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Objective: The aim of this study was to evaluate the effect of continuous positive airway pressure (CPAP) treatment on the Fatigue Severity Scale (FSS, preplanned primary outcome), another fatigue measure, sleep quality, somnolence, pain, disability, and quality of life in multiple sclerosis (MS) patients with obstructive sleep apnea-hypopnea (OSAH). Methods: In a randomized, double-blind trial (NCT01746342), MS patients with fatigue, poor subjective sleep quality, and OSAH (apnea-hypopnea index of ⩾ 15 events per hour/sleep), but without severe OSAH (apnea-hypopnea index > 30, and 4% oxygen desaturation index > 15 events/hour or severe somnolence), were randomized to fixed CPAP or sham CPAP for 6 months. Outcome assessments were performed at 3 and 6 months. Results: Of 49 randomized patients, 34 completed the protocol. Among completers, FSS did not improve with CPAP compared to sham at 6 months. FSS tended to improve ( p = 0.09), and sleepiness (Epworth Sleepiness Scale) improved significantly ( p = 0.03) at 3 months with CPAP compared to sham, but there were no other improvements with CPAP at either study evaluation. Conclusion: In non-severe OSAH patients, CPAP did not significantly improve the primary outcome of FSS change at 6 months. In secondary analyses, we found a trend to improved FSS, and a significant reduction in somnolence with CPAP at 3 months.

Life-long maintenance of brain health is important for the prevention of cognitive impairment in older age. Low-grade peripheral inflammation associated with excess visceral fat (VF) may influence brain structure and function. Here we examined (i) if this type of inflammation is associated with altered white-matter (WM) microstructure and lower cognitive functioning in adolescents, and (ii) if recently identified circulating glycerophosphocholines (GPCs) can index this type of inflammation and associated variations in WM microstructure and cognitive functioning. We studied a community-based sample of 872 adolescents (12–18 years, 48% males) in whom we assessed VF and WM microstructure with magnetic resonance imaging, processing speed with cognitive testing, serum C-reactive protein (CRP, a common marker of peripheral inflammation) with a high-sensitivity assay, and serum levels of a panel of 64 GPCs with advanced mass spectrometry. VF was associated with CRP, and CRP in turn was associated with “altered” WM microstructure and lower processing speed (all p

Neurobiological underpinnings of cortical thickness in the human brain are largely unknown. Here we use cell-type-specific gene markers to evaluate the contribution of 9 neural cell-types in explaining inter-regional variations in cortical thickness and age-related cortical thinning in the adolescent brain. Gene-expression data were derived from the Allen Human Brain Atlas (and validated using the BrainSpan Atlas). Values of cortical thickness/thinning were obtained with magnetic resonance imaging in a sample of 987 adolescents. We show that inter-regional profiles in cortical thickness relate to those in the expression of genes marking CA1 pyramidal cells, astrocytes, and microglia; taken together, the 3 cell types explain 70% of regional variation in cortical thickness. We also show that inter-regional profiles in cortical thinning relate to those in the expression of genes marking CA1 and S1 pyramidal cells, astrocytes and microglia. Using Gene Ontology analysis, we demonstrate that the difference in the contribution of CA1 and S1 pyramidal cells may relate to biological processes such as neuronal plasticity and potassium channel activity, respectively. This "virtual histology" approach (scripts provided) can be used to examine neurobiological underpinnings of cortical profiles associated with development, aging, and various disorders.

Background: Parkinson’s disease (PD) is the second most frequent neurodegenerative disease and is associated with cognitive dysfunction. Obstructive sleep apnea (OSA) has been linked with cognitive dysfunction in the general population and in PD. Treatment with positive airway pressure (PAP), can improve cognition in the general population and in patients with other neurodegenerative diseases. However, the effect of PAP therapy on cognitive function has not been well studied in PD.Methods: This randomized controlled trial will assess the effect of 6 months of PAP therapy versus placebo on global cognitive function in PD patients with OSA and reduced baseline cognition. Secondary outcomes will include quality of life and other non-motor symptoms of PD. Exploratory outcomes will be specific domains of neurocognitive function and symptoms of REM sleep behaviour disorder.Conclusions: PD-related cognitive dysfunction often evolves towards dementia and has substantial personal, social and healthcare costs. Few interventions have been shown to improve cognition in PD to date. If positive, results from our study could prove OSA to be a new therapeutic target relevant to cognition and would support more systematic screening for OSA in PD patients with cognitive decline.Trial Registration: Trial registration number is NCT02209363.

Background: Glycerophosphocholine (GPC) metabolites modulate atherosclerosis and thus risk for cardiovascular disease (CVD). Preclinical CVD may start during adolescence. Here, we used targeted serum lipidomics to identify a new panel of GPCs, and tested whether any of these GPCs are associated, in adolescence, with classical risk factors of CVD, namely excess visceral fat (VF), elevated blood pressure, insulin resistance, and atherogenic dyslipidemia. Methods: We studied a population-based sample of 990 adolescents (12–18 years, 48% male), as part of the Saguenay Youth Study. Using liquid chromatography-electrospray ionization-mass spectrometry, we identified 69 serum GPCs within the 450 to 680 m / z range. We measured VF with MRI. Results: We identified several novel GPCs that were associated with multiple CVD risk factors. Most significantly, PC16:0/2:0 was negatively associated with VF ( P =1.4×10 –19 ), blood pressure ( P =7.7×10 –5 ), and fasting triacylglycerols ( P =9.0×10 –5 ), and PC14:1/0:0 was positively associated with VF ( P =3.0×10 –7 ), fasting insulin ( P =5.4×10 –32 ), and triacylglycerols ( P =1.4×10 –29 ). The Sobel test of mediation revealed that both GPCs mediated their respective relations between VF (as a potential primary exposure) and CVD risk factors (as outcomes, P values–3 ). Furthermore, a GPC shown recently to predict incident coronary heart disease in older adults, PC18:2/0:0, was associated with several CVD risk factors in adolescents; these associations were less strong than those with the newly identified GPCs. Conclusions: We identified novel GPCs strongly associated with multiple CVD risk factors in adolescents. These GPCs may be sensitive indicators of obesity-related risk for CVD outcomes in adults, and may improve biological understanding of CVD risk.

Our ability to process complex social cues presented by faces improves during adolescence. Using multivariate analyses of neuroimaging data collected longitudinally from a sample of 38 adolescents (17 males) when they were 10, 11.5, 13 and 15 years old, we tested the possibility that there exists parallel variations in the structural and functional development of neural systems supporting face processing. By combining measures of task-related functional connectivity and brain morphology, we reveal that both the structural covariance and functional connectivity among ‘distal’ nodes of the face-processing network engaged by ambiguous faces increase during this age range. Furthermore, we show that the trajectory of increasing functional connectivity between the distal nodes occurs in tandem with the development of their structural covariance. This demonstrates a tight coupling between functional and structural maturation within the face-processing network. Finally, we demonstrate that increased functional connectivity is associated with age-related improvements of face-processing performance, particularly in females. We suggest that our findings reflect greater integration among distal elements of the neural systems supporting the processing of facial expressions. This, in turn, might facilitate an enhanced extraction of social information from faces during a time when greater importance is placed on social interactions.

