A functional detection system and method for transocular degeneration of substantia nigra dopaminergic neurons

Abstract

The present invention discloses a functional detection system and method for nigral dopaminergic neurodegeneration via the eye. An optical vision device stimulates the eyes of a subject before and after a specific condition in which the dopamine level in the body of the subject increases, and simultaneously records a stimulation index; a fundus blood flow detection device detects and records the changes in the fundus blood vessels and blood flow parameter information of the subject before and after the increase in the dopamine level in the body and before and after visual stimulation to generate a blood flow index; a signal processing device receives the blood flow index and the stimulation index for processing to obtain a retinal neurovascular coupling function index; a computer or a chip receives the retinal neurovascular coupling function index to determine the risk or result of nigral dopaminergic neurodegeneration in the brain. The present invention uses the eye as a detection window, and can quickly and non-invasively detect nigral dopaminergic neurodegeneration in the brain, with high sensitivity and specificity.

Description

Technical Field

[0001] The present invention relates to the technical field of brain information detection, and particularly relates to a functional detection system and method for dopaminergic neurodegeneration of the substantia nigra through the eye. Background Art

[0002] Damage to dopaminergic neurons in the substantia nigra region of the brain can cause motor symptoms in the human body, seriously affecting the quality of life. Therefore, there is an urgent need for a reliable system working method that can achieve early detection of dopaminergic neurodegeneration of the substantia nigra. Existing positron emission tomography (PET) and single photon emission computed tomography (SPECT) based on brain imaging can specifically detect dopaminergic neurodegeneration in the brain substantia nigra, but the use of isotope tracers makes them have potential radiation hazards, and the long detection time and high detection cost limit their further application. The retina is an extension of the brain, and the detection of the retina can reflect dopaminergic neurodegeneration in the brain substantia nigra. Since dopaminergic neurodegeneration will lead to a decrease in retinal thickness and a decrease in vascular density, currently, optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) can be used to detect it. However, the sensitivity and specificity of these dopaminergic neurodegeneration detection methods based on retinal structural biomarkers are very limited.

[0003] Therefore, how to use this unique window of the retina to detect dopaminergic neuron damage in the brain substantia nigra region with high sensitivity and specificity is of crucial significance. Summary of the Invention

[0004] The purpose of the present invention is to address the deficiencies of the prior art and propose a functional detection system and method for dopaminergic neurodegeneration of the substantia nigra through the eye.

[0005] The present invention applies a stimulus to the subject to activate retinal nerve activity, uses the eye as a detection window to collect and record data, and thereby can detect dopaminergic neurodegeneration of the brain substantia nigra quickly, non-invasively, with high sensitivity and high specificity.

[0006] The purpose of the present invention is achieved through the following technical solutions:

[0007] I. A functional detection system for dopaminergic neurodegeneration of the substantia nigra through the eye:

[0008] The system includes an optical vision device for performing optical vision stimulation on the eyes of the subject before and after a specific condition in which the dopamine level in the subject's body increases, and simultaneously recording the stimulation index S during the optical vision stimulation and sending it to the signal processing device;

[0009] It includes a fundus blood flow detection device, which is a retinal blood vessel and blood flow detection device used to detect and record the changes in fundus blood vessel and blood flow parameter information before and after specific conditions of increased dopamine levels in the body of the subject, as well as before and after visual stimulation, and generate a blood flow index B and send it to the signal processing device;

[0010] It includes a signal processing device that receives the blood flow index B from the fundus blood flow detection device and the stimulation index S from the optical vision device, and then analyzes and processes them to obtain a retinal neurovascular coupling function index R containing dopamine-related information;

[0011] It includes a computer or chip that receives the retinal neurovascular coupling function index R from the signal processing device and determines the risk or result of degeneration of the substantia nigra dopaminergic neurons in the brain by analyzing the retinal neurovascular coupling function index R.

[0012] To obtain a rough risk of degeneration of the substantia nigra dopaminergic neurons, only stimulation is required without specific conditions, which can achieve a rough functional detection of degeneration of the substantia nigra dopaminergic neurons. However, to obtain an accurate result of degeneration of the substantia nigra dopaminergic neurons, only the combination of applying specific conditions and applying stimulation can be used to achieve an accurate functional detection of degeneration of the substantia nigra dopaminergic neurons.

[0013] The specific conditions include temporarily increasing the dopamine level in the body, and the increase in the dopamine level in the body can be achieved by taking dopamine-related drugs, and the dopamine-related drugs are drugs that regulate the dopamine content in the subject's body.

[0014] The optical vision device emits specific light through a visually perceivable method such as a display or a lighting lamp and applies it to the eyes of the subject to stimulate the retinal nerve activity of the subject's fundus. By applying visual light stimulation, the retinal nerve activity is activated, which will induce a hyperemic response, and then the retinal neurovascular coupling function index is detected. For example, the optical vision device can irradiate the eyes of the subject once every few seconds to hundreds of seconds with an LED, etc., but it is not limited specifically.

[0015] More specifically, the optical vision stimulation mode includes flicker light stimulation or pattern stimulation;

[0016] Furthermore, the color of the flicker light includes monochromatic visible light or composite visible light, and further includes green light or white light; the frequency, duty cycle, and illuminance of the flicker light are adjustable;

[0017] Furthermore, the pattern includes a checkerboard or a sine pattern; the contrast and inversion frequency of the checkerboard are adjustable; the contrast and spatial frequency of the sine pattern are adjustable;

[0018] The light-emitting device includes an LED, a laser, or a computer screen.

[0019] The present invention is based on the change information of blood vessel and blood flow signals (retinal neurovascular coupling function index) when the neural activity on the retina changes, so as to reflect the degeneration of nigrostriatal dopaminergic neurons in the detected brain.

[0020] The optical visual device can provide the same or different optical visual stimuli before and after the specific condition that causes the increase in the dopamine level in the subject. Preferably, they are the same.

