Cortical thickness asymmetry from childhood to older adulthood

NeuroImage 83 (2013) 66–74

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Cortical thickness asymmetry from childhood to older adulthood Dongming Zhou a,1, Catherine Lebel a,2, Alan Evans b,3, Christian Beaulieu a,⁎ a b

Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

a r t i c l e

i n f o

Article history: Accepted 25 June 2013 Available online 1 July 2013 Keywords: Brain maturity Cortical asymmetry Cortical thickness Development MRI

a b s t r a c t Age-related thinning of the cortical mantle varies regionally, leading to hemispheric asymmetries in cortical thickness that may emerge at various stages of development and aging. Cortical asymmetry may play a role in modulating the functional maturation (or degradation) of language and cognition in humans, but its evolution over the lifespan is unknown. Here cortical thickness was negatively correlated with age in 274 5–59 year old, right-handed healthy participants. Pre-adolescents showed limited regions of cortical asymmetry focused on medial occipital lobe (R N L) and inferior frontal gyrus (R N L), namely vision and language relevant areas. More extensive frontal (lateral R N L, medial L N R) and parietal lobe (lateral L N R, medial R N L) asymmetries emerged after adolescence, and increased during aging. Changes of cortical asymmetry in these regions may be linked to specialization of the brain with maturity. © 2013 Elsevier Inc. All rights reserved.

Introduction Hemispheric asymmetry in the human brain, particularly in cortical gray matter, is associated with language, motor and cognitive functions and may depend on a variety of factors related to heredity, development and pathology (Toga and Thompson, 2003). It has been observed, initially from autopsy and later from imaging, that the frontal right hemisphere protrudes more anteriorly and is often wider than the left, and the left occipital lobe extends beyond and is often wider than the right in many individuals, so-called “Yakovlevian torque” (LeMay, 1976; Toga and Thompson, 2003). This asymmetry extends to the thickness of the cortex, measured from in vivo T1-weighted magnetic resonance images (MRI) as the distance between the pial–cortical surface and gray–white matter surface (MacDonald et al., 2000), that differs in analogous regions of the left and right hemispheres in healthy young adults (Luders et al., 2006). This structural morphology reflects differences of gray matter volume (Takao et al., 2011; Tanaka et al., 2012; Weinberger et al., 1982) and cortical thickness (Luders et al.,

⁎ Corresponding author at: Department of Biomedical Engineering, 1098 Research Transition Facility, University of Alberta, Edmonton, AB T6G 2V2, Canada. Fax: +1 780 492 8259. E-mail addresses: [email protected] (D. Zhou), [email protected] (C. Lebel), [email protected] (A. Evans), [email protected] (C. Beaulieu). 1 Postal address: Department of Biomedical Engineering, 1098 Research Transition Facility, University of Alberta, Edmonton, AB T6G 2V2, Canada. 2 Postal address: Research Unit, Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta T3B 6A8, Canada. 3 Postal address: McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. 1053-8119/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neuroimage.2013.06.073

2006) in frontal (greater in the right), middle (greater in the left planum temporale) and occipital regions (greater in the left). The pattern of cortical asymmetry may inform about specific structural abnormalities linked to functional deficits associated with psychiatric (e.g. schizophrenia) and neurological (e.g. Alzheimer's) disease (Haller et al., 2009; Hamilton et al., 2007; Kim et al., 2012; Li et al., 2012; Long et al., 2012; Shaw et al., 2009). Although cortical asymmetry was not explicitly assessed versus human intelligence, there are some studies that have looked at relationships between cortical thickness and IQ which have found significant correlations that differed between hemispheres (Choi et al., 2008; Karama et al., 2011; Narr et al., 2007; Shaw et al., 2006; Yang et al., 2013). Cortical asymmetry can develop as a result of hemispheric counterparts not maturing at the same time, causing structural and functional asymmetries important for specialization and operational efficiency. From childhood to adulthood, the brain matures with a process of progressive myelination (Benes et al., 1994) and synapse elimination (Bourgeois and Rakic, 1993; Huttenlocher and Dabholkar, 1997). Myelination progresses from inferior to superior and posterior to anterior: the brain stem and cerebellum are myelinated first, followed by occipital, parietal and temporal cerebral areas, and lastly the frontal lobes (Benes et al., 1994). Patterns of cortical thinning, as measured on MRI, are in line with those of myelination: parietal and occipital areas exhibit greater thickness decreases than other regions during childhood to young adulthood (Sowell et al., 2004; Tamnes et al., 2010; van Soelen et al., 2012); while frontal and temporal areas show more age-related change from young to older adulthood (Fjell et al., 2009; Lemaitre et al., 2012; Westlye et al., 2010). As a result of bilateral cortical maturity, the asymmetry of regional gray matter volume, which is present at birth (Gilmore et al., 2007), undergoes a developmental progression in childhood and adolescence (Giedd et al., 1996; Reiss et al., 1996). The