This study examined cognitive predictors of sequential motor skills in 215 children with dyslexia and/or attention deficit/hyperactivity disorder (ADHD). Visual working memory and math fluency abilities contributed significantly to performance of sequential motor abilities in children with dyslexia (N = 67), ADHD (N = 66) and those with a comorbid diagnosis (N = 82), generally without differentiation between groups. In addition, primary diagnostic features of each disorder, such as reading and inattention, did not contribute to the variance in motor skill performance of these children. The results support a unifying framework of motor impairment in children with neurodevelopmental disorders such as dyslexia and ADHD.

SummaryBackground Excess visceral fat is a major risk factor for hypertension. Enhanced blood pressure (BP) reactivity and delayed BP recovery from physical and mental challenges predict future hypertension. Objectives Determine whether visceral fat is associated with higher BP reactivity and delayed BP recovery from physical and mental challenges during adolescence. Methods In a community-based sample of 283 male and 308 female adolescents, we measured visceral fat with magnetic resonance imaging, total body fat with bioimpedance, and beat-by-beat BP with a Finometer at rest and during physical (10-min standing) and mental (2-min math stress) challenges. Results Males vs. females showed greater BP reactivity and no differences in BP recovery from either type of challenges. Visceral fat was positively associated with BP reactivity to standing up only and in males only (+8.4 ± 3.6 mmHg per 1 log cm3 of visceral fat, P = 0.008), and this association was independent of total body fat. No association was seen between visceral fat and BP recovery from either type of challenge in either sex. All these associations were independent of age, puberty stage, height and initial BP. Conclusions Adolescent males vs. females demonstrate greater BP reactivity but similar BP recovery from physical and mental challenges. Excess visceral fat enhances BP reactivity to physical but not mental challenges in males only.

Income inequality is associated with poor health and social outcomes. Negative social comparisons and competition may involve the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes in underlying some of these complex inter-relationships. Here we investigate brain maturation, indexed by age-related decreases in cortical thickness, in adolescents living in neighborhoods with differing levels of income inequality and household income. We examine whether inter-regional variations relate to those in glucocorticoid receptor (HPA) and androgen receptor (HPG) gene expression. For each sex, we used a median split of income inequality and household income (income-to-needs ratio) to create four subgroups. In female adolescents, the high-inequality low-income group displayed the greatest age-related decreases in cortical thickness. In this group, expression of glucocorticoid and androgen receptor genes explained the most variance in these age-related decreases in thickness across the cortex. We speculate that female adolescents living in high-inequality neighborhoods and low-income households may experience greater HPA and HPG activity, leading to steeper decreases in cortical thickness with age.

Contains fulltext : 169834.pdf (Publisher’s version ) (Open Access) Contains fulltext : 169834pos.pdf (Author’s version postprint ) (Open Access) BACKGROUND: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. METHODS: In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0.0156. FINDINGS: Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0.15), amygdala (d=-0.19), caudate (d=-0.11), hippocampus (d=-0.11), putamen (d=-0.14), and intracranial volume (d=-0.10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0.95) and thalamus (p=0.39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (21 years): in the accumbens (Cohen's d=-0.19 vs -0.10), amygdala (d=-0.18 vs -0.14), caudate (d=-0.13 vs -0.07), hippocampus (d=-0.12 vs -0.06), putamen (d=-0.18 vs -0.08), and intracranial volume (d=-0.14 vs 0.01). There was no difference between children and adults for the pallidum (p=0.79) or thalamus (p=0.89). Case-control differences in adults were non-significant (all p>0.03). Psychostimulant medication use (all p>0.15) or symptom scores (all p>0.02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0.5). INTERPRETATION: With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING: National Institutes of Health. 10 p.

We used magnetic resonance (MR) images obtained in same-sex and opposite-sex dizygotic twins (n = 119, 8 years of age) to study possible effects of prenatal androgens on craniofacial features. Using a principal component analysis of 19 craniofacial landmarks placed on the MR images, we identified a principal component capturing craniofacial features that distinguished females with a presumed differential exposure to prenatal androgens by virtue of having a male (vs. a female) co-twin (Cohen's d = 0.76). Subsequently, we tested the possibility that this craniofacial "signature" of prenatal exposure to androgens predicts brain size, a known sexually dimorphic trait. In an independent sample of female adolescents (singletons; n = 462), we found that the facial signature predicts up to 8% of variance in brain size. These findings are consistent with the organizational effects of androgens on brain development and suggest that the facial signature derived in this study could complement other indirect measures of prenatal exposure to androgens.

Author(s): Lotfipour, Shahrdad; Lotfipour, Shahrdad; Ferguson, Eamonn; Leonard, Gabriel; Miettunen, Jouko; Perron, Michel; Pike, G Bruce; Richer, Louis; Seguin, Jean R; Veillette, Suzanne; Jarvelin, Marjo-Riitta; Moilanen, Irma; Maki, Pirjo; Nordstrom, Tanja; Pausova, Zdenka; Veijola, Juha; Paus, Tomas | Abstract: Background and aimsPrenatal exposure to maternal cigarette smoking (PEMCS) is associated with a higher probability of substance use in adolescence. We explore if externalizing behavior mediates this relationship, while controlling for a number of potential covariates of this mediation process.MethodsWe used data obtained in two geographically distinct community samples of adolescents. The first (cross-sectional) sample consisted of 996 adolescents (12-18 years of age) recruited from the Saguenay Youth Study (SYS) in Canada (47% with PEMCS). The second (longitudinal) sample consisted of 1141 adolescents (49% with PEMCS) from the Northern Finland Birth Cohort (NFBC1986). In both samples, externalizing behavior and substance use were assessed during adolescence. In the NFBC1986 cohort, externalizing behavior was also assessed in childhood.ResultsIn both populations, PEMCS is associated with a higher likelihood of adolescent drug experimentation. In the NFBC1986 cohort, exposed (versus non-exposed) adolescents experiment with an extra 1.27 [B = 0.24, 95% confidence intervals (CI) = 0.15, 0.33 P l 0.001] drugs. In the SYS cohort, a clear protective effect of not being exposed is shown: non-exposed (versus exposed) adolescents are 1.5 times [B = -0.42, 95% CI = -0.75, -0.09, P = 0.013] less likely to take drugs. These associations between PEMCS and drug experimentation remain in the multivariate and mediational analyses.ConclusionsPrenatal exposure to maternal cigarette smoking appears to be associated with a higher probability of experimenting with drugs during adolescence, both directly and indirectly via externalizing behavior and the number of peers reported as using drugs.

