Electroretinography system, stimulation device for an electroretinography system, method for electroretinography, control device for an electroretinography system, and computer program product

Abstract

The present invention relates to the field of medical technology and in particular to the field of electroretinography (ERG).An electroretinography system (1) is proposed comprising: a first signal generator (11) for generating a first stimulation signal; a first light source (12) for generating first optical stimuli in a visible spectral range based on the first stimulation signal; a second signal generator (21) for generating a second stimulation signal; a second light source (22) for generating second optical stimuli in a UV spectral range based on the second stimulation signal; a detection unit (31) for detecting a common ERG response signal; and an evaluation unit (41) configured to extract from the common ERG response signal a first ERG response signal component corresponding to the first stimulation signal and a second ERG response signal component corresponding to the second stimulation signal.The electroretinography system further comprises a control device (42), the control device being configured to: determine a first measurement of the first ERG response signal component and a second measurement of the second ERG response signal component; and adjust the first optical stimuli and / or the second optical stimuli such that the first and second ERG response signal components exhibit the predefined interaction characteristics. A stimulation device for an electroretinography system, a method for electroretinography, a control device for an electroretinography system, and a computer program product are also provided.

Description

[0001] The present invention relates to an electroretinography (ERG) system. The present invention further relates to a corresponding stimulation device for an electroretinography system, a method for electroretinography, a control device for an electroretinography system, and a corresponding computer program product.

[0002] Electroretinography (ERG) systems are used to examine retinal function. Light stimuli are applied, and the electrical responses generated by the retina during the visual process are recorded. Electroretinography can be considered a procedure in the field of ophthalmological electrodiagnostics in humans, animals, and ex vivo retinal preparations.

[0003] In an ERG system, electrical potentials generated by the retina can be recorded using one or more electrodes. These are transient potentials that reflect the electrical activity of the cones, rods, and bipolar cells. The electrical potentials can be recorded via an electrode placed on the cornea or conjunctiva. A counter electrode is located near the eye, for example, at the lateral canthus (eyelid angle). A grounding electrode to reduce electrical interference can be placed, for example, on the forehead or earlobe. A distinction can be made between scotopic (dark-adapted) and photopic (light-adapted) conditions. Under scotopic conditions, the retina is adapted for night vision; that is, the rod system dominates both vision itself and the electrical signals. Under photopic conditions,After light adaptation with a defined background light, the rod system is desensitized and the cone system becomes dominant. Therefore, under scotopic conditions, rod function is primarily tested, while under photopic conditions, cone function is primarily tested. ERG testing is used, for example, to monitor the progression of retinitis pigmentosa, in which the rods are primarily affected and later the cones. Electroretinography is also used in zoology—specifically in the sensory physiology of animals—to examine the eyes of vertebrates and invertebrates.

[0004] The inventor recognized that the development and preclinical evaluation of therapeutic strategies for use in human retinal diseases is predominantly based on murine models with gene defects homologous to those in humans. However, mice have a significantly differently organized cone system than humans. The rod system and the sparsely occurring "true" blue cones (also known as "true blue," visual pigment S-opsin) are, according to current knowledge, very similarly organized. The majority of cones in humans are formed by green cones (visual pigment M-opsin) and red cones (visual pigment L-opsin). In mice, however, these cones contain a mixture of the visual pigments mS-opsin and mM-opsin; an analogous mL-opsin is absent (the prefix "m" serves to distinguish mouse opsins from those of humans).The mixing ratio of opsins in the cones is not uniformly distributed in the mouse retina; rather, there is a distinct dorsoventral gradient, which, according to current knowledge, is attributable to living conditions (the upper hemisphere visualizes the ground, the lower hemisphere the sky, with correspondingly diverging visual demands). Additionally, the maximum spectral sensitivity of the mS opsin is shifted towards the UV range at 360 nm compared to that of the human S opsin (approx. 420 nm).

[0005] A disadvantage of conventional ERG systems is that they are designed for measurements in the visible spectrum. The inventor recognized that conventional systems are inadequate for measurements in nocturnal animals, such as mice, which have a different light sensitivity curve (V-lambda curve), particularly in the UV range. The inventor realized, for example, that electroretinography (ERG) measurements of cone function in mice using commercially available equipment do not capture the UV-sensitive component of the cones, even though mS opsin constitutes a large portion of the mixed visual pigment. Therefore, current measurements are inefficient, and the results of preclinical substance testing fall short of their potential.

[0006] US 2014 / 0 333 898 A1 discloses a system and method for assessing retinal function.

[0007] US 2014 / 0 080 900 A1 discloses reagents and methods for modulating the activity of cone photoreceptors.

[0008] Furthermore, US 2011 / 0116046A1 reveals a variable LED light source.

[0009] Starting from conventional ERG systems, one object of the invention may be to provide an improved ERG system.

[0010] The inventors recognized that it would be particularly desirable to extend conventional ERG systems to include measurements in the UV range, for example, to test the function of the cones in the retina of nocturnal animals. Alternatively or additionally, it would be desirable to provide an ERG system that enables more meaningful measurements in various spectral ranges in a simpler manner.

[0011] The inventors further recognized the desirability of providing an ERG system that would allow for the simple measurement of test subjects (e.g., mice) with light sensitivity curves that differ from those of humans. In particular, simplified system calibration would be desirable. Alternatively or additionally, it would be desirable to be able to retrofit existing ERG systems cost-effectively.

[0012] The claimed subject matter is defined in the independent claims. Advantageous further developments are described in the dependent claims.

[0013] According to a first aspect of the present invention, an electroretinography system is provided comprising: a first signal generator for generating a first stimulation signal; a first light source for generating first optical stimuli in a visible spectral range based on the first stimulation signal; a second signal generator for generating a second stimulation signal; a second light source for generating second optical stimuli in a UV spectral range based on the second stimulation signal; a detection unit for detecting a common ERG response signal; and an evaluation unit configured to extract from the common ERG response signal a first ERG response signal component corresponding to the first stimulation signal and a second ERG response signal component corresponding to the second stimulation signal.The electroretinography system further comprises a control device, the control device being configured to: determine a first measurement of the first ERG response signal component and a second measurement of the second ERG response signal component; and adjust the first optical stimuli and / or the second optical stimuli such that the first and second ERG response signal components exhibit the predefined interaction signs.

[0014] It is therefore proposed that, compared to a conventional ERG system designed solely for measurements in the visible spectrum, a second light source be added. This second light source is configured to generate a second optical stimuli in the UV spectral range. This includes not only a second light source but also a second signal generator to produce a second stimulation signal. The second light source is configured to generate further optical stimuli in the UV spectral range based on the second stimulation signal. This allows for the advantageous provision of optical stimuli in both the visible and UV spectral ranges, enabling parallel or alternating application of these stimuli.One advantage is that more meaningful measurement results can be achieved. Adaptation effects or a degrading measurement quality, which could occur if measurements with visible stimuli on the one hand and UV stimuli on the other were taken with a significant time interval, can be advantageously avoided.

[0015] In the proposed solution, the ERG response signal acquired by the acquisition unit includes contributions from both the optical and UV spectral ranges of stimulation. The evaluation unit is therefore configured to extract from the combined ERG response signal a first ERG response component corresponding to the first stimulation signal and a second ERG response component corresponding to the second stimulation signal. In other words, the evaluation unit can be configured to extract the degree of physiological interaction of the respective signals in the retina of the eye from the combined ERG response signal generated by the first ERG signal component corresponding to the first stimulation signal and the second ERG signal component corresponding to the second stimulation signal.