[0021] The fundus blood flow detection device records and collects the change information of fundus blood vessels and blood flow parameters at at least one moment in each of the pre-stimulus stage L0 before the start of the stimulus and the post-stimulus stage L1 after the start of the stimulus in both cases before and after the specific condition that causes the increase in the dopamine level in the subject, so as to generate a blood flow index B. Usually, the recording is a multiple-sampling recording of the entire processes of the pre-stimulus stage L0 and the post-stimulus stage L1, or the information data of several intervals at multiple moments with time intervals during the entire discrete sampling process.

[0022] More specifically, the fundus blood flow detection device includes an optical coherence tomography instrument, or a dynamic vascular analyzer, or a laser Doppler flowmeter, or a fluorescence angiography instrument, or an ultrasonic detector;

[0023] The fundus blood flow detection device has a synchronization device for automatically synchronizing the stimulus trigger with the fundus signal recording; or it does not have a synchronization device, and the stimulus trigger and the fundus signal recording are manually controlled.

[0024] The pre-stimulus stage L0 refers to the time period before the start of the stimulus.

[0025] The post-stimulus stage L1 mainly consists of the stimulus segment that only contains a complete stimulus after the start of the stimulus, or consists of the stimulus segment that only contains a complete stimulus and the recovery segment without stimulus after the stimulus after the start of the stimulus.

[0026] The drug is usually a drug that increases the dopamine content in the body, and further includes a dopamine precursor (such as levodopa), or a dopamine compound (such as dopamine hydrochloride), or a tyrosine hydroxylase inhibitor (such as carbidopa), or a dopamine reuptake inhibitor (such as theophylline), or a combination of multiple of the above drugs.

[0027] The signal processing device is embedded with a software module. The software module receives the blood flow index B and the stimulus index S and then performs data processing to obtain the retinal neurovascular coupling function index R, and then sends it to a computer / chip to judge the lesion risk or the result of nigrostriatal dopaminergic neuron degeneration according to the retinal neurovascular coupling function index R.

[0028] The computer or chip determines the risk level of degeneration of the substantia nigra dopaminergic neurons in the brain based on the amplitude attenuation characteristics / situations or time delay characteristics / situations associated with dopamine levels extracted from the retinal neurovascular coupling function index.

[0029] The computer or chip determines the accurate result of the degeneration of the substantia nigra dopaminergic neurons in the brain based on whether there is a reversible situation, i.e., reversibility, of the amplitude attenuation characteristics / situations or time delay characteristics / situations associated with dopamine levels extracted from the retinal neurovascular coupling function index after the increase in the dopamine level in the body.

[0030] The fundus blood vessels and blood flow parameters include vessel size, blood flow velocity, and blood flow volume.

[0031] It also includes the vessel diameter and vessel density in the OCTA image.

[0032] It also includes the mean value of the decorrelation coefficient of the blood flow region and the sum of the decorrelation coefficients of the blood flow region in the OCTA signal.

[0033] The information on the changes in the fundus blood vessels and blood flow parameters is the information of the above parameters.

[0034] The stimulation index S specifically refers to the dose of the optical visual stimulation.

[0035] The blood flow index B includes the absolute change values of the fundus blood vessels and blood flow parameters before and after the optical visual stimulation, and / or the relative change values of the fundus blood vessels and blood flow parameters before and after the optical visual stimulation; usually, the changes are the ratios or differences of the parameter values in the post-stimulation stage L1 compared to the parameter values in the pre-stimulation stage L0. And / or it includes the peak amplitude, peak time (the peak time refers to the moment corresponding to the peak amplitude), and the combination of the peak amplitude and peak time of the changes in the fundus blood vessels and blood flow parameters before and after the optical visual stimulation.

[0036] The retinal neurovascular coupling function index R is a combination of the blood flow index B and the stimulation index S, expressed as: R = B / S. Among them, the maximum value of the retinal neurovascular coupling function index R is the amplitude size, and the time corresponding to the amplitude is the delay time.

[0037] If it is necessary to determine the risk level of degeneration of the substantia nigra dopaminergic neurons in the brain, the control system works in the following manner:

[0038] Under the natural state D0 before the increase in the body's dopamine level in the subject, the subject is subjected to optical visual stimulation by an optical vision device. The signal processing device calculates the retinal neurovascular coupling function index R0 in the natural state D0 based on the blood flow index B obtained by the fundus blood flow detection device before and after the optical visual stimulation and the stimulation index S of the optical stimulation device. Then, it is judged by a software module inside the computer or chip:

[0039] If the peak amplitude A0 in the retinal neurovascular coupling function index R0 is less than or equal to the preset first peak amplitude threshold TA1, that is, the amplitude decays, it indicates that the amplitude decay characteristic / situation has occurred, and it is determined to be at high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is determined to be at low risk;

[0040] Or if the peak time T0 in the retinal neurovascular coupling function index R0 is greater than or equal to the preset first peak time threshold TT1, that is, there is a time delay, it indicates that the time delay characteristic / situation has occurred, and it is determined to be at high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is determined to be at low risk;

[0041] Or if the peak amplitude A0 in the retinal neurovascular coupling function index R0 is less than or equal to the preset first peak amplitude threshold TA1 and the peak time T0 is greater than or equal to the preset first peak time threshold TT1, it indicates that both the amplitude decay characteristic / situation and the time delay characteristic / situation have occurred, and it is determined to be at high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is determined to be at low risk.

