Hemispheric asymmetry and psychopathological dimensions in drug-free patients with schizophrenia

INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY ELSEVIER International Journal of Psychophysiology 34 (1999) 293-301

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Hemispheric asymmetry and psychopathological dimensions in drug-free patients with schizophrenia Silvana Galderisi*, Armida Mucci, Maria Laura Mignone, Paola Bucci, Mario Maj Department ofPsychiatry, Medical School, University ofNaples SUN, Largo Madonna delle Grazie, 1-80138 Naples, Italy

Received 10 January 1998; receivedin revisedform 12 August 1998; accepted 16 February 1999

Abstract Several neuropsychological models of schizophrenia have regarded the syndrome as a disorder of the left hemisphere. However, discrepant experimental findings have been reported. It has been proposed that the different psychopathological dimensions of the syndrome are associated with distinct patterns of hemispheric imbalance. The present study was aimed at exploring relationships of psychopathological dimensions of schizophrenia with frontoand temporo-hippocampal functioning of either hemisphere in 42 drug-free patients with a DSM-III-R diagnosis of schizophrenia. For the negative dimension, an inverse correlation with the performance on a verbal conditional associative task was found, consistent with the presence of a left fronto-hippocampal impairment in this dimension. As to the positive dimension, our results showed a direct correlation with perseveration on a verbal self-ordered pointing task, suggesting a hyperactivation of the left-hemisphere in this dimension. The disorganisation was found to be associated with a faster execution of a spatial memory task, probably reflecting increased perceptual priming and a right temporo-hippocampal disinhibition. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Schizophrenia; Hemispheric asymmetry; Psychopathological dimensions; Neuropsychological tests

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1. Introduction

The majority of investigations addressing the issue of lateralised hemispheric dysfunction in schizophrenia have reported positive findings. A greater involvement of the left hemisphere was found in most of the studies (Flor-Henry, 1976, 1979; Galderisi et a1., 1988; Crow et a1., 1989; Gur et a1., 1989; Lohr and Caligiuri, 1995, 1997), although discrepant findings suggesting a greater impairment of the right hemisphere were also reported (Cutting, 1985,1990; Bracha, 1987; David and Cutting, 1994). Gruzelier proposed that different patterns of hemispheric imbalance accounted for different aspects of the syndrome, namely a left hemisphere overactivation would account for florid psychotic symptoms, while a right hemisphere overactivation for the withdrawal syndrome (Gruzelier, 1984, 1986). More recently, a further elaboration of this model has been provided, based on investigations in which a dimensional approach to the study of schizophrenia was adopted. In this model, a higher left than right hemisphere activation is associated to the so-called active syndrome (characterised by nonSchneiderian positive symptoms, positive or labile affect and raised levels of behavioural activity), a higher right than left hemisphere activation is associated to the withdrawal dimension (involving social and emotional withdrawal, blunted affect, poverty of speech and motor retardation) and an inconsistent pattern of hemispheric asymmetry is related to the unreality dimension (including the 'first-rank' symptoms) (Gruzelier, 1991, 1994; Gruzelier and Richardson, 1994; Gruzelier et a1., 1995). The three syndrome model of schizophrenia proposed by Gruzelier is compatible with recently proposed dimensional models assuming that different psychopathological dimensions (positive: reality distortion; negative: psychomotor poverty; and disorganisation) are related to distinct pathophysiological mechanisms (Liddle, 1987; Liddle and Barnes, 1990; Peralta et a1., 1992). Lateralised findings have been reported by brain imaging studies of metabolic and cerebral blood flow correlates of these dimensions. In fact, negative correlations between psychomotor

poverty and the left prefrontal CBF and positive correlations between disorganisation and right cingulate CBF have been found by two independent groups (Liddle et a1., 1992; Ebmeier et a1., 1993). For reality distortion, positive correlations with the left medial temporal CBF and negative correlations with the left lateral temporal areas have been observed (Liddle et a1., 1992; Ebmeier et a1., 1993). Lateralised findings were also reported by Kaplan et a1. (1993), involving the same brain regions, although the direction of the observed correlations was not the same as those found in the other studies. Patterns of regional brain functioning associated with the three dimensions have also been investigated by using neuropsychological tests. Neuropsychological correlates reported for the negative dimension include a poor performance on executive tasks (such as the WCST, verbal fluency and trail making) (Liddle and Morris, 1991; Brown and White, 1992; Cuesta et a1., 1995) and on psychometric tests exploring verbal intelligence (WAIS subscales information, vocabulary and similarities) (Cuesta and Peralta, 1995). As to the positive dimension, neuropsychological correlates remain controversia1. In fact, some studies reported a lack of association between the positive dimension and cognitive deficits (Liddle and Morris, 1991), others found an association with a limited cognitive impairment (represented by a poor performance on the figure-ground perception task) (Liddle, 1987) or with an impairment of verbal memory (Norman et a1., 1997) and some others reported a positive correlation between this dimension and performance on tests of visual-motor processes (Cuesta and Peralta, 1995). Neuropsychological correlates of disorganisation have included an impaired ability to suppress irrelevant mental activity (Liddle, 1987; Liddle and Morris, 1991; Baxter and Liddle, 1998), a poor performance on visuomotor processes, verbal memory and verbal fluency tests (Liddle and Morris, 1991; Brown and White, 1992; Cuesta and Peralta, 1995). In summary, while brain imaging findings seem to support Gruzelier's model assuming that different patterns of hemispheric imbalance underlie the three syndromes of schizophrenia, the

