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Pupillography: Difference between revisions

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{{Article
{{Article
|Authors=Amirhossein.Vejdani
|Authors=Amirhossein.Vejdani
|Additional contributors=Alicia.Chen, Andrew.G.Lee, Caitlin.hackl, Claudia.Prospero.Ponce, Jennifer.Dunnigan, Sanjana.Jaiswal, Iris.zhuang, Nita.Bhat, Osama.deyabat
|Category=Neuro-ophthalmology/Orbit
|Category=Neuro-ophthalmology/Orbit
|Reviewer=Amirhossein.Vejdani
|Assigned editor=Osama.Deyabat
|Date reviewed=July 16, 2016
|Reviewer=Osama.Deyabat
|Date reviewed=October 08, 2024
|Article status=Up to Date
|Local Videos={{LocalVideo
|Local Videos={{LocalVideo
|File page=Tpxvidr.mp4
|File page=Tpxvidr.mp4
|Caption=Pupillography (Courtesy of Amirhossein Vejdani, MD.)
}}
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|Meta description=Pupillography is a formal method of recording and measuring reactions of the pupil.
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}}
= History and Development =
Pupillography was first termed by Lowenstein and Loewenfeld who developed the dynamic infrared-video technique to document the efferent and afferent ophthalmic pathways.<ref name=":0">Philibert M, Milea D. Basics, benefits, and pitfalls of pupillometers assessing visual function. ''Eye (Lond)''. 2024;38(12):2415-2421. doi:10.1038/s41433-024-03151-9</ref> Traditionally, pupillography was performed by hand to detect pathologic processes in the nervous system.<ref>LOWENSTEIN O, LOEWENFELD IE. Electronic pupillography; a new instrument and some clinical applications. ''AMA Arch Ophthalmol''. 1958;59(3):352-363.</ref> Technological advancements have allowed for electronic development of pupillography which has increased accuracy, consistency, and speed, as well as allowing for data storage and analysis of results. The term “pupillography” has also evolved. Today, “pupillometry” is also commonly used to describe the measurement of pupil size and the analysis of pupil responses. Recent technological evolution has led to the commercialization of new desktop and portable pupillometers, which when combined with artificial intelligence, improve the performance and objective quantifications of these devices.<ref name=":0" />


== Background ==
= Background =
Pupillography is a method of recording pupillary movements and study of changes and reactions to light and permits measurements of these movements. It is known that the pupillary pathways follow the optic nerve through the chiasma opticum and the pupil is an important oculomotor system that is affected by a diverse set of stimuli including changes in retinal luminance, sudden changes in stimulus motion, emotional and cognitive factors (1-5).
Pupillography is a formal method of recording and measuring reactions of the pupil often by using an
infrared video camera combined with computer software to analyze the images ([https://eyewiki.org/w/images/1/8/82/Tpxvidr.mp4 Video 1]). The pupillary afferent pathway starts at the retina, travels through the optic nerve, then goes through the optic chiasm and optic tract to reach the pretectal nucleus, where it communicates anteriorly with the Edinger Westphal nucleus that is in charge of the efferent pupillary pathway ([[#Figure1|Figure 1]]). This pupil pathway (afferent and efferent) can be affected by a diverse set of stimuli including changes in retinal luminance, sudden changes in stimulus motion, and emotional and cognitive factors. Thus, pupillography is a useful tool for studying, identifying, and treating the underlying stimuli and causes of certain pupillary reactions. It is also useful for obtaining exact measurements of the pupil during preparation for certain ophthalmic procedures. <ref name="hakerem1">Hakerem, G. & Sutton, S. Pupillary response at visual threshold. ''Nature'' '''212,''' 485–486 (1966).</ref> <ref name="kardon2">Kardon, R. Pupillary light reflex. ''Curr Opin Ophthalmol'' '''6,''' 20–26 (1995).</ref> <ref name="sahraie3">Sahraie, A. & Barbur, J. L. Pupil response triggered by the onset of coherent motion. ''Graefe’s Arch. Clin. Exp. Ophthalmol.'' '''235,''' 494–500 (1997).</ref> <ref name="goldwater4">Goldwater, B. C. Psychological significance of pupillary movements. ''Psychol. Bull.'' '''77,''' 340–355 (1972).</ref> <ref name="beatty5">Beatty, J. Task-evoked pupillary responses, processing load, and the structure of processing resources. ''Psychol. Bull.'' '''91,''' 276–292 (1982).</ref>


The measurement of pupil diameter in psychologic disorders provides an estimate of the intensity of mental activity and changes in mental estates. In fact, pupil dilation correlates with arousal so consistently that researchers use pupillometry, to investigate a wide range of psychological phenomena Researches in neuroscience has revealed a tight correlation between the activity of the locus coeruleus and pupillary dilation, so mental activity and pupillary responses have some correlations. Cognitive and emotional events can also dictate pupil constriction and expansion, though such events occur on a smaller scale than the light reflex, causing changes generally less than half a millimeter. By recording subjects’ eyes with infrared cameras and controlling for other factors that might affect pupil size, like brightness, color, and distance, scientists can use pupil movements as a proxy for other processes, like mental strain. It can be a sensitive indicator for Alzheimer's and Parkinson's diseases, Autism or even for opioid and alcohol  users (6-13).
= Procedure =
Pupillography is performed in an environment with low ambient light to minimize external influences on pupil size. Patients are positioned comfortably in front of a camera or specialized pupillometer, ensuring their eyes are aligned with the device. The baseline pupil size is then recorded in response to a neutral stimulus. Next, various stimuli, including light or visual patterns, are introduced while capturing the pupil's response with the device. It is crucial to maintain a consistent distance and angle throughout the recording process to ensure accuracy. Finally, the collected data are analyzed to assess parameters like latency, constriction, and dilation, which provide valuable insights into neurological function and autonomic responses.


