Neural correlates of memory organization deficits in schizophrenia

Schizophrenia Research 42 (2000) 209–222 www.elsevier.com/locate/schres

Neural correlates of memory organization deficits in schizophrenia A single photon emission computed tomography study with 99mTc-ethyl-cysteinate dimer during a verbal learning task Shigeru Nohara a, *, Michio Suzuki a, Masayoshi Kurachi a, Ikiko Yamashita a, Mie Matsui b, Hikaru Seto c, Osamu Saitoh d a Department of Neuropsychiatry, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan b Department of Psychology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan c Department of Radiology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan d Outpatient Department, National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Tokyo, Japan Received 28 December 1998; accepted 28 June 1999

Abstract Regional cerebral blood flow (rCBF ) during a verbal learning task was measured using 99mTc-ethyl-cysteinate dimer and single photon emission computed tomography in 10 patients with schizophrenia and nine normal controls. Verbal repetition was used as a control task. The schizophrenic patients showed failure to spontaneously utilize implicit category information to learn the word lists. In the normal controls, rCBF in the left inferior frontal and left anterior cingulate regions was significantly increased during the verbal learning task, compared with the verbal repetition task. In contrast, there was no significant frontal lobe activation by the verbal learning in the schizophrenic patients. The patients had lower rCBF during the verbal learning task than the controls in the bilateral inferior frontal, left anterior cingulate, right superior frontal, and bilateral middle frontal regions. Activation in the left inferior frontal region was significantly positively correlated with categorical clustering in the task in the controls, but no such correlation was found in the patients. These results indicate that memory organization deficits in schizophrenia may be related to dysfunction in the prefrontal areas, especially in the left inferior frontal region. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Frontal lobe; Memory organization; Regional cerebral blood flow; Schizophrenia; Single photon emission computed tomography

1. Introduction Memory impairment is one of the most consistent findings among the neuropsychological deficits * Corresponding author. Tel.: +81-764-34-2281; fax: +81-764-34-5030. E-mail address: [email protected] (S. Nohara)

reported in patients with schizophrenia (Goldberg et al., 1989; Saykin et al., 1991; Gold et al., 1992), and verbal memory has been reported to be especially impaired (Saykin et al., 1994). However, the nature of the specific cognitive defects responsible for poor memory performance has remained unclear. Gold et al. (1992) suggested that the memory impairment in schizophrenia is attribut-

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able to dysfunction intrinsic to the memory system rather than information-processing abnormalities that are not specific to the memory system, such as deficits in attention and motivation. They used a learning task that consisted of three word lists that differed in degree of semantic organization, and demonstrated that patients with schizophrenia failed to spontaneously make use of implicit semantic (categorical ) information, meaning that there is a deficit in the organization of information in schizophrenia. Some previous studies have also reported that schizophrenic patients do not utilize latent semantic organizational structure in their verbal recall, which leads to poor verbal memory performance ( Koh et al., 1973; Koh, 1978; McClain, 1983; Harvey et al., 1986; Paulsen et al., 1995; Kareken et al., 1996). List learning performance by schizophrenic patients has been reported to improve when an organizational strategy is induced ( Koh et al., 1976; Bauman, 1971). A substantial number of functional neuroimaging studies have been carried out during the performance of a specific task to investigate brain dysfunction in patients with schizophrenia ( Taylor, 1996). The Wisconsin Card Sorting Test has been the most frequently used task ( Weinberger et al., 1986; Rubin et al., 1991; Kawasaki et al., 1993). Other investigators have applied motor activations (Guenther et al., 1994), ocular movements (Nakashima et al., 1994), and other cognitive tasks, such as the Tower of London, verbal fluency, and Continuous Performance Test (Andreasen et al., 1992; Frith et al., 1995; Siegel et al., 1993). Many of these studies have demonstrated decreased activation of the prefrontal cortex or dysfunctions in the distributed networks including the prefrontal cortex in schizophrenic patients ( Taylor, 1996). Functional neuroimaging studies have also employed memory tasks in patients with schizophrenia (Andreasen et al., 1996; Busatto et al., 1994; Ganguli et al., 1997). In a positron emission tomography (PET ) study with recall of complex narrative material as the task, Andreasen et al. (1996) reported that the activation of the prefrontal–thalamic–cerebellar circuit seen in normal subjects did not occur in schizophrenic patients. Decreased activation in the frontal and superior temporal regions during an auditory

verbal supraspan memory task has been reported in schizophrenia (Ganguli et al., 1997). On the other hand, a resting PET study by Mozley et al. (1996) suggested that the impairment of several domains of verbal memory, including organization, was associated with relatively increased glucose metabolism in some regions of the left hemisphere. To our knowledge, however, no studies that have examined the organization deficits in schizophrenia by the activation paradigm of functional imaging have ever been reported. To clarify the neural mechanism underlying memory organization deficits in schizophrenia, we carried out an activation study using 99mTc-ethylcysteinate dimer (99mTc-ECD) and single photon emission computed tomography (SPECT ). A Japanese version of the verbal learning task constructed in accordance with the report by Gold et al. (1992) was employed as the activation task. We compared regional cerebral blood flow (rCBF ) in 26 brain regions during the verbal learning task with rCBF during a verbal repetition task as a baseline in 10 schizophrenic patients and nine normal controls.

