Full-cortical nerve-immune monitoring and closed-loop regulation and control system based on electrical nerve stimulation

Abstract

The invention relates to the technical field of medical monitoring, and provides a full cortical nerve-immune monitoring and closed-loop regulation and control system based on nerve electrical stimulation, and the system comprises a regulation and control electrode which is used for detecting the cerebral cortex of a target brain region and the neuroelectric signals of a deep brain region, and is used for the electrical stimulation regulation and control of neurons of the deep brain region; the brain temperature detection assembly is used for detecting temperature information of a target brain region in real time; the cortex imaging device is used for collecting nerve and immune activity images of the whole cortex; the external control device is electrically connected with the regulation and control electrode, the brain temperature detection assembly and the cortex imaging device, and the external control device is used for receiving temperature information detected by the brain temperature detection assembly and image information detected by the cortex imaging device and controlling the regulation and control electrode to work according to the temperature information. According to the invention, high-precision synchronous monitoring and closed-loop regulation and control of deep brain area nerve electrical stimulation and whole cortical nerve-immune activity are realized, an innovative technical means is provided for neuroscience, immunology and clinical medicine research, and the method has important scientific research and clinical application values.

Description

Technical Field

[0001] The present invention relates to the technical field of medical monitoring, and in particular, to a whole-cortex neuro-immune monitoring and closed-loop regulation system based on neural electrical stimulation. Background Art

[0002] Research has found that when the body is in a hypothermic state, the activities of immune cells and the firing patterns of neurons will show significant beneficial changes. Therefore, by controlling the body to be in a low-temperature state, the function of the whole body's immune system can be strengthened, which has important application values in many fields such as clinical medicine and brain injury repair.

[0003] For this reason, it is very important to monitor the neuroimmune dynamic information based on temperature regulation. Currently, in the research on the mechanism of in vivo neuroimmunity, wide-field imaging technology is used to obtain neuroimmune dynamic information.

[0004] Since the neuroimmune response in the in vivo environment (such as the brain tissue) is closely related to temperature, the existing wide-field imaging technology is difficult to synchronously adjust the temperature of the in vivo environment (such as the brain tissue) during the imaging process, and it is impossible to detect the neuroimmune dynamic information based on temperature regulation in in vivo experiments, which hinders the in-depth exploration of related mechanisms. Summary of the Invention

[0005] The present invention provides a whole-cortex neuro-immune monitoring and closed-loop regulation system based on neural electrical stimulation to solve the above technical defects in the prior art. By integrating a regulation electrode, a brain temperature detection component, a cortex imaging device, and an external control device, high-precision synchronous monitoring and closed-loop regulation of deep brain region neural electrical stimulation and whole-cortex neuro-immune activities are realized, providing an innovative technical means for neuroscience, immunology, and clinical medicine research, and having important scientific research and clinical application values.

[0006] The present invention provides a whole-cortex neuro-immune monitoring and closed-loop regulation system based on neural electrical stimulation, including: A regulation electrode for detecting the neural electrical signals of the cerebral cortex and deep brain regions of a target brain region, and for electrically stimulating and regulating the neurons in the deep brain region; A brain temperature detection component for real-time detecting the temperature information of the target brain region; A cortex imaging device for collecting images of neuro-immune activities of the whole cortex; An external control device electrically connected to the regulation electrode, the brain temperature detection component, and the cortex imaging device respectively. The external control device is used for receiving the temperature information detected by the brain temperature detection component and the image information detected by the cortex imaging device, and controlling the operation of the regulation electrode according to the temperature information.

[0007] According to the whole cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by the present invention, the regulation electrode includes: A microelectrode output interface, electrically connected to the external control device; A first long needle handle, connected to the microelectrode output interface, the end of the first long needle handle is provided with an electrical stimulation electrode for electrically stimulating and regulating neurons in the deep brain region; A second long needle handle, connected to the microelectrode output interface, the end of the second long needle handle is provided with a second micro-needle array for detecting nerve electrical signals in the deep brain region; A short needle handle, connected to the microelectrode output interface, the end of the short needle handle is provided with a first micro-needle array for detecting nerve electrical signals in the cerebral cortex.

[0008] According to the whole cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by the present invention, the electrical stimulation electrode includes: A stimulation electrode body for electrically stimulating and regulating neurons in the deep brain region to achieve nerve regulation of body temperature; A first ground electrode, surrounding the stimulation site of the stimulation electrode body in a semi-wrapped form, cooperating with the stimulation electrode body to form a current loop in biological tissue.

[0009] According to the whole cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by the present invention, the second micro-needle array includes: A second recording electrode, including a plurality of detection sites arranged in an array; A second ground electrode, surrounding the detection sites of the second recording electrode in a semi-wrapped form, cooperating with the second recording electrode to form a current loop in biological tissue.

[0010] According to the whole cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by the present invention, the first micro-needle array includes: A first recording electrode, including a plurality of detection sites arranged in an array; A third ground electrode, surrounding the detection sites of the first recording electrode in a semi-wrapped form, cooperating with the first recording electrode to form a current loop in biological tissue.

[0011] According to the whole cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by the present invention, the diameter range of the stimulation site of the stimulation electrode body is 50μm to 100μm; The diameter range of the detection sites of the first recording electrode and the second recording electrode is 18μm to 22μm; The shapes of the first ground electrode, the second ground electrode, and the third ground electrode are all bow-shaped, and the widths of the first ground electrode, the second ground electrode, and the third ground electrode range from 8 μm to 12 μm.

[0012] According to the whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by the present invention, the external control device includes: A central control module; An electrical stimulation module, electrically connected to the central control module, for controlling the regulation electrode to perform electrical stimulation operation; A temperature data acquisition module, electrically connected to the central control module, for receiving the temperature information detected by the brain temperature detection component and feeding back the temperature information to the central control module; An electrical signal data acquisition module, electrically connected to the central control module, for acquiring high-throughput nerve electrical signals detected by the regulation electrode and feeding back the nerve electrical signals to the central control module; An image analysis module, electrically connected to the central control module, for receiving the nerve and immune activity images of the cortex imaging device and feeding back the nerve and immune activity images to the central control module.

