Patent Abstract:
A device and method for desynchronizing a patient&#39;s neuronal brain activity in which the neuron population is firing in a pathologically synchronized manner. The device includes a stimulation unit that generates an acoustic stimulation signal that includes both a first tone and a second tone. The first tone is provided to shift the phase of the neuronal brain activity of a first subpopulation of the neuron population relative to the phase of the neuronal brain activity of a second subpopulation of the neuron population when the first tone is acoustically received by the patient. Further, the second tone is provided to shift the phase of the neuronal brain activity of the second subpopulation relative to the phase of the neuronal brain activity of the first subpopulation when the second tone is acoustically received by the patient. As a result, the acoustic stimulation signal desynchronizes the stimulated neuron population.

Full Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    The present application is a continuation of U.S. application Ser. No. 13/796,422, filed Mar. 12, 2013, which is a continuation of U.S. application Ser. No. 12/884,557, filed Sep. 17, 2010, which claims priority to International Application No. PCT/DE2009/000399, filed Mar. 20, 2009, which claims priority to German Application No. 10 2008 015 259.5, filed Mar. 20, 2008, the entire contents of each of which are incorporated herein by reference. 
     
    
     BACKGROUND 
       [0002]    There are excessively strong neuronal activity synchronization procedures in the brain in a number of neurological and psychiatric diseases and these have a very strong negative influence on the cerebral function. Tinnitus is such a disease. Tinnitus refers to a sound in the ear, mostly in the form of a high-pitched tone, but occasionally also having a knocking, pulsing or beating character. It is a widespread disease in the form of disturbing sensations that are of an agonizing nature for many patients. Currently available therapy methods for such diseases include pharmacotherapy, deep brain stimulation and the like. 
       SUMMARY 
       [0003]    The present application is directed to a device and method for desynchronizing a patient&#39;s neuronal brain activity involving a neuron population firing in a pathologically synchronized manner. The device includes a stimulation unit configured to generate an acoustic stimulation signal to stimulate the neuron population when the acoustic stimulation signal is aurally received by the patient. Furthermore, the acoustic stimulation signal has a first frequency and a second frequency, with the first frequency provided to reset the phase of the neuronal brain activity in a first sub-population of the stimulated neuron population, and the second frequency provided to reset the phase of the neuronal brain activity in a second sub-population of the stimulated neuron population. 
         [0004]    In another aspect of the present application, a device is provided for desynchronizing a patient&#39;s neuronal brain activity involving a neuron population firing in a pathologically synchronized manner. In this aspect, the device includes a stimulation unit to generate an acoustic stimulation signal to stimulate the neuron population when the acoustic stimulation signal is aurally received by the patient; a measurement unit to record a measurement signal on a patient, which measurement signal reproduces the neuronal activity in the auditory cortex of the patient or a region connected thereto; and a control unit to actuate the stimulation unit based on the measurement signal such that the stimulation unit converts the measurement signal into the acoustic stimulation signal. 
         [0005]    In further aspect of the present application, a method is provided for desynchronizing a patient&#39;s neuronal brain activity involving a neuron population firing in a pathologically synchronized manner, the method including generating an acoustic stimulation signal to stimulate the neuron population when the acoustic stimulation signal is aurally received by the patient, the acoustic stimulation signal having at least a first frequency and a second frequency; setting the first frequency to reset the phase of the neuronal brain activity in a first sub-population of the stimulated neuron population; and setting the second frequency to reset the phase of the neuronal activity in a second sub-population of the stimulated neuron population. 
         [0006]    In yet a further aspect of the application, a method is provided for desynchronizing a patient&#39;s neuronal brain activity involving a neuron population firing in a pathologically synchronized manner. In this aspect, the method includes recording a measurement signal on a patient, which measurement signal reproduces the neuronal activity in the auditory cortex or a region connected thereto; converting the measurement signal into an acoustic stimulation signal; and generating the acoustic stimulation signal to stimulate the neuron population when the acoustic stimulation signal is aurally received by the patient. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0007]      FIG. 1  shows a schematic illustration of a device  100  as per an exemplary embodiment. 
           [0008]      FIG. 2  shows an illustration of sinusoidal oscillations at the frequencies of f 1 , f 2 , f 3  and f 4  as per an exemplary embodiment. 
           [0009]      FIG. 3  shows an illustration of a sinusoidal oscillation amplitude-modulated by a rectangular function as per an exemplary embodiment. 
           [0010]      FIG. 4  shows a schematic illustration of a device  400  as per a further exemplary embodiment. 
           [0011]      FIG. 5  shows a schematic illustration of a device  500  as per a further exemplary embodiment. 
           [0012]      FIG. 6  shows a schematic illustration of a device  600  as per a further exemplary embodiment. 
           [0013]      FIG. 7  shows a schematic illustration of a device  700  as per a further exemplary embodiment. 
           [0014]      FIG. 8  shows a schematic illustration of a device  800  as per a further exemplary embodiment. 
           [0015]      FIG. 9  shows a schematic illustration of a device  900  as per a further exemplary embodiment. 
           [0016]      FIG. 10  shows a schematic illustration of an auditory stimulation method as per an exemplary embodiment. 
           [0017]      FIG. 11  shows a schematic illustration of a further auditory stimulation method as per an exemplary embodiment. 
           [0018]      FIG. 12  shows a schematic illustration of a further auditory stimulation method as per an exemplary embodiment. 
           [0019]      FIG. 13  shows a schematic illustration of a further auditory stimulation method as per an exemplary embodiment. 
           [0020]      FIG. 14  shows a schematic illustration of a further auditory stimulation method as per an exemplary embodiment. 
           [0021]      FIGS. 15A and 15B  show schematic illustrations of the generation of modulation signals as per an exemplary embodiment. 
       