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pattern of neuropsychological correlates reviewed above suggests a relationship between an impaired left frontal functioning and the negative dimension, but does not allow definite conclusions for the two positive dimensions. Several factors might account for such a complex picture. First, neuropsychological studies have not specifically addressed the issue of laterality, often including tests aimed to explore right and left hemispheric functioning not adequately matched for difficulty and task requirements. Second, for many of the tests used in these studies, the relative contribution of underlying brain circuits is poorly defined. Third, the influence of important variables, such as handedness and medication status (whose influence on laterality findings is well known), has not always been controlled for. In the present study we investigated relationships between patterns of hemispheric asymmetry and psychopathological dimensions identified by factor analysis in drug-free patients with a diagnosis of schizophrenia. To this aim, a neuropsychological battery including tests proven sensitive to lateralised frontohippocampal and temporohippocampal impairment in neurologic patients was used. Each test included a verbal and a non-verbal subtest, matched for task requirements. Correlations between neuropsychological indices and psychopathological dimensions were explored and the influence of several potentially confounding variables on the observed correlations was assessed.

2. Methods 2.1. Subjects

Forty-two patients with a DSM-III-R diagnosis of schizophrenia (23 males and 19 females) were included in the study. Diagnoses were established on the basis of extensive clinical interviews carried out by staff psychiatrists trained in clinical research work. Twelve patients were drug-naive and 30 had completed a wash-out period of at least 15 days from all psychotropic drugs (mainly

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typical antipsychotics, anticholinergics and benzodiazepines), They had a mean age of 26.1 years (S.D., 6.1; range, 15-43), a mean education of 9.9 years (S.D., 3.2; range, 5-17), a mean age at onset of illness of 21.0 years (S.D., 4.6; range, 11-33) and a mean duration of illness of 5.1 years (S.D., 4.6; range, 0.5-18). Six patients were in the acute phase of their first episode of illness, while the others presented a re-exacerbation of their symptoms. All patients had a negative neurological examination and no history of substance abuse or medical illnesses. They were all right-handed, as assessed by the Edinburgh Inventory (Oldfield, 1971). 2.2. Neuropsychological tests

The neuropsychological battery included: (a) the Spatial and Non-Spatial Conditional Associative Learning Tasks (Petrides, 1985); (b) the SelfOrdered Pointing Tasks (drawings and words) (Petrides and Milner, 1982); (c) Corsi's Block Tapping Task and Hebb's Digit Recurring Sequences (Milner, 1978). To each subject, neuropsychological tests were administered by the same examiner in one session and in the same order (the one in which they are mentioned above). 2.2.1. Spatial and Non-Spatial Conditional Associative Learning Tasks In the spatial task, six lamps and six cards are used, and the position of each lamp is associated with a card; in the non-spatial one, each of six coloured lights is associated with one of six hand postures. In these tests, the subject has to learn, by trial and error, the correct association between pairs of stimuli. Both tests were designed by Petrides (1985) as analogous of the delayed response tasks used in animal experiments, and tap the ability to learn externally-defined associations between pairs of stimuli, as well as to keep track of previous responses, in order to select and produce the appropriate response to each stimulus. These tests involve frontohippocampal functions. The spatial test has proven sensitive to bilateral frontal lesions and to extensive right hippocampal

