Brain-Computer Interface (BCI) and Evaluation of Visual and Task Performance in Subjects With Eye Diseases
Phase: NA
Conditions: Glaucoma, Macular Degeneration, Glaucoma Suspect, Optic Neuropathy, Retinal Degeneration, Visual Pathway Disorder
Sponsor: University of Miami

 
1 
 
NCT number: NCT03318549 
 
 
University of Miami IRB Protocol number: 20240020 
 
 
Duke University IRB Protocol number: Pro00088016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol title: BCI and Evaluation of Visual and Task Performance in Subjects With Eye 
Diseases 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator: Felipe A. Medeiros, MD PhD 
 
Protocol version: 1.25 
 
Protocol date: 19APR2022 

 
2 
1. RESEARCH ABSTRACT 
 
1. 
Better understand the impact of visual impairment on daily task performance in 
patients with eye diseases of the visual pathways, such as glaucoma and age-related 
macular degeneration (AMD). 
 
2. 
Longitudinal study, with biannual visits, including patients with: glaucoma, 
suspected of having glaucoma, non-glaucomatous optic neuropathies, AMD, retinal 
degenerations, other diseases involving the visual pathways, besides healthy controls. 
Subjects will perform standard ophthalmological exams, and the following research tests: 
psychophysical, eye tracking, electroencephalogram, driving simulator, virtual reality, 
balance assessment, and questionnaires. 
 
3. 
Statistical analyses will be performed by the PI using the software Stata, MATLAB, 
and MPLUS. Risks are low, consisting of some discomfort, fatigue, dizziness or motion 
sickness. 
 
2. RESEARCH PROTOCOL 
 
PURPOSE OF THE STUDY 
 
The purpose of the present study is to better understand the impact of visual impairment 
on daily task performance in patients with eye diseases and diseases of the visual 
pathways, such as glaucoma and age-related macular degeneration (AMD). 
 
BACKGROUND & SIGNIFICANCE 
 
Glaucoma is a progressive optic neuropathy that may result in signiﬁcant visual 
impairment. The loss of vision aRects the quality of life and also has economic 
consequences to the patient and to society.1 The fundamental goal of glaucoma 
management is to prevent patients from developing visual impairment suRicient to 
produce disability in their daily lives and impair their health-related quality of life (HRQOL). 
Although investigations of glaucoma diagnostics have focused largely on conventional 
testing with perimetry and optic nerve evaluation, there is a compelling need to better 
characterize measures of functional impairment and HRQOL in glaucoma and to 
understand how they relate to conventional clinical tests. Our previous results have shown 
important relationships between subjective measures of disability obtained through 
patient-reported outcomes and metrics of structural and functional damage in the disease. 
However, self-reported evaluations are based on each individual’s assessment of his or her 
ability to do a particular task and can be largely inﬂuenced by personal expectations, 
understanding of the degree of diRiculty involved, personality and emotions, and may not 
correspond well to objective measures of performance. Therefore, an assessment of 
disability in glaucoma and other eye diseases necessarily involves an understanding of 
how the disease objectively aRects patient performance on tasks, such as searching for 

 
3 
objects, navigating through an environment or driving. The ability to conduct such 
assessments, however, has been greatly limited by the diRiculty in conducting real-world 
standardized tests that can provide meaningful and reliable information. The recent 
progress in virtual reality (VR) technologies has brought the opportunity of simulating daily 
live activities in a way that was not previously possible. Although largely conﬁned to the 
gaming industry, VR techniques have the potential to transform health care by creating 
immersive and realistic scenarios that closely replicate diRiculties faced by subjects on 
daily tasks, allowing quantiﬁable and reproducible research that can also provide insight 
into mechanisms leading to impairment. 
The overall goal of this proposal is to improve our understanding of functional disability in 
glaucoma by using VR tests to investigate objective performance during simulated daily life 
activities. In addition, by contrasting patients with glaucoma from those of other eye 
conditions, such as macular degeneration, we may be able to better assess the 
relationship between patterns of visual damage (for example, central versus peripheral) 
and disability. We will conduct cross-sectional and longitudinal studies to quantify 
disabilities through objective VR-based tasks, study their relationship with conventional 
clinical measures, as well as to investigate basic vision and neurophysiologic mechanisms 
associated with task performance. 
 
