Titrating the Translational Relevance of a Low-Level Repetitive Head Impact Model

Abstract

Recently, there has been increased attention in the scientific community to the phenomenon of sub-concussive impacts, those hits to the head that do not cause the signs and symptoms of a concussion. Some authors suggest that sub-concussive impacts may alter behavior and cognition, if sustained repetitively, but the mechanisms underlying these changes are not well-defined. Here, we adapt our well-established weight drop model of repetitive mild traumatic brain injury (rmTBI) to attempt to produce a model of low-level repetitive head impacts (RHI). The model was modified to eliminate differences in latency to right following impact and gross behavioral changes after a single cluster of hits. Further, we varied our model in terms of repetition of impact over a 4-h span to mimic the repeated sub-concussive impacts that may be experienced by an athlete within a single day of play. To understand the effects of a single cluster of RHIs, as well as the effect of an increased impact frequency within the cluster, we evaluated classical behavioral measures, serum biomarkers, cortical protein quantification, and immunohistochemistry both acutely and sub-acutely following the impacts. In the absence of gross behavioral changes, the impact protocol did generate pathology, in a dose-dependent fashion, in the brain. Evaluation of serum biomarkers revealed limited changes in GFAP and NF-L, which suggests that their diagnostic utility may not emerge until the exposure to low-level head impacts reaches a certain threshold. Robust decreases in both IL-1β and IL-6 were observed in the serum and the cortex, indicating downregulation of inflammatory pathways. These experiments yield initial data on pathology and biomarkers in a mouse model of low-level RHIs, with relevance to sports settings, providing a starting point for further exploration of the potential role of anti-inflammatory processes in low-level RHI outcomes, and how these markers may evolve with repeated exposure.

Translating from mice to humans: using preclinical blood-based biomarkers for the prognosis and treatment of traumatic brain injury

“…Injury severity was moderate-to-severe TBI in 26 studies, smTBI in 15, and rmTBI in 7 studies. Twenty-six studies performed a longitudinal assessment of GFAP levels after TBI (41,42,55–80).…”

“…There was an exception in one study using a weight drop injury model that reported increased GFAP levels at 30d post-injury (73). In rmTBI models, GFAP was assessed at ’hours’ in 5 studies (42,56,66,81,83), at ’days’ in 3 studies (42,63,93), at ’weeks’ in 2 studies (42,66), and at ’months’ in 3 studies (63,88,92) ( Fig. 4C ).…”

“…4A). Following moderate-to-severe TBI, NfL increased and peaked at 1-3d (7,29,30,42) with NfL levels remaining elevated up to 6m after TBI (40). In smTBI models, NfL levels were assessed at 'hours' by 2 studies (43,46), at 'days' by 5 (43,(45)(46)(47)49), at 'weeks' by 4 studies (45)(46)(47)49), and at 'months' by 2 studies (45,49) (Fig.…”

“…NfL levels returned to baseline by 5w (45). In rmTBI models, NfL levels were assessed at ‘hours’ by 2 studies (42,46), at ‘days’ by 7 (42,45–49,54), at ‘weeks’ by 4 (42,46,47,49), and at ‘months’ by 4 studies (44,45,48,49) ( Fig. 4C ).…”

“…Injury severity was moderate-to-severe TBI in 8 studies, smTBI in 5 studies, and rmTBI in 8 studies. Twelve studies performed a longitudinal assessment of NfL after injury (7,(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49).…”