Longitudinal associations between paternal mental health and child behavior and cognition in middle childhood.

Introduction: Paternal mental health has been associated with adverse consequences on offspring psychosocial development, and family environmental factors may partly explain those associations. To clarify this, we need comprehensive prospective studies, particularly in middle-childhood when the child enters school and is expected to make use of behavioral and cognitive skills as part of their interactions and learning. Method: Using data from a sub-sample of the prospective 3D birth cohort study comprised of mother-father-child triads, and a follow-up of the parents and the children at 6-8 years of age (n = 61; 36 boys, 25 girls), we examined whether paternal anxious and depressive symptoms measured during the pregnancy period (i.e., prenatally) or concurrently when the child was assessed at 6-8 years old were associated with children's cognition/behavior. Results: In contrast to our hypotheses, we found that greater prenatal paternal depressive symptoms predicted fewer child behavioral difficulties; and that greater concurrent childhood paternal depression or anxiety symptoms were associated with higher child full-scale IQ, controlling for the equivalent maternal mental health assessment and parental education. Father parenting perception did not mediate these associations, nor were they moderated by maternal mental health at the concurrent assessment, or paternal ratings of marital relationship quality. Discussion: These findings suggest that higher symptoms of paternal mental health symptoms are associated with fewer child behavioral difficulties and higher cognitive performance in middle childhood. Potential clinical implications and future research directions are discussed.

Prenatal paternal anxiety symptoms predict child DHEA levels and internalizing symptoms during adrenarche.

Introduction: This study examined (1) whether measures of paternal anxious and depressive symptoms collected prenatally and during a follow-up assessment when the child was in middle childhood, predict child neuroendocrine outcomes, and (2) whether neuroendocrine outcomes are intermediate factors between paternal mental health and child cognitive/behavioral outcomes. Middle childhood coincides with increased autonomy as the child transitions into grade school, and with adrenarche, as the maturing adrenal gland increases secretion of dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEA-S), hormones that are implicated in corticolimbic development which regulate emotions and cognition. Methods: Participants were recruited from a subsample of a large prospective birth cohort study (3D study). We conducted a follow-up study when children were 6-8 years old (N = 61 families, 36 boys, 25 girls). Parental symptoms of anxiety, stress and depression were assessed via validated self-report questionnaires: prenatally using an in-house anxiety questionnaire, the Perceived Stress Scale (PSS) and the Center for Epidemiologic Studies Depression (CES-D), and at the follow up, using the Beck Anxiety and Beck Depression Inventories. Children provided salivary hormone samples, and their pituitary gland volume was measured from structural Magnetic Resonance Imaging (MRI) scans. Child behaviors were measured using the Strengths and Difficulties Questionnaire and cognitive outcomes using the WISC-V. Multiple regression analyses were used to test whether paternal mental health symptoms assessed prenatally and during childhood are associated with child neuroendocrine outcomes, adjusting for maternal mental health and child sex. Indirect-effect models assessed whether neuroendocrine factors are important intermediates that link paternal mental health and cognitive/behavioral outcomes. Results: (1) Fathers' prenatal anxiety symptoms predicted lower DHEA levels in the children, but not pituitary volume. (2) Higher prenatal paternal anxiety symptoms predicted higher child internalizing symptoms via an indirect pathway of lower child DHEA. No associations were detected between paternal anxiety symptoms measured in childhood, and neuroendocrine outcomes. No child sex differences were detected on any measure. Conclusion: These results highlight the often-overlooked role of paternal factors during pregnancy on child development, suggesting that paternal prenatal anxiety symptoms are associated with child neuroendocrine function and in turn internalizing symptoms that manifest at least up to middle childhood.

Developmental variation in testosterone:cortisol ratio alters cortical- and amygdala-based cognitive processes.

Testosterone (T) and cortisol (C) are the end products of neuroendocrine axes that interact with the process of shaping brain structure and function. Relative levels of T:C (TC ratio) may alter prefrontal-amygdala functional connectivity in adulthood. What remains unclear is whether TC-related effects are rooted to childhood and adolescence. We used a healthy cohort of 4-22-year-olds to test for associations between TC ratios, brain structure (amygdala volume, cortical thickness (CTh), and their coordinated growth), as well as cognitive and behavioral development. We found greater TC ratios to be associated with the growth of specific brain structures: 1) parietal CTh; 2) covariance of the amygdala with CTh in visual and somatosensory areas. These brain parameters were in turn associated with lower verbal/executive function and higher spatial working memory. In sum, individual TC profiles may confer a particular brain phenotype and set of cognitive strengths and vulnerabilities, prior to adulthood.