[0042] If it is necessary to judge whether there is substantia nigra dopaminergic neurodegeneration in the brain, when the control system determines that it is at high risk of substantia nigra dopaminergic neurodegeneration, it continues to work in the following manner:

[0043] Further, a specific condition for increasing the body's dopamine level in the subject is created. Then, after the dopamine in the subject has increased to the state D1, the subject is subjected to optical visual stimulation again by the optical vision device. The signal processing device calculates the retinal neurovascular coupling function index R1 in the state D1 after the dopamine increase based on the blood flow index B obtained by the fundus blood flow detection device before and after the optical visual stimulation and the stimulation index S of the optical stimulation device. Then, it is judged by the computer or chip:

[0044] If the peak amplitude A1 in the retinal neurovascular coupling function index R1 in the state D1 after the dopamine increase is greater than or equal to the preset second peak amplitude threshold TA2, that is, the amplitude decay is reversed, it indicates that the amplitude decay characteristic / situation has been reversed, and it is determined that there is substantia nigra dopaminergic neurodegeneration; otherwise, there is none;

[0045] Alternatively, if the peak time T1 in the retinal neurovascular coupling function index R1 in state D1 after dopamine increase is less than or equal to the preset second peak time threshold TT2, that is, the time delay is reversed, it indicates that the time delay feature / situation has been reversed, and it is determined that there is nigral dopaminergic neurodegeneration; otherwise, there is no such situation.

[0046] Alternatively, if the peak amplitude A1 in the retinal neurovascular coupling function index R1 in state D1 after dopamine increase is greater than or equal to the second peak amplitude threshold TA2, and its peak time T1 is less than or equal to the second peak time threshold TT2, it indicates that both the amplitude attenuation feature / situation and the time delay feature / situation have been reversed simultaneously, and it is determined that there is nigral dopaminergic neurodegeneration; otherwise, there is no such situation.

[0047] If it is determined that there is a low risk of nigral dopaminergic neurodegeneration, there is no need to perform the step of imposing specific conditions on the subject.

[0048] The peak amplitude threshold and peak time threshold in the state of increased dopamine level in the body can be the same as or different from the thresholds before the increase in dopamine level.

[0049] Each of the above-mentioned thresholds can be obtained by establishing a classification model through clinical data.

[0050] II. A functional detection method for nigral dopaminergic neurodegeneration via the eye:

[0051] It includes an optical visual stimulation method. Before and after the specific condition of the subject's increased dopamine level in the body, the eyes of the subject are optically visually stimulated, and the stimulation index S during the optical visual stimulation is recorded simultaneously.

[0052] It includes a fundus blood flow detection method. Specifically, the retinal blood vessels and blood flow are detected, and the change information of the fundus blood vessels and blood flow parameters is detected before and after the specific condition of the subject's increased dopamine level in the body and before and after visual stimulation to generate a blood flow index B.

[0053] It includes a quantification method for the retinal hyperemia response function index R. The retinal hyperemia response function index R containing dopamine-related information is obtained comprehensively based on the blood flow index B and the stimulation index S, including the amplitude size and the delay time.

[0054] It includes a method for evaluating the degree of nigral dopaminergic neurodegeneration. The degree of nigral dopaminergic neurodegeneration is evaluated based on the dopamine-related information contained in the retinal hyperemia response function index R, that is, the risk or result of nigral dopaminergic neurodegeneration in the brain is determined.

[0055] The above-mentioned optical visual stimulation method is carried out by means of a display or a lighting lamp that can be visually perceived, etc., to stimulate the neural activity of the fundus retina of the subject.

[0056] The fundus blood vessels and blood flow parameters include blood vessel size, blood flow velocity, and blood flow volume;

[0057] It also includes the blood vessel diameter and blood vessel density in the OCTA image;

[0058] It also includes the mean value of the decorrelation coefficient of the blood flow region and the total sum of the decorrelation coefficient of the blood flow region in the OCTA signal.

[0059] The stimulation index S specifically refers to the dose of optical visual stimulation;

[0060] The blood flow index B includes the absolute change values of the fundus blood vessels and blood flow parameters before and after optical visual stimulation, and / or the relative change values of the fundus blood vessels and blood flow parameters before and after optical visual stimulation; generally, the changes are the ratio or difference of the parameter values in the post-stimulation stage L1 compared to the parameter values in the pre-stimulation stage L0. And / or it includes the peak amplitude, peak time (the peak time refers to the moment corresponding to the peak amplitude), and the combination of peak amplitude and peak time of the changes in the fundus blood vessels and blood flow parameters before and after optical visual stimulation.

[0061] The retinal neurovascular coupling function index R is a combination of the blood flow index B and the stimulation index S, expressed as: R = B / S. Among them, the maximum value of the retinal neurovascular coupling function index R is the amplitude size, and the time corresponding to the amplitude is the delay time.

[0062] The specific method for evaluating the degree of degeneration of nigral dopaminergic neurons is as follows:

[0063] If the peak amplitude A0 in the retinal neurovascular coupling function index R0 before the increase in dopamine level in the subject is less than or equal to the preset first peak amplitude threshold TA1, or the peak time T0 in the retinal neurovascular coupling function index R0 is greater than or equal to the preset first peak time threshold TT1, or the peak amplitude A0 in the retinal neurovascular coupling function index R0 is less than or equal to the preset first peak amplitude threshold TA1, and the peak time T0 is greater than or equal to the preset first peak time threshold TT1, it indicates that the amplitude attenuation feature / time delay feature occurs, and it is determined to be at high risk of nigral dopaminergic neuron degeneration; otherwise, it is determined to be at low risk; when it is determined to be at high risk of nigral dopaminergic neuron degeneration, continue to judge according to the retinal neurovascular coupling function index R1 in the state D1 after the dopamine increase in the subject:

[0064] If the peak amplitude A1 in the retinal neurovascular coupling function index R1 in state D1 after the dopamine of the subject increases is greater than or equal to the preset second peak amplitude threshold TA2, or the peak time T1 in the retinal neurovascular coupling function index R1 in state D1 after the dopamine increases is less than or equal to the preset second peak time threshold TT2, or if the peak amplitude A1 in the retinal neurovascular coupling function index R1 in state D1 after the dopamine increases is greater than or equal to the second peak amplitude threshold TA2 and its peak time T1 is less than or equal to the second peak time threshold TT2, it indicates that the amplitude attenuation feature / situation or the time delay feature / situation has reversed, and it is determined that there is degeneration of the substantia nigra dopaminergic neurons; otherwise, there is none.

