Dissertations, Theses, and Capstone Projects

Date of Degree

6-2026

Document Type

Master's Thesis

Degree Name

Master of Science

Program

Cognitive Neuroscience

Advisor

Peter Serrano

Committee Members

David Johnson

Tony Ro

Subject Categories

Applied Statistics | Behavioral Neurobiology | Cognition and Perception | Cognitive Neuroscience | Computational Neuroscience | Disease Modeling | Epidemiology | Mental Disorders | Nervous System Diseases | Other Psychiatry and Psychology | Psychiatric and Mental Health | Statistical Methodology | Statistical Models | Statistical Theory | Translational Medical Research

Keywords

Rat TBI, Levetiracetam, Predictive Coding, Spatial Working Memory and Anxiety, RAM and EPM, Multiple Linear Regression Analysis

Abstract

Traumatic brain injury (TBI) symptom prevention and remediation is an important area of research that would benefit vulnerable groups, including active-duty and veteran soldiers. These patients can sustain penetrative forces in fields of combat or in training, which result in focal lesions that trigger inflammatory and degenerative processes in the brain. Both primary and secondary injuries are associated with changes to cognition, behavior and affective state. This disease poses increased risk of epileptogenesis, as well. Given these outcomes, prior research has evaluated levetiracetam (LEV) as a prophylactic treatment for seizures, cognitive deficits and negative emotionality. LEV acts as a presynaptic vesicle glycoprotein 2A inhibitor. It is used to treat seizures by keeping glutamate within the presynaptic cell. Reducing glutamatergic dysregulation with LEV can help prevent deficits related to secondary TBI.

The primary aim of this research was to investigate whether the prophylactic administration of 150 mg/kg of LEV 15 minutes prior to TBI can mitigate working memory deficits and anxiety-like behaviors during the five-week post-injury phase. We hypothesized that pre-injury administration of LEV would prevent or reduce these TBI-induced deficits. Using the controlled cortical impact model in male Sprague-Dawley rats, animals were randomly assigned to one of three groups: No TBI (saline), TBI (saline) and TBI+LEV groups. Spatial working memory was assessed with the radial arm maze (RAM). Performance was qualified by the percentage of working memory errors, which accounts for repeated arm entries as well as successful completion of all 8 arms. Anxiety-like behavior was evaluated by rodent performance on the elevated plus maze (EPM). The time spent in open and closed arms, as well as the frequency of open and closed arm entries, were recorded for this behavioral test.

Memory research applying computational frameworks to study episodic memory had influenced the adaptation of predictive coding theory to explain trends in spatial working memory tasks. Predictive coding suggests that cortical models of the contextual environment can influence behaviors and internal adaptative processes if these models lose their ability to accurately predict online experiences or if these experiences become less reliable. In practice, this means that experimental animals realize they had made a working memory error or that they become unsure of the sequence of arms they had attempted. Thus, TBI related deficits can be seen as inappropriate assignments of uncertainty. LEV prophylaxis can work to ameliorate these assignments and reduce anxiety.

The results of this paper suggest that TBI affects working memory performances under cognitive load and increases anxiety behaviors. TBI+LEV animals showed better arms five to eight performances than No TBI (saline) and TBI (saline) animals. TBI+LEV animals also spent more time in open arms. It seems that groups acquired a negative performance bias that resulted from No TBI and TBI procedures. TBI altered uncertainty assignments such that animals did not trust their ability to continue meeting the demands of new or changing environments. LEV acted as both an anxiolytic and nootropic by increasing time spent in open EPM arms, which is indicative of reduced anxiety, and improving performance expectations under conditions of uncertainty. Correlation analysis suggested multiple factors that may contribute to TBI (saline) and TBI+LEV performances, necessitating multiple linear regression analysis. The statistical models created to determine how well the predictive coding framework can explain total working memory scores suggested that the RAM can be used to study working memory under conditions of uncertainty, that animals seemed to suffer from both predictive error and generative model uncertainty, and that LEV specifically improved working memory under cognitive load. This drug effect seems to be the result of increased reassurance in the animal’s ability to navigate scenarios of uncertainty.

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