INTERTWISTED NEURAL STIMULATION

Abstract

INTERLEAVED NEURAL STIMULATION A neural stimulation device configured to apply neural activations comprising at least two interleaved current pulse sequences is disclosed. Abstract Figure: Fig. 3

Description

Title of the invention: INTERLACED NEURAL STIMULATION FIELD OF THE INVENTION

[0001] The present invention relates to neural stimulators, in particular stimulators intended for restoring movement to paralyzed limbs. These stimulators are intended to activate one or more muscles by exciting a nerve by means of an electrical stimulus. STATE OF THE ART

[0002] The proportion of people with tetraplegia following spinal cord or cervical trauma is constantly increasing. Improving the quality of life of these people is a challenge, and restoring gripping ability is a priority, as the use of the hands is a key factor in the quality of daily life. Different approaches have been developed to restore the functions of the hand, wrist and forearm, which contribute to the gripping mechanism. Surgical methods - muscle-tendon transfers or nerve transplants - are possible in cases where a sufficient number of muscles are still voluntarily controlled by the tetraplegic person. Alternatively, it is possible to use electrical stimulation methods, either applied directly to the muscles - which requires numerous invasive devices - or applied to intact nerves downstream of the injury.The latter method involves placing electrodes on the nerves that innervate the muscles controlling the hand and wrist, in particular: the median nerve, the ulnar (or cubital) nerve and the superficial branch of the radial nerve. The two approaches, muscle and neural stimulation, can be combined.

[0003] It is now known to selectively stimulate the median and radial nerves in order to restore elementary movements such as the subterminal opposition grip (pincer), the palmar penta-digital grip (spherical) or the full-hand grip for example - see Selective neural electrical stimulation restores hand and forearm movements in individuals with completed tetraplegia; Tigra et al. Journal of NeuroEn-gineering and Rehabilitation (2020) 17:66; DOI: 10.1186 / sl2984-020-00676-4.

[0004] However, these stimulation methods remain incomplete because they do not allow the restoration of gripping movements in all their complexity. The present invention aims to overcome these limits by proposing a stimulation device applying more complex stimulations, in particular neural stimulations. SUMMARY

[0005] The invention therefore relates to a neural stimulation device comprising • at least one neural electrode comprising at least two electrical contacts

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[0013] and intended to be implanted on at least one nerve; • a current pulse generator connected to the at least one neural electrode via a current distributor; • a storage means configured to contain a library of sequences, each sequence comprising a time series of current pulses associated with a configuration of electrical contacts; and • a sequencer configured to apply neural activation to the at least one neural electrode, said neural activation comprising at least two interleaved sequences. In one embodiment, the neural stimulation device further comprises a controller configured to apply a succession of neural activations. In one embodiment, the at least one neural electrode comprises a plurality of electrical contact configurations. In one embodiment, the current pulses are charge-balanced biphasic stimuli, the first phase of which has an amplitude of between 10 pA and 6000 pA and a duration of between 5 ps and 1 ms. In one embodiment, the sequences comprise a succession of 5 to 100 current pulses, said pulses being repeated at a frequency of between 1 Hz and 1 kHz. In one embodiment, the sequence library contains sequences customized for a patient. The invention also relates to a method of neurostimulation comprising • selecting at least two sequences from a sequence library, each sequence comprising a time series of current pulses associated with a configuration of electrical contacts; and • applying neural activation to at least one neural electrode comprising at least two electrical contacts and intended to be implanted on at least one nerve, said neural activation comprising interlacing the at least two sequences and addressing the current pulses of the at least two sequences to the at least two electrical contacts by a current distributor. In one embodiment, the neurostimulation method further comprises repeating the application of neural activation. The invention finally relates to a neural activation comprising • the interleaving of at least two sequences chosen from a sequence library, each sequence comprising a time series of current pulses associated with a distribution of current between several electrical contacts; and • addressing the current pulses of the at least two sequences to the at least two electrical contacts of a neural electrode intended to be implanted on a nerve. DEFINITIONS

[0014] In the present invention, the terms below are defined as follows:

[0015] “Electrical contact” relates to a surface of a neural electrode, this surface being in contact with the nerve to be stimulated and electrically connected to the neural stimulation device. A neural electrode may comprise several electrical contacts distributed on different rings.

