American Journal of Clinical Nutrition, Vol. 71, No.

1, 327S-330S, January 2000

2000 American Society for Clinical Nutrition
Supplements
Long-chain polyunsaturated fatty acids
in children with attention-deficit
hyperactivity disorder
1,2
John R ur!e"", #aura Ste$en", %en &han! an' #oui"e (ec)
1
*rom the +e,artment of *oo'" an' Nutrition, (ur'ue -ni$er"ity, %e"t #afayette, .N.
2
A''re"" re,rint re/ue"t" to JR ur!e"", +e,artment of *oo'" an' Nutrition, (ur'ue -ni$er"ity, %e"t
#afayette, .N 07107-1220. 3-mail4 5ur!e""67cf".,ur'ue.e'u.
ABSTRAT
Attention-'eficit hy,eracti$ity 'i"or'er 8A+9+: i" the 'ia!no"i" u"e' to 'e"cri5e
chil'ren ;ho are inattenti$e, im,ul"i$e, an' hy,eracti$e. A+9+ i" a ;i'e",rea'
con'ition that i" of ,u5lic health concern. .n mo"t chil'ren ;ith A+9+ the cau"e i"
un)no;n, 5ut i" thou!ht to 5e 5iolo!ical an' multifactorial. Se$eral ,re$iou" "tu'ie"
in'icate' that "ome ,hy"ical "ym,tom" re,orte' in A+9+ are "imilar to "ym,tom"
o5"er$e' in e""ential fatty aci' 83*A: 'eficiency in animal" an' human" 'e,ri$e' of
3*A". %e re,orte' ,re$iou"ly that a "u5!rou, of A+9+ "u56ect" re,ortin! many
"ym,tom" in'icati$e of 3*A 'eficiency 8#-A+9+: ha' "i!nificantly lo;er ,ro,ortion"
of ,la"ma arachi'onic aci' an' 'oco"ahe<aenoic aci' than 'i' A+9+ "u56ect" ;ith fe;
"uch "ym,tom" or control "u56ect". .n another "tu'y u"in! contra"t analy"i" of the
,la"ma ,olar li,i' 'ata, "u56ect" ;ith lo;er com,o"ition" of total n=3 fatty aci'" ha'
"i!nificantly more 5eha$ioral ,ro5lem", tem,er tantrum", an' learnin!, health, an' "lee,
,ro5lem" than 'i' tho"e ;ith hi!h ,ro,ortion" of n=3 fatty aci'". >he rea"on" for the
lo;er ,ro,ortion" of lon!-chain ,olyun"aturate' fatty aci'" 8#C(-*A": in the"e
chil'ren are not clear? ho;e$er, factor" in$ol$in! fatty aci' inta)e, con$er"ion of 3*A"
to #C(-*A ,ro'uct", an' enhance' meta5oli"m are 'i"cu""e'. >he relation 5et;een
#C(-*A "tatu" an' the 5eha$ior ,ro5lem" that the chil'ren e<hi5ite' i" al"o unclear.
%e are currently te"tin! thi" relation in a 'ou5le-5lin', ,lace5o-controlle' inter$ention
in a ,o,ulation of chil'ren ;ith clinically 'ia!no"e' A+9+ ;ho e<hi5it "ym,tom" of
3*A 'eficiency.
!ey "ords# 3""ential fatty aci'" @ 3*A @ attention-'eficit hy,eracti$ity 'i"or'er @
A+9+ @ thir"t @ 'ry ")in @ fre/uent urination @ n=3 fatty aci'" @ arachi'onic aci' @
2040n=2 @ 'oco"ahe<aenoic aci' @ 2242n=3 @ chil'ren
$%TR&'(T$&%
Chil'ren ;ith attention-'eficit hy,eracti$ity 'i"or'er 8A+9+: ha$e ,ro5lem" ,ayin!
attention, li"tenin! to in"truction", an' com,letin! ta")"? they al"o fi'!et an' "/uirm,
are hy,eracti$e, 5lurt out an";er", an' interru,t other". >he"e 5eha$ior" may "e$erely
affect "chool ,erformance, family relation", an' "ocial interaction" ;ith ,eer". Rou!hly
20=2AB of chil'ren ;ith A+9+ "ho; one or more ",ecific learnin! 'i"a5ilitie" in
math, rea'in!, or ",ellin! 81:. Chil'ren ;ith A+9+ often ha$e trou5le ,erformin!
aca'emically an' ,ayin! attention, an' may 5e 'i"or!aniCe', ha$e ,oor "elf-'i"ci,line,
an' ha$e lo; "elf-e"teem. A con"er$ati$e e"timate i" that 3=AB of the "chool-a!e
,o,ulation ha" A+9+ 82:. >reatment" for A+9+ inclu'e 5eha$ior thera,y an'
me'ication" 83:. ("ycho"timulant 'ru!" an' anti'e,re""ant" are often u"e' to calm
chil'ren ;ith A+9+, ;ith an effecti$ene"" rate of D7AB 80:. >he a'$anta!e" of u"in!
the"e me'ication" inclu'e ra,i' re",on"e, ea"e of u"e, effecti$ene"", an' relati$e "afety.
