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Published in final edited form as: J Child Psychol Psychiatry. 2023 Feb 14;64(7):1037–1044. doi: 10.1111/jcpp.13768

Prenatal exposure to air pollution and childhood internalizing problems: roles of shyness and anterior cingulate cortex activity

Ran Liu 1,2,3, David Pagliaccio 1,2, Julie B Herbstman 4,5, Nathan A Fox 6,7, Amy E Margolis 1,2
PMCID: PMC10272087  NIHMSID: NIHMS1884157  PMID: 36789477

Abstract

Background:

Prenatal exposure to air pollution increases risk for psychiatric disorders characterized by internalizing problems. In this study, we examined the roles of shyness and anterior cingulate cortex (ACC) activity in the association between prenatal exposure to polycyclic aromatic hydrocarbons (PAH) and children’s internalizing problems at 7–9 years old.

Methods:

Participants include 53 children (31 girls, 22 boys). Personal air monitoring was conducted over 48 continuous hours during the third trimester of pregnancy to measure 8 PAHs. Mothers reported on children’s shyness (Emotionality Activity Sociability Temperament Survey) at age 5 and internalizing problems (Child Behavior Checklist) at ages 7 to 9. ACC activity was measured by fMRI during the Simon Spatial Incompatibility task at ages 7 to 9.

Results:

shyness mediated the association between prenatal PAH exposure and internalizing problems. Higher prenatal PAH exposure predicted increased shyness, which in turn predicted greater internalizing problems. Moreover, left ACC activity during the Simon task moderated the association between prenatal PAH exposure and internalizing problems. Prenatal PAH exposure predicted increased risk for internalizing problems only when children showed heightened left ACC activity during the resolution of cognitive conflict.

Conclusions:

Our study innovatively synthesizes the fields of developmental psychology and environmental health science to offer new insights into the risk factors for anxiety disorders. Facilitating the development of healthy reactive and regulatory processes may improve the developmental outcomes for children highly exposed to air pollution.

Keywords: Air pollution, polycyclic aromatic hydrocarbons, prenatal, internalizing problems, shyness, anterior cingulate cortex

Polycyclic aromatic hydrocarbons (PAH) are air pollutants generated by incomplete combustion of fossil fuel, tobacco, and other organic material (Boström et al., 2002). PAH enter the human body mainly through food consumption, air inhalation, dust ingestion, and dermal contact (Zhang et al., 2021) and can cross the placenta and fetal blood brain barrier (Drwal et al., 2019). Critically, the fetal brain is extremely vulnerable to PAH exposure because it is undergoing rapid development, particularly in the third trimester of pregnancy (Andescavage et al., 2017). Human epidemiologic studies have linked prenatal exposure to PAH with dimensions of psychiatric symptoms (Volk et al., 2021) including internalizing problems, attention problems, and ADHD (Genkinger et al., 2015; Perera et al., 2011, 2012, 2014). Little is understood, however, about the biological and cognitive pathways that link prenatal exposure to PAH with psychiatric problems.

Shyness is a key risk factor for the onset of internalizing problems (Liu et al., 2021; Poole et al., 2021) and refers to heightened wariness and anxiety when faced with novel people and situations (Rubin et al., 2009). Other risk markers for internalizing problems that share conceptual similarities with shyness include behavioral inhibition, social wariness, and fear (Buss et al., 2013; Fox et al., 2021). Animal models document effects of gestational exposure to PAH on animal behaviors that are analogous to human risk markers of behavioral inhibition (Margolis et al., 2022). For example, gestational exposure to PAH increases fearful behaviors in zebrafish (Gao et al., 2017). In rodent models, prenatal PAH-exposed offspring spent more time immobile and less time exploring the inner area of the open field, reflecting avoidant behaviors (Miller et al., 2016). Consistent with these findings from animal models, we recently showed that prenatal exposure to PAH was associated with lowered infant approach behaviors as measured by decreased surgency (Liu et al., 2022). Such evidence linking gestational PAH with fear and avoidance behaviors suggests that prenatal PAH exposure may be associated with shyness in humans. Herein, we investigate if the effects of prenatal exposure to PAH on internalizing problems may occur via exposure-related effects on shyness.

