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Cognitive Impairment and Cerebral Structure by MRI in Bipolar Disorder Jeffrey A° Coffman, Robert A. Bornstein, Stephen C. Olson, Steven B. Schwarzkopf, and Henry A. Nasra!!ah
The distinction between bipolar disorder and schizophrenia customarily follows examip..ation of the clinical symptomatology and course of illnes5~. The presence of cognitive impairment has been held t,o be uncommon in bipolar disorder and more likely in schizophrenia. This study ezpiored neuropsychological function in 30 ambulatory outpatients with a DSM-111-fl diagnosis of bipolar affective disorder (all of whom had been psychotic during manic episodes), ct:mparing their performance with that of controls. These bipolar patients prove£ to have significant levels of diffusely represented cognitive impairment when compared with controls. Further, the degree of impairment was significantly correlated with reduction in midsagittal areas of bra~n strucy~res measured on magnetic resonance imaging scans. The implications of thesefindings in relation to bipolar disorder are discussed.
Introduction "£he cardinal distinction upon which Kraepelin (191f, 1921) separated manic depressive psychosis from dementia praecox (schizophrenia) was that those suffering from the former tended to experience natural remission whereas those with the la~er did not. This premise has influenced many studies in the 20th century and continues to do so because no completely reliable distinguishing features have emerged (Pope and Lipinski 1978). For example, the brain imaging studies of the last decade do not adequately discriminate between schizophrenia and bipolar disorder. Substantial proportions of both groups show increased dimensions of the CSF-filled spaces around the brain by pneumoencephalo~raphy and computed tomography (Coffman 1988; Nasrallah et al. 1989). As a result, "e,~t4 if, t" many investigators continue to rely on course of illness as the principal dto~,,wa,,a,mg variable. Various studies have reported that outcome for manic-depressive illness is generally good (Hastings 1958; Astrup et al. 1959; Brati0s and Haug 1968; Winokur et al. 1969; Carlson et al. 1974; Tsuang et al. 1979; Goodwin and Jamison 1985; Johnstone et al. 1985; Angst 1986). They have cautioned, however, that from 10%-30% of patients with
From the Department of Psychiatry and Neuroscienee Program, The Ohio State University College of Medicine, Columbus, OH. Address reprint requests to Jeffrey A. Coffman, M.D., 473 W. 12th Avenue, Columbus, OH 43210. Received February 10, 1989; revised October 15, 1989. This research was supportedby a research grant from the Board of Regents of the State of Ohio to Henry A. Nasrallah, M.D.
© 1990 Society of Biological Psychiatry
0006-3223/90/$03.$0
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bipolar disorder show poor social outcome, particularly those with continued affective symptoms. Several studies that examined combined groups of unipolar and bipolar ¢atients noted that the latter fared worse (Astrup 1959; Braffos and Haug 1968). Furthermore, studies of bipolar disorder alone, excluding unipolar patients (Winokur et al. 1969; Carlson et al. 1974; Tsuang et al. 1979) found evidence of social impairment, in spite ~" symptomatic improvement, in 20%-30% of patients. Cognitive impairment seems to occur in a minority of patients with manic depressive illness. Astmp (1959) found 5 of 96 (approx. 5%) manic depressive patients were demented on follow-up whereas Bratfos and Haug (1968) found that 11% of subjects in a mixed unipolar/bipolar group had become demented. Johnstone et al. (1985) found that, overall, a group of chror:ical!y ill bipolar patients showed similar degrees of cognitive impairment to those seen in similarly institutionalized chronic schizophrenics. However, other features of social it~uctioning and behavior distinguished the groups. These included a greater preponderance of overactivity among ~ e bipolar patients and more social withdrawal among the schizophrenics. The degree and nature of cognitive irnpairment seen in bipolar affective disorder remains poorly characterized at present. Agreement on its presence, ~t least in some, approaches the limit of our knowledge. Relationships with other features of the illness are unclear. The present study delineates a detailed neuropsychological assessment of a sample of rO~atively young individuals with psychotic bipolar disorder and relates these findings to indices of cerebral structure obtained through magnetic resonance imaging (MRI). It is, to our knowledge, one of the first such studies reported.
Method Thirty individuals with bipolar "dfective disorder and psychotic features (11 men, 19 women, mean age 32.0 --. 6.2 years) examined as part of a larger study population and 52 normal volunteer controls (33 men, 29 women, mean age 28.8 _ 7.2 years) participated in this study after giving informed consent. Inclusion of individuals ages 20-50 followed establishment of a diagnosis by DSMIII-R c~.teria tbr the bipelar groups and lack of psychiatric diagnosis for the control groups as ascertained by the Structured Clinical Interview for Diagnosis (Spitzer et al. 1987). Erzclusion criteria included (!)serious or debilitating medical illness including seizure disorder; (2) past history of penetrating head injury or neurosurgery; (3) metallic implants in the body; ~ d (4) a 2-year history, preceding entry, of chronic substance abuse.
Imaging Parameters Subjects underwent a sagittal series of MRIs using a GE 1.5 Tesla scanner ~ d an inversion recovery pulse sequence (TI = 800 msec, TR = 1500 msec). The series comprised eight slices about the midline with a slice thickness of 3 mm and an interslice interval of 1 ram. One of the authors (J.C.) selected the midsagittal slice from photograpt~ic representations based on the following criteria: (1) clearest visualization of the corpus callosum; (2) the smallest dimension of the ventriculoseptal region; (3) minimal inclusion of white matter adjacent to the interhemispheric suleus. In addition to the midsagittal slice, the adjacent left and fight parasagittal slices were included for study.
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Measurement Procedure The leh and right parasagittal and midsagittal slice images were projected, enlarged to normal head size, and traced. The tracings were processed by digi~ai planimeterization using a digitizing tablet and VIAS image processing software. For each slice, measurements were made of cranial area (defined by the marrow line), cerebral area, frontal area (defined as the cerebr~ co~ical area anterior to a line perpendicular to the midpoint of the maximum length of the corpus callosum), corpus callosum, and cerebellar area. Average values were calculated from the three slice measurements for structures showing high position-related variance (cerebral and frontal area). The midsagittal slice value was used for structures with little position-related variance (cranial, callosal, aM cerebellar areas) (Coffman et al. 1989). It should be noted that only 29 controls (11 men, 18 women) and 25 bipolar patients (10 ~en, 15 women) underwent MRI study.
