Dopamine modulates the functional organization of the orbitofrontal cortex

Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2017

Dopamine modulates the functional organization of the orbitofrontal cortex

Kahnt, Thorsten ; Tobler, Philippe N

Abstract: Neuromodulators such as dopamine can alter the intrinsic firing properties of neurons, and may thereby change the configuration of larger functional circuits. The primate orbitofrontal cortex (OFC) receives dopaminergic input from midbrain nuclei, but the role of dopamine in the OFC is still unclear. Here we tested the idea that dopaminergic activity changes the pattern of connectivity between the OFC and the rest of the brain, and thereby reconfigures functional networks in the OFC. To this end, we combined double-blind, placebo-controlled pharmacology (D2 receptor [D2R] antagonist amisulpride) in humans with resting-state functional magnetic resonance imaging (fMRI) and clustering methods. In the placebo group, we replicated previously observed parcellations of the OFC into two and six subregions based on connectivity patterns with the rest of the brain. Most importantly, while the 2-fold clustering did not differ significantly between groups, blocking D2R receptors significantly changed the composition of the 6-fold parcellation, suggesting a dopamine-dependent reconfiguration of functional OFC subregions. Moreover, multivariate decoding analyses revealed that amisulpride changed the whole-brain connectiv-ity patterns of individual OFC-subregions. In particular, D2R blockade shifted the balance of OFC connectivity from associative areas in the temporal and parietal lobe toward functional connectivity with the frontal cortex. In summary, our results suggest that dopamine alters the composition of functional OFC circuits, possibly indicating a broader role for neuromodulators in the dynamic reconfiguration of functional brain networks. SIGNIFICANCE STATEMENT: A key role of any neuromodulator may be the reconfiguration of functional brain circuits. Here we test this idea with regard to dopamine and the organization of functional networks in the OFC. We show that blockade of dopamine D2-receptors has profound effects on the functional connectivity patterns of the OFC, yielding in altered connectivity-based subdivisions of this region. Our results suggest that dopamine changes the connectional configuration of the OFC, possibly leading to transitions between different operating modes that favor either sensory input or recurrent processing in the prefrontal cortex. More generally, our findings support a broader role for neuromodulators in the dynamic reconfiguration of functional brain networks and may have clinical implications for understanding the actions of antipsychotics.

DOI: https://doi.org/10.1523/JNEUROSCI.2827-16.2016

Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-132178

Journal Article Accepted Version

The following work is licensed under a Creative Commons: Attribution 4.0 International (CC BY 4.0) License.

Originally published at:

Kahnt, Thorsten; Tobler, Philippe N (2017). Dopamine modulates the functional organization of the orbitofrontal cortex. Journal of Neuroscience, 37(6):1493-1504.

DOI: https://doi.org/10.1523/JNEUROSCI.2827-16.2016

Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process.

Copyright © 2017 the authors

This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version.

Research Articles: Behavioral/Cognitive

Dopamine modulates the functional organization of the orbitofrontal cortex

Thorsten Kahnt1 and Philippe N. Tobler2

1

Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA 2

Department of Economics, Laboratory for Social and Neural Systems Research, University of Zurich, Zürich, 8006, Switzerland DOI: 10.1523/JNEUROSCI.2827-16.2016 Received: 8 September 2016 Revised: 18 November 2016 Accepted: 28 December 2016 Published: 9 January 2017

Author contributions: T.K. and P.T. designed research; T.K. performed research; T.K. analyzed data; T.K. and P.T. wrote the paper.

Conflict of Interest: The authors declare no competing financial interests.

. Research reported in this publication was supported by the NIDCD of the NIH under Award Number

R01DC015426 (to T.K.) and by Swiss National Science Foundation Grants PP00P1_128574, PP00P1_150739, CRSII3_141965, and 00014_165884 (to P.N.T.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors thank H. Haker, T. Baumgartner, S. Weber, and M. Wälti for assistance in subject recruitment and data acquisition, and M. Mesulam, L.J. Chang, and J.D. Howard for helpful discussions, comments and suggestions.

Correspondence should be addressed to Thorsten Kahnt, Northwestern University, Feinberg School of Medicine, Department of Neurology, 303 E Chicago Ave, Ward 13-006, Chicago, IL 60611, USA. E-Mail: [email protected]

Cite as: J. Neurosci 2017; 10.1523/JNEUROSCI.2827-16.2016

Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published.

%HKDYLRUDO&RJQLWLYH6HFWLRQ ϭ Ϯ 'RSDPLQHPRGXODWHVWKHIXQFWLRQDORUJDQL]DWLRQRIWKHRUELWRIURQWDOFRUWH[ ϯ ϰ ϱ 7KRUVWHQ.DKQW _{3KLOLSSH17REOHU} ϲ 1

Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

ϳ

2

Department of Economics, Laboratory for Social and Neural Systems Research, University of Zurich, Zürich, 8006,

ϴ Switzerland ϵ ϭϬ $EEUHYLDWHGWLWOH5HFRQILJXUDWLRQRI2)&QHWZRUNVE\GRSDPLQH ϭϭ ϭϮ 1XPEHURISDJHV ϭϯ 1XPEHURIILJXUHVDQGWDEOHV ϭϰ 1XPEHURIZRUGVIRU$EVWUDFW,QWURGXFWLRQ'LVFXVVLRQ ϭϱ ϭϲ ϭϳ &RUUHVSRQGHQFHVKRXOGEHDGGUHVVHGWR7KRUVWHQ.DKQW1RUWKZHVWHUQ8QLYHUVLW\)HLQEHUJ6FKRRORI ϭϴ 0HGLFLQH'HSDUWPHQWRI1HXURORJ\(&KLFDJR$YH:DUG&KLFDJR,/86$(0DLO ϭϵ WKRUVWHQNDKQW#QRUWKZHVWHUQHGX ϮϬ Ϯϭ ϮϮ $FNQRZOHGJHPHQWV5HVHDUFKUHSRUWHGLQWKLVSXEOLFDWLRQZDVVXSSRUWHGE\WKH1,'&'RIWKH1,+XQGHU$ZDUG Ϯϯ 1XPEHU5'&WR7.DQGE\6ZLVV1DWLRQDO6FLHQFH)RXQGDWLRQ*UDQWV333B Ϯϰ 333B&56,,BDQGBWR3177KHFRQWHQWLVVROHO\WKHUHVSRQVLELOLW\RIWKH Ϯϱ DXWKRUVDQGGRHVQRWQHFHVVDULO\UHSUHVHQWWKHRIILFLDOYLHZVRIWKH1,+7KHDXWKRUVWKDQN++DNHU7 Ϯϲ %DXPJDUWQHU6:HEHUDQG0:lOWLIRUDVVLVWDQFHLQVXEMHFWUHFUXLWPHQWDQGGDWDDFTXLVLWLRQDQG00HVXODP Ϯϳ /-&KDQJDQG-'+RZDUGIRUKHOSIXOGLVFXVVLRQVFRPPHQWVDQGVXJJHVWLRQV Ϯϴ Ϯϵ &RQIOLFWRI,QWHUHVW7KHDXWKRUVGHFODUHQRFRPSHWLQJILQDQFLDOLQWHUHVWV ϯϬ

$EVWUDFW ϯϭ 1HXURPRGXODWRUVVXFKDVGRSDPLQHFDQDOWHUWKHLQWULQVLFILULQJSURSHUWLHVRIQHXURQVDQGPD\WKHUHE\FKDQJH ϯϮ WKHFRQILJXUDWLRQRIODUJHUIXQFWLRQDOFLUFXLWV7KHSULPDWHRUELWRIURQWDOFRUWH[2)&UHFHLYHVGRSDPLQHUJLF ϯϯ LQSXWIURPPLGEUDLQQXFOHLEXWWKHUROHRIGRSDPLQHLQWKH2)&LVVWLOOXQFOHDU+HUHZHWHVWHGWKHLGHDWKDW ϯϰ GRSDPLQHUJLFDFWLYLW\FKDQJHVWKHSDWWHUQRIFRQQHFWLYLW\EHWZHHQWKH2)&DQGWKHUHVWRIWKHEUDLQDQGWKHUHE\ ϯϱ UHFRQILJXUHVIXQFWLRQDOQHWZRUNVLQWKH2)&7RWKLVHQGZHFRPELQHGGRXEOHEOLQGSODFHERFRQWUROOHG ϯϲ SKDUPDFRORJ\'UHFHSWRU>'5@DQWDJRQLVWDPLVXOSULGHLQKXPDQVZLWKUHVWLQJVWDWHIXQFWLRQDOPDJQHWLF ϯϳ UHVRQDQFHLPDJLQJI05,DQGFOXVWHULQJPHWKRGV,QWKHSODFHERJURXSZHUHSOLFDWHGSUHYLRXVO\REVHUYHG ϯϴ SDUFHOODWLRQVRIWKH2)&LQWRWZRDQGVL[VXEUHJLRQVEDVHGRQFRQQHFWLYLW\SDWWHUQVZLWKWKHUHVWRIWKHEUDLQ ϯϵ 0RVWLPSRUWDQWO\ZKLOHWKHIROGFOXVWHULQJGLGQRWGLIIHUVLJQLILFDQWO\EHWZHHQJURXSVEORFNLQJ'5UHFHSWRUV ϰϬ VLJQLILFDQWO\FKDQJHGWKHFRPSRVLWLRQRIWKHIROGSDUFHOODWLRQVXJJHVWLQJDGRSDPLQHGHSHQGHQW ϰϭ UHFRQILJXUDWLRQRIIXQFWLRQDO2)&VXEUHJLRQV0RUHRYHUPXOWLYDULDWHGHFRGLQJDQDO\VHVUHYHDOHGWKDW ϰϮ DPLVXOSULGHFKDQJHGWKHZKROHEUDLQFRQQHFWLYLW\SDWWHUQVRILQGLYLGXDO2)&VXEUHJLRQV,QSDUWLFXODU'5 ϰϯ EORFNDGHVKLIWHGWKHEDODQFHRI2)&FRQQHFWLYLW\IURPDVVRFLDWLYHDUHDVLQWKHWHPSRUDODQGSDULHWDOOREHWRZDUG ϰϰ IXQFWLRQDOFRQQHFWLYLW\ZLWKWKHIURQWDOFRUWH[,QVXPPDU\RXUUHVXOWVVXJJHVWWKDWGRSDPLQHDOWHUVWKH ϰϱ FRPSRVLWLRQRIIXQFWLRQDO2)&FLUFXLWVSRVVLEO\LQGLFDWLQJDEURDGHUUROHIRUQHXURPRGXODWRUVLQWKHG\QDPLF ϰϲ UHFRQILJXUDWLRQRIIXQFWLRQDOEUDLQQHWZRUNV ϰϳ ϰϴ 6LJQLILFDQFH6WDWHPHQW ϰϵ $NH\UROHRIDQ\QHXURPRGXODWRUPD\EHWKHUHFRQILJXUDWLRQRIIXQFWLRQDOEUDLQFLUFXLWV+HUHZHWHVWWKLVLGHD ϱϬ ZLWKUHJDUGWRGRSDPLQHDQGWKHRUJDQL]DWLRQRIIXQFWLRQDOQHWZRUNVLQWKH2)&:HVKRZWKDWEORFNDGHRI ϱϭ GRSDPLQH'UHFHSWRUVKDVSURIRXQGHIIHFWVRQWKHIXQFWLRQDOFRQQHFWLYLW\SDWWHUQVRIWKH2)&\LHOGLQJLQ ϱϮ DOWHUHGFRQQHFWLYLW\EDVHGVXEGLYLVLRQVRIWKLVUHJLRQ2XUUHVXOWVVXJJHVWWKDWGRSDPLQHFKDQJHVWKH ϱϯ FRQQHFWLRQDOFRQILJXUDWLRQRIWKH2)&SRVVLEO\OHDGLQJWRWUDQVLWLRQVEHWZHHQGLIIHUHQWRSHUDWLQJPRGHVWKDW ϱϰ IDYRUHLWKHUVHQVRU\LQSXWRUUHFXUUHQWSURFHVVLQJLQWKHSUHIURQWDOFRUWH[0RUHJHQHUDOO\RXUILQGLQJVVXSSRUWD ϱϱ EURDGHUUROHIRUQHXURPRGXODWRUVLQWKHG\QDPLFUHFRQILJXUDWLRQRIIXQFWLRQDOEUDLQQHWZRUNVDQGPD\KDYH ϱϲ FOLQLFDOLPSOLFDWLRQVIRUXQGHUVWDQGLQJWKHDFWLRQVRIDQWLSV\FKRWLFV ϱϳ ϱϴ