[0016] A further advantage of the proposed solution is that conventional ERG systems can be retrofitted with a second signal generator to produce a second stimulation signal and a second light source to generate second optical stimuli in a UV spectral range based on the second stimulation signal. An existing first signal generator in a conventional ERG system for generating a first stimulation signal and an existing first light source for generating first optical stimuli in a visible spectral range based on the first stimulation signal can still be used. An existing acquisition unit, for example, with a signal amplifier and A / D converter connected to a measuring electrode, can also still be used. However, the response signal now also contains additional signal components.According to the proposed solution, an evaluation unit is provided which is configured to extract from the combined ERG response signal a first ERG response component corresponding to the first stimulation signal and a second ERG response component corresponding to the second stimulation signal. The corresponding evaluation can preferably be implemented as a computer-based solution and therefore easily added retroactively to extend the functionality of conventional ERG systems. This enables cost-effective retrofitting.

[0017] Against this background, a stimulation device for an electroretinography (ERG) system is proposed according to a further aspect of the present disclosure. The ERG system comprises a first signal generator for generating a first stimulation signal; a first light source for generating first optical stimuli in a visible spectral range based on the first stimulation signal; a second signal generator for generating a second stimulation signal; a second light source for generating second optical stimuli in a UV spectral range based on the second stimulation signal; a detection unit for detecting a common ERG response signal; and an evaluation unit configured to extract from the ERG response signal a first ERG response signal component corresponding to the first stimulation signal and a second ERG response signal component corresponding to the second stimulation signal.The proposed stimulation device includes a second signal generator for producing the second stimulation signal and a second light source for producing the second optical stimuli in a UV spectral range based on the second stimulation signal. A control device is also provided, configured to: determine a first measurement of the first ERG response signal component and a second measurement of the second ERG response signal component; and adjust the first optical stimuli and / or the second optical stimuli such that the first and second ERG response signal components exhibit predefined interaction characteristics.

[0018] One advantage of this design is that such a stimulation device allows for cost-effective retrofitting of an existing ERG system and / or retrofitting with minimal technical effort. A particular advantage is that no modification to the existing interaction between the first signal generator and the first light source is necessary.

[0019] Furthermore, according to another aspect of the present disclosure, a method for electroretinography is proposed comprising the steps of: generating a first stimulation signal; generating first optical stimuli in a visible spectral range based on the first stimulation signal; generating a second stimulation signal; generating second optical stimuli in a UV spectral range based on the second stimulation signal; acquiring a common ERG response signal; and extracting a first ERG response signal component corresponding to the first stimulation signal and a second ERG response signal component corresponding to the second stimulation signal from the common ERG response signal.

[0020] It is understood that the aforementioned stimulation device, method, control device and computer program product may have identical or similar features and / or advantages as the electroretinography system according to the first aspect of the present disclosure, as described above and below.

[0021] The following section defines and explains some of the terms and designations used in this disclosure.

[0022] Within the scope of this disclosure, a visible spectral range can be understood to mean a portion of the spectrum normally visible to humans, in particular a spectral range between 380 nm and 780 nm, and especially between 400 nm and 780 nm. A UV spectral range is understood to mean light or electromagnetic radiation in the optical frequency range with wavelengths shorter than visible light, in particular in the UV-A, UV-B and / or UV-C spectral range, and especially in a spectral range between 315 nm and 380 nm.

[0023] The acquisition unit can be a functional unit designed to capture an ERG response signal. Electrical potentials generated by the retina can be recorded using one or more electrodes. These potentials could, for example, be measured against a reference electrode using an electrode placed on the cornea or conjunctiva. The one or more electrodes can be coupled to an analog-to-digital converter via an optional signal amplifier to capture the ERG response signal. Signal processing can be analog or digital.

[0024] Preferably, the electroretinography system is configured such that the first signal generator, together with the first light source, and the second signal generator, together with the second light source, are configured to operate in parallel. In other words, a measurement can be performed with both light sources active. An advantage of this is that measurements in the visible and UV spectral ranges can be performed with a comparable state of adaptation in the subject or test object. Adaptation effects or other changes in measurement quality therefore do not distort the measurement. Adaptation effects could occur, for example, if visible and UV stimuli were measured with a significant time interval.When stimulation is applied simultaneously in the visible and UV spectral ranges, the corresponding response components can be separated and assigned to the stimuli by subsequent signal processing using the evaluation unit. The evaluation unit can also be configured to extract the degree of physiological interaction of the signals in the retina from the combined ERG response signal generated by the first ERG signal component corresponding to the first stimulation signal in the visible spectral range, and the second ERG signal component corresponding to the second stimulation signal in the UV spectral range. This is particularly relevant when both light sources are active during measurement and generate pulsed stimulation signals, also known as flicker stimuli, which primarily result in alternating light pulses in the visible and UV spectral ranges.

[0025] Accordingly, the electroretinography system can be configured to alternate between an optical stimulus in the visible spectral range and an optical stimulus in the UV spectral range. An advantage of this configuration is that the evaluation unit can separate the response signal components in the time domain, despite parallel measurements in the UV and visible spectral ranges, i.e., with a single acquisition of a common ERG response signal. The electroretinography system can be configured to generate the first and second optical stimuli in an interleaved operating mode, producing an alternating sequence of optical stimuli in the visible spectral range and optical stimuli in the UV spectral range. An optical stimulus can be a light pulse or flash.

[0026] The first or second signal generator can include an adjustable delay element and be configured to delay the second optical stimuli relative to the first optical stimuli by a defined amount. By delaying the first and second optical stimuli relative to each other, it is possible to ensure that they do not arrive at the eye simultaneously, thus generating temporally separated contributions to the response signal. It is also possible for both the first and second signal generators to include a delay element. An advantage of this configuration is that the desired interactions of the response signal components can be obtained more precisely and therefore more quickly than with a series of measurements using random time differences between the two stimuli. This can facilitate subsequent signal processing.Furthermore, the adjustable delay can also be used to determine the assignment of ERG response signal components, i.e., whether they are elicited by the first or the second optical stimuli. For example, if the delay is set to delay the generation of the second stimulation signal, the effect on the overall ERG response signal can be observed. The response signal component that is detected with the corresponding delay can then be assigned to the second stimulation signal.

[0027] The first signal generator for generating the first stimulation signal and the second signal generator for generating the second stimulation signal can each have independent clocks. In other words, the first signal generator, in conjunction with the first light source, and the second signal generator, in conjunction with the second light source, can be configured to generate the first and second optical stimuli independently. "Independent" can mean that the frequency and / or phase of the first and second optical stimuli are not synchronized.For example, the first optical stimuli can be generated using a first signal generator and a first light source of a conventional ERG system, and the second optical stimuli can be generated using a second signal generator and a second light source of a retrofitted stimulation device according to one aspect of the present disclosure. This facilitates the retrofitting of conventional ERG systems.

[0028] In a training system, the acquisition unit can be synchronized with either the first or the second signal generator. The acquisition unit can be configured to sample the combined ERG response signal synchronized with the first stimulation signal generated by the first signal generator. Alternatively, the acquisition unit can be configured to sample the combined ERG response signal synchronized with the second stimulation signal generated by the second signal generator. According to one embodiment, the acquisition unit is therefore synchronized only with either the first or the second signal generator. By synchronizing the acquisition unit with one of the signal generators, signal generation and signal acquisition are correlated.For example, the first signal generator and the acquisition unit may be integral components of an existing ERG system, configured such that signal generation and acquisition are strictly correlated. In this case, the signal generator and acquisition unit may be synchronized with a common clock. The second signal generator, however, may be part of a retrofitted or added stimulation device. The first ERG response signal component, corresponding to the first stimulation signal generated by the first signal generator, is therefore strictly correlated with the timing or sampling by the acquisition unit, whereas ERG response signal components corresponding to the second stimulation signal generated by the second signal generator do not exhibit such a strict correlation, for example, varying randomly in phase or temporal position between the two optical stimuli.The evaluation unit can be configured to use this information to distinguish and extract the first and second response signal components.