BIBLIOGRAPHY 
 
1. 
Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet 2004;363:1711-20. 
2. 
Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J 
Ophthalmol 2006;90:262-7. 
3. 
Schappert SM. OQice visits for glaucoma: United States, 1991-92. Adv Data 1995:1-14. 
4. 
Medeiros FA, Alencar LM, Zangwill LM, Bowd C, Sample PA, Weinreb RN. Prediction of 
functional loss in glaucoma from progressive optic disc damage. Arch Ophthalmol 2009;127:1250-6. 
5. 
Medeiros FA, Zangwill LM, Bowd C, Weinreb RN. Comparison of the GDx VCC scanning laser 
polarimeter, HRT II confocal scanning laser ophthalmoscope, and stratus OCT optical coherence 
tomograph for the detection of glaucoma. Arch Ophthalmol 2004;122:827-37. 
6. 
Medeiros FA, Sample PA, Weinreb RN. Frequency doubling technology perimetry abnormalities 
as predictors of glaucomatous visual ﬁeld loss. Am J Ophthalmol 2004;137:863-71. 
7. 
Sample PA, Bosworth CF, Blumenthal EZ, Girkin C, Weinreb RN. Visual function-speciﬁc 
perimetry for indirect comparison of diQerent ganglion cell populations in glaucoma. Invest Ophthalmol 
Vis Sci 2000;41: 1783-90. 
8. 
Gupta N, Greenberg G, de Tilly LN, Gray B, Polemidiotis M, Yucel YH. Atrophy of the lateral 
geniculate nucleus in human glaucoma detected by magnetic resonance imaging. Br J Ophthalmol 
2009;93:56-60. 
9. 
Gupta N, Yucel YH. What changes can we expect in the brain of glaucoma patients? Surv 
Ophthalmol 2007; 52 Suppl 2:S122-6. 
10. 
Gupta N, Yucel YH. Glaucoma as a neurodegenerative disease. Curr Opin Ophthalmol 
2007;18:110-4. 
11. 
Yucel Y, Gupta N. Glaucoma of the brain: a disease model for the study of transsynaptic neural 
degeneration. Prog Brain Res 2008;173:465-78.  
12. 
Yucel YH, Zhang Q, Weinreb RN, Kaufman PL, Gupta N. EQects of retinal ganglion cell loss on 
magno-, parvo-, koniocellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma. 
Prog Retin Eye Res 2003;22:465-81. 

 
4 
13. 
DeCarlo DK, Scilley K, Wells J, Owsley C. Driving habits and health-related quality of life in 
patients with age-related maculopathy. Optom Vis Sci 2003;80:207-13. 
14. 
Ragland DR, Satariano WA, MacLeod KE. Driving cessation and increased depressive 
symptoms. J Gerontol A Biol Sci Med Sci 2005;60:399-403. 
15. 
Fonda SJ, Wallace RB, Herzog AR. Changes in driving patterns and worsening depressive 
symptoms among older adults. J Gerontol B Psychol Sci Soc Sci 2001;56:S343-51. 
16. 
Marottoli RA, Mendes de Leon CF, Glass TA, et al. Driving cessation and increased depressive 
symptoms: prospective evidence from the New Haven EPESE. Established Populations for 
Epidemiologic Studies of the Elderly. J Am Geriatr Soc 1997;45:202-6. 
17. 
Ramulu PY, West SK, Munoz B, Jampel HD, Friedman DS. Driving cessation and driving limitation 
in glaucoma: the Salisbury Eye Evaluation Project. Ophthalmology 2009;116:1846-53. 
18. 
Ramulu P. Glaucoma and disability: which tasks are aQected, and at what stage of disease? Curr 
Opin Ophthalmol 2009;20:92-8. 
19. 
Janz NK, Musch DC, Gillespie BW, Wren PA, Niziol LM. Evaluating clinical change and visual 
function concerns in drivers and nondrivers with glaucoma. Invest Ophthalmol Vis Sci 2009;50:1718-25. 
20. 
Haymes SA, LeBlanc RP, Nicolela MT, Chiasson LA, Chauhan BC. Glaucoma and on-road driving 
performance. Invest Ophthalmol Vis Sci 2008;49:3035-41. 
21. 
Szlyk JP, Mahler CL, Seiple W, Edward DP, Wilensky JT. Driving performance of glaucoma 
patients correlates with peripheral visual ﬁeld loss. J Glaucoma 2005;14:145-50. 
22. 
McGwin G, Jr., Mays A, Joiner W, Decarlo DK, McNeal S, Owsley C. Is glaucoma associated with 
motor vehicle collision involvement and driving avoidance? Invest Ophthalmol Vis Sci 2004;45:3934-9. 
23. 
Owsley C, McGwin G, Jr. Vision and driving. Vision Research 2010. 
24. 
McGwin G, Jr., Xie A, Mays A, et al. Visual ﬁeld defects and the risk of motor vehicle collisions 
among patients with glaucoma. Invest Ophthalmol Vis Sci 2005;46:4437-41. 
25. 
McGwin G, Jr., Owsley C. Risk factors for motor vehicle collision-related eye injuries. Arch 
Ophthalmol 2005;123:89-95. 
26. 
Owsley C, McGwin G, Jr. Vision impairment and driving. Surv Ophthalmol 1999;43:535-50. 
27. 
Owsley C, Stalvey BT, Wells J, Sloane ME, McGwin G, Jr. Visual risk factors for crash involvement 
in older drivers with cataract. Arch Ophthalmol 2001;119:881-7. 
28. 
Owsley C, Ball K, McGwin G, Jr., et al. Visual processing impairment and risk of motor vehicle 
crash among older adults. JAMA 1998;279:1083-8. 
29. 
McCloskey LW, Koepsell TD, Wolf ME, Buchner DM. Motor vehicle collision injuries and sensory 
impairments of older drivers. Age Ageing 1994;23:267-73. 
30. 
Cross JM, McGwin G, Jr., Rubin GS, et al. Visual and medical risk factors for motor vehicle 
collision involvement among older drivers. Br J Ophthalmol 2009;93:400-4. 
31. 
Rubin GS, Ng ES, Bandeen-Roche K, Keyl PM, Freeman EE, West SK. A prospective, population-
based study of the role of visual impairment in motor vehicle crashes among older drivers: the SEE 
study. Invest Ophthalmol Vis Sci 2007;48:1483-91. 
32. 
Haymes SA, Leblanc RP, Nicolela MT, Chiasson LA, Chauhan BC. Risk of falls and motor vehicle 
collisions in glaucoma. Invest Ophthalmol Vis Sci 2007;48:1149-55. 
33. 
Bedard MB, Parkkari M, Weaver B, Riendeau J, Dahlquist M. Assessment of driving performance 
using a simulator protocol: validity and reproducibility. Am J Occup Ther 2010;64:336-40. 
34. 
de Winter JC, de Groot S, Mulder M, Wieringa PA, Dankelman J, Mulder JA. Relationships 
between driving simulator performance and driving test results. Ergonomics 2009;52:137-53. 
35. 
Yan X, Abdel-Aty M, Radwan E, Wang X, Chilakapati P. Validating a driving simulator using 
surrogate safety measures. Accid Anal Prev 2008;40:274-88. 
36. 
Fildes B, Charlton J, Muir C, Koppel S. Driving responses of older and younger drivers in a driving 
simulator. Annu Proc Assoc Adv Automot Med 2007;51:559-72. 
37. 
Lew HL, Poole JH, Lee EH, JaQe DL, Huang HC, Brodd E. Predictive validity of driving-simulator 
assessments following traumatic brain injury: a preliminary study. Brain Inj 2005;19:177-88. 

