ArticlePDF AvailableLiterature Review

The effects of stress and stress hormones on human cognition: Implications for the field of brain and cognition

January 2008
Brain and Cognition 65(3):209-37

DOI:10.1016/j.bandc.2007.02.007

Source
PubMed

Authors:

Sonia J Lupien

Université de Montréal

Françoise S Maheu

CHU Sainte-Justine

Mai Thanh Tu

Institut de la statistique du Québec

Alexandra J Fiocco

Toronto Metropolitan University

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In this review, we report on studies that have assessed the effects of exogenous and endogenous increases in stress hormones on human cognitive performance. We first describe the history of the studies on the effects of using exogenous stress hormones such as glucocorticoids as anti-inflammatory medications on human cognition and mental health. Here, we summarize the cases that led to the diagnosis of glucocorticoid-induced 'steroid psychosis' in human populations and which demonstrated that these stress hormones could thus cross the blood-brain barrier and access the brain where they could influence cognition and mental health. We then summarize studies that assessed the effects of the exogenous administration of glucocorticoids on cognitive performance supported by the hippocampus, the frontal lobes and amygdala. In the second section of the paper, we summarize the effects of the endogenous release of glucocorticoids induced by exposure to a stressful situation on human cognition and we further dissociate the effects of emotion from those of stress on human learning and memory. Finally, in the last section of the paper, we discuss the potential impact that the environmental context to which we expose participants when assessing their memory could have on their reactivity to stress and subsequent cognitive performance. In order to make our point, we discuss the field of memory and aging and we suggest that some of the 'age-related memory impairments' observed in the literature could be partly due to increased stress reactivity in older adults to the environmental context of testing. We also discuss the inverse negative correlations reported between hippocampal volume and memory for young and older adults and suggest that these inverse correlations could be partly due to the effects of contextual stress in young and older adults, as a function of age-related differences in hippocampal volume.

Schematic representation of the sensitive volume threshold hypothesis. The arrows represent changes in memory processing during stress as a function of hippocampal volume and age of the participant.

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The eﬀects of stress and stress hormones on human

cognition: Implications for the ﬁeld of brain and cognition

S.J. Lupien

a,*

, F. Maheu

, M. Tu

, A. Fiocco

, T.E. Schramek

Center for Studies on Human Stress, Douglas Hospital Research Center, McGill University, Montreal, Que., Canada

Mood and Anxiety Disorders Program, Emotional Development and Aﬀective Neuroscience Branch,

National Institute of Mental Health, NIH, Bethesda, MD 20892, USA

University of British Columbia, Centre for Community Child Health Research, 480 Oak Street, L408, Vancouver, BC, Canada V6H 3V4

Accepted 21 February 2007

Available online 26 April 2007

Abstract

In this review, we report on studies that have assessed the eﬀects of exogenous and endogenous increases in stress hormones on human

cognitive performance. We ﬁrst describe the history of the studies on the eﬀects of using exogenous stress hormones such as glucocor-

ticoids as anti-inﬂammatory medications on human cognition and mental health. Here, we summarize the cases that led to the diagnosis

of glucocorticoid-induced ‘steroid psychosis’ in human populations and which demonstrated that these stress hormones could thus cross

the blood–brain barrier and access the brain where they could inﬂuence cognition and mental health. We then summarize studies that

assessed the eﬀects of the exogenous administration of glucocorticoids on cognitive performance supported by the hippocampus, the

frontal lobes and amygdala. In the second section of the paper, we summarize the eﬀects of the endogenous release of glucocorticoids

induced by exposure to a stressful situation on human cognition and we further dissociate the eﬀects of emotion from those of stress on

human learning and memory. Finally, in the last section of the paper, we discuss the potential impact that the environmental context to

which we expose participants when assessing their memory could have on their reactivity to stress and subsequent cognitive performance.

In order to make our point, we discuss the ﬁeld of memory and aging and we suggest that some of the ‘age-related memory impairments’

observed in the literature could be partly due to increased stress reactivity in older adults to the environmental context of testing. We also

discuss the inverse negative correlations reported between hippocampal volume and memory for young and older adults and suggest that

these inverse correlations could be partly due to the eﬀects of contextual stress in young and older adults, as a function of age-related

diﬀerences in hippocampal volume.

!2007 Published by Elsevier Inc.

Keywords: Stress; Glucocorticoids; Catecholamines; Memory; Aging; Hippocampus

1. Introduction

Stress is a popular topic these days. A week seldom

passes without hearing or reading about stress and its del-

eterious eﬀects on health. Given this negative impact of

stress on human health, many types of stress management

therapies have been put forward to decrease stress and

thus, promote health. However, there is a great paradox

in the ﬁeld of stress research, and it relates to the fact that

the popular deﬁnition of stress is very diﬀerent from the sci-

entiﬁc deﬁnition of stress. This has left a multitude of peo-

ple and experts talking about, and working on, very

diﬀerent aspects of the stress response.

In popular terms, stress is mainly deﬁned as time pres-

sure. We feel stressed when we do not have the time to per-

form the tasks we want to perform within a given period of

time. This time pressure usually triggers a set of physiolog-

ical reactions that give us the indication that we are

stressed. Although this deﬁnition is certainly accurate

in terms of one component of the stress response, it is

0278-2626/$ - see front matter !2007 Published by Elsevier Inc.

doi:10.1016/j.bandc.2007.02.007

Corresponding author. Fax: +1 514 888 4064.

E-mail address: sonia.lupien@mcgill.ca (S.J. Lupien).

www.elsevier.com/locate/b&c

Available online at www.sciencedirect.com

Brain and Cognition 65 (2007) 209–237

important to acknowledge that in scientiﬁc terms, stress is

not equivalent to time pressure. If this were true, every indi-

vidual would feel stressed when pressured by time. However,

we all know people that seek time pressure in order to per-

form adequately and others that are extremely stressed by

time pressure. This shows that stress is a highly individual

experience that does not depend on a particular event such

as time pressure, but rather, it depends on speciﬁc psycho-

logical determinants that trigger a stress response.

2. What is stress?

Prior to becoming part of our day-to-day conversations,

the term ‘‘stress’’ was used by engineers to explain forces

that can put strain on a structure. For example, one could

place strain on a piece of metal in such a way that it would

break like glass when it reached its stress level. In 1936,

Hans Selye (reproduced in Selye, 1998) borrowed the term

of ‘stress’ from the ﬁeld of engineering and talked about

stress as being a non-speciﬁc phenomenon representing

the intersection of symptoms produced by a wide variety

of noxious agents. For many years, Selye tested various

conditions (e.g., fasting, extreme cold, operative injuries,

and drug administration) that would produce morphologi-

cal changes in the body that were representative of a stress

response, such as enlargement of the adrenal glands, atro-

phy of the thymus, and gastric ulceration. Selye’s view of

the concept of stress was that the determinants of the stress

response are non-speciﬁc, that is, many unspeciﬁc condi-

tions can put strain on the organism and lead to disease,

the same way that many unspeciﬁc conditions can put

strain on a piece of metal and break it like glass.

Not all researchers agreed with Selye’s model, particu-

larly with the notion that the determinants of the stress

response are non-speciﬁc. The reason for this was simple.

While Selye spent his entire career working on physical

stressors (e.g., heat, cold, and pain), we all know that some

of the worst stressors we encounter in life are psychological

in nature, and are induced by our interpretation of events.

For this reason, a physician named John Mason (1968)

spent many years measuring stress hormone levels in

humans subjected to various conditions that he thought

would be stressful in order to describe the psychological

characteristics that would make any condition stressful,

to anyone exposed to it. By summarizing the results of

studies measuring the circulating levels of stress hormones

before and after individuals were exposed to various jobs

or situations that were deemed to be stressful (e.g., air-traf-

ﬁc controllers or parachute jumping), Mason (1968) was

able to describe three main psychological determinants that

would induce a stress response in any individual exposed to

them. Using this methodology, he showed that in order for

a situation to induce a stress response by the body, it has to

be interpreted as being novel, and/or unpredictable, and/or

the individual must have the feeling that he/she does not

have control over the situation. Although this work led to

a general debate between Selye and Mason (Selye, 1975a,

1975b), further studies conﬁrmed that the determinants

of the stress response are highly speciﬁc, and therefore,

potentially predictable and measurable. More recently, a

meta-analysis conﬁrmed the importance of these character-

istics, and added that the presence of a social evaluative

threat to a situation constitutes the fourth characteristic

that leads to physiological stress reactivity in humans

(Dickerson & Kemeny, 2002) (Table 1).

2.1. The relativity of stress

Stress can be absolute (a real threat induced by an earth-

quake in a town, leading to a signiﬁcant stress response in

every person facing this threat) or it can be relative (an

implied threat induced by the interpretation of a situation

as being novel, and/or unpredictable and/or uncontrolla-

ble, for example, a public speaking task; for a complete

review of these concepts, see Lupien et al., 2006). The

body’s response to absolute stressors is adaptive in nature.

Being in or witnessing an accident, confronting a danger-

ous animal, and being submitted to extreme cold or heat

are all examples of absolute stressors that will necessarily

lead to a stress response in the majority (if not the totality)

of individuals when they are ﬁrst confronted with it. These

extreme and particular situations constitute absolute stress-

ors in that, due to their aversive nature, a stress response

has to be elicited for one’s survival and/or well-being. In

our western societies, absolute stressors are rare, but are

nonetheless those that elicit the greatest physiological

response.

Conversely, relative stressors are those events or situa-

tions that will elicit a stress response only in a certain pro-

portion of individuals. Moreover, this response may be

mild or pronounced (Lupien et al., 2006). For example,

having to unexpectedly deliver a videotaped speech may

be very stressful for a given individual, and not at all

for another. Large inter-individual variations in the

Table 1

The four grades of steroid psychosis as described by Rome and Braceland

in 1952

Grade 1 Mild euphoria

Lessened fatigue

Improved concentration

Elevated mood

Grade 2 Heightened euphoria

Flight of ideas

Impaired judgment

Insomnia

Increased appetite

Memory impairment

Grade 3 Anxiety

Phobia

Rumination

Hypomania

Depression

Grade 4 Psychosis

210 S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237

stress-response to psychological challenges have been fre-

quently reported (Hellhammer, Buchtal, Gutberlet, & Kirs-

chbaum, 1997; Kirschbaum & Hellhammer, 1989;

Kirschbaum, Klauer, Filipp, & Hellhammer, 1995a,

1995b, Kirschbaum, Kudielka, Gaab, Schommer, & Hell-

hammer, 1999; Kudielka, Buske-Kirschbaum, Hellham-

mer, & Kirschbaum, 2004a; Kudielka, Schommer,

Hellhammer, & Kirschbaum, 2004b; Lupien et al., 1997;

Pruessner, Hellhammer, Pruessner, & Lupien, 2003; Rohle-

der, Wolf, & Kirschbaum, 2003; Roy, Steptoe, & Kirsch-

baum, 1998). It may be argued that absolute stressors are

closely linked to physiological systems due to their life-

or self-threatening nature. On the contrary, relative stress-

ors, because they are milder or because they necessitate a

cognitive interpretation in order to elicit a response, will

not necessarily lead to a physiological response, and the

presence or absence of a physiological response will depend

on the outcome of the cognitive analysis.

The stressor is the event itself, such as the earthquake in

the case of the absolute stressor, or the public speech in the

case of the relative stressor. The stress response is the

body’s reaction to the event (Selye, 1975a, 1975b, 1998),

and it is this body’s response to stress that is the foundation

for the studies that determined the impact of stress on cog-

nitive function. The reason for this is that the stress hor-

mones that are secreted in response to an absolute or

relative stressor are steroids that can easily cross the

blood–brain barrier and access the brain, where they can

inﬂuence learning and memory by binding to receptors

localized in various brain regions known to be involved

in learning and memory.

2.2. Stress hormones

As presented in Fig. 1, when a situation is interpreted as

being stressful, it triggers the activation of the hypotha-

lamic–pituitary–adrenal (HPA) axis whereby neurons in

the hypothalamus, a brain structure often termed the

‘‘master gland’’, releases a hormone called corticotropin-

releasing hormone (CRH). The release of CRH triggers

the subsequent secretion and release of another hormone

called adrenocorticotropin (ACTH) from the pituitary

gland, also located in the brain. When ACTH is secreted

by the pituitary gland, it travels in the blood and reaches

the adrenal glands, which are located above the kidneys,

and triggers secretion of the so-called stress hormones.

There are two main classes of stress hormones, the glu-

cocorticoids (called corticosterone in animals, and cortisol

in humans), and the catecholamines (adrenaline and nor-

adrenaline). The acute secretion of glucocorticoids and cat-

echolamines in response to a stressor constitutes the

primary mediators in the chain of hormonal events trig-

gered in response to stress. When these two hormones are

secreted in response to stress, they act on the body to give

rise to the ﬁght-or-ﬂight response whereby one would, for

instance, experience an increase in heart rate and blood

pressure (for a review, see Lupien et al., 2006).

Glucocorticoids have a variety of diﬀerent eﬀects in tar-

get systems throughout the organism, which can be sum-

marized as aiming to increase the availability of energy

substrates in diﬀerent parts of the body, and allow for opti-

mal adaptations to changing demands of the environment.

While the activation of the HPA axis can be regarded as a

basic adaptive mechanism in response to change, pro-

longed activation of this system presents a health risk to

the organism. The highly catabolic glucocorticoids antago-

nize insulin and increase blood pressure, thus increasing the

risk for developing diabetes, hypertension, and arterial dis-

ease. Also, growth and tissue repair are impaired. Further-

more, activation of the HPA axis suppresses immune

functions, which in a chronic state can be considered harm-

ful for the organism, since it is associated with increased

risk of infection (for a general review, see McEwen, 1998,

2000).

Given their liposoluble characteristics, the glucocorti-

coids can easily cross the blood–brain barrier and access

the brain where they bind to receptors. Three of the most

important brain areas containing glucocorticoid receptors

are the hippocampus, amygdala, and frontal lobes, which

are brain structures known to be involved in learning and

memory. Although adrenaline does not readily access the

brain, it can still impact the brain through its actions on

the sensory vagus outside of the blood–brain barrier, with

information transmitted into the brain via the nucleus of

the solitary tract. The most important brain area contain-

ing adrenergic receptors is the amygdala, which has been

shown to play an important role in fear processing, and

memory for emotionally relevant information.

Because of their actions on brain structures known to be

involved in fear detection and memory for emotionally rel-

evant information, the stress mediators enhance the forma-

tion of so-called ‘ﬂashbulb memories’ of events associated

with strong emotions, including fear but also positive emo-

Fig. 1. Schematic representation of the hypothalamic-pituitary–adrenal

(HPA) axis. Following the perception of a stressor, the hypothalamus

releases CRF, which activates the pituitary and leads to secretion of

ACTH. The levels of ACTH are detected by the adrenal cortex which then

secretes glucocorticoids and catecholamines (illustration: !Jason

Blaichman).