[0029] The electroretinography system can be configured such that the first and second stimulation signals do not have a fixed phase relationship. Alternatively, the system can be configured to introduce random delays between the first and second stimulation signals. A fixed phase relationship between the first and second stimulation signals is also possible, but not required. In particular, synchronization can be omitted in an ERG system created by retrofitting an existing system. This can significantly simplify the retrofit process, as no major hardware modifications to the existing components are necessary.It may be sufficient if a stimulation device with the second signal generator and the second light source is started at approximately the same time as, for example, an already existing internal first signal generator with the first light source. The acquisition unit detects the combined ERG response signal. The evaluation unit can again differentiate between the various ERG signal components, for example, because only the first ERG signal component, based on an internal first signal generator, has a fixed phase relationship with a detection, e.g., sampling, by another internal acquisition unit.

[0030] The electroretinography system, as described above, includes a control device configured to: determine a first measurement (e.g., amplitude and / or latency information of the signal) of the first ERG response signal component and a second measurement of the second ERG response signal component; and adjust the first optical stimuli and / or the second optical stimuli such that the first and second ERG response signal components exhibit the predefined interaction characteristics. The first measurement of the first ERG response signal component and the second measurement of the second ERG response signal component can each contain amplitude and / or latency information. The first measurement of the first ERG response signal component can be the amplitude of the first ERG response signal component. The second measurement of the second ERG response signal component can be the amplitude of the second ERG response signal component.Alternatively or additionally, the first measurement of the first ERG response signal component can be or contain latency information of the signal. Similarly, the second measurement of the first ERG response signal component can alternatively or additionally be or contain latency information of the signal. Alternatively or additionally, the first measurement of the first ERG response signal component can contain amplitude and latency information of a scalar product of the first ERG response signal component with a predefined signal template. Similarly, the second measurement of the second ERG response signal component can contain amplitude and latency information of a scalar product of the second ERG response signal component with a predefined (same or different) signal template.One advantage is that a flexible approach can be provided for determining a species-specific equivalent biological effectiveness of first optical stimuli in a visible spectral range and second optical stimuli in a UV spectral range. Another advantage is that calibration can be simplified. The ERG responses to (a) stimulation in the visible spectral range (e.g., with white light) and (b) stimulation with UV light are evaluated. The intensity of the stimuli can be adjusted so that both stimuli elicit the same (or equally strong) ERG response. An advantage is that calibration can be performed in this way with simultaneous or alternating pulsed exposure to white and UV light. As described above, pulses of white and UV light can be measured alternately. Synchronization is not strictly necessary, as separation, among other things,This is possible by evaluating different phase positions. For example, the intensity of the first and second optical stimuli is adjusted so that they each elicit equally strong ERG response signal components.

[0031] In a further development process, the control device can be configured to gradually and repeatedly adjust the first and / or second optical stimuli until the first and second ERG response signal components exhibit the predefined interaction characteristics. This allows the first and second optical stimuli to be iteratively adjusted until the desired interaction characteristics are achieved. This can be particularly advantageous when the effect of adjusting the first and / or second optical stimuli on the first and second ERG response signal components is not known in advance; that is, it is not yet definitively known which specific adjustment is required to achieve the desired interaction characteristics, such as an equal amplitude for the first and second ERG response signal components.

[0032] The control device can be configured to: determine a first amplitude of the first ERG response signal component and a second amplitude of the second ERG response signal component; and adjust the first optical stimuli and / or the second optical stimuli such that the first and second ERG response signal components have the same amplitude. An advantage is that a flexible approach can be provided for determining a species-specific equivalent biological effectiveness of first optical stimuli in a visible spectral range and second optical stimuli in a UV spectral range. The amplitude of the first and / or second optical stimuli is thus varied or adjusted until they have the same amplitude with respect to the first and second ERG response signal components and therefore produce an equivalent biological effect. This adjustment can be made stepwise.It is not necessary to know a luminous sensitivity curve (V-lambda curve) in the respective spectral ranges beforehand. One advantage is that the system can be used flexibly for measurements on different species.

[0033] In particular, the control device can be configured to: determine a first amplitude and first phase of the first ERG response signal component and a second amplitude and second phase of the second ERG response signal component; and adjust the first optical stimuli and / or the second optical stimuli such that the ERG response signal, i.e., the jointly generated ERG response signal, exhibits a maximum amplitude at a first defined phase difference between the first and second response signal components and a minimum amplitude at twice the frequency at a second defined phase difference, for example, a phase difference of 180°. The respective phase values ​​can depend on the waveform of the ERG response signal components.

[0034] The electroretinography system can be configured such that the first and second optical stimuli have different radiometric intensities. Specifically, the different radiometric intensities of the first and second optical stimuli can be designed to elicit ERG response signal components of the rod and / or cone systems with identical characteristics (e.g., amplitude, waveform). In other words, the first and second optical stimuli are configured to elicit first and second ERG response signal components with identical characteristics, such as identical amplitude. An advantage of this approach is that the response signal itself is used as the criterion, rather than identical radiometric intensity.Despite differing luminous efficacy curves in the visible and UV spectral ranges, an ERG response signal can be generated with the same amplitude for both the first and second optical stimuli. A further advantage is the ability to flexibly perform measurements of different species, potentially with differing luminous efficacy curves (also known as V-lambda curves).

[0035] The electroretinography system can be configured such that the first and / or second optical stimuli are a pulse train with a pulse frequency between 0.3 Hz and 100 Hz, particularly between 1 Hz and 50 Hz, particularly between 3 Hz and 30 Hz, and particularly with a pulse frequency of 6 Hz. The first and / or second light source can be configured to generate repetitive stimuli with a predetermined repetition frequency. Such stimuli can also be referred to as flicker stimuli. For example, a pulse train of short, particularly narrowband, UV light pulses with a predetermined repetition frequency, or pulse frequency, of e.g., 6 Hz, can be used.

[0036] The second light source can comprise one or more UV LEDs, particularly in conjunction with a (narrowband) bandpass filter configured to allow light with a wavelength in the range of 360 nm to 365 nm (and not in the visible range) to pass through. An advantage of this is that the effects of SWS opsin and MWS opsin in the murine cones can be distinguished during measurement. An advantage of the additional specific bandpass filter is that a measurement can be taken at the maximum sensitivity of SWS opsin while simultaneously preventing stimulation of MWS opsin, thus achieving a particularly informative measurement with reduced energy input to the eye. The second light source can be part of a retrofit solution with an additional module. The second light source can also be part of a stimulation device according to any aspect of this disclosure.

[0037] The stimulation device, for example in the form of an add-on module for an existing ERG system, also referred to as the host system, can preferably be configured to generate an additional, independent ERG signal component, wherein the resulting total ERG response signal, originally consisting only of a first signal component generated by a host system based on stimulation with light in a visible spectral range, is amplified or extended by the second signal component based on stimulation with light of a different quality, such as in the UV spectral range.This allows for a modified response characteristic of the resulting overall ERG response signal, originally consisting only of a first signal component generated by a host system based on transient and optionally constant stimulation (background light) with light in a visible spectral range, by means of a second signal component generated by an additional module based on transient stimulation and optionally constant stimulation (background light) with light of a different quality, such as in a UV spectral range. A measurable physiological interaction in the visual system can be determined between the ERG signal component generated by the stimulation device, which initially has an unknown physiological effect, and the signal component generated by the host system, which has a known physiological effect, for the purpose of calibrating the stimulus generated by the stimulation device.Equivalence of effect (for stimuli of the same frequency) is achieved, for example, when stimulation with a specific phase difference results in an increase in amplitude, while stimulation with another specific phase difference, such as antiphase stimulation, results in a decrease in amplitude when the frequency is doubling. The respective phase values ​​depend on the waveform of the ERG response signal components.

