Affective Neuroscience and Psychopathology

Anxiety and Depression

Dr. G. Buodo
 Anxiety disorders Bipolar and related disorders
• Separation Anxiety disorder • Bipolar I Disorder
• Selective mutism • Bipolar II Disorder
• Specific phobia • Cyclothymic Disorder
• Social anxiety disorder (Social
phobia) Depressive disorders
• Panic Disorder • Dysruptive mood dysregulation disorder
• Agoraphobia • Major Depressive Disorder
• Generalized Anxiety disorder
• Persistent depressive disorder
Trauma- and stressor-related (Dysthymia)
disorders • Premenstrual dysphoric disorder
• Post-traumatic Stress Disorder Although they differ from one another in duration, timing,
etiology, the common feature consists in abnormal changes
• Acute Stress Disorder in mood that markedly impair functioning
• Reactive attachment disorder, Disinhibited social
engagement disorder, Adjustment disorders

Obsessive-compulsive and
Although they differ from one another in the types of objects
related disorders or situations that induce fear, anxiety, or avoidance
• Obsessive-compulsive disorder behavior, and the content of the associated thoughts or
• Body dysmorphic disorder, hoarding disorder, beliefs, the common feature is persistent and excessive
trichotillomania (hairpulling disorder), excoriation (skin- fear/anxiety in response to imminent or anticipated danger
picking)

Common and disabling disorders: combined lifetime prevalence is about

28% for anxiety disorders and 10 (men)-25 (women)% for depression
Anxiety and Depression will be considered together for
several reasons:
• high comorbidity (about 50% of patients with
depression have an anxiety disorder; about ¼ of
patients with anxiety disorders have depression);
• highly overlapping symptoms (e.g., insomnia,
irritability, difficulty concentrating);
• the neural circuits involved in both disorders can be
difficult to distinguish;
• some treatments are effective for both disorders,
including antidepressants such as SSRIs and
cognitive behavioral therapy
 Animal models of anxiety and depression
• Among mammals, and frequently across other
vertebrate classes, the neural structures, the circuits
that interconnect them, and many fundamental
physiological and behavioral responses have marked
similarities
• Therefore, we can investigate in lower species the
neural circuits and genetic factors underlying specific
behavioral responses, that are considered as models
of clinical symptoms in humans
• Animal models are “experimental preparations
developed in one species for the purpose of studying
phenomena occurring in another species” (McKinney, 1984)
Beware anthropomorphization! Mice are not miniature
versions of human beings!
• there are considerable differences in brain
anatomy (esp. the cerebral cortex) between
humans and mice we cannot truly know whether
a mouse is feeling depressed or anxious certain
symptoms are impossible to model in mice it is
impossible to fully recapitulate human anxiety or
depression in the mouse
• animal paradigms often fail to reproduce complex
multi-syndromal human disorders
• animal paradigms may have variable
reproducibility even within the same laboratory
Cryan & Holmes, 2005
An experimental procedure in an animal has validity as a model of
a mental disorder if:
• it is “reasonably analogous” to the human disorder in its
manifestations or symptomatology (face validity, construct
validity);
• it causes a behavioral change that can be monitored objectively;
• it produces behavioral changes that are reversed by the same
treatment modalities that are effective in humans;
• it is reliable, i.e., reproducible between investigators (McKinney &
Bunney, 1969)

Animal models are most effective when used in conjunction with

other techniques to generate converging lines of evidence
Neuroimaging findings should serve to inform laboratory research
using animal models and so facilitate the testing of experimental
hypotheses that are not feasible in human studies (e.g., the
influence of genetic manipulations on the function of neural
circuits and the emotional responses they mediate)
 Animal models of anxiety and depression
Exploration-based “approach- “Behavioral despair” paradigms:
avoidance” paradigms: tail suspension, forced
open field, elevated plus maze, swimming, inescapable shock
elevated zero-maze, light-dark box
 Treatment with diazepam consistently
reduces the typical anxiety-like
behaviors of stretch-attend (risk-
assessment behavior involving the
mouse stretching its body from a more
protected area, e.g., corners, towards a
less “safe” area, e.g., the central part of
the arena) and wall-following
Choleris et al., 2001
Administration of antidepressants causes mice
to actively and persistently engage in escape-
directed behaviors for longer periods of time
(increased climbing, reduced immobility)