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leftward asymmetry in the occipital region seen at birth (Gilmore et al., 2007) appears preserved at adolescence (Giedd et al., 1996; Reiss et al., 1996), while rightward asymmetry of prefrontal areas in children and adolescents (Giedd et al., 1996; Reiss et al., 1996) emerges from symmetric volumes at birth (Gilmore et al., 2007). The cortical asymmetry has shown alterations in childhood neurological disorders, such as autism (Herbert et al., 2005) or prenatal alcohol exposure (Sowell et al., 2002). Only one study has investigated typical developmental trends of cortical thickness asymmetry, specifically over an age range of 3–22 years (Shaw et al., 2009). Relative to the contra-lateral hemisphere, the left inferior frontal and the right occipital–parietal areas were thicker in healthy children, but there was an inversion of this asymmetry pattern after adolescence. However, the progression of cortical thickness asymmetry throughout the lifespan is unknown. In addition to charting the typical development and aging profile for use as a baseline to better understand clinical disorders, observed structural changes in cortical asymmetry may underpin developmental milestones in specialization of brain regions (Jung and Haier, 2007). In the current cross-sectional study, we investigate patterns of cortical maturation and asymmetry in 274 healthy subjects over a wide age range of 5 to 59 years to determine the trajectory of cortical asymmetry in healthy development and aging from childhood to older adulthood. Materials and methods Participants and imaging Participants for this study were 274 healthy (150 females/124 males), right-handed individuals aged 5–59 years recruited from the Edmonton area. Original recruitment pooled 288 participants, but only scans of right handed participants with good quality of images (visual inspection and CIVET quality control) were analyzed in the current study. Health of participants was verified by asking a series of questions to ensure there was no history of neurological or psychiatric disease or brain injury. High resolution (1 × 1 × 1 mm3) 3D T1-weighted images were acquired on a 1.5 T Sonata (Siemens Medical Systems, Erlangen, Germany) using MPRAGE with TE = 4.38 ms, TR = 1870 ms, and TI = 1100 ms, 4:29 min. Total acquisition time was approximately 25 min and also included diffusion tensor imaging, T2-weighted, and fluid-attenuated inversion recovery (FLAIR) imaging, although none of that data is presented here. Head motion was minimized using ear pads. The study was approved by the institution's health research ethics board and written informed consent was obtained from all participants. Handedness was self-reported for older children and adults. For most of the younger children under 13 years, the Edinburgh Handedness Inventory was given to the parents. Only scans of right handed participants were selected to be analyzed in the current study. The images of 274 participants were processed with the CIVET 1.1.11 pipeline online with CBRAIN (https://cbrain.mcgill.ca/) at the Montreal Neurological Institute (MNI) with normalization to the ICBM-152 symmetric template (Lyttelton et al., 2007). Whole brain, total gray matter and total white matter volume were obtained by the tissue-classification algorithm in the CIVET pipeline (Tohka et al., 2004). Cortical thickness was measured as the distance between corresponding vertices of inner and outer surfaces of gray matter across 40,962 vertices in each hemisphere (Kim et al., 2005). Thickness data were blurred using a surface-based diffusion smoothing kernel of 20 mm FWHM that preserves cortical topology (Chung et al., 2003). Statistical analysis An asymmetry index (AI) was calculated at each vertex by AI = (Left − Right)/(0.5 × (Left + Right)). Positive asymmetry indices indicate leftward asymmetry (left thicker than right) and negative

