(19)
(11)EP 3 610 916 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
28.04.2021 Bulletin 2021/17

(21)Application number: 18306123.3

(22)Date of filing:  17.08.2018
(51)Int. Cl.: 
A61N 1/36  (2006.01)
A61B 5/00  (2006.01)

(54)

AN APPARATUS FOR CLOSED-LOOP MODEL-BASED ELECTRICAL BRAIN STIMULATION

VORRICHTUNG ZUR ELEKTRISCHEN HIRNSTIMULATION BASIEREND AUF EINEM MODELL MIT GESCHLOSSENER SCHLEIFE

APPAREIL DE STIMULATION ÉLECTRIQUE DU CERVEAU À BASE DE MODÈLE EN BOUCLE FERMÉE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(43)Date of publication of application:
19.02.2020 Bulletin 2020/08

(73)Proprietor: Corstim
34070 Montpellier (FR)

(72)Inventors:
  • BEUTER, Anne
    34070 MONTPELLIER (FR)
  • VOLPERT, Vitaly
    69100 VILLEURBANNE (FR)

(74)Representative: Plasseraud IP 
66, rue de la Chaussée d'Antin
75440 Paris Cedex 09
75440 Paris Cedex 09 (FR)


(56)References cited: : 
WO-A1-2016/023126
US-A1- 2009 118 787
US-A1- 2014 018 882
WO-A1-2017/223564
US-A1- 2012 071 947
  
  • MODOLO: "Using a virtual cortical module implementing a neural field model to modulate brain rhythms in Parkinson's disease", FRONTIERS IN NEUROSCIENCE, 1 January 2010 (2010-01-01), XP055199697, DOI: 10.3389/fnins.2010.00045
  • KUNZE TIM ET AL: "Transcranial direct current stimulation changes resting state functional connectivity: A large-scale brain network modeling study", NEUROIMAGE, ELSEVIER, AMSTERDAM, NL, vol. 140, 13 February 2016 (2016-02-13), pages 174-187, XP029723964, ISSN: 1053-8119, DOI: 10.1016/J.NEUROIMAGE.2016.02.015
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

TECHNICAL FIELD



[0001] The instant description relates to an apparatus and method suitable for electrical brain stimulation, providing an adaptive stimulation signal in space and time in order to modulate the propagation of electrical waves of cortical activity.

BACKGROUND



[0002] The brain can be stimulated by way of either one of electrical, magnetic and optogenetic means in order to treat various neurological conditions. The stimulation of brain can be invasive, implying the need to open the skull and implant some stimulation means directly on and/or inside the brain tissue. The stimulation of brain can be non-invasive, leaving the skull intact and applying the stimuli from outside thereof.

[0003] WO2017/223564 for example describes systems, methods and devices for promoting recovery from a stroke which induced loss of motor function in a subject. The system includes (an) electrode(s), and an operations system in electrical communication with (an) electrode(s), wherein the electrode(s) is/are constructed and arranged to apply current across the brain of the subject and to record low frequency oscillations (LFO) from a perilesional region of the subject. A recording electrode can be placed in electrical communication in a perilesional region of the subject; a stimulation electrode can be placed in electrical communication with the brain of the subject; low frequency oscillations (LFO) from the perilesional region of the subject are recorded; and current stimulation is delivered to the brain of the subject.

[0004] In the above example of prior art, focus is made on treatment of loss of motor functions after stroke. This is why low frequency oscillations are detected, since the low frequency oscillations are considered to be associated to motor functions in an individual. Here in this prior art example the LFO recorded at the perilesional site is used to determine stimulation parameters of alternating current stimulation. Then, wave form and frequency of the alternating current stimulation is calculated to match the recorded LFO. Discrete pulses of current stimulation are then applied to perilesional areas to potentiate motor task related LFOs.

[0005] Also, in the above prior art the LFO stimulation occurs at one electrode or, possibly, simultaneously at several electrodes with the same signal at each electrode, without considering spatial propagation (travelling) of waves. "Wave" in the above cited prior art example concerns the form of time oscillations but it does not concern spatial propagation. Nevertheless, recent experimental and clinical data suggest that the information in the brain cortex propagates in space between cortical nodes in the form of travelling waves. The speed, the amplitude, and the form (frequency) of travelling waves between different cortical nodes have a primary importance for the normal brain functioning. In the case of cortical damage, all these vast signalling pathways cannot be stimulated by a single signal with LFO.

[0006] The instant disclosure has notably for object to improve the existing invasive and non-invasive brain stimulation apparatuses and methods by stimulation of spatially propagating travelling waves between pairs of cortical nodes participating in language function or in the other brain functions.

[0007] Further examples of background art can be found in US2009/0118787A1 describing closed-loop feedback for steering stimulation energy within tissue, and US2012/0071947A1 describing method and apparatus for event-triggered reinforcement of a favourable brain state. Yet, another example of background art can be found in scientific publication of MODOLO: "Using a virtual cortical module implementing a neural field model to modulate brain rhythms in Parkinson's disease", FRONTIERS IN NEUROSCIENCE, 1 January 2010.

SUMMARY



[0008] In contrast to the above cited prior art, the below disclosure has been motivated in particular by finding solution to post-stroke treatment of aphasia consisting in stimulation of spatially propagating (travelling) waves between pairs of cortical nodes participating in language function. Nevertheless, other stroke related disorders can be treated with the very same method and apparatus and it has also been confirmed that other than stroke-related brain dysfunctions can be treated as well. To this aim, the present disclosure provides an apparatus for electrical brain stimulation comprising:
  • a two dimensional electrode array designed to be implanted at the surface of the cortex of a person, said cortex having pre-identified crucial neural nodes and including healthy cortical tissue and damaged and/or partially damaged cortical tissue, said damaged and/or partially damaged cortical tissue having at least one parameter of cortical waves which is different from parameter of healthy cortical tissue, said at least one parameter being one of cortical wave propagation speed, amplitude and frequency,
    said electrode array including electrodes for emitting stimulation electrical signals in the cortex and measuring electrical cortical waves in the cortex,
    and said electrode array being designed to cover at least part of said healthy cortical tissue and said damaged and/or partially damaged cortical tissue;
  • a processor communicating with the electrodes and configured to:
    • based on the measured signals, evaluate said at least one parameter of cortical waves between at least a first electrode and at least a second electrode corresponding respectively to a first pre-identified crucial neural node and a second pre-identified crucial neural node in the cortex, said first pre-identified crucial node and second pre-identified crucial node being situated such that a rectilinear line joining the first pre-identified crucial node and the second pre-identified crucial node crosses said damaged and/or partially damaged cortical tissue;
    • compute in real time, stimulation signals required to maintain said at least one parameter of cortical waves in a predetermined range between said first electrode and said second electrode and apply said computed stimulation signals to the electrodes, and
      wherein each stimulation signal is determined by a stimulation function I(x,t), and the computer processor is configured to calculate numerically the stimulation function I(x,t), applied to each electrode at the damaged and/or partially damaged cortical tissue and the healthy tissue by numerically solving the equation:

      where K is a total neuron density, K-u is a density of not activated neurons, Wa is an intensity of the activating signal, Wi is an intensity of the inactivating signal, superscript (1) corresponds to the healthy tissue and superscript (2) to the damaged or partially damaged tissue, g(u) and H(W) are growing functions of said intensity of activating signal, (K-u)Wa represents a rate of neuron activation and uWi represents a rate of neuron inactivation.


[0009] Especially, compared to the prior art cited in the background section, the present disclosure relies on identifying at least two crucial neural nodes (based on structural and functional relations) and applying external stimulation signal between these pre-identified crucial nodes, thereby restoring functions of the brain. In the above prior art, wave form and frequency of the alternating current stimulation is calculated to match the recorded LFO. In contrast, the present disclosure does not intent to find match between applied alternating current and detected LFOs (nor other oscillations). Instead, the claimed subject matter has to purpose of restoring a match between brain waves in the healthy and damaged cortical tissue. This is done by restoring match between parameters of the brain waves of the healthy and damaged cortical tissue.

[0010] The features of the above defined apparatus respectively comprise means for measuring electrical cortical waves in the cortex, means for evaluating at least one parameters of cortical waves based on the measured signals, and means for computing and applying in real time the stimulation signals required said at least one parameter of cortical waves in a predetermined range. This sequence of steps creates a closed-loop, such that the apparatus can continuously receive input from the electrodes and react by appropriate modifications of the external stimulation signal.

[0011] With these features, the claimed apparatus acts to restore the parameter of cortical waves in the case of reduced connectivity and excitability among individual nodes of the cortical tissue. Two cases may occur. First, the electrical stimulation may increase the connectivity of the damaged and/or partially damaged cortical tissue, in which case the effect of external stimulation may last beyond the stimulation (i.e. after the stimulation is stopped), thereby effectively restoring brain functionality. Second, the external stimulation signal may modify excitability, leading at least to temporal stimulation and improvement of brain function, thereby effectively assisting to restore some brain function, but however not leading to complete recovery of the brain functionality.

[0012] With the claimed apparatus, it is possible to induce propagation of waves of electric potential in the cortical tissue thereby generating electrical activity across the cortex at different speeds and progressing in different directions, such as straight, spiral and other possible directions.

[0013] Relevance of pre-identifying crucial neural nodes prior to application of the external stimulation lies in the fact that it allows to apply the external stimulation signal to the most appropriate location on the cortex. This enhances efficiency of the apparatus. Also, locating electrodes on predetermined crucial nodes allows to apply the external stimulation signal having spatial dependency, i.e. the external stimulation signal is determined according to its position in space (location on the cortex).

[0014] The claimed apparatus enables to sustain wave propagation in the cortex and contributes to cortical network reactivation.

[0015] The closed-loop approach has the advantage that the signal reaching the brain area is programmed to adapt to coexisting brain activity with the consequence that the external stimulation signal does not have to be regularly adjusted manually by the clinician and the external stimulation can be tailored to the individual's needs.

[0016] Further, the arrays of electrodes can provide information about speed of wave propagation in the diseased (damaged or partially damaged) cortical tissue.

[0017] In some embodiments of the above defined apparatus, one might also use one or more of the following features:
  • said predetermined range corresponds to values of said at least one parameter of cortical waves in the healthy cortical tissue;
  • said processor is configured to compute said stimulation signals for the first electrode and second electrode and apply said computed stimulation signals to the first electrode and the second electrode;
  • said at least one parameter of cortical waves is maintained between said first electrode and second electrode via at least one third electrode,
    and wherein said processor is configured to (i) based on the measured signals from said first electrode, second electrode and at least one third electrode, evaluate said at least one parameter of cortical waves between pairs of adjacent electrodes among said first electrode, second electrode and at least one third electrode; (ii) compute said stimulation signals for said first electrode, second electrode and at least one third electrode, and apply said computed stimulation signals to said first electrode, second electrode and at least one third electrode;
  • said at least one third electrode includes a plurality of third electrodes;
  • said plurality of third electrodes form a path designed to be situated at least in part in the damaged and/or partially damaged cortical tissue;
  • said plurality of third electrodes form a path designed to be situated in the healthy cortical tissue;
  • said path is designed to be situated at the edge of the damaged and/or partially damaged cortical tissue;
  • the apparatus is configured to simultaneously stimulate selected pair of electrodes associated with specific pair of pre-identified crucial neural nodes.
  • said processor is configured to compute said stimulation signals by using a mathematical model of propagation of cortical waves;
  • the processor is configured to apply the mathematical model of propagation of cortical waves, such that each stimulation signal is determined by a stimulation function I(x,t), where the stimulation function is a function of space coordinates (this allows to apply external stimulation signal in each electrode of the electrode array differently, such that the spatial propagation of wave - travelling - in the brain cortex is properly respected during treatment);
  • the processor is configured to operate the electrode array such that each electrode in the electrode array applies external stimulation signal (determined by value of stimulation function) dependent on electrode's location on the brain cortex (by applying different stimulation signal in each electrode of the electrode array the spatial propagation of brain waves is respected and the efficiency of the apparatus may be improved; of course this embodiment also includes case where a number of electrodes applies the same external stimulation and one or more other electrodes apply different external stimulation signal; the most appropriate value of external stimulation can be selected for each electrode individually);
  • the processor is configured to apply external stimulation signal determined by the stimulation function I(x,t) having the lowest value of the total stimulation

  • the processor is configured to apply external stimulation signal determined by the stimulation function I(x,t), having the lowest value of maximal stimulation = max I(x,t) ;
  • the processor is configured to determine the value of external stimulation signal determined by the stimulation function I(x,t), such that the process determines wave speed in the cortical tissue according to the formula

    where σ characterizes cortical tissue excitability and γ characterizes cortical tissue connectivity;
  • the processor is configured to determine whether the condition of

    is satisfied in the cortical tissue,
    where σ is a parameter characterizing cortical tissue excitability of healthy cortical tissue and γ is a parameter indicating cortical tissue connectivity.


