Behavioral and Structural Effects of Single and Repeat Closed-Head Injury.

Abstract

The effects of multiple head impacts, even without detectable primary injury, on subsequent behavioral impairment and structural abnormality is yet well explored. Our aim was to uncover the dynamic changes and long-term effects of single and repetitive head injury without focal contusion on tissue microstructure and macrostructure. We introduced a repetitive closed-head injury rodent model (n = 70) without parenchymal lesions. We performed a longitudinal MR imaging study during a 50-day study period (T2-weighted imaging, susceptibility-weighted imaging, and diffusion tensor imaging) as well as sequential behavioral assessment. Immunohistochemical staining for astrogliosis was examined in a subgroup of animals. Paired and independent t tests were used to evaluate the outcome change after injury and the cumulative effects of impact load, respectively. There was no gross morphologic evidence for head injury such as skull fracture, contusion, or hemorrhage on micro-CT and MR imaging. A significant decrease of white matter fractional anisotropy from day 21 on and an increase of gray matter fractional anisotropy from day 35 on were observed. Smaller mean cortical volume in the double-injury group was shown at day 50 compared with sham and single injury (P < .05). Behavioral deficits (P < .05) in neurologic outcome, balance, and locomotor activity were also aggravated after double injury. Histologic analysis showed astrogliosis 24 hours after injury, which persisted throughout the study period. There are measurable and dynamic changes in microstructure, cortical volume, behavior, and histopathology after both single and double injury, with more severe effects seen after double injury. This work bridges cross-sectional evidence from human subject and pathologic studies using animal models with a multi-time point, longitudinal research paradigm.