Tuong-Vi Nguyen

Trajectories of cortical thickness maturation in normal brain development--The importance of quality control procedures.

Several reports have described cortical thickness (CTh) developmental trajectories, with conflicting results. Some studies have reported inverted-U shape curves with peaks of CTh in late childhood to adolescence, while others suggested predominant monotonic decline after age 6. In this study, we reviewed CTh developmental trajectories in the NIH MRI Study of Normal Brain Development, and in a second step, evaluated the impact of post-processing quality control (QC) procedures on identified trajectories. The quality-controlled sample included 384 individual subjects with repeated scanning (1-3 per subject, total scans n=753) from 4.9 to 22.3years of age. The best-fit model (cubic, quadratic, or first-order linear) was identified at each vertex using mixed-effects models. The majority of brain regions showed linear monotonic decline of CTh. There were few areas of cubic trajectories, mostly in bilateral temporo-parietal areas and the right prefrontal cortex, in which CTh peaks were at, or prior to, age 8. When controlling for total brain volume, CTh trajectories were even more uniformly linear. The only sex difference was faster thinning of occipital areas in boys compared to girls. The best-fit model for whole brain mean thickness was a monotonic decline of 0.027mm per year. QC procedures had a significant impact on identified trajectories, with a clear shift toward more complex trajectories (i.e., quadratic or cubic) when including all scans without QC (n=954). Trajectories were almost exclusively linear when using only scans that passed the most stringent QC (n=598). The impact of QC probably relates to decreasing the inclusion of scans with CTh underestimation secondary to movement artifacts, which are more common in younger subjects. In summary, our results suggest that CTh follows a simple linear decline in most cortical areas by age 5, and all areas by age 8. This study further supports the crucial importance of implementing post-processing QC in CTh studies of development, aging, and neuropsychiatric disorders.

Comorbidity of migraine and mood episodes in a nationally representative population-based sample.

Objective.— To examine the lifetime comorbidity of migraine with different combinations of mood episodes: (1) manic episodes alone; (2) depressive episodes alone; (3) manic and depressive episodes; (4) controls with no lifetime history of mood episodes, as well as sociodemographic and clinical correlates of migraine for each migraine–mood episode combination.

A testosterone-related structural brain phenotype predicts aggressive behavior from childhood to adulthood

Structural covariance, the examination of anatomic correlations between brain regions, has emerged recently as a valid and useful measure of developmental brain changes. Yet the exact biological processes leading to changes in covariance, and the relation between such covariance and behavior, remain largely unexplored. The steroid hormone testosterone represents a compelling mechanism through which this structural covariance may be developmentally regulated in humans. Although steroid hormone receptors can be found throughout the central nervous system, the amygdala represents a key target for testosterone-specific effects, given its high density of androgen receptors. In addition, testosterone has been found to impact cortical thickness (CTh) across the whole brain, suggesting that it may also regulate the structural relationship, or covariance, between the amygdala and CTh. Here, we examined testosterone-related covariance between amygdala volumes and whole-brain CTh, as well as its relationship to aggression levels, in a longitudinal sample of children, adolescents, and young adults 6-22 years old. We found: (1) testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC); (2) a significant relationship between amygdala-mPFC covariance and levels of aggression; and (3) mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression. These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms. These findings are consistent with prior evidence that testosterone targets the neural circuits regulating affect and impulse regulation, and show, for the first time in humans, how androgen-dependent organizational effects may regulate a very specific, aggression-related structural brain phenotype from childhood to young adulthood.

Trajectories of cortical surface area and cortical volume maturation in normal brain development

This is a report of developmental trajectories of cortical surface area and cortical volume in the NIH MRI Study of Normal Brain Development. The quality-controlled sample included 384 individual typically-developing subjects with repeated scanning (1–3 per subject, total scans n=753) from 4.9 to 22.3 years of age. The best-fit model (cubic, quadratic, or first-order linear) was identified at each vertex using mixed-effects models, with statistical correction for multiple comparisons using random field theory. Analyses were performed with and without controlling for total brain volume. These data are provided for reference and comparison with other databases. Further discussion and interpretation on cortical developmental trajectories can be found in the associated Ducharme et al.׳s article “Trajectories of cortical thickness maturation in normal brain development – the importance of quality control procedures” (Ducharme et al., 2015) [1].

