Systems and methods for remote neurobehavioral testing

Abstract

A system and method for air-puff-free neurobehavioral testing, including eyeblink reflex conditioning and prepulse inhibition, utilizing an electronic device with a light source, camera, and speaker, and assessing a user based on the degree to which their eyelids close after exposure to conditioned and unconditioned stimuli.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 111,960 filed on 10 November 2020, U.S. Provisional Patent Application No. 63 / 197,002 filed on 4 June 2021, and U.S. Provisional Patent Application No. 63 / 218,607 filed on 6 July 2021, all of which are incorporated herein by reference in their entirety. Description of federally funded research and development.

[0002] This invention was made with government support under license number R01-NS045193 granted by the National Institutes of Health. The government has certain rights to this invention. [Background technology]

[0003] To study the function and dysfunction of specific brain regions, researchers and clinicians have developed a wide range of so-called neurobehavioral tests. Neurobehavioral tests can be defined as tasks specifically designed to investigate dysfunction of particular brain structures. Two tasks that have proven particularly useful in psychology and neuroscience are eyeblink conditioning (EBC) and prepulse inhibition (PPI) of the auditory startle reflex. EBC is a common variation of the classical conditioning experiment performed by Ivan Pavlov and is considered one of the best behavioral methods for specifically investigating cerebellar dysfunction.

[0004] In an EBC experiment, subjects hear a tone and, half a second later, perform an air puff to their eye to induce a blink reflex. As the tone-puff pairing is repeated, subjects eventually learn to close their eyes in response to the tone, a process known as a conditioned response (CR). While simple in form, the EBC measures several aspects of how we learn in everyday life. This includes associative learning, where subjects learn to make correct new associations, and motor learning, where they learn eyelid movement responses with millisecond precision.

[0005] PPI is a behavioral phenomenon in which the magnitude of the startle response is suppressed when a weaker sound (prepulse) that does not elicit a startle reflex precedes a short, loud startle sound (pulse). In this way, PPI measures sensorimotor gating, a neural mechanism that filters irrelevant sensory information to protect the brain from overstimulation and respond to appropriate stimuli. PPI has low brain region specificity and is used to investigate the function of the midbrain and the regulatory effects that the midbrain receives from the limbic system, thalamus, and prefrontal cortex.

[0006] Blink conditioning and PPIs have been used for over a century, and as a result, the underlying neural mechanisms of these tasks have been elucidated in great detail. In addition, both blink conditioning and PPIs can be easily performed in both humans and animals, making both tasks potentially valuable for translational clinical research. Furthermore, the results of both studies show a strong correlation with neuropsychiatric disorders, including autism spectrum disorder (ASD), and their potential as biomarkers or diagnostic tools has been repeatedly suggested. For these reasons, both tasks are expected to be beneficial at some point for patients suffering from neuropsychiatric disorders.

[0007] However, blink conditioning and PPIs are not yet used as translational or diagnostic methods in routine clinical practice. Why not? Firstly, the sensitivity and specificity of tests for diagnosing heterogeneous neurodevelopmental disorders and neuropsychiatric disorders have not yet been characterized. Secondly, studies on human blink conditioning and PPIs often suffer from inclusion bias, overrepresenting certain groups (often psychology students acting as "healthy controls"), limiting their value in understanding society as a whole. Thirdly, the setups for blink conditioning and PPIs are rarely commercially available and are often expensive. Fourthly, current tasks are unpleasant, require equipment on the participant's face, and often use air puffs that cause eye aversion, making them nearly impossible to administer to infants, especially those with ASD. Finally, the tasks lack any form of standardization; for example, the behavior of the experimenter conducting the experiment and the emotional state of the participants can significantly influence the results, potentially leading to low interlaboratory reproducibility. Driven by variability among patients treated at different hospitals, clinicians are hesitant to use blink reflex conditioning and PPIs in their daily practice. At the same time, researchers continue to routinely conduct blink reflex conditioning and PPI experiments in their laboratories, albeit in a well-controlled manner, often consisting of unique sets of stimulus parameters.

[0008] As a result, after a century of scientific investment in blink reflex conditioning and PPIs, the efforts have either not directly benefited patients or have been minimal. Therefore, systems and methods that bridge this gap between fundamental knowledge of neurological processing and its clinical application, and that have the utility to effectively enhance the diagnosis in patients with neurodevelopmental and neuropsychiatric disorders, are useful and desirable. [Overview of the project]

[0009] A first aspect of this disclosure is shown in a method for neurobehavioral testing, including non-air puff blink reflex conditioning. The method, without requiring any device to be attached to the head or face, includes the steps of: (i) beginning to emit sound from a speaker of a device (preferably a mobile device such as a smartphone); (ii) capturing one or more initial images of at least one eye while the sound is being emitted; (iii) emitting light from a light source of the mobile device while the sound is being emitted, the emission of light beginning a certain period (e.g., between 100 milliseconds and 1 second) after the sound has begun to be emitted; (iv) capturing one or more final images of at least one eye while the light and sound are being emitted; and (v) stopping the emission of sound and light, and repeating steps (i)-(v).

