Device and method for auditory stimulation

A device and method for desynchronizing a patient'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.

BACKGROUND

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

The present application is directed to a device and method for desynchronizing a patient'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.

In another aspect of the present application, a device is provided for desynchronizing a patient'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.

In further aspect of the present application, a method is provided for desynchronizing a patient'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.

In yet a further aspect of the application, a method is provided for desynchronizing a patient'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.

DETAILED DESCRIPTION

FIG. 1illustrates in a schematic fashion a device100, which consists of a control unit10and a stimulation unit11connected to the control unit10.FIG. 1furthermore illustrates an ear12of a patient and the auditory cortex13in the brain of the patient in a schematic fashion.

The stimulation unit11is actuated by the control unit10by means of one or more control signals14during the operation of the device100, and the stimulation unit11generates one or more acoustic stimulation signals15with the aid of the control signal14. The frequency spectrum of the acoustic stimulation signal15may lie completely or partly in the range audible to a human. The acoustic stimulation signal15is taken in by the patient by one or both ears12and is transmitted to neuron populations in the brain via the cochlear nerve or nerves16. The acoustic stimulation signal15is developed such that it stimulates neuron populations in the auditory cortex13. At least a first frequency f1and a second frequency f2are present in the frequency spectrum of the acoustic stimulation signal15. The acoustic stimulation signal15can furthermore contain additional frequencies or frequency mixtures; in the exemplary embodiment shown inFIG. 2, these are a third frequency f3and a fourth frequency f4.

The device100can 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.

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.

The acoustic stimulation signal15generated by the stimulation unit11is converted into nerve impulses in the inner ear and transmitted to the auditory cortex13via the cochlear nerve16. The tonotopic arrangement of the auditory cortex13means that a particular part of the auditory cortex13is 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 NeuroImage 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).

In the example as perFIG. 1, the acoustic stimulation signal15is developed such that it stimulates a neuron population in the auditory cortex13with 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-populations17,18,19and20shown inFIG. 1. Before the stimulation is initiated, the neurons of all sub-populations17to20for the most part fire synchronously and on average with the same pathological frequency. Due to the tonotopic organization of the auditory cortex13, the first sub-population17is stimulated by means of the first frequency f1, the second sub-population18is stimulated by means of the second frequency f2, the third sub-population19is stimulated by means of the third frequency f3and the fourth sub-population20is stimulated by means of the fourth frequency f4. The stimulation by the acoustic stimulation signal15brings about a resetting, a so-called reset, of the phase of the neuronal activity in the stimulated neurons in the respective sub-populations17to20. 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-populations17to20is controlled by means of a targeted stimulation.

The pathological neuron population can be stimulated in a targeted fashion at the different sites17to20as a result of the tonotopic arrangement of the auditory cortex13and the plurality of frequencies f1to f4contained in the acoustic stimulation signal15. This affords the possibility of resetting the phase of the neuronal activity of the pathological neuron population at different times at the different stimulation sites17to20by applying the frequencies f1to f4at 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-populations17to20. Within each of the sub-populations17to20, the neurons are still synchronous and also on average still fire with the same pathological frequency, but each of the sub-populations17to20has the phase in respect of its neuronal activity that was imposed on it by the stimulation stimulus with the associated frequency f1to f4.

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 signal15via the stimulation unit11, but usually sets in within a few periods or even within less than one period of the pathological activity.

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.

Moreover, the stimulation with the device100can 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.

In order to stimulate the auditory cortex13at different sites focally, e.g. the sites or sub-populations17to20shown inFIG. 1, pure tones of the associated frequencies f1, f2, f3and f4have to be dispensed. As a result of the tonotopic arrangement of the auditory cortex13, different parts of the brain are stimulated by the simultaneous dispensation of the associated various pure tones f1to f4, i.e. by the superposition of various sinusoidal oscillations. If the four different sites17to20are intended to be stimulated e.g. at different times, the four different frequencies f1to f4are applied at the respective times. This is shown in an exemplary fashion inFIG. 2. Here sinusoidal oscillations at the frequencies f1=1000 Hz, f2=800 Hz, f3=600 Hz and f4=400 Hz are applied successively and as pulses, which leads to a successive focal stimulus at the four different sites17to20in the auditory cortex13. The strength of the stimulus of the respective area in the auditory cortex13generated by the respective sinusoidal oscillation corresponds to the amplitude of the respective sinusoidal oscillation.

