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During development, cellular events such as cell proliferation, migration, and synaptogenesis determine the structural organization of the brain. These processes are driven in part by spatiotemporally regulated gene expression. We investigated how the genetic signatures of specific neural cell types shape cortical organization of the human brain throughout infancy and childhood. Using a transcriptional atlas and in vivo magnetic resonance imaging (MRI) data, we demonstrated time-dependent associations between the expression levels of neuronal and glial genes and cortical macro- and microstructure. Neonatal cortical phenotypes were associated with prenatal glial but not neuronal gene expression. These associations reflect cell migration and proliferation during fetal development. Childhood cortical phenotypes were associated with neuronal and astrocyte gene expression related to synaptic signaling processes, reflecting the refinement of cortical connections. These findings indicate that sequential developmental stages contribute to distinct MRI measures at different time points. This helps to bridge the gap between the genetic mechanisms driving cellular changes and widely used neuroimaging techniques.

Background Prenatal maternal depression may have long-term impacts on amygdala-cortical development. This study explored associations of prenatal maternal depressive symptoms on the amygdala-cortical structural covariance of the offspring from birth to early childhood, derived from a longitudinal birth cohort. Methods Structural magnetic resonance imaging was performed to obtain the amygdala volume and cortical thickness at each time point. Prenatal maternal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale at 26 weeks of pregnancy. Regression analysis was used to examine the effects of the Edinburgh Postnatal Depression Scale on a structural coupling between the amygdala volume and cortical thickness at birth (n = 167) and 4.5 years of age (n = 199). Results Girls whose mothers had high prenatal maternal depressive symptoms showed a positive coupling between the amygdala volume and insula thickness at birth (β = .617, p = .001) but showed a negative coupling between the amygdala volume and inferior frontal thickness at 4.5 years of age (β = −.369, p = .008). No findings were revealed in boys at any time point. Conclusions The development of the amygdala–prefrontal circuitry is vulnerable to environmental factors related to depression. Such a vulnerability might be sex dependent.

Early numeracy provides the foundation of acquiring mathematical skills that is essential for future academic success. This study examined numerical functional networks in relation to counting and number relational skills in preschoolers at 4 and 6 years of age. The counting and number relational skills were assessed using school readiness test (SRT). Resting-state fMRI (rs-fMRI) was acquired in 123 4-year-olds and 146 6-year-olds. Among them, 61 were scanned twice over the course of 2 years. Meta-analysis on existing task-based numeracy fMRI studies identified the left parietal-dominant network for both counting and number relational skills and the right parietal-dominant network only for number relational skills in adults. We showed that the fronto-parietal numerical networks, observed in adults, already exist in 4-year and 6-year-olds. The counting skills were associated with the bilateral fronto-parietal network in 4-year-olds and with the right parietal-dominant network in 6-year-olds. Moreover, the number relational skills were related to the bilateral fronto-parietal and right parietal-dominant networks in 4-year-olds and had a trend of the significant relationship with the right parietal-dominant network in 6-year-olds. Our findings suggested that neural fine-tuning of the fronto-parietal numerical networks may subserve the maturation of numeracy in early childhood.

Statistical inference on neuroimaging data is often conducted using a mass-univariate model, equivalent to fitting a linear model at every voxel with a known set of covariates. Due to the large number of linear models, it is challenging to check if the selection of covariates is appropriate and to modify this selection adequately. The use of standard diagnostics, such as residual plotting, is clearly not practical for neuroimaging data. However, the selection of covariates is crucial for linear regression to ensure valid statistical inference. In particular, the mean model of regression needs to be reasonably well specified. Unfortunately, this issue is often overlooked in the field of neuroimaging. This study aims to adopt the existing Confounder Adjusted Testing and Estimation (CATE) approach and to extend it for use with neuroimaging data. We propose a modification of CATE that can yield valid statistical inferences using Principal Component Analysis (PCA) estimators instead of Maximum Likelihood (ML) estimators. We then propose a non-parametric hypothesis testing procedure that can improve upon parametric testing. Monte Carlo simulations show that the modification of CATE allows for more accurate modelling of neuroimaging data and can in turn yield a better control of False Positive Rate (FPR) and Family-Wise Error Rate (FWER). We demonstrate its application to an Epigenome-Wide Association Study (EWAS) on neonatal brain imaging and umbilical cord DNA methylation data obtained as part of a longitudinal cohort study. Software for this CATE study is freely available at http://www.bioeng.nus.edu.sg/cfa/Imaging_Genetics2.html.

