Brain MRI Abnormalities in Angelman Syndrome: Volumetric and Shape Analyses of Cortical and Subcortical Structures

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(22) $IBQUFS .BUFSJBM "OE .FUIPET. *NBHJOH 1SPUPDPM. *NBHJOH 1SPUPDPM $IJMESFO XJUI "4 XFSF TFEBUFE GPS UIF FYBN BOE NPOJUPSFE CZ USBJOFE BOFTUIF TJPMPHJTUT $POUSPM DIJMESFO XFSF BMTP TFEBUFE BDDPSEJOH UP UIF QSPUPDPM UP XIJDI UIFZ IBE CFFO BTTJHOFE &BDI TVCKFDU‫۝‬T .3* TDBO XBT FWBMVBUFE CZ UXP FYQFSJFODFE OFVSPSBEJPMPHJTU %. BOE 1# GPS HSPTT BOBUPNJDBM BCOPSNBMJUJFT "MM EBUBTFUT XFSF BTTFTTFE GPS B RVBMJUZ DPOUSPM BOE EFFNFE BDDFQUBCMF GPS BOBMZTJT. .3* BDRVJTJUJPO "MM QBUJFOUT BOE DPOUSPMT VOEFSXFOU .3* CSBJO TDBOT XJUI 5 TZTUFN (& &YDJUF )%Y (& .FEJDBM 4ZTUFNT 8JTDPOTJO .JMXBVLFF 64" BU UIF 'PVOEBUJPO $/ 33FHJPOF 5PTDBOB ( .POBTUFSJP 1JTB *UBMZ " 5XFJHIUFE TQPJMFE HSBEJFOU FDIP 41(3 TFRVFODF HFOFSBUFE DPOUJHVPVT BYJBM TMJDFT 535& NTFD '07 DN BDRVJTJUJPO NBUSJY Y UIJDLOFTT NN TMJDF HBQ NN #8 L)[ /&9 VTFE UP PCUBJO IJHI SFTPMVUJPO UISFFEJNFOTJPOBM JNBHFT. *NBHF QPTUQSPDFTTJOH 7PYFM CBTFE NPSQIPNFUSZ 4USVDUVSBM EBUB XBT BOBMZTFE XJUI '4-7#. %PVBVE FU BM I॒QGTMGN SJCPYBDVLGTMGTMXJLJ'4-7#. BO PQUJNJTFE 7#. QSPUPDPM (PPE FU BM . DBSSJFE PVU XJUI '4- UPPMT 4UFQIFO . 4NJUI FU BM 'JSTU TUSVDUVSBM JNBHFT XFSF CSBJOFYUSBDUFE BOE HSFZ NB॒FSTFHNFOUFE CFGPSF CFJOH SFHJTUFSFE UP UIF ./* TUBOEBSE TQBDF VTJOH OPOMJOFBS SFHJTUSBUJPO "O EFSTTPO FU BM य़F SFTVMUJOH JNBHFT XFSF BWFSBHFE BOE ੘JQQFE BMPOH UIF YBYJT UP DSFBUF B MFॏSJHIU TZNNFUSJD TUVEZTQFDJ੗D HSFZ NB॒FS UFNQMBUF 4FDPOE BMM OBUJWF HSFZ NB॒FS JNBHFT XFSF OPOMJOFBSMZ SFHJTUFSFE UP UIJT TUVEZTQFDJ੗D UFNQMBUF BOE ۡNPEVMBUFEۡ UP DPSSFDU GPS MPDBM FYQBOTJPO PS DPOUSBDUJPO EVF UP UIF OPOMJOFBS DPNQPOFOU PG UIF TQBUJBM USBOTGPSNBUJPO य़F NPEVMBUFE HSFZ NB॒FS '4-. JT BO PQFO TPVSDF DPNQSFIFOTJWF MJCSBSZ PG BOBMZTJT UPPMT GPS G.3* .3* BOE EJ੖VTJPO UFOTPS JNBHJOH %5* CSBJO JNBHJOH EBUB BOE JT BWBJMBCMF UISPVHI UIF GPMMPXJOH MJOL I॒QXXXGN SJCPYBDVLGTM. ‫ڶ ڶ‬.

(23) $IBQUFS .BUFSJBM "OE .FUIPET. *NBHJOH 1SPUPDPM. JNBHFT XFSF UIFO TNPPUIFE XJUI BO JTPUSPQJD (BVTTJBO LFSOFM XJUI B TJHNB PG NN 'JOBMMZ WPYFMXJTF (-. XBT BQQMJFE VTJOH QFSNVUBUJPOCBTFE OPOQBSBNFUSJD UFTUJOH DPSSFDUJOH GPS NVMUJQMF DPNQBSJTPOT BDSPTT TQBDF '4-'*345 '4-JOUFHSBUFE SFHJTUSBUJPO BOE TFHNFOUBUJPO UPPMCPY '4-'*345 TPॏXBSF WFSTJPO I॒QXXXGNSJCPYBDVLGTM੗STUJOEFYIUNM XBT VTFE GPS UIF FWBMVBUJPO PG EFFQ TVCDPSUJDBM TUSVDUVSFT 1BUFOBVEF FU BM '4-'*345 JT B NPEFM CBTFE BVUPNBUFE UPPM UIBU VTFT UIF TIBQFBQQFBSBODF PG UIF NBOVBMMZ DPOTUSVDUFE NPEFMT QSPWJEFE CZ UIF $FOUFS GPS .PSQIPNFUSJD "OBMZTJT $." .() #PTUPO य़F TVCDPSUJDBM TUSVDUVSFT CJMBUFSBM IJQQPDBNQVT BNZHEBMB DBVEBUF QVUBNFO QBMMJEVN BOE UIBMBNVT XFSF TFHNFOUFE GSPN UIF 5XFJHIUFE .3 JNBHFT VTJOH '4-'*345 य़F EFGPSNBCMF TVSGBDFT PG EFFQ (. TUSVDUVSFT XFSF VTFE UP BVUP NBUJDBMMZ QBSBNFUFSJ[F UIF WPMVNFUSJD MBCFMT JO UFSNT PG NFTIFT य़F OPSNBMJ[FE JOUFOTJUJFT BMPOH UIF TVSGBDF PG NFTIFT XFSF TBNQMFE BOE NPEFMFE य़F TIBQF BOE BQQFBSBODF NPEFM XBT CBTFE PO NVMUJWBSJBUF (BVTTJBO BTTVNQUJPOT 4IBQF XBT UIFO FYQSFTTFE BT B NFBO XJUI NPEFT PG WBSJBUJPO QSJODJQBM DPNQPOFOUT. 1BUFOBVEF FU BM "ॏFS UIF BVUPNBUFE TFHNFOUBUJPO CZ UIF TPॏXBSF UIF TFHNFOUBUJPOT XFSF NBOVBMMZ DIFDLFE BOE DPO੗SNFE GPS UIF QSPQFS TFHNFOUBUJPO PG BMM UIF TVCDPSUJDBM TUSVDUVSFT य़F WFSUFYXJTF TIBQF BOBMZTJT BMPOH XJUI UIF TVSGBDF PG UIF TFHNFOUFE TVCDPSUJDBM TUSVDUVSFT XBT QFSGPSNFE XJUI VTF3FDPO./* PQUJPO XIJDI USBOTGPSNT UIF DPPSEJOBUFT JOUP TUBOEBSU ./* TQBDF F੖FDUJWFMZ OPSNBMJ[JOH GPS UIF CSBJOIFBE TJ[F य़F WFSUFYXJTF BOBMZTJT VTFT B VOJWBSJBUF UFTU BU FBDI WFSUFY UP NFBTVSF EJ੖FSFODF JO MPDBUJPO FH CFUXFFO NFBOT PG UXP HSPVQT PG TVCKFDUT य़F 'DPOUSBTU IBT CFFO TQFDJ੗FE JO UIF EFTJHO NBUSJY TJODF XF MPPLFE GPS BOZ DIBOHF JO WFSUFY QPTJUJPO *O BEEJUJPO UIF WPMVNFT PG UIBMBNVT IJQQPDBNQVT BNZHEBMB DBVEBUF BOE QVUBNFO XFSF FYUSBDUFE BOE UIF BDRVJSFE WPMVNF PG FBDI TVCDPSUJDBM TUSVDUVSF XBT OPSNBMJTFE UP UIF UPUBM CSBJO WPMVNF XJUIPVU DFSFCSPTQJOBM ੘VJE UP PCUBJO B GSBDUJPOBM WPMVNFSBUJP WBMVF. ‫ڶ ڶ‬.

