Neural electrode for recording and / or stimulation purposes which is intended to be adhered to brain surface upon use, and recording or stimulation method using same

Abstract

Provided are: a neural electrode for recording and / or stimulation purposes, which is flexible, can be closely adhered onto the surface of the brain and is not deteriorated with respect to adhesiveness under a long-term embedded state; and a method using the neural electrode.　The neural electrode 1 according to the present invention is intended to be used for recording and / or stimulation purposes, and is configured such that a sticking part 2 that is a sheet-like electrode is adhered onto the surface of the brain upon use. The neural electrode is characterized in that the sticking part comprises at least: an insulation sheet 3 of which one surface serves as a sticking surface to the surface of the brain; and an electroconductive wiring 4 which is positioned on a surface of the insulation sheet which is opposite to the sticking surface. The neural electrode is also characterized in that multiple dot-like electrode parts 4a in the electroconductive wiring are exposed from pores 3a formed in the insulation sheet, the insulation sheet is an elastomeric thin film having a thickness of 2 to 100 μm, and the electroconductive wiring has a thickness of 10 μm or less.

Description

Neural electrodes for recording and / or stimulation that are attached to the brain surface and recording or stimulation methods using the same

[0001] The present invention relates to a neural electrode for recording and / or stimulation that is attached to the brain surface, and a recording or stimulation method using the same.

[0002] Electrocorticogram (ECoG) electrodes, which can be attached to the brain surface to measure neural potentials, are used to identify lesions in intractable epilepsy for which antiepileptic drugs are ineffective. However, current ECoG electrodes have issues with positioning and increased intracranial pressure due to a mechanical mismatch between the electrode substrate and brain tissue.

[0003] In addition, a Responsive Neurostimulation (RNS) system has been developed that detects epileptic seizures and immediately suppresses them by electrically stimulating the epileptic focus, and this system is being clinically applied by NeuroPace in the United States. However, bioadhesion is impaired when implanted for a long period of time. For patients with intractable epilepsy for whom antiepileptic drugs are not effective, there is a need for a technology that can place multiple cortical electrodes over a wide area of ​​the brain surface without compressing the brain and without causing them to shift, in order to identify the epileptic focus over a long period of time and treat seizures by locally providing electrical stimulation.

[0004] These problems are due to the thick electrode film thickness. Conventional neural electrodes have a silicone rubber substrate, but they suffer from similar issues with both the substrate and the wiring. Technologies for electrodes affixed to the brain surface have been reported, including those using soluble silk fibroin membranes as the substrate for forming the electrodes (Non-Patent Document 1) and those using paraxylylene-based polymers (Non-Patent Document 2). However, adhesion to the brain surface remains an issue in this field. Recently, the development of electrodes based on hydrogel has been reported (Non-Patent Document 3). While these electrodes conform to the brain surface during the acute phase, their bioadhesion is impaired during long-term implantation due to material deformation (e.g., gel swelling).

[0005] Meanwhile, a technique using flexible polymer nanosheets has been proposed as a method for directly fixing electronic devices to arms, legs, etc. (Patent Document 1). However, there is no disclosure about the applicability of such nanosheets to neural electrodes for recording and / or stimulation that are attached to the brain surface, or about the configurations suitable for such applications.

[0006] NATURE MATERIALS j VOL 9 j JUNE 2010 j www. nature. com / naturalmaterialsScientific Reports | (2018) 8:3825 | DOI:10.1038 / s41598-018-22051-zScientific Reports | (2019) 9:13379 | https: / / doi. org / 10.1038 / s41598-019-49772-z

[0007] International Publication No. 2016 / 181958

[0008] For example, in the diagnosis and treatment of intractable epilepsy, the current clinical flow involves implanting intracranial electrodes, recording via wired connection for approximately two weeks while tapering off medication, and then manually and visually analyzing EEG recordings. This necessitates device implantation for surgical procedures and neuromodulation. This places a burden on patients, requiring hospitalization while the intracranial electrodes are in place and connected to an EEG monitor via wired connection. Furthermore, undergoing chronic intracranial EEG recordings while tapering off antiepileptic medications carries the risk of generalized convulsions and status epilepticus. This places a burden on medical professionals, requiring them to manually and visually analyze the vast amount of EEG data obtained within a limited time frame to formulate a treatment plan. Furthermore, performing chronic intracranial EEG recordings while tapering off antiepileptic medications requires dedicated observation staff for patient safety.

[0009] In response to this long-term hospitalization management, future clinical flows aim to implant devices including intracranial electrodes, and then perform home care for one to six months after a short hospital stay, recording EEG data under normal conditions without medication reduction. This fully implanted, wireless system allows automated EEG analysis. This clinical flow is expected to reduce the burden on patients and healthcare professionals. An integrated device incorporating an implantable device and a remote monitoring system would be clinically significant, allowing continuous therapeutic use from the time of diagnosis without electrode replacement. Since the device remains in place during surgery or neuromodulation, eliminating the need for reoperation, it is expected to offer two benefits: improved treatment outcomes for intractable epilepsy and reduced burden on patients and healthcare professionals. However, conventional electrodes have issues with their thickness and rigidity, making stable placement of multiple electrodes difficult, compressing brain tissue and making long-term implantation difficult, and limiting the number of electrodes and the area in which they can be placed. These factors make it difficult to apply this future clinical flow.

[0010] The present invention has been made in consideration of the above circumstances, and aims to provide a neural electrode for recording and / or stimulation that is flexible, can be adhered closely to the brain surface, and does not lose its adhesion even when implanted for a long period of time, and a method using the same.

