Shackman Psyc210 Module15 TPandMentalDisordersFocusExtendedAmygdala 041615

Nuts
& Bolts Plan for Today

Lecture (Davis, Fox, Feinstein papers)
Focus on the neurobiology of BI, N/NE, and
Emo;onal Disorders
PSYC 210:

How does N/NE contribute to

emoKonal disorders?

Part 3 of 3

Focus on the Extended
A
mygdala

AJ Shackman
16 April 2015
Conceptual Roadmap for Today

What is the role of the amygdala in states of fear
and anxiety?

How might it contribute to individual dierences
in N/NE/BI? What about social anxiety disorder?

Does the amygdala only contribute to arousal, or
does it contribute to more complex features of
T&P, such as aTenKon, social aliaKon, and
relaKonship building?

and anxiety?


does it contribute to more complex features of
T&P, such as aTenKon, social aliaKon, and

and anxiety?


does it also contribute to more complex features
of T&P, such as aTenKon, social aliaKon, and
Jerry Kagan (Harvard)
The Hypothesized Root Cause

In the brain, these thoughts can oEen be traced
to overreacFvity in the amygdala, a small site in the
middle of the brain thatresponds to novelty and
threat.

In people born with a parFcular brain circuitry,
the kind seen in Kagans high-reacFve study Ss, the
amygdala is hyperreacKve, prickly as a haywire
moFon-detector light that turns on when nothings
moving but the rain.
Students?
The Hypothesized Root Cause
More Amygdala
decreased threshold
increased peak
increased recovery Fme
How did Kagan come to this view?

Why the amygdala?

Why not the more ambiguous limbic
system (a.k.a. Papez circuit) iden;ed
by Hans Eysenck?

Students, why was Kagan
more specic?
For a scathing criFque of the limbic system concept, see JE LeDoux Concepts Neurosci. 1991
How did Kagan come to this view?

Why the amygdala?

Why not the more ambiguous limbic
system (a.k.a. Papez circuit) iden;ed
by Hans Eysenck?

Students, why was Kagan
more specic?
For a scathing criFque of the limbic system concept, see JE LeDoux Concepts Neurosci. 1991
Kagans view was profoundly

inuenced by
Joe LeDoux and Mike Davis
Ledoux (NYU)
Davis (Yale, Emory)
Ledouxs band @ hYp://www.amygdaloids.com

inuenced by
Ledoux (NYU)
Davis (Yale, Emory)
Pavlovian Fear
CondiKoning
in Rats

inuenced by
Ledoux (NYU)
Davis (Yale, Emory)
Lesion studies demonstrate

that the amygdala is required
for the normal acquisiKon
of new fear learning
Pavlovian Fear
CondiKoning
in Rats
Not just rats

Students What have we already
learned about amygdala damage and
the condi;oned emo;onal response?
CondiKoned EmoKonal Response

(SCR; Skin Conductance Response)
Amygdala Lesions Block

CondiKoned Fear
Amygdala lesions aYenuate condiFoned
Freezing (behavioral inhibiFon)
High-frequency vocalizaFons (help!)

Shock-probe avoidance
PotenFaFon of the startle reex (a.k.a. fear-
potenFated startle)
Normal Full-Body Startle Reex
0:13 ; watch using HD mode at 0.25x normal speed
Fear-PotenKated Startle in Humans
Measure muscle acKvity (EMG) from

the orbicularis oculi (muscle responsible
for blinking the eye lid shut (and
protecKng the eye) in response to startling
sKmuli
Schmitz & Grillon Nature Prot 2012

sKmuli

sKmuli

sKmuli
Poten;a;on
Safe/CS-
Threat/CS+
Fear-PotenKated Startle in Rats
hYps://techtv.mit.edu/videos/16346-neurobiology-of-fear-anxiety-and-exFncFon-implicaFons-for-psychotherapy
(6:55 8:45)
accelerometer
(6:55 8:45)
accelerometer
(6:55 8:45)
Not Just Learned Fear and Anxiety

Innate Fear in Rodents
Davis & Whalen Mol Psych 2001 describing Blanchard & Blanchard 1972

Innate Fear in Rodents
amygdala lesions dramaFcally increase the
number of contacts a rat will make with a
sedated cat. In fact, some of these lesioned
animals crawl all over the cat and even nibble its
ear, a behavior never shown by the non-
lesioned animals.