(24) $IBQUFS .BUFSJBM "OE .FUIPET. 4UBUJTUJDBM BOBMZTJT. 4*&/"9 #SBJO UJTTVF WPMVNF OPSNBMJTFE GPS TVCKFDU IFBE TJ[F XBT FTUJNBUFE XJUI 4*&/"9 4 . 4NJUI FU BM 4UFQIFO . 4NJUI QBSU PG '4- 4UFQIFO . 4NJUI FU BM 4*&/"9 TUBSUT CZ FYUSBDUJOH CSBJO BOE TLVMM JNBHFT GSPN UIF TJOHMF XIPMFIFBE JOQVU EBUB य़F CSBJO JNBHF JT UIFO Bਖ਼OFSFHJTUFSFE UP ./* TQBDF . +FOLJOTPO BOE 4 4NJUI VTJOH UIF TLVMM JNBHF UP EFUFSNJOF UIF SFHJTUSBUJPO TDBMJOH UIJT JT QSJNBSJMZ JO PSEFS UP PCUBJO UIF WPMVNFUSJD TDBMJOH GBDUPS UP CF VTFE BT B OPSNBMJTBUJPO GPS IFBE TJ[F /FYU UJTTVFUZQF TFHNFOUBUJPO XJUI QBSUJBM WPMVNF FTUJNBUJPO JT DBSSJFE PVU ;IBOH #SBEZ BOE 4 4NJUI JO PSEFS UP DBMDVMBUF UPUBM WPMVNF PG CSBJO UJTTVF JODMVEJOH TFQBSBUF FTUJNBUFT PG WPMVNFT PG HSFZ NB॒FS XIJUF NB॒FS QFSJQIFSBM HSFZ NB॒FS BOE WFOUSJDVMBS $4' . 4UBUJTUJDBM BOBMZTJT $PNQBSJTPO CFUXFFO HSPVQT XBT EPOF CZ JOEFQFOEFOU TBNQMF U UFTU PS OPO QBSBNFUSJD .BOO8IJUOFZ 6UFTUT य़F BOBMZTJT BॏFS BEKVTUJOH GPS DPWBSJBUFT BHF TFY BOE *$7 XBT DBSSJFE PVU CZ (-. XJUI DBUFHPSJDBM WBSJBCMFT BT ੗YFE F੖FDU BOE DPOUJOVPVT WBSJBCMFT BT DPWBSJBUFT 4UBUJTUJDBM EFQFOEBODF CFUXFFO WPMVNF PG UIF TUSVDUVSFT BOE BHF XBT BTTFTTFE CZ 4QFSNBO‫۝‬T SBOL DPSSFMBUJPO DPFਖ਼DJFOU 4UBUJTUJDBM TJHOJ੗DBODF XBT TFU BU GPS UXPUBJMFE UFTUT "OBMZTJT XBT QFSGPSNFE CZ VTJOH 3 TPॏXBSF WFSTJPO I॒QXXXSQSPKFDUPSH 7PYFMXJTF TUBUJTUJDBM BOBMZTJT XFSF DBSSJFE PVU VTJOH 3BOEPNJ[F 8JOLMFS FU BM XIJDI JT B '4-‫۝‬T UPPM GPS OPOQBSBNFUSJD QFSNVUBUJPO JOGFSFODF PO OFVSPJNBH JOH EBUB 3BOEPNJTF BMMPXT NPEFMMJOH BOE JOGFSFODF VTJOH TUBOEBSE HFOFSBM MJOFBS NPEFM 'PS WPYFMXJTF 7#. BOBMZTJT UISFTIPMEGSFF DMVTUFS FOIBODFNFOU 5'$&. PQUJPO XBT BQQMJFE BT SFDPNNFOEFE XJUI QFSNVUBUJPOT XIJDI JT BO PQUJ NJ[FE NFUIPE UP EFUFDU DMVTUFST XJUIPVU IBWJOH UP EF੗OF DMVTUFST JO B CJOBSZ XBZ 'PS WFSUFYXJTF TIBQF BOBMZTJT DMVTUFSCBTFE PQUJPO XBT VTFE XJUI QFSNVUB UJPOT 'PS BMM UIF WPYFMXJTF BOBMZTJT B QSJPSJ EFDJEFE TJHOJ੗DBODF MFWFM PG Q . 4*&/"9 TUBOET GPS. 4USVDUVSBM *NBHF &WBMVBUJPO VTJOH /PSNBMJTBUJPO PG "USPQIZ $SPTTTFDUJPOBM. ‫ڶ ڶ‬.

(25) $IBQUFS .BUFSJBM "OE .FUIPET. 4UBUJTUJDBM BOBMZTJT. XBT DPOTJEFSFE TUBUJTUJDBMMZ TJHOJ੗DBOU XJUI NVMUJQMF DPNQBSJTPO DPSSFDUJPO 5'$& PS DMVTUFSCBTFE BQQMJFE GPS NVMUJQMF UFTUJOH. ‫ڶ ڶ‬.

(26) 3FTVMUT "MM SFTVMUT BSF SFQSFTFOUFE BT NFBO ± TUBOEBSE EFWJBUJPO x ± x $IJMESFO JO UIF "4 BOE DPOUSPM HSPVQT EJE OPU EJ੖FS JO UFSNT PG BHF BOE HFOEFS EJTUSJCVUJPO य़F EFNPHSBQIJD DIBSBDUFSJTUJDT PG UIF QBUJFOU BOE DPOUSPM HSPVQT BSF QSFTFOUFE JO 5BCMF . 7#. "OBMZTJT &YQMPSBUPSZ XIPMFCSBJO 7#. BOBMZTJT SFWFBMFE MBSHF DMVTUFST 'JH PG EF DSFBTFE HSFZ NB॒FS WPMVNF JO "4 DPNQBSFE UP DPOUSPM DIJMESFO Q '8& DPSSFDUFE JO UIF EPSTBM TUSJBUB CJMBUFSBMMZ य़F DMVTUFST PO CPUI IFNJTQIFSF FY UFOEFE JOWPMWJOH UIF IJQQPDBNQJ BOE BNZHEBMBF UIF JOGFSJPS GSPOUBM BOE TVQFSJPS GSPOUBM HZSJ CJMBUFSBMMZ 4FF "QQFOEJY 'JH " -BSHF DMVTUFS PG EFDSFBTFE HSFZ NB॒FS WPMVNF JO "4 DIJMESFO FODPNQBTTFE BMTP DFSFCFMMBS IFNJTQIFSFT BOE WFSNJT 4FF "QQFOEJY 'JH " *O BEEJUJPO B TNBMM DMVTUFS PG SFEVDFE (. WPMVNF XFSF GPVOE JO UIF BOUFSJPS BOE QPTUFSJPS EJWJTJPOT PG UIF DJOHVMBUF HZSVT QSFDVOFPVT DPSUFY BOE QBSBIJQQPDBNQBM HZSVT XJUI NBYJNVN JOUFOTJUZ QJDL PO UIF QPTUFSJPS EJWJTJPO PG UIF DJOHVMBUF HZSVT 5BCMF QSPWJEFT BO PWFSWJFX GPS FBDI DMVTUFS DIBSBDUFSJTUJD TJ[F BOE MPDBUJPO DFOUSF PG HSBWJUZ NBYJNVN JOUFOTJUZ WBMVFT BOE ./* DPPSEJOBUFT GPS MPDBUJPO PG NBYJNVN /P JODSFBTF PG (. WPMVNF XBT GPVOE CFUXFFO "4 BOE DPOUSPM DIJMESFO. ‫ڶ ڶ‬.