[0010] The method further includes determining the degree of openness of at least one eye in both the initial and final images. Advantageously, the method further includes transmitting the degree of openness, the initial image, and / or the final image to a remote device or server (for example, so that a researcher or physician can review the findings).

[0011] Preferably, the method further includes determining the extent to which a conditioned response is acquired based on the determined openness of at least one eye in one or more initial images.

[0012] The method may further advantageously include testing the degree to which a conditioned response has been acquired by (i) beginning to emit sound from the speaker of a mobile device; (ii) capturing one or more images of at least one eye while the sound is being emitted; (iii) stopping the emission of sound; and (iv) determining the degree of openness of the captured images, and determining the degree to which a conditioned response has been acquired based on the determined degree of openness of the captured images.

[0013] In some preferred embodiments, the method may include initiating steps a to f of the disclosed method based on a signal received from a remote device or server.

[0014] Advantageously, the method further includes activating the vibration motor when sound emission begins and deactivating the vibration motor when sound emission stops.

[0015] A second aspect of this disclosure describes a method for neurobehavioral testing in which the test includes detecting prepulse suppression in a user. The method includes emitting a white noise prepulse, the white noise prepulse having a first intensity configured not to induce a startle reflex in the user, and then emitting a white noise pulse having a second intensity configured to induce a startle reflex in the user after a delay in which no white noise is emitted, the second intensity being greater than the first intensity. Blink detection as described above can be used to measure the degree of eye opening. By comparing with standards, or...

[0016] A third aspect of this disclosure is shown in a device (preferably a mobile or portable device such as a smartphone) configured to perform the above method for blink conditioning without air puffing. The device comprises a light source (such as a camera flash, a separate LED, or a display screen), a camera, a speaker, one or more processors, optionally a wireless transceiver, and optionally a vibration generating motor. The processor, when executed, consists of instructions that cause the processor to perform several tasks: (a) trigger a speaker configured to begin emitting sound at a first time point; (b) trigger a light source configured to begin emitting light at a second time point following the first time point after a fixed delay interval (e.g., a time between 100 milliseconds and 1 second) (e.g., begin emitting light a certain time after it begins emitting sound); (c) stop emitting sound and stop emitting light at a third time point; (d) receive one or more first images of at least one eye from a camera while the speaker is emitting sound and the light source is not emitting light; (e) receive one or more second images of at least one eye from a camera while the speaker is emitting sound and the light source is emitting light; and (f) determine the degree of openness of at least one eye in each of the one or more first images and each of the one or more second images.

[0017] In some embodiments, the processor is further configured to transmit the degree of openness to a remote device or server (e.g., via a wireless transceiver) and / or transmit one or more first images, one or more second images, or a combination thereof to the remote device or server.

[0018] Advantageously, in some embodiments, the processor is further configured to determine the extent to which a conditioned response is acquired based on the determined openness of at least one eye in one or more first images.

[0019] Advantageously, in some embodiments, the vibration motor is configured to start vibrating at a first point in time and stop vibrating at a third point in time.

[0020] In some embodiments, the device comprises a display screen configured to display a video or image, an augmented reality video or image, or a virtual reality video or image during the test process.

[0021] Advantageously, one or more processors are further configured to cause prepulse inhibition by causing a white noise prepulse to be emitted and, after a delay period, by causing a white noise pulse to be emitted, the strength of the pulse being greater than the strength of the prepulse.

Brief Description of the Drawings

[0022] [Figure 1A] It is a simplified flowchart of an embodiment of a method for a neurobehavioral test. [Figure 1B] It is a simplified flowchart of an embodiment of steps for blink reflex conditioning without an air puff. [Figure 1C] It is a simplified flowchart of an embodiment of steps for testing prepulse inhibition. [Figure 2A] It is an image of a template for tracking facial landmarks, particularly eye landmarks. [Figure 2B] It is an image of a baby with open eyes having an overlay of a template for tracking eyelid positioning. [Figure 2C] It is an image of a baby with closed eyes having an overlay of a template for tracking eyelid positioning. [Figure 2D] It is a graph showing representative normalized fractional eyelid closure (FECNORM) values determined from an image using the disclosed method. [Figure 2E] This is a representation of blink reflex conditioning that is detected over several repetitions. [Figure 2F] This is a description of a process that tests prepulse suppression. [Figure 3] This is a simplified schematic diagram of the system and device according to the embodiments of the present disclosure. [Modes for carrying out the invention]

[0023] Embodiments of this disclosure are described in detail with reference to drawings in which similar reference numerals identify similar or identical elements. It should be understood that the disclosed embodiments are merely examples of the disclosure, which can be embodied in various forms. Known functions or structures are not described in detail to avoid obscuring the disclosure with unnecessary detail. Therefore, certain structural and functional details disclosed herein are not to be constrained, but merely representative grounds for the claims and for teaching those skilled in the art to employ the disclosure in various substantially arbitrary and appropriately detailed structures.