S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237 211

tions. This process involves the amygdala, and the pathway

for encoding these memories involves the interaction

between neurotransmitters in the amygdala and in related

brain areas such as the hippocampus along with circulating

stress hormones (McGaugh, 2000; Roozendaal, Hahn,

Nathan, de Quervain, & McGaugh, 2004; Roozendaal,

McReynolds, & McGaugh, 2004; van Stegeren, Everaerd,

Cahill, McGaugh, & Gooren, 1998). The importance of

these stress mediators on memory for emotionally relevant

information has been recently conﬁrmed by studies in

which blockade of either glucocorticoids (Maheu, Joober,

Beaulieu, & Lupien, 2004) or noradrenaline (Cahill, Prins,

Weber, & McGaugh, 1994) activity impaired the recall of

emotionally relevant information. Consequently, secretion

of these primary stress mediators is necessary for the ade-

quate encoding of emotionally relevant information. This

enhancement of memory for stimuli inducing stressful

and/or emotional responses may be essential for species’

survival. A recent study published by Zorawski and collab-

orators goes along with this suggestion. They had subjects

participate in a fear conditioning task and assessed the

association between fear-induced increase in cortisol, and

the consolidation of the memory. Results showed that par-

ticipants whose fear learning was accompanied by high cor-

tisol levels presented a better consolidation of this memory.

Interestingly, this eﬀect was more important in men

(Zorawski, Blanding, Kuhn, & LaBar, 2006). Similar gen-

der diﬀerences in the pattern of cortisol activation in

response to fear have recently been observed using func-

tional brain imaging (Stark et al., 2006).

While short-term responses of the brain to novel and

potentially threatening situations may be adaptive and

result in new learning and acquired behavioral strategies

for coping, as may be the case for certain types of fear-

related memories, repeated stress can cause both cognitive

impairments, and structural changes in the hippocampus,

mainly through the actions of glucocorticoids. Conse-

quently, in this paper, we will concentrate our eﬀorts on

describing the eﬀects of glucocorticoids on human cogni-

tive function and their potential impact on studies of brain

and cognition.

2.3. Important characteristics of glucocorticoids

Under basal conditions, glucocorticoid secretion exhib-

its a 24-h circadian proﬁle in which glucocorticoid concen-

trations present a morning maximum in humans (the

circadian peak), and slowly declining levels in the late after-

noon, evening and nocturnal period (the circadian trough),

and an abrupt elevation after the ﬁrst few hours of sleep

(see Fig. 2).

Circulating glucocorticoids bind with high aﬃnity to

two receptor subtypes; the mineralocorticoid (hereafter

called Type I) and glucocorticoid (hereafter called Type

II) receptors. Although both receptor types have been

implicated in mediating glucocorticoid feedback eﬀects,

there are two major diﬀerences between Type I and Type

II receptors. First, Type I receptors bind glucocorticoids

with an aﬃnity that is about 6–10 times higher than that

of Type II receptors. This diﬀerential aﬃnity results in a

striking diﬀerence in occupation of the two receptor types

under diﬀerent conditions and time of day. Thus, during

the circadian trough (the PM phase in humans and the

AM phase in rats), the endogenous hormone occupies

more than 90% of Type I receptors, but only 10% of Type

II receptors. However, during stress and/or the circadian

peak of glucocorticoid secretion (the AM phase in humans

and the PM phase in rats), Type I receptors are saturated,

and there is occupation of approximately 67–74% of Type

II receptors (see Fig. 2).

The second major diﬀerence between these two receptor

types is related to their distribution in the brain. The Type I

receptor is exclusively present in the limbic system, with a

preferential distribution in the hippocampus, parahippo-

campal gyrus, entorhinal, and insular cortices. The Type

II receptor, however, is present in both subcortical (para-

ventricular nucleus and other hypothalamic nuclei, the hip-

pocampus and parahippocampal gyrus) and cortical

structures, with a preferential distribution in the prefrontal

cortex. As we will see in the following sections, the impact

of glucocorticoids on cognitive function can be best under-

stood in terms of the diﬀerential eﬀects of Type I and Type

II receptor activation.

3. Eﬀects of exogenous glucocorticoids on cognition

In an attempt to present the reader with a clear and

complete view of the eﬀects of glucocorticoids on human

cognition, our background will be historical, as we will

present the various models of glucocorticoid-eﬀects on

human cognition as a function of new approaches and

models that have been described from the nineteenth to

the twenty-ﬁrst century. We use this approach for two

main reasons. First, history will teach us that our view

of glucocorticoid eﬀects on human cognition remained

stable from 1970 to 1999, after which time new data

obtained in both animals and humans dramatically mod-

iﬁed our views. Second, because the history of the search

for glucocorticoid eﬀects on cognitive function took place

in many diﬀerent laboratories across the world, sometimes

simultaneously, our historical report of the search for glu-

cocorticoid eﬀects on human cognition will describe one

of the best attributes of this ﬁeld of research, i.e. its rich

multidisciplinary nature.

3.1. The era of clinical descriptions

The study of the eﬀects of glucocorticoids on human

behavior has always been an emotional one, ﬁlled with

debate, reconciliations, and the advancement of science.

The story starts in 1855, when Thomas Addison described

for the ﬁrst time a ‘‘dark skin disease’’, a pigmentary char-

acteristic that he found to be associated with pathological

modiﬁcations of the adrenal glands (Addison, 1855). One

212 S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237

year later, Brown-Se

´quard (1856) showed the importance

of these ‘‘small capsules’’ for an animal’s life and conﬁrmed

Addison’s observations. At about the same time, a debate

exploded at the Socie

´te

´de Biologie de Paris, when Dr.

Bouillaud publicly accused Brown-Se

´quard of only doing

some ‘‘amusing physiology’’, which is said to have pro-

foundly insulted Dr. Brown-Se

´quard. In order to clear

the name of his colleague, Dr. Armand Trousseau came

to the rescue of Brown-Se

´quard at the Socie

´te

´de Biologie

de Paris and defended both his study and the clinical obser-

vations of Dr. Addison. He further proposed to name the

syndrome described by Addison, ‘‘Addison’s disease’’, a

disease that later became a textbook clinical description

(see Olmsted, 1946). In 1889, after Brown-Se

´quard had

succeeded Claude Bernard as professor of medicine at the

Colle

`ge de France, he reported another controversial ﬁnd-

ing to the Socie

´te

´de Biologie de Paris (Brown-Se

´quard,

1889). In experiments performed on himself, he had shown

the rejuvenating eﬀects of testicular extracts from healthy

young guinea pigs (Brown-Se

´quard, 1889). By 1890, an

estimated 12,000 physicians were giving testicular extracts

to their patients, despite the skepticism and embarrassment

expressed by many medical journals (see Olmsted, 1946).

This was the birth of ‘‘organotherapy’’ (see Borell, 1976a;

Borell, 1976b).

Twelve years later, in 1901, Harvey Cushing, known as

the father of neurosurgery, misdiagnosed a patient with

headaches, visual troubles and sexual immaturity as hav-

ing a cerebellar tumor and operated three times in this

location (Cushing, 1913). The patient did not survive. A

couple of months later, Fro

¨hlich described the case of a

young boy with headaches, visual troubles and sexual

immaturity in whom he successfully diagnosed a pituitary

tumor. The patient did survive (see Fulton, 1946). The

disease is now named ‘‘Fro

¨hlich syndrome’’. It is said that

Cushing never really accepted this defeat and always

remained very alert for pituitary tumors and their mani-

festations (Fulton, 1946). This vigilance paid oﬀsince he

described in 1932, at the end of his career, the basophil

tumors of the pituitary, leading to hypersecretion of glu-

cocorticoids (Cushing, 1932). The disease is now named

‘‘Cushing’s disease’’. However, 19 years earlier, in 1913,

Cushing had already described cases of basophil tumors

of the pituitary who presented psychic disturbances

(Cushing, 1913). In his biography, Dr. Cushing reports

that his task had been facilitated by the fact that one of

his ﬁrst patients was in an asylum, due to the psychic dis-

turbances associated with this endocrinological disorder

(Fulton, 1946).

3.2. Glucocorticoids and steroid psychosis

In 1949, a century after Addison’s observation, occurred

what some authors have named the ‘‘most cataclysmic

event in the history of glucocorticoid endocrinology’’

(Munck, Guyre, & Holbrook, 1984), that is, the discovery,

by Hench, Kendall, Slocumb, and Polley (1949), of the

therapeutic eﬀects of glucocorticoids on inﬂammatory dis-

eases such as rheumatoid arthritis and asthma. Regarded

by many scientists and clinicians as the ‘‘wonder drugs’’,

glucocorticoids soon became very popular for the treat-

ment of various inﬂammatory diseases. Besides being

employed in hormone replacement therapy in Addison’s

disease or after adrenalectomy, they have also been used

in treating rheumatoid arthritis, ulcerative colitis, asthma,

Hodgkins’ disease, systemic lupus erythematosus, and var-

ious dermatological disorders (Munck et al., 1984). How-

ever, no more than 2 years after their introduction as

anti-inﬂammatory drugs, the enthusiasm engendered by

glucocorticoids was dampened by the ﬁnding that the ther-

apeutic use of glucocorticoids was followed by several side

eﬀects, particularly on aﬀect and cognition. The ﬁrst case

was published in 1951 by Borman and Schmallenberg

who reported suicide following cortisone treatment (Bor-

man & Schmallenberg, 1951). A year later, three papers

were published reporting severe mental disturbances in

patients under glucocorticoid therapy (Brody, 1952; Clark,

Bauer, & Cobb, 1952; Rome & Braceland, 1952).

The mental side eﬀects of glucocorticoid therapy consti-

tuted a full spectrum of psychotic disorders. Most often,

a ‘‘vitalization eﬀect’’ was observed, particularly in the

aged patient (Kountz, Ackermann, & Kheim, 1953) or in

8am

9am

Cortisol

Time (8am-7am)

Type I/Type II

receptors activation

Type I

activation

10am

11am

12pm

1pm

2pm

3pm

4pm

5pm

6pm

7pm

8pm

9pm

10pm

11pm

12am

1am

2am

3am

4am

5am

6am

7am

Fig. 2. Example of a circadian rhythm of serum cortisol levels. There is an abrupt elevation a few hours before awakening, and slowly declining levels

across the day. At the time of cortisol peak (early AM phase in humans), there is activation of both Type I and Type II glucocorticoid receptors, while at

the time of the cortisol trough (PM phase in humans), there is mainly activation of the high aﬃnity, Type I glucocorticoid receptors.

S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237 213

individuals with reduced vitality due to the underlying

illness (von Zerssen, 1976 cited in von Zerssen, 1976). In

these cases, the patient displayed an elevation of mood,

varying in degree from a feeling of well-being to abnormal

degrees of euphoria, psychomotor activation, increased

appetite and reduced sleep. However, these changes of

mood and behavior were generally observed in the ﬁrst days

or weeks of glucocorticoid therapy (Brody, 1952; Dordick &

Gluck, 1955; Rees, 1953), and it was not clear whether these

signs were related to glucocorticoid actions or to the relief

from severe physical complaints and handicap related to

the underlying disease treated with glucocorticoids (Lidz,

Carter, Lewis, & Surratt, 1952; Rees, 1953).

In a large proportion of patients, euphoria was not pres-

ent in the ﬁrst days or weeks of treatment. Rather, tension,

irritability, and sleeplessness were present. Both the eupho-

ric and dysphoric states could gradually increase to a full-

blown manic episode in which the patient would present

marked euphoria or dysphoria, pronounced self-assertive-

ness, hyperactivity, logorrhea, and ﬂight of ideas (Cobb,

Quarton, & Clark, 1954). These are the mental symptoms

that have led some scientists and clinicians to name the side

eﬀects of glucocorticoid therapy a ‘‘steroid psychosis’’

(Clark et al., 1952; Rome & Braceland, 1952).

There were other types of aberrant behaviors that could

appear with glucocorticoid therapy and these later behav-

iors closely resembled those observed in Cushing’s disease

patients (Trethowan & Cobb, 1952). These mood and

behavioral changes covered a wide range of symptoms

and included feelings of weakness, fatigue and drowsiness,

lack of concentration, apathy, anxiety, depression, and

sometimes suicide as reported by Borman and Schmallen-

berg (1951). These behavioral changes were also associated

with changes in brain activity as measured by EEG. In one

man, glucocorticoid therapy sometimes led to epileptic sei-

zures and even to status epilepticus (Loewenberg, 1954;

Stephen & Noad, 1951). Similarly, some EEG abnormali-

ties were also found in patients with Cushing’s disease

(Glaser, Kornfeld, & Knight, 1955; Plotz, Knowlton, &

Ragan, 1952). On the whole, the clinical descriptions of

cases of steroid psychosis following glucocorticoid therapy

were strikingly similar to the mental disturbances associ-

ated with Cushing’s disease, leading to the idea that gluco-

corticoids might be the underlying causes of steroid

psychosis.

Despite the adverse mental reactions that were reported

to occur in glucocorticoid-treated patients in 1951, it is

interesting to note that at about the same time, these com-

pounds were also being tested for their possible psychotro-

pic properties in the treatment of mental disorders (Rees &

King, 1952). The rationale for testing the possible positive

eﬀects of glucocorticoids on mental disturbances in psychi-

atric patients was the fact that these compounds could

induce euphoric or dysphoric states, and that by doing

so, could potentially reverse mental states in depressed

and schizophrenic patients respectively. However, the

results of these trials were disappointing since neither in

neurotic nor in endogenous psychotic disorders was there

any striking amelioration of the symptoms. In fact, the

reverse was observed in both schizophrenia and depression

(Rees & King, 1952).

Today, however, glucocorticoid-induced mood distur-

bances are recognized and classiﬁed in the DSM-IV as sub-

stance-induced mood disorders, with an associated

speciﬁcation of depressive, manic or mixed features,

throughout history certain authors questioned whether glu-

cocorticoids really could cause psychiatric adverse eﬀects

(Mitchell & Collins, 1984). A meta-analysis of randomized

controlled trials has provided ﬁrm conﬁrmation that they

can indeed (Conn & Poynard, 1994). In general, prednisone

has been most frequently implicated in causing psychiatric

side eﬀects (for a review, see Hall, Popkin, Stickney, &

Gardner, 1979), but other less widely used steroids such

as methylprednisone (Greeves, 1984; Perry, Tsuang, &

Hwang, 1984), dexamethasone (Bick, 1983), and even

inhaled beclomethasone (Annett, Stansbury, Kelly, &

Strunk, 2005; Kreus, Viljanen, Kujala, & Kreus, 1975)

have also been reported to induce mental disturbances.

Most patients exhibiting side eﬀects are between 21 and

60 years of age (Ling, Perry, & Tsuang, 1981), but adverse

mental changes are also being reported in children (Bender

& Milgrom, 1995; de La Riva, 1958; Milgrom & Bender,

1995; Sullivan & Dickerman, 1979), and older individuals

(Varney, Alexander, & MacIndoe, 1984). Finally, females

appear to be at somewhat greater risk than males, even

after controlling for diseases that are more common to

women (Lewis & Smith, 1983). Importantly however, a

recent study showed that in most patients, the cognitive

impairments induced by high doses of exogenous cortico-

steroids are reversible (Brunner et al., 2006).

3.3. Glucocorticoids, the brain, and vigilance

Armed with a large quantity of clinical and psychiatric

data revealing mental disturbances after long-term gluco-

corticoid treatment in patients, researchers then took over

the ﬁeld of human glucocorticoid research, and started to

perform psychopharmacological studies, measuring the

eﬀects of acute administrations of glucocorticoids in nor-

mal individuals.