[0016] “Electrical contact configuration” relates to a configuration in which each electrical contact of a neural electrode is associated with a role of anode “a”, cathode “c” or is not connected “-”.

[0017] “Stimulation configuration” relates to a configuration in which the amplitudes of the current pulses which are sent to each contact are defined for a given configuration of electrical contacts.

[0018] “Neural electrode” relates to an electrode intended to be implanted in contact with a nerve in order to apply electrical stimuli to it.

[0019] “Interleaving” concerns the temporal superposition of two or more series of electrical signals, in part two or more sequences of current pulses.

[0020] “Current pulse” refers to a brief electrical signal, characterized by its shape, amplitude and duration. The current pulse is typically rectangular, but can adopt any other shape - triangular, asymmetric, biphasic... - depending on the needs of the neural stimulation. The amplitude of the pulse is typically between 10 pA and 10 mA. The duration of the pulse is typically between 5 ps and 1 ms. In addition, the current pulse can be positive - injection of electrical charges - or negative - withdrawal of electrical charges.

[0021] “Biphasic stimulus” relates to a stimulus comprising two phases, separated by an interstimulation time intended to maintain the pre-polarization induced by the first phase of the biphasic stimulus. The interstimulation time is typically between 25 ps and 150 ps.

[0022] “Charge-balanced biphasic stimulus” refers to a biphasic stimulus for which the quantity of charges implemented during the first phase - charges injected - is equal to the quantity of charges implemented during the second phase - charges withdrawn - the signs of the charges being, however, opposite in the two phases. In total, no net charge is injected or withdrawn by a charge-balanced biphasic stimulus. The two phases may have different shapes, amplitudes and durations provided that the quantities of charges are identical. DETAILED DESCRIPTION

[0023] The present invention relates to a neural stimulation device.

[0024] This device comprises at least one neural electrode intended to be implanted on at least one nerve. In the particular case of neural stimulation for the restoration of grip, the neural electrode is implanted on one of the following nerves: the median nerve, the ulnar (or cubital) nerve or the radial nerve. The neural electrode comprises at least two electrical contacts.

[0025] The neural electrode can be chosen from flat matrix electrodes, intended to be placed on the nerve; intrafascicular electrodes, intended to be placed inside the nerve; or cuff electrodes intended to be placed around the nerve. Gutter electrodes are particularly suitable because they allow several electrical contacts to be distributed regularly all around the nerve. Advantageously, the electrical contacts are distributed on the gutter electrode on three rings: two outer rings on which a single electrical contact completely surrounds the nerve and an inner ring on which several contacts - typically from four to ten - are distributed regularly. The self-adjusting gutter electrodes allow the contacts of the inner ring to be distributed on the nerve by adapting to its diameter.

[0026] The neural stimulation device comprises a current pulse generator. This generator is connected to the neural electrode via a current distributor. The current distributor makes it possible to distribute the injection or withdrawal of the electrical charges associated with the current pulse between the different electrical contacts of the neural electrode. This distribution is subsequently called an electrical contact configuration. Preferably, the neural electrode comprises a plurality of electrical contact configurations. Thus, by distributing the current pulses over different areas of the nerve - on the surface of the nerve for a gutter electrode - it is possible to stimulate the fascicles of the nerve differently, each fascicle contributing to the control of at least one muscle.

[0027] Preferably, the current distributor can amplify the electrical pulse for each electrical contact. Thus, the current pulse generator defines the shape, duration and reference amplitude of the pulse when the current distributor defines the actual amplitude - after amplification - and the distribution of the actual amplitudes on the different electrical contacts. This weighted distribution is subsequently called a stimulation configuration.