Most individuals identified as ultra-high-risk (UHR) for psychosis do not develop frank psychosis. They continue to exhibit subthreshold symptoms, or go on to fully remit. Prior work has shown that the volume of CA1, a subfield of the hippocampus, is selectively reduced in the early stages of schizophrenia. Here we aimed to determine whether patterns of volume change of CA1 are different in UHR individuals who do or do not achieve symptomatic remission. Structural MRI scans were acquired at baseline and at 1-2 follow-up time points (at 12-month intervals) from 147 UHR and healthy control subjects. An automated method (based on an ex vivo atlas of ultra-high-resolution hippocampal tissue) was used to delineate the hippocampal subfields. Over time, a greater decline in bilateral CA1 subfield volumes was found in the subgroup of UHR subjects whose subthreshold symptoms persisted (n=40) and also those who developed clinical psychosis (n=12), compared with UHR subjects who remitted (n=41) and healthy controls (n=54). No baseline differences in volumes of the overall hippocampus or its subfields were found among the groups. Moreover, the rate of volume decline of CA1, but not of other hippocampal subfields, in the non-remitters was associated with increasing symptom severity over time. Thus, these findings indicate that there is deterioration of CA1 volume in persistently symptomatic UHR individuals in proportion to symptomatic progression.

The amygdala and hippocampus undergo rapid development in early life. The relative contribution of genetic and environmental factors to the establishment of their developmental trajectories has yet to be examined. We performed imaging on neonates and examined how the observed variation in volume and microstructure of the amygdala and hippocampus varied by genotype, and compared with prenatal maternal mental health and socioeconomic status. Gene × Environment models outcompeted models containing genotype or environment only to best explain the majority of measures but some, especially of the amygdaloid microstructure, were best explained by genotype only. Models including DNA methylation measured in the neonate umbilical cords outcompeted the Gene and Gene × Environment models for the majority of amygdaloid measures and minority of hippocampal measures. This study identified brain region-specific gene networks associated with individual differences in fetal brain development. In particular, genetic and epigenetic variation within CUX1 was highlighted. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) National Medical Research Council (NMRC) National Medical Research Council, Grant/Award Numbers: NMRC/TCR/004-NUS/2008,NMRC/TCR/012-NUHS/2014; NUS Instituteof Data Science, Singapore; Singapore Ministryof Education; Agency for Science Technologyand Research (ASTAR); Singapore Institute forClinical Sciences; Singapore National ResearchFoundation

Maternal depression is associated with disrupted neurodevelopment in offspring. This study examined relationships among postnatal maternal depressive symptoms, the functional reward network and behavioral problems in 4.5-year-old boys (57) and girls (65). We employed canonical correlation analysis to evaluate whether the resting-state functional connectivity within a reward network, identified through an activation likelihood estimation (ALE) meta-analysis of fMRI studies, was associated with postnatal maternal depressive symptoms and child behaviors. The functional reward network consisted of three subnetworks, that is, the mesolimbic, mesocortical, and amygdala–hippocampus reward subnetworks. Postnatal maternal depressive symptoms were associated with the functional connectivity of the mesocortical subnetwork with the mesolimbic and amygdala–hippocampus complex subnetworks in girls and with the functional connectivity within the mesocortical subnetwork in boys. The functional connectivity of the amygdala–hippocampus subnetwork with the mesocortical and mesolimbic subnetworks was associated with both internalizing and externalizing problems in girls, while in boys, the functional connectivity of the mesocortical subnetwork with the amygdala–hippocampus complex and the mesolimbic subnetworks was associated with the internalizing and externalizing problems, respectively. Our findings suggest that the functional reward network might be a promising neural phenotype for effects of maternal depression and potential intervention to nurture child behavioral development.

