Intraoperative cortex function visual fluorescence labeling method, device and system

Abstract

The invention relates to an intraoperative cortex function visualization fluorescence labeling method, device and system, and the method is executed by a processor and comprises the steps: receiving electrophysiological response data from a multi-channel flexible electrode array; determining at least one target channel based on the electrophysiological response data; a target channel selection instruction input by a user is responded, an electrical stimulation trigger signal corresponding to the target channel is generated, and the electrical stimulation trigger signal is used for triggering release of the fluorescent dye loaded on the surface of the target channel; and outputting an electrical stimulation trigger signal to the target channel, and sending a fluorescence imaging trigger signal to an external fluorescence imaging device. According to the application, the fluorescent dye which can be electrically stimulated and released is immobilized on the surface of the electrode contact, so that fixed-point marking of the cortex function response area is realized, in combination with intraoperative fluorescence imaging, a functional area visualization result with high spatial precision can be provided under the condition of not additionally arranging instruments, and the intuition and accuracy of intraoperative positioning are improved.

Description

Technical Field

[0001] This application relates to the field of intraoperative neurosurgical auxiliary technology, and in particular to an intraoperative cortical function visualization fluorescent labeling method, device and system, flexible electrode, computing device and storage medium. Background Technology

[0002] In neurosurgery, accurate localization and spatial labeling of specific functional areas of the cerebral cortex are crucial for ensuring surgical safety and precision. Current intraoperative aids mainly include preoperative image navigation, electrophysiological localization, and fluorescence visualization, but these techniques still have significant limitations in providing real-time, intuitive, and stable labeling of functional areas.

[0003] 1. Technical limitations of preoperative functional imaging and neuronavigation techniques By using preoperative fMRI, DTI, task-state / resting-state functional connectivity and other technologies to image specific brain regions, and integrating them with neuronavigation technology, surgical planning can be achieved through the fusion navigation system for guidance and localization.

[0004] This approach relies solely on preoperative images of the patient and cannot address the issue of brain tissue drift caused by factors such as cerebrospinal fluid release, tumor resection, and changes in posture during surgery. This leads to deviations between the intraoperative navigation position and the actual anatomical structure, reducing positioning accuracy. Furthermore, the navigation system only provides on-screen guidance and cannot generate physical markers or fluorescent indicators within the surgical field, lacking intuitive visual feedback.

[0005] 2. Limitations of intraoperative electrical stimulation and electrophysiological monitoring Intraoperative motor evoked potentials (MEP), somatosensory evoked potentials (SEP), brainstem evoked potentials (BAEP), and direct cortical / subcortical electrical stimulation have become standard techniques in neurosurgery and standard means of locating functional areas in neurosurgery.

[0006] While the methods described above can identify functional areas, their output is typically in the form of stimulation results, potential waveforms, or numerical values ​​from monitoring instruments, failing to directly and visually mark the localization results on the brain surface. After functional area localization, surgeons often have to rely on memory, re-stimulation, or temporary marking with cotton pads. Such markings are easily covered or displaced due to bleeding, brain tissue movement, or obstruction by surgical instruments; they are difficult to maintain long-term effectiveness; and they are difficult to form a continuous and stable spatial representation.

[0007] 3. Limitations of intraoperative fluorescence imaging Fluorescent agents such as 5-ALA and sodium fluorescein have been used for tumor boundary visualization; indocyanine green (ICG) is used to assess vascular blood flow.

[0008] However, existing fluorescence imaging techniques mainly target tumor tissues or blood vessel structures, and cannot be used for selective labeling of functional areas. They also do not form an integrated workflow with electrical stimulation functional localization techniques.

[0009] 4. Although flexible electrodes and drug loading techniques exist, they are not used for functional area visualization ECoG electrodes, microelectrode arrays, and other devices can achieve multi-channel electrical stimulation and electrical recording. Studies on local sustained-release patches show that drugs can be loaded on the implanted surface and released locally.

[0010] However, these techniques have not been combined with functional area localization, and the integrated mechanism of "electrical stimulation localization + fluorescence labeling + synchronous imaging" has not been achieved.

[0011] The main drawbacks of existing technologies include: 1. Cannot directly and stably visualize the location of functional areas on the brain surface Navigation systems and electrophysiological monitoring rely on screen displays or the memory of the surgeon, and lack physical and visual markers. Cotton swab markers can be easily obscured or displaced by blood, leading to the "loss" of functional areas; 2. Navigation schemes are difficult to cope with intraoperative brain tissue drift Preoperative image fusion navigation systems only represent the location of brain tissue before surgery. However, brain tissue drift caused by the release of cerebrospinal fluid, changes in body position, and the cavity after tumor removal can cause deviations in the preoperative image relative to the actual location, making navigation instructions inaccurate; 3. It is difficult to spatially integrate and maintain the results of electrophysiological localization in the long term The results of intraoperative electrophysiological monitoring are often limited to a few discrete points of stimulation, and the significance of each point is clear. However, once the cotton swab is displaced, the electrode is displaced, or the brain surface is covered with blood, the original point is difficult to reproduce; 4. Existing marking methods rely on manual and temporary physical markers Currently, the main method of marking brain functional areas is to use small cotton swabs or rely on the memory of the surgeon, but there are problems such as cotton swab obstruction of the field of view, impact on operation, and memory bias.

[0012] In summary, existing intraoperative assistance technologies have significant gaps in the following areas: real-time, direct, and visual marking of functional areas; spatial integration and long-term maintenance of electrical stimulation localization results; dynamic marking mechanisms that can cope with brain tissue drift; and functional visualization schemes that can be synchronized with fluorescence imaging equipment. Therefore, there is an urgent need for a technology that can achieve "electrical stimulation to identify functional areas, fluorescence point release, and real-time imaging" integration during surgery to provide intuitive, objective, stable, and sustainable cortical functional visualization results. SUMMARY

[0013] In view of the problems of invisible intraoperative functional positioning, inability to maintain for a long time, easy loss of markers, and navigation affected by brain tissue drift in the background art, the present application provides an intraoperative cortical function visualization fluorescent marker method, device and system, flexible electrode, computing device and storage medium, which loads controllable release fluorescent dye on the surface of the electrode contact, combines electrophysiological response positioning and intraoperative fluorescence imaging, generates real-time, stable and intuitive optical markers on the surface of the cerebral cortex, and provides accurate and repeatable functional area spatial reference for the operator.

