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Diffusion MRI streamlines tractography has become a major technique for inferring structural networks through reconstruction of brain connectome. However, quantification of structural connectivity based on the number of streamlines interconnecting brain grey matter regions is known to be problematic in a number of aspects, such as the ill-posed nature of streamlines terminations and the non-quantitative nature of streamline counts. This study investigates the effects of state-of-the-art connectome construction methods on the subsequent analyses of structural brain networks using graph theoretical approaches. Our results demonstrate that the characteristics of structural connectivity, including connectome variability, global network metrics, small-world attributes and network hubs, alter significantly following the improvement in biological accuracy of streamlines tractograms provided by anatomically-constrained tractography (ACT) and spherical-deconvolution informed filtering of tractograms (SIFT). Importantly, the commonly-used correction for connection density based on scaling the contribution of each streamline to the connectome by its inverse length is shown to provide incomplete correction, highlighting the necessity for the use of advanced tractogram reconstruction techniques in structural connectomics research.

When using diffusion MRI streamlines tractograms to construct structural connectomes, ideally, each streamline should connect exactly 2 regions-of-interest (i.e. network nodes) as defined by a given brain parcellation scheme. However, the ill-posed nature of termination criteria in many tractography algorithms can cause streamlines apparently being associated with zero, one, or more than two grey matter (GM) nodes; streamlines that terminate in white matter or cerebrospinal fluid may even end up being assigned to nodes if the definitions of these nodes are not strictly constrained to genuine GM areas, resulting in a misleading connectome in non-trivial ways. Based on both in-house MRI data and state-of-the-art data provided by the Human Connectome Project, this study investigates the actual influence of streamline-to-node assignment methods, and their interactions with fibre-tracking terminations and brain parcellations, on the construction of pairwise regional connectivity and subsequent connectomic measures. Our results show that the frequency of generating successful pairwise connectivity is heavily affected by the convoluted interactions between the applied strategies for connectome construction, and that minor changes in the mechanism can cause significant variations in the within- and between-module connectivity strengths as well as in the commonly-used graph theory metrics. Our data suggest that these fundamental processes should not be overlooked in structural connectomics research, and that improved data quality is not in itself sufficient to solve the underlying problems associated with assigning streamlines to brain nodes. We demonstrate that the application of advanced fibre-tracking techniques that are designed to correct for inaccuracies of track terminations with respect to anatomical information at the fibre-tracking stage is advantageous to the subsequent connectome construction process, in which pairs of parcellation nodes can be more robustly identified from streamline terminations via a suitable assignment mechanism.

Recent advances in diffusion MRI tractography permit the generation of dense weighted structural connectomes that offer greater insight into brain organization. However, these efforts are hampered by the lack of consensus on how to extract topological measures from the resulting graphs. Here we evaluate the common practice of removing the graphs' weak connections, which is primarily intended to eliminate spurious connections and emphasize strong connections. Because this processing step requires arbitrary or heuristic-based choices (e.g., setting a threshold level below which connections are removed), and such choices might complicate statistical analysis and inter-study comparisons, in this work we test whether removing weak connections is indeed necessary. To this end, we systematically evaluated the effect of removing weak connections on a range of popular graph-theoretical metrics. Specifically, we investigated if (and at what extent) removal of weak connections introduces a statistically significant difference between two otherwise equal groups of healthy subjects when only applied to one of the groups. Using data from the Human Connectome Project, we found that removal of weak connections had no statistical effect even when removing the weakest ∼70-90% connections. Removing yet a larger extent of weak connections, thus reducing connectivity density even further, did produce a predictably significant effect. However, metric values became sensitive to the exact connectivity density, which has ramifications regarding the stability of the statistical analysis. This pattern persisted whether connections were removed by connection strength threshold or connectivity density, and for connectomes generated using parcellations at different resolutions. Finally, we showed that the same pattern also applies for data from a clinical-grade MRI scanner. In conclusion, our analysis revealed that removing weak connections is not necessary for graph-theoretical analysis of dense weighted connectomes. Because removal of weak connections provides no practical utility to offset the undesirable requirement for arbitrary or heuristic-based choices, we recommend that this step is avoided in future studies.

