WO2025255968A1 - 一种经眼的黑质多巴胺能神经退变的功能检测系统和方法 - Google Patents

一种经眼的黑质多巴胺能神经退变的功能检测系统和方法

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WO2025255968A1
WO2025255968A1 PCT/CN2024/116488 CN2024116488W WO2025255968A1 WO 2025255968 A1 WO2025255968 A1 WO 2025255968A1 CN 2024116488 W CN2024116488 W CN 2024116488W WO 2025255968 A1 WO2025255968 A1 WO 2025255968A1
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blood flow
substantia nigra
index
stimulation
retinal
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French (fr)
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李鹏
刘开元
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Zhejiang University
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Zhejiang University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/50—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications
    • A61B6/501—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications for diagnosis of the head, e.g. neuroimaging or craniography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B3/00—Apparatus for testing the eyes; Instruments for examining the eyes
    • A61B3/10—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions
    • A61B3/12—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for looking at the eye fundus, e.g. ophthalmoscopes
    • A61B3/1225—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for looking at the eye fundus, e.g. ophthalmoscopes using coherent radiation
    • A61B3/1233—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for looking at the eye fundus, e.g. ophthalmoscopes using coherent radiation for measuring blood flow, e.g. at the retina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B3/00—Apparatus for testing the eyes; Instruments for examining the eyes
    • A61B3/10—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions
    • A61B3/12—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for looking at the eye fundus, e.g. ophthalmoscopes
    • A61B3/1241—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for looking at the eye fundus, e.g. ophthalmoscopes specially adapted for observation of ocular blood flow, e.g. by fluorescein angiography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/02—Arrangements for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
    • A61B6/03—Computed tomography [CT]
    • A61B6/037—Emission tomography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/50—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications
    • A61B6/504—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications for diagnosis of blood vessels, e.g. by angiography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/06—Measuring blood flow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/48—Diagnostic techniques
    • A61B8/488—Diagnostic techniques involving Doppler signals

Definitions

  • This invention relates to the field of brain information detection technology, specifically to a functional detection system and method for dopaminergic neurodegeneration in the substantia nigra of the eye.
  • dopaminergic neurodegeneration in the substantia nigra leads to decreased retinal thickness and reduced vascular density, it can currently be detected using optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA).
  • OCT optical coherence tomography
  • OCTA optical coherence tomography angiography
  • the purpose of this invention is to address the shortcomings of existing technologies by proposing a functional detection system and method for dopaminergic neurodegeneration in the substantia nigra of the eye.
  • This invention applies stimulation to the test subject to activate retinal nerve activity, uses the eye as a detection window to collect and record data, and thus can quickly, non-invasively, with high sensitivity and high specificity, detect dopaminergic neurodegeneration in the substantia nigra of the brain.
  • the system includes an optical vision device for stimulating the eyes of the subject before and after a specific condition in which the subject’s dopamine level increases, while recording the stimulation index S during the optical vision stimulation and sending it to a signal processing device.
  • fundus blood flow detection equipment which is a retinal blood vessel and blood flow detection device, used to detect and record changes in fundus blood vessel and blood flow parameters of subjects before and after specific conditions of increased dopamine levels in the body and before and after visual stimulation, to generate blood flow index B and send it to signal processing equipment;
  • the specific conditions include temporarily increasing the body's dopamine levels, which can be achieved by taking dopamine-related drugs, which are drugs that regulate the dopamine content in the subject's body.
  • the optical vision device applies specific light to the subject's eyes in a visually perceptible manner, such as through a display or lamp, thereby stimulating retinal nerve activity.
  • the application of visual light stimulation activates retinal nerve activity, inducing a hyperemia response, which in turn allows for the detection of the retinal neurovascular coupling function index.
  • the optical vision device may use an LED to illuminate the subject's eyes once every few seconds to several hundred seconds, but is not specifically limited to this.
  • the optical visual stimulation pattern includes flashing light stimulation or pattern stimulation
  • 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 illuminance of the flashing light are adjustable;
  • the pattern includes a checkerboard pattern or a sine wave pattern; the contrast and reversal frequency of the checkerboard pattern are adjustable; the contrast and spatial frequency of the sine wave pattern are adjustable.
  • the light-emitting device includes an LED, a laser, or a computer screen.
  • This invention is based on the changes in blood vessels and blood flow signals when retinal neural activity changes (retinal neurovascular coupling function index), which reflects the degeneration of dopaminergic neurons in the substantia nigra of the brain.
  • optical visual stimuli provided by the optical vision device before and after the subject experiences a rise in dopamine levels can be the same or different. Preferably, they are the same.
  • the fundus blood flow detection device records data in real time from the pre-stimulation stage L0 to the start of stimulation in two scenarios: before and after a specific condition in which the subject's dopamine level rises.
  • the blood flow index B is generated by recording changes in fundus blood vessels and blood flow parameters at at least one moment in each of the post-stimulation phase L1.
  • the recording involves multiple sampling records of the entire process of the pre-stimulation phase L0 and the post-stimulation phase L1, or discrete sampling of information data at several intervals within a time interval throughout the entire process.
  • the fundus blood flow detection device includes an optical coherence tomography (OCT) system, or a dynamic vascular analyzer, or a laser Doppler flowmeter, or a fluorescence angiography system, or an ultrasound detector.
  • OCT optical coherence tomography
  • a dynamic vascular analyzer or a laser Doppler flowmeter, or a fluorescence angiography system, or an ultrasound detector.
  • the fundus blood flow detection device has a synchronization device for automatically synchronizing stimulation triggering with fundus signal recording; or it does not have a synchronization device and the stimulation triggering and fundus signal recording are manually controlled.
  • the pre-stimulus phase L0 refers to the period before the stimulus begins.
  • the post-stimulation phase L1 mainly consists of a stimulation segment containing only the complete stimulus after the stimulus initiation time, or it consists of a stimulation segment containing only the complete stimulus after the stimulus initiation time and a recovery segment without stimulation after the stimulus.
  • the drug is typically a drug that increases the level of dopamine in the body, and may further include dopamine precursors (such as levodopa), or dopamine compounds (such as dopamine hydrochloride), or tyrosine hydroxylase inhibitors (such as carbidopa), or dopamine reuptake inhibitors (such as theophylline), or a combination of several of the above drugs.
  • dopamine precursors such as levodopa
  • dopamine compounds such as dopamine hydrochloride
  • tyrosine hydroxylase inhibitors such as carbidopa
  • dopamine reuptake inhibitors such as theophylline
  • the signal processing device has an embedded software module. After receiving the blood flow index B and the stimulation index S, the software module processes the data to obtain the retinal neurovascular coupling function index R, which is then sent to a computer/chip. Based on the retinal neurovascular coupling function index R, the risk of brain lesions or the result of dopaminergic neurodegeneration in the substantia nigra is determined.
  • the computer or chip determines the risk of dopaminergic neurodegeneration in the substantia nigra of the brain based on amplitude attenuation characteristics/conditions or time delay characteristics/conditions extracted from the retinal neurovascular coupling function index and correlated with dopamine levels.
  • the computer or chip determines the reversibility of dopaminergic neurodegeneration in the substantia nigra by analyzing the amplitude decay characteristics/conditions or time delay characteristics/conditions extracted from the retinal neurovascular coupling function index and associated with dopamine levels after an increase in dopamine levels in the body.
  • the fundus vascular and blood flow parameters include vascular size, blood flow velocity, and blood flow volume;
  • the information on changes in fundus blood vessels and blood flow parameters refers to the information of the aforementioned parameters.
  • the stimulation index S specifically refers to the dose of optical visual stimulation.
  • the blood flow index B includes the absolute changes in the fundus blood vessels and blood flow parameters before and after optical visual stimulation, and/or the relative changes in the fundus blood vessels and blood flow parameters before and after optical visual stimulation; typically, the changes are the ratio or difference between the parameter values in the post-stimulation stage L1 and the parameter values in the pre-stimulation stage L0. And/or it includes the peak amplitude, peak time (peak time refers to the moment corresponding to the peak amplitude), and a combination of the peak amplitude and peak time of the changes in the fundus blood vessels and blood flow parameters before and after optical visual stimulation.
  • 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.
  • control system To determine the risk of dopaminergic neurodegeneration in the substantia nigra of the brain, the control system operates as follows:
  • optical visual stimulation is applied to the subjects using optical vision devices.
  • the signal processing device calculates the retinal neurovascular coupling function index R0 under 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. The judgment is then made by the software module inside the computer or chip.
  • 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, i.e. amplitude decay, it indicates that amplitude decay characteristics/conditions have occurred, and is judged as a high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is judged as a low risk.
  • 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, i.e. time delay, it indicates that a time delay feature/condition has occurred, and is judged as a high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is judged as a low risk.
