Multiple Sclerosis

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Multiple sclerosis
Jurnal 1
BMC Neurol. 2013; 13: 16.
Published online 2013 February 6. doi: 10.1186/141!23!13!16
PMC"#: PMC3$%%013
Mental comorbidity and multiple
sclerosis: validating administrative data
to support population-based surveillance
&u'h (nn Marrie)
1)2)12
*ohn # Fis+)
3
Bo Nan,y -u)
2
.'ella /eun0)
2
/a1ren,e 2llio'')
2

Pa'ri,ia Cae'ano)
2
.haron 3arren)
4
Chari'y 24ans)
$
Chris'ina 3ol5son)
6)
/a1ren,e 3
.4enson)
8)%)10
6elen 7re8le'')
11
*a8es F Blan,hard)
2
and .,o'' B Pa''en
8
) 5or 'he C"6&
7ea8 in 'he 29ide8iolo0y and "89a,' o5 Co8orbidi'y on Mul'i9le .,lerosis
(u'hor in5or8a'ion : (r'i,le no'es : Co9yri0h' and /i,ense in5or8a'ion :
;o 'o:
Abstract
Background
3hile 8en'al ,o8orbidi'y is ,onsidered ,o88on in 8ul'i9le s,lerosis <M.=) i's i89a,' is
9oorly de5ined; 8e'hods are needed 'o su99or' s'udies o5 8en'al ,o8orbidi'y. 3e
4alida'ed and a99lied ad8inis'ra'i4e ,ase de5ini'ions 5or any 8en'al ,o8orbidi'ies in M..
Methods
>sin0 ad8inis'ra'i4e heal'h da'a 1e iden'i5ied 9ersons 1i'h M. and a 8a',hed 0eneral
9o9ula'ion ,ohor'. (d8inis'ra'i4e ,ase de5ini'ions 5or any 8en'al ,o8orbidi'y) any 8ood
disorder) de9ression) an?ie'y) bi9olar disorder and s,hi@o9hrenia 1ere de4elo9ed and
4alida'ed a0ains' 8edi,al re,ords usin0 a a +a99a s'a'is'i, <+=. >sin0 'hese de5ini'ions 1e
es'i8a'ed 'he 9re4alen,e o5 'hese ,o8orbidi'ies in 'he s'udy 9o9ula'ions.
Results
Co89ared 'o 8edi,al re,ords) ad8inis'ra'i4e de5ini'ions sho1ed 8odera'e a0ree8en' 5or
any 8en'al ,o8orbidi'y) 8ood disorders and de9ression <all + A 0.4%=) 5air a0ree8en' 5or
an?ie'y <+ B 0.23= and bi9olar disorder <+ B 0.30=) and near 9er5e,' a0ree8en' 5or
s,hi@o9hrenia <+ B 1.0=. 7he a0e!s'andardi@ed 9re4alen,e o5 all 8en'al ,o8orbidi'ies 1as
hi0her in 'he M. 'han in 'he 0eneral 9o9ula'ions: de9ression <31.C 4s. 20.$C=) an?ie'y
<3$.6C 4s. 2%.6C=) and bi9olar disorder <$.83C 4s. 3.4$C=) e?,e9' 5or s,hi@o9hrenia
<0.%3C 4s. 0.%3C=.
Conclusions
(d8inis'ra'i4e da'a are a 4alid 8eans o5 sur4eillan,e o5 8en'al ,o8orbidi'y in M.. 7he
9re4alen,e o5 8en'al ,o8orbidi'ies) e?,e9' s,hi@o9hrenia) is in,reased in M. ,o89ared
'o 'he 0eneral 9o9ula'ion.
Keywords: Mul'i9le s,lerosis) (d8inis'ra'i4e da'a) Dalida'ion) Pre4alen,e) #e9ression)
(n?ie'y) Bi9olar disorder) .,hi@o9hrenia
;o 'o:
Background
(l'hou0h de9ression and an?ie'y are ,onsidered ,o88on in M. E1)2F) 9o9ula'ion!based
9re4alen,e es'i8a'es 5or 'hese ,ondi'ions are rare. 24en 5e1er 9re4alen,e es'i8a'es e?is'
5or bi9olar disorder and s,hi@o9hrenia in 'he M. 9o9ula'ion) and 'hey 4ary 1idely E3)4F.
7he 9au,i'y o5 9o9ula'ion!based s'udies o5 8en'al ,o8orbidi'y 8ay re5le,' 'he ,hallen0es
o5 ,ondu,'in0 su,h s'udies. 6o1e4er) su,h s'udies are needed 0i4en 'he i89a,' o5 8en'al
,o8orbidi'y in M.) in,ludin0 lo1er Guali'y o5 li5e and redu,ed adheren,e 'o 'rea'8en'
E$)6F; and 'o 8ini8i@e 'he biases 5ro8 usin0 ,lini,!based sa89les.
.'udies o5 8en'al ,o8orbidi'y ,ould 9o'en'ially use one o5 se4eral da'a sour,es in,ludin0
8edi,al re,ords re4ie1) sel5!re9or') in'er4ie1s) or ad8inis'ra'i4e da'a. (d8inis'ra'i4e
da'a are 9o9ula'ion!based in 9ubli,ly 5unded heal'h sys'e8s su,h as Canada and are ,os'!
e55e,'i4e and a,,essible EF. .u,h da'a are use5ul 5or assessin0 'he burden o5 disease a'
'he 9o9ula'ion le4el) in,ludin0 heal'h ser4i,es use and ,os's E8F. Men'al ,o8orbidi'ies
,an be assessed in ,lini,al sa89les usin0 s'ru,'ured dia0nos'i, in'er4ie1s su,h as 'he
Co89osi'e "n'erna'ional #ia0nos'i, "n'er4ie1 <C"#"= al'hou0h 'hese are 'i8e ,onsu8in0
and de9end hea4ily on re,all o5 9as' e9isodes E%F. (d8inis'ra'i4e da'a ha4e 'he ad4an'a0e
'ha' 'hey are re,orded durin0 an e9isode and need no' be re,alled la'er. (d8inis'ra'i4e
da'a) ho1e4er) are ,olle,'ed 5or heal'h sys'e8 8ana0e8en' and are o5'en inadeGua'ely
4alida'ed E)10F. "ndeed) 5e1 9ublished ,ase de5ini'ions 5or 8en'al ,o8orbidi'y ha4e been
4alida'ed) and e55or's 'o de4elo9 and 4alida'e ,ase de5ini'ions 5or de9ression ha4e
iden'i5ied 9oor ,on,ordan,e 1i'h 'he C"#" .hor' For8 E11F) and di55i,ul'ies
dis'in0uishin0 de9ression 5ro8 an?ie'y E12F.
3e ai8ed 'o 4alida'e ad8inis'ra'i4e ,ase de5ini'ions 5or se4eral 8en'al ,o8orbidi'ies in
M.) and 'o des,ribe 'heir 9re4alen,e a8on0 9ersons 1i'h M. 4ersus a 8a',hed ,ohor'
5ro8 'he 0eneral 9o9ula'ion. 3e hy9o'hesi@ed 'ha' 'he 9re4alen,e o5 de9ression) an?ie'y)
bi9olar disorder and s,hi@o9hrenia 1ould be hi0her in 'he M. 9o9ula'ion 'han in 'he
0eneral 9o9ula'ion.
;o 'o:
Methods
Administrative data
3e ,ondu,'ed 'his s'udy in Mani'oba) Canada) usin0 anony8i@ed ad8inis'ra'i4e da'a
ob'ained 5ro8 Mani'oba 6eal'h <M6= 1hi,h 9ro4ides heal'h ,are ser4i,es 5or 8ore 'han
%8C o5 Mani'oba residen's E13F. .in,e 1%84) M6 has 8ain'ained ,o89u'eri@ed re,ords
o5 heal'h ser4i,es ,lai8s) 1hi,h ,an be lin+ed usin0 a uniGue 9ersonal heal'h
iden'i5i,a'ion nu8ber <P6"N= iden'i5yin0 'he 9erson 1ho re,ei4ed 'he ser4i,e. Physi,ian
,lai8s in,lude 'he P6"N) ser4i,e da'e) and 'hree!di0i' "n'erna'ional Classi5i,a'ion o5
#isease <"C#=!%!CM ,ode 5or one 9hysi,ian!assi0ned dia0nosis. 6os9i'ali@a'ion re,ords
in,lude 'he P6"N) ad8ission and dis,har0e da'es) and u9 'o 16 dis,har0e dia0noses.
Be5ore 2004) dia0noses 1ere lis'ed usin0 5i4e!di0i' "C#!%!CM ,odes and sin,e 2004 'hey
ha4e been lis'ed usin0 "C#!10!C( ,odes. .in,e 1%%6) 'he #ru0 Pro0ra8s "n5or8a'ion
Ne'1or+ ,a9'ures ou'9a'ien' 9res,ri9'ion dru0 dis9ensa'ions in,ludin0 da'e) dru0 na8e)
and dru0 iden'i5i,a'ion nu8ber 5or Mani'oba residen's) re0ardless o5 9ayer. 7he
9o9ula'ion re0is'ry is u9da'ed 1hen an indi4idual 8i0ra'es in'o or ou' o5 Mani'oba) or
dies.
Study populations and validation cohort
>sin0 da'a 5ro8 1%84 'o 2006) 1e iden'i5ied all Mani'obans 1i'h M. usin0 a 9re4iously
4alida'ed ad8inis'ra'i4e ,ase de5ini'ion E14F. 3e iden'i5ied u9 'o $ ,on'rols 5ro8 'he
0eneral 9o9ula'ion 5or ea,h M. ,ase) 8a',hed on se?) year o5 bir'h and re0ion o5
residen,e <9os'al ,ode=) and e?,ludin0 anyone 1i'h an "C#%/10!,ode 5or any
de8yelina'in0 disease as 9re4iously des,ribed E14F. (s des,ribed in de'ail 9re4iously) 'he
8edi,al re,ords o5 430 9ersons 1i'h M. 1ere re4ie1ed by a 'rained abs'ra,'or usin0 a
s'andardi@ed da'a ,olle,'ion 5or8 E14)1$F. >sin0 ea,h 9ar'i,i9an'Hs P6"N) 'hese ,lini,al
da'a 1ere lin+ed 1i'h 'he ad8inis'ra'i4e da'abases.
Administrative case deinitions
3e ai8ed 'o de4elo9 ,ase de5ini'ions 5or de9ression) an?ie'y) bi9olar disorder and
s,hi@o9hrenia usin0 es'ablished a99roa,hes E16F. #e4elo9in0 ,ase de5ini'ions 5or 8en'al
,o8orbidi'y raised ,hallen0es. (l'hou0h hos9i'al ,lai8s 9ro4ide $!di0i' "C# ,odes)
9hysi,ian ,lai8s in Mani'oba ha4e only 'hree di0i's) redu,in0 'he s9e,i5i,i'y o5 ,odin0.
For e?a89le) a' 'he 3!di0i' le4el) 'he sa8e ,ode <2%6= des,ribes bi9olar " disorder) 8os'
re,en' e9isodi, 8ani, <2%6.4= and 8aIor de9ressi4e disorder re,urren' e9isode <2%6.3=.
7here5ore) 1e ini'ially ,rea'ed an Jo8nibusH de5ini'ion 5or 8en'al ,o8orbidi'y 'o ,a9'ure
9ersons 1i'h any o5 'he 8en'al ,o8orbidi'ies o5 in'eres') 5ollo1ed by an Jany 8ood or
an?ie'y disordersH de5ini'ion 1hi,h ,a9'ured de9ressi4e disorders) an?ie'y disorders and
bi9olar disorder. Finally) 1e de4elo9ed ,ase de5ini'ions 5or indi4idual 8en'al
,o8orbidi'ies. 3e iden'i5ied "C#!%/10 ,odes 5or 'he indi4idual ,o8orbidi'ies and 'he
,o8bina'ion de5ini'ions <(ddi'ional 5ile 1: 7able .1=.
3hile in,or9ora'in0 9res,ri9'ion ,lai8s 8i0h' i89ro4e s9e,i5i,i'y o5 'he ,ase de5ini'ions)
8any 8edi,a'ions used 5or 8en'al ,o8orbidi'ies are used o55!label 5or o'her 9ur9oses)
9ar'i,ularly in M. E1F. 7o de'er8ine 1hi,h 8edi,a'ions 'o in,lude in our de5ini'ions 1e
,o89iled a lis' o5 an'ide9ressan's <N06(=) an'i!an?ioly'i,s <N0$B=) an'i!9sy,ho'i,s
<N0$(=) ,o8bina'ion a0en's <N06C=) and 8ood!s'abili@in0 a0en's in,ludin0
an'i,on4ulsan's <N0$(N01) N03(;01) N03(K0%) N03(K12= a4ailable in Canada based
on 'he (na'o8i, 7hera9eu'i, Che8i,al Classi5i,a'ion .ys'e8 E18F. ( 8ul'idis,i9linary
9anel ,o89rised o5 '1o 9har8a,is's <C2) MM=) a 9sy,hia'ris' <.BP=) a neuro9sy,holo0is'
<*#F=) an e9ide8iolo0is' <.3=) and a neurolo0is' <&(M= inde9enden'ly re4ie1ed 'his lis'
and indi,a'ed 1he'her ea,h 8edi,a'ion 1as used <i= 5or ea,h o5 'he 8en'al ,o8orbidi'ies
o5 in'eres'; <ii= o'her on!label uses in,ludin0 'he s9e,i5i, ,ondi'ion; and <iii= o55!label
uses) es9e,ially 5or M.. 7o 8ee' our 0oal o5 enhan,in0 'he s9e,i5i,i'y o5 ,ase de5ini'ions
1i'h 9res,ri9'ion ,lai8s) 1e sele,'ed 8edi,a'ions ,onsidered 'o be 8odera'ely s9e,i5i,
5or 'he ,o8orbidi'ies o5 in'eres' <(ddi'ional 5ile 1: 7able .1=) 8eanin0 'ha' 'he
8edi,a'ion ,ould no' be used o55!label 5or M.) and ,ould no' be used on or o55!label 5or
,ondi'ions o'her 'han 8en'al ,o8orbidi'ies unless an "C# ,ode ,ould easily e?,lude 'he
,ondi'ion <e.0. e9ile9sy=.
3e de4elo9ed se4eral ,ase de5ini'ions 5or ea,h ,o8orbidi'y by 4aryin0 'he nu8ber o5
9hysi,ian) hos9i'al and 9res,ri9'ion ,lai8s reGuired and 'he years o5 da'a reGuired 'o
,lassi5y a 9erson as a55e,'ed. >sin0 our 4alida'ion ,ohor') 1e ,o89ared 'he ,lassi5i,a'ion
o5 8en'al ,o8orbidi'y a,,ordin0 'o 'he ad8inis'ra'i4e ,ase de5ini'ions 4ersus dia0noses
based on 8edi,al re,ords re4ie1 5or 'he 1 'o $ year 9eriods endin0 in 5is,al year 200$/06.
3e re9or' a +a99a <L= s'a'is'i, 5or a0ree8en' be'1een ad8inis'ra'i4e and 8edi,al re,ords
da'a E1%F) and 'he %$C ,on5iden,e in'er4al <C"= based on 'he nor8al a99ro?i8a'ion 'o 'he
bino8ial dis'ribu'ion. 3e in'er9re'ed L as 5ollo1s: sli0h' <0!0.20=) 5air <0.21!0.40=)
8odera'e <0.41!0.60=) subs'an'ial <0.61!0.80=) and al8os' 9er5e,' a0ree8en' <0.81!1.0=
E1%F. Ma99a indi,a'es 'he 9ro9or'ion o5 a0ree8en' beyond ,han,e and is ,al,ula'ed as
<obser4ed a0ree8en' N ,han,e a0ree8en'= O <1 N ,han,e a0ree8en'=. Ma99a is a55e,'ed
by 'he 9re4alen,e o5 'he ,ondi'ion o5 in'eres') ho1e4er) su,h 'ha' i5 9re4alen,e is 4ery
hi0h or 4ery lo1) ,han,e a0ree8en' is hi0h and +a99a is redu,ed 1i'h a 8a?i8u8 4alue
o5 less 'han one E20F. Bias re5ers 'o 'he e?'en' 'o 1hi,h 'he ra'ers <i.e. ad8inis'ra'i4e da'a
4ersus 8edi,al re,ords da'a= disa0ree on 'he 9ro9or'ion o5 9osi'i4e <a55e,'ed= ,ases;
0rea'er bias) 8eanin0 a 0rea'er di55eren,e in 'he 9ro9or'ion <9re4alen,e= o5 9osi'i4e ra'es)
is 9arado?i,ally asso,ia'ed 1i'h hi0her +a99as. Be,ause bo'h 9re4alen,e and bias
in5luen,e 'he 8a0ni'ude o5 +a99a) 1e also ,al,ula'ed 'he 9re4alen,e inde?) bias inde?)
and 'he 9re4alen,e and bias!adIus'ed +a99a 5or our 9re5erred ,ase de5ini'ions E20F. 3e
es'i8a'ed 'ha' a sa89le o5 400 9ersons ,an de'e,' a + o5 A0.60 <subs'an'ial a0ree8en'= 5or
,o8orbidi'ies 1i'h A4C 9re4alen,e i5 'he null hy9o'hesis is + B 0.41) P B 0.0$) and Q B
0.20. ;i4en 'he an'i,i9a'ed hi0her + <A 0.0= 5or bi9olar disorder and s,hi@o9hrenia 1e
es'i8a'ed 'ha' our sa89le 1ould 9ro4ide adeGua'e 9re,ision 5or es'i8a'es o5 + 1i'h
9re4alen,es A 3C 5or 'hese disorders.
3e ,o89u'ed sensi'i4i'y) s9e,i5i,i'y) 9osi'i4e 9redi,'i4e 4alue <PPD= and ne0a'i4e
9redi,'i4e 4alue <NPD= 5or ad8inis'ra'i4e de5ini'ions 4ersus 'he R0old s'andardS o5
8edi,al re,ords re4ie1 'o iden'i5y 1he'her an al0ori'h8 1ould be 4ulnerable 'o o4er! or
under!es'i8a'in0 'he 9re4alen,e o5 'he ,o8orbidi'y. Fur'her) 1e e?9lored 'he i89a,' o5
'hese 8is,lassi5i,a'ions on e9ide8iolo0i, es'i8a'es by 0enera'in0 a ran0e o5 J'rueH
9re4alen,e es'i8a'es) and ,al,ula'in0 'he e?9e,'ed 4alue o5 obser4ed 9re4alen,e based on
'he sensi'i4i'y and s9e,i5i,i'y 5or 'he ,ase de5ini'ion o5 in'eres' E)21F.
!revalence
For ea,h ,o8orbidi'y) 1e re9or' 'he 9re4alen,e in 'he M. and 8a',hed ,ohor's. Tn,e a
9erson 8e' 'he ,ase de5ini'ion) he or she 1as ,onsidered a55e,'ed in all subseGuen' years
1hile ali4e and residen' in Mani'oba. 3e es'i8a'ed 'he 9oin' 9re4alen,e o5 'he
,o8orbidi'y on T,'ober 1) 200$ usin0 8id!year 9o9ula'ion 5i0ures 5or deno8ina'ors and
also ,al,ula'ed 9re4alen,e ra'ios <P&= by di4idin0 'he 9re4alen,e in 'hose 1i'h M. by
'ha' o5 'he ,on'rol 0rou9. 7o enhan,e ,o89arabili'y 1i'h o'her s'udy 9o9ula'ions) 1e a0e!
s'andardi@ed 'he 5indin0s 'o 'he 2001 Canadian 9o9ula'ion) and ,al,ula'ed %$C C"s usin0
'he e?a,' bino8ial dis'ribu'ion. >sin0 Poisson re0ression 1e ,al,ula'ed P&s and %$C C"s
,o89arin0 'he M. and 0eneral 9o9ula'ions adIus'in0 5or a0e 0rou9 <20!44) 4$!$%) A
60 years= and se?. Cell si@es U $ 1ere su99ressed.
7he >ni4ersi'y o5 Mani'oba 6eal'h &esear,h 2'hi,s Board and 'he Mani'oba 6eal'h
"n5or8a'ion Pri4a,y Co88i''ee a99ro4ed 'he s'udy and da'a a,,ess. Par'i,i9an's in 'he
4alida'ion ,ohor' 9ro4ided 1ri''en in5or8ed ,onsen'. .'a'is'i,al analyses 1ere 9er5or8ed
usin0 .(. D%.2 <.(. "ns'i'u'e "n,.) Cary NC=.
;o 'o:
Results
7he M. 9o9ula'ion in,luded 41%2 9ersons and 'he 8a',hed ,ohor' in,luded 20)%40
9ersons <1.C 5e8ale=. "n 'he 4alida'ion ,ohor' 8os' 9ar'i,i9an's 1ere 3hi'e <%1.6C=)
1o8en <.0C=) 1i'h a 8ean <s'andard de4ia'ion= a0e a' M. sy89'o8 onse' o5 33.2
<11.1= years E16F. Men'al ,o8orbidi'y 1as ,o88on in 'he 4alida'ion ,ohor') 1i'h 2%.C
ha4in0 any 8en'al ,o8orbidi'y) 2%.2C ha4in0 a 8ood or an?ie'y disorder) 2.$C ha4in0
a de9ressi4e disorder) 6.$C ha4in0 an an?ie'y disorder) 0.%8C ha4in0 bi9olar disorder
and 0.4%C ha4in0 s,hi@o9hrenia.
"mnibus deinition: any mental comorbidity
(0ree8en' be'1een 'he ad8inis'ra'i4e ,ase de5ini'ions <labeled ( 'o V= and 8edi,al
re,ords ran0ed 5ro8 sli0h' 'o 8odera'e <+ B 0.11 'o 0.$1) (ddi'ional 5ile 2: 7able .2=. 7he
de5ini'ion 1i'h 'he hi0hes' le4el o5 a0ree8en' reGuired A 1 hos9i'al or A $ 9hysi,ian
,lai8s or A 1 9hysi,ian ,lai8 and A 4 9res,ri9'ion ,lai8s in 2 years <de5ini'ion JWH) + B
0.$1=; i' had a sensi'i4i'y o5 63C and a s9e,i5i,i'y o5 86.8C. >sin0 de5ini'ion JWH) 'he
a0e!s'andardi@ed 9re4alen,e o5 any 8en'al ,o8orbidi'y in 200$ 1as 33.%C <%$C C"
32.0!3$.%C= in 'he M. 9o9ula'ion and 21.%C <%$C C": 21.2!22.6C= in 'he 0eneral
9o9ula'ion <P& 1.$$; %$C C": 1.36!1.6=. "n bo'h 9o9ula'ions) 'he 9ea+ 9re4alen,e
o,,urred in 9ersons a0ed 4$!$% years <Fi0ure 1=.
Fi0ure 1
Age-speciic prevalence o mental comorbidity in the MS #A$ and general
populations #B$% (d8inis'ra'i4e ,ase de5ini'ions used:T8nibus A 1 6os9i'al or A $
Physi,ian T& <A 1 Physi,ian (N# A 4 Pres,ri9'ion ,lai8s= in 2 years. %%%
Any mood or an&iety disorder
(0ree8en' be'1een 'he ,ase de5ini'ions <labeled ( 'o -= and 8edi,al re,ords ran0ed
5ro8 sli0h' 'o 8odera'e <+ B 0.10 'o 0.$0) (ddi'ional 5ile 3: 7able .3=. 7he hi0hes' le4el
o5 a0ree8en' <+ B 0.$0= 1as a,hie4ed by se4eral si8ilar de5ini'ions) in,ludin0 de5ini'ion
JTH <see belo1=; all used 9res,ri9'ion ,lai8s. >sin0 de5ini'ion JTH) <A 1 hos9i'al or A $
9hysi,ian or EA 1 9hysi,ian (N# A 4 9res,ri9'ionF ,lai8s= 'he a0e!s'andardi@ed
9re4alen,e o5 any 8ood or an?ie'y disorder in 200$ 1as 34.8C <%$C C" 32.8!36.8C= in
'he M. 9o9ula'ion and 22.0C <%$C C": 21.3!22.C= in 'he 0eneral 9o9ula'ion <P& 1.$8;
%$C C": 1.3%!1.80=. 7he si8ilari'y o5 'he es'i8a'es o5 any 8ood or an?ie'y disorder 'o
'hose 5or any 8en'al ,o8orbidi'y re5le,'s 'he 9redo8inan,e o5 8ood and an?ie'y
disorders. "n bo'h 9o9ula'ions) 'he 9ea+ 9re4alen,e o,,urred in 9ersons a0ed 4$!$% years
<Fi0ure 1=.
'epressive disorders
(0ree8en' be'1een 'he ,ase de5ini'ions <labeled ( 'o -) (ddi'ional 5ile 4: 7able .4= and
8edi,al re,ords ran0ed 5ro8 sli0h' 'o 8odera'e <+ B 0.11 'o 0.4%=. 7he hi0hes' le4el o5
a0ree8en' 5or a de5ini'ion 1hi,h did no' use 9res,ri9'ion ,lai8s 1as 8odera'e <+ B 0.44=)
and used A 1 hos9i'al or A4 9hysi,ian ,lai8s in $ years. (8on0 all ,ase de5ini'ions 'he
hi0hes' le4el o5 a0ree8en' <+ B 0.4%= 1as a,hie4ed by '1o si8ilar de5ini'ions <J;H and
JPH=; bo'h used 9res,ri9'ion ,lai8s. >sin0 de5ini'ion JPH) 1hi,h reGuired <A 1 hos9i'al or
A $ 9hysi,ian ,lai8s= or <A 1 9hysi,ian ,lai8 and A 9res,ri9'ion ,lai8s= in 2 years) 'he
a0e!s'andardi@ed 9re4alen,e o5 de9ression in 200$ 1as 31.C <%$C C" 2%.8!33.$C= in
'he M. 9o9ula'ion and 20.$C <%$C C": 1%.8!21.2C= in 'he 0eneral 9o9ula'ion <P& 1.60;
%$C C": 1.41!1.82=. "n bo'h 9o9ula'ions) 'he 9ea+ 9re4alen,e o,,urred in 9ersons a0ed
4$!$% years <Fi0ure 1=.
An&iety disorders
(0ree8en' be'1een 'he ad8inis'ra'i4e ,ase de5ini'ions and 8edi,al re,ords ran0ed 5ro8
sli0h' 'o 5air <+ B 0.02 'o 0.23) (ddi'ional 5ile $: 7able .$=. 7he hi0hes' le4el o5
a0ree8en' 5or any de5ini'ion 1as 5air <de5ini'ion JNH) + B 0.23=) and reGuired <A 1 hos9i'al
or A 2 9hysi,ian ,lai8s= or <A 1 9hysi,ian and A 2 9res,ri9'ion ,lai8s= in 2 years. >sin0
de5ini'ion JNH) 'he a0e!s'andardi@ed 9re4alen,e o5 an?ie'y in 200$ 1as 3$.6C <%$C C"
33.!3.C= in 'he M. 9o9ula'ion and 2%.6C <%$C C": 28.8!30.$C= in 'he 0eneral
9o9ula'ion <P& 1.24; %$C C": 1.12!1.38=. "n bo'h 9o9ula'ions) 'he 9ea+ 9re4alen,e
o,,urred in 9ersons a0ed 4$!$% years <Fi0ure 1=.
Bipolar disorder
(0ree8en' be'1een 'he ad8inis'ra'i4e ,ase de5ini'ions <labeled ( 'o >= and 8edi,al
re,ords ran0ed 5ro8 sli0h' 'o 8odera'e <+ B 0.20 'o 0.42) (ddi'ional 5ile 6: 7able .6=.
.e4eral de5ini'ions had 'he hi0hes' sensi'i4i'y o5 $C 1i'h s9e,i5i,i'ies o5 %C or hi0her.
(0ree8en' 5or 'hese de5ini'ions 4aried sli0h'ly) bu' ,on5iden,e in'er4als o4erla99ed.
>sin0 de5ini'ion J3H) 1hi,h reGuired <A 1 hos9i'al or A 3 9hysi,ian ,lai8s= or <A 1
9hysi,ian and A 3 9res,ri9'ion ,lai8s= in $ years <+ B 0.34=) 'he a0e!s'andardi@ed
9re4alen,e o5 bi9olar disorder in 200$ 1as $.83C <%$C C": $.01!6.6$C= in 'he M.
9o9ula'ion and 3.4$C <%$C C": 3.1!3.3C= in 'he 0eneral 9o9ula'ion <P& 1.0; %$C C":
1.$$!1.8=. (l'hou0h 'he a55e,'ed nu8ber o5 indi4iduals 1as s8all) 'he 9re4alen,e o5
bi9olar disorder 1as si8ilar a,ross a0e 0rou9s <Fi0ure 1=.
Schi(ophrenia
(0ree8en' be'1een all o5 'he ,ase de5ini'ions <labeled ( 'o T= and 8edi,al re,ords
ran0ed 5ro8 subs'an'ial 'o 9er5e,' <+ B 0.6 'o 1.0) (ddi'ional 5ile : 7able .=. (8on0
,ase de5ini'ions 1i'h 9er5e,' a0ree8en') 'he si89les' de5ini'ion 1i'h 'he hi0hes'
sensi'i4i'y <100C= and s9e,i5i,i'y <%%C= reGuired A 1 hos9i'al or A 2 9hysi,ian ,lai8s in
2 years <de5ini'ion J;H=. (99lyin0 de5ini'ion J;H) 'he a0e!s'andardi@ed 9re4alen,e o5
s,hi@o9hrenia in 200$ 1as 0.%3C <%$C C": 0.61!1.26C= in 'he M. 9o9ula'ion and 0.%3C
<0.8!1.0%C= in 'he 0eneral 9o9ula'ion <P& 0.%$; %$C C": 0.60!1.$1=. (l'hou0h 'he s8all
nu8ber o5 indi4iduals a55e,'ed reGuires ,au'ious in'er9re'a'ion) 'he 9re4alen,e o5
s,hi@o9hrenia 1as si8ilar a,ross a0e 0rou9s <Fi0ure 1=.
Misclassiication bias
7able 1 sho1s 'he sensi'i4i'y) s9e,i5i,i'y) +a99a) 9re4alen,e inde? and bias inde? 5or ,ase
de5ini'ions 5or 1hi,h 1e 9resen'ed 9re4alen,e es'i8a'es. 7he de5ini'ions 5or bi9olar
disorder) an?ie'y and s,hi@o9hrenia ha4e hi0h 4alues 5or 'he 9re4alen,e inde? indi,a'in0
'ha' +a99a 4alues 1ill be redu,ed as ,o89ared 'o 9o9ula'ions in 1hi,h 'hese ,ondi'ions
are 8ore 9re4alen'. 2?,e9' 5or an?ie'y) 'he bias inde? 1as 8ini8al. (5'er adIus'8en' 5or
9re4alen,e and bias) all L in,reased e?,e9' 5or s,hi@o9hrenia 1hi,h 1as already 1.0.
;ra9hi,al analysis o5 8is,lassi5i,a'ion bias su00es'ed 'ha' 'he ,ase de5ini'ions 9er5or8
reasonably 1ell in 'he e?9e,'ed ran0e o5 9re4alen,e 5or 8en'al ,o8orbidi'y in M.
<(ddi'ional 5ile 8: Fi0ure .1= E1)2)22!28F.
7able 1
"89a,' o5 9re4alen,e and bias on a0ree8en' <+a99a= be'1een ad8inis'ra'i4e ,ase
de5ini'ions and 8edi,al re,ords
;o 'o:
'iscussion
Fe1 9o9ula'ion!based s'udies ha4e e4alua'ed 'he 9re4alen,e o5 8en'al ,o8orbidi'y in
M. E4F. 7o 5a,ili'a'e su,h s'udies) 1e 4alida'ed ,ase de5ini'ions 5or 8en'al ,o8orbidi'ies
based on hos9i'al) 9hysi,ian and 9res,ri9'ion ,lai8s. Tur ,ase de5ini'ions sho1ed al8os'
9er5e,' a0ree8en' 4ersus 8edi,al re,ords 5or s,hi@o9hrenia) and 8odera'e a0ree8en' 5or
any 8en'al ,o8orbidi'y) any 8ood or an?ie'y disorder) and de9ression. 7he ,ase
de5ini'ion 5or bi9olar disorder had lo1er a0ree8en') bu' a,,e9'able sensi'i4i'y o5 $C
and hi0h s9e,i5i,i'y o5 %.$C. 7he ,ase de5ini'ion 5or an?ie'y had 'he lo1es' a0ree8en'
bu' a s9e,i5i,i'y o5 82C. Fur'her) 9ersons 1i'h M. 1ere a' in,reased ris+ o5 de9ression)
an?ie'y and bi9olar disorder) bu' no' s,hi@o9hrenia 1hen ,o89ared 'o 'he 0eneral
9o9ula'ion.
Pre4ious 4alida'ion s'udies o5 ad8inis'ra'i4e ,ase de5ini'ions 5or 8en'al ,o8orbidi'y
1ere o5'en disa99oin'in0) and ha4e hi0hli0h'ed 'he ,hallen0es o5 dis'in0uishin0
de9ression 5ro8 an?ie'y 1hen usin0 3!di0i' "C# ,odes E11)12F. "n a Mani'oba s'udy)
a0ree8en' 1as only 5air <+ B 0.26= be'1een sur4eys and ad8inis'ra'i4e de5ini'ions 5or
de9ression 1hi,h used hos9i'al) 9hysi,ian and 9res,ri9'ion ,lai8s E11F al'hou0h 'his
lo1er a0ree8en' 8ay re5le,'ed 'heir use o5 sur4ey da'a and a broader ran0e o5
9res,ri9'ion ,lai8s 'han in our s'udy. (8on0 9ersons ne1ly 'rea'ed 1i'h an'ide9ressan's
in .as+a',he1an) Canada) a0ree8en' be'1een de9ression iden'i5ied on 9hysi,ian ,lai8s
and 8edi,al re,ords 1as 8odera'e <+ B 0.$4=) si8ilar 'o our 5indin0s E2%F. 3e ,ould no'
iden'i5y any 9ublished) 4alida'ed ,ase de5ini'ions 5or an?ie'y. 7hus 'hese 4alida'ed ,ase
de5ini'ions au08en' 'he abili'y 'o ,ondu,' 9o9ula'ion!le4el sur4eillan,e o5 de9ression and
an?ie'y. #es9i'e ,hallen0es in de4elo9in0 ,ase de5ini'ions 5or de9ressi4e and an?ie'y
disorders sensi'i4e and s9e,i5i, de5ini'ions 1ere a4ailable 5or bi9olar disorder <sensi'i4i'y
$C) s9e,i5i,i'y %C=. (8on0 22$ (8eri,ans) in9a'ien' dia0noses o5 bi9olar disorder)
ou'9a'ien' dia0noses o5 bi9olar disorder by 8en'al heal'h 9ro4iders) and ou'9a'ien'
dia0noses o5 bi9olar disorder by non!8en'al heal'h 9ro4iders 'ha' 1ere a,,o89anied by a
9res,ri9'ion 5or li'hiu8) ,arba8a@e9ine or 4al9roa'e) had 5alse 9osi'i4e ra'es belo1 10C
E30F. 6o1e4er) 1e 5ound 'ha' bi9olar disorder ,ould be iden'i5ied 1i'hou' su,h ,lai8s.
Consis'en'ly) ad8inis'ra'i4e ,ase de5ini'ions 5or s,hi@o9hrenia ha4e 9er5or8ed 1ell) 1i'h
a0ree8en' be'1een hos9i'al ,lai8s 5or s,hi@o9hrenia and 8edi,al re,ords o5 %3.%!100C
E31)32F. "n (8eri,an Medi,aid da'a) 'he ,ase de5ini'ion 'ha' 1e 4alida'ed o5 ei'her one
hos9i'al or '1o 9hysi,ian ,lai8s 5or s,hi@o9hrenia in '1o years iden'i5ied only 6C 5alse
9osi'i4es <+ B 0.6= E33F.Colle,'i4ely) 'his su00es's 'ha' ad8inis'ra'i4e da'a ,an a,,ura'ely
iden'i5y bi9olar disorder and s,hi@o9hrenia in 'he M. and 0eneral 9o9ula'ions.
Tur a99roa,h is in5or8a'i4e 5or resear,hers 1ishin0 'o s'udy 8en'al ,o8orbidi'y in o'her
,hroni, neurolo0i, diseases) 1hi,h share 'he 9o'en'ial 9roble8 o5 under!re9or'in0 o5
,o8orbidi'ies due 'o ,odin0 biases E34F. 3hile 9res,ri9'ion ,lai8s 8ay add sensi'i4i'y)
'heir use 5or 8en'al ,o8orbidi'y is ,hallen0in0 in ,hroni, neurolo0i, diseases be,ause o5
'he 5reGuen' o55!label use o5 'hera9ies. By res'ri,'in0 'he bread'h o5 9res,ri9'ions used)
and usin0 'he8 in ,o8bina'ion 1i'h a 9hysi,ian ,lai8 5or 8en'al ,o8orbidi'y 1e
su,,ess5ully ,rea'ed 4alid ,ase de5ini'ions.
Prior s'udies su00es' 'ha' 'he annual 9re4alen,e o5 de9ression in M. is u9 'o 14C 1i'h a
li5e'i8e 9re4alen,e o5 u9 'o $0C E1F) and 'ha' an?ie'y disorders a55e,' 8ore 'han 30C o5
9ersons 1i'h M. E2)22F. Tur ,rude 9re4alen,e es'i8a'es o5 33C 5or de9ression and 3C
5or an?ie'y based on '1o years o5 ad8inis'ra'i4e da'a are ,onsis'en' 1i'h 'hose
obser4a'ions. 7he a0e!s'andardi@ed 9re4alen,e o5 bi9olar disorder in 'he M. 9o9ula'ion
1as $.83C <,rude 9re4alen,e 6.3C=) 0C hi0her 'han in 'he 0eneral 9o9ula'ion. .'udies
in hos9i'al or ,lini, 9o9ula'ions su00es'ed 'ha' bi9olar disorder a55e,'s 0.30C 'o 13C o5
'he M. 9o9ula'ion E24!28F. 7he only one o5 'hese s'udies 'ha' used a 'rue 0eneral
9o9ula'ion ,on'rol 0rou9 re9or'ed 'ha' hos9i'ali@ed 9ersons 1i'h M. had bi9olar disorder
'1i,e as o5'en as hos9i'ali@ed ,on'rols <1.%C 4s. 0.%2C= E2$F. .in,e 'ha' s'udy 1as
li8i'ed 'o hos9i'ali@ed 9ersons) 'he 9re4alen,e o5 bi9olar disorder 8ay ha4e been
underes'i8a'ed) al'hou0h 'he in,reased ris+ o5 bi9olar disorder in M. 1as si8ilar 'o our
5indin0s.
7he 9re4alen,e o5 s,hi@o9hrenia 1as 'he sa8e in 'he M. and 0eneral 9o9ula'ions
<0.%3C=. 71o 9o9ula'ion!based s'udies) bo'h usin0 ad8inis'ra'i4e da'a) e4alua'ed 'he
9re4alen,e o5 9sy,hosis) no' li8i'ed 'o s,hi@o9hrenia. "n 7ai1an) 9sy,hosis a55e,'ed .$C
o5 'he M. 9o9ula'ion and 2.0C o5 'he 0eneral 9o9ula'ion <odds ra'io 4.0= E3$F. "n (lber'a)
Canada only 0.8C o5 M. 9a'ien's had non!or0ani, 9ys,hoses in,ludin0 s,hi@o9hrenia!
s9e,'ru8 disorders) and o'her non!or0ani, 9sy,hoses) bu' 'his 1as 8ore 'han in 'he
0eneral 9o9ula'ion E4F. Tur 5indin0s o5 an absen,e o5 an in,reased 9re4alen,e o5
s,hi@o9hrenia in our M. 9o9ula'ion su00es' a la,+ o5 in,reased ris+ 1hi,h 8ay re5le,'
di55eren,es in 'he 9sy,ho'i, disorders s'udied <all 4ersus s,hi@o9hrenia alone=) as 1ell as
'he s8all nu8ber o5 9ersons 1i'h s,hi@o9hrenia.
Medi,al re,ords re4ie1 5or 'he 4alida'ion ,ohor' did no' in4ol4e all re,ords o5 all heal'h
,are 9ro4iders o4er 'he li5e'i8e o5 s'udy 9ar'i,i9an's. For 9ra,'i,al reasons 1e also
,o89ared 8edi,al re,ords 'o ad8inis'ra'i4e da'a 5or 'he 1 'o $ year 9eriod endin0 in
5is,al year 200$/06) ra'her 'han 5ro8 1%84 on1ard. Bo'h 5a,'ors 8ay ha4e redu,ed
a0ree8en' be'1een 'he da'a sour,es. /i+e 8edi,al re,ords) ad8inis'ra'i4e da'a only allo1
us 'o iden'i5y 8en'al ,o8orbidi'ies 5or 1hi,h 'he 9a'ien' has been 'rea'ed; undia0nosed
8en'al ,o8orbidi'y ,anno' be ,a9'ured 1i'hou' a dire,' 9a'ien' assess8en'. 7his s'udy
had se4eral s'ren0'hs) ho1e4er. 3e 4alida'ed 'he ,ase de5ini'ions in a 9o9ula'ion si8ilar
'o 'he one in 1hi,h i' 1as a99lied) 'he desi0n 1as 9o9ula'ion!based) 1e used 8a',hed
0eneral 9o9ula'ion ,on'rols) and 1e used 8ul'i9le 'y9es o5 ad8inis'ra'i4e da'a.
;o 'o:
Conclusions
Tur 5indin0s su00es' 'ha' ad8inis'ra'i4e da'a ,an be used 5or sur4eillan,e 5or 8en'al
,o8orbidi'ies in M.) and should 5a,ili'a'e s'udies o5 'he i89a,' o5 8en'al ,o8orbidi'y on
heal'h ou',o8es ,a9'ured by ad8inis'ra'i4e da'a su,h as heal'h ,are u'ili@a'ion. Tur
5indin0s also 9ro4ide 9o9ula'ion!based da'a e89hasi@in0 'he in,reased 9re4alen,e o5 a
ran0e o5 8ood and an?ie'y disorders in M..
;o 'o:
Abbreviations
C"#": Co89osi'e "n'erna'ional #ia0nos'i, "n'er4ie1;C": Con5iden,e in'er4al;"C#:
"n'erna'ional Classi5i,a'ion o5 #isease;M: Ma99a;M6: Mani'oba 6eal'h;M.: Mul'i9le
s,lerosis;NPD: Ne0a'i4e 9redi,'i4e 4alue;P6"N: Personal 6eal'h "den'i5i,a'ion
Nu8ber;PPD: Posi'i4e 9redi,'i4e 4alue;P&: Pre4alen,e ra'io. C"6& 7ea8 in 'he
29ide8iolo0y and "89a,' o5 Co8orbidi'y on Mul'i9le .,lerosis in,ludes. &u'h (nn
Marrie <>ni4ersi'y o5 Mani'oba=) Bo Nan,y -u <>ni4ersi'y o5 Mani'oba=) .'ella /eun0
<>ni4ersi'y o5 Mani'oba=) /a1ren,e 2llio'' <>ni4ersi'y o5 Mani'oba=) Pa'ri,ia Cae'ano
<>ni4ersi'y o5 Mani'oba=) *a8es F Blan,hard <>ni4ersi'y o5 Mani'oba=) /a1ren,e 3.
.4enson <>ni4ersi'y o5 (lber'a=) *oanne Pro5e''o!M,;ra'h <>ni4ersi'y o5 (lber'a=)
.haron 3arren <>ni4ersi'y o5 (lber'a=) Chris'ina 3ol5son <M,;ill >ni4ersi'y=) Na'halie
*e''e <>ni4ersi'y o5 Cal0ary=) .,o'' B Pa''en <>ni4ersi'y o5 Cal0ary=) Chari'y 24ans
<>ni4ersi'y o5 .as+a',he1an=) 6elen 7re8le'' <>ni4ersi'y o5 Bri'ish Colu8bia=) *ohn
Fis+ <#alhousie >ni4ersi'y=) Dirender Bhan <#alhousie >ni4ersi'y=) Mi,helle Plou0h8an
<Me8orial >ni4ersi'y=
;o 'o:
Competing interests
&u'h (nn Marrie re,ei4es resear,h 5undin0 5ro8: Canadian "ns'i'u'es o5 6eal'h &esear,h)
Publi, 6eal'h (0en,y o5 Canada) Mani'oba 6eal'h &esear,h Coun,il) 6eal'h .,ien,es
Cen're Founda'ion) Mul'i9le .,lerosis .o,ie'y o5 Canada) Mul'i9le .,lerosis .,ien'i5i,
Founda'ion) &? X # 6eal'h &esear,h Founda'ion) and has ,ondu,'ed ,lini,al 'rials
5unded by Bayer "n,. and .ano5i!(4en'is.
*ohn Fis+ is 'he #ire,'or o5 'he endM. ('lan'i, &e0ional &esear,h and 7rainin0 Cen're
1hi,h is 5unded by 'he Mul'i9le .,lerosis .o,ie'y o5 Canada. 6e re,ei4es resear,h
5undin0 5ro8 'he Canadian "ns'i'u'es o5 6eal'h &esear,h <C"6&= and in 'he 9as' has
re,ei4ed 0ran's) honoraria and ,onsul'a'ion 5ees 5ro8 (s'raVene,a) Bayer) Bio0en!"de,
Canada) 6eron 24iden,e #e4elo98en' /i8i'ed) 6o558ann!/a &o,he) M(P" &esear,h
7rus') No4ar'is) .ano5i!(4en'is) .erono Canada) and Wuali'yMe'ri, "n,or9ora'ed.
Nan,y -u re,ei4es resear,h su99or' 5ro8 'he Canadian "n'erna'ional #e4elo98en'
(0en,y) 'he Mul'i9le .,lerosis .o,ie'y o5 Canada) C"6&) and Mani'oba 6eal'h and
6eal'hy /i4in0.
.'ella /eun0 re9or's no dis,losures.
/a1ren,e 2llio'' re,ei4es resear,h su99or' 5ro8 'he Canadian "ns'i'u'es o5 6eal'h
&esear,h) 6eal'h .,ien,es Cen're Founda'ion) Publi, 6eal'h (0en,y o5 Canada) and 'he
Mul'i9le .,lerosis .o,ie'y o5 Canada.
Pa'ri,ia Cae'ano has 1or+ed on a resear,h 9roIe,' 5unded by (80en.
Chari'y 24ans re9or's no dis,losures.
.haron 3arren re,ei4es resear,h 5undin0 5ro8 'he C"6&) 'he Canadian 6eal'h .er4i,es
&esear,h Founda'ion) (lber'a 6eal'h .er4i,es and ..6&C.
Chris'ina 3ol5son re,ei4es resear,h 5undin0 5ro8 'he Mul'i9le .,lerosis .o,ie'y o5
Canada) Canadian "ns'i'u'es o5 6eal'h &esear,h) Canada Founda'ion 5or "nno4a'ion) and
Publi, 6eal'h (0en,y o5 Canada.
/arry .4enson re9or's no dis,losures.
6elen 7re8le'' ,urren'ly re,ei4es 5undin0 5ro8: 'he Mul'i9le .,lerosis .o,ie'y o5 Canada
E#on Pa'y Career #e4elo98en' (1ardF; >. Na'ional M. .o,ie'y EY&; 4202!(!2 <P"=F;
Canadian "ns'i'u'es o5 6eal'h &esear,h EMTP: Y1%08%8 <P"= and MTP!%3646 <P"=F;
Mi,hael .8i'h Founda'ion 5or 6eal'h &esear,h <.,holar a1ard= and 'he Canada &esear,h
Chair 9ro0ra8. .he has re,ei4ed s9ea+er honoraria and/or 'ra4el e?9enses 'o a''end
,on5eren,es 5ro8: 'he Consor'iu8 o5 M. Cen'res) >. Na'ional M. .o,ie'y) .1iss
Mul'i9le .,lerosis .o,ie'y) 'he >ni4ersi'y o5 Bri'ish Colu8bia Mul'i9le .,lerosis
&esear,h Pro0ra8) 7e4a Phar8a,eu'i,als and Bayer Phar8a,eu'i,al <honoraria de,lined=
and 2C7&"M.. >nless o'her1ise s'a'ed) all s9ea+er honoraria are ei'her dona'ed 'o an
M. ,hari'y or 'o an unres'ri,'ed 0ran' 5or use by her resear,h 0rou9.
*a8es Blan,hard re,ei4es resear,h su99or' 5ro8 'he Mul'i9le .,lerosis .o,ie'y o5
Canada) C"6&) Bill X Melinda ;a'es Founda'ion) Canadian "n'erna'ional #e4elo98en'
(0en,y and 'he >ni'ed .'a'es (0en,y 5or "n'erna'ional #e4elo98en'.
.,o'' Pa''en 1as a 8e8ber o5 an ad4isory board 5or .er4ier) Canada. 6e has re,ei4ed
honoraria 5or re4ie1in0 in4es'i0a'or!ini'ia'ed 0ran' a99li,a'ions sub8i''ed 'o /undbe,+
and P5i@er and has re,ei4ed s9ea+in0 honoraria 5ro8 7e4a and /undbe,+. 6e is an
(sso,ia'e 2di'or 5or 'he Canadian *ournal o5 Psy,hia'ry and a 8e8ber o5 'he edi'orial
board o5 Chroni, #iseases and "nIuries in Canada. 6e is 'he re,i9ien' o5 a salary su99or'
a1ard <.enior 6eal'h .,holar= 5ro8 (lber'a "nno4a'es) 6eal'h .olu'ions and re,ei4es
resear,h 5undin0 5ro8 'he Canadian "ns'i'u'es 5or 6eal'h &esear,h) 'he "ns'i'u'e o5 6eal'h
2,ono8i,s and 'he (lber'a Collabora'i4e &esear,h ;ran's "ni'ia'i4e.
;o 'o:
Authors) contributions
&(M) *#F) .3) .BP) and 67 ,on,ei4ed o5 and desi0ned 'he s'udy ini'ially. &(M) *#F)
/2) PC) C2) .3 and .BP re4ie1ed and sele,'ed dia0nos'i, ,odes and 9har8a,o'hera9ies
5or al0ori'h8 de4elo98en'. &(M) N- and ./ analy@ed 'he da'a. (ll au'hors assis'ed in
'he in'er9re'a'ion o5 'he da'a. &(M dra5'ed 'he 8anus,ri9'. (ll au'hors re4ised 'he
8anus,ri9' and a99ro4ed 'he 5inal 4ersion 5or 9ubli,a'ion.
;o 'o:
!re-publication history
7he 9re!9ubli,a'ion his'ory 5or 'his 9a9er ,an be a,,essed here:
h''9://111.bio8ed,en'ral.,o8/141!23/13/16/9re9ub
;o 'o:
Supplementary Material
Additional ile *: +able S*:
#ia0nosis and 8edi,a'ion ,odes used 'o iden'i5y ,o8orbidi'ies.
Cli,+ here 5or 5ile
<3%M) do,=
Additional ile ,: +able S,:
Omnibus Definition: (d8inis'ra'i4e Clai8s Case #e5ini'ions as Co89ared 'o Medi,al
&e,ords &e4ie1.
Cli,+ here 5or 5ile
<8$M) do,=
Additional ile -: +able S-:
Mood and Anxiety Disorders: (d8inis'ra'i4e Clai8s Case #e5ini'ions as Co89ared 'o
Medi,al &e,ords &e4ie1.
Cli,+ here 5or 5ile
<8M) do,=
Additional ile .: +able S.:
Depression: (d8inis'ra'i4e Clai8s Case #e5ini'ions as Co89ared 'o Medi,al &e,ords
&e4ie1.
Cli,+ here 5or 5ile
<8$M) do,=
Additional ile /: +able S/:
Anxiety Disorders: (d8inis'ra'i4e Clai8s Case #e5ini'ions as Co89ared 'o Medi,al
&e,ords &e4ie1.
Cli,+ here 5or 5ile
<82M) do,=
Additional ile 0: +able S0:
Bipolar Disorder: (d8inis'ra'i4e Clai8s Case #e5ini'ions as Co89ared 'o Medi,al
&e,ords &e4ie1.
Cli,+ here 5or 5ile
<%M) do,=
Additional ile 1: +able S1:
Schizophrenia: (d8inis'ra'i4e Clai8s Case #e5ini'ions as Co89ared 'o Medi,al &e,ords
&e4ie1.
Cli,+ here 5or 5ile
<$%M) do,=
Additional ile 2: 3igure S*:
(ssess8en' o5 8is,lassi5i,a'ion bias 5or ad8inis'ra'i4e ,ase de5ini'ions 5or 8en'al
,o8orbidi'ies.
Cli,+ here 5or 5ile
<6%M) do,=
;o 'o:
Acknowledgement
7he resul's and ,on,lusions 9resen'ed are 'hose o5 'he au'hors. No o55i,ial endorse8en'
by Mani'oba 6eal'h is in'ended or should be in5erred. 7he au'hors 'han+ Melanie
M,/eod) Phar8# 5or her assis'an,e in re4ie1in0 9har8a,o'hera9ies 5or 'his 9roIe,'.
;o 'o:
3unding
7his s'udy 1as 5unded by o9era'in0 0ran's and a #on Pa'y Career #e4elo98en' (1ard
5ro8 'he Mul'i9le .,lerosis .o,ie'y o5 Canada) 'he Mani'oba 6eal'h &esear,h Coun,il)
'he Canadian "ns'i'u'es 5or 6eal'h &esear,h) and 'he &? X # 6eal'h &esear,h
Founda'ion. 7he s9onsors had no role in 'he desi0n) in 'he ,olle,'ion) analysis or
in'er9re'a'ion o5 'he da'a; in 'he 1ri'in0 o5 'he 8anus,ri9'; or in 'he de,ision 'o sub8i' 'he
8anus,ri9' 5or 9ubli,a'ion.
;o 'o:
Reerences
1. ;old8an Consensus ;rou9. 7he ;old8an Consensus s'a'e8en' on de9ression in
8ul'i9le s,lerosis. Mul' .,ler. 200$;11:328N33. EPubMedF
2. Moros'il M) Feins'ein (. (n?ie'y disorders and 'heir ,lini,al ,orrela'es in 8ul'i9le
s,lerosis 9a'ien's. Mul' .,ler. 200;13:6N2. doi: 10.11/13$24$8$0601161.
EPubMedF ECross &e5F
3. &od0ers *) Bland &. Psy,hia'ri, 8ani5es'a'ions o5 8ul'i9le s,lerosis: a re4ie1.
Can * Psy,hia'ry. 1%%6;41:441N44$. EPubMedF
4. Pa''en .B) .4enson /3) Me'@ /M. Psy,ho'i, disorders in M.: Po9ula'ion!based
e4iden,e o5 an asso,ia'ion. Neurolo0y. 200$;6$<=:1123N112$. doi:
10.1212/01.1nl.000018%%8.%$2%3.2%. EPubMedF ECross &e5F
$. Marrie &() 6or1i'@ &) Cu''er ;) 7yry 7. Cu8ula'i4e i89a,' o5 ,o8orbidi'y on
Guali'y o5 li5e in M.. (,'a Neurol .,and. 2012;12$<3=:180N186. doi:
10.1111/I.1600!0404.2011.01$26.?. EPubMedF ECross &e5F
6. Mohr #C) ;ood+in #2) /i+os+y 3) ;a''o N) Bau8ann M() &udi,+ &(.
7rea'8en' o5 de9ression i89ro4es adheren,e 'o in'er5eron be'a!1b 'hera9y 5or
8ul'i9le s,lerosis. (r,h Neurol. 1%%;$4:$31N$33. doi:
10.1001/ar,hneur.1%%.00$$01001$00%. EPubMedF ECross &e5F
. Pa''en .. "n'e0ra'in0 da'a 5ro8 ,lini,al and ad8inis'ra'i4e da'abases in
9har8a,oe9ide8iolo0i,al resear,h. Can * Clin Phar8a,ol. 1%%8;$<2=:%2N%.
8. (s,he CD) .in0er M2) *ha4eri M) Chun0 6) Miller (. (ll!,ause heal'h ,are
u'ili@a'ion and ,os's asso,ia'ed 1i'h ne1ly dia0nosed 8ul'i9le s,lerosis in 'he
>ni'ed .'a'es. * Mana0 Care Phar8. 2010;16<%=:03N12. EPubMedF
%. 6aro *M) (rbab@adeh!Bou,he@ .) Bru0ha 7.) #e ;irola8o ;) ;uyer M2) *in &)
/e9ine *P) Ma@@i F) &eneses B) Dila0u' ;. Con,ordan,e o5 'he ,o89osi'e
in'erna'ional dia0nos'i, in'er4ie1 4ersion 3.0 <C"#" 3.0= 3i'h s'andardi@ed
,lini,al assess8en's in 'he 36T 1orld 8en'al heal'h sur4eys. "n' * Me'hods
Psy,hia'r &es. 2006;1$<4=:16N180. doi: 10.1002/89r.1%6. EPubMedF ECross &e5F
10. 7ri,,o (C) Pha8 B) &a1son N.B. Mani'oba and .as+a',he1an ad8inis'ra'i4e
heal'h ,are u'ili@a'ion da'abases are used di55eren'ly 'o ans1er e9ide8iolo0i,
resear,h Gues'ions. * Clin 29ide8iol. 2008;61<2=:1%2N1%. doi:
10.1016/I.I,line9i.200.03.00%. e112. EPubMedF ECross &e5F
11. Mar'ens P) Fransoo &) M,Meen N) Burland 2) *eba8ani /) Bur,hill C) Cos'er C#)
2+u8a T) Prior 6) Cha'eau #. Pa''erns o5 re0ional 8en'al illness disorder
dia0noses and ser4i,e use in Mani'oba: a 9o9ula'ion!based s'udy. 3inni9e0:
Mani'oba Cen're 5or 6eal'h Poli,y) >ni4ersi'y o5 Mani'oba; 2004.
12. Misely .) /in 2) ;ilber' C) .8i'h M) Ca89bell /!() Dasiliadis 6!M. >se o5
ad8inis'ra'i4e da'a 5or 'he sur4eillan,e o5 8ood and an?ie'y disorders. (us' N V *
Psy,hia'ry. 200%;43<12=:1118N112$. doi: 10.310%/0004860%032%838.
EPubMedF ECross &e5F
13. Bran,h 6"M. Po9ula'ion re9or'. 3inni9e0) Mani'oba: Mani'oba 6eal'h and
6eal'hy /i4in0; 2008.
14. Marrie &() -u N) Blan,hard *F) /eun0 .) 2llio'' /. 7he risin0 9re4alen,e and
,han0in0 a0e dis'ribu'ion o5 8ul'i9le s,lerosis in Mani'oba. Neurolo0y.
2010;4<6=:46$N41. doi: 10.1212/3N/.0b013e3181,56e,0. EPubMedF ECross
&e5F
1$. 6or'on M) &udi,+ &() 6ara!Clea4er C) Marrie &(. Dalida'ion o5 a sel5!re9or'
,o8orbidi'y Gues'ionnaire 5or 8ul'i9le s,lerosis. Neuroe9ide8iolo0y.
2010;3$<2=:83N%0. doi: 10.11$%/000311013. EPubMedF ECross &e5F
16. Marrie &) -u B) /eun0 .) 2llio'' /) Cae'ano P) 3arren .) 3ol5son C) Pa''en .)
.4enson /) 7re8le'' 6. &isin0 9re4alen,e o5 4as,ular ,o8orbidi'ies in M.:
4alida'ion o5 ad8inis'ra'i4e de5ini'ions 5or diabe'es) hy9er'ension) hy9erli9ide8ia.
Mul'i9le .,lerosis *ournal. 2012. EPubMedF ECross &e5F
1. .a8+o55 /M) ;ood8an (#. .y89'o8a'i, 8ana0e8en' in 8ul'i9le s,lerosis.
Neurol Clin. 2011;2%<2=:44%N463. doi: 10.1016/I.n,l.2011.01.008. EPubMedF
ECross &e5F
18. (na'o8i, 'hera9eu'i, ,he8i,al ,lassi5i,a'ion sys'e8.
h''9://111.1ho,,.no/a',/s'ru,'ureZandZ9rin,i9les/
1%. /andis *&) Mo,h ;;. 7he 8easure8en' o5 obser4er a0ree8en' 5or ,a'e0ori,al
da'a. Bio8e'ri,s. 1%;33:1$%N14. doi: 10.230/2$2%310. EPubMedF ECross &e5F
20. .i8 *) 3ri0h' CC. 7he +a99a s'a'is'i, in reliabili'y s'udies: use) in'er9re'a'ion) and
sa89le si@e reGuire8en's. Phys 7her. 200$;8$:2$N268. EPubMedF
21. Mleinbau8 #) Mu99er /) Mor0ens'ern 6. 29ide8iolo0i, resear,h: 9rin,i9les and
Guan'i'a'i4e 8e'hods. Ne1 -or+: Dan Nos'rand &einhold; 1%82. "n5or8a'ion bias;
99. 220N241.
22. #ahl T!P) .'ordal 2) /ydersen .) Mid0ard &. (n?ie'y and de9ression in 8ul'i9le
s,lerosis. ( ,o89ara'i4e 9o9ula'ion!based s'udy in nord!'rondela0 ,oun'y)
nor1ay. Mul' .,ler. 200%;1$<12=:14%$N1$01. doi: 10.11/13$24$8$0%3$1$42.
EPubMedF ECross &e5F
23. 3ood B) 4an der Mei ") Ponsonby (!/) Pi''as F) Wuinn .) #1yer 7) /u,as &)
7aylor B. Pre4alen,e and ,on,urren,e o5 an?ie'y) de9ression and 5a'i0ue o4er 'i8e
in 8ul'i9le s,lerosis. Mul'i9le .,lerosis *ournal. 2012. 29ub ahead o5 9rin'.
EPubMedF ECross &e5F
24. 2d1ards /*) Cons'an'ines,u C.. ( 9ros9e,'i4e s'udy o5 ,ondi'ions asso,ia'ed
1i'h 8ul'i9le s,lerosis in a ,ohor' o5 6$8 ,onse,u'i4e ou'9a'ien's a''endin0 a
8ul'i9le s,lerosis ,lini,. Mul' .,ler. 2004;10:$$N$81. doi:
10.11%1/13$24$8$048s108oa. EPubMedF ECross &e5F
2$. Fis+ *) Morehouse .() Bro1n M;) .+ed0el C) Murray 7*. 6os9i'al!based
9sy,hia'ri, ser4i,e u'ili@a'ion and 8orbidi'y in 8ul'i9le s,lerosis. Can * Neurol
.,i. 1%%8;2$:230N23$. EPubMedF
26. *o55e &7) /i99er' ;P) ;ray 7() .a1a ;) 6or4a'h V. Mood disorder and 8ul'i9le
s,lerosis. (r,h Neurol. 1%8;44:36N38. doi:
10.1001/ar,hneur.1%8.00$2016001800. EPubMedF ECross &e5F
2. *a,obs /#) 3ende M2) Bro1ns,heidle CM) (9a'o55 B) Coyle PM) ;ood8an ()
;o''es8an M6) ;ran0er CD) ;reenber0 .*) 6erber' *. ( 9ro5ile o5 8ul'i9le
s,lerosis: 'he Ne1 yor+ s'a'e 8ul'i9le s,lerosis ,onsor'iu8. Mul' .,ler.
1%%%;$<$=:36%N36. EPubMedF
28. Marrie &() 6or1i'@ &") Cu''er ;) 7yry 7) Ca89a0nolo #) Doll8er 7. 7he burden
o5 8en'al ,o8orbidi'y in 8ul'i9le s,lerosis: FreGuen') underdia0nosed) and under!