[0014] To achieve the above-mentioned purpose, the first aspect of the present application provides an intraoperative cortical function visualization fluorescent marker method, which is executed by a processor and includes the following steps: Receiving electrophysiological response data from a multi-channel flexible electrode array, the electrophysiological response data corresponding to bioelectric signals recorded by each electrode channel under electrical stimulation; Determining at least one target channel based on the electrophysiological response data; In response to a target channel selection instruction input by a user, generating an electrical stimulation trigger signal corresponding to the target channel, the electrical stimulation trigger signal being used to trigger the release of fluorescent dye loaded on the surface of the target channel; Outputting the electrical stimulation trigger signal to the target channel and sending a fluorescence imaging trigger signal to an external fluorescence imaging device.

[0015] As a possible implementation manner of the first aspect, the electrophysiological response data includes at least one of a motor evoked potential, a somatosensory evoked potential or a cortical direct electrical stimulation response signal.

[0016] As a possible implementation manner of the first aspect, the determination of at least one target channel includes identifying an electrode channel corresponding to a functional area according to the electrophysiological response data and marking it as a target channel.

[0017] As a possible implementation manner of the first aspect, the fluorescent dye is loaded on the electrode surface of the target channel by electrostatic adsorption, electrochemical deposition or interface coordination; The electrical stimulation trigger signal adopts an electrochemical release driving waveform form.

[0018] As a possible implementation manner of the first aspect, the electrochemical release driving waveform is a single-phase square wave, a two-phase balanced square wave, an exponential decay pulse, a constant potential step or a constant current step signal.

[0019] As a possible implementation manner of the first aspect, the fluorescent dye is a near-infrared or visible light band fluorescent agent.

[0020] As a possible implementation manner of the first aspect, the sending of the fluorescence imaging trigger signal to the external fluorescence imaging device comprises: The fluorescence imaging trigger signal is synchronously sent to the external fluorescence imaging device to realize time synchronization of the fluorescence release event and the intraoperative fluorescence imaging.

[0021] As a possible implementation manner of the first aspect, the method is repeatedly performed multiple times intraoperatively; each time of execution, the electro-physiological response data is re-received, and the target channel and the corresponding electrical stimulation trigger signal are updated.

[0022] The second aspect of the present application provides an intraoperative cortical function visualization fluorescent labeling device, comprising: An electro-physiological response data receiving module is configured to receive electro-physiological response data from a multi-channel flexible electrode array, the electro-physiological response data corresponding to bioelectric signals recorded by each electrode channel under electrical stimulation; A target channel determining module is configured to determine at least one target channel based on the electro-physiological response data; An electrical stimulation trigger signal generating module is configured to generate an electrical stimulation trigger signal corresponding to the target channel in response to a target channel selection instruction input by a user, the electrical stimulation trigger signal being used to trigger the release of fluorescent dye loaded on the surface of the target channel; A trigger signal output module is configured to output the electrical stimulation trigger signal to the target channel and send a fluorescence imaging trigger signal to an external fluorescence imaging device.

[0023] The third aspect of the present application provides a flexible electrode, comprising: A flexible substrate; A conductive layer encapsulated on the flexible substrate; An electrode contact integrated on the conductive layer, the contact having both electrical stimulation and recording functions; A fluorescent dye region loaded on the surface of the contact, the fluorescent dye loading region being capable of releasing fluorescent dye under the stimulation of an electrical stimulation trigger signal.

[0024] As a possible implementation manner of the third aspect, the fluorescent dye can be fixed on the surface of the electrode contact through electrostatic adsorption, electrochemical deposition or other surface loading methods; The electrical stimulation trigger signal adopts an electrochemical release driving waveform form.

[0025] As a possible implementation manner of the third aspect, the electrochemical release driving waveform is a single-phase square wave, a two-phase balanced square wave, an exponential decay pulse, a constant potential step or a constant current step signal.

[0026] As a possible implementation manner of the third aspect, the fluorescent dye is a near-infrared or visible light band fluorescent agent.

[0027] The fourth aspect of the present application provides an intraoperative cortical function visualization fluorescent labeling system, comprising: A flexible electrode array composed of the flexible electrode of the third aspect is attached to the surface of the cerebral cortex, used for applying electrical stimulation, recording electrophysiological response data, and locally releasing fluorescent dyes; An electrophysiological monitoring device connected to the flexible electrode array is used for collecting and processing electrophysiological response data of each channel; The intraoperative cortical function visualization fluorescent labeling device of the second aspect is in communication connection with the electrophysiological monitoring device and is configured to execute the intraoperative cortical function visualization fluorescent labeling method of the first aspect; A fluorescent imaging device is in signal connection with the intraoperative cortical function visualization fluorescent labeling device, used for receiving the fluorescent imaging trigger signal and performing real-time fluorescent imaging on the release area.

[0028] The fifth aspect of the present application provides a computing device, comprising: a processor, and a memory having program instructions stored thereon, the program instructions causing the processor to execute the method of any one of the first aspect when executed by the processor.

[0029] The sixth aspect of the present application provides a computer readable storage medium having program instructions stored thereon, the program instructions causing the computer to implement the method of any one of the first aspect when executed by the computer.

