Our understanding of the pathways by which maternal mental health influences the risk for psychopathology in the offspring remains incomplete despite an obvious importance for prevention. This gap, in part, derives from a largely unique focus on maternal symptoms of psychopathology despite evidence for an influence of positive mental health states on a wide range of neurodevelopmental outcomes in the offspring. In this analysis we used a prospective longitudinal cohort study to compare the influence of positive and negative maternal mental health conditions on offspring language and executive function as potential mediators for the influence of maternal mental health on depressive symptoms in the offspring. Our results show that language and executive function were significantly and specifically correlated to positive and negative maternal mental health, respectively. Both functions were significantly correlated with self-reported depressive symptoms at 9 years of age. A serial mediation model showed that language mediated the relation between positive maternal mental health and childhood depressive symptoms. In contrast, executive function mediated the relation between negative maternal mental health and childhood depressive symptoms. Neuroimaging analysis showed that positive and negative maternal mental health were linked to different offspring functional connectivity profiles and highlight the Orbitofrontal-Somatomotor Network B connectivity as a possible neural pathway for the impact of positive maternal mental health on offspring language ability. These results highlight the different operative pathways that link positive and negative maternal mental health to childhood depressive symptoms and provide potential modifiable targets for early intervention.
Article
Pathways for Intergenerational Transmission of Depression: Differentiating between Positive and Negative Maternal Mental Health
https://doi.org/10.21203/rs.3.rs-4917604/v1
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Maternal mental health profoundly affects offspring neurodevelopment and long-term outcomes1,2. These effects include changes in brain structure and connectivity3–5, cognitive and emotional function1,6 and risk of depression in later life7,8. The London School of Economics estimates the annual cost of prenatal maternal health problems to be a shocking 8.1 billion pounds, of which 72% are associated with child outcomes9. It is worth noting that this estimate does not include effects on human capital, such as academic performance and later employment. Importantly, maternal mental health represents a modifiable intervention target to improve child outcomes10,11.
Research on maternal mental health has generally focused on the negative aspects of mental health, including psychological distress, symptoms of depression and anxiety, all henceforth referred to as negative maternal mental health12,13. However, negative maternal mental health is only one facet of maternal mental well-being. It is crucial that a comprehensive evaluation of maternal mental well-being encompasses both negative and positive mental health. Positive maternal mental health is not simply the absence of illness or negative symptoms14,15. Positive maternal mental health is the combined self-perceived well-being and psychosocial functioning in mothers that improves personal competency for overcoming life challenges and flourishing in life16–18. Despite the absence of a specific tool for assessment of positive maternal mental health, pre-existing psychiatric screening measures such as the State-Trait Anxiety Inventory (STAI)19 comprise positively worded items that can reflect positive mental health and can thus be used to study and assess positive maternal mental health effects20. Example items include “I feel pleasant” and “I am content”. This approach is further supported by a study reporting that positively worded items on the General Health Questionnaire, which included positive affect and mental functioning, could be utilized for the assessment of positive maternal mental health21.
Positive maternal mental health has distinct effects on offspring outcomes when compared to negative maternal mental health. Positive maternal mental health is associated with better language development and increased social competence in the offspring20 and these effects were independent of negative mental health measures. Positive maternal mental health also exhibits a protective role on the psychopathology and development of the offspring, whereby children of mothers with higher levels of positive maternal mental health exhibited reduced risk of developmental delays and lower prevalence of behavioural and mental disorders in later childhood22–24. Positive maternal mental health also attenuates the association between prenatal negative maternal mental health and offspring internalizing symptoms25. In summary, positive maternal mental health and negative maternal mental health should be viewed as distinct constructs with partially overlapping biological, developmental and health factors20,22,26–28.
