CN116271534A - Nerve microprobe for positioning deep nucleus double-mode function of non-human primate brain and precise electric stimulation - Google Patents
Nerve microprobe for positioning deep nucleus double-mode function of non-human primate brain and precise electric stimulation Download PDFInfo
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- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
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Abstract
The invention discloses a nerve microprobe for positioning deep nucleus of brain of a non-human primate and accurately electrically stimulating. The metal conductive layer is composed of a basal layer, a metal conductive layer and an insulating layer, wherein the conductive layer comprises a detection site group and a stimulation site. The invention adopts double insulating layers with opposite stress to simultaneously dry etch silicon oxide materials on the back of the silicon substrate layer, balances the difference of the stress of different materials, overcomes the technical difficulty of the process of lengthening the version of silicon micro probe, and solves the problems of easy bending and small mechanical stress caused by the large aspect ratio of the silicon probe of the non-human primate. The detection site obtains a dual-mode signal as a positioning mark through modifying the nano metal material and the polymer anti-interference ion membrane to perform functional positioning. The detection sites are arranged between the electric stimulation anode and the electric stimulation cathode, so that the stimulation range is controlled near the detection sites, and the accurate electric stimulation is realized. The invention can provide a new research means and method for treating diseases such as Parkinson and the like by deep brain electrical stimulation.
Description
Technical Field
The invention relates to the research field of deep brain electrical stimulation for treating diseases such as Parkinson and the technical field of micro-electromechanical systems, in particular to a nerve micro-probe for positioning dual-mode functions of deep brain nuclei of non-human primates and precise electrical stimulation.
Background
Deep brain electrical stimulation has become an effective treatment for diseases such as parkinsonism, epilepsy, dystonia and the like. In order to optimize the therapeutic effect without damaging the surrounding nucleus, it is necessary to achieve accurate localization of the deep brain nucleus and to perform accurate electrical stimulation. The physiological structure of the non-human primate is closer to that of human, so that the non-human primate is taken as an animal model to play an important role in researching human diseases.
The combined detection of the neuro-electrophysiologic signals and the neuro-electrochemical signals has very important significance for the identification and differentiation of cerebral nucleus and the diagnosis and control of the nervous system. In order to achieve accurate target positioning, the spatial resolution of detection needs to be improved, so that more nerve information is acquired. The multichannel detection tool can realize the detection of electrophysiological signals and electrochemical signals at the same time, and can be helpful for realizing the accurate positioning of brain regions.
The traditional brain electrical stimulation mode mainly adopts millimeter and centimeter level electrodes to stimulate, so that the brain tissue is greatly damaged, and other nuclear clusters are easily damaged. The positioning electrode and the stimulating electrode are independently used to generate deviation at the stimulating part, so that accurate electric stimulation is difficult to realize, and the change of the nerve electrophysiological signal and the nerve electrochemical signal under the regulation and control of the electric stimulation cannot be detected in real time.
Primate models have a larger brain volume and require longer silicon probes than rat models. Silicon-based probes are prone to curling due to the superposition of different material stresses, and are difficult to use for implanting primates.
Therefore, a tool capable of realizing dual-mode functional positioning of deep nucleolus of brain of non-human primate and performing accurate electrical stimulation on target nucleolus is lacking at present.
Disclosure of Invention
First, the technical problem to be solved
Aiming at the technical problems, the invention provides a nerve microprobe for positioning deep nucleus of brain and dual-mode function and accurately electrically stimulating of a non-human primate, which is used for solving the technical problems.
(II) technical scheme
The invention provides a neural micro-probe for non-human primate deep brain nuclear cluster dual-mode functional localization and accurate electrical stimulation, the microelectrode array comprises:
a base layer: the material is an insulating material; preferably, the substrate layer is made of rigid insulating material;
metal conductive layer: is positioned on the substrate layer and comprises: the electrophysiological detection site and the electrochemical detection site are positioned between the electrostimulation anode and the electrostimulation cathode; the reference electrode and the counter electrode are positioned at two sides of the lower end of the detection site, and the detection site, the electric stimulation anode and the electric stimulation cathode are connected with the bonding pad through wires;
insulating layer: the material is a double insulating layer with opposite stress and is positioned above the conductive layer.
Preferably, there are 12 electrophysiological detection sites and 4 electrochemical detection sites.
Furthermore, the microprobe is made of SOI (silicon on insulator) as a substrate, in order to avoid the problems of electrode bending and low mechanical strength caused by overlong silicon probes for non-human primates, silicon oxide on the back of the microprobe is removed by dry etching, and meanwhile, the difference of different material stresses is balanced by adopting double insulating layers with opposite stresses, so that the long probe for non-human primates implantation is realized.
