Apparatus for acquiring ERG signals during retinal heating and controlling retinal heating based thereon

Abstract

An apparatus for providing retinal ERG stimulation and heating, wherein the control device comprises at least one processor and at least one light source for providing at least one stimulation beam to induce an ERG signal from a target region of the retina, the control device further comprising a heating system for increasing the temperature of at least the control target region, the control processor receiving the retinal ERG signal induced by the control stimulation beam during retinal heating and indicating a control retinal temperature based on the control ERG signal.

Description

[Technical Field]

[0001] The present invention relates generally to electroretinograms (ERGs) and retinal heating. More particularly, the present invention relates to acquiring ERG signals during retinal heating and controlling retinal heating based on the acquired ERG signals. [Background technology]

[0002] Electroretinography (ERG) is a method in which the electrical signal (electrical response) of the retina is recorded during exposure of the retina to a stimulus such as a light flash, which can be useful in a variety of cases, such as diagnosing retinal diseases.

[0003] It has also been discovered that, due to the temperature dependence of retinal electrical signals, ERG signals obtained during retinal heating (e.g., photothermal retinal therapy) can be used to determine retinal temperature. Thus, ERG signals obtained during retinal heating can indicate the temperature occurring in the retina (or at least the temperature difference between two time points). The temperature determination associated with heating can then be used, for example, to control retinal heating so that retinal temperature is maintained at a desired level or so that a desired amount of heat is delivered during a retinal heating therapy procedure.

[0004] It is important to maintain the temperature of the retina at a therapeutically effective level while avoiding temperatures high enough to cause retinal damage. Prior art devices do not provide effective dosimetry for reaching the optimal temperature, nor do they allow for the detection of overtreatment before damage occurs. Summary of the Invention

[0005] It is an object of the present invention to alleviate at least some of the problems in the prior art. According to one aspect of the present invention, there is provided an apparatus for providing retinal ERG stimulation and heating, the apparatus comprising: at least one processor; and at least one light source for providing at least one stimulation beam to induce an ERG signal from a target region of the retina, the apparatus further comprising a heating system for increasing a temperature of at least the target region, the processor being configured to receive the retinal ERG signal induced by the stimulation beam during retinal heating, determine one or more indicators indicative of retinal temperature based on the ERG signal, and control the heating system based on the indicators.

[0006] Given the utility of embodiments of the present invention, retinal heating can be performed more safely: retinal heating can be controlled to raise the temperature of the retina to a level of heating that is below that which could cause retinal damage, yet high enough to induce therapeutic benefit.

[0007] One embodiment of the present invention provides an apparatus and method for performing a calibration protocol to determine the temperature rise of retinal tissue per unit of heating power as an index. The inventors have noted that the retinal temperature rise caused by the same laser power varies between patients, or even between different retinal regions. The present invention provides a method for performing power calibration, which can therefore be used in such calorimetry. Retinal heating can then be delivered in a manner that is individually optimized for the treatment region to reach a therapeutic temperature window. Based on the determined temperature rise per unit of heating power, the heating system can be controlled to provide a calibrated heating power to raise the temperature of the retina, the heating power being within a predetermined range to induce a predetermined retinal temperature rise in a particular case.

[0008] The power calibration protocol can include a processor configured to: a. initiating retinal stimulation by controlling at least one light source to provide a stimulation beam; b. determining a first pre-heat baseline ERG signal; c. Initiating retinal heating by controlling the heating system to provide retinal heating to the target area at a first power and continuing retinal heating for a preset duration; d. determining the first heated ERG signal; e. Optionally, repeating steps c-d with a second or subsequent laser power to determine a second or subsequent heating ERG signal; f. Stop retinal heating; g. determining a baseline ERG signal after the first heating; h. comparing the first pre-heating ERG signal and / or the first post-heating ERG signal to the heating ERG signal to determine the temperature rise of the retinal tissue at the heating power used; i. Using the determined temperature rise, determine the temperature rise of the target area per unit heating power.

[0009] The processor may be configured to repeat at least steps c-d using a predetermined set of heating powers and determine an overall temperature rise of the target area per unit of heating power as an index based on the obtained multiple temperature rises of the target area per unit of heating power.

[0010] When the heating system is turned on, the retinal temperature rises sharply for the first second of heating, followed by a slow drift as the temperature slowly changes and the retinal temperature stabilizes (i.e., no longer changes as rapidly as during the first second of heating). In one embodiment, the heating ERG signal obtained between a predetermined time after changing or starting retinal heating and the subsequent termination or change of retinal heating can be used as the heating ERG signal for temperature determination. Here, a target area temperature can be obtained that better reflects or more efficiently represents the peak temperature rise induced by heat exposure. Since retinal temperature rise is expected to be linearly dependent on heating power, a calibration procedure can first extrapolate the required heating power by determining the amount of heating power required per unit temperature rise and multiplying this number by the desired temperature rise to determine the power required to reach the desired target temperature. To reach the retinal target temperature, a heating power corresponding to the power required to raise the retinal temperature by an amount corresponding to the difference between the determined body temperature and the target temperature, the target temperature difference / rise, can be applied.