'rea'ed. Mul' .,ler. 200%;1$<3=:38$N3%2. doi: 10.11/13$24$8$080%%4.
EPubMedF ECross &e5F
2%. 3es' ./) &i,h'er () Mel5i C() M,Nu'' M) Nenns'iel M2) Maus+o95 *(.
(ssessin0 'he .as+a',he1an da'abase 5or ou',o8es resear,h s'udies o5 de9ression
and i's 'rea'8en'. * Clin 29ide8iol. 2000;$3<8=:823N831. doi: 10.1016/.08%$!
43$6<%%=0023!1. EPubMedF ECross &e5F
30. >n['@er *) .i8on ;) Pabinia+ C) Bond M) Ma'on 3. 7he use o5 ad8inis'ra'i4e
da'a 'o assess Guali'y o5 ,are 5or bi9olar disorder in a lar0e s'a55 8odel 6MT. ;en
6os9 Psy,hia'ry. 2000;22<1=:1N10. doi: 10.1016/.0163!8343<%%=000$!2.
EPubMedF ECross &e5F
31. &a1son N.) Mal,ol8 2) #\(r,y C. &eliabili'y o5 'he re,ordin0 o5 s,hi@o9hrenia
and de9ressi4e disorder in 'he .as+a',he1an heal'h ,are da'a5iles. .o, Psy,hia'ry
Psy,hia'r 29ide8iol. 1%%;32<4=:1%1N1%%. doi: 10.100/BF0088238. EPubMedF
ECross &e5F
32. Mashner 7M. (0ree8en' be'1een ad8inis'ra'i4e 5iles and 1ri''en 8edi,al
re,ords: a ,ase o5 'he #e9ar'8en' o5 De'erans (55airs. Med Care.
1%%8;36<%=:1324N1336. doi: 10.10%/0000$6$0!1%%80%000!0000$. EPubMedF
ECross &e5F
33. /urie N) Po9+in M) #ys+en M) Mos,o4i,e ") Fin,h M. (,,ura,y o5 dia0noses o5
s,hi@o9hrenia in Medi,aid ,lai8s. 6os9 Co88uni'y Psy,hia'ry. 1%%2;43<1=:6%N
1. EPubMedF
34. 2li?hauser () .'einer C) 6arris #&) Co55ey &M. Co8orbidi'y 8easures 5or use
1i'h ad8inis'ra'i4e da'a. Med Care. 1%%8;36:8N2. doi: 10.10%/0000$6$0!
1%%801000!00004. EPubMedF ECross &e5F
3$. Man0 *!6) Chen -!6) /in 6!C. Co8orbidi'ies a8on0s' 9a'ien's 1i'h 8ul'i9le
s,lerosis: a 9o9ula'ion!based ,on'rolled s'udy. 2ur * Neurol. 2010;1<%=:121$N
121%. doi: 10.1111/I.1468!1331.2010.02%1.?. EPubMedF ECross &e5F
Jurnal 2
PLoS One. 2012; 7(12): e50718.
Published online 2012 December 5. doi: 10.1371!ourn"l.#one.0050718
P$%&D: P$%3515'0(
Multiple Sclerosis 'ecreases 4&plicit
Counteractual !rocessing and Risk
+aking in 'ecision Making
S"m"n)" Simioni*
1
$+ri"m Schlue#*
1
,"d-.e /"ul)*
2
0ior.io %oricelli*
2
1oer.
2leeber.*
1
3en"ud 4. Du P"s5uier*
1
$"r6us 0sch7ind*
3
P")ri6 8uilleumier*
3
"nd
1e"n9$"rie 4nnoni
1*3*:*;
<hom"s /or"ud* =di)or
4u)hor in>orm")ion ? 4r)icle no)es ? %o#+ri.h) "nd License in>orm")ion ?
<his "r)icle h"s been ci)ed b+ o)her "r)icles in P$%.
0o )o:
Abstract
5ntroduction
#e5i,i's in de,ision 8a+in0 <#M= are ,o88only asso,ia'ed 1i'h 9re5ron'al ,or'i,al
da8a0e) bu' 8ay o,,ur 1i'h 8ul'i9le s,lerosis <M.=. 7here are no da'a ,on,ernin0 'he
i89a,' o5 M. on 'as+s e4alua'in0 #M under e?9li,i' ris+) 1here di55eren' e8o'ional and
,o0ni'i4e ,o89onen's ,an be dis'in0uished.
Methods
3e assessed 2 rela9sin0!re8i''in0 M. <&&M.= 9a'ien's 1i'h 8ild 'o 8odera'e disease
and 38 heal'hy ,on'rols in '1o #M 'as+s in4ol4in0 ris+ 1i'h e?9li,i' rules: <1= 7he 3heel
o5 For'une <3TF=) 1hi,h 9robes 'he an'i,i9a'ed a55e,'s o5 de,isions ou',o8es on 5u'ure
,hoi,es; and <2= 7he Ca8brid0e ;a8ble 7as+ <C;7= 1hi,h 8easures ris+ 'a+in0.
Par'i,i9an's also under1en' a neuro9sy,holo0i,al and e8o'ional assess8en') and s+in
,ondu,'an,e res9onses <.C&s= 1ere re,orded.
Results
"n 'he 3TF) &&M. 9a'ien's sho1ed de5i,i's in in'e0ra'in0 9osi'i4e ,oun'er5a,'ual
in5or8a'ion <9]0.00$= and 0rea'er ris+ a4ersion <9]0.001=. 7hey re9or'ed less ne0a'i4e
a55e,' 'han ,on'rols <disa99oin'8en': 9 B 0.00; re0re': 9 B 0.01=) al'hou0h 'heir i89li,i'
e8o'ional rea,'ions as 8easured by 9os'!,hoi,e .C&s did no' di55er. "n 'he C;7) &&M.
9a'ien's di55ered 5ro8 ,on'rols in Guali'y o5 #M <9 B 0.01= and delibera'ion 'i8e <9 B
0.0002=) 'he la''er di55eren,e bein0 ,orrela'ed 1i'h a''en'ion s,ores. .u,h ,han0es did no'
resul' in o4erall de,reases in 9er5or8an,e <'o'al 0ains=.
Conclusions
7he Guali'y o5 #M under ris+ 1as 8odi5ied by M. in bo'h 'as+s. 7he redu,'ion in 'he
e?9ression o5 disa99oin'8en' ,oe?is'ed 1i'h an in,reased ris+ a4ersion in 'he 3TF and
ale?i'hy8ia 5ea'ures. 7hese ,on,o8i'an' e8o'ional al'era'ions 8ay ha4e i89li,a'ions 5or
be''er unders'andin0 'he ,o89onen's o5 e?9li,i' #M and 5or 'he ,lini,al su99or' o5 M.
9a'ien's.
0o )o:
5ntroduction
Mul'i9le s,lerosis <M.= is a 1ides9read ,hroni, in5la88a'ory disease o5 'he ,en'ral
ner4ous sys'e8 'ha' a55e,'s 9ri8arily 'he 1hi'e 8a''er bu' is also asso,ia'ed 1i'h early
,or'i,al de8yelina'ion and a'ro9hy E1F. Fun,'ional al'era'ions in ,o0ni'i4e and a55e,'i4e
5un,'ions are ,o88only obser4ed and 9lay an i89or'an' role in 'he e4eryday disabili'ies
o5 M. 9a'ien's. .e4eral s'udies ha4e de8ons'ra'ed de5i,i's in 5ron'al lobe 5un,'ions)
in,ludin0 i89aired 1or+in0 8e8ory E2F) di8inished 4erbal 5luen,y E3F) in,reased
sensi'i4i'y 'o in'er5eren,e E3F and i89aired ,on,e9'ual reasonin0 E4F. T'her beha4ioral
s'udies re9or'ed asso,ia'ions be'1een 'he o,,urren,e o5 de9ression and da8a0e in 5ron'al
and 'e89oral ,or'i,es E$F) as 1ell as a la,+ o5 5un,'ional ,onne,'i4i'y lin+in0 9re5ron'al
areas 'o 'he a8y0dala durin0 e8o'ional 9ro,essin0 E6F.
#e,ision 8a+in0 <#M= is ano'her i89or'an' 5un,'ion +no1n 'o i89li,a'e 9re5ron'al areas)
bu' is o5'en ne0le,'ed in ,lini,al neuro9sy,holo0i,al assess8en' and rarely s'udied in M.
9a'ien's. ( ,er'ain nu8ber o5 s'udies o5 M. 9a'ien's <EF) see also belo1= ha4e 5o,used on
#M under a8bi0uous ,ondi'ions <i.e.) 1here 'he ris+ asso,ia'ed 1i'h a ,hoi,e is no'
e?9li,i'ly 0i4en= by usin0 'he "o1a ;a8blin0 7as+ <";7= E8F. 7his 'es' allo1s a sensi'i4e
de'e,'ion o5 #M i89air8en's in se4eral neurolo0i,al ,ondi'ions and in5or8s on 'he
abili'y o5 a subIe,' or a 9a'ien' 'o 8odi5y i's Guali'y o5 #M) or on i's e4en'ual
insensibili'y 'o 8one'ary losses. 7o sol4e 'he 'as+ su,,ess5ully) subIe,'s ha4e 'o de,i9her
'he rele4an' bu' i89li,i' rules based on 'he 5eedba,+ re,ei4ed 5ollo1in0 ea,h ,hoi,e) as
1ell as 'o deal 1i'h lon0!'er8 s'ra'e0ies 'o 8a?i8i@e 0ains) 1hi,h ,an be a,,o89lished
by 5ollo1in0 'heir subIe,'i4e a55e,'i4e 5eelin0s and hun,hes as 9ro9osed by 'he .o8a'i,
Mar+er hy9o'hesis E%F. ";7 9er5or8an,es and s'ra'e0ies are in5luen,ed by bo'h e?e,u'i4e
E10F and e8o'ional 9ro,esses E8F.
&e,en' s'udies usin0 'he ";7 ha4e sho1n 'ha' #M 9ro,esses are de5e,'i4e in all M.
sub'y9es) i.e.) rela9sin0!re8i''in0 <&&= E11FNE13F) as 1ell as 9ri8ary 9ro0ressi4e and
se,ondary 9ro0ressi4e M. E14F) 1hi,h is ,onsis'en' 1i'h 'he i89a,' o5 1hi'e!8a''er loss
on bo'h e?e,u'i4e and e8o'ional 5un,'ions. 3hile #M ,an be 9reser4ed in 4ery early
&&M. 9a'ien's E1$F) 1e 5ound by 8eans o5 a '1o!year 5ollo1!u9 s'udy 'ha' su,h abili'ies
ra9idly de,lined o4er 'i8e) inde9enden'ly o5 o'her disease!e4olu'ion 8ar+ers EF. (ll
'hese resul's unders,ore 'he 5a,' 'ha' M. 9a'ien's 8ay 5ail in ,hoosin0 ad4an'a0eously
1hen ,on5ron'ed 1i'h a8bi0uous si'ua'ions.
7he e?a,' 8e,hanis8s underlyin0 a8bi0uous #M de5i,i's in M. are ,o89le?) bu' see8
'o rely a' leas' 9ar'ly on a55e,'i4e 8odi5i,a'ions asso,ia'ed 1i'h 'he disease. M. 9a'ien's
do indeed ha4e di55i,ul'ies in e?9ressin0 or des,ribin0 e8o'ions E16F) E1F. 3e 9re4iously
5ound an asso,ia'ion o5 9er5or8an,e in 'he ";7 1i'h lo1er an?ie'y s,ores and de,reased
e8o'ional e?9erien,e as 8easured by s+in ,ondu,'an,e res9onses E11F) bu' no' 1i'h
,lassi,al e?e,u'i4e 'es's) su00es'in0 s9e,i5i,ally i89aired a55e,'i4e 9ro,esses in #M
under a8bi0ui'y. "n 5a,') a55e,'i4e 8odi5i,a'ions indu,ed by M. in,lude ale?i'hy8ia and
so8e di55i,ul'ies in re,o0ni'ion o5 5a,ial e8o'ions) and i89aired e8o'ional rea,'i4i'y 'o
ne0a'i4e s'i8uli is e8er0in0 as a ,onsis'en' 5ea'ure o5 9a'ien's 1i'h M. E18F) E1%F. By
usin0 al'erna'i4e 4ersions o5 'he ";7) Na0y e' al. E13F also sho1ed 'ha' #M de5i,i's in
M. see8ed 'o 8i8i, 'hose o5 9a'ien's 1i'h 4en'ro8edial 9re5ron'al ,or'e? <DMPFC=
da8a0e) and a99eared 'o be dri4en by re,en' ou',o8es inde9enden'ly 5ro8 0ains or
losses) ra'her 'han by an o4erall in,reased sensi'i4i'y 'o re1ard and ris+ 'a+in0 beha4ior.
.u,h beha4ior) dri4en by shor'!'er8 bene5i's) has so8e'i8es been ,alled J8yo9ia 5or 'he
5u'ureH E20F.
"n daily li5e) a ,er'ain nu8ber o5 si'ua'ions in 1hi,h de,isions ha4e 'o be 8ade o55er
e?9li,i' in5or8a'ion abou' 'he 9o'en'ial ,onseGuen,es o5 'he ,hoi,e) 'hus reGuirin0 'he
subIe,'s 'o de,ide be'1een al'erna'i4es 'ha' are de5ined in 'er8s o5 9robabili'ies and
asso,ia'ed 1i'h +no1n re1ards and 9unish8en's. 7hese +inds o5 e?9li,i' de,isions) ,alled
Rde,isions under ris+S E21F) also see8 'o i89li,a'e ,o0ni'i4e <9robabilis'i,= and
e8o'ional 9ro,esses E22F. (8on0 'he 4arious 'as+s de4elo9ed 'o 'es' #M under ris+) 'he
3heels o5 For'une 'as+ <3TF= is an e?9li,i' 'as+ in 1hi,h 'he subIe,'s see online 1ha'
'hey ,ould ha4e 1on or los' i5 'hey had ,hosen di55eren'ly. 7his 'as+ has been used 'o
sho1 'ha' #M s'ra'e0ies ,an be in5luen,ed by an'i,i9a'ion o5 re0re' E23F. 7he 3TF 1as
de4elo9ed on 'he basis o5 'he #e,ision (55e,' 7heory E24F 1hi,h e89hasi@es 'he role o5
an'i,i9a'ed a55e,'i4e i89a,'s o5 de,isions on 5u'ure ,hoi,es. By ,on5ron'in0 'he
9ar'i,i9an' 1i'h 'he ,o89arison o5 R1ha' isS 1i'h R1ha' 8i0h' ha4e beenS
<,oun'er5a,'ual 'hin+in0=) 'his 'as+ allo1s ,o0ni'i4ely!0enera'ed e8o'ions su,h as
disa99oin'8en' and re0re' 'o be 8easured E23F) E2$F) E26F. 7he 3TF 9ro4ides a 8easure
o5 ho1 de,isions and ris+ 'a+in0 are 8odi5ied under 'he 9ressure o5 su,h e8o'ions.
(no'her e?9li,i' #M 'as+ is 'he Ca8brid0e ;a8ble 7as+ <C;7=) a 1ell +no1n 9aradi08
in 1hi,h 'he subIe,' ,an 4isuali@e o9'ions 1hile de,idin0 'he e?a,' ,han,e o5 1innin0 or
losin0 his be') 1hi,h allo1s a di55eren'ia'ed assess8en' o5 i89ulsi4e res9onse 'enden,ies
and real ris+ 'a+in0. Moreo4er) ,lassi,al e?e,u'i4e 9ro,esses su,h as 1or+in0 8e8ory are
8ini8i@ed in 'he C;7) sin,e 'he in5or8a'ion reGuired 'o 8a+e 'he de,ision is 9resen'ed
e?9li,i'ly on ea,h 'rial. 7he C;7 1as de4elo9ed 'o assess #M and ris+ 'a+in0 E21F in
9a'ien's 1i'h da8a0e 'o 'he DMPFC E10F) E2F) E28F. 7his 'as+ has re4ealed in,reased ris+
9re5eren,e in 'hese 9a'ien's) 1hereas 'heir 9robabilis'i, Iud08en' <i.e.) Guali'y o5 #M=
1as si8ilar 'o 'ha' o5 'he ,on'rols. Per5or8an,e o5 5o,al brain!da8a0ed 9a'ien's on 'his
'as+ su00es' 'ha' DMPFC lesions lead 'o sele,'i4e in,reases in ris+!'a+in0 beha4iors)
1hile lesions in 'he insular ,or'e? <"C= lead 'o di55i,ul'ies in be''in0 ,al,ula'ions E2%F)
E30F.
;i4en 'he 9re4ious e4iden,e 5or a 8odi5i,a'ion o5 bo'h e8o'ional e?9erien,es E11F and
,o0ni'i4e ,o89e'en,ies E3F rela'ed 'o M.) as 1ell as 'he 9o'en'ial i89a,' o5 M. lesion on
'he in'e0ra'ion o5 'hese '1o 'y9es o5 in5or8a'ion ne,essary 5or o9'i8al #M) i' is li+ely
'ha' e?9li,i' #M 8i0h' also be i89aired or 8odi5ied in 'hese 9a'ien's. 6o1e4er) 'he
absen,e o5 lesions li8i'ed 'o 'he DMPFC) and 'he 5reGuen' o,,urren,e o5 an?ie'y
disorders in M. 9a'ien's E31F) 8i0h' 9redi,' 'ha' 'he 9a'holo0i,al 8odi5i,a'ion in #M
8i0h' no' ne,essarily in4ol4e an in,rease in e?9li,i' ris+ 'a+in0 E32F) bu' ,ould ins'ead
redu,e ris+ 'a+in0 s'ra'e0ies. 7o our +no1led0e) 'here are no da'a ,on,ernin0 'he e55e,' o5
M. on #M ,o89e'en,e under ris+) and no ,orrela'ions be'1een e?9li,i' #M
9er5or8an,e and s9e,i5i, 9er5or8an,es o5 ,o0ni'i4e or a55e,'i4e 5un,'ionin0 in su,h
9a'ien's. 7here5ore) 1e e?a8ined here 'he 9er5or8an,es o5 M. 9a'ien's in '1o e?9li,i'
de,ision si'ua'ions. 3e as+ed 1he'her M. 9a'ien's 1ould beha4e di55eren'ly 5ro8 heal'hy
,on'rols) 9ar'i,ularly in si'ua'ions 1here de,isions are based on e8o'ional si0nals. For
'his 9ur9ose) 1e used 'he '1o ,lassi, e?9li,i' 0a8blin0 'as+s) 'he 3TF and C;7
8en'ioned abo4e) all 0i4en 'o 'he sa8e 9a'ien's.
3e 9redi,'ed 'ha' M. 9a'ien's 1ould sho1 ,han0es in e?9li,i' #M 5or bo'h 'he 3TF and
C;7) and 'his should be asso,ia'ed 1i'h 8odi5i,a'ions in e8o'ional do8ains in 'hese
9a'ien's. Tur 8ain hy9o'heses 1ere 'he 5ollo1in0:
1= M. 9a'ien's 1ill 9resen' a di55eren' ,hoi,e beha4ior o5 #M under ris+ 'han ,on'rols;
'his 8i0h' be 'he ,ase in bo'h 'he 3TF and C;7; 2= .u,h 8odi5i,a'ions 1ill no'
ne,essarily re5le,' in,reased ris+ 'a+in0 !unli+e in 9a'ien's 1i'h res'ri,'ed lesions 'o
DMPFC! bu' M. 9a'ien's 8i0h' e4en ra'her 9resen' ris+ a4ersion) a' leas' in si'ua'ions
1here 'he an'i,i9a'ed a55e,'i4e i89a,' o5 de,isions ,an in5luen,e 5u'ure ,hoi,es <su,h as
'he 3TF=; 3= .u,h #M 8odi5i,a'ions in M. 9a'ien's 8i0h' be asso,ia'ed 1i'h s9e,i5i,
e8o'ional ,han0es) as 9re4iously obser4ed 5or i89li,i' #M E11F) bu' no' ne,essarily
asso,ia'ed 1i'h ,o0ni'i4e ,han0es. 7here5ore) all 9a'ien's 1ere ,are5ully e?a8ined 1i'h a
sys'e8a'i, ,o0ni'i4e e4alua'ion and 8easures Ndurin0 'he 3TF! o5 bo'h e?9li,i' and
i89li,i' e8o'ional rea,'ions.
0o )o:
Materials and Methods
Study Sub6ects
&&M. 9a'ien's ,on5or8in0 'o 'he M,#onald dia0nos'i, ,ri'eria E33F) E34F 1ere ,on'a,'ed
5or 'he s'udy. "n,lusion ,ri'eria 1ere: <1= 8ild 'o 8odera'e neurolo0i,al disabili'y) bu'
1i'h uni89aired a8bula'ion <2?9anded #isabili'y .'a'us .,ale E2#..F ran0in0 5ro8 1.$
'o 3.$= E3$F; <2= no ,lini,al rela9se and no ,or'i,os'eroid 'hera9y 5or a' leas' si? 1ee+s
be5ore in,lusion in 'he s'udy; <3= no dia0nosis o5 8aIor de9ression) al,ohol or dru0 abuse
or o'her 9sy,hia'ri, disorders a,,ordin0 'o 'he #.M!"D ,ri'eria. .e4en'y!'1o 9a'ien's)
a0ed be'1een 18 and 48 years old) 1ere analy@ed. 7hir'y!nine 9a'ien's 1ere 'rea'ed 1i'h
disease!8odi5yin0 'hera9ies <in'er5eron Q!1a or 1b in 8os' ,ases= 5or a 8ean 9eriod o5 3.3
years <ran0in0 5ro8 '1o 8on'hs 'o nine years=) 'en 1ere 'a+in0 an'ide9ressan's 5or 8inor
8ood sy89'o8s 1hi,h 1ere no' se4ere enou0h 'o 5ul5ill 'he dia0nos'i, ,ri'eria 5or
de9ression as assessed in a 9sy,hia'ri, in'er4ie1) and 5i4e had had sy89'o8a'i, 'rea'8en'
5or 5a'i0ue <a8an'adine or 8oda5inil=. 7he ,on'rol 0rou9 ,onsis'ed o5 38 heal'hy
4olun'eers 8a',hed 5or a0e) 0ender and edu,a'ion) 1i'h no his'ory o5 al,ohol or dru0
abuse) 8aIor 9sy,hia'ri, disorders <8aIor de9ression) 9sy,hosis) un'rea'ed bi9olar
disorders=) head 'rau8a) o'her neurolo0i,al disorders) or sys'e8i, illness.
Standard !rotocol Approvals7 Registrations and !atient Consents
7he s'udy 1as a99ro4ed by 'he lo,al uni4ersi'yHs 2'hi,s Co88i''ee) and all subIe,'s 0a4e
1ri''en in5or8ed ,onsen' 5or 'heir 9ar'i,i9a'ion in a,,ordan,e 1i'h 'he #e,lara'ion o5
6elsin+i. 7he Na8e o5 'he 2'hi, Co88i''ee is 'he 5ollo1in0: RCo88ission dH2'hiGue de
la re,her,he ,liniGue) Fa,ul'^ de 8^de,ine e' de biolo0ie) >ni4ersi'^ de /ausanne)
.1i'@erlandS. 7he na8e o5 'he a,,e9'ed 9roIe,' <200= 1as: R#isse,'in0 'he de,isional
9ro,ess in 9a'ien's 1i'h Mul'i9le .,lerosisS. "n order 'o 8ain'ain 8o'i4a'ion) 9ar'i,i9an's
1ere in5or8ed 'ha' 'hey 1ould re,ei4e 8oney as a 5un,'ion o5 'heir 5inal 0ains in 'he #M
'as+s. For e'hi,al reasons) in a,'ual 5a,' 'hey all re,ei4ed 20 .1iss Fran,s a' 'he end o5
'he s'udy.
8europsychological 4&amination
(ll 9ar'i,i9an's under1en' a neuro9sy,holo0i,al e?a8ina'ion) 'o 'es' 1he'her #M
de5i,i's 1ere asso,ia'ed 1i'h s9e,i5i, 9a''ern o5 ,o0ni'i4e de5i,i's. 7he Brie5 &e9ea'able
Ba''ery o5 Neuro9sy,holo0i,al 7es's <B&B!N= E36F) E3F 1as used 'o assess 4erbal
8e8ory <.ele,'i4e &e8indin0 7es' E.&7F=) s9a'ial 8e8ory <10/36 .9a'ial &e,all 7es'=)
sus'ained a''en'ion/in5or8a'ion 9ro,essin0 s9eed <3!se,ond 4ersion o5 'he Pa,ed (udi'ory
.erial (ddi'ion 7es' EP(.(7F) .y8bol #i0i' Modali'ies 7es' E.#M7F=) and 4erbal
5luen,y in se8an'i, ,ues <3ord /is' ;enera'ion E3/;F=. "n addi'ion 'o 'he B&B!N) 1e
ad8inis'ered a 'as+ 1hi,h assessed 8ore ,o89le? e?e,u'i4e s+ills <.'o,+in0s o5
Ca8brid0e E.TCF 5ro8 'he Ca8brid0e Neuro9sy,holo0i,al 7es' (u'o8a'ed Ba''ery
EC(N7(BF= E38F.
4motional and Behavioral 4&amination
(' 'he end o5 'he se,ond 'es'in0 session) subIe,'s 5illed ou' Gues'ionnaires assessin0 8ood
<6os9i'al (n?ie'y and #e9ression s,ale) 6(#= E3%F and beha4ioral ,han0es
<#yse?e,u'i4e Wues'ionnaire) #2K= E40F. 7he #2K 1as used 5or Guan'i5yin0 beha4ioral
dis'urban,es ,o88only asso,ia'ed 1i'h e?e,u'i4e i89air8en' and has already been used
in M. s'udies E41F. 7his las' Gues'ionnaire 1as ai8ed a' in4es'i0a'in0 1he'her s9e,i5i,
beha4ioural ,han0es/sy89'o8s in M. are asso,ia'ed 1i'h e4en'ual #M ,han0es. 7he 20
i'e8s o5 'he #2K en,o89ass broad areas o5 li+ely ,han0es <i89ulsi4i'y) a9a'hy)
desinhibi'ion) in'en'ionali'y) e',.=. 2a,h i'e8 is s,ored on a $!9oin' s,ale ran0in0 5ro8
Rne4erS 'o R4ery o5'enS <0 'o 4=.
9heels o 3ortune
7he 3heels o5 For'une <3TF= 'as+ E23F 1as used 'o 8easure 'he e8o'ional s'ra'e0ies
asso,ia'ed 1i'h #M under ris+. 7his 'as+ had 9re4iously sho1n 'ha' ad4an'a0eous
de,isions in heal'hy ,on'rols ,ould be indu,ed 'hrou0h 9rior e?9erien,in0 disa99oin'8en'
and re0re' <Fi0. 1(= E23F.
@i.ure 1
Description of the two gambling tasks.
71o 1heels 1ere 9resen'ed on a ,o89u'er s,reen <;a8ble 1 and ;a8ble 2=. 2a,h 1heel
1as di4ided in'o '1o se,'ors <bla,+ and li0h' blue= asso,ia'ed 1i'h di55eren' a8oun's o5
8oney. 7he si@e o5 ea,h se,'or re9resen'ed 'he 9robabili'y o5 ob'ainin0 'he 9ro9osed
ou',o8e. 7he 9ossible ou',o8es 5or ea,h indi4idual 0a8ble 1ere 4isible on 'he s,reen
and 1ere 5or8ed by any 9air o5 'he 5ollo1in0 4alues: _$0) `$0) _200) `200 <uni's
,orres9ondin0 'o ,en's in .1iss 5ran,s=) and asso,ia'ed 1i'h di55eren' ou',o8e
9robabili'ies <0.8) 0.2) and 0.$=. 7he subIe,' 1as as+ed 'o ,hoose one o5 'he '1o 1heels
by 9ressin0 a le5' or a ri0h' bu''on <,hoi,e 9eriod=. ( s9innin0 arro1 'hen a99eared a' 'he
,en'er o5 'he 1heel) 'urned 5or a 4ariable dura'ion <1ai' 9eriod=) and s'o99ed in one o5 'he
'1o se,'ors) re4ealin0 'he ou',o8e 1hi,h resul'ed in a 5inan,ial 0ain or loss <5eedba,+
9eriod=. (' 'he end o5 ea,h 'rial) subIe,'s had 'o indi,a'e 'heir a55e,'i4e s'a'e usin0 a ra'in0
s,ale ran0in0 5ro8 _$0 <e?'re8ely sad= 'o `$0 <e?'re8ely ha99y=.
7he 'as+ in,luded '1o ,ondi'ions 0i4en in se9ara'e blo,+s. "n 'he R9ar'ial 5eedba,+S
,ondi'ion <PF; 30 'rials=) 'he s9innin0 arro1 and 'he rela'ed ou',o8e 1ere a99aren' 5or
'he sele,'ed 1heel only. "n 'his ,ondi'ion) 'he un5a4orable ,o89arison o5 'he ob'ained
ou',o8e 1i'h a 8ore 5a4orable ,oun'er5a,'ual <i.e.) unob'ained= ou',o8e 8ay ha4e
indu,ed disa99oin'8en' rela'ed 'o 'he 5inan,ial ,onseGuen,e o5 a de,ision E23F. By
,on'ras') in 'he R,o89le'e 5eedba,+S ,ondi'ion <CF; 30 'rials=) s9innin0 arro1s a99eared)
ro'a'ed and s'o99ed in bo'h 'he sele,'ed and 'he non!sele,'ed 1heels) re4ealin0 bo'h
ou',o8es 'o 'he 9ar'i,i9an's. CF 'rials indu,ed no' only disa99oin'8en' bu' also re0re')
by sho1in0 'he ou',o8e 'ha' 1ould ha4e been ob'ained i5 9ar'i,i9an's had sele,'ed 'he
o'her 0a8ble <,oun'er5a,'ual ou',o8e=.
Skin Conductance Response Recording
.+in ,ondu,'an,e res9onses <.C&s= 1ere re,orded durin0 'he 3TF 'as+ usin0 'he
Po1er/ab/;.& a89li5ier sys'e8 <(# "ns'ru8en's ;8b6) .9e,hba,h) ;er8any=. 7his
1as done in order 'o ob'ain 'he 9hysiolo0i,al ,orrela'e o5 re0re') 1hi,h ,onsis'ed o5 an
in,rease o5 .C&s in 'he CF ,ondi'ion due 'o ,oun'er5a,'ual 9ro,essin0) as ,o89ared 'o
'he PF ,ondi'ion o5 'he 3TF. 7he .C&s re9resen' an indi,a'or o5 sy89a'he'i, ner4ous
sys'e8 a,'i4a'ion) 1hi,h is belie4ed 'o ,on'ribu'e 'o 'he 9ro,ess o5 8a+in0 ad4an'a0eous
,hoi,es 5or 'he or0anis8.
.C& da'a 1ere a,Guired ,on'inuously usin0 5la'!sur5a,e ele,'rodes 9la,ed on 'he non!
do8inan' hand and s'ored 5or o55!line analysis usin0 a se,ond ,o89u'er runnin0 Char'
44.2 so5'1are. 7he .C&s o5 in'eres' 1ere 'hose 0enera'ed durin0 'he 5i4e!se,ond in'er4al
5ollo1in0 'he 4ie1in0 o5 'he ob'ained ou',o8e <5eedba,+ 9eriod) 9os'!,hoi,e .C&s=.
.i?'y 5i4e!se,ond 'i8e 9oin's 1ere re,orded 5or ea,h subIe,'. (r'e5a,'ual si0nals <e.0.) 'he
subIe,'Hs 8o4e8en's= 1ere ,leared 8anually. Mean a89li'udes <8i,ro.ie8ens) a.=
re,orded durin0 ea,h 5i4e!se,ond 'i8e 1indo1 1ere analy@ed <i.e.) 'he 8ean o5 'he da'a
9oin's ob'ained in 'he 5i4e!se,ond sele,'ion=. Baseline .C& a,'i4i'y 1as assessed usin0
'hree 8easure8en's 9er subIe,' re,orded: <1= a' res'; <2= in res9onse 'o a loud noise; and
<3= a5'er a dee9 brea'h. 7his 8e'hod had been a99lied in a 9re4ious s'udy E11F and had
been sho1n 'o be reliable.
Cambridge :amble +ask
7he Ca8brid0e ;a8ble 7as+ <C;7= E21F 1as used 'o 8easure #M <Fi0. 1B=.
Par'i,i9an's sa' in 5ron' o5 a ,o89u'er 'ou,h s,reen. 7rials 1ere run in blo,+s <'1o se's o5
5our blo,+s 9er subIe,'=) ea,h ,on'ainin0 nine 'rials. ( blo,+ ,ould 5inish 9re8a'urely i5 i'
ended in ban+ru9',y. (' 'he be0innin0 o5 ea,h blo,+) 'hey 1ere 0i4en 100 9oin's. ( ro1
o5 'en bo?es <red or blue) 1i'h a ra'io 4aryin0 a,ross 'he 'rials= 1as 9resen'ed a' 'he 'o9 o5
'he s,reen and 9ar'i,i9an's 1ere 'old 'ha' a yello1 'o+en 1as hidden in one o5 'he bo?es.
7hey 'hen had 'o 0uess 1he'her i' 1as in a red or blue bo? and 'o de,ide ho1 8any o5
'heir 9oin's 'hey 1an'ed 'o 0a8ble on 'heir ,hoi,e <$C) 2$C) $0C) $C or %$C) 0i4en in
a 9ro0ressi4ely as,endin0 or des,endin0 order de9endin0 on 'he blo,+s=. ( 1innin0
,hoi,e 1as re1arded by 'he 'o'al o5 9oin's 0a8bled) 1hereas a losin0 ,hoi,e 1as
9unished by sub'ra,'in0 'ha' nu8ber o5 9oin's. 7he 9robabili'y o5 ea,h ,hoi,e bein0
,orre,' 1as indi,a'ed 'o 'he subIe,'s by 'he ra'io be'1een red and blue bo?es. 7his
9rodu,ed a 4arie'y o5 si'ua'ions) ran0in0 5ro8 'hose in 1hi,h one ou',o8e 1as 'he 8os'
li+ely <e.0.) nine red bo?es 'o one blue bo?= 'o 'hose in 1hi,h bo'h ou',o8es 1ere al8os'
eGually li+ely <si? 'o 5our=. 3e used 'he s'andard 4ersion 9ro4ided by C(N7(B
<h''9://111.,an'ab.,o8/,an'ab!'es's!,a8brid0e!0a8blin0!'as+.as9= 1i'h a $ $ ra'io o5
red!blue bo?es also in,luded in 'he desi0n 'o ensure 'ha' 9ar'i,i9an's 9er,ei4ed 'he 'as+ as
a rando8 'rial seGuen,e. 7here5ore) i' 1as hy9o'hesi@ed 'ha' 'he C;7 allo1ed
9ar'i,i9an's 'o a99ly ,o0ni'i4e s'ra'e0ies) su,h as 9robabilis'i, Iud08en') in order 'o
de,ide ad4an'a0eously. 7he as,endin0 and des,endin0 seGuen,e in 1hi,h 9o'en'ial 1ins
1ere 9ro9osed enabled us 'o di55eren'ia'e 9a'ien's 1i'h i89ulsi4e res9onse 'enden,ies
5ro8 9a'ien's 1i'h real ris+ 9re5eren,e <i.e.) ris+!9re5eren' 9a'ien's had 'o 1ai' i5 'hey
1an'ed 'o 9la,e hi0h be's in 'he as,endin0 ,ondi'ions=. Measures o5 beha4ior ,hoi,es
1ere Guali'y o5 #M <'he 9ro9or'ion o5 'rials 1here 9ar'i,i9an's ,hose 'he 8ore li+ely
ou',o8e= and delibera'ion 'i8e.
Statistical Analyses
.'a'is'i,al analyses 1ere ,ondu,'ed usin0 a .7(7( so5'1are 9a,+a0e <Dersion 10.0=.
Non!9ara8e'ri, 'es's 1ere a99lied 'o all 'he de8o0ra9hi, and beha4ioral da'a be,ause <1=
'he C;7 and 3TF da'a ,ould no' be 'rans5or8ed su,,ess5ully 'o rea,h nor8ali'y) and <2=
'he dis'ribu'ion o5 'he 3TF e8o'ional ra'in0s is by de5ini'ion non!nor8al as 'he s,ale is
res'ri,'ed <4alues a4ailable 5ro8 _$0 'o `$0= and 'hus ,anno' be ,onsidered as a
,on'inuous 4ariable. #i55eren,es 1ere e?a8ined usin0 Chi2 'es's 5or 'he ,o89arison o5
,a'e0ori,al 4ariables and 3il,o?on si0ned ran+ 'es's 5or 'he ,o89arison o5 ,on'inuous
4ariables. 7o 8easure 'he 9ossible in5luen,es o5 e?e,u'i4e) a''en'ional and e8o'ional
4ariables on de,isional 9er5or8an,es) 1e 'hen ,o89u'ed sin0le .9ear8an ,orrela'ion
analyses 1i'h ,er'ain ou',o8e 8easures in 'he 5ollo1in0 e?e,u'i4e 'as+s: .TC) .#M7)
and P(.(7.
For 'he 3TF 'as+) 1e 5irs' analy@ed 'he e8o'ional e4alua'ions o5 de,isional ou',o8es
and 'hen 'es'ed '1o 8odels o5 ,hoi,e ,o89u'ed by re0ression analyses) usin0 a 9anel
lo0i' 9ro,edure 1i'h an indi4idual rando8 e55e,'. 7he 9anel da'a analysis 'oo+ ea,h
subIe,' as 'he uni' and 'he 'rial as 'he 'i8e. 7he rando8 e55e,'s 8odel 1as used as 'he
de5aul' 8odel) and 'he 9ara8e'ers 1ere es'i8a'ed by 8a?i8u8 li+elihood. 7his s'a'is'i,al
9ro,edure is e?'ensi4ely des,ribed else1here E23F) E26F. 7he 5irs' 8odel in'e0ra'ed 'he
e55e,'s o5 an'i,i9a'in0 disa99oin'8en' <d) ne0a'i4e e8o'ion e?9ressed in 'he PF ,ondi'ion
1hen 5a,in0 a ne0a'i4e ou',o8e= and re0re' <r) ne0a'i4e e8o'ion indu,ed by 'he
,oun'er5a,'ual ,o89arison o5 a ne0a'i4e ob'ained ou',o8e 1i'h a 8ore ad4an'a0eous
ou',o8e 5or 'he reIe,'ed al'erna'i4e= in addi'ion 'o 'he 8a?i8i@a'ion o5 e?9e,'ed 4alues
<2D) ,hoi,es o5 'he 8os' 5a4orable odds) re5le,'in0 Guali'y o5 #M and ris+ 'a+in0=. "n
5a,') as 1e ha4e already 8en'ioned) a subIe,' ob'ainin0 an ou',o8e lo1er 'han e?9e,'ed
8i0h' e?9erien,e disa99oin'8en' or re0re'. 7he 0rea'er 'he di55eren,e be'1een 'he
e?9e,'ed and 'he ob'ained ou',o8e) 'he 8ore in'ense 'his ne0a'i4e 5eelin0 1ill be. 7hus)
'o a4oid 5u'ure disa99oin'8en' or re0re') 'he subIe,' 8i0h' 9ro0ressi4ely ada9' his or her
,hoi,e beha4ior by sele,'in0 a 0a8ble 'ha' 8ini8i@es 'he di55eren,e be'1een 'he lo1es'
and hi0hes' ou',o8es) 1ei0h'ed by 'he 9robabili'y o5 'he 1ors' 9ossible ou',o8e. 7his is
1ha' 1e ,all an'i,i9a'ion o5 disa99oin'8en' and re0re'.
"n 'he se,ond 8odel E42F) 1e used 'he lo0i' re0ression 'o es'i8a'e 'he 9robabili'y o5 'he
9ar'i,i9an' ,hoosin0 'he 5irs' 0a8ble) as a 5un,'ion o5 'he di55eren,e in 2D <d2D= and
s'andard de4ia'ion <a 8easure o5 ris+= be'1een 'he 5irs' and se,ond lo''ery:
7he 4ariables d2D and ris+ are de5ined as 5ollo1s:
1here ?1) y1 and ?2) y2 are 'he '1o 9ossible ou',o8es o5 'he 5irs' and 'he se,ond lo''eries
res9e,'i4ely) 1i'h ?1by1) and ?2by2. 7he 9robabili'y o5 ?1 is 9 and 'he 9robabili'y o5 y1 is
<1N9=. 7he 9robabili'y o5 ?2 is G and 'he 9robabili'y o5 y2 is <1NG=. 7hus a 9osi'i4e
<ne0a'i4e= and si0ni5i,an' d2D or ris+ ,oe55i,ien' indi,a'es 'ha' subIe,'s ,onsis'en'ly
,hoose 'he lo''ery 1i'h 'he hi0hes' <lo1es'= e?9e,'ed 4alue or le4el o5 ris+ res9e,'i4ely.
For 'he C;7) ,hoi,e beha4ior and be''in0 beha4ior 1ere analy@ed se9ara'ely E30F on 'he
basis o5 'he s,ores ,al,ula'ed 'hrou0h 'he C;7 9ro0ra8. "' should be no'ed 'ha' 'rials
1i'h a $ $ ra'io o5 red!blue bo?es) in,luded in 'he desi0n 'o 8i8i, a rando8 'rial
seGuen,e) 1ere e?,luded 5ro8 'he s'a'is'i,al analyses. 7he analysis o5 'he 9ar'i,i9an'Hs
be''in0 beha4ior 1as also li8i'ed 'o 'he 'rials in 1hi,h 'he subIe,'s ,hose 'he 8os' li+ely
,olor) in order 'o 8ain'ain inde9enden,e 5ro8 ,hoi,e beha4ior. 7he 9a'ien'sH and
,on'rolsH s,ores 1ere dire,'ly ,o89ared usin0 Mann!3hi'ney non 9ara8e'ri, 'es's.
0o )o:
Results
'emographic7 Clinical and 8europsychological 'ata
7he de8o0ra9hi,) ,lini,al and neuro9sy,holo0i,al ,hara,'eris'i,s o5 all 'he 9ar'i,i9an's
are re9or'ed in 7able 1. &&M. 9a'ien's and ,on'rols did no' di55er in 'er8s o5 a0e) years
o5 edu,a'ion or 0ender.
<"ble 1
Demographics, clinical neuropsychological characteristics of MS
patients and controls.
(5'er ,orre,'ion 5or 8ul'i9le ,o89arisons) 'he &&M. 9a'ien's s,ored lo1er 'han 'he
,on'rols in 8easures o5 a''en'ion/9ro,essin0 s9eed <.#M7: @ B _2.%) 9 B 0.003=) and
e?e,u'i4e 5un,'ionin0 <.TC!subseGuen' 'hin+in0 'i8e: @ B _2.81) 9 B 0.00$=. Con,ernin0
e8o'ional s,ores) 'he &&M. 9a'ien's re9or'ed hi0her an?ie'y <@ B _2.$1) 9 B 0.012= s,ores
in 'he 6(#.
4motional 'ecision Making: +he 9heels o 3ortune +ask
Choice behavior
&esul's based on re0ression analyses <7able 2() Fi0. 2= sho1ed 'ha' 'he ,on'rols) bu' no'
M. 9a'ien's) ,hose by an'i,i9a'in0 disa99oin'8en' <Q B _0.0036) 9]0.001=. 7he se,ond
re0ression analysis <7able 2B) Fi0. 2= re4ealed 'ha' 'he &&M. 9a'ien's 1ere 8ore ris+
a4erse <Q B _0.002%) 9]0.001= rela'i4e 'o 'he heal'hy ,on'rols) 1ho 1ere ris+ neu'ral <Q B
0.0013) 9 B 0.1=.
@i.ure 2
Model of choice integrating the efects of disappointment and risk in
addition to the maimi!ation of epected "alues.
<"ble 2
#hoice beha"ior in the $heels of %ortune task for MS patients and
healthy controls &regression analyses, panel logit with indi"idual
random efect'.
4motional evaluation
&esul's 5ro8 'he e8o'ional ra'in0s in 'he 3TF sho1ed 'ha' 'he &&M. 9a'ien's re9or'ed
less ne0a'i4e a55e,'i4e rea,'ions) as ,o89ared 1i'h 'he ,on'rols) 5or bo'h disa99oin'8en'
<@ B _2.4$) 9 B 0.01= and re0re' <@ B _2.38) 9 B 0.02=. "n ,on'ras') 'heir e?9li,i' e?9ression
o5 9osi'i4e e8o'ion 1as ,o89arable <Fi0ure 3(=. 7o 'es' 'he hy9o'hesis o5 a 0eneral
de5i,i' in e4alua'in0 ne0a'i4e 5eedba,+s) a linear re0ression 1as run se9ara'ely 5or
9osi'i4e and ne0a'i4e ou',o8es 'es'in0 'he in5luen,e o5 ob'ained ou',o8e) ,oun'er5a,'ual
ou',o8e <i.e.) unob'ained by a ,hosen 0a8ble durin0 'he PF and ob'ained by an un,hosen
0a8ble durin0 'he CF=) and 0rou9 on 'he a55e,'i4e ra'in0s. 3e 5ound no e55e,' o5 'he
Eob'ained ou',o8e ? 0rou9F in'era,'ion 5or 9osi'i4e ou',o8es <Q B 0.01) 9 B 0.2=) 8eanin0
'ha' bo'h 0rou9s ra'ed 9osi'i4e ou',o8es in 'he sa8e 1ay. By ,on'ras') 'he e55e,' o5 'he
Eob'ained ou',o8e ? 0rou9F in'era,'ion sho1ed a s'ron0 'rend a5'er Bon5erroni ,orre,'ion
'o1ards ne0a'i4e ou',o8es <Q B 0.04) 9]0.00$=) ,on5ir8in0 'ha' &&M. 9a'ien's ra'ed
ne0a'i4e ou',o8es less ne0a'i4ely 'han 'he ,on'rols. Finally) ,on,ernin0 ,oun'er5a,'ual
ou',o8es) 'here 1as an e55e,' o5 ,oun'er5a,'ual ou',o8e ? 0rou9 5or bo'h 'he 9osi'i4e <Q
B 0.01) 9]0.00$= and ne0a'i4e <Q B 0.01) 9]0.0$= ,ondi'ions) indi,a'in0 a 0eneral de5i,i'
in 'he in'e0ra'ion o5 ,oun'er5a,'ual in5or8a'ion in 'he e?9li,i' e4alua'ion 9ro,ess 5or 'he
&&M. 9a'ien's. 7here 1ere no si0ni5i,an' ,orrela'ion be'1een 8easure o5 re0re' and
,o0ni'i4e s,ores.
@i.ure 3
(motional processing in the $)% task.
Skin conductance response recording
.C& baseline rea,'i4i'y 1as ,o89arable in &&M. 9a'ien's and ,on'rols a' res' <@ B _1.46)
9 B 0.1=) in res9onse 'o loud noise <@ B _1.43) 9 B 0.1= and a5'er dee9 brea'hs <@ B _1.18) 9
B 0.2=. 7hese baseline e55e,'s rule ou' any 0lobal dys5un,'ion o5 'he au'ono8i, ner4ous
sys'e8 in 'he 9a'ien's. #urin0 'he 3TF 'as+) .C&s 1ere si0ni5i,an'ly in,reased in bo'h
'he &&M. 9a'ien's and ,on'rols in res9onse 'o 'he 9resen'a'ion o5 'he ou',o8e o5 'he
reIe,'ed al'erna'i4e) re5le,'in0 'he e8o'ional na'ure o5 'his in5or8a'ion <&&M. 9a'ien's: @
B 2.%0) 9 B 0.004; ,on'rols: @ B 2.0%) 9 B 0.04=. 7his 9reser4ed e55e,' in &&M. also
re4eals an i89li,i' in'e0ra'ion o5 ,oun'er5a,'ual in5or8a'ion 'ha' di55ered 5ro8 'he la,+ o5
e?9li,i' use in 'heir a55e,'i4e ra'in0s. "n ,on'ras' 1i'h e8o'ional ra'in0s re9or'ed by
9ar'i,i9an's a5'er ea,h 'rial) .C&s rea,'i4i'y did no' di55er be'1een 'he &&M. 9a'ien's
and ,on'rols) nei'her 5or 9osi'i4e <@ B _0.63) 9 B 0.$0= nor 5or ne0a'i4e ou',o8es <@ B
_0.1) 9 B 0.$0= <Fi0ure 3B=.
Cognitive 'ecision Making: the Cambridge :amble +ask
Choice behavior
7he &&M. 9a'ien's di55ered 5ro8 'he ,on'rols <7able 3) Fi0. 4= 5or bo'h 8easures o5
,hoi,e beha4ior: 'hey sele,'ed 'he 8os' 5a4orable odds less o5'en <%$C c0.$ o5 'rials 4s.
%8C c0.8 5or ,on'rols; @ B 2.44) 9 B 0.01= and e?hibi'ed lon0er delibera'ion 'i8es be5ore
,hoosin0 <2413c%0$ 8s 4s. 1%34c$41 8s 5or ,on'rols; @ B _3.38) 9]0.001=. 6o1e4er)
1hen ,o89u'in0 'he 'o'al nu8ber o5 blo,+s endin0 u9 in ban+ru9',y <i.e. blo,+s
in'erru9'ed 1hen 'he 'o'al s,ore rea,hed U1 9oin'=) no di55eren,e be'1een 0rou9s 1as
obser4ed <@ B _1.32) 9 B 0.2=.
@i.ure :
*uality of DM in the #ambridge +ambling ,ask.
<"ble 3
#omparisons in terms of choice beha"ior and betting beha"ior
between MS patients and controls in the #+,.
"n 'he M. 0rou9) se4eral ,orrela'ion analyses 1ere ,o89u'ed be'1een 'he Guali'y o5 #M
and rele4an' e?e,u'i4e 9er5or8an,e <'hree ou',o8e 8easures o5 'he .TC and
9er5or8an,es in 'he 3/; 'as+=) a''en'ion s,ores <.#M7) P(.(7=) a55e,'i4e s'a'e <4alues
o5 'he 6(#=) and beha4ioral ,han0es <#2K Gues'ionnaire=. Follo1in0 7y9e 1 error
,orre,'ion) .9ear8an ,orrela'ion 'es' sho1ed 'ha') in &&M. 9a'ien's) 'he Guali'y o5 #M
sho1ed no dire,' rela'ions 1i'h 8easures o5 e?e,u'i4e 5un,'ionin0. By ,on'ras')
delibera'ion 'i8es ,orrela'ed ne0a'i4ely 1i'h a''en'ion/9ro,essin0 s9eed 8easures
<P(.(7: r B _0.364) 9 B 0.002=.
0o )o:
'iscussion
7he 9resen' s'udy is) 'o our +no1led0e) 'he 5irs' 'o assess #M in &&M. 9a'ien's usin0
'1o e?9li,i' 'as+s 1i'h +no1n ou',o8e 9robabili'ies) and a di55eren'ial re,rui'8en' o5
,o0ni'i4e and e8o'ional ,o89onen's. Tur 8ain hy9o'hesis 1as 'ha' &&M. 9a'ien's
1ould sho1 8odi5ied s'ra'e0ies in e?9li,i' #M. Moreo4er) 1e loo+ed 5or de,reased ris+
'a+in0) and 8odi5i,a'ions in e8o'ional e?9erien,e. Tur resul's su99or' 'hese hy9o'heses:
<1= &&M. 9a'ien's sho1ed) in ,o89arison 'o ,on'rols) a 9oorer Guali'y o5 #M) as
indi,a'ed by 'he 5a,' 'ha' 'hey did no' 8a?i8i@e 'he e?9e,'ed 4alues in 'he 3TF 'as+) and
'ha' 'hey sele,'ed less o5'en 'he 8os' li+ely odds in 'he C;7; <2= &&M. sho1ed 0rea'er
ris+ a4ersion; <3= &&M. 9a'ien's 1ere less sensi'i4e 'o ,oun'er5a,'ual in5or8a'ion in 'he
3TF 'as+ and e?hibi'ed a de,reased sensi'i4i'y 'o e?9li,i' ne0a'i4e e8o'ional e?9erien,e
<8easured by Gues'ionnaire=) bu' no' in ,o4er' e8o'ional rea,'ions <8easured by .C&=.
Tn 'he ,on'rary) a si0ni5i,an' asso,ia'ion 1i'h ,o0ni'i4e 5un,'ions <bu' no' e8o'ional
indi,es= 1as 5ound 5or 'he C;7 'as+) 1i'h a sele,'i4e ,orrela'ion be'1een ini'ial de,ision
'i8e and 9er5or8an,e in an a''en'ional 'as+ <P(.(7=) su00es'in0 'ha' o4erall ,o0ni'i4e
,han0es had li''le i89a,' on ,hoi,e beha4ior. 7hese 8odi5i,a'ions in M. 9a'ien's are
si0ni5i,an' al'hou0h o5 s8aller 8a0ni'ude in ,o89arison 1i'h 'hose re9or'ed a5'er
orbi'o5ron'al E23F and insular lesions E30F) or in ,o89arison 1i'h ,han0es de'e,'ed in #M
under a8bi0ui'y E11F. "n addi'ion) 'hey did no' ,ause in,reased ban+ru9',y in #M or
o4erall 0ain de,rease. 7his su00es's 'ha' M. 8odi5ies) ra'her 'han 'o'ally disru9's)
e?9li,i' #M abili'ies) a' leas' in 'he 8ild 'o 8odera'e 9hase o5 'he disease.
7hese beha4ioral resul's ,on4er0e ne4er'heless 1i'h 'hose ob'ained in s'udies dealin0
1i'h #M under a8bi0ui'y in si8ilar 9a'ien's. 7he la''er s'udies used 'he ";7 and re9or'ed
a ,onsis'en' 5ailure o5 'he de,isional 9ro,ess 1i'hin a learnin0 ,on'e?' o5 si89le 5eedba,+
,on'in0en,ies EF) E11F) E13F. Moreo4er) 'he 5indin0 o5 Na0y e' al. E13F) i.e.) 'ha' #M
i89air8en' in M. is no' ne,essarily asso,ia'ed 1i'h in,reased sensi'i4i'y 'o re1ard and
in,reased ris+ 'a+in0) ni,ely do4e'ail 1i'h our da'a) 1hi,h su00es' 0rea'er ris+ a4ersion.
7he role o5 a de,reased e8o'ional rea,'i4i'y rela'ed 'o ,han0es in #M 1as hy9o'hesi@ed
based on redu,ed .C&s E11F. "n 'he ,urren' s'udy) 1e no1 sho1 'ha' &&M. 9a'ien's 8ay
8odi5y 'heir s'ra'e0ies in #M under e?9li,i' ris+ ,ondi'ions.
Associated Mechanisms
7he ,orrela'ion o5 #M 8e,hanis8s 1i'h o4erall ,o0ni'i4e and beha4ioral <#2K=
5un,'ionin0 1as 1ea+. 7he only si0ni5i,an' asso,ia'ion 1i'h ,o0ni'i4e 9er5or8an,es 1as
5ound be'1een 'he C;7 delibera'ion 'i8e 'as+ and a 8easure o5 a''en'ional/1or+in0
8e8ory 9er5or8an,e <P(.(7=. 7his ,orrela'ion 8ay re5le,' 'he +no1n slo1er
9ro,essin0 s9eed in 'he M. 0rou9) and e?9lains also 1hy delibera'ion 'i8e a' 'he C;7 is
9rolon0ed in M. 9a'ien's.
Con,ernin0 e8o'ional 9ro,essin0) 1e 5ound a si0ni5i,an' rela'ion be'1een ,oun'er5a,'ual
ou',o8e and 0rou9 in 'he 3TF) su00es'in0 'ha' a 0lobal de5i,i' by M. 9a'ien's in
in'e0ra'in0 ,oun'er5a,'ual in5or8a'ion in 'he e4alua'ion 9ro,ess 8ay 9lay a dire,' role in
'he 8odi5i,a'ion o5 #M. #i55eren' s'udies ha4e 9ro4ided beha4ioral e4iden,e 5or a role o5
,oun'er5a,'ual an'i,i9a'ion o5 re0re' and relie5 in #M) bu' also in 9robabilis'i, learnin0
E43F. 7his raises 'he Gues'ion o5 1he'her 9robabilis'i, learnin0 8i0h' be 8ore 0lobally
de,reased in M. 9a'ien's and 'hus 8i0h' a,,oun' 5or 'his di55i,ul'y. 7o our +no1led0e)
'his Gues'ion) i.e.) ho1 9a'ien's learn 'he ,on'in0en,ies be'1een en4iron8en'al s'i8uli
and 'heir ,onseGuen,es) has been addressed only in5reGuen'ly in neurolo0i,al diseases
E44F. Tn 'he o'her hand) 'he de5i,i's in 'he 3TF 'as+ in our 9a'ien's 1ere asso,ia'ed 1i'h
a 5ailure 'o ra'e and use e8o'ional e?9erien,es adeGua'ely in order 'o 8a?i8i@e e?9e,'ed
4alues. 7hese resul's su00es' 'ha') li+e in 'he ";7 E11F) 8odi5i,a'ions in e8o'ional
e?9erien,e 8ay be asso,ia'ed 1i'h ,han0es in #M under e?9li,i' ris+. Moreo4er) 'hey
9oin' 'o 'he role o5 an o4er' e8o'ional e4alua'ion ra'her 'han a so8a'i, i89li,i' 8ar+er.
8euroanatomical ;ypotheses
7he ,orrela'ion be'1een lesion load and ,o0ni'i4e 5un,'ions 1as o4erall 1ea+ in M. and
1e did no' 9er5or8 a sys'e8a'i, Guan'i'a'i4e lesion analysis in our s'udy E4$F) E46F.
6o1e4er) our &&M. 9a'ien's sho1ed a de,rease in be''in0 beha4ior bu' 1i'h an in,rease
in ris+ a4ersion durin0 bo'h #M 'as+s) su00es'in0 'ha' ,han0es in be''in0 1as no' due 'o
hi0h ris+ biases li+e in DMPFC 9a'ien's. 7his resul' adds 5ur'her 1ei0h' 'o 'he 5indin0 o5
Na0y e' al. E13F 'ha' #M i89air8en' in M. 9a'ien's is no' rela'ed 'o an in,reased
sensi'i4i'y 'o re1ard. "n addi'ion) 'his 9a''ern su00es's disso,ia'ion be'1een 'he
8e,hanis8s 9ro8o'in0 ris+y ,hoi,es and ris+ a4ersion) 1hi,h 8ay be di55eren'ially
a55e,'ed by 5o,al da8a0e 'o 'he DMPFC and by 8ore di55use 1hi'e!8a''er lesions)
res9e,'i4ely.
Risk Aversion and 4motional Reactivity
(n i89or'an' resul' 1hi,h 1as 5ound in bo'h 0a8blin0 'as+s ,on,erned ris+ a4ersion)
9ar'i,ularly 9resen' in 'he 3TF 'as+. "' has been 9ro9osed 'ha') in ,ases o5 i89aired #M
or 9robabilis'i, Iud08en') 'he redu,'ion o5 ris+ 8i0h' re5le,' a ,o89ensa'ory 8e,hanis8
desi0ned 'o 8ain'ain 'he 5inal 9er5or8an,e E4F. 7his ,ould 9o'en'ially 9ro4ide an
e?9lana'ion 5or our obser4a'ions. &&M. 9a'ien's 8i0h' beha4e in a 8ore ,onser4a'i4e
8anner be,ause o5 a loss o5 ,on5iden,e in 'heir ,hoi,es. ( 5ur'her 9ossible e?9lana'ion
5or ris+ a4ersion 8i0h' s'e8 5ro8 our 5indin0s in 'he 3TF 'as+) 1here 'he &&M.
9a'ien's de8ons'ra'ed a dis'in,'i4e al'era'ion o5 e8o'ional 9ro,essin0. 3hen ,on5ron'ed
1i'h ne0a'i4e ou',o8es durin0 'he 'as+) 'he 9a'ien's e?9ressed si0ni5i,an'ly less
disa99oin'8en' and less re0re' 'han 'he ,on'rols) 1hereas 'he ra'in0 o5 9osi'i4e e8o'ions
1as ,o89arable in bo'h 0rou9s. 7his beha4ior e,hoes o'her si8ilar 5indin0s in e8o'ional
'as+s in M. 9a'ien's E1%F) and ,anno' be due 'o a 0eneral disin'eres' in 'he 'as+) sin,e 'his
1ould ra'her lead 'o an o4erall redu,'ion o5 8a0ni'ude o5 e8o'ional ra'in0. 7he
a89li5i,a'ion e55e,' <i.e.) 'he di55eren,e in ne0a'i4e ra'in0s ob'ained in PF 4s. CF
,ondi'ions= 1hi,h is an indi,a'ion o5 re0re' 1as also non!si0ni5i,an' in 'hese 9a'ien's)
indi,a'in0 de,reased ,oun'er5a,'ual 9ro,essin0 and de5i,ien' an'i,i9a'ion o5 'he ne0a'i4e
e8o'ions o5 losses. "n 8ore 0eneral 'er8s) 'hese da'a su00es' a de5i,i' in in,or9ora'in0
,oun'er5a,'ual in5or8a'ion in'o 'he e?9li,i' e8o'ional e4alua'ion 9ro,ess. 7his ,ould
re5le,' a de5i,i' in ,ons,iously in'e0ra'in0 di55eren' sour,es o5 in5or8a'ion durin0 #M)
9erha9s due 'o dis,onne,'ion lesions in M. 9a'ien's) and de8ons'ra'es 'ha' a la,+ o5
e?9li,i' ,oun'er5a,'ual re0re' 8ay arise 1i'hou' da8a0e 'o 'he orbi'o5ron'al ,or'e? <TFC=
i'sel5 <see E23F=.
.'ri+in0ly) al'hou0h &&M. 9a'ien's re9or'ed disa99oin'8en' and re0re' 'o a si0ni5i,an'ly
lesser e?'en' as ,o89ared 'o heal'hy 9ar'i,i9an's) 1e ,ould no' de8ons'ra'e any
di55eren,es in .C&s be'1een 'he &&M. 9a'ien's and heal'hy ,on'rols. (l'hou0h .C&
si0nals are 8u,h 8ore 4ariable 'han sel5!re9or' s,ales) and 8ay 'here5ore be 'oo noisy 'o
de8ons'ra'e reliable di55eren,es be'1een 'hese 0rou9s) our 5indin0 ,on'ras's 1i'h
9re4ious resul's 'ha' su00es'ed 'ha' a de,reased e8o'ional rea,'i4i'y 8ay underlie
i89aired #M in a8bi0uous si'ua'ions E11F. (l'hou0h 'he role 5or di55eren,es be'1een 'he
'as+s used a,ross s'udies ,anno' be e?,luded) one e?9lana'ion 5or 'his di55eren,e in .C&s
4alues 8i0h' be 5ound in 'he 9o9ula'ion 'ha' 1as in4es'i0a'ed in 'he ,urren' s'udy. "ndeed)
in 'his 9resen' ,ase) 1e enrolled only &&M. 9a'ien's 1i'h lo1 neurolo0i,al disabili'y. By
,on'ras') Mleeber0 e' al. E11F s'udied bo'h &&M. and se,ondary 9ro0ressi4e M. 9a'ien's
1ho had 8ore se4ere neurolo0i,al disabili'y <2#.. be'1een 1.$ and 6.$= and lon0er
disease dura'ion <8ean 103 8on'hs=. "' 8i0h' 'hus be hy9o'hesi@ed 'ha' e8o'ional
rea,'i4i'y de,lines o4er 'i8e as a resul' o5 disease 9ro0ression bu' is s'ill 9reser4ed in
early &&M..
