Function detection system and method for ocular nigra dopaminergic neurodegeneration

Abstract

The invention discloses a function detection system and a function detection method for ocular nigra dopaminergic neurodegeneration. The optical vision equipment stimulates the eyes of the tested object before and after the specific condition that the dopamine level in the tested object is improved, and meanwhile, a stimulation index is recorded; the fundus blood flow detection equipment is used for detecting and recording fundus blood vessel and blood flow parameter change information of the tested object before and after in-vivo dopamine level improvement and before and after visual stimulation so as to generate a blood flow index; the signal processing equipment receives and processes the blood flow index and the stimulation index to obtain a retina nerve blood vessel coupling function index; the computer or the chip receives the retina nerve-blood vessel coupling function index to judge the risk or the result of the brain nigra dopaminergic neurodegeneration. According to the invention, the eyes are used as a detection window, so that the brain nigra dopaminergic neurodegeneration can be rapidly and non-invasively detected, and the method has high sensitivity and specificity.

Description

Technical Field

[0001] The present invention relates to the technical field of brain information detection, and in particular to a system and method for detecting the function of substantia nigra dopaminergic nerve degeneration 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 systematic working method that can achieve early detection of substantia nigra dopaminergic neurodegeneration. Existing brain neuroimaging-based positron emission tomography (PET) and single photon emission computed tomography (SPECT) can specifically detect substantia nigra dopaminergic neurodegeneration in the brain, but the use of isotope tracers makes it a potential radiation hazard, and the long detection time and high detection costs limit its further application. The retina is an extension of the brain, and the detection of the retina can reflect the degeneration of substantia nigra dopaminergic neurons in the brain. Since substantia nigra dopaminergic neurodegeneration can lead to a decrease in retinal thickness and vascular density, it can currently be detected using optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA). However, the sensitivity and specificity of these dopaminergic neurodegeneration detection methods based on retinal structural biomarkers are very limited.

[0003] Therefore, it is of vital importance to utilize the retina as a unique window to detect dopaminergic neuron damage in the substantia nigra region of the brain with high sensitivity and specificity. Summary of the invention

[0004] The purpose of the present invention is to address the deficiencies of the prior art and to provide a system and method for detecting the functional degeneration of substantia nigra dopaminergic nerves through the eye.

[0005] The present invention applies stimulation to the subject to activate retinal neural activity, uses the eye as a detection window to collect and record data, and thereby can rapidly, non-invasively, highly sensitively, and highly specifically detect dopaminergic neurodegeneration in the substantia nigra of the brain.

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

[0007] 1. A functional detection system for substantia nigra dopaminergic nerve degeneration through the eye:

[0008] The system 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 in which 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;

[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 change information of the 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;

[0010] 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;

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

[0012] To obtain an approximate risk of substantia nigra dopaminergic neurodegeneration, it is only necessary to apply stimulation without specific conditions, which can achieve an approximate functional test of substantia nigra dopaminergic neurodegeneration. However, to obtain an accurate result of substantia nigra dopaminergic neurodegeneration, only a combination of applying specific conditions and applying stimulation can achieve an accurate functional test of substantia nigra dopaminergic neurodegeneration.

[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, which are drugs that regulate the dopamine content in the subject.

[0014] The optical visual device emits a specific light to the subject's eyes in a visually perceptible manner such as a display or a lighting lamp, thereby stimulating the retinal neural activity of the subject's fundus. The application of visual light stimulation activates the retinal neural activity, induces a congestion response, and then detects and obtains the retinal neurovascular coupling function index. For example, the optical visual device can illuminate the subject's eyes once every few seconds to hundreds of seconds using an LED, but is not limited to this.

[0015] More specifically, the optical visual stimulation mode includes flickering light stimulation or pattern stimulation;

[0016] Furthermore, the color of the flashing light includes monochromatic visible light or polychromatic visible light, and further includes green light or white light; the frequency, duty cycle and illumination of the flashing light are adjustable;

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

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

[0019] The present invention is based on the change information of blood vessels and blood flow signals when the neural activity on the retina changes (retinal neurovascular coupling function index) to reflect the degeneration of dopaminergic nerves in the substantia nigra of the brain.

