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Structural Maturation of Neural Pathways in Children and Adolescents: In Vivo Study

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Science  19 Mar 1999:
Vol. 283, Issue 5409, pp. 1908-1911
DOI: 10.1126/science.283.5409.1908

Abstract

Structural maturation of fiber tracts in the human brain, including an increase in the diameter and myelination of axons, may play a role in cognitive development during childhood and adolescence. A computational analysis of structural magnetic resonance images obtained in 111 children and adolescents revealed age-related increases in white matter density in fiber tracts constituting putative corticospinal and frontotemporal pathways. The maturation of the corticospinal tract was bilateral, whereas that of the frontotemporal pathway was found predominantly in the left (speech-dominant) hemisphere. These findings provide evidence for a gradual maturation, during late childhood and adolescence, of fiber pathways presumably supporting motor and speech functions.

Structural maturation of individual brain regions and their connecting pathways is a condition sine qua non for the successful development of cognitive, motor, and sensory functions. The smooth flow of neural impulses throughout the brain allows for information to be integrated across the many spatially segregated brain regions involved in these functions. The speed of neural transmission depends not only on the synapse, but also on structural properties of the connecting fibers, including the axon diameter and the thickness of the insulating myelin sheath (1). Axons constituting major fiber pathways in the human brain, such as those of the corpus callosum or the corticospinal tract, continue to develop throughout childhood and adolescence. Postmortem studies suggest that axon diameter and myelin sheath undergo conspicuous growth during the first 2 years of life, but may not be fully mature before adolescence (2) or even late adulthood (3). However, the scarcity of brain specimens makes it difficult to draw definite conclusions about the timetable of myelination during childhood and adolescence. In vivo studies with magnetic resonance imaging (MRI) therefore play a major role in filling this gap. Previous developmental MRI studies have provided evidence for a continuous increase in the overall volume of white matter and the area of the corpus callosum well into adolescence (4), but the analytic procedures used in these studies did not allow the investigators to detect changes in specific corticocortical or corticofugal white matter pathways. Here, we report findings obtained with a technique for computational analysis of age-related changes in local white matter signal throughout the brain. Similar techniques have been used in adults to detect subtle regional differences in gray matter signal between healthy subjects and patients with psychiatric or neurological disorders (5, 6).

We obtained brain MRI scans of 111 children and adolescents aged 4 to 17 years (7). The images were then processed in a fully automatic system that included the following steps: (i) nonlinear transformation of images into standardized stereotactic space to remove global and local differences in the size and shape of the individual brains; (ii) classification of brain tissue into white matter, gray matter, and cerebrospinal fluid; and (iii) blurring of white matter binary masks to generate three-dimensional (3D) maps of white matter “density” (8). Using a linear regression model, we correlated the 111 individual maps of white matter density with the subject's age on a voxel-by-voxel basis (9).

Regression analysis revealed significant (t > 5.0,P < 0.04, corrected) age-related increases in white matter density within the left (t = 8.9,r = 0.65) and right (t = 8.0,r = 0.60) internal capsule (Fig. 1) and the posterior portion of the left arcuate fasciculus (t = 6.6, r = 0.54;Fig. 2). The location of the changes in the posterior limb of the internal capsule suggested that the changes involved the corticospinal and, possibly, thalamocortical tracts. Changes in white matter density within the internal capsule were small but consistent, increasing linearly from age 4 to age 17 by about two standard deviations (Fig. 3). The arcuate fasciculus contains fibers connecting frontal and temporal cortical regions involved in speech. It is therefore noteworthy that age-related white matter increases in this pathway reached significance only in the left but not the right hemisphere; the left hemisphere can be assumed to be dominant for speech in the majority of our right-handed subjects (10). The mean white matter density was significantly higher in the left than in the right arcuate fasciculus (paired ttest, t = 2.3, P < 0.05), whereas the variance of age-related changes was lower in the left hemisphere (Fig. 3). In addition to MRI scans, we have also collected several indicators of language skills, including the Vocabulary subscale of the Wechsler Intelligence Scale for Children–Revised (WISC-R) and the Tests of Achievement from the Woodcock-Johnson Psycho-Educational Battery. We carried out multiple regression analyses of these data and, after removing the effect of age, found no significant relations between any of these behavioral measures and white matter densities in the arcuate fasciculus (11).

Figure 1

Age-related changes in white matter density in the internal capsule. The thresholded maps of t-statistic values (t > 4.0) are superimposed on axial sections through the magnetic resonance (MR) image of a single subject. The images depict the exact locations in the internal capsule that showed statistically significant correlations between white matter density and the subject's age. The red outline identifies the left internal capsule; its location was derived by registering the MR image with the appropriate sections of the Schaltenbrand and Wahren atlas (27). All images are aligned within the standardized stereotactic space, with the Z values indicating the distance (in millimeters) of a given axial section from the horizontal plane passing through the anterior and posterior commissures.

Figure 2

Age-related changes in white matter density in the left arcuate fasciculus. The thresholded maps oft-statistic values (t > 4.0) are superimposed on the sagittal (A) and coronal (B) sections through the MR image of a single subject. The images depict the locations along the putative arcuate fasciculus that showed statistically significant correlations between white matter density and the subject's age. The t-maps are aligned with the MR image within the standardized stereotactic space, with the X andY values indicating the distance (in millimeters) from the midline (sagittal section) and the anterior commissure (coronal section), respectively. The dotted line in (A) indicates the level at which the coronal section displayed in (B) was taken and similarly for the dotted line in (B) for the sagittal section displayed in (A).

