Hippocampal volume and depression among young children
Introduction
Clinical depression has been validated to manifest as early as age 3 (Egger and Angold, 2006, Luby et al., 2009a, 2002, Luby et al., 2003, Luby et al., 2004), with prevalence rates similar to those found at school age (1–2%) (Egger and Angold, 2006, Gleason et al., 2011, Lavigne et al., 2009, Wichstrom et al., 2012). Importantly, young children with this preschool onset form of Major Depressive Disorder (PO-MDD) show many of the same clinical features as adults (Luby et al., 2009a, 2009b), including sad mood, excessive guilt, a reduction in the ability to experience pleasure (anhedonia), and disrupted sleep and eating. Further, PO-MDD shows homotypic continuity, such that young children with depression are at increased risk of depression at school age (Gaffrey et al., 2018b, Luby et al., 2009b).Importantly, there is also growing evidence that children with PO-MDD show many of the same disruptions in neural systems found in adolescents and adults with MDD (Belden et al., 2016, Gaffrey et al., 2017a). The goal of the current study is to test hypotheses about the continuity of PO-MDD with depression that onsets later in childhood or adulthood in terms of similar neural alterations, with a specific focus on hippocampal volume, a structural difference robustly associated with MDD in older children, adolescents and adults (McKinnon et al., 2009, Santos et al., 2018b, Schmaal et al., 2016, Wise et al., 2017, Zhao et al., 2014).
A growing body of literature examining very young children with depression (e.g., ages 3–7) has begun to show evidence of disruptions in brain structure and function similar to those seen in older individuals with depression (Belden et al., 2016, Gaffrey et al., 2018a, Whalen et al. 2019). One neural difference robustly associated with major depression in adults is a reduction in hippocampal volume, as confirmed by numerous meta-analyses (McKinnon et al., 2009, Santos et al., 2018b, Schmaal et al., 2016, Wise et al., 2017, Zhao et al., 2014). However, there is debate as to the nature of the relationship between MDD and hippocampal volume. Some have argued that hippocampal volume reductions potentially occur prior to the onset of MDD and contribute to risk for depression. For example, it has been argued that early life adversity, poverty, and stress contribute to disruptions in hippocampal structure and function (Hanson et al., 2011, Johnson et al., 2016, Luby et al., 2013), that in turn contribute to dysregulated function of the hypothalamus-pituitary-adrenal (HPA) axis and disordered emotional regulation, which in turn contribute to risk for depression (Anacker et al., 2014, Frodl and O'Keane, 2013, Lajud and Torner, 2015, Pagliaccio and Barch, 2019, van Bodegom et al., 2017). The hippocampus is important for regulating the response to stress via the inhibition of the hypothalamus-pituitary-adrenal (HPA) axis through the presence of glucocorticoid receptors that are part of a negative feedback loop (Frodl and O'Keane, 2013). This hypothesis that hippocampal impairments are part of the path to risk for depression is consistent with findings of reduced hippocampal volume even among first episode patients with depression (Cole et al., 2011), though not every study has found this (McKinnon et al., 2009, Schmaal et al., 2016). Further, this hypothesis is consistent with work that has found hippocampal volume reductions even among school age children and adolescents with depression (McKinnon et al., 2009, Rao et al., 2010), as well as among individuals at high risk for depression but whom have not yet experienced an episode of clinically diagnosable depression (Rao et al., 2010). This hypothesis would predict that we should see reductions in hippocampal volume even among young children with depression, though it may be that the magnitude of such reductions covary with the severity of clinical depression in children.
However, it has also been argued that hippocampal volume deficits emerge as a function of experience with depression, potentially reflecting a type of neuro-toxicity associated with a cumulative history of stress and adversity, disrupted emotion regulation, stress reactivity and excessive HPA mediated glucocorticoid release (Sheline, 1996, Sheline, 2011). This latter hypothesis is consistent with evidence that hippocampal volume reductions are even more apparent among individuals with longer illness duration or more than one episode of MDD (Cheng et al., 2010, McKinnon et al., 2009, Sheline et al., 1999, 1996). This hypotheses would suggest that we might not see reductions in hippocampal volume among children with depression, as reductions might only emerge after children have experienced a longer duration of depression or repeated episodes. In prior work with a different sample of children with depression followed through school age and adolescence, evidence was found for reductions in hippocampal volume at school age/preadolescence (8–12 years old) among children who had experienced early signs and symptoms of depression during the pre-school period (Suzuki et al., 2013). However, to our knowledge, no one has examined whether reductions in hippocampal volume are related to depression in very young children, when they first experience depression.
The hypothesis that hippocampal deficits contribute to risk for depression would suggest that we should see a relationships between depression and hippocampal volume even in very young children with depression. However, the hypothesis that the experience of depression contributes to hippocampal deficits suggests that we might not see such a relationship in young children with PO-MDD. Thus, the goal of the current study was to examine whether depression severity would be related to hippocampal volume even among preschoolers. To do so, we used structural MRI data acquired from a unique sample of 4–7 years old children who were participating in a randomized clinical trial of a novel treatment for PO-MDD called Parent-Child Interaction Therapy-Emotion Development (PCIT-ED) (Luby et al., 2018) as well as young children recruited from the community. Given the evidence reviewed above that children with preschool onset depression show many of the same neural differences seen in older children, adolescents, and adults with depression, we hypothesized that we would see reductions in hippocampal volume associated with depression in very young children. Further, we hypothesized that these relationships would be present even when controlling for whole brain volume, which would suggest evidence of specificity. We also examined whether hippocampal volume deficits associated with depression remained when controlling for early stress/adversity factors such as life events or poverty. As noted above, one hypothesis about the role of hippocampal volume reduction in depression is that it reflects experiences with early stress and adversity that disruption hippocampal contributions to stress reactivity and emotion regulation, putting children at risk for depression. If so, then it is possible that life-events and poverty will be more strongly related to hippocampal volume than depression, and will account for any relationship between hippocampal volume and depression.
Section snippets
Participants
Children (aged 3.0–6.11) were either participants in a single-blind randomized control trial (RCT) of PCIT-ED compared to a waitlist (WL) control or they were community children. Analyses of the primary depression outcome measures are reported elsewhere (Luby et al., 2018). Further details about recruitment are provided in the Supplemental Materials. Inclusion criteria for the RCT were: (1) meeting early onset major depressive disorder (MDD) symptom criteria on the K-SADS-early childhood (see
Demographic and clinical characteristics
The demographic and clinical characteristics of the children in the PCIT-ED RCT and the community children are shown in Table 1. There were a total of 35 children who provided 45 scan observations, though as noted above, the analyses described below provided essentially the same results when only one observation per child was used.
Relationship between CBCL depression and hippocampal volume
CBCL Depression T-scores were significantly associated with reduced hippocampal volume across all children (Table 2A and Fig. 1), even when controlling for total gray
Discussion
The goal of the current study was to examine whether hippocampal volume reductions would be associated with depression severity even very early in childhood. We found that greater depression severity was associated with reduced hippocampal volume, both in the combined group of children with PO-MDD and community children, and within just the PO-MDD children. These data are the first to show evidence of hippocampal volume reductions at first onset of depression in very young children with more
Funding, acknowledgments and financial disclosures
Conflict of interest disclosures
Dr. Luby receives royalties from Guildford Press. No other authors report disclosures.
Funding/support
This work was supported by the National Institute of Mental Health, grant # 5R01MH098454 and K23MH115074 and K23 MH118426.
Role of the funder/sponsor
The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.
Additional contributions
We thank the families participating in this study and the staff who helped make the project a success.
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