Davis & Whalen Mol Psych 2001 describing Blanchard & Blanchard 1972
What about innate fear in primates?
Assessing snake fear

Reach for Treat
Details Are Not Important
Shackman, Fox et al., in prep
Assessing snake fear

Reach for Treat
Real Snake
ArKcial Rubber Snake
Roll of Tape
Nothing
Shackman, Fox et al., in prep
Amygdala Lesions Reduce BI

to Snake in Young Monkeys
Lesion Group
Asymmetric = lesion in only one hemisphere
Kalin Shelton Davidson J Neuro 2004
How is this related to childhood BI?
Scary Robot
Choi & Kim PNAS 2010
Scary robot (kids)
Scary robot (kids)
Scary robo-gator (rats)
Scary robot (kids)
Each ;me the animal approached the vicinity

of the pelletthe Robogator surged, snapped
its jaws once, and returned to its original
posi;on. The rat immediately ed to the
nes;ng area.
hYp://www.youtube.com/watch?v=rnxwQpDisRE
Scary robot (kids)
Excitotoxic lesions of the amygdala abolish

rats innate fear of the RoboGator
Maybe its just rats

What about primates?
Amygdala Lesions Reduce BI

to Human Intruder in Young Monkeys
Kalin Shelton Davidson J Neuro 2004
Amygdala lesions a[enuate freezing

in response to poten;al threat,
consistent with a role in BI

But what about individual dierences
in BI?

Does varia;on in amygdala ac;vity
predict individual dierences in BI?
Amygdala lesions a[enuate freezing

in response to poten;al threat,
consistent with a role in BI

But what about individual dierences
in BI?

Does varia;on in amygdala ac;vity
predict individual dierences in BI?
Amygdala Metabolism Predicts Trait-Like Dierences in

Freezing/Cooing (BI) and CorKsol in Young Monkeys
Shackman et al PNAS 2013
N = 238
N = 238
N = 238
N = 238
OK, so we have mechanis;c (and

imaging) evidence in rats and
monkeys

What about people?
hYp://abcnews.go.com/Health/MindMoodNews/woman-iowa-
damaged-amygdala-shows-fear/story?id=12404875

hYp://blogs.discovermagazine.com/notrocketscience/2010/12/16/
meet-the-woman-without-fear/#.UpH-MsSsjJ8
Feinstein, Adolphs, Damasio & Tranel Curr Biol 2011
2 tests pet store, haunted house

While others show trepidaFon before walking down empty corridors, she leads the way and
beckons her companions to follow. When monsters leap out, she never screams in fright;
instead, she laughs, approaches and talks to them. She even scares one of the monsters by
poking it in the head.

SM is a woman without fear. She doesnt feel it. She has been held at knifepoint without a Fnge
of panic. Shell happily handle live snakes and spiders, even though she claims not to like them.
She can sit through reels of upseqng footage without a single start.

During her visit to Waverley Hills [Haunted House], SM rated her level of fear throughout the
experience. She said that she was excited and enthusiasFc in the same way that she feels when
she rides a rollercoaster, but never scared her scores always stayed at zero.

In a similar trip to an exoFc pet store, her levels of fear never climbed over a score of 2/10. Even
though she claimed to hate snakes and spiders, she was drawn to the snake enclosure, was
excited about holding a serpent (This is so cool!) and had to be told not to touch or poke the
bigger, more dangerous snakes (and a nearby tarantula). Why? She was overcome with
curiosity.




curiosity.




curiosity.




curiosity.

When Feinstein showed SM a set of lm clips, she generally behaved on cue, laughing at the
happy clips and shouFng in revulsion at the disgusFng ones. But in response to 10 scary lm
clips (including The Shining, Seven, and The Ring) nothing. She showed no signs of terror, nor
did she report any. She said that most people would probably be scared by the lms but she
herself felt nothing.

SMs unusual reacFons during these isolated scenarios are reected in her day-to-day life. When
Feinstein gave her an electronic handheld emoFon diary, she reported feeling every basic
emoFon other than fear. In fact, out of a range of 50 possible emoFonal descripFons, the one
she rated most highly over 3 months was fearless.

