Abstract
Traumatic brain injury is a major source of global disability and mortality. Preclinical TBI models are a crucial component of therapeutic investigation. We report a tunable, monitored model of murine non-surgical, diffuse closed-head injury—modCHIMERA—characterized by impact as well as linear and rotational acceleration. modCHIMERA is based on the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) platform. We tested this model at 2 energy levels: 1.7 and 2.1 Joules—substantially higher than previously reported for this system. Kinematic analysis demonstrated linear acceleration exceeding injury thresholds in humans, although outcome metrics tracked impact energy more closely than kinematic parameters. Acute severity metrics were consistent with a complicated-mild or moderate TBI, a clinical population characterized by high morbidity but potentially reversible pathology. Axonal injury was multifocal and bilateral, neuronal death was detected in the hippocampus, and microglial neuroinflammation was prominent. Acute functional analysis revealed prolonged post-injury unconsciousness, and decreased spontaneous behavior and stimulated neurological scores. Neurobehavioral deficits were demonstrated in spatial learning/memory and socialization at 1-month. The overall injury profile of modCHIMERA corresponds with the range responsible for a substantial portion of TBI-related disability in humans. modCHIMERA should provide a reliable platform for efficient analysis of TBI pathophysiology and testing of treatment modalities.
Highlights
Traumatic brain injury (TBI) occurs in 2.4 million people per year in the United States[1] and has been described by the Centers for Disease Control and Prevention as a ‘silent epidemic’ with an annual cost of $76.5 billion in 20102,3
Recognizing the broad spectrum of injury that can meet these definitions, a subclass of more significantly-injured mild TBI patients is often identified by the presence of one or more “complications.” Such complicated-mild TBI patients are generally identified by the presence of a radiologically detectable brain injury[12,13,14], but have been defined as exhibiting a GCS at the lower end of the mild spectrum[15], prolonged loss of consciousness or post-traumatic amnesia, and/or electroencephalographic evidence of brain injury[16]
We report a non-surgical murine model of diffuse, closed-head injury called modCHIMERA. modCHIMERA is based on the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) platform, previously utilized as a model of mild, repetitive TBI24. modCHIMERA was designed to expand the range of injury severities achievable with this platform, by targeting the complicated-mild/ moderate span of the TBI severity spectrum that is responsible for a substantial portion of potentially-reversible TBI-related disability in humans. modCHIMERA is characterized by direct impact followed by semi-restrained linear and rotational acceleration. modCHIMERA incorporates additional key strengths of the CHIMERA platform, namely a highly-reliable, tunable, and monitored injury mechanism of defined energy
Summary
Traumatic brain injury (TBI) occurs in 2.4 million people per year in the United States[1] and has been described by the Centers for Disease Control and Prevention as a ‘silent epidemic’ with an annual cost of $76.5 billion in 20102,3. These definitions stipulate that patients with mild TBI have a Glasgow coma scale (GCS11) of 13–15 and may experience a short period of unconsciousness (in most definitions under 30 minutes) and/or post-traumatic amnesia (generally defined as less than 24 hours), and sometimes additional transient neurological dysfunction. The great majority of mild TBI patients make an excellent recovery Those patients at the complicated-mild end of the spectrum often do significantly worse, with longer return to work times[17] and poorer performance on neuropsychological tests even to 23 years post-injury[16,18]. Patients with complicated-mild TBI bear a disproportionate burden of the impairment attributed to TBI classically defined as mild This burden is shared with moderate and severe TBI patients, groups that are often considered together though they encompass a tremendous range of severities and heterogeneity of injuries. Some have suggested that moderate TBI patients suffer from many of the same pathophysiological processes that characterize severe TBI, but that this subgroup may be more amenable to intervention making them an attractive focus for therapeutic development[20]
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