[0038] According to a further aspect of the present disclosure, a control device for an electroretinography system is proposed, wherein the control device is configured to: receive a common ERG response signal, wherein the common ERG response signal comprises a first ERG response signal component corresponding to a first stimulation signal and based on first optical stimuli with light in a visible spectral range, and a second ERG response signal component corresponding to a second stimulation signal and based on second optical stimuli with light in a UV spectral range; extract the first ERG response signal component and the second ERG response signal component from the received common ERG response signal; determine a first measurement value (e.g.,Amplitude and / or latency information of the signal), in particular a first amplitude, the first ERG response signal component, and a second measured value, in particular a second amplitude, the second ERG response signal component; and generating a control signal for adjusting the first optical stimuli and / or the second optical stimuli such that, by (stepwise, repeated) adjustment of the first optical stimuli and / or the second optical stimuli, the first and second ERG response signal components exhibit the desired or predefined interaction characteristics, in particular such that the first and second ERG response signal components have the same amplitude. The control device may have the configurations and advantages described above with regard to the control device.

[0039] According to another aspect of the present disclosure, a computer program product is proposed, comprising instructions which, when executed by a computer, cause the computer to perform the following steps: receiving a common ERG response signal, wherein the common ERG response signal has a first ERG response component corresponding to a first stimulation signal and based on first optical stimuli with light in a visible spectral range, and a second ERG response component corresponding to a second stimulation signal and based on second optical stimuli with light in a UV spectral range; extracting the first ERG response component and the second ERG response component from the received common ERG response signal; determining a first measured value (e.g.,Amplitude and / or latency information of the signal), in particular a first amplitude, the first ERG response signal component and a second measured value, in particular a second amplitude, the second ERG response signal component; and generating a control signal to adjust the first optical stimuli and / or the second optical stimuli such that by (stepwise, repeated) adjustment of the first optical stimuli and / or the second optical stimuli the first and second ERG response signal components exhibit the desired or predefined interaction characteristics, in particular such that the first and second ERG response signal components have the same amplitude.

[0040] In other words, the proposed signal processing can also be performed on a computer appropriately configured by the proposed computer program. It is understood that, in this context, receiving an ERG response signal can be understood as receiving data representing the ERG response signal. For example, the data can be acquired by a sensor unit, such as a detector or electrode array, an optional signal amplifier, and an analog-to-digital converter, and made available as a digital ERG response signal for further processing by a computer. Similarly, generating a control signal can be understood as generating data representing a control signal or control commands.Within the scope of this disclosure, a computer can be understood to mean any data processing device and can also refer to an office computer, a laboratory computer, a microcontroller, a server, a cloud-based data processing device, and / or (integrated) circuits as well as application-specific circuits or ASICs. A further advantage of this design is that the functionality of conventional ERG systems can be easily extended retroactively with the proposed solution.

[0041] Further advantages are outlined in the description and the accompanying drawings.

[0042] It is understood that the features mentioned above and those to be explained below can be used not only in the combinations specified, but also in other combinations or on their own, without leaving the scope of the present invention.

[0043] Exemplary embodiments of the invention are shown in the accompanying drawings and are explained in more detail in the following description. They show: Fig. 1 a schematic representation of an electroretinography system according to an embodiment of the disclosure; Fig. 2 a schematic representation of an electroretinography system according to a further embodiment of the disclosure with a stimulation device and a control device according to further aspects of the present disclosure; Fig. 3 graphical representations of ERG response signals with first and second ERG response signal components from experimental measurement data, from a simulation and as a superposition; Fig. 4. A flowchart showing the process steps for adjusting the first and / or second optical stimuli; Fig. 5 a graphical representation of experimental measurement data; Fig. 6 another graphical representation with to Fig. 5 associated experimental measurement data, wherein the first optical stimuli and second optical stimuli are adapted such that the first and second ERG response signal components have the same amplitude; Fig. 7 a graphical representation with experimental measurement data from a mouse model lacking sensitivity in the white light range (Opn1 mw mutant); Fig. 8 a flowchart of a procedure for electroretinography.

[0044] In Fig. Figure 1 is a schematic representation of an electroretinography or ERG system 1 according to an embodiment of the disclosure. The ERG system 1 is used in particular for examining the retinal function of a subject 200. The ERG system 1 is configured to record electrical potentials generated by the retina of the eye 201 of the subject 200 using one or more electrodes.

[0045] The ERG system 1 comprises a first signal generator 11 for generating a first stimulation signal and a first light source 12 for generating first optical stimuli in a visible spectral range based on the first optical stimulation signal. The first signal generator 11 and the first light source 12 are located in the Fig. The first light source 12 shown in Figure 1 is connected to each other via a connection 13. The first light source 12 can, for example, comprise one or more white LEDs or other light sources that emit visible light in a spectral range typically visible to humans between 380 nm and 780 nm, in particular between 400 nm and 780 nm.

[0046] The ERG system 1 further comprises a second signal generator 21 for generating a second stimulation signal and a second light source 22 for generating second optical stimuli in a UV spectral range based on the second stimulation signal. The second signal generator 21 and the second light source 22 are located in the Fig. The second light source 22, as shown in the example in Figure 1, is connected to each other via a connection 23. The second light source 22 can, for example, comprise one or more UV LEDs or other light sources configured to emit UV light. Optionally, the second light source 22 can include a bandpass filter configured to allow light with a wavelength in the range of 360 nm to 365 nm, but not in the visible range, to pass through. Unlike conventional systems, the second optical stimuli make it possible not only to perform measurements in the visible spectrum but also measurements on test subjects, such as nocturnal animals, especially mice, with a different luminous efficacy curve (V-lambda curve).

[0047] The ERG system 1 further comprises a detection unit 31, which is configured to detect an ERG response signal. The detection unit may preferably include a measuring amplifier or preamplifier 32, which may be provided as part of the detection unit 31 or as a separate element. Fig. Figure 1 shows the preamplifier as an example of an external operational amplifier. The ERG response signal is preferably acquired by means of an electrode 33 applied to the cornea or conjunctiva. Preferably, a counter electrode 34 is provided in the vicinity of the eye, for example, in a corner of the eyelid. However, a counter electrode at another location in the vicinity of the eye is also conceivable, such as at the temple 202 or the earlobe 203. The evaluation unit 31 is configured to acquire a combined ERG response signal. This combined ERG response signal comprises a first ERG response signal component corresponding to the first stimulation signal in response to the first optical stimuli from the first light source 12 and a second ERG response signal component corresponding to the second stimulation signal in response to the second optical stimuli from the second light source 22.

[0048] The ERG system 1 further comprises an evaluation unit 41. The evaluation unit 41 is configured to extract from the combined ERG response signal the first ERG response component corresponding to the first stimulation signal and the second ERG response component corresponding to the second stimulation signal. In the proposed solution, the ERG response signal acquired by the acquisition unit includes contributions elicited by stimulation in the visible spectral range as well as contributions elicited by stimulation in the UV spectral range. The evaluation unit 41 is configured to evaluate the ERG response signal in such a way that the respective ERG response signal components elicited by stimulation in the visible spectral range and by stimulation in the UV spectral range can be separated from one another, or rather, the degree of physiological interaction of the respective stimuli in the retina of the eye can be determined.

