Physical symptoms and brain morphology: a population neuroimaging study in 12,286 pre-adolescents

Abstract

Physical symptoms, also known as somatic symptoms, are those for which medical examinations do not reveal a sufficient underlying root cause (e.g., pain and fatigue). The extant literature of the neurobiological underpinnings of physical symptoms is largely inconsistent and primarily comprises of (clinical) case-control studies with small sample sizes. In this cross-sectional study, we studied the association between dimensionally measured physical symptoms and brain morphology in pre-adolescents from two population-based cohorts; the Generation R Study (n = 2649, 10.1 ± 0.6 years old) and ABCD Study (n = 9637, 9.9 ± 0.6 years old). Physical symptoms were evaluated using continuous scores from the somatic complaints syndrome scale from the parent-reported Child Behavior Checklist (CBCL). High-resolution structural magnetic resonance imaging (MRI) was collected using 3-Tesla MRI systems. Linear regression models were fitted for global brain metrics (cortical and subcortical grey matter and total white matter volume) and surface-based vertex-wise measures (surface area and cortical thickness). Results were meta-analysed. Symptoms of anxiety/depression were studied as a contrasting comorbidity. In the meta-analyses across cohorts, we found negative associations between physical symptoms and surface area in the (i) left hemisphere; in the lateral orbitofrontal cortex and pars triangularis and (ii) right hemisphere; in the pars triangularis, the pars orbitalis, insula, middle temporal gyrus and caudal anterior cingulate cortex. However, only a subset of regions (left lateral orbitofrontal cortex and right pars triangularis) were specifically associated with physical symptoms, while others were also related to symptoms of anxiety/depression. No significant associations were observed for cortical thickness. This study in preadolescents, the most representative and well-powered to date, showed that more physical symptoms are modestly related to less surface area of the prefrontal cortex mostly. While these effects are subtle, future prospective research is warranted to understand the longitudinal relationship of physical symptoms and brain changes over time. Particularly, to elucidate whether physical symptoms are a potential cause or consequence of distinct neurodevelopmental trajectories.

Fig. 1. Flowchart of participants.

ABCD Adolescent Brain Cognitive Development. MRI magnetic resonance imaging.

Fig. 2. Significant associations between surface area and continuous scores of physical symptoms, anxiety/depression symptoms and both types of symptoms from meta-analyses after correction for multiple testing (n = 12,286).

Significant clusters of <45 mm² are not annotated in the figure because they were considered exceedingly small. Specific findings for anxiety/depression symptoms are not annotated because are not the primary focus of this work. The models were adjusted for age, sex, national origin (Generation R) or race/ethnicity (ABCD), estimated intracranial volume, maternal education (Generation R) or parental education (ABCD), household income, body mass index and non-verbal intelligence quotient. ABCD analyses were additionally adjusted for the 21 study sites. Physical symptoms were assessed using the school-age version (for ages 6–18) of the Child Behavior Checklist (CBCL). The cluster annotated as “lateral orbitofrontal cortex” in the left hemisphere also included regions in the insula, pars triangularis and pars orbitalis. The cluster annotated as “pars triangularis” in the right hemisphere also included regions in the insula, lateral orbitofrontal cortex and pars orbitalis. For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.