Title of Invention

AN APPARATUS FOR DESYNCHRONIZATION ON NEURAL BRAIN ACTIVITY

Abstract The invention relates to an apparatus for desynchronization of neural, illness-synchronous brain activity in which, according to the invention, the activities in at least two subareas of a brain area or at least two functionally associated brain areas are stimulated by means of at least two electrodes, on the basis of which, in the case of a person with an illness, desynchronization surprisingly occurs in the relevant neuron population and the symptoms are suppressed. The feedback stimulation signal, that is to say the measured, time-delayed and process neural activity, is used as an individual stimulus. In consequence, this results in demand control, which is self-regulating according to the invention, of the amplitude of the stimulation signal thus minimizing the intensity of the stimulation stimuli automatically after successful desynchronization. For successful operation, the apparatus requires neither complex calibration nor control of the stimulation parameters and, instead, these can preferably be adapted and optimized by the additional controller. The apparatus has at least two stimulation electrodes (2) and at least one sensor (3), which are driven by a controller such that they result in desynchronization in their local environment.
Full Text AN APPARATUS FOR DESYNCHRONIZATION
OF NEURAL BRAIN ACTIVITY
The invention relates to an apparatus for desynchronization of neural brain
activity.
In the case of patients with neurological or psychiatric illnesses, for
example Parkinson's disease, essential tremor, dystonia or compulsion
disorders, nerve cell groups in defined areas of the brain, for example the
thalamus and the basal ganglia are active because of the illness, for
example being excessively synchronous. In this case, a large number of
neurons form synchronous action potentials; the neurons involved fire
excessively synchronously. In healthy persons, in contrast, the neurons fire
qualitatively differently in these brain regions, for example in an
uncorrelated manner.
In the case of Parkinson's disease, the pathologically synchronous activity,
for example of the thalamus and of the basal ganglia, changes the neural
activity in other brain regions, for example in areas of the cerebral cortex,
such as the primary motor cortex. In this case, the pathologically
synchronous activity in the area of the thalamus and of the basal ganglia
forces itself, for example, on the rhythm of the cerebral cortex so that, in
the end, the muscles which are controlled by these areas carry out a
pathological activity, for example a rhythmic tremor.
In the case of patients who cannot (can no longer) be treated with
medicaments, a deep electrode is implanted on one side or both sides
depending on the clinical signs and depending on whether the illness
occurs on one side or both sides. In this case, a cable leads under the skin
from the head to the so-called generator, which comprises a controller with
a battery and, for example, is implanted under the skin in the area of the
clavicle. The deep electrodes are used to carry out a continuous stimulus
with a high-frequency periodic sequence (pulse train at a frequency of

AN APPARATUS FOR DESYNCHRONIATION
OF NEURAL BRAIN ACTIVITY
The invention relates to an apparatus for desynchronization of neural brain
activity.
In the case of patients with neurological or psychiatric illnesses, for
example Parkinson's disease, essential tremor, dystonia or compulsion
disorders, nerve cell groups in defined areas of the brain, for example the
thalamus and the basal ganglia are active because of the illness, for
example being excessively synchronous. In this case, a large number of
neurons form synchronous action potentials; the neurons involved fire
excessively synchronously. In healthy persons, in contrast, the neurons fire
qualitatively differently in these brain regions, for example in an
uncorrelated manner.
In the case of Parkinson's disease, the pathologically synchronous activity,
for example of the thalamus and of the basal ganglia, changes the neural
activity in other brain regions, for example in areas of the cerebral cortex,
such as the primary motor cortex. In this case, the pathologically
synchronous activity in the area of the thalamus and of the basal ganglia
forces itself, for example, on the rhythm of the cerebral cortex so that, in
the end, the muscles which are controlled by these areas carry out a
pathological activity, for example a rhythmic tremor.
In the case of patients who cannot (can no longer) be treated with
medicaments, a deep electrode is implanted on one side or both sides
depending on the clinical signs and depending on whether the illness
occurs on one side or both sides. In this case, a cable leads under the skin
from the head to the so-called generator, which comprises a controller with
a battery and, for example, is implanted under the skin in the area of the
clavicle. The deep electrodes are used to carry out a continuous stimulus
with a high-frequency periodic sequence (pulse train at a frequency of


> 100 Hz) of individual pulses, for example square-wave pulses. The aim of
this method is to suppress the firing of the neurons in the target regions.
The effective mechanism on which the standard deep stimulation is based
has not yet been adequately explained. The results of a number of studies
indicate that standard deep stimulation acts in the same way as reversible
lesion formation, that is to say in the same way as reversible deactivation
of the tissue: standard deep stimulation suppresses the firing of the
neurons in the target regions and/or in brain areas linked thereto.
This type of stimulation has the disadvantage that the power consumption
of the generator is very high, so that the generator including the battery
frequently has to be replaced operatively after only about one to three
years. It is even more disadvantageous that the high-frequency continuous
stimulation, as a non-physiological (unnatural) input in the area of the brain,
for example of the thalamus or of the basal ganglia, can lead to adaptation
of the relevant nerve cell groups over the course of a few years. In order to
achieve the same stimulation success, a greater stimulus amplitude must
then be used for stimulation, as a consequence of this adaptation. The
greater the stimulus amplitude is, the greater is the probability that the
stimulation of adjacent areas will lead to side-effects - such as dysarthria
(speech disturbances), dysesthesia (in some cases highly painful false
sensations), cerebellary ataxia (incapability to stand safely without an
external aid), or symptoms similar to schizophrenia, etc. These side-effects
cannot be tolerated by the patient. In these situations, the treatment thus
loses its effectiveness after a few years.
In the case of other stimulation methods, such as those described in
DE 10211 766.7 "Vorrichtung zur Behandlung von Patienten mittels
Hirnstimulation, ein elektronisches Bauteil sowie die Verwendung der
Vorrichtung und des elektronischen Bauteils in der Medizin" [Apparatus for
the treatment of patients by means of brain stimulation, an electronic
component as well as the use of the apparatus and of the electronic
component in medicine] and in DE 103 18 071.0-33 "Vorrichtung zur
Desynchronisation von neuronaler Hirnaktivitat" [Apparatus for


desynchronization of neural brain activity], it has been proposed that stimuli
be applied in the respective target region on a demand-controlled basis.
The aim of these methods/these apparatuses is not simply to suppress the
illness-synchronous firing - as in the case of standard deep stimulation -
but to change this to be closer to the physiological, uncorrelated firing
pattern. The aims of this are on the one hand to reduce the power
consumption and on the other hand to use the demand-controlled
stimulation to reduce the amount of energy introduced into the tissue in
comparison to the standard deep stimulation. These demand-controlled,
desynchronizing methods also have relevant disadvantages, however.
The disadvantages of the demand-controlled, desynchronizing stimulation
methods according to DE 102 11 766.7 result from the following fact: in
order to desynchronize a synchronized nerve cell group with an electrical
stimulus, an electrical stimulus of specific duration must be administered in
the target area precisely with respect to the specific phase of the illness-
related rhythmic activity. Since such precision cannot yet be reliably
achieved experimentally at the moment, composed stimuli are used. The
first stimulus of a composed stimulus such as this controls the dynamics of
the population to be desynchronized by means of a reset, that is to say a
restart, while the second stimulus in the composed stimulus strikes the
nerve cell group in a vulnerable state, and desynchronizes it. However, it is
essential for this purpose that the quality of the monitoring, that is to say
the quality of the reset, is adequate, which in some circumstances may
mean that a major stimulus must be used for the reset. However, this
should be avoided in the sense of reducing the side-effects. However, it is
even more critical that the desired desynchronizing effect occurs only when
the stimulation parameters, that is to say the duration of the individual
stimuli and in particular the pause between the first and the second
stimulus, are optimally chosen. This has serious consequences:
1. A time-consuming calibration procedure is required, and
typically lasts for more than 30 minutes.
2. Because of the time-consuming calibration procedure, the


effect of the desynchronizing stimulation according to
DE 102 11 766.7 cannot be used for intra-operative selection of
the most suitable target point for the deep electrode. The effect
of the desynchronizing stimulation according to
DE 10211 766.7 would have to be tested separately for
different target points for this purpose, which would require a
separate calibration for each target point; this would lengthen
the duration of electrode implantation in a manner that is
unacceptable to the patient.
3. When relatively major fluctuations occur in the network
characteristics, that is to say fluctuations in the parameters
which describe the activity of the nerve cell population, such as
synaptic strengths and firing rates, recalibration must be carried
out. This has the disadvantage that no therapeutic effect can be
achieved during the calibration.
4. Since the desynchronizing stimulation according to
DE 102 11 766.7 occurs only when the frequency of the neuron
population to be desynchronized is not subject to relatively
major fluctuations, it cannot be used for illnesses with epochs
which occur for a short time of synchronous activity that is
excessive by virtue of the illness, at a highly varying frequency,
that is to say for example in the case of epilepsies.
Disadvantages of the demand-controlled, desynchronizing stimulation
methods according to DE 103 18 071.0-33 result from the following fact: in
order to desynchronize a synchronized nerve cell group by means of an
electrical stimulus, a multiple electrode stimulation is carried out. A high-
frequency pulse train or a low-frequency pulse train of short duration is
applied to the individual electrodes. This leads to a phase reset of the
stimulated neuron population. The times at which stimulation is applied via
the various electrodes are chosen such that there is an equidistant phase
shift between the neural sub-populations associated with the stimulation
electrodes. After the completion of a stimulus such as this which is
administered via a plurality of electrodes the pathologically increased


interaction between the neurons automatically results in complete
desynchronization.
This method has the advantage of rapid calibration and robustness to
fluctuations in the parameters, so that this stimulation method can also be
used in situations in which epochs which only occur for a short time of
synchronous activity at a highly varying frequency. However, the method in
DE 103 18 071.0-33 also has serious disadvantages:
1. In order to produce a complete and uniform phase reset in
the relevant neuron population, a very strong stimulus must be
applied to the respective electrodes. The uniform phase shift is
necessary since the pathological interaction can lead to
complete desynchronization only with an equidistant phase
reset. The use of very strong stimuli should, however, be
avoided in order to reduce side effects.
2. One major feature of the method registered in
DE 10318 071.0-33 is the recurrent, possibly demand-
controlled, application of an overall stimulus. The stimulated
tissue is resynchronized between the overall stimuli. This means
that the nerve population to be desynchronized oscillates
between two unphysiological states: an N-cluster state, where N
represents the number of electrodes used for stimulation, and a
transient state of resynchronization. The population to be
desynchronized is therefore never in the desired state of
desynchronization for a lengthy time, although this is what is to
be aimed for in order to reduce the illness-dependent symptoms
and the stimulation-dependent side-effects.
3. The demand controller registered in DE 103 18 071.0-33
requires a complex controller, which has complicated control
electronics and necessarily a greater power consumption.
The stimulation methods mentioned above use individual pulses, high-
frequency pulse trains and low-frequency pulse trains as stimulation