[0028] In one embodiment, the current pulses are charge-balanced biphasic stimuli. In this case, the shape of the pulse comprises two phases: the first phase - called stimulation - is an injection of electrical charges and the The second phase - called the balancing phase - is a withdrawal of electrical charges. The pulse is charge balanced when the amount of electrical charge injected is equal to the amount of electrical charge removed, generally leading to avoiding the accumulation of electrical charges on the stimulated nerve and / or on the electrical contacts between the neural electrode and the stimulated nerve. The first phase of a charge-balanced biphasic stimulus has an amplitude between 10 pA and 6 mA and a duration between 5 ps and 1 ms. The second phase is then defined in amplitude and duration by the charge balance. The two phases can be separated by an interstimulation time. More generally, current pulses can be multiphasic stimuli - several phases of charge injection or charge withdrawal - as long as the quantities of injected and withdrawn charges remain equal.

[0029] For example, the current generator may define a charge-balanced biphasic stimulus comprising a first rectangular phase with a reference amplitude of 100 pA and a duration of 20 ps and a second rectangular phase with a reference amplitude of 50 pA and a duration of 40 ps. Then, the current distributor applies this balanced biphasic stimulus between the anodes: the two outer rings and contacts 1 and 3 of the inner ring and the cathode: contact 2 of the inner ring - contacts 5 to 8 being unconnected in this electrical contact configuration - of a gutter electrode in a TTR electrical contact configuration. In addition, the pulse is amplified by a factor of 3 on the outer rings and on contacts 1 and 3 and amplified by a factor of -12 on contact 2 - leading to a balanced amplification balance - and defining a stimulation configuration.

[0030] The neural stimulation device further comprises a storage means configured to contain a library of sequences. This storage means may be a memory included in the neural stimulation device or an external storage means in wireless communication with the neural stimulation device. A sequence is a time series of pulses, in which a pulse is repeated several times. This repetition may be strictly periodic: the same pulse repeated at a given frequency, or modulated. The modulation may relate to the frequency - the repetition period of the pulses is variable during the sequence - the amplitude - the amplitude of each pulse varies during the sequence - and / or the duration of the pulse. In addition, the sequence is associated with a configuration of electrical contacts defining how the current pulses of the sequence must be distributed on the nerve.Each sequence in this library is associated with the stimulation of one or more muscles, leading to a complex movement.

[0031] Finally, the neural stimulation device comprises a sequencer configured to applying neural activation to the neural electrode. This neural activation comprises at least two interleaved sequences. Interleaving is understood here to mean that the time series of current pulses applied to the neural electrode is the superposition of the time series of current pulses of each sequence. However, the neural stimulation device can only implement one stimulation configuration at a time, so the interleaving must lead to applying the current pulse of one sequence between two current pulses of the other sequence (or other sequences). In particular, the application of two interleaved sequences corresponds to defining a succession of stimulation configurations on the neural electrode, the stimulation configurations being associated with two different sequences. In certain embodiments, the interleaving may concern three sequences, four sequences or more.

[0032] By interlacing two sequences, it is possible to stimulate two simultaneous and / or cooperative responses by a single nerve. In the case of muscular responses, this leads to a complex synergistic movement (cooperation in movement) or antagonistic movement (stabilization effect or increase in joint stiffness), for example.

[0033] In one embodiment, the neural stimulation device further comprises a controller configured to apply a succession of neural activations. This makes it possible to create a succession of complex movements, the sequence of which leads to the performance of a motor function, for example the opening of the hand followed by a palmar grip, thus restoring the grasp. Alternatively, the succession of neural activations - at a determined frequency - may simply lead to the maintenance of one - or more - muscle contractions.

[0034] In one embodiment, the sequences comprise a succession of 5 to 100 current pulses, preferably 10 to 100 current pulses. These current pulses are repeated at a frequency of between 1 Hz and 1 kHz, this frequency possibly being modulated. In the case of efferent stimulations (for motor purposes), the current pulses are preferably repeated at a frequency of between 1 Hz and 250 Hz, typically between 20 Hz and 100 Hz. The duration of a complete sequence is very variable, depending on the task to be performed. In particular, to maintain a muscular contraction, the sequence must last for the entire time that the muscular contraction is maintained. Preferably, a complete sequence lasts at least 0.5 s and comprises at least 10 pulses.