Background Obesity, a major risk factor for cardiometabolic disease, is associated with lower cognitive performance from childhood to senescence, especially on tasks of executive function. In the cardiovascular domain, fat stored viscerally rather than elsewhere in the body carries particularly high risk. It is unknown whether this is also true in case of obesity-cognition relationships. The aim of this study is to assess the cross-sectional relationship between visceral fat (VF) and cognitive performance in a community sample of healthy adolescents. Methods In a community-based sample of 983 adolescents (12–18 years old, 480 males), VF was quantified using magnetic resonance imaging, total body fat was measured using a multifrequency bioimpedance and cognitive performance was assessed using a battery of cognitive tests measuring executive function and memory. Results We found that larger volumes of VF were associated with lower performance on six measures of executive function (p=0.0001 to 0.02). We also found that the association of VF with executive function was moderated by sex for a subset of measures, such that relationship was present mainly in females and not in males (sex-by-VF interaction: p=0.001 to 0.04). These relationships were independent of the quantity of total body fat and a number of potential confounders, including age, puberty stage and household income. Conclusions Our results suggest that the adverse association between obesity and executive function may be attributed to fat stored viscerally and not to fat stored elsewhere in the body. They also suggest that females compared with males may be more sensitive to the potentially detrimental effects of VF on cognition.

BackgroundMultiple sclerosis (MS) patients have central nervous system (CNS) lesions that may impede cognitive and sensorimotor function. Few rehabilitative therapies are available.ObjectivesThe objective of this paper is to study effects of noninvasive tongue stimulation using the Portable Neuromodulation Stimulator (PoNS™) combined with intensive cognitive and physical rehabilitation on working memory, gait, balance and concomitant changes in the brain.MethodsFourteen MS patients, seven each in an active and a sham stimulation group, participated. Participants received intensive physical therapy and working memory training for 14 weeks. Functional magnetic resonance imaging (fMRI) using motor imagery and working-memory tasks were completed prior to and following therapy, as were sensory organization tests (SOT), motor performance measures, and neuropsychological assessment.ResultsOn the SOT, the active group showed significant improvement from baseline. fMRI revealed significant blood oxygen level-dependent signal changes in the left primary motor cortex for the Active Group, while the sham group had increased activity in bilateral premotor cortices. All individuals improved on working-memory tasks, but only the active group showed increased dorsolateral prefrontal cortex activity.ConclusionsIn this cohort of MS patients, the results suggest that PoNS stimulation can enhance motor performance and working memory while also driving neuroplasticity. Further studies are warranted to explore these findings.

Age-related decreases in cortical thickness observed during adolescence may be related to fluctuations in sex and stress hormones. We examine this possibility by relating inter-regional variations in age-related cortical thinning (data from the Saguenay Youth Study) to inter-regional variations in expression levels of relevant genes (data from the Allen Human Brain Atlas); we focus on genes coding for glucocorticoid receptor (NR3C1), androgen receptor (AR), progesterone receptor (PGR), and estrogen receptors (ESR1 and ESR2). Across 34 cortical regions (Desikan-Killiany parcellation), age-related cortical thinning varied as a function of mRNA expression levels of NR3C1 in males (R(2) = 0.46) and females (R(2) = 0.30) and AR in males only (R(2) = 0.25). Cortical thinning did not vary as a function of expression levels of PGR, ESR1, or ESR2 in either sex; this might be due to the observed low consistency of expression profiles of these 3 genes across donors. Inter-regional levels of the NR3C1 and AR expression interacted with each other vis-à-vis cortical thinning: age-related cortical thinning varied as a function of NR3C1 mRNA expression in brain regions with low (males: R(2) = 0.64; females: R(2) = 0.58) but not high (males: R(2) = 0.0045; females: R(2) = 0.15) levels of AR mRNA expression. These results suggest that glucocorticoid and androgen receptors contribute to cortical maturation during adolescence.

The Saguenay Youth Study (SYS) is a two-generational study of adolescents and their parents (n = 1029 adolescents and 962 parents) aimed at investigating the aetiology, early stages and trans-generational trajectories of common cardiometabolic and brain diseases. The ultimate goal of this study is to identify effective means for increasing healthy life expectancy. The cohort was recruited from the genetic founder population of the Saguenay Lac St Jean region of Quebec, Canada. The participants underwent extensive (15-h) phenotyping, including an hour-long recording of beat-by-beat blood pressure, magnetic resonance imaging of the brain and abdomen, and serum lipidomic profiling with LC-ESI-MS. All participants have been genome-wide genotyped (with ∼ 8 M imputed single nucleotide polymorphisms) and a subset of them (144 adolescents and their 288 parents) has been genome-wide epityped (whole blood DNA, Infinium HumanMethylation450K BeadChip). These assessments are complemented by a detailed evaluation of each participant in a number of domains, including cognition, mental health and substance use, diet, physical activity and sleep, and family environment. The data collection took place during 2003-12 in adolescents (full) and their parents (partial), and during 2012-15 in parents (full). All data are available upon request.

Adults show great variation in their auditory skills, such as being able to discriminate between foreign speech-sounds. Previous research has demonstrated that structural features of auditory cortex can predict auditory abilities; here we are interested in the maturation of 2-Hz frequency-modulation (FM) detection, a task thought to tap into mechanisms underlying language abilities. We hypothesized that an individual's FM threshold will correlate with gray-matter density in left Heschl's gyrus, and that this function-structure relationship will change through adolescence. To test this hypothesis, we collected anatomical magnetic resonance imaging data from participants who were tested and scanned at three time points: at 10, 11.5 and 13 years of age. Participants judged which of two tones contained FM; the modulation depth was adjusted using an adaptive staircase procedure and their threshold was calculated based on the geometric mean of the last eight reversals. Using voxel-based morphometry, we found that FM threshold was significantly correlated with gray-matter density in left Heschl's gyrus at the age of 10 years, but that this correlation weakened with age. While there were no differences between girls and boys at Times 1 and 2, at Time 3 there was a relationship between gray-matter density in left Heschl's gyrus in boys but not in girls. Taken together, our results confirm that the structure of the auditory cortex can predict temporal processing abilities, namely that gray-matter density in left Heschl's gyrus can predict 2-Hz FM detection threshold. This ability is dependent on the processing of sounds changing over time, a skill believed necessary for speech processing. We tested this assumption and found that FM threshold significantly correlated with spelling abilities at Time 1, but that this correlation was found only in boys. This correlation decreased at Time 2, and at Time 3 we found a significant correlation between reading and FM threshold, but again, only in boys. We examined the sex differences in both the imaging and behavioral data taking into account pubertal stages, and found that the correlation between FM threshold and spelling was strongest pre-pubertally, and the correlation between FM threshold and gray-matter density in left Heschl's gyrus was strongest mid-pubertally.