Detke et al., 1997

Mouse models of “trait” anxiety and depression:
genetically modified mice
• A mutation is artificially produced by inactivating a
selected gene (knock-out), causing altered expression
of a specific protein (a receptor, transporter, enzyme or
signal transduction molecule)
• The resultant phenotype provides some indication
about the normal function of the gene, or the role of a
molecule in a neural pathway
The serotonin transporter (5-HTT)
knock-out mouse shows anxiety-
and depression-like behavior in a
variety of tests importance of
serotonergic neurotransmission in
the pathophysiology of anxiety
and depression

Olivier et al., 2008

Cryan & Holmes, 2005

• Mutant mice models are based on
the deletion of a single gene, but it
is now clear that the modulation of
anxiety and depression processes
involves multiple genes
• Some in-bred mouse strains (e.g.,
BALB/c) may be more suitable
models of pathological, trait anxiety, Depino & Gross, 2007
in that they exhibit spontaneously
elevated anxiety as an enduring
feature of the strain (due to
neuroanatomical/neurochemical/
genetic factors), not because of the
deletion of a single gene

Griebel et al., 2000

• The in-bred mouse strain called
Rouen is considered as a suitable
model of depression, as Rouen mice
exhibit enduring features of
depressive-like behavior
(helplessness)

• “Helpless mice” also exhibit

alterations in sleep architecture
(lighter and more fragmented
sleep, and decreased REM sleep
latency), and a disturbance of the
hypothalamic-pituitary-adrenal axis
(elevated serum corticosterone)

El Yacoubi et al., 2003

 The brain areas most reproducibly found to show
functional alterations in anxiety and depression are:

The PFC and ACC, which

are involved in cognitive
control, decoding the
reward/punishment value
of stimuli, conflict
monitoring, anticipation,
emotion experience and
regulation, integration of
visceral/emotional
information
The hippocampus and amygdala,
which are involved in fear learning
and expression, emotional
memory formation and retrieval
 Dorso-medial PFC
Ventro-medial PFC includes
includes • Supragenual
• Subgenual anterior cingulate
anterior cingulate • Medial frontal gyrus
• Medial
orbitofrontal cortex
 From normal to pathological fear/anxiety
In normal fear/anxiety, bottom-up and top-down processes interact
adaptively to shape behavior in a given situation
What brain regions are involved in modulating behavior according
to the emotional consequences of a stimulus?

One way to address this question is to study the neural

mechanisms underlying extinction of conditioned fear, an
important mechanism of emotional change that has direct
relevance to the treatment of human fear and anxiety disorders
 Neural model of fear extinction
1) In the early stage, after fear
3a) After extinction learning, acquisition, tone-alone
2) Next, during
when the animal is required presentations cause some
consolidation of extinction,
to retrieve the already- amygdala neurons to decrease
an inhibitory memory trace
consolidated extinction their firing rate, through fear
is established between the
memory, the vmPFC learning reversal and/or new
vmPFC and LA
suppresses activity in the inhibitory learning
amygdala through inhibition
of LA neurons, resulting in a
rapid decrease in freezing

3b) At the same time, during

extinction expression
hippocampus-based
contextual memory
modulates neural activity of
the vmPFC and/or LA, to
regulate the animal’s
behavioral response (i.e.,
decrease freezing) if in the
appropriate environment
Sotres-Bayon et al., 2006
Rats with mPFC lesions have difficulty recalling the extinction that
was learned and take longer to extinguish the freezing response,
as indicated by more time spent freezing and more days to reach
extinction criterion (≤ 5 s of freezing to CS) the vmPFC facilitates
rapid consolidation/retention/recall of extinction so that it is
available to the animal after a long delay

Quirk et al., 2000 Morgan et al., 2003

Studies on healthy human subjects show
that amygdala activity is increased during
fear conditioning and the presentation of
non-conditioned fear-related stimuli

Activity in the ventromedial PFC is Phelps et al., 2004

stronger during the expression of

extinction learning (retention) on
day 2, along with decrease in
amygdala activity (top-down
inhibition): the mPFC acts as an
inhibitor for the amygdala,
suppressing a CR after the CS has Phelps et al., 2004

been presented a number of times

without pairing with the US
In healthy subjects, emotion regulation is another process that
allows changing, in whole or in part, conditioned fear responses

Emotion regulation and extinction are suggested to have

overlapping underlying neural mechanisms, since the essence of
both processes involves reevaluating emotionally relevant stimuli