"n our 4ie1) 'he la,+ o5 sel5!re9or'ed disa99oin'8en' and re0re' ,ould re5le,' a de5i,i'
a+in 'o ale?i'hy8ia. 7he 'er8 ale?i'hy8ia 1as 5irs' de5ined by .i5neos E48F 'o des,ribe an
inabili'y 'o 5ind a99ro9ria'e 1ords 'o iden'i5y) e?9ress or des,ribe e8o'ions) and a
di55i,ul'y in di55eren'ia'in0 5eelin0s 5ro8 bodily sensa'ions. "' has been re9or'ed in a
4arie'y o5 neurolo0i,al diseases E4%FNE$1F. "n M.) ale?i'hy8ia has also been re9or'ed in a
lar0e 9ro9or'ion o5 9a'ien's) ran0in0 5ro8 13C 'o 43C a,,ordin0 'o 4arious s'udies E16F)
E1F. Tur 1or+ rein5or,es 'hese ,lini,al obser4a'ions by 9ro4idin0 8ore e?9eri8en'al
9ers9e,'i4e on 'his 9heno8enon) and by sho1in0 5or 'he 5irs' 'i8e 'ha' redu,ed use o5
e8o'ional si0nals or Rale?i'hy8ia!li+eS 8e,hanis8s 8i0h' underlie i89air8en's in #M
beha4ior. Fur'her8ore) i' has been sho1n 'ha' e?9li,i' e8o'ional e4alua'ion <i.e.)
e8o'ional Ra99raisalS= 8ay also ,on'ribu'e 'o e55e,'i4e #M and 'ha' e8o'ion re0ula'ion
s'ra'e0ies <in 9ar'i,ular ,o0ni'i4e rea99raisal= 8ay ha4e bene5i,ial e55e,'s on #M bo'h
under ris+ and under un,er'ain'y E$2F. 7hus) i' is 9lausible 'ha' so8e 5or8 or ,o89onen's
o5 ale?i'hy8ia 8i0h' be dire,'ly rela'ed 'o in,reased ris+ a4ersion and de,reased #M) as
obser4ed in our M. 9a'ien's.
Finally) by sho1in0 'ha' ale?i'hy8i, losses 8ay arise ,on,o8i'an'ly 'o i89aired #M
9er5or8an,e in &&M. 9a'ien's) our resul's hi0hli0h' 'ha' a55e,'i4e 9ro,esses 8i0h'
,on'ribu'e 'o nor8al #M and i's i89air8en' in M.. Fro8 a neurobiolo0i,al 9oin' o5
4ie1) re,en' neuroi8a0in0 s'udies ha4e e89hasi@ed 'he i89li,a'ion o5 s9e,i5i, brain
areas in ale?i'hy8ia 9heno8ena) in,ludin0 'he an'erior ,in0ula'e ,or'e? <(CC=) 'he
9re8o'or ,or'e? and 'he a8y0dala E$3F) E$4F. 7here5ore) 1e s9e,ula'e 'ha' 'he 1hi'e!
8a''er 9re5ron'al lesion load ,aused by M. E$$F 8i0h' lead 'o a de,reased s'ru,'ural and
5un,'ional ,onne,'i4i'y 1i'hin a 1ide brain ne'1or+) ,o89osed o5 'he TFC) #/PFC) and
li8bi, areas) 1hi,h 8i0h' in 'urn ,on'ribu'e 'o 'he i89aired in'e0ra'ion o5 ,o0ni'i4e and
a55e,'i4e si0nals) and 'hus de5i,ien' de,isional 9ro,esses in M.. 7o su99or' 'his
hy9o'hesis a' leas' in 9ar') a la,+ o5 5un,'ional ,onne,'i4i'y be'1een 9re5ron'al areas and
'he a8y0dala durin0 e8o'ional 9ro,essin0 has been re,en'ly re9or'ed in 9a'ien's 1i'h
early M. in a 5un,'ional 8a0ne'i, resonan,e i8a0in0 s'udy E6F.
"n ,on,lusion) #M under ris+ 1as 5ound 'o be 8odi5ied in M. 9a'ien's. 6o1e4er) unli+e
5ron'al 9a'ien's) &&M. 9a'ien's e?hibi'ed an in,reased ris+ a4ersion durin0 'he de,isional
9ro,ess 1hi,h 8i0h' re9resen' a ,onser4a'i4e bias due 'o redu,ed ,on5iden,e in 'heir
,hoi,es. Moreo4er) i89air8en' o5 e?9li,i' e8o'ional 9ro,esses <as illus'ra'ed by 'he
9resen,e o5 ale?i'hy8ia and de,reased ,oun'er5a,'ual 'hin+in0= 1as also asso,ia'ed 1i'h
'his de5i,i'. #M is an i89or'an' 5a,'or 5or a,'i4e 9a'ien's 1i'h M.) 5or e?a89le 1hen
de,idin0 5or 9ro5essional) 9ri4a'e li5e) or 'hera9ies. "n5or8in0 'he8 'ha' 'he disease 8ay
ha4e an in5luen,e on 8ana0e8en' o5 ,oun'er5a,'ual in5or8a'ion and ris+ 8ay hel9 'he8
in ,er'ain ,ru,ial si'ua'ion. 7hese 5indin0s 8ay hel9 no' only 'o be''er unders'and 'he
neural bases o5 #M and 'heir disorders) bu' also hel9 be''er lis'en 'o and su99or' 'hese
<'y9i,ally youn0= 9a'ien's.
0o )o:
Acknowledgments
3e 'han+ #r. C. &u55ieu? 5or her ,on'ribu'ion 'o 'he s'a'is'i,al analyses) #r. (. .iri0u 5or
her use5ul ad4i,e durin0 'he ,on,e9'ion o5 'his s'udy) #r. ".M. Penner 5or 9ro4idin0 a,,ess
'o 'he Fren,h 4ersion o5 'he F.MC Gues'ionnaire) as 1ell as #r (. Ve+eridou and (.
/ysandro9oulos 1ho 9er5or8ed 'he M. 9a'ien'sH neurolo0i,al e?a8ina'ions) and (.
7ra4is 5or 9re,ious hel9 1i'h edi'in0.
0o )o:
3unding Statement
<his 7or6 7"s su##or)ed b+ )he S7iss $S Socie)+ (@orn"me @und )o $+ri"m
Schlue#)* )he S7iss ,")ion"l Science @ound")ion (0r"n) 3200/O911820') "nd
)he SociA)A 4c"dAmi5ue de 0en-Be (@orem"ne @und )o P")ri6 8uilleumier).
<he .r"n)s 7ere used >or )he s"l"ries o> SS "nd $0 "nd >or )he
reimbursmen)s o> #")ien)sC )r"Bel "nd con)rolsC )ime. <he >unders h"d no role
in s)ud+ desi.n* d")" collec)ion "nd "n"l+sis* decision )o #ublish* or
#re#"r")ion o> )he m"nuscri#).
0o )o:
Reerences
1. %"l"brese $* 4.os)" @* 3in"ldi @* $"))isi &* 0rossi P* e) "l. (200() %or)ic"l
lesions "nd ")ro#h+ "ssoci")ed 7i)h co.ni)iBe im#"irmen) in rel"#sin.9
remi))in. mul)i#le sclerosis. 4rch ,eurol '': 11::D1150. EPub$edF
2. DeLuc" 1* %helune 01* <uls6+ DS* Len.en>elder 1* %hi"r"B"llo)i ,D (200:) &s
s#eed o> #rocessin. or 7or6in. memor+ )he #rim"r+ in>orm")ion #rocessin.
deGci) in mul)i#le sclerosisH 1 %lin =I# ,euro#s+chol 2': 550D5'2. EPub$edF
3. 3"o S$* Leo 01* /ern"rdin L* JnBerK".) @ (1((1) %o.ni)iBe d+s>unc)ion in
mul)i#le sclerosis. &. @re5uenc+* #"))erns* "nd #redic)ion. ,eurolo.+ :1: '85D
'(1. EPub$edF
:. 4rne)) P4* 3"o S$* /ern"rdin L* 0r">m"n 1* Le)6in @M* e) "l. (1((:)
3el")ionshi# be)7een >ron)"l lobe lesions "nd Nisconsin %"rd Sor)in. <es)
#er>orm"nce in #")ien)s 7i)h mul)i#le sclerosis. ,eurolo.+ ::: :20D:25.
EPub$edF
5. MorKon $* de $"si 3* ,"suelli D* J6m"r $* $ucelli 3P* e) "l. (2001)
De#ression "nd "nIie)+ in mul)i#le sclerosis. 4 clinic"l "nd $3& s)ud+ in (5
sub!ec)s. 1 ,eurol 2:8: :1'D:21. EPub$edF
'. P"ss"mon)i L* %er"s" 4* Li.uori $* 0ioi" $%* 8"len)ino P* e) "l. (200()
,eurobiolo.ic"l mech"nisms underl+in. emo)ion"l #rocessin. in rel"#sin.9
remi))in. mul)i#le sclerosis. /r"in 132: 3380D33(1. EPub$edF
7. Simioni S* 3uOeuI %* 2leeber. 1* /ru..im"nn L* du P"s5uier 34* e) "l.
(200() Pro.ressiBe decline o> decision9m"6in. #er>orm"nces durin. mul)i#le
sclerosis. 1 &n) ,euro#s+chol Soc 15: 2(1D2(5. EPub$edF
8. /ech"r" 4* D"m"sio 43* D"m"sio P* 4nderson SN (1((:) &nsensi)iBi)+ )o
>u)ure conse5uences >ollo7in. d"m".e )o hum"n #re>ron)"l cor)eI. %o.ni)ion
50: 7D15. EPub$edF
(. D"m"sio 43 (1((:) Desc"r)esC error: =mo)ion* 3e"son "nd )he Pum"n
/r"in. &n:0rosse) Pu)m"nn* ,e79Lor6.
10. $"nes @* S"h"6i"n /* %l"r6 L* 3o.ers 3* 4n)oun ,* e) "l. (2002) Decision9
m"6in. #rocesses >ollo7in. d"m".e )o )he #re>ron)"l cor)eI. /r"in 125: '2:D
'3(. EPub$edF
11. 2leeber. 1* /ru..im"nn L* 4nnoni 1$* B"n $elle 0* /o.oussl"Bs6+ 1* e) "l.
(200:) 4l)ered decision9m"6in. in mul)i#le sclerosis: " si.n o> im#"ired
emo)ion"l re"c)iBi)+H 4nn ,eurol 5': 787D7(5. EPub$edF
12. 3oc" $* <orr"lB" <* $eli @* @iol $* %"lc".no $* e) "l. (2008) %o.ni)iBe
deGci)s in mul)i#le sclerosis correl")e 7i)h ch"n.es in >ron)o9subcor)ic"l
)r"c)s. $ul) Scler 1:: 3':D3'(. EPub$edF
13. ,".+ P* /encsi6 2* 3"!d" %* /enede6 2* /enicK6+ S* e) "l. (200') <he
eQec)s o> re7"rd "nd #unishmen) con)in.encies on decision9m"6in. in
mul)i#le sclerosis. 1 &n) ,euro#s+chol Soc 12: 55(D5'5. EPub$edF
1:. 0"rci"9$olin" 4* =nsen")9%"n)"llo#s 4* S"ncheK9%"rrion 3* 3oi.93oBir" <
(200() 4ssessmen) o> decision9m"6in. c"#"ci)+ in #rim"r+ "nd second"r+
#ro.ressiBe mul)i#le sclerosis. ,eurolo.i" 2:: (:D(7. EPub$edF
15. Simioni S* 3uOeuI %* 2leeber. 1* /ru..im"nn L* 4nnoni 1$* e) "l. (2008)
PreserBed decision m"6in. "bili)+ in e"rl+ mul)i#le sclerosis. 1 ,eurol 255:
17'2D17'(. EPub$edF
1'. %h"hr"oui 2* Pinoi) 1$* 8ie."s ,* 4dne) 1* /onin /* e) "l. (2008)
4leIi)h+mi" "nd lin6s 7i)h de#ression "nd "nIie)+ in mul)i#le sclerosis. 3eB
,eurol (P"ris) 1':: 2:2D2:5. EPub$edF
17. /odini /* $"nd"relli 0* <om"ssini 8* <"rsi)"ni L* Pes)"loKK" &* e) "l. (2008)
4leIi)h+mi" in mul)i#le sclerosis: rel")ionshi# 7i)h >")i.ue "nd de#ression.
4c)" ,eurol Sc"nd 118: 18D23. EPub$edF
18. Prochno7 D* Donell 1* Sch">er 3* 1or.ens S* P"r)un. PP* e) "l. (2011)
4leIi)h+mi" "nd im#"ired >"ci"l "Qec) reco.ni)ion in mul)i#le sclerosis. 1
,eurol 258: 1'83D1'88. EPub$edF
1(. Di /i)on)o L* Lon.")o ,* 1un. /* @leur+ $* $"rcel %* e) "l. (2011) 3educed
emo)ion"l re"c)iBi)+ )o ne.")iBe s)imuli in mul)i#le sclerosis* #relimin"r+
resul)s. 3eB ,eurol (P"ris) 1'7: 820D82'. EPub$edF
20. /"r9On 3* <r"nel D* Denbur. ,L* /ech"r" 4 (2003) =I#lorin. )he
neurolo.ic"l subs)r")e o> emo)ion"l "nd soci"l in)elli.ence. /r"in 12': 17(0D
1800. EPub$edF
21. 3o.ers 3D* O7en 4$* $iddle)on P%* Nilli"ms =1* Pic6"rd 1D* e) "l. (1((()
%hoosin. be)7een sm"ll* li6el+ re7"rds "nd l"r.e* unli6el+ re7"rds "c)iB")es
in>erior "nd orbi)"l #re>ron)"l cor)eI. 1 ,eurosci 1(: (02(D(038. EPub$edF
22. /r"nd $* L"budd" 2* $"r6o7i)sch P1 (200') ,euro#s+cholo.ic"l
correl")es o> decision9m"6in. in "mbi.uous "nd ris6+ si)u")ions. ,eur"l ,e)7
1(: 12''D127'. EPub$edF
23. %"mille ,* %oricelli 0* S"lle) 1* Pr"d")9Diehl P* Duh"mel 13* e) "l. (200:)
<he inBolBemen) o> )he orbi)o>ron)"l cor)eI in )he eI#erience o> re.re).
Science 30:: 11'7D1170. EPub$edF
2:. $ellers /* Sch7"r)K 4* Po 2* 3i)oB & (1((7) =l")ion "nd dis"##oin)men):
emo)ion"l res#onses )o ris6+ o#)ions. Ps+chol Sci 8: :23D:2(.
25. %"mille ,* Piron)i 84* Dodds %$* 4i)6en $3* 3obbins <N* e) "l. (2010)
S)ri")"l sensi)iBi)+ )o #erson"l res#onsibili)+ in " re.re)9b"sed decision9
m"6in. )"s6. %o.n 4Qec) /eh"B ,eurosci 10: :'0D:'(. EPub$edF
2'. %oricelli 0* %ri)chle+ PD* 1oOl+ $* OCDoher)+ 1P* Siri.u 4* e) "l. (2005)
3e.re) "nd i)s "Boid"nce: " neuroim".in. s)ud+ o> choice beh"Bior. ,")
,eurosci 8: 1255D12'2. EPub$edF
27. $"B"dd") ,* 2ir6#")ric6 P1* 3o.ers 3D* S"h"6i"n /1 (2000) DeGci)s in
decision9m"6in. in #")ien)s 7i)h "neur+sms o> )he "n)erior communic")in.
"r)er+. /r"in 123: 210(D2117. EPub$edF
28. 3"hm"n S* S"h"6i"n /1* Pod.es 13* 3o.ers 3D* 3obbins <N (1((()
S#eciGc co.ni)iBe deGci)s in mild >ron)"l B"ri"n) >ron)o)em#or"l demen)i".
/r"in 122: 1:'(D1:(3. EPub$edF
2(. %l"r6 L* $"nes @* 4n)oun ,* S"h"6i"n /1* 3obbins <N (2003) <he
con)ribu)ions o> lesion l")er"li)+ "nd lesion Bolume )o decision9m"6in.
im#"irmen) >ollo7in. >ron)"l lobe d"m".e. ,euro#s+cholo.i" :1: 1:7:D1:83.
EPub$edF
30. %l"r6 L* /ech"r" 4* D"m"sio P* 4i)6en $3* S"h"6i"n /1* e) "l. (2008)
DiQeren)i"l eQec)s o> insul"r "nd Ben)romedi"l #re>ron)"l cor)eI lesions on
ris6+ decision9m"6in.. /r"in 131: 1311D1322. EP$% >ree "r)icleF EPub$edF
31. 2oros)il $* @eins)ein 4 (2007) 4nIie)+ disorders "nd )heir clinic"l
correl")es in mul)i#le sclerosis #")ien)s. $ul) Scler 13: '7D72. EPub$edF
32. 0ior.e))" %* 0recucci 4* Mu"non S* Perini L* /"les)rieri $* e) "l. . (2012)
3educed 3is69<"6in. /eh"Bior "s " <r"i) @e")ure o> 4nIie)+. =mo)ion.
EPub$edF
33. $cDon"ld N&* %om#s)on 4* =d"n 0* 0ood6in D* P"r)un. PP* e) "l. (2001)
3ecommended di".nos)ic cri)eri" >or mul)i#le sclerosis: .uidelines >rom )he
&n)ern")ion"l P"nel on )he di".nosis o> mul)i#le sclerosis. 4nn ,eurol 50: 121D
127. EPub$edF
3:. Polm"n %P* 3ein.old S%* =d"n 0* @ili##i $* P"r)un. PP* e) "l. (2005)
Di".nos)ic cri)eri" >or mul)i#le sclerosis: 2005 reBisions )o )he R$cDon"ld
%ri)eri"S. 4nn ,eurol 58: 8:0D8:'. EPub$edF
35. 2ur)K6e 1@ (1(83) 3")in. neurolo.ic im#"irmen) in mul)i#le sclerosis: "n
eI#"nded dis"bili)+ s)")us sc"le (=DSS). ,eurolo.+ 33: 1:::D1:52. EPub$edF
3'. 3"o S$ (1((0) 4 m"nu"l >or )he /rie> 3e#e")"ble /"))er+ o>
,euro#s+cholo.ic"l <es)s in mul)i#le sclerosis. &n:$edic"l %olle.e o>
Nisconsin* $il7"u6ee.
37. /orin." 1/* L"Keron 3P* 3eulin. &=* 4der P1* P>ennin.s L* e) "l. (2001) <he
brie> re#e")"ble b"))er+ o> neuro#s+cholo.ic"l )es)s: norm")iBe B"lues "llo7
"##lic")ion in mul)i#le sclerosis clinic"l #r"c)ice. $ul) Scler 7: 2'3D2'7.
EPub$edF
38. S"h"6i"n /1* O7en 4$ (1((2) %om#u)eriKed "ssessmen) in
neuro#s+chi")r+ usin. %4,<4/: discussion #"#er. 1 3 Soc $ed 85: 3((D:02.
EP$% >ree "r)icleF EPub$edF
3(. Mi.mond 4S* Sn"i)h 3P (1(83) <he hos#i)"l "nIie)+ "nd de#ression sc"le.
4c)" Ps+chi")r Sc"nd '7: 3'1D370. EPub$edF
:0. Nilson /4* 4lderm"n ,* /ur.ess P* =mslie P* =B"ns 1 (1((') /eh"Biour"l
"ssessmen) o> )he d+seIecu)iBe s+ndrome (/4DS) m"nu"l. &n:<h"mes 8"lle+
<es) %om#"n+* /ur+ S) =dmonds* =n.l"nd.
:1. Lim" @S* Simioni S* /ru..im"nn L* 3uOeuI %* Dudler 1* e) "l. (2007)
PerceiBed beh"Bior"l ch"n.es in e"rl+ mul)i#le sclerosis. /eh"B ,eurol 18:
81D(0. EPub$edF
:2. /urne)) S* /"ul) ,* %oricelli 0* /l"6emore S1 (2010) 4dolescen)sC
hei.h)ened ris69see6in. in " #rob"bilis)ic ."mblin. )"s6. %o.n DeB 25: 183D
1('. EP$% >ree "r)icleF EPub$edF
:3. PreuschoQ 2* Tu"r)K S3* /oss"er)s P (2008) Pum"n insul" "c)iB")ion
reUec)s ris6 #redic)ion errors "s 7ell "s ris6. 1 ,eurosci 28: 27:5D2752.
EPub$edF
::. P)"6 3* 0u)brod 2* Perri. N* Schnider 4 (2001) Prob"bilis)ic con)in.enc+
le"rnin. 7i)h limbic or #re>ron)"l d"m".e. /eh"Bior"l neuroscience 115: ((3D
1001. EPub$edF
:5. @ul)on 1%* 0rossm"n 3&* Jdu#" 1* $"nnon L1* 0rossm"n $* e) "l. (1((() $3
lesion lo"d "nd co.ni)iBe >unc)ion in #")ien)s 7i)h rel"#sin.9remi))in. mul)i#le
sclerosis. 41,3. 4meric"n !ourn"l o> neuror"diolo.+ 20: 1(51D1(55. EPub$edF
:'. 2incses M<* 3o#ele S* 1en6inson $* 2h"lil $* Pe)roBic 2* e) "l. (2011)
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#er>orm"nce in mul)i#le sclerosis. $ul) Scler 17: '81D'8(. EPub$edF
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durin. 8isu"l =mo)ion"l Processin. in $"le Sub!ec)s 7i)h Pi.h De.rees o>
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370. EPub$edF
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"r)icleF EPub$edF
Jurnal -
Pro, Na'l (,ad .,i > . (. 2012 #e,e8ber 4; 10%<4%=: 20101N20106.
Published online 2012 No4e8ber 1%. doi: 10.103/9nas.120%%3410%
PMC"#: PMC3$2386%
Neuros,ien,e
5nhibition o :lutamate
Carbo&ypeptidase 55 #:C!55$ activity as a
treatment or cognitive impairment in
multiple sclerosis
Mris'en (. &ahn)
a
Crys'al C. 3a'+ins)
a
*esse (l')
b
&ana &ais)
,
Mari0o .'a'his)
b
"nna
;rish+an)
,
Ci9rian M. Craini,eau)
d
Mar'in ;. Po89er)
a)e
Ca8ilo &oIas)
b
Mi+hail D.
Ple'ni+o4)
a
Pe'er (. Calabresi)
,
*ason Brand')
a),
Pe'er B. Bar+er)
e
Barbara .. .lusher)
a)b),)1

and (da8 ". Ma9lin
a),)1
(u'hor in5or8a'ion : Co9yri0h' and /i,ense in5or8a'ion :
;o 'o:
ABS+RAC+
6al5 o5 all 9a'ien's 1i'h 8ul'i9le s,lerosis <M.= e?9erien,e ,o0ni'i4e i89air8en') 5or
1hi,h 'here is no 9har8a,olo0i,al 'rea'8en'. >sin0 8a0ne'i, resonan,e s9e,'ros,o9y
<M&.=) 1e e?a8ined 8e'aboli, ,han0es in 'he hi99o,a89i o5 M. 9a'ien's) ,o89ared 'he
5indin0s 'o 9er5or8an,e on a neuro,o0ni'i4e 'es' ba''ery) and 5ound 'ha' N!
a,e'ylas9ar'yl0lu'a8a'e <N((;= ,on,en'ra'ion ,orrela'ed 1i'h ,o0ni'i4e 5un,'ionin0.
.9e,i5i,ally) M. 9a'ien's 1i'h ,o0ni'i4e i89air8en' had lo1 hi99o,a89al N((; le4els)
1hereas 'hose 1i'h nor8al ,o0ni'ion de8ons'ra'ed hi0her le4els. 3e 'hen e4alua'ed
0lu'a8a'e ,arbo?y9e9'idase "" <;CP""= inhibi'ors) +no1n 'o in,rease brain N((; le4els)
on ,o0ni'ion in 'he e?9eri8en'al au'oi88une en,e9halo8yeli'is <2(2= 8odel o5 M..
3hereas ;CP"" inhibi'or ad8inis'ra'ion did no' a55e,' 9hysi,al disabili'ies) i' in,reased
brain N((; le4els and dra8a'i,ally i89ro4ed learnin0 and 8e8ory 'es' 9er5or8an,e
,o89ared 1i'h 4ehi,le!'rea'ed 2(2 8i,e. 7hese da'a su00es' 'ha' N((; is a uniGue
bio8ar+er 5or ,o0ni'i4e 5un,'ion in M. and 'ha' inhibi'ion o5 ;CP"" 8i0h' be a uniGue
'hera9eu'i, s'ra'e0y 5or re,o4ery o5 ,o0ni'i4e 5un,'ion.
Keywords: neuroradiolo0y) hi99o,a89us) 2!<9hos9hono8e'hyl=9en'anedioi, a,id <2!
PMP(=
;lu'a8a'e ,arbo?y9e9'idase "" <;CP""=) 9re4iously ,alled N!a,e'yla'ed!P!lin+ed a,idi,
di9e9'idase <N((/(#ase=) is a 8e8brane!bound en@y8e e?9ressed on 'he sur5a,e o5
as'ro,y'es 'ha' ,a'aly@es 'he ,lea4a0e o5 N!a,e'ylas9ar'yl0lu'a8a'e <N((;= in'o N!
a,e'ylas9ar'a'e <N((= and 0lu'a8a'e <Fi0. 1= <1) 2=. N((;) 'he 8os' abundan'
neuro9e9'ide in 'he 8a88alian brain) is a sele,'i4e a0onis' 5or 8e'abo'ro9i, 0lu'a8a'e
re,e9'or 3 <8;lu&3= <1) 2=. 8;lu&3s are e?9ressed on 'he sur5a,e o5 9resyna9'i,
neurons and as'ro,y'es in 'he CN.. (,'i4a'ion o5 8;lu&3s by N((; redu,es ,(MP and
,;MP le4els) inhibi's 0lu'a8a'e release) and s'i8ula'es a release o5 'rans5or8in0 0ro1'h
5a,'or be'a <1) 2=. ( re,en' s'udy re9or'ed i89aired 9er5or8an,e on s9a'ial re5eren,e and
1or+in0 8e8ory 'as+s in 8;lu&2/3 +no,+ou' 8i,e <3=) su00es'in0 a role 5or 0rou9 ""
8;lu&s in ,o0ni'i4e 5un,'ion.
Fi0. 1.
;CP"" rea,'ion. ;CP"" ,lea4es N((; in'o N(( and 0lu'a8a'e.
Co0ni'i4e i89air8en' is a 5reGuen' ,o8orbidi'y o5 8any neurolo0i,al diseases) in,ludin0
8ul'i9le s,lerosis <M.=. M. a55e,'s o4er 2 8illion indi4iduals 1orld1ide) and 40N6$C ∼
o5 all M. 9a'ien's e?9erien,e ,o0ni'i4e i89air8en' <4=. 7he 8os' ,o88only and se4erely
a55e,'ed 5a,e's o5 ,o0ni'ion in M. 9a'ien's are an'ero0rade e9isodi, 8e8ory) 1or+in0
8e8ory) and 9ro,essin0 s9eed <$N=) and 'hese i89air8en's s'ron0ly ,on'ribu'e 'o 'he
hi0h 5reGuen,y o5 une89loy8en' in M. 9a'ien' 9o9ula'ions <8=. ;lobal brain a'ro9hy)
,andida'e 0ene'i, ris+ 5a,'ors) a,,elera'ed in5la88a'ory 9ro,esses <=) and dysre0ula'ed
si0nalin0 9a'h1ays <%= ha4e been i89li,a'ed as ,on'ribu'in0 5a,'ors) bu' an in,o89le'e
unders'andin0 o5 'he 8ole,ular 8e,hanis8s behind ,o0ni'i4e i89air8en' in M. has
9re4en'ed 'he de4elo98en' and Food and #ru0 (d8inis'ra'ion <F#(= a99ro4al o5 dru0
'hera9ies.
7he 8os' 1idely used ani8al 8odel o5 M.) e?9eri8en'al au'oi88une en,e9halo8yeli'is
<2(2=) is a 4aluable 'ool 5or de4elo9in0 'rea'8en's 5or M.. 7hree F#(!a99ro4ed
disease!8odi5yin0 a0en's 1ere de4elo9ed in 2(2 8odels be5ore su,,ess5ully 8o4in0
in'o M. 'rialsd0la'ira8er a,e'a'e) na'ali@u8ab <10=) and 5in0oli8od <11=. ( re,en' s'udy
re9or'ed 8e8ory i89air8en' in 2(2 8i,e ,o89ared 1i'h nor8al ,on'rols <12=.
6o1e4er) 'o 'he bes' o5 our +no1led0e) no dru0s ha4e de8ons'ra'i4ely i89ro4ed 2(2!
indu,ed ,o0ni'i4e i89air8en'.
( 1.$!7 8a0ne'i, resonan,e s9e,'ros,o9y <M&.= s'udy in M. 9a'ien's re4ealed no
,orrela'ions be'1een ,o0ni'i4e 9er5or8an,e and 'he ,on,en'ra'ions o5 8e'aboli'es
,o88only al'ered in neurode0enera'i4e disorders) in,ludin0 inosi'ol and N(( <13=.
6o1e4er) use o5 a 8a0ne' a' hi0her 5ield s'ren0'h <3 7= i89ro4es s9e,'ral resolu'ion and
sensi'i4i'y and 8ay also be used 'o es'i8a'e N((;) a neuro9e9'ide 'ha' is si0ni5i,an'ly
redu,ed in 'he brains o5 9a'ien's 1i'h neurode0enera'i4e diseases <14) 1$=) by allo1in0 i'
'o be resol4ed 5ro8 'he N(( 9ea+ <16=. "n 'he 9resen' s'udy) 1e 5ound 'ha' ri0h'
hi99o,a89al N((;/,rea'ine <Cr= ,on,en'ra'ions 9osi'i4ely ,orrela'e 'o ,o0ni'i4e
5un,'ion in M. 9a'ien's. Based on 'hese da'a) 1e used a 9o'en' and sele,'i4e s8all
8ole,ule inhibi'or o5 ;CP"" <1= 'o in,rease brain N((; le4els in an ani8al 8odel o5
M. 1i'h ,o0ni'i4e i89air8en' <12=.
;o 'o:
R4S<=+S
Right ;ippocampal 8AA: Correlates with Cognitive 3unction in MS%
7o de'er8ine i5 rela'ionshi9s e?is' be'1een CN. 8e'aboli'e ,on,en'ra'ions and ,o0ni'i4e
5un,'ion in 9a'ien's 1i'h M.) a neuro,o0ni'i4e ba''ery and M&. 1ere ,ondu,'ed in ne1ly
dia0nosed rela9sin0Nre8i''in0 M. 9a'ien's a' baseline and 6N12 8o a5'er 'he ini'ial
,lini,al 4isi'. 7he le5' and ri0h' hi99o,a89i 1ere e4alua'ed 5or N((;) N(() inosi'ol)
and ,holine le4els and nor8ali@ed 'o Cr) a rela'i4ely ,ons'an' 8e'aboli'e in 'he brain. P
4alues 1ere se' a' 0.01 'o eli8ina'e 'he ,han,e o5 bo'h 'y9e " and "" errors) and a,,ordin0
'o 'hese 9ara8e'ers) ri0h' hi99o,a89al N((;/Cr si0ni5i,an'ly ,orrela'ed 1i'h 'he
subIe,'sH s,ores on 1 ,o0ni'i4e 4ariables <7able 1=. 7hese s'ri+in0 ,orrela'ions 1ere
obser4ed in a 1ide ran0e o5 ,o0ni'i4e 'es's) in,ludin0 8easures o5 9ro,essin0 s9eed <i.e.)
.y8bol #i0i' Modali'ies 7es') Fi0. 2 A and B=) non4erbal learnin0 and 8e8ory <i.e.)
Brie5 Disuos9a'ial Me8ory 7es') &ey!Ts'errie'h Co89le? Fi0ure Co9y 7es'=) sus'ained
a''en'ion <i.e.) Pa,ed (udi'ory .erial (ddi'ion 7es') Fi0. 2 C and D=) and ,o0ni'i4e
5le?ibili'y <i.e.) #!M2F. .or'in0 7es'=. No ,orrela'ions 1ere dis,erned be'1een ,o0ni'i4e
9er5or8an,e and ei'her ri0h' or le5' N(() inosi'ol) ,holine <Fi0. 2 E=) or le5' hi99o,a89al
N((; le4els.
7able 1.
Co0ni'i4e 'es' s,ores ,orrela'ed 'o ri0h' hi99o,a89al N((;/Cr ,on,en'ra'ions in M.
9a'ien's
Fi0. 2.
Posi'i4e ,orrela'ions o5 ,o0ni'i4e 'as+ 9er5or8an,es 'o ri0h' hi99o,a89al <N((;/Cr=.
Per5or8an,e on 'he 1ri''en <A= and oral <B= .y8bol #i0i' Modali'ies 7es' 9osi'i4ely
,orrela'ed 'o ri0h' hi99o,a89al <N((;/Cr= in M. 9a'ien's. <A) P ] 0.001) %%%
( rela'ionshi9 be'1een ,o0ni'i4e i89air8en' and lo1er le4els o5 N((; su00es'ed 'ha'
in'er4en'ions 'o raise N((; le4els 8i0h' enhan,e ,o0ni'ion in M. 9a'ien's. 7o 'es' 'his
hy9o'hesis) 1e 'urned 'o 2(2 and 'he use o5 a ,lass o5 dru0s 'ha' ele4a'e brain N((;
le4els.
,-#!hosphonomethyl$!entanedioic Acid Administration 'oes 8ot Aect
4A4 Severity%
7o de'er8ine 'he e55e,'s o5 ;CP"" inhibi'ion in 2(2) 8i,e 1ere ad8inis'ered daily
inIe,'ions o5 ei'her 2!<9hos9hono8e'hyl=9en'anedioi, a,id <2!PMP(= or 4ehi,le <saline=.
2!PMP( is a 9o'en' and sele,'i4e ;CP"" inhibi'or 'ha' 9ene'ra'es 'he blood brain barrier
<BBB= and raises N((; le4els <18=. Mi,e de4elo9ed si0ns o5 2(2 10 d ∼
9os'i88uni@a'ion. 2(2 disabili'y s,ores did no' di55er be'1een 0rou9s 5or 'he dura'ion
o5 'he e?9eri8en' <Fi0. 3 A=) indi,a'in0 'ha' 2!PMP( does no' a55e,' se4eri'y and
9ro0ression o5 2(2.
Fi0. 3.
255e,' o5 2!PMP( on disease s,ore) ,o0ni'ion) and 5ron'al ,or'e? N((; ,on,en'ra'ion in
2(2 8i,e. <A= #aily ad8inis'ra'ion o5 2!PMP( does no' a55e,' 2(2 se4eri'y ,o89ared
1i'h 4ehi,le!'rea'ed 8i,e. <B= 2(2 8i,e 'rea'ed 1i'h 2!PMP( de8ons'ra'ed i89ro4ed %%%
:C!55 5nhibition 4nhances Cognitive !erormance in 4A4 Mice%
3e 'es'ed 1he'her ;CP"" inhibi'ion ,ould lead 'o i89ro4ed ,o0ni'ion in 2(2 8i,e as
assessed by Barnes 8a@e 9er5or8an,e. (5'er 4 1+ o5 'rea'8en') 2(2 ` 2!PMP( and ∼
2(2 ` 4ehi,le de8ons'ra'ed si8ilar ini'ial learnin0 abili'ies) 1i'h 8ean 9ri8ary la'en,y
<'i8e be5ore head 9o+e in'o 'ar0e' bo?=) 'o'al la'en,y <'i8e be5ore 'ar0e' bo? en'ry=) and
9a'h e55i,ien,y <'o'al dis'an,e 'ra4eled/dis'an,e 5ro8 s'ar'in0 9oin' 'o 'ar0e' bo?= eGual
be'1een 0rou9s on 'he 5irs' 2 d o5 Barnes 8a@e 'es'in0. 7rends e8er0ed on day 3) and
si0ni5i,an' di55eren,es be'1een 2(2 ` 2!PMP( and 2(2 ` 4ehi,le 8i,e 1ere obser4ed
on day 4. 3hen ,o89arin0 9er5or8an,e be'1een 'he 5irs' 'rial o5 day 4 'o baseline <day
1) 'rial 1=) 2(2 ` 2!PMP( 8i,e 1ere si0ni5i,an'ly di55eren' ,o89ared 1i'h 2(2 `
4ehi,le 8i,e in 9ri8ary la'en,y <8ean c .2M: 16.4 c 1.1% 4s. 134.0 c 10.30)
res9e,'i4ely; P ] 0.01=) 'o'al la'en,y <8ean c .2M: 16.4 c 1.1% 4s. %8.42 c 24.66)
res9e,'i4ely; P ] 0.0$=) and 9a'h e55i,ien,y <8ean c .2M: _0.28 c 0.030 4s. _0.324 c
0.10) res9e,'i4ely; P ] 0.01= <Fi0. 3 B and C=) a,,oun'in0 5or a 2$) 0) and 12$C
i89ro4e8en' in 9er5or8an,e in 2(2 ` 2!PMP( 8i,e. (no'her resear,h 0rou9 usin0 'he
Barnes 8a@e de'er8ined 'ha' ,o89arison o5 ba,+!'o!ba,+ 'rials on ,onse,u'i4e days <e.0.)
'rial 4 o5 day 3 4s. 'rial 1 o5 day 4= 1as an indi,a'ion o5 lon0!'er8 8e8ory in 8i,e <1%=.
>sin0 'his 8e'hodolo0y) 2!PMP( enhan,ed lon0!'er8 8e8ory in 2(2 8i,e by
si0ni5i,an'ly de,reasin0 'o'al la'en,y <8ean c .2M: 13.14 c .6% 4s. _38.82 c 1%.04)
res9e,'i4ely; P ] 0.0$= and in,reasin0 9a'h e55i,ien,y <8ean c .2M: _0.138 c 0.0%4 4s.
0.20% c 0.0%8) res9e,'i4ely; P ] 0.0$= ,o89ared 1i'h 2(2 ` 4ehi,le 8i,e. Ma?i8u8
s9eed in 'he 8a@e 1as eGual be'1een 0rou9s.
7o as,er'ain i5 2!PMP( 'rea'8en' al'ered 5ear 8e8ory in 2(2 8i,e <20=) 5ear
,ondi'ionin0 'es's 1ere ad8inis'ered 5ollo1in0 ,o89le'ion o5 Barnes 8a@e 'es'in0.
Free@in0 le4els 1ere eGual be'1een 0rou9s on days 1N3. Tn day $) ho1e4er) 8i,e 'rea'ed
1i'h 2!PMP( had in,reased ,ued 5ree@in0 in res9onse 'o 'he 120!s 'one) s9e,i5i,ally in
'he las' 60 s) indi,a'in0 a s'ron0er 5ear 8e8ory <Fi0. 3 D=.
,-!M!A +reatment 5s 8ot An&iolytic in 4A4 Mice%
7o ,on5ir8 'ha' 2!PMP(Hs ,o0ni'i4e!enhan,in0 e55e,'s 1ere due 'o di55eren,es in 8e8ory
and no' an?ie'y) ele4a'ed 9lus 8a@e 'es's 1ere ,ondu,'ed 4 1+ 9os'i88uni@a'ion in
se9ara'e ,ohor's <n B 10=. No di55eren,es 1ere no'ed be'1een 2(2 ` 2!PMP( and 2(2 `
4ehi,le 0rou9s re0ardin0 'he 'i8e s9en' in o9en ar8s <8ean c .2M: 34.10 c %.22 4s.
3$.%0 c 6.%%) res9e,'i4ely= and ,losed ar8s <8ean c .2M: 224.2 c 10.0 4s. 22$.6 c
13.6$) res9e,'i4ely= o5 'he 8a@e) indi,a'in0 eGual an?ie'y le4els.
,-!M!A 5s BBB !enetrable and Alters 8AA: in 4A4%
Mass s9e,'ro8e'ry 1as used 'o ,on5ir8 'ha' 2!PMP( 9ene'ra'ed 'he CN. and in,reased
brain N((; le4els. 2!PMP( 1as de'e,'ed in 'he ,erebellu8 <8ean c .2M: 0.832 c
0.0$6 a0/0 'issue=) hi99o,a89us <8ean c .2M: 0.83$ c 0.264 a0/0 'issue=) and 5ron'al
,or'e? <8ean c .2M: 1.1%3 c 0.222 a0/0 'issue=) areas 'ha' re0ula'e ,o0ni'i4e 5un,'ion in
roden's and hu8ans <21) 22=. 3hen 8easurin0 N((; ,on,en'ra'ions be'1een 2(2 ` 2!
PMP( and 2(2 ` 4ehi,le 8i,e) no di55eren,e 1as de'e,'ed in 'he hi99o,a89i <8ean c
.2M: $4.%8 c 2.03 4s. $$.$4 c 2.2$) res9e,'i4ely=) a 'rend o5 in,rease 1as 5ound in 'he
,erebella <8ean c .2M: 102.4 c 2.3 4s. %4.23 c 3.$) res9e,'i4ely; P B 0.06$$= and a
si0ni5i,an' in,rease 1as de'er8ined in 'he 5ron'al ,or'e? o5 2(2 ` 2!PMP( <8ean c
.2M: 32.%1 c 0.%3 4s. 26.22 c 0.82) res9e,'i4ely; P ] 0.001= <Fi0. 3 E=. No di55eren,es
in N(( le4els 1ere de'e,'ed.
,-!M!A 'oes 8ot Alter =ymphocyte !opulations in 4A4%
Fluores,en,e!a,'i4a'ed ,ell sor'in0 <F(C.= analysis 1as ,ondu,'ed a' 'he 'i8e 1hen
,o0ni'i4e di55eren,es 1ere de'e,'ed be'1een 0rou9s) 28 d 9os'!2(2 indu,'ion) 'o
de'er8ine i5 daily 2!PMP( ad8inis'ra'ion a55e,'ed i88une ,ell e?9ression. No
di55eren,es 1ere no'ed in 7 ly89ho,y'es in 'he s9leen or brain o5 2(2 ` 2!PMP( 8i,e
,o89ared 1i'h 2(2 ` 4ehi,le 8i,e <Fi0. .1=.
;ippocampal :C!55 Activity 'oes 8ot Change in 4A4%
2n@y8a'i, a,'i4i'y o5 ;CP"" 1as 8easured in 'he hi99o,a89i o5 ,on'rol 8i,e and 2(2
8i,e 'rea'ed 1i'h ei'her 4ehi,le or 2!PMP( 1$ d a5'er i88uni@a'ion. 7here 1ere no
di55eren,es de'e,'ed be'1een ,on'rol and 2(2 0rou9s 'rea'ed 1i'h 4ehi,le) indi,a'in0 'ha'
disease s'a'e does no' a55e,' 5un,'ional en@y8a'i, a,'i4i'y. ;CP"" a,'i4i'y in 'he brains o5
,on'rol and 2(2 8i,e 'rea'ed daily 1i'h 2!PMP( did no' di55er as 1ell. 6o1e4er) 1i'hin
ea,h 0rou9) 'here 1as a si0ni5i,an' de,rease in ;CP"" a,'i4i'y in 2!PMP(N'rea'ed 8i,e
,o89ared 1i'h 4ehi,le!'rea'ed 8i,e <Fi0. .2=.
:C!55 5nhibition ;as 8o 4ect on Control Mice%
Con'rol <nor8al) non!2(2= 8i,e 'rea'ed 5or a' leas' 4 1+ 1i'h 2!PMP( did no' di55er
5ro8 4ehi,le!'rea'ed nor8al ,on'rols in 'heir Barnes 8a@e) 5ear ,ondi'ionin0) or ele4a'ed
9lus 8a@e 9er5or8an,es. 2!PMP( 1as de'e,'ed in 'he brains o5 'rea'ed 8i,e) bu' no
di55eren,es in CN. N((; le4els 1ere obser4ed be'1een ,on'rol ` 4ehi,le and ,on'rol `
2!PMP( 8i,e.
,-#!hosphonomethyl$Succinic Acid 'oes 8ot Aect Cognition and Severity
o 4A4%
2!<Phos9honoMe'hyl=.u,,ini, (,id <2!PM.(=) a s'ru,'urally si8ilar bu' ina,'i4e analo0
o5 2!PMP() 1as 'es'ed in 'he 2(2 8odel 'o de'er8ine i5 'he ,o0ni'ion enhan,in0 e55e,'s
1ere s9e,i5i, 'o ;CP"" inhibi'ion. (l'hou0h 'heir s'ru,'ures di55er by one 8e'hyl 0rou9)
2!PM.( is o4er 1)000!5old less 9o'en' 5or ;CP"" inhibi'ion <18=. Mi,e 1ere i88uni@ed
'o indu,e 2(2) and daily 2!PM.( 'rea'8en' did no' a55e,' disease se4eri'y and ele4a'ed
9lus 8a@e) Barnes 8a@e) and 5ear ,ondi'ionin0 9er5or8an,es <Fi0. .3=.
;o 'o:
'5SC<SS5"8
7he 9resen' s'udy is uniGue in su00es'in0 'ha' ri0h' hi99o,a89al N((;/Cr
,on,en'ra'ions 9osi'i4ely ,orrela'e 1i'h ,o0ni'i4e 5un,'ion in M. 9a'ien's. 7he
de4elo98en' o5 e55e,'i4e 'rea'8en's 5or ,o0ni'i4e i89air8en' in M. ,ould bene5i' o4er 1
8illion 9eo9le 1orld1ide. M. 9a'ien's 1i'h ,o0ni'i4e i89air8en' early in disease
9ro0ression are 8ore 9rone 'o se4ere learnin0 and 8e8ory i89air8en's la'er in li5e <23=.
7he a4era0e a0e o5 M. onse' is 20N40 y o5 a0e) and M. is 'he se,ond leadin0 ,ause o5
neurolo0i,al disabili'y in youn0 adul's in 'he >ni'ed .'a'es. (n es'i8a'ed $0N80C o5 all
M. 9a'ien's are une89loyed 1i'hin 10 y o5 disease onse' <6=) and 'hese s'ar'lin0ly hi0h
une89loy8en' ra'es are o5'en a''ribu'ed 'o ,o0ni'i4e i89air8en' <24) 2$=. 7here5ore)
early de'e,'ion and 'rea'8en' o5 ,o0ni'i4e i89air8en' in M. 1ould ha4e a 're8endous
i89a,' on Guali'y o5 li5e.
Based on our ini'ial 5indin0 o5 a 9osi'i4e rela'ionshi9 be'1een hi99o,a89al N((;/Cr
,on,en'ra'ion and ,o0ni'i4e 5un,'ion in M. 9a'ien's) 1e 'es'ed a ,o89ound 9re4iously
de8ons'ra'ed 'o in,rease brain N((; le4els) 2!PMP( <1) 26=) in an ani8al 8odel o5
M. and 8easured ,o0ni'i4e 9er5or8an,e. #a'a 5ro8 'he 9resen' e?9eri8en' re4eal 'ha'
u9!re0ula'ion o5 CN. N((; ,on,en'ra'ion 'hrou0h inhibi'ion o5 ;CP"" i89ro4es
,o0ni'i4e 5un,'ion in 2(2 8i,e. 7he Barnes 8a@e 1as used be,ause i' is a 8ini8ally
s'ress5ul land 8a@e <2=) and 2(2 8i,e ha4e i89aired 9er5or8an,e in 'his hi99o,a89al!
de9enden' beha4ioral 'as+ ,o89ared 1i'h heal'hy 1ild!'y9e 8i,e <12=. 6i99o,a89al
de0enera'ion is 1ell do,u8en'ed in M. 9a'ien's <28=) 'hus 8a+in0 2(2 and 'he Barnes
8a@e 'he ideal 8odel 'o s'udy M.!rela'ed ,o0ni'i4e i89air8en'. 2!PMP(N8edia'ed
;CP"" inhibi'ion dra8a'i,ally enhan,ed 8e8ory) as 8easured by 'he Barnes 8a@e and
5ear ,ondi'ionin0. 2(2 disease s,ore and 8a?i8u8 8a@e s9eed did no' di55er be'1een
2(2 ` 4ehi,le and 2(2 ` 2!PMP( 8i,e) indi,a'in0 'ha' 'he i89ro4ed 9er5or8an,e o5 2!
PMP( 8i,e in 'he 8a@e 1as no' due 'o enhan,ed 9hysi,al abili'ies. 7o our +no1led0e)
'he 9resen' s'udy is uniGue in de8ons'ra'in0 si0ni5i,an' a8eliora'ion o5 ,o0ni'i4e
5un,'ion in 2(2 8i,e. 6is'ori,ally) 9o'en'ial M. 'rea'8en's are dee8ed ine55e,'i4e and
dis,arded i5 'here is no i89ro4e8en' o5 2(2 disease s,ore. 7he 9resen' s'udy
de8ons'ra'es 'ha' 2(2 disease s,ore is no' 'he only end9oin' 5or 'he e4alua'ion o5 M.
'hera9ies and i89lies 'he 9re8a'ure abandon8en' o5 9as' 'rea'8en' o9'ions.
7he de'e,'ion o5 2!PMP( in 'he brains o5 8i,e 'rea'ed 1i'h 'he ;CP"" inhibi'or
de8ons'ra'es 'ha' 2!PMP( 9ene'ra'es 'he BBB and is res9onsible 5or 'he obser4ed
in,reases in N((; ,on,en'ra'ion. 7he 8os' 9ronoun,ed in,rease in N((; le4els
o,,urred in 'he 5ron'al ,or'e?) 1hi,h is res9onsible 5or e?e,u'i4e 5un,'ion and 9lannin0 o5
8o'or 8o4e8en') '1o +ey ,on'ribu'ors 'o su,,ess5ul Barnes 8a@e na4i0a'ion. 7he
hi99o,a89us also ,on'ribu'es 'o s9a'ial na4i0a'ion abili'ies. 6i99o,a89al N((;
,on,en'ra'ions <ri0h' and le5'= 1ere una55e,'ed by 2!PMP( 'rea'8en' in 2(2 8i,e. 3e
hy9o'hesi@e 'ha' 'here 8ay be ,han0es in N((; ,on,en'ra'ion) a,'i4i'y) and/or 'urno4er
in s9e,i5i, re0ions o5 'he hi99o,a89us <e.0.) C(1= <2%= 'ha' are no' de'e,'able in 1hole
5ra,'ion analysis. Fu'ure s'udies usin0 8ore s9e,i5i, analyses o5 hi99o,a89al
subs'ru,'ures are reGuired.
"' is no'e1or'hy 'ha' 2!PMP( 1as de'e,'ed in all brain re0ions o5 2!PMP(N'rea'ed
,on'rol <i.e.) nor8al) non!2(2= 8i,e bu' did no' a55e,' ,o0ni'i4e 9er5or8an,e. "' is
9ossible 'ha' a diseased s'a'e is reGuired 5or 2!PMP( 'o e?er' obser4able) bene5i,ial
e55e,'s. 7his ,on,lusion is ,onsis'en' 1i'h s'udies re9or'in0 'ha' ;CP"" inhibi'ors ha4e no
e55e,' on s9a'ial learnin0) 8e8ory) and basal 0lu'a8a'er0i, 'rans8ission in nor8al 8i,e)
bu' sele,'i4ely 8i'i0a'e inIury!indu,ed ,han0es <18=. 6o1e4er) i' is 9ossible 'ha'
ad8inis'ra'ion o5 a ;CP"" inhibi'or 8i0h' a55e,' ,o0ni'i4e 5un,'ion in nor8al 8i,e bu'
1as no' de'e,'able in our beha4ior 'es'in0 9aradi08s due 'o 'he ,eilin0 e55e,' or la,+ o5
doseNres9onse 'es'in0. Fu'ure e?9eri8en's 1ill in4es'i0a'e 'his 9ossibili'y.
7he 9re,ise 8e,hanis8 o5 a,'ion o5 ;CP"" inhibi'ion in alle4ia'in0 ,o0ni'i4e i89air8en'
in 2(2 8i,e is un+no1n. 7he subs'ra'e and 9rodu,'s o5 ;CP"" a,'i4i'y are asso,ia'ed
1i'h ,o0ni'i4e 5un,'ion and neuronal sur4i4al. (4ailabili'y o5 e?'ra,ellular N(( is 'he
ra'e!li8i'in0 5ea'ure 'o N((; 5or8a'ion in as'ro,y'es <30=. "8balan,es in N((
,on,en'ra'ion) bo'h in ,ases o5 ele4a'ed N(( <Cana4an disease= or hy9oa,e'ylas9ar'ia <a
sin0le do,u8en'ed hu8an ,ase= <31=) lead 'o ,o0ni'i4e dys5un,'ion. .i8ilarly)
insu55i,ien' 0lu'a8a'e si0nalin0 leads 'o ,o0ni'i4e dys5un,'ion) 1hereas e?,ess 0lu'a8a'e
si0nalin0 is neuro'o?i, <32=. 6i0h 0lu'a8a'e ,on,en'ra'ions ha4e been obser4ed in 'he
brains <33= and ,erebros9inal 5luid <34= o5 M. 9a'ien's) and e?,ess 0lu'a8a'e si0nalin0
has been i89li,a'ed in a hos' o5 neurolo0i,al disorders in,ludin0 s,hi@o9hrenia)
Par+inson disease) 6un'in0'on disease) (l@hei8erHs disease) and M.. 3hereas de,reased
0lu'a8a'e ,on,en'ra'ion due 'o ;CP"" inhibi'ion ,ould ,er'ainly ,on'ribu'e 'o ,o0ni'i4e
s9arin0 in 2(2) i' is hy9o'hesi@ed 'ha' N((; is 'he ,ru,ial si0nalin0 8essen0er 'ha'
a8eliora'ed ,o0ni'i4e 5un,'ion in 'he 9resen' s'udy. "nhibi'ion o5 ;CP"") 1hi,h indu,es a
8easurable u9!re0ula'ion in N((;) has 9ro4ed 'o be bene5i,ial in 'rea'in0 4arious
9re,lini,al 8odels o5 neurolo0i,al disease <18) 3$) 36=. (,'i4a'ion o5 8;lu&3 on
9resyna9'i, neurons by N((; de,reases 0lu'a8a'e release <3N3%=) 9o'en'ially
9ro8o'in0 'he sur4i4al o5 neurons ,ru,ial 'o ,o0ni'i4e 5un,'ion. (ddi'ionally) a,'i4a'ion
o5 8;lu&3 on as'ro,y'es s'i8ula'es 'he release o5 'rans5or8in0 0ro1'h 5a,'or be'a) a
,y'o+ine 1i'h de8ons'ra'ed in 4i'ro neuro9ro'e,'i4e e55e,'s <40) 41=. "' is 9ossible 'ha'
one or bo'h o5 'hese N((;!8edia'ed 9a'h1ays re0ula'es ,o0ni'i4e 5un,'ion in M.)
reGuirin0 5u'ure s'udies 'o elu,ida'e 'he e?a,' 8e,hanis8. F(C. analysis ,ondu,'ed in
2(2 a' 'he 'i8e di55eren,es in ,o0ni'i4e 5un,'ion 1ere obser4ed <i.e.) 28 d
9os'i88uni@a'ion= indi,a'e 'ha' 'he s9leen and brain ly89ho,y'e 9o9ula'ions 1ere no'
a55e,'ed by daily 2!PMP( 'rea'8en') su00es'in0 'ha' a neural si0nalin0 9a'h1ay and no'
i88une sys'e8 re0ula'ion is res9onsible 5or 'he i89ro4e8en' o5 ,o0ni'i4e 5un,'ion in
2(2.
7he dis,o4ery o5 in'erde9enden,e be'1een ,o0ni'i4e 9er5or8an,e and ri0h' bu' no' le5'
hi99o,a89al N((; ,on,en'ra'ions in 'he 9resen' s'udy 1as une?9e,'ed and 1arran's
dis,ussion. (sy88e'ry o5 hi99o,a89al si@e is 1ell do,u8en'ed <ri0h' b le5'= <42) 43=)
bu' 'he roles o5 ri0h' 4ersus le5' hi99o,a89i in ,o0ni'i4e 5un,'ion are no' ,o89le'ely
unders'ood. ( body o5 li'era'ure is e8er0in0 'ha' su99or's la'erali@a'ion o5 hi99o,a89al
5un,'ion. ( re,en' roden' s'udy re9or'ed 'ha' N(( ,on,en'ra'ions 9osi'i4ely asso,ia'e
1i'h learnin0 and 8e8ory 9er5or8an,e) bu' only in 'he ri0h' hi99o,a89us <44=. ( hu8an
s'udy re9or'ed a si0ni5i,an' de,rease in 'he le4el o5 ri0h' hi99o,a89al a,'i4i'y durin0
en,odin0 o5 su,,ess5ully re,alled i'e8s in ,o0ni'i4ely i89aired M. 9a'ien's ,o89ared
1i'h bo'h ,o0ni'i4ely 9reser4ed M. 9a'ien's and heal'hy ,on'rols <4$=. Fur'her8ore) a
re,en' s'udy in heal'hy 4olun'eers sho1ed a 9osi'i4e ,orrela'ion be'1een ,o0ni'i4e
9er5or8an,e and an'erior ri0h' bu' no' an'erior le5' hi99o,a89al si@e <42=. 7a+en
'o0e'her) 'hese s'udies su00es' 'ha' 'he ri0h' hi99o,a89us 9lays a si0ni5i,an' role in 'he
8ain'enan,e o5 ,o0ni'i4e 5un,'ion in bo'h heal'hy subIe,'s and 9a'ien's 1i'h M.. Tur
resul's also de8ons'ra'e a rela'ionshi9 be'1een ,o0ni'i4e 5un,'ion and 'he ri0h'
hi99o,a89us bu' no' 'he le5' hi99o,a89us. 3hereas o'hers ha4e de8ons'ra'ed eGual
bila'eral hi99o,a89al 4olu8e loss in M. 9a'ien's o4er 'he ,ourse o5 3N13 y a5'er disease
onse' <28=) our s'udies 5o,us on 8e'aboli'e ,han0es in re,en'ly dia0nosed 9a'ien's and no'
0ray 8a''er brain s'ru,'ure loss. 7here5ore) i' is 9ossible 'ha' 'he ri0h' and le5' hi99o,a89i
ha4e so8e se9ara'e and/or uniGue 5un,'ions 'ha' 8ay be a55e,'ed di55eren'ly by ,han0es
in 8e'aboli'e ,on,en'ra'ions.
Nei'her brain N((; le4els in M. 9a'ien's nor 'he rela'ionshi9 o5 brain N((; le4els 'o
,o0ni'ion are 1ell de5ined. 7o our +no1led0e only one o'her M&. s'udy has a''e89'ed 'o
e?a8ine brain N((; ,on,en'ra'ions in M. 9a'ien's <46=. 7his s'udy did no' 8easure
hi99o,a89al N((; le4els or ,orrela'e ,o0ni'i4e 5un,'ion 'o N((; le4els) 8a+in0 a
,o89arison be'1een s'udies i89ossible. ( re,en' 9reli8inary s'udy re9or'ed a 9osi'i4e
,orrela'ion be'1een N((; ,on,en'ra'ion and 8e8ory in 9a'ien's 1i'h s,hi@o9hrenia
<4=. 6o1e4er) 'he sele,'ion o5 a 9a'ien' 9o9ula'ion on a'y9i,al an'i9sy,ho'i,s) a
'rea'8en' 'ha' u9!re0ula'es N((; 9rodu,'ion in 4i'ro <48= and i89ro4es ,o0ni'i4e
5un,'ion in 9a'ien's 1i'h s,hi@o9hrenia <4%=) 8a+es 'he 5or8a'ion o5 ,ausa'i4e
,on,lusions i89ossible. 7hus) 'he use o5 a'y9i,al an'i9sy,ho'i,s in s,hi@o9hreni, subIe,'s
is a ,on5oundin0 4ariable 'ha' 'he resear,hers did no' ,on'rol 5or) 1hi,h 8ay ha4e led 'o a
'y9e " error 1here 'here is a s9urious ra'her 'han a ,ausal rela'ionshi9 obser4ed be'1een
N((; le4els and ,o0ni'ion.
7he 9resen' s'udy has li8i'a'ions 'ha' 8us' be addressed. 3e did no' 8easure
hi99o,a89al 4olu8e or in,lude heal'hy ,on'rols) 8a+in0 i' un,lear i5 'here is a bi! or
unila'eral loss o5 hi99o,a89al 4olu8e in our 9a'ien' 9o9ula'ion ,o89ared 1i'h heal'hy
,on'rols. (ddi'ionally) 'he M. 9a'ien' 9o9ula'ion 1as 4ery s8all) 1i'h only si? uniGue
9a'ien's in,luded. 3e a99lied a99ro9ria'e s'a'is'i,al ,orre,'ions 'o use 9a'ien' da'a a' '1o
uniGue 'i8e 9oin's and a99lied a 8ore s'rin0en' al9ha <P B 0.01= 'o 5ur'her 8ini8i@e 'y9e
" error) bu' se9ara'e baseline and 5ollo1!u9 analyses 1i'h lar0er 9a'ien' 9o9ula'ions are
reGuired 'o ,on5ir8 'he ,urren' s'udy. 3e 5o,used on 8e'aboli'e 8easure8en's in 'he
hi99o,a89i due 'o re9or'ed a'ro9hy in 'he hi99o,a89i o5 M. 9a'ien's ,o89ared 1i'h
heal'hy ,on'rols <$0=) bu' o'her areas o5 'he brain) s9e,i5i,ally sub,or'i,al 0ray 8a''er
s'ru,'ures) also a'ro9hy in M. 9a'ien' 9o9ula'ions <$1=. Fu'ure hu8an s'udies 1ill 5o,us
on 'he 8easure8en' o5 8e'aboli'e ,on,en'ra'ions in dee9 0ray s'ru,'ures) su,h as 'he
'hala8us. Fu'ure 2(2 s'udies are also reGuired 'o de'er8ine 'he 8e,hanis8 o5 a,'ion o5
;CP"" inhibi'ion in ,o0ni'i4e i89air8en'. Be,ause N((; si0nalin0 and ;CP""
e?9ression are al'ered in o'her neurode0enera'i4e diseases) 'his 1or+ also has broad
a99li,a'ions 'o o'her nonde8en'in0 CN. disorders. Fur'her 1or+ 8us' be done 'o
e4alua'e 'he 'hera9eu'i, 9o'en'ial o5 ;CP"" inhibi'ion 5or 'he 'rea'8en' o5 ,o0ni'i4e
i89air8en' in o'her neurode0enera'i4e disorders.
;o 'o:
MA+4R5A=S A8' M4+;"'S
Study !articipants%
Par'i,i9an's 1ere a ,ohor' o5 ne1ly dia0nosed M. 9a'ien's in an on0oin0 lon0i'udinal
s'udy o5 neuro9sy,holo0i,al and neuroi8a0in0 ou',o8e 8easures a' 'he *ohns 6o9+ins
6os9i'al. M. 9a'ien's 1ho had ,o89le'ed neuro9sy,holo0i,al 'es'in0 and 8a0ne'i,
resonan,e i8a0in0 a' a baseline and/or 5ollo1!u9 4isi' 1ere in,luded in 'he analyses.
