Ex vivo 100 µm isotropic diffusion MRI-based tractography of connectivity changes in the end-stage R6/2 mouse model of Huntington's disease.

Background: Huntington's disease is a progressive neurodegenerative disorder. Brain atrophy, as measured by volumetric magnetic resonance imaging (MRI), is a downstream consequence of neurodegeneration, but microstructural changes within brain tissue are expected to precede this volumetric decline. The tissue microstructure can be assayed non-invasively using diffusion MRI, which also allows a tractographic analysis of brain connectivity. Methods: We here used ex vivo diffusion MRI (11.7 T) to measure microstructural changes in different brain regions of end-stage (14 weeks of age) wild type and R6/2 mice (male and female) modeling Huntington's disease. To probe the microstructure of different brain regions, reduce partial volume effects and measure connectivity between different regions, a 100 µm isotropic voxel resolution was acquired. Results: Although fractional anisotropy did not reveal any difference between wild-type controls and R6/2 mice, mean, axial, and radial diffusivity were increased in female R6/2 mice and decreased in male R6/2 mice. Whole brain streamlines were only reduced in male R6/2 mice, but streamline density was increased. Region-to-region tractography indicated reductions in connectivity between the cortex, hippocampus, and thalamus with the striatum, as well as within the basal ganglia (striatum-globus pallidus-subthalamic nucleus-substantia nigra-thalamus). Conclusions: Biological sex and left/right hemisphere affected tractographic results, potentially reflecting different stages of disease progression. This proof-of-principle study indicates that diffusion MRI and tractography potentially provide novel biomarkers that connect volumetric changes across different brain regions. In a translation setting, these measurements constitute a novel tool to assess the therapeutic impact of interventions such as neuroprotective agents in transgenic models, as well as patients with Huntington's disease.

Mesoscale diffusion magnetic resonance imaging of the ex vivo human hippocampus.

Mesoscale diffusion magnetic resonance imaging (MRI) endeavors to bridge the gap between macroscopic white matter tractography and microscopic studies investigating the cytoarchitecture of human brain tissue. To ensure a robust measurement of diffusion at the mesoscale, acquisition parameters were arrayed to investigate their effects on scalar indices (mean, radial, axial diffusivity, and fractional anisotropy) and streamlines (i.e., graphical representation of axonal tracts) in hippocampal layers. A mesoscale resolution afforded segementation of the pyramidal cell layer (CA1-4), the dentate gyrus, as well as stratum moleculare, radiatum, and oriens. Using ex vivo samples, surgically excised from patients with intractable epilepsy (n = 3), we found that shorter diffusion times (23.7 ms) with a b-value of 4,000 s/mm2 were advantageous at the mesoscale, providing a compromise between mean diffusivity and fractional anisotropy measurements. Spatial resolution and sample orientation exerted a major effect on tractography, whereas the number of diffusion gradient encoding directions minimally affected scalar indices and streamline density. A sample temperature of 15°C provided a compromise between increasing signal-to-noise ratio and increasing the diffusion properties of the tissue. Optimization of the acquisition afforded a system's view of intra- and extra-hippocampal connections. Tractography reflected histological boundaries of hippocampal layers. Individual layer connectivity was visualized, as well as streamlines emanating from individual sub-fields. The perforant path, subiculum and angular bundle demonstrated extra-hippocampal connections. Histology of the samples confirmed individual cell layers corresponding to ROIs defined on MR images. We anticipate that this ex vivo mesoscale imaging will yield novel insights into human hippocampal connectivity.

Association Between Duration of Untreated Psychosis and Frontostriatal Connectivity During Maintenance of Visuospatial Working Memory.

BACKGROUND: A longer duration of untreated psychosis (DUP) has been linked with poor clinical outcomes and variation in resting-state striatal connectivity with central executive regions. However, the link between DUP and task-based activation of executive neurocognition has not previously been examined. This functional magnetic resonance imaging study examined the association between DUP and both activation and frontostriatal functional connectivity during a visual working memory (WM) paradigm in patients with first-episode psychosis. METHODS: Patients with first-episode psychosis (n = 37) underwent functional magnetic resonance imaging scanning while performing a visual WM task. At the single-subject level, task conditions were modeled; at the group level, each condition was examined along with DUP. Activation was examined within the dorsolateral prefrontal cortex, a primary region supporting visual WM activation. Frontostriatal functional connectivity during the WM was examined via psychophysical interaction between the dorsal caudate and the dorsolateral prefrontal cortex. Results were compared with a reference range of connectivity values in a matched group of healthy volunteers (n = 25). Task performance was also examined in relation to neuroimaging findings. RESULTS: No significant association was observed between DUP and WM activation. Longer DUP showed less functional frontostriatal connectivity with the maintenance of increasing WM load. Results were not related to task performance measures, consistent with previous work. CONCLUSIONS: Our data suggest that DUP may affect frontostriatal circuitry that supports executive functioning. Future work is necessary to examine if these findings contribute to the mechanism underlying the relationship between DUP and worsened clinical outcomes.