[0018] Another object of the present description is a method for electrical brain stimulation comprising the steps of:
  • providing a two-dimensional electrode array including electrodes;
    • implanting the two-dimensional electrode array at the surface of the cortex of a person, said cortex having pre-identified crucial neural nodes and including healthy cortical tissue and damaged and/or partially damaged cortical tissue, said damaged and/or partially damaged cortical tissue having at least one parameter of cortical waves which is different from parameter of a healthy cortical tissue, said at least one parameter being one of cortical wave propagation speed, amplitude and frequency;
  • emitting by the electrodes a stimulation electrical signals in the cortex and measuring electrical cortical waves in the cortex;
  • covering by the electrode array at least part of the healthy cortical tissue and the damaged and/or partially damaged cortical tissue;
  • based on the measured signals, evaluating said at least one parameter of cortical waves between at least a first electrode and at least a second electrode corresponding respectively to a first pre-identified crucial neural node and a second pre-identified crucial neural node in the cortex, said first pre-identified crucial neural node and second pre-identified crucial neural node being situated such that a rectilinear line joining the first pre-identified crucial neural node and the second pre-identified crucial neural node crosses said damaged and/or partially damaged cortical tissue;
    • computing in real time, stimulation signals required to maintain said at least one parameter of cortical waves in a predetermined range between said first electrode and said second electrode and applying said computed stimulation signals to the electrodes


[0019] In some embodiments of the above defined method, one might also use one or more of the following additional steps:
  • the method is used to treat post-stroke aphasia and/or other brain disorders in which traveling waves parameters need to be restored
  • the method is used along with active participation of the patient during the external stimulation
  • the method is used to treat post-stroke aphasia
  • the applied computed stimulation signal are not applied to the electrode continuously, more particularly the applied computed stimulation signal is applied to the electrodes at discrete moments in time (such feature is designed for optimizing battery use and provide a more appropriate patient specific treatment, since the external stimulation can be reinjected only when necessary, for example only when the match between parameters of the brain waves of the healthy cortical tissue and the parameters of the brain waves in the damaged cortical tissue becomes larger than a predetermined tolerance).


[0020] Other characteristics and advantages will readily appear from the following description of one embodiment, provided as a non-limitative example, and of the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS



[0021] 

Fig. 1 illustrates a brain showing areas of healthy cortical tissue, damaged and partially damaged cortical tissue.

Fig. 2 illustrates different ways to reconnect pre-identified crucial neural nodes according to the recent disclosure.

Fig. 3 is an illustration of propagation of a monotonic wave with a wave speed c.

Fig. 4 is an illustration of propagation of an oscillating wave with an average wave speed c.

Fig. 5 shows periodic waves propagation in numerical simulations similar to those registered experimentally in electrode arrays (as shown on Fig. 6)

Fig. 6 shows experimentally registered periodic waves registered in electrode arrays (the illustration is taken from a scientific publication of Zhang H, Watrous AJ, Patel A, & Jacobs J., Theta and alpha oscillations are traveling waves in the human neocortex, (2018) Neuron, 98, 1-13 June 27)

Fig. 7 is a schematic illustration of the components of the claimed apparatus.



[0022] On the different Figures, the same reference signs designate like or similar elements.

DETAILED DESCRIPTION



[0023] One of the applications of the disclosure lies in treating aphasia, which is an impairment of language processing (often resulting from stroke). Long term aphasia is increasingly common among the population and since the post-stroke language disorders are closely related to poor quality of life, there is an increased need for providing suitable method and apparatuses for treatment and possible recovery of the brain tissue. Even when the brain functions cannot be re-established completely, partial recovery of brain tissue is often possible and/or the patient can be assisted by the apparatus to maintain, improve or gradually restore the brain function.

[0024] Even though the focus is made on stroke disorders in the brain, it has been studied and concluded that the below described method and apparatus can be equally used to address other brain disorders as well. Comparable results with those presented below are obtained for other brain disorders. Generally, the disclosure could relate to any neurological disorder of the nervous system causing structural, biochemical, and/or electrical abnormalities in the brain, spinal cord or other nerves.

[0025] Generally, there is increasing pressure to find new therapeutic options to help stroke patients recover normal functions or at least to optimize their residual functions when all other options have been exhausted. During early recovery phase following stroke therapies such as neuroprotection, blood flow restoration, pharmacotherapy, and intensive training may improve symptoms significantly. Still yet, estimates conclude that post-stroke impairments persist in up to 40% of patients for more than a year.

[0026] Recovery of the damaged brain tissue can occur spontaneously but can be amplified and accelerated by the use of non-invasive and/or invasive brain stimulation techniques. During the very late stage of recovery improvements appear to reach a plateau. The problem solved thus lies in finding how brain stimulation techniques could enhance remaining cortical excitability in the affected hemisphere. Solutions to this problem are provided by the technique of the present method and apparatus.

[0027] Generally, the method and apparatus presented in the current application introduces a mathematical model adapted to determine external electrical stimulation signal adjusted in such a way that wave speed or other parameters of the brain waves can be reconstructed. Simultaneously, with the treatment present in this application, a patient can undertake any standard rehabilitation therapy available, in order to enhance the effect of the electrical stimulation. The rehabilitation therapy may involve activities related to language such as exercising lexical memory or phonological processing.

[0028] In comparison with existing non-invasive brain stimulation and recovery techniques the present disclosure is advantageous, since it does not have the usual drawbacks of the non-invasive techniques. Non-invasive techniques have limited spatial and temporal resolution. As far as the existing deep brain stimulation techniques are concerned, these techniques are also associated with certain drawbacks. Especially, deep brain stimulation has limitations such as presence of side effects or limited battery life necessitating surgery for its replacement. Finally, it should be noted that the current optogenetic techniques are not yet ready for human cortical stimulation.