Neuropsychological Measurements Neuropsychological examination included the Wechsler Adult Intelligence Scale Revised (WAIS-R), Wechsler Memory Scale Revised (WMS.R), Wisconsin Card Sorting Test (WCST), Verbal Concept Formation Test (VCAT), and an expanded Halstead Reimn Battery. Most subjects received the WMS-R, but some patients and controls examined prior to the availability of this test were given the WMS with 30 delayed recall trials for Logical Memory and Visual Reproduction. These two subtests with delayed recall are common to both versions, and the proportional recall scores (delayed recall/immediate recall) are widely used as measures of verbal and nonverbal memory. Therefore, the measures of verbal and nonverbal memory used in this study were the proportional recall score for Logical Memory and Visual Reproductioa. The groups did not differ regarding educational attainment but did differ on age (see Results). The method used in this study differs from that of some other investigations in that the perseverative errer score from the WCST is based on a modification of the scoring rules proposed by tleaton (1981). The first response in a new set (following acquisition of a set) is not counted as a perseverative error. This modification was used because it seemed to provide a more accurate measure of perseveration. Thus, the scores for a subiect may be reduced by as many as five errors. As most controls achieved all six categories, and most patients did not, the extent of correction may be somewhat greater in the control group. In order to provide a global assessment of cognitive function, summary scores were created according to formulae described previously (Bornstein et al. 1990). The sunmlary scores res, flt from conversion of the raw scores to t-scores (mean = 50, SD = 10) based on the normal distribution of normal subjects. Thus, performance on each of the variables appears on a common metric, which facilitates examination of performance on a range of tests. I'hese t-scores were then combined into summary indexes based on the nature of the tasks. For each of the indexes, the score represents the mean t-score for the tests included in that summary score. A left iiemisphere index included those measures generally thought to primarily reflect left hemisphere function (verbal IQ, % retention of verbal material from the WMS-R, VCAT, and fight hand scores on: finger agnosia, dysgm phesthesia, Finger Tapping, and Grooved Pegboard Test). The fight hemisphere index summarizes results on tests generally thought to primarily reflect right hemisphere function
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Table I. Demographic Characteristics of Sample Characteristics
Bipolar patients
Normal controls
Total sample Total women Mean age - sD Mean years of education +_ SD
30 19 32.97 _ 6.20 14.67 _ 2.07
52 29 28.77 _ 7.17 15.52.4- 2.15
(!x~rformance IQ, % retention of nonverbal material from the WMS-R, and left hand scores on finger agnosia, dysgraphesthesia, finger rapping, and Grooved Pegboard Test). A general index pertained to tests that have been shown to be generally sensitive to cerebral integrity, but with little localizing or lateralizing value [Category Test, Tactile Performance Test, Memory and Location scores, Trail-Making Test (parts A and B), Speech Sounds Perceptions Test, Seashore Rhythm Test, and the Knox Cube Test]. The perseverative error score from the WCST was included in the General Index because most of the studies to date indicate that this measure may show impairment in patients with dysfunction in either frontal lobe.
Statistical Methods Comparisons between groups were made using an~Jysis of variance relying on SPSS-X software routines. Potential covafiates of age, symptomatic severity [total of positive and negative symptom scores on the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) (Andreasen 1982; Andreas~n and Olsen 1982)], years of education, and average daily neuroleptic dosage in chlorpromazine equivalents were evaluated by calculation of Pearson correlation coefficients with neuropsychological performance. For those neuropsychological tests showing significant correlation (p ~< 0.05) with any of the potential clinical covariates, analysis of covariance followed, rather than analysis of variance alone. Pearson correlation coefficients between MRI measures and global scales (general, left, and right hemispheric functions) for neuropsychological performance served to assess the contribution of cerebral structure to the variance observed in cognitive performance. Performance on individual neuropsychological measures distinguishing the groups served to confirm the pattern seen on the global scales.
Results Demographic characteristics apl~:ar in Table 1. Age differed significantly between groups but years of education did not. Neuropsychological test results can be seen in Table 2 and reveal marked differences between groups due to diagnosis, even where covariance was ~ppljed for symptomatic severity, age, education, and neuroleptic dose. It should be noted that the differences in performance observed did not occur in any particular pattern but were diffuse. In general, these differences occur on both verbal and nonverbal tasks, as well as sensory and motor tasks on both sides of the body. Nevertheless, there was some suggestion of greater right hemisphere impairment in the bipolar group. In particular,
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Table 2. Neuropsychological Test Results Test Halstead Category Test Tactile Performance Test Memory
Covariates S A
Time
Location Seashore Rhythm Test Speech sounds perception
A S A
Trail-Making Tes t. A B
A
Verbal concept attainment Verbal fluency WCST--persevemtive
Bipo!ars
Controls
(n - 30)
(n - 52)
F
Value
73.11 - 30.17
34.11 ± 20.59
6.37
0.014
1.13 241.30 2.21 2.12 3.83 6.52 20.49 1.84 24.00 6.48
16.16 38.66 13.08 1.78 3.62 18.46 13.87 24.67 12.57 13.93
0.000 0.000 0.001 0.186 0.061 0.000 0.000 0.000 0.001 0.000
0.95 0.95 5.86 4.99 7.97 9.65 1.03 1.43 1.37 0.97 1//.08 12.44 9.02 11.67
6.93 4.74 1.49 9.16 12.88 10.90 4.76 1.65 7.25 12.29 0.001 13.001 0.846 2.187
0.010 0.032 0.226 0.003 0.001 0.001 0.032 0.203 0.009 0.001 0.981 0.001 0.361 0.143
6.63 1099.;0 2.,o0 2_5,.07 6.67 29.37 81.73 17.13 52.80 13.60
.4± ± ± ± ± -± ±
1.92 401.00 2.30 3.62 3.33 10.61 42.82 5.36 28.34 18.00
8.29 658.80 4.81 27.96 4.54 21.25 49.06 21.17 73.65 3.33
± ± ± ± ± ± ± ± ±
5.33 5.23 44.63 40.01 81.63 86.40 1.07 0.90 2.13 2.07 84.72 79.94 97.47 93.50
± ± ± ± ± ± ± ± ± ± ± ± ±
1.03 1.19 6.57 5.99 18.73 21.62 1.72 1.58 2.44 1.84 13.29 18.85 9.66 14.65
5.92 ± 5.87 ± 47.73 ± 43.77 60.98 ± 64.65 ± 0.40 ± 0.46 1.00 ± 0.73 ± 84.65 ± 92.40 ± 107.23 ± 106.44.4-
p
erro~
Knox Cube Test im,,nediate delayed Finger Tap right left Pegboard right left Sensory agnosia right left Graphe~thesia right Graphesthe~ia left Verbal memory Nonverbal memory Verbal I.Q. Performance I.Q.
