Commentary: Three questions for the study of traumatic brain injury in animals

It will likely not be news to this audience that, for much of the 21st century, sports have been in the midst of a "concussion crisis" (e.g., Carroll Malcolm, 2020; Nowinski, 2007). This crisis has a number of constituent parts, including an increasing concern with the acute effects of brain injury. Nonetheless, the links between brain trauma and neurodegenerative disease—most prominently an Alzheimer's-like dementia known as Chronic Traumatic Encephalopathy, or CTE—holds center-stage. the most important sports story of the 21st century… Concerns about CTE have inspired a global revolution in concussion safety and fueled an ongoing existential crisis for American's most popular sport. (Hobson, 2020) In fact, in the 2020s, it feels increasingly inappropriate to talk about a concussion crisis in sport. In 2021, CTE was posthumously diagnosed in a victim of domestic abuse (Danielsen et al., 2021) and the risk of brain injury resulting from intimate partner violence is increasingly being foregrounded (For historical and social scientific work on the relationship between gender and brain injury see, for example: Casper Henne, 2020). Furthermore, and as I write, there is a renewed focus upon the effects of brain injury suffered as part of military activity—a focus which follows suggestions that an army reservist who killed 18 people in a mass shooting may have been exposed to as many as 10,000 blasts on a grenade training range (Philipps, 2023). Given this cultural milieu, it is unsurprising to see a vast, interdisciplinary body of science developing that aims to better understand the links between brain trauma and neurodegenerative disease. It is similarly unsurprising that some of these scientists aim to achieve insight through the use of animal modeling. I am a sociologist of science, and my research involves observing laboratory work and speaking to scientists about their own research. For several years I have worked with scientists exploring the relationship between traumatic brain injury and neurodegenerative disease, including a number who engage in various forms of animal modeling. There is nothing new in the idea that we can study both neurodegenerative disease and traumatic brain injury through animal modeling. In the case of the former we need only think of the various mouse models of Alzheimer's Disease; in the case of the latter we can go back to studies on automotive safety that have long involved pigs, baboons, and various other species (e.g., Mertz et al., 1982). (Or simply peruse the abstracts for the latest Society for Neuroscience conference.) Nonetheless, when one speaks to animal modelers or goes into their laboratories, there is a distinct sense that when it comes to animal modeling and the long-term effects of brain injury, we are dealing with a nascent research area in which comparatively little is known and a great deal remains uncertain. In the rest of this commentary, I take these claims of newness and uncertainty seriously, and (re)pose three questions which, based upon my work, researchers ask most frequently and, in turn, seek to answer. My hope is that, first, scientists will recognize these questions from their own lab' discussions and, second, that posing these questions in a clear and public forum will contribute to a healthy debate about the nature of research in this area. One obvious concern within the field is that there may be divergent views, and significant uncertainty, over what constitutes a "good" animal model of CTE. For many researchers, the species of choice are those most commonly used within laboratory settings, most notably mice and rats. There are a host of both pragmatic and epistemological reasons why these species appeal. Pragmatically, they are small, relatively cheap, and have well established care guidelines. Epistemologically, the species are well known both biologically and socially, so an exploration of experimentally-induced change is easier to conduct. The widespread availability of transgenetic animals provides another level of experimental control (Ojo et al., 2013). These species are examples of what Hans-Jörg Rheinberger calls "technical objects" (Rheinberger, 1997, p. 29)—they are sufficiently well known that they act as an instrument of knowledge, allowing the effects of intervention to present themselves relatively clearly. For other researchers, however, no amount of certainty makes up for the fact that many frequently used animal models are profoundly flawed. Chronic traumatic encephalopathy, for example, is definitionally defined by tau depositions at the depth of the sulci (Bieniek et al., 2021). Given that mice and rats are smooth brained, however, we appear to have a fairly fundamental problem. For some of the researchers to whom I've spoken this is a fairly minor matter: rats and mice don't enjoy the taste of alcohol, either, and yet they're frequently used to model alcoholism (Nelson, 2018, p. 145). Primates don't get Parkinson's Disease, and yet they are still used to model it (Giraud, 2019, p. 108). For other researchers, the neuroanatomy of these murine species makes them next to useless. Scholars who, for one reason or another, reject the use of these standardized animal models frequently turn to the use of novel or unusual species in their work (Ackermans et al., 2021): we see a number of these species drawn upon in this special collection, in fact. When non-standardized species are utilized, a whole different set of issues emerge. Some researchers, for example, use ferrets: these are gyrencephalitic animals, they're small, and these researchers describe them as an obvious improvement over mice and rats from a neuroanatomical point of view, and over sheep and pigs from an animal husbandry point of view. But these same researchers also describe a great deal of uncertainty about whether the behavioral tests designed for mice and rats—certain mazes, for example—are in any way appropriate with ferrets. How do we know if a ferret is "anxious"? Do ferrets exhibit anxiety in the same way as a rat? Probably not. There may be, then, a need to reimagine a whole suite of behavioral tests. Other scholars turn to more naturalistic models. An increasing amount of scientific and popular attention has turned towards woodpeckers as an animal model for CTE, for example (Hollin, 2022). Other than the fairly obvious fact that woodpeckers hit their heads a lot, it is still unclear what exactly it is that woodpeckers are taken to model. Is a woodpecker interesting because it has evolved a number of protective mechanisms and therefore doesn't develop any CTE-adjacent neurodegenerative disease, or is it interesting for precisely the opposite reason, because it does suffer brain injury and therefore offers the opportunity to study the long-term effects of trauma acquired naturally and, perhaps, in a less ethically fraught manner? The woodpecker has, returning to Rheinberger, an "irreducible vagueness" that embodies "what one does not know" (Rheinberger, 