Shackman Psyc210 Module08 IntermediatePhenotypesImaging1

7/21/2019 Shackman Psyc210 Module08 IntermediatePhenotypesImaging1

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Nuts & Bolts Plan forToday

Any questions from the BrainImaging lecture? (Module 9)

Todays !ecture Intermediate phenotypes

Ta"e#home critical thin"ingquestion


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P$% '*

Intermediate Phenotypes, Markers, &Endophenotypes

AJ Shackman5 March 2015


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Todays once+tual ,oadma+

-hat is the .asis of T&P?

This is a /ery hard question

Phenoty+e* Broad#.and dimensions of T&P are

com+le0 and heterogeneous 1$ is not one +sychological or .iological 2thing

This com+le0ity suggests that trait#li"e indi/idual

di3erences in T&P re4ect multi+le causes(etiologies) su++orted .y multi+le .iologicalsystems (2+atho+hysiologies)

5o6 can 6e sim+lify the +ro.lem?


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This is a very hard question

Broad#.and dimensions of T&P are com+le0 andheterogeneous 1$ is not one +sychological7 neuro.iological7 or genetic

2thing


di3erences in T&P re4ect multi+le causes (etiologies)su++orted .y multi+le .iological systems(2+atho+hysiologies)



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Broad#.and dimensions of T&P are com+le0 andheterogeneous 1$ is not one +sychological7 neuro.iological7 or genetic

2thing





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By their nature7 .road#.and dimensions of T&P arecom+le0 and heterogeneous 1$ is not one +sychological7 neuro.iological7 or genetic

2thing





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2thing


di3erences in T&P re4ect multi+le causes(2etiologies) su++orted .y multi+le .iologicalsystems (2+atho+hysiologies)



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2thing


di3erences in T&P re4ect multi+le causes(2etiologies) su++orted .y multi+le .iologicalsystems (2+atho+hysiologies)



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T&P is a Hard Problem: CaseStudies


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Mayor 8ord (Toronto) Mayor Barry ()


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Students: Who are these haraters! What do they have in om

i $h


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:an 99* ,;ININ


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:an 99* ,;ININ


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Marion Barry

ts " What does it mean to reverse en#ineer a system or arti$at %e# aar, re$ri#erator, or iPad'!

rown 4rontiers in e"ro 20167 8a%enik Cancer Cell


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Marion Barry



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Marion Barry

t is the soure, the roote o$ (arry)s diverse troubles!

understood the #eneral priniples,ould intervene

ust help (arry, but help others *hor $rom similar problems



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Students " What)s your dia#nosis!

Ho* *ould you harateri.eMayors (arry and /ord!


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Marshmallow .est 9 https:;;www&yo"t"e&com;watch


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Marshmallow .est 9 https:;;www&yo"t"e&com;watch


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Ho* mi#ht *e #o about disoverin# the psyholo#ial, neural, or

#eneti bases o$ lo* C0SC!


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Try to forge a lin".et6eenF

T&P* ariation in C;SC and

andidate ause* Some other process ormeas"re Perormance on a cogniti,e task attention+

inhiitionK Perormance on a risk taking task or L8 task

DActi,ationE or resting acti,ity or "nctional conny

Htc etc etc


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Try to forge a lin".et6eenF

T&P* ariation in C;SC and

andidate ause* Some other process ormeas"re Perormance on a cogniti,e task attention+

inhiitionK Perormance on a risk taking task or L8 task

DActi,ationE or resting acti,ity or "nctional conny

Htc&


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Ho* mi#ht *e #o aboutthis1!


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Guantify indi/idual di3erences in1$


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ne#$hot $elf#,e+ort

Students2Potential limitations!Psyhometri onerns!


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ne#$hot $elf#,e+ort Multi#Informant Beha/ioral om+osite


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ne#$hot $elf#,e+ort Multi#Informant Beha/ioral om+osite

In either case7 you end u+ 6ith a single num.er


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Is 2one num.er a sensi.lea++roach?


Is there only one +rocess at

6or"?


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+o3

1$ is om+le0


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1$ is om+le0

1$ is om+le0


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1$ is om+le0

om+le0ity im+edes the search forsim+le su.strates

Need to sim+lifyH 8ocus on one "ey

element at a time

eEned .y constellation of sym+tonot causes (2+atho+hysiology)7 inclalterations in thought7 language7.eha/ior7 and mood

om+le0ity is com+ounded .y theJim $um Bu3etK +ro.lem

dierent ways to get thereNpolythetic diagnostic categoriesK

ut6ard manifestations are oftennon#s+eciEc (a"a transdiagnostic)

1$ is om+le0


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1$ is om+le0



element at a time




ut6ard manifestations are oftennon#s+eciEc (a"a transdiagnostic)

1$ is om+le0


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1$ is om+le0



element at a time




ut6ard manifestations are oftennon#s+eciEc (a"a 2transdiagnostic)

1$ is om+le0


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1$ is om+le0

om+le0ity im+edes the search forsim+le su.strates (+sychl or .iol)


element at a time




ut6ard manifestations are oftennon#s+eciEc (a"a 2transdiagnostic)

1$ is om+le0


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1$ is om+le0

$im+ler Intermediate Phenoty+es

4elay o$ 5rati6ation


Need to sim+lifyH


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Ho* mi#ht *e 7uanti$y putativeIP!