,QWURGXFWLRQ ϱϵ $NH\IXQFWLRQRIDQ\QHXURPRGXODWRUPD\EHWRDOWHUWKHG\QDPLFVDQGFRPSRVLWLRQRIIXQFWLRQDOEUDLQFLUFXLWV ϲϬ 0DUGHU%\FKDQJLQJWKHLQWULQVLFSURSHUWLHVRIQHXURQVQHXURPRGXODWRUVFDQGLIIHUHQWLDOO\DIIHFWWKH ϲϭ VWUHQJWKRILQGLYLGXDOV\QDSVHVDQGPD\WKHUHE\ELDVQHXURQVWRWUDQVLWLRQEHWZHHQDQGSDUWLFLSDWHLQGLIIHUHQW ϲϮ IXQFWLRQDOFLUFXLWV+DUULV:DUULFNDQG0DUGHU:HLPDQQDQG0DUGHU,PSRUWDQWO\VXFKQHWZRUN ϲϯ UHFRQILJXUDWLRQVVKRXOGEHUHIOHFWHGLQWKHIXQFWLRQDOFRQQHFWLYLW\SURILOHRIWKHEUDLQUHJLRQVKRVWLQJWKH ϲϰ IXQFWLRQDOFLUFXLW ϲϱ 7KHRUELWRIURQWDOFRUWH[2)&LVRQHRIWKHPRVWFRQQHFWHGUHJLRQVRIWKHEUDLQDQGSDUWLFLSDWHVLQVHYHUDO ϲϲ IXQFWLRQDOFLUFXLWV.ULQJHOEDFKDQG5ROOV=DOGDQG5DXFK,WUHFHLYHVKLJKO\SURFHVVHGLQSXWIURP ϲϳ HYHU\VHQVHDQGLVFRQQHFWHGWRRWKHUSUHIURQWDODUHDVSUHPRWRUFRUWH[DQGVXEFRUWLFDODUHDVVXFKDVWKH ϲϴ VWULDWXPDP\JGDODKLSSRFDPSXVDQGK\SRWKDODPXV0RUHFUDIWHWDO&DYDGDHWDO7KLVGHQVH ϲϵ FRQQHFWRPHVXJJHVWVWKDWIXQFWLRQDOLQWHUDFWLRQVZLWKRWKHUEUDLQUHJLRQVDUHNH\WRWKHSURFHVVHVWKDWDUHFDUULHG ϳϬ RXWE\WKH2)& ϳϭ ,PSRUWDQWSURJUHVVKDVEHHQPDGHLQXQGHUVWDQGLQJKRZWKH2)&FRQWULEXWHVWRUHZDUGH[SHFWDWLRQ ϳϮ YDOXDWLRQDQGGHFLVLRQPDNLQJ6HVFRXVVHHWDO3DGRD6FKLRSSD5XVKZRUWKHWDO5XGHEHFN ϳϯ DQG0XUUD\+RZDUGHWDO6WDOQDNHUHWDO+RZHYHUDOWKRXJKWKHIURQWDOOREHVUHFHLYH ϳϰ VWURQJSURMHFWLRQVIURPGRSDPLQHUJLF'$QHXURQVLQWKHPLGEUDLQ6ZDQVRQ*ROGPDQ5DNLFHWDO ϳϱ DQG'$LQWKHSUHIURQWDOFRUWH[3)&KDVEHHQDVVRFLDWHGZLWKVSHFLILFFRJQLWLYHIXQFWLRQVVXFKDV ϳϲ ZRUNLQJPHPRU\DQGFRJQLWLYHFRQWURO0LOOHUDQG&RKHQ&RROVFKDUDFWHUL]DWLRQVRIWKHUROHRI ϳϳ '$LQWKH2)&KDYHUHPDLQHGUHODWLYHO\YDJXH6SHFLILFDOO\'$LQWKH2)&KDVEHHQOLQNHGWRDVVRFLDWLYH ϳϴ UHZDUGSURFHVVLQJ:DONHUHWDOUHZDUGUHODWHGLQVWUXPHQWDOEHKDYLRU&HWLQHWDODQGHYHQPRUH ϳϵ JHQHUDOO\WRDWWHQWLRQPRWLYDWLRQDQGLPSXOVLYHUHVSRQGLQJ:LQVWDQOH\HWDO,QWHUHVWLQJO\V\VWHPLF ϴϬ PRGXODWLRQVRI'$KDYHEHHQVKRZQWRDOWHUORQJUDQJHIXQFWLRQDOFRQQHFWLRQV1DJDQR6DLWRHWDO&ROH ϴϭ HWDOD&ROHHWDOEDQG'$LQWKH2)&KDVEHHQOLQNHGWRGRSDPLQHUJLFQHXURWUDQVPLVVLRQLQWKH ϴϮ VWULDWXP&ODUNHHWDOVXJJHVWLQJWKDW'$PD\DOWHUWKHIXQFWLRQDOFRQQHFWLYLW\EHWZHHQWKH2)&DQG ϴϯ UHPRWHEUDLQUHJLRQV ϴϰ +HUHZHWHVWHGWKHLGHDWKDW'$PRGXODWHVWKHFRQILJXUDWLRQRIIXQFWLRQDO2)&QHWZRUNV7RWKLVHQGZH ϴϱ FRPELQHG'$SKDUPDFRORJ\XVLQJWKHVSHFLILF''UHFHSWRU>'5@DQWDJRQLVWDPLVXOSULGHZLWKUHVWLQJVWDWH ϴϲ IXQFWLRQDOPDJQHWLFUHVRQDQFHLPDJLQJI05,DQGFRQQHFWLYLW\EDVHGFOXVWHULQJDSSURDFKHV:HSDUFHOODWHGWKH ϴϳ 2)&LQWRKRPRJHQHRXVVXEUHJLRQVEDVHGRQWKHLUIXQFWLRQDOFRQQHFWLYLW\SDWWHUQVZLWKWKHUHVWRIWKHEUDLQ,Q ϴϴ WKHSODFHERJURXSZHUHSOLFDWHGDSUHYLRXVO\REVHUYHGSDUFHOODWLRQLQWRWZRDQGVL[VXEGLYLVLRQV.DKQWHWDO ϴϵ ,PSRUWDQWO\ZKLOHWKHIROGFOXVWHULQJGLGQRWGLIIHUEHWZHHQJURXSVWKHIROGSDUFHOODWLRQGLIIHUHG ϵϬ

VLJQLILFDQWO\EHWZHHQJURXSVVXJJHVWLQJWKDWEORFNLQJ'5UHFRQILJXUHGIXQFWLRQDOQHWZRUNVLQWKH2)& ϵϭ 0RUHRYHUPXOWLYDULDWHGHFRGLQJDQDO\VHVUHYHDOHGWKDWZKROHEUDLQFRQQHFWLYLW\SDWWHUQVRILQGLYLGXDO2)& ϵϮ VXEUHJLRQVZHUHPRGXODWHGE\DPLVXOSULGHVXFKWKDWIXQFWLRQDOFRQQHFWLYLW\ZLWKIURQWDOFRUWH[ZDVHQKDQFHG ϵϯ ZKHUHDVFRQQHFWLRQVZLWKKLJKHUVHQVRU\DUHDVZHUHUHGXFHGE\'5EORFNDGH7KHVHUHVXOWVVXJJHVWWKDW ϵϰ PRQRDPLQHVSOD\DQLPSRUWDQWUROHIRUWKHFRPSRVLWLRQRIIXQFWLRQDO2)&FLUFXLWVSRVVLEO\LQGLFDWLQJDEURDGHU ϵϱ UROHRIQHXURPRGXODWRUVLQWKHG\QDPLFUHFRQILJXUDWLRQRIIXQFWLRQDOEUDLQQHWZRUNV ϵϲ ϵϳ 0DWHULDOVDQG0HWKRGV ϵϴ Participants ϵϵ $WRWDORIKHDOWK\PDOHVXEMHFWVPHDQ“6(0“\HDUVSDUWLFLSDWHGLQDUHVWLQJVWDWHI05,VHVVLRQ ϭϬϬ 6XEMHFWVUHFHLYHGQRYLVXDOVWLPXODWLRQDQGZHUHDVNHGWRUHVWEXWWRVWD\DZDNHGXULQJWKHPLQXWHVRIVFDQQLQJ ϭϬϭ 2QHDQGDKDOIKRXUVEHIRUHWKHVWDUWRIWKHUHVWLQJVWDWHVFDQPHDQ“PLQXWHVVXEMHFWVHLWKHUUHFHLYHG ϭϬϮ

DSLOOFRQWDLQLQJSODFHERn RUPJRIWKH'5EORFNHUDPLVXOSULGHn LQDGRXEOHEOLQG ϭϬϯ SVHXGRUDQGRPL]HGIDVKLRQUDWLRSODFHERWRDPLVXOSULGH*URXSVGLGQRWGLIIHUVLJQLILFDQWO\LQDJHSODFHER ϭϬϰ “\HDUVDPLVXOSULGH“\HDUVt76 p ZHLJKWSODFHER “NJ ϭϬϱ DPLVXOSULGH“NJt76 íp DQGVXEMHFWVZHUHQRWDZDUHRIZKHWKHUWKH\UHFHLYHGSODFHER ϭϬϲ RUDPLVXOSULGHDVDVVHVVHGE\DSRVWH[SHULPHQWDOTXHVWLRQQDLUHȤ2 _{p 7KHVWXG\ZDVDSSURYHG} ϭϬϳ E\WKH&DQWRQDO(WKLFV5HYLHZ%RDUGRI=XULFKDQGVXEMHFWVSURYLGHGLQIRUPHGFRQVHQWWRSDUWLFLSDWH ϭϬϴ ϭϬϵ fMRI acquisition ϭϭϬ )XQFWLRQDOLPDJLQJZDVSHUIRUPHGRQD3KLOLSV$FKLHYD7VFDQQHUHTXLSSHGZLWKDQHLJKWFKDQQHOKHDGFRLO$ ϭϭϭ WRWDORI7ZHLJKWHGZKROHEUDLQHFKRSODQDULPDJHV(3,ZLWKWUDQVYHUVHVOLFHVZHUHDFTXLUHGZLWKD ϭϭϮ UHSHWLWLRQWLPH75RIPV,PDJLQJSDUDPHWHUVZHUHDVIROORZVVOLFHWKLFNQHVVPPLQSODQHUHVROXWLRQ ϭϭϯ [PPHFKRWLPH7(PVIOLSDQJOHƒ7HPSRUDOVLJQDOWRQRLVHUDWLRW615LQWKH2)&GLG ϭϭϰ QRWGLIIHUEHWZHHQJURXSVt76 íp )RUQRUPDOL]DWLRQSXUSRVHVD7ZHLJKWHGKLJKUHVROXWLRQ[ ϭϭϱ [PPVWUXFWXUDOLPDJHZDVDFTXLUHGXVLQJWKHIROORZLQJLPDJLQJSDUDPHWHUVPDWUL[VL]H[ILHOGRI ϭϭϲ YLHZVOLFHVIOLSDQJOHƒ75 PV7( PV ϭϭϳ ϭϭϴ ϭϭϵ

Preprocessing of fMRI images ϭϮϬ 3UHSURFHVVLQJRIIXQFWLRQDOLPDJHVZDVSHUIRUPHGXVLQJ630:HOOFRPH'HSDUWPHQWRI,PDJLQJ ϭϮϭ 1HXURVFLHQFH,QVWLWXWHRI1HXURORJ\/RQGRQ8.DQGFRQVLVWHGRIVOLFHWLPHFRUUHFWLRQUHDOLJQPHQWDQG ϭϮϮ FRUHJLVWUDWLRQRIVWUXFWXUDODQGIXQFWLRQDOLPDJHV6SDWLDOQRUPDOL]DWLRQWRWKHVWDQGDUGWHPSODWHRIWKH0RQWUHDO ϭϮϯ 1HXURORJLFDO,QVWLWXWH01,ZDVSHUIRUPHGE\HVWLPDWLQJGHIRUPDWLRQILHOGVEDVHGRQWKHDQDWRPLFDOLPDJH ϭϮϰ 'HIRUPDWLRQILHOGVZHUHXVHGWRZULWHWZRVHWVRIQRUPDOL]HGIXQFWLRQDOLPDJHVRQHZLWKDYR[HOVL]HRI[[ ϭϮϱ PPPPVHWDQGRQHZLWKDYR[HOVL]HRI[[PPPPVHW%RWKVHWVZHUHVSDWLDOO\VPRRWKHGZLWKD ϭϮϲ *DXVVLDQNHUQHORIPPIXOOZLGWKDWKDOIPD[LPXP):+0 ϭϮϳ ϭϮϴ

Filtering of fMRI time series ϭϮϵ ,QGLYLGXDOI05,WLPHVHULHVZHUHILOWHUHG)R[HWDO9DQ'LMNHWDOXVLQJDJHQHUDOOLQHDUPRGHO ϭϯϬ */07KH*/0FRQWDLQHGVL[UHJUHVVRUVUHODWHGWREHWZHHQVFDQKHDGPRYHPHQWVIURPWKHUHDOLJQPHQW ϭϯϭ SURFHGXUHDFRQVWDQWWHUPDOLQHDUWUHQGWKHDYHUDJHVLJQDOIURPDZKLWHPDWWHUPDVNWKH ϭϯϮ DYHUDJHVLJQDOIURPD&6)PDVNDQGWKHDYHUDJHVLJQDOIURPDJUD\PDWWHUPDVN7KHWLPHVHULHVLQHDFK ϭϯϯ YR[HOZDVSUHGLFWHGXVLQJWKLVVHWRIUHJUHVVRUVDQGWKHUHVXOWLQJUHVLGXDOVZHUHKLJKSDVVILOWHUHGFXWRII ϭϯϰ VDQGXVHGIRUDOOVXEVHTXHQWDQDO\VHV ϭϯϱ ϭϯϲ

Orbitofrontal cortex and rest-of-brain mask ϭϯϳ 7KH2)&PDVNZDVGHILQHGXVLQJWKHIROORZLQJ$$/PDSODEHOV/HIWDQGULJKWVXSHULRURUELWDOJ\UXV ϭϯϴ OHIWDQGULJKWPLGGOHRUELWDOJ\UXVOHIWDQGULJKWLQIHULRURUELWDOJ\UXVOHIWDQG ϭϯϵ ULJKWPHGLDORUELWDOJ\UXVDQGOHIWDQGULJKWUHFWDOJ\UXV7KHUHVXOWLQJ2)&PDVN ϭϰϬ FRPELQHGYR[HOVLQWKHOHIWDQGULJKWPHGLDODQGODWHUDORUELWRIURQWDOFRUWH[7KLV2)&PDVNZDVVXEWUDFWHGIURP ϭϰϭ DZKROHEUDLQJUD\PDWWHUPDVNDQGWKHUHVXOWLQJYR[HOVZHUHGHILQHGDVWKHUHVWRIEUDLQPDVN7KXVWKHUHZDV ϭϰϮ QRRYHUODSEHWZHHQWKHUHVWRIEUDLQPDVNDQGWKH2)&PDVN ϭϰϯ ϭϰϰ Connectivity-based parcellation ϭϰϱ :HVXEGLYLGHGWKH2)&XVLQJDSUHYLRXVO\SXEOLVKHGPHWKRG.DKQWHWDO,QEULHIIRUHDFK2)&YR[HO ϭϰϲ

WKH WLPHVHULHV FRUUHODWLRQ ZLWK HYHU\ RWKHU YR[HO LQ WKH UHVWRIEUDLQ PDVN ZDV FRPSXWHG 7KH UHVXOWLQJ ϭϰϳ

FRQQHFWLYLW\ YHFWRUV RQH SHU 2)& YR[HO ZHUH WKHQ XVHG WR JURXS WRJHWKHU 2)& YR[HOV WKDW KDYH D VLPLODU ϭϰϴ FRQQHFWLYLW\SURILOHZLWKWKHUHVWRIWKHEUDLQ6LPLODUPHWKRGVKDYHEHHQXVHGWRVXEGLYLGHEUDLQUHJLRQVXVLQJ ϭϰϵ GLIIHUHQWPHDVXUHVRIFRQQHFWLYLW\VXFKDVGLIIXVLRQWUDFWRJUDSK\-RKDQVHQ%HUJHWDOUHVWLQJVWDWHI05, ϭϱϬ .HOO\HWDODQGFRDFWLYDWLRQV(LFNKRIIHWDO ϭϱϭ :HILUVWFRPSXWHGWKH3HDUVRQFRUUHODWLRQFRHIILFLHQWEHWZHHQWKHWLPHVHULHVLQHDFK2)&YR[HOIURPWKH ϭϱϮ PPVHWDQGWKHWLPHVHULHVLQHYHU\RWKHUYR[HOLQWKHUHVWRIEUDLQPDVNIURPWKHPPVHWIRUHDFKVXEMHFW ϭϱϯ

'LIIHUHQW YR[HO VL]HV ZHUH XVHG WR PDLQWDLQ KLJK VSDWLDO UHVROXWLRQ LQ WKH 2)& ZKLOH DFFRPPRGDWLQJ ϭϱϰ

FRPSXWDWLRQDODQGPHPRU\OLPLWDWLRQV7KLVUHVXOWHGLQD'FRUUHODWLRQPDWUL[1 2)&E\0 ϭϱϱ

UHVWRIEUDLQYR[HOVZKHUHHDFKURZUHIOHFWVWKHE\0ZKROHEUDLQFRQQHFWLYLW\SDWWHUQRIRQH2)&YR[HO ϭϱϲ

,PSRUWDQWO\ EHFDXVH YR[HOV ZHUH LQ 01, VSDFH HDFK YR[HO KDV DSSUR[LPDWHO\ WKH VDPH DQDWRPLFDO SRVLWLRQ ϭϱϳ

DFURVV VXEMHFWV DOORZLQJ DYHUDJLQJ RI FRQQHFWLYLW\ PDWULFHV $FFRUGLQJO\ LQGLYLGXDO PDWULFHV ZHUH DYHUDJHG ϭϱϴ DFURVVVXEMHFWVDIWHUWUDQVIRUPLQJWKHFRUUHODWLRQFRHIILFLHQWVLQWR)LVKHU¶V=VFRUHV7KHUHVXOWLQJ1E\0PDWUL[ ϭϱϵ ZDVEDFNWUDQVIRUPHGLQWR3HDUVRQFRUUHODWLRQFRHIILFLHQWVDQGFRQWDLQHGWKHDYHUDJHZKROHEUDLQFRQQHFWLYLW\ ϭϲϬ SDWWHUQVRIDOO2)&YR[HOV ϭϲϭ

