Prenatal exposure to maternal cigarette smoking and structural properties of the human corpus callosum.

Alterations induced by prenatal exposure to nicotine have been observed in experimental (rodent) studies. While numerous developmental outcomes have been associated with prenatal exposure to maternal cigarette smoking (PEMCS) in humans, the possible relation with brain structure is less clear. Here we sought to elucidate the relation between PEMCS and structural properties of human corpus callosum in adolescence and early adulthood in a total of 1,747 youth. We deployed three community-based cohorts of 446 (age 25-27 years, 46% exposed), 934 (age 12-18 years, 47% exposed) and 367 individuals (age 18-21 years, 9% exposed). A mega-analysis revealed lower mean diffusivity in the callosal segments of exposed males. We speculate that prenatal exposure to maternal cigarette smoking disrupts the early programming of callosal structure and increases the relative portion of small-diameter fibres.

Maturation of the Human Cerebral Cortex During Adolescence: Myelin or Dendritic Arbor?

Previous in vivo studies revealed robust age-related variations in structural properties of the human cerebral cortex during adolescence. Neurobiology underlying these maturational phenomena is largely unknown. Here we employ a virtual-histology approach to gain insights into processes associated with inter-regional variations in cortical microstructure and its maturation, as indexed by magnetization transfer ratio (MTR). Inter-regional variations in MTR correlate with inter-regional variations in expression of genes specific to pyramidal cells (CA1) and ependymal cells; enrichment analyses indicate involvement of these genes in dendritic growth. On the other hand, inter-regional variations in the change of MTR during adolescence correlate with inter-regional profiles of oligodendrocyte-specific gene expression. Complemented by a quantitative hypothetical model of the contribution of surfaces associated with dendritic arbor (1631 m2) and myelin (48 m2), these findings suggest that MTR signals are driven mainly by macromolecules associated with dendritic arbor while maturational changes in the MTR signal are associated with myelination.

Differences in maternal smoking across successive pregnancies - dose-dependent relation to BMI z-score in the offspring: an individual patient data (IPD) meta-analysis.

INTRODUCTION: Uncontrolled family factors may bias the estimation of the association between maternal smoking during pregnancy and offspring body mass index (BMI). The objective was to assess if there is an association between maternal smoking during pregnancy and offspring BMI z-score independent of factors in the siblings' shared environment and if such association is linear. METHODS: We performed an individual patient data meta-analysis using five studies providing sibling data (45,299 children from 14,231 families). In a multi-level model, separating within-family and between-family effects and with random intercept for families, we analysed the dose-response association between maternal number of cigarettes per day during pregnancy and offspring's BMI z-score using B-splines to allow for non-linear associations. RESULTS: A linear within-family effect for number of cigarettes smoked in the range from 1 to 30 cigarettes per day on the offspring's BMI z-score was observed. Each additional cigarette per day between sibling pregnancies resulted in an increase in BMI z-score of 0.007 (95% CI [0.006, 0.009]). A between family-effect emerged only with doses ≥25 cigarettes per day. CONCLUSIONS: The number of cigarettes mothers smoke per day during pregnancy is positively associated with offspring BMI z-score even among siblings, suggesting that the association is not entirely explained by confounding by family factors.

Visceral fat enhances blood pressure reactivity to physical but not mental challenges in male adolescents.

BACKGROUND: 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 cm(3) 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.

Resilience and corpus callosum microstructure in adolescence.

BACKGROUND: Resilience is the capacity of individuals to resist mental disorders despite exposure to stress. Little is known about its neural underpinnings. The putative variation of white-matter microstructure with resilience in adolescence, a critical period for brain maturation and onset of high-prevalence mental disorders, has not been assessed by diffusion tensor imaging (DTI). Lower fractional anisotropy (FA) though, has been reported in the corpus callosum (CC), the brain's largest white-matter structure, in psychiatric and stress-related conditions. We hypothesized that higher FA in the CC would characterize stress-resilient adolescents. METHOD: Three groups of adolescents recruited from the community were compared: resilient with low risk of mental disorder despite high exposure to lifetime stress (n = 55), at-risk of mental disorder exposed to the same level of stress (n = 68), and controls (n = 123). Personality was assessed by the NEO-Five Factor Inventory (NEO-FFI). Voxelwise statistics of DTI values in CC were obtained using tract-based spatial statistics. Regional projections were identified by probabilistic tractography. RESULTS: Higher FA values were detected in the anterior CC of resilient compared to both non-resilient and control adolescents. FA values varied according to resilience capacity. Seed regional changes in anterior CC projected onto anterior cingulate and frontal cortex. Neuroticism and three other NEO-FFI factor scores differentiated non-resilient participants from the other two groups. CONCLUSION: High FA was detected in resilient adolescents in an anterior CC region projecting to frontal areas subserving cognitive resources. Psychiatric risk was associated with personality characteristics. Resilience in adolescence may be related to white-matter microstructure.

