Neurobiologia Del TB

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Bipolar Disorders 2001: 3: 106 150Printed in Ireland. All rights reser6ed

Review Article

The neuropsychology and neuroanatomy ofbipolar affective disorder: a critical review

Bearden CE, Hoffman KM, Cannon TD. The neuropsychology andneuroanatomy of bipolar affective disorder: a critical review.Bipolar Disord 2001: 3: 106150. Munksgaard, 2001

Objecti7es: To present a comprehensive review of the existing neuropsy-chological and neuroimaging literature on bipolar affective disorder.This review critically evaluates two common conceptions regarding theneuropsychology of bipolar disorder: 1) that, in contrast to schizophre-nia, bipolar affective disorder is not associated with general cognitiveimpairment independent of illness episodes, and 2) relative right hemi-sphere (RH) dysfunction is implicated in bipolar illness patients, sup-ported by reports of relatively greater impairment in visuospatialfunctioning, lateralization abnormalities, and mania secondary to RH

lesions.

Methods: The major computerized databases (Medline and PSYCInfo)were consulted in order to conduct a comprehensive, integrated reviewof the literature on the neuropsychology and neuroanatomy of bipolardisorder. Articles meeting specified criteria were included in this review.

Results: In a critical evaluation of the above notions, this paper deter-mines that: 1) while there is little evidence for selective RH dysfunc-tion, significant cognitive impairment may be present in bipolar illness,particularly in a subgroup of chronic, elderly or multiple-episode pa-tients, suggesting a possible toxic disease process, and 2) the underlyingfunctional correlate of these cognitive deficits may be white matterlesions (signal hyperintensities) in the frontal lobes and basal ganglia,

regions critical for executive function, attention, speeded informationprocessing, learning and memory, and affect regulation. While this hy-pothesized neural correlate of cognitive impairment in bipolar disorderis speculative, preliminary functional neuroimaging evidence supportsthe notion of frontal and subcortical hypometabolism in bipolar illness.

Conclusions: The etiology of the structural brain abnormalities com-monly seen in bipolar illness, and their corresponding functionaldeficits, remains unknown. It is possible that neurodevelopmentalanomalies may play a role, and it remains to be determined whetherthere is also some pathophysiological progression that occurs with re-peated illness episodes. More research is needed on first-episode pa-tients, relatives of bipolar probands, and within prospectivelongitudinal paradigms in order to isolate disease-specific impairmentsand genetic markers of neurocognitive function in bipolar disorder.

Carrie E Beardena, KathleenM Hoffmanb and Tyrone

D Cannonc

a Department of Psychiatry, University of

Pennsylvania, bThe Childrens Hospital of

Philadelphia, Philadelphia, PA, andc Department of Psychology, UCLA, Los

Angeles, CA, USA

Key words: affective disorders bipolar

disorder cognition depression mania

neuroanatomy neuroimaging

neuropsychology

Received 27 March 2000, revised and

accepted for publication 5 January 2001

Corresponding author: Carrie E Bearden,

PhD, Psychology Department, VA Medical

Center, 3350 La Jolla Village Drive, San

Diego, CA 92161, USA; fax: +1 619 229-

1715; e-mail: [email protected]

There is no doubt that depression and mania affectthe ability to think, concentrate, reason, and re-member. The nature and extent of such changes,however, is less clear, and their specificity to mooddisorder, their existence before the onset of affec-tive symptoms, their etiology, and their relation-

ship to underlying neuroanatomical abnormalitiesremain poorly understood.

Historically, two common conceptions regardingthe neuropsychology of bipolar disorder have beenthat: 1) in contrast to schizophrenia, bipolar affec-tive disorder is not associated with general cogni-

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Neuropsychology of bipolar disorder

tive impairment independent of illness episodes, orin the premorbid state (1), and 2) relative righthemisphere (RH) dysfunction is implicated inbipolar illness, supported by reports of relativelygreater impairment in visuospatial functioning,anomalous lateralization of function, and maniasecondary to RH lesions (2, 3). In an attempt tocritically evaluate these notions, this paper willattempt to answer the following questions:

1. Are there stable neuropsychological deficits inbipolar illness that exist independently of clini-cal state?

2. Do bipolar patients exhibit selective impair-ments in specific domains, or do they demon-strate a more diffuse cognitive impairment?

3. What are the most consistently reported struc-tural brain abnormalities? Are these abnormali-ties characteristic of bipolar disorder in general,or only characteristic of particular subgroupsof patients (e.g., severe, chronic, or elderly)?

4. Are there neuropsychological deficits and/orstructural and functional brain abnormalitiesthat are unique to bipolar disorder?

5. What is the possible etiology of the neuropsy-chological and neuroanatomical abnormalities?

In answering these questions, this paper will at-tempt to present a unified model of the potentialneuroanatomical substrates for the pattern of cog-nitive impairment seen in bipolar disorder, utilizingevidence from neuropsychological studies, struc-tural and functional neuroimaging data, neu-ropathological findings, and secondary affectivedisorders. The methods used for study inclusionare described in the Appendix.

The abnormal laterality/RH dysfunction hypothesis

Support for this hypothesis has been drawn fromthree general lines of research: 1) neuropsychologi-cal studies that reported lower Performance IQ(PIQ) than Verbal IQ (VIQ) scores in bipolar pa-tients, or relative impairment in visuospatial func-tioning, 2) studies of lateralization of function(dichotic listening tasks, handedness and lateralityof grip strength, and emotional discriminationtasks), and 3) studies of secondary affective disor-ders caused by lesion or stroke, in which RHlesions are reported to result in manic symptoms.

Each of these areas will be reviewed in turn in aneffort to critically evaluate this hypothesis.

Cognitive function in bipolar disorder

Because of the increasing role for neuropsychologi-cal tests as cognitive tasks used in conjunction with

brain imaging techniques, and the increasing rele-vance of cognitive impairments for treatment andrehabilitation in psychiatric disorders, it is particu-larly important to gain an understanding of thenature of the neuropsychological function of bipo-lar affective patients (4). One of the questions thispaper will attempt to answer is whether it is indeedsensible to examine a disorder that is by naturecyclical and episodic from the perspective of more

enduring structural abnormalities and correspond-ing functional manifestations of such abnormali-ties.

VIQ and PIQ. The increase in the number ofinvestigations of cognition in relation to affectivedisorder has been stimulated to a large degree bythe hypothesis, first fully formulated by Flor-Henry and Yeudal (5), that affective disorder isassociated with RH dysfunction. Indeed, many re-ported findings have consistently shown an associ-ation between cognitive functions thought to belinked to the right, or non-dominant, hemisphere

and disorders of mood (2, 6 8). Support for thenotion of RH dysfunction, or abnormal lateraliza-tion of function, in bipolar disorder was generatedlargely by early studies of Wechsler IQ scores inbipolar patients, which often reported relativelylower PIQ than VIQ in bipolar patients (6, 9).Although the findings are not unanimous, the ma-jority of such studies suggest that bipolar patientsindeed show a pattern similar to the one producedby lateralized RH lesions, thus leading to the con-clusion of the presence of predominant RH dys-function in bipolar illness (10, 11). Table 1 presentsthe results of studies of IQ in bipolar disorder.

As Table 1 demonstrates, bipolar patients onaverage do indeed display a relatively higher VIQthan PIQ. However, examining the absolute scoresreveals that the mean VIQ among these samples ofbipolar subjects is above average (102.8), and themean PIQ of 96.7 is still well within the normalrange (100915) (12). While the mean V PIQ dis-crepancy is slightly greater among this sample ofbipolar patients than controls, this discrepancy isstill quite small (6 points). Further, the majority ofthese studies did not describe the patients clinicalstate at the time of testing; thus, it is unclear whateffects clinical symptomatology may have poten-tially had on IQ performance.

Kluger and Goldberg (11) have suggested analternative explanation for the findings of de-creased PIQ in bipolar disorder. Because the RHhas greater ability to perform novel, not yet rou-tinized, tasks, RH damage will selectively interferewith the ability to process novel information.However, this ability could also be more severely

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108

Table1.

WechslerIQ

scores

inbipolarpatientsversuscontrols

SD

MeanV-PIQ

Mean

Contro

lsubjects

Mean

P

atients

SD

Mean

Study

SD

Me

an

MeanV-PIQ

SD

V-IQ

P-IQ

P-IQ

discrepancy

discrepancy

V-IQ

8.1

WaldfogelandGuy,

1

6BPmanic

109.2

101.1

1951(193)

2

2

1BP

117.2

115.2

d

epressed

13.4

1.35

87.29

6

0psychotic

Flor-Henryand

15.9

88

.64

Yeudall,1979(5)

B

P

13.25

Abramsetal.,1981

4

3BPmanic

101.75

88

.5

(14)

14.98

6.92

108.74

14.31

101.82

3

4BP+UP

Donnellyetal.,1982

(40)

d

epressed

4.82

P

atientsat

111.97

14.98

107.15

15.73

r

emissiona

93

.4

2

5BPmanic

103.8

9.8

10.4

Flor-Henry,1983(2)

9.5

14.93

DalbyandWilliams,

10.53

21nor

mal

1

5BP

93.38

10.65

99

10.81

0.62

95.33

10.98

84

.8

1986(9)

controls

Dewanetal.,1988

13.4

3.2

2

6BP

112.3

11.9

109.1

(172)

3.82

52nor

mal

93

.65

107.23

9.02

106.94

9.66

11.67

14.65

0.29

97.47

3

0BP

Coffmanetal.,1990

(20)

controls

5.8

30sch

izophrenic

92.6

13.9

83.6

12.8

9.0

9.9

3

5BPmanic

Hoffetal.,1990(22)

82

.9

14.0

88.7

in-patients

in-patients

Morice,1990(30)

5.5

34nor

mal

2

0BP

104.5

15.2

101.7

12.1

2.8

99.9

13.9

94

.4

12.3

controls

10.18

6.08

Totaln

=

137

99.43

7.52

97.8

10.03

2.87

Overall

T

otaln=

325

102.8

9.50

96

.7

(SD=

4.07)

(SD=

4.34)

BP=

bipolar;UP=

unipolar.

aSignificantlyhigherscoresatremission.