  • TT1 preset first peak time threshold
  • 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
  • the peak time T0 is greater than or equal to the preset first peak time threshold TT1
  • control system To determine whether there is substantia nigra dopaminergic neurodegeneration in the brain, the control system continues to operate as follows when it determines a high risk of substantia nigra dopaminergic neurodegeneration:
  • the subjects are subjected to another optical visual stimulation by an optical vision device.
  • the signal processing device calculates the retinal neurovascular coupling function index R1 in 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.
  • a computer or chip makes the judgment.
  • the peak amplitude A1 in the retinal neurovascular coupling function index R1 under state D1 after dopamine rise 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/condition has been reversed, and it is determined that there is substantia nigra dopaminergic neurodegeneration; otherwise, it does not exist.
  • the peak time T1 in the retinal neurovascular coupling function index R1 under state D1 after dopamine rise is less than or equal to the preset second peak time threshold TT2, i.e. the time delay is reversed, it indicates that the time delay feature/condition has been reversed, and it is determined that there is substantia nigra dopaminergic neurodegeneration; otherwise, it does not exist.
  • the peak amplitude A1 in the retinal neurovascular coupling function index R1 under state D1 after dopamine rise 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/condition and the time delay feature/condition have been reversed simultaneously, and it is determined that there is substantia nigra dopaminergic neurodegeneration; otherwise, it does not exist.
  • the step of applying specific conditions to the subject is not required.
  • the peak amplitude threshold and peak time threshold during the dopamine rise state in the body can be the same as or different from the threshold before the dopamine rise state.
  • Each of the aforementioned thresholds can be obtained by establishing a classification model using clinical data.
  • optical visual stimulation methods which involve performing optical visual stimulation on the eyes of subjects before and after a specific condition in which the body's dopamine levels increase, while simultaneously recording the stimulation index S during optical visual stimulation.
  • the quantitative method for the retinal congestion response function index R is obtained by comprehensively considering the blood flow index B and the stimulation index S to obtain the retinal congestion response function index R containing dopamine-related information, including amplitude and delay time.
  • the optical visual stimulation method is performed through a visually perceptible means such as a display or a lamp to stimulate the retinal nerve activity of the subject.
  • the fundus vascular and blood flow parameters include vascular size, blood flow velocity, and blood flow volume;
  • the stimulation index S specifically refers to the dose of optical visual stimulation.
  • the blood flow index B includes the absolute changes in the fundus blood vessels and blood flow parameters before and after optical visual stimulation, and/or the relative changes in the fundus blood vessels and blood flow parameters before and after optical visual stimulation; typically, the changes are the ratio or difference between the parameter values in the post-stimulation stage L1 and the parameter values in the pre-stimulation stage L0. And/or it includes the peak amplitude, peak time (peak time refers to the moment corresponding to the peak amplitude), and a combination of the peak amplitude and peak time of the changes in the fundus blood vessels and blood flow parameters before and after optical visual stimulation.
  • 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.
  • the specific method for assessing the degree of dopaminergic neurodegeneration in the substantia nigra is as follows:
  • the peak amplitude A0 in the retinal neurovascular coupling function index R0 before the rise in dopamine levels 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, then it indicates that an amplitude attenuation characteristic/time delay characteristic has occurred, and it is judged as a high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is judged as a low risk; when a high risk of substantia nigra dopaminergic neurodegeneration is judged, the retinal neurovascular coupling function index R1 under the subject's dopamine rise state D1 is further judged:
  • the peak amplitude A1 of the retinal neurovascular coupling function index R1 in the dopamine-promoted state D1 of the subject is greater than or equal to the preset second peak amplitude threshold TA2, or the peak time T1 of the retinal neurovascular coupling function index R1 in the dopamine-promoted state D1 is less than or equal to the preset second peak time threshold TT2, or if the peak amplitude A1 of the retinal neurovascular coupling function index R1 in the dopamine-promoted 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 indicates that the amplitude attenuation feature/condition or the time delay feature/condition has been reversed, and it is determined that there is substantia nigra dopaminergic neurodegeneration; otherwise, it does not exist.
  • PET and SPECT detection systems based on brain neuroimaging use X-rays as detection signals, posing a potential radiation hazard.
  • This invention utilizes optical or acoustic signals to detect the retinal neurovascular coupling function index caused by dopaminergic neurodegeneration in the substantia nigra. It is radiation-free, safer, and suitable for large-scale screening and longitudinal monitoring.
  • Figure 1 is a schematic diagram of the device of the present invention
  • FIG. 2 is a flowchart of an embodiment of the system working method of the present invention
  • Figure 3 is a schematic diagram of an embodiment of the device of the present invention.
  • Figure 4 shows the detection results of retinal blood flow response in healthy and substantia nigra dopaminergic neurodegenerative mice under scintillation stimulation in an untreated state, in an exemplary embodiment of the present invention.
  • Figure 5 shows the changes in relative retinal blood flow induced by scintillation stimulation in healthy and substantia nigra dopaminergic degeneration mice under three states: before administration of levodopa, after administration of levodopa, and after levodopa metabolism.
  • the sample measurement space is represented by three-dimensional x-y-z coordinates based on spatial orientation.
  • the depth z-direction is along the incident optical axis
  • the x-y plane is a plane perpendicular to the optical axis, where x and y are orthogonal, and x represents the OCT lateral fast scan direction, and y represents the slow scan direction.
  • Step 1 Before and after the subject experiences an increase in dopamine levels, optical visual stimulation is applied to the subject's eyes.
  • the stimulation index S during the optical visual stimulation is recorded and sent to the signal processing device.
  • the specific implementation device system is shown in Figure 1, which mainly consists of two parts: 11-12 and 14-15.
  • the light stimulation module 12 with LED light is used as an optical vision device
  • the fundus blood flow detection device includes a detection signal generation module 11 and a detection signal acquisition module 14, the eye of the test subject is used as a sample 13, and the signal processing module 15 is used as a signal processing device for data processing.
  • the signal generation module 11 transmits the detection signal to the sample 13, and the photostimulation 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.
  • the retina of sample 13 is stimulated with flickering visible light generated by the light stimulation module 12.
  • the wavelength range is 380-760 nm
  • the stimulation time is 30 s
  • the illuminance is 1000 lux
  • the frequency is 10 Hz
  • the duty cycle is 50%.
  • the stimulation dose corresponds to the stimulation index S.
  • the same dose of optical visual stimulation is applied to the eyes of the test subjects before and after a specific condition in which the dopamine level in the body increases.
  • Step 2 The dopamine level in the test subjects is increased by using drugs.
  • the retinal neurovascular coupling function index is obtained by stimulating the retinal blood vessels and blood flow parameters from the pre-stimulation stage (L0) to the post-stimulation stage (L1) using the fundus blood flow detection device.
  • the subjects then take the drug, which increases the dopamine level in their bodies.
  • the same stimulation is performed again by an optical vision device.
  • the fundus blood flow detection device records the changes in fundus blood vessels and blood flow parameters from the pre-stimulation stage L0 to the post-stimulation stage L1, thereby obtaining the retinal neurovascular coupling function index.
  • the fundus blood flow detection device records the retinal neurovascular coupling function index.
  • Clock signal control is used to synchronize the two processes of stimulus application and retinal neurovascular coupling function index recording, enabling precise control of the recording time points.
  • the signal processing device can be embedded with a software module. After receiving information on 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. Then, based on the retinal neurovascular coupling function index, the risk of brain lesions or the result of dopaminergic neurodegeneration in the substantia nigra can be judged.
  • control system operates as follows:
  • optical visual stimulation is applied to the subject using an optical vision device.
  • the signal processing device calculates the retinal neurovascular coupling function index R0 (before and after optical visual stimulation) 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 result is then determined by the software module within the computer or chip.
  • 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, i.e. amplitude decay, it indicates that amplitude decay characteristics/conditions have occurred, and is judged as a high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is judged as a low risk.
  • 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, i.e. time delay, it indicates that a time delay feature/condition has occurred, and is judged as a high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is judged as a low risk.
  • TT1 preset first peak time threshold
  • the peak amplitude A0 in the retinal neurovascular coupling function index R0 is less than the preset first peak amplitude threshold TA1
  • the peak time T0 is greater than or equal to the preset first peak time threshold TT1
  • control system continues to operate as follows when it determines a high risk of substantia nigra dopaminergic neurodegeneration:
  • the subjects are subjected to another optical visual stimulation by an optical vision device.
  • the signal processing device calculates the retinal neurovascular coupling function index R1 in 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.
  • a computer or chip makes the judgment.
  • the peak amplitude of the retinal neurovascular coupling function index R1 in state D1 after dopamine rise is... If A1 is greater than or equal to the preset second peak amplitude threshold TA2, meaning the amplitude decay is reversed, it indicates that the amplitude decay characteristic/condition has been reversed, and it is determined that there is substantia nigra dopaminergic neurodegeneration; otherwise, it does not exist.