    
    
     DETAILED DESCRIPTION 
       [0022]      FIG. 1  illustrates in a schematic fashion a device  100 , which consists of a control unit  10  and a stimulation unit  11  connected to the control unit  10 .  FIG. 1  furthermore illustrates an ear  12  of a patient and the auditory cortex  13  in the brain of the patient in a schematic fashion. 
         [0023]    The stimulation unit  11  is actuated by the control unit  10  by means of one or more control signals  14  during the operation of the device  100 , and the stimulation unit  11  generates one or more acoustic stimulation signals  15  with the aid of the control signal  14 . The frequency spectrum of the acoustic stimulation signal  15  may lie completely or partly in the range audible to a human. The acoustic stimulation signal  15  is taken in by the patient by one or both ears  12  and is transmitted to neuron populations in the brain via the cochlear nerve or nerves  16 . The acoustic stimulation signal  15  is developed such that it stimulates neuron populations in the auditory cortex  13 . At least a first frequency f 1  and a second frequency f 2  are present in the frequency spectrum of the acoustic stimulation signal  15 . The acoustic stimulation signal  15  can furthermore contain additional frequencies or frequency mixtures; in the exemplary embodiment shown in  FIG. 2 , these are a third frequency f 3  and a fourth frequency f 4 . 
         [0024]    The device  100  can be used in particular for treating neurological or psychiatric diseases, such as tinnitus, migraine, headaches of different form and genesis (e.g. cluster headache), trigeminal neuralgia, sleep disorders, neuralgias and headaches in the case of neuroborreliosis, attention deficit syndrome (ADS), attention deficit hyperactivity syndrome (ADHS), neuroses, compulsion neuroses, depressions, mania, schizophrenia, tumors, arrhythmias, addiction diseases, bruxism (nocturnal teeth grinding), eating disorders, and the like. 
         [0025]    The aforementioned diseases can be caused by a disorder in the bioelectric communication of neural networks connected in specific circuits. Herein, a neuron population continuously generates pathological neuronal activity and possibly a pathological connectivity (network structure) associated therewith. In the process, a large number of neurons form action potentials at the same time, i.e. the involved neurons fire in an overly synchronous fashion. Additionally, the sick neuron population exhibits an oscillatory neuronal activity, i.e. the neurons fire rhythmically. In the case of the aforementioned diseases, the mean frequency of the pathological rhythmic activity of the affected neural networks lies approximately in the range between 1 and 30 Hz, but it can also lie outside of this range. The neurons fire qualitatively differently in healthy humans, e.g. in an uncontrolled fashion. 
         [0026]    The acoustic stimulation signal  15  generated by the stimulation unit  11  is converted into nerve impulses in the inner ear and transmitted to the auditory cortex  13  via the cochlear nerve  16 . The tonotopic arrangement of the auditory cortex  13  means that a particular part of the auditory cortex  13  is activated in the case of the acoustic stimulation of the inner ear with a particular frequency. The tonotopic arrangement of the auditory cortex is described, for example, in the following articles: “Tonotopic organization of the human auditory cortex as detected by BOLD-FMRI” by D. Bilecen, K. Scheffler, N. Schmid, K. Tschopp and J. Seelig (published in Hearing Research 126, 1998, pages 19 to 27), “Representation of lateralization and tonotopy in primary versus secondary human auditory cortex” by D. R. M. Langers, W. H. Backes and P. van Dijk (published in Neurolmage 34, 2007, pages 264 to 273) and “Reorganization of auditory cortex in tinnitus” by W. Mühlnickel, T. Elbert, E. Taub and H. Flor (published in Proc. Natl. Acad. Sci. USA 95, 1998, pages 10340 to 10343). 
         [0027]    In the example as per  FIG. 1 , the acoustic stimulation signal  15  is developed such that it stimulates a neuron population in the auditory cortex  13  with a pathologically synchronous and oscillatory activity. Before the stimulation is initiated, this neuron population can at least be thought of being subdivided into various sub-populations, inter alia the sub-populations  17 ,  18 ,  19  and  20  shown in  FIG. 1 . Before the stimulation is initiated, the neurons of all sub-populations  17  to  20  for the most part fire synchronously and on average with the same pathological frequency. Due to the tonotopic organization of the auditory cortex  13 , the first sub-population  17  is stimulated by means of the first frequency f 1 , the second sub-population  18  is stimulated by means of the second frequency f 2 , the third sub-population  19  is stimulated by means of the third frequency f 3  and the fourth sub-population  20  is stimulated by means of the fourth frequency f 4 . The stimulation by the acoustic stimulation signal  15  brings about a resetting, a so-called reset, of the phase of the neuronal activity in the stimulated neurons in the respective sub-populations  17  to  20 . The reset sets the phase of the stimulated neurons to a certain phase value, e.g. 0°, independently of the current phase value. Hence the phase of the neuronal activity of the pathological sub-populations  17  to  20  is controlled by means of a targeted stimulation. 
         [0028]    The pathological neuron population can be stimulated in a targeted fashion at the different sites  17  to  20  as a result of the tonotopic arrangement of the auditory cortex  13  and the plurality of frequencies f 1  to f 4  contained in the acoustic stimulation signal  15 . This affords the possibility of resetting the phase of the neuronal activity of the pathological neuron population at different times at the different stimulation sites  17  to  20  by applying the frequencies f 1  to f 4  at different times. As a result, this subdivides the pathological neuron population, the neurons of which were previously active in a synchronous fashion and with the same frequency and phase, into the sub-populations  17  to  20 . Within each of the sub-populations  17  to  20 , the neurons are still synchronous and also on average still fire with the same pathological frequency, but each of the sub-populations  17  to  20  has the phase in respect of its neuronal activity that was imposed on it by the stimulation stimulus with the associated frequency f 1  to f 4 . 
