Defining an Approach to Monitoring Brain Health in Individuals Exposed to Repetitive Head Impacts: Lessons Learned from Radiation Safety

Abstract

Recently, there has been increased concern over the effect of repetitive head impacts (RHIs, both concussive and subconcussive impacts) on long-term brain health. This concern has led researchers and policy makers to consider establishing RHI thresholds in order to mitigate the potential long-term effects of RHI exposure. However, the concept of thresholding relies on twin streams of information: 1) biomedical research relevant to the short and long-term risks of exposure to RHIs, and 2) societal standards for “acceptable risk.” In the case of RHI, these streams of information have not been cogently combined to inform sensible policy making. In the current editorial, we discuss how the history of radiation safety provides an instructive example of an approach to ford these two streams to derive actionable clinically relevant policies surrounding RHI exposures.

Recently, there has been increased concern over the effect of repetitive head impacts (RHIs) on long-term brain health. The term ‘‘RHIs” is meant to capture the cumulative exposure to recurrent concussive events (e.g., head impacts or blast exposures that result in microstructural changes in the brain and overt symptomatology) and subconcussive events (e.g., head impacts that may result in microstructural changes in the brain in the absence of overt symptoms).^1

–5 Particular concern has been directed to subconcussive RHI exposures where the transfer of mechanical energy results in altered axonal integrity, but without an easily detectable clinical signal to guide decision making around limiting these exposures. Several lines of investigation have suggested that subconcussive RHI exposures may be associated with long-term degradation in brain health.^6,7 In fact, Juan et al.⁸ highlight in their review article the lack of evidence about how the brain changes at acute time points after RHI and how these acute changes might mechanistically link to long-term outcomes, such as pathological tau formation, metal ionic dyshomeostasis, and motor and cognitive deficits. Indeed, despite emerging data in preclinical and clinical RHI studies such as those reviewed by Juan et al., translation to clinical practice has been stalled, leaving clinicians with no clear guidance to manage patients at risk for RHI exposures in real time.⁹

Most of the data relevant to the long-term risks of subconcussive RHI exposures are derived from retrospective case series, predominantly from boxers and professional players of American football. Recent case series have also suggested that law enforcement and military personnel are at risk for adverse outcomes after RHI. These case reports have described neuropathological changes consistent with chronic traumatic encephalopathy (CTE) in the brains of former athletes, law enforcement officials, and veterans who manifested with mood disorders, headaches, cognitive difficulties, suicidal ideation, post-traumatic stress disorder, difficulties with speech, and aggressive behavior.^10

–13 Most individuals in these studies had, presumably, experienced thousands of RHIs, especially subconcussive RHIs, throughout their careers. The possibility that subconcussive injuries could lead to CTE has raised the concern that a high number of athletes, law enforcement officials, and veterans might be at risk of CTE in the absence of concussion history. Some experts have argued that it is the chronic and repetitive nature of head trauma, irrespective of concussive symptoms, that is the most important driver of CTE.¹⁴ For this reason, at least one group has sought to quantify or “threshold” the cumulative number of RHIs associated with adverse long-term adverse clinical outcomes.¹⁵ Similar to much of the RHI outcomes literature, these thresholds were based on data derived from self-referred patients who may or not represent the general population of the “exposed”; therefore, the relevance of these thresholds to the general population remains essentially unknown. Despite this limitation, the concept of “thresholding” exposure is important with potential for practicable clinical translation. However, the concept of thresholding relies on twin streams of information: 1) biomedical research relevant to the short and long-term risks of exposure to RHIs, and 2) societal standards for “acceptable risk.” The history of radiation safety provides an instructive example of an approach to ford these two streams.

A Brief History of the Field of Radiation Safety

Since the discovery of radiation and radioactivity more than 100 years ago, radiation protection standards and the philosophy underlying those standards have evolved considerably (Fig. 1). In the late nineteenth and early twentieth centuries, physicians and scientists collected anecdotal data regarding the potential hazards of radiation exposure.¹⁶ Despite these data, the first proposed radiation dose limits (about 10 rad per day or 3000 rad per year) was based not on biological data but rather on the lowest amount that could be easily detected.¹⁷ Soon thereafter, animal studies demonstrated both acute radiation-induced damage to skin, bone marrow, and reproductive organs as well as delayed effects including cancer. However, most of the early limits in radiation exposure were based on preventing the onset of acute and obvious effects such as skin ulcerations and erythema that appeared after intense exposure to radiation fields. Early efforts at limiting radiation exposure were therefore based on a qualitative assessment of the acute “erythema dose,” with the important underlying assumption of the absence of biologic harm for doses below this erythema dose threshold.

FIG. 1.

Historical Contrasts between Radiation and Head Impact Exposures.