Pupil size affects vision with any IOL and pupillography is very important in IOL selection especially in premium IOLs. Accurate pupillography is an essential part of the evaluation, screening, and refractive surgery planning process (14-19).  
= Benefits =
As pupillography offers a standardized recording, it may be preferred over a typical flashlight exam due to its accurate measurements. Pupillography also allows additional parameters to be measured, such as pupil latency time. The findings from each exam can be documented and compared, without examiner bias. These findings allow ophthalmologists to have a better understanding of the physiology and pathophysiology of pathologic and normal findings.<ref name="wilhelm8" /><span id="Figure1"></span>[[File:Pupil pathway AAO.jpg|thumb|'''Figure 1.''' '''Pupillary afferent and efferent pathways. '''The solid line represents the afferent pupillary pathway and the dotted line represents the efferent pupillary pathway. Light stimulating the left retina generates impulses that travel down the left optic nerve and divide at the optic chiasm, where some impulses continue down the left optic tract and others cross over to the right optic tract. These impulses stimulate the pretectal nuclei which then  stimulate both Edinger Westphal nuclei of CN III.   CN III acts on the iris sphincter muscles, causing both pupils to contract. Because of this double decussation, first in the chiasm and then in the pretectal and Edinger-Westphal nuclei, the direct pupil response in the left eye is equivalent to the indirect consensual response in the right eye. (Image obtained from <nowiki>http://www.aao.org</nowiki>).]]


Scientists have since used pupillography to assess everything from sleepiness to introversion, race bias ,schizophrenia, sexual interest, moral judgment, autism, and depression. And while they haven’t been reading people’s thoughts per se, they’ve come pretty close (20-26).
= Uses in Ophthalmology =


Most of ophthalmologists take advantage of pupillography because pupil size measurement during a pre-operative evaluation is particularly helpful for optimizing the premium IOL selection for the patient based on the patient's stated preferences about the level of vision he or she values most (e.g., distance, intermediate or near), occupation, lifestyle, and frequency of nighttime driving.
== Visual Acuity ==
Pupillography might be used to give an approximation of visual acuity in settings where patients cannot (e.g., nonverbal) or will not (e.g., nonorganic) provide the information using subjective assessments.<ref name="girkin6">Girkin, C. A. Evaluation of the pupillary light response as an objective measure of visual function. ''Ophthalmol. Clin. North Am.'' '''16,''' 143–153 (2003).</ref> While the classic pupillary light reflex is luminance-driven, a secondary reflex involving pupillary constriction to isoluminous stimuli (e.g. chromatic and achromatic gratings, coherent motion set) has also been documented. Both reflexes are mediated by the same retino-cortical pathway, the afferent arm of which is also involved in visual perception. However, the secondary reflex has a longer latency, and thus may have potential use as an objective indicator of visual acuity. In fact, it has already been shown to correlate with measurements of visual acuity but is currently limited to use in research settings due to the small amplitude of pupillary responses and the need for repeated measurements


A special designed device that can be used to measure pupils and screen candidates for refractive procedures and other ophthalmic applications such as the fitting of premium IOLs would be useful. It can also work best for diagnostic approaches to mental disorders and addiction.  
== Relative afferent pupillary defect (RAPD) ==
Pupillography also provides a standardized, quantifiable, and reproducible way of measuring the relative afferent pupillary defect (RAPD) compared to the conventional swinging flashlight test performed by a clinician.  The RAPD is seen in many different ocular diseases that can affect the afferent pupillary pathway (e.g., diffuse retinopathy, optic neuropathy, optic tract lesions and pretectal lesions). In a patient with head trauma, the RAPD may be the only sign of traumatic optic nerve injury and pupillography might be useful to assess the afferent pupillary pathway in a comatose trauma patient. Pupillographic investigation of RAPD may also help assess for less common afferent pupillary pathway lesions in the midbrain and tectum (e.g., tectal RAPD).<ref name="kawasaki7">Kawasaki, A., Miller, N. R. & Kardon, R. Pupillographic Investigation of the Relative Afferent Pupillary Defect Associated with a Midbrain Lesion. ''Ophthalmology'' '''117,''' 175–179 (2010).</ref>


== Pattern Recognition and System Auto-Calibration ==
== Dilation Lag ==
In order to track the size of the pupil, a segmentation algorithm can be used. The simplest method to perform this is using the well-known Hugh Transform method, as the pupil is usually in the shape of a circle. Although this method will work in many cases, it will not provide proper accuracy in all different conditions, such as abnormal pupil shapes, and misplaced pupils. As the camera is located exactly in front of the pupil (when the pupils are in the middle of the eye), any movements of the pupil will change its shape from the viewpoint of the camera (it will be more elliptic-shaped rather than a circle). Therefore, Hugh Transform algorithm alone cannot provide the required accuracy.  
Additionally, pupillography can be used to measure dilation lag, which refers to the delayed relaxation-dilation of the pupil when the light is withdrawn. Dilation lag is a characteristic feature of oculosympathetic denervation (i.e., the Horner's syndrome). The dilation of the pupil in the Horner's syndrome can take up to 15-20 seconds (i.e., dilation lag) compared to 5 seconds in normal individuals. Infrared light  provides optimal visualization of the dilation dynamics, and pupillography can accurately measure the dilation speed and difference in dilation between the pupils. Pupillography may be the only reliable method of diagnosis for dilation lag in bilateral Horner's syndrome (where the relative anisocoria is obscured by bilaterality).<ref name="wilhelm8">Wilhelm, H. & Wilhelm, B. Clinical applications of pupillography. ''J.  Neuro-Ophthalmology'' '''23,''' 42–49 (2003).</ref> <ref name="smith9">Smith, S. A. & Smith, S. E. Bilateral Horner’s syndrome: detection and occurrence.  ''J. Neurol. Neurosurg. Psychiatry'' '''66,''' 48–51 (1999).</ref>


To enhance the performance of the detection system, a more intelligent pattern recognition system should utilize . Although, these systems need a training set and an experienced user to train the network, it can eventually adapt itself to detect the desired item (such as pupil) with a very high accuracy regardless of its exact shape. Therefore, in the cases of abnormal pupil shape, or misplaced pupil, the algorithm can still accurately detect the pupil and its position.  
== Refractive Surgery ==
Furthermore, pupillography can be an essential part of the refractive surgery evaluation and planning process. For refractive surgery, measuring the pupil size in low light conditions helps determine the most accurate ablation zone. If the ablation zone is smaller than the dilated pupil, then patients can develop halos that disrupt their nighttime vision.<ref name="boxer10">Boxer Wachler, B. S. & Krueger, R. R. Agreement and repeatability of pupillometry using videokeratography and infrared devices. ''J. Cataract Refract. Surg.'' '''26,''' 35–40 (2000).</ref> <ref name="schnitzler11">Schnitzler, E. M., Baumeister, M. & Kohnen, T. Scotopic measurement of normal pupils: Colvard versus Video Vision Analyzer infrared pupillometer. ''J. Cataract Refract. Surg.'' '''26,''' 859–866 (2000). </ref>


