1 Department of Neuropsychiatry, Toyama Medical and Pharmaceutical University, Toyama, Japan, 2 Department of Psychology, Toyama Medical and Pharmaceutical University, Toyama, Japan, 3 Department of Radiology, Toyama Medical and Pharmaceutical University, Toyama, Japan and 4 Department of Physiology, Toyama Medical and Pharmaceutical University, Toyama, Japan
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Abstract |
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Key Words: developmental change gender difference MRI myelination
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Introduction |
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As evidenced by post-mortem and animal studies, one of the most prominent changes in the adolescent brain is a massive elimination or pruning of cortical synapses (Huttenlocher, 1994; Rakic et al., 1994
). Post-mortem studies have also revealed a protracted progression of myelination during adolescence and adulthood (Yakovlev and Lecours, 1967
; Benes, 1989
; Benes et al., 1994
). In vivo examinations of normal brain development by magnetic resonance imaging (MRI) have demonstrated that gray matter decreases and white matter increases from childhood through adulthood (Jernigan et al., 1991
; Pfefferbaum et al., 1994
; Caviness et al., 1996
; Reiss et al., 1996
; Sowell et al., 1999a
, 2002
, 2003
; De Bellis et al., 2001
). The changes in gray and white matter volumes are considered to reflect the dendritic pruning process and myelination/axonal growth, respectively. These maturational changes have been reported to show regionally variable patterns; a reduction in cortical gray matter occurs primarily in the dorsal parietal and frontal regions (Giedd et al., 1999
; Sowell et al., 1999b
, 2001
), along with a decrease in subcortical gray matter (Giedd et al., 1996a
; Thompson et al., 2000
) and an increase in white matter in the internal capsule and arcuate fasciculus (Paus et al., 1999
). Some reports have highlighted gender-specific maturational changes of the developing brain (Giedd et al., 1996a
,b
, 1999
; De Bellis et al., 2001
). However, the full spatial and temporal distribution and significance of structural changes in the brain during adolescence are not yet established. Notably, only a few MRI studies have focused on the developmental changes of the hippocampus during adolescence (Giedd et al., 1996b
; Sowell and Jernigan, 1998
). Further, to our knowledge, few studies have focused on the age range of adolescence by comparing the brain morphology between the beginning and the end of adolescent period.
We performed cross-sectional comparisons of high-resolution MRI between younger adolescent and elder adolescent subjects using both a whole-brain analysis by voxel-based morphometry (VBM) and a volumetric region-of-interest (ROI) analysis of the hippocampus and parahippocampal gyrus.
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Materials and Methods |
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Twenty-three healthy younger adolescent subjects (10 males and 13 females; age range = 1314 years) and 30 healthy elder adolescent subjects (15 males and 15 females; 1821 years) were included in this study. Demographic data of the subjects are presented in Table 1. All subjects were right-handed, and were screened by interviews using questionnaires for perinatal, early developmental, educational, medical, neurological or psychiatric abnormalities. Parents were also interviewed for the younger adolescent subjects. Digit Span, Vocabulary, and Block Design subtests of the Wechsler Intelligence Scale for Children-Third Edition (WISC-III) were administered to all younger adolescent subjects. Nineteen of the 30 elder adolescent subjects completed the homologous three subtests of the Wechsler Adult Intelligence Scale Revised (WAIS-R). The Vocabulary and Block Design subtests provided an estimate of full-scale IQ (Silverstein, 1982). The Minnesota Multphasic Personality Inventory (MMPI) was administered to all late adolescent subjects, and subjects were excluded if any T-score exceeded 70. The subjects were recruited from among the community by an advertisement except 11 elder adolescent subjects who were recruited from among medical and pharmaceutical students in the early phase of this study and did not undergo the WAIS-R subtests. There was no significant difference between younger adolescent subjects and elder adolescent subjects in gender, handedness, parental education or estimated IQ. Written informed consent was obtained from all subjects and also from parents of the younger adolescent subjects. This study was approved by the Committee on Medical Ethics of Toyama Medical and Pharmaceutical University.
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MRI scans were acquired with a 1.5 T scanner (Vision, Siemens Medical System, Inc., Erlangen, Germany). A three-dimensional (3-D) T1-weighted gradient-echo sequence FLASH (Fast Low-Angle Shots) with 1 x 1 x 1 mm voxels was used. Imaging parameters were: TE = 5 ms; TR = 24 ms; flip angle = 40°; field of view = 256 mm; matrix size = 256 x 256.
