EP3773147A1

EP3773147A1 - Method and device for examining the neurovascular coupling at the eye of a patient

Info

Publication number: EP3773147A1
Application number: EP19717114.3A
Authority: EP
Inventors: Walthard Vilser; Martin SKORSETZ; Thomas Riemer
Original assignee: Imedos Systems UG
Current assignee: Imedos Systems UG
Priority date: 2018-03-29
Filing date: 2019-03-29
Publication date: 2021-02-17
Also published as: US20210113080A1; DE102018107623A1; JP7373502B2; WO2019185096A1; KR20200138332A; CN112004456A; DE112019001645A5; JP2021519177A

Abstract

The invention relates to a method and to a device for examining the neurovascular coupling at the eye (A) of a patient, an image series of images of the fundus of the eye (A) being captured by means of an imaging method, preferably over a baseline phase (BP), a stimulation phase (SP), in which the fundus is stimulated with a flickering light, and a post-phase (NP). For at least one capillary vessel region of the fundus, signals, in particular an averaged quotient signal (Q(t)) representing a vessel response of the vessels of the capillary vessel region to the stimulation, are derived from the image series. The absolute or percentage maximum change (Qmax) of the averaged quotient signal (Q(t)) is then used as an evaluation criterion for the neurovascular coupling.

Description

Method and device for the examination of the neurovascular coupling on the eye of a patient

The field of application of the invention relates to the entire vascular medicine, z. In ophthalmology, neurology, cardiology, nephrology, diabetology, hypertensiology.

Studies have shown that microvascular vascular changes are often systemic, i. H. occur in the vessels, in particular the vessels of the microcirculation of all organs of the human and animal body, similar and depending on the organ to different manifestations of cardiovascular diseases, such as atherosclerosis, atherosclerosis, heart failure, renal insufficiency, eye diseases such. As retinopathy and glaucoma, cerebrovascular diseases such. As vascular dementia, and ultimately cardiovascular events, such as heart attack and stroke, can trigger or are predictors. The eye as a unique optical window for microcirculation allows the retinal vessels to be examined as a mirror image of the vessels in inaccessible areas of the other organs of the body. The field of application of the invention is to investigate vascular endothelial function in human vessels and neurovascular coupling.

At present, ophthalmology mainly uses imaging techniques and devices for clinical issues that investigate structural, morphological changes in the eye, especially in the retina. These include conventional fundus cameras, OCT, laser scanners, adaptive optics systems, and other vascular investigations using static vessel analysis, such as: B. with the VesselMap Imedos, begin to enter the clinical routine for microvascular risk stratification and therapy control.

Functional investigations of the retinal vessels have so far found predominantly application in research, such. B. Apparatus and methods for measuring blood velocity and indicator-based vessel diameters, and systems for dynamic vessel analysis. The areas of application of the systems on Doppler or OCT basis provide statements that describe the vascular or flow state and thus have little relevance to vascular non-ophthalmic diagnostics and are unable to detect the function of vascular regulations.

Dynamic vessel analysis allows the study of various autoregulation mechanisms based on continuous measurements of vessel diameter over time and along the location of the so-called large arteries and veins of the microcirculation. The retinal vessels are stimulated or provoked during vascular recording and accordingly respond with a constriction or dilatation that describes the vascular response of the respective retinal autoregulatory mechanisms addressed by the type of stimulation or provocation, and their operability.

With such methods of stimulation or provocation, one can examine various autoregulatory mechanisms of microcirculation. One of the autoregulatory mechanisms is the flow-induced autoregulation.

The state-of-the-art dynamic vessel analysis system is the Dynamic Vessel Analyzer (DVA) from Imedos (Garhofer, G., Bek, T., Böhm, AG, Gherghel, D., Grunwald, J., Jeppesen, P. , Kergoat, Fl., Kotliar, K., Lanzl, I., Lovasik, JV, Nagel, E., Vilser, W., Orgul, S., Schmetterer, L.: "The retinal vessel analyzer in ocular blood flow research. "Acta Ophthalmologica 2010: 88: pp. 717-722). The standard provocation used in the DVA is Flickerlicht, which works in a frequency range of 12.5 Hz and interrupts the green measuring light with an optical shutter flickering for 20 s. This procedure is repeated three times and the vascular responses are then superimposed for averaging and evaluated for maximum dilation and subsequent constriction.

These measurements are limited in the DVA to the large vessels of microcirculation between 60 and 300 pm.

The parameters of the evaluation (dilation maximum) as well as other derivable parameters are interpreted as biomarkers for the functional diagnosis of the microvascular endothelial function. By some authors, the parameters of the vascular response are also mistaken as parameters of the neurovascular Coupling designates and interprets. However, it has been proven that although the neurovascular coupling represents the initial stimulus and thus influences the vascular response, the vascular response of the large vessels describes the function of the endothelial function.

