Tracking neuronal fiber pathways in the living human brain

T Conturo

N Lori

T Cull

E Akbudak

^{Department of Radiology and Neuroimaging Laboratory, Mallinckrodt Institute of Radiology and Departments of}^{Neurology and}^{Anatomy and Neurobiology, Washington University School of Medicine, 4525 Scott Avenue, St. Louis, MO 63110; and}^{Department of Physics, Washington University, One Brookings Drive, St. Louis, MO 63130}

^{To whom reprint requests should be addressed. E-mail:}ude.ltsuw.gpn@orutnoct.

Contributed by Marcus E. Raichle

Accepted 1999 Jul 12.

Abstract

Functional imaging with positron emission tomography and functional MRI has revolutionized studies of the human brain. Understanding the organization of brain systems, especially those used for cognition, remains limited, however, because no methods currently exist for noninvasive tracking of neuronal connections between functional regions [Crick, F. & Jones, E. (1993) Nature (London) 361, 109–110]. Detailed connectivities have been studied in animals through invasive tracer techniques, but these invasive studies cannot be done in humans, and animal results cannot always be extrapolated to human systems. We have developed noninvasive neuronal fiber tracking for use in living humans, utilizing the unique ability of MRI to characterize water diffusion. We reconstructed fiber trajectories throughout the brain by tracking the direction of fastest diffusion (the fiber direction) from a grid of seed points, and then selected tracks that join anatomically or functionally (functional MRI) defined regions. We demonstrate diffusion tracking of fiber bundles in a variety of white matter classes with examples in the corpus callosum, geniculo-calcarine, and subcortical association pathways. Tracks covered long distances, navigated through divergences and tight curves, and manifested topological separations in the geniculo-calcarine tract consistent with tracer studies in animals and retinotopy studies in humans. Additionally, previously undescribed topologies were revealed in the other pathways. This approach enhances the power of modern imaging by enabling study of fiber connections among anatomically and functionally defined brain regions in individual human subjects.

Abstract

Knowledge of the link between functional brain regions and anatomical fiber connections is essential to an integrated understanding of the organization of the human nervous system. Optimally, both functional domains and their anatomical connections would be mapped in the same subject. The pathways involved in specific functions could thereby be inferred and hypotheses about brain networks formulated and tested. This combined approach has established the complex organization of the nonhuman primate visual system (1). In humans, positron emission tomography (2, 3) and functional MRI (fMRI) (4–6) have provided considerable insight into regional functional specialization, especially for cognitive tasks. However, an understanding of connections between activated regions in humans relies on older, and admittedly impoverished (7), descriptions of gross dissections (e.g., ref. 8) or clinical-pathological correlations (e.g., ref. 9), the latter often based on stained patterns of demyelination (10). Connectional studies in animals use a variety of invasive tracer injections (e.g., refs. 11, 12–18) that cannot be performed in humans. Animal studies also yield limited information regarding human cognitive functions such as language or pathological conditions such as psychiatric disorders. Passive diffusive tracer studies of the postmortem human brain [e.g., by using 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine (17)] require months to trace very short distances (≈mm) and are affected by crossfiber diffusion. Some information on human fiber trajectories can be obtained by imaging fiber degeneration (19) but only in pathologic cases and in selected fiber pathways. The ability to track white matter fibers noninvasively in humans would enable comparison of structural differences in brain organization between subjects in normal and abnormal states and enable study of potential fiber connections between functional brain regions.

By using the general principle that brain water preferentially diffuses in the direction of white matter fibers (20–22), we computationally traced neuronal fiber bundles in human subjects with optimized diffusion tensor-encoded MRI (DT-MRI) (23–25). This procedure monitors rapid microscopic (≈μm) self-diffusive water movements rather than slow macroscopic (≈mm) tracer displacements. From 1.25 × 1.25 × 2.5 mm image data acquired in a 2-hr session, we reconstructed diffusion tracks throughout the brain by repeatedly stepping along the direction of fastest diffusion, starting from a 1-mm grid of seed points covering the entire brain. We then identified subsets of tracks that linked regions initially selected on the basis of anatomical landmarks or fMRI activated foci. Results were obtained in commissural and projection systems where anisotropy is high (26) and fibers are highly parallel and in more complex association fiber systems having relatively low anisotropy (26). Prior studies that used diffusion imaging evaluated trajectory data only in limited regions acquired from excised fixed rat brain with long scan times (27).

Acknowledgments

This work was supported in part by the Major Grants Program of the McDonnell Center for Higher Brain Function, the Charles A. Dana Foundation Consortium on Neuroimaging Leadership Training, and National Institutes of Health Grant P01 NS06833. We thank Thomas A. Woolsey and Joseph L. Price for review of the manuscript before submission and Robin K. Guillory for assistance with figures.

Acknowledgments

ABBREVIATIONS

MR	magnetic resonance
DT-MRI	diffusion tensor-encoded MRI
fMRI	functional MRI
3D	three-dimensional
2D	two-dimensional
LGN	lateral geniculate nucleus

ABBREVIATIONS

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