soares et al 1997

8/3/2019 soares et al 1997

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REVIEW ARTICLE

T h e A n a t o m y o f M o o d D i s o r d e r s

Structural Neuroimaging Studies

J a ir C . S o a r e s a n d J . J o h n M a n n

R e v i e w o f

Th e s t r u c t u ra l n e u r o i m a g i n g f i n d i n g s i n m o o d d i s o r d e r s w e r e r e v i e w e d , t o e v a l u a te e v i d e n c e f o r

a n e u r o a n a t o m i c m o d e l o f p a t h o p h y s i o l o g y , i n v o l v in g t h e p r e f r o n t a l c o r t ex , t h e b a s a l g a ng l ia , t h e

a m y g d a l a - h i p p o c a m p u s c o m p l e x , t ha l a m u s , a n d co n n e c t i o n s a m o n g t h e s e s t ru c t u re s . G l o b a l

a t r o p h y i s n o t c o n s i s t e n tl y f o u n d . Th e b e s t r e p l i c a t ed f i n d i n g i s a n i n c r e a s e d r a t e o f w h i t e m a t t e r

a n d p e r i v e n t r i c u l a r h y p e r in t e n si t ie s . A s m a l l e r f r o n t a l l o b e, c e r e b e l l u m , c a u d a t e , a n d p u t a m e n

a p p e a r p r e s e n t i n u n i p o l a r d ep r e s s io n . A l a r g e r t h i rd v e n t ri c le , a n d s m a l l e r c e r e b e l l u m a n d

p e r h a p s t e m p o r a l l o b e a p p e a r p r e s e n t i n b i p o l a r d i s o rd e r . Th e s e l o c a l i z e d s t r u c tu r a l c h a n g e s

i n v o l v e r e g i o n s t h a t m a y b e c r i ti c a l i n t he p a t h o g e n e s i s o f m o o d d i s o r d e rs . G e n e r a l i z e d a n d

l o c a l i z e d a n a t o m i c a l t e r a t i o n s m a y b e r e l a t e d t o a g e o r v a s c u l a r d i s e a s e . Th e c l i n i c a l a n d

b i o l o g ic a l c o r r e l a t e s o f th e s e c h a n g e s n e e d t o b e i n v e s t i g a te d t o a l l o w d e v e l o p m e n t o f a m o r e

c o m p l e t e m o d e l o f p a t h o p h y s i o l o g y o f m o o d d i s or d er s . © 1997 J.C. Soares and J.J. Mann

Ke y W ord s: M ood disorders , n euroanatomy, s t ruc tural , neuroimaging, pa thophysiology,

magnet ic resonance imaging, computed tomography

BIOL PSYCHIATRY 199 7;41:8 6--10 6

Introduct ion

Som e di f ference I f in d am ongst wri ters, abou t the pr incipal

par t a f fected in th& disease , wh ether i t be the brain , o r heart,

o r some o ther member . Mos t a re o f op inion tha t i t is t he

brain: fo r being a k ind o f dotage, as a s imilar part , be i t by

consent or essence, not in his ventricles, or any obstructions

in them, fo r then i t wo uld be an apoplexy, or epilepsy , . . . . but

in a cold, dry dis tempera ture of i t in h is substance, which is

corrupt and become too cold , or too dry , or e lse too hot , as

in madmen and such as a re inc l ined to i t . . .(Sir Robert Burton, 157 7-1640, in Th e An a t o m y

o f M e lancho ly)

From the L a bo ra to r i e s o f N e u ro pha rm a c o logy , W e s t e rn Ps yc h ia t r i c In s t i tu t e a nd

C l in i c , U n ive r s i t y o f P i t t s bu rgh M e d ic a l C e n te r , P i t t s bu rgh , Pe nns y lva n ia .

A ddre s s r e p r in t r e que s t s t o J . J ohn M a nn , M D , D e pa r tme n t o f N e u ros c i e nc e , N e wY ork S t a t e Ps yc h ia t r i c In s t i tu t e , 722 W . 168 th S t ree t , B ox 28 , N e w Y ork , N Y10032 .

R e c e ive d Se p te mbe r 27 , 1995 ; r e v i s e d D e c e mbe r 18 , 1995 .

The pos sibil i ty that brain abnormalities respo nsible for

depression may be detectable has st imulated structural

brain imaging studies. D evelop me nts in structural neuro-

imaging by computed tomography (CT) and magnet ic

resonance imaging (MRI) in the past 15 years have

facilitated th e direct examination of specific brain struc-

tures, making pos sible the study of the relationship be-

tween anatomy and psychopathology.

In 1980, Jacob y and Levi publ ished the f irs t CT study o f

mood disorder pa t ients . The f i rs t MRI study of th isdisorder was pub lished in 1983 (Rangel-Guerra et al

1983). The advent of MRI brought several advantages,

allowing more accurate localization and high-resolution

meas urem ent o f brain structures, not involving radiation,

and providing unprecedented gray-w hi te m at ter resolut ion

(Ste iner and Bydder 1984) . Developments in MRI pro-

cessing have impro ved quantitative volum etric analysis of

© 1997 J .C . Soa re s a nd J . J . M a n n 0006 -32 23 /97 /$17 .00

PI I S0006 -3 2 2 3 9 6 ) 0 0 0 0 6 -6

8/3/2019 soares et al 1997


Anatom y of Mood Disorders BIOLPSYCHIATRY 871997 ; 4 1 : 8 6 - 1 0 6

I P r e f r o n t a l Cor tex [ (

l m , g d , I , ]. . . . . . . . . . . . . . . .

H l p p o c a m p u s IC o m p l e x J

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I e , e b e ll m l

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Figure 1. Neuroanatomic model of mood regulation.

r eg io n s o f co r t i ca l an d su b co r t i ca l g r ay mat t e r a t h ig h er

l ev e l s o f r eso lu t i o n (Kr i sh n an e t a l 1 9 9 3 a) .

I t i s r eco g n i zed t h a t l e s i o n s i n so me sp ec i f i c n eu ro an a-

tomic areas due to b rain d isease, e .g . , s t roke or b rain

t u m o r , m a y l e a d t o d e v e l o p m e n t o f s e c o n d a r y d e p r e s si o n(Robinson et a l 1984a; S tarkstein and Robinson 1989;

Cu m min g s 1 9 9 3 ). I n p r imary (n o t d u e to k n o wn asso c i a t ed

b ra in d i sease ) mo o d d i so rd er s, eme rg in g f i n d in g s b eg in t o

ch a l l en g e t h e p rev io u s n o t i o n o f " fu n c t i o n a l " i n o p p o s i t i o n

to "o rg an i c" d i so rd er s , w i th su g g es t i o n s t h a t an a to mic

b ra in ch an g es can b e i d en t i f i ed . We an d o th e r s p ro p o se

th a t b o th p r imary an d seco n d ary mo o d d i so rd er s may

in v o lv e ab n o rmal i t i e s i n sp ec i f i c b r a in f ro n to su b co r t i ca l

n eu ro an a to m ic c i rcu i t s (Ro b in so n e t a l 1 9 8 4a ; Bu ch sb a u m

1986; Jes te et a l 1988; Nasral lah et a l 1989; S tarkstein and

Robinson 1989; Beats 1991; Drevets et a l 1992; Mc-

Do n a ld an d Kr i sh n an 1 99 2 ; Cu m min g s 1 99 3 ; Geo rg e e t a l

1 9 9 3 ; Gu ze an d Gi t l i n 1 9 9 4 ; M ay b erg 1 9 9 4 ; M eg a an dCu m min g s 1 9 9 4 ; Au s t i n an d M i t ch e l l 1 9 9 5 ) . Th e p re f ro n -

t a l co r t ex h as ex t en s iv e co n n ec t i v i t y t o co r t i ca l an d su b -

co r t i ca l c i r cu i t s t h a t may u n d er l i e i t s imp o r t an ce i n co g -

n i t i v e fu n c t i o n s an d mo d u la t i o n o f l imb ic ac t i v i t y

(Wein b erg er 1 9 9 3 ) . Th e main su b co r t i ca l s t ru c tu res p a r -

t ic ipat ing in these ci rcu i t s are the basal gangl ia , thalamus,

h y p o th a l amu s , b r a in s t em, an d t h e wh i t e m at t e r t rac t s t h a t

co n n ec t t h ese s t ru c tu res amo n g t h emse lv es an d t o t h e

cereb ra l co r t ex (S a l l o way an d Cu mmin g s 1 9 9 4 ) . A l im-

b i c - t h a l amic-co r t i ca l c i r cu i t co n s i s t i n g o f t h e amy g d a l a ,

t h e med io d o r sa l n u c l eu s o f t h e t h a l amu s , an d t h e med ia l

an d v en t ro l a t e r a l p r e f ro n t a l co r t ex , an d a l imb ic - s t r i a t a l -

p a l l i d a l - t h a l amic c i r cu i t co mp r i s i n g t h e s t r ia t u m, t h e v en -

t r a l p a l l i d u m, an d t h e co m p o n en t s o f t h e o th e r c i r cu i t a r e

th e main n eu ro an a to mic c i r cu i t s t h a t h av e b een p ro p o sed

to p a r t i c i p a t e i n t h e p a th o p h y s io lo g y o f mo o d d i so rd er s

( see F ig u re 1 ). Th e b asa l g an g l i a c o n n ec t wi th co r t i ca l an d

l imb ic r eg io n s t h ro u g h c i r cu i t s t h a t , d esp i t e fu n c t i o n in g

seg reg a t ed ly , a r e o rg an i zed i n p a ra l l e l (Alex an d er e t a l

1986 , 1990) , in such a wa y that les ions in d i f feren t par ts o f

t h ese c i r cu i ts co u ld r esu l t i n m al fu n c t i o n . Ad d i t i o n a l l y , t h e

cereb e l l u m, t h ro u g h co n n ec t i o n s wi th b ra in s t em an d

l imb ic s t ru c tu res , may a l so b e i n v o lv ed i n mo o d r eg u l a t i o n

(Ber to n an d To re l l o 1 9 8 2 ) . Ab n o rmal i t i e s i n t h ese b ra in

reg io n s , o r i n co n t i g u o u s a r eas t h a t can a f f ec t t h e co n n ec-

t i o n s b e tween t h ese r eg io n s , co u ld r e f l ec t mal fu n c t i o n o f

t h ese c i r cu it s , a s so c i a ted w i th d ev e lo p m en t o f mo o d d i s -

o rd er s . A l t e rn a t i v e ly , ab n o rmal i t ie s i n t h ese c i r cu i t s co u ld

co n fe r v u ln erab i l i t y to m o o d d i so rd er s , an d i t s o n se t co u ld

b e d e t e rmin ed b y i n t e r ac t i o n s wi th en v i ro n men ta l an d

g en e t i c f ac to r s . Def i c i t s d u r in g b ra in d ev e lo p men t d u e t o

th ese f ac to r s co u ld r esu l t in h y p o d ev e lo p me n t o f p a r t i cu l a r

b ra in a r eas , wh ich co u ld b e r e l a t ed su b seq u en t l y wi th

mo o d d i so rd er s . Th e ag in g p ro cess o r p a th o lo g y su ch as

v ascu l a r b r a in d i sease co u ld r esu l t i n a t ro p h y o f so me o f

th ese r eg ion s . Th u s , t h e i n f l u en ce o f g en e t ic , en v i ro n m en -

t a l , d ev e lo p men ta l , an d d eg en era t i v e f ac to r s d u r in g t h e

d ev e lo p men t o f t h ese b ra in s t ru c tu res , i n way s s t i l l n o t

u n d er s to o d , may d e t e rmin e t h e o n se t o f mo o d d i so rd er s .

Th ere i s a d ev e lo p in g co n f lu en ce wi th ev id en ce f ro mfu n c t i o n a l n eu ro imag in g s t u d ies su g g es t i n g ab n o rmal i t i e s

i n so me o f t h e same k ey b ra in r eg io n s p a r t i c i p a ti n g i n

th ese n eu ro an a to mic c i r cu i t s (Bu sch b au m 1 9 8 6 ; Bax t e r

1 9 9 1 ; Cu m min g s 1 9 9 3 ; Geo rg e 1 9 9 4 ; Geo rg e e t a l 1 9 9 3 ,

1994; K et ter et a l 1994; May berg 1994; May ber g et a l

1 9 9 4 ) ; h o wev er , t h e re i s a n eed fo r sy s t emat i c s t u d y o f

t h ese r eg io n s b y b o th s t ru c tu ra l an d fu n c t i o n a l n eu ro im-

ag ing .

Th i s s t u d y r ev i ews t h e s t ru c tu ra l CT an d M RI f i n d in g s

in mo o d d i so rd er p a t i en t s t o ex amin e t h e ab o v e p ro p o sed

n eu ro an a to mic mo d e l . We h y p o th es i zed t h a t mo o d d i so r -

d er s a r e ch arac t e r i zed b y l o ca l i zed r a th e r t h an g en era l i zed

st ructural a l terat ions in the b rain , invo lv ing reg ions inth ese n eu ro an a to mic c i r cu i t s . Ad d i t i o n a l l y , t h e c l i n i ca l

an d b io lo g i ca l co r r e l a t es o f t h ese b ra in ab n o rmal i t i e s a r e

r e v i e w e d .

G e n e r a l i z e d B r a i n A b n o r m a l i t i e s

Dif fu se b ra in ab n o rmal i t i e s may d amag e amo n g o th er

r eg io n s t h e sp ec i f i c s t ru c tu res p a r t ic i p a t i n g i n m o o d r eg -

u l a t io n , an d t h u s b e r e l a t ed t o d ev e lo p m en t o f d ep ress io n .

We wi l l s t a r t b y r ev i ewin g t h e ev id en ce fo r g en era l i zed

b ra in ab n o rmal i t i e s , an d t h en c o n s id e r s t u d i es o f sp ec i f i c

b ra in r eg io n s . Ge n era l i zed d i sease i n c lu d es g lo b a l ce reb ra la t ro p h y , an d wh i t e mat t e r o r p e r i v en t r i cu l a r h y p er in t en s i -

t ies.

Cerebral Atrophy

S ev era l i n d i ces o f g en era l i zed ce reb ra l a t ro p h y were u sed

in d i f f e r en t s t u di es , i n c lu d in g v en t r i cu l a r s i ze o r v o lu me,

su l ca l w id th , ce r eb ra l v o lu me, an d m o s t r ecen t l y g ray an d

wh i t e mat t e r v o lu me. Th e i n i t i a l s t u d i es u sed g ro ss mea-

su res o f g lo b a l a t ro p h y , wi th ex am in er ' s r a t in g s o f su l ca l

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88 BIOLPSYCHIATRY J.C. Soare s and J.J . Ma nn1997;41:86-106

a t ro p h y o r v en t r i cu l a r d i la t a t io n . S o m e o f t h e s t u d i es u sed

man u a l t r ac in g t o measu re v en t r i cu l a r -b ra in r a t i o (VBR) ,

h av in g t h e l imi t a t i o n s o f l e s s accu racy imp l i c i t i n t h i s

meth o d . S u b seq u en t l y , s emiau to mated ap p ro ach es t o t h e

ca l cu l a t i o n o f t h e VBR in M RI s t u d i es were d ev e lo p ed ,

b r i n g in g mo re p rec i s i o n . M o s t r ecen t s t u d i es u sed semi -

au to mated o r au to mated measu res o f g r ay an d wh i t e

mat t e r v o lu me, as a mo re r e f i n ed way o f s t u d y in g t h e

v o lu me o f d i f f e r en t b r a in r eg io n s (Co h en e t a l 1 9 9 2 ;

Krishnan et a l 1993a) .