[0065] The beneficial effects of the present invention are as follows:

[0066] Existing PET and SPECT detection systems based on brain imaging use rays as detection signals, making the detection have potential radiation hazards. The present invention uses optical signals or acoustic signals to detect the retinal neurovascular coupling function index caused by the degeneration of the substantia nigra dopaminergic neurons, which is radiation-free and has better safety, and is suitable for large-scale screening and longitudinal monitoring.

[0067] Existing detection systems based on traditional OCT use the change in retinal thickness caused by the degeneration of the substantia nigra dopaminergic neurons as a detection marker. However, the axial resolution of the OCT system is ~4 - 7 microns, while this thinning of the retinal thickness is only 1 - 2 microns, resulting in poor detection sensitivity; in addition, factors such as aging can also cause a decrease in retinal thickness, making the detection specificity poor.

[0068] Existing detection systems based on traditional OCTA use the change in the morphology of retinal microvessels caused by the degeneration of the substantia nigra dopaminergic neurons as a detection marker. However, factors such as intraocular pressure can also cause changes in retinal microvessels, making the detection specificity poor. Description of the Drawings

[0069] Figure 1 It is a schematic diagram of the device of the present invention;

[0070] Figure 2 It is a flowchart of the working method embodiment of the system of the present invention;

[0071] Figure 3 It is a schematic diagram of the device embodiment of the present invention;

[0072] Figure 4 It is the detection result of the retinal blood flow response induced by flash light stimulation in healthy and substantia nigra dopaminergic neuron - degenerated mice in the non - drug - administered state in the exemplary embodiment of the present invention;

[0073] Figure 5In exemplary embodiments of the present invention, changes in the relative change of retinal blood flow induced by flickering light stimulation in three states: before levodopa administration, after levodopa administration, and after levodopa metabolism is completed, in healthy and substantia nigra dopaminergic neurodegenerative mice;

[0074] Figure 6 In exemplary embodiments of the present invention, classification results of healthy and substantia nigra dopaminergic neurodegenerative mice based on the peak amplitude of retinal blood flow induced by light stimulation in the states before and after levodopa administration;

[0075] Wherein: 11 - detection signal generation module; 12 - light stimulation module; 13 - sample; 14 - detection signal acquisition module; 15 - signal processing module;

[0076] 31 - broadband light source; 32 - 80:20 fiber optic coupler; 33 - polarization controller; 34 - reference arm collimator; 35 - dispersion matching module; 36 - reference arm focusing lens; 37 - reference arm mirror; 38 - sample arm collimator; 39 - sample arm OCT scanning device; 40 - sample arm dichroic mirror; 41 - visible light stimulation light source; 42 - sample arm doublet lens; 43 - eyepiece; 44 - sample eye; 45 - detection module collimator; 46 - grating; 47 - focusing lens; 48 - high - speed linear array camera; 49 - signal processing module. Detailed implementation manners

[0077] The following will describe the detailed implementation manners of the present invention in conjunction with the accompanying drawings, which form a part of this text. It should be noted that these descriptions and examples are merely exemplary and should not be construed as limiting the scope of the present invention. The scope of protection of the present invention is defined by the appended claims, and any modification based on the claims of the present invention falls within the scope of protection of the present invention.

[0078] To facilitate the understanding of the embodiments of the present invention, each operation is described as a plurality of discrete operations. However, the described order does not represent the order of performing the operations.

[0079] In this description, the sample measurement space is represented by a three - dimensional x - y - z coordinate system based on spatial directions. This description is only used to facilitate the discussion and is not intended to limit the application of the embodiments of the present invention. Wherein: the depth z - direction is along the incident optical axis direction; the x - y plane is a plane perpendicular to the optical axis, where x and y are orthogonal, and x represents the OCT transverse fast scanning direction, and y represents the slow scanning direction.

[0080] Variables such as i and t are used to facilitate the discussion and are not intended to limit the application of the embodiments of the present invention, and can be any value such as 1, 2, 3, etc.

[0081] The specific implementation process of the working method of the system of the present invention includes the following steps:

[0082] Step 1: Before and after a specific condition in which the dopamine level in the subject increases in vivo, perform optical visual stimulation on the eyes of the subject, and at the same time record the stimulation index S during the optical visual stimulation and send it to the signal processing device.

[0083] The specific implementation device system is as Figure 1 shown, mainly consisting of two parts, 11 - 12 and 14 - 15: Using the light stimulation module 12 with an LED lamp as the optical visual device, the fundus blood flow detection device includes a detection signal generation module 11 light and a detection signal acquisition module 14, the eyes of the subject as the sample 13, and using the signal processing module 15 as the signal processing device for data processing.

[0084] The signal generation module 11 transmits the detection signal to the sample 13, and the light stimulation module 12 generates stimulation light to activate the neuronal activity on the sample 13. Subsequently, the signal detection module 14 collects the signal returned from the sample 13 and transmits it to the signal processing module 15 for further processing.