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109

Ta

ble2a

.Resu

ltso

fs

tudiescomparing

bipo

lar

disorderan

dcon

tro

lgroupson

tes

tso

fa

tten

tionan

d

vigilance

Bipolareuthymic

Bipolarpatients

Bipolarmanic

Unipolar

Mixed/Unspec.

Sch

izophrenics

Medical/Other

Bipolar

Task

Normalcontrols

AffectiveDx

(mixed/unspec.

depressed

controls*

depressed

moodstate)

23/30

23/14;71/7a

CPT

71/7a

79/12

79/10

79/12

79/11

Perceptualspan

55/50;31/22;

190/16;5/46;

42/20

14/43;5/29;

DigitSpans

14/9;5/31

32/100

5/54;31/46;

14/8

71/7

190/11

32/100;14/17;

Regular/Reverse

42/20;71/7;

31/26

190

;38

18/26;16/36

Recurring

16/29;18/27

18/19

16/9

16/12

24/11;25/25

5/29

24/21;5/31

32/100

32/100;31/46;

TrailmakingPartA

71/7;24/19;

71/7;31/22

5/54

31/26;25/22;

5/4

6

5/29

44/10;17/29;

TrailmakingPartB

32/100

32/100;17/57;

25/22;71/7;

71/7;114/20;

24/11;25/25;

88/21;5/31

88/28;31/46;

17/16;31/22

44/16

31/26;24/19;

5/24

114/10;5/46

32/100

32/100

DigitCancellation

190

/38

190/11

190/16

ShapeCancellation

32/100

32/100

DividedAttention

24/21

19/22

55/50

19/21;25/25;

19/22;24/19;

Stroop

25/22

24/11

19/22

Letter-Digit

19/22

19/21

substitution

Blacktext:Resultswithin

normallimits.

Greentext:Nodifferences

betweenpatientgroups.

Bluetext:Performancesig

nificantlypoorerthancontrols.

Redtext:Performancesig

nificantlypoorerthanotherpatientgroups.

Valuesrepresentstudyreference/numberofsubjects.

a

BPswerediscordanttwinpairs;NCswerenormaltwinpairs

*IncludespatientswithHu

ntingtonsDisease,

OrganicBrainDisease,

AlzheimersDisease,

AlcoholAbuseorAntisocialPersonalityDisorder.


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111

Ta

ble2c

.Resu

ltso

fs

tudiescomparing

bipo

laran

d

con

tro

lgroupson

tes

tsof

verba

la

bility/s

kill

Bipolarpatients

Bipolarmanic

Unipolar

Normalcontrols

Mixed/Unspec.

Task

Sch

izophrenics

Medical/Other

Bipolareuthymic

Bipolar

depressed

AffectiveDx

depressed

Controls*

(mixed/unspec.

moodstate)

5/31

3/105

5/54;3/22

AphasiaScreening

5/4

6;3/99

5/29

Test

BostonNaming

71/7a

71/7a

Test

14/9

14/17;31/46

14/8

Vocabulary

192/20;31/22

31/26;192/10

14/43

(WAIS-R)

14/43

14/9

4/30

14/17;31/46

14/8

31/26;4/41

31/22

Similarities

(WAIS-R)

14/9

14/17

14/8

Information

14/43

(WAIS-R)

19/22;18/27;

19/21

21/12

16/9;5/29

5/31;16/12;

Verbalfluency

4/30

5/54;16/36;

21/10

18/19;20/30

21/20

20/52;16/29;

19/22

21/20;4/41;

5/4

6

25/25

ControlledOral-

71/7a;192/20;

31/46

25/22;71/7a;

31/22

192/10;31/26

WordAssociation

Test

Confrontation

31/46

192/10;31/26

192/20;31/22

NamingTest

44/10

44/16

Synonym

Test

9/15

17/29

9/30;17/57

9/45

9/2

1;71/7

71/7;17/16

WRAT-R(Reading)

18/26

18/19

NationalAdult

18/27

ReadingTest

Writingspeed/

31/46

31/26

31/22

production

LegendasforTable2a.


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112

Ta

ble2d

.Resu

ltso

fs

tudiescomparing

bipo

laran

dcon

tro

lgroupson

tes

tsof

verba

lmemory

Bipolareuthymic

Bipolarpatients

Bipolarmanic

Unipolar

Mixed/Unspec.

Sch

izophrenics

Medical/Other

Bipolar

Task

Normalcontrols

AffectiveDx

(mixed/unspec.

depressed

Controls*

depressed

moodstate)

16/9;22/30

16/12

22/30;16/36

AssociateLearning

16/29

19/22

21/10

21/20

21/12

19/21

ListRecall

ReyAuditory

21/20;19/22

5/54

Williams

5/29

5/31

5/4

6

Animalnames

60/14

60/14

60/14

CERADTrial1

24/19

24/11

24/21

192/20;71/7a

CaliforniaVerbal

25/25;62/31

71/7a;192/10;

LearningTest

62/18;25/22

(CVLT)

9/15

17/29

17/57;9/30;

9/45

18/27;20/52;

18/19;20/30;

Verbalmemory

18/26

(Wechsler

17/16

9/2

1

MemoryScale)

17/29

32/100

22/30;32/100;

StoryMemory

71/7a;55/50;

71/7a

22/30

17/57

17/16

71/7a

71/7a

Brown-Peterson

VerbalMemory

BentonSentence

14/43

14/9

14/17

14/8

repetition

LegendasforTable2a.


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113

Ta

ble2e

.Resu

ltso

fs

tudiescomparing

bipo

laran

d

con

tro

lgroupson

tes

tsof

non-verba

lan

d

visua

lmemory

Bipolarpatients

Bipolarmanic

Unipolar

Normalcontrols

Mixed/Unspec.

Task

Sch

izophrenics

Medical/Other

Bipolareuthymic

Bipolar

depressed

AffectiveDx

depressed

Controls*

(mixed/unspec.

moodstate)

14/9

14/17;22/30

BentonVisual

14/8

42/20

42/20

22/30;14/43

Retention

17/29

20/52;71/7a

17/57

20/30;71/7a;

DesignMemory

Wechsler(Visual

17/16

Reproduction

5/54

5/4

6

Graham-Kendall

5/29

5/31

Rey-Osterreith

25/22

25/25

delayedrecall

60/14

60/14

60/14

Complexdesigns

16/12

18/26;16/36

Corsiblock

16/29;18/27

18/19

16/9

tapping

5/31

5/54

5/4

6

TactualPerformance

5/29

Memory

SpatialAssociate

16/9

16/12

16/36

16/29

LearningTest

62/18

62/31

StarMirror

Tracing

b

62/31

62/18

PursuitRotorb

5/29

5/31

5/54

SeashoreSpeech

5/4

6

Sounds

17/57

42/20

17/16;71/7

17/29

Facerecall

42/20;71/7a

Visualretention

4/30

4/4

1

(pictures)

LegendasforTable2a.

b

Proceduralmemorytask.


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Bearden et al.

114

Ta

ble2f.Resu

ltso

fs

tudiesc

omparing

bipo

laran

d

con

tro

lgroupson

tes

tsofv

isuospa

tia

lan

d

visuomo

tors

kill

Bipola

reuthymic

Bipolarpatients

Bipolarmanic

Unipolar

Mixed/Unspec.

Sch

izophrenics

Medical/Other

Bipolar

Task

No

rmalcontrols

AffectiveDx

(mixed/unspec.

depressed

Controls*

depressed

moodstate)

17/29

192/10;71/7a

17/57

192/20;71/7a;

LineOrientation

17/16

14/9

14/17;22/30

14/8

14/43;22/30

HooperVisual

Organization

22/30;5/29

5/31

32/100

32/100;22/30;

5/4

6

RavensProgressive

Matrices

5/5

4

5/5

4

5/31

5/29

TactualFormboard

5/4

6

ReyFigureCopy

71/7a;25/22

71/7a

25/25

EmbeddedFigures

192/10

192/20

40/56;14/43

40/40;14/9

4/30

14/17

14/8

25/22;42/20;

BlockDesign

25/25;42/20

4/4

1

(WASI-R)

40/56;14/43

40/40;14/9;

24/11

14/17;31/46

192/20;31/22

14/8

DigitSymbol

192/10;24/19;

(WAIS-R)

24/21

31/26

40/56;14/43

40/40;14/9

14/17

14/8

ObjectAssembly

(WAIS-R)

14/43

14/9

4/30

14/17

14/8

4/4

1

PictureCompletion

(WAIS-R)

4/30

4/4

1

PictureArrangement

(WAIS-R)

34/18

34/18

34/16

GibsonSpiralMaze

4/30

VisualRecognition

4/4

1

Task

AphasiaScreening

3/105

3/2

2

3/9

9

Motor/perceptual

22/30

22/30

SymbolDigit

ModalitiesTest

LegendasforTable2a.