The effects of maternal mental health on offspring depression are likely to be mediated by multiple factors29–31. Language and executive function are two such candidate factors, as both have been linked to maternal mental health32–35, academic and social competence36,37 and depression in children and adolescents 38–40. Maternal depression influences socio-emotional development and academic achievement in the offspring41–43, whereby positive maternal mental health is associated with increased language competencies15,20,24 while negative maternal mental health predicts delayed language abilities 44–47. Children and adolescents with language impairments also exhibit more depressive symptoms than healthy children48–50 and are at an increased risk of developing depressive symptoms in the future51,52. Furthermore, toddlers with impaired expressive language have 17-times higher depression and withdrawal ratings than their healthy counterparts40. Executive function at 3 years mediates the association between maternal depressive symptoms and internalizing problems at 6 years53. Executive function in childhood also mediates the association between perinatal maternal mental health and offspring academic achievement at 16 years36.
In summary, while there is extensive research examining the impact of maternal mental health on offspring depression, there are two key gaps in the current literature. First, there are very few longitudinal studies that examine the comprehensive relation between maternal mental health, mediating factors and child outcome. Most studies are either cross-sectional or only examine the link between maternal mental health and the mediating factor, or the mediating factor and the child outcome. Second, the impact of positive maternal mental health on childhood depression is understudied. Given that positive and negative maternal mental health should be viewed as distinct constructs, a more comprehensive analysis of the pathways from maternal mental health to childhood depression should include positive as well as negative maternal mental health. The evidence cited above suggests that positive mental health influences the development of processes that predict the later risk for depression.
To address these knowledge gaps, we utilized the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) birth cohort to examine the longitudinal path between maternal mental health and offspring depressive symptoms, focussing on positive and negative dimensions of maternal mental health as well as plausible mediating pathways (language and executive function). The study design is illustrated in Fig. 1. We first examined the correlation between the two facets of perinatal maternal mental health with offspring language and executive function, followed by the correlation between these two maternal mental health measures and childhood depressive symptoms. We then utilized a serial mediation model to explore the pathways of intergenerational transmission of depression, with positive and negative maternal mental health as independent factors, language and executive function as serial mediators and childhood depression as the outcome. Lastly, we employed resting state functional MRI at 7.5 years of age to examine if the two distinct facets of maternal mental health have differential effect of brain development, in terms of whole-cortex functional connectivity profiles. We hypothesized that both language and executive function would serve as mediators for intergenerational transmission of maternal mental health, with differential pathways of influence for positive and negative maternal mental health. Additionally, we hypothesized that the two distinct facets of maternal mental health would be associated with different functional connectivity profiles in offspring.
Cohort Profile
The population demographics are shown in Table 1. Demographics were collected at recruitment. No significant differences between the full cohort, mediation analysis cohort and neuroimaging analysis cohort were observed except for ethnicity, which was a feature of the study recruitment design that reflects the population distribution in Singapore. Post-hoc comparison showed significant differences in distribution between the full cohort and the neuroimaging analysis cohort (χ2 = 18.13, p < 0.01). As such, ethnicity was included as a covariate in all neuroimaging analysis.
Table 1: Summary of demographics for the full cohort, mediation analysis cohort and neuroimaging cohort. Numbers in brackets indicate the number of subjects as a percentage of the cohort. Chi-square test was used to test for significant differences between the three cohorts for categorical variables and 1-way ANOVA was used to test for significant differences between the three cohorts for continuous variables. Note: BRIEF-2: Behaviour Rating Inventory for Executive Function 2nd edition, GEC: Global Executive Composite, CDI: Children’s Depression Inventory 2, WIAT-3: Wechsler Individual Achievement Test, 3rd Edition
Correlation Analysis with Maternal Mental Health Measures
Positive and negative maternal mental health measures were obtained from a bifactor analysis performed using all the items from three maternal mental health questionnaires conducted at pregnancy week 26: Beck Depression Inventory 2 (BDI), State-Trait Anxiety Inventory (STAI) and Edinburgh Postnatal Depression Scale (EPDS). The positive factor was used as the measure of positive maternal mental health as previous described by Phua et al.20. Examples of positively worded items included in the positive factor include: “I feel pleasant”, “I feel comfortable” and “I am content”. The general factor was used as the measure of negative maternal mental health and consisted of contributions from all items. Positive and negative maternal mental health were not significantly correlated with each other (r=-0.029, 95% CI: (-0.092, 0.035), p = 0.379). This finding is consistent with previous studies20,54 and supports the exploration of positive and negative maternal mental health as distinct constructs.