[0011] The ERG signals may of course be acquired / recorded essentially continuously, or it may be only the ERG signals acquired after a predetermined time delay determined as the heating ERG signal that is used to determine retinal temperature.

[0012] Additionally or alternatively, an ERG signal obtained essentially immediately after heating begins may be used as the heating ERG signal for temperature determination to determine the rate of temperature rise in the target area of ​​the retina caused by heating at the beginning of the heating procedure. When the initial rate of temperature rise per unit of heating power is known, the processor can determine the appropriate power and / or pulse duration to deliver the desired thermal dose. This can be done by assuming that when the pulse is sufficiently short, the temperature rise is directly proportional to the laser power and pulse duration. If different spot sizes are used in calibration and treatment, the treatment power can be adjusted proportionally to the diameter of the treatment spot.

[0013] In different embodiments of the invention where an indicator is used to control heating, the heating may be terminated or adjusted. Additionally or alternatively, controlling the heating may refer to notifying or configuring the user to be notified. Notification may include, for example, providing the user with auditory and / or visual information indicative of a characteristic of the heating, such as retinal temperature. Based on this notification, the user of the device can adjust or terminate the heating.

[0014] In one embodiment, heating can be terminated or adjusted, or the user can be notified by one or more indicators indicating that the retinal temperature may be excessively high. As demonstrated, the indicators may essentially relate to changes in the amplitude and / or kinetics of the ERG response / signal obtained and recorded during heating, compared to a previously determined baseline ERG response recorded at the corresponding heating power or an ERG response recorded before heating. One or more indicators may be used to determine retinal temperature or retinal temperature change; if this temperature differs from the target retinal temperature by more than a threshold amount, this may be an indication that the retinal temperature determined from the indicators is not actually accurate, but that indicators such as kinetic parameters are not behaving as they should be in the target temperature range (e.g., the acceleration of the kinetics is not linear), and therefore, retinal heating may proceed to temperatures outside the therapeutic window and cause damage.

[0015] The processor may be further configured to extrapolate a heating power that provides a predetermined temperature increase in the target region. If the patient's core body temperature is determined as part of the calibration protocol, the processor may be configured to determine a laser power that leads to a predetermined absolute temperature in the target region of the retina.

[0016] In one embodiment, the processor can extrapolate how ERG signaling kinetics should change during treatment with higher laser powers and can be configured to terminate retinal heating or reduce treatment power if the change in kinetics deviates from expected values ​​by more than a given threshold.

[0017] The processor may be configured to determine the signal-to-noise ratio of the acquired ERG signal and disable the initiation of retinal heating by turning off the heating system or, if retinal heating has not yet been initiated, if the determined signal-to-noise ratio falls below a predetermined threshold. Thus, retinal heating may be prevented or discontinued if the acquired ERG signal cannot be effectively used to obtain information about the target area. This may occur, for example, if ERG electrode contact deteriorates or if the patient undergoing retinal treatment flexes a facial muscle. In such cases, it is safer not to perform retinal heating treatment.

[0018] In some embodiments, the processor may be configured to receive or determine impedance between an ERG electrode, such as an ocular electrode and a reference electrode, as an indicator, and may terminate retinal heating or disable initiation of retinal heating if the impedance exceeds a predetermined threshold.

[0019] In one embodiment, the processor may be configured to determine the amplitude of the ERG signal as an indicator to terminate or adjust retinal heating and / or notify the user if the amplitude during retinal heating falls below a predetermined threshold relative to a previously determined baseline ERG signal amplitude. This may ensure that retinal heating is terminated if the retinal temperature becomes dangerously high and the ERG signal amplitude begins to decrease excessively. Even if a calibration protocol is performed (e.g., in the manner disclosed later herein), the calibration protocol may be erroneous, thereby monitoring the ERG signal amplitude may be a safety mechanism to prevent excessively high retinal temperatures, which may be harmful to the patient.

[0020] The threshold relative amplitude between the amplitude of the ERG signal determined during retinal heating and the amplitude of a predetermined reference ERG response amplitude may be, for example, 0.4 to 0.9, advantageously 0.5 to 0.7.

[0021] In a further embodiment, the processor may be configured to determine the dynamics of the ERG signal as an index and terminate retinal heating if the dynamics, such as its acceleration, differ from a predetermined dynamic value by more than a predetermined threshold amount. ERG signal response kinetics exponentially accelerates over a certain temperature range. In a configuration using an impulse ERG response to determine temperature, the temperature change depends on temperature as follows: ΔT=kln(Δx), where ΔT is the change in temperature, Δx is the relative change in a feature representing the acceleration of the signal, and k is the temperature dependence of the feature.

[0022] At sufficiently high retinal temperatures, the temperature-dependent acceleration no longer follows the relationship described above; when the temperature is high enough, the response speed slows with increasing temperature. If the signal kinetics slows excessively, for example, by more than a threshold amount compared to the baseline value, this can be used to determine that the retinal temperature is excessively high. Thus, monitoring the determined ERG signal kinetics and then terminating or adjusting retinal heating in such cases can also provide a safety mechanism that can prevent harmful heating of the retina.

