Marmoset

Marmosets paralysed for cognition research at Monash University

Research paper citation

Feizpour, Azadeh; Majka, Piotr; Chaplin, Tristan A.; Rowley, Declan; Yu, Hsin-Hao; Zavitz, Elizabeth; Price, Nicholas S.C.; Rosa, Marcello G.P. and Hagan, Maureen A. 2021. “Visual responses in the dorsolateral frontal cortex of marmoset monkeys” Journal of Neurophysiology
https://doi.org/10.1152/jn.00581.2020

Associated Institutions

Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Australia , Australian Research Council, Centre of Excellence for Integrative Brain Function, Monash 12 University Node, Clayton, Australia, Laboratory of Neuroinformatics, Nencki Institute of Experimental Biology of the Polish 14 Academy of Sciences, 02-093 Warsaw, Poland

Animal Ethics Committee

This experiment was approved by the Monash Animal Research Platform Animal Ethics Committee, Monash University, Victoria, Australia.

Terminology

Tracheotomy – an incision into the windpipe (trachea)
Vein cannulation – inserting a catheter into a vein
Craniotomy – surgery to create a hole into the skull to access the brain
Callithrix jacchus – the common marmoset – one of the smallest monkey species
Frontal cortex – the front part of the brain directly behind the forehead
‘Utah’ array – patented microelectrode
Lissencephalic cortex – smooth cortex
Frontal eye fields (FEF) – a region (area 8 or BA8) located in the frontal cortex of the primate brain
Visuomotor cognition – the ability to synchronize visual information with physical movement
Pancuronium bromide – a neuromuscular blocking agent which works by stopping messages being sent from the nerves to the muscles; paralyses most muscles in the body, including those involved in breathing, but not the heart
Sufentanil – a potent synthetic opioid analgesic drug
Dexamethasone – an anti-inflammatory drug

The experiment

The frontal cortex of the brain is involved in aspects relevant to behaviour and cognition in humans and other primates.

This research aimed to identify receptive field properties and neural response latencies in the marmoset dorsolateral frontal cortex, such as location of the frontal eye fields (FEF).

Whilst the visual response properties of neurons in areas across the dorsolateral frontal cortex have been studied in macaques, the researchers here turn to the marmoset. They have justified their use in neurophysiology due to marmosets having a lissencephalic cortex, making multi-electrode, optogenetic and calcium imaging techniques more accessible than other primate ‘models’. However, it is not clear whether their brain circuits for visual behaviour are comparable to humans, as has been found with macaques. The aim was to establish whether the marmoset ‘model’ is suitable for the study of visuomotor cognition.

In the experiment, recordings were obtained following acute implantation of 96-channel Utah arrays in the marmoset frontal cortex of marmosets (Callithrix jacchus). Five adult marmosets were used (one female, four males). They were anaesthetised and subjected to invasive surgery: a tracheotomy, vein cannulation and a craniotomy to implant electrodes into their brains.

Once the surgical procedures were undertaken, while still anaesthetised, the animals were given pancuronium bromide, together with sufentanil and dexamethasone.

The animals were then artificially ventilated with a mixture of nitrous oxide (commonly known as laughing gas) and oxygen. Recordings were made while visual stimuli were presented to the animals via a 3D monitor and the receptive fields mapped. The recordings went on for 2-3 days, with no mention of whether any additional anaesthesia was provided during these 3 days. At the end of the experiment, the animals were killed by a lethal dose of sodium pentobarbital. Brain tissue was preserved and magnetic resonance imaging (MRI) was done for data analysis.

Relevance to Humans

This experiment is basic research and no particular human benefit is stated in the publication.  Tragically for the common marmoset, the experimenters are looking to this species as a new non-human primate ‘model’ to be used in neurophysiology for visual processing and behaviour. In providing the first evidence of visual receptive fields in the marmoset dorsolateral frontal cortex, they consider this “an important step towards future studies of visual cognitive behavior”. This does not bode well for marmosets at Monash University.

Whilst the subdivisions of visual areas and their anatomical connections may be consistent between humans and other primates, they are not identical.  There are major anatomical, genetic and physiological differences between humans and other animals, making non-human animals inappropriate for use in studying human disease. Many studies and systematic reviews show that there is discordance between non-human animal and human studies, and that non-human animal ‘models’ fail to mimic clinical disease adequately. (1,2)

Animal Welfare Concerns

The paper does not adequately describe how depth of anaesthesia was determined and how the deleterious effects of pancuronium bromide were evaluated and mitigated. Sufentanil is metabolised and removed from the body very quickly. Because pancuronium bromide provides no pain relief, its use is extremely problematic in that the animal cannot ‘show’ in the usual way that he or she is in pain and experiencing anxiety and distress.