In addition, WO 2005/094668 A1 describes a device for the photometric measurement of the vessel diameter of smaller vessels. The disclosed technical solution allows the measurement of vessel diameters in the arterioles and venules, provided that the vessels in the fundus image are selectable as vessels. For this purpose, two different spectral ranges and a color camera are used. This considerably increases the light load of the retina. Another significant disadvantage of the disclosed solutions, however, is also in the rigid lighting side arrangement of a light modulator in the common illumination side beam path, which also can only make the temporal modulation flexible and significantly limits the scope and adaptability, ultimately has the same disadvantages of DVAs, except for Advantage, even on small retinal vessels, but which are significantly larger than capillaries, to be able to measure.

Another technical solution for capturing capillary "perfusion" is the article by Vilser et. al, 2008 (Vilser, W., Nagel, E., Seifert, BU, Riemer, T., Weisensee, J., Flammer, M: "Quantitative Assessment of Optic Nerve Head Pallor." Physiological Measurement 29 (2008), p 451-457). Two spectral ranges in the red and green spectral range of the white illumination light are selected via a dual band pass filter in the illumination beam path of a conventional retinal camera and assigned to the red and green color channels of a 3-chip CCD color camera in such a way that the two selected illumination-side spectral ranges of the measurement light are separated from each other the two associated red and green color channels of the CCD camera are received. From the detected intensity values of the two color channels (red and green) by pixels, which can each be assigned to the same fundus location, quotients are formed and reassigned to the fundus location. The quotient image thus generated is then evaluated for capillary perfusion on the optic nerve head. Although this method does not allow perfusion of the optic nerve head when perfusion is understood as meaning the capillary blood flow, it does provide a measure of the blood volume and thus of the capillary vessel diameter and the capillarization of the considered tissue volumes. The disadvantage of this method is that it can not, as described in the aforementioned work, provide functional information about the regulation of capillary "perfusion".

A first major disadvantage of the prior art is the lack of opportunities to study neurovascular coupling in the retina. Methods for the investigation of neurovascular coupling in the brain are purely experimental, invasive, very expensive and not suitable for clinical use. Neurovascular coupling plays a key role in retinal and cerebral blood flow as well as in various diseases.

A further disadvantage of the prior art is that the results of studies on vascular endothelial function are very strong and that the connection between endothelial dysfunction and cardiovascular risk factors, events and diseases is unclear, with clinical use for individual endothelial function evaluation and diagnosis of endothelial dysfunction Endothelial dysfunction is flawed and unsettled.

It is the object of the invention to find a method by which the neurovascular coupling in the retina and on the optic nerve head can be examined non-invasively, without contact and simply and which is suitable for clinical non-invasive use.

Furthermore, it is the object of the invention to find an apparatus for carrying out the method.

The object is achieved for a method for the examination of the neurovascular coupling on the eye of a patient with a first method in which an image sequence of images of the fundus of the eye is created and recorded while the fundus is stimulated with a flicker light, wherein from the images of the image sequence for at least one capillary vessel region of the fundus Signals are derived, the capillary vascular responses of the capillary capillary of the capillary area on the stimulation with the flicker light and their maximum absolute or percentage change is determined and used as an evaluation criterion for the neurovascular coupling.

Advantageously, signals are also derived from the images of the image sequence for at least one vessel section of arterial or venous vessels of the fundus, which represent arterial or venous vascular responses to the stimulation and whose maximum absolute or percentage change is determined, which represents an evaluation criterion for the endothelial function.

It is irrelevant whether the basic imaging technology is realized by conventional fundus camera, OCT, adaptive optics or scanning technology, provided an image sequence of sufficient temporal resolution is generated. Furthermore, it is not important whether the signals derived from the image z. For example, vessel diameter, blood volume, blood velocity, blood flow, capillary density, or other parameters may be reflected, as long as these signals describe a response of the retinal vessels including the capillaries to the stimulation (vascular response).

By using the maximum absolute or percentage change in capillary vascular responses as the reference value for the maximum absolute or percentage change in arterial and / or venous vascular responses, e.g. For example, if a quotient is calculated, it is advantageous to obtain an evaluation criterion for a rating of the vascular endothelial function that is independent of the influence of the neurovascular coupling.

The signals describing the vascular responses may represent intensities, vascular diameters, blood volume values, quotient signals from various spectral ranges, blood flow values, vascular densities or blood velocity values of the capillary or larger arterial or venous vessels.

The recording of the sequence of images of the fundus of the eye is advantageously carried out via a baseline phase, a stimulation phase in which the fundus is stimulated by the flicker light, and a post-phase (NP). Advantageously, the method integrates the study of endothelial function in the large retinal vessels using the vascular response describing the neurovascular coupling as a reference for evaluating the vascular response describing endothelial function. It does not matter how the reference is implemented. An example is the formation of a quotient of the percent maximal dilatation of the large vessels and the maximum percentage change of the vascular response of the neurovascular coupling. Already the information about the strength of the neurovascular coupling is sufficient to evaluate the investigated vascular endothelial function. Thus, the influence of the neuronal coupling on the study of the vascular endothelial function can be eliminated, thus avoiding errors in the evaluation of the endothelial function and significantly improving the diagnostic safety.