Child language ability was measured at age 2 years using the composite language score from the Bayley Scales of Infant and Toddler Development. Executive function was measured at age 7 years using the Global Executive Composite (GEC) score from the Behaviour Rating Inventory of Executive Function, 2nd Edition (BRIEF-2). Childhood depressive symptoms were assessed at age 9 years using the Children’s Depression Inventory 2 (CDI-II)55, which is a clinically validated, self-report of depressive symptoms.
| Positive Maternal Mental Health (PW 26) | Negative Maternal Mental Health (PW 26) | |||
|---|---|---|---|---|
| Positive Maternal Mental Health (PW 26) | - | -0.029 | (-0.092, 0.035) | |
| Negative Maternal Mental Health (PW 26) | -0.029 | (-0.092, 0.035) | - | |
| Bayley Composite Language Score (Y2) | 0.130 | (0.031, 0.225)* | -0.103 | (-0.200, -0.005)+ |
| BRIEF-2 GEC Score (Y7) | 0.057 | (-0.031, 0.144) | 0.176 | (0.089, 0.259)* |
| CDI-II Total Score (Y9) | -0.021 | (-0.102, 0.060) | 0.080 | (-0.002, 0.160) |
The results from the Pearson’s correlation analysis between the maternal mental health measures and offspring outcome measures are shown in Table 2. Perinatal positive maternal mental health was significantly and positively correlated with language ability at 2 years (r = 0.130 (0.031, 0.225), p = 0.005), even after Bonferroni correction. In contrast, positive maternal mental health was not significantly correlated with executive functioning at 7 years in the offspring. Perinatal negative maternal mental healthwas significantly correlated with poorer executive function performance at 7 years in the offspring (r = 0.176 (0.089, 0.259), p < 0.001), which remained significant after Bonferroni correction for multiple comparisons. Perinatal negative maternal mental health was also correlated with poorer language skills at 2 years, but this correlation did not survive Bonferroni correction. These results suggest that language in toddlers is primarily linked to positive, rather than negative maternal mental health20. Scatterplots of these correlations were shown in Supplementary Fig. 1. Interestingly, we did not find a significant direct correlation between either facet of maternal mental health with child’s depressive symptoms at 9 years.
Validation of Maternal Mental Health Correlates using an Independent Cohort
We validated the maternal mental health correlates in the GUSTO cohort using an independent sample of mother-child dyads, the Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) cohort56. The demographics profile of the S-PRESTO cohort was tabulated in Supplementary Table 1. We again found a significant correlation between the positive maternal mental health factor and language, measured using Peabody Picture Vocabulary Test (PPVT-5; r = 0.131, 95% CI: (0.008, 0.249), p = 0.004) at age 4 years. We also found a significant correlation between the general negative maternal mental health factor and executive function, measured using Behaviour Rating Inventory of Executive Function - Preschool Version (BRIEF-P) (r = 0.310, 95% CI: (0.172, 0.437), p < 0.001). Different measures of language and executive function were used as Bayley Scales of Infant and Toddler Development and BRIEF-2 were not collected in the S-PRESTO cohort. These findings provided a replication of the relation between maternal mental health, language and executive function found in our main study persist across variations in cohort and assessment instruments.
Correlational analysis with CDI-II Scores
We then examined the correlation between language and executive function with child’s depressive symptoms in the GUSTO cohort (Fig. 2). Child’s depressive symptoms at 9 years of age were significantly and negatively correlated with composite language competency scores at 2 years (r=-0.16 (-0.252, -0.057), p = 0.002) and positively with problems of executive function scores at 7 years (r = 0.17 (0.085, 0.248), p < 0.001). The scatterplots show a continuous correlation between the variables and that the relation was not driven by outliers with extreme language or executive function scores.