The electrophysiological detection sites and the electrochemical detection sites are densely distributed, so that a plurality of sites are contacted with or close to the same nerve cell at the same time, the detection sites are more easily contacted with neurons in the brain of a non-human primate, and electrophysiological and electrochemical signals are conveniently obtained. The electrophysiology wire is connected with the electrophysiology detection site. An electrochemical lead is connected to the electrochemical detection site.
The electrochemical detection site is used for modifying the nano material and the polymer anti-interference ionic membrane and detecting neurotransmitters to obtain neuroelectrochemical signals; the electrophysiological detection site is modified by nano materials and is used for detecting nerve cell discharge signals to obtain nerve electrophysiological signals.
The reference electrode and the counter electrode are 300 micrometers in size and 20 micrometers in width and are used for providing reference points and keeping potential stable.
The width of the electric stimulation positive electrode and the electric stimulation negative electrode is 150 micrometers, the length of the electric stimulation positive electrode and the electric stimulation negative electrode is 200 micrometers, the electrophysiological detection site and the electrochemical detection site are contained in the electric stimulation positive electrode and the electric stimulation negative electrode, the electric stimulation positive electrode and the electric stimulation negative electrode are both positioned inside the target nucleus, and the formed electric field is limited to the inside of the target nucleus.
The line width of the electric stimulation lead is 80 microns, the number of the electric stimulation leads is two, one electric stimulation lead is connected with the electric stimulation positive electrode, and the other electric stimulation lead is connected with the electric stimulation negative electrode. The line width is positively correlated with the applicable current, the maximum passable current reaches 3.2mA, and the electric stimulation current required by disease treatment can be satisfied.
The invention also provides a preparation method for any one of the neural micro-probes, which comprises the following steps:
operation S1: and (4) taking SOI front-side silicon as a substrate, and performing a first photoetching process. Sputtering nano metal platinum and stripping to form a conductive layer pattern;
operation S2: silicon nitride and silicon oxide with opposite stress are deposited by adopting a plasma chemical vapor deposition (PECVD) method to serve as double insulating layers, and stress differences among different materials are balanced. Performing second photoetching, and etching to expose the sites and the bonding pads;
operation S3: performing third photoetching, and deeply etching the top silicon to form a probe pattern;
operation S4: wet etching the SOI bottom silicon structure, and separating the silicon probe from the substrate;
operation S5: the released silicon probe is attached to a silicon wafer with uniform photoresist in a spin coating mode, silicon oxide on the back of the probe is etched, and stress superposition of different materials is avoided, so that the problems that the silicon probe for non-human primates is large in length-width ratio, small in electrode thickness, easy to bend and low in mechanical strength are solved.
The present disclosure also provides a method for using any one of the above-described neural microprojections, comprising:
implanting the microprojections into subthalamic nucleus (STN) as target areas; receiving through the detection site the neuroelectrophysiologic and electrochemical signals of a non-human primate thalamous reticulum core (reticular thalamic nucleus, rt), an uncertainty Zone (ZI) and a subthalamic core (subthalamic nucleus, STN), and a substantia nigra below STN (SN); classifying according to the distribution mode of the neuro-electro-physiological signals and the concentration characteristics of the neuro-electro-chemical signals of each brain region, and finally realizing the accurate functional positioning of the subthalamic nucleus; by electrically stimulating the brain area after positioning, the changes of nerve electrophysiological signals and nerve electrochemical signals before and after the electric stimulation are detected, an electric stimulation regulation and control mechanism is explored, and the stimulation parameters are reversely regulated, so that long-term closed-loop accurate electric stimulation regulation and control is realized.
(III) beneficial effects
From the technical scheme, the invention provides the nerve microprobe for positioning and electrically stimulating and regulating deep brain nucleolus function, which has the beneficial effects that:
(1) The positioning and the stimulation of the deep brain nucleus of the non-human primate can be realized;
(2) The synchronous detection of the nerve electrophysiological signal and the nerve electrochemical signal can be realized, and the acquisition of more comprehensive nerve information is facilitated;
(3) The diameter of the electrode detection site is small, so that single-cell horizontal nerve information can be acquired, and the positioning accuracy is improved;
(4) The electrophysiological electrochemical detection and the electrical stimulation are integrated, so that the accurate electrical stimulation of locating the nucleus can be realized, and the damage to brain tissues is reduced;
(5) The method synchronously realizes the electric stimulation and the detection of the change of the nerve electrophysiological signal and the nerve electrochemistry signal, is favorable for exploring an electric stimulation regulation mechanism, and provides a basis for long-term closed-loop regulation.