[0030] Compared with the prior art, the intraoperative cortical function visualization fluorescent labeling method, device and system, and flexible electrode provided by the present application have the following beneficial effects: 1. Based on electrophysiological function positioning, direct fluorescent visualization labeling of specific brain regions in the surgical field is realized, so that the operator can directly "see" the functional area boundary or key connection point under the fluorescent imaging device; 2. The fluorescent dye is loaded on the surface of the electrode and controlled release is realized, avoiding additional placement of other dye carriers or repeated operations; 3. The controlled release of the fluorescent dye at specific electrode points is realized, avoiding non-target area dyeing and ensuring the accuracy and safety of labeling; 4. Without significantly changing the original intraoperative electrophysiological workflow, compatibility and integration with existing devices are realized, ensuring generalizability. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 is a structural schematic diagram of a flexible electrode provided by an embodiment of the present application; Figure 2 is a flow chart of a method for intraoperative cortical functional visualization fluorescent labeling provided by an embodiment of the present application; Figure 3 is a fluorescent labeling effect diagram (left: white light mode without labeling; right: fluorescent mode display region of interest) provided by an embodiment of the present application; Figure 4 is a structural schematic diagram of a device for intraoperative cortical functional visualization fluorescent labeling provided by an embodiment of the present application; Figure 5 is a structural schematic diagram of a system for intraoperative cortical functional visualization fluorescent labeling provided by an embodiment of the present application; Figure 6 is a structural schematic diagram of a computing device provided by an embodiment of the present application.

[0032] It should be understood that in the above structural schematic diagram, the size and shape of each block diagram are only for reference, and should not constitute an exclusive interpretation of the embodiments of the present application. The relative position and inclusion relationship between the block diagrams presented by the structural schematic diagram are only used to represent the structural association between the block diagrams, and not to limit the physical connection mode of the embodiments of the present application. DETAILED DESCRIPTION

[0033] The technical solutions provided by the present application will be further described below in conjunction with the drawings and embodiments. It should be understood that the system structure and business scenarios provided in the embodiments of the present application are mainly used to illustrate possible implementation modes of the technical solutions of the present application, and should not be interpreted as the only limitation of the technical solutions of the present application. Those skilled in the art can know that the technical solutions provided by the present application are also applicable to similar technical problems as the system structure evolves and new business scenarios appear.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. If there is any inconsistency, the meaning explained in the specification or derived from the content described in the specification shall prevail. In addition, the terms used herein are only for the purpose of describing the embodiments of the present application, and are not intended to limit the present application.

[0035] Embodiment of flexible electrode The existing technology, whether it is a navigation system or a cortical electrical stimulation, the result is an electrical signal or coordinate information on the screen, which can only be remembered by the operator or temporarily marked on the brain surface with a cotton piece, and does not have the limitations of intuitive and stable visual effects of fluorescent imaging. The application proposes to load fluorescent dyes on the surface of flexible electrodes through electrostatic modification, integrate electrical stimulation / recording function and controllable release ability on the same electrode, break through the limitation of existing electrodes only for signal acquisition, and realize direct and naked-eye visible fluorescent labeling of specific brain regions in the surgical field.

[0036] Based on this, the application proposes a flexible electrode as shown in Figure 1 , which comprises: a flexible substrate; a conductive layer encapsulated on the flexible substrate; an electrode contact integrated on the conductive layer, which has both electrical stimulation and recording functions; a fluorescent dye area loaded on the surface of the contact, which can release fluorescent dyes under the stimulation of an electrical stimulation trigger signal.

[0037] Among them, the specific substrate form and electrode form are determined according to actual needs.

[0038] In some embodiments, the flexible substrate can be selected from polyimide (PI), polydimethylsiloxane (PDMS), Parylene-C or other biocompatible and flexible polymer materials, and a gold (Au), platinum (Pt), platinum-iridium alloy, PEDOT conductive layer is formed on the surface thereof. The electrode contact can be processed into a circular, square, micro-columnar structure, etc., with a size of 10-200 μm, so as to balance the spatial resolution and electrical stimulation and recording performance.

[0039] The fluorescent dye loading area is arranged on the surface of the electrode contact, and the fluorescent dye can be immobilized on the electrode surface by electrostatic adsorption, electrochemical deposition or interface coordination, etc. In order to obtain stable dye immobilization effect, the electrode surface can be further modified with charged functional groups (such as , , etc.), or the interface charge characteristics of the metal conductive layer are used to form a controllable and reducible adsorption layer of charged small molecule fluorescent probes on the electrode surface.

[0040] The electrical stimulation trigger signal is in the form of an electrochemical release driving waveform, which can include constant potential, pulsed voltage, constant current or pulsed current mode, the parameters (amplitude, frequency, duty cycle, duration, etc.) of which are optimized according to the charge characteristics of the fluorescent dye and the desired release rate to achieve quantitative, time-controlled in-situ release. Among them, the polarity of the driving waveform is preferably opposite to the charge of the fluorescent dye, and through the instantaneous polarity regulation or the disturbance of the electrode-electrolyte interface double layer, the electrostatic adsorption between the dye and the electrode is weakened or destroyed, so as to realize the rapid and local in-situ electrochemical desorption.

[0041] The way to stimulate the release of the fluorescent dye is to apply a potential pulse to regulate the electrode / solution interface double layer structure, reverse or shield the surface charge, thereby destroying the electrostatic interaction between the fluorescent dye and the electrode, and realizing controllable desorption and release.

[0042] Among them, when a voltage / current pulse of a specific polarity is applied to the counter electrode: If the fluorescent dye is cationic, a positive potential is applied → the electrode surface is positively charged → electrostatic repulsion → the fluorescent dye is desorbed and released; If the fluorescent dye is anion, a negative potential is applied → the electrode surface is negatively charged → electrostatic repulsion → the fluorescent dye is released.

[0043] In some embodiments, the driving waveform can be a single-phase square wave, a two-phase balanced square wave, an exponential decay pulse, a constant potential step or a constant current step signal. The electrochemical release driving waveform is preferably a single-phase or two-phase current pulse with a preset pulse width and amplitude, so as to form an instantaneous electrochemical environment opposite to the charge of the fluorescent dye by changing the polarity, thereby triggering local controllable release based on the electrostatic repulsion mechanism. The typical parameters of the driving waveform are: pulse width 0.1-5 ms, amplitude 0.1-5 mA, frequency not higher than 50 Hz, and the specific values can be adjusted according to the charge characteristics of the fluorescent dye, the adsorption strength and the desired release rate.

