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 Amygdala

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?

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 also contribute to more complex features of T&P, such as aTenKon, social aliaKon, and relaKonship building?

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

Kagans view was profoundly inuenced by

Joe LeDoux and Mike Davis

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

Ledoux (NYU) Davis (Yale, Emory)




Pavlovian Fear CondiKoning in Rats



Pavlovian Fear CondiKoning in Rats


Lesion studies demonstrate that the amygdala is required for the normal acquisiKon of new fear learning

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

Schmitz & Grillon Nature Prot 2012

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

Fear-PotenKated Startle in Humans

Schmitz & Grillon Nature Prot 2012

Safe/CS- Threat/CS+

Poten;a;on 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

Fear-PotenKated Startle in Rats

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

Fear-PotenKated Startle in Rats


accelerometer

Not Just Learned Fear and Anxiety

Amygdala Lesions Block Innate Fear in Rodents

Davis & Whalen Mol Psych 2001 describing Blanchard & Blanchard 1972

Amygdala Lesions Block 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?

Nothing (Empty Control)

Assessing snake fear

Reach for Treat

Shackman, Fox et al., in prep Details Are Not Important

Reach for Treat

Real Snake ArKcial Rubber Snake Roll of Tape Nothing

Shackman, Fox et al., in prep

Assessing snake fear

Details Are Not Important

Kalin Shelton Davidson J Neuro 2004

Amygdala Lesions Reduce BI to Snake in Young Monkeys

Lesion Group

Asymmetric = lesion in only one hemisphere

How is this related to childhood BI?

Scary Robot

Choi & Kim PNAS 2010

Scary robot (kids)


Scary robot (kids) Scary robo-gator (rats)


hYp://www.youtube.com/watch?v=rnxwQpDisRE

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.




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 Details Are Not Important

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

Shackman et al PNAS 2013 N = 238

OK, so we have mechanis;c (and imaging) evidence in rats and

monkeys

What about people?

Feinstein, Adolphs, Damasio & Tranel Curr Biol 2011

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

2 tests pet store, haunted house


hYp://blogs.discovermagazine.com/notrocketscience/2010/12/16/meet-the-woman-without-fear/#.UpH-MsSsjJ8


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.



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.


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

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?

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 anxiety pa;ents?

Meta-Analysis of Imaging Studies; Etkin & Wager Amer J Psychiatry 2007

Yes. Amygdala is More ReacKve

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?

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?



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 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?

Yes! Amygdala acKvaKon is aTenuated by anxiolyKc administraKon

Paulus et al Arch Gen Psychiatry 2005

Dose-dependent decrease

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

Amygdala is a Neural Hub: Receives Rich Sensory InformaKon About the World (Inputs)

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

Vuillemier et al. Nat Neurosci 2004 FFA: Fusiform Face Area

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, 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).

hYp://blogs.discovermagazine.com/notrocketscience/2009/08/30/brain-damage-pops-womans-personal-bubble/#.UpIB98SsjJ8

Kennedy, Glaescher, Tyszka JM & Adolphs Nat Neurosci 2009

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)

PNAS 2013

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?

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

Adolphs ANYAS 2010 Details Are Not Important

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

Take Home Points 1. The root cause of BI is thought to be elevated amygdala

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


reacFvity (exact parameter unclear). 2. Amygdala Orchestrates broad spectrum of responses 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




reacFvity (exact parameter unclear). 2. Amygdala Orchestrates broad spectrum of responses Required for new fear condiFoning and innate fear e.g. snakes 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




reacFvity (exact parameter unclear). 2. Amygdala Orchestrates broad spectrum of responses Required for new fear condiFoning and innate fear e.g. snakes Amyg damage in humans reduces fear and disposiFonal anxiety 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




reacFvity (exact parameter unclear). 2. Amygdala Orchestrates broad spectrum of responses Required for new fear condiFoning and innate fear e.g. snakes Amyg damage in humans reduces fear and disposiFonal anxiety CeA damage in rats/monkeys Reduces freezing CeA metabolism predicts individual dierences in BI in monkeys Amygdala more reacFve in BI kids all grown up and paFents with a





variety of anxiety disorders Amygdala acFvaFon prospecFvely predicts the rst onset of anx. Dx AnF-anxiety drugs reduce amygdala acFvaFon Amygdala not just fear/anxiety




variety of anxiety disorders 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 ..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.

CriKcal Thinking QuesKon #2 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

CriKcal Thinking QuesKon #2 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). In part, she pointed out that 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.

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

CriKcal Thinking QuesKon #2 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 this work: hYps://www.youtube.com/watch?v=-dKlKaMwoVE) 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. 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.

CriKcal Thinking QuesKon #3 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.

CriKcal Thinking QuesKon #4 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

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 1. BI is an early-emerging facet of N/NE

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


Amygdala is a Neural Hub: 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 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

Documents

amygdala damage

joe ledoux

states of fear

social anxiety disorder

rats ledoux nyu davis

extended amygdala aj

social aliakon

emory kagans view