Drawings
For a more complete understanding of the present invention, and the advantages thereof, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, which are incorporated in and constitute a part of this specification, in which:
FIG. 1 is a neural microprojection for dual-mode functional localization and precise electrical stimulation of the deep nucelomic brain of a non-human primate;
FIG. 2 is a partial enlarged view of a neural microprojection detection and stimulation portion for dual-mode functional localization and precise electrical stimulation of the deep nucelomic brain of a non-human primate;
FIG. 3 is a schematic diagram of a process flow for preparing a neural microprojection for dual-mode functional localization and precise electrical stimulation of deep nucelomic of a non-human primate brain;
FIG. 4 is a schematic diagram of the functional localization of the subtotal nucleus of the brain of a non-human primate in combination with the precise electro-stimulated neural microprojections to achieve functional localization of the subthalamic nucleus of the macaque;
fig. 5 is an electric field simulation of electrical stimulation formation of neural microprojections for deep nuclear cluster dual mode functional localization and precise electrical stimulation of the non-human primate brain.
In the above figures, the reference numerals have the following meanings:
1-an electrophysiological detection site; 2-an electrochemical detection site; 3-electrically stimulating the positive electrode; 4-electrically stimulating the negative electrode; 5-a reference electrode; 6-a pair of electrodes; 7-electrophysiology leads; 8-electrochemical wires; 9-electrical stimulation leads; 10-pad sites; 11-pad wires; 12-substrate.
Detailed Description
Hereinafter, embodiments of the present invention will be described with reference to the accompanying drawings. It should be understood that the description is only illustrative and is not intended to limit the scope of the invention. In the following detailed description, for purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the embodiments of the invention. It may be evident, however, that one or more embodiments may be practiced without these specific details. In addition, in the following description, descriptions of well-known structures and techniques are omitted so as not to unnecessarily obscure the present invention.
In disclosed embodiments, a neural microprojection for deep brain nuclear cluster dual mode functional localization and electrical stimulation modulation is provided, as shown in fig. 1 and 2, the neural microprojection for deep brain nuclear cluster dual mode functional localization nuclear electrical stimulation modulation comprising: an electrophysiology detection site 1, an electrochemical detection site 2, an electrostimulation anode 3, an electrostimulation cathode 4, a reference electrode 5, a counter electrode 6, an electrophysiology lead 7, an electrochemical lead 8, an electrostimulation lead 9, a bonding pad site 10, a bonding pad lead 11, and a substrate 12; the electrophysiological detection site 1 and the electrochemical detection site 2 are positioned between the electrostimulation anode 3 and the electrostimulation cathode 4; the pad sites 10 are respectively connected with the electrophysiology lead 7, the electrochemical lead 8 and the electrical stimulation lead 9; the electrophysiology detection site 1, the electrochemical detection site 2, the electro-stimulation positive electrode 3, the electro-stimulation negative electrode 4, the reference electrode 5, the counter electrode 6, the electrophysiology lead 7, the electrochemical lead 8, the electro-stimulation lead 9, the bonding pad site 10 and the bonding pad lead 11 are all arranged on the substrate 12.
The microprobe is made of SOI (silicon on insulator) by adopting a substrate 12, and in order to avoid the problems of electrode bending and low mechanical strength caused by overlong silicon probes for non-human primates, silicon oxide on the back surface of the microprobe is removed by adopting dry etching, and meanwhile, the difference of different material stresses is balanced by adopting double insulating layers with opposite stresses, so that the long probe for non-human primates implantation is realized.
The electrophysiological detection site 1 and the electrochemical detection site 2 are round with the diameter of 10 micrometers; the number of the electrophysiological detection sites is 12, the number of the electrochemical detection sites is 4, and the total number of the detection sites is 16, and all the detection sites are positioned between the electrostimulation anode 3 and the electrostimulation cathode 4.
The electrochemical detection site 2 is used for modifying a nanomaterial and a polymer anti-interference ionic membrane and detecting neurotransmitters to obtain neuroelectrochemical signals; the electrophysiological detection site 1 is modified by nano materials and is used for detecting nerve cell discharge signals to obtain nerve electrophysiological signals.
The electrophysiological detection sites 1 and the electrochemical detection sites 2 are densely distributed, so that a plurality of sites are contacted with or close to the same nerve cell at the same time, the detection sites are more easily contacted with neurons in the brain of a non-human primate, and electrophysiological and electrochemical signals are conveniently obtained.