Maternal care may predict limbic development, though relations may vary by age and type of assessment. Here, we examined maternal behavior during early infancy (i.e., six months postpartum) in relation to offspring hippocampal and amygdala volume and microstructure development between 4.5 (n = 99) and 6 (n = 111) years. In interaction with offspring sex, maternal sensitivity predicted left amygdala volume at 6.0 years (β=-0.214, p = 0.032, df = 89) and independently predicted predominately left lateralized aspects of amygdala and hippocampal microstructure at both time points (hippocampus: left FA at 4.5 years [β=-0.241, p = 0.043, df = 68], and, in interaction with sex, left [(β = 0.349, p = 0.022, df = 86) and right FA at 6 years (β = 0.357, p = 0.016, df = 86] and left MD growth [β = -0.517, p = 0.021, df = 37]; amygdala: left MD at 4.5 years [β = -0.319, p = 0.007, df = 69] and, in interaction with offspring sex, left MD growth [β = -0.546, p = 0.019, df = 37]). Results suggest exposure to non-extreme, early insensitive care impacts neuroanatomy important to learning and stress regulation, perhaps by accelerating development. This underscores the need to promote sensitive caregiving during early infancy within community samples. Keywords: Maternal sensitivity, Infancy, Hippocampus, Amygdala, MRI, DTI, Accelerated development

BackgroundSalience network (SN) dysconnectivity has been hypothesized to contribute to schizophrenia. Nevertheless, little is known about the functional and structural dysconnectivity of SN in subjects at risk for psychosis. We hypothesized that SN functional and structural connectivity would be disrupted in subjects with At-Risk Mental State (ARMS) and would be associated with symptom severity and disease progression.MethodWe examined 87 ARMS and 37 healthy participants using both resting-state functional magnetic resonance imaging and diffusion tensor imaging. Group differences in SN functional and structural connectivity were examined using a seed-based approach and tract-based spatial statistics. Subject-level functional connectivity measures and diffusion indices of disrupted regions were correlated with CAARMS scores and compared between ARMS with and without transition to psychosis.ResultsARMS subjects exhibited reduced functional connectivity between the left ventral anterior insula and other SN regions. Reduced fractional anisotropy (FA) and axial diffusivity were also found along white-matter tracts in close proximity to regions of disrupted functional connectivity, including frontal-striatal-thalamic circuits and the cingulum. FA measures extracted from these disrupted white-matter regions correlated with individual symptom severity in the ARMS group. Furthermore, functional connectivity between the bilateral insula and FA at the forceps minor were further reduced in subjects who transitioned to psychosis after 2 years.ConclusionsOur findings support the insular dysconnectivity of the proximal SN hypothesis in the early stages of psychosis. Further developed, the combined structural and functional SN assays may inform the prognosis of persons at-risk for psychosis.

Maternal care influences child hippocampal development. The hippocampus is functionally organized along an anterior–posterior axis. Little is known with regards to the extent maternal care shapes offspring anterior and posterior hippocampal (aHPC, pHPC) functional networks. This study examined maternal behavior, especially maternal sensitivity, at 6 months postpartum in relation to aHPC and pHPC functional networks of children at age 4 and 6 years. Maternal sensitivity was assessed at 6 months via the “Maternal Behavior Q Sort (MBQS) mini for video”. Subsequently, 61 and 76 children underwent resting-state functional magnetic resonance imaging (rs-fMRI), respectively, at 4 and 6 years of age. We found that maternal sensitivity assessed at 6 months postpartum was associated with the right aHPC functional networks in children at both 4 and 6 years of age. At age 4 years, maternal sensitivity was associated positively with the right aHPC’s functional connectivity with the sensorimotor network and negatively with the aHPC’s functional connectivity with the top–down cognitive control network. At 6 years of age, maternal sensitivity was linked positively with the right aHPC’s functional connectivity with the visual-processing network. Our findings suggested that maternal sensitivity in infancy has a long-term impact on the anterior hippocampal functional network in preschool children, implicating a potential role of maternal care in shaping child brain development in early life.

