LECTURE 6: PSYCHONEUROENDOCRINOLOGY
Objectives:
 Know which hormones can influence our mood and how (i.e, having too much or too little).
 Know where they are produced.
 Know “conditions” (very broadly defined) that can help us understand how hormones influence our mood and
know a sample study/paradigm to study affective influences ( ‘experiments of nature’).
 Know some ways (procedures/tasks) in which we can change hormone levels in the lab.
This is a lecture in three ‘acts’…
ACT I: Background and hormonal fluctuations in healthy
populations
Hormones: typology
Types of hormones
 Amino acid: e.g., melatonin, thyroxine
 Eicosanoid: prostaglandins
 Peptide: adrenocorticotropic (ACTH); Enkephalin (pain regulation); Ghrelin + Leptin; Oxytocin; Insulin; Luteinizing
hormone (LH)
 Steroid: testosterone, estradiol, cortisol, aldosterone, progesterone
The relevant hormones for affective disorders
1)
2)
3)
4)
5)
Testosterone
Estradiol (= the general human form of estrogen)
Progesterone
Oxytocin
Cortisol
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Hormones: functions
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Stimulation/inhibition of growth
Sleep regulation
Regulation of metabolism
Preparation for 3 f's: fighting, fleeing, mating
Control of reproductive cycle
Activation/inhibition of immune system
Preparing body for major transitions: puberty, parenting, menopause
Hormonal production sites in the brain
The hypothalamus and the (posterior and anterior) pituitary are very important.
2
Hormonal production sites in the body
Adrenal glands (NL: bijnieren)
The adrenal glands are involved in response to stressful
conditions. All adrenal hormones help one cope with danger,
terror, or stress.
The adrenal medulla (NL: bijniermerg):
 the inner part of an adrenal gland
 consists out of nervous tissue
 is part of the sympathic nervous system
The adrenal medulla secretes two important hormones:
epinephrine and norepinephrine. These hormones help to
fight with the stressful condition, control blood pressure,
increase heart rate, effect body metabolism and various other
functions.
The adrenal cortex (NL: bijnierschors):
 the outer part of an adrenal gland
 consists three layers
 Adrenal cortical hormones secretion is controlled by the
level of ACTH (adrenocortico-trophic hormone), which is
secreted by pituitary gland.
Zona glomerulosa secretes minrelo-corticoids especially
aldosterone. Aldosterone controls blood volume and blood
pressure. It is involved in haemodynamics.
Zona fasciculata secretes glucocorticoids. The most important
one is called cortisol. Cortisol is involved in stress and it is an
important hormone in managing stress.
Zona reticularis secretes androgens. These hormones are
responsible for development of sexual characteristics.
3
Hormones and the medical context: usages
Many hormones and analogues are used in medication.
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Contraception: Estrogens + progesterons
Autoimmune diseases: Steroids
Respiratory disorders: Steroids
Endocrine disorders: Diabetes: insulin
Dermatology: Steroid creams
Inflammation: Glucocorticoids
How to measure hormones
 Saliva: Cortisol (some do T as well but not as accurate as blood)
 Blood: Testosterone (free [circulating] and total)/estradiol (E2)/progesterone, FSH, LH, Insulin
 Urine: Estrogen metabolites, assessment of adrenal function: glucocorticoids and mineralcorticoid metabolites
Hormones vs. Neurotransmitters
Hormones
Larger spatial and temporal scale
Unrestricted travel in circulatory system
Slow signaling (sec/min/hours)
Continuous/dimensional
Neurotransmitters
Smaller spatial and temporal scale
Travel restricted to pre-existing nerve tracts
Fast signalling (ms)
All-or-nothing/dichotomous
4
“Normal” covariation of sex hormones and grey matter volume
Little is known about the hormonal effects of puberty on the anatomy of the developing human brain. In this study,
sex-related differences in gray matter volume were examined in 46 subjects aged 8–15 years. Regardless of sex,
amygdala and hippocampal volumes varied as a function of the Tanner stages of pubertal development and were
associated with circulating testosterone (TEST) levels. By contrast, striatal grey matter volumes were unrelated to
pubertal development and circulating steroid hormones. Whole-brain regression analyses revealed positive
associations between circulating estrogen (EST) levels and parahippocampal grey volumes as well as between TEST
levels and diencephalic brain structures. In addition, a negative association was found between circulating TEST and
left parietal grey matter volumes. These data suggest that grey matter development in certain brain regions is
associated with sexual maturation and that pubertal hormones might have organizational effects on the developing
human brain.