(27) $IBQUFS 3FTVMUT. 4FHNFOUBUJPO BOE 7PMVNFUSJD "OBMZTJT. 5BCMF 4VNNBSZ EFNPHSBQIJD UBCMF GPS "4 BOE DPOUSPM DIJMESFO. "HF ZFBST (FOEFS .BMF. $POUSPM. "OHFMNBO. $PNCJOFE. N = 17. N = 18. N = 35. . . ±. . . . ±. . . . ±. . 1WBMVF 0.921 0.392. SFQSFTFOU UIF MPXFS RVBSUJMF a UIF NFEJBO b BOE UIF VQQFS RVBSUJMF c GPS DPOUJOVPVT WBSJBCMFT x ± s SFQSFTFOUT X¯ ± 1 4%/VNCFST BॏFS QFSDFOUT BSF GSFRVFODJFT5FTUT VTFE 8JMDPYPO UFTU 1FBSTPO UFTU. ab c. 4FHNFOUBUJPO BOE 7PMVNFUSJD "OBMZTJT य़F WPMVNFT PG BMM TFHNFOUFE TVCDPSUJDBM TUSVDUVSFT BOE UPUBM (.8. BOE $4' WPMVNFT BSF TVNNBSJ[FE JO UIF 5BCMF *O DPNQBSJTPO UP DPOUSPM TVCKFDUT UIF "4 QBUJFOUT TIPXFE TNBMMFS WPMVNFT PG UIF MFॏ BOE SJHIU UIBMBNJ IJQQPDBNQJ DBVEBUF OVDMFJ QVUBNFOT QBMMJEVN BNZHEBMBF UPUBM 8. BOE UPUBM (. य़F WPMVNF EJ੖FSFODFT SFNBJOFE TJHOJ੗DBOU GPS BMM TUSVDUVSFT FWFO BॏFS SFHSFTTJOH PVU UIF F੖FDUT PG BHF *$7 BOE HFOEFS 'JH SF੘FDUT UIF EJ੖FSFODFT CFUXFFO TVCDPSUJDBM WPMVNF GSBDUJPOT JO "4 BOE DPOUSPM HSPVQT 8F PCTFSWFE HPPE DPSSFMBUJPO QBSUJDVMBSMZ DPOTJTUFOU GPS DPOUSPM TVCKFDUT CF UXFFO FBDI TFHNFOUFE TVCDPSUJDBM TUSVDUVSF WPMVNFT PO UIF MFॏ BOE SJHIU IFNJ TQIFSF "QQFOEJY 'JH" BOE 'JH" "HF JO DPOUSPM HSPVQ XBT JO TUSPOH OFHBUJWF SFMBUJPOTIJQ XJUI UPUBM (. S Q BOE JO QPTJUJWF SFMBUJPOTIJQ XJUI UPUBM 8. WPMVNFT S Q .FBOXIJMF BHF PG "4 QBUJFOUT XFSF OFHBUJWFMZ DPSSFMBUFE XJUI UPUBM (. S Q CVU OPU XJUI 8. WPMVNF 'JH . ‫ڶ ڶ‬.

(28) $IBQUFS 3FTVMUT. 4FHNFOUBUJPO BOE 7PMVNFUSJD "OBMZTJT. 'JHVSF ࡋF SFTVMUT PG 7#. BOBMZTJT Q '8& DPSSFDUFE BSF SFQSFTFOUFE PO UIF TUVEZTQFDJटD HSFZ NBࡇFS UFNQMBUF PO UIF BYJBM QMBOF 3FEZFMMPX DMVTUFST TIPX HSFZ NBࡇFS SFEVDUJPO JO DIJMESFO XJUI "OHFMNBO TZOESPNF DPNQBSFE UP DPOUSPMT 5BCMF 4JHOJटDBOU DMVTUFST PG MPDBM HSFZ NBࡇFS WPMVNF DIBOHFT Bࡄ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‫ڶ ڶ‬.

(29) $IBQUFS 3FTVMUT. 7FSUFYXJTF 4IBQF "OBMZTJT. 5BCMF 4FHNFOUFE TVCDPSUJDBM BOE DPSUJDBM WPMVNFT CZ HSPVQT. 7FOUSJDVMBS $4' DN3 5PUBM (SFZ .B॒FS DN3 5PUBM 8IJUF .B॒FS DN3 5PUBM #SBJO DN3 -Fॏ )JQQPDBNQVT DN3 3JHIU )JQQPDBNQVT DN3 -Fॏ $BVEBUF DN3 3JHIU $BVEBUF DN3 -Fॏ य़BMBNVT DN3 3JHIU य़BMBNVT DN3 -Fॏ 1VUBNFO DN3 3JHIU 1VUBNFO DN3 -Fॏ 1BMMJEVN DN3 3JHIU 1BMMJEVN DN3 -Fॏ "NZHEBMB DN3 3JHIU "NZHEBMB DN3. $POUSPM. "OHFMNBO. N = 17. N = 18. . ± . ± . ± . ± . ±. ±. ±. ±. ±. ±. ±. ±. ±. ±. ±. ±. . . ±. ± . ± . ± . ±. ±. ±. ±. ±. ±. ±. ±. ±. ±. ±. ±. . 1WBMVF 0.012 0.003 0.007 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.01. SFQSFTFOU UIF MPXFS RVBSUJMF a UIF NFEJBO b BOE UIF VQQFS RVBSUJMF c GPS DPOUJOVPVT WBSJBCMFT x ± s SFQSFTFOUT X¯ ± 1 4%5FTU VTFE8JMDPYPO UFTU. ab c. 7FSUFYXJTF 4IBQF "OBMZTJT 'PS BMM TVCDPSUJDBM TUSVDUVSFT CFUXFFO HSPVQ DPNQBSJTPO PG WFSUFY MPDBUJPOT TIPXFE MPDBM EJTQMBDFNFOU JOXBSE EF੘FDUJPO PG WFSUJDFT य़F TVSGBDF EFGPSNBUJPO NBQT SBX QWBMVFT PG UIF DBVEBUF QVUBNFO BOE HMPCVT QBMMJEVT BSF SFQSFTFOUFE JO UIF 'JH IJQQPDBNQVTBNZHEBMB DPNQMFY JO UIF 'JH BOE CJMBUFSBM UIBMBNJ JO UIF 'JH य़F TIBQF BOBMZTJT SFWFBMFE SFHJPOBM BSFBT PG TJHOJ੗DBOU TIBQF EJ੖FSFODF JO "4 HSPVQ DPNQBSFE UP UIF IFBMUIZ DPOUSPMT JO UIF DBVEBUF OVDMFJ BOE BNZHEBMBF CJMBUFSBMMZ BOE JO UIF QVUBNFO QBMMJEVN BOE IJQQPDBNQVT PO UIF SJHIU IFNJTQIFSF 3FTVMUT CBTFE VQPO UIF '8& DPSSFDUFE QWBMVFT Q DPSSFDUFE GPS CBTBM HBOHMJB BSF QSFTFOUFE JO UIF 'JH BOE "QQFOEJY 'JH " XIJMF GPS IJQQPDBNQVT BOE BNZHEBMB JO UIF 'JH /P TJHOJ੗DBOU TIBQF EJ੖FSFODFT XFSF GPVOE JO UIF. ‫ڶ ڶ‬.

(30) $IBQUFS 3FTVMUT. 7FSUFYXJTF 4IBQF "OBMZTJT. 0.5 Control AS. 0.4. 0.3. 0.2. po. H. H. ip. R. L. ip. 0.0. ca m po pu ca s L mpu C au s R da t C a e L uda Th t a e R lam Th u al s a m L Pu us ta m R Pu en ta m L Pa en ll R idu Pa m ll L idu Am m yd R Am ala yg da la. 0.1. 'JHVSF %JञFSFODFT JO TVCDPSUJDBM WPMVNF GSBDUJPOT CFUXFFO "4 BOE DPOUSPM HSPVQT. ‫ڶ ڶ‬.

(31) $IBQUFS 3FTVMUT. 7FSUFYXJTF 4IBQF "OBMZTJT. Grey Matter [cm^3]. 1400. AS Control. ●. r = −0.5, p = 0.03 r = −0.6, p = 0.02. 1200. 1000. ●. ●●● ● ●. ● ●. ● ●. ● ● ●. ●. ●. ●. ●. 800. ●. 5. 10. 15. Age [years]. 'JHVSF 3FMBUJPOTIJQ CFUXFFO UPUBM HSFZ NBࡇFS WPMVNF BOE BHF JO DIJMESFO XJUI "OHFMNBO TZOESPNF BOE DPOUSPMT. Grey Matter [cm^3]. 900. AS Control. ●. r = 0.2, p = 0.3 r = 0.6, p = 0.003. 800 700 600. ●. ●. ●. ● ●. ● ● ●● ●. ●. ●. ●. ●. ● ● ●. ●. 500. 5. 10. 15. Age [years]. 'JHVSF 3FMBUJPOTIJQ CFUXFFO UPUBM XIJUF NBࡇFS WPMVNF BOE BHF JO DIJMESFO XJUI "OHFMNBO TZOESPNF BOE DPOUSPMT. ‫ڶ ڶ‬.

(32) $IBQUFS 3FTVMUT. 7FSUFYXJTF 4IBQF "OBMZTJT. CPUI UIBMBNJ .PSF QSPNJOFOU EF੘BUJPO XFSF PCTFSWFE JO UIF CJMBUFSBM EPSTBM TUSJBUB JODMVEJOH UIF IFBE CPEZ BOE UBJM PG WFOUSPNFEJBM DBVEBUF OVDMFVT PO CPUI IFNJTQIFSF BOE UIF EPSTPMBUFSBM UBJM PG UIF DBVEBUF OVDMFVT PO UIF SJHIU TJEF 'JH 0WFSBMM DIBOHFT XFSF OPUJDFBCMZ MBSHFS PO UIF SJHIU IFNJTQIFSF JO SFTQFDU UP BMM TVCDPSUJDBM TUSVDUVSFT /P BSFBT PG SFHJPOBM FYQBOTJPO XFSF OPUFE JO DPNQBSJTPO UP UIF IFBMUIZ DPOUSPMT. ‫ڶ ڶ‬.