The generation of the pulsed sinusoidal oscillations shown inFIG. 2is illustrated inFIG. 3in an exemplary fashion. There, a sinusoidal oscillation21is multiplied by a rectangular function22, which can for example assume the values 0 or 1. At the times at which the rectangular function22has a value of 0 the associated stimulus is switched off and while the rectangular function22equals 1 the stimulus is switched on. The sinusoidal oscillation21can be multiplied by any other function instead of the rectangular function22. As a result this multiplication corresponds to an amplitude modulation of the sinusoidal oscillation21.

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 signal15.

Provided that a less focal stimulation that activates relatively large parts of the auditory cortex13is 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 flowerand an upper frequency fupperstimulates all those parts of the auditory cortex13that are stimulated by the frequencies between flowerand fupperdue to the tonotopic arrangement. If, for example, four different, relatively large regions of the auditory cortex13are intended to be stimulated at different times, the four associated frequency mixtures with the boundaries fjlowerand fjupper(j=1, 2, 3, 4) are applied at the desired times.

In the exemplary embodiment, the device100can be operated in a so-called “open-loop” mode, in which the control unit10actuates the stimulation unit11such that the latter generates prescribed acoustic stimulation signals15during a defined stimulation time (e.g. over a plurality of hours). Moreover, the device100can also be developed to form a device400shown inFIG. 4, the latter device constituting a so-called “closed-loop” system. In addition to the components known fromFIG. 1, the device400also contains a measurement unit23, which provides one or more measurement signals24recorded on the patient and transmits said signals to the control unit10. In a refinement of this embodiment, provision can be made for the control unit10to actuate the stimulation unit11on the basis of the measurement signals24recorded by the measurement unit23. The measurement unit23can 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 unit23in 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 unit23can be used to measure the physiological activity in the stimulated target region or in a region connected therewith.

Various refinements are feasible in respect of the interaction of the control unit10with the measurement unit23. By way of example, the control unit10can perform a demand-driven stimulation. For this, the control unit10detects the presence and/or the development of one or more pathological features on the basis of the measurement signals24recorded by the measurement unit23. By way of example, the amplitude or the magnitude of the neuronal activity can be measured and compared to a predetermined threshold. The control unit10can 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 signals15, such as the amplitudes of the respective sinusoidal oscillations or the pauses between stimulation sequences, can be set by the control unit10on 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 signals24exceeds or drops below a certain threshold, the control unit10varies a particular parameter of the acoustic stimulation signal15, such as the amplitude of one or more sinusoidal oscillations from which the acoustic stimulation signal15is composed.

In a further refinement, provision can be made for the measurement signals24recorded by the measurement unit23to be converted directly or if need be after one or more processing steps into acoustic stimulation signals15and to be applied by the stimulation unit11. By way of example, the measurement signals24, 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 unit11. Herein, the combination mode is selected such that the pathological neuronal activity is counteracted and the acoustic stimulation signals15likewise disappear or are at least significantly reduced in strength (amplitude) as the pathological neuronal activity reduces.

FIG. 5schematically illustrates a device500that constitutes a development of the device100shown inFIG. 1. In the exemplary embodiment, there is no need to implant any component of the device500, and so the entire device500is located outside of the body of the patient. Moreover, in this embodiment, the device500does 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 unit11in the device500, which sound generator is surrounded by an earplug30. The earplug30is inserted into the outer auditory canal of an ear12of the patient and attached to the ear12with or without a holder or another suitable mechanical aid. The control unit10, which actuates the sound generator, and also a battery or a rechargeable battery for supplying the electrical components of the device500with current can be housed in one or more separate units31. The unit31can be connected to the earplug30by means of a mechanical fastener, e.g. a holder. A connection cable32connects the earplug30to the control unit10and the battery.

