Bipolar Disorders 2001: 3: 106150 Printed in Ireland.

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Review Article

The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review

Bearden CE, Hoffman KM, Cannon TD. The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. Bipolar Disord 2001: 3: 106 150. Munksgaard, 2001 Objecti7es: To present a comprehensive review of the existing neuropsychological and neuroimaging literature on bipolar affective disorder. This review critically evaluates two common conceptions regarding the neuropsychology of bipolar disorder: 1) that, in contrast to schizophrenia, bipolar affective disorder is not associated with general cognitive impairment independent of illness episodes, and 2) relative right hemisphere (RH) dysfunction is implicated in bipolar illness patients, supported by reports of relatively greater impairment in visuospatial functioning, 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 review of the literature on the neuropsychology and neuroanatomy of bipolar disorder. Articles meeting specied criteria were included in this review. Results: In a critical evaluation of the above notions, this paper determines that: 1) while there is little evidence for selective RH dysfunction, signicant cognitive impairment may be present in bipolar illness, particularly in a subgroup of chronic, elderly or multiple-episode patients, suggesting a possible toxic disease process, and 2) the underlying functional correlate of these cognitive decits may be white matter lesions (signal hyperintensities) in the frontal lobes and basal ganglia, regions critical for executive function, attention, speeded information processing, learning and memory, and affect regulation. While this hypothesized neural correlate of cognitive impairment in bipolar disorder is speculative, preliminary functional neuroimaging evidence supports the notion of frontal and subcortical hypometabolism in bipolar illness. Conclusions: The etiology of the structural brain abnormalities commonly seen in bipolar illness, and their corresponding functional decits, remains unknown. It is possible that neurodevelopmental anomalies may play a role, and it remains to be determined whether there is also some pathophysiological progression that occurs with repeated illness episodes. More research is needed on rst-episode patients, relatives of bipolar probands, and within prospective longitudinal paradigms in order to isolate disease-specic impairments and genetic markers of neurocognitive function in bipolar disorder.

Carrie E Beardena, Kathleen M Hoffmanb and Tyrone D Cannonc

a

Department of Psychiatry, University of Pennsylvania, b The Childrens Hospital of Philadelphia, Philadelphia, PA, and c 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 2291715; e-mail: bearden@psych.upenn.edu

There is no doubt that depression and mania affect the ability to think, concentrate, reason, and remember. The nature and extent of such changes, however, is less clear, and their specicity to mood disorder, their existence before the onset of affective symptoms, their etiology, and their relation106

ship to underlying neuroanatomical abnormalities remain poorly understood. Historically, two common conceptions regarding the neuropsychology of bipolar disorder have been that: 1) in contrast to schizophrenia, bipolar affective disorder is not associated with general cogni-

Neuropsychology of bipolar disorder

tive impairment independent of illness episodes, or in the premorbid state (1), and 2) relative right hemisphere (RH) dysfunction is implicated in bipolar illness, supported by reports of relatively greater impairment in visuospatial functioning, anomalous lateralization of function, and mania secondary to RH lesions (2, 3). In an attempt to critically evaluate these notions, this paper will attempt to answer the following questions: 1. Are there stable neuropsychological decits in bipolar illness that exist independently of clinical state? 2. Do bipolar patients exhibit selective impairments in specic domains, or do they demonstrate a more diffuse cognitive impairment? 3. What are the most consistently reported structural brain abnormalities? Are these abnormalities characteristic of bipolar disorder in general, or only characteristic of particular subgroups of patients (e.g., severe, chronic, or elderly)? 4. Are there neuropsychological decits and/or structural and functional brain abnormalities that are unique to bipolar disorder? 5. What is the possible etiology of the neuropsychological and neuroanatomical abnormalities? In answering these questions, this paper will attempt to present a unied model of the potential neuroanatomical substrates for the pattern of cognitive impairment seen in bipolar disorder, utilizing evidence from neuropsychological studies, structural and functional neuroimaging data, neuropathological ndings, and secondary affective disorders. The methods used for study inclusion are described in the Appendix.
The abnormal laterality/RH dysfunction hypothesis

brain imaging techniques, and the increasing relevance of cognitive impairments for treatment and rehabilitation in psychiatric disorders, it is particularly important to gain an understanding of the nature of the neuropsychological function of bipolar affective patients (4). One of the questions this paper will attempt to answer is whether it is indeed sensible to examine a disorder that is by nature cyclical and episodic from the perspective of more enduring structural abnormalities and corresponding functional manifestations of such abnormalities. VIQ and PIQ. The increase in the number of investigations of cognition in relation to affective disorder has been stimulated to a large degree by the hypothesis, rst fully formulated by FlorHenry and Yeudal (5), that affective disorder is associated with RH dysfunction. Indeed, many reported ndings have consistently shown an association between cognitive functions thought to be linked to the right, or non-dominant, hemisphere and disorders of mood (2, 6 8). Support for the notion of RH dysfunction, or abnormal lateralization of function, in bipolar disorder was generated largely by early studies of Wechsler IQ scores in bipolar patients, which often reported relatively lower PIQ than VIQ in bipolar patients (6, 9). Although the ndings are not unanimous, the majority of such studies suggest that bipolar patients indeed show a pattern similar to the one produced by lateralized RH lesions, thus leading to the conclusion of the presence of predominant RH dysfunction in bipolar illness (10, 11). Table 1 presents the results of studies of IQ in bipolar disorder. As Table 1 demonstrates, bipolar patients on average do indeed display a relatively higher VIQ than PIQ. However, examining the absolute scores reveals that the mean VIQ among these samples of bipolar subjects is above average (102.8), and the mean PIQ of 96.7 is still well within the normal range (100 915) (12). While the mean V PIQ discrepancy is slightly greater among this sample of bipolar patients than controls, this discrepancy is still quite small (6 points). Further, the majority of these studies did not describe the patients clinical state at the time of testing; thus, it is unclear what effects clinical symptomatology may have potentially had on IQ performance. Kluger and Goldberg (11) have suggested an alternative explanation for the ndings of decreased PIQ in bipolar disorder. Because the RH has greater ability to perform novel, not yet routinized, tasks, RH damage will selectively interfere with the ability to process novel information. However, this ability could also be more severely 107

Support for this hypothesis has been drawn from three general lines of research: 1) neuropsychological studies that reported lower Performance IQ (PIQ) than Verbal IQ (VIQ) scores in bipolar patients, or relative impairment in visuospatial functioning, 2) studies of lateralization of function (dichotic listening tasks, handedness and laterality of grip strength, and emotional discrimination tasks), and 3) studies of secondary affective disorders caused by lesion or stroke, in which RH lesions are reported to result in manic symptoms. Each of these areas will be reviewed in turn in an effort to critically evaluate this hypothesis.
Cognitive function in bipolar disorder

Because of the increasing role for neuropsychological tests as cognitive tasks used in conjunction with

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Patients Mean V-IQ 109.2 117.2 87.29 101.75 108.74 111.97 103.8 95.33 112.3 97.47 88.7 99.9 102.8 9.50 96.7 13.9 94.4 12.3 10.18 14.0 82.9 9.9 5.8 5.5 6.08 (SD =4.07) 9.66 93.65 14.65 3.82 11.9 109.1 13.4 3.2 52 normal controls 30 schizophrenic in-patients 34 normal controls Total n=137 10.98 84.8 14.93 10.53 9.5 93.4 9.8 10.4 21 normal controls 14.98 107.15 15.73 4.82 93.38 107.23 92.6 104.5 99.43 14.31 101.82 14.98 6.92 88.5 13.25 10.65 9.02 13.9 15.2 7.52 15.9 88.64 13.4 1.35 115.2 2 99 106.94 83.6 101.7 97.8 101.1 8.1 SD Mean P-IQ SD Mean V-P IQ discrepancy Control subjects Mean V-IQ SD Mean P-IQ SD Mean V-P IQ discrepancy 10.81 11.67 12.8 12.1 10.03 0.62 0.29 9.0 2.8 2.87 (SD=4.34) 16 BP manic 21 BP depressed 60 psychotic BP 43 BP manic 34 BP+UP depressed Patients at remissiona 25 BP manic 15 BP 26 BP 30 BP 35 BP manic in-patients 20 BP Total n= 325

Bearden et al.

Table 1. Wechsler IQ scores in bipolar patients versus controls

Study

Waldfogel and Guy, 1951 (193)

Flor-Henry and Yeudall, 1979 (5)

Abrams et al., 1981 (14)

Donnelly et al., 1982 (40)

Flor-Henry, 1983 (2)

Dalby and Williams, 1986 (9)

Dewan et al., 1988 (172)

Coffman et al., 1990 (20)

Hoff et al., 1990 (22)

Morice, 1990 (30)

Overall

BP= bipolar; UP=unipolar. a Signicantly higher scores at remission.

Table 2a. Results of studies comparing bipolar disorder and control groups on tests of attention and vigilance Bipolar patients (mixed/unspec. mood state) 71/7a 23/30 79/11 55/50; 31/22; 71/7 42/20 14/43; 5/29; 190/11 14/9; 5/31 32/100 79/12 79/12 5/54; 31/46; 32/100; 14/17; 190;38 18/26; 16/36 32/100 32/100; 31/46; 5/54 79/10 14/8 Bipolar euthymic Bipolar depressed Bipolar manic Unipolar depressed Mixed/Unspec. Affective Dx Schizophrenics Medical/Other controls*

Task

Normal controls

CPT

23/14; 71/7a

Perceptual span

Digit Spans Regular/Reverse

190/16; 5/46; 42/20; 71/7; 31/26 18/19 71/7; 31/22 24/11; 25/25 5/29 24/21; 5/31 16/9 16/12

Recurring

16/29; 18/27

Trailmaking Part A

71/7; 24/19; 31/26; 25/22; 5/46 71/7; 114/20; 17/16; 31/22 24/11; 25/25; 44/16 5/29 44/10; 17/29; 88/21; 5/31

Trailmaking Part B

25/22; 71/7; 31/26; 24/19; 114/10; 5/46

32/100

32/100; 17/57; 88/28; 31/46; 5/24 32/100 32/100 190/38 32/100 32/100 24/21 19/22

Digit Cancellation 190/11

Shape Cancellation

190/16

Divided Attention 55/50 19/21; 25/25; 24/11 19/21

Stroop

19/22; 24/19; 25/22

Letter-Digit substitution

19/22

19/22

Neuropsychology of bipolar disorder

Black text: Results within normal limits. Green text: No differences between patient groups. Blue text: Performance signicantly poorer than controls. Red text: Performance signicantly poorer than other patient groups. Values represent study reference/number of subjects. a BPs were discordant twin pairs; NCs were normal twin pairs *Includes patients with Huntingtons Disease, Organic Brain Disease, Alzheimers Disease, Alcohol Abuse or Antisocial Personality Disorder.

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Bipolar patients (mixed/unspec. mood state) 31/22 14/43; 9/15 14/9 Bipolar euthymic Bipolar depressed Bipolar manic Unipolar depressed Mixed/Unspec. Affective Dx Schizophrenics Medical/Other Controls* 31/46; 14/17; 9/30 17/57 9/45; 14/8 40/35 26/15 17/16 26/11; 17/29; 40/29 5/31 32/100 22/30; 5/29 5/54; 32/100; 22/30 27/954 71/7a; 29/10; 20/30 25/25 17/16 42/20 71/7a 17/29 32/100 17/57; 32/100; 29/30 20/30 19/21 19/22

Bearden et al.

Table 2b. Results of studies comparing bipolar and control groups on tasks of abstraction, problem solving and executive function

Task

Normal controls

Arithmetic

9/21; 31/26

Halstead Category Test

26/14; 40/49

Ravens Progressive Matrices

5/46

Shipley Abstraction

27/98

Wisconsin Card Sort

71/7a; 20/52; 25/22

Gestalt Completion

42/20

Wechsler Mental Control

71/7a

Verbal Concept Formation

20/52

Concept-shifting Test

19/22

Legend as for Table 2a.

Table 2c. Results of studies comparing bipolar and control groups on tests of verbal ability/skill Bipolar patients (mixed/unspec. mood state) 5/29 5/31 3/105 5/54; 3/22 Bipolar euthymic Bipolar depressed Bipolar manic Unipolar depressed Mixed/Unspec. Affective Dx Schizophrenics Medical/Other Controls*

Task

Normal controls

Aphasia Screening Test 71/7a

5/46; 3/99

Boston Naming Test 192/20; 31/22 14/43 14/9

71/7a

Vocabulary (WAIS-R) 31/22 14/43 14/9 4/30

31/26; 192/10

14/17; 31/46

14/8

Similarities (WAIS-R) 14/43 14/9

31/26; 4/41

14/17; 31/46

14/8

Information (WAIS-R) 18/19; 20/30 19/21 21/12 16/9; 5/29

14/17

14/8

Verbal uency

19/22; 18/27; 20/52; 16/29; 21/20; 4/41; 5/46 71/7a; 192/20; 31/22 25/25

5/31; 16/12; 21/20

4/30

5/54; 16/36; 19/22

21/10

Controlled OralWord Association Test 192/20; 31/22

25/22; 71/7a; 192/10; 31/26

31/46

Confrontation Naming Test 44/16 71/7; 17/16 18/19

192/10; 31/26

31/46

Synonym Test

44/10 9/15 17/29 9/30; 17/57 18/26 9/45

WRAT-R (Reading)

9/21; 71/7

National Adult Reading Test 31/22

18/27

Writing speed/ production

31/26

31/46

Neuropsychology of bipolar disorder

Legend as for Table 2a.

111

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Bipolar patients (mixed/unspec. mood state) 16/9; 22/30 19/21 21/12 21/20 16/12 Bipolar euthymic Bipolar depressed Bipolar manic Unipolar depressed Mixed/Unspec. Affective Dx Schizophrenics Medical/Other Controls* 22/30; 16/36 19/22 21/10 5/29 60/14 24/11 192/20; 71/7a 25/25; 62/31 24/21 60/14 5/31 5/54 18/19; 20/30; 17/16 9/15 17/29 17/57; 9/30; 18/26 9/45 71/7a; 55/50; 17/16 71/7a 22/30 17/29 32/100 22/30; 32/100; 17/57 14/43 14/9 14/17 14/8

Bearden et al.

Table 2d. Results of studies comparing bipolar and control groups on tests of verbal memory

Task

Normal controls

Associate Learning

16/29

List Recall Rey Auditory

21/20; 19/22

Williams

5/46

Animal names

60/14

CERAD Trial 1

24/19

California Verbal Learning Test (CVLT)

71/7a; 192/10; 62/18; 25/22

Verbal memory (Wechsler Memory Scale)

18/27; 20/52; 9/21

Story Memory

71/7a

Brown-Peterson Verbal Memory

71/7a

Benton Sentence repetition

Legend as for Table 2a.

Table 2e. Results of studies comparing bipolar and control groups on tests of non-verbal and visual memory Bipolar patients (mixed/unspec. mood state) 42/20 22/30; 14/43 14/9 14/17; 22/30 Bipolar euthymic Bipolar depressed Bipolar manic Unipolar depressed Mixed/Unspec. Affective Dx Schizophrenics Medical/Other Controls*

Task

Normal controls

Benton Visual Retention 20/30; 71/7a; 17/16 17/29 17/57

42/20

14/8

Design Memory Wechsler (Visual Reproduction 5/29 25/25 5/31

20/52; 71/7a

Graham-Kendall

5/46

5/54

Rey-Osterreith delayed recall 60/14 18/19 16/9 16/12

25/22

Complex designs

60/14

60/14 18/26; 16/36

Corsi block tapping 5/29 5/31

16/29; 18/27

Tactual Performance Memory 16/9

5/46

5/54

Spatial Associate Learning Test 62/31

16/29

16/12

16/36

Star Mirror Tracingb 62/31

62/18

Pursuit Rotorb

62/18

Seashore Speech Sounds 17/16; 71/7 42/20

5/46

5/29

5/31

5/54

Face recall

42/20; 71/7a

17/29 4/30

17/57

Visual retention (pictures)

4/41

Neuropsychology of bipolar disorder

Legend as for Table 2a. b Procedural memory task.