 Positive correlation between
testosterone (TEST) and grey matter
volume of the thalamus
 Negative correlation between
testosterone (TEST) and grey matter
volume of the precuneus/grey matter
volume in the superior parietal area
 Positive correlation between estrogen
(EST) and grey matter volume of the
uncus/parahippocampal grey matter
volume
5
The menstrual cycle (and the changing levels of hormones)
The menstrual cycle consists a few main phases…
1) The first phase, which is menstruation, begins on the first day of your period. During menstruation hormones,
oestrogen and progesterone, are relatively low.
2) In the second phase, also known as the follicular phase, FSH (or follicle-stimulating hormone) is released, which
causes immature eggs to develop. These follicles cause a lot of oestrogen to be produced, and the lining of the
uterus thickens, for a possible egg to be embedded.
3) The third phase in ovulation, and is when a mature egg is released from the ovary. It is triggered by an abrupt rise
in LH (or luteinising hormone). At ovulation, the cervix moves higher and its opening widens. The release of the
egg and the movement of the cervix is why some women experience cramps or aches at ovulation, and why some
women experience ovulation spotting. After ovulation, the egg enters the fallopian tube and moves along the
uterus.
4) The fourth phase, also known as the luteal phase is when oestrogen production drops and progesterone
increases. This further thickens the uterine lining to allow for a fertilized egg to embed. If fertilization doesn’t
occur, the egg breaks down, and progesterone levels drop, which disintegrates the uterine lining, in preparation
for a period. This drop in progesterone is why some women experience mood swings, bloating, tender breasts or
tiredness.
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Hulk or teddy bear? Menstrual cycle effects of male attractiveness
Two testing sessions were arranged for the sampling of individuals' preferences during phases of both high and low
conception risk in their menstrual cycles. Ovulation was assumed to occur 14 days before the onset of menses.
Sessions after ovulation and before the onset of menses (the luteal phase) and sessions during menses were
classified as 'low conception risk'. Sessions in the follicular phase (between the end of menses and ovulation) were
classified as 'high conception risk'.
Subjects were asked to select the face that they considered most 'physically attractive' from five Caucasian and,
separately, five Japanese male faces (40% and 20% feminized, on average, and 20% and 40% masculinized). There
was a significant main effect of conception risk, with subjects preferring faces that were less feminized in the highconception-risk phase than in the low-conception-risk phase.
In a second experiment, an interactive method was used that allowed British subjects (mean age 20 years) to alter
composite male face shapes along continua ranging from 50% feminized to 50% masculinized. Subjects were asked
to choose the most attractive face for a 'long-term relationship' or a 'short-term sexual relationship' (a fling, a onenight-stand). Responses to faces were averaged over 'low-risk' and over 'high-risk' sessions. There was no main
effect of conception risk. However, conception risk interacted with type of relationship (short-term or long-term).
For a short-term sexual relationship, the preferred face shape was less feminine during the high-conception-risk
phase, whereas preferences remained constant when women judged attractiveness for a long-term relationship. An
analysis of data from subjects that were using oral contraception revealed no cyclic changes in face shape preference
or interactions.
Dominance and quality as a parent are attributions made at opposite ends of the continuum relating to facial
masculinity, and each might be associated with costs and benefits to reproductive success. A preference for males
with a more masculine appearance might confer benefits for offspring in terms of resistance to disease but confer
costs due to potentially decreased paternal investment. A female might choose a primary partner whose low
masculine appearance suggests cooperation in parental care ('long-term' preferences are unchanged across the
menstrual cycle) but occasionally copulate with a male with a more masculine appearance (indicating good
immunocompetence) when conception is most likely.
Cyclic shifts in the degree of femininity preferred in male faces:
Face shapes that are 50% feminized (left) and 50% masculinized (right).
Mean feminization preferred in Japanese and Caucasian composites by Japanese subjects in
high- and low-conception-risk phases.
Mean femininity preferred across faces for short-term (as a one night stand, a fling) and longterm conditions in high-risk and low-risk phases.
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Diving into psychoneuroendocrinology: the tasks
Given what we know about affective disorders, what kind of tasks might we be interested in?
