Department of Psychiatry, University Medical Centre Utrecht, The Netherlands
Department of Psychonomics, University of Utrecht
Department of Neuropsychology, University of Groningen, The Netherlands
Correspondence: Iris Sommer, Department of Psychiatry, University Medical Centre Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands. Tel: ++31 30 2508352; fax: ++31 30 2505443; e-mail: I.Sommer{at}AZU.nl
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ABSTRACT |
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Aims To review quantitatively the literature on decreased lateralisation in schizophrenia.
Method Meta-analyses were conducted on 19 studies on handedness, 10 dichotic listening studies and 39 studies investigating anatomical asymmetry in schizophrenia.
Results The prevalence of mixed- and left-handedness (non-right-handedness) was significantly higher in patients with schizophrenia as compared to healthy controls, and also as compared to psychiatric controls. The analysis of dichotic listening studies revealed no significant difference in lateralisation in schizophrenia. However, when analysis was restricted to studies using consonantvowel or fused word tasks, significantly decreased lateralisation in schizophrenia emerged. Asymmetry of the planum temporale and the Sylvian fissure was significantly decreased in schizophrenia, while asymmetry of the temporal horn of the lateral ventricle was not.
Conclusion Strong evidence is provided for decreased cerebral lateralisation in schizophrenia.
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INTRODUCTION |
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METHOD |
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Inclusion
The included studies had to meet the following criteria.
Analyses
After computing effect sizes for each study
(Hedges & Olkin, 1985), meta-analytic methods were applied in order to obtain a combined effect size,
which indicated the magnitude of the association across all studies (cf
Aleman et al, 1999).
In addition, Stouffer's Z, weighted for sample size, provided an
indication of the significance of the difference between the patient and the
comparison group. Finally, a homogeneity statistic (Q) was
calculated, to assess heterogeneity of results across studies
(Shadish & Haddock, 1994).
If heterogeneity reached significance, further analyses were carried out to
examine potential moderators on the effect size. In order to investigate such
potential moderators, correlations (Pearson coefficients, two-tailed) were
calculated between the effect size of the studies and available variables.
Handedness
Prevalences of mixed- and left-handedness were grouped together as
non-right-handedness. For each study, odds ratios were
calculated from the prevalence of non-right-handedness in schizophrenia or
pre-schizophrenia subjects and in the comparison subjects. Odds ratios were
combined by applying the method of logarithmic odds ratio meta-analysis
(Shadish & Haddock,
1994).
Dichotic listening studies
Effect sizes (Hedges & Olkin,
1985) were calculated from the right-ear advantages
(score right ear minus score left ear) of patients and controls, from the
laterality index (score right ear minus score left ear, divided
by score right ear plus score left ear) or from F values.
Anatomical asymmetry
Brain torque
Only two studies on brain torque
(Luchins et al, 1981;
Guerguerian & Lewine, 1998) reported means and standard deviations of an
asymmetry index for patients and controls, while others gave frequencies of
abnormal frontal and occipital asymmetry. On these studies, meta-analysis was
performed using the difference rate, i.e. the difference between
the proportion of individuals with absent or reversed asymmetry in the patient
group and in the control group. For the meta-analyses on asymmetry of the
planum temporale, Sylvian fissure, temporal horn of the lateral ventricle and
superior temporal gyrus, effect sizes were computed from the mean size (and
standard deviation) of left and right structures. The measurements concerned
absolute structure sizes, not corrected for total brain volume, and total
structure sizes (not only grey matter volumes). When studies gave separate
data for men and women, these were included as two independent effect sizes,
thereby increasing the total number of effect sizes (K).
Each study was used for three meta-analyses. In the first, asymmetry of the structure was calculated for the control subjects. In the second, asymmetry was calculated for the patients. The third meta-analysis was conducted on the difference of the two d values of each group and compared asymmetry in patients to that in controls. In this way, differences in overall brain size between patients and controls could not influence the outcome, as every structure was compared to its contralateral homologue first, after which the resulting standardised asymmetry indices were compared between the groups. Differences in measurement technique between the studies were largely controlled for, as well as the statistic results from within-study comparisons.
When studies that measured the superior temporal gyrus provided separate data on anterior, middle and posterior segments, these were pooled.
All studies had included predominantly right-handed subjects, except for Holinger et al (1999), who measured superior temporal gyral volumes in left-handed patients with schizophrenia and left-handed controls. To increase homogeneity among studies, this study was excluded in the meta-analysis, but included for the calculation of a possible correlation between handedness distribution and asymmetry.
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RESULTS |
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Meta-analysis on these studies showed that the prevalence of non-right-handedness was significantly higher in patients with schizophrenia than in healthy subjects (Table 1). The magnitude of the odds ratios of each study is shown in Fig. 1.