The object of a method for the examination of the neurovascular coupling on the eye of a patient is also solved by a second method, in which an image-forming method is used to sequence images of the fundus of the eye over a baseline phase, a stimulation phase in which the fundus a flare light is stimulated, and a post-phase (NP) is recorded, wherein the fundus is illuminated with measuring light of two different spectral ranges, derived from intensity values of the images of the image sequence for at least one capillary vascular area of the fund quotient signals that a capillary vascular response of the vessels of at least represent a capillary vascular area on the stimulation, and from the quotient signals and / or a quotient signal averaged from the quotient signals, an absolute or percentage maximum change is determined and used as an evaluation criterion for the neurovascular coupling.

Advantageously, diameter signals are derived from the images of the image sequence for at least one vessel section of arterial or venous vessels of the fundus in the second method, which represent an arterial or venous vascular response of the at least one vessel section to the stimulation, and an average diameter signal is formed from the diameter signals Absolute or percentage maximum change is determined, which is an evaluation criterion for endothelial function. By forming a quotient of the maximum change in the averaged quotient signal and the maximum change in the averaged diameter signal, it is advantageous to provide an evaluation criterion for evaluation of the vascular endothelial function that is independent of the influence of the neurovascular coupling.

By illuminating the fundus with measuring light of two different spectral ranges, the images can be assigned to two color channels, determined by one of the spectral ranges, and a quotient signal derived from the intensity values of the two color channels can be formed as the signal.

It is advantageous if the imaging method is based on optical coherence tomography and the images are OCT images.

The flicker light preferably has a spectral range that differs from the measurement light, with which the measurement light and the flicker light can be adjusted independently of one another.

Advantageously, the maximum change in the quotient signal and / or the diameter signal is color-coded in a mapping image to which at least one capillary vessel region and / or the at least one vessel section are assigned.

The object of a device for the examination of the neurovascular coupling on the eye of a patient is achieved with a first device which comprises: an imaging system for generating an image sequence of images of the fundus of the eye, the image intensities of the fundus-characterizing structures, the capillary density , which represent blood velocity, the blood flow or the blood volume of the vessels, with a lighting unit for generating flicker light, with which at least a portion of the fundus is stimulated, a data and image processing unit, designed for the selection of capillary vascular areas and vascular sections of arterial and venous vessels the pictures of the sequence, a unit for deriving signals associated with the selected capillary vascular areas and the selected vascular sections; a signal analysis unit and a result and presentation unit.

The object of a device for the examination of the neurovascular coupling on the eye of a patient is also achieved with a second device which comprises: an imaging system for generating an image sequence of images of the fundus of the eye, with a lighting unit designed to generate a measuring light, with at least two spectral ranges for illumination, as well as for generating a flicker light for stimulating the fundus, a data and image processing unit, designed for the selection of capillary vascular areas and vascular sections of arterial and venous vessels in the images of the image sequence, a unit for the derivation of quotient signals, assigned to the selected capillary vascular regions, a unit for deriving diameter signals associated with the selected vascular sections, a signal analysis unit and a result and presentation unit, the illumination unit being characterized by a structured arrangement is formed by adaptively controllable LEDs as a lighting structure with at least three different spectral ranges which can be changed in terms of geometry and dimension, with which selected capillary vessel areas and / or selected vessel sections can be adaptively illuminated and stimulated. The imaging system is advantageously implemented as a fundus camera with a digital image sensor, an optical coherence tomograph (OCT), a scanning imaging system or an adaptive optics system.

Advantageously, the LEDs of two spectral regions generate the measuring light and, independently of this, the LEDs of the third spectral range generate the flicker light.

Furthermore, the spectral ranges of the LEDs that generate the measurement light are preferably green and red, and the spectral range of the LEDs that produce the flicker light is blue.

The digital image sensor is advantageously a color image sensor with at least two color channels.

Alternatively, it is advantageous if the digital image sensor is a monochromatic image sensor, wherein the spectral ranges of the measuring light within and the spectral range of the flicker light are outside the spectral sensitivity of the digital image sensor.

The invention will be explained in more detail with reference to embodiments and drawings.

Show:

1 shows the time course of a quotient signal and a diameter signal over the duration of the method,

2 shows a block diagram of a device suitable for carrying out the method,

3 shows an image of the fundus, in which exemplary capillary vascular areas, one of which is indicated on the optic nerve head, measuring locations and vessel sections, and

4 shows a block diagram of a further device suitable for carrying out the method. In a method for the examination of the neurovascular coupling on the eye A, an image sequence of images of the fundus of the eye A is preferred over a baseline phase BP, a stimulation phase SP, in which the fundus is stimulated with a flicker light, and a postphase NP recorded, see Fig- 1.

From the image sequence, a signal is derived for at least one capillary vessel region KGB, which represents a capillary vascular response (signal of a measured variable) of the capillary vessels to the stimulation of the retina and whose maximum change during the stimulation phase SP represents an evaluation criterion (biomarker) for the NPC. Basically, such a capillary vascular response (vessel signal) may be the changes in capillary blood flow or capillary blood velocity, capillary vessel diameter, or capillary blood volume in the retina or on the optic nerve head during the stimulation phase SP.