2. Methods 2.1. Subjects Ten right-handed male patients with schizophrenia were recruited from the inpatient and outpatient clinics of the Department of Neuropsychiatry, Toyama Medical and Pharmaceutical University Hospital. All patients fulfilled the ICD-10 diagnostic criteria for research on schizophrenia ( World Health Organization, 1993). Their mean age was 27.2±5.8 (SD) years (range, 20– 39). Psychopathology was assessed by two psychiatrists using the Scale for the Assessment of Positive Symptoms (SAPS; Andreasen, 1984a) and the Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1984b). The patients were in stable clinical condition with no marked positive symptoms. The total SAPS and SANS scores were 6.1±5.3 and 40.6±16.8, respectively. All patients were on neuroleptic medication (mean haloperidol equivalent dose, 6.4±6.4 mg/day). Seven patients

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were also being treated with anticholinergic drugs (biperiden hydrochloride, 2.5±2.0 mg/day), and some patients were taking anxiolytics (four patients) and hypnotics (six patients) of benzodiazepine derivatives. The mean age at the onset of schizophrenia was 21.8±4.8 years, and the mean duration of illness was 5.5±5.4 years. All patients were physically healthy at the time of the study, and none had a history of head trauma, serious medical or surgical illness, or substance abuse. The control subjects consisted of nine healthy male volunteers recruited from among the hospital staff and medical students. All control subjects were right-handed, and their mean age was 25.8± 3.7 years (range, 20–33). Subjects were excluded if they had a history of psychiatric illness, head trauma, neurological illness, serious medical or surgical illness, or substance abuse. The control subjects matched the schizophrenic patients for age and handedness, but had significantly higher educational achievement than the patients (control subjects, 16.4±1.6 years; patients, 15.1±1.3 years; p<0.05, Mann–Whitney U test). The purpose and procedures of the study were explained to the patients and the control subjects, and written informed consent was obtained. In another four healthy male subjects, repeated measurements of rCBF were performed during a verbal repetition task to assess the reproducibility and validity of the consecutive SPECT scans, as described below. Their mean age was 25.8±1.5 years.

appeared consecutively. Thus, the semiblocked list is a memory task for implicitly categorized words. The list words were selected from common Japanese words, so that familiarity with each word was approximately the same. The subjects were instructed to try to learn the items they heard. They were not informed of the existence of the categories in the blocked and semiblocked lists before the examination. The random, blocked, and semiblocked lists were presented in that order, and three trials of each list were repeated consecutively. The words were presented by means of a tape recording at a rate of one word per second, and the subjects were required to recall the words by speaking them after each 20-word set was presented. After the task had been completed, the subjects were asked whether they had noticed the categories in the semiblocked list, and what strategy they had used to learn the items. Categorical clustering was evaluated as stimulus category repetition (SCR) (Bousfield and Bousfield, 1966) in recall of the semiblocked list. SCR is defined as the total number of occasions on which an item in a category is immediately followed by an item in the same category in the recall, and it reflects the degree to which the subject has utilized the conceptual categories provided implicitly to assist in organization ( Koh et al., 1973). SCR was calculated from the performance of the third trial of the semiblocked list by each subject to measure categorical clustering.

2.2. Verbal learning task

2.3. Verbal repetition task

The Japanese version of the verbal learning task was constructed in accordance with the report by Gold et al. (1992). The verbal learning task was composed of three 20-word lists: a random list, a blocked list, and a semiblocked list. These three lists differed in degree of semantic organization. The random list was composed of 20 unrelated nouns. The blocked list contained four sets of five consecutively presented exemplars from each of four taxonomic categories (stationery, vehicles, colors, and sports). In the semiblocked list, five exemplars from each of four categories (animals, countries, musical instruments, and vegetables) were constructed so that related items never

A verbal repetition task was applied as a control task following the recall trials of the verbal learning task. This task was composed of 60 unrelated nouns, and presented by tape recording at a rate of one word per 3 s. The subjects were required to repeat the items word by word. Two 60-word sets were used. 2.4. SPECT procedures 2.4.1. rCBF during the verbal learning task and verbal repetition task Serial rCBF measurements were performed by the split-dose method. After a venous access was

