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Elderly individuals (65 years and older) represent the fastest-growing demographic of new clinical traumatic brain injury (TBI) cases, yet there is a paucity of preclinical research in aged animals. The limited preclinical work available aligns with the clinical literature in that there appear to be significant differences in pathophysiology, recovery potential, and response to medications between animals at different points across the age spectrum. The aim of this review is to discuss the limited studies and highlight critical age-related differences in affective, cognitive, and neurobehavioral deficits, to discuss factors that influence functional outcomes, and to identify targets for future research. The consensus is that aged rodents face challenges related to dysregulated inflammation, reduced neuroplasticity, and age-related cellular changes, which hinder their recovery after TBI. The most successful intervention studies in animal models to date, of the limited array available, have explored interventions targeting inflammatory downregulation. Current standards of neuropsychopharmacology for post-TBI neurocognitive recovery have not been investigated in a significant capacity. In addition, currently available animal models do not sufficiently account for important age-related comorbidities, dual insults, or differences in TBI mechanism of injury in elderly individuals. TBI in the aged population is more likely to lead to additional neurodegenerative diseases that further complicate recovery. The findings underscore the need for tailored therapeutic interventions to improve outcomes in both adult and elderly populations., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Sixty-nine million traumatic brain injuries (TBIs) are reported worldwide each year, and, of those, close to 3 million occur in the United States. In addition to neurobehavioral and cognitive deficits, TBI induces other maladaptive behaviors, such as agitation and aggression, which must be managed for safe, accurate assessment and effective treatment of the patient. The use of antipsychotic drugs (APDs) in TBI is supported by some expert guidelines, which suggests that they are an important part of the pharmacological armamentarium to be used in the management of agitation. Despite the advantages of APDs after TBI, there are significant disadvantages that may not be fully appreciated clinically during decision making because of the lack of a readily available updated compendium. Hence, the aim of this review is to integrate the existing findings and present the current state of APD use in pre-clinical models of TBI. The studies discussed were identified through PubMed and the University of Pittsburgh Library System search strategies and reveal that APDs, particularly those with dopamine 2 (D 2 ) receptor antagonism, generally impair the recovery process in rodents of both sexes and, in some instances, attenuate the potential benefits of neurorehabilitation. We believe that the compilation of findings represented by this exhaustive review of pre-clinical TBI + APD models can serve as a convenient source for guiding informed decisions by critical care clinicians and physiatrists contemplating APD use for patients exhibiting agitation., Competing Interests: No competing financial interests exist., (© Nicholas S. Race et al., 2023; Published by Mary Ann Liebert, Inc.)

Impaired attention is central to the cognitive deficits associated with long-term sequelae for many traumatic brain injury (TBI) survivors. Assessing complex sustained attention post-TBI is clinically-relevant and may provide reliable avenues towards developing therapeutic and rehabilitation targets in both males and females. We hypothesized that rats subjected to a moderate TBI will exhibit attentional deficits seen as reduced accuracy and increased distractibility in an operant 3-choice serial reaction time task (3-CSRT), designed as an analogue of the clinical continuous performance test. Upon reaching baseline of 70% accuracy at the 300 ms cue, adult male and female Sprague-Dawley rats were subjected to a controlled cortical impact (2.8 mm deformation at 4 m/s) or sham injury over the right parietal cortex. After two weeks of recovery, they were retested on the 3-CSRT for ten days. Dependent measures include percent accuracy (overall and for each of the three cue ports), percent omissions, as well as latency to instrumental poke and retrieve reward. Results demonstrate that both males and females displayed reduced percent accuracy and increased omissions when re-tested post-TBI on 3-CSRT compared to Sham rats and to their own pre-insult baseline (p's < 0.05). Performance accuracy was impaired consistently throughout the ten days of post-surgery re-testing, suggesting pronounced and long-lasting dysfunction in sustained attention processes. Deficits were specifically more pronounced when the cue was pseudorandomly presented in the left-side cue port (p < 0.05), mirroring clinical hemispatial neglect. These data demonstrate significant and persistent complex attention impairments in both sexes after TBI, rendering identifying efficient therapies for cognitive recovery as pivotal., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Second impact syndrome (SIS) is an uncommon, but devastating sports-related structural brain injury that results from a second head injury before complete recovery from an initial concussion. The pathophysiology of second impact syndrome is poorly understood, but is hypothesized to involve loss of autoregulation, diffuse cerebral edema, with progression to rapid brain herniation syndromes. Here, we present a case of second impact syndrome in an adolescent high school football player who experienced acute brain herniation and coma. Following stabilization, the patient underwent comprehensive, multidisciplinary rehabilitation in order to achieve significant recovery. A narrative detailing the patient's recovery from one-year post-injury is reviewed.

Traumatic brain injuries (TBIs) affect more than 10 million patients annually worldwide, causing long-term cognitive and psychosocial impairments. Frontal lobe TBIs commonly impair executive function, but laboratory models typically focus primarily on spatial learning and declarative memory. We implemented a multi-modal approach for clinically relevant cognitive-behavioral assessments of frontal lobe function in rats with TBI and assessed treatment benefits of the serotonin-norepinephrine reuptake inhibitor, milnacipran (MLN). Two attentional set-shifting tasks (AST) evaluated cognitive flexibility via the rats' ability to locate food-based rewards by learning, unlearning, and relearning sequential rule sets with shifting salient cues. Adult male rats reached stable pre-injury operant AST (oAST) performance in 3-4 weeks, then were isoflurane-anesthetized, subjected to a unilateral frontal lobe controlled cortical impact (2.4 mm depth, 4 m/sec velocity) or Sham injury, and randomized to treatment conditions. Milnacipran (30 mg/kg/day) or vehicle (VEH; 10% ethanol in saline) was administered intraperitoneally via implanted osmotic minipumps (continuous infusions post-surgery, 60 μL/h). Rats had a 10-day recovery post-TBI/Sham before performing light/location-based oAST for 10 days and, subsequently, odor/media-based digging AST (dAST) on the last test day (26-27 days post-injury) before sacrifice. Both AST tests revealed significant deficits in TBI+VEH rats, seen as elevated total trials and errors ( p  < 0.05), which generally normalized in MLN-treated rats ( p  < 0.05). This first simultaneous dual AST assessment demonstrates oAST and dAST are sufficiently sensitive and robust to detect subtle attentional and cognitive flexibility executive impairments after frontal lobe TBI in rats. Chronic MLN administration shows promise for attenuation of post-TBI executive function deficits, thus meriting further investigation.