Diffusion Tensor Imaging Study of the Cortical Origin and Course of the Corticospinal Tract in Healthy Children

Localization of the Primary Motor Cortex

Despite investigations performed for more than a century, the exact localization of the primary motor cortex remains controversial. Classically, the motor cortex was thought to be located in the precentral gyrus.¹ Several recent studies of patients with focal epilepsy have localized the primary motor cortex not only in the precentral gyrus but also in the postcentral gyrus.^2–5 Our recent studies showed that hand motor responses could be induced by electric stimulation of the postcentral gyrus in >80% of children with focal epilepsy.^2,3 A study by using the technique of retrograde labeling with horseradish peroxidase in monkeys revealed that both precentral and postcentral gyri contained corticospinal cells.³⁶ Later, functional studies demonstrated that a lesion³⁷ or cooling,³⁸ confined to the presumed postcentral gyrus, resulted in hemiparesis of the contralateral upper extremity in monkeys. Neuroimaging studies by using fMRI revealed that motor tasks such as finger tapping or hand grasping consistently activated the contralateral postcentral gyrus defined by anatomic landmarks, in addition to the precentral, premotor, and supplementary motor areas.³⁴ Therefore, our findings in a large cohort of healthy children are consistent with and confirm the observations from these studies. An advantage of our study is that in isolating the whole CST, unlike previous DTI studies regarding the CST, we did not assume a priori that the precentral gyrus is the primary motor cortex. Therefore, we believe that the present observations can be extrapolated to the healthy population with more certainty and confidence compared with previous studies.

Localization of CST in the Internal Capsule

The somatotopic organization of the CST in the PLIC has been a matter of considerable debate for more than a century. Traditionally, the CST was thought to pass through the anterior one third of the PLIC.^6,7 Although many subsequent studies by using brain dissection or stereotactic procedures have challenged this view and have suggested that the CST may be localized in the posterior portion of the PLIC,^9–14 the classic view is still persisting and finds mention in anatomy textbooks.¹⁶ Recent DTI studies have also challenged this old view,^20,39,40 and our results, derived from a large healthy population studied without preselecting the precentral gyrus as the primary motor cortex, are consistent with a more posterior location of the CST in the PLIC. Thus, the present study has reconfirmed the findings of the previous stereotactic, neuropathologic, and macroscopic observations and provided a detailed pattern of localization and spread of the CST in the PLIC. Most interesting, the spread of the CST in the left PLIC was significantly larger than that in the right PLIC. This may be related to the higher volume of the left CST, particularly its precentral portion, when the CST originated from both pre- and postcentral gyri.

Volume and Diffusion Property

Although there was no statistical difference in FA values between the left or right CST or the pre- and postcentral portions of the CST (FA usually reflects the microstructural integrity of white matter, including myelination), the volume of the precentral portion of the left CST was larger than its right counterpart as well as the left postcentral portion. This finding is consistent with that reported by Rademacher et al,⁴¹ who showed larger volumes of the precentral portion of the CST in the left hemisphere than in the right hemisphere in a postmortem study. Similarly, by using voxel-based morphometry, Herve et al⁴² found higher values of white matter corresponding to the CST in the left hemisphere than in the right. Westerhausen et al⁴³ also reported a trend toward a larger relative size of the CST in the left compared with the right hemisphere. The larger volume of the precentral portion of the CST may be related to the left hemispheric dominance, not only in right- handed but also in most left-handed subjects.

Effect of Age

Most interesting, we found that children with the CST originating from both the pre- and postcentral gyri were older than children in whom the CST originated from the precentral gyrus. Although the reason for this finding remains to be clarified, a possible explanation could be a more myelinated and mature CST, associated with more complex fine-motor activity in older children.

Many previous DTI studies have demonstrated an increase in FA and volume with age, in different parts and levels of white matter, including centrum semiovale, corona radiata, and the PLIC,^43–48 which is consistent with our finding of increased volume and FA of the CST with age. However, we found this specifically in the precentral portion of the left and postcentral portion of the right CST. This difference may be methodologic, because we isolated the whole CST along with its pre- and postcentral portion, unlike in previous studies which selectively focused on white matter regions assumed to belong to the CST. However, why these changes are restricted only to specific portions of the CST is not clear to us.