[0085] Use the light stimulation module 12 to generate flickering visible light to stimulate the retina of the eyes of the sample 13. Its wavelength range is 380 - 760 nanometers, the stimulation time is 30 s, the illuminance is 1000 lux, the frequency is 10 Hz, and the duty cycle is 50%. Its stimulation dose corresponds to the stimulation index S. Perform optical visual stimulation with the same dose on the eyes of the subject before and after a specific condition in which the dopamine level in the subject increases in vivo. Step 2: Use drugs to increase the dopamine level in the subject. Record the changes in fundus blood vessel and blood flow parameter information from the pre - stimulation stage L0 to the post - stimulation stage L1 in two different states, before drug administration D0 and after drug administration D1, and then obtain the retinal neurovascular coupling function index of the current state; specifically:

[0086] As Figure 2 shown, the general implementation process of the system of the present invention is:

[0087] In the case of D0 before drug administration without taking drugs, perform stimulation by the optical visual device, and record the changes in fundus blood vessel and blood flow parameter information from the pre - stimulation stage L0 to the post - stimulation stage L1 by the fundus blood flow detection device to obtain the retinal neurovascular coupling function index;

[0088] Then the subject takes the drug to increase the dopamine content in the subject. In the case of D1 after drug administration, perform the same stimulation again by the optical visual device, and record the changes in fundus blood vessel and blood flow parameter information from the pre - stimulation stage L0 to the post - stimulation stage L1 by the fundus blood flow detection device to obtain the retinal neurovascular coupling function index.

[0089] In specific implementation, the fundus blood flow detection device records the retinal neurovascular coupling function index by using a clock signal to control and synchronize the two processes of stimulus application and retinal neurovascular coupling function index recording, so as to achieve precise control of the recording time node.

[0090] The signal processing device can be embedded with a software module. After receiving the information on the changes in fundus blood vessels and blood flow parameters from the blood flow detection instrument, the software module processes the data to obtain the retinal neurovascular coupling function index, and then judges the lesion risk of the brain or the result of substantia nigra dopaminergic neurodegeneration based on the retinal neurovascular coupling function index.

[0091] As Figure 2 shown, if it is necessary to judge the risk level of substantia nigra dopaminergic neurodegeneration in the brain, the control system works in the following way:

[0092] In the natural state D0 before the dopamine level in the subject rises, the optical vision device performs optical vision stimulation on the subject. The signal processing device calculates the retinal neurovascular coupling function index R0 in the natural state D0 without applying the stimulus to the subject according to the blood flow index B obtained by the fundus blood flow detection device before and after the optical vision stimulation and the stimulation index S of the optical stimulation device, and then judges by the software module inside the computer or chip:

[0093] If the peak amplitude A0 in the retinal neurovascular coupling function index R0 is less than or equal to the preset first peak amplitude threshold TA1, that is, the amplitude decays, it indicates that the amplitude decay characteristic / situation has occurred, and it is determined that there is a high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is determined to be a low risk;

[0094] Or if the peak time T0 in the retinal neurovascular coupling function index R0 is greater than or equal to the preset first peak time threshold TT1, that is, the time is delayed, it indicates that the time delay characteristic / situation has occurred, and it is determined that there is a high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is determined to be a low risk;

[0095] Or if the peak amplitude A0 in the retinal neurovascular coupling function index R0 is less than the preset first peak amplitude threshold TA1, and the peak time T0 is greater than or equal to the preset first peak time threshold TT1, it indicates that both the amplitude decay characteristic / situation and the time delay characteristic / situation have occurred, and it is determined that there is a high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is determined to be a low risk.

[0096] As can be seen from the above, without stimulation, it is impossible to accurately judge whether there is substantia nigra dopaminergic neurodegeneration, but only the risk of substantia nigra dopaminergic neurodegeneration can be judged.

[0097] As Figure 2As shown, to determine whether there is degeneration of substantia nigra dopaminergic neurons in the brain, when the control system determines that there is a high risk of degeneration of substantia nigra dopaminergic neurons, it continues to work in the following manner:

[0098] Further, a specific condition that causes an increase in the dopamine level in the subject's body is induced. Then, after the dopamine in the subject has increased and is in state D1, the subject is subjected to another optical visual stimulation by an optical vision device. Next, a signal processing device calculates the retinal neurovascular coupling function index R1 of state D1 after dopamine increase based on the blood flow index B obtained by the fundus blood flow detection device before and after the optical visual stimulation and the stimulation index S of the optical stimulation device. Then, a computer or chip makes a judgment:

[0099] If the peak amplitude A1 in the retinal neurovascular coupling function index R1 in state D1 after dopamine increase is greater than or equal to the preset second peak amplitude threshold TA2, that is, the amplitude attenuation is reversed, it indicates that the amplitude attenuation feature / situation has been reversed, and it is determined that there is degeneration of substantia nigra dopaminergic neurons; otherwise, it does not exist;

[0100] Or if the peak time T1 in the retinal neurovascular coupling function index R1 in state D1 after dopamine increase is less than or equal to the preset second peak time threshold TT2, that is, the time delay is reversed, it indicates that the time delay feature / situation has been reversed, and it is determined that there is degeneration of substantia nigra dopaminergic neurons; otherwise, it does not exist;

[0101] Or if the peak amplitude A1 in the retinal neurovascular coupling function index R1 in state D1 after dopamine increase is greater than or equal to the second peak amplitude threshold TA2 and its peak time T1 is less than or equal to the second peak time threshold TT2, it indicates that both the amplitude attenuation feature / situation and the time delay feature / situation have been reversed simultaneously, and it is determined that there is degeneration of substantia nigra dopaminergic neurons; otherwise, it does not exist.

[0102] In a specific embodiment, an OCT device based on weak coherence interference is used to record the changes in the fundus blood vessel and blood flow parameter information before (D0) and after (D1) drug administration. A clock signal is used to precisely synchronize the two processes of stimulus application and fundus parameter recording. The post-light stimulation stage L1 includes a flashing light stimulation segment and a recovery segment without stimulation. OCT is used to scan the entire process of the pre-light stimulation stage L0 and the stimulation segment L1 to obtain retinal interference signals at different time points.