Meditation Pathway Analysis
The lack of a direct correlation between both dimensions of perinatal maternal mental health and childhood depressive symptoms shown in the previous section motivated the exploration of a mediational model. Language and executive functions were used as candidate mediators given their association with both maternal mental health and childhood depressive symptoms. We used a serial mediation model (n = 256) to analyse the pathways between positive and negative maternal mental health to offspring depressive symptoms (Fig. 3, Panel A). Our serial mediation analysis showed two significant mediational pathways between maternal mental health and childhood depressive symptoms. Child’s language competency scores at 2 years significantly mediated the relation between positive, but not negative, perinatal maternal mental health and childhood depressive symptoms (β=-0.018 (-0.055, -0.001)). In contrast, problems of executive function at 7 years significantly mediated the relation between negative, but not positive, maternal mental health and childhood depressive symptoms (β = 0.020 (0.001, 0.058)) (Fig. 3, Panel B). No other mediational pathways were significant. The full regression values and mediation pathways are presented in Supplementary Tables 2 and 3.
Neuroimaging Analysis
A broad whole cortex approach was used to examine whether the two distinct dimensions of maternal mental health have a differential effect on brain development, in terms of functional connectivity profiles (n = 378). We focused on resting state functional MRI data collected at 7.5 years of age, which precedes the collection of self-reported depressive symptoms. We noted that the pattern of significant correlations (p < 0.05, uncorrected) differed between the two perinatal maternal mental health measures and was not simply an inverse of each other (Fig. 4). Negative maternal mental health was correlated with changes in the pattern of functional connections predominantly associated with the Salience, Limbic A and Default Mode networks. However, none of the connections were significant after Bonferroni correction. Positive maternal mental health was predominately associated with a pattern of altered functional connectivity between Limbic networks and various brain regions. Notably, an extremely strong, positive correlation was observed with the Limbic B–Somatomotor Network B connection (r = 0.18, p = 0.0006). The Limbic B network consists solely of the orbitofrontal cortex. After Bonferroni correction for multiple comparisons, the Orbitofrontal–Somatomotor Network B connection remained significantly associated with positive maternal mental health. All the significant functional connections (p < 0.05, uncorrected) were tabulated in Supplementary Table 4.
In our follow-up analysis, we found a significant mediational effect of the Orbitofrontal–Somatomotor Network B functional connection on the association between positive perinatal maternal mental health and child’s language ability at 9 years of age, assessed using the Oral Fluency Standard Score (Supplementary Fig. 2, β = 0.039 (0.005, 0.108)) in Wechsler Individual Achievement Test, 3rd Edition (WIAT-3). Higher positive perinatal maternal mental health was associated with greater Orbitofrontal-Somatomotor Network B functional connectivity at 7.5 years that, in turn, was associated with better language ability at 9 years. The Oral Fluency score at 9 years was used instead of the Composite Language score at 2 years to ensure the temporal directionality of the relation between the functional connectivity and language measures. Oral Fluency score at 9 years is strongly correlated with the Composite Language score from Bayley Scales of Infant and Toddler Development (r = 0.283 (0.163,0.395),p < 0.001), and shows similar correlations with child’s depressive symptoms as the Composite Language score (r=-0.115 (-0.212,-0.015),p = 0.024).
