A Preclinical Rodent Model for Repetitive Subconcussive Head Impact Exposure in Contact Sport Athletes

Abstract

Repetitive subconcussive head impact exposure has been associated with clinical and MRI changes in some non-concussed contact sport athletes over the course of a season. However, analysis of human tolerance for repeated head impacts is complicated by concussion and head impact exposure history, genetics, and other personal factors. Therefore, the objective of the current study was to develop a rodent model for repetitive subconcussive head impact exposure that can be used to understand injury mechanisms and tolerance in the human. This study incorporated the Medical College of Wisconsin Rotational Injury Model to expose rats to multiple low-level head accelerations per day over a 4-week period. The peak magnitude of head accelerations were scaled from our prior human studies of contact sport athletes and the number of exposures per day were based on the median (moderate exposure) and 95th percentile (high exposure) number of exposures per day across the human sample. Following the exposure protocol, rats were assessed for cognitive deficits, emotional changes, blood serum levels of axonal injury biomarkers, and histopathological evidence of injury. High exposure rats demonstrated cognitive deficits and evidence of anxiety-like behaviors relative to shams. Moderate exposure rats did not demonstrate either of those behaviors. Similarly, high exposure rats had histopathological evidence of gliosis [i.e., elevated Iba1 intensity and glial fibrillary acidic protein (GFAP) volume relative to shams] in the basolateral amygdala and other areas. Blood serum levels of neurofilament light (NFL) demonstrated a dose response relationship with increasing numbers of low-level head acceleration exposures with a higher week-to-week rate of NFL increase for the high exposure group compared to the moderate exposure group. These findings demonstrate a cumulative effect of repeated low-level head accelerations and provide a model that can be used in future studies to better understand mechanisms and tolerance for brain injury resulting from repeated low-level head accelerations, with scalable biomechanics between the rat and human.

Time Delta Head Impact Frequency: An Analysis on Head Impact Exposure in the Lead Up to a Concussion: Findings from the NCAA-DOD Care Consortium

“… 4 , 20 , 21 Preclinical studies highlighted neuroinflammatory responses, 52 as well as dose-dependent microgliosis and axonal damage that were correlated to the level of HIE. 55 Chronic studies identified higher later-life t-tau concentrations in former professional football athletes that had sustained higher estimated levels of HIE. 2 These studies have formed the foundation of our understanding of how repetitive subconcussive HIE influences concussion and concussion-like symptoms.…”

“… 39 , 42 , 58 Recent preclinical modeling also identified significant dose-dependent behavioral changes in rats receiving repeated low-level head accelerations scaled from human contact sport HIE 52 or repeated ‘mild’ exposures. 8 , 47 , 52 , 55 From a mechanistic standpoint, imaging studies identified changes in brain white matter integrity that were positively correlated to levels of HIE. 4 , 20 , 21 Preclinical studies highlighted neuroinflammatory responses, 52 as well as dose-dependent microgliosis and axonal damage that were correlated to the level of HIE.…”

“…However, aside from preclinical studies that provided definitive evidence of pathophysiology and behavioral changes linked to repetitive HIE, 55 some debate remains regarding the mechanistic role of subconcussive HIE in acute sport-related concussion or the development of concussion-like symptoms in uninjured athletes. In 2016, Belanger et al .…”

Subconcussion, Concussion, and Cognitive Decline: The Impact of Sports Related Collisions

“…In 2022, Stemper and colleagues developed a preliminary preclinical model incorporating head rotational acceleration. Their data suggests the ability to scale human subconcussive injury characteristics down to a rodent model with greater accuracy in order to assess the behavioral and physical consequences [ 119 ]. Further research in understanding the mechanism and thresholds of subconcussive injury specific to humans is necessary and ongoing, particularly in regard to frequency of injury exposures and resulting long-term symptoms.…”

Change in Head Impact Exposure following Return to Play in Concussed Football Athletes

“…This has led to the line of thought that each injurious impact an individual sustains may cause physiological and structural changes to the brain, leading to reduced tolerance and increased risk of further injury. Recent preclinical studies have supported this assertion by demonstrating dose-dependent behavioral and pathological changes associated with repeated subconcussive head accelerations [13].…”