+i"a'$anta!e" inclu'e ,o""i5le "i'e effect", inclu'in! 'ecrea"e' a,,etite an' !ro;th,
in"omnia, increa"e' irrita5ility, an' re5oun' hy,eracti$ity ;hen the 'ru! ;ear" off 8A:.
9o;e$er, the"e me'ication" 'o not a''re"" the un'erlyin! cau"e" of A+9+. >hu",
"tu'ie" to eluci'ate the ,otential contri5utor" to the 5eha$ior ,ro5lem" in A+9+ may
lea' to more effecti$e treatment "trate!ie" for "ome chil'ren.
#inoleic aci' 8#A? 1E42n=2: an' F-linolenic aci' 81E43n=3: are e""ential fatty aci'"
83*A": an' mu"t 5e con"ume' in the 'iet 5ecau"e human" an' mo"t other mammal"
lac) the a5ility to "ynthe"iCe them 82:. >he"e fatty aci'" are con$erte' to a $ariety of
lon!er, more hi!hly ,olyun"aturate' ,ro'uct" that maintain cell mem5rane "tructure an'
are a "ource of material for the formation of localiCe' hormone" calle' eico"anoi'",
;hich are in$ol$e' in almo"t e$ery 5iolo!ically "i!nificant ,roce"" in the 5o'y 87:.
A''itionally, n=3 fatty aci'" are ",ecifically im,licate' in maintainin! central ner$ou"
"y"tem function. +eficiency of n=2 fatty aci'" lea'" to im,aire' !ro;th, 'ry an' "caly
")in, ,oly'i,"ia, an' ,olyuria, amon! other "ym,tom" 8E, 1:. +eficiency of n=3 fatty
aci'" in rat" an' mon)ey" i" a""ociate' ;ith 5eha$ioral, "en"ory, an' neurolo!ic
'y"function 810=12:.
)ATT* A$' STAT(S &) +$L'R,% "$T+
A'+'
Se$eral "tu'ie" ha$e focu"e' on e""ential fatty aci' meta5oli"m in chil'ren ;ith A+9+.
Chil'ren ;ith hy,eracti$ity ha$e 5een re,orte' to 5e more thir"ty than normal chil'ren
an' ha$e "ym,tom" of ecCema, a"thma, an' other aller!ie" 813:. .n a cro""-"ectional
"tu'y in 2=12-y-ol' 5oy" recruite' from central .n'iana, ;e "ho;e' that A3 "u56ect"
;ith A+9+ ha' "i!nificantly lo;er ,ro,ortion" of )ey fatty aci'" in the ,la"ma ,olar
li,i'" Garachi'onic aci' 8AA? 2040n=2:, eico"a,entaenoic aci' 8204An=3:, an'
'oco"ahe<aenoic aci' 8+9A? 2242n=3:H an' in re' 5loo' cell total li,i'" 82040n=2 an'
2240n=2: than 'i' 03 control "u56ect" 810:. >hi" fin'in! a!ree" ;ith a ,re$iou" re,ort
813:. 9o;e$er, a further fin'in! ;a" that a "u5!rou, of 21 "u56ect" ;ith A+9+ ;ho
e<hi5ite' a !reater fre/uency of 3*A 'eficiency "ym,tom" 8thir"t, fre/uent urination,
an' 'ry hair: 800B of the "am,le: ha' "i!nificantly lo;er ,la"ma ,ro,ortion" of AA
an' 2242n=3 than 'i' the other 32 "u56ect" ;ith A+9+ 820B of the "am,le:, ;ho ha'
fe; "ym,tom" of 3*A 'eficiency 8Ta-le 1:. Ioreo$er, the ,la"ma fatty aci'
com,o"ition in the "u56ect" ;ith fe; "ym,tom" ;a" not "i!nificantly 'ifferent from
tho"e in the control "am,le. >hi" i" im,ortant 5ecau"e ,re$iou" "tu'ie" that te"te' the
role of fatty aci' "u,,lementation in treatin! A+9+ 'i' not re,ort "election on the
5a"i" of 3*A "tatu" or fre/uency of "ym,tom" 81A, 12:.