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established in the left forearm with a 22-gauge needle, the subjects performed the verbal learning task while lying supine with their eyes closed. Their responses were tape-recorded and scored. Thirty seconds after the start of the semiblocked memory task, a 555 MBq (15 mCi) dose of 99mTc-ECD was injected intravenously. Five minutes after the task had been completed, the subjects were then taken to the SPECT scanner. Thereafter the subjects continued to lie supine with their head in a belted support. The first acquisition of projection data, for 12.5 min, was performed to obtain SPECT images during the verbal learning task. Since distribution of 99mTc-ECD in the brain is established within a few minutes after administration and remains stable for an extended period ( Walovitch et al., 1989), relocation of the subjects several minutes after the injection does not affect 99mTcECD distribution in the brain. After completion of the first data acquisition, the verbal repetition task was started with the subjects’ eyes closed, and 30 s after the start of the task, an additional dose of 925 MBq (25 mCi) of 99mTc-ECD was injected. Five minutes after completion of the task, the second acquisition of projection data, for 7.5 min, was carried out without any change in the position of the subject’s head. SPECT was performed with a three-head rotating gamma camera system (GCA9300A; Toshiba, Tokyo, Japan) employing general-purpose fan beam collimators combined with a workstation (GMS 5500; Toshiba, Tokyo, Japan). The resolution was 8 mm full width at half maximum in the center of the reconstructed slice, with the rotating radius at 13.2 cm. The SPECT data were obtained in a 128×128 format for 30 angles in a 120° arc for each camera, with 25 s per angle in the first scan and 15 s per angle in the second scan. The ramp back projection method was used for SPECT image reconstruction after preprocessing projection data with a Butterworth filter. The voxel size of the reconstructed images was 1.7×1.7×1.7 mm3. After correction for differences in the acquisition time between the first and second scans, tomographic images in the first scan (during the verbal learning task) were subtracted from the images in the second scan to obtain images during

the verbal repetition task (Matsuda et al., 1991; Kawasaki et al., 1993). 2.4.2. Reproducibility of repeated rCBF measurements during the verbal repetition task The reproducibility of repeated rCBF measurements by the subtraction technique was assessed. Four healthy subjects were asked to perform the verbal repetition task twice in a row. Thirty seconds after the start of the first verbal repetition task, 555 MBq (15 mCi) of 99mTc-ECD was injected. The first acquisition of projection data, for 12.5 min, was started 5 min after completion of the task. An additional dose of 925 MBq (25 mCi) of 99mTc-ECD was injected 30 s after the start of the second task. The second verbal repetition task consisted of 60 nouns that differed from those in the first verbal repetition task. After 5 min, the second acquisition of projection data, for 7.5 min, was started. The tomographic images in the first scan (during the first verbal repetition task) were subtracted from the images in the second scan to obtain images during the second verbal repetition task, as described above. 2.5. Magnetic resonance imaging (MRI) data acquisition Magnetic resonance images were acquired on a 1.5 T Siemens Magnetom Vision (Siemens, Erlangen, Germany) with a three-dimensional gradient-echo sequence FLASH (fast low-angle shots) yielding 160–180 contiguous T1-weighted slices of 1.0 mm thickness in the sagittal plane. Imaging parameters were: TR=24 ms; TE=5 ms; flip angle=40°; field of view=256 mm; and matrix size=256×192. Voxel size was 1.0×1.0× 1.0 mm3. 2.6. Image analysis SPECT and MR images were transferred to a Sun SPARC 20 workstation (Sun Microsystems, Palo Alto, CA, USA) and processed using the software package ANALYZE@ version 7.5.5 (BRU, Mayo Foundation, Rochester, MN, USA). The anterior and posterior commissures (AC–PC ) line was identified in the mid-sagittal plane of the

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Fig. 1. Delineation of regions of interest (ROIs). The top row shows coregistered coronal MRI and SPECT images in the same subject. The middle row shows the regional schema of each ROI delineated on the MRI images. Each ROI is transposed onto the corresponding SPECT image in the bottom row. (Level 1) 1, anterior cingulate; 2, superior frontal; 3, middle frontal; 4, inferior frontal; 5, orbitofrontal. (Level 2) 6, basal ganglia. (Level 3) 7, anterior part of the medial temporal. (Level 4) 8, thalamus; 9, superior temporal; 10, middleinferior temporal; 11, posterior part of the medial temporal. (Level 5) 12, parietal. (Level 6) 13, cerebellum.