Like in extinction, during successful emotional regulation the

prefrontal cortex exerts control over the amygdala  increased
prefrontal activity and concomitant decreased amygdala activity

Unlike extinction, though, during regulation the vlPFC and dlPFC,

in addition to the vmPFC, are critical for regulating amygdala
activity deploying a cognitive strategy to change stimulus
representation
Individuals who show larger reductions in the
response of the amygdala when decreasing
negative affect to aversive pictures
compared with the “attend” condition also
show greater responses in bilateral vmPFC,
suggesting that functional coupling between
the vmPFC and the amygdala enables
effective regulation of negative emotion
Urry et al., 2006
 Drabant et al., 2009

Individual differences in spontaneous reappraisal use predict activity in

the same neural systems involved in instructed regulation: greater
everyday reappraisal use predicts decreased amygdala activation and
increased activation in dlPFC (deploying a cognitive strategy) and dmPFC
(appraising emotional states of self and others) during the processing of
negative facial expressions
More than one prefrontal-subcortical pathway mediating successful
emotion regulation: activation of the vlPFC correlates with reappraisal
success (reduced negative emotional experience) during the viewing of
aversive pictures through two independent PFC-subcortical pathways: (1)
a path through the activation of the nucleus accumbens (generation of
positive interpretation), and (2) a path through inhibition of the amygdala
(blunting negative interpretation) reappraisal success involves both
limiting negative appraisals and generating positive appraisals

Wager et al., 2008

A third example of adaptive PFC-amygdala interaction is the
interpretation of ambiguous stimuli (e.g., facial expressions of
surprise)

Surprised faces signals the occurrence of an unknown

environmental event (predictive uncertainty) but valence is unclear
Interpretation of the face as
positive is associated with greater
activity in the right and left vmPFC,
whereas interpretation as negative
with increased amygdala
activation upon encountering a
surprised face, the amygdala
sends out an initial potential threat
signal in all subjects; individual
differences in the strength of the
vmPFC response back to the
amygdala, communicating the
potential positivity of these faces,
could account for individual
differences in signal at both loci
Kim et al., 2003
 The dynamic interactions between the
amygdala and the mPFC can be
usefully conceptualized as a circuit
that both allows us to react
automatically to biologically relevant
predictive stimuli as well as regulate
these reactions when the situation
calls for it

In anxiety and mood disorders, the

Kim et al., 2011 interaction between bottom-up and
top-down processes is hypothesized to
be impaired, as reflected in a
dysfunctional crosstalk between
cortical (PFC) and subcortical
(amygdala) structures
There appears to be a distinction between two classes of
anxiety disorders:
• Disorders involving intense fear (specific phobias, social
phobia, PTSD, panic disorder) seem to be characterized
by hypoactivity of distinct prefrontal cortex areas, thus
failing to inhibit the amygdala
• Disorders which mainly involve worry and rumination
(repetitive patterns of thoughts that involve engaging in
mental problem-solving on an issue whose outcome is
uncertain but contains the possibility of one or more
negative outcomes, or focus an individual’s attention on
his/her symptoms of distress and their implications),
such as GAD or OCD, seem to be characterized by
hyperactivity of some prefrontal cortex areas
 Specific Phobia (animal type)
When animal phobics watch
fear-relevant but nonphobic
stimuli, there is a negative
functional connectivity
(negative co-variation)
between the ACC and the
amygdala (inhibitory
influence, emotional control)

When watching phobia-

related stimuli, functional
connectivity between PFC
and amygdala is absent
disruption of the
negative feedback loop
that results in phobic fear
Åhs et al., 2009
 Specific Phobia (blood-injection-injury type)

During the viewing of 1, 2 = bilateral dmPFC; 3, 4 = bilateral vmPFC

phobic, but not fear,
pictures blood phobics
show hypoactivation of the
mPFC ,suggesting a deficit
in the automatic (vm) and
controlled (dm) regulation
of emotional responses to
phobic stimuli
Hermann et al., 2007
 Social Anxiety Disorder

