Patent Application
20230355162
The invention relates to electroretinography (ERG) and retinal heating in general. More specifically, the invention relates to obtaining ERG signals during retinal heating and controlling of the retinal heating based on the obtained ERG signals.
Electroretinography (ERG) is a method where electrical signals (electrical response) of the retina are recorded during exposure of the retina to stimuli, such as light flashes, which may be useful in various cases, such as in diagnosis of retinal diseases.
It has also been discovered that ERG signals obtained during retinal heating (e.g. photothermal retinal therapies) could be used to determine the temperature of the retina, due to the temperature dependence of the electrical signalling of the retina. An obtained ERG signal during retinal heating can therefore be indicative of a temperature (or at least a difference in temperature between two timepoints) that is occurring at the retina. The temperature determination related to heating could then be used e.g. for controlling the retinal heating so that the retinal temperature is kept at a desired level or a desired thermal dose is delivered during a retinal heating therapy procedure.
It is important to keep the retinal temperature at a level that is therapeutically effective while still avoiding temperatures that are high enough to cause damage to the retina. Prior art devices have not provided effective dosimetry to reach the optimal temperature and have not enabled the detection of overtreatment before damage occurs.
An object of the invention is to alleviate at least some of the problems in the prior art. In accordance with one aspect of the present invention, an arrangement is provided for providing retinal ERG stimulus and heating, the arrangement comprising at least one processor and at least one light source for providing at least a stimulus beam to induce an ERG signal from a target area of the retina, the arrangement additionally comprising a heating system for elevating the temperature of at least the target area, wherein the processor is configured to receive a retinal ERG signal induced by the stimulus beam during retinal heating, and determine, based on said ERG signal, one or more indicators being indicative of a temperature of the retina, and control the heating system based on said indicator.
Having regard to the utility of embodiments of the invention, retinal heating may be conducted more safely. Retinal heating may be controlled to elevate retinal temperature to a predetermined level, such as below a level of heating that could cause damage to the retina, but sufficiently high to induce therapeutic benefits.
One embodiment of the invention provides a device and method for carrying out a calibration protocol for determining temperature elevation of retinal tissue per unit heating power as an indicator. It has been noted by the inventors that the temperature elevation in the retina caused by the same laser power varies between patients, or even between different retinal areas. The invention provides a way of performing a power calibration and may therefore be used in such thermal dosimetry. Retinal heating may then be delivered in a way that is individually optimized for the treated area to reach the therapeutic temperature window. Based on the determined temperature elevation per unit heating power, the heating system can be controlled to provide a calibrated heating power to elevate the temperature of the retina, where the heating power is within a predetermined range to induce a predetermined temperature elevation of the retina in a specific case.
A power calibration protocol may comprise the processor being configured to:
The processor may be configured to repeat at least steps c-d with a predetermined set of heating powers and based on the obtained plurality of temperature increases of the target area per unit of heating power, determine an aggregate temperature increase of the target area per unit of heating power as an indicator.
As the heating system is turned on, the temperature of the retina rises precipitously for the first seconds of heating, followed by a slow drift where the temperature changes slowly and the change in retinal temperature is stabilized (i.e. no longer changes as fast as during the first seconds of heating). In one embodiment, heating ERG signal(s) obtained between a predetermined time after changing or initiating retinal heating and a subsequent termination or change in retinal heating may be used as the heating ERG signals for temperature determination. Here, a temperature of the target area that better reflects or is more efficiently indicative of (closer to) the peak temperature elevation induced by the heat exposure may be obtained. The temperature elevation of the retina is expected to depend linearly on heating power, and the calibration procedure may extrapolate the required heating power by first determining the amount of heating power required per unit temperature elevation,and multiplying this number by the desired temperature elevation to determine the power required to reach the desired target temperature. To reach the target temperature of the retina, a heating power corresponding to a power required for increasing retinal temperature by an amount corresponding to a difference between a determined bodily temperature to the target temperature, the target temperature difference/elevation, may be applied.
ERG signals may, of course, be obtained/registered essentially continuously but it may be only those ERG signals obtained after the predetermined time delay which are determined as the heating ERG signals used in the determining of retinal temperature.
