Prenatal stress and its association with amygdala-related structural covariance patterns in youth

Early life stress is known to influence mothers and consequently also the infant pre-, peri-, and postnatally. Both stress sensitization and inoculation theories have speculated about the conflicting previous findings of beneficial as well as impairing influences of early life stress. Findings of an impact on infant development, behavior and later vulnerability for cognitive and emotional problems, physical diseases and mental disorders, suggested the need to identify possible pathways between early life stress and infant outcome. Suggested underlying processes, such as fetal programming, were discussed. The present thesis focused on the possible impact of prenatal maternal stress on mother-infant dyadic behavior in a standardized observation paradigm, i.e. the still-face paradigm. Study I aimed to illuminate the prospective influence of psychological and physiological stress during pregnancy on mother-infant dyadic behavior in the first play episode of the still-face paradigm. In Study II, both the first play episode and the reunion episode were investigated. In Study I, the first play episode of the still-face paradigm was investigated. The findings provided evidence of an impact of psychosocial prenatal stress on mother-infant dyadic behavior during the normal mother-infant play, as it was expected for the first play episode. Mother-infant dyads with more psychosocial PS in pregnancy showed significantly more positive dyadic behavior then the less stressed dyads. The same was found for perceived maternal prenatal stress, although the effect vanished when analyses were conducted including all covariates. Hence, the findings were considered as providing only restricted evidence. No other stress index (i.e., psychopathological PS, cortisol decline and cortisol AuCg) reached significance in predicting mother-infant dyadic play behavior. In Study II, the impact of prenatal stress on mother-infant dyadic behavior in both play situations of the still-face paradigm was investigated. The dyadic behavior in the first play episode was compared with that in the reunion episode. The results provided evidence for the “still-face” and “carry-over” effect, with mother-infant dyads in both the high- and low-stress groups showing decreasing positive and increasing negative dyadic behavior in the reunion episode. Here too, mother-infant dyads with higher psychosocial prenatal stress showed significantly more positive dyadic behavior in the first play episode, but not in the reunion episode. In the latter episode, the positive behavior of the dyads with high prenatal stress decreased to approximately the same level as that of the dyads with low stress. In Study II, significant results emerged for physiological stress dimensions, with mother-infant dyads with a prenatally flat diurnal cortisol decline and low diurnal cortisol AUCg levels showing a distinctive, significant increase in negative dyadic behavior in the reunion episode. Mediation analyses run in both studies showed that maternal behavior was not a significant mediator between prenatal stress and infant behavior. The present findings contribute to inoculation theories on the impact of stress. Nevertheless, both studies provide merely a glimpse into the complex relationship of early life stress factors, maternal and environmental factors, and the infant’s development. Taken together, given the vast amount of studies reporting an impairing impact of prenatal stress on the infant, the present results should be interpreted with caution. The results add further support to the idea of individual resilience factors, suggesting that some individuals are not influenced by stressors or even benefit from them. Future research should focus on the underlying mechanisms, such as early programming, sensitive time periods in infant development, as well as possible influencing factors, in order to contribute to the explaining the mixed results, and to inform the creation of preventive programs for mothers and infants.

Many studies during the past 50 years have found an association between father absence and earlier menarche. In connection with these findings, several evolutionary theories assume that father absence is a causal factor accelerating reproductive development. However, a recent study analysing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) found that father absence does not predict age at menarche when adjusted for sibling relatedness. In this study, we have replicated these results in the Czech section of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC), which used the same questionnaires as ALSPAC to study a geographically distinct population. Our results support the conclusion that sibling relatedness rather than father absence predicts age at menarche. Furthermore, our results show that age at menarche in 1990s UK and Czech cohorts is very similar despite socioeconomic differences between the two countries.

Associations between prenatal stress with offspring inflammation, depression and anxiety

Decision letter: Stage-dependent differential influence of metabolic and structural networks on memory across Alzheimer’s disease continuum

Stress reactivity in preschool-aged children: Evaluation of a social stress paradigm and investigation of the impact of prenatal maternal stress