7KH SDUFHOODWLRQ ZDV SHUIRUPHG XVLQJ WKHKPHDQV FOXVWHULQJ DOJRULWKP kmeans DV LPSOHPHQWHG LQ ϭϲϮ

0$7/$%XVLQJWKHµFRUUHODWLRQ¶RSWLRQLHRQHPLQXVWKHFRUUHODWLRQEHWZHHQWKHFRQQHFWLYLW\SDWWHUQVRI2)& ϭϲϯ

YR[HOVDVGLVWDQFHPHDVXUH%DVHGRQRXUSUHYLRXVVWXG\.DKQWHWDOZHFRPSXWHGFOXVWHUVROXWLRQV ϭϲϰ

ZLWKK . DQGK . FOXVWHUV )RU HDFKK WKH SDUFHOODWLRQ ZDV SHUIRUPHG WLPHV RQFH IRU WKH ϭϲϱ

SODFHERJURXSRQFHIRUWKHDPLVXOSULGHJURXSDQGRQFHIRUDOOVXEMHFWVWRJHWKHUXVLQJDZHLJKWHGDYHUDJHWR ϭϲϲ

DFFRXQW IRU WKH XQHTXDO JURXS VL]HV 7KH SDUFHOODWLRQ ZDV SHUIRUPHG IRU DOO YR[HOV LQ ERWK KHPLVSKHUHV ϭϲϳ VLPXOWDQHRXVO\7KDWLVIRUHDFKKWKHFRQQHFWLYLW\SDWWHUQVIURPDOO2)&YR[HOVZHUHVXEMHFWHGWRDVLQJOH ϭϲϴ SDUFHOODWLRQLUUHVSHFWLYHRIWKHDQDWRPLFDOSRVLWLRQLHKHPLVSKHUHRIDJLYHQYR[HO)RUHDFKKZHXVHGWKH ϭϲϵ EHVWVROXWLRQIURPUHSHWLWLRQVZLWKGLIIHUHQWLQLWLDOFHQWURLGV ϭϳϬ

1RWH WKDW WKH QRPLQDO ODEHOV DVVLJQHG WR WKH FOXVWHUV DUH DUELWUDU\ DQG GR QRW PHDVXUH DQ\WKLQJ EH\RQG ϭϳϭ

FOXVWHUidentity 7R DLG YLVXDO LQVSHFWLRQ DQG YLVXDO FRPSDULVRQ EHWZHHQ JURXSZLVH SDUFHOODWLRQV DQG DV ϭϳϮ UHTXLUHPHQWIRUFRPSDULQJWKHQXPEHURIYR[HOVSHUFOXVWHUEHWZHHQJURXSVWKHJURXSZLVHSDUFHOODWLRQVZHUH ϭϳϯ UHODEHOHGWRREMHFWLYHO\PDWFKDWHPSODWHODEHOLQJVFKHPHWDNHQIURPRXUSUHYLRXVVWXG\.DKQWHWDO ϭϳϰ )RUWKLVZHSHUPXWHGDOOKSRVVLEOHFOXVWHUODEHODVVLJQPHQWVDQGFRXQWHGWKHQXPEHURIYR[HOVIRUZKLFKWKH ϭϳϱ FOXVWHUODEHOVPDWFKHGWKHWHPSODWH:HWKHQUHODEHOHGWKHSDUFHOODWLRQZLWKWKHDVVLJQPHQWWKDWPD[LPL]HGWKLV ϭϳϲ QXPEHU9R[HOZLVHFOXVWHUPDSVLQ01,VSDFHFDQEHREWDLQHGIURPWKHFRUUHVSRQGLQJDXWKRU ϭϳϳ ϭϳϴ ϭϳϵ

Between-group comparison of parcellations ϭϴϬ :HFRPSDUHGWKHSDUFHOODWLRQVEHWZHHQWKHSODFHERDQGDPLVXOSULGHJURXSXVLQJWKHYDULDWLRQRILQIRUPDWLRQVI ϭϴϭ PHWULF0HLODZKLFKKDVSUHYLRXVO\EHHQDSSOLHGWRI05,FRQQHFWLYLW\EDVHGSDUFHOODWLRQV.HOO\HWDO ϭϴϮ .DKQWHWDO7KHVIPHWULFLVEDVHGRQPXWXDOLQIRUPDWLRQDQGPHDVXUHVWKHGLVWDQFHEHWZHHQWZR ϭϴϯ FOXVWHUVROXWLRQVCDQGC’ ϭϴϰ ܸܫሺܥǡ ܥԢሻ ൌ ܪሺܥሻ ൅ ܪሺܥԢሻ െ ʹܫሺܥǡ ܥԢሻ

ZKHUHܪሺܥሻDQGܪሺܥԢሻDUHWKHHQWURSLHVRIFOXVWHUVROXWLRQVCDQGC’UHVSHFWLYHO\DQGܫሺܥǡ ܥԢሻLVWKHPXWXDO ϭϴϱ LQIRUPDWLRQEHWZHHQCDQGC’ܪሺܥሻDQGܫሺܥǡ ܥԢሻDUHFRPSXWHGDFFRUGLQJWR ϭϴϲ ܫሺܥǡ ܥԢሻ ൌ ෍ ෍ ܲሺ݇ǡ ݇ᇱ_{ሻ݈݋݃ ቆ} ܲሺ݇ǡ ݇ᇱሻ ܲሺ݇ሻܲሺ݇ᇱ_ሻቇ ௄ᇲ ௞ᇲ_ୀଵ ௄ ௞ୀଵ ܪሺܥሻ ൌ െ ෍ ܲሺ݇ሻ݈݋݃൫ܲሺ݇ሻ൯ ௄ ௞ୀଵ ܲሺ݇ሻLVWKHSUREDELOLW\WKDWDYR[HOLQFOXVWHUVROXWLRQKEHORQJVWRFOXVWHUkDQGܲሺ݇ǡ ݇ᇱ_{ሻLVWKHSUREDELOLW\WKDWD} ϭϴϳ

YR[HOEHORQJVWRFOXVWHUkLQCDQGFOXVWHUk’LQC’)ROORZLQJ0HLODܲሺ݇ሻDQGܲሺ݇ǡ ݇ᇱሻDUHFRPSXWHG ϭϴϴ DFFRUGLQJWR ϭϴϵ ܲሺ݇ሻ ൌ݊_݊௞ ܲሺ݇ǡ ݇ᇱ_{ሻ ൌ}หܥ௞ת ܥ௞ᇱ೔ห ݊

ZKHUHnk LVWKHQXPEHURIYR[HOVLQFOXVWHUkDQGnLVWKHWRWDOQXPEHURI2)&YR[HOV/RZYDOXHV RI VILQGLFDWH

ϭϵϬ

KLJKVLPLODULW\EHWZHHQWKHWZRFOXVWHUVROXWLRQVZKHUHDVKLJKVIYDOXHVLQGLFDWHODUJHGLIIHUHQFHV ϭϵϭ

)RUVWDWLVWLFDOLQIHUHQFHZHHPSOR\HGDSHUPXWDWLRQWHVWXVLQJWKHSDUFHOODWLRQVREWDLQHGIURPn ϭϵϮ

UDQGRP JURXS DVVLJQPHQWV :H FRPSDUHG WKHVI RI WKH WZR HPSLULFDO JURXSZLVH SDUFHOODWLRQV ZLWK WKH ϭϵϯ

GLVWULEXWLRQRIVI’sRISDLUVRISDUFHOODWLRQVREWDLQHGIURPUDQGRPO\DVVLJQHGJURXSV)RUHDFKSHUPXWDWLRQZH ϭϵϰ

UDQGRPO\ DVVLJQHG VXEMHFWV WR WZR JURXSV NHHSLQJ WKH RULJLQDO JURXS VL]HV FRPSXWHG WKH JURXSZLVH ϭϵϱ SDUFHOODWLRQVIRUWKHVHQHZJURXSVDQGFRPSXWHGWKHVIEHWZHHQWKHWZRSDUFHOODWLRQV7KHHPSLULFDOO\REVHUYHG ϭϵϲ VIZDVFRQVLGHUHGVLJQLILFDQWLIODUJHUVIYDOXHVZHUHIRXQGLQOHVVWKDQRIWKHUDQGRPSDUFHOODWLRQSDLUV ϭϵϳ p ϭϵϴ ϭϵϵ

ϮϬϬ Hemispheric Symmetry ϮϬϭ 7RTXDQWLI\WKHKHPLVSKHULFV\PPHWU\RIWKHREWDLQHGSDUFHOODWLRQVZHFRPSXWHGDV\PPHWU\LQGH[SI .DKQWHW ϮϬϮ DO7KLVPHDVXUHUHIOHFWVWKHRYHUODSLQFOXVWHUODEHOVEHWZHHQKHPLVSKHUHVLIRQHKHPLVSKHUHLVPLUURUHG ϮϬϯ DWWKHPLGOLQH ϮϬϰ ܵܫ ൌ_{ܰ ෍}ͳ _ቄͳͲ ே ௜ ݂݅ݔ௜ൌ ݔԢ௜ ݋ݐ݄݁ݎݓ݅ݏ݁

ZKHUHNLVWKHQXPEHURIYR[HOVLQRQHKHPLVSKHUHDQGxDQGx’DUHWKHFOXVWHUODEHOVRIYR[HOiLQWKHRULJLQDODQG ϮϬϱ

PLUURUHGSDUFHOODWLRQUHVSHFWLYHO\%HFDXVHWKLVPHDVXUHUHTXLUHVWKDWHDFKYR[HOH[LVWVLQERWKKHPLVSKHUHVZH ϮϬϲ

RQO\LQFOXGHGYR[HOVWKDWDUHSUHVHQWLQERWKKHPLVSKHUHVDQGGLVFDUGHGDOOYR[HOVWKDWDUHSUHVHQWRQRQHVLGH ϮϬϳ

RQO\ 'LIIHUHQFHV LQ KHPLVSKHULF V\PPHWU\ ZHUH FRPSDUHG EHWZHHQ JURXSV DQG VWDWLVWLFDO LQIHUHQFH ZDV ϮϬϴ

SHUIRUPHGXVLQJDSHUPXWDWLRQWHVWZLWKn UDQGRPJURXSDVVLJQPHQWVVHHBetween-group comparison of ϮϬϵ

parcellations ϮϭϬ

Ϯϭϭ

Connectivity-based decoding of drug condition ϮϭϮ

,QRUGHUWRWHVWZKHWKHU'5EORFNDGHDOWHUHGWKHIXQFWLRQDOFRQQHFWLYLW\SURILOHRI2)&VXEUHJLRQVZHXVHGD Ϯϭϯ

EHWZHHQVXEMHFW PXOWLYDULDWH GHFRGLQJ DSSURDFK :H DLPHG WR GHFRGH WKH GUXJ FRQGLWLRQ DPLVXOSULGH YV Ϯϭϰ

SODFHER EDVHG RQ WKH ZKROHEUDLQ FRQQHFWLYLW\ SDWWHUQV RI LQGLYLGXDO 2)& VXEUHJLRQV LQ WKH . DQG . Ϯϭϱ SDUFHOODWLRQV7RDYRLGELDVHVZHXVHGWKH.DQG.SDUFHOODWLRQVFRPSXWHGIURPDOOVXEMHFWV,QFRQWUDVWWR Ϯϭϲ FRQYHQWLRQDO093$DSSURDFKHVWKDWXWLOL]HPXOWLYR[HOSDWWHUQVRIDFWLYLW\KHUHZHXVHGPXOWLYR[HOSDWWHUQVRI Ϯϭϳ IXQFWLRQDOFRQQHFWLYLW\RILQGLYLGXDO2)&VXEUHJLRQV)RUHDFKVXEMHFWZHFRPSXWHGWKHIXQFWLRQDOFRQQHFWLYLW\ Ϯϭϴ 3HDUVRQFRUUHODWLRQEHWZHHQWKHWLPHVHULHVLQHDFK2)&VXEUHJLRQDYHUDJHGDFURVVYR[HOVDQGHYHU\RWKHU Ϯϭϵ

YR[HO LQ WKH UHVWRIEUDLQ PDVN UHVXOWLQJ LQ WZR DQG VL[ E\0 FRQQHFWLYLW\ SDWWHUQV IRU . DQG . ϮϮϬ

UHVSHFWLYHO\)RUHDFKkLQKWKHVXEMHFWZLVHE\0FRQQHFWLYLW\SDWWHUQVZHUHPHDQQRUPDOL]HGDFURVVYR[HOV ϮϮϭ

UHVXOWLQJ LQ ]HURPHDQ YHFWRUV DQG XVHG DV IHDWXUH YHFWRUV LQ D VXSSRUW YHFWRU PDFKLQH 690 FODVVLILHU ϮϮϮ

ZZZFVLHQWXHGXWZaFMOLQOLEVYP ZLWK D OLQHDU NHUQHO DQG UDQGRP OHDYH WZRVXEMHFWVRXW FURVV ϮϮϯ YDOLGDWLRQVWHSV)RUHDFKFURVVYDOLGDWLRQVWHSZHUDQGRPO\GUHZVXEMHFWVIURPHDFKJURXSDVWUDLQLQJGDWD ϮϮϰ DQGIURPWKLVVXEVHWUDQGRPO\GHVLJQDWHGRQHVXEMHFWSHUJURXSDVWHVWGDWD:HWKHQXVHGWKHWUDLQLQJGDWDWR ϮϮϱ WUDLQWKH690WRGLVWLQJXLVKEHWZHHQVXEMHFWVIURPWKHWZRJURXSVEDVHGRQWKHZKROHEUDLQFRQQHFWLYLW\SDWWHUQ ϮϮϲ RIWKHkWK2)&VXEUHJLRQ7KHFODVVLILHUZDVWKHQWHVWHGRQWKHWZROHIWRXWVXEMHFWVDQGWKHSURFHGXUHZDV ϮϮϳ

UHSHDWHGIRUWKHQH[WFURVVYDOLGDWLRQVWHS'HFRGLQJDFFXUDF\LHFRUUHFWFODVVLILFDWLRQLQWKHWHVWGDWDZDV ϮϮϴ DYHUDJHGDFURVVWKHFURVVYDOLGDWLRQVWHSV ϮϮϵ )RUVWDWLVWLFDOLQIHUHQFHZHSHUIRUPHGDSHUPXWDWLRQWHVWn LQZKLFKZHFRPSDUHGWKHHPSLULFDO ϮϯϬ GHFRGLQJDFFXUDF\WRWKHGLVWULEXWLRQRIGHFRGLQJDFFXUDFLHVUHVXOWLQJIURPUDQGRPSHUPXWDWLRQVRIJURXSODEHOV Ϯϯϭ