Baseline 1as de5ined as 'he 4isi' in 1hi,h 'he 9a'ien' re,ei4ed a 9osi'i4e dia0nosis o5 M.
and be5ore any disease!8odi5yin0 'hera9y had ,o88en,ed) 1hereas 5ollo1!u9 1as
de5ined as 6N12 8o 5ollo1in0 'he ini'ial dia0nosis. Fi4e M. 9a'ien's 1ere re4ie1ed a'
baseline <one 8ale) 5our 5e8ale; a4era0e a0e B 44.4 y old= and 5our 9ar'i,i9an's 1ere
re4ie1ed a' 5ollo1!u9 <5our 5e8ale; a4era0e a0e B 3%.8 y old=) 'hree o5 1ho8 had
,orres9ondin0 baseline da'a. T5 'he 5our 5ollo1!u9 9a'ien's) 'hree 1ere on disease!
8odi5yin0 'hera9ies <2 0la'ira8er a,e'a'e) 1 "FNQ!1a=. Pa'ien' 1ri''en ,onsen' 1as
ob'ained and 9ro,edures 1ere a99ro4ed by 'he *ohns 6o9+ins Medi,ine "ns'i'u'ional
&e4ie1 Board.
Cognitive +esting%
M. 9a'ien's under1en' a 8odi5ied Mini8u8 (ssess8en' o5 Co0ni'i4e Fun,'ion "n
Mul'i9le .,lerosis <M(CF"M.= neuro9sy,holo0i,al ba''ery <$2= a' baseline and/or
5ollo1!u9. Co0ni'i4e 'es's 1ere .y8bol #i0i' Modali'ies 7es') Pa,ed (udi'ory .erial
(ddi'ion 7es') Derbal Fluen,y 7es') *ud08en' o5 /ine Trien'a'ion) &ey!Ts'errie'h
Co89le? Fi0ure Co9y 7es') Cali5ornia Derbal /earnin0 7es' "") Brie5 Disuos9a'ial
Me8ory 7es' &e4ised) and 'he #elisNMa9lan 2?e,u'i4e Fun,'ion .ys'e8 <#!M2F.=
.or'in0 7es'.
Magnetic Resonance Spectroscopy%
M& i8a0in0 and s9e,'ros,o9y 1ere 9er5or8ed on a 3!7 Phili9s "n'era s,anner 1i'h a si?!
,hannel .2N.2 head ,oil as 9re4iously des,ribed <$3=. .9e,'ra 1ere analy@ed usin0 'he
/CModel al0ori'h8 <$4= and Guan'i5ied in 8illi8olar ,on,en'ra'ions usin0 'he
unsu99ressed 1a'er si0nal as an in'ernal in'ensi'y re5eren,e. Dalues 1ere only in,luded i5
Cra8^rN&ao lo1er bounds 1ere $0C or less <$4=.
Animals and ;ousing%
.e4en! 'o 8!1+!old 5e8ale C$B//6 8i,e 1ere 9ur,hased 5ro8 'he Na'ional Can,er
"ns'i'u'e. (ll 9ro,edures 1ere a99ro4ed by 7he *ohns 6o9+ins >ni4ersi'y (ni8al Care
and >se Co88i''ee.
4A4 5nduction%
Mi,e 1ere i88uni@ed as 9re4iously des,ribed <$$= 1i'h 'he 5ollo1in0 8inor
8odi5i,a'ions. Mi,e 1ere i88uni@ed 1i'h '1o $0!a/ s.,. 5lan+ inIe,'ions) and 300 n0 o5
9er'ussis 'o?in 1as e89loyed on #ay 0 and 2.
+reatment Administration and Behavioral Scoring%
Dehi,le <$0 8M 6e9es bu55er=) 2!PMP( E100 80/+0 in 4ehi,le <96 .4= 1i'h 10N
NaT6F) or 2!PM.( E100 80/+0 in 4ehi,le <96 .4= 1i'h 10N NaT6F 1as deli4ered daily
4ia 0.1!8/ i.9. inIe,'ions 5ro8 'he 'i8e o5 2(2 i88uni@a'ion un'il sa,ri5i,e. 2!PMP() 2!
PM.() or 4ehi,le 'rea'8en' ad8inis'ra'ion on beha4ior 'es'in0 days o,,urred 30 8in ∼
be5ore 'he 5irs' 'es'.
(ni8als 1ere 8oni'ored daily 5or 9hysi,al si0ns o5 2(2) and s,ores 1ere assi0ned as
9re4iously des,ribed <$6=.
Barnes Ma(e%
Mi,e 1ere i88uni@ed 'o indu,e 2(2 and 'rea'ed daily 1i'h ei'her 4ehi,le or 2!PMP( 5or
4 1+ and subIe,'ed 'o Barnes 8a@e 'es'in0 as 9re4iously des,ribed < ∼ $=. Pa'hs 1ere
re,orded and la'en,y 'o 'he 'ar0e' hole) 9a'h e55i,ien,y) s9eed) and dire,'ional 'i8es 1ere
,al,ula'ed usin0 (N-!8a@e so5'1are <.'oel'in0=. #i55eren' ,ohor's o5 8i,e 1ere 'es'ed in
2!PMP( and 2!PM.( s'udies.
3ear Conditioning%
Follo1in0 'he Barnes 8a@e 'es'in0) ani8als 1ere 0i4en 1N2 1+ res' 'hen subIe,'ed 'o 5ear
,ondi'ionin0. (ni8als 1ere 9la,ed in a ,ha8ber 5or 240 s on 3 ,onse,u'i4e days. Tn day
1) a 2)000!6@ 'one 1as 9layed 5or 28 s <se,onds 180N208=) i88edia'ely 5ollo1ed by a 2!s
s,ra8bled 5oo'sho,+. Tn day 2) ani8als 1ere 9la,ed ba,+ in 'he sa8e 'es'in0
en4iron8en') bu' nei'her sound nor sho,+ 1as ad8inis'ered. Tn days 3 and $) 8i,e 1ere
9la,ed in a no4el 1ooden bo? inside 'he ,ha8ber) and a 2)000!6@ 'one 1as 9layed 5or
120 s <se,onds 121N240=. 7he dura'ion o5 5ree@in0 beha4ior on ea,h day 1as 8easured
usin0 Free@e.,an so5'1are <Cle4er .ys=.
4levated !lus Ma(e%
Mi,e 1ere 9la,ed in 'he ,en'er o5 'he 8a@e and 0i4en $ 8in 'o 5reely e?9lore 'he 8a@e.
7i8e s9en' in o9en and ,losed ar8s o5 'he 8a@e 1ere 'ra,+ed usin0 (N-!8a@e so5'1are
<.'oel'in0=.
Mass Spectrometry%
(ni8als 1ere eu'hani@ed by ,er4i,al dislo,a'ion $0 d a5'er 2(2 i88uni@a'ion and 1 h
5ollo1in0 'he las' inIe,'ion o5 4ehi,le or 2!PMP(. 6i99o,a89i) 5ron'al lobe) and
,erebellu8 1ere disse,'ed) and N(() N((;) and 2!PMP( ,on,en'ra'ions 1ere
8easured 4ia 8ass s9e,'ro8e'ry as 9re4iously des,ribed <$8=. <Fi0. .4=.
!erusion and 3ACS 5mmunostaining%
Tn day 28 9os'i88uni@a'ion) 8i,e 1ere anes'he'i@ed 1i'h iso5lurane) s9leens 1ere
re8o4ed) and 8i,e 1ere 9er5used 1i'h 6B.. by 'he in'ra,ardia, rou'e 'o re8o4e
,ir,ula'in0 leu+o,y'es. .9leno,y'es and 8ononu,lear ,ells 5ro8 'he CN. 1ere sur5a,e
s'ained 1i'h an'i!C#4 Peridinin!,hloro9hyll 9ro'eins <PerCP=) an'i!C#8 (llo9hy,o,yanin
<(PC=) an'i!C#44 F"7C) and an'i!C#62/ Phy,oery'hrin <P2= <all 5ro8 B# Bios,ien,es=.
Flo1 ,y'o8e'ry analyses 1ere 9er5or8ed on a F(C.Calibur ins'ru8en' <B#
Bios,ien,es= and analy@ed usin0 Flo1*o so5'1are <7ree.'ar=.
:C!55 Activity Assay%
Con'rol 8i,e or 8i,e i88uni@ed 5or 2(2 1ere 'rea'ed 1i'h 4ehi,le or 2!PMP( 5or 1$ d.
Mi,e 1ere eu'hani@ed 4ia ,er4i,al dislo,a'ion 20 8in a5'er 'heir 'rea'8en' on day 1$) and
hi99o,a89i 1ere disse,'ed and sna9 5ro@en. ;CP"" a,'i4i'y le4els 1ere 8easured as
9re4iously des,ribed <$8=.
Statistical Analyses%
.'a'is'i,al analyses 1ere ,o89le'ed usin0 ;ra9hPad Pris8 $.0 and o9en sour,e so5'1are
&. "n hu8an s'udies) Pearson ,orrela'ions 1ere 9er5or8ed be'1een 'he 8e'aboli'es and
neuro,o0ni'i4e 'es's. ;enerali@ed es'i8a'in0 eGua'ion <;22= 1as used 'o s'udy 'he
asso,ia'ion be'1een N((; and ,o0ni'i4e ou',o8es and ,orre,' 5or 1i'hin!subIe,'
,orrela'ions. Co89arisons be'1een 0rou9s in 'he ani8al s'udies 1ere 8ade 1i'h t 'es's)
1hereas '1o!1ay (NTD( 1as ,o89le'ed 'o 8easure 'rea'8en' e55e,'s o4er 'i8e. P
4alues ]0.01 1ere ,onsidered s'a'is'i,ally si0ni5i,an' 5or 'he hu8an ,orrela'ion da'a)
1hereas P 4alues ]0.0$ 1ere ,onsidered s'a'is'i,ally si0ni5i,an' in ani8al da'a analysis.
.'a'is'i,al su99or' 1as 9ro4ided by 'he *ohns 6o9+ins "ns'i'u'e 5or Clini,al and
7ransla'ional &esear,h Bios'a'is'i,s Cen'er.
;o 'o:
S<!!=4M48+AR> MA+4R5A=
Supporting 5normation:
Cli,+ here 'o 4ie1.
;o 'o:
ACK8"9=4':M48+S
7he au'hors 'han+ *. Cou0hlin) *. Chen0) (. Ba+are) (. &ieh8) (. Barano1s+i) and C.
Ma'rini, 5or 'heir assis'an,e in da'a ,olle,'ion and 'e,hni,al e?9er'ise. 7his 1or+ 1as
su99or'ed by 'he Na'ional "ns'i'u'es o5 6eal'h ;ran's M23 M606%02 <'o (.".M.=) 732
M601$330 <'o M.(.&.=) and P412B01$%0% <'o P.B.B.=; 'he Mon'el 3illia8s Mul'i9le
.,lerosis Founda'ion; 'he Nan,y #a4is Mul'i9le .,lerosis Founda'ion; 'he 7rans4erse
Myeli'is (sso,ia'ion; and 'he *ohns 6o9+ins Brain .,ien,e "ns'i'u'e.
;o 'o:
3""+8"+4S
7he au'hors de,lare no ,on5li,' o5 in'eres'.
7his ar'i,le is a PN(. #ire,' .ub8ission.
7his ar'i,le ,on'ains su99or'in0 in5or8a'ion online a'
111.9nas.or0/loo+u9/su99l/doi:10.103/9nas.120%%3410%/!/#C.u99le8en'al.
;o 'o:
R434R48C4S
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$$. *ones MD) e' al. Beha4ioral and 9a'holo0i,al ou',o8es in MT; 3$!$$ e?9eri8en'al
au'oi88une en,e9halo8yeli'is. * Neuroi88unol. 2008;1%%<1!2=:83N%3. EPubMedF
$6. (hen0 C) e' al. #ele'ion o5 >CP2 in iNT. de5i,ien' 8i,e redu,es 'he se4eri'y o5 'he
disease durin0 e?9eri8en'al au'oi88une en,e9halo8yeli'is. P/o. TN2.
2011;6<8=:e22841. EPMC 5ree ar'i,leF EPubMedF
$. Ber'a .) ;er' /) 6arald 6) .udarshan P. Barnes 8a@e) a use5ul 'as+ 'o assess s9a'ial
re5eren,e 8e8ory in 'he 8i,e. (4ailable a' h''9://d?.doi.or0/10.1038/n9ro'.200.3%0.
200
$8. &oIas C) e' al. ;lu'a8a'e ,arbo?y9e9'idase a,'i4i'y in hu8an s+in bio9sies as a
9har8a,odyna8i, 8ar+er 5or ,lini,al s'udies. * 7ransl Med. 2011;%:2. EPMC 5ree
ar'i,leF EPubMedF
Jurnal .
P/o. Tne. 2012; <11=: e4%%%6.
Published online 2012 No4e8ber 14. doi: 10.131/Iournal.9one.004%%%6
PMC"#: PMC34%81%1
!oor Sleep in !atients with Multiple
Sclerosis
6anne Marie Bee /unde)
1)f
7o88y F. (ae)
1)2
3illia8 "ndre4g0)
1)2
*an (arse'h)
1
BIern
BIor4a'n)
3)4
MIell!Mor'en Myhr)
1)2
and /ars Be
1)2
Friede8ann Paul) 2di'or
(u'hor in5or8a'ion : (r'i,le no'es : Co9yri0h' and /i,ense in5or8a'ion :
;o 'o:
Abstract
Background
Poor slee9 is a 5reGuen' sy89'o8 in 9a'ien's 1i'h 8ul'i9le s,lerosis <M.=. .lee9 8ay be
in5luen,ed by M.!rela'ed sy89'o8s and ad4erse e55e,'s 5ro8 i88uno'hera9y and
sy89'o8a'i, 8edi,a'ions. 3e ai8ed 'o s'udy 'he 9re4alen,e o5 9oor slee9 and 'he
in5luen,e o5 so,io!de8o0ra9hi, and ,lini,al 5a,'ors on slee9 Guali'y in M.! 9a'ien's.
Methods
( 'o'al o5 %0 M. 9a'ien's and 108 se?!and a0e! 8a',hed ,on'rols 1ere in,luded in a
Gues'ionnaire sur4ey. .lee9 ,o89lain's 1ere e4alua'ed by Pi''sbur0h .lee9 Wuali'y "nde?
<P.W"= and a 0lobal P.W" s,ore 1as used 'o se9ara'e 0ood slee9ers <U$= 5ro8 9oor
slee9ers <b$=. 2?,essi4e day'i8e slee9iness) 'he use o5 i88uno'hera9y and
an'ide9ressan' dru0s) sy89'o8s o5 9ain) de9ression) 5a'i0ue and M.!s9e,i5i, heal'h
rela'ed Guali'y o5 li5e 1ere re0is'ered. &esul's 1ere ,o89ared be'1een 9a'ien's and
,on'rols and be'1een 0ood and 9oor slee9ers a8on0 M. 9a'ien's.
Results
M. 9a'ien's re9or'ed a hi0her 8ean 0lobal P.W" s,ore 'han ,on'rols <8.6 4s. 6.3) 9 B
0.001=) and 6.1C o5 'he M. 9a'ien's ,o89ared 'o 43.%C o5 'he ,on'rols <9 B 0.002= 1ere
9oor slee9ers. Pain <9 B 0.02=) 5a'i0ue <9 B 0.001=) de9ression <9 B 0.01= and 5e8ale
0ender <9 B 0.04= 1ere asso,ia'ed 1i'h slee9 dis'urban,e. Mul'i4aria'e analyses sho1ed
'ha' 5e8ale 0ender <9 B 0.02=) use o5 i88uno'hera9y <9 B 00$= and a hi0h 9sy,holo0i,al
burden o5 M. <9 B 0.001= 1ere asso,ia'ed 1i'h 9oor slee9 a8on0 M. 9a'ien's.
Conclusions
Poor slee9 is ,o88on in 9a'ien's 1i'h M.. 2arly iden'i5i,a'ion and 'rea'8en' o5
8odi5iable ris+ 5a,'ors 8ay i89ro4e slee9 and Guali'y o5 li5e in M..
;o 'o:
5ntroduction
Pa'ien's 1i'h 8ul'i9le s,lerosis <M.= 5reGuen'ly re9or' 9oor slee9) and slee9 disorders are
8ore ,o88on in M. 9a'ien's ,o89ared 'o heal'hy ,on'rols E1F. Causes o5 9oor slee9 in
M. are li+ely 8ul'i5a,'orial) and 9o'en'ial 'ri00ers 8ay rela'e 'o ad4erse e55e,'s 5ro8
i88uno'hera9y and sy89'o8a'i, 8edi,a'ions and 'o M.!asso,ia'ed sy89'o8s) su,h as
9ain and 5a'i0ue E2F. Cer'ain sy89'o8s rela'ed 'o M.) 8ay lead 'o e?a,erba'ion o5 o'hers
i5 le5' un'rea'ed E3F. Pa'ien's su55erin0 5ro8 a slee9 dis'urban,e ha4e an in,reased ris+ o5
de4elo9in0 ,o!8orbid ,ondi'ions li+e hear' disease) obesi'y and diabe'es 'ha' 8ay ha4e a
9ro5ound i89a,' on lon0!'er8 heal'h E4F) E$F. "n order 'o i89ro4e slee9 and 9ossibly
redu,e lon0!'er8 heal'h ,onseGuen,es o5 9oor slee9 in M.) iden'i5i,a'ion o5 8odi5yin0
ris+ 5a,'ors o5 9oor slee9 is needed. 7here5ore 1e ai8ed 'o s'udy 'he 9re4alen,e o5 slee9
dis'urban,e in M.) ,o89ared 'o 'he heal'hy Nor1e0ian 9o9ula'ion. Fur'her) a8on0 M.!
9a'ien's) 1e ai8ed 'o iden'i5y 9ossible so,io!de8o0ra9hi, and ,lini,al 5a,'ors asso,ia'ed
1i'h 'he ris+ o5 bein0 a 9oor slee9er. 71o 9rior s'udies ha4e des,ribed 'he so,io!
de8o0ra9hi, and ,lini,al 5a,'ors asso,ia'ed 1i'h 9oor slee9) bo'h la,+in0 a ,on'rol 0rou9
5or ,o89arisons E1F) E6F. 7o our +no1led0e) a ,ase!,on'rol s'udy loo+in0 a' 'he so,io!
de8o0ra9hi, and ,lini,al asso,ia'ions 1i'h 9oor slee9 in M.) has no' been 9ublished
9re4iously.
;o 'o:
Materials and Methods
4thics statement
7he s'udy 1as based on 1ri''en in5or8ed ,onsen') and a99ro4ed by 'he &e0ional
Co88i''ee 5or Medi,al and 6eal'h &esear,h 2'hi,s o5 3es'ern Nor1ay.
!atients and controls
3e ai8ed 'o in,lude 9a'ien's\ 1i'h 1ell!es'ablished disease. (ll 140 9a'ien's dia0nosed
1i'h M. 5ro8 1%%3N1%%8 a' 'he #e9ar'8en' o5 Neurolo0y) 6au+eland >ni4ersi'y
6os9i'al) Ber0en) Nor1ay 1ere in4i'ed 'o 9ar'i,i9a'e in 'he s'udy. (ll M.!9a'ien's
5ul5illin0 'he dia0nos'i, ,ri'eria o5 Poser 1ere in,luded) inde9enden' o5 sub'y9e. 7he
9a'ien's 1ere iden'i5ied 'hou0h hos9i'al re,ords and re,rui'ed a' 'he #e9ar'8en' o5
Neurolo0y) 6au+eland >ni4ersi'y 6os9i'al. ( 'o'al o5 280 a0e! and 0ender!8a',hed
,on'rols 1ere dra1n 5ro8 'he Nor1e0ian Na'ional Po9ula'ion &e0is'ry. 7here 1ere no
e?,lusion ,ri'eria. 7he da'a 1ere ,olle,'ed by use o5 4alida'ed sel5!ad8inis'ered
Gues'ionnaires and re'urned by 8ail in 9re!s'a89ed addressed re'urn en4elo9es. (ll
9ar'i,i9an's re,ei4ed 'he sa8e se' o5 s'udy in5or8a'ion and Gues'ionnaires) e?,e9' 5or 'he
M.".!2% Gues'ionnaire) s9e,i5i,ally desi0ned 5or M. 9a'ien's. ( re8inder 1as sen' 'o
ea,h non!res9onden' 9ar'i,i9an' 4ia 'he 8ail '1o 8on'hs a5'er 'he ini'ial Gues'ionnaires
1ere 8ailed ou'. 7he ,olle,'ed da'a 5ro8 'he Gues'ionnaires 1ere re0is'ered and en'ered
in a da'abase 'ha' 1as ,are5ully double and 'ri9le ,he,+ed 5or any 8is'a+es in da'a en'ry.
?ariables
(0e) 0ender) 8ari'al s'a'us and 'he use o5 8edi,a'ion 1ere re0is'ered. 7he re0ular
8edi,a'ions 1ere re,orded and 0rou9ed in'o 'hree ,lasses: an'ide9ressan' dru0s)
i88uno'hera9y and o'hers. 7he Gues'ionnaires used are all 4alida'ed) and all bu' 'he D(.
9ain s,ale are also 4alida'ed in Nor1e0ian EFNE11F.
Pi''sbur0h .lee9 Wuali'y "nde? <P.W"= 1as in,luded 'o 8easure slee9 and iden'i5y slee9
,o89lain's durin0 'he 9re4ious 8on'h E12F. "' has se4eral ,lini,al and resear,h
a99li,a'ions and ,an be used 'o se9ara'e R0oodS 5ro8 R9oorS slee9ers) s,reen 5or ni0h'
'i8e slee9 dis'urban,es and 'o 8oni'or 'he 9ro0ression o5 slee9 disorders E13F) E14F.
6o1e4er) i' ,anno' be used 'o dia0nose s9e,i5i, slee9 disorders and does no' 9ro4ide
in5or8a'ion on slee9 s'a0es or slee9 ar,hi'e,'ure 'ha' ,an be 8easured by
9olyso8no0ra9hy <P.;= E1$F. "' ,onsis's o5 1% sel5! ra'ed Gues'ionnaires and $ addi'ional
Gues'ionnaires 5or bed 9ar'ner.
"' 9ro4ides a 0lobal s,ore o5 slee9 on a s,ale 5ro8 1 'o 21) 1i'h hi0her s,ores indi,a'in0
8ore slee9 ,o89lain's. ( 0lobal P.W" s,ore b$ is sho1n 'o ha4e a dia0nos'i, sensi'i4i'y
o5 8%.6C and a s9e,i5i,i'y o5 86.$C and 1as used 'o se9ara'e 0ood slee9ers <U$= 5ro8
9oor slee9ers <b$= E12F. 7es'!re'es' reliabili'y has sho1n ,onsis'en,y o4er 'i8e E16F.M.!
s9e,i5i, heal'h rela'ed Guali'y o5 li5e 1as re,orded by 'he Mul'i9le .,lerosis "89a,' .,ale
<M.".!2%=) 'ha' in,ludes 'he 9hysi,al <20 i'e8s= and 9sy,holo0i,al <% i'e8s= i89a,' o5
M.. 6i0h s,ores on M.".!2% indi,a'e 0rea'er i89a,' o5 M.. Na'urally) only M. 9a'ien's
ans1ered 'hese Gues'ions) and asso,ia'ions 'o 9oor slee9 1as analysed se9ara'ely 5or 'he
9hysiolo0i,al and 9sy,holo0i,al subs,ales o5 M.".!2% <6ober' *= E1F.
2?,essi4e day'i8e slee9iness 1as re0is'ered by 'he 291or'h slee9iness s,ale <2..=) 'ha'
is a 4alida'ed and 1idely used sel5!ad8inis'ered Gues'ionnaire used 'o in4es'i0a'e
e?,essi4e day'i8e slee9iness/hy9erso8nia E18F. "' ,an be used as a s,reenin0 'es' 5or
e?,essi4e slee9iness or lon0i'udinally 'o 5ollo1 a 9a'ien'\s res9onse 'o an in'er4en'ion. "'
8easures 'he 9roneness 'o 5all aslee9 or do@e o55 in ei0h' s9e,i5i, si'ua'ions. (n 2..
s,ore abo4e 10 is re0arded as an indi,a'or o5 e?,essi4e slee9iness.
3e assessed a,u'e 9ain by usin0 'he 4alida'ed Disual (nalo0ue .,ale 5or 9ain assess8en'.
7he D(. 9ain s,ale ,onsis's o5 a 10 ,8 <3.%4 in,hes= line 1i'h one end labelled Rno 9ainS
and 'he o'her end labelled R1ors' i8a0inable 9ain e4erS. 7he 9ar'i,i9an's 1ere as+ed 'o
8ar+ 'he line a' 'he 9oin' 'ha' bes' des,ribed 'he 9ain in'ensi'y. For Guali'a'i4e analysis
1e se9ara'ed 'he da'a in '1o 0rou9s Rno 9ain <0N1 9oin's=S and R9ain <b1 9oin'= E1%F. 7he
9resen,e o5 9ain a' 'he 'i8e o5 ,o89le'in0 'he Gues'ionnaire 1as re0is'ered as 9resen' or
no' E20F.
Fa'i0ue 1as re0is'ered by 'he Fa'i0ue Wues'ionnaire <FW= 'ha' is a 4alida'ed Gues'ionnaire
used 'o assess 5a'i0ue se4eri'y. "' is an 11 i'e8 Gues'ionnaire used 'o 8easure 9hysi,al and
8en'al 5a'i0ue durin0 'he 9re4ious 8on'h <s,ale 0N3= 1i'h a ,u' o55 s,ore a' 4 ,onsidered
indi,a'i4e o5 e?,essi4e 5a'i0ue E21F.
.y89'o8s o5 de9ression 1ere s,reened by 'he Be,+ #e9ression "n4en'ory <B#"N""= 'ha'
in,ludes 21!Gues'ion sel5!re9or'in0 8ul'i9le ,hoi,e Gues'ions. 7he 9a'ien's B#" s,ore 1as
,a'e0ori@ed as no' de9ressed <s,ore 0N1%= and de9ressed <s,oreb20= E11F) E22F.
Statistical analysis
.o,io!de8o0ra9hi, 4ariables <a0e) 0ender) and 8ari'al s'a'us=) 8edi,a'ion) and ,lini,al
,hara,'eris'i,s as 1ell as 'he se4en ,o89onen's o5 'he P.W" Gues'ionnaire 1ere ,o89ared
be'1een 9a'ien's and ,on'rols. (8on0 M. 9a'ien's) 'he sa8e 4ariables in addi'ion 'o
heal'h rela'ed Guali'y o5 li5e <M.".!2%= 1as ,o89ared be'1een 0ood! and 9oor slee9ers.
7he Fis,her 2?a,' 7es' 1as a99lied 'o ,o89are 0rou9s 5or no8inal 4ariables. 7he
Man'el!6aens@el 'es' 1as used 5or ordinal 4ariables and inde9enden' '1o sa89le '! 'es'
1as a99lied 5or ,on'inuous 4ariables. Nor8al dis'ribu'ion and eGuali'y o5 4arian,e 1as
,he,+ed be5ore a99lyin0 'he 9ara8e'ri, '!'es'. Crude 9!4alues are re9or'ed.
"nde9enden' '1o sa89le '! 'es' 1as a99lied 5or ,on'inuous 4ariables. Nor8al dis'ribu'ion
and eGuali'y o5 4arian,e 1as ,he,+ed be5ore a99lyin0 'he 9ara8e'ri, '!'es'. Crude 9!
4alues are re9or'ed.
(n analysis 1as 9er5or8ed 'o iden'i5y 5a,'ors asso,ia'ed 1i'h 9oor slee9. /o0is'i,
re0ression 1as 9er5or8ed 'o es'i8a'e odds ra'ios) 5irs' in uni4aria'e 8odels un'il a
8ul'i4aria'e 8odel 1as 5i''ed. Dariables 1i'h uni4aria'e P]0.2$ 1ere sele,'ed as
,andida'es in 'he 8ul'i4aria'e analysis 5ollo1in0 a 8odel!buildin0 s'ra'e0y as des,ribed
by 6os8er X /e8esho1 E23F.
#a'a analyses 1ere ,arried ou' usin0 .P.. so5'1are 5or 3indo1s <4ersion 1$.0) .P..)
Chi,a0o "/=) 9!4alues ]0.0$ 1ere ,onsidered s'a'is'i,ally si0ni5i,an'.
;o 'o:
Results
Comparisons o patients and controls
( 'o'al o5 %0 M. 9a'ien's <64.3C= and 108 <38.6C= ,on'rol 9ersons res9onded 'o 'he
in4i'a'ion 'o 9ar'i,i9a'e in 'he sur4ey. .o,io!de8o0ra9hi, ,hara,'eris'i,s and 'he use o5
an'ide9ressan' dru0s did no' di55er si0ni5i,an'ly a8on0 9a'ien's and ,on'rols <7able 1=.
7he a4era0e a0e o5 'he 9a'ien's 1ere 4$c10.4 and 'he ,on'rols 1ere 44.3c10.2 <9 B 0.6$=.
T5 'he 9a'ien's) 41<4$.6C= 1ere 8en and 4% <$4.4C= 1ere 1o8en) and 4$<41.C= 8en
and 63<$8.3C= 1o8en 8ade u9 'he ,on'rol 0rou9 <9 B 0.66= <7able 1=. 7he 8ean s,ore
o5 e?,essi4e day'i8e slee9iness <2..= did no' di55er be'1een 9a'ien's and ,on'rols and
8ean 4alues 1ere belo1 ,u'!o55 5or e?,essi4e slee9iness <da'a no' sho1n=. Pain <9 B
0.01=) 5a'i0ue <9 B 0.004= and de9ression <9 B 0.02= 1ere re9or'ed 8ore 5reGuen'ly a8on0
9a'ien's 'han ,on'rols. 7hir'y!5i4e <42.C= 9a'ien's re,ei4ed i88uno'hera9y <in'er5eron
be'a <n B 24=) 0la'ira8er a,e'a'e <n B =) na'ali@u8ab <n B 2== <7able 1=. M. 9a'ien's had a
si0ni5i,an'ly hi0her 8ean 0lobal P.W" s,ore <8.6c4.6= ,o89ared 'o ,on'rols <6.3c4.1=)
indi,a'in0 a 9oorer slee9 Guali'y <9 B 0.001= <7able 2=. P.W" slee9 onse' la'en,y 1as
si0ni5i,an'ly hi0her <1.4c1.1= a8on0 9a'ien's 'han ,on'rols <1.1c1.1= <0.04= <7able 2=.
7he 9ro9or'ion o5 M. 9a'ien's <6.1C= 'ha' re9or'ed 9oor Guali'y o5 slee9 1as
si0ni5i,an'ly hi0her 'han 'he ,on'rols <43.%C= <9 B 0.002=.
7able 1
Clinical and socio-demographic parameters among patients and controls%
7able 2
!ittsburgh Sleep @uality 5nde& #!S@5$ scores among patients and controls%
Risk actors associated with poor sleep among patients with MS
More 1o8en <8.0C= 'han 8en <$3.1C= su55ered 5ro8 9oor slee9 a8on0 'he M. 9a'ien's
<9 B 0.04=. Fur'her) 9ain <9 B 0.02= and 5a'i0ue <9 B 0.001= 1ere asso,ia'ed 1i'h hi0her
ris+ 5or bein0 a 9oor slee9er <7able 3=. (ll 9a'ien's ,lassi5ied 1i'h 8odera'e de9ression <9
B 0.01= and all 9a'ien's on an'ide9ressan' 8edi,a'ions su55ered 5ro8 9oor slee9 <9 B
0.03=. 2?,essi4e day'i8e slee9iness 1as no' si0ni5i,an'ly asso,ia'ed 1i'h 9oor slee9
a8on0 9a'ien's <9 B 0.12= <7able 3=. 6i0her s,ore on 8ean M.".!2% 9hysiolo0i,al and
9sy,holo0i,al sub s,ores) 1ere asso,ia'ed 1i'h hi0her ris+ o5 bein0 a 9oor slee9er
<9]0.001=.
7able 3
Comparisons o clinical and socio-demographic parameters in MS patients
categori(ed as good sleepers versus poor sleepers%
Mul'i4aria'e lo0is'i,al re0ression analyses sho1ed 'ha' 5e8ale 0ender) <T& B 6.8) %$C
C": 1.33N3$.3=) i88uno'hera9y <T&B 4.) %$C C": 0.%8N23.3= and redu,ed Guali'y o5
li5e <M.".!2% 9sy,holo0i,al subs,ale= <T&B 1.12) %$C C": 1.0$N1.1%= 1ere asso,ia'ed
1i'h 9oor slee9 <7able 4=.
7able 4
5ndependent actors associated with poor sleep in patients with MS%
;o 'o:
'iscussion
Poor slee9 is a ,o88on 5indin0 in M. 9a'ien's) and 9re4ious s'udies ha4e indi,a'ed a
9re4alen,e o5 $0C in 'his 9a'ien' 0rou9 E24F) E2$F. "n 'he 9resen' sur4ey) 1e re9or' a
hi0her 5reGuen,y o5 M. 9a'ien's <6.1C= 1i'h dis'urbed slee9. 7he 5o,us o5 'his s'udy
1as 'o dis,lose 9o'en'ial 8odi5iable ,lini,al and so,io!de8o0ra9hi, <a0e) 0ender) 8ari'al
s'a'us= ris+ 5a,'ors asso,ia'ed 1i'h slee9 dis'urban,e in M. 9a'ien's. (8on0 de8o0ra9hi,
4ariables 'ha' 1ere asso,ia'ed 1i'h slee9 dis'urban,e) 5e8ale 0ender 1as 5ound 'o be
s'ron0ly asso,ia'ed 1i'h 9oor slee9. 7his is in ,on'ras' 'o a 9re4ious s'udy 'ha' re9or'ed
no in5luen,e o5 0ender on slee9 Guali'y a8on0 M. 9a'ien's E1F.
Psy,hia'ri, disorders) and es9e,ially de9ression) are 9re4alen' in M. and ha4e 8aIor
i89a,' on Guali'y o5 li5e E26F.3e 5ound a 3! 5old hi0her 9re4alen,e o5 de9ressi4e
sy89'o8s a8on0 9a'ien's ,o89ared 'o ,on'rols) ,onsis'en' 1i'h 'he resul's o5 a 9re4ious
s'udy E2F. (ll 9a'ien's ,lassi5ied as ha4in0 8odera'e de9ression in our s'udy su55ered
5ro8 9oor slee9. "nso8nia and de9ression are ,losely lin+ed) and a99ear 'o ha4e a
bidire,'ional rela'ionshi9 1here inso8nia 1orsens de9ression and 4i,e 4ersa E28F) E2%F.
M. 9a'ien's re9or'in0 9oor slee9 should 'here5ore be s,reened 5or de9ression) and 'rea'ed
a,,ordin0ly.
.ubIe,'i4e slee9 disorders in M. and in 'he 0eneral 9o9ula'ion ha4e in nu8erous
e9ide8iolo0i,al s'udies sho1ed a ,lose a ,lose asso,ia'ion 1i'h sy89'o8s o5 5a'i0ue E1F)
E30F) E31F. .lee9 dis'urban,e has been re9or'ed as a si0ni5i,an' inde9enden' ,on'ribu'or 'o
5a'i0ue in M.) and in our s'udy) as 8any as %2C o5 'he 9a'ien's su55erin0 5ro8 5a'i0ue
1as ,lassi5ied as 9oor slee9ers. ( re,en' rando8i@ed ,on'rolled 'hera9y s'udy re4ealed
i89ro4e8en' in 5a'i0ue by 'rea'8en' o5 slee9 disorders in M. E32F. 6o1e4er) 'he
9a'ho9hysiolo0y o5 M.!rela'ed 5a'i0ue is 9oorly unders'ood and 'he ,ause and e55e,'
rela'ionshi9 be'1een dis'urbed slee9 and M.! rela'ed 5a'i0ue is ,urren'ly an eni08a.
Poor Guali'y o5 slee9 in M. 9a'ien's 1as no' asso,ia'ed 1i'h e?,essi4e day'i8e
slee9iness) des9i'e in,reased 5reGuen,ies o5 5a'i0ue and slee9 ,o89lain's in 9a'ien's
,a'e0ori@ed as 9oor slee9ers. 7hese resul's are ,o89a'ible 1i'h a 9u9illo0ra9hi, and
Gues'ionnaire <2..)...= s'udy o5 61 M. 9a'ien's) 'ha' re9or'ed no e4iden,e o5 e?,essi4e
day'i8e slee9iness in M. E33F. .y89'o8s o5 5a'i0ue and slee9iness in M. 9a'ien's are
o5'en ,on5used and used in'er,han0eably E34F. .ubIe,'i4e slee9iness and subIe,'i4e
5a'i0ue in M. 9a'ien's and heal'hy ,on'rols ha4e sho1n 'o be inde9enden'ly asso,ia'ed
1i'h slee9 disorders) al'hou0h ,orrela'ed 1i'h ea,h o'her E34F. Pa'ien's 1i'h inso8nia
o5'en ,o89lain o5 5a'i0ue) bu' no' slee9iness or 'he 9ro9ensi'y 'o 5all aslee9 E34F. 7hese
s'udies su00es' 'ha' 5a'i0ue and e?,essi4e day'i8e slee9iness are di55eren'ia'ed ,ondi'ions
and should be assessed inde9enden'ly in 9a'ien's ,o89lainin0 o5 9oor slee9.
(,u'e and ,hroni, 9ain is a 5reGuen' sy89'o8 in M.) and in,lude neuro9a'hi, 9ain and
8us,ulos+ele'al 9ain se,ondary 'o o'her M. sy89'o8s su,h as s9as'i,i'y E3$F.
Po9ula'ion s'udies ha4e es'i8a'ed 'ha' $$N6$C o5 M. 9a'ien's su55er 5ro8 a,u'e)
suba,u'e or ,hroni, 9ain syndro8e E36F. 3e 5ound 'ha' 'he 9resen,e o5 9ain 1as re9or'ed
abou' '1i,e as 5reGuen' a8on0 M.!9a'ien's ,o89ared 'o ,on'rols. Pain 1as also
si0ni5i,an'ly 8ore 5reGuen' in 9oor slee9ers 'han in 0ood slee9ers. .i8ilar 5indin0s 1as
re9or'ed in a 9re4ious s'udy) 'ha' in addi'ion 5ound 9ain 'o be 'he 8ain ,ause o5 ini'ial
inso8nia E3F. "n an e9ide8iolo0i, s'udy o5 1o8en 1i'h &&M.) slee9 dis'urban,e
in'ensi'y 1ere hi0her 5or 1o8en 1i'h &&M. 1i'h 9ain 'han 5or 1o8en 1i'hou' 9ain
E38F. Pain is a ,o88on) bu' o5'en inadeGua'ely 'rea'ed sy89'o8 in M. E3%F. By
8odi5yin0 9ain) i89ro4ed slee9 8ay be ob'ained.
.e9ara'e analyses o5 ea,h P.W" ,o89onen' sho1ed 'ha' in,reased slee9 la'en,y 1as 'he
8os' 5reGuen' ,o89lain' a8on0 M. 9a'ien's) 5ollo1ed by slee9 dis'urban,e and day'i8e
dys5un,'ion. 7his 1as in line 1i'h a 9re4ious s'udy) 1here ini'ial inso8nia 1as ra'ed as
'he 8os' ,o88on ,o89lain' o5 'he P.W" ,o89onen' 4alues E1F.
No si0ni5i,an' di55eren,es 1ere no'ed be'1een 9a'ien's and ,on'rols re0ardin0 slee9
dis'urban,e and slee9 e55i,ien,y.
7he resul's 5ro8 our s'udy re4eal 'ha' 'he 9sy,holo0i,al and 9hysiolo0i,al i89a,' o5 M.
is 0rea'er a8on0 9oor slee9ers 'han a8on0 0ood slee9ers. "n our s'udy a hi0h
9sy,holo0i,al burden o5 M. 1as inde9enden'ly asso,ia'ed 1i'h 9oor slee9. Nearly hal5 o5
M. 9a'ien's ha4e re9or'ed si0ni5i,an' an?ie'y le4els 1i'hin 'he 5irs' year o5 dia0nosis
E40F. 7radi'ionally) 8ana0e8en' o5 M. ha4e 5o,used 9ri8arily on 'rea'8en' o5 8o'or
sy89'o8s E41F. 7rea'8en' o5 non!8o'or sy89'o8s su,h as 9sy,holo0i,al i89a,' o5 M.
is usually asso,ia'ed 1i'h i89ro4e8en' o5 6&Wo/ E41F. .lee9 disru9'ion e4iden' by
9oly0ra9hi, re0is'ra'ion is asso,ia'ed 1i'h 0rea'er 9sy,holo0i,al i89a,' on Guali'y o5 li5e
E42F. More e89hasis on 'he relie5 o5 9sy,holo0i,al dis'ress o5 M. 8ay li+ely 5a4our 0ood
slee9.
"n 'his s'udy) 'he use o5 i88uno'hera9y 1as inde9enden'ly asso,ia'ed 1i'h 9oor Guali'y
o5 slee9. (n a,'i0ra9hy s'udy o5 rela9sin0!re8i''in0 M. 9a'ien's usin0
i88uno8odula'ory <in'er5eron be'a) 0la'ir8aer a,e'a'e= dru0s) sho1ed a redu,'ion in
slee9 e55i,ien,y in '1o!'hirds on 'he ni0h' 5ollo1in0 in'er5eron be'a inIe,'ion) irres9e,'i4e
o5 'he 5reGuen,y o5 inIe,'ions E43F. (no'her s'udy re,en'ly re9or'ed redu,ed 5lu!li+e
sy89'o8s and i89ro4ed slee9 e55i,a,y by s1i',hin0 5ro8 e4enin0 'o 8ornin0 inIe,'ions
o5 in'er5eron be'a E44F.
"' is a usual re,o88enda'ion 5ro8 neurolo0is's) 'ha' in'er5eron be'a should be inIe,'ed in
'he e4enin0) so 'ha' 'he 9a'ien' ,an slee9 'hrou0h 'he side!e55e,'s E4$F. 3e ha4e
sys'e8a'i,ally ad4ised 9a'ien's 'o 'a+e e4enin0 inIe,'ions o5 "FNB. (l'hou0h our resul's
re4eal no ,ausali'y be'1een use o5 i88uno'hera9y and 9oor slee9) 1e belie4e ho1e4er)
'ha' our 5indin0s are su55i,ien'ly su00es'i4e 'o in'rodu,e a 9ossible 'heory on 'he
rela'ionshi9 be'1een 'i8in0 o5 i88uno8odula'ory dru0s and i89a,' on slee9. 7he
9ossibili'y 'ha' i89ro4ed slee9 8ay be ob'ained by ,han0in0 ad8inis'ra'ion 'i8e o5
i88uno8odula'ory 8edi,a'ion) is i89or'an' in re0ards 'o slee9 8ana0e8en') and 5ur'her
s'udies should be 1arran'ed in 'his re0ard.
7here are se4eral li8i'a'ions in our s'udy. (s 'his is a ,ross se,'ional s'udy) 1e ,anno'
de'er8ine 'he dire,'ions o5 'he 9redi,'ors o5 9oor slee9. 3e ,an only sho1 si0ni5i,an'
,lini,al and de8o0ra9hi, asso,ia'ions 'o 9oor slee9 Guali'y. 7he lo1er res9onse ra'e in
'he ,on'rol 0rou9 ,an be e?9lained by 'he ,olle,'ion o5 in5or8a'ion by 8ail) and by a se'
o5 Gues'ionnaires 'ha' 1as ,o89rehensi4e and 'i8e de8andin0. Con'rols su55erin0 5ro8
9oor slee9 8ay ha4e had 9ar'i,ular in'eres' in 'his subIe,'; 'his 8ay ha4e s+e1ed 'he da'a
'o1ards s8aller di55eren,es be'1een 9a'ien's and ,on'rols.
Mi,'uri'ion!rela'ed sy89'o8s su,h as ur0e and no,'uria 1ere no' analysed se9ara'ely) as
'hese 9ara8e'ers 1ere in,luded in 'he slee9 Guali'y ,o89onen' o5 M.". !2% and P.W"
res9e,'i4ely. Fur'her8ore) 'he 9ain assess8en' 1as li8i'ed and 8ul'idi8ensional
8easures su,h as M,;ill Pain Wues'ionnaire or Mul'idi8ensional 9ain in4en'ory) 1ould
9ossibly ha4e added 8ore in5or8a'ion. 7he e?9anded disabili'y s,ale <2#..= 1as no'
assessed) and 'here5ore a 9ossible rela'ionshi9 be'1een disabili'y s'a'us and slee9
dis'urban,e ,ould no' be es'ablished.
7he resul's o5 'his s'udy indi,a'e 'ha' 9oor slee9 is a 5reGuen' ,o89lain' a8on0 9a'ien's
1i'h M. and inde9enden'ly asso,ia'ed 1i'h 5e8ale 0ender) use o5 i88uno'hera9y and a
hi0h 9sy,holo0i,al burden o5 M.. .lee9 dis'urban,e is a 9o'en'ially 'rea'able ,ondi'ion.
"n,reased a1areness o5 8odi5iable ris+ 5a,'ors o5 9oor slee9 in M. 8ay be i89or'an' 5or
early 'hera9eu'i, and 9ro9hyla,'i, in'er4en'ions.
;o 'o:
Acknowledgments
7he au'hors 1ould li+e 'o 'han+ resear,hers Nina ;ry''en 7or+ildsen and Mris'o55er
6au0ar4oll 5or hel95ul dis,ussions re0ardin0 'he 8anus,ri9'.
;o 'o:
3unding Statement
7his resear,h 1as 5unded by 'he Nor1e0ian Mul'i9le .,lerosis Co89e'en,e Cen're)
Ber0en) Nor1ay; and unres'ri,'ed 0ran's 5ro8 No4ar'is Nor1ay. 7he 5unders had no role
in s'udy desi0n) da'a ,olle,'ion and analysis) de,ision 'o 9ublish) or 9re9ara'ion o5 'he
8anus,ri9'.
;o 'o:
Reerences
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o5 J9oor slee9H a8on0 9a'ien's 1i'h 8ul'i9le s,lerosis: an inde9enden' 9redi,'or o5 8en'al
and 9hysi,al s'a'us. .lee9 Med 10: 26N34. EPubMedF
2. Brass .#) #uGue''e P) Proul?!7herrien *) (uerba,h . <2010= .lee9 disorders in
9a'ien's 1i'h 8ul'i9le s,lerosis. .lee9 Med &e4 14: 121N12%. EPubMedF
3. Cray'on 6) 6ey8an &() &oss8an 6. <2004= ( 8ul'i8odal a99roa,h 'o 8ana0in0 'he
sy89'o8s o5 8ul'i9le s,lerosis. Neurolo0y 63: .12N18. EPubMedF
4. (''arian 6 <200%= "89or'an,e o5 slee9 in 'he Guali'y o5 li5e o5 8ul'i9le s,lerosis
9a'ien's: a lon0 under!re,o0ni@ed issue. .lee9 Med 10: N8. EPubMedF
$. Ma8ins+a M) Mi8o55 &) Benede''i () &obinson () Bar!Tr () e' al. <2011= Tbs'ru,'i4e
slee9 a9nea is asso,ia'ed 1i'h 5a'i0ue in 8ul'i9le s,lerosis. Mul' .,ler . EPubMedF
6. Ba8er (M) *ohnson M/) (8'8ann #() Mra5' ;6 <2010= Beyond 5a'i0ue: (ssessin0
4ariables asso,ia'ed 1i'h slee9 9roble8s and use o5 slee9 8edi,a'ions in 8ul'i9le
s,lerosis. Clin 29ide8iol 2010: %%N106. EPMC 5ree ar'i,leF EPubMedF
. Beis+e MM) MIelsber0 FN) &uud 2() .'a4e8 M <200%= &eliabili'y and 4alidi'y o5 a
Nor1e0ian 4ersion o5 'he 291or'h slee9iness s,ale. .lee9 and Brea'hin0 13: 6$N2.
EPubMedF
8. /o0e *6) 2+eber0 T) Maasa . <1%%8= Fa'i0ue in 'he 0eneral Nor1e0ian 9o9ula'ion:
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%. .8edal 7) *ohansen 66) Myhr MM) .'rand /" <2010= Psy,ho8e'ri, 9ro9er'ies o5 a
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.,andina4i,a 122: 244N2$1. EPubMedF
10. Pallesen .) Nordhus "6) T84i+ .) .i4er'sen B) Ma''hiesen .B <200$= BIor4a'n B
<200$= Pi''sbur0h .lee9 Wuali'y "nde?. 7idss+ri5' 5or Nors+ Psy+olo05orenin0 14N1.
11. (asen 6 <2001= (n e89iri,al in4es'i0a'ion o5 de9ression sy89'o8s: nor8s)
9sy,ho8e'ri, ,hara,'eris'i,s and 5a,'or s'ru,'ure o5 'he Be,+ #e9ression "n4en'ory ""
Ber0en.
12. Buysse #*) &eynolds CF 3rd) Mon+ 76) Ber8an .&) Mu95er #* <1%8%= 7he
Pi''sbur0h .lee9 Wuali'y "nde?: a ne1 ins'ru8en' 5or 9sy,hia'ri, 9ra,'i,e and resear,h.
Psy,hia'ry &es 28: 1%3N213. EPubMedF
13. Doderhol@er >) &ie8ann #) 6ornya+ M) Ba,+haus *) Fei0e B) e' al. <2001= ( double!
blind) rando8i@ed and 9la,ebo!,on'rolled s'udy on 'he 9olyso8no0ra9hi, 1i'hdra1al
e55e,'s o5 @o9i,lone) @ol9ide8 and 'ria@ola8 in heal'hy subIe,'s. 2ur (r,h Psy,hia'ry
Clin Neuros,i 2$1: 11N123. EPubMedF
14. 6o0l B) (rnul5 ") Co8ella C) Ferreira *) "ran@o () e' al. <2010= .,ales 'o assess slee9
i89air8en' in Par+inson\s disease: ,ri'iGue and re,o88enda'ions. Mo4 #isord 2$: 204N
216. EPubMedF
1$. #y+en M2) (5i5i (M) /in!#y+en #C <2012= .lee9!rela'ed 9roble8s in neurolo0i,
diseases. Ches' 141: $28N$44. EPubMedF
16. Buysse #*) 6all M/) .'rollo P*) Ma8ar,+ 73) T1ens *) e' al. <2008= &ela'ionshi9s
be'1een 'he Pi''sbur0h .lee9 Wuali'y "nde? <P.W"=) 291or'h .lee9iness .,ale <2..=) and
,lini,al/9olyso8no0ra9hi, 8easures in a ,o88uni'y sa89le. * Clin .lee9 Med 4: $63N
$1. EPMC 5ree ar'i,leF EPubMedF
1. 6obar' *) /a89in0 #) Fi'@9a'ri,+ &) &ia@i () 7ho89son ( <2001= 7he Mul'i9le
.,lerosis "89a,' .,ale <M.".!2%=: a ne1 9a'ien'!based ou',o8e 8easure. Brain 124:
%62N%3. EPubMedF
18. *ohns M3 <1%%1= ( ne1 8e'hod 5or 8easurin0 day'i8e slee9iness: 'he 291or'h
slee9iness s,ale. .lee9 14: $40N$4$. EPubMedF
1%. Collins ./) Moore &() M,Wuay 6* <1%%= 7he 4isual analo0ue 9ain in'ensi'y s,ale:
1ha' is 8odera'e 9ain in 8illi8e'resh Pain 2: %$N%. EPubMedF
20. Mane &/) Bershads+y B) &o,+1ood 7) .aleh M) "sla8 NC <200$= Disual (nalo0
.,ale 9ain re9or'in0 1as s'andardi@ed. * Clin 29ide8iol $8: 618N623. EPubMedF
21. Chalder 7) Berelo1i'@ ;) Pa1li+o1s+a 7) 3a''s /) 3essely .) e' al. <1%%3=
#e4elo98en' o5 a 5a'i0ue s,ale. * Psy,hoso8 &es 3: 14N1$3. EPubMedF
22. .4anbor0 P) (sber0 M <2001= ( ,o89arison be'1een 'he Be,+ #e9ression "n4en'ory
<B#"= and 'he sel5!ra'in0 4ersion o5 'he Mon'0o8ery (sber0 #e9ression &a'in0 .,ale
<M(#&.=. * (55e,' #isord 64: 203N216. EPubMedF
23. 6os8er #3 /. <2000= (99lied lo0is'i, re0ression) 2nd edn 3iley.
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9roble8s in 8ul'i9le s,lerosis. 2ur Neurol 34: 320N323. EPubMedF
2$. Ba8er (M) *ohnson M/) (8'8ann #) Mra5' ;6 <2008= Pre4alen,e o5 slee9 9roble8s
in indi4iduals 1i'h 8ul'i9le s,lerosis. Mul' .,ler 14: 112N1130. EPMC 5ree ar'i,leF
EPubMedF
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in5luen,in0 Guali'y o5 li5e in 8ul'i9le s,lerosis 9a'ien's: disabili'y) de9ressi4e 8ood)
5a'i0ue and slee9 Guali'y. (,'a Neurol .,and 110: 6N13. EPubMedF
2. Clar+ CM) Fle8in0 *() /i #) T0er *) Mlono55 6) e' al. <1%%2= .lee9 dis'urban,e)
de9ression) and lesion si'e in 9a'ien's 1i'h 8ul'i9le s,lerosis. (r,h Neurol 4%: 641N643.
EPubMedF
28. Pa9arri0o9oulos 7) Feren'inos P) Mou@ou9is () Mou'sis ;) Pa9adi8i'riou ;N <2010=
7he neuro9sy,hia'ry o5 8ul'i9le s,lerosis: 5o,us on disorders o5 8ood) a55e,' and
beha4iour. "n' &e4 Psy,hia'ry 22: 14N21. EPubMedF
2%. &ie8ann #) Ber0er M) Doderhol@er > <2001= .lee9 and de9ressionNresul's 5ro8
9sy,hobiolo0i,al s'udies: an o4er4ie1. Biol Psy,hol $: 6N103. EPubMedF
30. Mayna+ 6) (l'in'as () Mayna+ #) >yani+ T) .ai9 .) e' al. <2006= Fa'i0ue and slee9
dis'urban,e in 8ul'i9le s,lerosis. 2ur * Neurol 13: 1333N133%. EPubMedF
31. Mer+elba,h .) .,hul@ 6) Fa'i0ue Collabora'i4e .'udy ; <2006= 3ha' ha4e 5a'i0ue
and slee9iness in ,o88onh * .lee9 &es 1$: 10$N106. EPubMedF
32. Co'e ") 7roIan #) Ma8ins+a M) Cardoso M) Benede''i () e' al. <2012= "89a,' o5 slee9
disorder 'rea'8en' on 5a'i0ue in 8ul'i9le s,lerosis. Mul' .,ler . EPubMedF
33. Fraus,her B) 200 &) Brandauer 2) >l8er 6) Ber0er 7) e' al. <200$= #ay'i8e
slee9iness is no' in,reased in 8ild 'o 8odera'e 8ul'i9le s,lerosis: a 9u9illo0ra9hi, s'udy.
.lee9 Med 6: $43N$4. EPubMedF
34. 6ossain */) (h8ad P) &einish /3) Mayu8o4 /) 6ossain NM) e' al. <200$= .ubIe,'i4e
5a'i0ue and subIe,'i4e slee9iness: '1o inde9enden' ,onseGuen,es o5 slee9 disordersh *
.lee9 &es 14: 24$N2$3. EPubMedF
3$. .'ena0er 2) Mnudsen /) *ensen M <1%%$= (,u'e and ,hroni, 9ain syndro8es in
8ul'i9le s,lerosis. ( $!year 5ollo1!u9 s'udy. "'al * Neurol .,i 16: 62%N632. EPubMedF
36. T\Connor (B) .,h1id .&) 6err8ann #N) Mar+8an *#) #1or+in &6 <2008= Pain
asso,ia'ed 1i'h 8ul'i9le s,lerosis: sys'e8a'i, re4ie1 and 9ro9osed ,lassi5i,a'ion. Pain
13: %6N111. EPubMedF
3. .'an'on B&) Barnes F) .ilber 2 <2006= .lee9 and 5a'i0ue in 8ul'i9le s,lerosis. Mul'
.,ler 12: 481N486. EPubMedF
38. Ne1land PM) Nais8i'h &7) >llione M <200%= 7he i89a,' o5 9ain and o'her sy89'o8s
on Guali'y o5 li5e in 1o8en 1i'h rela9sin0!re8i''in0 8ul'i9le s,lerosis. * Neuros,i Nurs
41: 322N328. EPMC 5ree ar'i,leF EPubMedF
3%. 3ri0h' /* <2012= "den'i5yin0 and 'rea'in0 9ain ,aused by M.. * Clin Psy,hia'ry 3:
e23. EPubMedF
40. *anssens (C) 4an #oorn P() de Boer *B) 4an der Me,he F;) Pass,hier *) e' al. <2003=
"89a,' o5 re,en'ly dia0nosed 8ul'i9le s,lerosis on Guali'y o5 li5e) an?ie'y) de9ression and
dis'ress o5 9a'ien's and 9ar'ners. (,'a Neurol .,and 108: 38%N3%$. EPubMedF
41. Mi',hell (*) Beni'o!/eon *) ;on@ale@ *M) &i4era!Na4arro * <200$= Wuali'y o5 li5e
and i's assess8en' in 8ul'i9le s,lerosis: in'e0ra'in0 9hysi,al and 9sy,holo0i,al
,o89onen's o5 1ellbein0. /an,e' Neurol 4: $$6N$66. EPubMedF
42. 7roIan #() Ma8ins+a M) Bar!Tr () Benede''i () /a9ierre -) e' al. <2012=
Polyso8no0ra9hi, 8easures o5 dis'urbed slee9 are asso,ia'ed 1i'h redu,ed Guali'y o5 li5e
in 8ul'i9le s,lerosis. * Neurol .,i 316: 1$8N163. EPubMedF
43. Mendo@@i /) 7ron,i F) ;are0nani M) Pu0ne''i / <2010= .lee9 dis'urban,e and 5a'i0ue
in 8ild rela9sin0 re8i''in0 8ul'i9le s,lerosis 9a'ien's on ,hroni, i88uno8odulan'
'hera9y: an a,'i0ra9hi, s'udy. Mul' .,ler 16: 238N24. EPubMedF
44. NadIar -) Cou'elas 2) Prou'eau P) Pan@er F) PaGue' #) e' al. <2011= "nIe,'ion o5
in'er5eron!be'a in 'he 8ornin0 de,reases 5lu!li+e syndro8e in 8any 9a'ien's 1i'h
8ul'i9le s,lerosis. Clin Neurol Neurosur0 113: 316N322. EPubMedF
4$. /ublin F#) 3hi'a+er *N) 2idel8an B6) Miller (2) (rnason B;) e' al. <1%%6=
Mana0e8en' o5 9a'ien's re,ei4in0 in'er5eron be'a!1b 5or 8ul'i9le s,lerosis: re9or' o5 a
,onsensus ,on5eren,e. Neurolo0y 46: 12N18. EPubMedF
Jurnal /
* Child Neurol. (u'hor 8anus,ri9'; a4ailable in PMC 2013 May 13.
Published in 5inal edi'ed 5or8 as:
* Child Neurol. 2013 *anuary; 28<1=: 102N10.
Published online 2012 No4e8ber 1$. doi: 10.11/088303812464816
PMC"#: PMC36$26$1
N"6M."#: N"6M.46$426
Cognitive 5mpairment "ccurs in Children
and Adolescents 9ith Multiple Sclerosis:
Results 3rom a <nited States 8etwork
/aura *ulian) Ph#)
1
#ana .era5in) B.)
2
/ei0h Char4e') Ph#)
2
*ose9h (,+erson) Ph#)
3

&al9h Benedi,') Ph#)
4
2llen Braa'en) Ph#)
$
7anya Bro1n) Ph#)
6
2llen TH#onnell) Ph#)
$

*oy Parrish) Ph#)

7ho8as Pres'on) Ph#)
8
Mi,hael Va,,ariello) Ph#)
6
(ni'a Bel8an)
M#)
2
7anuIa Chi'nis) M#)
%
Mar+ ;or8an) M#)
%
*ayne Ness) M#)
10
Mar, Pa''erson)
M#)
11
Moses &odri0ue@) M#)
11
288anuelle 3auban') M#)
12
Bian,a 3eins'o,+!
;u''8an) M#)
4
(nn -eh) M#)
4
and /auren B. Mru99) M#
2
) 5or 'he Ne'1or+ o5 Pedia'ri,
M. Cen'ers o5 2?,ellen,e
(u'hor in5or8a'ion : Co9yri0h' and /i,ense in5or8a'ion :
7he 9ublisher\s 5inal edi'ed 4ersion o5 'his ar'i,le is a4ailable a' * Child Neurol
;o 'o:
Abstract
"n 'he lar0es' sa89le s'udied 'o da'e) 1e 8easured ,o0ni'i4e 5un,'ionin0 in ,hildren and
adoles,en's 1i'h 9edia'ri, 8ul'i9le s,lerosis <n B18= as 1ell as 'hose 1i'h ,lini,ally
isola'ed syndro8e <n B44=. Par'i,i9an's 1ere ,onse,u'i4ely enrolled 5ro8 si? >ni'ed
.'a'es Pedia'ri,Mul'i9le .,lerosis Cen'ers o5 2?,ellen,e. Par'i,i9an's had a8ean o5 14.8
c 2.6 years o5 a0e and an a4era0e disease dura'ion o5 1.% c 2.2 years. ( 'o'al o5 6$ <3$C=
,hildren 1i'h 8ul'i9le s,lerosis and 8 <18C= 1i'h ,lini,ally isola'ed syndro8e 8e'
,ri'eria 5or ,o0ni'i4e i89air8en'. 7he 8os' 5reGuen' areas in4ol4ed 1ere 5ine 8o'or
,oordina'ion <$4C=) 4isuo8o'or in'e0ra'ion <$0C=) and s9eeded in5or8a'ion 9ro,essin0
<3$C=. ( dia0nosis o5 8ul'i9le s,lerosis <odds ra'io B 3.60) ,on5iden,e in'er4al B 1.0)
12.36) P B .04= and o4erall neurolo0i, disabili'y <odds ra'io B 1.4) ,on5iden,e in'er4al B
1.10) 2.10) P B .03= 1ere 'he only inde9enden' 9redi,'ors o5 ,o0ni'i4e i89air8en'.
Co0ni'i4e i89air8en' 8ay o,,ur early in 'hese 9a'ien's) and 9ro89' re,o0ni'ion is
,ri'i,al 5or 'heir ,are.
Keywords: 8ul'i9le s,lerosis) ,o0ni'ion) ,lini,ally isola'ed syndro8e) de8yelina'ion
(s 8any as $C o5 indi4iduals 1i'h 8ul'i9le s,lerosis de4elo9 sy89'o8s durin0
,hildhood or adoles,en,e.
1N3
(8on0 disorders in ,hildhood) 9edia'ri, 8ul'i9le s,lerosis is
uniGuely ,hallen0in0. "n 'he ,on'e?' o5 ,hildhood de4elo98en') i' a''a,+s 'he ,en'ral
ner4ous sys'e8 1i'h a,u'e 1a4es o5 in5la88a'ion and de8yelina'ion and 9ro0resses 1i'h
a neurode0enera'i4e ,ourse. >nders'andin0 'he in5luen,e o5 9edia'ri, 8ul'i9le s,lerosis
on ,o0ni'i4e 5un,'ionin0 is ,ri'i,al 5or 'hese 9a'ien's.