VENTRICLESM EAS URES . Tw elv e co n t ro l l ed CT s tu d i es

(P ear l so n an d Ve ro f f 1 9 8 1 ; Nas ra ll ah e t a l 1 9 8 2 a ; Tan ak a

et al 1982; Sco t t e t a l 1983; Pear lson et a l 1984a; Sh ima et

al 1984; Dolan et a l 1985; Lippman et a l 1985; Kolbein-

s so n e t a l 1 9 8 6 ; S ch l eg e l an d K re t zsch m ar 1 9 8 7 ; Am es e t

a l 1 9 9 0; W u r th man n e t a l 1 9 9 5 ) o f 2 2 ( Jaco b y an d Lev i

1980; W einb erge r et a l 1982; Rossi e t al 1987 , 1989;Dewan e t a l 1 9 8 8 a ; I aco n o e t a l 1 9 8 8 ; Ab as e t a l 1 9 9 0 ;

Beats et a l 1991; van den Bossche et a l 1991; Sh i ralsh i e t

al 1992) found s ign i f ican t ly increased lateral ven t r icle s ize

in mo o d d i so rd er p a t i en t s . Two s tu d i es u sed ca t eg o r i ca l

r a t in g s d o n e b y c l i n i c i an ( Jaco b y an d Le v i 1 9 8 0 ; L ip p ma n

e t a l 1 9 8 5 ) , two u sed l i n ea r measu res (Tan ak a e t a l 1 9 8 2;

v an d en Bo ssch e e t a l 1 9 9 1 ) , t h r ee u sed VBR an d l i n ea r

measu res (S ch l eg e l an d Kre t zsch mar 1 9 8 7 ; Dewan e t a l

1 9 8 8 a; Wu r th m an n e t a l 1 9 9 5 ) , an d t h e o th e r s t ud i es u sed

VB R m easu res . E ig h t o f th e 1 7 VB R s tu d ies d id n o t fi n d

s ig n i f ican t d i f f e r en ces co mp are d t o co n t ro l s . F o u r o f t h ese

s tu d ies w ere d o n e i n e ld e r l y p a t i en ts ( Jaco b y an d Lev i

1 9 8 0 ; Am es e t a l 1 9 9 0 ; Ab as e t a l 1 9 9 0 ; Wu r th man n e t a l1 9 9 5 ) , an d o n ly two h ad p o s i t i v e f i n d in g s (Ames e t a l

1 9 9 0 ; Wu r th man n e t a l 1 9 9 5 ) . Th ese s t u d i es i n v o lv ed

samp les o f u n ip o l a r (UP ) an d b ip o l a r (BP ) p a t i en t s , an d

resu l t s s eem in d ep en d en t o f d i ag n o s t i c su b ty p e .

U n c o n t r o l le d M R / s t u d i e s i n e l d e r l y d e pr e s s e d p a ti e n ts

r e f e r r ed fo r e l ec t ro co n v u l s iv e t h e rap y (E CT) fo u n d r a t es

o f l a te r a l v e n tr i c le e n l a r g e m e n t o f 6 7 - 6 9 % ( C o f f e y e t a l

1988 , 1989; F ig iel e t a l 1989a) . In con t ras t , on ly th ree

(Andreasen et a l 1990; F ig iel e t a l 1991b; Rabins et a l

1 9 9 1 ) o f 1 2 co n t ro l l ed M R/s tu d i es fo u n d en l a rg ed l a te r a l

v en t r i c l es i n UP o r BP p a t i en t s co mp ared t o co n t ro l s

(Du p o n t e t a l 1 9 8 7 ; Jo h n s to n e e t a l 1 9 8 9 ; S way ze e t a l

1 9 9 0 ; Lesse r e t al 1 9 9 1 ; M cD o n a ld e t a l 1 9 9 1; R i sch e t a l

1 9 9 2; S h ah e t a l 1 9 9 2 ; Co f fey e t a l 1 9 9 3 a ; Harv e y e t a l

1 9 9 4 ) . Th ese s t u d i es h ad v ar i ed meth o d o lo g y , wi th f i v e

s tu d i es u s in g ex amin er ' s r a t i n g s (Du p o n t e t a l 1 9 8 7 ;

Johnstone et a l 1989; McDonald et a l 1991; F ig iel e t a l

1 9 9 1 b; Rab in s e t a l 1 9 9 1 ) , t h r ee VBR measu res (Lesse r e t

al 1991; Andreasen et a l 1990; Risch et a l 1992) , and four

au to mated a r ea an d v o lu me measu res (S way ze e t a l 1 9 9 0 ;

Shah et a l 1992; Co ffe y et a l 1993a; Har vey et a l 1994).

Th ree (Rab in s e t a l 1 9 9 1 ; M cD o n a ld e t a l 1 9 9 1 ; Lesse r e t

a l 1 9 9 1 ) o f t h e 1 0 s t u d i es were d o n e i n e ld e r l y samp les ;

o n ly o n e fo u n d en l a rg ed v en t r i c l es (Rab in s e t a l 1 9 91 ). S ix

(Du p o n t e t a l 1 9 8 7 ; Jo h n s to n e e t a l 1 9 8 9 ; S way ze e t a l

1 9 9 0 ; M c Do n a ld e t a l 1 9 9 1 ; R i sch e t a l 1 9 9 2 ; Harv ey e t a l

1994) o f n ine (Andrea sen et a l 1990; F ig iel e t a l 1991b;

S t r ak o wsk i e t a l 1 9 9 3 a) s tu d i es i n BP s w ere n eg a t i v e ; o n e

o f t h e m f o u n d i n c re a s e d V B R m e a s u r e s o n l y in m a l e B P s

(Andreasen et a l 1990) . In UPs, th ree s tud ies (Lesser et a l

1991; Risch e t a l 1992; Shah et a l 1992) o f four (Rabins et

al 1991) had negat ive resu l t s .

Tw o (S ch l eg e l an d Kre t zsch mar 1 9 8 7 ; Bea t s e t a l 1 9 9 1 )

o f fo u r (Tan ak a e t a l 1 9 8 2; I aco n o e t a l 1 9 8 8 ) co n t ro l led

CT s tu d ies fo u n d i n c reased measu res o f t h i rd v en t r ic l es i n

mo o d d i so rd er p a t i en t s . Th ese s t u d i es u sed l i n ea r mea-

su res o f t h ird v en t r i c le , an d i n v o lv ed mix ed samp les o f

UP s a n d BP s . On e s t u d y (Dewan e t a l 1 9 8 8 a) fo u n d t h ird

v en t r i c l e wid th s i g n i f i can t l y i n c reased i n BP s , b u t wh en

measu res o f 3 VB R (a rea o f th i rd v en t r i c le /b ra in a rea ) wereco n s id ered , n o s t a t i s t i ca l l y s i g n i f i can t d i f f e r en ces were

fo u n d . An o th er s t u d y (S t r ak o wsk i e t a l 1 9 9 3 a) u s in g M RI

v o lu met r i c measu res fo u n d i n c reased t h i rd v en t r i c l e i n

f i r s t ep i so d e man ics . I n UP s , o n e M RI s t u d y wi th ex am-

in er ' s r a t in g s fo u n d i n c reased t h i rd v en t r i c l e measu res

(Rab in s e t a l 1 9 9 1 ) , b u t t h i s was n o t co n f i rmed i n a CT

s tu d y wi th a r ea measu res (Wu r th man n e t a l 1 9 9 5 ) o r a

M R I v o lu m et r i c s t u d y (Co f fey e t a l 1 9 9 3 a) .

Th ere i s su g g es t i o n t h a t v en t r i cu l a r en l a rg em en t may b e

re l a t ed t o d ep ress io n i n p a t i en t s wi th i s ch emic l e s i o n s ,

b ased i n o n e co n t ro l l ed CT s tu d y in a smal l s amp le (n =

1 3 ) o f p o s t s tro k e m ajo r d ep ress io n p a t i en t s (S t a rk s t e in e t

al 1988) . In th is s tudy , s ign i f ica n t ly larger la teral and th i rdV B R s w e r e f o u n d i n d e p r e s s e d c o m p a r e d t o n o n d e p r es s e d

p a t i en ts , su g g es t i n g t h a t su b co r t i ca l a t ro p h y p reced in g t h e

s t ro k e may p ro d u ce a v u ln erab i l i t y fo r d ep ress io n .

On e r e t ro sp ec t i v e CT s tu d y (Wo o d s e t a l 1 9 9 0 ) in v es -

t i g a t ed VB R m easu res i n a samp le o f BP s o v e r p e r i o d s o f

1 -4 .5 y ear s , an d n o ev id en ce o f p ro g ress io n i n v en t r icu l a r

s i ze was fo u n d i n t h e BP g ro u p .

Th u s , m o s t s t u d i es r ep o r t ed n eg a t iv e r esu l ts , an d an y

d i sag reemen t was n o t ex p l i cab l e o n t h e b as i s o f ag e o r

su b ty p e o f mo o d d i so rd er . S u g g es t i o n s o f en l a rg emen t o f

t h e t h i rd v en t r i c l e i n BP s n eed t o b e r ep l i ca t ed i n co n -

t ro l l ed v o lu met r i c s t u d i es . Th e p o ss ib i l i t y o f p r eex i s t i n g

su b co r t i ca l a t ro p h y i n p o s t s t ro k e d ep ress io n n eed s t o b e

p ro v en .

SULCAL MEASURES. Su lcal m easure s we re no t s ign i f i -

can t l y d i f f e r en t f ro m co n t ro l s i n CT s tu d ies o f e l d e r l y an d

n o n e ld er ly d ep ressed L IPs o r BP s ( Jaco b y an d Lev i 1 9 8 0 ;

Nas ra l l ah e t a l 1 9 8 2 b ; L ip p man e t a l 1 9 8 5 ; I aco n o e t a l

1988; Ames et a l 1990) , bu t no t in al l s tud ies (Dolan et a l

1986; Kolbeinsson et a l 1986; Wurthmann et a l 1995) .

Th ree u n co n t ro l l ed M RI s t u d i es wi th e ld e r l y d ep ressed

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Anatomy o f Mood Disorders BIOLPSYCHIATRY 891997;41:86-106

p a t i en t s r ep o r t ed co n s id e rab l e r a t es (9 1 -9 6 % ) o f su l ca l

at roph y (Co ffey et a l 1988 , 1989; F ig iel e t a l 1989a) , bu t

o n ly o n e (Rab in s e t a l 1 9 9 1 ) o f fo u r (Zu b en k o e t a l 1 9 9 0;

Lam me rs e t a l 1 9 9 1; Co f fey e t a l 1 9 9 3 a) co n t ro l l ed M RI

s tu d ies fo u n d s i g n i f ican t l y i n c reased su l ca l a t ro p h y i n U P

p a t i en t s . Th ese s t u d ies u se d ex a min e r ' s q u a l i t a t i v e r at i n g s

o f su l ca l a tro p h y . Two co n t ro l l ed M RI s t u d ies d id n o t f i n d

ev id en ce o f ab n o rmal i t i e s i n co r t i ca l v o lu me o f BP s

(Harv e y e t a l 1 9 9 4 ) o r e l d e r l y UP s (Kr i sh n an e t a l 1 9 9 3 b ) .

Co mp ared t o t h e CT scan s , t h e M RI wi th i t s b e t t e r imag e

q u a l i t y a l l o ws mo re accu ra t e d e t e rmin a t i o n o f su l ca l

en l a rg emen t . Th u s , t h e re i s n o co n s i s t en t ev id en ce fo r

su l ca l en l a rg emen t i n mo o d d i so rd er s .

CEREBRAL VOLUME, Seve n cont ro l le d MR I s tud ies d id

n o t f i n d s i g n i f i can t d i f f e r en ces i n measu res o f ce reb ra l

v o l u m e b e t w e e n d e p r e s s e d U P s o r B P s a n d c o n t r o l s

(Hu sa in e t a l 1 9 9 1 a ; Kr i sh n an e t a l 1 9 9 2 ; Ax e l so n e t a l1 9 9 3; Co f fe y e t a l 1 9 9 3 a ; Ay lw ard e t a l 1 9 9 4 ; Harv ey e t

a l 1 9 9 4 ; Du p o n t e t a l 1 9 9 5 ) ; Ho wev er , o n e s t u d y (S t r a -

k o wsk i e t a l 1 9 9 3 a) fo u n d d ecreased t o t a l wh i t e mat t e r

v o lu me, an d a r e l a t i v e i n c rease i n g ray mat t e r i n f i r s t -

ep i so d e man ic p a t i en t s . Du p o n t e t a l ( 1 9 9 5 ) d id n o t f i n d

s ig n i f i can t d i f f e r en ces i n co r t i ca l g r ay mat t e r v o lu me

co mp ar in g UP s , BP s , an d n o rmal co n t ro l s .

Ov era l l , a l l b u t o n e s t u d y d id n o t f i n d ev id en ce o f

ab n o rmal i t i e s i n ce reb ra l v o lu me in UP s o r BP s . S tu d i es

d i f f e r en t ia t i n g g ray an d wh i t e m at t e r v o lu me a re r eq u i r ed

to d e t e rmin e wh e th er t o t a l g r ay mat t e r v o lu me i s ab n o rma l

in mo o d d i so rd er s .

White Matter Lesions

CT d en s i t i e s o f r i g h t an d l e f t an t e r i o r wh i t e mat t e r were

fo u n d t o b e s i g n i f i can t l y i n c reased i n BP s i n a co n t ro l l ed

s tu d y (Dewan e t a l 1 9 8 8 a) . A f ew u n co n t ro l l ed M RI

s tu d i es fo u n d i n c reased r a t es o f su b co r t i ca l wh i t e mat t e r

h y p er in t en s i t i e s i n ECT- re fe r r ed d ep ressed p a t i en t s (Co f -

fey et a l 1987 , 1989; F ig iel e t a l 1989a) . S ix (C offe y et a l

1990; Zubenko et a l 1990; Lesser et a l 1991; Rabins et a l

1991; Ho wa rd et a l 1993; Krishna n et a l 1993b) o f seven

(Gu ze an d S zu b a 1 9 9 2 ) co n t ro l led s t ud i es i n e l d e r l y majo r

d ep ress io n p a t i en t s (mo s t l y UP s) sh o wed s i g n i f i can t l y

in c reased r a t es o f su b co r t i ca l wh i t e mat t e r o r p e r i v en t r i cu -

lar hyper in tensi t ies in pat ien ts , bu t in nonelder ly pat ien ts ,

o n ly o n e (C o f fey e t al 1 9 9 3 a) o f two s t u d i es (Gu ze an d

S zu b a 1 9 9 2 ) fo u n d an i n c rease . F u r th e rmo re , t h e samp le

in t h e Co f fey e t a l ( 1 9 93 a) s t u d y , wi th a mea n ag e o f

62 .4 ___ 16 .4 years , includ ed m any o lder sub jects . One

M RI s t u d y fo u n d i n c reased r a t es o n ly fo r sev ere wh i t e

mat t e r h y p er in t en s i t i e s i n UP s co mp ared t o co n t ro l s

(Bro wn e t a l 1 9 9 2 ) . An o th er M RI s t u d y fo u n d s i g n i f i -

can t l y i n c reased r a t es o f wh i t e mat t e r h y p er in t en s i t i e s i n

e ld e r l y co mp ared t o n o n e ld er ly UP s (Gu ze an d S zu b a

1 99 2 ). On e an ecd o t a l r ep o r t acco u n t ed fo r i n c reased

su b co r t i ca l wh i t e mat t e r h y p er in t en s i t i e s i n a y o u n g ad o -

lescen t in the f i rs t manic ep isode (Bot teron et a l 1992) .

Fou r (Dupon t et al 1987, 1990; Swa yze et al 1990; Figiel

et al 1991b) o f six (Brow n et al 1992; SW akowski et al 1993b)

cont ro l led MR I s tud ies found increased rates o f subcor t ical

whi te m at ter o r per iven t r icu lar hyper in tensit ies in BPs. One

study wi th elder ly BPs found s ign i f ican t d i f ferences on ly fo r

large whi te mat ter les ions (McDonald et a l 1991) , and

another on ly in o lder pat ien ts (Aylward et a l 1994) . One

recen t s tudy d id no t fmd s ign i f ican t d i f ferences in the rates

of deep whi te mat ter hyper in tensi t ies , bu t d id f ind s ign i f i -

can t ly increased per iven t r icu lar hyper in tensit ies in B P type I

compared to BP type I I pat ien ts o r con t ro ls (Al tshu ler et a l

1995) . Dupo nt et a l (1995) used quant i ta t ive MRI techniques

to study wh ite ma tter abnormalities, and foun d increase d

v o lu me o f ab n o rmal wh i t e mat t e r i n BP s co mp ared t oage-ma tched cont ro ls , bu t no t in UP s.

Th ere i s a l so ev id en ce f ro m o n e case r ep o r t o f i n c rease

in s i ze an d n u mb er o f wh i t e mat t e r h y p er in t en s i t i e s t em-

p o ra l l y co r r e l a t ed wi th d ev e lo p men t o f d ep ress io n i n a

p rev io u s ly h ea l t h y p a t i en t (Lesse r e t a l 1 9 9 3) . P ro sp ec t i v e

s tu d i es sh o u ld fu r t h e r i n v es t i g a t e t h ese f i n d in g s u n d er

co n t ro l l ed c o n d i t i o n s.