 
5 
38. 
Lee HC, Lee AH. Identifying older drivers at risk of traQic violations by using a driving simulator: a 
3-year longitudinal study. Am J Occup Ther 2005;59:97-100. 
39. 
Lee HC, Lee AH, Cameron D, Li-Tsang C. Using a driving simulator to identify older drivers at 
inﬂated risk of motor vehicle crashes. Journal of Safety Research 2003;34:453-9. 
40. 
Godley ST, Triggs TJ, Fildes BN. Driving simulator validation for speed research. Accid Anal Prev 
2002;34: 589-600. 
41. 
Lengenfelder J, Schultheis MT, Al-Shihabi T, Mourant R, DeLuca J. Divided attention and driving: a 
pilot study using virtual reality technology. J Head Trauma Rehabil 2002;17:26-37. 
42. 
Rizzo M, McGehee DV, Dawson JD, Anderson SN. Simulated car crashes at intersections in 
drivers with Alzheimer disease. Alzheimer Dis Assoc Disord 2001;15:10-20. 
43. 
Rizzo M, Reinach S, McGehee D, Dawson J. Simulated car crashes and crash predictors in 
drivers with Alzheimer disease. Arch Neurol 1997;54:545-51. 
44. 
Klimkeit EI, Bradshaw JL, Charlton J, Stolwyk R, Georgiou-Karistianis N. Driving ability in 
Parkinson's disease: current status of research. Neurosci Biobehav Rev 2009;33:223-31. 
45. 
Daga FB, Macagno E, Stevenson C, et al. Wayﬁnding and Glaucoma: A Virtual Reality 
Experiment. Invest Ophthalmol Vis Sci 2017;58(9):3343-9. 
46. 
Nakanishi M, Wang YT, Jung TP, et al. Detecting Glaucoma With a Portable Brain-Computer 
Interface for Objective Assessment of Visual Function Loss. JAMA Ophthalmol 2017;135(6):550-7. 
47. 
De Moraes CG, Susanna R, Jr., Sakata LM, Hatanaka M. Predictive Value of the Water Drinking 
Test and he Risk of Glaucomatous Visual Field Progression. J Glaucoma 2017;26(9):767-73. 
48. 
Susanna R, Jr., Clement C, Goldberg I, Hatanaka M. Applications of the water drinking test in 
glaucoma management. Clin Exp Ophthalmol 2017;45(6):625-31. 
49. 
Susanna CN, Susanna R, Jr., Hatanaka M, et al. Comparison of Intraocular Pressure Changes 
During the Water Drinking Test Between DiQerent Fluid Volumes in Patients With Primary Open-angle 
Glaucoma. J Glaucoma 2018;27(11):950-6. 
  
 
DESIGN & PROCEDURES 
 
This will be a longitudinal study in which patients will be examined with a cluster of visits 
biannually. We will recruit patients with: 
 
1. 
Glaucoma; 
2. 
Suspicion of having glaucoma; 
3. 
Non-glaucomatous optic neuropathies; 
4. 
Age-related macular degeneration (AMD); 
5. 
Retinal degenerations; 
6. 
Other diseases involving the visual pathways such as optic neuritis, tumors or 
ischemic neuropathy. 
 
Patients with eye diseases or suspected of having eye diseases will be recruited from Dr. 
Medeiros's clinic by verbal communication. StaR members at the Duke Eye Center will also 
be invited to recommend potential participants for the study, in conformance with the 
Duke Human Subjects Committee Guidelines. Healthy participants will be recruited from 
patient’s spouses or relatives for comparison and to establish normative levels, and will 
also be recommended from eye doctors from the comprehensive clinic who treat this 
population. 