In 1970, Kopell and collaborators were the ﬁrst to study

the eﬀects of exogenous administrations of glucocorticoids

in human subjects. Averaged event-related potentials

(ERPs) were introduced at approximately the same time

(1968), and based on the rationale that glucocorticoid-ther-

apy could induce changes in EEG activity (Loewenberg,

1954; Stephen & Noad, 1951), Kopell, Wittner, Lunde,

Warrick, and Edwards (1970) measured whether exoge-

nous administrations of glucocorticoids could have a sig-

niﬁcant impact on brain activity. Averaged ERPs reﬂect

electrical activity produced by the brain in response to sen-

sory stimulation and/or activity associated with the execu-

tion of speciﬁc cognitive tasks. Using this paradigm, Kopell

and collaborators found that after glucocorticoid

214 S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237

treatment, ERP amplitudes to visual stimuli were signiﬁ-

cantly decreased. They concluded from these results that

glucocorticoids may have decreased the participants ability

to attend to the stimuli and thus reﬂected a state of hypo-

vigilance. This suggestion corroborated a clinical observa-

tion made by Henkin and collaborators 3 years earlier

(Henkin, McGlone, Daly, & Bartter, 1967) in Addison’s

patients who present very low levels of circulating gluco-

corticoids. These authors described how sensory acuity is

strangely elevated in Addison’s patients and that treatment

of the hypocorticolism with steroids returns sensory acuity

to normal. This led Henkin and collaborators to suggest

that glucocorticoids act by inhibiting the central nervous

system, possibly leading to a state of hypovigilance.

In 1987, Born and collaborators (1987) performed a

study in which they infused glucocorticoids for 2 h, and

measured ERPs to auditory stimulation. They conﬁrmed

the hypovigilance hypothesis and showed a signiﬁcant

reduction in ERP amplitude after glucocorticoid treatment

without changes in behavioral performance. In a second

study a year later, however, the same authors found that

glucocorticoid treatment had enhanced ERP amplitudes

to auditory stimuli (Born, Hitzler, Pietrowsky, Pauschin-

ger, & Fehm, 1988) and improved behavioral performance.

Naturally, such a result would suggest that glucocorticoids

instead increased vigilance, which contradicted the hypo-

vigilance hypothesis described in their earlier paper (Born,

Kern, Fehm-Wolfsdorf, & Fehm, 1987), and others (Kopell

et al., 1970).

Although diﬀerences in methodology could in part

account for these contradictory results (e.g., slight diﬀer-

ences in stimulus intensity) one ﬁrm conclusion reached

by the authors was that glucocorticoids had a signiﬁcant

impact on vigilance (Born et al., 1988). In addition, the dif-

ferential eﬀects observed on behavioral performance and

ERP amplitudes led them to allude to the existence of a

more complex relationship between glucocorticoids and

cognitive processing that could be akin to the notion pro-

posed by Yerkes and Dodson in 1908 (Yerkes & Dodson,

1908) stating that an inverted-U shape curve describes

the relationship between vigilance and cognitive eﬃciency.

Optimal states of vigilance should be related to the optimal

state of cognitive eﬃciency, while signiﬁcant decrease or

increase in vigilance should lead to impaired cognitive

eﬃciency.

3.4. Glucocorticoids, the hippocampus, and declarative

memory

At about the same time, and in very diﬀerent laborato-

ries, researchers were intrigued by the fact that glucocorti-

coid treatment could lead to psychiatric symptoms. Indeed,

for many years, endocrinologists and neuroscientists

thought that hormones, which are biological products,

secreted by peripheral glands, did not access the brain

and acted mainly at the level of the peripheral nervous sys-

tem. However, in the early 1960s, the discovery of neuro-

peptides as substances having not only classical endocrine

eﬀects, but also aﬀecting brain and behavior, signiﬁcantly

extended our view of hormones and opened the door to

new possibilities of hormonal actions on the brain (for a

complete historical background, see de Kloet, 2000). The

observation that glucocorticoid treatment could lead to ste-

roid psychosis suggested that the excessive concentrations

of the steroid may access the brain and exacerbate, perpet-

uate or modify the presentation of mental symptoms asso-

ciated with glucocorticoid administration. Such a

hypothesis was appropriate since in 1943, Harris had com-

pleted a series of landmark anatomical studies that clearly

established that the central nervous system regulates the

HPA axis (Harris, 1972).

The search for brain receptors able to recognize periph-

eral hormones began. In 1968, it culminated with Bruce

McEwen’s seminal Nature paper showing that the rodent

brain was indeed able to recognize glucocorticoids (McE-

wen, Weiss, & Schwartz, 1968). The story then took a very

important detour when McEwen and collaborators

reported that the brain region showing the highest density

of receptors for glucocorticoids was the hippocampus, a

brain region signiﬁcantly involved in learning and memory.

At this point in history, one observes a tremendous

switch in scientiﬁc studies of glucocorticoids from ERP

studies to memory-related studies. The rationale was based

on the fact that the largest amount of glucocorticoid recep-

tors is found in the hippocampus, a structure now known

to be involved in speciﬁc types of memory functions in

humans. Scoville and Milner (1957) were the ﬁrst to report

that the hippocampus is essential for declarative memory,

while it is not essential for non-declarative memory (Squire,

1992). The former underlies the conscious acquisition and

recollection of facts and event, while the latter holds infor-

mation regarding processes and procedures for completing

highly practiced tasks such as riding a bike, (Scoville &

Milner, 1957). Thus, this somewhat specialized role of the

hippocampus served as the basis for speciﬁc hypotheses

regarding the relation between increased cortisol secretion

and impaired cognitive function in humans.

What is very interesting with the history of the search

for glucocorticoid eﬀects on human cognition is that from

now on, scientists will be interested in showing that

glucocorticoids have speciﬁc eﬀects on human declarative

memory function that cannot be explained by glucocorti-

coid-induced changes in vigilance or attention. In general,

the majority of human studies that have measured the

impact of glucocorticoids on cognitive function report

impaired declarative memory function after acute adminis-

trations of synthetic glucocorticoids (for a complete review,

see Lupien & McEwen, 1997).

The ﬁrst study performed on the acute eﬀects of gluco-

corticoids on human memory process was a dose–response

study that showed that the eﬀects of hydrocortisone on

human memory performance depend upon the dose admin-

istered (Beckwith, Petros, Scaglione, & Nelson, 1986). Only

the highest doses of hydrocortisone (40 mg) enhanced

S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237 215

recall when subjects were presented with lists of words.

Hydrocortisone administration in the morning (at the time

of cortisol peak) impaired declarative memory function,

while it had no eﬀect on cognitive performance when

administered at night (Fehm-Wolfsdorf, Reutter, Zenz,

Born, & Lorenz-Fehm, 1993). Kirschbaum, Wolf, May,

Wippich, and Hellhammer (1996) showed that 60 min after

the oral administration of 10 mg of hydrocortisone, declar-

ative memory performance was signiﬁcantly impaired while

non-declarative memory performance remained intact,

thus supporting the view that glucocorticoids aﬀect hippo-

campal-dependent cognitive functions.

More recently, de Quervain, Roozendaal, Nitsch,

McGaugh, and Hock (2000) tested the impact of an acute

increase in glucocorticoids as a function of the nature of

memory processing. High doses of synthetic glucocorti-

coids were administered either before the acquisition of a

list of words, immediately after or just before the retrieval

of the list. The results revealed signiﬁcant impairments in

memory when the drug was administered just before retrie-

val, thus suggesting speciﬁc eﬀects of glucocorticoids on the

retrieval of previously learned information (see also

Domes, Rothﬁscher, Reichwald, & Hautzinger, 2005).

A speciﬁc eﬀect of acute glucocorticoid elevations on

retrieval processes in humans has recently been replicated

by Wolkowitz et al. (1990). Young and older men were

given a medium dose of synthetic glucocorticoids after hav-

ing learned a list of 10 words. A second word list was

learned and recalled after drug administration. Results

showed that glucocorticoids impaired recall of the word list

learned before treatment in both groups but did not inﬂu-

ence recall of the list learned after treatment. These results

agree with previous data showing that acute exogenous

administrations of glucocorticoids have impairing eﬀects

on retrieval processes (de Quervain et al., 2000).

The in vivo demonstration of glucocorticoid eﬀects on

memory retrieval processes was recently performed by the

group of de Quervain et al. (2003) using positron emission

tomography (PET). Young subjects were given a medium

dose of synthetic glucocorticoids 24 h after learning various

declarative memory tasks. Brain activation was measured

by PET 1 h after drug administration. Results showed that

glucocorticoids induced a large decrease in regional cere-

bral blood ﬂow in the right posterior medial temporal lobe

coupled with impaired cued recall of word pairs learned

24 h earlier. These results were the ﬁrst to provide an

in vivo demonstration that acutely elevated glucocorticoid

levels can impair declarative memory retrieval processes

that are related to measurable changes in medial temporal

lobe function. A similar impairment of retrieval function

was recently reported by Buss, Wolf, Witt, and Hellham-

mer (2004). These authors administered a small dose of

synthetic glucocorticoids to young adults, and measured

retrieval of past events in their life (autobiographical mem-

ory). Results showed that when compared to placebo, glu-

cocorticoids signiﬁcantly impaired retrieval of past

personal events.

Besides acute actions, delayed eﬀects of glucocorticoids

were reported in several memory studies in human subjects.

Impaired memory performance was observed in normal

adults following 5 days administration of high doses of

prednisone (80 mg p.o. daily), but normal memory perfor-

mance in another group of subjects following a more acute

administration of 1 mg of dexamethasone (Wolkowitz

et al., 1990). Similarly, a 4-day administration procedure

with 0.5,1, 1, 1 mg/day of dexamethasone in normal con-

trols produced impaired declarative memory performance

(acquisition and recall) on the fourth day of treatment only

(Newcomer, Craft, Hershey, Askins, & Bardgett, 1994).

Similar results were obtained by the same group using

hydrocortisone (Newcomer et al., 1999). In both studies,

no immediate or delayed eﬀects of dexamethasone were

observed on non-declarative memory or on selective atten-

tion performance. Similar results were obtained using a 4-

day regimen of 160 mg of prednisone. Taken together,

these results were in accordance with a hippocampal

involvement in glucocorticoid-related cognitive deﬁcits

and argued against a nonspeciﬁc eﬀect of the steroid on

attention and arousal (Schmidt, Fox, Goldberg, Smith, &

Schulkin, 1999).

In summary, the majority of studies performed in

human populations tend to conﬁrm the rodent literature

reporting acute negative eﬀects of glucocorticoids on hip-

pocampal-dependent forms of memory (for a recent

meta-analysis, see Het, Ramlow, & Wolf, 2005). Alto-

gether, the rodent and human data strengthened the view

that stress hormones have a speciﬁc impact on the hippo-

campus (for a complete critical review of the glucocorti-

coid-hippocampus link, see Lupien & Lepage, 2001).

3.4.1. Interim: Lessons from history

Let us stop time and go back to Bruce McEwen et al.’s,

1968 discovery of glucocorticoid receptors in the rodent

hippocampus (McEwen et al., 1968). It is clear from the lit-

erature summarized above that the presence of glucocorti-

coid receptors in the rodent hippocampus served as the

basis for the hypothesis that glucocorticoids should signif-

icantly and speciﬁcally impair declarative memory function

in humans. However, and although the hypothesis was sim-

ple, economical, and easy to test, a closer look at history

teaches us that the glucocorticoid-hippocampus link might

not be the best hypothesis to fully explain glucocorticoid-

induced cognitive changes in humans (for a complete

review on this topic, see Lupien & Lepage, 2001). Here is

what history has to tell us.

In their 1968 paper, McEwen and collaborators

described the retention of corticosterone, a naturally occur-

ring glucocorticoid, in the rodent brain (McEwen et al.,

1968). The rats were ﬁrst adrenalectomized (the adrenal

glands were removed and the animal was kept alive with

physiological doses of corticosterone) in order to deplete

the rat’s system of any endogenous circulating glucocorti-

coids, and then corticosterone was injected and the reten-

tion of this naturally occurring glucocorticoid was

216 S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237

assessed. Using this method, they showed that corticoste-

rone was highly retained by the hippocampus.

Researchers then sought to determine whether other

synthetic glucocorticoids would be retained by the hippo-

campus. Notable among these was dexamethasone. de

Kloet, Wallach, and McEwen (1975) found the compound

to be very poorly retained by the rodent hippocampus, irre-

spective of the route of administration (peripheral vs. intra-

cerebroventricular). Later, it was shown that the small

amount of dexamethasone that did penetrate the brain

was retained in a regional pattern that was distinct from

that of corticosterone (McEwen, 1976). In the same study,

another steroid (cortisol) that is not a natural glucocorti-

coid in the rat (although it is in humans) was very poorly

retained in the rodent brain, while corticosterone and aldo-

sterone (another naturally occurring glucocorticoid) were

highly retained by the rodent hippocampus and surround-

ing limbic structures.

The diﬀerent modes of action of dexamethasone and

corticosterone on the rodent brain indicated that these

two compounds might bind to diﬀerent types of glucocorti-

coid receptors. This idea was conﬁrmed six years later by

the presence of mineralocorticoid (Type I) and glucocorti-

coid (Type II) receptors in the rodent hippocampus (Vel-

dhuis, van Koppen, van Ittersum, & de Kloet, 1982). The

trace amounts of corticosterone that were previously

retained so abundantly by the rodent hippocampus were

actually bound to Type I and not to Type II receptors

(Reul & De Kloet, 1985). In fact, these authors showed

that aﬃnity of hippocampal Type II for corticosterone in

the rat brain was actually too low for any signal to be

detected. At this point in time, history taught us one impor-

tant fact about Type I and Type II receptors, i.e. that there

exists a tremendous diﬀerence in the two receptor types in

terms of aﬃnity.

We now know that Type I receptors bind glucocorti-

coids with an aﬃnity that is about 6- to 10 times higher

than that of Type II (Reul & De Kloet, 1985). This diﬀer-

ential aﬃnity results in a striking diﬀerence in occupation

of the two receptor types under diﬀerent conditions and

time of day. Speciﬁcally, during the circadian trough (the

PM phase in humans), the endogenous hormone occupies

more than 90% of Type I receptors, but only 10% of Type

II receptors. However, during stress and/or the circadian

peak of glucocorticoid secretion (the AM phase in

humans), Type I receptors are saturated, and there is occu-

pation of approximately 67–74% of Type II receptors (Reul

& De Kloet, 1985). This diﬀerential aﬃnity of Type I and

Type II opened the door to a brand new hypothesis about

glucocorticoid eﬀects on cognitive function, i.e. that gluco-

corticoids could also have positive eﬀects on cognitive

function.

3.5. Positive eﬀects of glucocorticoids on human cognition

In contrast to human studies in which glucocorticoids

were consistently shown to have detrimental eﬀects on

declarative memory function (see above), many studies per-

formed in rodents reported that the ratio of Type I/Type II

occupation is a major determinant of the direction of glu-

cocorticoid-induced cognitive changes (for a review, see

de Kloet, Oitzl, & Joels, 1999). For example, long-term

potentiation (LTP), a proposed neurobiological substrate

of memory formation, has been shown to be optimal when

glucocorticoid levels are mildly elevated, i.e., when the

ratio of Type I/Type II occupation is high (see Diamond,

Bennett, Fleshner, & Rose, 1992). In contrast, signiﬁcant

decreases in LTP are observed after adrenalectomy, when

Type I occupancy is very low (Dubrovsky, Liquornik,

Noble, & Gijsbers, 1987; Filipini, Gijsbers, Birmingham,

& Dubrovsky, 1991), or after exogenous administration

of synthetic glucocorticoids (Bennett, Diamond, Fleshner,

& Rose, 1991; Pavlides, Watanabe, & McEwen, 1993),

which activate Type II and deplete glucocorticoids, again

resulting in low occupancy of Type I.