6SHFLILFDOO\ZH UHSHDWHG WKH LGHQWLFDO VWHS FURVVYDOLGDWLRQSURFHGXUH GHVFULEHG DERYH ZLWK WKH H[FHSWLRQ ϮϯϮ WKDWDIWHUUDQGRPO\GUDZLQJVXEMHFWVDQGDVVLJQLQJWZRVXEMHFWVDVWHVWGDWDZHUDQGRPO\VKXIIOHGWKHJURXS Ϯϯϯ ODEHOVLQWKHWUDLQLQJDQGWKHWHVWGDWD7KLVZDVUHSHDWHGWLPHVWRJHQHUDWHDGLVWULEXWLRQRIDFFXUDFLHV7KH Ϯϯϰ HPSLULFDOO\REVHUYHGGHFRGLQJDFFXUDF\ZDVFRQVLGHUHGVLJQLILFDQWLIODUJHUGHFRGLQJDFFXUDFLHVZHUHIRXQGLQ Ϯϯϱ OHVVWKDQRIWKHUDQGRPSHUPXWDWLRQVp Ϯϯϲ Ϯϯϳ

Mapping of informative voxels Ϯϯϴ 7RLOOXVWUDWHWKHUHVWRIEUDLQYR[HOVIRUZKLFKIXQFWLRQDOFRQQHFWLRQVZLWK2)&VXEUHJLRQVZHUHPRGXODWHGE\ Ϯϯϵ '$ZHH[DPLQHGWKHZHLJKWYHFWRURIWKH690FODVVLILHU+RZHYHUUDWKHUWKDQGLUHFWO\XVLQJWKHZHLJKWYHFWRUV ϮϰϬ IURPWKH690GHFRGLQJLHEDFNZDUGPRGHOZHILUVWFRQVWUXFWHGDQHQFRGLQJLHIRUZDUGPRGHOEDVHGRQ Ϯϰϭ WKHVHZHLJKWVDFFRUGLQJWR+DXIHHWDO ϮϰϮ ܣ ൌ ܵ௫ܹܵ௚ିଵ

:KHUHWLV WKHZHLJKWYHFWRURIWKH690GHFRGHUDQG6[DQG6JDUHWKHFRYDULDQFH PDWULFHVRIWKHWUDLQLQJ Ϯϰϯ

IHDWXUHVDQGODEHOVUHVSHFWLYHO\ Ϯϰϰ

,Q FRQWUDVW WR WKH ZHLJKWV RI EDFNZDUG PRGHOV WKH ZHLJKWV RI IRUZDUG PRGHOV FDQ EH LQWHUSUHWHG DV Ϯϰϱ UHIOHFWLQJWKHFRQWULEXWLRQRILQGLYLGXDOYR[HOVWRWKHVHSDUDWLRQEHWZHHQWKHWZRJURXSV:HDYHUDJHGWKHYR[HO Ϯϰϲ ZLVHIRUZDUGZHLJKWVDFURVVWKHFURVVYDOLGDWLRQVWHSVDQGGLYLGHGHDFKZHLJKWDYHUDJHE\WKHFRUUHVSRQGLQJ Ϯϰϳ VWDQGDUGGHYLDWLRQ7KLVUHVXOWHGLQZVFRUHVWKDWIRUDJLYHQ2)&VXEUHJLRQUHIOHFWWKHFRQWULEXWLRQRIYR[HO Ϯϰϴ ZLVHFRQQHFWLYLW\WRWKHVHSDUDWLRQEHWZHHQJURXSV:HUHSRUWFRQQHFWLRQVWKDWH[FHHGDWKUHVKROGRIp Ϯϰϵ

%RQIHUURQL FRUUHFWHG IRU WKH QXPEHU RI UHVWRIEUDLQ YR[HOV Z ! DQG WKDW H[FHHG D FOXVWHU H[WHQW RI ϮϱϬ YR[HOV)RULOOXVWUDWLRQSXUSRVHVZHGLVSOD\WKHFRQQHFWLYLW\PDSVDWDWKUHVKROGRIpXQFRUUHFWHGZ! Ϯϱϭ ZLWKDFOXVWHUVL]HRI!YR[HOV ϮϱϮ Ϯϱϯ 5HVXOWV Ϯϱϰ

Connectivity-based parcellation of the OFC Ϯϱϱ

%DVHGRQRXUSUHYLRXVILQGLQJV.DKQWHWDOZHVXEGLYLGHGWKH2)&LQWR.DQG.VXEUHJLRQVE\ Ϯϱϲ JURXSLQJWRJHWKHUYR[HOVWKDWKDYHDVLPLODUSDWWHUQRIFRQQHFWLYLW\ZLWKWKHUHVWRIWKHEUDLQ,QDILUVWVWHSZH Ϯϱϳ IRFXVHGRQWKHSODFHERJURXSWRUHYHDOWKHIXQFWLRQDORUJDQL]DWLRQZKHQQHXURPRGXODWRU\DFWLYLW\LVXQGLVWXUEHG Ϯϱϴ 7KH.SDUFHOODWLRQVHSDUDWHGHDFKKHPLVSKHUHLQWRDPHGLDODQGDQWHULRUODWHUDOVXEUHJLRQ)LJXUH$ Ϯϱϵ 7KHYHQWURPHGLDOZDOODUHDVP0DFNH\DQG3HWULGHVWKHJ\UXVUHFWXVDUHDVPUF ϮϲϬ SRVWHULRUDQGSRVWHULRUODWHUDODUHDVDUHDRIRUPHGDQHWZRUNZKHUHDVWKHUHPDLQGHURIWKH2)&LH Ϯϲϭ FHQWUDODUHDDQWHULRUDUHDDQGDQWHULRUODWHUDODUHDVPIRUPHGDQRWKHUQHWZRUNZLWKFRKHVLYH ϮϲϮ FRQQHFWLYLW\SDWWHUQV Ϯϲϯ ,QOLQHZLWKRXUSUHYLRXVILQGLQJV.DKQWHWDOWKH.SDUFHOODWLRQUHYHDOHGDPHGLDOD Ϯϲϰ SRVWHULRUPHGLDODFHQWUDODQGWKUHHODWHUDOFOXVWHUVVSDQQLQJWKHDQWHULRUSRVWHULRUJUDGLHQW)LJXUH Ϯϲϱ $,QWHUPVRIF\WRDUFKLWHFWXUHWKHPHGLDOFOXVWHURFFXSLHGPRVWRIWKHYHQWURPHGLDOZDOODUHDVP Ϯϲϲ PLQDGGLWLRQWRDVPDOOIRFDOSDUWRIWKHODWHUDOSRVWHULRU2)&DUHD7KHSRVWHULRUPHGLDOFOXVWHU Ϯϲϳ FRQVLVWHGRIODUJHSDUWVRIWKHJ\UXVUHFWXVDUHDPUFDVZHOODVSDUWVRIPRUHODWHUDOSRVWHULRUDUHDV Ϯϲϴ DUHD5HJLRQVDWWKHLQWHUVHFWLRQRIWKHWUDQVYHUVHDQGPHGLDORUELWDOVXOFXVDUHDIRUPHGDFHQWUDO Ϯϲϵ FOXVWHU)LQDOO\WKHWKUHHODWHUDOFOXVWHUVRFFXSLHGWKHSRVWHULRUODWHUDODUHDRPLGODWHUDODUHDVP ϮϳϬ DQGDQWHULRUODWHUDODUHDVVXUIDFH2YHUDOOERWKWKH.DQG.SDUFHOODWLRQVLQWKHSODFHERJURXSZHUH Ϯϳϭ KLJKO\VLPLODUWRRXUSUHYLRXVILQGLQJV.DKQWHWDO ϮϳϮ Ϯϳϯ

Dopamine changes the connectivity-based parcellation of the OFC Ϯϳϰ

:HQH[WH[DPLQHGKRZDOWHULQJGRSDPLQHUJLFQHXURWUDQVPLVVLRQWKURXJK'5EORFNDGHPRGXODWHGWKH Ϯϳϱ

FRQQHFWLYLW\EDVHGSDUFHOODWLRQVGHVFULEHGDERYH6LPLODUWRWKHSODFHERJURXSWKH.VROXWLRQLQWKH Ϯϳϲ

DPLVXOSULGHJURXSUHYHDOHGDPHGLDODQGDDQWHULRUODWHUDOFOXVWHU)LJXUH%&RPSDUHGWRWKHSODFHER Ϯϳϳ JURXSWKHDQWHULRUODWHUDOFOXVWHUDSSHDUHGQDUURZHUDQGPRUHVWUHWFKHGDORQJWKHDQWHULRUSRVWHULRUD[LVGLYLGLQJ Ϯϳϴ WKHPHGLDOFOXVWHULQWRDPHGLDODQGSRVWHULRUODWHUDOVHJPHQW+RZHYHUGHVSLWHWKHVHTXDOLWDWLYHGLIIHUHQFHVD Ϯϳϵ TXDQWLWDWLYHVWDWLVWLFDOFRPSDULVRQRIWKHSDUFHOODWLRQVEHWZHHQWKHWZRJURXSVXVLQJWKHVIPHWULFUHYHDOHGWKDW ϮϴϬ WKHGLIIHUHQFHVLQWKH.SDUFHOODWLRQDUHZLWKLQWKHUDQJHRIZKDWFDQEHH[SHFWHGE\FKDQFHp )LJXUH Ϯϴϭ &,QOLQHZLWKWKLVWKHUHZHUHQRVLJQLILFDQWGLIIHUHQFHVEHWZHHQJURXSVLQKHPLVSKHULFV\PPHWU\SODFHERSI ϮϴϮ

DPLVXOSULGHSI p SHUPXWDWLRQWHVW)LJXUH$RUFOXVWHUVL]HVp )LJXUH&

Ϯϴϯ 7KHVHILQGLQJVPD\LQGLFDWHWKDWWKHFOXVWHURUJDQL]DWLRQRIWKH2)&ZDVQRWVXEVWDQWLDOO\DOWHUHGE\FKDQJHVLQ Ϯϴϰ GRSDPLQHUJLFQHXURWUDQVPLVVLRQ Ϯϴϱ ,QFRQWUDVW'5EORFNDGHDSSHDUHGWRKDYHFDXVHGPRUHSURQRXQFHGFKDQJHVLQWKH.SDUFHOODWLRQ Ϯϴϲ )LJXUH%,QGHHGDSHUPXWDWLRQWHVWXVLQJWKHVIPHWULFUHYHDOHGWKDWWKH.SDUFHOODWLRQVZHUHVLJQLILFDQWO\ Ϯϴϳ

GLIIHUHQWEHWZHHQWKHWZRJURXSVp )LJXUH&4XDOLWDWLYHO\ZKLOHWKHPHGLDODQGSRVWHULRU Ϯϴϴ PHGLDOFOXVWHUDSSHDUHGUHODWLYHO\VLPLODUWRWKHSODFHERJURXSQRFOHDUO\GHILQHGFHQWUDOFOXVWHUFRXOGEH Ϯϴϵ REVHUYHGLQWKHDPLVXOSULGHJURXS,QVWHDGDIRXUWKFOXVWHUZDVUHYHDOHGRQWKHODWHUDOVXUIDFHEHWZHHQWKH ϮϵϬ DQWHULRUODWHUDODQGPLGODWHUDOFOXVWHUV,QOLQHZLWKWKLVWKHQXPEHURIYR[HOVDVVLJQHGWRWKHFHQWUDOFOXVWHU Ϯϵϭ ZDVVLJQLILFDQWO\ODUJHULQWKHDPLVXOSULGHFRPSDUHGWRWKHSODFHERJURXSDPLVXOSULGHN SODFHERN ϮϵϮ p )LJXUH'ZKLOHWKHVL]HRIWKHRWKHUFOXVWHUVGLGQRWGLIIHUVLJQLILFDQWO\DOOp!,Q Ϯϵϯ DGGLWLRQWKHKHPLVSKHULFV\PPHWU\ZDVVLJQLILFDQWO\ODUJHULQWKHSODFHERJURXSSODFHERSI DPLVXOSULGH Ϯϵϰ SI p )LJXUH%VXJJHVWLQJWKDW'5EORFNDGHGLVWXUEHGWKHV\PPHWU\RIWKHIXQFWLRQDO2)& Ϯϵϱ QHWZRUNV7DNHQWRJHWKHUWKHVHUHVXOWVGHPRQVWUDWHWKDWWKHFRQQHFWLYLW\EDVHGSDUFHOODWLRQRIWKH2)&ZDV Ϯϵϲ FKDQJHGE\'5EORFNDGHVXJJHVWLQJWKDW'$UHFRQILJXUHVIXQFWLRQDO2)&QHWZRUNV Ϯϵϳ Ϯϵϴ

Dopamine alters connectivity patterns of individual OFC subregions Ϯϵϵ 7KHUHVXOWVUHSRUWHGDERYHVXJJHVWWKDWWKHIXQFWLRQDOFRQQHFWLYLW\EHWZHHQLQGLYLGXDO2)&YR[HOVDQGWKHUHVWRI ϯϬϬ WKHEUDLQZDVV\VWHPDWLFDOO\DOWHUHGE\'5EORFNDGHLQGLFDWLQJD'$GHSHQGHQWUHFRQILJXUDWLRQRIIXQFWLRQDO ϯϬϭ 2)&QHWZRUNV,QSULQFLSOH'$LQGXFHGFKDQJHVLQWKHIXQFWLRQDOFRQQHFWLYLW\RIWKH2)&FRXOGEHORFDOL]HGWR ϯϬϮ VSHFLILFSDUWVRIWKHEUDLQRUFRXOGLQYROYHWKHVLPXOWDQHRXVPRGXODWLRQRIGLVWULEXWHGORQJUDQJHFRQQHFWLRQV ϯϬϯ 7RGLUHFWO\WHVWIRUVXFKFKDQJHVLQWKHFRQQHFWLYLW\SDWWHUQVRI2)&VXEUHJLRQVZHXWLOL]HGDPXOWLYDULDWH ϯϬϰ GHFRGLQJDSSURDFK6SHFLILFDOO\IRUHDFKVXEUHJLRQLQWKH.DQG.SDUFHOODWLRQZHXVHGLWVZKROHEUDLQ ϯϬϱ FRQQHFWLYLW\SDWWHUQWRGHFRGHZKHWKHUVXEMHFWVKDGUHFHLYHGSODFHERRUDPLVXOSULGHSULRUWRVFDQQLQJ,QRUGHUWR ϯϬϲ

DYRLGELDVHVZHXVHGDSDUFHOODWLRQWKDWZDVEDVHGRQDOOVXEMHFWV)LJXUH$DQG%KRZHYHUFRPSDUDEOH ϯϬϳ UHVXOWVZHUHREWDLQHGZKHQXVLQJWKHSDUFHOODWLRQEDVHGRQWKHSODFHERJURXSRQO\ ϯϬϴ 'HFRGLQJRIJURXSPHPEHUVKLSIURPWKHZKROHEUDLQFRQQHFWLYLW\SDWWHUQVRIERWKFOXVWHUVLQWKH. ϯϬϵ SDUFHOODWLRQZDVVLJQLILFDQWO\DERYHFKDQFHPHGLDOFOXVWHU>@DFFXUDF\ pDQWHULRUODWHUDO ϯϭϬ