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Bipolar patients (mixed/unspec. mood state) 192/20; 71/7a; 17/16 17/29 17/57 14/43; 22/30 14/9 Bipolar euthymic Bipolar depressed Bipolar manic Unipolar depressed Mixed/Unspec. Affective Dx Schizophrenics 14/17; 22/30 14/8 22/30; 5/29 5/31 32/100 32/100; 22/30; 5/54 5/54 5/29 71/7a 25/25 192/20 25/25; 42/20 40/56; 14/43 40/40; 14/9 4/30 14/17 14/8 5/31 192/20; 31/22 24/11 40/56; 14/43 40/40; 14/9; 24/21 40/40; 14/9 14/17; 31/46 14/8 40/56; 14/43 14/17 14/8 14/43 14/9 4/30 14/17 14/8 4/30 34/16 34/18 34/18 4/30 3/105 3/22 22/30 22/30

Table 2f. Results of studies comparing bipolar and control groups on tests of visuospatial and visuomotor skill Medical/Other Controls*

Bearden et al.

Task

Normal controls

Line Orientation

192/10; 71/7a

Hooper Visual Organization

Ravens Progressive Matrices

5/46

Tactual Formboard

5/46

Rey Figure Copy

71/7a; 25/22

Embedded Figures

192/10

Block Design (WASI-R)

25/22; 42/20; 4/41

Digit Symbol (WAIS-R)

192/10; 24/19; 31/26

Object Assembly (WAIS-R)

Picture Completion (WAIS-R)

4/41

Picture Arrangement (WAIS-R)

4/41

Gibson Spiral Maze

Visual Recognition Task

4/41

Aphasia Screening Motor/perceptual

3/99

Symbol Digit Modalities Test

Legend as for Table 2a.

Neuropsychology of bipolar disorder

Table 2g. Results of studies comparing bipolar and control groups on tests of motor-speed/performance

Bipolar patients (mixed/unspec. mood state)

disrupted following diffuse bilateral central nervous system (CNS) damage. Thus, bilateral, diffuse damage will affect performance on tests sensitive to RH functions more than it will affect performance on tests sensitive to left hemisphere (LH) functions. Furthermore, PIQ tasks are more dependent on speed, which would be affected by a bilateral lesion, as well as the psychomotor retardation associated with depressed mood state, thereby resulting in a greater decrement in PIQ than in VIQ. In a meta-analysis of 38 WAIS and Wechsler Bellevue studies, consisting of 22 affective disorder groups (14 bipolar and unipolar depressed, 4 manic, 4 mixed) in 14 studies, 30 bilateral/diffuse brain-damage (BI) groups in 23 studies, 20 RH damage groups in 18 studies, and 20 LH damage groups in 18 studies (with damage due to tumor, vascular event, head trauma, epilepsy, infectious/degenerative disease, or dementia), Kluger and Goldberg (11) determined that 19 of 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 the Affective Disorder groups were one depressed group and two mixed groups), while 15 of 20 LH groups had lower VIQ than PIQ. While the PIQ/ VIQ ratio was almost identical for the Affective Disorder group and BI groups, this ratio was signicantly lower for the RH group. The absolute mean values of PIQ for Affective Disorder groups overall was 99.21, and the mean VIQ was 103.65, which is quite similar to the mean scores obtained here from studies of predominantly bipolar patients alone (see Table 1). Thus, these investigators found that the test prole for affective patients was signicantly closer to that of the BI group than to the RH prole, suggesting that there may be bilateral, diffuse cerebral involvement in affective disorders, rather than a predominantly RH dysfunction. Neuropsychological test batteries. More recent studies have explored the notion of selective decits in cognitive function with more comprehensive neuropsychological batteries geared at testing specic domains of cognitive function. Tables 2a g present the results of studies comparing bipolar subjects to normal controls, as well as other patient groups, on individual neuropsychological tests, categorized by domain of function. As Tables 2a g show, evidence of some degree of cognitive dysfunction in bipolar disorder is more apparent in studies employing neuropsychological batteries, rather than general intelligence tests. This is unsurprising, given that clinical neuropsychological batteries sample a greater variety of sensorimotor and cognitive skills than those 115

Schizophrenics

Medical/Other Controls*

5/54; 22/30

5/54; 22/30

5/54

Unipolar depressed

Mixed/Unspec. Affective Dx

5/54

5/54

5/31

5/31

5/29; 22/30

5/31

Bipolar manic

5/29; 22/30

5/31

5/31

Bipolar depressed

20/30

Normal controls

5/46; 20/52

5/46; 20/52

20/30

5/29

5/29

5/29

5/46

5/46

5/46

5/46 Non-dominant

5/29 Legend as for Table 2a.

Finger tapping Dominant

Purdue Pegboard Dominant

Non-dominant

Non-dominant

Task

Dynamometer Dominant

5/31

5/54

Bearden et al.

encompassed by traditional IQ tests. If patients show particular areas of impairment, these will be highlighted by neuropsychological batteries that examine specic domains of cognitive function (13). Nevertheless, while bipolar patients exhibit impairment in comparison to normal controls on many neuropsychological tasks, they generally appear to exhibit relatively less severe impairment than schizophrenic patients and patients with other medical disorders such as Huntingtons disease (HD) and organic brain disease (14, 15). In the majority of studies comparing bipolars to schizophrenics, schizophrenic patients were found to exhibit relatively worse performance, particularly in domains of verbal function (16). Indeed, few studies have reported signicant differences between normal controls and bipolar subjects on measures of VIQ and verbal uency (9, 17 19). While one study found superiority of performance on VIQ measures in affectively ill subjects compared to non-psychiatric controls (4), this study was conducted in a prison, and the normal control subjects were male prisoners with no psychiatric diagnosis. They had lower Full-Scale IQs and less education than population norms, and thus are not a very representative sample. Only two studies have reported decreased verbal uency in bipolar patients compared to normal controls (20, 21). One of these (21) tested bipolar subjects in a depressed state, while the other (20) tested a sample of bipolar patients with denite psychotic features. Thus, both investigations employed fairly impaired subjects by virtue of current mood state or severity of illness. Upon examining the qualitative ndings, neither of these investigations found bipolar subjects to be decient in the number of responses generated; rather, they generated more incorrect responses (e.g., perseverative responses), a nding that does not reect decreased uency per se, but perhaps diminished ability to follow task instructions. While studies that have included measures of attention and concentration have frequently shown attentional decits in bipolar patients (5, 10, 17, 22, 23), little is known about attentional function across different phases of illness. In general, studies showing attentional decits in bipolar disorder have examined patients that were symptomatic at time of testing (22, 23). Tasks of selective attention, such as the Stroop Color-Word Test, appear to be preserved in euthymic bipolar patients (24, 25). With regard to visuospatial impairments in bipolar illness, impairments generally do not appear to manifest in simpler visuospatial tasks such as Judg116

ment of Line Orientation, but are more reliably demonstrated on tasks of complex non-verbal memory or conceptualization skills, such as the Halstead Category Test, in which subjects must arrive at an organizing principle which differentiates one visual stimuli in a set (26, 27) and Ravens Progressive Matrices, a task of visuospatial pattern completion and abstract reasoning (2). This pattern of decit is not consistent with a hypothesis of localized RH dysfunction, but implicates dysfunction of integrated neuroanatomical systems, including frontal-executive, attentional, and memory functions (28). Bipolar disorder 6ersus other psychiatric disorders. Schizophrenic patients have often been found to exhibit more dysfunction than affectively ill patients in tasks attributed to frontal lobe (executive) function: a neuropsychological study of 30 schizophrenic and 10 manic patients found no differences between schizophrenics and manic patients in the degree of dominant and non-dominant hemisphere dysfunction, but schizophrenics exhibited signicantly more frontal lobe dysfunction (e.g., Shipley Abstraction, Wisconsin Card Sort) than bipolars after controlling for demographic variables (29). Goldberg et al. (17) found the greatest degree of overlap between schizophrenic and bipolar patients to be in the domain of non-verbal and visuospatial memory; they found that schizophrenics performed signicantly below affective disorder subjects on every test except Trailmaking B and Facial Recognition, while there were virtually no differences in performance between bipolar and unipolar subjects. The group overlap between schizophrenia and affective disorder was least for IQ, memory, and problem solving; however, there was substantially greater overlap for visuospatial measures. Nevertheless, some studies have reported a similar degree of impairment in adult schizophrenic and affectively ill patients: Morice (30) found no difference in Wisconsin Card Sort performance between bipolar manic and schizophrenic patients, suggesting cognitive inexibility and prefrontal cortical dysfunction may not be specic to schizophrenia. Hoff et al. (22) also failed to differentiate between schizophrenics and bipolar patients in the acute manic phase of illness on any measure of neuropsychological function, after controlling for the effects of age, sex, education, duration and severity of illness, and medication status. Further, these investigators did not nd distinctive patterns of lateralized decit; only medication status was related to poorer performance on some motor tasks, regardless of diagnosis (22).

Neuropsychology of bipolar disorder

In general, when symptomatic, cognitive abilities in bipolar patients appear to more closely resemble those of schizophrenic patients. Hawkins et al. (31) found that a sample of bipolar patients exhibiting mild levels of depression and no psychotic symptoms at testing performed better than schizophrenic patients on all neurocognitive measures, and not signicantly different from normal controls. However, the weakest performance of both patient groups was found in tests of speeded visual-motor sequencing (Digit Symbol/Trailmaking). These are tasks that require the smooth integration of multiple processes and, while highly sensitive to brain dysfunction, lack precise localizing signicance. Similarly, Zihl et al. (32) found those patients with schizophrenia and affective dis order to display a similar degree of cognitive decit, especially in tasks of attention and problem solving, suggesting that this pattern of cognitive decit may reect a nal common pathway disorder in the two patient groups. Disparate ndings across studies are thus likely to be a function of varying symptomatic state of the patient groups at the time of testing and small sample sizes. Bipolar 6ersus unipolar depression. An early review by Miller (1) concluded that bipolar and unipolar psychotic illnesses are both associated with impairment of serial learning. However, when studies used other psychiatric groups for comparison, Miller concluded that no impairment could be found which was unique to depression. Miller also noted that severe depression is often associated with a marked degree of impairment, similar to that exhibited by schizophrenics. Neuropsychological decit may be a function of severity of psychopathology, in that increasing psychopathology may correlate with decreasing motivation to perform well on experimental tasks. One reason these decits may not be specic or unique to bipolar disorder is because they are due to some common feature shared by different forms of psychopathology, such as impaired attention or insufcient motivation. Consistent with Millers (1) conclusions, the results of the neuropsychological studies presented here reveal that bipolar patients, in general, appear to differ little from unipolar depressed patients, both in terms of severity and pattern of impairment. Both unipolar and bipolar patients show impairments in verbal learning (21, 25), though one investigation found bipolar depressed patients to be more impaired than unipolar depressed patients on both verbal recall and recognition (21). Normal controls also showed more improvement over trials than all patient groups, suggesting that

decits in memory-encoding strategies may exist in the depressed state. Bipolar patients in this study also showed some impairment in a verbal uency task, while unipolar subjects did not. These ndings may reect the severity of disorder, as the bipolars in this study had twice the rate of hospitalization of unipolar depressed subjects. Consistent with this interpretation, Kessing (33) found no differences in global cognitive function between multiple-episode euthymic bipolar and unipolar patients, but that patients with recurrent episodes had signicantly more impairment than singleepisode patients. In contrast, Paradiso et al. (24) reported no signicant differences between euthymic bipolar patients and normal controls, while unipolar patients with comparable depression scores were signicantly impaired on measures of visual-motor sequencing (Trailmaking) and immediate memory and attention (Digit Symbol and List Learning). There is some evidence that unipolar depressed patients may exhibit more psychomotor slowing (34), but this is likely to be linked to mood state and severity of depression at time of testing. It is unclear whether bipolar patients in a comparably severe state of depression exhibit the same degree of psychomotor slowing. Further, psychomotor speed, as measured with tools such as Trailmaking, appears to normalize when patients are euthymic, suggesting psychomotor slowing may be state-dependent (25). Presently, comparisons between unipolar and bipolar patients are difcult to assess, due to the generally small sample sizes and the fact many studies grouped bipolar and unipolar patients together as an affective disorder group. Effects of clinical state at time of testing. While the results in Table 1 do not indicate a global intellectual decit in bipolar disorder, it is unclear whether this represents a signicant decline from the premorbid state. Some investigators have reported that bipolar illness is associated with intellectual deterioration that is at least as great as that found in schizophrenia. Payne (35) reported that the IQs of manic-depressives during periods of depression are lower than those of normal controls, and not signicantly different from the illness IQs of schizophrenics. Masons early report (36) that the premorbid IQs of bipolars were signicantly higher than those of normals, while those of schizophrenics were signicantly lower, would indicate that bipolar disorder involves greater intellectual deterioration at onset, or during the course of the disorder. Several early investigations reported increased Stanford Binet IQ scores following clinical improvement (37 39), suggesting that affective illness 117

Bearden et al.

may not lead to a permanent or progressive deterioration in intellectual functioning. Consistent with these data, Goldberg et al. (17) reported that, based on correlations between neuropsychological scores and clinical state at testing, psychiatric symptoms in schizophrenic patients accounted for less than 5% of variance in cognition, while in Affective Disorder groups, symptoms accounted for 30% of variance in cognition, suggesting cognitive abilities vary more with mood state in affective disorders than in schizophrenia. Only a few studies have employed a within-subjects design, in which the same patients were tested at different timepoints, in order to compare their performance in manic, depressed, and remitted states. These studies found evidence that the same patients, when in a hypomanic or euthymic state, have higher IQs than when depressed (40, 41). In the investigation of Donnelly et al. (40), this could not be attributed to practice effects, as the patients IQ scores decreased again when retested in the depressed state. Consistent with these ndings, Henry et al. (41) reported that bipolar patients in the manic state displayed decreased serial learning on a verbal learning task, relative to their own performance in a remitted mood state. However, they showed no impairment on short-term free recall, regardless of mood state, suggesting the experience of mania or depression may affect complex processing or memory functions, but not simpler tasks. Episode 6ersus inter-episode functioning. Only recently have investigators begun to focus on neurocognitive function in euthymic bipolar patients. While three such studies found little evidence of generalized cognitive impairment (24, 42, 43), there is nevertheless some evidence that euthymic bipolar patients exhibit limitations in some types of information-processing strategies (e.g., synthesizing multiple aspects of a stimulus) (42). Specically, euthymic patients were found to exhibit signicant impairment on a Gestalt completion task and had difculty recognizing masked faces. Given that these bipolar subjects displayed normal performance on Block Design, a task of visuoconstructive ability, and showed no increase in errors on left-sided (RH) visual eld presentations, these ndings are unlikely to represent specic RH dysfunction. Further, several recent investigations have reported signicantly lowered cognitive function in a substantial number of euthymic bipolar patients with longstanding illness (25, 44, 45). In addition, Atre-Vaidya and colleagues (45) found that euthymic bipolar patients with more negative fea118

tures, particularly anhedonia, showed more cognitive impairment. In this study, cognitive impairment was also associated with poorer psychosocial functioning. Conicting ndings in studies of euthymic or remitted patients are unsurprising, given discrepancies between studies regarding the criteria of remission, as well as different tests employed. Longitudinal studies including cognitive assessment prior to illness onset and later, during periods of illness and clinical remission, are needed to ascertain whether changes in intellectual function are due to treatment variables, genetic predisposition, or clinical state. Effect of psychotic features. Albus et al. (46) recently reported that, while rst-episode non-psychotic affective disorder patients performed similar to controls on cognitive measures, affective patients with psychotic features performed as poorly as rst-episode schizophrenics, suggesting that the presence or absence of psychotic features has more impact on neuropsychological function than diagnosis (46). Indeed, one of the few studies to nd evidence of severe and diffuse cognitive impairment in bipolar patients (20) examined a sample of 30 bipolar outpatients, all of whom had psychotic features and a long history of illness. While there was some suggestion of relatively greater RH impairment (i.e., bipolar patients performed signicantly worse than controls on non-verbal, but not verbal, memory), there was little evidence for strictly localized decits in these patients. Many studies have reported that bipolar patients with psychotic features are likely to have worse outcome and a more chronic, severe course of illness, suggesting that these patients may also experience greater deterioration in cognitive function over time (47 50). However, the specic effect of psychotic features on cognitive function in bipolar disorder has not been adequately examined. Effects of se6erity/chronicity of illness. There is a growing body of evidence that chronic, multipleepisode patients exhibit more severe cognitive impairments than younger patients or patients with a more remitting course of illness. McKay et al. (51) found that none of the young or elderly nonchronic bipolar patients scored in the impaired range on tests of memory, executive function, and overall intellectual function, as compared to 5 of 10 chronic, severe patients who had suffered from multiple episodes requiring many hospitalizations. On a more detailed neuropsychological evaluation, these ve patients showed a variable impairment pattern, ranging from isolated executive, visuospa-