MR images, and the MR images were resliced in coronal planes of 1.0 mm thick vertical to the AC– PC line. The SPECT images of each subject were coregistered to the individual MR images by using a surface-matching algorithm, and then resliced in coronal planes corresponding to the MR images. In this process, the SPECT images were interpolated to a voxel size of 1.0×1.0×1.0 mm3. Regions of interest (ROIs) were delineated manually on the coronal MR images and transposed onto the corresponding SPECT images to measure the count of each ROI. To determine the relative rCBF distribution in the brain, the percentile ratio of counts/voxel of each ROI to counts/voxel of the whole brain was calculated. Thirteen ROIs were drawn in each hemisphere on six levels (Fig. 1). Each level consisted of five contiguous slices. A total of 30 coronal slices was used in each subject. The first level started at the slice through the rostral end of the genu of the corpus callosum, and extended caudally. The

second level started at the most rostral slice through the optic chiasm, and extended rostrally. The third level was composed of slices extending rostrally from the slice through the mid-portion of the mamillary bodies. The fourth level extended caudally from the slice in which the cerebral peduncle began to be connected with the midbrain. The fifth level extended caudally from the slice through the caudal end of the splenium of the corpus callosum. The sixth level started at the most caudal slice through the inferior cerebellar peduncle and extended caudally. Each of these levels included the following ROIs: level 1, anterior cingulate, superior frontal, middle frontal, inferior frontal, and orbitofrontal; level 2, basal ganglia; level 3, anterior part of medial temporal (composed mainly of the amygdala and parahippocampal gyrus); level 4, thalamus, superior temporal, middle-inferior temporal, and posterior part of medial temporal (composed mainly of the hippocampus and parahippocampal gyrus); level 5, parietal; and level

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6, cerebellar cortex. The ROIs were delineated separately on each hemisphere on the MR images. The same set of ROIs was used for analysis of both scans during the verbal learning and verbal repetition tasks. 2.7. Statistical analysis Statistical analysis was carried out using the software package STATISTICA 4.1J for Macintosh (StatSoft, Tulsa, OK, USA). The total number of correct words recalled on each list over the three trials was compared between the schizophrenic patients and control subjects by a repeatedmeasures analysis of variance (ANOVA) and Scheffe´’s multiple comparison test. The mean SCR scores were compared between the groups by the Mann–Whitney U test. To assess functional activity changes, a repeated-measures multivariate analysis of variance (MANOVA) for the relative rCBF was performed initially. ‘Diagnosis (patients vs. controls)’ was the ‘between-subject factor’, whereas ‘task condition (verbal learning vs. verbal repetition)’, ‘hemispheres ( left vs. right)’, and ‘ROIs’ were the ‘within-subject factors’. Acrossdiagnosis and condition comparisons were then designed for each ROI by using a two-way repeated-measures ANOVA and Scheffe´’s test. Spearman’s rank correlation coefficient was used for the correlation analyses. Reproducibility of relative rCBF during the verbal repetition task was assessed for each ROI by using a repeatedmeasures ANOVA and the post hoc Scheffe´’s test. Coefficients of variation (CV ), defined as the standard deviation divided by the mean, were also calculated for the relative rCBF of each ROI. Statistical significance was defined as p<0.05. In the post hoc Scheffe´’s test, however, it was defined as p<0.01 to reduce the probability of a Type I error.

3. Results 3.1. Performance on the verbal learning task The mean total numbers of correct words recalled in each list over three trials in the patients

and control subjects are shown in Fig. 2. Repeatedmeasures ANOVA revealed significant main effects of diagnosis (F=20.57; df=1, 17; p<0.001) and list type (F=41.03; df=2, 34; p<0.001). There was a non-significant trend in diagnosis×list type interaction (F=2.90; df=2,34; p=0.069). The post hoc Scheffe´’s tests demonstrated that the recall of the patients was significantly lower than that of the normal controls for all three lists (all p values <0.001). In the control subjects, recall increased significantly from the random to the semiblocked and blocked lists ( p=0.027 and p<0.001, respectively), and recall of the blocked list was insignificantly higher than that of the semiblocked list ( p=0.163). In contrast, recall of the random and semiblocked lists did not differ in the patients, but recall of the blocked list was significantly higher than that of the random and the semiblocked list (both p values <0.001). All control subjects utilized the implicit categories in the semiblocked list, whereas only two of the 10 patients utilized them (x2=12.43, p<0.001), and none of the patients relied on another strategy to facilitate their recall. The mean SCR score of the patients for the semiblocked list was significantly lower than that of the controls (1.7±2.7 and 7.0±4.9, respectively; p<0.016, Mann– Whitney U test). In the patients, there was a significant negative correlation between the SCR score and the score on the affective flattening or blunting in SANS (Spearman’s rho=−0.691, p=0.027). Recall of the three lists and the SCR scores were not significantly correlated with the dosage of neuroleptics or anticholinergic drugs in the patients. 3.2. Comparison of relative rCBFs 3.2.1. Brain activation during the verbal learning task Table 1 shows the relative rCBF values during the verbal learning task and verbal repetition task and the differences in rCBF between the tasks (DrCBF, verbal learning minus verbal repetition) in the 26 regions examined. MANOVA revealed significant main effects of hemispheres (F=22.50; df=1, 17; p<0.001) and ROIs (F=85.08; df=12,

