The Impact of Sex, Puberty, and Hormones on White Matter Microstructure in Adolescents

Herting, Megan M.; Maxwell, Emily C.; Irvine, Christy; Nagel, Bonnie J.

doi:10.1093/cercor/bhr246

Cited by 302 publications

(268 citation statements)

References 55 publications

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“…Given that lithium showed progressive effects on GM structure during treatment in BD (Lyoo et al, 2010;Moore et al, 2009), to investigate the effect of lithium, we correlated the duration of lithium treatment in months with DTI measures of WM microstructure. We accounted for the effects of nuisance covariates which could influence WM structure: age (Kochunov et al, 2007), sex (Herting et al, 2011), and age at onset of illness. Voxelwise DTI analyses were performed using nonparametric permutation-based testing (Nichols and Holmes, 2002) as implemented in randomized FSL.…”

Section: Data Processing and Analysesmentioning

confidence: 99%

Lithium and GSK3-β Promoter Gene Variants Influence White Matter Microstructure in Bipolar Disorder

Benedetti

Bollettini

Barberi

et al. 2012

Neuropsychopharmacol

142

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Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase 3-b (GSK3-b). The less active GSK3-b promoter gene variants have been associated with less detrimental clinical features of BD. GSK3-b gene variants and lithium can influence brain gray matter structure in psychiatric conditions. Diffusion tensor imaging (DTI) measures of white matter (WM) integrity showed widespred disruption of WM structure in BD. In a sample of 70 patients affected by a major depressive episode in course of BD, we investigated the effect of ongoing long-term lithium treatment and GSK3-b promoter rs334558 polymorphism on WM microstructure, using DTI and tract-based spatial statistics with threshold-free cluster enhancement. We report that the less active GSK3-b rs334558*C gene-promoter variants, and the long-term administration of the GSK3-b inhibitor lithium, were associated with increases of DTI measures of axial diffusivity (AD) in several WM fiber tracts, including corpus callosum, forceps major, anterior and posterior cingulum bundle (bilaterally including its hippocampal part), left superior and inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left posterior thalamic radiation, bilateral superior and posterior corona radiata, and bilateral corticospinal tract. AD reflects the integrity of axons and myelin sheaths. We suggest that GSK3-b inhibition and lithium could counteract the detrimental influences of BD on WM structure, with specific benefits resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections.

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Section: Data Processing and Analysesmentioning

confidence: 99%

Lithium and GSK3-β Promoter Gene Variants Influence White Matter Microstructure in Bipolar Disorder

Benedetti

Bollettini

Barberi

et al. 2012

Neuropsychopharmacol

142

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“…In humans, white matter sexual dimorphisms also become more prominent during puberty and adolescence: in boys, white matter microstructure increases more steeply than in girls (Bava et al, 2011), possibly under the influence of pubertal hormones. Recent human evidence indicates that the pubertal reorganization of white matter pathways is associated with increased levels of pubertal sex steroid hormones (Herting et al, 2012). Lombardo and colleagues (2012) point out that some of their participants (8 -11 years) might have already entered puberty.…”

Section: Review Of Lombardo Et Almentioning

confidence: 99%

Sex Steroids and the Organization of the Human Brain

Peper

Koolschijn²

2012

J. Neurosci.

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Review of Lombardo et al.Studying the biological mechanisms underlying sexual differentiation in the human brain provides important insights into the etiology and trajectory of neurodevelopmental disorders in males and females (Baron-Cohen et al., 2011). Sex steroid hormones, the end products of the hypothalamus-pituitary-gonadal axis, exert powerful effects on the organization and sexual differentiation of brain structures. From animal studies, it has become clear that during early development, exposure of the brain to testosterone and estradiol leads to irreversible changes in the nervous system (McCarthy et al., 2012). Moreover, fetal exposure to sex steroids has a major impact on the sexual differentiation of the brain (McCarthy et al., 2012). For example, high levels of fetal testosterone (FT) result in brain masculinization in experimental animals, such as enlargements of the volume and soma size of the suprachiasmatic nucleus, bed nucleus of the stria terminalis, and ventromedial hypothalamus (Zuloaga et al., 2008).In humans, studies of the effects of FT often rely on indirect measures such as the ratio between the index finger (2D) and ring finger (4D) or on opposite-sex twin studies. Specifically, a smaller 2D:4D ratio correlates with higher FT exposure, and through the intrauterine presence of a male fetus, opposite-sex twin girls are exposed to higher FT levels than same-sex twin girls. Using the latter indirect measure of FT, earlier reports showed that total brain volume and cerebellum volume, typically found to be larger in males, were positively correlated with higher FT exposure (Peper et al., 2009).A recent paper by Lombardo et al. (2012) provided direct evidence for an association between FT levels and sexual differentiation of brain gray matter in humans. In this pioneering study of 28 developing boys, FT levels were determined from amniotic fluid. Amniocentesis was performed between 13 and 20 weeks of gestation, which is a critical period of brain masculinization. When these boys were 8 -11 years old, a structural MRI was made. Using voxel-based morphometry, gray matter regions within the whole brain of these 28 boys were identified showing significant correlations with FT levels. The amygdala and hypothalamus were included as a priori regions of interest. Then, in a second normative sample of 217 (101 boys) children (NIH Pediatric MRI Data Repository), sexual dimorphisms in gray matter were determined. Finally, a conjunction analysis was performed to isolate brain regions whose direction of the FT correlation was congruent with the direction of sexual dimorphism. Lombardo et al. (2012) hypothesized that the size of brain areas that were normally larger in males than in females would correlate positively with FT, whereas the size of brain areas that are normally larger in females would correlate negatively with FT. Results showed that higher levels of FT were associated with larger right temporal/parietal junction and posterior superior temporal sulcus. As predicted, these brain areas were la...