[0044] Specifically, by applying a pulse polarity opposite to the charge of the fluorescent dye, an instantaneous electrostatic repulsion field can be formed on the electrode surface, thereby triggering desorption of the dye. For example, when the fluorescent dye is a negative molecule (such as fluorescein sodium), a negative current pulse (such as -2 mA, 1 ms) can be applied to make the electrode surface negatively charged and achieve desorption through electrostatic repulsion; if the fluorescent dye is a positive molecule (such as methylene blue), a positive pulse can be applied. The above driving waveform can be generated by an external constant current stimulator or a digital-to-analog conversion control circuit integrated in the device, to ensure the locality, controllability and tissue safety of the release process.

[0045] In some embodiments, the fluorescent dye is a near-infrared or visible light band fluorescent agent. It includes but is not limited to fluorescein, rhodamine, methylene blue, or near-infrared fluorescent agents such as ICG, IR-Dye800CW, Cy7 and its derivatives. The fluorescent probe can also be a small molecule probe with specific functional groups, an aggregation-induced emission (AIE) dye, or a nanoparticle or polymer probe to obtain higher light stability, signal intensity and tissue penetration ability.

[0046] Since the release result needs to be observed by an external fluorescence imaging device (such as a microscope or an intraoperative imaging system) finally, a small molecule probe with strong fluorescence signal in the visible or near-infrared band is preferably used to ensure good microscopic imaging effect.

[0047] The flexible electrode structure proposed in the present application integrates fluorescent labeling and electrical stimulation positioning functions in the same electrode contact, so that the same device has stimulation, recording and dye release capabilities at the same time, avoiding additional dye carrier arrangement or repeated dyeing operation, thereby significantly simplifying the operation steps and improving the positioning accuracy and spatial consistency.

[0048] Embodiment of the intraoperative cortical functional visualization fluorescent labeling method The method described in the present application belongs to the intraoperative auxiliary visualization technology of neurosurgery and does not involve the judgment or intervention of any pathological state, and the output is only a physical space marker.

[0049] The embodiment of the present application provides an intraoperative cortical functional visualization fluorescent labeling method, which loads controllable release fluorescent dye on the surface of the electrode, combines electrical stimulation function area positioning and intraoperative fluorescence imaging, and constructs a complete technical chain of "intraoperative function area identification-accurate labeling". As shown in the figure, Figure 2 The method is executed by a processor and includes the following steps: S210: receiving electrophysiological response data from a multi-channel flexible electrode array, the electrophysiological response data corresponding to the bioelectric signal recorded by each electrode channel under electrical stimulation.

[0050] In some embodiments, the flexible electrode in the multi-channel flexible electrode array mentioned herein uses the flexible electrode mentioned above, and the multi-channel flexible electrode array composed of the flexible electrode.

[0051] Specifically, the multi-channel flexible electrode array can include no less than 8 independently addressable electrode contacts, and the typical channel number is 16, 32, 64 or 128. The array geometry layout includes a matrix type (such as 4×4, 8×8), a line type (1×N) or a fan shape, and the center distance between adjacent contacts is 2-10 mm. Each channel is connected to an electrophysiological monitoring device and an intraoperative cortical functional visualization fluorescent labeling device described below through an independent lead, supporting channel-by-channel stimulation, recording and dye release control.

[0052] Before performing S210, the following two steps are needed: I. Tumor / functional area preparation and electrode placement Under the microscope, the tumor / suspected functional area surrounding brain tissue is exposed, and a multi-channel flexible electrode array is attached to the target area (such as the surface of the cerebral cortex), so that the electrodes cover the target functional area and its surrounding cortex.

[0053] II. Functional area positioning by electrical stimulation Then, using conventional electrophysiological methods, the multi-channel flexible electrode is recorded / stimulated channel by channel. Different electrophysiological modes are selected as needed. In the sensory area, the peripheral sensory evoked potential is recorded on the cortex, the central sulcus is stimulated to observe the phase inversion of the cortical evoked potential, and the motor area is stimulated to monitor the peripheral motor evoked potential. Therefore, in some embodiments, the electrophysiological response data includes at least one of a motor evoked potential, a somatosensory evoked potential, or a cortical direct electrical stimulation response signal.

[0054] Then, the electrophysiological response data of the multi-channel flexible electrode array is collected by the electrophysiological monitoring device connected to the flexible electrode array, and the electrophysiological response data of the multi-channel flexible electrode array is input into the processor, and S210 is performed by the processor.

[0055] S220: Based on the electrophysiological response data, at least one target channel is determined.

[0056] In some embodiments, the determination of at least one target channel includes identifying an electrode channel corresponding to a functional area according to the electrophysiological response data, and marking it as a target channel.

[0057] In some embodiments, the determination of at least one target channel includes identifying an electrode channel corresponding to a functional area according to the electrophysiological response data, and marking it as a target channel.

[0058] Specifically, the determination of at least one target channel can include any of the following ways: When the electrophysiological response data is a motor evoked potential, if a peak value of a compound muscle action potential (CMAP) of not less than 50 μV is detected in the peripheral electromyographic electrode after stimulation of a certain electrode channel, the electrode channel is marked as a target channel; When the electrophysiological response data is a somatosensory evoked potential, if a N20 / P25 phase inversion waveform is recorded in a certain channel, the electrode channel is marked as a target channel; In a conscious surgery, if a certain channel stimulation induces a repeatable behavioral response (such as finger twitching, naming interruption), the electrode channel is marked as a target channel.

[0059] The threshold or criterion can be adjusted by the operator according to the baseline electrophysiological level in the operation. The processor can automatically highlight the candidate target channel according to the determination result and provide it to the user for final confirmation, so as to improve the visualization degree of the determination and the operation efficiency.