In a review of these issues, de Kloet et al. (1999) re-inter-

preted the eﬀects of glucocorticoids on cognitive perfor-

mance in line with the Type I/Type II ratio hypothesis,

suggesting that cognitive function can be enhanced when

most of the Type I and only part of the Type II are acti-

vated (top of the inverted-U shape function; increased

Type I/Type II ratio; see Fig. 3). However, when circulat-

ing levels of glucocorticoids are signiﬁcantly decreased or

increased (extremes of the inverted-U shape function; low

Type I/Type II ratio), cognitive impairments will result.

The authors suggested that the negative view of glucocorti-

coid actions on human cognitive function could be partly

explained by limitations in previous human experimental

designs, which did not allow for the diﬀerential manipula-

tion of Type I and Type II levels. In order to do this, such

studies should measure cognitive function when glucocorti-

coid receptors occupancy is decreased (rather than

increased), thus allowing for functional measures of Type

I/Type II occupancy on learning and memory. One way

Memory Performance

Type I

Type II

Type I

saturated

50% Type II

Occupied

Type II

saturated

Circulating Levels of GCs

Fig. 3. The Type I/Type II glucocorticoid ratio hypothesis of the

association between circulating levels of glucocorticoids, and memory

performance (de Kloet et al., 1999). The ﬁgure shows occupancy of GC

receptors as a function of circulating levels of GCs and resulting

modulation of memory. When Type I glucocorticoid receptors are

saturated and there is partial occupancy of Type II glucocorticoid

receptors, there is maximization of memory, while when both Type I and

Type II glucocorticoid receptors are not occupied (left side of the inverted-

U shape function) or are saturated (right side of the inverted-U shape

function), there is an impairment in memory performance.

S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237 217

to test such a hypothesis is the use of a hormone removal–

replacement protocol.

In a hormone removal–replacement protocol, the behav-

ior resulting from the absence of the hormone of interest is

ﬁrst measured, and then baseline hormonal levels are

restored to normal values and the same behavior is mea-

sured once again. If the hormone of interest has a real

impact in the behavior tested, then this behavior should

be restored to normal value after hormonal replacement

(see Brown, 1998).

In order to test this suggestion, our group performed a

hormone removal–replacement study in a population of

young normal controls (Lupien et al., 2002). In this proto-

col, we used a within-subject double-blind experimental

protocol in which we ﬁrst pharmacologically lowered glu-

cocorticoids levels by administrating metyrapone, a potent

inhibitor of glucocorticoid synthesis, we then restored base-

line circulating glucocorticoid levels by infusing hydrocor-

tisone, a synthetic glucocorticoid. Memory performance of

participants under each of these conditions was compared

to that measured on a placebo day. The results showed that

when compared to placebo, the pharmacological decrease

of circulating levels of glucocorticoids induced by metyra-

pone signiﬁcantly impaired memory performance. Most

importantly, we showed that this impairment was com-

pletely reversed after hydrocortisone replacement (see

Fig. 4 for a schematic representation of the results). These

results showed that glucocorticoids can modulate memory

function, and most importantly, they showed that the

absence of circulating glucocorticoid levels is as detrimen-

tal for human memory function as is a signiﬁcant increase

in glucocorticoids.

We have suggested that this modulation can happen

through a diﬀerential activation of Type I and Type II

receptors. Indeed, during the metyrapone condition, Type

I occupancy was low, given the signiﬁcant decrease of glu-

cocorticoid secretion induced by metyrapone. At this point,

impairment in memory was observed. In contrast, during

the hydrocortisone replacement condition, glucocorticoid

levels were restored to the those typically found in the

AM phase, i.e. leading to a saturation of Type I, with par-

tial occupancy of Type II. This diﬀerential occupation thus

led to an increased Type I/Type II ratio, and a restoration

of baseline cognitive performance.

In a second study (also in Lupien et al., 2002), we took

advantage of the circadian variation in circulating levels of

glucocorticoids and tested the impact of a bolus injection

of glucocorticoids in the late afternoon, at a time of very

low glucocorticoid concentrations. In a previous study with

young normal controls, we injected a similar dose of gluco-

corticoids in the morning, at the time of the circadian peak,

and reported detrimental eﬀects of glucocorticoids on

memory (Lupien, Gillin, & Hauger, 1999). Here, when

we injected a similar dose of hydrocortisone in the after-

noon, at the time of the circadian trough, we observed that

although glucocorticoids did not change memory perfor-

mance they nonetheless had a positive impact on cognitive

eﬃciency and vigilance by signiﬁcantly decreasing reaction

times on a recognition memory task when compared to the

placebo condition.

Data obtained by Oitzl and de Kloet in 1999 led them to

propose that each glucocorticoid receptor type contributes

to diﬀerent aspects of cognitive processing. They found

that Type I receptor activation is important for behavioral

reactivity in response to environmental cues aﬀecting vigi-

lance and attention. Type II activation on the other hand

is essential for the consolidation of events/items in

memory.

In this view, the delayed memory impairment observed

after Metyrapone administration (i.e. due to the lack of

Type II activation) in our ﬁrst experiment is consistent with

a Type II receptor-mediated eﬀect on consolidation pro-

cesses. The signiﬁcant decreases in reaction times observed

in our second experiment are in line with a Type I-mediated

eﬀect on behavioral reactivity and vigilance. Taken

together these ﬁndings oﬀer further support for the notion

that the Type I/Type II occupancy ratio is an important

factor in determining the direction and magnitude of gluco-

corticoids eﬀects on cognitive processing and that each

receptor type plays a distinct yet complimentary role at dif-

ferent stages of processing.

3.5.1. Interim: Lessons from history

Now, let us stop time again, and go back to Reul and De

Kloet’s, 1985 work on Type I and Type II receptors. The

study of Type I and Type II activity in the brain showed

that there exist large diﬀerences in terms of aﬃnity for Type

I and Type II, a ﬁnding that led to the view that glucocor-

ticoids are not only destructive (de Kloet et al., 1999).

However, the search for Type I and Type II receptors in

the brain led to another important discovery, i.e. the diﬀer-

ential distribution of Type I and Type II receptors in the

rodent brain. Following the work by Reul and De Kloet

Memory

Performance

CIrculating Levels of Glucocorticoids

facilitation inhibition

Decrease (full line) and restoration (dashed line)

in Cortisol levels

Hormone

Removal-Replacemen

Protocol

8% decrease

In memory

Restoration of

Baseline Memory

Performance

Fig. 4. Schematic representation of the modulation of memory perfor-

mance by pharmacological inhibition of cortisol secretion (full arrow), and

by hydrocortisone replacement (dashed arrow) in young human partic-

ipants. After corticol decrease, we observed a 8% decrease in declarative

memory performance that was restored to placebo level after restoration

of circulating levels of cortisol by pharmacological infusion of hydrocor-

tisone (see Lupien et al., 2002).

218 S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237

(1985), it was established that in the rodent brain, the Type

I is present exclusively in the limbic system, with a prefer-

ential distribution in the hippocampus, parahippocampal

gyrus, entorhinal, and insular cortices. In contrast, the

Type II receptor is present in both subcortical (paraventric-

ular nucleus and other hypothalamic nuclei, the hippocam-

pus and parahippocampal gyrus) and cortical structures,

with a preferential distribution in the prefrontal cortex

(Diorio, Viau, & Meaney, 1993; McEwen, De Kloet, &

Rostene, 1986; McEwen et al., 1968; Meaney, Sapolsky,

Aitken, & McEwen, 1985). Still, in the rodent brain, the

largest concentration of both Type I and Type II receptors

was found in the hippocampus, which again led to the glu-

cocorticoid-hippocampus link described before.

However, in 2000, two papers were published which

described the distribution of Type I and Type II receptors

in the primate brain, more closely related to the human

brain in terms of neocortical development. These two

recent studies mapping both Type I and Type II receptor

distribution in the primate brain strongly suggested that

extrapolation from rat brain to primate brain may be mis-

leading when discussing the impact of glucocorticoids on

the hippocampus.

The ﬁrst study reported that, in contrast to its well estab-

lished distribution in the rat brain, Type II mRNA is only

weakly detected in the dentate gyrus and Cornu Ammonis

of the macaque hippocampus (Sanchez, Young, Plotsky, &

Insel, 2000). In contrast, Type II mRNA is strongly detected

in the pituitary, cerebellum, hypothalamic paraventricular

nucleus and prefrontal cortices. In a second study, it was

reported that Type II receptors were well-expressed in the

hippocampus, but were more prominently found in the pre-

frontal cortex (Patel et al., 2000). Thus, Type I receptors are

present in large quantities in the hippocampus and limbic

structures in the primate brain, while Type II receptors are

present in all these structures and additionally in frontal

regions. This latter ﬁnding suggested that in humans, gluco-

corticoids should not only aﬀect the hippocampus, but also

the frontal lobes. This has been recently supported.

3.6. Glucocorticoids, the frontal lobe, and working memory

Studies in nonhuman primates (Goldman-Rakic, 1987,

1995), and humans (Owen, Downes, Sahakian, Polkey, &

Robbins, 1990; Petrides & Milner, 1982) show that lesions

of the dorsolateral prefrontal cortex (DLPFC) give rise to

impairments in working memory. Working memory is the

cognitive mechanism that allows us to keep a small amount

of information active for a limited period of time (see

Baddeley, 1995). In these working memory tasks, a tempo-

ral gap is introduced between a stimulus and a response,

which creates the need to maintain the stimulus in tempo-

rary memory storage. Data obtained in monkeys showed

that cells in the lateral prefrontal cortex become particu-

larly active during delayed response tasks, suggesting that

these cells are actively involved in holding on to the infor-

mation during the delay (Goldman-Rakic, 1990, 1995).

Neuropsychological evidence suggests that humans with

DLPFC damage are impaired in working memory (Fuster,

1980; Luria, 1966). These patients are also highly suscepti-

ble to cognitive interference and they perform poorly on

neuropsychological tests that require response inhibition

such as the Wisconsin Card Sorting Test (Shimamura,

1995; Stuss et al., 1982). Moreover, neuroimaging data

show a signiﬁcant relation between working memory pro-

cessing and the activations observed in the prefrontal cor-

tex (Smith, Jonides, Marshuetz, & Koeppe, 1998; but

also see Ungerleider, Courtney, & Haxby, 1998).

Working memory appears to be more sensitive than

declarative memory to the eﬀects of acute and short-term

administrations of glucocorticoids. Young, Sahakian,

Robbins, and Cowen (1999) administered glucocorticoids

for 10 days to young normal male volunteers and mea-

sured various cognitive functions in a randomized, pla-

cebo control, crossover, within-subject design. They

showed that this regimen of glucocorticoids led to deﬁcits

in cognitive function sensitive to frontal lobe dysfunction

(working memory), while it did not impact on cognitive

function sensitive to hippocampal damage (declarative

memory).

Similar results were obtained by our group using an

acute dose–response neuroendocrine protocol (Lupien

et al., 1999). In this study, 40 young subjects were infused

for 100 min with either glucocorticoids or placebo, and

declarative and working memory were tested during the

infusion period. Performance on the working memory

task decreased signiﬁcantly whereas performance on the

declarative memory task remained the same following

an acute elevation of glucocorticoids. Curve ﬁt estima-

tions revealed the existence of a signiﬁcant quadratic

function (U-shape curve) between performance on the

working memory task and changes in glucocorticoids lev-

els after hydrocortisone infusion. The results of these two

studies suggested that in young individuals, working

memory is more sensitive than declarative memory to

an acute elevation of glucocorticoids, supporting the sug-

gestion that glucocorticoids have a signiﬁcant impact on

frontal lobe functions in humans.

Similar results were obtained by Hsu, Garside, Mas-

sey, and McAllister-Williams (2003). In their study,

twenty healthy subjects were treated with a high dose

of synthetic glucocorticoids or placebo orally, in a dou-

ble-blind, two-way crossover study. It was found that glu-

cocorticoids impaired performance on an attentional task

(Stroop), while they did not impair performance on a

declarative memory task. Other studies, however, report

an opposite pattern of ﬁndings. Monk and Nelson

(2002) for instance showed that working memory task

(n-back) performance was unaﬀected by a moderate dose

of exogenous glucocorticoids but that declarative memory

performance (intentional face recognition) suﬀered as a

result of the increase in glucocorticoids. These data may

in part be explained by the fact that face encoding is

not an entirely hippocampus-dependent process and that

S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237 219

it in fact recruits frontal regions (Sergerie, Lepage, &

Armony, 2005).

3.7. Glucocorticoids and emotional memory

In humans, the frontal lobes have been shown to be sig-

niﬁcantly involved in emotional processing (for a review,

see Damasio, 1995), and given the impact of glucocorti-

coids on human frontal lobe function (Lupien et al.,

1999; Young et al., 1999), it might be asked whether gluco-

corticoids also impact on human emotional memory. In a

recent study, Buchanan and Lovallo (2001) exposed young

participants to pictures varying in emotional arousal after

they received a small dose of synthetic glucocorticoids

(Buchanan & Lovallo, 2001). During acquisition, subjects

were not aware that their memory for the pictures would

be tested a week later (incidental memory). Results

revealed that glucocorticoid elevations during memory

encoding enhanced the delayed recall performance of emo-

tionally arousing pictures while it had no impact on the

delayed recall of the neutral pictures.

Similarly, Abercrombie, Kalin, Thurow, Rosenkranz,

and Davidson (2003) tested the eﬀects of an exogenous

administration of two doses of synthetic glucocorticoids

on emotional memory using a dose–response study. Young

men were presented with emotionally arousing and neutral

stimuli after receiving either a placebo or a low or medium

dose of synthetic glucocorticoids. Free recall of the stimuli

was assessed 1 h after drug administration and recognition

memory of the stimuli was assessed two evenings later.

Results showed that glucocorticoid elevations decreased

the number of errors committed on the free-recall tasks

(increased performance). More importantly, the authors

showed that when tested for recognition two evenings later,

when cortisol levels were no longer manipulated, recogni-

tion performance presented an inverted-U quadratic curve.

Glucocorticoid-induced enhancements of recognition

memory were only observed in the low-dose condition. In

contrast to the data obtained by Buchanan and Lovallo

(2001), these results showed beneﬁcial eﬀects of synthetic

glucocorticoids on both emotionally arousing and neutral

material.