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Emotion processing
Emotional memory
Emotion regulation
Emotion identification
Emotional learning
Cognitive control
Spatial navigation
Face processing
Error monitoring
The (human) startle response
Startle response = eye blink reflex in humans.
In animals, including humans, the startle response is a largely unconscious defensive response to sudden or
threatening stimuli, such as sudden noise or sharp movement, and is
associated with negative affect. Usually the onset of the startle
response is a startle reflex reaction. The startle reflex is a
brainstem reflectory reaction (reflex) that serves to protect
vulnerable parts, such as the back of the neck (wholebody startle) and the eyes (eyeblink) and facilitates
escape from sudden stimuli. It is found across the
lifespan of many species. An individual's emotional
state may lead to a variety of responses.
A subject’s eyeblink response can be captured and charted
in a wave form for review.
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Premenstrual Dysphoric Disorder (PMDD)
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affects 3-8% of women in childbearing ages.
Symptoms include depression, irritability, moodswings, feelings of tension + anxiety.
Symptoms typically occur 5-11 days before onset of menstrual cycle (thus during luteal phase of the cycle).
Symptoms cease during or after menstruation
The relative relationship/the ratio between estradiol and progesterone in the luteal phase is disturbed in
Premenstrual Dysphoric Disorder (PMDD). Women with Premenstrual Dysphoric Disorder (PMDD) have a smaller
estradiol-progesterone ratio since they have less progesterone.
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Study 1
Women with and without Premenstrual Dysphoric Disorder (PMDD) were presented with pleasant and unpleasant
images. Images were preceded by coloured squares to indicate valence. Each session consisted of 34 blocks
containing three different startle conditions: (1) a black screen during which baseline ASR was measured (control
condition), (2) a red or green screen as the negative or positive anticipation stimuli, (3) an unpleasant or pleasant
picture stimulus. The red screen always preceded unpleasant pictures and the green screen always preceded
pleasant pictures.
Premenstrual Dysphoric Disorder (PMDD) patients displayed an increased difference in startle response to positive
and negative anticipation stimuli in the luteal phase in comparison to control subjects and in comparison to their
own follicular phase responses. This suggests that the neural circuits underlying response to emotional anticipation
are more sensitive during this period. Positive anticipation here isn’t really important for us.
Startle amplitude during positive and negative anticipation stimuli:
10
Study 2
Women with Premenstrual Dysphoric Disorder (PMDD) also have greater difficulty discriminating between
emotional expressions and have greater bias in judging faces as negative during luteal relative to follicular phase.
There were no such effects in comparison women.
There was a significant luteal phase increase in symptom rating scales scores
in women with Premenstrual Dysphoric Disorder (PMDD), but not in
comparison women. Here, we are talking about the Steiner–Carroll
Premenstrual Tension Syndrome Scale (PMTS-S Scale), self-rated version.
There was a significant luteal phase increase in symptom rating scales scores
in women with Premenstrual Dysphoric Disorder (PMDD), but not in
comparison women. Here we are talking about the Beck Depression
Inventory (BDI).
There was a significant luteal phase-related increase in negative bias in
women with Premenstrual Dysphoric Disorder (PMDD), but not comparison
women.
There was a significant luteal phase-related increase in neutral to sad
misjudgment in women with Premenstrual Dysphoric Disorder (PMDD), but
not in comparison women.
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Menopause
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Transition period in a woman when she will stop cycling and her periods will stop
No longer able to become pregnant
Ages (very roughly – big individual differences) between 45-55
Associated with feelings of irritability, anxiety, depression, decreased interest in sexual activity, sleeping problems
Few studies!
A study
 Weak association between higher-level cognitive function and ovarian hormones
 Progesterone levels positively associated with verbal memory and global cognition – no relationship between
estrogens and cognitive performance
 But GIANT design problem of the study: The study only compared two groups of postmenopusal women, but
failed to include peri- or premenopausal women.
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ACT II: “Experiments of Nature”
 “Experiments of nature” (e.g., Bronfenbrenner, 1979; O'Connor, 2003)
 O'Connor (2003): “Experiments in nature — naturally arising conditions in which there is a possibility of
separating otherwise confounded processes or opportunities to examine processes that for ethical or practical
reasons would come in a variety of forms.”
 can be all areas of psychology/medicine. Examples:
- Studies of adopted children following severe deprivation
- Prenatal famine and stress on development
- Prenatal radiation exposure on cognitive development
- In utero hormonal changes
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Endocrine dysfunction: Genetically-linked Disorders
 Changes in DNA can be responsible for endocrine dysfunction.