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disrupted following diffuse bilateral central ner-vous system (CNS) damage. Thus, bilateral, diffusedamage will affect performance on tests sensitiveto RH functions more than it will affect perfor-mance on tests sensitive to left hemisphere (LH)functions. Furthermore, PIQ tasks are more de-pendent on speed, which would be affected by abilateral lesion, as well as the psychomotor retar-dation associated with depressed mood state,

thereby resulting in a greater decrement in PIQthan in VIQ. In a meta-analysis of 38 WAIS andWechsler Bellevue studies, consisting of 22 affec-tive disorder groups (14 bipolar and unipolar de-pressed, 4 manic, 4 mixed) in 14 studies, 30bilateral/diffuse brain-damage (BI) groups in 23studies, 20 RH damage groups in 18 studies, and20 LH damage groups in 18 studies (with damagedue to tumor, vascular event, head trauma,epilepsy, infectious/degenerative disease, or demen-tia), Kluger and Goldberg (11) determined that 19of 22 affective disorder groups, 28 of 30 BI groups,and 20 of 20 RH groups had lower absolute scores

on WAIS PIQ than VIQ (the exceptions in theAffective Disorder groups were one depressedgroup and two mixed groups), while 15 of 20 LHgroups had lower VIQ than PIQ. While the PIQ/VIQ ratio was almost identical for the AffectiveDisorder group and BI groups, this ratio was sig-nificantly lower for the RH group. The absolutemean values of PIQ for Affective Disorder groupsoverall was 99.21, and the mean VIQ was 103.65,which is quite similar to the mean scores obtainedhere from studies of predominantly bipolar pa-tients alone (see Table 1). Thus, these investigatorsfound that the test profile for affective patients was

significantly closer to that of the BI group than tothe RH profile, suggesting that there may be bilat-eral, diffuse cerebral involvement in affective disor-ders, rather than a predominantly RH dysfunction.

Neuropsychological test batteries. More recentstudies have explored the notion of selectivedeficits in cognitive function with more compre-hensive neuropsychological batteries geared at test-ing specific domains of cognitive function. Tables2a g present the results of studies comparing bipo-lar subjects to normal controls, as well as otherpatient groups, on individual neuropsychologicaltests, categorized by domain of function.

As Tables 2a g show, evidence of some degreeof cognitive dysfunction in bipolar disorder ismore apparent in studies employing neuropsycho-logical batteries, rather than general intelligencetests. This is unsurprising, given that clinical neu-ropsychological batteries sample a greater varietyof sensorimotor and cognitive skills than those

115

Ta

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tudiescomparing

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laran

dcon

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tes

tsof

mo

tor-spee

d/performance

Bipolarpatients

Task

Bipolar

Normalcontrols

Bipolar

Unipolar

Medical/Other

Schizophrenics

Mixed/Unspec.

depressed

manic

AffectiveDx

(mixed/unspec.

depressed

Controls*

moodstate)

5/31

5/29

20/30

5/4

6;20/52

5/54

Fingertapping

Dominant

Non-dominant

5/4

6;20/52

20/30

5/29

5/54

5/31

5/31

5/54;22/30

PurduePegboard

5/4

6

5/29;22/30

Dominant

5/29;22/30

5/31

5/54;22/30

5/4

6

Non-dominant

5/29

5/31

5/54

5/4

6

Dynamometer

Dominant

5/54

5/31

Non-dominant

5/29

5/4

6

LegendasforTable2a.


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Bearden et al.

encompassed by traditional IQ tests. If patientsshow particular areas of impairment, these will behighlighted by neuropsychological batteries thatexamine specific domains of cognitive function(13).

Nevertheless, while bipolar patients exhibit im-pairment in comparison to normal controls onmany neuropsychological tasks, they generally ap-pear to exhibit relatively less severe impairment

than schizophrenic patients and patients with othermedical disorders such as Huntingtons disease(HD) and organic brain disease (14, 15). In themajority of studies comparing bipolars toschizophrenics, schizophrenic patients were foundto exhibit relatively worse performance, particu-larly in domains of verbal function (16). Indeed,few studies have reported significant differencesbetween normal controls and bipolar subjects onmeasures of VIQ and verbal fluency (9, 17 19).While one study found superiority of performanceon VIQ measures in affectively ill subjects com-pared to non-psychiatric controls (4), this study

was conducted in a prison, and the normal controlsubjects were male prisoners with no psychiatricdiagnosis. They had lower Full-Scale IQs and lesseducation than population norms, and thus are nota very representative sample. Only two studieshave reported decreased verbal fluency in bipolarpatients compared to normal controls (20, 21). Oneof these (21) tested bipolar subjects in a depressedstate, while the other (20) tested a sample of bipo-lar patients with definite psychotic features. Thus,both investigations employed fairly impaired sub-jects by virtue of current mood state or severity ofillness. Upon examining the qualitative findings,

neither of these investigations found bipolar sub-jects to be deficient in the number of responsesgenerated; rather, they generated more incorrectresponses (e.g., perseverative responses), a findingthat does not reflect decreased fluency per se, butperhaps diminished ability to follow taskinstructions.

While studies that have included measures ofattention and concentration have frequently shownattentional deficits in bipolar patients (5, 10, 17,22, 23), little is known about attentional functionacross different phases of illness. In general, studiesshowing attentional deficits in bipolar disorderhave examined patients that were symptomatic attime of testing (22, 23). Tasks of selective atten-tion, such as the Stroop Color-Word Test, appearto be preserved in euthymic bipolar patients (24,25).

With regard to visuospatial impairments in bipo-lar illness, impairments generally do not appear tomanifest in simpler visuospatial tasks such as Judg-

ment of Line Orientation, but are more reliablydemonstrated on tasks of complex non-verbalmemory or conceptualization skills, such as theHalstead Category Test, in which subjects mustarrive at an organizing principle which differenti-ates one visual stimuli in a set (26, 27) and Raven sProgressive Matrices, a task of visuospatial patterncompletion and abstract reasoning (2). This pat-tern of deficit is not consistent with a hypothesis of

localized RH dysfunction, but implicates dysfunc-tion of integrated neuroanatomical systems, in-cluding frontal-executive, attentional, and memoryfunctions (28).

Bipolar disorder 6ersus other psychiatric disorders.Schizophrenic patients have often been found toexhibit more dysfunction than affectively ill pa-tients in tasks attributed to frontal lobe (executive)function: a neuropsychological study of 30schizophrenic and 10 manic patients found no dif-ferences between schizophrenics and manic pa-tients in the degree of dominant and non-dominant

hemisphere dysfunction, but schizophrenics exhib-ited significantly more frontal lobe dysfunction(e.g., Shipley Abstraction, Wisconsin Card Sort)than bipolars after controlling for demographicvariables (29). Goldberg et al. (17) found the great-est degree of overlap between schizophrenic andbipolar patients to be in the domain of non-verbaland visuospatial memory; they found thatschizophrenics performed significantly below affec-tive disorder subjects on every test except Trail-making B and Facial Recognition, while there werevirtually no differences in performance betweenbipolar and unipolar subjects. The group overlap

between schizophrenia and affective disorder wasleast for IQ, memory, and problem solving; how-ever, there was substantially greater overlap forvisuospatial measures.

Nevertheless, some studies have reported a simi-lar degree of impairment in adult schizophrenicand affectively ill patients: Morice (30) found nodifference in Wisconsin Card Sort performancebetween bipolar manic and schizophrenic patients,suggesting cognitive inflexibility and prefrontalcortical dysfunction may not be specific toschizophrenia. Hoff et al. (22) also failed to differ-entiate between schizophrenics and bipolar pa-tients in the acute manic phase of illness on anymeasure of neuropsychological function, after con-trolling for the effects of age, sex, education, dura-tion and severity of illness, and medication status.Further, these investigators did not find distinctivepatterns of lateralized deficit; only medicationstatus was related to poorer performance on somemotor tasks, regardless of diagnosis (22).

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In general, when symptomatic, cognitive abilitiesin bipolar patients appear to more closely resemblethose of schizophrenic patients. Hawkins et al. (31)found that a sample of bipolar patients exhibitingmild levels of depression and no psychotic symp-toms at testing performed better thanschizophrenic patients on all neurocognitive mea-sures, and not significantly different from normalcontrols. However, the weakest performance of

both patient groups was found in tests of speededvisual-motor sequencing (Digit Symbol/Trailmak-ing). These are tasks that require the smooth inte-gration of multiple processes and, while highlysensitive to brain dysfunction, lack precise localiz-ing significance. Similarly, Zihl et al. (32) foundthose patients with schizophrenia and affective disorder to display a similar degree of cognitivedeficit, especially in tasks of attention and problemsolving, suggesting that this pattern of cognitivedeficit may reflect a final common pathway disor-der in the two patient groups. Disparate findingsacross studies are thus likely to be a function of

varying symptomatic state of the patient groups atthe time of testing and small sample sizes.

