Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Bartha, Robert

Affiliation

Robarts Research Institute

Abstract

After a concussion there is a complex cascade of events, termed the neurometabolic cascade, that includes changes in ion flux, neurotransmission, and cellular energetics. How this pathophysiological process translates into cognitive deficits remains poorly understood. Magnetic resonance spectroscopy (MRS) provides a non-invasive technique that allows for the quantification of brain metabolites that are involved in these processes, including glutamate and glutamine, which are involved in neurotransmission. Moreover, female athletes are underrepresented in studies on concussion, limiting our knowledge and understanding of sex differences. The overall goal of this thesis was to examine metabolite changes using MRS in female athletes before and after concussion, with the added goal of quantifying glutamate and glutamine separately. The second objective was to replicate metabolite changes in an animal model of concussion, to position future studies to probe the reasons for these changes, and to explore whether these changes represent potential therapeutic targets.

MRS was acquired from the prefrontal WM of female athletes (contact and non-contact sports) and sedentary women at 3T to explore metabolite differences between groups and changes after concussion. In addition, an animal model of repeated closed head impacts was studied at 9.4T, in an effort to replicate the findings observed in humans.

In the contact athlete cohort, reduced glutamine and glutamine/total creatine (Gln/Cr) were found following concussion, and after a season of play in non-concussed athletes. In the non-contact athlete cohort, metabolite levels did not change over the course of a season, and they did not differ from age matched sedentary women, except for a small difference in myo-inositol. Most interestingly, glutamine levels were significantly elevated in contact athletes compared to sedentary and non-contact groups, suggesting that sub-concussive impacts may have a long-term effect on brain metabolite levels. Furthermore, the large difference in glutamine levels between contact and non-contact athletes has implications in study design in regards to control groups versus test-retest paradigm.

In the final study, we used a murine model (C57BL6) of repeated closed head injury to investigate metabolite level changes post-injury. Elevated Gln/Cr was observed 10-weeks post-injury, suggesting that the model may be appropriate to study sub-concussive injury.

Together, these studies suggest that there exists a cumulative effect on the brain from sub-concussive impacts in contact sports, that manifests as elevated glutamine levels. Moreover, concussion in the same cohort of athletes results in reduced glutamine levels. Further work aimed at replicating these findings in animal models will be crucial to understanding the effects of cumulative impacts and concussion.

Summary for Lay Audience

After a concussion there is a complex cascade of events, termed the neurometabolic cascade, that includes changes in ion flux, neurotransmission, and cellular energetics. How this process translates into cognitive deficits remains poorly understood. Magnetic resonance spectroscopy (MRS) provides a non-invasive technique that allows for the quantification of brain metabolites that are involved in these processes, including glutamate and glutamine, which are involved in neurotransmission. Moreover, female athletes are underrepresented in studies on concussion, limiting our knowledge and understanding of sex differences. The overall goal of this thesis was to examine metabolite changes using MRS in female athletes before and after concussion, with the added goal of quantifying glutamate and glutamine separately. The second objective was to replicate metabolite changes in an animal model of concussion, to position future studies to probe the reasons for these changes, and to explore whether these changes represent potential therapeutic targets.

MRS was acquired from the prefrontal white matter of female athletes (contact and non-contact sports) and sedentary women to explore metabolite differences between groups and changes after concussion. In the non-contact athlete cohort, metabolite levels did not change over the course of a season, and they did not differ from age matched sedentary women, except for a small difference in myo-inositol. Most interestingly, glutamine levels were significantly elevated in these contact athletes compared to sedentary and non-contact groups, suggesting that sub-concussive impacts may have a long-term effect on brain metabolite levels. Moreover, reduced glutamine levels were found following concussion in the contact cohort.

In the final study, we used a mouse model of repeated closed head injury to investigate metabolite level changes post-injury. Elevated Glutamine/Creatine was observed 10-weeks post-injury, suggesting that the model may be appropriate to study sub-concussive injury.

Together, these studies suggest that there exists a cumulative effect on the brain from sub-concussive impacts in contact sports, that manifests as elevated glutamine levels. Moreover, concussion in the same cohort of athletes results in reduced glutamine levels. Further work aimed at replicating these findings in animal models will be crucial to understanding the effects of cumulative impacts and concussion.

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