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The associations among hippocampal volume, cortisol reactivity, and memory performance in healthy young men
Psychiatry Research: Neuroimaging 155 (2007) 1 – 10 www.elsevier.com/locate/psychresns
The associations among hippocampal volume, cortisol reactivity, and memory performance in healthy young men Marita Pruessner a,b,⁎, Jens C. Pruessner b , Dirk H. Hellhammer c , G. Bruce Pike d , Sonia J. Lupienb a
Prevention and Early Intervention Program for Psychoses, Douglas Hospital Research Center, 6875 Boulevard LaSalle, Verdun, Montreal, Quebec, Canada H4H 1R3 b Center for Studies on Human Stress, Douglas Hospital Research Center, McGill University, 6875 Boulevard LaSalle, Verdun, Montreal, Quebec, Canada H4H 1R3 c Center for Psychobiological and Psychosomatic Research, University of Trier, Johanniterufer 15, 54290 Trier, Germany d McConnell Brain Imaging Centre, Montréal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4 Received 22 April 2006; received in revised form 20 October 2006; accepted 23 December 2006
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. Stressinduced 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. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Hippocampus; Magnetic resonance imaging; HPA axis; Psychosocial stress; Awakening response; Cognition
1. Introduction ⁎ Corresponding author. Prevention and Early Intervention Program for Psychoses, Douglas Hospital Research Center, Wilson Pavilion, 6875 Boulevard LaSalle, Montreal, Quebec, Canada H4H 1R3. Tel.: +1 514 761 6131x3381; fax: +1 514 888 4458. E-mail address: [email protected] (M. Pruessner).
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
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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, 1999, 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, 2000, 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 contrib-
ute 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
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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.
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associated with higher measures of self-reported stress (Schulz et al., 1998; Pruessner et al., 1999, 2003a; Wust et al., 2000). In the context of the present study, we were interested in the association of this marker for HPA activity with hippocampal volume. In order to minimize the impact of situational effects on the CRA, subjects collected saliva repeatedly (once a week, Wednesday or Thursday) for 4 consecutive weeks. Samples were taken at 0, 30, and 60 min after awakening in the morning with strict reference to the time of awakening. Participants were asked to refrain from drinking caffeinated beverages and smoking before saliva sampling. Furthermore, they were instructed not to brush their teeth before the end of the sampling time in the morning, not to eat or drink in the 10 min before sampling, and to rinse their mouth with water before sampling.
2. Methods 2.4. The Trier Social Stress Test (TSST) 2.1. 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 lefthanded and twelve subjects were right-handed. The study was approved by the research ethics boards of the Montreal Neurological Institute and the Douglas Hospital, and subjects gave written informed consent prior to participation. 2.2. Experimental protocol Subjects collected three saliva samples during the first hour after awakening once a week, over a period of 4 consecutive weeks. Subsequently, subjects reported to the laboratory two times. During the first session, the cortisol response to a psychosocial stress task was determined, and declarative memory was tested before and after stress. The second time, subjects reported to the Brain Imaging Center, where magnetic resonance imaging scans were acquired for hippocampal volume assessment. Details for each experimental part are provided below. 2.3. Cortisol response to awakening (CRA) The pronounced cortisol increase during the first hour after awakening in the morning has been found to be
The “Trier Social Stress Test” (TSST) is an established and highly effective instrument to stimulate activity of the HPA axis (for a recent review, see Dickerson and Kemeny, 2004). In the present study, subjects were asked to deliver a free speech and to perform mental arithmetic in front of a false mirror and a camera. The subject was shown the testing room and was instructed to prepare his speech within 10 min (anticipation phase). Immediately before testing onset, a person in a white lab-coat was introduced to the subject as an expert judging his non-verbal behavior and linguistic skills. Both the “expert” and the experimenter were sitting behind the false mirror during the performance, and it was pretended that the subject's presentation was recorded with the camera. Instructions were given to the subject via a microphone. The actual speech (a pretended job interview) lasted 5 min followed by 5 min of mental arithmetic. A total of eight saliva samples for cortisol assessment were taken 45, 15 min and immediately before the TSST, and immediately, 10, 20, 40 and 60 min thereafter. All subjects were tested between 1300 h and 1500 h in the afternoon. 2.5. Declarative memory assessment Declarative memory was assessed by a cued recall test that has previously been shown to be sensitive to increased basal levels of cortisol (Lupien et al., 1994) as well as to stress-induced cortisol increase (Lupien et al., 1997). This test has been described in detail elsewhere (Lupien et al., 1994). Two parallel lists that each comprised 12 word pairs each (six moderately related and six unrelated word pairs) were presented before and (in counterbalanced order) after the exposure to the TSST. The task was presented on a
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Fig. 1. Comparison of coronal, sagittal and axial (along the long axis of the hippocampus) Magnetic Resonance Imaging sections from two subjects with small (A) and large (B) hippocampi.
laptop computer, and subjects were instructed to read aloud the list of word pairs. Recall for each list was tested within 40 min before and after the TSST. Subjects were presented only one member of the pair and tested for recall of the other member.