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S. Nohara et al. / Schizophrenia Research 42 (2000) 209–222 Table 1 Relative rCBF values in 26 brain regions in normal controls and schizophrenic patientsa ROI

Anterior cingulate Superior frontal Middle frontal Inferior frontal Orbito-frontal Basal ganglia Thalamus Superior temporal Middle temporal Medial temporal, anterior Medial temporal, posterior Parietal Cerebellar

Control

Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left

Schizophrenia

Verbal learning

(DrCBF )

Repetition

Verbal learning

(DrCBF )

Repetition

117.0±12.3 118.4±6.5** 108.9±9.3 108.0±10.4 121.2±11.4 118.4±9.5 121.7±5.8 118.2±7.4** 103.7±7.1 101.9±5.7 109.7±10.4 109.3±9.5 100.7±14.7 103.9±10.2 120.1±3.3 115.9±5.4 106.1±6.3 104.9±5.0 83.2±8.9 85.6±7.0 81.2±7.3 82.2±8.8 114.7±6.1 105.9±6.7 116.3±5.5 114.7±4.8

(+1.0) (+10.6) (+1.9) (−0.1) (+3.5) (+2.3) (+1.9) (+10.5) (+1.2) (+4.4) (−1.8) (−6.7) (−3.4) (−7.5) (−1.4) (−1.6) (−0.4) (+5.4) (+0.5) (+5.4) (−4.6) (−2.4) (+1.1) (−2.1) (+2.6) (−1.9)

116.1±10.5 107.8±6.6 106.9±9.5 108.1±10.1 117.7±7.9 116.1±10.3 119.8±11.3 107.7±6.7 102.5±6.2 97.5±8.6 111.5±8.4 115.7±7.7 104.1±8.5 110.4±12.4 121.5±10.7 117.5±10.1 106.6±7.0 99.5±7.5 82.7±11.1 80.3±6.0 85.7±10.7 84.6±5.6 113.7±5.3 108±6.4 113.6±7.6 116.5±5.8

110.9±6.8 110.6±5.1# 100.6±9.8# 102.9±7.3 111.0±8.4# 110.0±5.2# 107.6±4.0## 107.0±8.3## 104.3±5.2 98.7±2.7 116.6±7.5 113.1±5.8 106.5±5.6 106.2±8.7 116.7±3.4 111.3±5.6 108.6±8.3 101.1±7.6 91.0±7.1 86.5±8.5 85.9±6.5 82.8±6.7 111.6±4.3 107.5±5.0 116.2±6.7 116.2±6.4

(+1.9) (+2.9) (+0.9) (+2.6) (+5.6) (+0.5) (−5.1) (−1.1) (+2.1) (+0.6) (+0.4) (+1.9) (−1.5) (−0.3) (−2.3) (−4.5) (−3.1) (+3.2) (+3.4) (−3.8) (+0.1) (−1.2) (−1.4) (−2.5) (−2.2) (−3.7)

109±9.5 107±4.4 99.7±9.0 100.3±11.8 105.4±8.8## 10.9.4±7.7 112.8±8.3 108.1±5.9 102.3±5.7 98.3±5.2 116.2±11.1 111.2±6.4 108.1±8.6 106.5±10.9 119.1±5.8 115.8∞±6.7 111.8±7.8 97.9±7.5 87.6±10.0 90.3±7.2# 85.8±8.0 83.9±6.6 113.0±6.5 110.0±7.2 118.4±7.6 120,0±6.6

a Values are means±SDs. DrCBF indicates the difference in relative rCBF between the tasks (verbal learning minus verbal repetition). Repeated measures MANOVA result: no main effect of group or task; main effect of hemisphere, F(1, 17)=22.50, p<0.001; main effect of region, F(12, 204)=85.08, p<0.001; group by region interaction, F(12, 204)=4.20, p<0.001; task by region interaction, F(12, 204)=1.84, p<0.05; hemisphere by region interaction, F(12, 204)=3.97, p<0.001; group by hemisphere by region interaction, F(12, 204)=1.82, p<0.05; other interactions not significant. Post hoc Scheffe´’s test: **p<0.01, compared to the verbal repetition task; #p<0.05, ##p<0.01, compared to the controls.

