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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Baron, Corey A.

Abstract

Mild traumatic brain injury (mTBI), also called concussion, has become a significant public health concern. Current clinical neuroimaging techniques lack the sensitivity and specificity required to reliably detect signs of concussion, as large-scale changes are absent. Diffusion magnetic resonance imaging (dMRI) has arguably had the greatest influence to-date of neuroimaging modalities in mTBI, but previous studies have reported inconsistent findings, as standard dMRI lacks specificity and provides a limited model of neuroanatomy. This thesis explores the application of microstructural MR methods, that go beyond standard dMRI to improve sensitivity and specificity, to a preclinical model of mTBI and adult brain maturation. These methods include: frequency-dependent dMRI, which can probe smaller spatial scales than standard dMRI; tensor-valued dMRI, which removes the confound of fiber orientation dispersion on the diffusion measurement; and magnetization transfer saturation (MTsat) MRI, which provides specificity to myelin content.

We first characterize the reproducibility of the microstructural MR metrics applied and provide preclinical sample sizes required to detect relevant effect sizes. Given feasible sample sizes (10-15), tensor-valued and frequency-dependent dMRI metrics may provide sensitivity to subtle microstructural changes (4-8%) and moderate changes (>6%), respectively, while MTsat could detect small changes (in vivoevidence of changes post-mTBI detectable with microstructural MR methods in subacute and chronic stages, while the standard dMRI metrics did not show changes. The sexually dimorphic patterns observed here, both during brain maturation and concussion recovery, may motivate more sex-dependent mTBI research, as females remain underrepresented in mTBI research.

Summary for Lay Audience

Concussion, also known as mild traumatic brain injury (mTBI), has become a significant public health concern, with 200,000 new concussion cases in Canada every year. Many concussion patients develop long-term impairments, and the underlying brain changes remain largely unknown. Unfortunately, current clinical computed tomography (CT) and magnetic resonance imaging (MRI) techniques are unable to detect mTBI, as large-scale changes, such as hemorrhages, are absent. The changes that occur after an mTBI are on the cellular scale and include changes to cell shape and size, loss of myelin (electrical insulator that helps with brain signal transmission), and damage to cells, to name a few. As the presence and resolution of these subtle “microstructural” changes to cells cannot be detected, this results in an inability to predict who will recover completely, who will have long-term impairments, or when it is safe to return to play in contact sports. The 'microstructure' refers to brain tissue components on the micrometer scale, such as cells and axon fibers (pathways through which information is transmitted).

MRI is a good candidate to identify brain microstructural changes due to its strong soft tissue contrast. Conventional MRI techniques lack the specificity and sensitivity required to inform about the distinct pathological changes post-concussion. This thesis explores the capabilities of microstructural MRI methods, which focus on identifying cellular changes, in a mouse model of mTBI and healthy brain maturation. The microstructural MRI methods applied here (1) probe smaller length scales (<5 >µm) than conventionally possible, providing sensitivity to cellular length scales; (2) remove the confounds that can happen when cells are not neatly aligned with each other; (3) provide specificity to myelin content.

During healthy brain maturation, continuing microstructural changes are observed, even after 3 months of age, when mice are considered adults. Overall, the trends observed in conventional metrics are comparable to previous brain maturation studies, while the trajectories of the more advanced metrics provide novel insight. We provide for the first time, in vivo evidence of changes post-mTBI detectable with microstructural MR methods 1-5 months post-mTBI, while the standard metrics did not show changes. This thesis indicates that these microstructural MR techniques have potential to be further optimized to better understand concussion neuropathology and its time-course, and to be applied in clinical settings to study human mTBI.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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