[0020] The optical visual stimulation of the optical visual device before and after the specific condition of the subject's dopamine level rising in vivo occurs can be the same or different. Preferably, they are the same.

[0021] The fundus blood flow detection device records and collects information on fundus blood vessels and blood flow parameter changes in real time at least one moment from the pre-stimulation stage L0 before the start of stimulation to the post-stimulation stage L1 after the start of stimulation, both before and after the specific condition of the subject's body dopamine level rising, and then generates a blood flow index B. Usually, the record is a multiple sampling record of the entire process of the pre-stimulation stage L0 and the post-stimulation stage L1, or a plurality of interval information data of multiple moments in the interval time period 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 blood flow meter, or a fluorescent angiography instrument, or an ultrasonic detector;

[0023] The fundus blood flow detection device has a synchronization device for automatically synchronizing the stimulation triggering with the fundus signal recording; or does not have a synchronization device and manually controls the stimulation triggering and the fundus signal recording.

[0024] The pre-stimulus phase L0 refers to the period before the stimulation starts.

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

[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 drugs thereof.

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

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

[0029] The computer or chip extracts the amplitude attenuation characteristics / conditions or time delay characteristics / conditions associated with the dopamine level from the retinal neurovascular coupling function index after the dopamine level in the body rises and determines whether there is a reversible situation, that is, reversibility, and then determines the accurate result of the substantia nigra dopaminergic nerve degeneration in the brain.

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

[0031] It also includes vessel diameter and vessel density in OCTA images;

[0032] 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.

[0033] The fundus blood vessels and blood flow parameter change information is the information of the above parameters.

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

[0035] The blood flow index B includes the absolute change value of the fundus blood vessels and blood flow parameters before and after the optical visual stimulation, and / or the relative change value of the fundus blood vessels and blood flow parameters before and after the optical visual stimulation; usually the change is the ratio or difference of the parameter value in the post-stimulation stage L1 to the parameter value in the pre-stimulation stage L0. And / or includes the peak amplitude, peak time (peak time refers to the moment corresponding to the peak amplitude), and the combination of peak amplitude and peak time of 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. The maximum value of the retinal neurovascular coupling function index R is the amplitude, and the time corresponding to the amplitude is the delay time.

[0037] To determine the risk of degeneration of the substantia nigra dopaminergic neurons in the brain, the control system works as follows:

[0038] 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 signal processing device calculates the retinal neurovascular coupling function index R0 in the natural state D0 according to 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 the computer or the software module inside the chip makes a judgment:

[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 is attenuated, it indicates that the amplitude attenuation feature / situation has occurred, and it is determined to be a high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is determined to be a 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, time delay, it indicates that a time delay feature / situation has occurred, and it is determined to be a high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is determined to be a low risk;

[0041] 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 indicates that the amplitude attenuation feature / situation and the time delay feature / situation have occurred simultaneously, and it is judged to be a high risk of substantia nigra dopaminergic nerve degeneration; otherwise, it is judged to be a low risk.

[0042] 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:

[0043] 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:

[0044] 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, that is, the amplitude attenuation is reversed, it indicates that the amplitude attenuation feature / situation has been reversed, and it is determined that substantia nigra dopaminergic neurodegeneration exists; otherwise, it does not exist;

[0045] 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, that is, the time delay is reversed, it indicates that the time delay feature / situation has been reversed, and it is determined that substantia nigra dopaminergic nerve degeneration exists; otherwise, it does not exist;

[0046] 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 indicates that the amplitude attenuation characteristics / conditions and the time delay characteristics / conditions have reversed at the same time, and it is determined that substantia nigra dopaminergic nerve degeneration exists; otherwise, it does not exist.