Diffusion-weighted imaging can potentially be used to infer the connectivity of the human brain in vivo using fibre-tracking techniques, and is therefore of great interest to neuroscientists and clinicians. A key requirement for fibre tracking is the accurate estimation of white matter fibre orientations within each imaging voxel. The diffusion tensor model, which is widely used for this purpose, has been shown to be inadequate in crossing fibre regions. A number of approaches have recently been proposed to address this issue, based on high angular resolution diffusion-weighted imaging (HARDI) data. In this study, an experimental model of crossing fibres, consisting of water-filled plastic capillaries, is used to thoroughly assess three such techniques: constrained spherical deconvolution (CSD), super-resolved CSD (super-CSD) and Q-ball imaging (QBI). HARDI data were acquired over a range of crossing angles and b-values, from which fibre orientations were computed using each technique. All techniques were capable of resolving the two fibre populations down to a crossing angle of 45 degrees , and down to 30 degrees for super-CSD. A bias was observed in the fibre orientations estimated by QBI for crossing angles other than 90 degrees, consistent with previous simulation results. Finally, for a 45 degrees crossing, the minimum b-value required to resolve the fibre orientations was 4000 s/mm(2) for QBI, 2000 s/mm(2) for CSD, and 1000 s/mm(2) for super-CSD. The quality of estimation of fibre orientations may profoundly affect fibre tracking attempts, and the results presented provide important additional information regarding performance characteristics of well-known methods.

An essential step for fibre-tracking is the accurate estimation of neuronal fibre orientations within each imaging voxel, and a number of methods have been proposed to reconstruct the orientation distribution function based on sampling three-dimensional q-space. In the q-space formalism, very short (infinitesimal) gradient pulses are the basic requirement to obtain the true spin displacement probability density function. On current clinical MR systems however, the diffusion gradient pulse duration (delta) is inevitably finite due to the limit on the achievable gradient intensity. The failure to satisfy the short gradient pulse (SGP) requirement has been a recurrent criticism for fibre orientation estimation based on the q-space approach. In this study, the influence of a finite delta on the DW signal measured as a function of gradient direction is described theoretically and demonstrated through simulations and experimental models. Our results suggest that the current practice of using long delta for DW imaging on human clinical MR scanners, which is enforced by hardware limitations, might in fact be beneficial for estimating fibre orientations. For a given b-value, the prolongation of delta is advantageous for estimating fibre orientations for two reasons: first, it leads to a boost in DW signal in the transverse plane of the fibre. Second, it stretches out the shape of the measured diffusion profile, which improves the contrast between DW orientations. This is especially beneficial for resolving crossing fibres, as this contrast is essential to discriminate between different fibre directions.

Q-ball imaging (QBI) has been proposed for the mapping of multiple intravoxel fiber structures using the Funk-Radon transform on high angular resolution diffusion images (HARDI). However, the accuracy and the angular resolution of QBI to define fiber orientations and its dependence on diffusion imaging parameters remain unclear. The phantom models, made up of sheets of parallel capillaries filled with water, were designed to evaluate the accuracy and the angular resolution of QBI at different |q| values. With an inner diameter of 20 mum and an outer diameter of 90 mum, the capillaries afforded a restrictive environment compared with the diffusion measurement scale. Further, the angular resolutions of QBI at various |q| value were also quantified on the corpus callosum in the human brain. The full width at half maximum (FWHM) of the main lobe of normalized orientation distribution function (nODF) was calculated and adopted to quantify the angular resolution of QBI. With the phantom model, a higher |q| value resulted in worse accuracy but better angular resolution for QBI. The same trend where a higher |q| value yielded a better angular resolution was also observed in the human study. Upon comparison of QBI with T2WI, QBI with |q|=277 cm(-1) (b=3000 s/mm(2)) was found to be insufficient to differentiate capillaries crossing at 45 degrees . However, when encoding with |q|=320, 358, and 392 cm(-1) (b=4000, 5000, and 6000 s/mm(2)), the deviation angles between the primary ODF and the 45 degrees phantoms were -4.91 degrees +/-2.72 degrees , -1.37 degrees +/-2.32 degrees , and -0.69 degrees +/-1.54 degrees with adequate signal-to-noise ratio (SNR). These results were consistent with the FWHM-nODF, which showed that a |q| value of 320 cm(-1) was the threshold to resolve capillaries intersecting at 45 degrees . Additionally, it was demonstrated in both the phantom model and the human brain that QBI encoding with lower |q| values may result in underestimation of the orientations of the crossing fibers. In conclusion, QBI was found to accurately resolve crossing fiber orientations and was highly dependent on the selected |q| value.

