Development of the corpus callosum in childhood, adolescence and early adulthood
Introduction
The development of the human brain occurs along a complex yet systematic schedule dictated by genetic and environmental influences [2]. Development begins prenatally with neurogenesis, neural differentiation and migration and synaptogenesis, and continues post-natally with synaptic pruning and myelination, followed by the formation of stable neural networks in cortical and sub-cortical circuits [3]. It has been suggested that neuro-development in early childhood and adolescence follows different timetables across brain regions [4]. However, the pattern and time course of this development across brain regions is not well known. We used magnetic resonance imaging (MRI) to assess age-related changes from childhood to young adulthood.
Our investigation focused on the corpus callosum (CC), a white-matter structure that is the major commissure connecting the cerebral hemispheres. The development of this white-matter region is of particular interest because of its role in corticocortical and interhemispheric connectivity [5]. Furthermore, the CC is topographically mapped to cortical brain regions; thus, specific regions of the CC (i.e., the genu, body, isthmus and splenium) respectively comprise of fibres connecting heteromodal and unimodal association cortical regions (i.e., prefrontal, sensory motor, temporoparietal and occipital cortices) [6], [7]. Finally, morphological abnormalities of the CC are correlated with abnormalities in cognitive processes and cognitive and behavioral development in humans and primates [8], [9]. These lines of evidence indicate that the CC is a vital structure important for development and cortico-cortical connectivity, and that an analysis of age-related changes in its size and properties may provide information regarding global processes of normal or abnormal development [10]. Furthermore, information on normal maturational processes within each of the CC sub regions can serve as indices of developmental processes across cortical regions [11], [12].
Grey and white matter follow different developmental paths: age related decreases in grey matter [13], [14] occur in conjunction with age-related increases in white matter [15], presumably reflecting increasing interconnectivity between cortical regions with age. In normal development, the CC is among the last structures to complete postnatal maturation. Its size increases with age into early adulthood [1], long after other brain regions have ceased to mature or have stabilized. The precise reasons for the increase in size remain unclear. It has been hypothesized that the increases may be due to myelination that is known to occur through adolescence [16], [17]. Myelinated axons permit the fast propagation of neural impulses that are considered prerequisites for normal cognitive and motor development. However, the rate of changes in myelination in the CC is most rapid in the early post-natal stages [18]. Though myelination is thought to extend into the third decade of life, there is no evidence that the rate of myelination into that stage of life remains constant [17].
Other processes may also contribute to increases in CC size. Callosal area may increase through age-related increases in the diameter of axonal fibres [19] that are distinctive of white matter. Such an increase in axonal size (apart from leading to an increase in callosal size) has implications for other aspects of the cytoskeletal architecture of neurons. Neuronal development is intimately linked to the role of microtubules and microskeletal elements that are among the most dynamic of the cytoskeletal structures. Microtubular distribution and orientation within a neuron varies for the different neuronal elements; the arrangement of microtubules within the axonal shaft is dense and uniformly oriented [20], unlike the arrangement in the centrosome and the dendrites. Increases in axonal size are correlated with a decrease in microtubular density presumably leading to an increase in the axonal free cytosolic contents [21].
Increases in myelination are not necessarily tied to increases in axonal size and vice versa. Whereas both processes will lead to increases in callosal size, they can lead to opposite changes in signal intensity of Magnetic Resonance Images (MRI). MRIs are an informative measure by which to study changes in white matter tissue precisely because the intensity of the MRI signal is sensitive to the cellular properties of tissue, particularly the content of MR-“visible” free water. The content of MR-visible free water is in turn related to the onset of specific cellular events [22]. For example, changes such as decreases in the microtubular density in the cytoarchitecture of callosal axons will lead to an increase in the cytoplasmic component of the axons. This in turn will result in an increase in MR-visible free water. The resultant increase in the relaxation time of T1-weighted images will result in a decrease in MR signal intensity. Myelination by contrast occurs in conjunction with decreases in brain tissue water content, gliosis (thought to precede myelination) and the accumulation of lipids in cells [23]. Correspondingly, the decrease in the water content in myelinating white matter results in a decrease in the relaxation times of T1-weighted images; MRI-measured post-natal changes of the corpus callosum a time-frame during which myelination is rapid, show an increase in signal intensity from birth to early infancy, concurrent with known changes in myelination of the structure [24], [25], [26], and explaining the increasing “whiteness” of white matter in early development [27]. Relatedly, patients with known myelin disorders such as multiple sclerosis show a decrease in MRI signal intensity [28].
Thus, the above outlined mechanisms for maturational change lead to alternative predictions concerning age-related changes in MR signal intensity. If the normal development of the CC into young adulthood is dominated by uniform increases in myelination across all the sub-regions of the structure, analyses of the MRI signal will show an age-related increase in signal intensity of T1-weighted MRI images into young adulthood. Alternatively, if development of the CC into young adulthood is dominated by increases in axonal width, the content of free water in the structure will increase. This will be expressed in an increase in the relaxation time of T1-weighted images, resulting in a decrease in MR signal intensity. Thus, while both these processes will lead to an increase in the size of the CC, they will be expressed differently in the MR signal intensity.