[0024] The disclosed methods for neurobehavioral testing may include, for example, blink reflex conditioning or prepulse inhibition, and can be described with reference to Figures 1A, 1B, and 1C.

[0025] In Figure 1A, Method 1 for neurobehavioral testing can be understood to generally require at least one of the following: Test 3 for blink reflex conditioning without air puff, Test 4 for prepulse inhibition, or a combination thereof. If both are tested, the order of the tests is not a concern; that is, the prepulse inhibition test can be performed before blink reflex conditioning, or vice versa.

[0026] In some embodiments, the test also includes a calibration sequence 2 in which multiple images of the subject are captured, at least one of which shows the eyes fully open and at least one of which shows the eyes fully closed. In some embodiments, this is done by capturing a short video sequence (e.g., 30 seconds), and each image in the video sequence is then analyzed as described below to determine the maximum and minimum degree of eyelid opening.

[0027] Blinking reflex conditioning Figure 1B shows an embodiment of a method for blink conditioning without an air puff 3. This method generally requires the user to access a device, preferably a mobile or portable device, most preferably a smartphone or tablet. The device generally requires a camera, a light source, and a speaker, and optionally a vibration motor and / or wireless transceiver. No (or no) equipment is attached to the user's face and / or head. In some embodiments, the device may come into contact with the user's face or head during use, but is not attached (for example, the device may be placed in contact with the user's face, such as in front of the user's eyes, but the user can pull their face away from the device without assistance, such as by using their hands). In some embodiments, the device does not come into contact with the user's face or head during use.

[0028] Method 3 generally begins by initiating the emission of sound from a speaker on the device. This is the conditioned stimulus. In some embodiments, the user initiates Method 3. In preferred embodiments, a remote device or server is used to send a signal to the device, and Method 3 is initiated based on that signal.

[0029] In some preferred embodiments, in addition to emitting sound, a vibration motor is operated within the device, causing the user to experience vibrations simultaneously with the emission of sound.

[0030] While sound is emitted and the user is facing the camera, the camera is used to capture one or more initial images of at least one of the user's eyes. In a preferred embodiment, both eyes are captured. In some embodiments, only one eye is captured.

[0031] In some embodiments, the camera captures one or more initial images as a video. In some embodiments, the camera captures one or more initial images as discontinuous photographs captured at a set frequency (e.g., every 50 milliseconds, every 100 milliseconds, or every 200 milliseconds).

[0032] Optionally, one or more captured initial images are stored in a non-temporary computer-readable storage medium 11. In some embodiments, the non-temporary computer-readable storage medium is located on the device. In some embodiments, the device sequentially transmits the images to a remote device or server for storage in a database.

[0033] A delay occurs for a certain period of time after the sound emission begins. After the delay, light is emitted from the light source toward the user's eyes while the sound is still being emitted. The delay is preferably less than 1 second, and more preferably between 100 milliseconds and 1 second. In some embodiments, this period can be set or adjusted by a remote device or server. For example, in some embodiments, a physician or researcher can adjust the period before method 3 is initiated, taking into account differences in subjects, etc.

[0034] For the light flash, white is preferably used, but the color can be any color and the color temperature can be any color (e.g., 2800K to 5500K). When using a display screen as the light source, preferably the maximum brightness that can be generated by the smartphone is used for the emitted light 15.

[0035] The light is preferably a bright, intense white or substantially white light from an LED or similar light source, such as a camera flash or a similar relatively short burst. This includes alternative approaches such as, for example, displaying a smartphone's full white screen at its brightest intensity for a short period of time. In some embodiments, the light source is configured to output at least 2,500 lumens of light. In some embodiments, the light source is configured to emit this light for less than 1 second, preferably less than 1 / 10 second, and more preferably less than 1 / 100 second.

[0036] Sound and light are emitted, and while the user is facing the camera, the camera is used to capture one or more final images of at least one of the user's eyes. In a preferred embodiment, both eyes are captured. In some embodiments, only one eye is captured.