.iew this ta-le#
.n thi" ;in'o;
.n a ne; ;in'o;

TABL, 1/ (la"ma ,ho",holi,i' fatty aci' com,o"ition of control "u56ect" an' "u56ect"
;ith attention-'eficit hy,eracti$ity 'i"or'er re,ortin! fe; 8A+9+ !rou,: or many 8#-
A+9+: "ym,tom" in'icati$e of e""ential fatty aci' 'eficiency
1

n01 A%' n02 )ATT* A$'S A%' B,+A.$&R
3R&BL,4S
>he relation 5et;een the ty,e of fatty aci', n=3 or n=2, an' 5eha$ioral "ym,tom" ha"
not 5een "tu'ie' in chil'ren ;ith A+9+. %e foun', 5y further analy"i" of the 'ata for
all of the "u56ect" in our cro""-"ectional "tu'y, an in$er"e relation 5et;een total ,la"ma
n=3 fatty aci' ,ro,ortion" an' 5eha$ioral a""e""ment "core" 8Conner"J (arent Ratin!
Scale: an' teacher "core" of aca'emic a5ilitie" 817:. >hi" ;a" not the ca"e for n=2 fatty
aci'". 9o;e$er, lo; ,la"ma ,ro,ortion" of 5oth ty,e" of fatty aci'" ;ere a""ociate'
;ith a hi!her fre/uency of "ym,tom" in'icati$e of 3*A 'eficiency. >he"e re"ult"
"u,,ort a relation 5et;een n=3 fatty aci' "tatu" an' 5eha$ior in chil'ren that ,arallel"
the relation o5"er$e' in rat" 810: an' mon)ey" 811:. (re$iou" inter$ention "tu'ie" ha$e
u"e' a "ource of n=2 fatty aci'" 8e$enin! ,rimro"e oil: to treat 5eha$ior ,ro5lem" an'
re,orte' $aria5le an' un"ucce""ful re"ult" 81A, 12, 1E:. 9o;e$er, 5ecau"e n=3 fatty
aci'" a,,ear to 5e the fatty aci'" im,ortant for 5rain an' $i"ual function 811, 20: an' n=
2 fatty aci' "u,,lementation 'oe" not im,ro$e n=3 fatty aci' "tatu", e$enin! ,rimro"e
oil "u,,lementation alone ;oul' not 5e e<,ecte' to im,ro$e 5eha$ior.
3&T,%T$AL A(SAT$., )AT&RS )&R T+,
L&",R &43&S$T$&% &) L3()AS $%
S&4, +$L'R,% "$T+ A'+'
Kne ;oul' not e<,ect to fin' that a "in!le cau"e or e$en a han'ful of factor" coul'
e<,lain ;hy A+9+ a,,ear" to 5e "o ram,ant in our "ociety. ecau"e it i" acce,te' that
5oth !enetic an' en$ironmental factor" ,lay a role in A+9+, many other factor"L5oth
intrin"ic an' e<trin"icLcoul' influence an in'i$i'ualJ" fatty aci' "tatu". A,,lyin! thi"
ar!ument to the "u5,o,ulation of chil'ren ;ith A+9+ ;ho e<hi5it fre/uent "ym,tom"
of 3*A 'eficiency an' lo; #C(-*A "tatu" 8#-A+9+:, ;e con"i'ere' "e$eral factor"
that mi!ht contri5ute to the lo;er ,ro,ortion of AA an' +9A o5"er$e' in the ,la"ma
,ho",holi,i'" of the"e chil'ren. Althou!h many other ,otential e<,lanation" are
,o""i5le, ;e con"i'ere' 1: inta)e-relate' factor" "uch a" mar!inal con"um,tion of 3*A,
2: inefficient con$er"ion to #C(-*A from 3*A, an' 3: enhance' meta5oli"m of
#C(-*A".
)atty acid inta5e
Iany "tu'ie" ha$e relate' ,rotein or total ener!y 'eficit ;ith 5eha$ior or co!niti$e
,ro5lem". A 'eficiency of ",ecific micronutrient" 8e!, iron, io'ine, an' $itamin A: ha"
al"o 5een relate' to 5eha$ioral chan!e" 821=20:. >he"e "tu'ie" re,orte' on ,o,ulation"
at ri") in 'e$elo,in! countrie" an' may ha$e 5een confoun'e' 5y other factor" "uch a"
,arental "ocioeconomic "tatu", e'ucation, or intelli!ence. 3n$ironmental factor", "uch
a" !eneral li$in! con'ition", re,eate' infection", an' nutrient interaction", may al"o
confoun' re"ult". (oor /uality of the total 'iet in the"e !rou," i" ,ro5a5ly more of a
,ro5lem than are ",ecific nutrient 'eficiencie". A 'iet lo; in ener!y, ,rotein, or 5oth
;oul' ,ro5a5ly 5e lo; in ",ecific lon!-chain fatty aci'" a" ;ell.
