Elsevier

NeuroImage

Volume 35, Issue 2, 1 April 2007, Pages 501-510
NeuroImage

White matter development during late adolescence in healthy males: A cross-sectional diffusion tensor imaging study

https://doi.org/10.1016/j.neuroimage.2006.10.047Get rights and content

Abstract

Background:

Previous MRI studies of healthy children have reported age-related white matter (WM) changes in language and motor areas of the brain. The authors investigated WM development in healthy adolescent males through age-associated changes in fractional anisotropy (FA), radial (λ) and axial (λ||) diffusivity.

Methods:

Twenty-four healthy adolescent males (mean age = 16.6, SD = 2.5 years) were divided into two groups with an age split of 16.9 years and underwent a whole-brain voxelwise analysis.

Results:

At a threshold of p < 0.001 and extent threshold of 100 contiguous voxels, several clusters with increased FA and axial diffusivity and no differences in radial diffusivity were observed in older adolescents compared to the younger adolescents in the left arcuate fasciculus, bilateral posterior internal capsule/thalamic radiation, bilateral prefrontal gyrus, right superior temporal gyrus, and posterior corpus callosum. Increased FA and λ|| of several clusters along the arcuate fasciculus significantly correlated with a test of language and semantic memory.

Conclusions:

These results suggest ongoing maturational changes especially in the arcuate fasiculus during late adolescence. Increased FA and λ|| with no changes in radial diffusivity may reflect a developmental pattern of reduced tortuousity toward more straightened fibers and/or increased axonal fiber organization during late adolescence.

Introduction

Changes in brain anatomy during human development represents one of the most challenging and important topics of research in all areas of translational neuroscience. Adolescence is a critical period of brain development for an individual’s affective and cognitive functions (Johnston et al., 2003). Observations of brain vulnerability during the critical age period of late adolescence has driven considerable research toward understanding the neural substrates underlying cognitive development. During adolescence, developmental changes occur in gray and white matter (WM) microstructure and organization of the brain. White matter provides the physical basis for connectivity in the brain and supports the efficient transfer of information between brain structures. Cross-sectional data from postmortem studies show axonal diameter increases and myelin sheath growth from birth to childhood, which continues during adolescence and adulthood in the parahippocampal region (Benes et al., 1994). However, little postmortem information is available regarding the development of other brain regions for children and adolescents. Compared to postmortem studies, in vivo assessments of brain development are advantageous in that it is possible to simultaneously acquire behavioral data, making it possible to explore structure–function relationships.

Detection of subtle brain anatomical changes during adolescent brain development has been greatly served by recent longitudinal studies of healthy children and adolescents that have utilized computational MR image analysis methods. Cortical gray matter volumes have been found to change in a non-linear fashion across different brain regions throughout childhood and adolescence (Gogtay et al., 2004). In healthy adolescents, the loss of cortical gray matter (GM) density in the dorsolateral prefrontal cortex and the posterior part of the superior temporal gyrus, which is critically involved in language and auditory processing, does not become apparent until after age 16–17 years (Gogtay et al., 2004). These age-related decreases in the volume of gray matter might equally represent loss (“pruning”) or gain (intra-cortical myelination) of tissue (Paus, 2005). A summary of the recent findings on normal brain development using brain morphometric techniques and diffusion tensor imaging is presented in Table 1. A number of serious emotional disorders that often have their onset during adolescence, such as schizophrenia, are hypothesized to be neurodevelopmental disorders that may be triggered by abnormalities in cortical “pruning” or myelination (Vidal et al., 2006). Also, anatomical abnormalities in the left superior temporal gyrus region and dorsolateral prefrontal cortex have been consistently found in post mortem and in structural imaging studies (Shenton et al., 2001, Cullen et al., 2006) in the brains of patients with schizophrenia.

Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique suited to the study of WM axonal structure because it can be used to quantify the magnitude and directionality of tissue water mobility in three dimensions. DTI has been utilized for the evaluation of changes in WM diffusion properties as a function of age throughout the first decade of life (McGraw et al., 2002, Mukherjee et al., 2002) and during adolescence (Klingberg et al., 1999). Three recent papers in particular (Schmithorst et al., 2002, Barnea-Goraly et al., 2005, Schmithorst et al., 2005) have shown prominent age-related increases in fractional anisotropy (FA) in the left arcuate fasciculus, prefrontal cortex, internal capsule, corpus callosum, areas extending from sensorimotor regions that appear to correspond to the corticothalamic and cortico-spinal tracts, and ventral visual stream WM (Schmithorst et al., 2002, Barnea-Goraly et al., 2005, Schmithorst et al., 2005). However, these DTI data (see Table 1) included much younger cohorts than the present sample. To date, the number of healthy children examined using DTI has been small, highlighting the need for additional normative data, particularly in older adolescents. Identifying brain regions where WM maturation occurs during the latter part of adolescence in normative samples may help isolate white matter fiber tracts that could be susceptible to adverse environmental exposures. The availability of such data will also aid in understanding the potential mechanism(s) for neurodevelopmental psychiatric disorders that often start during late adolescence, such as schizophrenia (Hafner, 1998).

Based on data supporting cortical gray matter density loss in healthy adolescents after age 17 years (Gogtay et al., 2004), we conducted a cross-sectional comparison of whole-brain voxelwise analysis of DTI maps of older (age range 17.3–20.5, n = 12) and younger (age range 10.6–16.9, n = 12) healthy male adolescents. The purpose of this study was to identify brain fiber pathways with significant differences in WM diffusion properties as a function of age. In addition to FA, which has already been examined in previous developmental studies using DTI in younger samples (Schmithorst et al., 2002, Barnea-Goraly et al., 2005), we also examined the water diffusion parallel (λ||) and perpendicular (λ) to axonal fibers, which are also referred to as axial and radial diffusivity, respectively. These parameters may be more closely connected to changes in tissue morphology related to axonal myelination and/or organization during adolescence (Takahashi et al., 2000, Beaulieu, 2002, Song et al., 2002). We restricted our analysis to males in order to eliminate gender-related variance in WM microstructure development (Szeszko et al., 2003, Westerhausen et al., 2004).

Based on the findings of previous voxel-based conventional MRI (Paus et al., 1999) and diffusion tensor imaging studies during childhood and early adolescence (Schmithorst et al., 2002, Barnea-Goraly et al., 2005), we hypothesized age-related changes in diffusion parameters in prefrontal regions, corticospinal tracts and fronto-temporal tracts.

Section snippets

Subjects

Study participants consisted of twenty-four males with the mean age of 16.6 years (range 10.6 to 20.5) and group median of 16.9 years. The mean age for the younger sample of 12 healthy male volunteers was 14.7 years (SD = 2.2 years, range 10.6 to 16.9) and the mean age for the older sample of 12 healthy male volunteers was 18.4 years (SD = 0.9, range 17.3 to 20.5). Recruitment and diagnostic procedures have been described in detail elsewhere (Kumra et al., 2005, Rhinewine et al., 2005). Briefly,

Results

The groups were similar in terms of socio-economic status, handedness, ethnicity, and full scale IQ (see Table 2). All scans were read as clinically “normal” by a board certified clinical neuroradiologist.

The demographic characteristics (i.e., parental socioeconomic status, ethnicity) of participants with and without complete neurocognitive data were compared. No significant differences in demographics or diffusion measures were found (all p-values > 0.10).

Discussion

In this cross-sectional MRI study, we found statistically significant differences in fractional anisotropy and axial diffusivity with no differences in radial or mean diffusivity in several brain areas such as bilateral arcuate fasciculus, bilateral corticospinal tracts, splenium of corpus callosum, and bilateral frontal areas in healthy older as compared to younger males at a conservative statistical threshold (p < 0.001, extent threshold of 100 contiguous voxels).

Our results of significant

Acknowledgments

The authors would like to thank Grace Kim for her wonderful efforts in recruitment for this study.

This study was supported by NIMH grants MH-60221 to Dr. Kumra; MH-070612 to Dr. Ashtari; and support was provided by the General Clinical Research Center of the North Shore-LIJ Health System's Feinstein Institute for Medical Research, Grant #M01 RR018535. Presented in part at the 14th International Society for Magnetic Resonance in Medicine, Seattle Washington, 2006 and the 43rd American College of

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