         [0029]    Due to the pathological interaction between the neurons, the state with at least two sub-populations, which state was generated by the stimulation, is unstable and the entire neuron population quickly approaches a state of complete desynchronization, in which the neurons fire in an uncorrelated fashion. The desired state, i.e. the complete desynchronization, thus is not available immediately after the application of the acoustic stimulation signal  15  via the stimulation unit  11 , but usually sets in within a few periods or even within less than one period of the pathological activity. 
         [0030]    In the type of stimulation described above, the ultimately desired desynchronization is only made possible by the pathologically increased interaction between the neurons. Hereby, a self-organization process is utilized, which is responsible for the pathological synchronization. The same process brings about a desynchronization following a subdivision of an entire population into sub-populations with different phases. 
         [0031]    Moreover, the stimulation with the device  100  can obtain a reorganization of the connectivity of the dysfunctional neural networks and so long-lasting therapeutic effects can be brought about, which last significantly longer than the acoustic stimulation. 
         [0032]    In order to stimulate the auditory cortex  13  at different sites focally, e.g. the sites or sub-populations  17  to  20  shown in  FIG. 1 , pure tones of the associated frequencies f 1 , f 2 , f 3  and f 4  have to be dispensed. As a result of the tonotopic arrangement of the auditory cortex  13 , different parts of the brain are stimulated by the simultaneous dispensation of the associated various pure tones f 1  to f 4 , i.e. by the superposition of various sinusoidal oscillations. If the four different sites  17  to  20  are intended to be stimulated e.g. at different times, the four different frequencies f 1  to f 4  are applied at the respective times. This is shown in an exemplary fashion in  FIG. 2 . Here sinusoidal oscillations at the frequencies f 1 =1000 Hz, f 2 =800 Hz, f 3 =600 Hz and f 4 =400 Hz are applied successively and as pulses, which leads to a successive focal stimulus at the four different sites  17  to  20  in the auditory cortex  13 . The strength of the stimulus of the respective area in the auditory cortex  13  generated by the respective sinusoidal oscillation corresponds to the amplitude of the respective sinusoidal oscillation. 
         [0033]    The generation of the pulsed sinusoidal oscillations shown in  FIG. 2  is illustrated in  FIG. 3  in an exemplary fashion. There, a sinusoidal oscillation  21  is multiplied by a rectangular function  22 , which can for example assume the values 0 or 1. At the times at which the rectangular function  22  has a value of 0 the associated stimulus is switched off and while the rectangular function  22  equals  1  the stimulus is switched on. The sinusoidal oscillation  21  can be multiplied by any other function instead of the rectangular function  22 . As a result this multiplication corresponds to an amplitude modulation of the sinusoidal oscillation  21 . 
         [0034]    Alternatively, instead of the above-described sinusoidal oscillations, use can also be made of oscillating signals with a different signal form, e.g. rectangular signals oscillating with the corresponding base frequency, for generating the acoustic stimulation signal  15 . 
         [0035]    Provided that a less focal stimulation that activates relatively large parts of the auditory cortex  13  is intended to be carried out instead of a focal stimulation, frequency mixtures are applied, e.g. in a pulsed fashion, instead of individual frequencies. Using a frequency mixture bounded between a lower frequency f lower  and an upper frequency f upper  stimulates all those parts of the auditory cortex  13  that are stimulated by the frequencies between f lower  and f upper  due to the tonotopic arrangement. If, for example, four different, relatively large regions of the auditory cortex  13  are intended to be stimulated at different times, the four associated frequency mixtures with the boundaries f j   lower  and f j   upper  (j=1, 2, 3, 4) are applied at the desired times. 
         [0036]    In the exemplary embodiment, the device  100  can be operated in a so-called “open-loop” mode, in which the control unit  10  actuates the stimulation unit  11  such that the latter generates prescribed acoustic stimulation signals  15  during a defined stimulation time (e.g. over a plurality of hours). Moreover, the device  100  can also be developed to form a device  400  shown in  FIG. 4 , the latter device constituting a so-called “closed-loop” system. In addition to the components known from  FIG. 1 , the device  400  also contains a measurement unit  23 , which provides one or more measurement signals  24  recorded on the patient and transmits said signals to the control unit  10 . In a refinement of this embodiment, provision can be made for the control unit  10  to actuate the stimulation unit  11  on the basis of the measurement signals  24  recorded by the measurement unit  23 . The measurement unit  23  can involve non-invasive sensors, such as electroencephalography (EEG) electrodes, magnetoencephalography (MEG) sensors, accelerometers, electromyography (EMG) electrodes and sensors for determining blood pressure, respiration or skin resistance. Furthermore, the measurement unit  23  in the form of one or more sensors can be implanted into the body of the patient. By way of example, epicortical, intracortical or subcutaneous electrodes can be used as invasive sensors. In particular, the measurement unit  23  can be used to measure the physiological activity in the stimulated target region or in a region connected therewith. 
         [0037]    Various refinements are feasible in respect of the interaction of the control unit  10  with the measurement unit  23 . By way of example, the control unit  10  can perform a demand-driven stimulation. For this, the control unit  10  detects the presence and/or the development of one or more pathological features on the basis of the measurement signals  24  recorded by the measurement unit  23 . By way of example, the amplitude or the magnitude of the neuronal activity can be measured and compared to a predetermined threshold. The control unit  10  can be configured such that stimulation of one or more target areas in the auditory cortex is initiated as soon as the prescribed threshold is exceeded. Furthermore, parameters of the acoustic stimulation signals  15 , such as the amplitudes of the respective sinusoidal oscillations or the pauses between stimulation sequences, can be set by the control unit  10  on the basis of the development of the pathological features. By way of example, one or more thresholds can be prescribed, and if the amplitude or the magnitude of the measurement signals  24  exceeds or drops below a certain threshold, the control unit  10  varies a particular parameter of the acoustic stimulation signal  15 , such as the amplitude of one or more sinusoidal oscillations from which the acoustic stimulation signal  15  is composed. 
