Nuts

& Bolts Plan for Today

Next week: Review session (bring clicker!) and exam
Lecture (Grupe & Nitschke; Shackman)
Take-home criHcal thinking quesHons

We probably will not have Hme to review together

You are free to answer 2 of the quesHons detailed in this
powerpoint -or- to address quesHons from the last lecture
Q #4 is to peer review a paper that I am wriHng

How many would be interested in hearing the 5-min ash

talk that I will be giving in Boston on Saturday?

PSYC 210:

DissecHng broad-band N/NE
into its key consHtuents

Part 2 of 2
AJ Shackman
22 April 2014

Dan & Jack (UW-Madison)

John Cur@n (UW)

David Walker (Emory)

Chris@an Grillon (NIMH)

Mike Davis (Emory)

Me (UMD)

DissecHng Uncertainty: 5 Components

Students

What were the 3 components or intermediate phenotypes that we
discussed last Hme?

DissecHng Uncertainty: 5 Components

1. Elevated esHmates of threat likelihood and intensity
2. Hyper-vigilance
3. Decient safety learning (and over-generalizaHon)
4. Elevated threat avoidance
5. Elevated reacHvity (or decient regulaHon of reacHons) to
uncertain or ambiguous threat


. 5 transdiagnosHc intermediate phenotypes


that support chronically elevated NE and


pervasive anxiety

DissecHng Uncertainty: 5 Components

1. Elevated esHmates of threat likelihood and intensity
2. Hyper-vigilance
3. Decient safety learning (and over-generalizaHon)
4. Elevated threat avoidance
5. Elevated reacHvity (or decient regulaHon of reacHons) to
uncertain or ambiguous threat


. 5 transdiagnosHc intermediate phenotypes


that support chronically elevated NE and


pervasive anxiety

4. Avoidance: Deleterious Consequences

Concerned for his safety, Paul locks his bedroom door instead of inves8ga8ng. Having
avoided exploring the situa8on, Paul is le> withunresolved uncertaintyabout the
source of the noisesFurthermore, not having learned that the situa8on was safe, Paul
will be more likely to assume the worst the next 8me he hears a noise in the night.

4. Avoidance: Deleterious Consequences

4. Avoidance: Deleterious Consequences

Avoidant behavior and thoughts, including worrisome thoughts and
safety behaviors, prevent anxious individuals from being exposed to
evidence that might contradict negaHve predicHons about the future


Avoidance can therefore heighten threat expectancies under
condiHons of uncertainty


Because events that are avoided or worried about typically fail to
occur, maladapHve avoidance tendencies are reinforced and anxious
individuals develop false beliefs that they prevented these negaHve
outcomes

In short, they do not take advantage of opportuniHes for exHncHon

4. Avoidance: Deleterious Consequences

Avoidant behavior and thoughts, including worrisome thoughts and
safety behaviors, prevent anxious individuals from being exposed to
evidence that might contradict negaHve predicHons about the future


Avoidance can therefore heighten threat expectancies under
condiHons of uncertainty


Because events that are avoided or worried about typically fail to
occur, maladapHve avoidance tendencies are reinforced and anxious
individuals develop false beliefs that they prevented these negaHve
outcomes

In short, they do not take advantage of opportuniHes for exHncHon

4. Avoidance: Deleterious Consequences

Avoidant behavior and thoughts, including worrisome thoughts and
safety behaviors, prevent anxious individuals from being exposed to
evidence that might contradict negaHve predicHons about the future


Avoidance can therefore heighten threat expectancies under
condiHons of uncertainty


Because events that are avoided or worried about typically fail to
occur, maladapHve avoidance tendencies are reinforced and anxious
individuals develop false beliefs that they prevented these negaHve
outcomes

In short, they do not take advantage of opportuniHes for exHncHon

4. Avoidance: Deleterious Consequences

Avoidant behavior and thoughts, including worrisome thoughts and
safety behaviors, prevent anxious individuals from being exposed to
evidence that might contradict negaHve predicHons about the future


Avoidance can therefore heighten threat expectancies under
condiHons of uncertainty


Because events that are avoided or worried about typically fail to
occur, maladapHve avoidance tendencies are reinforced and anxious
individuals develop false beliefs that they prevented these negaHve
outcomes

In short, they do not take advantage of opportuniHes for exHncHon

Everyday manifestaHons of avoidance

Students

What might anxious avoidance
look like in daily life?