 
6 
 
General evaluation: 
 
As part of the study all participants will undergo the following general exams: 
 
1. 
Review of medical history; 
2. 
Blood pressure and heart rate; 
3. 
Height and weight; 
 
 
Ophthalmological evaluation: 
 
As part of the study all participants will undergo a comprehensive ophthalmologic 
examination including: 
1. 
Low contrast sensitivity testing; 
2. 
Best-corrected visual acuity; 
3. 
Slit lamp biomicroscopy; 
4. 
Serial measurement of the intraocular pressure measurement before and after 
drinking water; 
5. 
Gonioscopy; 
6. 
Corneal thickness measurement (pachymetry); 
7. 
Corneal hysteresis measurement (Ocular Response Analyzer, Reichert, Inc.); 
8. 
Ocular axial length; 
9. 
Corneal curvature; 
10. 
Anterior chamber measurement; 
11. 
Dilated funduscopy examination; 
12. 
Stereoscopic optic disc photography; 
13. 
Measurement of amount of lens opacity (cataract) by the HD Analyzer system 
(Visiometrics, Inc.); 
14. 
Automated perimetry with the 24-2 and 10-2 Swedish Interactive Threshold 
Algorithm (SITA; Carl Zeiss Meditec, Inc.) and fundus perimetry with Compass (CenterVue, 
Inc); 
15. 
Spectral domain optical coherence tomography (SDOCT); 
16. 
Swept-source optical coherence tomography (SSOCT); 
17. 
Optical coherence tomography angiography (OCTA); 
18. 
Macular pigment optical density (MPOD). 
19. 
Diopsys NOVA (Diopsys, Inc.) visual evoked potentials (VEP) and electroretinogram 
(ERG). 
 
The following tests are considered research related: 
 
Questionnaires: 
 

 
7 
Patients will respond a series of questionnaires to assess quality of life as well as factors 
that may be associated with it. In addition, patients will answer questionnaires addressing 
susceptibility to motion sickness. This will be done so that patients with increased 
sensitivity to motion sickness may be excluded from test with a driving simulator. A study 
team member will read aloud the questionnaires to subjects with impaired vision who are 
unable to read for themselves. Team members administering the MoCA electronic test app 
will have MoCA certiﬁcation. The questionnaires include: 
 
1. 
Short structured interview to obtain information on sensitivity to motion sickness 
using the Motion Sickness Questionnaire; 
2. 
Simulation sickness using the Pre- and Post-Simulation Sickness Questionnaire; 
3. 
Depression using the Geriatric Depression Scale; 
4. 
Physical Activity Scale for the elderly questionnaire (PASE); 
5. 
Driving habits questionnaire using the Driving Habits Questionnaire from the 
American Academy of Neurology; 
6. 
Sense of direction evaluated through the Santa Barbara Sense of Direction Scale 
(SBSOD); 
7. 
Socioeconomic status information using the Socioeconomic Form; 
8. 
History of falls and fear of falling using the University of Illinois at Chicago Fear of 
Falling Measure Scoring Sheet; 
9. 
Cognitive function using the Montreal Cognitive Assessment (MoCA) using the 
MoCA Electronic Test app (www.mocatest.org); 
10. 
Short structured interview to obtain vision-related quality of life information using 
the National Eye Institute 25-Item Visual Functioning Questionnaire (NEI VFQ-25). 
11. 
Short structured interview to obtain glaucoma-related quality of life information 
using the Glaucoma Activity Limitation Questionnaire (GAL-9). 
 
 
Psychophysics tests: 
 
Patients will undergo psychophysics tests in order to better characterize their degree of 
visual function impairment and how it relates to performance. These psychophysics tests 
include investigation of visual processing speed, visual crowding and target detection 
under a variety of scenarios. The tests use simple LCD monitors or tablets. 
The UFOV is a simple computerized test performed on a single computer touchscreen. It 
comprises three subtests that measure visual processing speed with increasing diRiculty. 
The ﬁrst subtest is an evaluation of central visual and processing speed and requires the 
identiﬁcation of a central target. The second subtest evaluates divided attention by adding 
an addition stimulus to the central target. The last subtest evaluates selective attention by 
adding visual distractions (triangles) around the central and peripheral stimuli. All stages of 
the test are performed using a computer monitor. The stimuli are displayed for between 17 
and 500 ms, and patient response is recorded. 
All participants will also undergo a series of psychophysical tests on a digital tablet 
including visual acuity, contrast sensitivity and acuity, visual processing speed and divided 

 
8 
attention. The tests include the presentation of visual targets on the screen of an iPad 
(Apple, Inc.) or similar tablet, such as letters, images or Gabor patches. The targets may be 
presented in isolation or with additional targets. The time of presentation is shortened over 
time in order to obtain a threshold for target detection. 
Visual crowding tests will also be performed. This test investigates the ability to detect 
targets in cluttered visual environments. Test is conducted on an LCD monitor where 
targets are shown in isolation or in situations of crowding (with ﬂankers). Ability to detect 
the targets is then assessed. Visual crowding sets a fundamental limit on the peripheral 
vision. Therefore, its study may provide fundamental insights on how loss of vision in 
diseases such as glaucoma may aRect task performance. 
Duration of psychophysical testing is expected by be approximately 45 to 60min. 
 
 
Eye Tracking: 
 
Eye tracking will be used to monitor patient eye ﬁxations and eye movements during the 
visual tests. The eye tracking consists of glasses (ETG, SMI Sensorimotor instruments), 
Tobii eye tracking monitor (Tobii instruments) and virtual reality goggles equipped with eye 
tracker (FOVE and HTC Vive). 
 
  
Depending on the speciﬁc visual task performance, a diRerent type of eye tracker will be 
used. Monitoring eye movements is essential in order to better evaluate where the patient 
is looking during the visual tests. In addition, investigations of eye movements may provide 
insight on how diRerent eye diseases aRect patterns of gaze and their impact on task 
performance. The SMI eye tracking glasses are similar to a regular pair of glasses. Eye 
movement is monitored by cameras and data is transmitted to a computer. The Tobii eye 
tracking is coupled to a regular LCD monitor and can be used to monitor eye gaze while 
allowing for complete freedom of head and eye movement. Depending on the task being 
performed, we may also use virtual reality goggles equipped with eye tracking to monitor 
eye movements. 
 