[0060] S230: In response to the target channel selection instruction input by the user, an electrical stimulation trigger signal corresponding to the target channel is generated, and the electrical stimulation trigger signal is used to trigger the release of the fluorescent dye loaded on the surface of the target channel.

[0061] In the method, the target channel to be subjected to fluorescent dyeing is selected by manual determination or input by the user after the electrophysiological signal is received and the target channel is determined.

[0062] After the target channel is determined, the position information of the electrode is directly obtained because the position of each electrode is fixed. The sending time of the electrical stimulation trigger signal can be set, and the electrical stimulation trigger signal can be sent at a specific time and at a specific position.

[0063] In the method, the multi-channel flexible electrode array used in the method is the flexible electrode mentioned above, and in some embodiments, the flexible substrate can be selected from polyimide (PI), polydimethylsiloxane (PDMS), Parylene-C or other polymer materials with good biocompatibility and flexibility, and a conductive layer of gold (Au), platinum (Pt), platinum-iridium alloy or PEDOT is formed on the surface of the flexible substrate. The conductive material can form a stable double-layer structure at the electrode-electrolyte interface and has good surface modifiability. By constructing charged functional groups (such as 、 , etc.) on the surface or regulating the resting interface potential, controllable adsorption sites can be provided for charged fluorescent molecules, so that stable immobilization can be achieved.

[0064] The electrode contact can be prepared into a microstructure such as a circle, a square or a microcolumn, and the typical size is 10-200 μm, so as to balance the high spatial resolution and the electrical stimulation and electrical signal recording performance. The fluorescent dye can be loaded on the surface of the electrode corresponding to the target channel by electrostatic adsorption, electrochemical deposition or interface coordination.

[0065] The electrical stimulation trigger signal takes the form of an electrochemical release driving waveform. The electrochemical release driving waveform can include constant potential, pulsed voltage, constant current or pulsed current mode, the parameters (amplitude, frequency, duty cycle, duration, etc.) of which are optimized according to the charge characteristics of the fluorescent dye and the desired release rate to achieve quantitative, time-controllable in-situ release. Its typical parameter range is pulse width 0.1-5 ms, amplitude 0.1-5 mA, frequency not higher than 50 Hz. Among them, the polarity of the driving waveform is preferably opposite to the charge carried by the fluorescent dye, and the electrostatic adsorption force between the dye and the electrode is destroyed by instantaneously regulating the electrode-electrolyte double-layer structure, thereby triggering local desorption.

[0066] The above waveform can be generated by an external constant current stimulator or a digital-to-analog conversion circuit integrated in the system to ensure the locality, controllability and tissue safety of the release process.

[0067] In some embodiments, the fluorescent dye can be selected from small molecule probes in the visible or near-infrared waveband, including fluorescein, rhodamine, methylene blue dyes, and near-infrared fluorescent probes such as ICG, IR Dye800CW, Cy7, etc. It can also be in the form of an aggregation-induced emission (AIE) dye or a nanoparticle, polymer probe to obtain higher light stability, signal strength and intraoperative visualization performance.

[0068] In specific implementation, the receiving operator determines the input instruction of one or more target regions to be fluorescently dyed, then obtains the electrode position information corresponding to the target region, then generates the corresponding electrochemical release driving waveform, which can be sent to the target channel (i.e. to the corresponding electrode position) at a preset time, or can be sent to the target channel immediately after generation. This can achieve controllable release of fluorescent dyes at specific electrode points / specific times, avoid non-target region dyeing, and ensure the accuracy and safety of the marker.

[0069] S240: outputting the electrical stimulation trigger signal to the target channel, and sending a fluorescent imaging trigger signal to an external fluorescent imaging device.

[0070] In some embodiments, sending a fluorescent imaging trigger signal to an external fluorescent imaging device includes: Synchronizing the sending of the fluorescent imaging trigger signal to the external fluorescent imaging device to achieve time synchronization of the fluorescent release event and intraoperative fluorescent imaging, so that the external imaging device can observe the spatial distribution of the fluorescent release in real time.

[0071] The synchronous sending of the fluorescence imaging trigger signal refers to: at the same time (the time deviation can be ≤10 ms) of outputting the electrical stimulation trigger signal to the target channel, sending a frame trigger signal to the fluorescence imaging device through a TTL level signal or a USB communication instruction, so that the fluorescence imaging device captures a fluorescence image in the first imaging period after the dye is released to perform imaging, and motion artifact interference is avoided.

[0072] In specific implementation, after exposing the target cortical area during surgery, the multi-channel flexible electrode array is attached to the area. By electrically stimulating each channel and collecting electrophysiological response data (such as motor evoked potential, somatosensory evoked potential or direct cortical stimulation response), the electrode channel related to a specific neural function is determined and marked as a target channel. Subsequently, an electrochemical release driving waveform is applied to the target channel to trigger local fluorescent dye release. The released dye adheres to the corresponding cortical position and presents a highlighted area under the fluorescence imaging device, as shown in Figure 3 The left white light mode in the figure has no marker, and the right fluorescence mode shows the region of interest. The operator can directly observe the marked position in the anatomical field by switching the white light / fluorescence mode, serving as a spatial reference for subsequent operations. Even if the electrode shifts or the field is blocked, the fluorescent marker can still provide a continuous visual cue, reducing the dependence on repeated electrical stimulation or temporary manual marking.

[0073] In some embodiments, the method can be repeatedly performed multiple times during surgery; each time the method is performed, electrophysiological response data is re-received, and the target channel and the corresponding electrical stimulation trigger signal are updated.

[0074] The method can be run in an in vitro experiment, an animal model or a clinical environment, and the technical essence is an electrical-chemical signal cooperative control logic.

[0075] Embodiment of in-situ cortical function visualized fluorescent marker device As shown in Figure 4 The embodiment of the present application provides an in-situ cortical function visualized fluorescent marker device, which can be used to implement the in-situ cortical function visualized fluorescent marker method in the above embodiment, as shown in Figure 4 The in-situ cortical function visualized fluorescent marker device has an electrophysiological response data receiving module 310, a target channel determining module 320, an electrical stimulation trigger signal generating module 330, and a trigger signal output module 340.