BDNF Val66Met and reward-related brain function in adolescents: role for early alcohol consumption.

Changes in reward processing have been identified as one important pathogenetic mechanism in alcohol addiction. The nonsynonymous single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene (rs6265/Val66Met) modulates the central nervous system activity of neurotransmitters involved in reward processing such as serotonin, dopamine, and glutamate. It was identified as crucial for alcohol consumption in healthy adults and, in rats, specifically related to the function in the striatum, a region that is commonly involved in reward processing. However, studies in humans on the association of BDNF Val66Met and reward-related brain functions and its role for alcohol consumption, a significant predictor of later alcohol addiction, are missing. Based on an intermediate phenotype approach, we assessed the early orientation toward alcohol and alcohol consumption in 530 healthy adolescents that underwent a monetary incentive delay task during functional magnetic resonance imaging. We found a significantly lower response in the putamen to reward anticipation in adolescent Met carriers with high versus low levels of alcohol consumption. During reward feedback, Met carriers with low putamen reactivity were significantly more likely to orient toward alcohol and to drink alcohol 2 years later. This study indicates a possible effect of BDNF Val66Met on alcohol addiction-related phenotypes in adolescence.

Genomic architecture of human neuroanatomical diversity.

Human brain anatomy is strikingly diverse and highly inheritable: genetic factors may explain up to 80% of its variability. Prior studies have tried to detect genetic variants with a large effect on neuroanatomical diversity, but those currently identified account for <5% of the variance. Here, based on our analyses of neuroimaging and whole-genome genotyping data from 1765 subjects, we show that up to 54% of this heritability is captured by large numbers of single-nucleotide polymorphisms of small-effect spread throughout the genome, especially within genes and close regulatory regions. The genetic bases of neuroanatomical diversity appear to be relatively independent of those of body size (height), but shared with those of verbal intelligence scores. The study of this genomic architecture should help us better understand brain evolution and disease.

Single nucleotide polymorphism in the neuroplastin locus associates with cortical thickness and intellectual ability in adolescents.

Despite the recognition that cortical thickness is heritable and correlates with intellectual ability in children and adolescents, the genes contributing to individual differences in these traits remain unknown. We conducted a large-scale association study in 1583 adolescents to identify genes affecting cortical thickness. Single-nucleotide polymorphisms (SNPs; n=54,837) within genes whose expression changed between stages of growth and differentiation of a human neural stem cell line were selected for association analyses with average cortical thickness. We identified a variant, rs7171755, associating with thinner cortex in the left hemisphere (P=1.12 × 10(-)(7)), particularly in the frontal and temporal lobes. Localized effects of this SNP on cortical thickness differently affected verbal and nonverbal intellectual abilities. The rs7171755 polymorphism acted in cis to affect expression in the human brain of the synaptic cell adhesion glycoprotein-encoding gene NPTN. We also found that cortical thickness and NPTN expression were on average higher in the right hemisphere, suggesting that asymmetric NPTN expression may render the left hemisphere more sensitive to the effects of NPTN mutations, accounting for the lateralized effect of rs7171755 found in our study. Altogether, our findings support a potential role for regional synaptic dysfunctions in forms of intellectual deficits.

Saguenay Youth Study: a multi-generational approach to studying virtual trajectories of the brain and cardio-metabolic health.

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.

Opioid receptor mu 1 gene, fat intake and obesity in adolescence.