It does not matter with which imaging method the at least one image sequence is formed or based on which measured variables the NVK is determined.

The sequence of images z. B. by optical coherence tomography OCT, via a scan method or by other optical imaging methods are generated.

Advantageously, and described in the following exemplary embodiment for a method, the change of the capillary blood volume or the vessel diameter of the capillary vessels, which is a change in the retinal capillary vessel areas KGB or the papillary capillary vessel areas KGB (on the papilla) reflected portion of the measurement light result, detected by a normalized intensity signal (quotient signal Q (t, x, y)), which is used as a capillary vascular response to study the NVK.

Advantageously, the method integrates the examination of the endothelial function in the large arterial and / or venous retinal vessels.

Step 0:

At the beginning of the procedure, the examiner is given an examination program menu for various examinations with different medical procedures Issues offered. The parameters of the measuring light and the parameters of the flicker light are set by selecting the examination parameters.

The examiner can choose between setting 0-1: freely selected parameters (free parameter selection),

0-2: of comparison parameters (comparison mode) and

0-3: select from repeat parameters (repeat mode) as described in the following steps.

Step 0-1: Free parameter selection

For questions of research, a free choice of parameters often makes sense. The examiner is preferably offered the following parameters for automatic presetting and after selection the parameter set is stored under a name to be given by the examiner as a new program for comparison and repeat examinations.

Step 0-1 -1: Setting the measuring light (measuring light parameter)

Determining two spectral ranges of the measuring light, preferably green and red, when a normalized intensity signal (quotient signal Q (t, x, y)) is to be derived from the image sequences, and defining a spectral range, eg. B. green, when a non-normalized intensity signal is to be derived from the image sequences

- Determination of the radiation intensity of the measurement light (manually or automatically readjusted, controlled by image brightness)

- Determination of the time behavior during the stimulation phase SP. In the event that the measuring light and the flicker light have the same spectral range (eg green), z. B. at a frame rate of 25 Hz, the measuring light during the stimulation phase SP at every second image with a predetermined Modulation depth turned off to realize a flicker stimulation frequency of 12.5 Hz. Advantageously, a different spectral range is determined for the measuring light and the flicker light. Thus, blue is also preferred as additional measuring light in conjunction with red.

Step 0-1 -2: Setting the Flicker Light (Flicker Light Parameter)

Setting to Luminanzflicker or Farbflicker

In the luminance flicker, the specified spectral range of the flicker light is only modulated according to the other flicker parameters. In the case of Farbflickers flicker light changes only the spectral range with the flicker frequency, which means a mutual switching of different color LEDs.

The adjustment of the spectral ranges of the colored LEDs is made depending on the flicker type, eg. For example, in the case of color treaters, the flicker light change is determined by a blue LED with a green LED.

Setting the modulation of the flicker light

In the present example, the examiner can set the stimulation shape for each half period of the flicker light with the following parameters:

intensity maximum

intensity minimum

modulation depth

increase in intensity

intensity drop

Length of the intensity maximum wave-shaped or step-shaped modulation For the embodiment in which the spectral regions have been selected green and red as measuring light, a color, for. B. blue, set for the flicker, which is not in the spectral range of the measuring light. Thus, the flicker frequency can basically be set independently of the frame rate.

Step 0-1 -3: Setting the examination phases (phase parameters)

The length of the examination phases baseline phase BP, stimulation phase SP and postphase NP are set.

Step 0-1 -4:

All freely set parameters are summarized in a parameter set and stored with an examination name and offered when the examination program is selected again.

Step 0-2: Comparison mode (assures same examination conditions for different eyes A for the same medical question)

The desired examination program for the medical question is retrieved from the examination menu and the associated parameter set for the selected examination program is loaded. Via control algorithms provided, the LEDs of a device for carrying out the method are correspondingly driven, whereby the measuring light and the flicker light are variably and adaptively adapted to the selected examination program.

Step 0-3: Repeat mode (secures equal examination conditions in subsequent sessions for the same eye A) with reference measurement locations

Via a patient-related database, the previously examined eye A is searched out and the parameter sets of the examination carried out by the last examination are preset. During the adjustment of the device to the eye A, a movement correction ensures the exact match of the areas of the fundus between the sessions recorded in the images of the image sequences.

After setting all parameters, the examination procedure begins

Step 1 :

The head of the patient is fixed over a head and chin rest against an imaging system 1. The imaging system 1 is adjusted to the eye A to be examined in such a way that it provides a low-scattering and reflection-free image of the fundus.

Step 2:

With the beginning of the baseline phase BP, the imaging system 1 starts taking a sequence of images. When using a color sensor as a digital image sensor 2, images of two color channels are generated synchronously when the fundus is illuminated with measuring light of two spectral ranges, for example with green and with red measuring light. They are understood below as images to which two color channels are assigned. Alternatively, a monochromatic image sensor may be used as the digital image sensor 2. With a temporally changing, synchronous to the image sequence lighting, for example, with red and green measuring light, images are also generated, which are assigned to a pseudo-green color channel and a pseudo-red color channel and are subsequently understood in pairs as images to which two color channels are assigned. In order to avoid unintentional stimulation with the change of the measuring light, the image change and the spectral change of the measuring light are carried out at such a high frequency that a possible stimulation effect is negligible. The flicker light remains off during the baseline phase BP.