[0037] In some embodiments, the camera captures one or more final images as a video. In some embodiments, the camera captures one or more final images as discontinuous photographs captured at a set frequency (e.g., every 50 milliseconds, every 100 milliseconds, or every 200 milliseconds).

[0038] Optionally, one or more captured final images are stored in a non-temporary computer-readable storage medium 21. In some embodiments, the non-temporary computer-readable storage medium is located on the device. In some embodiments, the device sequentially transmits the images to a remote device or server for storage in a database.

[0039] After the final image is captured, the emission of sound and light (and vibration motors, if used) is stopped.

[0040] Generally, the above steps (5-25) are repeated at least once, preferably multiple times, and more preferably at least five times.

[0041] At any point after at least one initial image has been captured 10, preferably the method includes determining the degree of openness of at least one eye in each captured image 30.

[0042] Preferably, computer vision and image processing techniques can be used to detect fully automated, real-time landmarks on human faces. More preferably, the algorithm is optimized to provide fast and accurate tracking of eyelids in both adults and infants. Any suitable techniques known for training machine learning algorithms can be utilized here.

[0043] In a preferred embodiment, the algorithm is used to detect multiple landmarks on the face. Figure 2A shows an example of template 100 using 68 landmarks. In a preferred embodiment, template 100 consists of or comprises six landmarks for each eye captured in the image. These six landmarks are the left corner 101, the upper left eyelid mark 102, the upper right eyelid mark 103, the right corner 104, the lower right eyelid mark 105, and the lower left eyelid mark 106, as seen in Figure 2A.

[0044] Once the landmark is identified, the calculation can be performed.

[0045] Specifically, for each image, the Fraction Eyelid Closure (FEC) can be calculated. Using six preferred landmarks as an example, conceptually, the calculation is performed by looking at the differences in the positions of the six marks, specifically as follows:

number

[0046] When viewing multiple images of the same individual, normalized (FEC) NORM ) is the minimum FEC (FEC MIN)) and the maximum FEC (FEC MAX ) can be determined based on. Specifically, FEC NORM = 1 - (FEC - FEC MIN ) / (FEC MAX ). FEC of 0 NORM corresponds to a fully open eye, and FEC of 1 NORM corresponds to a fully open eye.

[0047] In some embodiments, when two eyes are detected, the FEC is calculated for each eye and the results are averaged together. In some embodiments where two eyes are detected, the FEC is calculated for each eye and the minimum value is utilized. In some embodiments where two eyes are detected, the FEC is calculated for each eye and the maximum value is utilized. In some embodiments where two eyes are detected, the FEC is calculated for each eye and the difference between the two FEC values is determined. If the difference exceeds a threshold, the value of the flag is set to 1 or the variable is incremented to indicate that an abnormal reaction has occurred.

[0048] In some embodiments, if no eye is detected in a given image or if more than two eyes are detected, the image is skipped.

[0049] In some embodiments, a calibration sequence 2 occurs before this step and the FEC MIN value and the FEC MAX value are determined based on the images or videos captured during calibration. In a preferred embodiment, the FEC MIN value and the FEC MAX value are determined based only on the images or videos captured as part of the initial image or final image described above. <00002​​Referring to Figures 2B and 2C, the images show identified landmarks around the eyes of babies with their eyes fully open (Figure 2B) and babies with their eyes fully closed (Figure 2C). As seen in Figure 2D, by analyzing multiple images before and after the flash occurs (in Figure 2D, the flash occurs at time t=0), FEC can be determined. MIN Identify the image corresponding to 121 (in this case, Figure 2B), and FEX MAX It can be confirmed that 122 (in this case, Figure 2C) can be identified. By looking at the FECNORM value in Figure 2D, and by looking at multiple images, it can be seen that the degree of eyelid opening can be tracked over time.

[0051] In some embodiments, the method further includes determining the extent to which a conditioned response is acquired based on the determined openness of at least one eye in one or more initial images.

[0052] Blinking reflex conditioning can be seen with respect to Figure 2E. In the first iteration 130 of the steps described above (5-25), the tone is first emitted 133, the light flashes 134 after a time (400 ms in this case), and immediately afterward the eyeball closes completely. It is noteworthy that before the light flashes, even when the tone is emitted, the eyeball is fully open. In a later iteration 131, it can be seen that after the sound is emitted, and before the light flashes 400 ms later, the eyeball begins to blink (close) 138. However, there is still a peak in the time after the light flash begins. At this stage, some degree of blinking reflex conditioning has occurred, but it is not complete conditioning. The degree of conditioning can be determined in various ways. In some embodiments, the degree is simply the FEC at the time the light flash begins. NORM This is the maximum value. In Figure 2E, in the subsequent iteration 131, the FEC at the start of the optical flash is NORM Since this is approximately 0.2, the degree of conditioning is about 0.2, or about 20%.