[0011] In order to solve the above problems, the inventors conducted extensive research and found that a thin-film electrode was fabricated by combining an elastomer polymer thin film with printed electronics, and that the electrode was flexible, capable of adhering closely to the brain surface, and capable of recording neural potentials and providing electrical stimulation, leading to the completion of the present invention. In other words, the inventors have achieved a recording / stimulation electrode that is thinner, lighter, and softer than conventional electrodes, and allows for stable placement of multiple electrodes and long-term implantation without compressing brain tissue. This enables wide-area and high-density electroencephalogram recording, and is also suitable for implementing a wireless remote monitoring system, which is the goal of clinical procedures such as the diagnosis and treatment of intractable epilepsy.

[0012] That is, the following inventions are disclosed. [1] A neural electrode for recording and / or stimulation used by attaching an attachment part that is a sheet-like electrode to the brain surface, wherein the attachment part has at least an insulating sheet having one side that is attached to the brain surface and conductive wiring on the side of the insulating sheet opposite the attachment side, wherein multiple electrode portions on the conductive wiring are exposed through holes in the insulating sheet, the insulating sheet being an elastomer thin film having a thickness of 2 to 100 μm, and the conductive wiring being 10 μm or less in thickness. [2] The neural electrode for recording and / or stimulation according to [1], comprising a base sheet on which the conductive wiring is formed, the base sheet being in close contact with the insulating sheet at the attachment part, sandwiching the conductive wiring therebetween, the base sheet being an elastomer thin film having a thickness of 100 μm or less. [3] The neural electrode for recording and / or stimulation according to [2], wherein the conductive wiring is a printed wiring. [4] The neural electrode for recording and / or stimulation according to [3], wherein the surface of the base sheet facing the conductive wiring is hydrophilized. [5] The neural electrode for recording and / or stimulation according to any one of [1] to [4], wherein the insulating sheet is a styrene-based elastomer. [6] The attachment portion has a bending stiffness of 1×10 -3 [7] The neural electrode for recording and / or stimulation according to any one of [1] to [5], wherein the neural electrode has a resistance of 0.1 Nm or less. [7] The neural electrode for recording and / or stimulation according to any one of [1] to [6], wherein a support film for supporting the base sheet is in close contact with a portion extending continuously from the attachment portion to the opposite side of the multipoint electrode portion. [8] A method for recording weak potentials or currents associated with brain activity or for transmitting currents to the brain to stimulate the brain, comprising the steps of: attaching the neural electrode according to any one of [1] to [7] to the brain surface so that the multipoint electrode portion is in contact with the brain surface; and receiving the weak potentials or currents associated with brain activity with the multipoint electrode portion and recording them with a measuring device electrically connected to the conductive wiring, or supplying and transmitting currents to the brain from a stimulating device electrically connected to the conductive wiring, thereby stimulating the brain.

[0013] According to the neural electrode for recording and / or stimulation and the method using the same of the present invention, the neural electrode is flexible and can be adhered closely to the brain surface, and the adhesion is not lost even when implanted for a long period of time.

[0014] 1 is a top view (rear view) schematically showing one embodiment of the neural electrode of the present invention. It is a bottom view (surface to be attached to the brain surface) of the neural electrode of FIG. 1. (A) is a partial cross-sectional view showing an enlargement of line A-A in FIG. 1, and (B) is a partial cross-sectional view showing an enlargement of line B-B. It is a diagram schematically showing an example of a manufacturing procedure for the neural electrode of the present invention. It is a photograph showing the state of printed wiring on an SBS thin film plasma-treated for different times in an example. It is a diagram schematically showing a measurement system for the insulating layer in an example. It is a graph showing the resistivity of an SBS thin film of each film thickness measured using the measurement system of FIG. 6. It is a diagram schematically showing a resistivity measurement system in an example. It is a graph showing the rate of change in conductor resistance versus the reciprocal of conductor width measured using the measurement system of FIG. 8. It is a graph showing the measurement results of impedance in an electrode of an example (electrode diameter 250 μm). 13 is a diagram illustrating a stimulation potential measurement experiment using a whisker-brain response circuit in an example; (A) is a photograph showing the state in which electrodes have been attached to the surface of a rat's brain, and (B) and (C) are schematic diagrams showing the correspondence between the whisker stimulation site and the multi-point electrode array (4 x 4). 14 is a graph showing the stimulation potential measurement results measured using the measurement system of FIG. 11. 15 is a diagram showing a schematic diagram of a current load test system in an example. 16 is a graph showing the output current waveform measured using the measurement system of FIG. 13. 17 is a graph showing the whisker myoelectric potential during electrical stimulation measured by attaching an electrode of an example to the surface of a rat's brain. The stimulation current is shown as a thick straight line, and the EMG is shown as a thin curve representing the recording of each of 46 trials, with the average shown as a thick curve. 18 is a photograph showing the state in which an electrode of an example has been attached to a brain gel model.

[0015] Hereinafter, specific embodiments of the present invention will be described with reference to the accompanying drawings. Note that the drawings are shown for the purpose of explaining the embodiments, and the actual dimensions are not intended to be those of the drawings, and reference is made to the description in the specification.

[0016] In the present invention, the thicknesses of the insulating sheet, base sheet, conductive wiring, and other components of the neural electrode are considered to be average values ​​determined using a measuring device such as a surface profiler.