In addition to behavioral reactivity, cognitive factors also serve as risk markers of later internalizing problems. The Risk Potential Model of Control posits that exaggerated neural responses on cognitive control tasks maintain and amplify the aberrant automatic information processing bias of children with high behavioral inhibition, thus increasing the risk for internalizing problems (Buzzell et al., 2018; Henderson et al., 2015). Anterior cingulate cortex (ACC) performs a key role in cognitive control by monitoring conflicts, evaluating the benefits of applying different intensities of control, and allocating appropriate control by maximizing the expected control value (Botvinick et al., 2001; Shenhav et al., 2016). Herein, we measure ACC activity during the Simon Spatial Incompatibility task using fMRI. This task measures the ability to resolve cognitive conflict stemming from incongruence between task-irrelevant stimuli (i.e., location of an arrow stimulus) and responses (i.e., direction of the arrow). Children have slower responses during incongruent trials as these trials involve more cognitive conflict and higher demand for cognitive control (e.g., Saby et al., 2014). Thus, reaction time (RT) can indicate trial-wise cognitive conflict, with longer RT characterizing trials with more cognitive conflict.

We investigate the pathway from prenatal exposure to PAH to internalizing problems and hypothesize that exposure-related internalizing problems are mediated by shyness and moderated by cognitive control. Participants are from economically disadvantaged families enrolled in a prospective longitudinal birth cohort. Given our small sample size, we tested the roles of shyness and ACC activity in separate models. Particularly, we hypothesized that greater prenatal PAH exposure would predict increased shyness, which in turn would predict increased internalizing problems. We also hypothesized that prenatal PAH exposure would predict increased internalizing problems only when children showed heightened ACC activity on trials with longer reaction time (RT; larger ACC-RT association) in the Simon task.

Methods

Participants

Participants are a subset of the Sibling-Hermanos birth cohort (N = 121). Details regarding the cohort have been described previously (Cowell et al., 2017). Briefly, beginning in 2008, African American and Dominican women who resided in North Manhattan the South Bronx in New York City (NYC) were enrolled in the Sibling-Hermanos Birth Cohort. These women have been part of a larger cohort (Columbia Center for Children’s Environmental Health Mothers and Newborns birth cohort; 1998–2006), and were invited to participate in the Sibling-Hermanos birth cohort if they became pregnant with another child.

We invited children from the Sibling-Hermanos birth cohort to patriciate in our neuroimaging study based on their age. The oldest 53 children were invited to participate in this study. Five children refused to participate. Among the remaining 48 children, five did not complete a structural scan and two were excluded after the quality control procedures due to excessive head motion, leaving 41 with usable structural data. Of these 41, 39 children completed the Simon task. Six were excluded for poor task accuracy (<50% correct on each run), two for excessive head motion (>20% of frames were outliers with >1 mm frame-wise displacement on each run (Centanni et al., 2018; Siegel et al., 2014), and one for a technical error, leaving 30 with useable task data.

Ethical Considerations

The study protocol was approved by the institutional review boards at Columbia University and New York State Psychiatric Institute. Mothers and children provided informed consent and assent.

Measures

Prenatal PAH.

Personal air monitoring was conducted during the third trimester of pregnancy. Over the 48-hours monitoring, participants wore a backpack designed to measure air quality when awake and placed it next to their beds when sleeping (Perera et al., 2013). Vapors and particles of ≤2.5 μm in diameter were collected on a precleaned quartz microfiber filter and a precleaned polyurethane foam cartridge backup (University Research Glassware, Chapel Hill, NC). Samples were analyzed at Southwest Research Institute for benzo[a]pyrene (B[a]P), benz[a]anthracene, chrysene, benzo[b]fluoranthene, benzo[k] fluoranthene, indeno[1,2,3-cd]pyrene, dibenz[a,h]anthracene, and benzo[g,h,i]perylene. An additional assessment was performed on each personal air monitoring results for completeness of documentation and accuracy of flow rate and time. Exposure levels were computed by totaling across the components examined. The natural log-transformed total scores were used in this study.

Shyness.