[0053] In the final iteration 132, blink reflex conditioning is complete. In Figure 2E, the eyes are completely closed for the time at which a flash would normally occur 139. In this case, no flash occurred, only sound was emitted, and an image was captured and analyzed.

[0054] In some embodiments, the method includes testing the degree to which a conditioned response has been acquired 40. The last iteration 132 in Figure 2E is representative of this test. Specifically, to test the degree of conditioning, the test may include starting to emit sound from the speaker, as in step 5. The vibration motor may also start vibrating at this time. Then, while the sound is being emitted, one or more images of at least one eye are captured, and then the sound emission is stopped. The captured images are then analyzed as described above with respect to determining the degree of openness of at least one eye in each captured image 30.

[0055] In some embodiments, the method further includes transmitting at least a portion of an image or calculated value to a remote device or server.45 In some embodiments, this includes transmitting the determined degree of openness to a remote device or server. In some embodiments, this includes transmitting one or more initial images, one or more final images, or a combination thereof to a remote device or server. In some embodiments, this includes transmitting the degree of conditioned response to a remote device or server.

[0056] In a preferred embodiment, all image processing for determining the degree of openness, etc. (e.g., steps 30, 35, 40) is performed on the device. In another preferred embodiment, the image processing for determining openness, etc. (e.g., steps 30, 35, 40) is not performed on the device, and all processing is performed on a remote device or server.

[0057] In some embodiments, the ambient light level is detected before the test is performed. For example, in some embodiments, an excessively high ambient light level may reduce or eliminate the blink response. In such cases, if the ambient light level exceeds a predetermined threshold, the test may be stopped, the user may be instructed to move to a darker location or turn off the lights, or the ambient light intensity may be used as a dependent variable when analyzing the data.

[0058] Prepulse suppression As stated above, Method 1 may also, or alternatively, include testing prepulse suppression in user 4 according to claim 1.

[0059] Referring to Figure 1C, Method 4 generally involves several steps. To test prepulse suppression, the method optionally begins by first emitting a white noise prepulse 50, the white noise prepulse having a first intensity configured not to induce a startle reflex in the user. The absence of a startle reflex following this prepulse 50 can optionally be confirmed by capturing one or more images 65 after the prepulse has been emitted and not detecting a substantial degree of eye closure as described above with respect to blink reflex conditioning.

[0060] The method may then optionally include emitting a white noise pulse 55 having a second intensity configured to induce a startle reflex in the user, the second intensity being greater than the first intensity. The presence of a startle reflex following this pulse 55 can optionally be confirmed by capturing one or more images 65 after the pulse has been emitted and determining a first degree of eye closure as described above with respect to blink reflex conditioning.

[0061] This method includes cases where both a prepulse and a pulse are emitted with a delay 60 between them. Specifically, this step includes emitting a white noise prepulse 50, the white noise prepulse having a first intensity configured not to induce a startle reflex in the user, and then, after a delay in which no white noise is emitted, emitting a white noise pulse having a second intensity configured to induce a startle reflex in the user, the second intensity being greater than the first intensity.

[0062] The presence of prepulse suppression can be confirmed following the pulse in step 60 by capturing one or more images 65 after the pulse is emitted and then determining another degree of eye closure as described above with respect to blink reflex conditioning. In some cases, step 60 is sufficient. In some cases, steps 60 and 65 are sufficient. In some embodiments, the method also includes comparing the degree of eye closure 70 determined after only the pulse 55 has been emitted with the degree of eye closure 60 determined after both the prepulse and the pulse have been emitted. In some embodiments, the difference between the two can be determined. In some embodiments, the ratio of the two can be determined.

[0063] As can be seen in Figure 2F, the process described above is shown. In the first step 140, the prepulse 143 is emitted at time t < 0. FEC NORM As can be seen in the graph, no blinking occurs. In the second step 141, pulse 144 is emitted at time t=0. Within 200ms, the eye is closed a considerable amount but not completely closed (FEC). NORM The peak value is approximately 0.67. In the third step, prepulse 143 is released at time t<0 and pulse 144 is released at time t=0. As can be seen, prepulse suppression occurs within 200 ms, and here the initiation reflex, which correlates with the degree of eye closure, is detected but significantly reduced (FEC). NORM The peak value is approximately 0.1.

[0064] In some embodiments, the process uses a closed-loop system to measure the user's response (e.g., blinking / not blinking) induced by a white noise pulse / prepulse. If the volume is too loud (e.g., the prepulse elicits a startle response), the process will decrease the volume, and / or if the volume is too weak (e.g., the pulse does not elicit a startle response), the process will increase the volume. Volume adjustment is continued until an appropriate intensity is reached.