We used Magnetic Resonance Imaging (MRI), to assess changes in the size and in the signal intensities of the corpus callosum in a cross-sectional sample of 109 healthy individuals ranging from adolescence to young adulthood. The changes were assessed separately in the four sub-regions of the corpus callosum: the genu, body, isthmus and splenium. The pons, a sub-cortical structure that matures earlier in life, was used as the control region [29].
The parcellation of the structure and an age-related analysis of changes in size and signal intensity allowed us to address separate questions. The first was whether maturation into adulthood occurs in a synchronous or asynchronous manner [4]. Parallel trends across all the sub-regions of the corpus callosum would provide evidence for largely synchronous development. Alternatively dissociations in the developmental profiles of the sub-regions would argue for largely asynchronous development. Secondly, the large cross sectional sample also allowed us to assess whether the rate of maturational change varied as a function of developmental stage (childhood vs. adulthood vs. young adulthood). Extant investigations of callosal development have suggested that the growth of the structure is generally linear [16] into late adolescence. Such a conjecture is not consistent with observations that cognitive development proceeds non-linearly and that the most rapid expansion of cortical capabilities occurs in childhood and early adolescence. Given the corpus callosum's crucial role in integrating interhemispheric interactions, it is likely that its developmental timetable varies as a function of developmental stage. To that end our pool of subjects was categorized by developmental stage; children, adolescents and young adults. In the analyses mean differences between developmental stages were assessed. Age-related changes were assessed in greater detail by searching for the best mathematical functions that fit the entire range of data and by assessing age-related changes within each developmental stage.
Section snippets
Subjects
The morphometric and the SI analyses of the CC was conducted on the T1-weighted MRI scans of 109 healthy subjects. The sample consisted of 57 males (mean age=17.2 yrs., s.d.=6.9; range: 7–32 yrs; 2 left-handed.) and 52 females (mean age=16.6 yrs., s.d.=6.5; range: 7–32 yrs.; 1 left-handed). All subjects provided written informed consent, and the studies were approved by the Biomedical Institutional Review Board of the University of Pittsburgh Medical Center. No subjects had any personal or
Results
Analysis of the signal intensity and the morphometry data were conducted using two-way Multiple Analysis of Variance (MANOVA) with Developmental Stage (Children: ages 7–12, n=36; adolescents: ages 13–20, n=37; young adults: ages 21–32, n=36) and Gender as factors.
Conclusions
Whereas morphometric studies have revealed that callosal maturation occurs into early adulthood [16], changes in callosal signal intensities into that stage in human development have not been adequately studied [32]. To our knowledge, developmental changes have not been tracked by segmenting the CC into its cortically mapped sub-regions. We demonstrate three principal results concerning CC development into young adulthood.
Callosal maturation occurs well into young adulthood, a finding that is
Acknowledgements
This work was supported in part by NIMH grants, MH01180 (MSK), MH45203 (MSK), MH45156-01A1 (JWP), MH01372 (DRR), MH46614 (JWP), MH62134 (JAS), a Scottish Rite Schizophrenia Foundation Grant (MSK) and the Center for Neurosciences in Mental Disorders, (MH 45156), and by funds received from the NIH/NCRR/GCRC, grant #M01 RR00056. Werner Bagwell contributed to morphometric measurements.
References (42)
- et al.
Brain structure and neurocognitive and behavioral function in adolescents who were born very preterm
Lancet
(1999) Some new trends in the study of the corpus callosum
Behavioral Brain Research
(1994)- et al.
Localizing age-related changes in brain structure between childhood and adolescence using statistical parametric mapping
Neuroimage
(1999) - et al.
A quantitative MRI study of the corpus callosum in children and adolescents
Brain Research: Developmental Brain Research
(1996) The role of motor proteins in establishing the microtubule arrays of axons and dendrites
Journal of Chemical Neuroanatomy
(1998)- et al.
Abnormal callosal morphology in male adult dyslexics: relationships to handedness and phonological abilities
Brain & Language
(1998) - et al.
A.E. Bennett Research Award. Developmental traumatology. Part II: Brain development
Biological Psychiatry
(1999) - et al.
When does human brain development end? Evidence of corpus callosum growth up to adulthood
Annals of Neurology
(1993) - et al.
Genetic control of cortical development
Cerebral Cortex
(1999) The importance of being well placed and having the right connections
Annals of the New York Academy of Science
(1999)
Regional differences in synaptogenesis in human cerebral cortex
Journal of Comparative Neurology
Cerebral specialization and interhemispheric communication: does the corpus callosum enable the human condition?
Brain
Topography of the human corpus callosum
Journal of Neuropathology and Experimental Neurology
The topography of commissural fibers
Differential rearing affects corpus callosum size and cognitive function of rhesus monkeys
Brain Research
Magnetic resonance imaging correlates of neuropsychological impairment in multiple sclerosis
Journal of Neuropsychiatry & Clinical Neuroscience
Abnormalities of the corpus callosum in first-episode treatment-naive schizophrenia
Journal of Neurology, Neurosurgery, & Psychiatry (Submitted)
In vivo evidence for post-adolescent brain maturation in frontal and striatal regions [letter]
Nature Neuroscience
Development of the human corpus callosum during childhood and adolescence: a longitudinal MRI study
Progress in Neuropsychopharmacology & Biological Psychiatry
The myelogenetic cycles of regional maturation of the brain
MR imaging of the developing human brain. Part 2. Postnatal development
Radiographics
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