During the anticipation of

a public speech,
participants with social
phobia showed greater
neural activity in
subcortical regions
(including the amygdala)
and less cortical activity
in prefrontal regions Lorberbaum et al., 2004

compared with healthy

controls
 Post-traumatic Stress Disorder
• Across various tasks (symptom
provocation, e.g., recall of the trumatic
event, and presentation of emotional stimuli
that do not explicitly cue the patient to their
traumatic event, e.g., fearful faces), the
regions most consistently hyperactivated in
PTSD patients include midACC and bilateral
amygdala (detection and attribution of
heightened salience to potential threats)
• Widespread hypoactivity has been
observed in the vmPFC and the inferior
frontal gyrus (defective regulatory control,
reduced inhibition from emotional
distracters)
 hyperarousal symptoms, hypervigilance
Hayes et al., 2012
to potential threats, deficits in extinguishing
responses to threat-related stimuli and
persistent fear responses in daily life
 Generalized Anxiety Disorder

In both normal subjects and subjects

with GAD, worry triggered by worry-
inducing sentences activates the medial
PFC and ACC (mentalization and
introspective thinking)

However, GAD subjects show a

persistent activation of these areas
even during the resting state that
follows the worrying phase

A dysregulation of the activity of this

region and its circuitry may underpin
the inability of GAD patients to stop
worrying Paulesu et al., 2010
During resting-state conditions,
functional connectivity between bilateral
amygdala and DLPFC/posterior parietal
cortex is only observed in GAD patients
 abnormal amygdalofrontoparietal
coupling may reflect the habitual
engagement of a cognitive control
system to regulate excessive anxiety
with compensatory cognitive strategies,
such as worry

DLPFC-amygdala connectivity in GAD

patients was negatively correlated with
all self-report measures of anxiety 
strongest connectivity in the least
anxious patients suggests a relationship
between this adaptation and successful
control of anxiety
Etkin et al., 2009
 Obsessive-compulsive Disorder

Following symptom provocation,

OCD patients show significantly
increased activity in orbitofrontal
cortex and dlPFC  intrusive,
repetitive thoughts, reduced
cognitive/affective flexibility
and increased activity in the ACC 
excessive conflict monitoring and
deficient action control and
inhibition (compulsions) Adler et al., 2000
 The cortico-striatal-thalamic-
cortical model of obsessive-
compulsive disorder

The primary pathology lies

within the striatum (specifically,
the caudate nucleus), which
would lead to inefficient
sensorimotor gating at the level
of the thalamus. This would Deckersbach et al., 2006
result in hyperactivity of the
OFC (intrusive, repetitive
thoughts, reduced
cognitive/affective flexibility)
and of the ACC (excessive GPe
conflict monitoring) and SThN
deficient action control and
inhibition (compulsions) Saxena & Rauch, 2000
 Fear and anxiety are supported by partially different
neural circuits
• Work using animal models (e.g.,
Davis and colleagues) has
dissociated profiles of transient
and sustained threat processing
that map onto the constructs of
fear and anxiety

• Whereas cued threat processing

is initiated by the amygdala,
sustained vigilance associated
with ambiguous or distant threat
Davis et al., 2010
cues is represented by tonic
engagement of the bed nucleus
of the stria terminalis (BNST)
The bed nucleus of the stria terminalis is a limbic structure
located superior, medial, and rostral to the amygdala, that
receives heavy projections from, among other areas, the
basolateral amygdala, and projects in turn to hypothalamic and
brainstem target areas that mediate many of the autonomic and
behavioral responses to aversive or threatening stimuli

Walker et al., 2003

Startle reflex unconditioned automatic
defensive response to sudden and
intense stimuli with rapid onset (e.g.,
100dB, 50ms white noise), involving
flexor contractions from head to neck,
trunk and limbs
Fear-potentiated & light-enhanced startle

Davis et al., 1998

 Anxiety-provoking task: participants
continuously monitor the environment for
cues signaling risk for a forthcoming
aversive event, i.e., fluctuation in the height
of the line dynamically represents increasing
future environmental threat level with
increasing proximity to the shock threshold

A region consistent with the BNST

demonstrates a linear increase in
response as a function of line height
( tracking of threat proximity) that
was additionally exaggerated in
individuals with greater trait anxiety
 vigilant threat-monitoring
behavior characteristic of anxious
individuals is mediated by
exaggerated responding in the BNST Somerville et al., 2010
Compared to controls, GAD patients
demonstrated decreased activity in
the bilateral amygdala and increased
activity in the bilateral BNST in the
high vs. low uncertainty condition
GAD patients disengage the
amygdala during prolonged anxiety-
eliciting uncertainty earlier and more
quickly than non-anxious controls,
making way for the BNST to maintain
a more sustained anxious state Yassa et al., 2012
Depression
• First leading cause of years lived
with disability (WHO)
• Lifetime prevalence 8-12%; 12-
month prevalence 6.7%, of which
30.4% (2%) are classified as
“severe”
• Prevalence for women (~ 9%) is
about twice that for men (~ 5%)
• Heterogeneous syndrome (subtypes
based on symptomatic differences)
• Highly heritable: 40-50% of risk is
genetic
• Genetic predisposition interacts
with environmental factors (stress)
• ~80% of patients improve (partial
response) with antidepressant
medications; only ~50% remit
completely
• … the pathogenesis of depressive disorder remains largely
unknown

