Longitudinal trajectories of anterior cingulate glutamate and subclinical psychotic experiences in early adolescence: the impact of bullying victimization

Abstract

Previous studies reported decreased glutamate levels in the anterior cingulate cortex (ACC) in non-treatment-resistant schizophrenia and first-episode psychosis. However, ACC glutamatergic changes in subjects at high-risk for psychosis, and the effects of commonly experienced environmental emotional/social stressors on glutamatergic function in adolescents remain unclear. In this study, adolescents recruited from the general population underwent proton magnetic resonance spectroscopy (MRS) of the pregenual ACC using a 3-Tesla scanner. We explored longitudinal data on the association of combined glutamate-glutamine (Glx) levels, measured by MRS, with subclinical psychotic experiences. Moreover, we investigated associations of bullying victimization, a risk factor for subclinical psychotic experiences, and help-seeking intentions, a coping strategy against stressors including bullying victimization, with Glx levels. Finally, path analyses were conducted to explore multivariate associations. For a contrast analysis, gamma-aminobutyric acid plus macromolecule (GABA+) levels were also analyzed. Negative associations were found between Glx levels and subclinical psychotic experiences at both Times 1 (n = 219, mean age 11.5 y) and 2 (n = 211, mean age 13.6 y), as well as for over-time changes (n = 157, mean interval 2.0 y). Moreover, effects of bullying victimization and bullying victimization × help-seeking intention interaction effects on Glx levels were found (n = 156). Specifically, bullying victimization decreased Glx levels, whereas help-seeking intention increased Glx levels only in bullied adolescents. Finally, associations among bullying victimization, help-seeking intention, Glx levels, and subclinical psychotic experiences were revealed. GABA+ analysis revealed no significant results. This is the first adolescent study to reveal longitudinal trajectories of the association between glutamatergic function and subclinical psychotic experiences and to elucidate the effect of commonly experienced environmental emotional/social stressors on glutamatergic function. Our findings may deepen the understanding of how environmental emotional/social stressors induce impaired glutamatergic neurotransmission that could be the underpinning of liability for psychotic experiences in early adolescence.

Fig. 1. Longitudinal proton magnetic resonance spectroscopy (MRS) measurements of a representative participant.

Voxel-of-interest (VOI) placements for the participant at Time 1 (a) and Time 2 (b) are demonstrated. A VOI for ¹H MRS was placed at the anterior cingulate cortex (ACC) in 3D-T1 anatomical images (left, axial plane; middle, sagittal plane; right, coronal plane). VOIs were highlighted for visual purposes. The analysis results of ¹H MRS spectra of the participant collected at Time 1 (c) and Time 2 (d) are shown. MEGA-editing was achieved with 15-ms Gaussian editing pulses applied at 1.90 ppm (ON) and 7.46 ppm (OFF) in alternate spectral lines. Actual spectra (the difference between edit ON and OFF spectra) (gray line) and their LCModel fits (red line) are displayed, where co-edited Glx signal peaks (~3.75 ppm) are clearly detectable.

Fig. 2. Associations over time between Glx levels and signs of subclinical psychotic experiences.

a The association at Time 1, b the association at Time 2, and c the association between longitudinal changes are illustrated. Significant negative associations between Glx levels in the pregenual ACC and subclinical psychotic experiences at both Times 1 (a) and 2 (b) as well as between over-time changes in the two variables were found (c). Glx combined glutamate-glutamine, SPE subclinical psychotic experience, i.u. institutional units.

Fig. 3. Effects of bullying victimization and help-seeking intention on longitudinal Glx levels.

Light blue-colored bars represent Glx levels at Time 1, and pink-colored bars represent Glx levels at Time 2. Bullying victimization and bullying victimization × help-seeking intention interaction had significant effects on Glx levels. The bullied group showed lower ACC Glx levels than the non-bullied group for all participants. Post hoc tests revealed that while the help-seeking and non-help-seeking groups showed similar Glx levels within the non-bullied group, the help-seeking group showed higher Glx levels than the non-help-seeking group within the bullied group. BV bullying victimization, HSI help-seeking intention, Glx combined glutamate-glutamine, i.u. institutional units.

Fig. 4. Results of PLS-SEM analysis for the associations among bullying victimization, help-seeking intention, Glx, and subclinical psychotic experiences.

Path analyses were performed to determine the relationships among variables including bullying victimization, help-seeking intention, age-sex-SES-IQ-adjusted Glx levels, and subclinical psychotic experiences using PLS-SEM. Results of a the time lagged model and of b the latent change score model are illustrated here. Squares represent observed variables and circles represent latent variables. Solid arrows represent direct effects and dashed arrows represent moderation effects. Path coefficients (p values in parentheses) are shown on corresponding arrows. Indirect effects were also assessed. In the time lagged model (a), Glx levels at Time 1 had a significant total indirect effect on subclinical psychotic experience at Time 2, and bullying victimization had a trend-level significant total indirect impact on subclinical psychotic experience at Time 2. In the latent change score model (b), bullying victimization and bullying victimization × help-seeking intention interaction had significant total indirect effects on differences in Glx levels. BV bullying victimization, HSI help-seeking intention, GLX combined glutamate-glutamine, SPE subclinical psychotic experience, T1 Time 1, T2 Time 2 BASE baseline, DIFF difference.