Applying Translational Tests in Cognitive Research

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13 February 2017

Applying Translational Tests in Cognitive Research

Research using animals has long played an important role in neuroscience research and in the development of treatments for mental health and neurological disorders. Using CANTAB to assess cognition in human studies can be an important component of implementing the same guiding principles across species.

Research using animals has long played an important role in neuroscience research and in the development of treatments for mental health and neurological disorders. Studies on animals are a mandated component of the regulatory process governing the development of new medications, designed to protect the human volunteers first exposed to a “new chemical entity”. Unlike human research participants, animals do not have a choice whether or not to take part in experiments, and it is therefore important that researchers carry out such studies in the most humane and ethical manner possible. Given the ethical considerations which surround animal research, it is important that it provides valuable information which cannot be obtained by other means. The guiding principles underpinning the humane use of animals in scientific research are called the three Rs: Replace, Reduce, and Refine. Using CANTAB to assess cognition in human studies can be an important component of implementing those principles. 

Creating translational cognitive tests


One of the first characteristics which psychologists remark on when encountering CANTAB for the first time is that, unlike many paper-and-pencil neuropsychological tests most of the tests in the battery do not use words, numbers, or recognizable symbols from everyday life. That’s because CANTAB was originally designed as a test battery which could be used in both human and non-human test participants. Adapting a test from animals to humans requires methods that prevent humans using intellectual strategies which are not available to animals, such as counting, labelling, sub-vocal rehearsal, and so on, while maintaining the critical components of the procedure which ensure that it validly measures the target cognitive domain. One example is the Spatial Working Memory (SWM) test, which can be considered the human version of the 8-arm radial maze.  Other tests have been created by redesigning a human test for use in animals. The five choice serial reaction time test (5CSRTT), translated from the Reaction Time (RTI) task is a simple example of this, and the Intra-Extra Dimensional Set Shift (IED) test of cognitive flexibility is another, more complex example. The IED task was designed to assess similar cognitive domains as the Wisconsin Card Sorting Test (WCST), the ability to learn new problems and shift to a new strategy based on feedback. To do this it was necessary to extract the critical elements of the WCST, which involves a human participant sorting pieces of card with coloured shapes printed on them, and reconfigure them to test cognitive flexibility in monkeys or rats. By focusing on the most important features of the test, it was possible to come up with a procedure that also eliminated some confounding features of the original WCST.

Learning from translational cognitive tests

There are obvious differences in size and structure between the brain of a rat and that of a human. Critics of animal research often raise the concern that rats and monkeys use different strategies involving different neurobiological mechanisms, and so experiments involving animals are of little use in understanding human disease. Experiments on complex cognitive function are especially vulnerable to this criticism, since we often think of complex thought as something uniquely human.

However, experiments using tests like CANTAB have shown that this is not the case (Brown and Tait, 2016, Nithianantharajah et al, 2015). First, by hindering humans from using short-cuts which exploit uniquely human capabilities, we can push our research volunteers into using more basic strategies which we share with non-human animals, for example by using abstract patterns in a memory test instead of words. This also works the other way around; researchers who work with animals try to prevent them from using their species-specific capabilities, such as following odour trails. Second, by using similar test procedures in humans and non-humans, we can often show that similar areas of the brain and similar pharmacological interventions are involved in behavior in a similar way across species. This does not necessarily mean using methods involving touch screens or abstract pattern, which can be difficult to do in rats. In the CANTAB Spatial Working Memory (SWM) task, the human participant has to search through “boxes” displayed on a computer screen to find hidden tokens, in the comparable rodent task, the 8-arm radial maze, the rat has to search a maze to find hidden food items. The rodent ID/ED task is a great example where the adaptation of the test retains all the critical components of the human version, but has stimuli that are meaningful to rodents and a response which it is natural for them to do.

Image from Neurowiki2012

Applying translational cognitive tests


By developing tests that work for humans and animals, we can also make sure that the same procedures work for all sorts of different human beings. By avoiding language-based material, we can use the same behavioral tests across many different language groups and cultures and be confident that the test participants are having the same experience. We also know that we cannot explain to animals how to do a test; we have to build the test bit by bit, increasing the complexity and difficulty as the animal learns to master each step. By employing a similar strategy in CANTAB, we can use the same tests in human populations with vastly different skill levels and linguistic capabilities from young children, mature adults and the elderly. This also means that CANTAB tests are applicable to people with mental health problems, neurological or developmental disorders, as well as the healthy college students often used in psychological experiments. 

Some limitations of translational cognitive tests


There are some cognitive domains which are relatively easy to test in humans, but difficult to test in animals. One example is planning, where there is no equivalent for animals of the “Stockings of Cambridge” (SOC) task and the one-touch equivalent (One-Touch Stockings of Cambridge or OTS), derived from the “Tower of London” test and based on the classic Tower of Hanoi children’s game. Perhaps more importantly, it is often difficult to model the biological mechanisms of important human diseases in animals, even when we have a pretty good idea of some important components, such as in Alzheimer’s disease. In schizophrenia or depression we have little idea of the biological mechanisms, only that there may be many different ones. Measuring the equivalent cognitive domain in animals and humans can help us understand the level of similarity between the biological model and the human disease.

What is the impact of using translational cognitive tests for research?


An animal experiment which does not provide useful information is wasted work and can be criticized as unethical. It is important to ensure that what is learned from the animal experiments can be directly translated to subsequent human research (or sometimes, vice versa). One excellent way to do this is to use animal equivalents to CANTAB tests in preclinical studies, and then the corresponding CANTAB tests in human studies.

For preclinical researchers: consider using preclinical CANTAB or CANTAB-equivalent tests for your studies and be confident that you have a large number of human studies you can use to justify your research and provide context for the relevance of your results for human health.

For clinical researchers:  Use CANTAB tests in your clinical research and be able to refer to all the basic neuroscience which been carried out in animals using preclinical CANTAB or CANTAB-equivalent tests.

For teams doing drug discovery and development:  Consider developing a translational strategy which uses CANTAB and CANTAB-like tests throughout your program.  In that way you can reduce the risk associated with translating from animal studies to healthy human volunteers and on to patients.  You will also be able to use information gained in clinical studies to guide the selection of new targets for the drug discovery process.

For more background information on animal research visit:

http://www.understandinganimalresearch.org.uk/

http://grants.nih.gov/grants/olaw/olaw.htm

For support with your study design or further information on which CANTAB tests have pre-clinical equivalents, please contact us.

 

References

Brown VJ, Tait DS.  Attentional Set-Shifting Across Species.  Curr Top Behav Neurosci. 2016;28:363-95. doi: 10.1007/7854_2015_5002.

Nithianantharajah J, McKechanie AG, Stewart TJ, Johnstone M, Blackwood DH, St Clair D, Grant SG, Bussey TJ, Saksida LM.  Bridging the translational divide: identical cognitive touchscreen testing in mice and humans carrying mutations in a disease-relevant homologous gene.  Sci Rep. 2015 Oct 1;5:14613.

Tags : translational neuroscience | translational cognitive tests | cognitive science

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By John Evenden, PhD
Director of Science

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