 This can lead to increases or decreases in testosterone/estrogen in men and women…
 … which can in turn affect physical and cognitive development and psychological functioning (and wellbeing).
Possible mechanisms:
Aldosterone, cortisol and testosterone
are derived from cholesterol and use
many of the same enzymes for their
synthesis in the adrenal cortex.
Therefore, defects in any of the
enzymes that are common to the
synthesis pathway of these hormones
can result in the loss of a combination
of some or all of these products.
21-Hydroxylase is an enzyme used in
the synthesis of aldosterone and
cortisol.
An example of a possible mechanism:
Because of an 21-hydroxylase deficiency, the synthesis of aldosterone and cortisol is blocked. The pituitary gland will
try to stimulate the synthesis of aldosterone and cortisol in the adrenal gland by releasing the ACTH hormone.
Because of this, the pituitary gland will keep stimulating the adrenal glands to produce these hormones, and the
adrenal glands will become bigger and will work harder. However, it isn’t possible to produce aldosterone and
cortisol, and therefore, the extra activity will result in an testosterone excess.
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Possible changes of sex hormones (testosterone/estrogen):
Left: too many sex hormones…
Right: too few sex hormones…
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Too many sex hormones
1. FMPP/Testotoxicosis
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Androgen (testosterone) excess
~ gonadotropin-independent
Precocious (early) puberty (Hypothalamic–pituitary–adrenal axis (HPA-) axis activated – peripheral)
Prevalence: 1-9/1.000.000
Male-limited
Early puberty: 3-4 y.o.
Often, when having a son, the son is affected as well.
Patients have to take testosterone suppression medication.
2. Congenital Adrenal Hyperplasia (CAH)
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Androgen (testosterone) excess; cortisol deficiency
~ gonadotropin-dependent
Precocious (early) puberty (Hypothalamic–pituitary–adrenal axis (HPA-) axis activated – central)
Prevalence: 1/15.000
Affects both males ( micropenis) and females ( born intersex, followed by a soul crisis)
Different forms of severity, masculinization
(In females, it’s often the most severe.)
Introduction to fMRI studies on emotion (fear) processing
There are two components:
1) Attention
2) Memory
( Surprise memory test: “Which faces have you already seen?”, “Which are new?”)
Design of the following study:
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fMRI study on FMPP and emotion (fear) processing: Attention
We used functional magnetic resonance imaging (fMRI) to examine emotional processing in FMPP. We compared
this group (n = 7, mean age = 13 ± 3.3 years) to healthy age and sex-matched controls (n = 14, mean age = 13 ± 2.3
years). Participants were presented with emotional and neutral face stimuli.
In the “threat” attention condition, participants were asked to rate the hostility of the presented face. During the
“fear” attention condition, participants were asked how afraid they were of the presented face. During the
“nonemotional judgment” condition, participants were asked to rate the width of the nose of the presented face.
During the passive attention condition, they were asked to simply look at the pictures without having to make a
rating.
 Boys with FMPP responded faster to fearful faces during perception of threat compared to unaffected controls.
Concurrently, fMRI data revealed significant differences in hippocampus activation in response to fearful faces
relative to baseline whereas controls showed no differences.
The ANOVA showed a significant three-way interaction
among Group (FMPP vs. control), Attention (hostility
rating vs. fear rating vs. nose width rating), and
Emotion (angry, fearful, happy, and neutral). This
interaction reflected that, during the threat-rating
condition, response times to fearful faces were
significantly shorter for the FMPP group than for the
control group. By contrast, reaction times did not differ
between groups when rating the other face emotions
in either the threat attention condition, the fear
attention condition, or the nonemotional judgement
condition. As expected, main effects of Emotion and
Attention were also present. Moreover, Emotion
interacted with Attention. The reaction times (in msec)
in each attention condition are presented on the left.
Functional imaging data showing bilateral hippocampal
activation in the FMPP group in the fearful versus
happy faces contrast during the threat attention
condition. The figure displays sagittal, (upper left),
coronal (upper right), and transaxial (lower left) slices.
(The more activation, the shorter the response times.)