AEer more digging, Feinstein uncovered a history of behavior consistent with lack of fear. SMs
eldest son cant remember a single instance when mom felt fear or looked like she was scared.
His anecdotes even support the results of Feinsteins pet store trip. Me and my brothers see
this snake on the road, he writes. I was like, Holy cow, thats a big snake! Well mom just ran
over there and picked it up and brought it out of the street, put it in the grass and let it go on its
way She would always tell me how she was scared of snakes and stu like that, but then all of
a sudden shes fearless of them. I thought that was kind of weird.







Other events in SMs life are less benign. Fourteen years ago, she was walking through a small
park at 10pm, when a man beckoned her over to a bench. As she approached, he pulled her
Down, stuck a knife to her throat, and said, Im going to cut you, bitch! SM didnt panic; she
didnt feel afraid. Hearing a church choir sing in the distance, she condently said, If youre
going to kill me, youre gonna have to go through my Gods angels rst. The man let her go and
she walked (not ran) away. The next day, she returned to the same park.

These sorts of things happen to her a lot.

Its not that SM has had a cosseted life. She lives in a poor area replete with crime, drugs and
danger. As Feinstein writes, she has been held up at knife point and at gun point, she was once
physically accosted by a woman twice her size, she was nearly killed in an act of domesFc
violence, and on more than one occasion she has been explicitly threatened with death.
But in most of these situaFons, she didnt act with urgency or desperaFon, something that
police reports have corroborated.

InteresFngly, a few years back, the team asked 2 clinical psychologists to interview SM without
any knowledge of her lesions. They described her as a
survivor, as resilient and even heroic in how she coped with adversity.

Other events in SMs life are less benign. Fourteen years ago, she was walking through a small
park at 10pm, when a man beckoned her over to a bench. As she approached, he pulled her
Down, stuck a knife to her throat, and said, Im going to cut you, bitch! SM didnt panic; she
didnt feel afraid. Hearing a church choir sing in the distance, she condently said, If youre
going to kill me, youre gonna have to go through my Gods angels rst. The man let her go and
she walked (not ran) away. The next day, she returned to the same park.

These sorts of things happen to her a lot.

Its not that SM has had a cosseted life. She lives in a poor area replete with crime, drugs and
danger. As Feinstein writes, she has been held up at knife point and at gun point, she was once
physically accosted by a woman twice her size, she was nearly killed in an act of domesFc
violence, and on more than one occasion she has been explicitly threatened with death.
But in most of these situaFons, she didnt act with urgency or desperaFon, something that
police reports have corroborated.

InteresFngly, a few years back, the team asked 2 clinical psychologists to interview SM without
any knowledge of her lesions. They described her as a
survivor, as resilient and even heroic in how she coped with adversity.

So amygdala damage reduces

norma;ve, adap;ve fear in humans

What about self-reported trait
anxiety?
Adolphs in press
So amygdala damage reduces

nega;ve emo;on
(states/traits) in humans

What about Kagan-ian BI?
See Blackford & Pine for a review of other relevant data
See Blackford & Pine for a review of other relevant data
Not just Schwartz
Fox & Kalin Amer J Psychiatry 2014
BI is a facet of N/NE

Does the amygdala
predict individual
dierences in N/NE?
BI is a facet of N/NE

Do individual
dierences in N/NE also
predict amygdala ac;va;on?
High-N/NE Individuals Show Increased

Amygdala AcKvaKon to Threat
Meta-Analysis of Imaging Studies: Calder et al PTRSB 2011
N/NE and BI are associated with heightened

amygdala ac;va;on

Kids with stable, high levels of BI
are more likely to develop
anxiety disorders (e.g., SAD)

Do we see increased amygdala
ac;va;on in pa;ents?

amygdala ac;va;on


ac;va;on in pa;ents?

amygdala ac;va;on


ac;va;on in anxiety pa;ents?
Yes. Amygdala is More ReacKve
Meta-Analysis of Imaging Studies; Etkin & Wager Amer J Psychiatry 2007
The imaging data are cross-sec;onal

and could represent a symptom
rather than a cause

Does amygdala reac;vity
prospec;vely predict disorder onset?
The imaging data are cross-sec;onal

and could represent a symptom
rather than a cause

Does amygdala reac;vity
prospec;vely predict disorder onset?
Serendipitous
study of the Boston
Marathon bombing