.n rat", malnutrition in the ,renatal or imme'iate ,o"tnatal ,erio' i" "ufficient to
,ro'uce ,ermanent alteration" in 5rain "tructure, re"ultin! in en'urin! chan!e" in
5eha$ior 82A, 22:. Nutrient "u,,lementation of human infant" ha" "ho;n 5eneficial
re"ult" on co!niti$e function 823, 27:. Stu'ie" ha$e "ho;n that chil'ren ;ho ha'
formerly recei$e' motherJ" mil) "core' 5etter on te"t" of ,erformance after A y than 'i'
tho"e ;ho ha' not 82E:. .t ha" 5een "u!!e"te' that malnutrition lea$e" the 5rain
"ufficiently intact to function un'er "ta5le con'ition", 5ut en'urin! chan!e" that may
alter an in'i$i'ualJ" "u"ce,ti5ility to affecti$e 'i"or'er" 5ecome e$i'ent un'er "tre""ful
con'ition" 82A, 22:.
Althou!h there i" no lac) of a$aila5le nutrient" in the %e"tern ;orl', a ,rimary
'eficiency may occur 5ecau"e of in"ufficient nutrient inta)e. %ith the em,ha"i" on lo;-
fat 'iet" for control of $ariou" chronic 'i"ea"e", inta)e of foo'" containin! lon!-chain
fatty aci'" may 5e unnece""arily re"tricte'. Al"o, inta)e may 5e affecte' 5ecau"e of
foo' aller!ie" or intolerance to certain foo'", re"ultin! in a ,rimary 'eficiency of lon!-
chain fatty aci'". Kur ori!inal analy"i" of all 21 #-A+9+ "u56ect" 'i' not in'icate that
,rimary 3*A 'eficiency cau"e' the o5"er$e' lo; #C(-*A concentration" 810:.
(rimary 3*A 'eficiency i" in'icate' 5y a lo; ,ro,ortion of #A in 5oth ,la"ma
,ho",holi,i'" an' re' 5loo' cell" an' a ,ro,ortion of Iea' aci' 82: M0.21B of total
fatty aci'" 821:. Althou!h occa"ional e<am,le" in'icatin! 5or'erline ,rimary 3*A
'eficiency coul' 5e foun' ;ithin the #-A+9+ ,o,ulation, mo"t of the chil'ren 'i' not
fit thi" ,rofile.
$nefficient conversion of ,)As to L3()As
A "econ' ,o""i5le cau"e for the lo; #C(-*A "tatu" of the #-A+9+ !rou, may 5e
im,aire' con$er"ion of the fatty aci' ,recur"or" #A an' F-linolenic aci' to their lon!er
an' more hi!hly un"aturate' ,ro'uct". (o""i5le "ite" of thi" inefficiency inclu'e the
'e"atura"e "te,", the malonyl-CoA='e,en'ent elon!ation "te,", an' the ,ero<i"omal N=
o<i'ation "te,". .n'irect e$i'ence for "uch inefficiencie" come" from "tu'ie" in
ne;5orn" an' in in'i$i'ual" ;ith inherite' ,ero<i"omal 'i"or'er", neural ceroi'-
li,ofuc"ino"i", an' retiniti" ,i!mento"a 830:. 3$aluation of the 5loo' fatty aci' ,rofile"
of the #-A+9+ ,o,ulation in'icate' that the inefficient con$er"ion of #C(-*A
,recur"or" may ha$e 5een a contri5utin! factor to the lo; ,ro,ortion" of AA an' +9A
in the 5loo' of the"e chil'ren. >he ratio of ,recur"or" to meta5olite" for n=2 fatty aci'"
;a" !reater in the #-A+9+ chil'ren than in 5oth the A+9+ chil'ren re,ortin! fe;
3*A 'eficiency "ym,tom" an' the control chil'ren 8>a5le 1 :.
.ntere"tin!ly, the chil'ren ;ith A+9+ ;ere 5rea"t-fe' le"" often a" infant" than ;ere
the control chil'ren 810:. >he relation 5et;een thi" fin'in! an' the 5eha$ioral ,ro5lem"
that the"e chil'ren e<hi5it i" not clear. Ne;5orn", 5oth ,reterm an' full term, are
inefficient at con$ertin! ,recur"or" to #C(-*A", an' ne;5orn" an' infant" fe' formula
lac)in! #C(-*A" ha$e lo;er ,ro,ortion" of re' 5loo' cell AA an' +9A than 'o
5rea"t-fe' infant" 831, 32:. rea"t mil) contain" a'e/uate #C(-*A" an' "e$eral "tu'ie"
ha$e "ho;n that $i"ual an' 5rain function" mature fa"ter in 5rea"t-fe' than in 5ottle-fe'
infant" 833=3A:. +elaye' 5rain maturation i" one factor im,licate' in the 'e$elo,ment
of A+9+ 832:. #C(-*A" may ha$e a role to ,lay in thi" ,roce"". Se$eral "tu'ie"
e<amine' the relation 5et;een infant fee'in! an' lon!-term co!niti$e 'e$elo,ment.
