Nuts

and Bolts Plan for Today

Lecture (Grupe & Nitschke; Macleod)
If we run low on @me, we will nish during the
next lecture

Take-home cri@cal thinking ques@ons

PSYC 210:

Dissec@ng broad-band N/NE
into its key cons@tuents

Part 1 of 2
AJ Shackman
20 April 2015

Todays Conceptual Roadmap

In prior lectures, weve talked about N/NE and its
facet, BI.

Exploded View of Porsche 917 Engine

Todays Conceptual Roadmap

But what exactly does it mean to be neuro@c, to
show high levels of NE or BI?
What are the key ingredients of this anxious phenotype?
How are these components physically organized in the brain?
Can we break it down,
psychologically and neurally?
What do you guys think?

Exploded View of Porsche 917 Engine

Todays Conceptual Roadmap

But what exactly does it mean to be neuro@c, to
show high levels of NE or BI?
What are the key ingredients of this anxious phenotype?
How are these components physically organized in the brain?
Can we break it down,
psychologically and neurally?
What is the value of dissecBng?

Exploded View of Porsche 917 Engine

Brief reminder of what we already

know about intermediate
phenotypes, using C/SC as an
illustra@on

Students:
How Might We Go About Determining
the Substrates of a Trait (e.g., C/SC)?

Try to forge a link between

T&P: Varia4on in C/SC and

Candidate Cause: Some other process or measure

(psychological or biological cause)

Students
How might we go about this?

Quan@fy individual dierences in C/SC

One-Shot Self-Report

Mul@-Informant Behavioral Composite

In either case, you end up with a single number

Students: Why is this potenBally problemaBc??

Quan@fy individual dierences in C/SC

One-Shot Self-Report

Mul@-Informant Behavioral Composite

In either case, you end up with a single number

Students: Why is this potenBally problemaBc??

But one number is not

a sensible approach

Mayor Ford (Toronto)

Mayor Barry (DC)

More than one process at work

(psychological process, neural circuit, gene@c variants)

C/SC is Complex

C/SC is Complex

Dened by constella@on of symptoms,

not causes (pathophysiology), including
altera@ons in thought, language,
behavior, and mood

Complexity is compounded by the
Dim Sum Buet problem
dierent ways to get there
(polythe4c diagnos4c categories)

Outward manifesta@ons are oaen
non-specic (aka transdiagnos@c)

Complexity impedes the search for
simple substrates

Need to simplify! Focus on one key
element at a @me.

C/SC is Complex

Dened by constella@on of symptoms,

not causes (pathophysiology), including
altera@ons in thought, language,
behavior, and mood

Complexity is compounded by the
Dim Sum Buet problem
dierent ways to get there
(polythe4c diagnos4c categories)

Outward manifesta@ons are oaen
non-specic (aka transdiagnos@c)

Complexity impedes the search for
simple substrates

Need to simplify! Focus on one key
element at a @me.

C/SC is Complex

Dened by constella@on of symptoms,

not causes (pathophysiology), including
altera@ons in thought, language,
behavior, and mood

Complexity is compounded by the
Dim Sum Buet problem
dierent ways to get there
(polythe4c diagnos4c categories)

Complexity and heterogeneity impedes
the search for simple substrates

Need to dissect or decompose! Focus on
one key element at a @me.

Simpler Intermediate Phenotypes

Complexity impedes the search for
simple substrates

Need to simplify!

Delay of GraBcaBon

Lets apply this strategy to N/NE

Hang on! - Why Bother?

Students: What do we know about
the impact of N/NE on important,
real-world outcomes
such as mental health

Kessler et al 2012; Bystritsky 2006; Whiteford et al 2013

Disposi@onal anxiety is a key risk factor

increased risk

Anxiety, mood, and substance

disorders

Barlow et al. 2013; Clauss & Blackford 2012; Kotov et al. 2010; Watson & Naragon-Gainey 2014

Students

But exactly do we mean by N/NE?

What kinds of processes
seem to be involved?

Barlow et al. 2013; Clauss & Blackford 2012; Kotov et al. 2010; Watson & Naragon-Gainey 2014

Neuro9cism, as measured by factor-analy9c [self-report]

scales, is a conceptual hodgepodge ofcogni9ons,
behavior, emo9ons, and symptoms





Seymour Epstein 1994

Epstein Psychol Inquiry 1994

Dan & Jack (UW-Madison)

John Cur4n (UW)

David Walker (Emory)

Chris4an Grillon (NIMH)

Mike Davis (Emory)

Me (UMD)

Dan & Jack (UW-Madison)

John Cur4n (UW)

David Walker (Emory)

Chris4an Grillon (NIMH)

Mike Davis (Emory)

Me (UMD)

Uncertainty is the Core Feature of Anxiety

Anxiety can be thought of as a future-oriented emo@onal state

Characterized by an@cipatory cogni@ve, behavioral, physio, and
emo@onal changes in response to uncertain threat
Normal and adap@ve when appropriately @trated to the
likelihood and severity of threat

Maladap@ve when conducted excessively, e.g.,

when threat is distal, improbable, inconsequen@al

Mountain out of a molehill
Lost opportunity for alloca@ng resources to other ac@vi@es
that are rewarding & promote posi@ve aect, e.g.,
foraging, fornica@ng, playing, paren@ng, etc.

Uncertainty is the Core Feature of Anxiety

Anxiety can be thought of as a future-oriented emo@onal state

Characterized by an@cipatory cogni@ve, behavioral, physio, and
emo@onal changes in response to uncertain threat
Normal and adap@ve when appropriately @trated to the
likelihood and severity of threat

Maladap@ve when conducted excessively, e.g.,

when threat is distal, improbable, inconsequen@al

Mountain out of a molehill
Lost opportunity for alloca@ng resources to other ac@vi@es
that are rewarding & promote posi@ve aect, e.g.,
foraging, fornica@ng, playing, paren@ng, etc.

Uncertainty is the Core Feature of Anxiety

Anxiety can be thought of as a future-oriented emo@onal state

Characterized by an@cipatory cogni@ve, behavioral, physio, and
emo@onal changes in response to uncertain threat
Normal and adap@ve when appropriately @trated to the
likelihood and severity of threat

Maladap@ve when conducted excessively, e.g.,

when threat is distal, improbable, inconsequen@al

Mountain out of a molehill
Lost opportunity for alloca@ng resources to other ac@vi@es
that are rewarding & promote posi@ve aect, e.g.,
foraging, fornica@ng, playing, paren@ng, etc.

Uncertainty is the Core Feature of Anxiety

Anxiety can be thought of as a future-oriented emo@onal state

Characterized by an@cipatory cogni@ve, behavioral, physio, and
emo@onal changes in response to uncertain threat
Normal and adap@ve when appropriately @trated to the
likelihood and severity of threat (false alarms can be good)

Maladap@ve when conducted excessively, e.g.,

when threat is remote, improbable, inconsequen@al

Mountain out of a molehill
Lost opportunity for alloca@ng resources to other ac@vi@es
that are rewarding & promote posi@ve aect, e.g.,
foraging, fornica@ng, playing, paren@ng, etc.