[0017] Figures 1 to 3 are schematic diagrams showing one embodiment of the neural electrode of the present invention, in which Figure 1 is a top view (back view), Figure 2 is a bottom view (the surface attached to the brain surface), Figure 3 (A) is a partial cross-sectional view showing an enlargement of line A-A in Figure 1, and Figure 3 (B) is a partial cross-sectional view showing an enlargement of line B-B.

[0018] The neural electrode 1 of this embodiment is a neural electrode for recording and / or stimulation, which is used by adhering an attachment part 2, which is a sheet-like electrode, to the brain surface. The attachment part 2 has at least an insulating sheet 3, one side of which is to be attached to the brain surface, and a conductive wiring 4 on the surface of the insulating sheet 3 opposite to the attachment surface 2, and multiple electrode parts 4a on the conductive wiring 4 are exposed through holes 3a in the insulating sheet 3. The insulating sheet 3 is an elastomer thin film having a thickness of 2 to 100 μm, and the conductive wiring 4 has a thickness of 10 μm or less.

[0019] The neural electrode 1 has a base sheet 5 on which conductive wiring 4 is formed, and the base sheet 5 is in close contact with the insulating sheet 3 at the attachment portion 2, sandwiching the conductive wiring 4 therebetween, and the base sheet 5 is an elastomer thin film having a thickness of 100 μm or less.

[0020] The neural electrode 1 is for recording and / or stimulation. Specifically, the weak electrical potentials associated with brain activity are received by the multiple electrode portions 4a and recorded by a measuring device electrically connected to the conductive wires 4. Examples of applications include intracranial electrodes for diagnosing epilepsy foci and electrodes for brain-machine interfaces (BMIs). In particular, the neural electrode can be used as a recording neural electrode with the high spatial distribution density required for BMIs. Furthermore, a current is supplied from a stimulator electrically connected to the conductive wires 4 and transmitted to the brain to stimulate the brain. Examples of applications include systems that detect epileptic seizures and immediately suppress them by electrically stimulating the epileptic focus, and neuromodulation.

[0021] The neural electrode 1 can be used, for example, as a subdural electrode, which is an intracranial electrode placed on the brain surface under the dura mater. A subdural electrode is an electrode for detecting electroencephalograms on the brain surface, and can also be used as an electrode for stimulating the brain.

[0022] The insulating sheet 3 is a thin elastomer film having a thickness of 2 to 100 μm. When the thickness of the insulating sheet 3 is 100 μm or less, it is flexible and can be adhered closely to the brain surface. When the thickness of the insulating sheet 3 is 2 μm or more, insulation of the conductive wiring 4 from the brain surface can be ensured. From these points of view, the upper limit of the thickness of the insulating sheet 3 is preferably 90 μm or less, more preferably 70 μm or less, even more preferably 50 μm or less, and particularly preferably 30 μm or less. The lower limit of the thickness of the insulating sheet 3 is preferably 3 μm or more, more preferably 4 μm or more.

[0023] The elastomer that is the material of the insulating sheet 3 is not particularly limited as long as it is safe and suitable for use in contact with the brain surface when attached to the brain surface. Elastic polymers such as thermoplastic or thermosetting elastomers can be used.

[0024] Specific examples include styrene-based elastomers, silicone-based elastomers, olefin-based elastomers, ester-based elastomers, urethane-based elastomers, amide-based elastomers, and vinyl chloride-based elastomers. These may be used alone or in combination of two or more. Furthermore, the insulating sheet 3 may be made of a polymer other than elastomer, such as polylactic acid.

[0025] Examples of styrene-based elastomers include styrene-butadiene-styrene block copolymer (SBS), styrene-ethylene-butylene-styrene block copolymer (SEBS), styrene-isoprene-styrene block copolymer (SIS), styrene-ethylene-propylene-styrene block copolymer (SEPS, a hydrogenated product of SIS), styrene-ethylene-propylene block copolymer (SEP, a hydrogenated product of styrene-isoprene block copolymer), and styrene-isobutylene-styrene block copolymer (SIBS).

[0026] Silicone-based elastomers are primarily composed of organopolysiloxane, and examples thereof include polydimethylsiloxane, polymethylphenylsiloxane, and polydiphenylsiloxane. They may also be partially modified with vinyl groups, alkoxy groups, or the like. A thin film of organopolysiloxane can be obtained, for example, by treating a base material containing a siloxane compound with a curing agent to polymerize and / or crosslink the material. Depending on the type of primary reactive group in the base material, a compound having an alkenyl group can be used as the curing agent if the base material has a hydrosilyl group as the primary reactive group, and a compound having a hydrosilyl group can be used if the base material has an alkenyl group as the primary reactive group. Among these, styrene-based elastomers and silicone-based elastomers are preferred, with styrene-based elastomers being more preferred.

[0027] The elastomer thin film of the insulating sheet 3 may contain other components such as known additives within the scope of the present invention, as long as the effects of the present invention are not impaired. Examples of known additives include antioxidants, weather stabilizers, heat stabilizers, lubricants, crystal nucleating agents, ultraviolet absorbers, colorants, surfactants, and fillers. These may be used alone or in combination of two or more.

[0028] The conductive wiring 4 is formed on one side of the elongated base sheet 5. The conductive wiring 4 has multi-point electrode portions 4a at the position of the attachment portion 2, which contact the brain surface when the neural electrode 1 is attached to the brain surface. That is, the multi-point electrode portions 4a are exposed through holes 3a formed in the insulating sheet 3 and contact the brain surface to ensure electrical connection. The number and dimensions of the multi-point electrode portions 4a are not particularly limited, depending on the intended use (e.g., human or other animal) and the intended use. The width of the electrode portions 4a can be, for example, 20 μm to 10 mm, and their shape is not particularly limited and may be, for example, round, square, rectangular, etc. The spacing between the electrode portions 4a can be, for example, 20 μm to 20 mm, and they can be arranged in any desired pattern, such as a square or rectangular array. The external dimensions of the attachment portion 2 can be determined according to the spacing between the electrode portions 4a.