McLaughlin et al Dep and Anx 2014; see also Admon et al. (Talma Hendlers group at Tel Aviv) Cer Cortex and PNAS
Serendipitous
study of the Boston
Marathon bombing
Terrorist aTack at the 2013 Boston Marathon
Killed three spectators and injured hundreds
Four days aEer the aYack, a manhunt for the perpetrators resulted in an unprecedented
shelter in place order that required residents of Boston and surrounding communiFes to
remain indoors
Public transportaFon, educaFonal insFtuFons, government oces, and most businesses
were closed
Although direct exposure to the aYack was limited to spectators at the nish line of the
marathon, hundreds of thousands of Boston residents watched the manhunt unfold live
on television, while the shelter in place order was in eect (~12 hr)
This kind of indirect media exposure to terrorist aYacks can precipitate PTSD symptoms
in individuals living in proximity to the aYack
Does amygdala funcFon assessed 1 year prior to the bombing predict PTSD onset?
Serendipitous
study of the Boston
Marathon bombing
remain indoors
were closed
Serendipitous
study of the Boston
Marathon bombing
remain indoors
were closed
Serendipitous
study of the Boston
Marathon bombing
remain indoors
were closed
Does amygdala func;on assessed 1 year prior to the bombing predict PTSD onset?
Yes.
Not just in Boston
Not just in Boston
2015
Sugges;ng that heightened amygdala reac;vity represents a diathesis for the development of
mood and anxiety disorders in the presence of stressors, trauma, and nega;ve life events
The imaging data are correla;onal

Do anxiety-reducing drugs reduce
amygdala reac;vity?
The imaging data are correla;onal

Do anxiety-reducing drugs reduce
amygdala reac;vity?
Yes! Amygdala acKvaKon is aTenuated by

anxiolyKc administraKon
Dose-dependent decrease
Paulus et al Arch Gen Psychiatry 2005
Yes! Amygdala acKvaKon in response to public speaking

is aTenuated in social phobia by anxiolyKcs and CBT
Arch Gen Psychiatry 2002
The amygdala orchestrates fear

This is consistent with the amygdalas
connec;vity, its inputs and outputs
The amygdala orchestrates fear

This is consistent with the amygdalas
connec;vity, its inputs and outputs
Amygdala is a Neural Hub:

Receives Rich Sensory InformaKon About the World (Inputs)

Receives Rich Sensory InformaKon About the World (Inputs)
Amygdala projects to the regions that

mediate components of fear
Amygdala projects to the regions that

mediate components of fear
Students Are these data sucient to

explain the BI Phenotype (or SAD)?

Is high BI more than
just a pounding heart and distress?

What are some other hallmarks?
If low on ;me, skip this next chunk
The amygdala does much more than

just orchestrate arousal:

Vigilance

Vigilance / Risk Assessment

BI. Toddlers who avoid unfamiliar events and people. When faced
with such challenges, these children ceased their play and
withdrew to the proximity of their caregivers. They remained
vigilant and rarely approached novel objects or unfamiliar people.
Amaral Biol Psych 2002
FFA: Fusiform Face Area

Vuillemier et al. Nat Neurosci 2004
The amygdala does much more than

just orchestrate arousal:

Trust & Social Re;cence

Trust and Social ReKcence

BI. Toddlers who avoid unfamiliar events and people. When faced
with such challenges, these children ceased their play and
withdrew to the proximity of their caregivers. They remained
vigilant and rarely approached novel objects or unfamiliar
people.
Perhaps high BI individuals

perceive others as less trustworthy
or more threatening?
Faces dier in how

trustworthy they appear
Faces dier in how

trustworthy they appear
Does the amygdala contribute to these

kinds of trustworthiness percep;ons?
Does amygdala damage change

how much trust others?
Yes. Amygdala damage increases

trust / approachability raKngs
Yes. Amygdala damage increases

trust / approachability raKngs
Yes, but thats just self-report ra;ngs

What about actual behavior?

Does amygdala damage alter
actual social approach?
Amygdala Damage
Reduces Social Distance
Or, Amygdala Damage Makes You a Close-Talker
We all have a personal bubble, an invisible zone of privacy around our bodies. When
strangers cross this boundary, it makes us feel uncomfortable.

Kennedy asked PaFent SM to say when she felt most comfortable as a female
experimenter walked towards her. On average, she preferred a distance of around a
foot, about half the usual two-foot gap that 20 other normal people demanded.