[0049] Preferably, the first signal generator 11 together with the first light source 12 and the second signal generator 21 together with the second light source 22 are configured to operate in parallel. This allows measurements in the visible and UV spectral ranges to be performed with a comparable state of adaptation of the subject or test object. Adaptation effects or other changes in measurement quality therefore do not distort the measurement. For example, so-called flicker stimuli can be delivered. The first and / or second optical stimuli can be a pulse train with a pulse frequency between 0.3 Hz and 100 Hz, particularly between 1 Hz and 50 Hz, particularly between 3 Hz and 30 Hz, and particularly with a pulse frequency of 6 Hz. An optical stimulus or light pulse in the visible spectral range and an optical stimulus or light pulse in the UV spectral range preferably alternate.

[0050] In the illustrated embodiment, the ERG system 1 further comprises a control device 42. The control device 42 is configured to determine a first measured value, for example, amplitude and / or latency information, of the first ERG response signal component, and a second measured value, for example, amplitude and / or latency information, of the second ERG response signal component. Furthermore, the control device 42 is configured to adapt the first optical stimuli and / or the second optical stimuli such that the first and second ERG response signal components exhibit predefined interaction characteristics. An iterative approach is possible here, as described below with regard to Fig. 4 will be described as an example.

[0051] In the Fig. In the example shown, the first signal generator 11, the second signal generator 12, the acquisition unit 31, the evaluation unit 41, and the control device 42 are arranged together. For example, these elements can be provided as a common arrangement 10, for instance, in a common housing. This facilitates synchronization of the elements. For example, a common clock generator can be provided, which enables synchronized operation.

[0052] The first light source 12 and the second light source 22 can also be integrated into the common housing. However, to allow for a flexible experimental setup, the light sources are preferably provided as separate elements that can be flexibly positioned to apply the first and second stimuli in a targeted manner to the eye 201 of the test subject 200.

[0053] In contrast, in the Fig. Example 2 shows a different arrangement with a separate stimulation device 20. This enables cost-effective retrofitting of existing systems. Elements designated with the same reference numerals in Fig. 2 correspond to the corresponding elements in Fig. 1. Therefore, the following will primarily highlight the differences.

[0054] In the Fig. In the example shown, the first signal generator 11, connected to the first light source, and the detection unit 31 form a common arrangement 10 and can, for example, be arranged in a common housing. The signal generator and detection unit from an existing ERG system can also be used. However, an additional stimulation device 20 is provided. The second signal generator 21 and the second light source 22 are arranged separately and form a separate stimulation device 20. The stimulation device 20 includes the second signal generator 21 for generating the second stimulation signal and the second light source 22 for generating the second optical stimuli in a UV spectral range based on the second stimulation signal.

[0055] In the Fig. In the example shown in Figure 2, the evaluation unit 41 is also arranged separately. However, it is also possible for the evaluation unit 41 to be part of the stimulation device 20 or to be provided as part of the common arrangement 10. Preferably, the evaluation unit 41 can be implemented by means of a computer or computing device. In this case, the common ERG response signal acquired by the acquisition unit 31 can, for example, be provided to the computer for evaluation in the form of digitized measurement data. The computer is specially configured in terms of software and, in this case, serves as the evaluation unit 41, which is configured to extract from the common ERG response signal a first ERG response signal component corresponding to the first stimulation signal and a second ERG response signal component corresponding to the second stimulation signal.This enables cost-effective implementation and flexible evaluation of the measurement data.

[0056] The stimulation device 20 can be implemented as a completely independent unit. This allows for particularly easy retrofitting of an existing ERG system. For measurements in the UV spectral range, the stimulation device can be put into operation approximately simultaneously with the common arrangement 10. In this case, the first signal generator 11 for generating the first stimulation signal and the second signal generator 21 for generating the second stimulation signal can have independent clocks 15, 25. In particular, the first and second stimulation signals do not have a fixed phase relationship to each other, resulting in random delays between the first and second stimulation signals. This can prevent the first and second optical stimuli generated by the first and second stimulation signals from always occurring at the same time or at the same interval.with a fixed phase relationship to each other, affecting the eye 201 of the subject 200 and possibly always hitting simultaneously.

[0057] The detection unit 31 can be synchronized with the first signal generator 11. This is in Fig. Figure 2 schematically illustrates the connection of the clock generator 15 to both the first signal generator 11 and the acquisition unit 31. The acquisition unit 31 can sample the combined ERG response signal synchronously with the first stimulation signal generated by the first signal generator. By correlating the generation of the first stimulation signal with the sampling signal, the first ERG response component within the combined ERG response signal can be separated from the second ERG response component. However, the separation and extraction of the first and second ERG response components is not limited to this.

[0058] Alternatively, the acquisition unit 31 can also be synchronized with the second signal generator 21, as schematically represented by the dashed line connecting the clock 15 and the second signal generator 21. In this case, the acquisition unit 31 can be configured to sample the common ERG response signal synchronously with the second stimulation signal generated by the second signal generator 21.

[0059] Furthermore, it is possible to synchronize both the first signal generator 11 and the second signal generator 21 with the acquisition unit. This ensures that the first and second ERG response signal components, generated in response to the first and second stimuli, are always located at a defined temporal position within the combined ERG response signal recorded by the acquisition unit.

[0060] Optionally, the ERG system 1 can include an adjustable delay element 26, which is configured to delay the second optical stimuli relative to the first optical stimuli by a defined amount. In the Fig. In the example shown in Figure 2, the delay element 26 is schematically depicted in a control line from the first evaluation unit 41 or the control device 42 to the second signal generator. A delay element in an incoming or outgoing control or connection line of a signal generator can be understood, within the scope of this disclosure, as part of the signal generator. In principle, the first and / or second signal generator can have an adjustable delay element and be configured to delay the second optical stimuli relative to the first optical stimuli by a defined amount. For example, if there is a superposition of the first ERG response signal component and the second ERG response signal component, the response signal components can be separated by delaying the first or second optical stimuli.Furthermore, the adjustable delay element can be used to perform comparative measurements at different delays. This comparison allows the determination of which part of the ERG response signal has been shifted, thereby enabling the assignment of response signal components to the first and second optical stimuli.

[0061] Fig. Figure 3 shows graphical representations of ERG response signals, including first and second ERG response signal components derived from experimental measurement data, a simulation, and a superposition. The horizontal axis represents time, and the vertical axis represents the amplitude of the combined ERG response signal. The first column displays experimental measurement data from a mouse ERG measurement. The second column shows a model of the ERG response signals. The third column shows a superposition of the measurement data from column 1 and the model from column 2.

[0062] In Fig. Figure 3, in the first row, depicts a first case, also referred to as Case 1, where the first light source emits initial optical stimuli in a visible spectral range, here white light, and is set to an intensity "A". This could be a white light source from a conventional ERG device. The second light source generates second optical stimuli in a UV spectral range with an initially unknown intensity X. Even if the optical intensity is known, the amplitude of the elicited ERG response signal may initially be unknown. The graph with the experimental measurement data is labeled 311. The graph with the modeling is labeled 312. The graph with the superposition is labeled 313.

[0063] In Fig. Figure 3, in the second row, depicts a second case, also referred to as Case 2. The first light source emits initial optical stimuli in a visible spectral range, here white light, and is set to an intensity "B", where "B" > "A", i.e., intensity "B" is greater than intensity "A". The second light source generates further optical stimuli in a UV spectral range with an initially unknown intensity X, as in Case 1. The graph with the experimental measurement data is labeled 321. The graph with the modeling is labeled 322. The graph with the superposition is labeled 323.