[0029] The conductive wires 4 extend continuously from each of the multiple electrode portions 4a in the longitudinal direction of the base sheet 5 so that adjacent wires are spaced apart and parallel to each other. The width and spacing of the conductive wires 4 are not particularly limited, depending on the width and spacing of the electrode portions 4a. Considering the allowable impedance in electroencephalogram measurement, the amount of current expected for a subdural electrode, and the like, the width of the conductive wires 4 can be, for example, 20 μm to 10 mm, and the spacing can be, for example, 20 μm to 20 mm.

[0030] The conductive wiring 4 has a thickness of 10 μm or less. When the thickness of the conductive wiring 4 is 10 μm or less, the conductive wiring 4 is flexible and can be closely attached to the brain surface. From this viewpoint, the upper limit of the thickness of the conductive wiring 4 is preferably 5 μm or less, and more preferably 1 μm or less. The lower limit of the thickness of the conductive wiring 4 is not particularly limited, but from the viewpoint of conductivity such as impedance, it is preferably 200 nm or more, and more preferably 500 nm or more.

[0031] The conductive wiring 4 having the thickness and line width as described above can be formed on the base sheet 5, for example, by a printing method using a conductive ink, or by a vapor deposition method or a sputtering method using conductive nanoparticles. Commercially available conductive inks and conductive nanoparticles can be obtained and used.

[0032] Among these, it is preferable that the conductive wiring 4 is a printed wiring. In the case of a printing method, for example, the conductive wiring 4 can be formed as a wiring pattern by printing a conductive ink on the base sheet 5 with an inkjet printer. As a method for forming a wiring pattern, the conductive wiring 4 can be printed on the base sheet 5 using a simple method such as offset printing or screen printing in addition to the inkjet printing described above.

[0033] In this specification, "metal nanoparticles" used as a conductive material for forming the conductive wiring 4 refer to metallic particles having a diameter of less than 1000 nm, preferably several tens of nm to 300 nm. "Ink" is used synonymously with "ink" and refers to a printing dispersion in which a conductive material such as metal nanoparticles is dispersed in a liquid, and may include a conductive paste used for printing conductive materials in the field of printed electronics.

[0034] Examples of materials for the conductive ink or conductive nanoparticles include, but are not limited to, metals such as gold, platinum, silver, copper, nickel, rhodium, palladium, magnesium, chromium, titanium, and iron, as well as oxides thereof and alloys of these metals and / or their oxides. These may be used alone or in combination of two or more. Metal nanoparticles such as gold, platinum, silver, copper, and nickel are particularly preferred because they are relatively easy to obtain and have low resistivity.

[0035] Furthermore, for example, a conductive organic material can be used as the material for the conductive ink. The conductive organic material can be selected from, for example, a conductive carbon material or a conductive polymer. The conductive carbon material can be selected from, for example, conductive carbon black, carbon nanotubes, carbon nanotube derivatives, graphene, graphite, and conductive carbon fiber. These materials can be used alone or in combination of two or more. The conductive polymer can be selected from, for example, polythiophenes, polypyrroles, polyanilines, polyazulenes, polyindoles, polycarbazoles, polyacetylenes, polyfurans, polyparaphenylene vinylenes, polyazulenes, polyparaphenylenes, polyparaphenylene sulfides, polyisothianaphthenes, and polythiazyls. An example of a polythiophene is PEDOT / PSS (poly(styrene sulfonic acid)) containing PEDOT (poly(3,4-ethylenedioxythiophene)).

[0036] Although not shown, a lead wire for drawing a conductive path outside the body may be electrically connected to the portion extending continuously from the attachment portion 2 to the opposite side of the multi-point electrode portion 4a. Also, a connector may be provided for connecting the terminals to a measuring device for recording or a stimulating device for electrical stimulation.

[0037] The base sheet 5 is an elastomer thin film having a thickness of 100 μm or less. When the thickness of the base sheet 5 is 100 μm or less, it is flexible and can be adhered closely to the brain surface. From this viewpoint, the upper limit of the thickness of the base sheet 5 is preferably 90 μm or less, more preferably 70 μm or less, even more preferably 50 μm or less, and particularly preferably 30 μm or less. The lower limit of the thickness of the base sheet 5 is not particularly limited, but from the viewpoint of ensuring the strength as a base for the conductive wiring 4 and ensuring the insulation of the conductive wiring 4, it is preferably 3 μm or more, more preferably 4 μm or more.

[0038] The elastomer that is the material for the base sheet 5 is not particularly limited as long as it is safe and suitable for use in contact with the brain surface when applied to the brain surface. Specific examples of the elastomer that is the material for the base sheet 5 include those exemplified above as the elastomers for the insulating sheet 3, and reference is made to the description thereof. Among these, styrene-based elastomers and silicone-based elastomers are preferably used. Among these, styrene-based elastomers are more preferred because, when printed wiring is used as the conductive wiring 4, hydrophilization of the base sheet 5 improves affinity with conductive ink, allowing for the formation of a stable wiring pattern without interruption of the conductive wiring 4.

[0039] The elastomer thin film of the base sheet 5 may contain other components such as known additives within the range that does not impair the effects of the present invention. Examples of known additives include those listed above as examples of additives for the insulating sheet 3.