The fact that SM had a boundary at all was probably because at close distances, its hard
to see people. She said Fme and Fme again that she was actually comfortable at any
distance, and during one trial, she actually walked all the way to her partner unFl they
were actually touching. Even when they were making direct eye contact and touching
nose-to-nose, she only rated the experience as 1 on a comfort scale of 1 to 10, where 1 is
perfectly comfortable and 10 is a level of discomfort that only the BriFsh can survive.
When a male stranger talked to her up close, she again rated the chat as a 1 (even
though he gave it a 7).
brain-damage-pops-womans-personal-bubble/#.UpIB98SsjJ8
Kennedy, Glaescher, Tyszka JM & Adolphs Nat Neurosci 2009
Amygdala Damage


Amygdala Damage


What about more complex

choices and decisions?

Or situa;ons where there is a
poten;al downside to trus;ng?

(Remember the MTV pa;ents)
1. Subject is endowed with 12 points

PNAS 2013
2. Subject chooses how much to keep vs. invest

PNAS 2013
3. Invested points are mulKplied by 3 and given to trustee

PNAS 2013
4. Trustee can back-transfer none, some, or all of it.

If the trustee is fair, both benet. If the trustee is
selsh, you lose.
PNAS 2013
What happens when paKents with amygdala

damage play the trust game?
PNAS 2013
humans with selec;ve [amydala] damage invest nearly 100% more money in
unfamiliar others in [an economic game that requires trus;ng the other player]
than do healthy controls.
PNAS 2013
In short, a circuit centered on the

amygdala likely contributes to diverse
features of N/NE, BI, and social
phobia

From a basic neuroscience
perspec;ve, the amygdala does so
much more than just orchestrate fear
and anxiety

In short, a circuit centered on the

amygdala likely contributes to diverse
features of N/NE, BI, and social
phobia

From a basic neuroscience
perspec;ve, the amygdala does so
much more than just orchestrate fear
and anxietyFor instance

The point here is that the

amygdala is not a fear center
in the brain

It contributes to a broad
spectrum of funcFons, including

EmoFonal learning
EmoFonal memory
Processing of social cues, like

faces and voices

NormaFve social interacFons

Adolphs ANYAS 2010
Take Home Points

to be elevated amygdala
1. The root cause of BI is thought
reacFvity (exact parameter unclear).
2. Amygdala
Required for new fear condiFoning and innate fear e.g. snakes
Orchestrates broad spectrum of responses
Amyg damage in humans reduces fear
CeA damage in rats/monkeys Reduces BI
CeA metabolism predicts individual dierences in BI in monkeys
Amygdala more reacFve in BI kids all grown up and paFents with a
variety of anx dis
Amygdala acFvaFon prospecFvely predicts the rst onset of anx. Dx
AnF-anxiety drugs reduce amygdala acFvaFon
Amygdala not just fear/anxiety
Vigilance
Social distance
Trust
Take Home Points

2. Amygdala
variety of anx dis
Vigilance
Social distance
Trust
Take Home Points

2. Amygdala

variety of anx dis
Vigilance
Social distance
Trust
Take Home Points

2. Amygdala

variety of anx dis
Vigilance
Social distance
Trust
Take Home Points

2. Amygdala

Amyg damage in humans reduces fear and disposiFonal anxiety
variety of anx dis
Vigilance
Social distance
Trust
Take Home Points

2. Amygdala

CeA damage in rats/monkeys Reduces freezing
variety of anx dis
Vigilance
Social distance
Trust
Take Home Points

2. Amygdala

variety of anx dis
Vigilance
Social distance
Trust
Take Home Points

2. Amygdala

variety of anxiety disorders
Vigilance
Social distance
Trust
Take Home Points

2. Amygdala

Vigilance
Social distance
Trust
Take Home Points

2. Amygdala

Vigilance
Social distance
Trust
Take Home Points

2. Amygdala

Vigilance
Social distance
Trust ..and, as we shall see later in the term, substance abuse
CriKcal Thinking QuesKons

Please respond to any 2
CriKcal Thinking QuesKon #1

Watch Ralph Adolphs TEDx Lecture
hYps://www.youtube.com/watch?v=nPj01uzRHY0
-or-

Watch Joe LeDouxs Copernicus Lecture
hYps://www.youtube.com/watch?v=tjhCPhhzBqQ
-or-

Watch Paul Whalens Copernicus Lecture
hYps://www.youtube.com/watch?v=nLTJaqew7I8

What do you think??