         [0038]    In a further refinement, provision can be made for the measurement signals  24  recorded by the measurement unit  23  to be converted directly or if need be after one or more processing steps into acoustic stimulation signals  15  and to be applied by the stimulation unit  11 . By way of example, the measurement signals  24 , amplified and if need be after mathematical combination (e.g. after mixing the measurement signals) with a time delay and linear and/or nonlinear combination steps, can be fed as control signals into the control input of the stimulation unit  11 . Herein, the combination mode is selected such that the pathological neuronal activity is counteracted and the acoustic stimulation signals  15  likewise disappear or are at least significantly reduced in strength (amplitude) as the pathological neuronal activity reduces. 
         [0039]      FIG. 5  schematically illustrates a device  500  that constitutes a development of the device  100  shown in  FIG. 1 . In the exemplary embodiment, there is no need to implant any component of the device  500 , and so the entire device  500  is located outside of the body of the patient. Moreover, in this embodiment, the device  500  does not use any signal measured by a sensor for the demand-driven variation of the stimulation. A sound generator (loudspeaker) is used as a stimulation unit  11  in the device  500 , which sound generator is surrounded by an earplug  30 . The earplug  30  is inserted into the outer auditory canal of an ear  12  of the patient and attached to the ear  12  with or without a holder or another suitable mechanical aid. The control unit  10 , which actuates the sound generator, and also a battery or a rechargeable battery for supplying the electrical components of the device  500  with current can be housed in one or more separate units  31 . The unit  31  can be connected to the earplug  30  by means of a mechanical fastener, e.g. a holder. A connection cable  32  connects the earplug  30  to the control unit  10  and the battery. 
         [0040]    Alternatively, headphones containing the control unit  10  and the battery can also be used instead of the earplug  30 . The device  500  can be switched on by the patient by means of an operating unit (e.g. switch-on button and/or control dial), which is attached either to the unit  31  or directly to the earplug  30 . The control dial can be used, for example, to set the maximum stimulation strength. In addition to the aforementioned components, the device  500  can comprise a control medium  33 , which for example is connected to the control unit  10  in a telemetric fashion (e.g. by radio waves) or by means of a connection cable. In the case of a cabled connection, plug-in connections can be used for connection and disconnection. 
         [0041]    Furthermore, the device  500  can also comprise an additional control medium (not illustrated) operable by e.g. the medical practitioner, which control medium is connected to the control unit  10  in a telemetric fashion or by means of a connection cable. In the case of a cabled connection, plug-in connections can be used for connection and disconnection. 
         [0042]    Moreover, one or more sensors, such as. EEG electrodes or an accelerometer or the like, can be provided for registering and/or documenting the stimulation success or for the examination by the medical practitioner. 
         [0043]      FIGS. 6 to 9  schematically illustrate devices  600 ,  700 ,  800  and  900  as developments of the device  400 . The devices  600  to  900  in each case comprise a measurement unit  23 , by means of which demand-driven control can be performed and/or the measurement signals  24  can be fed back into the stimulation unit  11 . In this case, the devices  600  and  700  constitute non-invasive variants, while the devices  800  and  900  are partly implanted into the body of the patient. Like the device  500 , the devices  600  to  900  comprise an earplug  30  or headphones with a sound generator. 
         [0044]    In addition to the above-described components of the device  500 , the device  600  illustrated in  FIG. 6  comprises epicutaneous, i.e. attached to the skin of the patient, EEG electrodes  34  that are connected to the control unit  10  in the unit  31  via connection cables  35 ,  36 . The control unit  10  amplifies the potential difference measured by means of the EEG electrodes  34  and uses said potential difference for actuating the sound generator in the earplug  30  after an optional linear or nonlinear combination. As an alternative to the connection cables  35 ,  36 , the EEG electrodes  34  can also be connected wirelessly, i.e. telemetrically, to the control unit  10 . The advantage of this is that the patient is not impeded by connection cables and can not be caught in obstacles, for example. 
         [0045]    The device  700  illustrated in  FIG. 7  has an accelerometer  37  as a measurement unit instead of an EEG electrode. The accelerometer  37  is attached, like a watch, to a limb of the patient that trembles due to disease. The acceleration signals recorded by the accelerometer  37  are amplified in the control unit  10  and are used for actuating the sound generator in the earplug  30  after an optional linear or nonlinear combination. The accelerometer  37  can be connected to the control unit  10  in a telemetric fashion or by means of a connection cable. 
         [0046]      FIG. 8  shows an invasive variant. In the illustrated exemplary embodiment, the device  800  comprises one or more subcutaneously implanted electrodes  38  as a measurement unit, a connection cable  39  and a transmission and reception unit  40 , which are implanted into the body of the patient under the scalp  41  and outside of the bony skull  42 . Outside of the body of the patient there is a transmission and reception unit  43 , which is connected to the unit  31  and the control unit  10  situated therein via a connection cable  44 . The measurement signals  24  recorded by the electrode  38  are transmitted to the control unit  10  via the transmission and reception units  40  and  43 , which for example are each implemented as a coil and which allow the wireless and bidirectional transmission of signals and electrical power therebetween. The potential differences measured by the electrode  38  are amplified in the control unit  10  and are used for actuating the sound generator integrated into the earplug  30  after an optional linear or nonlinear combination. 
