Rudolf Magnus Institute of Neuroscience Psychiatry Department,University Medical Center, Utrecht
Department of Public Health, Academic Medical Center, Amsterdam
Rudolf Magnus Institute of Neuroscience, Department of Psychiatry,University Medical Center,Utrecht, The Netherlands
Correspondence: Dr Iris Sommer, Rudolf Magnus Institute of Neuroscience Psychiatry Department, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands. Tel: 30 2508352; fax: 30 2505443; e-mail: I.Sommer{at}azu.nl
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ABSTRACT |
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Aim To determine whether decreased lateralisation and increased right cerebral language activation constitute genetic predispositions for schizophrenia.
Method Language activation was measured using fMRI in 12 right-handed monozygotic twin pairs discordant for schizophrenia and12 healthy right-handed monozygotic twinpairswhowere twin pairs who were matched for gender, age and education.
Results Language lateralisation was decreased in discordanttwin pairs compared withthe healthy twin pairs. The groups did notdiffer in activation of the language-related areas of the left hemisphere, but language-related activation in the right hemisphere was activationinthe significantly higher in the discordanttwin pairs than in the healthy pairs. Within the discordanttwin pairs, language lateralisation was not significantly different between patients with schizophrenia and their co-twins.
Conclusions Decreased language lateralisation may constitute a genetic predisposition for schizophrenia.
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INTRODUCTION |
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METHOD |
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At the time of scanning, six patients were experiencing psychotic symptoms, as indicated by a score of more than 2 on one or more of the following items from the Positive and Negative Syndrome Scale (PANSS; Kay et al, 1987): hallucinations, delusions, suspiciousness or grandiosity. None of the patients with schizoaffective disorder was in a depressed or manic state at the time of scanning. Hallucinations, if present, were experienced infrequently (once a day or several times a week). In the group of discordant twin pairs, the co-twins of the patients by exclusion had never experienced hallucinations or delusions as assessed in the CASH and SADS-L interview; however, these co-twins were not necessarily free of other psychiatric disorders. Clinical data for the patients and their co-twins are listed in Table 1. Of the co-twins free from schizophrenia, one participant was clinically depressed at the time of scanning. In the discordant twin pairs, the mean time after onset of the first psychotic episode of the twin with schizophrenia was 17 years (s.d.=10). Belmaker et al (1974) reported that approximately 70% of monozygotic twin pairs become concordant for schizophrenia within 4 years of the first twin's hospitalisation. Therefore, it is unlikely that these discordant twin pairs would become concordant for schizophrenia in the future.
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Twelve healthy monozygotic twin pairs were included who were matched pair-wise for gender, age and education. Individuals with medical or neurological illness were excluded. Participants met research diagnostic criteria for never mentally ill according to the CASH and SADS-L interview. In all twin pairs monozygosity was confirmed by genotyping, using ten highly polymorphic markers (Wijmenga et al, 1998). All twins were native Dutch speakers and all were right-handed as assessed with the Edinburgh Handedness Inventory (Oldfield, 1971). Familial left-handedness was scored positive if one or more first-degree relatives preferred their left hand for writing. Educational levels were measured by the total number of years of education. Information on birth weight, gestational age at birth and chorionicity was collected from a questionnaire filled out by the mothers of the twins. Demographic characteristics of the patients, the co-twins and the healthy twin pairs are detailed in Table 2. The participants were given a complete description of the study and their written informed consent was obtained, approved by the human ethics committee of the University Medical Centre, Utrecht.
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Symptom assessment
The Positive and Negative Syndrome Scale was used for symptom assessment
immediately prior to the scan session. Mean scores on the positive and
negative items of the PANSS are listed in
Table 1.
Scans
Functional scans were acquired with a Philips ACS-NT 1.5 T clinical scanner
(Philips Medical Systems, Best, The Netherlands), using the blood oxygen level
dependent (BOLD) sensitive, navigated three-three-dimensional(3D) PRESTO
(principles dimensional(3D) of echo-shifting with a train of observation)
pulse sequence (Ramsey et al,
1998) with the following parameter settings: echo time/repetition
time (TE/TR) 35/24 ms, flip angle 9°, field of view (FOV) 18 mm x 91
mm, matrix 52x64x26, voxel size 3.51 mm isotropic, scan time per
fMRI volume 2.4 s. Following the fMRI procedure, an anatomical scan was
acquired (3D fast field echo TE/TR 4.6/30 ms, flip angle 30°, FOV
25x25x180 mm, matrix 128x128x150, slice thickness 1.2
mm).
Activation tasks
Tasks and scan technique have been described in detail by Ramsey et
al (2001). Briefly, two
word tasks were used: a paced verb-generation task and a semantic decision
task. For the verb-generation task, a noun appeared on the screen every 3.6s,
and the participant was instructed to generate a verb appropriate for that
noun. To avoid head motion, silent vocalisation was used. During the baseline
condition of the verb-generation task, participants were instructed to fixate
on a number of squares projected on the screen at the same frequency as the
words. For the semantic decision task, the participant had to decide if the
concrete noun presented on the screen signified an animal. Affirmative
responses were given by pushing an air-mediated button with the right hand.
The control task included the same number of button press responses, which
were cued with a fixed number of asterisks which appeared at random intervals.