Alternatively, headphones containing the control unit10and the battery can also be used instead of the earplug30. The device500can 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 unit31or directly to the earplug30. The control dial can be used, for example, to set the maximum stimulation strength. In addition to the aforementioned components, the device500can comprise a control medium33, which for example is connected to the control unit10in 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.

Furthermore, the device500can also comprise an additional control medium (not illustrated) operable by e.g. the medical practitioner, which control medium is connected to the control unit10in 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.

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.

FIGS. 6 to 9schematically illustrate devices600,700,800and900as developments of the device400. The devices600to900in each case comprise a measurement unit23, by means of which demand-driven control can be performed and/or the measurement signals24can be fed back into the stimulation unit11. In this case, the devices600and700constitute non-invasive variants, while the devices800and900are partly implanted into the body of the patient. Like the device500, the devices600to900comprise an earplug30or headphones with a sound generator.

In addition to the above-described components of the device500, the device600illustrated inFIG. 6comprises epicutaneous, i.e. attached to the skin of the patient, EEG electrodes34that are connected to the control unit10in the unit31via connection cables35,36. The control unit10amplifies the potential difference measured by means of the EEG electrodes34and uses said potential difference for actuating the sound generator in the earplug30after an optional linear or nonlinear combination. As an alternative to the connection cables35,36, the EEG electrodes34can also be connected wirelessly, i.e. telemetrically, to the control unit10. The advantage of this is that the patient is not impeded by connection cables and can not be caught in obstacles, for example.

The device700illustrated inFIG. 7has an accelerometer37as a measurement unit instead of an EEG electrode. The accelerometer37is attached, like a watch, to a limb of the patient that trembles due to disease. The acceleration signals recorded by the accelerometer37are amplified in the control unit10and are used for actuating the sound generator in the earplug30after an optional linear or nonlinear combination. The accelerometer37can be connected to the control unit10in a telemetric fashion or by means of a connection cable.

FIG. 8shows an invasive variant. In the illustrated exemplary embodiment, the device800comprises one or more subcutaneously implanted electrodes38as a measurement unit, a connection cable39and a transmission and reception unit40, which are implanted into the body of the patient under the scalp41and outside of the bony skull42. Outside of the body of the patient there is a transmission and reception unit43, which is connected to the unit31and the control unit10situated therein via a connection cable44. The measurement signals24recorded by the electrode38are transmitted to the control unit10via the transmission and reception units40and43, 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 electrode38are amplified in the control unit10and are used for actuating the sound generator integrated into the earplug30after an optional linear or nonlinear combination.

A further invasive variant is illustrated schematically inFIG. 9. One or more epicortically implanted electrodes45serve as a measurement unit in the device900shown therein. One skilled in the art understand that “epicortical” means “situated on the cerebral cortex.” As shown inFIG. 9, the cerebral cortex46,47of both hemispheres is shown schematically for illustrative purposes. The control unit10amplifies the potential difference measured by means of the epicortically implanted electrode45and uses said potential difference for actuating the sound generator in the earplug30after an optional linear or nonlinear combination.

The epicortical electrode45shown inFIG. 9can for example also be replaced by an intracortical electrode (not illustrated).

The measurement signals recorded by the differently developed measurement units23, i.e. the EEG-electrodes34, the accelerometer37or the electrodes38or45, 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 signals24. 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 signals24. This type of demand-driven control will be explained in still more detail further below in conjunction withFIGS. 10 to 12.

The four frequencies f1to f4are 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 f1to f4should 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 f1to f4have been selected such that they in each case stimulate particular regions17to20of the auditory cortex13. This affords the above-described subdivision of a pathological neuron population into sub-populations17to20. In order for the sub-populations17to20to have different phases after the stimulation, the frequencies f1to f4can for example be applied with a time offset.

