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(Radiology. 2000;216:881-885.)
© RSNA, 2000

Experimental Studies

Diffusional Anisotropy in Cranial Nerves with Maturation: Quantitative Evaluation with Diffusion MR Imaging in Rats1

Masaya Takahashi, PhD, Jiro Ono, MD, PhD, Koushi Harada, MD, PhD, Mitsuyo Maeda, PhD and David B. Hackney, MD

1 From the Department of Radiology, University of Pennsylvania Medical Center, Founders Basement/MRI, 3400 Spruce St, Philadelphia, PA 19104 (M.T., D.B.H.); the Research Department, Nihon Schering K.K., Osaka, Japan (M.T.); the Department of Pediatrics D-5, Developmental Medicine (J.O.), and First Department of Anatomy (M.M.), Osaka University Graduate School of Medical Science, Osaka, Japan; and the Division of Radiology, Kaizuka City Hospital, Osaka, Japan (K.H.). Received July 27, 1999; revision requested September 29; revision received January 11, 2000; accepted February 1. Address correspondence to M.T. (e-mail: takahash@oasis.rad.upenn.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To investigate the correlation between diffusional anisotropy and developmental changes in anatomy, which include myelination, in central and peripheral nerves in an animal model by using quantitative diffusion magnetic resonance (MR) imaging and electron microscopy.

MATERIALS AND METHODS: In vivo transverse and longitudinal apparent diffusion coefficients (ADCs) of the optic and trigeminal nerves in 2–10-week-old rats were measured with MR imaging. Then the animals were sacrificed at each time point, and transverse and longitudinal sections of optic and trigeminal nerves were studied with electron microscopy.

RESULTS: In the optic nerve, the ADC parallel to the neurofibers increased with development and increased contemporaneously with myelination, while the ADC perpendicular to the nerve did not change. This resulted in a significant increase in diffusional anisotropy. There were no significant changes in ADCs in either direction in the trigeminal nerve. Longitudinal sections of optic nerve showed a marked change in the orientation of each fiber. As development proceeded, the axons, which initially followed tortuous courses, assumed straighter and more parallel orientations. Trigeminal nerves displayed straight parallel courses at 2 weeks that did not change over the study period.

CONCLUSION: Changes in fiber anatomy in maturation from tortuous to straighter and more parallel orientation can account for changes in longitudinal ADC and in diffusional anisotropy.

Index terms: Animals • Nerves, cranial, 144.91, 151.91 • Nerves, optic, 144.91 • Nerves, MR, 144.121411, 151.121411 • Nerves, trigeminal, 151.91


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It has long been known that magnetic resonance (MR) technique can be used to measure the diffusion coefficient of liquids; in particular, it can be used to measure that of water in tissues (1–3). The potential benefits of diffusion-weighted MR imaging have been reported to include the earlier detection of ischemic regions than is possible with T2-weighted imaging (4–7), the characterization of edematous changes in tissues (8,9), and the identification of axonal damage in patients with spinal cord injury (10). Diffusion-weighted imaging also enables in vivo visualization of the orientation of fiber tracks in the white matter of the brain and in the spinal cord in animals and humans (11–14). This is due to diffusional anisotropy, which reflects a larger apparent diffusion coefficient (ADC) of water molecules parallel to the longitudinal axis of the axon than along the transverse axis. The cause of diffusional anisotropy has been hypothesized to be the restriction of water movement by the myelin sheath (11). Diffusional anisotropy has been used to assess the development of myelination in humans (15,16) and to monitor spinal cord injury (17).

However, there are other studies in which investigators have questioned the importance of the myelin sheath for diffusional anisotropy. For example, Le Bihan and colleagues (18) measured water diffusion in human white matter and found that the ADC did not vary over a range of experimental diffusion times. They speculated that the myelin sheath allowed rapid exchange between myelin and extracellular and axonal water. Sakuma et al (15) reported a weak diffusional anisotropy in the optic nerves of newborns in whom myelination had not occurred (19). Further, Beaulieu and Allen (20) reported diffusional anisotropy in the nonmyelinated giant axon of the squid. In our previous study (21), in which mutant mice were used as models of dysmyelination and demyelination, we demonstrated that diffusional anisotropy could be a discriminator of dysmyelination and demyelination. This observation was confirmed in patients with myelination deficiency (22). These results suggest that mechanisms other than myelin must be involved in diffusional anisotropy. Clarification of the origin of diffusional anisotropy and of the determinants of ADC in white matter would be helpful for noninvasive diagnosis and for further investigation of the development of axons and of the mechanisms of axonal degeneration that accompany dysmyelination and demyelination.