[0065] System / Device Referring to Figure 3, embodiments of a system 200 and device 210 useful for carrying out the above method can be seen. System 200 broadly includes a device 210 that can be held and / or used by a user or participant 220, a remote location 230 that includes, for example, one or more databases 231 with which the device 210 can communicate, and optionally a remote user 240 (such as a clinician, researcher, or physician) that can interact with the device and user directly or indirectly.

[0066] Disclosed is a device 210 for neurobehavioral testing (such as blink reflex conditioning and prepulse suppression) that does not use an air puff or require a gaseous (such as compressed air) supply source. The device 210 generally comprises a light source 211, a camera 212, a speaker 213, one or more processors 215, an optional wireless transceiver 216, and an optional vibration motor 217. All components are preferably at least partially housed in an outer housing 219. In some embodiments, the device 210 includes a second light source 214. In some preferred embodiments, the device 210 includes a light sensor 209.

[0067] In some embodiments, the device is a desktop or laptop computing device. Preferably, the device is a mobile or portable device such as a smartphone or tablet. Then, one or more processors run a program (such as an app on a smartphone) that causes the processors to execute specific instructions.

[0068] The light source can be any suitable light source capable of producing light that causes a person to blink under normal use conditions. In one preferred embodiment, the light source is a camera flash (such as a smartphone camera flash) or a display screen. For example, a processor may be configured to generate a camera flash or to display a pure white (or substantially white) screen at full brightness on a display screen for a short period of time. In a preferred embodiment, the device includes both a display screen and a camera flash. In some embodiments, only a single light source is used to emit light as described above. In other embodiments, all light sources are used to emit light as described above.

[0069] In some embodiments, one or more processors are configured to connect to a camera and / or light source contained in a separate housing, either via a wired connection (e.g., via a USB cable) or wirelessly (e.g., via Bluetooth®). For example, in some embodiments, a desktop computer can be connected to a suitable device, such as the Bulbicam neuro-ophthalmic diagnostic tool from Bulbitech.

[0070] In a preferred embodiment, the device 210 includes a light sensor 209 for detecting the ambient light level. If the ambient light level exceeds a threshold level, the user may be prompted to move to a darker location or turn off some lights. If the ambient light level is below a different threshold level, the user may be prompted to move to a brighter location or turn on some lights.

[0071] If device 210 is configured to perform blink-reflection conditioning as described above, then one or more processors, when executed, will cause one or more processors to (i) cause speaker 213 to begin emitting sound at a first time point and to stop emitting sound at a second time point, and (ii) cause light source 211 to begin emitting light 218 towards at least one eye 221 of user or participant 220 at a third time point (i.e., the light is directed so as to illuminate the eye) and to stop emitting light at a second time point. The instructions cause the following to occur, with the third time point following the first time point after a fixed delay interval (e.g., between 100 milliseconds and 1 second): (iii) receiving one or more first images of at least one eye from camera 212 while speaker 213 is emitting sound and light source 211 is not emitting light; and (iv) receiving one or more second images of at least one eye 221 from camera 212 while speaker 213 is emitting sound and light source 211 is emitting light 218. The processor may be configured to repeat the processing after the delay.

[0072] Preferably, one or more processors are also configured to determine the openness of at least one eye in each of one or more first images and one or more second images. This is achieved, as previously described, by using face detection and / or image processing software to identify face and eye landmarks, for example, by calculating the FEC for each image.

[0073] As described above, in some embodiments, the device comprises a vibration motor, and the processor is further configured to cause the vibration motor to start / operate vibration at a first time point and to stop / operate vibration at a second time point (i.e., to coincide with the emission of sound).

[0074] One or more processors may be configured to display or play video or images, augmented reality video or images, or virtual reality video or images on the device's display screen. In some embodiments, this display may begin before sound is emitted, end after the test is completed (for example, when virtual reality or augmented reality video and objects are used in the test), or end before light is emitted from a light source (if the entire display needs to generate bright light).

[0075] Because this process requires capturing participants' faces and measuring unique characteristics of their brain capacity, privacy and security must be considered when determining what information to store and where to store it.

[0076] In preferred embodiments, the raw facial image never leaves the device. The image is stored locally on the device (e.g., in flash memory) for a short time, allowing a processor on the device to analyze the image and make a determination using the aforementioned facial landmark detection algorithms and equations. In some of these embodiments, one or more processors are configured to provide a performance report (e.g., on a display screen) after making a determination, and optionally show a comparison with the scores of other users matched for gender and / or age. In some of these embodiments, the user may optionally transmit their score and / or determination to one or more databases 231 (not including the raw image) at a remote location 230 where the data will be stored anonymously. In some embodiments, the databases 231 may be managed and / or queried by a computer 232 at a remote location. In other embodiments, the databases 231 may be managed and / or queried by a remote user 240 (such as a clinician or researcher).