[0047] If the risk of substantia nigra dopaminergic neurodegeneration is determined to be low, the step of imposing specific conditions on the subject is not performed.

[0048] The peak amplitude threshold and the peak time threshold in the state of rising dopamine levels in the body may be the same as or different from the thresholds before the dopamine levels rise.

[0049] The various thresholds described above can be obtained by establishing a classification model through clinical data.

[0050] 2. A functional detection method for substantia nigra dopaminergic nerve degeneration through the eye:

[0051] The method includes an optical visual stimulation method, wherein the subject's eyes are subjected to optical visual stimulation before and after a specific condition occurs in which the subject's dopamine level in the body is increased, and a stimulation index S during the optical visual stimulation is recorded;

[0052] It includes a fundus blood flow detection method, specifically performing retinal blood vessel and blood flow detection, detecting the change information of fundus blood vessels and blood flow parameters before and after specific conditions in which the dopamine level in the subject is increased and before and after visual stimulation to generate a blood flow index B;

[0053] The invention comprises a quantitative method of the retinal hyperemia response function index R, which is obtained by comprehensively using the blood flow index B and the stimulation index S to obtain the retinal hyperemia response function index R containing dopamine-related information, including amplitude and delay time;

[0054] It includes a method for evaluating the degree of substantia nigra dopaminergic nerve degeneration, which evaluates the degree of substantia nigra dopaminergic nerve degeneration based on dopamine-related information contained in the retinal congestion response function index R, that is, determines the risk or result of substantia nigra dopaminergic nerve degeneration in the brain.

[0055] The optical visual stimulation method is performed in a visually perceptible manner such as a display or a lighting fixture to stimulate the retinal neural activity of the subject's fundus.

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

[0057] It also includes vessel diameter and vessel density in OCTA images;

[0058] 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.

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

[0060] The blood flow index B includes the absolute change value of the fundus blood vessels and blood flow parameters before and after the optical visual stimulation, and / or the relative change value of the fundus blood vessels and blood flow parameters before and after the optical visual stimulation; usually the change is the ratio or difference of the parameter value in the post-stimulation stage L1 to the parameter value in the pre-stimulation stage L0. And / or includes the peak amplitude, peak time (peak time refers to the moment corresponding to the peak amplitude), and the combination of peak amplitude and peak time of the fundus blood vessels and blood flow parameters before and after the 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. The maximum value of the retinal neurovascular coupling function index R is the amplitude, and the time corresponding to the amplitude is the delay time.

[0062] The method for evaluating the degree of degeneration of substantia nigra dopaminergic nerves is specifically as follows:

[0063] If the peak amplitude A0 in the retinal neurovascular coupling function index R0 before the subject's dopamine level rises in vivo 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 has occurred, and it is determined to be at high risk of substantia nigra dopaminergic nerve degeneration; otherwise, it is determined to be low risk; when it is determined to be at high risk of substantia nigra dopaminergic nerve degeneration, continue to judge according to the retinal neurovascular coupling function index R1 of the subject in the state D1 after the dopamine rise:

[0064] If the peak amplitude A1 in the retinal neurovascular coupling function index R1 of the subject in the dopamine rising state D1 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 the dopamine rising state D1 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 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 indicates that the amplitude attenuation feature / situation or the time delay feature / situation has reversed, and it is determined that substantia nigra dopaminergic nerve degeneration exists; otherwise, it does not exist.

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

[0066] Existing PET and SPECT detection systems based on brain neuroimaging use radiation as detection signals, which makes the detection potentially harmful to radiation. The present invention uses optical or acoustic signals to detect the retinal neurovascular coupling function index caused by substantia nigra dopaminergic nerve degeneration, which is radiation-free, safer, and suitable for large-scale screening and longitudinal monitoring.

