Interplay between pro-inflammatory cytokines, childhood trauma, and executive function in depressed adolescents

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Abstract

Background

Pro-inflammatory cytokines have been linked to depression, early childhood trauma, and impairment in executive function in adults. Whether these links are present during adolescence, a time when vulnerability to depression is heightened, a point more proximal to childhood trauma, and a critical period of brain development, is not well understood.

Method

Serum levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNF-α) were measured in 70 adolescents aged 12–17, including 40 with a DSM-IV depressive disorder (DEP), a sub-set (n = 22) of whom reported a history of childhood trauma (DEP-T), and 30 healthy controls (HCs). Participants completed performance-based (Parametric Go/No-Go Task) and observer-rated (Behavior Rating Inventory of Executive Function) measures of executive function. Procedures were conducted at a subspecialty clinic (Dec 2015–June 2017).

Results

IL-6 was elevated in DEP and DEP-T adolescents compared to controls (p = .014) and TNF-α was elevated in DEP participants only (p = .040) compared to controls, whereas no group differences were found in IL-1β (p = .829). Additionally, DEP-T participants demonstrated relative deficits in performance-based (p = .044) and observer-rated inhibitory control (p = .049) compared to controls. Across the whole sample, TNF-α was associated with performance-based (r = −0.25, p = .039) and observer-rated (r = 0.32, p = .009) inhibitory control deficits. In subgroup analyses, TNF-α was associated with increased observer-rated inhibitory deficits in DEP, and at the trend level, with reduced inhibitory control performance in DEP-T.

Conclusions

The current results suggest that inflammation may be a marker of disease processes in adolescent depression. Though longitudinal studies are needed, depressed adolescents with childhood trauma exposure appear to constitute a uniquely vulnerable group in terms of objective risk for executive dysfunction. Immune dysregulation may partly contribute to this risk.

Introduction

There is growing awareness that inflammation affects brain health (Miller and Raison, 2016) and may sub-serve neuropsychological dysfunction in depression (Bollen et al., 2017). Indeed, peripheral inflammation correlates with executive functioning and processing speed in depressed adults (Benson et al., 2017; Goldsmith et al., 2016; Krogh et al., 2014; Smagula et al., 2017). Conceptually, neuropsychological studies converge with neuroimaging, where peripheral cytokines are associated with altered dorsal anterior cingulate (Holmes et al., 2018; Meier et al., 2016; van Velzen et al., 2017), dorsolateral prefrontal cortex (Muscatell et al., 2015), and basal ganglia (Eisenberger et al., 2010; Felger et al., 2016; Haroon et al., 2014, 2016; Savitz et al., 2015; Treadway et al., 2017) structure and function. These brain regions are essential for executive function and common nodes of dysfunctional neurocircuitry in depression (Felger, 2017). It is also appreciated that executive dysfunction is observable in adolescent depression (Joseph et al., 2008; Nieto and Castellanos, 2011; Pavuluri et al., 2009; Wagner et al., 2014), possibly involved in depression risk (Davidovich et al., 2016), and especially pronounced amongst adults with childhood trauma exposure (Marshall et al., 2016). Yet, existing peripheral immune alterations in adolescent depression are somewhat variable, and it is not yet known if inflammation influences executive dysfunction in adolescents, or whether early life trauma affects this possible relationship.

Initial studies of youth with various depressive disorders, including major depression, dysthymia, and suicidality, report alterations in serum cytokine levels (for a review (Mitchell and Goldstein, 2014); also see (Belem da Silva et al., 2017; Pallavi et al., 2015)). The most consistent finding is increased IL-6, whereas evidence for reproducible patterns in other cytokines is equivocal (Kim et al., 2014; Mills et al., 2013; Mitchell and Goldstein, 2014). Studies are heterogeneous and vary in psychiatric medication status (Gabbay et al., 2009; Henje Blom et al., 2012), primary depressive disorder (Brambilla et al., 2004), suicidality (Gabbay et al., 2009; Pandey et al., 2012), childhood trauma (G. E. Miller and Cole, 2012)], and the cytokines of interest. Put together, IL-6 may indeed represent an early sign of immune dysregulation, but the variability in existing designs calls for further exploration of peripheral inflammation in adolescents that accounts for these factors.

While the abovementioned literature suggests that immune dysregulation may be present in depressed adolescents, whether this inflammation relates to the emergence of cognitive deficits typically present in the initial stages of depression is largely unknown (Cullen et al., 2017). A meta-analysis of neuropsychological studies in youth depression identified a domain specific deficit in inhibitory control (Wagner et al., 2015), an aspect of executive function that involves selecting, maintaining, and updating goal representations, while overriding pre-potent responses. Because impaired inhibitory control predicts behavioral, academic, and psychological difficulties (Biederman et al., 2011; Pavuluri et al., 2006; Peters et al., 2014a), it is prudent to understand whether inflammation disrupts development and functioning of inhibitory skills in adolescence.