Briey describe the most important or interesFng things that you learned and a
key challenge for future research.


Animal research is controversial. This plays out in my own Facebook
news feed. One dear friend, from undergraduate days at Wisconsin, is
vehemently opposed to the kinds of work that I did in nonhuman
primates and posted a peFFon denouncing the research on the grounds
that it is inhumane. Another friend, from my post-doc years, recently
wrote a long post defending the research (see following slides for
excerpts).

What do you think?
Briey describe the potenFal pros and cons (scienFc and/or ethical) of
using nonhuman animal models to understand the mechanisms
underlying psychiatric disease.

(OpDonal Video: Bioethics roundtable on the work:

You should feel comfortable opposing or aFacking animal research. You
have complete freedom of expression and it will not aect your grade in
any way.
FB Post #1

excerpts). In part, she pointed out that

What do you think?

(OpDonal Video: Bioethics roundtable on the work:

any way.
The goal of the work is to discover,

understand, and ulKmately treat the root
causes of severe childhood anxiety
hYps://www.youtube.com/watch?v=4VbxjsO9IYI


excerpts).

What do you think?

(OpDonal Video: Bioethics roundtable on this work:
hYps://www.youtube.com/watch?v=-dKlKaMwoVE)

any way. I only ask that you take the Dme to reect before wriDng.
Excerpts from FB Post #2

The University of Wisconsin responds to the Animal Rights controversy regarding Dr. Kalin's research and it is spot on! Go UW, go Dr. Kalin!!!
Responding to Ruth Deckers change.org peFFon

Since September, many people have taken interest in a University of WisconsinMadison study on the impact of early life stress on young rhesus monkeys. Thousands have added their names to a peFFon on the website change.org, calling for an end to the work, and
we appreciate and share their concern for animals.

But we dont appreciate the way peFFons author, Dr. Ruth Decker, misrepresents the research. By piling up mistakes, myths and exaggeraFons, and omiqng important informaFon, she asks well-meaning people to speak out with liYle understanding of the real
science and the long, deliberaFve process through which it was approved.

This isnt fair to the people who signed the peFFon, or to UWMadison psychiatry professor Ned Kalin and the scienFsts involved in the work, or to the millions of people who suer from mental illness for whom available treatment methods oer liYle relief.

The truth is of liYle concern to acFvists who wish to end animal research, no maYer the benet to humans and animals. We dont share that senFment. We prefer people make their judgments on animal research with a fuller understanding of the research of both
its costs and potenFal benets.

So, if you have read the change.org peFFon, please also consider these correcFons and addiFonal informaFon:
This is not a repeat of experiments UWMadison psychology professor Harry Harlow conducted as many as ve decades ago, some of which subjected animals to extreme stress and isolaFon. The methods for the modern work were selected specically because they
can reliably create mild to moderate symptoms of anxiety in the monkeys. They were chosen to minimize discomfort for the animals, and to minimize the number of animals required to provide researchers with answers to their quesFons.

There is no solitary connement. The animals live in cages with other monkeys of their own age, a method of care called peer rearing. This method is oEen used when mothers reject their infant monkeys, which happens regularly in situaFons from nature to zoos to
clinical nurseries with rst-Fme mothers or following caesarean-secFon births. In a group seqng, even veterinarians would have diculty disFnguishing the peer-reared animals from those that that were maternally reared.

The purpose of peer rearing is not to demonstrate that removing a monkey from its mother causes anxiety, a common misconcepFon we have heard from people who have signed the peFFon.

Again: peer rearing was chosen because it is known to produce mild to moderate anxiety symptoms. With a group of animals predisposed to anxiety raised in a controlled seqng, researchers can use state-of-the-art techniques to observe and measure even very subtle
dierences in brain chemistry and structure. Those chemical and anatomical dierences may suggest new treatments via nutriFon, exercise, meditaFon, drugs or another approach for people suering from mental illness.

The animals in the study are not terrorized, and do not experience relentless torture. Most of their Fme is spent as a house pet would spend its days grooming, sleeping, eaFng and playing with toys, puzzles and other animals.

On occasion, to assess the monkeys level of anxious temperament, they are observed under two anxiety-provoking condiFons. The rst involves the presence of an unknown person who briey enters the room, but does not make eye contact with the monkey. The
second involves the monkey being able to see a snake, which is enclosed in a covered Plexiglas container in the same room, but outside the monkeys cage.

