Blood–brain barrier disruption and ventricular enlargement are the earliest neuropathological changes in rats with repeated sub-concussive impacts over 2 weeks

Abstract

Repeated sub-concussive impact (e.g. soccer ball heading), a significantly lighter form of mild traumatic brain injury, is increasingly suggested to cumulatively alter brain structure and compromise neurobehavioural function in the long-term. However, the underlying mechanisms whereby repeated long-term sub-concussion induces cerebral structural and neurobehavioural changes are currently unknown. Here, we utilised an established rat model to investigate the effects of repeated sub-concussion on size of lateral ventricles, cerebrovascular blood–brain barrier (BBB) integrity, neuroinflammation, oxidative stress, and biochemical distribution. Following repeated sub-concussion 3 days per week for 2 weeks, the rats showed significantly enlarged lateral ventricles compared with the rats receiving sham-only procedure. The sub-concussive rats also presented significant BBB dysfunction in the cerebral cortex and hippocampal formation, whilst neuromotor function assessed by beamwalk and rotarod tests were comparable to the sham rats. Immunofluorescent and spectroscopic microscopy analyses revealed no significant changes in neuroinflammation, oxidative stress, lipid distribution or protein aggregation, within the hippocampus and cortex. These data collectively indicate that repeated sub-concussion for 2 weeks induce significant ventriculomegaly and BBB disruption, preceding neuromotor deficits.

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

“…Hence, these changes could represent an overall trend toward anti-inflammation, or immune suppression. Interestingly, Hiles-Murison et al, also found suppression of several pro-inflammatory chemokines and cytokines (CXCL1 and MCP-1), although they saw no changes in IL-1β or IL-6 ( 16 ). In a clinical study, Huibregtse et al subjected soccer players to 10 controlled headers and tested plasma levels of pro-inflammatory chemokines (CCL11 and CCL2) and an anti-inflammatory cytokine (IL-10) immediately post-heading, as well as 2 h and 24 h later ( 62 ).…”

A Suggested New Term and Definition to Describe the Cumulative Physiological and Functional Effects of Non-injurious Head Impacts

“…In a recent study from our group, we reported ventricular enlargement and blood brain barrier (BBB) disruption after 60 subconcussive impacts over 2 weeks with no disruption to neuronal function ( 13 ). Parenchymal perivascular extravasation of plasma IgG was quantified to assess integrity of BBB integrity in the cortex and the hippocampal formation in these rats which exhibited significantly exaggerated cortical perivascular IgG extravasation and significant leakage of parenchymal IgG in the hippocampal region compared with the rats in the sham group ( 13 ).…”

“…In a recent study from our group, we reported ventricular enlargement and blood brain barrier (BBB) disruption after 60 subconcussive impacts over 2 weeks with no disruption to neuronal function ( 13 ). Parenchymal perivascular extravasation of plasma IgG was quantified to assess integrity of BBB integrity in the cortex and the hippocampal formation in these rats which exhibited significantly exaggerated cortical perivascular IgG extravasation and significant leakage of parenchymal IgG in the hippocampal region compared with the rats in the sham group ( 13 ). Furthermore, the “silent” cerebro-structural and -vascular alterations were observed not only at the impact site (cortex), but also in the deeper regions of the brain; the hippocampus and lateral ventricle, indicating a potentially distinct neuropathological pathway from those ordinarily observed in concussion.…”

Repeat Closed-Head Injury in Male Rats Impairs Attention but Causes Heterogeneous Outcomes in Multiple Measures of Impulsivity and Glial Pathology

“…However, it should be noted that for the lone study which used an easier variant of the 5CSRT task, this was limited to omissions ( Kaukas et al, 2021 ). Additional studies have indicated that “subconcussive” impacts may also generate pathology and ultimately functional impairment if repeated frequently enough ( Lavender et al, 2020 ; Hiles-Murison et al, 2021 ).…”