[0076] The electrophysiological response data receiving module 310 is configured to receive electrophysiological response data from the multi-channel flexible electrode array, and the electrophysiological response data corresponds to bioelectric signals recorded by each electrode channel under electrical stimulation. The target channel determination module 320 is used to determine at least one target channel based on the electrophysiological response data; The electrical stimulation trigger signal generation module 330 is used to generate an electrical stimulation trigger signal corresponding to the target channel in response to the target channel selection command input by the user. The electrical stimulation trigger signal is used to trigger the release of fluorescent dye loaded on the surface of the target channel. The trigger signal output module 340 is used to output the electrical stimulation trigger signal to the target channel and send the fluorescence imaging trigger signal to an external fluorescence imaging device.

[0077] For details, please refer to the detailed description in the method embodiments, which will not be repeated here.

[0078] Example of an intraoperative cortical function visualization fluorescent labeling system The fourth aspect of this application provides an intraoperative cortical function visualization fluorescent labeling system, such as... Figure 5 As shown, it includes: The flexible electrode array composed of the aforementioned flexible electrodes is attached to the surface of the cerebral cortex to apply electrical stimulation, record electrophysiological response data, and locally release fluorescent dyes. An electrophysiological monitoring device, connected to the flexible electrode array, is used to collect and process electrophysiological response data from each channel; The intraoperative cortical function visualization fluorescent labeling device proposed above is communicatively connected to the electrophysiological monitoring device and is configured to perform the intraoperative cortical function visualization fluorescent labeling method proposed above. A fluorescence imaging device is signal-connected to the intraoperative cortical function visualization fluorescence labeling device, used to receive the fluorescence imaging trigger signal and perform real-time fluorescence imaging of the release area.

[0079] In summary, the intraoperative cortical functional visualization fluorescent labeling method, device, system, and flexible electrode proposed in this application can achieve the following beneficial effects: 1. For the first time, fluorescent dyes are combined with flexible electrodes to achieve direct visualization of specific brain regions through controlled release. In existing technologies, electrodes are only used for stimulating / recording signals and do not have dye release capabilities. This application loads fluorescent dyes onto the surface of flexible electrodes through electrostatic modification, integrating electrostimulation / recording functions and controllable release capabilities on the same electrode, achieving direct, visible fluorescent labeling of specific brain regions in the surgical field. This is the first time that "electrophysiological localization + fluorescent visualization labeling" has been integrated.

[0080] 2. The fusion of electrical stimulation localization and fluorescence imaging enables real-time and precise navigation of functional areas during surgery. In the prior art, the functional channel only corresponds to the electrophysiological signal. The application forms a one-to-one correspondence of "electrical signal-fluorescent region" by triggering dye release at the target electrode channel, so that the functional area position is directly reflected on the brain surface fluorescence image. This method is based on real-time electrical stimulation positioning during surgery, avoiding the positioning errors of simply relying on preoperative image fusion navigation system, and effectively overcoming the positioning inaccuracy problem caused by brain tissue drift in preoperative image navigation.

[0081] 3. Forming a complete intraoperative workflow of "electrical stimulation positioning-controllable release-fluorescence imaging" In the prior art, electrical stimulation is not directly related to fluorescence imaging. The application serially connects electrical stimulation positioning, channel selection, dye controllable release, fluorescence imaging, and surgical guidance into a complete process that can be repeatedly executed, avoiding the disconnection between electrical stimulation and fluorescence imaging, and realizing function-driven accurate marking.

[0082] 4. Compared with traditional intraoperative fluorescence imaging, realizing "function-driven" fluorescence marking instead of structure or tumor staining Existing fluorescence multi-needle targets tumor cells, blood vessels, etc., and is not coupled with electrophysiological positioning; while the application first determines the functional area through electrophysiology, and then realizes controllable release of dye, realizing a kind of "function-dependent" accurate marking, which is more targeted in technology.

[0083] 5. Significantly reducing the dependence on the surgeon's memory / hand marking The fluorescence marking is permanently attached to the brain surface and is not affected by blood infiltration, flushing or cotton pad displacement. The application converts abstract electrophysiological response into intuitive spatial identification. The visualized marking makes the functional area persist throughout the entire surgical process, significantly reducing the number of repeated stimulations, and improving the stability and safety of the surgery.

[0084] 6. Compatible with existing equipment, good promotion and expansion The application belongs to the cross field of intraoperative multi-channel signal processing, artificial intelligence assisted analysis and medical information visualization technology in neurosurgery. Without significantly changing the traditional intraoperative electrophysiological workflow, only by modifying the electrode structure and adding the release control part, it can be integrated with existing electrophysiological systems and fluorescence surgical microscopes and other medical terminals to form an innovative technical solution for clinical needs; supporting the selection of different fluorescent dyes or electrode shapes as needed, suitable for neurosurgical operation scenarios involving cortical functional areas, and having wide clinical transformation potential.

[0085] It should be particularly noted that the method described in the application belongs to the intraoperative auxiliary visualization technology in neurosurgery, and does not involve the determination of any pathological state, disease diagnosis or treatment intervention. Its output is only a physical space marker, which is used to provide anatomical-functional position reference, and all clinical decisions are still made by the surgeon based on comprehensive information.

[0086] Embodiment of the computing device of the application Figure 6 is a structural schematic diagram of a computing device 900 provided by an embodiment of the present application. The computing device can be used as an intraoperative cortical function visualization fluorescent marker device to perform each optional embodiment of the intraoperative cortical function visualization fluorescent marking method described above. The computing device can be a terminal, or a chip or chip system inside the terminal. As shown in the figure, the computing device 900 includes a processor 910, a memory 920, and a communication interface 930. Figure 6

[0087] It should be understood that the communication interface 930 in the computing device 900 shown can be used for communication with other devices, and can specifically include one or more transceiver circuits or interface circuits. Figure 6

[0088] The processor 910 can be connected with the memory 920. The memory 920 can be used to store program codes and data. Therefore, the memory 920 can be a storage unit inside the processor 910, or an external storage unit independent of the processor 910, or a component including the storage unit inside the processor 910 and the external storage unit independent of the processor 910.

