Aspects of stability of regional cerebral blood flow in chronic schizophrenia: An 18-year followup study

Psychiato, Research: Neuroimaging, 40:253-266

Elsevier

253

Aspects of Stability of Regional Cerebral Blood Flow in Chronic Schizophrenia: An 1 8-Year Fol|owup Study Elizabeth Cantor-Graae, Siegbert Warkentin, GOran Franz~n, Jarl Risberg, and David H. Ingvar Received March 26, 1991; revised version received September 9, 1991; accepted October 6, 1991. Abstract. Regional cerebral blood flow (rCBF) measurements and psychiatric ratings were performed on seven schizophrenic patients (mean age = 41.4 years) who had been examined ! 8 years previously in a study that used similar psychiatric ratings and a comparable rCBF technique. Neither the clinical symptomatology nor the rCBF level and distribution had changed appreciably between 1972 and 1990. The findings indicate that cerebral functional activity in chronic schizophrenia remains constant in spite of continuous neuroleptic medication.

Key Words. Schizophrenia, regional cerebral blood flow, symptoms, followup. Since the first demonstration of a "hypofrontar' regional cerebral blood flow (rCBF) pattern in chronic schizophrenia (lngvar and Franz6n, 1974; Franz6n and Ingvar, 1975; lngvar, 1980), a number of studies have confirmed subtle signs of frontal brain dysfunction associated with this disorder. The hypofrontal rCBF pattern has been observed in schizophrenic patients both at rest (Ariel et al., 1983; Kurachi et al., 1985; Chabrol et al., 1986) and during frontal lobe challenge (Weinberger et al., 1986; Berman, 1987). Little is known, however, about the long-term stability of the rCBF landscape in chronic schizophrenic patients and its relation to neuroleptic z~edication. Recent reviews of long-term followup studies (Harding, 1988; McGlashan, 1988) indicate that most patients reach a clinical plateau of deterioration after 5 to l0 years of illness. Only a minority of patients show a course of progressive deterioration. High variability in course (Westermeyer and Harrow, 1988) makes it difficult to regard schizophrenia as a slowly progressive brain disease, Nonetheless, the finding of significantly lowered frontal blood flow in the brains of elderly chronic schizophrenic patients (lngvar and Franz6n, 1974; Franz6n and lngvar, 1975) raises the question of whether long-term schizophrenia may be accompanied by changes in cerebral functional activity, either caused by the disease process itself or related to secondary aspects associated with age or with psychiatric treatment, including neuroleptic medication. A low anteroposterior gradient of CBF has been shown to be related to illness duration (Mathew et al., 1988; Mathew and Wilson, 1990) and thus possibly a characteristic of the disease process. The stress of repeated Elizabeth Cantor-Graae, M.A., Siegbert Warkentin, Ph. D., and Jarl Risberg, Ph. D., are in the Department of Psychogeriatrics, St. Lars Hospital, Lund, Sweden. G6ran Franz6n, M.D., Ph.D., is in the Department of Psychiatry, Asgard Hospital, Troms6, Norway. David H. lngvar, M.D., Ph.D., is in the Department of Clinical Neurophysiology, University Hospital, Lund, Sweden. (Reprint requests to E. Cantor-Graae, Dept. of Psychiatry, Lund University; MalmG,Sweden S-214 01.) 0165-1781/ 91/ $03 50 © 1991 Elsevier Scientific Publishers Ireland Ltd.

254 hospitalizations and other nonspecific factors could also conceivably influence the functional activity in the brain. The d e m o n s t r a t i o n by I n g v a r and F r a n z 6 n ( 1 9 7 4 ) o f relatively n o r m a l r C B F values in a y o u n g e r group of schizophrenic patients provided the impetus for a followup study of the present seven patients 18 years later, in which we have done a psychiatric reevaluation and used a c o m p a r a b l e r C B F technique t o g e t h e r with functional challenge.