[0103] The retinal structure signal is obtained after performing Fourier transform on the interference signal. The first-order and zero-order autocovariance are used to calculate and analyze this signal, and two features, the inverse signal-to-noise ratio (I) and the decorrelation coefficient (D), are obtained. Then, an I-D two-dimensional feature space is constructed, and a linear classifier is used to analyze and judge the dynamic blood flow signal. OCTA angiography image sequences of the retina in the pre-drug state D0 and the post-drug state D1, in the pre-light stimulation stage L0 and the post-light stimulation stage L1, are obtained. For the generated OCTA angiography image sequences, first, they are binarized to eliminate the interference of noise. Subsequently, the binarized OCTA matrix is skeletonized, the intersection points of the retinal microvascular skeleton are located and removed, and the vascular skeleton fragments with each segment of blood vessel as a single connected domain are obtained and numbered as i. The blood flow of each segment of blood vessel at each time node is extracted.

[0104] The blood flow at each time node of each segment of blood vessel before light stimulation at t0 is averaged to obtain the baseline value of the blood flow before the hyperemic response corresponding to blood vessel i:

[0105] where N represents the number of data collected within the base segment t0, and t is the time dimension, representing the blood flow of blood vessel i at the time point.

[0106] Subsequently, the relative change in blood flow in the stimulation segment and the recovery segment of the blood flow is calculated as the blood flow index B:

[0107] where the blood flow index is the relative change in the blood flow of blood vessel i at the time point.

[0108] The retinal neurovascular coupling function index of blood vessel i at the time point is obtained by comprehensively considering the blood flow index and the stimulation index S:

[0109] where the specific implemented stimulation index S is the stimulation dose under the conditions of a wavelength range of 380 - 760 nm, a stimulation time of 30 s, an illuminance of 1000 lux, a frequency of 10 Hz, and a duty cycle of 50%, but is not limited to this.

[0110] During the entire sampling process, at the same sampling time point, the retinal neurovascular coupling function indices of all blood vessels within the scanned field of view are averaged to obtain the retinal overall neurovascular coupling function index R. The maximum value of this function index in the stimulation segment and the recovery segment is taken as the peak amplitude A, and this peak amplitude A is used as an indicator for judging the degeneration of dopaminergic neurons in the substantia nigra of the brain. In the natural state D0 before the increase in the body's dopamine level in the subject, if the peak amplitude A0 in the retinal neurovascular coupling function index R0 is less than or equal to the preset first peak amplitude threshold TA1, it is determined that there is a high risk of degeneration of dopaminergic neurons in the substantia nigra; otherwise, it is determined to be a low risk.

[0111] When it is determined that there is a high risk of degeneration of substantia nigra dopaminergic neurons, the subject is orally administered levodopa (250 mg) to increase the dopamine level in the body. After the dopamine level of the subject has increased and is in state D1, the following judgment is made: If the peak amplitude A1 in the retinal neurovascular coupling function index R1 in state D1 after the dopamine increase is greater than or equal to the preset second peak amplitude threshold TA2, it is determined that there is degeneration of substantia nigra dopaminergic neurons; otherwise, there is no such degeneration.

[0112] According to different signal detection methods, Figure 1 Devices such as the fundus blood flow detection device shown may specifically include:

[0113] 1) Optical coherence tomography device. It uses low-coherence interference light to detect retinal signals and uses a spectrometer or a balanced detector to receive the signals, thereby obtaining a depth-resolved OCT sampling volume.

[0114] 2) Dynamic vascular analyzer. It directly records retinal signals using a fundus camera and uses a CMOS or CCD sensor to receive the signals, thereby obtaining a planar image of the retinal surface layer.

[0115] 3) Laser Doppler flowmeter. It uses monochromatic infrared laser to detect retinal signals and uses a photodetector to receive the returned optical signals, thereby obtaining retinal blood flow information.

[0116] 4) Fundus fluorescein angiography instrument. It uses a specific wavelength to excite fundus fluorescence and uses a camera to detect the emitted fluorescence, thereby obtaining a retinal fluorescence sampling volume.

[0117] 5) Ultrasound imaging device. It emits ultrasonic signals to the retina using an ultrasonic transducer and receives the ultrasonic signals returned from the retina, thereby obtaining a depth-resolved ultrasonic sampling volume.

[0118] For the above different measurement devices, retinal angiography can be generated by analyzing the signal differences between blood flow and surrounding tissues.

[0119] Figure 3 Shown is an exemplary embodiment of the present invention disclosed herein. The system includes a broadband light source 31, an 80:20 fiber coupler 32, a polarization controller 33, a reference arm collimator 34, a dispersion matching module 35, a reference arm focusing lens 36, a reference arm mirror 37, a sample arm collimator 38, a sample arm OCT scanning device 39, a sample arm dichroic mirror 40, a visible light stimulation light source 41, a sample arm doublet lens 42, an eyepiece 43, a sample eye 44, a detection module collimator 45, a grating 46, a focusing lens 47, a high-speed linear array camera 48, and a signal processing module 49.

[0120] The broadband light source 31 is connected to one of the branches at one end of the 80:20 fiber coupler 32. The other branch at one end of the 80:20 fiber coupler 32 is connected to the signal processing module 49 via the collimating mirror 45, grating 46, focusing lens 47, and linear array camera 48 of the detection module. One of the branches at the other end of the 80:20 fiber coupler 32 is connected to the reference arm. The reference arm includes a polarization controller 33, a reference arm collimating mirror 34, a dispersion matching module 35, a reference arm focusing lens 36, and a reference arm mirror 37 arranged in sequence. One of the branches at the other end of the 80:20 fiber coupler 32 is connected to one end of the polarization controller 33. The other end of the polarization controller 33 is connected to the incident end of the reference arm collimating mirror 34. The dispersion matching module 35 and the reference arm focusing lens 36 are arranged in sequence between the reference arm collimating mirror 34 and the reference arm mirror 37. The dispersion matching module 35 is close to the reference arm collimating mirror 34, and the reference arm focusing lens 36 is close to the reference arm mirror 37. One of the branches at the other end of the 80:20 fiber coupler 32 is connected to the sample arm. The sample arm includes a sample arm collimating mirror 38, a sample arm OCT scanning device 39, a sample arm dichroic mirror 40, a sample arm doublet lens 42, an eyepiece 43, and a sample eye 44 arranged in sequence. The sample arm OCT scanning device 39, the sample arm dichroic mirror 40, the sample arm doublet lens 42, and the eyepiece 43 are arranged in sequence between the sample arm collimating mirror 38 and the sample eye 44. The eyepiece 43 coincides with the focal point of the sample arm doublet lens 42, so as to irradiate the ocular surface of the sample eye 44 with parallel light and converge on the retina through the eyeball. The stimulating light emitted by the visible light stimulating light source 41 is coupled into the sample arm detection optical path through the sample arm dichroic mirror 40 and is transmitted to the sample eye 44 after passing through the sample arm doublet lens 42 and the eyepiece 43.