signals, which either suppress the dedicated dynamics of the stimulated
neurons or change the neuron population to be desynchronized to an N-
cluster state by means of a phase reset. The stimulation pulse trains are
constructed without using the dedicated dynamics of the neuron population
to be desynchronized and, in this sense, are external and unphysiological
signals for the neuron population to be desynchronized. In order to
suppress the illness symptoms, the stimulation pulse trains would have to
be applied with a high intensity, which leads to the expectation that the
neuron population to be desynchronized would adapt itself to the
unphysiological stimuli, and possible side-effects.
The subject matter of the invention is thus to provide an apparatus for
desynchronization of neural brain activity, by means of which patients with
illness-synchronized brain activity can be treated mildly and efficiently. One
aim in this case is to suppress adaptation to an unphysiological continuous
stimulus. Tedious calibration processes should be avoided, and the
stimulation should also be successful even when the main-frequency
component of the pathologically rhythmic activity is subject to major
fluctuations. Furthermore, the apparatus is intended to achieve long-term
desynchronization, while very largely avoiding transient, stimulation-
dependent unphysiological states. The apparatus according to the
invention does not require any additional demand controller, which may be
added optionally as described in Section 6.3, so that it can be implemented
easily and only minor demands are placed on the complexity of the control
electronics, and thus on the power consumption as well. The stimulation
apparatus according to the invention is intended to operate in a power-
saving manner, so that the batteries of the stimulator which is implanted in
the patient need not be operatively replaced as often.
Accordingly, the present invention provides an apparatus for
desynchronization of neural brain activity, having at least one sensor for
measurement of a signal which reproduces the time development of the
activity of the neuron population to be desynchronized, as well at least two
electrodes, characterized by a controller which is designed in such a


manner that it records the measurement signal from the sensor (3) and
feeds the measurement signal as a stimulation signal or the measurement
signal, once it has been processed, as a stimulation signal into each of the
at least two electrodes .
Against the background of the precharacterizing clause of claim 1, the
object is achieved according to the invention by means of the features
specified in the characterizing part of claim 1. Using the measured and
processed activity of the neuron population to be desynchronized as a
feedback stimulation signal, see Section 3, the object is achieved of the
neurons in at least two subareas of a brain area or at least two functionally
associated brain areas each having their activity influenced by the use of at
least two electrodes for stimulation with individual stimuli with different time
delays, in such a way that this surprisingly results in complete
desynchronization of the stimulated neuron population, thus suppressing
the symptoms in a person with an illness. For this purpose, the apparatus
according to the invention has a controller 4 which records the
measurement signal from the sensor 3 or the sensors 3, generates at least
two stimulation signals from this signal, and passes them to the electrodes
2.
The apparatus according to the invention operates in a power-saving
manner, so that batteries that have been implanted in the patient may be
replaced less often.
The apparatus according to the invention makes it possible to use the
effect, achieved intraoperatively by the desynchronizing stimulation, for
selection of the most suitable target point for the deep electrode. For this
purpose, a test stimulus is carried out in advance in millimetric steps using
the apparatus according to the invention in the area of the target point as
calculated anatomically in advance, during the implantation of the deep
electrode. The target point at which the best therapeutic effect can be
achieved is chosen as the target point for the long-term implantation.
Furthermore, in addition to the illnesses which have been mentioned above


and which frequently have long-lasting pathologically synchronous activity
at a relatively constant frequency, illnesses can also be treated in which
pathologically synchronous activity occurs only intermittently (occurring for
a short time). One major indication in this case is the treatment of epileptics
who cannot (can no longer) be treated with medicaments. For example, the
apparatus according to the invention can be used to achieve
desynchronization in the illnesses of Parkinson's disease, essential tremor,
dystonia, epilepsy and compulsive disorders.
Advantageous developments of the invention are specified in the
dependent claims.
The accompanying drawings show exemplary embodiments of the
invention, in which:
Figure 1 shows an apparatus according to the invention,
Figure 2a shows the waveform of the synchronization measure during one
stimulation interval. Low (high) values correspond to low (high)
synchronization. The stimulation starts at the time 2 seconds and is ended
at the time 25 seconds.
Figure 2b shows the waveform of the neural activity of the nerve cells
measured using the sensor 3 during the stimulation in Figure 2.
Figure 2c shows the waveform of the individual stimulus applied via an
electrode 2 during the stimulation in Figure 2.
Figure 3 shows an example of one application of a stimulation pattern via 4
electrodes with four different time delays.
Figure 4 shows an example of a stimulus application using 4 electrodes
and two different time delays, and different polarity.


In Figures 2a, b and c, the abscissas denote the time axes in seconds,
while the synchronization measure (Figure 2a), the measured neural
activity (Figure 2b) and an example of a single stimulus (Figure 2c) are
plotted, in each case in arbitrary units, on the ordinates. The neural activity
(Figure 2b) measured by means of the sensor 3 is used as the basis for
creation of the individual stimuli. The neural activity (Figure 2b) measured
using the sensor 3 is used as a control signal for the stimulus application.
In Figure 3, the abscissa is the time axis in seconds, while the measured
neural activity and the individual stimuli, for example in the sense of the
applied current, are illustrated, in each case in arbitrary units, on the
ordinate. The same stimulation pattern with the same polarity is applied via
the four electrodes 2, but with four different, for example equidistant, time
delays.
In Figure 4, the abscissa is the time axis in seconds, while the measured
neural activity and the individual stimuli, for example in the sense of the
applied current, are illustrated, in each case in arbitrary units, on the
ordinate. The polarity of the individual stimuli can also be varied, as an
alternative to variation of the time delays. For example, a stimulation
stimulus with the same time delay but with different polarity can be applied
via the first two electrodes 2. In a corresponding manner, a stimulation
stimulus with a different time delay but with a different polarity is applied via
the third and fourth electrodes 2. The respective polarity of the individual
stimuli is indicated by the symbols"+" and "-".
The apparatus shown in Figure 1 comprises an isolation amplifier 1 to
which at least two electrodes 2 as well as at least one sensor 3 are
connected in order to detect physiological measurement signals. The
isolation amplifier is also connected to a unit 4 for signal processing and
control, which is connected to an optical transmitter for the stimulation 5.
The optical transmitter 5 is connected via optical waveguides 6 to an
optical receiver 7, which is connected to a stimulator unit 8 for signal
production. The stimulator unit 8 for signal production is connected to at


least two electrodes 2. A relay 9 or a transistor is located in the input area
of the electrodes 2 into the isolation amplifier 1. The unit 4 is connected via
a line 10 to a telemetry transmitter 11, which is connected to a telemetry
receiver 12 which is located outside the appliance to be implanted and to
which a means for visualization, processing and storage of the data 13 is
connected. By way of example, epicortical electrodes, deep electrodes,
brain electrodes or peripheral electrodes may be used as sensors 3.
The electrodes 2 each comprise at least two wires, to whose ends a
potential difference is applied for stimulation purposes. These may be
macro-electrodes or micro-electrodes. Alternatively, the electrodes 2 may
also each be individual wires. In this case, a potential difference is in each
case applied for stimulation purposes between an individual wire and the
metallic part of the housing of the generator. In addition, but not
necessarily, a potential difference can be measured across the electrodes
2 in order to detect pathological activity. In a further embodiment, the
electrodes 2 may also comprise more than two individual wires, which can
be used both for the determination of a measurement signal in the brain
and for stimulation purposes. By way of example, four wires may be
accommodated in one conductor cable, in which case a potential difference
can be applied or measured between different ends. This makes it possible
to vary the magnitude of the derived or stimulated target region. The
number of wires from which the electrode is formed is limited in the upward
direction only by the thickness associated with it of the cable to be inserted
into the brain, with the aim of damaging as little brain material as possible.
Commercially available electrodes comprise four wires, although the
electrodes may also have five, six or more wires, or else only three wires.
In a situation where the electrodes 2 comprise more than two wires, at
least one of these wires may also act as a sensor 3, so that this results in
an embodiment in which the electrodes 2 and the sensor 3 are combined in
a single component. The wires of the electrodes 2 may have different
lengths, so that they can penetrate to different brain depths. If the
electrodes 2 comprise n wires, where n is an integer, then stimulation can


be carried out via at least one pair of wires, in which case any sub-
combination of wires is possible in order to form pairs. In addition to this
component, it is also possible to provide sensors 3 which are not physically
combined with the electrodes 2.
By way of example and in plain words, the apparatus according to the
invention is used, in a first step, to measure the neural activity by means of
the sensors. In a second step, the stimulation signals are generated by
means of a time delay and if required by means of further processing of the
neural activity. These stimulation signals are then used via at least two
implanted electrodes for stimulation, preferably with different time delays, in
a third process step. This stimulation results in desynchronization in the
stimulated tissue. Details of the method of operation of the apparatus
according to the invention are explained in Section 1.
As described in Section 6, the apparatus according to the invention can be
implemented in various embodiments of the time control for stimulus
application. The variants of time control for stimulus application are
permanent, repetitive and demand-controlled stimulus application.
The permanent stimulus application according to the invention is one
simple embodiment of the apparatus according to the invention which
operates without any additional demand control and applies stimuli
permanently, as described in Section 6.1. Permanent stimulus application
therefore represents an embodiment of the apparatus according to the
invention which can be implemented easily. At the same time, the self-
regulating demand control according to the invention as described in
Section 5 provides a good desynchronizing effect of permanent stimulation
with little energy being introduced into the target population.
In the case of the repetitive stimulus application according to the invention,
the apparatus according to the invention has a controller which is
programmed such that it applies the stimulation signals to the electrodes 2
only during specific time intervals. There is no stimulation outside these


time intervals. The control unit 4 is thus programmed such that, in the
embodiment of the repetitive stimulation as described in Section 6.2 a
stimulation signal which is generated with a duration that is calculated by
the control unit 4 is generated at times which preferably follow one another
periodically and are determined by the control unit 4, with this stimulation
signal being emitted to the electrodes 2. As in the case of permanent
stimulus application, self-regulating demand control of the amplitude of the
stimulation signal also takes place in repetitive stimulus application.
In the case of the demand-controlled stimulus application according to the
invention, the apparatus according to the invention has an additional
demand controller. For this purpose, the apparatus according to the
invention is preferably equipped with means which identify the signals of
the electrodes 2 and/or of the sensors 3 as pathological and, when a
pathological pattern is present, emit stimuli via the electrodes 2 which
result in the pathological neural activity in the sub-populations that are
stimulated by the individual electrodes 2 being desynchronized, and thus
coming closer to the natural, physiological activity. The pathological activity
differs from the healthy activity by a characteristic change in its pattern
and/or its amplitude and/or its frequency content. The means for
identification of the pathological pattern are in this case a computer, which
processes the measured signals from the electrodes 2 and/or from the
sensor 3 and compares them with data stored in the computer. The
computer has a data storage medium which stores data and can be used in
accordance with Sections 6 and 7 for calibration and/or control purposes.
For example, the control unit 4 may comprise a chip or some other
electronic apparatus with comparable computation power.
Depending on the occurrence and the extent of pathological features in the
processed neural activity, a stimulus signal is emitted to the electrodes 2 in
the embodiment of the demand-controlled stimulus application as
described in Section 6.3, thus resulting in stimulation of the brain tissue.
The apparatus according to the invention has means for identification of the
occurrence and/or of the extent of the pathological features in the neural


activity as measured by means of the sensor 3. The control unit 4 is
programmed such that, in the embodiment of the demand-controlled
stimulus application as described in Section 6.3, a stimulation signal is
generated at a time defined by the control unit 4, and is emitted to the
electrodes 2. Overall, the aim is to store all of those parameters that are
relevant for the respective procedure for the apparatus according to the
invention, relating to the nature and intensity of the stimuli, together with
their time delays as well as information relating to the electrode-specific
application, as well as those measured values which are relevant for the
demand-controlled methods of operation and have been determined by
means of the sensor 3, or parameters derived from them.
The control unit 4 preferably drives the electrodes 2 in the following
manner: the control data is passed on from the control unit 4 to an optical
transmitter for stimulation 5, which drives the optical receiver 7 via the
optical fiber 6. Optical injection of the control signals into the optical
receiver 7 provides DC isolation between the stimulation controller and the
electrodes 2. This means that this prevents interference signals from the
unit for signal processing and the controller 4 from being injected into the
electrodes 2. By way of example, a photocell may be used as the optical
receiver 7. The optical receiver 7 passes on to the stimulator unit 8 the
signals which are input for the stimulation 5 via the optical transmitter.
Specific stimuli are then passed on via the stimulator unit 8 and via the
electrodes 2 to the target region in the brain. In the situation where the
electrodes 2 are also used for measurement purposes, a relay 9 is also
driven from the optical transmitter for stimulation 5 via the optical receiver
7, thus preventing the injection of interference signals. The relay 9 or the
transistor ensures that the neural activity can be measured again
immediately after each stimulus, without overdriving the isolation amplifier.
The DC isolation need not necessarily be provided by optical injection of
the control signals and, in fact, other alternative control processes can also
be used. These may, for example, be acoustic inputs, for example in the
ultrasound band. Interference-free control can also be achieved, for
example, with the assistance of suitable analog or digital filters.