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8isk9Takin# Task Eample

;(alloon


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Earn as muh money as you an3

The more you pump up the balloon,the more you earn %=>0pump'

(ut i$ you pop it be$ore youhave a hane to ash out,

you #et nothin#


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you #et nothin#


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you #et nothin#


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Press/Cash Out

or-

Pump/Inflate


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Press this button to pump

up the balloon

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Collect $$$

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EXPLOSION TEMPORARY $$$ LOST


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COLLECTION - $$$ MOVED TO PERMANENT BANK


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Then Searh $or the Even More Elementary (iolo#ial Substrates

+ot o$


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Then Searh $or the Even More Elementary (iolo#ial Substrates

+ot o$


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Eample o$ ?inkin# (


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e St"dy ; )etails Are ot Important


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is no* a 8esearh


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*sed MLI and machinelearning techniO"es

DMind readingE

Is the subject going to pump(risky!) or cash out (safe!) onthe following trial?

e"ral signat"re was oc"sed

on regions that seem to ein,ol,ed in risk a,ersion

oth perormance on the AL.and this ne"ral signat"re cane tho"ght o as candidate

phenotypes

is no* a 8esearh


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DMind readingE


e"ral circ"it or Nsignat"re was

oc"sed on regions in,ol,ed inrisk a,ersion

is no* a 8esearh


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DMind readingE


e"ral circ"it or Nsignat"re was

oc"sed on regions in,ol,ed inrisk a,ersion

oth perormance on the AL.and this ne"ral signat"re cane tho"ght o as candidate

intermediate phenotypes o

is no* a 8esearh


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The Premise* ecom+ose om+le0 Phenoty+es

(Traits) Into More Managea.le ausalIntermediates

I P s are a Bridge to


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IP s are a Bridge toisco/ery

I P s are a Bridge to


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$im+ler Intermediate ause*Hle,ated Lisk.aking on the AL.

om+le07 MultidimensionalTraits* C;SC

Psychological & Biological $u.strates*e&g&+ Altered Acti,ity in theLisk A,ersion etwork

IP s are a Bridge toisco/ery

B,I9all K

Ba,e "n

Guestion1& .oday we talked ao"t Mayors arry - 4ord with respect to C;SC


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y y y p ;and anti$social eha,ior&

-hat do you thin"?

Pick a great sportswoman or sportsman chess and ASCALco"ntK&

rieYy descrie how yo" might apply the IP strategy to"nderstand the so"rcesK o her or his prowess& 3hat CA*SH) theathlete to e a Ball o 4amer&

PS: Fo" might en!oy peeking at

https:;;en&wikipedia&org;wiki;Saermetrics

https:;;en&wikipedia&org;wiki;Money>all K

Ba,e "n

Guestion


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2& .he optional reading yLeardon Nature2015Khighlights recent eorts toring iomarkers opsychological states+ like pain+into the co"rtroom&

-hat do you thin"?

ased on yo"r reading o thisshort+ entertaining piece+ what

do yo" think ao"t "sing MLIor other kinds o iomarkers tomake high$impact decisionse&g& O"aliy or disailityK>>>>>>>>> can e assayed "sing similar e'perimental proced"res&

A& Childhood eha,ioralinhiition IK

& eha,ioral Acti,ationSystem ASK

C& Conscientio"sness;Sel$

Control C;SCK

)rew 4o' and colleag"es in the alin la demonstrated thatd l t li di t d di i di iti l


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amygdala metaolism predicted dierences in dispositional

an'iety an'io"s temperamentK when it was collected

A& In stress"l conte'ts alonein the no,el testing cage+h"man intr"derK

& In more sec"re conte'tshome cage alone+ home

cage with "s"al cagemateKC& oth stress"l and sec"reconte'ts

.hese res"lts s"ggest that the V.raits '.rait$Lele,ant C"es = StatesV model is


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.rait$Lele,ant C"es = States model is

A& .r"e

& 4alse

C& .r"e "t incomplete

Indi,id"als high in ;Htend to


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tend to

A& Show ele,ated reactions tothreat igger peak+ slower

reco,eryK& Show chronically ele,ated

metaolism in regions othe rain that help toorchestrate states o

an'iety and aro"salC& oth

.rait$like dierences in ;H reYect ]pickthe most correct / complete response^


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the most correct / complete response^

