Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression

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Abstract

Early emotional stress is associated with a life-long burden of risk for later depression and stressful life events contribute to the development of depressive episodes. In this study we investigated whether childhood stress is associated with structural brain alterations in patients with major depression (MD). Forty-three patients with MD and 44 age as well as gender matched healthy control subjects were investigated using high-resolution magnetic resonance imaging (MRI). Region of interest analysis of the hippocampus, whole brain voxel-based morphometry (VBM) and assessment of childhood stress was carried out. Significantly smaller hippocampal white matter and prefrontal gray matter volume was observed in patients with MD compared to healthy controls. In particular left hippocampal white matter was smaller in patients, who had emotional childhood neglect, compared to those without neglect. For male patients this effect was seen in the left and right hippocampus. Moreover, physical neglect during childhood affected prefrontal gray matter volume in healthy subjects. Both emotional neglect and brain structural abnormalities predicted cumulative illness duration and there was a significant interaction between emotional neglect and prefrontal volumes as well as hippocampal white matter on the illness course. Childhood neglect resulted in hippocampal white matter changes in patients with major depression, pronounced at the left side and in males. Most interestingly, childhood stress and brain structure volumes independently predicted cumulative illness course. Subjects with both, structural brain changes and childhood emotional neglect seem to be at a very high risk to develop a more severe illness course.

Introduction

Major depression (MD) is one of the most common human diseases, with a lifetime prevalence of 16% and a 12-month prevalence of 6.6% (Kessler et al., 2003). Physical and sexual abuse as well as emotional neglect in early life is associated with a life-long increased burden of risk for later depression (Heim and Nemeroff, 2001). A recent meta-analysis based on 14,250 participants clearly demonstrated that stressful life events have a potent association with the risk of developing depression (Risch et al., 2009). Studies have found that the S-allele of 5-HTTLPR increases the vulnerability to depression only in the presence of significant adverse life events. Relative to homozygous individuals for the L-allele, young adult carriers of the S-allele were more vulnerable to major depression when exposed to adverse events (Caspi et al., 2003, Kendler et al., 2005, Zalsman et al., 2006). However, in the meta-analysis, neither the serotonin transporter genotype nor the interaction between serotonin transporter genotype stress did predict the risk of depression beyond that associated with exposure to negative life events (Risch et al., 2009).

Experimental animal studies concerning depression have shown altered function of the stress axis (Joels et al., 2003) and stress-related neuroplastic changes in the brain (Nestler et al., 2002), which reverse under effective antidepressant treatment (Santarelli et al., 2003). Pre-clinical studies suggest that hyperactivity of the HPA axis and the resulting increased glucocorticoid (GC) levels in the brain (Swaab et al., 2005) might be associated with early stage reversible dendritic remodelling in the C1 and C3 pyramidal granule neurons, paralleled by reversible remodelling of synaptic terminal structures (Sapolsky et al., 1985, Sapolsky et al., 1990, Sousa et al., 2000, Uno et al., 1989). At later stages, in cases of extreme chronic stress, volume decline has been observed in the hippocampal formation, with an increased vulnerability to metabolic insults and even death of the CA3 region (Czeh and Lucassen, 2007, Harlan et al., 2006, Sousa and Almeida, 2002). Prolonged stress and increased levels of glucocorticoids have also been shown to disrupt hippocampal neurogenesis (reviewed in Dranovsky and Hen, 2006, Duman, 2004, Gould and Cameron, 1997) and to increase extracellular glutamate in the prefrontal cortex (Bagley and Moghaddam, 1997), as well as in the regions CA1 and CA3 (Lowy et al., 1993, Venero and Borrell, 1999) of the hippocampus. Convergent evidence suggests that an excess of glutamatergic transmission in the hippocampus may worsen cell damage and, in extreme cases, induce cell death (Sapolsky, 2000, Sapolsky, 2003). However, whether these mechanisms apply to humans and furthermore if so result in changes early during hippocampal development or later during depressive episodes, remains unclear.