[0035] In one embodiment, the pulse generator is designed to very precisely control the charges injected or withdrawn at the neural electrodes. For this, the pulse generator may rely on a symmetrical design comprising anode current sources and cathode current sources. configured to copy a determined control current and so that the sum of the copied anode currents is equal to the sum of the copied cathode currents.

[0036] In one embodiment, the sequence library contains personalized sequences for a patient. Indeed, the stimulation configurations and current pulses that allow a patient to be effectively stimulated vary from one patient to another. It is therefore necessary to define the personalized sequences during a learning process. This learning process can take place in the following manner.

[0037] After the neural stimulation device has been set up by implanting a neural electrode on a patient's nerve, model sequences are applied. These model sequences are defined by the following parameters: shape, amplitude and duration of the current pulse; stimulation configuration - electrical contacts used, and associated amplification -; number of current pulses and repetition frequency of the current pulses. A succession of sequences in which the parameters are varied one by one makes it possible to identify the thresholds at which the patient's muscles act, making it possible to construct a recruitment curve for each of them. [Fig.2] illustrates for a patient, with a gutter electrode implanted around the median nerve, for configurations of electrical contacts of the TLR, STR and TTR type whose cathode is successively defined on each of the eight electrical contacts of the inner ring - each sector corresponds to one of the electrical contacts taken as cathode in this graphic representation -, for stimulation sequences of 15 repetitions at 25 Hz of a balanced biphasic stimulus of duration 150 ps, ​​the real amplitudes being increasing - after amplification by the sequencer - of the pulse selectively stimulating the APB, FDS, FPL, PT or FCR muscles. We see for example that the configuration of electrical contacts TLR makes it possible to recruit with the lowest intensity (therefore first) the FPL muscle for positions 6-7-8 of the cathode, the other contacts making it possible to preferentially activate other muscles.In addition, each contact and each type of configuration (TLR, STR, TTR) allows for a succession of muscle activation, and therefore a different muscle synergy. For example, it is possible to obtain flexion of the fingers and then of the thumb to obtain a pinch by stimulating only the median nerve with a configuration preferentially recruiting the FDS and FPL muscles.

[0038] Thus, for each muscle taken individually, and more broadly each sequence of muscle contractions linked to the increase in intensity, it is possible to define the sequence which makes it possible to activate a synergistic and functional muscle contraction, for a given patient. Then, on the basis of the personalized sequences, it is possible to intertwine at least two sequences to apply neural stimulation and cause a complex compound movement, for example the opening of the hand and the simultaneous extension of the wrist, then to define a succession of neural activations to restore a motor function, for example opening the hand then closing it in pincer mode.

[0039] In one embodiment, the entire stimulation device is implantable and further comprises a wireless communication means. Thus, a patient can be equipped during a surgical procedure with the stimulation device. Then, commands can be transmitted to the sequencer and / or to the stimulation device controller by a control device positioned in contact with the patient - held by an armband for example - and controlled by the patient himself. The patient can activate the control device vocally, by the voluntary activation of muscles equipped with electromyographic detectors, by the realization of stereotyped voluntary movements detected by inertial sensors or by a brain / machine interface, for example.

[0040] In one embodiment, the stimulation device comprises at least two neural electrodes, intended to be implanted on at least two different nerves. Thus, complex stimulations using muscles activated by the different nerves equipped with neural electrodes can be carried out, for example to obtain the closing of the hand in the form of a clamp (stimulation on the median nerve) and the balance of the wrist by its antagonistic extension (stimulation on the radial nerve).

[0041] The invention also relates to a method of neurostimulation, in which the characteristics described above for the neural stimulation device apply.

[0042] This method comprises a step of selecting from a sequence library at least two sequences, each comprising a time series of current pulses associated with a configuration of electrical contacts. In a second step, a neural activation is applied to at least one neural electrode comprising at least two electrical contacts and intended to be implanted on at least one nerve. This neural activation results from the interleaving of the at least two sequences and the addressing of the current pulses of the at least two sequences to the at least two electrical contacts by a current distributor.

[0043] In one embodiment, the neurostimulation method further comprises repeating the application of a neural activation. Thus, several neural activations, each resulting from the interleaving of at least two sequences, are applied successively.

