Alain Pitiot

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.

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.

Visualization of nigrosome 1 and its loss in PD Pathoanatomical correlation and in vivo 7 T MRI

Objective: This study assessed whether high-resolution 7 T MRI allowed direct in vivo visualization of nigrosomes, substructures of the substantia nigra pars compacta (SNpc) undergoing the greatest and earliest dopaminergic cell loss in Parkinson disease (PD), and whether any disease-specific changes could be detected in patients with PD. Methods: Postmortem (PM) midbrains, 2 from healthy controls (HCs) and 1 from a patient with PD, were scanned with high-resolution T2*-weighted MRI scans, sectioned, and stained for iron and neuromelanin (Perl), TH, and calbindin. To confirm the identification of nigrosomes in vivo on 7 T T2*-weighted scans, we assessed colocalization with neuromelanin-sensitive T1-weighted scans. We then assessed the ability to depict PD pathology on in vivo T2*-weighted scans by comparing data from 10 patients with PD and 8 age- and sex-matched HCs. Results: A hyperintense, ovoid area within the dorsolateral border of the otherwise hypointense SNpc was identified in the HC brains on in vivo and PM T2*-weighted MRI. Location, size, shape, and staining characteristics conform to nigrosome 1. Blinded assessment by 2 neuroradiologists showed consistent bilateral absence of this nigrosome feature in all 10 patients with PD, and bilateral presence in 7/8 HC. Conclusions: In vivo and PM MRI with histologic correlation demonstrates that high-resolution 7 T MRI can directly visualize nigrosome 1. The absence of nigrosome 1 in the SNpc on MRI scans might prove useful in developing a neuroimaging diagnostic test for PD.

Magnetization transfer phenomenon in the human brain at 7 T.

Magnetization transfer is an important source of contrast in magnetic resonance imaging which is sensitive to the concentration of macromolecules and other solutes present in the tissue. Magnetization transfer effects can be visualized in magnetization transfer ratio images or quantified via the z-spectrum. This paper presents methods of measuring the z-spectrum and of producing high-resolution MTR images and maps of z-spectrum asymmetry in vivo at 7 T, within SAR limits. It also uses a 3-compartment model to measure chemical exchange and magnetization transfer parameters from the z-spectrum data. The peak in the z-spectrum associated with chemical exchange between amide and water protons (amide proton transfer, APT, effects) is much more apparent at 7 T than at 3 T. Furthermore at 7 T quantitative APT results varied between the corpus callosum and other white matter structures, suggesting that quantitative APT imaging could be used as a method of measuring myelination. The results also suggest that chemical exchange is not responsible for the phase shift observed in susceptibility weighted images between grey matter and white matter.

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.

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.

Brain volumes and Val66Met polymorphism of the BDNF gene: local or global effects?

A common Single-Nucleotide Polymorphism in the Brain-Derived Neurotrophic Factor (BDNF) gene coding the Val66Met substitution in the pro-BDNF protein has been associated with a number of behavioural and neuroanatomical phenotypes; the latter include, for example, regional differences in volumes of the hippocampus and prefrontal grey matter. Here, we show that the observed regional differences may not stem from a localised effect of this gene. Our analysis of regional brain volume in a cohort of 331 adolescents indicates that the Val66Met substitution has a global effect on brain volume, and that the observed local differences are to be expected if brain allometry—the covariance pattern of regional brain volumes—is taken into account.

Smoothness-guided 3-D reconstruction of 2-D histological images

This paper tackles two problems: (1) the reconstruction of 3-D volumes from 2-D post-mortem slices (e.g., histology, autoradiography, immunohistochemistry) in the absence of external reference, and (2) the quantitative evaluation of the 3-D reconstruction. We note that the quality of a reconstructed volume is usually assessed by considering the smoothness of some reconstructed structures of interest (e.g., the gray-white matter surfaces in brain images). Here we propose to use smoothness as a means to drive the reconstruction process itself. From a pair-wise rigid reconstruction of the 2-D slices, we first extract the boundaries of structures of interest. Those are then smoothed with a min-max curvature flow confined to the 2-D planes in which the slices lie. Finally, for each slice, we estimate a linear or flexible transformation from the sparse displacement field computed from the flow, which we apply to the original 2-D slices to obtain a smooth volume. In addition, we present a co-occurrence matrix-based technique to quantify the smoothness of reconstructed volumes. We discuss and validate the application of both our reconstruction approach and the smoothness measure on synthetic examples as well as real histological data.

Geometrical regularization of displacement fields for histological image registration.

This article tackles the registration of 2-D biomedical images (histological sections, autoradiographs, cryosections, etc.). Our goal is to adequately match anatomical features of interest without inducing biologically improbable tissue distortions. We observe that the large variety of registration applications--3-D volume reconstruction, multimodal molecular mapping, etc.--induce a no less diverse set of requirements in terms of accuracy and robustness. In turn, these directly translate into regularization constraints on the deformation model, which should ideally be specifiable by the user. We propose an adaptive regularization approach where the rigidity constraints are informed by the registration application at hand and whose support is controlled by the geometry of the images to be registered. For each site of a sparse lattice over which a displacement field has been computed, our algorithm estimates, in a robust fashion, a rigid or affine transformation within a circular neighbourhood cut to fit the local geometry around the site. We investigate the behaviour of this technique and discuss its sensitivity to the rigidity parameter.

Stress during puberty boosts metabolic activation associated with fear-extinction learning in hippocampus, basal amygdala and cingulate cortex.

Adolescence is characterized by major developmental changes that may render the individual vulnerable to stress and the development of psychopathologies in a sex-specific manner. Earlier we reported lower anxiety-like behavior and higher risk-taking and novelty seeking in rats previously exposed to peri-pubertal stress. Here we studied whether peri-pubertal stress affected the acquisition and extinction of fear memories and/or the associated functional engagement of various brain regions, as assessed with 2-deoxyglucose. We showed that while peri-pubertal stress reduced freezing during the acquisition of fear memories (training) in both sexes, it had a sex-specific effect on extinction of these memories. Moreover hippocampus, basal amygdala and cingulate and motor cortices showed higher metabolic rates during extinction in rats exposed to peri-pubertal stress. Interestingly, activation of the infralimbic cortex was negatively correlated with freezing during extinction only in control males, while only males stressed during puberty showed a significant correlation between behavior during extinction and metabolic activation of hippocampus, amygdala and paraventricular nucleus. No correlations between brain activation and behavior during extinction were observed in females (control or stress). These results indicate that exposure to peri-pubertal stress affects behavior and brain metabolism when the individual is exposed to an additional stressful challenge. Some of these effects are sex-specific.