Bipolar 6ersus unipolar depression. An early reviewby Miller (1) concluded that bipolar and unipolarpsychotic illnesses are both associated with impair-ment of serial learning. However, when studiesused other psychiatric groups for comparison,Miller concluded that no impairment could befound which was unique to depression. Miller alsonoted that severe depression is often associatedwith a marked degree of impairment, similar tothat exhibited by schizophrenics. Neuropsychologi-

cal deficit may be a function of severity of psycho-pathology, in that increasing psychopathology maycorrelate with decreasing motivation to performwell on experimental tasks. One reason thesedeficits may not be specific or unique to bipolardisorder is because they are due to some commonfeature shared by different forms of psychopathol-ogy, such as impaired attention or insufficientmotivation.

Consistent with Millers (1) conclusions, the re-sults of the neuropsychological studies presentedhere reveal that bipolar patients, in general, appearto differ little from unipolar depressed patients,both in terms of severity and pattern of impair-ment. Both unipolar and bipolar patients showimpairments in verbal learning (21, 25), thoughone investigation found bipolar depressed patientsto be more impaired than unipolar depressed pa-tients on both verbal recall and recognition (21).Normal controls also showed more improvementover trials than all patient groups, suggesting that

deficits in memory-encoding strategies may exist inthe depressed state. Bipolar patients in this studyalso showed some impairment in a verbal fluencytask, while unipolar subjects did not. These find-ings may reflect the severity of disorder, as thebipolars in this study had twice the rate of hospi-talization of unipolar depressed subjects. Consis-tent with this interpretation, Kessing (33) found nodifferences in global cognitive function between

multiple-episode euthymic bipolar and unipolarpatients, but that patients with recurrent episodeshad significantly more impairment than single-episode patients. In contrast, Paradiso et al. (24)reported no significant differences between eu-thymic bipolar patients and normal controls, whileunipolar patients with comparable depressionscores were significantly impaired on measures ofvisual-motor sequencing (Trailmaking) and imme-diate memory and attention (Digit Symbol andList Learning).

There is some evidence that unipolar depressedpatients may exhibit more psychomotor slowing

(34), but this is likely to be linked to mood stateand severity of depression at time of testing. It isunclear whether bipolar patients in a comparablysevere state of depression exhibit the same degreeof psychomotor slowing. Further, psychomotorspeed, as measured with tools such as Trailmaking,appears to normalize when patients are euthymic,suggesting psychomotor slowing may be state-de-pendent (25). Presently, comparisons betweenunipolar and bipolar patients are difficult to assess,due to the generally small sample sizes and the factmany studies grouped bipolar and unipolar pa-tients together as an affective disorder group.

Effects of clinical state at time of testing. While theresults in Table 1 do not indicate a global intellec-tual deficit in bipolar disorder, it is unclear whetherthis represents a significant decline from the pre-morbid state. Some investigators have reportedthat bipolar illness is associated with intellectualdeterioration that is at least as great as that foundin schizophrenia. Payne (35) reported that the IQsof manic-depressives during periods of depressionare lower than those of normal controls, and notsignificantly different from the illness IQs ofschizophrenics. Masons early report (36) that thepremorbid IQs of bipolars were significantly higherthan those of normals, while those of schizophren-ics were significantly lower, would indicate thatbipolar disorder involves greater intellectual deteri-oration at onset, or during the course of the disor-der. Several early investigations reported increasedStanford Binet IQ scores following clinical im-provement (37 39), suggesting that affective illness

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may not lead to a permanent or progressive deteri-oration in intellectual functioning. Consistent withthese data, Goldberg et al. (17) reported that,based on correlations between neuropsychologicalscores and clinical state at testing, psychiatricsymptoms in schizophrenic patients accounted forless than 5% of variance in cognition, while inAffective Disorder groups, symptoms accountedfor 30% of variance in cognition, suggesting cogni-

tive abilities vary more with mood state in affectivedisorders than in schizophrenia.Only a few studies have employed a within-sub-

jects design, in which the same patients were testedat different timepoints, in order to compare theirperformance in manic, depressed, and remittedstates. These studies found evidence that the samepatients, when in a hypomanic or euthymic state,have higher IQs than when depressed (40, 41). Inthe investigation of Donnelly et al. (40), this couldnot be attributed to practice effects, as the patientsIQ scores decreased again when retested in thedepressed state. Consistent with these findings,

Henry et al. (41) reported that bipolar patients inthe manic state displayed decreased serial learningon a verbal learning task, relative to their ownperformance in a remitted mood state. However,they showed no impairment on short-term freerecall, regardless of mood state, suggesting theexperience of mania or depression may affect com-plex processing or memory functions, but not sim-pler tasks.

Episode 6ersus inter-episode functioning. Only re-cently have investigators begun to focus on neu-rocognitive function in euthymic bipolar patients.

While three such studies found little evidence ofgeneralized cognitive impairment (24, 42, 43), thereis nevertheless some evidence that euthymic bipo-lar patients exhibit limitations in some types ofinformation-processing strategies (e.g., synthesiz-ing multiple aspects of a stimulus) (42). Specifi-cally, euthymic patients were found to exhibitsignificant impairment on a Gestalt completiontask and had difficulty recognizing masked faces.Given that these bipolar subjects displayed normalperformance on Block Design, a task of visuocon-structive ability, and showed no increase in errorson left-sided (RH) visual field presentations, thesefindings are unlikely to represent specific RHdysfunction.

Further, several recent investigations have re-ported significantly lowered cognitive function in asubstantial number of euthymic bipolar patientswith longstanding illness (25, 44, 45). In addition,Atre-Vaidya and colleagues (45) found that eu-thymic bipolar patients with more negative fea-

tures, particularly anhedonia, showed morecognitive impairment. In this study, cognitive im-pairment was also associated with poorer psycho-social functioning.

Conflicting findings in studies of euthymic orremitted patients are unsurprising, given discrepan-cies between studies regarding the criteria of remis-sion, as well as different tests employed.Longitudinal studies including cognitive assess-

ment prior to illness onset and later, during periodsof illness and clinical remission, are needed toascertain whether changes in intellectual functionare due to treatment variables, genetic predisposi-tion, or clinical state.

Effect of psychotic features. Albus et al. (46) re-cently reported that, while first-episode non-psy-chotic affective disorder patients performed similarto controls on cognitive measures, affective pa-tients with psychotic features performed as poorlyas first-episode schizophrenics, suggesting that thepresence or absence of psychotic features has more

impact on neuropsychological function than diag-nosis (46). Indeed, one of the few studies to findevidence of severe and diffuse cognitive impair-ment in bipolar patients (20) examined a sample of30 bipolar outpatients, all of whom had psychoticfeatures and a long history of illness. While therewas some suggestion of relatively greater RH im-pairment (i.e., bipolar patients performed signifi-cantly worse than controls on non-verbal, but notverbal, memory), there was little evidence forstrictly localized deficits in these patients. Manystudies have reported that bipolar patients withpsychotic features are likely to have worse out-

come and a more chronic, severe course of illness,suggesting that these patients may also experiencegreater deterioration in cognitive function overtime (47 50). However, the specific effect of psy-chotic features on cognitive function in bipolardisorder has not been adequately examined.

Effects of se6erity/chronicity of illness. There is agrowing body of evidence that chronic, multiple-episode patients exhibit more severe cognitive im-pairments than younger patients or patients with amore remitting course of illness. McKay et al. (51)found that none of the young or elderly non-chronic bipolar patients scored in the impairedrange on tests of memory, executive function, andoverall intellectual function, as compared to 5 of10 chronic, severe patients who had suffered frommultiple episodes requiring many hospitalizations.On a more detailed neuropsychological evaluation,these five patients showed a variable impairmentpattern, ranging from isolated executive, visuospa-

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tial and memory deficits to widespread poor per-formance. The authors conclude from these find-ings that in chronic severe patients,neuropsychological deficits are not restricted toperiods of affective illness, but instead reflect en-during cognitive deficits. In this study, 40% of thechronic patients had a rapid-cycling illness; as theeffects of rapid cycling on cognitive function havenot been investigated, it is unclear which aspect of

illness may have contributed to their severe impair-ment.Supporting a hypothesis of an aggregate nega-

tive effect of lifetime duration of the illness oncognitive function, one recent study of euthymicbipolar patients with longstanding illness foundthat performance on several tests, including gen-eral intelligence, was negatively correlated with thenumber of hospitalization episodes (44), and an-other (25) found that the number of months ofmania or depression that patients had experiencedduring the course of illness was significantly nega-tively correlated with performance. Denicoff et al.