[0077] In another preferred embodiment, such as when a test or examination is being performed, a remote user 240 (e.g., a professional user) preferably uses the application to perform a neurobehavioral test on a given number of participants or patients. The professional user is able to control all stimulus parameters and data acquisition parameters. In some embodiments, the device 210 communicates directly with the remote user 240 251. However, in a preferred embodiment, the device 210 communicates with a remote location 230 (e.g., a remote server and one or more databases 231), and the remote user 240 communicates with the remote location 230 (e.g., the same remote server and one or more databases 231). The professional user is preferably able to access some or all of the acquired data, including raw images of faces, calculated or determined values, etc., which are typically available among normal neurobehavioral data. The data can be easily exported to any desired platform, preferably a SQL relational database system, and can be analyzed using facial landmark detection algorithms such as those described above, running on a typical desktop computer or CPU / GPU cluster.

[0078] Accordingly, in some embodiments, one or more processors 215 are further configured to determine the extent to which a conditioned response is acquired based on the determined openness of at least one eye in one or more first images. This determination can then be transmitted 251, 253 to a remote device or server. In some embodiments, one or more processors 215 are further configured to transmit 251, 253 the openness to a remote device or server. In some embodiments, one or more processors 215 are further configured to transmit 251, 253 one or more first images, one or more second images, or a combination thereof to a remote device or server.

[0079] If device 210 is configured to perform a prepulse suppression test as described above, one or more processors, when executed, consist of instructions that cause one or more processors to (i) emit a white noise prepulse, and (ii) emit a white noise pulse after a delay period, wherein the intensity of the pulse is greater than the intensity of the prepulse. As described above, one or more images of one or more eyes may be captured after the emission of the white noise pulse and used to determine the maximum closure by the white noise pulse. This determined value may optionally be compared to a previous determination of suppression, or to a previous determination of closure immediately following the pulse (without a prepulse being emitted), or to a threshold. In some embodiments, this determined value, and / or any comparison, is transmitted to a remote device or server 251, 253.

[0080] In some embodiments, the device is configured to perform only blink reflex conditioning or prepulse suppression testing. In some embodiments, the device is configured to perform both.

[0081] In some embodiments, the device may be configured to utilize a virtual reality (VR) type viewer (e.g., similar to the Google Cardboard® viewer) to prevent a significant amount of ambient light from reaching the eyes. For example, the housing may include or be connected to a flexible opaque polymer that surrounds the eyes and allows the camera and light source to be positioned at an appropriate distance from the eyes for effective operation.

[0082] Other exams As the systems and methods described above already include eye detection, other eye-related tracking embodiments can be incorporated into the methods or devices.

[0083] In some embodiments, one or more processors may also be configured to include eye position tracking. Eye position tracking includes (i) tracking of rapid eye movements (saccades and microsaccades), (ii) tracking of smooth tracking movements, and / or (iii) tracking of vestibulo-ocular movements. In preferred embodiments, when eye position tracking is utilized, the device is configured to utilize a VR-type viewer as described above.

[0084] In some embodiments, one or more processors may also be configured to include pupil size tracking to measure the user's arousal during a smartphone neurobehavioral test. As is known in the art, pupil size decreases as arousal declines. By analyzing captured images to measure the diameter of the pupil and optionally normalizing them, pupil size may be tracked over time to determine whether the user is sufficiently aroused. In some embodiments, the arousal level is determined by comparing the pupil size with other pupil size measurements collected during the user's test. In some embodiments, the arousal level is determined by comparing the measured pupil size with a threshold.

[0085] In some embodiments, one or more processors may also be configured to include pupil size tracking to measure conditioned pupil response. This is similar to blink reflex conditioning, but pupil size may be measured instead of eyelid position. That is, as is done using FEC for blink reflex conditioning, after experiencing conditioned and unconditioned stimuli, an image including the pupil is captured, the pupil diameter is measured, and preferably normalized.

[0086] In some embodiments, one or more processors can also be configured to measure reaction time conditioning. In one such embodiment, the user plays a simple video game for a period of time, for example, 5, 10, or 20 minutes. During the game, cues repeatedly appear on the screen. The user is instructed to tap the screen immediately after the cues appear. The app measures the user's reaction time, and the user receives feedback on their performance by displaying their most recent or fastest reaction time on the screen. The user is motivated to improve (reduce) their reaction time. During the game, the background on the screen gradually changes color. A randomly selected color (for example, purple) always precedes the appearance of a cues within a fixed time interval of, for example, 100 milliseconds to 1 second. The user is unaware of this beforehand. In Pavlovian terms, this selected color (purple in this example) is the conditional stimulus (CS). The cues are the unconditional stimulus (US). The response is an unconditional response (UR). After training, a finger tap in response to the CS is a conditioned response (CR). As a specific example, this game was tested using a small dragon (US) as the signal (CS) that appears in a sky that gradually changes color.