Our study found that neither measures of positive nor negative maternal mental health showed a direct correlation with childhood depressive symptoms, consistent with the previous findings of Han et al. using the GUSTO cohort.31. This finding contrasts with previous reports such as those from the Avon Longitudinal Study of Parents and Children examining perinatal maternal negative mental health and later risk for depression in the offspring57. We note, however, that our sample size was smaller and was focused on depressive symptoms in childhood. Nevertheless, a serial mediation analysis showed that the path between positive and negative maternal mental health and depressive symptoms in offspring was mediated by language and executive function, respectively. Language competency and executive functions are both essential for academic success. Thus, our findings are in concordance with the existing literature that supports the association between academic performance and depressive symptoms in childhood and adolescent58–60. Specifically, our mediational analysis demonstrated that positive maternal mental health was associated with improved language competencies, which was linked to a subsequent decrease in child’s depressive symptoms. In contrast, negative maternal mental health was associated with increased problems of executive function, which was associated with higher subsequent levels of child’s depressive symptoms. These findings highlight that the operative pathways from positive and negative maternal mental health to childhood depression are distinctively separate. While these findings are correlational, the longitudinal analyses are consistent with an inference of causal relations, whereby the mediators preceded depressive symptom outcomes in children. Furthermore, we showed that positive and negative maternal mental health revealed different neuroimaging correlates in the child, suggesting substantially different influences on offspring brain development and hence may have significantly different pathways in influencing childhood depressive symptoms.
The mediating effect of executive function on the relation between negative maternal mental health and offspring depressive symptoms is consistent with previous literature demonstrating that executive function is associated with both negative maternal mental health and childhood depression32,33,61,62. Emerging evidence also supports the role of executive function as a potential mediator between negative maternal mental health and childhood internalizing problems53 as well as depressive symptoms31. In our study, language function did not mediate the effect of negative maternal mental health on childhood depression. While there are partially conflicting results in the literature, of which some found that negative maternal mental health predicts poorer language ability 44–47, we postulate that a major confound in previous studies is the omission of positive maternal mental health as a correlate for language development. We also note that our study involved a community sample and did not include children with more severe language impairments. We found a significant correlation between negative maternal mental health and language function using a simple correlation analysis. However, the correlation loses its significance once positive maternal mental health is included in our mediation model. This finding implies that language ability is more strongly associated with positive rather than negative maternal mental health.
Importantly, our findings extend preexisting findings25 by suggesting that positive maternal mental health may reduce childhood depressive symptoms in the offspring through enhanced language competency. Our results agree with previous findings that positive maternal mental health predicts better language abilities in the offspring20,24, and demonstrates the role of language as a mediator for the effects of positive maternal mental health on childhood depressive symptoms. Furthermore, we utilized a continuous measure of language ability in our study, which showed that not only do language deficits increase depressive symptoms, as evident in previous literature 48,49,51,52, but also that increased language competency in typically developing children decreases depressive symptoms in later childhood. It is interesting to note how positive and negative maternal mental health reveal two distinct, non-interacting pathways to influence the level of offspring depressive symptoms. We postulate that this could be due to the high level of heterogeneity within depression itself. Specifically, it is plausible that positive and negative maternal mental health, and in turn language and executive function, interact and associate with different facets of depression, such as poor self-perception, intrusive thoughts, rumination, and anhedonia. This could be an interesting area to explore in future work.
Our functional connectivity correlation analysis showed that positive and negative maternal mental health were associated with different functional connectivity profiles in the offspring. The present results build on and extend previous studies that show maternal mental health is associated with brain functional connectivity in the offspring3,5. However the existing literature has focused on negative maternal mental health, with results predominantly reflecting significant changes in the language, executive function, and emotion regulation networks5,63–65. This pattern accords with our finding of altered connectivity between the Default Mode, Salience and Limbic A networks in relation to elevated negative maternal mental health. In contrast, we found that positive maternal mental health correlated with functional connectivity between the Orbitofrontal Cortex and Somatomotor Network B. Interestingly, the Orbitofrontal-Somatomotor Network B connectivity was also found to be significantly correlated with elevated childhood depressive symptom scores in a previous study in the same cohort66. The Orbitofrontal Cortex is thought to be involved in intergenerational transmission of depression67 and has been implicated in multiple studies on depression across different cohorts68–70. Although it might at first appear unexpected, the literature provides evidence supporting the involvement of the Somatomotor Network in mental health disorders. The Somatomotor Network is a transdiagnostic hub implicated across multiple psychopathology dimensions71 and mental health disorders72–74,75. Furthermore, changes in psychomotor functions are a key feature in depression76, impacting speech, posture, movement and facial expressions77. Psychomotor retardation may contribute to learning differences in depressed patients, potentially creating a self-reinforcing feedback loop78 and improved psychomotor functioning is a positive indicator for treatment efficacy in depressed patients79. In a follow-up analysis, we demonstrated that the Orbitofrontal-Somatomotor Network B connectivity mediates the relation between positive maternal mental health and offspring language at 9 years. The orbitofrontal cortex is involved in language and communication80–82, lending credence to the role of this functional connection as a potential mediator to language outcomes in the offspring. Taken together, these results suggest the probability of Orbitofrontal-Somatomotor Network B connectivity as the neural pathway that underlies the impact of maternal mental health on offspring language, and in turn, offspring mental health.
