How repetitive traumatic injury alters long-term brain function

Abstract

BACKGROUND How recurrent traumatic brain injury (rTBI) alters brain function years after insult is largely unknown. This study aims to characterize the mechanistic cause for long-term brain deterioration following rTBI using a rat model. METHODS Eighteen Sprague-Dawley wild-type rats underwent bilateral rTBI using a direct skull impact device or sham treatment, once per week for 5 weeks, and were euthanized 56 weeks after the first injury. Weekly rotarod performance measured motor deficits. Beam walk and grip strength were also assessed. Brain tissue were stained and volume was computed using Stereo Investigator's Cavalieri Estimator. The L5 cortical layer proximal to the injury site was microdissected and submitted for sequencing with count analyzed using R “DESeq2” and “GOStats.” Brain-derived neurotrophic factor (BDNF) levels were determined using enzyme-linked immunosorbent assay. RESULTS Rotarod data demonstrated permanent deficits 1 year after rTBI. Decreased beam walk performance and grip strength was noted among rTBI rodents. Recurrent traumatic brain injury led to thinner cortex and thinner corpus callosum, enlarged ventricles, and differential expression of 72 genes (25 upregulated, 47 downregulated) including dysregulation of those associated with TBI (BDNF, NR4A1/2/3, Arc, and Egr) and downregulation in pathways associated with neuroprotection and neuroplasticity. Over the course of the study, BDNF levels decreased in both rTBI and sham rodents, and at each time point, the decrease in BDNF was more pronounced after rTBI. CONCLUSION Recurrent traumatic brain injury causes significant long-term alteration in brain health leading to permanent motor deficits, cortical and corpus callosum thinning, and expansion of the lateral ventricles. Gene expression and BDNF analysis suggest a significant drop in pathways associated with neuroplasticity and neuroprotection. Although rTBI may not cause immediate neurological abnormalities, continued brain deterioration occurs after the initial trauma in part due to a decline in genes associated with neuroplasticity and neuroprotection.

Chronic motor performance following different traumatic brain injury severity—A systematic review

“…In contrast, diffuse moderate TBI did produce deficits in grip strength at 28 days post-injury, the latest time point assessed ( 32 , 33 , 101 ). For repeated mild injury, bilateral mTBI weekly for 5 weeks led to impaired grip strength at 40–45 weeks post-injury ( 100 ), whereas 3 impacts 24 h apart led to no deficits at 30 days post-injury, ( 99 ) with these the only time points assessed in these studies. Notably, with the negative result, the average of three trials relative to body weight was recorded ( 99 ), whereas the positive result was only one trial reported as maximum force achieved, introducing a potential confound ( 100 ).…”

“…Grip strength and fine motor ability were assessed via the grip strength meter ( 30 , 93 , 97 – 100 ), isometric pull task ( 33 , 101 ), pellet reaching tasking ( 34 ), and Montoya staircase test ( 94 ) ( Table 4 ). The grip strength meter requires minimal pre-training, whereas the other tasks involve more extensive training with food restriction, with the test relying on the animal's desire to obtain sugar pellets as a reward for completing the task successfully.…”

“…Balance and coordination were the most common motor domains evaluated in preclinical studies via tasks encompassing the balance beam ( 28 , 81 , 83 , 84 , 90 , 96 , 100 , 103 , 111 , 115 – 122 ), ladder, ( 80 , 93 , 99 , 123 ) rotating pole ( 79 , 83 , 114 ), grid walk, ( 31 , 103 ), string suspension ( 124 ), pole climbing ( 99 , 109 ), and rotarod tasks ( 28 , 35 , 36 , 83 , 88 – 90 , 93 , 96 – 98 , 100 , 103 – 106 , 113 – 115 , 119 , 124 – 132 ) ( Table 6 ). The tests conducted varied between studies including variation in the size of the beam and speed of the rotarod and rotating pole.…”

“…In models of repeated mTBI, a higher number of injuries or a shorter interval between injuries were generally associated with more persistent balance deficits. Following 5–7 injuries, chronic deficits on the balance beam, string suspension, and rotarod were noted up to 12 months post-injury ( 100 , 104 , 124 , 125 ), although no deficits were seen by 24 months post-injury ( 36 ). Only the Mannix et al ( 125 , 126 ) and the Mouzon et al ( 35 ) studies failed to find chronic balance deficits following 4–7 impacts.…”

Immunocal® limits gliosis in mouse models of repetitive mild-moderate traumatic brain injury

“…Approximately 80 % of TBIs sustained worldwide are mild in severity ( McCrory et al, 2013 ). Repetitive TBIs (rTBIs), even of mild severity, can prolong and worsen TBI secondary injury ( Fujita et al, 2012 ; Bailes et al, 2013 ; Fehily and Fitzgerald, 2017 ; Mouzon et al, 2018 ; Dhillon et al, 2020 ). Continual treatment of secondary injury is necessary for patients that suffer rmTBI as they may have an increased risk for neurodegeneration ( Faden and Loane, 2015 ; Edwards et al, 2017 ; Gao et al, 2017 ).…”