Barlow et al. Clin Psychol Sci 2013; Grupe & Nitschke Nature Rev Neurosci 2013

Everyday manifestaHons of avoidance

I cross the street to avoid talking to

someone I know.




I avoid doing thingslike picking up the
phone when it rings or going to parHes
because of my anxiety.

Barlow et al. Clin Psychol Sci 2013; Grupe & Nitschke Nature Rev Neurosci 2013

What mechanisms support

elevated avoidance?
I cross the street to avoid talking to
someone I know.




I avoid doing thingslike picking up the
phone when it rings or going to parHes
because of my anxiety.

Barlow et al. Clin Psychol Sci 2013; Grupe & Nitschke Nature Rev Neurosci 2013

Hyper-sensiHvity to punishment and errors

I cross the street to avoid talking to

someone I know.




I avoid doing thingslike picking up the
phone when it rings or going to parHes
because of my anxiety.

Barlow et al. Clin Psychol Sci 2013; Grupe & Nitschke Nature Rev Neurosci 2013

Hyper-sensiHvity to errors

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Hyper-sensiHvity to errors

ploBed nega8ve up

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

The Error-Related NegaHvity (ERN) is

generated in the midcingulate cortex

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

The Error-Related NegaHvity (ERN)

is emoHonal

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

The Error-Related NegaHvity (ERN)

is emoHonal
Error-Related NegaHvity
(reduced by anxiolyHcs)
MCC

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

The Error-Related NegaHvity (ERN)

is emoHonal
Error-Related NegaHvity
(reduced by anxiolyHcs)
MCC

Error-PotenHated Startle

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

CogniHve potenHals are also

generated in the midcingulate cortex

MCC

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

CogniHve potenHals are also

generated in the midcingulate cortex
N2

MCC

Cogni@ve Control Models: e.g., Yeung, Botvinick & Cohen, Psych Bull, 2004
Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

These cogniHve potenHals are also

enhanced in anxious individuals

Shackman, Shackman et al. under review

Both emoHonal (ERN, FRN) and cogniHve

(N2) potenHals are consistently enhanced

Ticks indicate the correla@on

between anxiety and
one of the ERP components
for each of the 47 studies

FRN: feedback-related nega@vity

Cavanagh & Shackman J Physiol Paris in press

Large-scale meta-analysis of the imaging literature

FDR q<.05

~3,000 healthy subjects

shackmanlab.org

Shackman et al. Nature Reviews Neurosci 2011

Large-scale meta-analysis of the imaging literature

FDR
FDR q<.05
q<.05

~3,000 healthy subjects

shackmanlab.org

Shackman et al. Nature Reviews Neurosci 2011

Regions of 3-way overlap

FDR q<.05

~3,000 healthy subjects

shackmanlab.org

Shackman et al. Nature Reviews Neurosci 2011

Co-localization in the mid-cingulate cortex

FDR q<.05

~3,000 healthy subjects

shackmanlab.org

Shackman et al. Nature Reviews Neurosci 2011

Replicated using dierent databases, studies,

and more recently developed analytic tools

FDR q<.05

Maps are freely available for download @ NeuroVault.org and NeuroSynth.org

FDR q<.05

Payano Sosa, Seminowicz & Shackman in prep.

Replicated using dierent databases, studies,

and more recently developed analytic tools

AI

FDR q<.05

Maps are freely available for download @ NeuroVault.org and NeuroSynth.org

AI

FDR q<.05

Payano Sosa, Seminowicz & Shackman in prep.

But theres a problem

Meta-analysis entails an enormous loss of information

compared to any particular imaging study

Meta-analysis entails an enormous loss of information

compared to any particular imaging study

Peakify
Clusters

Meta-analysis entails an enormous loss of information

compared to any particular imaging study

Bunch of
Studies

Meta-analysis entails an enormous loss of information

compared to any particular imaging study

Bunch of
Studies

Bunch of
Domains

Meta-analysis entails an enormous loss of information

compared to any particular imaging study

Bunch of
Studies

Bunch of
Domains

Smooth

Threshold

A unique dataset

shackmanlab.org

Furman, Keaser, Payano Sosa, Padmala, Smith, Pessoa, Seminowicz & Shackman in prep.

A unique dataset

shackmanlab.org

Furman, Keaser, Payano Sosa, Padmala, Smith, Pessoa, Seminowicz & Shackman in prep.