[0013] According to the whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by the present invention, the brain temperature detection component includes: A brain temperature detection probe, inserted into the target brain region for detecting the temperature information of the target brain region; the probe diameter of the brain temperature detection probe is less than or equal to 200 μm.

[0014] According to the whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by the present invention, the cortex imaging device includes: a light intensity modulation element, a dispersion device, a collimating lens, an objective lens, a dichroic mirror, a tube lens, and a camera; Wherein, after the light source passes through the light intensity modulation element, it enters the dispersion device for dispersion, and after passing through the collimating lens and the objective lens, it converges on the sample again, transmits through the dichroic mirror, the fluorescence of the sample is collected by the objective lens and reflected by the dichroic mirror, and then converges through the tube lens and is collected by the camera. The camera respectively collects low-light intensity images and high-light intensity images, and performs linear transformation on the low-light intensity images and the high-light intensity images according to the illumination relationship in the collection of the low-light intensity images and the high-light intensity images to obtain a wide-field high-resolution image.

[0015] According to the whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by the present invention, the cortex imaging device further includes: A control unit, which is respectively connected to the light intensity modulation element and the camera, is configured to control the light intensity modulation element and the camera to work synchronously.

[0016] The whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by the present invention integrates a regulation electrode, a brain temperature detection component, a cortical imaging device and an external control device, realizing high-precision synchronous monitoring and closed-loop regulation of deep brain region nerve electrical stimulation and whole-cortex nerve-immune activities, providing an innovative technical means for neuroscience, immunology and clinical medical research, and having important scientific research and clinical application values.

[0017] Compared with the prior art, the whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by the present invention has the following remarkable advantages through multimodal joint detection and closed-loop regulation: Synchronous monitoring of the whole cortex and deep brain regions: By combining wide-field imaging and deep micro-brain region electrophysiological detection technologies, high-resolution dynamic observation of nerve-immune activities in each sub-brain region of the whole cortex is realized, and at the same time, nerve electrical signals of micro-nuclei in the deep brain region are recorded, breaking through the limitation that it is difficult to coordinate wide-field imaging and deep brain region detection in traditional technologies, and providing comprehensive data support for studying nerve-immune interactions.

[0018] Closed-loop nerve electrical regulation of body temperature: The temperature of the target brain region is monitored in real time through the brain temperature detection component, and the regulation electrode is linked for precise electrical stimulation to form a closed-loop feedback system to ensure the stability and accuracy of temperature regulation. This technology can simulate clinical hypothermia treatment conditions and provide a new paradigm for studying the mechanism of action of hypothermia on neuroprotection and immune regulation.

[0019] Research on nerve-immune mechanisms: Synchronously obtaining nerve electrical signals and immune activity images can dynamically analyze the interaction mechanisms between neurons and immune cells such as microglia and astrocytes under temperature regulation, reveal the sensitivity differences of different brain regions to temperature regulation, and provide experimental basis for discovering treatment targets and optimizing treatment plans for diseases such as neuroinflammation and ischemic brain injury.

[0020] Clinical application potential: This technology can be directly applied to the hypothermia treatment research of acute brain injuries (such as stroke, traumatic brain injury). By optimizing parameters such as the cooling rate and temperature maintenance time, the neuroprotective effect is verified, providing technical support for improving clinical treatment strategies and increasing the success rate of treatment.

[0021] High stability and reliability: The external control device integrates multi-module collaborative work to ensure the stability of temperature regulation and signal monitoring during long-term experiments, is suitable for chronic nerve-immune research, and provides a reliable tool for long-term observation of nerve-immune dynamic changes. Description of the Drawings

[0022] To more clearly illustrate the technical solutions in the present invention or the prior art, the following briefly introduces the drawings required for use in the description of the embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0023] Figure 1 It is a schematic structural diagram of a whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by an embodiment of the present invention.

[0024] Figure 2 is Figure 1 The system block diagram of the whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation shown.

[0025] Figure 3 It is a schematic diagram of the usage state of a regulation electrode in a whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by an embodiment of the present invention.

[0026] Figure 4 It is a schematic structural diagram of a regulation electrode in a whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by an embodiment of the present invention.

[0027] Figure 5 is Figure 4 The local structural diagram of the regulation electrode in the whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation shown.

[0028] Figure 6 It is a schematic structural diagram of an external control device in a whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by an embodiment of the present invention.

[0029] Figure 7 It is a schematic diagram of a cortex imaging device in a whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by an embodiment of the present invention.

[0030] Reference numerals: 10. Regulation electrode; 11. First long needle handle; 111. Stimulation electrode body; 112. First ground electrode; 12. Second long needle handle; 121. Second recording electrode; 122. Second ground electrode; 13. Short needle handle; 131. First recording electrode; 132. Third ground electrode; 14. Microelectrode output interface; 20. Brain temperature detection component; 30. External control device; 31. Central control module; 32. Electrical stimulation module; 33. Temperature data acquisition module; 34. Electrical signal data acquisition module; 35. Image analysis module; 40. Cortical imaging device; 41. Light source; 42. Light intensity modulation element; 43. Dispersion device; 44. Collimating lens; 45. Dichroic mirror; 46. Objective lens; 47. Sample; 48. Tube lens; 49. Camera; 410. Control unit; 50. Target brain region; 60. Transparent glass. Detailed implementation manner

[0031] In order to make the objectives, technical solutions and advantages of the present invention clearer, the technical solutions in the present invention will be clearly and completely described below with reference to the accompanying drawings in the present invention. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0032] In the description of the embodiments of the present application, it should be noted that, unless otherwise clearly defined and limited, the terms "connected" and "connected" should be understood in a broad sense. For example, it may be a fixed connection, a detachable connection, or an integral connection; it may be a mechanical connection or an electrical connection; it may be directly connected, or indirectly connected through an intermediate medium. For those of ordinary skill in the art, the specific meanings of the above terms in the embodiments of the present application can be understood according to specific circumstances.