Over the next few decades, the field began to shift the standards of “acceptable risks” of radiation dose exposure based on concerns relevant to the long-term effects of exposure. The observation of an increased rate of cancer amongst atomic bomb survivors radically reframed the conceptual framework of risk thresholding and risk mitigation. Indeed, scientists working on the mitigation of radiation exposure risk refocused from short-term effects (e.g., erythema dose) to long-term effects (e.g., malignancy). Importantly, the data regarding malignancies were obtained from populations receiving high doses at high dose rates; risk estimates for low doses could only be made by extrapolating the high-dose data, and that procedure suggested that the cancer risks from low doses were quite small. However, even with those low dose exposures, no safe threshold could be theoretically derived. Moreover, the growing awareness that potentially carcinogenic radiation exposures could be clinically silent for decades required a new approach to mitigate risks.

This growing understanding of the need to mitigate both the short-term and long-term risks of radiation, along with the recognition of the utility and benefits of radiation generating procedures and practices, has led to a sophisticated interplay of science, philosophy, and ethics designed to regulate radiation dosing and exposure. It is notable that the radiation safety field has not sought to eradicate exposure but rather limit or mitigate the effects of exposure by reducing the cumulative dose of exposure through the strict implementation of safety standards. The International Commission on Radiological Protection (ICRP) has delineated a system of dose mitigation consisting of three parts: justification, optimization, and limitation. Justification requires that a new radiation procedure or practice produces a positive net benefit. Optimization requires that all doses shall be kept as low as reasonably achievable, balancing economic and social factors. Limitation requires guardrails for any individual dose. These principles continue to be iterated over time, with evolving standards based on technology, economics, and societal norms. In practice, radiation dose mitigation relies heavily on real-time monitoring by dosimeters, which can warn the wearer when a specified dose rate or a cumulative dose is exceeded. Such monitoring remains the mainstay of radiation safety.

Mitigating the Long-Term Effects of Exposure: Parallels between Radiation and RHI

The parallels between the science of radiation safety and RHI exposure are instructive. Much like the initial scientific emphasis on the early, detectable effects of radiation (i.e., the erythema dose), early RHI science focused on concussion (i.e., detectable injury), and mitigating the risks of concussion. However, as the RHI science has evolved, there is increased interest in how to mitigate the effects of the long-term effects of subconcussive injuries. Similar to the field of radiation safety, some experts have advocated for a “dosimeter” approach whereby exposures, e.g., head impacts, are prospectively collected and monitored, for example, through helmet- and mouthguard-based sensors. Such monitoring would theoretically allow for ascertainment of cumulative RHI exposure, such that individuals who reach a predefined threshold could be removed from the exposure context (e.g., removed from play, not redeployed into combat zones) This type of approach has been supported by prior research demonstrating a threshold dose-response relationship between estimated cumulative head impact exposure from American football and later-life risk for cognitive and neurobehavioral impairment.¹⁵

However, it is more likely that the philosophical construct of dosimetry approach should be expanded to a rubric designed to detect the biologic effects of RHI on brain health. The immense variability in long-term cognitive outcomes after cumulative head exposure¹⁵ suggests that a head-impact-threshold approach may lack fidelity to identify early threats to brain health in individual athletes, law enforcement officials, and members of the military. Moreover, while wearable head impact sensors (or RHI dosimeters) allow for real-time data relevant to impact count/frequency, they do not offer insight into the brain's response to biomechanical injury. Physical head impact event reconstruction and finite element analysis provide useful information to investigate the link between head motion and brain tissue strain^18
–20 but are not necessarily practical tools for real-time management. Such modeling also doesn't necessarily account for pre- and post-injury factors including underlying individual susceptibility or resilience. What is needed is technology capable of offering an acceptable proxy for injury-related changes in brain microstructure. Imaging studies have demonstrated potential in this regard, but advanced imaging is neither a widely available nor economically feasible strategy for most individuals exposed to RHIs.^21,22 Fluid and physiological biomarkers may offer the most practical opportunities to monitor real-time brain health in the setting of RHIs. In addition, clinical and animal studies demonstrating the link of fluid and physiological biomarkers to tissue level changes after RHIs would offer additional confirmation of the biological soundness of this approach.

The article by Juan et al.⁸ answers the call to develop mechanistic lines of inquiry relevant to the biologic underpinnings of RHI-associated neurodegenerative disease. The article also highlights that an incomplete neurobiological understanding of RHI-associated neurodegenerative disease has hampered the field's ability to mitigate the risks of exposure and the development of targeted interventions. They martial provocative evidence suggesting that metal ionic dyshomeostasis may play a crucial early role in triggering tau phosphorylation, leading acute RHI into chronic neurodegeneration. This novel hypothesis depicts a strong rationale for exploring the bidirectional effects of metal dyshomeostasis on tau hyperphosphorylation. An initial step may be to study RHI at acute and sub-acute post-RHI time points to better characterize how pathological tau formation, metal dyshomeostasis, motor and cognitive deficits to collectively initiate a neurodegenerative cascade of events. Indeed, it is only through the study of early time points after RHI that the field can develop biologic monitors of brain health after RHI exposure, offering a more precision approach than sensor-based dosimetry.