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“…This capacity facilitates enquiries on large samples and investigation of possible differences between males and females. Several research groups [19][20][21][22][23] including ours [17] have used diffusion tensor imaging (DTI) [24] to study sex-related structural differences in the brain, as characterized by alterations in white matter (WM) microstructure and fibre tracts that connect different grey matter (GM) regions, as well as in overall communication architecture of the brain network. Studying the structural brain network, also known as the structural connectome [25], enables the inference of current and future states of brain connectivity at local, global and intermediate (meso) scales.…”

Section: Introductionmentioning

confidence: 99%

“…Previous work on sex differences in brain structure suggested diverse outcomes including microstructural differences demonstrated via changes in DTI-based measures, like fractional anisotropy (FA); namely, increased FA values in major WM regions and tracts in males [19,20,23], and in the corpus callosum in females [22]. Consistent with these findings, we have performed a comprehensive analysis on the structural connectome to elucidate sex differences in terms of individual connections [17], revealing stronger intrahemispheric connectivity (within both hemispheres) in males and stronger inter-hemispheric connectivity in females.…”

Section: Introductionmentioning

confidence: 99%

Establishing a link between sex-related differences in the structural connectome and behaviour

Tunç

Solmaz

Parker

et al. 2016

Phil. Trans. R. Soc. B

133

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One contribution of 16 to a theme issue 'Multifaceted origins of sex differences in the brain'. Recent years have witnessed an increased attention to studies of sex differences, partly because such differences offer important considerations for personalized medicine. While the presence of sex differences in human behaviour is well documented, our knowledge of their anatomical foundations in the brain is still relatively limited. As a natural gateway to fathom the human mind and behaviour, studies concentrating on the human brain network constitute an important segment of the research effort to investigate sex differences. Using a large sample of healthy young individuals, each assessed with diffusion MRI and a computerized neurocognitive battery, we conducted a comprehensive set of experiments examining sex-related differences in the meso-scale structures of the human connectome and elucidated how these differences may relate to sex differences at the level of behaviour. Our results suggest that behavioural sex differences, which indicate complementarity of males and females, are accompanied by related differences in brain structure across development. When using subnetworks that are defined over functional and behavioural domains, we observed increased structural connectivity related to the motor, sensory and executive function subnetworks in males. In females, subnetworks associated with social motivation, attention and memory tasks had higher connectivity. Males showed higher modularity compared to females, with females having higher inter-modular connectivity. Applying multivariate analysis, we showed an increasing separation between males and females in the course of development, not only in behavioural patterns but also in brain structure. We also showed that these behavioural and structural patterns correlate with each other, establishing a reliable link between brain and behaviour. BackgroundWhile the presence of sex differences in human behaviour and cognition is well documented [1,2], our knowledge of anatomical foundations for such sex differences, specifically in the brain, is still relatively limited. The enigmatic interplay between brain and behaviour, and its modulation by sex, has intrigued scientists, philosophers and the general public for decades. Behavioural differences include, but are not limited to, enhanced motor [3,4] and spatial skills [5,6] in males and improved memory [7,8] and social cognition [9,10] skills in females [11]. These differences may be attributed to the complementary roles that the sexes play in procreation and social structure; however, increasing evidence suggests the presence of corresponding sex differences in brain structure and function [12][13][14][15][16][17], as well as the presence of a strong connection between behaviour and brain structure [12,18]. Thus, relying merely on social and cultural effects to explain sex-induced variance in behaviour seems insufficient. Notably, although sex differences in the brain are present even in childhood [16,17], the

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The Impact of Sex, Puberty, and Hormones on White Matter Microstructure in Adolescents

Abstract: Sex differences and puberty uniquely relate to white matter microstructure in adolescents, which can partially be explained by sex steroids.

Cited by 302 publications

References 55 publications

Lithium and GSK3-β Promoter Gene Variants Influence White Matter Microstructure in Bipolar Disorder

Lithium and GSK3-β Promoter Gene Variants Influence White Matter Microstructure in Bipolar Disorder

Sex Steroids and the Organization of the Human Brain

Establishing a link between sex-related differences in the structural connectome and behaviour

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