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fMRI study on CAH and emotion (fear) processing: Memory
Hormonal imbalances during development may have long-lasting effects. Using functional magnetic resonance
imaging (fMRI), we compared 14 youths with Congenital Adrenal Hyperplasia (CAH), a genetic disorder of hormonal
dysfunction, with 22 healthy controls on memory encoding of emotional faces. Patients remembered fewer faces
than controls, particularly fearful faces. FMRI data to successfully
encoded fearful faces revealed that males with CAH showed significant
activations in amygdala, hippocampus, and anterior cingulate relative to
unaffected males, while females with CAH demonstrated deactivations
relative to unaffected females in these regions. Findings indicate that
steroid abnormalities during development can have important effects on
neural correlates of emotional memory
Comparison to fMRI study on Posttraumatic Stress Disorder (PTSD) and emotion (fear) processing:
Hypothalamic-pituitary-adrenal axis activity and cortisol release are consequences of central stress system
activation, but they may also influence cognitive and emotional processes within the brain.
Participants of following study were combat-Posttraumatic Stress Disorder (PTSD) patients (such as Vietnam
veterans), combat-exposed healthy comparison subjects, and noncombat-exposed healthy comparison subjects.
Participants were scanned using Positron Emission Tomography (PET) while they experienced a series of emotionalinduction conditions, which included aversive pictures and autobiographic narratives (having to tell a bad war
memory). Blood samples were obtained 2 minutes before and 5 minutes after each activation scan in order to
measure the subjects’ cortisol levels.
Prestimulus cortisol levels covaried with regional cerebral blood flow (rCBF) responses in the rostral anterior
cingulate cortex. In combat- Posttraumatic Stress Disorder (PTSD) patients only, prestimulus cortisol levels covaried
with regional cerebral blood flow (rCBF) in the subgenual anterior cingulate cortex.
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The covariation of cortisol levels with activity in the rostral and subgenual anterior cingulate cortex, which are
regions associated with self-induced sadness/depression, suggests that activity in the anterior cingulate cortex may
be modulated by circulating cortisol during emotional processing
So maybe, the effects on memory, found in the fMRI study on Congenital Adrenal Hyperplasia (CAH) and emotion
(fear) processing, can be the result of the cortisol deficit in Congenital Adrenal Hyperplasia (CAH), instead of the
excess of testosterone in the disease.
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Congenital Adrenal Hyperplasia (CAH) and the amygdala
Study 1: Congenital Adrenal Hyperplasia (CAH) and amygdala volume
Children with Congenital Adrenal Hyperplasia (CAH) have decreased amygdala volume.
Study 2: Congenital Adrenal Hyperplasia (CAH) and amygdala function
In response to negative facial emotions, females with Congenital Adrenal Hyperplasia (CAH) activated the amygdala
significantly more than healthy females, whereas males with Congenital Adrenal Hyperplasia (CAH) did not differ
from control males. Furthermore, female patients showed a similar pattern of amygdala activation to control males,
suggesting virilized (= masculinized) amygdala function in female patients. These findings suggest a prominent effect
of early hyperandrogenism on the development and function of the amygdala in females with Congenital Adrenal
Hyperplasia (CAH), whereas no effects were detected in males with Congenital Adrenal Hyperplasia (CAH).
Means (standard error) of ratings (= perception of the faces) on the left and means (standard error) of reaction times
on the right for negative (fearful and angry) and neutral facial expressions:
Bilateral amygdala activation in the contrast of diagnosis-by-gender interaction:
Note:
The past two studies illustrate the structure-function paradox.
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Too many sex hormones and anxiety
Patients of disorders caused by too many sex hormones experience more anxiety, compared to patients of other
chronic diseases.
Let’s compare (1): Brain activation in adolescents with generalized anxiety disorder (GAD)::
This study was conducted to determine whether attention modulates amygdala and cortical responses to facialthreat cues differentially in adolescents with generalized anxiety disorder (GAD) and in healthy adolescents. During
this functional Magnetic Resonance Imaging (fMRI) study, participants completed a face-emotion rating task that
systematically manipulated attention.
While attending to their own subjective fear, patients, but not controls, showed greater activation to fearful faces
than to happy faces in a distributed network including the amygdala, ventral prefrontal cortex, and anterior
cingulate cortex. Right amygdala findings appeared particularly strong. Functional connectivity analyses
demonstrated positive correlations among the amygdala, ventral prefrontal cortex, and anterior cingulate cortex.