ERG signal(s) obtained essentially immediately after the heating is initiated may additionally or alternatively be used as the heating ERG signals for temperature determination to determine a rate of temperature increase in the target area of the retina caused by the heating at the beginning of the heating procedure. When the initial rate of temperature increase per unit heating power is known, the processor may determine an appropriate power and/or pulse duration to deliver a desired thermal dose. This can be done by presuming the temperature elevation to be directly proportional to laser power and pulse duration when the pulses are sufficiently short. If a different spot size is used in calibration and treatment, the treatment power may be adjusted in proportion to the diameter of the treatment spot.
In different embodiments of the invention where indicators are used to control the heating, the heating may be terminated or adjusted. Additionally or alternatively, the controlling of the heating may refer to a user of the arrangement being notified or informed. The informing may e.g. comprise providing auditory and/or visual information to the user that is indicative of a property of the heating, such as a temperature of the retina. Based on the informing, the user of the arrangement may be able to adjust or terminate the heating.
In one embodiment, the heating may be terminated or adjusted or a user may be informed one or more indicators indicates that the temperature of the retina may be excessively high. As will be demonstrated, the indicator(s) may be related to changes in amplitude and/or kinetics of the recorded ERG response/signal obtained during heating either compared to an earlier previously determined reference ERG response recorded with an essentially corresponding heating power or an ERG response recorded prior to the heating. The one or more indicators may be used to determine a temperature of the retina or a temperature change of the retina and if this temperature differs from a target retinal temperature by over a threshold amount, this may a sign that the retinal temperature determined from the indicator is actually not accurate but the indicator, such as kinetics parameter, does not behave as it should in the target temperature range (e.g. acceleration of kinetics is not linear) and thus the retinal heating has advanced to temperatures outside of the therapeutic window and could be damaging.
The processor may additionally be configured to extrapolate a heating power that provides a predetermined temperature elevation in the target area. In cases where the core body temperature of the patient is determined as a part of a calibration protocol, the processor may be configured to determine a laser power that leads to a predetermined absolute temperature at the target area of the retina.
In one embodiment, the processor may extrapolate how the ERG signaling kinetics should change during the treatment with higher laser power, and may be configured to terminate the retinal heating or lower the treatment power if the change in kinetics deviates from the expectation more than a given threshold.
The processor may be configured to determine a signal-to-noise ratio of the obtained ERG signal and terminate the retinal heating by powering off the heating system or in a case where the retinal heating has not been initiated, the initiation of retinal heating may be disabled if the determined signal-to-noise ratio falls below a predetermined threshold value. The retinal heating may thus be prevented or aborted if the obtained ERG signal cannot effectively be used to obtain information relating to the target area. This may occur e.g. if an ERG electrode contact deteriorates or if the patient whose retina is being treated flexes their facial muscles. It may be safer to not perform retinal heat treatment in these cases.
A processor may in some embodiments be configured to receive or determine an impedance between ERG electrodes, such as the ocular electrode and reference electrode, as an indicator, and may terminate retinal heating or disable initiation of the retinal heating if the impedance is above a predetermined threshold value.
In one embodiment, a processor may be configured to determine an amplitude of the ERG signal as an indicator and terminate or adjust the retinal heating and/or inform a user if the amplitude during retinal heating falls below a predetermined threshold value with respect to a previously determined reference ERG signal amplitude. This may ensure that the retinal heating is terminated if the temperature of the retina becomes dangerously high, where the ERG signal amplitude begins to decrease excessively. Even in cases where a calibration protocol is carried out (e.g. in a manner disclosed later herein), the calibration protocol may have been erroneous, whereby monitoring of the ERG signal amplitude may be a safety mechanism for preventing excessively high retinal temperatures, which may be harmful for a patient.
The threshold relative amplitude between the amplitude of the ERG signal determined during the retinal heating and the amplitude of a previously determined reference ERG response amplitude may for instance be between 0.4 and 0.9, advantageously between 0.5 and 0.7.