[0023] In one embodiment of the present invention, a slowing of ERG signal velocity due to excessively high temperatures can be detected by essentially continuously recording ERG signals during retinal heating and comparing the most recent ERG response signal with the fastest ERG response previously recorded during retinal heating involving substantially the same heating power. A threshold amount of kinetic slowing can be determined to correspond to a temperature change of 0.5°C to 4°C, preferably 1°C to 2°C.

[0024] The relationship between ERG signal kinetics and retinal temperature changes may vary slightly based on the chosen method of retinal stimulation. Known data show that when a bright photopic flash is used for retinal stimulation on a bright, constant background, the temperature dependence of ERG signaling rate acceleration is 3.6% / °C. This proved to be an advantageous method for eliciting ERG signals during laser heating application. However, with other stimulation paradigms, this value may vary, for example, in the range of 3%–6% / °C.

[0025] We found that the reduction in ERG signal amplitude and the slowing of ERG kinetics occurred at temperatures lower than the retinal temperature at which damage occurs and higher than the retinal temperature at which therapeutic benefit is induced. After 1 minute of laser exposure, increased production of the molecular chaperones HSP70 and HSP90, which are thought to mediate the therapeutic effects of retinal laser therapy, was detected at retinal temperatures above 44°C and stable treatment, but the injury threshold was determined to be approximately 48°C.

[0026] For example, through a calibration protocol, it may be determined that a known kinetic acceleration of the ERG signal (e.g., given by the formula ΔT = kln(Δx)) is expected. If, during retinal heating, the kinetics of the ERG signal are observed to accelerate by a threshold amount less than this predetermined expected acceleration, this may be an indicator that the temperature has increased to a point where the aforementioned ΔT = kln(Δx) relationship no longer holds.

[0027] In one embodiment, the indicator may be a kinetic parameter of the ERG signal, where, for example, the change in ERG response kinetics induced by laser exposure at a known target temperature of the retina is compared to the predicted kinetic acceleration from the aforementioned formula ΔT = kln(Δx). A change in the acceleration of the ERG response kinetics that is significantly less than this prediction indicates an excessively high temperature, i.e., an increase above the target temperature or above the therapeutic range. The aforementioned difference threshold may correspond to a temperature decrease of preferably 2°C to 8°C, advantageously 4°C to 6°C.

[0028] We also discovered that the optimal therapeutic temperature for retinal heating is the temperature range in which the resulting ERG signal kinetics is fastest, i.e., the temperature range in which the temperature rises or falls. When retinal temperature rises above the optimal therapeutic temperature, ERG signaling begins to rapidly slow down. This rapid slowing of ERG signaling kinetics was found to precede retinal damage, making it suitable for detecting inadvertent overtreatment.

[0029] We further discovered that while the amplitude of the ERG signal does not change dramatically at optimal treatment temperatures, it begins to rapidly decrease as retinal temperatures rise above the optimal treatment temperature. This rapid decrease in ERG amplitude was found to precede retinal damage and is suitable for detecting inadvertent overtreatment.

[0030] The exemplary embodiments presented herein should not be construed as limiting the applicability of the appended claims. The verb "to comprise" is used in this text as an open limitation that does not exclude the presence of unrecited features. Features recited in the dependent claims may be freely combined with each other unless expressly stated otherwise.

[0031] The novel features which are believed to be characteristic of the invention are set forth with particularity in the appended claims. However, the invention itself, both as to its structure and method of operation, together with further objects and advantages thereof, will best be understood from the following description of certain illustrative embodiments when read in connection with the accompanying drawings.

[0032] The invention will now be described in more detail with reference to exemplary embodiments according to the accompanying drawings. [Brief explanation of the drawings]

[0033] [Figure 1] FIG. 1 illustrates a portion of an exemplary configuration related to a device for performing retinal heating while acquiring ERG signals, according to an embodiment of the present invention. [Figure 2]FIG. 2 shows a schematic diagram of an exemplary configuration according to one embodiment of the present invention. [Figure 3] FIG. 3 shows a plot of the relative amplitude between the ERG signals determined compared to the reference ERG signal as a function of retinal temperature. [Figure 4] FIG. 4 shows a plot of the determined temperature difference between the target temperature and the temperature determined from the ERG signal as a function of retinal temperature. DETAILED DESCRIPTION OF THE INVENTION

[0034] FIG. 1 illustrates an apparatus for obtaining retinal ERG signals during retinal heating, the apparatus including components at least partially included in a configuration according to an embodiment of the present invention. The apparatus includes at least one light source configured to provide at least one stimulation beam for illuminating a target area of ​​the retina to stimulate the target area of ​​the retina to elicit a focal ERG signal. Other light sources or light beams, such as a central background beam for illuminating at least the target area of ​​the retina, may also be optionally provided within the apparatus. The light sources (if multiple) are preferably separately controllable. The apparatus further includes a heating system for increasing the temperature of the retina.

[0035] In the embodiment of FIG. 1, a stimulus beam is provided by a stimulus light source LED3. The stimulus beam is used to illuminate at least a target region of the retina, where the target region is the region from which an ERG signal is obtained and, optionally, the region that is heated during retinal heating. The target region may also refer to the region that is heated, in which case the region illuminated by the stimulus beam may not correspond to the entire target region. The stimulus beam is used to elicit / induce an ERG signal from the target region. The stimulus beam source LED3 may be a light-emitting diode (LED) light source configured to provide a stimulus beam having a wavelength of 500-600 nm, for example, approximately 555 nm. Red and green cone cells have similar sensitivity at a wavelength of 555 nm, and therefore, a stimulus beam exhibiting a wavelength close to this wavelength may stimulate both cell types similarly. The stimulus beam may include white light, which can equally stimulate all retinal cone cells.