[0121] The system of this embodiment, where the central wavelength of the broadband light source 31 is 850 nm and the bandwidth is 120 nm. The OCT signal of the sample is collected in real time by the high-speed linear array camera 48 and transmitted to the signal processing module 49. The parallel light emitted by the sample arm collimator 38 is incident on the sample arm OCT scanning device 39. After the parallel light emitted by the sample arm OCT scanning device 39 passes through the sample arm dichroic mirror 40, it is incident on the sample arm doublet lens 42. The sample arm OCT scanning device 39 consists of two planar scanning galvanometers, and the acquisition range of the OCT signal is controlled by adjusting the relative positions of the two planar scanning galvanometers. The detection light emitted by the broadband light source 31 used in the device of the present invention is transmitted to the 80:20 fiber coupler 32 through an optical fiber and is divided into two beams of light that enter the reference arm and the sample arm respectively. Among them, 80% of the detection light enters the reference arm, passes through the polarization controller 33 and then is transmitted to the reference arm collimator 34. After being collimated, it passes through the dispersion matching module 35 and the reference arm focusing lens 36 and converges on the reference arm mirror 37. Subsequently, this beam of light returns to the 80:20 fiber coupler 32 along the original path. 20% of the detection light enters the sample arm, passes through the sample arm collimator 38 and the scanning galvanometer 39, and then passes through the sample arm dichroic mirror 40, the sample arm doublet lens 42 and the eyepiece 43 in sequence and enters the sample eye 44. The light beam in the sample eye 44 is focused on the retina by the eye. The visible light stimulation light source 41 emits white light with a wavelength range of 360 - 780 nm. The stimulation light emitted by it is coupled into the sample arm detection optical path through the sample arm dichroic mirror 40, and after passing through the sample arm doublet lens 42 and the eyepiece 43, it is transmitted to the sample eye 44 to achieve optic nerve stimulation. Subsequently, the detection light beam carrying the fundus information of the sample eye 44 returns to the 80:20 fiber coupler 32 along the original path. The backscattered light returned from the reference arm and the sample arm interferes in the 80:20 fiber coupler 32. The generated interference light passes through the detection module collimator 45 and the grating 46 in sequence, and then is converged on the linear array camera 48 through the focusing lens 47 to achieve signal detection and recording. Subsequently, the signal processing module 49 collects and further processes it.

[0122] The present invention can obtain the microvascular hyperemic response of the retina after visible light excitation. Each pulse width, frequency and amplitude of the light stimulation pulse sequence are adjustable. In a specific embodiment, each pulse width is 100 ms, the frequency is 10 Hz, the amplitude is 3.0 V, and the stimulation time is 30 s, that is, 300 pulse sequences.

[0123] Figure 4 Shown are the detection results of retinal neurovascular coupling in healthy and substantia nigra dopaminergic neurodegenerative mice. Among them Figure 4The ordinate in (A) is the relative change in capillary blood flow, and the abscissa is the monitoring time node. The period from 0 to 30 s is the light stimulation period. It can be found that, compared with healthy mice (n = 13), the peak amplitude of the retinal blood flow response in mice with substantia nigra dopaminergic neurodegeneration (n = 13) decreased significantly. The statistical results are as shown in Figure 4 (B) in

[0124] Figure 5 Shown are the changes in the relative change in retinal blood flow in healthy and substantia nigra dopaminergic neurodegeneration mice in three states: before levodopa administration, after levodopa administration, and after drug metabolism. Figure 5 (A) and (B) in show the relative changes in retinal capillary blood flow in mice with substantia nigra dopaminergic neurodegeneration (n = 6) and healthy mice (n = 7) before and after light stimulation, respectively. The period from 0 to 30 s is the light stimulation period. It can be found that after drug administration, the neurovascular coupling response in mice with substantia nigra dopaminergic neurodegeneration was significantly improved, while the neurovascular coupling response in healthy mice tended to be inhibited. This phenomenon is more intuitively reflected in the comparison of the peak amplitudes of the responses in Figure 5 (C)

[0125] Figure 6 Shown are the classification results of healthy and substantia nigra dopaminergic neurodegeneration mice based on the peak amplitude of retinal blood flow induced by light stimulation before and after drug administration. It can be found that by combining the retinal neurovascular coupling function index after levodopa administration, substantia nigra dopaminergic neurodegeneration can be distinguished with high accuracy and high specificity.

[0126] The above experimental results fully demonstrate that the present invention can combine light stimulation with the regulation of in vivo dopamine concentration, and based on the retinal neurovascular coupling mechanism, perform non-invasive detection of retinal function damage caused by substantia nigra dopaminergic neurodegeneration with high sensitivity, high specificity, and high accuracy.

[0127] Finally, it should be noted that the above embodiments and descriptions are only used to illustrate the technical solutions of the present invention and not to limit them. Those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced. Without departing from the spirit and scope of the disclosure of the technical solutions of the present invention, they should all be covered by the protection scope of the claims of the present invention.