Background Converging evidence suggests that the lateral and medial orbitofrontal cortices (lOFC and mOFC) may contribute distinct neural mechanisms in depression. This study investigated the relations of their functional and structural organizations with postnatal maternal depressive symptoms in young children. Methods Resting-state functional magnetic resonance imaging and structural magnetic resonance imaging were acquired in children at age 4 (n = 199) and 6 years (n = 234). Child's withdrawal behavior problems were assessed using Child's Behavior Checklist. Results In 4-year-old girls, postnatal maternal depressive symptoms were positively associated with the lOFC functional connectivity with the visual network but negatively with the cognitive control network. The lOFC functional connectivity with the visual network and cerebellum, which was influenced by postnatal maternal depressive symptoms, was also associated with child's withdrawal behavior problems in 6-year-old girls. Moreover, postnatal maternal depressive symptoms were also negatively associated with the mOFC functional connectivity with the cognitive control and motor networks in 4-year-old girls. Furthermore, postnatal maternal depressive symptoms influenced the structural connectivity of left mOFC with the right middle frontal cortex and left inferior temporal cortex in 4-year-old girls. Unlike girls, boys showed that postnatal maternal depressive symptoms selectively impacted the mOFC functional connectivity with the memory system at age 6 years. Conclusion Our study provided novel evidence on the distinct neural mechanisms of the lOFC and mOFC structural and functional organizations for intergenerational transmission of maternal depression to the offspring. Boys and girls may potentially employ different neural mechanisms to adapt to maternal environment at different timings of early life.

This study aimed to identify distinct behavioral profiles in a population-based sample of 654 4-year-old children and characterize their relationships with brain functional networks using resting-state functional magnetic resonance imaging data. Young children showed 7 behavioral profiles, including a super healthy behavioral profile with the lowest scores across all Child Behavior CheckList (CBCL) subscales (G1) and other 6 behavioral profiles, respectively with pronounced withdrawal (G2), somatic complaints (G3), anxiety and withdrawal (G4), somatic complaints and withdrawal (G5), the mixture of emotion, withdrawal, and aggression (G6), and attention (G7) problems. Compared with children in G1, children with withdrawal shared abnormal functional connectivities among the sensorimotor networks. Children in emotionally relevant problems shared the common pattern among the attentional and frontal networks. Nevertheless, children in sole withdrawal problems showed a unique pattern of connectivity alterations among the sensorimotor, cerebellar, and salience networks. Children with somatic complaints showed abnormal functional connectivities between the attentional and subcortical networks, and between the language and posterior default mode networks. This study provides novel evidence on the existence of behavioral heterogeneity in early childhood and its associations with specific functional networks that are clinically relevant phenotypes for mental illness and are apparent from early childhood.

Perinatal maternal depressive symptoms influence brain development of offspring. Such effects are particularly notable in the amygdala, a key structure involved in emotional processes. This study investigated whether the functional organization of the amygdala varies as a function of pre‐ and postnatal maternal depressive symptoms. The amygdala functional network was assessed using resting‐state functional magnetic resonance imaging (rs‐fMRI) in 128 children at age of 4.4 to 4.8 years. Maternal depressive symptoms were obtained at 26 weeks of gestation, 3 months, 1, 2, 3, and 4.5 years after delivery. Linear regression was used to examine associations between maternal depressive symptoms and the amygdala functional network. Prenatal maternal depressive symptoms were significantly associated with the functional connectivity between the amygdala and the cortico‐striatal circuitry, especially the orbitofrontal cortex (OFC), insula, subgenual anterior cingulate (ACC), temporal pole, and striatum. Interestingly, greater pre‐ than post‐natal depressive symptoms were associated with lower functional connectivity of the left amygdala with the bilateral subgenual ACC and left caudate and with lower functional connectivity of the right amygdala with the left OFC, insula, and temporal pole. These findings were only observed in girls but not in boys. Early exposure to maternal depressive symptoms influenced the functional organization of the cortico‐striato‐amygdala circuitry, which is intrinsic to emotional perception and regulation in girls. This suggests its roles in the transgenerational transmission of vulnerability for socio‐emotional problems and depression. Moreover, this study underscored the importance of gender‐dependent developmental pathways in defining the neural circuitry that underlies the risk for depression.