[0040] The surface of the base sheet 5 facing the conductive wiring 4 is preferably subjected to a hydrophilic treatment. The hydrophilic treatment reduces the contact angle on the surface of the base sheet 5. This makes it possible to form fine conductive wiring more accurately when using printed wiring as the conductive wiring 4 without ink containing a conductive material being repelled by printing. In other words, when the base sheet 5 is subjected to a hydrophilic treatment, it has a good affinity with conductive ink, allowing a stable wiring pattern to be formed without the conductive wiring 4 being interrupted. Furthermore, there is no need to provide an additional ink-receiving layer on the surface of the base sheet 5.

[0041] The hydrophilization treatment is not particularly limited, but examples thereof include air plasma treatment using a plasma cleaner or the like, oxygen plasma treatment, carbon dioxide plasma treatment, hydrogen plasma treatment, nitrogen plasma treatment, argon plasma treatment, helium plasma treatment, polyethylene glycol modification, polydopamine modification, 2-methacryloyloxyethyl phosphorylcholine modification, etc. In the air plasma treatment, it is desirable to appropriately adjust the treatment time so that the hydrophilization does not proceed excessively.

[0042] The attachment part 2 of the neural probe 1 has a bending stiffness of 1×10 -3 Nm or less. If the bending rigidity is small, the attachment part 2 is flexible and can be closely attached to the brain surface. From this point of view, the bending rigidity of the attachment part 2 is preferably 1×10 -4 Nm or less, more preferably 1×10 -5 Nm or less, more preferably 1×10 -6 Nm or less, particularly preferably 1 × 10 -7 The lower limit of the bending rigidity is not particularly limited, but from the viewpoint of practical use as the neural probe 1, it is preferably 1×10 -10 Nm or more.

[0043] A support film 6 that supports the base sheet 5 is adhered to the portion that continues from the attachment portion 2 and extends to the opposite side of the multipoint electrode portion 4a. The provision of this support film 6 gives stiffness, i.e., appropriate rigidity, to the flexible sheet made of the flexible insulating sheet 3 and the base sheet 5, thereby improving handling such as attachment to the brain surface and removal after placement, and also facilitating connection to lead wires.

[0044] The material of the support film 6 is not particularly limited as long as it is a resin material that has appropriate flexibility and is safe when attached to the brain surface. When connecting the neural electrode 1 to a lead wire, a heat-resistant resin material is preferred, and examples of the resin material include polyimide, polydimethylsiloxane, and PET film. The thickness of the support film 6 is preferably 5 μm to 300 μm in terms of appropriate rigidity and flexibility.

[0045] The neural probe 1 of this embodiment can be manufactured by any method, for example, as follows: FIG. 4 is a diagram schematically showing an example of a manufacturing procedure for the neural probe 1.

[0046] The insulating sheet 3 and the substrate sheet 5, such as the SBS thin film 9 shown in Fig. 4(A), can be produced by a known film-forming method such as a roll-to-roll method using a gravure coater or spin coating. The roll-to-roll technique allows for film formation over a larger area than when a spin coater is used.

[0047] For example, an aqueous solution of polyvinyl alcohol (PVA) for the first layer, which will be the sacrificial layer, is applied onto a polyethylene terephthalate (PET) film 7, which will be the substrate, and then dried to form a PVA layer.

[0048] The substrate can be made of PET (polyethylene terephthalate), PP (polypropylene), PPE (polyphenylene ether), COP (cycloolefin), PI (polyimide), aluminum foil, a conductive polymer film, paper, a polysaccharide film, silicone resin, oblate (gelatin), a silicon wafer, glass, etc. The sacrificial layer is used to separate the insulating sheet 3 such as the SBS thin film 9 and the base sheet 5 from the substrate after film formation.

[0049] Next, a solution for forming the elastomer layer, such as a solution of SBS in tetrahydrofuran (SBS solution 8), is applied to the sacrificial layer and dried to form the second layer, thereby forming a laminated film consisting of the first layer (sacrificial layer) and the second layer (SBS thin film 9).

[0050] The surface of the SBS thin film 9 that will become the base sheet 5 is hydrophilized using air plasma or the like, and conductive wiring 4 having multiple electrode portions 4a is formed on this hydrophilized surface by printing or the like (FIG. 4(B)). The printed wiring using nanoink is sintered by heating if necessary.

[0051] A frame such as a paper tape frame 10 is attached to the surface on which the second layer is formed so as to outline the required shape, and by peeling it off from the edge, the two-layer film including the first and second layers is peeled off from the substrate (PET film 7) while still being held by the frame. The base sheet 5 is peeled off together with the conductive wiring 4 using the paper tape frame 10.

[0052] The two-layer film held by this paper tape is floated or immersed in pure water so that the PVA surface of the first layer (sacrificial layer) is in contact with the substrate, dissolving only the first PVA layer and separating the nano-thin film consisting of the elastomer layer held by the paper tape from the substrate. A support film 6 is attached to the backside of the base sheet 5 that has been peeled off (Figure 4(C)).

[0053] The SBS thin film 9 that will become the insulating sheet 3 is cut out with a laser processing machine or the like to form holes 3a so that the holes have the same size as the multi-point electrode portions 4a formed on the base sheet 5 (FIG. 4(D)). The insulating sheet 3 made of this SBS thin film 9 is then placed over the conductive wiring 4 so that only the multi-point electrode portions 4a are exposed, and is then tightly adhered to the conductive wiring 4 (FIG. 4(E)). To bond the base sheet 5 and the insulating sheet 3 together, it is preferable to thermocompress the base sheet 5 and the insulating sheet 3 together by, for example, fusing the periphery of the electrodes with a laser processing machine.