[0029] With reference to Fig. 1, following a stroke, the tissue in the brain 1 is affected in some areas. Generally, the areas can be divided into four types. The central infarct area 2 containing dead cells is called umbra 2 and this area contains damaged neural cells. In the present application, umbra is also referred to as damaged cortical tissue 2. Around the umbra 2, there is ischemic tissue called penumbra 3, this area contains partially damaged neural cells and may recover after the stroke. In penumbra 3 brain neural networks are fragmented and partly deactivated. In the present application, penumbra 3 is also referred to as partially damaged cortical tissue. Around the penumbra 3, there could optionally be identified so called perilesional area 4, which could have partially retained its functions but which had also usually been affected by the stroke (having effect for example on its structure). For the purposes of this disclosure, perilesional area will also be referred to as partially damaged cortical tissue, unless specific difference between the penumbra 3 and the perilesional area will be specifically pointed out in the text. Finally, around the neural cortical area of the brain affected by the stroke there is the area which remains fully structurally intact and entirely functional. This area either referred to as viable cortex 5 or as healthy cortical tissue 5.

[0030] Concerning the partially damaged cortical tissue, it is considered that wave speed of propagation of electrical signal between neurons in penumbra 3 and in perilesional area 4 is affected by the stroke. Generally, a wave speed can be determined by tissue excitability and connectivity, which are parameters associated with applied model for brain waves. How these parameters can be defined in terms of concrete physical and mathematical terms will be explained later below. Post-stroke tissue damage in penumbra or perilesional area 4 creates hypoconnectivity and decreases the speed of wave propagation. According to the present disclosure, wave speed or other parameters of the waves can be restored through external electrical stimulation.

[0031] The regions of the brain 1 relevant for the present disclosure are the area of cerebral cortex. Cortex is the outer covering of grey matter over brain's hemispheres. The layer or cortex is typically 2-3 mm thick. Different areas of cortex receive various sensory inputs such as vision, hearing and similar, or could be directly involved in functions such as production of limb or eye movements. Cortical areas may further be related to more complex functions such as memory, language, abstraction, creativity, emotion and similar.

[0032] Studies of brain structure and brain function have revealed the existence of complex and multiple brain networks. In the present disclosure, pre-identified crucial nodes refer to nodes connecting different networks by virtue of their numerous and diverse connections (i.e., connector nodes). Crucial nodes are located differently in each person. For that reason, the model according to which the external stimulation is applied is individualized to characteristics of specific subject and to every person's therapeutic needs. Stimulated crucial neural nodes are pre-identified via structural and functional connectivity measures. The external electrical stimulation method of this application and the associated apparatus can be used along with active participation of the patient during the external stimulation or it can be used while the subject is at rest.

[0033] Considering the specific application of treating aphasia and adjustments made in order to address complex human brain structure, the present disclosure is specifically adapted for use with human patients. Both the method and the apparatus are thus applied to humans only.

[0034] In the present disclosure, the method and apparatus are based on use of a two dimensional electrode array 6 adapted to be implanted at the surface of the cortex, as known in the art. The electrode array 6 includes electrodes 7 for emitting stimulation electrical signals in the cortex and measuring electrical cortical waves in the cortex. Further, the position of at least some of said electrodes 7 correspond respectively to pre-identified crucial neural nodes in the cortex. This means that the electrodes 7 are positioned at selected areas of brain tissue with regard to brain structure and functionality, as well as with regard to which part of the brain 1 is damaged and/or partially damaged. The electrode array 6 may be integrated in a flexible material suitable for closely covering the surface of the cortex.

[0035] Both Fig. 1 and Fig. 2 illustrate electrodes 7 as dots. Every single dot represents one electrode 7. The electrodes can be provided in any desired number and any desired density on the surface of the brain tissue. Schematic representation of electrodes 7 on the drawings is not intended as limitation. Rather, the drawings merely illustrate such a number of electrodes required for easy understanding of the principles of the disclosed method and apparatus.

[0036] Referring to Fig. 7, the apparatus for performing the electrical brain stimulation of the present disclosure may include a computer 20, where the computer includes database 24 comprising data 25, where the data 25 are related to models of the brain tissue and include relevant input parameters which are used in the equations below. Relevant input parameters could be for example neuron density K, excitation speed q, neuron connection strength ϕ0 or neuron connection distance a. The computer 20 may further include a program code 23 implementing all relevant mathematical equations. The computer 20 may further include a software 22, which could be in a form a user interface or and/or an application allowing an operator to select and/or modify input parameters, or to select/modify relevant equations to be used for the computations.

[0037] The array 6 of electrodes may include a control unit 18 driving the electrodes 7 individually and receiving sensed signals from said electrodes 7. The control unit 18 may be located near the electrodes 7 or at another appropriate location on the patient. The control unit 18 is powered by a power source 17, such as battery or other suitable power source.

[0038] Both the electrode array 6 and the computer 20 include a communication interface 16, 26. A communication interface 16 is associated with the electrode array 6 and a communication interface 26 is associated with the computer 20, enabling communication between processor 21 and control unit 18. The communication interfaces 16, 26 allow for transfer of signals, data and instructions about the form and intensity of the stimulation signal to be applied by the electrodes 7. The communication interfaces 16, 26 may communicate via a communication link 30 which could be wired or wireless communication or a combination thereof.

[0039] Fig. 2 illustrates a brain 1 including a damaged and/or partially damaged cortical tissue (continuous white area of Fig. 2). Fig. 2 shows electrodes 7 and electrodes paths relevant for successful restoration of the wave speed and/or other wave parameters.

[0040] Fig. 2 further illustrates that an exemplary connection 10 between a pair of neural nodes might have been lost due to stroke or other reasons in the brain, since the connection 10 leads through the damaged and/or partially damaged area, but communication between the nodes is recreated by stimulation of the electrodes 7 which correspond to these neural nodes as explained below. As shown, the connection path 10 involves only communication between a pair of neural nodes (represented by two stimulation electrodes 7). Such communication is the most direct and could be successful in recreating some of the brain functions especially when the damaged brain area is not large.

[0041] Various other stimulation configurations are contemplated in the present disclosure.