Excess body fat deposited viscerally rather than elsewhere in the body is associated with higher risk for hypertension; this relationship is stronger in men than in women. Here we investigated whether similar sex dimorphism exists already in adolescence. A population-based sample of adolescent boys (n=237) and girls (n=262), age 12 to 18 years, was studied. Total body fat (TBF) was assessed with multifrequency bioelectrical impedance, and visceral fat (VF) was quantified with MRI. Blood pressure (BP) was measured beat by beat during an hour-long protocol, including supine, standing, sitting, mental stress, and poststress sections. Multivariate mixed-model analysis was used to assess the relative contributions of TBF and VF to BP during these sections. In boys, BP was strongly positively associated with VF ( P P =0.004); these relationships did not substantially vary during the protocol. In contrast, in girls, BP was strongly positively associated with TBF ( P =0.0006), whereas it was not associated with VF ( P =0.08); the relationship with TBF varied during the protocol and was most apparent during mental stress (TBF*section interaction: P =0.002). Furthermore, when waist circumference was included in multivariate models instead of VF, it was not associated with BP in either sex; this indicates that waist circumference may not be an appropriate surrogate for VF. Thus, in adolescence, adiposity-related BP elevation is driven mainly by visceral fat in males and by fat deposited elsewhere in females. This dimorphism suggests sex-specific mechanisms of obesity-induced hypertension and the need for sex-specific criteria of its prevention.

Hypertension, typically considered a disorder of adulthood, is now emerging in adolescence. This is mainly due to the growing prevalence of obesity and the fact that excess body fat increases blood pressure (BP).The objective of the study was to investigate whether genome-wide identified gene loci of obesity are associated with elevated BP in adolescence.This was a genotype-phenotype association study.The study was conducted in a French-Canadian founder population.Participants included 598 adolescents, aged 12-18 yr.Testing associations between 530,011 single-nucleotide polymorphisms (SNP; Human610W-Quad BeadChip) and obesity measures and between identified SNP and BP.Total fat mass (TFM) was assessed with bioelectrical impedance, and body mass index (BMI) was determined with anthropometry. BP was measured beat by beat during an hour-long protocol.The genome-wide association studies of TFM and BMI revealed two novel and several previously identified loci of obesity. The former were PAX5 (rs16933812, TFM: P = 9.3 × 10(-9)) and MRPS22 (rs7638110, BMI: P = 4.6 × 10(-8)), and the top ones among the latter (P5 × 10(-4)) were MC4R (rs17773430, BMI: P = 5.8 × 10(-6)), FTO (rs9930333, BMI: P = 1.9 × 10(-4)), and MTCH2 (rs7120548, BMI: P = 1.9 × 10(-4)). From these five, only the PAX5, MRPS22, and FTO were also associated with BP; their minor allele homozygotes vs. major allele homozygotes showed greater TFM by 2.9-8.0 kg and higher BP by 3.3-6.7 mm Hg.Genome-wide association studies conducted in an adolescent founder population revealed two new and a number of previously identified loci of obesity and demonstrated that several but not all of these loci are also associated with elevated BP. These results begin to reveal the genetic architecture of obesity-induced hypertension.

Sex identification of a face is essential for social cognition. Still, perceptual cues indicating the sex of a face, and mechanisms underlying their development, remain poorly understood. Previously, our group described objective age- and sex-related differences in faces of healthy male and female adolescents (12-18 years of age), as derived from magnetic resonance images (MRIs) of the adolescents' heads. In this study, we presented these adolescent faces to 60 female raters to determine which facial features most reliably predicted subjective sex identification. Identification accuracy correlated highly with specific MRI-derived facial features (e.g. broader forehead, chin, jaw, and nose). Facial features that most reliably cued male identity were associated with plasma levels of testosterone (above and beyond age). Perceptible sex differences in face shape are thus associated with specific facial features whose emergence may be, in part, driven by testosterone.

This study investigated the fine-grained development of the EEG power spectra in early adolescence, and the extent to which it is reflected in changes in peak frequency. It also sought to determine whether sex differences in the EEG power spectra reflect differential patterns of maturation. A group of 56 adolescents were tested at age 10 years and then at two further time-points approximately 18 months apart. The EEG was recorded during both eyes-closed and eyes-open conditions and Fourier transformed to provide estimates of absolute and relative spectral power at 0.5 Hz intervals from 0.5 to 40 Hz. The peak alpha frequency for each individual at each time-point was also determined for relative spectral power. Partial Least Squares (PLS) analysis was used to determine the combination of electrodes and frequencies that showed developmental change, or differed between the sexes. As a function of age, absolute delta and theta frequencies power decreased, and relative alpha2 and beta frequencies increased, replicating the standard findings of a decrease in lower, and increase in higher, frequencies with age. A small but significant increase in peak alpha frequency with age was detected. Moreover PLS analysis performed with individual alpha frequencies aligned to 10 Hz suggested that the age-related increase seen in alpha2 relative power was driven by changes in the peak frequency. Although males demonstrated higher alpha power than females, there were no sex differences in peak frequency, suggesting that there may be more to sex differences in EEG power than simply different rates of maturation between the two sexes.

Adolescence places high demands on inter-personal interactions and, hence, on the extraction and processing of social cues. Here we assess longitudinally the development of brain activity within a network implicated in social cognition--the action observation network. We performed activation likelihood estimation meta-analyses to define regions of interest based upon the mature action observation network of adults. Using functional magnetic resonance imaging, we then examined developmental trajectories of functional brain activity within these brain regions. Using this approach, we reveal quadratic trajectories within a fronto-parietal network previously shown to demonstrate correlated morphological development.

In industrialized countries, prenatal exposure to maternal cigarette smoking (PEMCS) is the most common environmental insult to the fetus. Here, we tested the hypothesis that PEMCS amplifies accumulation of abdominal fat during the accelerated weight gain occurring in late puberty. This hypothesis was tested in 508 adolescents (12-18 years, 237 exposed prenatally to maternal cigarette smoking) in whom subcutaneous and intra-abdominal fat were quantified with magnetic resonance imaging (MRI). We found that, in early puberty, exposed and nonexposed adolescents did not differ in MRI-based measures of adiposity. In late puberty, on the other hand, exposed compared with nonexposed adolescents demonstrated markedly higher quantities of both subcutaneous fat (by 26%, P = 0.004) and intra-abdominal fat (by 33%, P = 0.001). These group differences remained virtually unchanged after adjusting for sex and potential confounders, including birth weight and breastfeeding. As such, our results suggest that PEMCS may represent a major risk factor for the development of abdominal obesity at the later stages of puberty.