4. Stress, emotion, and cognition

Now that we have described the exogenous eﬀects of

glucocorticoids on cognition, it is important to turn our

attention to the fact that endogenously released glucocorti-

coids in the face of stress can also impact cognitive perfor-

mance. Indeed, most of the previous literature covered used

exogenous administrations of synthetic glucocorticoids in

order to delineate the eﬀects of glucocorticoids on human

cognitive function. Yet, and as presented in Fig. 1, gluco-

corticoids are natural substances that are secreted in the

face of a challenge. Interestingly, glucocorticoids that are

secreted endogenously in the face of a challenge still have

the ability to cross the blood–brain barrier and impact cog-

nitive performance through binding to Type I and Type II

glucocorticoid receptors in the brain. However, before

describing the eﬀects of stress and related stress hormones

on cognitive performance, it is important to dissociate the

eﬀects of emotions from those of stress on human

cognition.

4.1. Stress versus emotion

Emotionally arousing and stressful experiences are often

cited as the cause of many psychological and physical prob-

lems. Many of us have experienced emotionally arousing

and stressful experiences at one point or another in life,

and noted that these experiences can have important eﬀects

on our memory. One can have forgotten an important

meeting or anniversary due to work overload, or else,

one can have a vivid recollection of a car accident or any

other emotionally arousing experience. Because of their

impact on our lives, we have a tendency to pay more atten-

tion to the negative eﬀects of stress on our memory, and to

forget that under certain conditions, emotionally arousing

and stressful experiences can also have a positive impact

on memory function.

Emotion and stress share many characteristics. A stress-

ful experience will often cause a particular emotion (e.g.,

surprise, fear, joy, etc.), and particular emotions can create

stressful situations (e.g., blushing due to extreme timidity

can cause a stressful situation for an individual). Moreover,

an emotion possesses many of the properties of a stressor.

First, it often has an identiﬁable source. Second, it is usu-

ally brief and leads to an intense and conscious experience

of short duration. Finally, an emotion creates bodily reac-

tions (e.g., increase in heart rate, perspiration, etc.) that are

similar to those induced by a stressor, and both states act

by increasing arousal. Because of these similarities between

emotion and stress, most of the literature on emotion,

stress and memory intermixes the eﬀects of emotion and

those of stress upon memory function. However, emotion

and stress are two diﬀerent entities. Although a stressful

experience will almost always trigger a speciﬁc emotion, a

particular emotion does not always elicit a stress reaction

(for a complete review on the diﬀerence between a stress

and an emotion, see Lupien & Brie

`re, 2000).

As far as laboratory settings are concerned, emotion and

stress diﬀer in the way they are induced and thus, in the

way they inﬂuence memory in humans. Hence, emotions

are usually induced by the presentation of emotional

words, ﬁlms or pictures, while stress is usually induced by

putting the individual in a social situation known to create

stress (e.g., a public speaking task). Because of this impor-

tant diﬀerence between the experimental paradigms used to

measure the eﬀects of emotion and stress on memory, dif-

ferent questions have been asked. Induction of emotion

has been used to measure memory for emotionally arousing

events, while induction of stress has been used to measure

the speciﬁc eﬀects of stress on subsequent memory

function.

220 S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237

4.1.1. Mechanisms underlying memory for emotionally

arousing events

It is well known that what we encode and remember

from an event depends primarily on the attention that is

devoted to this event and its components. If you do not

pay attention to what you are reading right now, there is

less chance for you to remember it at a later time than if

you give all your attention to your reading. This is because

the more attention given to an event, the higher the prob-

ability that this event will be elaborated (relating the infor-

mation from this event to other situations and related

concepts in memory) at the time of encoding.

The level of attention devoted to an event at the time of

encoding will greatly depend on the emotional salience of

this event. Most of us remember what we were doing and

with whom we were at the time we learned about the World

Trade Center attacks, but the majority of us may have dif-

ﬁculty remembering what we were doing and with whom

we were 13 days before or after the attacks. This ‘‘ﬂashbulb

memory’’ phenomenon may be explained by the fact that

the emotions (e.g., surprise, anger, fear etc.) that were trig-

gered by the announcement of the World Trade Center

attacks directed the totality of our attention to the event,

leading to a deeper elaboration and thus, to an optimiza-

tion of our memory for this event.

Studies with trauma victims have reported how vividly

the traumatic event is recalled, in the absence of any mem-

ory for information surrounding the traumatic event. A

closely analogous situation appears in the ﬁeld of law

enforcement and describes the ‘‘weapon focus’’ phenome-

non. Witnesses to violent crimes demonstrate a weapon

focus eﬀect in which the weapon captures most of the vic-

tim’s attention, resulting in a reduced ability to recall other

details of the scene and to recognize the assailant at a later

time (see Christianson, 1992). This phenomenon has been

explained by Easterbrook’s (1959; see Christianson 1992)

cue utilization theory which suggests that emotionally

arousing events narrow subjects’ attention and lead them

to attend only to the center of an event, and to exclude

more peripheral information. In general, laboratory exper-

iments have conﬁrmed this hypothesis (Christianson,

1992). Recently, Cahill, Gorski, Belcher, and Huynh

(2004) pushed this analysis further and reported gender-

related inﬂuences in the recall of central vs. peripheral

information from an emotional story (Cahill et al., 2004).

Men and women with high male-related traits on the

Bem Sex-Role Inventory show better memory for central

aspects of an emotional story, relative to peripheral details.

On the other hand, women and men with high female-

related traits on the Bem Sex-Role Inventory have a better

memory for peripheral details of an emotional story, as

opposed to central information (Cahill et al., 2004; Cahill,

Gorski, & Le, 2003).

Studies have examined the relation between emotion,

retention intervals and memory. What these studies have

shown so far is that emotionally arousing events delay for-

getting. In a highly cited study, Kleinsmith and Kaplan

(1963) asked participants to learn neutral and emotionally

laden (e.g., ‘‘rape’’, ‘‘mutilation’’) word pairs. Both short-

term (2 min) and long-term (1 week later) declarative mem-

ory for the words pairs was assessed. The results showed

that emotional word pairs were better recalled after a long

retention delay (Kleinsmith & Kaplan, 1963; Kleinsmith,

Kaplan, & Tarte, 1963). These results have been replicated

many times and the majority of studies have shown

enhanced memory for emotionally arousing material, pro-

vided that memory is tested at longer retention intervals.

There are extensive data showing that the observed ret-

rograde enhancement of long-term memory for emotion-

ally arousing events is related to the hormones released

during these experiences. Emotionally arousing events give

rise to the secretion of the peripheral catecholamines adren-

aline and noradrenaline by the adrenal medulla, central

noradrenaline secretion by the locus coeruleus and to glu-

cocorticoids secretion by the adrenal glands. Glucocorti-

coids readily access the brain and can thus act directly to

impact emotional memory processing (Roozendaal, 2002;

Roozendaal, Brunson, Holloway, McGaugh, & Baram,

2002). The peripheral catecholamines on the other hand,

enhance memory by reaching the vagus nerve, the nucleus

of the solitary tract and the locus ceruleus. Central nor-

adrenaline is then secreted by the locus ceruleus, activating

noradrenergic neurons throughout the brain (Roozendaal,

2002). Importantly, central noradrenaline is also triggered

as soon as an emotionally arousing event occurs, indepen-

dently of peripheral catecholamines (McGaugh & Roo-

zendaal, 2002; Roesler, Roozendaal, & McGaugh, 2002;

Roozendaal, 2002). Speciﬁcally though, hormonal eﬀects

on emotional memory processing are achieved via the

interactions between adrenergic hormones and glucocorti-

coids and their respective receptors in the amygdala (Roo-

zendaal, 2002). This then results in a modulation of

hippocampal activity and ultimately, enhanced long-term

memory for emotional material (Roozendaal, 2002; Roo-

zendaal et al., 2002; Roozendaal, Quirarte, & McGaugh,

2002).

Animal and human studies have conﬁrmed the role of

these hormones in the memory-modulating eﬀects of

emotionally arousing events. In rodents, post-learning

stimulation of the noradrenergic system enhances, whereas

post-learning blockade inhibits, long-term declarative

memory of an inhibitory avoidance task (McGaugh,

2000). Likewise, post-training injections of moderate doses

of synthetic glucocorticoids enhance, and pre-training glu-

cocorticoid synthesis inhibition impairs, long-term expres-

sion of inhibitory avoidance in animals (Roozendaal,

2002; Sandi, 1998). In humans, pre-learning blockade of

central b-adrenergic receptors or pre-learning glucocorti-

coid synthesis inhibition impairs long-term declarative

memory for emotionally arousing material (Cahill et al.,

1994; Maheu et al., 2004), whereas pre-learning or post-

learning stimulation of the noradrenergic or glucocorticoid

systems enhances it (Abercrombie et al., 2003; Buchanan &

Lovallo, 2001; Cahill & Alkire, 2003). Although psycholog-

S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237 221

ical and biological explanations of the arousal hypothesis

were used to explain the positive eﬀects of emotion on

memory function, research performed to this day shows

that arousal is signiﬁcant as an intervening variable only

when the source of the arousal (in this case, the emotionally

arousing event) is directly related to the information to be

remembered (Gore, Krebs, & Parent, 2006; Kuhlmann &

Wolf, 2006). However, when the source of emotion is not

directly related to the information to be remembered, other

psychological and biological mechanisms come into play

and have a stronger impact on memory function than arou-

sal itself. Consistent with this suggestion, Rimmele,

Domes, Mathiak, and Hautzinger (2003) reported that cor-

tisol administration increased memory for details of neutral

pictures, while it impaired memory for details of emotional

pictures (Rimmele et al., 2003), showing the intricate rela-

tionship existing between stress, emotion, and memory.

4.2. Eﬀects of stress on human memory

Remembering with great accuracy a particular emotion-

ally arousing event is very diﬀerent from performing vari-

ous tasks involving memory in a day-to-day situation

when one is faced with stress. We may remember with great

accuracy the events in our lives surrounding the World

Trade Center attacks, but we may also have forgotten an

important appointment due to work stress.

Interestingly, rodent studies have shown that, when a

laboratory stressor (e.g., tailshocks, water immersion or

restraint stress) is administered at various time-points

before or after learning, as well as before recall, stress-

induced elevations in glucocorticoid levels modulate

declarative memory according to an inverted U-shaped

function, a ﬁnding that is equivalent to the observed eﬀects

of exogenous glucocorticoids on human cognition. Optimal

declarative memory for material unrelated to the stressor

(e.g., inhibitory avoidance protocols or spatial water-maze

tasks) occur at moderate levels of stress and stress-induced

increases in circulating glucocorticoid levels, whereas lower

(i.e., boredom or drowsiness) or higher stress levels and

stress-induced increases in circulating glucocorticoid levels

are less eﬀective or may even impair declarative memory

performance on these tasks (Roozendaal, 2002; Sauro, Jor-

gensen, & Pedlow, 2003).

In humans, when a laboratory stressor (e.g., a public

speaking task or a public mental arithmetic task) is admin-

istered before learning or retrieval, high glucocorticoid lev-

els following these stressors are associated with memory

impairments for material unrelated to the stressor such as

neutral words lists (see Jelici, Geraerts, Merckelbach, &

Guerrieri, 2004; Lupien, Buss, Schramek, Maheu, & Pru-

essner, 2005;Lupien, Fiocco, Wan, Maheu, Lord, Schram-

ek, et al., 2005;Sauro et al., 2003; Takahashi et al., 2004;

cf. Domes, Heinrichs, Reichwald, & Hautzinger, 2002;

Wolf, Schommer, Hellhammer, Reischies, & Kirschbaum,

2002). Recently, studies measuring the inﬂuence of stress

on memory for emotional material unrelated to the stressor

reported more heterogeneous ﬁndings. Thus, when a labo-

ratory stressor was presented before learning or retrieval of

emotional and neutral information unrelated to the stres-

sor, high glucocorticoid levels following stress were associ-

ated with memory impairments for emotional information

(whether positive or negative), while they had no inﬂuence

on memory for neutral material (Abercrombie, Speck, &

Monticelli, 2006; Domes, Heinrichs, Rimmele, Reichwald,

& Hautzinger, 2004; Kuhlmann, Piel, & Wolf, 2005;

Maheu, Collicutt, Kornik, Moszkowski, & Lupien, 2005;

but see Elzinga, Bakker, & Bremner, 2005). However,

two other studies showed that stress administered before

(Jelici et al., 2004) or after (Cahill et al., 2003) learning

enhanced memory for emotional material, while it had no

impact (Cahill et al., 2003), impaired (Buchanan, Tranel,

& Adolphs, 2006) or increased (Andreano & Cahill,

2006) subsequent memory for neutral information (Jelici

et al., 2004).

Altogether, these results show that stress-related eleva-

tions in glucocorticoids can have diﬀerent eﬀects on subse-

quent memory for material unrelated to the stressor. The

eﬀects of emotionally arousing and/or stressful events on

declarative memory vary according to the nature of the

to-be-remembered material, with elevated levels of gluco-

corticoids enhancing memory for the emotionally arousing

event itself but leading, more often than not, to poor mem-

ory for material unrelated to the source of stress/emotional

arousal.

The time of day (morning vs. afternoon) and levels of

circulating glucocorticoids at the time of testing could also

be important factors inﬂuencing the eﬀects of stress-related

elevations in glucocorticoids on subsequent memory for

material unrelated to the stressor. Glucocorticoid receptors

diﬀer in terms of their aﬃnity for circulating levels of glu-

cocorticoids. As we have discussed previously, Type I

receptors have a 6- to 10-times higher aﬃnity for glucocor-

ticoids than Type II receptors. A wealth of evidence now

demonstrates that activation of Type I receptor is manda-

tory for successful acquisition of environmental cues neces-

sary to encode information, whereas activation of Type II

receptors is necessary for long-term memory consolidation

of this information (Oitzl & de Kloet, 1992). Endogenous

levels of glucocorticoids and thus, activation of Type I

and Type II receptors will vary across the day, with higher

endogenous levels of glucocorticoids in the AM phase com-

pared to the PM phase. Consequently, the addition of a

stressful event in the AM or PM phase, which by itself will

trigger a signiﬁcant increase in endogenous levels of gluco-

corticoids, should have a diﬀerential impact on activation

of Type I and Type II receptor as a function of time of

day, and consequently, on memory performance. As indi-

cated earlier, in the AM phase, most of the Type I receptors

and about half of the Type II receptors are activated, while

in the PM phase, most of the Type I receptors and about a

tenth of the Type II receptors are activated. If one applies a

stressor in the AM phase, the endogenous increase in glu-

cocorticoid levels that will be induced by the stressor will

222 S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237

act by saturating Type II receptors, while the same stressor

applied in the PM phase will act by activating about half of

the Type II receptors. Since stress-induced elevations in

glucocorticoid levels have been shown to modulate declar-

ative memory for material unrelated to the stressor accord-

ing to an inverted U-shaped function, the diﬀerential

activation of Type I and Type II receptors at diﬀerent times

of the day thus implies that a stressor applied in the morn-

ing should impair memory function (right hand-side of the

inverted U-shaped curve), while the same stressor applied

in the PM phase should increase or have no impact on

memory (left-hand-side or top of the inverted U-shaped

curve; see Lupien, Fiocco et al., 2005).