A& .he amygdala

& .he amygdala and other regionse&g&+ the ed n"cle"s o the striaterminalis S.K+ hippocamp"s+and periaO"ed"ctal gray PAQKK&

C& Hle,ated metaolism in theamygdala and other regionse&g&+ the ed n"cle"s o the striaterminalis S.K+ hippocamp"s+and periaO"ed"ctal gray PAQKK

as well as altered "nctionalconnecti,ity etween theamygdala and prerontal corte'P4CK&

.-P potentially reYects


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p y

A& )ierences in the peakresponse to pert"ration

& )ierences in thethreshold+ rise time+ peakamplit"de+ and reco,ery to

aseline&

+one ased on sensiti,ity toreward$predicting c"es


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reward predicting c"es

#incenti,es#K+ the other ased onsensiti,ity to p"nishment orthreat$predicting c"es& .hese

reYect dierences in the AS andIS+ respecti,ely& Bigh$AS

indi,id"als tend toA& e more sociale+ sociallydominant+ and en!oy socialattention

& Are predisposed to engagein appetiti,ely$moti,atedapproachK eha,iors&

C& H'perience less anger whentheir goals are thwarted&

In principle+ high$AS indi,id"alstend to e'perience more intense


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tend to e'perience more intense

A& V3antingV relatedemotional statese'citement+ !oy+ angerK

& V8ikingV related emotional

states contentment+hedonic or sens"alpleas"reK

stale indi,id"al dierences inrontal HHQ asymmetry& Bigh$IS


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indi,id"als tend to show >>>>>>+whereas Bigh$AS indi,id"als

tend to show >>>>>>>> &

A& Light __ 8et asymmetryand 8et __ Lightasymmetry&

& Light `` 8et asymmetryand 8et `` Light

asymmetry&

e&g&+ anti$an'iety dr"gsK andne"roeedack manip"lations


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ptargeting rontal HHQ asymmetrydon#t !"st change the HHQ+ they

also change reactions to emotionalchallenges& .his s"ggests thatA& .he ne"ral mechanisms that

"nderlie the scalp$recordedHHQ asymmetry make aCA*SA8 contri"tion to .-P&

& .he ne"ral mechanisms that"nderlie the scalp$recorded

HHQ asymmetry reYect aCULLH8A.H o .-P

C& .he ne"ral mechanisms that"nderlie the scalp$recordedHHQ asymmetry reYect a

CUCUMI.A. o .-P

icotine$depri,ed smokers anticipating a p" and inants


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anticipating a re"nion with their mother oth show

A& 8 __ L rontal HHQ

asymmetry+ s"ggestingthat this iologicalmeas"re reYects appetiti,edri,e wantingK

& 8 ` L rontal HHQ

asymmetry+ s"ggestingthat this iologicalmeas"re reYects liking andpleas"re

*sing daily diary techniO"es+ Qale andcolleag"es pro,ided e,idence that

dierences in .-P reYect


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dierences in .-P reYect

A& )ierential reacti,ity tomoti,ationally$signifcant

daily e,ents& )ierential e'pos"re to

moti,ationally$signifcantdaily e,ents

C& oth


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Con,erging with the res"lts o the VrestingV rain acti,ityst"dies+ Qale#s res"lts s"ggest that .-P can ias transient

moods+ eelings+ and eha,iors when

A& .rait$rele,ant c"es areasent or presentK

& .rait$rele,ant c"es areacti,ely ignored

C& oth

Implicit;a"tomatic and e'plicitdeclarati,e knowledgeK processes can


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dec a a e o edgeK p ocesses ca

A& e "ncorrelated+s"ggesting distinct ne"ralcirc"its

& Q"ide eha,ior

C& e disr"pted y

circ"mscried hippocampaland oritorontal lesions+respecti,ely

)& A -

H& A+ - C

Hlectrodermal acti,ity a&k&a&H)A;SCL;QSLK


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A& LeYects changes in theskin#s resistance& Sweatypalms aro"salK red"ce theskin#s resistance+increasing cond"ctance&

& Is a meas"re o aro"sal andcan e amplifed ypositi,e stresse'citementK+ negati,estress earK+ and cogniti,echallenges&

C& Is ,alence$sensiti,e:ma'imal when one ise'periencing a negati,eemotional state+intermediate or ne"tral


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The End

$tu3 for 8uture$emesters


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$emesters

8uture Thought G


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4oc"sed on comp"tational models o .-P

4"t"re .ho"ght ?