3arly chil'hoo' 5rea"t-fee'in! ;a" re,orte' to 5e a""ociate' ;ith more a'$ance'
co!niti$e 'e$elo,ment in later chil'hoo' 837, 3E:. +9A i" the hy,othetical factor
re",on"i5le for thi" co!niti$e 'e$elo,ment. (erha," infant e<,o"ure to ,reforme' +9A
facilitate" 5rain maturation an' "timulate" #C(-*A 5io"ynthetic enCyme" a" ;ell.
,nhanced meta-olism
Another ,o""i5le e<,lanation for the lo;er 5loo' #C(-*A com,o"ition" in the #-
A+9+ "u56ect" i" enhance' cellular meta5oli"m of the"e fatty aci'" throu!h
nonenCymatic mechani"m". 3nhance' nonenCymatic o<i'ation 'ue to im,aire' cellular
'efen"e "y"tem" ha" 5een "ho;n to lea' to the 'e,letion of many #C(-*A" in rat li$er"
831:. ecau"e thi" ;a" the ,attern in'icate' 5y many of the "u56ect" in the #-A+9+
!rou,, ;e 'eci'e' to e<,lore thi" ,o""i5ility a" a contri5utin! factor to the lo;er
#C(-*A "tatu" in the"e chil'ren. ecau"e o<i'ati$e "tre"" can lea' to utiliCation of
en'o!enou" cellular antio<i'ant" "uch a" F-toco,herol 800:, ;e cho"e to mea"ure thi"
fat-"olu5le $itamin in the #-A+9+ an' the A+9+ "u56ect" ;ith normal fatty aci'
"tatu" an' no "ym,tom" of 'eficiency. >hi" analy"i" ;a" con'ucte' on froCen ,la"ma
"am,le" "tore' at =E0OC 5y the metho' u"e' in our la5oratory 801:. >he ,la"ma F- an'
P-toco,herol concentration" for all the A+9+ "u56ect" te"te', e<clu'in! tho"e ta)in!
"u,,lement", ;ere not "i!nificantly 'ifferent from tho"e of the control "u56ect" 8'ata not
"ho;n:. Similarly, no "i!nificant 'ifference in mean 8Q S+: ,la"ma F-toco,herol ;a"
note' 5et;een the #-A+9+ !rou, an' the A+9+ !rou, re,ortin! fe; "ym,tom" of
3*A 'eficiency GA.1 Q 2.7 RmolS# 8n T 11: an' 21.0 Q 0.2 RmolS# 8n T 1E:,
re",ecti$elyH. >hi" ;a" not the ca"e for P-toco,herol4 chil'ren in the #-A+9+ !rou,
ha' "i!nificantly hi!her ,la"ma concentration" than chil'ren ;ith A+9+ re,ortin! fe;
"ym,tom" of 3*A 'eficiency 82.0 Q 2.1 an' 0.1 Q 1.2 RmolS#, re",ecti$ely, P U 0.01:.
Althou!h thi" 'ifference ;a" "tati"tically "i!nificant, it" ,ractical "i!nificance i"
/ue"tiona5le 5ecau"e F-toco,herol concentration" ;ere not "i!nificantly 'ifferent
5et;een !rou,".
(RR,%T R,S,AR+
A" in'icate' ,re$iou"ly, the 'ifference" in ,ro,ortion" of #C(-*A" 5et;een the #-
A+9+ an' the control "u56ect" ;ere "i!nificant, 5ut the $alue" 'i' not in'icate clinical
'eficiency. Ioreo$er, the relation 5et;een #C(-*A "tatu" an' the 5eha$ioral ,ro5lem"
that the"e chil'ren e<hi5it i" not clear. %e hy,othe"iCe' that the lo;er ,ro,ortion" of
5loo' AA, eico"a,entaenoic aci', an' +9A o5"er$e' in the A+9+ chil'ren may reflect
a "u5clinical 'eficiency of the"e )ey fatty aci'" throu!hout the 5o'y. ecau"e n=3 fatty
aci'", e",ecially +9A, are ,re"ent in lar!e /uantitie" in the retina of the eye an' in
certain re!ion" of the 5rain, 'e,letion of +9A from the"e re!ion" may com,romi"e
"en"ory an' 5rain function. A "u5clinical +9A 'eficiency may 5e re",on"i5le for the
a5normal 5eha$ior of the"e chil'ren. >hrou!hout the re"t of the 5o'y, 'e,letion of n=3
an' n=2 #C(-*A" may 5e re",on"i5le for the out;ar' "ym,tom" of 'eficiency that
the"e chil'ren re,ort.