Furthermore, the apparatus according to the invention is preferably
connected to means for visualization and processing of the signals, and for
data back-up 13, via the telemetry receiver 12. In this case, the unit 13 may
comprise the methods mentioned in the following text for data analysis.
Furthermore, the apparatus according to the invention may be connected
via the telemetry receiver 13 to an additional reference database in order,
for example, to monitor correct operation of the appliance and, possibly, to
design the control mechanisms as described in Section 7.2 to be more
efficient, by modification of the parameters.
The stimulation mechanism is explained in detail in Section 1. Section 2
contains a definition of the most important terms. The process steps for
measurement of the neural activity via their processing as far as the
generation of the overall stimuli is explained in Section 3. The physical
arrangement of the electrodes and sensors is the subject matter of
Section 4. Section 5 deals with the self-regulating demand control of the
stimulation amplitude. The control of the stimulus application and the
calibration and adaptation of the stimulation parameters are described in
Sections 6 and 7. The advantages of the apparatus according to the
invention are described in Section 8.
1 Stimulation mechanism
The aim of the stimulation is to counteract illness-dependent
synchronization in a nerve cell population, by desynchronization. This is
done by applying stimuli at at least two points, which stimuli are generated
by measuring the neural activity, by converting this to a stimulation signal
on the basis of a processing step which may be provided, and by
application, preferably with a time delay, so that, surprisingly, this results in
desynchronization. The desynchronizing effect of the stimulation is assisted
by the illness-dependent interaction between the neurons and the decrease
in the stimulation effect with the distance between the stimulated tissue and


the electrode. In plain words, the energy of the system to be influenced is
utilized in order to achieve a therapeutic effect with minimal intervention.
The apparatus according to the invention changes the nerve cell population
to be desynchronized directly to a desynchronized state. The desired state,
that is to say complete desynchronization, typically occurs within a few
periods of the neural activity, frequently in less than one period.
There is typically a need for permanent or repetitive stimulation, since the
nerve cell population to be desynchronized becomes resynchronized again,
from experience, once the stimulation is switched off. Since the stimulation
is directly related to the neural activity of the target area, or of an
associated area, the stimulation amplitude is automatically minimized after
successful desynchronization. This is made possible by using the feedback
stimulation signal, that is to say the processed neural activity, as the
stimulation stimulus, that is to say the extent of synchronization
permanently controls the intensity of the stimulation. This process works for
a wide range of stimulating parameters which can be modified, such as the
stimulation period T, the time delay and the intensity, does not require any
complex calibration, and has a high degree of tolerance to faults and
errors. Furthermore, the amount of energy which is introduced into the
tissue to be desynchronized is minimized because of the direct relationship
between neural activity and the stimulation pattern, thus leading to the
expectation of reduced side-effects.
The apparatus according to the invention and its operation will be
explained using examples in the following text.
The apparatus according to the invention and the controller are equipped
with means which can carry out all of the steps of the treatment process
according to the invention. The disclosed method steps are thus also
intended to implicitly disclose means for carrying out the method step. The
method steps thus also at the same time represent the functionalized
apparatus features.


According to the invention, the electrodes are introduced into the brain
region which is responsible for the creation of the clinical signs. According
to the invention, at least two or preferably four or else three or more
electrodes are introduced either directly into the region or into one or more
nerve cell populations or nerve fiber groups which are linked to this region.
The number of electrodes is restricted only by the need to ensure that there
is not an unrestricted density of electrodes in one brain region, in order that
the tissue is not unnecessarily damaged and, in particular, to reduce the
risk of bleeding on insertion of the electrodes. In any case, the number of
electrodes introduced into the region should be N, where N> 2.
In this case, each electrode emits a signal in its surrounding area, which,
while propagating either directly in its surrounding area or via a nerve fiber
group, results in desynchronization in a different area. In order to achieve
desynchronization, the measured and processed neural activity is used as
a stimulation stimulus, in each case with a time delay, see Section 3. The
apparatus according to the invention thus has a controller which drives at
least two electrodes 2 such that they produce desynchronization in the
area relatively closely surrounding them and/or by passing on the
stimulation via a fiber group in another brain area.
According to the invention, N electrodes, where N> 2, are preferably driven
such that there is a time delay of T/N between the individual electrode
signals, assuming that the stimulating electrodes 2 are in the area to be
desynchronized. In this case, as described below, T is the period of the
rhythmic neural activity to be desynchronized. If at least one of the
stimulating electrodes 2 is not located in the area to be desynchronized,
the delay time between the stimulus location and the location of the neuron
population which is influenced in this way must be taken into account in the
drive for an electrode 2 such as this. This is described in Section 7.3. The
apparatus according to the invention accordingly has a controller which, in
the case of N electrodes, preferably produces a stimulation signal which is
shifted in time through essentially one A/-th of the period of the activity to be
desynchronized. The time shift is in this case preferably essentially


equidistant.
Surprisingly, in the case of this equidistant time shift of the neuron
populations which are each influenced by the N electrodes 2 this does not
simply result in the neuron population being subdivided into N sub-
populations which are each synchronized in their own right. In fact, this
stimulation surprisingly leads to desynchronization of the entire neuron
population to be desynchronized, thus leading to suppression of the
pathological symptoms. If at least one electrode 2 is located outside the
area to be desynchronized, then the effects of the indirect stimulation must
be taken into account, as described in Section 7.3.
The new method and the new apparatus result in the desynchronization
being achieved in a qualitatively different manner to that in the prior art
cited above. Instead of acting specifically on the illness-synchronous nerve
cell group in a vulnerable phase of its rhythm, the relevant nerve cell group
is simply stimulated on a time-coordinated basis at a plurality of locations,
see Section 3.3, in such a manner that desynchronization occurs. The
neural activity process as described in Section 3.2 at the individual stimulus
locations is used for this purpose. Stimulation must be applied to at least
two, and preferably more than two, stimulus locations. The
desynchronization that surprisingly occurs is assisted by the interaction,
which is increased by the illness, between the neurons and by the
stimulation effect which decreases with the distance between the
stimulation location and the neuron to be stimulated. In this case, use is
made of an effect mechanism which is responsible for the illness-related
synchronization. In plain words, the energy of the system to be influenced
is utilized in order to achieve a therapeutic effect with minimal intervention.
The best results are achieved when overall stimuli with essentially
equidistant time delays are used. However, treatment successes are also
achieved when the time delays between the stimuli emitted via the
electrodes 2 are not equidistant. In a case such as this, at least partial
desynchronization is achieved. The treatment results become better the
closer the chosen time delays become to equidistant time delays.


2 Definition of terms
Target population:
In the following text, the expression target population means the nerve cell
population which is directly stimulated by an implanted stimulation
electrode.
A target population is stimulated directly by means of an electrode which is
implanted in it or close to it.
The nerve cell population which is synchronously active as a result of the
illness is referred to as the area to be desynchronized, as the nerve cell
population to be desynchronized, or as the neuron population to be
desynchronized. The area to be desynchronized is not associated with
anatomical boundaries. In fact, this can also be understood as meaning at
least one component, comprising the following group:
at least a part of at least one anatomical area,
at least one complete anatomical area.
The area to be desynchronized may be stimulated either directly or
indirectly.
Direct stimulation:
In this case, the stimulation electrode 2 is located directly in the area to be
desynchronized.
This electrode 2 in this case influences the target population which is
located in the area to be desynchronized.
Indirect stimulation:
In this case, the area to be desynchronized is not stimulated directly by
means of the stimulation electrode 2. In fact, a target position or a fiber


group which is functionally closely linked to the area to be desynchronized
is stimulated via the electrode 2. In this case, the stimulation effect
preferably propagates to the area to be desynchronized via anatomical
links. The expression target area is introduced as a generic term for the
target population and the fiber group, for indirect stimulation. In the
following text, the expression target area should be understood as the
neuron population, which is functionally closely linked to the area to be
desynchronized, and the connecting fiber group, which are directly
stimulated by implanted electrodes 2.
Neural activity:
The description of the mechanism of the apparatus according to the
invention is based essentially on the term neural activity. The neural activity
of the neuron population to be desynchronized and/or of a neuron
population which is closely linked to it is measured, stored, and processed
in accordance with Section 3.2, and is used as a stimulation signal, thus
providing the self-regulating demand control according to the invention. In
the following text, the expression the measured neural activity of the
neuron population to be desynchronized means a signal which reproduces
the time development of the activity of the neuron population to be
desynchronized. By way of example, local field potentials can reproduce
the time development of the activity of the neuron population to be
desynchronized. The neural activity can preferably be measured directly in
the area to be desynchronized, although it is also possible to measure an
activity which is associated with the neural activity of the area to be
desynchronized, for example a different brain area, in this case by way of
example the motor cortex, or the activity of a muscle group which is
controlled by the area to be desynchronized. In a further embodiment of the
apparatus according to the invention, neural activities are measured at
different locations and are combined in order to obtain an adequate
representation of the neural activity of the neuron population to be
desynchronized. These variables which are associated with the neural
activity of the area to be desynchronized are also referred to as neural
activity in the following text.


Feedback stimulation signal:
The expression feedback stimulation signal means that signal which,
according to Section 3.2, represents the measured and processed neural
activity and is used as the basis for the individual stimuli.
Rhythm:
The expression rhythm is used to mean the rhythmic, that is to say
approximately periodic, neural activity which results from nerve cell activity
that is excessively synchronous because of an illness. A rhythm can occur
briefly or on a long-lasting basis.
Period:
One central term for the apparatus according to the invention is the period
of the rhythmic neural activity, and this is used as a time reference for the
application of the individual stimuli. Adaptation of the stimulation T, as
described in Section 7.2.1, preferably results in the period of the rhythmic
neural activity matching the stimulation period T.
Time delay:
The apparatus according to the invention causes signals to be passed to
the stimulation electrode 2 which correspond to the neural activity, as
measured in accordance with Section 3.1 and possibly processed, relating
to an earlier time. This time shift is referred to in the following text as the
time delay and represents one important stimulation parameter, which is
related to the period of the rhythmic neural activity.
Individual stimulus:
The expression an individual stimulus, see Section 3.3, in the following text
means a stimulation stimulus which is applied via a single electrode and
acts over a time interval. The neural activity processed in accordance with
Section 3.2 is used for these stimulation stimuli.
Overall stimulus:


An overall stimulus is the totality of the individual stimuli applied via the
electrodes, see Section 3.4.
3 Nature of the stimulation stimulus
3.1 Measurement of the neural activity
The time profile of the neural activity of the area to be desynchronized can
be measured directly or indirectly by means of the sensors 3.
The sensors 3 (see Figure 1) are located in the brain and/or outside the
brain. In the brain, they are positioned in the area to be desynchronized
and/or in at least one other area which is functionally linked to it. Outside
the brain, the sensors 3 are located at body parts which are linked to the
neural activity that is synchronized because of the illness, for example as
electrodes on a trambling muscle. The measurement signals of the neural
and/or non-neural, for example muscular, activity are processed in a unit
for signal processing 4, and are stored. In this case, these measurement
signals can be processed and stored permanently and/or at discrete time
intervals. In the latter case, the duration and/or the intervals between the
discrete measurement intervals are/is determined by means of a
deterministic and/or stochastic algorithm.
3.2 Processing of the neural measurement signals
The measurement signals which are stored in the unit for signal processing
4 are then processed in order to be made available as stimulation signals.
The following processing steps may be carried out:
1. The measured neural activity may be filtered, for example
bandpass filtering may be carried out on the neural activity. The
filtering may be necessary when activity which is not yet illness-
specific, for example from other neuron populations, is
additionally measured in addition to the illness-specific activity
by means of the sensor 3. Since the illness-specific activity


typically occurs in a frequency range which differs from the
frequency range of non-illness-specific activity, the activity in the
illness-specific frequency range is preferably determined in this
case. This is done, for example, by means of a frequency
analysis. It may likewise be necessary to carry out a wavelet
analysis and/or a Hilbert transformation and/or filtering in the
time domain.
2. When the neural activity of the neuron population to be
desynchronized is measured by means of a plurality of sensors
3, then a linear and/or non-linear combination and/or
transformation can be carried out, for example multiplication,
addition or calculation of a function, of the measured neural
activity.
3. The measured neural activity is delayed in time. The time
delays which are used for this purpose are defined in
Sections 3.3 and 3.4 and also, in accordance with Section 7.3,
take account of the position of the stimulation electrodes with
respect to the neuron population to be desynchronized.
Furthermore, the time delays can preferably be adapted during
the stimulation, in accordance with Sections 7.2.1 and 7.2.2.
4. The measured neural activity is amplified. The measured
neural activity is several orders of magnitude less than the
stimulation amplitudes which, from experience, lead to a
stimulation effect. Amplification must therefore be carried out,
and can be adapted in accordance with Section 7.2.3 during the
stimulation.
5. Since signals with high gradients have a major effect on the
neural dynamics, the measured neural activity is coded, for
example, in the form of pulse trains or high-frequency pulse
trains comprising short square-wave pulses. Other coding


methods can also be used in order to increase the stimulation
effect.
6. The polarity of the neural activity is changed. By way of
example, this has been used for the overall stimulus sketched in
Figure 4.
7. The maximum amplitude of the stimulation signal is restricted.
8. The measured neural activity is in contrast transformed so as
to produce stimulation signals whose net charge introduced is
essentially zero.
Except for item 3, items 1,2 and 4 to 6 can be used optionally.
The processed neural activity is determined by the use of any desired
combination of the processing steps mentioned above.
3.3 Form of the individual stimuli
In the following text, the expression an individual stimulus means a
stimulation stimulus which is applied via a single electrode and acts in a
time interval. The feedback stimulation signal, that is to say the neural
activity processed in accordance with Section 3.2, is used for these
stimulation stimuli.
In this case, the expression time-coordinate stimulation means, by way of
example, that the individual stimuli are applied via the respective electrode
2 with respectively suitable time delays, preferably different time delays,
and also for a different duration - as described in Section 3.4 - in order to
produce desynchronization between the stimulated sub-populations and
within the sub-populations of the neuron populations to be desynchronized.
The time delays are stated, for example, as fractions of the period of the
oscillatory neural activity to be desynchronized and are preferably


essentially a multiple of one N-th of the period, where N is a small integer,
for example 4. N is in this case an integer, preferably below 1000,
particularly preferably less than 100 and in particular less than 10.
The time delays of the individual stimuli can also be chosen, for example,
to be greater than the stimulation period T. For this purpose, the apparatus
according to the invention has means which apply the described electrical
stimulation stimuli in the described manner. The means are electrodes 2,
and a controller 4 which emits control signals to be electrodes 2 in order to
emit these stimuli. Furthermore sensors 3 and the unit for signal processing
4, which records the neural activity and prepares for the further use as
stimulation stimuli. The individual stimuli which are applied via the
electrodes 2 are referred to as the overall stimulus, and achieve
desynchronization in the neuron population to be desynchronized on the
basis of the active mechanism of the apparatus according to the invention.
Examples of overall stimuli are shown in Figures 3 and 4. One individual
stimulus is preferably emitted via each electrode in the course of one
overall stimulus.
If overall stimuli are applied repetitively, the electrodes 2 which are driven
in the course of an overall stimulus may be varied. In particular, the subset
of the electrodes 2 which are driven for the respective overall stimulus can
be selected by means of a stochiostic and/or deterministic algorithm.
3.4 Pattern of the overall stimuli
In the course of the application of an overall stimulus, one individual
stimulus is applied via at least two stimulation electrodes 2, but preferably
via each individual stimulation electrode 2. Overall stimuli are preferably
generated whose net charge introduced is essentially zero. The individual
stimulus may assume the forms described in Section 3.3.
The individual stimuli which are applied via the various electrodes 2 may


but need not be different in terms of the nature and/or intensity, for
example governed by the gain. For this purpose, the apparatus according
to the invention has a controller which is programmed such that it can vary
the nature and/or the intensity of the individual stimuli. The nature and the
intensity of the individual stimuli are governed by the parameters which are
used for the processing steps as described in Section 3.2.
By way of example, in the case of direct stimulation via N electrodes 2, the
same individual stimulus, in the form of the same processed neural activity
in accordance with Section 3.2, can in each case be applied with a
difference in the time delay of in each case T/N, where T is the stimulation
period. By way of example, the same continuous stimulation stimuli can be
administered via the first, second, third and fourth electrodes 2 for N = 4
with time delays which are in each case shifted by 774, as is illustrated in
Figure 3.
For this purpose, the apparatus according to the invention has a controller
which is programmed such that it drives N electrodes 2 with individual
stimuli, whose time delays are essentially a multiple of T/N.
As a further example, time delays for the stimulus application can be
replaced by changing the polarity of the individual stimuli. For this purpose,
the apparatus according to the invention has a controller which is
programmed such that it can drive at least one of the electrodes 2 with a
changing polarity in each case. For example, for N = 4, one pair of
individual stimuli of opposite polarity can in each case be applied via the
first and the second electrode 2, and with a time delay of 774 via the third
and the fourth electrode 2, as shown in Figure 4.
As an alternative to this, by way of example, particularly in the case of the
demand-controlled stimulus application as described in Section 6.3, the
time delays and/or the polarity and/or the application duration and/or the
intensity of the individual stimuli within an overall stimulus may be varied
systematically or on a randomly controlled basis, that is to say on the basis


of a deterministic or stochastic rule. For this purpose, the apparatus
according to the invention has a controller which is programmed such that
it drives the time delays and/or the polarity and/or the application duration
and/or the intensity of the individual stimuli within an overall stimulus
deterministically and/or stochastically.
By variation of the time delays and/or the polarity and/or the application
duration and/or the intensity of the individual stimuli within the overall
stimuli, it is possible to prevent adaptation processes in the neuron
populations which result in an increase in the stimulation intensity in order
to achieve the same therapeutic effect.
4 Number and spatial arrangement of the electrodes and sensors
4.1 Number of stimulation electrodes
The number of electrodes 2 is a compromise between two opposing aims:
On the one hand, the neuron population to be desynchronized should be
split into as many functional sub-populations as possible by the stimulation.
This is achieved to a greater extent the greater the number of electrodes
used for stimulation. On the other hand, the number of electrodes to be
implanted should be kept as small as possible in order to prevent
unnecessary tissue damage and, in particular, brain bleeding during the
implantation. At least two electrodes may be used. By way of example, it is
also possible to use three electrodes. It is particularly preferable to use four
electrodes, since the desynchronization is more pronounced and longer
lasting when using four electrodes. If the number of electrodes is increased
to five or up to 100 or more, the desynchronization effect is improved in
terms of the extent and duration. The use of a greater number of electrodes
may be feasible, for example, when micro-electrodes and/or modern
neurochip technologies are used.
4.1.1 Embodiment for the situation in which all the electrodes 2
are positioned in the nerve cell population to be


desynchronized
The N electrodes, where N is an integer greater than 1, should preferably
be arranged such that approximately one N-th of the nerve cell population
to be desynchronized can be stimulated by each individual electrode. This
can be achieved with a different number of electrodes and with a different
geometric arrangement of the electrodes with respect to one another. By
way of example, it is possible to choose any desired asymmetric
arrangement. However, essentially symmetrical arrangements are
preferable, particularly when a small number of stimulation electrodes are
being used since, in this case, it is possible for the same distances to occur
between the electrodes, thus allowing the stimulation-dependent functional
splitting into equivalent sub-populations with the least amount of power
being introduced. By way of example, the end points of the electrodes,
projected along the electrodes, may essentially form a square. By way of
example, it is also possible to use six electrodes. In this case, four are
preferably arranged essentially in a square on one plane, while the other
two are located essentially equidistantly at right angles to this plane, with
their connecting line essentially forming the axis of rotation of the four
electrodes which are arranged in a square. At least some of the electrodes
may also have different lengths in order to produce different geometric
arrangements. According to the prior art, it is possible to combine a
plurality of stimulation electrodes in one stimulation electrode to be
implanted, for example by positioning the stimulation contacts at different
distances from the end of the electrode. This makes it possible to achieve
the same stimulation effect with a small number of electrodes to be
implanted, thus further reducing the occurrence of brain damage.
4.1.2 Embodiment for the situation in which at least one
electrode 2 is not positioned in the nerve cell population to
be desynchronized
In this stimulation form, stimulation is carried out in at least one target area,
which is different from the area to be desynchronized. In this case, the


indirect stimulation can be carried out by stimulation of a neuron population
which is not the same as the nerve cell population to be desynchronized,
and/or by stimulation of a fiber group which is linked to the nerve cell
population to be desynchronized. In this case, either at least one electrode
2 or a multiple electrode arrangement as described in Section 4.1.1 can be
1 used in a target area, for example in the area to be desynchronized.
4.2 Number of sensors
The mechanism of the apparatus according to the invention essentially
comprises, as described in Sections 1 and 3, the measured and processed
neural activities of the neuron population to be desynchronized being
applied again as stimulation. The sensors 3 are one of the most important
components of the apparatus according to the invention and, as described
in Section 3.1, may be positioned either outside the neuron population to
be desynchronized or preferably directly in the neuron population to be
desynchronized. Only one sensor 3 is preferably used, in order to detect
the activity of the neuron population to be desynchronized. This keeps the
number of sensors to be implanted as small as possible, in order to prevent
unnecessary tissue damage and, in particular, brain bleeding during the
implantation. However, for example, it is also possible to use two or more
sensors in order to reconstruct the neural activity of the neuron population
to be desynchronized much more completely as a combination of the
measured activities.
Furthermore, possible brain damage caused by the implantation is further
reduced or avoided, and the stimulation effect is improved, by combining
the sensors 3 and stimulation electrodes 2 in one electrode to be
implanted.
4.2.1 Embodiment for the situation in which the sensors 3 are all
positioned in the nerve cell population to be
desynchronized