Shyness at age 5 was assessed via the Emotionality Activity Sociability (EAS) Temperament Survey (Buss & Plomin, 1984). The survey contains 20 items tapping into four dimensions of temperament described by Buss and Plomin (1984): Shyness (tendency to be inhibited and awkward in novel social situations), Emotionality (tendency to show distress and to become easily aroused, Activity (preferred levels of activity and speed of action), and Sociability (tendency to prefer the company of others). Parents rated children’s temperament on a 5-point Likert scale from 1 (my child’s behavior is never like this) to 5 (my child’s behavior is always like this). The EAS temperament survey demonstrated good reliability in prior research (e.g., Beier et al., 2017). The Shyness subscale (5 items, score range: 1–5) was used in this study (e.g., “Child takes a long time to warm up to strangers.”). The Cronbach’s α of the scale was .77.

Internalizing problems.

Children’s internalizing problems at ages 7–9 were measured using the Child Behavior Checklist (CBCL; Achenbach & Rescorla, 2001). CBCL is a 118-item parent report widely used to examine children’s emotional and behavioral problems. Parents rated their children’s emotional and behavioral problems on a 3-point Likert scale from 0 (not true) to 2 (very true or often true). Previous research has shown good reliability and validity for the CBCL (Achenbach & Rescorla, 2001). Our primary interest was the internalizing problems domain, including three syndrome scales: Anxious/Depressed, Withdrawn/Depressed, and Somatic Complaints. The norm-referenced T-score was used in this study. The Cronbach’s α of the scale was .65.

MRI acquisition.

Data were acquired on a 3T GE 750 scanner with a 32-channel head coil. Two structural T1 images were collected for each participant using a 3D-FSPGR sequence (flip angle = 11, TE = 2.588 ms, TR = 6.412 ms, 180 slices, 1 mm isotropic resolution). Three runs of Simon task data were acquired with an echo planar imaging sequence (flip angle = 77, TE = 25 ms, TR = 2000 ms, 44 slices, 3.0 mm isotropic resolution, 160 acquisition frames, 5 min and 32 s long).

Image processing.

Functional data was performed using Statistical Parametric Mapping 12 (Wellcome Department of Imaging Neuroscience, London, UK, http://www.fil.ion.ucl.ac.uk/spm/) and selected functions from AFNI and FSL. AFNI despiking was used to mitigate spikes in voxel-level timeseries. Slice-timing correction was applied using the first slice of each volume as the reference image. Distortion correction was applied based on the FSL Topup procedure. Images were corrected for motion in three translational directions and three rotations 6. Task runs were visually inspected and discarded if artifacts were found. Each participant’s structural images were first coregistered to their functional image. The structural image was skull-stripped, segmented, and normalized to the MNI template, and parameters determined from this normalization were applied to functional images. Normalized images were spatially smoothed with a Gaussian kernel of 6 mm full-width half-maximum.

Simon Spatial Incompatibility task.

Children performed the Simon task as way to assess their cognitive control ability. Stimuli were presented with E-Prime 2.0 (Psychology Software Tools, Inc., Sharpsburg, PA) and projected onto a screen in the fMRI scanner. An arrow stimulus was shown on each trial and participants were required to indicate the direction that the arrow was facing on a button box. Trials differ by the facing direction of arrows (i.e., pointing to left or right) and the position of arrows (i.e., showing on left or right side of the screen). Congruent trials refer to trials in which the facing direction of arrows match the position of arrows (e.g., left facing arrow showed on the left side of the screen); incongruent trials include those for which the facing directions of arrows were opposite to the positions of arrows (e.g., left facing arrow showed on the right side of the screen).

Prior studies indicate that RT is associated with activity in ACC (Grinband et al., 2011). Therefore, we examined the trial-wise association between activity in a left ACC region-of-interest [ROI; x = −6, y = 12, z = 48, 515 voxels, voxel size 2 × 2 × 2 mm, extracted using a spherical approach with MarsBaR (https://marsbar-toolbox.github.io/index.html)] and RT, as prior findings pointed to greater left ACC activation during resolution of cognitive conflict on the Simon task (Li et al., 2017). We used this parametric modulation to understand trial-level differences in activity associated with engagement of cognitive control. More positive associations indicate greater activity within left ACC as cognitive conflict increases (i.e., longer RT). Similar parametric modulation has been applied in prior research (e.g., Margolis et al., 2021). First-level general linear model includes a regressor of interest for correct trials parametrically modulated by trial-wise RT and one for error trials with duration as RT. All analyses included 24 head motion regressors (translation/rotation, their derivatives, and squares) and regressed out frames with framewise displacement >1 mm, as in pediatric task-based studies with similar TR (van Hulst et al., 2017). Beta maps for the association between BOLD signal and RT were generated for each participant.