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Three prospective follow-up studies measured hand preference in children of large birth cohorts, who were screened for schizophrenia in adult life (David et al, 1995; Crow et al, 1996; Cannon et al, 1997). From these, only one study (Crow et al, 1996) provided quantitative indices on the degree of handedness. In the meta-analysis of these studies, pre-schizophrenic subjects were significantly more often non-right-handed than were the general population (Table 1).
Additional analysis was performed on nine studies where the comparison group consisted of non-schizophrenia psychiatric or neurological patients (Chaugule & Master, 1981; Piran et al, 1982; Manschreck & Ames, 1984; Merrin, 1985; Shan-Ming et al, 1985; Clementz et al, 1994; Taylor & Amir, 1995; Malesu et al, 1996; Orr et al, 1999). The results indicated that the prevalence of non-right-handedness was significantly higher in schizophrenia subjects than in other psychiatric and neurological patients (Table 1).
Dichotic listening studies
Meta-analysis was conducted on 10 dichotic listening studies that compared
patients with schizophrenia to healthy controls
(Hatta et al, 1984;
Wexler et al, 1991;
Carr et al, 1992;
Ragland et al, 1992;
Seidman et al, 1993;
Grosh et al, 1995;
Sakuma et al, 1996;
Oie et al, 1998;
Bruden et al, 1999;
Løberg et al,
1999). The right-ear advantage was not significantly decreased in
schizophrenia, with significant heterogeneity among studies
(Table 1). The magnitude of the
effect size of each study is represented in
Fig. 2.
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A possible cause for the inhomogeneity in these studies may be the difference in verbal tasks the studies used to elicit a right-ear advantage. Four different tasks were used: the triad task, the fused-word task, the consonantvowel task and the word-monitoring task. The fused-word and the consonantvowel tasks are considered to reflect cerebral dominance most accurately (see Discussion). When only studies that used the fused-word and the consonant-vowel tasks were included, the right-ear advantage was significantly lower in schizophrenia and studies were no longer heterogeneous (Table 1).
Anatomical asymmetry
Brain torque
Meta-analyses were conducted on the frequency of abnormal asymmetry of the
frontal lobe (Andreasen et al,
1982; Jernigan et al,
1982; Falkai et al,
1995b) and the occipital lobe
(Andreasen et al,
1982; Jernigan et al,
1982; Luchins & Meltzer,
1983,
1986;
Falkai et al,
1995b). The results showed that the frequency of abnormal
asymmetry was significantly higher in schizophrenia for both the frontal and
the occipital lobe, but studies were heterogeneous
(Table 1). The small number of
studies allowed no further investigation of potential moderators.
Planum temporale
Meta-analysis was performed on 10 studies that measured the planum
temporale in schizophrenia (Rossi et al,
1992,
1994;
Kleinschmidt et al,
1994; Falkai et al,
1995a; Kulynych
et al, 1995; Petty
et al, 1995; Jacobsen
et al, 1996; Barta
et al, 1997; Frangou
et al, 1997; Kwon
et al, 1999). In the meta-analysis, significant asymmetry
favouring the left hemisphere was found for the healthy comparison subjects,
but not for the patients (Table
2). Studies were homogeneous for the comparison subjects, but
heterogeneous for the patients, subjects, but heterogeneous for the patients,
indicating that difference in measurement technique is not a factor. Possible
moderators may be found in characteristics of the patient samples. Only three
variables were reported frequently enough to calculate correlations, but no
significant result emerged: gender distribution n=10,
r=-0.25, NS; handedness distribution n=9, r=0.38,
NS; duration of illness n=6, r=-0.29, NS.
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In the meta-analysis directly comparing patients and controls, asymmetry of the planum temporale was significantly reduced in patients (Table 1). The magnitude of the difference in effect sizes of asymmetry between patients and controls is shown in Fig. 3.
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Sylvian fissure
In the meta-analysis on studies on asymmetry of the Sylvian fissure
(Falkai et al, 1992;
Hoff et al, 1992;
Bartley et al, 1993),
both controls and patients showed significant asymmetry favouring the left
hemisphere (Table 2), but
studies were heterogeneous for both groups. The small number of studies
allowed no further investigation of potential moderators. When asymmetry of
the Sylvian fissure was directly compared between patients with schizophrenia
and healthy subjects, patients showed significantly decreased asymmetry
(Table 1).
Temporal horn of the lateral ventricle
Eight studies on asymmetry of the temporal horn of the lateral ventricle
were included (Bogerts et al,
1990; Dauphinais et
al, 1990; DeLisi et
al, 1991; Zipursky et
al, 1994; Flaum et
al, 1995; Becker et
al, 1996; Marsh et
al, 1997; Pearlson et
al, 1997). In healthy as well as in schizophrenia subjects,
rightward asymmetry was found (Table
2). Studies were homogeneous for the analysis of control subjects,
but heterogeneous in the patients' analysis
(Table 2). Correlations between
asymmetry in patients and possible moderators were not significant: gender
distribution n=8, r=-0.44, NS; handedness distribution
n=5, r=0.27, NS; duration of illness n=6,
r=-0.7, NS. In the meta-analysis directly comparing patients and
controls, asymmetry of the temporal horn was not significantly different
between schizophrenia and healthy subjects
(Table 1).