FOXVWHU>@DFFXUDF\ p )LJXUH&,QWKH.SDUFHOODWLRQZHIRXQGWKDWGUXJFRQGLWLRQFRXOG ϯϭϭ EHGHFRGHGVLJQLILFDQWO\DERYHFKDQFHIURPWKHFRQQHFWLYLW\SDWWHUQVRIDOOEXWWZR2)&VXEUHJLRQV6LJQLILFDQW ϯϭϮ GHFRGLQJDFFXUDFLHVZHUHIRXQGLQWKHPHGLDODFFXUDF\ p SRVWHULRUPHGLDODFFXUDF\ ϯϭϯ pFHQWUDODFFXUDF\ pDQGDQWHULRUODWHUDOFOXVWHUDFFXUDF\ p ϯϭϰ 7KHGHFRGLQJDFFXUDFLHVLQWKHSRVWHULRUODWHUDODFFXUDF\ p DQGPLGODWHUDO ϯϭϱ FOXVWHUDFFXUDF\ p ZHUHQRWVLJQLILFDQWO\GLIIHUHQWIURPFKDQFH,QVXPPDU\'5EORFNDGH ϯϭϲ PRGXODWHGWKHZKROHEUDLQFRQQHFWLYLW\SDWWHUQVRIPHGLDODQGFHQWUDO2)&VHFWRUVZKLOHOHDYLQJFRQQHFWLYLW\RI ϯϭϳ WKHSRVWHULRUODWHUDOFOXVWHUVXQDIIHFWHG ϯϭϴ

7RUHYHDOWKHEUDLQUHJLRQVLQZKLFKWKHFRQQHFWLYLW\WRLQGLYLGXDO2)&VXEUHJLRQVZDVPRGXODWHGE\'5 ϯϭϵ EORFNDGHZHXVHGWKHZHLJKWVRIWKH690FODVVLILHUWRHVWLPDWHYR[HOZLVHFRQQHFWLYLW\SDWWHUQVWKDW ϯϮϬ GLVWLQJXLVKHGEHWZHHQJURXSV+DXIHHWDO)RUWKH.SDUFHOODWLRQ'5EORFNDGHHQKDQFHGFRQQHFWLYLW\ ϯϮϭ RIWKHPHGLDO2)&FOXVWHUZLWKWKHDP\JGDODKLSSRFDPSXVWKHVXSHULRUIURQWDOJ\UXVWKHDQWHULRUFLQJXODWH ϯϮϮ

FRUWH[WKHSRVWHULRULQVXODDQGWKHDQWHULRULQIHULRUDQGPLGGOHWHPSRUDOJ\UXV)LJXUH$7DEOH ϯϮϯ &RQYHUVHO\DPLVXOSULGHUHGXFHGFRQQHFWLYLW\RIWKHPHGLDO2)&FOXVWHUZLWKSRVWHULRULQIHULRUWHPSRUDOJ\UXV ϯϮϰ IXVLIRUPJ\UXVSUHFXQHXVDQGLQIHULRUDQGVXSHULRUSDULHWDOOREH,QWKHDQWHULRUODWHUDOFOXVWHU'5 ϯϮϱ EORFNDGHHQKDQFHGFRQQHFWLYLW\ZLWKWKHPHGLDODQGPLGGOHIURQWDOJ\UXVDQGWKHSRVWHULRULQVXODDQGUHGXFHG ϯϮϲ FRQQHFWLYLW\ZLWKWKHPLGEUDLQWKHIXVLIRUPJ\UXVWKHSUHFXQHXVDQGWKHVXSHULRUSDULHWDOOREH)LJXUH% ϯϮϳ 7DEOH ϯϮϴ ,QWKH.SDUFHOODWLRQ'5EORFNDGHHQKDQFHGFRQQHFWLYLW\EHWZHHQWKHPHGLDO2)&FOXVWHUDQGWKH ϯϮϵ VXSHULRUDQGPLGGOHIURQWDOJ\UXVWKHDQWHULRUFLQJXODWHFRUWH[DQGWKHLQIHULRUDQGPLGGOHWHPSRUDOJ\UXV,Q ϯϯϬ FRQWUDVWVXEMHFWVLQWKHDPLVXOSULGHJURXSVKRZHGUHGXFHGPHGLDO2)&FRQQHFWLYLW\ZLWKWKHIXVLIRUPJ\UXVDQG ϯϯϭ

VXSHULRUSDULHWDOOREH)LJXUH$7DEOH,QWXUQ'5EORFNDGHHQKDQFHGFRQQHFWLYLW\RIWKHSRVWHULRUPHGLDO ϯϯϮ

2)&FOXVWHUZLWKWKHOHIWDP\JGDODKLSSRFDPSXVDQGWKHPLGGOHIURQWDOJ\UXVZKLOHFRQQHFWLYLW\ZLWKWKH ϯϯϯ

DQWHULRULQVXODDQGWKHSUHFXHQXVZDVUHGXFHG)LJXUH%7DEOH)RUWKHFHQWUDOFOXVWHU'5EORFNDGH ϯϯϰ

HQKDQFHGFRQQHFWLYLW\ZLWKWKHPLGGOHWHPSRUDOOREHDQGWKHIXVLIRUPJ\UXV+RZHYHUWKHPRVWSURIRXQG ϯϯϱ

FKDQJHZDVDPDUNHGUHGXFWLRQLQFRQQHFWLYLW\WRWKHPLGEUDLQDQGWKHVXSHULRUWHPSRUDOJ\UXVSRVWHULRULQVXOD ϯϯϲ

)LJXUH&7DEOH)LQDOO\IRUWKHDQWHULRUODWHUDO2)&FOXVWHU'5EORFNDGHHQKDQFHGFRQQHFWLYLW\ZLWK ϯϯϳ

ODWHUDODQGPHGLDODUHDVRIWKH3)&WKHDQWHULRUFLQJXODWHFRUWH[DQGWKHPLGGOHWHPSRUDOJ\UXV,QFRQWUDVW ϯϯϴ

DPLVXOSULGHUHGXFHGFRQQHFWLYLW\RIWKHDQWHULRUODWHUDO2)&ZLWKWKHHQWRUKLQDOFRUWH[WKHSRVWHULRU ϯϯϵ

KLSSRFDPSXVDQGWKHSUHFXQHXV)LJXUH'7DEOH:HGLGQRWH[DPLQHGRSDPLQHGHSHQGHQWPRGXODWLRQRI ϯϰϬ FRQQHFWLYLW\LQWKHSRVWHULRUODWHUDODQGPLGODWHUDO2)&FOXVWHUVEHFDXVHWKHGHFRGLQJDQDO\VHVUHSRUWHG ϯϰϭ DERYHLQGLFDWHGWKDWWKHFRQQHFWLYLW\SDWWHUQVRIWKHVH2)&VXEUHJLRQVZHUHQRWVLJQLILFDQWO\PRGXODWHGE\'5 ϯϰϮ EORFNDGH ϯϰϯ ϯϰϰ 'LVFXVVLRQ ϯϰϱ ,QWKHFXUUHQWVWXG\ZHXVHGUHVWLQJVWDWHI05,FRQQHFWLYLW\DQGKPHDQVFOXVWHULQJDQGGHPRQVWUDWHGWKDW ϯϰϲ V\VWHPLFDGPLQLVWUDWLRQRIDPLVXOSULGHDGRSDPLQHUJLF'5DQWDJRQLVWDOWHUHGWKHFRQILJXUDWLRQRIFRQQHFWLRQDO ϯϰϳ DQGSUHVXPDEO\IXQFWLRQDOVXEUHJLRQVLQWKH2)&0RUHRYHU'5EORFNDGHKDGVSHFLILFHIIHFWVRQYR[HOZLVH ϯϰϴ FRQQHFWLYLW\SDWWHUQVRILQGLYLGXDO2)&VXEUHJLRQVDVLQGLFDWHGE\VLJQLILFDQWGHFRGLQJRIJURXSPHPEHUVKLS ϯϰϵ DPLVXOSULGHYVSODFHERIURPWKHVHSDWWHUQV$PLVXOSULGHGHFUHDVHGWKHFRQQHFWLYLW\EHWZHHQ2)&DQG ϯϱϬ

DVVRFLDWLYHSDULHWDODQGWHPSRUDOUHJLRQVDQGHQKDQFHGFRQQHFWLYLW\RI2)&VXEUHJLRQVZLWKWKHPHGLDODQG ϯϱϭ VXSHULRUODWHUDOIURQWDOFRUWH[ ϯϱϮ 3UHYLRXVVWXGLHVKDYHH[DPLQHGWKHHIIHFWVRIGRSDPLQHUJLFQHXURWUDQVPLVVLRQRQODUJHVFDOHI05, ϯϱϯ FRQQHFWLYLW\GXULQJUHVW&ROHHWDOD&ROHHWDOEDQGWDVNSHUIRUPDQFH+RQH\HWDO ϯϱϰ 1DJDQR6DLWRHWDO5HVXOWVRIWKHVHHDUOLHUVWXGLHVLQGLFDWHWKDW'$KDVSURIRXQGHIIHFWVRQORQJUDQJH ϯϱϱ FRQQHFWLYLW\EHWZHHQIURQWDOSDULHWDODQGVXEFRUWLFDOEUDLQUHJLRQV+RZHYHUWKHVHVWXGLHVFRPSDUHG ϯϱϲ FRQQHFWLYLW\ZLWKLQSUHGHILQHGUHJLRQVRILQWHUHVWRU³UHVWLQJVWDWHQHWZRUNV´HJWKHVRFDOOHG³GHIDXOWPRGH´ ϯϱϳ QHWZRUNDQGZHUHWKHUHIRUHQRWVXLWDEOHWRH[DPLQHWKHHIIHFWVRI'$RQWKHFRQILJXUDWLRQRIIXQFWLRQDOFLUFXLWV ϯϱϴ WKHPVHOYHV ϯϱϵ ,QFRQWUDVWKHUHZHXVHGDGDWDGULYHQPHWKRGWRGHILQHIXQFWLRQDO2)&VXEUHJLRQVEDVHGRQZKROHEUDLQ ϯϲϬ FRQQHFWLYLW\SDWWHUQVRILQGLYLGXDO2)&YR[HOV%DVHGRQRXUHDUOLHUVWXG\.DKQWHWDODQDWRPLFDO ϯϲϭ WUDFLQJZRUNLQSULPDWHV&DUPLFKDHODQG3ULFH2QJXUDQG3ULFHDQGWKHUHVXOWVRIDPHWDDQDO\WLF ϯϲϮ FRQQHFWLYLW\PRGHOLQJVWXG\=DOGHWDOZHIRFXVHGRQWKHSDUFHOODWLRQVZLWKDQGVXEGLYLVLRQV7KH ϯϲϯ SDUFHOODWLRQVREWDLQHGLQWKHSODFHERJURXSZHUHKLJKO\VLPLODUWRWKRVHIRXQGLQRXUSUHYLRXVVWXG\.DKQWHWDO ϯϲϰ ZKHUHDVWKHSDUFHOODWLRQLQWKHDPLVXOSULGHJURXSUHYHDOHGVSHFLILFFKDQJHVLQWKHRUJDQL]DWLRQRI ϯϲϱ IXQFWLRQDO2)&VXEUHJLRQV6SHFLILFDOO\ZKHUHDVWKH.SDUFHOODWLRQGLGQRWGLIIHUEHWZHHQJURXSVWKH ϯϲϲ RUJDQL]DWLRQRIWKH.SDUFHOODWLRQGLIIHUHGIXQGDPHQWDOO\SDUWLFXODUO\ZLWKUHJDUGWRWKHFHQWUDO2)&FOXVWHU ϯϲϳ )ROORZXSDQDO\VHVLQGLFDWHGWKDW'5EORFNDGHZDVDVVRFLDWHGZLWKDPDUNHGUHGXFWLRQLQWKHFRQQHFWLYLW\ ϯϲϴ EHWZHHQWKHFHQWUDO2)&DQGWKHPLGEUDLQVXJJHVWLQJWKDWUHODWLYHWRRWKHUSDUWVRI2)&FHQWUDO2)&UHFHLYHV ϯϲϵ WKHVWURQJHVW'$SURMHFWLRQVIURPWKHPLGEUDLQ ϯϳϬ :KLOHQXOOUHVXOWVVKRXOGEHLQWHUSUHWHGZLWKFDXWLRQWKHDEVHQFHRIVLJQLILFDQW'$GHSHQGHQWFKDQJHVLQ ϯϳϭ WKH.VXEGLYLVLRQPD\LPSO\WKDWWKLVVXEGLYLVLRQVFKHPHLVQRWPRGXODWHGE\'$DQGWKDW'$GHSHQGHQW ϯϳϮ PRGXODWLRQVRQO\RFFXUDWDILQHUVFDOH6XEUHJLRQVLQWKH.SDUFHOODWLRQDUHZHOOLQOLQHZLWKDQDWRPLFDO ϯϳϯ ERXQGDULHVGHILQHGF\WRDUFKLWHFWRQLFDOO\DQGEDVHGRQDQDWRPLFDOFRQQHFWLRQV7KHPHGLDOFOXVWHUFRUUHVSRQGVWR ϯϳϰ WKHDJUDQXODUDQGG\VJUDQXODULHQRQLVRFRUWLFDOSDUWRI2)&DQGUHFHLYHVVXEVWDQWLDOLQSXWIURPWKH ϯϳϱ KLSSRFDPSXVDQGWKHDP\JGDOD,QFRQWUDVWWKHODWHUDODQWHULRUFOXVWHUFRUUHVSRQGVFORVHO\WRWKHJUDQXODULH ϯϳϲ LVRFRUWLFDO2)&DQGUHFHLYHVVWURQJSURMHFWLRQVIURPWKH3)&WKHLQVXODWKHWHPSRUDOFRUWH[DQGWKHPHGLDO ϯϳϳ GRUVDOWKDODPXV0RUHFUDIWHWDO7KLVIROGSDUFHOODWLRQVFKHPHLVDOVRFRQVLVWHQWZLWKVXEGLYLVLRQV ϯϳϴ EDVHGRQLQWULQVLFDQDWRPLFDOFRQQHFWLRQVRIWKHSULPDWH2)&&DUPLFKDHODQG3ULFH.DKQWHWDO ϯϳϵ +RZHYHUDOWKRXJK'5EORFNDGHGLGQRWDOWHUWKHRXWOLQHVRIWKH.VXEGLYLVLRQLWGLGPRGXODWHWKHIXQFWLRQDO ϯϴϬ FRQQHFWLYLW\SDWWHUQVRIWKHVHVXEUHJLRQVVXJJHVWLQJWKDWZKLOHWKHFRQILJXUDWLRQRIWKHFRDUVHIXQFWLRQDOQHWZRUN ϯϴϭ ZDVQRWDIIHFWHGE\'$WKHVSHFLILFEDODQFHRIFRQQHFWLRQVZLWKLQWKHQHWZRUNZDVFKDQJHG ϯϴϮ