[0033] In the embodiments of the present application, unless otherwise clearly defined and limited, the first feature being "on" or "under" the second feature may be that the first and second features are in direct contact, or the first and second features are indirectly in contact through an intermediate medium. Moreover, the first feature being "above", "over" and "on" the second feature may be that the first feature is directly above or obliquely above the second feature, or merely indicates that the fluid level height of the first feature is higher than that of the second feature. The first feature being "under", "beneath" and "under" the second feature may be that the first feature is directly below or obliquely below the second feature, or merely indicates that the fluid level height of the first feature is lower than that of the second feature.

[0034] In the description of this specification, the descriptions with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples", etc. mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the embodiments of the present application. In this specification, the schematic representations of the above terms are not necessarily directed to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, without conflict, those skilled in the art can combine the different embodiments or examples described in this specification and the features of the different embodiments or examples.

[0035] Acute brain injuries (such as stroke, traumatic brain injury) have a high fatality rate and high disability rate. The key to clinical treatment lies in seizing the time window and delaying secondary injuries. Research shows that local brain hypothermia can effectively reduce the cerebral metabolic rate and inhibit neuroinflammation, thereby extending the treatment time window.

[0036] However, traditional whole-body cooling can lead to immunosuppression, and simple physical cooling (such as an ice cap) is difficult to precisely control brain temperature and is easily interfered by the external environmental temperature and the human body's thermostatic regulation system, resulting in unstable temperature control and unable to avoid the antagonistic effect of the thermoregulation system. For this reason, the embodiment of the present invention provides a schematic diagram of a whole-cortex neuro-immune monitoring and closed-loop regulation system based on neuroelectrical stimulation.

[0037] Figure 1 It is a schematic structural diagram of a whole-cortex neuro-immune monitoring and closed-loop regulation system based on neuroelectrical stimulation provided by the embodiment of the present invention. Figure 2 is Figure 1 The system block diagram of the whole-cortex neuro-immune monitoring and closed-loop regulation system based on neuroelectrical stimulation shown. Figure 3 It is a schematic diagram of the usage state of the regulation electrode in the whole-cortex neuro-immune monitoring and closed-loop regulation system based on neuroelectrical stimulation provided by the embodiment of the present invention.

[0038] Refer to Figures 1 to 3 , the embodiment of the present invention provides a whole-cortex neuro-immune monitoring and closed-loop regulation system based on neuroelectrical stimulation, which provides an innovative idea for the hypothermic treatment of acute brain injuries, and at the same time promotes the research on neuroimmune mechanisms, and has important clinical transformation value and scientific research application prospects.

[0039] The whole-cortex neuro-immune monitoring and closed-loop regulation system based on neuroelectrical stimulation includes a regulation electrode 10, a brain temperature detection component 20, a cortical imaging device 40, and an external control device 30.

[0040] The regulation electrode 10 adopts a high-density flexible microelectrode array, covers the whole-cortex target brain region 50, and is implanted into deep brain micro-nuclei (such as temperature regulation-related regions such as the hypothalamus, amygdala, etc.). During the implantation process, it is precisely implanted into the target brain region 50 through a stereotaxic apparatus, such as the hypothalamus of a rat (a brain region closely related to body temperature regulation).

[0041] The regulation electrode 10 is in the form of a microelectrode array, with detection and stimulation functions. It can simultaneously detect the electrical activities of multiple neurons and perform precise electrical stimulation. In the detection function, it can collect local field potential (LFP) and single neuron discharge signals in real time. In the stimulation function, it can output precise electrical pulses (frequency 1 - 100 Hz, pulse width 0.1 - 1 ms) through a programmable current source to regulate the neural activities in the deep brain region to affect body temperature. Thus, it is used to detect the neural electrical signals in the cerebral cortex and deep brain region of the target brain region 50, and for electrical stimulation to regulate the neurons in the deep brain region, realizing synchronous high-precision detection of neural electrical signals in the entire cortex and deep brain region, and avoiding tissue damage caused by the rigidity of traditional electrodes.

[0042] Among them, the electrode material is selected from materials with good biocompatibility, such as platinum-iridium alloy, to reduce damage to brain tissue and inflammatory reactions.

[0043] The brain temperature detection component 20 is inserted into the target brain region 50, used to detect the temperature information of the target brain region 50 in real time, and feedback the temperature information to the external control device 30. The brain temperature detection component 20 can include a temperature sensor and corresponding connecting wires. The temperature sensor in the brain temperature detection component 20 can form a brain temperature detection probe using a micro thermocouple probe or a thermistor probe. The micro thermocouple probe has the characteristics of fast response speed and high measurement accuracy, and can accurately sense the temperature change of the target brain region 50 in a short time. The thermistor probe has high sensitivity, especially in the case of a narrow temperature change range, and can accurately measure small temperature fluctuations. Among them, the diameter of the brain temperature detection probe is less than 200 μm.

[0044] It should be noted that multiple temperature sensors can be evenly distributed around the target brain region 50. For example, for the detection of the mouse cerebral cortex, 3 to 5 temperature sensors can be arranged. The sensors are accurately placed at positions that can represent the average temperature of the target brain region 50 to ensure that the collected temperature information can accurately reflect the actual temperature state of the target brain region 50.

[0045] The cortical imaging device 40 is used to collect images of neural and immune activities of the entire cortex.

[0046] Among them, the cortical imaging device 40 can adopt two-photon microscopy imaging technology. The two-photon microscope can penetrate a certain depth of brain tissue and perform high-resolution imaging of neural and immune activities in the target brain region 50. The two-photon microscope uses two low-energy photons to simultaneously excite fluorescently labeled cells or molecules, reducing light scattering and damage to surrounding tissues, thereby obtaining clear cell structure and activity images.