In one more embodiment, the processor may be configured to determine the kinetics of the ERG signal as an indicator and terminate retinal heating if the said kinetics, such as an acceleration thereof, differs from a predetermined kinetics value by over a predetermined threshold amount. The ERG signal response kinetics is exponentially accelerating at a certain temperature range. In a configuration where impulse ERG responses are used for temperature determination, a temperature change depends on temperature in the following way: ΔT=k In(Δx), where ΔT is the change in temperature, Δx is a relative change in a feature value describing the acceleration of the signal, and k is the temperature dependence of the feature.
In sufficiently high retinal temperatures, the temperature dependent acceleration no longer follows the aforementioned relationship, and when the temperature is sufficiently high, the response kinetics becomes slower with rising temperatures. If the signal kinetics slows excessively, e.g. slows by over a threshold amount compared to a reference value, this may be used to determine that the retinal temperature is excessively high. Monitoring kinetics of a determined ERG signal and subsequently terminating or adjusting retinal heating in the aforementioned case may therefore also provide a safety mechanism that may prevent harmful heating of the retina.
In one embodiment of the invention, the deceleration of ERG signaling kinetics due to excessively high temperatures may be detected by essentially continuously recording the ERG signal during retinal heating and comparing the most recent ERG response signal to the fastest ERG response recorded previously during the retinal heating involving substantially the same heating power. A threshold amount of slowing in kinetics may be determined to correspond to a change of temperature between 0.5° C. to 4° C., advantageously between 1° C. to 2° C.
The relationship between kinetics of the ERG signal and change in retinal temperature may vary slightly based on the chosen method of retinal stimulation. With preknown data, the temperature dependence of ERG signaling kinetics acceleration was found to be 3.6%/° C. when bright photopic flashes are used in retinal stimulation over a bright constant background, which was found to be an advantageous method for eliciting and ERG signal during laser heating application. However, with other stimulation paradigms, this value might vary e.g. in the range of 3%-6% /° C.
The inventors have discovered that a drop in ERG signal amplitude as well as deceleration of ERG kinetics occur below retinal temperatures where damage occurs and above retinal temperatures where therapeutic benefits are triggered. When using a 1 minute laser exposure, increased production of molecular chaperones HSP70 and HSP90, which are believed to relay the therapeutic effect of retinal laser therapy, were detected in treatments where the retinal temperature stabilized above 44° C., while the damage threshold was determined to be approximately 48° C.
It may be determined, e.g. via a calibration protocol, that a known kinetics acceleration, e.g. given by equation ΔT=k In(Δx), of the ERG signal may be expected. If it is observed during heating of the retina that the kinetics of the ERG signal accelerate an amount less than this predetermined expected acceleration value by more than a threshold amount, it may be an indicator that the temperature has risen to a point where the aforementioned ΔT=k In(Δx) relationship does not hold.
In one embodiment, an indicator may be a kinetics parameter of the ERG signal, where the change in ERG response kinetics induced by e.g. laser exposure with a known target temperature of the retina is compared to the expected kinetics acceleration from the aforementioned equation ΔT=kln(Δx). If the change in the acceleration of ERG response kinetics is significantly less than this expectation, it is an indication that the temperature has risen excessively high, i.e. over the target temperature or beyond a therapeutic window. The threshold for the aforementioned difference may correspond to a temperature decrease of preferably between 2° C. and 8° C., advantageously between 4° C. and 6° C.
The inventors have also discovered that an optimal treatment temperature for retinal heating is in a temperature range where an obtained ERG signal kinetics is at its fastest, i.e. when the temperature is either increased or decreased. When retinal temperature rises above the optimal treatment temperature, ERG signaling starts to decelerate rapidly. This rapid deceleration of ERG signaling kinetics was found to precede retinal damage, making it suitable for detecting inadvertent overtreatment.
The inventors have yet additionally discovered that the amplitude of the ERG signal does not exhibit dramatic changes at the optimal treatment temperature, but the amplitude starts to drop rapidly when the retinal temperature is increased beyond the optimal treatment temperature. This rapid drop in ERG amplitude was found to precede retinal damage, making it suitable for detecting inadvertent overtreatment.