Statistical analyses

Because not all participants had available MRI data, we tested the mediating effect of shyness (Figure 1) and the moderating effect of ACC activity (Figure 2) in separate models to leverage the larger sample that had available behavioral data. Two linear regression models were tested in a structural equation modeling framework with maximum likelihood estimation using Mplus version 8 (Muthén and Muthén 1998–2017). Little’s MCAR test failed to reject the hypothesis that the data were missing completely at random (p = .52), therefore missing values were handled with full information maximum likelihood (FIML). Good model fit was indicated by a non-significant chi-square statistic value, a CFI value greater than .95, and a standardized root mean squared residual (SRMR) value less than .08 (Hu & Bentler, 1999). Covariates included children’s age at the neuroimaging visit, sex, total household income last year, presence of a smoker in house (yes/no) when mothers were pregnant, and children’s average head motion during the Simon task. Given that maternal psychopathology is related to child internalizing problems, which in this study were also reported by mothers, we controlled for maternal demoralization/distress in the models. We assessed maternal demoralization/distress using the 27-item Psychiatric Epidemiology Research Instrument Demoralization Scale (Dohrenwend et al., 1980; see Appendix S1).

Figure 1.

Figure 1.

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Conceptual model of the mediating effect of shyness on the association between prenatal exposure to PAH and children’s internalizing problems (n = 53). Covariates include children’s age, sex, household income, smokers in house, maternal demoralization (demo).

Figure 2.

Figure 2.

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Conceptual model of the ACC-RT modulation of PAH-related effects on internalizing problems (n = 30).Covariates include children’s age, sex, household income, smokers in house, maternal demoralization (demo), average motion during the Simon task.

We examined the mediating effect of shyness on the association between prenatal exposure to PAH and internalizing problems in n = 53 children using the bootstrapping method (N = 5000; Hayes, 2009). A mediated effect is considered significant if the confidence interval (CI) does not include zero. We examined ACC-RT modulation of PAH-related effects on internalizing problems in n = 30 children with useable task fMRI data. We tested the statistical significance for simple slopes and plotted the significant interaction terms at mean ± 1SD of the moderator.

Results

Participants

Demographic data of all participants and those with fMRI data are shown in Table 1. Children who had useable fMRI task data (n = 30) were not different from those without useable data (n = 23) on sex, household income, smokers in house, prenatal exposure to PAH, shyness, or internalizing problems (all ps > .17). Children who had fMRI data (M = 105.83 months) were older than children without the data on average (M = 99.43 months, t = −2.32, p = .03). Correlations between variables of interest and covariates are presented in Appendix S2 and Table S1. One-sample t-test showed that the group average of the activity-RT associations within the ROI (i.e., left ACC) was different from zero (t = 3.089, p = .004).

Table 1.

Demographic Data

All participants (n = 53) % Participants with fMRI data (n = 30) %
Sex (female) 31 58.5 20 66.7
Smokers (yes) 8 15.1 4 13.3
Household income (<$10000) 6 11.3 1 3.3
$10001-$20000 17 32.1 11 36.7
$20001-$30000 12 22.6 7 23.3
>$30001 17 32.1 11 36.7
Mean (SD) Range Mean (SD) Range
Age (months) 103.06 (9.83) 84 – 118 105.83 (7.35) 87 – 118
Maternal demoralization .19 (.15) 0 −.62 .20 (.54) 1 – 3.4
Prenatal PAH exposure .43 (.66) −.96 – 1.75 .37 (.70) −.96 – 1.75
Shyness 2.07 (.54) 1– 3.8 2.05 (.54) 1 – 3.40
Internalizing problems 45.25 (8.44) 33 – 67 43.93 (6.73) 33 – 54
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Note. age = child’s age at the neuroimaging visit, smoker = smokers in house (yes/no) during prenatal.

