Louis Richer

Growth of White Matter in the Adolescent Brain: Role of Testosterone and Androgen Receptor

The growth of white matter during human adolescence shows a striking sexual dimorphism; the volume of white matter increases with age slightly in girls and steeply in boys. Here, we provide evidence supporting the role of androgen receptor (AR) in mediating the effect of testosterone on white matter. In a large sample of typically developing adolescents (n = 408, 204 males), we used magnetic resonance imaging and acquired T1-weighted and magnetization transfer ratio (MTR) images. We also measured plasma levels of testosterone and genotyped a functional polymorphism in the AR gene, namely the number of CAG repeats in exon 1 believed to be inversely proportional to the AR transcriptional activity. We found that the testosterone-related increase of white-matter volume was stronger in male adolescents with the lower versus higher number of CAG repeats in the AR gene, with testosterone explaining, respectively, 26 and 8% of variance in the volume. The MTR results suggest that this growth is not related to myelination; the MTR decreased with age in male adolescents. We speculate that testosterone affects axonal caliber rather than the thickness of the myelin sheath.

Brain Size and Folding of the Human Cerebral Cortex

During evolution, the mammalian cerebral cortex has expanded disproportionately to brain volume. As a consequence, most mammals with large brains have profusely convoluted cortices. The human cortex is a good example of this trend, however, given the large variability in human brain size, it is not clear how cortical folding varies from the smallest to the largest brains. We analyzed cortical folding in a large cohort of human subjects exhibiting a 1.7-fold variation in brain volume. We show that the same disproportionate increase of cortical surface relative to brain volume observed across species can be also observed across human brains: the largest brains can have up to 20% more surface than a scaled-up small brain. We introduce next a novel local measure of cortical folding, and we show that the correlation between cortical folding and size varies along a rostro-caudal gradient, being especially significant in the prefrontal cortex. The expansion of the cerebral cortex, and in particular that of its prefrontal region, is a major evolutionary landmark in the emergence of human cognition. Our results suggest that this may be, at least in part, a natural outcome of increasing brain size.

Maternal smoking during pregnancy is associated with epigenetic modifications of the brain-derived neurotrophic factor-6 exon in adolescent offspring.

Prenatal exposure to maternal cigarette smoking (PEMCS) is associated with variations in brain and behavior in adolescence. Epigenetic mechanisms may mediate some of the consequences of PEMCS through methylation of deoxyribonucleic acid (DNA) in genes important for brain development, such as the brain‐derived neurotrophic factor (BDNF). In the current study, we used bisulfite sequencing to assess DNA methylation of the BDNF promoter in the blood of adolescents whose mothers smoked during pregnancy. We demonstrate that PEMCS is associated with higher rates of DNA methylation in the BDNF‐6 exon. These results suggest that PEMCS may lead to long‐term down‐regulation of BDNF expression via the increase of DNA methylation in its promoter region. Such mechanisms could, in turn, lead to modifications in both development and plasticity of the brain exposed in utero to maternal cigarette smoking.

Genes, maternal smoking, and the offspring brain and body during adolescence: Design of the Saguenay Youth Study

