Systemic inflammation and grey matter volume in schizophrenia and bipolar disorder: Moderation by childhood trauma severity
Introduction
Early childhood trauma increases the risk of developing a range of psychopathologies in adulthood (Kessler et al., 2010; Vachon et al., 2015; van Nierop et al., 2015), including psychosis (Varese et al., 2012). Childhood trauma is also associated with alterations in brain structure and function (Hart and Rubia, 2012; Lim et al., 2014; Teicher and Samson, 2013; Teicher et al., 2016), yet the role of trauma-related processes in contributing to morphological brain changes in psychotic and mood disorders remains unclear. Parallel evidence has shown that childhood trauma exposure is associated with increased inflammatory responses (Baumeister et al., 2016; Coelho et al., 2014). Accumulating evidence suggests that chronic inflammation is associated with brain alterations typically reported in schizophrenia and bipolar disorder: for example, increased levels of pro-inflammatory interleukin 6 (IL-6) have been associated with reduced hippocampal volume in middle-aged adults without a psychiatric diagnosis (Marsland et al., 2008) and in patients with first-episodes psychosis (FEP) (Mondelli et al., 2011). It is possible that these associations between inflammatory markers and brain morphology in people with psychosis may be moderated by childhood trauma exposure, and it is likely that these effects of trauma would be trans-diagnostic.
Previous studies, including reviews (Bergink et al., 2014; Miller et al., 2014a; Potvin et al., 2008; Rodrigues-Amorim et al., 2017) and meta-analyses (Fernandes et al., 2016a; Fernandes et al., 2016b; Goldsmith et al., 2016; Miller et al., 2011; Modabbernia et al., 2013), show heightened levels of peripheral inflammatory markers in both bipolar disorder and schizophrenia patients, compared to healthy controls. Findings include increased IL-6, tumor necrosis factor alpha (TNF-α; a pro-inflammatory cell signaling cytokine involved in the acute phase inflammatory reaction) and C-reactive protein (CRP; a pro-inflammatory acute-phase protein expressed following IL-6 secretion). In particular, both FEP patients and those with chronic schizophrenia (Fernandes et al., 2016a; Goldsmith et al., 2016) show higher peripheral levels of IL-6 and TNF-α. Other studies of people with chronic bipolar disorder show increased levels of IL-6 and CRP (but not TNF-α) during acute mania (Fernandes et al., 2016b; Goldsmith et al., 2016). Elevated levels of IL-6 and TNF-α (but not CRP) were found in participants during the euthymic (but not depressive) phase of illness (Goldsmith et al., 2016). This is in contrast to reports of no increase of CRP levels during depressive or euthymic phases (Fernandes et al., 2016b).
Release of pro-inflammatory markers activates the hypothalamic-pituitary-adrenal (HPA)-axis, which in turn regulates the immune system (Raison and Miller, 2003). Several studies of schizophrenia have reported childhood trauma-related decreases in grey matter volume among stress-sensitive brain regions [hippocampus, amygdala, dorsolateral prefrontal cortex (DLPFC)] (Cancel et al., 2015; Hoy et al., 2012; Sheffield et al., 2013). These brain regions are consistently implicated in studies of trauma exposure conducted in both non-clinical cases and other psychiatric diagnoses (e.g., Hart and Rubia, 2012; Lim et al., 2014; Teicher and Samson, 2013; Teicher et al., 2016). However, different methodologies have been employed to characterize the effects of trauma exposure on specific Regions of Interest (ROIs; e.g., hippocampus and/or amygdala volumes extracted from automated parcellation) (Aas et al., 2013; Aas et al., 2014; Hernaus et al., 2014) versus whole-brain analyses of the effects of individual abuse/neglect subtypes (Cancel et al., 2015; Sheffield et al., 2013). Notably, whole-brain univariate studies of grey matter abnormalities (e.g., using voxel-based morphometry, VBM) do not account for spatial dependencies between different brain locations. In contrast, (multivariate) independent component analysis allows investigation of grey matter volume co-variation (GMC) abnormalities among independent components emerging across the ‘whole brain’ in a given set of subjects (Xu et al., 2009), without the need for stringent significance thresholds as required for VBM. This data-reduction approach has been successfully used in previous case-control studies of psychosis (Castro et al., 2014; Gupta et al., 2015; Kasparek et al., 2010; Kubera et al., 2014; Palaniyappan et al., 2015; Turner et al., 2012; Wolf et al., 2014; Xu et al., 2009), and in association studies of common and rare genetic variants in schizophrenia (Quidé et al., 2018b; Reay et al., 2018), but not in the context of trauma exposure in psychotic disorders.