Intra-abdominal accumulation of fat is a hallmark of male body-fat distribution and a major risk factor for hypertension. Sympathoactivation may be one of the mechanisms linking intra-abdominal obesity to hypertension. The aim of the present study was to investigate whether a functional variation in the androgen-receptor gene ( AR , a variable number of CAG repeats in exon 1) is associated with intra-abdominal adiposity, sympathetic modulation of vasomotor tone, and blood pressure in adolescent boys but not girls. We studied 223 boys and 259 girls (age 12 to 18 years) from a French-Canadian founder population. Intra-abdominal fat and subcutaneous-abdominal fat were quantified with an MRI. Blood pressure was recorded beat-to-beat during an hour-long protocol including physical and mental challenges, and these blood pressure time series were used to assess sympathetic modulation of vasomotor tone by power spectral analysis. The results showed that boys with a “low” versus “intermediate” or “high” CAG-repeat number in AR demonstrated higher intra-abdominal fat (by 28% and 48%, respectively) but not subcutaneous-abdominal fat. These intra-abdominal fat differences remained significant after adjusting for serum levels of sex hormones and subcutaneous-abdominal fat. Furthermore, boys with low versus intermediate or high CAG-repeat numbers also showed higher blood pressure, with the differences being most pronounced during mental stress (8.0 and 8.5 mm Hg, respectively) and higher sympathetic modulation of vasomotor tone. As expected, no such differences were seen among girls. In adolescent boys, low CAG-repeat numbers in AR may be a genetic risk factor for intra-abdominal obesity and hypertension; sympathoactivation may be an underlying link between the 2 conditions.

Here we examined sex differences in the volumes of grey and white matter, and in grey-matter "density," in a group of typically developing adolescents participating in the Saguenay Youth Study (n=419; 12-18 years). In male adolescents, we also investigated the role of a functional polymorphism in androgen-receptor gene (AR) in moderating the effect of testosterone on volumes of grey and white matter and grey-matter density. Overall, both absolute and relative volumes of white matter were larger in male vs. females adolescents. The relative grey-matter volumes were slightly larger in female than male adolescents and so was the grey-matter density in a large number of cortical regions. In male adolescents, functional polymorphism of AR moderated the effect of testosterone on relative white- and grey-matter volumes. Following a discussion of several methodological and interpretational issues, we outline future directions in investigating brain-behavior relationships vis-à-vis psychopathology.

With anatomical magnetic resonance imaging, the signal intensity of the corticospinal tract (CST) at the level of the internal capsule is often paradoxically similar to that of grey matter. As shown previously in histological studies, this is likely due to the presence of very large axons. We measured the apparent grey‐matter density (aGMd) of the putative CST (pCST) in a large cohort of adolescents (n = 409, aged 12–18 years). We tested the following hypotheses: (1) The aGMd in the pCST shows a hemispheric asymmetry that is, in turn, related to hand preference; (2) the maturation of the CST during adolescence differs between both sexes, due to the influence of testosterone; (3) variations in aGMd in the pCST reflect inter‐individual differences in manual skills. We confirmed the first two predictions. Thus, we found a strong left > right hemispheric asymmetry in aGMd that was, on average, less marked in the 40 left‐handed subjects. Apparent GMd in the pCST increased with age in adolescent males but not females, and this was particularly related to rising plasma levels of testosterone in male adolescents. This finding is compatible with the idea that testosterone influences axonal calibre rather than myelination. The third prediction, namely that of a relationship between age‐related changes in manual skills and maturation of the pCST, was not confirmed. We conclude that the leftward asymmetry of the pCST may reflect an early established asymmetry in the number of large corticomotoneuronal fibres in the pCST. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.

Background— FTO is the first gene established as contributing to common forms of obesity. The gene is highly expressed in the hypothalamus and is thought to mediate this effect through its influence on energy homeostasis. The hypothalamus, however, also regulates blood pressure (BP). Therefore, we investigated whether the FTO -risk variant is associated not only with increased adiposity but also with elevated BP and whether the latter may be mediated, in part, by increased sympathetic modulation of vasomotor tone. Methods and Results— The primary study was carried out in 485 adolescents recruited from a French Canadian founder population who underwent detailed body-composition and cardiovascular phenotyping. Body fat was examined with MRI, bioimpedance, and anthropometry. BP was recorded beat to beat at rest and during physical and mental challenges. Sympathetic modulation of vasomotor tone was assessed with power spectral analysis of BP. We found that individuals with the FTO- risk genotype compared with those without it demonstrate greater adiposity, including the amount of intra-abdominal fat (by 38%). They also showed higher systolic BP throughout the entire protocol, with a maximum difference during a mental stress (6.4 [1.5 to 11.3] mm Hg). The difference in BP was accompanied by elevated index of sympathetic modulation of vasomotor tone. A replication in an independent sample of adults from the same founder population confirmed the association between FTO and BP. Conclusions— These results suggest that, in a French Canadian founder population, FTO may increase not only risk for obesity, as demonstrated in other populations, but also for hypertension. The latter may be related, at least in part, to the regulation of sympathetic vasomotor tone.

The purpose of this study was to examine sex differences in the maturation of white matter during adolescence (12 to 18 years of age). We measured lobular volumes of white matter and white-matter “density” throughout the brain using T1-weighted images, and estimated the myelination index using magnetisation-transfer ratio (MTR). In male adolescents, we observed age-related increases in white-matter lobular volumes accompanied by decreases in the lobular values of white-matter MTR. White-matter density in the putative cortico-spinal tract (pCST) decreased with age. In female adolescents, on the other hand, we found only small age-related increase in white-matter volumes and no age-related changes in white-matter MTR, with the exception of the frontal lobe where MTR increased. White-matter density in the pCST also increased with age. These results suggest that sex-specific mechanisms may underlie the growth of white matter during adolescence. We speculate that these mechanisms involve primarily age-related increases in axonal calibre in males and increased myelination in females.

Teratogens, such as alcohol or anti-epileptic drugs, affect the size of the corpus callosum. Here we report findings obtained in a case-control study that investigated possible effects of teratogens contained in cigarette smoke on the size and structural properties of this structure. We recruited and scanned with magnetic resonance imaging a total of 408 adolescents (12 to 18 years of age); a subsample of 300 adolescents is considered in this report. Cases (n=146) were exposed to maternal cigarette smoking during pregnancy; non-exposed controls (n=154) were matched to cases by maternal education. We measured the size of corpus callosum (CC) and its sections (corrected for brain size), as well as mean values of magnetization-transfer ratio (MTR) in each CC section. Corpus callosum, and especially its posterior part, was smaller in the exposed vs. non-exposed female adolescents; no significant effects were found in males. Exposed and non-exposed subjects did not differ in the MTR-based index of myelination in either gender in any CC section. Given the lack of exposure effect on the myelination index, this finding might reflect a lower number of inter-hemispheric connections in female offspring of mothers who smoked during pregnancy.