There is cumulative evidence that young people in an "at-risk mental state" (ARMS) for psychosis show structural brain abnormalities in frontolimbic areas, comparable to, but less extensive than those reported in established schizophrenia. However, most available data come from ARMS samples from Australia, Europe, and North America while large studies from other populations are missing. We conducted a structural brain magnetic resonance imaging study from a relatively large sample of 69 ARMS individuals and 32 matched healthy controls (HC) recruited from Singapore as part of the Longitudinal Youth At-Risk Study (LYRIKS). We used 2 complementary approaches: a voxel-based morphometry and a surface-based morphometry analysis to extract regional gray and white matter volumes (GMV and WMV) and cortical thickness (CT). At the whole-brain level, we did not find any statistically significant difference between ARMS and HC groups concerning total GMV and WMV or regional GMV, WMV, and CT. The additional comparison of 2 regions of interest, hippocampal, and ventricular volumes, did not return any significant difference either. Several characteristics of the LYRIKS sample like Asian origins or the absence of current illicit drug use could explain, alone or in conjunction, the negative findings and suggest that there may be no dramatic volumetric or CT abnormalities in ARMS.

Background: Prenatal maternal depression and genetic risks for depression may have long-term impacts on amygdala-cortical development. This study explored influences of genetic and prenatal maternal depression risk factors on the amygdala-cortical structural covariance in a relatively large sample at birth (n=180), 4.5 (n=225) and 6 (n=256) years of age. Methods: Structural magnetic resonance imaging was performed to obtain the amygdala volume and cortical thickness at each time point and to assess structural covariance of amygdala-cortical circuits. Prenatal maternal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS). Genetic risk was quantified using a polygenic risk score for major depressive disorder (PRSMDD). Regression analysis was used to examine effects of EPDS and PRSMDD on structural coupling between the amygdala volume and cortical thickness at each time point. Findings: Girls with high PRSMDD showed negative coupling between the amygdala volume and inferior temporal/fusiform thickness at both 4.5 (β=- 0.303, p= 0.028) and 6 years of age (β=-0.372, p=0.004) and negative coupling between the amygdala volume and middle frontal thickness only at 6 years of age (β=-0.315, p=0.019). On the other hand, girls with high prenatal maternal depressive symptoms showed positive coupling between the amygdala volume and insula thickness at birth (β=0.617, p=0.001) but negative coupling between amygdala volume and inferior frontal thickness at age of 4.5 years (β=-0.369, p=0.008). No findings were found in boys at any time point. Interpretation: The vulnerability of the development of the amygdala-cortical circuitry to environmental and genetic risk factors related to depression might be sex-dependent. Funding Statement: This research is supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC), SingaporeNMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014. Additional funding is provided by the Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore Ministry of Education (Academic research fund tier 1; NUHSRO/2017/052/T1-SRP-Partnership/01), and NUS Institute of Data Science, Singapore. Declaration of Interests: No author has conflict of interest. Ethics Approval Statement: The prospective Growing Up in Singapore Towards healthy Outcomes (GUSTO) longitudinal birth cohort study was approved by the National Healthcare Group Domain Specific Review Board (NHG DSRB) and the Sing Health Centralized Institutional Review Board (CIRB). Written informed consent was obtained from mothers.

Most individuals identified as ultra-high-risk (UHR) for psychosis do not develop frank psychosis. They continue to exhibit subthreshold symptoms, or go on to fully remit. Prior work has shown that the volume of CA1, a subfield of the hippocampus, is selectively reduced in the early stages of schizophrenia. Here we aimed to determine whether patterns of volume change of CA1 are different in UHR individuals who do or do not achieve symptomatic remission. Structural MRI scans were acquired at baseline and at 1-2 follow-up time points (at 12-month intervals) from 147 UHR and healthy control subjects. An automated method (based on an ex vivo atlas of ultra-high-resolution hippocampal tissue) was used to delineate the hippocampal subfields. Over time, a greater decline in bilateral CA1 subfield volumes was found in the subgroup of UHR subjects whose subthreshold symptoms persisted (n=40) and also those who developed clinical psychosis (n=12), compared with UHR subjects who remitted (n=41) and healthy controls (n=54). No baseline differences in volumes of the overall hippocampus or its subfields were found among the groups. Moreover, the rate of volume decline of CA1, but not of other hippocampal subfields, in the non-remitters was associated with increasing symptom severity over time. Thus, these findings indicate that there is deterioration of CA1 volume in persistently symptomatic UHR individuals in proportion to symptomatic progression.