Th u s , t h e re i s s t ro n g ev id en ce t h a t i n c reased r a t es o f

su b co r t i ca l wh i t e m at t e r an d p er i v en t r i cu l a r h y p er in t en s i -

t i e s a r e p resen t i n BP s an d e ld e r l y UP s . F o r n o n e ld er ly

UP s t h e ev id en ce i s s t i l l eq u iv o ca l . Th ese wh i t e mat t e r

l es i o n s may i n t e r ru p t f i b e r s in t h e p ro p o sed n e u ro an a to m ic

mo d e l o f mo o d r eg u l a t i o n , r esu l t i n g i n d i sco n n ec t i o namo n g t h o se r eg io n s , wh ich may r esu l t i n d ep ress io n .

Th e e t i o lo g y o f t h ese wh i t e mat t e r h y p er in t en s i t i e s i s

n o t e s t ab l i sh ed , b u t a v ascu l a r cau se h as b een p ro p o sed

(Aw ad et a l 1986a; Cof fey et a l 1989; Lesse r et a l 1991;

Schmidt et a l 1991) . I t i s possib le that they are associated

wi th d ep ress io n d u e t o ce reb ro v ascu l a r d i sease , wh ich i s

mo re co mmo n in t h e e ld e r l y , an d d i f f e r s f ro m cau ses i n

y o u n g er p a t i en t s.

Regional Brain Abno rmal i t ies

Cortical Regions

F RONTAL LOBE. Th ese s t u d ies a r e s u mm ar i zed i n Ta-

b l e 1 . I n c reased T1 v a lu es were fo u n d i n t h e f ro n t a l wh i t e

mat t e r o f d ep ressed UP s , b u t n o t i n BP s (Do lan e t a l

1 9 9 0 ). Th ese f i n d in g s were n o t co n f i rm ed fo r e l d e r l y UP s

(Kr i sh n an e t a l 1 9 9 1 a) . I n c reased T1 v a lu es may r e f l ec t

i n c reased f r ee wa t e r i n t h e b ra in w h i t e mat t e r (Co n lo n an d

Tr imb le , 1 9 87 ). I t is n o t c l ea r wh a t sp ec i f i c n eu ro p a th o l -

o g y co r r e l a t es wi th t h ese T1 ch an g es , b u t t h ey may b e

in d i ca t i v e o f p r e f ro n t a l l o ca t i o n o f r e l ev an t b r a in ab n o r -

mal i t y .

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90 B1OLPSYCHIATRY J.C. St are s and J.J. M ann1997;41:86-106

Table 1. Frontal Lobe Findings in Mood Disorders

Author Sample Age Subtype Methods Results

Dolan et al (1990) 24 RDC MDD 42.0 _+ 10 10 UP MRI 0.08T

13 normal controls 46.0 -+ 7.0 14 BP

Coffman et al (1990) 30 BP DSM-III -R 33.0 _+ 6.2 Psychotic MRI 1.5T52 normal controls 28.8 _+ 7.2

Krish nan et al (1991a) 20 MDD DSM-III -R 69 _+ 12.3 UPs MRI 1.5T

29 normal controls 71.5 - 5.0

Krish nan et al (1992) 50 MD DSM- III 48.3 + 17 UPs MRI 1.5T

50 normal controls 49.3 _+ 18

Coffey et al (1993a) 48 MD DSM- III 62.4 + 16.4 44 UPs, 4 BPs, MRI 1.5T

76 normal controls 61.6 -+ 15.9 ECT referred

Schlaepfer et al (1994) 27 BPs DSM- III -R 34.9 _+ 8.6 BPs MRI 1.5T

60 normal controls 31.6 _+ 8.0

Significantly higher T1 values in frontal

WM of LIPs but not BPs

Trend to smaller mean frontal area inpatients

T1 relaxation times not significantly

different

Frontal brain width significantly smaller

in patients

Mean total frontal volume significantly

smaller in patients

No significant difference in gray matter

volume of dorsolateral PFC

UP, unipolars; BP, bipolar; MD, major depression; MDD, major depressive disorder; WM, white matter; PFC, prefrontal cortex; MRI, magnetic resonance maging; RDC,research diagnostic criteria.

I n U Ps , K r i shnan e t a l ( 1992) f ound a sma l l e r f r on t a l

b r a i n w i d t h . C o f f ey e t a l ( 1993a ) f o und a 7% sma l l e r t o ta lf r o n ta l v o l u m e i n s e v e r e l y d e p r e s s e d E C T - r e f e r r e d L IP s

and B Ps . I n B Ps , C of f man e t a l ( 1990) f ound a t r end f o r

sma l l e r f r on t a l a r ea s i n pa t i en t s ; Sch l aep f e r e t a l ( 1994)

d i d no t f i nd s i gn i f i can t d i f f e r ences i n g r ay ma t t e r vo l ume

of do r so l a t e r a l p r e f r on t a l co r t ex compar ed t o con t r o l s .

T hese s t ud i e s mos t l y measur ed a c r ude l y de f i ned f r on t a l

l o b e, o n l y o n e s t u d y a n a l y z i n g m o r e d e f i n e d r e g i o n s o f t h e

pr e f r on t a l co r t ex ( S ch l aepf e r e t a l 1994) .

I n conc l us i on , t he r e i s some ev i dence o f s t r uc t u r a l

abnor ma l i t i e s i n t he f r on t a l l obe o f U Ps , bu t no t i n B Ps .

T he r e i s a need f o r w e l l - des i gned s t ud i e s o f p r e f r on t a l

co r t i ca l g r ay ma t t e r vo l ume , w i t h be t t e r l oca l i za t i on o f

med i a l , do r so l a t e r a l , and ven t r o l a t e r a l p r e f r on t a l co r t ex , t o

i n v e s ti g a te m o r e p r e c i s e l y t h e i n v o l v e m e n t o f t h e s e s u b -

r eg i ons o f t he f r on t a l l obe i n moo d d i so r de r s . T he p r e f r on-

t a l co r t ex appea r s t o be a key r eg i on i n t he neur oan a t om i c

m o d e l o f m o o d r e g u la t io n , b e i n g p r o b a b l y a n i m p o r t a n t

ana t om i c a r ea i m pl i ca t ed i n L I P depr es s i on .

T EMPOR AL L O B E . A ne cdo t a l ev i dence sugges t s a r e l a -

t i onsh i p be t w een t empor a l l obe abnor ma l i t i e s and deve l -

opment o f man i a , pa r t i cu l a r l y f o r f i gh t t empor a l l e s i ons

( Johnson and C ampb e l l 1990 ; S t a r ks t e i n e t a l 1990) . MR I

s t ud i e s r epor t t ha t T 1 r e l axa t i on t i mes ( D ol an e t a l 1990 ;

K r i shnan e t a l 1991a ) and t empor a l l obe vo l ume ( C of f ey

e t a l 1993a ) i n U Ps a r e no r ma l . O ne C T s t udy f ound

i nc r eased dens i t y o f t he r igh t t empor a l l obe o f B Ps

( D ew an e t a l 1988a ) . O ne ( H ause r e t a l 1989a ) o f t w o

( Johns t one e t a l 1989) MR I s t ud i e s r epor t ed sma l l e r

t empo r a l l obe a r eas i n pa ti en t s . O ne ( A l t shu l e r e t a l 1991)

o f t h r ee ( Sw ayze e t a l 1992 ; H ar v ey e t a l 1994) MR I

s t ud i e s f ound sma l l e r t empor a l l obe vo l umes i n pa t i en t s .

Pa r adox i ca l l y , one o f t he se s t ud i e s ( H ar vey e t a l 1994)

f o u n d i n c r e a s e d l e ft te m p o r a l v o l u m e s i n B P s c o m p a r e d t o

con t r o l s , r e su l t i ng f r om i nc r eased g r ay ma t t e r . C or t i ca l

g r a y m a t t e r v o l u m e o f s u p e r i o r t e m p o r a l g y r u s w a s n o t

s i gn i f i can t l y d i f f e r en t f r om con t r o l s ( Sch l aepf e r e t a l1994) . T hese s t ud i e s a r e summar i zed i n T ab l e 2 .

R e g a r d i n g t e m p o r a l l o b e a s y m m e t r i e s i n B P p a t i e n t s ,

four s tudies (Al t shuler e t a l 1991; Ross i e t a l 1991;

Sw ayze e t a l 1992 ; H ar ve y e t a l 1994) f ound s i gn i f i can t l y

sma l l e r l e f t t han r i gh t t empor a l l obe vo l umes i n pa t i en t s

and con t r o l s , bu t Johns t one e t a l ( 1989) f ound r i gh t

t empor a l l obe a r eas s i gn i f i can t l y sma l l e r t han l e f t . B P

f e m a l e s d i d n o t h a v e t h i s n o r m a l t e m p o r a l a s y m m e t r y i n

one s t udy ( Sw ayze e t a l 1992) .

O ver a l l , t he r e i s d i s ag r eemen t a s t o t he p r e sence o f

s t r uc t u r a l t empor a l l obe abnor ma l i t i e s i n B Ps . T empor a l

l o b e c h a n g e s h a v e b e e n f o u n d i n f o u r o f s e v e n M R I

s t ud i e s in B Ps , bu t no t i n U Ps . I n B Ps , bo t h de c r eased and

i n c r e a se d t e m p o r a l l o b e v o l u m e s h a v e b e e n r e p o r t e d , a n d

t he mean i ng o f t he se conf l i c t i ng f i nd i ngs needs t o be

c l a r i f i ed . Mos t o f t he s t ud i e s t ha t f ound abnor ma l i t i e s

r epor t ed dec r eased t empor a l l obe measur es . Fur t he r s t ud -

i e s w i t h be t t e r de l i nea t i on o f t empor a l l obe s t r uc t u r e s a r e

needed t o addr es s t h i s ques t i on . T he t empor a l l obe con-

t a in s k e y s t ru c t u re s i n t h e n e u r o a n a t o m i c m o d e l o f m o o d

r egu l a t i on , and ana t omi c chan ges i n t h is a r ea appea r m or e

spec i f i c t o B P depr es s i on .

PA RIE TA L L O B E . T he f ew s t ud i e s t ha t ha ve i nves t i -

ga t ed t he pa r i e t a l l obe i n mood d i so r de r s d i d no t f i ndabnor ma l i t i e s . I n one s t udy ( D ol an e t a l 1990) , T 1 r e l ax -

a t i on t i mes i n r i gh t o r l e f t pa r i e t a l l obes w er e no t s i gn i f -

i can t l y d i f f e r en t amo ng B P s , U Ps , and con t r o l s . In ano t he r

s t udy ( Sch l aep f e r e t a l 1994) , g r ay ma t t e r vo l um e i n

i n f e r i o r pa ri e t a l co r t ex o f B Ps w as no r ma l .

Subcortical Regions

T H A L A MU S. A necdo t a l ev i dence sugges t ed t ha t f i gh t

t h a l a m i c i n f a r c t i o n s m i g h t b e r e l a t e d t o d e v e l o p m e n t o f

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Table 2. Temporal Lobe Findings in Mood Disorders

A u t h o r S a m p l e A g e S u b t y p e M e t h o d s R e s u l t s

D e w a n e t a l ( 1 9 8 8 a) 2 6 D S M - I I I B P s 3 2 . 7 B P s C T G E 8 8 0 0

2 2 c o n t r o l s 3 1 . 1

H a u s e r e t a l ( 1 9 8 9 a ) 1 7 R D C A D 4 0 . 5 ± 1 2 .8 1 5 B P s , 2 U P s M R I 0 . 5 T2 1 n o r m a l c o n t r o l s 3 3 . 8 ± 6 . 2

J o h n s t o n e e t a l ( 1 9 8 9 ) 2 0 D S M - I I I B P s 3 5 . 2 M / 4 2 . 5 F B P s M R I 0 . 1 5 T

2 1 n o r m a l c o n t r o l s 3 2 . 9 M / 3 9 F

D o l a n e t a l ( 1 9 9 0) 2 4 R D C M D D 4 2 ± 1 0 1 0 U P s , 1 4 B P s M R I 0 . 0 8 T

1 3 n o r m a l c o n t r o l s 4 6 ± 7

K r i s h n a n e t a l ( 1 9 9 1 a ) 2 0 M D D D S M - I I I - R 6 9 ± 1 2 .3 U P s M R I 1 . 5 T

2 9 n o r m a l c o n t r o l s 7 1 . 5 ± 5

A l t s h u l e r e t a l ( 1 9 9 1 ) 1 0 R D C B P s 3 9 . 8 ± 9 . 0 B P s M R I 0 . 5 T

1 0 n o r m a l c o n t r o l s 3 7 ± 1 2 . 0

S w a y z e e t a l ( 1 9 9 2 ) 4 8 D S M ° I I I B P s 3 3 . 4 M / 3 4 . 6 F B P s M R I 0 . 5 T

4 7 n o r m a l c o n t r o ls A g e n o t s t at e d

C o f f e y e t a l ( 1 9 9 3 a ) 4 8 M D D S M - I I I 6 2 . 4 ± 1 6 . 4 4 4 U P s , 4 B P s , M R I 1 . 5 T

7 6 n o r m a l c o n t r o l s 6 1 . 6 ± 1 5 . 9 E C T r e f e r re d

H a r v e y e t a l ( 1 9 9 4) 2 6 R D C B P s 3 5 . 6 ( 2 1 - 4 9 ) B P s M R I 0 . 5 T

3 4 n o r m a l c o n t r o ls 3 1 . 6 ( 1 9 - 4 9 )

S c h l a e p f e r e t a l ( 1 9 9 4 ) 2 7 D S M - I I I B P s 3 4 . 9 ± 8 . 6 B P s M R I 1 . 5 T

6 0 n o r m a l c o n t r o l s 3 1 . 6 ± 8 . 0

S i g n i f i c a n t l y i n c r e a s e d d e n s i t y i n R

t e m p o r a l l o b e , a n d t r e n d o n L

T e m p o r a l l o b e / c e r e b r a l a r e a

s i g n i f i c a n t l y s m a l l e r i n p a t i e n t s

T e m p o r a l h o r n a r e a a n d t e m p o r a l

l o b e a r e a n o t s i g n i f i c a n t l y

d i f f e r e n t

N o s i g n i f i c a n t d i f f e r e n c e s i n T 1

v a l u e s i n R o r L t e m p o r a l l o b e s

T 1 r e l a x a t i o n t i m e n o t s i g n i f i c a n t l y

d i f f e r e n t i n t e m p o r a l l o b e

R a n d L t e m p o r a l l o b e v o l u m e

s i g n i f i c a n t l y s m a l l e r i n p a t i e n t s

N o s i g n i f i c a n t d i f f e r e n c e s i n

t e m p o r a l l o be v o l u m e

N o s i g n i f i c a n t d i f f e re n c e s i n

t e m p o r a l lo b e v o l u m e

L t e m p o r a l l o b e v o l u m e

s i g n i f i c a n t l y l a r g e r i n p a t i e n t s , d u e

t o i n c r e a s e i n g r a y m a t t e r

N o s i g n i f i c a n t d i f f e r e n c e s i n g r a y

m a t t e r v o l u m e o f s u p e r i o r t e m p o r al

g y m s

UP, unipolar; BP, bipolar; MD, major depression; AD, affective disorder; R, right; L, left; M, male; F, female; CT, computed tomography; MRI, magnetic resonanceimaging; RDC, research diagnostic criteria; ECT, electroconvulsive therapy.

man ia (Cu m min g s an d M en d e z 1 9 8 4) . I n c reased CT

d en s i t y was fo u n d i n t h a l amu s o f BP s i n o n e co n t ro l l ed

s tu d y (Dew an e t a l 1 9 8 8 a), b u t two l a t e r M RI s t u d ies d id

n o t f i n d s i g n i f ican t d i f f e r en ces i n T1 v a lu es i n B P s (Do lane t a l 1 9 9 0 ) o r e l d e r l y UP s (Kr i sh n an e t a l 1 9 9 1 a) co m -

p ared t o co n t ro l s . On e co n t ro l l ed M RI s t u d y d id n o t f i n d

ev id en ce o f ab n o rmal i t i e s i n t h a l amu s v o lu me in e ld e r l y

UP s (Kr i sh n an e t a l 1 9 9 3 b) . No s i g n i f ican t d i f f e r en ces in

measu res o f t h a l amu s v o lu me were fo u n d i n f i r s t - ep i so d e

man ics co mp ared t o n o rmal s (S t r ak o wsk i e t a l 1 9 9 3 a) ;

h o we v er , o n e r ecen t M RI s t u d y (D u p o n t e t al 1 9 9 5 ) fo u n d

s ig n i f i can t l y i n c reased t h a l amu s v o lu me measu res i n BP

p a t i en t s co mp ared t o n o rmal co n t ro l s , an d s i g n i f i can t l y

d ecreased measu res i n UP s co mp ared t o co n t ro l s .