[0089] Optionally, the computing device 900 can further include a bus. The memory 920 and the communication interface 930 can be connected with the processor 910 through the bus. The bus can be a Peripheral Component Interconnect (PCI) bus or an Extended Industry Standard Architecture (EISA) bus, etc. The bus can be divided into an address bus, a data bus, a control bus, etc. For ease of representation, Figure 6 a line without an arrow is used in the figure, but it does not mean that there is only one bus or only one type of bus.

[0090] ​​It should be appreciated that the processor 910 can be a central processing unit (CPU) in the embodiments of the present application. The processor can also be other general-purpose processors, digital signal processors (DSP), application specific integrated circuits (ASIC), field programmable gate arrays (FPGA) or other programmable logic devices, discrete gates or transistor logic components, discrete hardware components, etc. The general-purpose processor can be a microprocessor or the processor can also be any conventional processor. Alternatively, the processor 910 can be one or more integrated circuits for performing related programs to implement the technical solutions provided by the embodiments of the present application.

[0091] The memory 920 can include read-only memory and random access memory, and provide instructions and data to the processor 910. Part of the processor 910 can also include non-volatile random access memory. For example, the processor 910 can also store device type information.

[0092] When the computing device 900 is running, the processor 910 executes computer execution instructions in the memory 920 to perform any operation step of the above method and any optional embodiment thereof.

[0093] It should be appreciated that the computing device 900 according to the embodiments of the present application can correspond to the execution of the corresponding subject in the method according to the embodiments of the present application, and the above and other operations and / or functions of each module in the computing device 900 are respectively for implementing the corresponding process of each method of the embodiments, and for brevity, will not be repeated here.

[0094] Those of ordinary skill in the art can realize that the units and algorithm steps of the examples described in combination with the embodiments disclosed herein can be realized in electronic hardware or a combination of computer software and electronic hardware. Whether the functions are performed in hardware or software depends on the specific application and design constraints of the technical solutions. Those skilled in the art can use different methods to implement the described functions for each specific application, but such implementation should not be considered beyond the scope of the present application.

[0095] Those skilled in the art can clearly understand that, for the convenience and brevity of the description, the specific working processes of the above-described system, device and unit can refer to the corresponding processes in the foregoing method embodiments, which will not be repeated here.

[0096] In several embodiments provided in the present application, it should be understood that the disclosed system, device and method can be implemented in other manners. For example, the described device embodiments are merely schematic. The division of the units is merely a logical function division. There can be another division manner for the actual implementation, for example, multiple units or components can be combined or integrated into another system, or some features can be ignored or not executed. In addition, the displayed or discussed mutual couplings or direct couplings or communication connections can be indirect couplings or communication connections through some interfaces, devices or units, and can be in electrical, mechanical or other forms.

[0097] The units described as separate components can or can not be physically separate, and the components shown as units can or can not be physical units, i.e., can be located in one place, or can be distributed on multiple network units. Some or all of the units can be selected according to actual needs to achieve the purpose of the embodiment.

[0098] In addition, each functional unit in the various embodiments of the present application can be integrated into a processing unit, or each unit can exist physically, or two or more units can be integrated into one unit.

[0099] If the functions are realized in the form of software function units and sold or used as independent products, they can be stored in a computer readable storage medium. Based on this understanding, the technical solutions of the present application or the essential part or part of the technical solutions that make contributions to the prior art can be embodied in the form of a software product. The computer software product is stored in a storage medium and includes several instructions for causing a computer device (which can be a personal computer, a server, or a network device, etc.) to execute all or part of the steps of the methods described in the various embodiments of the present application. The aforementioned storage medium includes: a U disk, a mobile hard disk, a read-only memory (ROM), a random access memory (RAM), a magnetic disk or an optical disk, and various program codes that can be stored in the medium.

[0100] The embodiments of the present application also provide a computer readable storage medium, which stores a computer program. The program is executed by a processor to execute the above method. The method includes at least one of the schemes described in the various embodiments.

[0101] The computer storage medium of the embodiments of the present application can adopt any combination of one or more computer-readable media. The computer-readable medium can be a computer-readable signal medium or a computer-readable storage medium. The computer-readable storage medium may, for example, but is not limited to, an electrical, magnetic, optical, electromagnetic, infrared, or semiconductor system, device or apparatus, or any combination thereof. More specific examples (non-exhaustive list) of the computer-readable storage medium include an electrical connection having one or more wires, a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or flash memory), an optical fiber, a portable compact disc read-only memory (CD-ROM), an optical storage device, a magnetic storage device, or any suitable combination of the above. In this document, the computer-readable storage medium can be any tangible medium that contains or stores a program that can be used by or in connection with an instruction execution system, apparatus or device.

[0102] The computer-readable signal medium can include a data signal propagated in baseband or propagated as a carrier wave, in which computer-readable program code is embodied. Such propagated data signals can take a wide variety of forms, including but not limited to electro-magnetic signals, optical signals, or any suitable combination thereof. Computer-readable signal media can also be any computer-readable medium that is not a storage medium, that is, that is not a tangible medium, and that can communicate, propagate or transport programming for use by or in connection with an instruction execution system, apparatus or device.

[0103] The program code embodied on the computer-readable media can be transmitted using any appropriate medium, including but not limited to wireless, wired, optical fiber cable, RF, etc., or any suitable combination of the above.

[0104] Computer program code for carrying out operations of the present application can be written in any combination of one or more programming languages, including an object oriented programming language such as Java, Smalltalk, C++ or the like and conventional procedural programming languages, such as the "C" programming language or similar programming languages. The program code can execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server. In the latter scenario, the remote computer can be connected to the user's computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection can be made to an external computer (for example, through the Internet using an Internet Service Provider). In some embodiments, electronic circuitry including, for example, programmable logic circuitry, application specific circuitry, or field programmable gate array (FPGA) circuitry can execute the computer program code.