Methods Patients. Twenty patients were examined by lngvar and Franz6n in 1972. Nine of these were older women in an advanced state of clinical deterioration with long histories of schizophrenia (mean age = 61 years, range = 49-72; mean illness duration = 40 years; range = 29-48). As a comparison group, I I younger patients were selected randomly from consecutive admissions to the psychiatric clinic at St. Lars hospital in Lund and studied in a postpsychotic phase (7 males and 4 females, mean age = 25 years, range : 17-34; mean illness duration = 5 years, range = 0.75-15). Patients in both groups had uneventful previous histories with regard to severe somatic disorder, head injury, cerebrovascular disorder, or other brain disorders. Nine of the I ! patients in the original younger group could be located, and 7 of these (nos. 2, 3, 5, 6, 9, 10, and I I ) agreed to participate in the present study. The diagnosis of schizophrenia was confirmed using D S M - i l l - R criteria (American Psychiatric Association, 1987). None of them were excluded due to somatic illness, cerebral injury, or substance abuse. The mean age for the group in 1990 was 41.4 years (SD = 5.0, range = 34-49). All were right-handed, as determined by the Oldfield (1971) assessment of handedness.

History and Current Status. Since 1972, all of the seven present patients have had frequent contacts with psychiatric health care facilities, and none of them have achieved full recovery. Thus, in 1990 the mean illness duration for the group was 22.9 years (SD = 2.9, range = 20-28). The mean number of days of hospitalization since illness onset was 3104 days (SD = 201 I, range = 926-6065). Although two of the patients had recently been hospitalized for exacerbation of symptoms, none of them currently had florid symptomatology. None of ttle patients w e r e employed or living independently. Only one of the patients had had a period of regular employment since the onset of the illness. None had married. The mean educational 1¢v¢! of the group was 9.7 school years (SD = 3.0, range = 8-16). Although free of other medicationg r, II patients at the time of study were medicated with neuroleptic drugs, with considerable variation in pharmacology and dosages. Converted into chlorpromazine (CPZ) equivalencies (Cummings, 1985), the mean daily neurolcptic dosage for the group in 1990 was 352 mg (SD = 340, range = 25-1120). To investigate the possible cumulative effect of neuroleptic medication, the total amount of daily medication prescribed since contact with psychiatric services, as well as since rCBF measurement in 1972, was computed on the basis of hospital records. The group mean fcr total amount of medication, converted into CPZ, was 3437 grams per patient (SD = 1371, range = 1582-5286). All but two of the patients had received electroconvulsive therapy, but none more recently than 2 years before the present study. Although it was not possible to ask the subjects to refrain from nicotine and caffeine intake before the studies, only low to moderate usage of these substances was recorded, and the patients did not drink coffee or smoke just before the actual rCBF measurements. Routine clinical laboratory tests were performed on each patient on the day of the rCBF procedure. Blood values, liver and kidney functions, and blood sedimentation rates were found to be normal. In general, the patients were silent, but cooperative during the rCBF measurements. Few active psychotic symptoms were observed, and only one patient reported hallucinations afterwards. Self-reported anxiety levels were low.

255

Ratings of Psychiatric Symptomatology. The patients were reevaluated by one of the authors (G.F.) on the day of the rCBF measurements. Three rating scales were used. The Rockland-Pollin (RP) scale (Rockland and Pollin, 1965), with its good reliability and validity (Franzen, 1971), was chosen for direct comparison with the RP ratings in 1972. The RP scale consists of !'6 items rated on a positive and a negative dimension, distributed across three categories: Behavior (l), Affectivity (II), and Cognition (Ill). The positive dimension assesses the overt quality of the symptoms, while the negative dimension assesses the "defect" or deficit quality. Cognition (category Ill) is rated on a positive dimension only. The Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962) and the Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1981) were included in 1990.