(52) recently reported that several different mea-sures of a more severe course of prior illness (num-ber of episodes, longer duration of illness, morehospitalizations) were related to poorer perfor-mance on tasks of memory, attention and abstrac-tion. Further, only one study (33) has attempted totease apart the separate effects of number ofepisodes versus duration of illness. This study founda significant linear association between two mea-sures of global cognitive function and number ofepisodes, but no association between total durationof illness and cognitive measures. Moreover, fur-ther analysis revealed that it was the number of

depressive episodes, not manic or mixed episodes,that correlated with cognitive decline. Thus, al-though generally undemented and asymptomatic,patients in these studies still displayed substantialinter-episode cognitive impairment and likely dete-rioration from previous levels of functioning.

One of the few studies to conduct a longitudinalassessment of bipolar patients (53) also foundsome evidence for cognitive deterioration over thecourse of the disorder: in a follow-up assessment of25 bipolar patients initially hospitalized for maniawith no signs of cognitive impairment, one-third ofthese patients were found to show significant cog-nitive impairment 5 7 years later. Savard et al.(26) reported that older bipolar patients had sig-nificantly more errors on the Halstead CategoryTest, a test of non-verbal conceptual ability, andthat the degree of cognitive deficit was more uni-form among older bipolar subjects. At retest (uponremission), the error scores of the younger bipolarpatients were within the normal range, but the

older bipolar patients still showed significant im-pairment in the recovered state. Because this study(26) did not report the severity of illness of theseolder patients, it is unclear whether their continuedimpairment in the euthymic state was related totheir advanced age or the chronicity and severity ofthe disorder.

These findings suggest that there may be endur-ing cognitive impairment in some bipolar patients,

even after remission of an affective episode, andthat these deficits may worsen with time. Altshuler(54) has posited that cognitive impairment in bipo-lar disorder may result from repeated episodes ofillness. That is, episodes of mania and depressionmay cause destructive damage to brain tissue, witha functional correlate of such damage being persis-tent cognitive deficits in the euthymic period, par-ticularly in learning and memory functions.Because very few follow-up studies of cognitivefunction in bipolar disorder have been conducted,none of which have tested large numbers of sub-jects, this hypothesis awaits further testing.

Effects of medication status. It is possible thatcognitive impairment in bipolar disorder may bedue, not to the illness itself, but to effects oflong-term psychotropic medication. Lund et al.(55) examined the long-term effects of lithiumtreatment and found chronic bipolar patients (sta-bilized on lithium) to be in the low average rangeon functions of attention and memory, based onpopulation norms. Thus, while long-term lithiumtreatment does not appear to substantially effectcognitive function, the authors point out that, con-sidering the high education level of the subjects

(32% of whom had a university degree), a higherlevel of performance might be expected.

Engelsmann et al. (56) also found that in bipolarpatients treated with lithium, mean memory testscores remained remarkably stable over a 6-yearinterval, with only one of the 10 memory subtestsshowing a statistically, but not clinically, signifi-cant decrease. Further, there were no significantdifferences between patients with short- versuslong-term lithium treatment on any measure, aftercontrolling for age and initial memory scores.However, Kessing (33) found both the number ofepisodes and lithium treatment to correlate withtwo of five tests of diffuse cognitive function. Aqualitative review of the literature (57) concludedthat lithium had a negative effect on memory andspeed of information processing, although patientsthemselves were often unaware of these deficits.

Additionally, other mood stabilizers such as car-bamazepine and valproate can also produce con-centration problems, though there is some evidence

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that epilepsy patients show improved attentionalcapacity during carbamazepine treatment, as com-pared to other anticonvulsants (58). Neurolepticsand antidepressant drugs may also influence cogni-tive performance; however, recent reviews haveconcluded that conventional neuroleptics do notcause cognitive deficits, though they do little toimprove them (28). Further, the effect of electro-convulsive therapy (ECT) on cognitive function in

bipolar disorder has not been adequately investi-gated; one study of bipolar patients (33) reportedno effect of the number of ECT treatments, nor ofduration of convulsions, on five measures of globalcognitive function. However, in patients with ma-jor depression, ECT has been reported to causeshort-term memory deficits, particularly in theacute stages of treatment, and memory complaintsare one of the most common subjective side effectsof ECT treatment (1). Thus, this topic warrantsfurther investigation in patients with bipolarillness.

Taken together, these findings suggest that,

while medication may cause some degree of cogni-tive slowing, the cognitive impairments in chronicbipolar illness do not appear to be a primary effectof medication treatment. However, many bipolarpatients take several psychotropic medications,and it is presently unknown what the combinedeffects of these various medications may be, partic-ularly over time. An additional complication is theinfluence of the dosage, as presumably, higherdoses may have greater impact on cognitive func-tion. The effects of pharmacological treatmentmust be carefully controlled and examined in fu-ture studies.

A subcortical cogniti6e impairment in bipolar dis -order?. Given the inconsistency of the evidence forRH dysfunction in bipolar disorder, investigatorshave more recently examined the notion of a sub-cortical cognitive impairment. The neuropsycho-logical evidence that supports such a possibilitycomes from two studies comparing mood disordersubjects to patients with HD, a disorder known toinvolve subcortical dysfunction (15, 59). The mem-ory profile of such patients involves impairment onfree recall but little deficit in recognition memory,suggesting difficulties with systematic memory re-trieval strategies (15). Such difficulties in planningsuggest deficits in executive function, governed bysubcortical and frontal structures (28).

Massman et al. (15) used a factor analysis toclassify depressed bipolar and unipolar patientsbased on their neuropsychological performance,compared to patients with HD and Alzheimersdisease (AD). Of the depressed subjects (including

four bipolar subjects), 65.3% were classed as nor-mals, 34.7% were classified as HD patients (includ-ing five bipolar patients), while none was classifiedas an AD patient. These findings support the no-tion of subcortical dysfunction in a subgroup ofdepressed patients; like HD patients, they hadseverely impaired performance on free recall, in-consistent item recall from trial to trial, and inade-quate use of semantic clustering strategy. They

displayed a deficient rate of improvement acrosstrials, suggesting difficulty in utilizing systematicorganizational strategies. Like HD patients, theydisplayed great improvement on recognition test-ing, indicating a deficit primarily in retrieval frommemory, but evidenced some mild encodingdifficulties as well. Others have reported a similarimpairment in recall without corresponding recog-nition deficits, particularly in measures of visualmemory (60).

Further, Wolfe et al. (21) found bipolar patientsshowed a pattern of impairment that was qualita-tively similar to HD patients, though they gener-

ally showed less impairment. Given the knowninvolvement of basal ganglia structures, includingthe putamen and caudate, in HD, the authors (21)conclude from these findings that bipolar de-pressed patients may resemble HD patients in thetype of memory dysfunction, suggesting that dam-age to basal ganglia structures may also be in-volved in the cognitive impairments seen in bipolardisorder. This possibility is supported by studies ofsecondary mood disorders, as well as functionaland structural neuroimaging studies, which impli-cate the basal ganglia in the pathophysiology ofmood disorder (59, 61).

The findings of van Gorp et al. (62) are slightlyat odds with this conclusion, as they found eu-thymic bipolar patients to be impaired on a task ofdeclarative memory (CVLT), which is typically dis-rupted by temporal-hippocampal damage, but notin tasks of procedural memory (star mirror tracingand pursuit rotor task), which is typically impairedin patients with predominantly subcortical dys-function, including damage to basal ganglia. Theauthors conclude from this pattern of findings thatdisturbance of temporal lobe/hippocampal struc-tures, but not basal ganglia, is implicated in bipo-lar disorder. However, this result may be due todifferential test sensitivity, as tests are rarely stan-dardized for difficulty. Interpreting results acrossstudies is also problematic due to the use of dis-crete or over-specialized tests, which cannot ad-dress deficits in other domains of cognitivefunction. In general, disparate methodologies anddissimilar patient groups of the various studiesmake cross-study comparison difficult.

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While at present, the neuropsychological find-ings do not point to strictly localized subcortical

dysfunction, given converging evidence of disrup-

tion in cortical-subcortical circuits in particular,

the frontal-basal ganglia circuit in bipolar disor-der (61, 63 65), such disruption would be likely to

cause impairment in cognitive function attributed

to subcortical structures.

State 6ersus trait abnormalities: high-risk and twinstudies. Because the findings of cognitive impair-

ment in adult bipolar disorder are obscured by

differences in symptomatology and medicationstatus, any findings in offspring of bipolar parents

that is, individuals at high genetic risk for bipo-

lar disorder, but without outright expression of thedisorder are an ideal group on which to examine

a neuropsychological profile that may be indicative

of a state-independent, genetic vulnerability to the

disorder. In schizophrenia research, the high-riskparadigm has elucidated patterns of neuropsycho-

logical and behavioral dysfunction in young chil-

dren at genetic risk for schizophrenia that resemblethose seen in adult schizophrenics, thus indicating

potential markers of a genetic vulnerability to the

disorder (66, 67). Unfortunately, the high-risk

paradigm has thus far been employed very infre-quently in bipolar research.

