Introduction

An altered brain connectivity is present in a variety of neurologic and psychiatric conditions, yet identifying affected pathways in animal models remains difficult. High spatial and angular resolution are required for dissecting vulnerable pathways and networks, but these requirements need to be balanced against time and cost. Here we simulated the effect of relaxing acquisition parameters on the accuracy of the reconstructed tracts and connectome, with reference to a high spatial and angular resolution protocol1. Our results can inform population studies for models of neurodegenerative disease.

Methods

We produced simulations based on a published data set, acquired on a 9.4 T small animal imaging system controlled by an Agilent VnmrJ4 console1. We used a 3D diffusion-weighted spin-echo pulse sequence with repetition time (TR) = 100 ms, echo time (TE) = 15 ms, 568 ´ 284 ´ 228 matrix, 24.4´12.2 ´9.8 mm field of view, reconstructed at 43 µm resolution. 120 diffusion directions2, 3 were acquired using bvalues of 4000 s/mm2 , interspersed with 11 non-diffusion-weighted (b0) measurements. Angular downsampling of the diffusion data was performed by obtaining the optimal diffusion directions for each angular subset2, 3 and extracting the closest gradient vector from the 120 unique directions. The closest gradient was chosen by maximizing the dot product between the optimal gradient vector and the possible vectors found in the original gradient table. Spatial downsampling was performed in k space, resulting in 3 levels of isotropic resolution: 43, 86,172 µm. Data processing was done on a high-performance computing cluster with 96 physical cores and 1.5 TB of RAM. All 131 image volumes were affinely registered to the first b0 image using Advanced Normalization Tools (ANTs)4 to correct for eddy current distortions. Scalar volumes were reconstructed using FSL’s DTIFIT5. Fiber data for probabilistic tractography were reconstructed using FSL’s BEDPOSTX6 with maximum four fiber orientations/voxel. Atlas-based segmentation7 relied on a symmetric 332 regions atlas, combining the Waxholm atlas8 for subcortical labels, and the Ullmann atlas of the neocortex 9. Connectomes were constructed using SAMBA10, and DSIStudio11.

Results

Down sampled diffusion data sets were used to estimate the total number of fibers per voxel in each set (Fig. 1). At each down sampling of diffusion directions there was a slight decrease in calculated fibers but the largest change occurred below 45 directions. We focused our analysis on the hippocampus, septum, hypothalamus and the lateral geniculate for gray matter, and we selected the fimbria and fornix as white matter regions relevant to Alzheimer’s disease (AD). A qualitative evaluation of the fimbria tract density maps reconstructed from 12 directions did not capture the cortical-cortical connectivity with the same sensitivity as the 45 or 120 direction schemes (Fig 2). Our quantitative analysis of the dyad dispersion (Fig 3) showed that errors decayed as the number of angular samples increases, and increased as we relaxed the spatial resolution. Probabilistic tractography was used to generate connectivity matrices between the selected regions at 43 µm (Fig. 4). While the correlation between the three connectivity matrices was always significant (p<0.001), the values increased from 0.65 for the Spearman correlation between 12 and 120 directions; to 0.76 between 12 and 45 directions and to 0.90 between 45 and 120 directions. Moreover, we computed the pairwise graph similarity for these subgraphs (Fig 4B), thresholding at 0.05 to illustrate the differences in sparsity, which is lowest in between the 45 and 120 directions sets. The sensitivity to capturing connectivity of smaller region is evident in the chord diagrams (Fig 4C) which are sparser for 12 directions relative to 45, and 120 directions. Our results support that angular and spatial resolution need to be balanced with respect to time and cost demands to enable population studies, and recommend parameters for efficient protocols with minimum loss of sensitivity.

Discussion and Conclusion

Our previous study produced a diffusion MRI data set with the highest reported resolution for the whole mouse brain12, with a scan time of 235 hours. Replicating this acquisition for population studies has prohibitive cost and time. To address this problem, we must develop techniques that produce similar outcomes to our reference protocol, but with greatly reduced time. In our simulations, we found that 45-60 angular samples and 43 or 86 µm spatial resolution achieved a good tradeoff between cost and performance. We evaluated regions of interest in Alzheimer’s research, from hippocampus (5% of brain volume) to fimbria and fornix (0.05% of brain volume 13). Our study can inform the design of future experiments for statistical connectomics in mouse models of neurological conditions, such as AD.

Acknowledgements

NIH awards K01 AG041211 (Badea), P41 EB015897 and 1S10OD010683-01 (Johnson).

References

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