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damage; the non-spatial is also sensitive to bilateral frontal lesions, as well as to extensive left hippocampal lesions (Petrides, 1985). For both tests, the index of accuracy was represented by the number of learned associations (an association is considered learned when it is correctly identified in three consecutive trials). The speed index is the mean time per trial (total time to complete the test/number of trials). 2.2.2. Self-Ordered Pointing Tasks, drawings and words In these tests, the subject is presented with sets of cards. Each card contains several drawings or words, and the subject has to touch a different item on each card, in any sequence he/she wishes, but without touching any item more than once. Both tests tap the ability of the subject to initiate and organise sequences of responses, and to carry them out with constant monitoring of their execution. The tests are sensitive to left frontal lobe lesions, due to the crucial role played by this area in the programming of responses, whereas right frontal lobe lesions and extensive damage to the ipsilateral hippocampus have been related to a mildly impaired performance only on the test using drawings (Petrides and Milner, 1982). According to Petrides and Milner (1982), these tasks tap the ability to organise and carry out a sequence of responses that is internally-generated. The accuracy measure is represented by the perseveration index that is the ratio between the mean number of omitted (number of non-indicated items) and that of repeated items (i.e. the number of items indicated more than once). The higher this index the more perseverative is the performance because it means that the subject fails to indicate several items (high number of omissions) and repeats many times the same itemts) (low number of repeated items). The speed index is the total time to complete the test.

presented. The starting length is of three items and three correct sequences are required before administering a longer one. The span of the subject corresponds to the longest correctly repeated sequence. 2.2.4. Corsi's Block Tapping Task and Hebb's Digit Recurring Sequences In these tests, 24 sequences of blocks and digits are used. All sequences are one item in excess of the subject's immediate memory span, preliminarily assessed. In Corsi's test, the examiner taps sequences of blocks and the subject has to repeat each sequence immediately; in Hebb's test, the patient listens to the examiner presenting sequences of digits and has to repeat each sequence immediately; unknown to the subject, the same sequence recurs every third tria1. Both tests provide an evaluation of the perceptual priming effect of repetition on memory (Tulving and Schacter, 1990). In fact, although the subject is not aware of the recurrence of one sequence, a progressive learning effect occurs for this sequence with respect to the non-recurring ones (Gruzelier et a1., 1988). Hebb's test is impaired by left temporo-hippocampal dysfunction, while Corsi's test is sensitive to right temporo-hippocampal dysfunction (Milner, 1978). The accuracy indices include the ratio between percent of correct recurring and non-recurring sequences. The speed index is the ratio between the mean time for the recurring and that for non-recurring sequences. The use of the ratio is important because it allows one to control for the immediate memory effect concerning both the recurring and the non-recurring sequences. In fact, the greater the learning effect (perceptual priming) the larger the ratio between recurring and non-recurring. 2.3. Psychopathological evaluation

2.2.3. Block Span and Digit Span In these tests, block or digit sequences of increasing length are presented by the examiner to the subject, who has to repeat them immediately. A maximum of five sequences for each length are

Psychopathological evaluation was carried out at the end of the wash-out period for drug-free patients, and on the day before the neuropsychological assessment for all subjects, by using An-

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dreasen's scales for the assessment of positive and negative symptoms (SAPS and SANS; Andreasen, 1981, 1984).

2.4. Statistical analysis A principal component analysis (PCA) with varimax rotation was carried out on total scores for all SANS and SAPS subscales, except the attentional impairment subscale. This last subscale was omitted because in previous studies Peralta et al. (1992) have shown inconsistent loadings on the positive and negative dimensions, and because it provides, by itself, an evaluation of cognitive functioning, potentially biasing the results of correlations between clinical and neuropsychological data. On the basis of a preliminary data distribution analysis, we used a log transform [log (x + 1), where x is the considered index] for speed indices, while we retained the original data for accuracy indices. Correlations between cognitive and clinical variables were investigated by means of the Spearman rank test (significance level: P < 0.05). In order to evaluate whether significant correlations between cognitive indices and psychopathological dimension factor scores were substantial and unconfounded, a stepwise multiple regression analysis was performed, in which the effects of age, education, dimension factor scores, age of onset and duration of illness were simultaneously controlled for. 3. Results Table 1 reports patients' mean scores on psychopathological rating scales and neuropsychological tests. The PCA carried out on total scores for all SANS and SAPS subscales produced three factors, accounting for 33%, 19% and 14% of the total variance, respectively. All SANS subscales loaded on the first factor (negative dimension); SAPS subscales for delusions and hallucinations loaded on the second factor (positive dimension), while those for positive formal thought disorder and bizarre behaviour loaded on the third factor (disorganisation dimension) (Table 2).

Table 1 Patients' mean scores on SANS, SAPS and neuropsychological tests Testa

Mean ±S.D.