Step 3: The images of the image sequences are motion-corrected with respect to the eye movements. Capillary vascular areas KGB are selected in the images of the fundus, and quotient signals Q (t, x, y) are preferably formed beginning with the acquisition of the images from the intensity values of the red and green color channels of the images and assigned to one of the selected capillary vascular areas KGB stored.

The values of the parameters of the quotient signals Q (t, x, y) over the duration of the baseline phase BP provide baseline values from which a mean baseline value is determined.

Step 4:

Advantageously, diameter signals D (t, x, y) are derived at the same time from the intensity values of the green color channels of the images of the image sequence. For this purpose, the vessel diameter along the selected vessel sections GA segment by segment, which are each assigned to a measurement site M (x, y), determined, stored with location correction and assigned to a synchronization signal or the individual images of the image sequence. From the determined diameters, diameter signals D (t, x, y) are formed for each vessel segment. The values of the parameters of the diameter signals D (t, x, y) over the duration of the baseline phase BP provide baseline values from which a mean baseline value is determined.

Step 5:

The baseline phase BP is automatically followed by the stimulation phase SP with the stimulation time and the parameter set transferred for the flicker light stimulation. Said vessel signals, that is, the quotient signals Q (t, x, y) and the diameter signals D (t, x, y) are further derived from the image sequences during the stimulation phase SP. In the case of the use of a monochromatic image sensor as a digital image sensor 2, the measuring light of both spectral regions is switched off synchronously to the image sequence in the flicker phases of the blue flicker light, while in the dark phase of the flicker light the measuring light is switched on and the images and consequently the vessel signals are generated. If the monochromatic image sensor is not sensitive to the blue flicker light, the Recording of the images and the derivation of the vessel signals also take place during the bright phase of the flicker light. The flicker-related changes of the quotient signals Q (t, x, y) and the diameter signals D (t, x, y) are evaluated for their scattering and dilation. It is separated for the individual quotient signals Q (t, x, y) or for an averaged quotient signal Q (t) or for the individual diameter signals D (t, x, y) or respectively for the arterial vessel sections GA and the venous vessel sections GA an average diameter signal D (t) is formed. From the averaged quotient signal Q (t) becomes Q _ma x and from the averaged diameter signals D (t) D _{max is determined} as maximum change of the signal.

Step 6:

After completion of the stimulation phase SP, the post-phase NP of the examination begins, the flicker light is switched off and the continuous measurements are continued until the post-phase NP is ended. The stimulation phase SP and the post-phase NP can be repeated several times, preferably three times alternately, to average the signals.

Step 7:

The signals Q (t, x, y) and D (t, x, y) are averaged over the selected KGB and GA, recorded and output as a measurement protocol with the derived maximum values of the signal changes.

An exemplary embodiment of a device suitable for carrying out the method will be described below.

Such a device contains, as shown in a block diagram in Fig. 2, an imaging system 1, here a modified retinal camera, with a digital image sensor 2 and a lighting unit 3 for generating a measuring light and a Flickerlichtes, a control unit 4, a data and Image processing unit 5, a unit for deriving diameter signals 6, a signal analysis unit 7, a result and presentation unit 8, an input and output unit 9 and a unit for deriving quotient signals 10.

The illumination unit 3 is arranged in an illumination beam path of the retinal camera in a plane conjugated to the eye pupil, that is to say it is imaged into the eye pupil of the eye A. The fundus of the eye A is imaged sharply on a receiving surface of the digital image sensor 2.

The lighting unit 3 is a preferably adaptive, structured, annular arrangement of small light sources, for. As LEDs with three different spectral properties, preferably in the blue, green and red spectral range. The LEDs are controlled via the control unit 4 in such a way that the LED light intensity of the differently colored LEDs is modeled separately and independently of one another. The modulation of the LED light should allow both the adjustment of the radiation intensity of light as measuring light, as well as the setting of flicker light by switching between high and low radiation intensity, with adjustable parameters of the frequency, the degree of modulation and the alternating light form (eg wavy to step-shaped, symmetrical or asymmetric change between light and dark phase). Advantageously, the luminous structure formed by the active (luminous) LEDs in their geometry and dimension, z. As the width and the diameter of an active light ring formed, adaptively adaptable. About the adaptivity of the time-geometric active LED structure as z. B. temporally changing thin or wide ring or half ring or point, the annular LED array in the lighting side aperture can be used to reduce stray light or reflection light (especially on the vessels). This also makes it possible to very quickly switch the dynamic vessel analysis into the mode of nonmydriatic static vessel analysis and vice versa. At the same time, this adaptivity can be used to focus the fundus on the principle of Scheiner ^'s diaphragms. It is also possible to use a structural change that is rotating during the examination to acquire image sequences with different illumination geometries.