During the shift from a parent-dependent child to a fully autonomous adult, peers take on a significant role in shaping the adolescent's behavior. Peer-derived influences are not always positive, however. Here, we explore neural correlates of interindividual differences in the probability of resisting peer influence in early adolescence. Using functional magnetic resonance imaging, we found striking differences between 10-year-old children with high and low resistance to peer influence in their brain activity during observation of angry hand movements and angry facial expressions: compared with subjects with low resistance to peer influence, individuals with high resistance showed a highly coordinated brain activity in neural systems underlying perception of action and decision making. These findings suggest that the probability of resisting peer influence depends on neural interactions during observation of emotion-laden actions.

Circulating second-messenger glycerophosphocholines (smGPCs), including lysophosphatidylcholines and platelet-activating factors, are low-abundance plasma phospholipids that modulate atherosclerosis and inflammation and, in turn, the risk for cardiovascular disease (CVD). Although CVD is a slow-progressing disease culminating in middle-to-late adulthood, its initial stages may be seen already in adolescence. Here, we investigated whether circulating smGPCs are associated with classical CVD risk factors - excess body fat, elevated BP, insulin resistance and low-grade inflammation - during adolescence. We studied a population-based sample of 1029 adolescents (52% females, 12-18 years), as part of the Saguenay Youth Study. We used targeted serum lipidomics (LC-ESI-MS) to identify and quantify circulating smGPCs within the 440-640 Da range. In all participants, we also measured: (i) visceral fat with MRI and total body fat with bioimpedance; (ii) blood pressure (BP) beat-by-beat for five minutes under standard clinical conditions; and (iii and iv) fasting serum insulin (as an index of insulin resistance) and CRP (as an index of low-grade inflammation). We identified a total of 81 smGPCs that varied by the length and saturation of their fatty acyl residues and the type of linkage these residues are attached to the glycerol backbone. Over 30 of them were associated with multiple CVD risk factors (p-4 ). Most of these associations were inverse and involved ‘medium’ mass smGPCs. Positive associations were also seen and these involved ‘low’ or ‘high’ mass smGPCs. Most strongly inversely associated smGPCs were: (i) PC(20:6/0:0) and PC(O-18:6/2:0), which were associated with total body fat (p-14 ) and CRP (p-36 ); and (ii) PC(16:0/2:0), which was associated with visceral fat (p=2x10 -18 ) and BP (p-5 ). The most strongly positively associated smGPC was PC(14:1/0:0), which was associated with visceral fat (p=8x10 -8 ) and fasting insulin (p=2x10 -24 ). Thus, specific circulating smGPCs are strongly associated with multiple CVD risk factors in adolescence; some of these associations may be ‘protective’ whereas others ‘adverse’. Circulating smGPCs may serve as novel biomarkers of early risk for CVD.

Background/Aims: Visceral fat (VF) compared with subcutaneous fat (SF) is more closely associated with cardiometabolic disease. Dietary vitamin A (retinol) may reduce adiposity through its effects on adipogenesis differentially in VF and SF, and this effect may be modulated by retinol-binding protein-4 (RBP4). We investigated whether intake of vitamin A is associated with either VF or SF, and whether this association is moderated by the RBP4 genotype (rs10882272, C/T) previously associated with circulating retinol levels. Methods: This was a cross-sectional association study in a sample of 947 adolescents from a French-Canadian founder population. VF and SF were quantified with magnetic resonance imaging, and vitamin A intake was assessed with a 24-hour food recall. All participants were genotyped to determine their RBP4 variant. Results: Dietary intake of vitamin A was negatively associated with VF; however, it was not associated with SF. These relationships were independent of age, sex, height and energy intake, and were modulated by the RBP4 variant. The T allele promoted adiposity-reducing effects of vitamin A in VF and adiposity-enhancing effects in SF, while the C allele had adiposity-reducing effects in both VF and SF. Conclusions: Dietary vitamin A may reduce abdominal adiposity and promote visceral to subcutaneous body fat redistribution during adolescence in an RBP4-dependent manner. These observational findings provide the basis for future interventional studies, which together with genetic information may inject further causality in the association between dietary vitamin A intake and abdominal adiposity.

Background The World Health Organization recommends artemisinin-based combination (ACT) for the treatment of uncomplicated malaria. Post-licensure safety data on newly registered ACT is critical for evaluating their risk/benefit profile in malaria endemic countries. The clinical safety of the newly registered combination, Eurartesim®, following its introduction into the public health system in four African countries was assessed. Methods This was a prospective, observational, open-label, non-comparative, longitudinal, multi-centre study using cohort event monitoring. Patients with confirmed malaria had their first dose observed and instructed on how to take the second and the third doses at home. Patients were contacted on day 5 ± 2 to assess adherence and adverse events (AEs). Spontaneous reporting of AEs was continued till day 28. A nested cohort who completed full treatment course had repeated electrocardiogram (ECG) measurements to assess effect on QTc interval. Results A total of 10,925 uncomplicated malaria patients were treated with Eurartesim®. Most patients,95% (10,359/10,925), did not report any adverse event following at least one dose of Eurartesim®. A total of 797 adverse events were reported. The most frequently reported, by system organ classification, were infections and infestations (3. 24%) and gastrointestinal disorders (1. 37%). In the nested cohort, no patient had QTcF > 500 ms prior to day 3 pre-dose 3. Three patients had QTcF > 500 ms (509 ms, 501 ms, 538 ms) three to four hours after intake of the last dose. All the QTcF values in the three patients had returned to

Adolescents who exhibit exaggerated blood pressure (BP) reactivity to physical and mental challenges are at increased risk of developing hypertension in adulthood. BP at rest and in response to challenges is higher in males than females, beginning in early adolescence.CYP17A1is one of the well-established gene loci of adult hypertension. Here, we investigated whether this gene locus is associated with elevated BP at rest and in response to physical (active standing) and mental (math stress) challenges in adolescence. We studied 496 male and 532 female adolescents (age 12–18 years) who were recruited from a genetic founder population. Our results showed that the variant ofCYP17A1rs10786718 was associated with enhanced BP reactivity to the mental but not physical challenge and in males but not females. In males, BP increase in response to math stress was higher in major versus minor allele homozygotes by 7.6 mm Hg (P=8.3×10-6). Resting BP was not associated with theCYP17A1variant in either sex. These results suggest that, in adolescent males but not females,CYP17A1enhances BP reactivity to mental stress. Whether this effect contributes to the higher prevalence of hypertension in males than females later in life remains to be determined.