Background Variation in trajectories of Ultra high-risk (UHR) psychosis mental state posts challenge to schizophrenia prevention or onset delay intervention. Our previous work described the heterogeneity at this prodromal stage of schizophrenia in both brain structure changes and resting-state functional network differences. Functional dysconnectivity can be one of the altered brain substrates underlying clinical symptoms. Lower resting-state functional connectivity (FC) within the salience network (SN) in schizophrenia was detectable at the UHR stage. FC between the frontoparietal network (FPN) and the SN was disrupted when network integration fell apart in the UHR state. FPN and SN are important for working memory (WM), which is largely compromised in schizophrenia and lesser in UHR group. Our previous work showed that WM task-related activation in the FPN and SN differed between the UHR and controls. Importantly, such differences varied with WM demands. Evidence has demonstrated that compared to resting-state FC, task-based FC may better predict behavioral performance. However, the WM-related FC in UHR group and its longitudinal changes are still largely unknown. To cover the gap, we sought to examine the heterogeneity in the WM task-related FC changes in a group of UHR participants over time. We expected WM-related FC would link to individual differences in clinical trajectories. Methods Based on the longitudinal changes of UHR state within 2 years, participants were divided into 3 groups: 42 controls, 34 UHR remitters (UHR-R) and 42 UHR non-remitters (UHR-NR). We acquired fMRI (TR/TE = 2000/30 ms, 3 x 3 x 4 mm3, 28 slices) when participants performed WM task at different WM demands, varying from information maintenance alone (low) to requiring both maintenance and manipulation (high). We used seed-based approach (gPPI) to compare task-related FC of the FPN and the SN among groups. Voxel-wise FC with six seeds (bilateral anterior insula, parietal, and dorsal lateral prefrontal cortex, identified based on task activation) was regressed on WM demands and groups, controlling for age, gender, education, ethnicity, handedness and task accuracy. Linear mixed modeling methods were used to test longitudinal FC changes and the association between FC and clinical syndromes. Results Task performance was worse at high WM demand as expected, but no significant difference was found between groups or over time. Compared to controls, higher FC between the FPN (superior parietal gyrus) and the SN (insula) at low demand was observed in the UHR-NR group at baseline. Within the SN, WM-demand related FC between right insula and thalamus varied among 3 groups: low FC at low demand and high FC at high demand in controls; high FC at low demand but low FC at high demand in the UHR-R group. In contrast, UHR-NR group had high thalamus-insula FC in both WM demands. Moreover, longitudinal FC increase only occurred within the SN at high WM demand in the UHR-R group, while other task-related baseline group differences of FC remained stable over time. Importantly, the rate of intra-SN increase of FC over time at higher WM demand was associated with decline of the positive psychosis syndromes in the UHR-R group. Discussion In support of the functional dysconnectivity hypothesis, our study indicated that UHR state was accompanied by altered brain FC during WM task performance. In contrast to lower SN FC at rest, UHR state showed SN hyper-connectivity in task with low WM demand, suggesting the importance of studying UHR both at resting and in task. Importantly, intra-SN FC increase at high WM demand was linked to positive psychosis syndrome reduction in remitters, while no FC changes if UHR state persisted. We argued that task FC could reflect the clinical heterogeneity of the UHR group.

This study investigated the relationships between pre- and early post-natal maternal depression and their changes with frontal electroencephalogram (EEG) activity and functional connectivity in 6- and 18-month olds, as well as externalizing and internalizing behaviors in 24-month olds (n = 258). Neither prenatal nor postnatal maternal depressive symptoms independently predicted neither the frontal EEG activity nor functional connectivity in 6- and 18-month infants. However, increasing maternal depressive symptoms from the prenatal to postnatal period predicted greater right frontal activity and relative right frontal asymmetry amongst 6-month infants but these finding were not observed amongst 18-month infants after adjusted for post-conceptual age on the EEG visit day. Subsequently increasing maternal depressive symptoms from the prenatal to postnatal period predicted lower right frontal connectivity within 18-month infants but not among 6-month infants after controlling for post-conceptual age on the EEG visit day. These findings were observed in the full sample and the female sample but not in the male sample. Moreover, both prenatal and early postnatal maternal depressive symptoms independently predicted children’s externalizing and internalizing behaviors at 24 months of age. This suggests that the altered frontal functional connectivity in infants born to mothers whose depressive symptomatology increases in the early postnatal period compared to that during pregnancy may reflect a neural basis for the familial transmission of phenotypes associated with mood disorders, particularly in girls.