 
Electroencephalogram (EEG) and Visual Evoked Potentials (VEP): 
 
Electroencephalogram will also be obtained while patients perform visual tasks. This will 
allow us to understand the relationship between visual and brain functioning and their 
interplay in task performance. The electroencephalogram (EEG) is a well-established 
procedure for measuring the surface electrical potentials on a patient's scalp. The 
procedure involves the use of sensors placed on the surface of the skin and is generally 
considered safe and non-invasive for both clinical and research use. Participants will 
undergo the EEG test (Cognionics, Inc.) when performing visual tasks presented on a 
standard LCD display or tablet. Visual evoked potentials (VEP) will be evaluated with 
Diopsys NOVA (Diopsys, Inc.), which is a well-established conventional multifocal VEP 
device to assess brain functioning following visual stimuli from a computer screen. It is a 

 
9 
non-invasive, safe testing and patient is prepared in a similar fashion than EEG: three small 
areas in the scalp are cleaned and dried and then sensory pads are placed on the cleansed 
areas. 
 
 
Driving simulator: 
 
Participants will be tested on a driving simulator. The simulator system consists of a panel 
of screens, a wheel drive, and a foot pedal, similar to a real car, all connected into a 
computer. Participants are asked to perform simple tasks such as follow a vehicle, keep up 
with the speed limit and avoid obstacles. Data collection includes several variables such 
as speed, lane deviation, time of reaction, vehicle control and obstacle avoidance. If a 
patient feels dizzy the exam can be interrupted at any time. The duration of testing with the 
simulator is about 15 minutes. As this is an experimental procedure, no results will be 
reported to the DMV with regard to driving ability. 
 
 
Virtual Reality Tests: 
 
Virtual reality tests will be conducted using virtual reality goggles (HTC Vive, Samsung Gear 
VR or FOVE). The tasks include scenarios replicating daily activities such as driving through 
a road, walking through a virtual environment or searching for objects. In order to navigate 
through the environment, subjects will use a steering wheel or joystick. The estimated 
duration of the test is 30 minutes. In the task of navigation, the subject will ﬁnd him or 
herself near a wall in a rectangular room with colored walls, diRerent objects on each wall, 
and diRerent objects (couch, table statue, etc.) at various locations. The subject will be 
asked to move to and step upon a green tile that is displayed at some random location in 
the room. Once the target location is attained, the display is turned oR for a short period. 
The task will then begin again, but with a diRerent starting position. These initial tests are 
designed to assess the subject’s ability to move from one location to another in a virtual 
environment. Subjects that can achieve suRicient proﬁciency in the target-visible protocols 
will then be instructed that the next series of tests will require them to ﬁnd a hidden target 
tile and that they will be asked to remember its location. In these protocols, the subjects 
will be given a limited amount of time (2 minutes) to locate the target, which will become 
visible when it is reached, and their path and time to target discovery recorded. Path length 
and path topology will be measured in real time. The test will be repeated, from the same 
starting location, at least 5 times or until no improvement in time/distance to target is 
observed by the experimenter, who is analyzing the test outcomes on a tablet in real time. 
After a 5-minute rest period with no visual stimulus, the subject will be asked to repeat the 
task for a “probe” trial. This time the search will be limited to 30 seconds or to the shortest 
time attained in the prior trials, without the target becoming visible. The outcome 
measurement will be time spent and path length in the vicinity of the target, as a measure 
of spatial memory and spatial navigation strategy. Depending on the data obtained in this 
set of trials, the subject will be asked to continue with further tests of increasing diRiculty, 

 
10 
as for example with reduced numbers of distinct landmarks or with random starting 
locations for a constant target position. Visual search task will consist of a virtual 
environment (e.g., an apartment) and the patient will be given a speciﬁc task of object 
ﬁnding. The time and path to complete the task will be obtained. For driving tasks, the 
subject will use a driving wheel to guide a car through a virtual environment and complete a 
simple task of wayﬁnding, following a car or negotiating a curve. 
 
 
Balance Assessment: 
 
  
During this test subjects will stand on a force platform while diRerent visual stimuli will be 
presented. The force platform (AMTI Optima Human Performance System, Advanced 
Mechanical Technology, Inc., Watertown, MA) is used to evaluate the posture and balance 
by recording pressure changes at the four corners of the platform that change as the 
subjects stabilize themselves. For this test we will use virtual reality goggles (Oculus Rift, 
Oculus VR, LLC, Irvine, CA) to deliver the visual stimuli. Such a system is appealing since it 
provides whole-eye coverage allowing a controlled environment for the visual input. The 
subject will be required to ﬁxate the gaze at the center of the scene, while diRerent visual 
stimuli will be presented, such as rotating rings. A harness system (Handrail and Harness 
Safety Structure, Bertec Corp., Columbus, OH) will be used to prevent subjects from 
falling. The experiment will consist of a number of short (approximately 1 minute) sessions 
with pauses to rest in between. The total duration of the test will be approximately 20 
minutes. 
 