(33) $IBQUFS 3FTVMUT. 7FSUFYXJTF 4IBQF "OBMZTJT. 'JHVSF #BTBM HBOHMJB % TVSGBDF EFGPSNBUJPO NBQT JODMVEJOH CJMBUFSBM DBVEBUF OVDMFJ QVUBNFO BOE QBMMJEVN " TVQFSJPS WJFX # JOGFSJPS WJFX ࡋF TUSVDUVSFT BSF DPMPS DPEFE UP JMMVTUSBUF SBX 'TUBUJTUJD WBMVFT ࡋF BSSPX WFDUPST SFQSFTFOU UIF NFBO EJञFSFODF PG FBDI WFSUFY EJTQMBDFNFOU CFUXFFO UIF HSPVQT BOE BSF DPMPVSFE CZ NBHOJUVEF SFE NN EBSLCMVF NN. ‫ڶ ڶ‬.

(34) $IBQUFS 3FTVMUT. 7FSUFYXJTF 4IBQF "OBMZTJT. 'JHVSF )JQQPDBNQVT"NZHEBMB DPNQMFY % TVSGBDF EFGPSNBUJPO NBQT " TVQFSJPS WJFX # SJHIU MBUFSBM WJFX ࡋF TUSVDUVSFT BSF DPMPS DPEFE UP JMMVTUSBUF SBX 'TUBUJTUJD WBMVFT ࡋF BSSPX WFDUPST SFQSFTFOU UIF NFBO EJञFSFODF PG FBDI WFSUFY EJTQMBDFNFOU CFUXFFO UIF HSPVQT BOE BSF DPMPVSFE CZ NBHOJUVEF SFE NN EBSLCMVF NN . ‫ڶ ڶ‬.

(35) $IBQUFS 3FTVMUT. 7FSUFYXJTF 4IBQF "OBMZTJT. 'JHVSF #JMBUFSBM UIBMBNJ % TVSGBDF EFGPSNBUJPO NBQT " JOGFSJPS WJFX # TVQFSJPS WJFX ࡋF TUSVDUVSFT BSF DPMPS DPEFE UP JMMVTUSBUF SBX 'TUBUJTUJD WBMVFT ࡋF BSSPX WFDUPST SFQSFTFOU UIF NFBO EJञFSFODF PG FBDI WFSUFY EJTQMBDFNFOU CFUXFFO UIF HSPVQT BOE BSF DPMPVSFE CZ NBHOJUVEF SFE NN EBSLCMVF NN. ‫ڶ ڶ‬.

(36) $IBQUFS 3FTVMUT. 7FSUFYXJTF 4IBQF "OBMZTJT. 'JHVSF 7FSUFYXJTF TIBQF BOBMZTJT PG UIF CBTBM HBOHMJB Q '8& DPSSFDUFE BSF SFQSFTFOUFE PO UIF NN ./* TUBOEBSE TQBDF % WJFX 3FE DPMPVS TIPXT TJHOJटDBOU HSPVQ EJञFSFODF JO UIF TIBQF PG UIF TUSVDUVSFT CFUXFFO OPSNBM BOE "4 DIJMESFO UIBU DPSSFTQPOET UP UIF DPSSFDUFE QWBMVFT VTJOH '8& $BVEBUF OVDMFJ EBSLCMVF 1VUBNFOT EBSL ZFMMPX 1BMMJEB MJHIU CMVF. 'JHVSF 7FSUFYXJTF TIBQF BOBMZTJT PG CJMBUFSBM IJQQPDBNQJ BOE BNZHEBMBF Q '8& DPSSFDUFE BSF SFQSFTFOUFE PO UIF NN ./* TUBOEBSE TQBDF % WJFX 3FE DPMPVS TIPXT TJHOJटDBOU HSPVQ EJञFSFODF JO UIF TIBQF PG IJQQPDBNQJ BOE BNZHEBMBF CFUXFFO OPS NBM BOE "4 DIJMESFO UIBU DPSSFTQPOET UP UIF DPSSFDUFE QWBMVFT VTJOH '8& ࡋF CMVF DPMPVS DPSSFTQPOET UP UIF TUBEZTQFDJटD UFNQMBUF PG UIF IJQQPDBNQVT HSFFO DPMPVS DPSSFTQPOET UP BNZHEBMB. ‫ڶ ڶ‬.

(37) %JTDVTTJPO 0VS TUVEZ GPDVTFE PO WPMVNFUSJD TUSVDUVSBM BCOPSNBMJUJFT PG UIF DPSUJDBM BOE TVC DPSUJDBM (. JO ZPVOH DIJMESFO XJUI "4 VTJOH IJHI SFTPMVUJPO 5XJHIUFE .3* य़F RVBOUJUBUJWF XIPMFCSBJO 7#. BOBMZTJT EFNPOTUSBUFT TNBMMFS (. WPMVNF JO "4 DPNQBSFE UP DPOUSPM DIJMESFO JO UIF DFSFCFMMVN UIF SJHIU BOE MFॏ TUSJBUVN UIF GSPOUBM DPSUFY CJMBUFSBMMZ BOE UIF MJNCJD TUSVDUVSFT IJQQPDBNQJ BNZHEBMBF QBSBIJQQPDBNQBM BOE DJOHVMBUF DPSUJDFT &YFDVUJOH GVMMZ BVUPNBUFE TFHNFOUBUJPO UFDIOJRVF XF FYUSBDUFE UPUBM DPSUJDBM (.8. BOE TVCDPSUJDBM TUSVDUVSFT‫ ۝‬WPMVNFT XIJDI XFSF TJHOJ੗DBOUMZ MPXFS GPS "4 DIJMESFO DPNQBSFE UP DPOUSPMT FWFO BॏFS SFHSFTTJOH PVU UIF F੖FDUT PG BHF *$7 BOE HFOEFS 5BCMF 'VSUIFS BQQMZJOH OFP UFSJD WFSUFYXJTF TIBQF BOBMZTJT PG UIF TVCDPSUJDBM TUSVDUVSFT XF EFNPOTUSBUFE MPDBM EJTQMBDFNFOU XJUI JOXBSE EF੘FDUJPO PG WFSUJDFT JO UIF EPSTBM TUSJBUB BOE BNZHEBMBF CJMBUFSBMMZ XIJMF EFGPSNBUJPOT XFSF OPUFE PO UIF SJHIU IFNJTQIFSF JO UIF IFBE PG UIF IJQQPDBNQVT WFOUSPNFEJBM TVSGBDF PG UIF QVUBNFO BOE QBMMBEJVN "MUIPVHI CSBJO .3* JO QBUJFOUT XJUI "4 JT PॏFO OPSNBM PO WJTVBM JOTQFDUJPO VTJOH BEWBODF RVBOUJUBUJWF .3* XF XFSF BCMF UP EFNPOTUSBUF GPS UIF ੗STU UJNF SFHJPO TQFDJ੗D DPSUJDBM BOE TVCDPSUJDBM (. BMUFSBUJPOT UIBU NJHIU TIFE MJHIU PO VOEFSTUBOEJOH UIF EJWFSTF DMJOJDBM TZNQUPNT PG "4 य़F NBJO DMJOJDBM GFBUVSFT PG "4 BSF TFWFSF JOUFMMFDUVBM EJTBCJMJUZ TQFFDI JN QBJSNFOU TFJ[VSFT BOE CBMBODF EJTPSEFS (VFSSJOJ FU BM $IBSMFT " 8JMMJBNT य़FZ PॏFO NBOJGFTU XJUI CFIBWJPSBM VOJRVFOFTT TVDI BT BQQBSFOUMZ IBQQZ EFNFBOPS FBTJMZ FYDJUBCMF QFSTPOBMJUZ XJUI IZQFSBDUJWF CFIBWJPS JODMVEJOH SFTU MFTTOFTT PS EJTUSBDUJCJMJUZ $IBSMFT " 8JMMJBNT य़FTF DPSF DMJOJDBM GFBUVSFT PG UIF "4 DBO CF B॒SJCVUFE UP EJTSVQUJPO PG UIF 6#&" HFOF SFHBSEMFTT PG UIF VOEFSMZJOH NPMFDVMBS NFDIBOJTN /FWFSUIFMFTT TPNF BVUIPST JOEJDBUF UIBU UIF. ‫ڶ ڶ‬.