The exemplary embodiments presented in this text are not to be interpreted to pose limitations to the applicability of the appended claims. The verb “to comprise” is used in this text as an open limitation that does not exclude the existence of unrecited features. The features recited in depending claims are mutually freely combinable unless otherwise explicitly stated.
The novel features which are considered as characteristic of the invention are set forth in particular in the appended claims. The invention itself, however, both as to its construction and its method of operation, together with additional objects and advantages thereof, will be best understood from the following description of specific example embodiments when read in connection with the accompanying drawings.
Next the invention will be described in greater detail with reference to exemplary embodiments in accordance with the accompanying drawings, in which:
In the embodiment of
The stimulus light source LED3 may be configured to provide a stimulus light beam that is modulated. The stimulus beam therefore may not be provided as a continuous beam of light, but may comprise sequences, such as impulse-like flashes of light. The modulation may be implemented e.g. at a frequency between 4 and 40 Hz, advantageously between 10 and 25 Hz.
The device of
In the device of
The brightness of the central background beam may be configured to be reduced as a heating laser or other heating means is turned on, to maintain a steady illuminance at the target area.
In use case scenarios where e.g. infrared imaging is used for fundus imaging, the central background light beam may not be needed.
A device also comprises means for obtaining an ERG signal, i.e. means for obtaining a response signal of the target area to the stimulus provided by the stimulus beam. The ERG signal may be an electrical response that may be recorded/collected or obtained by one or more ERG electrodes. The electrodes may comprise one or more ocular electrodes and one or more reference electrodes. The ERG signal may be obtained as a voltage change between at least two electrodes over time.
The device may comprise or be usable in connection with a fundus lens L6. The fundus lens L6 may direct the provided light beams to the fundus of the eye. The fundus lens L6 may for instance be an inverting fundus lens with a field of view >120 degrees.
In one embodiment, a fundus lens may be integrated into the device, whereby a lens is not required to be placed on the cornea.
In one embodiment, a device comprises a fundus lens and ocular electrodes may be integrated into the fundus lens.
A heating system comprises at least a heat source, such as heating laser LF that is configured to elevate the temperature of the target area on the fundus. A heating light source LF may be configured to provide a heating beam that is directed to at least the target area.
The heating beam may comprise wavelength in the near-IR area. Wavelengths of light comprised in the heating beam may be 700-1000 nm, while the heating beam may be provided by a heating light source LF that is a fiber coupled diode laser.
In one embodiment, a heating beam has a homogenous irradiance profile and spot diameter of 1-6 mm on the fundus.
Also other heating systems or means for heating may be utilized in connection with devices that are associated with retinal heating. For instance, the heating system may be implemented through ultrasound.
Considering the functioning of the device shown in
The fundus lens L6 may project the light profile at CP1 onto the fundus. The first imaging module IM1 is configured such that CP1 is either projected onto a camera sensor, or that the eyes of the treating physician are able to focus onto CP1 through biomicroscope eyepieces. The beams passed through a fifth lens L5 are directed towards the eye by a first mirror M1. The first mirror M1 may be placed directly in front of the first optics module IM1 (such as biomicroscope), so that the left eye has a view to the fundus on the left side of the first mirror Ml, and the right eye has a view to the fundus on the right side of the first mirror Ml. The fifth lens L5 may project images from masks M1, M3 and M4 onto the conjugate plane CP1, meaning that the light profile emitted through the masks are imaged onto CP1. Beam splitters BS2 and BS3 may combine beams arising from the heating laser fiber output LF, and light sources LED2, and LED3.
In
Preferably, an arrangement comprises at least one processor 102, a stimulus light source LED3, and a heating light source LF (or some other heating system). The arrangement 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 system). Controlling may be powering on and off of the light sources or controlling of any other aspect of the light sources, such as power or illuminance delivered by a provided light beam. The processor 102 is configured to receive obtained ERG signals, which may be obtained by electrodes 104. The electrodes 104 may comprise a plurality of electrodes, such as at least one ocular electrode and at least one reference electrode. The processor 102 may be configured to analyze the obtained ERG signals and determine one or more related parameters. Electrodes 104 may in some embodiments be comprised in the arrangement.