Available online 22 August 2021. White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process. This work was conducted in part using the resources of the Ad- vanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. KS, BL, CH were supported by the Na- tional Institutes of Health under award numbers R01EB017230, and T32EB001628, and in part by ViSE/VICTR VR3029 and the National Center for Research Resources, Grant UL1 RR024975-01. This work was also possible thanks to the support of the Institutional Research Chair in NeuroInformatics of Universitéde Sherbrooke, NSERC and Compute Canada (MD, FR). MP received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sk ł odowska-Curie grant agreement No 754462. The Wisconsin group acknowledges the support from a core grant to the Waisman Cen- ter from the National Institute of Child Health and Human Develop- ment (IDDRC U54 HD090256). NSF OAC-1916518, NSF IIS-1912270, NSF IIS-1636893, NSF BCS-1734853, NIH NIBIB 1R01EB029272-01, and a Microsoft Faculty Fellowship to F.P. LF acknowledges the sup- port of the Cluster of Excellence Matters of Activity. Image Space Mate- rial funded by the Deutsche Forschungsgemeinschaft (DFG, German Re- search Foundation) under Germany´s Excellence Strategy –EXC 2025. SW is supported by a Medical Research Council PhD Studentship UK [MR/N013913/1]. The Nottingham group’s processing was performed using the University of Nottingham’s Augusta HPC service and the Pre- cision Imaging Beacon Cluster. JPA, MA and SMS acknowledges the support of FCT - Fundação para a Ciência e a Tecnologia within CIN- TESIS, R&D Unit (reference UID/IC/4255/2013). MM was funded by the Wellcome Trust through a Sir Henry Wellcome Postdoctoral Fellow- ship [213722/Z/18/Z]. EJC-R is supported by the Swiss National Sci- ence Foundation (SNSF, Ambizione grant PZ00P2 185814/1). CMWT is supported by a Sir Henry Wellcome Fellowship (215944/Z/19/Z) and a Veni grant from the Dutch Research Council (NWO) (17331). FC acknowledges the support of the National Health and Medical Re- search Council of Australia (APP1091593 and APP1117724) and the Australian Research Council (DP170101815). NSF OAC-1916518, NSF IIS-1912270, NSF IIS-1636893, NSF BCS-1734853, Microsoft Faculty Fellowship to F.P. D.B. was partially supported by NIH NIMH T32- MH103213 to William Hetrick (Indiana University). CL is partly sup- ported by NIH grants P41 EB027061 and P30 NS076408 “Institutional Center Cores for Advanced Neuroimaging. JYMY received positional funding from the Royal Children’s Hospital Foundation (RCH 1000). JYMY, JC, and CEK acknowledge the support of the Royal Children’s Hospital Foundation, Murdoch Children’s Research Institute, The Uni- versity of Melbourne Department of Paediatrics, and the Victorian Gov- ernment’s Operational Infrastructure Support Program. C-HY is grateful to the Ministry of Science and Technology of Taiwan (MOST 109-2222- E-182-001-MY3) for the support. LC acknowledges support from CONA- CYT and UNAM. ARM acknowledges support from CONACYT. LJO, YR, and FZ were supported by NIH P41EB015902 and R01MH119222. AJG was supported by P41EB015898. NM was supported by R01MH119222, K24MH116366, and R01MH111917. This project has received funding from the European Union’s Horizon 2020 Research and Innovation Pro- gramme under Grant Agreement No. 785907 & 945539 (HBP SGA2 & SGA3), and from the ANR IFOPASUBA- 19-CE45-0022-01. PG, CR, NL and AV were partially supported by ANID-Basal FB0008 and ANID- FONDECYT 1190701 grants. We would like to acknowledge John C Gore, Hiromasa Takemura, Anastasia Yendiki, and Riccardo Galbusera for their helplful suggestions regarding the analysis, figures, and discussions.