Of the existing high-risk studies (Table 3), two

found that, consistent with findings from cognitivestudies of adult bipolar patients, high-risk children

performed markedly more poorly on the Perfor-

mance portion than on the Verbal portion of theWISC (68, 69). Moreover, Decina et al. (68) found

a significant (greater than 15-point) discrepancybetween VIQ and PIQ in a significant number of

high-risk children, which was greater in the off-spring of bipolar-I parents than in offspring of

bipolar-II parents. Of the high-risk children, those

who showed expansive behavior patterns simi-lar to adult hypomanic behavior were more

likely to show this cognitive pattern, suggesting

that this discrepancy might be a trait marker of a

genetic vulnerability to bipolar disorder. However,given that the only other study to employ the

WISC in a sample of offspring of bipolar parents

found no significant differences between children

of bipolars and control children (70), any conclu-sions drawn from the high-risk literature are

clearly premature. Nevertheless, while there maybe some evidence of relatively poorer visuospatial

performance, there does not appear to be evidence

of general cognitive impairment in high-risk chil-

dren, suggesting that much of the intellectual im-pairment takes place after onset of the disorder.

Further, one study to date has examined cogni-tive function in monozygotic twin pairs discordantfor bipolar disorder (71). They found that affectedtwins showed specific deficits in measures of visu-ospatial function (i.e., face recognition) and verballearning and memory, as compared to unaffectedcotwins and a control group of normalmonozygotic twins. Unaffected twins performedworse than controls on some verbal learning mea-sures. This paradigm allows for examination ofboth disease-specific impairments and genetic riskfactors, suggesting that, while some visuospatialdeficits and verbal memory impairment may relateto disease parameters, mild deficits in overall ver-bal learning and retrieval may be a genetic markerof risk for the disorder. However, given the ex-tremely small sample size of seven twin pairs, theauthors caution that these results must be viewedas exploratory.

Summary of cogniti6e findings. While an older re-view (10) concluded that patients with manic-de-pressive illness .. . typically demonstrate deficits inright hemisphere or non-dominant hemispherefunctions (p. 279), the results of the present reviewdo not support this conclusion. While there is somesuggestion that verbal skills, with the exception ofcomplex verbal learning and memory, appear to beless impaired in bipolar patients than are visuospa-tial, non-verbal memory, and abstraction skills,these tests are likely to be more susceptible to theeffects of mood symptomatology, as they requireincreased motivation, attention, and speed. Impair-ments can also be seen in verbal memory whensubjects are in an affective episode (21, 41), and inpatients with longstanding illness (25, 45, 62). Itseems that the more clinically reliable decrementsin performance are observed in memory functions,tasks requiring serial processing, and higher ordercognitive functioning (abstraction, flexibility, andconceptual development) (72).

The results to date do not suggest a specificcognitive profile in bipolar disorder; rather, themore consistent finding across studies appears tobe that cognitive impairments are fewer and rela-tively less severe in younger and/or euthymic pa-tients (9), whereas studies of symptomatic,psychotic or chronic elderly patients were likely tofind more diffuse impairment (20, 22, 46, 51).Findings of persistent neuropsychological deficitsin euthymic patients with longstanding illness, andthe relationship of this impairment to length ofillness, suggest that episodes of depression andmania may exact damage to learning and memorysystems (25).

Thus, this performance deficit appears to bemore consistent with impairment in frontal-tempo-

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Bearden et al.

122

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aRetrospectivestudy.


18/45


ral and subcortical systems rather than an underly-ing selective RH impairment. Nevertheless, resultsvaried greatly across studies, due in large part toheterogeneity in sample populations. Patients dif-fered widely in diagnostic status (e.g., bipolar-Iversus bipolar-II, rapid-cycling, psychotic fea-tures), medication status, mood state at time oftesting, age, severity, and chronicity of illness. It isimperative that future studies of cognitive function

in bipolar disorder consider these methodologicalissues carefully in order to clarify whether bipolarpatients show a particular pattern of cognitivedeficit, whether there is significant decline in cogni-tive function over the course of illness, andwhether such impairments are limited to a sub-group of patients.

Studies of laterality of function

In addition to the neuropsychological tests de-scribed above, laterality of function in bipolar ill-ness has also been the focus of investigation in

studies of dichotic listening, handedness, and emo-tional discrimination tasks. In general, the lateral-ity research field is clouded by controversy overbasic interpretations of findings. For instance, thesame experimental observation can be understoodas a right-sided o6eracti6ation, or left-sidedunderacti6ation.

Studies of dichotic listening, in which hemi-spheric dominance is determined by greater effi-ciency of auditory processing in one ear, havereported widely disparate findings (73 76). In gen-eral, dichotic listening anomalies in bipolar disor-der appear to be highly state-dependent. Further,

while these findings have been interpreted as indi-cations of right-temporal lobe dysfunction in bipo-lar disorder, performance is likely to be stronglyaffected by attentional capacity, which may pre-sumably be quite diminished during a manicepisode.

Studies of handedness in bipolar disorder aresimilarly difficult to interpret. While the literaturesuggests a relatively normal distribution of left andright handers, when controlling for gender (77),Decina et al. (68) reported significantly higher ratesof left-handedness among children of bipolar par-ents, and there have been isolated case reports ofbipolar patients who changed handedness from leftto right when switching from depression to mania(5, 78).

Tasks of emotional discrimination have alsobeen employed in laterality studies, as the litera-ture on hemispheric activation and affect has sug-gested that the RH is dominant in the perceptionof affect (79, 80). The chimeric face task, in which

subjects are asked to determine which is the hap-pier of two composite facial photographs, is re-ported to reliably elicit a RH advantage. Normalright-handed subjects show a consistent bias to-ward the composite whose smiling half-face is ontheir left, or a LH bias. David and Cutting (81)found that manics showed greater LH bias thannormals; depressives (predominantly unipolar)showed reduced LH bias compared to normals;

schizophrenia showed no bias to either side. Theyinterpret this finding as suggestive of RH hyper-function in mania and RH hypofunction in depres-sion and schizophrenia a conclusion quiteinconsistent with the notion of a stable RH dys-function or lesion in bipolar disorder, which high-lights the importance of mood state at time oftesting.

Secondary affective disorders

Insights into the localization of the pathophysiol-ogy of symptom production in mood disorders canbe gained from secondary mood disorders. Theseclinical problems suggest the brain regions that,when altered, are associated with specific symp-toms. The frontal lobes, basal ganglia and tempo-ral lobes are the most commonly dysfunctionalregions in those patients who have a comorbidoccurrence of depression with neurological disease(59). Depression and mania secondary to CNSlesions resulting from cerebrovascular accident, tu-mor, head injuries, Huntingtons choreas, AD, andAIDS have been reported in the literature (10, 82,83). In particular, disorders manifesting focal sub-cortical neuropathology, such as HD, are fre-quently associated with mood changes, includingboth depression and mania (64).

In a review of the literature on secondary affec-tive disorders, Jeste et al. (84) identified 13 cases ofmania and 24 cases of depression, secondary toknown focal lesions, associated with tumors,stroke, or surgical procedure. From these findings,they conclude that while the data do not pointconclusively to lesions in any single area that areconsistently associated with secondary depressionor mania ... there is a general tendency for depres-sive symptoms to be associated with left fronto-temporal or right parieto-occipital lesions, whereasmania is more often associated with right fronto-temporal or left parieto-occipital lesions. How-ever, they caution that several large-scale studies ofsecondary affective disorders did not report suchan association.

Migliorelli et al. (85) also observed that patientswith secondary mania were more likely to haveRH versus LH lesions, usually in right basal fron-tal and temporal cortices, the right head of the

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caudate, and right thalamus. Sackeim et al. (6)observed that the depressed state is more frequentfollowing left-sided stroke and they cite reports ofa left-sided lesion causing uncontrollable crying inpatients, whereas a right-sided lesion resulted inuncontrollable laughing.

Secondary affective disorders are important toconsider as they challenge the notion that a fixedstructural lesion cannot lead to an episodic illness

(86). However, given that bipolar mood disorderinvolves fluctuations between mood states, anymodel based on a structural lesion that resultssolely in symptoms of mania or depression is un-likely to be directly relevant to the pathophysiol-ogy of bipolar illness. The existence of affectivedisorders secondary to structural brain lesions nev-ertheless provides further impetus for structuraland functional imaging studies in primary affectivedisorder.

While the neuropsychological and behavioralfindings are provocative, they are clearly indirectmethods of revealing an underlying brain anomaly.

In order to truly examine the possibility of anoma-lous lateralization or RH dysfunction in bipolardisorder, it is necessary to examine the brain itself.While neuropathological studies have providedsome information in this regard, the majority ofthe work has been in the field of in 6i6o structuraland functional neuroimaging. Thus, we now turnto recent work in these areas.

Neuroimaging findings in bipolar disorder

Using the new generation of brain imaging tech-nology, researchers now have the potential to ex-amine specific brain regions of interest in bipolardisorder in order to understand the underlingpathophysiological mechanism responsible for theproduction of affective symptomatology, as well asthe accompanying cognitive impairments. Becausebipolar disorder is cyclical by nature, with periodsof remission between episodes of illness, researchon the affective disorders has generally focused onbiochemical and neuroendocrine aspects of the ill-ness, while paying little attention to potentialstructural neuroanatomical defects. However, a va-riety of structural brain abnormalities have beenconsistently reported in at least a portion of bipo-lar patients. Both structural and functional brainimaging suggest specific regions where abnormali-ties may be associated with symptoms of mooddisorder. Data that emerge from these studies haveimplicated the frontal cortex, basal ganglia andtemporal lobes in the production of symptoms ofaffective disorder (84, 86 89).