Th u s , t h e re i s co n f l i c t i n g ev id en ce o f ab n o rmal i t i e s i n

th e t h a l amu s o f mo o d d i so rd er p a ti en t s . Th ere i s a p au c i t y

o f h ig h - r eso lu t i o n M RI v o lu met r i c s t u d i es. Th i s r eg io n i s

p a r t o f a n eu ro an a to mic mo d e l o f mo o d r eg u l a t i o n , an d

fur ther s tud ies should invest igate i t s ro le in mood d isor-

d er s . Th e s i ze an d l ack o f d em arca t i o n o f t h a l amic n u c l e i

mak e i t d i f fi cu l t t o o b t a in r e l i ab l e measu res . T h ere i s a l so

th e p o ss ib i l it y o f i so l a t ed cases d u e t o a sp ec i f i c acq u i r ed

d amag e t o t h i s a r ea .

A M Y G D A L A , HIPPOCAMPUS. Decreased T1 relaxat ion

t imes were fo u n d i n t h e h ip p o camp u s o f UP s i n o n e

co n t ro l l ed M RI s t u d y , p a r t i cu l a r l y i n e l d e r l y p a t i en t s

(Kr i sh n an e t a l 1 9 9 1 a). Tw o o th er M RI s t u d ies (Co f fey e t

al 1993a; Axelson et a l 1993) d id no t f ind s ign i f ican t

d i f fe r e n c e s i n a m y g d a l a - h i p p o c a m p u s c o m p l e x v o l u m e sb e tween UP p a t i en t s an d co n t ro l s . I n BP s , M RI measu res

o f h ip p o cam p al a r ea were n o t s i g n i f i can t l y d i f f e r en t f ro m

co n t ro l s (Hau ser e t a l 1 9 8 9 a) , b u t v o lu met r i c M RI mea-

su res o f f ig h t h ip p o camp u s were r ep o r t ed t o b e sm al l e r in

o n e co n t ro l l ed s tu d y (S w ay ze e t a l 1 9 9 2 ). Am y g d a l a a r ea

o r a m y g d a l a - h i p p o c a m p a l c o m p l e x v o l u m e w e r e n o t

s i g n i f i can t l y d i f f e r en t (S way ze e t a l 1 9 9 2 ) . On e r ecen t

co n t ro l l ed M RI s t u d y p arad o x i ca l l y fo u n d i n c reased v o l -

u m e measu res o f h ip p o cam p u s i n BP s , w i th l e f t h ip p o cam -

pus s ign i f ican t ly larger than f igh t in pat ien ts and cont ro ls

(Ke mm erer e t a l 1 9 9 4 ) .

Th u s , t h e re i s n o co n s i s t en t ev id en ce o f s t ru c tu ra l

ab n o rmal i t i e s i n amy g d a l a -h ip p o camp u s . Th e co n f l i c t i n g

f in d in g s r eg ard in g h ip p o camp al v o lu m e in BP s n eed t o b e

fu r th e r ex p lo red , p a r t i cu l a r l y i n l i g h t o f f i n d in g s o f a

p o ss ib l e smal l e r t emp o ra l co r t ex (Hau ser e t a l 1 9 8 9 a ;

Al tshu ler et a l 1991) . Disagreements in s tud ies may be

p ar t l y ex p l a in ed b y d i f f i cu l t i e s i n t h e d e l imi t a t i o n an d

mea su rem en t o f t h is s t ru c tu re . An a to m ic ch an g es i n t h ese

s t ru c tu res , i f p r esen t , l en d fu r t h e r su p p o r t f o r t h e n eu ro -

an a to mic m o d e l o f mo o d r eg u l a t i o n p ro p o sed t o b e imp l i -

ca t ed i n mo o d d i so rd er s .

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Table 3. Basal Ganglia Findings in Mood Disorders

A u t h o r S a m p l e A g e S u b t y p e M e t h o d s R e s u l t s

D e w a n e t a l ( 1 9 8 8 a ) 2 6 D S M - I I I B P s 3 2 . 7 B P s C T G E 8 8 0 0

2 2 c o n t r o l s 3 1 . 1

D o l a n e t a l ( 1 9 9 0 ) 2 4 R D C M D D 4 2 _+ 1 0 1 0 L I Ps , 1 4 B P s M R I 0 . 0 8 T1 3 n o r m a l c o n t r o l s 4 6 _+ 7

R a b i n s e t a l ( 1 9 9 1 ) 2 1 D S M - I I I - R M D D A g e n o t r e p o rt e d E l d e rl y U P s M R I 1 . 5T

1 4 n o r m a l c o n t r o l s

H u s a i n e t a l ( 1 9 9 1 a ) 4 1 D S M - I I I M D 5 5 . 3 -+ 1 8 .8 U P s M R I 1 . 5 T

44 norm al contro ls 56 .4 - -- 19 .2

K r i s h n a n e t a l ( 1 9 9 2 ) 5 0 D S M - I I I M D 4 8 . 3 + - 1 7 U P s M R I 1 . 5 T

5 0 n o r m a l c o n t r o l s 4 9 . 3 _+ 1 8

S w a y z e e t a l ( 1 9 9 2 ) 4 8 D S M - I I I B P s 3 3 . 4 M / 3 4 . 6 F B P s M R I 0 . 5 T

4 7 n o r m a l c o n t r o ls A g e n o t s t a te d

K r i s h n a n e t a l ( 1 9 9 3 b ) 2 5 D S M - I I I M D 7 4 . 1 _+ 6 . 6 E l d e r l y M R ! 1 . 5 T

2 0 n o r m a l c o n t r o l s 7 2 . 5 _+ 3 . 6

S t r a k o w s k i e t a l ( 1 9 9 3 a ) 1 7 D S M - I I I - R B P s 2 8 . 4 _+ 6 . 8 F i r s t e p i s o d e M R I 1 . 5 T

1 6 n o r m a l c o n t r o l s 3 0 . 9 - 7 . 3 m a n i c s

A y l w a r d e t a l ( 1 9 9 4 ) 3 0 D S M - I I I - R B P s 3 9 . 3 --_ 1 1 .1 B P s M R I 1 . 5 T

30 norm al contro ls 37 .6 ___ 9 .0

H a r v e y e t a l ( 1 9 9 4 ) 2 6 R D C B P s 3 5 . 6 ( 2 1 - 4 9 ) B P s M R 1 0 . 5 T

3 4 n o r m a l c o n t r o l s 3 1 . 6 ( 1 9 - 4 9 )

D u p o n t e t a l ( 1 9 9 5 ) 3 6 D S M - I I I - R B P s 3 6 . 6 --_ 1 0 .8 3 0 U P s , 3 6 B P s M R I 1 . 5 T

30 DS M- I I I -R UP s 38 .6 -_+ 10 .6

2 6 n o r m a l c o n t r o l s 3 9 . 1 4 - 9 . 4

S i g n i f i c a n t l y i n c r e a s e d d e n s i t y i n

R a n d L c a u d a t e i n p a t i e n t s

N o s i g n i f i c a n t d i f f e r e n c e s i n T 1

v a l u e s i n R o r L c a u d a t e

S i g n i f i c a n t l y i n c r e a s e d r a t e s o f

B G l e s i o n s i n p a t i e n t s

S i g n i fi c a n t ly s m a l l e r p u t a m e n

v o l u m e i n p a t i e n t s

S i g n i f i c a n t l y s m a l l e r c a u d a t e

v o l u m e i n p a t i e n ts

C a u d a t e a n d p u t a m e n v o l u m e s

n o t s i g n i f i c a n t l y d i f f e re n t

S i g n i f i c a n t l y s m a l l e r c a u d a t e a n d

p u t a m i n a l c o m p l e x v o l u m e s i n

p a t i e n t s


c a u d a t e m e a s u r e s

S i g n i f i c a n t l y l a r g e r R a n d L

c a u d a t e v o l u m e i n m a l e B P s


v o l u m e o f s u b c o r t i c a l t i s s u e

C a u d a t e a n d l e n t i c u l a r n u c l e u s

v o l u m e s n o t s i g n i fi c a n tl y

d i f f e r e n t

UP, unipolar; BP, bipolar; MDD, major depression disorder; MD, major depression; BG, basal ganglia; R, right; L, left; M, male; F, female; CT, computed tomography;MRI, magnetic resonance imaging; RDC, research diagnostic criteria.

BASAL GANGLIA, Tw o (K rishnan et a l 1992; Hu sain et

a l 1 9 9 1 a) o f t h r ee (Du p o n t e t a l 1 9 9 5 ) co n t ro l l ed M RI

s tu d i es fo u n d s i g n i f i can t l y smal l e r p u t amen an d cau d a t e

v o lu mes i n UP s b i l a t e r a l l y . Th e o n e n eg a t i v e s t u d y (Du -

p o n t e t a l 1 9 9 5 ) fo u n d a t r en d fo r smal l e r cau d a t e an dlen t icu lar vo lumes in UPs, bu t th is was no t s tat i s t ical ly

s ig n i f i can t . S in ce t h e samp le i n t h i s s t u d y was y o u n g er ,

t h i s co u ld r e f l ec t d i f f e r en ces i n p a t i en t p o p u l a t i o n . In

e ld e r l y UP s , o n e M R I s t u d y fo u n d s i g n i f i can tl y d ecreased

v o l u m e s o f c a u d a t e a n d p u t a m e n c o m p l e x c o m p a r e d t o

ag e-m atch ed co n t ro l s (Kr i sh n an e t a l 1 9 9 3 b ). I n BP s , o n e

co n t ro l l ed CT s tu d y (Dewa n e t a l 1 9 8 8 a) fo u n d i n c reased

d en s i t y o n r i g h t an d l e f t cau d a t e n u c l eu s i n p a t i en t s ; an d

o n e (Ay lward e t a l 1 9 9 4 ) o f fo u r (S way ze e t a l 1 9 9 2 ;

S t r ak o wsk i e t a l 1 9 9 3 a ; Du p o n t e t a l 1 9 9 5 ) co n t ro l l ed M RI

s tu d i es fo u n d l a rg er cau d a t e v o lu mes b i l a t e r a l l y i n male

p a t i en t s . On e s t u d y (H arv ey e t a l 1 9 9 4 ) u sed v o lu m e

measu res o f b ro ad ly d e f i n ed " su b co r t i ca l t i s su e , " an d d id

n o t f i n d s i g n i f i can t d i f f e r en ces f ro m co n t ro l s . Th ese r e -

su i t s a r e su mmar i zed i n Tab l e 3 .

Th ese f i n d in g s t ak en t o g e th er wi th ev id en ce o f i n -

c r eased wh i t e mat t e r h y p er in t en s i t i e s i n su b co r t i ca l r e -

g i o n s o f U P s a n d B P s c o m p a r e d t o a g e - m a t c h e d c o n tr o l s

(Du pont et a l 1987 , 1990; Co ffey et a l 1990 , 1993a;

Sw ayz e et a l 1990; Zuben ko et a l 1990; F ig iel e t a l 1991b;

Le sse r et a l 1991; M cD ona ld et a l 1991; Rabins et a l 1991;

Brown et a l 1992; Howard et a l 1993; Krishnan et a l

1 9 9 3b ; Du p o n t e t a l 1 9 9 5 ) su g g es t t h a t th ese an a to m ic

reg io n s may i n d eed h av e s t ru ctu ra l ab n o rmal i ti e s i n mo o d

d i so rd ers . S ig n i f i can t ly i n c reased C T d en s i t i e s i n t h e l e f t

an d r i g h t h ead s o f t h e cau d a t e were fo u n d i n e ld e r l y

d ep ressed p a t i en t s (mo s t l y UP s) co mp ared t o co n t ro l s(Beats et a l 1991) . The re i s a l so ev ide nce that s i len t

ce reb ra l i n f a r c t i o n i n v o lv in g su b co r f ica l s t ru c tu res m ay b e

in v o lv ed i n a g rea t p a r t ( 6 5 .9 -9 3 .7 % ) o f sen i l e an d

p resen i l e majo r d ep ress io n (F u j i k awa e t a l 1 9 9 3 ) , h ig h -

l i g h t i n g t h e p o t en t i a l imp o r t an ce o f t h e b asa l g an g l i a i n

mo o d d i so rd er s .

Th u s , t h e re is ev id en ce t h a t d ep ressed UP s h av e sm al l e r

b asa l g an g l i a v o lu mes . Th i s d o es n o t ap p ear t o b e t h e case

fo r BP s . Cau d a t e n u c l eu s m ay ac tu a l l y b e en l a rg ed in BP s ,

i n co n t r as t t o UP s , b u t t h i s f i n d in g h as n o t b ee n r ep l i ca t ed .

Th ese ap p ear t o b e c ru c i a l a r eas i n t h e n eu ro an a to mic

m o d e l o f m o o d d i so r d er s .

Posterior Fossa Structures

CEREBELLUM . In creased r a t es o f ce reb e l l u m a t ro p h y

were r ep o r t ed i n a co n t ro l l ed CT s tu d y o f y o u n g m an ic

p a t i en t s (Nas ra l l ah e t a l 1 9 8 2 b ) . An o th er co n t ro l l ed CT

s tu d y (Wein b erg er e t a l 1 9 8 2 ) fo u n d i n c reased r a t es o f

v ermian a t ro p h y i n a samp le o f a f f ec t i v e d iso rd er p a t ien t s ;

h o wev e r , in o n e co n t ro l l ed s t u d y (Dew an e t a l 1 9 8 8 a) CT

d en s i t i e s o f v e rmi s an d f i g h t o r l e f t ce r eb e l l u m were

8/3/2019 soares et al 1997


An atom y of Mo od Diso rders BIOL PSYCHIATRY 931997;41:86-106

n o rmal i n BP s . A co n t ro l l ed CT s tu d y i n a samp le o f UP s

an d BP s d id n o t f i n d s i g n i f i can t d i f f e r en ces i n r a t es o f

ce reb e l l a r a t ro p h y (Ya t es e t al 1 9 87 ). Tw o co n t ro l l ed M RI

s tu d ies fo u n d d ecre ased ce reb e l l a r v e rmi s a r ea (S h ah e t a l

1 9 9 2) an d me an ce reb e l l a r v o lu m e (Esca lo n a e t a l 1 9 9 3 ) i n

UP s , i n samp les o f mo s t l y n o n e ld er ly p a t i en t s .

Th u s , t h e re i s ev id en ce o f smal l e r ce reb e l l u m in UP s

an d BP s . Th e ev id en ce fo r ab n o rmal i t i e s i n UP s i s

s t ro n g er , b ecau se i t co mes f ro m co n t ro l l ed a r ea an d

v o lu me s tu d i es , wh i l e t h e ev id en ce i n BP s co mes main ly

f ro m s tu d ies u s in g ex am in er ' s r a t i n g s . F u r th e r v o lu met r i c

s tu d i es a r e n eed ed t o r ep l i ca t e t h ese f i n d in g s . Th e ce re -

b e l l u m, t h ro u g h i t s p ro j ec t i o n s t o l imb ic a r eas , may b e an

i m p o r t a n t r e g i o n i n a n e u r o a n a t o m i c m o d e l o f m o o d

disorders .

BRAIN STEM . Sm al ler areas o f med ul la and to tal b rain

s t em, b u t n o t mid b ra in o r p o n s , were fo u n d i n o n e M RIs tu d y i n UP s co mp ared t o co n t ro l s (S h ah e t a l 1 9 9 2 ) .

Based o n t h e ev id en ce r ep o r t ed i n t h i s o n e s t u d y , fu r t h e r

s t u d i es sh o u ld ev a lu a t e t h ese b ra in r eg io n s i n UP s an d

BP s .

Othe r s

CORPUS CALLOSUM. Corpus ca l l o su m area i n BP s was

n o rmal i n o n e co n t ro l l ed M RI s t u d y (Hau ser e t a l 1 9 8 9 b ),

b u t i t was s i g n i f i can t l y d ecreased i n an o th er co n t ro l l ed

s tu d y i n p sy ch o t i c BP s (C o f fma n e t a l 1 9 9 0 ). I n UP s , o n e

M RI s t u d y (Wu e t a l 1 9 9 3 ) fo u n d l a rg er an t e r i o r an d

p o s t e r i o r q u ar t e r s o f co rp u s ca l l o su m co mp ared t o co n -t ro is , b u t an o th er co n t ro l l ed M R I s t u d y d id n o t f i n d

ev id en ce o f ab n o rmal i t i e s i n co rp u s ca l l o su m area (Lam-

mers et a l 1991) .