Neuropsychology of bipolar disorder

tial and memory decits to widespread poor performance. The authors conclude from these ndings that in chronic severe patients, neuropsychological decits are not restricted to periods of affective illness, but instead reect enduring cognitive decits. In this study, 40% of the chronic patients had a rapid-cycling illness; as the effects of rapid cycling on cognitive function have not been investigated, it is unclear which aspect of illness may have contributed to their severe impairment. Supporting a hypothesis of an aggregate negative effect of lifetime duration of the illness on cognitive function, one recent study of euthymic bipolar patients with longstanding illness found that performance on several tests, including general intelligence, was negatively correlated with the number of hospitalization episodes (44), and another (25) found that the number of months of mania or depression that patients had experienced during the course of illness was signicantly negatively correlated with performance. Denicoff et al. (52) recently reported that several different measures of a more severe course of prior illness (number of episodes, longer duration of illness, more hospitalizations) were related to poorer performance on tasks of memory, attention and abstraction. Further, only one study (33) has attempted to tease apart the separate effects of number of episodes versus duration of illness. This study found a signicant linear association between two measures of global cognitive function and number of episodes, but no association between total duration of illness and cognitive measures. Moreover, further analysis revealed that it was the number of depressive episodes, not manic or mixed episodes, that correlated with cognitive decline. Thus, although generally undemented and asymptomatic, patients in these studies still displayed substantial inter-episode cognitive impairment and likely deterioration from previous levels of functioning. One of the few studies to conduct a longitudinal assessment of bipolar patients (53) also found some evidence for cognitive deterioration over the course of the disorder: in a follow-up assessment of 25 bipolar patients initially hospitalized for mania with no signs of cognitive impairment, one-third of these patients were found to show signicant cognitive impairment 5 7 years later. Savard et al. (26) reported that older bipolar patients had signicantly more errors on the Halstead Category Test, a test of non-verbal conceptual ability, and that the degree of cognitive decit was more uniform among older bipolar subjects. At retest (upon remission), the error scores of the younger bipolar patients were within the normal range, but the

older bipolar patients still showed signicant impairment in the recovered state. Because this study (26) did not report the severity of illness of these older patients, it is unclear whether their continued impairment in the euthymic state was related to their advanced age or the chronicity and severity of the disorder. These ndings suggest that there may be enduring cognitive impairment in some bipolar patients, even after remission of an affective episode, and that these decits may worsen with time. Altshuler (54) has posited that cognitive impairment in bipolar disorder may result from repeated episodes of illness. That is, episodes of mania and depression may cause destructive damage to brain tissue, with a functional correlate of such damage being persistent cognitive decits in the euthymic period, particularly in learning and memory functions. Because very few follow-up studies of cognitive function in bipolar disorder have been conducted, none of which have tested large numbers of subjects, this hypothesis awaits further testing. Effects of medication status. It is possible that cognitive impairment in bipolar disorder may be due, not to the illness itself, but to effects of long-term psychotropic medication. Lund et al. (55) examined the long-term effects of lithium treatment and found chronic bipolar patients (stabilized on lithium) to be in the low average range on functions of attention and memory, based on population norms. Thus, while long-term lithium treatment does not appear to substantially effect cognitive function, the authors point out that, considering the high education level of the subjects (32% of whom had a university degree), a higher level of performance might be expected. Engelsmann et al. (56) also found that in bipolar patients treated with lithium, mean memory test scores remained remarkably stable over a 6-year interval, with only one of the 10 memory subtests showing a statistically, but not clinically, signicant decrease. Further, there were no signicant differences between patients with short- versus long-term lithium treatment on any measure, after controlling for age and initial memory scores. However, Kessing (33) found both the number of episodes and lithium treatment to correlate with two of ve tests of diffuse cognitive function. A qualitative review of the literature (57) concluded that lithium had a negative effect on memory and speed of information processing, although patients themselves were often unaware of these decits. Additionally, other mood stabilizers such as carbamazepine and valproate can also produce concentration problems, though there is some evidence 119

Bearden et al.

that epilepsy patients show improved attentional capacity during carbamazepine treatment, as compared to other anticonvulsants (58). Neuroleptics and antidepressant drugs may also inuence cognitive performance; however, recent reviews have concluded that conventional neuroleptics do not cause cognitive decits, though they do little to improve them (28). Further, the effect of electroconvulsive therapy (ECT) on cognitive function in bipolar disorder has not been adequately investigated; one study of bipolar patients (33) reported no effect of the number of ECT treatments, nor of duration of convulsions, on ve measures of global cognitive function. However, in patients with major depression, ECT has been reported to cause short-term memory decits, particularly in the acute stages of treatment, and memory complaints are one of the most common subjective side effects of ECT treatment (1). Thus, this topic warrants further investigation in patients with bipolar illness. Taken together, these ndings suggest that, while medication may cause some degree of cognitive slowing, the cognitive impairments in chronic bipolar illness do not appear to be a primary effect of medication treatment. However, many bipolar patients take several psychotropic medications, and it is presently unknown what the combined effects of these various medications may be, particularly over time. An additional complication is the inuence of the dosage, as presumably, higher doses may have greater impact on cognitive function. The effects of pharmacological treatment must be carefully controlled and examined in future studies. A subcortical cogniti6e impairment in bipolar disorder?. Given the inconsistency of the evidence for RH dysfunction in bipolar disorder, investigators have more recently examined the notion of a subcortical cognitive impairment. The neuropsychological evidence that supports such a possibility comes from two studies comparing mood disorder subjects to patients with HD, a disorder known to involve subcortical dysfunction (15, 59). The memory prole of such patients involves impairment on free recall but little decit in recognition memory, suggesting difculties with systematic memory retrieval strategies (15). Such difculties in planning suggest decits in executive function, governed by subcortical and frontal structures (28). Massman et al. (15) used a factor analysis to classify depressed bipolar and unipolar patients based on their neuropsychological performance, compared to patients with HD and Alzheimers disease (AD). Of the depressed subjects (including 120

four bipolar subjects), 65.3% were classed as normals, 34.7% were classied as HD patients (including ve bipolar patients), while none was classied as an AD patient. These ndings support the notion of subcortical dysfunction in a subgroup of depressed patients; like HD patients, they had severely impaired performance on free recall, inconsistent item recall from trial to trial, and inadequate use of semantic clustering strategy. They displayed a decient rate of improvement across trials, suggesting difculty in utilizing systematic organizational strategies. Like HD patients, they displayed great improvement on recognition testing, indicating a decit primarily in retrieval from memory, but evidenced some mild encoding difculties as well. Others have reported a similar impairment in recall without corresponding recognition decits, particularly in measures of visual memory (60). Further, Wolfe et al. (21) found bipolar patients showed a pattern of impairment that was qualitatively similar to HD patients, though they generally showed less impairment. Given the known involvement of basal ganglia structures, including the putamen and caudate, in HD, the authors (21) conclude from these ndings that bipolar depressed patients may resemble HD patients in the type of memory dysfunction, suggesting that damage to basal ganglia structures may also be involved in the cognitive impairments seen in bipolar disorder. This possibility is supported by studies of secondary mood disorders, as well as functional and structural neuroimaging studies, which implicate the basal ganglia in the pathophysiology of mood disorder (59, 61). The ndings of van Gorp et al. (62) are slightly at odds with this conclusion, as they found euthymic bipolar patients to be impaired on a task of declarative memory (CVLT), which is typically disrupted by temporal-hippocampal damage, but not in tasks of procedural memory (star mirror tracing and pursuit rotor task), which is typically impaired in patients with predominantly subcortical dysfunction, including damage to basal ganglia. The authors conclude from this pattern of ndings that disturbance of temporal lobe/hippocampal structures, but not basal ganglia, is implicated in bipolar disorder. However, this result may be due to differential test sensitivity, as tests are rarely standardized for difculty. Interpreting results across studies is also problematic due to the use of discrete or over-specialized tests, which cannot address decits in other domains of cognitive function. In general, disparate methodologies and dissimilar patient groups of the various studies make cross-study comparison difcult.

Neuropsychology of bipolar disorder

While at present, the neuropsychological ndings do not point to strictly localized subcortical dysfunction, given converging evidence of disruption in cortical-subcortical circuits in particular, the frontal-basal ganglia circuit in bipolar disorder (61, 6365), such disruption would be likely to cause impairment in cognitive function attributed to subcortical structures. State 6ersus trait abnormalities: high-risk and twin studies. Because the ndings of cognitive impairment in adult bipolar disorder are obscured by differences in symptomatology and medication status, any ndings in offspring of bipolar parents that is, individuals at high genetic risk for bipolar disorder, but without outright expression of the disorder are an ideal group on which to examine a neuropsychological prole that may be indicative of a state-independent, genetic vulnerability to the disorder. In schizophrenia research, the high-risk paradigm has elucidated patterns of neuropsychological and behavioral dysfunction in young children at genetic risk for schizophrenia that resemble those 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 infrequently in bipolar research. Of the existing high-risk studies (Table 3), two found that, consistent with ndings from cognitive studies of adult bipolar patients, high-risk children performed markedly more poorly on the Performance portion than on the Verbal portion of the WISC (68, 69). Moreover, Decina et al. (68) found a signicant (greater than 15-point) discrepancy between VIQ and PIQ in a signicant number of high-risk children, which was greater in the offspring of bipolar-I parents than in offspring of bipolar-II parents. Of the high-risk children, those who showed expansive behavior patterns similar 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 signicant differences between children of bipolars and control children (70), any conclusions drawn from the high-risk literature are clearly premature. Nevertheless, while there may be some evidence of relatively poorer visuospatial performance, there does not appear to be evidence of general cognitive impairment in high-risk children, suggesting that much of the intellectual impairment takes place after onset of the disorder.

Further, one study to date has examined cognitive function in monozygotic twin pairs discordant for bipolar disorder (71). They found that affected twins showed specic decits in measures of visuospatial function (i.e., face recognition) and verbal learning and memory, as compared to unaffected cotwins and a control group of normal monozygotic twins. Unaffected twins performed worse than controls on some verbal learning measures. This paradigm allows for examination of both disease-specic impairments and genetic risk factors, suggesting that, while some visuospatial decits and verbal memory impairment may relate to disease parameters, mild decits in overall verbal learning and retrieval may be a genetic marker of risk for the disorder. However, given the extremely small sample size of seven twin pairs, the authors caution that these results must be viewed as exploratory. Summary of cogniti6e ndings. While an older review (10) concluded that patients with manic-depressive illness ... typically demonstrate decits in right hemisphere or non-dominant hemisphere functions (p. 279), the results of the present review do not support this conclusion. While there is some suggestion that verbal skills, with the exception of complex verbal learning and memory, appear to be less impaired in bipolar patients than are visuospatial, non-verbal memory, and abstraction skills, these tests are likely to be more susceptible to the effects of mood symptomatology, as they require increased motivation, attention, and speed. Impairments can also be seen in verbal memory when subjects are in an affective episode (21, 41), and in patients with longstanding illness (25, 45, 62). It seems that the more clinically reliable decrements in performance are observed in memory functions, tasks requiring serial processing, and higher order cognitive functioning (abstraction, exibility, and conceptual development) (72). The results to date do not suggest a specic cognitive prole in bipolar disorder; rather, the more consistent nding across studies appears to be that cognitive impairments are fewer and relatively less severe in younger and/or euthymic patients (9), whereas studies of symptomatic, psychotic or chronic elderly patients were likely to nd more diffuse impairment (20, 22, 46, 51). Findings of persistent neuropsychological decits in euthymic patients with longstanding illness, and the relationship of this impairment to length of illness, suggest that episodes of depression and mania may exact damage to learning and memory systems (25). Thus, this performance decit appears to be more consistent with impairment in frontal-tempo121

122
High-risk children 13 M 23 M, 30 F 10.2 13 SCZ Fa, 17 SCZ Mo 51 M, 43 F 9.5 None None Clinical report, WISC WISC, TAT, Rorschach, Draw-a-Person, Beery Buktecnica, Developmental Form Sequence Mean age Comparison parents Comparison children Mean age Measures Results V-IQ\P-IQ in six/nine children tested No signicant differences 14 M, 17 F 11 9 PI Fa, 10 PI Mo 38 normal Negative history for AD in rst-degree relatives or BP in second-degree relatives 30 M, 43 F 63 M, 56 F 9 M, 9 F 9.2 9.2 11.4 WISC-R, Interview, Global Assessment Scale, Motor Lateralization Questionnaire 24 M, 29 F Adulta SADS-L, Educational/ Occupational history, Medical history 29% HRC vs. 6% CC lefthanded (pB0.05). V-IQ: no differences. P-IQ: CC\ HRC (pB0.05), Verbal \ Performance discrepancy\ 15 patients in 39% HRC vs. 11% CC (pB0.05) Educational problems/perinatal complications not associated with increased risk of AD, but signicantly associated with earlier onset of AD

Bearden et al.

Table 3. High-risk studies: cognitive ndings

Study

High-risk parents

Kestenbaum, 1979 (69) Worland et al., 1979 (70)

Not specied

7 BP Fa, 11 BP Mo

Decina et al., 1983 (68)

11 BPI, 7 BPII

Waters et al., 1983 (163)

17 BP

Fa= fathers; Mo= mothers; PI= physically ill; SCZ = schizophrenic; CC=comparison children; HRC=high-risk children; AD= affective disorder; BP=bipolar. Retrospective study.