However, the pupil size scaling is still an issue, which should be pointed out. In other words, if a pupil has a displacement from the center, its measured size may not be accurate enough due to perspective issues. However, when  the device frame is symmetric, the scaling factor of both eyes would be the same for each patient. It is worth mentioning that this scaling factor varies from patient to patient, but it will be constant for each patient. Therefore, neglecting this scaling factor (or reporting the normalized outputs rather than the actual values), will not affect the accuracy of the device in the cases of different shapes of patients’ faces (different eye-camera distance).  
== Intraocular Lens Placement ==
Pupil size measurement is also important during pre-operative evaluation of intraocular lens (IOL) placement, especially for premium IOLs. IOL selection is a complicated process that involves a variety of factors, including the patient's stated preferences about the level of vision he or she values most (e.g. distance, intermediate or near), occupation, lifestyle, and frequency of nighttime driving, and pupillography can help optimize this decision.<ref name="wang12">Wang, M., Corpuz, C. C. C., Huseynova, T. & Tomita, M. Pupil Influence on the Visual Outcomes of a New-Generation Multifocal Toric Intraocular Lens With a Surface-Embedded Near Segment. ''J. Refract. Surg.'' '''32,''' 90–95 (2016).</ref> <ref name="kim13">Kim, M.  J., Yoo, Y. S., Joo, C. K. & Yoon, G. Evaluation of optical performance of 4 aspheric toric intraocular lenses using an optical bench system: Influence of pupil size, decentration, and rotation. ''J. Cataract Refract. Surg.'' '''41,''' 2274–2282 (2015).</ref> <ref name="vega14">Vega, F. ''et al.'' Halo and through-focus performance of four diffractive multifocal intraocular lenses. ''Investig. Ophthalmol. Vis. Sci.'' '''56,''' 3967–3975 (2015).</ref> <ref name="garcíadomene15">García-Domene, M. C. ''et al.'' Image Quality Comparison of Two Multifocal IOLs: Influence of the Pupil. ''J. Refract. Surg.'' '''31,''' 230–235 (2015).</ref>  <ref name="fliedner16">Fliedner, J., Heine, C., Bretthauer, G. & Wilhelm, H. The pupil can control an artificial lens intuitively. ''Investig. Ophthalmol. Vis. Sci.'' '''55,''' 759–766 (2014).</ref> <ref name="watanabe17">Watanabe, K. ''et al.'' Effect of Pupil Size on Uncorrected Visual Acuity in Pseudophakic Eyes With Astigmatism. ''J. Refract. Surg.'' '''29,''' 25–30 (2013). </ref>


To compensate for the eye movement, another scaling factor can be utilized to scale the size of the pupil, as it is located in the middle of the eye. This can be done by simple mathematical expressions, since the location of the pupil with respect to the camera can be easily calculated and used to find the variations from the center. This method is a well-known method in image processing algorithms and can be easily implemented in the proposed device.  
= Uses in Neuropsychiatry =
Additionally, the measurement of pupil diameter in psychiatric disorders provides an estimate of the intensity of mental activity and changes in mental states. In fact, pupil dilation correlates with arousal so consistently that pupillometry has been used to investigate a wide range of neuropsychiatric phenomena.<ref name="wilhelm8"/> A tight correlation between the activity of the locus coeruleus and pupillary dilation has also been evidenced, further suggesting a link between mental activity and pupillary responses. Although cognitive and emotional events can affect  pupil constriction and dilation,  such events occur on a smaller scale than the light reflex, causing changes generally less than half a millimeter. By controlling for other factors that might affect pupil size, like brightness, color, and distance, scientists can use pupil movements as a proxy for other processes, like mental strain. These movements may prove to be  sensitive indicators for neurodegenerative disease (e.g., Alzheimer's and Parkinson's  disease), autism, or even opioid and alcohol abuse.<ref name="fotiou18">18 Fotiou, D. F. ''et al.'' Cholinergic deficiency in Alzheimer’s and Parkinson’s disease: Evaluation with pupillometry. ''Int. J. Psychophysiol.'' '''73,''' 143–149 (2009).</ref> <ref name="stergiou19">Stergiou, V. ''et al.'' Pupillometric findings in patients with Parkinson’s disease and cognitive disorder. ''Int. J. Psychophysiol.'' '''72,''' 97–101 (2009).</ref> <ref name="fotiou20">Fotiou, D. F. ''et al.'' Pupil reaction to light in Alzheimer’s disease: evaluation of pupil size changes and mobility. ''Aging Clin. Exp. Res.'' '''19,''' 364–371 (2007).</ref> <ref name="fotiou21">Fotiou, F., Fountoulakis, K. N., Tsolaki, M., Goulas, A. & Palikaras, A. Changes in pupil reaction to light in Alzheimer’s disease patients: A preliminary report.  in ''International Journal of Psychophysiology'' '''37,''' 111–120 (2000).</ref> <ref name="ghodse22">Ghodse, H., Taylor, D., Greaves, J., Britten, A. & Lynch, D. The opiate addiction test: a clinical evaluation of a quick test for physical dependence on opiate drugs. ''Br. J. Clin. Pharmacol.'' '''39,''' 257–259 (1995).</ref> <ref name="krach23">Krach, S.  ''et al.'' Evidence from pupillometry and fMRI indicates reduced neural response during vicarious social pain but not physical pain in autism. ''Hum.  Brain Mapp.'' '''36,''' 4730–4744 (2015).</ref> <ref name="nuske24">Nuske, H.  J., Vivanti, G., Hudry, K. & Dissanayake, C. Pupillometry reveals reduced unconscious emotional reactivity in autism. ''Biol. Psychol.'' '''101,''' 24–35 (2014).</ref> <ref name="blaser25">Blaser, E., Eglington, L., Carter, A. S. & Kaldy, Z. Pupillometry reveals a mechanism for the Autism Spectrum Disorder (ASD) advantage in visual tasks. ''Sci.  Rep.'' '''4,''' (2014).</ref>