hippocampal volume, total gray matter was determined by automatic classification into gray matter, white matter and cerebrospinal fluid (Kamber et al., 1995; Zijdenbos et al., 2002). 2.7. Biochemical analyses
2.6. Hippocampal volume assessment High-resolution T1 weighted anatomical MRI volumes (1 mm isotropic voxels) were acquired on a 1.5 T Siemens Magnetom Vision Scanner. The raw images were transferred to a Silicon Graphics workstation (Silicon Graphics, Mountain View, CA). Pre-processing included correction for image intensity non-uniformities (Sled et al., 1998) and linear stereotaxic transformation (Collins et al., 1994) into coordinates based on the Talairach atlas (Talairach and Tournoux, 1988). Hippocampal volume analysis was performed using the interactive software package DISPLAY developed at the Brain Imaging Center of the Montreal Neurological Institute. This program allows simultaneous segmentation of brain structures in coronal, sagittal and axial orientations and calculates their volumes. Anatomical boundaries used for the hippocampus and a step-by-step segmentation protocol are described in detail elsewhere (Pruessner et al., 2000). As a control measure for
Salivary free cortisol was sampled using the Salivette sampling device (Sarstedt, Rommelsdorf, Germany). Biochemical analysis of the saliva samples was performed using a time-resolved immunoassay with fluorescence detection (DELFIA; Dressendorfer et al., 1992). Interassay and intra-assay coefficients of variance were below 12% and 10%, respectively, for all analyses. 2.8. Statistical analyses Since a normal distribution could not be expected in a small sample size, Spearman's rank correlation tests were used to assess the associations among hippocampal volume, memory performance, and cortisol levels. In order to obtain single cortisol values to enter into the correlational analyses, first the Area Under the Curve (Pruessner et al., 2003b) was calculated for the cortisol response to the TSST and for each of four cortisol assessments to awakening. Then, to obtain a single
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value that best reflects the individual's cortisol response to awakening and to reduce the number of multiple comparisons, the median of the four AUC measures in the morning was calculated. 3. Results 3.1. 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 b 0.02). Mean cortisol levels after awakening increased from 17.9 at awakening to 26.4 at 30 min (t = −3.37; P b 0.01). Cortisol responses to awakening and to the TSST were not significantly related (P N 0.2). Fig. 1 contrasts coronal, sagittal and axial sections of the hippocampus (roughly outlined in white) in the two subjects with the largest (R: 4.86 cm3 and L: 4.53 cm3) and smallest hippocampi (R: 3.64 cm3 and 3.44 cm3). All images are in standard stereotaxic space. Coronal and sagittal images for both subjects show the same x y coordinates. Axial images are in an angle along the long axis of the hippocampus. In order to test the association between hippocampal volume and the cortisol response to the TSST, Spearman correlations were calculated between the mean hippocampal volume and AUC cortisol levels during the TSST. We found a significant positive correlation (r = 0.62, P = 0.02; N = 13; see Fig. 2) showing that
Fig. 2. Spearman correlation between mean hippocampal volume and cortisol levels (Area Under the Curve with respect to ground; AUCg) obtained in response to the Trier Social Stress Test (TSST); r = 0.62; P b 0.02; N = 13.
Fig. 3. Spearman correlation between hippocampal volume and cortisol levels obtained in response to awakening (AUCg; median over four weekly testing times); r = 0.60; P b 0.03; N = 13.
individuals with larger hippocampal volumes presented a greater increase in cortisol in response to stress than individuals with smaller hippocampal volumes. The correlation between cortisol AUC and hippocampal volume was significant for both hemispheres (r = 0.63; P b 0.02 for the left and r = 0. 60; P b 0.03 for the right hippocampal volume; N = 13). Our analysis also revealed a positive correlation between mean hippocampal volume and the cortisol response to awakening (r = 0.60; P b 0.03; see Fig. 3). When looking at the hemispheres separately, the effect was significant for the right hippocampus (r = 0.62; P b 0.02), but not for the left (P N 0.20). 3.2. Hippocampal volume and memory performance Two-tailed t-tests revealed that memory performance on the related and unrelated word pairs did not differ before and after stress (88.5% vs. 90.3% for the related pairs and 55.1% vs. 50.69% for the unrelated pairs [all P N 0.1]). Since performance for the unrelated pairs was at chance level, subsequent results will only be reported for the related word pairs. Cognitive performance before and after the TSST was not related to the cortisol response to the stress task or to awakening (all P N 0.1). Spearman correlations were calculated to test the association between hippocampal volume and memory performance before and after stress. In line with previous studies in young subjects (Chantome et al., 1999; Foster et al., 1999), we found a significant negative correlation between hippocampal volume and pre-stress memory performance on the related word-pairs (r = − 0.56; P = 0.05; see Fig. 4). The negative correlation between hippocampal volume and recall of the related word pairs
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Fig. 4. Spearman correlation between mean hippocampal volume and recall rate in the ‘paired associates’ memory task; r = − 0.56; P b 0.05; N = 13.