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

[0068] Existing detection systems based on traditional OCTA use changes in retinal microvascular morphology caused by substantia nigra dopaminergic nerve degeneration as detection markers, but factors such as intraocular pressure can also cause changes in retinal microvasculature, resulting in poor detection specificity. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0070] Figure 2 A flowchart of an embodiment of the system working method of the present invention;

[0071] Figure 3 A schematic diagram of an embodiment of the device of the present invention;

[0072] Figure 4 The results are test results of retinal blood flow response of healthy mice and mice with substantia nigra dopaminergic neurodegeneration under flickering light stimulation in an exemplary embodiment of the present invention without drug administration;

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

[0074] Figure 6 In an exemplary embodiment of the present invention, the classification results of healthy mice and mice with substantia nigra dopaminergic neurodegeneration based on the peak amplitude of retinal blood flow induced by light stimulation before and after administration of levodopa are presented;

[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 coupler; 33- polarization controller; 34- reference arm collimator; 35- dispersion matching module; 36- reference arm focusing lens; 37- reference arm reflector; 38- sample arm collimator; 39- sample arm OCT scanning device; 40- sample arm dichroic mirror; 41- visible light stimulation light source; 42- sample arm double glue and 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 DESCRIPTION

[0077] The specific implementation of the present invention will be described in detail below in conjunction with the accompanying drawings, which form a part of this document. It should be noted that these descriptions and examples are only exemplary and cannot be understood as limiting the scope of the present invention. The scope of protection of the present invention is defined by the attached claims, and any changes based on the claims of the present invention are within the scope of protection of the present invention.

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

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

[0080] The use of i, t, etc. to represent variables is only used to facilitate discussion and is not intended to limit the application of the embodiments of the present invention. Any value such as 1, 2, 3, etc. may be used.

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

[0082] Step 1: Perform optical visual stimulation on the eyes of the subject before and after the subject experiences a specific condition in which the dopamine level in the body is increased, and simultaneously record the stimulation index S during the optical visual stimulation and send it to a signal processing device.

[0083] The specific implementation of the device system is as follows Figure 1 As shown, it is mainly composed of two parts 11-12 and 14-15: a light stimulation module 12 with an LED light is used as an optical visual device, the fundus blood flow detection device includes a detection signal generating module 11 and a detection signal acquisition module 14, the subject's eye is used as a sample 13, and a signal processing module 15 is used as a signal processing device for data processing.

[0084] The signal generation module 11 transmits the detection signal to the sample 13, the light stimulation module 12 generates stimulation light to activate the neuronal activity on the sample 13, and then 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] The light stimulation module 12 is used to generate flickering visible light to stimulate the retina of the eye of the sample 13. The wavelength is 380-760 nanometers, the stimulation time is 30 seconds, the illumination is 1000 lux, the frequency is 10Hz, the duty cycle is 50%, and the stimulation dose corresponds to the stimulation index S. The same dose of optical visual stimulation is performed on the eyes of the subjects before and after the specific conditions in which the dopamine level in the body of the subjects is increased. Step 2: Use drugs to increase the dopamine level in the body of the subjects. Under two different states, D0 before administration and D1 after administration, record the change information of the fundus blood vessels and blood flow parameters from the pre-stimulation stage L0 to the post-stimulation stage L1 to obtain the retinal neurovascular coupling function index of the current state; specifically:

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

[0087] Under the condition of D0 before drug administration without taking the drug, the optical visual device is used for stimulation, and the fundus blood flow detection device records the change information of fundus blood vessels and blood flow parameters from the pre-stimulation stage L0 to the post-stimulation stage L1 to obtain the retinal neurovascular coupling function index;

[0088] The subjects then take the drug to increase the dopamine content in their bodies. D1 after the drug administration, the optical vision device performs the same stimulation again, and the fundus blood flow detection device records the change information of the fundus blood vessels and blood flow parameters from the pre-stimulation stage L0 to the post-stimulation stage L1 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 clock signal control to achieve synchronization between the two processes of stimulus application and retinal neurovascular coupling function index recording, thereby achieving precise control of the recording time node.