The sensors 3 should preferably be arranged such that a large proportion
of the nerve cell population to be desynchronized can be detected by
means of the sensors. This can be achieved with a different geometric
arrangement of the sensors with respect to the tissue to be
desynchronized. In the case of an arrangement with only one sensor 3, this
may be located, for example, in the center of the tissue. In the case of
arrangements having a plurality of sensors, as described in Section 4.1.1,
the sensors may be arranged in a similar manner to that which has been
described for the stimulation electrodes.
4.2.2 Embodiment for the situation in which at least one of the
sensors 3 is not positioned in the nerve cell population to
be desynchronized
In this form of the activity measurement, an activity which is associated
with the neural activity of the neuron population to be desynchronized is
measured in at least one area which is not the same as the area to be
desynchronized. In this case, as described in Section 3.1, the indirect
measurement can be carried out by measurement of the activity of a
neuron population which is not the same as the nerve cell population to be
synchronized and/or of a fiber group and/or of a body part which is linked to
the nerve cell population to be desynchronized.
5 Self-regulating demand control of the stimulation amplitude
One of the most important characteristics of the mechanism of the
apparatus according to the invention is self-regulating demand control of
the amplitude of the stimulation signal which is applied to the area to be
desynchronized. The described self-regulation is carried out by the applied
individual stimuli comprising the processed neural activity. When there is
relatively strong synchronous activity in the area to be desynchronized, a
large variance can be expected in the measured neural activity, as is
known to those skilled in the art. This leads directly to a time-delayed
stimulation according to the invention, with an increased stimulation


amplitude. After achieving desynchronization, only neural activity with a
small variance will be expected, as a result of which the stimulation
amplitude is directly influenced, and is automatically reduced. If
resynchronization occurs again, then the apparatus according to the
invention can automatically take account of the increased requirement for
desynchronizing stimulation, by the greater variance in the neural activity
leading to the formation of stronger individual stimuli. This represents self-
regulating demand control of the apparatus according to the invention, see
also Figure 2c.
The mechanism on which the self-regulating demand control is based is
used in all the embodiments of the apparatus according to the invention
that are described in more detail in the following text.
6 Control of the stimulus application
The expression time control of the stimulus application means an
embodiment of the apparatus according to the invention which is preferably
programmed in advance, with the overall stimuli being applied in the
specific manner by means of the stimulator unit 8. The variants of time
control of the stimulus application are permanent, repetitive and demand-
controlled stimulus application. In addition, manual demand control can be
implemented, for example for a stimulus application carried out by the
patient or by the doctor.
6.1 Permanent stimulus application
In the case of permanent stimulus application, the apparatus according to
the invention has a controller which is programmed such that it
continuously applies the stimulation signals to the electrodes 2. Permanent
stimulus application represents the simplest embodiment, which is the
easiest to implement, of the apparatus according to the invention. At the
same time, the self-regulating demand control according to the invention as
described in Section 5 results in a good desynchronizing effect of


permanent stimulation while introducing little energy into the target
population.
During permanent stimulus application, the intensity parameters can be
adapted in accordance with Section 7.2.3. In the same way, the time
parameters - the stimulation period Tand/or time delays -can be adapted
during permanent stimulation in accordance with Sections 7.2.1 and 7.2.2
in conjunction with adaptation of the stimulation intensity, or independently
of it.
6.2 Repetitive stimulus application
In the case of repetitive stimulus application, the apparatus according to
the invention has a controller which is programmed such that it applies the
stimulation signals to the electrodes 2 only during specific time intervals.
There is no stimulation outside these time intervals.
In the case of repetitive stimulus application, the overall stimuli can be
administered on a strictly periodic time basis or on a non-periodic time
basis. In this embodiment, the apparatus according to the invention has a
controller which is programmed such that it periodically and/or non-
periodically monitors the time intervals between the stimulation intervals
and/or the duration of the intervals. A sequence of overall stimuli which is
not periodic in time can be generated by means of a stochastic and/or
deterministic algorithm, in order to achieve the desired desynchronized
state of the population to be desynchronized. The stimulation and
measurement intervals may be arranged such that they overlap, occur at
the same time, or occur at separate times.
During repetitive stimulus application, the intensity parameters can be
adapted in accordance with Section 7.2.3. In the same way the time
parameters - the stimulation period T and/or time delays - can be adapted
during repetitive stimulation in accordance with Sections 7.2.1 and 7.2.2 in
conjunction with adaptation of the stimulation intensity, or independently of


it.
6.3 Demand-controlled stimulus application
In the case of demand-controlled stimulus application, the apparatus
according to the invention has a controller which is programmed such that
it switches the stimulation signals on and off in a manner corresponding to
the specific states of the neuron population to be desynchronized. By way
of example, the stimulation is switched on as described in the following
text.
The activity of the neuron population to be desynchronized is measured by
means of the sensor 3. The neural activity is passed to the unit 4 for signal
processing and/or closed-loop control which, inter alia, acts as means for
identification of a pathological feature. As soon as the unit 4 for signal
processing and/or closed-loop control identifies a pathological feature in
the neural activity, the application of an overall stimulus is started. As soon
as the pathological feature disappears as a result of the effect of the
applied stimulation, stimulation is preferably switched off. In one possible
embodiment as a unit 4 for signal processing and/or open-loop/closed-loop
control, the apparatus according to the invention therefore has a computer
which contains a data storage medium, in which the data relating to the
clinical signs is stored and is compared with the measurement data. The
expression the data relating to the clinical signs means parameters and
measurement variables which are relevant for the stimulation, for example
the instantaneous frequency of the neural activity measured by means of
the sensor 3, of the threshold value which is required for the procedure for
demand-controlled stimulus application, and the stimulation parameters
which define the stimulus intensity. The expression a pathological feature
means, for example, illness-dependent synchronization of the neuron
population to be desynchronized, and can be identified by the following
characteristics of the neural activity:
a) If the pathological activity of the neuron population to be


desynchronized and/or of a neuron population which is closely
linked to this neuron population and/or a closely linked part of the
nervous system or the musculature is measured exclusively or
predominantly by means of the sensor 3, for example in the case of
the direct measurement as described in Section 3.1 and
Section 4.2.1, the neural activity is used directly to determine
whether the amplitude of the neural activity exceeds a threshold
value. The apparatus according to the invention is thus, in one
preferred embodiment, equipped with means for identification of a
value of the amplitude of the neural activity corresponding to the
threshold value. In this case, the neural activity itself, and/or its
magnitude and/or its amplitude are/is preferably compared with the
threshold value. The means for identification of the threshold value
may in this embodiment be programmed such that, for example, it
compares the neurai activity itself and/or its magnitude and/or its
amplitude with the threshold value. The amplitude is determined
either in a simple version by determination of the magnitude of the
signal, and/or with bandpass filtering and subsequent Hilbert
transformation, or wavelet analysis. The unit 4 for signal processing
and/or closed-loop control is in this case programmed such that it
can determine the magnitude of the signal and/or bandpass filtering
with Hilbert transformation and/or wavelet analysis. The neural
activity or its magnitude is particularly preferably used, since the
calculation of the amplitude involves considerably more computation
effort, and the determination of the amplitude cannot be carried out
on a single measured value of the neural activity but must be carried
out at a sufficiently long time interval, as is known by those skilled in
the art, and this can somewhat delay the identification of the
pathological feature,
b) If activity which is not yet illness-specific, for example from other
neuron populations, is additionally measured by means of the
sensor 3 as well as this pathological activity of the neuron population
to be desynchronized, for example as in the case of the indirect
measurement described in Sections 3.1 and 4.2.2, a further


algorithm step must be introduced during the analysis of the neural
activity. Since the illness-specific activity typically occurs in a
frequency range which is different from the frequency range of the
non-illness-specific activity, it is preferably suitable for this purpose
to estimate the activity in the illness-specific frequency range. The
frequency of the illness-specific activity is determined, for example,
by determination of the difference between successive trigger
points. Trigger points are points such as maxima, minima, points of
inflection and zero crossings. This analysis preferably carried out
using a sliding time window, with the mean value of a plurality of
time differences being formed, thus improving the stability.
Alternatively, the frequency estimate can also be determined by
spectral estimation methods and other frequency estimators, which
are known to those skilled in the art. For this purpose, one particular
embodiment of the apparatus according to the invention has means
for estimation of the activity in the illness-specific frequency range,
such as spectral estimation methods, wavelet analysis etc. This is
achieved, by way of example, by means for carrying out a frequency
analysis. By way of example, the spectral energy in the illness-
specific frequency range can be determined using a sliding window.
Alternatively, after bandpass filtering, the amplitude in the illness-
specific frequency range can be determined by determination of the
maximum of the bandpass-filtered signal or by determination of the
mean value of the magnitude of the bandpass-filtered signal, or with
subsequent Hilbert transformation or by means of wavelet analysis.
For this purpose, the apparatus according to the invention has, for
example, means for bandpass filtering of the amplitude and means
for determination of the maximum of the bandpass-filtered signal,
and/or means for determination of the mean value of the magnitude
of the bandpass-filtered signal, and/or means for carrying out a
Hilbert transformation and/or a wavelet analysis.
By way of example, the same overall stimulus is always used for demand-
controlled stimulus application. The stimulation period T is preferably


matched to the instantaneous frequency of the neuron population to be
desynchronized, as described in Section 7.2.1. When the pathological
feature is present, a stimulus is then applied with a stimulation period T
matched to the instantaneous frequency. The time delays can likewise be
adapted in accordance with Section 7.2.2, and/or the intensity of this
stimulus in this case preferably remains constant. However, as in
Section 7.2.3, the intensity parameters can be modified in accordance with
the stimulation effect.
6.3.1 Definition of the requirement
For at least two reasons, there is no unique relationship between the extent
of the pathological feature and the extent of the illness-specific symptoms.
On the one hand, the distance between the sensor 3 and the area to be
desynchronized, in which the neural activity to be measured is generated,
results in a change in the amplitude in the illness-specific frequency range.
On the other hand, a specific extent of the illness-specific feature, that is to
say the extent of the rhythmic activity in the illness-specific frequency
range, is not unambiguously linked with the illness-specific symptoms.
Since the illness-specific rhythm affects complex nerve networks in the
brain which typically, on top of everything else, do not satisfy simple linear
dynamic laws, there are no unambiguous relationships between the illness-
specific rhythm and the extent of the symptoms. If, for example, the illness-
specific rhythm does not sufficiently well match the biomechanically
predetermined natural frequency of an extremity, the tremor which is
caused by the illness-specific rhythm is considerably less than if the illness-
specific rhythm were to resonantly match the biomechanically
predetermined natural frequency of the extremity.
The characteristic property, such as the dominant frequency and the
amplitude, of the measured neural activity are in an empirical range which
is known to those skilled in the art. The value of the extent of the illness-
specific feature of the neural activity measured by means of the sensor 3 is
referred to as a threshold which, if exceeded, typically results in the


occurrence of symptoms, for example of the tremor. The threshold is a
parameter which must be chosen for the embodiment of the demand-
controlled stimulus application as described in Section 6.3. The apparatus
according to the invention thus has means, in the form of the control unit 4,
for identification of a threshold value. The method according to the
invention for demand-controlled stimulus application results in the
advantage that the effectiveness of the apparatus according to the
invention does not critically depend on the choice of the threshold, but
there is a wide error tolerance with regard to the choice of the threshold, for
example in a range of up to 50% of the maximum extent of the illness-
specific feature. The choice of the threshold is determined either
intraoperatively or preferably in the initial days after the operation by
measurement of the neural activity by means of the sensor 3, with the
extent of the illness-specific feature being determined, and being compared
with the extent of the symptoms, for example the intensity of the tremor.
In a less preferred embodiment of the demand-controlled stimulus
application, a representative value, for example the mean value, of a range
of a threshold values measured in patients is adopted as the threshold.
In one preferred embodiment, the choice of the threshold is checked
essentially at regular intervals, for example in the course of six-monthly
inspections.
In the repetitive stimulation embodiment with demand-controlled stimulus
intensity as described in Section 6.2, there is no need for threshold value
detection.
The three stimulation methods described above can preferably be used in
a different combination with the methods for adaptation of the stimulation
parameters as described in Section 7.2.
The inherent self-regulating demand control according to the invention is a
common feature of all three stimulation methods. The direct relationship