[0036] The stimulus light source LED3 may be configured to provide a modulated stimulus light beam. Thus, the stimulus beam does not have to be provided as a continuous beam of light, but may comprise a sequence of impulse flashes of light or the like. The modulation may be performed at a frequency of, for example, 4 to 40 Hz, advantageously 10 to 25 Hz.

[0037] 1 is shown in relation to a fundus imaging system IS (which may also be realized as part of the device in some embodiments). The fundus imaging system IS may be, for example, an eyepiece, a fundus camera, or a scanning laser ophthalmoscope. The fundus imaging system may include a first imaging module IM1 and a second imaging module IM2, and one or more filters, such as a second filter F2 (e.g., an optical filter) and a third filter F3 (e.g., an infrared cut filter), that block laser light from being directed toward the imaging module IM2.

[0038] In the device of FIG. 1 , a central background light beam is provided by a central background light source LED2. The central background light beam is configured to illuminate at least a target area of ​​the retina and maintain a light adaptation level in the target area. The central background light beam may be concentric with the target area or may be limited to essentially illuminating only the target area. The central background light source LED2 may be an LED light source. The central background light beam may include white light and / or have a brightness greater than 100 lux at the fundus.

[0039] The brightness of the central background beam can be configured to be reduced when the heating laser or other heating means is turned on to maintain a stable illumination intensity in the target area.

[0040] For example, in a use case scenario where infrared imaging is used for fundus imaging, a central background light beam may not be required.

[0041] The device also includes a means for acquiring an ERG signal, i.e., a means for acquiring a response signal of the target area to the stimulation provided by the stimulation beam. The ERG signal can be an electrical response that can be recorded / collected or acquired by one or more ERG electrodes. The electrodes may include one or more ocular electrodes and one or more reference electrodes. The ERG signal can be obtained as a voltage change between at least two electrodes over time.

[0042] The device may include or be operable in conjunction with a fundus lens L6, which can direct the provided light beam to the fundus of the eye. The fundus lens L6 may be, for example, an inverted fundus lens with a field of view of more than 120 degrees.

[0043] In one embodiment, a fundus lens can be incorporated into the device, thereby eliminating the need to place a lens on the cornea.

[0044] In one embodiment, the device comprises an ocular lens, and the ocular electrodes may be integrated into the ocular lens.

[0045] The heating system includes at least one heat source, such as a heating laser LF, configured to increase the temperature of a target area on the fundus. The heating laser LF may be configured to provide a heating beam directed at at least the target area.

[0046] The heating beam may include wavelengths in the near-infrared region. The wavelength of the light included in the heating beam may be 700 to 1000 nm, and the heating beam may be provided by a heating light source LF that is a fiber-coupled diode laser.

[0047] In one embodiment, the heating beam has a homogeneous irradiance profile and spot diameter of 1-6 mm on the fundus.

[0048] Other heating systems or heating means may also be utilized in connection with devices related to retinal heating. For example, the heating system may be implemented by ultrasound.

[0049] Considering the functionality of the device shown in FIG. 1 in relation to its configuration, one use case scenario will now be described. The three beams mentioned above can be brought onto the same channel and projected onto a conjugate plane CP1. Thus, three optical channels corresponding to a stimulus beam, a central background light beam, and a heating beam can be involved. The heating beam can be directed onto a first mask M1 by a first lens L1. The central background light beam can be directed onto a third mask M3 by a third lens L3. The stimulus beam can be directed onto a fourth mask M4 by a fourth lens L4.

[0050] The fundus lens L6 can project the optical profile of CP1 onto the fundus. The first imaging module IM1 is configured so that CP1 is projected onto a camera sensor or the treating physician's eye can focus on CP1 through the eyepiece of a biomicroscope. The beam passing through the fifth lens L5 is directed toward the eye by the first mirror M1. The first mirror M1 may be positioned directly in front of the first optical module IM1 (such as a biomicroscope), so that the left eye has a view of the fundus to the left of the first mirror M1, and the right eye has a view of the fundus to the right of the first mirror M1. The fifth lens L5 can project images from the masks M1, M3, and M4 onto the conjugate plane CP1, meaning that the optical profile emitted through the mask is imaged onto CP1. Beam splitters BS2 and BS3 may combine the beams originating from the heating laser fiber output LF with the light sources LED2 and LED3.

[0051] In Figure 1, masks M1, M3, and M4 are holes through which the light profile is projected onto conjugate plane CP1. Masks can also be shaped mirrors or digital micromirror devices, in which case light is reflected from the mask instead of passing through it.

[0052] 2 schematically illustrates an exemplary configuration according to an embodiment of the present invention. The configuration includes at least one processor 102 and at least one light source for providing at least one stimulation beam, and the configuration further includes a heating system for increasing the temperature of a target region of the retina. The device may also include or be used in conjunction with other components such as those depicted in FIG. 1.