New insights into the link between childhood adversity and epigenetic changes

Child maltreatment is a major cause of pediatric posttraumatic stress disorder (PTSD). Previous studies have not investigated potential differences in network architecture in maltreated youth with PTSD and those resilient to PTSD. High-resolution magnetic resonance imaging brain scans at 3 T were completed in maltreated youth with PTSD (n = 31), without PTSD (n = 32), and nonmaltreated controls (n = 57). Structural covariance network architecture was derived from between-subject intraregional correlations in measures of cortical thickness in 148 cortical regions (nodes). Interregional positive partial correlations controlling for demographic variables were assessed, and those correlations that exceeded specified thresholds constituted connections in cortical brain networks. Four measures of network centrality characterized topology, and the importance of cortical regions (nodes) within the network architecture were calculated for each group. Permutation testing and principle component analysis method were employed to calculate between-group differences. Principle component analysis is a methodological improvement to methods used in previous brain structural covariance network studies. Differences in centrality were observed between groups. Larger centrality was found in maltreated youth with PTSD in the right posterior cingulate cortex; smaller centrality was detected in the right inferior frontal cortex compared to youth resilient to PTSD and controls, demonstrating network characteristics unique to pediatric maltreatment-related PTSD. Larger centrality was detected in right frontal pole in maltreated youth resilient to PTSD compared to youth with PTSD and controls, demonstrating structural covariance network differences in youth resilience to PTSD following maltreatment. Smaller centrality was found in the left posterior cingulate cortex and in the right inferior frontal cortex in maltreated youth compared to controls, demonstrating attributes of structural covariance network topology that is unique to experiencing maltreatment. This work is the first to identify cortical thickness-based structural covariance network differences between maltreated youth with and without PTSD. We demonstrated network differences in both networks unique to maltreated youth with PTSD and those resilient to PTSD. The networks identified are important for the successful attainment of age-appropriate social cognition, attention, emotional processing, and inhibitory control. Our findings in maltreated youth with PTSD versus those without PTSD suggest vulnerability mechanisms for developing PTSD.

Specific language impairment (SLI) is a common developmental disorder characterized by difficulties in language acquisition despite otherwise normal development and in the absence of any obvious explanatory factors. We performed a high-density screen of SLI1, a region of chromosome 16q that shows highly significant and consistent linkage to nonword repetition, a measure of phonological short-term memory that is commonly impaired in SLI. Using two independent language-impaired samples, one family-based (211 families) and another selected from a population cohort on the basis of extreme language measures (490 cases), we detected association to two genes in the SLI1 region: that encoding c-maf-inducing protein (CMIP, minP = 5.5 × 10−7 at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 × 10−5 at rs11860694). Regression modeling indicated that each of these loci exerts an independent effect upon nonword repetition ability. Despite the consistent findings in language-impaired samples, investigation in a large unselected cohort (n = 3612) did not detect association. We therefore propose that variants in CMIP and ATP2C2 act to modulate phonological short-term memory primarily in the context of language impairment. As such, this investigation supports the hypothesis that some causes of language impairment are distinct from factors that influence normal language variation. This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides molecular evidence for the importance of phonological short-term memory in language acquisition.

Radiation-induced brain injury (RBI) is a common complication in patients with nasopharyngeal carcinoma (NPC) who have undergone radiotherapy (RT), which is characterized by significant cognitive and psychological impairments. Although radiation-induced regional structural abnormalities have been well-reported, the effects of RT on the whole brain structural covariance networks are mostly unknown. Here, we performed a source-based morphometry (SBM) study to solve this issue. In this cross-sectional study, 131 NPC patients with pre- and post-RT were stratified into pre-RT (n=47) and post-RT (n=84) groups. The SBM method was adopted to investigate the radiation-induced alterations in structural covariance networks in patients with NPC. Compared to the pre-RT group, our SBM analyses revealed increased z-scores in the independent component 05 (IC05; mainly located in the posterior cingulate, precuneus areas, and superior parietal lobe) (P=0.040) and decreased z-scores in the temporal-occipital network (P=0.015) and cerebellar network (P=0.023) in post-RT NPC patients. Compared to the pre-RT group, voxel-based morphometry (VBM) revealed reduced gray matter volume in the left temporal lobe, cerebellum, bilateral thalamus, left insular, and occipital lobe in the post-RT group. Notably, a significant negative correlation was observed between the mean radiation doses of the right temporal lobe and the z-score of the cerebellar network (r=-0.349, P=0.027). This present study revealed radiation-induced changes in structural covariance networks and cortical volume in patients with NPC. These findings shed some light on the neural basis of symptom patterns in RBI and may support the development of new intervention strategies to prevent progression to radiation-induced brain necrosis.

The Czech ELSPAC study was set up as a part of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC). ELSPAC was designed as a population-based prospective longitudinal birth cohort study to investigate the effects of biological, psychosocial, economic and environmental factors on pregnancy, delivery and subsequent child´s development and health. The study was initiated by the World Health Organization (WHO) Regional Office for Europe in 1985, with the aim to enrol 40 000 children across Europe. Seven independent centres—ALSPAC, Isle of Man, the Czech Republic, Slovakia, Ukraine, Greece and Russia—joined the project, coordinated by Professor Golding at Bristol University, UK. The coordination centre was also responsible for most of the protocol development, including follow-up planning and questionnaire design. Enrolment of the Czech participants started in 1991. In addition to the primary aims of ELSPAC, the Czech team was interested also in the effects of the profound socioeconomic changes related to the societal transformation after the fall of Communism in 1989.