[0064] In Fig. Figure 3, in the third row, depicts a third case, also referred to as Case 3. The first light source emits initial optical stimuli in a visible spectral range, here white light, and is set to an intensity "C", where "C">B", meaning the intensity "C" is greater than the intensity "B". The second light source generates further optical stimuli in a UV spectral range with an initially unknown intensity X, as in Case 1. The graph with the experimental measurement data is labeled 331. The graph with the modeling is labeled 332. The graph with the superposition is labeled 333.

[0065] In case 1, the (biological effect of) intensity A is much smaller than X. Curves 314 and 315 represent separate measurements of the combined ERG response signal. Corresponding simulations are shown in the second column with curves 316 and 317. Curves 314 and 315, and 316 and 317, respectively, are not temporally correlated with the acquisition unit 31 of the ERG system 1, as they are all caused or dominated by the second light source 22 of the stimulation device 20 of the ERG system 1, while the stimuli from the first light source 21 of the ERG system 1 are negligible. In the example shown, the first signal generator 11 and the second signal generator 21 are not synchronized with each other and have independent clocks 15 and 25. However, the acquisition unit 31 is synchronized with the first signal generator 11.

[0066] In case 2, the (biological effect of) intensity A is comparable to X. Curves 324 and 325 represent separate measurements of the combined ERG response signal. Corresponding simulations are shown in the second column with curves 326 and 327.

[0067] Curves 324, 325 and 326, 327 are at least partially temporally correlated with the detection unit 31 of the ERG system 1, as they exhibit both response signal components elicited by the first optical stimuli from the first light source 11 of the ERG system 1 (this component is correlated) and response signal components elicited by the second optical stimuli from the second light source 21 of the (non-synchronized) second light source 22 of the ERG system 1 (this component is uncorrelated). Interference or superposition of the two response signal components occurs. If both response signal components happen to occur simultaneously (curve 324 in the measurement data, curve 326 in the model), this results in a maximum amplitude with an unchanged curve shape.If both signals occur in opposite phase (approximately the case with curve 325 in the measurement data, curve 327 in the model), positive and negative components partially cancel each other out, resulting in a minimal amplitude with twice the frequency (i.e., twice as many "peaks").

[0068] In case 3, the (biological effect of) intensity A is much greater than X. Curves 334 and 335 represent separate measurements of the combined ERG response signal. Corresponding simulations are shown in the second column with curves 336 and 337, which are superimposed. Curves 334 and 335, as well as 336 and 337, are all temporally correlated with the detection unit 31 of the ERG system 1, since they are all caused or dominated by the first light source 11, while the second optical stimuli from the second light source 22 of the ERG system are negligible.

[0069] Fig. Figure 4 shows a flowchart with procedural steps for adjusting the first and / or second optical stimuli. An exemplary algorithm for finding the equivalence of the two stimuli (UV stimulus of unknown intensity vs. white light stimulus of known intensity) is explained using graphical representations of ERG response signals with first and second ERG response signal components from a simulation. The graph in the left column in Fig. 4 corresponds to the scenario in Graph 312 in Fig. 3. The graph in the middle column in Fig. 4 corresponds to the scenario in Graph 322 in Fig. 3. The graph in the right column in Fig. 4 corresponds to the scenario in Graph 332 in Fig. 3.

[0070] In step 410, a common ERG response signal is received, wherein the common ERG response signal has (a) a first ERG response signal component corresponding to a first stimulation signal and based on first optical stimuli with light in a visible spectral range, and (b) a second ERG response signal component corresponding to a second stimulation signal and based on second optical stimuli with light in a UV spectral range. As with respect to Fig. As described in point 3, different scenarios can arise.

[0071] The left column shows the case in which Fig. Figure 3, designated as Case 1, shows that the (biological effect of) the intensity of the first optical stimuli A is much smaller than the (biological effect of) the intensity of the second optical stimuli X. In step 411, an evaluation is performed to determine that the joint ERG response signal, or the position of curves 317, 318, 319, is uncorrelated with a time window of the acquisition unit for capturing the joint ERG signal. In step 412, an adjustment is made to the first optical stimuli and / or the second optical stimuli. Since the (uncorrelated) second optical stimuli dominate in this case, the intensity of the second optical stimuli can be reduced, the intensity of the first optical stimuli can be increased, or both. The algorithm then leads back to step 410, where the joint ERG response signal is measured again using the adjusted first and / or second optical stimuli.

[0072] The right-hand column shows the case in which Fig. Figure 3, designated as Case 3, shows that the (biological effect of) intensity C of the first optical stimuli is much greater than the (biological effect of) intensity X of the second optical stimuli. In step 431, an evaluation is performed to determine that the joint ERG response signal, or the position of curves 336 and 337, correlates completely with a time window of the acquisition unit for capturing the joint ERG signal. In step 432, an adjustment is therefore made to the first optical stimuli and / or the second optical stimuli. Since the correlated first optical stimuli dominate in this case, the intensity of the first optical stimuli can be reduced, the intensity of the second optical stimuli can be increased, or both. The algorithm then leads back to step 410, where the joint ERG response signal is measured again using the adjusted first and / or second optical stimuli.

[0073] The middle column shows the case in which Fig. Figure 3, referred to as Case 2, shows that the (biological effect of) the intensity of the first optical stimuli and the (biological effect of) the intensity of the second optical stimuli elicit ERG response signals with the same amplitude. This is considered to be an at least approximately equivalent physiological effect. In successive measurements, curves 326, 227, and 328 can be obtained, where the ERG response signals (a) correlate with the time window of the detection unit, which uses visible light as the stimulus, and (b) vary depending on the phase difference between the first and second optical stimuli, ranging from increased amplitude and frequency corresponding to the stimulus (curve 326) to decreased amplitude at twice the frequency (curve 327) and intermediate forms (curve 328).The algorithm ends in step 422, where the first optical stimuli and / or the second optical stimuli are adjusted such that the first and second ERG response signal components have the same amplitude or produce the same biological effect.

[0074] Fig. 5 and Fig. Figure 6 are graphical representations that are at least partially based on the same experimental measurement data. Fig. Figure 5 is another graphical representation, where the first and second optical stimuli are adjusted such that the first and second ERG response signal components have the same amplitude. It is an exemplary representation of a successful determination of the physiological effectiveness of UV stimuli using the parameters related to… Fig. The equivalence method described in section 4. The one with “flash intensity [log (cd*s / m²)” 2The horizontal axis labelled “)” indicates the intensity of an optical stimulus. The vertical axis labelled “b-wave amplitude [µV]” indicates the amplitude of the measured ERG response signal.

[0075] The measurements were performed on a rhodopsin knockout mouse under dark-adapted (scotopic) conditions, as this mouse exhibits normal cone function with a complete absence of rod function, thus reliably eliminating any influence of the rods on the measurements. Measuring cone function would otherwise only be possible under light-adapted (photopic) conditions, but this adaptation also affects cone function (reducing responses), and this effect varies spectrally for white and UV light, since the standard adaptation background consists of white light.

[0076] Fig. Figure 5 shows an intensity-response function. The intensity-response function is a method for visualizing statistical ERG data from multiple entities at different intensities. It displays box-and-whisker plots (representing the 5%, 25%, 50%, 75%, and 95% quantiles of measurement data) of one group (here, UV data) compared to the limiting 5% and 95% quantiles of the other, typically a control group (here, white light data). Curve 521 shows the 50% quantile of the ERG response signals in response to second optical stimuli in the UV spectral range. Curve 511 shows the 5% quantile of the ERG response signals in response to first optical stimuli in the visible spectral range. Curve 512 indicates the 95th percentile of ERG response signals in response to initial optical stimuli in the visible spectral range.