The mediating effect of shyness

The mediation model fitted the data well, χ2 (1, N = 53) = .57, p = .45, CFI = 1.00, SRMR = .02. Controlling for child age, sex, household income, maternal demoralization/distress, and smokers in house, prenatal exposure to PAH significantly predicted shyness at age 5 (β = .38, p = .01), which in turn predicted internalizing problems at ages 7–9 (β = .39, p = .01; Table 2). The direct effect of prenatal PAH exposure on internalizing problems was not significant (β = .21, p = .23). Prenatal PAH exposure indirectly predicted children’s internalizing problems through shyness (95% CI, .02 to .32). The total effect of prenatal PAH exposure on internalizing problems was significant (β = .36, p = .03).

Table 2.

Prenatal Exposure to PAH Predicts Shyness at Age 5 and Internalizing Problems at Ages 7–9

Shyness Internalizing problems
b β SE p b β SE p
age .01 .23 .01 .09 −.09 −.11 .13 .48
sex .14 .13 .14 .32 3.28 .20 2.26 .15
smoker −.31 −.21 .26 .23 1.91 .08 3.70 .61
income −.05 −.19 .04 .12 .73 .16 .54 .18
demo / / / / 10.63 .19 7.72 .17
PAH .28 .38 .11 .01 2.52 .21 2.06 .22
shyness / / / / 6.12 .39 2.26 .01
indirect effect
b β 95% CI
PAH > shyness > problems 1.82 .15 [.02 .32]
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Note. age = child’s age at the neuroimaging visit, smoker = smokers in house (yes/no) during prenatal, demo = maternal demoralization.

The moderation effect of the trial-wise association between left ACC activity and RT

The moderating model was saturated, meaning the model fitted the data perfectly (CFI = 1.00, SRMR = .00). The trial-wise association between ACC activity and RT significantly moderated the association between prenatal PAH exposure and internalizing problems (β = .30, p = .03), controlling for child age, sex, average motion during the Simon task, household income, maternal demoralization/distress, and smokers in house (Table 3). Specifically, increased prenatal PAH exposure predicted greater internalizing problems when the ACC-RT association was high (b = 5.35, p=.004) but not low (b = .82, p=.70; Figure 3).

Table 3.

Prenatal Exposure to PAH and ACC Activity Interactively Predict Internalizing Problems at Ages 7–9

Internalizing problems
b β SE p
age −.13 −.14 .09 .15
sex 1.82 .13 2.62 .49
smoker 1.25 .06 3.22 .70
income .43 .13 .45 .33
motion 5.96 .06 10.52 .57
demo 4.04 .09 6.86 .56
PAH 1.72 .18 1.88 .36
ACC_RT −2.25 −.24 .99 .02
PAH*ACC_RT 3.02 .30 1.42 .03
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Note. age = child’s age at the neuroimaging visit, smoker = smokers in house (yes/no) during prenatal, motion = average motion during the Simon task, demo = maternal demoralization; ACC_RT = association between left ACC and reaction time.

Figure 3.

Figure 3.

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Upper: Anterior cingulate cortex (xyz = −6, 12, 48). Lower: ACC-RT association moderates the association between prenatal exposure to PAH and children’s internalizing problems.*p <.05.

Discussion

We report here the indirect effects of prenatal exposure to air pollution on children’s internalizing problems through an early-emerging behavioral phenotype. Higher prenatal PAH exposure predicted increased shyness, which in turn predicted greater internalizing problems. These findings are in line with animal models pointing to the effects of gestational air pollution exposure on behavioral phenotypes (Margolis et al., 2022; Gao et al., 2017; Miller et al., 2016). Moreover, our findings demonstrate the moderating effect of left ACC activity during the engagement of cognitive control on the association between prenatal exposure to air pollution and internalizing problems, consistent with theoretical models pointing to the role of high monitoring in the manifestation of social anxiety (Buzzell et al., 2018).

Greater prenatal exposure to PAH is associated with increased shyness in early childhood. Animal models suggest that prenatal exposure to air pollution increases risk for adverse behavioral phenotypes (i.e., behavioral inhibition, irritability) through various mechanisms, including altered dopaminergic signaling, neuroinflammatory responses and hippocampal structure, BDNF expression in the hippocampus (Margolis et al., 2022). Notably, humans with higher exposure to air pollution have reduced BDNF (Tang et al., 2014). Future studies should investigate the neural mechanisms underlying effects of prenatal exposure to air pollution on adverse behavioral phenotypes in humans. Moreover, we found that shyness mediated the effect of prenatal PAH exposure on children’s internalizing problems. The findings elucidate an important developmental pathway through which PAH-associated internalizing problems may emerge. Targeting these early-emerging behavioral phenotypes may be an effective way to improve the mental health of children, especially those living in economically disadvantaged communities with high levels of PAH exposure.