Neuropsychology of bipolar disorder

ral and subcortical systems rather than an underlying selective RH impairment. Nevertheless, results varied greatly across studies, due in large part to heterogeneity in sample populations. Patients differed widely in diagnostic status (e.g., bipolar-I versus bipolar-II, rapid-cycling, psychotic features), medication status, mood state at time of testing, age, severity, and chronicity of illness. It is imperative that future studies of cognitive function in bipolar disorder consider these methodological issues carefully in order to clarify whether bipolar patients show a particular pattern of cognitive decit, whether there is signicant decline in cognitive function over the course of illness, and whether such impairments are limited to a subgroup of patients.
Studies of laterality of function

subjects are asked to determine which is the happier of two composite facial photographs, is reported to reliably elicit a RH advantage. Normal right-handed subjects show a consistent bias toward the composite whose smiling half-face is on their left, or a LH bias. David and Cutting (81) found that manics showed greater LH bias than normals; depressives (predominantly unipolar) showed reduced LH bias compared to normals; schizophrenia showed no bias to either side. They interpret this nding as suggestive of RH hyperfunction in mania and RH hypofunction in depression and schizophrenia a conclusion quite inconsistent with the notion of a stable RH dysfunction or lesion in bipolar disorder, which highlights the importance of mood state at time of testing.
Secondary affective disorders

In addition to the neuropsychological tests described above, laterality of function in bipolar illness has also been the focus of investigation in studies of dichotic listening, handedness, and emotional discrimination tasks. In general, the laterality research eld is clouded by controversy over basic interpretations of ndings. For instance, the same experimental observation can be understood as a right-sided o6eracti6ation, or left-sided underacti6ation. Studies of dichotic listening, in which hemispheric dominance is determined by greater efciency of auditory processing in one ear, have reported widely disparate ndings (73 76). In general, dichotic listening anomalies in bipolar disorder appear to be highly state-dependent. Further, while these ndings have been interpreted as indications of right-temporal lobe dysfunction in bipolar disorder, performance is likely to be strongly affected by attentional capacity, which may presumably be quite diminished during a manic episode. Studies of handedness in bipolar disorder are similarly difcult to interpret. While the literature suggests a relatively normal distribution of left and right handers, when controlling for gender (77), Decina et al. (68) reported signicantly higher rates of left-handedness among children of bipolar parents, and there have been isolated case reports of bipolar patients who changed handedness from left to right when switching from depression to mania (5, 78). Tasks of emotional discrimination have also been employed in laterality studies, as the literature on hemispheric activation and affect has suggested that the RH is dominant in the perception of affect (79, 80). The chimeric face task, in which

Insights into the localization of the pathophysiology of symptom production in mood disorders can be gained from secondary mood disorders. These clinical problems suggest the brain regions that, when altered, are associated with specic symptoms. The frontal lobes, basal ganglia and temporal lobes are the most commonly dysfunctional regions in those patients who have a comorbid occurrence of depression with neurological disease (59). Depression and mania secondary to CNS lesions resulting from cerebrovascular accident, tumor, head injuries, Huntingtons choreas, AD, and AIDS have been reported in the literature (10, 82, 83). In particular, disorders manifesting focal subcortical neuropathology, such as HD, are frequently associated with mood changes, including both depression and mania (64). In a review of the literature on secondary affective disorders, Jeste et al. (84) identied 13 cases of mania and 24 cases of depression, secondary to known focal lesions, associated with tumors, stroke, or surgical procedure. From these ndings, they conclude that while the data do not point conclusively to lesions in any single area that are consistently associated with secondary depression or mania ... there is a general tendency for depressive symptoms to be associated with left frontotemporal or right parieto-occipital lesions, whereas mania is more often associated with right frontotemporal or left parieto-occipital lesions. However, they caution that several large-scale studies of secondary affective disorders did not report such an association. Migliorelli et al. (85) also observed that patients with secondary mania were more likely to have RH versus LH lesions, usually in right basal frontal and temporal cortices, the right head of the 123

Bearden et al.

VBR= mean ventricle:brain ratio; aBVR=abnormal VBR; BP= bipolar; OPP=other psychiatric patients; NL= normal; SZA=schizoaffective; HA= headache patients; UP=unipolar. These 22 included 7 UP, 7 BP depressed, 6 BP manic, and 2 SZA patients. These 101 included 74 BP depressed and 27 UP patients. c These 60 included 33 UP, 5 BP manic, 17 BP depressed and 5 SZA patients.

caudate, and right thalamus. Sackeim et al. (6) observed that the depressed state is more frequent following left-sided stroke and they cite reports of a left-sided lesion causing uncontrollable crying in patients, whereas a right-sided lesion resulted in uncontrollable laughing. Secondary affective disorders are important to consider as they challenge the notion that a xed structural lesion cannot lead to an episodic illness (86). However, given that bipolar mood disorder involves uctuations between mood states, any model based on a structural lesion that results solely in symptoms of mania or depression is unlikely to be directly relevant to the pathophysiology of bipolar illness. The existence of affective disorders secondary to structural brain lesions nevertheless provides further impetus for structural and functional imaging studies in primary affective disorder. While the neuropsychological and behavioral ndings are provocative, they are clearly indirect methods of revealing an underlying brain anomaly. In order to truly examine the possibility of anomalous lateralization or RH dysfunction in bipolar disorder, it is necessary to examine the brain itself. While neuropathological studies have provided some information in this regard, the majority of the work has been in the eld of in 6i6o structural and functional neuroimaging. Thus, we now turn to recent work in these areas.
Neuroimaging ndings in bipolar disorder

Negative symptoms, increased number of hospital stays, persistent unemployment Psychotic features

Aging, in both patients and controls Normal controls

Lower frequency of hospital stays

Other control subjects

\Control mean by 2 SD \Control mean by 2 SD ?

\Control mean by 2 SD \10

Denition of aVBR

\10

Other control subjects

Normal subjects

Normal subjects

No differences

% aVBR

7.4

6.7

Other control subjects

2.6

3.8

2.6

2.0

3.3

VBR

3.6

3.9

2.6

SD

4.5

4.7

3.0

5.6

6.9

6.3

1.9

No signicant difference in VBR between patients and controls, but increased linear ventricular values of frontal horns. No BP/ UP difference No signicant difference between BPs and SZA controls Non-signicant trend for SCZ initial scans to be larger than BPs (pB0.1)

Affective patients different from:

Aging, maleness, psychotic symptoms

Large VBR associated with:

Using the new generation of brain imaging technology, researchers now have the potential to examine specic brain regions of interest in bipolar disorder in order to understand the underling pathophysiological mechanism responsible for the production of affective symptomatology, as well as the accompanying cognitive impairments. Because bipolar disorder is cyclical by nature, with periods of remission between episodes of illness, research on the affective disorders has generally focused on biochemical and neuroendocrine aspects of the illness, while paying little attention to potential structural neuroanatomical defects. However, a variety of structural brain abnormalities have been consistently reported in at least a portion of bipolar patients. Both structural and functional brain imaging suggest specic regions where abnormalities may be associated with symptoms of mood disorder. Data that emerge from these studies have implicated the frontal cortex, basal ganglia and temporal lobes in the production of symptoms of affective disorder (84, 86 89). Structural neuroanatomical studies have employed two techniques: computerized tomography

35 OPP

15 SZA

46 NL

62 HA

27 NL

22 SZA 2.9 6.9 26 BP ?

52

% aVBR

34.5

Patients with schizophrenia

10.9

23

7.1

Table 4a. Computerized tomography (CT) scan abnormalities: ventricular enlargement

2.9

4.0

3.4

2.6

2.7

SD

60

VBR

7.5

8.7

3.7

6.2

4.1

22

55

28

19

45

Patients with affective disorders

% aVBR

12.5

29.2

10.5

31

18

3.3

3.2

3.7

3.4

2.7

4.6

2.4

SD

VBR

6.5

7.5

5.3

6.6

4.5

7.3

7.4

16 BP

24 BP

19 BP

27 BP

101b

22a

Pearlson and Veroff, 1981 (98) Nasrallah et al., 1982 (96) Rieder et al., 1983 (97) Pearlson et al., 1984 (194) Luchins et al., 1984 (92) Dolan et al., 1985 (95) Schlegel and Kretschmar, 1987 (90)

60

Study

Dewan et al., 1988 (172) Woods et al., 1990 (161)

9 BP

None

124

Neuropsychology of bipolar disorder

(CT) and magnetic resonance imaging (MRI). CT measures the degree to which a beam of X-rays is attenuated along its path through the tissues, thus producing high-resolution pictures of brain morphology, and readily detects most structural pathology. However, the value of CT investigations is limited because cerebral regions most likely to be associated with affective disorder, such as limbic structures, are not measurable by CT due to artifact. Thus, CT can provide a description only of more gross structural pathology, such as ventricular enlargement and brain atrophy. MRI offers the advantages of allowing excellent gray and white matter resolution in cortical and subcortical areas and, because it permits imaging in the sagittal plane, it permits visualization of the corpus callosum and other midline structures. MRI is also superior in detecting brain tissue pathology, particularly in the temporal lobes (88). Thus, relatively greater weight will be given to the MRI ndings in this review. Nevertheless, a large body of research has been conducted with CT, comparing brain structure of different psychiatric populations (primarily schizophrenic and affective disorder patients) to normal control subjects. Because of the differences in methodology, the CT ndings are presented separately. Tables 4a d summarize studies of ventricular enlargement, cortical atrophy and cerebellar vermal atrophy on CT scans of patients with major affective disorders, compared with those of schizophrenic patients, patients with other psychiatric disorders, and normal control subjects. Diagnoses in these studies were generally based on standard diagnostic criteria. Most of the studies attempted to control for age and history of alcohol and drug abuse. Many of the published CT scan studies did not separate unipolar from bipolar subjects in their analyses; however, for purposes of clarity, this review includes only those studies of purely bipolar subjects or those that included a large number of bipolar subjects in the combined affective disorder groups. Of the six studies that compared the ventricle:brain ratio (VBR) of patients with affective disorder to those of non-schizophrenic/schizoaffective control subjects, all but one (90) found signicant differences between affective patients and controls. However, while Schlegel and Kretzchmar (90) did not nd a VBR difference, they did nd increased linear ventricular values in affective patients compared to controls. No differences were found in any study between bipolar and schizophrenic or schizoaffective patients. While the mean VBRs of schizophrenics were slightly larger across these studies, on average, the mean ratio of 125

No signicant difference between SCZ, BP, and SZA patients

Patients had signicantly greater sulcal widening, especially frontotemporal No signicant differences between BP patients and controls

No signicant difference between SCZ and BP patients

Table 4b. Computerized tomography (CT) scan abnormalities: sulcal widening (cortical atrophy)

Pearlson and Veroff, 1981 (98) Nasrallah et al., 1982 (195) Rieder et al., 1983 (97) Dolan et al., 1986 (196) Dewan et al., 1988 (172)

Study

UP=unipolar; OPP= other psychiatric patients; BP=bipolar; NL=normal; SCZ= schizophrenic; SZA=schizoaffective; HA= headache patients. These included 74 BP depressed and 27 UP depressed patients.

Other control subjects

% Abnormal

Comments

3.7

33

35 OPP

15 SZA

? ? 101a 52

Patients with schizophrenia

% Abnormal

22

55

Patients with affective disorders

% Abnormal

12.5

25

21

28

17.9

18

40

19 BP

24 BP

26 BP

16

22 HA

27 NL

Bearden et al.

the VBR of affective patients to that of schizophrenic patients was 1:1, while the mean VBR of affective disorder patients was 1.4 times that of control subjects from the same studies. It seems that a proportion of patients with bipolar affective disorder, ranging from approximately 10 to 31%, have abnormally large ventricles. This proportion is similar to that seen in schizophrenic patients, and greater than that observed in agematched normal control subjects or nonschizophrenic psychiatric patients (84). Many studies of schizophrenic patients have noted that schizophrenics with large ventricles are generally characterized by more negative symptoms and poorer responses to neuroleptic treatment (91). Attempts to characterize affective disorder patients along these dimensions have met with mixed results; while some have reported that such a subgroup may be associated with more psychotic or delusional symptoms and poor outcome (92 94), Dolan et al. (95) found no relationship between VBR and course of illness. CT studies of sulcal widening (an indication of cortical atrophy) and cerebellar atrophy reveal that roughly 8 25% of bipolar patients display some degree of cortical or cerebellar atrophy. This is somewhat less than the number of schizophrenics with cortical atrophy. While two studies found no differences between schizophrenics and bipolars in the degree of sulcal widening (96, 97), Pearlson and Veroff (98) found a sulcal widening to be relatively more common in schizophrenics. However, both schizophrenics and bipolars showed more sulcal widening than controls. Only Nasrallah et al. (99) reported signicantly greater cerebellar atrophy in bipolars than schizophrenics; indeed, this nding is notable in that it is the only type of structural brain abnormality found in any CT study to be relatively more apparent in bipolars than schizophrenics. The mean prevalence rate of cerebellar atrophy in the three studies that compared bipolar patients to controls was 15.3% in bipolar patients, while the mean prevalence rate for schizophrenics was 7.6% (97, 99, 100). While the methods of determining abnormality differ widely between studies, these ndings nevertheless suggest a high degree of overlap between CT measures of structural anatomical abnormality in bipolars and schizophrenics. Furthermore, in a quantitative review of the structural neuroimaging literature (primarily CT studies) in the major psychoses, Raz and Raz (101) found the mean effect size for the difference in size of lateral ventricles between patients with affective disorders and controls to be 0.55 (SD =0.43). They found no relation between effect size and

Cerebellar atrophy signicantly greater in BP (but not SCZ) patients than in controls No signicant differences among SCZ, SZA, and BP patients 15 SZA 6.7 3 36 NL

Other control subjects

% Abnormal

74 NL

2.7

No BP patientsB50 years had cerebellar atrophy vs. two/ve BP patients \50 years vs. zero NL, UP, or SCZ patients over 50 years

Comments

Table 4c. Computerized tomography (CT) scan abnormalities: cerebellar vermis atrophy

126

Nasrallah et al., 1981 (99) Rieder et al., 1983 (97) Yates et al., 1987 (100)

Study

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

Patients with schizophrenia

% Abnormal

12

7.1 10.5 28

Patients with affective disorders

% Abnormal

27

8.3

108

43

3.7

15 BP

19 BP

26 UP

24 BP

Neuropsychology of bipolar disorder

Table 4d. Computerized tomography (CT) scan abnormalities: other CT ndings Study Patients with affective disorders 22 BP, 33 UP, 5 SZA Other control subjects 60 NL Findings

Schlegel and Kretschmar, 1987 (90)

Schlegel and Kretschmar, 1987 (150) Dewan et al., 1988 (172)

21 BP, 27 UP, 5 SZA 26 BP

60 NL

Affective disorder patients had signicantly greater third ventricle width than controls; no signicant differences in third ventricle width when BP patients alone compared to controls; BP patients had signicantly greater density than controls in left caudate/thalamus, left frontal and parietal gray matter, right parietal white matter and right occipital region Frontal horn distance/bicaudate distance abnormally large in affective patients, especially older and psychotic pts

Iacono et al., 1988 (103)

18 BP, 16 UP

Andreasen et al., 1990 24 BP, 27 UP (197)

BP patients had signicantly greater third ventricle width and signicantly greater cortical density in right temporal lobe, anterior white matter, and diencephalic nuclei. No correlation between increased density and neuropsychological test performance, family history, psychotic symptoms, or lithium response 30 medical No signicant differences in third ventricle width between BP controls, 44 NL group and either control group; UP group had signicantly wider third ventricles than medical controls only. 110 SCZ, 75 NL After controlling for age, ventricular enlargement present only in male BP group; no correlation between clinical variables and ventriculomegaly

22 HA

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

sample size. The mean effect size for lateral ventriculomegaly in affective disorder was determined to be smaller, although not signicantly smaller, than that obtained for schizophrenia. (0.70, SD= 0.54). Third ventricle dilation was investigated in mood disorder in three studies: Schlegel and Kretzschmar (90) obtained an effect size of 0.51, Dewan et al. (102) of 0.49, while Iacono and colleagues (103) reported a negligible effect of 0.02. The rst two studies used older and more chronic patients, which could account for this difference. The mean effect size for global cortical atrophy (as measured by dilation of cortical ssures and sulci) in seven studies of patients with mood disorders was 0.42 (SD=0.25), very close to that obtained for studies of schizophrenia. (0.35, SD=0.34). In this review (101), measures of sulcal prominence yielded signicantly smaller effects than measures of ventricular volume for both mood disorder and schizophrenia (the mean effect size for global sulcal dilation corresponded to an approximately 2528% overlap between patients and controls). However, the poor gray/white matter resolution of CT may contribute to error variance, making this a less reliable measure than ventricle size. From this review, Raz and Raz (101) conclude that CT measures are unable to distinguish schizophrenia from mood disorders. A later review (104) that incorporated ndings from 10 additional studies found a moderate composite effect when comparing affective disorder patients to controls of 0.44 for lateral ventricles, and 0.42 for

cortical sulci; although there was less ventricular enlargement in affective disorder patients than schizophrenics, the difference in effect sizes was small, suggesting that this type of structural brain anomaly is relatively nonspecic with regard to diagnosis.
MRI studies