A A D,A D
A A
S S,E
S : total symptoms; D = drug dosage (average daily chlorpromazineequivalence); A = age; E = education; F : F value (and related p) for diagnostic group as main effect after covariance has been removed (if applicable).
the patient group differed from controls in nonverbal memory but did not di~er on verbal memory. Similarly, the patients differed significantly from controls on the left but not the right hand score for Finger Tapping. Although these findings could be interpreted to suggest right hemisphere dysfunction, these deficits appear in the context of a much broader pattern of cognitive impairment. Therefore, this study offers no clear support for the view of affective disorder as a "right hemisphere disorder" as proposed by some investigators (Flor-Henry and Yeudall 1979). Table 3 illustrates the results of correlation analysis between the global neuropsychological performance scales and midsagittal MRI measures. Smaller cerebral and frontal areas appeared to be associated with global impairment (correlations ranging frown0.3342 to 0.4397). No lateralization of the structure-function relationship appeared as reflected in the minimal differences between the general, left, and right indexes. In these comparisons, smear structural areas accounted for 11%-19% (R-squared ranging from 0o112 to 0.193) of the performance variance observed. Table 4 shows further results of MRI/neuropsychological performance comparisons. The table demonstrates that impaired performance, on a number of tests broadly representing cerebral functions, was significantly correlated with smaller areas of me cerebrum and the frontal portion of the cerebrum as seen in the midsagi~3 plane. Fewer significant
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Table 3. Correlations Between Summary Neuropsychological Test Scores and Midsagittal Brain Area Measures (n = 27 Bipolars, n - 27 Controls) MRI area measures
Summary score General index Left index Right indz~
Cranial
Cerebral
Frontal
Callosal
0.1880 p = 0.068 0.2489 p - 0.024 0.3243 p - 0.004
0.3342 p = 0.003 0.3386 p = 0.003 0.4373 p = 0.0o0
0.3916 p = 0.001 0.3871 p = 0.001 0.4397 p = 0.000
0.2455 p = 0.025 0.2427 p = 0.027 0.2854 p = 0.011
c o r r e l a t i o n s a p p e a r e d b e t w e e n c a l l o s a l a n d c r a n i a l m e a s u r e s a n d n e ~ o p s y c h o ! o g i c ~ results. N o n e o f the n e u r o p s y c h o l o g i c a l m e a s u r e s that correlated w i t h f r o n t a l l o b e M R I m e a s u r e s are g e n e r a l l y a c c e p t e d as b e i n g s p e c i f i c a l l y s e n s i t i v e to f r o n t a l l o b e f u n c t i o n s . A g a i n , t h e r e w a s little e v i d e n c e o f strictly l o c a l i z e d deficits. It is i m p o r t a n t to note that the b i p o l a r g r o u p h a d a s m a l l e r m e a n area for t h e c o r p u s c a l l o s u m ( 6 . 8 3 - 1.60 v e r s u s 7 . 6 4 + 0 . 9 7 , p = 0 . 0 3 , t w o - t a i l e d t-test) a n d t e n d e d to h a v e a s m a l l e r m e a n frontal a r e a ( 3 5 . 0 2 ± 3 . 9 2 v e r s u s 3 6 . 7 0 4- 3 . 2 6 , p = 0 . 0 9 , t w o - t a i l e d t-test). T h e r e m a i n d e r
Table 4. Pearson Correlation Coefficients (>0.3000) Between Midsagittai Brain Measures and Those Neuropsychological Results that Distinguished t h e Groups (n = 27 Bipolars, n = 27 Controls) MRI area measures Test Finger Tap left
Cranial
Cerebral
Frontal
0.3441 p - 0.006
0.3106 p - 0.013
0.3856 p -- 0.002 0.3929 p = 0.002
Knox Cube Test--immediate Pegboard right Pegboard left Graphesthesia
-0.4096 p = 0.001
Halstead Category Test
Tactile PerformanceTest Memory Time
0.3560 p = 0.004 - 0.3085 p -- 0.012
Location Trail-Mekmg Test A Trail-Making Test B
Callosal
- 0.3805 p - 0.002 - 0.3811 p - 0.002
-0.3043 p - 0.013 -0.3034 p - 0.013 -0.3400 p -- 0.006 - 0.3061 p = 0.014 0.3769 p - 0.002 - 0.4175 p -- 0.001 0.3043 p = 0.013 - 0.3983 p = 0.001 - 0.3569 p = 0.004
- 0.3003 p - 0,014
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of the mean areas was uniformly larger in controls, but not significantly so. Given the number of comparisons by t-test, the differences between groups on mean MRI measures should be regarded only as trends.