[0105] In addition, the words "first", "second", "third", etc., or "module A", "module B", "module C" and the like in the description and claims are used only to distinguish similar objects, and do not represent a specific order or sequence of the objects. It is understood that, if permitted, the specific order or sequence of the objects can be interchanged, so that the embodiments of the present application described herein can be implemented in an order other than that illustrated or described herein.

[0106] In the above description, the reference signs representing the steps, such as S110, S120, etc., do not necessarily mean that the steps are executed in the order, and the order of the steps can be interchanged, or the steps can be executed simultaneously, if permitted.

[0107] The term "comprising" used in the description and claims should not be interpreted as limiting to the listed elements; it does not exclude other elements or steps. It means that the specifying mentioned features, integers, steps or components are present, but do not preclude the presence or addition of one or more other features, integers, steps or components thereof. Thus, the expression "a device comprising means A and B" should not be limited to a device only consisting of means A and B.

[0108] The phrase "one embodiment" or "an embodiment" appearing in the present specification means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the application. The appearances of the phrase "in one embodiment" or "in an embodiment" in various places in the specification are not necessarily all referring to the same embodiment, but can refer to different embodiments. Furthermore, in one or more embodiments, the particular features, structures, or characteristics can be combined in any suitable manner, as will be apparent to one of ordinary skill in the art from this disclosure.

[0109] Note that the above only describes the preferred embodiments of the present application and the principles of the technology applied. Those skilled in the art will understand that the present application is not limited to the specific embodiments described herein, and that various obvious changes, readjustments and substitutions can be made without departing from the scope of the present application. Therefore, although the present application has been described in detail through the above embodiments, the present application is not limited to the above embodiments, and can include more other equivalent embodiments without departing from the concept of the present application, and all fall within the scope of the present application.

Claims

1. A fluorescent labeling device for intraoperative cortical function visualization, characterized in that, include: An electrophysiological response data receiving module is used to receive electrophysiological response data from a multi-channel flexible electrode array, wherein the electrophysiological response data corresponds to the bioelectrical signals recorded by each electrode channel under electrical stimulation. A target channel determination module is used to determine at least one target channel based on the electrophysiological response data; An electrical stimulation trigger signal generation module is used to generate an electrical stimulation trigger signal corresponding to the target channel in response to a user-input target channel selection command. The electrical stimulation trigger signal is used to trigger the release of fluorescent dye loaded on the surface of the target channel. The trigger signal output module is used to output the electrical stimulation trigger signal to the target channel and send the fluorescence imaging trigger signal to an external fluorescence imaging device.

2. The apparatus as claimed in claim 1, characterized in that, The electrophysiological response data includes at least one of motor evoked potentials, somatosensory evoked potentials, or direct cortical electrical stimulation response signals. And / or, The target channel determination module is specifically used to determine at least one target channel in the following manner: identifying electrode channels corresponding to functional areas based on the electrophysiological response data and marking them as target channels; And / or, The fluorescent dye is loaded onto the electrode surface of the target channel via electrostatic adsorption, electrochemical deposition, or interfacial coordination. The electrostimulation trigger signal adopts an electrochemical release driving waveform, which is used to change the interfacial charge state of the electrode surface and destroy the adsorption of fluorescent dye, thereby triggering the release of fluorescent dye.

3. The apparatus as described in claim 2, characterized in that, The electrochemical release driving waveform is a single-phase square wave, a two-phase balanced square wave, an exponentially decaying pulse, a constant potential step, or a constant current step signal. And / or, The fluorescent dye is a near-infrared or visible light fluorescent agent.

4. The apparatus as claimed in claim 1, characterized in that, The trigger signal output module is specifically used to send a fluorescence imaging trigger signal to an external fluorescence imaging device in the following manner: Simultaneously send fluorescence imaging trigger signals to external fluorescence imaging equipment to achieve time synchronization between fluorescence release events and intraoperative fluorescence imaging.

5. The apparatus as claimed in claim 1, characterized in that, The method applied in the device can be repeated multiple times during the procedure; each time it is executed, the electrophysiological response data is received again, and the target channel and the corresponding electrical stimulation trigger signal are updated.

6. A flexible electrode, characterized in that, include: Flexible substrate; A conductive layer encapsulated on a flexible substrate; Electrode contacts integrated on a conductive layer, the contacts having both electrical stimulation and recording functions; A fluorescent dye region is loaded on the surface of the contact point, and the fluorescent dye loaded region can release fluorescent dye under the stimulation of an electrical stimulation trigger signal.

7. The flexible electrode as described in claim 6, characterized in that, The fluorescent dye is loaded onto the surface of the electrode contact via electrostatic adsorption, electrochemical deposition, or interfacial coordination. The electrical stimulation trigger signal adopts an electrochemical release-driven waveform.

8. The flexible electrode as described in claim 7, characterized in that, The electrochemical release driving waveform is a single-phase square wave, a two-phase balanced square wave, an exponentially decaying pulse, a constant potential step, or a constant current step signal. And / or, The fluorescent dye is a near-infrared or visible light fluorescent agent.

9. A fluorescent labeling system for intraoperative cortical function visualization, characterized in that, include: A flexible electrode array composed of the flexible electrodes described in any one of claims 6-8 is attached to the surface of the cerebral cortex for applying electrical stimulation, recording electrophysiological response data and locally releasing fluorescent dyes. An electrophysiological monitoring device, connected to the flexible electrode array, is used to collect and process electrophysiological response data from each channel; The intraoperative cortical function visualization fluorescent labeling device as described in any one of claims 1-5 is communicatively connected to the electrophysiological monitoring device; A fluorescence imaging device is signal-connected to the intraoperative cortical function visualization fluorescence labeling device, used to receive the fluorescence imaging trigger signal and perform real-time fluorescence imaging of the release area.

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