Measurement of rCBF. The rCBF was measured by the 133Xeinhalation method as developed by Obrist et al. (1975) and modified by Risberg et al. (1975). A high-resolution system for noninvasive two-dimensional recording of rCBF (Cortexplorer, Scan Detectronic Inc., Hadsund, Denmark) was used with 254 collimated scintillation detectors mounted in a fixed helmet (Risberg, 1987). The inert gamma-radiating tracer ~3aXe (90 MBq/l) was inhaled for l minute followed by 10-minute breathing of ordinary air. The air-passage artifact was corrected as suggested by Risberg (1987). Lowest acceptable peak counts for the head curves were about 200 counts per second. Either 30 seconds of background (first measurement) or 5 minutes of remaining activity (repeated measurements) were recorded before isotope administration. The 1972 measurements of rCBF were performed using the intra-arterial ,33Xe injection method (Hoedt-Rasmussen et al., 1966), a technique that yields results comparable to those obtained with the inhalation method ([ngvar et ai., 1965; Wilkinson et al., 1969). Dt~e to technical differences between the isotope injection method and the present high-resoh~tion inhalation technique, however, only approximate comparisons between the rCBF parameters used in 1972 and in 1990 were possible. For the purpose of data analysis, the f, measure of gray matter perfusion (Obrist et al., 1975) was chosen as the parameter most similar to the Fg gray matter blood flow parameter used by Ingvar and Franz6n (1974), calculated from the fastclearing (gray matter) compartments of the brain. Regional values were represented as distribution values (in % of hem;spheric mean). The present rCBF measurements were performed on reclining patients, with the ~3~Xe administered in a tightly fitting face mask. Face-mask leakage was monitored by a special scintillation detector. To ensure standardized placement of the detectors, head position was aligned with reference to the bony landmarks (nasion and ear channels). Continuous recordings of pulse, respiratory rate, capillary oxygen saturation, and end-expiratory partial pressure of carbon dioxide (PCO2) were obtained using an O H M E D A 4700 OxiCap capnograph. The arterial PCO2 level was estimated from expired end-tidal CO2 values.

Procedural Design. The patients were introduced to the measurement situation in a gradual and unobtrusive manner. Four rCBF measurements were performed in a fixed order, during a morning or an afternoon session. Measurements were separated by about 20 minutes, during which the patients were inactive. A resting measurement was followed by three measurements during activation procedures: (l) the Chicago word fluency test (FAS; Benton, 1968; Benton and Hamsher, 1977), (2) a baseline procedure designed to control for motor and attentional components of the Wisconsin Card Sort test (WCST; Milner, 1963), and (3) the WCST. As the resting state has been shown to be highly variable even in normal subjects, the use of activation procedures controls for some of the ambiguities associated with the resting variance (Duara et al., 1987). While the 1972 study made use of the Ravens matrice~ as an activation procedure, this test appears relatively insensitive to prefrontal lobe activity (Berman et al., 1988). Thus, the tests used in this study were specifically chosen for their ability to challenge dorsolateral prefrontal functions (Berman, 1987; Warkentin et al., in press). Both the FAS and the WCST rely on the subject's ability to organize a cognitive strategy and both are sensitive to cognitive inflexibility (Lezack, 1983). The FAS test provokes a repeated mobilization of volition and memory search and is conducted with help from the examiner. However, it has auditory and vocalization

256 components. The WCST relies more on the silent subject's capacity to direct his own efforts, in combination with error information feedback. All four rCBF measurements were performed on six of the seven subjects. (One subject refused to participate in the WCST and its baseline task.) No activation was initiated until it was certain that the instructions had been perfectly understood. The patients collaborated well and did not require extra prompting during the tests. During the resting measurements, the subjects were instructed to keep their eyes shut and to relax. Eye pads were placed over the eyes and background noise was kept to a minimum. The actual measurement, with the initial background count, was not begun before the subjects' respiratory rate indicated adaptation to the face mask. A microphone mounted in the mask facilitated communication with the patients. The resting measurement was followed by an rCBF measurement during activation with a version of the word fluency test adapted for rCBF conditions (Warkentin et al., in press). Patients (eyes closed) were instructed to produce out loud as many words as possible starting with a given letter, which was changed every minute. The second activation procedure consisted of a baseline task designed to control for those situational aspects of the WCST not directly related to the task of category formation. With the help of a mouse driver device, subjects were asked to move blank cards to one of four positions or windows on a computer screen, designated by the random "lighting up" of a window. A text message gave immediate feedback as to whether the move had been successfully completed. The third activation procedure consisted of a computerized version of the WCST (Milner, 1963), where symbol cards were sorted with the mouse device. A text message gave immediate feedback ("right" or "wrong"). Responses were recorded automatically by the computer. Activations were initiated 2 minutes before isotope inhalation and continued throughout the measurements.