[0053] Preferably, the device comprises at least one processor 102, a stimulus light source LED3, and a heating light source LF (or some other heating system). This configuration may also comprise a central background light source LED2. The processor 102 is configured to control some or all of the light sources (and / or other heating systems). Control may include powering the light source on / off or controlling any other aspect of the light source, such as the power or illuminance provided by the provided light beam. The processor 102 is configured to receive an acquired ERG signal, which may be obtained by electrodes 104. The electrodes 104 may comprise multiple electrodes, such as at least one ocular electrode and at least one reference electrode. The processor 102 may be configured to analyze the acquired ERG signal and determine one or more relevant parameters. The electrodes 104 may be included in the configuration in some embodiments.

[0054] The ERG signals obtained from the electrodes 104 may be directed through an ERG amplifier-digitizer system for processing, such as amplification, filtering, and digitization, before being received by the processor 102. Such an ERG amplifier-digitizer system may be considered part of an arrangement that is part of the processor 102 in some embodiments.

[0055] The processor 102 may be configured to initiate retinal heating by providing power to the heating light source LF. The processor may be configured to initiate stimulation of a target area of ​​the retina using the stimulation beam by powering the stimulation light source LED3. The processor 102 may then be configured to receive retinal ERG signals evoked by the stimulation beam during retinal heating, determine one or more indicators indicative of retinal temperature based on the acquired ERG signals, and control the heating system based on the indicators.

[0056] Controlling the heating system may include controlling a heating system, such as a heating light source LF, to provide a determined heating power (and may not necessarily mean power) to provide a retinal temperature that is within a predetermined range, so that the retinal temperature may remain in a safe and / or therapeutic range and / or may be prevented from rising above a certain threshold to maintain safe retinal heating.

[0057] In one embodiment, the device can be configured to determine that retinal heating is occurring in a temperature range where ERG signal dynamics accelerate exponentially with increasing temperature. If it is determined that the signal dynamics determined from the ERG signal accelerate an amount significantly different from that expected based on the target temperature increase, the heating system can be controlled to, for example, terminate or adjust heating.

[0058] In the temperature range where the dynamics of the ERG signal depend exponentially on temperature, the amplitude is less sensitive to temperature changes: at higher temperatures the amplitude begins to decrease, which can be used as an indicator to terminate treatment or adjust the heating power.

[0059] The calibration protocol can be performed using one or more heating powers that result in a temperature increase within this range (the range in which ERG signal kinetics exponentially accelerates with increasing temperature).

[0060] The processor 102 may be configured to determine the signal-to-noise ratio of the obtained ERG signal and disable initiation of retinal heating by turning off the heating light source LF or if retinal heating has not been initiated, if the determined signal-to-noise ratio falls below a predetermined threshold. The signal-to-noise ratio determination may be performed essentially continuously. The predetermined threshold may be a signal-to-noise ratio value below which a reliable ERG signal cannot be obtained.

[0061] In some embodiments, the processor 102 may be configured to determine the impedance between an ERG electrode, such as an ocular electrode and a reference electrode, based on the received ERG signal, and may terminate retinal heating or disable initiation of retinal heating if the impedance exceeds a predetermined threshold.

[0062] In one embodiment, the processor 102 may be configured to determine the amplitude of the ERG signal and terminate retinal heating if the amplitude during retinal heating is below a predetermined threshold relative to a previously determined baseline ERG signal amplitude.

[0063] Figure 3 shows the relative amplitude determined between the ERG signal compared to a reference ERG signal on the vertical axis and the experimental target retinal temperature on the horizontal axis. The target temperature range is shown as 44-45 °C, which can be considered the therapeutic window for treatment in typical use cases. The relative amplitude refers to the value of the determined ERG signal during heating divided by the ERG signal determined in the reference case, preferably using the same heating power, or immediately before heating, such as laser application. The dots in the figure represent unique treatments performed in preclinical studies, where a calibration procedure was performed to determine the appropriate laser power for the treatment to reach the experimental target temperature. Treatments that resulted in retinal coagulation (lesions) are marked with an asterisk, while treatments without coagulation are marked with a circle. Therefore, treatments marked with an asterisk may induce damage to the retina, and in these cases, the heating power provided may be too high.

[0064] From Figure 3, as an example, it can be seen that if a relative amplitude threshold of 0.6 is used to terminate treatment, treatment is unlikely to terminate when the treatment temperature is below 45°C, but is certainly terminated if laser exposure causes cell damage.

[0065] The device may be configured to execute a power calibration protocol to determine a heating power corresponding to a desired retinal temperature or change in retinal temperature. The temperature increase per unit heating power for a target area may be determined as an indicator that may be used to control the heating system to provide a calibrated heating power to increase the retinal temperature.