== More Advantages ==
Pupillography has also been used to assess  other mental states (e.g., sleepiness,  introversion, race bias, sexual interest, moral judgment, schizophrenia, and depression).<ref name="merritt26">Merritt, S. L., Schnyders, H. C., Patel, M., Basner, R. C. & O’Neill, W. Pupil staging and EEG measurement of sleepiness. in ''International Journal of Psychophysiology'' '''52,''' 97–112 (2004).</ref> <ref name="stelmack27">Stelmack, R. M. & Mandelzys, N. Extraversion and Pupillary Response to Affective and Taboo Words. ''Psychophysiology'' '''12,''' 536–540 (1975).</ref> <ref name="wu28">Wu, E. X.  W., Laeng, B. & Magnussen, S. Through the eyes of the own-race bias: Eye-tracking and pupillometry during face recognition. ''Soc. Neurosci.'' '''7,''' 202–216 (2012).</ref> <ref name="granholm29">29 Granholm, E. & Verney, S. P. Pupillary responses and attentional allocation problems on the backward masking task in schizophrenia. in ''International Journal of Psychophysiology'' '''52,''' 37–51 (2004).</ref> <ref name="laeng30">Laeng, B.  & Falkenberg, L. Women’s pupillary responses to sexually significant others during the hormonal cycle. ''Horm. Behav.'' '''52,''' 520–530 (2007).</ref> <ref name="decety31">Decety, J., Michalska, K. J. & Kinzler, K. D. The contribution of emotion and cognition to moral sensitivity: A neurodevelopmental study. ''Cereb. Cortex'' '''22,''' 209–220 (2012).</ref> <ref name="sepeta32">Sepeta, L. ''et al.'' Abnormal social reward processing in autism as indexed by pupillary responses to happy faces. ''J. Neurodev. Disord.'' '''4,''' (2012).</ref>
The most pertinent information will be obtained by measuring a patient's pupils under varying light conditions which simulate real life conditions a patient may experience in daily life such as darkness, a dimly lit room, and driving at night with streetlights.
Measurement of the pupil is more difficult than it might seem because of the phenomenon of pupillary hippus or noise. The pupil is never entirely at rest but rather has normal, small continuous oscillations (±0.5mm). Therefore, when trying to measure the pupil, a single “snapshot” estimate is not a reliable predictor of the true mean size (because the clinician might catch the pupil at the maximum or minimum.) so , a proposed device should  record pupillary movements for further processing and analysis so that any technician can perform the test automatically.  


== References ==
=Uses in Pharmacology=
1. Hakerem G., Sutton S. Pupillary response at visual threshold. Nature. 1966; 212:485–486.  
Pupillography has also been used to test and study the autonomic effects of certain drugs. For instance, pupillography can demonstrate whether a drug has cholinergic or adrenergic effects based on the reaction size of the pupil. <ref name="wilhelm8">Wilhelm, H. & Wilhelm, B. Clinical applications of pupillography. ''J.  Neuro-Ophthalmology'' '''23,''' 42–49 (2003).</ref> Pupillography can also be used to study sedative effects of drugs since sleepiness can be measured by the degree of spontaneous and involuntary fluctuations in pupil size. <ref name=phillips33">Phillips, M. A., Bitsios, P., Szabadi, E., & Bradshaw, C. M. Comparison of the antidepressants reboxetine, fluvoxamine and amitriptyline upon spontaneous pupillary fluctuations in healthy human volunteers. ''Psychopharmacology'' '''149, ''' 72-76 (2000).</ref>


2. Kardon K. Pupillary light reflex. Curr Opin Ophthalmol. 1995; 6:20–26.  
= Device Considerations =
Measurement of the pupil size and function may be challenging secondary to the phenomenon of pupillary hippus or noise. The pupil is never entirely at rest but rather has normal, small continuous oscillations (±0.5mm). Therefore, when trying to measure the pupil, a single “snapshot” estimate is not a reliable predictor of the true mean size because the clinician might catch the pupil at the maximum or minimum. Consequently, most current pupillographic devices involve recording the pupil with a specialized infrared video camera, whose video frames are then transferred to a personalized computer that uses imaging processing software (discussed in the next section) to calculate pupil size in each individual frame.<ref name="wilhelm8"/><ref name="nowak34">Nowak, W., Zarowska, A., Szul-Pietrzak, E. & Misiuk-Hojło, M. System and measurement method for binocular pupillometry to study pupil size variability. ''Biomed.  Eng. Online'' '''13,''' (2014).</ref> Commercially available devices differ significantly from each other because they are usually designed for a specific task. This means that some instruments are optimized for high spatial or temporal resolution, while others are optimized for stable, long-term recordings. There are also different systems for monocular (sampling frequency of 5-25 Hz) versus binocular (sampling frequency of 25-60 Hz) recording, as well as different levels of light stimulus.<ref name="wilhelm8"/><ref name="nowak34"/>


3. Sahraie A., Barbur J.L. Pupil response triggered by the onset of coherent motion. Graefes Arch Clin Exp Ophthalmol. 1997; 235:494–500.  
= Pattern Recognition and System Auto-Calibration =
In order to track the size of the pupil, a segmentation algorithm can be used. The simplest of these is the well-known Hough Transform method ([[#Figure2|Figure 2]]). This method will work in many cases because the pupil is usually in the shape of a circle, but it will not provide proper accuracy in all conditions, such as when the pupil is misplaced or abnormally shaped. Pupil movements can also affect the accuracy of this method, as they can make the pupil appear more elliptical (rather than circular) from the fixed perspective of the camera. Therefore, the Hough Transform cannot alone provide the required accuracy.<ref name="espinosa35">Espinosa, J., Roig, A. B., Pérez, J. & Mas, D. A high-resolution binocular video-oculography system : assessment of pupillary light reflex and detection of an early incomplete blink and an upward eye movement. 1–12 (2015). doi:10.1186/s12938-015-0016-6</ref>


4. Goldwater B.C. Psychological significance of pupillary movements. Psychol Bull. 1972; 77:340–355.
More intelligent pattern recognition models can be used for higher accuracy. Although these models need training data and experts to train them, they can eventually adapt themselves to detect the desired item (such as the pupil) with very high accuracy regardless of its exact shape. Therefore, these models can accurately detect even misplaced or abnormally shaped pupils and their positions.