Discussion This study demonstrates the presence of prominent, diffuse, neuropsychological deficits among individuals suffering from psychotic bipolar affective disorder. Further, it documents the possible contribution of relative reduction in cerebral tissue to some of the differences in cognitive performance. Although the presence of cerebral anatomic differences distinguishes between bipolar patients and controls, with bipolars showing re~ duction in cerebral substance (Rieder et al. 1983; Pearlson and Veroff 1981; Nasrallah et al. 1981, 1982a, 1982b; Coffman and Nasrallah 1984), relatively little attention has been paid to cognitive performance in this regard. On the other hand, quite a few studies of schizophrenics have drawn attention to a link between indices of impairment and reduced cerebral substance (Johnstone et al. 1976, 1978; Donnelly et al. 1980; Golden et al. 1980, 1982). One somewhat contrasting report is that of Owens et al. (1985) who found a curvilinear (inverted U) relationship between ventricular enlargement and cognitive impairment. Unfortunately, variability in the methodology used to establish the presence of impairment creates some difficulty for those interested in drawing comparisons across studies. However, in the aggregate, there seems to be agreement that those schizophrenics functioning the least well are most likely to show diminished cerebral substances both centrally and peripherally. Certain features of the present sample suggest that a pattern similar to that seen in schizophrenics may also apply in some individuals suffering from bipolar disorder. First, in order to be included in the study, psychotic symptoms had to have been present during episodes of illness. Some groups (Targum et al. 1983; Luchins et al. 1984) have drawn a link between the presence of delusional symptoms in affective disorders and lateral ventricular enlargement (relative dearth of brain tissue). Second, many of the patients in the study had had frequent hospitalizations. Third, most had been treated with neuroleptic medication. The latter two factors are much more strongly related to cognitive than to structural deficits. Therefore, this group of bipolar patients may represent a sample biased toward the demonstration of cognitive and cerebral deficits. It is not clear in exantining the literatu~ which of these factors might be the most likely contributing factor present among this population. However, the historical existence of a subgroup of bipolar patients with a dementing course suggests that at least a significant mincrity is susceptible to cognitive impairment on the basis of illness alone. One caveat is that the discovery of a reduction in cerebral structural areas in a single plane may not be an adequate predictor of a widespread diminution of cerebral volume. However, much of ",he literature dealing with the presence of lateral ventricular enlargement in populations of psychiatric patients has been derived from the study of single computed tomographic (CT) slices in the transverse plane (Coffman 1988). It should be noted that in our sample, ventricular measures in all planes are well correlated (Olson et al. in press) and therefore predictive of each otker. Certainly, both types of single slice examinations, (CT or MRI) are limited in scope, but this would be an unlikely enhancer of sensitivity in either case. In conclusion, this study identifies an unexpected degree of diffuse cognitive impairment among patients with psychotic bipolar disorder and demonstrates a major contribution
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to the variance in performance by cerebral and frontal size as measured by midsagittal MRI. These findings are consistent with older reports of a dementing course in some bipolar patients, and may be related to the presence of psychotic symptoms in this group of patients. It is, at present, impossible to determine whether the presence of psychosis predicts a higher likelihood of cognitive impairment. If predictive power can be established, the prognosis for those thus afflicted could be approximately tempered. Such findings, if confirmed, might provide impetus for the reexamination of prognostic indicators in the major psychoses and would cast some doubt on the power of a simple kraepelinian dichotomy to d~lineate the boundary between schizophrenia and manic depressive disorder.
References Andreasen NC (1982): Negative symptoms in schizophrenia: Definition and reliability. Arch Gen Psychiatry 39:784-788. Andreasen NC, Olsen S (1982): Negative v positive schizophrenia: Definition and validation. Arch Gen Psychiatry 39:789-794. Angst J (1986): The course of affective disorders. Psychopathology 19(Suppl 2):47-52. Astrup C, Fossum A, Holmboe R (1959): A follow-up study of 270 p~fients with acute affcctive psychoses. Acta Psychiatr $cand 34(Suppl 135):1-65. Bornstein RA, Nasrallah HA, Olson SC, Coffman JA, Schwarzkopf SB, Torello MW (1990): Neuropsychological deficit in subtypes of schizophrenia: Comparison of paranoid, nonparanoid and schizoaffective groups. Psychiatry Res (in press). Bratfos O, Hang JO (1968): The course of manic-depressive psychosis. Acta Psychiatr Scand 44:88-1 i2. Carlson GA, Kotin J, Davenport Y, Adland M (1974): Follow-up of 53 bipol~ manic patients. Br J Psychiatry 124:134-139. Coffman JA (1988): Computed tomography in psychiatry. In Andreasen NC (ed), Brain Imaging in Psychiatry. Washington, DC: American Psychiatric Press, pp 1-65. Coffman JA, Nasrallah HA (1984): Brain density patterns in schizophrenia and mania. J Affective Disord 6:307-315. Coffman JA, Schwarzkopf SB, Olson SC, Nasrallah HA (1989): Midsagittal cerebral anatomy by magnetic resonance imaging: The importance of slice position and thickness. 5chizophr Res 2:287-294. Donnelly EF, Weinberger DR, Waldman IN, et al (1980): Cognitive impairments associated with morphological brain abnormalities on computed tomography in schizophrenic p.~tients. J Nert, Ment Dis 168:305-308. Flor-Henry P, Yeudall LT (1979): Neuropsychological investigation of schizophrenia and numicdepressive psychoses. In J Gnm~fier, P Flor-Henry (eds), Hemisphere Asymmetries of Function in Psychopathology. Amsterdam: Elsevier/North Holland. Golden CI, Maclnnes WD, Ariel RN, et al (1982): Cross-validation of the ability of the LuriaNebraska Neuropsychological Battery to differentiate chronic schizophrenics with and without ventricular enlargement. J Consult Clin Psychol 50:87-95. Golden CJ, Moses JA, Zelazowski R, et ~1(1980): Cerebral ventricular size and neuropsychological impairment in young chronic schizophrenics, measured by the ~,tandardized Luria-Nebraska neuropsychological battery. Arch Gen Psychiatry 37:619-623. Goodwin FK, Jamison KR (1985): The natural course of manic-depressive illness. In Post R, Ballenger J (eds), Neurobiology of Mood Disorders. Baltimore: Wilfiams and Wilkins, pp 2037. Hastings DW (1958): Follow-up results in psychiatric illness. Am J Psychiatry 115:1057-1066.
