Interaction between hypothalamic-pituitary-adrenal axis genetic variation and maternal behavior in the prediction of amygdala connectivity in children.

High levels of negative, and low levels of positive parenting behaviors can increase the risk of internalizing symptoms in children, but the mechanisms underlying this association are still unclear. One possibility is that parenting behaviors affect the neural correlates of emotion processing in children. Further, genetic variants relevant to the function of the hypothalamic-pituitary-adrenal (HPA) axis are thought to moderate the effect of early experiences on the brain circuits underlying emotion processing, particularly those involving the amygdala. However, no studies have investigated the interactive effect of parenting behaviors and HPA axis-related genes on amygdala activity and connectivity during emotion processing, and in turn internalizing symptoms in children. Participants comprised 80 children (46 females, mean age = 10.0 years) from the community. Observational measures of maternal behavior were collected during mother-child interactions. Children underwent functional magnetic resonance imaging while performing an implicit emotion-processing task, and mothers and children completed measures of child internalizing symptoms. Genetic risk was calculated using an HPA genetic risk score. HPA genetic risk score was indirectly associated with greater child self-reported depressive symptoms via increased amygdala-precuneus connectivity during the emotion-processing task, and interacted with negative maternal parenting behavior to predict increased connectivity between amygdala and superior frontal gyrus, anterior cingulate cortex and parietal cortex. HPA-related genetic variation appears to moderate the effect of negative maternal parenting behavior on the neural underpinnings of emotion processing in children, and may confer risk for depressive symptoms via modulation of amygdala connectivity.

Dual-axis hormonal covariation in adolescence and the moderating influence of prior trauma and aversive maternal parenting.

Adversity early in life can disrupt the functioning of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes and increase risk for negative health outcomes. The interplay between these axes and the environment is complex, and understanding needs to be advanced by the investigation of the multiple hormonal relationships underlying these processes. The current study examined basal hormonal associations between morning levels of cortisol, testosterone, and dehydroepiandrosterone in a cohort of adolescents (mean age 15.56 years). The moderating influence of childhood adversity was also examined, as indexed by self-reported trauma (at mean age 14.91), and observed maternal aggressive parenting (at mean age 12.41). Between-person regressions revealed significant associations between hormones that were moderated by both measures of adversity. In females, all hormones positively covaried, but also interacted with adversity, such that positive covariation was typically only present when levels of trauma and/or aggressive parenting were low. In males, hormonal associations and interactions were less evident; however, interactions were detected for cortisol-testosterone - positively covarying at high levels of aggressive parenting but negatively covarying at low levels - and DHEA-cortisol - similarly positively covarying at high levels of parental aggression. These results demonstrate associations between adrenal and gonadal hormones and the moderating role of adversity, which is likely driven by feedback mechanisms, or cross-talk, between the axes. These findings suggest that hormonal changes may be the pathway through which early life adversity alters physiology and increases health risks, but does so differentially in the sexes; however further study is necessary to establish causation.

Study protocol: imaging brain development in the Childhood to Adolescence Transition Study (iCATS).

BACKGROUND: Puberty is a critical developmental phase in physical, reproductive and socio-emotional maturation that is associated with the period of peak onset for psychopathology. Puberty also drives significant changes in brain development and function. Research to date has focused on gonadarche, driven by the hypothalamic-pituitary-gonadal axis, and yet increasing evidence suggests that the earlier pubertal stage of adrenarche, driven by the hypothalamic-pituitary-adrenal axis, may play a critical role in both brain development and increased risk for disorder. We have established a unique cohort of children who differ in their exposure to adrenarcheal hormones. This presents a unique opportunity to examine the influence of adrenarcheal timing on brain structural and functional development, and subsequent health outcomes. The primary objective of the study is to explore the hypothesis that patterns of structural and functional brain development will mediate the relationship between adrenarcheal timing and indices of affect, self-regulation, and mental health symptoms collected across time (and therefore years of development). METHODS/DESIGN: Children were recruited based upon earlier or later timing of adrenarche, from a larger cohort, with 128 children (68 female; M age 9.51 years) and one of their parents taking part. Children completed brain MRI structural and functional sequences, provided saliva samples for adrenarcheal hormones and immune biomarkers, hair for long-term cortisol levels, and completed questionnaires, anthropometric measures and an IQ test. Parents completed questionnaires reporting on child behaviour, development, health, traumatic events, and parental report of family environment and parenting style. DISCUSSION: This study, by examining the neurobiological and behavioural consequences of relatively early and late exposure to adrenarche, has the potential to significantly impact our understanding of pubertal risk processes.

Maternal parenting behavior and functional connectivity development in children: A longitudinal fMRI study.