5. Beatty J. Task-evoked pupillary responses, processing load, and the structure of processing resources.Psychol Bull. 1982; 91:276–292.
To compensate for eye movement, we can multiply the measured pupil size by another scaling factor. Because the pupil is normally located in the center of the eye, we can easily determine the location of the pupil with respect to the camera. This allows us to calculate the appropriate scaling factor with mathematical expressions.<ref name="chennamma36">Chennamma, H. R. & Yuan, X. A Survey on Eye-Gaze Tracking Techniques. '''4,''' 388–393 (2013). </ref>


6. Fotiou DF, Stergiou V, Tsiptsios D, Lithari C, Nakou M, Karlovasitou A. Cholinergic deficiency in Alzheimer's and Parkinson's disease: evaluation with pupillometry. Int J Psychophysiol. 2009;73(2):143-9.  
= Limitations =
The diagnostic accuracy of pupillometers can vary greatly based on the type of device, the stimulation methods used, and the algorithms employed for analysis. Reproducibility can be a challenge between models as each device has varying protocols. Patient non-visual parameters can also be influenced by caffeine, fatigue, stress, as well as drug use.<ref name=":0" /> Studies are still needed to explore the intra-and-inter-personal reproducibility between devices as it is crucial for diagnostic precision and management.[[File:Pupil reaction.jpg|thumb|'''Figure 2. Image processing phases.'''
'''a)''' Original frame, '''b)''' Weiner-filtered region of interest, '''c)''' circle drawn after determining its center using the Circular Hough Transform. <ref>Obtained from Espinosa, J., Roig, A. B., Pérez, J. & Mas, D. A high-resolution binocular video-oculography system : assessment of pupillary light reflex and detection of an early incomplete blink and an upward eye movement. 1–12 (2015).  doi:10.1186/s12938-015-0016-6  <nowiki>https://biomedical-engineering-online.biomedcentral.com/articles/10.1186/s12938-015-0016-6</nowiki>. Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/</ref>]]


7. Stergiou V, Fotiou D, Tsiptsios D, Haidich B, Nakou M, Giantselidis C, Karlovasitou A. Pupillometric findings in patients with Parkinson's disease and cognitive disorder. Int J Psychophysiol. 2009;72(2):97-101.
= References =
 
<references />
8. Fotiou DF, Brozou CG, Haidich AB, Tsiptsios D, Nakou M, Kabitsi A, Giantselidis C, Fotiou F. Pupil reaction to light in Alzheimer's disease: evaluation of pupil size changes and mobility. Aging Clin Exp Res. 2007;19(5):364-71.
 
9. Fotiou F, Fountoulakis KN, Tsolaki M, Goulas A, Palikaras A. Changes in pupil reaction to light in Alzheimer's disease patients: a preliminary report. Int J Psychophysiol. 2000;37(1):111-20.
 
10. Ghodse H, Taylor DR, Greaves JL, Britten AJ, Lynch D. The opiate addiction test: a clinical evaluation of a quick test for physical dependence on opiate drugs. Br J Clin Pharmacol. 1995;39(3):257-9.
 
11. Krach S, Kamp-Becker I, Einhäuser W, Sommer J, Frässle S, Jansen A, Rademacher L, Müller-Pinzler L, Gazzola V, Paulus FM. Evidence from pupillometry and fMRI indicates reduced neural response during vicarious social pain but not physical pain in autism. Hum Brain Mapp. 2015;36(11):4730-44.
 
12. Nuske HJ, Vivanti G, Hudry K, Dissanayake C. Pupillometry reveals reduced unconscious emotional reactivity in autism. Biol Psychol. 2014;101:24-35.
 
13. Blaser E, Eglington L, Carter AS, Kaldy Z. Pupillometry reveals a mechanism for the Autism Spectrum Disorder (ASD) advantage in visual tasks. Sci Rep. 2014 7;4:4301.
 
14. Wang M, Corpuz CC, Huseynova T, Tomita M. Pupil Influence on the Visual Outcomes of a New-Generation Multifocal Toric Intraocular Lens With a Surface-Embedded Near Segment. J Refract Surg. 2016;32(2):90-5.
 
15. Kim MJ, Yoo YS, Joo CK, Yoon G. Evaluation of optical performance of 4 aspheric toric intraocular lenses using an optical bench system: Influence of pupil size, decentration, and rotation. J Cataract Refract Surg. 2015;41(10):2274-82.
 
16. Vega F, Alba-Bueno F, Millán MS, Varón C, Gil MA, Buil JA. Halo and Through-Focus Performance of Four Diffractive Multifocal Intraocular Lenses. Invest Ophthalmol Vis Sci. 2015;56(6):3967-75.
 
17. García-Domene MC, Felipe A, Peris-Martínez C, Navea A, Artigas JM, Pons ÁM. Image quality comparison of two multifocal IOLs: influence of the pupil. J Refract Surg. 2015;31(4):230-5.
 
18. Fliedner J1, Heine C, Bretthauer G, Wilhelm H. The pupil can control an artificial lens intuitively. Invest Ophthalmol Vis Sci. 2014;55(2):759-66.
 
19. Watanabe K, Negishi K, Dogru M, Yamaguchi T, Torii H, Tsubota K. Effect of pupil size on uncorrected visual acuity in pseudophakic eyes with astigmatism. J Refract Surg. 2013;29(1):25-9.
 
20.   Merritt SL , Schnyders HC, Patel M, Basner RC, O'Neill W. Pupil staging and EEG measurement of sleepiness.  Int J Psychophysiol. 2004 Mar;52(1):97-112.
 
21.   Robert M. Stelmack* and Nathan Mandelzys. Psychophysiology Volume 12, Issue 5, pages 536–540, September 1975.
 
22. Wu EX , Laeng B, Magnussen S. Through the eyes of the own-race bias: eye-tracking and pupillometry during face recognition. Soc Neurosci. 2012;7(2):202-16.
 
23.   Eric Granholm  ,  Steven P. Verney. Pupillary responses and attentional allocation problems on the backward masking task in schizophrenia. International Journal of Psychophysiology Volume 52, Issue 1, March 2004, Pages 37–51.
 
24. Laeng B , Falkenberg L. Women's pupillary responses to sexually significant others during the hormonal cycle. Horm Behav. 2007 Nov;52(4):520-30. Epub 2007 Aug .
 
25.   Jean Decety ,  Kalina J. Michalska and Katherine D. Kinzler. The Contribution of Emotion and Cognition to Moral Sensitivity: A Neurodevelopmental Study. Cerebral Cortex Advance Access published May 26, 2011.
 
26. Leigh Sepeta1  , Naotsugu Tsuchiya  , Mari S Davies , Marian Sigman , Susan Y Bookheimer  and Mirella Dapretto. Abnormal social reward processing in autism as indexed by pupillary responses to happy faces.  Journal of Neurodevelopmental Disorders 2012, 4:17.