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asymmetry indices indicate rightward asymmetry. Statistical analyses were conducted using the SurfStat toolbox (www.math.mcgill.ca/ keith/surfstat/) for Matlab (R2009a, The MathWorks, Natick, MA, USA) in the following analyses. Significance values were corrected by false discovery rate (FDR) with a level of 0.05. For a visual presentation of the cortical thickness and asymmetry at different age spans, participants were separated into six groups based on their ages to yield similar sample sizes per group, with the number of males and females roughly balanced in each group (see Fig. 1). The mean thickness and AI in each vertex were obtained per group. Statistical analyses of group comparisons with a linear model controlling for gender were first applied between each of the 6 groups to determine cortical thickness and asymmetry differences among age spans. Within each of the six groups, one sample t-tests of AI were performed for each vertex pair (comparing to a test statistic of 0) with a linear model controlling for age and gender. Age effects on either cortical thickness or its asymmetry were tested with linear models controlling gender, overall brain volume and interactions between age and gender in all participants. To better illustrate the evolving asymmetry in the context of bi-hemispherical cortical morphology, the mean thickness and mean AI in the largest and the second largest clusters of significant age effect on AI were fit with linear regressions. Cortical thickness differences between genders were compared using a linear model controlling for age and overall brain volume. Age effect on cortical thickness in males and females, respectively, as well as age–gender interactions were tested controlling for overall brain volume. Likewise, cortical asymmetry differences between males and females were tested with a linear model of AI controlling for age. Trajectory differences in asymmetry development between genders were evaluated by testing age effects and age-by-gender interactions on AI in each gender. Movie 1 was made to better appreciate the life span development of cortical thickness and its asymmetry across the age groups. A “sliding window” approach was used to generate mean maps in 225 subgroups, where each group contained 50 participants. Group 1 contained the first 50 youngest participants, and then Group 2 were those counted from the second youngest one to the 51st participant, and so on (this is reflected by vertical yellow bars in the movie). The mean age was 8.3 years for the first group and 49.8 years for the last group. But because we had more participants in younger ages than in older ages, the mean ages for these 225 subgroups were not evenly distributed across the full age range. In order to display the thickness and AI morphology in a constant speed, we calculated the vertex thickness and AI on the sequence of 8.4, 8.5, … 49.7 years with 0.1 year interval with a linear interpolation algorithm from two groups whose mean age is closest to the years in the sequence. Thus we obtained 414 maps of vertex thickness and AI. We added these maps as each frame of the movie with the first frame as the map of Group 1 and the last frame (i.e., the 416th frame) as the map of group 225. The full movie length is 16.6 s with a speed of 25 frames per second.

Results Regional decrease in cortical thickness with age Mean cortical thickness in our six age groups (Group 1: 5–9 years, n = 45, 21 females; Group 2: 10–14 years, n = 41, 22 females; Group 3: 15–19 years, n = 47, 24 females; Group 4: 20–29 years, n = 51, 28 females; Group 5: 30–39 years, n = 44, 25 females; Group 6: 40– 59 years, n = 46, 29 females) is shown in Fig. 1. Thickness patterns were similar across all the age groups, with greatest thickness observed in bilateral insula, temporal lobe, temporal pole and medial frontal lobe, and the thinnest cortex in the bilateral parietal and occipital lobes. Qualitatively, most regions appeared thinner in older groups than in young groups, except the temporal poles, which remained relatively stable

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Fig. 1. Mean cortical thickness from children to older adults for six age groups. Participants were assigned to groups according to age, while ensuring that sample sizes were similar between groups and that sex was balanced. Colors from purple, blue, green, yellow to red, represent cortical thickness from thinner to thicker. The brain stem was not included in any analysis. Most regions showed smaller cortical thickness in older groups except the temporal poles, but similar patterns of thickness were observed in all groups, with the thickest regions found in the medial frontal cortex while the paracentral and occipital areas were thinnest.

across age groups. Quantitative between group analysis showed significant cortical thickness reductions with age in extended regions among almost all the comparisons between each of the 6 groups except between Groups 1 and 2 (Supplementary Fig. 1). Notably, comparisons among adjacent older groups showed more focal regions of reduced cortical thickness such as: medial cingulate between Groups 3 and 4; motor cortex and lateral frontal and temporal lobes between Groups 4 and 5; and mainly frontal between Groups 5 and 6. The age-effect on thickness (modeled linearly on the whole sample) revealed a significant decrease in most vertices (Fig. 2a). The lateral and medial paracentral regions, medial middle frontal gyrus, left inferior frontal gyrus, bilateral superior temporal areas and fusiform gyrus had more substantial age effects than other cortical regions (dark blue or purple vertices in Fig. 2a), with steeper slopes of thickness decrease with age (Fig. 2b).