Our study is the first to show that left ACC activity during a cognitive control task moderated the association between prenatal PAH exposure and children’s internalizing problems. High levels of cognitive control have been associated with a greater risk for anxiety symptoms in children, particularly those with high shyness or behavioral inhibition, by leading to an inflexible and rigid over-controlled behavioral system (Henderson et al., 2015; White et al., 2011). Our findings support and expand prior evidence by demonstrating that exaggerated activity in control-related regions increased risk for internalizing problems among children with high levels of prenatal exposure to air pollution, which was also associated with shyness. Due to our limited sample size, we did not test shyness and ACC activity in a mediated moderation model. Future research with larger samples should examine the moderated mediation model of these variables to directly test the moderating effect of ACC activity on the pathways from prenatal PAH exposure to internalizing problems via shyness.

Other limitations of the present study should also be noted. First, both shyness and internalizing problems are reported by mothers. Future research should apply behavioral characterization of temperament phenotypes to improve the understanding of effects of prenatal exposure to air pollution on children’s behaviors and psychopathology. Second, we only measured shyness at one time point, which excluded us from examining effects of prenatal exposures on the developmental trajectories of shyness. Longitudinal studies with multiple assessments should be implemented to better understand effects of air pollution on human behavioral phenotypes. Third, cognitive control can be parsed into different subdomains based on its function and when it occurs (e.g., before or after a demanding event; Buzzell et al., 2018; Fox et al., 2021). Future research should examine how brain activity during the engagement of different subdomains of cognitive control impacts risk for psychopathology among children with high levels of prenatal exposure. Fourth, our prenatal PAH measurements came from a single 48-hour air monitoring. Future research should consider including multiple measures (e.g., DNA adducts, questionnaires) to better indicate the level of PAH exposure. Finally, we were not able to control for any heritable or other important contributions to shyness. Nonetheless, our study has several strengths, including the use of gold-standard environmental epidemiological measures of prenatal exposure to air pollution, the implementation of longitudinal design across wide age ranges from prenatal to late childhood, and the unique features of the sample characterizing children from economically disadvantaged backgrounds who are disproportionately exposed to air pollution.

Our study contributes to the literature in an important way by synthesizing two distinct fields and thereby offering new insights into the risk factors of developmental psychopathology. The findings are important from a theoretical perspective and also have significant clinical implications. Awareness of environmentally-associated phenotypes of developmental psychopathology can improve access to care and earlier intervention. Specifically, interventions that involve group activities such as play and modeling as well as clinical methods such as social skills training have been effective in reducing shyness (Cordier et al., 2021). Such interventions may also improve developmental outcomes for children highly exposed to air pollution who show signs of shyness. Moreover, school-based training curricula (Diamond et al., 2007) and physical activities (Chaddock-Heyman et al., 2013) that aim to improve the efficacy of children’s cognitive control may also mitigate these exposure-related risks.

Supplementary Material

supinfo

Appendix S1. Psychiatric Epidemiology Research Instrument Demoralization Scale.

Appendix S2. Correlations between variables of interest and covariates.

Table S1. Correlations between variables of interest and covariates.

Acknowledgements

This research was financially supported by NIEHS R01 ES030950, K23 ES026239, UH3 OD023290. The authors thank the research assistants who collected and managed all the data. The authors have declared that they have no competing or potential conflicts of interest.

Footnotes

Conflict of interest statement: No conflicts declared.

Supporting information

Additional supporting information may be found online in the Supporting Information section at the end of the article:

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supinfo

Appendix S1. Psychiatric Epidemiology Research Instrument Demoralization Scale.

Appendix S2. Correlations between variables of interest and covariates.

Table S1. Correlations between variables of interest and covariates.

NIHMS1884157-supplement-supinfo.docx (18.5KB, docx)

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