AEer each event, the animals brain acFvity is monitored by a non-invasive funcFonal magneFc resonance scan, and blood samples are taken. The stress the monkeys experience is comparable to what an anxious human might feel when encountering a stranger or a
snake or a nurse with a needle.

No one was leE out of the review by UWMadison oversight commiYees. Several university commiYees spent a great deal of Fme assessing Dr. Kalins anxiety research, and each commiYee found it to be acceptable and ethical. These were groups of researchers,
veterinarians and public representaFves tasked with considering animal research on ethical grounds, and with ensuring potenFally benecial research will subject the fewest animals to the least invasive measures.

As the peFFon notes, an animal rights group took allegaFons about the commiYee process to the U.S. Department of Agriculture. What the peFFon does not menFon is that USDA conducted an invesFgaFon in August in response to that complaint. Inspectors found
the complaint lacking merit, and the process to be enFrely within compliance with federal regulaFons.

And, as with all animal research on campus, specially trained veterinarians will care for the monkeys involved and ensure that all the work is done in accordance with federal regulaFons enforced by the NaFonal InsFtutes of Health and the USDA.

Most importantly, the peFFon repeatedly maligns the research as needless and unnecessary. We and many others think otherwise. Dr. Kalin, who treats human paFents with anxiety and depression disorders, has worked for more than 30 years to understand
both inherited and environmental causes of mental illness. His research was also reviewed and supported by panels of scienFsts at the NaFonal InsFtutes of Mental Health.

The decision to study animal models to understand human psychiatric disorders is not made lightly. Roughly a quarter of the people in the United States, including children, suer from mental illness. Their condiFons subject them to immeasurable disability and
dysfuncFon. And the worst outcome, suicide, is increasing and already among the leading causes of death in adolescents. To develop eecFve treatments that may alleviate the suering of millions, it is necessary to understand the root cause of psychiatric illnesses.

In this case, the human suering is so great that Kalin, the NaFonal InsFtutes of Health and UWMadisons review commiYees believe the potenFal benet of the knowledge gained from this research jusFes the use of an animal model.

More informaFon on the anxiety and depression research is available at animalresearch.wisc.edu.

Listen to this brief NPR podcast on PaFent SM
(includes the 1st ever public interview)

hYp://www.npr.org/programs/invisibilia/
377515477/fearless?showDate=2015-01-16

Briey comment on what you found most
interesFng about the podcast, as well as any
concerns or criFcisms you have about the way in
which emoFon, fear, or the amygdala was framed
in the story.

Scanning the amygdala is hard! Read this brief excerpt from RuFshauser and
colleagues (Trends in the Neurosciences, 2015)

What do you think?

Briey comment on the implicaFons of these concerns for what we have learned in
class about the role of the extended amygdala in T&P and psychopathology


What do you think?



What do you think?

The End
Turn this into a cri;cal thinking

ques;on
Things to Consider Tweaking

Spring 2015
Nims 2011 paper would be good for a

Take Home Q so would Gamers J
Neuro
Alex fox thesis
Alex - mohanty
Extra Slides
N/BI Take Home Points

of N/NE
1. BI is an early-emerging facet
2. BI is a risk factor for the development of psychopathology,
esp SAD
3. BI is moderately heritable and stable over Fme; its a
candidate (transdiagnosFc) endophenotype
4. Given that most kids with extreme BI very early in life grow
out of it, BI is not isomorphic with psychopathology more
likely a diathesis that precedes onset of Dx and requires
adversity, sub-opFmal parenFng, or stress to present
Amygdala Damage Reduces Fear &

Anxiety
If you ask the woman herself, shell say that she feels upset or angry in the face of danger, but
never fearful. Feinstein even thinks that because of her brain damage, she could be immune to
posYraumaFc stress disorder, a trait that she shares with some combat veterans.