Statistical Analysis. The raw rCBF values of each probe were used to compute mean hemispheric flow values. Due to the constraints of the intra-arterial rCBF method, only one (left) hemisphere was studied in 1972.Thus, values for the left hemisphere served as the primary basis of comoarison for blood flow measures between 1972 and 1990. All other analyses used values for both the right and left hemispheres. Between-group differences in CBF values were analyzed by two-tailed Student's t test before and after correction to a standard PCO2 level of 40 mmHg (Maximilian et al., 1980). The rCBF values were transformed into distributionnormalized values, as % of the hemispheric mean. To ='educethe probability of Type ! errors, the 254 probes were combined into seven regions within each hemisphere: t~refrontal (10 probes), superior frontal ( 18 probes), fronto-temporal (21 probes), temporal t i,, probes), central (23 probes), parieto-temporai (26 probes), and occipital ( 13 probes). Although detector placement in the 1972study was not replicable with the 254 detector technique, detectors were assigned to regions that were the most approximate to those precentral and postcentral regions used in lngvar and Franz~n's calculation of the anteroposterior index in 1972. Careful examination of the data-analytic methods from 1972 provided the basis for the definition of the precentral and postcentral areas to be used in the present study, to ensure maximum equivalence of methods at followup. Thus, an anteroposterior (AP) index or gradient for 1990 was calculated, based on mean regional distribution values in the following areas: prefrontal and superior frontal regions divided by parietotemporal and occipital regions. These were the regions that corresponded to the pre-Rolandic, frontal, and occipito-temporo-parietal regions used by lngvar and Franzdn (1974). Paired and unpaired t tests were used in the analysis of the AP gradient (1972 to 1990), left-right asymmetries, and between-test blood flow measures. The effect of medication on blood flow measures (including AP gradient) was evaluated by regression analysis. Changes in clinical ratings between 1972 and 1990 were analyzed by the Wilcoxon matched-pairs signed-rank test, and relations between clinical scores and blood flow measures were analyzed by the Spearman rank order correlation coefficient.

Results K:~,~:,.~nH e m i s p h e r i c Flow. Table I s h o w s the m e a n h e m i s p h e r i c b l o o d flow levels for

257

Table 1. Mean hemispheric blood flew in schizophrenic patients at rest and during mental activation 1972 1990 Rest Rest FAS WCS-B WCS-T (n = 7) R hemisphere

(n = 7)

(n = 7)

(n = 6)

(n -- S)

67.5 _+ 7.7

68.2 ± 7.6

80.8 +_ 9.11

78.8 +_ 7.4

L hemisphere

74.6 _+ 19.2

67.5 +_ 6.9

68.2 _+ 8.0

80.6 + 9.11

78.7 +_ 7.1

PCO2

43.1 _

36.4 _+ 3.3

35.4 +_ 2.7

37.2 _ 2.4

36.1 +_ 2.6

R hemisphere

70.3 __ 5.9

71.6 ____7.6

82.9 __ 7.82

80.0 +__9.0

L hemisphere

70.1 +___5.3

71.6 +__8.3

82.7 +__7.72

81.6 __+8.0

2.0

Correction for PCO2

Note. Results are presented as mean _+SD. PCO2 values from the older study are not directly comparable to the present values. FAS = Chicago Word Fluency Test. WCS-B = baseline control for the Wisconsin Card Sort, WCS-T = Wisconsin Card Sort Test,

1. p < 0.05, paired t test, vs. resting condition. 2. p < 0.01, paired t test, vs. resting condition.