between the stimulation signals and the measured neural activity results in
self-regulating demand control as described in Section 5, thus minimizing
the amount of energy introduced into the target population. This self-
regulating demand control acts independently of the implementation of the
additional demand control as described in Section 6.3, and of the
calibration and closed-loop control of the parameters as is described in
Section 7.
7 Calibration and adaptation of the parameters
The following text is based on the assumption that all the electrodes 2 are
located in the neuron population to be desynchronized. The situation in
which at least one electrode is located outside the neuron population to be
desynchronized will be considered separately at the end of the section. By
way of example, a calibration and adaptation can be carried out for the
following parameters of the apparatus according to the invention: the
frequency of the stimulation signal, whose reciprocal corresponds to the
stimulation period, the time delays of the individual stimuli, and the intensity
of the individual stimuli.
7.1 Stimulation parameters at the start of the stimulation
7.1.1 Frequency, stimulation period
Choice of the frequency without previous operation of the apparatus: the
frequency range of the pathological neural activity for the respective clinical
signs is known to those skilled in the art (Elble R.J. and Koller W.C. (1990):
Tremor, John Hopkins University Press, Baltimore). The mean value can
preferably be taken from this frequency range. Alternatively, instead of this,
the frequency value to be expected on an age- and gender-specific basis
can be used from a database.
For successful operation of the apparatus according to the invention, there
is no need for the initially predetermined frequency to match the actually


occurring frequency of the activity of the neuron population to be
desynchronized. The control of the stimulation period T as described in
7.2.1 operates even when an initial value which differs to a major extent
from the correct frequency value is used. In this case, differing to a major
extent means that the value may even be too large or too small by a factor
of at least 10. Alternatively, it is thus also preferably possible to start with a
frequency value which is in the typical frequency range for the illness, as is
known to those skilled in the art. The value of the frequency at the start of
the stimulation can also preferably be obtained by individual matching to
the respective patient. This may be done, for example, by means of a
measurement of the neural activity prior to the stimulation, and estimation
of the dominant frequency in the activity of the neuron population to be
desynchronized, as described in Section 6.3b.
Choice of the frequency with previous operation of the apparatus: the mean
value of the frequency during the previous operation of the apparatus is
chosen as the start value for the frequency.
In both cases, that is to say with and without previous operation of the
apparatus, the stimulation period T is calculated as the reciprocal of the
start value of the frequency.
7.1.2 Time delays
The time delays for the individual stimuli are preferably determined after
initial definition of the stimulation frequency and of the stimulation period T.
The time delays are preferably chosen as fractions of the stimulation period
7", with a different time delay preferably being assigned to each individual
stimulus. The time delays are preferably determined in such a way that the
difference between the time delays corresponds to fractions of the
stimulation period 7", so that the difference between the time delays would
thus be a multiple of 7/N in the situation in which the time delays are
equidistant. Equidistant time delays are, however, not necessary for
successful desynchronization of the neuron population to be


desynchronized. It is also preferable to choose time delays which
correspond to a multiple of fractions of the stimulation period T and which
may exceed the stimulation period T. The adaptation of the time delays as
described in Section 7.2.2 also works in the situation described above, in
which at least some of the time delays exceed the stimulation period T.
7.1.3 Intensity
The initial values of the stimulation parameters which determine the
intensity of the individual stimuli (for example the gain of the feedback
stimulation signal) are defined in accordance with the empirical values
which are known to those skilled in the art (for example a maximum
amplitude of 5 V). The intensity control as described in 7.2.3 works even
when an initial value is used which differs to a major extent from the best
intensity value. In this case, differing to a major extent means that the value
may even be too large (maximum amplitude 5 V) or too small by a factor of
at least 10. Alternatively, it is thus also preferable to start with an intensity
value which is in the range that is known to those skilled in the art. In
particular, it is preferable to start a stimulation with low values of the
intensity, for example a maximum amplitude of 0.5 V, for the stimulation
signals, in order in this way to reduce as far as possible the side-effects of
the stimulation. If there is a need to use stronger stimulation signals, the
intensity can be increased in small steps, as described in Section 7.2.3.
The initial values for the frequency and intensity can thus be
predetermined, but in particular need not be predetermined in the course of
a time-consuming calibration.
7.2 Adaptation of the stimulation parameters
7.2.1 Adaptation of the stimulation period T
The neural activity is measured in the area to be desynchronized or in an
area which is closely linked to it, and is used, after processing, as the


stimulation signal. By way of example, in the case of Parkinson's disease,
instead of a measurement by means of the sensors 3, a measurement of
the activity in a subsequent area, for example the premotor cortex, by
means of epicortical sensors, can also be carried out directly in the area to
be desynchronized. The dominant mean period is determined in a time
window with a length as stated in the following text. Various algorithms can
be used for this purpose. For example, the instantaneous period can be
determined as the time difference between two successive maxima of the
measured neural activity. It is also, for example, possible to first of all
estimate the mean frequency of the neural activity, and to define the
stimulation period T as the reciprocal of the mean frequency. If not only
illness-specific activity is measured by means of the sensor 3, the illness-
specific activity must first of all be extracted, by bandpass filtering of the
frequency range that is specific for that illness, for this type of frequency
estimation. Alternatively, by way of example, the frequency can be
determined by means of the frequency estimator that is mentioned in
Section 6.3. The time window which is used for this frequency estimate has
a length which may be open towards upper values and corresponds, for
example, to 10 000 periods, preferably to 1000 periods and particularly
preferably to 100 periods of the activity relating to the illness, or else to any
other desired values.
7.2.2 Adaptation of the time delays
As described in Sections 3.3, 3.4 and 7.1.2, the time delays for the
individual stimuli are typically chosen as fractions of the stimulation period
T. By way of example, the time delays may be fixed during the stimulation,
or may preferably be matched to the stimulation period that has been
adapted in accordance with Section 7.2.1. In order to make it possible to
achieve optimum desynchronization with a low stimulation intensity, the
time delays of the individual stimuli are preferably varied during the
stimulation by means of a deterministic or stochastic algorithm. For this
purpose, the apparatus according to the invention has means in the form of
the control unit 4 which allow the time delays of the individual stimuli to be


varied during the stimulation. Furthermore, for example, the time delays
can be varied not only within a stimulation period but also over a plurality of
periods. In this case, the individual stimuli correspond to the processed
neural activity which was measured at a time several periods earlier.
7.2.3 Adaptation of the intensity
The sensor 3 is used to measure the neural activity which represents the
activity of the neuron population to be desynchronized. This neural activity
is passed to the unit 4 for signal processing and/or control purposes. The
unit 4 for signal processing and/or control carries out a permanent,
repetitive or demand-controlled stimulation in accordance with Section 6,
with the intensity of the overall stimuli which are applied at the respective
time being dependent on the extent of the pathological feature in the neural
activity. The intensity can preferably be adapted for this purpose. The
relationship between the stimulus intensity and the extent of the
pathological feature can be controlled either manually or automatically as a
function of the stimulation success. The extent of the pathological feature is
determined in a time window with a freely variable, preferably constant,
length, which ends at a constant time interval before the respective
stimulus, in the following manner:
a) In the situation when the sensor 3 is used to measure exclusively or
predominantly the pathological activity to be desynchronized and/or
a neural or muscular activity which is closely linked to it, the
amplitude of the extent of the synchronization corresponds to the
neuron population to be desynchronized. The amplitude thus
represents the pathological feature. The amplitude can in this case
be estimated by determination of the maximum of the signal or by
means of the mean value of the magnitude of the signal, or by
bandpass filtering with subsequent Hilbert transformation or wavelet
analysis. The first two variants (determination of the maximum of the
signal or determination of the mean value of the magnitude of the
signal) are particularly preferably used, since the calculation of the
amplitude by means of a Hilbert transformation or wavelet analysis


involves considerably more computation complexity, their accuracy
depends on the correct choice of algorithmic parameters,
b) If the sensor 3 is used to measure not only the illness-specific
activity but additionally inactivity which is not yet illness-specific, for
example from other neuron populations, the neural activity cannot
be used directly for estimation of the extent of the pathological
feature. Since the illness-specific activity typically occurs in a
frequency range which is not the same as the frequency range of
the non-illness-specific activity, the activity in the illness-specific
frequency range is preferably estimated in this situation. This is
done, for example, by means of a frequency analysis. For example,
the spectral energy can be determined in the illness-specific
frequency range. As an alternative to this, the amplitude can be
determined after bandpass filtering by determination of the
maximum of the bandpass-filtered signal or by determination of the
mean value of the magnitude of the signal, or by subsequent Hilbert
transformation or wavelet analysis.
If the desired effect is not achieved, that is to say the target population is
not desynchronized to an adequate extent and the pathological feature of
the neural activity is therefore not shifted below the threshold value, the
maximum intensity of the stimulus is slowly increased up to a maximum
value, for example of 5 V, which is stringently predetermined for safety
reasons (for example in steps of 0.5 V per 50 periods). For this purpose,
the apparatus according to the invention has a controller which identifies
any change in the neural activity and adapts the stimulating signals in the
direction of higher values if there is no change in the neural activity. After
about 20 successful periods of the stimulation, the apparatus can start to
slowly reduce the maximum intensity of the stimulus (for example in steps
of 0.5 V per 50 periods), provided that the stimulation is still successful.
The stimulation success is determined during this process as described
above. The controller is in this case programmed such that it identifies the
change in the neural activity, and thus the stimulation success. The
maximum stimulus intensity is preferably controlled on a time scale of


between 10 and 1000 periods of the neural activity, such that the neuron
population to be desynchronized is adequately desynchronized.
Independently of the value of the stimulation intensity as defined above, the
amplitude of the stimulation signal is automatically minimized as a
consequence of the characteristics, as described in Section 5, of the
stimulation mechanism of the apparatus according to the invention after
successful desynchronization.
7.3 Stimulation parameters for the situation in which at least one
electrode 2 is not located in the neuron population to be
desynchronized
As in the situation described in Section 3.3 of an electrode 2 which is not
located in the neuron population to be desynchronized, the neuron
population to be desynchronized is influenced via an indirect stimulation, as
described in Section 4.1.2. Since, in the case of indirect stimulation, the
conduction times between the stimulated neuron populations on the one
hand and the neuron population to be desynchronized on the other hand
may each be of a different magnitude, the respective conduction times are
first of all measured before carrying out the desynchronizing stimulation.
Stimulation is for this purpose carried out via in each case one stimulation
electrode 2, and the stimulus response is measured by means of the
sensors 3 which are placed in the neuron population to be desynchronized.
This is done separately n-times for all stimulation electrodes 2 which are
used for indirect stimulation, with n typically being a small integer, up to for
example 200. The mean conduction time is preferably estimated from this
in the following manner:
The duration between the start of the stimulus application via the j-th
electrode 2 and the first maximum in the stimulation response or in the
magnitude of the stimulation response, is determined for each
individual stimulus application. In the case of , the index j represents the
j-th electrode 2, while the index k represents the k-th applied stimulus.