Additionally, there is no clear reporting of whether the tests were staggered over several days, requiring re-anaesthesia of the animals, or whether the animals were subjected to one continuous period of anaesthesia and paralysis.

Communication with Monash University has confirmed that the marmosets were anaesthetised once. It was stated that marmosets were continually monitored for signs indicative of the level of consciousness and pain, and that precautions were taken in the event of equipment failure. However, we remain concerned that researchers may not have been paying sufficient attention to the ‘monitoring’, whilst focused on the tests being conducted. This is why, in human or veterinary medicine, there is a dedicated anaesthetist involved, whose sole responsibility is the patient’s well-being and survival. With a situation in which a neuromuscular blocking agent is used, this is essential.

The procedures taken to ensure animal ‘welfare’ were not reported adequately in this paper. Given that the intention was to establish whether the marmoset ‘model’ is suitable for the study of visuomotor cognition, and therefore potentially could lead to similar research in the future, these details should have been provided to guide future protocols. These omissions also have an impact on research quality and replicability.

The lack of adequate reporting of anaesthesia and analgesics in animal experiments such as in this experiment is not unique. It has been an issue raised by others in the scientific community for some time. For example, a ‘Retrospective review of anesthetic and analgesia regimens used in animal research proposals’ by Herrmann & Flecknell (3) has highlighted the need for improvement of reporting in research publications to fulfil legal requirements and to improve animal welfare. They note that severity of pain is often underestimated and that analgesic regimens are often not adequate and pain assessment is often not done.

Further, a publication by Bertrand et al (4) in an assessment of the anaesthetic and analgesic regimens in publications on studies involving non-human primates, concluded there is a lack of detailed description of protocols in many publications.

Cost Benefit Assessment

According to the publication, grants were provided from various sources. The total of grants awarded for research related to this project was over 2 million dollars and its nature is basic research with speculative value only.

This research is curiosity driven and animals used in laboratories clearly suffer when subjected to experiments such as these ‘basic research’ projects. Aside from animal welfare issues, at a cost of millions of dollars without clear translatable advances in human health, such use of finite resources is simply unacceptable.

Whilst researchers continue to look to the marmoset as a ‘new’, non-human primate, ‘model’ to be used in neurophysiology valuable resources in both time and animal lives are wasted when these unreliable and non relevant animal ‘models’ are used.

From a utilitarian perspective, a view often used by animal researchers to justify their work, it can be argued that the many animal lives lost in basic research do not justify the benefits (5).

Basic research rarely results in practical outcomes. Contopoulos-Ioannidis et al (6) examined articles in six highly-cited basic science journals over a five-year period. They found that fewer than 10% of highly promising basic science discoveries enter routine clinical use within 20 years.

Funding

This project was funded by the Australian Research Council and by the National Health and Medical Research Council of Australia. T. Chaplin was also funded by an Australian Postgraduate Award, a Monash University Faculty of Medicine Bridging Postdoctoral Fellowship. P. Majka was funded by the International Neuroinformatics Coordinating Facility Seed funding and the National Science Centre.
Funding was made by way of grants totalling $2,243,192.

This case study has been compiled in partnership with Action for Primates.

What you can Do

Please sign our Ban Primate Experiments Petition

Please also use the form below to tell the Monash University how disappointed you are with their use of animals in this experiment. You can use the text provided or compose your own.

Your message will be sent via email to Prof Rebeka Brown, Vice-Provost (Research) Monash University.

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References:
1. Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, et al. 2007. ‘Comparison of treatment effects between animal experiments and clinical trials: systemic review’, BMJ, 334:197.
2. Van der Worp H, Howells DV, Sena ES, Porritt MJ, Rewell S, O”Collins V, et al. 2010. ‘Can animal models of disease reliably inform human studies?’, PLoS Med.
3. Herrmann, K, Flecknell, PA 2018 Retrospective Review of Anesthetic and Analgesic Regimens Used in Animal Research Proposals ALTEX 36(1), 65-80. doi:10.14573/altex.1804011
4. Bertrand, HGMJ, Sandersen, C, Flecknell , PA 2018 Reported analgesic and anaesthetic administration to non-human primates undergoing experimental surgical procedure: 2010-2015, J Med Primatol. 2018;1–9. DOI: 10.1111/jmp.12346
5. Merkes,M. Better ways to do research: An overview of methods and technologies that can replace animals in biomedical research and testing. BetterWaysToDoResearch.pdf (humaneresearch.org.au)
6. Contopoulos-Ioannidis, D.G. Ntzani, EE. Ioannidis, JPA (2003). Translation of highly promising basic science research into clinical applications, 114(6), 0–484. doi:10.1016/s0002-9343(03)00013-5

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