Sex-specific contribution of DHEA-cortisol ratio to prefrontal-hippocampal structural development, cognitive abilities and personality traits.

Although dehydroepiandrosterone (DHEA) may exert neuroprotective effects in the developing brain, prolonged or excessive elevations in cortisol may exert neurotoxic effects. The ratio between DHEA and cortisol (DC ratio) has been linked to internalising and externalising disorders, as well as cognitive performance, supporting the clinical relevance of this hormonal ratio during development. However, the brain mechanisms by which these effects may be mediated have not yet been identified. Furthermore, although there is evidence that the effects of cortisol in the central nervous system may be sexually dimorphic in humans, the opposite is true for DHEA, with human studies showing no sex-specific associations in cortical thickness, cortico-amygdalar or cortico-hippocampal structural covariance. Therefore, it remains unclear whether sex moderates the developmental associations between DC ratio, brain structure, cognition and behaviour. In the present study, we examined the associations between DC ratio, structural covariance of the hippocampus with whole-brain cortical thickness, and measures of personality, behaviour and cognition in a longitudinal sample of typically developing children, adolescents and young adults aged 6-22 years (N = 225 participants [F = 128]; 355 scans [F = 208]), using mixed effects models that accounted for both within- and between-subject variances. We found sex-specific interactions between DC ratio and anterior cingulate cortex-hippocampal structural covariance, with higher DC ratios being associated with a more negative covariance between these structures in girls, and a more positive covariance in boys. Furthermore, the negative prefrontal-hippocampal structural covariance found in girls was associated with higher verbal memory and mathematical ability, whereas the positive covariance found in boys was associated with lower cooperativeness and reward dependence personality traits. These findings support the notion that the ratio between DHEA and cortisol levels may contribute, at least in part, to the development of sex differences in cognitive abilities, as well as risk for internalising/externalising disorders, via an alteration in prefrontal-hippocampal structure during the transition from childhood to adulthood.

Age-specific associations between oestradiol, cortico-amygdalar structural covariance, and verbal and spatial skills.

Oestradiol is known to play an important role in the developing human brain, although little is known about the entire network of potential regions that might be affected and how these effects may vary from childhood to early adulthood, which in turn can explain sexually differentiated behaviours. In the present study, we examined the relationships between oestradiol, cortico-amygdalar structural covariance, and cognitive or behavioural measures typically showing sex differences (verbal/spatial skills, anxious-depressed symptomatology) in 152 children and adolescents (aged 6-22 years). Cortico-amygdalar structural covariance shifted from positive to negative across the age range. Oestradiol was found to diminish the impact of age on cortico-amygdalar covariance for the pre-supplementary motor area/frontal eye field and retrosplenial cortex (across the age range), as well as for the posterior cingulate cortex (in older children). Moreover, the influence of oestradiol on age-related cortico-amygdalar networks was associated with higher word identification and spatial working memory (across the age range), as well as higher reading comprehension (in older children), although it did not impact anxious-depressed symptoms. There were no significant sex effects on any of the above relationships. These findings confirm the importance of developmental timing on oestradiol-related effects and hint at the non-sexually dimorphic role of oestradiol-related cortico-amygdalar structural networks in aspects of cognition distinct from emotional processes.

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-Children's 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.

Dehydroepiandrosterone impacts working memory by shaping cortico-hippocampal structural covariance during development.

Existing studies suggest that dehydroepiandrosterone (DHEA) may be important for human brain development and cognition. For example, molecular studies have hinted at the critical role of DHEA in enhancing brain plasticity. Studies of human brain development also support the notion that DHEA is involved in preserving cortical plasticity. Further, some, though not all, studies show that DHEA administration may lead to improvements in working memory in adults. Yet these findings remain limited by an incomplete understanding of the specific neuroanatomical mechanisms through which DHEA may impact the CNS during development. Here we examined associations between DHEA, cortico-hippocampal structural covariance, and working memory (216 participants [female=123], age range 6-22 years old, mean age: 13.6 +/-3.6 years, each followed for a maximum of 3 visits over the course of 4 years). In addition to administering performance-based, spatial working memory tests to these children, we also collected ecological, parent ratings of working memory in everyday situations. We found that increasingly higher DHEA levels were associated with a shift toward positive insular-hippocampal and occipito-hippocampal structural covariance. In turn, DHEA-related insular-hippocampal covariance was associated with lower spatial working memory but higher overall working memory as measured by the ecological parent ratings. Taken together with previous research, these results support the hypothesis that DHEA may optimize cortical functions related to general attentional and working memory processes, but impair the development of bottom-up, hippocampal-to-cortical connections, resulting in impaired encoding of spatial cues.