Changes in the morphology of optic (23) and trigeminal (24) nerves in rats have been studied by using electron microscopy. Investigators in the former study demonstrated that the number of myelinated fibers in the optic nerve increased during development. In the optic nerve, the reported percentage of myelinated fibers was approximately 20% in a 2-week-old rat, 50% in a 3-week-old rat, and 85% in a 4-week-old rat. In the trigeminal nerve, more than 80% of fibers are myelinated at postnatal day 8 (24). The purpose of our study was to investigate the correlation between diffusional anisotropy and age-dependent changes in anatomy, which include myelination, in the optic and trigeminal nerves with quantitative diffusion-weighted MR imaging and with electron microscopy.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
MR Imaging
Two-, 3-, and 4-week-old Wistar rats (seven per age group) (Japan Clea, Kanagawa, Japan), born of two age-matched dams, and seven 10-week-old Wistar rats that were not litter mates were used. All animals were anesthetized with 0.2–0.5 g/kg of body weight of subcutaneously injected urethane (Tokyo Kasei Kogyo, Tokyo, Japan) and 20–30 mg/kg of intraperitoneally injected diazepam (Cercine; Takeda Chemical Industry, Osaka, Japan) or pentobarbital (Nembutal; Dainippon Pharmaceutical, Osaka, Japan) and underwent imaging with a home-made birdcage radio-frequency coil. A test tube filled with distilled water was placed beside the animals as a reference. A 2-mm-thick transverse section was selected to delineate the optic and trigeminal nerves on the same image. The animals were oriented so that both sets of nerves were parallel to the magnetic field (z axis) (21).

A 4.7-T animal MR imager (Omega CSI-II; GE-Bruker, Fremont, Calif) equipped with self-shielded gradient coils was used. The parameters for the diffusion-weighted spin-echo imaging were as follows: repetition time, 600 msec; echo time, 70 msec (600/70), 35–60-mm field of view, 256 x 256 matrix, and two signals acquired, which resulted in a total imaging time of approximately 21/2 minutes. The b values of the diffusion-sensitive and nonsensitive sequences were 1,019 sec/mm2 and less than 19 sec/mm2, respectively (see reference 11 for details). Transverse ADC (ADCy) and longitudinal ADC (ADCz) were calculated as the ADC of water in the optic nerve, in the trigeminal nerve, in the gray matter (striatum), and in the water phantom when the diffusion-sensitive gradients were applied along the y axis (perpendicular to the neurofibers) and along the z axis (parallel to the neurofibers), respectively. The ratios of these values (ADCz to ADCy) were calculated to assess anisotropic diffusion in each region and in the water phantom.

Electron Microscopic Examination
Under anesthesia lasting until immediately after MR imaging, four of the seven rats in each age group (total, 16 animals) underwent perfusion with phosphate-buffered saline (Cosmo-Bio, Tokyo, Japan), and their brains were removed for overnight fixation with 2% formalin (Aldrich Chemical, Milwaukee, Wis) that included 2.5% glutaraldehyde (Aldrich Chemical). Semithin and ultrathin sections were prepared for toluidine blue staining and uranyl-lead staining, respectively. Transverse and longitudinal sections of the optic and trigeminal nerves were prepared for electron microscopic examination to evaluate orientation, myelination, and the number of nerve fibers.

The care and maintenance of the experimental animals in this study were approved by the animal committee of the research department of Nihon Schering K.K., which requires adherence to the standards set forth in the Animal Welfare Act (as amended) or in the U.S. Department of Health and Human Services publication "Guide for the Care and Use of Laboratory Animals."

Statistical Analysis
All calculated ADCs were expressed as means plus or minus the SD. Differences among the four groups were evaluated with the one-way analysis of variance with the Tukey multiple comparison test by using commercially available software (SAS/Stat; SAS Institute, Cary, NC). A P value of .05 was considered to indicate a significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Figure 1 shows typical MR images with and without diffusion-sensitive gradients in the same section in a 3-week-old rat. When the diffusion-sensitive gradients were applied perpendicular to the axons, the optic nerve and the trigeminal nerve were delineated clearly (Fig 1, part B) compared with those on the baseline image (Fig 1, part A). In contrast, the signal intensities of both nerves were greatly attenuating and were almost invisible in all groups when diffusion-sensitive gradients were applied parallel to the orientation of the fibers (Fig 1, part C).



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  		Figure 1. Typical transverse MR images (600/70) with and without diffusion-sensitive gradients in the same section in a 3-week-old rat. A, Baseline image. B, When the diffusion-sensitive gradients were applied perpendicular to the axons, the optic nerve (arrow) and the trigeminal nerve (arrowhead) were clearly delineated compared with those in A. C, In contrast, both nerves were almost invisible in all groups when diffusion-sensitive gradients were applied parallel to the orientation of the fibers.