Superior temporal gyrus
Meta-analysis was performed on 15 studies measuring superior temporal gyrus
in schizophrenia subjects and healthy controls
(Barta et al, 1990;
Zipursky et al, 1994;
Flaum et al, 1995;
Menon et al, 1995;
Vita et al, 1995;
Kulynych et al, 1996;
Frangou et al, 1997;
Marsh et al, 1997;
Pearlson et al, 1997;
Reite et al, 1997;
Hirayasu et al, 1998;
Jacobsen et al, 1998;
Bryant et al, 1999;
Havermans et al,
1999; Highley et al,
1999).
The results showed that the superior temporal gyrus was larger in the right hemisphere in schizophrenia subjects, while controls showed a trend towards asymmetry in the same direction (Table 2). Studies were heterogeneous for both groups and thus differences in measurement technique may have acted as moderators. The only study on post-mortem brains (Highley et al, 1999) found larger volumes of the superior temporal gyrus in the left hemisphere in controls, while 13 of 14 magnetic resonance imaging (MRI) studies found larger volumes in the right hemisphere in controls. However, when the post-mortem study was excluded from analysis, heterogeneity among studies remained high. Correlations between the effect size of asymmetry in controls and other potential moderators were not significant (slice and gap thickness n=15, r=-0.039, NS; sample size n=15, r=-0.22, NS; gender distribution n=15, r=-0.29, NS; handedness distribution n=15, r=0.32, NS). Correlations between potential moderators and the effect size of asymmetry in patients were not significant either (slice and gap thickness n=15, r=0.15, NS; sample size n=15, r=-0.18, NS; gender distribution n=15, r=-0.27, NS; handedness distribution n=15, r=-0.29, NS; duration of illness n=5, r=-0.51, NS).
In the meta-analysis directly comparing patients and controls, the patients with schizophrenia tended to have increased asymmetry of the superior temporal gyrus favouring the right hemisphere, but statistical significance was not reached (Table 1).
Posterior segment of the superior temporal gyrus
A separate analysis on five studies
(Menon et al, 1995;
Kulynych et al, 1996; Pearlson et al, 1997;
Hirayasu et al, 1998;
Jacobsen et al, 1998)
was performed to assess asymmetry of the posterior segment of the superior
temporal gyrus. Rightward asymmetry was found for the patients, while the
controls showed a trend towards asymmetry in the same direction
(Table 2). In the meta-analysis
directly comparing patients and controls, rightward asymmetry of the posterior
segment of the superior temporal gyrus was significantly larger in patients
(Table 1).
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DISCUSSION |
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Hand preference
In the meta-analysis on handedness in cross-sectional studies,
schizophrenia subjects were more frequently non-right-handed than healthy
persons. However, these studies mainly included hospitalised patients with
schizophrenia, thus tending to overrepresent severe cases. Prospective cohort
studies do not have this limitation, since they are population-based. In the
meta-analysis on three prospective cohort studies, the prevalence of
non-right-handedness in subjects that later developed schizophrenia was
significantly increased.
However, many diseases that involve subtle brain damage may be accompanied by increased prevalence of non-right-handedness (Satz & Green, 1999). To investigate the specificity of increased non-right-handedness in schizophrenia, an additional analysis was conducted comparing schizophrenia patients with non-schizophrenia psychiatric and neurological patients. In that analysis, non-right-handedness was still significantly increased in schizophrenia, suggesting that a specific cerebral lesion cannot explain the increased prevalence of non-right-handedness in schizophrenia. Thus, a more fundamental, possibly genetic mechanism may be involved. Interestingly, several studies report increased non-right-handedness in healthy relatives of patients with schizophrenia (Hallett et al, 1986; Chapman & Chapman, 1987; Orr et al, 1999), suggesting a genetic cause for decreased cerebral dominance in schizophrenia (Crow et al, 1989).
Dichotic listening studies
In the analysis of dichotic listening studies, the right-ear advantage was
not significantly decreased in schizophrenia, while heterogeneity among
studies was high. This may be attributable to the differences in verbal tasks
used to elicit a right-ear advantage. For the triad task and the
word-monitoring task, subjects have to respond to all stimuli on either ear.