Figure 3

Values of white matter density in internal capsule and arcuate fasciculus. The plots show means and SDs of white matter density values calculated for each age group. The values were extracted from the individual blurred white matter images at theX, Y, and Z locations corresponding to the voxel with the highest t value in a given region, namely in the left internal capsule (X = –17,Y = –12, Z = 0; t = 8.9, r = 0.65), right internal capsule (X = 15, Y = –4, Z = 4; t = 8.0, r = 0.60), left arcuate fasciculus (X = –43, Y = –32,Z = 26; t = 6.6, r = 0.54) and right arcuate fasciculus (X = 40,Y = –25, Z = 23; t = 4.5,r = 0.4). Numbers of subjects in each age group: 4 years, n = 7; 5 years, n = 10; 6 years,n = 3; 7 years, n = 5; 8 years,n = 12; 9 years, n = 10; 10 years,n = 7; 11 years, n = 11; 12 years,n = 7; 13 years, n = 10; 14 years,n = 10; 15 years, n = 8; 16 years,n = 7; and 17 years, n = 4.

The impressive consistency of the age-related changes found at the level of the internal capsule may be attributable to a relatively high density of fibers funneled through the narrow space between the thalamus and the globus pallidus and, in turn, a high signal-to-noise ratio. It should be pointed out, however, that similar albeit less robust age-related increases in white matter density were detected at different levels along the putative corticospinal tract (Figs. 1 and4).

Figure 4

Age-related changes in white matter density along the putative corticospinal tract. The thresholded maps oft-statistic values (t > 3.0) are superimposed on the axial (A) and coronal (B) sections through the MR image of a single subject. The images depict correlations between white matter density and the subject's age along the putative corticospinal tract. Note that the correlations are not limited only to the internal capsule, shown on the coronal section (B), but extend between the capsule and the central sulci, which are indicated by arrows (A). Positive but nonsignificant correlations can also be seen along the corpus callosum and in the left temporal stem (B). The t-maps are aligned with the MR image within the standardized stereotactic space, with the Z and Yvalues indicating the distance (in millimeters) from the horizontal (axial section) and the vertical (coronal section) planes passing through the anterior commissure, respectively. The dotted line in (A) indicates the level at which the coronal section displayed in (B) was taken and similarly for the dotted line in (B) for the axial section displayed in (A).

The observed changes in white matter density in the internal capsule and the left arcuate fasciculus may reflect age-related increases in the diameter or myelination of the axons forming these fiber tracts. It has been suggested that the diameter of the thickest fibers in the corticospinal tract increases linearly as a function of body height (12). Significant shortening of the central conduction time during childhood and adolescence has been observed in the motor pathway of both human and nonhuman primates (13). These observations, as well as our findings, are thus consistent with the relatively protracted development of motor skills believed to be dependent on the corticospinal system, namely those requiring fine finger movements (14). Faster conduction velocity can facilitate information flow not only by speeding it up but also by allowing for precise temporal coding of high-frequency bursts of neuronal activity (15). It has been proposed that processing of speech sounds requires a neural system capable of tracking rapid changes in acoustic input (16). Rapid transfer of information to the auditory cortex and beyond would require fast-conducting fiber systems. A recent observation by Penhune et al. (17) of larger left than right white matter volume in Heschl's gyrus in the adult human brain is consistent with this notion. Moore et al. (18) examined brain specimens of children aged 5 to 11 years and observed gradual maturation of axons originating in the superficial layers of the auditory cortex; these axons may contribute to corticocortical connections contained in the arcuate fasciculus.

Thus, the age-related increases in white matter density along the arcuate fasciculus observed here may represent a structural correlate of another component of the audiovocal system, namely the corticocortical pathway mediating sensory-motor interactions between the anterior and posterior speech regions. The interruption of the arcuate fasciculus in adulthood causes conduction aphasia, perhaps as a result of the disruption of both feedforward and feedback mechanisms (19). The importance of the feedback mechanism is also shown by the presence of significant modulation of neuronal activity in the human and monkey auditory cortex during speech and vocalization, respectively (20). The engagement of such feedback mechanisms may facilitate late stages of speech development, requiring a fast bidirectional transfer of information between the auditory and motor cortical regions. It is also possible that the age-related increases in white matter density, both along the arcuate fasciculus and the putative corticospinal tract, reflect the effect of extensive use of these systems during the individual's life.

Our findings provide evidence for the protracted structural maturation of fiber pathways, which support motor and speech functions, during childhood and adolescence. Age-related changes in white matter density observed along these pathways may reflect increases in axon diameter, myelination, or concentration of iron, separately or in combination (21). Further studies are required to provide a link between the observed MRI-derived structural changes and the speed of neural transmission. This could be achieved, for example, by combining transcranial magnetic stimulation and multichannel electroencephalography (22). Our findings may also provide guidance for future investigations of neurodevelopmental disorders such as schizophrenia; the abnormal rate of myelination during childhood or adolescence may very well underlie the emergence of psychotic symptomatology (23). Overall, the demonstrated possibility of detecting subtle structural variations in white matter in the living human brain opens up new avenues of research on normal and abnormal cognitive development and the evaluation of long-term effects of various treatment strategies.

  • * To whom correspondence should be addressed. E-mail: tomas{at}bic.mni.mcgill.ca

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