[0044] The invention finally relates to neural activation, which is a particular form of electrical signal. The characteristics described above for the neural stimulation device apply here.

[0045] This neural activation comprises on the one hand the interlacing of at least two sequences chosen from a sequence library, each sequence comprising a time series of current pulses associated with a current distribution between several electrical contacts. It also comprises the addressing of the current pulses of the at least two sequences to the at least two electrical contacts of a neural electrode intended to be implanted on a nerve.

[0046] In other words, a neural activation is an electrical signal associated with a configuration of electrical contacts and which makes it possible to obtain a response, for example muscular. A neural activation is an elementary instruction which can then be inserted into a series of instructions making it possible to carry out functions, in particular motor functions.

[0047] In one embodiment, addressing the current pulses comprises the electrical contact configurations of the at least one neural electrode.

[0048] In one embodiment, the current pulses are charge-balanced biphasic stimuli, the first phase of which has an amplitude of between 10 pA and 6000 pA and a duration of between 5 ps and 1 ms.

[0049] In one embodiment, the sequences comprise a succession of 1 to 100 current pulses. These current pulses are repeated at a frequency of between 1 Hz and 1 kHz, this frequency possibly being modulated. In the case of efferent stimulations (for motor purposes), the current pulses are preferably repeated at a frequency of between 1 Hz and 250 Hz, typically between 20 Hz and 100 Hz. The duration of a complete sequence is very variable, depending on the task to be performed. In particular, to maintain a muscular contraction, the sequence must last for the entire time that the muscular contraction is maintained. Preferably, a complete sequence lasts at least 0.5 s and comprises at least 10 pulses. DESCRIPTION OF FIGURES

[0050] [Fig. 1][Fig. 1] is a representation of a gutter-type neural electrode. This electrode (top left) consists of three rings A, B and C. Each ring has four electrical contacts labeled 1, 2, 3 and 4. On the outer rings A and C, the four contacts are connected to form a single electrical potential all around the nerve. On the inner ring B, the four contacts are separate and can be connected differently. The anodic connections are labeled "a", the cathodic connection is labeled "c" and the unconnected electrical contacts are labeled "-". In the TLR electrical contact configuration, the outer rings form two anodes and the inner ring has a cathode on one of its electrical contacts. In the TTR electrical contact configuration, the TLR electrical contact configuration is completed by two anodes located on the inner ring, immediately adjacent to the cathode. In the STR electrical contact configuration, the TLR electrical contact configuration is completed by an anode located on the inner ring, diametrically opposite the cathode. Finally, in the TT electrical contact configuration, only one ring is used (here, the inner ring denoted B, but it could be an outer ring A or C) and has a cathode on one of its electrical contacts and two anodes immediately adjacent to the cathode.

[0051] [Fig.2][Fig.2] represents the order of muscle recruitment for a patient in various electrical contact configurations; left dial: TLR; central dial: STR; right dial: TTR. Each dial contains eight sectors corresponding to the eight electrical contacts of the inner ring of the gutter-type neural electrode. Each sector represents the successive recruitment order of each muscle (as soon as it exceeds 10% of its recruitment) when the electrical contact of the inner ring corresponding to the sector is used as a cathode.

[0052] [Fig.3][Fig.3] represents a neural activation resulting from the interleaving of two sequences, each sequence comprising current pulses in the form of balanced biphasic stimuli. ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

[0053] The present invention will be better understood by reading the following examples which illustrate the invention in a non-limiting manner.

[0054] A patient suffering from tetraplegia underwent surgery to implant two gutter electrodes, one on the median nerve and the other on the radial nerve. The gutter electrodes had the structure described in [Fig.l], with two outer rings and a central ring having 8 electrical contacts for the median nerve and 6 electrical contacts for the radial nerve. The electrical contact configurations used are the TTR (transverse tripolar), TLR (longitudinal tripolar) and STR (steering current) configurations, shown in [Fig.l].