Th u s , i t is u n c l ea r wh e th er an a to mic ch an g es a r e p resen t

i n t hi s r eg io n . A r ed u c t i o n i n co rp u s ca l l o su m area ma y b e

co n f in ed t o p sy ch o t i c p a t i en t s , b u t t h ese i n i t i a l f i n d in g s

n eed t o b e fu r t h e r i n v es t i g a ted .

SEPTUM PELLUCIDUM. Me asure s o f sep tum pel luci -

d u m area i n UP s w ere n o rmal i n o n e co n t ro l l ed M R I s t u d y

(Lammers e t a l 1 9 9 1 ) . A h ig h er r a t e o f cav u m sep tu m

p el lu c id u m was fo u n d i n sch i zo p h ren i cs co mp ared t o

mo o d d i so rd er p a t i en t s, b u t n o t i n m o o d d i so rd er p a t i en t s

co m p ared t o co n t ro l s ( Ju r j u s e t a l 1 9 9 3) .

In co n c lu s io n , t h e re i s n o ev id en ce o f sep tu m p e l l u c i -

d u m ab n o rmal i t i e s i n mo o d d i so rd er s i n t h e f ew s tu d i es

co n d u c t ed so f a r .

PITUITARY. In c reased p i t u i t a ry v o lu me was fo u n d i n

d ep ressed p a t i en t s co mp ared t o co n t ro l s (Kr i sh n an e t a l

1 9 9 l b ) . A s i g n i f ican t co r r e l a t i o n b e tween p i t u i t a ry v o lu m e

an d 1 0-P M p o s td ex am eth aso n e p l asm a c o r t i so l co n cen t r a -

t i o n was fo u n d i n d ep ressed p a t i en t s , su g g es t i n g t h a t

ac t i v a t i o n o f h y p o th a l amic-p i t u i t a ry -ad ren a l (HP A) ax i s

may b e r e l a t ed t o p i t u i t a ry v o lu me in t h ese p a t i en t s

(Ax e l so n e t a l 1 9 9 2 ). Kr i sh n an (1 9 9 3 ) co n c lu d ed t h a t t h is

en l a rg em en t i s an t e r i o r , b ecau se t h e p o s t e r i o r p i t u i t a ry i s

o f n eu ra l o r i g in , an d co n s t i t u tes l e s s t h an 2 0 % o f t h e

g l an d . Th ese r esu l t s a r e co n s i s t en t w i th h y p erac t i v i t y o f

t h e HP A sy s t em, as a r e r ep o r t s o f ad ren a l g l an d en l a rg e-

men t i n p a t i en t s wi th majo r d ep ress io n (Amste rd am e t a l

1987; Rubin et a l 1995) .

LATERALITY OF ANATOMIC LESIONS. L e f t f ro n ta l l o b e

l e s i o n s seco n d ary t o s t ro k e o r tr au ma were as so c i a t ed wi th

h ig h er r a t es an d i n c reased sev er i t y o f d ep ress io n (L ip se y

et al 1983; Robinso n et a l 1984a, 1984b , 1988; Eastw ood

et al 1989; Ast rom et a l 1993; Hen-mann et a l 1993; Jorge

et al 1993) , bu t no t in all s tud ies (S iny or et a l 1986; Ho use

et al 1990; Sharpe et a l 1990; Agrel l and Dehl in 1994;

An d er sen e t a l 1 9 9 5 ; Ng e t a l 1 9 9 5 ) . Th ese l e s i o n s were

ei ther cor t ical o r subcor t ical (S tarkstein et a l 1987) ;

h o wev er , an as so c i a t i o n b e tween d ep ress io n an d r i g h t -

s i d ed l es i o n s h as a l so b een d esc r i b ed (F o l s t e in e t a l 1 9 7 7 ) ,

b u t t h ese l e s i o n s ap p eared t o b e m o re p o s t e r i o r (Ro b in so n

et al 1984a) . In one s tudy (Starkstein et a l 1987) , post -

s t ro k e l e s i o n s o n t h e r i g h t h emi sp h ere were as so c i a t ed

wi th eu p h o r i a o r i n d i f f e r en ce . Les io n s cau sed b y t u mo r

resec t i o n f ro m f ro n t a l o r p a r i e t a l a s so c i a t i o n co r t ex es ,

co mb in ed wi th p a ra l imb ic l e s i o n s , were as so c i a t ed wi th

mo re d ep ress iv e sy mp to ms , an d i n t h i s s t u d y l a t e r a l i t y o f

les ion was no t impor tan t ( l r le et a l 1994) . Overal l , lef tan t e r i o r l e s i o n s h av e b een mo re as so c i a t ed wi th d ep res -

s i o n . Co n f l i c t i n g f i n d in g s i n d i f f e r en t s t u d i es may b e

ex p l a in ed b y d i f f e r en t p a t ien t p o p u l a t i o n s ( e .g . , i n p a t i en t

v er su s co mmu n i ty -b ased samp les ) , d i f f e r en t d i ag n o s t i c

c r i t e r ia an d fo l l o w -u p i n s t ru men t s , an d t ime i n t e rv a l s fo r

as sessmen t s .

M an ia i s l e s s f r eq u en t t h an d ep ress io n fo l l o win g a

s t ro k e o r b r a in i n ju ry . Cu mmin g s an d M en d ez (1 9 8 4 )

su g g es t ed , b ased o n an ecd o t a l r ep o r t s , t h a t r i g h t - s i d ed

l es io ns , m a in ly i n t h e d i en cep h a l i c r eg io n , co u ld b e r e l a t ed

t o d e v e l o p m e n t o f m a n i a . R i g h t h e m i s p h e r e c t o m y w a s

a l so su g g es t ed i n o n e case r ep o r t t o r esu l t i n BP sy mp -

to mato lo g y (F o r r es t 1 9 8 2) . A co n t ro l l ed s t u d y o f p a t i en ts

wi th seco n d a ry man ia sh o w ed t h a t th e r i g h t h emi sp h ere i s

mo re f r eq u en t l y t h e s i t e o f t h e l e s i o n (S t a rk s t e in e t a l

1987) . Based in a smal l case ser ies , S tarkstein et a l (1990)

su g g es t ed t h a t d ev e lo p men t o f man ia a f t e r b r a in i n ju ry

co u ld b e r e l a t ed t o r i g h t - s i d ed l es io n s , i n t h e b asa l r eg io n

o f t h e r i g h t t emp o ra l l o b e . I n an o th er s t u d y , man ia was

re l a t ed t o su b co r t i ca l an d c o r t i ca l ri g h t h emi sp h ere l e s i o n s

(S t a rk s t e in e t a l 1 9 9 1 ) . S in ce man ia i s l e s s co mmo n th an

d ep ress io n a f t e r s t ro k e o r b r a in i n ju ry , i t may b e mo re

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94 BIOL PSYCHIATRY J.C. Soares and J.J. Mann1997;41:86-106

d i f f i cu l t t o cau se , o r t h e re may b e f ewer v u ln erab l e

in d iv id u a l s i n wh o m i t can b e t r i g g ered .

Al th o u g h t h e s t u d i es o f p o s t s t ro k e o r h ead t r au ma-

re l a t ed mo o d d i so rd er s h av e so me d i sag reemen t r eg ard in g

th e imp o r t an ce o f l e s i o n l a t e r a l i t y , r i g h t h emi sp h ere l e -

s i o n s seem to b e mo re f r eq u en t l y as so c i a t ed wi th man ia ,

and lef t -s ided les ions , par t icu lar ly f ron tal , are associated

wi th d ep ress io n .

Clin ica l and Bio log ica l Corre la tes o fN e u r o r a d io lo g ic a l F in d in g s

S ev era l s t u d i es h av e i n v es t i g a ted t h e c l i n i ca l an d b io lo g -

ical correlates o f these d i f feren t s t ructural f ind ings. These

s tu d ies fo cu sed o n i n v es t i g a t i o n o f r e l a t io n sh ip wi th ag e o f

o n se t , su b ty p e , i n c lu d in g t h e UP v er su s BP d i ch o to my ,

co g n i t i v e imp a i rmen t , co u r se o f i l ln es s , t r ea tmen t r esp o n -

s iv en ess , an d sp ec i f i c a sp ec ts o f p sy ch o p a th o lo g y .

Ear ly versus L ate O nset o f I l lness

En la rg ed v en t r i c l es were su g g es t ed t o b e as so c i a t ed wi th

l a t e o n se t o f d ep ress io n ( Jaco b y an d Lev i 1 9 8 0; S h ima e t

a l 1 9 8 4 ) . S ev era l au th o r s t r i ed su b seq u en t l y t o co r r e l a t e

g lo b a l o r l o ca l i zed s t ru c tu ra l n eu ro imag in g ch an g es wi th

age at onset o f i l lness . Three (Rossi e t a l 1987; Rabins et

a l 1 9 9 1 ; Alex o p o u lo s e t a l 1 9 9 2 ) o f f i v e (Ro y -By rn e e t al

1988; Church i l l e t a l 1991) s tud ies found a posi t ive

co r r e l a t i o n b e twee n ag e a t o n se t an d g lo b a l measu res o f

b ra in a t ro p h y . Th ese s t u d i es i n v o lv ed mo s t l y UP s . Inan o th er s t u d y , i n c reased l a t e r a l an d t h i rd v en t r i c l e mea-

su res were fo u n d i n l a t e -o n se t co mp ared t o ea r l y -o n se t

UPs (Alexopoulos et a l 1992) . Four (Church i l l e t a l 1991;

Fig iel e t a l 1991a; Howard et a l 1993; Hick ie et a l 1995)

of s ix (Zub enk o et al 1990; F ig iel e t a l 1991c) s tud ies

fo u n d a p o s i t i v e co r r e l a t i o n b e tween ag e a t o n se t an d

wh i t e mat t e r h y p er in t en s i t i e s i n UP s , an d o n e s t u d y

(Du p o n t e t a l 1 9 9 0 ) d id n o t f i n d s i g n i f i can t co r r e l a t io n fo r

BP s . No s i g n i f i can t co r r e l a t i o n b e tween ag e a t o n se t an d

T1 r e l ax a t i o n t imes was fo u n d i n UP s o r BP s (Do lan e t a l

1 99 0 ). Th ree s t u d ies l o o k e d a t t h e co r r e l a t i o n b e tween ag e

a t o n se t an d r eg io n a l a t ro p h y . Cau d a t e (Kr i sh n an e t a l

1 9 9 2 ) a n d r i g h t a m y g d a l a - h i p p o c a m p u s ( A x e l s o n e t a l

1 9 9 3 ) v o lu mes co r r e l a t ed n eg a t i v e ly wi th ag e o f o n se t i n

UP s ; an d t em p o ra l l o b e a r eas i n BP s d id n o t (Hau ser e t a l

1 9 8 9 a) . No s i g n i f i can t co r r e l a t i o n b e tween ag e a t o n se t

an d mea su res o f CT d en s i t y was fo u n d i n a samp le o f

e ld e r l y d ep ressed p a t i en ts (m o s t l y UP s) (B ea t s e t a l 1 9 9 1 ) .

Th u s , a l a t e r ag e o f o n se t s eems t o co r r e l a t e wi th

in c reased measu res o f g lo b a l a t ro p h y an d wh i t e mat t e r

h y p er in t en s i t i e s , an d p erh ap s wi th r eg io n a l a t ro p h y i n

so me sp ec i f i c b r a in r eg io n s . Th e imp l i ca t i o n o f t h ese

resu l t s i s that there i s an age-related degenerat ive b rain

ch an g e r e l a t ed t o l a t e -o n se t d ep ress io n .

Bipolar versus Unipolar Dichotomy

In UPs, the main s t ructural f ind ings are: 1 ) increased rateso f su b co r t i ca l wh i t e m at t e r an d p er i v en t r i cu l a r h y p er in t en -

s i t ies in elder ly pat ien ts (C offe y et a l 1990 , 1993a;

Zubenko et a l 1990; Rabins et a l 1991; Lesser et a l 1991;

Ho ward e t a l 1 9 9 3 ; Kr i sh n an e t a l 1 9 9 3 b ) ; 2 ) d ec reased

cereb e l l a r v e rmi s a r ea (S h ah e t a l 1 9 9 2 ) an d mea n ce re -

b e l l a r v o lu me (Esca lo n a e t a l 1 9 9 3 ) ; an d 3 ) d ec reased

v o lu m e o f cau d a t e an d p u t ame n (Hu sa in e t a l 1 9 9 1a ;

Krishnan et a l 1992 , 1993b) . In BPs, the most consis ten t

ab n o rmal i t i e s a r e : 1 ) in c reased r a t es o f su b co r t i ca l wh i t e

mat t e r an d p er i v en t r i cu l a r h y p er in t en s i t i e s i n n o n e ld er ly

and elder ly pat ien ts (Dup ont et a l 1987 , 1990 , 1995;

S way ze e t a l 1 9 9 0 ; F ig i e l e t a l 1 9 9 1 b ; M cDo n a ld e t a l

1991; Aylward et a l 1994; Al tshu ler et a l 1995) ; 2 )

i n c reased t h i rd v en t r i c l e measu res (S ch l eg e l an d

Kre t zsch mar 1 9 8 7 ; Dewan e t a l 1 9 8 8 a ; S t r ak o wsk i e t a l

1 9 9 3 a); an d 3 ) smal l e r ce reb e l l a r measu res (Nas ra l l ah e t a l

1 9 8 2b ; We in b erg er e t a l 1 9 8 2) .

Th e f i n d in g s o f d ec reased r ig h t h ip p o camp u s v o lu m e in

BP s (S way ze e t a l 1 9 9 2 ) may b e r e l a t ed t o eq u iv o ca l

ev id en ce o f t emp o ra l l o b e ab n o rmal i t i e s (Dewan e t a l

1988a; Ha user et a l 1989a; John stone et a l 1989; Al tsh u ler

et a l 1991; Sway ze et a l 1992; Sch lae pfer et a l 1994) ;

h o wev er , t h i s f i n d in g h as r ecen t l y b een d i sp u t ed wi th

r e p o rt s o f i n c re a s e d h i p p o c am p u s v o l u m e i n B P s ( K e m -

me rer e t a l 1 9 94 ). O n e s t u d y fo u n d i n c reased cau d a t ev o lu mes i n male BP p a t i en t s (Ay lward e t a l 1 9 9 4 ) , i f

co r r ec t , su g g es t i n g t h a t i n BP s t h e b asa l g an g l i a may b e

af f ec t ed i n a d i f f e r en t man n er t h an UP s . Reg ard in g t h e

ev id en ce o f i n c reased t h i rd v en t r i c l e in B P s , i t i s u n c l ea r

w h y B P s a n d n o t U P s w o u l d s e l e c ti v e ly h a v e e n l a rg e m e n t

in t h i s r eg io n . On e p o ss ib l e ex p l an a t i o n i s t h a t b ecau se

th i rd ven t r icle i s l imi ted lateral ly by d iencephal ic s t ruc-

t u res , i n c lu d in g t h a l amu s an d h y p o th a l amu s , t h i s mig h t

ev en tu a l l y r e f l ec t d ec rease i n t h e s i ze o f t h ese n earb y

s t ru c tures i n BP s . N o n e th e l es s , t h e re i s n o co n s i s t en t d i r ec t

ev id en ce so f a r t h a t t h ese a r eas a r e s t ru c tu ra l l y ab n o rmal

in BP s (S t r ak o wsk i e t a l 1 9 9 3 b ) . F ro n t a l l o b e may b e

af f ec t ed in UP d ep ress io n (Do lan e t a l 1 99 0 ; Kr i sh n an e t

a l 1 9 9 2 ; Co f fey e t a l 1 9 9 3 a) , b u t n o t c l ea r l y in BP (Do lan

et al 1990; Sch la epfe r et a l 1994) , suggest ing that ana-

to mic ch an g es i n t h e p re f ro n t a l co r t ex may b e mo re

sp ec i f i c fo r UP d i so rd er .

Th i s d i f f e r en t i a l p a t t e rn o f b r a in i n v o lv emen t i n UP s

an d BP s su g g es t s t h a t t h ese two t y p es o f mo o d d i so rd er s

a re b io lo g i ca l l y d i ff e r en t . Th a t co u ld u n d er l i e d i f f e r en ces

in t h e p resen t a t i o n o f d ep ress io n i n t h ese two su b ty p es .

