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

Abstract

BACKGROUND AND PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Diffusion Tensor Imaging-Based Studies at the Group-Level Applied to Animal Models of Neurodegenerative Diseases

“…In a similar repeated-hit model, DTI has revealed disruption of axonal integrity in multiple white matter structures, irrespective of microhemorrhage detection (Robinson et al, 2017 ); substantial white matter damage was detected by DTI, together with histological approaches, in juvenile mice subject to repeated mild TBI (Yu et al, 2017 ; Lee et al, 2018 ). Similar alterations have been detected in rat models of repeated TBI (Calabrese et al, 2014 ; Singh et al, 2016 ; Wright et al, 2016 ; Qin et al, 2018 ; Kao et al, 2019 ) as well as in juvenile rat (Fidan et al, 2018 ; Wortman et al, 2018 ; Wright et al, 2018 ) or mouse (Rodriguez-Grande et al, 2018 ; Clément et al, 2020 ) cohorts subject to TBI. A few studies have applied ex-vivo DTI to obtain high-resolution maps of axonal disruption upon TBI, both in mouse (Weiss et al, 2020 ) and in rat (Donovan et al, 2014 ; Laitinen et al, 2015 ) models of brain trauma.…”

The ketone ester, 3-hydroxybutyl-3-hydroxybutyrate, attenuates neurobehavioral deficits and improves neuropathology following controlled cortical impact in male rats

“…Although different neurobehavioral tests have been used to assess functional impairment following TBI and the effectiveness of therapeutic intervention, NSS-R was selected as the main functional outcome in the present study. Assessment of motor and sensory reflexes has been extensively used to evaluate functional impairment following different models of TBI, including fluid percussion injury [36][37][38], blast overpressure [24], closed-head injury [39][40][41][42], and controlled cortical impact [37,[43][44][45][46][47]. Not all these studies used NSS-R; some employed its non-revised version, the Neurological Severity Score (NSS) [40][41][42][43][44] and others selected a few specific tests to assess sensory and motor deficits [37,38,[45][46][47].…”

“…Assessment of motor and sensory reflexes has been extensively used to evaluate functional impairment following different models of TBI, including fluid percussion injury [36][37][38], blast overpressure [24], closed-head injury [39][40][41][42], and controlled cortical impact [37,[43][44][45][46][47]. Not all these studies used NSS-R; some employed its non-revised version, the Neurological Severity Score (NSS) [40][41][42][43][44] and others selected a few specific tests to assess sensory and motor deficits [37,38,[45][46][47]. Nonetheless, TBI-induced sensory and motor deficits is observed in male and female mice [38][39][40]42,46] and rats [36,37,41,[43][44][45]47] up to four weeks after TBI [42,45,46].…”

“…Not all these studies used NSS-R; some employed its non-revised version, the Neurological Severity Score (NSS) [40][41][42][43][44] and others selected a few specific tests to assess sensory and motor deficits [37,38,[45][46][47]. Nonetheless, TBI-induced sensory and motor deficits is observed in male and female mice [38][39][40]42,46] and rats [36,37,41,[43][44][45]47] up to four weeks after TBI [42,45,46]. Our data show the NSS-R total score was positively correlated with and can be predicted from morphological parameters herein investigated.…”

“…Although Yarnell et al did not include descriptive statistics in the manuscript describing NSS-R methodology, the graph provided does show a small increase in total NSS-R score after blast injury relative to baseline [24]. Studies that have used the NSS (non-revised version) to assess neurobehavioral deficits following closed-head injury (CHI) and CCI in rats, also report small changes in scores from 24 h up to 28 days after injury [41,43]. TBI-induced neurobehavioral deficits assessed by NSS and NSS-R partially improve over time and the time points selected for behavioral assessments should be considered when comparing studies [41].…”