A stimulation method that is suitable for the above-described purposes and can for example be performed by one of the devices100to900is illustrated schematically inFIG. 10. The upper four rows ofFIG. 10plot, one below the other, four sinusoidal oscillations with frequencies f1, f2, f3and f4over time t. The acoustic stimulation signal15is 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 fstim. The frequency fstim=1/Tstimpreferably 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-population17,18,19or20if said oscillations are applied as acoustic stimulation signals15. 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 inFIG. 10may be required to reset the neuronal phase of the respective sub-population17,18,19or20.

By way of example, the frequency fstimcan 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.

The mean peak frequency of the pathological rhythmic activity of the patient can for example be determined in order to calculate the frequency fstim. This peak frequency can then be used as stimulation frequency fstim, or else be varied, for example in a range between fstim−3 Hz and fstim+3 Hz. However, alternatively it is also possible for a frequency fstimto 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 fstimis 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 fstim. If need be, this value can still be varied until for example optimum stimulation results are obtained.

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 Tstim/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 Tstim/2−Tstim/10 and Tstim/2+Tstim/10. Other stimulation times are also possible, for example, the stimulation duration is Tstim/4 in the stimulations shown inFIGS. 11 and 12. The stimulation durations can for example be determined experimentally.

According to the refinement shown inFIG. 10, the individual frequencies f1to f4are dispensed with a time delay between the individual frequencies f1to f4. By way of example, the beginning of temporally successive pulses having different frequencies can be offset by a time τ.

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 Tstim=1/fstim. In the exemplary embodiment (N=4) shown inFIG. 10, the time delay τ correspondingly is Tstim/4. In one embodiment, there can be a certain amount of deviation from the specification that the time delay τbetween two respectively successive sinusoidal oscillation pulses is Tstim/N. By way of example, there can be a deviation of up to ±10%, ±20% or ±30% from the value Tstim/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.

In the exemplary embodiment, the acoustic stimulation signal15is formed by superposition of the periodic sinusoidal oscillation pulses with the frequencies f1to f4. 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 f1to f4need not necessarily be combined with the same amplitudes in order to form the acoustic stimulation signal15. The frequency spectrum of the acoustic stimulation signal15at four different times t1, t2, t3and t4is illustrated in the bottom row ofFIG. 10in 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 f1occurs in the acoustic stimulation signal15at the time t1. At the time t2, these are the frequencies f3and f4; at the time t3, these are the frequencies f2to f4; and at the time t4, these are the frequencies f2and f3.

According to an alternative refinement, four frequency mixtures with the boundaries fjlowerand fjupper(j=1, 2, 3, 4) are used instead of the frequencies f1to f4. There can be any number of frequencies in the range between fjlowerand fjupperin a frequency mixture j.

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 f1to f4. 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.

FIG. 11illustrates the stimulation shown previously inFIG. 10over a relatively long period of time. The individual sinusoidal oscillations, with the frequencies f1=1000 Hz, f2=800 Hz, f3=600 Hz and f4=400 Hz, have not been shown inFIG. 11, but only the respective rectangular envelopes. Furthermore,FIG. 11illustrates a measurement signal24recorded by the measurement unit23for example, which measurement signal reproduces the neuronal activity in the auditory cortex before and during the stimulation. In the present case, the period Tstimis 1/(3.5 Hz)=0.29 s.

As shown in this example, the stimulation is started at the time tstart. It can be gathered from the measurement signal24, 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.

There can be various deviations from the strictly periodic stimulation pattern shown inFIGS. 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.

Furthermore, in one refinement of the exemplary embodiment, pauses can be provided during the application of the acoustic stimulation signal15, 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 Tstim. 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 Tstim, and there can subsequently be a stimulation pause over M periods of length Tstim, 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.