[0090] The signal processing device may be embedded with a software module, which receives information on fundus blood vessels and blood flow parameter changes from a blood flow detection instrument and performs data processing to obtain a retinal neurovascular coupling function index, and then determines the risk of brain lesions or the results of substantia nigra dopaminergic nerve degeneration based on the retinal neurovascular coupling function index.

[0091] like Figure 2 As shown, to determine the risk 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 increases, the optical visual device performs optical visual stimulation on the subject, and the signal processing device calculates the retinal neurovascular coupling function index R0 without applying the natural state D0 to the subject 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 the computer or the software module inside the chip makes a judgment:

[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 is attenuated, it indicates that the amplitude attenuation feature / situation has occurred, and it is determined to be 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, time delay, it indicates that a time delay feature / situation has occurred, and it is determined to be a high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is determined to be a low risk;

[0095] Alternatively, 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 the amplitude attenuation feature / situation and the time delay feature / situation occur simultaneously, and it is judged as a high risk of substantia nigra dopaminergic nerve degeneration; otherwise, it is judged as a low risk.

[0096] As can be seen from the above, without stimulation, it is impossible to accurately determine whether substantia nigra dopaminergic nerve degeneration exists, but only the risk of substantia nigra dopaminergic nerve degeneration can be determined.

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

[0098] 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:

[0099] 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, that is, the amplitude attenuation is reversed, it indicates that the amplitude attenuation feature / situation has been reversed, and it is determined that substantia nigra dopaminergic neurodegeneration exists; otherwise, it does not exist;

[0100] 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, that is, the time delay is reversed, it indicates that the time delay feature / situation has been reversed, and it is determined that substantia nigra dopaminergic nerve degeneration exists; otherwise, it does not exist;

[0101] 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 indicates that the amplitude attenuation characteristics / conditions and the time delay characteristics / conditions have reversed at the same time, and it is determined that substantia nigra dopaminergic nerve degeneration exists; otherwise, it does not exist.

[0102] In a specific embodiment, an OCT device based on weak coherence interference is used to record the change information of fundus blood vessels and blood flow parameters before drug administration D0 and after drug administration D1, and a clock signal is used to accurately 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 non-stimulated recovery segment. 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 interference signal was Fourier transformed to obtain the retinal structure signal, and the first-order and zero-order autocovariance were used to calculate and analyze the signal to obtain the two features of inverse signal-to-noise ratio (I) and de-correlation coefficient (D). Then, the ID two-dimensional feature space was constructed, and the linear classifier was used to analyze and judge the dynamic blood flow signal to obtain the OCTA blood flow angiography image sequence of the retina in the two states of D0 before drug administration and D1 after drug administration, the stage before light stimulation L0 and the stage after light stimulation L1. The generated OCTA blood flow angiography image sequence was first binarized to eliminate the interference of noise, and then the binarized OCTA matrix was skeletonized to locate the intersection of the retinal microvascular skeleton and eliminate it, and each blood vessel was obtained as a single connected domain. The vascular skeleton fragment was numbered as i, and the blood flow Flow of each blood vessel at each time node was extracted. i (t j ).

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

[0105]

[0106] Where N represents the number of data collected in the baseline segment t0, t is the time dimension, and Flow i (t j ) represents the time point t j The blood flow rate of blood vessel i at this time.

[0107] Then the relative change of blood flow in the stimulation and recovery segments of the flickering light is calculated as the blood flow index B:

[0108]

[0109] Among them, blood flow index B i (t k ) is the time point t k The relative change in blood flow in vessel i at time .

[0110] Recombinant blood flow index B i (t k ) and stimulation index S obtained at time point t j The retinal neurovascular coupling function index R of vessel i i (t k ):

[0111]

[0112] The specific stimulation index S is a stimulation dose under the conditions of 380-760 nanometer band, 30 second stimulation time, 1000 lux illumination, 10 Hz frequency, and 50% duty cycle, but is not limited thereto.