Uncertainty is the Core Feature of Anxiety

Anxiety can be thought of as a future-oriented emo@onal state

Characterized by an@cipatory cogni@ve, behavioral, physio, and
emo@onal changes in response to uncertain threat
Normal and adap@ve when appropriately @trated to the
likelihood and severity of threat (false alarms can be good)

Maladap@ve when conducted excessively, e.g.,

when threat is remote, improbable, inconsequen@al

Mountain out of a molehill
Lost opportunity for alloca@ng resources to other ac@vi@es
that are rewarding & promote posi@ve aect, e.g.,
foraging, fornica@ng, playing, paren@ng, etc.

Uncertainty is the Core Feature of Anxiety

Anxiety can be thought of as a future-oriented emo@onal state

Characterized by an@cipatory cogni@ve, behavioral, physio, and
emo@onal changes in response to uncertain threat
Normal and adap@ve when appropriately @trated to the
likelihood and severity of threat (false alarms can be good)

Maladap@ve when conducted excessively, e.g.,

when threat is remote, improbable, inconsequen@al

Mountain out of a molehill
Lost opportunity for alloca@ng resources to other ac@vi@es
that are rewarding & promote posi@ve aect, e.g.,
foraging, fornica@ng, playing, paren@ng, etc.

Uncertainty is the Core Feature of Anxiety

Grupes central claim is that the common denominator across
disposi@onal anxiety (T&P) and the anxiety disorders is aberrant
and excessive an@cipatory responding under condi@ons of
uncertain or ambiguous threat
And this reects altera@ons in
a core set of brain regions

Focus on the MCC

What if??

Uncertainty is the Core Feature of Anxiety

Grupes central claim is that the common denominator across
disposi@onal anxiety (T&P) and the anxiety disorders is aberrant
and excessive an@cipatory responding under condi@ons of
uncertain or ambiguous threat
And that this reects altera@ons in
5 key neuropsychological processes

Including the MCC

What if??

Dissec@ng Uncertainty: 5 Components

1. Elevated es@mates of threat likelihood and intensity
2. Elevated vigilance
3. Decient safety learning
4. Elevated threat avoidance (behavioral / cogni@ve)
5. Elevated reac@vity (or decient regula@on of reac@ons) to
uncertain or ambiguous threat

. 5 transdiagnos@c intermediate phenotypes

that support chronically elevated distress

Dissec@ng Uncertainty: 5 Components

1. Elevated es@mates of threat likelihood and intensity
2. Elevated vigilance
3. Decient safety learning
4. Elevated threat avoidance (behavioral / cogni@ve)
5. Elevated reac@vity (or decient regula@on of reac@ons) to
uncertain or ambiguous threat

. 5 transdiagnos@c intermediate phenotypes

that support chronically elevated distress

Dissec@ng Uncertainty: 5 Components

1. Elevated es@mates of threat likelihood and intensity
2. Elevated vigilance
3. Decient safety learning
4. Elevated threat avoidance (behavioral / cogni@ve)
5. Elevated reac@vity (or decient regula@on of reac@ons) to
uncertain or ambiguous threat

. 5 transdiagnos@c intermediate phenotypes

that support chronically elevated distress

Dissec@ng Uncertainty: 5 Components

1. Elevated es@mates of threat likelihood and intensity
2. Elevated vigilance
3. Decient safety learning
4. Elevated threat avoidance
5. Elevated reac@vity (or decient regula@on of reac@ons) to
uncertain or ambiguous threat

. 5 transdiagnos@c intermediate phenotypes

that support chronically elevated distress

Dissec@ng Uncertainty: 5 Components

1. Elevated es@mates of threat likelihood and intensity
2. Elevated vigilance
3. Decient safety learning
4. Elevated threat avoidance
5. Elevated reac@vity (or decient regula@on of reac@ons) to
uncertain or ambiguous threat

. 5 transdiagnos@c intermediate phenotypes

that support chronically elevated distress

Dissec@ng Uncertainty: 5 Components

1. Elevated es@mates of threat likelihood and intensity
2. Elevated vigilance
3. Decient safety learning
4. Elevated threat avoidance
5. Elevated reac@vity (or decient regula@on of reac@ons) to
uncertain or ambiguous threat

. 5 transdiagnos@c intermediate phenotypes


that support chronically elevated NE and


pervasive anxiety
transdiagnos4c = more than one anxiety disorder (diagnosis)

Dissec@ng Uncertainty: 5 Components

1. Elevated es@mates of threat likelihood and intensity
2. Elevated vigilance
3.
4.
5.

Under scru@ny, these

Decient safety learning
processes tend to blur together.

For eaxample,
heightened
vigilance /a nd
arousal
Elevated threat
voidance
(behavioral
cogni@ve)
(startle) during periods of learned safety

So, (or
5 d
mecient
ay be more
heuris@c than
Elevated reac@vity
regula@on
o f reac@ons) to
carving
nature at her joints
uncertain or ambiguous
threat

. 5 transdiagnos@c intermediate phenotypes

that support chronically elevated distress
transdiagnos4c = more than one anxiety disorder (diagnosis)

Lets meet Pete and Paul

Adap@ve Anxiety: The Case of Pete

Pete, home alone one night, hears rustling in the bushes and loud
banging sounds outside his house. Pete feels uncertain about
whether these noises are benign (curious raccoons) or threatening
(burglars). An adap4ve response to this uncertainty begins with a
ra4onal assessment of the probability of threat [EST]: few burglaries
occur in this neighborhood, and similar noises have never turned out
to be dangerous before. Pete turns down the television to give more
aben4on to what may be outside, but this heightened vigilance
[VIGIL] is balanced by aben4on to cues that indicate safety [SAFE
LEARN]. Because Petes security system is silent and the windows
and doors are locked, he has reliable signs that nobody has entered
his house. Nevertheless, Pete explores the situa4on to reduce
nagging ques4ons [AVOID]. Heading downstairs, he sees trash
strewn about the garbage cans and surmises the likely culprit was a
raccoon. Despite some unresolved uncertainty, Pete can calm his
racing heart [REACT/REG] and fall asleep knowing that all signs point
towards safety.

Adap@ve Anxiety: The Case of Pete

Pete, home alone one night, hears rustling in the bushes and loud
banging sounds outside his house. Pete feels uncertain about
whether these noises are benign (curious raccoons) or threatening
(burglars). An adap4ve response to this uncertainty begins with a
ra4onal assessment of the probability of threat [EST]: few burglaries
occur in this neighborhood, and similar noises have never turned out
to be dangerous before. Pete turns down the television to give more
aben4on to what may be outside, but this heightened vigilance
[VIGIL] is balanced by aben4on to cues that indicate safety [SAFE
LEARN]. Because Petes security system is silent and the windows
and doors are locked, he has reliable signs that nobody has entered
his house. Nevertheless, Pete explores the situa4on to reduce
nagging ques4ons [AVOID]. Heading downstairs, he sees trash
strewn about the garbage cans and surmises the likely culprit was a
raccoon. Despite some unresolved uncertainty, Pete can calm his
racing heart [REACT/REG] and fall asleep knowing that all signs point
towards safety.