SANS Affective flattening Alogia Avolition Anhedonia Total

8.39±7.17 5.49 ± 5.05 6.05 ± 3.41 10.15 ± 4.85 33.29 ± 17.39

SAPS Hallucinations Delusions Bizarre behaviour Formal thought disorder Total

4.95 ± 9.12 ± 2.46 ± 8.39 ± 25.17 ±

6.01 7.54 3.11 8.20 15.39

SCAL Learned associations Mean time

2.42 ± 1.89 1.63±0.17

NSCAL Learned associations Mean time

4.32 ± 2.19 1.56 ± 0.21

SOPT-drawings Perseveration index Mean time

1.13 ± 0.14 1.66 ± 0.15

SOPT-words Perseveration index Mean time

1.11 ± 0.18 1.63 ± 0.16

Block Span

4.37 ± 0.92

Digit Span

4.95 ± 1.06

CBTT CS ratio Mean time ratio

1.76 ± 1.75 0.94 ± 0.08

HDRS CS ratio Mean time ratio

0.68 ± 0.76 1.01 ± 0.09

aSANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive Symptoms; SCAL, Spatial Conditional Associative Learning; NSCAL, Non-Spatial Conditional Associative Learning; SOPT, Self-Ordered Pointing Task; CBTT, Corsi's Block Tapping Task; HDRS, Hebb's Digit Recurring Sequences; CS ratio, Percent Correct Recurring Sequences/Percent Correct Non-Recurring Sequences; Mean time ratio, Mean time on Recurring Sequences/Mean time on Non-Recurring Sequences (mean time is always expressed as log of mean time in seconds).

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Table 2 Psychopathological dimensions: factor loadings from the principal component analysis Factor 1: Negative dimension Affective flattening Alogia Avolition Anhedonia

0.65 0.79 0.79 0.81

Factor 2: Positive dimension Hallucinations Delusions

0.87 0.82

Factor 3: Disorganisation Bizarre behaviour Formal thought disorder

0.80 0.75

Table 3 summarises the results of the correlation analyses. The factor scores for the negative dimension showed a significant inverse correlation with the number of learned associations on the NSCAL (r = -0.45, P < 0.004), indicating that the more represented this dimension the more impaired is the ability to learn externallydefined associations between pairs of non-spatial stimuli. The factor scores for the positive dimension were directly correlated with the mean perseveration index on the SOPT-words (r = 0.35, P = 0.04): the higher the scores for this dimension, the more perseverative the performance on the verbal self-

Table 3 Correlations between factor scores for the psychopathological dimensions and neuropsychological indices Neuropsychological indices

a

Psychopathological dimension Negative

Positive

Disorganisation

SCAL Learned associations Mean time

0.002 -0.28

-0.06 0.14

0.15 -0.05

NSCAL Learned associations Mean time

-0.45** 0.12

0.05 -0.05

-0.12 0.06

SO PT-drawings Perseveration index Mean time

0.02 0.07

0.20 0.02

0.06 -0.27

SOPT-words Perseveration index Mean time

0.04 0.02

0.35* 0.13

0.16 -0.14

Block Span

0.21

-0.12

-0.17

Digit Span

0.04

-0.10

0.06

CBTT CS ratio Mean time ratio

0.01 0.02

0.30 0.20

0.07 -0.34*

HDRS CS ratio Mean time ratio

0.13 -0.11

0.20 0.01

0.13 0.02

aSCAL, Spatial Conditional Associative Learning; NSCAL, Non-Spatial Conditional Associative Learning; SOPT, Self-Ordered Pointing Task; CBTT, Corsi's Block Tapping Task; HDRS, Hebb's Digit Recurring Sequences; CS ratio, Percent Correct Recurring Sequences/Percent Correct Non-Recurring Sequences; Mean time ratio, Mean time on Recurring Sequences/Mean time on Non-Recurring Sequences (mean time is always expressed as log of mean time in seconds). *P < 0.04, ** P < 0.004.

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generated sequences of responses. The factor scores for the disorganisation were inversely correlated with the mean time on the spatial recurring sequences of the CBTT (r = - 0.34, P < 0.04), indicating that the more represented the disorganisation, the faster the execution of the spatial memory test. In the stepwise regression analysis carried out to simultaneously test the effect of confounding variables on the correlation between the negative dimension and the number of learned associations on the NSCAL, the duration of illness was the first variable entering the regression equation, with an F to enter of 6.69 and a multiple R 2 of 0.15. After removing the effect of the duration of illness, no other variable met the F to enter criterion (at least 4) and the partial correlation between the negative dimension and the number of learned associations on the NSCAL was no more significant (R = - 0.25). In the stepwise regression analysis on the SOPT-words perseveration index, the first variable entering the regression equation was again the duration of illness, with an F to enter of 13.79 and a multiple R 2 of 0.31; however, after removing its effect, the partial correlation between the positive dimension and the SOPT-words perseveration index remained significant (R = 0.34). The only other variable that met the F to enter criterion was the positive dimension itself (F to enter = 4.06, multiple R 2 = 0.39). After removing its effect, no other variable entered the regression equation. In the stepwise regression analysis on the mean time on the CBTT, the first variable entering the regression equation was the disorganisation dimension (F to enter = 5.32; multiple R 2 = 0.13). After removing this effect, no other variable met the F to enter criterion.