 
In the quantitative analysis of the optic nerve (Table), ADCy showed no age-dependent change. Although ADCy decreased from 0.61 x 10-3 mm2/sec to 0.46 x 10-3 mm2/sec in the optic nerve, this difference was not significant (P > .05). In contrast, ADCz significantly increased with maturation. Thus, there was significant development of the diffusional anisotropy, expressed as ADCz/ADCy. In the trigeminal nerve, however, ADCs changed only slightly during development. Small increases in ADCz and decreases in ADCy at 10 weeks were not significant in themselves but, in combination, produced a significant increase in anisotropy versus at 2, 3, and 4 weeks.


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  		Apparent Diffusion Coefficients
 
Measured ADCy and ADCz in the gray matter (approximately 0.6 x 10-3 mm2/sec) and in the water phantom (approximately 2.0 x 10-3 mm2/sec) were isotropic (Table), which indicated good agreement with previous findings in the literature (25).

Electron microscopic study of transverse sections of the optic nerve confirmed in all animals that some of the axon fibers were myelinated at 2 postnatal weeks and that the diameter and percentage of myelinated fibers increased rapidly with maturation (Fig 2), as has been reported (23).



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  		Figure 2. Electron micrographs of transverse sections of the optic nerve in each postnatal group at A, 2 weeks; B, 3 weeks; C, 4 weeks; and D, 10 weeks. Note that some of the axon fibers were myelinated at 2 postnatal weeks and that the diameter and percentage of myelinated fibers ( in B) rapidly increased with maturation. Semithin and ultrathin sections were prepared for toluidine blue staining and uranyl-lead staining, respectively (bar scale = 1 µm). (Original magnification, x50,000.)

 
As demonstrated in Figure 3, longitudinal sections in 2-week-old rats showed a tortuous orientation of the axons. The orientation of the axons in the optic nerve became much straighter with maturation and formed orderly parallel bundles simultaneously with the development of myelination. In contrast, almost all axon fibers in the trigeminal nerve of the 2-week-old rats showed multiple layers of myelin sheath (Fig 4, part A), as previously reported (24); these axons have straight parallel courses even at the earliest time studied (Fig 4, part B).



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  		Figure 3. Electron micrographs of longitudinal sections of the optic nerve in each postnatal group at 2 weeks (A); 3 weeks (B); 4 weeks (C); and 10 weeks (D). Two-week-old rats show a tortuous orientation of the axons. The orientation of axons ( in B) in the optic nerve becomes straighter with maturation and forms orderly parallel bundles contemporaneous with development of myelination. Semithin and ultrathin sections were prepared for toluidine blue staining and uranyl-lead staining, respectively (bar scale = 1 µm). (Original magnification, x50,000.)

 


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  		Figure 4. Electron micrograph of transverse (A) and longitudinal (B) sections of the trigeminal nerve in a 2-week-old rat. Multiple layers of ensheathing myelin ( in A and B) are present at this age, and these axons have straight parallel courses. Semithin and ultrathin sections were prepared for toluidine blue staining and uranyl-lead staining, respectively (bar scale = 1 µm). (Original magnification, x50,000.)

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
From 2 to 10 weeks of age, there was marked development of diffusional anisotropy in the optic nerve. These results agree with those in previous studies (11,13–16), in which it was hypothesized that the development of myelin causes the restriction of water diffusion perpendicular to the neurofibers and as a result causes greater anisotropy. However, in our study, increased anisotropy was due not to decreasing ADCy but to increasing ADCz.

Electron microscopic findings in longitudinal sections of the optic nerve demonstrated marked changes in the orientation of the neurofibers. As development proceeded, the axons progressed from tortuous to straighter and more parallel courses and formed orderly bundles (Fig 3). Studies of central and peripheral nervous system development (26–28) in a wide variety of animal models have shown that axons seek their courses and connections by initially following undulating paths under the influence of attractant and repellant chemical signals. This observation could explain the increasing ADCz. We postulate that the lesser ADCz of the optic nerve that we observed in developing rats was due to restriction by cell membranes and myelin sheaths in this direction. Water molecules encounter these structures in "longitudinal" motion because the anatomy of the fibers precludes the acquisition of diffusion gradients parallel to their long axes for any reasonable section thickness. As the fibers assume parallel courses, it becomes possible to apply gradients that are truly parallel to the axons. Thus, ADCz increases because of less restriction along this orientation. This interpretation is consistent with our observations in 2- and 4-week-old intact normal dysmyelinated and demyelinated mice (21). Our hypothesis could also account for the findings in the trigeminal nerve—no increase of ADC—because the axons were straight and parallel at 2 postnatal weeks, and no further increase in ADCz was observed. We conclude that, although myelination proceeds at the same time as these changes in axonal orientation, it is the change in fiber orientation rather than the development of myelin that is responsible for the evolution of ADCz and diffusional anisotropy.