[0042] For example, the stimulation path 11 of Fig. 2 between two nodes leads through the damaged cortical area through a number of intermediate electrodes 7. The stimulation path 11 may lead to wave propagation reconstruction between its endpoints by applying stimulation signals to all electrodes 7 of path 11 and sensing cortical waves by said electrodes 7, in order to restore at least one cortical wave parameter as explained below. In some cases, the stimulation route 11 may lead to restoration of brain functions only temporarily, since the damaged brain tissue does not allow to restore all functions completely. In certain cases therefore, the stimulation route 11 may be used for the purposes of neural assistance, i.e. to use the electrodes 7 permanently in order to substitute for the normal brain functions.

[0043] The advantage of stimulation path 11 is that the connection between two endpoints (neural nodes represented by two endpoint-electrodes 7) can be selected through a specific route according to every person's needs. The stimulation signal can thus be designed with a concrete purpose according to the special needs of each and every individual. On the practical level, the electrode array 6 may contain any appropriate density of electrodes 7. The number of electrodes 7 in the array 6 may be selected such that each single neural node is covered by an associated electrode 7. However, during application of the external stimulation signal only some of the electrodes can be activated (thus generating the external electrical signal), for example only those electrodes 7 may be activated which are positioned along a specific path 11. However, if another path is selected other electrodes 7 representing another path may be activated instead.

[0044] Alternatively, to the above approach, the carrier (such as a flexible material for closely covering the surface of the cortex) of the electrode array 6 may only contain those electrode 7 which represent the path 11. Therefore, the brain is not covered with electrodes 7 which are not used.

[0045] The stimulation path 12 may be used similarly as stimulation path 11 but creates a relay route around the damaged and/or partially damaged cortical tissue, thus enabling to permanently restore communication between its endpoints at least in some cases.

[0046] Once two crucial nodes are reconnected via stimulation, a pairwise neural node communication in the cortex becomes possible.

[0047] The stimulation route 13 illustrates paired communication between two groups of electrodes 7, each group corresponding to one neural node in the cortex.

[0048] The local density distribution u of activated neurons at point x and time t in the healthy cortical tissue of the cortex can be expressed as:

Furthermore,

represents the rate of neuron activation and

represents the rate of neuron inactivation. Here, K is total neuron density, K-u is density of not activated neurons, g and H are positive growing functions, in particular, these functions can be sigmoid functions.

is the intensity of activating signal and

is the intensity of inactivating signal in the healthy cortical tissue. Both

and

depend on the local density distribution of activated neurons in space and in time. More particularly,

and

can be expressed (without using the superscript (1)) as:



Here ϕa and ϕi are connectivity functions, Sa and Si are the neuron response functions, qa and qi are the speeds of signal propagation in neuron axons (excitation speeds). With regard to equations (1), (2) and (3) various particular and mathematically limiting cases can be considered where the functions g and H are linear, or where the neuron connectivity functions ϕa and ϕi have narrow distributions, or where the excitation speeds (speeds of signal propagation) qa and qi are large, or where the neuron response functions Sa and Si (which will be described in more detail below) are approximated by sigmoid or step-wise constant functions, or where the integral terms are expanded leading to the appearance of the diffusion term in the equation. A system of equations similar to equation (1) can be considered for different neuron subpopulations.

[0049] The mathematical model presented in the current disclosure describes propagation of various wave types (waves generally denoted by a reference number 8), including monotonic waves and oscillating waves (see Figure 3 illustrating a monotonous wave and see Figure 4 illustrating an oscillating wave). The model describes high frequency oscillations with low frequency amplitude modulations in the form of periodic waves (Figure 5) resembling those registered experimentally in the electrode arrays (see experimental results illustrated on Figure 6).

[0050] The local density v of activate neurons at point x and time t in the damaged or partially damaged cortical tissue can be expressed as:

Here

is the intensity of activating signal and

is the intensity of inactivating signal in the damaged cortical tissue. Further, the value of external stimulation signal can be expressed as given by a stimulation function I(x,t).

[0051] The computer processor may be configured to numerically calculate the stimulation function I(x,t), applied to each electrode 7 at the damaged cortical tissue 3,4 and healthy cortical tissue 5:

in order to restore the total properties of wave propagation between the neural nodes of the damaged cortex to the corresponding properties in the healthy cortical tissue, including wave speed, frequency, and amplitude.

[0052] The connectivity function ϕ used in equations (2) and (3) represents the physical parameter of connectivity between neural nodes in the cortical tissue in the brain. The connectivity function ϕ can be defined for example as a simple step-wise constant function:

where ϕ0 is a parameter which characterizes connection strengths between neural nodes and where a is a parameter which characterizes neuron connection distance, i.e. a distance across which the connection between two neurons can take place. The step-wise function is a simple and generic approximation of nonlocal interaction which occurs between neural nodes. Other model functions can be selected for the connectivity function ϕ instead of the step-wise constant function, for example a decreasing exponential function ϕ = ϕ0 exp(-r|x|), with ϕ0 and r having similar meaning as ϕ0 and a above. The connectivity function ϕ can also be a sum of two or more exponential functions, where these function will also be based on parameters characterizing connection strength and connection distance. Parameters like ϕ0, a, or r mentioned above can be based experimental data indicative of range of neural fibers and/or strength of inhibitory/excitatory connections. Depending on the model, the connectivity function can be a one dimensional or multidimensional function, such as two-dimensional or three-dimensional.

[0053] Another characteristic of the brain tissue is the excitability of the nodes. Excitability is essentially equivalent to capability of neural nodes to transmit electrical signal. The electrical signal travels through cortical tissue in the form of electrical waves. The electrical waves are characterized by their speed c that can be determined by the approximate formula:



[0054] Concerning the process of application of the external stimulation, the processor 21 can be configured to apply external stimulation signal determined by the stimulation function I(x,t) having the lowest value of the total stimulation

= or the lowest value of the maximal stimulation = max I(x,t). This is an optimal control problem giving the opportunity to reconstruct the solution u(x,t) not for all values of x, but only in one or several points xi, i.e. for one or several electrodes associated with locations xi.