Sex-specific associations of testosterone with prefrontal-hippocampal development and executive function

Testosterone is thought to play a crucial role in mediating sexual differentiation of brain structures. Examinations of the cognitive effects of testosterone have also shown beneficial and potentially sex-specific effects on executive function and mnemonic processes. Yet these findings remain limited by an incomplete understanding of the critical timing and brain regions most affected by testosterone, the lack of documented links between testosterone-related structural brain changes and cognition, and the difficulty in distinguishing the effects of testosterone from those of related sex steroids such as of estradiol and dehydroepiandrosterone (DHEA). Here we examined associations between testosterone, cortico-hippocampal structural covariance, executive function (Behavior Rating Inventory of Executive Function) and verbal memory (California Verbal Learning Test-Childrens Version), in a longitudinal sample of typically developing children and adolescents 6-22 yo, controlling for the effects of estradiol, DHEA, pubertal stage, collection time, age, handedness, and total brain volume. We found prefrontal-hippocampal covariance to vary as a function of testosterone levels, but only in boys. Boys also showed a specific association between positive prefrontal-hippocampal covariance (as seen at higher testosterone levels) and lower performance on specific components of executive function (monitoring the action process and flexibly shifting between actions). We also found the association between testosterone and a specific aspect of executive function (monitoring) to be significantly mediated by prefrontal-hippocampal structural covariance. There were no significant associations between testosterone-related cortico-hippocampal covariance and verbal memory. Taken together, these findings highlight the developmental importance of testosterone in supporting sexual differentiation of the brain and sex-specific executive function.

Effects of Sex Steroids in the Human Brain

Sex steroids are thought to play a critical developmental role in shaping both cortical and subcortical structures in the human brain. Periods of profound changes in sex steroids invariably coincide with the onset of sex differences in mental health vulnerability, highlighting the importance of sex steroids in determining sexual differentiation of the brain. Yet, most of the evidence for the central effects of sex steroids relies on non-human studies, as several challenges have limited our understanding of these effects in humans: the lack of systematic assessment of the human sex steroid metabolome, the different developmental trajectories of specific sex steroids, the impact of genetic variation and epigenetic changes, and the plethora of interactions between sex steroids, sex chromosomes, neurotransmitters, and other hormonal systems. Here we review how multimodal strategies may be employed to bridge the gap between the basic and clinical understanding of sex steroid-related changes in the human brain.

Developmental Effects of Androgens in the Human Brain

Neuroendocrine theories of brain development posit that androgens play a crucial role in sex‐specific cortical growth, although little is known about the differential effects of testosterone and dehydroepiandrosterone (DHEA) on cortico‐limbic development and cognition during adolescence. In this context, the National Institutes of Health Study of Normal Brain Development, a longitudinal study of typically developing children and adolescents aged 4‐24 years (n=433), offers a unique opportunity to examine the developmental effects of androgens on cortico‐limbic maturation and cognition. Using data from this sample, our group found that higher testosterone levels were associated with left‐sided decreases in cortical thickness (CTh) in post‐pubertal boys, particularly in the prefrontal cortex, compared to right‐sided increases in CTh in somatosensory areas in pre‐pubertal girls. Prefrontal‐amygdala and prefrontal‐hippocampal structural covariance (considered to reflect structural connectivity) also varied according to testosterone levels, with the testosterone‐related brain phenotype predicting higher aggression levels and lower executive function, particularly in boys. By contrast, DHEA was associated with a pre‐pubertal increase in CTh of several regions involved in cognitive control in both boys and girls. Covariance within several cortico‐amygdalar structural networks also varied as a function of DHEA levels, with the DHEA‐related brain phenotype predicting improvements in visual attention in both boys and girls. DHEA‐related cortico‐hippocampal structural covariance, on the other hand, predicted higher scores on a test of working memory. Interestingly, there were significant interactions between testosterone and DHEA, such that DHEA tended to mitigate the anti‐proliferative effects of testosterone on brain structure. In sum, testosterone‐related effects on the developing brain may lead to detrimental effects on cortical functions (ie, higher aggression and lower executive function), whereas DHEA‐related effects may optimise cortical functions (ie, better attention and working memory), perhaps by decreasing the influence of amygdalar and hippocampal afferents on cortical functions.