The present findings offer insights into the differential pathways between positive maternal mental health and negative maternal mental health on childhood depression via language and executive function. However, limitations need to be considered when interpreting our findings. First, other behavioral constructs closely related to depression such as emotional processing and reward learning83–85 were not evaluated. These important behavioral constructs exhibit overlapping functional brain regions with executive function and language abilities and hence may confound the results reported in this study. Second, our study data represents a Singaporean population, and replication in other cohorts is needed to assess the generalizability of our findings. Lastly, motion is a possible confounder in neuroimaging studies, and collecting high-quality neuroimaging data is especially challenging in pediatric populations. Thus, we accounted for motion in our pre-processing and analysis.
In conclusion, this study discovered novel evidence indicating notable distinction between positive and negative maternal mental health in terms of their influence on functional connectivity profiles in their children, as well as pathways to depression in their children. Our results also established the directionality of the association between academic performance and childhood depression and confirmed the protective role of positive maternal mental health in ameliorating depression severity in children via enhanced language competencies. Preexisting literature on perinatal maternal mental health have predominantly focused on negative maternal mental health outcomes in the offspring. Hence, our study presents a more comprehensive picture of how the quality of maternal mental health influences outcomes in the offspring by examining both prenatal positive maternal mental health and negative maternal mental health and exemplifies the benefits of promoting positive maternal mental health support programs to mothers in the perinatal period. Finally, our mediational analysis has implications for prevention. We suggest that language competency and executive functions, both of which are highly trainable in young children, represent targets for effective prevention of depression in later childhood.
Participants
Healthy participants for this study were recruited from Growing Up in Singapore Towards Healthy Outcomes (GUSTO), a longitudinal, population-based birth cohort. Pregnant women aged 18 years or older were recruited at their first trimester of pregnancy from two main public hospitals in Singapore between June 2009 and December 201086. Mother-child dyads were followed throughout pregnancy and beyond. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines for cohort studies87. To minimize potential birth complication effects, we only included children with gestational age at birth ≥ 34 weeks, birth weight ≥ 2000 g, and a 5-minute Apgar score ≥ 8 in our analysis. Furthermore, children with a neuropsychiatric diagnosis or on psychoactive mediations were also excluded. All mother-child dyads utilized in this study were healthy with no pre-identified neurodevelopmental problems.
Maternal Mental Health
Prenatal maternal mental health measures were collected during week 26 of the pregnancy. Parents completed three mental health questionnaires: BDI, STAI and EPDS.
The Beck Depression Inventory, Second Edition (BDI)88 is a list of 21 items describing common depressive symptoms. Each item contains four or seven statements describing varying severity of a common depressive symptom. Participants selected the statement that best described how they felt for the past 2 weeks. The EPDS89 has 10 items of depressive symptoms, and participants indicated how much each item described how they were feeling for past 7 days on a 4-point Likert scale. The STAI19 consisted of 40 items that are associated with the presence or absence of anxiety. For the first 20 items, participants responded to how much each item described how they felt right now on a 4-point Likert scale; for the next 20 items, they responded to how much the item described how they generally felt.