Advanced spatial normalization techniques

shackmanlab.org

Furman, Keaser, Payano Sosa, Padmala, Smith, Pessoa, Seminowicz & Shackman in prep.

Advanced spatial normalization techniques

Mean of 23 fMRI (EPI) Datasets

ConvenHonal
(SPM)

Advanced

(FSL-BBR + ANTS)

shackmanlab.org

Furman, Keaser, Payano Sosa, Padmala, Smith, Pessoa, Seminowicz & Shackman in prep.

Furman, Keaser, Payano Sosa, Padmala, Smith, Pessoa, Seminowicz & Shackman in prep.

Furman, Keaser, Payano Sosa, Padmala, Smith, Pessoa, Seminowicz & Shackman in prep.

Payano Sosa & Shackman in prep.

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Whadya mean control behavior?

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

shackmanlab.org

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

shackmanlab.org

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

shackmanlab.org

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Three generic ways to control behavior

to avoid aversive outcomes

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Three generic ways to control behavior

to avoid aversive outcomes
1. If you get nega@ve feedback or commit an
error, act in a more cau@ous, inhibited
manner in the future.

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Three generic ways to control behavior

to avoid aversive outcomes
1. If you get nega@ve feedback or commit an
error, act in a more cau@ous, inhibited
manner in the future.
2. Avoid cues associated with nega@ve
feedback (especially if its worse-than-
expected). If there only 2 op@ons, pick the
other one.

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Three generic ways to control behavior

to avoid aversive outcomes
1. If you get nega@ve feedback or commit an
error, act in a more cau@ous, inhibited
manner in the future.
2. Avoid cues associated with nega@ve
feedback (especially if its worse-than-
expected). If there only 2 op@ons, pick the
other one.
3. Once you get nega@ve feedback, con@nue to
avoid that cue.
Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Midcingulate signals predict inhibited,

threat-avoidant behavior

Cavanagh & Shackman J Physiol Paris in press

Midcingulate signals predict inhibited,

threat-avoidant behavior

Cavanagh & Shackman J Physiol Paris in press

Midcingulate signals predict inhibited,

threat-avoidant behavior
Reten@on

Cavanagh & Shackman J Physiol Paris in press

Pharmacological manipulations reinforce the idea that

emotion and cognition are functionally integrated in MCC

Similar eects reported for benzodiazepines

Structural equa@on model adapted from Bartholow et al J Abnormal Psychol 2012

Pharmacological manipulations reinforce the idea that

emotion and cognition are functionally integrated in MCC

Similar eects reported for benzodiazepines

Structural equa@on model adapted from Bartholow et al J Abnormal Psychol 2012

Pharmacological manipulations reinforce the idea that

emotion and cognition are functionally integrated in MCC

Similar eects reported for benzodiazepines

Structural equa@on model adapted from Bartholow et al J Abnormal Psychol 2012

Pharmacological manipulations reinforce the idea that

emotion and cognition are functionally integrated in MCC

Similar eects reported for benzodiazepines

Structural equa@on model adapted from Bartholow et al J Abnormal Psychol 2012

Shackman et al. Nature Rev Neurosci 2011; Shackman , Shackman et al. under review; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Shackman , Shackman et al. under review; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Shackman , Shackman et al. under review; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Shackman , Shackman et al. under review; Cavanagh & Shackman J Physiol Paris in press

Deep phenotyping in the wild

anxiety in the lab

fMRI

eyetracking

Deep phenotyping in the wild

mood

context / activities (GPS)

4
2
0
1 1 1 1 1 2 2 2 2 2 3 3 3 3 3 4 4 4 4 4 5 5 5 5 5 6 6 6 6 6 7 7 7 7 7
day

social behavior (text, voice)

anxiety in the lab

fMRI

eyetracking

5. Increased ReacHvity to Uncertainty/Ambiguity

Anxiety-related reacHons are enhanced when there is uncertainty
about the nature, probability, or Hming of threat

e.g., Cues that precede either low- or high-intensity shocks vs.
cues that invariably precede high-intensity shocks

e.g., Cues preceding shock on either 20% or 60% of trials vs.
100% certainty

e.g., Unpredictably @med, neutral tones elicit more amygdala
ac@vity and anxious behaviour in mice and humans than than the
iden@cal tones when they are predictable