Voxel-based Comparison of Whole Brain Gray Matter
Voxel-based morphometry was performed according to the methods described by Ashburner and Friston (2000). After transformation of 3-D magnetic resonance images to the ANALYZE format, they were processed using the Statistical Parametric Mapping (SPM) 99 software (Wellcome Department of Cognitive Neurology, Institute of Neurology, London, UK) running in MATLAB 5.3 (Mathworks Inc., Sherborn, MA) on a Windows-platform computer. The images of each subject were spatially normalized by transforming all subjects' data to the same standard stereotactic space (Talairach and Tournoux, 1988
). The normalization procedure includes estimation of the optimum 12-parameter affine transformation (linear normalization) and 7 x 8 x 7 basis functions (nonlinear normalization). The spatially normalized images were then segmented into gray matter, white matter, and cerebrospinal fluid (CSF) (Ashburner and Friston, 1997
) with a correction for non-uniformity of image intensity. The segmentation procedure in SPM99 employs a modified mixture model cluster analysis to identify voxel intensities matching particular tissue types (gray matter, white matter and CSF) combined with an a priori knowledge of the spatial distribution of these tissues in normal subjects, derived from probability maps. The segmented images were processed to automatically remove any remaining non-brain matter. The gray matter segments were smoothed with a 12 mm full width at half maximum isotropic Gaussian kernel to reduce confounds caused by individual differences in gyral anatomy. The intensity in each voxel of the smoothed data is a locally weighted average of gray matter concentration from a region of surrounding voxels, the size of the region being defined by the size of the smoothing kernel (Ashburner and Friston, 2000
).
Comparison between the younger and elder adolescent groups was performed by an analysis of covariance (AnCova) model for global normalization with overall grand mean scaling (Friston et al., 1990). This statistical option normalizes the segmented brain images to the same total amount of gray matter while preserving regional differences in gray matter concentration. Gender was also treated as a nuisance covariate. To test the statistical significance of regionally specific group effects, the SPM{T} statistic was used to evaluate two linear contrasts (more or less gray matter in younger adolescents than in elder adolescents). Statistical significance was defined as P < 0.05 corrected for all voxels.
Volumetric Analysis of Regions of Interest
Image processing for volumetric ROI analysis has previously been described in detail (Takahashi et al., 2002; Zhou et al., 2003
). Briefly, on a Unix workstation (Silicon Graphics, Inc., Mountain View, CA), the image data were processed with the software package Dr. View 5.0 (Asahi Kasei Joho System Co., Ltd., Tokyo, Japan). Brain images were realigned in three dimensions and reconstructed into entire contiguous coronal slices of 1 mm thickness, perpendicular to the anterior commissureposterior commissure line. The whole cerebrum was separated from the brainstem and cerebellum. According to the Alpert algorithm (Alpert et al., 1996
), the signal-intensity histogram distributions across the whole cerebrum were used to segment the voxels semi-automatically into gray matter, white matter and CSF. Using the thresholds between the tissue compartments, volumes of whole hemispheric gray matter and white matter were calculated. Intracranial volume (ICV) was also measured as described previously (Zhou et al., 2003
). Cerebrospinal fluid volume was calculated by subtracting the whole cerebral volume from the volume of the supratentorial part of the intracranial cavity.
The hippocampus and the parahippocampal gyrus were manually outlined on consecutive 1 mm coronal slices, from anterior to posterior, with the corresponding sagittal and axial planes simultaneously presented for reference. The demarcations of the hippocampus and parahippocampal gyrus in a representative subject are presented in Figure 1. The anterior boundary of the hippocampus was determined by reference to the sagittal plane since the boundary between the hippocampus and the amygdala is more readily identified on the sagittal plane (Convit et al., 1999). The alveus was used to differentiate the hippocampal head from the amygdala and served as the superior boundary of the whole hippocampus. The inferior boundary was the white matter of the parahippocampal gyrus. The lateral and medial boundaries were the inferior horn of the lateral ventricle and the mesial edge of the temporal lobe, respectively. For the parahippocampal gyrus, the most anterior slice was defined by the appearance of the white matter tract (temporal stem) linking the temporal lobe with the rest of the brain. The parahippocampal gyrus was separated laterally by using a line drawn from the most lateral border of the hippocampal flexure to the collateral sulcus, and superiorly by the inferior gray border of the hippocampal formation. The most posterior slice for both the hippocampus and the parahippocampal gyrus was at the level of the last appearance of the fiber of the fornix. Volumes of gray and white matter of the hippocampus or of the parahippocampal gyrus were measured together.
