ARTICLE :Electrical Field Shaping Techniques in a Feline Model of Retinal Degeneration (2018)
40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC). doi:10.1109/embc.2018.8512473
Thomas C. Spencer, James B. Fallon, Member, IEEE, Carla J. Abbott, Penny J. Allen, Alice Brandli, Chi D. Luu, Stephanie B. Epp and Mohit N. Shivdasani, Senior Member, IEEE
T. C. Spencer, J. B. Fallon and S.B. Epp are with the Bionics Institute and the Department of Medical Bionics, University of Melbourne, East Melbourne, Australia. C. J. Abbott, P. J. Allen, A. Brandli, and C. D. Luu are with the Centre for Eye Research Australia and the Department of Surgery (Opthalmology), East Melbourne,. M. N. Shivdasani was with the Bionics Institute, East Melbourne, now with the Graduate School of Biomedical Engineering, University of New South Wales
NHMRC Grant 1063093
Improving Spatial Resolution in Retinal Prostheses through Novel Electrical Stimulation Techniques University of Melbourne $359,501
Electric field shape – the shape of an electric line of force
Photoreceptors – the main cells of the retina that defect light. They convert light into electrical signals which are sent to the brain.
Degeneration – declining/deterioration.
FMP – Focused multipolar stimulation is a technique that aims to spatially restrict the electric field.
MP – traditional monopolar stimulation
Tracheostomy– a surgical procedure that involves making a cut in the trachea (windpipe) and inserting a tube into the opening
Area centralis – a small region near the center of the retina
Macula – an oval-shaped pigmented area near the center of the retina of the human eye
The experiment was aimed at re-assessing the effectiveness of electrical field shaping techniques previously conducted in normally-sighted animals by testing in cats who had undergone chemically induced photoreceptor degeneration.
Four cats were used in this study. They were anaesthetised to allow injection of adenosine triphosphate (ATP) into the vitreal cavity of one eye each, the other eye acting as a ‘control’. Adenosine triphosphate apparently disrupts retinal tissue and leads to possibly permanent damage to the photoreceptors (the visual cells).
After two weeks, the cats were evaluated to see if the researchers’ criteria for retinal damage were reached. Fourteen weeks later, the cats were again anaesthetised, tracheostomies were performed for artificial respiration and electrodes were implanted into the suprachoroidal space (between the choroid and sclera) in the region of the area centralis. The centralis is the most visually-sensitive portion of the retina in many species, including the cat.
It is noted that the cats in this experiment were not blind. The researchers caused damage to the retinae, but the degree of damage may not have been sufficient to cause blindness in that eye (and the cats were only injected in one eye). It may be that the cats would have been able to see using the damaged eye, even though vision might be limited.
Craniotomies were done on each side of the skull (skin incised, bone removed, brain exposed). Electrodes were inserted into the brain. The retinas were stimulated and the responses in the brain (visual cortex) at various currents and MP and FMP responses recorded.
In this study, contrary to previous studies in cats with healthy vision, the researchers found no significant difference between the spread of cortical activation from the FMP and MP stimulations. Nor were they able to reproduce cortical responses to single electrode retinal stimulation using two-dimensional current steering.
RELEVANCE TO HUMANS
According to Combes & Shah (2016) when referring to vision research and therapy in various species, they note that “in the case of cats, there are important differences, both in structure and reactions, between the eyes of this species and those of humans”. The researchers themselves point out that current ‘models’ of retinal degeneration are insufficient to answer important questions revolving around naturally occurring retinal degeneration in people.
Species differences aside, the research in this publication is of questionable clinical relevance.
Dr Nedim Buyukmihci, Veterinary Opthalmologist, and Emeritus Professor of Veterinary Medicine, University of California-Davis) on reviewing the publication notes;
“Just because ATP destroys photoreceptor cells does not mean that the retinal degeneration produced in any way mimics that seen in human (or other) patients with heritable forms of retinal degeneration. The authors have not demonstrated this to be the case in their ‘model’. Yet, this is critical in that the cause of retinal degeneration is pivotal to finding a treatment or prevention for it.”
ANIMAL WELFARE CONCERNS
Although not stated specifically in the current paper, the authors refer to their previous studies with ATP as a ‘model’ for causing retinal degeneration (eg see https://doi.org/10.1167/iovs.14-15732) in which they state that intravitreal and intraretinal inflammation was present after the injections.
According to Dr Buyukmihci, ‘Inflammation, by its very nature, is associated with some degree of pain, although one cannot determine how much in this situation. Just inserting a needle through the ocular tissues to reach the vitreous body would itself cause inflammation in at least the conjunctiva and sclera and it would be inconceivable to think that the cats would not have had at least some discomfort for a short period (how long is conjecture) after recovery from anaesthesia ”.
There is no reference as to whether the cats were killed on completion of the experiments. Why was their fate not deemed significant enough to merit a mention in the study?
It is of grave concern that the Bionics Institute’s Animal Ethics Committee approved these invasive experiments and HRA questions upon what grounds these experiments have been approved.
COST BENEFIT ANALYSIS
Although the area centralis is similar in broad respects to the human macula there are substantial differences. The macula, however, is so important in people that even relatively minor degradations can lead to severe visual impairment. The same cannot be said for the area centralis.
The cats were not tested to see if what had been done to them had caused diminishment to, or loss of, vision in either eye but instead the study was narrowed to electrophysiologic evaluation of the retina and visual cortex in anaesthetised cats.
The cats in the experiment were not blind but the researchers caused damage to the retinae, but the degree of damage may not have been sufficient to cause blindness in that eye. It is unclear but it is suspected that the cats would have been able to see using the damaged eye, even though vision might be limited.
This is removed from vision, which requires the awake individual capable of either expressing their experience (as with people) or behaving in a way that demonstrates that they are recognising their environment (such as navigating a maze).
“There is little point in continuing to cause retinal damage through toxins such as ATP when the causes of natural retinal degeneration are, as we know to be generally the case, due to defective genes and altered biochemistry that prevents the retinas from either developing normally or dying after seemingly normal development.”
Dr Nedim Buyukmihci, Veterinary Opthalmologist
It is of concern that this experiment was funded in part by Australia’s leading medical research funding organsiation, the National Health and Medical Research Council. It is wasteful to use tax payer funds on this type of ‘animal based model’ of research that has very little cost benefit and no direct application to people who suffer retinal degeneration.
ALTERNATIVES TO ANIMALS IN VISION RESEARCH
Studying human tissues, in vivo and in vitro, is far more likely to lead to significant discoveries to help people. Animals are simply not good models for predicting human clinical outcomes because of the differences in metabolism as well as the anatomical and physiological differences. Better options need to be explored – options that negate the risk of error through species differences and hence result in data that is more likely to result in genuine cures for humans.
Therefore whilst this type of irrelevant research, outlined in this publication, continues to be funded, it takes precious resources away from those scientists in the field who indeed wish to develop human-relevant research – research that uses human stem cells, retinal organoids, human cell culture – much of which has been commenced by progressive Australian researchers.
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