In line with this hypothesis neuroimaging studies have demonstrated that the hippocampus is about 4–5% smaller in patients with major depression than in healthy controls and that reduced hippocampal volumes are consistently found in major depression (Campbell et al., 2004, Frodl et al., 2008b, Videbech and Ravnkilde, 2004). Also pediatric patients with familial MDD showed decreased hippocampal volumes indicating that reduced hippocampal volume may be present at very early stages and may be suggestive of a risk factor for developing MDD (MacMaster et al., 2008). In first episode patients with major depression a decrease of hippocampal volume was detected in male patients with MDD (Frodl et al., 2002b). Therefore, gender seems to be an important cofactor and differences between male and female subjects need to be taken into consideration. With respect to the effects that stress has on the hippocampus, one meta-analysis in post traumatic stress disorder (PTSD) found that adults with childhood maltreatment-related PTSD have reduced bilateral hippocampal volume compared with healthy controls, but that this deficit was not seen in children with maltreatment-related PTSD, suggesting hippocampal volume deficits from childhood maltreatment may not be apparent until adulthood (Woon and Hedges, 2008).

On the other hand larger hippocampal volumes predict a better long term clinical outcome (Frodl et al., 2008a) and larger posterior hippocampal volumes foresaw even the response to a treatment trial (MacQueen et al., 2008). Additionally, volumes of other brain regions like the prefrontal cortex, orbitofrontal cortex, gyrus cinguli and the basal ganglia had been found to be reduced in patients with major depression compared to healthy controls (Frodl et al., 2008b).

So far, although shown in animal studies, the association between structural changes in brains of patients with major depression with stress factors has not been clarified. Since decreased hippocampal volumes can even be found in pediatric patients with MDD, changes in the hippocampus may even be driven by childhood stress factors. The aim of this study was to investigate whether reduced hippocampal volumes and overall brain structural changes measured with voxel-based morphometry (VBM) are associated with childhood stress and whether childhood stress and/or hippocampal volume predict cumulative illness duration.

Section snippets

Participants

Forty-three inpatients (age: 18–65 years) being treated for major depression at the Department of Psychiatry and Psychotherapy of the Ludwig-Maximilian University, Munich, were investigated with structural MRI and childhood stress (Table 1). Thirty-two patients were admitted for the first time, 11 had previous hospital admissions because of other severe depressive episodes. Psychiatric diagnoses were made according to DSM-IV criteria and the structured clinical interview for DSM-IV (SCID). They

Results

Age, gender, handedness, height and weight were similar in patients and controls. Patients and healthy controls had the same age ranges since they were age matched one to one within a range of 2 years (Table 1). Patients showed significantly increased values compared to healthy controls for emotional neglect (t = −2.5, df = 1, 85, p = 0.015) and physical neglect (t = −2.9, df = 1, 85, p = 0.004). Sexual abuse, physical abuse, and emotional abuse did not differ significantly between groups (Table 2).

Discussion

Whether and how stress and in particular early life stress influences brain morphology in patients with major depression has been unclear for a long time. It was already known that childhood stress is associated with a life-long burden of risk for later depression (Heim and Nemeroff, 2001) and that it has a potent relationship to the risk of depression (Risch et al., 2009). The present study bridges a gap between clinical as well as animal experimental findings showing that structural brain

Role of funding source

This study was supported by the German Federal Research Ministry within the promotion “German Research Networks in Medicine” as part of the project “German Research Network on Depression”. The grant was a peer reviewed grant and the grant institution did not interfere with the programme.

Author contributions

T.F. planed the study, wrote the manuscript and performed most of the experiments and analysis with help from E.R., E.M. and N.K. were responsible and supervised the collecting and analysing of data. M.R. supervised the neuroimaging investigations.

Conflict of interest statement

The authors declare competing financial interests.

Acknowledgements

This study was supported by the German Federal Research Ministry within the promotion “German Research Networks in Medicine” as part of the project “German Research Network on Depression”, and Elena Reinhold carried out here doctoral thesis within this study. The authors thank Jacqueline Klesing for English-language editing.

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