[0047] In addition, the cortical imaging device 40 can also adopt the miniaturization of functional magnetic resonance imaging (fMRI) technology for detecting small animals or clinical local brain regions. It can indirectly reflect the nerve and immune activities by detecting the blood flow changes in the cerebral cortex.

[0048] It should be noted that during the image acquisition process, continuous image acquisition can be performed according to a preset time interval. For example, for detecting rapidly changing nerve activities, images can be acquired every 1 / 4 second; for the relatively slow process of immune activities, images can be acquired every 1 second. The acquired images are analyzed by specialized image processing software. The software can quantitatively analyze features such as cell morphology, fluorescence intensity changes, and blood flow signal changes in the images, so as to obtain relevant parameters of nerve and immune activities in the target brain region 50, such as the firing frequency of neurons and the migration speed of immune cells.

[0049] When selecting an experimental animal (such as a mouse) as the research object, a small window is opened on the skull of the experimental animal, and the two-photon microscope is fixed in a suitable position using a fixing device so that it can focus on the cortical surface of the target brain region 50.

[0050] Due to the high scattering of the skull affecting the imaging quality, and wide-field imaging being sensitive to the refractive index and working distance of the sample 47, it is difficult to maintain high resolution in deep brain regions. Therefore, a transparent glass 60 can be set in the small window to replace the skull, and the cortical imaging device 40 can collect images of nerve and immune activities in the cerebral cortex of the target brain region 50 through the transparent glass 60 to eliminate skull scattering and optimize the wide-field imaging quality.

[0051] The shape of the transparent glass 60 is designed to fit the shape of the target brain region 50. For example, for the cerebral cortex of a mouse, it can be a thin sheet-like structure with a certain curvature. The material of the transparent glass 60 can be selected from transparent and biocompatible materials such as quartz, polycarbonate, or polymethyl methacrylate (PMMA). The transparent glass 60 can be fixed in the target brain region 50 through a bioadhesive fluid or the like to replace the skull corresponding to the position of the target brain region 50. The bioadhesive fluid uses a material that is non-irritating to brain tissue and can maintain viscosity in a physiological environment, such as fibrin glue.

[0052] The external control device 30 is an integrated electronic device, including a high-performance microprocessor (central control module 31), a data acquisition module, etc. The external control device 30 is electrically connected to the regulation electrode 10, the brain temperature detection component 20, and the cortical imaging device 40 through flexible cables respectively. The microprocessor runs the corresponding developed control software and can perform real-time processing and analysis on the acquired data. The external control device 30 is used to receive the temperature information detected by the brain temperature detection component 20 and the image information detected by the cortical imaging device 40, and control the operation of the regulation electrode 10 according to the temperature information.

[0053] After receiving the temperature information detected by the brain temperature detection component 20 and the image information detected by the cortical imaging device 40, the external control device 30 performs comprehensive analysis. For example, if the brain temperature rises and at the same time the cortical imaging device 40 detects abnormal aggregation of immune cells in a specific brain region, the external control device 30 may adjust the electrical stimulation parameters of the regulation electrode 10, increase the stimulation intensity or change the stimulation frequency, so as to regulate body temperature and inhibit excessive immune responses simultaneously. At the same time, the external control device 30 can also store the collected data in the local hard disk for subsequent data analysis and research.

[0054] By analyzing the collected nerve electrical signals, temperature information and image information, researchers can deeply understand the interaction mechanism among nerves, body temperature and immunity. For example, by analyzing the correlation between the frequency and amplitude changes of nerve electrical signals and body temperature changes, a mathematical model (such as a linear regression model) is established to predict the body temperature change trend under different nerve activity states.

[0055] Quantitative analysis is performed on the images collected by the cortical imaging device 40 to calculate the number, density and distribution range of immune cells, as well as the activity level of neurons (such as by measuring the fluorescence intensity change of neurons). These data are integrated with nerve electrical signals and temperature information to explore the internal mechanism of the nerve-immune-body temperature regulation network.

[0056] In terms of research, the embodiments of the present invention can be used to study the abnormal interaction mechanism among nerves, body temperature and immunity in neurodegenerative diseases (such as Alzheimer's disease). In terms of clinical treatment, for example, in brain infections or inflammatory diseases, the system can be used to monitor and regulate body temperature in real time, and at the same time regulate nerve and immune functions to reduce the inflammatory response and promote the recovery of patients.

[0057] It can be understood that the whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by the embodiments of the present invention realizes high-precision synchronous monitoring and closed-loop regulation of deep brain region nerve electrical stimulation and whole-cortex nerve-immune activities by integrating the regulation electrode 10, the brain temperature detection component 20, the cortical imaging device 40 and the external control device 30, providing an innovative technical means for neuroscience, immunology and clinical medical research, and having important scientific research and clinical application values.

[0058] Compared with the prior art, the whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided by the present invention has the following remarkable advantages through multimodal joint detection and closed-loop regulation: Whole cortex and deep brain region synchronous monitoring: By combining wide-field imaging and deep brain region electrophysiological detection techniques, high-resolution dynamic observation of neuro-immune activities in each sub-brain region of the whole cortex is achieved, while simultaneously recording the neural electrical signals of micro-nuclei in the deep brain region, breaking through the limitation that it is difficult to coordinate wide-field imaging and deep brain region detection in traditional technologies, and providing comprehensive data support for studying neuro-immune interactions.

[0059] Closed-loop neural electrical regulation of body temperature: The temperature of the target brain region 50 is monitored in real time through the brain temperature detection component 20, and the regulation electrode 10 is linked to perform precise electrical stimulation to form a closed-loop feedback system to ensure the stability and accuracy of temperature regulation. This technology can simulate clinical hypothermia treatment conditions and provides a new paradigm for studying the mechanism of action of hypothermia on neuroprotection and immune regulation.