(4ailable da'a su00es' 'ha' a99ro?i8a'ely one!'hird o5 ,hildren and adoles,en's 1i'h
8ul'i9le s,lerosis e?9erien,e ,o0ni'i4e i89air8en'. (s 1i'h adul' 8ul'i9le s,lerosis)
areas o5 ,o0ni'i4e de5i,i' ,an 4ary bu' o5'en in,lude a''en'ion and s9eeded 9ro,essin0)
4isuo8o'or 5un,'ions) 8e8ory) and lan0ua0e.
4N%
Be,ause o5 s8all sa89le si@es and li8i'ed ra,ial or e'hni, di4ersi'y in 9rior s'udies)
de8o0ra9hi, and disease!rela'ed 9redi,'ors o5 ,o0ni'i4e i89air8en' re8ain un,lear.
(nalyses o5 9edia'ri, 8ul'i9le s,lerosis sa89les 5ro8 Canada) 2uro9e) and 'he >ni'ed
.'a'es ha4e 4ariably no'ed i89air8en' 'o be asso,ia'ed 1i'h a ran0e o5 5a,'ors) in,ludin0
a0e a' disease onse')
$)6
disease dura'ion)
6
2?9anded #isabili'y .'a'us .,ale s,ore)
4

"n'elli0en,e Wuo'ien')
$
and 'hala8i, 4olu8e.

7his s'udy le4era0ed 'he 0eo0ra9hi, di4ersi'y o5 'he Pedia'ri, Mul'i9le .,lerosis Cen'ers
o5 2?,ellen,e) a ne'1or+ desi0na'ed in 2006 by 'he Na'ional Mul'i9le .,lerosis .o,ie'y)
and enrolled ,hildren 5ro8 si? di55eren' re0ions 1i'hin 'he >ni'ed .'a'es. 24alua'in0 a
lar0e and di4erse sa89le 1i'h a s'andardi@ed ,lini,al and neurolo0i, assess8en' ,an
,lari5y 'he asso,ia'ions be'1een ,lini,al and de8o0ra9hi, 5ea'ures asso,ia'ed 1i'h
,o0ni'i4e i89air8en'. "n addi'ion) 'his is 'he 5irs' s'udy 'o in,lude ,hildren 1i'h ,lini,ally
isola'ed syndro8e as 1ell as 'hose 1i'h 8ul'i9le s,lerosis.
;o 'o:
Methods
Study !opulation
7his ,ross!se,'ional s'udy analy@ed 'he neuro9sy,holo0i,al 9er5or8an,e o5 231
9ar'i,i9an's e4alua'ed be'1een 2006 and 2011 and dra1n 5ro8 a 8ul'i,en'er s'udy o5
9a'ien's 1i'h 9edia'ri, onse' 8ul'i9le s,lerosis. Par'i,i9an's 1ere seen a' one o5 si?
Pedia'ri, M. Cen'ers o5 2?,ellen,e lo,a'ed in .an Fran,is,o) Cali5ornia <>ni4ersi'y o5
Cali5ornia) .an Fran,is,o=; &o,hes'er) Minneso'a <Mayo Clini,=; Bir8in0ha8) (laba8a
<>ni4ersi'y o5 (laba8a a' Bir8in0ha8=; Bu55alo) Ne1 -or+ <.'a'e >ni4ersi'y o5 Ne1
-or+) Bu55alo=; .'ony Broo+) Ne1 -or+ <.'a'e >ni4ersi'y o5 Ne1 -or+) .'ony Broo+=;
and Bos'on) Massa,huse''s <6ar4ard >ni4ersi'y) Massa,huse''s ;eneral 6os9i'al) and
Par'ners 6eal'h! Care=. 7he ne'1or+ o5 ,en'ers is su99or'ed by 'he Na'ional Mul'i9le
.,lerosis .o,ie'y and 9ros9e,'i4ely ,olle,'s neuro9sy,holo0i,al and o'her ,lini,al da'a
re0ardin0 ,hildren 1i'h 8ul'i9le s,lerosis) ,lini,ally isola'ed syndro8e) and o'her
de8yelina'in0 disorders. 2a,h si'e re,ei4ed a99ro4al by i's res9e,'i4e ins'i'u'ional re4ie1
board 5or hu8an subIe,' da'a ,olle,'ion and sharin0.
2li0ibili'y ,ri'eria 5or 'his analysis in,luded 'hose 9ar'i,i9an's 1ho 1ere youn0er 'han 18
years o5 a0e a' disease onse' <8ee'in0 ,ri'eria 5or a dia0nosis o5 9edia'ri, 8ul'i9le
s,lerosis
10
or ,lini,ally isola'ed syndro8e
10
= 1i'h no o'her neurolo0i, dia0nosis.
Par'i,i9an's 1ere also reGuired 'o be youn0er 'han a0e 18 years a' 'he 'i8e o5
neuro9sy,holo0i,al 'es'in0) 'o ha4e ,o89le'ed a' leas' % o5 'he 11 neuro9sy,holo0i,al
'es's 5ro8 'he ba''ery) 'o be 2n0lish s9ea+in0 and readin0) and 'o ha4e su55i,ien' 4isual or
8o'or abili'y 'o ,o89le'e 'he neuro9sy,holo0i,al 'es's. Pa'ien's in 'he 8ids' o5 a 8ul'i9le
s,lerosis rela9se) or 1ho had re,ei4ed 'rea'8en' 1i'h 0lu,o,or'i,oids 1 8on'h or less
9rior 'o 'he 'i8e o5 ,o0ni'i4e assess8en' 1ere e?,luded.
8europsychological Battery
7he Pedia'ri, Mul'i9le .,lerosis Cen'ers o5 2?,ellen,e used a ,o89rehensi4e ne'1or+
ba''ery ,onsis'in0 o5 11 'es's 1hose s,ores addressed 'he 5ollo1in0 ,o0ni'i4e do8ains:
<1= 0eneral abili'y le4eld3e,hsler (bbre4ia'ed .,ale o5 "n'elli0en,eN2 sub'es' ba''ery
11

in,ludin0 Do,abulary and Ma'ri? &easonin0 sub'es's; <2= readin0 and lan0ua0ed
3e,hsler "ndi4idual (,hie4e8en' 7es' "" Pseudo1ord #e,odin0)
12
2?9ressi4e Tne 3ord
Pi,'ure Do,abulary 7es' )
13
and 'he 3e,hsler (bbre4ia'ed .,ale o5 "n'elli0en,e
Do,abulary sub'es'; <3= a''en'ion) 1or+in0 8e8ory) and s9eeded 9ro,essin0d#i0i' .9an
'es' 5ro8 'he 3e,hsler (dul' "n'elli0en,e .,ale "D <5or a0e 16 years and abo4e= or 'he
3e,hsler "n'elli0en,e .,ale 5or Children "D <5or youn0er 'han a0e 16 years=) 3e,hsler
(dul' "n'elli0en,e .,ale or 3e,hsler "n'elli0en,e .,ale 5or Children ,odin0 'es'; <4=
e?e,u'i4e 5un,'ionin0dCon'in0en,y Na8in0 7es')
14
#elis Ma9lan 2?e,u'i4e Fun,'ion
.ys'e8 7rail Ma+in0 7es'
1$
; <$= 4erbal e9isodi, learnin0 and re,alldCali5ornia Derbal
/earnin0 7es'NChild 4ersion or "" <as a0e a99ro9ria'e=
16)1
; <6= 4isuos9a'ial 5un,'ionin0d
Beery!Bu+'eni,a #e4elo98en'al 7es' o5 Disual!Mo'or "n'e0ra'ionNsi?'h edi'ion
18
and 'he
3e,hsler (bbre4ia'ed .,ale o5 "n'elli0en,e Ma'ri? &easonin0; <= 5ine 8o'or s9eed and
,oordina'iond ;roo4ed Pe0board 7es'
1%
and #elis Ma9lan 2?e,u'i4e Fun,'ion .ys'e8
7rail Ma+in0 7es'NMo'or .9eed Condi'ion.
7he 'es'in0 ba''ery 1as ad8inis'ered by a ,lini,al neuro9sy,holo0is' or 'rained and
su9er4ised 9sy,ho8e'ri,ian and 'oo+ a99ro?i8a'ely 2.$ hours 'o ,o89le'e. Par'i,i9an's
1ere 0i4en brea+s as needed.
3e es'i8a'ed i89air8en' ra'in0s 5or ea,h o5 'he 2$ 'es' s,ores <5ro8 'he 11
neuro9sy,holo0i,al 'es's= usin0 9ublished) a0e!s'ra'i5ied nor8a'i4e da'a. 3e ado9'ed 'he
'radi'ional ben,h8ar+ de5ini'ion 5or 8ild i89air8en' as a s,ore 5allin0 a' leas' 1 s'andard
de4ia'ion belo1 'he nor8a'i4e 8ean) 1i'h 8odera'e i89air8en' reGuirin0 s,ores 2
s'andard de4ia'ions or 8ore belo1 9o9ula'ion nor8s.
20N23
Par'i,i9an's 1ere ,lassi5ied
1i'h 0eneral ,o0ni'i4e i89air8en' usin0 'he su8 o5 'he nu8ber o5 i89aired 'es' s,ores
di4ided by 'he 'o'al nu8ber o5 ,o89le'ed 'es' s,ores <ou' o5 2$ 'o'al=. ( 9ar'i,i9an' 1as
,onsidered 'o be i89aired 1hen 'his 9ro9or'ion o5 i89aired s,ores 1as 0rea'er 'han one!
'hird.
Sociodemographic and Clinical ?ariables
.o,iode8o0ra9hi, 4ariables in,luded a0e a' sy89'o8 onse') a0e a' neuro9sy,holo0i,al
e4alua'ion) 0ender) ra,e) and e'hni,i'y <6is9ani, or no' 6is9ani,=. Clini,al 4ariables
a4ailable 5or analyses in,luded disease dura'ion <years=) a0e a' sy89'o8 onse' <years=)
dia0nos'i, s'a'us <8ul'i9le s,lerosis 4s ,lini,ally isola'ed syndro8e=) and disabili'y as
8easured by 'he 2?9anded #isabili'y .'a'us .,ale.
24
'ata Analyses
#es,ri9'i4e ,hara,'eris'i,s o5 'he 0rou9 and i89air8en' ra'in0s o5 neuro9sy,holo0i,al
s,ores 1ere 9resen'ed ei'her as 9er,en'a0es <C= or usin0 a 8ean c s'andard de4ia'ion.
Ne?') 1e ran a 8ul'i4aria'e lo0is'i, re0ression de'er8inin0 9redi,'ors o5 0eneral
,o0ni'i4e i89air8en' usin0 so,iode8o0ra9hi, and ,lini,al 4ariables. Tnly 9a'ien's 1i'h
,o89le'e so,iode8o0ra9hi, and ,lini,al da'a <n B164= 1ere in,luded in 'he 8ul'i4aria'e
analysis.
;o 'o:
Results
7able 1 sho1s 'he de8o0ra9hi, and ,lini,al ,hara,'eris'i,s 5or 'he 231 ,hildren and
adoles,en's 1i'h 8ul'i9le s,lerosis or ,lini,ally isola'ed syndro8e. 7he 8aIori'y <80C=
o5 indi4iduals 8e' dia0nos'i, ,ri'eria 5or 8ul'i9le s,lerosis 1i'hin 2 years o5 sy89'o8
onse' <8ean c s'andard de4ia'ion B1.% c 2.2=.
7able 1
#e8o0ra9hi, and Clini,al Chara,'eris'i,s
7he 8edian nu8ber o5 'es's ,lassi5ied as Ri89airedS 1as 4 <ran0e B0N20=) and 32C o5
'he en'ire sa89le 8e' ,ri'eria 5or 0eneral i89air8en'. 7hir'y!5i4e 9er,en' o5 9ar'i,i9an's
1i'h 9edia'ri, 8ul'i9le s,lerosis and 18C o5 'hose 1i'h ,lini,ally isola'ed syndro8e 1ere
,lassi5ied as i89aired. For 'he ,o8bined 'o'al sa89le) 9er5or8an,es 4aried a,ross 'he
indi4idual neuro9sy,holo0i,al 'es's <7able 2=. T4erall) ra'es o5 8ild i89air8en' on any
indi4idual 'es' s,ore ran0ed 5ro8 %C </an0ua0e= 'o 34C <Disuo8o'or=. Modera'e!'o!
se4ere i89air8en' 1as rela'i4ely less ,o88on) ran0in0 5ro8 0.4C i89air8en'
</an0ua0e= 'o 43C<Fine8o'or s9eed/8ani9ula'ion=.
7able 2
Pa'ien' Per5or8an,e on 'he Neuro9sy,holo0i,al Ba''ery <n B 231=
7able 3 sho1s a 8ul'i4aria'e analysis o5 9redi,'ors o5 0eneral ,o0ni'i4e i89air8en')
,on'rollin0 5or so,iode8o0ra9hi, 5a,'ors. #ia0nos'i, s'a'us <8ul'i9le s,lerosis 4s
,lini,ally isola'ed syndro8e= 1as si0ni5i,an'ly asso,ia'ed 1i'h 'he 9resen,e o5 9oorer
,o0ni'i4e 5un,'ionin0 <odds ra'io B3.60) ,on5iden,e in'er4al B1.0) 12.36) P B.04=.
Neurolo0i, disabili'y) 8easured by 'he 2?9anded #isabili'y .'a'us .,ale) 1as 'he only
si0ni5i,an' ,lini,al 9redi,'or <odds ra'io B1.4) ,on5iden,e in'er4al B1.0$) 2.06) P B.03=.
Pos' ho, bi4aria'e analyses o5 'he 9ro9or'ion o5 'es' s,ores ,onsidered 'o be i89aired
a,ross 'er'iles o5 2?9anded #isabili'y .'a'us .,ale s,ores sho1ed in,reasin0 disabili'y
asso,ia'ed 1i'h an in,reasin0 burden o5 ,o0ni'i4e i89air8en' <Fi0ure 1=. Bo'h 6is9ani,
e'hni,i'y <odds ra'io B2.0$) ,on5iden,e in'er4al B0.%3) 4.$6) P B.08= and 'o'al years o5
9aren' edu,a'ion <odds ra'io B1.02) ,on5iden,e in'er4al B0.%%) 1.0$) P B.06= 'rended
'o1ard si0ni5i,an,e as 9redi,'ors o5 ,o0ni'i4e i89air8en'.
Fi0ure 1
Bi4aria'e (nalyses: Co0ni'i4e "89air8en' "n,reases 1i'h Neurolo0i, #isabili'y
7able 3
/o0is'i, &e0ression: #e8o0ra9hi, and #isease!&ela'ed Predi,'ors o5 Co0ni'i4e
"89air8en' in Pedia'ri, Mul'i9le .,lerosis and Clini,ally "sola'ed .yndro8e <n B 164=
a
;o 'o:
'iscussion
3e 5ound 'ha' a99ro?i8a'ely one!'hird o5 9edia'ri, 9a'ien's 1i'h 8ul'i9le s,lerosis or
,lini,ally isola'ed syndro8e 8e' ,ri'eria 5or 0eneral ,o0ni'i4e i89air8en') de5ined here
as ha4in0 a' leas' one!'hird o5 ,o89le'ed 'es' s,ores 5allin0 1 s'andard de4ia'ion or 8ore
belo1 9ublished nor8a'i4e da'a. 7he 9ro9or'ion o5 i89air8en' in our sa89le is 0enerally
,onsis'en' 1i'h 9re4ious re9or's 5ro8 8u,h s8aller s'udies)
4)2$
al'hou0h dire,'
,o89arisons are di55i,ul' a,ross s'udies be,ause o5 i89or'an' di55eren,es in 'he
assess8en' ba''ery and ,ri'erion 5or ,o0ni'i4e i89air8en'.
3e re9or' 'he 5irs' neuro9sy,holo0i,al da'a 5ro8 ,hildren and adoles,en's 1i'h ,lini,ally
isola'ed syndro8e. Co0ni'i4e i89air8en' is 1ell re,o0ni@ed in adul's 1i'h ,lini,ally
isola'ed syndro8e. Co0ni'i4e i89air8en' 1as iden'i5ied in 8 o5 44 <18C= ,hildren 1i'h
,lini,ally isola'ed syndro8e and 6% <3$C= ,hildren 1i'h 8ul'i9le s,lerosis. "den'i5i,a'ion
o5 i89air8en' a' 'he early ,lini,ally isola'ed syndro8e s'a0e o5 disease is 1orriso8e. 7he
rela'i4e in,reased 5reGuen,y o5 i89air8en' a8on0 9ar'i,i9an's 1i'h 8ul'i9le s,lerosis
,o89ared 'o ,lini,ally isola'ed syndro8e is ,onsis'en' 1i'h 'he obser4a'ion 'ha' ,o0ni'i4e
i89air8en's in ,hildren 1i'h 8ul'i9le s,lerosis 9ro0ress o4er 'i8e.
26)2
7he 'es' 1i'h 'he 8os' 5reGuen' ra'e o5 i89air8en' 1as 'he 0roo4ed 9e0board) a 8easure
o5 5ine 8o'or s9eed and ,oordina'ion. 3e re,o0ni@e 'ha' 'his 5indin0 8ay be a''ribu'able
'o 'he diseaseHs e55e,'s on 8o'or as 1ell as ,o0ni'i4e 5un,'ionin0. Fu'ure s'udies 8i0h'
s9e,i5i,ally address 'he se9ara'e ,on'ribu'ions o5 8o'or and ,o0ni'i4e 5un,'ionin0 'o
8ul'i9le s,lerosis 9a'ien'sH 9er5or8an,e on 'his 8easure.
FreGuen' i89air8en' 1as also 5ound on 'he Beery!Bu+'eni,a #e4elo98en'al 7es' o5
Disual!Mo'or "n'e0ra'ion) a 8easure 'ha' is de9enden' in 9ar' on 5ine 8o'or ,oordina'ion
as 1ell. "n ,on'ras') 9er5or8an,es on a 8easure o5 4isuos9a'ial 5un,'ionin0 'ha' is no'
de9enden' on 8o'or 5un,'ionin0 <3e,hsler (bbre4ia'ed .,ale o5 "n'elli0en,eNMa'ri?
&easonin0= 1ere rela'i4ely nor8al. Pre4ious s'udies o5 adul's and ,hildren ha4e
do,u8en'ed 4isuo8o'or 5un,'ions as 4ulnerable 'o i89air8en') bo'h 1i'h res9e,' 'o
4isuos9a'ial 5un,'ionin0 and 4isuos9a'ial learnin0 and re,all. 7here5ore) assess8en's o5
'his do8ain should in,lude 8ul'i9le 8easures) bo'h 1i'h and 1i'hou' de9enden,e on
u99er!e?'re8i'y 8o'or 5un,'ionin0.
(no'her area o5 i89air8en' 1as iden'i5ied by 'es's reGuirin0 s9eeded 9ro,essin0
<Codin0/#i0i' .y8bol and #elis Ma9lan 2?e,u'i4e Fun,'ion .ys'e8 'rail 8a+in0 'es'=.
.lo1ed in5or8a'ion 9ro,essin0 is one o5 'he 8os' ,o88only obser4ed do8ains o5
,o0ni'i4e i89air8en' in bo'h adul' and 9edia'ri, 8ul'i9le s,lerosis 9a'ien's) and 'he
resul's o5 'his s'udy ,on5ir8 'ha' 'his ,o0ni'i4e do8ain is hi0hly sus,e9'ible 'o 'he e55e,'s
o5 8ul'i9le s,lerosis a,ross 'he li5es9an.
T'her 'han 'he dia0nosis o5 8ul'i9le s,lerosis) neurolo0i, disabili'y as 8easured by 'he
2?9anded #isabili'y .'a'us .,ale 1as 'he only 4ariable si0ni5i,an'ly and inde9enden'ly
asso,ia'ed 1i'h redu,ed ,o0ni'i4e 5un,'ion. .o8e s'udies)
4
bu' no' o'hers)
$)6
ha4e 5ound
si8ilar asso,ia'ions and i' is li+ely 'ha' ,o0ni'i4e i89air8en' 9ro0resses as does 'he
neurolo0i, burden o5 disease. 7his in'er9re'a'ion is also su99or'ed by 'he hi0her
5reGuen,y o5 i89air8en' in 8ul'i9le s,lerosis 'han in ,lini,ally isola'ed syndro8e. 7here
1ere also 'rends su00es'in0 an asso,ia'ion be'1een redu,ed ,o0ni'i4e 5un,'ionin0 1i'h
bo'h 5e1er years o5 9aren' edu,a'ion as 1ell as 6is9ani, e'hni,i'y. (l'hou0h ra,e has
been 9re4iously re9or'ed 'o be asso,ia'ed 1i'h ,o0ni'i4e i89air8en')
28
1e did no' 5ind i'
'o be a si0ni5i,an' 9redi,'or.
7his s'udy had se4eral li8i'a'ions. Firs') 1e used a rela'i4ely liberal ,u'!o55 9oin' o5 1
s'andard de4ia'ion belo1 9ublished nor8s 'o de'er8ine i89air8en' on indi4idual 'es'
s,ores. 3e ,hose 'his 'radi'ional ben,h8ar+ in order 'o in,lude ,hildren 1i'h e4en 8ilder
de0rees o5 i89air8en' 'ha' are li+ely ,lini,ally 8eanin05ul 5or a,ade8i, 9er5or8an,e and
o'her as9e,'s o5 5un,'ionin0.
20)22
6o1e4er) 1e used a 8ore s'rin0en' ,u'!o55 9oin' 'o
,lassi5y 9ar'i,i9an's as ,o0ni'i4ely i89aired) 1i'h i89aired 9er5or8an,es on a' leas' one!
'hird o5 'es' s,ores 5ro8 'he ,o89le'ed ba''ery <e0) a' leas' % o5 2$ 9ossible s,ores= in
,on'ras' 'o 'hree i89aired 'es' s,ores used in 9rior s'udies.
$
.e,ond) al'hou0h our
neuro9sy,holo0i,al ba''ery 1as Gui'e ,o89rehensi4e) 1e e?,luded so8e 'es's in order 'o
+ee9 'he ba''ery brie5; so8e e?,luded 'es's 1ould ha4e assessed do8ains 'ha' ha4e been
5ound 'o be sensi'i4e indi,a'ors o5 ,o0ni'i4e s'a'us in bo'h ,hildren and adul's 1i'h
8ul'i9le s,lerosis) in,ludin0 8easures o5 4isuos9a'ial learnin0 and re,all and 8easures o5
readin0 ,o89rehension.
4)8)%
7hird) our 8ul'i4aria'e analyses did no' in,lude de'ailed
4ariables a4ailable re0ardin0 9aren' lan0ua0e s'a'us and so,ioe,ono8i, s'a'us des,ri9'ors
+no1n 'o in5luen,e neuro9sy,holo0i,al 9er5or8an,e in ,hildren. "n addi'ion) 5a'i0ue and
'he 9resen,e o5 9sy,hia'ri, dis'ress 1ere no' in,luded in 'hese analyses bu' re9resen'
i89or'an' ,hara,'eris'i,s in5luen,in0 ,o0ni'i4e 5un,'ions in 8ul'i9le s,lerosis.
2%)30
(s9e,'s
o5 disease burden as sho1n on 8a0ne'i, resonan,e i8a0in0 <M&"=
)31)32
,an also in5luen,e
,o0ni'i4e 5un,'ions in 9edia'ri, 8ul'i9le s,lerosis. Finally) 'his s'udy is ,ross!se,'ional;
asso,ia'ions a8on0 so,iode8o0ra9hi, and ,lini,al 4ariables in rela'ion 'o ,o0ni'i4e
5un,'ion ,anno' be in'er9re'ed as ,ausal rela'ionshi9s.
#es9i'e 'hese li8i'a'ions) 'his is 'he lar0es' s'udy 'o da'e 'ha' uses a ,o89rehensi4e
neuro9sy,holo0i,al ba''ery 'o des,ribe neuro9sy,holo0i,al 5un,'ion in ,hildren and
adoles,en's 1i'h 8ul'i9le s,lerosis. 7his s'udy dra1s 5ro8 a di4erse ,a',h8en' area
a,ross 'he >ni'ed .'a'es and sho1s 'ha' ,o0ni'i4e i89air8en' is a 8aIor 5ea'ure o5
9edia'ri, 8ul'i9le s,lerosis 'ha' ,an o,,ur a' 'he earlies' s'a0es o5 'he disease. Co0ni'i4e
i89air8en' re9resen's an i89or'an' ,lini,al 9roble8 5or all 9a'ien's 1i'h 8ul'i9le
s,lerosis and ,on5ers s9e,i5i, ,hallen0es 1hen i' o,,urs durin0 'he ,on'e?' o5 ,hildhood
de4elo98en'. Fur'her resear,h is needed 'o de4elo9 s'ra'e0ies 5or 9ro89' iden'i5i,a'ion o5
,hildren 1i'h 8ul'i9le s,lerosis a' ris+ 5or ,o0ni'i4e 9roble8s so 'ha' 'rea'8en' ,an be
ini'ia'ed.
;o 'o:
Acknowledgments
3unding
7he au'hors dis,losed re,ei9' o5 'he 5ollo1in0 5inan,ial su99or' 5or 'he resear,h)
au'horshi9) and/or 9ubli,a'ion o5 'his ar'i,le: 7his s'udy 1as su99or'ed in 9ar' by 'he
Na'ional Mul'i9le .,lerosis .o,ie'y.
;o 'o:
3ootnotes
(u'hor Con'ribu'ions
/*) /C) *() &6BB) 2B) 7B) 26T#) *P) 7P) MV) and /BM 1ere res9onsible 5or 'he
desi0n and ,on,e9'uali@a'ion o5 'he s'udy. /*) #.) /C) and /BM analy@ed and in'er9re'ed
'he da'a. /*) #.) /C) (B) 7C) M;) *N) MP) M&) 23) B3;) (-) and /BM dra5'ed and
re4ised 'he 8anus,ri9'.
#e,lara'ion o5 Con5li,'in0 "n'eres's
7he au'hors de,lared 'he 5ollo1in0 9o'en'ial ,on5li,'s o5 in'eres' 1i'h res9e,' 'o 'he
resear,h) au'horshi9) and/or 9ubli,a'ion o5 'his ar'i,le: /* is ,urren'ly e89loyed by
;enen'e,h. &6BB has ser4ed as a ,onsul'an' 5or (,'elion) Bio0en "de,) Bayer) and
No4ar'is; re,ei4ed 0ran'/resear,h su99or' 5ro8 (,,orda) Bio0en "de,) and .hire; and also
re,ei4es royal'ies 5ro8 Psy,holo0i,al (ssess8en' &esour,es. 7C has ser4ed as a
,onsul'an' 5or Bio0en!"de,) .ano5i (4en'is) No4ar'is) 2M#!.erono) and 7e4a
Neuros,ien,es) and has re,ei4ed 0ran' su99or' 5ro8 Mer,+!.erono 5or unrela'ed
a,'i4i'ies. M; has resear,h 5undin0 5ro8 N"6 and (,'elion. 6e has done ,onsul'in0 5or
(,'elion) .hire 6;7 and Tr9ha@y8e and #M.B 5or .'e8 ,ells) "n,; (8i,us and .hire
6;7. 23has a,'ed as an ad4isor/,onsul'an'/ad4isory board 8e8ber or s9ea+er 5or
(,'elion) &o,he) .ano5i (4en'is) and 7e4a) and has re,ei4ed resear,h su99or' 5ro8
Bio0en "de,) &o,he) and .ano5i!(4en'is. B3; has 9ar'i,i9a'ed in s9ea+ers bureaus and
ser4ed as a ,onsul'an' 5or Bio0en "de,) 7e4a Neuros,ien,es) 2M# .erono) P5i@er)
No4ar'is) ;en@y8e) and (,orda; e?,ludin0 ;en@y8e) she also has re,ei4ed
0ran'/resear,h su99or' 5ro8 'he a0en,ies lis'ed abo4e as 1ell as "7N) Wues',or) and
.hire. /BM ser4es as a ,onsul'an' and/or on 'he s9ea+ersH bureau 5or 7e4a Neuros,ien,es)
Bio0en "de,) 2M# .erono)M2#( Cor9) (,orda) Be'aseron/Bayer 6eal'h,are
Phar8a,eu'i,als) ;erson /ehr8an ;rou9) ;uide9oin' ;lobal) (dler) Cohen) 6ar4ey)
3a+e8an X ;ue+0ue@ian) and #aniel *. 2del8an; re,ei4es royal'ies 5ro8 ;en@y8e)
Vy8o0ene'i,s) Tr'ho!M,Neill Phar8a,eu'i,al) and 2& .Guibb X .ons; and re,ei4es
resear,h su99or' 5ro8 ;enen'e,h) Bio0en"de,) 7e4a Neuros,ien,es) Cel0ene
Cor9ora'ion) ;arne'' M,Meen /abora'ory "n,or9ora'ed) N"6) .lo8o and Cindy .il4ian
Founda'ion) M. Founda'ion) and 'he /ourie Founda'ion. &es' o5 'he au'hors re9or' no
dis,losures.
4thical Approval
2a,h si'e re,ei4ed a99ro4al by i's res9e,'i4e ins'i'u'ional re4ie1 board 5or hu8an subIe,'
da'a ,olle,'ion and sharin0. For 'hose si'es 1hose ins'i'u'ions did no' 9ro4ide a 1ai4er)
in5or8ed ,onsen' 9ro,edures 1ere 5ollo1ed.
;o 'o:
Reerences
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in 12$ 9a'ien's. * Pedia'r. 1%8;111:3$%N363. EPubMedF
2. ;he@@i () #e9lano D) Faroni *) e' al. Mul'i9le s,lerosis in ,hildhood: ,lini,al 5ea'ures
o5 14% ,ases. Mul' .,ler. 1%%;3:43N46. EPubMedF
3. Chi'nis 7) ;lan@ B) *a55in .) 6ealy B. #e8o0ra9hi,s o5 9edia'ri,!onse' 8ul'i9le
s,lerosis in an M. ,en'er 9o9ula'ion 5ro8 'he Nor'heas'ern >ni'ed .'a'es. Mul' .,ler.
200%;1$:62N631. EPubMedF
4. Ma,(llis'er 3.) Bel8an (/) Mila@@o M) e' al. Co0ni'i4e 5un,'ionin0 in ,hildren and
adoles,en's 1i'h 8ul'i9le s,lerosis. Neurolo0y. 200$;64:1422N142$. EPubMedF
$. (8a'o MP) ;ore''i B) ;he@@i () e' al. Co0ni'i4e and 9sy,hoso,ial 5ea'ures o5
,hildhood and Iu4enile M.. Neurolo0y. 2008;0:18%1N18%. EPubMedF
6. Ban1ell B/) (nderson P2. 7he ,o0ni'i4e burden o5 8ul'i9le s,lerosis in ,hildren.
Neurolo0y. 200$;64:8%1N8%4. EPubMedF
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,hildhood!onse' 8ul'i9le s,lerosis. Neuro9sy,holo0y. 2011;2$:31%N332. EPubMedF
8. .8erbe,+ (M) Parrish *) .era5in #) e' al. Disual!,o0ni'i4e 9ro,essin0 de5i,i's in
9edia'ri, 8ul'i9le s,lerosis. Mul' .,ler. 2011;1:44%N4$6. EPubMedF
%. (8a'o MP) ;ore''i B) ;he@@i () e' al. Co0ni'i4e and 9sy,hoso,ial 5ea'ures in
,hildhood and Iu4enile M.: '1o!year 5ollo1!u9. Neurolo0y. 2010;$:1134N1140.
EPubMedF
10. Mru99 /B) Ban1ell B) 7ene8bau8 .. Consensus de5ini'ions 9ro9osed 5or 9edia'ri,
8ul'i9le s,lerosis and rela'ed disorders. Neurolo0y. 200;68<16 su99l 2=:.N.12.
EPubMedF
11. 7he Psy,holo0i,al Cor9ora'ion. 7he 3e,hsler (bbre4ia'ed .,ale o5 "n'elli0en,e. .an
(n'onio) 7K: 6ar,our' (ssess8en'; 1%%%.
12. 3e,hsler "ndi4idual (,hie4e8en' 7es'. 2. .an (n'onio) 7K: 6ar,our' (ssess8en';
200$.
13. ;ardner MF. 2?9ressi4e Tne!3ord Pi,'ure Do,abulary 7es'. No4a'o) C(: (,ade8i,
7hera9y Publi,a'ions; 1%%.
14. (nderson P) (nderson D) Nor'ha8 2) 7aylor 6;. .'andardi@a'ion o5 'he Con'in0en,y
Na8in0 7es': ( 8easure o5 rea,'i4e 5le?ibili'y. Clin Neuro9sy,hol (ssess. 2000;1:24N
23.
1$. #elis #C) Ma9lan 2) Mra8er *6) Tber B(. #elis!Ma9lan 2?e,u'i4e Fun,'ion .,ale
<#!M2F.= .an (n'onio) 7K: Psy,holo0i,al Cor9ora'ion; 2001.
16. #elis #) Mra8er *) Ma9lan 2) Tber B. Cali5ornia Derbal /earnin0 7es' Manual. 2. .an
(n'onio) 7K: Psy,holo0i,al Cor9ora'ion; 2000. (dul' Dersion.
1. #elis *6) Mra8er *6) Ma9lan 2) Tber B. Cali5ornia Derbal /earnin0 7es'dChildrenHs
Dersion. .an (n'onio) 7K: Psy,holo0i,al Cor9ora'ion; 1%%4.
18. Beery M2) Beery N(. 7he Beery!Bu+'eni,a #e4elo98en'al 7es' o5 Disual!Mo'or
"n'e0ra'ion. $. Minnea9olis) MN: NC. Pearson; 2006.
1%. Ma''he1s C;) Mlo4e 6. "ns'ru,'ion Manual 5or 'he (dul' Neuro9sy,holo0i,al 7es'
Ba''ery. Madison) 3": >ni4ersi'y o5 3is,onsin Medi,al .,hool; 1%64.
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9re4alen,e o5 8ild ,o0ni'i4e i89air8en' in a ,o88uni'y based sa89le. * (l@hei8ers
#is. 2011;2$:163N13. EPMC 5ree ar'i,leF EPubMedF
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Neurosur0 Psy,hia'ry. 2003;4:443N446. EPMC 5ree ar'i,leF EPubMedF
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(ssess8en'. Ne1 -or+) N-: T?5ord >ni4ersi'y Press; 2004.
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>ni4ersi'y Press; 1%%0.
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disabili'y s'a'us s,ale <2#..= Neurolo0y. 1%83;33:1444N14$2. EPubMedF
2$. (8a'o MP) Vi9oli D) Por'a,,io 2. Co0ni'i4e ,han0es in 8ul'i9le s,lerosis. 2?9er' &e4
Neuro'her. 2008;8:1$8$N1$%6. EPubMedF
26. Ma,(llis'er 3.) Chris'odoulou C) Mila@@o M) Mru99 /B. /on0i'udinal
neuro9sy,holo0i,al assess8en' in 9edia'ri, 8ul'i9le s,lerosis. #e4 Neuro9sy,hol.
200;32:62$N644. EPubMedF
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2010;$:20%N2102. EPMC 5ree ar'i,leF EPubMedF
2%. Ma,(llis'er 3.) Boyd *&) 6ollans N*) Mila@@o MC) Mru99 /B. 7he 9sy,hoso,ial
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EPubMedF
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EPubMedF
31. Fuen'es () Collins #/) ;ar,ia!/oren@o #) e' al. Me8ory 9er5or8an,e and
nor8ali@ed re0ional brain 4olu8es in 9a'ien's 1i'h 9edia'ri,!onse' 8ul'i9le s,lerosis. *
"n' Neuro9sy,hol .o,. 2012;18:41N480. EPubMedF
32. 7ill C) #eo''o () 7i9u D) e' al. 3hi'e 8a''er in'e0ri'y and 8a'h 9er5or8an,e in
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2011;22:100$N100%. EPubMedF
Jurnal 0
PLoS One. 2012; 7(10): e:720'.
Published online 2012 Oc)ober 5. doi: 10.1371!ourn"l.#one.00:720'
P$%&D: P$%3:'52(3
"ccupational Attainment as a Marker o
Cognitive Reserve in Multiple Sclerosis
Om"r 0h"Q"r*
1*2*3*;
$"r)+ @i")i*
1
"nd 4n)hon+ @eins)ein
1*3
1erson L"6s* =di)or
4u)hor in>orm")ion ? 4r)icle no)es ? %o#+ri.h) "nd License in>orm")ion ?
0o )o:
Abstract
Co0ni'i4e dys5un,'ion a55e,'s hal5 o5 M. 9a'ien's. (l'hou0h brain a'ro9hy 0enerally
yields 'he 8os' robus' M&" ,orrela'ions 1i'h ,o0ni'ion) si0ni5i,an' 4arian,e in ,o0ni'ion
be'1een indi4idual M. 9a'ien's re8ains une?9lained. &e,en'ly) 8ar+ers o5 ,o0ni'i4e
reser4e su,h as 9re8orbid in'elli0en,e ha4e e8er0ed as i89or'an' 9redi,'ors o5
neuro9sy,holo0i,al 9er5or8an,e in M.. "n 'he 9resen' s'udy) 1e ai8ed 'o e?'end 'he
,o0ni'i4e reser4e ,ons'ru,' by e?a8inin0 'he 9o'en'ial ,on'ribu'ion o5 o,,u9a'ional
a''ain8en' 'o ,o0ni'i4e de,line in M. 9a'ien's. Brain a'ro9hy) es'i8a'ed 9re8orbid "W)
and o,,u9a'ional a''ain8en' 1ere assessed in 2 M. 9a'ien's. 7he Mini8al (ssess8en'
o5 Co0ni'i4e Fun,'ionin0 in M. 1as used 'o e4alua'e indi,es o5 in5or8a'ion 9ro,essin0
s9eed) 8e8ory) and e?e,u'i4e 5un,'ion. &esul's sho1ed 'ha' o,,u9a'ional a''ain8en' 1as
a si0ni5i,an' 9redi,'or o5 in5or8a'ion 9ro,essin0 s9eed) 8e8ory) and e?e,u'i4e 5un,'ion
in hierar,hi,al linear re0ressions a5'er a,,oun'in0 5or brain a'ro9hy and 9re8orbid "W.
7hese da'a su00es' 'ha' M. 9a'ien's 1i'h lo1 o,,u9a'ional a''ain8en' 5are 1orse
,o0ni'i4ely 'han 'hose 1i'h hi0h o,,u9a'ional a''ain8en' a5'er ,on'rollin0 5or brain
a'ro9hy and 9re8orbid "W. T,,u9a'ion) li+e 9re8orbid "W) 'here5ore 8ay 8a+e an
inde9enden' ,on'ribu'ion 'o ,o0ni'i4e ou',o8e in M.. "n5or8a'ion re0ardin0 an
indi4idual\s o,,u9a'ion is easily a,Guired and 8ay ser4e as a use5ul 9ro?y 5or ,o0ni'i4e
reser4e in ,lini,al se''in0s.
0o )o:
5ntroduction
For'y 'o si?'y 9er,en' o5 8ul'i9le s,lerosis <M.= 9a'ien's are a55e,'ed by ,o0ni'i4e
i89air8en' o5 su55i,ien' se4eri'y 'o i89ede 'heir Guali'y o5 li5e E1F. #es9i'e 'his
,onsiderable 8orbidi'y) 1hy so8e 9a'ien's de4elo9 ,o0ni'i4e dys5un,'ion and o'hers do
no' re8ain in,o89le'ely unders'ood.
Co0ni'i4e reser4e is de5ined as 'he di55eren,e be'1een obser4ed neuro9sy,holo0i,al
9er5or8an,e and 9er5or8an,e 9redi,'ed on 'he basis o5 brain 9a'holo0y E2FNE4F. /i5e
e?9erien,es 'ha' see8 'o delay or li8i' ,o0ni'i4e dys5un,'ion ha4e been delinea'ed in
(l@hei8er disease E$F. More re,en'ly) 'he ,on,e9' o5 ,o0ni'i4e reser4e has been a99lied
'o M. <re4ie1ed in E1F=. Pre8orbid in'elli0en,e E6FNE10F and ,o0ni'i4e leisure E11F 1ere
sho1n 'o inde9enden'ly a,,oun' 5or 4arian,e in ,o0ni'i4e 5un,'ion 'ha' 1as une?9lained
by M.. 7hese da'a su00es' 'ha' 'he disso,ia'ion o5 brain 9a'holo0y 5ro8 ,o0ni'i4e
5un,'ion in M. 8ay be resol4ed by a 8ore ,o89le'e unders'andin0 o5 'he ele8en's 'ha'
,o89rise ,o0ni'i4e reser4e. "n 'he 9resen' s'udy) 1e ai8ed 'o e?'end 'he ,o0ni'i4e reser4e
,ons'ru,' by e?a8inin0 'he 9o'en'ial ,on'ribu'ion o5 o,,u9a'ional a''ain8en' 'o ,o0ni'i4e
de,line in M..
0o )o:
Materials and Methods
Recruitment
M. 9a'ien's 1ere re,rui'ed ,onse,u'i4ely 5ro8 '1o uni4ersi'y M. ,lini,s. No 5inan,ial
,o89ensa'ion 1as o55ered. "n,lusion ,ri'eria ,onsis'ed o5 a dia0nosis o5 M. by 'he
8odi5ied Ma,donald ,ri'eria E12F) 5luen,y in 2n0lish) and 'he abili'y 'o 9ro4ide in5or8ed
,onsen'. 2?,lusion ,ri'eria ,onsis'ed o5 a0e b6$ years) ,or'i,os'eroid 'rea'8en' in 'he 4
1ee+s 9re,edin0 assess8en') his'ory o5 any addi'ional neurolo0i,al dia0nosis or 8edi,al
illness 'ha' ,ould in5luen,e ,o0ni'ion in,ludin0 head inIury 1i'h loss o5 ,ons,iousness o5
any dura'ion. #e8o0ra9hi, and disease 4ariables in,ludin0 'he 2?9anded #isabili'y
.e4eri'y .,ale <2#..) E13F= and Mul'i9le .,lerosis Fun,'ional Co89osi'e .,ore E14F
1ere ,olle,'ed on 'he sa8e day as ,o0ni'i4e reser4e 4ariables) neuro9sy,holo0i,al
'es'in0) and 8a0ne'i, resonan,e i8a0in0 des,ribed belo1.
Cognitive reserve variables
!remorbid 5@
7he (8eri,an Na'ional (dul' &eadin0 7es' <(MN(&7= 1as used 'o es'i8a'e 9re8orbid
4erbal "W <D"W= ,orre,'ed 5or edu,a'ional a''ain8en' E1$F. 7es's o5 a,Guired 4o,abulary
+no1led0e su,h as 'he (MN(&7 ha4e been used e?'ensi4ely in 'he ,o0ni'i4e reser4e
li'era'ure <e.0. E16F= be,ause 'hey 9ro4ide es'i8a'es o5 in'elle,'ual enri,h8en'
inde9enden' o5 ,erebral 9a'holo0y E1F.
"ccupational attainment
7he o,,u9a'ion held 5or 'he lon0es' 9eriod 1as de'er8ined durin0 9a'ien' in'er4ie1 1i'h
in5or8a'ion su99le8en'ed 5ro8 8edi,al re,ords. T,,u9a'ions 1ere ,lassi5ied a,,ordin0
'o >... #e9ar'8en' o5 /abors\ #i,'ionary o5 T,,u9a'ional 7i'les <#T7=) &e4ised 4
'h

edi'ion E18F and di4ided in'o hih or lo! a''ain8en' based on o,,u9a'ional ,a'e0ory E1%F.
"ih o,,u9a'ional a''ain8en' 1as de5ined as 9ro5essional) 'e,hni,al) and 8ana0erial
o,,u9a'ions <#T7 ,ode 0!1=. #o! o,,u9a'ional a''ain8en' 1as de5ined as ,leri,al/sales)
a0ri,ul'ural/5ishery/5ores'ry) 9ro,essin0) 8a,hine 'rades) ben,h1or+) and s'ru,'ural
o,,u9a'ions <#T7 ,ode 2N8=. .i8ilar di4isions o5 o,,u9a'ion ha4e been u'ili@ed 'he
,o0ni'i4e reser4e li'era'ure <E1%F) E20F) re4ie1ed in E21F=.
8europsychological assessment
7hree ,o0ni'i4e do8ains 5ro8 'he Mini8al (ssess8en' o5 Co0ni'i4e Fun,'ion in M.
<M(CF"M.= ba''ery E22F 1ere assessed: 1. "n5or8a'ion 9ro,essin0 s9eed 1as e4alua'ed
1i'h 'he Pa,ed (udi'ory .erial (ddi'ion 7as+ <P(.(7) 3 s 4ersion= and 'he .y8bol #i0i'
Modali'ies 7es' <.#M7=; 2. Me8ory 1as assessed 1i'h 'he Cali5ornia Derbal /earnin0
7es' N "" <CD/7!""=; and 3. 2?e,u'i4e 5un,'ion 1as 'es'ed 1i'h 'he #elis!Ma9lan
2?e,u'i4e Fun,'ion .ys'e8s .or'in0 7es' <#M2F.=. 7hese indi,es 1ere sele,'ed on 'he
basis o5 9re4ious resear,h on ,o0ni'i4e reser4e in M. E6FNE11F and (l@hei8er\s disease
E23F. &a1 s,ores 5or ea,h inde? 1ere ,on4er'ed 'o a0e! and edu,a'ion!,orre,'ed @!s,ores
based on 'he re,o88ended E22F 9ublished nor8a'i4e 4alues. Mean @!s,ores 1ere
,al,ula'ed 5or 'he CD/7!"" <8ean o5 total learnin and delayed recall nor8!re5eren,ed @!
s,ores= and #M2F. <8ean o5 number of correct sorts and description score nor8!
re5eren,ed @!s,ores=.
Brain volume
Brain 9aren,hy8al 5ra,'ion <BPF= 1as used as a 8ar+er o5 brain 9a'holo0y E24F. "8a0es
1ere a,Guired on a 37 .i0na s,anner <;2 Medi,al .ys'e8s) Mil1au+ee) 3"= 1i'h a
Guadra'ure head ,oil E2$F. .eGuen,es ,onsis'ed o5: 1. ( hi0h resolu'ion 71!1ei0h'ed
a,Guisi'ion <a?ial 3# in4ersion re,o4ery <"&=!9re99ed 5as' s9oiled 0radien' e,ho <F.;&=
seGuen,e 1i'h a 3.2 8s e,ho 'i8e <72=) 8s re9e'i'ion 'i8e <7&=) 300 8s in4ersion 'i8e
<7"=) 1$i 5li9 an0le) 22 ,8j16.$ ,8 5ield o5 4ie1 <FTD=) 2$6j1%2 8a'ri?) 1.4 88 sli,e
'hi,+ness) 2 e?,i'a'ions <N2K==; 2. ( P#/72!1ei0h'ed seGuen,e <2# in'erlea4ed a?ial
dual!e,ho 5as'!s9in e,ho 1i'h a 72 o5 20 8s and 102 8s) 7& o5 2%00 8s) e,ho 'rain
len0'h o5 12) 22 ,8j16.$ ,8 FTD) 2$6j1%2 8a'ri?) 3.0 88 sli,e 'hi,+ness) 2 N2K=; and
3.( 5luid!a''enua'ed in4ersion re,o4ery <F/("&= seGuen,e <2# 72F/("& 1i'h a 72 o5
140 8s) a 7& o5 %300 8s) a 7" o5 2200 8s) 2$6j1%2 8a'ri?) 22j16.$ ,8 FTD) 3.0 88
sli,e 'hi,+ness) 2 N2K=.
F./\s F/"&7 E26F 1as used 'o ,ore0is'er and resli,e 'he P#/72 and F/("& in 71 s9a,e.
Brain e?'ra,'ion 1as ,o89le'ed usin0 B27 E2F on P#/72 and F/("& i8a0es. #e'ails o5
'he 9ro'o,ol 5or 'issue ,lass se08en'a'ion E28F and 1hi'e 8a''er lesion se08en'a'ion are
des,ribed 9re4iously E2$F) E2%F. Dolu8es o5 0rey 8a''er) 1hi'e 8a''er) and C.F 1ere
ob'ained 5ro8 se08en'ed 71!1ei0h'ed i8a0es a5'er sub'ra,'in0 lesions and ,orre,'in0 5or
head si@e E30F. 3hole brain 4olu8e 1as 8easured by BPF) 1here BPF B E<0ray 8a''er
4olu8e=`<1hi'e 8a''er 4olu8e=F/E<0ray 8a''er 4olu8e=`<1hi'e 8a''er 4olu8e=`<C.F
4olu8e=F.
Statistics
.'a'is'i,al analyses 1ere 9er5or8ed usin0 "BM!.P.. 20.0 1i'h al9ha se' a' 0.0$.
&ela'ionshi9s be'1een 9a'ien' ,hara,'eris'i,s and ,o0ni'i4e reser4e 4ariables 1ere
e4alua'ed 1i'h inde9enden' '!'es's or Mann!3hi'ney 'es's and Pearson or .9ear8an\s
,orrela'ions. Correla'ions o5 BPF and ,o0ni'i4e ou',o8es in lo! and hih o,,u9a'ional
0rou9s 1ere ,o89ared 1i'h Fisher 'rans5or8a'ion a5'er s'a'is'i,ally!adIus'in0 5or D"W.
6ierar,hi,al re0ression 1as used 'o assess 'he ,on'ribu'ion o5 o,,u9a'ion <s'e9 3= 'o
,o0ni'i4e ou',o8es a5'er a,,oun'in0 5or brain 4olu8e <s'e9 1= and D"W <s'e9 2=.
Standard protocol approvals7 registrations7 and patient consent
7his s'udy 1as a99ro4ed by 'he &esear,h 2'hi,s Boards o5 .'. Mi,hael\s 6os9i'al and
.unnybroo+ 6eal'h .,ien,es Cen're) >ni4ersi'y o5 7oron'o) in a,,ordan,e 1i'h 'he
re,o88enda'ions 5or bio8edi,al resear,h in hu8ans in 'he 1%64 #e,lara'ion o5 6elsin+i.
(ll 9ar'i,i9an's 9ro4ided in5or8ed) 1ri''en ,onsen'.
0o )o:
Results
7able 1 sho1s de8o0ra9hi, and disease 4ariables 5or 'he 2 M. 9a'ien's. T4erall) 26
9a'ien's <36.1C= 1ere ,o0ni'i4ely!i89aired by 'he M(CF"M. ,ri'eria E22F. For'y M.
9a'ien's <$$.6C= 1ere ,lassi5ied 1i'h hih o,,u9a'ional a''ain8en' and 32 <44.4C= 1i'h
lo!. 7he '1o 0rou9s did no' di55er 1i'h res9e,' 'o e89loy8en' s'a'us. 7hose in 'he hih
o,,u9a'ion 0rou9 had 0rea'er D"W and 8ore years o5 edu,a'ion 'han 'he lo! 0rou9 <'able
1=. ( 0rea'er 9ro9or'ion o5 indi4iduals in 'he hi0h o,,u9a'ion 0rou9 1ere re,ei4in0
disease!8odi5yin0 'rea'8en' a' 'he 'i8e o5 'es'in0. (8on0 de8o0ra9hi, and disease
4ariables) D"W 1as asso,ia'ed only 1i'h years o5 edu,a'ion <k B 0.$0) 9]0.001 =. 7he
5reGuen,y o5 o4erall ,o0ni'i4e i89air8en' did no' di55er be'1een 'he hih <30.0C= and
lo! <43.8C= o,,u9a'ion 0rou9s <$
2
B 1.4$) 9 B 0.324=.
<"ble 1
Demographic and disease "ariables.
Correla'ions o5 neuro9a'holo0y <BPF= 1i'h ,o0ni'i4e ou',o8e di55ered be'1een hih and
lo! o,,u9a'ional 0rou9s a5'er adIus'in0 5or D"W <P(.(7) @ B 3.26) 9 B 0.001; .#M7) @ B
3.1) 9 B 0.001; CD/7!"") @ B 3.31) 9 B 0.001; #M2F.) @ B 3.31) 9 B 0.001=. 7he
,on'ribu'ion o5 o,,u9a'ion 'o ,o0ni'i4e ou',o8e 1as assessed by hierar,hi,al re0ression.
BPF <s'e9 1=) D"W <s'e9 2=) and o,,u9a'ion <s'e9 3= 1ere en'ered as 9redi,'ors o5
9er5or8an,e on 'he P(.(7) .#M7) CD/7!"") and #M2F.. 7he 5ull re0ressions
a,,oun'ed 5or 'he 5ollo1in0 4arian,e: 20.4C 5or 'he P(.(7) 1.C 5or 'he .#M7) 33.2C
5or CD/7!"") and 1%.2C 5or 'he #M2F.. BPF and D"W 9redi,'ed 9er5or8an,e on all 5our
,o0ni'i4e 'es's in 'he 5ull re0ressions <7able .1=. T,,u9a'ion a,,oun'ed 5or addi'ional
4arian,e in 'he P(.(7) CD/7!"") and #M2F.) bu' no' 'he .#M7 <'able 2 and 5i0ure 1=.
-ears o5 edu,a'ion did no' 9redi,' any ,o0ni'i4e ou',o8e in 'he re0ressions <s'e9 1 B
BPF) s'e9 2 B D"W) s'e9 3 B years o5 edu,a'ion) s'e9 4 B o,,u9a'ion=) bu' 'he s'a'is'i,al
si0ni5i,an,e o5 o,,u9a'ion 1as los' 5or 'he #M2F. 1hen edu,a'ion 1as in,luded.
#isease!8odi5yin0 'rea'8en' did no' 9redi,' any ,o0ni'i4e ou',o8e in 'he re0ressions
<s'e9 1 B BPF) s'e9 2 B D"W) s'e9 3 B disease!8odi5yin0 'rea'8en') s'e9 4 B o,,u9a'ion=)
and 'he s'a'is'i,al si0ni5i,an,e o5 o,,u9a'ion 1as un,han0ed 1i'h 'he in,lusion o5 'his
4ariable.
@i.ure 1
)ccupational attainment and cogniti"e outcome in MS patients.
<"ble 2
1ssociation of occupational attainment and cogniti"e outcomes in
MS by hierarchical regression.
0o )o:
'iscussion
7his s'udy is 'he 5irs' 'o our +no1led0e 'o re9or' an asso,ia'ion be'1een o,,u9a'ional
a''ain8en' and ,o0ni'i4e ou',o8e in M.. (5'er a,,oun'in0 5or brain a'ro9hy and
9re8orbid "W) o,,u9a'ional a''ain8en' added si0ni5i,an' 4arian,e 'o indi,es o5
in5or8a'ion 9ro,essin0 s9eed <P(.(7=) 8e8ory <CD/7!""=) and e?e,u'i4e 5un,'ion
<#M2F.=. 7hese da'a su00es' 'ha' M. 9a'ien's 1i'h lo1 o,,u9a'ional a''ain8en' 5are
1orse ,o0ni'i4ely 'han 'hose 1i'h hi0h o,,u9a'ional a''ain8en' a5'er ,on'rollin0 5or brain
a'ro9hy and 9re8orbid "W. 7he i89li,a'ion is 'ha' o,,u9a'ional a''ain8en') li+e
9re8orbid "W E6F) EF) E8F) E%F and ,o0ni'i4e leisure E11F) 8a+es an inde9enden'
,on'ribu'ion 'o ,o0ni'i4e reser4e in M..
7he ,on,e9' o5 ,o0ni'i4e reser4e e8er0ed 5ro8 e9ide8iolo0i,al resear,h in de8en'ia E3F)
E$F) E31F. 7he ,o0ni'i4e reser4e 'heory hel9ed e?9lain 'he 1ea+ a55ilia'ion o5
neuro9a'holo0y 1i'h ,o0ni'ion) 9o'en'ially resol4in0 ,onundra su,h as nor8al an'e!
8or'e8 neuro9sy,holo0i,al 5un,'ion in elders 1ho 8e' 5ull 9a'holo0i,al ,ri'eria 5or
(l@hei8er disease a' au'o9sy E32F. T4er 'he las' '1o de,ades) 'he no'ion 'ha' li5e
e?9erien,es ,an 8odi5y a0e!rela'ed neuro9a'holo0i,al ,han0es has 0arnered ,onsiderable
e89iri,al su99or'. Be,ause ,o0ni'i4e reser4e ,anno' be dire,'ly Guan'i5ied) 9ro?y
8easures ha4e ser4ed as surro0a'es. Pre!8orbid "W) edu,a'ion) o,,u9a'ional a''ain8en')
and ,o0ni'i4ely!s'i8ula'in0 leisure a,'i4i'ies are ,onsidered 8ar+ers o5 ,o0ni'i4e reser4e)
5or e?a89le) be,ause 'hey ,an a,,oun' 5or in'er!indi4idual di55eren,es in 'he in,iden,e o5
de8en'ia 1hen o'her rele4an' 4ariables are ,on'rolled E3F) E$F) E31F. ( 8e'a!analysis o5
o4er 2% 000 9ar'i,i9an's 5ound 'ha' hi0h ,o0ni'i4e reser4e 1as asso,ia'ed 1i'h a $0C
de,rease in 'he ris+ o5 in,iden' de8en'ia E21F. 7he bene5i's o5 hi0h ,o0ni'i4e reser4e 1ere
dose!de9enden' and ,o89arable in 8a0ni'ude 'o ris+ redu,'ion 1i'h blood 9ressure
,on'rol and an'i!in5la88a'ory 8edi,a'ion. 7he asso,ia'ion be'1een enri,hin0 li5e
e?9erien,es and ,o0ni'i4e 9reser4a'ion in 'he 5a,e o5 neuro9a'holo0y has been e?'ended
'o s'ro+e E33F and 'rau8a'i, brain inIury E34F.
( hand5ul o5 s'udies ha4e e?a8ined ,o0ni'i4e reser4e in M.. "n 'he 5irs') .u8o1s+i e' al.
E%F ,o89ared 'he 9er5or8an,e o5 $8 M. 9a'ien's 'o heal'hy ,on'rols on 'he .#M7) 'he
P(.(7) and indi,es o5 4erbal 8e8ory deri4ed 5ro8 'he /o0i,al Me8ory sub'es's o5 'he
3es,hler Me8ory .,ale!&e4ised. M. 9a'ien's 1i'h hi0h ,o0ni'i4e reser4e) es'i8a'ed
1i'h a 1ord!readin0 9ro?y o5 D"W) s,ored si8ilarly 'o heal'hy ,on'rols on 'he P(.(7
and 4erbal 8e8ory 'es's. /o1 ,o0ni'i4e reser4e) in ,on'ras') 1as asso,ia'ed 1i'h
si0ni5i,an'ly 9oorer 8easures on 'hese ,o0ni'i4e ou',o8es in 'he M. 9a'ien's. T5 no'e is
'ha' 'he 9ro'e,'i4e e55e,' o5 hi0h reser4e did no' a99ly 'o 'he .#M7NM. 9a'ien's)
irres9e,'i4e o5 hi0h or lo1 ,o0ni'i4e reser4e) 9er5or8ed si0ni5i,an'ly 1orse 'han ,on'rols
on 'his 'as+. "n our s'udy) o,,u9a'ional a''ain8en' 1as also unasso,ia'ed 1i'h 'he .#M7
ye' 1as an i89or'an' 9redi,'or o5 'he P(.(7. Bo'h 8easures are ,onsidered indi,es o5
in5or8a'ion 9ro,essin0 s9eed. #isso,ia'ion be'1een 'he .#M7 and P(.(7 1i'h res9e,'
'o ,o0ni'i4e reser4e has been su00es'ed 'o rela'e 'o 'he 5or8er 8obili@in0 a 8ore li8i'ed
ran0e o5 ,o0ni'i4e s'ra'e0ies E%F. 7he P(.(7) in ,on'ras') 'es's no' only 9ro,essin0 s9eed
and 1or+in0 8e8ory bu' also reGuires nu8eri, ,al,ula'ion E1F. "' is a8enable 'o
di55eren' ,o0ni'i4e s'ra'e0ies su,h as R,hun+in0S o5 s'i8ulus dyads E3$F. 7he rela'i4e
inde9enden,e o5 'he .#M7 5ro8 9ro?ies o5 ,o0ni'i4e reser4e ,ould also e?9lain 1hy i' is
0enerally 'he 8os' robus' ,orrela'e o5 brain 9a'holo0y in M. E1F.
More re,en' resear,h has 9ar'i'ioned 'he e?'en' o5 ,o0ni'i4e ,han0e 'ha' ,an be a''ribu'ed
'o 8easurable brain 9a'holo0y 4ersus ,o0ni'i4e reser4e. .u8o1s+i e' al. E6F) EF
in,or9ora'ed a brain a'ro9hy 8easure) na8ely) 'hird 4en'ri,ular 1id'h) in hierar,hi,al
re0ressions 9redi,'in0 ,o0ni'i4e ou',o8e in M.. 3i'h 'he in,lusion o5 a'ro9hy)
9re8orbid "W re8ained a si0ni5i,an' de'er8inan' o5 in5or8a'ion 9ro,essin0 s9eed
<Guan'i5ied by 'he a4era0e o5 'he .#M7 and P(.(7= and 4erbal 8e8ory <8easured 1i'h
'he .ele,'i4e &e8indin0 7es'=. 6i0her reser4e 'hus lessened 'he e55e,' o5 brain a'ro9hy on
,o0ni'ion in M. 9a'ien's.
Mo4in0 beyond "W as a 9ro?y o5 ,o0ni'i4e reser4e in M.) 9re8orbid ,o0ni'i4e leisure
1as sur4eyed in 36 9a'ien's by 'he sa8e resear,h 0rou9 usin0 a Gues'ionnaire 'ha'
re'ros9e,'i4ely 9robed a,'i4i'ies su,h as readin0) hobbies) 9layin0 a 8usi,al ins'ru8en')
9rodu,in0 ar') e',. in 9a'ien's\ early 20 s E11F. Par'i,i9a'ion in 'hese in'elle,'ually!
enri,hin0 a,'i4i'ies 1as 5ound 'o be 9osi'i4ely ,orrela'ed 1i'h ,o0ni'i4e ou',o8e <a
,o89osi'e 8easure o5 4erbal 8e8ory and in5or8a'ion 9ro,essin0 s9eed= a5'er ,on'rollin0
5or brain a'ro9hy) 9re8orbid "W) and edu,a'ion.
Tur da'a ,on5ir8 9re4ious s'udies lin+in0 9re8orbid "W 'o ,o0ni'i4e 5un,'ion in M.. 3e
5ound si0ni5i,an' asso,ia'ions o5 D"W 1i'h in5or8a'ion 9ro,essin0 s9eed <P(.(7= and
8e8ory <CD/7!""= 1hen ,on'rollin0 5or BPF. 3e used BPF as our 8easure o5 brain
a'ro9hy ra'her 'han 'hird 4en'ri,ular 1id'h 0i4en 'ha' i' 5urnishes a dire,' inde? o5 1hole
brain 4olu8e ,orre,'ed 5or lesion 4olu8e. T5 no'e is 'ha' 1e also e?'ended 'he ran0e o5
,o0ni'i4e indi,es lin+ed 'o ,o0ni'i4e reser4e by in,ludin0 a 8easure o5 e?e,u'i4e
5un,'ion) 'he #M2F.) an i89or'an' de'er8inan' o5 indi4iduals\ daily 5un,'ionin0)
in,ludin0 8edi,al and 5inan,ial de,ision!8a+in0 E36F. By doin0 so) 1e 9ro4ide a 8ore
,o89rehensi4e 8easure o5 1ha' ,o0ni'i4e reser4e en'ails in M.. 7he e?e,u'i4e 5un,'ion
5indin0 is ,onsis'en' 1i'h 1ha' has been re9or'ed in ,o0ni'i4e reser4e s'udies o5
(l@hei8er disease E23F.