FIG. 12shows such a stimulation. Here N=2 and M=1 hold true. Otherwise the stimulation corresponds to the stimulation shown inFIG. 11.

In one refinement, a further option for deviating from the strictly periodic stimulation pattern shown inFIG. 10consists of stochastic or deterministic or mixed stochastic-deterministic variation of the time separations between successive pulses with a frequency fjor a frequency mixture with the boundaries fjlowerand fjupper(j=1, 2, 3, 4).

Additionally, the order in which the involved frequencies fjor frequency mixtures with the boundaries fjlowerand fjupperare applied can be varied during each period Tstim(or during other time steps). Preferably, this variation can be stochastic or deterministic or mixed stochastic-deterministic.

Furthermore, it is possible for only a certain number of the frequencies fjor frequency mixtures with the boundaries fjlowerand fjupperto be applied in each period Tstim, (or another time interval) and the frequencies fjor frequency mixtures with the boundaries fjlowerand fjupperinvolved in the stimulation can be varied during each time interval. This variation can also be stochastic or deterministic or mixed stochastic-deterministic.

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.

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 signal24exceeds 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 signal24, which can for example be recorded during stimulation pauses. Moreover, it is possible for the frequency fstimto be set or readjusted on the basis of the mean frequency of the (possibly band-pass filtered) measurement signal24.

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.

Herein below, further refinements of the “closed-loop” stimulation are described, which can for example be performed by means of the device400shown inFIG. 4or one of the exemplary devices600to900. As already described previously, the measurement signal24recorded by the measurement unit23can be used to generate a control signal14, by means of which the stimulation unit11is actuated. Here, the measurement signal24can be converted directly or if need be after one or more processing steps into the acoustic stimulation signal15and can be applied by the stimulation unit11. Herein, the combination mode can be selected such that the pathological neuronal activity is counteracted and the acoustic stimulation signal15likewise disappears or is at least significantly reduced in its strength as the pathological neuronal activity reduces.

In one embodiment, before the measurement signal24is fed into the control input of the stimulation unit11, the measurement signal24can be processed in a linear or nonlinear fashion. By way of example, the measurement signal24can be filtered and/or amplified and/or acted upon with a time delay and/or mixed with another measurement signal24. Furthermore, the measurement signal24or the processed measurement signal24can 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 signal15or part thereof by means of the sound generator.

It should be noted that it is not necessary for the entire measurement signal24to 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 signal24or the processed measurement signal24to be used for this, for example, the part lying above or below a particular threshold. Such an amplitude modulation is illustrated inFIG. 13in an exemplary fashion. The uppermost graph inFIG. 13plots the band-pass filtered measurement signal24over time t; furthermore, the start time tstartof the stimulation is specified. The middle graph illustrates the modulation signal50obtained from the measurement signal24. The measurement signal24has been processed in a nonlinear fashion and all negative values of the measurement signal24or the processed measurement signal24have been set to zero in order to generate the modulation signal50. Furthermore, the modulation signal50has a time delay compared to the measurement signal24. The half-wave signal50obtained in this fashion has subsequently been multiplied with a sinusoidal oscillation at a frequency of f1=1000 Hz. The modulation signal50constitutes the envelope of the sinusoidal oscillation, as shown in the lowermost graph ofFIG. 13for a small time interval. The amplitude-modulated sinusoidal oscillation obtained thereby has subsequently been coupled back into the stimulation unit11in order to be converted into the acoustic stimulation signal15by the sound generator.

Instead of a sinusoidal oscillation with a single frequency, the modulation signal50can 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.

It can be read out from the profile of the measurement signal24illustrated inFIG. 13that 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 inFIG. 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.

The following text explains with the aid of an example how a measurement signal24obtained by the measurement unit20can be subjected to nonlinear processing before it is used as an actuation signal for the stimulation unit11.