Finally, very few studies have measured the inﬂuence of

the central noradrenergic system, activated following

stress, on subsequent memory for material unrelated to

the stressor. Animal studies report that stress-induced

elevations in noradrenaline levels (following footshocks)

modulate declarative memory according to an inverted

U-shaped function, with optimal levels enhancing, and

lower or higher levels of noradrenaline, impairing memory

for information unrelated to the source of stress (e.g., pas-

sive aversive conditioning; Gold & McGaugh, 1975; Gold,

van Buskirk, & McGaugh, 1975). In humans, one recent

study showed that blockade of peripheral and central nor-

adrenergic b-receptors before the administration of a stres-

sor did not impair memory for material unrelated to the

source of stress (Maheu et al., 2005). These results suggest

that the b-adrenergic system is not implicated in the eﬀects

of stress on subsequent declarative memory function, con-

trasting with the well-established role of this system during

the memorization of events that are emotionally arousing

in nature. Further studies in humans will be needed to

determine the exact role played by the central noradrener-

gic system in the eﬀects of stress on subsequent memory for

information unrelated to the stressor.

5. Stress, memory, and the testing environment

In previous sections, we have summarized the studies

showing that both exogenous and endogenous increases

in stress hormones can impact on cognitive function. We

have also shown that the memory-enhancing eﬀects of

emotions are mainly sustained by the catecholaminergic

system, while the memory-impairing eﬀects of stress on

neutral memory are sustained by the glucocorticoid system.

Now, can these studies showing impairing eﬀects of stress

on neutral memory have any implications for the ﬁeld of

brain and cognition? We would like to end this large review

of the literature on the eﬀects of stress and stress hormones

on cognition by arguing that this ﬁeld of research is of

great importance for research on brain and cognition,

and particularly for neuropsychology. The reason for this

lies in the potential eﬀects that the environmental context

in which we test our study participants may have on their

stress response, and what this stress response could induce

in terms of neuropsychological performance. In order to

make our point, we chose to discuss potential stress eﬀects

of the testing environment in young versus older adults and

the impact that testing-induced stress could have on the

obtained results.

5.1. When we test, do we stress?

In the early 1990s, when most models of human memory

function were developed, they were based on the computer-

model of information processing (Schacter, 1992; Squire,

1992). These models were tested in both animals and

humans, most of the time without taking into consider-

ation the physiological and/or neural mechanisms underly-

ing memory function. However, in the last decade, new

data emerged showing that memory performance in ani-

mals can be acutely modulated by manipulations of the

testing environment itself. More often than not, the para-

digms used to study learning and memory in animals are

aversive in nature, involving either shock, water immer-

sion, restraint, or challenge to the homeostasis of the

organism through food restriction or deprivation. All these

parameters have been shown to activate, during the train-

ing procedure, the physiological stress response (Cordero,

Kruyt, Merino, & Sandi, 2002; Sandi, Loscertales, &

Guaza, 1997; Sandi & Rose, 1997).

Given that circulating levels of glucocorticoids change in

response to various stressors, it has been postulated that

changes in circulating levels of glucocorticoids, induced

by the nature of the learning procedure used in animal pro-

tocols, might be one of the most important factors inﬂuenc-

ing the strength of the memory trace obtained in these

studies (Cordero et al., 2002; de Kloet et al., 1999; Sandi

& Rose, 1997). This hypothesis has been conﬁrmed by

studies showing that training conditions that result in

long-term memory formation are the same training condi-

tions that induce a release of glucocorticoids.

For example, it has been shown that in the Morris

Water maze, in which a rat is immersed in water and has

to ﬁnd a platform using spatial cues in the room, the water

temperature is a potent modulator of the rate of acquisition

of the task. Rats that are trained at 19 "C learn faster and

display better long-term retention than those trained at

25 "C (Sandi et al., 1997). Glucocorticoid levels are signif-

icantly higher in rats in the 19 "C group relative to those in

the 25 "C group (cold water is a stressor). The role of glu-

cocorticoids in the strength of memory consolidation has

further been conﬁrmed using pharmacological protocols.

So, when one combines a stimulus that leads to an endog-

enous release of glucocorticoids (e.g. water temperature)

with a pharmacological dose of glucocorticoids, this leads

to a modulation of the consolidation process. In the Morris

water maze, rats that are trained at 25 "C (low endogenous

release of glucocorticoids), and given synthetic glucocorti-

coids show good long-term retention, while rats trained

at 19 "C (high endogenous release of glucocorticoids),

and given synthetic glucocorticoids (same dose) show

impaired long-term retention (Sandi & Rose, 1997).

S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237 223

These results again reveal the presence of a biphasic

modulation of memory formation by glucocorticoids,

whereby an increase of glucocorticoids up to an optimum

level should lead to enhanced consolidation, while gluco-

corticoid levels above this optimum level should lead to a

decrease in the consolidation process. These results con-

ﬁrmed the presence of an inverted-U shaped function relat-

ing the circulating levels of glucocorticoids induced by the

experimental context and the memory performance

obtained on the task.

Now, let us be frank. Although most rodent studies use

aversive tasks to assess learning and memory, most human

studies assess learning and memory with tools that are not

thought to be stressful by nature, such as word lists and

story recall. Consequently, many would say that the proto-

cols used in humans are non-aversive and non-stressful by

nature.

However, this may not be the case, as the testing envi-

ronment itself may lead to a diﬀerent stress response in

young and aged humans. In 1968, Mason published a sem-

inal literature review in which he described the most impor-

tant psychological determinants of a stress response, i.e.

those psychological determinants that would lead to the

secretion of glucocorticoids in most of the subjects, what-

ever their age, origin or background. The most important

variables found were novelty, unpredictability, and lack

of control over the situation to which individuals are

exposed (Mason, 1968).

Since then, a large number of human studies have doc-

umented the provocative nature of the anticipation of a

novel, unpredictable or uncontrollable situation on gluco-

corticoid levels. For example, admission to a hospital has

been noted to be very provocative of glucocorticoids

(Mason, 1968), and other studies have shown that individ-

uals anticipating exhausting exercise show signiﬁcant rise in

glucocorticoids that are comparable to that seen during the

actual practice of the physical task (Mason, 1968).

From these studies, it is apparent that individuals show

a signiﬁcant activation of the hypothalamic–pituitary–

adrenal (HPA) axis when they are exposed to important

changes in their environment. With regard to the aging

population, various studies have shown that they are signif-

icantly more reactive to the testing environment when com-

pared to young individuals (Kudielka et al., 2004a, 2004b;

Wolf et al., 2001).

Fig. 5 shows the glucocorticoid levels of 18 young and

18 older participants who came to our laboratory in 1995

(S.J.L.’s ﬁrst stress study) for a study on stress reactivity.

The results showed that when compared to young partici-

pants, the glucocorticoid levels of older participants were

signiﬁcantly elevated at the time of arrival at the laboratory,

60 min before exposure to stress (participants were not

aware that they would be exposed to a stressor, but were

rather told that their verbal capacity would be tested). In

contrast, 45 min after exposure to the stressor, older adults

presented the same glucocorticoid levels as young adults.

Clearly, coming to a laboratory for a particular test

induced a larger increase in glucocorticoids in older adults

compared to young adults.

These results were never published due to this spurious

result, and great care is now taken in our studies to accli-

matize the older participant to the testing environment

before exposing them to any test (memory or stress). This

is achieved by inviting them to a group session with other

older participants. This procedure increases the sense of

aﬃliation, which has been shown to be a potent moderat-

ing variable on stress reactivity (Hellhammer et al., 1997;

Kirschbaum & Hellhammer, 1989; Kirschbaum et al.,

1995a). During this session, we introduce our laboratory

(members, space facility, etc.), and explain the study. Par-

ticipants are then invited for a second session for testing,

and during this session, they are once again acclimatized

to the laboratory environment for 60 min by interacting

with the lab members that they now know, and discuss var-

ious topics of interest to them. Memory is assessed after

this period of acclimatization. Our subsequent studies on

stress and memory in aged humans were successful at

showing equivalent glucocorticoid levels before exposure

to stress.

In 1997, we published a study assessing the eﬀects of a

psychosocial laboratory stressor on memory performance

in acclimatized older adults (Lupien et al., 1997). The

results revealed similar glucocorticoid levels before expo-

sure to stress, and also showed that older participants

who presented an early increase in glucocorticoid levels

in anticipation of the stressor had poor memory perfor-

mance before and after being confronted with the stressor,

while older participants not showing any change in gluco-

corticoid levels in anticipation of the stressor did not pres-

ent changes in memory performance before or after the

stressor. These results showed that increases of glucocorti-

coids in response to environmental changes are potent pre-

dictors of memory performance in older adults.

Now, a close look at the studies that reported impaired

memory performance in older adults when compared to

young show that the majority of studies tested memory

Reactivity to Stress in Young and Aged

-60 0 +10 +15 +20 +25 +30 +35 +40 +45

0.0

0.5

1.0

1.5

2.0

Young

Aged

Cortisol

Stressor

Arrival to Lab

Salivary Cortisol (microgram/dl)

Fig. 5. Salivary cortisol levels in a group of young and aged humans upon

their arrival to the laboratory and before and after exposure to a

psychosocial stress (personal data from Lupien, S.J.). The Figure shows

that older adults presented an increase in cortisol levels upon arrival to the

laboratory, 1 h before actual exposure to the laboratory stress.

224 S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237

in undergraduate students directly at their university

department. Consequently, when tested for memory, these

university students were in a familiar (they did not have to

ﬁnd their way to the department), predictable (they had

been there before) and controlled (they were familiar with

the setting of university life) environment, and were pre-

sented with a task that was unchallenging for them, such

as learning a list of words (Chantome et al., 1999), or learn-

ing a short story (Foster et al., 1999). These are tasks that

are intrinsically related to the life of university students

who have to perform similar tasks on a daily basis (Hasher,

Zacks, & Rahhal, 1999; Radvansky, Zacks, & Hasher,

1996).

Many studies have now revealed that these memory

tests, which emphasize the memory component of the task,

put older adults at a disadvantage relative to younger

adults (Hasher et al., 1999; Radvansky et al., 1996; Rahhal,

Colcombe, & Hasher, 2001; Rahhal, May, & Hasher,

2002). These studies revealed that if instructions on the

same memory test are modiﬁed in order to de-emphasize

the memory component of the test, the age diﬀerences pre-

viously observed on the memory test are absent (Hasher

et al., 1999; Rahhal et al., 2001). Other studies showed that

age-related diﬀerences in memory performance on tests of

short narratives can be abolished when the information

to be remembered convey information about the character

(a good or a bad person), more than about perceptual

details (a man or a woman) (Fung & Carstensen, 2003;

Radvansky et al., 1996; Rahhal et al., 2002). So when the

testing environment allows for more control from the older

adults, age diﬀerences in memory performance are

abolished.

Also, and although time of testing in the various studies

that have assessed memory performance in young and

older adults is not seldom provided, there is some evidence

that many studies tend to be scheduled in the afternoon

hours (May, Hasher, & Stolzfus, 1993). Numerous studies

have revealed that older adults perform better on various

cognitive tasks when tested in the morning (between 8

and 11am), while young adults perform better when tested

in the afternoon hours (between 1 and 5 pm) (Hasher et al.,

1999; Li, Hasher, Jonas, Rahhal, & May, 1998; May &

Hasher, 1998; May et al., 1993; Winocur & Hasher, 2004;

Winocur & Hasher, 1999). Given that optimal levels of glu-

cocorticoids are reached at the time of awakening and not

at a particular time (e.g. 8 am) of the day, and since young

adults tend to wake up later than older adults, this ‘‘syn-

chrony eﬀect’’ reported in the literature could partly be

explained by the circadian variations of glucocorticoids

that occur as a function of awakening time in young and

older participants.

In contrast to young participants, in most of the studies

measuring memory in older adults, the older individual had

to travel (by car, taxi or by bus) to the location (in most

cases, a hospital or a university setting) where the study

was performed, and once there, was asked to perform tasks

of word lists, paragraph recall, etc. In summary, the neces-

sity for these older participants to ﬁnd their way to the uni-

versity or hospital, enter an unfamiliar building, and meet

with new people who would test their ‘‘maybe declining’’

memory (see Lupien & Wan, 2004) with tasks that did

not provide any meaning for them constituted the perfect

cocktail of novelty, unpredictability and uncontrollability

that deﬁnes a stressful situation. Given the well-known

eﬀects of stress-induced endogenous increase in glucocorti-

coids on learning and memory, it might be possible that

due to the larger stress response induced by the testing

environment in older adults, a certain proportion of the

‘age-related memory impairments’ reported in this popula-

tion is spurious, and induced by the testing environment

(and the stress response that goes with it) to which we

expose them when we test their memory performance.

The data and points presented above could just as well

be related to memory performance and have little impact

on our general models of brain and cognition in human

populations. Yet, we believe that a closer look at various

models of brain and cognition in terms of the potential

impact of stress are necessary in order to understand some

of the discrepancies reported in the ﬁeld of brain and cog-

nition. Here, we would like to discuss the association

between memory and hippocampal volume in young and

older populations.

5.2. The association between memory and hippocampal

volume: A potential impact of stress?

One day, I was giving a presentation to a group of 5-

year-old children about the basis of memory function in

humans. I told them that in our brains, we have a small

structure that looks like a sea horse (which is why we call

it the ‘hippocampus’), which varies in size from 2 to 5 cc.

I continued my story by telling them that we know that

the hippocampus helps us to memorize things and that

the bigger it is, the better is our memory. A little girl sitting

in the front row then looked at me very seriously and asked

me the following very interesting question: ‘‘Are you sure?’’

The response of many of us to this blunt question would

likely be ‘‘no’’, mainly because the macroscopic size of the

hippocampus as revealed by magnetic resonance imaging

(MRI) studies is still a very crude neurobiological measure,

and also because this little girl’s question elicits in most of

us memories of the failures of phrenology a century ago.

However, when carefully reading the literature on memory

and hippocampal volumes (HVs) in human populations,

one can easily grasp the implicit assumption that such a

relation exists, and this assumption ﬁnds its origins in

two very diﬀerent ﬁelds.

The ﬁrst one concerns the study of the eﬀects of hippo-

campal resection on memory function (Milner, 1972; Sco-

ville & Milner, 1957). In humans, studies of temporal lobe

epilepsy patients whose epileptogenic focus was surgically

excised have shown relations between the extent of resection

and the degree of memory impairment (Corkin, Amaral,

Gonzalez, Johnson, & Hyman, 1997; Rempel-Clower, Zola,

S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237 225

Squire, & Amaral, 1996; Stefanacci, Buﬀalo, Schmolck, &

Squire, 2000; Zola-Morgan, Squire, & Amaral, 1986). Sim-

ilarly, studies in monkeys showed that monkeys with cir-

cumscribed hippocampal lesions were moderately

impaired, whereas monkeys with lesions that included the

hippocampal region as well as adjacent cortex were severely

impaired (Zola-Morgan, Squire, & Ramus, 1994). The sec-

ond ﬁeld of research that contributed to the notion that big-

ger HVs are associated with better memory performance

concerns studies of brain morphology in older individuals

suﬀering from Alzheimer’s disease (AD). In this population,

studies revealed the presence of a signiﬁcant positive

association between HV and memory performance (Bondi

& Kaszniak, 1991; Kohler et al., 1998). Further post-mor-

tem studies conﬁrmed that a signiﬁcant pathological pro-

cess was under way in the hippocampus of these

populations (Braak & Braak, 1991; Mann, 1991; McKhann

et al., 1984), which lent unequivocal support to the notion

that hippocampal atrophy is related to memory

impairments.