[0055] The processor 21 may further be configured to determine the value of external stimulation signal (defined by the stimulation function I(x,t)) in order to restore the wave speed determined by the formula

in the particular case where the neuron activation response function Sa is approximated by a step function, under the condition σγ > 2. Here σ characterizes tissue excitability and γ characterizes tissue connectivity. If the condition is satisfied it is ensured that the mathematical model outputs positive values of the wave speed, which is the necessary condition for the model to give realistic results.
σ is the parameter characterizing cortical tissue excitability of healthy cortical tissue and γ is a parameter indicating cortical tissue connectivity. The positive value of wave speed can thus be only achieved if the product of tissue excitability and connectivity is sufficiently large. It is also implied by the above expressions that the excitability and connectivity of the cortical tissue increases the wave speed of electrical waves propagating trough the cortical tissue as signal.


Claims

1. An apparatus for electrical brain stimulation comprising:

- a two dimensional electrode array configured to be implanted at the surface of the cortex of a person, said cortex having pre-identified crucial neural nodes and including healthy cortical tissue and damaged and/or partially damaged cortical tissue, the electrode array covering at least part of said healthy cortical tissue and said damaged and/or partially damaged cortical tissue, said damaged and/or partially damaged cortical tissue having at least one parameter of cortical waves which is different from parameter of healthy cortical tissue, said at least one parameter being one of cortical wave propagation speed, amplitude and frequency, said electrode array including electrodes for emitting stimulation electrical signals in the cortex and measuring electrical cortical waves in the cortex;

- a processor communicating with the electrodes and configured to:

- based on the measured signals, evaluate said at least one parameter of cortical waves between at least a first electrode and at least a second electrode corresponding respectively to a first pre-identified crucial neural node and a second pre-identified crucial neural node in the cortex, said first pre-identified crucial node and second pre-identified crucial node being situated such that a rectilinear line joining the first pre-identified crucial node and the second pre-identified crucial node crosses said damaged and/or partially damaged cortical tissue;

- compute in real time, stimulation signals required to maintain said at least one parameter of cortical waves in a predetermined range between said first electrode and said second electrode and apply said computed stimulation signals to the electrodes,
characterized in that the processor is configured to apply a mathematical model of propagation of cortical waves, such that each stimulation signal is determined by a stimulation function I(x,t), and
wherein the computer processor is configured to calculate numerically the stimulation function I(x,t), applied to each electrode (7) at the damaged and/or partially damaged cortical tissue and the healthy cortical tissue by numerically solving the equation:

where K is a total neuron density, K-u is a density of not activated neurons, Wa is an intensity of activating signal, Wi is an intensity of inactivating signal, superscript (1) corresponds to the healthy tissue and superscript (2) to the damaged or partially damaged tissue, g(u) and H(W) are growing functions of said intensity of activating signal, (K-u)Wa represents a rate of neuron activation and uWi represents a rate of neuron inactivation.


 
2. The apparatus according to claim 1, wherein said predetermined range corresponds to values of said at least one parameter of cortical waves in the healthy cortical tissue.
 
3. The apparatus according to claim 1 or claim 2, wherein said processor is configured to compute said stimulation signals for the first electrode and second electrode and apply said computed stimulation signals to the first electrode and the second electrode.
 
4. The apparatus according to any one of the preceding claims further comprising at least one third electrode, wherein said at least one parameter of cortical waves is maintained between said first electrode and second electrode via the at least one third electrode, and wherein said processor is configured to:

- based on the measured signals from said first electrode, second electrode and at least one third electrode, evaluate said at least one parameter of cortical waves between pairs of adjacent electrodes among said first electrode, second electrode and at least one third electrode;

- compute said stimulation signals for said first electrode, second electrode and at least one third electrode, and apply said computed stimulation signals to said first electrode, second electrode and at least one third electrode.


 
5. The apparatus according to claim 4, wherein said at least one third electrode includes a plurality of third electrodes
 
6. The apparatus according to any one of the preceding claims, wherein the apparatus is configured to simultaneously stimulate selected pair of electrodes associated with specific pair of neural nodes.
 
7. The apparatus according to any one of the preceding claims, wherein said processor is configured to compute said stimulation signals by using a mathematical model of propagation of cortical waves.
 
8. The apparatus according to any one of the preceding claims, wherein the processor is configured to apply external stimulation signal determined by the stimulation function I(x,t), having the lowest value of the total stimulation

=
 
9. The apparatus according to any one of the preceding claims, wherein the processor is configured to apply external stimulation signal determined by the stimulation function I(x,t) having the lowest value of maximal stimulation = max I(x,t).
 
10. The apparatus according to any one of claims 8-9 wherein the processor is configured to determine the value of external stimulation signal determined by the stimulation function I(x,t), such that the process determines wave speed in the cortical tissue according to the formula

where σ characterizes cortical tissue excitability and γ characterizes cortical tissue connectivity.
 
11. The apparatus according to any one of claims 8-10, wherein the stimulation signal determined by the stimulation function I(x,t), is an increasing function of wave speed c in the cortical tissue.
 
12. The apparatus according to any one of claims 8-11, wherein the processor is configured to determine whether the condition of

is satisfied in the cortical tissue,
where σ is a parameter characterizing cortical tissue excitability of healthy cortical tissue and γ is a parameter indicating cortical tissue connectivity.
 


Ansprüche

1. Vorrichtung zur elektrischen Gehirnstimulation, umfassend:

- ein zweidimensionales Elektrodenarray, welches dazu eingerichtet ist, an der Oberfläche des Kortex einer Person implantiert zu sein, wobei der Kortex voridentifizierte wichtige Nervenknoten aufweist und gesundes Kortexgewebe und beschädigtes und/oder teilweise beschädigtes Kortexgewebe umfasst,
wobei das Elektrodenarray wenigstens einen Teil des gesunden Kortexgewebes und des beschädigten und/oder teilweise beschädigten Kortexgewebes bedeckt,
wobei das beschädigte und/oder teilweise beschädigte Kortexgewebe wenigstens einen Parameter von Kortexwellen aufweist, welcher verschieden ist von einem Parameter von gesundem Kortexgewebe, wobei der wenigstens eine Parameter eines ist aus einer Kortexwellen-Propagationsgeschwindigkeit, einer Amplitude und einer Frequenz,
wobei das Elektrodenarray Elektroden zum Emittieren von elektrischen Stimulationssignalen in den Kortex und Messen von elektrischen Kortexwellen in dem Kortex umfasst;

- einen Prozessor, welcher mit den Elektroden kommuniziert und dazu eingerichtet ist:

∘ auf Grundlage der gemessenen Signale den wenigstens einen Parameter von Kortexwellen zwischen wenigstens einer ersten Elektrode und wenigstens einer zweiten Elektrode zu evaluieren, welche jeweils einem ersten voridentifizierten wichtigen Nervenknoten und einem zweiten voridentifizierten wichtigen Nervenknoten in dem Kortex entsprechen, wobei der erste voridentifizierte wichtige Knoten und der zweite voridentifizierte wichtige Knoten derart angeordnet sind, dass eine geradlinige Linie, welche den ersten voridentifizierten wichtigen Knoten und den zweiten voridentifizierten wichtigen Knoten verbindet, das beschädigte und/oder teilweise beschädigte Kortexgewebe kreuzt;

∘ in Echtzeit Stimulationssignale zu berechnen, welche benötigt werden, um den wenigstens einen Parameter von Kortexwellen in einem vorbestimmten Bereich zwischen der ersten Elektrode und der zweiten Elektrode zu halten und die berechneten Stimulationssignale an die Elektroden anzulegen,

dadurch gekennzeichnet, dass der Prozessor dazu eingerichtet ist, ein mathematisches Modell einer Propagation von Kortexwellen anzuwenden, so dass jedes Stimulationssignal durch eine Stimulationsfunktion I(x,t) bestimmt wird, und
wobei der Computerprozessor dazu eingerichtet ist, numerisch die Stimulationsfunktion I(x,t) zu berechnen, welche an jede Elektrode (7) an dem beschädigten und/oder teilweise beschädigten Kortexgewebe und dem gesunden Kortexgewebe angelegt wird, indem numerisch die Gleichung gelöst wird:

Wobei K eine totale Neuronendichte ist, K-u eine Dichte von nicht aktivierten Neuronen ist, Wa eine Intensität eines Aktivierungssignals ist, Wi eine Intensität eines Inaktivierungssignals ist, oberer Index (1) dem gesunden Gewebe entspricht und oberer Index (2) dem beschädigten oder teilweise beschädigten Gewebe entspricht, g(u) und H(W) wachsende Funktionen der Intensität des Aktivierungssignals sind, (K-u)Wa eine Rate einer Neuronenaktivierung repräsentiert und uWi eine Rate einer Neuroneninaktivierung repräsentiert.
 
2. Vorrichtung nach Anspruch 1, wobei der vorbestimmte Bereich Werten des wenigstens einen Parameters von Kortexwellen in dem gesunden Kortexgewebe entspricht.
 
3. Vorrichtung nach Anspruch 1 oder Anspruch 2, wobei der Prozessor dazu eingerichtet ist, die Stimulationssignale für die erste Elektrode und die zweite Elektrode zu berechnen und die berechneten Stimulationssignale an die erste Elektrode und die zweite Elektrode anzulegen.
 
4. Vorrichtung nach einem der vorhergehenden Ansprüche, ferner umfassend wenigstens eine dritte Elektrode, wobei der wenigstens eine Parameter von Kortexwellen zwischen der ersten Elektrode und der zweiten Elektrode mittels der wenigstens einen dritten Elektrode gehalten wird, und wobei der Prozessor dazu eingerichtet ist:

- auf Grundlage der gemessenen Signale von der ersten Elektrode, der zweiten Elektrode und der wenigstens einen dritten Elektrode den wenigstens einen Parameter von Kortexwellen zwischen Paaren von benachbarten Elektroden aus der ersten Elektrode, zweiten Elektrode und wenigstens einen dritten Elektrode zu evaluieren;

- die Stimulationssignale für die erste Elektrode, zweite Elektrode und wenigstens eine dritte Elektrode zu berechnen und die berechneten Stimulationssignale an die erste Elektrode, zweite Elektrode und wenigstens eine dritte Elektrode anzulegen.


 
5. Vorrichtung nach Anspruch 4, wobei die wenigstens eine dritte Elektrode eine Mehrzahl von dritten Elektroden umfasst.
 
6. Vorrichtung nach einem der vorhergehenden Ansprüche, wobei die Vorrichtung dazu eingerichtet ist, gleichzeitig ein ausgewähltes Paar von Elektroden zu stimulieren, welches einem spezifischen Paar von Nervenknoten zugeordnet ist.
 
7. Vorrichtung nach einem der vorhergehenden Ansprüche, wobei der Prozessor dazu eingerichtet ist, die Stimulationssignale durch Verwenden eines mathematischen Modells einer Propagation von Kortexwellen zu berechnen.
 
8. Vorrichtung nach einem der vorhergehenden Ansprüche, wobei der Prozessor dazu eingerichtet ist, ein externes Stimulationssignal, welches durch die Stimulationsfunktion I(x,t) bestimmt ist, anzulegen, welche den geringsten Wert der gesamten Stimulation

aufweist.
 
9. Vorrichtung nach einem der vorhergehenden Ansprüche, wobei der Prozessor dazu eingerichtet ist, ein externes Stimulationssignal anzulegen, welches durch die Stimulationsfunktion I(x,t) bestimmt ist, welche den geringsten Wert einer maximalen Stimulation = max I(x,t), aufweist.
 
10. Vorrichtung nach einem der Ansprüche 8-9, wobei der Prozessor dazu eingerichtet ist, den Wert eines externen Stimulationssignals zu bestimmen, welcher durch die Stimulationsfunktion I(x,t) bestimmt ist, so dass der Prozess eine Wellengeschwindigkeit in dem Kortexgewebe gemäß der Formel bestimmt:

wobei σ eine Anregbarkeit von Kortexgewebe charakterisiert und γ eine Verbindbarkeit von Kortexgewebe charakterisiert.
 
11. Vorrichtung nach einem der Ansprüche 8-10, wobei das durch die Stimulationsfunktion I(x,t) bestimmte Stimulationssignal eine zunehmende Funktion einer Wellengeschwindigkeit c in dem Kortexgewebe ist.
 
12. Vorrichtung nach einem der Ansprüche 8-11, wobei der Prozessor dazu eingerichtet ist, zu bestimmen, ob die Bedingung

in dem Kortexgewebe erfüllt ist,
wobei σ ein Parameter ist, welcher eine Anregbarkeit von Kortexgewebe von gesundem Kortexgewebe charakterisiert und γ ein Parameter ist, welcher eine Verbindbarkeit von Kortexgewebe anzeigt.
 