[0054] The neural electrode 1 of the present invention described above can be used in a method for recording weak potentials or currents associated with brain activity or for stimulating the brain by transmitting currents to the brain, which includes the following steps (A) and (B): (A) a step of attaching the neural electrode 1 to the brain surface so that the multipoint electrode portions 4a are in contact with the brain surface; and (B) a step of receiving weak potentials or currents associated with brain activity with the multipoint electrode portions 4a and recording them with a measuring device to which the conductive wiring 4 is electrically connected, or supplying currents from a stimulating device to which the conductive wiring 4 is electrically connected and transmitting them to the brain, thereby stimulating the brain.

[0055] In step (A), for example, the neural electrode 1 may be embedded in the skull. When embedding the neural electrode 1, the skull is opened at the site where the neural electrode 1 is to be placed, and the neural electrode 1 is attached and placed on the brain surface so as to achieve the expected electrode arrangement. A lead wire may be connected to the neural electrode 1, and the lead wire may be brought out, closed, and fixed to the scalp or the like.

[0056] In step (B), for example, the neural electrode 1 is connected to the terminals of a measuring device or a stimulating device via lead wires or connectors, and electroencephalograms are recorded or electrical stimulation is performed.

[0057] According to the neural electrode 1 of the present invention and the above-mentioned method using it, the therapeutic purpose is not particularly limited, based on wide-area and high-density electroencephalogram recording that takes advantage of the strengths of flexible thin-film electrodes, and can be applied to, for example, an integrated device for diagnosis and treatment of intractable epilepsy.

[0058] Epilepsy clinical practice presents challenges at both the diagnostic and treatment stages. At the time of diagnosis, conventional electrodes are thick and have large interelectrode distances, limiting the placement area and making sampling errors more likely. Excessive placement of current electrodes can lead to increased intracranial pressure, which is dangerous, necessitating limited placement area. Furthermore, current chronic electrode recording is wired, which poses a risk of infection and limits the recording period, resulting in insufficient and incomplete recording. Due to recording time constraints, patients' usual antiepileptic medications are reduced before chronic intracranial EEG recording, resulting in EEG recordings of seizures other than those being treated, reducing the quality of diagnosis. The low accuracy of identifying the epileptogenic zone contributes to the limited treatment outcomes of focal resection. Regarding treatment challenges, in Japan, the only neuromodulation available for cases where focal resection is difficult is vagus nerve stimulation (VNS), limiting the range of treatment options. Seizure-responsive neurostimulation (RNS), used in Europe and the United States, requires dedicated electrodes and requires the replacement of EEG recording electrodes for treatment. Furthermore, the number of electrodes that can be used for RNS is limited, and stimulation effects can only be achieved in a narrow range of brain regions. These factors contribute to the limited treatment results of electrical stimulation therapy.

[0059] Future clinical workflows aim to address these issues by implementing remote monitoring systems that utilize wireless power supply, remote monitoring, and data accumulation and automatic data analysis to provide clinically valuable information tailored to each diagnostic and treatment objective. This system allows patients to return home within the measurement period, eliminates wired connections, and allows for electrode placement for up to six months. Wireless data transfer allows for extended EEG data measurement periods. The electrodes of the present invention are thinner, lighter, and softer than conventional recording and stimulation electrodes, enabling the measurement of wide-area, high-density EEG data through the placement of, for example, 128 to 256 channels. In other words, even with a large number of electrodes placed, symptoms of increased intracranial pressure are not caused, and the large placement area reduces sampling errors. The electrodes of the present invention enable wide-area, high-density EEG recording, stable placement of multiple electrodes, and long-term implantation without compressing brain tissue, making them suitable for implementing wireless remote monitoring systems, which are the goal of clinical workflows such as the diagnosis and treatment of intractable epilepsy.

[0060] Although the present invention has been described above based on the embodiment, the present invention is not limited to this embodiment, and various modifications are possible within the scope of the gist of the present invention.

[0061] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples.

[0062] Example 1: Fabrication of Flexible Thin-Film Electrodes. A thin film (7 wt %, 4 μm) of styrene-butadiene-styrene block copolymer (SBS, polystyrene-block-polybutadiene-block-polystyrene, Sigma-Aldrich Japan) was fabricated using a bar coater on a PET film (Lumirror 25t60, Panac Corporation) on which a polyvinyl alcohol (7 wt %) layer (Polyvinyl Alcohol, Kanto Chemical Co., Inc.) had been formed by gravure printing (Figure 4(A)). The surface of the resulting SBS thin film was hydrophilized using a plasma cleaner (PDC-001, Harrick Plasma, NY) (Figure 4(B)). Treatment times (7 W, 0, 1, 2, and 3 min) were investigated. The contact angle of the SBS thin film treated with air plasma was measured at each time point, and the structure of the printed wiring was evaluated.

[0063] The longer the air plasma treatment time, the smaller the contact angle of the SBS thin film surface, promoting surface hydrophilicity (Table 1). When gold nanoink was inkjet printed on each plasma-treated thin film, the wiring was partially broken on the surface without plasma treatment, while the wiring smudged on the surface treated for 3 minutes (Figure 5). Based on these results, the plasma treatment time for electrode fabrication was set to 2 minutes.