White matter hyperintensities. T2 weighted MRI images allow for the detection of tissue abnormalities in the form of regions of greater signal intensity, or hyperintensities. The presence of such signal hyperintensities reects a change of water content in the brain. Also referred to as leukoaraiosis or lesions, they are usually not present in healthy persons under 45 years of age. Their presence is known to increase with age and with the existence of comorbid medical conditions (105 107). In particular, their presence has been associated with hypertension, carotid arteriosclerosis, and dilated perivascular spaces, and may indicate an underlying ischemia process (106, 108). Recently, many studies have found higher rates of hyperintensities in bipolar patients of all ages, particularly in periventricular white matter, subcortical gray matter and deep white matter brain regions. Table 5 summarizes the ndings of MRI studies comparing bipolar patients to normal control subjects in the presence of signal hyperintensities. Effect sizes were calculated using both an odds ratio (109) and r (110). 127

128
Comparison subjects (n= 338) n Mean age SD Slice thickness (mm) 5 10 5 5 7 5 5 10 5 5 5 6.1 2.9 2.98 4.23 ** 7.2 15.71 1.9 0.56 0.2 0.25 0.4 0.32 0.22 0.16 ** 0.28 9.3 0.52 13.6 0.39 + + + + + + 1.94 0.19 + 19 0.57 Odds ratio Effect size (r) White matter Presence of T2 lesions Hyperintensities located in: Gray matter Deep white matter + + + + + + + + + + + + + + + + + + Mean age SD 36.5 33.9 37.5 68.3 37.7 31 39.3 41.6 36.6 11.3 47.7 38.3 7.9 32.7 37.3 8.6 8.3 22 41.4 11.3 3.1 5 11.8 2.9 10.8 26 39.1 9.4 11.6 20 35.2 9.9 1.1 31 37.6 9.0 11.8 15 32.4 8.8 7.6 154 34 9.5 7 12 68.7 7 18 34.7 47 34.4 10 10 41 10

Bearden et al.

Table 5. Studies of T2 hyperintensities in bipolar patientsa

Bipolar patients (n=242)

Study (year)

19

48

18

12

22

18

32

29

36

Dupont et al., 1990 (192) Swayze et al., 1990 (118) Figiel et al., 1991 (115) McDonald et al., 1991 (124) Brown et al., 1992 (112) Strakowski et al., 1993 (122) Aylward et al., 1994 (113) Altshuler et al., 1995b (106) Dupont et al., 1995 (120) Botteron et al., 1995 (123) Krabbendam et al., 2000c (19)

21

Mean across studies

23.9

+ = assessed; included in overall T2 abnormality estimate in study. a Table updated from Altshuler et al, 1995 (106). b Bipolar I patients. c Twelve with psychotic features, 10 without. **Could not be calculated from data presented.

Neuropsychology of bipolar disorder

Because of differences in study groups and methodology, there is a wide range in frequency of T2 hyperintensities found in both patients (5 62%) and normal control groups (0 42%). However, in all but one study, the odds ratio is in the same direction. The mean effect size of 0.28 indicates a moderate overall effect. Moreover, the test for heterogeneity of effect sizes (110) did not reveal signicant differences between effect sizes, indicating little variability across studies, and the overall effect size, calculated using the Stouffer method (110), was shown to be highly signicant (p = 0.0001). A recent meta-analysis (111) reported a similar result, nding a common odds ratio of 3.29 (95% CI=2.14 5.07) across studies of white matter hyperintensities in bipolar patients. The only study that did not nd an increased prevalence of white matter hyperintensities in bipolar subjects compared to controls (112) nevertheless did nd increased severity of deep white matter hyperintensities in unipolar depressed patients. This study differed from the others in two ways: 1) they recruited a large number of patients with a wide variety of psychiatric diagnoses from newspaper advertisements, resulting in potential sampling bias, and 2) subjects were tested in two different scanners (one 0.5 T and the other 1.5 T), which may contribute to some ambiguity in the ndings. Two studies found the increased incidence of white matter hyperintensities only in older bipolar patients, while younger patients were no more likely than controls to display such abnormalities (106, 113). Another found increased volume of abnormal white matter to be associated with later age of onset in bipolars, but found no age differences at the time of testing between subjects with high and low volumes of abnormal white matter (114). While Hickie et al. (107) also found the presence of white matter hyperintensities to be associated with later age of onset in bipolar patients, they also reported a strong correlation between increased age and the extent of white matter hyperintensities. Aylward et al. (113) did not nd the presence of white matter hyperintensities to be related to history of psychosis, number of previous hospitalizations, or lithium treatment. While increased age may be related to the presence of increased white matter hyperintensities in bipolar patients, medical risk factors do not appear to be a cause of such abnormalities. Two studies that examined the effects of medical risk factors (e.g., high blood pressure, vascular disease) found that, after excluding bipolar patients with such risk factors from the analysis, bipolars were still signicantly more likely to have white matter hyperintensities (106, 107). Thus, while white matter

hyperintensities may be relatively more common in older bipolar patients, perhaps reecting an interaction of the disease with processes of normal aging, the presence of vascular risk factors does not appear to be a signicant cause of the pathophysiology of this abnormality in bipolar disorder. In bipolar patients, these hyperintensities have been found most frequently in the frontal lobes, and frontal/parietal junction (113, 115, 116), but have also been reported with somewhat less frequency in the occipital and temporal lobes (113, 117). No studies have reported lateralization of signal hyperintensities; that is, there is no evidence that they appear more frequently in the RH or LH. Specicity to bipolar disorder. Swayze et al. (118) hypothesized that focal signal hyperintensities would be more common in schizophrenia due to evidence suggesting periventricular gliosis in schizophrenia, secondary to trauma or an infectious process, which could result in higher rates of periventricular focal signal hyperintensities. However, the few studies that have compared the presence of white matter hyperintensities in bipolar disorder and schizophrenia have found them to be markedly more frequent among bipolars than schizophrenics (107, 118, 119). Specically, Swayze et al. (118) reported signal hyperintensities in 19% of bipolar patients compared to only 9.3% of schizophrenics, and only bipolars had more than one. In a study of qualitative brain morphology, Lewine et al. (119) found that, while schizophrenic males had the highest rate of morphological anomalies overall, hyperintensity signals were more common in bipolar patients. Further, two recent reviews of the imaging literature have concluded that there is little evidence that schizophrenia is associated with an excess of white matter hyperintensities (64, 111). This suggests a different pathophysiological origin for the structural brain abnormalities in bipolar disorder than those seen in schizophrenia. Nevertheless, as very few studies have directly compared age-matched bipolar and schizophrenic patients with regard to the presence of hyperintensities, this conclusion remains tentative. There is also some suggestion that white matter hyperintensities are more common in bipolar mood disorder than in other affective disorders: Dupont et al. (120) found a slightly higher rate of signal hyperintensities in bipolar than unipolar depressed subjects, and Altshuler et al. (106) reported higher rates in bipolar-I than bipolar-II patients (those without clear manic episodes). A recent meta-analysis (111) found a common odds ratio of 3.2 across studies of white matter hyperintensities 129

Bearden et al.

in unipolar depression, though only 6 of 10 studies reported statistically signicant differences between depressed patients and controls. Moreover, there is some evidence that when signal hyperintensities are present in unipolar depressed patients, they are much more common in elderly, late-onset depression, and are associated with the presence of vascular risk factors (107, 108, 115, 121). This appears to be less true for bipolar patients, as signal hyperintensities have been found to be signicantly increased even in younger and rst-episode patients (122, 123). One case report found marked white matter signal hyperintensities in a rst-onset bipolar presenting at 16 years of age (117). Videbechs (111) recent meta-analytic review concludes that debut age apparently plays only a minor role in the bipolar patients who develop the lesions and speculates that this could be due to greater importance of genetic factors in the etiology of bipolar disorder. Nevertheless, examining the effects of age with respect to effect size is difcult, as only one study (124) examined bipolar patients with a mean age of over 40 years. However, the effect size in this study (0.52) was among the largest of the studies conducted to date (see Table 5), suggesting that the relationship between age and increased white matter hyperintensities in bipolar disorder bears further investigation. Pathophysiological signicance of white matter hyperintensities. There is some evidence that the presence of white matter hyperintensities may be associated with cognitive impairment, particularly in functions requiring complex processing (125, 126). In a study of 41 elderly depressed patients with vascular risk factors (hypertension, diabetes, history of minor stroke, or presence of some white matter changes, but no cortical lesions). Junque and colleagues (127) found that tests involving speeded information processing and attention correlated more signicantly with white matter hyperintensities than with age. However, leuko-araiosis was not shown to be related to simple reaction time, nger tapping, or language ability, suggesting that it does not correlate with all measures of mental speed, but only those that require speeded performance and more complex processing some of the features of a subcortical dementia. Leukoaraiosis was also found to be related to the presence of some primitive reexes, behavioral disturbances, and cognitive slowing, thus bearing a resemblance to frontal lobe syndrome. This suggests that loss of several subcortico-frontal connections may be responsible for a frontal system decit. Moreover, Bondareff et al. (128) found the magnitude of periventricular white matter lesions 130

to be closely correlated with severity of dementia in elderly patients with probable AD. In general, ndings in healthy older adults indicate that severe white matter disease is probably associated with cognitive dysfunction, suggesting that a threshold of white matter lesion area must be present before cognitive decits are observed (125, 129). It has been suggested that these signal hyperintensities represent astrogliosis, demyelination and loss of axons (127). Others hypothesize that they represent arteriosclerotic disease of arteries supplying subcortical brain regions (108). These changes would be expected to cause slowed mental processing, which could affect encoding and retrieval processes in memory (127). Post-mortem studies have reported a variety of histological abnormalities in these areas, including minute brain cysts, infarctions, small vascular malformations, and necrosis (106, 114). Which of these many etiologies is implicated in bipolar disorder is unknown. Temporal lobe structure. Given the many reports of temporal lobe volume reduction and abnormalities of temporal lobe structure in schizophrenia [see Swayze et al. (130) for a review], it is of interest to determine whether similar abnormalities may be seen in bipolar disorder. Table 6a summarizes the MRI ndings with regard to temporal lobe volume in bipolar disorder. Of six studies that compared bipolar subjects to normal controls, two found decreased temporal lobe volume in bipolars (87, 131). One reported signicantly greater left temporal lobe volume in bipolars (132) and three reported no overall group differences in tissue volume (130, 133, 134), although Roy et al. (134) did nd increased temporal horn volume in both bipolar and schizophrenic patients. Of these studies, Johnstone et al. (133) found normal asymmetry in bipolar subjects, while Swayze et al. (130) found sex differences between male and female bipolar subjects in the degree of temporal lobe asymmetry. Additionally, while Swayze et al. (130) found smaller right hippocampal volume in bipolars, they speculate that this nding may have been a result of type I error as no differences were found when the amygdala and hippocampus were summed together. Rossi et al. (135) found schizophrenics had signicantly smaller temporal lobes than bipolars, although another study of qualitative abnormalities seen on MRI scans found a similar degree of medial temporal lobe hypoplasia in both schizophrenics and bipolars (136). Further, a more recent study by Altshuler et al. (137) using more rened methods of analysis did not replicate their previous ndings of decreased temporal lobe volume, although they

Table 6a. Other MRI ndings: temporal lobe structure in bipolar disorder Normal controls Imaging technique Bilateral temporal lobe measurements used Results

Study

Number of subjects 21 0.5 T scanner, 12 1-cm. coronal slices

Hauser et al., 1989 (87)

15 BP, 2 UP

Affective patients had signicantly smaller temporal lobe:cerebral area ratio; left side only when controlling for age/education Left temporal lobe smaller than right in SCZ; result reversed in controls and BPs

Johnstone et al., 1989 (133) 10 None

20 BP, 21 SCZ

21

10 BP

Altshuler et al., 1991 (131) Rossi et al., 1991 (135)

16 BP, 10 SCZ

Area ratios for temporal lobe:cerebrum, hippocampal complex:temporal lobe, hippocampal complex:cerebrum, temporal lobe white:gray matter 0.15 T scanner, 610 8-mm coronal All coronal temporal lobe and temporal slices horn areas (reported slice with largest area for each structure) 0.5 T scanner, 12 10-mm coronal slices Temporal lobe measured on 56 consecutive slices 0.5 T scanner, 15 5-mm coronal slices, Temporal lobes measured on 5 2-mm interslice gap consecutive slices

Swayze et al., 1992 (130) 47

48 BPa, 54 SCZ 0.5 T scanner, 8 coronal slices at 1-cm intervals, no interslice gaps

Temporal lobe area measured on consecutive slices using manual planimetry

Harvey et al., 1994 (132)

26 BP, 48 SCZ

34

0.5 T scanner, 20 5-mm coronal slices

Roy et al., 1998 (134)

14 BP, 22 SCZ

15

Altshuler et al., 1998 (137)

12 BP, 14 SCZ

12

Used segmentation procedure to distinguish CSF/white/gray matter; calculated volume of temporal lobe white and gray matter 1.5 scanner, 5-mm coronal slices, Obtained 10 coronal sections per subject; 1-mm interslice gap used tracing and uid/tissue thresholding to measure 11 ROIs, inc. temporal lobes/horns, STG, ventricles and hemispheres 1.5 T scanner SPGR sequence, 1.5 mm Rater measured ROIs using images coronal slices normalized in 3-D

Volumes smaller bilaterally in BPs than in controls Temporal lobe area smaller in SCZs in 2 slice areas on right and 4 on left; SCZs had reduced total volume compared with BPs Temporal lobe size larger on right than left in groups; difference between right and left temporal volume greatest in male BPs and signicantly greater than female BPs BPs had signicantly greater left temporal lobe volume than controls and SCZs (due to increased gray matter in left temporal lobe in BPs) Increased temporal horn volume in both BPs and SCZs; patients did not differ from controls on any other tissue/uid measures; BPs and SCZs did not differ on any measure No difference in temporal lobe volume between BPs and NCs; decreased hippocampal volume in SCZs only; increased amygdala volume in BPs

Neuropsychology of bipolar disorder

BP= bipolar; UP=unipolar; SCZ= schizophrenic; NC=normal controls. All manic at time of testing; early onset, severe.

131

132
Normal controls 10 21 47 16 1.5 T scanner, 6-mm coronal slices 0.5 T scanner, 8 1-cm coronal slices Imaging technique Measurements used Results 0.04 T scanner, supraventricular transverse slices at 1-cm intervals 0.15 T scanner, 8-mm coronal slices at 1-cm intervals Used VBR as measure of ventricular enlargement Area of right/left lateral ventricle, right/left temporal horn 37 60 1.5 T scanner, 5-mm axial slices 1.5 T scanner, 2430 5-mm coronal slices 5 1.5 T scanner, 38 4-mm T1 coronal slices, 24 5-mm T1 sagittal slices 17 1.5 T scanner, 8 sections of 5-mm axial images 1.5 T scanner, 5-mm axial slices with 2-mm interslice gap 16 16 1.5 T scanner, 7 consecutive 5-mm slices with 2.5-mm interslice gap

Table 6b. Other MRI ndings: lateral and third ventricle enlargement

Study

Number of subjects

Bearden et al.