Parenting behavior is associated with internalizing symptoms in children, and cross-sectional research suggests that this association may be mediated by the influence of parenting on the development of frontoamygdala circuitry. However, longitudinal studies are lacking. Moreover, there is a paucity of studies that have investigated parenting and large-scale networks implicated in affective functioning. In this longitudinal study, data from 95 (52 female) children and their mothers were included. Children underwent magnetic resonance imaging that included a 6 min resting state sequence at wave 1 (mean age = 8.4 years) and wave 2 (mean age = 9.9 years). At wave 1, observational measures of positive and negative maternal behavior were collected during mother-child interactions. Region-of-interest analysis of the amygdala, and independent component and dual-regression analyses of the Default Mode Network (DMN), Executive Control Network (ECN) and the Salience Network (SN) were carried out. We identified developmental effects as a function of parenting: positive parenting was associated with decreased coactivation of the superior parietal lobule with the ECN at wave 2 compared to wave 1. Thus our findings provide preliminary longitudinal evidence that positive maternal behavior is associated with maturation of the connectivity between higher-order control networks.

A Researcher's Guide to the Measurement and Modeling of Puberty in the ABCD Study® at Baseline.

The Adolescent Brain Cognitive Development℠ (ABCD) Study is an ongoing, diverse, longitudinal, and multi-site study of 11,880 adolescents in the United States. The ABCD Study provides open access to data about pubertal development at a large scale, and this article is a researcher's guide that both describes its pubertal variables and outlines recommendations for use. These considerations are contextualized with reference to cross-sectional empirical analyses of pubertal measures within the baseline ABCD dataset by Herting, Uban, and colleagues (2021). We discuss strategies to capitalize on strengths, mitigate weaknesses, and appropriately interpret study limitations for researchers using pubertal variables within the ABCD dataset, with the aim of building toward a robust science of adolescent development.

The Influence of Maternal Parenting Style on the Neural Correlates of Emotion Processing in Children.

OBJECTIVE: The importance of parenting in influencing mental health outcomes, particularly depression, during childhood and adolescence is well known. However, the mechanisms are unclear. Emotion processing impairments in children are believed to be influenced by negative parenting behaviors and fundamental to depression. As such, investigating the association between parenting behavior and the neural underpinnings of emotion processing in children could provide fundamental clues as to the link between parenting and depression. METHOD: Eighty-six children (49 girls, mean age 10.1 years), as part of a longitudinal study, participated. Observational measures of maternal behavior were collected during 2 mother-child interactions. Children underwent functional magnetic resonance imaging while performing an implicit emotion-processing task, and measures of child internalizing symptoms were collected. RESULTS: Maternal negative behavior exhibited during an event-planning interaction was associated with decreased activation in the lingual gyrus in girls, whereas maternal negative behavior during a problem-solving interaction was associated with increased amygdala activation in the entire sample during processing of angry and fearful faces. Maternal communicative behavior during the 2 mother-child interactions was associated with increased activity in the bilateral middle orbitofrontal cortex in the entire sample. Negative behavior during the problem-solving interaction was associated with connectivity between the amygdala and superior parietal lobe. Brain activity/connectivity was not related to internalizing symptoms. CONCLUSION: Results suggest that, in children, maternal behavior could be associated with activity in brain regions involved in emotion processing. However, more research is needed to elucidate the link among parenting, emotion processing, and depressive symptoms in young people.

The lifetime experience of traumatic events is associated with hair cortisol concentrations in community-based children.

Adversity early in life can disrupt the functioning of the hypothalamic-pituitary-adrenal axis (HPAA) and increase risk for negative health outcomes. Recent research suggests that cortisol in scalp hair represents a promising measure of HPAA function. However, little is known about the relationship between early exposure to traumatic events and hair cortisol concentrations (HCC) in childhood, a critical period of HPAA development. The current study measured HCC in scalp hair samples collected from 70 community-based children (14 males, mean age=9.50) participating in the Imaging Brain Development in the Childhood to Adolescence Transition Study (iCATS). Data were also collected on lifetime exposure to traumatic events and current depressive symptoms. Lifetime exposure to trauma was associated with elevated HCC; however, HCC was not associated with current depressive symptoms. Consistent with some prior work, males were found to have higher HCC than females, although results should be treated with caution due to the small number of males who took part. Our findings suggest that hair cortisol may represent a biomarker of exposure to trauma in this age group; however, further study is necessary with a particular focus on the characterization of trauma and other forms of adversity.

Sulcogyral pattern and sulcal count of the orbitofrontal cortex in individuals at ultra high risk for psychosis.

Three types of orbitofrontal cortex (OFC) sulcogyral patterns have been identified in the general population. The distribution of these three types has been found to be altered in individuals at genetic risk of psychosis, and in patients with first episode psychosis (FEP) and chronic schizophrenia. This study aims at establishing whether altered OFC sulcogyral patterns were present in a large cohort of individuals at ultra high risk (UHR) for psychosis. OFC pattern type was classified and the number of posterior and intermediate sulci present on the surface of the OFC was counted. OFC sulcogyral type and the number of sulci were compared between controls (n=58) and UHR participants who transitioned (n=49) versus those who did not transition (n=77) to psychosis. Finally, the relationship between sulcogyral type and number of sulci with intellectual quotient (IQ), symptom severity and social functioning of UHR individuals was explored. In line with other studies conducted in chronic schizophrenia and FEP, UHR individuals who later transitioned to psychosis showed a reduced incidence of the Type I OFC on the right hemisphere compared to controls (χ(2)=19.847, p<0.001). These highly consistent results point towards the protective effect of possessing a Type I OFC in the right hemisphere. Furthermore, OFC sulcus counts revealed that controls presented with a higher number of posterior (right hemisphere; χ(2)=11.658, p=0.003) and intermediate sulci (left: χ(2)=6.643, p=0.036; right: χ(2)=11.726, p=0.020) when compared to UHR individuals. However, no associations between OFC types or sulcus count and IQ, symptoms and functioning were observed.