It wasnt always like this. She remembers being afraid of the dark as a young child, running away
screaming when her older brother jumped out from behind a tree, and being pinned to a corner
by a large Doberman (Thats the only Fme I really felt scared. Like gut-wrenching scared).
But all of these events happened before her disease wrecked her amygdalae. During her adult
life, Feinstein couldnt nd a single episode where she clearly experienced fear.

hYp://abcnews.go.com/Health/
MindMoodNews/woman-iowa-damaged-
amygdala-shows-fear/story?id=12404875
Alex add susskind/anderson paper

Jackie Clauss (Grad Student) & Jenni Blackford (Asst Prof), Vanderbilt Psychiatry
Friends and colleagues who collaborate with Ned Kalins lab at Wisconsin, where I did
postdoctoral work
Aside: Fear-Poten;ated Startle in

Rats
hYps://techtv.mit.edu/videos/16346-neurobiology-of-fear-anxiety-and-exFncFon-implicaFons-
for-psychotherapy (6:55 8:45)

Orchestrates Fear (Outputs I)
If low on ;me, skip the next study
Does the amygdala play a role in

switching the focus of a[en;on?

the ac;ve scanning
for poten;al threat?

Amygdala AcKvity Predicts the AcKve
InterrogaKon of the Environment (Risk Assessment)

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




Amygdala damage aTenuates this acKve risk assessment behavior

Monkeys with precise amygdala lesions

are less socially reKcient / inhibited
Amygdala-lesioned animals are socially disinhibited
Across social partners, amygdala-lesioned animals iniFated more aliaFve social
behaviors
Amygdala-lesioned animals showed heightened aliaFve social behaviors (e.g.,

approaches, withdrawals, solicitaFons for grooming, physical contact, grooming)
These overtures were reciprocated by control animals; amygdala-lesioned animals also

received more groom solicitaFons, walk-bys (transient proximity) and extended Fme in
close proximity from control animals than did other control animals
Suggests that heightened aliaFve social interacFons following amygdala lesions stems
from a more general inability to properly perceive danger or threat in the environment
and use such informaFon to modulate social behavior adapFvely.
In line with this view, decits in threat detecFon or fear reacFvity have been specically
demonstrated for monkeys with bilateral neurotoxic amygdala lesions in both social
and nonsocial seqngs
David Amarals Group: Machado et al Behav Neurosci 2008; Mason et al., EmoFon 2006

Shackman Psyc210 Module15 TPandMentalDisordersFocusExtendedAmygdala 041615

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Nuts

& Bolts Plan for Today

How does N/NE contribute to

Conceptual Roadmap for Today

Conceptual Roadmap for Today

Conceptual Roadmap for Today

Jerry Kagan (Harvard)

Jerry Kagan (Harvard)

The Hypothesized Root Cause

The Hypothesized Root Cause

Jerry Kagan (Harvard)

How did Kagan come to this view?

How did Kagan come to this view?

Kagans view was profoundly

Davis (Yale, Emory)

Ledouxs band @ hYp://www.amygdaloids.com

Kagans view was profoundly

Davis (Yale, Emory)

Kagans view was profoundly

Davis (Yale, Emory)

Lesion studies demonstrate

Not just rats

CondiKoned EmoKonal Response

Amygdala Lesions Block

Normal Full-Body Startle Reex

0:13 ; watch using HD mode at 0.25x normal speed

Fear-PotenKated Startle in Humans

Measure muscle acKvity (EMG) from

Schmitz & Grillon Nature Prot 2012

Fear-PotenKated Startle in Humans

Measure muscle acKvity (EMG) from

Schmitz & Grillon Nature Prot 2012

Fear-PotenKated Startle in Humans

Measure muscle acKvity (EMG) from

Schmitz & Grillon Nature Prot 2012

Fear-PotenKated Startle in Humans

Measure muscle acKvity (EMG) from

Fear-PotenKated Startle in Rats

Fear-PotenKated Startle in Rats

Fear-PotenKated Startle in Rats

Not Just Learned Fear and Anxiety

Amygdala Lesions Block

Amygdala Lesions Block

What about innate fear in primates?

Assessing snake fear

Details Are Not Important

Shackman, Fox et al., in prep

Assessing snake fear

ArKcial Rubber Snake

Details Are Not Important

Shackman, Fox et al., in prep

Amygdala Lesions Reduce BI

Asymmetric = lesion in only one hemisphere

Kalin Shelton Davidson J Neuro 2004

How is this related to childhood BI?

Choi & Kim PNAS 2010

Scary robot (kids)

Choi & Kim PNAS 2010

Scary robot (kids)

Scary robo-gator (rats)

Choi & Kim PNAS 2010

Scary robot (kids)

Scary robo-gator (rats)