Previous work by Desiree et al.20 identified a bi-factor model by combining all the items from these three questionnaires, with a specific positive mental health factor and a general negative mental health factor. We used this positive mental health factor as our measure of positive maternal mental health and the general negative factor as our measure of negative maternal mental health.
Language
At 24 months of age, the Bayley Scales of Infant and Toddler Development, Third Edition90, was used to assess the child’s development in the domains of cognition, language, motor skills, socioemotional behaviours, and adaptability. For this study, we combined the child’s receptive and expressive communication language scores into a composite language score for further analysis.
At 9 years of age, the Wechsler Individual Achievement Test, 3rd Edition (WIAT-3) was administered. WIAT-3 assesses the child’s development in terms of spelling, oral fluency, pseudoword decoding and numerical ability. We used the oral fluency score as a measure of language ability at later timepoints.
Executive Function
Behaviour Rating Inventory of Executive Function, 2nd Edition (BRIEF-2; parent-report form)91 was administered at age 7 years (n = 620). BRIEF-2 is a rating scale that assesses everyday behaviours reflecting executive functions across the school-age span (ages 5–18) and contains 63 items within nine clinical scales and three indexes. The Shift and Emotional Control scales comprise the Emotional Regulation Index, the Inhibit and Self-Monitor scales comprise the Behavior Regulation Index, and the Initiate, Working Memory, Plan/Organize, Task Monitor, and Organization of Materials scales comprise the Cognitive Regulation Index. For this study, we combined the 3 indexes into a total score as a singular measure of executive function for further analysis.
Childhood Depression
Children completed the Children’s Depression Inventory 2 (CDI-II)55, a modified version of the BDI for children. This evaluation was carried out once per child, at either their year 8.5, year 9 or year 10 visit. This variability in evaluation time was due to experimental limitations. The CDI-II consists of 28 questions scored on a 3-point Likert scale. The questions were divided into Emotional and Functional subscales and the sum of all the responses provide the scores for the corresponding subscales and total CDI-II score. A total score of 20 or above (13.3% of girls and 13.5% of boys) indicates clinical levels of depressive symptoms. The CDI-II is stable across ages, applicable for both depressed and normal children92,93 and has good test-retest reliability and high internal consistency94. In this study, the total score was utilized as the outcome measure.
Correlation Analysis
We calculated the simple Pearson’s correlation between both positive maternal mental health and negative maternal mental health with all the outcome measures. We also calculated the Pearson’s correlation between our candidate mediators, language and executive function, and childhood depression.
Serial Mediation Analysis
We carried out mediation analysis using the Lavaan Toolbox95 in R. Specifically, we built a serial mediation model, with language at 2 years as the first mediator, executive function at 7 years as the second mediator, and childhood depressive symptoms at 8.5–10 years as the outcome. Prenatal negative maternal mental health and positive maternal mental health were used as independent predictors in the serial mediation model. The bias-corrected significance of the mediation pathways were estimated using bootstrapping with 10,000 iterations.
MRI Data Acquisition
The MRI data was acquired via a 3-Tesla (Magnetom Prisma; Siemens, Germany). The mean age of participants at time of scan 7.46, with a standard deviation of 0.14 years. We acquired 3D T1-weighted MPRAGE images with the following imaging parameters: repetition time = 2000 ms, echo time = 2.08 ms, field of view = 192×192 mm2, matrix size = 192×192, number of slices = 192, slice thickness = 1 mm. We also acquired one run of resting-state fMRI data: 5.24 min (120 timepoints), repetition time = 2620 ms, echo time = 27 ms, flip angle = 90 degrees, 3 mm isotropic voxels, matrix = 64×64, 48 interleaved axial slices with no gap.