BACKGROUND: Preference for fatty foods is a risk factor for obesity. It is a complex behaviour that involves the brain reward system and is regulated by genetic and environmental factors, such as the opioid receptor mu-1 gene (OPRM1) and prenatal exposure to maternal cigarette smoking (PEMCS). We examined whether OPRM1 and PEMCS interact in influencing fat intake and whether exposure-associated epigenetic modifications of OPRM1 may mediate this gene-environment interaction. METHODS: We studied adolescents from a French Canadian genetic founder population, half of whom were exposed prenatally to maternal cigarette smoking. Fat intake was assessed with a 24-hour food recall in the form of a structured interview conducted by a trained nutritionist. The OPRM1 variant rs2281617 was genotyped for the whole sample with the Illumina Human610-Quad and HumanOmniExpress BeadChips. Methylation of blood DNA was assessed at 21 CpGs across OPRM1 in a subset of the sample using the Illumina HumanMethylation450 BeadChip. RESULTS: We included 956 adolescents in our study. In the whole sample, OPRM1 (T carrier in rs2281617) was associated with lower fat intake (-1.6%, p = 0.017), and PEMCS was associated with higher fat intake (+1.6%, p = 0.005). OPRM1 and PEMCS interacted with each other (p = 0.003); the "protective" (fat intake-lowering) allele of OPRM1 was associated with lower fat intake in nonexposed (-3.2%, p < 0.001) but not in exposed individuals (+0.8%, p = 0.42). Further, PEMCS was associated with lower DNA methylation across multiple CpGs across OPRM1 in exposed versus nonexposed individuals (p = 0.031). LIMITATIONS: A limitation of our study was its cross-sectional design. CONCLUSION: Our study suggests that PEMCS may interact with OPRM1 in increasing fat preference. Silencing of the protective OPRM1 allele in exposed adolescents might be related to epigenetic modification of this gene.

We used a perturb-and-measure approach, by combining transcranial magnetic stimulation (TMS) and positron emission tomography (PET), to examine changes in the primary motor area (M1) and its effective connectivity in stroke patients with chronic motor deficits (>1-year post-stroke) who underwent 3 weeks of constraint-induced movement therapy. During the 3-week period, 7 patients spent 4 h per day performing shaping exercises with the affected arm under our supervision for 14 days and wore a mitt on the unaffected arm at home in situations where safety was not compromised. Anatomical magnetic resonance imaging confirmed that all patients had lesions that encompassed the white matter; no patient had damage in the hand representation of M1. Improvements on various motor tests were observed immediately after therapy and 1 month afterwards. During the TMS/PET sessions, we applied trains of subthreshold 10-Hz repetitive TMS over the hand representation of the ipsilesional and contralesional M1s and varied the number of TMS trains delivered during each scan. The results demonstrate changes in the local response of TMS in the ipsilesional and contralesional M1, changes in the strength of interhemispheric connectivity between M1s, and changes in the effective connectivity of the ipsilesional and contralesional M1s with the non-primary motor areas, the basal ganglia, and the motor nuclei of the thalamus.

When lifting small objects, people apply forces that match the expected weight of the object. This expectation relies in part on information acquired during a previous lift and on associating a certain weight with a particular object. Our study examined the role of the primary motor and dorsal premotor cortices in predicting weight based either on information acquired during a previous lift (no-cue experiment) or on arbitrary color cues associated with a particular weight (cue experiment). In the two experiments, subjects used precision grip to lift two different weights in a series of trials both before and after we applied low-frequency repetitive transcranial magnetic stimulation over the primary motor and dorsal premotor cortices. In the no-cue experiment, subjects did not receive any previous information about which of two weights they would have to lift. In the cue experiment, a color cue provided information about which of the two weights subjects would have to lift. Our results demonstrate a double dissociation in the effects induced by repetitive stimulation. When applied over the primary motor cortex, repetitive stimulation disrupted the scaling of forces based on information acquired during a previous lift. In contrast, when applied over the dorsal premotor cortex, repetitive stimulation disrupted the scaling of forces based on arbitrary color cues. We conclude that the primary motor and dorsal premotor cortices have unique roles during the anticipatory scaling of forces associated with the lifting of different weights.

Our study uses the combined transcranial magnetic stimulation/positron emission tomography (TMS/PET) method for elucidating neural connectivity of the human motor system. We first altered motor excitability by applying low-frequency repetitive TMS over two cortical motor regions in separate experiments: the dorsal premotor and primary motor cortices. We then assessed the consequences of modulating motor excitability by applying single-pulse TMS over the primary motor cortex and measuring: 1) muscle responses with electromyography and 2) cerebral blood flow with PET. Low-frequency repetitive stimulation reduced muscle responses to a similar degree in both experiments. To map networks of brain regions in which activity changes reflected modulation of motor excitability, we generated t-statistical maps of correlations between reductions in muscle response and differences in cerebral blood flow. Low-frequency repetitive stimulation altered neural activity differently in both experiments. Neural modulation occurred in multiple brain regions after dorsal premotor cortex stimulation; these included motor regions in the frontal cortex as well as more associational regions in the parietal and prefrontal cortices. In contrast, neural modulation occurred in a smaller number of brain regions after primary motor cortex stimulation, many of these confined to the motor system. These findings are consistent with the known differences between the dorsal premotor and primary motor cortices in the extent of cortico-cortical anatomical connectivity in the monkey.

Distinct differences in the human voice emerge during adolescence, with males producing deeper and more resonant voices than females by the end of sexual maturation. Using magnetic resonance images of heads and voice recordings obtained in 532 typically developing adolescents, we investigate what might be the drivers of this change in voice, and the subjective judgment of the voice "maleness" and "femaleness". We show clear sex differences in the morphology of voice-related structures during adolescence, with males displaying strong associations between age (and puberty) and both vocal-fold and vocal-tract length; this was not the case in female adolescents. At the same time, males (compared with females) display stronger associations between age (and puberty) with both fundamental frequency and formant position. In males, vocal morphology was a mediator in the relationship between bioavailable testosterone and acoustic indices. Subjective judgment of the voice sex could be predicted by the morphological and acoustic parameters in males only: the length of vocal folds and its acoustic counterpart, fundamental frequency, is a larger predictor of subjective "maleness" of a voice than vocal-tract length and formant position.

Obesity, a major risk factor for cardiometabolic disease, is associated with variations in a number of structural properties in the adult brain, as assessed with magnetic resonance imaging (MRI). In this study, we investigated the cross-sectional relationship between visceral fat (VF), total body fat (TBF) and three MRI parameters in the brains of typically developing adolescents: (i) T1-weighted (T1W) signal intensity; (ii) T1W signal contrast between white matter (WM) and gray matter (GM); and (iii) magnetization transfer ratio (MTR). In a community-based sample of 970 adolescents (12–18 years old, 466 males), VF was quantified using MRI, and total body fat was measured using a multifrequency bioimpedance. T1W images of the brain were used to determine signal intensity in lobar GM and WM, as well as WM:GM signal contrast. A magnetization transfer (MT) sequence of MTON and MTOFF was used to obtain MTR in GM and WM. We found that both larger volumes of VF and more TBF were independently associated with higher signal intensity in WM and higher WM:GM signal contrast, as well as higher MTR in both GM and WM. These relationships were independent of a number of potential confounders, including age, sex, puberty stage, household income and height. Our results suggest that both visceral fat and fat deposited elsewhere in the body are associated independently with structural properties of the adolescent brain. We speculate that these relationships suggest the presence of adiposity-related variations in phospholipid composition of brain lipids.