• Several functions are dysregulated in depression:

 mood regulation
 emotional expression
 reward processing
 attention
 motivation
 stress responses
 neurovegetative functions (sleep, appetite, energy,
libido)

How do symptoms relate to anatomical and functional brain

abnormalities? Which brain networks are implicated?
 The functional neuroanatomy of depression:
the visceromotor network
The pathophysiology of depression implicates dysfunction within two
extended cortical systems associated with the orbital and medial PFC
The Orbital prefrontal network primarily
connects central and lateral OFC with
primary and association sensory cortices
and functions as a system of both multi-
modal sensory integration and coding of the
affective characteristics of stimuli and
relative value

Öngur & Price, 2000 Price & Drevets, 2012

 The Medial prefrontal Network
comprises prominent
connections between the
medial PFC and anterior OFC,
limbic structures (e.g.,
amygdala, striatum),
structures that modulate
visceral function (NTS, PAG,
hypothalamus), and a specific
set of other cortical regions
Drevets et al., 2008
(posterior cingulate, dlPFC,
It is a visceromotor network, involved in temporal and
affective, cognitive, behavioral, parahippocampal cortex, STS)
neuroendocrine, and visceral/somatomotor
responses to stress-, reward-related, and
aversive stimuli
Depressed subjects show abnormalities in both networks during fMRI studies
involving reward and emotional processing tasks, although the Medial
Network and related structures are more specifically related to mood
dysfunction
 • The Medial Prefrontal
Network is part of the
system that has been
defined in humans as the
default mode network, a set
of interconnected areas that
are coherently more active
at rest, but decrease activity
during extrinsic, externally-
oriented sensory-motor
tasks
• Default-mode activity (see
Price & Drevets, 2012 Raichle et al., 2001) is viewed as
an “intrinsic”, self-
• Hyperactivity of the default mode network in referential activity, including
depression might explain self-absorption, self-representations,
perseveration on negative, self-referential thoughts episodic memory, mind
• Different depression subtypes and symptom wandering, imagination and
profiles may be mediated by dysfunctions of stimulus-independent
different nature (e.g., increased/reduced), localized thoughts
to specific brain areas and/or imbalances in
synaptic interactions within and between particular
subcomponents of the circuitry
 Structural brain abnormalities in depression
The magnitude and prevalence of morphological abnormalities
depend partly on age-at-onset, presence of mania or psychosis,
presence of familial aggregation of illness

Reduced grey matter of left

subgenual ACC (20-50%),
observed:
- early in the course of illness
- in young adults at high familial risk
- in both males and females
Persists despite successful in Drevets et al., 2008

treatment with antidepressants

Reduced volume of OFC and

vlPFC (~30%)

Bremner et al., 2002

Reduced volume of the
hippocampus (8-19%),
although not always replicated
- glucocorticoid neurotoxicity
- possibly reversed by antidepressant
treatment through neurogenesis
stimulation (increase in BDNF levels)

Sheline et al., 2003

Reduced volume of the

caudate, putamen, and NAc

Kim et al., 2008

Reduced volume of the amygdala?
(inconsistent)

Kronenberg et al., 2009

 Functional brain abnormalities in depression

Drevets et al., 2008

Price & Drevets, 2010

Basal activity is increased in Dep vs Con and Dep vs Rem in the

vlPFC (inferior frontal cortex), sgACC, medial orbital cortex and the
amygdala
How is hyperactivation of some brain structures related
to depression symptoms?