was present for both the left (r = −0.61; P b 0.03), and right hippocampal volume (r = −0.55; P b 0.05). The negative correlation between hippocampal volume and memory performance previously observed before stress (r = −0.56) was not significant when assessed after exposure to stress (r = −0.05). 3.3. Total gray matter, cortisol response and memory performance Total gray matter (GM) was calculated as a control region to hippocampal volume. Gray matter was not related to the cortisol response to awakening, the awakening cortisol response or to memory performance (all P N 0.2). 4. 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 exposure to a stressor. At first glance, our results seem surprising, since they appear to contradict previous findings showing a negative association between hippocampal volume and basal cortisol levels (Sapolsky et al., 1986; Starkman et al., 1992; O'Brien et al., 1996; Sheline et al., 1996; Lupien et al., 1998; Sapolsky, 2000a). At closer inspection
however, a number of recent studies allow to at least question the previously observed linear negative association between cortisol levels and hippocampal volume. In a study with rodents, hippocampal damage did not lead to a corticosterone hypersecretion and a decrease in negative feedback function of the structure (Tuvnes et al., 2003). In a study with aged non-human primates, chronic high-dose cortisol administration over 12 months did not have an effect on hippocampal volume (Leverenz et al., 1999). In human subjects, maltreated children with PTSD did not show reductions in hippocampal volume (De Bellis et al., 2001), and a study in healthy pre-adolescent children did not find the expected negative association between cortisol levels and hippocampal volume (Wiedenmayer et al., 2006). Here, it has to be noted that because of the low density of GR receptors in the primate hippocampus, it can be expected that stress effects on the hippocampus in the primate brain are less severe than those observed in rodents (Sanchez et al., 2000). Also, the direction of the association between cortisol levels and hippocampal volume is debated, since research in twins suggest that smaller hippocampal volume could be a pre-existing vulnerability factor for the development of a pathological stress response (Gilbertson et al., 2002). It is also possible that the different results are related to the different markers of HPA activity used in each study. In the present study reactive cortisol levels (to a psychological stress as well as to awakening) were assessed whereas other studies have assessed diurnal or 24-h cortisol levels or cortisol levels at pre-defined times. Indeed, two recent studies report a missing awakening response but a normal diurnal cortisol profile in patients with hippocampal lesions or amnesia, suggesting a different significance of both measures (Buchanan et al., 2004; Wolf et al., 2005). Another way to explain the current results obtained in a young healthy population is to consider that a cortisol response is beneficial and essential in helping the body to cope with a challenging situation (Selye, 1936; Mason, 1968; Sapolsky, 2000b). In a young healthy population, both a pronounced cortisol response to acute stress and to awakening, along with a large hippocampus could be regarded as parts of a healthy and functional HPA system, allowing successful adaptation to short-term stress. Thus, a positive correlation between cortisol and hippocampal volume appears plausible. In our group, all cortisol levels were recorded in a non-pathological range (Thomas, 1992), and mean hippocampal volumes correspond to earlier findings for young adulthood (Pruessner et al., 2001). The finding of a negative relationship between hippocampal volume and memory performance in
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young healthy subjects is supported by a recent metaanalysis (Van Petten, 2004) showing that in children and young adults, the correlation between hippocampal volume and memory performance is negative, while in older populations the correlation becomes positive. The authors discuss different mechanisms that might determine the correlation between hippocampal volume and memory performance in young and older populations. In healthy young people, the factor explaining the observed negative correlation between hippocampal volume and memory could be the degree of neural pruning that has taken place during childhood and adolescence. In older people, the factor explaining the observed positive correlation between hippocampal volume and memory could be the degree of hippocampal atrophy that has taken place as a result of aging. Indeed, many studies have reported significant negative correlations between age and hippocampal volume (Gur et al., 1991; Goldstein et al., 2001; Good et al., 2001; Pruessner et al., 2001), suggesting that there is a gradual loss of hippocampal tissue with aging. However, it has to be noted that some recent studies fail to find a significant positive relationship between hippocampal volume and declarative memory performance in healthy elderly control subjects (Petersen et al., 2000; Basso et al., 2006). Finally, another factor could be responsible for the negative correlation between memory and hippocampal volume that was not mentioned in the Van Petten study: the relationship of the hippocampal structure to other structures in the brain. In the case where a normal sized hippocampus is situated in a brain with small frontal lobes, the normalization (or correction for intracranial volume) would lead to an overrepresentation of the hippocampus. Thus, a seemingly larger hippocampus would go along with smaller memory performance that might be due to small frontal lobes. To control for this methodological issue, future studies should report raw volumes together with the corrected ones. The finding that cognitive performance was not related to cortisol levels and did not differ before and after stress could be due to the fact that encoding and retrieval were not assessed separately and that for the second task, cortisol levels were already increased at the time of encoding. This is in line with the finding that where cortisol was administered before learning, cortisol effects were not present (Het et al., 2005). Interestingly, the negative correlation between hippocampal volume and declarative memory performance that was obtained before exposure to stress was absent when participants were tested after exposure to stress, at a time of endogenous elevations of cortisol. It is possible that exposure to stress affects memory processes