1997, p. 28) and this means that a whole lot of work will need to go into describing woodpeckers (and/or ferrets) before we are able to use them to study CTE. And for critics, it will simply never be possible to study the number of woodpeckers necessary to obtain the levels of statistical power needed to answer core questions (or match the insights arising from standardized species). Historians and philosophers of science have long debated the superior approach to selecting model organisms. Some stress the need for a species to be extensively described prior to transformative insight (Ankeny, 2001). Others stress the value of pluralism and cross-fertilization (Longino, 2013). Resolving these differences may never be possible, but dialogue and a sense of where others are coming from remains hugely important. A second question concerns what, exactly, animals are taken to model. It does not escape the notice of scientists in this area that, approximately once every 15 minutes, there is a new consensus conference intended to bring people together so that we might agree what it is that we're all talking about. We have, for example, the Concussion In Sport Group's quadrennial consensus conference—the most recent of which occurred in 2022 (Patricios et al., 2023)—in which panelists seek to clarify, amongst other things, the definition of concussion and the long term effects of brain trauma. We have the National Institute of Neurological Disorders and Stroke (NINDS)/National Institute of Biomedical Imaging and Bioengineering (NIBIB) consensus statement into the neuropathological criteria for CTE, the second iteration of which was published in 2021 (Bieniek et al., 2021). We have the NINDS consensus criteria for traumatic encephalopathy syndrome, or TES, which is the clinical manifestation of CTE (Katz et al., 2021). I have no doubt that there are many others. These consensus statements often differ considerably from each other, and there is an increasing suspicion that definitions may be becoming siloed within disciplines. Dominic Malcolm, for example, has observed an increasing tendency on the part of the Concussion In Sport Group to distinguish between "sports-related concussions" (often abbreviated to "SRCs") on the one hand, and concussions that result from other forms of activity, on the other. Malcolm (2020, p. 39) suggests that this demarcation may need to be understood as a response to an increasingly fractious relationship between sports scientists and neuroscientists, with the former coining the term "SRC" in order to assert a domain of expertise. It is perhaps unsurprising, therefore, that Concussion In Sport Group consensus statements have, first, been critiqued for failing to represent a consensus and, second, that these critiques are often shouted from across a disciplinary divide. Neuropathologist Willie Stewart, a co-author on the NINDS/NIBIB definition of CTE, has, for example, been openly critical of the Concussion in Sport Group (Belson, 2022) while other prominent researchers have also elected to ignore their consensus conferences (Bull, 2022). At the same time, those who have not been invited to contribute to the NINDS/NIBIB definition, notably Bennet Omalu, have been critical of that process and the resulting definitions (Hammers Omalu, 2020). I have also spoken to some researchers who feel incredibly confident that they are able to clinically diagnosis traumatic encephalopathy syndrome and are happy to say that a patient has "probable CTE"; I speak to others who say that this is essentially impossible; that the diagnostic criteria for traumatic encephalopathy syndrome lack sensitivity and specificity; and that we really know next to nothing about the clinical manifestations of CTE. In many ways, these debates happen at quite some distance from the animal modeling community: consensus committees tend, after all, to exclude all research on non-human animals when coming to their definitions. Nonetheless, there is a pervasive sense of a moving and diffuse target here. It is clearly important to know what one is modeling, and a sense of working upon shifting sands, necessarily, makes animal research in this area all the harder. These are not problems unique to the study of brain injury. The writing of contentious consensus making procedures such as the Diagnostic and Statistical Manual for Mental Disorders and the Intergovenmental Panel on Climate Change have been extensively considered (see, for example, Adler and Pickersgill, 2012, 2024 for a consideration of the DSM). There is not necessarily a need to reinvent the wheel here, but there is, perhaps, a need to get under the hood in order to understand the type of machine we're building. A final area that requires careful consideration concerns the constitution of ethical conduct in relation to the animal modeling of neurodegenerative disease. Rather than re-litigate any overarching questions about the ethics of animal experimentation, I here want to focus upon two very particular, if quite different, issues that face researchers in this area. First, while there has been, understandably, a good deal of attention paid to how research is funded (e.g., Bachynski "What are we modelling?", and "What constitutes ethical research?"—that I have heard frequently in my discussions with researchers studying traumatic brain injury and neurodegenerative disease. My hope is that readers will see the relevance of these questions when reading the rest of this special issue and, perhaps, recognize them from their own work. As this special issue shows, this is still a nascent field of research and there is thus the opportunity to imagine things differently, to make clear-eyed decisions about what the future of the field will look like. Having hard discussions about difficult questions will, I think, be key to this work. Gregory Hollin: Conceptualization; data curation; formal analysis; funding acquisition; investigation; methodology; project administration; resources; writing – original draft; writing – review and editing. My ongoing work has been made possible by a Wellcome University Award in Humanities and Social Science, awarded by The Wellcome Trust (2022-2027, grant reference: 222157/Z/20/Z). For the purpose of Open Access, I have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The proposed research for this project was reviewed and given a favorable opinion by an ethics committee at The University of Sheffield (13 April 2022). Participants can ask for their data to be withdrawn until the project concludes and anonymized data from consenting participants will be made available after this point. This particular commentary arose from the session "Traumatic Brain Injury: Not Just for Humans" which was organized by Nicole Ackermans and which took place on the 29 July 2023 as part of the International Congress of Vertebrate Morphology conference in Cairns, Australia. I thank Nicole for inviting me to this conference and the Department of Sociological Studies at The University of Sheffield for providing financial support for my attendance.