The associations among hippocampal volume, cortisol reactivity, and memory performance in healthy young men

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Abstract

In aged and pathological populations, reduced hippocampal volume is frequently described in association with impairment of hippocampus-dependent cognitive processes and chronically elevated cortisol levels. Recent studies in young healthy subjects show a negative association between hippocampal volume and memory. The aim of the present study was to investigate the associations among hippocampal volume, cortisol levels and memory performance in a group of healthy young men. Hippocampal volume was determined by manual segmentation of high-resolution 3D Magnetic Resonance Images from 13 subjects. Stress-induced cortisol levels in response to the “Trier Social Stress Test” (TSST) as well as the cortisol response to awakening (CRA) over four weeks were assessed. Declarative memory performance was tested before and after exposure to the TSST. The results show that larger hippocampal volume was associated with a significantly stronger cortisol increase in response to the TSST and a significantly greater CRA. Moreover, larger hippocampal volume was associated with significantly lower memory performance before the TSST. Our results challenge the direction of the frequently observed relationships among hippocampal volume, cortisol reactivity and memory performance and question the relevance of findings in clinical and aged subjects for young healthy populations.

Introduction

The hippocampus is a prominent brain structure studied extensively for its role in cognition and the regulation of the hypothalamic–pituitary–adrenal (HPA) axis. Early evidence for a significant role of the hippocampus in memory processes in humans stems from the observation of profound impairments of memory function in patients who underwent bilateral removal of the hippocampus and neighboring brain areas (Scoville and Milner, 1957, Milner, 1972). More recent studies support the notion of a specific role of the hippocampus for declarative (Squire, 1992, Eichenbaum, 1999) and spatial memory processes (Handelmann and Olton, 1981, Bohbot et al., 1998).

The hippocampus is also critically involved in the regulation of the hormonal response to psychological and physiological challenges. Activation of the HPA axis results in the release of glucocorticoids (GCs; corticosterone in animals and cortisol in humans), which help the body to adapt to stress and maintain homeostasis by a number of metabolic actions (Sapolsky et al., 2000). With its large number of GC receptors, the hippocampus is a primary target site for GCs (De Kloet et al., 1998) and plays a major role in the negative feedback regulation of the HPA axis (Jacobson and Sapolsky, 1991). At the same time, hippocampal function appears to be compromised by elevated GC levels. Acute administration of hydrocortisone or exposure to stress with subsequent cortisol increase can lead to a significant decrease in declarative memory performance (Wolkowitz et al., 1990, Kirschbaum et al., 1996, Lupien et al., 1997, Lupien et al., 1999, Lupien et al., 2002a). Moreover, recent literature suggests the presence of an inverted U-shape relationship between GCs and cognitive performance in young and older individuals, with beneficial effects of moderately elevated GC levels on cognition (Lupien and McEwen, 1997, De Kloet et al., 1999), and impaired memory performance at very low or very high circulating levels of GCs (for a recent review, see Lupien and Lepage, 2001). Whereas memory consolidation seems to be enhanced by elevated cortisol levels (Buchanan and Lovallo, 2001, Roozendaal, 2002, Cahill et al., 2003, Andreano and Cahill, 2006), it is mostly memory retrieval that is compromised (De Quervain et al., 1998, De Quervain et al., 2000, De Quervain et al., 2003, Roozendaal, 2002, Buchanan et al., 2006). The modulatory effect of stress and elevated cortisol levels on memory also seem to depend on the nature and valence of the material to be remembered (Buchanan and Lovallo, 2001, Maheu et al., 2005), the time of day (morning or afternoon), the duration of stress and elevated cortisol levels (chronic or acute), and – in case of GC administration studies – the timing of GC treatment (before learning or before retrieval). For a recent review and meta-analysis on cortisol administration studies see Het et al. (2005).