Highlights • Psychiatric conditions contribute the most to global health burden. • Developmental cascades provide a framework for understanding causes and consequences. • Multi-generational design enables studies of virtual health trajectories. • Saguenay Youth Study is a multi-generational and multi-system cohort designed along these lines., This paper provides an overview of the Saguenay Youth Study (SYS) and its parental arm. The overarching goal of this effort is to develop trans-generational models of developmental cascades contributing to the emergence of common chronic disorders, such as depression, addictions, dementia and cardio-metabolic diseases. Over the past 10 years, we have acquired detailed brain and cardio-metabolic phenotypes, and genome-wide genotypes, in 1029 adolescents recruited in a population with a known genetic founder effect. At present, we are extending this dataset to acquire comparable phenotypes and genotypes in the biological parents of these individuals. After providing conceptual background for this work (transactions across time, systems and organs), we describe briefly the tools employed in the adolescent arm of this cohort and highlight some of the initial accomplishments. We then outline in detail the phenotyping protocol used to acquire comparable data in the parents.

Some of the known sex differences in white matter emerge during adolescence. Here, we replicate and extend our previous findings of sex differences in the structure of the corticospinal tract (Perrin et al. 2009; Herve et al. 2009). In a large normative sample of adolescents, we observed age × sex interactions in the signal intensity of T1-weighted (T1W) images (n = 941) and in magnetization transfer ratio (MTR; n = 761); both features were inversely associated with age in males but not in females. Moreover, we hypothesized that the age-related differences in CST structure exhibited by males would be mediated by differences in puberty stage and levels of bioavailable testosterone. We confirmed this prediction using mediation analysis with bootstrapping. These findings suggest that sex differences in the CST structure observed during male adolescence may be due to multiple processes associated with puberty, including (but not limited to) the rising levels of testosterone.

This review focuses on the maturation of brain white-matter, as revealed by magnetic resonance (MR) imaging carried out in healthy subjects. The review begins with a brief description of the nature of the MR signal and its possible biological underpinnings, and proceeds with a description of MR findings obtained in newborns, infants, children and adolescents. On MR images, a significant decrease in water content leads to a decrease of longitudinal relaxation times (T1) and transverse relaxation times (T2) and consequent “adult-like” appearance of T1-weighted and T2-weighted images becomes evident towards the end of the first year of life. Owing to the onset of myelination and the related increase of lipid content, MR images gradually acquire an exquisite grey-white matter contrast in a temporal sequence reflecting the time course of myelination. Albeit less pronounced, age-related changes in white matter continue during childhood and adolescence; white matter increases its overall volume and becomes more myelinated in a region-specific fashion. Detection of more subtle changes during this “late” phase of brain development is greatly aided by computational analyses of MR images. The review also briefly outlines future directions, including the use of novel MR techniques such as diffusion tensor imaging and magnetization transfer, as well as the suggestion for the concurrent use of experimental behavioral test-batteries, with structural MR imaging, to study developmental changes in structure-function relationships.

The pituitary gland is a key structure in the hypothalamic-pituitary-gonadal (HPG) axis--it plays an important role in sexual maturation during puberty. Despite its small size, its volume can be quantified using magnetic resonance imaging (MRI). Here, we study a cohort of 962 typically developing adolescents from the Saguenay Youth Study and estimate pituitary volumes using a newly developed multi-atlas segmentation method known as the MAGeT Brain algorithm. We found that age and puberty stage (controlled for age) each predicts adjusted pituitary volumes (controlled for total brain volume) in both males and females. Controlling for the effects of age and puberty stage, total testosterone and estradiol levels also predict adjusted pituitary volumes in males and pre-menarche females, respectively. These findings demonstrate that the pituitary gland grows during adolescence, and its volume relates to circulating plasma-levels of sex steroids in both males and females.

Prenatal exposure to maternal cigarette smoking interacts with a polymorphism in the α6 nicotinic acetylcholine receptor gene to influence drug use and striatum volume in adolescence

Objective : Visceral fat (VF) increases cardiometabolic risk more than fat stored subcutaneously. Here, we investigated how well routine clinical measures of adiposity, namely body mass index (BMI) and waist circumference (waist), predict VF and subcutaneous fat (SF) in a large population-based sample of adolescents. As body-fat distribution differs between males and females, we performed these analyses separately in each sex. Design and Methods : VF and SF were measured by magnetic resonance imaging in 1,002 adolescents (482 males, age 12–18 years). Relationships of BMI and waist with VF and SF were tested in multivariable analyses, which adjusted for potentially confounding effects of age and height. Results : In both males and females, BMI and waist were highly correlated with VF and SF, and explained 55–76% of their total variance. When VF was adjusted for SF, however, BMI and waist explained, respectively, only 0% and 4% of VF variance in males, and 4% and 11% of VF variance in females. In contrast, when SF was adjusted for VF, BMI and waist explained, respectively, 36% and 21% of SF variance in males, and 48% and 23% of SF variance in females. These relationships were similar during early and late puberty. Conclusions and Relevance : During adolescence, routine clinical measures of adiposity predict well SF but not VF. This holds for both sexes and throughout puberty. Further longitudinal studies are required to assess how well these measures predict changes of VF and SF over time. Given the clinical importance of VF, development of cost-effective imaging techniques and/or robust biomarkers of VF accumulation that would be suitable in everyday clinical practice is warranted.

In our previous work, we described facial features associated with a successful recognition of the sex of the face ( Mareckova et al., 2011 ). These features were based on landmarks placed on the surface of faces reconstructed from magnetic resonance (MR) images; their position was therefore influenced by both soft tissue (fat and muscle) and bone structure of the skull. Here, we ask whether bone structure has dissociable influences on observers' identification of the sex of the face. To answer this question, we used a novel method of studying skull morphology using MR images and explored the relationship between skull features, facial features, and sex recognition in a large sample of adolescents (n = 876; including 475 adolescents from our original report). To determine whether skull features mediate the relationship between facial features and identification accuracy, we performed mediation analysis using bootstrapping. In males, skull features mediated fully the relationship between facial features and sex judgments. In females, the skull mediated this relationship only after adjusting facial features for the amount of body fat (estimated with bioimpedance). While body fat had a very slight positive influence on correct sex judgments about male faces, there was a robust negative influence of body fat on the correct sex judgments about female faces. Overall, these results suggest that craniofacial bone structure is essential for correct sex judgments about a male face. In females, body fat influences negatively the accuracy of sex judgments, and craniofacial bone structure alone cannot explain the relationship between facial features and identification of a face as female.