         [0047]    A further invasive variant is illustrated schematically in  FIG. 9 . One or more epicortically implanted electrodes  45  serve as a measurement unit in the device  900  shown therein. One skilled in the art understand that “epicortical” means “situated on the cerebral cortex.” As shown in  FIG. 9 , the cerebral cortex  46 ,  47  of both hemispheres is shown schematically for illustrative purposes. The control unit  10  amplifies the potential difference measured by means of the epicortically implanted electrode  45  and uses said potential difference for actuating the sound generator in the earplug  30  after an optional linear or nonlinear combination. 
         [0048]    The epicortical electrode  45  shown in  FIG. 9  can for example also be replaced by an intracortical electrode (not illustrated). 
         [0049]    The measurement signals recorded by the differently developed measurement units  23 , i.e. the EEG-electrodes  34 , the accelerometer  37  or the electrodes  38  or  45 , can be used for feed-back control, as will be described in still more detail further below, and in one embodiment can be fed into the sound generator as actuation signals. Alternatively, demand-driven control can be carried out on the basis of the measurement signals  24 . In the case of a stimulation targeted at resetting the neuronal phases of neuron sub-populations, certain parameters of the stimulation method, such as the stimulation strength or the stimulation duration, can be set with the aid of the measurement signals  24 . This type of demand-driven control will be explained in still more detail further below in conjunction with  FIGS. 10 to 12 . 
         [0050]    The four frequencies f 1  to f 4  are intended to be used below to explain in an exemplary fashion as to how a time-offset reset of the phases of the neuronal activity of sub-populations of a pathologically synchronous and oscillatory neuron population can achieve a desynchronization of the entire neuron population. The four frequencies f 1  to f 4  should merely be understood as exemplary, and it should be understood that any other number of frequencies or frequency mixtures can be used for stimulation purposes. The frequencies f 1  to f 4  have been selected such that they in each case stimulate particular regions  17  to  20  of the auditory cortex  13 . This affords the above-described subdivision of a pathological neuron population into sub-populations  17  to  20 . In order for the sub-populations  17  to  20  to have different phases after the stimulation, the frequencies f 1  to f 4  can for example be applied with a time offset. 
         [0051]    A stimulation method that is suitable for the above-described purposes and can for example be performed by one of the devices  100  to  900  is illustrated schematically in  FIG. 10 . The upper four rows of  FIG. 10  plot, one below the other, four sinusoidal oscillations with frequencies f 1 , f 2 , f 3  and f 4  over time t. The acoustic stimulation signal  15  is formed from the illustrated sinusoidal oscillations. The four sinusoidal oscillations have been multiplied by rectangular functions for generating pulsed sinusoidal oscillations. Each sinusoidal oscillation pulse is repeated periodically with a frequency f stim . The frequency f stim =1/T stim  preferably lies in the range between 1 and 30 Hz and more particularly in the range between 5 and 20 Hz, but it can also assume smaller or greater values as should be understood to one skilled in the art. Such sequences of pulsed sinusoidal oscillations are suitable for resetting the neuronal phase of the respectively stimulated pathological neuron sub-population  17 ,  18 ,  19  or  20  if said oscillations are applied as acoustic stimulation signals  15 . Here the phase reset does not necessarily already result after one or a few pulses, but a certain number of the sinusoidal oscillation pulses shown in  FIG. 10  may be required to reset the neuronal phase of the respective sub-population  17 ,  18 ,  19  or  20 . 
         [0052]    By way of example, the frequency f stim  can lie in the vicinity of the mean frequency of the pathologically rhythmic activity of the target network. In the case of neurological and psychiatric diseases, the mean frequency typically lies in the range between 1 and 30 Hz, but it can also lie outside of this range as noted above. In the case of tinnitus, there is overly synchronous neuronal activity in, for example, the frequency range between 1.5 and 4 Hz. It should be noted herein that the frequency at which the pathological neurons fire synchronously is usually not constant, but can by all means have variations and moreover has individual deviations in each patient. 
         [0053]    The mean peak frequency of the pathological rhythmic activity of the patient can for example be determined in order to calculate the frequency f stim . This peak frequency can then be used as stimulation frequency f stim , or else be varied, for example in a range between f stim −3 Hz and f stim +3 Hz. However, alternatively it is also possible for a frequency f stim  to be selected in the range between 1 and 30 Hz without a preceding measurement and this frequency can for example be varied during the stimulation until the frequency f stim  is found, by means of which the best stimulation successes can be obtained. As a further alternative, a known value found in the literature for the respective disease can be used for the stimulation frequency f stim . If need be, this value can still be varied until for example optimum stimulation results are obtained. 
         [0054]    The duration of a sinusoidal oscillation pulse, i.e. the period of time during which the rectangular function assumes a value of 1 in the present refinement, can for example be T stim /2. In this case, the period of time during which the respective frequency contributes to the stimulation and the subsequent stimulation pause have the same length. However, other stimulation durations can also be selected, for example in the range between T stim /2−T stim /10 and T stim /2+T stim /10. Other stimulation times are also possible, for example, the stimulation duration is T stim /4 in the stimulations shown in  FIGS. 11 and 12 . The stimulation durations can for example be determined experimentally. 