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differently in young individuals with small versus large hippocampal volumes. However, the small sample size of this study did not allow us to perform a mediansplit analysis to test this association. Given the previously observed inverted-U shape function between circulating levels of cortisol and memory performance in humans (Lupien et al., 1999, 2002a,b), it can be also be speculated that a large hippocampus requires increased cortisol concentrations for optimal functioning, perhaps due to a greater number of GC receptors. Circulating GCs bind with high affinity to two GC receptor subtypes: the mineralocorticoid receptors (MRs) and the glucocorticoid receptors (GRs). Although both receptor types have been implicated in mediating GC feedback effects (see Reul and de Kloet, 1985), MRs bind GC with an affinity that is about 6- to 10 times higher than that of GRs. Recent human studies have shown that memory performance is at optimal levels when GC concentrations are mildly elevated, ie. when the ratio of MR/GR occupation is high (Lupien et al., 2002a, b). In contrast, decreased memory ability is observed when MR occupancy is very low (Lupien et al., 2002a,b; Maheu et al., 2004) or when GRs occupancy is elevated (Lupien et al., 1999). However, we are not aware of any evidence for a positive relationship between hippocampal volume and GC receptor numbers. Despite the small sample size of this study, we consider our data relevant, since a strong relationship with hippocampal volume has been shown for both the cortisol response to awakening and to acute stress. Furthermore, our testing group was fairly homogeneous since it consisted of only male subjects in a similar age range and with similar educational background. Including female subjects would have introduced considerably more variability in cortisol measures due to menstrual cycle phase (Kirschbaum et al., 1999). On the other hand, the small number of only male subjects requires that the current results be considered preliminary. The fact that we have recently observed low hippocampal volumes in young healthy men with low self-esteem and high cortisol stress responses in another study calls for further caution (Pruessner et al., 2005). Future studies should include larger groups of participants and both genders, controlling for menstrual cycle phase in women. Comparing men and women will be important given that hippocampal volume loss with age is greater in men compared to women (Pruessner et al., 2001) and that men present a greater stress-induced GC increase in response to the TSST when compared to women (Kirschbaum et al., 1999). In order to gain a better understanding of the relationships among cortisol levels, hippocampal
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volume and declarative memory performance over the life span, individuals of different ages should also be included and/or a longitudinal study should be designed. A better understanding of the relationship between HPA activity and hippocampal volume can be expected to help our understanding and to guide further research of these factors in disorders like depression or schizophrenia. 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. References Andreano, J.M., Cahill, L., 2006. Glucocorticoid release and memory consolidation in men and women. Psychological Science 17, 466–470. Basso, M., Yang, J., Warren, L., MacAvoy, M.G., Varma, P., Bronen, R.A., van Dyck, C.H., 2006. Volumetry of amygdala and hippocampus and memory performance in Alzheimer's disease. Psychiatry Research. Neuroimaging 146, 251–261. Bohbot, V.D., Kalina, M., Stepankova, K., Spackova, N., Petrides, M., Nadel, L., 1998. Spatial memory deficits in patients with lesions to the right hippocampus and to the right parahippocampal cortex. Neuropsychologia 36, 1217–1238. Buchanan, T.W., Lovallo, W.R., 2001. Enhanced memory for emotional material following stress-level cortisol treatment in humans. Psychoneuroendocrinology 26 (3), 307–317. Buchanan, T.W., Kern, S., Allen, J.S., Tranel, D., Kirschbaum, C., 2004. Circadian regulation of cortisol after hippocampal damage in humans. Biological Psychiatry 56, 651–656. Buchanan, T.W., Tranel, D., Adolphs, R., 2006. Impaired memory retrieval correlates with individual differences in cortisol response but not autonomic response. Learning and Memory 13 (3), 382–387. Cahill, L., Gorski, L., Le, K., 2003. Enhanced human memory consolidation with post-learning stress: interaction with the degree of arousal at encoding. Learning and Memory 10, 270–274. Chantome, M., Perruchet, P., Hasboun, D., Dormont, D., Sahel, M., Sourour, N., Zouaoui, A., Marsault, C., Duyme, M., 1999. Is there a negative correlation between explicit memory and hippocampal volume? NeuroImage 10, 589–595. Cho, K., 2001. Chronic ‘jet lag’ produces temporal lobe atrophy and spatial cognitive deficits. Nature Neuroscience 4, 567–568. Collins, D.L., Neelin, P., Peters, T.M., Evans, A.C., 1994. Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. Journal of Computer Assisted Tomography 18, 192–205. Corcoran, C., Walker, E., Huot, R., Mittal, V., Tessner, K., Kestler, L., Malaspina, D., 2003. The stress cascade and schizophrenia: etiology and onset. Schizophrenia Bulletin 29, 671–692. De Bellis, M.D., Hall, J., Boring, A.M., Frustaci, K., Moritz, G., 2001. A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder. Biological Psychiatry 50, 305–309.