[0113] The retinal neurovascular coupling function index of all blood vessels in the scanned visual field at the same sampling time point during the entire sampling process is averaged to serve as the neurovascular coupling function index R of the retina as a whole. The maximum value of the function index in the stimulation segment and the recovery segment is taken as the peak amplitude A, and the peak amplitude A is used as an indicator for determining the degeneration of dopaminergic nerves in the substantia nigra of the brain. In the natural state D0 before the dopamine level in the subject increases, 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 at high risk of dopaminergic nerve degeneration in the substantia nigra; otherwise, it is determined to be at low risk.

[0114] When it is determined that there is a high risk of substantia nigra dopaminergic nerve degeneration, the subject is allowed to take levodopa (250 mg) orally to increase the dopamine level in the body. In the subject's dopamine-elevated state D1, the following judgment is made: if the peak amplitude A1 in the retinal neurovascular coupling function index R1 in the dopamine-elevated 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.

[0115] According to different signal detection methods, Figure 1 The fundus blood flow detection device and other devices shown may specifically include:

[0116] 1) Optical coherence tomography device: Use low-coherence interference light to detect retinal signals, and use a spectrometer or balanced detector to receive the signals, thereby obtaining a depth-resolved OCT sample volume.

[0117] 2) Dynamic vascular analyzer: Use a fundus camera to directly record retinal signals, and use a CMOS or CCD sensor to receive the signals, thereby obtaining a planar image of the retinal surface.

[0118] 3) Laser Doppler blood flow meter: It uses monochromatic infrared laser to detect retinal signals and uses photodetectors to receive the returned light signals to obtain retinal blood flow information.

[0119] 4) Fundus fluorescein angiography instrument: It uses a specific wavelength to stimulate fundus fluorescence and uses a camera to detect the emitted fluorescence to obtain a retinal fluorescence sample.

[0120] 5) Ultrasonic imaging device: Use an ultrasonic transducer to send ultrasonic signals to the retina and receive ultrasonic signals returned from the retina, thereby obtaining a depth-resolved ultrasonic sampling volume.

[0121] For the above different measurement devices, retinal blood flow angiography can be generated by analyzing the signal difference between blood flow and surrounding tissue.

[0122] Figure 3 An exemplary embodiment utilizing the present invention disclosed herein is shown. 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 reflector 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 double glue and 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.

[0123] The broadband light source 31 is connected to one of the branches at one end of the 80:20 fiber coupler 32, and the other branch at one end of the 80:20 fiber coupler 32 is connected to the signal processing module 49 after passing through the detection module collimator 45, the grating 46, the focusing lens 47, and the linear array camera 48. One of the branches at the other end of the 80:20 fiber coupler 32 is connected to the reference arm, and the reference arm includes a polarization controller 33, a reference arm collimator 34, a dispersion matching module 35, a reference arm focusing lens 36 and a reference arm reflector 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, and the other end of the polarization controller 33 is connected to the incident end of the reference arm collimator 34, and the reference arm collimator 34 and the reference arm reflector 37 are connected in sequence. A dispersion matching module 35 and a reference arm focusing lens 36 are arranged in sequence, the dispersion matching module 35 is close to the reference arm collimator 34, and the reference arm focusing lens 36 is close to the reference arm reflector 37; one of the branches at the other end of the 80:20 fiber coupler 32 is connected to the sample arm, and the sample arm includes a sample arm collimator 38, a sample arm OCT scanning device 39, a sample arm dichroic mirror 40, a sample arm double-cemented lens 42, an eyepiece 43 and a sample eye 44 which are arranged in sequence; a sample arm OCT scanning device 39, a sample arm dichroic mirror 40, a sample arm double-cemented lens 42 and an eyepiece 43 are arranged between the sample arm collimator 38 and the sample eye 44, and the focus of the eyepiece 43 coincides with that of the sample arm double-cemented lens 42, so that parallel light is irradiated on the ocular surface of the sample eye 44 and converged on the retina through the eyeball. The stimulation light emitted by the visible light stimulation light source 41 is coupled into the sample arm detection light path through the sample arm dichroic mirror 40 , and is transmitted to the sample eye 44 after passing through the sample arm double cemented lens 42 and the eyepiece 43 .