Adap@ve Anxiety: The Case of Pete

Pete, home alone one night, hears rustling in the bushes and loud
banging sounds outside his house. Pete feels uncertain about
whether these noises are benign (curious raccoons) or threatening
(burglars). An adap4ve response to this uncertainty begins with a
ra4onal assessment of the probability of threat [EST]: few burglaries
occur in this neighborhood, and similar noises have never turned out
to be dangerous before. Pete turns down the television to give more
aben4on to what may be outside, but this heightened vigilance
[VIGIL] is balanced by aben4on to cues that indicate safety [SAFE
LEARN]. Because Petes security system is silent and the windows
and doors are locked, he has reliable signs that nobody has entered
his house. Nevertheless, Pete explores the situa4on to reduce
nagging ques4ons [AVOID]. Heading downstairs, he sees trash
strewn about the garbage cans and surmises the likely culprit was a
raccoon. Despite some unresolved uncertainty, Pete can calm his
racing heart [REACT/REG] and fall asleep knowing that all signs point
towards safety.

Adap@ve Anxiety: The Case of Pete

Pete, home alone one night, hears rustling in the bushes and loud
banging sounds outside his house. Pete feels uncertain about
whether these noises are benign (curious raccoons) or threatening
(burglars). An adap4ve response to this uncertainty begins with a
ra4onal assessment of the probability of threat [EST]: few burglaries
occur in this neighborhood, and similar noises have never turned out
to be dangerous before. Pete turns down the television to give more
aben4on to what may be outside, but this heightened vigilance
[VIGIL] is balanced by aben4on to cues that indicate safety [SAFE
LEARN]. Because Petes security system is silent and the windows
and doors are locked, he has reliable signs that nobody has entered
his house. Nevertheless, Pete explores the situa4on to reduce
nagging ques4ons [AVOID]. Heading downstairs, he sees trash
strewn about the garbage cans and surmises the likely culprit was a
raccoon. Despite some unresolved uncertainty, Pete can calm his
racing heart [REACT/REG] and fall asleep knowing that all signs point
towards safety.

Maladap@ve Anxiety: The Case of Paul

Next door lives Paul, a chronic worrier with GAD, who hears the
same noises and experiences similar feelings of uncertainty. Instead
of objec4vely weighing the likelihood of alterna4ve outcomes, Paul
immediately imagines burglars entering his home [EST].
Uncontrollable worries and cascading what if thoughts course
through his head, and he generates increasingly elaborate scenarios
of what evils may befall him. He becomes increasingly abuned to
every movement in the branches or creak in the oorboards of his
old house [VIGIL]. Owing to Pauls exclusive aben4on towards
poten4al threat, he does not no4ce that his security system is silent
[SAFE LEARN]. Concerned for his safety, Paul locks his bedroom door
instead of inves4ga4ng [AVOID]. Having avoided exploring the
situa4on, Paul is leg with greater unresolved uncertainty than Pete
about the source of the noises. He tries to sleep but his racing heart
and sweaty palms keep him from relaxing [REACT/REG]. Not having
learned that the situa4on was safe, Paul will be more likely to
assume the worst the next 4me he hears a noise in the night.

Maladap@ve Anxiety: The Case of Paul

Next door lives Paul, a chronic worrier with GAD, who hears the
same noises and experiences similar feelings of uncertainty. Instead
of objec4vely weighing the likelihood of alterna4ve outcomes, Paul
immediately imagines burglars entering his home [EST].
Uncontrollable worries and cascading what if thoughts course
through his head, and he generates increasingly elaborate scenarios
of what evils may befall him. He becomes increasingly abuned to
every movement in the branches or creak in the oorboards of his
old house [VIGIL]. Owing to Pauls exclusive aben4on towards
poten4al threat, he does not no4ce that his security system is silent
[SAFE LEARN]. Concerned for his safety, Paul locks his bedroom door
instead of inves4ga4ng [AVOID]. Having avoided exploring the
situa4on, Paul is leg with greater unresolved uncertainty than Pete
about the source of the noises. He tries to sleep but his racing heart
and sweaty palms keep him from relaxing [REACT/REG]. Not having
learned that the situa4on was safe, Paul will be more likely to
assume the worst the next 4me he hears a noise in the night.

Maladap@ve Anxiety: The Case of Paul

Next door lives Paul, a chronic worrier with GAD, who hears the
same noises and experiences similar feelings of uncertainty. Instead
of objec4vely weighing the likelihood of alterna4ve outcomes, Paul
immediately imagines burglars entering his home [EST].
Uncontrollable worries and cascading what if thoughts course
through his head, and he generates increasingly elaborate scenarios
of what evils may befall him. He becomes increasingly abuned to
every movement in the branches or creak in the oorboards of his
old house [VIGIL]. Owing to Pauls exclusive aben4on towards
poten4al threat, he does not no4ce that his security system is silent
[SAFE LEARN]. Concerned for his safety, Paul locks his bedroom door
instead of inves4ga4ng [AVOID]. Having avoided exploring the
situa4on, Paul is leg with greater unresolved uncertainty than Pete
about the source of the noises. He tries to sleep but his racing heart
and sweaty palms keep him from relaxing [REACT/REG]. Not having
learned that the situa4on was safe, Paul will be more likely to
assume the worst the next 4me he hears a noise in the night.

Not just grown ups

See what it is, you might feel beber

See what it is, you might feel beber
Once you know what's there
You might nd you don't need to be
scared

I couldn't help but feel royally scared
When I saw a strange lump on the
oor
But when I saw what was there
My favorite stued bear
I wasn't afraid anymore

You know, I was grrr-icly scared
When I saw a creepy shadow on the
wall
But it was just a light shining
On silly Mr. Lizard
That made him look so very very tall
Once we saw what was there
We knew he had nothing to fear

See what it is, you might feel beber

See what it is, you might feel beber
Once you know what's there
You might nd you don't need to be
scared

I heard a sound that gave me such a fright
I couldn't see what it was, it was out of
sight
Let's see what it is
It's a frog
See what it is, you might feel beber
See what it is, you might not be afraid

We saw a large shape that gave us a scare
It looked like a really really big bear
Let's see what it is
It's a rock
See what it is, you might feel beber
See what it is, you might not be afraid
See what it is, you might feel beber
Once you see what's there you might not
feel so afraid

Start @ 19:15 hbps://www.youtube.com/watch?v=nisqIXwxHms

Drill into the 5 consBtuents

1. Inated Es@mates of Threat Likelihood/

Intensity

Instead of objec9vely weighing the likelihood of alterna9ve

outcomes, Paul immediately imagines burglars entering his home

1. Inated Es@mates of Threat Likelihood/

Intensity
Evidence for inated es@mates of threat?

Judgment Biases
Anxious individuals overweight the probability of
nega@ve events

1. Inated Es@mates of Threat Likelihood/

Intensity
Evidence for inated es@mates of threat?