Progressive cortical asymmetry with age Cortical asymmetry was similar in all six age groups in the lateral frontal and the medial occipital regions which were thicker in the right hemisphere and conversely, the lateral occipital region which was thicker in the left (Figs. 3a, b). However, the asymmetry index (AI) became more prominent and widespread in the older groups post-adolescence (N15 years). Fewer vertices show significant asymmetry at younger ages than in middle-aged and older adults (Fig. 3b). In Groups 1 and 2 (age range 5–14 years), only the orbital frontal gyrus, portions of anterior cingulate, medial temporal pole, and medial occipital areas were significantly right-lateralized, and there was only one left-lateralized cluster in the lateral superior occipital area. The adolescent Group 3 (14–19 years) shows more rightward

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Fig. 2. Cortical thickness morphology in all participants. (a) t statistic values showing regions where cortical thickness was significantly affected by age from 5 to 59 years (FDR corrected). The thickness decreased with age over much of the brain (cold colors), whereas no areas showed increased thickness (warm colors). (b) The slope of thickness changes, calculated using a linear regression approximation (Δthickness, mm/year), shows the largest reductions in the bilateral paracentral lobule and medial superior frontal cortex.

asymmetry in the lateral frontal lobe and newly emerged medial parietal, while also showing more leftward asymmetry in lateral parietal and newly emerged medial superior frontal gyrus. In contrast, in the oldest Groups 5 and 6 (30–59 years), the laterality gets more progressive: the left-lateralized cluster in the region where the lateral occipital, parietal and temporal areas converge became larger and moved more anterior, the left-lateralized medial superior frontal gyrus remains, the right-lateralized cluster in the lateral inferior frontal region became larger with age, and the medial occipital region became more right-lateralized, expanding to include the medial parietal region. Notably, a small portion of the anterior cingulate is the only region that becomes more symmetric with age, as it loses the rightward asymmetry present in the younger groups. With the exception of the rightward temporal pole, most of the temporal lobe shows little cortical thickness asymmetry in any age group, although there are more scattered regions in Group 6 (40–59 years) (Fig. 3b). However, there were no significant group differences of AI between any pair of the 6 groups. The age-effect on AI of the whole sample revealed significant decreases in lateral inferior frontal regions, and in medial parietal and paracentral regions, indicating that they became more right-lateralized (Fig. 4a). Significant increases of AI (indicating more left-lateralization) with age were found in lateral parietal, and in medial inferior and middle frontal areas (Fig. 4a). The mean thickness and AI of the four largest clusters with significant age effects (either positive or negative) are shown in Figs. 4b–e to illustrate the regional development of AI with age. In the orbital frontal gyrus cluster (b; showing a negative age effect), most of the vertices were thicker in the right hemispheres across the entire age range, and this asymmetry increased with age, due to more substantial reductions of cortical thickness with age in the left hemisphere (Fig. 4b). The medial parietal and paracentral areas were symmetric in children and young adults, with roughly half of participants showing some degree of leftward asymmetry and half demonstrating rightward asymmetry. However, because the left side demonstrated greater reductions during aging, this region became more rightward lateralized after young adulthood (Fig. 4c). The cluster on supramarginal gyrus was symmetric in early years but leftward asymmetry increased with age (Fig. 4d). The cluster in medial superior frontal gyrus became left-

lateralized in adolescence and then progressively more leftward in older years (Fig. 4e). Gender differences of age effect Regional AI patterns and age effects were similar when genders were analyzed separately, and when they were combined. There were no significant differences of AI between genders nor were there any age by gender interactions, suggesting that males and females underwent similar trajectories of asymmetry development (data not shown). However, after controlling for total brain volume, analysis of thickness difference between genders revealed relative thinner cortex in males than females in bilateral para-central, inferior orbital frontal, superior and middle temporal, fusiform and medial occipital areas. Although there were thickness differences between genders, age effect on thickness showed that rates of reductions of cortical thickness are similar in both genders: most regions appeared to be thinner with age, except the temporal poles, without age and gender interactions. Discussion In this study, hemispheric differences in cortical thickness were observed to change with age. There was an interesting dichotomy of asymmetry patterns between the frontal and posterior parts of the brain. In the frontal part of the brain, the left lateral vertices were thinner than the right, and the left medial vertices were thicker. Conversely, in the posterior part of the brain, left lateral vertices were thinner and left medial vertices were thicker than their right hemisphere counterparts. This regional asymmetry pattern, particularly in the lateral aspects of the brain, is consistent with previously reported hemispheric distortions (“Yakovlevian torque”), specifically that the right frontal region is geometrically wider than the left, and the left occipital lobe wider than the right (LeMay, 1976; Toga and Thompson, 2003). Also, the lateral frontal lobes develop more rightward asymmetry while the medial frontal lobes develop more leftward asymmetry with age. In contrast, the lateral side of parietal lobes developed more leftward