F o r i n s tan ce , BP d ep ress io n t en d s t o h av e m o re sev ere an d

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Ana tomy of M ood Disor ders BIOL PSYCHIATRY 951997;41:86 106

melan ch o l i c f ea tu res , wh i l e UP d ep ress io n ap p ear s t o h av e

a b ro ad er p a t t e rn o f sy mp to m p resen t a t i o n . To wh ich

ex t en t t h i s r esu lt s f ro m d i f f e r en t p a t te rn s o f b r a in i n v o lv e-

ment has s t i l l to be invest igated .

Relationship with Psychopathology

P sy ch o s i s b eg in n in g a t l a t e ag e h as b een co r r e l a t ed wi th

in c reased r a t es o f n o n sp ec i f i c b r a in ab n o rmal i t i e s , su ch as

in c reased wh i t e m at t e r h y p er in ten s i t i e s o r i n c reased g lo b a l

a t ro p h y (Lesse r e t a l 1 9 9 2 ) . In m o o d d i so rd er s , measu res

o f g lo b a l a t ro p h y h av e b een co r r e l a t ed wi th p sy ch o t i c

sy mp to ms . F iv e (Targ u m e t a l 1 9 8 3 ; Lu ch in s e t a l 1 9 8 4 ;

S ch l eg e l an d Kre t zsch mar 1 9 8 7 ; Ro th sch i l d e t a l 1 9 8 9 ;

Shi raish i e t a l 1992) o f n ine CT s tud ies (Pear lson et a l

1 9 8 4 b ; S t an d i sh -Bar ry e t al 1 9 8 5 ; Ro y -By r n e e t a l 1 9 8 8 ;

DeLi s i e t a l 1 9 9 2 ) fo u n d a p o s i t i v e co r r e l a t i o n b e tween

l a t e r a l v en t r i c l e measu res an d p sy ch o t i c sy mp to ms ; h o w-ev er , wh en d e lu s io n a l an d n o n d e lu s io n a l e l d e r l y UP s w ere

d i r ec t l y co mp ared i n sev era l M RI co r t i ca l measu res n o

sign i f ican t d i f ferenc es we re found (Rabins et a l 1991). In

o n e CT s tu d y (Ro th sch i l d e t a l 1 9 8 9 ), p sy ch o t i c d ep ressed

UP s h ad i n c reased a t ro p h y i n i n f e r i o r p a r i e ta l b r a in b i l a t-

e r a l l y co mp ared t o n o n p sy ch o t i c d ep ressed p a t i en t s , an d

n o d i f f e r en ces i n p re f ro n t a l o r su p er io r t emp o ra l r eg io n s .

Hi s to ry o f p sy ch o s i s was n o t co r r e l a t ed wi th M R I m ea-

su res o f t emp o ra l l o b e i n UP s o r BP s (Hau ser e t a l, 1 9 8 9 a) .

Th ree s t u d ies d id n o t f i n d s i g n i f i can t co r r e l a t io n b e tween

wh i t e mat t e r h y p er in t en s i t i e s an d h i s t o ry o f p sy ch o s i s i n

BPs (Dupont et a l 1987 , 1990; F ig iel e t a l 1991b) . F ive

s tu d i es d id n o t f i n d s i g n i f i can t co r r e l a t i o n b e tween p res -e n c e o f p s y c h o t i c s y m p t o m s a n d w h i t e m a t t e r h y p e ri n t e n -

s i t ies in mood d isorder pat ien ts (Dupont et a l 1987 , 1990;

Co ffe y et a l 1989; F ig iel e t a l 1991b; Rab ins et a l 1991) .

In co n c lu s io n , t h e re i s ev id en ce su g g es t i n g t h a t l a t e r a l

v en t r i c l e measu res a r e co r r e l a t ed wi th p sy ch o t i c sy mp -

to ms i n d ep ressed p a t i en t s , b u t n o t wh i t e mat t e r h y p er in -

tensi t ies .

No s i g n i f i can t d i f f e r en ces i n VBR were fo u n d b e tween

en d o g en o u s an d n o n en d o g en o u s p a t i en t s i n o n e CT s tu d y

(S ch l eg e l e t a l 1 9 8 9 a) . I n t h i s s t u d y , VBR an d wid th o f

t h i rd v en t r i c l e were p o s i t i v e ly co r r e l a t ed wi th melan ch o l i a

sco res , mo s t s i g n i f i can t l y wi th r e t a rd a t i o n - r e l a t ed i t ems .In t e r es ti n g ly , an o th er s t u d y su g g es t ed t h a t n o n m elan ch o l i c

p a t i en ts h ad g rea t e r VB R m easu res , b u t n o d i r ec t co m p ar -

i so n b e twe en melan ch o l i c an d n o n m elan ch o l i c g ro u p s was

p ro v id ed (S h im a e t a l 1 9 8 4 ) .

Chronicity and Severity o f Illness

A p o s i t i v e co r r e l a t i o n b e tween i n d i ces o f g lo b a l a t ro p h y

an d ch ro n i c i t y h as b een su g g es t ed i n mo o d d i so rd er an d

sch iz oaffe ct ive pat ien ts (Pear lson et a l 1984a, 1984b;

Shim a et a l 1984; Johnsto ne et a l 1989; DeL isi e t a l 1992) ,

b u t so me s tu d i es i n mo o d d i so rd er s d id n o t co n f i rm th ese

f ind ings (Dolan et a l 1985; S tand ish-Barry et a l 1985;

Ko lb e in sso n e t a l 1 9 8 6 ; S ch l eg e l an d Kre t zsch mar 1 9 8 7 ;

Ro y -By rn e e t a l 1 9 8 8 ). On e s t u d y su g g es t ed t h a t in c reased

v en t r i cu l a r measu res w ere r e l a t ed t o i n c reased mo r t a l i t y in

e ld e r l y mo o d d i so rd er p a t i en ts ( Jaco b y e t a l 1 9 8 1 ). Wh i t e

mat t e r h y p er in t en s i t i e s ap p ear p o s i t i v e ly co r r e l a t ed wi th

n u m b er o f h o sp i t a l iza t i o n s (Du p o n t e t a l 1 9 8 7 , 1 9 9 0 ), b u t

no t wi th durat ion of i l lness (D upont et a l 1990 , 1995) .

Th ere a r e a l so su g g es t i o n s o f n eg a t i v e co r r e l a t i o n s b e -

t w e e n c h r o n i c i ty o f i l ln e s s a n d V B R ( R o y - B y r n e e t a l

1 9 8 8 ), f i g h t temp o ra l l o b e v o lu m e (Al t sh u l e r e t a l 1 9 9 1 )

a n d a m y g d a l a - h i p p o c a m p u s v o l u m e ( A x e l s o n et a l 1 9 93 ).

No s i g n i f i can t co r r e l a t i o n b e tween g ray an d wh i t e mat t e r

d en s i t ie s an d i n d i ca to r s o f ch ro n i c i t y o f i ll n es s were fo u n d

in a CT s tudy (Beats et a l 1991) .

On e CT s tu d y su g g es t ed a p o s i t i v e co r r e l a t i o n b e tweenVB R an d u n e mp lo y m en t (P ear l so n e t a l , 1 9 8 4a , 1 9 8 4 b ) ,

b u t an o th er (De wan e t a l 1 9 8 8 b ) d id n o t f i n d a s i g n if i can t

r e l at i on s h i p b e t w e e n e m p l o y m e n t h i s t o r y a n d C T a b n o r -

mal i t ies .

S ev era l s t u d i es t r i ed t o co r r e l a t e CT o r M RI an a to mic

measu res wi th sev er i t y o f d ep ress io n . On e (S ch l eg e l e t a l

1 9 8 9 a) o f fo u r (Ke l l n e r e t a l 1 98 3 ; Ro y -B y rn e e t a l 1 9 8 8 ;

P ear l so n e t a l 1 9 8 9 ) CT s tu d i es fo u n d a p o s i t i v e co r r e l a -

t i o n o f VBR measu res an d sev er i t y o f d ep ress io n i n

samp les o f BP s an d UP s . Tw o M R I s t u d i es d id n o t f i n d

s ig n i f ican t co r r e l a t i o n b e twe en w h i t e mat t e r h y p er in t en s i -

t i e s an d sev er i t y o f d ep ress io n i n UP s o r BP s (Co f fe y e t a l

1989; Dupont et a l 1990) . One s tudy d id no t f ind s ign i f i -

can t d i f f e r en ces i n CT v en t r i cu l a r measu res b e tween

sev ere ly d ep ressed an d m in o r d ep ress iv e p a t i en t s (v an d en

Bo ssch e e t a l 1 9 9 1 ) . F o u r M RI s t u d i es l o o k ed a t o th e r

measu res , su ch as cau d a t e v o lu me (Kr i sh n an e t a l 1 9 9 2 ) ,

ce reb e l l a r v o lu m e (Esca lo n a e t a l 1 9 9 3 ) , am y g d a l a -h ip -

p o camp u s v o lu me (Ax e l so n e t a l 1 9 9 3 ) , an d T1 v a lu es i n

caudate, thalamus, f ron tal , par ietal , and temporal reg ions

(Do lan e t a l 1 9 9 0 ), w i th o u t f i n d in g an y s i g n i f ican t co r r e -

l a t io n s w i th sev er i t y o f d ep ress io n .

Th u s , ch ro n i c i t y may p o s i t i v e ly co r r e l a t e wi th wh i t e

mat t e r h y p er in t en s i t i e s o r d i f f e r en t measu res o f r eg io n a l

a t ro p h y , b u t n o t c l ea r l y w i th g lo b a l a t ro p h y . S ev er i t y d o esn o t ap p ear t o co r r e l a t e wi th v en t r i cu l a r s i ze o r wi th o th e r

an a to mic measu res .

Treatment Responsiveness

F ew s tu d i es h av e l o o k ed a t t h e r e l a t i o n sh ip b e tween

an a to mic l e s i o n s an d r esp o n s iv en ess t o t r ea tmen t . BP s

wi th an d w i th o u t CT ab n o rmal i t i e s d id n o t d i f f e r i n

r esp o n s iv en ess t o l i t h iu m th e rap y (Dewan e t a l 1 9 8 8 b ) .

Three s tud ies (F ig iel e t a l , 1989b , 1990a, 1990b) found a

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r e l a t i o n sh ip b e twe en b asa l g an g l i a l e s i o n s , p e r i v en t r i cu l a r

an d d eep w h i t e h y p er in ten s i t i e s , an d t h e d ev e lo p me n t o f

d e l i r i u m in d u ced b y an t i d ep ressan t s an d ECT in e ld e r l y

d ep ressed p a t i en t s . G lo b a l ev id en ce o f a t ro p h y was n o t

as so c i a t ed wi th d e l i r i u m. A n eg a t i v e co r r e l a t i o n b e tween

sev er i t y o f wh i t e mat t e r h y p er in t en s i t i e s an d t r ea tmen t

r esp o n se was r ep o r t ed i n d ep ressed p a t i en t s (Hick i e e t a l

1995) . Another s tudy (F ig iel e t a l 1991c) suggested that

cau d a t e wh i t e mat t e r h y p er in t en s i t i e s were r e l a t ed t o

su scep t i b i l i t y t o n eu ro l ep t i c - i n d u ced p ark in so n i sm in e l -

d e r l y d ep ressed p a t i en t s . An d reasen e t a l ( 1 9 9 0 ) d id n o t

f i n d s i g n i f i can t co r r e l a t i o n b e tween v en t r i cu l a r en l a rg e-

men t an d t r ea tmen t r esp o n se i n UP s an d BP s . Ven t r i cu l a r

s i ze h as n o t b een fo u n d t o co r r e l a t e wi th p rev io u s r esp o n se

to ECT (S t an d i sh -Bar ry e t a l 1 9 8 5) . On e s t u d y su g g es t ed

in creased measu res o f t h i rd v en t r i c l e a r ea i n p sy ch o t i c

p a t i en t s wi th d e l ay ed r esp o n se t o n eu ro l ep t i cs (Kap l an e t

al 1990).Th u s , t h e f ew s tu d ies t h a t l o o k ed a t t h i s q u es t i o n d id n o t

f i n d co n c lu s iv e ev id en c e o f co r r e l a t i o n b e tween s t ru c tu ra l

b ra in ch an g es an d t r ea tmen t r esp o n se . S u b co r t i ca l wh i t e

m a t t e r c h a n g e s s e e m r e l a te d t o d e v e l o p m e n t o f t r e a t m e n t

co mp l i ca t i o n s , su ch as ECT- in d u ced d e l i r i u m o r p a rk in -

so n i sm se co n d ary t o n eu ro l ep t i c t r ea tmen t , an d p erh ap s t o

wo rse t r ea tmen t r esp o n se .

Cognitive Impairment

F iv e (P ear l so n e t a l 1 9 8 9 ; Ro th sch i l d e t a l 1 9 8 9; Ab as e t

al 1990; Co ffm an et a l 1990; De wa n et a l 1988b) o f s ix

(An d reasen e t a l 1 9 9 0 ) co n t ro l l ed s t u d i es fo u n d s i g n i f i -can t l y h ig h er co g n i t i v e imp a i rmen t i n d ep ressed p a t i en t s

wi th ev id en ce o f g lo b a l b r a in a t ro p h y . In o n e o f t h ese

s tu d i es , i t was a l so co r r e l a t ed wi th smal l e r f ro n t a l a r eas

(Co f fm an e t a l 1 9 9 0 ), an d i n a n o th er wi th i n f e r i o r p a r ie t a l

a t ro p h y (Ro th sch i l d e t a l 1 9 8 9 ) . Ex t en s iv e wh i t e mat t e r

l es i o n s were a l so r e l a t ed t o co g n i t i v e imp a i rm en t (Du p o n t

et a l 1990 , 1995; S teingar t e t a l 1986 , 1987; Junque et a l

1990; Hic k ie et a l 1995) . In posts t roke depress io n , an ter io r

an d l e f t - s i d ed l es i o n s were co r r e l a t ed wi th i n c reased

co g n i t i v e imp a i rmen t (R o b in so n e t a l 1 9 8 8 ; Bo l l a -Wi l so n

et al 1989) .

Th u s , co g n i t i v e imp a i rmen t i n mo o d d i so rd er s ap p ear sto b e r e l a t ed t o g lo b a l a t ro p h y , ex t en s iv e wh i t e mat t e r

l es i o n s, an d p erh ap s l o ca l i zed l e s i o n s t o t h e f ro n t a l l o b e .

i n o n e (Ke l l n e r e t a l 1 9 8 3 ) o f two (R i sch e t a l 1 9 9 2 )

s tu d i es . P l asma co r t i so l was p o s i t i v e ly co r r e l a t ed wi th

VBR in o n e (S ch l eg e l e t a l 1 9 8 9 b ) o f fo u r (Dewan e t a l

1 9 8 8 c ; v an d en Bo ssch e e t a l 1 9 9 1 ; Co f fey e t a l 1 9 9 3 b )

s tu d ies . P o s td ex am eth aso n e co r t i so l l ev e l s co r r e l a t ed wi th

f ro n t a l lo b e (Co f fey e t a l 1 9 9 3 b ) an d p i t u i ta ry (Ax e l so n e t

a l 1 9 9 2 ) v o lu mes . Dex ameth aso n e su p p ress io n t es t (DS T)

n o n su p p resso r s were fo u n d t o h av e i n c reased VBRs i n two

stud ies (Rao et a l 1989; Rothsch i ld et a l 1989) , bu t th ree

o th er s t u d i es d id n o t co n f i rm th ese f i n d in g s (S t an d i sh -

Bar ry e t a l 1 9 8 5 ; S ch l eg e l an d Kre t zsch mar 1 9 8 7 ; S ch l e -

g e l e t a l 1 9 8 9 b ) . In Cu sh in g ' s sy n d ro me, w h ere t h e re i s an

ex cess o f g lu co co r t i co id s , th e re were f i n d in g s o f d ec reased

v o lu me o f h ip p o camp al fo rmat io n , w i th a s i g n i f i can t

n eg a t i v e co r r e l a t i o n b e tween p l asma co r t i so l l ev e l s an d

h ip p o camp al v o lu me (S t a rk man e t a l 1 9 9 2 ) ; h o wev er ,

h ip p o camp al v o lu me was n o t s i g n i f i can t l y d i f f e r en t b e -

tween DS T su p p resso r s an d n o n su p p resso r s , i n a samp leo f d ep ressed p a t i en t s (Ax e l so n e t a l 1 9 9 3 ) . On e s t u d y

in v o lv in g UP an d BP p a t i en t s d id n o t f i n d s i g n i f i can t

co r r e l a t i o n s b e tween VBR measu res an d ce reb ro sp in a l

f l u id co r t i co t ro p in - re l eas in g f ac to r (CRF ) o r ad ren o co r t i -

co t ro p i c h o rmo n e (ACTH) l ev e l s (R i sch e t a l 1 9 9 2 ) .