The digital image sensor 2 may be a color sensor that synchronously generates images that are green and red when illuminated with green and red measurement light red color channel can be assigned. The two synchronous images are each understood as an image to which two color channels are assigned.

Advantageously, a monochromatic image sensor is used as the digital image sensor 2, which is preferably sensitive only to the two spectral ranges of the measurement light, but not to the spectral range of the flicker light. When the fundus is illuminated synchronously with the image sequence, alternately with red and green measuring light, the images are alternately assigned to a pseudo-green or a pseudo-red color channel. Two consecutively taken pictures are understood as one picture to which two color channels are assigned. The frame rate is set so high that the color change of the measurement light does not lead to a stimulation effect.

Advantageously, the two pseudocolor channels of the monochromatic image sensor have a higher sensitivity and the monochromatic image sensor a higher resolution than the color image sensor.

Both the use of a color image sensor and the use of a monochromatic image sensor as a digital image sensor allow a free choice of spectral ranges for the measuring light and the flicker light, which only need to be different.

The adaptive control unit 4 is connected to the data and image processing unit 5, which in turn is connected to the digital image sensor 2. It controls the individual LEDs of the illumination unit 3 separately from each other and with different radiation intensity, but at least when they emit the measurement light, synchronized to the image sequence. The frequency of the flicker light (change between light and dark) is controlled by a synchronization signal which is generated by the digital image sensor 2 and transferred to the control unit 4. With the synchronization signal, the signals formed during the method steps are synchronized with the image sequence recorded by the digital image sensor 2. It does not matter whether the synchronization signal is given by the digital image sensor 2 or by the data and image processing unit 5, which also controls the recording of the images of the image sequence. In contrast to the monochromatic image sensor, the color image sensor records images of the fundus at a frame rate of preferably 25 Hz, which yields preferably 12.5 Hz as the flicker frequency. According to the invention, however, any other frame rate can be used synchronized to a flicker frequency for the device and the method. The frame rate and the flicker frequency also need not be synchronized with each other if there is no overlap of the spectral ranges of the measuring light and the flicker light.

The data and image processing unit 5 connected to the digital image sensor 2 receives the image sequence. The examiner selects via the data and image processing unit 5 and the input and output unit 9 in the images, see FIG. 3, the capillary vessel areas KGB in the retina or the optic nerve head and assigns them each a measuring location M (x, y) , A measuring location M (x, y) can be defined by a pixel or an image area and thus a pixel or a pixel group of the digital image sensor 2. The measurement location M (x, y) may be the centroid of the KGB or another selected point in the KGB. In addition, larger venous and arterial vessel sections GA are selected in the images, which also have measuring locations M (x, y) and thus image points or individual pixels, which preferably represent the center point of the respective vessel segment, or image areas, in this case the vessel segments. or a pixel group on the digital image sensor 2 are assigned. The selected KGB are advantageously between the selected vessel sections GA.

The coordinates of the measurement locations M (x, y) assigned to the KGBs and the green and red intensity values generated by the green and red measurement light at the measurement locations M (x, y) are transferred to the unit for deriving quotient signals 10.

The coordinates of the vessel segments or the associated measuring locations M (x, y) and the intensity values generated by the green measuring light are forwarded to the unit for deriving diameter signals 6.

The unit for deriving quotient signals 10 forms on-line from image to image and as a function of time quotients of the green and red intensity values of Images for all measuring locations M (x, y) of the KGBs and forwards these values as quotient signals Q (t, x, y) to the signal analysis unit 7.

The unit for deriving diameter signals 6 only has to be present if the device is also to be used advantageously to examine the vascular endothelial function in addition to the investigation of the neurovascular coupling. The unit for deriving diameter signals 6 determines the diameter on-line via image processing of the green color signals segment by segment and image by image, forms time and location-dependent diameter signals D (t, x, y) and forwards them to the signal analysis unit 7. There are formed from the diameter signals D (t, x, y) of the vessel segments by combining several vessel segments diameter signals D (t, x, y) for whole vessel sections GA or over all arterial or venous detected averaged diameter signals D (t), the Examiners on the result and presentation unit 8 graphically displayed and output. In the signal analysis unit 7 are also typical, the endothelium-descriptive parameters of the vessels, such. For example, the dilation maximum in the stimulation phase SP is calculated and output via the result and presentation unit 8 and the input and output unit 9. The result and presentation unit 8 also serves to create mapping images.

The signal analysis unit 7 determines as parameters of the signals the maximum change in the vessel diameter, equal to the maximum dilation D _max , from the diameter signals D (t, x, y) for the vessel segments or vessel sections GA or from the averaged diameter signals D (t) and the maximum change Q _max from the quotient signals Q (t, x, y) for the capillary vessel areas KGB. The maximum dilation D _max describes the endothelial function and the maximum change Qmax describes the NKV. The parameters are transferred to the result and presentation unit 8, entered in a result image (mapping image) in the correct position (motion-corrected) and output as an examination result.