%e recently com,lete' a "tu'y to te"t the relation 5et;een the lo; ,ro,ortion of fatty
aci' an' a5normal 5eha$ior in the"e chil'ren 8JR ur!e"", # Ste$en", % &han!, et al,
un,u5li"he' o5"er$ation", 11116. >he "tu'y in$ol$e' te"tin! a 2-,art hy,othe"i" that
oral "u,,lementation of ",ecific fatty aci'" ;ill increa"e the com,o"ition" of lon!-chain
n=2 an' n=3 fatty aci'" in the 5loo' an' ,re"uma5ly throu!hout the 5o'y an' that
increa"e' ,ro,ortion" of fatty aci'", e",ecially 5rain +9A, ;ill re"ult in im,ro$e'
5eha$ior. >o te"t the"e hy,othe"e", ;e recruite' "u56ect" ;ith A+9+ ;ho re,orte'
many "ym,tom" of 3*A 'eficiency an' ha' lo;er ,or,ortion" of 3*A" 8#-A+9+: than
the control "u56ect", ;ho "ho;e' no 5eha$ioral ,ro5lem" or "i!n" of 3*A 'eficiency. A
"u,,lement containin! the ",ecific #C(-*A" that ;ere 'e,lete' in the"e chil'ren ;a"
u"e' in a 'ou5le-5lin' inter$ention "tu'y la"tin! 0 mo ;ith a 2-!rou, ,arallel
8noncro""o$er: 'e"i!n. >he "u56ect num5er an' 'uration ;ere "electe' on the 5a"i" of
the re"ult" of a re,ort 5y Arnol' et al 81E: an' the ,arallel 'e"i!n ;a" cho"en on the
5a"i" of o5"er$ation" ma'e 5y 3n're" et al 802, 03: in'icatin! that 5iochemical effect"
of n=3 "u,,lementation lin!er for u, to A mo after "u,,lementation cea"e". >he an";er
to ;hether #C(-*A 'eficiency contri5ute" to a5normal 5eha$ior in "ome chil'ren
'ia!no"e' ;ith A+9+ a;ait" the re"ult" of thi" an' other inter$ention "tu'ie".
R,),R,%,S
1. 1. ar)ley RA. Attention-'eficit hy,eracti$ity 'i"or'er4 a han'5oo) for
'ia!no"i" an' treatment. Ne; Vor)4 Wuilfor' (re"", 1110.
2. American ("ychiatric A""ociation. +ia!no"tic an' "tati"tical manual of mental
'i"or'er". 0th e'. %a"hin!ton, +C4 American ("ychiatric A""ociation, 1110.
3. 9oCa , Vallano W, (elham %3. Attention-'eficit hy,eracti$ity 'i"or'er. .n4
Ammerman R>, 9er"en I, e'". 9an'5oo) of chil' 5eha$ior thera,y in the
,"ychiatric "ettin!. Ne; Vor)4 %iley, 111A.
0. S;an"on JI, Icurnett X, %i!al >, et al. 3ffect of "timulant me'ication on
chil'ren ;ith attention 'eficit 'i"or'er4 a Yre$ie; of re$ie;".Y 3<ce,t Chil'
1113?2041A0=21.
A. Ahmann (A, %altonen SJ, Kl"on XA, >heye *%, Van 3rem AJ, #e(lant RJ.
(lace5o-controlle' e$aluation of Ritalin "i'e effect". (e'iatric" 1113?1141101=2.
GA5"tractS*ree *ull >e<tH
2. 9olman R>. A lon! "caly taleLthe "tu'y of e""ential fatty aci' 'eficiency at
the -ni$er"ity of Iinne"ota. .n4 Sinclair A, Wi5"on R, e'". 3""ential fatty aci'"
an' eico"anoi'"4 in$ite' ,a,er" from the thir' international con!re"".
Cham,ai!n, .#4 AKCS oo)" 111243=17.
7. Smith %#. (ro"tanoi' 5io"ynthe"i" an' mechani"m" of action. Am J (hy"iol
1112?2234*1E1=11.
E. urr WK, urr II. Kn the nature an' role of the fatty aci'" e""ential in
nutrition. J iol Chem 1130?E24AE7=221.G*ree *ull >e<tH
1. 9an"en A3, 9a!!ar' I3, oel"che AN, A'am +J+, %ie"e 9*. 3""ential
fatty aci'" in infant nutrition. .... Clinical manife"tation" of linoleic aci'
'eficiency. J Nutr 11AE?224A2A=72.
