Anatomical accuracy of brain connections derived from diffusion MRI tractography is inherently limited

Abstract

Tractography based on diffusion-weighted MRI (DWI) is widely used for mapping the structural connections of the human brain. Its accuracy is known to be limited by technical factors affecting in vivo data acquisition, such as noise, artifacts, and data undersampling resulting from scan time constraints. It generally is assumed that improvements in data quality and implementation of sophisticated tractography methods will lead to increasingly accurate maps of human anatomical connections. However, assessing the anatomical accuracy of DWI tractography is difficult because of the lack of independent knowledge of the true anatomical connections in humans. Here we investigate the future prospects of DWI-based connectional imaging by applying advanced tractography methods to an ex vivo DWI dataset of the macaque brain. The results of different tractography methods were compared with maps of known axonal projections from previous tracer studies in the macaque. Despite the exceptional quality of the DWI data, none of the methods demonstrated high anatomical accuracy. The methods that showed the highest sensitivity showed the lowest specificity, and vice versa. Additionally, anatomical accuracy was highly dependent upon parameters of the tractography algorithm, with different optimal values for mapping different pathways. These results suggest that there is an inherent limitation in determining long-range anatomical projections based on voxelaveraged estimates of local fiber orientation obtained from DWI data that is unlikely to be overcome by improvements in data acquisition and analysis alone.T he creation of a comprehensive map of the connectional neuroanatomy of the human brain would be a fundamental achievement in neuroscience. However, despite the numerous efforts to date (for a historical review, see ref. 1), creating this map remains a challenge. A major limitation is that the current goldstandard technique for mapping structural connections, which requires the injection of axonal tracers, cannot be used in humans. The introduction of diffusion-weighted MRI (DWI) (2-4) and the subsequent advent of diffusion tensor MRI (DTI) (5) opened the possibility of exploring the structural properties of white matter in the living human brain (6). Local DWI measures are used clinically for the early detection of stroke and for the characterization of neurological disorders such as multiple sclerosis, epilepsy, and brain gliomas, among others (7). In addition, tractography approaches (8-12) that can infer structural brain connectivity based on brain-wide local DWI measurement have been developed (for reviews, see refs. 13 and 14). The success of DWI tractography as a method for studying fiber trajectories has led to a systematic characterization of large white-matter pathways of the living human brain (e.g., ref. 15), and now it is used routinely to provide a structural explanation for aspects of human brain function (16).A major limitation of DWI tractography is that its characterization of axonal pathways is based on indirec...

Superficial white matter fiber systems impede detection of long-range cortical connections in diffusion MR tractography

“…However, our findings demonstrate that some biases affecting cortical tractography are fundamental and cannot be overcome by the adjustment of parameters and the selection of waypoints. In that sense, they are consistent with and provide a mechanistic understanding for recent empirical work showing that even advanced tractography methods are unable to achieve simultaneously both high sensitivity and high specificity in the identification of cortical connections (35).…”

“…The second practice of using waypoints to include only tracts that are explicitly in the desired position is questionable, in that it implicitly assumes that diffusion tractography is little more than a visualization tool, lacking in intrinsic anatomical accuracy. There is an inherent trade-off in the detection of fiber tracts that can be negotiated by changing the tractography parameter settings: Liberal parameter settings that are sensitive to more subtle connections necessarily increase the detection of false connections, whereas conservative settings that minimize incorrect detections will miss more true connections (35). However, our findings demonstrate that some biases affecting cortical tractography are fundamental and cannot be overcome by the adjustment of parameters and the selection of waypoints.…”

“…The dMRI datasets were obtained ex vivo on a 7-T horizontal Bruker scanner, with each brain specimen scanned over a period exceeding 61 h (Methods). Data from one of the brains were used in our previously published study (35). The resulting dMRI data had an isotropic spatial resolution of 250 μm and a diffusion orientation resolution of 60 or 126 directions.…”

“…A recent study comparing tract-tracer and dMRI tractography concluded that the anatomical accuracy of dMRI tractography is intrinsically limited, but it did not investigate the specific factors leading to this finding (35). In the present study, we investigate the viability of tractography at high resolution, addressing the critical question of whether projections could be followed accurately between the cortex and deep white matter.…”

Motion‐related artifacts in structural brain images revealed with independent estimates of in‐scanner head motion

“…Substantial emphasis has been placed on characterizing how motion‐induced artifacts affect echo‐planar imaging (EPI): both in functional MRI [fMRI; Power et al, 2014; Satterthwaite et al, 2012; Siegel et al, 2014; Van Dijk et al, 2012; Zeng et al, 2014] and diffusion weighted imaging [DWI; Koldewyn et al, 2014; Thomas et al, 2014; Yendiki et al, 2013]. There has been less focus on characterizing how spurious motion‐related biases impact high‐resolution T1‐weighted (T1w) images.…”