SBIR-STTR Award

?Preclinical evaluation of treatment strategies for retinal neurodegenerative diseases is highly dependent on mouse models. Classical methods to assess the visual function of animals, such as electroretinogram (ERG), which measures electrical responses in the retina, do not address connections between the eye and brain or visual perception by the visual system. This often raises concerns regarding the functional relevance of the therapeutic benefit. Difficulty in assessing visual perception and related behavior in mice and rats, largely due to their subtle visual behavior cues and the lack of adequate measuring devices, presents a critical barrier to the application of mouse models for evaluating treatment efficacy of new drugs, and for scaling up for behavior phenotyping to screen genetic vision defects. Pupillary light reflex (PLR) and optokinetic reflex (OKR) tests are useful methods in clinics for assessing human visual responses and perception. However, such tests have been difficult to conduct in rodents because current rodent visual testing methods or devices either do not allow accurate quantitative assessment for PLR or OKR or use subjective measures to score visual responses. To address these challenges, we propose to advance the technology by designing an easy-to-use automated platform that employs an eye/pupil tracking device equipped with a computer vision system (chiefly the interactive tracking system) for unambiguous objective scoring of visual responses. Our proposed new device will allow real-time quantitative and accurate assessment of rodent visual function including light responses, visual acuity and contrast sensitivity. The novelty of our system also lies in that it does not require complicated calibration procedures needed in commonly used human eye tracking. Rather than precisely measuring the extent of eye turning (or orientation), we propose to detect the signature eye movement in accordance with the speed and direction of visual stimuli. The system will be validated using normal wildtype mice and mouse models of retinal neurodegeneration known to develop visual behavior changes in the parameters mentioned above. Although rodent eye tracking has been investigated before, this proposed visual assessment system would be the first commercially viable product that uses an eye/pupil tracking device to automatically assess visual perception in rodents. The combined PLR and OKR tests and vastly simplified and automated quantification methods will also provide the first scalable behavior platform for phenotyping and drug discovery in the vision research area. In the future, this technology has the potential of being expanded to measure responses from various visual stimuli. This may translate into broader applications for evaluating brain diseases that afflict the visual pathways. This platform for mouse visual behavior assessment will therefore greatly facilitate drug discovery and development aimed at preventing and slowing vision loss or restoring sight, helping to combat devastating blinding conditions such as age-related macular degeneration (AMD) and glaucoma.

Public Health Relevance Statement:


Public Health Relevance:
The objective of the current proposal is to design and develop an automated system for the measure of rodent (mice and rats) light response, visual acuity, and contrast sensitivity. The system will apply human eye/pupil tracking techniques for objective and unambiguous evaluation of light response and visual perception. This platform will provide a powerful tool for phenotypic studies as well as for discovery of new drugs that can prevent or restore sight caused by blinding conditions such as age-related macular degeneration and glaucoma.

NIH Spending Category:
Aging; Basic Behavioral and Social Science; Behavioral and Social Science; Bioengineering; Eye Disease and Disorders of Vision; Neurodegenerative; Neurosciences

Project Terms:
Address; Age related macular degeneration; Algorithms; Animal Model; Animals; approach behavior; Area; base; Behavior; Behavior assessment; behavior change; Behavior monitoring; Behavioral; Biological Assay; Blindness; Brain; Brain Diseases; Calibration; Clinic; Collaborations; Coma; combat; commercialization; computer generated; Computer Vision Systems; Contrast Sensitivity; Cues; data acquisition; Data Analyses; Defect; design; Development; Devices; Disease; drug development; drug discovery; Electroretinography; Evaluation; Eye; Eye diseases; Eye Movements; Funding; Future; genetic approach; Genetic Screening; Glaucoma; Head; Head Movements; Human; Image; Impairment; innovation; instrument; Laboratory Animals; Lead; Light; liquid crystal; Marketing; Measurement; Measures; Medical; Methods; mouse model; Mus; Nerve Degeneration; Neurodegenerative Disorders; new technology; Patients; Pattern; Perception; Performance; performance tests; Pharmaceutical Preparations; Phase; Phenotype; Photic Stimulation; photoreceptor degeneration; Preclinical Drug Evaluation; preclinical evaluation; prevent; Procedures; prototype; public health relevance; Pupil; Pupil light reflex; Rattus; Reflex action; Research Institute; response; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Rodent; scale up; Small Business Technology Transfer Research; Speed (motion); success; System; Techniques; Technology; Technology Transfer; Testing; Therapeutic; Time; tool; touchscreen; Training; Transgenic Mice; Translating; Translations; Treatment Efficacy; treatment strategy; Vision; Vision research; Visual; Visual Acuity; Visual Pathways; Visual Perception; visual performance; visual stimulus; Visual system structure