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Statistical analyses were performed using repeated measures multivariate analysis of variance with ICV as a covariate (MANCOVA) for each region, with group (younger adolescents, elder adolescents) and gender (male, female) as between-subject factors and hemisphere (right, left) as a within-subject factor. Post hoc Tukey's honestly significant difference tests modified for unequal sample sizes were employed to follow up the significant main effects or interactions yielded by MANCOVA. Statistical significance was defined as P < 0.05 (two-tailed).
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Results |
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SPM maps showing regional gray matter differences between the groups are illustrated in Figure 2 in which the presetting of height threshold, P = 0.001 (uncorrected) was adopted, for illustrative purposes only, to demonstrate also tendencies toward more or less gray matter. In this presetting, the elder adolescent subjects had more gray matter than the younger adolescents in the bilateral medial temporal regions and the hypothalamus (Fig. 2A). On the other hand, the elder adolescents had less gray matter than the younger adolescents in the dorsolateral frontal and parietal regions, and in the right cerebellum (Fig. 2B).
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Volumes of the intracranial cavity, CSF, whole hemispheric gray matter and white matter, hippocampus, and parahippocampal gyrus are presented in Table 3. MANCOVA for the whole gray matter revealed significant main effects of group (F = 49.52, df = 1, 48, P < 0.001) and hemisphere (F = 19.40, df = 1, 49, P < 0.001); the elder adolescent subjects had significantly smaller gray matter volumes than the younger adolescent subjects (post hoc test, P < 0.001), and the gray matter volume was larger in the left hemisphere than in the right hemisphere (post hoc test, P < 0.001). In MANCOVA for the whole white matter, there were also significant main effects of group (F = 13.27, df = 1, 48, P < 0.001) and hemisphere (F = 127.67, df = 1, 49, P < 0.001); in contrast to gray matter, the elder adolescent subjects had significantly larger white matter volumes than the younger adolescent subjects (post hoc test, P = 0.005), and the white matter volume was larger in the right hemisphere than in the left hemisphere (post hoc test, P < 0.001). There was no other main effect or interaction in MANCOVAs for the whole gray or white matter volume. Further, the CSF volume was significantly larger in elder adolescent subjects than in the younger adolescent subjects (main effect of group in ANCOVA; F = 22.09, df = 1, 48, P < 0.001 and post hoc test; P < 0.001).
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Discussion |
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The present VBM analysis could compare relative amount of gray matter between the groups, since the images of each individual were normalized to the same total amount of gray matter (see Materials and Methods). This means that an increase or decrease in gray matter in circumscribed areas might lead not only to the appearance of change in these areas, but also to an apparent change in the opposite direction in unchanged areas. In the present case, however, such false-positive results seem unlikely to have occurred in the VBM results, because similar findings were obtained from the volumetric ROI comparisons controlled for ICV, which was almost perfectly matched between the younger and elder groups.
To our knowledge, there have been two MRI studies which examined the maturational changes in the hippocampus during the age range covering adolescence (Giedd et al., 1996b; Sowell and Jernigan, 1998
). The volume of the mesial temporal lobe, including the hippocampus, amygdala, uncal cortex and parahippocampal gyrus, was reported to show age-related increase in healthy subjects aged 838 years (Sowell and Jernigan, 1998
). Another study also demonstrated an age-related increase in volume of the hippocampus in female subjects aged 418 years (Giedd et al., 1996b
). The result of the present study is consistent with those of the previous studies in suggesting that volume expansion of the hippocampus occurs, but indicates volume changes more specifically during adolescence. However, it should be noted that the present study is limited by the fact that the trajectories of hippocampal development can not be examined by regression analyses because of a gap of five years between the younger and elder adolescent groups.
In the hippocampal formation, postnatal neuronal proliferation occurs only in the dentate gyrus, in both rodents and primates. In rats, the numbers of dentate granule cells have been reported to increase during both the juvenile and adult periods (Bayer et al., 1982: Kuhn et al., 1996
). There has also been evidence for continuous generation of neurons in the hippocampal dentate gyrus of adult monkeys (Kornak and Rakic, 1999
). These reports suggest the occurrence of neurogenesis in the dentate gyrus during adolescence and adulthood in humans, but direct data have not been available.
In contrast, myelination, a broadly accepted marker for the functional maturation of the central nervous system, appears to continue long after birth in the human hippocampus. Postnatal increases of myelination in the superior medullary lamina, which links the hippocampal formation with the entorhinal and cingulate cortices, have been reported to occur during childhood, adolescence, and even adulthood (Benes, 1989; Benes et al., 1994
). It has also been demonstrated that myelination in the perforant path lasts in childhood until adolescence, after which, however, the pattern remains unchanged (Arnold and Trojanowski, 1996
). Considering the robust increases in the extent of myelination reported in post-mortem studies (Benes, 1989
; Benes et al., 1994
), it is likely that the volume of the hippocampus is expanded by an increase in myelination in adolescence.