The test results on NVK and on the endothelial function can be evaluated separately, but advantageously medically related. The investigation of the NVK on the basis of quotient signals Q (t, x, y) has the advantage that the blood volume of the KGBs is detected on the basis of spectrally normalized intensity values. Since these intensity values are independent of illumination, a different illumination of the measuring locations M (x, y) as a result of eye movements has at most negligible influence on the parameters describing the NVK.

Simplifying, instead of the quotient signal Q (t, x, y), formed from the intensity values of two spectral regions, also an intensity signal of only one spectral range, eg. B. the green spectral range, are formed to investigate the NVK. In this case, however, motion-dependent lighting changes must be accepted or other options for their elimination be taken. So z. B. the normalization of the intensity signal on sites on the fundus or on the optic nerve head done, which are not within the range of the flicker stimulation.

A further exemplary embodiment of a method and a device according to the invention results if, instead of a modified fundus camera as described above, a laser scanner is used as the imaging system 1, with laser beams whose wavelengths are matched to the spectral ranges of the measurement light and the flicker light already described above are. The method and the device are carried out analogously to the above description.

The use of an adaptive optics as an imaging system 1 or as components of the imaging system 1 is also encompassed by a device according to the invention. In these cases, both quotient signals Q (t, x, y) and diameter signals D (t, x, y) can also be formed, as described above.

Further exemplary embodiments result from the use of imaging systems 1 based on optical coherence tomography (OCT). Signals are derived from the images, here called OCT images, which describe both the local vessel diameter of larger vessels and / or the local blood volume or the local perfusion of the capillaries. Such signals may be derived from local blood flow, local blood or cell velocity, or capillary density An imaging system 1 based on optical coherence tomography is, for example, an angiograph (OCT-A), in whose OCT images the signals are due to the moving blood cell density or those with blood cells perfused capillaries are shown.

In principle, the device for examining the neurovascular coupling on the eye A of a patient, as shown in FIG. 4, may contain any imaging system 1 for generating an image sequence of images of the fundus of the eye A. The imaging system 1 merely has to be designed to produce images in which imagewise intensities of the structures characterizing the fundus, the capillary density, the blood velocity, the blood flow or the blood volume of the vessels are shown. In addition, a lighting unit 3 for generating flicker light is present, with which at least a section of the fundus can be stimulated. In addition, the device has a data and image processing unit 5, designed for the selection of capillary vascular areas KGB and vascular sections GA arterial and venous vessels from the images of the image sequence, a unit for deriving signals 1 1, associated with the selected capillary vascular areas KGB and the selected Vessel sections GA, a signal analysis unit 7 and a result and presentation unit 8 have.

LIST OF REFERENCE NUMBERS

D (t, x, y) diameter signal (as a function of time and location x, y)

D (t) averaged diameter signal

D _max maximum change of the diameter signal D (t, x, y)

Q (t, x, y) quotient signal (as a function of time and location x, y)

Q (t) averaged quotient signal

Qmax maximum change of the quotient signal Q (t, x, y)

M (x, y) location

BP baseline phase

SP stimulation phase

NP postphase

GA vessel section

KGB capillary vascular area

A eye

1 imaging system

2 digital image sensor

3 lighting unit

4 control unit

5 data and image processing unit

6 Unit for deriving diameter signals

7 signal analysis unit

8 result and presentation unit

9 input and output unit

10 unit for the derivation of quotient signals

1 1 Unit for the derivation of signals

Claims

claims

A method of examining the neurovascular coupling on the eye (A) of a patient, in which

an image sequence of images of the fundus of the eye (A) is created and recorded while the fundus is stimulated with a flicker light using an imaging process, wherein

From the images of the image sequence for at least one capillary vessel region (KGB) of the fundus, signals are derived which represent capillary vascular responses of the capillary capillary vessels (KGB) to the stimulation with the flicker light and their maximum absolute or percentage change is determined and used as an evaluation criterion for the neurovascular coupling is used.

2. A method for examining the neurovascular coupling on the eye (A) of a patient according to claim 1, characterized in that

in that signals are derived from the images of the image sequence for at least one vessel section (GA) of arterial or venous vessels of the fundus, which represent arterial or venous vascular responses to the stimulation and whose maximum absolute or percentage change is determined which represents an evaluation criterion for the endothelial function.

3. A method for examining the neurovascular coupling on the eye (A) of a patient according to claim 2, characterized in that

that the maximum absolute or percentage change in the capillary vascular responses is used as a reference value for the maximum absolute or percentage change in arterial and / or venous vascular responses, calculating a quotient that is an evaluation criterion for evaluation of vascular endothelial function free from the influence of neurovascular coupling represents.

4. A method for the examination of the neurovascular coupling on the eye (A) of a patient according to one of claims 1 to 3, characterized the signals describing the vascular responses represent intensities, vascular diameters, blood volume values, quotient signals (Q (t, x, y)) from different spectral ranges, blood flow values and blood velocity values of the capillary or larger arterial or venous vessels.

5. A method for the examination of the neurovascular coupling on the eye (A) of a patient according to one of claims 1 to 4, characterized

that the sequence of images of the fundus of the eye (A) over a baseline phase (BP), a stimulation phase (SP), in which the fundus is stimulated with the flicker light, and a post-phase (NP) is recorded.