Effect of Sex and Handedness

We did not find any effect of sex or handedness on the pattern of cortical origin of the CST, its location on the PLIC, or its volume and FA. Although our sample size is small to perform a conclusive subgroup analysis, particularly for handedness, our results are similar to those reported by other studies,^43,46,47 which did not find any sex effect on diffusion parameters or volume for any of the white matter areas or tracts, including the CST. Significant asymmetry in the thresholds for electromyographic activation by using transcranial magnetic stimulation,⁴⁹ in activation shown by fMRI⁵⁰ and in motor cortex volume (gray matter),⁴² has been reported to be related to handedness; however, studies directly evaluating the white matter have not found the effect of handedness on the CST.^42,43 In a group of 56 right-handed and 56 left-handed males, by using voxel-based morphometry, Herve et al⁴² could not find any differences in CST white matter between left- and right-handed subjects. Similarly, Westerhausen et al⁴³ could not find any effect of handedness on CST in a DTI study in 30 left-handed and 30 right-handed subjects. A possible reason for the absence of any effect of handedness could be because handedness may depend on the pyramidal decussation and be related to the number of fibers passing to the other side, particularly fibers of the left CST, originating from the presumably dominant left hemisphere. Indeed, it has been found that more fibers cross from the left to right side than vice versa at the level of medulla oblongata.⁵¹ In fact, a higher number of CST fibers has been found in the right side of the spinal cord.⁵² Therefore, handedness would mostly affect the postdecussational segment of CST, rather than before decussation. Another plausible explanation could be that handedness is a cortical phenomenon and does not depend on the CST. In fact, a study found handedness related to asymmetry in the precentral cortex but not in the white matter along the course of CST.⁴² Or simply, handedness may be related to hemispheric dominance, which is left-sided even in most left-handed subjects. This would explain the left-sided asymmetry of CST white matter found by us and others.^41–43

Methodologic Issues

There were several methodologic limitations in the present study. DTIs were acquired in 6 directions with 6 repetitions. In DTI, all data are ultimately fitted to obtain only the 6 tensor elements. Therefore, mathematically one needs only 6 directions to calculate the tensor and do further processing. However, such measurement does not have enough signal intensity–to-noise ratio (SNR). To enhance the SNR, one needs to acquire more data. For this, there are several options. One can repeat the 6-orientation measurement 6 times (ie, each direction is scanned 6 times, thus making a total of 36 acquisitions at each plane or section, which we did in this study), or one can acquire one 12-, 25-, 30-, or more orientation measurements within the given amount of time (ie, more number of directions or orientations is acquired, but only 1 time. Therefore, ultimately a total of only 12, 25, and ≥30 acquisitions are made at each plane or section). However in the latter case, though there are acquisitions in more directions, they are acquired only once, thus leading to a lower SNR for each direction compared with 6 directions × 6 repetitions.

Although increasing both the directions and repetitions will lead to better quality data, there are time and logistic constraints, particularly in a pediatric population. Therefore, there is always a trade-off between directions and repetitions. Also, purely from a mathematic point of view, we do not think 6 directions × 6 repetitions versus 12-, 25-, or 30-orientations × 1 repetition have that much difference in terms of overall SNR. However, it is true that the 6-orientation measurement has more orientation-dependent inhomogeneity in SNR. This means that certain orientations can be measured with higher SNR, whereas some orientations have poorer SNR. By adopting more orientations, such orientation-dependent SNR profile becomes more homogeneous (less orientation-dependent). In reality, within practical imaging time, this difference is hardly noticeable, particularly with well-oriented fiber bundles. Our study aim was to evaluate only the CST, which is a robust, well-defined, and thick fiber bundle, pretty much oriented in 1 direction. Therefore, we did not expect that our DTI acquisition protocol would have substantially affected the CST measurement because similar protocol across the subjects would have given the consistent results. Therefore, we believe that the data generated from 6 directions × 6 repetitions DTI should be appropriate and reasonable to achieve the goal of the present study, and also the consistency and homogeneity in data acquisition, throughout this study, made our results more meaningful and comparable.

Another issue of DTI deterministic tractography (used in the present study) is that even though it identifies the CST reliably, the uncertainty of the tract increases as the tracking algorithm approaches the low anisotropy areas such as motor cortex. Thus, precise characterization of the origin of tracts within small gyri may be difficult with DTI because the tract does not extend into the cortex. However, this may not be a major issue in the present study because we only attempted to localize the motor cortex between the pre- versus postcentral gyrus, and this does not require the tract to extend into the cortex itself within a gyrus. Moreover, the uncertainty of tracking is significantly smaller than the thickness of the gyri, and Hua et al⁵³ have recently shown that there is a good concordance between the white matter fiber tracts including the CST, isolated by deterministic tractography, and the overlying cortex. They demonstrated that the isolated fiber tracts tend to end in the subcortical white matter regions of the corresponding cortical regions, known to be associated with that tract. Because of these factors, the localization of the motor cortex to the post- and precentral gyrus, by tracing the origin of CST, can be reliably performed by using DTI deterministic tractography. Similarly, DTI might be affected by the presence of other tracts in the isolated CST, thus resulting in decreased specificity. To minimize such contamination, we selected our seed region to include anterior descending fibers in the midpons region, where the contribution from other nonmotor tracts is negligible.¹⁷

The sensitivity of DTI could also be diminished by crossing and merging fibers, particularly as the tract descends into the internal capsule where the attenuation of white matter is quite high. This problem was reduced by reconstructing only the core of white matter tracts with known trajectories. Given that the CST is a large tract, we found that it was identifiable with DTI technique in almost all cases, suggesting that crossing fibers perhaps were not a major confounding factor. In a few cases in which we concluded that the CST was not identifiable, we could still isolate the CST, but it was not continuous from the brain stem to the primary motor cortex. Therefore, we considered the CST as unidentifiable and did not include these cases in further analyses.