Hyperactivity in the sgACC may account for:

- exaggerated feeling of sadness
- increased sensitivity to affective conflict (mood vs.
contextual demands; rumination vs. current information
from the environment)
- excessive/dysregulated visceral and autonomic
responses to stressful and emotional events
- anhedonia (through dysregulated influence over the
ventral striatum)
Experimentally-induced
transient sadness increases
activity in subgenual ACC in
healthy individuals

Activity in subgenual ACC

decreases with chronic
fluoxetine treatment

in Ressler & Mayberg, 2007

Hyperactivity in the vlPFC/OFC may reflect:
- endogenous (unsuccessful) attempts to interrupt or inhibit
unreinforced maladaptive emotional, cognitive and behavioral
responses perseverative responses to stressors, poor flexibility
in adapting behavior to changing reinforcement contingencies
- exaggerated sensitivity to mistakes, negative feedback and
failures

Hyperactivity in the amygdala may account for:

- dysregulation of autonomic and neuroendocrine functions
through excessive stimulation of subcortical and brainstem
structures (hypothalamus excessive response to stress; locus
coeruleus and PAG excessive autonomic arousal)
- “seeing the bad side of everything”: enhanced (and sustained)
processing of negative stimuli, rumination, facilitated access to
negative memories, negative interpretation of neutral or
ambiguous stimuli
- anxiety symptoms (and high comorbidity with anxiety disorders)
When a personally
relevant negative word
is presented briefly
(150 msec), depressed
individuals appear to
continue to process
that information
(sustained amygdala
activation) for up to 30
sec, even when they
are given a subsequent
nonemotional
distracting task,
designed to elicit
activation in brain Siegle et al.,2002
areas hypothesized to
be active in shutting off A depressed person’s experience of an emotional
the amygdala (negative) stimulus could persist well beyond that
stimulus and into the time the person is expected to
be engaging in other activities
The PFC in depression: distinct roles for ventromedial and
dorsolateral PFC
Projections to
hypothalamus, PAG,
ventral striatum,
amygdala
Affective functions

Afferences from
sensory cortices,
reciprocal
connections to
premotor areas,
frontal eye fields,
parietal cortex
Cognitive/executive
functions
Depression is associated with opposite activity profiles
(imbalance) in vmPFC/vlPFC and dlPFC:
• basal resting-state activity in depressed patients as compared
with non-depressed individuals is abnormally high in the vmPFC
and abnormally low in the dlPFC
• recovery from depressive episode is associated with increased
activity in the dlPFC, and decreased activity in the vmPFC

Is the imbalance in vmPFC/dlPFC activity a cause or a correlate of

depression?
If vmPFC hyperactivity and dlPFC hypoactivity are causally involved
in the pathogenesis of depression, then damage to either area
would presumably affect the development of depression, but with
opposite effects vmPFC lesions would confer resistance to
depression, whereas dlPFC lesions would confer vulnerability to
depression
Patients with bilateral vmPFC
lesions have significantly lower
levels of depression, whereas
patients with bilateral dlPFC
lesions have significantly
higher levels of depression as
compared with patients with
non-PFC brain lesions

Koenigs & Grafman, 2009

Koenigs et al., 2008
A depressed
patient who
attempted suicide
by a gunshot and
destroyed most of
the ventral PFC
(including vmPFC)
while leaving
intact most of the
dorsal PFC

Koenigs & Grafman, 2009

Depression markedly diminished following ventral PFC injury, and

the patient reported a complete absence of sadness or suicidal
ideation
 Transcranial magnetic Deep brain stimulation
stimulation

Stimulation of left dlPFC Inhibition of vmPFC is

is effective in treating effective in treating
refractory depression refractory depression
 How is the function of each PFC subregion related to
depression?

The vmPFC might play a basic role in the generation of negative

emotion (resting vmPFC activity correlates with self-
reported negative affect), and coordinate the physiological
components of negative emotion through its projections to
PAG, hypothalamus, amygdala
The vmPFC might play a crucial role in self-awareness and self-
reflection (vmPFC lesions are associated with loss of self-
insight and reduction of negative self-referential emotions,
such as shame, guilt, regret, sadness, self-depreciation)
The dlPFC plays a role in cognitive-executive functions such as
attentional control, working memory, goal-directed action,
and abstract reasoning, but also in emotion regulation
through reappraisal/suppression
Stress & depression

Maletic et al., 2007

Dysregulation of the hypothalamic-pituitary-adrenal axis in
depression
Activation of the HPA axis is a prominent
mechanism by which the brain responds to acute
and chronic stress
• Stress induces the release of CRF from the
hypothalamus, which stimulates the synthesis and
release of ACTH from the pituitary and ultimately
leads to the release of glucocorticoids (cortisol)
from the adrenal glands
• Circulating cortisol provides negative feedback
effects by binding to glucocorticoids receptors in
the pituitary, hypothalamus and hippocampus
• Altered function of the HPA axis has consistently
been found in individuals with major depression
and anxiety (about 50% of cases)
• The negative feedback loop is deficient in
Nestler et al., 2002 depression despite high levels of circulating
cortisol, leading to excessive activity of the HPA axis
It is still unknown whether HPA axis dysfunction is a
primary pathophysiological disturbance in depression,
or it is secondary to dysfunction in other brain
system(s)

