Traumatic brain injury (TBI) resulting in poor neurological outcome is predominantly associated with diffuse brain damage and secondary hypoxic insults. Post-traumatic hypoxia is known to exacerbate primary brain injury; however, the underlying pathological mechanisms require further elucidation. Using a rat model of diffuse traumatic axonal injury (TAI) followed by a post-traumatic hypoxic insult, we characterized axonal pathology, macrophage/microglia accumulation, and astrocyte responses over 14 days. Rats underwent TAI alone, TAI followed by 30 min of hypoxia (TAI + Hx), hypoxia alone, or sham-operation (n = 6/group). Systemic hypoxia was induced by ventilating rats with 12% oxygen in nitrogen, resulting in a ∼ 50% reduction in arterial blood oxygen saturation. Brains were assessed for axonal damage, macrophage/microglia accumulation, and astrocyte activation at 1, 7, and 14 days post-treatment. Immunohistochemistry with axonal damage markers (β-amyloid precursor protein [β-APP] and neurofilament) showed strong positive staining in TAI + Hx rats, which was most prominent in the corpus callosum (retraction bulbs 69.8 ± 18.67; swollen axons 14.2 ± 5.25), and brainstem (retraction bulbs 294 ± 118.3; swollen axons 50.3 ± 20.45) at 1 day post-injury. Extensive microglia/macrophage accumulation detected with the CD68 antibody was maximal at 14 days post-injury in the corpus callosum (macrophages 157.5 ± 55.48; microglia 72.71 ± 20.75), and coincided with regions of axonal damage. Astrocytosis assessed with glial fibrillary acidic protein (GFAP) antibody was also abundant in the corpus callosum and maximal at 14 days, with a trend toward an increase in TAI + Hx animals (18.99 ± 2.45 versus 13.56 ± 0.81; p = 0.0617). This study demonstrates for the first time that a hypoxic insult following TAI perpetuates axonal pathology and cellular inflammation, which may account for the poor neurological outcomes seen in TBI patients who experience post-traumatic hypoxia.

Objective: Mild traumatic brain injury (mTBI) is associated with depressed mood acutely post-injury, but there is little evidence regarding long-term depression. The aim of this study was to determine the odds ratio of depression chronically following mTBI. Methods: We searched Medline (PubMed), ProQuest and Web of Science from date of database creation to January 23, 2019 for eligible studies examining depression at least six months post-injury in adult subjects with mTBI of any aetiology, including civilians and military. Three authors independently reviewed titles and abstracts for study eligibility. Data was extracted and collated by two investigators. Risk of bias was assessed with the SIGN methodology. Study data were pooled using random-effects meta-analysis. The primary exposure was mTBI, and the primary outcome was depression. Secondary exploratory variables were time of assessment, age at injury, age at assessment, sex, and aetiology. Results: We included 47 cross-sectional studies (n=25,103 mTBI and 29,982 control), 26 cohort studies (n=70,119 mTBI, 262,034 control), four prospective observational studies (n=1,058 mTBI and 733 control), two prospective longitudinal studies (n=119 mTBI, 81 control), two case-control studies (n=56 mTBI, 56 control) and one randomised controlled trial (n=252 mTBI, 3,214 control). mTBI was associated with a 3.29-fold increased risk of depression (OR 3.29 [95% CI 2.68–4.03], I2=96%). The OR for depression did not change when subjects were assessed at 6–12 months (OR 2.43, 1.45–4.07), years 1–2 (OR 4.12, 2.10–8.07); 2–10 (OR 3.28, 2.42–4.46) or 10+ (OR 3.42, 1.51–7.77). Similar risk of depression was sustained across different age at injury (: OR 2.69 1.42–5.10) and different age at assessment (40 years: OR 4.57, 2.54–8.24). Female sex had a non-significant increase in OR (OR 19.97, 2.39–166.93) compared to male (OR 3.0, 2.33–3.86). mTBI aetiology had no impact on depression. Conclusions: Those experiencing mTBI are more than three times more likely to experience depression compared to those without a history of mTBI, and this risk remains decades beyond the mTBI event. Future longitudinal studies are needed to identify and mitigate this risk.

Diffuse axonal injury is a common consequence of traumatic brain injury (TBI) and often co-occurs with hypoxia, resulting in poor neurological outcome for which there is no current therapy. Here, we investigate the ability of the multifunctional compound erythropoietin (EPO) to provide neuroprotection when administered to rats after diffuse TBI alone or with post-traumatic hypoxia.

Cuprizone is a copper-chelating agent that induces pathology similar to that within some multiple sclerosis (MS) lesions. The reliability and reproducibility of cuprizone for inducing demyelinating disease pathology depends on the animals ingesting consistent doses of cuprizone. Cuprizone-containing pelleted feed is a convenient way of delivering cuprizone, but the efficacy of these pellets at inducing demyelination has been questioned. This study compared the degree of demyelinating disease pathology between mice fed cuprizone delivered in pellets to mice fed a powdered cuprizone formulation at an early 3 week demyelinating timepoint. Within rostral corpus callosum, cuprizone pellets were more effective than cuprizone powder at increasing astrogliosis, microglial activation, DNA damage, and decreasing the density of mature oligodendrocytes. However, cuprizone powder demonstrated greater protein nitration relative to controls. Furthermore, mice fed control powder had significantly fewer mature oligodendrocytes than those fed control pellets. In caudal corpus callosum, cuprizone pellets performed better than cuprizone powder relative to controls at increasing astrogliosis, microglial activation, protein nitration, DNA damage, tissue swelling, and reducing the density of mature oligodendrocytes. Importantly, only cuprizone pellets induced detectable demyelination compared to controls. The two feeds had similar effects on oligodendrocyte precursor cell (OPC) dynamics. Taken together, these data suggest that demyelinating disease pathology is modelled more effectively with cuprizone pellets than powder at 3 weeks. Combined with the added convenience, cuprizone pellets are a suitable choice for inducing early demyelinating disease pathology.