  • the peak time T1 in the retinal neurovascular coupling function index R1 under state D1 after dopamine rise is less than or equal to the preset second peak time threshold TT2, i.e. the time delay is reversed, it indicates that the time delay feature/condition has been reversed, and it is determined that there is substantia nigra dopaminergic neurodegeneration; otherwise, it does not exist.
  • the peak amplitude A1 in the retinal neurovascular coupling function index R1 under state D1 after dopamine rise 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/condition and the time delay feature/condition have been reversed simultaneously, and it is determined that there is substantia nigra dopaminergic neurodegeneration; otherwise, it does not exist.
  • a weakly coherent interferometry (OCT) device is used to record changes in fundus vascular and blood flow parameters before drug administration (D0) and after drug administration (D1).
  • a clock signal is used to precisely synchronize the two processes of stimulation application and fundus parameter recording.
  • the post-stimulation stage L1 includes a flickering stimulation segment and a non-stimulated recovery segment.
  • OCT is used to scan the entire process of the pre-stimulation stage L0 and the stimulation stage L1 to obtain retinal interference signals at different time points.
  • the retinal structure signal was obtained.
  • the first-order and zero-order autocovariances were used to calculate and analyze this signal, yielding two features: inverse signal-to-noise ratio (I) and decorrelation coefficient (D).
  • I inverse signal-to-noise ratio
  • D decorrelation coefficient
  • ID two-dimensional feature space
  • OCTA blood flow angiography image sequences of the retina were obtained in two states: before drug administration (D0) and after drug administration (D1), specifically in the pre-stimulation stage (L0) and post-stimulation stage (L1).
  • the generated OCTA blood flow angiography image sequences were first binarized to remove noise interference.
  • the binarized OCTA matrix was skeletonized, and the intersections of the retinal microvascular skeleton were located and removed, obtaining vascular skeleton segments where each vessel is a single connected domain. These segments were numbered i, and the blood flow rate Flow i (t j ) of each vessel at each time point was extracted.
  • the blood flow rate of each blood vessel at each time point t0 before light stimulation is averaged to obtain the baseline blood flow rate Flow_base i for blood vessel i before the congestion response.
  • N represents the number of data points collected within the baseline segment t0
  • t is the time dimension
  • Flow i (t j ) represents the blood flow rate of blood vessel i at time point t j .
  • the blood flow index Bi ( tk ) is the relative change in blood flow in vessel i at time point tk .
  • the retinal neurovascular coupling function index Ri ( tk ) of vessel i at time point tj is obtained:
  • the stimulation index S is the stimulation dose under the conditions of 380-760 nanometer wavelength, 30s stimulation time, 1000 lux illuminance, 10Hz frequency, and 50% duty cycle, but is not limited to these.
  • the retinal neurovascular coupling function index of all blood vessels within the scanned field of view at the same sampling time point throughout the entire sampling process is averaged and used as the overall retinal neurovascular coupling function index R.
  • the maximum value of this function index in the stimulation and recovery phases is taken as the peak amplitude A, which is used as an indicator to determine dopaminergic neurodegeneration in the substantia nigra of the brain.
  • the peak amplitude A0 of the retinal neurovascular coupling function index R0 is less than or equal to the preset first peak amplitude threshold TA1, it is judged as a high risk of substantia nigra dopaminergic neurodegeneration; otherwise, it is judged as a low risk.
  • the subject When a high risk of substantia nigra dopaminergic neurodegeneration is identified, the subject is given oral levodopa (250 mg) to increase dopamine levels.
  • oral levodopa 250 mg
  • the peak amplitude A1 in the retinal neurovascular coupling function index R1 in state D1 after the dopamine rises is greater than or equal to the preset second peak amplitude threshold TA2, then substantia nigra dopaminergic neurodegeneration is identified; otherwise, it is not identified.
  • the fundus blood flow detection equipment and other devices shown in Figure 1 can specifically include:
  • OCT Optical coherence tomography
  • This instrument uses a fundus camera to directly record retinal signals and a CMOS or CCD sensor to receive the signals, thereby obtaining a planar image of the retinal surface.
  • This device uses a monochromatic infrared laser to detect retinal signals and a photodetector to receive the returned light signals, thereby obtaining retinal blood flow information.
  • Fundus fluorescein angiography instrument uses a specific wavelength to excite the fluorescence in the fundus, and uses a camera to detect the emitted fluorescence, thereby obtaining a retinal fluorescence sample.
  • Ultrasonic imaging device uses an ultrasonic transducer to send ultrasonic signals to the retina and receive the ultrasonic signals returning from the retina, thereby obtaining a depth-resolved ultrasonic sample.
  • All of the above-mentioned measuring devices can generate signals by analyzing the signal differences between blood flow and surrounding tissues. Retinal blood flow angiography.
  • FIG. 3 illustrates an exemplary embodiment of the 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 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 gel 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.
  • a broadband light source 31 is connected to one branch of an 80:20 fiber optic coupler 32.
  • the other branch of the 80:20 fiber optic coupler 32 is connected to a signal processing module 49 via a collimating lens 45, a grating 46, a focusing lens 47, and a linear array camera 48.
  • One branch of the other end of the 80:20 fiber optic coupler 32 is connected to a reference arm, which includes a polarization controller 33, a reference arm collimating lens 34, a dispersion matching module 35, a reference arm focusing lens 36, and a reference arm reflector 37 arranged sequentially.
  • Another branch of the other end of the 80:20 fiber optic 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 collimating lens 34.
  • the reference arm collimating lens 34 and the reference arm reflector 37 are connected in a specific configuration.
  • the sample arm is equipped with a dispersion matching module 35 and a reference arm focusing lens 36.
  • the dispersion matching module 35 is close to the reference arm collimating lens 34, and the reference arm focusing lens 36 is close to the reference arm reflecting mirror 37.
  • One branch of the other end of the 80:20 fiber coupler 32 is connected to the sample arm.
  • the sample arm includes a sample arm collimating lens 38, a sample arm OCT scanning device 39, a sample arm dichroic mirror 40, a sample arm cemented 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 cemented doublet lens 42, and the eyepiece 43 are arranged in sequence between the sample arm collimating lens 38 and the sample eye 44.
  • the eyepiece 43 and the sample arm cemented doublet lens 42 have the same focal point, so that parallel light is irradiated onto the ocular surface of the sample eye 44 and converged onto the retina through the eyeball.
  • the stimulation light emitted by the visible light stimulation source 41 is coupled into the sample arm detection light path through the sample arm dichroic mirror 40, and then transmitted to the sample eye 44 after passing through the sample arm double cemented lens 42 and the eyepiece 43.
  • the broadband light source 31 has a center wavelength of 850 nm and a bandwidth of 120 nm.
  • a high-speed linear array camera 48 acquires the OCT signal of the sample in real time and transmits it to the signal processing module 49.
  • Parallel light emitted from the sample arm collimating lens 38 is incident on the sample arm OCT scanning device 39.
  • the parallel light emitted from the sample arm OCT scanning device 39 passes through the sample arm dichroic mirror 40 and then enters the sample arm doublet lens 42.
  • the sample arm OCT scanning device 39 consists of two planar scanning mirrors, and the range of OCT signal acquisition is controlled by adjusting the relative position of the two planar scanning mirrors.
  • the probe light emitted by the broadband light source 31 used in this invention is transmitted via optical fiber to an 80:20 fiber coupler 32 and split into two beams, which enter the reference arm and the sample arm respectively.
  • 80% of the probe light enters the reference arm, passes through the polarization controller 33, and is transmitted to the reference arm collimating lens 34. After collimation, it passes through the dispersion matching module 35 and the reference arm focusing lens 36, and then converges onto the reference arm reflecting mirror 37. Subsequently, the beam returns along its original path to the 80:20 reference arm.
  • 20% of the probe light enters the sample arm, passes through the sample arm collimating lens 38 and scanning galvanometer 39, and then sequentially passes through the sample arm dichroic mirror 40, the sample arm doublet lens 42, and the eyepiece 43 before entering the sample eye 44.
  • the beam in the sample eye 44 is focused onto the retina.
  • the visible light stimulation source 41 emits white light with a wavelength of 360-780nm. The stimulation light emitted by it is coupled into the sample arm probe light path through the sample arm dichroic mirror 40, and then transmitted to the sample eye 44 after passing through the sample arm doublet lens 42 and the eyepiece 43, thereby stimulating the optic nerve.
  • 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 returning from the reference arm and the sample arm interferes in the 80:20 fiber coupler 32, and the resulting interference light passes through the collimating lens 45 and the grating 46 of the detection module in sequence, and then converges on the linear array camera 48 through the focusing lens 47 to realize the detection and recording of the signal, which is then acquired and further processed by the signal processing module 49.
  • each pulse width is 100 ms
  • the frequency is 10 Hz
  • the amplitude is 3.0 V
  • the stimulation time is 30 s, i.e., 300 pulse sequences.
  • Figure 4 shows the detection results of retinal neurovascular coupling in healthy and substantia nigra dopaminergic neurodegenerative mice.