A Significantly greater activation is seen in patients than in
controls during the “How afraid are you?” attention state
for fearful faces vs. happy faces in the right amygdala.
Highlighted areas indicate regions where the differences in
activation between groups were significant.
B Here you see the group × face emotion type interaction in
the “how afraid” attention set, in which patients showed
greater relative activation (relative to the task null-event
baseline) than controls to fearful faces.
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Let’s compare (2): BDNF and clinical anxiety and their associations with grey matter volumes:
This study examined associations of BDNF and clinical anxiety with regional grey matter volumes of the anterior
cingulate cortex (ACC), insula, amygdala, and hippocampus in 39 affected (17 Met allele carriers, 22 Val/Val
homozygotes) and 63 nonaffected adolescents (27 Met allele carriers, 36 Val/Val homozygotes).
Amygdala and anterior hippocampal grey matter volumes were significantly smaller in patients than healthy
adolescents, with a reverse pattern for the insula. A specific contribution of social phobia to the reductions in grey
matter volumes in the amygdala and hippocampus was indicated.
Additionally, insula and dorsal anterior cingulate cortex (ACC) grey matter volumes were modulated by BDNF
genotype. In both regions, grey matter volumes were larger in the Val/Val homozygote patients than in those
carrying the Met allele.
This figure displays the decreased
gray matter volume in the amygdala
and anterior hippocampus for the
patient relative to the comparison
group regardless of BDNFValMet
polymorphism. Scatterplots for the
amygdala cluster show significant
differences in the post-hoc tests.
Note:
Once more, there’s a structure-function paradox, when you take the fMRI study on FMPP and emotion (fear)
processing (attention) on page 17 in account again. That study showed bilateral hippocampal activation in the FMPP
group in the fearful versus happy faces contrast during the threat attention condition. Whereas this study showed a
smaller grey matter volume in the anterior part of the hippocampus for clinical anxious adolescents compared with
healthy adolescents.
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Testosterone and reaction time to fearful faces
Women get a placebo pill or a pill with testosterone…
Women who got the testosterone pill react faster to fearful faces,
compared with women who got the placebo pill.
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Too few sex hormones
1. Klinefelter Syndrome (KS)
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Androgen (testosterone) deficiency
Affects males
one (or more) extra X-chromosome(s) (47, XXY)
Prevalence 0.1-0.2% of population
Small testes ( growth begins to early) and various degrees of androgen insufficiency
2. Turner Syndrome (TS)
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Estrogen deficiency
Affects females
Partial or complete absence of an X-chromosome
Prevalence 1:2000 live births
Infertility, pubertal delay, short stature ( growth begins to early)
Turner’s affective responding
Emotion recognition:
This bar chart shows the
performance in terms of
accuracy of emotion
recognition for six standard
emotions. There are
significant differences
between groups for fear and
anger, with X-monosomic
(Turner Syndrome) females
performing less well than
normal 46,XX females.
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Time-dependent changes in left amygdala responses to fearful faces:
A region of the left amygdala showed in a group (46,XX–45,X) by condition (fearful–neutral faces) by time
(exponentially decreasing course of activation) interaction, significantly different patterns of activation in Turner
syndrome compared to normal females. Three-dimensional plots of time-dependent changes in fMRI responses to
prototypical fearful faces in maximal left amygdala voxel are shown.
The peristimulus time is similar in both plots, but
the magnitude of the left amygdala activation is
substantially greater in the early phase of the scan
in normal females and then rapidly reduces,
whereas the left amygdala of the sample 45,X
female shows a persisting pattern of activation,
which varies little in magnitude during the course
of the experiment.
Klinefelter’s affective processing
Similar to girls with Turner Syndrome, boys with Klinefelter Syndrome also show deficits in labelling affective
expressions, but also show higher emotional arousal.
E.g.: the Ultimatum Game:
When the Ultimatum Game was played with a human
proposer, Klinefelter males rejected significantly more
offers compared to control subjects in the most unfair
(€9:€1) condition.
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Overview
Patients of an disorder
caused by too much
testosterone (T) show
amygdala activity
during fear/treat
processing.
Healthy individuals who
took a testosterone (T)
pill were less fearful,
compared to individuals
who took a placebo pill.