7 BP, 3 UP

Besson et al., 1987a (143) Johnstone et al., 1989 (133)

20 BP, 21 SCZ

Swayze et al., 1990 (118)

48 BP, 54 SCZ

Strakowski et al., 1993b (122)

17 BP

Jurjus et al., 1993 (138)

63 BP/SZA, 67 SCZ

Kato et al., 1994a,c (139)

40 BP

Botteron et al., 1995d (123)

8 BPI

Zipursky et al., 1997 (141)

14 BP, 23 SCZ

Friedman et al., 15 BP, 20 SCZ 1999e (140)

Lim et al., 1999f (142)

9 BP, 9 SCZ

Patients had slightly, but not signicantly, larger ventricles than normal controls No differences between patients and controls overall, but ventricles 30% larger in poor vs. good outcome BP and SCZ patients Volume of lateral ventricles Male SCZs had signicantly larger ventricles than controls; male BPs had non-signicantly larger ventricles than controls (pB0.1) Thresholding procedure to segment white/gray BPs had signicantly larger third ventricles matter/CSF; obtained volumetric measure of volume than controls (nearly twice normal); lateral/third ventricles trend toward increased lateral ventricle volume (signicant when controlled for other variables) Neuroradiologist qualitatively assessed 23 SCZs and BPs had signicantly larger developmental anomalies of ventricles than normal controls cortical/subcortical structures Used ER, HR, and minimum distance of Ventricle size (ER and MDCN measures) caudate nuclei as measure of ventricle signicantly greater in BPs than normal enlargement controls, BPs with psychotic features had signicantly greater ventricular enlargement than those without Ratio of right and left ventricular volume: No signicant differences in lateral or third cerebral volume; absolute values of right and ventricle volume between BPs and normals, left lateral and third ventricles but four/eight BPs had ventricular abnormalities; highly signicant correlation between age and ventricular volume Used BrainImage software to segment BPs had signicantly greater ventricles than images, calculate CSF/gray/white matter NCs; SCZs had larger ventricles than NCs, volume, measure lateral ventricles but not BPs; decreased cortical gray matter volume in SCZs, not BPs Used Lim and Pfefferbaum (198) methods to No differences between SCZs and BPs on calculate lateral ventricular and intracranial any measure; combined patient groups had volume, frontal/temporal/occipital sulcal uid lower intracranial volume, increased ventricular percentage volume, frontal and temporal uid percentage compared to controls Semi-automated technique used to segment BPs had widespread cortical gray matter each slice into CSF/gray/white matter decit, but not white matter; SCZs had an compartments; obtain global cortical even greater gray matter decit; also, greater measures, lateral and third ventricle volume, sulcal and lateral ventricular enlargement in globar ROIs SCZs than BPs

BP= bipolar; UP= unipolar; VBR= ventricle:brain ratio; SCZ=schizophrenic; SZA= schizoaffective; ER=Evans ration; HR=Huckmann ratio; NC= normal controls. a All patients euthymic at testing; all on lithium. b First-episode, never-medicated patients. c 31 bipolar I, 9 BP NOS, 10 with psychotic features. d All patients bipolar I or bipolar II with past history of mania; aged 616 years, illness duration at least 2 weeks. e All patients aged 1018 years. f 3 with psychotic features; 4 manic, 3 depressed, 2 mixed.

Table 6c. Other MRI ndings: other cortical/subcortical structures Normal controls Imaging technique Measurements used Results

Study

Number of subjects 37 0.5 T scanner Abnormalities qualitatively assessed by two neuroradiologists: sulcal widening, lateral/third ventricle size, medial temporal dysplasia Used manual planimetry to estimate volume of small subcortical gray matter structures

Olson et al., 1990 (136)

60 BP/SZA, 66 SCZ

Swayze et al., 1992 (130) 0.5 T scanner, 8 coronal slices at 1-cm interval gaps, no interslice gaps

48 BPa,b, 54 SCZ 47

Strakowski et al., 1993 (122) 16 32 1.5 T scanner, T2 and proton density weighted 5-mm axial slices

17 BPc 1.5 T scanner, 6-mm coronal slices

SCZs had higher rate of at least one denite abnormality than BPs/SZAs and controls; males more structurally abnormal in all groups; rate of medial temporal dysplasia similar in BPs and SCZs No differences between BPs and normals except smaller right hippocampal volume in BPs (but no differences found when amygdala/hippocampus summed together) No differences in thalamic volume; BP females had signicantly greater gray:white matter ratio than all other groups

Aylward et al., 1994 (113)

33 BPd

Thresholding procedure to segment white/gray matter/CSF; calculated volume for hemispheres, caudate, thalamus, cingulate gyrus Volumes estimated from area measure of each ROI; volume measures obtained for subcortical structures

Bullmore et al., 26 BP, 60 SCZ 1994 (148) 34 0.5 T scanner, 20 5-mm coronal slices

36

0.5 T scanner, 20 5-mm coronal slices

Male BPs had signicantly larger caudate volumes bilaterally than male controls; no difference in volume of globus pallidus, putamen Global mean FD greatest in BPs, least in SCZs, intermediate in controls

Harvey et al., 1994 (132)

26 BP, 48 SCZ

Measured volume of ROI, FD estimated across all slices (measure of structural complexity) Used segmentation procedure to distinguish CSF/white/gray matter

Schlaepfer et al., 1994 (149)

27 BP, 46 SCZ

60

1.5 T scanner, 5-mm axial slices

Used segmentation technique (198) to dene heteromodal association cortex; calculate regional volumes of CSF/gray/white matter Each pixel classied as white/gray matter/CSF; volume of subcortical structures estimated

Neuropsychology of bipolar disorder

Dupont et al., 1995 (114) 26

36 BPe, 20 UP

1.5 T scanner, full axial and coronal 5-mm series, partial sagittal series

Sylvian ssure asymmetry decreased in BPs but normal cerebral volume; no differences between BPs and normals on any volume measure; SCZs had signicantly greater sulcal/Sylvian ssure volume than BPs No signicant differences in gray matter volume of heteromodal association cortex regions (superior temporal gyrus/DLPFC/inferior parietal cortex) between BPs and controls BPs had signicantly larger thalamus than UPs and normal controls

133

134
Normal controls Imaging technique Measurements used Results 150 1.5 T scanner, 40 5-mm coronal slices, 6 5-mm mid-sagittal and 14 8-mm transaxial T2 images 1.5 T scanner, 11 5-mm T-1 axial images Visual inspection of CSP by two raters; severity grade of 04 assigned Neuroradiologist made qualitative assessment of anomaly 92 16 1.5 T scanner, T-2 5-mm axial images, with 2-mm interslice gap Two blind raters selected slice best representing thalamus; manually measured thalamic area BrainImage software used for semiautomated ROI tracing of cerebellum, volume of cerebellar hemispheres 15 1.5 T scanner, 3-D RF-spoiled FAST sequence, 1-mm coronal slices 12 1.5 T scanner, 3-D FAST sequence 22 1.5 T scanner, 3-D SPGR sequence, 1-mm coronal slices BrainImage software used for morphometric measures of PFC, caudate, thalamus, hippocampus, and cerebral cortex BrainImage software used to dene ROIs; manual tracing used for volumetric measurements of subcortical structures, prefrontal cortex

Table 6c. (continued)

Bearden et al.

Study

Number of subjects

Lewine et al., 1995 (119)

20 BP, 27 UP, 20 SZA, 108 SCZ

Shioiri et al., 1996 (162)

69 BP, 44 UP, 40 SCZ

Dasari et al., 1999f (145)

15 BP, 20 SCZ

DelBello et al., 1999 (199)

30 BPg

Sax et al., 1999 (23)

17 BPa

Strakowski et al., 1999 (144)

24 BPh

Normal controls had a signicantly higher proportion of normal scans than all patient groups, but no signicant association between diagnosis and type of anomaly Signicantly higher incidence of grade 14 CSP in BPs and SCZs than NCs. Prevalence of grade 34 CSP signicantly higher in SCZs, but not BPs. No differences between BP and SCZ groups; combined SCZ and BP patient group had signicantly lower thalamic area compared to NCs Cerebellar V3 area decreased in multiple-episode patients vs. rst-episode patients and NCs; volume loss associated with number of previous episodes of depression but not mania No differences in whole-brain volume; BPs had decreased PFC volume only; performance on CPT task correlated with PFC and hippocampal volume Signicantly increased amygdala volume in BPs; thalamus, globus pallidus and striatum also larger in BPs than controls; no differences between rst-episode and multiple-episode patients

BP= bipolar; UP=unipolar; SZA= schizoaffective; SCZ= schizophrenic; FD=fractal dimension; PFC=prefrontal cortex; NC=normal controls. All manic at time of testing. b Early onset, severe. c First-episode, never-medicated patients. d Patients rst treated for BP no more than 18 months prior to testing. e 6 depressed, 7 hypomanic at testing. f Adolescent patients. g 16 rst-episode manic patients; 14 BP patients with prior manic episodes. h 14 manic, 10 mixed (83% were psychotic) at testing.

Neuropsychology of bipolar disorder

did nd increased amygdala volume, a nding that had not previously been reported. Taken together, these ndings suggest that, if temporal lobe volume reduction does exist in bipolar disorder, it is highly variable and may only characterize a small subgroup of patients. Given that this has been a fairly consistent nding in the schizophrenia literature, particularly in terms of gray matter reduction (130), reduced temporal lobe volume appears to be more characteristic of schizophrenia than bipolar disorder. Ventricular enlargement. Table 6b summarizes results of MRI studies of ventricular enlargement in bipolar disorder. Of 10 studies that examined enlargement of third and lateral ventricles, ve (122, 138141) found signicantly larger third and lateral ventricles, and three found ventricles to be slightly larger in bipolar patients than in controls, but not signicantly so (130, 142, 143). Furthermore, this nding was reported in both rstepisode and adolescent bipolar subjects (122, 140), suggesting that, similar to schizophrenia (101), ventricular enlargement is present at the onset of bipolar illness. Of the two studies that found no overall differences between patients and controls, one (123) studied a very small sample of bipolar children, aged 616 years, and found lateral ventricular enlargement to be highly correlated with age. Thus, normal developmental changes may have obscured any potential differences between the groups. The other study (133), although lacking signicant group differences overall, found ventricles to be signicantly larger in poor-outcome bipolar and schizophrenic patients than in those with more positive outcomes. Kato et al. (139) also found signicantly greater ventricles in bipolar patients with psychotic features, suggesting that ventricular enlargement may reect greater illness severity. Other structural abnormalities. Abnormalities of limbic regions are of particular interest in bipolar disorder, as these brain regions are thought to be centrally involved in mood regulation (137, 144). As can be seen in Table 6c, MRI studies have generally revealed little evidence of volume reduction in limbic structures. Rather, there is some preliminary evidence of increased structural volume in certain areas, particularly the amygdala (137, 144). Aylward et al. (113) also reported larger caudate volume in male bipolar patients, but found no differences in volume for the other structures examined (globus pallidus, putamen). The thalamus, which functions as a relay station between the prefrontal cortex and the limbic system, has also

been implicated in the pathophysiology of mood disorder (61). However, imaging ndings to date are quite inconsistent; while Altshuler et al. (131) found larger thalamic volumes in bipolars than in unipolars and controls, Dasari et al. (145) reported signicantly reduced thalamic volume in adolescent bipolar patients, and Strakowski and colleagues (122) found no differences in thalamic volume between rst-episode bipolar patients and controls. However, given the noted effects that neuroleptic and mood-stabilizing medications may have on subcortical structures, differences may be due to medication effects (146, 147). Several investigations have reported no overall cerebral volume reductions in bipolar illness (130, 132, 148). Findings with regard to volumes of specic tissue types are varied: while one study reported reduced cortical gray matter volume in bipolar patients compared to controls (142), two others did not (141, 149). Two intriguing ndings are those of an increased gray:white matter ratio in bipolar females (122) and increased fractal dimension (FD) in bipolar patients compared to controls and schizophrenics (148). The FD methodology involves the identication of the cortical/subcortical boundary by the abrupt local transition from high signal intensity values, associated with relatively watery, predominantly cellular gray matter, to lower signal intensity values associated with relatively fatty, predominantly axonal white matter. As FD is a measure of structural complexity, this nding may reect abnormalities of the cortical/subcortical interface in bipolars that is, the shape may be anatomically more complex than normal. These results appear to be consistent with two earlier CT reports of increased density in specic regions in bipolar patients compared to controls, one of which found increased density of the left caudate and thalamus, left frontal and parietal gray matter, right parietal white matter and the right occipital region (150), while another (102) found greater cortical density in the right temporal lobe, anterior white matter and diencephalic nuclei. While the nding of higher global mean FD in bipolars (148) is provocative, the authors speculate that this nding may reect altered brain water metabolism, due to illness or treatment (although there were no differences due to medication status), and may also be related to the ndings of focal subcortical signal hyperintensities in bipolar patients. Neuropathological studies. The limited number of studies of the neuropathological basis of mood disorders may be due in part to the recurrent, rather than chronic, pattern of these disorders. The 135

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associated symptom-free periods have suggested to many that etiologic factors are more likely biochemical than histopathological although diseases such as epilepsy would suggest this assumption may not necessarily be valid. While some post mortem studies have reported similarities between affective disorder patients and schizophrenics, including swelling of oligodendroglia in biopsy tissue of the parieto-occipital cortex and excessive branching of motor nerves (151), others have failed to nd signicant pathology in affective disorder cases (152). Moreover, it is likely that these similar ndings could reect effects of long-term antipsychotic medication in both patient groups. Brown et al. (153) found the brains of schizophrenics to be signicantly lighter (by 6%) than brains of affective disorder cases, with 19% larger anterior ventricles, particularly in the temporal horn area (by 97%), as well as signicantly thinner paraluppocampal cortices (by 11%), suggesting more extensive structural pathology in schizophrenia. However, a recent neuropathological study (154) reported a reduction in glial number in the prefrontal cortex of affective disorder patients, which was most prominent in patients with familial forms of major depressive disorder or bipolar disorder. This is consistent with these investigators report of reduced glucose metabolism in subgenual prefrontal cortex in bipolar and unipolar depressed subjects (155). Additionally, the reports of abnormal histoarchitecture of the enthorhinal cortex in bipolar disorder (156) are suggestive of a migration disruption in the second trimester, strengthening the argument for a common neurodevelopmental mechanism in the major psychoses.
Structural neuroanatomical ndings: summary

lar mood disorder and schizophrenia, and thus may reect a common feature of psychosis. Nevertheless, volumetric reduction in brain tissue both overall and of specic structures does not appear to be as consistent nding in bipolar disorder as it is in schizophrenia. Further, a recent review comparing structural imaging and post mortem neurohistological studies of schizophrenia and mood disorder (147) concluded that, despite the broad overlap in structural ndings, the limbic system, heteromodal association cortex and mesiotemporal structures appear to be more affected in schizophrenia, while subtle structural abnormalities in basal ganglia structures may be a primary focus of anatomical change in mood disorders. In light of the laterality hypotheses and early cognitive ndings, it is of particular interest to evaluate the structural anatomical (MRI and CT) ndings in terms of specic RH abnormalities. Aside from an isolated report of smaller right hippocampal structure in bipolar patients (118), there appears to be little evidence of specic RH abnormalities or of abnormal asymmetry.
Etiology of structural and metabolic abnormalities

In summary, it appears that structural abnormalities are quite common in bipolar disorder. Some of these abnormalities (i.e., white matter hyperintensities) appear to be more common to mood disorders than to schizophrenia, and are possibly more relevant to the pathophysiology of bipolar than unipolar mood disorder. While the few studies examining rst-episode patients have generally not reported such robust ndings as studies of older and previously hospitalized patients, given the extremely small sample sizes of these studies (some consisting only of a single case study), this is unsurprising. Nevertheless, studies of younger and rst-episode patients have reported such ndings in at least a portion of patients (122, 123). Other abnormalities in particular, ventricular enlargement appear to be common to both bipo136