Judgment Biases
Anxious individuals overweight the probability of
nega@ve events

2. Hypervigilance
Paul becomes increasingly aHuned to
every movement in the branches or
creak in the oorboards of his old house

2. Hypervigilance
Paul becomes increasingly aHuned to
every movement in the branches or
creak in the oorboards of his old house

9me

Dot-Probe Vigilance Task

Hypervigilance: Meta-AnalyBc Evidence

see also Van Boekstaele et al Psychol Bull in press

Hypervigilance: Meta-AnalyBc Evidence

see also Van Boekstaele et al Psychol Bull in press

Hypervigilance: Meta-AnalyBc Evidence

see also Van Boekstaele et al Psychol Bull in press

Can Hypervigilance be Re-Trained?

see also Van Boekstaele et al Psychol Bull in press

Ann Rev Clin Psychol 2012

Can Hypervigilance be Re-Trained?

see also Van Boekstaele et al Psychol Bull in press

Ann Rev Clin Psychol 2012

Students


Whats at stake? Whats the clinical
or scienBc value of studying
retraining?

Retraining Vigilance: Goals

1. Manipulate vigilance to test whether it causally contributes to
anxiety
2. Test the therapeu@c ecacy of aqen@on retraining
- Conven@onal CBT
- Introspec@ve insight into thoughts that trigger anxiety
and mentally challenging those thoughts
- Retraining
- Directly modify cogni@ve biases thru extended task
prac@ce
- Not dependent on introspec@on
- More akin to learning a new motor skill

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015 Ann Rev Clin Psychol 2012

Retraining Vigilance: Goals

1. Manipulate vigilance to test whether it causally contributes to
anxiety
2. Test the therapeu@c ecacy of aqen@on retraining
- Conven@onal CBT
- Introspec@ve insight into thoughts that trigger anxiety
and mentally challenging those thoughts
- Retraining
- Directly modify cogni@ve biases thru extended task
prac@ce
- Not dependent on introspec@on
- More akin to learning a new motor skill

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015 Ann Rev Clin Psychol 2012

Retraining Vigilance: Goals

1. Manipulate vigilance to test whether it causally contributes to
anxiety
2. Test the therapeu@c ecacy of aqen@on retraining
- Conven@onal Cogni@ve-Behavioral Therapy (CBT)
- Introspec@ve insight into thoughts that trigger anxiety
and mentally challenging those thoughts
- Retraining
- Directly modify cogni@ve biases thru extended task
prac@ce
- Not dependent on introspec@on
- More akin to learning a new motor skill

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015 Ann Rev Clin Psychol 2012

Retraining Vigilance: Goals

1. Manipulate vigilance to test whether it causally contributes to
anxiety
2. Test the therapeu@c ecacy of aqen@on retraining
- Conven@onal Cogni@ve-Behavioral Therapy (CBT)
- Introspec@ve insight into thoughts that trigger anxiety
and mentally challenging those thoughts
- Retraining
- Directly modify cogni@ve biases thru extended task
prac@ce
- Not dependent on introspec@on
- More akin to learning a new motor skill (or exposure Tx)
- Focused and can be gameied
Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015 Ann Rev Clin Psychol 2012

Dennis Clin Psychol Sci 2014

In this game two animated characters will

appear on the screen. Shortly aPer, they
will burrow into a hole. One of them will
cause a path of grass to rustle behind it.
With your nger, trace the path of the
rustling grass, beginning from the burrow.
Try to complete this task as quickly and as
accurately as possible.

Dennis Clin Psychol Sci 2014

In this game two animated characters will

appear on the screen. Shortly aPer, they
will burrow into a hole. One of them will
cause a path of grass to rustle behind it.
With your nger, trace the path of the
rustling grass, beginning from the burrow.
Try to complete this task as quickly and as
accurately as possible.

In the ABM condi4on, a trail of grass
appeared in the loca4on of the non-threat
sprite on every trial, whereas in the placebo
training condi4on, trails were equally likely
to appear in the loca4on of the
angry/threat or neutral/non-threat sprites


Dennis Clin Psychol Sci 2014

Retraining Vigilance: Lessons Learned

Vigilance causally contributes to elevated anxiety

In nonclinical samples exposed to one-shot lab sessions, retraining
has been found to reduce

stress elicited by subsequent exposure to simple cogni@ve
stressors (anagram/puzzle challenges)
anxiety ra@ngs and behaviors (assessed by raters) when
delivering a public speech
intrusive, apprehensive thoughts during a worry induc@on

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015 Ann Rev Clin Psychol 2012

Retraining Vigilance: Lessons Learned

Vigilance causally contributes to elevated anxiety

In nonclinical samples exposed to one-shot lab sessions, retraining
has been found to reduce

stress elicited by subsequent exposure to simple cogni@ve
stressors (anagram/puzzle challenges)
anxiety ra@ngs and behaviors (assessed by raters) when
delivering a public speech
intrusive, apprehensive thoughts during a worry induc@on

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015 Ann Rev Clin Psychol 2012

Retraining Vigilance: Lessons Learned

Vigilance causally contributes to elevated anxiety

In nonclinical samples exposed to one-shot lab sessions, retraining
has been found to reduce

stress elicited by subsequent exposure to simple cogni@ve
stressors (anagram/puzzle challenges)
anxiety ra@ngs and behaviors (assessed by raters) when
delivering a public speech
intrusive, apprehensive thoughts during a worry induc@on

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015 Ann Rev Clin Psychol 2012

Retraining Vigilance: Lessons Learned

Vigilance causally contributes to elevated anxiety

In nonclinical samples exposed to one-shot lab sessions, retraining
has been found to reduce

stress elicited by subsequent exposure to simple cogni@ve
stressors (anagram/puzzle challenges)
anxiety ra@ngs and behaviors (assessed by raters) when
delivering a public speech
intrusive, apprehensive thoughts during a worry induc@on

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015 Ann Rev Clin Psychol 2012

Retraining Vigilance: Lessons Learned

Vigilance causally contributes to elevated anxiety

In nonclinical samples exposed to one-shot lab sessions, retraining
has been found to reduce

stress elicited by subsequent exposure to simple cogni@ve
stressors (anagram/puzzle challenges)
anxiety ra@ngs and behaviors (assessed by raters) when
delivering a public speech (e.g. Dennis mobile app study)
intrusive, apprehensive thoughts during a worry induc@on

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015 Ann Rev Clin Psychol 2012

Retraining Vigilance: Lessons Learned

Vigilance causally contributes to elevated anxiety

In nonclinical samples exposed to one-shot lab sessions, retraining
has been found to reduce

stress elicited by subsequent exposure to simple cogni@ve
stressors (anagram/puzzle challenges)
anxiety ra@ngs and behaviors (assessed by raters) when
delivering a public speech (e.g. Dennis mobile app study)
intrusive, apprehensive thoughts during a worry induc@on

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015 Ann Rev Clin Psychol 2012

Retraining Vigilance: Lessons Learned

Vigilance causally contributes to elevated anxiety

In nonclinical samples exposed to one-shot lab sessions, retraining
has been found to reduce

stress elicited by subsequent exposure to simple cogni@ve
stressors (anagram/puzzle challenges)
anxiety ra@ngs and behaviors (assessed by raters) when
delivering a public speech
intrusive, apprehensive thoughts during a worry induc@on

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015 Ann Rev Clin Psychol 2012