Observa@ons indicate that uncertainty itself without aversive
outcomes causes elevated anxiety

5. Increased ReacHvity to Uncertainty/Ambiguity

Anxiety-related reacHons are enhanced when there is uncertainty
about the nature, probability, or Hming of threat

e.g., Cues that precede either low- or high-intensity shocks vs.
cues that invariably precede high-intensity shocks

e.g., Cues preceding shock on either 20% or 60% of trials vs.
100% certainty

e.g., Unpredictably @med, neutral tones elicit more amygdala
ac@vity and anxious behaviour in mice and humans than than the
iden@cal tones when they are predictable

Observa@ons indicate that uncertainty itself without aversive
outcomes causes elevated anxiety

5. Increased ReacHvity to Uncertainty/Ambiguity

Anxiety-related reacHons are enhanced when there is uncertainty
about the nature, probability, or Hming of threat

e.g., Cues that precede either low- or high-intensity shocks >>
cues that invariably precede high-intensity shocks

e.g., Cues preceding shock on either 20% or 60% of trials >>
100% certainty

e.g., Unpredictably @med, neutral tones elicit more amygdala
ac@vity and anxious behavior in mice and humans than the
iden@cal tones when they are predictable

Observa@ons indicate that uncertainty itself without aversive
outcomes causes elevated anxiety

5. Increased ReacHvity to Uncertainty/Ambiguity

Anxiety-related reacHons are enhanced when there is uncertainty
about the nature, probability, or Hming of threat

e.g., Cues that precede either low- or high-intensity shocks >>
cues that invariably precede high-intensity shocks

e.g., Cues preceding shock on either 20% or 60% of trials >>
100% certainty

e.g., Unpredictably @med, neutral tones elicit more amygdala
ac@vity and anxious behavior in mice and humans than the
iden@cal tones when they are predictable

Observa@ons indicate that uncertainty itself without aversive
outcomes causes elevated anxiety

5. Increased ReacHvity to Uncertainty/Ambiguity

Anxiety-related reacHons are enhanced when there is uncertainty
about the nature, probability, or Hming of threat

e.g., Cues that precede either low- or high-intensity shocks >>
cues that invariably precede high-intensity shocks

e.g., Cues preceding shock on either 20% or 60% of trials >>
100% certainty

e.g., Unpredictably @med, neutral tones elicit more amygdala
ac@vity and anxious behavior in mice and humans than the
iden@cal tones when they are predictable

Observa@ons indicate that uncertainty itself without aversive
outcomes causes elevated anxiety

5. Increased ReacHvity to Uncertainty/Ambiguity

Unpredictably Hmed, neutral tones:

Details Are Not Important

Herry et al J Neurosci 2007

5. Increased ReacHvity to Uncertainty/Ambiguity

Unpredictably Hmed, neutral tones:
Increase Amyg
AcHvaHon

Details Are Not Important

Herry et al J Neurosci 2007

5. Increased ReacHvity to Uncertainty/Ambiguity

Unpredictably Hmed, neutral tones:
Increase Amyg
AcHvaHon

Increase
Anxiety

Details Are Not Important

Herry et al J Neurosci 2007

5. Increased ReacHvity to Uncertainty/Ambiguity

Unpredictably Hmed, neutral tones:
Increase Amyg
AcHvaHon

Increase
Anxiety

Increase
Both
Details Are Not Important

Herry et al J Neurosci 2007

5. Increased ReacHvity to Uncertainty/Ambiguity

Unpredictably Hmed, neutral tones:
Increase Amyg
AcHvaHon

Increase
Anxiety

Increase
Both
Details Are Not Important

Herry et al J Neurosci 2007

Observa6ons indicate that

uncertainty itself, in the absence of
poten6al danger, can increase
anxiety

Suggests that uncertainty is another
ac6ve ingredient that causally
contributes to the anxious phenotype

Pharmacological Evidence
Clinically eecHve anH-anxiety agents, such as benzodiazepines and
mild alcohol intoxicaHon, selecHvely reduce anxiety elicited by
uncertain threat (but are relaHvely ineecHve for acute fear in
response to imminent, certain danger)


This indicates that elevated reacHvity to uncertainty is another key
acHve ingredient in the anxious phenotype