The ERG signals obtained from the electrodes 104 may be directed through an ERG amplifier-digitizer system for processing, such as amplification, filtering and digitizing, before being received at the processor 102. Such an ERG amplifier-digitizer system may in some embodiments be considered as part of the arrangement, in some embodiments part of the processor 102.
The processor 102 may be configured to initiate retinal heating by powering on a heating light source LF. The processor may be configured to initiate stimulation of a target area of the retina using the stimulus beam by powering on the stimulus light source LED3. The processor 102 may then be configured to receive retinal ERG signals induced by the stimulus beam during retinal heating and determine, based on the obtained ERG signal, one or more indicators being indicative of a temperature of the retina, and control the heating system based on said indicator.
The controlling of the heating system may comprise controlling the heating system such as heating light source LF to provide a determined heating power (could also mean essentially no power) to provide a retinal temperature that is within a predetermined range, such that the retinal temperature may remain at a safe and/or therapeutic range and/or be prevented from rising above a certain threshold to retain safety of the retinal heating.
is In one embodiment, the arrangement may be configured to determine that retinal heating is being conducted in a temperature range where the ERG signal kinetics accelerate exponentially with rising temperatures. A heating system may be controlled to e.g. terminate or adjust heating if it is determined that the signal kinetics determined from the ERG signal accelerates an amount that is significantly different from what is expected based on the target temperature elevation.
In the temperature range where the ERG signal kinetics depend exponentially on temperature, the amplitude is not highly sensitive to temperature changes. At higher temperatures, the amplitude starts to reduce with higher temperatures, which may be used as an indicator for terminating the treatment or adjusting the heating power.
A calibration protocol may be conducted with one or more heating powers resulting in temperature elevations within this range (the range where the ERG signal kinetics accelerate exponentially with rising temperatures).
The processor 102 may be configured to determine a signal-to-noise ratio of the obtained ERG signal and terminate the retinal heating by powering off the heating light source LF or in a case where the retinal heating has not been initiated, the initiation of retinal heating may be disabled if the determined signal-to-noise ratio falls below a predetermined threshold value. The determining of the signal-to-noise ratio may be conducted essentially continuously. The predetermined threshold value may be a value for the signal-to-noise ratio where obtaining of a reliable ERG signal is not feasible.
A processor 102 may in some embodiments be configured to determine an impedance between ERG electrodes, such as the ocular electrode and reference electrode, based on the received ERG signal and may terminate retinal heating or disable initiation of the retinal heating if the impedance is above a predetermined threshold value.
In one embodiment, a processor 102 may be configured to determine an amplitude of the ERG signal and terminate the retinal heating if the amplitude during retinal heating falls below a predetermined threshold value with respect to a previously determined reference ERG signal amplitude.
It may be seen from
An arrangement may be configured to perform a power calibration protocol for determining a heating power that corresponds to a desired retinal temperature or change in retinal temperature. Temperature elevation per unit heating power for the target area, may be determined as an indicator that may be used to control the heating system to provide a calibrated heating power to elevate the temperature of the retina. The power calibration protocol may for instance be carried out before performing of a retinal heating treatment, where the processor 102 may be configured to
The processor 102 may be configured to repeat at least the above mentioned steps c-d with a predetermined set of heating powers and based on the obtained plurality of temperature increases of the target area per unit of heating power, determine an aggregate temperature increase of the target area per unit of heating power. For instance, a zero intersecting linear fit between heating power and temperature elevation may be utilized, the temperature increase per unit power being the slope of the linear fit.
In some embodiments, heating ERG signals may be selected to exclude the ERG responses within a predetermined time duration after initiating or changing retinal heating and only include responses obtained after said time duration and before a subsequent change or termination of retinal heating. Here, it may be known or determined that a change in retinal temperature has stabilized or changes slowly (increases slowly towards a peak retinal temperature) after the predetermined time duration. The change in retinal temperature may occur slowly after the predetermined time period, e.g. after the first seconds of heating as compared to the change in retinal temperature occurring during the first seconds of heating, where during these first seconds of heating, the change in retinal temperature is faster. Utilizing ERG responses obtained after said predetermined time duration for temperature determination may result in a determined retinal temperature that is closer to an actual peak retinal temperature that is caused by the heating power used.