Retraining Vigilance: Lessons Learned

Retraining appears to be eec@ve at reducing clinical anxiety

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015

Biol Psychiatry 2010

Retraining Vigilance: Lessons Learned

Retraining appears to be eec@ve at reducing clinical anxiety

Trained 57 individuals with social phobia
Those trained to abend to nonthreatening
cues demonstrated greater reduc4ons in
self-reported, behavioral, and physiological
(CSR) measures of anxiety in response to a
public speaking challenge than those in the
abend to threat and control condi4ons

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015

Biol Psychiatry 2010

Retraining Vigilance: Lessons Learned

Retraining appears to be eec@ve at reducing clinical anxiety

Trained 57 individuals with social phobia
Those trained to abend to nonthreatening
cues demonstrated greater reduc4ons in
self-reported, behavioral, and physiological
(CSR) measures of anxiety in response to a
public speaking challenge than those in the
abend to threat and control condi4ons

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015

Biol Psychiatry 2010

Retraining Vigilance: Lessons Learned

Retraining appears to be eec@ve at reducing clinical anxiety

Trained 57 individuals with social phobia
Those trained to abend to nonthreatening
cues demonstrated greater reduc4ons in
self-reported, behavioral, and physiological
(CSR) measures of anxiety in response to a
public speaking challenge than those in the
abend to threat and control condi4ons
Similar eects reported for cor4sol and
examina4on stress

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015

Biol Psychiatry 2010

Retraining Vigilance: Lessons Learned

Retraining appears to be eec@ve at reducing clinical anxiety

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015

Biol Psychiatry 2010

Retraining Vigilance: Lessons Learned

Retraining appears to be eec@ve at reducing clinical anxiety

Van Boekstaele et al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015

Biol Psychiatry 2010

Retraining Vigilance: Lessons Learned

Retraining appears to be eec@ve at reducing clinical anxiety

Furthermore Van Boekstaele et al review evidence that conven@onal CBT reduces the
aqen@onal bias to threat, consistent with the idea that hypervigilance is one
of the ac@ve ingredients in clinically signicant anxiety (see also Reinecke
et al Biol Psychiatry 2013)
Van Boekstaele e t al Psychol Bull in press [see also Tobon JCP 2011]; MacLeod & Clarke CPS 2015
Biol Psychiatry 2010

Where do hyper-vigilance and related

kinds of risk assessment behaviors
come from?

May reect the direct inuence of the

amygdala on sensory cortex

FFA: Fusiform Face Area

Vuillemier et al. Nat Neurosci 2004

FFA: Fusiform Face Area

Vuillemier et al. Nat Neurosci 2004

Hyper-vigilance could also reect an

indirect inuence of the amygdala on
corBcal sensory systems

Indirect Inuence via the Basal Forebrain

Details Are Not Important

Details Are Not Important

Wake Up!

Details Are Not Important

Basal Forebrain (N.B. of M.)

Basal Forebrain (N.B. of M.)

Basal Forebrain (NB of M): CorBcal Arousal

Rabbits: Whalen et al J Neurosci; Kapp et al Beh Neurosci

Basal Forebrain (NB of M): CorBcal Arousal

Learned Threat (CS+)

Increases Neuronal Spiking
in the NB of M

Learned Threat
Increases Cor@cal Arousal
(EEG Desynchroniza@on;
Less is More)

NB of M Spiking
Predicts
Cor@cal Arousal

CeA S@mula@on
Can Drive This Eect
(CeA NB of M Arousal

Rabbits: Whalen et al J Neurosci; Kapp et al Beh Neurosci

Details Are Not Important

Basal Forebrain (NB of M): CorBcal Arousal

Learned Threat (CS+)

Increases Neuronal Spiking
in the NB of M

Learned Threat (CS+)

Increases Cor@cal Arousal
(EEG Desynchroniza@on;
Less is More)

NB of M Spiking
Predicts
Cor@cal Arousal

CeA S@mula@on
Can Drive This Eect
(CeA NB of M Arousal

Rabbits: Whalen et al J Neurosci; Kapp et al Beh Neurosci

Details Are Not Important

Basal Forebrain (NB of M): CorBcal Arousal

Learned Threat (CS+)

Increases Neuronal Spiking
in the NB of M

Learned Threat (CS+)

Increases Cor@cal Arousal
(EEG Desynchroniza@on;
Less is More)

NB of M Spiking
Predicts
Cor@cal Arousal

CeA S@mula@on
Can Drive This Eect
(CeA NB of M Arousal

Rabbits: Whalen et al J Neurosci; Kapp et al Beh Neurosci

Details Are Not Important

Basal Forebrain (NB of M): CorBcal Arousal

Learned Threat (CS+)

Increases Neuronal Spiking
in the NB of M

Learned Threat (CS+)

Increases Cor@cal Arousal
(EEG Desynchroniza@on;
Less is More)

CeA S@mula@on
Can Drive This Eect
(CeA NB of M Arousal)

Rabbits: Whalen et al J Neurosci; Kapp et al Beh Neurosci

NB of M Spiking
Predicts
Cor@cal Arousal

Indirect Inuence via the Basal Forebrain

3. Decient Safety Learning

3. Decient Safety Learning

Pete [aHends to] to cues that indicate safety. Because
his security system is silent and the windows and doors
are locked, he has reliable signs that nobody has
entered his house.

Owing to Pauls exclusive aHen9on towards poten9al

threat, he does not no9ce that his security system is silent
[and so remains in a state of apprehensive distress]

3. Decient Safety Learning

Safety signals indicate the absence of threat; relieve individuals
from a state of an@cipatory anxiety
Under condi@ons of uncertainty,
weak or non-existent con@ngencies
between cues and aversive
outcomes make it dicult to
discriminate safety from threat
(CS- vs. CS+)
Heightened reac@vity (startle) to
objec@vely safe condi@ons (CS-, ITI)
has been observed across anxiety
disorders
Lissek et al Biol Psychiatry in press

3. Decient Safety Learning

Safety signals indicate the absence of threat; relieve individuals
from a state of an@cipatory anxiety
Heightened reac@vity (startle) to
objec@vely safe condi@ons (CS-, ITI)
has been consistently observed
across anxiety disorders

Lissek et al Biol Psychiatry in press

3. Decient Safety Learning

Safety signals indicate the absence of threat; relieve individuals
from a state of an@cipatory anxiety
Heightened reac@vity (startle) to
objec@vely safe condi@ons (CS-, ITI)
has been consistently observed
across anxiety disorders

Lissek et al Biol Psychiatry in press

3. Decient Safety Learning

Safety signals indicate the absence of threat; relieve individuals
from a state of an@cipatory anxiety
Heightened reac@vity (startle) to
objec@vely safe condi@ons (CS-, ITI)
has been consistently observed
across anxiety disorders

Lissek et al Biol Psychiatry in press

3. Decient Safety Learning

Safety signals indicate the absence of threat; relieve individuals
from a state of an@cipatory anxiety
Heightened reac@vity (startle) to
objec@vely safe condi@ons (CS-, ITI)
has been consistently observed
across anxiety disorders

Not just startle

Lissek et al Biol Psychiatry in press

3. Decient Safety Learning

Safety signals indicate the absence of threat; relieve individuals
from a state of an@cipatory anxiety
Heightened reac@vity (startle) to
objec@vely safe condi@ons (CS-, ITI)
has been consistently observed