[0066] The power calibration protocol may be performed, for example, before performing a retinal heating treatment, and the processor 102 may: a) initiating retinal stimulation by controlling at least one light source to provide a stimulation beam; b) determining a first pre-heat baseline ERG signal; c) initiating retinal heating by controlling the heating system to provide retinal heating to the target area at a first power and continuing the retinal heating for a preset duration d; d) After the retinal temperature changes have stabilized (e.g., after a predetermined duration, such as 10-20 seconds, after it is known or assumed that the temperature changes have significantly slowed), determine the first heating ERG signal, e) optionally repeating steps c-d with a second or subsequent laser output to determine a second or subsequent heating ERG signal f; f) retinal heating is terminated; g) optionally, determining a first post-heating baseline ERG signal after retinal temperature has returned to body temperature (e.g., after a predetermined duration after body temperature is known or assumed to have decreased to the initial body temperature); h) comparing the first pre-heating ERG signal and / or the first post-heating ERG signal with the heating ERG signal to determine the temperature rise of the retinal tissue at the heating power used; i) using the determined temperature rise to determine the temperature rise of the target area per unit of heating power. Several alternative methods for determining the temperature rise in retinal tissue using the heating power used based on a comparison of the pre-heating and / or post-heating ERG signals with the heating ERG signal are described later in this specification.

[0067] The processor 102 may be configured to repeat at least steps c-d above for a predetermined set of heating powers and determine a total temperature rise of the target area per unit of heating power based on the obtained multiple temperature rises of the target area per unit of heating power. For example, a zero-crossing linear fit between heating power and temperature rise may be utilized, where the temperature rise per unit power is the slope of the linear fit.

[0068] In some embodiments, the heating ERG signal may be selected to exclude ERG responses within a predetermined time period after the initiation or change of retinal heating, and include only responses obtained after that time period but before the subsequent change or termination of retinal heating. Here, it may be known or determined that the change in retinal temperature is stable or slowly changing (slowly increasing toward a peak retinal temperature) after the predetermined time period. The change in retinal temperature may occur slowly after a predetermined period, e.g., after the first seconds of heating, compared to the change in retinal temperature that occurs during the first seconds of heating, where the change in retinal temperature is more rapid during these first seconds of heating. Using ERG responses obtained after the predetermined time period for temperature determination may result in a determined retinal temperature that is closer to the actual peak retinal temperature caused by the heating power used.

[0069] Through a calibration protocol, using the determined or estimated body temperature and the determined target retinal temperature, a target temperature rise of the retinal tissue can be determined and a corresponding heating power can be delivered. However, even when a calibration protocol is performed, errors in the determined temperature rise of the target area per unit of heating power and / or body temperature can result in an actual rise of the retinal tissue that is excessive, and one or more additional indicators, such as ERG signal kinetics, can be used to control the heating to avoid overtreatment.

[0070] When a calibration protocol is used to determine the heating power that should be used to reach a retinal target temperature (or temperature rise), the retinal temperature (rise), determined from continuously recorded ERG signals, may indicate overtreatment if it falls significantly below the target temperature (rise) during heating exposure.

[0071] Figure 4 shows the determined temperature difference between the target temperature determined by the calibration protocol, the temperature determined based on the ERG signal determined during heating on the vertical axis, and the experimental target retinal temperature on the horizontal axis. As an example, if a threshold of a 5°C difference between the target temperature and the temperature determined during heating is used, it can be seen that treatment is rarely terminated if the temperature is below 45°C, a temperature reliably induced in treatment that causes cell damage.

[0072] In one or more embodiments, the processor 102 may be configured to determine the dynamics of the ERG signal and, for example, terminate or adjust retinal heating if the acceleration of the dynamics differs from a predetermined acceleration value by more than a predetermined threshold amount. In one embodiment, the predetermined acceleration value is determined based on a calibration protocol.

[0073] Dynamics can include, for example, the rate or speed or response time of the obtained / measured ERG signal (electrical response) of retinal tissue to stimulation by a stimulus beam. Features can be extracted from the ERG signal to reflect changes in response dynamics and, therefore, changes in retinal temperature. In embodiments where impulse ERG responses are used for temperature determination, these features can be, for example, the relative change in the b-wave time-to-peak relative to the moment of the impulse stimulus (the ratio of the time-to-peak value between two responses), or the overall time-axis compression applied to the ERG response to maximize its similarity to another response. The logarithm of these features can be used as an index that linearly depends on the temperature difference between the compared responses.

[0074] As retinal temperature increases slightly, the dynamics of the ERG signal accelerates, such that the implicit time of the ERG signal shifts toward the time of stimulation by an amount proportional to the logarithm of the retinal temperature change. As retinal temperature increases above 44°C, this relationship breaks down, and the ratio of dynamic acceleration to temperature change initially decreases. As the temperature increases further, the dynamics begin to slow down with increasing temperature. This effect can be used as a safety mechanism to terminate treatment or, for example, reduce laser power. The dynamics can be used as a safety mechanism with or without a calibration protocol.

[0075] Slowing of ERG kinetics at elevated temperatures may also be used as an indicator of overtreatment, for example, by continuously recording ERGs during laser exposure and terminating treatment if the kinetics of the ERG signal begin to slow during laser exposure. This can be done by comparing the kinetics of continuously updated or recorded ERG responses during heating with the baseline ERG response and the fastest kinetics previously obtained during the same heating power exposure.