  • the vertical axis represents the relative change in capillary blood flow
  • Figure 5 illustrates the relative changes in retinal blood flow in healthy and substantia nigra dopaminergic neurodegenerative mice before, after, and after drug metabolism.
  • Figure 6 shows the classification results of healthy and substantia nigra dopaminergic neurodegenerative mice based on the peak amplitude of photostimulation-induced retinal blood flow before and after drug administration. It can be found that combining the retinal neurovascular coupling function index after levodopa administration can distinguish substantia nigra dopaminergic neurodegenerative diseases with high accuracy and specificity.

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Abstract

本发明公开了一种经眼的黑质多巴胺能神经退变的功能检测系统和方法。光学视觉设备在受试对象发生体内多巴胺水平提升的特定条件前、后对受试对象的眼部进行刺激，同时记录刺激指数；眼底血流探测设备，检测记录受试对象在体内多巴胺水平提升前后以及视觉刺激前后的眼底血管和血流参数变化信息而生成血流指数；信号处理设备接收血流指数和刺激指数进处理获得视网膜神经血管耦合功能指数；计算机或芯片接收视网膜神经血管耦合功能指数判定脑部的黑质多巴胺能神经退变的风险或者结果。本发明将眼睛作为检测窗口，可以快速、非侵入地对脑部黑质多巴胺能神经退变进行探测，具有高敏感性和特异性。

Description

一种经眼的黑质多巴胺能神经退变的功能检测系统和方法 技术领域
本发明涉及脑部信息检测技术领域，具体涉及一种经眼的黑质多巴胺能神经退变的功能检测系统和方法。
背景技术
大脑黑质区域的多巴胺能神经元的损伤会导致人体出现运动症状，严重影响生活质量。因此，迫切需要一种可靠的系统工作方法，能够对黑质多巴胺能神经退变实现早期检测。已有的基于脑神经成像的正电子发射计算机断层扫描(PET)和单光子发射型计算机断层扫描仪(SPECT)可以特异性地探测脑部黑质多巴胺能神经退变，但是同位素示踪剂的使用使其具有潜在的辐射危害，并且较长的检测时间与较高的检测费用限制了其进一步应用。视网膜是大脑的外延，对视网膜的检测可以反应脑部黑质多巴胺能神经退变。由于黑质多巴胺能神经退变会导致视网膜厚度下降与血管密度降低，目前可以利用光学相干层析成像(OCT)和光学相干层析血流造影(OCTA)对其进行检测。然而这些基于视网膜结构生物标志物的多巴胺能神经退变检测方法的敏感性和特异性十分有限。
因此，如何利用视网膜这一独特的窗口，高灵敏并且特异性地检测大脑黑质区域的多巴胺能神经元损伤具有至关重要的意义。
发明内容
本发明的目的是针对现有技术的不足，提出了一种经眼的黑质多巴胺能神经退变的功能检测系统和方法。
本发明对受试对象施加刺激，用于激活视网膜神经活动，将眼睛作为检测窗口采集记录数据，并以此可以快速、非侵入、高灵敏性、高特异性地对脑部黑质多巴胺能神经退变进行检测。
本发明的目的是通过下述技术方案实现的：
一、一种经眼的黑质多巴胺能神经退变的功能检测系统：
系统包括光学视觉设备，用于在受试对象发生体内多巴胺水平提升的特定条件前、后对受试对象的眼部进行光学视觉刺激，同时记录光学视觉刺激时的刺激指数S并发送到信号处理设备；
包括眼底血流探测设备，是一种视网膜血管与血流检测设备，用于检测记录受试对象在体内多巴胺水平提升的特定条件前、后以及视觉刺激前、后的眼底血管和血流参数变化信息而生成血流指数B并发送到信号处理设备；
包括信号处理设备，接收来自眼底血流探测设备的血流指数B和来自光学视觉设备的刺激指数S进而分析处理获得含有多巴胺关联信息的视网膜神经血管耦合功能指数R；
包括计算机或芯片，接收来自信号处理设备的视网膜神经血管耦合功能指数R，通过分析视网膜神经血管耦合功能指数R从而判定脑部的黑质多巴胺能神经退变的风险或者结果。
要获得黑质多巴胺能神经退变的大致风险，只需施加刺激而无需特定条件，这能实现黑质多巴胺能神经退变的大致功能检测。但要获得黑质多巴胺能神经退变的准确结果，只能将施加特定条件和施加刺激进行结合使用，才能实现黑质多巴胺能神经退变的准确功能检测。
所述特定条件包括暂时性调升体内多巴胺水平，所述体内多巴胺水平提升可以通过服用多巴胺相关药物实现，多巴胺相关药物为调节受试对象体内多巴胺含量的药物。
所述光学视觉设备是通过显示器或照明灯等可以被视觉感知的方式在发出特定光施加到受试对象的眼部进而激发受试对象的眼底视网膜神经活动。通过视觉光刺激的施加，激活视网膜神经活动，会诱导充血响应，进而检测获得视网膜神经血管耦合功能指数。例如，所述光学视觉设备可以用LED等几秒到几百秒对受试对象眼部光照一次，但具体并不限于此。
更具体地，所述光学视觉刺激模式包括闪烁光刺激、或图案刺激；
进一步的，所述闪烁光的颜色包括单色可见光或复色可见光，进一步包括绿光或白光；所述闪烁光的频率、占空比、光照度可调；
进一步的，所述图案包括棋盘格或正弦图案；所述棋盘格的对比度、反转频率可调；所述正弦图案的对比度、空间频率可调；
所述发光器件包括LED、或激光器、或计算机屏幕。
本发明是基于视网膜上神经活动改变时血管、血流信号的变化信息(视网膜神经血管耦合功能指数)进而反映检测脑部的黑质多巴胺能神经退变情况。
所述光学视觉设备对受试对象发生体内多巴胺水平上升的特定条件前、后的光学视觉刺激是可以相同的，也可以是不同的。优选情况是相同的。
所述眼底血流探测设备在对受试对象发生体内多巴胺水平上升的特定条件前、后的两个情况下均实时记录采集从刺激开始前的刺激前阶段L0到刺激开始 后的刺激后阶段L1各自中的至少一个时刻的眼底血管和血流参数变化信息进而生成血流指数B。通常情况下，所述记录为多次采样记录刺激前阶段L0和刺激后阶段L1的全部过程，或者离散采样全部过程中间隔时间段的多次时刻的若干个间隔的信息数据。
更具体地，所述眼底血流探测设备包括光学相干层析成像仪、或动态血管分析仪、或激光多普勒血流仪、或荧光血管造影仪、或超声检测仪；
所述眼底血流探测设备具有同步装置，用于将刺激触发与眼底信号记录自动同步；或者不具有同步装置，手动控制刺激触发与眼底信号记录。
刺激前阶段L0是指刺激开始时刻前的时段。
所述刺激后阶段L1主要由刺激开始时刻之后的、仅包含完整刺激的刺激段组成，或者由刺激开始时刻之后的、仅包含完整刺激的刺激段与刺激之后无刺激的恢复段共同组成。
所述药物通常为提高体内多巴胺含量的药物，进一步包括多巴胺前体(如左旋多巴)、或多巴胺化合物(如多巴胺盐酸盐)、或酪氨酸羟化酶抑制剂(如卡比多巴)、或多巴胺再摄取抑制剂(如茶碱)、或上述其中多种药物的联合使用。
所述信号处理设备，内嵌有软件模块，所述的软件模块接收血流指数B和刺激指数S后进行数据处理获得视网膜神经血管耦合功能指数R，进而发送到计算机/芯片再根据视网膜神经血管耦合功能指数R判断脑部的病变风险或黑质多巴胺能神经退变结果。
所述计算机或芯片根据从视网膜神经血管耦合功能指数提取和多巴胺水平关联的幅度衰减特征/情况或时间延迟特征/情况，进而判定脑部的黑质多巴胺能神经退变风险高低；
所述计算机或芯片根据体内多巴胺水平上升后的从视网膜神经血管耦合功能指数提取和多巴胺水平关联的幅度衰减特征/情况或时间延迟特征/情况的是否有可逆转情况，即可逆转性，进而判定脑部的黑质多巴胺能神经退变准确结果。
所述眼底血管和血流参数包括血管尺寸、血流流速和血流流量；