Structural neuroanatomical studies have em-ployed two techniques: computerized tomography

124

Table4a.

Computerizedtomograp

hy(CT)scanabnormalities:ventricularenlargement

Patientswith

affectivedisorders

Patientswithschizophrenia

Othercontrolsubjects

Study

n

VBR

SD

%

aVBR

n

VBR

SD

%

aVBR

n

VBR

SD

%

aVBR

DefinitionofaVBR

Affectivepatientsdifferentfrom:

Larg

eVBRassociatedwith:

Pearlsonand

16BP

6.5

3.3

12.5

22

7.5

2.9

23

35OPP

3.6

2.6

?

\10


Veroff,

1981(98)

Nasrallahetal.,

Normalsubjects

24BP

7.5

3.2

29.2

55

8.7

4.0

34.5

27NL

4.5

2.6

7.4

\Controlmeanby2

Low

erfrequencyofhospitalstays

1982(96)

SD

Riederetal.,1983

19BP

5.3

3.7

10.5

28

3.7

3.4

7.1

15SZA

3.9

3.8

6.7

\10

Nodifferences

(97)

Pearlsonetal.,

Normalsubjects

27BP

6.6

3.4

31

19

6.2

2.6

?

46NL

4.7

2.0

?

\Controlmeanby2

Neg

ativesymptoms,

increasednumberof

1984(194)

h

ospitalstays,persistentunemployment

SD

Luchinsetal.,

1984


22a

4.5

2.7

18

45

4.1

2.7

10.9

62HA

3.0

?

\Controlmeanby2

Psychoticfeatures

(92)

SD

Dolanetal.,1985

Agin

g,

inbothpatientsandcontrols

101b

7.3

4.6

52

5.6

3.3

?

Normalcontrols

(95)

Schlegeland

NosignificantdifferenceinVBRbetween

Agin

g,maleness,psychoticsymptoms

60c

7.4

2.4

?

60

6.9

2.6

?

patientsandcontrols,

butincreasedlinear

Kretschmar,1987

(90)

ventricularvaluesoffrontalhorns.

NoBP/

UPdifference

Dewanetal.,1988

26BP

6.9

2.9

?

22SZA

6.3

1.9

?

NosignificantdifferencebetweenBPsand

(172)

SZAcontrols

Woodsetal.,1990

9BP

9

None

Non-significanttrendforSCZinitialscansto

belargerthanBPs(pB0.1

)

(161)

VBR=

meanventricle:brainratio;a

BVR=

abnormalVBR;BP=

bipolar;OPP=

otherpsychiatricpatients;NL=

normal;SZA=

schizoaffective;HA=

hea

dachepatients;UP=

unipolar.

aThese22included7UP,

7BPdepressed,

6BPmanic,and2SZApatients.

bThese101included74BPdepressedand27UPpatients.

cThese60included33UP,

5BPmanic,

17BPdepressedand5SZApatients.


20/45


(CT) and magnetic resonance imaging (MRI). CTmeasures the degree to which a beam of X-rays isattenuated along its path through the tissues, thusproducing high-resolution pictures of brain mor-phology, and readily detects most structuralpathology. However, the value of CT investiga-tions is limited because cerebral regions most likelyto be associated with affective disorder, such aslimbic structures, are not measurable by CT due to

artifact. Thus, CT can provide a description onlyof more gross structural pathology, such as ven-tricular enlargement and brain atrophy. MRI of-fers the advantages of allowing excellent gray andwhite matter resolution in cortical and subcorticalareas and, because it permits imaging in the sagit-tal plane, it permits visualization of the corpuscallosum and other midline structures. MRI is alsosuperior in detecting brain tissue pathology, partic-ularly in the temporal lobes (88). Thus, relativelygreater weight will be given to the MRI findings inthis review. Nevertheless, a large body of researchhas been conducted with CT, comparing brain

structure of different psychiatric populations (pri-marily schizophrenic and affective disorder pa-tients) to normal control subjects. Because of thedifferences in methodology, the CT findings arepresented separately.

Tables 4a d summarize studies of ventricularenlargement, cortical atrophy and cerebellar ver-mal atrophy on CT scans of patients with majoraffective disorders, compared with those ofschizophrenic patients, patients with other psychi-atric disorders, and normal control subjects. Diag-noses in these studies were generally based onstandard diagnostic criteria. Most of the studies

attempted to control for age and history of alcoholand drug abuse. Many of the published CT scanstudies did not separate unipolar from bipolarsubjects in their analyses; however, for purposes ofclarity, this review includes only those studies ofpurely bipolar subjects or those that included alarge number of bipolar subjects in the combinedaffective disorder groups.

Of the six studies that compared the ventri-cle:brain ratio (VBR) of patients with affectivedisorder to those of non-schizophrenic/schizoaffec-tive control subjects, all but one (90) found signifi-cant differences between affective patients andcontrols. However, while Schlegel and Kretzchmar(90) did not find a VBR difference, they did findincreased linear ventricular values in affective pa-tients compared to controls. No differences werefound in any study between bipolar andschizophrenic or schizoaffective patients. While themean VBRs of schizophrenics were slightly largeracross these studies, on average, the mean ratio of

125

Ta

ble4b

.Compu

terize

dtomo

grap

hy

(CT)scana

bnorma

lities:su

lca

lw

iden

ing(

cort

ica

la

trop

hy

)

Patientswithaffectivedisorders



Study

n

%

Abnormal

n

%

Abnormal

n

%

Abnormal

Comments

Pearlsonand

16

12.5

22

18

35OPP

?

Veroff,

1981

(98)

Nasrallahet

24BP

25

55

40

27NL

3.7

NosignificantdifferencebetweenSCZ

andBPpatients

al.,

1982(195)

Riederetal.,

19BP

21

NosignificantdifferencebetweenSCZ,

BP,andSZApatients

28

17.9

15SZA

33

1983(97)

Dolanetal.,

Patientshadsignificantlygreatersulcal

widening,especially

101a

?

52

?

1986(196)

frontotemporal

Dewanetal.,

NosignificantdifferencesbetweenBP

patientsandcontrols

26BP

?

22HA

?

1988(172)

UP=

unipolar;OPP=

othe

rpsychiatricpatients;BP=

bipolar;NL=normal;SCZ=

schizophrenic;SZA=

schizoaffective;HA=

headachepatients.

aTheseincluded74BPde

pressedand27UPdepressedpatients.


21/45

Bearden et al.

the VBR of affective patients to that of schizophrenic patients was 1:1, while the meanVBR of affective disorder patients was 1.4 timesthat of control subjects from the same studies. Itseems that a proportion of patients with bipolaraffective disorder, ranging from approximately 10to 31%, have abnormally large ventricles. Thisproportion is similar to that seen in schizophrenicpatients, and greater than that observed in age-

matched normal control subjects or non-schizophrenic psychiatric patients (84).Many studies of schizophrenic patients have

noted that schizophrenics with large ventricles aregenerally characterized by more negative symp-toms and poorer responses to neuroleptic treat-ment (91). Attempts to characterize affectivedisorder patients along these dimensions have metwith mixed results; while some have reported thatsuch a subgroup may be associated with morepsychotic or delusional symptoms and poor out-come (92 94), Dolan et al. (95) found no relation-ship between VBR and course of illness.

CT studies of sulcal widening (an indication ofcortical atrophy) and cerebellar atrophy reveal thatroughly 8 25% of bipolar patients display somedegree of cortical or cerebellar atrophy. This issomewhat less than the number of schizophrenicswith cortical atrophy. While two studies found nodifferences between schizophrenics and bipolars inthe degree of sulcal widening (96, 97), Pearlson andVeroff (98) found a sulcal widening to be relativelymore common in schizophrenics. However, bothschizophrenics and bipolars showed more sulcalwidening than controls. Only Nasrallah et al. (99)reported significantly greater cerebellar atrophy in

bipolars than schizophrenics; indeed, this finding isnotable in that it is the only type of structuralbrain abnormality found in any CT study to berelatively more apparent in bipolars thanschizophrenics. The mean prevalence rate of cere-bellar atrophy in the three studies that comparedbipolar patients to controls was 15.3% in bipolarpatients, while the mean prevalence rate forschizophrenics was 7.6% (97, 99, 100). While themethods of determining abnormality differ widelybetween studies, these findings nevertheless suggesta high degree of overlap between CT measures ofstructural anatomical abnormality in bipolars andschizophrenics.