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The associations among hippocampal volume, cortisol reactivity, and memory performance in healthy young men Marita Pruessner a,b,⁎, Jens C. Pruessner b , Dirk H. Hellhammer c , G. Bruce Pike d , Sonia J. Lupienb a
Prevention and Early Intervention Program for Psychoses, Douglas Hospital Research Center, 6875 Boulevard LaSalle, Verdun, Montreal, Quebec, Canada H4H 1R3 b Center for Studies on Human Stress, Douglas Hospital Research Center, McGill University, 6875 Boulevard LaSalle, Verdun, Montreal, Quebec, Canada H4H 1R3 c Center for Psychobiological and Psychosomatic Research, University of Trier, Johanniterufer 15, 54290 Trier, Germany d McConnell Brain Imaging Centre, Montréal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4 Received 22 April 2006; received in revised form 20 October 2006; accepted 23 December 2006
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. Stressinduced 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. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Hippocampus; Magnetic resonance imaging; HPA axis; Psychosocial stress; Awakening response; Cognition
1. Introduction ⁎ Corresponding author. Prevention and Early Intervention Program for Psychoses, Douglas Hospital Research Center, Wilson Pavilion, 6875 Boulevard LaSalle, Montreal, Quebec, Canada H4H 1R3. Tel.: +1 514 761 6131x3381; fax: +1 514 888 4458. E-mail address: [email protected] (M. Pruessner).
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
0925-4927/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2006.12.007
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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, 1999, 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, 2000, 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 contrib-
ute 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
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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.
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associated with higher measures of self-reported stress (Schulz et al., 1998; Pruessner et al., 1999, 2003a; Wust et al., 2000). In the context of the present study, we were interested in the association of this marker for HPA activity with hippocampal volume. In order to minimize the impact of situational effects on the CRA, subjects collected saliva repeatedly (once a week, Wednesday or Thursday) for 4 consecutive weeks. Samples were taken at 0, 30, and 60 min after awakening in the morning with strict reference to the time of awakening. Participants were asked to refrain from drinking caffeinated beverages and smoking before saliva sampling. Furthermore, they were instructed not to brush their teeth before the end of the sampling time in the morning, not to eat or drink in the 10 min before sampling, and to rinse their mouth with water before sampling.
2. Methods 2.4. The Trier Social Stress Test (TSST) 2.1. 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 lefthanded and twelve subjects were right-handed. The study was approved by the research ethics boards of the Montreal Neurological Institute and the Douglas Hospital, and subjects gave written informed consent prior to participation. 2.2. Experimental protocol Subjects collected three saliva samples during the first hour after awakening once a week, over a period of 4 consecutive weeks. Subsequently, subjects reported to the laboratory two times. During the first session, the cortisol response to a psychosocial stress task was determined, and declarative memory was tested before and after stress. The second time, subjects reported to the Brain Imaging Center, where magnetic resonance imaging scans were acquired for hippocampal volume assessment. Details for each experimental part are provided below. 2.3. Cortisol response to awakening (CRA) The pronounced cortisol increase during the first hour after awakening in the morning has been found to be
The “Trier Social Stress Test” (TSST) is an established and highly effective instrument to stimulate activity of the HPA axis (for a recent review, see Dickerson and Kemeny, 2004). In the present study, subjects were asked to deliver a free speech and to perform mental arithmetic in front of a false mirror and a camera. The subject was shown the testing room and was instructed to prepare his speech within 10 min (anticipation phase). Immediately before testing onset, a person in a white lab-coat was introduced to the subject as an expert judging his non-verbal behavior and linguistic skills. Both the “expert” and the experimenter were sitting behind the false mirror during the performance, and it was pretended that the subject's presentation was recorded with the camera. Instructions were given to the subject via a microphone. The actual speech (a pretended job interview) lasted 5 min followed by 5 min of mental arithmetic. A total of eight saliva samples for cortisol assessment were taken 45, 15 min and immediately before the TSST, and immediately, 10, 20, 40 and 60 min thereafter. All subjects were tested between 1300 h and 1500 h in the afternoon. 2.5. Declarative memory assessment Declarative memory was assessed by a cued recall test that has previously been shown to be sensitive to increased basal levels of cortisol (Lupien et al., 1994) as well as to stress-induced cortisol increase (Lupien et al., 1997). This test has been described in detail elsewhere (Lupien et al., 1994). Two parallel lists that each comprised 12 word pairs each (six moderately related and six unrelated word pairs) were presented before and (in counterbalanced order) after the exposure to the TSST. The task was presented on a
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Fig. 1. Comparison of coronal, sagittal and axial (along the long axis of the hippocampus) Magnetic Resonance Imaging sections from two subjects with small (A) and large (B) hippocampi.
laptop computer, and subjects were instructed to read aloud the list of word pairs. Recall for each list was tested within 40 min before and after the TSST. Subjects were presented only one member of the pair and tested for recall of the other member.