[0060] Research on neuro-immune mechanisms: Synchronously obtaining neural electrical signals and immune activity images can dynamically analyze the interaction mechanisms between neurons and immune cells such as microglia and astrocytes under temperature regulation, revealing the sensitivity differences of different brain regions to temperature regulation, and providing experimental basis for the discovery of treatment targets and the optimization of treatment plans for diseases such as neuroinflammation and ischemic brain injury.

[0061] Clinical application potential: This technology can be directly applied to the hypothermia treatment research of acute brain injuries (such as stroke and traumatic brain injury). By optimizing parameters such as the cooling rate and temperature maintenance time, the neuroprotective effect is verified, providing technical support for the improvement of clinical treatment strategies and increasing the success rate of treatment.

[0062] High stability and reliability: The external control device 30 integrates multi-module collaborative work to ensure the stability of temperature regulation and signal monitoring during long-term experiments, is suitable for chronic neuro-immune research, and provides a reliable tool for long-term observation of neuro-immune dynamic changes.

[0063] Figure 4 It is a schematic structural diagram of the regulation electrode in the whole cortex neuro-immune monitoring and closed-loop regulation system based on neural electrical stimulation provided by an embodiment of the present invention. Figure 5 is Figure 4 A partial structural schematic diagram of the regulation electrode in the whole cortex neuro-immune monitoring and closed-loop regulation system based on neural electrical stimulation shown.

[0064] Refer to Figure 4 and Figure 5 In some embodiments of the present invention, the regulation electrode 10 includes a microelectrode output interface 14, a first long needle handle 11, a second long needle handle 12, and a short needle handle 13.

[0065] The microelectrode output interface 14 is electrically connected to the external control device 30. The circuit inside the interface adopts micro-nano processing technology, and components such as signal transmission lines, amplifiers, and filters are integrated on a silicon substrate. For example, the line width of the signal transmission line can reach 1 - 2 μm to ensure stable signal transmission at high frequencies. The connection between the microelectrode output interface 14 and the external control device 30 uses a micro-gold finger plug to ensure reliable electrical connection and facilitate plugging and unplugging, which is convenient for equipment assembly and maintenance in experimental or clinical applications.

[0066] The first long needle handle 11 and the second long needle handle 12 can be made of titanium alloy, which has high strength, low specific gravity, and good biocompatibility. The length of each long needle handle is customized according to the depth of the target brain region 50. For example, in the study targeting the hypothalamus of rats, the length of the long needle handle is designed to be 8 - 10 mm. Each long needle handle is hollow inside to accommodate signal transmission wires. The wires are silver wires wrapped with polytetrafluoroethylene (PTFE) with good insulation performance to ensure the low-resistance characteristics of signal transmission.

[0067] The short needle handle 13 can also be made of titanium alloy. Since the short needle handle 13 is mainly used to detect the neural electrical signals of the cerebral cortex and has a short length, for example, in the application targeting the cerebral cortex of rats, the length is designed to be 3 - 5 mm.

[0068] Among them, the first long needle handle 11 is connected to the microelectrode output interface 14, and the end of the first long needle handle 11 has an electrical stimulation electrode, which is used for electrically stimulating and regulating the neurons in the deep brain region.

[0069] In the experiment of neural electrical stimulation and regulation of the deep brain region (such as the thalamus), the electrical stimulation electrode can adopt a spherical tip structure made of platinum-iridium alloy. The diameter size of the circular stimulation site of the electrical stimulation electrode is preferably 50 μm - 100 μm. This shape and material can ensure effective electrical stimulation at low voltage.

[0070] When the external control device 30 issues an electrical stimulation instruction, for example, to perform electrical stimulation with a frequency of 20 Hz and an intensity of 2 mV on specific neurons in the thalamus, the microelectrode output interface 14 transmits the instruction signal to the wire inside the first long needle handle 11 and reaches the electrical stimulation electrode. The electrical stimulation electrode generates a corresponding electric field in the deep brain region, changes the membrane potential of the neurons, and thus regulates the activities of the neurons.

[0071] Among them, the second long needle handle 12 is connected to the microelectrode output interface 14, and the end of the second long needle handle 12 has a second micro-needle array, which is used for detecting the neural electrical signals of the deep brain region.

[0072] The second microneedle array consists of multiple microneedles. When used to detect neural electrical signals in deep brain regions (such as the brainstem), the second microneedle array penetrates into the brainstem tissue. The surface of the microneedles is chemically modified and coated with a conductive polymer (such as polythiophene P-DOET) to improve the interfacial performance between the electrode and neural tissue. The neural electrical signals are conducted through the microneedles to the wires within the second long needle handle 12 and then transmitted to the external control device 30 through the microelectrode output interface 14. The signal amplifier in the external control device 30 amplifies the weak neural electrical signals to a processable range and then performs signal analysis.

[0073] The short needle handle 13 is connected to the microelectrode output interface 14. The end of the short needle handle 13 has a first microneedle array, which is used to detect neural electrical signals in the cerebral cortex.

[0074] The first microneedle array is similar to the second microneedle array and is optimized according to the characteristics of cerebral cortex neurons. The first microneedle array includes multiple microneedles. When detecting neural electrical signals in the cerebral cortex, the first microneedle array is in close contact with the cortical neurons. Due to the relatively complex activities of cortical neurons, the external control device 30 adopts high-speed data acquisition technology to capture the rapid electrical activity changes of cortical neurons. The collected signals are filtered to remove noise and then subjected to subsequent analysis and research.

[0075] Continue to refer to Figure 4 and Figure 5 , in some embodiments of the present invention, the electrical stimulation electrode includes a stimulation electrode body 111 and a first ground electrode 112.