Visual behavior abnormalities not only link directly to the retinal pathology and visual pathway disorders, but also associate with many neurodegenerative brain conditions, particularly with Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury. The optomotor reflex (OMR) consists of innate, reflexive head and/or body- movements during optomotor responses and has been a conventional method for measuring visual functions. It is emerging as a powerful tool for gene function phenotyping and drug screening in the vision research field, because it offers noninvasive and clinically-relevant assessments for contrast sensitivity and visual acuity. As preclinical development and evaluation of treatment strategies for neurodegenerative diseases are highly dependent on rodent models, especially mouse models, an OMR device for assessing rodent visual performance is in particular demand. However, existing OMR systems are either subjective (manually-scored OMR) or flawed as they rely on an arbitrary time window or an unmatched blind animal as a reference to determine vision limits. Also, the test procedure has not been optimized and is time consuming. The limitations of existing OMR technology and devices have largely hindered the evaluation of treatment efficacy and gene function behavior phenotyping in the field of vision science. In our completed Phase I project (R41 EY025913), we critically addressed the shortcomings of the existing OMR systems. Our effort has led to a new OMR system which utilizes patent-pending technology. The novelty of our system lies in the negative OMR indicator that underlies our unique algorithm. ; this algorithm enables researchers to distinguish between visually-impaired and noncompliant animals. Our optimized testing protocol uses a staircase reversal procedure, which allows for rapid, unbiased, and fully-automated visual assessment. The prototype of our system produces efficient and accurate real-time quantification of mouse visual performance with high sensitivity and reproducibility. The Specific Aims of this SBIR Phase II project are (1) to develop a “turnkey” OMR system, (2) to validate the system with multiple retina degenerative mouse models, and authenticate the test protocol as a guide to facilitate its application, and (3) to refine the system for rod- and cone-specific function discrimination. A platform for mouse and rat visual behavior assessment will greatly facilitate the drug discovery process aimed at preventing or slowing vision loss or restoring sight. Thereby, our product will accelerate the development of effective treatments for devastating blinding conditions including age-related macular degeneration and glaucoma. In the future, the system will be scaled up, and its application will be expanded to evaluate the aging brain and neurodegenerative disease models, such as Alzheimer’s disease, by measuring behavior responses toward various visual stimuli.

Public Health Relevance Statement:
8. Narrative Our proposal is to develop a fully-automated animal visual function testing device based on the optomotor reflex (OMR) behavior. Our new system enables efficient and unbiased assessment of visual functions including visual acuity and contrast sensitivity in rodents. This platform will provide a powerful “turnkey” toolkit to study eye disease models and discover drugs aimed at treating blinding conditions, such as age-related macular degeneration and glaucoma. It can also be extended to study neurodegenerative diseases, such as Alzheimer’s disease and the aging brain.

Project Terms:
Address; Age related macular degeneration; aging brain; Algorithms; Alzheimer's Disease; Animal Testing; Animals; Automation; base; Behavior; Behavior assessment; Behavior monitoring; behavioral response; blind; Blindness; Brain; Brain Diseases; Canada; Cerebrum; clinically relevant; commercialization; Comparative Study; Computational algorithm; Computer software; Cone; Consumption; Contrast Sensitivity; density; design; Development; Devices; Discrimination; Disease model; drug development; drug discovery; drug market; Drug Screening; effective therapy; Engineering; Evaluation; Eye; Eye diseases; Eye Movements; Future; gaze; gene function; Gene Mutation; Generations; Germany; Glaucoma; Goals; Grant; Head; Head Movements; Histology; Inherited; innovation; Laboratories; Legal patent; Light; Link; luminance; Manuals; Measurement; Measures; Mechanics; Mediating; Medical; medical schools; Methods; mouse model; Movement; Mus; Nerve Degeneration; Neurodegenerative Disorders; next generation; non-compliance; off-patent; open source; Optical Coherence Tomography; Parkinson Disease; Pathology; Pharmaceutical Preparations; Phase; Phenotype; Physiology; Point Mutation; Positioning Attribute; preclinical development; preclinical evaluation; prevent; Procedures; Process; Protocols documentation; prototype; Rattus; Reflex action; Reproducibility; Research Institute; Research Personnel; Resolution; response; Retina; Retinal; Retinal Degeneration; retinal rods; Retinitis Pigmentosa; rho; Rodent; Rodent Model; Running; scale up; Small Business Innovation Research Grant; Stimulus; System; Tablets; Technology; Testing; Time; tool; Transducin; Translating; Translations; Traumatic Brain Injury; Treatment Efficacy; treatment strategy; Validation; validation studies; Vertebrate Photoreceptors; Vision; Vision research; vision science; Visual; Visual Acuity; Visual impairment; Visual Pathway Disorder; visual performance; visual stimulus; Wild Type Mouse