Repeated Mild Traumatic Brain Injury

Abstract

Mild traumatic brain injury (mTBI) represents a significant public healthcare concern, accounting for the majority of all head injuries. While symptoms are generally transient, some patients go on to experience long-term cognitive impairments and additional mild impacts can result in exacerbated and persisting negative outcomes. To date, studies using a range of experimental models have reported chronic behavioral deficits in the presence of axonal injury and inflammation following repeated mTBI; assessments of oxidative stress and myelin pathology have thus far been limited. However, some models employed induced acute focal damage more suggestive of moderate–severe brain injury and are therefore not relevant to repeated mTBI. Given that the nature of mechanical loading in TBI is implicated in downstream pathophysiological changes, the mechanisms of damage and chronic consequences of single and repeated closed-head mTBI remain to be fully elucidated. This review covers literature on potential mechanisms of damage following repeated mTBI, integrating known mechanisms of pathology underlying moderate–severe TBIs, with recent studies on adult rodent models relevant to direct impact injuries rather than blast-induced damage. Pathology associated with excitotoxicity and cerebral blood flow-metabolism uncoupling, oxidative stress, cell death, blood-brain barrier dysfunction, astrocyte reactivity, microglial activation, diffuse axonal injury, and dysmyelination is discussed, followed by a summary of functional deficits and preclinical assessments of therapeutic strategies. Comprehensive characterization of the pathology underlying delayed and persisting deficits following repeated mTBI is likely to facilitate further development of therapeutic strategies to limit long-term sequelae.

Mild Traumatic Brain Injury Burden Moderates the Relationship Between Cognitive Functioning and Suicidality in Iraq/Afghanistan-Era Veterans

“…In terms of the pathophysiological outcomes resulting from multiple mTBIs, research using various experimental models has demonstrated diffuse axonal injury and demyelination (Bailes, Dashnaw, Petraglia, & Turner, 2014; Fehily & Fitzgerald, 2017), as well as cumulative damage to hippocampal cells (Slemmer, Matser, De Zeeuw, & Weber, 2002). Given that myelin plays a key role in information processing speed and that hippocampal functioning is essential for memory performance, it is not surprising that observed pathophysiological changes in white matter and the hippocampus have been linked to motor and memory dysfunction following multiple mTBIs in both animal and human studies (Mouzon et al, 2012; Multani et al, 2016; Niogi et al, 2008).…”

Mild Hyperthermia Aggravates Glucose Metabolic Consequences in Repetitive Concussion

“…Guskiewicz and colleagues [12] showed that collegiate football players with a history of concussion are 3.4 times more likely to sustain a second concussion within the same season. This potential for a second impact is important because several studies have shown that sustaining an additional injury when the brain is particularly susceptible can significantly exacerbate physiological damage and functional deficits [4,10,[15][16][17]. Giza and DiFiori [4] reported that if the brain is injured during this "window", there exists a cumulative effect of injurious processes and worsened neurological outcomes; however, when there is a greater interval between the mTBIs, cumulative deficits are not observed [18].…”

Expansion of a fly TBI model to four levels of injury severity reveals synergistic effects of repetitive injury for moderate injury conditions

“…Thus, dysregulation of neuronal excitability and extracellular potassium operate on short time-scales and are responsive to injury severity, which are compatible with our observed synergistic effects for injuries at short inter-injury intervals and for moderate, but not severe TBI. Downstream consequences of misregulated neurotransmission and extracellular potassium are varied, but may include changes in oxidative stress and inflammation (Guerriero et al 2015; Fehily and Fitzgerald 2017; Khatri et al 2018).…”