Maternal depressive symptoms influence neurodevelopment in the offspring. Such effects may appear to be gender-dependent. The present study examined contributions of prenatal and postnatal maternal depressive symptoms to the volume and microstructure of the amygdala in 4.5-year-old boys and girls. Prenatal maternal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS) at 26 weeks of gestation. Postnatal maternal depression was assessed at 3 months using the EPDS and at 1, 2, 3 and 4.5 years using the Beck’s Depression Inventory-II. Structural magnetic resonance imaging and diffusion tensor imaging were performed with 4.5-year-old children to extract the volume and fractional anisotropy (FA) values of the amygdala. Our results showed that greater prenatal maternal depressive symptoms were associated with larger right amygdala volume in girls, but not in boys. Increased postnatal maternal depressive symptoms were associated with higher right amygdala FA in the overall sample and girls, but not in boys. These results support the role of variation in right amygdala structure in transmission of maternal depression to the offspring, particularly to girls. The differential effects of prenatal and postnatal maternal depressive symptoms on the volume and FA of the right amygdala suggest the importance of the timing of exposure to maternal depressive symptoms in brain development of girls. This further underscores the need for intervention targeting both prenatal and postnatal maternal depression to girls in preventing adverse child outcomes.

The thalamus is a deep gray matter structure and consists of axonal fibers projecting to the entire cortex, which provide the anatomical support for its sensorimotor and higher-level cognitive functions. There is limited in vivo evidence on the normal thalamocortical development, especially in early life. In this study, we aimed to investigate the developmental patterns of the cerebral cortex, the thalamic substructures, and their connectivity with the cortex in the first few weeks of the postnatal brain. We hypothesized that there is developmental synchrony of the thalamus, its cortical projections, and corresponding target cortical structures. We employed diffusion tensor imaging (DTI) and divided the thalamus into five substructures respectively connecting to the frontal, precentral, postcentral, temporal, and parietal and occipital cortex. T2-weighted magnetic resonance imaging (MRI) was used to measure cortical thickness. We found age-related increases in cortical thickness of bilateral frontal cortex and left temporal cortex in the early postnatal brain. We also found that the development of the thalamic substructures was synchronized with that of their respective thalamocortical connectivity in the first few weeks of the postnatal life. In particular, the right thalamo-frontal substructure had the fastest growth in the early postnatal brain. Our study suggests that the distinct growth patterns of the thalamic substructures are in synchrony with those of the cortex in early life, which may be critical for the development of the cortical and subcortical functional specialization.

Patients with schizophrenia exhibit impairments in working memory that often appear in attenuated form in persons at high risk for the illness. The authors hypothesized that deviations in task-related brain activation and deactivation would occur in persons with an at-risk mental state performing a working memory task that entailed the maintenance and manipulation of letters.Participants at ultra high risk for developing psychosis (N=60), identified using the Comprehensive Assessment of At-Risk Mental States, and healthy comparison subjects (N=38) 14 to 29 years of age underwent functional MRI while performing a verbal working memory task. Group differences in brain activation were identified using analysis of covariance.The two groups did not show significant differences in speed or accuracy of performance, even after accounting for differences in education. Irrespective of task condition, at-risk participants exhibited significantly less activation than healthy comparison subjects in the left anterior insula. During letter manipulation, at-risk persons exhibited greater task-related deactivation within the default-mode network than comparison subjects. Region-of-interest analysis in the at-risk group revealed significantly greater right dorsolateral prefrontal cortex activation during manipulation of letters.Despite comparable behavioral performance, at-risk participants performing a verbal working memory task exhibited altered brain activation compared with healthy subjects. These findings demonstrate an altered pattern of brain activation in at-risk persons that contains elements of reduced function as well as compensation.