Pubertal timing and functional neurodevelopmental alterations independently mediate the effect of family conflict on adolescent psychopathology

Abstract

This study tested the hypothesis that early life adversity (ELA) heightens psychopathology risk by concurrently altering pubertal and neurodevelopmental timing, and associated gene transcription signatures. Analyses focused on threat- (family conflict/neighbourhood crime) and deprivation-related ELAs (parental inattentiveness/unmet material needs), using longitudinal data from 1514 biologically unrelated youths in the Adolescent Brain and Cognitive Development (ABCD) study. Typical developmental changes in white matter microstructure corresponded to widespread BOLD signal variability (BOLD_sv) increases (linked to cell communication and biosynthesis genes) and region-specific task-related BOLD_sv increases/decreases (linked to signal transduction, immune and external environmental response genes). Increasing resting-state (RS), but decreasing task-related BOLD_sv predicted normative functional network segregation. Family conflict was the strongest concurrent and prospective contributor to psychopathology, while material deprivation constituted an additive risk factor. ELA-linked psychopathology was predicted by higher Time 1 threat-evoked BOLD_SV (associated with axonal development, myelination, cell differentiation and signal transduction genes), reduced Time 2 RS BOLD_sv (associated with cell metabolism and attention genes) and greater Time 1 to Time 2 control/attention network segregation. Earlier pubertal timing and neurodevelopmental alterations independently mediated ELA effects on psychopathology. Our results underscore the differential roles of the immediate and wider external environment(s) in concurrent and longer-term ELA consequences.

Keywords: BOLD variability; Early life adversity; Externalizing problems; Functional brain networks; Neurodevelopment; Structure-function coupling; Transcriptomics.

Fig. 1

Outline of the conceptual model with the main measures mapped onto the constructs of interest.

Fig. 2

Results of the task-PLS analysis. The graphs in panels (a) and (c) show the average of the mean-centred LV1 and LV2 brain scores at each time point within each data group (error bars are the 95% confidence intervals [CI] from the bootstrap procedure). Non-overlapping CIs indicate differences between conditions. Panels (b) and (d) depict the Destrieux ROIs with positive loadings and negative loadings on the LVs graphed in panels (a) and (c), respectively, and visualised with the Freesurfer Surface (https://chrisadamsonmcri.github.io/freesurfer_statsurf_display). In the brain figures in panels (b) and (d), absolute BSR values lower than 4 have been set to zero. BSR = bootstrap ratio. LV = latent variable. Panels (e) and (f) depict the GO enrichment terms, which are most relevant to brain function and associated with each of the two developmental LVs.

Fig. 3

Results of the CCA linking the neurodevelopmental profiles (i.e., brain LVs) previously identified with task-PLS (panel a) to longitudinal increases in functional network segregation (panel c). The scatter plot in panel (b) describes the linear relationship between the predicted values of the two variates across all test CCAs and is based on standardised variables. The networks in panel (c) have been visualised with the Conncetome Workbench (https://www.humanconnectome.org/software/connectome-workbench). AUD = auditory; CON = cingulo-opercular; CP = cingulo-parietal; DMN = default mode; DAN = dorsal attention; FPC = frontoparietal; RSP = retrosplenial/temporal; SM-H = somatomotor-hand; SM-mouth = somatomotor mouth; SAL = salience; VAN = ventral attention; VIS = visual. LV = latent variable. WM = white matter.

Fig. 4

The relationship of Time 1 ELA with Time 1 and Time 2 psychopathology. Correlation [panels a, c] and standardised coefficients [panels b, d] describing the relationship between the observed variables and the predicted value of their corresponding canonical variate (“profile”) across all test CCAs. The scatter plots in panel (e) and (f) describe the linear relationship between the predicted values of the two variates (“profiles”) across all test CCAs and are based on standardised variables. ELA = early life adversity. AnxDep = Anxiety/Depression. Withd = Social Withdrawal. Somatic = Somatic Complaints.

Fig. 5

Results of the behavioural-PLS analysis linking baseline ELA/concurrent psychopathology to the BOLD_sv/WM microstructure variables (panel a). Panel (a) shows the correlations between the LV brain scores and the ELA-Psychopathology variate scores (previously estimated with CCA, as described in the main text). Error bars are the 95% CIs from the bootstrap procedure. CIs that do not include zero reflect robust correlations between the respective behavioural variable and the brain score in a given condition across all participants. Panel (b) depicts the Destrieux ROIs with robust loadings on the LV in panel (a) and visualised with the Freesurfer Surface (https://chrisadamsonmcri.github.io/freesurfer_statsurf_display). In the brain figure in panel (b), absolute BSR values lower than 4 have been set to zero. Panels (c) and (d) depict the brain-relevant GO enrichment terms, which are associated with upregulated genes likely to impact the Time 1 (panel c) and Time 2 (panel d) ELA/Psychopathology brain profile (i.e., PLS-derived brain LV) ( panel a). ELA = early life adversity. LV = latent variable. GO = gene ontology. WM = white matter.

Fig. 6

The relationship of baseline ELA and psychopathology with the profile of functional neurodevelopmental alterations. The left-to-right organisation of the brain variables in panel (a) reflects the magnitude of their loading on the CCA brain variate (i.e., “Brain Profile”) from the variable with the highest absolute value negative loading (“Rest”) to the variable with the highest absolute value positive loading (“Fear”). The scatter plot in panel (b) describes the linear relationship between the predicted values of the two variates (i.e., Brain Profile and ELA/Psychopathology Profile) across all test CCAs. The networks in panel (a) have been visualised with the Connectome Workbench (https://www.humanconnectome.org/software/connectome-workbench). ELA = early life adversity.

Fig. 7

Mediational model linking baseline ELA to average Time 1/Time 2 psychopathology via pubertal timing and neurodevelopmental alterations. ELA = early life adversity.