7he role o5 edu,a'ion in ,o0ni'i4e reser4e re8ains un,lear. 24iden,e in 'he a0in0 and
de8en'ia li'era'ure su00es' 'ha' 9re8orbid "W 8ay 5urnish a 8ore robus' 8easure o5
reser4e 'han edu,a'ion E3F) E38F. ( M. s'udy 'ha' la,+ed brain a'ro9hy 8easure8en'
re9or'ed 'ha' edu,a'ion a,,oun'ed 5or 2C o5 'he 4arian,e in ,o0ni'i4e ou',o8e
inde9enden' o5 9re8orbid in'elli0en,e E8F. 7he in,lusion o5 edu,a'ion as a 9u'a'i4e
reser4e 4ariable in o'her M. s'udies has been in,onsis'en'. "n our s'udy) edu,a'ion 1as
no' a 9redi,'or o5 ,o0ni'i4e ou',o8e. Me'hodolo0i,al issues ,anno' be e?,luded 5ro8 'his
5indin0) ho1e4er. "n 9ar'i,ular) s'andardi@in0 ,o0ni'i4e 4ariables 'o nor8a'i4e 4alues
,orre,'in0 5or a0e and edu,a'ion 8ay ha4e a di8inished an edu,a'ion e55e,'. (lso) Guali'y
o5 s,hoolin0) 1hi,h 1e did no' 8easure) 8ay ,on'ribu'e 'o ,o0ni'i4e reser4e E3%F in
addi'ion 'o years o5 edu,a'ion. Finally) in our sa89le o5 rela'i4ely 1ell!edu,a'ed
indi4iduals) a ,eilin0 e55e,' ,ould ha4e obs,ured a si0ni5i,an' e55e,' o5 edu,a'ion. "' is
no'able 'ha' 'he inde9enden' ,on'ribu'ion o5 o,,u9a'ional a''ain8en' 'o e?e,u'i4e
5un,'ion los' s'a'is'i,al si0ni5i,an,e 1i'h 'he in,lusion o5 edu,a'ion in 'he re0ression
8odel. Possibly) 'he di4erse li5e e?9erien,es 'ha' in5luen,e ,o0ni'i4e reser4e indi4idually
i89a,' di55eren' neuro9sy,holo0i,al 5un,'ions 'o 4aryin0 de0rees. 7en'a'i4e su99or' 5or
'his no'ion 8ay be 5ound in 'he 9resen' s'udy and in earlier 1or+ E%F re9or'in0
asso,ia'ions o5 ,o0ni'i4e reser4e 8ar+ers 1i'h 9er5or8an,e on 'he P(.(7 bu' no' on 'he
.#M7.
Tur s'udy is no' 1i'hou' i's li8i'a'ions and reGuires re9li,a'ion. 3hile our da'a and
earlier s'udies E20F) E40F su99or' an e55e,' o5 o,,u9a'ional a''ain8en' on ,o0ni'i4e reser4e
'ha' is se9ara'e 5ro8 'ha' i89ar'ed by inna'e in'elli0en,e and edu,a'ion) 'he ,ausal
8e,hanis8s and 8ul'i!dire,'ional 9a'h1ays 'ha' 8ay e?is' be'1een 'hese 4ariables
re8ain unde5ined. 7he o,,u9a'ional 0rou9s 1ere 1ell 8a',hed on a0e o5 onse') disease
dura'ion) disease ,ourse) and 9hysi,al disabili'y. None'heless) 'he 9ossibili'y 'ha'
indi4iduals 1i'h 1orse disease early on 1ere 5or,ed in'o less ,o0ni'i4ely!de8andin0 Iobs
,anno' be ruled ou' 1i'hou' lon0i'udinal da'a 'ha' has 'hus 5ar been la,+in0 in 'he M.!
,o0ni'i4e reser4e li'era'ure. Fa'i0ue) a ,o88on M. sy89'o8) ,an also in5luen,e
,o0ni'i4e ou',o8es bu' 1as no' 8easured in 'his s'udy. /i+e1ise) da'a re0ardin0 leisure
a,'i4i'ies 1as no' ,olle,'ed. (no'her 9o'en'ial li8i'a'ion is 'ha' 'he 0rou9s 1ere no'
8a',hed 1i'h res9e,' 'o disease!8odi5yin0 'rea'8en' a' 'he 'i8e o5 ,o0ni'i4e assess8en'.
24iden,e 5or an e55e,' o5 'hese 8edi,a'ions on ,o0ni'ion is 0enerally 1ea+) ho1e4er
Ere4ie1ed in 1F) and 1e did no' de'e,' an e55e,' on ,o0ni'i4e ou',o8es. Fur'her8ore)
be,ause edu,a'ional and o,,u9a'ional a''ain8en' ,o89rise 9ar' o5 1ha' de5ines
so,ioe,ono8i, s'a'us) 'he 9o'en'ially ,on5oundin0 e55e,'s o5 in,o8e) a,,ess 'o heal'h,are)
e',. are di55i,ul' 'o disen'an0le. 7his ,hallen0e is no' uniGue 'o our s'udy E4F.
"n su88ary) our da'a e89hasi@e 'he i89or'an,e o5 ,onsiderin0 ,o0ni'i4e reser4e in
de'er8inin0 M. 9a'ien's\ ,o0ni'i4e s'a'us. "n doin0 so) 1e add o,,u9a'ional a''ain8en' 'o
'he s8all lis' o5 4ariables 'ha' de5ine 1ha' ,o0ni'i4e reser4e en0enders. >nli+e i8a0in0
4ariables su,h as BPF or 'hird 4en'ri,ular 1id'h) in5or8a'ion re0ardin0 an indi4idual\s
o,,u9a'ion is easily a,Guired in ,lini,al se''in0s. 3he'her 'his in5or8a'ion ,an assis'
,lini,ians in 9redi,'in0 5u'ure ,o0ni'i4e i89air8en' in M. 9a'ien's a1ai's 5ur'her s'udy.
0o )o:
Supporting 5normation
+able S*
B!37 ?5@7 and occupational attainment as predictors o cognitive outcome in MS%
<K/.=
%lic6 here >or "ddi)ion"l d")" Gle.
(:32* Ils)
0o )o:
3unding Statement
<his 7or6 7"s su##or)ed b+ " .r"n) >rom )he %"n"di"n &ns)i)u)es o> Pe"l)h
3ese"rch (%&P3) )o 4n)hon+ @eins)ein "nd s"l"r+ su##or) "nd " rese"rch
s)i#end )o O0. <he >unders h"d no role in s)ud+ desi.n* d")" collec)ion "nd
"n"l+sis* decision )o #ublish* or #re#"r")ion o> )he m"nuscri#).
0o )o:
Reerences
1. /enedic) 3P/* MiB"dinoB 3 (2011) 3is6 >"c)ors >or "nd m"n".emen) o>
co.ni)iBe d+s>unc)ion in mul)i#le sclerosis. ,") 3eB ,eurol 10: 332D3:2.
EPub$edF
2. S)ern L (2002) Nh") is co.ni)iBe reserBeH <heor+ "nd rese"rch "##lic")ion
o> )he reserBe conce#). 1 &n) ,euro#s+chol Soc 8: ::8D:'0. EPub$edF
3. S)ern L (200() %o.ni)iBe reserBe. ,euro#s+cholo.i" :7: 2015D2028. EP$%
>ree "r)icleF EPub$edF
:. 1ones 3,* $"nl+ 1* 0l+mour $$* 3en)K D$* 1eQerson 4L* e) "l. (2011)
%once#)u"l "nd $e"suremen) %h"llen.es in 3ese"rch on %o.ni)iBe 3eserBe. 1
&n) ,euro#s+chol Soc 17: 5(3D'01. EP$% >ree "r)icleF EPub$edF
5. S)ern L (200') %o.ni)iBe reserBe "nd 4lKheimer dise"se. 4lKheimer Dis
4ssoc Disord 20: 112D117. EPub$edF
'. Sumo7s6i 1@* %hi"r"B"llo)i ,* N+lie 0* DeLuc" 1 (200() %o.ni)iBe reserBe
moder")es )he ne.")iBe eQec) o> br"in ")ro#h+ on co.ni)iBe eOcienc+ in
mul)i#le sclerosis. 1 &n) ,euro#s+chol Soc 15: '0'D'12. EPub$edF
7. Sumo7s6i 1@* N+lie 03* %hi"r"B"llo)i ,* DeLuc" 1 (2010) &n)ellec)u"l
enrichmen) lessens )he eQec) o> br"in ")ro#h+ on le"rnin. "nd memor+ in
mul)i#le sclerosis. ,eurolo.+ 7:: 1(:2D1(:5. EP$% >ree "r)icleF EPub$edF
8. /enedic) 3P/* $orro7 S4* Neins)oc690u))m"n /* %oo6>"ir D* Schre)len D1
(2010) %o.ni)iBe reserBe moder")es decline in in>orm")ion #rocessin. s#eed
in mul)i#le sclerosis #")ien)s. 1 &n) ,euro#s+chol Soc 1': 82(D835. EPub$edF
(. Sumo7s6i 1@* %hi"r"B"llo)i ,* DeLuc" 1 (200() %o.ni)iBe reserBe #ro)ec)s
"."ins) co.ni)iBe d+s>unc)ion in mul)i#le sclerosis. 1 %lin =I# ,euro#s+chol
31: (13D(2'. EPub$edF
10. Sumo7s6i 1@* N+lie 03* DeLuc" 1* e) "l. (2010) &n)ellec)u"l enrichmen) is
lin6ed )o cerebr"l eOcienc+ in mul)i#le sclerosis: >unc)ion"l m".ne)ic
reson"nce im".in. eBidence >or co.ni)iBe reserBe. /r"in 133: 3'2D37:. EP$%
>ree "r)icleF EPub$edF
11. Sumo7s6i 1@* N+lie 03* 0onnell" 4* %hi"r"B"llo)i ,* DeLuc" 1 (2010)
Premorbid co.ni)iBe leisure inde#enden)l+ con)ribu)es )o co.ni)iBe reserBe in
mul)i#le sclerosis. ,eurolo.+ 75: 1:28D1:31. EP$% >ree "r)icleF EPub$edF
12. Polm"n %P* 3ein.old S%* =d"n 0* @illi#i $* P"r)un. PP* e) "l. (2005)
Di".nos)ic cri)eri" >or mul)i#le sclerosis: 2005 reBisions )o )he W$cDon"ld
cri)eri"W. 4nn ,eurol 58: 8:0D8:'. EPub$edF
13. 2ur)K6 1@ (1(83) 3")in. neurolo.ic im#"irmen) in mul)i#le sclerosis: "n
eI#"nded dis"bili)+ s)")us sc"le (=DSS). ,eurolo.+ 33: 1:::D1:52. EPub$edF
1:. %u))er 03* /"ier $L* 3udic6 34* %oo6>"ir DL* @ischer 1S* e) "l. (1((()
DeBelo#men) o> " mul)i#le sclerosis >unc)ion"l com#osi)e "s " clinic"l )ri"l
ou)come me"sure. /r"in 122: 871D882. EPub$edF
15. 0rober =* Sli7ins6 $* 2ore+ S3 (1((1) DeBelo#men) "nd 8"lid")ion o> "
$odel >or =s)im")in. Premorbid 8erb"l &n)elli.ence in )he =lderl+. 1 %lin =I#
,euro#s+chol 13: (33D(:(. EPub$edF
1'. 3en)K D$* Loc"scio 11* /ec6er 14* $or"n =2* =n. =* e) "l. (2010) %o.ni)ion*
reserBe "nd "m+loid de#osi)ion in norm"l ".in.. 4nn ,eurol '7: 353D3':.
EP$% >ree "r)icleF EPub$edF
17. LeK"6 $D* Po7ieson D/* /i.ler =D* <r"nel D (2012) ,euro#s+cholo.ic"l
4ssessmen). 5)h ed. JS4: OI>ord JniBersi)+ Press.
18. Jni)ed S)")es De#"r)men) o> L"bor (1((1) Dic)ion"r+ o> Occu#")ion"l
<i)les. @our)h edi)ion. N"shin.)on: 0oBernmen) Prin)in. OOce.
1(. Sc"rme"s ,* LeB+ 0* <"n. $X* $"nl+ 1* S)ern L (2001) &nUuence o> leisure
"c)iBi)+ on )he incidence o> 4lKheimerYs dise"se. ,eurolo.+ 57: 223'D22:2.
EP$% >ree "r)icleF EPub$edF
20. S)ern L* 0url"nd /* <")emichi <2* <"n. $X* Nilder D* e) "l. (1((:)
&nUuence o> educ")ion "nd occu#")ion on )he incidence o> 4lKheimerYs
dise"se. 14$4 271: 100:D1010. EPub$edF
21. 8"lenKuel" $1* S"chdeB P (2005) /r"in reserBe "nd demen)i": "
s+s)em")ic reBie7. Ps+chol $ed ': ::1D:5:. EPub$edF
22. /enedic) 3P/* %oo6>"ir D* 0"Be)) 3* 0un)her $* $unsch"uer @* e) "l.
(200') 8"lidi)+ o> )he minim"l "ssessmen) o> co.ni)iBe >unc)ion in mul)i#le
sclerosis ($4%@&$S). 1 &n) ,euro#s+chol Soc 12: 5:(D558. EPub$edF
23. 3eed /* $un."s D* @"ri"s S* P"rBe+ D* /ec6e)) L* e) "l. (2010) $e"surin.
co.ni)iBe reserBe b"sed on )he decom#osi)ion o> e#isodic memor+ B"ri"nce.
/r"in 133: 21('D220(. EP$% >ree "r)icleF EPub$edF
2:. /ermel 34* /"6shi 3 (200') <he me"suremen) "nd clinic"l releB"nce o>
br"in ")ro#h+ in mul)i#le sclerosis. L"nce) ,eurol 5: 158D170. EPub$edF
25. 0h"Q"r O* Lob"u.h ,1* SKil".+i 0$* 3eis $* OY%onnor P* e) "l. (2011)
&m".in. .ene)ics in mul)i#le sclerosis: 4 Bolume)ric "nd diQusion )ensor $3&
s)ud+ o> 4PO= e:. ,euro&m".e 58: 72:D731. EPub$edF
2'. 1en6inson $* Smi)h S (2001) 4 .lob"l o#)imis")ion me)hod >or robus)
"One re.is)r")ion o> br"in im".es. $ed &m".e 4n"l 5: 1:3D15'. EPub$edF
27. Smi)h S$ (2002) @"s) robus) "u)om")ed br"in eI)r"c)ion. Pum /r"in $"##
17:1 :3D155. EPub$edF
28. 2oB"ceBic ,* Lob"u.h ,1* /rons6ill $1* LeBine /* @eins)ein 4* e) "l. (2002)
4 robus) me)hod >or eI)r"c)ion "nd "u)om")ic se.men)")ion o> br"in im".es.
,euro&m".e 17: 1087D1100. EPub$edF
2(. 0ibson =* 0"o @* /l"c6 S=* Lob"u.h ,1 (2010) 4u)om")ic se.men)")ion o>
7hi)e m"))er h+#erin)ensi)ies in )he elderl+ usin. @L4&3 im".es ") 3<. 1 $".n
3eson &m".in. 31: 1311D1322. EP$% >ree "r)icleF EPub$edF
30. @eins)ein 4* OY%onnor P* 46b"r ,* $or"dK"deh L* Sco)) %* e) "l. (2010)
DiQusion )ensor im".in. "bnorm"li)ies in de#ressed mul)i#le sclerosis
#")ien)s. $ul)i#le Sclerosis 1': 18(D1('. EPub$edF
31. S)ern L (2011) =l"bor")in. " P+#o)he)ic"l %once#): %ommen)s on )he
S#eci"l Series on %o.ni)iBe 3eserBe. 1 &n) ,euro#s+chol Soc 17: '3(D':2.
EPub$edF
32. ,euro#")holo.+ 0rou# $edic"l 3ese"rch %ouncil %o.ni)iBe @unc)ion "nd
4.in. S)ud+ (2001) P")holo.ic"l correl")es o> l")e9onse) demen)i" in "
mul)icen)re* communi)+9b"sed #o#ul")ion in =n.l"nd "nd N"les. L"nce) 357:
1'(D175. EPub$edF
33. =l6ins 1S* Lon.s)re)h N<* $"nolio <4* ,e7m"n 4/* /h"deli" 34* e) "l.
(200') =duc")ion "nd )he co.ni)iBe decline "ssoci")ed 7i)h $3&9deGned br"in
in>"rc). ,eurolo.+ '7: :35D::0. EPub$edF
3:. 2esler S3* 4d"ms P@* /l"se+ %$* /i.ler =D (2003) Premorbid in)ellec)u"l
>unc)ionin.* educ")ion* "nd br"in siKe in )r"um")ic br"in in!ur+: "n
inBes)i.")ion o> )he co.ni)iBe reserBe h+#o)hesis. 4##l ,euro#s+chol 10: 153D
1'2. EPub$edF
35. @is6 1D* 4rchib"ld %1 (2001) Limi)")ions o> )he P"ced 4udi)or+ Seri"l
4ddi)ion <es) "s " me"sure o> 7or6in. memor+ in #")ien)s 7i)h mul)i#le
sclerosis. 1 &n) ,euro#s+chol Soc 7: 3'3D372. EPub$edF
3'. 3o+"ll D3* L"u)erb"ch =%* 2"u>er D* $"llo+ P* %oburn 2L* e) "l. (2007) <he
co.ni)iBe correl")es o> >unc)ion"l s)")us: " reBie7 >rom )he %ommi))ee on
3ese"rch o> )he 4meric"n ,euro#s+chi")ric 4ssoci")ion. 1 ,euro#s+chi")r+
"nd %lin ,eurosc 1(: 2:(D2'5. EPub$edF
37. 4leI"nder 0=* @ure+ $L* 0r"d+ %L* Pie)rini P* /r"d+ D3* e) "l. (1((7)
4ssoci")ion o> #remorbid in)ellec)u"l >unc)ion 7i)h cerebr"l me)"bolism in
4lKheimerYs dise"se: im#lic")ions >or )he co.ni)iBe reserBe h+#o)hesis. 4m 1
Ps+chi")r+ 15:: 1'5D172. EPub$edF
38. 4lber) S$* <eresi 14 (1((() 3e"din. "bili)+* educ")ion* "nd co.ni)iBe
s)")us "ssessmen) "mon. older "dul)s in P"rlem* ,e7 Lor6 %i)+. 4m 1 Public
Pe"l)h 8(: (5D(7. EP$% >ree "r)icleF EPub$edF
3(. $"nl+ 11* 1"cobs D$* <our"d!i P* Sm"ll S4* S)ern L (2002) 3e"din. leBel
"))enu")es diQerences in neuro#s+cholo.ic"l )es) #er>orm"nce be)7een
4>ric"n 4meric"n "nd 7hi)e elders. 1 &n) ,euro#s+chol Soc 11: 37D:'.
EPub$edF
:0. S)ern L* 4leI"nder 0=* ProhoBni6 &* S)ric6s L* Lin6 /* e) "l. (1((5)
3el")ionshi# be)7een li>e)ime occu#")ion "nd #"rie)"l Uo7: im#lic")ions >or "
reserBe "."ins) 4lKheimerYs dise"se #")holo.+. ,eurolo.+ :5: 55D'0.
EPub$edF
Jurnal 2
BMC Neurol. 2013; 13: 83.
Published online 2013 *uly 12. doi: 10.1186/141!23!13!83
PMC"#: PMC3118$$
'eterminants o se&ual dysunction in
women with multiple sclerosis
MhadiIeh Moha88adi)
1
Par4in &ahna8a)
1
.a+ineh Moayed Mohseni)
2
Moha88ad (li
.ahraian)
3
and (li Mon'a@eri
4
(u'hor in5or8a'ion : (r'i,le no'es : Co9yri0h' and /i,ense in5or8a'ion :
;o 'o:
Abstract
Background
7he ai8 o5 9resen' s'udy 1as 'o de'er8ine disease!rela'ed and 9sy,holo0i,al ris+ 5a,'ors
5or se?ual dys5un,'ion in 1o8en 1i'h 8ul'i9le s,lerosis <M.=.
Methods
7his 1as a ,lini,al!based s'udy ,ondu,'ed 5ro8 .e9'e8ber 200% 'o *une 2010 in 7ehran)
"ran. ( ,onse,u'i4e sa89le o5 5e8ale 9a'ien's 1i'h M. 1as re,rui'ed 5ro8 an ou'9a'ien'
,lini,. 7he Fe8ale .e?ual Fun,'ion "nde? <F.F"= 1as used 'o e4alua'e se?ual 5un,'ion. "n
addi'ion neurolo0i,al i89air8en' 1as 8easured usin0 'he Mur'@+e 2?9anded #isabili'y
.'a'us .,ale <2#..=) and de9ression 1as assessed usin0 'he Be,+ #e9ression "n4en'ory!
"" <B#"!""=. >ni4aria'e and 8ul'i9le lo0is'i, re0ression analyses 1ere 9er5or8ed in order
'o e?a8ine 'he asso,ia'ion be'1een se?ual dys5un,'ion and inde9enden' 4ariables.
Results
"n all) 226 1o8en 9ar'i,i9a'ed in 'he s'udy. T5 'hese) 12$ 1o8en <$$.3C= 8e' 'he ,ri'eria
5or se?ual dys5un,'ion. 7he 8ean a0e o5 9ar'i,i9an's 1as 3$. years <.#B 8.0=. 7he
resul's ob'ained 5ro8 8ul'i9le lo0is'i, re0ression analysis indi,a'ed 'ha' 'he disease
dura'ion <T& 5or 'he disease dura'ion o5 eGual or 0rea'er 'han % years B 3.13) C%$ C" B
1.2%!.$) P B 0.01=) 'he disease ,ourse <T& 5or se,ondary 9ro0ressi4e M. B 3.%6) C%$
C" B 1.$$!10.10) P B 0.004= and 'he B#" s,ore <T&B 1.11) C%$ C" B 1.0!1.16) P ] 0.001=
1ere si0ni5i,an' 5a,'ors ,on'ribu'in0 'o se?ual dys5un,'ion in 'hese 9a'ien's.
Conclusions
7he 5indin0s 5ro8 'his s'udy indi,a'ed 'ha' 'he dura'ion and se4eri'y o5 'he disease in
addi'ion 'o de9ression 1ere 'he 8os' si0ni5i,an' 5a,'ors 'ha' ,on'ribu'ed 'o se?ual
dys5un,'ion in 1o8en 1i'h 8ul'i9le s,lerosis. 7he burden o5 disease and se?ual
dys5un,'ion su00es's 'he need 5or 5ur'her a''en'ion 'o 'his 9a'ien' 9o9ula'ion.
;o 'o:
Background
Mul'i9le s,lerosis <M.= is a ,hroni, neurolo0i,al disorder 'ha' is ,hara,'eri@ed by
disse8ina'ed de8yelina'ion o5 ner4e 5ibers o5 'he brain and s9inal ,ord E1F. M. a55e,'s
bo'h 8ale and 5e8ale 0ender) bu' 'he disease a55e,'s 1o8en 2 'o 3 'i8es 8ore 'han 8ales
E2F. 7hus i' is no' sur9risin0 'ha' 'here are 8any 1o8en 1ho are su55erin0 5ro8 'he
disease. M. se4erely des'roys 1o8enHs li5e in se4eral as9e,'s in,ludin0 disru9'ion in
se?ual 5un,'ionin0 E3!$F. 7he 9re4alen,e o5 se?ual dys5un,'ion in 5e8ale 9a'ien's 1i'h
M. 4aries 5ro8 40 'o 0C E6F.
.e4eral s'udies de8ons'ra'ed 'ha' di55eren' ris+ 5a,'ors ,on'ribu'e 'o 'he de4elo98en' o5
5e8ale se?ual dys5un,'ion in M. 9a'ien's in,ludin0 9resen,e o5 9hysi,al disorders)
neurolo0i,al i89air8en's) a0e a' onse' o5 'he disease) de9ression and an?ie'y E3)!10F.
7he 9re4alen,e o5 M. in "ranian 9o9ula'ion is es'i8a'ed 'o be a' leas' $1.% 9er 100)000
E11F. (lso) 5e8ale!'o!8ale ra'io 5or 'he disease is re9or'ed 'o be 3.11 E12F. T4erall se?ual
dys5un,'ion a8on0 "ranian 5e8ales has been re9or'ed in u9 'o 31C o5 1o8en E13F) bu' 'o
'he bes' +no1led0e o5 'he au'hors 9re4alen,e o5 se?ual dys5un,'ion in "ranian 1o8en
1i'h 8ul'i9le s,lerosis is un+no1n.
.e?uali'y is a sensi'i4e issue in al8os' e4ery ,ul'ure in,ludin0 "ran. 7hus 9a'ien's usually
are relu,'an' 'o 'al+ abou' 'heir se?ual 9roble8s and o5'en) se?ual dys5un,'ion 0oes under
re,o0ni@ed and under 'rea'ed. "5 5e8ale se?uali'y is dis'urbed 'hen i' 8i0h' lead 'o se4eral
9roble8s) e4en di4or,e and 5a8ily brea+do1n E14F. "' also a55e,'s re9rodu,'i4e heal'h
and 5a8ily 9lannin0. 7he ai8 o5 9resen' s'udy 1as 'o de'er8inan' disease!rela'ed and
9sy,holo0i,al ris+ 5a,'ors 5or se?ual dys5un,'ion in 1o8en 1i'h 8ul'i9le s,lerosis <M.=
in order 'o re,o0ni@e 'he e?'en' o5 'he 9roble8 and 9erha9s 9ro4ide a99ro9ria'e
0uidelines 5or 9lannin0 8ana0ed ,are 5or 'hese 9a'ien's.
;o 'o:
Methods
'esign and procedure
7his 1as a ,lini,al!based s'udy ,ondu,'ed in 7ehran) "ran) durin0 a %!8on'hs 9eriod 5ro8
.e9'e8ber 200% 'o *une 2010. ( ,onse,u'i4e sa89le o5 226 5e8ale 9a'ien's 1i'h 8ul'i9le
s,lerosis 1as re,rui'ed 5ro8 'he M. ou'9a'ien' ,lini, in a lar0e 'ea,hin0 and re5erral
hos9i'al a55ilia'ed 'o 7ehran >ni4ersi'y o5 Medi,al .,ien,es. Cri'eria 5or in,lusion 1ere:
dia0nosis o5 M. a,,ordin0 'o 'he M,#onald &e4ised ,ri'eria E1$F; bein0 8arried; ha4in0
2?9anded #isabili'y .'a'us .,ale <2#..= s,ore less 'han or eGual 'o 8 E16F) and
1illin0ness 'o 9ar'i,i9a'e in 'he s'udy. 2?,lusion ,ri'eria 1ere: 9re!e?is'in0 8aIor ,hroni,
illness) and no' ha4in0 se?ual e?9erien,e in li5e. (ll 9a'ien's had a 5ull neurolo0i,
e?a8ina'ion.
@uestionnaires
3e used se4eral Gues'ionnaires 'o ,olle,' da'a:
1. ( s'udy s9e,i5i, Gues'ionnaire in order 'o ,olle,' da'a on de8o0ra9hi,) ,lini,al) and
obs'e'ri, in5or8a'ion.
2. 7he Fe8ale .e?ual Fun,'ion "nde? <F.F"= 1as used 'o e4alua'e se?ual 5un,'ion E1F.
7he F.F" is a 4alida'ed and 1idely used 1%!i'e8s sel5!re9or'ed 8easure o5 1o8enHs
se?ual 5un,'ion in,ludin0 'he 5ollo1in0 di8ensions: desire) arousal) lubri,a'ion) or0as8)
sa'is5a,'ion) and 9ain. 7he 9sy,ho8e'ri, 9ro9er'ies o5 'he "ranian 4ersion o5 Fe8ale
.e?ual Fun,'ion "nde? are 1ell do,u8en'ed E18F. For'una'ely 'he au'hors 9er5or8ed
sensi'i4i'y analysis 5or 'he "ranian 4ersion and 'he ,u'!o55 9oin' 5or 'he s,ale 1as 5ound 'o
be 28 <sensi'i4i'y B 83C and s9e,i5i,i'y B 82C=. "n addi'ion 'he sa8e s'udy ,arried ou' 'he
&e,ei4er T9era'in0 Chara,'eris'i,s analysis <&TC= and re9or'ed 'ha' 'he (rea under 'he
Cur4e <(>C= 1as 0.%1. 7he s'udy used 'he ,lini,al dia0nos'i, as 'he 0old s'andard and
re9or'ed 'ha' 28 1as 'he bes' ,u'!o55 4alue 5or 9redi,'in0 se?ual dys5un,'ion. 7hus) 5or 'he
analysis 9ur9ose 1o8en 1ho s,ored eGual or less 'han 28 on 'he F.F" 1ere iden'i5ied as
'hose 1ho 1ere su55erin0 5ro8 se?ual dys5un,'ion. .i8ilarly 'he ,u'!o55 9oin's 5or 'he
subs,ales also 1ere indi,a'ed and re9or'ed as 5ollo1s: #esire B 3.3) (rousal B 3.4)
/ubri,a'ion B 3.) Pain B 3.8) Tr0as8B 3.4) .a'is5a,'ion B 3.8.
3. #e9ression 1as assessed usin0 'he Be,+ #e9ression "n4en'ory!"" <B#"!""= E1%F. "' is a
1idely used 21!i'e8s sel5!re9or'ed 8easure 'ha' assesses 'he 9resen,e and in'ensi'y o5
de9ressi4e sy89'o8s re5le,'in0 'he si8ilar sy89'o8s su00es'ed by 'he #ia0nos'i, and
.'a'is'i,al Manual o5 Men'al #isorders <#.M!"D= E20F. 7he Persian 4ersion o5 in4en'ory
already has been 4alida'ed in "ran E21F.
4. 7he neurolo0i,al i89air8en' 1as assessed usin0 'he 2?9anded #isabili'y .'a'us .,ale
<2#..=. 7he 2#.. is a 0old s'andard 5or assess8en' o5 disabili'y in 9eo9le 1i'h M.. (
neurolo0is' s,ored 'he 2#.. 5or ea,h 9a'ien' E16F. 7he s,ore on 'he 2#.. ran0es 5ro8 1
'o %.$ 1here s,ores 5ro8 1.0 'o 4.$ s9e,i5y 'ha' 9a'ien's are 5ully ,a9able o5 1al+in0
1hile hi0her s,ores indi,a'e 'ha' 9a'ien's are se4erely i89aired.
Analysis
#es,ri9'i4e analysis 1as ,arried ou' 'o e?9lore 'he da'a. Par'i,i9an's 1ere ,lassi5ied as
1i'h and 1i'hou' se?ual dys5un,'ion based on 'he F.F" ,u'!o55 s,ore as 8en'ioned earlier.
3e used bo'h uni4aria'e and 8ul'i9le lo0is'i, re0ression analyses 'o e?a8ine 'he
asso,ia'ion be'1een de9enden' <se?ual dys5un,'ion= and inde9enden' 4ariables. 7he le4el
o5 si0ni5i,an,e 1as se' a' $C. 7he .P.. 4ersion 16 1as used 'o analy@e 'he da'a.
4thics
7he e'hi,s ,o88i''ee o5 .hahed >ni4ersi'y a99ro4ed 'he s'udy. 3e ob'ained 1ri''en
in5or8ed ,onsen' 5ro8 9ar'i,i9an's a5'er ,o89rehensi4e e?9lana'ion o5 9ro,edure
in4ol4ed.
;o 'o:
Results
'emographic and clinical characteristics o the study sample
"n all) 320 9a'ien's 1ere a99roa,hed and 226 9ar'i,i9an's ha4e a0reed 'o 9ar'i,i9a'e in 'he
s'udy) 0i4in0 a res9onse ra'e o5 1C. T4erall) 12$ 1o8en <$$.3C= 8e' 'he ,ri'eria 5or
se?ual dys5un,'ion. 7he 8ean a0e o5 9ar'i,i9an's 1as 3$. years <.#B 8.0=. 7he 8ean
disease dura'ion o5 9ar'i,i9an's 1as 1.8 <.#B 0.%= years) and had 'he 5ollo1in0
dia0nosis: 16% 9a'ien's <4.8C= had rela9sin0 re8i''in0 M. <&&M.=) 4 1o8en <1.8C=
had 9ri8ary 9ro0ressi4e M. <PPM.= and $3 9a'ien's <23.$C= had se,ondary 9ro0ressi4e
M. <.PM.=. FreGuen,y o5 se?ual dys5un,'ion 1as 4%C in &&M.) $C in .PM. and
$0C in PPM.. 7he de'ailed resul's are sho1n in 7able 1.
7able 1
Chara,'eris'i,s o5 'he s'udy sa89le and odds ra'io 5or se?ual dys5un,'ion <n B 226=
Risk actors or se&ual dysunction
7he asso,ia'ion o5 se?ual dys5un,'ion and inde9enden' 4ariables 1as 5irs' e?a8ined by
uni4aria'e lo0is'i, re0ression analysis. 7he resul's sho1ed 'ha' 'here 1ere si0ni5i,an'
asso,ia'ions be'1een se?ual dys5un,'ion and a0e <T& 5or 36N0 years B 2.18) C%$ C" B
1.2!3.2=) edu,a'ion <T&B 2.42) C%$ C" B 1.34!4.3=) e89loy8en' s'a'us <T& 5or
house1i5e B 2.68) C%$ C" B 1.28!$.$%=) dura'ion o5 8arria0e <T& 5or 21N40 years B 2.83)
C%$ C" B 1.3$!$.%2=) 'he disease dura'ion <T& 5or A% years B 3.2$) C%$ C" B 1.66!6.3%=)
'he disease ,ourse <T& 5or .PM. B 3.18) C%$ C" B 1.$%!6.83=) 2#.. <T& 5or $N8 B 2.41)
C%$ C" B 1.28!4.$3=) and 'he B#" <T&B 1.11) C%$ C" B 1.0!1.1$=. 7he resul's are
sho1n in 7able 1.
(ll si0ni5i,an' 5indin0s in uni4aria'e analysis 'hen 1ere en'ered in'o a 8ul'i9le lo0is'i,
re0ression 8odel. (s sho1n in 7able 2 'he resul's indi,a'ed 'ha' 'he disease dura'ion <T&
5or A% years 3.13) C%$ C" B 1.2%!.$) P B 0.01=) 'he disease ,ourse <T& 5or se,ondary
9ro0ressi4e M. B 3.%6) C%$ C" B 1.$$!10.10) P B 0.004= and 'he B#" s,ore <T&B 1.11)
C%$ C" B 1.0!1.16) P ] 0.001= 1ere si0ni5i,an' ,on'ribu'in0 5a,'ors 'o se?ual
dys5un,'ion in 'hese 9a'ien's.
7able 2
7he resul's ob'ained 5ro8 8ul'i9le lo0is'i, re0ression analysis indi,a'in0 ris+ 5a,'ors 5or
se?ual dys5un,'ion <n B 226=
Fur'her analyses o5 'he da'a 5or 'he subs,ales o5 Gues'ionnaire <desire) arousal)
lubri,a'ion) or0as8) sa'is5a,'ion) and 9ain= are sho1n in 7ables 3 and and4 4.
7able 3
#es,ri9'i4e s'a'is'i,s 5or se?ual dys5un,'ions 5or subs,ales o5 'he F.F" <n B 226=
7able 4
7he resul's ob'ained 5ro8 'he lo0is'i, re0ression analyses 5or se?ual dys5un,'ions 5or
subs,ales o5 'he F.F" <n B 226=f
;o 'o:
'iscussion
7he 5indin0s 5ro8 'his s'udy indi,a'ed 'ha' ,onsiderin0 'he ,u'!o55 9oin' o5 28 on 'he
F.F") 'he 9re4alen,e o5 se?ual dys5un,'ion a8on0 "ranian 5e8ale 1i'h M. 1as hi0h
<$$.3C=. 6o1e4er) one 8i0h' ar0ue 'ha' 8os' s'udies ,hose a ,u'!o55 9oin' o5 lo1er 'han
26.$$ 5or di55eren'ia'in0 1o8en 1i'h and 1i'hou' se?ual dys5un,'ion E22F. 7hen) our
5indin0s 1ould ha4e been de,rease sli0h'ly. 7he 5indin0s also sho1ed 'ha' 'here 1as no
si0ni5i,an' asso,ia'ion be'1een se?ual dys5un,'ion and a0e. "n 5a,') al'hou0h a0e 1as
si0ni5i,an' 5a,'or in uni4aria'e analysis <see 7able 1=) i's e55e,' 1as di8inished 1hen
9er5or8in0 8ul'i9le lo0is'i, re0ression analysis. 7his obser4a'ion 8i0h' be e?9lained by
'he 5a,' 'ha' our sa89le ,onsis'ed o5 1o8en 1ho 9erha9s 1ere less se?ually a,'i4e.
(no'her reason 5or su,h obser4a'ion 8i0h' be rela'ed 'o 'he s8all sa89le si@e o5 'he
s'udy. .'udyin0 3 M. 9a'ien's a si8ilar 5indin0 1as re9or'ed by Mhan e' al. 1here 'hey
ha4e 5ound no asso,ia'ion be'1een a0e and se?ual dys5un,'ion as 8easured by 'he .e?ual
FreGuen,y .,ale E23F.
7he resul's o5 'his s'udy sho1ed 'ha' dura'ion o5 'he disease 1as asso,ia'ed 1i'h se?ual
dys5un,'ion. 7his i89lies 'ha' 'he 8ore 'i8e 9asses) in,reased se?ual dys5un,'ion 1ill
o,,ur. ( s'udy sho1ed 'ha' 'he e?'en' and 'he nu8ber o5 se?ual dys5un,'ion sy89'o8s
in,reased si0ni5i,an'ly in M. 9a'ien's durin0 2!years 5ollo1!u9 E24F. .i8ilarly ano'her
s'udy re4ealed 'ha' dura'ion o5 'he disease in M. 9a'ien's 1ho su55ered 5ro8 se?ual
dys5un,'ion 1as lon0er 'han 'he dura'ion in M. 9a'ien's 1i'hou' .# E2$F. 7his 8i0h' be
e?9lained by se4eral reasons in,ludin0 'he 5a,' 'ha' M. ,ould ha4e a ne0a'i4e i89a,' on
rela'ionshi9 be'1een 9a'ien's and 'heir se?ual 9ar'ners E26F) and 'ha' 'he hi0h le4els o5
s'ress a8on0 9a'ien'sH 9ar'ners 8i0h' a55e,' 'heir e8o'ional and se?ual 5un,'ionin0 E2F.
7he resul's o5 'his s'udy ,on5ir8ed 'he 9re4ious re9or's 1here i' has been sho1n 'ha' .#
1as asso,ia'ed 1i'h 9ro0ressi4e 5or8s o5 M. E26)28F. "' see8s 'ha' 'here is a 4ery
s'rai0h'5or1ard rela'ionshi9 be'1een se?ual dys5un,'ion in 1o8en 1i'h M. and
9ro0ressi4e ,ourse o5 'he disease.
7his s'udy also sho1ed 'ha' de9ression 1as asso,ia'ed 1i'h se?ual dys5un,'ion in 'his
9o9ula'ion. #e9ression in M. is a 8ul'idi8ensional 9roble8 'ha' 4aries by disease
rela'ed i89air8en's) a,'i4i'y res'ri,'ions and un9redi,'able 9ro0nosis E2%)30F. (lso) in
9a'ien's 1i'h M. i' is si0ni5i,an'ly hi0her 'han heal'hy indi4iduals E31)32F and is
,onsidered as a ,o88on ,o!8orbidi'y a8on0 9a'ien's 1i'h 8ul'i9le s,lerosis E33)34F.
Consis'en' 1i'h our 5indin0s) o'her s'udies ha4e re9or'ed 'ha' 'here 1as si0ni5i,an'
,orrela'ion be'1een 9resen,e o5 se?ual dys5un,'ion and de9ression E%)28)3$F. "' has been
su00es'ed 'ha' de9ression 8ay be a 9ro8inen' 4ariable ,on'ribu'in0 'o 'he se?ual
di55i,ul'ies in M. 9a'ien's. "n 5a,' de9ressed 1o8en 8i0h' su55er 5ro8 se4eral sy89'o8s
in,ludin0 a55e,'i4e and so8a'i, sy89'o8s. 7hese sy89'o8s all ,on'ribu'e 'o 5e8ale
se?ual dys5un,'ion sin,e 'hey 8i0h' ,ause 8ood and desire disorders E36)3F. "n addi'ion)
1o8en 1i'h de9ression 8i0h' use 8edi,a'ion and 'he rela'ionshi9 be'1een
an'ide9ressan' 8edi,a'ions and se?ual dys5un,'ion are 1ell do,u8en'ed E38F. .'udies
ha4e sho1n 'ha' se?ual dys5un,'ion ,o88only o,,urs durin0 an'ide9ressan' 'rea'8en'
and ,onsidered as ,o88on ad4erse e55e,' o5 an'ide9ressan' 'rea'8en' E3%F.
=imitations
7his s'udy had so8e li8i'a'ions. "' 1as a ,ross!se,'ional s'udy. (lso 1e ob'ained our
sa89le 5ro8 an ou'9a'ien' ,lini,. 7hus) 'he resul's 5ro8 'his s'udy 8us' be in'er9re'ed
1i'h ,au'ion.
;o 'o:
Conclusion
7he 5indin0s indi,a'ed 'ha' se?ual dys5un,'ion 1as 5reGuen' in 1o8en 1i'h 8ul'i9le
s,lerosis. 7he 5indin0s also indi,a'ed 'ha' ,lini,al and 9sy,holo0i,al 5a,'ors 1ere 'he
8os' i89or'an' ,on'ribu'in0 4ariables 'o se?ual dys5un,'ion in 1o8en 1i'h 8ul'i9le
s,lerosis. 7he burden o5 se?ual dys5un,'ion in addi'ion 'o 'he disease burden su00es's 'he
need 5or e?'ra a''en'ion 'o 'his 9a'ien' 9o9ula'ion.
;o 'o:
Competing interests
7he au'hors de,lare 'ha' 'hey ha4e no ,o89e'in0 in'eres's.
;o 'o:
Authors) contributions
MM 1as 'he 8ain in4es'i0a'or and in4ol4ed in 'he s'udy desi0n) da'a ,olle,'ion and
1ri'in0 9ro,ess. .MM ,on'ribu'ed 'o 'he 1ri'in0 9ro,ess. M(. ,on'ribu'ed 'o 'he s'udy
desi0n and re,rui'8en' o5 9a'ien's. P& analy@ed 'he da'a and 1ro'e 'he 9a9er. (M
,ri'i,ally e4alua'ed 'he 9a9er) hel9ed in analysis) res9onded 'o 'he re4ie1ersH ,o88en's
and 9ro4ided 'he 5inal 8anus,ri9'. (ll au'hors read and a99ro4ed 'he 5inal 8anus,ri9'.
;o 'o:
!re-publication history
7he 9re!9ubli,a'ion his'ory 5or 'his 9a9er ,an be a,,essed here:
h''9://111.bio8ed,en'ral.,o8/141!23/13/83/9re9ub
;o 'o:
Acknowledgments
7he au'hors 0ra'e5ully a,+no1led0e 'he "ns'i'u'ional &e4ie1 Board o5 'he .hahed
>ni4ersi'y) 1hi,h a99ro4ed and su99or'ed 'his 9roIe,'. 7hey also 1ish 'o 'han+ 'he
9ar'i,i9an's 5or 'heir ,oo9era'ion.
;o 'o:
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3. .'or,h 2() &ober'i *3) &o'h #(. Fa,'or s'ru,'ure) ,on,urren' 4alidi'y) and
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38. Clay'on (6) Prad+o *F) Cro5' 6() Mon'ano CB) /eadbe''er &() Bolden!3a'son
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3%. ;re0orian &.) ;olden M() Bah,e () ;ood8an C) M1on0 3*) Mhan VM.
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1$8%. EPubMedF
Jurnal 3
Mul' .,ler "n'. 2013; 2013: 1024$4.
Published online 2013 (9ril 16. doi: 10.11$$/2013/1024$4
PMC"#: PMC36$4321
Morphostructural MR5 Abnormalities
Related to 8europsychiatric 'isorders
Associated to Multiple Sclerosis
.i8ona Bona4i'a)
1 ) 2 )f
;ioa,,hino 7edes,hi)
1 ) 2
and (n'onio ;allo
1 ) 2
(u'hor in5or8a'ion : (r'i,le no'es : Co9yri0h' and /i,ense in5or8a'ion :
;o 'o:
Abstract
Mul'i9le .,lerosis asso,ia'ed neuro9sy,hia'ri, disorders in,lude 8aIor de9ression <M#=)
obsessi4e!,o89ulsi4e disorder <TC#=) bi9olar a55e,'i4e disorder) eu9horia) 9seudobulbar
a55e,') 9sy,hosis) and 9ersonali'y ,han0e. Ma0ne'i, &esonan,e "8a0in0 <M&"= s'udies
5o,used 8ainly on iden'i5yin0 8or9hos'ru,'ural ,orrela'es o5 M#; only a 5e1 ane,do'al
,ases on TC# asso,ia'ed 'o M. <TC#!M.=) eu9horia) 9seudobulbar a55e,') 9sy,hosis)
9ersonali'y ,han0e) and one resear,h ar'i,le on M&" abnor8ali'ies in TC#!M. ha4e
been 9ublished. 7here5ore) in 'he 9resen' re4ie1 1e 1ill re9or' 8ainly on neuroi8a0in0
abnor8ali'ies 5ound in M. 9a'ien's 1i'h M# and TC#. (ll 'o0e'her) 'he s'udies on M#
asso,ia'ed 'o M. su00es' 'ha') in 'his disease) de9ression is lin+ed 'o a da8a0e in4ol4in0
8ainly 5ron'o'e89oral re0ions ei'her 1i'h dis,re'e lesions <1i'h 'hose 4isible in 71
1ei0h'ed i8a0es 9layin0 a 8ore si0ni5i,an' role= or sub'le nor8al a99earin0 1hi'e 8a''er
abnor8ali'ies. 6i99o,a89al a'ro9hy) as 1ell) see8s 'o be in4ol4ed in M. rela'ed
de9ression. "' is ,on,ei4able 'ha' 0rey 8a''er 9a'holo0y <i.e.) 0lobal and re0ional a'ro9hy)
,or'i,al lesions=) 1hi,h o,,urs early in 'he ,ourse o5 disease) 8ay in4ol4e se4eral areas
in,ludin0 'he dorsola'eral 9re5ron'al ,or'e?) 'he orbi'o5ron'al ,or'e?) and 'he an'erior
,in0ula'e ,or'e? 1hose disru9'ion is ,urren'ly 'hou0h' 'o e?9lain la'e!li5e de9ression.
Fur'her M&" s'udies are ne,essary 'o be''er elu,ida'e TC# 9a'ho0enesis in M..
;o 'o:
*% 5ntroduction
Neuro9sy,hia'ri, disorders asso,ia'ed 'o Mul'i9le .,lerosis <M.= 8ay be di4ided in'o
'1o ,a'e0ories: 8ood disorders <in,ludin0 beha4ioural dis'urban,es= E1F and ,o0ni'i4e
i89air8en'. 7he hi0h 9re9onderan,e o5 9sy,hia'ri, sy89'o8s in 9a'ien's 1i'h M. has
led 'o 'he su00es'ion 'ha' 'his disease should be rou'inely in,luded in 'he di55eren'ial
dia0nosis o5 9a'ien's bein0 seen 5or 9sy,hia'ri, ,o89lain's E2N4F. #ia@!Tla4arrie'a e' al.
E$F) by ad8inis'erin0 'he Neuro9sy,hia'ri, "n4en'ory E6F 'o 44 9a'ien's 1i'h M. 1ho
1ere no' under s'eroid 'rea'8en' or 1ere no' under rela9se) 5ound 'ha' %$C o5 'he 9a'ien's
1ere e?9erien,in0 neuro9sy,hia'ri, sy89'o8s; in 9ar'i,ular) dys9horia or de9ressi4e
sy89'o8s 1ere 8os' ,o88on <%C=) 5ollo1ed by a0i'a'ion <40C=) an?ie'y <3C=)
irri'abili'y <3$C=) a9a'hy <20C=) eu9horia <13C=) disinhibi'ion <13C=) hallu,ina'ions
<10C=) and delusions <C=.
"n 'his re4ie1 1e 1ill 5o,us on M. asso,ia'ed 8ood and beha4ioural disorders and) in
9ar'i,ular) on 'heir neuroi8a0in0 as9e,'s.
M. asso,ia'ed neuro9sy,hia'ri, disorders in,lude 8aIor de9ression <M#=) obsessi4e!
,o89ulsi4e disorder <TC#!M.=) bi9olar a55e,'i4e disorder) eu9horia) 9seudobulbar
a55e,') 9sy,hosis) and 9ersonali'y ,han0e.
.o 5ar) neuroi8a0in0 s'udies on M. 5o,used 8ainly on iden'i5yin0 8or9hos'ru,'ural
,han0es 'y9i,al o5 'he disease and on re,o0ni@in0 9redi,'ors o5 disabili'y and/or ,o0ni'i4e
i89air8en'. ( 8ore li8i'ed nu8ber o5 ar'i,les re9or' on neuroi8a0in0 o5 9sy,hia'ri,
as9e,' o5 M.) 1i'h 'he 8aIori'y o5 'he8 ,on,ernin0 'he 8or9hos'ru,'ural ,orrela'es o5
M# asso,ia'ed 'o M.. 7o da'e) M&" s'udies in,lude only a 5e1 ane,do'al ,ases on TC#!
M.) eu9horia) 9seudobulbar a55e,') 9sy,hosis) 9ersonali'y ,han0e) and one resear,h
ar'i,le on TC# in M. 9a'ien's.
"n 'he 9resen' re4ie1 1e 1ill re9or' 8ainly on neuroi8a0in0 abnor8ali'ies 5ound in M.
9a'ien's 1i'h M# and TC#.
;o 'o:
,% 'epressive 'isorders
7he 8os' ,o88on 9sy,hia'ri, syndro8e in M.) and also in 0eneral 9o9ula'ion) is M#)
1hi,h is de5ined by 'he 5our'h edi'ion o5 'he #ia0nos'i, and .'a'is'i,al Manual o5 'he
(8eri,an Psy,hia'ri, (sso,ia'ion as 5ollo1s.
Fi4e or 8ore o5 'he 5ollo1in0 sy89'o8s o4er a 8ini8u8 '1o 1ee+ 9eriod:
i. de9ressed 8ood 5or 8os' o5 'he day)
ii. 8ar+edly di8inished in'eres' or 9leasure in all a,'i4i'ies)
iii. si0ni5i,an' 1ei0h' loss) or 1ei0h' 0ain <$C o5 body 1ei0h' in a 8on'h=)
i4. inso8nia or hy9erso8nia nearly e4ery day)
4. 9sy,ho8o'or re'arda'ion or a0i'a'ion <obser4able by o'hers=)
4i. 5a'i0ue or loss o5 ener0y nearly e4ery day)
4ii. 5eelin0s o5 1or'hlessness) e?,essi4e ina99ro9ria'e 0uil')
4iii. di8inished abili'y 'o 'hin+ or ,on,en'ra'e)
i?. re,urren' 'hou0h's o5 dea'h.
( 9oin' 9re4alen,e o5 1$C 'o 30C and a li5e'i8e 9re4alen,e o5 40CN60C o5 M# ha4e
been re9or'ed in M. 9a'ien's; 'his ra'e o5 de9ression is 3 'o 10 'i8es 'ha' o5 'he 0eneral
9o9ula'ion EF. 7he 5a,'ors res9onsible 5or 8ood dis'urban,es in M. are no' 1ell
es'ablished: a 9sy,holo0i,al rea,'ion 'o a 9ro0ressi4ely disablin0 and un9redi,'able
disease 8ay be a rele4an' ,on'ribu'or bu' rea,'i4e 8e,hanis8s alone are 9robably no'
su55i,ien' 'o a,,oun' 5or 'he hi0h 9re4alen,e and 1ide s9e,'ru8 o5 de9ression. Curren'ly
'he 9hysio9a'holo0y o5 M.!rela'ed de9ression is 'hou0h' 'o be 8ul'i5a,'orial and
neuroin5la88a'ory) neuroendo,rine and neuro'ro9hi, 8e,hanis8s ha4e been ad4o,a'ed
E8F. 7he asso,ia'ion be'1een a55e,'i4e illness and M. is 1ell des,ribed and 'o ,lari5y
1he'her 8ood dysre0ula'ion 5ollo1s 5a8ilial 9a''erns o5 'rans8ission si8ilar 'o 'hose
5ound in 9a'ien's 1i'h 9ri8ary a55e,'i4e illness) *o55e e' al. E%F assessed 'he 9re4alen,e o5
9sy,hia'ri, dia0noses in 'he rela'i4es o5 9a'ien's 1i'h M.) usin0 'he 5a8ily his'ory
a99roa,h 'o dia0nosis E10F. 7hey 5ound 'ha' 'he 9re4alen,e o5 9sy,hia'ri, disorders)
9ar'i,ularly a55e,'i4e illness) in 'he 5irs' de0ree rela'i4es o5 9a'ien's 1i'h M. is ,onsis'en'
1i'h 'ha' re9or'ed 5or 'he 0eneral 9o9ula'ion su00es'in0 'ha' a55e,'i4e disorders in 'his
disease 8ay be an in'rinsi, 9ar' o5 'he neurolo0i,al disorder ra'her 'han an inde9enden'ly
a,Guired 9sy,hia'ri, disorder. #ri4en by 'hese ,onsidera'ions 'here ha4e been 8any
a''e89's 'o iden'i5y 'he ana'o8i,al ,orrela'es e?9lainin0 M# in M. 9a'ien's.
Neuroi8a0in0 s'udies in 9a'ien's 1i'h M. ha4e re4ealed asso,ia'ions be'1een brain
abnor8ali'ies and de9ression; ,o89u'ed assis'ed 'o8o0ra9hy s'udies re9or'ed 'ha'
9a'ien's 1i'h brain lesions 1ere 8ore de9ressed 'han 9a'ien's 1i'h only s9inal ,ord
in4ol4e8en' E11F. T'her s'udies in4es'i0a'ed 'he ,orrela'ion be'1een lesions lo,a'ion and
o,,urren,e o5 de9ression. PuIol e' al. E12F s'udied 4$ 9a'ien's by M&" and 'es'ed 'he
9resen,e o5 de9ression by 'he Be,+ #e9ression "n4en'ory <B#"=. (?ial s9in!e,ho
seGuen,es 1ere used 'o Guan'i5y lesions obser4ed in 'hree 8aIor ana'o8i, di4isions
<basal) 8edial) and la'eral= o5 'he 5ron'o'e89oral 1hi'e 8a''er <3M= in ea,h he8is9here.
7hese re0ions 1ere ,hosen be,ause 'hey in4ol4e di55eren' ,erebral ,onne,'ions bu'
in,lude 'he 8ain 5ron'o'e89oral asso,ia'ions bundles <,onsidered 'o be in4ol4ed in M#
9a'ho0enesis=: 'he un,ina'e 5as,i,ulus <basal=) 'he ,in0ulu8 <8edial=) and 'he ar,ua'e
5as,i,ulus <la'eral=. 7he au'hors 5ound 'ha' 'he B#" s,ores si0ni5i,an'ly ,orrela'ed 1i'h
lesion load <//= o5 'he le5' ar,ua'e 5as,i,ulus re0ion <1hi,h ,on'ains neo,or'i,al!
neo,or'i,al ,onne,'ions= o5 'he le5' R4erbalS he8is9here; in 9ar'i,ular lesions in 'his area
a,,oun'ed 5or 1C o5 de9ression s,ore 4arian,e. No si0ni5i,an' ,orrela'ion 1as 5ound
be'1een lesions in 'he re0ions o5 'he ri0h' he8is9here <do8inan' in re0ula'in0 e8o'ional
beha4iour= and de9ression) su00es'in0 'ha' 8isre0ula'ion o5 e8o'ional beha4iour and
de9ressed 8ood are '1o di55eren' 9heno8ena 9rodu,ed by di55eren' 8e,hanis8s.
.ubseGuen'ly) Feins'ein e' al. E13F e4alua'ed M. subIe,'s 1i'h and 1i'hou' de9ression by
M&"; au'o8a'i, 'issue se08en'a'ion <0rey 8a''er <;M=) 3M) and ,erebros9inal 5luid
<C.F== and re0ional brain 8as+in0 1ere a99lied 'o M&" da'a; re0ional and 'o'al // 1ere
also ,al,ula'ed. 7hey 5ound 'ha' de9ressed M. 9a'ien's had 8ore hy9erin'ense lesions in
'he le5' in5erior 8edial 5ron'al re0ions and 0rea'er a'ro9hy o5 'he le5' an'erior 'e89oral
re0ions; 'hey 9os'ula'ed 'ha' a ,o8bina'ion o5 in5la88a'ion) de8yelina'ion) and a'ro9hy
1i'hin 8edial in5erior 5ron'al areas 1ould dis,onne,' neural ,onne,'i4i'y 1i'h an
asso,ia'ed 9er'urba'ion in se4eral neuro'rans8i''ers and 8odula'ors +no1n 'o be in4ol4ed
in 5ron'al sub,or'i,al ,ir,ui's) 1i'h 'he 8onoa8iner0i, ones bein0 'he 8os' in'i8a'ely
'ied 'o disorders o5 8ood. (l'era'ions o5 a55eren' and e55eren' ,onne,'ions 5ro8 5ron'al
sub,or'i,al areas 'o 'e89oral lobe li8bi, areas 8ay 9lay a si0ni5i,an' role in 8ood
re0ula'ion as 1ell.
( Guali'a'i4e R4isualS assess8en' o5 71) 72 //) and brain a'ro9hy 9er5or8ed by Ba+shi
e' al. E14F sho1ed 'ha' 'he only M&" abnor8ali'ies 'ha' ,ould si0ni5i,an'ly 9redi,' 'he
9resen,e o5 de9ression) be5ore and a5'er adIus'in0 5or 2#..) 1ere 71 // in su9erior
5ron'al) su9erior 9arie'al) and 'e89oral re0ions) 1hile 'he se4eri'y o5 de9ression 1as
9redi,'ed by 71 lesions in su9erior 5ron'al) su9erior 9arie'al and 'e89oral re0ions)
enlar0e8en' o5 la'eral and 'hird 4en'ri,ular) and 5ron'al a'ro9hy. 7he au'hors s9e,ula'ed
'ha' 3M lesions in M. 9a'ien's) es9e,ially 'hose in 5ron'al and 9arie'al areas) lead 'o
de9ression by dis,onne,'ion o5 brain ,or'i,al areas 'ha' re0ula'e 'he 8ood; in 9ar'i,ular)
5ron'al 3M disease in M. ,ould ha4e e55e,'s on sero'oniner0i, 9a'h1ays in 5ron'al!
li8bi, ,ir,ui's. Moreo4er) sin,e 71 hy9oin'ensi'ies a99ear 'o re9resen' 8ore s9e,i5i,
,hroni, des'ru,'i4e irre4ersible 'issue ,han0es su,h as hy9o,ellulari'y) ,o89le'e
de8yelina'ion) and a?onal loss) 'he asso,ia'ion be'1een de9ression and 71 lesions)
indi,a'es 'ha' ,hroni, irre4ersible da8a0e 'o ,ri'i,al 9a'h1ays is 8ore li+ely 'o ,ause
8ood dys5un,'ion. Tn 'he o'her hand) 'hese 9a'h1ays ,an 5un,'ion su55i,ien'ly 1ell in 'he
9resen,e o5 less se4ere insul's <ede8a) 9ar'ial de8yelina'ion) and in5la88a'ion= as
re5le,'ed by 72 //. Fur'her8ore) brain a'ro9hy 8easures asso,ia'ed 'o de9ression
su00es' 'ha' 9a'ien's 1i'h de9ression ha4e 8ore se4ere neuro9a'holo0i, subse's o5 M.
1i'h a 'enden,y 'o1ards 8ore 'issue des'ru,'ion and 'hus 8ay be 8ore sus,e9'ible 'o
dys5un,'ion o5 8ood re0ula'in0 9a'h1ays.
(n M&" s'udy o5 %$ ,onse,u'i4e M. 9a'ien's E1$F) in 1hi,h 1%C o5 'he 9a'ien's 8e' 'he
,ri'eria 5or M#) re9or'ed 'ha' 9resen,e o5 M# and se4eri'y o5 de9ression 1ere ,orrela'ed
1i'h ri0h' 5ron'al // and 1i'h ri0h' 'e89oral brain a'ro9hy; 5ur'her8ore) 71 lesions in 'he
su9erior 9arie'al and su9erior 5ron'al re0ions 9redi,'ed de9ression in M. 9a'ien's. T5
no'e) 'hese %$ M. 9a'ien's 1ere also 'es'ed 5or an?ie'y by 'he 6a8il'on (n?ie'y &a'in0
.,ale <6(&.= and 'he 6(&. s,ores did no' ,orrela'e si0ni5i,an'ly 1i'h any o5 'he M&"
8easures o5 re0ional and 'o'al // and brain a'ro9hy. 7he sa8e au'hors 9er5or8ed a '1o!
year 5ollo1!u9 s'udy E16F 'o de'er8ine 1he'her ,han0es in 'o'al or re0ional // and brain
a'ro9hy in s9e,i5i, re0ions o5 'he brain 8ay ,on'ribu'e 'o 'he de4elo98en' o5 de9ression
in 9a'ien's 1i'h M.. Brain a'ro9hy e4olu'ion 1as si0ni5i,an'ly 8ore ,ons9i,uous in 'he
le5' 5ron'al lobe o5 de9ressed 9a'ien's as ,o89ared 'o nonde9ressed 9a'ien's. 7he
,orrela'ion analysis) ,onsiderin0 'he 2!year ,han0es o5 M&" Guan'i'a'i4e 8easures o5
re0ional and 'o'al // and brain a'ro9hy and 'he 2!year ,han0es o5 'he 6a8il'on
#e9ression &a'in0 .,ale s,ore) sho1ed a si0ni5i,an' ,orrela'ion be'1een 'he la''er and
ri0h' 'e89oral brain a'ro9hy; 8oreo4er) ,han0es in ri0h' 'e89oral brain a'ro9hy 1ere
si0ni5i,an'ly and inde9enden'ly rela'ed 'o 'he se4eri'y o5 de9ressi4e sy89'o8s. 7he
au'hors su00es'ed 'ha' in M. 'he 'e89oral lobes in4ol4e8en' <and 'he subseGuen'
da8a0e in 'he 8ain 9roIe,'ion areas 'o 'he li8bi, sys'e8= 8ay 9lay a role in 'he
ae'iolo0y o5 de9ressi4e 8ood disorders.
More re,en'ly) a di55usion 'ensor i8a0in0 <#7"= s'udy E1F in4es'i0a'ed nor8al a99earin0
brain 'issue in 'he a''e89' o5 sheddin0 5ur'her li0h' on 'he 9a'ho0enesis o5 de9ression in
9a'ien's 1i'h M.. 71 and P#/72 // 1ere e4alua'ed; 'issue se08en'a'ion <nor8al
a99earin0 1hi'e <N(3M= and 0rey 8a''er <N(;M=) C.F=) re0ional a'ro9hy) and #7"
analysis 1ere 9er5or8ed as 1ell. #e9ressed 9a'ien's had a s8aller N(3M 4olu8e in 'he
le5' su9erior 5ron'al re0ion and a 0rea'er 71 // in 'he ri0h' 8edial in5erior 5ron'al re0ion.