Grupe & Nitschke NRN 2013; Bradford et al. Psychol Sci in press

Pharmacological Evidence
Clinically eecHve anH-anxiety agents, such as benzodiazepines and
mild alcohol intoxicaHon, selecHvely reduce anxiety elicited by
uncertain threat (but are relaHvely ineecHve for acute fear in
response to imminent, certain danger)


Reinforces the idea that elevated reacHvity to uncertainty is
another key acHve ingredient that causally contributes to N/NE
and clinical anxiety

Grupe & Nitschke NRN 2013; Bradford et al. Psychol Sci in press

Puong It All Back Together Again

Grupe & Nitschke NRN 2013

Puong It All Back Together Again

Details Are Not Important

Grupe & Nitschke NRN 2013

Puong It All Back Together Again

The arrows represent educated guesses

but we know that these processes
interact and recursively inuence one another
(as with the unpredictable tones and vigilance)

Details Are Not Important

Grupe & Nitschke NRN 2013

Key Take Homes

5 core consHtuents of the anxious phenotype
1. Inated esHmates of threat certainty or intensity/cost

2. Hypervigilance (apenHonal threat bias)

AcHve ingredient/Causal
Present in BI
Amygdala, direct or indirect inuence on sensory cortex
3. Decient safety learning and overgeneralizaHon
Anxious individuals learn certain, imminent threat just ne
Predicts rst onset; present in BI
dlPFC, vmPFC, BNST?
4. CogniHve and behavioral avoidance
MCC
Circuit centered on the MCC may help to orchestrate some of the other processes
Key hub
5. Hyper-reacHvity to uncertainty and ambiguity
AcHve 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 consHtuents of the anxious phenotype

1. Inated esHmates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hypervigilance (bias to allocate excess apenHon to threat or scanning for threat-relevant informaHon)
AcHve ingredient/Causal
Present in BI
Circuits centered on the amygdala, poised to directly/indirectly inuence sensory cortex
3. Decient safety learning and overgeneralizaHon of anxiety to other cues and contexts
Anxious individuals learn about clear and imminent threats just ne
Predicts rst onset; present in BI
4. Avoidance
Circuit centered on the MCC may help to orchestrate behavioral avoidance

5. Hyper-reacHvity to uncertainty and ambiguity
AcHve ingredient/Causal
Extended amygdala (amygdala, BNST)

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

Key Take Homes

5 core consHtuents of the anxious phenotype

1. Inated esHmates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hypervigilance (bias to allocate excess apenHon to threat or scanning for threat-relevant informaHon)
AcHve ingredient/Causal
Present in BI
Circuits centered on the amygdala, poised to directly/indirectly inuence sensory cortex
3. Decient safety learning and overgeneralizaHon of anxiety to other cues and contexts
Anxious individuals learn about clear and imminent threats just ne
Predicts rst onset; present in BI
4. Avoidance
Circuit centered on the MCC may help to orchestrate behavioral avoidance

5. Hyper-reacHvity to uncertainty and ambiguity
AcHve ingredient/Causal
Extended amygdala (amygdala, BNST)

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

Key Take Homes

5 core consHtuents of the anxious phenotype

1. Inated esHmates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hypervigilance (bias to allocate excess apenHon to threat or scanning for threat-relevant informaHon)
AcHve ingredient/Causal
Present in BI
Circuits centered on the amygdala, poised to directly/indirectly inuence sensory cortex
3. Decient safety learning and overgeneralizaHon 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)
4. Avoidance
Circuit centered on the MCC may help to orchestrate behavioral avoidance

5. Hyper-reacHvity to uncertainty and ambiguity
AcHve ingredient/Causal
Extended amygdala (amygdala, BNST)

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

Key Take Homes

5 core consHtuents of the anxious phenotype

1. Inated esHmates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hypervigilance (bias to allocate excess apenHon to threat or scanning for threat-relevant informaHon)
AcHve ingredient/Causal
Present in BI
Circuits centered on the amygdala, poised to directly/indirectly inuence sensory cortex
3. Decient safety learning and overgeneralizaHon 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)
4. Avoidance
Circuit centered on the MCC may help to orchestrate behavioral avoidance

5. Hyper-reacHvity to uncertainty and ambiguity
AcHve ingredient/Causal
Extended amygdala (amygdala, BNST)

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

Key Take Homes

5 core consHtuents of the anxious phenotype

1. Inated esHmates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hypervigilance (bias to allocate excess apenHon to threat or scanning for threat-relevant informaHon)
AcHve ingredient/Causal
Present in BI
Circuits centered on the amygdala, poised to directly/indirectly inuence sensory cortex
3. Decient safety learning and overgeneralizaHon 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)
4. Avoidance
Circuit centered on the MCC may help to orchestrate behavioral avoidance