 
Retinal metabolic analysis: 
 
The OcuMet Beacon is a novel medical device that non-invasively assesses retinal 
mitochondrial dysfunction. The device takes an infrared fundus image that highlights the 
acquisition area for the retinal metabolic image, takes a retinal ﬂavoprotein ﬂuorescence 
(FPF) metabolic image, and provides quantitative analysis of the retinal mitochondrial 
function and patient report printout. 
 
 
Assessment of intraocular pressure (IOP) with Tono-Vera: 
 
Tono-Vera measures IOP by analyzing acceleration changes of a light-weight, plastic-tipped 
probe as it brieﬂy contacts the cornea. The motion of the probe generates a voltage, which 
is recorded during the measurement process. The IOP value, which is displayed in the 
device, is intended to be a “Goldmann- equivalent” (Highly correlated to the gold-standard 
Goldmann applanation tonometer). The process described above takes only a few 
milliseconds and the sensation of the probe contacting the patient’s cornea is so light 
many patients cannot notice it. As such, the device is used without topical anesthesia. 
Probes are single-use, disposable. 

 
11 
 
 
Scheduled Visits 
 
Subjects will be scheduled for 1 visit every six months for a period of 5 years. The duration 
of each visit is expected to be 2 hours and 30min. Subjects may also elect to complete the 
tests in 2 separate visits, which will be scheduled within 4 weeks. A subgroup of 
participants will be scheduled to have visits every 2 months to assess short-term visual 
function changes. In addition, a subgroup of participants will have 6 visits within a two-
month period to assess test-retest reproducibility. Patients who elect to perform only a 
subset of the tests may still be included as long as the Principal Investigator decides that 
their inclusion is in line with the goals of the study and in maintaining the highest standards 
for research quality. 
 
* * Amendment Protocol version 1.21: 
Normal subjects will be invited to complete all tests and questionnaires listed in the 
section above only once, over 2 separate visits (visits "1" and "2"), within 4 weeks from 
enrollment. The duration of each visit is expected to be 2 hours. Subjects may also elect to 
complete the tests in 1 additional separate visit, which will be scheduled within 4 weeks. 
Normal subjects will not be followed longitudinally. All new subjects enrolled in the 
pathologies arms (glaucoma, AMD, and others) will be invited for a 7-visit regimen every 6 
months for the ﬁrst 2 years of the study (months 0, 6, 12, and 24 -- but not month 18). All 
visits in each cluster will be completed within a two-month period to reduce test-retest 
variability and provide better estimates of change. Over visits "1" and "2", subjects will 
complete all tests and questionnaires listed in the section above (i.e, each item only once, 
distributed over visits "1" and "2"). Visits "1" and "2" have an expected duration of 2 hours 
each and are the same for the normal group. Visits "3" through "7" will include only visual 
ﬁeld testing, OCT testing, and IOP check (items 4, 14, 15, and 17 in the "Ophthalmological 
evaluation" subsection above). The duration of visits “3”, “4”, “5”, “6”, and “7” is expected to 
be of 1 hour each. After month 24 of follow-up, subjects will continue a regular schedule of 
2 visits (visits "1" and "2" only) every 6 months until the 5 years of the study are completed. 
Subjects already enrolled in the study will be invited to transition to a 7-visit schedule for 2 
years, if not completed yet as part of the test-retest variability preliminary assessment. All 
active subjects will be re-consented. 
Patients who elect to perform only a subset of the tests or visits may still be included as 
long as the Principal Investigator decides that their inclusion is in line with the goals of the 
study and in maintaining the highest standards for research quality. 
 
Unscheduled visits 
 
An unscheduled visit may be any visit to the Investigator other than the speciﬁc visits 
requested in the protocol as possibly required for the subject’s ophthalmic condition. The 
Investigator will perform all procedures necessary to evaluate the study participant at 
these visits and record any adverse events in the source document. 
 

 
12 
 
SELECTION OF SUBJECTS 
 
Inclusion criteria: 
 
1. 
Subjects must be between the ages of 40 and 90 years old; 
2. 
Both males and females will be included. 
3. 
Be able and willing to provide signed informed consent and follow study instructions 
 
Exclusion criteria: 
 
 
1. 
Subjects will be excluded if they present with any systemic or ocular conditions that 
in the opinion of the Principal Investigator may prevent them from completing the tests (e.g. 
history of seizures or pathologies aRecting the vestibular system or lower limbs). 
2. 
Women of child-bearing potential will be excluded from tests that require pupil 
dilation, unless they have already received dilating drops as part of their standard of care. 
Pregnant women may self- report pregnancy testing and not undergo formal pregnancy 
testing since the SOC in ophthalmology is to not test for pregnancy or dilate the eyes of 
women who are of childbearing age. 
 
 
Glaucoma Arm 
 
To be considered glaucomatous, patients will be required to have at least two consecutive 
and reliable standard automated perimetry (SAP) examinations with either a pattern 
standard deviation (PSD) outside the 95% normal limits or a glaucoma hemiﬁeld test (GHT) 
result outside the 99% normal limits. Patients considered suspects for glaucoma must 
have an IOP greater than 21mmHg or suspicious appearance of the optic nerve head but 
with reliable normal visual ﬁelds, deﬁned as a PSD within 95% conﬁdence limits and a GHT 
result within normal limits. To be considered healthy, subjects have to have IOP<22mmHg 
with no history of elevated IOP and with at least two reliable normal visual ﬁelds, deﬁned 
as a PSD within 95% conﬁdence limits and a GHT result within normal limits. 
 