4. Discussion

According to our results, in a sample of unmedicated schizophrenic patients, the negative dimension is associated with a poor performance on the NSCAL. This correlation, together with the lack of a significant association between negative symptoms and performance on the SCAL, seems

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to exclude an involvement of the right hemisphere in the pathogenesis of this dimension, while suggesting an impairment of the left fronto-hippocampal circuitry. These findings are in line with those reported by our group in a previous independent study (Kemali et a1., 1987) and by Gruzelier et a1. (1988). According to our study, when the duration of illness is controlled for, the correlation between negative symptoms and poor performance on the NSCAL is no more significant, suggesting that chronicity might contribute to both cognitive dysfunction and negative symptomatology. However, since an association between the negative dimension and the impairment of left hemisphere functioning has been found in subjects with a schizotypal personality (Gruzelier, 1996; Gruzelier and Doig, 1996), a schizophrenia spectrum disorder, we cannot rule out the possibility that a left hemisphere impairment predates the onset of overt psychosis, and is only worsened by persistent psychotic states. Our results indicate that, in drug-free patients, the positive dimension is associated with perseveration on the SOPT-words. According to recent findings, perseverative behaviour is more likely to reflect increased dopaminergic activity (Bilder et a1., 1992); therefore, its association with positive symptoms in drug-free schizophrenic patients is not an unexpected finding. The correlation between the positive dimension and the SOPT perseveration index (significant for the verbal subtest, with a trend in the same direction for the drawing subtest) is consistent with an involvement of the left hemisphere. Tucker and Williamson (1984) argued that the dopamine pathways are lateralised to the left hemisphere and are critical for behavioural stereotypes. Therefore, our results are consistent with those reported by Gur et a1. (1989) and Gruzelier (1984), who found an association of positive symptoms with cognitive and neurophysiological measures of left hemisphere over-arousa1. Our findings also indicate that the disorganisation dimension (including thought disorder and bizarre behaviour) does not share any neuropsychological correlate with either the positive or the negative dimension, whereas it is associated with a higher speed in performing a spatial memory

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task, reflecting an increased perceptual priming, probably due to a right temporo-hippocampal disinhibition. In conclusion, our results confirm that the different dimensions of schizophrenia are related to distinct neuropsychological dysfunctions. They are consistent with the hypothesis that each syndrome might be related to a specific pattern of hemispheric imbalance. In fact, while the negative dimension resulted to be associated with a hypoactivation of the left hemisphere fronto-subcortical circuitry, the positivejunreality and the disorganisation dimension were found to be related to the hyperactivation of the left frontal and the right temporohippocampal regions, respectively. The pattern of hemispheric imbalance related to the three dimensions is compatible with that indicated by brain imaging studies. As mentioned in the introduction, two independent studies (Liddle et a1., 1992; Ebmeier et a1., 1993) have shown negative correlations between left frontal activity and psychomotor poverty, while reporting positive correlations between left medial temporal activity and reality distortion as well as right cingulate activity and disorganisation. Brain regions implied by our neuropsychological findings are not fully coincident with those indicated by brain imaging studies, but they might be functionally related. As a matter of fact, the volume reduction of the hippocampus in schizophrenic patients is associated with a poor performance on tests generally used to evaluate frontal functions (Bilder et a1., 1995). Further studies combining neuropsychological and brain imaging techniques in the evaluation of hemispheric functions and psychopathological dimensions in schizophrenia might promote our understanding of this issue. References Andreasen, N.C., 1981. Scale for the Assessment of Negative Symptoms (SANS). The University of Iowa, Iowa City, IA Andreasen, N.C., 1984. Scale for the Assessment of Positive Symptoms (SAPS). The University of Iowa, Iowa City, IA Baxter, R.D., Liddle, P.F., 1998. Neuropsychological deficits associated with schizophrenic syndromes. Schizophr. Res. 30,239-249. Bilder, R.M., Lieberman, J.A, Kim, Y., Alvir, J., Ma, J., Reiter, G., 1992. Methylphenidate and neuroleptic effects

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