Congenital Adrenal Hyperplasia
(CAH) patients, Turner
Syndrome (TS) patients, and
healthy individuals who were
given extra testosterone (T) are
worse as regards emotional
memory/recognition.
Klinefelter Syndrome
(KS) patients and
Turner Syndrom (TS)
patients are worse as
regards executive
function.
A model of hormone changes and their relation to affective disorders
* Complete Androgen Insensitivity Syndrome: women (XY) with an inactive Y. They develop as a female but have 26
* organs like men. Very traumatic!
ACT III: Changing variations in hormone levels in the lab;
relevance for affective disorders
Stress (cortisol) and affective disorders
High stress reactivity and hippocampal reduction documented in…
 depression,
 PTSD,
 bipolar disorder.
 Disturbed cortisol rhythm!
Stress and cortisol
Cortisol is a glucocorticoid (GC) and involved in regulation of stress. We could do a whole lecture on this topic (or
even a whole course).
So, what's the first cognitive function you associate with stress? The hippocampus! ( memory.)
There’s a high density of glucocorticoid (GC) receptors in the hippocampus (!)
Chronically high cortisol leads to…
 reduction of excitability of hippocampal neurons,
 inhibition of neurogenesis of hippocampal neurons,
 atrophy of dendrites in hippocampus.
The cortisol awakening response
The cortisol awakening response = an increase of approximately 50 percent in cortisol levels, 20-30 minutes after
waking up.
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The cortisol cycle and the possible disturbance of it is widely studied. Below there’s an example of a study (but there
are hundreds)…
Salivary cortisol levels decline significantly across the day in Russian
infants and toddlers who are family reared, but not for those who
are orphanage reared. For those who are orphanage reared we can’t
see variation in the levels of cortisol. Their levels of cortisol don’t
follow the normal pattern. The one moment they have too much
cortisol, the other too little.
Cortisol and major depressive episode (MDE) predicts hazard
Risk of incident depression during follow-up stratified on anticipatory stress cortisol levels during the initial evaluation
and the number of previous major depressive episodes (MDEs):
(chronic)
(The higher the levels of cortisol, the more risk of a new major depressive episode (MDE). The more previous major
depressive episodes (MDEs), the more risk of a new major depressive episode (MDE) as well.)
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Cortisol interacts with genotypes: risk for depression?
Probability of subsequent major depression by either (a) BDNF Val66Met or (b) 5-HTTLPR, and morning cortisol levels:
Increased risk for subsequent depression was found in carriers of the Val66Val genotype in BDNF with higher
morning waking cortisol. This remained present when the known interaction between carriers of a short allele of 5HTTLPR with higher morning salivary cortisol was taken into account.
We can conclude that both BDNF and 5-HTTLPR genes show evidence of modifying the risk of a subsequent new
depressive episode associated with elevated morning salivary cortisol. In adolescents morning salivary cortisol levels
may constitute a biomarker for some forms of unipolar depression.
How can I get your cortisol up? Eliciting stress (in the lab)....
Eliciting cortisol in the lab is very popular. It can be seen as a model to assess the impact of stress (or anticipatory
anxiety) on various cognitive and affective functions. For example, learning & memory, fear responsivity, cognitive
control (working memory/inhibition), visual processing…
Trier Social Stress Test (TSST):
The Trier Social Stress Test (TSST) can be described as a mock job interview. The participants are instructed to
imagine having applied for their “dream job” and that they are now invited to a job interview. The test consists of
three successive phases: (1) A preparation period (3 min), (2) a free speech task in which the participants have to
argue why they are the best candidate for the job they wish to apply for (5 min), and (3) a mental arithmetic task in
which participants have to sequentially subtract an odd two-digit number from an odd four-digit number (e.g., 17
from 2023; 5 min). The two tasks are performed in front of a selection committee (2-3 female and male members),
dressed in white lab coats, acting reserved and providing no facial or verbal feedback. Additionally, participants are
video-taped and told that their performance will be evaluated, and a voice analysis will be conducted.
BUT, recently emergenced a cohort effect…
The effect caused by generational differences could be caused by the fact that nowadays people are more used to
giving presentations, since they have to give them more frequently during their student life.