204; p<0.001). There was no significant main effect of diagnosis or task condition (F=1.95; df= 1, 17; p=0.181 and F=0.19; df=1, 17; p=0.667, respectively). Significant interactions were as follows: diagnosis×ROI (F=4.20; df=12, 204; p<0.001), task condition×ROI (F=1.84; df=12, 204; p=0.043), hemisphere×ROI (F=3.97; df= 12, 204; p<0.001), and diagnosis×hemisphere× ROI (F=1.82; df=12, 204; p=0.047). A two-way repeated-measures ANOVA, performed for each ROI, demonstrated significant across-condition differences in rCBF in the left inferior frontal (F=6.96; df=1, 17; p=0.017), left anterior cingulate (F=14.53; df=1, 17; p=0.001),

and right middle frontal region (F=5.37; df=1, 17; p=0.033), and significant across-diagnosis differences in the bilateral middle frontal ( left, F= 5.39; df=1, 17; p=0.032; right, F=9.13; df=1, 17; p=0.008) and right inferior frontal region (F= 13.82; df=1, 17; p=0.002). There were significant interactions between diagnosis and condition in the inferior frontal (F=10.63; df=1, 17; p=0.005), anterior cingulate (F=4.72; df=1, 17; p=0.044), and anterior part of the medial temporal region (F=6.00; df=1, 17; p=0.025) in the left hemisphere. The post hoc Scheffe´’s tests revealed that rCBF in the controls was significantly increased during the verbal learning task compared to the

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compared to the controls ( p=0.004), and a tendency to increase in the anterior part of the left medial temporal region ( p=0.014). 3.2.2. Reproducibility of rCBF during repeated verbal repetition tasks A repeated-measures ANOVA revealed no significant across-scan difference in any ROI. The mean within-subject difference in rCBF between the first and second scans was 2.4±1.8% for the 26 ROIs. The mean between-subject CV for these ROIs was 6.0±2.8%. 3.3. Correlations between rCBF changes and categorical clustering (SCR)

Fig. 2. Verbal learning task performance in normal controls and schizophrenic patients. The white and black columns indicate mean total numbers of words recalled by the control and schizophrenic subjects, respectively. Error bars indicate SDs. Repeated-measures ANOVA: main effect of diagnosis, F(1, 17)=20.57, p<0.001; main effect of list, F(2, 34)=41.03, p<0.001; diagnosis by list interaction, F(2, 34)=2.90, p= 0.069. Post hoc Scheffe´ test: 1p<0.05, 11p<0.01, compared to performance on the random lists within the group; ##p<0.01, compared to performance on the semiblocked lists within the group; ++p<0.01, comparison of performance on each list between the control and schizophrenic group.

verbal repetition task in the left inferior frontal and left anterior cingulate regions ( p=0.008 and p=0.007, respectively). In contrast, there was no significant activation by the verbal learning task in the schizophrenic patients. rCBF was higher in several frontal regions during the verbal learning task in the control subjects than in the patients. There were significant increases in the bilateral inferior frontal regions ( left, p=0.004; right, p= 0.003) and tendencies to increase in the left anterior cingulate ( p=0.048), right superior frontal ( p= 0.022), and bilateral middle frontal regions ( left, p=0.043; right, p=0.018). There was a significant decrease in rCBF in the right middle frontal region during the verbal repetition task in the patients

Correlations between the SCR scores of the semiblocked list and the rCBF changes (verbal learning minus verbal repetition) were examined in the 26 regions. In the control subjects, there was a significant positive correlation between the SCR scores and the rCBF changes in the left inferior frontal region (Spearman’s rho=0.756, p=0.018; Fig. 3A), but no such correlation was observed in the patients (Spearman’s rho= −0.585, p=0.076; Fig. 3B). In the schizophrenic patients, the SCR scores were inversely correlated with the rCBF changes in the left middle–inferior temporal region (Spearman’s rho=−0.655, p= 0.040).

4. Discussion The control subjects spontaneously utilized implicit category information to learn the word lists, and their recall, which increased from the random to the semiblocked and blocked lists, was significantly facilitated by semantic organization. In contrast to the controls, the schizophrenic patients showed failure to spontaneously make use of the implicit category organization, and performed poorly on the task, suggesting that memory organization as a mnemonic strategy is impaired in schizophrenia. This finding confirms the deficient semantic organization reported in patients with schizophrenia in previous studies ( Koh et al.,

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Fig. 3. Correlation between the rCBF changes (verbal learning minus verbal repetition) in the left inferior frontal region and the SCR scores. In the control subjects, there was a significant positive correlation between the SCR scores and the rCBF changes (Spearman’s rho=0.756, p=0.018) (A), whereas no such correlation was found in the schizophrenic patients (Spearman’s rho=−0.585, p= 0.076) (B).