(38) $IBQUFS %JTDVTTJPO EJ੖FSFODFT BNPOH UIF HFOFUJD TVCUZQFT EP FYJTU UIBU EFUFSNJO HFOPUZQFQIFOPUZQF DPSSFMBUJPOT " %BHMJ #VJUJOH BOE $ " 8JMMJBNT *OEJWJEVBMT XJUI EFMFUJPOT IBWF NPSF TFWFSF TZNQUPNT QSFTVNBCMZ EVF UP IBQMPJOTVਖ਼DJFODZ PG HFOFT BEKBDFOU UP 6#&" MPDVT य़FZ BSF NPSF MJLFMZ UP IBWF NJDSPDFQIBMZ TFJ[VSFT BOE NPSF TFWFSF MBOHVBHF JNQBJSNFOU DPNQBSFE UP UIPTF XJUI VOJQBSFOUBM EJTPNZ 6#&" NVUBUJPOT PS JNQSJOUJOH EFGFDUT -PTTJF FU BM 'PS UIF QVSQPTF PG UIJT TUVEZ JO PSEFS UP BWPJE UIF B॒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੖FDUJWF QSPDFTTJOH BOE UIF QPTUFSJPS DFSFCFMMVN DPOUSJCVUFT UP DPNQMFY DPHOJUJWF PQFSBUJPOT 4UPPEMFZ BOE 4DINBINBOO /PU TVSQSJTJOHMZ UIF TQFDUSVN PG DMJOJDBM NBOJGFTUBUJPOT JO "4 CSPBEMZ DPWFS FJUIFS NPUPS PS DPHOJUJWF BOE B੖FDUJWF TZNQUPNT MJOLJOH UIF "4 DMJOJDBM QIFOPUZQF XJUI XJEFTQSFBE (. MPTT JO UIF WFSNJT BOE DFSFCFMMBS IFNJTQIFSFT य़F SFMBUJPOTIJQ CFUXFFO NPSQIPMPHJDBM BCOPSNBMJUJFT BOE DMJOJDBM QIFOPUZQF NJHIU CF FWFO NPSF TUSBJHIUGPSXBSE MPPLJOH BU UIF NPMFDVMBS NFDIBOJTNT UISPVHI UIF BOJNBM NPEFMT PG "4 4UVEJFT XJUI BOJNBM NPEFMT PG "4 IBWF EFNPOTUSBUFE UIBU UIF DFSFCFMMBS 1VSLJOKF DFMMT BT XFMM BT IJQQPDBNQVT BOE PMGBDUPSZ CVMC BSF ESBNBUJDBMMZ B੖FDUFE XJUI UIF MPTT PG NBUFSOBMTQFDJ੗D FYQSFTTJPO PG 6#&" "MCSFDIU FU BM 0UIFS BOJNBM NPEFMT PG "4 XJUI JO TJUV IZCSJEJ[BUJPO TVDDFTTGVMMZ SFQMJDBUFE QSFWJPVTMZ SFQPSUFE SFTVMUT EFNPOTUSBUJOH UIBU JO UIF IJQQPDBNQVT BOE DFSFCFMMBS 1VSLJOKF OFVSPOT UIF. ‫ڶ ڶ‬.

(39) $IBQUFS %JTDVTTJPO 6#&" FYQSFTTJPO XBT VOEFUFDUBCMF JO UIF NPVTF NPEFM PG "4 CVU OPU GPS PUIFS CSBJO SFHJPOT )FODF NPOPBMMFMJD NBUFSOBM 6#&" FYQSFTTJPO XBT QSPQPTFE GPS UIF IJQQPDBNQVT PMGBDUPSZ CVMCT BOE DFSFCFMMBS 1VSLJOKF OFVSPOT XIJMF CJBMMFMJD FYQSFTTJPO XBT TVHHFTUFE GPS PUIFS CSBJO SFHJPOT : +JBOH FU BM 'VSUIFS SFTFBSDI JO UIF ੗FME EFNPOTUSBUFE UIBU UIF 6#&" FYQSFTTJPO GSPN UIF QBUFSOBM DISPNPTPNF JT TVQQSFTTFE UP WBSZJOH EFHSFFT JO EJ੖FSFOU UJTTVFT य़F NBUFSOBM FYQSFTTJPO PG 6#&" NBZ OPU CF SFTUSJDUFE UP UIF IJQQPDBNQVT DFSFCFMMVN BOE PMGBDUPSZ CVMCT CVU UIF QSFEPNJOBOU FYQSFTTJPO GSPN UIF NBUFSOBM DPQZ PG UIF DISPNPTPNF XFSF GPVOE UISPVHIPVU UIF DFSFCSBM DPSUFY TUSJBUVN BOE NJECSBJO :BTIJSP FU BM )PXFWFS JU JT TUJMM OPU DMFBS XIFUIFS UIF EFHSFF PG UIF 6#&" FYQSFTTJPO JT EVF UP UIF JNQSJOUJOH HFOPNJD NPEJ੗DBUJPOT UIBU QSPWJEF B HSBEFE MFWFMT PG FYQSFTTJPO SBUIFS UIBO BO ۠BMM PS OPOFۡ F੖FDU PS UIF QBUFSOBM 6#&" FYQSFTTJPO NJHIU CF DPNQMFUFMZ TVQQSFTTFE JO TPNF DFMMT CVU OPU B੖FDUFE JO PUIFST (VTUJO FU BM *O TIPSU UIF NBUFSOBM 6#&" EF੗DJFODZ B੖FDUT NVMUJQMF CSBJO SFHJPOT UP WBSZJOH EFHSFFT EFQFOEJOH PO UIF QSFEPNJOBODF PG JUT FYQSFTTJPO य़JT NBZ DPOUSJCVUF UP UIF NVMUJQMF TZNQUPNT BTTPDJBUFE XJUI UIF EJTPSEFS *U IBT CFFO TIPXO UIBU UIF NBUFSOBM EF੗DJFOU IFUFSP[ZHPVT 6#&" LOPDLPVU NJDF FYIJCJUFE SFEVDFE CSBJO XFJHIU : ) +JBOH FU BM *O BHSFFNFOU XJUI UIFTF SFTVMUT PVS WPMVNFUSJD BOBMZTJT TIPXFE TNBMMFS WPMVNFT PG TVCDPSUJDBM TUSVDUVSFT UPUBM 8. BOE (. WPMVNFT JO "4 QBUJFOUT DPNQBSF UP DPOUSPMT 5BLJOH JOUP BDDPVOU UIBU NJDSPDFQIBMZ JT B DPNNPO QIFOPUZQJD GFBUVSFT PG "4 DIJMESFO XF JODMVEFE *$7 BT XFMM BT UIF BHF BOE HFOEFS BT B OVJTBODF DPWBSJBUFT GPS HSPVQ DPNQBSJTPOT य़F WPMVNF EJ੖FSFODFT SFNBJOFE TJHOJ੗DBOUMZ TNBMMFS JO "4 DIJMESFO DPNQBSF UP DPOUSPMT 'JH "HF XBT OFHBUJWFMZ DPSSFMBUFE XJUI (. WPMVNFT BEKVTUFE GPS UIF IFBE TJ[F CPUI GPS "4 HSPVQ S Q BOE DPOUSPMT S Q XIJMF QPTJUJWF DPSSFMBUJPO XJUI 8. WPMVNF XBT PCTFSWFE POMZ GPS UIF DPOUSPM HSPVQ JOEJDBUJOH ESBNBUJD EFWFMPQNFOUBM 8. BCOPSNBMJUJFT JO "4 DIJMESFO 'JH *OUFSFTUJOHMZ FOPVHI OP NPSQIPMPHJDBM BCOPSNBMJUJFT IBWF CFFO GPVOE JO UIF CSBJO UJTTVFT BOE JO QBSUJDVMBSMZ JO UIF DFSFCFMMVN PG UIF NPVTF NPEFMT XJUI LOPDLPVU NBUFSOBM 6#&" : +JBOH FU BM .JVSB FU BM EFTQJUF UIF GBDU UIBU UIF MBDL PG 6#&" FYQSFTTJPO XBT TQFDJ੗DBMMZ EFNPOTUSBUFE JO UIF 1VSLJOKF. ‫ڶ ڶ‬.