还包括OCTA图像中的血管直径和血管密度；
还包括OCTA信号中的血流区域去相关系数的均值、血流区域去相关系数的总和。
所述眼底血管和血流参数变化信息即为上述参数的信息。
所述刺激指数S具体是指光学视觉刺激的剂量；
所述的血流指数B包含所述眼底血管和血流参数在光学视觉刺激前、后的绝对变化值，和/或所述眼底血管和血流参数在光学视觉刺激前、后的相对变化值；通常所述的变化均是刺激后阶段L1的参数值相比刺激前阶段L0的参数值的比值或者差值。和/或包含所述眼底血管和血流参数在光学视觉刺激前、后变化的峰值幅度、峰值时间(峰值时间是指峰值幅度对应的时刻)、峰值幅度和峰值时间的综合。
所述视网膜神经血管耦合功能指数R是综合了血流指数B和刺激指数S，表示为：R＝B/S。其中，视网膜神经血管耦合功能指数R的最大值为幅度大小，幅度对应的时间为延迟时间。
若要判断脑部有黑质多巴胺能神经退变的风险高低，则控制系统按照以下方式工作：
在受试对象发生体内多巴胺水平上升前的自然状态D0下，由光学视觉设备对受试对象进行光学视觉刺激，由信号处理设备根据眼底血流探测设备在光学视觉刺激前、后分别获得的血流指数B和光学刺激设备的刺激指数S计算自然状态D0下的视网膜神经血管耦合功能指数R0，再由计算机或芯片内部的软件模块进行判断：
若视网膜神经血管耦合功能指数R0中的峰值幅度A0小于等于预设的第一峰值幅度阈值TA1，即幅度衰减，则表明发生了幅度衰减特征/情况，判定为有黑质多巴胺能神经退变的高风险；否则判定为低风险；
或者若视网膜神经血管耦合功能指数R0中的峰值时间T0大于等于预设的第一峰值时间阈值TT1，即时间延迟，则表明发生了时间延迟特征/情况，判定为有黑质多巴胺能神经退变的高风险；否则判定为低风险；
或者若视网膜神经血管耦合功能指数R0中的峰值幅度A0小于等于预设的第一峰值幅度阈值TA1，且峰值时间T0大于等于预设的第一峰值时间阈值TT1，则表明同时发生了幅度衰减特征/情况以及时间延迟特征/情况，判定为有黑质多巴胺能神经退变的高风险；否则判定为低风险。
若要判断脑部是否存在黑质多巴胺能神经退变，则控制系统在判定为有黑质多巴胺能神经退变的高风险时，继续按照以下方式工作：
进一步让受试对象发生体内多巴胺水平上升的特定条件，然后在受试对象的多巴胺上升后状态D1下，由光学视觉设备对受试对象进行再次光学视觉刺激，再由信号处理设备根据眼底血流探测设备在光学视觉刺激前、后分别获得的血流指数B和光学刺激设备的刺激指数S计算多巴胺上升后状态D1的视网膜神经血管耦合功能指数R1，再由计算机或芯片进行判断：
若多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值幅度A1大于等于预设的第二峰值幅度阈值TA2即幅度衰减被逆转，则表明幅度衰减特征/情况发生了逆转，判定为有黑质多巴胺能神经退变存在；否则不存在；
或者若多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值时间T1小于等于预设的第二峰值时间阈值TT2即时间延迟被逆转，则表明时间延迟特征/情况发生了逆转，判定为有黑质多巴胺能神经退变存在；否则不存在；
或者若多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值幅度A1大于等于第二峰值幅度阈值TA2，且其峰值时间T1小于等于第二峰值时间阈值TT2，则表明幅度衰减特征/情况以及时间延迟特征/情况均同时发生了逆转，判定为有黑质多巴胺能神经退变存在；否则不存在。
若判定为有黑质多巴胺能神经退变的低风险时，不用进行对受试对象施加特定条件的步骤。
在体内多巴胺水平上升状态下的峰值幅度阈值和峰值时间阈值，可以与多巴胺水平上升状态前的阈值相同，也可以不同。
所述的各个阈值均是可以通过临床数据建立分类模型获得。
二、一种经眼的黑质多巴胺能神经退变的功能检测方法：
包括光学视觉刺激方法，在受试对象发生体内多巴胺水平提升的特定条件前、后对受试对象的眼部进行光学视觉刺激，同时记录光学视觉刺激时的刺激指数S；
包括眼底血流探测方法，具体进行视网膜血管与血流检测，在受试对象体内多巴胺水平提升的特定条件前、后以及视觉刺激前、后检测眼底血管和血流参数变化信息而生成血流指数B；
包括视网膜充血响应功能指数R的量化方法，综合根据血流指数B和刺激指数S获得含有多巴胺关联信息的视网膜充血响应功能指数R，包括幅度大小和延迟时间；
包括黑质多巴胺能神经退化程度评估方法，根据视网膜充血响应功能指数R中含有的多巴胺关联信息评估黑质多巴胺能神经退化程度，即判定脑部的黑质多巴胺能神经退变的风险或者结果。
所述光学视觉刺激方法是通过显示器或照明灯等可以被视觉感知的方式进行，激发受试对象的眼底视网膜神经活动。
所述眼底血管和血流参数包括血管尺寸、血流流速和血流流量；
还包括OCTA图像中的血管直径和血管密度；
还包括OCTA信号中的血流区域去相关系数的均值、血流区域去相关系数 的总和。
所述刺激指数S具体是指光学视觉刺激的剂量；
所述的血流指数B包含所述眼底血管和血流参数在光学视觉刺激前、后的绝对变化值，和/或所述眼底血管和血流参数在光学视觉刺激前、后的相对变化值；通常所述的变化均是刺激后阶段L1的参数值相比刺激前阶段L0的参数值的比值或者差值。和/或包含所述眼底血管和血流参数在光学视觉刺激前、后变化的峰值幅度、峰值时间(峰值时间是指峰值幅度对应的时刻)、峰值幅度和峰值时间的综合。
所述视网膜神经血管耦合功能指数R是综合了血流指数B和刺激指数S，表示为：R＝B/S。其中，视网膜神经血管耦合功能指数R的最大值为幅度大小，幅度对应的时间为延迟时间。
所述黑质多巴胺能神经退化程度评估方法具体为：
若受试对象发生体内多巴胺水平上升前的视网膜神经血管耦合功能指数R0中的峰值幅度A0小于等于预设的第一峰值幅度阈值TA1，或视网膜神经血管耦合功能指数R0中的峰值时间T0大于等于预设的第一峰值时间阈值TT1，或者视网膜神经血管耦合功能指数R0中的峰值幅度A0小于等于预设的第一峰值幅度阈值TA1，且峰值时间T0大于等于预设的第一峰值时间阈值TT1，则表明发生了幅度衰减特征/时间延迟特征情况，判定为有黑质多巴胺能神经退变的高风险；否则判定为低风险；在判定为有黑质多巴胺能神经退变的高风险时，继续根据受试对象的多巴胺上升后状态D1下的视网膜神经血管耦合功能指数R1判断：
若受试对象的多巴胺上升后状态D1下的视网膜神经血管耦合功能指数R1中的峰值幅度A1大于等于预设的第二峰值幅度阈值TA2，或者多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值时间T1小于等于预设的第二峰值时间阈值TT2，或者若多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值幅度A1大于等于第二峰值幅度阈值TA2，且其峰值时间T1小于等于第二峰值时间阈值TT2，则表明幅度衰减特征/情况或者时间延迟特征/情况发生了逆转，判定为有黑质多巴胺能神经退变存在；否则不存在。
本发明的有益效果为：
已有的基于脑神经成像的PET和SPECT的检测系统，使用射线作为探测信号，使得检测具有潜在的辐射危害。本发明利用光信号或声信号对由黑质多巴胺能神经退变导致的视网膜神经血管耦合功能指数进行探测，无辐射，安全性更好，适用于大规模筛查与纵向监测。
已有的基于传统OCT的检测系统，将由黑质多巴胺能神经退变导致的视网膜厚度变化作为探测标志物，但是OCT系统轴线分辨率～4-7微米，而这种视网膜厚度变薄仅为1-2微米，使得探测的敏感性较差；此外，衰老等因素也会导致视网膜厚度下降，使得探测的特异性较差。
已有的基于传统OCTA的检测系统，将将由黑质多巴胺能神经退变导致的视网膜微血管形态变化作为探测标志物，但是眼内压等因素也会导致视网膜微血管的变化，使得探测的特异性较差。
附图说明
图1为本发明装置的示意图；
图2为本发明系统工作方法实施例的流程图；
图3为本发明装置实施例的示意图；
图4为本发明示例性实施例中，在未给药状态，闪烁光刺激诱导下，健康和黑质多巴胺能神经退变小鼠视网膜血流流量响应的检测结果；
图5为本发明示例性实施例中，在给左旋多巴前、给左旋多巴后、左旋多巴代谢完毕三个状态下，闪烁光刺激诱导的健康和黑质多巴胺能神经退变小鼠视网膜血流流量相对变化的改变；