the group at rest in 1972 (left)and 1990 (left and right), as well as the mean hemispheric blood flow levels during the three activation conditions. No significant change in CBF (uncorrected for PCO2)at rest was observed from 1972 to 1990. Thus, in 1990 the mean hemispheric values were found to be similar to those seen in normal subjects (Prohovnik et al., 1980), as was the case in 1972 (lngvar and Franzgn, 1974). No hemispheric asymmetries were observed. It was not appropriate to compare directly the corrected PCO2 values between the two studies, as the 1972 correction factor was applied to PCO2 as measured in arterial blood samples. However, application of the Maximilian et al. (1980) correction factor to the PCO2 values in 1990 did not alter the flow value results in any significant way (Table I ). Significant increases in hemispheric flow (right and left) were seen from rest to the baseline task condition (p = 0.01) and from rest to the WCST (p - 0.01) (Table I). rCBF Distribution. Table 2 presents the regional flow values for the four measurement conditions in 1990. in the resting condition, the regional distribution of cerebral blood flow in 1990 showed the normal hyperfrontal pattern (Mamo et al., 1983), with higher values in the frontal as compared with postcentral regions. An AP index calculated for the left hemisphere showed no significant group differences from 1972 to 1990 (Fig. l), nor was there any significant AP index left/right asymmetry in 1990. Two subsets of changes from 1972 to 1990 were observed. Four patients decreased in AP index, from mean = 1.10 (SD = 0.04) to mean = !.03 (SD = 0.01), while the remaining three patients increased in AP index, from mean = 1.05 (SD = 0.04) to mean - l . l l (SD = 0.04). No significant relationship was observed between medication (current daily dosage 1990, total lifetime intake, total amount since rCBF in 1972) and any blood flow measures, nor were there any trends. For regional analysis, the resting condition was compared to the FAS activation, where flow changes observed in the prefrontal area in normal subjects are attributable to the cognitive challenge associated with verbal fluency (Warkentin et al., in press). The baseline "sorting" task was compared with the WCST, where it was expected that

258

Table 2. Regional flow distribution values obtained at rest and during mental activation Rest FAS WCS-B WCS-T (n = 7)

(n = 7)

(n = 6)

(n = 6)

R

L

R

L

R

L

R

L

104.0 5,5

104,0 3,4

103.9 4.4

103.2 5.2

102.0 4.6

99.1 4.5

103.0 6.8

103.6 5.2

101.5 3.1

101.9 2,8

101.5 3.6

100.2 3.9

101.2 3.3

100.2 3.2

100.4 2.2

99.0 2.6

102.5 2.8

104.4 2.3

105.3 2.9

104.1 3.0

101.3 2.5

99.5 2.9

103.9 5.1

99.7 1.8

98.7 1.9

98.4 4.0

99.6 4.1

97.6 2.6

99.9 4.2

98.4 2.9

98.7 2.6

101.0 3.4

101.1 4.4

98.7 1,5

98.2 1.2

100.2 4.8

102.0 4.0

101.9 5.8

97.1 3.8

99.1 0.9

98,3 3.1

98,2 2,4

9d.9 2,3

98.3 4,1

97,7 2.6

100.0 1.8

98.7 2.2

98.7 3.0

93,6 2.5

95,5 3,5

96.6 2.3

96,2 1,8

97,2 3.7

98,8 4.7

100.8 7,1

101.4 5.1

Prefrontal Mean SD

Superior frontal Mean SD

Frontotemporal Mean SD

Temporal Mean SD

Central Mean SD

Parletotemporal Mean SD

Occipital Mean SD

Note, FAS .....Chicago Word Fluency Test. WCS-B = baseline control for the Wisconsin Card Sort. WCS-T = Wisconsin Card Sort Test, R -=-right, L = left,

flow changes in the prefrontal area would be attributable to the increased cognitive complexity of the sorting task. Analysis by region (paired t tests) re~,ealed no significant changes for any region between the resting condition and the FAS activation or between the baseline condition and the WCST (Table 2). Thus, no significant changes in the rCBF landscape during tests were observed (see also Figs. 2 and 3).