Dietary preference for fat may increase risk for obesity. It is a complex behavior regulated in part by the amygdala, a brain structure involved in reward processing and food behavior, and modulated by genetic factors. Here, we conducted a genome-wide association study (GWAS) to search for gene loci associated with dietary intake of fat, and we tested whether these loci are also associated with adiposity and amygdala volume. We studied 598 adolescents (12-18 years) recruited from the French-Canadian founder population and genotyped them with 530 011 single-nucleotide polymorphisms. Fat intake was assessed with a 24-hour food recall. Adiposity was examined with anthropometry and bioimpedance. Amygdala volume was measured by magnetic resonance imaging. GWAS identified a locus of fat intake in the µ-opioid receptor gene (OPRM1, rs2281617, P=5.2 × 10(-6)), which encodes a receptor expressed in the brain-reward system and shown previously to modulate fat preference in animals. The minor OPRM1 allele appeared to have a 'protective' effect: it was associated with lower fat intake (by 4%) and lower body-fat mass (by ∼2 kg, P=0.02). Consistent with the possible amygdala-mediated inhibition of fat preference, this allele was additionally associated with higher amygdala volume (by 69 mm(3), P=0.02) and, in the carriers of this allele, amygdala volume correlated inversely with fat intake (P=0.02). Finally, OPRM1 was associated with fat intake in an independent sample of 490 young adults. In summary, OPRM1 may modulate dietary intake of fat and hence risk for obesity, and this effect may be modulated by subtle variations in the amygdala volume.

White-matter microstructure and gray-matter volumes in adolescents with subthreshold bipolar symptoms.

Abnormalities in white-matter (WM) microstructure, as lower fractional anisotropy (FA), have been reported in adolescent-onset bipolar disorder and in youth at familial risk for bipolarity. We sought to determine whether healthy adolescents with subthreshold bipolar symptoms (SBP) would have early WM microstructural alterations and whether those alterations would be associated with differences in gray-matter (GM) volumes. Forty-two adolescents with three core manic symptoms and no psychiatric diagnosis, and 126 adolescents matched by age and sex, with no psychiatric diagnosis or symptoms, were identified after screening the IMAGEN database of 2223 young adolescents recruited from the general population. After image quality control, voxel-wise statistics were performed on the diffusion parameters using tract-based spatial statistics in 25 SBP adolescents and 77 controls, and on GM and WM images using voxel-based morphometry in 30 SBP adolescents and 106 controls. As compared with healthy controls, adolescents with SBP displayed lower FA values in a number of WM tracts, particularly in the corpus callosum, cingulum, bilateral superior and inferior longitudinal fasciculi, uncinate fasciculi and corticospinal tracts. Radial diffusivity was mainly higher in posterior parts of bilateral superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi and right cingulum. As compared with controls, SBP adolescents had lower GM volume in the left anterior cingulate region. This is the first study to investigate WM microstructure and GM morphometric variations in adolescents with SBP. The widespread FA alterations in association and projection tracts, associated with GM changes in regions involved in mood disorders, suggest altered structural connectivity in those adolescents.

Visceral fat is associated with lower executive functioning in adolescents.

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 was 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=0.0001-0.02). 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 female subjects and not in male subjects (sex-by-VF interaction: P=0.001-0.04). 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 female subjects compared with male subjects may be more sensitive to the potentially detrimental effects of VF on cognition.

Genetic risk for nicotine dependence in the cholinergic system and activation of the brain reward system in healthy adolescents.

Genetic variation in a genomic region on chromosome 15q25.1, which encodes the alpha5, alpha3, and beta4 subunits of the cholinergic nicotinic receptor genes, confers risk to smoking and nicotine dependence (ND). Neural reward-related responses have previously been identified as important factors in the development of drug dependence involving ND. Applying an imaging genetics approach in two cohorts (N=487; N=478) of healthy non-smoking adolescents, we aimed to elucidate the impact of genome-wide significant smoking-associated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on reward-related neural responses in central regions such as the striatum, orbitofrontal and anterior cingulate cortex (ACC), and personality traits related to addiction. In both samples, carriers of the rs578776 GG compared with AG/AA genotype showed a significantly lower neural response to reward outcomes in the right ventral and dorsal ACC but not the striatum or the orbitofrontal cortex. Rs578776 was unrelated to neural reward anticipation or reward magnitude. Significantly higher scores of anxiety sensitivity in GG compared with AG/AA carriers were found only in sample 1. Associations with other personality traits were not observed. Our findings suggest that the rs578776 risk variant influences susceptibility to ND by dampening the response of the ACC to reward feedback, without recruiting the striatum or orbitofrontal cortex during feedback or anticipation. Thus, it seems to have a major role in the processing of and behavioral adaptation to changing reward outcomes.