[0076] The stimulation electrode body 111 is used for electrically stimulating and regulating neurons in the deep brain region to achieve neural regulation of body temperature. The stimulation electrode body 111 can be made of platinum-iridium alloy (Pt - Ir), which has good electrical conductivity, chemical stability, and biocompatibility, can stably exist in the living body for a long time, and can effectively conduct current for neural stimulation.

[0077] The stimulation electrode body 111 is an elongated needle-like structure, suitable for deeply penetrating into the deep brain region for neural stimulation. Its tip part is conical, which helps to accurately locate the target nerve cells and reduce unnecessary stimulation to the surrounding tissues. The diameter of the stimulation electrode body 111 is 0.2 - 0.3 mm, which can provide sufficient mechanical strength to prevent bending or breaking during the insertion into the brain tissue.

[0078] The first ground electrode 112 surrounds the stimulation site of the stimulation electrode body 111 in a semi-wrapped form and cooperates with the stimulation electrode body 111 to form a current loop in the biological tissue. Ensure that there is sufficient contact area between the ground electrode and the stimulation electrode body 111 within a limited space, and at the same time, it will not overly increase the overall diameter of the electrode, which is convenient for insertion into the brain tissue.

[0079] When the external control device 30 issues an electrical stimulation instruction to stimulate the nerves in the deep brain region (such as the preoptic area - anterior hypothalamus, PO / AH) to regulate body temperature, the current enters the biological tissue from the tip of the stimulation electrode body 111. The first ground electrode 112 serves as the other end of the circuit and cooperates with the stimulation electrode body 111 to enable the current to form a complete circuit in the biological tissue. Since the first ground electrode 112 surrounds the stimulation site of the stimulation electrode body 111 in a semi-wrapped form, the distribution of the current in the tissue is more concentrated and controllable. The formation of this circuit ensures that the stimulation current can accurately act on the target nerve cells, thereby effectively regulating nerve activities and further affecting the function of the thermoregulatory center.

[0080] Due to the cooperative work of the first ground electrode 112 and the stimulation electrode body 111, the distribution of the current density in the biological tissue is more uniform. Compared with using only the stimulation electrode body 111 for electrical stimulation, this structure can reduce the peak value of the current density in the local tissue and reduce tissue thermal damage and electrochemical damage caused by high current density.

[0081] In practical applications, through histological examination of brain tissue sections, it is found that after electrical stimulation using the stimulation electrode body 111 wrapped with the first ground electrode 112, the integrity of the cell structure of the brain tissue is better protected, and the inflammatory response is also significantly reduced. At the same time, due to the optimization of the current circuit, the effect of nerve stimulation is improved, manifested as more obvious changes in the electrical activities of the target nerve cells and more precise regulation of body temperature.

[0082] Continue to refer to Figure 4 and Figure 5 In some embodiments of the present invention, the second microneedle array includes a second recording electrode 121 and a second ground electrode 122.

[0083] The second recording electrode 121 and the second ground electrode 122 can be made of gold or platinum (Au / Pt) material. Gold or platinum has excellent electrical conductivity, chemical stability, and biocompatibility, and can effectively detect weak neural electrical signals. The electrode 122 can stably cooperate with the second recording electrode 121 to form a circuit. The second recording electrode 121 is integrally constructed on the silicon-based microneedle shank body. Multiple detection sites are provided on the microneedle shank body. The multiple detection sites are arranged in an array. Each detection site is circular, with a diameter of about 18μm - 22μm, preferably 20μm. The spacing between the detection sites is 50 - 100μm. Such a spacing can not only ensure the independent detection of different nerve cells but also set a sufficient number of detection sites on the limited microneedle area. The second ground electrode 122 surrounds the detection sites of the second recording electrode 121 in a semi-wrapping form, that is, the second ground electrode 122 wraps an area of about one-third to one-half of the height of the detection sites, which can ensure that the influence of external interference current on the detection signal can be reduced with the second recording electrode 121.

[0084] When the second microneedle array penetrates into the deep brain tissue, multiple detection sites of the second recording electrode 121 start to detect neural electrical signals. For example, when detecting the neuronal activity in the hippocampus of a rat, the detection sites can capture the action potential of a single neuron, and its amplitude may be between dozens of microvolts and hundreds of microvolts. The second ground electrode 122 cooperates with the second recording electrode 121 to form a circuit for the current in the biological tissue. Assuming the detected neural electrical signal is a weak current source, the current flows out from the detection site, passes through the surrounding biological tissue, and then returns through the second ground electrode 122. The formation of this circuit is crucial for accurately detecting neural electrical signals because it provides a stable electrical environment for the detection process. In a complex bioelectrical environment, other electrical activities in the surrounding tissue may interfere with the detection of the target neural electrical signal by the second recording electrode 121. The circuit formed by the second ground electrode 122 can effectively shield these interferences and improve the signal-to-noise ratio of the detection signal.

[0085] Continue to refer to Figure 4 and Figure 5 , in some embodiments of the present invention, the first microneedle array includes a first recording electrode 131 and a third ground electrode 132.

[0086] The first recording electrode 131 includes multiple detection sites arranged in an array; the third ground electrode 132 surrounds the detection sites of the first recording electrode 131 in a semi-wrapping form and cooperates with the first recording electrode 131 to form a circuit for the current in the biological tissue.

[0087] Since the first microneedle array is similar to the second microneedle array, therefore, the structural settings and functions of the first microneedle array are set with reference to the above-mentioned second microneedle array and will not be elaborated here.

[0088] It should be noted that, for the recording electrodes provided in the embodiments of the present invention, a 32-channel microelectrode is taken as an example for illustration. 16 microelectrodes are located in the cerebral cortex, and 16 microelectrodes are located in the nuclei of the deep microbrain regions. The nuclei in the deep brain regions are the preoptic area (POA) of the hypothalamus or the dorsomedial nucleus (DMH) of the hypothalamus that can regulate body temperature.

[0089] Figure 6 It is a schematic structural diagram of an external control device in the whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation provided in the embodiments of the present invention.

