Cerebral white matter
develops rapidly during the perinatal period and continues to mature in an
orderly pattern that parallels evolving neural functionality. Understanding the
changes that occur in white matter throughout the lifespan is therefore essential
to understanding brain function in states of health and disease. In the past
decade, rapid advancements in MR technology have resulted in more sophisticated
and higher strength magnets and gradient systems, introduction of new imaging sequences, and
refinement of existing protocols that have furthered the capability to probe cerebral white
matter microstructure. These newer methods have the potential to expand our
understanding of white matter on a microscopic level. I will discuss emerging techniques for imaging white matter based on
the main structural components of white matter from the inside out, focusing on
methods for probing axonal microstructure and the quantification of myelin.
Axons
are the structural and physiological conduit for signal transmission in the
brain and are one of the fundamental elements of brain function. The diameter
of both myelinated and unmyelinated axons is related to the speed at which
action potentials are conducted along the length of the axon (1, 2). Variations in axon diameter are
thought to be closely tied to function, with networks that demand fast response
times (such as motor networks) demonstrating larger axon diameters. Therefore,
non-invasive methods for mapping axon diameters in vivo would provide new insight into brain function and
connectivity.
Recognizing
the potential impact of an MRI technique to map axon diameters, several groups
have started to exploit the sensitivity of diffusion-weighted MRI (DW-MRI) to
tissue microstructure for the purpose of estimating axon diameter distributions
and fiber density in white matter bundles (3-15).
DW-MRI is well-established clinically and plays a key role in the
diagnosis of several neurological conditions including acute stroke (16-18) and the evaluation of brain tumors (19, 20) and traumatic brain injury (21, 22). DW-MRI is also used to map the
orientation of white matter tracts, which can be achieved by measuring
diffusion along multiple orientations and applying an analysis scheme such as
diffusion tensor imaging (23), high-angular resolution diffusion imaging (HARDI) (24), q-ball (25) or diffusion spectrum imaging (26). It is only more recently, however,
that there has been a heightened focus on using DW-MRI measurements to quantify
the size of restrictive spaces in brain tissue.
A
number of diffusion MRI techniques have emerged in the last decade that focus
on the quantification of axon diameter and packing density in white matter (3-15). This information is obtained by taking a series of
diffusion-weighted MR signals measured over a wide range of diffusion
weightings (q-values or
diffusion-encoding gradient areas) and diffusion times (time between
diffusion-encoding gradients). At different diffusion times, different
populations of axons exhibit restricted diffusion, thereby allowing axons of
varying sizes to be probed. A model of restricted diffusion within axons and
hindered diffusion outside the axons is then fit to the data. The sensitivity
of axon diameter mapping techniques to small diameter axons is limited by the
maximum gradient strength of clinical MR scanners (27, 28). The recent availability of higher maximum gradient
strengths on human MRI scanners (29-32) has enabled the translation of these methods from animal (8, 9, 27,
33) and ex vivo
studies (6, 10, 11,
13, 15) to the in vivo
human brain (10, 12, 14, 28, 34). Such technological advancements offer the possibility of in vivo diffusion microscopy with
unprecedented resolution of fine white matter structures (32) and micron-sized axons (28, 34) in the living human brain for the study of multiple
sclerosis (MS) (35) and other neurological disorders
affecting white matter. Related techniques such as NODDI measure orientational
dispersion and neurite density (36), which has been shown to provide better
distinction of microstructural disruption in MS lesions and normal-appearing
white matter compared to conventional DTI metrics (37).
Myelination increases conduction velocity
along an axon through a mechanism known as saltatory conduction. For myelinated
axons, ion channels and action potentials occur only at the gaps between the
myelin, known as the nodes of Ranvier. Between these nodes of Ranvier, the
current flows passively through the insulating myelinated portions, leading to
an increased rate of conduction. Larger axons and thicker myelin sheaths
contribute to faster conduction, but there is a trade-off between axon size and
myelin thickness due to spatial constraints imposed by the size of the brain.
The relationship between axon size and myelin thickness is captured in a
parameter known as the myelin g-ratio, defined as the ratio of the inner (axon)
to the outer (axon plus myelin) diameter of the fiber. The optimal g-ratio for
maximizing conduction speed is around 0.6 (38).
Determining the g-ratio
noninvasively by MRI could provide important information regarding the macromolecular
structure of white matter not available through other imaging approaches. The g-ratio can be
calculated based on knowledge of the myelin volume fraction and the axon volume
fraction (33,
39). Information
regarding the axon volume fraction is available through the diffusion MRI
methods described above, whereas myelin volume fraction can be determined
through a number of MRI biomarkers, including those based on T1/T2
relaxometry measurements (40,
41) and magnetization
transfer (MT) (42,
43). A number of
quantitative MT methods have been developed in recent years (44,
45) based on the magnetization
transfer ratio (MTR) (46,
47). The goal of
quantitative MT measurements is to determine the proportion of protons that are
bound to macromolecules and to quantify the rate of exchange of magnetization
between bound and free protons. Quantitative MT methods will be surveyed and their
strengths, weaknesses and applications to quantifying myelin content in white
matter will be discussed.
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