图6为本发明示例性实施例中，在给左旋多巴前和给左旋多巴后状态下，基于光刺激诱导的视网膜血流流量峰值幅度对健康和黑质多巴胺能神经退变小鼠的分类结果；
其中：11-探测信号发生模块；12-光刺激模块；13-样品；14-探测信号采集模块；15-信号处理模块；
31-宽带光源；32-80:20光纤耦合器；33-偏振控制器；34-参考臂准直器；35-
色散匹配模块；36-参考臂聚焦透镜；37-参考臂反射镜；38-样品臂准直器；39-样品臂OCT扫描装置；40-样品臂二色镜；41-可见光刺激光源；42-样品臂双胶和透镜；43-目镜；44-样本眼；45-探测模块准直器；46-光栅；47-聚焦透镜；48-高速线阵相机；49-信号处理模块。
具体实施方式
下面将结合附图对本发明的具体实施方式作详细说明，附图形成本文的一部分。需要注意的是，这些说明及示例仅仅为示例性的，不能被理解为限制了本发明的范围，本发明的保护范围由随附的权利要求书限定，任何在本发明权利要求基础上的改动都是本发明的保护范围。
为了便于理解本发明的实施例，将各操作描述成多个离散的操作，但是，描述的顺序不代表实施操作的顺序。
本描述中针对样品测量空间采用基于空间方向的x-y-z三维坐标表示。这种描述仅仅用于促进讨论，而不意欲限制本发明的实施例的应用。其中：深度z方向为沿入射光轴的方向；x-y平面为垂直于光轴的平面，其中x与y正交，且x表示OCT横向快扫描方向，y表示慢扫描方向。
采用i，t等表示变量，仅仅用于促进讨论，而不意欲限制本发明的实施例的应用，可以是1,2,3等任一数值。
本发明系统工作方法的具体实施过程包括以下步骤：
步骤1：在受试对象发生体内多巴胺水平提升的特定条件前、后对受试对象的眼部进行光学视觉刺激，同时记录光学视觉刺激时的刺激指数S并发送到信号处理设备。
具体实施的装置系统如图1所示，主要由11-12和14-15两部分构成：以带有LED灯的光刺激模块12作为光学视觉设备，眼底血流探测设备包括了探测信号发生模块11光和探测信号采集模块14，受试对象的眼睛作为样品13，采用信号处理模块15作为数据处理的信号处理设备。
信号发生模块11将探测信号传输至样品13，光刺激模块12产生刺激光，用于激活样品13上的神经元活动，随后信号探测模块14采集从样品13中返回的信号，并传输至信号处理模块15中进行进一步处理。
用光刺激模块12产生闪烁的可见光对样品13的眼部视网膜进行刺激，其波段为380-760纳米，刺激时间为30s，光照度为1000lux，频率为10Hz，占空比为50％,其刺激剂量对应刺激指数为S。在受试对象发生体内多巴胺水平提升的特定条件前、后对受试对象的眼部进行相同剂量的光学视觉刺激。步骤2：利用药物提升受试对象体内多巴胺水平，在给药前D0、给药后D1两个不同的状态下，记录从刺激前阶段L0到刺激后阶段L1的眼底血管和血流参数变化信息进而获得当前状态的视网膜神经血管耦合功能指数；具体为：
如图2所示，本发明系统的一般实施过程是：
在未服用药物的给药前D0情况下，由光学视觉设备进行刺激，由所述眼底血流探测设备记录从刺激前阶段L0到刺激后阶段L1的眼底血管和血流参数变化信息获得视网膜神经血管耦合功能指数；
然后受试对象服用药物，使得受试对象体内多巴胺含量提升，在给药后D1情况下，再次由光学视觉设备进行同样的刺激，由所述眼底血流探测设备记录从刺激前阶段L0到刺激后阶段L1的眼底血管和血流参数变化信息进而获得视网膜神经血管耦合功能指数。
具体实施中，眼底血流探测设备对视网膜神经血管耦合功能指数的记录是 采用时钟信号控制实现刺激施加与视网膜神经血管耦合功能指数记录两个过程的同步，实现对记录时间节点的精准控制。
信号处理设备可以内嵌有软件模块，由软件模块接收来自血流检测仪器的眼底血管和血流参数变化信息后进行数据处理获得视网膜神经血管耦合功能指数，进而根据视网膜神经血管耦合功能指数判断脑部的病变风险或黑质多巴胺能神经退变结果。
如图2所示，若要判断脑部有黑质多巴胺能神经退变的风险高低，则控制系统按照以下方式工作：
在受试对象发生体内多巴胺水平上升前的自然状态D0下，由光学视觉设备对受试对象进行光学视觉刺激，由信号处理设备根据眼底血流探测设备在光学视觉刺激前、后分别获得的血流指数B和光学刺激设备的刺激指数S计算未对受试对象施加自然状态D0下的视网膜神经血管耦合功能指数R0，再由计算机或芯片内部的软件模块进行判断：
若视网膜神经血管耦合功能指数R0中的峰值幅度A0小于等于预设的第一峰值幅度阈值TA1，即幅度衰减，则表明发生了幅度衰减特征/情况，判定为有黑质多巴胺能神经退变的高风险；否则判定为低风险；
或者若视网膜神经血管耦合功能指数R0中的峰值时间T0大于等于预设的第一峰值时间阈值TT1，即时间延迟，则表明发生了时间延迟特征/情况，判定为有黑质多巴胺能神经退变的高风险；否则判定为低风险；
或者若视网膜神经血管耦合功能指数R0中的峰值幅度A0小于预设的第一峰值幅度阈值TA1，且峰值时间T0大于等于预设的第一峰值时间阈值TT1，则表明同时发生了幅度衰减特征/情况以及时间延迟特征/情况，判定为有黑质多巴胺能神经退变的高风险；否则判定为低风险。
上述可见，在不进行刺激情况下，无法准确判断是否存在黑质多巴胺能神经退变，而仅仅只能判断黑质多巴胺能神经退变的风险。
如图2所示，若要判断脑部是否存在黑质多巴胺能神经退变，则控制系统在判定为有黑质多巴胺能神经退变的高风险时，继续按照以下方式工作：
进一步让受试对象发生体内多巴胺水平上升的特定条件，然后在受试对象的多巴胺上升后状态D1下，由光学视觉设备对受试对象进行再次光学视觉刺激，再由信号处理设备根据眼底血流探测设备在光学视觉刺激前、后分别获得的血流指数B和光学刺激设备的刺激指数S计算多巴胺上升后状态D1的视网膜神经血管耦合功能指数R1，再由计算机或芯片进行判断：
若多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值幅度 A1大于等于预设的第二峰值幅度阈值TA2即幅度衰减被逆转，则表明幅度衰减特征/情况发生了逆转，判定为有黑质多巴胺能神经退变存在；否则不存在；
或者若多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值时间T1小于等于预设的第二峰值时间阈值TT2即时间延迟被逆转，则表明时间延迟特征/情况发生了逆转，判定为有黑质多巴胺能神经退变存在；否则不存在；
或者若多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值幅度A1大于等于第二峰值幅度阈值TA2，且其峰值时间T1小于等于第二峰值时间阈值TT2，则表明幅度衰减特征/情况以及时间延迟特征/情况均同时发生了逆转，判定为有黑质多巴胺能神经退变存在；否则不存在。
具体实施例中，利用基于弱相干干涉的OCT装置对在给药前D0、后D1的眼底血管和血流参数变化信息进行记录，采用时钟信号对刺激施加和眼底参数记录两个过程进行精准同步。其中光刺激后阶段L1包含闪烁光刺激段和无刺激的恢复段，利用OCT对光刺激前阶段L0和刺激段L1阶段全过程进行扫描，获得不同时间点的视网膜干涉信号。
对干涉信号进行Fourier变换后获得视网膜结构信号，采用一阶和零阶自协方差对该信号计算分析，得到逆信噪比(I)和退相关系数(D)两个特征，接着构建I-D二维特征空间，利用线性分类器分析判断动态血流信号，获取在给药前D0、后D1两个状态下，光刺激前阶段L0与光刺激后阶段L1视网膜的OCTA血流造影图像序列。对生成的OCTA血流造影图像序列，首先对其进行二值化，剔除噪声的干扰，随后将二值化后的OCTA矩阵骨架化，定位视网膜微血管骨架的交叉点并将其剔除，获得每段血管为单个连通域的血管骨架片段，并将其编号为i，提取每段血管在各时间节点处的血流流量Flowi(tj)。
将每段血管在光刺激前t0各时间节点的血流流量做平均处理，得到血管i对应的充血响应前的血流流量基线值Flow_basei：
其中，N表示基线段t0内采集的数据个数，t为时间维度，Flowi(tj)表示在时间点tj时血管i的血流流量。
随后计算血流流量在闪烁光的刺激段和恢复段中的相对变化量作为血流指数B：
其中，血流指数Bi(tk)为在时间点tk时血管i的血流流量的相对变化量。
再综合血流指数Bi(tk)和刺激指数S获得在时间点tj时血管i的视网膜神经血管耦合功能指数Ri(tk)：