The results obtained in AD patients were then extended

to older human populations, who were also known to show

memory impairments when compared to younger popula-

tions (see above). In 1994, Golomb and collaborators

(Golomb et al., 1994) published the ﬁrst study showing a

positive correlation between HV and memory performance

in a group of healthy older adults, thus leading the way

toward the hypothesis that in terms of HV, ‘‘bigger is bet-

ter’’ (van Petten, 2004), even in normal populations. Over

the years, this result has been conﬁrmed on many occasions

(Convit et al., 1995; Convit et al., 1995; Convit, Wolf,

Tarshish, & de Leon, 2003; de Leon et al., 1995; de Leon

et al., 2001; de Leon et al., 1993; Golomb et al., 1994;

Golomb et al., 1994; Hackert et al., 2002; Lupien et al.,

1998; Reiman et al., 1998; Rusinek et al., 2003; Sullivan,

Marsh, Mathalon, Lim, & Pfeﬀerbaum, 1995), although

an absence of a signiﬁcant correlation between HV and

memory in older humans has also been frequently reported

(Cahn et al., 1998; de Toledo-Morrell et al., 2000; Laakso,

Hallikainen, Hanninen, Partanen, & Soininen, 2000; Mac-

Lullich et al., 2002; Marquis et al., 2002; Petersen, Jack,

Xu, Waring, & O’Brien, 2000; Raz, Gunning-Dixon, Head,

Dupuis, & Acker, 1998; Rodrigue & Raz, 2004; Tisserand,

Visser, van Boxtel, & Jolles, 2000; van Petten, 2004; Visser

et al., 1999).

Based on the hypothesis that there exists a positive cor-

relation between HV and memory, Foster et al. (1999) then

measured HV and memory performance in a group of 18

young university students. Results revealed the presence

of a signiﬁcant negative correlation between HV and mem-

ory performance in these young subjects. The same year,

Chantome et al. (1999) reported a similar negative correla-

tion between HV and memory performance in a group of

72 young adults. More recently, van Petten (2004) pub-

lished a meta-analysis on the correlations between HV

and memory across the lifespan. The results showed that

a negative relationship between HV and memory (‘‘smaller

is better’’) was signiﬁcant for studies with children, adoles-

cents, and young adults. For studies with older adults, the

meta-analysis revealed that the correlation between HV

and memory performance grew more positive as the age

of the sample increased. Consequently, the signiﬁcance of

small versus large HV for memory performance seems to

be diﬀerent in young and aged populations. How could this

be?

These results have been interpreted as suggesting that

there may be at least two diﬀerent mechanisms operating

in determining the direction of the correlation between

HV and memory performance in young and older popula-

tions. In healthy young people, the factor explaining the

observed negative correlation between HV and memory

would be the degree of neural pruning that has taken place

during childhood and adolescence. It is known that during

development, more neurons, axons, synapses and receptors

are generated than are subsequently retained in the brain

during adulthood (‘‘pruning’’, Cowan, Fawcett, O’Leary,

& Stanﬁeld, 1984). It has thus been suggested that an

‘‘inadequately pruned hippocampus may mediate memory

less eﬃciently than a well pruned hippocampus’’ (Foster

et al., 1999), which would explain why there is a negative

correlation between HV and memory performance in

young subjects. The meta-analysis by van Petten (2004)

also revealed that between the ages of 4 and 18, the volume

of the hippocampus shows little absolute change while

whole brain volume increases until the age of 15. Thus,

throughout development the hippocampus takes up a

declining percentage of the brain. One would therefore

expect memory performance to improve as hippocampal

volume decreases when taken as a proportion of whole

brain volume; hence the observed negative correlation

(van Petten, 2004). In older individuals, the factor explain-

ing the observed positive correlation between HV and

memory would 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 HV (Goldstein et al., 2001; Good et al., 2001a,

2001b; Grachev, Swarnkar, Szeverenyi, Ramachandran,

& Apkarian, 2001; Gur et al., 1991; Jernigan et al., 2001;

Sullivan et al., 1995), suggesting that with aging, there is

a gradual loss of hippocampal tissue. The ﬁrst eﬀect of this

age-related decline in HV would be greater variability in

the HV of older adults, when compared to young people.

The second eﬀect of this age-related decline in HV would

be the presence of poor memory abilities in older adults

with hippocampal atrophy. The net consequence of these

two eﬀects would be the presence of a positive correlation

between HV and memory performance in older adults

(Foster et al., 1999; van Petten, 2004).

However, there are two major problems with this inter-

pretation. The ﬁrst one relates to the notion that a signiﬁ-

cant age-related decline in HV has to be present in older

subjects in order to induce suﬃcient variability and observe

a positive correlation between HV and memory perfor-

mance. The problem with this postulate is that it implies

226 S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237

that the dispersion around the mean (i.e., the standard

deviation) of HV in young subjects should be smaller than

the dispersion observed in older individuals. However, this

is not the case. In fact, already in 1995, it was reported that

a wide range of ‘‘normal’’ HV was present in studies of nor-

mal young individuals (Jack, Theodore, Cook, & McCar-

thy, 1995). At the time, these authors attributed this

variability to inter-institutional diﬀerences in hippocampal

boundary criteria and in the software employed for assess-

ing HV. However, in 1993, the International Consortium

for Brain Mapping (ICBM) was formed with a grant from

the NIMH. This consortium is composed of four core

research sites (UCLA, MNI, U. Texas, Heine U. Ger-

many), and it allows for a distribution of labor into paral-

lel, complementary tasks and creates a ‘‘real world’’

environment among participants such that diﬀerences in

equipment, software, and protocols are minimized, thus

leading to a statistical atlas of the normal adult brain using

the same methodology. In order to assess the degree of var-

iability in HV in young and older adults, we have gathered

data on the HV of 177 individuals ranging from 18 to

86 years of age from the ICBM database. In this popula-

tion, we replicated the negative correlation between age

and HV usually obtained in the scientiﬁc literature (Lupien

et al., In press). In order to assess the degree of variability

in HV as a function of age, we split participants into 5 age

groups of 40 ± 2 individuals (18–24, 25–40, 41–59, 60–75,

and 76–85 years), and assessed the percentage of diﬀerence

in HV in the lowest and highest quartile of each age group.

In accordance with the results of previous studies on age

and HV, the ANOVA comparing HV across age groups

revealed a signiﬁcant main eﬀect of Group [F(4, 175) =

20.79, p< .0001], with a stepwise decline in HV across

groups. Although we replicated previous age diﬀerences

in HV, we were most interested in assessing whether young

individuals would present a smaller inter-individual vari-

ability (a signiﬁcantly smaller standard deviation) in HV

when compared to older individuals.

Here, ﬁve important results emerge from our analysis.

The ﬁrst thing that emerges from our data is that even if

we observed signiﬁcant age diﬀerences in HV, there is the

presence of a very large inter-individual variability of HV

in each group, as shown by the large SD of the mean HV

for each age group.

The second interesting observation that emerges is that

within the same age-range, the percentage of diﬀerence

between the lowest quartile of HV and the mean HV of

the age group is substantive, ranging from 12% in the

18–24 and 41–59 age groups, to an average of 21% in the

other age groups.

Third, we found that these diﬀerences in quartiles can be

attributed to age, only in the oldest group of individuals

(76–85 years). Age ranges below 76–85 years do not present

diﬀerences in the age of the lowest and highest quartiles,

although HV diﬀerences are substantial.

Four, these data show that the smallest HV in young

adults (lowest quartile in the 18–24 group being 3.82) is

equivalent to the highest HV in older adults (highest quar-

tile in the 76–85 group being 3.86), showing modest but sig-

niﬁcant overlap between the distributions of HV in these

two age groups (see Fig. 6).

Finally, there is a systematic diﬀerence of about 1 cubic

centrimeter (cc) between the HV of the lowest and highest

quartiles in each age group, and there is a similar diﬀerence

of about 1 cc in the mean HV of young adults (18–24) and

older adults (76–85 years). In summary, these results show

that even if older individuals present smaller HV when

compared to young individuals, the inter-individual vari-

ability in HV within the same age group is equal to, or lar-

ger than, the inter-individual variability across age groups.

The observation of a large inter-individual variability in

HV in young healthy participants has important implica-

tions for the notion of hippocampal ‘atrophy’ in older

adults. Indeed, our results showing that about 25% of 18-

to 24-year-old individuals present HV as small as those

observed in the average older adults aged 60–75 years raise

the issue of the signiﬁcance of the negative association usu-

ally obtained between age and HV (Goldstein et al., 2001;

Good et al., 2001a, 2001b; Grachev et al., 2001; Gur et al.,

1991; Jernigan et al., 2001; Sullivan et al., 1995). These cor-

relations have been interpreted as showing that during

aging, there is a gradual atrophy of the hippocampus.

However, given the fact that 25% of young adults present

very small HV that fall in the range of individuals aged

60–75 years, it might still be possible that the HV measured

at any given age reﬂects a volume that was pre-determined

based on early experiences.

Indeed, the signiﬁcant inter-individual variability in HV

that we observed in young adults could arise from both

genetic and experiential factors. From a study of monozy-

gotic and dizygotic elderly twins, Sullivan, Pfeﬀerbaum,

Swan, and Carmelli (2001) estimated that some 40% of

the variance in late-life HV can be attributed to genetics,

while the other 60% reﬂect experiential factors. Such expe-

riential factors could operate to increase or decrease HV

across the life span. Animal studies have shown that envi-

ronmental enrichment (Kempermann, Jessberger, Steiner,

2.57cc 4.26cc

Hippocampal Volumes

Frequency

3.65cc 5.13cc

Oldest

Mean Highest Quartile Oldest : 3.86cc

Mean Lowest Quartile Youngest : 3.82cc

Youngest

Fig. 6. Schematic representation of the distribution of HV in the age

groups in the Lupien et al., study (in press). The values displayed on

X-axis represent the minimum and maximum HV observed in each age

group in a total population of 177 individuals.

S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237 227

& Kronenberg, 2004; Kempermann, Kuhn, & Gage, 1997;

Kempermann, Kuhn, & Gage, 1998; Mlynarik, Johansson,

& Jezova, 2004) and nutritional factors (Will, Galani, Kel-

che, & Rosenzweig, 2004) are potent inducers of changes in

neurogenesis and/or dendritic arborization in the hippo-

campus, documented to lead to changes in HV (Clayton

& Krebs, 1994; Suzuki & Clayton, 2000). Also, glucocorti-

coids have been shown to be one of the most potent factors

acting on the volume of the hippocampus (Gould, Beylin,

Tanapat, Reeves, & Shors, 1999; Gould, Tanapat, Has-

tings, & Shors, 1999; Kozorovitskiy & Gould, 2004; Mires-

cu, Peters, & Gould, 2004). Studies showed that gestational

stress decreases hippocampal neurogenesis in adult rats

(Lemaire, Koehl, Le Moal, & Abrous, 2000) and juvenile

monkeys (Coe et al., 2003), and these deﬁcits are long-last-

ing since they are observed over the entire lifespan of the

animals (Lemaire et al., 2000). Also, post-natal handling

has been shown to prevent the prenatal stress-induced def-

icits in hippocampal neurogenesis (Lemaire, Lamarque, Le

Moal, Piazza, & Abrous, 2006).

The similar distribution of volumes across age groups

does not mean that normal aging could not have eﬀects

on HV. Here, a longitudinal study of both young and older

participants would help resolve this issue. Such a study

would be very important because any age eﬀect observed

in a cross-sectional study can be obscured by a cohort

eﬀect. Indeed, if experience has an impact on HV as sug-

gested by the studies reported above, then diﬀerent life

experiences as a function of date of birth could have a sig-

niﬁcant eﬀect on HV in humans. An individual born in

1915, during World War I, who lived through two major

wars, could present smaller HV due to exposure to these

stressful experiences, compared to an individual born in

1980, at a time of relatively peaceful events. Tested in

2001, the ﬁrst individual would be signiﬁcantly older than

the second, yet it does not mean that the ‘age diﬀerence’

observed in HV is mainly due to chronological age (for a

review on this issue, see Lupien & Wan, 2004). It could also

be related to diﬀerent life experiences, as a function of date

of birth. Fig. 7 presents the HV of the ICBM participants

as a function of the generation in which they fall given their

birth date. One can see from this ﬁgure that there may be

other ways to look at HV as a function of age. One way

to disentangle the eﬀects of life experience (cohort eﬀect)

versus age (age eﬀect) on HV would be to assess diﬀerences

in HV as a function of diﬀerent experiences (e.g., socioeco-

nomic status) in individuals of the same cohort or age. Any

diﬀerence in HV would then represent the eﬀect of experi-

ence, rather than age.

The second major problem with the interpretation that a

diﬀerent mechanism (pruning vs. atrophy) can explain the

inverse correlations between memory and HV in young

and older adults, is that such an interpretation would imply

the intriguing notion that there is something like an ‘‘expi-

ration date’’ on a small HV. Why would a small HV in an

individual be good for memory when this person is 25 years

old and suddenly turn bad when the individual is 65? If the

pruning hypothesis is taken as a plausible explanation for

the negative correlation between HV and memory obtained

in young people, then it would not apply to young individ-

uals with small HV, since this small HV would imply that

adequate pruning has been achieved. Clearly, no one would

suggest a pathological process leading to a small HV in a

young individual. Indeed, only in older individuals would

this interpretation seem plausible.

5.2.1. Hypothesis 1: Optimal hippocampal volume threshold

for memory processing

One way to interpret these results would be to suggest

that there exists an optimal hippocampal volume threshold

for memory processing in humans. In our study, the oldest

adults with the largest HV presented a mean HV of 3.86 cc.

This volume is similar to the one observed in the youngest

adults with the smallest HV (3.82 cc). Given the overlap

between the distribution of HV in young and older adults,

it might be possible that a hippocampal volume threshold

exists with regard to memory processing, thus ensuring

optimal memory performance at a certain HV (e.g.,

3.8 cc). Given that older populations present an age-related

decline in HV, this optimal HV would represent the largest

HV in the older adults, while it would represent the small-

est HV in younger populations, explaining the positive cor-

relation between HV and memory observed in older adults,

and the negative correlation between HV and memory

observed in younger adults (see Fig. 8).

One way to test this hypothesis would be to assess HV in

a large sample of young and older adults and test for the

Mean HC

5000

4000

3000

2000

World War I

1914-1919

Post World War I

1920-1938

World War II

1939-1945

BabyBoom

1945-1965

Generation X

1966-1981

GENDER

FEMALE

MALE

Fig. 7. Mean hippocampus (HC) of 177 individuals from 18 to 86 years of

age from the International Consortium for Brain Mapping project. The

hippocampal volume of participants is presented as a function of the

generation in which they fall given their birth date.

228 S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237

presence of a quadratic function between HV and memory

performance across the entire age range of participants.

5.2.2. Hippocampal volume and memory: An

epiphenomenon?