.i0ni5i,an'ly hi0her 8ean di55usi4i'y 1as 5ound in 'he de9ressed 0rou9 in 'he N(;M o5
'he le5' an'erior 'e89oral lobe re0ion. &edu,ed 5ra,'ional aniso'ro9y <F(= 1as 9resen' in
'he N(3M o5 'he le5' an'erior 'e89oral lobe in 'he de9ressed 0rou9. "n addi'ion) hi0her
8ean di55usi4i'y 1as 5ound in hy9erin'ense lesions in 'he ri0h' in5erior 5ron'al re0ion o5
'he de9ressed 0rou9. 7hese 5indin0s 9ro4ide i89or'an' da'a on s'ru,'ural brain ,han0es
beyond 'ha' ,a9'ured by lesion and a'ro9hy 8easure8en's and su00es' 'ha' 1hen
in5la88a'ion and de8yelina'ion disru9' ,ellular or0ani@a'ion and 'he lineari'y o5 5ibres
9a'h1ays in s9e,i5i, brain re0ions) e4en in 'he absen,e o5 dis,ernable lesions) ,lini,al
de9ression 8ay resul'. 7here5ore) i' 1as ,on,luded 'ha' 8ore des'ru,'i4e as9e,'s o5 brain
,han0e) 'ha' is) 'he bla,+ holes o5 71!1ei0h'ed i8a0es and redu,'ion in N(3M 4olu8e
are s'ri,'ly rela'ed 'o 8ood disorders in M. 9a'ien's.
.in,e a s8aller 4olu8e o5 'he hi99o,a89us 1as 5ound in 9sy,hia'ri, 9a'ien's 1i'h M#)
;old e' al. E18F in4es'i0a'ed 9a'ien's 1i'h M. and M# 'o e?9lore 1he'her subre0ional
4olu8es o5 'he hi99o,a89us 8ay be asso,ia'ed 1i'h 'he hi0h 5reGuen,y o5 de9ressi4e
sy89'o8s in M..
"n 'his so9his'i,a'ed s'udy 'he au'hors 9er5or8ed hi99o,a89al s'ru,'ural se08en'a'ion
iden'i5yin0 5our re0ions: ,ornu a88onis 1 <C(1=) C(2!C(3 and den'a'e 0yrus
<C(23#;=) subi,ulu8) and en'orhinal ,or'e?; 0lobal a'ro9hy and lesion Guan'i5i,a'ion
1ere e4alua'ed as 1ell. "n M. 9a'ien's 1i'h de9ressi4e sy89'o8s s8aller C(23#;
4olu8es 1ere 5ound <as a dis'in,'i4e 9a''ern o5 re0ional hi99o,a89al a'ro9hy=; 'he
,orrela'ion analysis re4ealed an in4erse ,orrela'ion be'1een B#" s,ores and C(23#;
4olu8es. 7he au'hors ,on,luded 'ha' so8e 5or8s o5 de9ression in M. 8ay be ,aused by
si8ilar 8e,hanis8s hy9o'hesi@ed 5or M# in 9sy,hia'ri, 9a'ien's. Moreo4er) sin,e
re,en'ly i' has been hy9o'hesi@ed a neuroendo,rine!li8bi, ae'iolo0y o5 de9ression and a'
'he sa8e 'i8e 'here is a,,u8ula'in0 e4iden,e 'ha' 'he hy9o'hala8i,!9i'ui'ary!adrenal a?is
<6P(= a,'i4i'y is in,reased in M. 9a'ien's E1%F) ;old e' al. E18F 'es'ed 1he'her s9e,i5i,
subre0ional 4olu8es 8ay be lin+ed 'o al'era'ions in diurnal ,or'isol se,re'ion. 7hey 5ound
'ha' M. de9ressed 9a'ien's) as ,o89ared 'o no' de9ressed 9a'ien's) had ,or'isol
hy9erse,re'ion <ele4a'ed e4enin0 le4els and un,han0ed ,or'isol le4els in 'he 8ornin0=
indi,a'in0 'ha' diurnal ,or'isol 5la''enin0) due 'o ele4a'ed e4enin0 ,or'isol <i.e.) 5ailure 'o
de,rease ,or'isol res9onses 'hrou0hou' 'he day=) 1as asso,ia'ed 1i'h de9ression in M.
and no' 1i'h M.. Fur'her8ore) 'here 1as an in4erse ,orrela'ion be'1een C(23#;
4olu8es) B#") s,ores and ,or'isol le4els. 7he au'hors su00es'ed 'ha' e4en sub'le
hy9era,'i4i'y o5 'he 6P( a?is 8ay 9rodu,e s8aller 4olu8es in 'he C(23#; re0ion and
'hereby lead 'o de9ressi4e sy89'o8s in M.. 7he sa8e au'hors) by usin0 sur5a,e 8a99in0
'e,hniGues) 9er5or8ed 4olu8e'ri, and sha9e analyses o5 'he hi99o,a89us 'o ,hara,'eri@e
neuroana'o8i,al ,orrela'es o5 de9ression in M. E20F. 71o 0rou9s o5 M. 9a'ien's)
res9e,'i4ely 1i'h lo1 and hi0h de9ression s,ores 1ere s'udied. &i0h' hi99o,a89al
4olu8es 1ere s8aller in 'he hi0h de9ression 4ersus 'he lo1 de9ression 0rou9) bu' 'here
1ere no si0ni5i,an' di55eren,es in le5' hi99o,a89al 4olu8es. .in,e in 'his s'udy only
5e8ale 9a'ien's 1ere in,luded) and one re,en' s'udy on 5a8ilial de9ression 1i'h a sa89le
in,ludin0 only 5e8ale 9a'ien's sho1ed redu,ed 4olu8es o5 'he ri0h' bu' no' 'he le5'
hi99o,a89us E21F) 'he au'hors in'er9re'ed 'heir 5indin0 as an indi,a'ion 5or se?!s9e,i5i,
asso,ia'ions be'1een la'erali@ed hi99o,a89al a'ro9hy and de9ression.
"' should be no'i,ed 'ha' all 'he abo4e!8en'ioned s'udies are no' 5ree 5ro8 li8i'a'ions: 'he
8aIori'y o5 'he8 did no' 'a+e in'o a,,oun' 9ossible ,on5ounders li+e 5a'i0ue) ,o0ni'i4e
i89air8en') and nu8ber o5 9re4ious s'eroids ,y,les; only so8e o5 'he8 in,luded a
heal'hy ,on'rol 0rou9) none'heless an a99ro9ria'e 9ro'o,ol desi0n in,ludin0 also
9sy,hia'ri, de9ressed 9a'ien's 1as ne4er done. Fur'her8ore) in 'hese s'udies de9ression
1as e4alua'ed by usin0 de9ression s,ales 8ainly 4alida'ed 5or 9sy,hia'ri, 9a'ien's and
no' 5or M. 9a'ien's in 1ho8 9hysi,al sy89'o8s 8ay be 9ossible ,on5ounders 5or
de9ression assess8en'.
(ll 'o0e'her 'hese s'udies su00es' 'ha' de9ression in M. is lin+ed 'o a da8a0e in4ol4in0
8ainly 5ron'o'e89oral re0ions ei'her 1i'h dis,re'e lesions <1i'h 'hose 4isible in 71
1ei0h'ed i8a0es 9layin0 a 8ore si0ni5i,an' role= or sub'le N(3M abnor8ali'ies.
6i99o,a89al a'ro9hy) as 1ell) see8s 'o be in4ol4ed in M. rela'ed de9ression.
7he 5ron'al lobe) and in 9ar'i,ular 'he 9re5ron'al ,or'e?) is in4ol4ed in in5or8a'ion
9ro,essin0. 7he 9re5ron'al ,or'e? role in,ludes 9lannin0) or0ani@a'ion) inhibi'ion)
e89a'hy) and 8o'i4a'ion 'ha' are de9enden' on 'hree dis'in,' ,or'i,al ne'1or+s: <i= 'he
dorsola'eral 9re5ron'al ,or'e?) <ii= 'he orbi'o5ron'al ,or'e?) and <iii= 'he an'erior ,in0ula'e
,or'e? E22) 23F. (?ons 9roIe,' 5ro8 'hese ,or'i,al areas) 'hrou0h 'he 3M) 'o sub,or'i,al
s'ru,'ures) and M. 9laGues) in4ol4in0 8ainly 3M <1here 'he 5ibre 'ra,'s 'ra4el
e?'re8ely ,lose=) 8ay disru9' 'hese ,ir,ui's i89a,'in0 dee9ly on 'heir 5un,'ion. 7he
dorsola'eral 9re5ron'al ,or'e? is in4ol4ed in e?e,u'i4e 5un,'ionin0 <i.e.) 9lannin0)
or0ani@a'ion) and a''en'ion= and i's da8a0e is res9onsible 5or 9erse4era'ion) di55i,ul'y in
shi5'in0 and s,reenin0 ou' en4iron8en'al dis'ra,'ions) i89air8en's in ,ons'ru,'ional
s+ills) and seGuen'ial 8o'or 'as+s. 7he orbi'o5ron'al ,or'e? ,on'rols so,ially a99ro9ria'e
beha4iour and e89a'hy) 'hus M. lesions 8ay resul' in i89ulsi4i'y) labili'y) 9ersonali'y
,han0es) and la,+ o5 hu8anis'i, sensi'i4i'y. 7he an'erior ,in0ula'e ,or'e? is 'hou0h' 'o
ha4e a' leas' '1o 5ur'her subdi4isions: 'he a55e,' and 'he ,o0ni'ion ones E24F. 7he a55e,'
9or'ion has ,onne,'ions 1i'h 'he li8bi, and 9arali8bi, re0ions) in,ludin0 'he
orbi'o5ron'al ,or'e?. 7he ,o0ni'ion subdi4ision ,onne,'s 1i'h 'he 9arie'al ,or'e?) 'he
s9inal ,ord) and 'he dorsola'eral 9re5ron'al ,or'e?. 7hese ,onne,'ions hi0hli0h' 'he
lin+a0e and in'erde9enden,e o5 'he 5ron'al ,ir,ui's. #isru9'ion o5 'he a5ore8en'ioned
brain ,ir,ui'ry is 'hou0h' 'o e?9lain la'e!li5e de9ression. "ndeed) a,,ordin0 'o 'his
hy9o'hesis) 7aylor e' al. E2$F by usin0 s'a'is'i,al 9ara8e'ri, 8a99in0 iden'i5ied 5ron'al
3M lesions in elderly de9ressed 9a'ien's and 5ound an asso,ia'ion be'1een lesions o5
3M 'ra,'s e?'endin0 5ro8 in5erior 5ron'al re0ions 'o1ard 'he basal 0an0lia and
de9ression. (le?o9oulos and ,oau'hors E26) 2F ha4e de5ined 'he Rde9ression!e?e,u'i4e
dys5un,'ion syndro8eS in 'he elderly) 1hi,h is 'hou0h' 'o be a dis'in,' de9ressi4e
disorder 8ar+ed by e?e,u'i4e dys5un,'ion as a resul' o5 lesions in 'he basal 0an0lia and
le5' 5ron'al re0ions.
7hus) i' ,an be hy9o'hesi@ed 'ha' M. 9a'ien's) 0enerally in youn0 adul' a0e) by ha4in0
3M 9laGues disru9'in0 'hese ,or'i,al ne'1or+s) are a' hi0her ris+ o5 de4elo9in0
de9ression 'han heal'hy 9eers.
Fur'her8ore) ne1 M&" a,Guisi'ion and i8a0e analysis 'e,hniGues) ,urren'ly bein0 used
5or resear,h 9ur9oses) su,h as #7") 'ra,'!based s9a'ial s'a'is'i,s <7B..=) 8a0ne'i@a'ion
'rans5er i8a0in0) #ouble "n4ersion &e,o4ery seGuen,es) 4o?el based <DBM= and sur5a,e
based 8or9ho8e'ry) lesion 9robabili'y 8a9s) ."2N(K) and res'in0 s'a'e 5un,'ional M&")
by allo1in0 a 8ore e?'ensi4e s'udy o5 bo'h 3M and ;M) ou'side 4isible M. 9laGues)
1ill 9robably hel9 in be''er unders'andin0 'he s9e,i5i, role o5 ;M and 3M in 'he
9a'ho0enesis o5 a55e,'i4e disorders asso,ia'ed 'o M..
"n 9ar'i,ular) sur5a,e based 8or9ho8e'ry 8ay be sui'able 5or 8a99in0 re0ional ,or'i,al
'hi,+ness in 'he brain ne'1or+s 9resu8ably in4ol4ed in M. rela'ed de9ression <see
Fi0ure 1) 9ersonal da'a=.
Fi0ure 1
/e5' he8is9here) la'eral sur5a,e. Cor'i,al 'hi,+ness 0rou9 analysis be'1een 9a'ien's 1i'h
M. rela'ed de9ression <M.!de9= and no' de9ressed M. 9a'ien's. (reas sho1in0 a
si0ni5i,an' ,or'i,al 'hinnin0 in 9a'ien's 1i'h M.!de9 <P ] 0.01= are ,oloured %%%
;o 'o:
-% "bsessive-Compulsive 'isorder #"C'$
7he li5e'i8e 9re4alen,e o5 TC# in M. is 8.6C ,o89ared 1i'h 2.$C in 'he 0eneral
9o9ula'ion E28F. "n 9ri8ary TC#) neuroi8a0in0 s'udies ha4e re4ealed s'ru,'ural and/or
5un,'ional abnor8ali'ies in s9e,i5i, brain s'ru,'ures) 9ar'i,ularly in 'he 5ron'o!s'ria'o!
'hala8i, ,ir,ui'ry E2%N31F 1hi,h 9oin's 'o an or0ani, ae'iolo0y o5 'his 9sy,hia'ri,
disease.
"n an M. 9a'ien') TC# de4elo9ed a5'er bein0 dia0nosed 1i'h M. ,on,urren'ly 1i'h 'he
a99earan,e o5 a ri0h' 9arie'al 3M 9laGue E32F; 'his sin0le ,ase raised 'he 9ossibili'y 'ha'
9arie'al lobe 3M 8i,ros'ru,'ure abnor8ali'ies 9lay a role in 8edia'in0 obsessions and
,o89ulsions 'hrou0h disru9'ions o5 'he 5un,'ional ,onne,'i4i'y be'1een ,or'i,al!,or'i,al
and/or ,or'i,al!sub,or'i,al brain re0ions i89li,a'ed in 'he 9a'ho9hysiolo0y o5 TC#.
&e,en'ly) 7inelli e' al. E33F e4alua'ed by M&" 'he rela'ionshi9 be'1een ;M and 3M
'issue da8a0e and TC# in 9a'ien's 1i'h M.. 7he au'hors s'udied 16 M. 9a'ien's 1i'h
and 1$ 1i'hou' TC#. "8a0e analysis in,luded //) DBM) F( ,al,ula'ion) and 7B... 7he
only si0ni5i,an' di55eren,es 1ere 5ound in 'he DBM analysis 'ha' re4ealed a se' o5
,lus'ers o5 redu,ed ;M 4olu8e in 9a'ien's 1i'h TC# in 'he ri0h' in5erior 5ron'al 0yrus)
in5erior 'e89oral 0yrus) and 8iddle 'e89oral 0yrus. 7he absen,e o5 any si0ni5i,an'
di55eren,e in 7B.. analysis in 'he '1o 0rou9s see8s 'o be in ,on'ras' 1i'h 'he resul's o5
re,en' #7" s'udies in 9ri8ary TC#) 1hi,h ha4e re9or'ed abnor8ali'ies in 'he ,or9us
,allosu8 and sub,or'i,al 5ron'al 3M asso,ia'ed 1i'h ei'her in,reased E34F or de,reased
E3$F s'ru,'ural ,onne,'i4i'y.
Probably) di55eren,es in 9a'ien's\ ,hara,'eris'i,s and/or in 8e'hods o5 M&" a,Guisi'ion
and da'a analysis ,ould a,,oun' 5or 'his dis,re9an,y 'hus lea4in0 s9a,e 'o 5ur'her s'udies
'o be''er elu,ida'e TC# 9a'ho0enesis in M..
"n ,on,lusion) des9i'e 'he 0rea' ad4an,e8en's a,hie4ed so 5ar) 1e an'i,i9a'e 'ha' 'he
a99li,a'ion o5 8odern ad4an,ed M&" 'e,hnolo0ies and be''er de5ini'ion o5 9a'ien's\
5ea'ures 1ill 9ro89' us 'o 0e' si0ni5i,an'ly ,loser 'o a 8ore in'i8a'e +no1led0e o5 'he
9hysio9a'holo0y and 5un,'ional basis o5 neuro9sy,hia'ri, disorders in M..
;o 'o:
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o'her an?ie'y disorders. Archi&es of 'eneral Psychiatry. 2010;6<=:01N11. EPubMedF
32. #ou@enis () Mi,halo9oulou P;) Dou84oura+is C) 7y9aldou M) Mi,ho9oulos ")
/y+ouras /. Tbsessi4e!,o89ulsi4e disorder asso,ia'ed 1i'h 9arie'al 1hi'e 8a''er
8ul'i9le s,lerosis 9laGues. *orld %ournal of Bioloical Psychiatry. 200%;10<4=:%$6N%60.
EPubMedF
33. 7inelli 2) Fran,ia () Wuar'u,,io 2M) e' al. .'ru,'ural brain M& i8a0in0 ,han0es
asso,ia'ed 1i'h obsessi4e!,o89ulsi4e disorder in 9a'ien's 1i'h 8ul'i9le s,lerosis.
American %ournal of Neuroradioloy. 2013;34<2=:30$N30%. EPubMedF
34. /i F) 6uan0 K) -an0 -) e' al. Mi,ros'ru,'ural brain abnor8ali'ies in 9a'ien's 1i'h
obsessi4e!,o89ulsi4e disorder: di55usion!'ensor M& i8a0in0 s'udy a' 3.0 7. (adioloy.
2011;260<1=:216N223. EPubMedF
3$. Th *.) *an0 *6) *un0 36) e' al. &edu,ed 5ron'o!,allosal 5iber in'e0ri'y in
un8edi,a'ed 9a'ien's 1i'h TC#: a di55usion 'ra,'o0ra9hy s'udy. "uman Brain Mappin.
2012;33<10=:2441N24$2. EPubMedF
Jurnal 4
BMC Publi, 6eal'h. 2013; 13: 224.
Published online 2013 Mar,h 1$. doi: 10.1186/141!24$8!13!224
PMC"#: PMC360611%
9ork capacity and health-related Auality
o lie among individuals with multiple
sclerosis reduced by atigue: a cross-
sectional study
;ull4i Flensner)
1)2
(nne!Marie /and'blo8)
3
Tlle .oderha8n)
2)4
and (nna!Chris'ina 2+
1
(u'hor in5or8a'ion : (r'i,le no'es : Co9yri0h' and /i,ense in5or8a'ion :
;o 'o:
Abstract
Background
(8on0 indi4iduals dia0nosed 1i'h 'he ,hroni, neurolo0i, disease) 8ul'i9le s,lerosis
<M.=) a 8aIori'y su55ers 5ro8 5a'i0ue) 1hi,h s'ron0ly in5luen,es 'heir e4ery!day!li5e. 7he
ai8 o5 'his s'udy 1as 'o in4es'i0a'e 1or+ ,a9a,i'y and heal'h!rela'ed Guali'y o5 li5e
<6&Wo/= in a 0rou9 o5 M. 9a'ien's and also 'o in4es'i0a'e i5 1or+ ,a9a,i'y and 6&Wo/
,ould be 9redi,'ed by ba,+0round 5a,'ors) 5a'i0ue) hea' sensi'i4i'y) ,o0ni'i4e dys5un,'ion)
e8o'ional dis'ress or de0ree o5 disabili'y.
Methods
( des,ri9'i4e) ,ross!se,'ional) desi0ned sur4ey 1as under'a+en ( Gues'ionnaire 1as sen'
'o 323 indi4iduals dia0nosed 1i'h M.) a0ed be'1een 20 and 6$ years) 1i'h 9hysi,al
disabili'y on 'he e?9anded disabili'y s'a'us s,ore <2#..= in 'he in'er4al 0 A 2#.. U 6.$)
li4in0 in ps'er0o'land ,oun'y in eas'ern .1eden. Wues'ions on ba,+0round 5a,'ors)
o,,u9a'ion and 1or+) 'o0e'her 1i'h 'he heal'h!rela'ed Guali'y o5 li5e shor' 5or8
ins'ru8en' <.F!36=) 'he 5a'i0ue se4eri'y s,ale <F..=) 'he 9er,ei4ed de5i,i' Gues'ionnaire
<P#W= and 'he hos9i'al an?ie'y de9ression s,ale <6(#= 1ere 9osed. (sso,ia'ions
be'1een 4ariables 1ere analy@ed usin0 PearsonHs and .9ear8anHs ,orrela'ions.
#i55eren,es be'1een 0rou9s 1ere 'es'ed usin0 'he Chi!sGuare 'es') 'he Mann 3hi'ney +!
'es') and 'he .'uden'Hs t!'es'. Predi,'i4e 5a,'ors 1ere analy@ed usin0 8ul'i9le linear and
8ul'i9le lo0is'i, re0ression analysis.
Results
T5 'hose 1ho ,o89le'ed 'he Gues'ionnaire <n B 2$) %.6C=) $%.8C 1ere 1or+in0. 3or+
,a9a,i'y 1as 5ound si0ni5i,an'ly 8ore a8on0 8en <9 ] 0.00$=) 'hose 1i'h a hi0her le4el
o5 edu,a'ion <9 ] 0.001=) 'hose re9or'in0 less 5a'i0ue <9 ] 0.001=) and 'hose ha4in0 no hea'
sensi'i4i'y <9 B 0.004=. For 1or+ ,a9a,i'y) si0ni5i,an' 9redi,'ors 1ere lo1 9hysi,al
disabili'y <2#..=) lo1 5a'i0ue) hi0her le4el o5 edu,a'ion) 8ale se? and lo1er a0e. 7hose
1i'h 1or+ ,a9a,i'y sho1ed si0ni5i,an'ly hi0her 6&Wo/ 'han 'hose 1ho had no 1or+
,a9a,i'y <9 ] 0.001=. /e4els o5 5a'i0ue) ,o0ni'ion and e8o'ional dis'ress 1ere 5ound 'o be
8aIor ,on'ribu'in0 5a,'ors 5or 6&Wo/.
Conclusions
3or+ ,a9a,i'y and 6&Wo/ a8on0 indi4iduals dia0nosed 1i'h M. are hi0hly in5luen,ed
by 5a'i0ue 1hi,h ,an be ,onsidered as a +ey sy89'o8. 3or+ ,a9a,i'y 1as in5luen,ed by
hea'!sensi'i4i'y) ,o0ni'i4e di55i,ul'ies and e8o'ional dis'ress and si0ni5i,an' 9redi,'i4e
5a,'ors besides 5a'i0ue) 1ere 9hysi,al disabili'y <2#..=) a0e) se?) and le4el o5 edu,a'ion.
&e8ainin0 a' 1or+ also 0i4es a be''er 6&Wo/.
Keywords: Co0ni'ion) 2du,a'ion) 28o'ional dis'ress) 6ea' sensi'i4i'y) &e0ression
analysis
;o 'o:
Background
(8on0 9eo9le 4isi'in0 0eneral 9ra,'i'ioners) 5a'i0ue is 'he 8aIor reason 5or 'he 4isi' in
5i4e 'o se4en 9er,en' E1F) and a8on0 9eo9le in 'he 1or+in0 9o9ula'ion) 21 ! 23C ha4e
been 5ound 'o su55er 5ro8 5a'i0ue E2)3F. 7here is no sin0le e?9lana'ion 5or 1ha' ,auses
5a'i0ue) bu' i' o5'en a,,o89anies ,hroni, diseases E4!6F.
(8on0 indi4iduals 1i'h 'he ,hroni, neurolo0i, disease) 8ul'i9le s,lerosis <M.=) 'he
8aIori'y) 60!80C) re9or' 'ha' 'hey su55er 5ro8 5a'i0ue E3)F. (s 8any as one 'hird o5 M.!
9a'ien's no'ed 5a'i0ue as 'heir 4ery 5irs' sy89'o8 and 'hey no'ed i' be5ore o'her
neurolo0i,al si0ns o5 'he disease be,a8e a99aren' E8F. 7he e?9erien,e o5 M.!rela'ed
5a'i0ue is des,ribed as Gui'e dis'in0uished 5ro8 any 9rior e?9erien,es o5 5eelin0 'ired E%F.
Fa'i0ue rela'ed 'o M. is s'ron0ly in5luen,in0 'he indi4idualsH daily li4es E3)$)10F) and
redu,es 'heir Guali'y o5 li5e E11)12F.
Tnse' o5 M. o5'en ha99ens in early adul'hood) 0C in 20N40 years o5 a0e E13F and li5e
e?9e,'an,y is lon0) abou' 6$ years o5 a0e E14F) 1hi,h 8eans 'ha' 8any 9eo9le in 'he
3es'ern 1orld are a55e,'ed. For e?a89le) in 2uro9ean ,oun'ries 'here are abou' hal5 a
8illion 9eo9le dia0nosed 1i'h M. E1$F. "n .1eden) 9re4alen,e s'udies sho1 'ha' abou'
180/100 000 inhabi'an's ha4e been dia0nosed 1i'h M. E16)1F. 7o a lar0e e?'en') M. is a
5e8ale 9roble8 and 1o8en 0e' M. abou' '1i,e as o5'en as 8en; in .1eden) re,en'ly
re9or'ed se? ra'ios are 2.6$ and 2.3$ <5e8ale/8ale= E16)18F. "n abou' 0!80C o5 ,ases) 'he
ini'ial ,ourse is rela9sin0!re8i''in0 <&&= E13F) ho1e4er) a5'er an a4era0e o5 1$ years and
in abou' 0C o5 ,ases) 'he && ,ourse ,han0es 'o a se,ondary 9ro0ressi4e ,ourse <.P=
,hara,'eri@ed by in,reasin0 disabili'y. "n 20C) 'he ,ourse is 9ro0ressi4e 5ro8 'he onse')
,alled 9ri8ary 9ro0ressi4e ,ourse <PP= E13F. (8on0 youn0 and 8iddle a0ed adul's) M.
is 'he 8ain reason 5or disabili'y and li8i'a'ions in 5un,'ional abili'ies E1%F. 7he youn0 a0e
o5 onse' in M. 8a+es i' one o5 'he 8aIor ,auses o5 redu,ed 1or+ ,a9a,i'y due 'o
neurolo0i, disease in 3es'ern so,ie'y. "89or'an'ly) o5 all i's sy89'o8s) a 8aIori'y o5 'he
indi4iduals 1i'h M. ,onsider 5a'i0ue as 'he 8os' handi,a99in0 and as 'heir 1ors'
9roble8 E3F. "ndi4iduals 1i'h a &&!,ourse o5 'he disease ha4e) in a lar0e sa89le and a
lon0i'udinal s'udy) been 5ound 'o ha4e less se4ere 5a'i0ue ,o89ared 'o indi4iduals 1i'h a
.P or PP!,ourse E20F.
Besides 5a'i0ue) indi4iduals 1i'h M. 8ay e?9erien,e o'her 9roble8s in5luen,in0 'heir
1or+ ,a9a,i'y and Guali'y o5 li5e. Co0ni'i4e di55i,ul'ies su,h as 8e8ory and a''en'ion
9roble8s E%)21F are 5ound as a55e,'in0 abou' hal5 o5 'he indi4iduals 1i'h M. and
des,ribed as a leadin0 ,ause o5 9er,ei4ed disabili'y in M. E22)23F. (8on0 a 0rou9 o5
youn0 M.!9a'ien's E24F) one 'hird sho1ed ,o0ni'i4e i89air8en' in ,o89le? a''en'ion) i.e.
in ra9id shi5'in0 be'1een ,o89e'in0 s'i8uli) 1hi,h 1as assu8ed 'o a55e,' 'heir 1or+ and
,areer E24F.
6o1e4er) 'here ha4e also been re9or'ed di55eren,es be'1een sel5! 0raded ,o0ni'i4e
5un,'ion and obser4ed neuro9sy,holo0i,al 9er5or8an,e E2$F.
(no'her 1ell!+no1n 5ea'ure o5 5a'i0ue in M. is i's asso,ia'ion 1i'h de9ression and o4er
$0C e?9erien,e e8o'ional dis'ress) a sy89'o8 in'er'1ined 1i'h 'he e?9erien,es o5
5a'i0ue and heal'h rela'ed Guali'y o5 li5e E26)2F. .ubseGuen'ly) se4eral 5reGuen' M.
sy89'o8s a99ear ,on,urren'ly: 5a'i0ue) de9ression) ,o0ni'i4e dys5un,'ion and) in
addi'ion 'o 'hese) hea' sensi'i4i'y 1hi,h has been in,reasin0ly 5o,used u9on E28!31F. 6ea'
sensi'i4i'y has been sho1n 'o in,rease 5a'i0ue and o'her ,o88on M.!sy89'o8s) li+e
9ain and di55i,ul'ies ,on,en'ra'in0 E31!33F) all o5 1hi,h 8ay in5luen,e indi4idualsH
disabili'y and 1or+ ,a9a,i'y.
&edu,ed ,a9a,i'y 'o 1or+ is a 8aIor ,ause o5 'he hi0h ,os' o5 M. in so,ie'y) as are 'he
,os's asso,ia'ed 1i'h 'he need 5or 9ersonal ,are in la'er s'a0es o5 'he disease. Tne s'udy
sho1ed 'ha' 'he ,os' o5 M. in .1eden is abou' q600 8illion a year) one 'hird o5 1hi,h
are indire,' ,os's asso,ia'ed 1i'h loss o5 9rodu,'ion E34F. "n a #anish s'udy E3$F) 9eo9le
1i'h M. le5' 9aid 1or+ earlier 'han 9eo9le in 'he 0eneral 9o9ula'ion. (5'er 5i4e years)
30C o5 M. 9a'ien's <n B 2 $38= had re'ired early) ,o89ared 'o 3C in 'he ,on'rol 0rou9
and '1en'y years la'er 'he 9ro9or'ions 1ere 8C ,o89ared 'o 14C res9e,'i4ely. "n a
.1edish s'udy 5ro8 'he early 1%%0s) abou' $0C o5 'hose 1i'h M. 1ere on 5ull si,+ lea4e
E36F) ,o89ared 'o 3.$C in a re,en' s'udy E3F. 7he earlier s'udies E3$)36F 1ere
9er5or8ed be5ore i88une!8odula'in0 dru0s 1ere in'rodu,ed and ,urren'ly 8any 9a'ien's
1i'h M. are 'rea'ed 1i'h su,h dru0s) 'he e55e,'s o5 1hi,h ha4e been 5o,used on in
rela'ion 'o bo'h 5a'i0ue and 1or+ abili'y. 7hese dru0s 8ay de,rease 'he de4elo98en' o5
disabili'y E38F and in,rease 1or+ abili'y E3F) bu' 'hey 8ay also in,rease 5a'i0ue E3%)40F.
7his s'udy is 9ar' o5 a 1ider 9roIe,' on 'he 'o9i, o5 M. 5a'i0ue ,arried ou' in
ps'er0o'land ,oun'y in eas'ern .1eden by our resear,h 0rou9 E3)31)41F. "n 'his s'udy)
1or+ ,a9a,i'y and heal'h rela'ed Guali'y o5 li5e <6&Wo/= a8on0 indi4iduals dia0nosed
1i'h M. a0ed 6$ or youn0er 1ere in4es'i0a'ed and) 5ur'her) 1he'her 1or+ s'a'us and
6&Wo/ ,an be 9redi,'ed by ba,+0round 5a,'ors) 5a'i0ue) hea' sensi'i4i'y) ,o0ni'i4e
dys5un,'ion) e8o'ional dis'ress or de0ree o5 disabili'y 1ere analy@ed.
;o 'o:
Methods
Study group
( des,ri9'i4e) ,ross!se,'ional) desi0ned sur4ey 1as under'a+en. &e,rui'8en' 'o 'he s'udy
1as done a8on0 9eo9le li4in0 in ps'er0o'land ,oun'y in eas'ern .1eden 1ho 1ere
re0is'ered in 'he .1edish M. re0is'er <.M. re0is'er=. 7he 5ollo1in0 ,ri'eria 5or
9ar'i,i9a'ion 1ere es'ablished: i= dia0nosed 1i'h M.) ii= o5 1or+in0 a0e) i.e. be'1een 20
and 6$ years) 6$ years is 'he o55i,ial re'ire8en' a0e in .1eden) and iii= ha4in0 an
2?9anded #isabili'y .'a'us .,ore <2#..= E42F in 'he in'er4al 0 A 2#.. U 6.$. >sin0
2#..) an indi4idualHs 9hysi,al disabili'y is 8easured based on ra'in0s o5 neurolo0i,al
si0ns o5 neurolo0i,al 5un,'ions and a8bula'ion) 0raded in '1en'y s'e9s ran0in0 5ro8 @ero
'o 'en. (n 2#.. B 0 indi,a'es nor8al neurolo0i,al ,ondi'ions) 1hile 2#.. B 10 indi,a'es
'he indi4idualHs dea'h due 'o M.. "n 'his s'udy) 'he ,hosen in'er4al o5 2#.. indi,a'es 'ha'
8os' o5 'he indi4iduals are 8obile and ,an 1al+ a' leas' shor' dis'an,es E42F.
( 9a,+a0e ,on'ainin0 an in5or8a'ion le''er abou' 'he s'udy) a Gues'ionnaire and a 9re!9aid
re9ly en4elo9e 1as sen' 'o ea,h o5 'he 323 indi4iduals 5ul5illin0 'he ,ri'eria) 23% 1o8en
and 84 8en. 7he Gues'ionnaires 1ere dis'ribu'ed in 200 and 2008. Tne re8inder 1as
sen' 'o 'hose 1ho had no' ans1ered 1i'hin 'hree 1ee+s. T'her analyses and resul's ha4e
been 9ublished 5ro8 'his s'udy E31F.
'ata collection
"n5or8a'ion abou' 'he 9ar'i,i9an'sH a0e and se?) disease ,ourse) a,'ual disabili'y assessed
1i'h 2#.. E42F and da'e o5 onse' 1as a,Guired 5ro8 'he .M. re0is'er. Bo'h 'he 9a'ien'Hs
disease!,ourse and 2#.. are ,on'inuously u90raded 1hen 4isi'in0 a 9hysi,ian a' 'he
neurolo0i,al 9oli,lini,. 7he 9ar'i,i9an's 1ere 0rou9ed a,,ordin0 'o nor8al neurolo0i,al
,ondi'ion <2#.. B 0=) 8ild disabili'y <1.0 A 2#.. U 3.$=) 8odera'e disabili'y <4.0 A 2#..
U $.$= and se4ere disabili'y <6.0 A 2#.. U 6.$=.
"n5or8a'ion on ba,+0round 5a,'ors su,h as 'he 9ar'i,i9an'sH ,i4il s'a'us) 5a8ily) le4el o5
edu,a'ion 'o0e'her 1i'h on!0oin0 8edi,al 'rea'8en' 1as reGues'ed in 'he Gues'ionnaire.
"n one Gues'ion) 'he 9ar'i,i9an'sH o,,u9a'ion and 'o 1ha' de0ree 'hey 1or+ed) 1ere
reGues'ed. 7he 9ar'i,i9an's s9e,i5ied i5 'hey 1ere 1or+in0 5ull!'i8e) 9ar'!'i8e or no'
1or+in0. "n 'he ,ase o5 9ar'!'i8e 1or+) 'he 9ar'i,i9an's re9or'ed 9er,en'a0es o5 5ull!'i8e.
7hey also re9or'ed i5 'hey 1ere on 5ull! or 9ar'!'i8e si,+ lea4e or re,ei4ed a disabili'y
9ension. Tn0oin0 edu,a'ion and 'rainin0 and 1or+in0 a' ho8e 1ere ,onsidered as
eGui4alen' 'o 1or+. "n one Gues'ion) 'he 9ar'i,i9an's 1ere as+ed R(re you sensi'i4e 'o
hea'hS <-es/No=.
6&Wo/ 1as assessed usin0 'he .1edish 4ersion o5 'he 1ell!'es'ed and e?'ensi4ely used
0eneri, ins'ru8en' shor' 5or8 .F!36 6eal'h .ur4ey E43!4$F. 7he Gues'ionnaire 8easures
ei0h' heal'h do8ains <subs,ales=: 9hysi,al 5un,'ionin0 <PF=) role!9hysi,al <&P=) bodily
9ain <BP=) 0eneral heal'h <;6=) 4i'ali'y <D7=) so,ial 5un,'ionin0 <.F=) role!e8o'ional
<&2=) and 8en'al heal'h <M6=. 2a,h subs,ale ,on'ains 2 'o 10 i'e8s) 5or a 'o'al o5 3$
Gues'ions. "n an addi'ional i'e8) 'he res9onden's ra'ed 'heir ,urren' heal'h s'a'us
,o89ared 'o one year 9re4iously on a 5i4e!9oin' s,ale <1 B 8u,h be''er 'o $ B 8u,h
1orse=. .ubs,ale s,ores are ,o89u'ed a,,ordin0 'o s'andardi@ed 9ro,edures and ran0e
5ro8 0 'o 100) in 1hi,h hi0her s,ores indi,a'e be''er heal'h rela'ed Guali'y o5 li5e E43)46F.
7o in4es'i0a'e 'he 9er,ei4ed se4eri'y o5 5a'i0ue) 'he Fa'i0ue .e4eri'y .,ale <F..= E4F
1as used) ,o89risin0 nine i'e8s 1i'h ea,h i'e8 0raded 5ro8 leas' 5a'i0ue <1= 'o se4ere
5a'i0ue <=. (s in earlier s'udies Ee.0. ) 48F) an F.. 8ean s,ore U4 1as re0arded as
indi,a'in0 no 5a'i0ue) b4 bu' ]$ indi,a'ed borderline 5a'i0ue) and A$ indi,a'ed se4ere
5a'i0ue. 7he F.. is 1idely used bo'h ,lini,ally and in resear,h E48F. "n 'his s'udy)
,on,urren' 4alidi'y 1as assessed 'hrou0h ,orrela'ions be'1een 'he F.. 'o'al 1i'h
Gues'ions abou' 'he i89a,' o5 5a'i0ue on daily li5e and 'he i89a,' on 'he abili'y 'o 1or+)
and resul'ed in r B0.% <p ] 0.01= and r B0.$ <p ] 0.01= res9e,'i4ely. &eliabili'y 1as
assessed usin0 Cronba,hHs al9ha E4%F) and 'he al9ha ,oe55i,ien' 1as 0.%3 E31F.
7o in4es'i0a'e 9er,ei4ed 9roble8s 1i'h 8e8ory) a''en'ion and ,on,en'ra'ion) 'he
Per,ei4ed #e5i,i' Wues'ionnaire <P#W= E$0F 1as 'ransla'ed 5ro8 'he ori0inal 2n0lish in'o
.1edish. 7he .1edish 4ersion 1as ba,+!'ransla'ed in a,,ordan,e 1i'h .'reiner and
Nor8an E$1F. "n P#W) 20 i'e8s are 0raded 5ro8 ne4er <0= 'o al1ays <4=) and su88a'ed
s,ores 4ary 5ro8 0 'o 80) hi0her s,ores indi,a'e 0rea'er ,o0ni'i4e 9roble8s. Con,urren'
4alidi'y 1as es'i8a'ed by ,al,ula'in0 ,orrela'ions be'1een 'he P#W su8 s,ore and 'he
0raded o,,urren,e o5 '1o M. sy89'o8s) 5or0e'5ulness and di55i,ul'ies ,on,en'ra'in0
<ne4er B 0 'o al1ays B $= and resul'ed in r B 0.$ <9 ] 0.010= and r B 0.3 <9 ] 0.010=
res9e,'i4ely. 7hese resul's indi,a'e 'ha' 'here is e4iden,e o5 ,on,urren' 4alidi'y 5or P#W
in 'his s'udy 0rou9. &eliabili'y 1as 'es'ed usin0 Cronba,hHs al9ha) 'he al9ha ,oe55i,ien'
1as 0.%$) and 'he s9li'!hal5 'e,hniGue <r B 0.8=.
7o in4es'i0a'e 'he o,,urren,e o5 e8o'ional dis'ress) 'he 1idely used 6os9i'al (n?ie'y
#e9ression <6(#= s,ale 1as a99lied E$2F. "n se4en i'e8s) o,,urren,e o5 sy89'o8s
8irrorin0 an?ie'y and de9ressi4e sy89'o8s res9e,'i4ely are 0raded 5ro8 @ero 'o 'hree.
.u88a'ed s,ores ran0e 5ro8 0 'o 21 and iden'i5y non!,ases <s,ore or less=) doub'5ul
,ases <s,ores in 'he in'er4al 8N10= and de5ini'i4e ,ases <s,ores 11 or hi0her=. "n 'his s'udy)
reliabili'y assessed usin0 Cronba,hHs al9ha) resul'ed in 'he al9ha ,oe55i,ien' 5or an?ie'y
bein0 0.88 and 5or de9ression 0.8.
Statistical analyses
7he des,ri9'i4e s'a'is'i,s used are nu8bers and 9er ,en's) 8edian and in'erGuar'ile!ran0e
<"W&= 8ean and s'andard de4ia'ion <.#=. 7he s,ales F..) P#W and .F!36 are 'rea'ed on
in'er4al le4els as in earlier s'udies. (sso,ia'ions be'1een 4ariables 1ere 'es'ed by
PearsonHs or .9ear8anHs ,orrela'ion ,al,ula'ions. #i55eren,es be'1een 0rou9s 1ere 'es'ed
1i'h 'he Chi!sGuare 'es' on da'a on a no8inal le4el) 1i'h 'he Mann 3hi'ney +!'es' on
da'a on an ordinal le4el) and .'uden'Hs t!'es' on da'a on an in'er4al le4el. "n 'he 8ul'i9le
lo0is'i, re0ression analyses <en'er=) 'he ,a9a,i'y 5or 1or+) di,ho'o8ised as ,a9a,i'y <5ull
or li8i'ed B 1= or no ,a9a,i'y <5ull!'i8e si,+ lea4e or disabili'y 9ension B 0= 1as en'ered
as a de9enden' 4ariable) and 5a'i0ue <F..!8ean=) hea' sensi'i4i'y) ,o0ni'ion) e8o'ional
dis'ress) disabili'y) a0e) 0ender <5e8ale B 1/8ale B 2=) and le4el o5 edu,a'ion <,o89ulsory
B 1) se,ondary s,hool or uni4ersi'y B 2= as inde9enden' 4ariables. 7he ,orrela'ion
be'1een a0e and ha4in0 ,hildren 1as rs B 0.8) 'here5ore) a0e 1as used in 'he lo0is'i,
analyses 8odel. "n 'he 8ul'i9le linear re0ression analyses <en'er= 'he do8ains in 6&Wo/
8easured by .F!36 1ere used as de9enden' 4ariables) and 5a'i0ue) hea' sensi'i4i'y)
,o0ni'ion) an?ie'y) de9ression) disabili'y) a0e and 0ender 1ere used as inde9enden'
4ariables.
4thical considerations
Co88on e'hi,al 9rin,i9als in resear,h) and in a,,ordan,e 1i'h 'he #e,lara'ion o5
6elsin+i E$3F) 1ere a99lied in 'he s'udy. (99ro4al 'o use 'he .M. re0is'er 1as re,ei4ed
5ro8 'he lo,al ad8inis'ra'or res9onsible 5or 'he re0is'er. 7he &e0ional 2'hi,al &e4ie1
Board a' 'he Fa,ul'y o5 6eal'h .,ien,es) /in+o9in0 >ni4ersi'y) .1eden <#nr M13!0=
also a99ro4ed 'he s'udy. ( ,o89le'ed and re'urned Gues'ionnaire 1as ,onsidered re,ei4ed
in5or8ed ,onsen'.
;o 'o:
Results
!articipants
71o hundred and 5i5'y se4en 9ar'i,i9an's <%.6C= res9onded 'o 'he in4i'a'ion and
re'urned a ,o89le'ed Gues'ionnaire; o5 'he sur4eyed) 6.3C 1ere 1o8en and 23.C 1ere
8en. 7here 1ere no si0ni5i,an' di55eren,es be'1een non!res9onden's and res9onden's
re0ardin0 se? <p B 0.066=) disease!,ourse <p B 0.064= or 2#.. s,ore <p B 0.142=. 7he
9ar'i,i9an'sH 8ean a0e 1as 4.$ years <.#10.8=) 'he 1o8en <n B 1%6= 1ere older
<48.2 years) .# 11.0= 'han 'he 8en <n B 61=) <44.8 years) .#10.1= <p B 0.033= <7able 1=)
1hile 'he non!res9onden's 1ere 5i4e years youn0er on a4era0e) 8B 42. years <.# 10.$=
<p ] 0.001=.
7able 1
.a89le ,hara,'eris'i,s
9ork capacity
T5 'he res9onden's) $%.8C re9or'ed 'ha' 'hey 1or+ed 5ull! or 9ar'!'i8e. &e0ardin0
ba,+0round 5a,'ors in rela'ion 'o 1or+ ,a9a,i'y) si0ni5i,an'ly 8ore 1o8en 'han 8en
1ere on 5ull!'i8e si,+ lea4e or disabili'y 9ension <7able 1=. 7hose 9ar'i,i9an's 1ho had
,a9a,i'y 'o 1or+ 1ere youn0er) 8ean a0e 44.$ years <.#10.4= ,o89ared 'o 'hose 1ho
had non!,a9a,i'y 'o 1or+) 8ean a0e $1.8 years <.#10.2= <p ] 0.001=. Besides disabili'y)
si0ni5i,an' di55eren,es be'1een 'he le4els o5 ,a9a,i'y 'o 1or+ 1ere 5ound) 5or e?a89le)
re0ardin0 5a'i0ue) hea' sensi'i4i'y) ,o0ni'i4e di55i,ul'ies and e8o'ional dis'ress <7able 2=.
7able 2
Par'i,i9an's in rela'ion 'o ,a9a,i'y 'o 1or+ or non ,a9a,i'y 'o 1or+
Fa'i0ue <F..!8ean= ,orrela'ed si0ni5i,an'ly 1i'h ,o0ni'i4e di55i,ul'ies <P#W!su8=) r B
0.$1 <9 ] 0.001=. 7he 9ar'i,i9an's 1ho re9or'ed 'ha' 'hey 1ere sensi'i4e 'o hea' <n B 146=
also re9or'ed si0ni5i,an'ly 8ore ,o0ni'i4e di55i,ul'ies ,o89ared 'o 'hose 1ho 1ere no'
sensi'i4e 'o hea' <n B 108=) 8ean 2%.$ <.#14.8= and 22.6 <.#14.4=) <9 ] 0.001=)
res9e,'i4ely.
.e4en'y 5i4e 9er,en' o5 'he 9ar'i,i9an's 1i'h a uni4ersi'y edu,a'ion <n B 88= re9or'ed 'ha'
'hey 1ere 1or+in0) ,o89ared 'o $1.$C o5 'he 9ar'i,i9an's 1i'h ,o89ulsory or se,ondary
s,hool edu,a'ion <n B 16= <9 ] 0.001=. 7he la''er 0raded si0ni5i,an'ly 8ore ,o0ni'i4e
di55i,ul'ies 'han 'he 9ar'i,i9an's 1i'h a uni4ersi'y edu,a'ion) 8ean 2%.3 <.#1$.3= and
21.6 <.#12.%=) <9 ] 0.001=) res9e,'i4ely.
"n a 8ul'i9le lo0is'i, re0ression analysis) <en'er=) $4C o5 'he ,a9a,i'y 5or 1or+ 1as
e?9lained by 'he 8odel. .i0ni5i,an' 5a,'ors in 'he 8odel 1ere 5a'i0ue <F..!8ean= <T& B
0.$) 9 B 0.041=) disabili'y assessed by 2#.. <T&B 0.$3) 9 ]0.001=) se? <T&B 4.34) 9 B
0.001=) le4el o5 edu,a'ion <T&B 3.88) 9 B 0.002= and a0e <T&B 0.%3) 9 ]0.001= <7able 3=.
7able 3
/o0is'i, re0ression analyses o5 ,a9a,i'y 5or 1or+
;ealth-related Auality o lie
Fa'i0ue si0ni5i,an'ly in5luen,ed daily li5e <9 ] 0.001=. (8on0 'hose 9ar'i,i9an's 1ho
re9or'ed 'ha' 'hey 1ere sensi'i4e 'o hea') sel5!ra'ed heal'h <5irs' i'e8 in 'he .F!36= 1as
ra'ed si0ni5i,an'ly 1orse <8ean 3.$) .# 0.83= ,o89ared 'o 'hose 1ho 1ere no' sensi'i4e
'o hea' <8ean 3.2) .# 0.%2= <p B 0.01$=. 6&Wo/ 1as 0raded si0ni5i,an'ly hi0her in all
.F!36 do8ains a8on0 'hose 1ho 1ere 1or+in0 5ull! or 9ar'!'i8e ,o89ared 'o 'hose 1ho
did no' 1or+ <7able 4=.
7able 4
6eal'h!rela'ed Guali'y o5 li5e
"n 'he 8ul'i9le linear re0ression analyses) 5a'i0ue 1as si0ni5i,an'ly rela'ed 'o 6&Wo/ in
all .F!36 do8ains e?,e9' role!e8o'ional and 8en'al heal'h <7able $=.
7able $
Mul'i9le re0ression analyses o5 'he do8ains in heal'h!rela'ed Guali'y o5 li5e
;o 'o:
'iscussion
7his s'udy is a ,ross!se,'ional s'udy and a Gues'ionnaire 1as used 'o ,olle,' 'he da'a. 7he
res9onse ra'e) nearly 80C) is ,onsis'en' 1i'h 1ha' is ,o88on in si8ilar s'udies. "n 'his
s'udy) 'he 1o8en 1ere so8e1ha' older 'han 'he 8en and 1ere also 8ore o5'en re'ired
due 'o 'he disease) 1hile 8ore 8en re9or'ed 'hey had 1or+ ,a9a,i'y. &e0ardin0 ,i4il
s'a'us) le4el o5 edu,a'ion) ,ourse o5 disease and disabili'y or 9har8a,olo0i,al 'rea'8en')
'here 1ere no si0ni5i,an' di55eren,es be'1een 1o8en and 8en) e?,e9' 5or 1or+ ,a9a,i'y.
Fa'i0ue 9ro4ed 'o be a si0ni5i,an' 5a,'or in5luen,in0 1or+ ,a9a,i'y. 7hose 9ar'i,i9an's
1ho had 'he ,a9a,i'y 'o 1or+ re9or'ed si0ni5i,an'ly less 5a'i0ue ,o89ared 'o 'hose 1i'h
no ,a9a,i'y 'o 1or+. (no'her 5a,' 1as 'ha' 'he le4el o5 1or+ ,a9a,i'y 1as s'a'is'i,ally
si0ni5i,an'ly hi0her a8on0 'hose 9ar'i,i9an's 1ho 1ere no' sensi'i4e 'o hea') 1hile 'hose
1ho 1ere sensi'i4e 'o hea' sho1ed si0ni5i,an'ly 8ore o5'en a non!,a9a,i'y 'o 1or+. "n a
9re4ious s'udy) hea' sensi'i4i'y 1as 5ound 'o si0ni5i,an'ly in'er5ere 1i'h and also in,rease
5a'i0ue E31F. "n 'his s'udy) 5a'i0ue ,ould be seen as a +ey sy89'o8 in5luen,in0 bo'h 1or+
,a9a,i'y and 6&Wo/.
.i8ilar 'o 'he 5indin0s in 'his s'udy) Mro+a4,o4a e' al. E$4F 5ound 'ha' 9a'ien's 1i'h sel5!
ra'ed 0ood heal'h are 8ore li+ely 'o be e89loyed. "n 'his s'udy) 9ar'i,i9an's 1ho had 'he
,a9a,i'y 'o 1or+ 0raded bo'h be''er heal'h and 6&Wo/ 'han 'hose 1i'h a non!,a9a,i'y 'o
1or+.
"n'eres'in0ly) a hi0her le4el o5 edu,a'ion 1as sho1n as a si0ni5i,an' 9redi,'i4e 5a,'or 5or
1or+ ,a9a,i'y in 'his s'udy. 7he reason 5or 'his 8ay be dis,ussed in 'er8s o5 disabili'y
le4el and 1or+ o5 a 9erson) 1hi,h de8ands 'ha' 'he 9erson is 8o4able) or 'ha'
edu,a'ional a''ain8en' has no' been disru9'ed due 'o M.. 7his 8i0h' be de9enden' o5 'he
a0e a' onse' o5 'he disease E24F. "n 'he 9resen' s'udy) Ius' a 5e1 9er,en' o5 'he 9ar'i,i9an's
<$.$C= had onse' o5 'he disease be5ore 20 years o5 a0e E31F. Blue ,ollar 1or+ usually
,onsis's o5 9hysi,al labor 1hi,h na'urally is in5luen,ed by a,'ual disabili'y) 1hile 1or+
reGuirin0 hi0her edu,a'ion 8i0h' 8ore o5'en be 9a9er1or+ or 1hi'e ,ollar 1or+. 7his
resul' indi,a'es 'he i89or'an,e o5 su99or'in0 youn0 M.!9a'ien's in ,on'inuin0 'heir
edu,a'ion) e4en a' a hi0her le4el. 7his 1ould also be in line 1i'h 'he resul's 9resen'ed by
;lad and ,ollea0ues E26F) 1ho 5ound 'ha' ha4in0 a &&!,ourse) hi0her edu,a'ion and li0h'
9hysi,al 1or+ 1ere 9redi,'in0 5a,'ors 5or bein0 able 'o re8ain e89loyed.
(no'her in'eres'in0 as9e,' o5 'he in,reased 1or+ ,a9a,i'y o5 9a'ien's 1i'h hi0her
edu,a'ion is 'ha' ,o0ni'i4e 9roble8s in M. are a ,o88on 5ea'ure. 6o1e4er) ob4iously) in
'his s'udy) su,h 9roble8s did no' in'er5ere 1i'h 1or+) 9robably based on in'elle,'ual
9ro,esses) 1hi,h reGuired hi0her edu,a'ion. 6o1e4er) M. is a ,o89le? disease and
re0ardin0 5a'i0ue) 8ul'i9le 5a,'ors 8i0h' in'era,' and in5luen,e bo'h 5a'i0ue and ,o0ni'i4e
5un,'ion. "n 'his s'udy in 'he linear re0ression analysis) 5a'i0ue and ,o0ni'ion 1ere 5ound
as ,on'ribu'in0 5a,'ors in 'he do8ain o5 bodily 9ain and 4i'ali'y. Pain 8ay in'er5ere 1i'h
and disru9' an indi4idualHs a''en'ion and ,on,en'ra'ion) bu' also in5luen,e 5a'i0ue. (n
i89or'an' Gues'ion is i5 ,o0ni'i4e 9roble8s in M. so8e'i8es 5lu,'ua'e and are se,ondary
'o 5a'i0ue. 7his should be o5 in'eres' 'o s'udy 5ur'her. 6o1e4er) 5lu,'ua'ions o5 ,o0ni'i4e
di55i,ul'ies in M. ha4e been 5ound in rela'ion 'o a hea' en4iron8en' E31!33F. "n one
s'udy) ,o0ni'i4e di55i,ul'ies 1ere re9or'ed as eased 1hen 'he indi4idual used a ,oolin0!
sui' E2%F) 1hi,h also should be o5 in'eres' 5or 5ur'her in4es'i0a'ions.
(0e a99eared as a 9redi,'or 5or ,a9a,i'y 5or 1or+. "n a ,orrela'ion analysis 1e 5ound 'ha'
a0e and ha4in0 ,hildren 1ere ,losely ,orrela'ed <rs B 0.8= 1hy 1e ,hose 'o +ee9 a0e as
'he inde9enden' 4ariable. "n our ori0inal hy9o'hesis) ho1e4er) 1e 9aid an in'eres' in M.
9a'ien's 1i'h s8all ,hildren sin,e 'his si'ua'ion 8ay in,rease 'heir le4el o5 5a'i0ue. (s a0e
a99eared as a 9redi,'or 1e also su00es' 'ha' i' s'ands 5or ha4in0 s8all ,hildren.
Wuali'y o5 li5e 1as assessed as si0ni5i,an'ly hi0her a8on0 'hose 1ho 1or+ed) a resul'
also 5ound in earlier s'udies. Tb4ious in 'his s'udy 1as 'ha' 5a'i0ue 1as a si0ni5i,an'
5a,'or in5luen,in0 all do8ains o5 heal'h!rela'ed Guali'y o5 li5e) e?,e9' role!e8o'ional and
8en'al heal'h) 1hile ,o0ni'ion 1as a si0ni5i,an' 5a,'or in5luen,in0 '1o o5 'he do8ains)
bodily 9ain and 4i'ali'y. "n 'he do8ain o5 role!e8o'ional) hea' sensi'i4i'y a99eared as a
si0ni5i,an' in5luen,in0 5a,'or 1hi,h 8i0h' be unders'ood as li8i'in0 'he indi4idualsH
so,ial li5e a,'i4i'ies.
7he i89a,' o5 5a'i0ue on Guali'y o5 li5e is ob4iously ,onne,'ed 'o 1or+ abili'y) a ,en'ral
5un,'ion in e4erybodyHs li5e. For na'ural reasons) 'he ris+ o5 isola'ion in so,ie'y in,reases
bo'h 'hrou0h une89loy8en' and 'he obs'a,les i' 9la,es 'o 9ar'i,i9a'in0 in 5a8ily li5e on
eGual 'er8s. "n ,on,lusion) 'he i89a,' on 'hese do8ains ,ould 4ery 1ell a55e,' 'he
indi4idualHs sense o5 ,oheren,e 1hi,h is ,en'ral 'o 'he indi4idualHs 9er,e9'ion o5
1ellbein0. (s 5a'i0ue is a sy89'o8 1i'h a se4ere i89a,' on Guali'y o5 li5e and 1or+
,a9a,i'y) i' is i89or'an' 'o 5ind 'he or0ani, ,ause 1hi,h) in 'he ,ase o5 M.) Ius'i5ies a
9a'ien'Hs si,+ lea4e and disabili'y 9ension.
(no'her 9oin' o5 4ie1 is 'ha' bein0 able 'o 1or+ is o5 i89or'an,e 5or 'he Guali'y o5 li5e o5
9eo9le 1i'h ,hroni, diseases. Peo9le 1i'h M.) should ha4e 'he o99or'uni'y 'o 1or+ 9ar'!
'i8e as lon0 as 9ossible. (s 9eo9le 1i'h M. are o5'en a55e,'ed early on in li5e) 'heir
o,,u9a'ional de4elo98en' is 8ore di55i,ul'. 7he 5a,' 'ha' youn0 9eo9le 8ay be s'o99ed
by M. 5ro8 1or+in0 a' all should also be 'a+en in'o a,,oun'.
(9ar' 5ro8 disabili'y 8easured by 2#..) 'he 5a,' 'ha' hea' sensi'i4i'y in'er5eres 1i'h
1or+ ,a9a,i'y su00es's 'ha' or0anisin0 ,ryo'hera9eu'i, a99roa,hes in 'he 1or+ 9la,e)
su,h as air ,ondi'ionin0) ,oolin0 0ar8en's and disabili'y 5riendly 8easures should be 9u'
in 9la,e.
7his ar'i,le also 5o,uses on 5a'i0ue as a ,o88on and serious sy89'o8 in M. already a'
'he onse' and 'he 5ollo1in0 s'a0es o5 'he disease. For e?a89le) 0eneral 9ra,'i'ioners
should 'a+e M.!5a'i0ue in'o ,onsidera'ion 1hen youn0 9a'ien's ,o89lain abou' 'iredness.
.ubseGuen'ly) i' is ne,essary 'ha' 9a'ien's are 9ro9erly dia0nosed early on in 'he ,ourse o5
a disease li+e M.) indi,a'in0 'ha' 9hysi,ians should be ,are5ul 1hen dia0nosin0 a
,o88on sy89'o8 li+e 'iredness or 8en'al/9hysi,al e?haus'ion in youn0 9eo9le)
es9e,ially 5e8ales. 6o1e4er) all 9a'ien's 1ho ,o89lain o5 5a'i0ue ,anno' be re5erred 'o a
neurolo0is'. 7he .1edish si,+ lea4e sys'e8 relies on 9a'ien's bein0 dia0nosed. Clear
re,o88enda'ions are 8ade in order 'o de'er8ine 'he a99ro9ria'e si,+ lea4e 9eriod 1i'h a
s9e,i5i, dia0nosis. 7his 8eans 'ha' a 9a'ien' 1i'hou' a s9e,i5i, dia0nosis) i.e. a ra'her
sy89'o8a'i, des,ri9'ion) li+e 'iredness) 9ain) e',.) 8ay 5ind i' di55i,ul' 'o re,ei4e
5inan,ial ,o89ensa'ion 5ro8 'he .1edish si,+ lea4e insuran,e sys'e8. Tne s'udy 5ro8
our 0rou9 has re4ealed 'ha' al'hou0h a 4ery hi0h 9er,en'a0e o5 M. 9a'ien's sho1ed no
si0n o5 neurolo0i,al dys5un,'ion 1hen 9hysi,ally e?a8ined) in 5a,') al8os' 2$C) su55ered
5ro8 9a'holo0i,al 'iredness N 5a'i0ue N as 'he only subIe,'i4e sy89'o8 E41F.
=imitations
( li8i'a'ion o5 'he s'udy is asso,ia'ed 1i'h 'he ,hosen desi0n) no ,ausal e?9lana'ions and
no 5ollo1 u9. 7he sa89le in,luded 323 indi4iduals 1hy sel5!assess8en' Gues'ionnaires
1ere used. 7hus) da'a rely on sel5!assess8en's and on 'he subIe,'i4e e?9erien,es o5 'he
9ar'i,i9an's. 7he use o5 a 0eneri, ins'ru8en' 'o in4es'i0a'e 6&Wo/ <.F36= ,an be
,ri'i,i@ed sin,e i' does no' ,o4er s9e,i5i, M.!sy89'o8s. 6o1e4er) 'he .F36 is a 1ell
+no1n ins'ru8en' and 1idely used in o'her s'udies) 1hy 'he resul's 8ay be easier 'o
in'er9re' and ,an also be ,o89ared 1i'h o'her 0rou9s in 'he 5u'ure.
;o 'o:
Conclusions
3or+ ,a9a,i'y and 6&Wo/ a8on0 indi4iduals dia0nosed 1i'h M. are hi0hly in5luen,ed
by 5a'i0ue 1hi,h) 'hus) ,an be ,onsidered as a +ey sy89'o8. 3or+ ,a9a,i'y 1as also
in5luen,ed by hea'!sensi'i4i'y) ,o0ni'i4e di55i,ul'ies and e8o'ional dis'ress and si0ni5i,an'
9redi,'i4e 5a,'ors besides 5a'i0ue 1ere 9hysi,al disabili'y) a0e) se?) and edu,a'ional le4el.
&e8ainin0 a' 1or+ also 0a4e a be''er 6&Wo/.
;o 'o:
Competing interests
7he au'hors de,lare 'ha' 'hey ha4e no ,o89e'in0 in'eres's.