[0077] The data here represent the statistical results of several measurements, as in Fig. Figure 6 shows this. In the left graph in Fig. Figure 6, labeled "dark adapted, UV flash", shows the ERG response signals 621 under dark-adapted conditions to a second optical stimulus in the UV spectral range. The graph on the right... Fig. Figure 6, labeled "dark adapted, white flash," shows the ERG response signals 611 under dark-adapted conditions to a first optical stimulus in the visible spectral range. The multiple superimposed curves represent the ERG response signals at different stimulus intensities. Intensity increases from top to bottom.

[0078] An exemplary approach for the in Fig. 5 and Fig. The 6 measurements shown can be described as follows: (a) First, for example, the one relating to Fig. In the procedures described in section 4, the first and / or second optical stimuli are adjusted such that the first and second ERG response signal components exhibit predefined interaction characteristics, in this case providing the same ERG response signal amplitude. During equivalence determination, an equivalent value B (white light) is established for the unknown value X (UV light). (b) From tabulated radiometric measurements of the UV light source, the desired relative values ​​with respect to X are determined (here logarithmic and semi-logarithmic steps upwards and downwards, as in Fig. 5 shown on the horizontal axis and for exemplary ERG response signals in Fig. (Figure 6). The table was then used to determine which setting (larger or smaller current through the LEDs) would yield, for example, 1 / 10 X, 1 / 100 X, etc., or 10 X, 100 X, etc. Since radiometric and photometric quantities behave proportionally in this context, equivalents to, for example, 1 / 10 B, 1 / 100 B, etc., or 10 B, 100 B, etc., can also be obtained without further measurement. In the example, equivalence was found at approximately B = 1 cd*s / m². 2 Given, this corresponds logarithmically to the value "0". With the existing setup, the range from -2 log (cd*s / m 2 ) corresponding to 1 / 100 X to 1 log (cd*s / m 2 ) correspondingly 10 X in a total of seven steps ( Fig. 5, X-values ​​for the black curve and the grey boxes). (c) Measurements are carried out with the first signal generator and the first light source at the various desired intensities of the first stimulus (white light, calibrated) (here B / 100 to 10 B, cf. Fig. 6, right). With the second signal generator and the second light source, measurements are carried out at the desired equivalent intensities using the second stimulus (UV light, equivalently calibrated) (here X / 100 to 10 X, cf. Fig. 6, left).

[0079] From the presentation in Fig. 6. It is readily apparent that the exemplary measurements shown in Fig. 5 and Fig. 6 yielded practically the same result. This underlines, firstly, that the equivalence determination was correct, and secondly, that the extension to other intensities is indeed feasible and effective.

[0080] d) The measurements according to c) are repeated on different entities until a meaningful amount of data is available. An example result is shown in Fig. Figure 5 illustrates this. The so-called flash intensity (X-axis) represents the equivalent values ​​for the measurement data using UV light (second stimulus), and the actual, calibrated values ​​for the measurement data using white light (first stimulus).

[0081] Fig. Figure 6 shows graphs with experimental measurement data from a model lacking sensitivity in the white light range (Opn1mw mutant) to illustrate the gain in response capacity using UV stimulation, based on ERG response signals generated by first optical stimuli in the visible spectral range (white stimulus 1) or second optical stimuli in the UV spectral range (UV stimulus 2).

[0082] Using the first signal generator and the first light source, which can be provided, for example, by a conventional ERG device, measurements were carried out at the various desired intensities of the first optical stimulus (white light, calibrated) (here B / 100 to 10 B, analogous to Fig. 6, right).

[0083] With the second signal generator and the second light source, which can be provided, for example, by a stimulation device proposed herein, measurements were carried out at the desired equivalent intensities using the second optical stimulus (UV light, equivalently calibrated) (here X / 100 to 10 X, analogous to Fig. 6, left).

[0084] In normal mice, in Fig. 7 designated C56BL / 6 Normal Control, and the Opn1mw mutants, in Fig. In the case of Opn1mw no MW opsin (7), a regular rod function is present. Therefore, rod responses dominate in the scotopic (dark-adapted) measurements using single flashes (no flicker) (top row, "scotopic flash," see, for example, curves 713, 711, 721, 723). However, the missing cone component in the Opn1 mw mutants during white light stimulation is due to an amplitude reduction immediately after the positive peak (see arrows in). Fig. 7) recognizable, which makes the sloping part convex instead of concave.

[0085] In the photopic ERG (bottom row in Fig. 7) The functional gain through the equivalence-calibrated UV-ERG is particularly evident.

[0086] Firstly, the response of the mouse without M-opsin (Opn1 mw mutant) to UV stimulation, see e.g. curve 724, is comparable to that of the normal mouse ( Fig. 7, bottom left, see e.g. curve 722), while in contrast to the control, no response is discernible with white light stimulation in the intensity range used here, see e.g. comparison of curve 714 with curve 712 in Fig. 7, bottom right.

[0087] Secondly, the response of the normal mouse (C57BL / 6) to UV stimulation is more sensitive (starting at lower intensity, higher amplitude at a given intensity) than to white light stimulation, because the background for suppressing rod influences by adaptation is spectrally white by default and thus only affects the M-opsin of the cones.

[0088] From the presentation in Fig. 7 It is readily apparent that the exemplary measurements shown in Fig. Figure 7 on the lower left yields practically the same result. This underscores, firstly, that the equivalence determination was correct, and secondly, that an extension can also be applied to the photopic range without further measurement. A key finding is the lack of a response from the Opn1 mw mutant upon white light stimulation.

[0089] Fig. Figure 8 shows a flowchart of procedure 800 for electroretinography. In step S801, a first stimulation signal is generated, and in step S802, based on the first stimulation signal, first optical stimuli in a visible spectral range are generated. In step S803, a second stimulation signal is generated, and in step S804, based on the second stimulation signal, second optical stimuli in a UV spectral range are generated.

[0090] In step S805, a common ERG response signal is acquired. In step S806, a first ERG response signal component corresponding to the first stimulation signal and a second ERG response signal component corresponding to the second stimulation signal are extracted from the common ERG response signal. The extracted first and second ERG response signal components can be used directly as measurement results, or optionally, further procedural steps can be performed.

[0091] In step S807, a first measurement, in particular a first amplitude, of the first ERG response signal component and a second measurement, in particular a second amplitude, of the second ERG response signal component can be determined. In an optional step S808, a control signal can be generated to adjust the first optical stimuli and / or the second optical stimuli such that, by (stepwise, repeated) adjustment of the first optical stimuli and / or the second optical stimuli, the first and second ERG response signal components exhibit predefined interaction characteristics, in particular such that the first and second ERG response signal components have the same amplitude. An example is provided in Fig.Figure 8 shows the adaptation of the first optical stimuli via a feedback path 809 to step S801 of the generation of the first stimulation signal. Alternatively or additionally, a corresponding feedback path to steps S802, S803, and / or S804 may also be provided.

[0092] In summary, the present disclosure enables the extension of conventional ERG systems to include measurements in the UV range, for example, for functional testing of the retinal cones in nocturnal animals. According to another aspect of the present disclosure, an ERG system can be provided that enables more meaningful measurements in various spectral ranges in a simpler manner. Furthermore, it is possible to provide an ERG system that allows for the simple measurement of test subjects (e.g., mice) with luminous efficacy curves that differ from human luminous efficacy. In particular, simplified system calibration can be enabled. Moreover, existing ERG systems can be retrofitted cost-effectively according to aspects of the present disclosure.