Latest revision as of 18:14, October 8, 2024

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Article initiated by:
Amirhossein Vejdani, MD
All contributors:
Alicia Chen, Andrew Go Lee, MD, Caitlin Makenzie Hackl, Claudia Prospero Ponce, MD, Jennifer Dunnigan, Sanjana Jaiswal, Iris Zhuang, Nita Bhat, MBBS, MS, Osama Al Deyabat, MBBS, Nagham Al-Zubidi, MD, Amirhossein Vejdani, MD, Claudia Prospero Ponce, MD, Shruthi Harish Bindiganavile, MBBS, MS, Farida Al Belushi MD, Osama Al Deyabat, MBBS, Sanjana Jaiswal
Assigned editor:
Osama Al Deyabat, MBBS
Review:
Assigned status Up to Date
 by Osama Al Deyabat, MBBS on October 08, 2024.


Pupillography (Courtesy of Amirhossein Vejdani, MD.)

History and Development

Pupillography was first termed by Lowenstein and Loewenfeld who developed the dynamic infrared-video technique to document the efferent and afferent ophthalmic pathways.[1] Traditionally, pupillography was performed by hand to detect pathologic processes in the nervous system.[2] Technological advancements have allowed for electronic development of pupillography which has increased accuracy, consistency, and speed, as well as allowing for data storage and analysis of results. The term “pupillography” has also evolved. Today, “pupillometry” is also commonly used to describe the measurement of pupil size and the analysis of pupil responses. Recent technological evolution has led to the commercialization of new desktop and portable pupillometers, which when combined with artificial intelligence, improve the performance and objective quantifications of these devices.[1]

Background

Pupillography is a formal method of recording and measuring reactions of the pupil often by using an infrared video camera combined with computer software to analyze the images (Video 1). The pupillary afferent pathway starts at the retina, travels through the optic nerve, then goes through the optic chiasm and optic tract to reach the pretectal nucleus, where it communicates anteriorly with the Edinger Westphal nucleus that is in charge of the efferent pupillary pathway (Figure 1). This pupil pathway (afferent and efferent) can be affected by a diverse set of stimuli including changes in retinal luminance, sudden changes in stimulus motion, and emotional and cognitive factors. Thus, pupillography is a useful tool for studying, identifying, and treating the underlying stimuli and causes of certain pupillary reactions. It is also useful for obtaining exact measurements of the pupil during preparation for certain ophthalmic procedures. [3] [4] [5] [6] [7]

Procedure

Pupillography is performed in an environment with low ambient light to minimize external influences on pupil size. Patients are positioned comfortably in front of a camera or specialized pupillometer, ensuring their eyes are aligned with the device. The baseline pupil size is then recorded in response to a neutral stimulus. Next, various stimuli, including light or visual patterns, are introduced while capturing the pupil's response with the device. It is crucial to maintain a consistent distance and angle throughout the recording process to ensure accuracy. Finally, the collected data are analyzed to assess parameters like latency, constriction, and dilation, which provide valuable insights into neurological function and autonomic responses.

Benefits

As pupillography offers a standardized recording, it may be preferred over a typical flashlight exam due to its accurate measurements. Pupillography also allows additional parameters to be measured, such as pupil latency time. The findings from each exam can be documented and compared, without examiner bias. These findings allow ophthalmologists to have a better understanding of the physiology and pathophysiology of pathologic and normal findings.[8]

Figure 1. Pupillary afferent and efferent pathways. The solid line represents the afferent pupillary pathway and the dotted line represents the efferent pupillary pathway. Light stimulating the left retina generates impulses that travel down the left optic nerve and divide at the optic chiasm, where some impulses continue down the left optic tract and others cross over to the right optic tract. These impulses stimulate the pretectal nuclei which then  stimulate both Edinger Westphal nuclei of CN III.  CN III acts on the iris sphincter muscles, causing both pupils to contract. Because of this double decussation, first in the chiasm and then in the pretectal and Edinger-Westphal nuclei, the direct pupil response in the left eye is equivalent to the indirect consensual response in the right eye. (Image obtained from http://www.aao.org).

Uses in Ophthalmology

Visual Acuity

Pupillography might be used to give an approximation of visual acuity in settings where patients cannot (e.g., nonverbal) or will not (e.g., nonorganic) provide the information using subjective assessments.[9] While the classic pupillary light reflex is luminance-driven, a secondary reflex involving pupillary constriction to isoluminous stimuli (e.g. chromatic and achromatic gratings, coherent motion set) has also been documented. Both reflexes are mediated by the same retino-cortical pathway, the afferent arm of which is also involved in visual perception. However, the secondary reflex has a longer latency, and thus may have potential use as an objective indicator of visual acuity. In fact, it has already been shown to correlate with measurements of visual acuity but is currently limited to use in research settings due to the small amplitude of pupillary responses and the need for repeated measurements

Relative afferent pupillary defect (RAPD)

Pupillography also provides a standardized, quantifiable, and reproducible way of measuring the relative afferent pupillary defect (RAPD) compared to the conventional swinging flashlight test performed by a clinician.  The RAPD is seen in many different ocular diseases that can affect the afferent pupillary pathway (e.g., diffuse retinopathy, optic neuropathy, optic tract lesions and pretectal lesions). In a patient with head trauma, the RAPD may be the only sign of traumatic optic nerve injury and pupillography might be useful to assess the afferent pupillary pathway in a comatose trauma patient. Pupillographic investigation of RAPD may also help assess for less common afferent pupillary pathway lesions in the midbrain and tectum (e.g., tectal RAPD).[10]

Dilation Lag

Additionally, pupillography can be used to measure dilation lag, which refers to the delayed relaxation-dilation of the pupil when the light is withdrawn. Dilation lag is a characteristic feature of oculosympathetic denervation (i.e., the Horner's syndrome). The dilation of the pupil in the Horner's syndrome can take up to 15-20 seconds (i.e., dilation lag) compared to 5 seconds in normal individuals. Infrared light  provides optimal visualization of the dilation dynamics, and pupillography can accurately measure the dilation speed and difference in dilation between the pupils. Pupillography may be the only reliable method of diagnosis for dilation lag in bilateral Horner's syndrome (where the relative anisocoria is obscured by bilaterality).[8] [11]

Refractive Surgery

Furthermore, pupillography can be an essential part of the refractive surgery evaluation and planning process. For refractive surgery, measuring the pupil size in low light conditions helps determine the most accurate ablation zone. If the ablation zone is smaller than the dilated pupil, then patients can develop halos that disrupt their nighttime vision.[12] [13]