Claims

1. A functional detection system for substantia nigra dopaminergic neurodegeneration through the eye, characterized in that: It includes an optical visual device for performing optical visual stimulation on the eyes of the subject before and after a specific condition occurs in the subject where the dopamine level in the body is increased, and simultaneously recording a stimulation index S during the optical visual stimulation and sending it to a signal processing device; It includes a fundus blood flow detection device, which is used to detect and record the change information of fundus blood vessels and blood flow parameters of the subject before and after the specific conditions of increased dopamine level in the body and before and after visual stimulation to generate a blood flow index B and send it to the signal processing device; It includes a signal processing device, which receives the blood flow index B from the fundus blood flow detection device and the stimulation index S from the optical vision device, and then analyzes and processes to obtain the retinal neurovascular coupling function index R containing dopamine-related information; A computer or chip is included, which receives the retinal neurovascular coupling function index R from the signal processing device, and determines the risk or result of substantia nigra dopaminergic nerve degeneration in the brain by analyzing the retinal neurovascular coupling function index R; The retinal neurovascular coupling function index R is a combination of the blood flow index B and the stimulation index S, expressed as: R = B / S; To determine the risk of degeneration of the substantia nigra dopaminergic neurons in the brain, the control system works as follows: In the natural state D0 before the dopamine level in the subject increases, the optical visual device performs optical visual stimulation on the subject, and the retinal neurovascular coupling function index R0 in the natural state D0 is calculated based on the blood flow index B obtained by the fundus blood flow detection device before and after the optical visual stimulation and the stimulation index S of the optical stimulation device, and then judged by a computer or chip: If the peak amplitude A0 in the retinal neurovascular coupling function index R0 is less than or equal to the preset first peak amplitude threshold TA1, it is determined to be a high risk of substantia nigra dopaminergic nerve degeneration; otherwise, it is determined to be a low risk; Or if the peak time T0 in the retinal neurovascular coupling function index R0 is greater than or equal to the preset first peak time threshold TT1, it is determined to be a high risk of substantia nigra dopaminergic nerve degeneration; otherwise, it is determined to be a low risk; Alternatively, if the peak amplitude A0 in the retinal neurovascular coupling function index R0 is less than or equal to the preset first peak amplitude threshold TA1, and the peak time T0 is greater than or equal to the preset first peak time threshold TT1, it is judged as a high risk of substantia nigra dopaminergic nerve degeneration; otherwise, it is judged as a low risk.

2. A functional detection system for substantia nigra dopaminergic nerve degeneration according to claim 1, characterized in that: The optical visual device is a display or a lighting device that emits light to the eyes of the subject to stimulate the retinal nerve activity of the subject's fundus.

3. The functional detection system for substantia nigra dopaminergic nerve degeneration according to claim 1, characterized in that: The fundus blood flow detection device records and collects fundus blood vessel and blood flow parameter change information at at least one moment from the pre-stimulation stage L0 to the post-stimulation stage L1 before and after the specific condition of increased dopamine level in the subject, thereby generating a blood flow index B.

4. The functional detection system for substantia nigra dopaminergic nerve degeneration according to claim 1, characterized in that: The computer or chip determines the risk of dopaminergic neurodegeneration in the substantia nigra of the brain based on the amplitude attenuation characteristics or time delay characteristics extracted from the retinal neurovascular coupling function index; The computer or chip determines the accurate result of dopaminergic neurodegeneration in the substantia nigra of the brain based on whether the amplitude attenuation feature or time delay feature extracted from the retinal neurovascular coupling function index after the dopamine level in the body is increased is reversible.

5. The functional detection system for substantia nigra dopaminergic nerve degeneration through the eye according to claim 1, characterized in that: The fundus blood vessels and blood flow parameters include blood vessel size, blood flow velocity and blood flow volume; It also includes vessel diameter and vessel density in OCTA images; It also includes the mean of the decorrelation coefficients of the blood flow areas in the OCTA signal and the sum of the decorrelation coefficients of the blood flow areas.

6. A functional detection system for substantia nigra dopaminergic nerve degeneration through the eye according to claim 5, characterized in that: The stimulation index S specifically refers to the dose of optical visual stimulation; The blood flow index B includes the absolute change values ​​of the fundus blood vessels and blood flow parameters before and after optical visual stimulation, and / or the relative change values ​​of the fundus blood vessels and blood flow parameters before and after optical visual stimulation; and / or includes the peak amplitude, peak time, peak amplitude and peak time of the changes of the fundus blood vessels and blood flow parameters before and after optical visual stimulation.

7. The functional detection system for substantia nigra dopaminergic nerve degeneration according to claim 1, characterized in that: If it is determined whether there is substantia nigra dopaminergic nerve degeneration in the brain, the control system will continue to work in the following manner when it is determined that there is a high risk of substantia nigra dopaminergic nerve degeneration: The subject is further exposed to a specific condition in which the dopamine level in the body increases. Then, in the state D1 after the dopamine level of the subject increases, the optical visual device performs optical visual stimulation on the subject again. The signal processing device calculates the retinal neurovascular coupling function index R1 of the state D1 after the dopamine level increases based on the blood flow index B obtained by the fundus blood flow detection device before and after the optical visual stimulation and the stimulation index S of the optical stimulation device. The computer or chip then makes a judgment: If the peak amplitude A1 in the retinal neurovascular coupling function index R1 in the dopamine rising state D1 is greater than or equal to the preset second peak amplitude threshold TA2, it is determined that substantia nigra dopaminergic nerve degeneration exists; otherwise, it does not exist; Or if the peak time T1 in the retinal neurovascular coupling function index R1 in the dopamine rising state D1 is less than or equal to the preset second peak time threshold TT2, it is determined that the substantia nigra dopaminergic nerve degeneration exists; otherwise, it does not exist; Alternatively, if the peak amplitude A1 in the retinal neurovascular coupling function index R1 in the dopamine rising state D1 is greater than or equal to the second peak amplitude threshold TA2, and its peak time T1 is less than or equal to the second peak time threshold TT2, it is determined that substantia nigra dopaminergic nerve degeneration exists; otherwise, it does not exist.

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