6. A method for studying the neurovascular coupling on the eye (A) of a patient, in which

using an imaging method to record an image sequence of images of the fundus of the eye (A) over a baseline phase (BP), a stimulation phase (SP) in which the fundus is stimulated with a flicker light, and a postphase (NP), wherein

the fundus is illuminated with measuring light of two different spectral ranges, from intensity values of the images of the image sequence for at least one capillary vessel area (KGB) of the fundus quotient signals (Q (t, x, y)) are derived, which are a capillary vascular response of the vessels of the at least one capillary Representing the vascular area (KGB) on the stimulation, and from the quotient signals (Q (t, x, y)) or / and one of the quotient signals (Q (t, x, y)) averaged quotient signal (Q (t)) an absolute or percentage maximum change (Q _ma x) is determined and used as the evaluation criterion for the neurovascular coupling.

7. A method for examining the neurovascular coupling on the eye (A) of a patient according to claim 6, characterized in that

in that diameter signals (D (t, x, y)) are derived from the images of the image sequence for at least one vessel section (GA) of arterial or venous vessels of the fundus, which represent an arterial or venous vascular response of the at least one vessel section (GA) to the stimulation , and from the Diameter signals (D (t, x, y)) an average diameter signal (D (t)) is formed, the absolute or percentage maximum change (D _max ) is determined, which is an evaluation criterion for Endothelfunktion.

8. A method for examining the neurovascular coupling on the eye (A) of a patient according to claim 7, characterized in that

a quotient of the maximum change (Q _ma x) of the averaged quotient signal (Q (t)) and the maximum change (D _max ) of the averaged diameter signal (D (t)) is formed, which is an evaluation criterion for one of the influence of the neurovascular Coupling represents free evaluation of vascular endothelial function.

9. A method for examining the neurovascular coupling on the eye (A) of a patient according to one of claims 6 to 8, characterized

the image-forming process is carried out on the basis of optical coherence tomography and the images are OCT images.

10. A method for the examination of the neurovascular coupling on the eye (A) of a patient according to one of claims 6 to 9, characterized

that the flicker light has a different spectral range from the measuring light and the measuring light of the different spectral ranges and the flicker light can be adjusted independently of each other.

11. A method for the examination of the neurovascular coupling on the eye (A) of a patient according to claim 8, characterized in that

the maximum change (Q _ma x) and / or (D _max ) is color-coded in a mapping image, to which at least one capillary vessel area (KGB) and / or the at least one vessel section (GA) are assigned.

12. An apparatus for examining the neurovascular coupling on the eye (A) of a patient, comprising an imaging system (1) designed to generate an image sequence of images of the fundus of the eye (A), the image intensities of the fundus characterizing structures, the capillary density , the blood velocity, represent the blood flow or the blood volume of the vessels, with a lighting unit (3) for generating flicker light, with which at least a section of the fundus is stimulated,

a data and image processing unit (5), designed for the selection of capillary vessel areas (KGB) and vessel sections (GA) of arterial and venous vessels from the images of the image sequence, a unit for deriving signals (1 1) associated with the selected capillary vessel areas (KGB) and the selected vessel sections (GA), a signal analysis unit (7) and a result and presentation unit (8).

13. A device for examining the neurovascular coupling on the eye (A) of a patient, comprising an imaging system (1), for generating an image sequence of images of the fundus of the eye (A), with a lighting unit (3), designed to generate a measurement light , with at least two spectral regions for illumination, as well as for generating a flicker light for stimulating the fundus, a data and image processing unit (5), designed for the selection of capillary vessel areas (KGB) and vessel sections (GA) of arterial and venous vessels in the images of the image sequence a unit for deriving quotient signals (10) associated with the selected capillary vascular areas (KGB), a unit for deriving diameter signals (6) associated with the selected vascular sections (GA), a signal analysis unit (7) and a result and Presentation unit (8), where

the illumination unit (3) is formed by a structured arrangement of adaptively controllable LEDs as an illumination structure having at least three different spectral ranges which can be temporally varied in geometry and dimension, whereby selected capillary vessel regions (KGB) and / or selected vessel segments (GA) are adaptively illuminated and stimulated can be.

14. The apparatus according to claim 13, characterized

the measuring light can be generated independently of one another by driving LEDs of two spectral ranges and the flicker light by controlling LEDs of a third spectral range.

15. The device according to claim 13, characterized in that the imaging system (1) is designed as a fundus camera with a digital image sensor (2).

16. The device according to claim 12, characterized in that the imaging system (1) is an optical coherence tomograph (OCT) or a scanning imaging system or an adaptive optics system.

17. The apparatus according to claim 14, characterized

the spectral ranges of the LEDs producing the measurement light are green and red and the spectral range of the LEDs producing the flicker light is blue.

18. Device according to claim 15, characterized in that

the digital image sensor (2) is a monochromatic image sensor, the spectral ranges of the measurement light within and the spectral range of the flicker light being outside the spectral sensitivity of the digital image sensor (2).