7KHUHFRQILJXUDWLRQREVHUYHGLQWKH.SDUFHOODWLRQLVOLNHO\WREHGULYHQE\D'$GHSHQGHQWPRGXODWLRQRI ϯϴϯ WKHFRQQHFWLRQVEHWZHHQLQGLYLGXDO2)&YR[HOVDQGUHPRWHEUDLQUHJLRQV$WWKHFHOOXODUOHYHODPLVXOSULGHDFWV ϯϴϰ DVDQDQWDJRQLVWRQ'DQG'UHFHSWRUVDQGUHGXFHVWKHSRVWV\QDSWLFHIIHFWVRI'$RQQHXURQV5RVHQ]ZHLJHW ϯϴϱ DO,QDGGLWLRQDPLVXOSULGHEORFNVSUHV\QDSWLFDXWRUHFHSWRUVHIIHFWLYHO\LQFUHDVLQJWKHDYDLODELOLW\RI'$ ϯϴϲ LQWKHV\QDSWLFFOHIW$FFRUGLQJO\DQ\FRPELQDWLRQRISUHDQGSRVWV\QDSWLFUHFHSWRUEORFNDGHZLOOWKHUHIRUH ϯϴϳ LQFUHDVHWKHUDWLRRI'WR'UHFHSWRUDFWLYDWLRQ%\PRGXODWLQJWKHLQWULQVLFILULQJSURSHUWLHVRILQGLYLGXDO ϯϴϴ QHXURQV'$PD\FKDQJHWKHVWUHQJWKRIVSHFLILFV\QDSVHVDQGWKHUHE\WKHFRQQHFWLYLW\WRRWKHUQHXURQV ϯϴϵ HIIHFWLYHO\DOWHULQJWKHUROHRILQGLYLGXDOQHXURQVLQLWVODUJHUFLUFXLW.ORSSHQEXUJHWDO+DUULV:DUULFN ϯϵϬ DQG-RKQVRQ6XFKFKDQJHVDUHQRWQHFHVVDULO\ELQDU\VZLWFKHVLHRQRIIEHWZHHQFRQQHFWLRQVEXW ϯϵϭ FRXOGLQYROYHVPRRWKWUDQVLWLRQVLQWKHFRPSRVLWLRQRILQWHUFRQQHFWHGQHWZRUNV,QWHUHVWLQJO\QHXURPRGXODWRU ϯϵϮ LQGXFHGFKDQJHVLQFRQQHFWLYLW\PD\EHDVVRFLDWHGZLWKGLIIHUHQWPRGHVRIRSHUDWLRQUHVSRQVLEOHIRUGLIIHUHQW ϯϵϯ EHKDYLRUV+DUULV:DUULFNDQG0DUGHU:HLPDQQDQG0DUGHU7KHKDUGZLUHGDQDWRPLFDO ϯϵϰ FRQQHFWLRQVEHWZHHQEUDLQUHJLRQVPD\WKHUHIRUHRQO\SURYLGHWKHVWUXFWXUHLQZKLFKVHYHUDOSRVVLEOHIXQFWLRQDO ϯϵϱ QHWZRUNVHDFKDVVRFLDWHGZLWKVSHFLILFSURFHVVLQJPRGHVDQGEHKDYLRUVFDQEHLQLWLDOL]HGGHSHQGLQJRQWKH ϯϵϲ FXUUHQWQHXURPRGXODWRU\HQYLURQPHQW%UH]LQD0DUGHU ϯϵϳ 2XUUHVXOWVVKRZWKDWFRQQHFWLRQVEHWZHHQLQGLYLGXDO2)&VXEUHJLRQVDQGKLJKHURUGHUVHQVRU\DQG ϯϵϴ PXOWLPRGDODVVRFLDWLRQDUHDVLQWKHSDULHWDODQGWHPSRUDOOREHVZHUHGDPSHQHGE\'5EORFNDGH,QFRQWUDVW ϯϵϵ FRQQHFWLYLW\EHWZHHQWKH2)&DQGWKHPHGLDODQGVXSHULRU3)&ZHUHXSUHJXODWHGE\DPLVXOSULGH7KLVVXJJHVWV ϰϬϬ WKDW'$DFWLYLW\RQ'5VZLWFKHVWKH2)&EHWZHHQWZRGLVWLQFWFRQQHFWLRQDOFRQILJXUDWLRQVWKDWPD\EH ϰϬϭ DVVRFLDWHGZLWKGLIIHUHQWSURFHVVLQJPRGHV7KHILUVWFRQILJXUDWLRQLQGXFHGE\KLJKOHYHOVRI'5DFWLYLW\LV ϰϬϮ FKDUDFWHUL]HGE\HQKDQFHGFRQQHFWLYLW\WRKLJKHUVHQVRU\DQGDVVRFLDWLYHDUHDVDQGPD\KHOSVHQVRU\LQIRUPDWLRQ ϰϬϯ WRDFFHVVWKH2)&$VHFRQGFRQILJXUDWLRQLQGXFHGE\ORZ'5DFWLYLW\LVFKDUDFWHUL]HGE\HQKDQFHGVKRUW ϰϬϰ UDQJHIXQFWLRQDOFRQQHFWLRQVZLWKWKHIURQWDOOREHVDQGPD\IDFLOLWDWHORFDOLQIRUPDWLRQSURFHVVLQJLQWKHIURQWDO ϰϬϱ FRUWH[ ϰϬϲ 7KLVSURSRVDOLVLQOLQHZLWKWKHHIIHFWVRIUHFHSWRUVSHFLILF'$DFWLYLW\LQDELRSK\VLFDOO\LQVSLUHGGXDO ϰϬϳ VWDWHPRGHORI'$LQWKH3)&'XUVWHZLW]HWDO6HDPDQVHWDO6SHFLILFDOO\LQWKLVPRGHOWKHUDWLR ϰϬϴ RI'DQG'UHFHSWRUDFWLYLW\PRGXODWHVORFDO*$%$HUJLFLQKLELWLRQDQGWKHUHE\FRQWUROVWKHEDODQFHEHWZHHQ ϰϬϵ WKHVWDELOLW\DQGIOH[LELOLW\RI3)&UHSUHVHQWDWLRQV5HGXFHG'5DFWLYLW\IDFLOLWDWHVUHFXUUHQWH[FLWDWLRQLQWKH ϰϭϬ QHWZRUNDQGVWDELOL]LQJ3)&UHSUHVHQWDWLRQVZKHUHDVHQKDQFHG'5DFWLYLW\LQKLELWVUHFXUUHQWH[FLWDWLRQDQG ϰϭϭ LQFUHDVHVWKHIOH[LELOLW\RI3)&UHSUHVHQWDWLRQV6HDPDQVDQG<DQJ6XSSRUWLQJWKLVPRGHOZHKDYH ϰϭϮ SUHYLRXVO\VKRZQWKDW'5EORFNDGHHQKDQFHVGHFRGLQJRIUHZDUGLQIRUPDWLRQIURP2)&DFWLYLW\SDWWHUQV ϰϭϯ VXJJHVWLQJWKDWFRUUHVSRQGLQJQHWZRUNVUHSUHVHQWDWLRQVZHUHVWUHQJWKHQHG.DKQWHWDO ϰϭϰ

,PSRUWDQWO\VZLWFKHVEHWZHHQWKHWZR2)&QHWZRUNFRQILJXUDWLRQVFRXOGEHLPSOHPHQWHGVROHO\E\ ϰϭϱ FKDQJHVLQORFDO'$FRQFHQWUDWLRQV6SHFLILFDOO\'$KDVDKLJKHUDIILQLW\IRU'WKDQ'UHFHSWRUV&UHHVHHW ϰϭϲ DODQGWKHUHIRUHORZOHYHOVRI'$PD\OHDGWRVWURQJHU'YV'DFWLYLW\ZKHUHDVUREXVWDFWLYLW\RI' ϰϭϳ UHFHSWRUVLVRQO\DFKLHYHGZLWKKLJKOHYHOVRI'$*RWRDQG*UDFH7KXVEXUVWVRI'$OLNHWKRVHHOLFLWHG ϰϭϴ E\XQH[SHFWHGUHZDUGVRUUHZDUGSUHGLFWLYHVWLPXOL6FKXOW]HWDO6FKXOW]PD\GULYHWKH2)&LQWR ϰϭϵ D'GRPLQDWHGVWDWHZLWKHQKDQFHGFRQQHFWLYLW\WRIURQWDOEUDLQUHJLRQVDQGUHGXFHGFRQQHFWLYLW\WRVHQVRU\ ϰϮϬ DUHDVSURPRWLQJORFDOLQIRUPDWLRQSURFHVVLQJDQGUHSUHVHQWDWLRQDOVWDELOLW\&RQYHUVHO\ORZOHYHOVRI'$OLNH ϰϮϭ WKRVHREVHUYHGZKHQH[SHFWHGUHZDUGVDUHRPLWWHG%D\HUDQG*OLPFKHU7DNDKDVKLHWDOPD\ ϰϮϮ SUHIHUHQWLDOO\DFWLYDWH'UHFHSWRUVZKLFKPD\UHGXFHFRQQHFWLRQVWRWKH3)&HQKDQFHVHQVRU\LQSXWWRWKH2)& ϰϮϯ DQGIDFLOLWDWHUHRULHQWDWLRQUHSUHVHQWDWLRQDOXSGDWLQJDQGEHKDYLRUDOIOH[LELOLW\,QWHUHVWLQJO\DUHFHQWPRGHORI ϰϮϰ 2)&IXQFWLRQLQJSURSRVHVWKDW2)&FRQWULEXWHVWRJRDOGLUHFWHGEHKDYLRUE\UHSUHVHQWLQJDFRJQLWLYHPDSRU ϰϮϱ DVVRFLDWLYHVWUXFWXUHIRUUHLQIRUFHPHQWOHDUQLQJ:LOVRQHWDO+RZDUGHWDO6FKXFNHWDO ϰϮϲ :LNHQKHLVHUDQG6FKRHQEDXP2XUUHVXOWVLQGLFDWHWKDW'$PD\SOD\DFULWLFDOUROHLQXSGDWLQJRI2)& ϰϮϳ VWDWHUHSUHVHQWDWLRQV ϰϮϴ ,WLVLPSRUWDQWWRQRWHWKDWDOWKRXJKDPLVXOSULGHLVRQHRIWKHIHZUHODWLYHO\VHOHFWLYHGUXJVDIIHFWLQJ'$ ϰϮϵ WUDQVPLVVLRQLWDOVRKDVKLJKDIILQLW\IRUVHURWRQLQUHFHSWRUV+7%DQG+7$FFRUGLQJO\WKHHIIHFWV ϰϯϬ REVHUYHGKHUHPD\QRWEHWKHUHVXOWRI'$DORQH+RZHYHULQVRIDUDVVHURWRQLQDQG'$DUHERWKPRQRDPLQHV ϰϯϭ ZHFDQFRQFOXGHWKDWRXUUHVXOWVDUHGULYHQE\PRQRDPLQHUJLFQHXURPRGXODWRUV:HDOVRQRWHWKDWFRQQHFWLYLW\ ϰϯϮ FKDQJHVEHWZHHQWKH2)&DQGDQ\RWKHUEUDLQUHJLRQPD\EHFDXVHGLQGLUHFWO\WKURXJKFRQQHFWLYLW\FKDQJHV ϰϯϯ EHWZHHQWKLVUHJLRQDQGDWKLUGUHJLRQZKRVHFRQQHFWLYLW\WR2)&LVPRGXODWHGE\'$7KXV2)&FRQQHFWLYLW\ ϰϯϰ FKDQJHVZLWKLQGLYLGXDODUHDVQHHGWREHLQWHUSUHWHGZLWKFDXWLRQDVLQGLUHFWPRGXODWLRQVFDQQRWEHUXOHGRXW ϰϯϱ )LQDOO\LQWKHFXUUHQWVWXG\ZHH[DPLQHGWKHHIIHFWVRI'5EORFNDGHRQFRQQHFWLYLW\GXULQJUHVW,WLVSRVVLEOH ϰϯϲ WKDW2)&QHWZRUNVDUHGLIIHUHQWLDOO\PRGXODWHGGXULQJSHUIRUPDQFHRIVSHFLILFWDVNV)XQFWLRQDOFRQQHFWLYLW\ ϰϯϳ EHWZHHQDUHDVSDUWLDOO\GHSHQGVRQWDVNGHSHQGHQWDFWLYLW\OHYHOVZKLFKPD\UHVXOWLQGLIIHUHQWSDUFHOODWLRQ ϰϯϴ VFKHPHV)XWXUHVWXGLHVDUHQHHGHGWRH[DPLQH2)&QHWZRUNFRQILJXUDWLRQVDVDIXQFWLRQRIGLIIHUHQWWDVNV ϰϯϵ ,QVXPPDU\KHUHZHKDYHVKRZQWKDW'5EORFNDGHFKDQJHVWKHIXQFWLRQDORUJDQL]DWLRQRIWKH2)&:H ϰϰϬ VSHFXODWHWKDWPLGEUDLQ'$PD\DOWHUWKHFRQQHFWLRQDOFRQILJXUDWLRQRIWKH2)&OHDGLQJWRWUDQVLWLRQVEHWZHHQ ϰϰϭ GLIIHUHQWRSHUDWLQJPRGHVWKDWIDYRUHLWKHUVHQVRU\LQSXWRUUHFXUUHQWSURFHVVLQJ)LQDOO\WKHUHVXOWVREWDLQHG ϰϰϮ KHUHIRU'$FRXOGH[HPSOLI\DPRUHJHQHUDOUROHRIQHXURPRGXODWRUVLQDOWHULQJWKHFRQQHFWLYLW\SDWWHUQVRIEUDLQ ϰϰϯ UHJLRQV7KLVFKDQJHLQFRQQHFWLYLW\PD\OHDGWRWKHUHFRQILJXUDWLRQRIVSHFLILFIXQFWLRQDOFLUFXLWVWKDWPD\EH ϰϰϰ DVVRFLDWHGZLWKGLIIHUHQWPRGHVRILQIRUPDWLRQSURFHVVLQJDQGXOWLPDWHO\GLVWLQFWEHKDYLRUV ϰϰϱ