P l asma t ry p to p h an was n eg a t i v e ly co r r e l a t ed wi th v en -

t r i cu l a r measu res i n d ep ressed p a t i en t s i n o n e (S t an d i sh -

Bar ry e t a l 1 9 8 6 ) o f two s t u d i es (v an d en Bo ssch e e t a l

1 9 9 1 ) . Lo wer l ev e l s o f ce reb ro sp in a l f l u id 5 -h y d ro x y in -

d o l eace t i c ac id (5 -HIAA) h av e b een as so c i a t ed wi th i n -

c r eased v e n t r i cu l a r s ize i n p sy ch o t i c p a t i en t s (Lew in e e t a l

1 9 9 1 ) . A s i g n i f i can t n eg a t i v e co r r e l a t i o n b e tween se ru m

d o p a m i n e - b e t a - h y d ro x y l a s e a n d V B R m e a s u r e s i n d e -p res sed p a t i en t s was a l so r ep o r t ed (M el t ze r e t a l 1 9 8 4 ) .

Deep wh i t e mat t e r h y p er in t en s i t i e s were as so c i a t ed wi th

lo wer p l a t e l e t imip ramin e b in d in g i n e ld e r l y d ep ressed

pat ien ts (Husain et a l 1991b) .

Th e s t u d i es o f t h e HP A ax i s su g g es t t h a t HP A o v e rac -

t i v i t y i s a s so c i a t ed wi th an en l a rg emen t o f t h e p i t u i t a ry

an d ad ren a l g l an d s . Wh eth er t h i s co r r e l a t es wi th g en era l -

i zed o r fo ca l b r a in a t ro p h y i s u n c l ea r .

On e s t u d y ( Jo h n s to n e e t a l 1 9 8 6 ) in a samp le o f BP an d

n eu ro t i c p a t i en t s fo u n d an u n ex p ec t ed co r r e l a t i o n o f i n -

c r eased VBRs an d h y p o th y ro id i sm, wh ich h as n o t b een

repor ted in o ther s tud ies . I t i s d i f f icu l t to exp lain how

d ecreased t h y ro id h o rmo n e l ev e l s co u ld b e r e l a t ed t o

in c reased l ev e l s o f b r a in a t ro p h y .

Relationship o f Neuroradiological a nd BiologicalMarkers in M ood Disorders

S ev era l s t u d ies ex am in ed t h e re l a t i o n sh ip b e twe en CT an d

M R I me asu res an d p o ss ib l e b io lo g ica l mark er s fo r d ep res -

s i o n . A lmo s t a l l s t u d i es h av e ad d ressed t h e HP A ax i s .

VB R was p o s i t i v e ly co r r e l a t ed wi th f r ee u r in a ry co r t i so l

Dis cus s i on

Th e s t ru c tu ra l n eu ro imag in g s t u d i es r ev i ewed h ere su g g es t

abnormal i t ies in speci f ic b rain reg ions in pat ien ts wi th

p r imary an d seco n d ary mo o d d i so rd er s , i n s t ru c tu res

p ar t i c i p a t i n g i n a p ro p o sed n eu ro an a to mic mo d e l o f mo o d

reg u l a t i o n . No c l ea r i n d i ca t i o n o f g lo b a l a t ro p h y was

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Anatom y of Mood Disorders BIOLPSYCHIATRY 971997;41:86-106

fo u n d . Th u s , t h e s t u d i es r ev i ewed su p p o r t o u r h y p o th es i s

t h a t mo o d d i so rd er s a r e as so c i a t ed wi th r eg io n a l s t ru c tu ra l

b ra in ab n o rmal i t i e s i n p a r t i cu l a r r eg io n s i n v o lv ed i n mo o d

reg u l a t i o n , r a t h e r t h an g lo b a l a t ro p h y . Th e main ab n o r -

mal i t i e s fo u n d i n UP s were ev id en ce o f smal l e r b asa l

g an g l ia , ce r eb e l l u m, an d p o ss ib ly f ro n t a l lo b e , wh ich m ay

re f l ec t l o ca l a t ro p h y . BP d i so rd er ap p eared t o b e as so c i -

a t ed wi th l a rg e r t h i rd v en t r i c l e , smal l e r ce reb e l l u m, p o s -

s i b ly smal l e r t emp o ra l l o b e , an d p erh ap s ch an g es i n t h e

h ip p o camp u s . Bo th BP s an d e ld e r l y UP s h av e i n c reased

ra t es o f su b co r t i ca l wh i t e mat t e r an d p er i v en t r i cu l a r h y -

p er in t en s i t i e s . Th e i n t e r ac t i o n o f f ac to r s i n v o lv ed i n t h e

p a th o g en es i s o f mo o d d i so rd er s , su ch as g en e t i c an d

en v i ro n m en ta l f ac to r s , w i th t h ese sp ec i f i c b r a in s t ru c tu res,

i s y e t t o b e c l a r i f i ed . Acq u i r ed i n ju r i es su ch as s t ro k e o r

t u mo rs ap p ear i n v o lv ed i n t h e p a th o g en es i s o f mo o d

d i so rd er s t h ro u g h l es io n s i n t h ese se l ec t ed b ra in r eg io n s .

Th e ag in g p ro cess , wh en i t i s a s so c i a t ed wi th fo ca l o rg lo b a l b r a in ch an g es , may co n t r i b u t e t o t h e emerg en ce o f

d ep ress io n b y cau s in g l es i o n s i n t h ese an a to mic a r eas .

Th e p re f ro n t a l co r t ex h as b een i n su f f i c i en t l y i n v es t i -

g a t ed i n s t ru c tu ra l imag in g s t u d i es . Th e s t u d i es r ev i ewed

u sed m o s t l y mea su res o f t o ta l f ro n t a l l o b e , w i th o u t d i st i n -

g u i sh in g sp ec i f i ca l l y t h e p re f ro n t a l co r t ex , o r i t s d i f f e r en t

an a to mic su b reg io n s . F u r th e r M RI s t u d i es a r e n eed ed w i th

d i r ec t v o lu met r i c measu res o f p r e f ro n t a l co r t i ca l g r ay

mat t e r , an d wi th fu r t h e r d e l imi t a t i o n o f i t s su b reg io n s .

Th i s b r a in s t ru c tu re may b e v e ry imp o r t an t i n mo o d

reg u l a t i o n an d i n t h e p a th o p h y s io lo g y o f mo o d d i so rd er s ,

p e rh ap s b ecau se o f i t s co n n ec t i o n s t o b asa l g an g l i a ,

t h a l amu s , an d l imb ic a r eas . I t s eems t o h av e an im p o r t an tro l e i n mo d u la t i n g l imb ic ac t i v i t y , t h ro u g h i t s co n n ec t i o n s

wi th t h o se a r eas . Th ere i s a l so co r ro b o ra t i n g ev id en ce

f ro m fu n c t i o n a l an d ac t i v a t i o n s t u d ies p o in t i n g t o d y s fu n c-

t i o n o f t h e p re f ro n t a l co r t ex in m o o d d i so rd er s (Geo rg e e t

a l 1 9 9 4 ) , wh ich m ay co r r e l a t e wi th s t ru c tu ra l ch an g es .

Di seases a f f ec t i n g t he b asa l g an g l i a a r e as so c i a t ed wi th

mo o d d i so rd er s (Ca in e an d S h o u l so n 1 9 8 3 ; Ro g u s e t a l

1 9 8 7 ). P a t i en t s w i th ce reb ro v asc u l a r l e s i o n s a f f ec t i n g t h e

cau d a t e n u c l eu s can h av e n eu ro p sy ch i a t r i c sy mp to ms

resemb l in g d ep ress io n (M en d ez an d Lewan d o wsk i 1 9 8 9 ) .

Th e f i n d in g s o f smal l e r cau d a t e an d p u t amen i n UP

depression (Husain et a l 1991a; Krishnan et a l 1992 ,

1 9 9 3 b ) su p p o r t t h e h y p o th es i s o f r eg io n a l ab n o rm al i t ie s i n

th ese s t ru c tu res . F o r BP d ep ress io n , t h e f i n d in g s o f en -

l a rg ed cau d a t e v o lu me in males (Ay lward e t a l 1 9 9 4 ) a r e

d i f f i cu lt t o ex p l a in , an d fu r t h e r s t u d i es a r e n ee d ed t o t ry t o

r ep l i ca t e an d c l a r i fy t h e mean in g o f t h ese ab n o rmal i t i e s .

Th e cau d a t e an d p u t am en a re p a r t o f b asa l g an g l i a c i r cu it s

t h a t r ece iv e in p u t s f ro m th e m ed ia l t emp o ra l s t ru c tu res

in v o lv ed i n r eg u l a t i o n o f emo t io n s , l i k e t h e amy g d a l a an d

h ip p o camp u s , an d h av e co n n ec t i o n s t o t h e p re f ro n t a l

co r t ex . Th u s , t h ese s t ru c tu res may b e r e l ev an t fo r mo o d

reg u l a t i o n , an d l es i o n s a f f ec t i n g t h ese c i r cu i t s may co n -

t r i b u te t o t h e p a th o g en es i s o f mo o d d i so rd er s .

Recu r r en t s t res s an d ag in g ap p e ar as so c i a t ed wi th g rad -

u a l d es t ru c t i o n o f h ip p o camp al n eu ro n s t h ro u g h l o s s o f

HP A feed b ack in h ib i t io n (S ap o l sk y an d M c Ew en 1 9 8 8 ). A

s imi l a r p ro cess may o ccu r i n d ep ress io n , an d t h i s wo u ld

ex p l a in t h e DS T n o n su p p ress io n fo u n d i n d ep ressed p a -

t i ent s . No n e th e l es s , mo s t o f t he s t u d i es co n d u c t ed so f a r

d i d n o t s h o w e v i d e n c e o f a m y g d a l a - h i p p o c a m p u s s t r u c -

t u ra l ch an g es i n mo o d d i so rd er s (Hau ser e t a l 1 9 8 9 a ;

Ax e l so n e t a l 1 9 9 3 ; Co f fey e t a l 1 9 9 3 a), an d t h e two

p o s i t i v e s t u d i es i n BP p a t i en t s (S way ze e t a l 1 9 9 2 ;

Kemmerer e t a l 1 9 9 4 ) p o in t ed i n o p p o s i t e d i r ec t i o n s , o n e

f in d in g i n c reased an d t h e o th e r d ec reased v o lu me mea-

sures .

Th e ce reb e l l u m h as ex t en s iv e p ro j ec t i o n s t o b ra in s t em

an d l imb ic s t ru c tu res . Th e mid l i n e ce reb e l l a r n u c l e i

p ro j ec t t o n o rep in ep h r in e an d d o p am in e ce l l g ro u p s i n th eb ra in s t em, an d i n f l u en ce co n cen t r a t i o n an d t u rn o v er o f

ca t ech o l amin es i n an imal mo d e l s (S n id er an d S n id er

1 9 7 7 ). Th e p a l eo cereb e l l u m h as p ro j ec t i o n s t o b ra in s t em

an d sp in a l co rd , an d t o l imb ic an d t e l en cep h a l i c a r eas

(Ber to n an d To re l l o 1 9 8 2 ) . Th ese co n n ec t i o n s may ex p l a in

i ts p o ss ib l e ro l e i n r eg u l a t i o n o f mo o d . Th e s t u d ies i n U P s

an d BP s r e v i ewe d h ere su g g es t s t ru c tu ra l ab n o rmal i t i e s in

th i s r eg io n , w h ich m ay r e f l ec t r eg io n a l a t ro p h y (Nas ra l l ah

et al 1982b; Wei nbe rger et a l 1982; Shah et a l 1992;

Esca lo n a e t a l 1 9 9 3 ) ; h o wev er , v o lu met r i c M RI s t u d i es

h av e b een co n d u c t ed o n ly i n UP s t o d a t e .

Th e f i n d in g s o f en l a rg ed t h i rd v en t r i c l e i n BP s (S ch l e -

g e l an d Kre t zsch m ar 1 9 8 7 ; Dew an e t a l 1 9 8 8 a ; S t r ak o wsk ie t a l 1 9 9 3 a) , i f r ep l i ca t ed i n fu r t h e r v o lu met r i c s t u d i es ,

ma y b e r e l a t ed t o i ts p ro x im i ty t o d i en cep h a l i c s t ru c tu res ,

su ch as h y p o th a l amu s an d t h a l amu s , wh ich may b e a f -

f ec t ed i n mo o d d i so rd er s ; h o wev er , t h e re i s n o d i r ec t

ev id en ce o f s t ru c tu ra l ab n o rmal i t i e s i n t h ese r eg io n s i n

mo o d d i so rd er s p a t i en ts (Do lan e t a l 1 9 9 0 ; Kr i sh n an e t a l

1991a, 1993b; S t rakow ski et a l 1993a) , excep t fo r one

s tu d y (Du p o n t e t a l 1 9 9 5 ) . No n e th e l es s , b ecau se o f s i g n if -

i can t t ech n i ca l l imi t a t i o n s i n t h e measu remen t o f t h ese

reg io n s , t h ese n eg a t i v e r esu l t s sh o u ld b e i n t e rp re t ed wi th

cau t ion .

No co n c lu s iv e ev id en ce was fo u n d t o su p p o r t a ro l e fo r

g lo b a l b r a in a t ro p h y i n t h e p a th o p h y s io lo g y o f mo o d

d i so rd er s . G lo b a l ce reb ra l a t ro p h y ap p ear s t o b e n o n sp e-

c i f i c , b e in g d esc r i b ed i n d i f f e r en t p sy ch i a t r ic an d med ica l

co n d i t i o n s (M o r r i s an d Rap o p o r t 1 9 9 0 ) . Reg io n a l b r a in

ab n o rmal i t i e s , r a t h e r t h an g lo b a l d i f fu se a t ro p h y , a r e

asso c i a t ed wi th mo o d d i so rd er s . A r ecen t l y p u b l i sh ed

meta -an a ly s i s o f t h i s l i t e r a tu re d o es n o t su p p o r t o u r

co n c lu s io n s r eg ard in g g lo b a l a t ro p h y (E lk i s e t a l 1 9 9 5 ) .

Th e au th o r s fo u n d ev id en ce fo r v en t r i cu l a r en l a rg emen t

an d i n c reased su l ca l measu res wh en t h ey p o o l ed 3 3

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98 BIOL PSYCHIATRY J.C . Soa res and J. J. M ann1997;41:86-106

d i f f e r en t s t u d i es . Th ey c l a imed t h a t i n a meta -an a ly s i s

mi ld o r mo d era t e e f f ec t s t h a t mig h t h av e b een mi ssed i n

in d iv id u a l s t u d i es co u ld b e r ev ea l ed , b eca u se o f i n c reased

p o w er o f s t a t is t i cal an a ly s i s ; h o wev er , o n e h as t o wo n d er

ab o u t t h e p o ss ib l e co n fo u n d in g e f f ec t s o f co mb in in g

sev era l s t u d i es wi th v e ry d iv e r se meth o d o lo g i es i n t h e

same s tat i s t ical analysis , such as done in that s tudy . The

in d iv id u a l an a ly s i s o f t h ese s t u d i es c l ea r l y d o es n o t p e rm i t

t h i s co n c lu s io n ; ac tu a l l y , t h e g rea t majo r i t y o f t h e b es t

con t ro l led s tud ies in th is f ie ld , us ing h igher- reso lu t ion

M RI measu res , p ro d u ced n eg a t i v e f i n d in g s (Du p o n t e t a l

1987; Johns tone et a l 1989; Sw ayz e et a l 1990; Zuben ko et

a l 1 9 9 0 ; Lam me rs e t a l 1 9 9 1 ; Lesse r e t a l 1 9 9 1; M c Do n a ld

et al 1991; Shah et a l 1992; Coff ey et a l 1993a; Krish nan

et al 1993b; Harvey et a l 1994) .

Ra t es o f su b co r t i ca l wh i t e mat t e r an d p er i v en t r i cu l a r

h y p er in t en s i t i e s a r e i n c reased i n mo o d d i so rd er p a t i en t s

(Du p o n t e t a l 1 9 8 7 , 1 9 9 0 ; S way ze e t a l 1 9 9 0 ; Zu b en k o e tal 1990; F ig iel e t a l 1991b; Lesser et a l 1991; McDonald

et al 1991; Rabins et a l 1991; Brow n et a l 1992; Cof fey et

a l 1 9 9 0 , 1 9 9 3 a ; Gu ze an d S zu b a 1 9 9 2 ; Ho w ard e t a l 1 9 9 3 ;

Kr i sh n an e t a l 1 9 9 3 b ; Ay lward e t a l 1 9 9 4 ; Du p o n t e t a l

1 9 9 5 ). Th ey a r e a l so fo u n d i n o th e r d i so rd ers , n o t b e in g i n

an y way sp ec i f i c t o t h i s co n d i t i o n (Gu p ta e t a l 1 9 8 8 ) .