(40) $IBQUFS %JTDVTTJPO DFMM MBZFS .JVSB FU BM %BJMZ " ( 4NJUI BOE 8FFCFS )FSFCZ GPS UIF ੗STU UJNF XJUI BEWBODF RVBOUJUBUJWF OFVSPJNBHJOH XF EFNPOTUSBUFE XJEFTQSFBE (. MPTT JO UIF DFSFCFMMBS DPSUFY QSPWJOH UIBU NPSQIPMPHJDBM BCOPSNBMJUJFT EP FYJTU JO UIF DFSFCFMMVN .PSFPWFS UIF QB॒FSO PG (. MPTT GSPN PVS 7#. BOBMZTJT GPMMPXT UIF SFHJPOT JH IJQQPDBNQVT BOE TUSJBUVN JO XIFSF BOJNBM NPEFMT PG "4 IBWF CFFO TQFDJ੗DBMMZ EFNPOTUSBUFE UIF MBDL PG 6#&" FYQSFTTJPO PS JUT NBSLFE SFEVDUJPO य़F MBSHF DMVTUFST PG (. WPMVNFUSJD SFEVDUJPOT JO UIF CJMBUFSBM TUSJBUB FODPNQBTTJOH QSFEPN JOBOUMZ JUT EPSTBM TVCEJWJTJPO XJUI NBTTJWF JOWPMWFNFOU PG UIF DBVEBUF OVDMFJ य़F DMVTUFST PO CPUI IFNJTQIFSFT BSF GVSUIFS FYUFOEFE JOWPMWJOH UIF IJQQPDBNQJ BOE BNZHEBMBF UIF JOGFSJPS GSPOUBM BOE TVQFSJPS GSPOUBM HZSJ CJMBUFSBMMZ 4FF "QQFOEJY 'JH " य़F JOWPMWFNFOU PG UIF IJQQPDBNQVT TVTUBJOT BMSFBEZ XFMM FTUBCMJTIFE MJOL CFUXFFO 6#&" EF੗DJFODZ BOE IJQQPDBNQBM BMUFSBUJPOT JO "4 )JQQPDBNQVT JT XFMM TUVEJFE CSBJO TUSVDUVSF JO "4 SFTFBSDI QSJNBSJMZ CFDBVTF UIF 6#&" EF੗DJFODZ XBT UIPVHIU UP CF UIF NPTU QSPOPVODFE JO UIF IJQQPDBNQVT BOE DFSFCFMMVN "MCSFDIU FU BM *U IBT CFFO TIPXO UIBU UIF EF੗DJFODZ PG 6#&" MFBET UP UIF EF੗DJUT JO IJQQPDBNQBM MPOHUFSN QPUFOUJBUJPO BOE DPOUFYUEFQFOEFOU MFBSOJOH : ) +JBOH FU BM DIBOHFT JO UIF IJQQPDBNQBM QMBTUJDJUZ BOE JNQBJSFE OFVSPHFOFTJT BOE .BSEJSPTTJBO FU BM 0O UIF PUIFS IBOE UIF CBTBM HBOHMJB DJSDVJUSZ JT HBJOJOH NPSF B॒FOUJPO JO "4 SFTFBSDI ੗STU CFDBVTF PG JUT SPMF JO UIF NPUPS BOE CBMBODF DPOUSPM BOE TFDPOE CFDBVTF PG JUT DPOUSJCVUJPO UP OPONPUPS EPNBJOT PG UIF "4 QIFOPUZQFT *OJUJBMMZ UIF NPUPS EF੗DJUT PCTFSWFE JO 6#&" LOPDLPVU NJDF BSF UIPVHIU UP CF EVF UP EZTGVODUJPO PG DFSFCFMMBS 1VSLJOKF DFMMT IPXFWFS SFDFOU SFQPSUT JOEJDBUFE QSPCBCMF BCOPSNBMJUJFT JO OJHSPTUSJBUBM QBUIXBZ .VMIFSLBS BOE +BOB य़F 6#&" LOPDLPVU NJDF TIPXFE SFEVDFE OVNCFS PG EPQBNJOFSHJD OFVSPOT JO UIF TVCTUBOUJB OJHSB BDDPNQBOJFE CZ QPPS QFSGPSNBODF JO CFIBWJPVSBM QBSBEJHNT TFOTJUJWF UP OJHSPTUSJBUBM EZTGVODUJPO .VMIFSLBS BOE +BOB .FBOXIJMF B NBSLFE MPTT PG 6#&" FYQSFTTJPO IBT CFFO EFNPOTUSBUFE JO UIF TUSJBUVN JO MJOF XJUI DFSFCSBM DPSUFY BOE NJECSBJO (VTUJO FU BM य़FTF TFMFDUJWF SFHJPOT TIPXFE DIBOHFT JO UIF NPOPBNJOF MFWFMT FMFWBUFE TFSPUPOJO BOE EPQBNJOF MJOLJOH UIF MBDL PG. ‫ڶ ڶ‬.

(41) $IBQUFS %JTDVTTJPO 6#&" FYQSFTTJPO XJUI TPNF CFIBWJPSBM NBOJGFTUBUJPOT JO "4 'BSPPL FU BM य़F 6#&" EF੗DJFODZ IBT CFFO BMTP GPVOE UP TFMFDUJWFMZ SFEVDF HMVUBNBUFSHJD USBOTNJTTJPO JO UIF EPSTPNFEJBM TUSJBUVN SFHJPO UIBU JT DSJUJDBM JO UIF BDRVJTJUJPO PG HPBMEJSFDUFE BDUJPOT JO JOTUSVNFOUBM DPOEJUJPOJOH )BZSBQFUZBO FU BM 8F GPVOE QSFEPNJOBOU TIBQF EFGPSNJUJFT JO UIF EPSTBM TUSJBUB JODMVEJOH UIF IFBE CPEZ BOE UBJM PG UIF WFOUSPNFEJBM TVSGBDF PG UIF DBVEBUF OVDMFJ CJMBUFSBMMZ XIJMF PO UIF SJHIU TJEF UIFSF XFSF BMTP EPSTPMBUFSBM JOWPMWFNFOU PG UIF UBJM PG UIF DBVEBUF OVDMFVT BOE WFOUSPNFEJBM TVSGBDF PG UIF QVUBNFO "T UIF NBJO JOQVU OVDMFVT UIF TUSJBUVN SFDFJWFT UPQPHSBQIJDBMMZ BOE GVODUJPOBMMZ PSHBOJ[FE QSPKFD UJPOT GSPN TQFDJ੗D SFNPUF DPSUJDBM BSFBT BOE USBOTNJUT JOGPSNBUJPO WJB UIF HMPCVT QBMMJEVT BOE UIF UIBMBNVT CBDL UP UIF OFPDPSUFY 1PTUVNB य़F USBEJUJPOBM WJFX JT UIBU UIF TUSJBUVN QMBZT B LFZ SPMF JO NPUPS DPOUSPM "MFYBOEFS %F-POH BOE 4USJDL )PXFWFS UIF SFDFOU BEWBODFT JO OFVSPJNBHJOH JOWPMWJOH TUVEJFT XJUI %5* BOE SFTUJOH TUBUF GVODUJPOBM DPOOFDUJWJUZ BOBMZTFT PG UIF IVNBO TUSJBUVN JOEJDBUF UIBU UIFSF BSF NVMUJQMF TVCVOJUT PG UIF DPSUJDPTUSJBUBM MPPQT UIBU EP OPU POMZ JODMVEF NPUPS BDUJWJUZ CVU BMTP B੖FDUJWF BOE DPHOJUJWF DPNQPOFOUT %SBHBOTLJ FU BM -FI FU BM 7FSTUZOFO FU BM .PSF SFDFOU DPOTJEFSBUJPO JT UIBU UIF TUSJBUVN GVODUJPOBMMZ EJWJEFE JOUP UISFF NBJO TVCSFHJPOT CBTFE PO UIF B੖FSFOU JOQVUT SFDFJWFE GSPN UIF GSPOUBM DPSUFY BOE GSPN UIF TVCTUBOUJB OJHSB य़FTF QSPKFDUJPOT BSF BSSBOHFE JO B WFOUSPNFEJBM UP EPSTPMBUFSBM HSBEJFOU GPMMPXJOH MJNCJD DPHOJUJWF BOE NPUPS JOQVUT )BCFS 'VEHF BOE .D'BSMBOE .BJOMZ UIF EPSTPMBUFSBM TUSJBUVN UIF NPUPS SFHJPO SFDFJWFT B੖FSFOU JOQVU GSPN NPUPS DPSUFY QSJNBSJMZ GSPN QSFNPUPS NPUPS BOE DJOHVMBUF NPUPS DPSUJDFT UIF DFOUSBM TUSJBUVN UIF DPHOJUJWF SFHJPO SFDFJWFT B੖FSFOU JOQVU GSPN BTTPDJBUJPO DPHOJUJWF. DPSUFY QSJNBSJMZ EPSTPMBUFSBM QSFGSPOUBM DPSUFY BOE UIF WFOUSPNFEJBM TUSJBUVN UIF MJNCJD SFHJPO SFDFJWFT B੖FSFOU JOQVU GSPN MJNCJD DPSUFY QSJNBSJMZ GSPN PSCJUBM BOE NFEJBM QSFGSPOUBM DPSUFY )BCFS 'VEHF BOE .D'BSMBOE 0VS SFTVMUT PG WFSUFYXJTF TIBQF BOBMZTJT SFWFBMFE JOXBSE EFGPSNBUJPO PG UIF EPSTBM TUSJBUB CJMBUFSBMMZ DPOTJTUJOH PG TJHOJ੗DBOU DIBOHFT JO UIF CPUI DBVEBUF OVDMFJ BOE WFO USPNFEJBM QVUBNFO PO UIF SJHIU IFNJTQIFSF 0VS SFTVMUT JOEJDBUFT UIBU JO "4 UIF NPUPS TUSJBUVN JT NPTUMZ B੖FDUFE *O BEEJUJPO UIF MFॏ BOE SJHIU GVODUJPOBM TVCVOJUT PG TUSJBUB NBZ EJ੖FSFOUMZ CF JOWPMWFE JO UIF OFVSPQBUIPMPHZ PG "4 QSPCBCMZ EVF UP. ‫ڶ ڶ‬.