[0090] Referring to Figure 6 , in some embodiments of the present invention, the external control device 30 includes a central control module 31, an electrical stimulation module 32, a temperature data acquisition module 33, an electrical signal data acquisition module 34, and an image analysis module 35.

[0091] Among them, the central control module 31 is centered on a high-performance microprocessor, such as an ARM Cortex - A9 processor. It is internally equipped with a large-capacity random access memory (RAM), such as a DDR3 memory of more than 2GB, for temporarily storing data received from each module and instructions and data required for running programs.

[0092] The central control module 31 also includes multiple communication interfaces, such as a USB interface for connecting to external devices for data transmission and program update, and an Ethernet interface for implementing network connection with other devices (such as a remote monitoring computer).

[0093] Among them, the internal of the electrical stimulation module 32 includes a signal generator circuit. The signal generator adopts direct digital frequency synthesis (DDS) technology and can accurately generate electrical stimulation signals of various frequencies and waveforms. For example, it can generate stimulation signals of different waveforms such as sine waves, square waves, and triangular waves.

[0094] The electrical stimulation module 32 is electrically connected to the central control module 31 and is also connected to the microelectrode output interface 14 of the regulation electrode 10 through a cable. The cable uses a shielded wire to reduce the influence of external electromagnetic interference on the stimulation signal and is used to control the regulation electrode 10 to perform electrical stimulation operation.

[0095] The electrical stimulation module 32 can accurately control the electrical stimulation electrodes in the regulation electrode 10 to perform electrical stimulation operation according to the instructions of the central control module 31. For example, when the central control module 31 detects a signal of too high body temperature fed back by the temperature data acquisition module 33, the electrical stimulation module 32 will perform electrical stimulation on specific nerves in the deep brain region according to preset parameters to regulate the body temperature.

[0096] Among them, the temperature data acquisition module 33 is electrically connected to the central control module 31. The temperature data acquisition module 33 has a temperature sensor interface, which is matched with the temperature sensor (such as a thermocouple probe or a thermistor probe) in the brain temperature detection component 20.

[0097] After receiving the digital temperature signal, the temperature data acquisition module 33 will perform data filtering processing to remove noise interference. The processed temperature data will be fed back to the central control module 31 in a specific format (such as updated once per second, and the data format is IEEE 754 floating-point number). The central control module 31 determines whether to activate the electrical stimulation module 32 or perform other operations based on the received temperature information.

[0098] Among them, the electrical signal data acquisition module 34 adopts a multi-channel and high-speed analog-to-digital conversion circuit to achieve the acquisition of high-throughput neural electrical signals detected by the regulation electrode 10. For example, it has more than 32 acquisition channels and can simultaneously collect the electrical activities of multiple neurons.

[0099] After the neural electrical signals collected by the electrical signal data acquisition module 34 are digitally processed, they are transmitted to the central control module 31 through a high-speed data bus (such as a PCI-Express bus). The central control module 31 can perform real-time analysis on these signals. For example, by calculating parameters such as the firing frequency and amplitude of neurons, it can evaluate the activity state of the nerves.

[0100] Among them, the image analysis module 35 is electrically connected to the central control module 31 and is used to receive the neural and immune activity images of the cortical imaging device 40 and feed back the neural and immune activity images to the central control module 31.

[0101] The image analysis module 35 has a dedicated image receiving interface and can receive the neural and immune activity images output by the cortical imaging device 40. The image analysis module 35 has a variety of image analysis algorithms. For example, to extract neurons, a machine learning-based image segmentation algorithm (such as a convolutional neural network, CNN) can be used to accurately identify the dynamic calcium activity curve of neurons.

[0102] In terms of immune activity analysis, by analyzing the morphology of immune cells (such as microglia) in the image (such as the size, shape, density, etc. of the cells), the intensity of the immune response can be evaluated.

[0103] The analyzed image data and related results will be fed back to the central control module 31 in a structured form (such as JSON format). The central control module 31 can comprehensively evaluate the operating state of the entire system based on these results, combined with temperature and neural electrical signal information.

[0104] Figure 7It is a schematic diagram of the cortical imaging device in the whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrostimulation provided by the embodiments of the present invention.

[0105] Referring to Figure 7 , in some embodiments of the present invention, the cortical imaging device 40 includes a light source 41, a light intensity modulation element 42, a dispersion device 43, a collimating lens 44, an objective lens 46, a sample 47, a dichroic mirror 45, a tube lens 48, a camera 49, and a control unit 410.

[0106] Among them, after passing through the light intensity modulation element 42, the light source 41 is incident on the dispersion device 43 for dispersion, and after passing through the collimating lens 44 and the objective lens 46, it converges again on the sample 47, where it passes through the dichroic mirror 45. The fluorescence of the sample 47 is collected by the objective lens 46 and then reflected by the dichroic mirror 45, and then converges through the tube lens 48 and is collected by the camera 49. The camera 49 respectively collects low-light intensity images and high-light intensity images, and performs a linear transformation on the low-light intensity images and the high-light intensity images according to the illumination relationship in the collection of the low-light intensity images and the high-light intensity images to obtain a wide-field high-resolution image.

[0107] That is, after passing through the light intensity modulation element 42, the light source 41 is incident on the dispersion device 43 for dispersion, and after passing through the collimating lens 44 and the objective lens 46, it converges again on the sample 47, where it passes through the dichroic mirror 45. The fluorescence of the sample 47 is collected by the objective lens 46 and then reflected by the dichroic mirror 45, and then converges through the tube lens 48 and is collected by the camera 49. The camera 49 respectively collects low-light intensity images and high-light intensity images, and performs a linear transformation on the low-light intensity images and the high-light intensity images according to the illumination relationship in the collection of the low-light intensity images and the high-light intensity images to obtain a wide-field high-resolution image.