5HIHUHQFHV ϰϰϲ %D\HU+0*OLPFKHU3:0LGEUDLQGRSDPLQHQHXURQVHQFRGHDTXDQWLWDWLYHUHZDUGSUHGLFWLRQHUURU ϰϰϳ VLJQDO1HXURQ ϰϰϴ %UH]LQD9%H\RQGWKHZLULQJGLDJUDPVLJQDOOLQJWKURXJKFRPSOH[QHXURPRGXODWRUQHWZRUNV3KLORV ϰϰϵ 7UDQV56RF/RQG%%LRO6FL ϰϱϬ &DUPLFKDHO673ULFH-/$UFKLWHFWRQLF6XEGLYLVLRQRIWKH2UELWDODQG0HGLDO3UHIURQWDO&RUWH[LQWKH ϰϱϭ 0DFDTXH0RQNH\-RXUQDORI&RPSDUDWLYH1HXURORJ\ ϰϱϮ &DUPLFKDHO673ULFH-/&RQQHFWLRQDOQHWZRUNVZLWKLQWKHRUELWDODQGPHGLDOSUHIURQWDOFRUWH[RI ϰϱϯ PDFDTXHPRQNH\V-&RPS1HXURO ϰϱϰ &DYDGD&&RPSDQ\77HMHGRU-&UX]5L]]ROR5-5HLQRVR6XDUH])7KHDQDWRPLFDOFRQQHFWLRQVRIWKH ϰϱϱ PDFDTXHPRQNH\RUELWRIURQWDOFRUWH[$UHYLHZ&HUHE&RUWH[ ϰϱϲ &HWLQ7)UHXGHQEHUJ))XFKWHPHLHU0.RFK0'RSDPLQHLQWKHRUELWRIURQWDOFRUWH[UHJXODWHVRSHUDQW ϰϱϳ UHVSRQGLQJXQGHUDSURJUHVVLYHUDWLRRIUHLQIRUFHPHQWLQUDWV1HXURVFL/HWW ϰϱϴ &ODUNH+)&DUGLQDO515\JXOD5+RQJ<7)U\HU7'6DZLDN6-)HUUDUL9&RFNFURIW*$LJELUKLR), ϰϱϵ 5REELQV7:5REHUWV$&2UELWRIURQWDOGRSDPLQHGHSOHWLRQXSUHJXODWHVFDXGDWHGRSDPLQHDQG ϰϲϬ DOWHUVEHKDYLRUYLDFKDQJHVLQUHLQIRUFHPHQWVHQVLWLYLW\-1HXURVFL ϰϲϭ &ROH'0%HFNPDQQ&)2HL1<%RWK6YDQ*HUYHQ-05RPERXWV6$D'LIIHUHQWLDODQGGLVWULEXWHG ϰϲϮ HIIHFWVRIGRSDPLQHQHXURPRGXODWLRQVRQUHVWLQJVWDWHQHWZRUNFRQQHFWLYLW\1HXURLPDJH ϰϲϯ &ROH'02HL1<6RHWHU53%RWK6YDQ*HUYHQ-05RPERXWV6$%HFNPDQQ&)E'RSDPLQH ϰϲϰ GHSHQGHQWDUFKLWHFWXUHRIFRUWLFRVXEFRUWLFDOQHWZRUNFRQQHFWLYLW\&HUHE&RUWH[ ϰϲϱ &RROV57KHFRVWVDQGEHQHILWVRIEUDLQGRSDPLQHIRUFRJQLWLYHFRQWURO:LOH\,QWHUGLVFLS5HY&RJQ6FL ϰϲϲ ϰϲϳ &UHHVH,6LEOH\'5+DPEOLQ0:/HII6(7KHFODVVLILFDWLRQRIGRSDPLQHUHFHSWRUVUHODWLRQVKLSWR ϰϲϴ UDGLROLJDQGELQGLQJ$QQX5HY1HXURVFL ϰϲϵ 'XUVWHZLW]'6HDPDQV-.6HMQRZVNL7-'RSDPLQHPHGLDWHGVWDELOL]DWLRQRIGHOD\SHULRGDFWLYLW\LQD ϰϳϬ QHWZRUNPRGHORISUHIURQWDOFRUWH[-1HXURSK\VLRO ϰϳϭ (LFNKRII6%%]GRN'/DLUG$55RVNL&&DVSHUV6=LOOHV.)R[37&RDFWLYDWLRQSDWWHUQVGLVWLQJXLVK ϰϳϮ FRUWLFDOPRGXOHVWKHLUFRQQHFWLYLW\DQGIXQFWLRQDOGLIIHUHQWLDWLRQ1HXURLPDJH ϰϳϯ )R[0'=KDQJ'6Q\GHU$=5DLFKOH0(7KHJOREDOVLJQDODQGREVHUYHGDQWLFRUUHODWHGUHVWLQJVWDWH ϰϳϰ EUDLQQHWZRUNV-1HXURSK\VLRO ϰϳϱ *ROGPDQ5DNLF36/LGRZ066PLOH\-):LOOLDPV067KHDQDWRP\RIGRSDPLQHLQPRQNH\DQGKXPDQ ϰϳϲ SUHIURQWDOFRUWH[-1HXUDO7UDQVP6XSSO ϰϳϳ *RWR<*UDFH$$'RSDPLQHUJLFPRGXODWLRQRIOLPELFDQGFRUWLFDOGULYHRIQXFOHXVDFFXPEHQVLQJRDO ϰϳϴ GLUHFWHGEHKDYLRU1DW1HXURVFL ϰϳϵ +DUULV:DUULFN500DUGHU(0RGXODWLRQRIQHXUDOQHWZRUNVIRUEHKDYLRU$QQX5HY1HXURVFL ϰϴϬ +DUULV:DUULFN50-RKQVRQ%5&KHFNVDQGEDODQFHVLQQHXURPRGXODWLRQ)URQW%HKDY1HXURVFL ϰϴϭ +DXIH60HLQHFNH)*RUJHQ.'DKQH6+D\QHV-'%ODQNHUW]%%LHVVPDQQ)2QWKHLQWHUSUHWDWLRQRI ϰϴϮ ZHLJKWYHFWRUVRIOLQHDUPRGHOVLQPXOWLYDULDWHQHXURLPDJLQJ1HXURLPDJH ϰϴϯ +RQH\*'6XFNOLQJ-=HOD\D)/RQJ&5RXWOHGJH&-DFNVRQ61J9)OHWFKHU3&:LOOLDPV6&%URZQ-ϰϴϰ %XOOPRUH(7'RSDPLQHUJLFGUXJHIIHFWVRQSK\VLRORJLFDOFRQQHFWLYLW\LQDKXPDQFRUWLFRVWULDWR ϰϴϱ WKDODPLFV\VWHP%UDLQ ϰϴϲ +RZDUG-'*RWWIULHG-$7REOHU31.DKQW7,GHQWLW\VSHFLILFFRGLQJRIIXWXUHUHZDUGVLQWKHKXPDQ ϰϴϳ RUELWRIURQWDOFRUWH[3URF1DWO$FDG6FL86$ ϰϴϴ -RKDQVHQ%HUJ+%HKUHQV7(5REVRQ0''UREQMDN,5XVKZRUWK0)%UDG\-06PLWK60+LJKDP'-ϰϴϵ 0DWWKHZV30&KDQJHVLQFRQQHFWLYLW\SURILOHVGHILQHIXQFWLRQDOO\GLVWLQFWUHJLRQVLQKXPDQ ϰϵϬ PHGLDOIURQWDOFRUWH[3URF1DWO$FDG6FL86$ ϰϵϭ .DKQW7&KDQJ/-3DUN64+HLQ]OH-+D\QHV-'&RQQHFWLYLW\EDVHGSDUFHOODWLRQRIWKHKXPDQ ϰϵϮ RUELWRIURQWDOFRUWH[-1HXURVFL ϰϵϯ .DKQW7:HEHU6&+DNHU+5REELQV7:7REOHU31'RSDPLQH'UHFHSWRUEORFNDGHHQKDQFHV ϰϵϰ GHFRGLQJRISUHIURQWDOVLJQDOVLQKXPDQV-1HXURVFL ϰϵϱ

.HOO\&8GGLQ/46KHK]DG=0DUJXOLHV'6&DVWHOODQRV);0LOKDP033HWULGHV0%URFDVUHJLRQ ϰϵϲ OLQNLQJKXPDQEUDLQIXQFWLRQDOFRQQHFWLYLW\GDWDDQGQRQKXPDQSULPDWHWUDFLQJDQDWRP\VWXGLHV(XU-ϰϵϳ 1HXURVFL ϰϵϴ .ORSSHQEXUJ3/HYLQL50+DUULV:DUULFN50'RSDPLQHPRGXODWHVWZRSRWDVVLXPFXUUHQWVDQGLQKLELWV ϰϵϵ WKHLQWULQVLFILULQJSURSHUWLHVRIDQLGHQWLILHGPRWRUQHXURQLQDFHQWUDOSDWWHUQJHQHUDWRUQHWZRUN-ϱϬϬ 1HXURSK\VLRO ϱϬϭ .ULQJHOEDFK0/5ROOV(77KHIXQFWLRQDOQHXURDQDWRP\RIWKHKXPDQRUELWRIURQWDOFRUWH[HYLGHQFHIURP ϱϬϮ QHXURLPDJLQJDQGQHXURSV\FKRORJ\3URJ1HXURELRO ϱϬϯ 0DFNH\63HWULGHV04XDQWLWDWLYHGHPRQVWUDWLRQRIFRPSDUDEOHDUFKLWHFWRQLFDUHDVZLWKLQWKH ϱϬϰ YHQWURPHGLDODQGODWHUDORUELWDOIURQWDOFRUWH[LQWKHKXPDQDQGWKHPDFDTXHPRQNH\EUDLQV(XU-ϱϬϱ 1HXURVFL ϱϬϲ 0DUGHU(1HXURPRGXODWLRQRIQHXURQDOFLUFXLWVEDFNWRWKHIXWXUH1HXURQ ϱϬϳ 0HLOD0&RPSDULQJFOXVWHULQJVDQLQIRUPDWLRQEDVHGGLVWDQFH-0XOWLYDULDWH$QDO ϱϬϴ 0LOOHU(.&RKHQ-'$QLQWHJUDWLYHWKHRU\RISUHIURQWDOFRUWH[IXQFWLRQ$QQX5HY1HXURVFL ϱϬϵ 0RUHFUDIW5-*HXOD&0HVXODP00&\WRDUFKLWHFWXUHDQGQHXUDODIIHUHQWVRIRUELWRIURQWDOFRUWH[LQWKH ϱϭϬ EUDLQRIWKHPRQNH\-&RPS1HXURO ϱϭϭ 1DJDQR6DLWR$/H\WRQ00RQFKL2*ROGEHUJ<.+H<'DJKHU$'RSDPLQHGHSOHWLRQLPSDLUV ϱϭϮ IURQWRVWULDWDOIXQFWLRQDOFRQQHFWLYLW\GXULQJDVHWVKLIWLQJWDVN-1HXURVFL ϱϭϯ 2QJXU'3ULFH-/7KHRUJDQL]DWLRQRIQHWZRUNVZLWKLQWKHRUELWDODQGPHGLDOSUHIURQWDOFRUWH[RIUDWV ϱϭϰ PRQNH\VDQGKXPDQV&HUHE&RUWH[ ϱϭϱ 3DGRD6FKLRSSD&1HXURELRORJ\RIHFRQRPLFFKRLFHDJRRGEDVHGPRGHO$QQX5HY1HXURVFL ϱϭϲ ϱϭϳ 5RVHQ]ZHLJ3&DQDO03DWDW$%HUJRXJQDQ/=LHOHQLXN,%LDQFKHWWL*$UHYLHZRIWKH ϱϭϴ SKDUPDFRNLQHWLFVWROHUDELOLW\DQGSKDUPDFRG\QDPLFVRIDPLVXOSULGHLQKHDOWK\YROXQWHHUV+XP ϱϭϵ 3V\FKRSKDUPDFRO ϱϮϬ 5XGHEHFN3+0XUUD\($7KHRUELWRIURQWDORUDFOHFRUWLFDOPHFKDQLVPVIRUWKHSUHGLFWLRQDQGHYDOXDWLRQ ϱϮϭ RIVSHFLILFEHKDYLRUDORXWFRPHV1HXURQ ϱϮϮ 5XVKZRUWK0).ROOLQJ16DOOHW-0DUV5%9DOXDWLRQDQGGHFLVLRQPDNLQJLQIURQWDOFRUWH[RQHRU ϱϮϯ PDQ\VHULDORUSDUDOOHOV\VWHPV"&XUU2SLQ1HXURELRO ϱϮϰ 6FKXFN1:&DL0%:LOVRQ5&1LY<+XPDQ2UELWRIURQWDO&RUWH[5HSUHVHQWVD&RJQLWLYH0DSRI ϱϮϱ 6WDWH6SDFH1HXURQ ϱϮϲ 6FKXOW]:'RSDPLQHUHZDUGSUHGLFWLRQHUURUVLJQDOOLQJDWZRFRPSRQHQWUHVSRQVH1DW5HY1HXURVFL ϱϮϳ ϱϮϴ 6FKXOW]:'D\DQ30RQWDJXH35$QHXUDOVXEVWUDWHRISUHGLFWLRQDQGUHZDUG6FLHQFH ϱϮϵ 6HDPDQV-.<DQJ&57KHSULQFLSDOIHDWXUHVDQGPHFKDQLVPVRIGRSDPLQHPRGXODWLRQLQWKHSUHIURQWDO ϱϯϬ FRUWH[3URJ1HXURELRO ϱϯϭ 6HDPDQV-.*RUHORYD1'XUVWHZLW]'<DQJ&5%LGLUHFWLRQDOGRSDPLQHPRGXODWLRQRI*$%$HUJLF ϱϯϮ LQKLELWLRQLQSUHIURQWDOFRUWLFDOS\UDPLGDOQHXURQV-1HXURVFL ϱϯϯ 6HVFRXVVH*5HGRXWH-'UHKHU-&7KHDUFKLWHFWXUHRIUHZDUGYDOXHFRGLQJLQWKHKXPDQRUELWRIURQWDO ϱϯϰ FRUWH[-1HXURVFL ϱϯϱ 6WDOQDNHU7$&RRFK1.6FKRHQEDXP*:KDWWKHRUELWRIURQWDOFRUWH[GRHVQRWGR1DW1HXURVFL ϱϯϲ ϱϯϳ 6ZDQVRQ/:7KHSURMHFWLRQVRIWKHYHQWUDOWHJPHQWDODUHDDQGDGMDFHQWUHJLRQVDFRPELQHGIOXRUHVFHQW ϱϯϴ UHWURJUDGHWUDFHUDQGLPPXQRIOXRUHVFHQFHVWXG\LQWKHUDW%UDLQ5HV%XOO ϱϯϵ 7DNDKDVKL<.5RHVFK056WDOQDNHU7$+DQH\5=&DOX'-7D\ORU$5%XUNH.$6FKRHQEDXP* ϱϰϬ 7KHRUELWRIURQWDOFRUWH[DQGYHQWUDOWHJPHQWDODUHDDUHQHFHVVDU\IRUOHDUQLQJIURPXQH[SHFWHGRXWFRPHV ϱϰϭ 1HXURQ ϱϰϮ 9DQ'LMN.5+HGGHQ79HQNDWDUDPDQ$(YDQV.&/D]DU6:%XFNQHU5/,QWULQVLFIXQFWLRQDO ϱϰϯ FRQQHFWLYLW\DVDWRROIRUKXPDQFRQQHFWRPLFVWKHRU\SURSHUWLHVDQGRSWLPL]DWLRQ-1HXURSK\VLRO ϱϰϰ ϱϰϱ

:DONHU6&5REELQV7:5REHUWV$&'LIIHUHQWLDOFRQWULEXWLRQVRIGRSDPLQHDQGVHURWRQLQWR ϱϰϲ RUELWRIURQWDOFRUWH[IXQFWLRQLQWKHPDUPRVHW&HUHE&RUWH[ ϱϰϳ :HLPDQQ-00DUGHU(6ZLWFKLQJ1HXURQV$UH,QWHJUDO0HPEHUVRI0XOWLSOH2VFLOODWRU\1HWZRUNV ϱϰϴ &XUUHQW%LRORJ\ ϱϰϵ :LNHQKHLVHU$06FKRHQEDXP*2YHUWKHULYHUWKURXJKWKHZRRGVFRJQLWLYHPDSVLQWKHKLSSRFDPSXV ϱϱϬ DQGRUELWRIURQWDOFRUWH[1DWXUHUHYLHZV1HXURVFLHQFH ϱϱϭ :LOVRQ5&7DNDKDVKL<.6FKRHQEDXP*1LY<2UELWRIURQWDOFRUWH[DVDFRJQLWLYHPDSRIWDVNVSDFH ϱϱϮ 1HXURQ ϱϱϯ :LQVWDQOH\&$=HHE)'%HGDUG$)X./DL%6WHHOH&:RQJ$&'RSDPLQHUJLFPRGXODWLRQRIWKH ϱϱϰ RUELWRIURQWDOFRUWH[DIIHFWVDWWHQWLRQPRWLYDWLRQDQGLPSXOVLYHUHVSRQGLQJLQUDWVSHUIRUPLQJWKHILYH ϱϱϱ FKRLFHVHULDOUHDFWLRQWLPHWDVN%HKDY%UDLQ5HV ϱϱϲ =DOG'+5DXFK6/7KHRUELWRIURQWDOFRUWH[VWSDSHUEDFN(GLWLRQ2[IRUG1HZ<RUN2[IRUG ϱϱϳ 8QLYHUVLW\3UHVV ϱϱϴ =DOG'+0F+XJR05D\./*ODKQ'&(LFNKRII6%/DLUG$50HWDDQDO\WLFFRQQHFWLYLW\PRGHOLQJ ϱϱϵ UHYHDOVGLIIHUHQWLDOIXQFWLRQDOFRQQHFWLYLW\RIWKHPHGLDODQGODWHUDORUELWRIURQWDOFRUWH[&HUHE&RUWH[ ϱϲϬ ϱϲϭ ϱϲϮ