Th ese l e s i o n s ma y b e r e l ev an t b y i n t e r ru p t in g co n n ec t i o n s

b e tween t h e d i f f e r en t b r a in r eg io n s p a r t i c i p a t i n g i n mo o d

reg u l a t i o n . Th ey ap p ea r t o b e as so c i a t ed wi th v ascu l a r r i sk

fac to r s (Awad e t a l 1 9 8 6 a ; Co f fe y e t al 1 9 8 9 ; Lesse r e t a l

1991; Schmidt et a l 1991) , bu t no t in al l s tud ies (Harrel e t

a l 1 9 9 1 ; Rab in s e t a l 1 9 9 1 ). Th e y may r e f l ec t ch an g es i n

wate r co n t en t o f ex t r ace l l u l a r sp ace , cau s in g an i n c rease i nth e M R I p ro to n s i g na l . Th ese l e s i o n s h av e b een co r r e l a t ed

in p o s tmo r t em samp les wi th l o s s o f my e l i n , o l ig o d en d ro -

g l i a l ce ll s , r eac t i v e g l io s i s , an d p resen ce o f m acro p h ag es

(Bru n an d En g lu n d 1 9 8 6 ; En g lu n d e t a l 1 9 8 7; Le i f e r e t a l

1 9 9 0 ; Gra f t o n e t a l 1 9 9 1 ; Ch imo w i t z e t a l 1 9 9 2 ; S ch e l t en s

e t a l 1 9 9 5 ) . Th e y h av e a l so b een as so c i a t ed wi th a r eas o f

ar ter iosclerosis , in farct ion , d i lated per ivascu lar spaces , o r

vascu lar ectas ia (Erk in jun t t i e t a l 1984; Awad et a l 1986b;

Geo rg e e t a l 1 9 8 6 ; Ch imo wi t z e t a l 1 9 9 2 ) ; h o wev er , t h e

re l a t i o n sh ip b e tween mo o d d i so rd er s an d wh i t e mat t e r

h y p er in t en s i t i e s i s n o t y e t u n d er s to o d . Th ey may p reced e

th e d ep ress io n , b e in g an an a to mic r i sk f a c to r fo r i ts

d ev e lo p men t d u e t o d i s ru p t i o n o f f i b e r p a th way s , o r b e a

co n seq u en ce o f d ep ress io n , fo r ex am p le , t h e we ig h t l o s s o r

t h e h y p o t en s iv e e f f ec t s o f an t i d ep ressan ts . W eig h t l o s s i n

an o rec t i c p a t ien t s h as b een fo u n d t o b e r e l a t ed t o i n c reased

b ra in a t ro p h y (Kr i eg e t a l 1 9 8 8 ); h o wev er , t h e h y p o th es i s

o f t h em resu l t i n g f ro m p rev io u s t r ea tmen t d o es n o t ap p ear

to have suppor t in the l i teratu re (S t rakowski et a l 1993b) .

Al t e rn a t i v e ly , th e l e s i o n s m ay n o t b e d i r ec t l y l i n k ed wi th

th e mo o d d i so rd er , b u t p a r t o f ag in g . S in ce s t u d i es

in v o lv ed ag e-match ed co n t ro l s , t h i s d o es n o t ap p ear t o

acco u n t fo r t h e ab o v e f i n d in g s . Th ese l e s i o n s may b e

re l ev an t b y d i sco n n ec t i n g d i f f e r en t f i b e r p a th way s i n t h e

p ro p o sed c i r cu i t o f mo o d r eg u l a t i o n , cau s in g a fu n c t i o n a l

d i sco n n ec t i o n b e tween t h ese b ra in r eg io n s . Th ere i s ev i -

d en ce f ro m o n e e l ec t ro en cep h a lo g rap h i c s t u d y i n d emen -

t i a p a t i en t s su g g es t i n g t h a t wh i t e mat t e r h y p er in t en s i t i e s

may i n d eed r esu l t i n fu n c t i o n a l b r a in d i sco n n ec t i o n

(Leu c h t e r e t a l 1 9 9 4 ) .

S in ce t h e re i s ev id en ce o f g en d er d i f f e r en ces i n b ra in

an a to m y (Hau ser e t a l 1 9 8 9 b ; Jo h n s to n e e t a l 1 9 8 9 ; Al l en

an d Go rsk i 1 9 9 0 ; An d reasen e t a l 1 9 9 0 ; Raz an d Raz

1990; Al len et a l 1991; Swayze et a l 1992; Escalona et a l

1991 , 1993; S t rakows ki et a l 1993a; Sch laep fer et a l

1 9 9 5 ) , t h i s f ac to r mu s t b e t ak en i n to co n s id e ra t i o n , an d

men an d wo men in c lu d ed i n t h e samp les s t u d i ed . S o me o f

th e s t u d i es r ev i ewed h ere i n v o lv ed u n b a l an ced samp les

r eg ard in g g en d er , wh ich mig h t h av e b een a p o t en t i a l b i as

fo r t h e f i n d in g s o b t a in ed .I t i s k n o wn th a t a l co h o l an d su b s t an ce ab u se may b e

resp o n s ib l e fo r b r a in an a to mic ch a n g es (La d er e t a l 1 9 8 4 ;

L ip p man e t a l 1 9 8 5 ; L i sh man 1 9 9 0 ; Je rn ig an e t a l 1 9 9 1 ;

P fe f f e rb a u m e t a l 1 9 9 2; A as ly e t a l 1 9 9 3 ; Ch amess 1 9 9 3;

S h ear e t a l 1 9 9 4 ). Ad d i t i o n a l l y , th e co m o rb id i t y o f mo o d

d i so rd er s an d su b s t an ce ab u se i s we l l -d o cu men ted (Re i ch

et al 1974; EI-Guebaly 1975; Hasin et a l 1985; Sonne et a l

1 9 94 ; Brad y an d S o n n e 1 9 9 5 ). Th e b es t co n t ro l l ed s tu d i es

r ev i ewed h ere in t o o k t h i s imp o r t an t f ac to r i n co n s id e r -

a t i o n , ex c lu d in g f ro m th e i r s amp les p a t i en t s wi th su ch

co mo rb id i t y , b u t so me d id n o t , ma in ly t h e ea r l i e r CT

stud ies . Thus, fo r fu r ther s tud ies in th is f ie ld i t i s most

imp o r t an t t o ex c lu d e f ro m th e s t u d i ed samp les p a t i en t swi th cu r r en t o r p as t su b s t an ce ab u se , wh ich may b e an

imp o r t an t co n fo u n d in g v ar i ab l e .

M RI b ro u g h t b e t t e r p o ss ib i l i t i e s o f d e l imi t a t i o n o f

sp ec i f i c b r a in r eg io n s , b u t o n e s i g n i f i can t meth o d o lo g y

p ro b l em i s t h a t smal l e r , mo re co mp lex an a to mic r eg io n s

can n o t b e eas i l y d emarca t ed an d measu red (Kr i sh n an e t a l

1 9 9 3b ) . Be cau se o f s i g n i f i can t d i f f i cu lt i e s i n d e t e rmin in g

an a to mic l an d mark s i n t h ese s t u d i es , f o r s t ru c tu res su ch as

amy g d a l a , h ip p o camp u s , an d p re f ro n t a l Co rt ex , it i s n ec -

es sa ry t o b e co n serv a t i v e i n i n t e rp re t i n g f i n d in g s . Th ese

d i f f i cu l t i e s co u ld u n d er l i e t h e co n f l i c t i n g f i n d in g s o b -

t a in ed fo r so me o f t h ese an a to mic r eg io n s . F u r th e r d ev e l -

o p m en t s i n t h e M R I r eso lu t i o n an d imag e p ro cess in g , w i th

mo re sen s i t i v e an d r e l i ab l e d e t e rmin a t i o n o f v o lu me o f

d i sc re t e an a to mic r eg io n s , i s mak in g i t p o ss ib l e t o ex amin e

th ese f i n d in g s mo re p rec i se ly . Becau se o f t h ese d i f f i cu l -

t i e s , t h e ev id en ce r ev i ewed h ere , wh ich g iv es su p p o r t t o

th e ab o v e-p ro p o se d n eu ro an a to m ic mo d e l , mu s t b e seen as

t en t a ti v e . On t h e o th e r h an d , s i n ce t h e re i s a l so co n s id e r -

ab l e ev id en ce f ro m fu n c t i o n a l n eu ro imag in g s t u d i es i n

su p p o r t o f t h i s mo d e l (Bu sc h b au m 1 98 6 ; Bax t e r 1 99 1 ;

Cu m min g s 1 9 9 3 ; Geo rg e e t a l 1 9 9 3 ; Geo rg e 1 9 9 4 ; Ke t t e r

8/3/2019 soares et al 1997


Anatomy of Mood Disorders BIOLPSYCHIATRY 991997;41:86-106

et a l 1994; Mayberg e t a l 1994b), these f indings may be

further repl ica ted in control led s tudies address ing the

me thodo log ica l l imi t a t ions po in ted ou t he re .

T he s pec i f i c i ty o f the above -d i s cus s ed ana tomic

changes ha s to be de te rmined . M os t o f the reg ions found

to be ana tomica l ly abnorma l in mood d i s o rde rs , s uch a s

f ron ta l and t empora l lobes, ba s a l gang l i a , and ce rebe l lum,

have a l s o been found to be abnorma l in s ch izophren ia

(B achne f f 1991 ; C leghorn e t a l 1991 ; Gur and Pea r l s on

1993) . Som e C T s tud ies fa i l ed to d i s t ingu i s h s ch izophren -

i c s and mood d i s o rde r pa t i en t s in meas u re s o f b ra in

a t rophy (Raz and Raz 1990 ; R iede r e t al 1983). But

apparent ly , the severi ty of the s t ruc tura l bra in changes in

mo od d i s o rde rs i s l e ss , and fo r s ch izophren ia more c l ea r

ev idence o f gene ra l i z ed b ra in changes ha s b een iden t i f i ed

(Raz 1993; Elkis et al 1995).

Wha t do dec rea s ed a rea and vo lume b ra in meas u re s a s

a s ce r t a ined by CT o r M RI re f l ec t a t t he neu ropa tho logyleve l? Do they re s u l t f rom a t rophy , o r a l t e rna t ive ly , do

they rep re s en t hypop la s i a o f the s e s t ruc tu re s ? Ana tomic

abnorma l i t i e s in mo od d i s o rde rs have no t been s ys tema t -

i ca l ly inves t iga ted in quan t i t a tive neu ropa tho logy s tud ie s .

T he neu ro imag ing changes tha t have been iden t i f i ed in

mood d i s o rde rs a re s ub t l e , and may no t be de tec ted in

mac ros cop ic pos tmor tem ana tomic s tud ie s . Add i t iona l ly ,

pos tmor tem s tud ie s have s ign i f i c an t l imi t a tions , i t be ing

d i f f i cu l t t o d i f fe ren t i a t e p re - and pos tmor tem changes . CT

and M RI have made pos s ib le the s tudy o f the in v ivo

ana tomy o f the human b ra in . T he M R/ s tud ie s a l lowed

h ighe r re s o lu t ion and more p rec i s e vo lume t r i c de te rmina -

t ions ; s emiau toma ted and au toma ted compute r i zed me th -ods fo r vo lume ca lcu la t ion o f who le b ra in o r ind iv idua l

s t ruc tu res have been found ve ry accu ra te , when com pared

to f ind ings in no rma l f re s h pos tmor tem b ra in s pec imens

(Fi l ipek e t a l 1989). MRI has a lso been val ida ted to s tudy

human b ra in deve lopmen t , w i th f ind ings o f pa t t e rns o f

g ray and w h i t e ma t t e r changes ve ry cons i s t en t w i th an im a l

and human pos tmor tem neuropa tho log ica l s tud ie s (P fe f -

ferbau m et a l 1994). For pa t ients with differe nt bra in

le s ions , t he re i s a good conf luence o f s t ruc tu ra l neu ro im-

ag ing f ind ings , c l in i ca l p re s en ta tion , and pos tmor tem s tud -

ies (Beck er e t a l 1995). As revie wed b y Jes te e t a l (1988),

the l i t e ra tu re in neu ropa tho logy pos tmor tem s tud ie s in

mo od d i s o rde rs i s i nconc lus ive , w i th few s tud ie s , mos t ly

wi th s ign i f i c an t l imi t a t ions in me tho ds and des ign . T hu s ,

fo r the reg iona l neu ro imag ing ana tomic changes he re

rev iewed , the re i s no p rope r ly conduc ted pos tmor tem

s tud ie s to da te tha t co r robora te and fu r the r inves t iga te

the s e f ind ings . Can the loca l i zed b rain changes iden t i f i ed

in mood d i s o rde rs be the re s u l t o f a neu rodeve lopmen ta l

abnorm a l i ty? In s ch izophren ia , t he re a re s eve ra l l i ne s o f

ev idence , f rom d i f fe ren t d i s c ip l ine s , s ugges t ing tha t t he

iden t i f i ed b ra in changes cou ld re s u l t f rom abnorma l i t i e s in

b ra in deve lopmen t ( Jones and M urray 1991 ; P i lows ky e t

a l 1993; W right e t a l 1993; Kesha van e t a l 1994). This has

a l s o been s pecu la t ed to be the ca s e fo r b ipo la r d i s o rde r

(Nasra l lah 1991). The decreased s ize of specif ic bra in

reg ions cou ld re s u l t f rom de f i c i t s i n b ra in deve lopmen t ,

or iginat ing, e .g . , f rom vira l infec t ion or genet ic fac tors ,

re f l ec t ing hypod eve lopm en t ra the r than a t rophy ; howeve r ,

there is no subs tant ia l evidence to va l ida te such c la ims in

mo od d i s o rde rs to da te . T hus , i t i s mos t p robab le tha t t he

reg iona l changes iden t i f i ed re f l ec t loca l a t rophy in a rea s o f

the neu roana tomic mode l , wh ich m ay be impor tan t in the

pa thoph ys io logy o f mood d i s o rde rs; howeve r , pos tmor temand long i tud ina l neu ro imag ing s tud ie s w i l l have to addre s s

and h e lp c l a r i fy th i s ques t ion .

In s ummary , foca l a t rophy o f the p re f ron ta l co r t ex ,

ba s a l gang l i a , and the ce rebe l lum may d i s rup t c i rcu i t ry ,

resul t ing in UP depress ion. BP disorder appears associa ted

wi th ce rebe l l a r and pos s ib ly t empora l lobe changes . O the r

a rea s invo lved in the s ame c i rcu i t , s uch a s the tha lamus

and am ygda la , may be s pa red . Bo th d i s o rde rs s eem to be

re la t ed to inc rea s ed w h i t e m a t t e r pe r iven t ri cu la r hype r in -

t ens it i e s. Wh e the r the s e b ra in neu roana tom ic changes a re

gene t i c o r a cqu i red , p recede o r fo l low ma jo r dep re s s ion ,

requ i re s s tud ie s in h igh - r i s k popu la t ion . Whi te ma t t e r

l e s ions m ay d i s rup t f ibe r pa thways , a pa thophys io log ica lp roces s tha t s eem s re l a t ed to ce reb rovas cu la r d i s ea s e.

T he in t eg ra ted s tudy o f the ana tom y and func t ion o f the

l i v i n g h u m a n b r a i n b y t h e c o m b i n a t i o n o f M R I w i t h

func t iona l neu ro imag ing t echn iques , l i ke s ing le pho ton

emis s ion comp uted tomograph y , pos i t ron emis s ion tomog-

raphy , o r func t iona l M RI , ha s the po ten t i a l fo r ana tomic

loca l i za tion o f abnorma l i t i e s a t t he neu ro t rans mi t t e r l eve l.

T he conf i rma t ion o f the s t ruc tu ra l changes rev iewed he re

and the e luc ida t ion o f the i r b iochemica l co r re l a t e s w i l l

he lp in deve lop ing an in t eg ra ted s t ruc tu ra l - func t iona l

m o d e l o f m o o d d i so r d er s .

This work was partly supported by grant MH 46745.

We thank Mrs. Geny H.U. Soares for technical assistance in the

manuscript preparation.

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