MRI Data Processing
Preliminary pre-processing of the data was performed using the default MNI pipeline in the CONN toolbox (release 20b)96 and SPM1297 in Matlab R2020a. For each session, all scans were co-registered and resampled to the first scan using b-spline interpolation in the SPM12 functional realignment and unwarp procedure98. Sinc interpolation using SPM1299 was applied for slice time correction. We flagged scan volumes with framewise displacement above 0.9 mm or global BOLD signal changes above 5 standard deviations as potential outliers for subsequent confound regression. Both functional and anatomical data were normalized into standard MNI space and segmented into grey matter, white matter and CSF tissue using SPM 12 unified segmentation and normalization procedure100 with 4th order spline interpolation. A kernel of 6 mm full width half maximum (FWHM) was used for gaussian smoothing of the functional data.
Denoising of the functional data was carried out in two steps. First, ordinary least squares regression was used to remove potential noise confounds (cerebral blood flow, subject motion parameters, identified outliers and constant and first-order linear session effects)101. Next, temporal band-pass filtering was used to remove signals below 0.008 Hz and above 0.09 Hz102. Subjects with greater than 6 mm maximum motion, 0.6 mm mean motion or more than 20% outlier scans were excluded from further analysis.
Functional Connectivity Matrices Analysis
Cortical regions were parcellated into 17 functional networks using the atlas of Yeo et al.103 which were used as our regions of interest (ROIs). For each ROI, we calculated the average ROI timeseries by averaging the time course across all voxels in the ROI. We then calculated Fisher-transformed bivariate correlation coefficients between the timeseries for each pair of ROIs to generate the functional connectivity matrix for that subject. Next, we calculated the Pearson’s correlation between each element of the functional connectivity matrix with the corresponding negative maternal mental health and positive maternal mental health total score across all subjects to obtain a matrix of the correlations of functional connectivity fluctuations with negative maternal mental health and positive maternal mental health respectively.
Validation using an independent cohort
A partial validation of the study was carried out using the Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) cohort56 as an independent replication cohort. As the children in the SPRESTO study were all below 7 years old at the time of this study, the CDI-II was not administered for them and we were only able to test the correlations between positive and negative maternal mental health and the respective mediators. Due to limited overlap of measures used in both cohorts, we utilized slightly different measures of language and executive function. However, this could also be viewed as a strength as a replication would suggest the observed effects arise from the underlying language and executive function abilities and is not instrument dependent.
We applied the same bifactor structure to the three maternal mental health questionnaires obtained from the S-PRESTO mothers at pregnancy week 26 to extract out the equivalent general negative mental health factor and positive maternal mental health factors. We used the Peabody Picture Vocabulary Test, 5th Ed (PPVT-5)104 as the measure of language ability. The Behaviour Rating Inventory of Executive Function, Preschool Version (BRIEF-P)105 was used as the measure of executive function. Both tests were administered during the same visit, with the child’s age at test between 4.5 to 6.3 years. Due to the wide range of ages, we utilized the standardized scores for both measures to adjust for age-related changes.
Acknowledgements
This research was supported by grants NMRC/TCR/004-NUS/2008 and NMRC/TCR/012-NUHS/2014 from the Singapore National Research Foundation under the Translational and Clinical Research Flagship and grant OFLCG/MOH-000504 from the Open Fund Large Collaborative Grant Programmes and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC), Singapore. In RIE2025, GUSTO is supported by funding from the NRF’s Human Health and Potential (HHP) Domain, under the Human Potential Programme. Additional funding was provided by the Institute for Human Development and Potential, Agency for Science Technology and Research, Singapore. M.J.M. is supported by funding from the Hope for Depression Research Foundation, USA, the Toxic Stress Network of the JPB Foundation, USA, and the Jacobs Foundation, Switzerland. P.H. is supported by funding from the A*STAR Career Development Fund (C222812035). A.P.T. is supported by funding from the NMRC Transition Award (MOH-001273-00).
Data availability
The GUSTO data are not deposited into a public repository due to multi-site partnership agreements and conditions for Internal Review Board approval. GUSTO data are routinely made available through submission and approval from the cohort executive committee of a data access form. Details may be obtained from the corresponding author upon reasonable request.
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There is NO Competing Interest.