[0055] In order to create a personalized sequence library for this patient; different stimulation configurations - contact configuration, pulse amplitudes and sequence - were applied and the muscle responses measured via electromyographic measuring devices, by image analysis of the induced movements or by measuring the forces exerted by the stimulated muscles. These measurements made it possible to define recruitment curves for each muscle. Thus, the responses induced by the median nerve of: • flexor carpi radialis (FCR) responsible for wrist flexion, • pronator teres (PT) responsible for pronation of the forearm and wrist, • flexor digitorum superficialis (FDS) responsible for flexion of the fingers (except the thumb) • flexorpollicis longus (FPL) responsible for thumb flexion, and • abductorpollicis brevis (APB) responsible for thumb abduction.

[0056] Furthermore, the responses induced by the radial nerve of • extensor carpi radialis (ECR) responsible for wrist extension, • extensorpollicis longus (EPL) responsible for thumb extension, and • extensor digitorum communis (EDC) responsible for finger extension.

[0057] [Fig. 2] represents the succession of muscle recruitments when the stimulation intensity increases for a configuration of electrical contacts - forming a stimulation configuration - allowing each muscle to be recruited: recruitment of APB, FDS, FPL, PT and FCR in the TLR, STR and TTR contact configurations. These graphs associated with the recruitment curves of each muscle make it possible to identify, for a given contact configuration, the levels from which said muscles are recruited and the order in which said muscles are activated. It is then possible to define personalized sequences for the patient, these sequences allowing selective activation of one muscle or several muscles simultaneously.

[0058] [Fig.3] represents in a simplified way two sequences of the library. A biphasic stimulus balanced in charge and symmetrical - [Fig.3]-a, first phase of amplitude 300 pA and duration 150 ps and second phase identical, but of opposite sign, after an interstimulation time of 25 ps - is repeated at a frequency of 25 Hz - period of 40 ms - to form a first sequence - [Fig.3]-b - of 15 pulses. A charge-balanced biphasic stimulus - [Fig.3]-c, first phase of linearly increasing amplitude up to 150 pA and duration 150 ps and second phase of amplitude 150 pA and duration 75 ps but of opposite sign, after an interstimulation time of 25 ps - is repeated at a frequency of 25 Hz - period of 40 ms - to form a second sequence - [Fig.3]-d - of 15 pulses.Each sequence allows for the successive recruitment of one or more of the patient's muscles, when associated with a particular contact configuration and amplification, defined by the corresponding recruitment curve. It is therefore a question of inducing synergies of different muscular actions. These synergies can then be combined by interlacing the sequences on one or more nerves.

[0059] In order to coordinate multiple muscle movements and achieve motor function, the two sequences are interleaved, as illustrated [Fig.3]-e. It should be noted that successive pulses are applied by different contact configurations, but after each pulse, no net charge has been injected into the patient, due to the charge-balanced nature of the pulses.

[0060] The application of neural stimulation of these two interlaced sequences leads to complex movements that cannot be obtained by successive application of two sequences. Indeed, if the sequences are applied successively, the Muscles activated by one sequence will relax when that sequence ends and will not be able to act in synergy with the muscles activated by the next sequence.

Claims

Claims

1. Neural stimulation device comprising • at least one neural electrode comprising at least two electrical contacts and intended to be implanted on at least one nerve; • a current pulse generator connected to the at least one neural electrode via a current distributor; • a storage means configured to contain a library of sequences, each sequence comprising a time series of current pulses associated with a configuration of electrical contacts; and • a sequencer configured to apply a neural activation to the at least one neural electrode, said neural activation comprising at least two interleaved sequences of the library of sequences.

2. The neural stimulation device of claim 1, further comprising a controller configured to apply a succession of neural activations.

3. A neural stimulation device according to claim 1 or 2, wherein the at least one neural electrode comprises a plurality of electrical contact configurations.

4. A neural stimulation device according to any one of claims 1 to 3, wherein the current pulses are charge-balanced biphasic stimuli and the first phase has an amplitude of between 10 pA and 6000 pA and a duration of between 5 ps and 1 ms.

5. A neural stimulation device according to any one of claims 1 to 4, wherein the sequences comprise a succession of 5 to 100 current pulses, said pulses being repeated at a frequency of between 1 Hz and 1 kHz.

6. A neural stimulation device according to any one of claims 1 to 5, wherein the sequence library contains sequences customized for a patient.

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