1973; McClain 1983; Harvey et al., 1986; Gold et al., 1992; Paulsen et al., 1995; Kareken et al., 1996). In the control subjects, rCBF during the verbal learning task was significantly higher than the baseline during the verbal repetition task in the left inferior frontal and left anterior cingulate regions. In the schizophrenic patients, however, there was no significant activation in any region. The patients had significantly reduced rCBF during the verbal learning task compared with the controls, with statistical significance in the bilateral inferior frontal regions and a tendency toward significance in the left anterior cingulate, left superior frontal, and bilateral middle frontal regions. In the control subjects, activation in the left inferior frontal region was significantly positively correlated with the categorical clustering in the task, but no such correlation was observed in the patients. In addition, the reproducibility of rCBF in the repeated measurements was sufficient. Several lines of evidence have demonstrated the importance of the frontal lobe in memory functions (Gabrieli et al., 1998; Dolan et al., 1997). It has been reported that the free recall impairment exhibited by patients with frontal lobe lesions may,

at least in part, be attributable to deficits in the use of organizational strategies (Gershberg and Shimamura, 1995). This finding suggests that an important aspect of the prefrontal contribution to memory function lies in organization of the material. Functional neuroimaging studies of episodic memory have consistently been reported to show an association between memory encoding operations and the left prefrontal cortex (Grasby et al., 1993; Fletcher et al., 1998). In particular, the left inferior prefrontal cortex (Brodmann’s areas 45, 46, 47) has been found to show increased activation during semantic encoding (Demb et al., 1995). In a PET study by Fletcher et al. (1998), a task requiring subjects to generate an organizational structure in a word list was associated with significant activation in the left prefrontal cortex in normal subjects, especially adjacent to the left inferior frontal sulcus. The activation of the left inferior frontal region during the verbal learning task in the control subjects in our own study is consistent with these previous reports. The significant correlation between left inferior frontal activation and categorical clustering also suggests the importance of this area in memory organization.

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The task-related activation in the left inferior frontal region was not observed in the schizophrenic patients, and they showed lower activity during the verbal learning task than the control subjects in various frontal lobe areas. These findings suggest that dysfunctions in the prefrontal cortex, especially in the left inferior frontal region, may underlie the memory organization impairment in schizophrenia. The reduced prefrontal response to the task in the schizophrenic patients is consistent with hypofrontality, namely decreased activity at rest and/or decreased activation during several cognitive tasks in the prefrontal cortex (Ingver and Franzen, 1974; Weinberger et al., 1986; Andreasen et al., 1992). However, the decreased activation in the prefrontal regions in the schizophrenic patients in this study may have been secondary to poor task performance rather than a specific dysfunction in this brain area (Andreasen et al., 1996). The results of two PET studies designed to resolve this issue contradicted each other ( Frith et al., 1995; Andreasen et al., 1996). The dysfunctional patterns of blood flow in the prefrontal–thalamic–cerebellar circuit occurred in schizophrenic patients during both the practiced and the novel conditions of the memory task in the study by Andreasen et al. (1996). Frith et al. (1995), however, reported that chronic schizophrenic patients showed a normal magnitude of frontal activation during a paced verbal fluency task when matched for performance with controls. A follow-up study investigating the effect of instructing or training patients to organize material to be remembered will be helpful in determining whether the frontal lobe areas is activated. Mozley et al. (1996) reported that deficits of verbal recall in schizophrenic patients were associated with increased metabolism in several regions of the left hemisphere, including the inferior frontal and midtemporal regions. Their findings are in contrast to the results in our study that reduced activation in the left inferior frontal and anterior cingulate areas occurred in association with verbal organization deficits in the schizophrenic patients. Although the reason for this discrepancy is unclear, there seem to be some significant differences between the designs of the two studies. First,

Mozley et al. (1996) correlated verbal memory performance with glucose metabolism under resting conditions, whereas our study examined the association between verbal organization and regional cerebral activity more directly by the activation paradigm; and second, patient sampling was different, especially because Mozley et al. (1996) included only patients who showed ‘good’ and ‘poor’ performance on the verbal recall task. Morphological abnormalities in the prefrontal cortex have been reported in several post-mortem (Benes et al., 1991; Selemon et al., 1995) and MRI ( Zipursky et al., 1992; Schlaepfer et al., 1994) studies of schizophrenia. In particular, Buchanan et al. (1998) reported that patients with schizophrenia exhibit relatively selective gray matter volume reductions in the bilateral inferior prefrontal cortex. Moreover, MRI measures of relative frontal volume have been reported to correlate highly with capacity to use context as an aid to recall in a verbal memory task in schizophrenic patients (Maher et al., 1995). This strongly suggests that the reduced prefrontal response to the task may be attributable to a primary abnormality of the prefrontal cortex, especially in the inferior frontal cortex in schizophrenia. The left anterior cingulate region is another area found to be activated during the verbal learning task in the control subjects. Activation of the anterior cingulate area is a common finding in PET studies involving selective attention to a stimulus or task (Frith et al., 1991; Fletcher et al., 1995). The anterior cingulate cortex is also activated during semantic processing of single words or letters (Peterson et al., 1988; Frith et al., 1991; Grossman et al., 1992), verb selection in response to presentations of a novel list of nouns (Raichle et al., 1994), and learning of word lists (Grasby et al., 1993). Furthermore, the widespread connections and functional heterogeneity of the anterior cingulate (Devinsky et al., 1995) suggest a role in the regulation or coordination of activity within interconnected brain areas. The activation in the left anterior cingulate region during the verbal learning task did not occur in the schizophrenic patients. It has been reported that the anterior cingulate gyrus fails to