The evidence for trauma-related increases in peripheral markers of the inflammatory response is accumulating in studies of people with psychosis. There is now consistent evidence for increased levels of CRP in trauma-exposed FEP patients relative to non-exposed FEP patients (Di Nicola et al., 2013; Hepgul et al., 2012), as well as in chronic schizophrenia (Quidé et al., 2019) and in a mixed sample of schizophrenia and bipolar disorder cases (Aas et al., 2017). However, at least two studies have reported mixed results for TNF-α in chronic schizophrenia (Dennison et al., 2012; Quidé et al., 2019). Specifically, Dennison et al. reported increased levels of TNF-α (but not IL-6) in trauma-exposed (compared to non-exposed) schizophrenia patients (Dennison et al., 2012), while Quidé et al. (2019) reported increased levels of CRP (but not IL-6 or TNF-α) in association with the severity of childhood sexual abuse in schizophrenia (but not bipolar disorder) (Quidé et al., 2019). Finally, in a mixed group of patients diagnosed with either bipolar disorder or schizophrenia, increased levels of CRP (but not gp130, an IL-6 antagonist) were associated with exposure to a greater number of abuse types (Aas et al., 2017). Childhood trauma potentiates the relationship between low-grade peripheral inflammation and brain circuits involved in threat, reward and executive control processes (Nusslock and Miller, 2016). In addition to the evidence linking increased IL-6 with reduced hippocampal volume in clinical and healthy cohorts (Marsland et al., 2008; Mondelli et al., 2011), there has also been some evidence for increased levels of CRP in association with decreased thickness in cortical regions including the insula, and the temporal and medial frontal cortices in schizophrenia (Fernandes et al., 2016a; Jacomb et al., 2018). As peripheral levels of pro-inflammatory markers (including IL-6, TNF-α and CRP) are highly correlated with each other, previous studies proposed to use a composite score representing systemic low-grade inflammation (Miller et al., 2014b; Nusslock et al., 2019). Instead of examining them separately, this approach has the advantage of determining the possible synergistic effects of these pro-inflammatory markers and enhances power by negating the need to correct for multiple testing. Therefore, owing to differences between studies in terms of the analytical methods employed, and the particular inflammatory markers and brain ROIs that were studied, the impact of peripheral inflammation on brain morphology in bipolar disorder and schizophrenia remains unclear, and may be moderated by the severity of trauma exposure.
To test potential moderation effects of childhood trauma severity on relationships between levels of peripheral inflammation and brain morphology, this study examined the direct and indirect relationships between childhood trauma severity, systemic inflammation (derived from serum levels of IL-6, TNF-α and CRP), and patterns of GMC among brain regions (derived from independent component analysis), in groups of adults diagnosed with schizophrenia or bipolar disorder, and healthy individuals. We expected that systemic inflammation and childhood trauma severity would each be negatively associated with changes in brain networks that comprised stress-sensitive regions (e.g., hippocampus and DLPFC), regardless of diagnostic status. We further hypothesized that the severity of childhood trauma exposure would moderate the relationship between systemic inflammation and brain morphology, and that these effects would be different among the diagnostic groups of clinical cases and healthy individuals.
Section snippets
Materials and methods
All participants were volunteers and provided informed consent according to procedures approved by the Human Research Ethics committees of the University of New South Wales (HC12384), the South East Sydney and Illawarra Area Health Service (HREC 09/081) and St Vincent's Hospital (HREC/10/SVH/9).
Sample characteristics
Clinical and demographic characteristics of the three groups are summarized in Table 1. There were no significant group differences in age (all p > .071), but the HC group was more educated than both the BD (p = .015, d = 0.54) and SZ groups (p < .001, d = 1.12), with the BD group also being more educated than the SZ group (p = .010, d = 0.56). Both the HC (p = .001, d = 0.65) and BD groups (p = .018, d = 0.55) had higher estimated IQ levels than the SZ group, but did not differ from each other
Discussion
This study aimed to determine whether the severity of childhood trauma exposure moderates associations between an index of systemic low-grade inflammation (represented by the total standardized levels of IL-6, TNF-α and CRP) and changes in GMC among networks of brain regions within groups of patients with chronic (psychotic) BD or SZ, compared to healthy individuals. Firstly, greater systemic inflammation was associated with increased cerebellar and striatal GMC in all-participant groups,
Disclosures
All of the authors declare that they have no conflicts of interest.
Ethical statement
All participants were volunteers and provided informed consent according to procedures approved by the Human Research Ethics committees of the University of New South Wales (HC12384), the South East Sydney and Illawarra Area Health Service (HREC 09/081) and St Vincent's Hospital (HREC/10/SVH/9).
Acknowledgements
We would like to thank the volunteers who participated in this study. We acknowledge recruitment assistance from the Australian Schizophrenia Research Bank (ASRB), which was supported by the National Health and Medical Research Council of Australia (NHMRC) Enabling Grant (#386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute.
This study was supported by a 2016 Early-Career Researcher Project Grant from the Society for
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2021, Brain, Behavior, and ImmunityCitation Excerpt :For instance, in individuals with chronic schizophrenia, both pro-inflammatory (Fillman et al., 2015; Kudo et al., 2018; Miller et al., 2020) anti-inflammatory (Bossu et al., 2015), as well as endothelial cell activation (Dieset et al., 2015; Pillai et al., 2015) markers have been associated with smaller grey matter volume of frontal, temporal regions and hippocampus. In contrast, pro-inflammatory cytokines have been associated with an increase in grey matter volume in the striatum, cerebellum (Quidé et al., 2020) and anterior cingulate cortex (ACC) regions (Tsai et al., 2020) in schizophrenia and an absence of an association between the hippocampus and seven pro-inflammatory molecules has also been reported (Hoseth et al. 2016). More consistent relationships have been found in individuals at the early stages of psychotic illness.