[0108] The control unit 410 is respectively connected to the light intensity modulation element 42 and the camera 49, and is used to control the synchronous operation of the light intensity modulation element 42 and the camera 49. The control unit 410 selects a PC and an NI card-level control unit 410.

[0109] The light intensity modulation element 42 in the embodiments of the present invention selects an electro-optic modulator, and the dispersion device 43 selects a grating. The light source 41 includes low illumination and high illumination. Among them, in the case of low illumination, when the fluorescence of the sample 47 does not saturate, low-light intensity images are collected. In the case of high illumination, when the fluorescence of the sample 47 saturates, high-light intensity images are collected.

[0110] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A whole-cortex neuro-immune monitoring and closed-loop regulation system based on neural electrical stimulation, characterized in that, Comprising: A regulation electrode, which is used to detect the neural electrical signals of the cerebral cortex and deep brain regions of the target brain region, and is used to electrically stimulate and regulate the neurons in the deep brain region; A brain temperature detection component, which is used to detect the temperature information of the target brain region in real time; A cortical imaging device, which is used to collect neural and immune activity images of the entire cortex; An external control device, which is electrically connected to the regulation electrode, the brain temperature detection component and the cortical imaging device respectively. The external control device is used to receive the temperature information detected by the brain temperature detection component and the image information detected by the cortical imaging device, and control the operation of the regulation electrode according to the temperature information.

2. The whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation according to claim 1, characterized in that The regulation electrode includes: A microelectrode output interface, which is electrically connected to the external control device; A first long needle handle, which is connected to the microelectrode output interface. The end of the first long needle handle has an electrical stimulation electrode, and the electrical stimulation electrode is used to electrically stimulate and regulate the neurons in the deep brain region; A second long needle handle, which is connected to the microelectrode output interface. The end of the second long needle handle has a second micro-needle array, and the second micro-needle array is used to detect the neural electrical signals of the deep brain region; A short needle handle, which is connected to the microelectrode output interface. The end of the short needle handle has a first micro-needle array, and the first micro-needle array is used to detect the neural electrical signals of the cerebral cortex.

3. The whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation according to claim 2, characterized in that The electrical stimulation electrode includes: A stimulation electrode body, which is used to electrically stimulate and regulate the neurons in the deep brain region to achieve neural regulation of body temperature; A first ground electrode, which surrounds the stimulation site of the stimulation electrode body in a semi-wrapping form and cooperates with the stimulation electrode body to form a current loop in biological tissue.

4. The whole cortex nerve-immunity monitoring and closed-loop regulation system based on nerve electrical stimulation according to claim 3, wherein The second micro-needle array includes: A second recording electrode, which includes a plurality of detection sites arranged in an array; A second ground electrode, which surrounds the detection sites of the second recording electrode in a semi-wrapping form and cooperates with the second recording electrode to form a current loop in biological tissue.

5. The whole cortex nerve-immunity monitoring and closed-loop regulation system based on nerve electrical stimulation according to claim 4, characterized in that, The first micro-needle array includes: A first recording electrode, which includes a plurality of detection sites arranged in an array; A third ground electrode, which surrounds the detection sites of the first recording electrode in a semi-wrapping form and cooperates with the first recording electrode to form a current loop in biological tissue.

6. The whole-cortex neural-immune monitoring and closed-loop regulation system based on neural electrical stimulation according to claim 5, wherein The diameter range of the stimulation site of the stimulation electrode body is 50μm to 100μm; The diameter range of the detection sites of the first recording electrode and the second recording electrode is 18μm to 22μm; The shapes of the first ground electrode, the second ground electrode and the third ground electrode are all bow-shaped, and the width range of the first ground electrode, the second ground electrode and the third ground electrode is 8μm to 12μm.

7. The whole cortex nerve-immunity monitoring and closed-loop regulation system based on nerve electrical stimulation according to claim 1, characterized in that The external control device includes: A central control module; An electrical stimulation module, which is electrically connected to the central control module and is used to control the regulation electrode to perform electrical stimulation operation; A temperature data acquisition module, electrically connected to the central control module, is configured to receive the temperature information detected by the brain temperature detection component and feedback the temperature information to the central control module; An electrical signal data acquisition module, electrically connected to the central control module, is configured to acquire the high-throughput neural electrical signals detected by the regulation electrode and feedback the neural electrical signals to the central control module; An image analysis module, electrically connected to the central control module, is configured to receive the neural and immune activity images of the cortical imaging device and feedback the neural and immune activity images to the central control module.

8. The whole cortex nerve-immunity monitoring and closed-loop regulation system based on nerve electrical stimulation according to claim 1, characterized in that, The brain temperature detection component includes: A brain temperature detection probe, inserted into the target brain region, is configured to detect the temperature information of the target brain region; the probe diameter of the brain temperature detection probe is less than or equal to 200 μm.

9. The whole-cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation according to any one of claims 1 to 8, characterized in that, The cortical imaging device includes: a light intensity modulation element, a dispersion device, a collimating lens, an objective lens, a dichroic mirror, a tube lens, and a camera; Wherein, after passing through the light intensity modulation element, the light source is incident on the dispersion device for dispersion, and after passing through the collimating lens and the objective lens, it is re-converged on the sample, transmitted through the dichroic mirror, the fluorescence of the sample is collected by the objective lens and reflected by the dichroic mirror, and then after passing through the tube lens and being converged, it is collected by the camera. The camera respectively collects low-light intensity images and high-light intensity images, and performs linear transformation on the low-light intensity images and the high-light intensity images according to the illumination relationship in the acquisition of the low-light intensity images and the high-light intensity images to obtain a wide-field high-resolution image.

10. The whole cortex nerve-immune monitoring and closed-loop regulation system based on nerve electrical stimulation according to claim 9, characterized in that, The cortical imaging device further includes: A control unit, respectively connected to the light intensity modulation element and the camera, is configured to control the light intensity modulation element and the camera to work synchronously.

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