[0124] In the system of this embodiment, the central wavelength of the broadband light source 31 is 850nm, and the bandwidth is 120nm. The OCT signal of the sample is collected in real time by a high-speed linear array camera 48, and transmitted to a signal processing module 49; the parallel light emitted by the sample arm collimator 38 is incident on the sample arm OCT scanning device 39, and the parallel light emitted by the sample arm OCT scanning device 39 is incident on the sample arm double-cemented lens 42 after passing through the sample arm dichroic mirror 40. The sample arm OCT scanning device 39 is composed of two planar scanning galvanometers, and the range of OCT signal collection 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 via optical fiber, and is divided into two light beams 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 is transmitted to the reference arm collimator 34, and after collimation, passes through the dispersion matching module 35 and the reference arm focusing lens 36, and converges on the reference arm reflector 37. Then the light beam 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 double-glued lens 42 and the eyepiece 43 to enter the sample eye 44. The light beam in the sample eye 44 is focused on the retina through the eye. The visible light stimulation light source 41 is white light with a wavelength band of 360-780nm. The stimulation light it emits is coupled into the sample arm detection light path through the sample arm dichroic mirror 40, and is transmitted to the sample eye 44 after passing through the sample arm double-glued lens 42 and the eyepiece 43 to achieve optic nerve stimulation. Subsequently, the detection 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 by the reference arm and the sample arm interferes in the 80:20 fiber coupler 32, and the generated interference light passes through the detection module collimator 45 and the grating 46 in turn, and then converges on the linear array camera 48 through the focusing lens 47 to realize signal detection and recording, and then is collected and further processed by the signal processing module 49.

[0125] The present invention can obtain the microvascular congestion response of the retina after visible light excitation. The width, frequency and amplitude of each pulse of the light stimulation pulse sequence are adjustable. In a specific embodiment, the width of each pulse is 100ms, the frequency is 10Hz, the amplitude is 3.0V, and the stimulation time is 30s, that is, 300 pulse sequences.

[0126] Figure 4 The results of the detection of retinal neurovascular coupling in healthy mice and mice with substantia nigra dopaminergic neurodegeneration are shown. Figure 4The ordinate of (A) is the relative change of capillary blood flow, the abscissa is the monitoring time node, and 0-30 s is the light stimulation time period. It can be found that compared with healthy mice (n = 13), the peak amplitude of retinal blood flow response in mice with substantia nigra dopaminergic neurodegeneration (n = 13) is significantly reduced. The statistical results are shown in Figure 4 (B) shown.

[0127] Figure 5 The graph shows the relative changes in retinal blood flow in healthy mice and mice with substantia nigra dopaminergic neurodegeneration under three conditions: before administration of L-dopa, after administration of L-dopa, and after drug metabolism. Figure 5 (A) and (B) show the relative changes in retinal capillary blood flow before and after light stimulation in mice with substantia nigra dopaminergic nerve degeneration (n=6) and healthy mice (n=7), respectively. 0-30s is the light stimulation time period. It can be found that after drug administration, the neurovascular coupling response of mice with substantia nigra dopaminergic nerve degeneration has been significantly improved, while the neurovascular coupling response of healthy mice has been inhibited. This phenomenon is Figure 5 This is more intuitively reflected in the comparison of the peak amplitude of the response in (C).

[0128] Figure 6 The results show the classification 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 the retinal neurovascular coupling function index after L-dopa administration can be combined with high accuracy and specificity to distinguish substantia nigra dopaminergic neurodegeneration.