Sexual dimorphism in the adolescent brain: Role of testosterone and androgen receptor in global and local volumes of grey and white matter.

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.

Sex differences in the growth of white matter during adolescence.

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.

Maternal cigarette smoking during pregnancy and cognitive performance in adolescence.

BACKGROUND: The incidence of cigarette smoking during pregnancy remains high. Maternal smoking during pregnancy is known to be associated with cognitive and behavioural sequelae in childhood and adolescence. We assessed the relationship between maternal cigarette smoking during pregnancy and cognitive abilities in adolescent offspring (n = 503, 12- to 18-years old) using an extensive 6-h battery of tests. METHODS: Non-exposed adolescents (controls) were matched to exposed adolescents (cases) by maternal education and school attended. Cognitive abilities were evaluated using a neuropsychological battery consisting of 33 tasks measuring verbal abilities, visuo-spatial skills, verbal and visual memory, processing speed, resistance to interference and motor dexterity. RESULTS: We found no differences between cases and controls in any of the cognitive domains whether potential confounders were included in the model or not. In addition to maternal smoking during pregnancy, we also evaluated the effect of sex and age on the various cognitive abilities in this large adolescent sample and found that most of the abilities continue to improve during adolescence to the same extent in girls and boys, with several age-independent sex differences. CONCLUSIONS: We found no effect of maternal cigarette smoking during pregnancy on cognitive abilities of the adolescent offspring when matching cases and controls by maternal education, the most common confounder of maternal cigarette smoking during pregnancy.

Corpus callosum in adolescent offspring exposed prenatally to maternal cigarette smoking.

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.

Quantitative founder-effect analysis of French Canadian families identifies specific loci contributing to metabolic phenotypes of hypertension.

The Saguenay-Lac St-Jean population of Quebec is relatively isolated and has genealogical records dating to the 17th-century French founders. In 120 extended families with at least one sib pair affected with early-onset hypertension and/or dyslipidemia, we analyzed the genetic determinants of hypertension and related cardiovascular and metabolic conditions. Variance-components linkage analysis revealed 46 loci after 100,000 permutations. The most prominent clusters of overlapping quantitative-trait loci were on chromosomes 1 and 3, a finding supported by principal-components and bivariate analyses. These genetic determinants were further tested by classifying families by use of LOD score density analysis for each measured phenotype at every 5 cM. Our study showed the founder effect over several generations and classes of living individuals. This quantitative genealogical approach supports the notion of the ancestral causality of traits uniquely present and inherited in distinct family classes. With the founder effect, traits determined within population subsets are measurably and quantitatively transmitted through generational lineage, with a precise component contributing to phenotypic variance. These methods should accelerate the uncovering of causal haplotypes in complex diseases such as hypertension and metabolic syndrome.

Gender-specific genetic determinants of blood pressure and organ weight: pharmacogenetic approach.

A total genome scan and pharmacogenetic study were designed to search for genetic determinants of blood pressure (BP) as well as heart and kidney weights. Genome scanning was carried out in 266 F(2) intercrosses from Prague hypertensive hypertriglyceridemic rats for phenotypes of organ weights, baseline BP, BP after blockade of the renin-angiotensin system (RAS) by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide (NO) synthase by N(G)-nitro-L-arginine methyl ester. Pharmacogenetic analysis showed that, in males, BP was controlled by two loci on chromosomes 1 and 5 (Chr1, Chr5) through the SNS, and these loci showed a positive contribution for relative kidney weight (KW/BW). On the other hand, baseline BP in females was controlled by two loci on Chr3 and Chr7. The effect of these loci was not mediated by the RAS, SNS or NO system. These loci did not show any effect for KW/BW. Negatively-linked loci for KW/BW and relative heart weight (HW/BW) were identified on Chr2 in both genders. Another negatively-linked locus for KW/BW, located on Chr8 in males, affected BP through the SNS. This locus on Chr8 overlapped with a previously-reported modifier locus for polycystic kidney disease (PKD). In conclusion, this pharmacogenetic study determined two loci for BP and relative organ mass implicating sympathetic overactivity. Concordance of the identified locus for KW/BW and BP through the SNS on Chr8 with the PKD locus revealed the importance of this region for renal complications in various diseases.