Clinical Ratings (Table 3). No significant change in symptomatology occurred between 1972 and 1990, as measured by the RP rating scale. Severity of illness, as indicated by total number of RP points (TTT), was unchanged, nor was there any change in any of the symptom subscales. Total number of positive (+TT) and total number of negative (-TT) symptom points remained the same. Scores for the 18 symptom subscales in the BPRS and the five SANS subscales (affective flattening, alogia, avolition-apathy, anhedonia, and attention) plus total scores were calculated. Table 3 shows only the composite scores for these scales. Clinical Ratings Related to Blood Flow Measures. Due to the number of comparisons (regions of interest, clinical symptoms), stringent criteria were used to

259

Fig. 1. Anteroposterior (AP) ratio in chronic schizophrenic patients 18 year schizophrenia followup study. FIO

FIPTO

1.20 O ;=

09

1.15

A

1.10 "C O Q.

9

011

oz &

9

~

.,0 3

1.05

o= ¢: tu

1.00

0.95

Mean SD

Left

Left Right

1.08 .O5

1.06 1.07 .O5 .0b

The AP ratio was calculated by dividing the mean of the frontal distribution values by the mean of the occipito-temporo-parietal (1972) or corresponding postcentral (1990) distribution values. F/O: F = prerolandic and frontal regions, O = occipito-temporo-parietal regions ,Ingvar and Franzen, 1974); F/PTO: F = prefrontal and superior frontal regions, PTO = parieto-temporal, occipital regions ~1990). Note that although individual changes were observed, the group mean of the ratios did not change. The subjects are identified by the numbers 2, 3, 5, 6, 9, 10, and 11, which correspond to the case identification numbers used for the younger subjects in 1972.

Fig. 2. Topographic group mean rCBF: Vertex view of cerebral cortex at rest and during the FAX task REST

FAS

(n=7)

1990

% jo.,.% a, %

l

I The frontal pole is shown at the top and the occipital pole, at the bottom. The colors represent flow distribution values (fl) (regional values in % of hemispheric mean) as defined by the key to the right. Top left shows the values obtained at rest; top right shows the values obtained during frontal lobe challenge with the verbal fluency test (FAS). The difference between the 2 flow maps (bottoml was calculated by subtracting each distribution value obtained during the FAS test with those at rest. No significant differences were seen from rest to test. rCBF = regional cerebral blood flow.

260

Fig. 3. Topographic group mean rCBF: Vertex view of cerebral cortex during the baseline task and during the WCST BASELINE

WCST

(n=6)

1990

a

~

DIFF

I

The frontal pole is shown at the top and the occipital pole, at the bottom. The color key to the right is the same as in Fig. 2. Top left shows the values obtained during the baseline task; top right shows the values obtained during frontal lobe challenge with the Wisconsin Card Sort Test ~WCST). The difference between the two flow maps (bottom ! was calculated by subtracting each distribution value obtained during theWCST from those during the baseline task, No significant differences were seen from baseline to WCST. rCBF = regional cerebral blood flow.

define statistical significance (p = 0.0 I). No significant relationships emerged between clinical ratings (RP scale, BPRS, and SANS) and any of the rCBF measures. Thus, there was no correlation between mean hemispheric flow level and total number of positive RP points in 1990, as there had been for the younger patient group asa whole in 1972 (lngvar and Franz6n, 1974), as well as no correlation in 1990 between postcentral flows and degree of cognitive disturbance, as measured by Category III of the RP scale. There was no correlation between change in the AP index over time and change in clinical symptoms (RP points), nor did the two subgroups (those who increased in AP/those who decreased in AP) differ on current clinical ratings, illness duration, age, age of onset, amount of cumulative medication, amount of medication since the CBF study in 1972, current medication, PCO2 (1990), or pulse rate (1990). Thus, the within-group and between-group comparisons yielded no particular symptomatic pattern that could be related to changes in AP index in the resting state. Similarly, no relationship was observed between activation response and any measure of clinical profile. Test Performance. After adjustments were made for age, sex, and educational level for performance on the FAS test (Benton and Hamsher, 1977), each subject had a score in the percentile range of < 1, or characteristic of "severe defect." WCST performance can be assessed on a number of different measures. The group mean number of categories achieved was < 1 (mean = 0.5, SD = 0.5), corresponding to a performance level worse than that of patients with known frontal lesions (Milner,

3

9

1 13 17 8 17

9.7 6.4 9.0 16

y 2

y 3

5 6 9 10 11

y y y y y

Mean SD Median Range

24.4 6.5 23.0 17

32 19 15 23 28

22

32

+TT

7.4 4.5 6.0 11

3 8 14 6 13

4

4

!