[0129] The above experimental results fully demonstrate that the present invention can combine light stimulation with dopamine concentration regulation in vivo, and based on the retinal neurovascular coupling mechanism, perform highly sensitive, highly specific, and highly accurate non-invasive detection of retinal function damage caused by substantia nigra dopaminergic nerve degeneration.

[0130] Finally, it should be noted that the above embodiments and explanations are only used to illustrate the technical solution of the present invention rather than to limit it. Those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the spirit and scope disclosed in the technical solution of the present invention, which should be included in the scope of protection 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; It includes a computer or a chip, which receives the retinal neurovascular coupling function index R from the signal processing device, and determines the risk or result of dopaminergic nerve degeneration in the substantia nigra of the brain by analyzing the retinal neurovascular coupling function index R.

2. A functional detection system for substantia nigra dopaminergic nerve degeneration according to claim 1, characterized in that: The optical visual device emits light to the eyes of the subject in a visually perceptible manner such as a display or a lighting fixture, thereby stimulating the retinal neural 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: The retinal neurovascular coupling function index R is a combination of the blood flow index B and the stimulation index S, and is expressed as: R=B / S.

8. A functional detection system for substantia nigra dopaminergic nerve degeneration through the eye according to claim 1 or 4, characterized in that: 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.

9. A functional detection system for substantia nigra dopaminergic nerve degeneration through the eye according to claim 8, 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.

10. A method for detecting the functional degeneration of substantia nigra dopaminergic nerves through the eye applied to the system of claim 1, characterized in that: The method includes an optical visual stimulation method, wherein the subject's eyes are subjected to optical visual stimulation before and after a specific condition occurs in which the subject's dopamine level in the body is increased, and a stimulation index S during the optical visual stimulation is recorded; It includes a fundus blood flow detection method, which generates a blood flow index B by detecting information on changes in fundus blood vessels and blood flow parameters before and after specific conditions in which dopamine levels in the subject are elevated and before and after visual stimulation; The invention comprises a quantitative method of the retinal hyperemia response function index R, which is obtained by comprehensively using the blood flow index B and the stimulation index S to obtain the retinal hyperemia response function index R containing dopamine-related information, including amplitude and delay time; The invention comprises a method for evaluating the degree of degeneration of the substantia nigra dopaminergic nerves, and the degree of degeneration of the substantia nigra dopaminergic nerves is evaluated according to the dopamine-related information contained in the retinal congestion response function index R.

11. A method for detecting the functional degeneration of substantia nigra dopaminergic nerves through the eye according to claim 10, characterized in that: The optical visual stimulation method is performed in a visually perceptible manner such as a display or a lighting fixture to stimulate the retinal neural activity of the subject's fundus.

12. The method for detecting the functional degeneration of substantia nigra dopaminergic nerves through the eye according to claim 10, 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.

13. The method for detecting the functional degeneration of substantia nigra dopaminergic nerves through the eye according to claim 10, 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.

14. The method for detecting the functional degeneration of substantia nigra dopaminergic nerves through the eye according to claim 10, characterized in that: The retinal neurovascular coupling function index R is a combination of the blood flow index B and the stimulation index S, and is expressed as: R=B / S.

15. The method for detecting the functional degeneration of substantia nigra dopaminergic nerves through the eye according to claim 10, characterized in that: The method for evaluating the degree of degeneration of substantia nigra dopaminergic nerves is specifically as follows: If the peak amplitude A0 in the retinal neurovascular coupling function index R0 before the subject's dopamine level in vivo rises 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, then it is determined to be at high risk of substantia nigra dopaminergic nerve degeneration; otherwise, it is determined to be at low risk; when it is determined to be at high risk of substantia nigra dopaminergic nerve degeneration, continue to judge based on the retinal neurovascular coupling function index R1 of the subject in the state D1 after the dopamine rise: If the peak amplitude A1 in the retinal neurovascular coupling function index R1 of the subject in the dopamine rising state D1 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 the dopamine rising state D1 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 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, then it is determined that substantia nigra dopaminergic nerve degeneration exists; otherwise, it does not exist.

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