In our volumetric ROI analysis, larger hippocampal volume observed in the elder adolescents in comparison with the younger adolescents may be explained by such volume expansion resulting from the increase in myelination during adolescence. In the VBM analysis, however, it is not clear how increased myelination in the hippocampus would result in an increase in tissue volume quantified as gray matter on MRI. In a small structure with complex gray and white matter composition, such as the human hippocampus, it can be speculated that an increase in myelination increases the volume of the structure but does not sufficiently alter tissue signal characteristics to change the classification of the automatically determined gray matter voxels, as discussed in the previous study (Sowell and Jernigan, 1998).
It is well known that normal gender differences exist in human brain anatomy (Nopoulos et al., 2000; Goldstein et al., 2001
; Gur et al., 2002
), although the timing and course of such differential development are not fully understood. With respect to the postnatal brain maturation, recent MRI studies demonstrated that males had more prominent age-related gray matter decreases (De Bellis et al., 2001
) and white matter increases (Giedd et al., 1999
; De Bellis et al., 2001
) compared with females during childhood and adolescence. The post-mortem study revealed that myelination in the hippocampus occurred earlier in females than in males during childhood and adolescence (Benes et al., 1994
). The MRI study also demonstrated hippocampal volume increases in female subjects aged 418 years, which were younger than our subjects (Giedd et al., 1996b
). Animal studies have suggested that estrogen has stimulating effects on neuron proliferation (Tanapat et al., 1999
), dendritic spine increases (Gould et al., 1990
) and synaptogenesis (Woolley et al., 1996
) in the hippocampus. Estrogen has also been reported to induce myelination in the rat brain (Prayer et al., 1997
). Considering these findings together, it may be suggested that, in our female subjects, maturational processes in the hippocampus had proceeded earlier than in males and had become blunted to be detected as a volume difference between the younger and elder subjects. However, it is necessary to include subjects with the age range missing in the present study or to longitudinally follow up the same subjects from childhood through late adolescence to specifically address this issue.
Links between the limbic structures and the neocortex are thought to be responsible for the integration of emotion with cognition (Benes, 1994). The hippocampus, which has reciprocal connections with the cingulate and entorhinal cortices, is one of the important components in the corticolimbic circuitry of the human brain. The volume expansion of the hippocampus in the advanced phase of human brain development during adolescence may involve a more effective interplay between cognitive processing and emotional reactivity mediated by such circuitry. The finding of male-specific changes in the hippocampal volume in the present study may have some relevance to the development of gender differences in cognition and emotion.
Another possible implication of the present findings may stem from recent neuroanatomic findings in schizophrenia, in which volume reduction in the hippocampal region has repeatedly been reported even in its first episode and predominantly in male patients (Lawrie and Abukmeil, 1998; Shenton et al., 2001
). Schizophrenia is associated with deterioration in emotional experience and cognition, and has a typical age at onset during late adolescence and early adulthood. A possibility is suggested that some abnormality in morphological maturation of the hippocampus resulting in disruption of normal volume expansion during adolescence may be involved in the development of psychotic symptoms in schizophrenia, or may increase the susceptibility to develop schizophrenia as has been hypothesized (Seidman et al., 2002
; Kurachi, 2003
). Given that the maturational process in the hippocampus during adolescence is more active in males than in females, an insult to it would be able to cause structural abnormalities in the hippocampus predominantly in male subjects. Indeed, there is evidence that the severity of psychotic symptoms is significantly correlated with the hippocampal volume reduction in male patients with schizophrenia (Bogerts et al., 1993
). Decreases in myelination-related gene expression observed in post-mortem brains of schizophrenia patients (Hakak et al., 2001
: Davis et al., 2003
) also lend support to the likelihood that disturbed myelination in the hippocampus during adolescence plays some role in the development of schizophrenia.
In conclusion, while the present data are from a cross-sectional sample and need to be replicated in a longitudinal study, the findings suggest that a robust maturational process is ongoing during adolescence in the human hippocampus. These findings may have some implications not only in normal development in cognition and emotion during adolescence, but possibly in the mechanisms underlying neuropsychiatric disorders such as schizophrenia.
Address correspondence to Michio Suzuki, Department of Neuropsychiatry, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. Email: suzukim{at}ms.toyama-mpu.ac.jp.
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Acknowledgments |
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