10. Vehu'a S, Cara""o R#. Io'ulation of learnin!, ,ain thre"hol'", an'
thermore!ulation in the rat 5y ,re,aration" of free ,urifie' al,ha-linolenic aci'"4
'etermination of the o,timal n=3 to n=2 ratio. (roc Natl Aca' Sci - S A
1113?1041030A=1.GA5"tractS*ree *ull >e<tH
11. Rei"5ic) S, Neurin!er I, 9a"nain R, Connor %3. 9ome ca!e 5eha$ior of
rhe"u" mon)ey" ;ith lon!-term 'eficiency of ome!a-3 fatty aci'". (hy"iol
eha$ 1110?AA4231=1.GIe'lineH
12. 3n"len I, Iilon 9, Ialnoe A. 3ffect of lo; inta)e of n=3 fatty aci'" 'urin!
the 'e$elo,ment of 5rain ,ho",holi,i', fatty aci' com,o"ition an' e<,loratory
5eha$ior in rat". #i,i'" 1111?224203=E.GIe'lineH
13. Iitchell 3A, Aman IW, >ur5ott S9, Ian)u I. Clinical characteri"tic" an'
"erum e""ential fatty aci' le$el" in hy,eracti$e chil'ren. Clin (e'iatr
11E7?224002=11.
10. Ste$en" #J, &entall SS, +ec) J#, et al. 3""ential fatty aci' meta5oli"m in
5oy" ;ith attention-'eficit hy,eracti$ity 'i"or'er. Am J Clin Nutr 111A?224721=
E.GA5"tractS*ree *ull >e<tH
1A. Aman IW, Iitchell 3A, >ur5ott S9. >he effect" of e""ential fatty aci'
"u,,lementation 5y 3famol in hy,eracti$e chil'ren. J A5norm Chil' ("ychol
11E7?1A47A=10.GIe'lineH
12. Arnol' #3, Xley)am, +, Votolato NA, >aylor %A, Xontra" S, >o5in X.
Wamma-linolenic aci' for attention-'eficit hy,eracti$ity 'i"or'er4 ,lace5o-
controlle' com,ari"on to +-am,hetamine. iol ("ychiatry 11E1?2A4222=E.
GIe'lineH
17. Ste$en" #J, &entall SS, A5ate I#, XucCe) >, ur!e"" JR. Kme!a-3 fatty
aci'" in 5oy" ;ith 5eha$ior, learnin!, an' health ,ro5lem". (hy"iol eha$
1112?A1411A=20.GIe'lineH
1E. Arnol' #3, Xley)am, +, Votolato N, Wi5"on RA, 9orroc)" #. (otential lin)
5et;een 'ietary inta)e of fatty aci'" an' 5eha$ior4 ,ilot e<,loration of "erum
li,i'" in attention-'eficit hy,eracti$ity 'i"or'er. J Chil' A'ole"c
("ycho,harmacol 1110?04171=E2.
11. Connor %3, Neurin!er I, #in +S. +ietary effect" on 5rain fatty aci'
com,o"ition4 the re$er"i5ility of n=3 fatty aci' 'eficiency an' turno$er of
'oco"ahe<aenoic aci' in the 5rain, erythrocyte", an' ,la"ma of rhe"u" mon)ey".
J #i,i' Re" 1110?314237=07.GA5"tractH
20. %ain;ri!ht (3, 9uan! VS, Co"cina +V, #e$e"/ue S, IcCutcheon +. rain
an' 5eha$ioral effect" of 'ietary n=3 'eficiency in mice, a three !enerational
"tu'y. +e$ ("ycho5iol 1110?274027=E7.GIe'lineH
21. Warcia S3, Xai"er ##, +e;ey XW. Self-re!ulation of foo' inta)e amon!
rural Ie<ican ,re"chool chil'ren. 3ur J Clin Nutr 1110? 004371=E0.GIe'lineH
22. IcCullou!h A#, Xir)"ey A, %ach" >+, et al. Vitamin -2 "tatu" of
3!y,tian mother"4 relation to infant 5eha$ior an' maternal-infant interaction"
Am J Clin Nutr 1110?A141027=70.GA5"tractS*ree *ull >e<tH
23. (ollitt 3, 9athirat (, Xotcha5ha)'i N, Ii""el #, Valya"$u A. .ron 'eficiency
an' e'ucational achie$ement in >hailan'. Am J Clin Nutr 11E1?A08"u,,l:42E7=
12.
20. Schurch . Ialnutrition an' 5eha$ioral 'e$elo,ment4 the nutrition $aria5le.
J Nutr 111A?12A422AAS=22S.
2A. #e$it")y +A, Stru,, J. Ialnutrition an' the 5rain4 chan!in! conce,t",
chan!in! concern". J Nutr 111A?12A42212S=20S.
22. Stru,, J, #e$it")y +A. 3n'urin! co!niti$e effect" of early malnutrition4 a
theoretical rea,,rai"al. J Nutr 111A?12A42221S=32S.
