Childhood trauma, IL-6 and weaker suppression of the default mode network (DMN) during theory of mind (ToM) performance in schizophrenia

Sinead King; David Mothersill; Laurena Holleran; Saahithh Patlola; Ross McManus; Marcus Kenyon; Colm McDonald; Brian Hallahan; Aiden Corvin; Derek W Morris; John P Kelly; Declan McKernan; Gary Donohoe

doi:10.1016/j.bbih.2022.100540

Childhood trauma, IL-6 and weaker suppression of the default mode network (DMN) during theory of mind (ToM) performance in schizophrenia

Brain Behav Immun Health. 2022 Oct 27:26:100540. doi: 10.1016/j.bbih.2022.100540. eCollection 2022 Dec.

Authors

Sinead King¹, David Mothersill^{1

2}, Laurena Holleran¹, Saahithh Patlola¹, Ross McManus³, Marcus Kenyon³, Colm McDonald⁴, Brian Hallahan^{1

4}, Aiden Corvin⁴, Derek W Morris^{1

5}, John P Kelly⁶, Declan McKernan⁶, Gary Donohoe¹

Affiliations

¹ Centre for Neuroimaging, Cognition and Genomics (NICOG), School of Psychology, National University of Ireland Galway, Ireland.
² Department of Psychology, National College of Ireland, School of Business, Dublin, Ireland.
³ Trinity Translational Medicine Institute, Department of Clinical Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland.
⁴ Department of Psychiatry, Clinical Science Institute, National University of Ireland Galway, Ireland.
⁵ School of Natural Sciences, National University of Ireland Galway, Ireland.
⁶ Pharmacology & Therapeutics, National University of Ireland Galway, Ireland.

Abstract

Background: Both low-grade systemic inflammation and functional connectivity of the default mode network (DMN) during rest have recently been observed to mediate the association between childhood trauma (CT) and behavioural performance on an emotion recognition task. Whether inflammation also mediates the association between CT and functional connectivity of the DMN during social cognitive task performance is unknown.

Methods: 51 patients with schizophrenia (SZ) or schizoaffective disorder (SZA) and 176 healthy participants completed a theory of mind (ToM) task during fMRI. IL-6 was measured in plasma using ELISA. DMN connectivity was measured during performance of the fMRI ToM task. To examine DMN connectivity, we selected 4 a priori seeds of the DMN, i.e., the medial prefrontal cortex (PFC), right lateral parietal (LP), left LP, and posterior cingulate cortex (PCC) according to the Harvard-Oxford Cortical and Subcortical Atlas (http://www.cma.mgh.harvard.edu/fsl_atlas.html) as implemented in CONN.

Results: Patients showed significantly increased DMN connectivity compared to healthy participants between each of the four seeds of the DMN and with other clusters in the brain. Across the entire sample, higher levels of IL-6 predicted increased connectivity between the mPFC and regions encompassing the cerebellum (<0.001 FWE). IL-6 mediated the association between physical neglect and weaker suppression of the posterior cingulate cortex (PCC) DMN seed -left precentral and postcentral gyrus (β_INDIRECT = .0170, CI: 0.0008 to.0506) connectivity during ToM performance.

Discussion: This is the first study to our knowledge that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during ToM task performance. Consistent with our previous study that IL-6 mediated the association between early life stress exposure and reduced connectivity of the DMN during rest, here IL-6 mediated the association between early life stress and increased connectivity of the DMN during ToM based cognitive processing. These findings suggest a biological mechanism for how chronic stress impacts social cognitive processing.