Through a calibration protocol and with a determined or estimated body temperature and a determined target retinal temperature, a target temperature elevation of the retinal tissue may be determined and a corresponding heating power may be delivered. However, even in cases where a calibration protocol is carried out, errors in the determined temperature increase of the target area per unit of heating power and/or in body temperature may lead to an actual elevation of retinal tissue that is excessive, and one or more additional indicators, such as kinetics of the ERG signal may be used to control the heating to avoid overtreatment.
When a calibration protocol is used to determine a heating power that should be used to reach a target temperature (or temperature elevation) of the retina, a retinal temperature (elevation) determined from a continuously recorded ERG signal may indicate overtreatment if it is significantly below the target temperature (elevation) during heating exposure.
In one more embodiment, the processor 102 may be configured to determine the kinetics of the ERG signal and e.g. terminate or adjust retinal heating if the acceleration of said kinetics differs from a predetermined acceleration value by over a predetermined threshold amount. In one embodiment, the predetermined acceleration value is determined based on a calibration protocol.
The kinetics may comprise e.g. speed or rate or response time of the obtained/measured ERG signal (electrical response) of the retinal tissue to the stimulation by the stimulation beam. Features may be extracted from ERG signals to reflect changes in response kinetics and therefore changes in retinal temperature. In embodiments where the impulse ERG response is used for temperature determination, these features may be e.g. relative changes in time-to-peak of the b-wave relative to the moment of the impulse stimulus (ratio of time-to-peak values between two responses) or the overall time axis compression applied on an ERG response to maximize the similarity with another response. A logarithm of these features may be used as an indicator that depends linearly on temperature differential between the compared responses.
As the retinal temperature increases mildly, the kinetics of the ERG signal accelerate in a way that implicit times in the ERG signal shift towards the time of the stimulus an amount that is proportional to the logarithm of the temperature change of the retina. When the retinal temperature increases above 44° C., this relationship breaks and the ratio between kinetics acceleration and temperature change first reduces, and when the temperature increases further, the kinetics start to decelerate with rising temperatures. This effect can be used as a safety mechanism to terminate the treatment or lower e.g. the laser power. The kinetics may be used as a safety mechanism with or without a calibration protocol.
The deceleration of ERG kinetics in high temperatures may also be used as an indicator of overtreatment by continuously recording ERG during e.g. laser exposure and terminating the treatment if the kinetics of the ERG signal start to decelerate during the laser exposure. This can be implemented by comparing the kinetics of the continuously updated or recorded ERG response during heating to a reference ERG response with the fastest kinetics that has been previously obtained during the same heating power exposure.
It may be determined that the kinetics of an ERG response accelerates 3-6%, e.g. about 3.6%, when then temperature of the retina is increased by 1° C. In one exemplary scenario, a heating treatment may be performed where at time t=0, the kinetics has accelerated by 0% at time t=5 s, the kinetics has accelerated by 10%, at time t=10 s, the kinetics has accelerated by 20%, at time t=15s , the kinetics has accelerated by 21%, and at time t=20 s, the kinetics has accelerated by 15%. With the fastest kinetics, the kinetics accelerated by 21% and after this the kinetics slowed by 6%, which may translate to a temperature change of the retinal tissue of slightly under 2° C. An increase in temperature may be estimated to be exceedingly high, because the acceleration of the kinetics slowed into deceleration during the treatment. In a normal or intended treatment session where the temperature of the retina is maintained at or near a target temperature or therapeutic window, the kinetics should accelerate and approach a stable value until treatment is terminated.
If the ERG response has decelerated an amount corresponding to, e.g., more than 1° C. of temperature compared to the fastest ERG response recorded during the same heating procedure, it may serve as an indicator for increased risk of overtreatment.
In one example, a calibration protocol may be carried out to determine a heating unit power that is required for temperature elevation of one unit, such as 1° C. E.g. if the target temperature elevation is determined as 8° C., then it is expected that 8 units of heating power are required. If during the treatment it is observed that the ERG signal kinetics is for example 10% accelerated as compared to a situation without retinal heating, which would be expected to correspond to about 3° C. temperature change, then it may be determined that the actual temperature change of the retina is much higher, as the temperature has already moved to an area where the ERG signal kinetics has decelerated.