The search for genes of complex traits is aided by the availability of multiple quantitative phenotypes collected in geographically isolated populations. Here we provide rationale for a large‐scale study of gene‐environment interactions influencing brain and behavior and cardiovascular and metabolic health in adolescence, namely the Saguenay Youth Study (SYS). The SYS is a retrospective study of long‐term consequences of prenatal exposure to maternal cigarette smoking (PEMCS) in which multiple quantitative phenotypes are acquired over five sessions (telephone interview, home, hospital, laboratory, and school). To facilitate the search for genes that modify an individuals response to an in utero environment (i.e. PEMCS), the study is family‐based (adolescent sibships) and is carried out in a relatively geographically isolated population of the Saguenay Lac‐Saint‐Jean (SLSJ) region in Quebec, Canada. DNA is acquired in both biological parents and in adolescent siblings. A genome‐wide scan will be carried out with sib‐pair linkage analyses, and fine mapping of identified loci will be done with family‐based association analyses. Adolescent sibships (12–18 years of age; two or more siblings per family) are recruited in high schools throughout the SLSJ region; only children of French‐Canadian origin are included. Based on a telephone interview, potential participants are classified as exposed or nonexposed prenatally to maternal cigarette smoking; the two groups are matched for the level of maternal education and the attended school. A total of 500 adolescent participants in each group will be recruited and phenotyped. The following types of datasets are collected in all adolescent participants: (1) magnetic resonance images of brain, abdominal fat, and kidneys, (2) standardized and computer‐based neuropsychological tests, (3) hospital‐based cardiovascular, body‐composition and metabolic assessments, and (4) questionnaire‐derived measures (e.g. life habits such as eating and physical activity; drug, alcohol use and delinquency; psychiatric symptoms; personality; home and school environment; academic and vocational attitudes). Parents complete a medical questionnaire, home‐environment questionnaire, a handedness questionnaire, and a questionnaire about their current alcohol and drug use, depression, anxiety, and current and past antisocial behavior. To date, we have fully phenotyped a total of 408 adolescent participants. Here we provide the description of the SYS and, using the initial sample, we present information on ascertainment, demographics of the exposed and nonexposed adolescents and their parents, and the initial MRI‐based assessment of familiality in the brain size and the volumes of grey and white matter. Hum Brain Mapp 2007.

Prenatal Exposure to Maternal Cigarette Smoking and the Adolescent Cerebral Cortex

Smoking during pregnancy is associated with long-term consequences on offspring behavior. We measured thickness of the cerebral cortex using magnetic resonance images obtained in 155 adolescents exposed in utero to maternal smoking and compared them with 159 non-exposed subjects matched by maternal education. Orbitofrontal, middle frontal, and parahippocampal cortices were thinner in exposed, as compared with non-exposed, individuals; these differences were more pronounced in female adolescents. In exposed females, the thickness of the orbitofrontal cortex correlated negatively with a self-rated assessment of caring, one of the components of a model of positive youth development. These findings provide evidence of the long-term impact of prenatal environment on a neural substrate of cognition and social behavior.

Orbitofrontal Cortex and Drug Use During Adolescence: Role of Prenatal Exposure to Maternal Smoking and BDNF Genotype

CONTEXT Prenatal exposure to maternal cigarette smoking (PEMCS) may affect brain development and behavior in adolescent offspring. OBJECTIVE To evaluate the involvement of the orbitofrontal cortex (OFC) in mediating the relationship between PEMCS and substance use. DESIGN Cross-sectional analyses from the Saguenay Youth Study aimed at evaluating the effects of PEMCS on brain development and behavior among adolescents. Nonexposed adolescents were matched with adolescents exposed prenatally to cigarette smoking by maternal educational level. PARTICIPANTS AND SETTING A French Canadian founder population of the Saguenay-Lac-Saint-Jean region of Quebec, Canada. The behavioral data set included 597 adolescents (275 sibships; 12-18 years of age), half of whom were exposed in utero to maternal cigarette smoking. Analysis of cortical thickness and genotyping were performed using available data from 314 adolescents. MAIN OUTCOME MEASURES The likelihood of substance use was assessed with the Diagnostic Interview Schedule for Children Predictive Scales. The number of different drugs tried by each adolescent was assessed using another questionnaire. Thickness of the OFC was estimated from T1-weighted magnetic resonance images using FreeSurfer software. RESULTS Prenatal exposure to maternal cigarette smoking is associated with an increased likelihood of substance use. Among exposed adolescents, the likelihood of drug experimentation correlates with the degree of OFC thinning. In nonexposed adolescents, the thickness of the OFC increases as a function of the number of drugs tried. The latter effect is moderated by a brain-derived neurotrophic factor (BDNF) genotype (Val66Met). CONCLUSIONS We speculate that PEMCS interferes with the development of the OFC and, in turn, increases the likelihood of drug use among adolescents. In contrast, we suggest that, among nonexposed adolescents, drug experimentation influences the OFC thickness via processes akin to experience-induced plasticity.