The putative contribution of genetic or environmental factors to the brain abnormalities in bipolar patients remain largely unexplored. Some of the most consistently reported structural ndings are lateral and third ventricular enlargement, sulcal enlargement and cerebellar atrophy (59, 157). Because similar structural changes are found in schizophrenia, these nding appear rather nonspecic with regard to diagnosis, and thus may reect nonspecic symptoms, such as psychosis. The presence of these structural defects in schizophrenic patients has been taken as evidence of a neurodevelopmental contribution to the pathology of the disease. Given that hypoplasia of the medial temporal lobe has been reported to occur with similar frequency in schizophrenia and bipolar disorder (158), it seems plausible that a neurodevelopmental etiology might also be important in primary bipolar disorder (159). Thus, it may be that the overlap in abnormalities in brain structure and function in schizophrenia and bipolar disorder may arise from similar anomalies in gene expression that affect brain growth and development in both patient populations. Indeed, while such ndings have been regarded as integral part of evidence for a neurodevelopmental origin of schizophrenia, few such claims have been made for bipolar illness. Nasrallah (159) puts forth the speculation that a disruption of brain development could contribute to bipolar disorder, citing the ndings of ventricu-

Neuropsychology of bipolar disorder

lar enlargement and medial temporal lobe hypoplasia in bipolar disorder as support for a neurodevelopmental origin for bipolar illness, possibly reecting a second trimester disruption of hippocampal development. In schizophrenia, the enlargement of CSF-lled spaces may serve as an indirect index of cerebral damage, sustained perhaps during the perinatal period; however, as very few neuroimaging studies have been conducted in rst-episode bipolar patients, it is not known at present whether this structural abnormality precedes the onset of clinical illness. Thus, it is unclear whether ventricular enlargement has a similar signicance in mood disorders. It is possible that CNS trauma during early development constitutes a risk-increasing factor in bipolar disorder in similar fashion to its putative role in schizophrenia (101). In support of this notion, Sigurdsson et al. (160) recently found neurodevelopmental antecedents (delayed language or motor development) to be more common in adolescents with early-onset bipolar disorder, particularly in those with psychotic features, compared to early-onset unipolar depression. Recent MRI studies of adolescent-onset patients found that both adolescent bipolar and schizophrenic patients had reduced brain size, reduced thalamic size, increased ventricular volume and increased frontal and temporal sulcal size compared to normal adolescents, but the two patient groups did not differ from each other on any measure (140), suggesting a neurodevelopmental etiology for both disorders. Further, the lack of progressive increase in cerebral ventricular size over time in bipolar patients (161) supports a neurodevelopmental hypothesis. It is possible that neurodevelopmental processes, including a disruption of gene expression of brain growth and sculpture, are an area in which the etiology of schizophrenia and bipolar disorder may overlap. The absence of gliosis in frontal or temporal regions suggests that it is not an ongoing neurodegenerative process, but rather a genetic defect or early brain damage that may impair neuronal growth. Consistent with this possibility is the nding of increased incidence of cavum septum pellucidum (CSP), a nonspecic developmental anomaly, in both bipolar disorder and schizophrenia (162). However, it is important to note that only schizophrenics showed moderate to large CSP; this nding was signicant for bipolar patients only when a broader denition of CSP was used, suggesting this developmental anomaly may only be relevant to some cases of bipolar disorder. Beckmann and Jacob (156) hypothesize that prenatal disturbances of nerve cell migration in entorhinal regions may be a common vulnerability factor

in functional psychosis. Given the high heritability of bipolar disorder (10), it seems plausible that genetic factors play some role in contributing to these abnormalities; however, the mechanism by which such a genetic predisposition might participate in the development of the particular neuroanatomical and functional anomalies remains to be elucidated. Because no high-risk neuroimaging studies of the offspring of bipolar patients, or of unaffected siblings, have been conducted to date, it is unknown whether such abnormalities reect an underlying genetic vulnerability to the disorder. Currently, little evidence exists for involvement of obstetric complications (OCs) or teratogenic inuence in early development in bipolar disorder (163), nor of a relationship between exposure to inuenza epidemics in fetal life and later affective disorder (164). Moreover, in contrast to schizophrenia, there is no evidence of early neuromotor abnormalities (165), nor of an increased number of minor physical anomalies in bipolar disorder, which are presumed to reect disturbances in second trimester development (166, 167). Foerster et al. (168) found OCs in 40% of schizophrenic probands, but only 7% of those with affective psychosis. Soft neurological signs and low birth weight were also more common to schizophrenia in this study. However, those bipolar patients that did have an early developmental risk factor (OCs, low birth weight, or childhood cerebral insult) or a family history of psychosis had an earlier hospitalization than those with no risk factors. Thus, while such difculties may hasten the onset of the disorder, early developmental injuries do not appear to be particularly relevant to the pathogenesis of the disorder. Consistent with the possibility that neurodevelopmental factors may play a greater role in the pathophysiology of early-onset affective disorder than in later-onset cases, van Os and colleagues (169) found elevated rates of delayed motor and speech development in patients with juvenile-onset affective disturbance, but not adult-onset patients. Contrary to these hypotheses, some researchers have suggested that, unlike schizophrenia, when structural abnormalities occur in affective psychosis, they are associated with late rather than early onset of illness (94, 170). Some investigators (65) have posited that when ventricular enlargement occurs in affective disorder, it is in late-onset cases in which affective disorder may be a manifestation of some primary brain disorder such as cerebral vascular disease, thus suggesting that, although structural abnormalities such as ventricular enlargement may not be specic to schizophrenia, they may reect a different pathophysiological process in bipolar illness. 137

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Thus, an alternative explanation for the structural changes in bipolar disorder is that an aspect of the disease may be destructive to brain tissue, thus resulting in enlarged ventricles and other structural abnormalities (54, 171). Altshuler (54) speculates that there may be an ongoing destructive process that accompanies the occurrence of each episode of depression or mania. As a possible mechanism, she postulates that stress-associated hypercortisolemia a common nding in bipolar disorder may result in toxicity to the hippocampus, decreased gluticocorticoid receptor numbers, and ultimately cell death and tissue loss in temporal lobe regions. Recurrent episodes may contribute insults to the CNS that impair efciency, thus resulting in cognitive decline. However, at present, the relationship of episode frequency and severity to structural and/or cognitive changes over time is unknown. Further, as there are very few existing studies of late-onset bipolar disorder, it is unknown whether it has a distinct etiology or whether it is continuous with the earlier-onset form of the disorder. Another area sorely in need of investigation is comparison of early-onset and lateonset cases, as such an analysis may provide important clues into differences in etiology.

Cognitive and neuroanatomical ndings: integration

Only a few studies have attempted to directly examine the relationship between brain morphometry and neuropsychological function in bipolar disorder. In a sample of psychotic bipolar patients, Coffman et al. (20) found fairly widespread cognitive impairment and that the degree of decit signicantly correlated with reduction in midsaggital brain areas, while Dewan et al. (102, 172) found that those bipolar patients with greater ventricular enlargement performed more poorly on the Halstead Reitan battery. Additionally, Sax et al. (23) found that bipolars in the acute manic stage performed more poorly than controls on attentional measures, and that task performance correlated signicantly with prefrontal and hippocampal volume, but not with volume of the caudate or thalamus. This suggests that abnormalities in the fronto-subcortical neuroanatomic circuit are associated with impaired attentional function in manic patients. Ali et al. (173) have recently reported that enlarged right hippocampal size (abnormalities of temporolimbic structures) was associated with decits in verbal memory, attention and concentration. However, the several limitations of this study (including lack of a control group) make the results very preliminary. 138

Hickie et al. (107) reported that performance on psychomotor speed tests declined as the extensiveness of white matter hyperintensities increased in a sample of depressed unipolar and bipolar patients. Dupont et al. (114) found that those bipolar subjects with high volumes of white matter hyperintensities performed signicantly worse in 9 of 12 cognitive tests than bipolars with low volumes of white matter hyperintensities. This difference was not attributable to medication treatment and was not found in unipolar depressed or control subjects. Specically, bipolars with high volumes of abnormal white matter performed signicantly worse on tests of verbal uency, psychomotor speed and sequencing, and verbal recall, which is suggestive of a subcortical cognitive dysfunction, and is similar to the pattern reported by Junque et al. (127) in nonpsychiatric elderly patients with white matter hyperintensities. Nevertheless, one recent study found no difference in performance on tests of memory, speed, and cognitive exibility between bipolar patients with white matter lesions and those without (19). However, the authors caution that the limited power of this study (22 patients) make these results tentative. Given the robust and highly consistent ndings of deep white matter hyperintensities in bipolar disorder, and their possible relationship to cognitive impairment (114, 127) it seems plausible to speculate that such abnormalities may play a role in the cognitive impairment seen in bipolar disorder. Given that there is little or no evidence to suggest that bipolar patients are globally intellectually impaired prior to onset, and the presence of white matter hyperintensities increases with age in normals and particularly in depressed patients, it seems reasonable that these lesions may play an increasing role in bipolar cognitive impairment with increasing age and chronicity of disorder. It may be the case that, while white matter hyperintensities do not cause the cognitive impairments seen in bipolar disorder in and of themselves, they may increase the likelihood that patients will manifest these decits, and thus may be considered a risk modier for cognitive dysfunction in bipolar disorder. The relationship between age, clinical severity, cognitive function, and underlying neuroanatomy is likely to be complex, but is an avenue that must be pursued in future research. Findings of impaired conceptual development, abstraction abilities, and decits in other functions generally attributed to frontal lobe function (27, 30) indicate that frontal cortex pathology may also be involved in the cognitive impairments seen in bipolar patients. It may be postulated that the defects in the frontal-basal ganglia circuit that have

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been proposed in bipolar disorder (121, 147, 154) may also be negatively impacting cognitive function (174). This is a potential anatomical substrate for the involvement of subcortical nuclei in cognitive processing, particularly working memory, rulebased learning, and planning future behavior. However, ndings of abnormalities in temporolimbic structures (130, 131, 134), coupled with evidence of learning and memory disturbance in bipolar disorder (62, 71), suggest temporolimbic dysfunction may also be involved. Given the widespread and variable pattern of cognitive decits seen, there is little evidence of localized dysfunction. However, this notion must be further investigated in order to determine whether particular subgroups of patients display particular patterns of impairment and corresponding structural abnormalities.
Functional neuroimaging studies

The methods that have been employed in studying the functional brain abnormalities underlying bipolar disorder are positron emission tomography (PET), single-photon emission computed tomography (SPECT) and nuclear magnetic resonance spectroscopy (Table 7). These techniques are potentially invaluable tools in understanding the specic biochemical processes involved. PET is an analytical imaging technique that provides in 6i6o measurements of the anatomic distribution and rates of specic biochemical reactions. It is unique in that it permits both visualization and quantication of cerebral biochemical processes (175). While early PET studies were acquired with spatial resolution of approximately 2 cm, the technology has been greatly rened in recent years, such that the spatial resolution has increased to about 4 mm (63). This is likely to contribute to disparate ndings and renders crossstudy comparisons difcult. Several investigators have noted globally reduced blood ow or metabolic rate in bipolar depressed patients, but not unipolar depressed patients (63). Additionally, three studies have reported bilateral hypofrontality in the depressed state in bipolar patients, relative to normal controls (176 178). Martinot et al. (178) reported this nding despite clinical improvement. Signicantly lower overall temporal lobe blood ow in bipolar depressed patients compared to normal controls, as well as decreased glucose metabolism in the basal ganglia relative to whole-slice metabolism, have also been reported (85, 177). Two studies also reported decreased caudate glucose use in affective disorder patients; while Baxter et al. (179) found

this only in unipolar depressed patients, Buchsbaum et al. (177) found caudate hypometabolism in both unipolar and bipolar patients. This structure has extensive connection with the prefrontal cortex, as does the amygdala, which is known to serve affective processes (61, 64). Using PET uoro-2-deoxy-D-glucose (FDG), Baxter et al. (179) found that, while all patient groups and controls had a signicantly higher metabolic rate in left than right frontal cortex, bipolars showed the greatest difference between the two. This research group (180) later reported that bipolar depressed patients rescanned in a euthymic state had a signicant increase in global metabolism, as well as a signicant increase in the left, but not the right, antero-lateral prefrontal cortex (ALPFC):hemisphere ratio. Both the left and right ALPFC:hemisphere ratios were decreased in both bipolar and unipolar depressed patients compared to normals and non-depressed obsessive-compulsive disorder (OCD) patients. Given that a depressed ALPFC:hemisphere ratio was also seen in OCD patients with secondary depression, Baxter et al. (179) interpret this nding as a suggestion that a depressed ALPFC:hemisphere ratio, particularly in the LH, may be a trait marker of a depressed mood state. Martinot and colleagues (178) also reported decreased glucose metabolism in left versus right prefrontal cortex in bipolar and unipolar depressed patients, which was absent after treatment. The authors conclude from this nding that medication may decrease this prefrontal asymmetry. A provocative study by Drevets et al. (181) recently reported abnormally decreased cerebral glucose metabolism and blood ow in the most anterior regions of the cingulate gyrus, the subgenual prefrontal cortex (PFC), in both unipolar and bipolar depressed subjects with familial forms of the disorder. The decrement in activity may be accounted for by a corresponding decrease in cortical volume as patients showed signicant reductions in gray matter volume in the same area. However, mean metabolism in manic bipolar patients was signicantly greater than bipolar and unipolar depressed patients and normal controls, suggesting that subgenual PFC metabolism is mood-state dependent. To date, there has been little research on functional abnormalities in the manic state. Using SPECT, Migliorelli et al. (85) found lower blood ow in the right basotemporal cortex in manics and this was inversely correlated with mania scores that is, lower right basotemporal blood ow was found in patients experiencing more severe mania. However, manics also had signicantly lower over139

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Normal controls 19 Forearm shock, eyes closed/ears open Resting state, eyes/ears open FDG 11-mm in plane, 12.5-mm axial FDG 1.75 cm in plane, 1.78-cm axial Conditions Tracer Resolution Findings 9 24 Forearm shock, eyes closed/ears open FDG 1.75 cm in plane, 1.78-cm axial 18 Forearm shock, eyes closed/ears open FDG 1.75 cm in plane, 1.78-cm axial 7 Resting state, eyes/ears open C-glucose 11 mm in plane, 12 mm in axial 12 Resting state, eyes/ears open FDG 11 mm in plane, 12.5 mm axial Lower frontal:occipital metabolic ratio in BPs vs. NCs (relative hypofrontality); relatively lower antero-posterior gradient BP depressed and BP mixed patients had lower whole brain metabolic rates; increased when rescanned in hypomanic or euthymic state. UPs had low caudate/hemisphere ratio BPs had relative hypofrontality/low basal ganglia/hemisphere ratios vs. controls; UPs and BPs had signicantly lower caudate glucose use vs. controls Max. glucose use relative to maximums elsewhere in same slice higher in right temporal lobe in moderately depressed patients (trend on the left); overall, affective patients had signicantly higher left temporal lobe glucose utilization, largely due to improved patients Controls had hyperfrontal patterns; C-glucose counts in brains of BP manics signicantly higher than controls; C-glucose counts in depressed patients signicantly lower than controls; C-glucose counts in remitted patients= to normals; BP manics had globally increased cortical amino acid pools For left and right ALPFC:hemisphere ratio, normal controls= OCD without depression\BP depressed= UP depressed; 12 depressed patients rescanned after successful treatment had signicant increases in left, but not right, ALPFC:hemisphere ratio

Bearden et al.