The reference electrode 5 and the counter electrode 6 are in a size of 300 microns long and 20 microns wide and are used for providing a reference point and keeping the potential stable.
The electro-stimulation positive electrode 3 and the electro-stimulation negative electrode 4 have a width of 150 micrometers and a length of 200 micrometers, and comprise an electrophysiology detection site and an electrochemical detection site.
The line width of the electrophysiology lead 7 is 4 micrometers, the length is 4 centimeters, the number of the electrophysiology leads is equal to that of the electrophysiology detection sites 1, and the electrophysiology lead 7 is connected with the electrophysiology detection sites 1; the line width of the electrochemical wires 8 is 4 micrometers, the length is 4 centimeters, the number of the electrochemical wires is equal to that of the electrochemical detection sites, and the electrochemical wires 8 are connected with the electrochemical detection sites 2. The line width of the electric stimulation lead 9 is 80 microns, two electric stimulation leads are arranged, one electric stimulation lead is connected with the electric stimulation positive electrode 3, and the other electric stimulation lead is connected with the electric stimulation negative electrode 4.
The pad sites 10 are square, and the number is 20.
The pad wire 11 is connected to the electrophysiology wire 7, the electrochemical wire 8 and the electro-stimulation wire 9, respectively.
The surfaces of the electrophysiology lead 7, the electrochemical lead 8, the electric stimulation lead 9 and the bonding pad lead 11 are covered with silicon nitride as an insulating layer, and the thickness of the insulating layer is 800 nanometers.
In a disclosed embodiment, as shown in fig. 3, the present disclosure further provides a preparation method for any one of the above-mentioned neural micro-probes, including:
operation S1: and (4) taking SOI front-side silicon as a substrate, and performing a first photoetching process. Sputtering nano metal platinum and stripping to form a conductive layer pattern;
operation S2: depositing silicon nitride and silicon oxide with opposite stress as double insulating layers by adopting a plasma chemical vapor deposition method, balancing stress differences among different materials, performing second photoetching, and etching to expose sites and bonding pads;
operation S3: performing third photoetching, and deeply etching the top silicon to form a probe pattern;
operation S4: wet etching the SOI bottom silicon structure, and separating the silicon probe from the substrate;
operation S5: the released silicon probe is attached to a silicon wafer with uniform photoresist in a spin coating mode, silicon oxide on the back of the probe is etched, and stress superposition of different materials is avoided, so that the problems that the silicon probe for non-human primates is large in length-width ratio, small in electrode thickness, easy to bend and low in mechanical strength are solved.
In the disclosed embodiment, as shown in fig. 4, the neural microprobe for deep brain nucleus dual-mode functional positioning and electrical stimulation regulation is implanted into a bilateral brain region of a macaque, and a subthalamic nucleus is used as a target brain region to acquire a neuro-electrophysiological signal and a neuro-electrochemical signal of a along-the-way neuro-nucleus, so that accurate positioning of STN is realized.
Specifically, MPTP damage modeling is injected to a single side of the macaque, and when the macaque shows parkinsonism, the macaque is applied to function positioning and electrical stimulation experiments.
The embodiment of the invention shows the functional localization and the electric stimulation regulation of the neural information of the hypothalamic nucleus (STN) of the macaque, and takes the macaque as a target area; the non-human primate thalamous reticulum nuclei (reticular thalamic nucleus, rt), the zona incerta, ZI, are received through the detection site to the subthalamic nuclei (subthalamic nucleus, STN) and penetrate the STN into the Substantia Nigra (SN). Feature extraction is carried out on the nerve electrophysiological signals and nerve electrochemistry signals of each brain region, and finally, accurate positioning of thalamo nuclei is realized.
In the disclosed embodiment, as shown in fig. 5, the electrical stimulation effect upon application of a voltage of 0.2 volts, with the direction of the arrow being the direction of the electric field, it can be seen that the electrical stimulation zone is completely covered and localized near the electrophysiological detection site.
Specifically, after the microprobe reaches the target nucleolus STN, positive and negative bidirectional voltage or current pulses are applied between the electric stimulation anode 3 and the electric stimulation cathode 4, the subthalamic nucleus is stimulated in situ to regulate and control the treatment of the parkinsonism, and the change of the electro-physiological signals of the hypothalamic subthalamic nucleus nerve electro-physiological signals and the nuclear nerve electrochemical signals are detected and controlled through the electro-physiological detection sites and the electrochemical detection sites, so that a regulation mechanism is explored.