)LJXUH/HJHQGV ϱϲϯ )LJXUH&RQQHFWLYLW\EDVHGSDUFHOODWLRQRIWKH2)&LQWR.VXEUHJLRQV$IROGFOXVWHULQJLQWKHSODFHER ϱϲϰ

JURXS%IROGFOXVWHULQJLQWKHDPLVXOSULGHJURXS&+LVWRJUDPRIYDULDWLRQRILQIRUPDWLRQVIYDOXHV ϱϲϱ FRPSDULQJSDLUVRI.SDUFHOODWLRQVIURPUDQGRPJURXSDVVLJQPHQWV5HGYHUWLFDOOLQHGHSLFWVWKHVIYDOXH ϱϲϲ FRPSDULQJWKHDFWXDOJURXSZLVHSDUFHOODWLRQVRIWKHSODFHERDQGDPLVXOSULGHJURXS ϱϲϳ ϱϲϴ )LJXUH&RQQHFWLYLW\EDVHGSDUFHOODWLRQRIWKH2)&LQWR.VXEUHJLRQV$IROGFOXVWHULQJLQWKHSODFHER ϱϲϵ

JURXS%IROGFOXVWHULQJLQWKHDPLVXOSULGHJURXS&+LVWRJUDPRIVIYDOXHVFRPSDULQJSDLUVRI. ϱϳϬ SDUFHOODWLRQVIURPUDQGRPJURXSDVVLJQPHQWV5HGYHUWLFDOOLQHGHSLFWVWKHVIYDOXHFRPSDULQJWKHDFWXDOJURXS ϱϳϭ ZLVHSDUFHOODWLRQVRIWKHSODFHERDQGDPLVXOSULGHJURXS$VWHULVNLQGLFDWHVDVLJQLILFDQWJURXSGLIIHUHQFHIURP ϱϳϮ FKDQFHDWp ϱϳϯ ϱϳϰ )LJXUH&RPSDULVRQRIJURXSZLVHSDUFHOODWLRQV$+LVWRJUDPRIWKHGLIIHUHQFHLQKHPLVSKHULFV\PPHWU\ ϱϳϱ EHWZHHQWKHSDLUVRI.SDUFHOODWLRQVIURPUDQGRPO\DVVLJQHGJURXSV5HGYHUWLFDOOLQHGHSLFWVWKHHPSLULFDO ϱϳϲ GLIIHUHQFHLQKHPLVSKHULFV\PPHWU\EHWZHHQWKHSODFHERDQGDPLVXOSULGHJURXS%VDPHDVLQ$EXWIRUWKH. ϱϳϳ

SDUFHOODWLRQ&(DFKKLVWRJUDPGHSLFWVWKHGLIIHUHQFHLQWKHFOXVWHUVL]HQXPEHURIYR[HOVEHWZHHQWZRJURXSV ϱϳϴ

UDQGRPO\DVVLJQHGJURXSVLQFOXVWHUWRSDQGERWWRPRIWKH.SDUFHOODWLRQ5HGYHUWLFDOOLQHVGHSLFWWKH ϱϳϵ

HPSLULFDOGLIIHUHQFHLQFOXVWHUVL]HEHWZHHQWKHSODFHERDQGDPLVXOSULGHJURXS'6DPHDVLQ&EXWIRUWKH. ϱϴϬ SDUFHOODWLRQ$VWHULVNVLQGLFDWHVLJQLILFDQWGLIIHUHQFHVIURP]HURDWp ϱϴϭ ϱϴϮ )LJXUH'HFRGLQJGUXJFRQGLWLRQIURPFRQQHFWLYLW\SDWWHUQVRILQGLYLGXDO2)&VXEUHJLRQV$. ϱϴϯ

SDUFHOODWLRQEDVHGRQDOOVXEMHFWV%.SDUFHOODWLRQEDVHGRQDOOVXEMHFWV&'HFRGLQJDFFXUDF\FRUUHFW ϱϴϰ JURXSFODVVLILFDWLRQVRISODFHERYVDPLVXOSULGHIRUHDFKRIWKHWZR2)&VXEUHJLRQVRIWKH.SDUFHOODWLRQ' ϱϴϱ 'HFRGLQJDFFXUDF\IRUHDFKRIWKHVL[2)&VXEUHJLRQVRIWKH.SDUFHOODWLRQ(UURUEDUVLQGLFDWH&,DURXQG ϱϴϲ HPSLULFDOFKDQFHOHYHOaEDVHGRQUDQGRPSHUPXWDWLRQV$VWHULVNVLQGLFDWHVLJQLILFDQWDERYHFKDQFH ϱϴϳ FODVVLILFDWLRQDWpFRUUHFWHG ϱϴϴ ϱϴϵ )LJXUH(IIHFWVRI'5EORFNDGHRQYR[HOZLVH2)&FRQQHFWLYLW\RI.VXEUHJLRQV0DSVGHSLFWWKH ϱϵϬ FRQWULEXWLRQRIWKHYR[HOZLVHFRQQHFWLYLW\RIWKHPHGLDO$DQGODWHUDO%2)&VXEUHJLRQRIWKH. ϱϵϭ SDUFHOODWLRQWRWKHVHSDUDWLRQEHWZHHQWKHDPLVXOSULGHDQGSODFHERJURXS&RQQHFWLYLW\SDWWHUQVDUHHVWLPDWHG ϱϵϮ

EDVHGRQ690ZHLJKWYHFWRUVDQGWKHQFRQYHUWHGLQWRZVFRUHV)RULOOXVWUDWLRQSXUSRVHVPDSVDUHWKUHVKROGHG ϱϵϯ DWpXQFRUUHFWHGZ!ZLWKDYR[HOH[WHQWWKUHVKROGRI ϱϵϰ ϱϵϱ )LJXUH(IIHFWVRI'5EORFNDGHRQYR[HOZLVH2)&FRQQHFWLYLW\RI.VXEUHJLRQV0DSVGHSLFWWKH ϱϵϲ

FRQWULEXWLRQRIWKHYR[HOZLVHFRQQHFWLYLW\RIWKHPHGLDO$SRVWHULRUPHGLDO%FHQWUDO&DQGDQWHULRU ϱϵϳ

ODWHUDO'2)&VXEUHJLRQRIWKH.SDUFHOODWLRQWRWKHVHSDUDWLRQEHWZHHQWKHDPLVXOSULGHDQGSODFHERJURXS ϱϵϴ

&RQQHFWLYLW\SDWWHUQVDUHHVWLPDWHGEDVHGRQ690ZHLJKWYHFWRUVDQGWKHQFRQYHUWHGLQWRZVFRUHV)RU ϱϵϵ

LOOXVWUDWLRQSXUSRVHVPDSVDUHWKUHVKROGHGDWpXQFRUUHFWHGZ!ZLWKDYR[HOH[WHQWWKUHVKROGRI ϲϬϬ

7DEOH/HJHQGV ϲϬϮ 7DEOH$QDWRPLFDOODEHOV01,FRRUGLQDWHV[\]ZVFRUHVDQGFOXVWHUVL]HQXPEHURIYR[HOVIRUZKROH ϲϬϯ EUDLQFRQQHFWLYLW\RILQGLYLGXDO2)&VXEUHJLRQVLQWKH.SDUFHOODWLRQFRQWULEXWLQJWRWKHVHSDUDWLRQEHWZHHQ ϲϬϰ JURXSVWKUHVKROGHGDWp%RQIHUURQLFRUUHFWHGZ!DQGk! ϲϬϱ ϲϬϲ 7DEOH$QDWRPLFDOODEHOV01,FRRUGLQDWHV[\]ZVFRUHVDQGFOXVWHUVL]HQXPEHURIYR[HOVIRUZKROH ϲϬϳ EUDLQFRQQHFWLYLW\RILQGLYLGXDO2)&VXEUHJLRQVLQWKH.SDUFHOODWLRQFRQWULEXWLQJWRWKHVHSDUDWLRQEHWZHHQ ϲϬϴ JURXSVWKUHVKROGHGDWp%RQIHUURQLFRUUHFWHGZ!DQGk! ϲϬϵ

120

2

2

1

1

2

1

1

2

80 40 0 1.4 1.2 1 .8 .6 .4 variation of information # clusterings

A

B

C

placebo vs. amisulpride

1

1

120 80 40 0 1.8 1.6 1.4 1.2 1 variation of information # clusterings

A

B

C

placebo vs. amisulpride

2

2

3

3

4

4

5

5

6

6

1

1

1

2

2

3

3

4

4

5

5

6

6

1

1

1

*

0.2 0 -0.2 hemispheric symmetry 0.2 0 -0.2 hemispheric symmetry 120 80 40 0 # clusterings # clusterings # clusterings 200 150 50 100 0 # clusterings K6: pla. > amisulp. K6: pla. > amisulp. K2: pla. > amisulp. K2: pla. > amisulp.

A

B

C

D

# voxel clust. 1 -1000 0 1000 0 # voxel clust. 2 -1000 0 1000 0 # voxel clust. 5 -500 0 500 0 300 150 300 200

*

# clusterings # clusterings # voxel clust. 3 -500 0 500 0 # voxel clust. 2 -500 0 500 0 # voxel clust. 6 -500 0 500 # voxel clust. 1 -500 0 500 # voxel clust. 4 -200 0 400 0 0 0 100 200 100 150

*

2 1 1 2 1 2 2 3 3 ₄ 4 5 5 6 6 _{1 1} 1 1

OFC subregion2 1 2OFC subregion3 4 5 6

70 %-correct classification 10 30 50 70 %-correct classification 10 30 50

*

*

*

*

*

*

A

C

B

D

K2 - cluster 1 K2 - cluster 2

A

B

placebo > amisulpride

K6 - cluster 1 K6 - cluster 3

A

B

K6 - cluster 2 K6 - cluster 6

C

D

placebo > amisulpride amisulpride > placebo Z = 3.72 Z = 4.72 Z = 3.72 Z = 4.72

ϭ

7DEOH'RSDPLQHGHSHQGHQWFRQQHFWLYLW\RIVXEUHJLRQVLQWKH.SDUFHOODWLRQ

6LGH $QDWRPLFDOODEHO 01,[\] 1YR[HO =VFRUH

Cluster 1 - Amisulpride > Placebo

/ DP\JGDODKLSSRFDPSXV / VXSHULRUIURQWDOJ\UXV 5 VXSHULRUIURQWDOJ\UXV / DQWHULRUFLQJXODWHFRUWH[ / VXSHULRUIURQWDOJ\UXV / PLGGOHIURQWDOJ\UXV / LQVXOD 5 LQVXOD / PLGGOHWHPSRUDOJ\UXV 5 PLGGOHWHPSRUDOJ\UXV / PLGGOHWHPSRUDOJ\UXV / LQIHULRUWHPSRUDOFRUWH[ 5 LQIHULRUWHPSRUDOFRUWH[ / SUHFXQHXV / LQIHULRUSDULHWDOOREH

Cluster 1 - Placebo > Amisulpride

5 PLGGOHIURQWDOJ\UXV 5 VXSHULRUIURQWDOJ\UXV 5 SUHFHQWUDOJ\UXV / SRVWFHQWUDOJ\UXV / PLGGOHWHPSRUDOJ\UXV / IXVLIRUPJ\UXV 5 IXVLIRUPJ\UXV / SUHFXQHXV 5 SUHFXQHXV 5 VXSHULRUSDULHWDOOREH / LQIHULRUSDULHWDOOREH 5 LQIHULRUSDULHWDOOREH 5 RFFLSLWDOFRUWH[

Cluster 3 - Amisulpride > Placebo

/ PHGLDOIURQWDOJ\UXV

/ PLGGOHIURQWDOJ\UXV

/ LQVXOD

Cluster 2 - Placebo > Amisulpride

5 PLGEUDLQ

/ )XVLIRUPJ\UXV

/ SUHFXQHXV

/ VXSHULRUSDULHWDOOREH

7DEOH'RSDPLQHGHSHQGHQWFRQQHFWLYLW\RIVXEUHJLRQVLQWKH.SDUFHOODWLRQ

6LGH 5HJLRQ 01,[\] 1YR[HO =VFRUH

Cluster 1 - Amisulpride > Placebo

/ VXSHULRUIURQWDOJ\UXV / VXSHULRUIURQWDOJ\UXV / VXSHULRUIURQWDOJ\UXV 5 VXSHULRUIURQWDOJ\UXV / PLGGOHIURQWDOJ\UXV / DQWHULRUFLQJXODWHFRUWH[ / LQVXOD 5 LQVXOD / PLGGOHWHPSRUDOJ\UXV 5 PLGGOHWHPSRUDOJ\UXV / LQIHULRUWHPSRUDOJ\UXV 5 LQIHULRUWHPSRUDOJ\UXV / LQIHULRUSDULHWDOOREH

Cluster 1 - Placebo > Amisulpride

5 VXSHULRUIURQWDOJ\UXV 5 PLGGOHIURQWDOJ\UXV / SRVWFHQWUDOJ\UXV 5 SRVWFHQWUDOJ\UXV / LQIHULRUWHPSRUDOJ\UXV 5 LQIHULRUWHPSRUDOJ\UXV / LQIHULRUWHPSRUDOJ\UXV 5 VXSHULRUSDULHWDOJ\UXV 5 SUHFXQHXV / SUHFXQHXV / LQIHULRUSDULHWDOOREH 5 LQIHULRUSDULHWDOOREH 5 RFFLSLWDOFRUWH[

Cluster 2 - Amisulpride > Placebo

/ DP\JGDODKLSSRFDPSXV

5 PLGGOHIURQWDOJ\UXV

5 SRVWFHQWUDOJ\UXV

Cluster 2 - Placebo > Amisulpride

/ LQVXOD

/ PLGGOHIURQWDOJ\UXV

5 VXSHULRUWHPSRUDOJ\UXV

/ SUHFXQHXV

/ SUHFXQHXV

Cluster 3 - Amisulpride > Placebo

/ PLGGOHWHPSRUDOJ\UXV 5 PLGGOHWHPSRUDOJ\UXV 5 PLGGOHWHPSRUDOJ\UXV / IXVLIRUPJ\UXV 5 IXVLIRUPJ\UXV

Cluster 3 - Placebo > Amisulpride

5 PLGEUDLQ

5 VXSHULRUWHPSRUDOJ\UXV

Cluster 6 - Amisulpride > Placebo

5 VXSHULRUIURQWDOJ\UXV 5 PHGLDOIURQWDOJ\UXV 5 DQWHULRUFLQJXODWHFRUWH[ 5 DQWHULRUFLQJXODWHFRUWH[ 5 VXSHULRUIURQWDOJ\UXV / PLGGOHWHPSRUDOJ\UXV 5 PLGGOHWHPSRUDOJ\UXV

Cluster 6 - Placebo > Amisulpride

5 HQWRUKLQDOFRUWH[

5 KLSSRFDPSXV

/ LQIHULRUWHPSRUDOJ\UXV

/ SUHFXQHXV