Scott Fujimoto

Motor and cognitive function evaluation following experimental traumatic brain injury

Traumatic brain injury (TBI) in humans may cause extensive sensorimotor and cognitive dysfunction. As a result, many TBI researchers are beginning to assess behavioral correlates of histologically determined damage in animal models. Although this is an important step in TBI research, there is a need for standardization between laboratories. The ability to reliably test treatments across laboratories and multiple injury models will close the gap between treatment success in the lab and success in the clinic. The goal of this review is to describe and evaluate the tests employed to assess functional outcome after TBI and to overview aspects of cognitive, sensory, and motor function that may be suitable targets for therapeutic intervention.

Temporal window of vulnerability to repetitive experimental concussive brain injury.

OBJECTIVE:Repetitive concussive brain injury (CBI) is associated with cognitive alterations and increased risk of neurodegenerative disease. METHODS:To evaluate the temporal window during which the concussed brain remains vulnerable to a second concussion, anesthetized mice were subjected to either sham injury or single or repetitive CBI (either 3, 5, or 7 days apart) using a clinically relevant model of CBI. Cognitive, vestibular, and sensorimotor function (balance and coordination) were evaluated, and postmortem histological analyses were performed to detect neuronal degeneration, cytoskeletal proteolysis, and axonal injury. RESULTS:No cognitive deficits were observed in sham-injured animals or those concussed once. Mice subjected to a second concussion within 3 or 5 days exhibited significantly impaired cognitive function compared with either sham-injured animals (P < 0.05) or mice receiving a single concussion (P < 0.01). No cognitive deficits were observed when the interconcussion interval was extended to 7 days, suggestive of a transient vulnerability of the brain during the first 5 days after an initial concussion. Although all concussed mice showed transient motor deficits, vestibulomotor dysfunction was more pronounced in the group that sustained two concussions 3 days apart (P < 0.01 compared with all other groups). Although scattered degenerating neurons, evidence of cytoskeletal damage, and axonal injury were detected in selective brain regions between 72 hours and 1 week after injury in all animals sustaining a single concussion, the occurrence of a second concussion 3 days later resulted in significantly greater traumatic axonal injury (P < 0.05) than that resulting from a single CBI. CONCLUSION:These data suggest that a single concussion is associated with behavioral dysfunction and subcellular alterations that may contribute to a transiently vulnerable state during which a second concussion within 3 to 5 days can lead to exacerbated and more prolonged axonal damage and greater behavioral dysfunction.

Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

Traumatic brain injury is a well‐recognized environmental risk factor for developing Alzheimers disease. Repetitive concussive brain injury (RCBI) exacerbates brain lipid peroxidation, accelerates amyloid (Aβ) formation and deposition, as well as cognitive impairments in Tg2576 mice. This study evaluated the effects of vitamin E on these four parameters in Tg2576 mice following RCBI. Eleven‐month‐old mice were randomized to receive either regular chow or chow‐supplemented with vitamin E for 4 weeks, and subjected to RCBI (two injuries, 24 h apart) using a modified controlled cortical impact model of closed head injury. The same dietary regimens were maintained up to 8 weeks post‐injury, when the animals were killed for biochemical and immunohistochemical analyses after behavioral evaluation. Vitamin E‐treated animals showed a significant increase in brain vitamin E levels and a significant decrease in brain lipid peroxidation levels. After RBCI, compared with the group on regular chow, animals receiving vitamin E did not show the increase in Aβ peptides, and had a significant attenuation of learning deficits. This study suggests that the exacerbation of brain oxidative stress following RCBI plays a mechanistic role in accelerating Αβ accumulation and behavioral impairments in the Tg2576 mice.

Hippocampal vulnerability following traumatic brain injury: a potential role for neurotrophin-4/5 in pyramidal cell neuroprotection.

Traumatic brain injury (TBI) causes selective hippocampal cell death, which is believed to be associated with cognitive impairment observed both in clinical and experimental settings. Although neurotrophin administration has been tested as a strategy to prevent cell death following TBI, the potential neuroprotective role of neurotrophin‐4/5 (NT‐4/5) in TBI remains unknown. We hypothesized that NT‐4/5 would offer neuroprotection for selectively vulnerable hippocampal neurons following TBI. Measurements of NT‐4/5 in rats subjected to lateral fluid percussion (LFP) TBI revealed two–threefold increases in the injured cortex and hippocampus in the acute period (1–3 days) following brain injury. Subsequently, the response of NT‐4/5 knockout (NT‐4/5–/–) mice to controlled‐cortical impact TBI was investigated. NT‐4/5–/– mice were more susceptible to selective pyramidal cell loss in Ahmons corn (CA) subfields of the hippocampus following TBI, and showed impaired motor recovery when compared with their brain‐injured wild‐type controls (NT‐4/5wt). Additionally, we show that acute, prolonged administration of recombinant NT‐4/5 (5 µg/kg/day) prevented up to 50% of the hippocampal CA pyramidal cell death following LFP TBI in rats. These results suggest that post‐traumatic increases in endogenous NT‐4/5 may be part of an adaptive neuroprotective response in the injured brain, and that administration of this neurotrophic factor may be useful as a therapeutic strategy following TBI.

Differential effects of the anticonvulsant topiramate on neurobehavioral and histological outcomes following traumatic brain injury in rats

The efficacy of topiramate, a novel therapeutic agent approved for the treatment of seizure disorders, was evaluated in a model of traumatic brain injury (TBI). Adult male rats were anesthetized (sodium pentobarbital, 60 mg/kg, i.p.), subjected to lateral fluid percussion brain injury (n = 60) or sham injury (n = 47) and randomized to receive either topiramate or vehicle at 30 min (30 mg/kg, i.p.), and 8, 20 and 32 h postinjury (30 mg/kg, p.o.). In Study A, memory was evaluated using a Morris water maze at 48 h postinjury, after which brain tissue was evaluated for regional cerebral edema. In Study B, animals were evaluated for motor function at 48 h and 1, 2, 3, and 4 weeks postinjury using a composite neuroscore and the rotating pole test and for learning ability at 4 weeks. Brains were analyzed for hemispheric tissue loss and hippocampal CA3 cell loss. Topiramate had no effect on posttraumatic cerebral edema or histologic damage when compared to vehicle. At 48 h, topiramate treatment improved memory function in sham but not brain-injured animals, while at one month postinjury it impaired learning performance in brain-injured but not sham animals. Topiramate significantly improved composite neuroscores at 4 weeks postinjury and rotating pole performance at 1 and 4 weeks postinjury, suggesting a potentially beneficial effect on motor function following TBI.

Corrigendum to “Motor and cognitive function evaluation following experimental traumatic brain injury” [Neurosci. Biobehav. Rev. 28 (2004) 365–378]

0149-7634/

Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model.

- see front matter Published by Elsevier Ltd.doi:10.1016/j.neubiorev.2004.10.002Neuroscience and Biobehavioral Reviews 28 (2005) 877www.elsevier.com/locate/neubiorevDOI of original article 10.1016/j.neubiorev.2004.06.002* Corresponding author. Tel.: C1 215 573 2871; fax: C1 215 573 3808.E-mail address: tkm53@comcast.net (T.K. McIntosh).