Age-related macular degeneration (AMD) Arm 
 
Patients will be considered as having AMD if one or more of the following are present on 
posterior biomicroscopy (fundoscopy), indirect ophthalmoscopy or Optical Coherence 
Tomography (OCT) exams: 
1. 
Presence of at least intermediate-size drusen (63µm or larger in diameter) 
 
2. 
Retinal pigment epithelium (RPE) abnormalities such as hypopigmentation or 
hyperpigmentation 
3. 
Reticular pseudodrusen (also called sub retinal drusenoid deposit) 

 
13 
4. 
Presence of any of the following features: geographic atrophy of the RPE, choroidal 
neovascularization (exudative, wet), polypoidal choroidal vasculopathy, or retinal 
angiomatous proliferation. 
 
Other pathologies Arm 
 
Patients with other retinal degenerations such as retinitis pigmentosa or with other 
diseases aRecting the visual pathways such as tumors, ischemic neuropathy or optic 
neuritis may also be included. Their diagnosis will be extracted from their clinical visits. 
 
Subject Recruitment and Compensation 
 
SUBJECT RECRUITMENT AND COMPENSATION 
 
Subject recruitment will be done at the Duke University Eye Center clinics. The study will 
also utilize D.E.D.U.C.E (Duke Enterprise Data Uniﬁed Content Explorer) an on-line 
research tool providing Duke investigators with access to clinical information collected as 
a by-product of patient care. The study will apply for a waiver of consent to identify 
potential subjects for the study. The PI will introduce potential eligible subjects to the study 
during their visit to the eye clinics, and if they are determined eligible a delegated key 
personnel will obtain consent from the subject. If the subject is not available for immediate 
consenting the PI will obtain the patient’s permission to be contacted by telephone at a 
later date. A telephone script will then be used for the conversation. In addition, once the 
subject has the consent signed we will request access to their medical records through a 
medical records release form to obtain the participant’s general medical history, previous 
use of systemic medications, previous use of ophthalmological medications, previous 
ocular examinations, previous ocular procedures, and results of other medical tests. 
There will be no additional costs as a result of being in this study. Subject will be 
compensated $30 for each visit. Additional $30 per visit will be provided for participants to 
additional visits, up to a maximum amount of $450/year (two scheduled visits plus a 
maximum of 13 extra visits per year). Extra visits may be necessary to assess short-term 
and changes reproducibility (test-retest variability) of the results obtained by diRerent 
tests. This compensation is for expenses related to subject participation (parking, gas, and 
time). 
 
**Amendment, Protocol version 1.21: 
All subjects will be compensated with $30 for each scheduled or additional visit. 
Normal subjects will undergo 2 scheduled visits. An additional $30 will be provided for 
participants who need 1 additional visit to complete all the tests. 
Subjects in the pathologies arms will undergo 14 visits in the ﬁrst year of the study, 9 visits 
in the second and third years of the study, and 4 visits per year (2 visits every 6 months) 
until the end of the study, up to 5 years of participation. Additional $30 per visit will be 
provided for participants who need additional visits to complete all the tests, up to a 
maximum amount of $450/year. 
 
 

 
14 
CONSENT PROCESS 
 
We will use protected health information to screen for possible/eligible subjects. No PHI 
will leave Duke. A member of the eye care team will approach the potential participant to 
introduce the study. Knowledgeable key personnel will explain the study to the potential 
subjects and the Principal Investigator will be available during the consenting process to 
answer any questions the potential subjects may have about the study. The consenting 
process will occur in a private room and no study related activities will begin until the 
subject’s consent is obtained. Only delegated key personnel can consent potential 
subjects. 
 
A waiver of consent and HIPAA authorization will be ﬁled with the Duke IRB to allow us to 
review PHI and health information to screen potential participants. 
A telephone script will be submitted to schedule potential subjects in Maestro Care for 
study screening prior to full consent, and in case subjects are interested in participating 
and they cannot discuss the study in person when they are initially seen, after the PI 
introduces the study and key personnel to them. 
 
Subject’s Capacity to Give Legally ERective Consent: Adult subjects able and willing to 
participate will sign the consent forms. If the vision of the potential subject is severely 
impaired enough to aRect reading the consent document, the person obtaining consent, a 
study team member or a witness will read aloud and a witness will be required to sign the 
consent. 
 
 
RISK/BENEFIT ASSESSMENT 
 
Include a thorough description of how risks and discomforts will be minimized (per 45 CFR 
46.111(a) (1 and 2)). Consider physical, psychological, legal, economic and social risks as 
applicable. If vulnerable populations are to be included (such as children, pregnant 
women, prisoners or cognitively impaired adults), what special precautions will be used to 
minimize risks to these subjects? Also identify what available alternatives the person has if 
he/she chooses not to participate in the study. Describe the possible beneﬁts to the 
subject. What is the importance of the knowledge expected to result from the research? 
 
