Zdenka Pausova

Neuropsychosocial profiles of current and future adolescent alcohol misusers

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention.

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.

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.

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.

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.

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.

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.

Handedness, motor skills and maturation of the corticospinal tract in the adolescent brain

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.

A Common Variant of the FTO Gene Is Associated Not Only With 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.

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.