(42) $IBQUFS %JTDVTTJPO IFNJTQIFSJD GVODUJPOBM EJ੖FSFOUJBUJPO BOEPS HFOPNJD DPOTFRVFODFT *OUFSFTUJOHMZ FOPVHI QSFEPNJOBOU SJHIU TJEF TIBQF EFGPSNJUJFT PG UIF TUSJBUVN IBWF CFFO BM SFBEZ EFTDSJCF JO BVUJTN TQFDUSVN EJTPSEFST 2JV FU BM XIJDI JT UIPVHIU UP TIBSF QPTTJCMF DPNNPO NPMFDVMBS NFDIBOJTN XJUI "4 JH UIF 6#&" HFOF XBT TVHHFTUFE BT B TUSPOH DBOEJEBUF HFOF GPS BVUJTN +BOB (JWFO UIF GVODUJPOBM IFUFSPHFOFJUZ PG UIF TUSJBUVN B NPSF SF੗OFE MFWFM PG BOBMZTJT XJUI UIF DPSSFMBUJPO PG UIF DMJOJDBM TZNQUPNT BOE UIF TIBQF BQQFBSBODF PG CBTBM HBOHMJB JT XBSSBOUFE JO UIF GVUVSF TUVEJFT -Fॏ BOE SJHIU IFNJTQIFSJD BTZNNFUSJFT JO UIF TIBQF EFGPSNBUJPO XBT GPVOE BMTP GPS IJQQPDBNQVT XJUI JOXBSE EF੘BUJPO PO UIF IFBE PG UIF SJHIU IJQQPDBN QVT XJUIPVU TJHOJ੗DBOU DIBOHFT PO UIF MFॏTJEF *O UIF IVNBO IJQQPDBNQVT UIF UBTLSFMBUFE IFNJTQIFSJD MBUFSBMJ[BUJPO EP FYJTU BOE FOBCMF UIF MFॏ BOE SJHIU IJQ QPDBNQVT UP TVQQPSU DPNQMFNFOUBSZ GVODUJPOT JO IVNBO FQJTPEJD NFNPSZ BOE TQBUJBM OBWJHBUJPO 4IJQUPO FU BM य़F MFॏ IJQQPDBNQBM BDUJWJUZ JT BTTPDJBUFE XJUI BO FHPDFOUSJD TFRVFOUJBM SFQSFTFOUBUJPO PG TQBDF XIJMF UIF SJHIU IJQQPDBNQVT TIPXT HSFBUFS BDUJWJUZ XIFO BO BMMPDFOUSJD SFQSFTFOUBUJPO JT VTFE *HM³J FU BM *U JT UIPVHIU UIBU IVNBO IJQQPDBNQBM BTZNNFUSZ JT QSJNBSJMZ EJDUBUFE CZ FYUFSOBM BTZNNFUSZ OBNFMZ UIF MFॏ IFNJTQIFSJD JOWPMWFNFOU JO MBOHVBHF QSPDFTTJOH BOE UIF TUSPOHFS DPOUSJCVUJPO PG UIF SJHIU IFNJTQIFSF UP WJTVPTQBUJBM B॒FOUJPO )VUTMFS BOE (BMVTLF *U JT OPU DMFBS UIPVHI XIFUIFS IFNJTQIFSJD IJQQPDBNQBM TIBQF EJTTPDJBUJPO JT EVF UP GVODUJPOBM EJTPSHBOJ[BUJPO PS JT SFMBUFE UP UIF QPTTJCMF MBUFSBMJ[BUJPO F੖FDU XJUI EJ੖FSFOU NBUFSOBM FYQSFTTJPO MFWFMT PG UIF 6#&" JO UIF MFॏ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‫ڶ ڶ‬.

(43) $IBQUFS %JTDVTTJPO QBSBIJQQPDBNQBM BOE DJOHVMBUF DPSUJDFT XIJDI JT SFMFWBOU UP TPNF DMJOJDBM NBO JGFTUBUJPOT JO "4 )PXFWFS UIF JEFB UIBU BNZHEBMB NJHIU DPOUSJCVUF UP B XJEF BSSBZ PG CFIBWJPSBM VOJRVFOFTT QSFTFOUFE JO QBUJFOUT XJUI "4 SFBDIFE VUNPTU FOEPSTFNFOU XIFO XF GPVOE EJTUJODU BOE NBSLFE TIBQF EFGPSNBUJPO QB॒FSO JO CJMBUFSBM BNZHEBMBF GPMMPXJOH WFSUFYXJTF TIBQF BOBMZTJT %FTQJUF UIF GBDU UIBU "4 JT B SBSF EJTPSEFS JO PVS TUVEZ XF XFSF BCMF UP SFBDI SFM BUJWFMZ MBSHF DPIPSU PG "4 DIJMESFO EVF UP NPMFDVMBSMZ DPOGPSNFE NBUFSOBM EFMFUJPO PG UIF DISPNPTPNF Rۗ HFOPNJD SFHJPO य़F 8. BCOPSNBMJUJFT BMSFBEZ IBWF CFFO EFTDSJCFE JO "4 CVU UP UIF CFTU PG PVS LOPXMFEHF UIJT JT UIF ੗STU TUVEZ UIBU FYQMPSFE DPSUJDBM BOE TVCDPSUJDBM (. BMUFSBUJPO QB॒FSO JO "4 *O TQJUF PG UIFTF BEWBOUBHFT PVS TUVEZ JT OPU MBDLJOH MJNJUBUJPOT य़F "4 QPQVMBUJPO JODMVEFE JO PVS TUVEZ NBZ OPU CF SFQSFTFOUBUJWF PG JOEJWJEVBMT XJUI PUIFS HFOFUJD TVCUZQFT PG "4 TVDI BT EVF UP VOJQBSFOUBM EJTPNZ 6#&" NVUBUJPOT PS JNQSJOUJOH EFGFDUT /FYU UIF DPODMVTJPOT GPMMPXJOH PVS BOBMZTFT BSF JOEJSFDU CFDBVTF RVBOUJUBUJWF OFVSPJNBHJOH TUSBUFHJFT SF੘FDU FNQJSJDBM CJPQIZTJDBM DIBSBDUFSJTUJDT PG UIF JOUFS SPHBUFE UJTTVF 5SFBUNFOU EJ੖FSFODFT FH BOUJQTZDIPUJDT IPSNPOF UIFSBQZ BT XFMM BT TFJ[VSF BDUJWJUZ BOE TFWFSJUZ NJHIU BMTP BMUFS CSBJO EFWFMPQNFOU BOE UIVT JO੘VFODF CSBJOUJTTVF WPMVNF BQQFBSJOH BT QPUFOUJBM DPOGPVOEFST $PODMVTJPOT य़F OFVSPCFIBWJPS NBOJGFTUBUJPOT PG "4 BSF CSPBE BOE UIF QBUIPQIZTJPMPHJDBM NFDIBOJTNT NFEJBUJOH UIFTF TZNQUPNT BSF MBSHFMZ OPU GVMMZ VOEFSTUPPE य़F SPVUJOF CSBJO .3* JO QBUJFOUT XJUI "4 JT PॏFO OPSNBM OFWFSUIFMFTT PVS SFTVMUT PG RVBOUJUBUJWF XIPMFCSBJO 7#. BOBMZTJT JOEJDBUF SFHJPOBM TQFDJ੗D (. MPTT PG UIF DPSUJDBM BOE TVCDPSUJDBM TUSVDUVSFT UIBU NJHIU TIFE MJHIU PO VOEFSTUBOEJOH UIF EJWFSTF DMJOJDBM TZNQUPNT PG "4 .PSFPWFS XF UIJOL UIBU NJDSPTUSVDUVSBM (. SFEVDUJPO NJHIU SF੘FDU UIPTF CSBJO SFHJPOT CSPBEMZ DPOTJTUJOH PG DFSFCFMMVN UIF SJHIU BOE MFॏ TUSJBUVN UIF GSPOUBM DPSUFY CJMBUFSBMMZ BOE UIF MJNCJD TUSVDUVSFT XIFSF UIF QSFEPNJOBOU MPTT PG NBUFSOBMTQFDJ੗D FYQSFTTJPO PG 6#&" UBLFT QMBDF 8F EFNPOTUSBUFE UIBU "4 DIJMESFO IBWF MPXFS UPUBM DPSUJDBM (.8. BOE TVCDPS UJDBM TUSVDUVSFT‫ ۝‬WPMVNF JO DPNQBSJTPO UP DPOUSPM DIJMESFO XIJDI JT JO BHSFFNFOU XJUI BOJNBM TUVEJFT *O BEEJUJPO OPWFM WFSUFYXJTF TIBQF BOBMZTJT PG TVCDPSUJDBM. ‫ڶ ڶ‬.