[0076] It can be determined that the kinetics of the ERG response accelerates by 3-6%, e.g., approximately 3.6%, with a 1°C increase in retinal temperature. In one exemplary scenario, a heat treatment can be performed at time t=0, where the kinetics accelerates by 0% at time t=5 s, by 10% at time t=10 s, by 20% at time t=15 s, by 21% at time t=20 s, and by 15% at time t=20 s. At the fastest kinetics, the kinetics accelerates by 21%, and then slows by 6%, which can translate to a temperature change of slightly less than 2°C in the retinal tissue. The temperature increase can be estimated to be very high because the kinetics slow down during treatment. In a typical or intended treatment session in which the retinal temperature is maintained at or near the target temperature or therapeutic range, the kinetics should accelerate and approach a plateau until treatment is completed.

[0077] If the ERG response slows down, for example, by an amount corresponding to a temperature greater than 1 °C, compared to the fastest ERG response recorded during the same heating procedure, it can serve as an indicator of an increased risk of overtreatment.

[0078] In one example, a calibration protocol can be performed to determine the heating unit power required to increase the temperature by one unit, such as 1°C. For example, if the target temperature increase is determined to be 8°C, then 8 units of heating power would be expected to be required. If, during treatment, ERG signal kinetics are observed to accelerate by, for example, 10% compared to a situation without retinal heating, which would be expected to correspond to a temperature change of approximately 3°C, then it can be determined that the actual temperature change in the retina is much higher because the temperature has already moved into a region where ERG signal kinetics has slowed.

[0079] In some embodiments, the temperature of the retina can be determined by determining the patient's core body temperature using known methods, determining the temperature rise that is or can be achieved at a target area of ​​the retina (and determining the temperature rise corresponding to a particular heating power), for example through a calibration procedure as described above, and then adding the determined temperature rise to the core body temperature to obtain the total temperature of the retinal tissue at the target area.

[0080] In one embodiment, a power calibration protocol may be performed over a temperature range where there is an exponential relationship between temperature and acceleration of signaling dynamics, and the predetermined set of heating powers used may be, for example, 20%, 35%, and 50% of an assumed or initially estimated heating power that can be used to induce the desired temperature increase.

[0081] In one embodiment, a confidence interval or error parameter may also be determined, and the arrangement may be configured, for example, to repeat the calibration protocol or some steps thereof until the confidence interval is sufficiently narrow, for example below some predetermined value.

[0082] The kinetics of ERG signals accelerate at higher temperatures near normal body temperature. This temperature-dependent acceleration of the ERG response can be used to determine the increase in retinal temperature caused by the application of retinal laser treatment / heating of the target area. Before retinal laser treatment begins, the retina is close to core body temperature. Therefore, ERG responses recorded without retinal heating serve as a reference for ERG signaling when the retina is at normal body temperature. When heat is applied to the retina, the temperature of the retinal tissue increases, and ERG responses recorded during heating represent ERG signaling at elevated temperatures compared to normal body temperature. Changes in signaling kinetics can be used to determine, for example, the amount of temperature increase caused by laser heating.

[0083] There are various methods for determining retinal temperature from ERG responses, and the accuracy of the temperature determination depends on both the stimulus protocol used to elicit the ERG signal and the algorithm used to determine temperature from the signal. Different stimulus protocols also produce different ERG responses, and temperature determination methods can be tailored to the type of retinal stimulus used.

[0084] One set of retinal temperature determination methods involves analyzing impulse ERG responses. Impulse ERG responses can be obtained, for example, by repeatedly stimulating a target area with flashes of light and averaging the response between two flashes. Another method for obtaining impulse responses is to stimulate a target area of ​​the retina with light modulated by white noise, determine the transfer function between the light stimulus and the ERG response, and use the transfer function to generate an impulse response.

[0085] One exemplary stimulation protocol for determining the temperature difference between two ERG impulse responses is by analyzing changes in the dynamics, such as the time delay, of the ERG impulse response. ERG impulse responses typically have one or more peaks, and the time delay between a flash stimulus and the signal peak is an example of a signal feature that can be used in temperature determination. The amount of time shift in the peak between ERG impulse responses recorded with and without (laser) heating is proportional to the degree of temperature increase in the retina and can be used to determine changes in retinal temperature.

[0086] Another exemplary method for determining the temperature difference from two ERG impulse responses works by compressing or expanding the time axis of one or both ERG signals, setting the compression origin at the time of the impulse stimulus, and determining the amount of time axis compression or expansion that maximizes the correlation between the responses. The amount of time axis compression or expansion that produces the greatest correlation between the responses can be used to determine the amount of temperature increase caused by retinal heating, which can then be used to determine the change in retinal temperature in the target area.

[0087] Another proposed method for ERG-based retinal temperature determination works by stimulating a target area of ​​the retina with a square wave and analyzing the resulting ERG signal in the frequency domain. Acceleration of signaling dynamics is reported to translate into a time shift in the frequency band of the ERG signal corresponding to the frequency of the square wave stimulus, which can reportedly be used to determine changes in retinal temperature in the target area.

[0088] The present invention has been described above with reference to the above-mentioned embodiments, and some advantages of the present invention have been demonstrated. It is clear that the present invention is not limited to these embodiments, but also encompasses all possible embodiments within the spirit and scope of the inventive concept, as well as the following patent claims.

