiment of stochastically reduced multichannel excitation, pulse trains are temporally offset by T / 4, where T is the mean period of the rhythm to be desynchronized.
  • This stimulation method is a mild, non-invasive procedure that exploits the neurons in the affected areas to undergo plastic processes that are dependent on the intensity of firing synchronicity. High synchronicity leads to the strengthening of the coupling between neurons and / or neuron polulations and low synchronicity reduces the coupling between neurons and / or neuron populations.
  • Example:
  • According to the pathological neuronal activity A) via a sensor such as a) brain electrode, z. B. a depth electrode, a b) epicortical electrode or c) measured a muscle electrode and serves as a feedback signal, ie control signal, for an on-demand stimulation B). The feedback signal from the sensor 3 is via a line to the isolation amplifier 1 transmitted. Alternatively, the feedback signal can also be transmitted telemetrically without the use of an isolation amplifier. In the case of telemetric transmission is sensor 3 connected to an amplifier via a cable. The amplifier 9 is with a telemetry transmitter 11 connected via a cable. In this case are sensor 3 and amplifiers 9 and telemetry transmitter, for example, implanted in the area of an affected limb, while the telemetry receiver via a cable with the control unit 4 connected is. This means that, unlike the standard continuous stimulus, the activity is measured and the measurement signal is used as the trigger for on-demand stimulation.
  • For the measurement A) of the neuronal activity, there are the following different possibilities:
    • I. Measurement via the sensor 3 for example, measurement of neuronal activity originating from the cerebral cortex, either via an implanted electrode b) or preferably an atraumatic epicortical electrode b) (sensor 3 ), ie an electrode which rests on the brain and is fixed, but does not penetrate into the tissue and in this way a local electroencephalogram of an affected area of the cerebral cortex, z. B. the primary motor cortex derived.
    • II. In patients with primary tremor, the measurement of muscular activity by electrodes may also be c) (Sensor 3 , preferably telemetric with control unit 4 connected) in the area of the affected musculature.
  • The pathological neuronal activity can in principle also occur in different neuron populations. That's why several, via sensors 3 Measured signals can be used to control the stimulation. Whenever a pathological feature of the activity is detected in at least one of the neuron polypulations, an irritation is triggered.
  • The measuring signal or the measuring signals serve or serve as feedback signals. This means that stimulation takes place as a function of the activity detected via the measuring signal. Whenever a pathological feature of neuronal activity (that is, pathologically increased amplitude or pathologically enhanced pattern of activity) begins and increases, it is stimulated.
  • The stimulation B) can take place in different ways.
  • Demand-driven stimulation to reduce synchronization:
  • These procedures are used when pathologically synchronized nerve cell activity in the target area (eg, in epilepsy disease in areas of the cortex) or in another area or muscle relevant to the disease (via sensors 3 derived) is present. This is for example determined by the fact that the sensors 3 measured signals in the frequency domain, which is characteristic of the pathological activity. As soon as a band-pass filtered measurement signal exceeds a threshold determined in the calibration procedure, it is transmitted via the control unit 4 the next control pulse to the stimulator unit 8th passing over the magnetic coil 2 Generates or passes on stimuli. The goal here is not simply to suppress the firing of the neurons as with the standard continuous stimulation. Instead, only the morbidly increased synchronization of the Nerver cells should be remedied as needed. That is, the nerve cell groups in the target area are uncorrelated, while they are still active, so form action potentials. This is to bring the affected nerve cells closer to their physiological - ie uncorrelated firing - state, rather than simply that their activity is completely suppressed. For this purpose, several different synchronization-reduction methods based on the principle of "stochastic phase resetting" can be used. It is exploited here that a synchronized neuron population can be desynchronized by applying an electrical stimulus of the correct intensity and duration, provided that the stimulus is administered in a vulnerable phase of the abnormal rhythmic activity. These optimal stimulation parameters (intensity, duration and vulnerable phase) are determined during the calibration procedure, for example by systematic variation of these parameters and comparison with the stimulation success (eg attenuation of the amplitude of the band-pass filtered feedback signal). In case of using the telemetry device 11 - 13 the calibration can be improved by using the above-mentioned frequency-dependent phase resetting curves. Single-pulse stimulation is only efficient if the stimulus is applied at or close enough to the vulnerable phase of the activity to be stimulated. Alternatively, complex forms of stimulation can be used. These consisted of a resetting (controlling the dynamics of the neuron subpopulation to be stimulated, for example restarting). The advantage of these more complex procedures is that the complex forms of stimulation, regardless of the dynamic state of the neuron population to be stimulated, cause a reduction in synchronization.
  • In the case of the use of individual stimuli must control unit 4 when the threshold value determined by the calibration is exceeded by means of the electronics (control unit 4 ) standard prediction algorithms predict the temporal occurrence of the vulnerable phase to make it precise enough. In the case of the use of complex stimuli must control unit 4 if the threshold value established by the calibration is exceeded, it will only give rise to a new complex stimulus of the same kind.
  • Simple stimuli are for example
    • a) single-pulse stimulations.
  • Complex stimuli are for example
    • b) double pulse stimulation,
    • c) stochastic multichannel stimulation
  • In a preferred embodiment, the apparatus is provided with means for wireless transmission of data, such as the measurement signals and pacing control signals, to allow data transfer from the patient to an external receiver, for example, for the purpose of monitoring and optimizing therapy. In this way it can be recognized early on whether the stimulation parameters used are no longer optimal. In addition, a wireless data transfer to a reference database can be used and early responses to typical changes in irritability in the target tissue.

Claims (9)

  1. A device for reducing the synchronization of neuronal brain activity, comprising: - a means for stimulating brain regions comprising a quad coil ( 2 ) for excitation of four subpopulations by means of a magnetic field, - a sensor ( 3 ) for measuring a pathological feature, and - a control unit ( 4 ), which is designed such that it the four-coil ( 2 ) in stochastic Reduced multichannel excitation drives so that it stimulates the individual subpopulations successively successively with pulse trains, the pulse trains are temporally offset by a value T / 4 and T is the mean period of the rhythm to be desynchronized.
  2. Apparatus according to claim 1, wherein the centers of the coils of the four-coil ( 2 ) essentially form the vertices of a square.
  3. Device according to claim 1 or 2, wherein the four coils of the four-coil ( 2 ) are given by two in the form of an 8 guided coils.
  4. Device according to one of the preceding claims, wherein the four-coil ( 2 ) forms a magnetic field strength of 1.1 to 2.3 Tesla.
  5. Device according to one of the preceding claims, wherein the control unit ( 4 ) includes univariate and / or bivariate and / or multivariate data analysis.
  6. Apparatus according to claim 5, wherein at least one of the univariate, bivariate and multivariate data analysis works with statistical physics methods.
  7. Device according to claim 6, wherein the methods of statistical physics originate from the field of stochastic phase resetting.
  8. A device for reducing the synchronization of neuronal brain activity, comprising: - a means for stimulating brain regions comprising a quad coil ( 2 ) for excitation of four subpopulations by means of a magnetic field, - a sensor ( 3 ) for measuring a pathological feature, and - a control unit ( 4 ), which is designed such that it the four-coil ( 2 ) so that it stimulates the individual subpopulations successively successively with pulse trains, wherein successive pulse trains are offset by a time interval and the time interval is the sum of a value T / 4 and a random value, where T is the mean period of desynchronizing Rhythm is.
  9. The apparatus of claim 8, wherein the random value is a value (S x epsilon), Epsilon is a normally distributed random process with an expected value of 0 and a variance of 1, and S = 0.2.
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