Toward Developing Biologic Monitors of Brain Health in the Context of RHI Exposure

Studies like Juan et al.⁸ give strong biologic rational for prospective monitoring of the earliest events that lead from RHI exposure to neurodegenerative changes. Imaging, physiologic, and fluid biomarkers have all shown some promise in this regard. However, the effectiveness of these emerging technologies may be hindered by the time, expense, and expertise necessary to deploy them in diverse care settings. What is needed is a translational technology that adapts well to conditions ranging from battlefield, to playing field, to emergency care.

For now, it is likely that fluid biomarkers offer the most cost-effective, scalable, and widely deployable means of assessing brain health after RHI. Recent technological advancements make possible the detection of blood biomarkers sensitive to low levels of brain injury. Moreover, numerous studies have demonstrated changes in fluid biomarkers at timepoints after RHI exposure in athletes,^23,24 law enforcement, and military personnel.^25,26 While the long-term significance of these acute or sub-acute changes in biomarkers has not been established (i.e., their predictive power for long term neurodegenerative disease), in some instances, these changes in biomarkers have been associated with functional impairment²⁶ further suggesting that they may serve as a good proxy for brain health. Going forward, the field needs to continue bolstering prospective animal and clinical studies using a multimodal approach that can inform the biological significance of RHI and associated risk factors in order to define standards by which RHI exposures and RHI dosages (magnitude/interval/frequency) can be managed to mitigate the short and long-term effects of the exposure.

Defining Acceptable Risk for RHI Exposure

The lack of mechanistic understanding of the dose-response characteristics of RHI exposure and neurodegenerative outcomes is paralleled by a lack of agreement regarding the acceptable risk threshold for these exposures, which may vary based on the context in which the exposures are accrued and other sociological determinants of acceptable risk. In some cases, the acceptable risk threshold may be elevated due to the societally determined necessity of the activity resulting in exposure, e.g., exposures in the context of law enforcement or military operations. In these instances, the threshold for acceptable risk may be quite high, and efforts may be directed toward risk reduction though occupational health measures, similar to those adopted to minimize radiation exposure for healthcare workers. In the case of RHI exposures in the context of sport, which may not be deemed a necessary activity, there is seemingly more controversy regarding acceptable risk. For example, some experts have called for the banning of American football based on the risks of RHI exposure though fewer experts have called for a similar ban on soccer despite recent data supporting long-term risks of neurodegenerative disease in professional soccer players.⁶ The lack of consensus regarding the acceptable risk of RHI exposure in the context of sport requires a comprehensive assessment of factors including: 1) the known benefits of sports participation; 2) the availability of alternative activities that confer similar benefits as well as replacement activities that might be detrimental; 3) an accurate assessment of the long-term risks of sports participation in the general population (i.e., different than those of professional athletes) compared to control groups with both active and sedentary life styles. Moreover, the determination of acceptable risk requires input from diverse stakeholders including scientists, ethicists, medical professionals, families, players, law enforcement, and military personnel.

Conclusion

The field of RHI science would benefit greatly from learning from and expanding upon the experience of the field of radiation safety in defining an approach to monitoring brain health of individuals exposed to RHI. Current limits of radiation exposure represent a culmination of intensive epidemiology and radiobiological research in both specialty populations and the general population. While the field of RHIs is relatively young, research based on exposures in the general population are desperately needed in order to develop thresholds relevant to exposures in diverse populations. Just as in the field of radiation safety, our standards of acceptable risk for RHI exposure will likely evolve as more data accrue regarding the short and long-term effects of RHI exposure. Notably, in both fields, there are still many open questions regarding the detailed mechanisms that cause biological effects. Juan et al.⁸ have provided a provocative new line of inquiry but more questions remain. What are the relative risks of different types of exposure, spacing between exposures, acute versus chronic exposure, age of exposure, biologic sex? Much like the early estimates of safe radiation thresholds, current thresholding limits for RHI exposure lack adequate biologic and epidemiologic underpinnings. Our current understanding of RHI biology is insufficient to inform practical decision making at the patient level.

Footnotes

Authors' Contributions

Rebekah Mannix, Keisuke Kawata, and Jeffrey Bazarian conceived of the article; Rebekah Mannix and Jeffrey Bazarian performed the literature search; Rebekah Mannix drafted the initial manuscript; Keisuke Kawata and Jeffrey Bazarian critically revised the manuscript

Funding Information

Dr. Mannix's research is funded, in part, by grants from the National Institutes of Health, the Department of Defense, and research funding from the National Football League and Abbott Laboratories. Dr. Bazarian reports funding from the National Institutes of Health, consulting for Abbott, research support from Abbott and BrainScope. Dr. Kawata reports funding from the National Institutes of Health.

Author Disclosure Statement

No competing financial interests exist.

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