Furthermore, in a quantitative review of thestructural neuroimaging literature (primarily CTstudies) in the major psychoses, Raz and Raz (101)found the mean effect size for the difference in sizeof lateral ventricles between patients with affectivedisorders and controls to be 0.55 (SD=0.43).They found no relation between effect size and

126

Ta

ble4c

.Compu

terize

d

tomo

grap

hy

(CT)scana

bnorma

lities:cere

be

llarverm

is

atrop

hy

Patients

withaffectivedisorders



Study

n

%

Abnormal

n

%

Abnormal

n

%

Abnorm

al

Comments

Nasrallahetal.,

Cerebellaratrophysignificantlygreater

inBP(butnotSCZ)patients

15BP

27

43

12

36NL

3

1981(99)

thanincontrols

Riederetal.,

NosignificantdifferencesamongSCZ,

SZA,andBPpatients

19BP

10.5

28

7.1

15SZA

6.7

1983(97)

Yatesetal.,

24BP

8.3

108

3.7

74NL

2.7

NoBPpatientsB50yearshadcerebe

llaratrophyvs.

two/fiveBP

1987(100)

patients\

50yearsvs.zeroNL,

UP

,orSCZpatientsover50

years

26UP

0

BP=

bipolar;NL=

normal;SCZ=

schizophrenic;SZA=

schizoaffective;UP=

unipolar.


22/45


Table 4d. Computerized tomography (CT) scan abnormalities: other CT findings

Study Patients with Other control Findings

affective disorders subjects

Schlegel and Affective disorder patients had significantly greater third ventricle22 BP, 33 UP, 5 60 NL

SZAKretschmar, 1987 (90) width than controls; no significant differences in third ventricle

width when BP patients alone compared to controls; BP

patients had significantly greater density than controls in left cau-

date/thalamus, left frontal and parietal gray matter, right parietal

white matter and right occipital region

Schlegel and Frontal horn distance/bicaudate distance abnormally large in21 BP, 27 UP, 5 60 NLKretschmar, 1987 SZA affective patients, especially older and psychotic pts

(150)

BP patients had significantly greater third ventricle width and26 BPDewan et al., 1988 22 HA

(172) significantly greater cortical density in right temporal lobe, anterior

white matter, and diencephalic nuclei. No correlation between in-

creased density and neuropsychological test performance, family

history, psychotic symptoms, or lithium response

Iacono et al., 1988 No significant differences in third ventricle width between BP18 BP, 16 UP 30 medical

(103) controls, 44 NL group and either control group; UP group had significantly wider

third ventricles than medical controls only.

Andreasen et al., 1990 24 BP, 27 UP 110 SCZ, 75 NL After controlling for age, ventricular enlargement present only in

(197) male BP group; no correlation between clinical variables and ven-

triculomegaly

BP=bipolar; UP=unipolar; SZA=schizoaffective; NL=normal; HA=headache patients; SCZ=schizophrenic.

sample size. The mean effect size for lateral ven-triculomegaly in affective disorder was determinedto be smaller, although not significantly smaller,than that obtained for schizophrenia. (0.70, SD=0.54). Third ventricle dilation was investigated inmood disorder in three studies: Schlegel and Kret-zschmar (90) obtained an effect size of 0.51, De-wan et al. (102) of 0.49, while Iacono andcolleagues (103) reported a negligible effect of 0.02. The first two studies used older and morechronic patients, which could account for this dif-

ference. The mean effect size for global corticalatrophy (as measured by dilation of corticalfissures and sulci) in seven studies of patients withmood disorders was 0.42 (SD=0.25), very close tothat obtained for studies of schizophrenia. (0.35,SD=0.34). In this review (101), measures of sulcalprominence yielded significantly smaller effectsthan measures of ventricular volume for bothmood disorder and schizophrenia (the mean effectsize for global sulcal dilation corresponded to anapproximately 25 28% overlap between patientsand controls). However, the poor gray/white mat-ter resolution of CT may contribute to error vari-ance, making this a less reliable measure thanventricle size. From this review, Raz and Raz (101)conclude that CT measures are unable to distin-guish schizophrenia from mood disorders. A laterreview (104) that incorporated findings from 10additional studies found a moderate composite ef-fect when comparing affective disorder patients tocontrols of 0.44 for lateral ventricles, and 0.42 for

cortical sulci; although there was less ventricularenlargement in affective disorder patients thanschizophrenics, the difference in effect sizes wassmall, suggesting that this type of structural brainanomaly is relatively nonspecific with regard todiagnosis.

MRI studies

White matter hyperintensities. T2 weighted MRIimages allow for the detection of tissue abnormali-

ties in the form of regions of greater signal inten-sity, or hyperintensities. The presence of suchsignal hyperintensities reflects a change of watercontent in the brain. Also referred to as leuko-araiosis or lesions, they are usually not present inhealthy persons under 45 years of age. Their pres-ence is known to increase with age and with theexistence of comorbid medical conditions (105107). In particular, their presence has been associ-ated with hypertension, carotid arteriosclerosis,and dilated perivascular spaces, and may indicatean underlying ischemia process (106, 108).

Recently, many studies have found higher ratesof hyperintensities in bipolar patients of all ages,particularly in periventricular white matter, sub-cortical gray matter and deep white matter brainregions. Table 5 summarizes the findings of MRIstudies comparing bipolar patients to normal con-trol subjects in the presence of signal hyperintensi-ties. Effect sizes were calculated using both anodds ratio (109) and r (110).

127


23/45

Bearden et al.

128

Ta

ble5

.Studieso

fT2hyperin

tens

ities

inbipo

larpa

tien

tsa

Bip

olarpatients(n=

242)

Comparisons

ubjects(n=

338)

Prese

nceofT2lesions

Hyperintensities

locatedin:

Study(year)

n

Meanage

SD

n

Meanage

SD

Deepwhite

Slicethickness

Odds

ratio

Effectsize(r)

Whitematter

Graymatter

(mm)

matter

Dupontetal.,

+

19

36.5

10

10

41

10

5

19

0.5

7

1990(192)

Swayzeetal.,

+

48

33.9

47

34.4

10

1.94

0.1

9

+

+

1990(118)

Figieletal.,

1991

+

18

37.5

18

34.7

5

13.6

0.3

9

+

(115)

McDonaldetal.,

+

12

68.3

7

12

68.7

7

5

9.3

0.5

2

+

+

1991(124)

Brownetal.,

1992

+

22

37.7

7.6

154

34

9.5

7

0.56

0.2

+

(112)

Strakowskietal.,

+

18

31

11.8

15

32.4

8.8

5

1.9

0.2

5

+

1993(122)

Aylwardetal.,

+

32

39.3

1.1

31

37.6

9.0

5

15.71

0.4

+

+

1994(113)

Altshuleretal.,

+

29

41.6

11.6

20

35.2

9.9

10

2.9

0.3

2

+

+

1995b

(106)

Dupontetal.,

+

36

36.6

10.8

26

39.1

9.4

5

2.98

0.2

2

+

1995(120)

Botteronetal.,

+

8

11.3

3.1

5

11.8

2.9

5

4.23

0.1

6

+

+

1995(123)

Krabbendam

etal.,

+

21

47.7

8.3

22

41.4

11.3

5

**

**

2000c

(19)

Meanacrossstud-

23.9

38.3

7.9

32.7

37.3

8.6

6.1

7.2

0.2

8

ies

+

=

assessed;includedin

overallT2abnormalityestimateinstudy.

aTableupdatedfrom

Altsh

uleretal,1995(106).

bBipolarIpatients.

cTwelvewithpsychoticfea

tures,

10without.

**Couldnotbecalculated

from

datapresented.


24/45


Because of differences in study groups andmethodology, there is a wide range in frequency ofT2 hyperintensities found in both patients (5 62%)and normal control groups (0 42%). However, inall but one study, the odds ratio is in the samedirection. The mean effect size of 0.28 indicates amoderate overall effect. Moreover, the test forheterogeneity of effect sizes (110) did not revealsignificant differences between effect sizes, indicat-

ing little variability across studies, and the overalleffect size, calculated using the Stouffer method(110), was shown to be highly significant (p=0.0001). A recent meta-analysis (111) reported asimilar result, finding a common odds ratio of 3.29(95% CI=2.14 5.07) across studies of white mat-ter hyperintensities in bipolar patients.

The only study that did not find an increasedprevalence of white matter hyperintensities in bipo-lar subjects compared to controls (112) neverthe-less did find increased severity of deep white matterhyperintensities in unipolar depressed patients.This study differed from the others in two ways: 1)

they recruited a large number of patients with awide variety of psychiatric diagnoses from newspa-per advertisements, resulting in potential samplingbias, and 2) subjects were tested in two differentscanners (one 0.5 T and the other 1.5 T), whichmay contribute to some ambiguity in the findings.

Two studies found the increased incidence ofwhite matter hyperintensities only in older bipolarpatients, while younger patients were no morelikely than controls to display such abnormalities(106, 113). Another found increased volume ofabnormal white matter to be associated with laterage of onset in bipolars, but found no age differ-

ences at the time of testing between subjects withhigh and low volumes of abnormal white matter(114). While Hickie et al. (107) also found thepresence of white matter hyperintensities to beassociated with later age of onset in bipolar pa-tients, they also reported a strong correlation be-tween increased age and the extent of white matterhyperintensities. Aylward et al. (113) did not findthe presence of white matter hyperintensities to berelated to history of psychosis, number of previoushospitalizations, or lithium treatment.

While increased age may be related to the pres-ence of increased white matter hyperintensities inbipolar patients, medical risk factors do not appearto be a cause of such abnormalities. Two studiesthat examined the effects of medical risk factors(e.g., high blood pressure, vascular disease) foundthat, after excluding bipolar patients with such riskfactors from the analysis, bipolars were still signi

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