Table 7. Functional neuroimaging studies (PET/SPECT)

Study

Patients

Buchsbaum et al., 1984 (176)

10 BP depressed, 1 UP, 16 SCZa

Baxter et al., 1985 (179)

13 BP (3 mixed, 5 depressed, 5 unspecied), 11 UP

Buschbaum et al., 1986 (177)

16 BP depressed, 4 UPa

Post et al., 1987 (200)

13 BP (5 moderately to severely depressed, 6 euthymic, 2 hypomanic)a, 17 SCZ

Kishimoto et al., 6 BP (3 manic, 3 remitted depressed), 1987)b (201) 9 UP depressed (moderately)c

Baxter et al., 1989) b (180)

10 BP depressed, 6 BP manic, 10 UP, 14 OCD without major depression, 10 OCD with secondary depression

Table 7. (continued) Normal controls 10 Resting state, eyes/ears open FDG 13-mm FWHM Conditions Tracer Resolution Findings

Study

Patients

Martinot et al., 1990) d (178)

7 BP depressed, 3 UP depressed

Suhara et al., 1992 (202) 7 Resting state rCBF (SPECT)

10 BP (6 euthymic, 3 depressed, 1 manic)c

21

Carbon-11

Migliorelli et al., 1993)b (85)

5 BP manicc

al-Mousawi et al., 1996 (182) 10 Resting state, eyes closed/ears open

16 BP (15 manic, 1 depressed)e, 9 UP depressedf, 17 SCZe FDG

Drevets et al., 1997b (181)

7 BP depressedg, 4 BP manic, 10 UP depressedg 12 Resting state, eyes closed/ears open FDG

Decreased left PFC metabolism in untreated depressed BPs and UPs, but not post-treatment; whole cortex and whole frontal metabolism lower in BPs and UPs than NCs, both pre- and post-treatment ? DA-binding potential (k3/k4) signicantly lower in BPs than NCs in frontal cortex, but no difference in striatum ? Signicant rightBleft asymmetry of temporal basal cortex in BPs; BPs had signicantly lower overall temporal blood ow; trend toward negative correlation between mania score and right basotemporal blood ow. 17.2 mm in plane Signicant bilateral anterior:posterior FWHM gradient in all patient groups; decreased left amygdala/increased right temporal uptake in BP manic and SCZ groups only 3-D 14-mm FWHM Lower cerebral blood ow and glucose metabolism of subgenual PFC in depressed BPs and UPs; correlated with decreased gray matter volume in left PFC. Mean metabolism in manic group higher than normals, BP depressed, and UP depressed patients.

BP= bipolar; UP= unipolar; SCZ =schizophrenic; FDG=uoro-2-deoxy-D-glucose; OCD= obsessive-compulsive disorder; ALPFC= antero-lateral prefrontal cortex; FWHM: full width at half maximum; PFC= prefrontal cortex. a All patients medication-free for at least 2 weeks. b All subjects right-handed. c Patients medication-free at testing. d Repeat testing after 1-month antidepressant treatment. e All patients actively psychotic at testing. f 5 with psychotic features, 4 without. g Familial form of depression.

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all temporal blood ow, thus offering little evidence of a specic RH abnormality. Others (182) have also found evidence for decreased frontal uptake in both acute mania and acute depression, comparable to that seen in schizophrenic patients. Further, decreased left-amygdala and increased right temporal metabolism was seen in symptomatic schizophrenic and manic patients, but not depressed patients, suggesting metabolic dysfunction in limbic regions is common to schizophrenia and mania. However, the authors caution that this may be an effect of medication treatment. Phosphorous-31 magnetic resonance spectroscopy (P-MRS) studies have also revealed statedependent abnormalities of brain phospholipid metabolism in bipolar illness. Deicken et al. (183) reported lower than normal phosphomonoester values and pH in the euthymic state in bipolars, which then became higher than normal in both the manic and depressed states. However, the authors stress that caution must be exercised in interpreting these ndings, as these subjects were medicated, and lithium treatment may alter phosphomonoester levels. In summary, functional neuroimaging ndings to date in bipolar disorder have come from relatively few studies using widely different methods, making cross-study interpretation difcult. Divergent ndings may be due to differences in spatial resolution, differences in clinical state at time of testing, or different conditions at the time of FDG uptake (i.e., relaxed state versus forearm shock). The main ndings of resting-state studies appear to be decreased blood ow to the prefrontal cortex, anterior cingulate and caudate associated with a depressed mood state in both bipolar and unipolar disorders, which appears to be highly state-dependent (63, 184). But because hypofrontality has also been reported in many studies of schizophrenic patients (185 188), it does not appear to be specic to a mood state of clinical depression. Further, it remains uncleat whether unipolar and bipolar patients can be distinguished on the basis of functional imaging studies (63). The ndings of decreased glucose metabolism in caudate and basal ganglia structures suggest the possibility of abnormal metabolism in subcortical structures in mood disorders. Such ndings are consistent with evidence that these structures are central to the regulation of mood and emotion (61, 184). Although highly speculative, it is possible that hypometabolism in these regions may also contribute to the subcortical cognitive impairments seen in some bipolar patients. Given the highly state-dependent nature of functional imaging measures, differences in methodology can greatly impact 142

upon ndings. Future studies must carefully control for clinical and diagnostic variables, medication status, and control group variables. Further, the relationship between the common structural abnormalities and functional metabolic abnormalities remains unknown. A recent study of normal adults found that subjects with a high volume of white matter hyperintensities had signicantly lower frontal lobe metabolism, as well as signicantly larger ventricular volume, and signicantly lower scores on frontal lobe-mediated neuropsychological tests than age-matched controls (189), which further underscores the importance of correlating anatomical and behavioral measures. Thus, PET scans should be co-registered with MRI scans to control for systematic structural differences both among and between patients and controls (63).
Conclusions and implications

The structural neuroanatomical data do not support the hypothesis of a selective RH lesion in bipolar illness. However, the functional neuroimaging data (PET) do suggest that there are some lateralized abnormalities in brain function that appear to be highly state-dependent and uctuate with mood state. This is consistent with earlier studies of lateralization of function in bipolar disorder (e.g., dichotic listening and motor performance studies), which suggest that the lateralization abnormalities may be highly variable and state-dependent. While speculative, it is possible that the laterality ndings may be reective of a state-dependent neurotransmitter imbalance that uctuates with mood state, whereas other, more enduring cognitive decits may reect disruptions in frontal-subcortical systems (possibly mediated by white matter hyperintensities). Specically, this paper has attempted to answer the following questions: 1) Are there stable neuropsychological decits in bipolar illness that exist independent of clinical state? Contrary to the traditional view, bipolar disorder may indeed be associated with signicant cognitive impairments, particularly in a subgroup of patients. Although the literature suggests that the cognitive decits are relatively more severe and pervasive in states of symptomatic exacerbation, cognitive decits appear to persist in the euthymic state in a subgroup of severely affected patients, though the characteristics of this patient group (i.e., elderly, psychotic features, early-onset) that lead to chronic cognitive impairment remain to be elucidated. While patients with a more severe

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course of illness and greater number of affective episodes have been consistently reported to have more impaired neuropsychological function (28, 52), the direction of causality and the pathophysiological mechanisms are unclear. 2) Do bipolar patients exhibit selective impairments in specic domains or do they demonstrate a more diffuse cognitive impairment? There is some preliminary evidence that relative decits in tasks of conceptual ability and memory processes may exist independent of current mood state, and perhaps in the premorbid state as well (1, 10). While there is some suggestion that verbal skills, with the exception of complex verbal learning and memory, appear to be relatively less impaired in bipolar patients than are visuospatial, non-verbal memory, and abstraction skills, these tests are likely to be more susceptible to the effects of mood symptomatology as they require increased motivation, attention, and speed. Impairments can also be seen in verbal memory when subjects are in an affective episode (21, 41), and in patients with longstanding illness (25, 45, 62). In general, ndings to date do not suggest a specic cognitive prole in bipolar disorder; rather, the more consistent nding across studies appears to be that cognitive decits are fewer and relatively less severe in younger and/or euthymic patients (9, 19, 24, 190), whereas studies of symptomatic, psychotic or chronic elderly patients were likely to nd more diffuse impairment (20, 22, 25, 46, 51). 3) What are the most consistently reported structural brain abnormalities? Are these abnormalities characteristic of bipolar disorder in general, or only characteristic of particular subgroups of patients (e.g., severe, chronic, or elderly)? The literature suggests that structural abnormalities are quite common in bipolar disorder. White matter hyperintensities appear to be the most consistently reported abnormality thus far, though they have also been the most well-researched (106, 111). Abnormalities of cortical and subcortical structures in particular, the temporal lobes, amygdala, basal ganglia and caudate have been described in a number of studies: whether bipolar patients show enlargement or reduction of many of these structures is controversial (64, 65, 130, 137). While reduced temporal lobe volume has been a fairly consistent nding in the schizophrenia literature, particularly in terms of gray matter reduction (130), ndings have been inconsistent in bipolar disorder. Thus, if temporal lobe volume reduction does exist in bipolar disorder, it is highly variable

and may only characterize a small subgroup of patients. While the few studies examining rst-episode patients have generally not reported such robust ndings as studies of older and previously hospitalized patients, given the extremely small sample sizes of these studies (some consisting only of a single case study), this is unsurprising. Nevertheless, studies of younger and rst-episode patients have reported such ndings in at least a portion of patients (122, 123), suggesting these abnormalities are present early in the course of illness. However, the relationship between age and structural brain abnormalities in bipolar disorder white matter hyperintensities, in particular bears further investigation. 4) Are there neuropsychological decits and/or structural and functional brain abnormalities that are unique to bipolar disorder? With regard to structural brain abnormalities, some (i.e., white matter hyperintensities) appear to be more common to mood disorders than to schizophrenia and are possibly more relevant to the pathophysiology of bipolar than unipolar mood disorder (111, 147). Nevertheless, as signal hyperintensities are correlated with cardiovascular risk factors, they occur frequently in diagnostic categories other than affective disorders (111, 127, 189, 191). It is possible that lesions, brain regions in particular specically, the frontal cortex and basal ganglia structures are most frequently associated with bipolar disorder (106, 115, 121, 192). Other abnormalities ventricular and sulcal enlargement, in particular appear to have a similar prevalence in both bipolar disorder and schizophrenia (101, 104). Because many of these studies grouped unipolar and bipolar patients together, it is presently unclear whether ventricular enlargement is more prevalent in bipolar than unipolar patients; however, this nding appears to be relatively nonspecic with regard to diagnosis. In contrast, volume reduction of heteromodal cortical areas and mesiotemporal structures is commonly reported in schizophrenia, but is less characteristic of bipolar disorder (147). With regard to cognitive impairment, there does not appear to be a pattern of decit that is unique to bipolar disorder. While some investigators have reported similarity between the prole of bipolar patients and those of patients with disorders of subcortical structures (15, 21), bipolar patients generally do not exhibit the same degree of decit, but often show a similar pattern of attenuated performance on tasks of speeded information processing, immediate and delayed memory, and 143

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executive functions. Given that studies of the cognitive sequelae of white matter abnormalities in normal, non-affectively ill adults show a similar pattern of impairment (129), we propose that these abnormalities may mediate the cognitive impairments seen in bipolar patients. 5) What is the possible etiology of the neuropsychological and neuroanatomical abnormalities? The etiology of the structural abnormalities of bipolar illness, and their corresponding functional manifestations, remains unknown. It is possible that neurodevelopmental anomalies may play a role, but that there is also some pathophysiological progression that occurs with repeated illness episodes. While it has been proposed that recurrent illness over the lifespan results in an accumulating set of neurobiological abnormalities, it is possible that patients with more severe forms of bipolar illness have lower cognitive capacity at illness onset, or that affective episodes interfere with cognitive development (52). Prospective studies are needed to clarify these issues. Moreover, as there have been so few studies of neuropsychological performance and neuroanatomy in relatives of bipolar probands, no conclusions can yet be drawn as to whether the abnormalities seen in bipolar patients reect an underlying genetic vulnerability to the disorder. The eld of schizophrenia research has made considerable advances in illuminating neuropsychological and neuroanatomical markers of genetic vulnerability to schizophrenia (66); surely, similar endophenotypic markers exist in bipolar disorder and await discovery. By examining bipolar affective disorder from the perspective of more enduring structural and functional abnormalities, considerable progress may be made in the understanding of its elusive etiology.

More studies of rst-episode, unmedicated patients are required to determine whether cognitive changes are due to treatment variables or to the effects of the illness itself, and to obviate chronicity-related confounds. Studies should statistically control for the effects of chronicity, medication (current and past), and the presence of subclinical psychopathology. Also, the selection of a control group that is carefully matched on demographic variables is a critical component of a well-designed study. While measures of depressive symptomatology are generally well documented, measurement of manic symptoms is often inadequate. Efforts must be made to disentangle the combined and independent effects of age, number of episodes of depression and mania, and lifetime duration of illness. Criteria for the denition of euthymia should be fully described and, if possible, standardized across studies. Within the domain of neuropsychology, most studies have concentrated on one or a few areas of cognition rather than using a comprehensive battery that would permit adequate proling of test results across neuropsychological dimensions. Comparison of the phenomenology, neuropsychology and neuroanatomy in early-onset versus late-onset forms of bipolar illness will help to elucidate whether these represent the same illness, and whether they differ in etiology. Studies of neuropsychological function and ERP in conjunction with brain imaging may provide information about diagnostic markers in bipolar disorder.

References Future directions

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Past approaches to the study of bipolar disorder have been at opposite ends of a continuum; at one end, studies have emphasized the analysis of functional units that bear an unknown relationship to brain structure, whereas others have focused entirely on the analysis of basic brain structures that bear an unknown relationship to integrated brain function (8). Studies that integrate these two approaches would help to illuminate the interactions of episode frequency and severity with structural and functional changes over time. This review has described several aws in the prevailing methodology that researchers must consider in future studies. Specically: 144

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Appendix: Selection of studies

To obtain a reasonable sample of studies, we rst searched the major computerized databases (PSYCInfo and Medline) using OVID, PubMed, and Grateful Med software (National Library of Medicine, Bethesda, MD). The searches were

based on the following medical subject heading (MeSH) categories: Neuropsychology or Cognitive Function, Tomography, X-ray Computed or Magnetic Resonance Imaging, Tomography, emission computed and Bipolar Disorder. To ensure that no study was missed, a free-text search was performed on the words affective disorders, mood disorders, mania, depression, psychosis, cognition, neuropsychological decits, cognitive decits, neuroimaging, PET and functional imaging in combination with the MeSH terms. The search was rst conducted in 1997, then was repeated in March of 2000 and July of 2000. The titles, abstracts, and MeSH categories for each article were subsequently examined, and those studies that were potential candidates for inclusion in the review were collected. Additionally, the reference lists of the obtained papers were scrutinized for studies not indexed in the electronic databases. To be considered a candidate for inclusion, a study had to meet the following criteria: 1) the study was selected for patients with bipolar disorder, diagnosed with standard diagnostic criteria, 2) the study presented data analyses that differentiated between unipolar and bipolar depressed patients, rather than using solely a combined affective disorder group, 3) results of individual tests were presented, 4) the study included a control group, whether normals, psychiatric or medical controls, and 5) results and methodology were described in adequate detail. In order to limit the scope of the functional neuroimaging studies, we focused our search on studies of cerebral blood ow or glucose metabolism (PET and SPECT). These were included in the paper if they met the above criteria. If, based on the title, abstract, or MeSH categories, it seemed reasonably likely that a study might possibly be appropriate, a reprint of the article was obtained and reviewed. This procedure resulted in the selection of over 300 studies. Based on inclusion and exclusion criteria detailed above, these studies were either entered into one or more of the tables or considered to be relevant, but not includable. While such methods forced the exclusion of several studies, this was determined to be the most effective way of integrating such a large body of information.

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