Insights into Brain Connectivity Using Quantitative MRI Measures of White Matter

Andrew L Alexander1 and Nancy J Lobaugh2

1 Medical Physics and Psychiatry, Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin - Madison

2 Cognitive Neurology, Sunnybrook Health Sciences Centre, University of Toronto

The vast majority of brain connectivity studies have focused on the activity of measurable brain signals in the cortex and deep gray matter nuclei regions. However, the axons in the white matter serve as the connectivity network of the brain between distant brain regions. Currently, there are not any noninvasive methods for mapping the signal conduction in specific white matter networks. Several MR imaging methods have the potential to provide information related to the physiology and pathology of the white matter tissue substrates, which may ultimately affect brain connectivity.

White matter (WM) is comprised of myelinated axons and glial cells. Axons are the thick branches of neurons, which conduct action potentials (signals) from the neuron cell body to remote target neurons. Myelin is an insulating layer of phospholipids and proteins, which significantly increase the speed of action potential conduction. Either demyelination, myelin degradation, or poor myelin development will impede the efficiency of action potentials and affect neural connectivity. The glia ("brain glue") are non-neural cells and are the supporting cells of the nervous system. They provide support, form myelin, respond to injury, maintain the blood-brain barrier, and regulate the chemical composition of tissue medium. Glial cells include oligodendrocytes (responsible for myelin generation and maintenance), astrocytes (support metabolic function and provide structural support including the blood brain barrier), and microglia (protect the brain from insult and injury). Imaging methods that can characterize the properties of this complex tissue matrix may be valuable for investigating the influence of tissue substrates on neural connectivity.

Conventional MRI is a noninvasive imaging method that can create images with exquisite anatomical detail. While standard MRI methods (e.g., T1-weighted, T2-weighted, proton-density-weighted) can differentiate gray matter and white matter, as well as localize certain brain lesions and abnormalities, it is not quantitative and does not provide information about specific changes in the tissue. However, several quantitative MRI methods have recently been developed which provide either direct or indirect measurements of relevant tissue properties including the microstructural tissue architecture, intra-myelin water, proteins associated with myelin, axon density, biochemical metabolite concentrations, and response to injury (e.g., inflammation, microglia). These MRI methods include diffusion tensor imaging, magnetization transfer imaging, T1 and T2 relaxometry, MR spectroscopy and spectroscopic imaging, and targeted contrast agents. This chapter will focus on diffusion tensor imaging (DTI), magnetization transfer imaging (MTI) and myelin water fraction imaging (MWFI) using multi-component T2 relaxometry. Although promising, MR spectroscopy is not covered here.

1 Diffusion Tensor Imaging

Diffusion tensor imaging (DTI) is currently the most widely used method for investigations of WM and anatomical connectivity. The diffusion tensor is a simple model of water diffusion in biological tissues and describes the magnitude, anisotropy (directional variation), and orientation of the diffusion distribution.

Diffusion is a random transport phenomenon, which describes the transfer of material (e.g., water molecules) from one spatial location to other locations over time. The Einstein diffusion equation (Einstein 1926):

states that the mean squared-displacement, (Ar2), from diffusion is proportional to the diffusivity, D (in mm2/s), over the diffusion time, At. The displacement is scaled by the spatial dimensionality, n, which is n = 3 in biological tissues. The diffusivity of pure water at 20°C is roughly 2.0 x 10-3 mm2/s and slightly higher at body temperature.

The molecules, sub-cellular organelles and cells within biological tissues are in a continuous state of kinetic motion. In particular, water molecules diffuse inside, outside, around, and through cellular structures. The diffusion of water molecules is first caused by random thermal fluctuations. The behavior of the diffusion is further modulated by cytoplasmic currents and the interactions with cellular membranes, and subcellular and organelles.

In fibrous tissues such as white matter tracts in the brain, water diffusion is less hindered or restricted in the direction parallel to the fiber orientation. Conversely, water diffusion is highly restricted or hindered in the directions perpendicular to the fibers. Thus, the diffusion in fibrous tissues is anisotropic. Early diffusion imaging experiments used measurements of parallel (D||) and perpendicular (D±) diffusion components to characterize the diffusion anisotropy (Chenevert et al. 1990; Moseley et al. 1990).

The diffusion tensor is an elegant model of water diffusion (Basser et al. 1994), which assumes that the diffusion is described by a 3D, multivariate normal distribution

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