hippocampal volume, total gray matter was determined by automatic classification into gray matter, white matter and cerebrospinal fluid (Kamber et al., 1995; Zijdenbos et al., 2002). 2.7. Biochemical analyses
2.6. Hippocampal volume assessment High-resolution T1 weighted anatomical MRI volumes (1 mm isotropic voxels) were acquired on a 1.5 T Siemens Magnetom Vision Scanner. The raw images were transferred to a Silicon Graphics workstation (Silicon Graphics, Mountain View, CA). Pre-processing included correction for image intensity non-uniformities (Sled et al., 1998) and linear stereotaxic transformation (Collins et al., 1994) into coordinates based on the Talairach atlas (Talairach and Tournoux, 1988). Hippocampal volume analysis was performed using the interactive software package DISPLAY developed at the Brain Imaging Center of the Montreal Neurological Institute. This program allows simultaneous segmentation of brain structures in coronal, sagittal and axial orientations and calculates their volumes. Anatomical boundaries used for the hippocampus and a step-by-step segmentation protocol are described in detail elsewhere (Pruessner et al., 2000). As a control measure for
Salivary free cortisol was sampled using the Salivette sampling device (Sarstedt, Rommelsdorf, Germany). Biochemical analysis of the saliva samples was performed using a time-resolved immunoassay with fluorescence detection (DELFIA; Dressendorfer et al., 1992). Interassay and intra-assay coefficients of variance were below 12% and 10%, respectively, for all analyses. 2.8. Statistical analyses Since a normal distribution could not be expected in a small sample size, Spearman's rank correlation tests were used to assess the associations among hippocampal volume, memory performance, and cortisol levels. In order to obtain single cortisol values to enter into the correlational analyses, first the Area Under the Curve (Pruessner et al., 2003b) was calculated for the cortisol response to the TSST and for each of four cortisol assessments to awakening. Then, to obtain a single
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value that best reflects the individual's cortisol response to awakening and to reduce the number of multiple comparisons, the median of the four AUC measures in the morning was calculated. 3. Results 3.1. 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 b 0.02). Mean cortisol levels after awakening increased from 17.9 at awakening to 26.4 at 30 min (t = −3.37; P b 0.01). Cortisol responses to awakening and to the TSST were not significantly related (P N 0.2). Fig. 1 contrasts coronal, sagittal and axial sections of the hippocampus (roughly outlined in white) in the two subjects with the largest (R: 4.86 cm3 and L: 4.53 cm3) and smallest hippocampi (R: 3.64 cm3 and 3.44 cm3). All images are in standard stereotaxic space. Coronal and sagittal images for both subjects show the same x y coordinates. Axial images are in an angle along the long axis of the hippocampus. In order to test the association between hippocampal volume and the cortisol response to the TSST, Spearman correlations were calculated between the mean hippocampal volume and AUC cortisol levels during the TSST. We found a significant positive correlation (r = 0.62, P = 0.02; N = 13; see Fig. 2) showing that
Fig. 2. Spearman correlation between mean hippocampal volume and cortisol levels (Area Under the Curve with respect to ground; AUCg) obtained in response to the Trier Social Stress Test (TSST); r = 0.62; P b 0.02; N = 13.
Fig. 3. Spearman correlation between hippocampal volume and cortisol levels obtained in response to awakening (AUCg; median over four weekly testing times); r = 0.60; P b 0.03; N = 13.
individuals with larger hippocampal volumes presented a greater increase in cortisol in response to stress than individuals with smaller hippocampal volumes. The correlation between cortisol AUC and hippocampal volume was significant for both hemispheres (r = 0.63; P b 0.02 for the left and r = 0. 60; P b 0.03 for the right hippocampal volume; N = 13). Our analysis also revealed a positive correlation between mean hippocampal volume and the cortisol response to awakening (r = 0.60; P b 0.03; see Fig. 3). When looking at the hemispheres separately, the effect was significant for the right hippocampus (r = 0.62; P b 0.02), but not for the left (P N 0.20). 3.2. Hippocampal volume and memory performance Two-tailed t-tests revealed that memory performance on the related and unrelated word pairs did not differ before and after stress (88.5% vs. 90.3% for the related pairs and 55.1% vs. 50.69% for the unrelated pairs [all P N 0.1]). Since performance for the unrelated pairs was at chance level, subsequent results will only be reported for the related word pairs. Cognitive performance before and after the TSST was not related to the cortisol response to the stress task or to awakening (all P N 0.1). Spearman correlations were calculated to test the association between hippocampal volume and memory performance before and after stress. In line with previous studies in young subjects (Chantome et al., 1999; Foster et al., 1999), we found a significant negative correlation between hippocampal volume and pre-stress memory performance on the related word-pairs (r = − 0.56; P = 0.05; see Fig. 4). The negative correlation between hippocampal volume and recall of the related word pairs
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Fig. 4. Spearman correlation between mean hippocampal volume and recall rate in the ‘paired associates’ memory task; r = − 0.56; P b 0.05; N = 13.