[0064]

[0065] Next, a multi-point electrode structure with 16 microelectrodes (250 μm × 250 μm, 1 mm spacing) made of Au nanoink (Au-J, C-INK) was printed using a material printer (Dimatix DMP-2831, Fujifilm) (Figure 4(B)). After sintering the printed wiring (110°C, 1 hour), the electrodes were peeled off using a paper tape frame. A polyimide film (Kapton®, DuPont-Toray Co., Ltd.) was attached to the back of the peeled sheet as a support (Figure 4(C)).

[0066] Next, an SBS thin film with the same thickness as the substrate was used as the insulating layer. The SBS thin film was then cut out using a laser processing machine (VLS2.30DT, manufactured by Universal Laser Systems) to the same size as the printed electrodes (250 μm × 250 μm, 1 mm spacing) ( Figure 4(D) ). This SBS thin film insulating layer was placed over the surface of the printed wiring, exposing only the measurement area of ​​the electrode ( Figure 4(E) ). The outer periphery of the electrode was then fused using the laser processing machine, thereby thermocompression bonding the insulating film to the substrate.

[0067] The thickness of the SBS thin film and Au wiring of the electrode prepared in Example 1 was measured using a surface profiler (Dektak, Bruker, MA), and the bending rigidity of this thin film electrode was compared with that of a comparative electrode. The bending rigidity (D) is defined by the following formula and was calculated from the Young's modulus (E), Poisson's ratio (γ), and film thickness (h) of the electrode material.

[0068]

[0069] The bending rigidity is the sum of the components. -9 Nm (Table 2). The comparative electrode using a silicone (PDMS) thin film and a stainless steel electrode (SUS304) had a resistance of 2.20 × 10 -3 Nm. Therefore, by thinning the electrode, the bending rigidity was 1.81 × 10 -6 It was found to have an extremely flexible structure.

[0070]

[0071] Example 3: Evaluation of Electrical Properties Resistance values ​​under direct current were measured and resistivities were calculated to evaluate the insulating performance of the SBS thin film used in the substrate and insulating layer of the electrode fabricated in Example 1. The resistivity measurement system shown in Figure 6 was used for the measurements, and comparisons were made between SBS thin films with thicknesses of 330 nm, 1 μm, 1.5 μm, 2 μm, 3.7 μm, and 6.7 μm.

[0072] When insulating printed wiring, we measured the resistance of SBS thin films with different thicknesses and found that a film with a thickness of 3.7 μm or more was insulating (Figure 7). Based on these results, we selected a 3.7 μm SBS thin film as an electrode protection material that is insulating while maintaining flexibility and conformability to biological tissue.

[0073] Next, a resistivity measurement system was constructed to analyze the resistance of the printed wiring (Figure 8). Specifically, the printed wiring was connected to the position marked "Measurement Target" using an FFC conversion connector. The position marked "Reference Voltage" was then used as the ground for analog voltage reading, and analog voltages were read at "Voltage Reading Positions 1 and 2." The voltage output to the load on the measurement target was a sine wave with an amplitude of 1 V and frequencies of 0.1, 0.2, 0.5, 1, 2, 5, 10, 20, 50, 100, 200, 500, 1 kΩ, 2 kΩ, 5 kΩ, 10 kΩ, 20 kΩ, and 25 kHz. A DA converter (PXI6289, National Instruments, TX) was used to read and output the analog voltage, and a switching module (PXI2536, National Instruments, TX) was used to switch targets on the same electrode. The potential difference between the two ends of the object to be measured was calculated by calculating the difference in the voltage readings, and the current flowing through the circuit was calculated from the potential difference between the two ends of the 1 kΩ resistor. The resistance was calculated from these potential differences and current. The resistivity of the printed wiring was calculated by setting the line width of the printed wiring to 140, 280, 420, 560, 700, 840, and 960 μm, the number of printed layers to 1, 2, 3, 4, and 5 layers (280 μm per layer), and the length of the conductor to 5 cm.

[0074] When the resistance of the printed wiring was measured, the volume resistivity was 3.70 × 10 -7 It was found that the resistance was Ωm (Figure 9). At this time, electrodes with a single printed layer had an unstable structure, resulting in variations in resistance values. When two or more layers were printed, the variations were reduced and low-resistance wiring was obtained. From these results, a method was discovered to form conductive wiring that falls within the desired resistance range by controlling the line width and thickness of the printed wiring.

[0075] Finally, the electrochemical impedance of the electrode was evaluated at 10 Hz to 10 kHz using an impedance analyzer (3532-80, manufactured by Hioki E.E. Corp.). A phosphate buffer solution (pH 7.6, manufactured by Fujifilm Corp.) was used as the solvent, and an Ag / AgCl electrode was used as the reference electrode.

[0076] The electrochemical impedance of the flexible thin-film electrode (electrode diameter 250 μm) fabricated for use on the rat brain surface at 1 kHz was 1.68 kΩ (Figure 10). Generally, it is considered desirable for the impedance in human ECoG measurements to be less than 20 kΩ (Japanese Society of Clinical Neurophysiology, "Revised Clinical Electroencephalography Testing Standards" (2002)), and this electrode is expected to fall within the optimal measurement range.

[0077] Example 4: In vivo neural potential recording Thin-film electrodes were attached to the brain surface of anesthetized rats, and the correlation between ECoG and mechanical stimulation of each whisker using the whisker-brain response circuit was evaluated (Figure 11).