Intraocular Lens Placement

Pupil size measurement is also important during pre-operative evaluation of intraocular lens (IOL) placement, especially for premium IOLs. IOL selection is a complicated process that involves a variety of factors, including the patient's stated preferences about the level of vision he or she values most (e.g. distance, intermediate or near), occupation, lifestyle, and frequency of nighttime driving, and pupillography can help optimize this decision.[14] [15] [16] [17] [18] [19]

Uses in Neuropsychiatry

Additionally, the measurement of pupil diameter in psychiatric disorders provides an estimate of the intensity of mental activity and changes in mental states. In fact, pupil dilation correlates with arousal so consistently that pupillometry has been used to investigate a wide range of neuropsychiatric phenomena.[8] A tight correlation between the activity of the locus coeruleus and pupillary dilation has also been evidenced, further suggesting a link between mental activity and pupillary responses. Although cognitive and emotional events can affect  pupil constriction and dilation,  such events occur on a smaller scale than the light reflex, causing changes generally less than half a millimeter. By controlling for other factors that might affect pupil size, like brightness, color, and distance, scientists can use pupil movements as a proxy for other processes, like mental strain. These movements may prove to be  sensitive indicators for neurodegenerative disease (e.g., Alzheimer's and Parkinson's disease), autism, or even opioid and alcohol abuse.[20] [21] [22] [23] [24] [25] [26] [27]

Pupillography has also been used to assess  other mental states (e.g., sleepiness, introversion, race bias, sexual interest, moral judgment, schizophrenia, and depression).[28] [29] [30] [31] [32] [33] [34]

Uses in Pharmacology

Pupillography has also been used to test and study the autonomic effects of certain drugs. For instance, pupillography can demonstrate whether a drug has cholinergic or adrenergic effects based on the reaction size of the pupil. [8] Pupillography can also be used to study sedative effects of drugs since sleepiness can be measured by the degree of spontaneous and involuntary fluctuations in pupil size. [35]

Device Considerations

Measurement of the pupil size and function may be challenging secondary to the phenomenon of pupillary hippus or noise. The pupil is never entirely at rest but rather has normal, small continuous oscillations (±0.5mm). Therefore, when trying to measure the pupil, a single “snapshot” estimate is not a reliable predictor of the true mean size because the clinician might catch the pupil at the maximum or minimum. Consequently, most current pupillographic devices involve recording the pupil with a specialized infrared video camera, whose video frames are then transferred to a personalized computer that uses imaging processing software (discussed in the next section) to calculate pupil size in each individual frame.[8][36] Commercially available devices differ significantly from each other because they are usually designed for a specific task. This means that some instruments are optimized for high spatial or temporal resolution, while others are optimized for stable, long-term recordings. There are also different systems for monocular (sampling frequency of 5-25 Hz) versus binocular (sampling frequency of 25-60 Hz) recording, as well as different levels of light stimulus.[8][36]

Pattern Recognition and System Auto-Calibration

In order to track the size of the pupil, a segmentation algorithm can be used. The simplest of these is the well-known Hough Transform method (Figure 2). This method will work in many cases because the pupil is usually in the shape of a circle, but it will not provide proper accuracy in all conditions, such as when the pupil is misplaced or abnormally shaped. Pupil movements can also affect the accuracy of this method, as they can make the pupil appear more elliptical (rather than circular) from the fixed perspective of the camera. Therefore, the Hough Transform cannot alone provide the required accuracy.[37]

More intelligent pattern recognition models can be used for higher accuracy. Although these models need training data and experts to train them, they can eventually adapt themselves to detect the desired item (such as the pupil) with very high accuracy regardless of its exact shape. Therefore, these models can accurately detect even misplaced or abnormally shaped pupils and their positions.

To compensate for eye movement, we can multiply the measured pupil size by another scaling factor. Because the pupil is normally located in the center of the eye, we can easily determine the location of the pupil with respect to the camera. This allows us to calculate the appropriate scaling factor with mathematical expressions.[38]

Limitations

The diagnostic accuracy of pupillometers can vary greatly based on the type of device, the stimulation methods used, and the algorithms employed for analysis. Reproducibility can be a challenge between models as each device has varying protocols. Patient non-visual parameters can also be influenced by caffeine, fatigue, stress, as well as drug use.[1] Studies are still needed to explore the intra-and-inter-personal reproducibility between devices as it is crucial for diagnostic precision and management.

Figure 2. Image processing phases. a) Original frame, b) Weiner-filtered region of interest, c) circle drawn after determining its center using the Circular Hough Transform. [39]