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Fig. 3. Cortical asymmetry for six age groups. (a) Asymmetry index (AI) for each of the six age groups. An AI was calculated for each corresponding pair of vertices in every individual. Positive asymmetry indices (rendered in yellow and red colors) indicate leftward asymmetry (left thicker than right). Green and blue colors represent rightward asymmetry. Asymmetry progresses as a function of age but some overall patterns persist. The rightward asymmetry stays in lateral inferior frontal gyrus and medial occipital gyrus while the leftward asymmetry moves more anterior from parietal–occipital areas to temporal–parietal–occipital areas, and the medial frontal became more leftward in older groups. (b) The one sample t statistic values of asymmetry index (compared with 0) are shown for vertices with significant asymmetry in each group. The brain progresses from being mostly symmetric at the youngest ages to being quite asymmetric at the older ages. In particular there is a very interesting pattern where the lateral and medial sides have reversed lateralities in the anterior and posterior regions.

asymmetry and the medial side developed more rightward asymmetry with age (Figs. 3 and 4a). The change in asymmetry pattern mirrors the asymmetric progression of myelination in each hemisphere, which may push the overlying cortex to expand tangentially (Seldon, 2005). This is in line with previous observations in the frontal part of the brain,

namely that rightward asymmetry of gray matter volume in the lateral inferior frontal gyrus occurred together with rightward asymmetry of diffusion parameters of frontal white matter tracts, while in posterior regions leftward asymmetry was observed on the lateral side and this occurred in conjunction with leftward asymmetry of white matter

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Fig. 4. Cortical asymmetry morphology over age in all participants. Age effect on asymmetry index (AI) is illustrated in (a). The vertices that became significantly more rightward lateralized with age are rendered in cold colors (green and blue), and vertices that become more leftward lateralized with age appear in warm colors (yellow and red). The scatter plots of the mean thickness of the four largest significant clusters are shown in (b) for decreased AI-age effect in the region of the inferior frontal gyrus, (c) for decreased AI-age effect in the medial parietal to paracentral gyrus, (d) for increased AI-age effect in the lateral parietal–temporal junctions, and (e) for increased AI-age effect in the medial frontal areas. The upper panels are the thickness in each of the hemispheres (left thickness in green triangles with a solid line; right thickness in red squares with a dashed line). The lower panels with blue circles are the asymmetry indices as a function of age. The zero asymmetry index is plotted in gray dashed line in each of panel to give an impression of how many participants showed leftward or rightward asymmetry for a given cluster.

diffusion parameters in healthy participants aged 21–29 years (Takao et al., 2011). The regional progression of cortical thickness asymmetry might relate to functional maturation of the brain with age, although links between cortical thickness asymmetry and cognitive function were not assessed in this study. Structural brain asymmetry can be measured in the fetus as early as 18–37 gestational weeks, as evidenced by a larger left temporal lobe (Kasprian et al., 2011) and in 1–4 month old infants by left lateralized diffusion parameters in the arcuate fasciculus and the cortico-spinal tract (Dubois et al., 2009). This structural asymmetry may underlie the functional response to language development at early stages. By presenting speech stimuli in a functional magnetic resonance (fMRI) study, greater activity in the left hemisphere planum temporale was observed in 2–3 month old infants (Dehaene-Lambertz et al., 2002), and progressively more lateralized responses to language have been observed during later stages of the first year of life (MinagawaKawai et al., 2012) continuing to increase with age up to 20 years (Szaflarski et al., 2006). Besides the development of language, the maturation of other cognitive functions may relate to regional asymmetry

between hemispheres. Leftward asymmetry of paracingulate gyrus thickness has been specifically associated with better performance on a test of spatial working memory ability in healthy subjects aged 16–51 years (Fornito et al., 2008). Moreover, the strength of right lateralized blood flow continued to increase with age for visuospatial memory function in 6–16 year old children (Groen et al., 2012). The patterns of asymmetry in both medial and lateral aspects of the frontal and parietal lobes are consistent with the theory that parieto-frontal integration (P-FIT) underpins the development of higher intelligence in humans (Jung and Haier, 2007). Some studies have looked at relationships between cortical thickness and IQ and have found significant correlations that differed between hemispheres (Choi et al., 2008; Karama et al., 2011; Narr et al., 2007; Shaw et al., 2006; Yang et al., 2013). For example, a recent paper by Yang et al. (2013) correlated cortical thickness versus full scale IQ and showed that frontal (left superior frontal gyrus) and parietal (left supramarginal gyrus) regions are only correlated in one hemisphere. The development of asymmetry might be associated with a difference in strength of specialized functionality between hemispheres (Ivry and Robertson, 1998). In the Ivry and