Chronic hyperactivity of the HPA axis in aging and various clinical conditions such as Alzheimer's disease, Cushing's disease and depression does not only contribute to memory deficits but also appears to be associated with smaller hippocampal volume (Starkman et al., 1992, O'Brien et al., 1996, Sheline et al., 1996, Lupien et al., 1998, Sapolsky, 2000a). Elevated cortisol levels and reduced hippocampal volume have also been observed in schizophrenia and their interplay is assumed to play an important role in etiology and exacerbation of the disease (Walker and Diforio, 1997, Corcoran et al., 2003). Several mechanisms such as disturbances in dendrite branching, reduced neurogenesis and impaired glucose metabolism have been suggested to underlie the smaller hippocampal volume in the presence of excessive GC levels (Reagan and McEwen, 1997, Gould and Tanapat, 1999, Sapolsky, 2000a). Evidence for associations among elevated cortisol levels, memory deficits and reduced hippocampal volume is not restricted to aged and clinical populations. Smaller temporal lobe volume together with spatial memory deficits and elevated cortisol levels was also reported in a group of young female flight attendants characterized by chronic disruption of their circadian rhythms (Cho, 2001).

Only a few studies investigated the relationship between GC levels and hippocampal volume in young healthy subjects. A study by Wolf and collaborators (Wolf et al., 2002) assessed young and older adults for hippocampal volume and baseline cortisol levels. The authors reported an inverse relation between hippocampal volume and 24-h urinary cortisol levels, after controlling for age. However, the association was not investigated separately for young subjects. Another recent study in 17 healthy pre-adolescent children found that cortisol levels between 9:30 and 10:30 in the morning were not associated with HC volume but with regionally specific measures of surface morphology (Wiedenmayer et al., 2006). Both studies did not consider the time of awakening when measuring cortisol levels.

Interestingly, recent studies in young healthy participants report the presence of a negative correlation between hippocampal volume and declarative memory performance (Chantome et al., 1999, Foster et al., 1999). More recently, Van Petten published a meta-analysis on the correlations between hippocampal volume and memory performance across the lifespan (Van Petten, 2004). The results showed that a negative relationship between hippocampal volume and memory was significant for studies with children, adolescents, and young adults, while the association between hippocampal volume and memory performance tended to grow more positive as the age of the sample increased.

Given the previously reported negative association between hippocampal volume and cortisol levels, and the related positive association between hippocampal volume and cognition in older and clinical populations, similar relationships in young healthy individuals can be hypothesized. However, in light of the above reported findings of a negative association between hippocampal volume and cognition in young healthy subjects, it is important to investigate whether the relationship between hippocampal volume and cortisol levels in this age group is also reversed and whether the relationship between hippocampal volume and memory performance could be modulated by stress and elevated cortisol levels. Consequently, in the present study, we assessed the relationships among hippocampal volume, basal and stress-induced cortisol levels, and declarative memory performance before and after exposure to a stressor in a group of healthy young men.

Section snippets

Subjects

Thirteen healthy young male volunteers (university students, age range 19–32 years, mean age 23.85) participated in the study. Any history of neurological or psychiatric disorder and a history of alcohol or drug abuse served as exclusion criteria. Furthermore, subjects had to be medication free at the time of testing. Handedness was assessed with the Edinburgh Handedness Inventory, which revealed that one subject was left-handed and twelve subjects were right-handed. The study was approved by

Hippocampal volume and basal and stress-induced cortisol levels

To test whether the stress test resulted in an increase in cortisol levels, a two-tailed t-test for correlated samples was calculated. Mean cortisol levels (in nmol/l) increased from 12.32 before the TSST to 21.09 ten minutes thereafter (t =  2.65 [DF = 12; N = 13]; P < 0.02). Mean cortisol levels after awakening increased from 17.9 at awakening to 26.4 at 30 min (t =  3.37; P < 0.01). Cortisol responses to awakening and to the TSST were not significantly related (P > 0.2).

Fig. 1 contrasts coronal, sagittal

Discussion

The present study is the first to simultaneously investigate the relationships among hippocampal volume, cortisol reactivity and memory performance in a group of young healthy men. We found that larger hippocampal volume was associated with greater cortisol levels in response to an acute stressor, and in response to awakening in the morning. We also report that a larger hippocampal volume is negatively correlated with memory performance before stress, but not with memory performance after

Acknowledgements

This research study was supported by a grant from the Canadian Institutes of Health Research (CIHR grant #15000) to SJL. SJL's work is funded through an Investigator Award from CIHR Institute of Aging.

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