Schizophrenia subjects generally have a lower performance on these tasks than
healthy subjects (Hatta et al,
1984; Carr et al,
1992; Seidman et al,
1993; Sakuma et al,
1996). On several items of these tasks, controls may have 100%
correct response, in which case no perceptual asymmetry is measured. These
ceiling effects in the control, but not in the schizophrenia group, may cause
relatively low ear asymmetry in the control group. For the consonant-vowel and
the fused-word tasks, subjects were asked to respond only to the most clearly
perceived item, thereby avoiding the problem of ceiling effects. When only
studies that applied the consonant-vowel or fused-word task were included,
patients with schizophrenia showed a significantly decreased right-ear
advantage and heterogeneity disappeared. A decreased right-ear advantage was
also reported in healthy parents (Grosh
et al, 1995) and children
(Hallett et al, 1986) of patients with schizophrenia, supporting the hypothesised genetic origin of
decreased lateralisation in schizophrenia.
Anatomical asymmetry
In the meta-analysis of anatomical studies, the direction of brain torque
was more frequently inverted, while the planum temporale and Sylvian fissure
showed reduced asymmetry in schizophrenia. The decreased temporo-parietal
asymmetries probably reflect decreased language dominance, since planum
temporale and Sylvian fissure asymmetries are strongly related to cerebral
dominance (Gerschlager et al,
1998). Shapleske et al
(1999) published an extensive
review on the planum temporale that also contained a meta-analysis on the
planum temporale in schizophrenia. The present study, using more stringent
inclusion criteria and including several recently published studies, confirms
Shapleske et al's finding of decreased asymmetry of the planum
temporale in schizophrenia.
Crow et al (1989) reported that the temporal horn of the lateral ventricle was larger in the right hemisphere in the normal control group of their post-mortem study, probably owing to the more extended language-related cortex at the dominant side. The present results from the meta-analysis on healthy subjects confirm this finding. However, while Crow reported reduced asymmetry of the temporal horn in schizophrenia, the present meta-analysis found no significantly decreased asymmetry in schizophrenia.
Asymmetry of the superior temporal gyrus is also frequently used as an indication of language lateralisation (Pearlson et al, 1997; Highley et al, 1999; Holinger et al, 1999; Levitan et al, 1999). However, direction and magnitude of asymmetry of this structure is not well established in healthy subjects. In this meta-analysis, controls showed a trend towards asymmetry favouring the right hemisphere, while the superior temporal gyrus was found to be greater on the right in patients. The trend towards rightward asymmetry in healthy subjects is surprising since it partly overlaps with Wernicke's area. However, the superior temporal gyrus also incorporates primary and secondary auditory cortex that generally shows rightward asymmetry, reflecting right hemispheric dominance for non-verbal sounds (Zattore et al, 1992). The posterior segment of the superior temporal gyrus might be a better candidate to reflect cerebral dominance for language, since it mainly consists of language-related hetero-modal cortex (Pearlson, 1997). However, in the current meta-analysis, this segment also showed a trend towards asymmetry favouring the right hemisphere in healthy subjects. Therefore, neither the superior temporal gyrus, nor its posterior segment appears suited for the assessment of cerebral dominance for language.
Limitations
The presented paper included only studies on language lateralisation that
used the dichotic listening paradigm. We were unable to retrieve enough visual
half-field studies using language stimuli to allow for meta-analysis. Data of
functional imaging studies are considered to be too diverse regarding
technical assessment and statistical analysis to allow for direct comparison
in a meta-analysis (Lange,
1999). A second limitation of the study is our choice to include
only studies on patients with strict diagnosis of schizophrenia, excluding
studies that used the broad DSM-II criteria for schizophrenia and studies that
used patients with schizophrenia-spectrum disorders. Another reason that
several studies could not be included was the absence of healthy control
groups. By applying these strict inclusion criteria, the total number of
studies was lower, but the contrast between the experimental and the
comparison group was maximal.
Clinical implications
The reported excess of non-right-handedness and decreased right-ear
advantage in healthy relatives of patients with schizophrenia suggest a
genetic cause underlying the decreased cerebral lateralisation in
schizophrenia. If this were true, a deviation of the genetic mechanism
underlying cerebral dominance, the hypothesised right-shift
factor may cause a vulnerability to schizophrenia
(Annett, 1999; Crow, 1999). This implies that
the search for genes predisposing for schizophrenia may focus on loci that
have a role in the establishment of cerebral dominance. In addition,
indicators of decreased cerebral dominance in individuals, such as
non-right-handedness, decreased right-ear advantage on the dichotic listening
paradigm or decreased asymmetry of the planum temporale may help to identify
subjects at increased risk for schizophrenia.
In sum, when literature on handedness, dichotic listening studies and asymmetry of language-related structures is reviewed quantitatively, compelling evidence emerged for decreased cerebral dominance in schizophrenia.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication April 27, 2000. Revision received September 11, 2000. Accepted for publication September 13, 2000.