3. Decient Safety Learning

Safety signals indicate the absence of threat; relieve individuals
from a state of an@cipatory anxiety
Heightened reac@vity (startle) to
objec@vely safe condi@ons (CS-, ITI)
has been consistently observed
44 studies (>2,000 Ss), including a
broad spectrum of self-report and
physiological measures of
condi@oned fear/anxiety

3. Decient Safety Learning

Safety signals indicate the absence of threat; relieve individuals
from a state of an@cipatory anxiety
Heightened reac@vity (startle) to
objec@vely safe condi@ons (CS-, ITI)
has been consistently observed
44 studies (>2,000 Ss), including a
broad spectrum of self-report and
physiological measures of
condi@oned fear/anxiety

Pa@ents with anxiety disorders
do not dier in their response to
condi@oned threat cues (CS+), but do
show elevated responses to safety cues
(CS-)

3. Decient Safety Learning

This is a Really Big Deal

For a long 4me, it was thought that

neuro4c, anxious individuals are
characterized by heightened fear learning
and excessive responsiveness to the CS+
(the black bars in the gure)and that we
could understand anxiety by elucida4ng the
substrates of fear learning
But it has grown increasingly clear that this
is generally not the case
Rather, neuro4c/anxious individuals show
dicul4es discrimina4ng threat from
safety, manifes4ng as heightened reac4ons
to ostensibly safe cues and contexts (white
and grey bars in the gure)

3. Decient Safety Learning

This is a Really Big Deal

For a long 4me, it was thought that

neuro4c, anxious individuals are
characterized by heightened fear learning
and excessive responsiveness to the CS+
and that we could understand anxiety by
elucida4ng the substrates of fear learning
But it has grown increasingly clear that this
is generally not the case
Rather, neuro4c/anxious individuals show
dicul4es discrimina4ng threat from
safety, manifes4ng as heightened reac4ons
to ostensibly safe cues and contexts (white
and grey bars in the gure)

3. Decient Safety Learning

This is a Really Big Deal

For a long 4me, it was thought that

neuro4c, anxious individuals are
characterized by heightened fear learning
and excessive responsiveness to the CS+
and that we could understand anxiety by
elucida4ng the substrates of fear learning
But it has grown increasingly clear that this
is generally not the case
Rather, neuro4c/anxious individuals show
dicul4es discrimina4ng threat from
safety, manifes4ng as heightened reac4ons
to ostensibly safe cues and contexts (white
and grey bars in the gure)

3. Decient Safety Learning

This is a Really Big Deal

For a long 4me, it was thought that

neuro4c, anxious individuals are
characterized by heightened fear learning
and excessive responsiveness to the CS+
and that we could understand anxiety by
elucida4ng the substrates of fear learning
But it has grown increasingly clear that this
is generally not the case
Rather, neuro4c/anxious individuals show
dicul4es discrimina4ng threat from
safety, manifes4ng as heightened reac4ons
to ostensibly safe cues and contexts (CS-,
ITI)

3. Decient Safety Learning

This is a Really Big Deal

This is specic to studies involving the use

of noxious electric shock (or darkness)
Anxious individuals show exaggerated FPS
when you turn out the lightsanother kind
of diuse threatand this is reduced by
benzodiazepines

Increased ITI/Baseline startle is not
observed in other kinds of non-emo4onal
startle studies
Suggests that it does not simply reect
hyper-reac4vity to the novelty of the lab,
personnel, or procedures, but instead
reects a response to diuse or remote
threat: being in a shock study / having
electrodes in-place / darkness

cf. Grillon et al PlosOne 2013

3. Decient Safety Learning

This is a Really Big Deal

This is specic to studies involving the use

of noxious electric shock (or darkness)
Anxious individuals show exaggerated FPS
when you turn out the lightsanother kind
of diuse threatand this is reduced by
benzodiazepines

Increased ITI/Baseline startle is not
observed in other kinds of non-emo4onal
startle studies
Suggests that it does not simply reect
hyper-reac4vity to the novelty of the lab,
personnel, or procedures, but instead
reects a response to diuse or remote
threat: being in a shock study / having
electrodes in-place / darkness

cf. Grillon et al PlosOne 2013

3. Decient Safety Learning

This is a Really Big Deal

This is specic to studies involving the use

of noxious electric shock (or darkness)
Anxious individuals show exaggerated FPS
when you turn out the lightsanother kind
of diuse threatand this is reduced by
benzodiazepines

Increased ITI/Baseline startle is not
observed in other kinds of non-emo4onal
startle studies
Suggests that it does not simply reect
hyper-reac4vity to the novelty of the lab,
personnel, or procedures, but instead
reects a response to diuse or remote
threat: being in a shock study / having
electrodes in-place / darkness

cf. Grillon et al PlosOne 2013

3. Decient Safety Learning

This is a Really Big Deal

This is specic to studies involving the use

of noxious electric shock (or darkness)
Anxious individuals show exaggerated FPS
when you turn out the lightsanother kind
of diuse threatand this is reduced by
benzodiazepines

Increased ITI/Baseline startle is not
observed in other kinds of non-emo4onal
startle studies
Suggests that it does not simply reect
hyper-reac4vity to the novelty of the lab,
personnel, or procedures, but instead
reects a response to diuse or remote
threat: being in a shock study / having
electrodes in-place / darkness

cf. Grillon et al PlosOne 2013

Lissek
(NIMH, Minnesota)

Hypothesized that heightened reac@ons to safety cues might reect a
kind of over-generaliza@on

Because the CS+ and CS, in a given study, are similar (e.g., both colored
lights, both faces), pa@ents appear to emo@onally mistake the CS- for the CS
+

Lissek
(NIMH, Minnesota)

Hypothesized that heightened reac@ons to safety cues might reect a
kind of over-generaliza@on

Noted that the CS+ and CS in a given study tend to be physically similar (e.g.,
both colored lights, both faces)
Anxious individuals appear to over-generalize from the CS+ to the CS-, in
terms of their emo@onal response (but not in terms of con@ngency reports)

Lissek
(NIMH, Minnesota)

Hypothesized that heightened reac@ons to safety cues might reect a
kind of over-generaliza@on

Noted that the CS+ and CS in a given study tend to be physically similar (e.g.,
both colored lights, both faces)
Hypothesized that anxious individuals over-generalize from the CS+ to the
physically similar CS-, in terms of their emo@onal response (but not in terms
of con@ngency reports)

Students: How might you test this

overgeneralizaBon hypothesis
in the lab?

Overgeneralize?

Lissek Dep and Anx 2012

Overgeneralize?

Lissek Dep and Anx 2012

Overgeneralize?

Elevated startle (FPS) rela@ve to CS-

Lissek Dep and Anx 2012

Overgeneralize?

Elevated startle (FPS) rela@ve to CS-

Lissek Dep and Anx 2012

Overgeneralized Fear Learning

Elevated startle (FPS) rela@ve to CS-

Lissek Dep and Anx 2012

Prospec@vely Predicts Disorder Onset

J Abnormal Psychol 2012

Prospec@vely Predicts Disorder Onset

J Abnormal Psychol 2012

Present in Teens with High Childhood BI

Reeb-Sutherland JAACAP 2009

Present in Teens with High Childhood BI

Reeb-Sutherland JAACAP 2009

What brain circuits support sustained

anxiety in response to diuse,
uncertain, or remote threat?