was present for both the left (r = −0.61; P b 0.03), and right hippocampal volume (r = −0.55; P b 0.05). The negative correlation between hippocampal volume and memory performance previously observed before stress (r = −0.56) was not significant when assessed after exposure to stress (r = −0.05). 3.3. Total gray matter, cortisol response and memory performance Total gray matter (GM) was calculated as a control region to hippocampal volume. Gray matter was not related to the cortisol response to awakening, the awakening cortisol response or to memory performance (all P N 0.2). 4. 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 exposure to a stressor. At first glance, our results seem surprising, since they appear to contradict previous findings showing a negative association between hippocampal volume and basal cortisol levels (Sapolsky et al., 1986; Starkman et al., 1992; O'Brien et al., 1996; Sheline et al., 1996; Lupien et al., 1998; Sapolsky, 2000a). At closer inspection
however, a number of recent studies allow to at least question the previously observed linear negative association between cortisol levels and hippocampal volume. In a study with rodents, hippocampal damage did not lead to a corticosterone hypersecretion and a decrease in negative feedback function of the structure (Tuvnes et al., 2003). In a study with aged non-human primates, chronic high-dose cortisol administration over 12 months did not have an effect on hippocampal volume (Leverenz et al., 1999). In human subjects, maltreated children with PTSD did not show reductions in hippocampal volume (De Bellis et al., 2001), and a study in healthy pre-adolescent children did not find the expected negative association between cortisol levels and hippocampal volume (Wiedenmayer et al., 2006). Here, it has to be noted that because of the low density of GR receptors in the primate hippocampus, it can be expected that stress effects on the hippocampus in the primate brain are less severe than those observed in rodents (Sanchez et al., 2000). Also, the direction of the association between cortisol levels and hippocampal volume is debated, since research in twins suggest that smaller hippocampal volume could be a pre-existing vulnerability factor for the development of a pathological stress response (Gilbertson et al., 2002). It is also possible that the different results are related to the different markers of HPA activity used in each study. In the present study reactive cortisol levels (to a psychological stress as well as to awakening) were assessed whereas other studies have assessed diurnal or 24-h cortisol levels or cortisol levels at pre-defined times. Indeed, two recent studies report a missing awakening response but a normal diurnal cortisol profile in patients with hippocampal lesions or amnesia, suggesting a different significance of both measures (Buchanan et al., 2004; Wolf et al., 2005). Another way to explain the current results obtained in a young healthy population is to consider that a cortisol response is beneficial and essential in helping the body to cope with a challenging situation (Selye, 1936; Mason, 1968; Sapolsky, 2000b). In a young healthy population, both a pronounced cortisol response to acute stress and to awakening, along with a large hippocampus could be regarded as parts of a healthy and functional HPA system, allowing successful adaptation to short-term stress. Thus, a positive correlation between cortisol and hippocampal volume appears plausible. In our group, all cortisol levels were recorded in a non-pathological range (Thomas, 1992), and mean hippocampal volumes correspond to earlier findings for young adulthood (Pruessner et al., 2001). The finding of a negative relationship between hippocampal volume and memory performance in
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young healthy subjects is supported by a recent metaanalysis (Van Petten, 2004) showing that in children and young adults, the correlation between hippocampal volume and memory performance is negative, while in older populations the correlation becomes positive. The authors discuss different mechanisms that might determine the correlation between hippocampal volume and memory performance in young and older populations. In healthy young people, the factor explaining the observed negative correlation between hippocampal volume and memory could be the degree of neural pruning that has taken place during childhood and adolescence. In older people, the factor explaining the observed positive correlation between hippocampal volume and memory could be the degree of hippocampal atrophy that has taken place as a result of aging. Indeed, many studies have reported significant negative correlations between age and hippocampal volume (Gur et al., 1991; Goldstein et al., 2001; Good et al., 2001; Pruessner et al., 2001), suggesting that there is a gradual loss of hippocampal tissue with aging. However, it has to be noted that some recent studies fail to find a significant positive relationship between hippocampal volume and declarative memory performance in healthy elderly control subjects (Petersen et al., 2000; Basso et al., 2006). Finally, another factor could be responsible for the negative correlation between memory and hippocampal volume that was not mentioned in the Van Petten study: the relationship of the hippocampal structure to other structures in the brain. In the case where a normal sized hippocampus is situated in a brain with small frontal lobes, the normalization (or correction for intracranial volume) would lead to an overrepresentation of the hippocampus. Thus, a seemingly larger hippocampus would go along with smaller memory performance that might be due to small frontal lobes. To control for this methodological issue, future studies should report raw volumes together with the corrected ones. The finding that cognitive performance was not related to cortisol levels and did not differ before and after stress could be due to the fact that encoding and retrieval were not assessed separately and that for the second task, cortisol levels were already increased at the time of encoding. This is in line with the finding that where cortisol was administered before learning, cortisol effects were not present (Het et al., 2005). Interestingly, the negative correlation between hippocampal volume and declarative memory performance that was obtained before exposure to stress was absent when participants were tested after exposure to stress, at a time of endogenous elevations of cortisol. It is possible that exposure to stress affects memory processes