5. Hyper-reacHvity to uncertainty and ambiguity
AcHve ingredient/Causal
Extended amygdala

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

Key Take Homes

5 core consHtuents of the anxious phenotype

1. Inated esHmates of threat certainty or intensity/cost (mountain out of a molehill)

2. Hypervigilance (bias to allocate excess apenHon to threat or scanning for threat-relevant informaHon)
AcHve ingredient/Causal
Present in BI
Circuits centered on the amygdala, poised to directly/indirectly inuence sensory cortex
3. Decient safety learning and overgeneralizaHon 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)

4. Avoidance
Circuit centered on the MCC may help to orchestrate behavioral avoidance

5. Hyper-reacHvity to uncertainty and ambiguity
AcHve ingredient/Causal
Extended amygdala

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

Take Home CriHcal Thinking QuesHons

Take Home CriHcal Thinking QuesHons

Please select any 2

You are also free to respond to any of the
ques6ons from the last lecture that you have not
already answered.

Take Home CriHcal Thinking QuesHons

1. Tradi@onally, psychology and philosophy have divided
the mind into 3 facul@es: emo@on, cogni@on, and
will. Does this trichotomy make sense? E.g.,
throughout the semester, we have discussed the key
features of E and N. Ojen@mes, these traits and their
associated states (PE and NE) are conceptualized as
emo@onal. Hence, their neural correlates have been
considered the emo@onal brain, consistent with the
tradi@onal trichotomy. But are they really just
emo@onal (hot) or do they fundamentally involve
processes that we usually consider
cogni@ve (cold)? What are the implica@ons for the
emo@onal vs. cogni@ve brain? For the trichotomy?

Take Home CriHcal Thinking QuesHons

2. Briey describe an example from your own life,
that of a friend, or a hypothe@cal example that
exemplies 1 of the 5 intermediate phenotypes
described by Grupe & Nitschke.

Take Home CriHcal Thinking QuesHons

3. Briey describe some specic ways (psychological
or neural) in which decient safety learning might be
related to heightened reac@vity to uncertain/
ambiguous threat.

Take Home CriHcal Thinking QuesHons

4. I am in the midst of wri@ng a review that closely
parallels the structure of our class.

Download the paper from Canvas:
shackman_stock_lemay_fox_Q2_041515.docx

What do you think?
What are your sugges@ons for strengthening the not-
quite-done manuscript? What are the most
important future research challenges for me to
highlight in the Discussion?

Time-Permiong
Review QuesHons

Individuals with high levels of N/NE

are characterized by
A. Inated es@mates of
threat likelihood
B. Abnormally low
es@mates of threat
intensity

0%

ly
or
m
al
Ab
n

In
fla

te

d
es

tim

lo
w

at
es

e
st

im
at

es

o
f t
hr
ea
.

...

..

0%

Anxious individuals aqen@onal bias to

threat can be re-trained using
computerized tasks. Which is the best
answer?

0%

0%

0%

p
ro
er
du
m
...
or
e,
C
Co
BT
lle
ta
ct
rg
ive
et
i. .
ly,
th
es
e m
ec
ha
...

ias

Fu
rth

in
in
Re
tra

is
is

cli
n

ica

g t
he
b

lly
e
ffe
ct

ive
, .
..

0%

Th

A. This is clinically eec@ve,

albeit weakly
B. Retraining the bias
produces a las@ng
diminu@on in anxiety (e.g.
in a public speaking task)
C. Furthermore, CBT
targe@ng excess anxiety
reduces the aqen@onal
bias (reverse eect)
D. Collec@vely, these
mechanis@c ndings
indicate a causal role

Anxious individuals tend to

Ar
e
fa

st

er
to
re
sp

on
d

to

...

n
..
nt
io
tte
a
e
ex
ce
ss
ca
t
Al
lo

0%

0%
h

0%

Bo
t

A. Allocate excess
aqen@on to threat
B. Are faster to
respond to the dot-
probe when it
occurs at the same
loca@on as a
nega@ve word
C. Both

Hypervigilance may reect

A. The direct inuence of the
amygdala on sensory
cortex
B. Robust projec@ons from
the amygdala to the visual
cortex
C. An indirect inuence of
the amygdala, mediated
by acetylcholine neurons
sirng in the basal
forebrain (nucleus basalis
of Meynert); wake up!
D. All of the above

fr
om
..
di

re
ct
i

ns

0%

0%

.
nf
lu
en
ce
o
f t
..
Al
l o
f t
he
ab
ov
e

0%

An
in

t p
us
Ro
b

Th

e d
i

re
ct
i

nf
lu

ro
je
ct
io

en
ce
o
f t
h

...