1972

8.6 1.6 9.0 4

10 10 6 8 7

10

9

II

18.1 4.5 17.0 13

20 14 12 17 25

17

22

III

34.1 5.0 32.0 14

33 32 32 31 45

31

35

TTT

11.4 7.2 11.0 21

6 2 7 14 23

11

17

-TT

21.4 9.5 20.0 28

21 41 18 13 24

13

20

+TT

Rockland-Pollin Scale

9.6 3.9 8.0 11

6 7 8 10 17

7

12

I

1990

6.6 2.0 6.0 6

8 6 4 5 10

7

6

ll

16.6 7.0 13.0 20

13 30 12 12 20

10

19

II!

32.9 9.4 27.0 23

27 43 25 27 47

24

37

TTT

58.3 24,5 53.0 70

34 70 39 67 104

41

53

SANS

28.3 10.7 26.0 29

21 40 21 26 46

17

27

BPRS

Note. SANS = Scale for the Assessment of Negative Symptoms. BPRS = Brief Psychiatric Rating Scale. Rockland-Pollin Scale: -TT = total number of negative symptom points. +TT = total number of positive symptoms points. I = Behavior. II = Affectivity. III = Cognition. TTT = total number of points on Rockland-Pollin Scale. Difference between 1972 and 1990 was not significant. The case numbers refer to those used by Ingvar and Franzen ,1974).

-'lit

Case

Table 3. Rating scores

t~ o~

262 1963). Mean % perseverative error as defined by Milner (1963) was40.8% (SD = 27.1). No significant relationships were observed between test performance on the FAS or WCST and the rCBF activation response. S u m m a r y . No significant change in mean hemispheric rCBF or regional distribution for the group as a whole was observed between 1972 and 1990. The clinical symptomatology was also unchanged. Psychological tests of frontal lobe function showed poor performance, and prefrontal activation responses during rCBF were nonsignificant.

Discussion The present CBF measurement in our seven chronic schizophrenic patients revealed no significant change in rCBF over a period of 18 years. Although the study is limited by the small sample size, the stability of the rCBF landscape for the group as a whole, as well as the lack of change in clinical symptoms from 1972 to 1990, confirms the notion of schizophrenia as a nonprogressive disease process in these patients. While its implications for the pathogenesis of schizophrenia are unclear, the finding is in agreement with those studies that sht~w a lack of progressive structural degeneration in schizophrenia, most notably seen as an absence of gliosis (Roberts et al., 1987; Crow et al., 1989) and a stability in computed tomographic findings over time (lllowsky et al., 1988; Vita et al., 1988). Because of differences in the sensitivities of the two rCBF techniques used, the 133Xe inhalation method would have tended, if anything, to underestimate the gray matter flow. The observed decrease of approximately 10% in mcatl (left) hemispheric flow values from 1972 to 1990 can be interpreted as an expected col lclate of normal aging. Previous studies have shown a similar progressive reduction in CBF with age in normal healthy subjects (Hagstadius and Risberg, 1989). Wl~ile minor fluctuations in the AP gradients were observed, the size of the present sample does not allow any conclusions to be drawn as to whether these fluctuations were due to chance or were significantly related to the subgroups observed. For the group as a whole, the AP gradient was unchanged, and there was no indication of an accelerated aging process in these patients. Previous studies have found differences between younger and older patients (lngvar and Franz6n, 1974; Mubrin et al., 1982; Mathew and Wilson, 1990). As illness duration is a confounding factor in attempts to isolate the effects of age, the issue is not whether differences observed between patients with short and long durations of illness may reflect time-related processes of deterioration, but whether illness duration itself may be a characteristic of a particular subgroup of patients--those who do not improve despite treatment. Long-term chronic patients may have a particularly severe, treatment-resistant form of schizophrenia. Thus, although our subjects were not floridly psychotic in 1990, they had shown little sign of clinical improvement since 1972. Persistence of symptoms characterized this particular group of patients, for whom the chances of complete recovery after more than 20 years of illness would now appear minimal. It should be noted, however, that in contrast to the findings in the original study (lngvar and Franz6n, 1974), no correlations were found in 1990 between blood flow measures and clinical symptoms. The restricted size of the present sample,