其中，具体实施的刺激指数S为在380-760纳米波段，30s刺激时间，1000lux光照度，10Hz频率，50％占空比条件下的刺激剂量，但不限于此。
将整个采样过程中相同采样时间点下，扫描视场内所有血管的视网膜神经血管耦合功能指数做平均处理，作为视网膜整体的神经血管耦合功能指数R。取该功能指数在在刺激段和恢复段中的最大值作为峰值幅度A，将该峰值幅度A作为判定脑部黑质多巴胺能神经退变的指标。在受试对象发生体内多巴胺水平上升前的自然状态D0下，若视网膜神经血管耦合功能指数R0中的峰值幅度A0小于等于预设的第一峰值幅度阈值TA1，则判定为有黑质多巴胺能神经退变的高风险；否则判定为低风险。
当判定为有黑质多巴胺能神经退变的高风险时，让受试对象口服左旋多巴(250mg)以提高体内多巴胺水平，在受试对象的多巴胺上升后状态D1下，进行如下判断：若多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值幅度A1大于等于预设的第二峰值幅度阈值TA2，则判定为有黑质多巴胺能神经退变存在；否则不存在。
依据信号探测的不同方式，图1所示的眼底血流探测设备等装置可以具体包括：
1)光学相干层析成像装置。利用低相干干涉光探测视网膜信号，利用光谱仪或平衡探测器接收信号，从而得到深度分辨的OCT采样体。
2)动态血管分析仪。利用眼底相机直接记录视网膜信号，利用CMOS或CCD传感器接收信号，从而得到视网膜表层的平面图像。
3)激光多普勒血流仪。利用单色红外激光探测视网膜信号，利用光电探测器接收返回的光信号，从而得到视网膜血流信息。
4)眼底荧光血管造影仪器。利用特定波长激发眼底荧光，利用相机探测发出的荧光，从而得到视网膜荧光采样体。
5)超声成像装置。利用超声换能器发出超声信号至视网膜，并接受从视网膜返回的超声信号，从而得到深度分辨的超声采样体。
对于上述不同的测量装置，均可通过分析血流与周围组织的信号差异生成 视网膜血流造影。
图3示出的是本文所公开的利用本发明的一个示例性实施例。系统包括宽带光源31、80:20光纤耦合器32、偏振控制器33、参考臂准直器34、色散匹配模块35、参考臂聚焦透镜36、参考臂反射镜37、样品臂准直器38、样品臂OCT扫描装置39、样品臂二色镜40、可见光刺激光源41、样品臂双胶和透镜42、目镜43、样本眼44、探测模块准直器45、光栅46、聚焦透镜47、高速线阵相机48和信号处理模块49。
宽带光源31与80:20光纤耦合器32的一端的其中一个分支相连，80:20光纤耦合器32的一端的另一个分支经探测模块准直镜45、光栅46、聚焦透镜47、线阵相机48后与信号处理模块49相连，80:20光纤耦合器32的另一端的其中一个分支与参考臂相连，参考臂包括依次布置的偏振控制器33、参考臂准直镜34、色散匹配模块35、参考臂聚焦透镜36和参考臂反射镜37；80:20光纤耦合器32的另一端的其中一个分支与偏振控制器33的一端相连，偏振控制器33的另一端与参考臂准直镜34的入射端相连，参考臂准直镜34和参考臂反射镜37之间依次设置有色散匹配模块35和参考臂聚焦透镜36，色散匹配模块35靠近参考臂准直镜34，参考臂聚焦透镜36靠近参考臂反射镜37；80:20光纤耦合器32的另一端的其中一个分支与样品臂相连，样品臂包括依次设置的样品臂准直镜38、样品臂OCT扫描装置39、样品臂二色镜40、样品臂双胶合透镜42、目镜43和样本眼44；样品臂准直镜38和样本眼44之间依次设置有样品臂OCT扫描装置39、样品臂二色镜40、样品臂双胶合透镜42和目镜43，目镜43与样品臂双胶合透镜42的焦点重合，从而以平行光照射于样本眼44的眼表，并经眼球汇聚于视网膜上。可见光刺激光源41发出的刺激光经样品臂二色镜40耦合进样品臂探测光路中，经样品臂双胶合透镜42和目镜43后传递至样本眼44。
本实施例的系统，其中宽带光源31的中心波长为850nm，带宽为120nm，通过高速线阵相机48对样品的OCT信号进行实时采集，并将其传输至信号处理模块49；样品臂准直镜38出射的平行光入射至样品臂OCT扫描装置39，样品臂OCT扫描装置39出射的平行光经样品臂二色镜40后，入射至样品臂双胶合透镜42中，样品臂OCT扫描装置39由两块平面扫描振镜组成，通过调节两块平面扫描振镜的相对位置控制OCT信号采集的范围。由本发明装置中所使用的宽带光源31所发出的探测光，经光纤传输至80:20光纤耦合器32中，并分为两路光束分别进入参考臂和样品臂中。其中，80％的探测光进入参考臂中，通过偏振控制器33后传输至参考臂准直镜34，经准直后通过色散匹配模块35和参考臂聚焦透镜36后，汇聚于参考臂反射镜37上，随后该光束按原路返回至80:20 光纤耦合器32中；20％的探测光进入样品臂中，经样品臂准直镜38和扫描振镜39后，依次通过样品臂二色镜40、样品臂双胶合透镜42和目镜43进入样本眼44中，样本眼44中光束经眼睛聚焦于视网膜上，可见光刺激光源41的为白光，波段360-780nm，其发出的刺激光经样品臂二色镜40耦合进样品臂探测光路中，经样品臂双胶和透镜42、目镜43后传输至样本眼44中，实现视神经刺激。随后，携带样本眼44眼底信息的探测光束原路返回至80:20光纤耦合器32；由参考臂和样品臂返回的背向散射光在80:20光纤耦合器32中发生干涉，所产生的干涉光依次通过探测模块准直镜45和光栅46后，经聚焦透镜47汇聚于线阵相机48上，实现信号的探测与记录，随后由信号处理模块49对其进行采集并进一步处理。
本发明可以得到在可见光激发后视网膜的微血管充血响应。其中光刺激脉冲序列的每个脉冲宽度可调、频率可调、幅度可调。在具体实施例中，每个脉冲宽度为100ms，频率为10Hz，幅度为3.0V，刺激时间为30s，即300个脉冲序列。
图4示出的是对健康和黑质多巴胺能神经退变小鼠视网膜神经血管耦合的检测结果。其中图4(A)的纵坐标为毛细血管血流流量相对变化，横坐标为监测时间节点，0-30s为光刺激时间段。可以发现，相比于健康小鼠(n＝13)，黑质多巴胺能神经退变小鼠(n＝13)的视网膜血流流量响应峰值幅度显著下降，其统计结果如图3(B)所示。
图5示出的是在给左旋多巴前、给左旋多巴后、以及药物代谢完毕三个状态下，健康和黑质多巴胺能神经退变小鼠视网膜血流流量相对变化的改变。图5(A)和(B)分别展示的是黑质多巴胺能神经退变小鼠(n＝6)和健康小鼠(n＝7)的视网膜毛细血管血流量在光刺激前后的相对变化，其中0-30s为光刺激时间段。可以发现，在给药后，黑质多巴胺能神经退变小鼠的神经血管耦合响应有了显著提升，而健康小鼠的神经血管耦合响应有了被抑制的趋势，这一现象在图5(C)中响应的峰值幅度对比中更为直观地体现。
图6示出的是在给药前、后状态下，基于光刺激诱导的视网膜血流流量峰值幅度对健康和黑质多巴胺能神经退变小鼠的分类结果。可以发现结合左旋多巴给药后的视网膜神经血管耦合功能指数，可以对黑质多巴胺能神经退变进行高准确率、高特异性区分。
上述实验结果充分说明：本发明可以将光刺激与体内多巴胺浓度调控相结合，基于视网膜神经血管耦合机制，对黑质多巴胺能神经退变导致的视网膜功能损伤进行高敏感性、高特异性、高准确度的非侵入检测。
最后所应说明的是，以上实施例和阐述仅用以说明本发明的技术方案而非进行限制。本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，不脱离本发明技术方案公开的精神和范围的，其均应涵盖在本发明的权利要求保护范围之中。

Claims (15)

  1. 一种经眼的黑质多巴胺能神经退变的功能检测系统，其特征在于：
    包括光学视觉设备，用于在受试对象发生体内多巴胺水平提升的特定条件前、后对受试对象的眼部进行光学视觉刺激，同时记录光学视觉刺激时的刺激指数S并发送到信号处理设备；
    包括眼底血流探测设备，用于检测记录受试对象在体内多巴胺水平提升的特定条件前、后以及视觉刺激前、后的眼底血管和血流参数变化信息而生成血流指数B并发送到信号处理设备；
    包括信号处理设备，接收来自眼底血流探测设备的血流指数B和来自光学视觉设备的刺激指数S进而分析处理获得含有多巴胺关联信息的视网膜神经血管耦合功能指数R；
    包括计算机或芯片，接收来自信号处理设备的视网膜神经血管耦合功能指数R，通过分析视网膜神经血管耦合功能指数R从而判定脑部的黑质多巴胺能神经退变的风险或者结果。