0%

Anxious individuals tend to show

A. Heightened anxiety
(startle) in response
to clear and
imminent threat (CS
+)
B. Excess anxiety to
uncertain and
ambiguous danger
(CS- , ITI)

0%

nx
ie
ty
to
u
a
Ex
ce
ss

He
igh

te

ne
d
a

nx
ie
ty
(s

ta

nc
er
ta

rtl
..

..

0%

Anxious individuals tend to

0%

Sh
o

an

xie
ty

ze

th

at

is

str

ict

nx
ie
ty
to
...

l..
.

0%

Ov
er
ge
ne
ra
li

A. Overgeneralize
anxiety to cues that
resemble genuine
dangers (e.g.,
Lisseks parametric
rings)
B. Show anxiety that is
strictly limited to
threat

Individuals with anxiety disorders

ov
e

0%

he
ab
of
t

ill
w
w
ho

Al
l

c,.
..
ct
s
p
re
di
An
d

0%
d
e.
..

0%

ro
ni
ch

to
es

is
pr
om
ot

Th

ve
d
if f
icu

lti

es
t
u

ni

ng
t
...

0%

Ha

A. Have dicul@es tuning

their anxiety and learning
what is safe (safety
learning decit)
B. This promotes to chronic,
pervasive anxiety, arousal,
and stress; they dont
know when its safe to
relax
C. And predicts who will
develop an anxiety
disorder
D. All of the above

Individuals with a childhood history of

extreme BI, a facet of N/NE, show

g p

0%
h

...

0%

ar
tl e
d
ur
in

ed
ev
at
El

Hy
pe
rv
ig

ila

st

nc
e o
n

th

e
do
...

0%

Bo
t

A. Hypervigilance on
the dot-probe task
B. Elevated startle
during periods of
objec@ve safety
C. Both

The End

Extra Slides

Cavanagh & Shackman J Physiol Paris in press

Cavanagh & Shackman J Physiol Paris in press

Cavanagh & Shackman J Physiol Paris in press

Cavanagh & Shackman J Physiol Paris in press

Cavanagh & Shackman J Physiol Paris in press; Cavanagh & Frank TiCS 2014

Cavanagh & Shackman J Physiol Paris in press; Cavanagh & Frank TiCS 2014

N2

Cavanagh & Shackman J Physiol Paris in press; Cavanagh & Frank TiCS 2014

Cavanagh & Shackman J Physiol Paris in press; Cavanagh & Frank TiCS 2014

ERN

Cavanagh & Shackman J Physiol Paris in press; Cavanagh & Frank TiCS 2014

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Shackman et al. Nature Rev Neurosci 2011; Cavanagh & Shackman J Physiol Paris in press

Payano Sosa & Shackman in prep.

Payano Sosa & Shackman in prep.

Neurosynth.org search terms: anxiety, pain, cogni@ve control (forward inference)

Payano Sosa & Shackman in prep.

Neurosynth.org search terms: anxiety, pain, cogni@ve control (forward inference)

Payano Sosa & Shackman in prep.

Neurosynth.org search terms: anxiety, pain, cogni@ve control (forward inference)

Payano Sosa & Shackman in prep.

Neurosynth.org search terms: anxiety, pain, cogni@ve control (forward inference)

Payano Sosa & Shackman in prep.

Furman, Keaser, Payano Sosa, Padmala, Smith, Pessoa, Seminowicz & Shackman in prep.

Furman, Keaser, Payano Sosa, Padmala, Smith, Pessoa, Seminowicz & Shackman in prep.

Furman, Keaser, Payano Sosa, Padmala, Smith, Pessoa, Seminowicz & Shackman in prep.

Furman, Keaser, Payano Sosa, Padmala, Smith, Pessoa, Seminowicz & Shackman in prep.