Carpal tunnel syndrome (CTS) is a common peripheral entrapment neuropathy. However, CTS-related changes of brain structural covariance and structural covariance networks (SCNs) patterns have not been clearly studied. To explore CTS-related brain changes from perspectives of structural connectivity and SCNs. Brain structural magnetic resonance images were acquired from 27 CTS patients and 19 healthy controls (HCs). Structural covariance and SCNs were constructed based on gray matter volume. The global network properties including clustering coefficient (Cp), characteristic path length (Lp), small-worldness index, global efficiency (Eglob), and local efficiency (Eloc) and regional network properties including degree, betweenness centrality (BC), and Eloc of a given node were calculated with graph theoretical analysis. Compared with HCs, the strength of structural connectivity between the dorsal anterior insula and medial prefrontal thalamus decreased (P <.001) in CTS patients. There was no intergroup difference of area under the curve for Cp, Lp¸ Eglob, and Eloc (all P >.05). The real-world SCN of CTS patients showed a small-world topology ranging from 2% to 32%. CTS patients showed lower nodal degrees of the dorsal anterior insula and medial prefrontal thalamus, and higher Eloc of a given node and BC in the lateral occipital cortex (P <.001) and the dorsolateral middle temporal gyrus (P <.001) than HCs, respectively. CTS had a profound impact on brain structures from perspectives of structural connectivity and SCNs.

Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T1-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z-score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions.

Brain structural covariance networks (SCNs) composed of regions with correlated variation are altered in neuropsychiatric disease and change with age. Little is known about the development of SCNs in early childhood, a period of rapid cortical growth. We investigated the development of structural and maturational covariance networks, including default, dorsal attention, primary visual and sensorimotor networks in a longitudinal population of 118 children after birth to 2 years old and compared them with intrinsic functional connectivity networks. We found that structural covariance of all networks exhibit strong correlations mostly limited to their seed regions. By Age 2, default and dorsal attention structural networks are much less distributed compared with their functional maps. The maturational covariance maps, however, revealed significant couplings in rates of change between distributed regions, which partially recapitulate their functional networks. The structural and maturational covariance of the primary visual and sensorimotor networks shows similar patterns to the corresponding functional networks. Results indicate that functional networks are in place prior to structural networks, that correlated structural patterns in adult may arise in part from coordinated cortical maturation, and that regional co-activation in functional networks may guide and refine the maturation of SCNs over childhood development.

Identifying Subgroups of Major Depressive Disorder Using Brain Structural Covariance Networks and Mapping of Associated Clinical and Cognitive Variables

BackgroundThere is considerable discussion over the possible harm caused by fetal exposure to mercury, but evidence of such harm is contradictory at levels commonly found in populations with moderate intakes of fish. Further information is needed to inform debate and clarify policy recommendations. MaterialData were collected prospectively for the Avon Longitudinal Study of Parents and Children (ALSPAC). Whole blood taken in the first half of pregnancy was assayed for mercury. The outcomes were offspring behavioural assessments collected using the Strengths and Difficulties Questionnaire at seven time points between ages 4 and 16–17 years; five were completed by the mother and two by the teacher. Socioeconomic and biological confounders were first taken into account; further analyses added maternal blood selenium. Separate analyses compared the relationships between prenatal mercury levels and behaviour traits treated as continuous measures in women who ate fish with those who ate no fish in order to determine whether the relationships differed; the hypothesis was that fish consumption had benefits on the brain and masked any mercury effects. In order to prevent Type II errors, the P value for significance was set at 0.10. ResultsPrenatal mercury measurements and offspring behaviour results were available for between 2776 (at 47 months) to 1599 mother-child pairs (at 16–17 years). Even given a P value of 0.10, the number of significant results was no greater than expected apart from the relationships with peer problems at 4, 6 and 10–11 years where the relationships with prenatal mercury were negative (i.e. the greater the level of mercury the fewer the problems the child had with his/her peers). There were no significant differences between the associations with mercury found among the offspring of women who ate fish in pregnancy and those who did not, nor did adjustment for selenium make a difference. ConclusionsThere were no adverse effects of maternal prenatal mercury levels on the behaviour of the offspring. A similar lack of relationship was found when the analyses were confined to those offspring whose mothers had eaten fish in pregnancy, and no consistent differences were found between the fish and non-fish eaters.