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… But let us review a study using the Trier Social Stress Test (TSST) anyways…
Effects of stress on physiological and subjective measures:
a The cortisol data showed a strong
response to acute psychosocial
stress as implemented by the Trier
Social Stress Test (TSST).
b Acute psychosocial stress
significantly increased systolic
blood pressure.
c Acute psychosocial stress
significantly increased pulse rate.
d After the Trier Social Stress Test
(TSST) treatment, participants
reported decreased mood. The
good mood score was significantly
lower after the Trier Social Stress
Test (TSST) in the stress as
compared to the control group and
still significantly lower after the end
of scanning.
Neural activity in the inferior frontal cortex:
a
b
c
d
Simple main effect of emotion in the control
condition
Simple main effect of emotion in the stress
condition
The main aim of the present study was to test
whether stress differentially impacts
recognition-related neural activity to neutral
and fearful faces. Therefore we performed a
stress condition by emotion interaction. We
found an effect in the left inferior frontal
cortex.
The bar charts shows estimated mean betas of
the activated cluster as a function of stress
condition (control/stress), emotion
(fearful/neutral) and novelty (old/new). The
mean beta estimates suggest that the
interaction was mainly seen when volunteers
rejected new faces, rather than recognizing old
faces.
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Cold Pressor Task (CPT):
The Cold Pressor Task (CPT) is a commonly used experimental method of inducing pain. Completion of the Cold
Pressure Task (CPT) typically requires an individual to submerse his/her hand or forearm in cold water for as long as
can be tolerated, lasting up to several minutes.
An example of a study using the Cold Pressure Task (CPT):
Overview of the experimental procedure:
In Session 1, participants
encoded animal and object
images. In Session 2, half of the
animal images were presented
again to reactivate the
associated object images, and
then the stress versus control
treatment was applied. Saliva
samples were taken from a
subset of the participants in
each group. In Session 3,
participants were asked to freely
recall the objects from Session 1.
( How good is memory under
stress?)
Mean salivary cortisol levels in the stress and control group in Session 2 before and after memory reactivation, and
immediately before and 25 minutes after the Cold Pressure Task (CPS) versus warm water treatment:
Cortisol levels increased in the Cold
Pressure Task (CPS) group.
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Proportions of objects recalled in Session 3 in the stress and control group:
Proportions were calculated as the number of objects
recalled in Session 3 in relation to the number of
objects recalled at the end of the first session. For
each participant, half of the objects had been
reactivated, and half had not been reactivated in
Session 2.
Participants under stress reminded relatively less
reactivated items than control participants.
Treat of shock paradigms:
An example of a study using a treat of shock paradigm:
In this study, the virtual Morris water maze task was modified to extend the significance of human hippocampal
theta to anxiety. While undergoing whole-head MEG, participants (N = 25) navigated two virtual pools in search of
an escape platform, one in which they risked receiving electric shocks before reaching the platform and one in which
they were safe from shocks
T = “We could shock you at any time”. ;S = “You’re safe”.
Results showed that threat of shock elevated anxiety level and enhanced navigation performance compared to the
safe condition.
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Tasks revisited:

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





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Emotion processing
Emotional memory
Emotion regulation
Emotion identification
Emotional learning
Cognitive control
Spatial navigation
Face processing
Error monitoring
Oxytocin and emotions
Oxytocin has become infamously known as the “love” hormone. It increases…
 interpersonal trust,
 (in-group) social support,
 processing social information,
BUT, the effects may be context dependent. E.g. oxytocin increases envy and gloating and defensiveness toward outgroup members.
Study: Oxytocin *might* have anxiolytic properties
Oxytocin might reduce social threat and thus facilitate pro-social behavior.
18 patients with Generalized Social Anxiety Disorder (GSAD) and 18 healthy controls (CON) took oxytocin (OXT) or
placebo (PBO)…
GSAD subjects talking placebo (GSAD PBO) had greater
amygdala reactivity to fearful faces in both left and right
amygdala, compared with control subjects during placebo
treatment (CON PBO).
Following oxytocin treatment, the exaggerated amygdala
response to fearful faces in GSAD subjects observed during the
placebo session was no longer evident. As expected, in GSAD
subjects, amygdala reactivity to fearful faces was greater during
placebo than during oxytocin treatment, showing that oxytocine
reduced fear-related amygdala activation.
Unlike GSAD subjects, control participants did not exhibit
differences in amygdala activation to fearful faces between
oxytocin and placebo treatments.
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