         [0055]    According to the refinement shown in  FIG. 10 , the individual frequencies f 1  to f 4  are dispensed with a time delay between the individual frequencies f 1  to f 4 . By way of example, the beginning of temporally successive pulses having different frequencies can be offset by a time τ. 
         [0056]    In the case where N frequencies are used for the stimulation, the time delay τ between two respectively successive pulses can for example lie in the vicinity of an N-th of the period T stim =1/f stim . In the exemplary embodiment (N=4) shown in  FIG. 10 , the time delay τ correspondingly is T stim /4. In one embodiment, there can be a certain amount of deviation from the specification that the time delay τ between two respectively successive sinusoidal oscillation pulses is T stim /N. By way of example, there can be a deviation of up to ±10%, ±20% or ±30% from the value T stim /N for the time delay τ. Stimulation successes were still obtained in the case of such a deviation, i.e. a desynchronizing effect could still be observed. 
         [0057]    In the exemplary embodiment, the acoustic stimulation signal  15  is formed by superposition of the periodic sinusoidal oscillation pulses with the frequencies f 1  to f 4 . The individual sinusoidal oscillation pulses can in this case for example be combined in a linear or nonlinear fashion. This means that the sinusoidal oscillations with the individual frequencies f 1  to f 4  need not necessarily be combined with the same amplitudes in order to form the acoustic stimulation signal  15 . The frequency spectrum of the acoustic stimulation signal  15  at four different times t 1 , t 2 , t 3  and t 4  is illustrated in the bottom row of  FIG. 10  in an exemplary fashion. The frequency spectra illustrated there, more particularly the height and shape of the frequency peaks, should be understood to be merely exemplary and can also have completely different shapes. In detail, the following statements can be gathered from the illustrated frequency spectra: Only the frequency f 1  occurs in the acoustic stimulation signal  15  at the time t 1 . At the time t 2 , these are the frequencies f 3  and f 4 ; at the time t 3 , these are the frequencies f 2  to f 4 ; and at the time t 4 , these are the frequencies f 2  and f 3 . 
         [0058]    According to an alternative refinement, four frequency mixtures with the boundaries f j   lower  and f j   upper  (j=1, 2, 3, 4) are used instead of the frequencies f 1  to f 4 . There can be any number of frequencies in the range between f j   lower  and f j   upper  in a frequency mixture j. 
         [0059]    According to a further alternative refinement, other functions are used instead of the rectangular functions in order to modulate the amplitude of the sinusoidal oscillations, e.g. sinusoidal half-waves with frequencies lower than f 1  to f 4 . By way of example, it is furthermore feasible for triangular pulses to be used as modulation functions. Such a pulse can have a jump-like onset (from 0 to 1) and thereafter decrease to 0, wherein the decrease can for example be given by a linear or exponential function. The modulation function ultimately determines the shape of the envelope of the individual pulses. 
         [0060]      FIG. 11  illustrates the stimulation shown previously in  FIG. 10  over a relatively long period of time. The individual sinusoidal oscillations, with the frequencies f 1 =1000 Hz, f 2 =800 Hz, f 3 =600 Hz and f 4 =400 Hz, have not been shown in  FIG. 11 , but only the respective rectangular envelopes. Furthermore,  FIG. 11  illustrates a measurement signal  24  recorded by the measurement unit  23  for example, which measurement signal reproduces the neuronal activity in the auditory cortex before and during the stimulation. In the present case, the period T stim  is 1/(3.5 Hz)=0.29 s. 
         [0061]    As shown in this example, the stimulation is started at the time t start . It can be gathered from the measurement signal  24 , which has been band-pass filtered in the present example, that the neurons in the auditory cortex have a synchronous and oscillatory activity before the start of the stimulation. The pathologically synchronous neuronal activity in the target area has already been suppressed shortly after the start of the stimulation. 
         [0062]    There can be various deviations from the strictly periodic stimulation pattern shown in  FIGS. 10 and 11 . By way of example, the time delay τ between two successive sinusoidal oscillation pulses need not necessarily always be of the same magnitude. It should be understood that provision can be made for the time separations between the individual sinusoidal oscillation pulses to be selected such that they differ. Furthermore, the delay times can also be varied during the treatment of a patient. The delay times can also be adjusted in respect of the physiological signal run times. 
         [0063]    Furthermore, in one refinement of the exemplary embodiment, pauses can be provided during the application of the acoustic stimulation signal  15 , during which pauses there is no stimulation. The pauses can be selected to have any duration and more particularly are an integer multiple of the period T stim . The pauses can be held after any number of stimulations. By way of example, a stimulation can be performed over N successive periods of length T stim , and there can subsequently be a stimulation pause over M periods of length T stim , wherein N and M are small whole numbers, for example in the range between 1 and 15. This scheme can be either continued periodically or modified stochastically and/or deterministically, for example, chaotically. 
         [0064]      FIG. 12  shows such a stimulation. Here N=2 and M=1 hold true. Otherwise the stimulation corresponds to the stimulation shown in  FIG. 11 . 
         [0065]    In one refinement, a further option for deviating from the strictly periodic stimulation pattern shown in  FIG. 10  consists of stochastic or deterministic or mixed stochastic-deterministic variation of the time separations between successive pulses with a frequency f j  or a frequency mixture with the boundaries f j   lower  and f j   upper  (j=1, 2, 3, 4). 
         [0066]    Additionally, the order in which the involved frequencies f j  or frequency mixtures with the boundaries f j   lower  and f j   upper  are applied can be varied during each period T stim  (or during other time steps). Preferably, this variation can be stochastic or deterministic or mixed stochastic-deterministic. 
