Objective: To examine in-vivo functional connectivity and free-water diffusion imaging in dystonic mutant Tor1a knock-in (DYT1) and wild-type (WT) control mice. We test the hypothesis that striatal and sensory circuits are functionally and structurally abnormal in the DYT1 mouse model.

Background: Human DYT1 dystonia is characterized by sustained and involuntary muscle contractions resulting in twisting, repetitive movements and disabling posture. DYT1 is an inherited movement disorder caused by a trinucleotide (ΔGAG) deletion encoding a glutamic acid residue in the TorsinA protein. In the in-vivo DYT1 mouse model, a reduction in dopamine receptor binding results in impaired cortico-striatal inhibitory control and long-term depression deficit. Previous imaging studies have shown that the DYT1 mouse model is associated with increased metabolic activity in the cerebellar vermis in-vivo, and reduced structural integrity of the fiber tracts linking cerebellum and cortex ex-vivo. To our knowledge, no previous research has examined both functional connectivity and free-water of DYT1 dystonia in-vivo.

Methods: We used in-vivo resting-state functional and diffusion MRI at 11 Tesla to examine functional connectivity and extracellular free-water differences in 20 DYT1 and 19 WT mice. Temporally correlated blood oxygenation level dependent signal fluctuations and functional connectivity were examined using an independent component analysis, whereas a bi-tensor diffusion analysis model was employed to evaluate free-water diffusion imaging.

Results: DYT1 mice exhibited increased functional connectivity in the right striatum, right thalamus, and right somatosensory cortex – and increased free-water in the right striatum and cerebellar vermis compared to WT. A support vector machine classification algorithm that combined functional connectivity and free-water values in a training cohort of 15 DYT1 and 15 WT mice rendered a classification accuracy of approximately 98%, and 8 of 9 mice were accurately classified in an independent cohort.

Conclusions: DYT1 mice evidenced increased functional connectivity in the striatum, thalamus, and somatosensory cortex, and elevated free-water in the striatum and cerebellum. These effects were robust in the classification algorithm in a large cohort of mice. Thus, it is clear that mutant torsinA impairs the cortical, striatal, and cerebellar regions in living mice.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/in-vivo-free-water-imaging-and-functional-connectivity-in-a-knock-in-mouse-model-of-dyt1-dystonia/