Toward a Unified Lexicon in Traumatic Brain Injury: Defining the Mechanism of Injury

Abstract

In the field of traumtic brain injury (TBI) we have often witnessed miscommunication arise when articles and presentations are not adequately precise with the language describing their TBI models and/or findings. The lack of precise, consistent terminology to describe injury mechanisms across biological scales and temporal phases impedes communication. We propose that at the cellular scale, standardizing the definitions of primary and secondary injury as distinct biological mechanisms—rather than sequential stages—can help advance our understanding of TBI, facilitate interdisciplinary collaboration, and enable more effective comparisons across experimental models, ultimately leading to improved diagnosis and treatment strategies.

Introduction

TBI research spans numerous disciplines—from biomechanics to molecular neuroscience and this diversity, while vitally important, can result in inconsistent terminology that confounds precise communication. Nowhere is this more evident than in the use of the terms primary and secondary to describe injury. While in a clinical setting, these terms often describe temporal stages of TBI, they denote, at a cellular scale, distinct, nonsequential mechanisms of injury with uniquely associated cellular pathologies.

Ambiguity in the use of primary and secondary hampers comparison between in vitro and in vivo models, complicates interpretation of injury progression, and obscures translational relevance. Therefore, we propose a refined nomenclature rooted in mechanistic biology to clarify the conceptual framework surrounding TBI at the cellular scale.

Defining the Injury: Biological and Cellular Mechanisms

The complexity of TBI lies in the multiscale nature of its pathophysiology in time and size—spanning molecular to systemic levels and microseconds to years. To better characterize this complexity, we assert that the terms primary and secondary injury should be defined as distinct biological cellular mechanisms.

Primary injury is defined as the immediate physical damage to biological structures resulting from mechanical loading. This occurs on a time scale consistent with the insult itself and results in instantaneous and irreversible cellular damage, such as membrane rupture, cytoskeletal failure, or macroscopic tissue laceration.

Secondary injury is defined as any time-dependent, cascading biochemical process that leads to permanent cellular dysfunction and death. This includes processes such as apoptosis, necrosis, or ferroptosis. It also umbrellas the hyperphosphorylation of tau proteins and their associated tauopathies. Secondary injury typically begins within seconds yet produces no detectable sign of gross morphological or permanent functional change until several hours post-insult.

Finally, it is crucial to distinguish these injury mechanisms from the source of injury, which refers to the initiating physical event (e.g., impact, blast, acceleration, or scratch in vitro). Importantly, not all sources result in injury; exposure to a source may impose mechanical stress without crossing the threshold for primary or secondary injury.

Mechanistic Precision: Clarifying the Language

Drawing on definitions from Merriam-Webster, ¹ we frame our terminology as follows:

Injury refers to damage or sustained biological loss.

Mechanism denotes the fundamental process by which a natural phenomenon occurs.

Thus, a biological mechanism of injury is defined as the process responsible for producing damage. By this definition, primary and secondary injuries are distinct, not sequential, cellular mechanisms that may or may not co-occur, depending on the context and magnitude of the insult.

Cells sustaining primary injury are structurally compromised and thus biologically inert, rendering them incapable of undergoing the processes involved in secondary injury. A single cell can only sustain either a primary or secondary injury but not both, yet a single insult may invoke both mechanisms within adjacent cells, creating mixed injury zones at the tissue level.

Temporal Phases of TBI: Adopting Neuroinflammatory Nomenclature

While primary and secondary refer to cellular injury mechanisms, the temporal evolution of TBI can be described using established clinical staging. Borrowing from the neuroinflammation literature, we endorse a temporal classification agnostic to injury mechanism:

Hyperacute: Seconds post-insult.

Acute: First 24 hours

Subacute: Days to weeks.

Chronic: Months to years.

These phases correspond to the activation and resolution (or persistence) of neuroinflammatory agonists. ² Microglial activity, cytokine expression, and immune cell recruitment evolve across these phases and may differ depending on whether the mechanism of injury is primary or secondary in nature. ³

Notably, damage-associated molecular patterns (DAMPs) may differ in character depending on the injury mechanism¹: Primary injury immediately releases cellular debris, while the cellular process of secondary injury may involve the time-dependent release of molecules with bioactive signaling properties. These differences could modulate the immune response and are likely to have implications for diagnostic and therapeutic targeting.

Experimental Considerations for Translational Relevance

Understanding whether an insult causes primary or secondary injury is critical for interpreting preclinical models. Most civilian mild-TBIs elicit secondary injury, whereas the high loading rates and magnitudes induced by blast exposures appear to induce predominantly primary injury.

Thus, each experiment should be carefully designed to match its intended application. For example, an assay that slices cells induces primary injury along the lesion line but would rarely induce secondary injury within the surrounding cells. ⁴ In contrast, assays that deliver an impact to the brain through a cranial window or stretch cultured cells on a membrane are likely to induce secondary injury but could induce primary injury depending on the rate and magnitude of the impact.^5,6 Assay selection requires careful consideration of the target mechanism of injury.

Therefore, to evaluate data across studies, the mechanism of injury, not merely the injury source, method, or timing, must be clearly defined and identified. Failure to do so risks overgeneralization and limits reproducibility.

Implications for Diagnosis and Chronic Outcomes

Recognizing and accurately classifying injury mechanisms will improve our understanding of how acute events lead to chronic outcomes. Particularly, as post-mortem analysis continues to reveal pathological differences between the brains of people with repetitive-blunt TBI and the brains of people with blast-TBI, ⁷ the mechanism of cellular injury may have paramount significance to the chronic state of the disease, but its effect could easily be overlooked.

For insults where primary injury is the predominant mechanism, there may be different clinical sequelae of neuroinflammation and healing. As a consequence, if the means of TBI diagnosis relies on a biomarker of secondary injury, some TBIs are likely to evade detection and vice versa.

Conclusion

Traumatic brain injury is a complicated multiscale disease with a wide spectrum of presentations. Research breakthroughs can be significantly accelerated if we adopt a unified and biologically grounded terminology distinguishing primary and secondary injury at the cellular scale as independent, nonsequential mechanistic phenomena. Clear and precise terminology will help advance the field and improve the clarity of communication across disciplines and experimental investigations.

Such precision is foundational for cross-study comparisons, developing targeted interventions, and ultimately, translating laboratory findings for clinical benefit. The path forward in TBI research begins with getting on the same page.

Transparency, Rigor, and Reproducibility Statement

There are no new experimental results included in this submission, nor is it a review article.

Authors’ Contributions

A.L.F.: Conceptualization (supporting), writing—original draft (lead), and writing—review and editing (equal). C.F.: Conceptualization (lead) and review and editing (equal).