         [0067]    Furthermore, it is possible for only a certain number of the frequencies f j  or frequency mixtures with the boundaries f j   lower  and f j   upper  to be applied in each period T stim  (or another time interval) and the frequencies f j  or frequency mixtures with the boundaries f j   lower  and f j   upper  involved, in the stimulation can be varied during each time interval. This variation can also be stochastic or deterministic or mixed stochastic-deterministic. 
         [0068]    The above-described stimulation signals bring about a reset at different times in the phase of the neuronal activity of the pathological neuron population at the different stimulation sites. This splits the pathological neuron population, the neurons of which were previously active in a synchronous fashion and with the same frequency and phase, into a plurality of sub-populations, which ultimately leads to a desynchronization. 
         [0069]    In one embodiment, all stimulation forms described above can also be performed in a “closed-loop” mode. Resetting the phases of the individual sub-populations can for example be linked to a demand-driven control. By way of example, a threshold can be prescribed and if the amplitude of the measurement signal  24  exceeds or drops below the threshold the stimulation can be started or interrupted. Furthermore, certain stimulation parameters, such as the amplitude/strength of the stimulation signals or the duration of the stimulation, can be set on the basis of the amplitude of the measurement signal  24 , which can for example be recorded during stimulation pauses. Moreover, it is possible for the frequency f stim  to be set or readjusted on the basis of the mean frequency of the (possibly band-pass filtered) measurement signal  24 . 
         [0070]    Moreover, it is feasible for the stimulation to be started by the patient, for example by means of a telemetric activation. In this case, the patient can activate the stimulation for a prescribed period of time (e.g., 5 minutes) or the patient can independently start and stop the stimulation. 
         [0071]    Herein below, further refinements of the “closed-loop” stimulation are described, which can for example be performed by means of the device  400  shown in  FIG. 4  or one of the exemplary devices  600  to  900 . As already described previously, the measurement signal  24  recorded by the measurement unit  23  can be used to generate a control signal  14 , by means of which the stimulation unit  11  is actuated. Here, the measurement signal  24  can be converted directly or if need be after one or more processing steps into the acoustic stimulation signal  15  and can be applied by the stimulation unit  11 . Herein, the combination mode can be selected such that the pathological neuronal activity is counteracted and the acoustic stimulation signal  15  likewise disappears or is at least significantly reduced in its strength as the pathological neuronal activity reduces. 
         [0072]    In one embodiment, before the measurement signal  24  is fed into the control input of the stimulation unit  11 , the measurement signal  24  can be processed in a linear or nonlinear fashion. By way of example, the measurement signal  24  can be filtered and/or amplified and/or acted upon with a time delay and/or mixed with another measurement signal  24 . Furthermore, the measurement signal  24  or the processed measurement signal  24  can modulate the amplitude of a sinusoidal oscillation with a frequency in the audible range and the amplitude-modulated sinusoidal oscillation can thereafter be applied as an acoustic stimulation signal  15  or part thereof by means of the sound generator. 
         [0073]    It should be noted that it is not necessary for the entire measurement signal  24  to be used for modulating the amplitude of a sinusoidal oscillation or another oscillating oscillation. By way of example, provision can be made for only part of the measurement signal  24  or the processed measurement signal  24  to be used for this, for example, the part lying above or below a particular threshold. Such an amplitude modulation is illustrated in  FIG. 13  in an exemplary fashion. The uppermost graph in  FIG. 13  plots the band-pass filtered measurement signal  24  over time t; furthermore, the start time t start  of the stimulation is specified. The middle graph illustrates the modulation signal  50  obtained from the measurement signal  24 . The measurement signal  24  has been processed in a nonlinear fashion and all negative values of the measurement signal  24  or the processed measurement signal  24  have been set to zero in order to generate the modulation signal  50 . Furthermore, the modulation signal  50  has a time delay compared to the measurement signal  24 . The half-wave signal  50  obtained in this fashion has subsequently been multiplied with a sinusoidal oscillation at a frequency of f 1 =1000 Hz. The modulation signal  50  constitutes the envelope of the sinusoidal oscillation, as shown in the lowermost graph of  FIG. 13  for a small time interval. The amplitude-modulated sinusoidal oscillation obtained thereby has subsequently been coupled back into the stimulation unit  11  in order to be converted into the acoustic stimulation signal  15  by the sound generator. 
         [0074]    Instead of a sinusoidal oscillation with a single frequency, the modulation signal  50  can also be multiplied by any mixture of sinusoidal oscillations (or other oscillations) in the audible frequency range depending on in which sites in the auditory cortex the desynchronization should be brought about. 
         [0075]    It can be read out from the profile of the measurement signal  24  illustrated in  FIG. 13  that the acoustic nonlinear time-delayed half-wave stimulation leads to a robust suppression of the pathologically synchronous neuronal activity. However, the mechanism of action of this stimulation differs from the mode of operation of the stimulation method shown in e.g.  FIG. 10 . In the stimulation illustrated in  FIG. 13 , it is not the phase of the neuronal activity in the respectively stimulated sub-populations that is reset, but the synchronization in the pathologically active neuron population is suppressed by influencing the saturation process of the synchronization. 
         [0076]    The following text explains with the aid of an example how a measurement signal  24  obtained by the measurement unit  20  can be subjected to nonlinear processing before it is used as an actuation signal for the stimulation unit  11 . 
         [0077]    The start point is an equation for the actuation signal S(t): 
         [0000]        S ( t )= K·  Z     2 ( t )·   Z   *( t− τ).   (1)
 
