Functional MRI characterization of animal models of parkinsonism

Parkinson's disease (PD) is the second most common neurological disorder. It is characterized by the progressive development of motor symptoms - bradykinesia, resting tremor, muscular rigidity and difficulty with postural control - which serve as criterias for its clinical diagnosis. However, there is a need for biomarkers to detect PD early before the appearance of the symptoms, but also to evaluate efficacy of treatments. Such biomarkers would also to evaluate the translational value of models of the disease. In recent years, magnetic resonance imaging (MRI) has been used by researchers to identify biomarkers of PD in the patients' brain. One MRI method that is gradually becoming more popular is resting-state functional MRI (rs-fMRI). It consists in tracking the activity of brain by acquiring the MRI signal of the brain over time for several minutes while the patient is at rest, i.e. when he/she tries not to think about anything in particular. Compared to task-based fMRI, it is advantageous for studying PD as patients have problems to perform tasks, both because of motor symptoms but also cognitive symptoms which are common in PD.

In this thesis, after successfully demonstrating the translational value of rs-fMRI by comparing a set of functional networks in naive Sprague-Dawley and healthy human subjects (paper I), several rat models of parkinsonism were characterized. These models consisted in a well-established model, the unilateral 6-hydroxydopamine (6-OHDA) model (paper II), and two progressive models of parkinsonism, the alpha-synuclein adeno-associated virus overexpression model, a genetic model (paper III), and the β-sitosterol-β-D-glucoside model, a new toxin-based model (paper IV). By acquiring rs-fMRI datasets and analysing them using seed-based correlation analysis, functional connectivity maps were generated. We could reproducibly demonstrate that sensorimotor corticostriatal functional connectivity is increased in the 6-OHDA lesioned animals compared to their control counterparts, while in models with milder parkinsonian pathology, the sensorimotor corticostriatal functional connectivity is decreased. We therefore emit the hypothesis that there is a U-shaped function describing corticostriatal functional connectivity relative to the level of striatal dopaminergic innervation. We also observed in both models of mild parkinsonism a reinforcement of negative functional connectivity between the prefrontal cortex, in particular the orbital cortex, and the primary somatosensory cortex compared to their healthy counterparts.

These results demonstrate that rs-fMRI is a valid method to observe alterations in the brain related to parkinsonism in animals and that both motor and non-motor areas of the brain are affected by the loss of dopaminergic neurons. Further investigations must be conducted to understand the mechanisms involved in these changes and evaluate their translational value.

List of scientific papers

I. Default Mode Network, Motor Network, Dorsal and Ventral Basal Ganglia Networks in the Rat Brain: Comparison to Human Networks Using Resting State-fMRI. A. Sierakowiak, C. Monnot, S. NikkhouAski, M. Uppman, T.Q. Li, P. Damberg and S. Brené. (2015). PLoS One. 10(3):e0120345.
https://doi.org/10.1371/journal.pone.0120345

II. Asymmetric dopaminergic degeneration and levodopa alter functional corticostriatal connectivity bilaterally in experimental parkinsonism. C. Monnot, X. Zhang, S. Nikkhou-Aski, P. Damberg and P. Svenningsson. (2017). Experimental Neurology. 292: 11-20.
https://doi.org/10.1016/j.expneurol.2017.02.014

III. Overexpression of human alpha-synuclein in the Substantia Nigra of rats alters functional connectivity in motor and default mode networks. C. Monnot, J. Zareba-Paslawska, J. Perens, P. Damberg and P. Svenningsson. [Manuscript]

IV. Resting-state functional MRI characterization of the beta sitosterol betaD-glucoside rat model of parkinsonism. C. Monnot, M. Kalomoiri, P. Damberg, J.M. Van Kampen, H. Robertson and P. Svenningsson. [Manuscript]