Relationship between amygdala volume and emotion recognition in adolescents at ultra-high risk for psychosis.

Amygdala volume has been proposed as a neural risk biomarker for psychotic illness, but findings in the ultra-high risk for psychosis (UHR) population have been somewhat inconsistent, which may be related to underlying social cognitive abilities. The current study investigated whether amygdala volumes were related to emotion-recognition impairments in UHR individuals, and whether volumes differed by sex. Secondary aims were to assess whether (a) emotion-recognition performance was associated with interhemispheric amygdala volume asymmetry and (b) amgydala volume and volume asymmetry acted as a mediator between emotion-recognition and outcome measures. The amygdala was manually delineated from magnetic resonance images for 39 UHR individuals who had also completed facial and prosody emotion-recognition tasks. Partial correlations were conducted to examine associations between amydgala volume/asymmetry and recognition of negative emotions. Mediation analyses were conducted using regression and bootstrapping techniques. Amygdala volume was positively correlated with sadness emotion recognition, in particular prosody, for females only. Left amygdala volume mediated the effect of sadness recognition on depressive symptoms, negative symptoms, overall psychopathology, and global functioning in females. Findings suggest a complex relationship between emotion recognition, the structure of the amygdala and illness outcome, where recognition of sadness appears to be the precipitator of this relationship in UHR females. Further research is needed to determine illness specificity and to confirm our sex- and emotion-specific results.

Relationship between membrane fatty acids and cognitive symptoms and information processing in individuals at ultra-high risk for psychosis.

Cognitive symptoms and impairment are central to schizophrenia and often an early sign of this condition. The present study investigated biological correlates of cognitive symptoms and performance in individuals at ultra-high risk (UHR) for psychosis. The study sample comprised 80 neuroleptic-naïve UHR individuals aged 13-25 years. Associations among erythrocyte membrane fatty acid levels, measured by gas chromatography, and cognitive functioning were investigated in UHR patients. Subjects were divided into terciles based on their scores on the cognitive factor of the Positive and Negative Syndrome Scale. The Zahlen-Verbindungs Test (ZVT) (the number-combination test) was also used as a measure of information-processing speed. Exploratory analysis was conducted to investigate the relationship between membrane fatty acid levels with the size of the intracranial area (ICA), a neurodevelopmental measure relevant to schizophrenia, in half of subjects (n=40) using magnetic resonance imaging. The adjusted analysis revealed that omega-9 eicosenoic and erucic acid levels were significantly higher, but omega-3 docosahexaenoic acid levels were significantly lower, in the cognitively impaired than in the cognitively intact group. We found a significant negative association of eicosenoic, erucic, and gamma-linoleic acids with ZVT scores. A negative association between ICA and membrane levels of eicosenoic acid was also found. This is the first study to demonstrate the relationship between membrane fatty acids and cognitive function in neuroleptic-naïve subjects at UHR for psychosis. The study findings indicate that abnormalities in membrane fatty acids may be associated with the neurodevelopmental disruption associated with the cognitive impairments of individuals at UHR for psychosis.

Sulcogyral patterns and morphological abnormalities of the orbitofrontal cortex in psychosis.

Three types of OFC sulcogyral patterns have been identified in the general population. The distribution of these three types has been found altered in individuals at genetic risk of psychosis, first episode psychosis (FEP) and chronic schizophrenia. The aim of this study was to replicate and extend previous research by additionally investigating: intermediate and posterior orbital sulci, cortical thickness, and degree of gyrification/folding of the OFC, in a large sample of FEP patients and healthy controls. OFC pattern type was classified based on a method previously devised, using T1-weighted magnetic resonance images. Cortical thickness and local gyrification indices were calculated using FreeSurfer. Occurrence of Type I pattern was decreased and Type II pattern was increased in FEP patients for the right hemisphere. Interestingly, controls displayed an OFC pattern type distribution that was disparate to that previously reported. Significantly fewer intermediate orbital sulci were observed in the left hemisphere of patients. Grey matter thickness of orbitofrontal sulci was reduced bilaterally, and left hemisphere reductions were related to OFC pattern type in patients. There was no relationship between pattern type and degree of OFC gyrification. An interaction was found between the number of intermediate orbital sulci and OFC gyrification; however this group difference was specific to only the small subsample of people with three intermediate orbital sulci. Given that cortical folding is largely determined by birth, our findings suggest that Type II pattern may be a neurodevelopmental risk marker while Type I pattern may be somewhat protective. This finding, along with compromised orbitofrontal sulci thickness, may reflect early abnormalities in cortical development and point toward a possible endophenotypic risk marker of schizophrenia-spectrum disorders.