In understanding the possible role of inflammation in inhibitory control deficits during adolescence, it is essential to consider differences in childhood trauma exposure, which has been implicated in both immune dysregulation and increased risk of inhibitory control deficits. Childhood trauma exposure may increase risk for inhibitory control deficits and inflammation in depression. For instance, in adults, the coupling together of childhood trauma and depression predicts alterations in brain structure and function, including reduced processing speed, attention, and executive function (Quinn et al., 2018; Saleh et al., 2017). Moreover, childhood trauma predicts the co-occurrence of depression and alterations in inflammatory activity later in life (Baumeister et al., 2016a; Coelho et al., 2014; Danese et al., 2007, 2009; Grosse et al., 2014; Lu et al., 2013; Miller and Cole, 2012). However, whether childhood trauma exaggerates inhibitory controls deficits, inflammation, or their co-occurrence during adolescence is unclear. Because brain development is ongoing and uneven during this period, especially in regions essential for regulation of behavior, the adolescent brain may be particularly vulnerable to the effects of early childhood trauma.

To unite these fragmented areas of research, it is important to study inflammation and its role in regulating cognition, both in the context of adolescent depression, childhood trauma, and their combination. In particular, evaluating these constructs during adolescence could help identify a critical period for when and how inflammatory-related mood and cognitive changes develop. Findings cannot be extrapolated from adult studies due to possible contributions of chronic depression burden and comorbidities (Berk et al., 2014; Weisenbach et al., 2014). Adolescence is a compelling window due to (a) minimized confounds of prolonged illness duration, allostatic load, chronic medical co-morbidities, and obesity (Berk et al., 2014; Lopresti and Drummond, 2013); (b) differences in the phenomenology of depression in adolescence, such as increased anhedonia and irritability (Bemporad, 1982; Birmaher et al., 1998); (c) protracted period of cognitive development that differs in maturity and plasticity from adults (Brooks et al., 2010; Hongwanishkul et al., 2005; Huizinga et al., 2006), and d) differences in cytokine production (Lilic et al., 1997).

To address these gaps in the literature, we measured three of the most extensively studied pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and inhibitory control (performance-based and observer-rated) amongst adolescents with depressive disorders (naïve to psychotropic treatment for their mood disorder), with and without exposure to significant childhood trauma, and healthy control (HC) adolescents. These cytokines, in particular, were selected because IL-6 and TNF-α negatively impact serotonin production and integrity (Linthorst et al., 1995), which may increase risk for depression. Further, the release of TNF-α, as well as IL-1β, is thought to induce synaptic pruning, leading to impaired neuroplasticity and structural brain changes that then negatively impact cognition (Rosenblat et al., 2014). Consistent with the Research Domain Criteria Framework (RDoC), our sampling strategy aimed to capture the full range of negative mood disturbance, including major depression, dysthymia, adjustment disorder with depressed mood, and depression not otherwise specified diagnoses. The first aim was to compare groups in inflammation. We expected elevated cytokines in depressed adolescents, especially those with childhood trauma, relative to HC. The second aim was to compare groups in inhibitory control. We predicted inhibitory control deficits in depressed adolescents, especially those with childhood trauma, relative to HC. The third aim was to evaluate associations between inflammation and inhibitory control. We anticipated that inflammation would predict poorer inhibitory control, and that this association would be strongest in depressed adolescents with childhood trauma.

Section snippets

Participants and procedures

This study was designed in-line with the RDoC initiative and supported by the National Institute of Mental Health. All study procedures were approved by the appropriate Institutional Review Board. Participants were assenting adolescents (and their consenting parent), ages 12–17 with any depressive mood disorder (DEP: depression, dysthymia, adjustment disorder with depressed mood, sub-threshold and unspecified depressive symptoms [n = 40]) and HC (n = 30) adolescents with no psychiatric history,

Childhood trauma exposure

Twenty-two DEP met threshold for significant maltreatment, forming a sub-group of DEP with childhood trauma history (DEP-T). We note that this classification was not altered when using slight variations in the cut-offs reported in select prior studies (Bevilacqua et al., 2012; Walker et al., 1999). The cluster solution identified the same subset of twenty-two DEP-T as most similar to each other relative to DEP-only and HCs. Of note, one additional HC participant reported CTQ score above

Discussion

In this study, depressed adolescents with and without a history of childhood trauma and naïve to pharmacological treatment for depression showed higher serum levels of IL-6 compared to HCs. Adolescents with depression and no trauma history demonstrated elevated TNF-α. Additionally, DEP-T demonstrated deficits in inhibitory control. Increased TNF-α was associated with poorer inhibitory control. Moreover, there was a trend to suggest that the association between TNF-α and performance-based

Summary and clinical implications

In sum, both immune function and childhood trauma impact inhibitory control early in the disease process of adolescent depression. The coupling of early childhood adversity and depression may potentiate a phenotype of executive dysfunction, which may be partly related to inflammation. Specifically, TNF-α may be a target of interest, which if demonstrated in future studies, could have clinical applications for anti-inflammatory therapy. More broadly, the findings contribute to an emerging

Previous presentation of data

May 2018 Meeting of the Society for Biological Psychiatry.

Conflicts of interest

None of the authors have conflicts of interests to report.

Disclosures

None.

Acknowledgements

This research was designed under and supported by the National Institute of Mental Health F31 MH108258-01 (ATP) and the American Psychological Foundation (ATP). Additional laboratory support for the current study was also provided by R01 MH098554 (GNP). ATP is currently supported by T32 MH 112485-1.

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