         [0078]    In equation (1), K is an amplification factor that can be selected in a suitable fashion and  Z (t) is an average state variable of the measurement signal  24 .  Z (t) is a complex variable and can be represented as follows: 
         [0000]          Z   ( t )= X ( t )+ iY ( t ).   (2)
 
         [0000]    wherein X(t) can correspond to e.g. the neurological measurement signal  24 . Since the considered frequencies lie in the vicinity of 10 Hz= 1/100 ms=1/T α , the imaginary part Y(t) can be approximated by X(t−τ α ), wherein for example T=T α /4 holds true. This results in: 
         [0000]        S ( t )= K·[X ( t )+ iX ( t−τ   α )] 2   ·[X ( t−τ )− iX ( t−τ−τ   α )].   (3)
 
         [0079]    Equation (3) can be rewritten as follows: 
         [0000]    
       
         
           
             
               
                 
                   
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         [0080]    The real part of equation (4) is used as the actuation signal for the stimulation unit  11 : 
         [0000]      real[ S ( t )]= K·[X ( t ) 2   ·X ( t− τ)− X ( t−τ   α )· X ( t− τ)+2 X ( t )· X ( t−τ   α )· X ( t−τ−τ   a )]  (5)
 
         [0081]    The auditory cortex can furthermore be stimulated at different sites in a targeted fashion by using the fed-back and possibly further-processed measurement signal  24 . In the case of the above-described four different frequencies f 1  to f 4 , the possibly further-processed measurement signal  24  is acted upon by an appropriate time delay and multiplied by the frequencies f 1  to f 4 . Provided that the stimulation is intended to be less focal and over a larger area, four different frequency mixtures with the boundaries f j   lower  and f j   upper =1, 2, 3, 4) are used instead of the pure sinusoidal oscillations at the frequencies f 1  to f 4 . 
         [0082]      FIG. 14  illustrates such a stimulation in an exemplary fashion. The modulation signals  51 ,  52 ,  53  and  54  have been obtained here from the band-pass filtered measurement signal  24  by means of linear processing steps, by means of which modulation signals the amplitude of frequencies f 1  to f 4  has been modulated. The control signal  14  has been generated by the superposition of the modulated sinusoidal oscillations, which control signal has been converted into the acoustic stimulation signal  15  by the sound generator  11 . 
         [0083]    Herein below,  FIGS. 15A and 15B  are used to explain in an exemplary fashion how the modulation signals  51  to  54  can be obtained from the measurement signal  24 . For this, a delay time τ is first of all fixed, which has been set to be τ=T stim /2 in the present example (other values, such as τ=T stim  or τ=3T stim /2, are likewise possible). By way of example, the frequency f stim =1/T stim  can lie in the vicinity of the mean frequency of the measurement signal  24 , e.g. in the range between 1 and 30 Hz, more particularly in the range between 5 and 20 Hz. Particular delay times τ 1 , τ 2 , τ 3  and τ 4  can be calculated for each of the modulation signals  51  to  54  with the aid of the delay time i, for example with the aid of the following equation: 
         [0000]    
       
         
           
             
               
                 
                   
                     
                       τ 
                       j 
                     
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         [0084]    By way of example, the modulation signals  51  to  54  can be obtained from the measurement signal  24  by the measurement signal  24  in each case being delayed by the delay times τ 1 , τ 2 , τ 3  and τ 4 : 
         [0000]        S   j ( t )= K·Z ( t−τ   j )   (7)
 
         [0085]    In equation (7), S 1 (t), S 2 (t), S 3 (t) and S 4 (t) represent the modulation signals  51  to  54  and Z(t) represents the measurement signal  24 . K is an amplification factor, which can be selected in a suitable fashion. Furthermore, all negative values (or all values above or below a particular threshold) of the modulation signals S 1 (t) to S 4 (t) can be set to zero. 
         [0086]    According to one refinement illustrated in  FIGS. 15A and 15B , the modulation signals S 1 (t) to S 4 (t) are calculated from only the delay times τ 1  and τ 2 , wherein the modulation signals S 1 (t) and S 2 (t), and S 3 (t) and S 4 (t) in each case have different polarities: 
         [0000]        S   1 ( t )= K·Z ( t−τ   1 )   (8)
 
         [0000]        S   2 ( t )= K·Z ( t−τ   1 )   (9)
 
         [0000]        S   3 ( t )= K·Z ( t−τ   2 )   (10)
 
         [0000]        S   4 ( t )= K·Z ( t−τ   2 ).   (11)
 
         [0087]    In  FIGS. 15A and 15B  the modulation signals S 1 (t) and S 3 (t) have been displaced upward by a value of 0.5 and the modulation signals S 2 (t) and S 4 (t) have been displaced downward by a value of 0.5 for the purpose of a clearer illustration. 
         [0088]    As shown in  FIG. 15B , all negative values (or all values above or below a certain threshold) of the modulation signals S 1 (t) to S 4 (t) can be set to zero. The generation of the modulation signals  51  to  54  shown in  FIG. 14  corresponds to the generation of the modulation signals S 1 (t) to S 4 (t) shown in  FIGS. 15A and 15B . While the foregoing has been described in conjunction with exemplary embodiments, it is understood that the term “exemplary” is merely meant as an example, rather than the best or optimal. Accordingly, the application is intended to cover alternatives, modifications and equivalents, which may be included within the spirit and scope of the disclosure herein. 
         [0089]    Additionally, in the preceding detailed description, numerous specific details have been set forth in order to provide a thorough understanding of the present application. However, it should be apparent to one of ordinary skill in the art that the present device and method disclosed herein may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail so as not to unnecessarily obscure aspects of the present application.

Technology Classification (CPC): 0