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Robertson theory, the same local region of both hemispheres is specialized for the same functionality, but the strength of processing is lateralized for each side (Ivry and Robertson, 1998). The cortical thickness asymmetry pattern in the current study was also observed in a previous developmental study of 358 typically developing children for their adolescent healthy group (Shaw et al., 2009), but notably was opposite to that reported for their younger children; in particular, the lateral occipital lobe was rightward in their paper and leftward in ours and the inferior frontal region was leftward in their paper and rightward in ours. Therefore, in contrast to their asymmetry inversion suggested to occur ~11 years and ~16 years for inferior frontal and lateral occipital gyri, respectively, we see asymmetry in the younger ages that stays with the same laterality, but strengthens as a function of age. One histological study of cortical thickness in postmortem samples of 19–59 years observed that the superior temporal cortex was slightly leftward (Bogolepova and Belogrud, 2005). The leftward asymmetry of medial frontal area and rightward asymmetry of medial parietal, occipital and inferior frontal gyri in our adult age groups were also observed in a previous study of ~25 year old young adults (Luders et al., 2006). The leftward regional thickness asymmetry in parietal, supramarginal and angular gyri, and the rightward asymmetry in lateral frontal areas were observed in 15–17 year old adolescents (Frye et al., 2010), comparable to our Group 3 (15–19 years). Rightward thickness lateralization in orbito-frontal gyrus has been observed at ~30 years which is comparable to our Groups 4 and 5 (20–39 years), but the asymmetry pattern in their lateral parietal–occipital junctions, medial occipital and frontal areas (Hamilton et al., 2007) was opposite to our study. Discrepancies between these results and those of previous studies may be related to different subject groups (e.g., age range, handedness, sample size) or differences in data acquisition and processing (e.g., scanning parameters, modeling approach, software differences). The pattern of decrease in cortical thickness across the cortical mantle observed in this study is in line with previous cross-sectional findings that cortical thickness decreased across the lifespan (Brown et al., 2012; Fjell et al., 2009; Lemaitre et al., 2012; McGinnis et al., 2011; Salat et al., 2004; Tamnes et al., 2010; Westlye et al., 2010). Also there are longitudinal results that show cortical thickness decreases between ages 9 and 13 years in the frontal pole, parietal and lateral occipital cortices (van Soelen et al., 2012), and between ages 5 and 11 years in the right frontal and bilateral parieto-occipital regions (Sowell et al., 2004). Previous studies demonstrate cortical thickness increases in childhood, starting at age 3.5 years, with peaks before adolescence in the lateral frontal, temporal, parietal and occipital cortices, demonstrating overall cubic trends (Shaw et al., 2008). Similar trajectories were observed in regional gray matter volumes that increase in early childhood, peak in adolescence and decrease afterwards (Giedd et al., 1999; Tanaka et al., 2012). However, in our current study (Figs. 4b–e), we did not observe similar increases of cortical thickness in the young children. Instead, we observed progressive decreases from 5 years, though the lack of participants younger than 5 years in this study precludes observation of cortical changes during this time. These decreasing trends (without an initial thickening) have also been observed in previous studies starting in late childhood to young adulthood age ranges (Tamnes et al., 2010) as well as thinning at young and middle ages (18–59 years) until older ages (60–96 years) (McGinnis et al., 2011). The decreases with age trajectories were also observed in the development of regional gray matter density from 7 to 87 years (Sowell et al., 2003). Regional thickness develops differently across the cortical mantle (Fig. 2). A study of adults aged 60–84 years found that most of the left frontal, parietal, temporal and occipital lobes continued to progressively thin, yet in the right hemisphere only parietal regions continued to thin (Thambisetty et al., 2010). They also observed that the cortex thinned with an anterior–posterior gradient such that cortical thickness decreased at greater rates in frontal and parietal regions relative to temporal and occipital regions (Thambisetty et al., 2010). Postmortem studies of brain myelination (Benes et al., 1994) and synapse