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Extra Slides


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EEG Intro Video, Version #1(1:12 to end)

https://www.youtube.com/watch?v=kGuayTwqieM


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*pper wa,e in each pair = signal7 lower = resid"al noise est


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0M(I 12peime+t 3ta4es: *+atomica5s'$ Take a+atomica5 !T6$ ima4es

hi4h7eso5utio+ ima4es !e.4.8 #.9 2 #.9 2 ,.# mm$


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4 4 ! 4 8 $ ,D ata: , spatia5 ime+sio+s8 samp5e at o+e poi+t i+ time

"' a+atomica5 s5ices takes ;' mi+utes

"' s5ices2 , mm

$1T$

$ome 8M,I ata


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Left = ece+t 5ooki+4 si+45e sub-ect activatio+ map

Bemodynamic Lesponse 4"nctionBL4K


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.ime co"rse o MLI is [( secondslood Yow is slowK

)ip eca"sene"rons eginto e'tracto'ygen eore

o'yB arri,es

Increase in o'yB eca"senew o'yB haso,ercompensated

ack to aselineeca"se ne"ronse'tract o'ygen soo'yB ecomes

deo'yB

10 seconds

6$( seconds


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MLI Analysis


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Condition I R

Condition SI

signifcantWK

o'elI = Intact ace

S = Scramled ace

MLI relies on s"tractionmethod


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0M(I 12peime+t 3ta4es:


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y 4 ! $ a55 s5ices at o+e time = a vo5ume !sometimes a5so ca55e a+ ima4e$

samp5e ma+y vo5umes !time poi+ts$ !e.4.8 6 vo5ume evey seco+s 0o 6,"vo5umes = 9 sec = ':,$

'D ata: , spatia58 6 tempoa5

A

.iomar"ersPromise: no,el ne"roiological ramework or "nderstanding clinicalphenomena pain+ aerrant emotionK and accelerating the rationale


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orsook et al at"re Le, )r"g )isco,ery 2

p p gde,elopment o impro,ed inter,ention strategies

!imitations*nderstanding the ca"se o phenotypes is


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hard

Models are too sim+leand do notacco"nt or rec"rrent relations etweenca"ses and eects+ within and o"tside othe indi,id"al+ at dierent le,els o analysis

e&g&+ genome

en,ironment

gene e'pressionetc&

Miller - Lockstroh ALCP 201/7 endler - eale Mol Psychiatry

onfusions & istinctions Bai+ vs. Mi+

$1XT$


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)euoscie+ce vs. Co4+itive scie+ce Mass 5eve5 vs. Mico7cicuity

Co++ecti+4 b5obs to ce5575eve5 actio+s?

12citatio+ I+hibitio+ both co+sume e+e4y Ehat oes Factive mea+?

*ctive vs. )ecessay !e.4.8 5esio+ stuies$

Mou5ate hee? H thee? MV&* vs. 3peci0icity

(esti+4 3tate: F


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Compute simu5ate seque+ce o0 ba55oo+s

#.# pe ba55oo+ pump !i+ tempoay ba+k$

Must hit Fco55ect butto+ to ea+ mo+ey Ba55oo+ e2p5osio+ = tempoay mo+ey 5ost

12p5osio+ poi+t 0o ba55oo+s !6 6J$

1a+i+4s a0te sessio+ i+ 4i0t ceti0icates

)$

O

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Endophenotypes are a (rid#eom+le0 Phenoty+e


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$im+ler intermediate causes that lie .et6een (herita.le) disease

and genes

H&g&+ Schi%ophrenia working memory defcit systems iologygenes

H&g+ Schi%ophrenia sensory gating defcit systems iolygenes

e"rophysiological+ iochemical+ endocrinological+ ne"roanatomical+cogniti,e+ or ne"ropsychological $ does U. ha,e to e iological

Premise* om+le0 +henoty+es can .e decom+osed into sim+lerconstituents

4acilitates heritaility and ne"roiological analyses7 osters mechanisticanimal models

H&g&+ monkey model o 3M defcits SCGK

H&g&+ monkey model o childhood eha,ioral inhiition A@K systems microcirc"its ne"rochemistry;anatomy epigen

Endophenotypes are a (rid#eom+le0 Phenoty+e


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Miller - Lockstroh Ann Le, Clin Psychol 2

(& Can e meas"red relialy

.he state independence criterion has een challenged on thegro"nds that any f'ed ca"se is ins"cient to e'plain the onset otransient;rec"rrent disorders and is+ y defnition+ not e amenaleto treatment;inter,ention

2=ndo+henoty+e ,efers to 'Things


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A Thing heritale intermediate ca"se o a phenotype

C;SCK

,esearch $trategy Simpliy+ simpliy+ simpliy

Instead o looking or the Nca"se o low C;SC+

8ook or the "nderpinnings o hyper$reacti,ityto reward or whatnot

Promises to enhance*

The Promise


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Etiolo#y %ause'

3hat is the pro'imal iological ca"sesK o the disorder;.-P

Shackman Psyc210 Module08 IntermediatePhenotypesImaging1

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