263 however, would not have permitted an adequate investigation of the influence of symptomatology, and the relationship between clinical symptoms and rCBF remains unclear. While the relevance of clinical state for regional distribution patterns of CBF may emerge more clearly in studies with a focus on patients with prominent positive symptoms (Kurachi et al., 1985; Warkentin et al., 1990; in press), the patients in the present study had no current florid exacerbations of symptomatology. The rCBF at rest showed a slight hyperfrontal distribution, with frontal flow values approximately 7% over the hemispheric mean. In normal resting subjects under age 40, a 10-15% increase in frontal regions over the hemispheric mean can be observed (Mamo et al., 1983). The AP gradient mean of 1.07 in this patient group, although within the lower range of the hyperfrontal spectrum, nonetheless exceeds 1.00 and is similar to results found in other patient groups, with the exception of Ingvar and Franz6n's older patients (Buchsbaum and Haier, 1987). A true interpretation of the observed AP gradient level (whether or not the group values obtained thus constitute hyperfrontality or hypofrontality) is hindered by the lack of a control group. The major interest in this study was to investigate the long-term outcome of a unique group of patients for whom earlier rCBF data existed. The focus on progressive aspects of the disease in chronic patients with exceptionally loni illness histories made the choice of an appropriate control group in this case problematical. Therefore, we have chosen to present these patients primarily in reference to themselves and do not attempt to evaluate them relative to a normal reference group, other than to observe that they in 1990 have a hyperfrontal distribution which falls within the lower end of the expected normal hyperfrontal spectrum. While a clear-cut hypofrontal pattern was not observed in these patients at rest, it was not possible to elicit the activation responses ~ormaily seen in the prefrontal cortical areas during cognitive tasks that are known to activate these areas (Berman, 1987~ Warkentin et al., in press). It should be noted that some patients in remission show an adequate activation response on the FAS test (Warkentin et al., in press). As the mean illness history in the present group was exceptionally long (> 20 years), it is possible that the poor activation response may be a characteristic of a long-term course of schizophrenia with poor outcome. Only significant mean hemisphere flow increases were observed, from rest to baseline (and from rest to WCST). These correspond to an increase in the general level of cortical arousal and are probably related to an elevation in subjects' task expectancies. The absence of significant prefrontal activation during both the FAS and the WCST confirms previous reports of a subtle frontal dysfunction in the brain (Weinbe~'ger et al., 1986; Berman, 1987) in chronic schizophrenia. Finally, it should be emphasized that the present followup study demonstrates rather clearly that almost 20 years of chronic neuroleptic medication does not result in a progressive functional depression of brain functions. ~dmittedly, the medication in the group varied and there is uncertainty about the real :onsumption as related to the prescribed dose. Also, while some of the patients h~d adequate responses to the Ravens progressive matrices in 1972, the lack of direct comparability between this test and the tests used in the present study makes it difficult to establi:~h whether prefrontal dysfunction was present in 1972 and whether this also was stable over time. Neverthe-

264 less, there was no evidence of chronic deleterious effects on the rCBF due to neuroleptic treatment. Ill principle, the present results also provide evidence against the hypothesis that hypofrontality in schizophrenia is caused by neuroleptic drugs. In conclusion, this limited 18-year followup shows that in patients with stable psychotic symptomatology, the rCBF pattern also remains stable, and that this stability appears unaffected by neuroleptic medication. This does not exclude the possibility that the rCBF pattern may change over time in patient groups with other forms of symptomatology. Acknowledgments. This study was supported by grants from the Swedish Medical Research Council (project 4969), the BiSrje Bengtsson-Lindhes Fund, and Stiftelsen Stiderstr~mKtinigskasjukhemmet. Special thanks are owed to Siv Karisson, eng., for technical assistance in preparation of the manuscript.

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