To understand the relevance of this

circuit in primates, we focused on a
group of young monkeys with stable
and extreme behavioral inhibiBon (BI)


Extreme behavioral inhibi@on (BI) confers risk


Stable and extreme behavioral inhibi@on (BI)

Total N = 109

Details Are Not Important

Control

Assessing sustained anxiety following threat

18-FDG
Injec@on

Ac@ve

No Intruder

No Intruder
(FDG uptake)

18-FDG
Injec@on

Intruder Threat
Details Are Not Important

No Intruder
(FDG uptake)

Shackman*, Fox* et al in prep

Control

Assessing sustained anxiety following threat

18-FDG
Injec@on

Ac@ve

No Intruder

No Intruder
(FDG uptake)

18-FDG
Injec@on

Intruder Threat
Details Are Not Important

No Intruder
(FDG uptake)

Shackman*, Fox* et al in prep

Control

Assessing sustained anxiety following threat

18-FDG
Injec@on

Ac@ve

No Intruder

No Intruder
(FDG uptake)

18-FDG
Injec@on

Intruder Threat
Details Are Not Important

No Intruder
(FDG uptake)

Shackman*, Fox* et al in prep

Control

Assessing sustained anxiety following threat

18-FDG
Injec@on

Ac@ve

No Intruder

No Intruder
(FDG uptake)

18-FDG
Injec@on

Intruder Threat
Details Are Not Important

No Intruder
(FDG uptake)

Shackman*, Fox* et al in prep

Shackman*, Fox* et al in prep

Paxinos et al 2009

Shackman*, Fox* et al in prep

Shackman et al. PNAS 2013; Birn*, Shackman* et al. under review; Shackman, Fox et al., in prep

Key Take Homes

5 core cons@tuents of the anxious phenotype (3 down, 2 to go!)
1. Inated es@mates of threat certainty or intensity/cost

2. Hypervigilance (aqen@onal threat bias)

Ac@ve ingredient/Causal
Present in BI
Amygdala, direct or indirect inuence on sensory cortex
3. Decient safety learning and overgeneraliza@on
Anxious individuals learn certain, imminent threat just ne
Predicts rst onset; present in BI
dlPFC, vmPFC, BNST?
4. Cogni@ve and behavioral avoidance
MCC
Circuit centered on the MCC may help to orchestrate some of the other processes
Key hub
5. Hyper-reac@vity to uncertainty and ambiguity
Ac@ve ingredient/Causal
Extended amygdala (amygdala, BNST)

6. These processes interact in ways that reinforce pervasive, chronic distress and arousal a la Pete and
Paul.

Key Take Homes

5 core cons@tuents of the anxious phenotype (3 down, 2 to go!)
1. Inated es@mates of threat certainty or intensity/cost

2. Hypervigilance (aqen@onal threat bias)

Ac@ve ingredient/Causal
Present in BI
Amygdala, direct or indirect inuence on sensory cortex
3. Decient safety learning and overgeneraliza@on
Anxious individuals learn certain, imminent threat just ne
Predicts rst onset; present in BI
dlPFC, vmPFC, BNST?
4. Cogni@ve and behavioral avoidance
MCC
Circuit centered on the MCC may help to orchestrate some of the other processes
Key hub
5. Hyper-reac@vity to uncertainty and ambiguity
Ac@ve ingredient/Causal
Extended amygdala (amygdala, BNST)

6. These processes interact in ways that reinforce pervasive, chronic distress and arousal a la Pete and
Paul.

Key Take Homes

5 core cons@tuents of the anxious phenotype (3 down, 2 to go!)
1. Inated es@mates of threat certainty or intensity/cost (mountain out of a molehill)
2. Hypervigilance (aqen@onal threat bias)
Ac@ve ingredient/Causal
Present in BI
Amygdala, direct or indirect inuence on sensory cortex
3. Decient safety learning and overgeneraliza@on
Anxious individuals learn certain, imminent threat just ne
Predicts rst onset; present in BI
dlPFC, vmPFC, BNST?
4. Cogni@ve and behavioral avoidance
MCC
Circuit centered on the MCC may help to orchestrate some of the other processes
Key hub
5. Hyper-reac@vity to uncertainty and ambiguity
Ac@ve ingredient/Causal
Extended amygdala (amygdala, BNST)

6. These processes interact in ways that reinforce pervasive, chronic distress and arousal a la Pete and
Paul.

Key Take Homes

5 core cons@tuents of the anxious phenotype (3 down, 2 to go!)
1. Inated es@mates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hyper-vigilance (bias to allocate excess aqen@on to threat or scanning for threat-relevant

informa@on)
Ac@ve ingredient/Causal
Present in BI
Circuits centered on the amygdala, poised to directly/indirectly inuence sensory cortex
3. Decient safety learning and overgeneraliza@on
Anxious individuals learn certain, imminent threat just ne
Predicts rst onset; present in BI
dlPFC, vmPFC, BNST?
4. Cogni@ve and behavioral avoidance
MCC
Circuit centered on the MCC may help to orchestrate some of the other processes
Key hub
5. Hyper-reac@vity to uncertainty and ambiguity
Ac@ve ingredient/Causal
Extended amygdala (amygdala, BNST)

6. These processes interact in ways that reinforce pervasive, chronic distress and arousal a la Pete and
Paul.

Key Take Homes

5 core cons@tuents of the anxious phenotype (3 down, 2 to go!)
1. Inated es@mates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hyper-vigilance (bias to allocate excess aqen@on to threat or scanning for threat-relevant

informa@on)
Ac@ve ingredient/Causal
Circuits centered on the amygdala, poised to directly/indirectly inuence sensory cortex
3. Decient safety learning and overgeneraliza@on
Anxious individuals learn certain, imminent threat just ne
Predicts rst onset; present in BI
dlPFC, vmPFC, BNST?
4. Cogni@ve and behavioral avoidance
MCC
Circuit centered on the MCC may help to orchestrate some of the other processes
Key hub
5. Hyper-reac@vity to uncertainty and ambiguity
Ac@ve ingredient/Causal
Extended amygdala (amygdala, BNST)

6. These processes interact in ways that reinforce pervasive, chronic distress and arousal a la Pete and
Paul.

Key Take Homes

5 core cons@tuents of the anxious phenotype (3 down, 2 to go!)
1. Inated es@mates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hyper-vigilance (bias to allocate excess aqen@on to threat or scanning for threat-relevant

informa@on)
Ac@ve ingredient/Causal
Circuits centered on the amygdala, poised to directly/indirectly inuence sensory cortex
3. Decient safety learning and overgeneraliza@on of anxiety to other cues and contexts
Anxious individuals learn about clear and imminent threats just ne
Predicts rst onset; present in BI

Key Take Homes

5 core cons@tuents of the anxious phenotype (3 down, 2 to go!)
1. Inated es@mates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hyper-vigilance (bias to allocate excess aqen@on to threat or scanning for threat-relevant

informa@on)
Ac@ve ingredient/Causal
Circuits centered on the amygdala, poised to directly/indirectly inuence sensory cortex
3. Decient safety learning and overgeneraliza@on of anxiety to other cues and contexts
Anxious individuals learn about clear and imminent threats just ne
Predicts rst onset; present in BI
Reects extended amygdala (BNST)

Take Home Cri@cal Thinking Ques@ons

1. Dan Grupe highlighted the importance of 5
intermediate phenotypes. Did he miss anything
important?

Take Home Cri@cal Thinking Ques@ons

2. Watch Paul Whalens brief TEDx talk (
hbps://www.youtube.com/watch?v=DeAMRUnrgbA) [<20 min].
Briey comment on what you found most interes4ng, thought-
provoking, mind-blowing, entertaining, objec4onable, or misleading
about Pauls claims.