elimination (Huttenlocher and Dabholkar, 1997) demonstrate a progression of maturation from inferior to superior and posterior to anterior during childhood to adulthood. A histological observation cited by Seldon (2005) describes lateralization of myelination between hemispheres and asymmetric cortical thickness over 3 months to 97 years (Kaes, 1907). It should be noted that we've used a simple linear model of cortical changes of thickness or asymmetry with age; but we also observed greater decrease in regional thickness at younger ages that then level off in older adulthood (Figs. 4b–e, Movie 1), with a developmental trajectory similar to previous studies (Brown et al., 2012; Fjell et al., 2009; Lemaitre et al., 2012; McGinnis et al., 2011; Salat et al., 2004; Tamnes et al., 2010; Westlye et al., 2010). So, other models for these cortical thickness trajectories could be investigated in the future. Besides the cortical thickness studies, gray matter density studies show the parietal and visual cortices maturing earlier than frontal cortices (Sowell et al., 1999), which may relate to the importance of early visual experiences in shaping the cortex, or vice-versa (Jiang et al., 2009). The gray matter volume measures showed that fronto-occipital asymmetry is already seen in infants, and that the cortex matures differently between hemispheres mainly in occipital and frontal areas in 0.4– 49 month infants (Tzarouchi et al., 2009). As a result of cortical change, the asymmetry of regional gray matter volume was present as early as a few months after birth such that a leftward asymmetry emerged in the occipital region (Gilmore et al., 2007). This volumetric asymmetry is also observed later in 5–17 year children and adolescents (Reiss et al., 1996). The rightward asymmetry in lateral prefrontal regions was seen at 5–17 years (Reiss et al., 1996), at 4–11 years (Giedd et al., 1996) and at 1 month–25 years (Tanaka et al., 2012), but this regional asymmetry was not present yet in neonates in the first few weeks after birth (Gilmore et al., 2007). At ~65 years regional volume asymmetry patterns were similar to the cortical thickness asymmetry seen in adults of our current study (Kim et al., 2012). No significant cortical thickness asymmetry age-by-gender interactions or differences between males and females were found. This observation is consistent with the previous findings that no statistical significance was found in cortical asymmetry between genders (Hamilton et al., 2007; Luders et al., 2006). This lack of asymmetry differences in gender follows from similar developmental trends in cortical thickness, which is consistent with data from 7 to 87 years (Sowell et al., 2007), suggesting both genders undergo similar development trajectories throughout childhood to older adulthood. Cortical thickness asymmetry may be mediated by neurological pathology, though this complex relationship has not been fully explored. Progressive rightward-lateralization with age in the frontal cortex may be disrupted in attention-deficit/hyperactivity disorder (ADHD) (Shaw et al., 2009) and schizophrenia (Hamilton et al., 2007). The gray matter volume asymmetry can also be altered in autistic children (Herbert et al., 2005) and prenatal alcohol exposed adolescents (Sowell et al., 2002), together suggesting that lack of asymmetry development may relate to pathology. However, greater cortical thickness and asymmetry in adolescents were associated with non-consistent parenting style in their childhood (Frye et al., 2010). A reduction of neocortical asymmetries occurs in patients with Alzheimer's disease (AD) in aging subjects (Kim et al., 2012). Thus the development of cortical thickness asymmetry may be sensitive to early developmental experiences and aging. Likewise, lateralization analysis could be more accurate than direct cortical thickness analysis in distinguishing healthy participants from an at-risk mental state group and a first episode of psychosis group (Haller et al., 2009), again revealing the potential for cortical thickness asymmetry to be used as a clinical marker. This study has several limitations. We only analyzed developmental cortical thickness and asymmetry in right handed participants given the limited number of left handed persons in our subject pool, but developmental asymmetry pattern in left handed subjects should be investigated. Cross-sectional studies such as this have less statistical power than longitudinal studies, and are more at risk of sampling