Risks: 
Risks from participating in the study are very low. The primary risks for all participants are 
some discomforts, which are similar to those encountered in any complete eye 
examination. Participants will undergo non-invasive procedures used for diagnostic 
purposes that are used in standard clinical care. The software for Macular pigment optical 
density analysis is currently undergoing FDA review and is not currently approved. The 
software for measurement of the trabecular meshwork stiRness (OCT/iFEM) from OCT is 
not currently approved. The OcuMet Beacon and Tono-Vera devices are currently 
undergoing FDA review and are not currently approved. The subject may experience mild 
discomfort due to drying of the eye during the study. Should a patient note drying, a drop of 

 
15 
artiﬁcial tears will be placed over the eye by the study key personnel. In very rare cases, 
artiﬁcial eye tear drops may cause irritation or allergy. There are no known risks associated 
with the psychophysics tests, EEG and eye tracking other than discomfort and fatigue. 
Subjects might become bored, fatigued or distressed while participating in the virtual 
reality and driving simulator tests. To minimize these potential eRects, the tasks will be 
kept short and subjects will be instructed that they may request to interrupt the test 
anytime. The driving simulator, virtual reality tests, and balance assessment may cause 
dizziness or motion sickness in susceptible patients. Every precaution will be taken to 
minimize this possibility of motion sickness (e.g., by limiting the speed of linear or 
rotational motion). For the balance assessment task, falls will be prevented by the use of a 
harness system. All assessments, software, instruments that are not FDA approved will be 
used as tools to assess disability and device eRicacy, and will not be used as a diagnostic 
procedure without conﬁrmation of the diagnosis by another, medically established 
diagnostic product or procedure. There is, however, the potential risk of loss of 
conﬁdentiality. Every eRort will be made to keep the information conﬁdential; however, this 
cannot be guaranteed. Some of the questions that will be asked as part of this study may 
make the patients feel uncomfortable. Patients may refuse to answer any of the questions 
and may take a break at any time during the study. Patient may stop their participation in 
this study at any time. 
 
Unknown/Unforeseeable Risks 
 
In addition to the risks and discomforts listed here, there may be other risks that are 
currently not known. Subjects will be informed if any other potential risk becomes known 
through the duration of the study. Also, the risks and discomforts may occur more often or 
be more severe than have been seen before and written in this form. 
 
Beneﬁts: 
 
Subjects will be referred from the Duke Eye Center care providers after a comprehensive 
clinical eye examination from a routine visit. If the last clinical eye examination is not within 
6 months of the study visit, the participant will be examined by the PI, with no additional 
cost to the patient. Participants will also undergo other tests that will allow a better 
understanding of the relationship between potential visual impairment caused by their 
diseases and the ability to perform daily tasks. The results of the study are likely to provide 
important information on how eye diseases are associated with visual impairment, task 
performance and quality of life. This may lead to development of better tests to predict 
patient performance and visual loss, which could beneﬁt patients with these diseases. 
  
COSTS TO THE SUBJECT 
 
All procedures described here, including both visits, will be free of charge to patients. There 
is no additional cost for the subject if they participate in the study. Study related 
activities/procedures will be paid by the study. 
 

 
16 
 
DATA ANALYSIS & STATISTICAL CONSIDERATIONS 
 
Describe endpoints and power calculations. Provide a detailed description of how study 
data will be analyzed, including statistical methods used, and how ineligible subjects will 
be handled and which subjects will be included for analysis. Include planned sample size 
justiﬁcation. Provide estimated time to target accrual and accrual rate. Describe interim 
analysis including plans to stop accrual during monitoring. Phase I studies, include dose 
escalation schema and criteria for dose escalation with deﬁnition of MTD and DLT. 
 
For all test results and variables, an extensive data preparation will be performed, with 
analysis of distributions, error checking and cross-tabulation. We will investigate 
diRerences in the results of the tests between diseased and healthy participants. Normality 
of variables will be assessed using histograms and Shapiro-Wilk tests. Student t tests will 
be used for comparison of means of normally distributed variables, whereas Mann-
Whitney tests will be used for non-normally distributed variables. Generalized estimating 
equations (GEE) will be used to take into account potential correlations between tests 
results from the two eyes of the same subject. 
Mixed models will be used for analysis of longitudinal data collected over time. These 
methods can successfully take into account longitudinal correlations among observations 
as well as correlations of results of eyes nested within patients. We will also use methods 
such as survival analysis (Weibull and Cox models) to assess prediction and joint 
longitudinal survival models. 
All statistical analyses will be performed by Dr. Medeiros and associates using 
commercially available statistical and mathematics software Stata (version 15; StataCorp 
LP, College Station, TX, USA), MATLAB (Mathworks, Inc.), and MPLUS (Muthen & Muthen). 
Additional analysis and image processing from de-identiﬁed data will be performed by GA 
Tech's PI Dr Ethier, and Dr Farsiu and associates. An alpha level will be generally set at 0.05, 
unless there is a need to correct for multiple comparison testing which will then be 
performed by procedures such as false discovery rate. 
 
 
3. DATA & SAFETY MONITORING 
 
In accordance with federal regulations the PI will monitor for, review, and promptly report to 
the IRB, appropriate institutional oRicials, and the appropriate regulatory agency head all 
unanticipated problems involving risks to subjects or others that occur in the course of a 
subject’s participation in a research study (45 CFR 46.103(b)(5)(i) and 21 CFR 56.108(b)(1)), 
and all reportable adverse events (AEs) will be submitted per the DUHS IRB policies. 
All examinations will be performed by appropriately trained personnel. If any incidental 
ﬁndings are discovered during the routine examination, during visual ﬁeld testing or during 
the driving simulator testing, the patient will be verbally informed and referred to a 
physician of the appropriate specialty, and eligibility to the study will be reassessed. If 
responses to the Depression questionnaire appear to indicate a signiﬁcant level of 

 
17 
depression (below 20 on the Geriatric Depression Scale), patients will be oRered referral to 
a psychiatric clinic.