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Heaton RK (1981): Wisconsin Card Sorting Test, Manual. Odessa, Florida: Psychological Assessment Resources. Johnstone EC, Crow TJ, Frith CD, et al (1976): Cerebral ventricular size and cognitive impairment in schizophrenia. Lancet ii:924-926. Johnstone EC, Crow TJ, Frith CD, et ~ (1978): The dementia of dementia praecox. Acta Psychiatr Scand 57:305-324. Johnstone EC, Owens DGC, Frith CD, Calvert LM (1985): Institutionalisation and the outcome of functional psychoses. P~ J Psychiatry 146:36-44. Kraepelin E (1919): Dementia Praecox and Paraphrenia. Translated by RM Barclay, reprinted in 1971. New York: RE Krieger. Kraepelin E (1921): Manic-Depressive Insanity and Paranoia. Translated by RM Barclay, Rober~son GM (ed). Edinburgh: Churchill Livingstone. Luci-~insDJ, Lewine RJ, Melzer HY (1984): Lateral ventricular size, psychopathology and medication response in the psychoses. Biol Psychiatry 19:29-34. Nesrallah HA, Coffman JA, Olson SC (1989): Structural brain imaging findings in affective disorders: An overview. J Neuropsychiatr Clin Neurosci 1:21-26. Nasrallah HA, McCalley-Whitters M, Jacoby CG (1982a): Cerebral ventricular enlargement in young manic males---A controlled CT study. J Affective Disord 4:15-19. Nasrallah HA, M,:Calley-Whitters M, Jacoby CG (1982b): Cortical atrophy in schizophrenia and mania---A comparative study. J Clin Psychia.'~ry 43:439-441. Nasrallah HA, Jacoby CG, McCalley-Whitters M (1981): Cerebral aaop:~y in schizophrenia and mama. Lancet ii: 1102. Olson SC, Nasrallah HA, Coffman JA, Schwarzkopf SB (1989): Structural abnormalities and negative symptoms in schizophrenia. In Greden JF, Tandon R (eds), CT and MRI Brain Abnormalities in Schizophrenia: Relationship with Negative Symptoms. Washington, DC: American Psychiatric Press (in press). Owens DGC, Johnstone EC, Crow TJ, et al (1985): Lateral ventricular size in schizophrenia: Relationship to the disease process and its clinical manifestations. Psychol Med 14:27--41. ?earlscn GD, Veroff AE (1981): Computerized tomogmphic changes in manic-depressive illness. Lancet ii:470. Pope HG, Lipinski JF (1978): Diagnosis of schizophrenia and manic-depressive illness: A reassessment of the specificity of "schizophrenic" symptoms in the light of current research. Arch Gen Psychiatry 35:811--828. Rieder RO, Mann LS, Weinberger DR, ~'an Kammen DP, Post RM (1983): Computed tomographic scans in patients with schizophrenia, schizoaffective and bipolar disorder. Arch Gen Psychiatry 40:735-739. Targum SD, Rosen LN, Citrin CM (1983): Delusional symptoms associated with enlarged cerebral ventricles in depressed patients. South Med J 76:985-987. Tsuang MT, Woolson RF, Fleming JA (1979): Long-term outcome of major psychoses. Arch Gen Psychiatry 36:1295-1304. Winokur G, Clayton PJ, Reich T (1969): Manic-Depressive Illness. St. Louis: Mosby.
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Cognitive Impairment and Cerebral Structure by MRI in Bipolar Disorder Jeffrey A° Coffman, Robert A. Bornstein, Stephen C. Olson, Steven B. Schwarzkopf, and Henry A. Nasra!!ah
The distinction between bipolar disorder and schizophrenia customarily follows examip..ation of the clinical symptomatology and course of illnes5~. The presence of cognitive impairment has been held t,o be uncommon in bipolar disorder and more likely in schizophrenia. This study ezpiored neuropsychological function in 30 ambulatory outpatients with a DSM-111-fl diagnosis of bipolar affective disorder (all of whom had been psychotic during manic episodes), ct:mparing their performance with that of controls. These bipolar patients prove£ to have significant levels of diffusely represented cognitive impairment when compared with controls. Further, the degree of impairment was significantly correlated with reduction in midsagittal areas of bra~n strucy~res measured on magnetic resonance imaging scans. The implications of thesefindings in relation to bipolar disorder are discussed.
Introduction "£he cardinal distinction upon which Kraepelin (191f, 1921) separated manic depressive psychosis from dementia praecox (schizophrenia) was that those suffering from the former tended to experience natural remission whereas those with the la~er did not. This premise has influenced many studies in the 20th century and continues to do so because no completely reliable distinguishing features have emerged (Pope and Lipinski 1978). For example, the brain imaging studies of the last decade do not adequately discriminate between schizophrenia and bipolar disorder. Substantial proportions of both groups show increased dimensions of the CSF-filled spaces around the brain by pneumoencephalo~raphy and computed tomography (Coffman 1988; Nasrallah et al. 1989). As a result, "e,~t4 if, t" many investigators continue to rely on course of illness as the principal dto~,,wa,,a,mg variable. Various studies have reported that outcome for manic-depressive illness is generally good (Hastings 1958; Astrup et al. 1959; Brati0s and Haug 1968; Winokur et al. 1969; Carlson et al. 1974; Tsuang et al. 1979; Goodwin and Jamison 1985; Johnstone et al. 1985; Angst 1986). They have cautioned, however, that from 10%-30% of patients with
From the Department of Psychiatry and Neuroscienee Program, The Ohio State University College of Medicine, Columbus, OH. Address reprint requests to Jeffrey A. Coffman, M.D., 473 W. 12th Avenue, Columbus, OH 43210. Received February 10, 1989; revised October 15, 1989. This research was supportedby a research grant from the Board of Regents of the State of Ohio to Henry A. Nasrallah, M.D.