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become activated in schizophrenic patients during tasks involving selective attention, such as the Continuous Performance Test (Siegel et al., 1993) and the Stroop Test (Carter et al., 1997), or involving frontal lobe functions, such as the Tower of London (Andreasen et al., 1992) and verbal fluency ( Fletcher et al., 1996). The anterior cingulate gyrus is one of the regions in which histopathological abnormalities have been reported in schizophrenia (Benes and Bird, 1987; Benes et al., 1991; Benes, 1993). The reduced activation in the left anterior cingulate region observed in this study may have been due to the attention deficits in the schizophrenic patients. In fact, most of the patients did not notice the implicit semantic categories in the semiblocked list. It would be helpful to use a concurrent distracting task, as in the study by Fletcher et al. (1998), to clarify the influence of attention on brain activation. In this study, the verbal learning task resulted in activation in restricted brain regions, such as the left inferior frontal and anterior cingulate cortex, in the controls. There was no significant rCBF change in the temporal lobe areas, which are thought to be important in memory. This may be due to the limited sensitivity or resolution of SPECT, or to the fact that absolute quantitative rCBF values were not available. Other explanations may also be possible. The verbal repetition task per se may have a considerable activating effect (Herholz et al., 1994), and as a result it may have reduced the difference in rCBF between the verbal learning and the verbal repetition task. The use of an active baseline as a control condition does not allow for interactions among the cognitive components of the tasks, and if present, they can lead to misleading conclusions (Friston et al., 1996). In addition, the complexity of the tasks used in this study may have influenced the detectability of significant changes. The verbal learning task involves several processes: (1) auditory perception, (2) short-term memory, (3) long-term memory, including the memory organization process, and (4) speech output, while the verbal repetition task involves: (1) auditory perception, (2) short-term memory, and (3) speech output. The normal controls showed left/right asymmetry of relative rCBF in the anterior cingulate and

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inferior frontal regions during the verbal repetition task, with lower values on the left. These asymmetries were not present in the schizophrenic patients. Although there were no statistically significant differences in the relative rCBFs during the verbal repetition task between the normal controls and schizophrenic patients in these areas, these findings may suggest a lack of hemispheric lateralization of brain activity during this task in the schizophrenic patients. However, since previous studies have demonstrated that the left hemispheric regions are more activated than the right during verbal repetition in normal subjects ( Howard et al., 1992; Karbe et al., 1998), these asymmetries may be due to the experimental paradigm in this study. All of the subjects in this study were males. Sex differences in verbal organization have been demonstrated in healthy subjects, in that women are more likely than men to use a semantic organizational strategy during recall ( Kramer et al., 1988). Furthermore, patients with bipolar disorder have also been reported to show deficient organization ( Yurgelun-Todd and Waternaux, 1991). Thus, patients with other psychiatric disorders and female subjects should be included in further studies to clarify the diagnostic specificity of our findings and to determine whether there are sex differences. Andreasen et al. (1996) have stated that investigators should attempt to identify fundamental cognitive processes that can account for the diversity of symptoms that occur in schizophrenia. The memory organization deficits in schizophrenia may have implications not only for verbal episodic memory, but for the processing of more general information. In other words, patients with schizophrenia may have difficulty in using implicit categories in general information, making its content almost the same as random information for them. Thus, because of the deficit in spontaneous organization of information, schizophrenic patients may be prone to fail in a variety of information processing tasks in their own personal lives and in society. Further study is needed to clarify the implications of the memory organization deficits in schizophrenia for the diversity of symptoms, including the disorganized thought and behavior.

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Acknowledgements This study was supported in part by a Research Grant (8B-1) for Nervous and Mental Disorders from the Ministry of Health and Welfare (Japan). We are grateful to Dr M. Shimizu for his kind cooperation, and to Mr M. Yasui and Mr S. Inagaki for their technical support.

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