The mean duration between the stimulus start and the stimulus response is
then determined separately from this for each stimulation electrode 2 that is
used for indirect stimulation, using the following formula 1:

Formula I
In this case, Lj is the number of stimuli applied via the j-th stimulation
electrode 2. Ls may but need not be the same for all stimulation electrodes
2 which are used for indirect stimulation.
The conduction time determined in this way for the stimulation is taken
into account in the following manner:
If a stimulus were applied by direct stimulation of the neuron population to
be desynchronized with a time delay f of 2 via the j-th stimulation electrode
2, then, in the case of indirect stimulation, the stimulus would be
administered with a time delay of , via the j-th stimulation electrode 2 for
indirect stimulation, in which case r must be greater than as can be
done in accordance with Section 7.2.2.
The determination of the stimulation parameters at the start of the
stimulation and the control mechanisms during the stimulation are
completely analogous when the conduction times are taken into account
as described above, as described in Sections 7.1 and 7.2.
8 Advantages
The apparatus according to the invention has a number of advantages over
existing apparatuses, for example DE 108 18 071.0-33 "Vorrichtung zur

Desynchronisation von neuronaler Hirnaktivitat" [Apparatus for
desynchronization of neural brain activity]:
1. The major advantage of the apparatus according to the
invention is that a physiological stimulus, specifically the
feedback stimulation signal, that is to say the measured and
processed neural activity of the neuron population to be
desynchronized, is used for the stimulation. The self-regulating
demand control of the stimulation amplitude as described in
Section 5 thus takes place, thus minimizing the amount of
energy introduced into the neuron population to be
desynchronized, and thus lead to side-effects that are minor.
2. Because of the self-regulating stimulation amplitude in
accordance with Section 5, the operation of the apparatus
according to the invention saves power, since not only is a
power-saving signal used for stimulation on the basis of the
demand-controlled stimulation amplitude, but a saving in energy
can also be expected in the case of the control apparatuses
according to the invention, as are required for stimulation
control. This makes it possible to achieve longer intervals
between the necessity for battery changes, which is
burdensome for the patient.
3. The embodiment of the repetitive or permanent application
with demand-controlled stimulus intensity is particularly
advantageous, since no threshold need be detected with this
method. This embodiment can thus be implemented with
considerably simpler algorithms. Its software and/or hardware
implementation is accordingly considerably less complex.
4. In the case of permanent and repetitive stimulation with
demand-controlled stimulus intensity and direct stimulation of
the neuron population to be desynchronized, no calibration is


required, that is to say there is no need to carry out a series of
test stimuli in which the stimulation parameters are varied
systematically, thus leading to the calibration duration being
shorter.
5. The calibration which is carried out according to the invention
is quicker, less susceptible to errors and is less complex since,
in the case of direct stimulation, it is possible to start stimulation
operation without any test stimulation, with the parameters being
optimized in the course of stimulation operation, as described in
Section 7.2. Because the calibration can be carried out quickly,
the apparatus according to the invention can even be used
intraoperatively, thus optimizing the placing of the deep
electrodes 2. This makes it possible to use the effect of the
desynchronizing stimulation on the extent of the symptoms, for
example the tremor, directly as a parameter, for the quality of
the placing.
6. The calibration according to the invention is less susceptible
to errors since the frequency and conduction time estimators
that are used in the course of the calibration according to the
invention do not depend critically on parameters such as the
limits and the characteristics of a bandpass filter. This
embodiment can thus be implemented with considerably simpler
algorithms. Its software and hardware implementation is
accordingly considerably less complex.
7. Overall, one major advantage is the general tolerance and
robustness of the apparatus according to the invention
compared to the estimation of the parameters of intensity,
stimulation period and time delays.
8. Because of the use of the possibly different stimulation effect
as a function of the distance between the electrode and the area


to be stimulated, and use of the pathologically increased
coupling between the neurons in the neuron population to be
desynchronized, the apparatus according to the invention
stabilizes the area to be desynchronized in a desynchronized
and desired state. This state is provided permanently and thus
brings the area to be desynchronized very close to the
physiological state. By way of example, long-lasting
desynchronization is attained without any fluctuation backwards
and forwards between resynchronization and a cluster state.
Example:
If stimulation is carried out, for example, at four locations, then, by way of
example, the following stimuli can be emitted via the four electrodes:
1. The feedback stimulation signal, that is to say the processed
neural activity, is applied via each of the electrodes, with the
stimulation signals in each case being offset by T/4 in time, as
shown in Figure 3, when T is the mean period of the rhythm of
the neuron population to be desynchronized.
2. As is illustrated in Figure 4, stimulation signals with the same
time delay but of different polarity are applied via the electrodes
1 and 2. The same stimulation signals with a different polarity
are likewise applied via the electrodes 3 and 4.
By way of example, the stimulation is carried out with three different control
mechanisms, as described in Section 6, for the stimulus application thus
preferably allowing demand-controlled and thus power-saving and mild
(avoiding side-effects) stimulation, as described in Section 7:
1. Permanent stimulus application: the stimulation is carried out
permanently, see Figure 2, preferably with adaptation of the
stimulation period. As can be seen by way of example in
Figure 2, desynchronization of the neuron population to be
desynchronized occurs directly after application of the


stimulation. This minimizes the amplitude of the measured
neural activity, see Figure 2b.
At the same time, as can be seen by way of example in
Figure 2c, the stimulation amplitude is minimized because of the
self-regulating demand control mechanism as described in
Section 5. Once the stimulation has been switched off,
resynchronization occurs after a short time, owing to the
pathological interaction between the neurons in the population.
2. Demand-controlled stimulus application (that is to say
demand-controlled choice of the start and end times of the
stimulation) of the overall stimuli: if the synchronization of the
nerve cell population exceeds a threshold value, the next overall
stimulus is emitted via all of the electrodes, as described in
Section 6.3.
3. Repetitive stimulus application: repetitive stimulation is
carried out with coordinated stimuli via all of the electrodes. In
this case, the intensity of the stimuli is matched to the intensity
of the synchronization of the neuron population: the greater the
synchronization, the stronger is the coordinated stimulus.
In this variant, can preferably be chosen rather than T/44
as the time delay between the individual stimuli, where T is the
period of the rhythm without stimulation ris the period forced on
the rhythm by the stimulation. In other words: 1/τ is the
frequency of the stimulation signal with which the individual
stimuli are applied. This results in the only critical stimulation
parameter to which the system is subject: instead of determining
this in a suitable form in the course of a complex calibration, it is
dictated by the stimulation. Furthermore, this form of demand-
controlled stimulation makes use of the fact that the neurons in
the relevant regions have a tendency (because of the illness) to
periodic firing or bursts (rhythmic production of groups of action
potentials). It is therefore possible to achieve an entrainment of


the neural activity of the neuron population to be
desynchronized, with respect to the applied frequency.
In all three of the control methods described by way of example above,
self-regulating demand control, as described in Section 5, results in the
amount of energy introduced into the target population being minimized. In
this case, it is preferably possible to adapt the only important stimulation
parameters, the stimulation period T and thus the time delays, between the
individual stimuli, by measurement of the frequency of the nerve cell
population in the target region, or of another nerve cell population which is
closely linked to it.
The lack of time-consuming calibration and stabilization of the effect even
in the event of relatively major frequency fluctuations - particularly in the
case of method 1 (permanent stimulation) - has important consequences:
1. The stimulation success can be checked immediately,
intraoperatively, during the insertion of the deep electrode. This
makes it possible to considerably improve the finding of the
suitable target point. A calibration process which lasts for more
than 30 minutes per electrode is required for the previous
demand-controlled methods. This cannot be carried out
intraoperatively and is not acceptable to the patient (who is not
anesthetized).
2. The new stimulation methods can also be used for
neurological and psychiatric illnesses in which pathological
rhythms have highly fluctuating frequencies. In particular, the
new methods can also be used to desynchronize rhythms which
occur intermittently (that is to say which occur for a short time).
This means that the new stimulation methods can be used for
many more illnesses, and particularly even in the case of
epilepsies.
The following illnesses and symptoms can be treated by means of the new


stimulation method with the apparatus according to the invention by
desynchronization of suitable brain areas.
In the case of all neurological and psychiatric illnesses in which
pathological neural synchronization plays a relevant role for the extent of
the illness-specific symptoms, for example: Parkinson's disease, essential
tremor, dystonia, compulsion disorder, tremor in the case of multiple
sclerosis, tremor as a consequence of a stroke or other tissue damage, for
example tumorous tissue damage, for example in the area of the thalamus
and/or the basal ganglia, choreoathetosis and epilepsy, although this list is
not intended to be restrictive.
By way of example, the following target areas are used for the standard
method of high-frequency continuous stimulation that is used at the
moment:
In the case of Parkinson's disease the nucleus subthalamicus or in the
case of tremor-dominant Parkinson's disease the thalamus, for example
the nucleus ventralis intermedius thalami.
In the case of essential tremor the thalamus, for example the nucleus
ventralis intermedius thalami.
In the case of dystonia and choreoathetosis the globus pallidum internum,
in the case of epilepsy the nucleus subthalamicus, the cerebellum, thalamic
core regions, for example the nucleus ventralis intermedius thalami, or the
nucleus caudatus.
In the case of compulsion disorders, the capsula interna or the nucleus
accumbens.
By way of example, the target areas listed above for the respective
illnesses may be chosen for the apparatus according to the invention.
Because either no calibration is required or the calibration can be carried


out very quickly for the apparatus according to the invention, this makes it
possible to test alternative target areas in the course of the electrode
implantation process, for which the desynchronizing effect of the apparatus
according to the invention may turn out to be even better.
The invention likewise covers a controller which controls the described
method of operation of the apparatus according to the invention, as well as
the use of the apparatus and of the controller for the treatment of illnesses
including Parkinson's disease, essential tremor, dystonia, compulsion
disorders, choreoathetosis, tremor in the case of multiple sclerosis, tremor
as a consequence of a stroke or of some other tissue damage, for example
tumorous tissue damage, for example in the area of the thalamus and/or
the basal ganglia, and epilepsy.
The apparatus according to the invention can be used both as an implant
for permanent therapy for the above-mentioned neurological and
psychiatric illnesses and for intraoperative target point diagnosis, that is to
say intraoperative finding of the optimum target point for the electrode
implantation.


WE CLAIM :
1. An apparatus for desynchronization of neural brain activity, having
at least one sensor (3) for measurement of a signal which
reproduces the time development of the activity of the neuron
population to be desynchronized, as well
at least two electrodes (2),
characterized by
a controller (4) which is designed in such a manner that it
records the measurement signal from the sensor (3) and
feeds the measurement signal as a stimulation signal or the
measurement signal, once it has been processed, as a
stimulation signal into each of the at least two electrodes (2).
2. The apparatus as claimed in claim 1,
characterized
in that the controller (4) produces stimulation signals which
are delayed in time with respect to the measurement signals.
3. The apparatus as claimed in claim 2,
characterized
in that the controller (4) emits stimulation signals to N
electrodes (2) with different time delays in at least some
cases, and/or
in that the controller (4) produces stimulation signals whose
time delays are essentially equidistant, and/or
in that the controller (4) produces stimulation signals whose
time delay corresponds to a fraction or to a multiple of the
fractions of the period T of the measurement signals.
4. The apparatus as claimed in one of claims 1 to 3,
characterized

in that the controller (4) uses the sensors (3) to directly
measure the time profile of the activity of the neuron
population to be desynchronized, or
in that the controller (4) uses at least one of the sensors (3) to
indirectly measure the time profile of the neural activity, in
which case, in particular, the controller (4) uses at least one
of the sensors (3) to measure the time profile of the activity of
a muscle group which is influenced by the area to be
desynchronized, and/or to measure the time profile of the
activity of a neuron population which is associated with the
area to be desynchronized.
5. The apparatus as claimed claim 4,
characterized
in that the controller (4) permanently measures the time
profile of the activity, or
in that the controller (4) measures the time profile of the
activity in discrete-time measurement intervals, in which case,
in particular, the controller (4) controls in the duration and/or
the intervals between the discrete measurement intervals by
means of a deterministic and/or stochastic algorithm.
6. The apparatus as claimed in one of claims 1 to 5,
characterized
in that the controller (4) stores the measurement signals.
7. The apparatus as claimed in one of claims 1 to 6,
characterized
in that the controller (4) processes the measurement signals,
in particular filtering them, in which case, in particular, the
controller (4) carries out a frequency analysis and/or a
wavelet analysis and/or bandpass filtering and/or filtering
and/or aHilbert transformation in the time domain for the
measurement signals, and/or transforms and/or combines