© 1990 Society of Biological Psychiatry
0006-3223/90/$03.$0
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bipolar disorder show poor social outcome, particularly those with continued affective symptoms. Several studies that examined combined groups of unipolar and bipolar ¢atients noted that the latter fared worse (Astrup 1959; Braffos and Haug 1968). Furthermore, studies of bipolar disorder alone, excluding unipolar patients (Winokur et al. 1969; Carlson et al. 1974; Tsuang et al. 1979) found evidence of social impairment, in spite ~" symptomatic improvement, in 20%-30% of patients. Cognitive impairment seems to occur in a minority of patients with manic depressive illness. Astmp (1959) found 5 of 96 (approx. 5%) manic depressive patients were demented on follow-up whereas Bratfos and Haug (1968) found that 11% of subjects in a mixed unipolar/bipolar group had become demented. Johnstone et al. (1985) found that, overall, a group of chror:ical!y ill bipolar patients showed similar degrees of cognitive impairment to those seen in similarly institutionalized chronic schizophrenics. However, other features of social it~uctioning and behavior distinguished the groups. These included a greater preponderance of overactivity among ~ e bipolar patients and more social withdrawal among the schizophrenics. The degree and nature of cognitive irnpairment seen in bipolar affective disorder remains poorly characterized at present. Agreement on its presence, ~t least in some, approaches the limit of our knowledge. Relationships with other features of the illness are unclear. The present study delineates a detailed neuropsychological assessment of a sample of rO~atively young individuals with psychotic bipolar disorder and relates these findings to indices of cerebral structure obtained through magnetic resonance imaging (MRI). It is, to our knowledge, one of the first such studies reported.
Method Thirty individuals with bipolar "dfective disorder and psychotic features (11 men, 19 women, mean age 32.0 --. 6.2 years) examined as part of a larger study population and 52 normal volunteer controls (33 men, 29 women, mean age 28.8 _ 7.2 years) participated in this study after giving informed consent. Inclusion of individuals ages 20-50 followed establishment of a diagnosis by DSMIII-R c~.teria tbr the bipelar groups and lack of psychiatric diagnosis for the control groups as ascertained by the Structured Clinical Interview for Diagnosis (Spitzer et al. 1987). Erzclusion criteria included (!)serious or debilitating medical illness including seizure disorder; (2) past history of penetrating head injury or neurosurgery; (3) metallic implants in the body; ~ d (4) a 2-year history, preceding entry, of chronic substance abuse.
Imaging Parameters Subjects underwent a sagittal series of MRIs using a GE 1.5 Tesla scanner ~ d an inversion recovery pulse sequence (TI = 800 msec, TR = 1500 msec). The series comprised eight slices about the midline with a slice thickness of 3 mm and an interslice interval of 1 ram. One of the authors (J.C.) selected the midsagittal slice from photograpt~ic representations based on the following criteria: (1) clearest visualization of the corpus callosum; (2) the smallest dimension of the ventriculoseptal region; (3) minimal inclusion of white matter adjacent to the interhemispheric suleus. In addition to the midsagittal slice, the adjacent left and fight parasagittal slices were included for study.
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Measurement Procedure The leh and right parasagittal and midsagittal slice images were projected, enlarged to normal head size, and traced. The tracings were processed by digi~ai planimeterization using a digitizing tablet and VIAS image processing software. For each slice, measurements were made of cranial area (defined by the marrow line), cerebral area, frontal area (defined as the cerebr~ co~ical area anterior to a line perpendicular to the midpoint of the maximum length of the corpus callosum), corpus callosum, and cerebellar area. Average values were calculated from the three slice measurements for structures showing high position-related variance (cerebral and frontal area). The midsagittal slice value was used for structures with little position-related variance (cranial, callosal, aM cerebellar areas) (Coffman et al. 1989). It should be noted that only 29 controls (11 men, 18 women) and 25 bipolar patients (10 ~en, 15 women) underwent MRI study.
Neuropsychological Measurements Neuropsychological examination included the Wechsler Adult Intelligence Scale Revised (WAIS-R), Wechsler Memory Scale Revised (WMS.R), Wisconsin Card Sorting Test (WCST), Verbal Concept Formation Test (VCAT), and an expanded Halstead Reimn Battery. Most subjects received the WMS-R, but some patients and controls examined prior to the availability of this test were given the WMS with 30 delayed recall trials for Logical Memory and Visual Reproduction. These two subtests with delayed recall are common to both versions, and the proportional recall scores (delayed recall/immediate recall) are widely used as measures of verbal and nonverbal memory. Therefore, the measures of verbal and nonverbal memory used in this study were the proportional recall score for Logical Memory and Visual Reproductioa. The groups did not differ regarding educational attainment but did differ on age (see Results). The method used in this study differs from that of some other investigations in that the perseverative errer score from the WCST is based on a modification of the scoring rules proposed by tleaton (1981). The first response in a new set (following acquisition of a set) is not counted as a perseverative error. This modification was used because it seemed to provide a more accurate measure of perseveration. Thus, the scores for a subiect may be reduced by as many as five errors. As most controls achieved all six categories, and most patients did not, the extent of correction may be somewhat greater in the control group. In order to provide a global assessment of cognitive function, summary scores were created according to formulae described previously (Bornstein et al. 1990). The sunmlary scores res, flt from conversion of the raw scores to t-scores (mean = 50, SD = 10) based on the normal distribution of normal subjects. Thus, performance on each of the variables appears on a common metric, which facilitates examination of performance on a range of tests. I'hese t-scores were then combined into summary indexes based on the nature of the tasks. For each of the indexes, the score represents the mean t-score for the tests included in that summary score. A left iiemisphere index included those measures generally thought to primarily reflect left hemisphere function (verbal IQ, % retention of verbal material from the WMS-R, VCAT, and fight hand scores on: finger agnosia, dysgm phesthesia, Finger Tapping, and Grooved Pegboard Test). The fight hemisphere index summarizes results on tests generally thought to primarily reflect right hemisphere function
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Table I. Demographic Characteristics of Sample Characteristics
Bipolar patients
Normal controls
Total sample Total women Mean age - sD Mean years of education +_ SD
30 19 32.97 _ 6.20 14.67 _ 2.07
52 29 28.77 _ 7.17 15.52.4- 2.15
(!x~rformance IQ, % retention of nonverbal material from the WMS-R, and left hand scores on finger agnosia, dysgraphesthesia, finger rapping, and Grooved Pegboard Test). A general index pertained to tests that have been shown to be generally sensitive to cerebral integrity, but with little localizing or lateralizing value [Category Test, Tactile Performance Test, Memory and Location scores, Trail-Making Test (parts A and B), Speech Sounds Perceptions Test, Seashore Rhythm Test, and the Knox Cube Test]. The perseverative error score from the WCST was included in the General Index because most of the studies to date indicate that this measure may show impairment in patients with dysfunction in either frontal lobe.