[0089] The features recited in the dependent claims may be freely combined with one another unless expressly stated otherwise.

Claims

1. 1. An apparatus for providing retinal ERG stimulation and heating, comprising: the device comprises at least one processor and at least one light source for providing at least one stimulation beam to induce an ERG signal from a target region of the retina; the apparatus further comprising a heating system for increasing the temperature of at least the target area; the processor receives retinal ERG signals induced by the stimulation beam during retinal heating, determines one or more indices indicative of a temperature of the retina based on the ERG signals, and controls the heating system based on the indices; the indicators include at least one of the amplitude of the ERG signal or the dynamics of the ERG signal; The processor is further configured to terminate or adjust retinal heating and / or notify a user of the device if at least one of the amplitude of the ERG signal during retinal heating falls below a predetermined threshold relative to a previously determined baseline ERG response amplitude or the kinetics are slower than predetermined kinetics by more than a predetermined threshold amount. Device.

2. Run the calibration protocol determining a temperature rise per unit of heating power for the target area of ​​the fundus; and controlling the heating system to provide a calibrated heating power to increase the temperature of the retina using a temperature increase per unit heating power for the target area of ​​the fundus. The device of claim 1 configured to:

3. The processor: a) initiating retinal stimulation by controlling at least one light source to provide a stimulation beam; b) determining a first pre-heat reference ERG signal; c) initiating retinal heating by controlling the heating system to provide retinal heating to the target area at a first power and continuing the retinal heating for a preset duration; d) determining a first heating ERG signal; e) optionally repeating steps c)-d) with a second or subsequent laser power to determine a second or subsequent heating ERG signal; f) stopping retinal heating; g) optionally determining a first post-heat baseline ERG signal; h) comparing the first pre-heating reference ERG signal and / or the first post-heating reference ERG signal with the heating ERG signal to determine a temperature rise in retinal tissue at the heating power used; i) using the determined temperature rise to determine the temperature rise of the target area per unit heating power; The device of claim 2 configured to:

4. the processor is configured to repeat at least steps c)-d) using a predetermined set of heating powers; The apparatus of claim 3 , further comprising: determining, as an index, an overall temperature increase of the target area per unit of heating power based on a plurality of obtained temperature increases of the target area per unit of heating power.

5. an ERG signal obtained between a predetermined time after changing or initiating retinal heating and a subsequent termination or change of retinal heating is used as the heating ERG signal for temperature determination; 5. The device according to claim 3 or claim 4.

6. an ERG signal obtained substantially immediately after heating is initiated is used as the heating ERG signal for temperature determination to determine the rate of temperature increase in the target region of the retina caused by heating at the start of the heating procedure; 5. The device according to claim 3 or claim 4.

7. 7. An apparatus according to any one of claims 1 to 6, wherein if the value of one or more of the indicators differs from an expected value by more than a threshold amount, heating is terminated or adjusted and / or a user of the apparatus is notified.

8. a calibration protocol is used to determine a heating power that is expected to raise the temperature of at least the target region to the target temperature or temperature increase; providing heating power based on the calibration protocol, whereby kinetic parameters of the ERG signal are determined essentially continuously during retinal heating; The change in the kinetic parameter of the ERG signal determined during retinal heating is compared to an expected change in the kinetic parameter based on the determined target temperature or temperature increase; 8. The apparatus of claim 7, wherein heating is terminated or adjusted and / or a user of the apparatus is notified if the determined change in the kinetic parameter differs from the expected change in the kinetic parameter by more than a threshold amount.

9. 9. The apparatus of claim 8, wherein the threshold amount of difference between the predicted and observed change in the kinetic parameter corresponds to a temperature change of between 2°C and 8°C, advantageously between 4°C and 6°C.

10. 10. The apparatus of claim 1, wherein the processor is configured to extrapolate a heating power that provides a predetermined temperature rise in the target area or a predetermined absolute temperature in the target area when the body temperature is determined.

11. 6. The device of claim 5, wherein the device is configured to extrapolate how ERG signaling dynamics should change during treatment at higher laser powers and terminate the retinal heating or reduce treatment power if the changes in dynamics deviate from expected values ​​by a predetermined amount.

12. 12. The apparatus of claim 1, wherein the processor is configured to determine a signal-to-noise ratio of the ERG signal and to terminate retinal heating if the signal-to-noise ratio is below a predetermined threshold.

13. 13. The apparatus of any one of claims 1 to 12, wherein a threshold relative amplitude between the amplitude of the ERG signal determined during the retinal heating and the amplitude of a predetermined reference ERG response amplitude is between 0.4 and 0.9, advantageously between 0.5 and 0.

7.

14. 14. The apparatus of claim 1, wherein the threshold amount of slowing down of the dynamics is determined to correspond to a temperature change of 0.5°C to 4°C, preferably 1°C to 2°C, and the relationship between the dynamics and temperature is determined based on a predetermined change in dynamics per degree of temperature change in a predetermined therapeutic window of retinal temperature.

15. 15. The device of claim 1, wherein the processor is configured to determine, as an indicator, an impedance between ERG electrodes based on the acquired ERG signal, and to terminate or disable initiation of retinal heating if the impedance is above a predetermined threshold.

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