Age-related volumetric change of limbic structures and subclinical anxious/depressed symptomatology in typically developing children and adolescents

OBJECTIVE To investigate the extent to which subclinical variation in anxious/depressed psychopathology is associated with volume and age-related volumetric change of limbic structures in a longitudinal sample of healthy youths. METHODS Linear mixed-effects models were used to analyze longitudinal behavioral and neuroimaging data (up to 3 data points per subject, collected at 2 year-intervals) in 371 typically developing youths, from 4 to 18 years of age (196 females; 723 MRIs). Volumetric measures were obtained using a validated segmentation method. The best-fit model (cubic, quadratic, or first-order linear) was determined for the effect of age on amygdalar and hippocampal volume (adjusted for total brain volume). Next, amygdalar and hippocampal volumes were regressed against Child Behavior Checklist Anxious/Depressed (A/D) scores. Age-by-A/D and sex-by-A/D interactions were tested. RESULTS Analyses revealed age-related linear and quadratic volumetric change in the amygdalae and hippocampi, respectively. A/D was positively associated with total amygdalar volume (p=0.045), independent of age and sex. Age-by-A/D and sex-by-A/D interactions were not associated with amygdalar or hippocampal volume. CONCLUSIONS Results suggest that amygdalar structure is tied to A/D among typically developing youths, independent of age and sex. Developmental trajectories of amygdalar and hippocampal volume were not associated with subclinical anxiety. Taken together, increased amygdalar volume may serve as a significant marker of anxiety, regardless of developmental phase.

Anxious/depressed symptoms are related to microstructural maturation of white matter in typically developing youths

There are multiple recent reports of an association between anxious/depressed (A/D) symptomatology and the rate of cerebral cortical thickness maturation in typically developing youths. We investigated the degree to which anxious/depressed symptoms are tied to age-related microstructural changes in cerebral fiber pathways. The participants were part of the NIH MRI Study of Normal Brain Development. Child Behavior Checklist A/D scores and diffusion imaging were available for 175 youths (84 males, 91 females; 241 magnetic resonance imagings) at up to three visits. The participants ranged from 5.7 to 18.4 years of age at the time of the scan. Alignment of fractional anisotropy data was implemented using FSL/Tract-Based Spatial Statistics, and linear mixed model regression was carried out using SPSS. Child Behavior Checklist A/D was associated with the rate of microstructural development in several white matter pathways, including the bilateral anterior thalamic radiation, bilateral inferior longitudinal fasciculus, left superior longitudinal fasciculus, and right cingulum. Across these pathways, greater age-related fractional anisotropy increases were observed at lower levels of A/D. The results suggest that subclinical A/D symptoms are associated with the rate of microstructural development within several white matter pathways that have been implicated in affect regulation, as well as mood and anxiety psychopathology.

Psychosomatic medicine and psychiatry residents: a pan-Canadian survey.

BACKGROUND Psychosomatic medicine (PM) is recognized as a psychiatric subspecialty in the US, but continues to be considered a focused area of general psychiatric practice in Canada. Due to the unclear status of PM in Canada, a national survey was designed to assess the perception of and training experiences in PM among psychiatry residents. METHODS Residents enrolled at one of 13 psychiatry programs in Canada participated in the study. Logistic regression analyses were conducted to assess the effect of PM training experiences and career interest in PM on the perception of PM, controlling for number of months already completed in PM, training level, and residency program. RESULTS The response rate was 35%, n = 199. 68% of respondents identified PM as a definite subspecialty, with the majority of respondents believing that PM was as important a subspecialty as child (53%), forensic (67%) and geriatric psychiatry (75%). Eighty percent of the respondents believed a PM specialist should complete more than 3 months of additional training to be competent/qualified. There was significant heterogeneity in training experiences across programs, with a differential effect of certain training components-seminar, journal club-associated with a more favorable perception of PM as a subspecialty. CONCLUSIONS The above results challenge the notion that PM represents only a focused area of general psychiatric practice in Canada. PM appears to require additional training beyond residency for trainees to feel competent and qualified. Results from this survey suggest Canada should follow the US lead on recognizing PM as a subspecialty.