and/or amplifies the measurement signals linearly and/or non-
linearly.
8. The apparatus as claimed in one of claims 1 to 7,
characterized
in that the controller (4) restricts the maximum amplitude of
the stimulation signal.
9. The apparatus as claimed in claim 7 or 8,
characterized
in that the controller (4) changes the polarity of the
measurement signals, and/or
in that the controller (4) time-codes the measurement signals,
in which case the controller (4) in particular codes the
measurement signals as pulse strings, in particular as radio-
frequency pulse strings, and/or
in that the controller (4) produces stimulation signals whose
net charge introduced is essentially zero.
10. The apparatus as claimed in one of claims 1 to 9,
characterized
in that the controller (4) produces individual stimuli from the
measurement signals, and/or
in that the controller (4) drives at least two electrodes (2) with
individual stimuli, and/or
in that the controller (4) drives at least two electrodes (2) with
different individual stimuli, in which case the controller (4) in
particular generates individual stimuli, which are generated by
different processing steps, and/or
in that the controller (4) detects differences in the conduction
time between the stimulus location of an individual electrode
(2) and the location of the neuron population stimulated by it,
in which case the controller (4) in particular also includes the
associated conduction times in the calculation of the time

delays of the individual stimuli of the individual electrodes (2)
and/or in the processing of the measurement signals, and/or
in that the controller (4) emits signals for overall stimuli to the
electrodes (2), which
signals comprise signals for individual stimuli, in which case,
in particular, the controller (4) emits in each case one
individual stimulus to at
least two electrodes (2) of N electrodes (2) in the course of an
overall stimulus, and/or the controller (4) produces overall
stimuli whose net charged introduced is essentially zero,
and/or the controller (4) emits signals to all N electrodes (2)
with essentially equidistant time delays in the course of the
application of an overall stimulus, and/or the controller (4)
determines and varies the sequence and/or the nature and/or
the intensity and/or the energy introduced by the individual
stimuli in an overall stimulus using a deterministic and/or
stochastic algorithm, and/or the controller (4) varies the
electrodes (2) which are driven in the course of an overall
stimulus, in which case, in particular, the controller (4) varies
the electrodes (2) which are driven in the course of an overall
stimulus by means of stochastic and/or deterministic
algorithms.
11. The apparatus as claimed in one of claims 1 to 10,
characterized
in that at least some of the electrodes (2) have different
lengths, and/or
in that the controller (4) feeds the stimulation signals
permanently or repetitively into at least one of the electrodes
(2), in which case, in particular, the controller (4) applies an
overall stimulus in a repetitive application in discrete-time
stimulation intervals, and/or the controller (4) controls the
duration and/or the intervals between the discrete stimulation
intervals by means of a deterministic and/or stochastic

algorithm.
12. The apparatus as claimed in one of claims 1 to 11,
characterized
in that the controller (4) contains an additional demand
controller.
13. The apparatus as claimed in claim 12,
characterized
in that the controller (4) uses the measurement signals
measured by means of the sensor (3) for demand control,
and/or
in that the controller (4) uses the amplitude of the
measurement signal measured by means of the sensor (3),
and/or
in that the controller (4) estimates the amplitude of the
measurement signal measured by means of the sensor (3) in
that it uses the measurement signal itself and/or the
magnitude of the measurement signal and/or the
measurement signal which has been bandpass-filtered in the
illness-specific frequency range, and/or the magnitude of the
measurement signal which has been bandpass-filtered in the
illness-specific frequency range and/or the instantaneous
amplitude determined using bandpass filters and downstream
Hilbert transformation and/or wavelet analysis, and/or
in that the controller (4) applies an overall stimulus when
detecting of a pathological feature in the measurement signal
measured by means of the sensor (3), and/or
in that the controller (4) detects a pathological feature by
detecting that a threshold value of the amplitude of the
measurement signal measured bymeans of the sensor (3)
has been exceeded, and/or
in that the controller (4) detects a pathological feature by
detecting that a threshold value of the amplitude of the

measurement signal measured by means of the sensor (3)
and bandpass-filtered in the illness-specific frequency range
has been exceeded, and/or
in that the controller (4) compares the amplitude of the
measurement signal measured by means of the sensor (3)
with the threshold value in a sliding time window in order to
detect a pathological feature.
14. The apparatus as claimed in one of claims 1 to 13,
characterized
in that the controller (4) contains an additional manual
demand controller.
15. The apparatus as claimed in one of claims 1 to 14,
characterized
in that the controller (4) matches the stimulation period T to
the instantaneous period of the neuron population to be
desynchronized, in which case, in particular, the controller (4)
determines the instantaneous period of the neuron population
to be desynchronized either by means of an estimate of the
time difference between trigger points or by means of
frequency estimators.
16. The apparatus as claimed in one of claims 1 to 14,
characterized
in that the controller (4) matches the stimulation period T to
the mean frequency of the neuron population to be
desynchronized.
17. The apparatus as claimed in one of claims 2 to 16,
characterized
in that the controller (4) matches the time delayof the
stimulation signals to the stimulation period T.

18. The apparatus as claimed in one of claims 1 to 17,
characterized
in that the controller (4) adapts the stimulus intensity, in which
case, in particular, in that the controller (4) controls the
stimulus intensity on a time scale between 10 and 1000
periods of the neural activity, such that the neuron population
to be desynchronized is adequately desynchronized, and/or in
that the controller (4) varies the gain of the stimulation signals
in order to control the stimulus intensity, and/or the controller
(4) is programmed such that the relationship between the
stimulus intensity and the extent of the pathological feature
can either be set manually and/or is automatically controlled
as a function of the stimulation success.
19. The apparatus as claimed in one of claims 1 to 18,
characterized
in that the controller (4) drives each electrode of at least some
of the N electrodes (2) such that the neuron population to be
desynchronized is either stimulated directly and/or a neuron
population which is connected to the neuron population to be
desynchronized via nerve fiber bundles is stimulated, and/or a
nerve fiber bundle which is connected to the neuron
population to be desynchronized is stimulated, and/or
in that at least one electrode (2) is physically combined with
at least one sensor (3), and/or
in that the controller (4) arranges the measurement and
stimulation intervals such that they overlap, occur at the same
time or are separated in time.
20. A controller, characterized
in that the controller is programmed such that it controls the
steps for carrying out the procedure for the apparatus as
claimed in one of claims 1 to 19.


ABSTRACT


AN APPARATUS FOR DESYNCHRONIZATION
OF NEURAL BRAIN ACTIVITY
The invention relates to an apparatus for desynchronization of
neural, illness-synchronous brain activity in which, according to the
invention, the activities in at least two subareas of a brain area or at least
two functionally associated brain areas are stimulated by means of at least
two electrodes, on the basis of which, in the case of a person with an
illness, desynchronization surprisingly occurs in the relevant neuron
population and the symptoms are suppressed. The feedback stimulation
signal, that is to say the measured, time-delayed and process neural
activity, is used as an individual stimulus. In consequence, this results in
demand control, which is self-regulating according to the invention, of the
amplitude of the stimulation signal thus minimizing the intensity of the
stimulation stimuli automatically after successful desynchronization. For
successful operation, the apparatus requires neither complex calibration
nor control of the stimulation parameters and, instead, these can preferably
be adapted and optimized by the additional controller. The apparatus has
at least two stimulation electrodes (2) and at least one sensor (3), which
are driven by a controller such that they result in desynchronization in their
local environment.

Documents:

01435-kolnp-2006 abstract.pdf

01435-kolnp-2006 assignment.pdf

01435-kolnp-2006 claims.pdf

01435-kolnp-2006 correspondence others-1.1.pdf

01435-kolnp-2006 correspondence others.pdf

01435-kolnp-2006 description(complete).pdf

01435-kolnp-2006 drawings.pdf

01435-kolnp-2006 form-1.pdf

01435-kolnp-2006 form-13.pdf

01435-kolnp-2006 form-3.pdf

01435-kolnp-2006 form-5.pdf

01435-kolnp-2006 international publication.pdf

01435-kolnp-2006 international search authority report.pdf

01435-kolnp-2006 pct form.pdf

01435-kolnp-2006 priority document.pdf

01435-kolnp-2006-correspondence-1.2.pdf

01435-kolnp-2006-form-18.pdf

1435-KOLNP-2006-(10-05-2012)-CORRESPONDENCE.pdf

1435-KOLNP-2006-(13-09-2012)-CORRESPONDENCE.pdf

1435-KOLNP-2006-ASSIGNMENT.pdf

1435-KOLNP-2006-CANCELLED PAGES.pdf

1435-KOLNP-2006-CORRESPONDENCE OTHERS 1.1.pdf

1435-KOLNP-2006-CORRESPONDENCE OTHERS 1.2.pdf

1435-KOLNP-2006-CORRESPONDENCE-1.3.pdf

1435-KOLNP-2006-CORRESPONDENCE.pdf

1435-KOLNP-2006-EXAMINATION REPORT.pdf

1435-KOLNP-2006-FORM 1-1.2.pdf

1435-KOLNP-2006-FORM 1.1.pdf

1435-KOLNP-2006-FORM 13-1.1.pdf

1435-KOLNP-2006-FORM 13-1.2.pdf

1435-KOLNP-2006-FORM 18-1.1.pdf

1435-KOLNP-2006-FORM 3-1.1.pdf

1435-KOLNP-2006-FORM 3-1.3.pdf

1435-KOLNP-2006-FORM 3.1.pdf

1435-KOLNP-2006-FORM 3.2.pdf

1435-KOLNP-2006-GRANTED-ABSTRACT.pdf

1435-KOLNP-2006-GRANTED-CLAIMS.pdf

1435-KOLNP-2006-GRANTED-DESCRIPTION (COMPLETE).pdf

1435-KOLNP-2006-GRANTED-DRAWINGS.pdf

1435-KOLNP-2006-GRANTED-FORM 1.pdf

1435-KOLNP-2006-GRANTED-FORM 3.pdf

1435-KOLNP-2006-GRANTED-FORM 5.pdf

1435-KOLNP-2006-GRANTED-SPECIFICATION-COMPLETE.pdf

1435-KOLNP-2006-INTERNATIONAL PUBLICATION.pdf

1435-KOLNP-2006-INTERNATIONAL SEARCH REPORT & OTHERS.pdf

1435-KOLNP-2006-OTHERS.pdf

1435-KOLNP-2006-PA.pdf

1435-KOLNP-2006-PETIOTION UNDER RULR 137.pdf

1435-KOLNP-2006-PETITION UNDER RULE 137.pdf

1435-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf

1435-KOLNP-2006-TRANSLATED COPY OF PRIORITY DOCUMENT 1.1.pdf

1435-KOLNP-2006-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf

abstract-01435-kolnp-2006.jpg


Patent Number 256694
Indian Patent Application Number 1435/KOLNP/2006
PG Journal Number 29/2013
Publication Date 19-Jul-2013
Grant Date 16-Jul-2013
Date of Filing 26-May-2006
Name of Patentee FORSCHUNGSZENTRUM JULICH GMBH
Applicant Address WILHELM-JOHNEN-STRASSE, 52425 JULICH
Inventors:
# Inventor's Name Inventor's Address
1 TASS, PETER MARKTSTR. 1, 52445 TITZ
2 HAUPTMANN, CHRISTIAN AUF DEM KONIGREICH 17, 52224 STOLBERG
3 POPOVYCH, OLEKSANDR MONSCHAUERSTR. 3, 52355 DUREN
PCT International Classification Number A61N 1/05 ;A61N 1/06
PCT International Application Number PCT/DE2004/002336
PCT International Filing date 2004-10-20
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 103 55 652.4 2003-11-28 Germany