It will be understood by those skilled in the art that while the present invention has been shown and described with reference to particular exemplary embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims and their equivalents. The scope of the disclosure should, therefore, not be limited to the above-described embodiments, but should be determined not only by the following claims, but also by the equivalents of the following claims.
Claims (9)
1. A neural microprojection for deep nuclear cluster dual-mode functional localization and precise electrical stimulation of a non-human primate brain, comprising:
a base layer: the material is an insulating material; preferably, the material is a rigid insulating material;
metal conductive layer: is positioned on the substrate layer and comprises: the electrophysiological detection site and the electrochemical detection site are positioned between the electrostimulation anode and the electrostimulation cathode; the reference electrode and the counter electrode are positioned at two sides of the lower end of the detection site, and the detection site, the electric stimulation anode and the electric stimulation cathode are connected with the bonding pad through wires;
insulating layer: the material is a double insulating layer with opposite stress and is positioned above the conducting layer; preferably, there are 12 electrophysiological detection sites and 4 electrochemical detection sites.
2. The microprojection of claim 1 wherein said microprojection is SOI in base fabrication material and wherein said silicon oxide on the back side of said microprojection is removed by dry etching with a double insulating layer of opposite stress to balance differences in stress between different materials to thereby provide a probe for non-human primate implantation.
3. The microprojection of claim 1 wherein said electrophysiological and electrochemical detection sites are densely arranged such that a plurality of sites are in contact with or near the same nerve cell at the same time and the detection sites are in contact with neurons in the brain of a non-human primate to obtain electrophysiological and electrochemical signals.
4. The microprojection of claim 1 wherein said electrochemical detection site is modified with nanomaterial and polymeric anti-interference ionic membrane for detection of neurotransmitters to obtain neuroelectrochemical signals; the electrophysiological detection site is modified by nano materials and is used for detecting nerve cell discharge signals to obtain nerve electrophysiological signals.
5. The microprojection of claim 1 wherein said reference and counter electrodes are sized to be 300 microns wide by 20 microns long for providing a reference point and maintaining potential stability.
6. The microprojection of claim 1 wherein said electro-stimulation anode and electro-stimulation cathode have a width of 150 microns and a length of 200 microns comprise electro-physiological detection sites and electrochemical detection sites therein, said electro-stimulation anode and cathode being both located within the target nucleus and forming an electric field limited to the interior of the target nucleus.
7. The microprojection of claim 1 wherein said electrical stimulation leads have a line width of 80 microns and are two in number, one being connected to the electrical stimulation anode and one being connected to the electrical stimulation cathode; the line width is positively correlated with the applicable current, and the maximum passable current reaches 3.2mA.
8. A method of preparing the microprojection as claimed in claim 1, comprising:
operation S1: and (4) taking SOI front-side silicon as a substrate, and performing a first photoetching process. Sputtering nano metal platinum and stripping to form a conductive layer pattern;
operation S2: depositing silicon nitride and silicon oxide with opposite stress as double insulating layers by adopting a plasma chemical vapor deposition (PECVD) method, balancing stress differences among different materials, performing second photoetching, and etching to expose sites and bonding pads;
operation S3: performing third photoetching, and deeply etching the top silicon to form a probe pattern;
operation S4: wet etching the SOI bottom silicon structure, and separating the silicon probe from the substrate;
operation S5: and sticking the front surface of the released silicon probe to a silicon wafer with spin-coating of uniform photoresist, and etching silicon oxide at the back of the probe to avoid stress superposition of different materials.
9. A method of using the microprojection of claim 1, wherein said microprojection is implanted in the subthalamic nucleus (STN) as a target area; receiving through the detection site the neuroelectrophysiologic and electrochemical signals of a non-human primate thalamous reticulum core (reticular thalamicnucleus, rt), zona Incerta (ZI), and subthalamic nucleus (STN), and substantia nigra below STN (SN); classifying according to the distribution mode of the nerve electrophysiological signals and the concentration characteristics of the nerve electrochemistry signals in each brain region, and finally realizing the functional positioning of the thalamus subthalamic nucleus; by electrically stimulating the brain area after positioning, the changes of nerve electrophysiological signals and nerve electrochemical signals before and after the electric stimulation are detected, an electric stimulation regulation and control mechanism is explored, and the stimulation parameters are reversely regulated so as to realize long-term closed-loop electric stimulation regulation and control.
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| CN202310326745.6A CN116271534A (en) | 2023-03-30 | 2023-03-30 | Nerve microprobe for positioning deep nucleus double-mode function of non-human primate brain and precise electric stimulation |
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