Criteria to define mild, moderate, and severe traumatic brain injury in the mouse controlled cortical impact model

Traumatic brain injury (TBI) is a major health concern in the United States resulting in a substantial number of hospitalizations and in a broad spectrum of symptoms and disabilities. In the clinical setting, neurological responsiveness and structural imaging are used to classify mild, moderate and severe TBI. To evaluate the complex secondary and severity-specific injury response, investigators have relied on pre-clinical rodent models. The controlled cortical impact (CCI) model in mice is a widely used to study TBI. The CCI method has demonstrated consistent intra-laboratory outcomes due to precise control of cortical depth penetration, dwell time and speed of impact. While the CCI method results in control of injury severity, there is no consensus regarding the injury parameters or behavioral and histological endpoints that constitute a mild, moderate or severe TBI in this model. This discrepancy has resulted in considerable variability across laboratories in the outcomes of CCI-induced mild, moderate, and severe TBI. Inconsistent with clinical evaluation, injury severity in the CCI model has predominately relied on the extent of tissue damage. In the present review, we discuss variations in surgical parameters for injury induction as well as the criteria used to determine injury severity. Additionally, we propose guiding principles for the induction and defining of mild, moderate and severe TBI in the craniectomy-dependent experimental mouse CCI model.