If the optimal volume threshold hypothesis is not valid,

then the data and arguments presented above would thus

tend to suggest that the reverse correlations between HV

and memory performance observed in young and older

humans are spurious results. However, there is a second

important factor that could explain these reverse correla-

tions without the necessity of using two diﬀerent mecha-

nisms (i.e., pruning vs. atrophy). This factor has its origin

in the diﬀerential stress reactivity of young and older

humans to the testing environment to which they are

exposed when their memory is assessed, and in the impact

of this stress reactivity on memory performance. As we

have seen earlier, there are many factors that are related

to stress responsivity in humans and that are more frequent

when we test older adults compared to young adults. It

might thus be possible that the inverse correlations

observed between HV and memory in young and older

adults is not due to an optimal threshold for memory in

HV (as suggested above in hypothesis # 1), but rather to

variation in memory performance as a function of the envi-

ronment in which we test young and older adults. Here,

older adults would be at a disadvantage because they are

more reactive to the environment in which we test their

memory and they have a smaller HV. We based this sugges-

tion on new studies showing that the price to pay for stress

seems to be greater in individuals with small hippocampal

volumes, when compared to individuals with large hippo-

campal volumes.

5.2.3. Stress, memory, and hippocampal volume—the debate

The same year that Golomb et al. (1994) published the

positive correlation between HV and memory in older

adults, we published the results of a longitudinal study

(Lupien et al., 1994) showing that one of the correlates of

memory impairments in older humans is chronic secretion

of elevated levels of glucocorticoids over years. A few years

later, we reported that older participants with chronic

exposure to high levels glucocorticoids over years had a

14% smaller HV when compared to older participants with

normal glucocorticoid levels over years (Lupien et al.,

1998). These results were in line with the ‘‘glucocorticoid

cascade hypothesis’’ proposed by Sapolsky, Krey, and

McEwen (1986), which stated that chronic secretion of high

levels of glucocorticoids can have neurotoxic eﬀects on the

hippocampus, with disturbances in dendrite branching,

neurogenesis and glucose metabolism, eventually resulting

in atrophy of the structure (Sapolsky et al., 1986).

Following the publication of this hypothesis, various

studies were performed in humans which revealed signiﬁ-

cant ‘‘atrophy’’ of the hippocampus in various psychiatric

disorders that present both memory impairments and high

reactivity to stress, such as depression (Krishnan et al.,

1991; Sheline, 1996; Sheline, Gado, & Kraemer, 2003; She-

line, Sanghavi, Mintun, & Gado, 1999; Sheline, Wang,

Gado, Csernansky, & Vannier, 1996; Vythilingam et al.,

2004), post-traumatic stress disorder (PTSD) (Bremner,

2003; Bremner, 2002; Vythilingam et al., 2002), and schizo-

phrenia (Heckers, 2001; Nelson, Saykin, Flashman, &

Riordan, 1998). Here, recent meta-analyses have calculated

HV reduction in the range of 4% in schizophrenia (Nelson

et al., 1998), 7% in PTSD (Smith, 2005), and 9% in depres-

sion (Videbech & Ravnkilde, 2004), when comparing the

HV of patients to that of healthy normal controls. These

percentages of HV diﬀerences between patients and control

groups were in line with experiments performed in rodents

that reported that chronic exposure to stress leads to hip-

pocampal atrophy (Magarinos & McEwen, 1995; Magari-

nos, Orchinik, & McEwen, 1998; Magarinos, Verdugo, &

McEwen, 1997; McEwen et al., 1997; McEwen & Magari-

nos, 1997; McEwen, Magarinos, & Reagan, 2002; McKit-

trick et al., 2000). However, in these animal post-mortem

studies, HVs were never measured before and after expo-

sure to chronic stress, given the invasive nature of the

assessment of hippocampal morphology in this species.

The use of repeated in vivo MRI assessments before and

after exposure to chronic stress in tree shrews (Ohl,

Michaelis, Vollmann-Honsdorf, Kirschbaum, & Fuchs,

2000) and monkeys (Lyons, Yang, Sawyer-Glover, Mose-

ley, & Schatzberg, 2001) failed to show changes in HV after

stress in these species.

Consequently, researchers started to look at the other

side of the correlation between HV and mental health,

and to raise the possibility that inherited variations in HV

may lead to variations in the vulnerability of humans to

the eﬀects of stress on cognition and mental health. Results

in humans in line with this suggestion have been obtained.

Remember that a signiﬁcant number of studies revealed the

presence of a hippocampal ‘‘atrophy’’ (in the range of 7%)

in patients suﬀering from PTSD when compared to individ-

uals exposed to the same trauma, but who did not develop

PTSD. In 2002, Gilbertson and collaborators (2002) pub-

lished a study in which they conﬁrmed the presence of

smaller HV in war-veterans suﬀering from PTSD (Gilbert-

son et al., 2002). However, in the same study, they showed

2.57cc 4.26cc

Hippocampal Volumes

Memory Performance

3.65cc 5.13cc

Optimal Volume Threshold

3.8cc??

HV in Older Adults HV in Younger Adults

Positive

Correlation Negative

Correlation

Fig. 8. Schematic representation of the optimal volume threshold

hypothesis. See text for a description of this hypothesis.

S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237 229

that these men’s monozygotic twin brother who never went to

war also had small HV when compared to the monozygotic

twin brother of the war-veterans who did not develop

PTSD. Given the large similarities of HV reported to occur

in human monozygotic twins (Sullivan et al., 2001), these

results strongly suggested that the men who went to war

and developed PTSD entered the war zone with a smaller

HV to begin with relative to the men who went to war

and did not develop PTSD. Consequently, the HV may

actually be a pre-existing condition that increases vulnera-

bility to PTSD upon exposure to a traumatic experience,

rather than the consequence of the trauma.

Support for the notion of inherited variations in HV

comes from studies that have revealed smaller HV in

ﬁrst-episode untreated depressed patients (Frodl et al.,

2002), and ﬁrst episode untreated schizophrenics (Narr

et al., 2004), a ﬁnding that goes against a neurotoxic eﬀect

of depression and/or schizophrenia on HV. In summary,

these results suggest that individuals with small HV may

be more reactive to environmental stress than individuals

with large hippocampal volumes. At ﬁrst glance this notion

would also seem to fall short in explaining the negative cor-

relation observed in young populations.

5.2.4. Hypothesis 2: Sensitive volume threshold for adequate

memory processing under stress

Given that older adults present smaller hippocampal vol-

umes when compared to young, it may be suggested that the

positive correlation reported between hippocampal vol-

umes and memory in older adults is due to the acute stress

response induced by the testing environment in these partic-

ipants. Taken in its purest form, this hypothesis implies that

the real association between hippocampal volumes and

memory is negative in both young and old. However, since

we have no indications that this might be the case, we have

to adopt the null hypothesis and postulate that under base-

line, non stressful conditions, there is no correlation

between hippocampal volumes and memory performance

in young or older adults. This postulate is represented by

the blue line in Fig. 9 below. We also postulate the presence

of a sensitive volume threshold for adequate memory pro-

cessing under stress. This sensitive volume threshold is rep-

resented by the red line in the Fig. 9.

Given that older adults present smaller hippocampal

volumes than younger adults, their hippocampal volume

has a greater probability of falling within the sensitive vol-

ume threshold range. If this is the case, any exposure to a

stressful event would have a signiﬁcant detrimental impact

on memory performance in older adults. Given that mem-

ory testing may be more stressful in older populations, this

factor could explain the presence of a positive correlation

between hippocampal volumes and memory performance

in older adults. In contrast, young adults present larger

HV than older adults, and consequently, they fall in the

range of lower sensitivity to stress and consequently, less

impairment of memory function under stress. Moreover,

most of the time, young adults are tested in non-stressful

conditions, which give them an additional advantage over

older adults. The main problem with this model is that it

does not explain the negative correlations obtained

between HV and memory performance in young adults.

Here, the model suggests the absence of any correlation

between HV and memory in young adults. The absence

of a correlation between HV and memory performance

could have been obtained in a large set of studies, but given

the fact that most of the negative ﬁndings are seldom pub-

lished, we may not be aware of these data in the develop-

ment of a scientiﬁc model of the association between

stress, HV, and memory performance in humans. It is clear,

however, that these associations need further investigation.

6. Conclusions

In this paper, we have reviewed the literature on the

eﬀects of stress and stress hormones on human cognitive

function with a special emphasis on glucocorticoids given

their capacity to cross the blood–brain barrier and access

the brain where they can inﬂuence learning and memory

through binding to speciﬁc receptors.

We have ﬁrst provided a historical background of the

eﬀects of glucocorticoids on cognitive function with a par-

ticular emphasis on steroid psychosis. Our goal here was to

inform the clinical neuropsychologist and other researchers

interested in cognitive function that some of the neuropsy-

chological impairments observed in certain patients could

be related to exogenous exposure to high levels of glucocor-

ticoids, due to certain medical conditions and/or steroid

medications.

In the second part of the paper, we have summarized the

literature showing the eﬀects of exogenous administration

of glucocorticoids on cognitive function sustained by the

hippocampus and frontal lobes, the two brain regions

containing the largest concentrations of glucocorticoid

receptors. We have shown here that the eﬀects of stress

Hippocampal Volumes

Memory Performance

Sensitive Volume Threshold

Memory Performance in Unstressful Conditions

Memory Performance in

Stressful Conditions

STRESS

Range of HV in

Older Adults Range of HV in

Youn

Adults

Fig. 9. Schematic representation of the sensitive volume threshold

hypothesis. The arrows represent changes in memory processing during

stress as a function of hippocampal volume and age of the participant.

230 S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237

hormones on human cognition are best understood in line

with the inverted-U shape function between glucocorti-

coids and cognitive performance. This inverted-U shape

function between circulating levels of glucocorticoids and

memory performance is explained by the presence of two

glucocorticoid receptor types that diﬀer greatly in terms

of their aﬃnity for glucocorticoids.

In the third part of the paper, we have summarized the

studies that have assessed the eﬀects of an endogenous

increase of glucocorticoids as induced by exposure to a

stressful situation, on cognitive performance. Here, it was

shown that an endogenous increase of glucocorticoids as

induced by exposure to environmental and/or psychosocial

stress is as eﬃcient at inducing cognitive impairments, as is

an exogenous increase of glucocorticoids.

Finally, in the last section of the paper, we have argued

that the environmental context in which we test our partic-

ipants might induce a stress response in sensitive individu-

als, which could then impact on their cognitive

performance. In order to delineate this point, we have used

the model of studies on human aging in which the majority

of studies reported impaired cognitive function in older

adults when compared to young. We have argued that

some of these eﬀects might be due to the stress that is gen-

erated by the testing conditions that we use to study young

and older adults. We went one step further in our analysis

by suggesting that the inverse correlations observed

between HV and memory performance in older and young

adults could also be due to a diﬀerential reactivity of young

and older adults to the testing environment.

Clearly, the ﬁeld of psychoneuroendocrinology, which

studies the eﬀects of hormones on human brain and behav-

ior, contributed signiﬁcantly at showing the impact of

stress on human cognitive function. It is our hope that

by combining our expertise with that of the ﬁeld of cogni-

tive neuropsychology, we will be able to delineate with high

accuracy the processes of cognitive function in humans that

are not tainted by stress eﬀects. We also hope that the com-

bination of our ﬁelds will help in the understanding of the

eﬀects that stress can have on learning and memory in

humans of all ages.

Acknowledgments

The studies of Lupien et al., reported in this paper have

been funded by grants from the Canadian Institutes of

Health Research, grants from the National Science and

Engineering Research Council of Canada, and The John

D. and Catherine T. MacArthur Foundation to S.J.L.

S.J.L. is funded by an Investigator Award from the Cana-

dian Institute of Aging of the Canadian Institutes of

Health Research.

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Effects of cognitive and stress management training in middle-aged and older industrial workers in different socioeconomic settings: a randomized controlled study

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Sep 2023

Introduction The demographic change requires longer working lifetime. However, fear of job loss may lead to chronic stress whereas aging and unchallenging work may accelerate cognitive decline and early retirement. Long-time repetitive work led to impairments of cognitive functions in middle-aged and older employees, as demonstrated in a previous study conducted in a large car manufacturer. In the present study, a training concept was implemented to enhance the cognitive and emotional competence of these employees. Methods A first group of employees received a trainer-guided cognitive training only, whereas a wait list control group received a cognitive training and stress management training. This design was applied in two independent samples separated by one year either during or after a socioeconomically tense situation of the factory. Results In sample 1, with a tense occupational situation, the cognitive training effects occurred with a delay of three months. In contrast, in sample 2, with less critical socioeconomic situation, the training effects occurred immediately and persisted three months later. Stress management training showed reduction of subjectively and objectively measured stress level. Discussion The results indicate that effects of cognitive interventions are diminished under chronic stress which can be reduced after a short stress management training. This leads also to enhanced attention and memory in daily life. In contrast, in Sample 2 with less chronic stress, effects of cognitive training were stronger and persisted at least three months later, whereas stress management training had less impact. This suggests that cognitive learning in occupational settings is only efficient at lower stress levels.

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Sep 2023
MED LITH

Background and Objectives: To date, understanding age-related changes in cognitive processes during heat exposure still needs to be better-understood. Thus, the main aim of the current study was to evaluate the effects of whole-body hyperthermia (WBH), i.e., a ≈2.5 °C increase in rectal temperature (Tre) from overnight-fast baseline value, on cognitive functioning in old and young men and to explore factors, such as stress and thermophysiological strain, that could influence such changes. Materials and Methods: Ten young (19-21 years of age) and nine old (61-80 years of age) healthy men underwent an experimental trial with passive lower-body heating in hot water immersion (HWI) at 43 °C (HWI-43 °C) until Tre reached 39 °C in old adults and 39.5 °C in young adults. Cognitive performance and cortisol concentration were assessed before and after HWI, and the physiological strain index (PSI) was assessed during HWI-43 °C. Results: PSI was lower and cortisol concentration was greater after HWI-43 °C in the old group compared with the young group (p < 0.05). Surprisingly, hyperthermia improved cognitive flexibility only in old adults, whereas short-term and visual recognition memories were maintained in both age groups. Conclusions: A ≈2.5 °C increase in rectal temperature can improve executive function in old adults, and this increase parallels the increased cortisol concentration and the lower thermophysiological strain under severe WBH conditions.

Association between childhood trauma, cognition, and psychosocial function in a large sample of partially or fully remitted patients with bipolar disorder and healthy participants

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Sep 2023

Background Childhood trauma (CT) are frequently reported by patients with bipolar disorder (BD), but it is unclear whether and how CT contribute to patients’ cognitive and psychosocial impairments. We aimed to examine the impact of CT on cognition and psychosocial functioning in a large sample of 345 patients with BD and 183 healthy control participants (HC) using the Childhood Trauma Questionnaire, neurocognitive tests and ratings of mood symptoms and functioning. Results Patients showed broad cognitive impairments across memory, attention and executive function and functional disability despite being in partial or full remission and had higher levels of CT than HC. Higher levels of CT correlated with impairments across almost all cognitive domains and lower psychosocial functioning across BD patients and HC. Of these, the associations between CT and poorer working memory and lower psychosocial functioning, respectively, prevailed after adjusting for clinical and demographical variables. Diagnosis of BD and estimated verbal intelligence did not moderate these associations. Analysis of CT sub-categories showed that working memory impairments were related particularly to childhood physical and emotional abuse, while psychosocial difficulties were related to physical and emotional neglect. Conclusions CT may have negative implications for working memory and psychosocial functioning across both BD and healthy populations. If the findings are replicated, this would suggest that early interventions that reduce the frequency of CT in vulnerable families may aid children’s cognitive and psychosocial development.

The effects of stress and stress hormones on human cognition: Implications for the field of brain and cognition

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