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bias and cohort effects. The cortical thickness measurement techniques depend on the contrast at the gray/white matter interface on T1-weighted images, which we assume reflects the actual cortex. As the cortical thickness differences are small, more accurate measurement may be possible in the future with higher resolution MRI (voxels less than 1 mm3) using ultrahigh magnetic fields and sensitive radiofrequency array coils. In conclusion, cortical asymmetry provides complementary data not available through absolute measurements of cortical thickness that reduces with age. Children demonstrate more symmetric brains than adults, and future studies may be able to link the development of this asymmetry with functional maturation of language and cognition in the human brain. The current study provides a baseline of how cortical asymmetry develops according to hemispheric thickness alterations across much of the life span, and has many possible applications for the study of neurological and psychiatric disease. Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.neuroimage.2013.06.073. Acknowledgments We thank the Canadian Institutes of Health Research (CIHR) and the Networks of Centres of Excellence (CLLRNet) for operating; Alberta Innovates — Health Solutions (CB) and Natural Sciences and Engineering Research Council (CL) for salary; and Sarah Treit for useful comments on the manuscript. Conflict of interest None. References Benes, F.M., Turtle, M., Khan, Y., Farol, P., 1994. Myelination of a key relay zone in the hippocampal formation occurs in the human brain during childhood, adolescence, and adulthood. Arch. Gen. Psychiatry 51, 477–484. Bogolepova, I.N., Belogrud, T.V., 2005. Some quantitative measures of structural asymmetry in fields 41 and 22 of the human auditory cortex. Neurosci. Behav. Physiol. 35, 379–382. Bourgeois, J.P., Rakic, P., 1993. Changes of synaptic density in the primary visual cortex of the macaque monkey from fetal to adult stage. J. Neurosci. 13, 2801–2820. Brown, T.T., Kuperman, J.M., Chung, Y., Erhart, M., McCabe, C., Hagler, D.J., Venkatraman, V.K., Akshoomoff, N., Amaral, D.G., Bloss, C.S., et al., 2012. Neuroanatomical assessment of biological maturity. Curr. Biol. 22, 1693–1698. Choi, Y.Y., Shamosh, N.A., Cho, S.H., DeYoung, C.G., Lee, M.J., Lee, J.M., Kim, S.I., Cho, Z.H., Kim, K., Gray, J.R., et al., 2008. Multiple bases of human intelligence revealed by cortical thickness and neural activation. J. Neurosci. 28, 10323–10329. Chung, M.K., Worsley, K.J., Robbins, S., Paus, T., Taylor, J., Giedd, J.N., Rapoport, J.L., Evans, A.C., 2003. Deformation-based surface morphometry applied to gray matter deformation. Neuroimage 18, 198–213. Dehaene-Lambertz, G., Dehaene, S., Hertz-Pannier, L., 2002. Functional neuroimaging of speech perception in infants. Science 298, 2013–2015. Dubois, J., Hertz-Pannier, L., Cachia, A., Mangin, J.F., Le Bihan, D., Dehaene-Lambertz, G., 2009. Structural asymmetries in the infant language and sensori-motor networks. Cereb. Cortex 19, 414–423. Fjell, A.M., Westlye, L.T., Amlien, I., Espeseth, T., Reinvang, I., Raz, N., Agartz, I., Salat, D.H., Greve, D.N., Fischl, B., et al., 2009. High consistency of regional cortical thinning in aging across multiple samples. Cereb. Cortex 19, 2001–2012. Fornito, A., Wood, S.J., Whittle, S., Fuller, J., Adamson, C., Saling, M.M., Velakoulis, D., Pantelis, C., Yücel, M., 2008. Variability of the paracingulate sulcus and morphometry of the medial frontal cortex: associations with cortical thickness, surface area, volume, and sulcal depth. Hum. Brain Mapp. 29, 222–236. Frye, R.E., Malmberg, B., Swank, P., Smith, K., Landry, S., 2010. Preterm birth and maternal responsiveness during childhood are associated with brain morphology in adolescence. J. Int. Neuropsychol. Soc. 16, 784–794. Giedd, J.N., Snell, J.W., Lange, N., Rajapakse, J.C., Casey, B.J., Kozuch, P.L., Vaituzis, A.C., Vauss, Y.C., Hamburger, S.D., Kaysen, D., et al., 1996. Quantitative magnetic resonance imaging of human brain development: ages 4–18. Cereb. Cortex 6, 551–560. Giedd, J.N., Blumenthal, J., Jeffries, N.O., Castellanos, F.X., Liu, H., Zijdenbos, A., Paus, T., Evans, A.C., Rapoport, J.L., 1999. Brain development during childhood and adolescence: a longitudinal MRI study. Nat. Neurosci. 2, 861–863. Gilmore, J.H., Lin, W., Prastawa, M.W., Looney, C.B., Vetsa, Y.S., Knickmeyer, R.C., Evans, D.D., Smith, J.K., Hamer, R.M., Lieberman, J.A., et al., 2007. Regional gray matter growth, sexual dimorphism, and cerebral asymmetry in the neonatal brain. J. Neurosci. 27, 1255–1260.

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