The start point is an equation for the actuation signal S(t):
S(t)=K·Z2(t)·Z*(t−τ).  (1)

In equation (1), K is an amplification factor that can be selected in a suitable fashion andZ(t) is an average state variable of the measurement signal24.Z(t) is a complex variable and can be represented as follows:
Z(t)=X(t)+iY(t),  (2)
wherein X(t) can correspond to e.g. the neurological measurement signal24. Since the considered frequencies lie in the vicinity of 10 Hz= 1/100 ms=1/Tα, the imaginary part Y(t) can be approximated by X(t−τα), wherein for example τα=Tα/4 holds true. This results in:
S(t)=K·[X(t)+iX(t−τα)]2·[X(t−τ)−iX(t−τ−τα)].  (3)
Equation (3) can be rewritten as follows:

The real part of equation (4) is used as the actuation signal for the stimulation unit11:
real[S(t)]=K·[X(t)2·X(t−τ)−X(t−τα)·X(t−τ)+2X(t)·X(t−τα)·X(t−τ−τα)]  (5)

The auditory cortex can furthermore be stimulated at different sites in a targeted fashion by using the fed-back and possibly further-processed measurement signal24. In the case of the above-described four different frequencies f1to f4, the possibly further-processed measurement signal24is acted upon by an appropriate time delay and multiplied by the frequencies f1to f4. Provided that the stimulation is intended to be less focal and over a larger area, four different frequency mixtures with the boundaries fjlowerand fjupper(j=1, 2, 3, 4) are used instead of the pure sinusoidal oscillations at the frequencies f1to f4.

FIG. 14illustrates such a stimulation in an exemplary fashion. The modulation signals51,52,53and54have been obtained here from the band-pass filtered measurement signal24by means of linear processing steps, by means of which modulation signals the amplitude of frequencies f1to f4has been modulated. The control signal14has been generated by the superposition of the modulated sinusoidal oscillations, which control signal has been converted into the acoustic stimulation signal15by the sound generator11.

Herein below,FIGS. 15A and 15Bare used to explain in an exemplary fashion how the modulation signals51to54can be obtained from the measurement signal24. For this, a delay time τ is first of all fixed, which has been set to be τ=Tstim/2 in the present example (other values, such as τ=Tstimor τ=3Tstim/2, are likewise possible). By way of example, the frequency fstim=1Tstimcan lie in the vicinity of the mean frequency of the measurement signal24, e.g. in the range between 1 and 30 Hz, more particularly in the range between 5 and 20 Hz. Particular delay times τ1, τ2, τ3and τ4can be calculated for each of the modulation signals51to54with the aid of the delay time τ, for example with the aid of the following equation:

By way of example, the modulation signals51to54can be obtained from the measurement signal24by the measurement signal24in each case being delayed by the delay times τ1, τ2, τ3and τ4:
Sj(t)=K·Z(t−τj).  (7)

In equation (7), S1(t), S2(t), S3(t) and S4(t) represent the modulation signals51to54and Z(t) represents the measurement signal24. 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 S1(t) to S4(t) can be set to zero.

According to one refinement illustrated inFIGS. 15A and 15B, the modulation signals S1(t) to S4(t) are calculated from only the delay times τ1and τ2, wherein the modulation signals S1(t) and S2(t), and S3(t) and S4(t) in each case have different polarities:
S1(t)=K·Z(t−τ1)  (8)
S2(t)=−K·Z(t−τ1)  (9)
S3(t)=K·Z(t−τ2)  (10)
S4(t)=−K·Z(t−τ2).  (11)

InFIGS. 15A and 15Bthe modulation signals S1(t) and S3(t) have been displaced upward by a value of 0.5 and the modulation signals S2(t) and S4(t) have been displaced downward by a value of 0.5 for the purpose of a clearer illustration.

As shown inFIG. 15B, all negative values (or all values above or below a certain threshold) of the modulation signals S1(t) to S4(t) can be set to zero. The generation of the modulation signals51to54shown inFIG. 14corresponds to the generation of the modulation signals S1(t) to S4(t) shown inFIGS. 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.

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.