3. Paul started his professional career performing mechanis4c
studies in a rabbit model (in Bruce Kapps lab at U VT), before doing a
post-doc at MGH with Scob Rauch and learning fMRI. As a professor
at Dartmouth, Paul and his students con4nue to use fMRI to
understand the role of the amygdala in humans. Briey comment on
the trade-os of Pauls professional decision in rela4on to
understanding the neurobiology of anxiety. What did he gain, what
did he lose?


(Please pick 2 of the 3 ques9ons)

Take Home Cri@cal Thinking Ques@ons

2. Watch Paul Whalens brief TEDx talk (
hbps://www.youtube.com/watch?v=DeAMRUnrgbA) [<20 min].
Briey comment on what you found most interes4ng, thought-
provoking, mind-blowing, entertaining, objec4onable, or misleading
about Pauls claims.


3. Paul started his professional career performing mechanis4c
studies in a rabbit model (in Bruce Kapps lab at U VT), before doing a
post-doc at MGH with Scob Rauch and learning fMRI. As a professor
at Dartmouth, Paul and his students con4nue to use fMRI to
understand the role of the amygdala in humans. Briey comment on
the trade-os of Pauls professional decision in rela4on to
understanding the neurobiology of anxiety. What did he gain, what
did he lose by switching from a rabbit model to fMRI studies of
humans?

Take Home Cri@cal Thinking Ques@ons

4. Researchers at Princeton set out to build a
tool that could show people what their brains are
doing in real 4me, and signal the moments when
their minds begin to wander. And they've largely
succeeded, a paper published today in the journal
Nature Neuroscience reports. The scien4sts who
invented this aben4on machine, led by professor
Nick Turk-Browne, are calling it a mind booster.
It could, they say, change the way we think about
paying aben4onand even introduce new ways
of trea4ng illnesses like anxiety

What do you think?

Read the brief popular press story in The Atlan4c
and then, based on what we discussed in class
today, comment on how this emergent
technology might be applied to anxiety disorders
(treatment) or N/NE (preven4on).



hbp://www.theatlan4c.com/technology/archive/2015/02/the-aben4on-machine/385284/ and hbp://www.nature.com/neuro/journal/v18/n3/abs/nn.3940.html

Take Home Cri@cal Thinking Ques@ons

4. Researchers at Princeton set out to build a
tool that could show people what their brains are
doing in real 4me, and signal the moments when
their minds begin to wander. And they've largely
succeeded, a paper published today in the journal
Nature Neuroscience reports. The scien4sts who
invented this aben4on machine, led by professor
Nick Turk-Browne, are calling it a mind booster.
It could, they say, change the way we think about
paying aben4onand even introduce new ways
of trea4ng illnesses like anxiety

What do you think?

Read the brief popular press story in The Atlan9c
and then, based on what we discussed in class
today, comment on how this emergent
technology might be applied to anxiety disorders
(treatment) or N/NE (preven4on). What are the
advantages of using signals from the brain to
boost or enhance learning (aka cogni4ve-
behavioral therapy)

hbp://www.theatlan4c.com/technology/archive/2015/02/the-aben4on-machine/385284/

The End (No Review Ques@ons)

Things to Consider Tweaking for

Spring 2015

Introduce duvarci/pare bnst?

Roy/Wager 2014 avoidance learning
Bradford baseline stl
Connec4on from mcc to grays model
Upon reec4on, do not merge the uncertainty
and safety learning into one sec4on (broken
out by learned/unlearned or cues/contexts)

due to a diminis
startle respondin
to the safety s4m
individuals who
more SR.

Summary fear condi9oning (Day 1). Together, our

main fear-condi4oning results indicated that enhanced SR
resulted in a weaker dieren4a4on between the threat
(CS1+) and the safety (CS2) s4mulus over the course of
fear condi4oning. This weakened dieren4al condi4oning
was due to a diminished reduc4on of startle responding
to the safety s4mulus (CS2) in individuals who show
more SR.
During fear condi4oning, individuals with high levels of
SR showed weaker discrimina4on between threat and
safety due to elevated fear responding to the safety s4mulus
(CS2).

The transi4on from normal

fear to pathological anxiety (Rosen & Schulkin, 1998)
is characterized by maladap4ve generaliza9on of specic
fear learning to other classes of s4muli or contexts
that are intrinsically safe but somehow related to the
original fear learning and persistence of fear responses
while the threat is no longer present.

Extra Slides

Hypervigilance in BI

Perez-Edgar et al JACP 2011

Hypervigilance in BI

Perez-Edgar et al JACP 2011

Discrimina@ng Threat from Safe

May reect aberrant interac@ons between the dorsolateral PFC and
the amygdala
dlPFC

Amyg

Lau et al PNAS 2011; Lissek et al SCAN in press

Discrimina@ng Threat from Safe

May reect aberrant interac@ons between the dorsolateral PFC and
the amygdala
dlPFC

Amyg

Lau et al PNAS 2011; Lissek et al SCAN in press

Discrimina@ng Threat from Safe

May reect aberrant interac@ons between the dorsolateral PFC and
the amygdala
dlPFC

Amyg

Lau et al PNAS 2011; Lissek et al SCAN in press


Amygdala Ac@vity Predicts the Ac@ve
Interroga@on of the Environment (Risk Assessment)

Gamer & Buchel J Neurosci 2009; Gamer et al Curr Biol 2013


Amygdala Ac@vity Predicts the Ac@ve
Interroga@on of the Environment (Risk Assessment)

Gamer & Buchel J Neurosci 2009; Gamer et al Curr Biol 2013


Amygdala Ac@vity Predicts the Ac@ve
Interroga@on of the Environment (Risk Assessment)

Amygdala damage aqenuates this ac@ve risk assessment behavior

Gamer & Buchel J Neurosci 2009; Gamer et al Curr Biol 2013

This hypothesis seems to map onto

the presentaBon of some
anxiety disorders,
such as PTSD

Kheirbek et al Nature Rev Neurosci 2012

Context = Fire/Smoke

Learn to associate context with anxiety and arousal

Kheirbek et al Nature Rev Neurosci 2012

Context = Fire/Smoke

Learn to associate context with anxiety and arousal

Kheirbek et al Nature Rev Neurosci 2012

Context = Fire/Smoke

Learn to associate context with anxiety and arousal

Kheirbek et al Nature Rev Neurosci 2012

Context = Fire/Smoke

Learn to associate context with anxiety and arousal

Kheirbek et al Nature Rev Neurosci 2012