Statistical Methods Comparisons between groups were made using an~Jysis of variance relying on SPSS-X software routines. Potential covafiates of age, symptomatic severity [total of positive and negative symptom scores on the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) (Andreasen 1982; Andreas~n and Olsen 1982)], years of education, and average daily neuroleptic dosage in chlorpromazine equivalents were evaluated by calculation of Pearson correlation coefficients with neuropsychological performance. For those neuropsychological tests showing significant correlation (p ~< 0.05) with any of the potential clinical covariates, analysis of covariance followed, rather than analysis of variance alone. Pearson correlation coefficients between MRI measures and global scales (general, left, and right hemispheric functions) for neuropsychological performance served to assess the contribution of cerebral structure to the variance observed in cognitive performance. Performance on individual neuropsychological measures distinguishing the groups served to confirm the pattern seen on the global scales.
Results Demographic characteristics apl~:ar in Table 1. Age differed significantly between groups but years of education did not. Neuropsychological test results can be seen in Table 2 and reveal marked differences between groups due to diagnosis, even where covariance was ~ppljed for symptomatic severity, age, education, and neuroleptic dose. It should be noted that the differences in performance observed did not occur in any particular pattern but were diffuse. In general, these differences occur on both verbal and nonverbal tasks, as well as sensory and motor tasks on both sides of the body. Nevertheless, there was some suggestion of greater right hemisphere impairment in the bipolar group. In particular,
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Table 2. Neuropsychological Test Results Test Halstead Category Test Tactile Performance Test Memory
Covariates S A
Time
Location Seashore Rhythm Test Speech sounds perception
A S A
Trail-Making Tes t. A B
A
Verbal concept attainment Verbal fluency WCST--persevemtive
Bipo!ars
Controls
(n - 30)
(n - 52)
F
Value
73.11 - 30.17
34.11 ± 20.59
6.37
0.014
1.13 241.30 2.21 2.12 3.83 6.52 20.49 1.84 24.00 6.48
16.16 38.66 13.08 1.78 3.62 18.46 13.87 24.67 12.57 13.93
0.000 0.000 0.001 0.186 0.061 0.000 0.000 0.000 0.001 0.000
0.95 0.95 5.86 4.99 7.97 9.65 1.03 1.43 1.37 0.97 1//.08 12.44 9.02 11.67
6.93 4.74 1.49 9.16 12.88 10.90 4.76 1.65 7.25 12.29 0.001 13.001 0.846 2.187
0.010 0.032 0.226 0.003 0.001 0.001 0.032 0.203 0.009 0.001 0.981 0.001 0.361 0.143
6.63 1099.;0 2.,o0 2_5,.07 6.67 29.37 81.73 17.13 52.80 13.60
.4± ± ± ± ± -± ±
1.92 401.00 2.30 3.62 3.33 10.61 42.82 5.36 28.34 18.00
8.29 658.80 4.81 27.96 4.54 21.25 49.06 21.17 73.65 3.33
± ± ± ± ± ± ± ± ±
5.33 5.23 44.63 40.01 81.63 86.40 1.07 0.90 2.13 2.07 84.72 79.94 97.47 93.50
± ± ± ± ± ± ± ± ± ± ± ± ±
1.03 1.19 6.57 5.99 18.73 21.62 1.72 1.58 2.44 1.84 13.29 18.85 9.66 14.65
5.92 ± 5.87 ± 47.73 ± 43.77 60.98 ± 64.65 ± 0.40 ± 0.46 1.00 ± 0.73 ± 84.65 ± 92.40 ± 107.23 ± 106.44.4-
p
erro~
Knox Cube Test im,,nediate delayed Finger Tap right left Pegboard right left Sensory agnosia right left Graphe~thesia right Graphesthe~ia left Verbal memory Nonverbal memory Verbal I.Q. Performance I.Q.
A A D,A D
A A
S S,E
S : total symptoms; D = drug dosage (average daily chlorpromazineequivalence); A = age; E = education; F : F value (and related p) for diagnostic group as main effect after covariance has been removed (if applicable).