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differently in young individuals with small versus large hippocampal volumes. However, the small sample size of this study did not allow us to perform a mediansplit analysis to test this association. Given the previously observed inverted-U shape function between circulating levels of cortisol and memory performance in humans (Lupien et al., 1999, 2002a,b), it can be also be speculated that a large hippocampus requires increased cortisol concentrations for optimal functioning, perhaps due to a greater number of GC receptors. Circulating GCs bind with high affinity to two GC receptor subtypes: the mineralocorticoid receptors (MRs) and the glucocorticoid receptors (GRs). Although both receptor types have been implicated in mediating GC feedback effects (see Reul and de Kloet, 1985), MRs bind GC with an affinity that is about 6- to 10 times higher than that of GRs. Recent human studies have shown that memory performance is at optimal levels when GC concentrations are mildly elevated, ie. when the ratio of MR/GR occupation is high (Lupien et al., 2002a, b). In contrast, decreased memory ability is observed when MR occupancy is very low (Lupien et al., 2002a,b; Maheu et al., 2004) or when GRs occupancy is elevated (Lupien et al., 1999). However, we are not aware of any evidence for a positive relationship between hippocampal volume and GC receptor numbers. Despite the small sample size of this study, we consider our data relevant, since a strong relationship with hippocampal volume has been shown for both the cortisol response to awakening and to acute stress. Furthermore, our testing group was fairly homogeneous since it consisted of only male subjects in a similar age range and with similar educational background. Including female subjects would have introduced considerably more variability in cortisol measures due to menstrual cycle phase (Kirschbaum et al., 1999). On the other hand, the small number of only male subjects requires that the current results be considered preliminary. The fact that we have recently observed low hippocampal volumes in young healthy men with low self-esteem and high cortisol stress responses in another study calls for further caution (Pruessner et al., 2005). Future studies should include larger groups of participants and both genders, controlling for menstrual cycle phase in women. Comparing men and women will be important given that hippocampal volume loss with age is greater in men compared to women (Pruessner et al., 2001) and that men present a greater stress-induced GC increase in response to the TSST when compared to women (Kirschbaum et al., 1999). In order to gain a better understanding of the relationships among cortisol levels, hippocampal
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volume and declarative memory performance over the life span, individuals of different ages should also be included and/or a longitudinal study should be designed. A better understanding of the relationship between HPA activity and hippocampal volume can be expected to help our understanding and to guide further research of these factors in disorders like depression or schizophrenia. 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. References Andreano, J.M., Cahill, L., 2006. Glucocorticoid release and memory consolidation in men and women. Psychological Science 17, 466–470. Basso, M., Yang, J., Warren, L., MacAvoy, M.G., Varma, P., Bronen, R.A., van Dyck, C.H., 2006. Volumetry of amygdala and hippocampus and memory performance in Alzheimer's disease. Psychiatry Research. Neuroimaging 146, 251–261. Bohbot, V.D., Kalina, M., Stepankova, K., Spackova, N., Petrides, M., Nadel, L., 1998. Spatial memory deficits in patients with lesions to the right hippocampus and to the right parahippocampal cortex. Neuropsychologia 36, 1217–1238. Buchanan, T.W., Lovallo, W.R., 2001. Enhanced memory for emotional material following stress-level cortisol treatment in humans. Psychoneuroendocrinology 26 (3), 307–317. Buchanan, T.W., Kern, S., Allen, J.S., Tranel, D., Kirschbaum, C., 2004. Circadian regulation of cortisol after hippocampal damage in humans. Biological Psychiatry 56, 651–656. Buchanan, T.W., Tranel, D., Adolphs, R., 2006. Impaired memory retrieval correlates with individual differences in cortisol response but not autonomic response. Learning and Memory 13 (3), 382–387. Cahill, L., Gorski, L., Le, K., 2003. Enhanced human memory consolidation with post-learning stress: interaction with the degree of arousal at encoding. Learning and Memory 10, 270–274. Chantome, M., Perruchet, P., Hasboun, D., Dormont, D., Sahel, M., Sourour, N., Zouaoui, A., Marsault, C., Duyme, M., 1999. Is there a negative correlation between explicit memory and hippocampal volume? NeuroImage 10, 589–595. Cho, K., 2001. Chronic ‘jet lag’ produces temporal lobe atrophy and spatial cognitive deficits. Nature Neuroscience 4, 567–568. Collins, D.L., Neelin, P., Peters, T.M., Evans, A.C., 1994. Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. Journal of Computer Assisted Tomography 18, 192–205. Corcoran, C., Walker, E., Huot, R., Mittal, V., Tessner, K., Kestler, L., Malaspina, D., 2003. The stress cascade and schizophrenia: etiology and onset. Schizophrenia Bulletin 29, 671–692. De Bellis, M.D., Hall, J., Boring, A.M., Frustaci, K., Moritz, G., 2001. A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder. Biological Psychiatry 50, 305–309.
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