In some embodiments, a temperature of the retina may be determined by determining a core body temperature of the patient using known methods, determining a temperature increase that is or may be achieved at the target area of the retina through e.g. a calibration procedure as above (and determining a temperature increase corresponding to a certain heating power), and then adding the determined temperature increase to the core body temperature to obtain a total temperature of the retinal tissue at the target area.
In one embodiment, the power calibration protocol may be performed in a temperature range where there is an exponential relationship between temperature and acceleration of signaling kinetics and a predetermined set of heating powers used may be e.g. 20%, 35%, and 50% of an assumed or initially estimated heating power that may be used to induce a desired temperature elevation.
In one embodiment, a confidence interval or error parameter may also be determined. The arrangement may be configured to repeat the calibration is protocol or some steps of it until e.g. the confidence interval is sufficiently narrow, such as below some predetermined value.
The kinetics of the ERG signal accelerates with higher temperatures near the normal body temperature. The temperature dependent acceleration of ERG responses can be used for determining the temperature elevation of the retina caused by the application of retinal laser therapy/heating of the target area.
Before retinal laser therapy is initiated, the retina is near core body temperature. ERG responses recorded without retinal heating thus serve as a reference for ERG signaling when the retina is at normal body temperature. When heating is applied to the retina, the temperature of the retinal tissue increases and ERG responses recorded during heating represent ERG signaling at an elevated temperature compared to normal body temperature, and changes in signaling kinetics can be used to determine the amount of temperature elevation caused by e.g. laser heating.
There are various methods for determining retinal temperature from the ERG response, and the accuracy of temperature determination depends both on the stimulation protocol used to elicit the ERG signal and the algorithm used to determine temperature from the signals. Different stimulation protocols also produce different ERG responses, and the temperature determination method may be tailored for the type of retinal stimulation used.
One set of retinal temperature determination methods relates to analyzing the impulse ERG-response. The impulse ERG response can be obtained, for example, by stimulating the target area repeatedly with flashes of light and averaging the responses between two flash stimuli. Another way for obtaining the impulse response is to stimulate the target area of the retina with light modulated by white noise, determining the transfer function between the light stimulus and the ERG response, and using the transfer function to generate the impulse response.
One exemplary stimulation protocol for determining the temperature difference between two ERG impulse responses is by analyzing changes in kinetics, such as time delays of the ERG impulse response. The ERG impulse response typically has one or more peaks, and the time delay between the 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(s) between ERG impulse responses recorded with and without (laser) heating is/are proportional to the extent of temperature elevation in the retina, and can be used to determine changes in retinal temperature.
Another exemplary method for determining the temperature difference from two ERG impulse responses works by compressing/expanding the time axis of ERG signal of one or both of them, with the compression origin set to the time of the impulse stimulus, and determining the amount of time-axis compression/expansion that maximizes the correlation between the responses. The amount of time axis compression/expansion producing the maximum correlation between the responses can be used to determine the amount of temperature elevation caused by the retinal heating and can be used to determine changes in retinal temperature of the target area.
Another proposed method for ERG-based retinal temperature determination works by stimulating the target area of the retina with a square wave and analyzing the resulting ERG signal in the frequency domain. The acceleration of signaling kinetics is reported to translate to a time shift in the frequency band of the ERG signal corresponding to the frequency of the square wave stimulus, and may reportedly be used to determine changes in retinal temperature of the target area.
The invention has been explained above with reference to the aforementioned embodiments, and several advantages of the invention have been demonstrated. It is clear that the invention is not only restricted to these embodiments, but comprises all possible embodiments within the spirit and scope of inventive thought and the following patent claims.
The features recited in dependent claims are mutually freely combinable unless otherwise explicitly stated.
| Number | Date | Country | Kind |
|---|---|---|---|
| 20205875 | Sep 2020 | FI | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/FI2021/050602 | 9/10/2021 | WO |