References

  1. ↑ Jump up to: 1.0 1.1 1.2 Philibert M, Milea D. Basics, benefits, and pitfalls of pupillometers assessing visual function. Eye (Lond). 2024;38(12):2415-2421. doi:10.1038/s41433-024-03151-9
  2. ↑ LOWENSTEIN O, LOEWENFELD IE. Electronic pupillography; a new instrument and some clinical applications. AMA Arch Ophthalmol. 1958;59(3):352-363.
  3. ↑ Hakerem, G. & Sutton, S. Pupillary response at visual threshold. Nature 212, 485–486 (1966).
  4. ↑ Kardon, R. Pupillary light reflex. Curr Opin Ophthalmol 6, 20–26 (1995).
  5. ↑ Sahraie, A. & Barbur, J. L. Pupil response triggered by the onset of coherent motion. Graefe’s Arch. Clin. Exp. Ophthalmol. 235, 494–500 (1997).
  6. ↑ Goldwater, B. C. Psychological significance of pupillary movements. Psychol. Bull. 77, 340–355 (1972).
  7. ↑ Beatty, J. Task-evoked pupillary responses, processing load, and the structure of processing resources. Psychol. Bull. 91, 276–292 (1982).
  8. ↑ Jump up to: 8.0 8.1 8.2 8.3 8.4 8.5 Wilhelm, H. & Wilhelm, B. Clinical applications of pupillography. J. Neuro-Ophthalmology 23, 42–49 (2003).
  9. ↑ Girkin, C. A. Evaluation of the pupillary light response as an objective measure of visual function. Ophthalmol. Clin. North Am. 16, 143–153 (2003).
  10. ↑ Kawasaki, A., Miller, N. R. & Kardon, R. Pupillographic Investigation of the Relative Afferent Pupillary Defect Associated with a Midbrain Lesion. Ophthalmology 117, 175–179 (2010).
  11. ↑ Smith, S. A. & Smith, S. E. Bilateral Horner’s syndrome: detection and occurrence. J. Neurol. Neurosurg. Psychiatry 66, 48–51 (1999).
  12. ↑ Boxer Wachler, B. S. & Krueger, R. R. Agreement and repeatability of pupillometry using videokeratography and infrared devices. J. Cataract Refract. Surg. 26, 35–40 (2000).
  13. ↑ Schnitzler, E. M., Baumeister, M. & Kohnen, T. Scotopic measurement of normal pupils: Colvard versus Video Vision Analyzer infrared pupillometer. J. Cataract Refract. Surg. 26, 859–866 (2000).
  14. ↑ Wang, M., Corpuz, C. C. C., Huseynova, T. & Tomita, M. Pupil Influence on the Visual Outcomes of a New-Generation Multifocal Toric Intraocular Lens With a Surface-Embedded Near Segment. J. Refract. Surg. 32, 90–95 (2016).
  15. ↑ Kim, M. J., Yoo, Y. S., Joo, C. K. & Yoon, G. Evaluation of optical performance of 4 aspheric toric intraocular lenses using an optical bench system: Influence of pupil size, decentration, and rotation. J. Cataract Refract. Surg. 41, 2274–2282 (2015).
  16. ↑ Vega, F. et al. Halo and through-focus performance of four diffractive multifocal intraocular lenses. Investig. Ophthalmol. Vis. Sci. 56, 3967–3975 (2015).
  17. ↑ García-Domene, M. C. et al. Image Quality Comparison of Two Multifocal IOLs: Influence of the Pupil. J. Refract. Surg. 31, 230–235 (2015).
  18. ↑ Fliedner, J., Heine, C., Bretthauer, G. & Wilhelm, H. The pupil can control an artificial lens intuitively. Investig. Ophthalmol. Vis. Sci. 55, 759–766 (2014).
  19. ↑ Watanabe, K. et al. Effect of Pupil Size on Uncorrected Visual Acuity in Pseudophakic Eyes With Astigmatism. J. Refract. Surg. 29, 25–30 (2013).
  20. ↑ 18 Fotiou, D. F. et al. Cholinergic deficiency in Alzheimer’s and Parkinson’s disease: Evaluation with pupillometry. Int. J. Psychophysiol. 73, 143–149 (2009).
  21. ↑ Stergiou, V. et al. Pupillometric findings in patients with Parkinson’s disease and cognitive disorder. Int. J. Psychophysiol. 72, 97–101 (2009).
  22. ↑ Fotiou, D. F. et al. Pupil reaction to light in Alzheimer’s disease: evaluation of pupil size changes and mobility. Aging Clin. Exp. Res. 19, 364–371 (2007).
  23. ↑ Fotiou, F., Fountoulakis, K. N., Tsolaki, M., Goulas, A. & Palikaras, A. Changes in pupil reaction to light in Alzheimer’s disease patients: A preliminary report. in International Journal of Psychophysiology 37, 111–120 (2000).
  24. ↑ Ghodse, H., Taylor, D., Greaves, J., Britten, A. & Lynch, D. The opiate addiction test: a clinical evaluation of a quick test for physical dependence on opiate drugs. Br. J. Clin. Pharmacol. 39, 257–259 (1995).
  25. ↑ Krach, S. et al. Evidence from pupillometry and fMRI indicates reduced neural response during vicarious social pain but not physical pain in autism. Hum. Brain Mapp. 36, 4730–4744 (2015).
  26. ↑ Nuske, H. J., Vivanti, G., Hudry, K. & Dissanayake, C. Pupillometry reveals reduced unconscious emotional reactivity in autism. Biol. Psychol. 101, 24–35 (2014).
  27. ↑ Blaser, E., Eglington, L., Carter, A. S. & Kaldy, Z. Pupillometry reveals a mechanism for the Autism Spectrum Disorder (ASD) advantage in visual tasks. Sci. Rep. 4, (2014).
  28. ↑ Merritt, S. L., Schnyders, H. C., Patel, M., Basner, R. C. & O’Neill, W. Pupil staging and EEG measurement of sleepiness. in International Journal of Psychophysiology 52, 97–112 (2004).
  29. ↑ Stelmack, R. M. & Mandelzys, N. Extraversion and Pupillary Response to Affective and Taboo Words. Psychophysiology 12, 536–540 (1975).
  30. ↑ Wu, E. X. W., Laeng, B. & Magnussen, S. Through the eyes of the own-race bias: Eye-tracking and pupillometry during face recognition. Soc. Neurosci. 7, 202–216 (2012).
  31. ↑ 29 Granholm, E. & Verney, S. P. Pupillary responses and attentional allocation problems on the backward masking task in schizophrenia. in International Journal of Psychophysiology 52, 37–51 (2004).
  32. ↑ Laeng, B. & Falkenberg, L. Women’s pupillary responses to sexually significant others during the hormonal cycle. Horm. Behav. 52, 520–530 (2007).
  33. ↑ Decety, J., Michalska, K. J. & Kinzler, K. D. The contribution of emotion and cognition to moral sensitivity: A neurodevelopmental study. Cereb. Cortex 22, 209–220 (2012).
  34. ↑ Sepeta, L. et al. Abnormal social reward processing in autism as indexed by pupillary responses to happy faces. J. Neurodev. Disord. 4, (2012).
  35. ↑ Phillips, M. A., Bitsios, P., Szabadi, E., & Bradshaw, C. M. Comparison of the antidepressants reboxetine, fluvoxamine and amitriptyline upon spontaneous pupillary fluctuations in healthy human volunteers. Psychopharmacology 149, 72-76 (2000).
  36. ↑ Jump up to: 36.0 36.1 Nowak, W., Zarowska, A., Szul-Pietrzak, E. & Misiuk-Hojło, M. System and measurement method for binocular pupillometry to study pupil size variability. Biomed. Eng. Online 13, (2014).
  37. ↑ Espinosa, J., Roig, A. B., Pérez, J. & Mas, D. A high-resolution binocular video-oculography system : assessment of pupillary light reflex and detection of an early incomplete blink and an upward eye movement. 1–12 (2015). doi:10.1186/s12938-015-0016-6
  38. ↑ Chennamma, H. R. & Yuan, X. A Survey on Eye-Gaze Tracking Techniques. 4, 388–393 (2013).
  39. ↑ Obtained from Espinosa, J., Roig, A. B., Pérez, J. & Mas, D. A high-resolution binocular video-oculography system : assessment of pupillary light reflex and detection of an early incomplete blink and an upward eye movement. 1–12 (2015). doi:10.1186/s12938-015-0016-6  https://biomedical-engineering-online.biomedcentral.com/articles/10.1186/s12938-015-0016-6. Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/
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