It is likely that dysfunction of the HPA axis is a core

feature of depression (endophenotype), or at least
that a considerable proportion of individuals who
develop depression have exaggerated stress
sensitivity (early life stress and subsequent HPA axis
sensitization)
Acutely depressed, unmedicated
subjects show an exaggerated
release of cortisol in saliva upon
awakening as compared with
controls

Euthymic, medication-free Bhagwagar et al., 2005

individuals with a past history of
recurrent depression, and
asymptomatic individuals at genetic
risk of depression have similarly
increased cortisol levels after
waking cortisol hypersecretion
might be a biological marker of
depression vulnerability, not just an
illness marker Mannie et al., 2007
HPA axis hyper-reactivity may mediate the higher rate of depression
as a function of exposure to stressful life events in genetically
predisposed individuals

The patterns of stress reactivity

vary as a function of genotype:
individuals who are homozygous
for the short allele in the
promoter region of the serotonin
transporter gene (5-HTTLPR)
exhibit greater and prolonged
cortisol production in response
to a laboratory stressor
serotonin has been found to
Gotlib et al., 2008
enhance the negative feedback
control of cortisol
 The mesolimbic dopamine reward circuit in depression
Anhedonia (lack of positive affect in response to pleasant stimuli), reduced
motivation, decreased energy and psychomotor slowing have led to the
hypothesis that mesolimbic dopaminergic dysfunction is involved in the
pathophysiology and (possibly) etiology of depression
• The mesolimbic dopamine
system is formed by the NAcc
(ventral striatum) and its
dopaminergic input from the VTA
and the SN
• The VTA sends dopaminergic
output to hippocampus,
amygdala, and hypothalamus; the
NAcc directly innervates the
hypothalamus
• The VTA and NAcc receive strong
All the above structures receive glutamatergic inputs from PFC,
norepinephrinergic and serotonergic input hippocampus and amygdala, and
from the locus coeruleus and dorsal raphe peptidergic projections from the
hypothalamus
The mesolimbic dopamine system plays a critical role in
mediating responses to natural rewarding stimuli (food,
sex, social interactions), in motivation and psychomotor
speed, and is involved in some pathological conditions
(e.g., drug addiction, overeating, gambling)

VTA-NAcc pathway may be also involved in mood

regulation  antidepressant treatment alters
dopaminergic activity in the VTA and related target
areas; experimental manipulation of dopaminergic
transmission in the pathway can regulate depression-
like behavior in animal models
In depressed patients (esp. those with severe psychomotor
slowing, anhedonia, and amotivation) lower concentrations of
dopamine metabolite homovanillic acid in cerebrospinal fluid
(reflects functional activity of dopaminergic neurons) have been
found with respect to healthy controls

Sher et al., 2006

Dopaminergic abnormalities may be associated with suicidality

(self-directed impulsive aggression), not with depression as such
A deficit in the anticipatory (goal- Monetary Incentive
directed behavior) and/or Delay Task
consummatory (pleasure
experience) phase of reward
processing?
Activity in the NAcc and VTA
areas did not differ between
depressed patients and
controls during anticipation
(reward cue-no incentive
cue)

Depressed patients showed

reduced activation in the
NAcc and caudate during
consummatory response to
reward (gain feedback-no
change feedback) deficit
in coding the hedonic value
& learning action-reward
contingencies Pizzagalli et al., 2009
Is anhedonia more than reduced
capacity to experience pleasure? Is it
due to an inability to sustain positive
affect over time (disordered positive
emotion regulation)?

During up-regulation of positive

affect, depressed individuals are
unable to sustain NAcc activity over
time as compared with controls,
suggesting that anhedonia in
depression might reflect the inability
to sustain engagement of structures
involved in positive affect, motivation Heller et al., 2009

and reward

Attenuated functional connectivity between the PFC

and the NAcc across time the inability to sustain
engagement of the NAcc during the “positive
enhance” condition may reflect a failure to engage
PFC regions implicated in emotion regulation