  2. 根据权利要求1所述的一种经眼的黑质多巴胺能神经退变的功能检测系统，其特征在于：所述光学视觉设备是通过显示器或照明灯等可以被视觉感知的方式在发出光施加到受试对象的眼部进而激发受试对象的眼底视网膜神经活动。
  3. 根据权利要求1所述的一种经眼的黑质多巴胺能神经退变的功能检测系统，其特征在于：所述眼底血流探测设备在对受试对象发生体内多巴胺水平上升的特定条件前、后的两个情况下均记录采集从刺激前阶段L0到刺激后阶段L1各自中的至少一个时刻的眼底血管和血流参数变化信息进而生成血流指数B。
  4. 根据权利要求1所述的一种经眼的黑质多巴胺能神经退变的功能检测系统，其特征在于：所述计算机或芯片根据从视网膜神经血管耦合功能指数提取的幅度衰减特征或时间延迟特征，进而判定脑部的黑质多巴胺能神经退变风险高低；
    所述计算机或芯片根据体内多巴胺水平上升后的从视网膜神经血管耦合功能指数提取的幅度衰减特征或时间延迟特征的是否有可逆转情况，进而判定脑部的黑质多巴胺能神经退变准确结果。
  5. 根据权利要求1所述的一种经眼的黑质多巴胺能神经退变的功能检测系统，其特征在于：所述眼底血管和血流参数包括血管尺寸、血流流速和血流流 量；
    还包括OCTA图像中的血管直径和血管密度；
    还包括OCTA信号中的血流区域去相关系数的均值、血流区域去相关系数的总和。
  6. 根据权利要求5所述的一种经眼的黑质多巴胺能神经退变的功能检测系统，其特征在于：所述刺激指数S具体是指光学视觉刺激的剂量；
    所述的血流指数B包含所述眼底血管和血流参数在光学视觉刺激前、后的绝对变化值，和/或所述眼底血管和血流参数在光学视觉刺激前、后的相对变化值；和/或包含所述眼底血管和血流参数在光学视觉刺激前、后变化的峰值幅度、峰值时间、峰值幅度和峰值时间的综合。
  7. 根据权利要求1所述的一种经眼的黑质多巴胺能神经退变的功能检测系统，其特征在于：所述视网膜神经血管耦合功能指数R是综合了血流指数B和刺激指数S，表示为：R＝B/S。
  8. 根据权利要求1或4所述的一种经眼的黑质多巴胺能神经退变的功能检测系统，其特征在于：若要判断脑部有黑质多巴胺能神经退变的风险高低，则控制系统按照以下方式工作：
    在受试对象发生体内多巴胺水平上升前的自然状态D0下，由光学视觉设备对受试对象进行光学视觉刺激，根据眼底血流探测设备在光学视觉刺激前、后分别获得的血流指数B和光学刺激设备的刺激指数S计算自然状态D0下的视网膜神经血管耦合功能指数R0，再由计算机或芯片进行判断：
    若视网膜神经血管耦合功能指数R0中的峰值幅度A0小于等于预设的第一峰值幅度阈值TA1，则判定为有黑质多巴胺能神经退变的高风险；否则判定为低风险；
    或者若视网膜神经血管耦合功能指数R0中的峰值时间T0大于等于预设的第一峰值时间阈值TT1，则判定为有黑质多巴胺能神经退变的高风险；否则判定为低风险；
    或者若视网膜神经血管耦合功能指数R0中的峰值幅度A0小于等于预设的第一峰值幅度阈值TA1，且峰值时间T0大于等于预设的第一峰值时间阈值TT1，则判定为有黑质多巴胺能神经退变的高风险；否则判定为低风险。
  9. 根据权利要求8所述的一种经眼的黑质多巴胺能神经退变的功能检测系统，其特征在于：若要判断脑部是否存在黑质多巴胺能神经退变，则控制系统在判定为有黑质多巴胺能神经退变的高风险时，继续按照以下方式工作：
    进一步让受试对象发生体内多巴胺水平上升的特定条件，然后在受试对象 的多巴胺上升后状态D1下，由光学视觉设备对受试对象进行再次光学视觉刺激，再由信号处理设备根据眼底血流探测设备在光学视觉刺激前、后分别获得的血流指数B和光学刺激设备的刺激指数S计算多巴胺上升后状态D1的视网膜神经血管耦合功能指数R1，再由计算机或芯片进行判断：
    若多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值幅度A1大于等于预设的第二峰值幅度阈值TA2，则判定为有黑质多巴胺能神经退变存在；否则不存在；
    或者若多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值时间T1小于等于预设的第二峰值时间阈值TT2，则判定为有黑质多巴胺能神经退变存在；否则不存在；
    或者若多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值幅度A1大于等于第二峰值幅度阈值TA2，且其峰值时间T1小于等于第二峰值时间阈值TT2，则判定为有黑质多巴胺能神经退变存在；否则不存在。
  10. 应用于权利要求1所述系统的一种经眼的黑质多巴胺能神经退变的功能检测方法，其特征在于：
    包括光学视觉刺激方法，在受试对象发生体内多巴胺水平提升的特定条件前、后对受试对象的眼部进行光学视觉刺激，同时记录光学视觉刺激时的刺激指数S；
    包括眼底血流探测方法，在受试对象体内多巴胺水平提升的特定条件前、后以及视觉刺激前、后检测眼底血管和血流参数变化信息而生成血流指数B；
    包括视网膜充血响应功能指数R的量化方法，综合根据血流指数B和刺激指数S获得含有多巴胺关联信息的视网膜充血响应功能指数R，包括幅度大小和延迟时间；
    包括黑质多巴胺能神经退化程度评估方法，根据视网膜充血响应功能指数R中含有的多巴胺关联信息评估黑质多巴胺能神经退化程度。
  11. 根据权利要求10所述的一种经眼的黑质多巴胺能神经退变的功能检测方法，其特征在于：所述光学视觉刺激方法是通过显示器或照明灯等可以被视觉感知的方式进行，激发受试对象的眼底视网膜神经活动。
  12. 根据权利要求10所述的一种经眼的黑质多巴胺能神经退变的功能检测方法，其特征在于：所述眼底血管和血流参数包括血管尺寸、血流流速和血流流量；
    还包括OCTA图像中的血管直径和血管密度；
    还包括OCTA信号中的血流区域去相关系数的均值、血流区域去相关系数 的总和。
  13. 根据权利要求10所述的一种经眼的黑质多巴胺能神经退变的功能检测方法，其特征在于：所述刺激指数S具体是指光学视觉刺激的剂量；
    所述的血流指数B包含所述眼底血管和血流参数在光学视觉刺激前、后的绝对变化值，和/或所述眼底血管和血流参数在光学视觉刺激前、后的相对变化值；和/或包含所述眼底血管和血流参数在光学视觉刺激前、后变化的峰值幅度、峰值时间、峰值幅度和峰值时间的综合。
  14. 根据权利要求10所述的一种经眼的黑质多巴胺能神经退变的功能检测方法，其特征在于：所述视网膜神经血管耦合功能指数R是综合了血流指数B和刺激指数S，表示为：R＝B/S。
  15. 根据权利要求10所述的一种经眼的黑质多巴胺能神经退变的功能检测方法，其特征在于：所述黑质多巴胺能神经退化程度评估方法具体为：
    若受试对象发生体内多巴胺水平上升前的视网膜神经血管耦合功能指数R0中的峰值幅度A0小于等于预设的第一峰值幅度阈值TA1，或视网膜神经血管耦合功能指数R0中的峰值时间T0大于等于预设的第一峰值时间阈值TT1，或者视网膜神经血管耦合功能指数R0中的峰值幅度A0小于等于预设的第一峰值幅度阈值TA1，且峰值时间T0大于等于预设的第一峰值时间阈值TT1，则判定为有黑质多巴胺能神经退变的高风险；否则判定为低风险；在判定为有黑质多巴胺能神经退变的高风险时，继续根据受试对象的多巴胺上升后状态D1下的视网膜神经血管耦合功能指数R1判断：
    若受试对象的多巴胺上升后状态D1下的视网膜神经血管耦合功能指数R1中的峰值幅度A1大于等于预设的第二峰值幅度阈值TA2，或者多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值时间T1小于等于预设的第二峰值时间阈值TT2，或者若多巴胺上升后状态D1下视网膜神经血管耦合功能指数R1中的峰值幅度A1大于等于第二峰值幅度阈值TA2，且其峰值时间T1小于等于第二峰值时间阈值TT2，则判定为有黑质多巴胺能神经退变存在；否则不存在。
PCT/CN2024/116488 2024-06-12 2024-09-03 一种经眼的黑质多巴胺能神经退变的功能检测系统和方法 Pending WO2025255968A1 (zh)

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