[0087] Those skilled in the art will be able to recognize or confirm, without the use of any means beyond routine experimentation, many equivalents to the specific embodiments of the present invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A method for conditioning the blink reflex without using an air puff, a. The mobile device's speaker begins to emit sound, b. Capturing one or more initial images of at least one eye while the sound is being emitted, c. Emitting light from the light source of the mobile device while the sound is being emitted, wherein the emission of light begins a certain period of time after the sound begins to be emitted. d. Capturing one or more final images of the at least one eye while the light and sound are being emitted, e. Stopping the emission of the sound and the light, f. Repeat steps a to e, g. Prepulse suppression is caused by emitting a white noise prepulse before or after steps a to f are completed, and by emitting a white noise pulse of greater intensity than the white noise prepulse after a delay period, and one or more additional images of the at least one eye are received from the camera after the white noise pulse, and the degree of openness of the at least one eye in the one or more additional images is determined. A method in which no devices are attached to the user's face.

2. The method according to claim 1, further comprising determining the degree of openness of the at least one eye in each of the initial image and the final image.

3. The method according to claim 2, further comprising transmitting the degree of openness to a remote device or server.

4. The method according to claim 3, further comprising transmitting the one or more initial images, the one or more final images, or a combination thereof, to a remote device or server.

5. The method according to claim 4, further comprising determining the extent to which a conditioned response is acquired based on the determined degree of openness of at least one eye in the one or more initial images.

6. The degree to which the aforementioned conditioned response has been acquired is, h. The mobile device's speaker begins to emit sound, i. Capturing one or more of the initial images of at least one eye while the sound is being emitted, j. The method according to claim 5, further comprising testing by stopping the emission of the sound.

7. The method according to claim 6, wherein the aforementioned period is between 100 milliseconds and 1 second.

8. The method according to claim 7, further comprising activating the vibration motor when the sound is being emitted and deactivating the vibration motor when the emission of the sound stops.

9. The method according to claim 8, further comprising initiating step (a) based on a signal received from a remote device or server.

10. A device for blink reflex conditioning without air puff, which, when executed, provides one or more processors, a. To cause a speaker configured to start emitting sound at a first time point and to stop emitting the sound at a second time point, b. Causing a light source configured to begin emitting light at a third time point and to cease emitting light at the second time point, wherein the third time point follows the first time point after a fixed delay interval. c. Receiving one or more first images of at least one eye from the camera while the speaker is emitting sound and the light source is not emitting light, d. Receiving one or more second images of the at least one eye from the camera while the speaker emits the sound and the light source emits the light, e. Determining the degree of openness of at least one eye in each of the one or more first images and the one or more second images, f. A device for blink reflex conditioning comprising one or more processors configured to cause prepulse suppression by emitting a white noise prepulse and, after a delay period, emitting a white noise pulse of greater intensity than the white noise prepulse; receiving one or more additional images of the at least one eye from the camera after the white noise pulse; and determining the degree of openness of the at least one eye in the one or more additional images.

11. The device for blink reflex conditioning according to claim 10, wherein the one or more processors are located within a mobile device.

12. The device for blink reflex conditioning according to claim 11, wherein the mobile device is a smartphone.

13. The device for blink-reflection conditioning according to claim 10, further comprising a wireless transceiver.

14. The device for blink reflex conditioning according to claim 13, wherein the processor is further configured to transmit the degree of openness to a remote device or server.

15. The device for blink reflection conditioning according to claim 13, wherein the processor is further configured to transmit the one or more first images, the one or more second images, or a combination thereof to a remote device or server.

16. The device for blink reflex conditioning according to claim 10, wherein the processor is further configured to determine the extent to which a conditioned response is acquired based on the determined openness of at least one eye in the one or more first images.

17. The device for blink reflex conditioning according to claim 10, wherein the fixed delay interval is between 100 milliseconds and 1 second.

18. The device for blink reflection conditioning according to claim 10, further comprising a vibration motor configured to begin vibrating at a first time and to stop vibrating at a second time.

19. The device for blink reflection conditioning according to claim 10, wherein the light source is a camera flash or a display screen.

20. The device for blink reflex conditioning according to claim 10, wherein the display screen displays video or images, augmented reality video or images, or virtual reality video or images.

Images