Claims

[1] Electroretinography system (1) with: - a first signal generator (11) for generating a first stimulation signal; - a first light source (12) for generating first optical stimuli in a visible spectral range based on the first stimulation signal; - a second signal generator (21) for generating a second stimulation signal; - a second light source (22) for generating second optical stimuli in a UV spectral range based on the second stimulation signal; - a detection unit (31) for detecting a common ERG response signal; and - an evaluation unit (41) which is configured to extract from the common ERG response signal a first ERG response signal component corresponding to the first stimulation signal and a second ERG response signal component corresponding to the second stimulation signal: characterized bya control device (42), wherein the control device is arranged to: - determining a first measured value of the first ERG response signal component and a second measured value of the second ERG response signal component; and - adapting the first optical stimuli and / or the second optical stimuli such that the first and second ERG response signal components have predefined interaction signs. [2] Electroretinography system (1) according to claim 1, wherein the first signal generator (11) together with the first light source (12) and the second signal generator (21) together with the second light source (22) are arranged to be operated in parallel with each other. [3] Electroretinography system (1) according to one of the preceding claims, wherein the electroretinography system is arranged to alternate an optical stimulus in the visible spectral range and an optical stimulus in the UV spectral range. [4] Electroretinography system (1) according to one of the preceding claims, wherein the first or second signal generator (11, 21) has an adjustable delay element (26) and is configured to delay the second optical stimuli relative to the first optical stimuli by a defined amount. [5] Electroretinography system (1) according to one of the preceding claims, wherein the first signal generator (11) for generating the first stimulation signal and the second signal generator (21) for generating the second stimulation signal have clock generators (15, 25) independent of one another. [6] Electroretinography system (1) according to claim 5, wherein the detection unit (31) is synchronized either with the first signal generator (11) or with the second signal generator (21); in particular wherein the detection unit (31) is either configured to sample the common ERG response signal synchronized with the first stimulation signal generated by the first signal generator (11) or wherein the detection unit (31) is configured to sample the common ERG response signal synchronized with the second stimulation signal generated by the second signal generator (21). [7] Electroretinography system (1) according to one of the preceding claims, wherein the first stimulation signal and the second stimulation signal do not have a fixed phase relationship to each other, whereby random delays arise between the first and second stimulation signals. [8] Electroretinography system (1) according to one of the preceding claims, wherein the first measured value of the first ERG response signal component and the second measured value of the second ERG response signal component each comprise amplitude and latency information of the signal. [9] Electroretinography system (1) according to one of the preceding claims, wherein the control device (42) is arranged to gradually, repeatedly adapt the first optical stimuli and / or the second optical stimuli until the first and second ERG response signal components have the predefined interaction signs. [10] Electroretinography system (1) according to one of the claims one of the preceding claims, wherein the control device (42) is arranged to: - determining a first amplitude of the first ERG response signal component and a second amplitude of the second ERG response signal component; and - adjusting the first optical stimuli and / or the second optical stimuli such that the first and second ERG response signal components have an equal amplitude. [11] Electroretinography system (1) according to one of the preceding claims, wherein the first optical stimuli and the second optical stimuli have a different radiometric intensity, in particular wherein the different radiometric intensity of the first optical stimuli and the second stimuli are arranged to each elicit an ERG response signal component of the rod and / or cone system with the same characteristic. [12] Electroretinography system (1) according to one of the preceding claims, wherein the first and / or second optical stimuli are a pulse sequence with a pulse frequency between 0.3 Hz and 100 Hz, in particular between 1 Hz and 50 Hz, in particular between 3 Hz and 30 Hz, in particular with a pulse frequency of 6 Hz. [13] Electroretinography system (1) according to one of the preceding claims, wherein the second light source (22) comprises one or more UV LEDs, in particular in conjunction with a bandpass filter which is designed to allow light to pass at a wavelength in a range of 360 nm to 365 nm, and not in the visible range. [14] Stimulation device (20) for an electroretinography system (1) with a first signal generator (11) for generating a first stimulation signal; a first light source (12) for generating first optical stimuli in a visible spectral range based on the first stimulation signal; a second signal generator (21) for generating a second stimulation signal; a second light source (22) for generating second optical stimuli in a UV spectral range based on the second stimulation signal; a detection unit (31) for detecting a common ERG response signal; and an evaluation unit (41) which is configured to extract from the ERG response signal a first ERG response signal component corresponding to the first stimulation signal and a second ERG response signal component corresponding to the second stimulation signal; wherein the stimulation device (20) comprises the second signal generator (21) for generating the second stimulation signal and the second light source (22) for generating the second optical stimuli in a UV spectral range based on the second stimulation signal; characterized by a control device (42), wherein the control device is arranged to: - determining a first measured value of the first ERG response signal component and a second measured value of the second ERG response signal component; and - adapting the first optical stimuli and / or the second optical stimuli such that the first and second ERG response signal components have predefined interaction signs. [15] Method (800) for electroretinography comprising the steps: - generating a first stimulation signal (S810); - generating first optical stimuli in a visible spectral range based on the first stimulation signal (S802); - generating a second stimulation signal (S803); - generating second optical stimuli in a UV spectral range based on the second stimulation signal (S804); - detecting a common ERG response signal (S805); and - extracting a first ERG response signal component corresponding to the first stimulation signal and a second ERG response signal component corresponding to the second stimulation signal from the common ERG response signal (S806); characterized by - determining a first measured value of the first ERG response signal component and a second measured value of the second ERG response signal component (S807); and - adapting the first optical stimuli and / or the second optical stimuli such that the first and second ERG response signal components have predefined interaction signs (S808). [16] Control device (42) for an electroretinography system (1), wherein the control device is arranged to - Receiving a common ERG response signal, wherein the common ERG response signal has a first ERG response signal component corresponding to a first stimulation signal and based on first optical stimuli with light in a visible spectral range and a second ERG response signal component corresponding to a second stimulation signal and based on second optical stimuli with light in a UV spectral range; - extracting the first ERG response signal component and the second ERG response signal component from the received common ERG response signal (S806); - determining a first measured value, in particular a first amplitude, of the first ERG response signal component and a second measured value, in particular a second amplitude, of the second ERG response signal component (S807); and - Generating a control signal for adapting the first optical stimuli and / or the second optical stimuli such that, by stepwise, repeated adaptation of the first optical stimuli and / or the second optical stimuli, the first and second ERG response signal components have predefined interaction signs, in particular such that the first and second ERG response signal components have an equal amplitude (S808). [17] Computer program product comprising instructions which, when executed by a computer, cause the computer to perform the following steps: - Receiving a common ERG response signal, wherein the common ERG response signal has a first ERG response signal component corresponding to a first stimulation signal and based on first optical stimuli with light in a visible spectral range and a second ERG response signal component corresponding to a second stimulation signal and based on second optical stimuli with light in a UV spectral range; - extracting the first ERG response signal component and the second ERG response signal component from the received common ERG response signal (S806); - determining a first measured value, in particular a first amplitude, of the first ERG response signal component and a second measured value, in particular a second amplitude, of the second ERG response signal component (S807); and - Generating a control signal for adapting the first optical stimuli and / or the second optical stimuli such that, by stepwise, repeated adaptation of the first optical stimuli and / or the second optical stimuli, the first and second ERG response signal components have predefined interaction signs, in particular such that the first and second ERG response signal components have an equal amplitude (S808).

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