the patient group differed from controls in nonverbal memory but did not di~er on verbal memory. Similarly, the patients differed significantly from controls on the left but not the right hand score for Finger Tapping. Although these findings could be interpreted to suggest right hemisphere dysfunction, these deficits appear in the context of a much broader pattern of cognitive impairment. Therefore, this study offers no clear support for the view of affective disorder as a "right hemisphere disorder" as proposed by some investigators (Flor-Henry and Yeudall 1979). Table 3 illustrates the results of correlation analysis between the global neuropsychological performance scales and midsagittal MRI measures. Smaller cerebral and frontal areas appeared to be associated with global impairment (correlations ranging frown0.3342 to 0.4397). No lateralization of the structure-function relationship appeared as reflected in the minimal differences between the general, left, and right indexes. In these comparisons, smear structural areas accounted for 11%-19% (R-squared ranging from 0o112 to 0.193) of the performance variance observed. Table 4 shows further results of MRI/neuropsychological performance comparisons. The table demonstrates that impaired performance, on a number of tests broadly representing cerebral functions, was significantly correlated with smaller areas of me cerebrum and the frontal portion of the cerebrum as seen in the midsagi~3 plane. Fewer significant
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Table 3. Correlations Between Summary Neuropsychological Test Scores and Midsagittal Brain Area Measures (n = 27 Bipolars, n - 27 Controls) MRI area measures
Summary score General index Left index Right indz~
Cranial
Cerebral
Frontal
Callosal
0.1880 p = 0.068 0.2489 p - 0.024 0.3243 p - 0.004
0.3342 p = 0.003 0.3386 p = 0.003 0.4373 p = 0.0o0
0.3916 p = 0.001 0.3871 p = 0.001 0.4397 p = 0.000
0.2455 p = 0.025 0.2427 p = 0.027 0.2854 p = 0.011
c o r r e l a t i o n s a p p e a r e d b e t w e e n c a l l o s a l a n d c r a n i a l m e a s u r e s a n d n e ~ o p s y c h o ! o g i c ~ results. N o n e o f the n e u r o p s y c h o l o g i c a l m e a s u r e s that correlated w i t h f r o n t a l l o b e M R I m e a s u r e s are g e n e r a l l y a c c e p t e d as b e i n g s p e c i f i c a l l y s e n s i t i v e to f r o n t a l l o b e f u n c t i o n s . A g a i n , t h e r e w a s little e v i d e n c e o f strictly l o c a l i z e d deficits. It is i m p o r t a n t to note that the b i p o l a r g r o u p h a d a s m a l l e r m e a n area for t h e c o r p u s c a l l o s u m ( 6 . 8 3 - 1.60 v e r s u s 7 . 6 4 + 0 . 9 7 , p = 0 . 0 3 , t w o - t a i l e d t-test) a n d t e n d e d to h a v e a s m a l l e r m e a n frontal a r e a ( 3 5 . 0 2 ± 3 . 9 2 v e r s u s 3 6 . 7 0 4- 3 . 2 6 , p = 0 . 0 9 , t w o - t a i l e d t-test). T h e r e m a i n d e r
Table 4. Pearson Correlation Coefficients (>0.3000) Between Midsagittai Brain Measures and Those Neuropsychological Results that Distinguished t h e Groups (n = 27 Bipolars, n = 27 Controls) MRI area measures Test Finger Tap left
Cranial
Cerebral
Frontal
0.3441 p - 0.006
0.3106 p - 0.013
0.3856 p -- 0.002 0.3929 p = 0.002
Knox Cube Test--immediate Pegboard right Pegboard left Graphesthesia
-0.4096 p = 0.001
Halstead Category Test
Tactile PerformanceTest Memory Time
0.3560 p = 0.004 - 0.3085 p -- 0.012
Location Trail-Mekmg Test A Trail-Making Test B
Callosal
- 0.3805 p - 0.002 - 0.3811 p - 0.002
-0.3043 p - 0.013 -0.3034 p - 0.013 -0.3400 p -- 0.006 - 0.3061 p = 0.014 0.3769 p - 0.002 - 0.4175 p -- 0.001 0.3043 p = 0.013 - 0.3983 p = 0.001 - 0.3569 p = 0.004
- 0.3003 p - 0,014
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of the mean areas was uniformly larger in controls, but not significantly so. Given the number of comparisons by t-test, the differences between groups on mean MRI measures should be regarded only as trends.
Discussion This study demonstrates the presence of prominent, diffuse, neuropsychological deficits among individuals suffering from psychotic bipolar affective disorder. Further, it documents the possible contribution of relative reduction in cerebral tissue to some of the differences in cognitive performance. Although the presence of cerebral anatomic differences distinguishes between bipolar patients and controls, with bipolars showing re~ duction in cerebral substance (Rieder et al. 1983; Pearlson and Veroff 1981; Nasrallah et al. 1981, 1982a, 1982b; Coffman and Nasrallah 1984), relatively little attention has been paid to cognitive performance in this regard. On the other hand, quite a few studies of schizophrenics have drawn attention to a link between indices of impairment and reduced cerebral substance (Johnstone et al. 1976, 1978; Donnelly et al. 1980; Golden et al. 1980, 1982). One somewhat contrasting report is that of Owens et al. (1985) who found a curvilinear (inverted U) relationship between ventricular enlargement and cognitive impairment. Unfortunately, variability in the methodology used to establish the presence of impairment creates some difficulty for those interested in drawing comparisons across studies. However, in the aggregate, there seems to be agreement that those schizophrenics functioning the least well are most likely to show diminished cerebral substances both centrally and peripherally. Certain features of the present sample suggest that a pattern similar to that seen in schizophrenics may also apply in some individuals suffering from bipolar disorder. First, in order to be included in the study, psychotic symptoms had to have been present during episodes of illness. Some groups (Targum et al. 1983; Luchins et al. 1984) have drawn a link between the presence of delusional symptoms in affective disorders and lateral ventricular enlargement (relative dearth of brain tissue). Second, many of the patients in the study had had frequent hospitalizations. Third, most had been treated with neuroleptic medication. The latter two factors are much more strongly related to cognitive than to structural deficits. Therefore, this group of bipolar patients may represent a sample biased toward the demonstration of cognitive and cerebral deficits. It is not clear in exantining the literatu~ which of these factors might be the most likely contributing factor present among this population. However, the historical existence of a subgroup of bipolar patients with a dementing course suggests that at least a significant mincrity is susceptible to cognitive impairment on the basis of illness alone. One caveat is that the discovery of a reduction in cerebral structural areas in a single plane may not be an adequate predictor of a widespread diminution of cerebral volume. However, much of ",he literature dealing with the presence of lateral ventricular enlargement in populations of psychiatric patients has been derived from the study of single computed tomographic (CT) slices in the transverse plane (Coffman 1988). It should be noted that in our sample, ventricular measures in all planes are well correlated (Olson et al. in press) and therefore predictive of each otker. Certainly, both types of single slice examinations, (CT or MRI) are limited in scope, but this would be an unlikely enhancer of sensitivity in either case. In conclusion, this study identifies an unexpected degree of diffuse cognitive impairment among patients with psychotic bipolar disorder and demonstrates a major contribution
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to the variance in performance by cerebral and frontal size as measured by midsagittal MRI. These findings are consistent with older reports of a dementing course in some bipolar patients, and may be related to the presence of psychotic symptoms in this group of patients. It is, at present, impossible to determine whether the presence of psychosis predicts a higher likelihood of cognitive impairment. If predictive power can be established, the prognosis for those thus afflicted could be approximately tempered. Such findings, if confirmed, might provide impetus for the reexamination of prognostic indicators in the major psychoses and would cast some doubt on the power of a simple kraepelinian dichotomy to d~lineate the boundary between schizophrenia and manic depressive disorder.
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