We did not attempt to quantify the severity of the tortuosity of the axon fibers in this study. For future investigations it would be desirable do so. One might describe the fiber orientation as a vector field and characterize the projection of these fibers as a two-dimensional correlation with an isotropic ideal vector field. One could then correlate this representation of fiber orientation with the ADC measurements.

While ADCy has been reported to depend on axonal diameter, spacing, and membrane permeability, with the diffusion times over the range of microseconds (29–31), the present study was conducted by using diffusion times (41 msec) well within the restricted regimen. The measured ADCys in the optic nerve were nearly constant from 2 to 4 weeks and decreased at 10 weeks, although this change was not statistically significant. Why was there no change in ADCy with increasing myelination of the axons in optic nerve? ADCy is a function of several factors. Although increasing myelination alone, with all other factors being equal, might be expected to decrease ADCy, there is no reason to assume that the intra- and extracellular volume fractions and ADCs were constant over time. Thus, it is possible that the stability of ADCy during the development of myelination reflects the combined effects of other factors rather than an independence of ADC from myelination. Another possibility is that the myelin present at 2 weeks was already sufficient to produce all the restriction we could observe under the experimental conditions. If this were the case, then further increases in myelin sheath myelination would not produce any increase in restriction at these diffusion times; thus, no decrease in ADCy. Finally, it is possible that the small decrease in ADCy that we observed at 10 weeks, although not statistically significant in this study, was real and was a consequence of increasing restriction by thickening of the myelin sheaths.

The trace of gray matter and white matter diffusion has been reported to decrease by approximately 40% from birth to 4 months of age in kittens (32). This finding of decreases in the trace differs from our observation of increases in ADCz with no changes in ADCy. These differences may be due to differences in tissue (white matter, in which one may not assume the voxels studied included only parallel fibers, vs cranial nerve, in which a single fiber orientation predominates), in species (rat vs cat), or in the interaction of these factors (ie, stage of development of cranial nerves in rats vs that of white matter in kittens). The authors of that study presented preliminary calculations to suggest that the tortuosity of the extracellular space decreases slightly and that the diffusion coefficient of the extracellular water increases substantially. Both of these effects would increase the diffusion coefficient. Thus, they postulated a set of tissue changes that would tend to exert opposing influences on the ADC, with the net effect being a decrease in the trace of the tensor.

The cause of larger ADCs in a longitudinal rather than in a transverse orientation remains unknown. Beaulieu and Allen (33) reported that the depolymerization of microtubules in the olfactory, trigeminal, and optic nerves of garfish produces decreases in both ADCzs and ADCys, with only slight declines in diffusional anisotropy. We confirmed in demyelinated mice that relatively larger ADCy and significantly smaller ADCz resulted in the complete loss of diffusional anisotropy in the optic nerve, in which the axons displayed tortuous orientations and contained abnormal tubular inclusions (21). This observation also was reported in patients with demyelinating disease (22).

In summary, our results imply that changes in fiber anatomy from tortuous to straighter and more parallel orientation can account for an increase in ADCz and in diffusional anisotropy.

Practical application: The increase in longitudinal diffusion coefficient associated with assumption of straight parallel courses of the nerve fibers demonstrated in this study implies that MR imaging determination of ADC can be used to monitor this process of development. Further research is indicated to determine whether diffusion MR imaging also can elucidate repair processes after central nervous system injury.


   ACKNOWLEDGMENTS
 
The authors greatly thank Felix W. Wehrli, PhD, and Nozomu Oshino, PhD, for helpful discussions and an anonymous reviewer for a suggested method for measuring fiber tortuosity.


   FOOTNOTES
 
Abbreviations: ADC = apparent diffusion coefficient, ADCy = transverse ADC, ADCz = longitudinal ADC

Author contributions: Guarantors of integrity of entire study, M.T., J.O.; study concepts, M.T., J.O.; study design, M.T., J.O., K.H.; definition of intellectual content, M.T., D.B.H.; literature research, M.T., D.B.H.; experimental studies, M.T., J.O., M.M.; data acquisition and analysis, M.T., M.M.; statistical analysis, M.T.; manuscript preparation and editing, M.T., D.B.H.; manuscript review, all authors.


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 ABSTRACT
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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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