Revendications

1. Appareil pour la stimulation électrique du cerveau comprenant :

- un réseau d'électrodes en deux dimensions configuré pour être implanté au niveau de la surface du cortex d'une personne, ledit cortex ayant des nœuds neuronaux cruciaux et comportant du tissu cortical sain et du tissu cortical endommagé et/ou partiellement endommagé, le réseau d'électrodes couvrant au moins une partie dudit tissu cortical sain et dudit tissu cortical endommagé et/ou partiellement endommagé, ledit tissu cortical endommagé et/ou partiellement endommagé présentant au moins un paramètre d'ondes corticales qui est différent d'un paramètre de tissu cortical sain, ledit au moins un paramètre étant l'une parmi la vitesse de propagation, l'amplitude et la fréquence d'onde corticale, ledit réseau d'électrodes comportant des électrodes pour émettre des signaux électriques de stimulation dans le cortex et mesurer des ondes corticales électriques dans le cortex ;

- un processeur communiquant avec les électrodes et configuré pour :

- sur la base des signaux mesurés, évaluer ledit au moins un paramètre d'ondes corticales entre au moins une première électrode et au moins une deuxième électrode correspondant respectivement à un premier nœud neuronal crucial pré-identifié et à un deuxième nœud neuronal crucial pré-identifié dans le cortex, lesdits premier nœud neuronal crucial pré-identifié et deuxième nœud neuronal crucial pré-identifié étant situés de telle sorte qu'une ligne rectiligne reliant le premier nœud neuronal crucial pré-identifié et le deuxième nœud neuronal crucial pré-identifié croise ledit tissu cortical endommagé et/ou partiellement endommagé ;

- calculer en temps réel, des signaux de stimulation nécessaires pour maintenir ledit au moins paramètre d'ondes corticales dans une plage prédéterminée entre ladite première électrode et ladite deuxième électrode et appliquer lesdits signaux de stimulation calculés aux électrodes,

caractérisé en ce que le processeur est configuré pour appliquer un modèle mathématique de propagation d'ondes corticales, de telle sorte que chaque signal de stimulation est déterminé par une fonction de stimulation I(x,t), et
dans lequel le processeur informatique est configuré pour calculer numériquement la fonction de stimulation I(x,t), appliquée à chaque électrode (7) au niveau du tissu cortical endommagé et/ou partiellement endommagé et du tissu cortical sain en résolvant numériquement l'équation :

K est une densité neuronale totale, K-u est une densité de neurones non activés, Wa est une intensité de signal d'activation, Wi est une intensité de signal d'inactivation, l'exposant (1) correspond au tissu sain et l'exposant (2) au tissu endommagé ou partiellement endommagé, g(u) et H(W) sont des fonctions de croissance de ladite intensité de signal d'activation, (K-u)Wa représente un taux d'activation neuronale et uWi représente un taux d'inactivation neuronale.
 
2. Appareil selon la revendication 1, dans lequel ladite plage prédéterminée correspond à des valeurs dudit au moins un paramètre d'ondes corticales dans le tissu cortical sain.
 
3. Appareil selon la revendication 1 ou la revendication 2, dans lequel ledit processeur est configuré pour calculer lesdits signaux de stimulation pour les première électrode et deuxième électrode et appliquer lesdits signaux de stimulation calculés à la première électrode et à la deuxième électrode.
 
4. Appareil selon l'une quelconque des revendications précédentes comprenant en outre au moins une troisième électrode, dans lequel ledit au moins un paramètre d'ondes corticales est maintenu entre lesdites première électrode et deuxième électrode via l'au moins une troisième électrode,
et dans lequel ledit processeur est configuré pour :

- sur la base des signaux mesurés à partir desdites première électrode, deuxième électrode et au moins une troisième électrode, évaluer ledit au moins paramètre d'ondes corticales entre des paires d'électrodes adjacentes parmi lesdites première électrode, deuxième électrode et au moins une troisième électrode ;

- calculer lesdits signaux de stimulation pour lesdites première électrode, deuxième électrode et au moins une troisième électrode, et appliquer lesdits signaux de stimulation calculés auxdites première électrode, deuxième électrode et au moins une troisième électrode.


 
5. Appareil selon la revendication 4, dans lequel ladite au moins une troisième électrode comporte une pluralité de troisièmes électrodes.
 
6. Appareil selon l'une quelconque des revendications précédentes, dans lequel l'appareil est configuré pour stimuler simultanément une paire sélectionnée d'électrodes associée à une paire spécifique de nœuds neuronaux.
 
7. Appareil selon l'une quelconque des revendications précédentes, dans lequel ledit processeur est configuré pour calculer lesdits signaux de stimulation en utilisant un modèle mathématique de propagation d'ondes corticales.
 
8. Appareil selon l'une quelconque des revendications précédentes, dans lequel le processeur est configuré pour appliquer un signal de stimulation externe déterminé par la fonction de stimulation I(x,t), ayant la valeur la plus basse de la stimulation


 
9. Appareil selon l'une quelconque des revendications précédentes, dans lequel le processeur est configuré pour appliquer un signal de stimulation externe déterminé par la fonction de stimulation I(x,t), ayant la valeur la plus basse de stimulation maximale = max I(x,t).
 
10. Appareil selon l'une quelconque des revendications 8 et 9, dans lequel le processeur est configuré pour déterminer la valeur de signal de stimulation externe déterminé par la fonction de stimulation I(x,t), de telle sorte que le processus détermine une vitesse d'onde dans le tissu cortical en fonction de la formule

où σ caractérise l'excitabilité du tissu cortical et γ caractérise la connectivité du tissu cortical.
 
11. Appareil selon l'une quelconque des revendications 8 à 10, dans lequel le signal de stimulation déterminé par la fonction de stimulation I(x,t), est une fonction d'augmentation de vitesse d'onde c dans le tissu cortical.
 
12. Appareil selon l'une quelconque des revendications 8 à 11, dans lequel le processeur est configuré pour déterminer si la condition de

est satisfaite dans le tissu cortical,
où σ est un paramètre caractérisant l'excitabilité de tissu cortical de tissu cortical sain et γ est un paramètre indiquant la connectivité de tissu cortical.
 




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REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




Non-patent literature cited in the description