The eﬀects of stress and stress hormones on human
cognition: Implications for the ﬁeld of brain and cognition
, 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
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
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
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Corresponding author. Fax: +1 514 888 4064.
E-mail address: firstname.lastname@example.org (S.J. Lupien).
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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
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
The four grades of steroid psychosis as described by Rome and Braceland
Grade 1 Mild euphoria
Grade 2 Heightened euphoria
Flight of ideas
Grade 3 Anxiety
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,
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
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
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
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
´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
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
succeeded Claude Bernard as professor of medicine at the
`ge de France, he reported another controversial ﬁnd-
ing to the Socie
´de Biologie de Paris (Brown-Se
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;
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
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
Type I/Type II
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
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-
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
3.4. Glucocorticoids, the hippocampus, and declarative
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
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, &
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
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
50% Type II
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–
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
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
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
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
CIrculating Levels of Glucocorticoids
Decrease (full line) and restoration (dashed line)
in Cortisol levels
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 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
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, &
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
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
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
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
220 S.J. Lupien et al. / Brain and Cognition 65 (2007) 209–237
4.1.1. Mechanisms underlying memory for emotionally
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,
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
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
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
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
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
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,
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
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
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
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
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
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,
Mean Highest Quartile Oldest : 3.86cc
Mean Lowest Quartile Youngest : 3.82cc
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
World War I
Post World War I
World War II
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
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-
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
Optimal Volume Threshold
HV in Older Adults HV in Younger Adults
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.
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
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
Sensitive Volume Threshold
Memory Performance in Unstressful Conditions
Memory Performance in
Range of HV in
Older Adults Range of HV in
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.
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-
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