Furman, Keaser, Payano Sosa, Padmala, Smith, Pessoa, Seminowicz & Shackman in prep.

Furman, Keaser, Payano Sosa, Padmala, Smith, Pessoa, Seminowicz & Shackman in prep.

Furman, Keaser, Payano Sosa, Padmala, Smith, Pessoa, Seminowicz & Shackman in prep.

Conclusions

Shackman, Fox & Seminowicz in press; Okon-Singer, Hendler, Pessoa & Shackman under review

Conclusions

Shackman, Fox & Seminowicz in press; Okon-Singer, Hendler, Pessoa & Shackman under review

Conclusions

Shackman, Fox & Seminowicz in press; Okon-Singer, Hendler, Pessoa & Shackman under review

Conclusions

Shackman, Fox & Seminowicz in press; Okon-Singer, Hendler, Pessoa & Shackman under review

Lyn = Lyn Abramson

Aberrant InterpretaHon of Ambiguity

Not just uncertainty, also ambiguity

InterpretaHon Biases:
Anxious individuals view ambiguous sHmuli as threatening

GAD (everything is poten@ally dangerous)
SAD (every face or social scenario is poten@ally dangerous)
PTSD (ambiguous cues are interpreted as combat-related)



Grupe & Nitschke NRN 2013

Aberrant InterpretaHon of Ambiguity

Not just uncertainty, also ambiguity

InterpretaHon Biases:
Anxious individuals view ambiguous sHmuli as threatening

GAD (everything is poten@ally dangerous)
SAD (every face or social scenario is poten@ally dangerous)
PTSD (ambiguous cues are interpreted as combat-related)



Grupe & Nitschke NRN 2013

Check Time, If Low, Skip

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Retraining the InterpretaHon of Ambiguity

see also Van Boekstaele et al Psychol Bull in press

Ann Rev Clin Psychol 2012

How might we re-train?

Retraining the InterpretaHon of Ambiguity

Present an ambiguous homograph (same lepers, dierent meaning)
e.g. growth

Followed by a target word fragment

NegaHve Training: fragment = C-NC-R (cancer)

PosiHve Training: fragment GR-AT-R (greater)

In eect, you train subjects to expect good or bad things following ambiguous
cues

Assessment
Latency to respond to posiHve and negaHve target words

Ann Rev Clin Psychol 2012

Retraining the InterpretaHon of Ambiguity

Present an ambiguous homograph (same lepers, dierent meaning)
e.g. growth

Followed by a target word fragment

NegaHve Training: fragment = C-NC-R (cancer)

PosiHve Training: fragment GR-AT-R (greater)

In eect, you train subjects to expect good or bad things following ambiguous
cues

Assessment
Latency to respond to posiHve and negaHve target words

Ann Rev Clin Psychol 2012

Retraining the InterpretaHon of Ambiguity

Present an ambiguous homograph (same lepers, dierent meaning)
e.g. growth

Followed by a target word fragment

NegaHve Training: fragment = C-NC-R (cancer)

PosiHve Training: fragment GR-AT-R (greater)

In eect, you train subjects to expect good or bad things following ambiguous
cues

Assessment
Latency to respond to posiHve and negaHve target words

Ann Rev Clin Psychol 2012

Retraining the InterpretaHon of Ambiguity

Limited evidence that the posiHve training procedure produces lasHng changes in
the interpretaHon of ambiguity

E.g., reduces trait anxiety (replicated in several studies)

E.g., Worriers report fewer worries during worry inducHon post training

Evidence that negaHve interpretaHons of ambiguity are another acHve ingredient
Ann Rev Clin Psychol 2012

Retraining the InterpretaHon of Ambiguity

Limited evidence that the posiHve training procedure produces lasHng changes in
the interpretaHon of ambiguity

E.g., reduces trait anxiety (replicated in several studies)

E.g., Worriers report fewer worries during worry inducHon post training

Evidence that negaHve interpretaHons of ambiguity are another acHve ingredient
Ann Rev Clin Psychol 2012

Retraining the InterpretaHon of Ambiguity

Limited evidence that the posiHve training procedure produces lasHng changes in
the interpretaHon of ambiguity

E.g., reduces trait anxiety (replicated in several studies)

E.g., Worriers report fewer worries during worry inducHon post training

Evidence that negaHve interpretaHons of ambiguity are another acHve ingredient
Ann Rev Clin Psychol 2012

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