;o 'o:
Authors) contributions
(ll au'hors ,on'ribu'ed 'o 'he 9lannin0 o5 'he s'udy. ;F ,olle,'ed all da'a and 'o0e'her
1i'h (!C2 ,ondu,'ed 'he s'a'is'i,al analyses. "n ,ollabora'ion) ;F) (!C2 and (!M/
1ro'e 'he dra5's 1hi,h ha4e been re9ea'edly dis,ussed and re4ised by all o5 'he au'hors.
Finally) all o5 'he au'hors ha4e read and a99ro4ed 'he 8anus,ri9' be5ore sub8ission.
;o 'o:
!re-publication history
7he 9re!9ubli,a'ion his'ory 5or 'his 9a9er ,an be a,,essed here:
h''9://111.bio8ed,en'ral.,o8/141!24$8/13/224/9re9ub
;o 'o:
Acknowledgements
7he s'udy 1as 5unded by 'he .1edish &esear,h Coun,il. 3e are 0ra'e5ul 'o all o5 'he
9ar'i,i9an's 1ho 5illed in 'he Gues'ionnaires and 9ar'i,i9a'ed in 'his s'udy; 'o 'he resear,h
nurses) ;unn *ohansson a' 'he >ni4ersi'y 6os9i'al) /in+o9in0 and Claes!;oran (hlin a'
Mo'ala 6os9i'al) 5or hel9 1i'h 'he .M.!re0is'er; 'o >ni4ersi'y 3es' 5or 5inan,ial su99or'.
Finally) 5or s,ru'ini@in0 'he 2n0lish lan0ua0e) 1e a,+no1led0e Moira #unne.
;o 'o:
Reerences
1. 6a8il'on 37) 6all ;6) &ound (P. FreGuen,y o5 a''endan,e in 0eneral 9ra,'i,e
and sy89'o8s be5ore de4elo98en' o5 ,hroni, 5a'i0ue syndro8e: a ,aseN,on'rol
s'udy. Bri' * ;en Pra,'. 2001;$1:$$3N$$8. EPMC 5ree ar'i,leF EPubMedF
2. Man' "*) B[l'8ann >) .,hroer M) Beurs+ens () 4an (8els4oor' /) .1aen ;. (n
e9ide8iolo0i,al a99roa,h 'o s'udy 5a'i0ue in 'he 1or+in0 9o9ula'ion: 'he
Maas'ri,h' ,ohor' s'udy. T,,u9 2n4 Med. 2003;60<.u99l "=:i32Ni3%. EPMC 5ree
ar'i,leF EPubMedF
3. Flensner ;) 2+ (!C) /and'blo8 (!M) .oderha8n T. Fa'i0ue in rela'ion 'o
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EPubMedF ECross &e5F
4. .ulli4an P.) #1or+in M.. and 'he (dul' and (doles,en' .9e,'ru8 o5 6"D
#isease "n4es'i0a'ors. Pre4alen,e and ,orrela'es o5 5a'i0ue a8on0 9ersons 1i'h
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3%24<02=0066!0. EPubMedF ECross &e5F
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2%. Flensner ;) /inden,rona C. 7he ,oolin0!sui': ,ase s'udies o5 i's in5luen,e on
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31. Flensner ;) 2+ (!C) .oderha8n T) /and'blo8 (M. .ensi'i4i'y 'o hea' in M.
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3$. P5le0er CC) Fla,hs 2M) Mo,h!6enri+sen N. .o,ial ,onseGuen,es o5 8ul'i9le
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42. Mur'@+e *. &a'in0 neurolo0i, i89air8en' in 8ul'i9le s,lerosis: (n e?9anded
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4$. .ulli4an M) Marlsson *. 7he .1edish .F!36 heal'h sur4ey """. 24alua'ion o5
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46. 7a5' C) Marlsson *) .ulli4an M. Per5or8an,e o5 'he .1edish .F! 36 2.0. Wual /i5e
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4. Mru99 /B) (l4are@ /() /a&o,,a N;) .,heinber0 /C. Fa'i0ue in 8ul'i9le
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48. *ohansson .) -''erber0 C) Ba,+ B) 3id^n 6ol8Guis' /) 4on Mo,h /. 7he .1edish
o,,u9a'ional 5a'i0ue in4en'ory in 9eo9le 1i'h 8ul'i9le s,lerosis. * &ehab Med.
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4%. Cronba,h /*. Coe55i,ien' al9ha and 'he in'ernal s'ru,'ure o5 'es's. Psy,ho8e'ri+a.
1%$1;16:2%N334. doi: 10.100/BF02310$$$. ECross &e5F
$0. .ulli4an *"/) 2d0eley M) #ehou? 2. ( sur4ey o5 8ul'i9le s,lerosis. Par' ":
9er,ei4ed ,o0ni'i4e 9roble8s and ,o89ensa'ory s'ra'e0y used. Can * &ehabil.
1%%0;4:%%N10$.
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.,and. 1%83;6<6=:361N30. doi: 10.1111/I.1600!044.1%83.'b0%16.?. EPubMedF
ECross &e5F
$3. 3M() 3orld Medi,al (sso,ia'ion. #e,lara'ion o5 6elsin+i: e'hi,al 9rin,i9les 5or
8edi,al resear,h in4ol4in0 hu8an subIe,'s. .eoul) Morea: $%'h 3M( ;eneral
(sse8bly; 2008.
$4. Mro+a4,o4a M) NaGyo4a ") Dan #iI+ *P) &osenber0er *) ;a4elo4a M) Middel B)
.@ilasio4a *) ;do4ino4a V) ;roo'ho55 *3. .el5!ra'ed heal'h and e89loy8en'
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Jurnal 15
PLoS One. 2013; 8(1): e53(23.
Published online 2013 1"nu"r+ 11. doi: 10.1371!ourn"l.#one.0053(23
P$%&D: P$%35:32'0
Cross-=anguage Measurement
4Auivalence o the Center or
4pidemiologic Studies 'epression
#C4S-'$ Scale in Systemic Sclerosis: A
Comparison o Canadian and 'utch
!atients
Lind" 27"66enbos*
1*2*7*;
=rin 4r)hurs*
2*7
@r"n6 P. 1. B"n den Poo.en*
1
$"rie
Pudson*
:*7
Nim 0. 1. $. B"n L"n6Beld*
1
$urr"+ /"ron*
:*7
%orneli" P. $. B"n den
=nde*
1
/re)) D. <hombs*
2*3*:*5*'*7
"nd >or )he %"n"di"n Scleroderm" 3ese"rch
0rou#
Z
1erson L"6s* =di)or
4u)hor in>orm")ion ? 4r)icle no)es ? %o#+ri.h) "nd License in>orm")ion ?
0o )o:
Abstract
"b6ectives
"n,reasin0ly) 8edi,al resear,h in4ol4es 9a'ien's 1ho ,o89le'e ou',o8es in di55eren'
lan0ua0es. 7his o,,urs in ,oun'ries 1i'h 8ore 'han one ,o88on lan0ua0e) su,h as
Canada <Fren,h/2n0lish= or 'he >ni'ed .'a'es <.9anish/2n0lish=) as 1ell as in
in'erna'ional 8ul'i!,en're ,ollabora'ions) 1hi,h are u'ili@ed 5reGuen'ly in rare diseases
su,h as sys'e8i, s,lerosis <..,=. "n order 'o 9ool or ,o89are ou',o8es) ins'ru8en's
should be 8easure8en' eGui4alen' <in4arian'= a,ross ,ul'ural or lin0uis'i, 0rou9s. 7his
s'udy 9ro4ides an e?a89le o5 ho1 'o assess ,ross!lan0ua0e 8easure8en' eGui4alen,e by
,o89arin0 'he Cen'er 5or 29ide8iolo0i, .'udies #e9ression <C2.!#= s,ale be'1een
2n0lish!s9ea+in0 Canadian and #u',h .., 9a'ien's.
Methods
7he C2.!# 1as ,o89le'ed by %22 2n0lish!s9ea+in0 Canadian and 213 #u',h ..,
9a'ien's. Con5ir8a'ory 5a,'or analysis <CF(= 1as used 'o assess 'he 5a,'or s'ru,'ure in
bo'h sa89les. 7he Mul'i9le!"ndi,a'or Mul'i9le!Cause <M"M"C= 8odel 1as u'ili@ed 'o
assess 'he a8oun' o5 di55eren'ial i'e8 5un,'ionin0 <#"F=.
Results
( '1o!5a,'or 8odel <9osi'i4e and ne0a'i4e a55e,'= sho1ed e?,ellen' 5i' in bo'h sa89les.
.'a'is'i,ally si0ni5i,an') bu' s8all!8a0ni'ude) #"F 1as 5ound 5or 3 o5 20 i'e8s on 'he
C2.!#. 7he 2n0lish!s9ea+in0 Canadian sa89le endorsed 8ore 5eelin0!rela'ed
sy89'o8s) 1hereas 'he #u',h sa89le endorsed 8ore so8a'i,/re'arded a,'i4i'y
sy89'o8s. 7he o4erall es'i8a'e in de9ression s,ores be'1een 2n0lish and #u',h 1as no'
in5luen,ed subs'an'i4ely by #"F.
Conclusions
C2.!# s,ores 5ro8 2n0lish!s9ea+in0 Canadian and #u',h .., 9a'ien's ,an be ,o89ared
and 9ooled 1i'hou' ,on,ern 'ha' 8easure8en' di55eren,es 8ay subs'an'i4ely in5luen,e
resul's. 7he i89or'an,e o5 assessin0 ,ross!lan0ua0e 8easure8en' eGui4alen,e in
rheu8a'olo0y s'udies 9rior 'o 9oolin0 ou',o8es ob'ained in di55eren' lan0ua0es should be
e89hasi@ed.
0o )o:
5ntroduction
6eal'h!rela'ed 9a'ien'!re9or'ed ou',o8e <6&!P&T= 8easures assess 9a'ien' heal'h) 1ell!
bein0) and res9onse 'o 'rea'8en' based on 9a'ien' 9ers9e,'i4es. 7hey 8ay re5le,' ,o89le?
,ons'ru,'s) su,h as heal'h!rela'ed Guali'y o5 li5e) or narro1er ,ons'ru,'s) su,h as
indi4idual sy89'o8s <e.0.) 9ain or 5a'i0ue= 'ha' are used 'o assess heal'h s'a'us in 9a'ien's
1i'h rheu8a'i, diseases E1FNE4F. ;ro1in0 re,o0ni'ion o5 'he i89or'an,e o5 6&!P&Ts and
'heir in,reasin0 in'e0ra'ion in'o bo'h resear,h and ,lini,al 9ra,'i,e has led 'o ini'ia'i4es 'o
i89ro4e 'heir o9era'ionali@a'ion.
"n 'he rheu8a'i, diseases) TM2&(C7 <Tu',o8e Measures in &heu8a'olo0y= E$F has
delinea'ed a se' o5 s'andards by 1hi,h 8easures ,an be e4alua'ed) in,ludin0 'he 'ru'h or
4alidi'y) dis,ri8ina'ion) and 5easibili'y o5 8easures. &e,en'ly) 'he CT.M"N ,he,+lis'
<Consensus!based .'andards 5or 'he sele,'ion o5 heal'h s'a'us Measure8en' "ns'ru8en's=
E6F 1as de4elo9ed 'o es'ablish ,ri'eria 5or e4alua'in0 'he 8e'hodolo0i,al Guali'y o5
s'udies on 6&!P&Ts. "n addi'ion 'o 'he s'andards des,ribed by TM2&(C7) 'he CT.M"N
,he,+lis' e89hasi@es 'he i89or'an,e o5 es'ablishin0 'he ,ross!,ul'ural 4alidi'y o5 6&!
P&Ts.
7he ,ross!,ul'ural 4alidi'y o5 6&!P&Ts is in,reasin0ly i89or'an' in 8edi,al resear,h)
sin,e 9a'ien's 1ho ,o89le'e ou',o8e 8easures in di55eren' lan0ua0es are ,o88only
in,luded in 'he sa8e s'udy. For ins'an,e) 'his o5'en o,,urs in ,oun'ries 1i'h 8ore 'han
one hi0hly ,o88on lan0ua0e) su,h as Canada <Fren,h/2n0lish= or 'he >ni'ed .'a'es
<.9anish/2n0lish=. "n addi'ion) 8ul'i,en'er 'rials 'ha' in,lude ,en'res 5ro8 di55eren'
,oun'ries are in,reasin0ly 5reGuen'. Par'i,ularly in rare diseases) su,h as sys'e8i,
s,lerosis <..,=) e55e,'i4e resear,h o5'en reGuires in'erna'ional ,ollabora'ion 'o in,lude a
su55i,ien' nu8ber o5 9a'ien's 5or adeGua'ely 9o1ered s'udies. 7he .,leroder8a Clini,al
7rials Consor'iu8 EF and 'he 2>/(& .,leroder8a 7rials and &esear,h 0rou9 E8F) 5or
ins'an,e) rou'inely ,ondu,' 8ul'i,en're dru0 'rials in4ol4in0 9a'ien's 5ro8 8ul'i9le
,oun'ries and 8easures 'ransla'ed in'o 8ul'i9le lan0ua0es. &e,en'ly) 'he .,leroder8a
Pa'ien'!,en'ered "n'er4en'ion Ne'1or+ 1as or0ani@ed 'o 'es' 9sy,hoso,ial and
rehabili'a'ion in'er4en'ions in 9a'ien's 5ro8 a,ross 2uro9e and Nor'h (8eri,a E%F.
(s des,ribed in 'he CT.M"N ,he,+lis' E6F) i' is i89or'an' 'o assess 'he de0ree 'o 1hi,h
ou',o8e 8easures 0enera'e s,ores 'ha' are eGui4alen' or in4arian' a,ross lin0uis'i, or
,ul'ural 0rou9s) 8eanin0 'ha' indi4iduals 5ro8 di55eren' 0rou9s 1i'h si8ilar le4els o5 an
ou',o8e o5 in'eres' should ob'ain eGual s,ores on 'he 8easure and res9ond si8ilarly 'o
indi4idual i'e8s o5 'he 8easure. 7his is be,ause di55eren,es in 'he 8eanin0 o5 i'e8s due
'o 'ransla'ion or ,ul'ural di55eren,es in i'e8 in'er9re'a'ion ,an lead 'o res9onses 'ha' di55er
a,ross 0rou9s e4en 1hen le4els o5 'he ou',o8e bein0 8easured are si8ilar. Measure8en'
di55eren,es be'1een 'ransla'ed Gues'ionnaires ,an be a serious 'hrea' 'o 'he 4alidi'y o5
,ross!,ul'ural ,o89arisons) be,ause 1hen 8easures are no' eGui4alen' 8e'ri,ally) i' is no'
9ossible 'o de'er8ine i5 any obser4ed di55eren,es be'1een 0rou9s re5le,' real di55eren,es
or are a ,onseGuen,e o5 8easure8en' ar'i5a,'s <e.0.) lin0uis'i,/,ul'ural di55eren,es= E10F.
7here5ore) ,ross!,ul'ural 4alidi'y should be es'ablished i5 6&!P&Ts are 'o be 9ooled
a8on0 s'udy 9ar'i,i9an's 5ro8 di55eren' ,oun'ries or used 'o ,o89are resul's be'1een
9a'ien's 5ro8 di55eren' ,ul'ural or lin0uis'i, 0rou9s E11F.
#i55eren'ial i'e8 5un,'ionin0 <#"F= is said 'o o,,ur 1hen an i'e8 o5 a 6&!P&T has
di55eren' 8easure8en' 9ro9er'ies 5or one 0rou9 ,o89ared 'o ano'her) irres9e,'i4e o5 'rue
di55eren,es o5 'he ,ons'ru,' 8easured. #i4erse s'a'is'i,al 8e'hods 5or assessin0 'he
9resen,e o5 #"F are a4ailable) based on non!9ara8e'ri,) 9ara8e'ri, or la'en' 4ariable
8odels) ea,h 1i'h i's o1n ad4an'a0es and disad4an'a0es E12F. ;enerally) ho1e4er) 'he
9resen,e o5 #"F is assessed by iden'i5yin0 di55eren,es in indi4idual i'e8 s,ores a,ross
0rou9s 'ha' are 9resen' e4en a5'er ,on'rollin0 5or le4els o5 'he o4erall ,ons'ru,' bein0
8easured. 3hen #"F is iden'i5ied) i' is assu8ed 'ha' s,ores on 'he i'e8 are in5luen,ed by
0rou9 ,hara,'eris'i,s 'ha' are no' dire,'ly rela'ed 'o 'he ,ons'ru,' bein0 8easured. 3hen
'ransla'ed 4ersions o5 6&!P&Ts are ad8inis'ered in di55eren' ,ul'ural se''in0s) #"F 8ay
o,,ur be,ause o5 al'era'ions in i'e8 8eanin0 due 'o 'ransla'ion or be,ause o5 ,ul'ural
5a,'ors 'ha' in5luen,e in'er9re'a'ion o5 i'e8 8eanin0.
6&!P&T 8easures 5or de9ressi4e sy89'o8s are in,reasin0ly used a8on0 9a'ien's 1i'h
,hroni, 8edi,al illness E13F) E14F. 7his is also 'he ,ase 5or 9a'ien's 1i'h ..,) 1hi,h is an
au'oi88une disease ,hara,'eri@ed by 'hi,+enin0 o5 'he s+in as a resul' o5 5ibrosis) as 1ell
as in4ol4e8en' o5 8ul'i9le in'ernal or0ans) 8os' ,o88only 'he lun0s) 0as'roin'es'inal
'ra,' and hear' E1$F. "n ..,) 'he Cen'er 5or 29ide8iolo0i, .'udies #e9ression .,ale
<C2.!#= E16F has been used 'o assess de9ressi4e sy89'o8s in 2n0lish E1FNE20F) Fren,h
E1%F) E20F) #u',h E21F) and ;er8an E22F. 7he C2.!# 1as ori0inally de4elo9ed in 'he
>.( 'o 8easure de9ressi4e sy89'o8a'olo0y in 'he 0eneral 9o9ula'ion E16F. 7he s,ale has
also sho1n 'o be a reliable and 4alid 8easure o5 de9ressi4e sy89'o8s a,ross 4arious
9a'ien' sa89les) in,ludin0 .., E23F. No s'udies) ho1e4er) in any 9a'ien' 0rou9 ha4e
assessed 'he de0ree 'o 1hi,h 'ransla'ed 4ersions o5 'he C2.!# are 8easure8en'
eGui4alen' 4ersus e?hibi'in0 subs'an'i4e #"F) 9ossibly due 'o 'he un5a8iliari'y o5
resear,hers and ,lini,ians 1i'h 'he need 5or assess8en' o5 ,ross!lan0ua0e 8easure8en'
9ro9er'ies or 'he 8e'hods by 1hi,h 'his ,an be done. 7his s'udy 9ro4ides an e?a89le o5
ho1 'o assess ,ross!lan0ua0e 8easure8en' eGui4alen,e by ,o89arin0 'he C2.!#
be'1een 2n0lish!s9ea+in0 Canadian and #u',h .., 9a'ien's.
0o )o:
Methods
4thics Statement
7he 2n0lish!s9ea+in0 sa89le o5 'his ,ross!se,'ional s'udy ,onsis'ed o5 9a'ien's 1i'h ..,
enrolled in 'he Canadian .,leroder8a &esear,h ;rou9 &e0is'ry <C.&;=. 7he s'udy 1as
a99ro4ed by 'he "ns'i'u'ional &e4ie1 Board o5 M,;ill >ni4ersi'y. 7he #u',h sa89le
,onsis'ed o5 9a'ien's 1i'h .., enrolled in a 3!year ,ohor' s'udy in NiI8e0en) 7he
Ne'herlands. 7he s'udy 1as a99ro4ed by 'he "ns'i'u'ional &e4ie1 Board o5 'he &adboud
>ni4ersi'y Medi,al Cen'er NiI8e0en <CMT2008/10%=. (ll 9a'ien's 9ro4ided 1ri''en
,onsen' 5or 'heir in5or8a'ion 'o be s'ored in a ,o89u'er da'abase and used 5or resear,h.
!atients and !rocedures
4nglish-speaking sample
7he 2n0lish!s9ea+in0 sa89le ,onsis'ed o5 9a'ien's enrolled in 'he C.&; 1ho ,o89le'ed
'he C2.!# in 2n0lish 5ro8 .e9'e8ber 2004 'hrou0h (9ril 2011. Pa'ien's in 'he &e0is'ry
are re,rui'ed 5ro8 1$ ,en'ers a,ross Canada. 7o be eli0ible 5or 'he &e0is'ry) 9a'ien's 8us'
ha4e a dia0nosis o5 .., ,on5ir8ed by a &e0is'ry rheu8a'olo0is') be 18 years o5 a0e) and
be 5luen' in 2n0lish or Fren,h. &e0is'ry 9a'ien's under0o e?'ensi4e 9hysi,al e4alua'ion a'
annual 4isi's and ,o89le'e a series o5 sel5!re9or' Gues'ionnaires in 'heir 9re5erred
lan0ua0e <2n0lish or Fren,h=. For 9a'ien's 1ho ,o89le'ed 'he C2.!# a' 8ul'i9le annual
4isi's) only da'a 5ro8 'he 8os' re,en' 4isi' 1as in,luded in analyses in 'he 9resen' s'udy.
'utch sample
7he #u',h sa89le ,onsis'ed o5 .., 9a'ien's 'rea'ed a' 'he .in' Maar'ens+linie+ or
&adboud >ni4ersi'y Medi,al Cen'er NiI8e0en) 7he Ne'herlands 1ho ,o89le'ed 'he
baseline assess8en' o5 a 3!year ,ohor' s'udy) in,ludin0 'he C2.!# in #u',h) be'1een
*une 2008 and February 2010. 7o be eli0ible) 9a'ien's had 'o ha4e a dia0nosis o5 ..,
a,,ordin0 'o 'he 9reli8inary (8eri,an Colle0e o5 &heu8a'olo0y ,lassi5i,a'ion ,ri'eria
E24F. 2?,lusion ,ri'eria 5or 9ar'i,i9a'ion in 'he ,ohor' 1ere a li5e e?9e,'an,y ]1 year)
a,u'e serious ,o89li,a'ions <e.0.) renal ,risis=) se4ere 9sy,hia'ri, ,o!8orbidi'y) o'her
serious ,o!8orbidi'ies <e.0.) ,an,er= and insu55i,ien' +no1led0e o5 'he #u',h lan0ua0e.
Measures
'emographics and disease characteristics
#e8o0ra9hi, 4ariables 5or bo'h sa89les in,luded a0e) se?) 8ari'al s'a'us) edu,a'ion and
,urren' e89loy8en' s'a'us. #isease ,hara,'eris'i,s 1ere assessed by s'udy
rheu8a'olo0is's in bo'h sa89les) in,ludin0 disease dura'ion) .., sub'y9e) and 'he
8odi5ied &odnan s+in s,ore <8&..=. #isease dura'ion 1as de5ined as 'i8e sin,e onse'
5ro8 5irs' non!&aynaud sy89'o8. Pa'ien's 1ere ,lassi5ied as ha4in0 li8i'ed or di55use
..,. /i8i'ed .., 1as de5ined as s+in in4ol4e8en' dis'al 'o 'he elbo1s and +nees only)
1hereas di55use .., 1as de5ined as s+in in4ol4e8en' 9ro?i8al 'o 'he elbo1s and +nees)
and 'he 'run+ also E2$F. 7he 8&.. is a s'andardi@ed ra'in0 o5 s+in in4ol4e8en' ran0in0
5ro8 0 <no in4ol4e8en'= 'o 3 <se4ere 'hi,+enin0= in 1 body areas <'o'al s,ore ran0e 0N
$1= E26F.
Symptoms o depression
7he C2.!# E16F is a 20!i'e8 8easure 'ha' assesses 'he 5reGuen,y o5 sy89'o8s durin0 'he
9as' 1ee+ on a 0N3 /i+er' s,ale <Rrarely or none o5 'he 'i8eS 'o R8os' or all o5 'he 'i8eS=.
.'andard ,u'o55s are A16 5or R9ossible de9ressionS and A23 5or R9robable de9ressionS
E16F. ( ,u'o55 o5 A1% has been su00es'ed in ar'hri'is E2F. 7he C2.!# used in 'he 2n0lish!
s9ea+in0 sa89le 1as 'he ori0inal 4ersion E16F) 1hi,h has sho1n 'o be a reliable and 4alid
8easure o5 de9ressi4e sy89'o8s in 9a'ien's 1i'h .., E23F. "n 'he #u',h sa89le) 'he
ori0inal 'ransla'ion E28F) 1hi,h has been sho1n 'o be reliable and 4alid a,ross di4erse
se''in0s 1as used.
Statistical Analyses
#e8o0ra9hi,s and disease ,hara,'eris'i,s 1ere ,o89ared be'1een 'he 2n0lish!s9ea+in0
and #u',h sa89les usin0 'he ,hi!sGuare s'a'is'i, 5or ,a'e0ori,al 4ariables and '!'es's 5or
,on'inuous 4ariables.
( 5lo1,har' o5 s'e9s under'a+en in 'he #"F analysis is de9i,'ed in Fi0ure 1. Firs') 'he
5a,'or s'ru,'ure o5 'he C2.!# 1as assessed 5or ea,h sa89le se9ara'ely usin0 ,on5ir8a'ory
5a,'or analysis <CF(=. "deally 5or #"F assess8en') 'he si89les' s'ru,'ure 1i'h reasonable
5i' 1ill be used. 7hus) an ini'ial CF( 8odel 1as ,ons'ru,'ed 1i'h M9lus E2%F 'o de'er8ine
i5 a sin0le!di8ensional s'ru,'ure o5 'he C2.!# in .., ,ould be reasonably used in 'he
#"F analysis 4ersus an al'erna'i4e s'ru,'ure. .ele,'ion o5 an al'erna'i4e s'ru,'ure 1as
based on a 9re4ious 4alida'ion s'udy o5 'he C2.!# in .., E23F. "'e8 res9onses 5or 'he
C2.!# 1ere ordinal /i+er' da'a) so 'he 1ei0h'ed leas' sGuares es'i8a'or 1i'h a dia0onal
1ei0h' 8a'ri?) robus' s'andard errors) and a 8ean! and 4arian,e!adIus'ed ,hi!sGuare
s'a'is'i, 1as used 1i'h del'a 9ara8e'eri@a'ion E2%F. Modi5i,a'ion indi,es 1ere used 'o
iden'i5y 9airs o5 i'e8s 1i'hin s,ales 5or 1hi,h 8odel 5i' 1ould i89ro4e i5 error es'i8a'es
1ere 5reed 'o ,o4ary and 5or 1hi,h 'here a99eared 'o be 'heore'i,ally Ius'i5iable shared
8e'hod e55e,'s <e.0.) si8ilar 1ordin0= E30F. 7o assess 8odel 5i') 'he ,hi!sGuare 'es') 'he
7u,+er!/e1is "nde? <7/"= E31F) 'he Co89ara'i4e Fi' "nde? <CF"= E32F and 'he &oo' Mean
.Guare 2rror o5 (99ro?i8a'ion <&M.2(= E33F 1ere used. .in,e 'he ,hi!sGuare 'es' is
hi0hly sensi'i4e 'o sa89le si@e) i' ,an lead 'o 'he reIe,'ion o5 1ell!5i''in0 8odels E34F.
7here5ore) 'he 7/") CF" and &M.2( 5i' indi,es 1ere e89hasi@ed. ;ood 5i''in0 8odels
are indi,a'ed by a 7/" and CF"A0.%$ and &M.2(U0.06 E3$F. Tn,e 'he 5a,'or s'ru,'ure
1as es'ablished 5or ea,h sa89le se9ara'ely) a CF( 8odel 1as 5i' 'ha' in,luded 9a'ien's
5ro8 bo'h sa89les ,o8bined.
@i.ure 1
%lowchart of steps to be undertaken in D6% analysis.
7he Mul'i9le!"ndi,a'or Mul'i9le!Cause <M"M"C= 8odel 1as u'ili@ed 'o de'er8ine i5
i'e8s o5 'he C2.!# e?hibi'ed #"F 5or 2n0lish!s9ea+in0 4ersus #u',h 9a'ien's. M"M"C
8odels 5or #"F assess8en' are based on s'ru,'ural eGua'ion 8odels) in 1hi,h 'he 0rou9
4ariable <2n0lish/#u',h= is added 'o 'he basi, CF( 8odel as an obser4ed 4ariable. 7hus)
'he base M"M"C 8odel ,onsis's o5 'he CF( 5a,'or 8odel 1i'h 'he addi'ional dire,' e55e,'
o5 0rou9 on 'he la'en' 5a,'ors) 1hi,h ser4es 'o ,on'rol 5or 0rou9 di55eren,es on 'he le4el
o5 'he la'en' 5a,'ors. .in,e 'here 1ere s'a'is'i,ally si0ni5i,an' di55eren,e be'1een our
sa89les) 1e also ,on'rolled 5or de8o0ra9hi, and disease 4ariables <a0e) se?) 8ari'al
s'a'us) edu,a'ion) ,urren' e89loy8en' s'a'us) .., sub'y9e) 8&.. and disease dura'ion=
by addin0 a dire,' e55e,' o5 'hese 4ariables on 'he la'en' 5a,'ors) 7hen) 'o assess 9o'en'ial
#"F) 'he dire,' e55e,' o5 0rou9 on C2.!# i'e8s is assessed 5or ea,h i'e8 se9ara'ely) by
re0ressin0 'he i'e8s) one a' a 'i8e) on 0rou9 <see Fi0ure 2=. 2a,h i'e8 is 'es'ed se9ara'ely
'o de'er8ine i5 'here is s'a'is'i,ally si0ni5i,an' #"F) re9resen'ed by a s'a'is'i,ally
si0ni5i,an' lin+ in 'he 8odel 5ro8 0rou9 'o 'he i'e8) a5'er ,on'rollin0 5or any di55eren,es
in 'he o4erall le4el o5 'he la'en' 5a,'or be'1een 0rou9s. "5 'here is #"F 5or one or 8ore
i'e8s) 'he i'e8 1i'h 'he lar0es' 8a0ni'ude o5 #"F is ,onsidered 'o ha4e #"F) and 'he lin+
be'1een 'he lin0uis'i, 0rou9 4ariable and 'ha' i'e8 is in,luded in 'he 8odel. 7hen) 'his
9ro,edure is re9ea'ed un'il none o5 'he re8ainin0 i'e8s sho1 si0ni5i,an' #"F. Tn,e all
i'e8s 1i'h si0ni5i,an' #"F are iden'i5ied) 'he 9o'en'ial 8a0ni'ude o5 #"F i'e8s
,olle,'i4ely) iden'i5ied 4ia assess8en' o5 s'a'is'i,al si0ni5i,an,e) ,an be e4alua'ed by
,o89arin0 'he di55eren,e on 'he la'en' 5a,'or be'1een 0rou9s in 'he baseline CF( 8odel
and a5'er ,on'rollin0 5or #"F. .in,e 'he C2.!# ,onsis's o5 a lar0e nu8ber o5 i'e8s)
6o88elsH E36F ,orre,'ion 5or 8ul'i9le 'es'in0 1as a99lied. CF( and #"F analyses 1ere
,ondu,'ed usin0 M9lus E2%F) all o'her analyses 1ere ,ondu,'ed usin0 .'a'a/"C 10.1
<.'a'aCor9 /P) Colle0e .'a'ion) 7K=.
@i.ure 2
,he M6M6# Model for the #entre for (pidemiologic Studies
Depression Scale &#(S7D'.
0o )o:
Results
Sample Characteristics
#e8o0ra9hi,s and disease ,hara,'eris'i,s 5or bo'h sa89les are dis9layed in 7able 1.
<"ble 1
Demographic and medical characteristics for both SSc samples.
4nglish-speaking sample
"n 'o'al) %6 9a'ien's ,o89le'ed 'he C2.!# in 2n0lish. .i? 9a'ien's 1ere e?,luded 5ro8
analysis) be,ause 'hey had b2 8issin0 4alues on 'he C2.!#. Fur'her8ore) 48 9a'ien's
1ere e?,luded be,ause 'hey 1ere dia0nosed 1i'h sine ..,) bu' no' di55use or li8i'ed ..,.
T5 'he re8ainin0 %22 9a'ien's) 84.8C 1ere 5e8ale. Mos' 9a'ien's <82.%C= 1ere 8arried
or ,ohabi'a'in0. 7he 8ean C2.!# s,ore 1as 14.3 <.#B 10.3= and 'he 9er,en'a0e o5
9a'ien's s,orin0 A16 1as 3.C. 7he 9er,en'a0e o5 9a'ien's 1i'h C2.!#A1% 1as 28.C.
'utch sample
"n 'o'al) 21$ 9a'ien's ,o89le'ed 'he baseline Gues'ionnaires. 71o 9a'ien's 1ere e?,luded
5ro8 'he analysis be,ause 'hey had b2 8issin0 4alues on 'he C2.!#. T5 'he 213 9a'ien's
in 'he sa89le) 6.6C 1ere 5e8ale. Mos' 9a'ien's <$.6C= 1ere 8arried or ,ohabi'a'in0.
7he 8ean C2.!# s,ore 1as 12.8 <.#B %.6= and 'he 9er,en'a0e o5 9a'ien's s,orin0 A16
1as 31.%C. 7he 9er,en'a0e o5 9a'ien's 1i'h C2.!#A1% 1as 24.%C.
Co89ared 1i'h 'he 2n0lish!s9ea+in0 sa89le) 9a'ien's in 'he #u',h sa89le 1ere
si0ni5i,an'ly 8ore li+ely 'o be 8ale and 'o ha4e li8i'ed disease. 7hey 1ere less li+ely 'o
ha4e ,o89le'ed 8ore 'han 12 years o5 edu,a'ion) or 'o be ,urren'ly 1or+in0.
Fur'her8ore) 9a'ien's in 'he #u',h sa89le had si0ni5i,an'ly shor'er disease dura'ion and
lo1er 8ean 8&.. s,ores. Mean C2.!# s,ores in 'he #u',h sa89le 1ere so8e1ha'
lo1er 'han in 'he 2n0lish!s9ea+in0 sa89le <P B 0.0$=. 7he 9ro9or'ion o5 9a'ien's 1i'h
C2.!#A16 <P B 0.11= and C2.!# A1% <P B 0.2= did no' di55er si0ni5i,an'ly.
Conirmatory 3actor Analysis
For bo'h sa89les) a sin0le!5a,'or s'ru,'ure 1as assessed ini'ially. "n bo'h 'he 2n0lish!
s9ea+in0 and #u',h sa89les) 'he 5i' 1as 9oor <2n0lish!s9ea+in0: s
2
<6= B 2218.8)
P]0.001) CF" B 0.1) 7/" B 0.88) &M.2(B 0.18; #u',h: s
2
<$0= B 2$%.0) P]0.001) CF" B
0.8) 7/" B 0.%4) &M.2(B 0.14=. "ns9e,'ion o5 'he 8odi5i,a'ion indi,es 5or bo'h
sa89les indi,a'ed ,orrela'ed error 'er8s o5 all 9osi'i4ely 1orded i'e8s <i'e8s 4) 8) 12 and
16=. .in,e allo1in0 'he error 'er8s o5 'hese i'e8s 'o be ,orrela'ed 1i'h ea,h o'her 1ould
essen'ially resul' in s9e,i5yin0 a se,ond 5a,'or) a '1o!5a,'or 8odel 1as re5i''ed) 1i'h '1o
,orrela'ed 5a,'ors: 9osi'i4e and ne0a'i4e E2F. 7he '1o!5a,'or 8odel sho1ed 0ood 5i' 'o
'he da'a in bo'h sa89les <2n0lish!s9ea+in0: s
2
<81= B $2.6) P]0.001) CF" B 0.%3) 7/" B
0.%8) &M.2(B 0.08; #u',h: s
2
<$1= B 128.3) P]0.001) CF" B 0.%$) 7/" B 0.%8) &M.2(B
0.08=. "n bo'h sa89les) ins9e,'ion o5 8odi5i,a'ion indi,es indi,a'ed 'ha' 5reein0 error
'er8s 'o ,o4ary 5or i'e8s 1$ and 1%) 1 and 18) and and 20) 1ould i89ro4e 8odel 5i')
and in ea,h ,ase 'here 1as ,learly re,o0ni@able o4erla9 in 'he i'e8sH ,on'en'. 7here5ore)
'he 8odel 1as re5i''ed 'o 'he da'a) allo1in0 'he error 'er8s 5or 'hose i'e8s 'o be
,orrela'ed. 7his ,han0e resul'ed in a 8odel 1i'h e?,ellen' 5i' 'o 'he da'a in bo'h sa89les
<2n0lish!s9ea+in0: s
2
<81= B 34$.1) P]0.0001) CF" B 0.%6) 7/" B 0.%%) &M.2(B 0.06;
#u',h: s
2
<$1= B %4.6) P]0.0001) CF" B 0.%) 7/" B 0.%%) &M.2(B 0.06=.
'ierential 5tem 3unctioning
7he '1o!5a,'or 8odel 'ha' 1as 5i' 5or ea,h sa89le indi4idually 1as 5i' 1i'h all 9a'ien's in
'he sa8e 8odel <7able 2=) alon0 1i'h a dire,' e55e,' o5 0rou9 <2n0lish/#u',h= on bo'h
5a,'ors <R9osi'i4eS/Rne0a'i4eS=. (s sho1n in 7able 3) 8odel 5i' 5or 'he ,o8bined sa89le
5or 'his base 8odel 1as e?,ellen'. Prior 'o a,,oun'in0 5or #"F) 2n0lish!s9ea+in0 9a'ien's
had hi0her la'en' 5a,'or s,ores 'han #u',h 9a'ien's: 0.1% s'andard de4ia'ions 5or
R9osi'i4eS 5a,'or s,ores) and 0.03 s'andard de4ia'ions 5or Rne0a'i4eS 5a,'or s,ores)
al'hou0h nei'her di55eren,e 1as s'a'is'i,ally si0ni5i,an'. "ni'ially) 'hree i'e8s sho1ed
si0ni5i,an' #"F: i'e8s 3) 4) and . "'e8 3 <@ B 4.4) P]0.001= and i'e8 4 <@ B 4.4) P]0.001=
had hi0her s,ores in 'he 2n0lish!s9ea+in0 sa89le) ,on'rollin0 5or di55eren,es on 'he la'en'
5a,'ors. Tn 'he o'her hand) i'e8 <@ B _3.6) P]0.001= had hi0her s,ores in 'he #u',h
sa89le. (ll 'hree i'e8s ,on'inued sho1in0 #"F) 'hrou0hou' 'he seGuen,e o5 ,orre,'in0 5or
#"F on 'he o'her i'e8s.
<"ble 2
%actor loadings on the 8positi"e9 and 8negati"e9 factors of the #(S7
D.
<"ble 3
%actor loadings of D6% items and in:uence on the o"erall estimates
of depression latent factor scores.
(5'er ,orre,'in0 5or #"F) ,o89ared 'o 'he base 8odel) 'here 1as a de,rease o5 0.10
s'andard de4ia'ions on 'he R9osi'i4eS la'en' 5a,'or and a de,rease o5 0.01 s'andard
de4ia'ions on 'he Rne0a'i4eS la'en' 5a,'ors in 'he di55eren,e be'1een 2n0lish!s9ea+in0
and #u',h 9a'ien's) and ,on5iden,e in'er4als 1ere o4erla99in0) as sho1n in 7able 3.
7hus) al'hou0h 'here 1as s'a'is'i,ally si0ni5i,an' #"F on 'hree C2.!# i'e8s) 'his did no'
in5luen,e 'he o4erall es'i8a'es o5 de9ression la'en' 5a,'or s,ores be'1een 2n0lish!
s9ea+in0 and #u',h 9a'ien's subs'an'i4ely.
0o )o:
'iscussion
"n order 'o ,o89are or 9ool da'a ob'ained 1i'h 6&!P&T 8easures 'ha' are ad8inis'ered
in di55eren' lan0ua0es) ,ross!,ul'ural or ,ross!lin0uis'i, eGui4alen,e o5 s,ores should be
es'ablished. (s an e?a89le o5 ho1 'o ,ondu,' su,h 'y9e o5 s'udies) in 'he 9resen' s'udy
'he ,ross!lin0uis'i, 8easure8en' eGui4alen,e 1as assessed 5or 'he C2.!# in 2n0lish!
s9ea+in0 Canadian and #u',h .., 9a'ien's. .i0ni5i,an' #"F 1as 5ound 5or 3 o5 20 i'e8s
on 'he C2.!#. 6o1e4er) 'he 8a0ni'ude o5 #"F 5or ea,h o5 'hese i'e8s 1as 4ery s8all)
and 'he e55e,' on o4erall C2.!# s,ores 1as ne0li0ible. 7his 8eans 'ha' i5 'here is #"F) i'
is so s8all 'ha' C2.!# s,ores 1ould no' be in5luen,ed 8eanin05ully by i'.
.8all!8a0ni'ude #"F 1as 5ound 5or so8e i'e8s in our s'udy. #"F in ,ross!lin0uis'i,
,o89arisons 8ay be ,aused by a la,+ o5 ,on,e9'ual eGui4alen,e due 'o di55eren,es in
,on'en') 5or8a') di55i,ul'y or ,ul'ural rele4an,e 5or 'he 2n0lish!s9ea+in0 ,o89ared 'o 'he
#u',h sa89le E10F. 7he #u',h sa89le s,ored hi0her) e4en a5'er ,on'rollin0 5or la'en'
de9ression sy89'o8 le4els) on 2 i'e8s 'ha' 1ere si8ilar in 8eanin0 and rela'ed 'o ener0y
le4els and e55or'. Canadian 2n0lish!s9ea+in0 9a'ien's) on 'he o'her hand) a99eared 'o
endorse 8ore J5eelin0H sy89'o8s. "' is 9ossible 'ha' 'his is rela'ed 'o ,ul'ural di55eren,es
in ho1 sy89'o8s are e?9erien,ed or e?9ressed. "' is also 9ossible) ho1e4er) 'ha' 'hese
di55eren,es 8ay be rela'ed 'o 'ransla'ion. For i'e8 <R255or'S=) no re8ar+able di55eren,es
1ere 5ound in 'he 'ransla'ions. 7his 1as no' 'he ,ase) ho1e4er) 5or i'e8s 3 <RBluesS= and
4 <R;oodS=. "n 5a,') 'here are 8any e?a89les o5 dis,ussions in 'he 9ublished li'era'ure
rela'ed 'o 'he di55i,ul'y o5 'ransla'in0 5ro8 2n0lish R5eelin0 blueS and rela'ed e?9ressions
su,h as Rha4in0 'he bluesS E3FNE3%F. "n 8any lan0ua0es) in,ludin0 #u',h) a s'ri,'ly
le?i,al 'ransla'ion 5or 'hese 'er8s is 8eanin0less. 7here5ore) in 'ransla'ed 4ersions) 1ords
need 'o be 5ound 1i'h su55i,ien' si8ilari'y 'o ,on4ey 'he ,on,e9') 1hi,h 8i0h' lead 'o
sli0h' di55eren,es be'1een 'ransla'ed 4ersions. For i'e8 4 <R" 5el' 'ha' " 1as Ius' as 0ood
as o'her 9eo9leS=) in 'he #u',h 4ersion o5 'he C2.!#) 'he 'ransla'ion o5 R0oodS is
in'er9re'ed as R1or'h)S 1hi,h has a sli0h'ly di55eren' ,onno'a'ion) and) 'here5ore) 8i0h'
ha4e in5luen,ed res9onses di55eren'ly a,ross 0rou9s.
#es9i'e 'he iden'i5i,a'ion o5 8inor #"F 5or se4eral i'e8s) 'his s'udy 5ound 'ha' C2.!#
s,ores 5or 2n0lish and #u',h .., 9a'ien's 1i'h eGual le4els o5 de9ressi4e sy89'o8s
1ould be e?9e,'ed 'o be hi0hly si8ilar. "n o'her 1ords) 9ossible #"F on sin0le i'e8s 1as
o5 4ery s8all 8a0ni'ude and had ne0li0ible in5luen,e on 'he o4erall s,ore. 7here5ore)
s,ores 0enera'ed 1i'h 'he 2n0lish and #u',h 4ersions o5 'he C2.!# are ,o89arable and
do no' reGuire adIus'8en' 5or lin0uis'i, di55eren,es. 7his is an i89or'an' resul' 0i4en 'he
in,reasin0ly ,o88on use o5 8ul'ina'ional ,ollabora'ions 'o ,ondu,' resear,h in rare
diseases) su,h as .., EFNE%F. Fu'ure s'udies should e?'end 'he ,urren' assess8en' o5 'he
C2.!# in'o o'her lan0ua0es. "n addi'ion) 8easure8en' eGui4alen,e should also be
assessed 5or o'her 5reGuen'ly used 6&!P&Ts ,en'ral 'o resear,h in rheu8a'i, diseases)
in,ludin0) 5or ins'an,e) 'he 6eal'h (ssess8en' Wues'ionnaire E40F and 'he .F!36 E41F.
7here are li8i'a'ions 'ha' should be ,onsidered in in'er9re'in0 'he resul's o5 'his s'udy.
Be,ause o5 'he di55eren,e in sa89le si@e be'1een 'he sa89les) 'he ,ore 8odel used 'o
assess #"F relied 8ore on da'a 5ro8 2n0lish!s9ea+in0 9a'ien's 'han #u',h 9a'ien's.
6o1e4er) sin,e 'he ini'ial 5a,'or analysis yielded 'he sa8e resul's in bo'h sa89les) i' does
no' see8 li+ely 'ha' 'his 1ould ha4e in5luen,ed resul's subs'an'ially. ( se,ond li8i'a'ion
rela'es 'o di55eren,es in sa89le re,rui'8en'. #u',h 9a'ien's 1ere re,rui'ed 5ro8 '1o
hos9i'als) be'1een 2008 and 2010) 1hereas 'he 2n0lish!s9ea+in0 9a'ien's 1ere re,rui'ed
5ro8 1$ ,en'ers 5ro8 a,ross Canada be'1een 2004 and 2011. Fur'her8ore) 'here 1ere
so8e di55eren,es in in,lusion ,ri'eria 5or 'he '1o sa89les and in 'he de8o0ra9hi, <in
9ar'i,ular) se?= and disease ,hara,'eris'i,s <in 9ar'i,ular) disease sub'y9e and dura'ion= o5
'he sa89les. 6o1e4er) 'he sensi'i4i'y analysis ,orre,'in0 5or di55eren,es in de8o0ra9hi,s
and disease ,hara,'eris'i,s be'1een sa89les yielded 4ir'ually 'he sa8e resul's as 'he non!
,orre,'ed 8odel) 1hi,h su00es's 'ha' di55eren,es in sa89le ,hara,'eris'i,s did no' li+ely
in5luen,e 'he resul's. Finally) M"M"C 8odels do no' 'es' 5or non!uni5or8 #"F. Non!
uni5or8 #"F 8eans 'ha' 'he a8oun' o5 #"F is uneGual 5or di55eren' le4els o5 'he ou',o8e
o5 in'eres') in our ,ase de9ression. Tn 'he o'her hand) M"M"C 8odels do allo1 5or
adIus'8en' 5or i89or'an' ,o4aria'es 'ha' 8ay di55er be'1een ,o89arison 0rou9s) 1hi,h is
an i89or'an' s'ren0'h o5 'he 8odel.
"n ,on,lusion) 'here 1ere 3 C2.!# i'e8s 1i'h e4iden,e o5 8inor #"F be'1een 'he
2n0lish and #u',h sa89les. T4erall) ho1e4er) 'here 1as no e4iden,e 'ha' 'hese 8inor
di55eren,es in5luen,ed o4erall s,ores. 7here5ore) C2.!# s,ores 5ro8 2n0lish!s9ea+in0
Canadian and #u',h .., 9a'ien's ,an be ,o89ared and 9ooled 1i'hou' ,on,ern 'ha'
8easure8en' di55eren,es 8ay subs'an'i4ely in5luen,e resul's.
;i4en 'he i89or'an,e o5 in'erna'ional ,ollabora'ions and 8ul'i!,en'er 'rials) in 9ar'i,ular
5or resear,h on rare diseases su,h as ..,) addi'ional s'udies are needed 'ha' assess 'he
8easure8en' o5 o'her +ey 6&!P&Ts a,ross lan0ua0es. &esear,hers a,ross areas o5
resear,h and lan0ua0es should be a1are o5 'he i89or'an,e o5 assessin0 ,ross!lan0ua0e
8easure8en' eGui4alen,e o5 6&!P&Ts 9rior 'o 9oolin0 resul's ob'ained in di55eren'
lan0ua0es.
0o )o:
Acknowledgments
C.&; &e,rui'in0 &heu8a'olo0is's: *. Po9e) >ni4ersi'y o5 3es'ern Tn'ario) /ondon)
Tn'ario; M. Baron) M,;ill >ni4ersi'y) Mon'real) Wuebe,; *. Mar+land) >ni4ersi'y o5
.as+a',he1an) .as+a'oon) .as+a',he1an; N. (. Mhalidi) M,Mas'er >ni4ersi'y) 6a8il'on)
Tn'ario; (. Mase''o) >ni4ersi'^ de .herbroo+e) .herbroo+e) Wuebe,; 2. .u''on)
#alhousie >ni4ersi'y) 6ali5a?) No4a .,o'ia; N. *ones) >ni4ersi'y o5 2d8on'on)
2d8on'on) (lber'a; #. &obinson) >ni4ersi'y o5 Mani'oba) 3inni9e0) Mani'oba; 2.
Ma8ins+a) M,Mas'er >ni4ersi'y) 6a8il'on) Tn'ario; P. #o,her'y) 7he Mon,'on 6os9i'al)
Mon,'on) Ne1 Bruns1i,+; *.!P. Ma'hieu) >ni4ersi'^ de Mon'r^al) Mon'real) Wuebe,; ..
/eCler,G) >ni4ersi'y o5 Cal0ary) Cal0ary) (lber'a; M. 6udson) M,;ill >ni4ersi'y)
Mon'real) Wuebe,; .. /i0ier) >ni4ersi'^ de Mon'r^al) Mon'real) Wuebe,) 7. ;rod@i,+y)
>ni4ersi'^ de Mon'r^al) Mon'real) Wuebe,; C. 7horne) .ou'hla+e &e0ional 6eal'h Cen're)
Ne18ar+e') Tn'ario; ;. ;y0er) M,;ill >ni4ersi'y) Mon'real) Wuebe,; #. .8i'h)
>ni4ersi'y o5 T''a1a) T''a1a) Tn'ario; X M. Fri'@ler) (d4an,ed #ia0nos'i,s /abora'ory
and >ni4ersi'y o5 Cal0ary) Cal0ary) (lber'a.
0o )o:
3unding Statement
$/ is )he direc)or o> )he %"n"di"n Scleroderm" 3ese"rch 0rou#* 7hich
receiBes .r"n) >undin. >rom )he %"n"di"n &ns)i)u)es o> Pe"l)h 3ese"rch* )he
Scleroderm" Socie)+ o> %"n"d" "nd i)s #roBinci"l ch"#)ers* Scleroderm"
Socie)+ o> On)"rio* SclArodermie TuAbec* )he On)"rio 4r)hri)is Socie)+* "nd
educ")ion"l .r"n)s >rom 4c)elion Ph"rm"ceu)ic"ls "nd PGKer &nc. /D< "nd $P
"re su##or)ed b+ ,e7 &nBes)i.")or 47"rds >rom )he %"n"di"n &ns)i)u)es o>
Pe"l)h 3ese"rch "nd [)"blissemen) de 1eunes %hercheurs "7"rds >rom )he
@onds de l" 3echerche en S"n)A du TuAbec. <he >unders h"d no role in s)ud+
desi.n* d")" collec)ion "nd "n"l+sis* decision )o #ublish* or #re#"r")ion o> )he
m"nuscri#).
0o )o:
Reerences
1. @"irclou.h DL (200:) P")ien) re#or)ed ou)comes "s end#oin)s in medic"l
rese"rch. S)") $e)hods $ed 3es 13: 115D38. EPub$edF
2. /ren L (200') <he im#or)"nce o> #")ien)9re#or)ed ou)comes\i)Cs "ll "bou)
)he #")ien)s. @D4 %onsum :0: 2'D32. EPub$edF
3. Nells 0* Li <* $"I7ell L* $"cle"n 3* <u.7ell P (2008) 3es#onsiBeness o>
#")ien) re#or)ed ou)comes includin. >")i.ue* slee# 5u"li)+* "c)iBi)+ limi)")ion*
"nd 5u"li)+ o> li>e >ollo7in. )re")men) 7i)h "b")"ce#) >or rheum")oid "r)hri)is.
4nn 3heum Dis '7: 2'0D5. EPub$edF
:. Per $* 2"B"n"u.h 4 (2012) P")ien)9re#or)ed ou)comes in rheum")oid
"r)hri)is. %urr O#in 3heum")ol 2:: 327D3:. EPub$edF
5. /oers $* /roo6s P* S)r"nd %8* <u.7ell P (1((8) <he O$=34%< Gl)er >or
Ou)come $e"sures in 3heum")olo.+. 1 3heum")ol 25: 1(8D(. EPub$edF
'. $o66in6 L/* <er7ee %/* P")ric6 DL* 4lonso 1* S)r")>ord PN* e) "l. (2010) <he
%OS$&, chec6lis) >or "ssessin. )he me)hodolo.ic"l 5u"li)+ o> s)udies on
me"suremen) #ro#er)ies o> he"l)h s)")us me"suremen) ins)rumen)s: "n
in)ern")ion"l Del#hi s)ud+. Tu"l Li>e 3es 1(: 53(D:(. EP$% >ree "r)icleF
EPub$edF
7. Scleroderm" %linic"l <ri"ls %onsor)ium. 4B"il"ble: h))#:777.sc)c9
online.or.4ccessed 2012 4#ril 12.
8. <+nd"ll 4* $ueller9L"dner J* $")ucci9%erinic $ (2005) S+s)emic sclerosis in
=uro#e: Grs) re#or) >rom )he =JL43 Scleroderm" <ri"ls "nd 3ese"rch
(=JS<43) .rou# d")"b"se. 4nn 3heum Dis ':: 1107. EP$% >ree "r)icleF
EPub$edF
(. <hombs /D* 1e7e)) L3* 4ss"ssi S* /"ron $* /"r)le)) S1* e) "l. (2012) ,e7
direc)ions >or #")ien)9cen)red c"re in scleroderm": )he Scleroderm" P")ien)9
cen)red &n)erBen)ion ,e)7or6 (SP&,). %lin =I# 3heum")ol 30: S23D(. EPub$edF
10. Mumbo /D (1((() 4 h"ndboo6 on )he )heor+ "nd me)hods o> diQeren)i"l
i)em >unc)ionin. (D&@): Lo.is)ic re.ression modelin. "s " uni)"r+ >r"me7or6
>or bin"r+ "nd li6er)9)+#e (ordin"l) i)em scores. O))"7" O,: Direc)or")e o>
Pum"n 3esources 3ese"rch "nd =B"lu")ion* De#"r)men) o> ,")ion"l De>ense.
11. <eresi 14 (200') DiQeren) "##ro"ches )o diQeren)i"l i)em >unc)ionin. in
he"l)h "##lic")ions. 4dB"n)".es* dis"dB"n)".es "nd some ne.lec)ed )o#ics.
$ed %"re ::: S152D70. EPub$edF
12. Mumbo /D (2007) <hree .ener")ions o> diQeren)i"l i)em >unc)ionin. (D&@)
"n"l+ses: %onsiderin. 7here i) h"s been* 7here i) is no7* "nd 7here i) is
.oin.. L"n. 4ssess T :: 223D33.
13. =B"ns DL* %h"rne+ DS* Le7is L* 0olden 3,* 0orm"n 1$* e) "l. (2005)
$ood disorders in )he medic"ll+ ill: scien)iGc reBie7 "nd recommend")ions.
/iol Ps+chi")r+ 58: 175D8(. EPub$edF
1:. <hombs /D* <"ille>er SS* Pudson $* /"ron $ (2007) De#ression in
#")ien)s 7i)h s+s)emic sclerosis: " s+s)em")ic reBie7 o> )he eBidence.
4r)hri)is 3heum 57: 108(D(7. EPub$edF
15. 2")sumo)o <3* Nhi)Geld $L* %onnoll+ $2 (2011) <he #")ho.enesis o>
s+s)emic sclerosis. 4nnu 3eB P")hol. 28: 50(D37. EPub$edF
1'. 3"dloQ LS (1((7) <he %=S9D Sc"le: 4 sel>9re#or) de#ression sc"le >or
rese"rch in )he .ener"l #o#ul")ion. 4##l Ps+chol $e"s 1: 385D:01.
17. /uc6 J* Poole 1* $endelson % (2010) @"c)ors rel")ed )o sel>9eOc"c+ in
#ersons 7i)h scleroderm". $usculos6ele)"l %"re 8: 1(7D203. EP$% >ree
"r)icleF EPub$edF
18. ,ie)er) P1* $i)chell P%* /ols)er $/* %urr"n $L* <ille+ /%* e) "l. (2005)
%orrel")es o> de#ression* includin. oBer"ll "nd ."s)roin)es)in"l >unc)ion"l
s)")us* "mon. #")ien)s 7i)h s+s)emic sclerosis. 1 3heum")ol 32: 51D7.
EPub$edF
1(. <hombs /D* Pudson $* <"ille>er SS* /"ron $ (2008) %"n"di"n
Scleroderm" 3ese"rch 0rou# (2008) PreB"lence "nd clinic"l correl")es o>
s+m#)oms o> de#ression in #")ien)s 7i)h s+s)emic sclerosis. 4r)hri)is 3heum
5(: 50:D(. EPub$edF
20. $ile))e 2* Pudson $* /"ron $* <hombs /D (2010) %"n"di"n Scleroderm"
3ese"rch 0rou# (2010) %om#"rison o> )he PPT9( "nd %=S9D de#ression
sc"les in s+s)emic sclerosis: in)ern"l consis)enc+ reli"bili)+* conBer.en)
B"lidi)+ "nd clinic"l correl")es. 3heum")olo.+ :(: 78(D('. EPub$edF
21. 27"66enbos L* B"n L"n6Beld N0* 8on6 $%* /ec6er =S* B"n den Poo.en
@P* e) "l. (2012) Dise"se9rel")ed "nd #s+chosoci"l >"c)ors "ssoci")ed 7i)h
de#ressiBe s+m#)oms in #")ien)s 7i)h s+s)emic sclerosis* includin. >e"r o>
#ro.ression "nd "##e"r"nce sel>9es)eem. 1 Ps+chosom 3es 72: 1((D20:.
EPub$edF
22. $]ller P* 3ehber.er P* 0]n)her %* Schmi)) 1 (2012) De)ermin"n)s o>
dis"bili)+* 5u"li)+ o> li>e "nd de#ression in derm")olo.ic"l #")ien)s 7i)h
s+s)emic scleroderm". /r 1 Derm")ol 1'': 3:3D53. EPub$edF
23. <hombs /D* Pudson $* Schieir O* <"ille>er SS* /"ron $* e) "l. (2008)
3eli"bili)+ "nd B"lidi)+ o> )he %en)er >or =#idemiolo.ic S)udies De#ression
Sc"le in #")ien)s 7i)h s+s)emic sclerosis. 4r)hri)is 3heum 5(: :38D:3.
EPub$edF
2:. Subcommi))ee >or Scleroderm" %ri)eri" o> )he 4meric"n 3heum")ism
4ssoci")ion Di".nos)ics "nd <her"#eu)ic %ri)eri" %ommi))ee (1(80)
Prelimin"r+ cri)eri" >or )he cl"ssiGc")ion o> s+s)emic sclerosis (scleroderm").
4r)hri)is 3heum 23: 581D(0. EPub$edF
25. Le3o+ =%* /l"c6 %* @leischm"!er 3* 1"blons6" S* 2rie. <* e) "l. (1(88)
Scleroderm" (s+s)emic sclerosis): cl"ssiGc")ion* subse)s "nd #")ho.enesis. 1
3heum")ol 15: 202D5. EPub$edF
2'. %lemen)s P* L"chenbruch P* Siebold 1* Nhi)e /* Neiner S* e) "l. (1((5)
&n)er "nd in)r"obserBer B"ri"bili)+ o> )o)"l s6in )hic6ness score (modiGed
3odn"n <SS) in s+s)emic sclerosis. 1 3heum")ol 22: 1281D5. EPub$edF
27. $"r)ens $P* P"r6er 1%* Sm"rr 2L* Pe7e)) 1=* Sl"u.h)er 13* e) "l. (2003)
4ssessmen) o> de#ression in rheum")oid "r)hri)is: " modiGed Bersion o> )he
%en)er >or =#idemiolo.ic S)udies De#ression Sc"le. 4r)hri)is 3heum :(: 5:(D
55. EPub$edF
28. /oum" 1* 3"nchor 48* S"nderm"n 3* 8"n Sonderen @LP (1((5) Pe) me)en
B"n s+m#)omen B"n de#ressie me) de %=S9D. =en h"ndleidin.. E$e"surin.
s+m#)oms o> de#ression usin. )he %=S9D. 4 m"nu"l.F 0ronin.en: ,oordeli!6
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4n.eles: $u)hAn* L2 ^ $u)hAn* /O.
30. $cDon"ld 3P* 3in.o Po $ (2002) Princi#les "nd #r"c)ice in re#or)in.
s)ruc)ur"l e5u")ion "n"l+ses. Ps+chol $e)hods 7: ':D82. EPub$edF
31. <uc6er L3* Le7is % (1(73) 4 reli"bili)+ coeOcien) >or m"Iimum li6elihood
>"c)or "n"l+sis. Ps+chome)ri6" 38: 1D10.
32. /en)ler P$ (1((0) %om#"r")iBe G) indeIes in s)ruc)ur"l models. Ps+chol
/ull 107: 238D:'. EPub$edF
33. S)ei.er 1P (1((0) S)ruc)ur"l model eB"lu")ion "nd modiGc")ion: 4n
in)erB"l es)im")ion "##ro"ch. $ul)iB"ri")e /eh"B 3es 25: 173D80.
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res#onse )heor+: <7o "##ro"ches >or eI#lorin. me"suremen) inB"ri"nce.
Ps+chol /ull 11:: 552D''. EPub$edF
35. Pu L* /en)ler P$ (1((() %u)oQ cri)eri" >or G) indeIes in coB"ri"nce
s)ruc)ure "n"l+sis: %onBen)ion"l cri)eri" Bersus ne7 "l)ern")iBes. S)ruc) =5u
$odelin. ': 1D55.
3'. Pommel 0 (1(88) 4 s)".e7ise re!ec)iBe mul)i#le )es) #rocedure on "
modiGed /on>erroni )es). /iome)ri6" 75: 383D'.
37. 2leinm"n 4 (1(87) 4n)hro#olo.+ "nd #s+chi")r+. <he role o> cul)ure in
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38. 3o.ler LP (1((() $e)hodolo.ic"l sources o> cul)ur"l insensi)iBi)+ in men)"l
he"l)h rese"rch. 4m Ps+chol 5::2:D33. EPub$edF
3(. Pun) S$* /ho#"l 3 (200:) Sel> re#or) in clinic"l "nd e#idemiolo.ic"l
s)udies 7i)h non9=n.lish s#e"6ers: )he ch"llen.e o> l"n.u".e "nd cul)ure. 1
=#idemiol %ommuni)+ Pe"l)h 58: '18D22. EP$% >ree "r)icleF EPub$edF
:0. @ries 1@* S#i)K P* 2r"ines 30* Polm"n P3 (1(80) $e"suremen) o> #")ien)
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:73D83. EPub$edF

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