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(47) " 'JHVSFT. ‫ڶ ڶ‬.

(48) "QQFOEJY " 'JHVSFT. 1050. 3.0. 2.0. 4.0. 4.0. 6.5. 3.0. 4.5. 0.9. 1.3. 0.5. 0.9. ** 0.04. 0.10. 0.22. 0.31. −0.052. −0.46. 0.36. 0.31. 0.12. 0.16. −0.32. −0.13. 0.13. 0.16. 0.046. 0.38. −0.46. −0.043. 0.28. 0.26. 0.088. −0.13. −0.14. −0.18. −0.40. −0.35. 0.36. −0.016. 0.67. 0.44. 0.29. 0.42. 0.30. −0.053. −0.25. 0.42. 0.29. 0.70. 0.22. 4. −0.63. 8. Density. Age. 1.5. 12. 800. 800 950 Density. ● ●● ●● ● ●. .. GM. ● ● ●● ●● ●. ●●. x●. Hp R. 4. 10. 0.59. 0.60. 0.52. −0.078. 0.32. 0.073. 0.49. 0.30. 0.44. 0.24. 0.50. 0.22. 0.40. 0.30. 550 700. 0.41. 0.00024. ● ● ●. 2.0. 2.0. .. *. 0.41. 0.00024. *. *. 0.53. 0.58. 0.39. 0.81. 0.28. 0.33. 0.57. 0.27. 0.36. 0.40. 0.27. 0.068. −0.23. 0.35. 0.46. ●. ●● ●● ● ● ● ●● ● ● ●. ●. ●● ●●. Th L. ***. 0.96. ●● ● ● ● ●● ● ●● ● ●. ●. ●● ● ● ●● ● ● ● ● ● ● ● ● ●●. ● ● ● ● ● ●● ●●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ●● ●. ●● ● ●. 4.0. ●. ●. ●●. ●. ●. ● ●● ● ● ●● ●● ●. ● ● ●● ● ● ● ●● ● ● ● ● ● ●● ● ● ●● ●● ● ●● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ●. ● ●. ●●● ●. 2.0. ● ● ● ●● ● ●●● ● ● ● ●●● ●● ● ● ● ●● ●● ● ● ● ● ●. ●. 2.8. ● ●. Putamen L ● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ●● ● ● ● ● ● ● ● ● ●● ● ●●● ● ●● ● ● ●. .. Putamen R. . 0.44. 0.17. 0.26. −0.0064. x. ●. ● ● ● Pallidum L ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ●● ●●●● ●●● ● ●● ● ● ● ● ● ● ●● ● ●● ● ● ● ●●● ● ● ● ● ● ● ● ● Pallidum ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ●● ●● ● ●● ● ● ● ●● ●. ***. 0.72. x. ● ●. R. ●●. 6.5. ● ●. ● ● ●. 3.0. ●. ● ●● ●. 4.5. ●●● ●. 1.0. Amyg L. *. 0.59. x. ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ● ●● ● ●● ● ● ● ● ●● ● ● ●● ● ● ●● ●● ● ● ● ● ● ● ● ●. 0.42. x. ●. ●. .. *. 0.48. ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●. ●●. 4.0. ***. 0.79. x. ●. ● ● ●● ●● ● ●● ●● ● ●● ● ● ● ●● ●● ● ● ● ● ● ●● ● ●●● ●● ● ●● ● ● ●● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ●. *. .. ●. ● ● ●. Th R. x. ● ● ● ● ● ●● ●●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ●. ● ●● ● ●● ● ● ●● ●● ●. ●. ● ● ●● ●● ●● ●● ● ● ● ● ●● ●. 4.0 5.5 7.0. ●. ● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ●. ●. *. 4.0. ●. ●● ● ●. ●. .. x. ● ●●. ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ●●. ***. ●. ● ●. ●. *. 2.0. Caudate R. 3.0. ● ● ● ●● ● ● ●● ● ● ● ● ●● ●● ●. ● ● ● ● ● ● ●● ●● ●● ● ●● ● ●● ●● ● ● ● ●● ● ● ●●. **. 1.0. ●. x. ● ● ● ● ● ●● ● ● ●●● ● ● ● ●. ●. ●. **. ●. ● ● ●● ● ● ● ● ●● ●● ● ●. Amyg R. 0.8. ●. ●●●. ●● ●● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ●. ●● ● ●. .. *. 0.52. x. ●● ●. 0.4. ●. ●. ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ●● ● ●● ●● ● ● ●. **. 0.60. Density. ●. **. 0.59. *. ● ●● ●● ● ● ● ● ●● ● ● ● ●. ● ● ●● ● ● ● ● ● ● ● ● ● ● ●●● ● ●● ●. ●● ●. 0.52. *. 0.48. x. ● ● ● ● ● ● ● ● ●● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ●● ● ● ● ● ●● ●● ● ●● ● ●●● ● ● ●● ● ● ●● ● ●●● ● ● ●● ● ● ● ● ● ●● ●. ●. 0.20. Caudate L. ● ●● ● ● ●. ●. 0.19. *. 0.59. ●. ●. ●. 0.0036. *. ●. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ●●● ● ●●● ●● ● ● ● ●● ● ● ●● ● ● ●● ● ● ● ● ● ●● ● ● ●● ● ● ● ●● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ●● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ●● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●● ●● ● ● ●● ●● ● ● ● ●● ● ● ● ●●. ● ● ●. 0.52. Density. ● ●. ● ●● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●. ● ● ● ●● ● ●● ● ● ●● ● ● ● ●. 0.20. Density. ●. ●. 0.19. Density. ●. ● ●●. ●. 0.0036. Density. 1.5 1.2 0.9 1.1 0.8. ●. ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ●● ● ● ●● ● ● ●●● ●● ● ● ● ●● ● ●● ● ● ●● ● ● ●● ● ●●● ● ● ● ●● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ●● ● ● ● ● ● ● ● ●. 0.19. x. ● ● ● ● ● ●● ●● ● ● ●● ●● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ●● ●● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ●. **. 0.72. *** 1.00. ●. ● ● ● ●● ● ●● ● ● ● ● ●●● ● ●●● ● ● ● ●● ● ●● ● ● ●● ● ● ●● ● ● ●● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ●● ●● ● ●● ● ● ●● ●● ● ●●● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ●● ● ● ●● ● ●● ● ●● ● ● ● ● ● ● ● ● ●● ●● ●● ● ●● ● ● ●● ● ●● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●. ●. .. ***. 0.72. Density. 4.0 3.0. ●. ***. 0.45. 3.5. ●. Density. 3.5 2.0 6.0 4.0. ●. ●. .. 2.6. ● ●. ● ● ●● ● ●● ● ● ● ●●● ● ●●● ● ● ● ●● ● ●● ● ●● ● ● ●● ● ●● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●. ●. .. x. ●. ●. .. 0.41. Density. ●. .. 0.41. Density. ●. ●. .. Hp L. Density. Density. ●. **. 0.65. 550. ●. ●. Density. ● ● ●. ● ● ● ● ● ●● ●● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ●● ● ● ● ●. **. 1.3. Density. 2.5 1.5. 0.42. x. ● ●. ● ●●. .. WM. 700. ●. ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ●● ●● ●● ● ● ●● ●. 0.5. .. ●. 1.4. 0.4. 1.0 x. 'JHVSF " $PSSFMBUJPO NBUSJY DPNQSJTFT PG NVMUJQMF WBSJBCMFT JODMVEJOH BHF UPUBM (.8. BOE TVCDPSUJDBM TUSVDUVSFT JO "4 DIJMESFO "NZH BNZHEBMB (. HSFZ NBࡇFS )Q IJQQPDBNQVT - MFࡄ 3 SJHIU ࡋ UIBMBNVT 8. XIJUF NBࡇFS. ‫ڶ ڶ‬.