27. Wrantham-IcWre!or SI. A""e""ment" of the effect" of nutrition on mental
'e$elo,ment an' 5eha$ior in Jamaican "tu'ie". Am J Clin Nutr
1113?A78"u,,l:4303S=1S.
2E. >aylor , %a'";orth J. rea"t fee'in! an' chil' 'e$elo,ment at fi$e year".
+e$ Ie' Chil' Neurol 11E0?22473=E0.GIe'lineH
21. Si!uel 3N, Chee XI, Won! JZ, Schaefer 3J. Criteria for e""ential fatty aci'
'eficiency in ,la"ma a""e""e' 5y ca,illary column !a"=li/ui' chromato!ra,hy.
Clin Chem 11E7?3341E21=73.GA5"tractS*ree *ull >e<tH
30. -auy R, (eirano (, 9offman +, Iena (, irch +, irch 3. Role of e""ential
fatty aci'" in the function of the 'e$elo,in! ner$ou" "y"tem. #i,i'"
1112?314S127=72.
31. #eaf AA, #ei!hfiel' IJ, Co"teloe X#, Cra;for' IA. *actor" affectin!
lon!-chain ,olyun"aturate' fatty aci' com,o"ition of ,la"ma choline
,ho",ho!lyceri'e" in ,reterm infant". J (e'iatr Wa"troenterol Nutr 1112?104300=
E.GIe'lineH
32. Clar) XJ, Ia)ri'e" I, Neumann IA, Wi5"on RA. +etermination of the
o,timal ratio of linoleic aci' to al,ha-linolenic aci' in infant formula". J (e'iatr
1112?1204S1A1=E.GIe'lineH
33. irch +W, irch, 33, 9offman +R, -auy R. +ietary e""ential fatty aci'
"u,,ly an' $i"ual acuity 'e$elo,ment. .n$e"t K,hthalmol Vi" Sci
1112?3343202=A3.GA5"tractS*ree *ull >e<tH
30. -auy R, irch, +W, irch 33, >y"on J3, 9offman +R. 3ffect of 'ietary
ome!a-3 fatty aci'" on retinal function of $ery lo; 5irth ;ei!ht neonate".
(e'iatr Re" 1110?2E40EA=12.GIe'lineH
3A. irch +W, irch 33, 9offman +R, -auy R+. Retinal 'e$elo,ment in $ery-
lo;-5irth-;ei!ht infant" fe' 'iet" 'ifferin! in ome!a-3 fatty aci'". .n$e"t
K,hthalmol Vi" Sci 1112?334232A=72.GA5"tractS*ree *ull >e<tH
32. -cle" (, #orente S, Ro"a *. Neuro,hy"iolo!ical metho'" te"tin! the
,"ychoneural 5a"i" of attention 'eficit hy,eracti$ity 'i"or'er. Chil'" Ner$ Sy"t
1112?12421A=7.GIe'lineH
37. Ro'!er" . *ee'in!" in infancy an' later a5ility an' attainment4 a
lon!itu'inal "tu'y. +e$ Ie' Chil' Neurol 117E?204021=2.GIe'lineH
3E. #antin! C., *i'ler V, 9ui"man I, >ou;en C, oer"ma 3R. Neurolo!ical
'ifference" 5et;een 1-year-ol' chil'ren fe' 5rea"t-mil) or formula-mil) a"
5a5ie". #ancet 1110?33041311=22.
31. uttri"" J#, +i,loc) A>. >he al,ha-toco,herol an' ,ho",holi,i' fatty aci'
content of rat li$er "u5cellular mem5rane" in $itamin 3 an' "elenium 'eficiency.
iochim io,hy" Acta 11EE?123421=1.GIe'lineH
00. Xehrer J. *ree ra'ical" a" me'iator" of ti""ue in6ury an' 'i"ea"e. Crit Re$
>o<icol 1113?23421=0E.GIe'lineH
01. ur!e"" JR, Xuo C-*. .ncrea"e' calcium-in'e,en'ent ,ho",holi,a"e A
2

acti$ity in $itamin 3 an' "elenium-'eficient rat lun!, li$er, an' ",leen cyto"ol i"
time-'e,en'ent an' re$er"i5le. J Nutr iochem 1112?74322=70.
02. 3n're" S, +e Caterina R, Schmi't 3, Xri"ten"en S+. n=3 (olyun"aturate'
fatty aci'"4 u,'ate 111A. 3ur J Clin .n$e"t 111A?2A4221=3E.GIe'lineH
03. 3n're" S, Whor5ani S, Xelley V3, et al. >he effect of 'ietary
"u,,lementation ;ith n=3 ,olyun"aturate' fatty aci'" on the "ynthe"i" of
interleu)in-1 an' tumor necro"i" factor 5y mononuclear cell". N 3n!l J Ie'
11E1?320422A=71.GIe'lineH