[0078] We successfully measured ECoG stably using thin-film electrodes with excellent conformability to the brain surface (Figure 12). When we investigated the spatial resolution of the electrodes based on the whisker-brain response circuit, we found a correspondence between any whisker stimulation site and a multi-point electrode array (4x4) in terms of columns. These in vivo results suggest that recording neural potentials using the thin-film electrodes of this example can also be applied to humans.

[0079] Example 5: In Vitro Electrical Stimulation A current load test system was constructed to measure the current output from a constant-current stimulator (Figure 13). Specifically, the constant current output from the + terminal passed through a 1 kΩ resistor and flowed to the - terminal. An AD converter (PXI6289, National Instruments, TX) was used to measure the potential difference across the 1 kΩ resistor, confirming that a current was being output. To measure the potential difference, an output waveform was programmed using a constant-current stimulator (STG4008-16 mA, multi-channel systems, Baden-Wuerttemberg, Germany). One cycle consisted of a 1-second stimulation followed by a 1-second rest, and this cycle was repeated 900 times. The amplitude of the single output waveform was set to 10 mA and approximately 300 Hz. In the current load test, it was confirmed by an AD converter that a current of 10 mA was flowing through the electrode of the single-layer, 140 μm-wide conductor (FIG. 14).

[0080] Furthermore, electrodes were attached to the motor cortex of anesthetized rats, and the rats' behavior was observed when they were electrically stimulated using a constant current stimulator (STG4008, multi-channel systems, Baden-Württemberg, Germany). It was shown that applying an electric current to electrodes attached to the motor cortex of a rat's brain caused site-specific movement of the arms and whiskers.

[0081] The electrode was used to stimulate one whisker region in the left hemispheric cortex of anesthetized rats, and electromyography (EMG) was recorded from the left base of the rat during stimulation. A 1.6 mA square wave current was applied five times (time width of the square wave: 260 μs, time interval between square waves: 3340 μs) for stimulation.

[0082] Electrical stimulation of the whiskers was confirmed by EMG recording at the base of one whisker (Figure 15). Following artifacts related to the stimulation current and the on / off state of the isolator output (potential changes recorded at -14.4 ms and 3.34 ms), EMG was recorded between 5 and 15 ms. These results suggest that electrical stimulation of the brain surface using the thin-film electrodes of this example may also be applicable to humans.

[0083] From the above, we were able to measure neural potentials by attaching the fabricated electrode to the surface of the rat brain. We were also able to record waveforms when whiskers were stimulated. We also demonstrated that similar thin-film electrodes can be attached to the brain surface for electrical stimulation.

[0084] Example 6: Application to a human-sized brain gel model The electrode was applied to a human-sized brain gel model (MR.Brain, Astec Corporation, headquartered in Higashimatsuyama, Saitama Prefecture) (Figure 16). This brain gel model is a product intended for doctors to practice anastomosis, and is soft and elastic, with surface irregularities that mimic cerebral sulci. It was possible to confirm that the electrode conformed to the surface irregularities that mimicked cerebral sulci. In other words, because the electrode is thin, light, and soft, it can be placed over a wide area and even with a large number of electrodes, it can be implanted for a long period of time without compressing brain tissue, suggesting that it will be possible to measure electroencephalogram data over a wide area and at high density.

[0085] 1: neural electrode 2: attachment part 3: insulating sheet 3a: hole part in insulating sheet 4: conductive wiring 4a: multi-point electrode part 5: base sheet 6: support film 7: PET film 8: SBS solution 9: SBS thin film 10: paper tape frame

Claims

1. A neural electrode for recording and / or stimulation used by attaching an attachment part, which is a sheet-like electrode, to the brain surface, The attachment part has at least an insulating sheet having one side to be attached to the brain surface, and a conductive wiring on the side of the insulating sheet opposite to the attachment side, and multiple electrode parts on the conductive wiring are exposed through holes in the insulating sheet, A nerve electrode for recording and / or stimulation, wherein the insulating sheet is an elastomer thin film having a thickness of 2 to 100 μm, and the conductive wiring has a thickness of 10 μm or less.

2. a base sheet on which the conductive wiring is formed, the base sheet is in close contact with the insulating sheet at the attachment portion, sandwiching the conductive wiring therebetween; 2. The recording and / or stimulating nerve electrode according to claim 1, wherein the base sheet is an elastomer thin film having a thickness of 100 μm or less.

3. 3. The recording and / or stimulating nerve electrode according to claim 2, wherein the conductive wiring is a printed wiring.

4. 4. The recording and / or stimulating nerve electrode according to claim 3, wherein the surface of the base sheet on the conductive wiring side is subjected to a hydrophilic treatment.

5. 2. The recording and / or stimulating nerve electrode according to claim 1, wherein the insulating sheet is made of a styrene-based elastomer.

6. The attachment portion has a bending rigidity of 1×10 -3 2. The recording and / or stimulating nerve electrode according to claim 1, wherein the electrode has a capacitance of 0.01 Nm or less.

7. A neural electrode for recording and / or stimulation as described in claim 1, wherein a support film supporting the base sheet is adhered to a portion extending continuously from the attachment portion to the opposite side of the multi-point electrode portion.

8. A method for recording weak potentials or currents associated with brain activity or for stimulating the brain by transmitting current to the brain, comprising the steps of: A step of attaching the neural electrode according to any one of claims 1 to 7 to the brain surface so that the multipoint electrode portion contacts the brain surface; and A process in which the weak potential or current associated with brain activity is received by the multipoint electrode portion and recorded by a measuring device electrically connected to the conductive wiring, or a current is supplied from a stimulation device electrically connected to the conductive wiring and transmitted to the brain, thereby stimulating the brain.