Early Cannabis Use, Polygenic Risk Score for Schizophrenia and Brain Maturation in Adolescence

IMPORTANCE Cannabis use during adolescence is known to increase the risk for schizophrenia in men. Sex differences in the dynamics of brain maturation during adolescence may be of particular importance with regard to vulnerability of the male brain to cannabis exposure. OBJECTIVE To evaluate whether the association between cannabis use and cortical maturation in adolescents is moderated by a polygenic risk score for schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Observation of 3 population-based samples included initial analysis in 1024 adolescents of both sexes from the Canadian Saguenay Youth Study (SYS) and follow-up in 426 adolescents of both sexes from the IMAGEN Study from 8 European cities and 504 male youth from the Avon Longitudinal Study of Parents and Children (ALSPAC) based in England. A total of 1577 participants (aged 12-21 years; 899 [57.0%] male) had (1) information about cannabis use; (2) imaging studies of the brain; and (3) a polygenic risk score for schizophrenia across 108 genetic loci identified by the Psychiatric Genomics Consortium. Data analysis was performed from March 1 through December 31, 2014. MAIN OUTCOMES AND MEASURES Cortical thickness derived from T1-weighted magnetic resonance images. Linear regression tests were used to assess the relationships between cannabis use, cortical thickness, and risk score. RESULTS Across the 3 samples of 1574 participants, a negative association was observed between cannabis use in early adolescence and cortical thickness in male participants with a high polygenic risk score. This observation was not the case for low-risk male participants or for the low- or high-risk female participants. Thus, in SYS male participants, cannabis use interacted with risk score vis-à-vis cortical thickness (P = .009); higher scores were associated with lower thickness only in males who used cannabis. Similarly, in the IMAGEN male participants, cannabis use interacted with increased risk score vis-à-vis a change in decreasing cortical thickness from 14.5 to 18.5 years of age (t137 = -2.36; P = .02). Finally, in the ALSPAC high-risk group of male participants, those who used cannabis most frequently (≥61 occasions) had lower cortical thickness than those who never used cannabis (difference in cortical thickness, 0.07 [95% CI, 0.01-0.12]; P = .02) and those with light use (<5 occasions) (difference in cortical thickness, 0.11 [95% CI, 0.03-0.18]; P = .004). CONCLUSIONS AND RELEVANCE Cannabis use in early adolescence moderates the association between the genetic risk for schizophrenia and cortical maturation among male individuals. This finding implicates processes underlying cortical maturation in mediating the link between cannabis use and liability to schizophrenia.

A Common Variant of the FTO Gene Is Associated With Not Only Increased Adiposity but Also Elevated Blood Pressure in French Canadians

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.

Prenatal exposure to maternal cigarette smoking and accumulation of intra-abdominal fat during adolescence.

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.

Predictors of Disrupted Social Participation in Myotonic Dystrophy Type 1

OBJECTIVE To identify personal and environmental predictors of the most disrupted participation domains in people with myotonic dystrophy type 1 (DM1). DESIGN Cross-sectional study. SETTING Outpatient neuromuscular clinic. PARTICIPANTS Adults (n=200; 121 women), age 18 years or older (mean age, 47 y), with a confirmed diagnosis of DM1 were selected from the registry of a neuromuscular clinic (N=416). Fifty-two participants had the mild phenotype and 148 the adult phenotype. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Social participation in mobility, housing, employment, and recreation was assessed with the Life Habits Measure. Disrupted participation was based on whether help was needed in performing most life habits because of incapacities or environmental barriers. Environmental factors were assessed by using the Measure of the Quality of the Environment. Personal factors were assessed with standardized instruments including the Berg Balance Scale, the Krupp Fatigue Severity Scale, and manual muscle testing. RESULTS A large proportion of participants (45%-61%) reported disrupted participation in all 4 domains. Lower-extremity strength (odd ratios [OR], 15.0-5.5; P<.050) and higher fatigue (OR, 6.0-2.6; P<.05) were present in participants with disrupted participation. With regard to environmental factors, family support (OR, 3.6-2.5; P<.05) and public services (OR, 2.8-2.2; P<.05) were perceived as barriers for participants with disrupted participation in most domains. CONCLUSIONS This study identified personal and environmental factors that may influence the trajectory toward disrupted participation in individuals with DM1. Fatigue, strength, family support, and public services were found to be independent predictors of disrupted participation.