Performance was recorded with a computer. Both tasks were performed during 10
periods of 29 s, alternated with 29 s of baseline conditions. Tasks were
projected in a fixed order: the verb-generation task first and the semantic
decision task second.
Combined task analysis
Brain activity maps were obtained by analysing the fMRI scans acquired
during both tasks together, i.e. onet-map was derived from each
participant during the performance of both tasks. The rationale for combined
analysis, similar to the conjunction analysis described by Price
& Friston (1997), is that
it combines methodological advantages of two tasks. Lateralisation varies
between individuals, but also between tasks
(Curtis et al, 1999). In an earlier study in healthy volunteers
(Ramsey et al, 2001) we found that lateralisation is generally low for semantic categorisation
tasks. When a task yields only low lateralisation indices, as with semantic
categorisation, it is difficult to detect a difference in lateralisation
between groups. In contrast, healthy volunteers showed extensive
lateralisation of language activity on a verb-generation task. However, the
verb-generation task has the disadvantage that performance cannot be recorded
(at least not in our laboratory). Combined analyses of these two tasks yields
relatively high lateralisation, and also provides a performance measurement.
We have previously shown that such an analysis improves reliability of the
subsequently computed laterality index, compared with that obtained with
individual task analyses (Ramsey et
al, 2001).
Scan analyses
The outer two slices (most dorsal and most ventral) of the transaxial fMRI
volumes were not analysed, since registration causes signal fluctuations at
the edges of the volume. Functional scans started and ended 7 s later than the
task, to compensate for the delay of the vascular response. All scans,
including the anatomical scan, were registered to the last volume of the last
block, to correct for head movements, and translated and rotated to the
standard brain from the Montreal Neurological Institute
(Collins et al, 1994)
without scaling. Functional images were analysed on a voxel-by-voxel basis
using multiple regression analysis
(Worsley & Friston, 1995)
with one factor coding for activation (task v. rest) and three for
signal drift (due to scanner hardware). The regression coefficient for
activation was converted to a t value for each voxel, yielding a
t-map. Significant activation was then determined in each voxel by
applying a threshold. The threshold corresponded to a P value of
0.05, Bonferroni-corrected for the total number of voxels in the fMRI scan
volume, and amounted to a t value of approximately 4.5 (depending on
the number of voxels for each individual).
Ten volumes of interest (VOIs) were manually delineated on the structural MRI scan of each participant, blind to diagnosis and to the statistical results. Manual delineation was performed in sagittal orientation using the DISPLAY tool from the Montreal Neurological Institute. For manual delineation, the following landmarks were used: lateral fissure, its ramus anterior and ramus ascendens and the sulcus temporalis superior. The VOI selection was based on the activation pattern of healthy individuals scanned with this protocol (Ramsey et al, 2001) and comprised the inferior frontal gyrus pars orbitalis and pars opercularis: Brodmann areas (BA) 44 and 45, middle temporal gyrus (BA 21), superior temporal gyrus (BA 22, 38, 41, 42 and 52), supramarginal gyrus (BA 40) and angular gyrus (BA 39). Together, these VOIs encompassed the main areas where language processing of visually presented words is thought to be mediated.
In each VOI the number of activated voxels was determined. For subsequent analyses the VOIs were combined, yielding one measure of language-related activation for each hemisphere. Finally, a lateralisation index was calculated, defined as the difference in the number of activated voxels in the left v. the right hemisphere (within the VOIs) divided by the total sum of activated voxels in the VOIs of both hemispheres. In fMRI scans there generally is a large variability in the total activation shown by an individual when presented with a task. The lateralisation index was used to correct for this large spread. This index divides the difference between left-sided and right-sided activation by the total number of activated voxels. Therefore, the relative measure of the lateralisation index is less susceptible to differences in signal-to-noise ratio than an absolute activation measurement (such as the language activation of the right hemisphere) could be.
Statistical analyses
For the discordant twin pairs, the data for the twins with schizophrenia
were placed in the first column (first twins) and the data for their co-twins
in the second column (second twins). Control twin pairs were divided in two
subgroups based on the birth order of the discordant twin pair that they were
matching, i.e. if the affected twin was born first, then the first-born twin
of the control pair was also placed in the first column. In this way, control
pairs were also matched for birth order. To assess if language lateralisation
differed between discordant and healthy pairs, lateralisation indices of the
discordant pairs were compared with the control pairs in a repeated-measures
analysis of variance (ANOVA). If significant differences emerged, language
activation per hemisphere was compared between discordant and control pairs,
to test whether decreased lateralisation resulted from decreased left
hemisphere activation or from increased right hemisphere activation. Possible
differences between discordant and control pairs in the activation of specific
VOIs were evaluated in a repeated-measures multivariate analysis of
variance.
To test the possible effects of schizophrenia or of antipsychotic medication use on language lateralisation, the twins of the discordant pairs were compared using a paired t-test. If significant differences emerged, language activation per hemisphere was also compared. To test the possible effect of increased genetic risk of schizophrenia on the lateralisation index, the co-twins of the participants with schizophrenia were compared with the control twins, matched for birth order, using an independent t-test. If the difference was significant, differences in activation per hemisphere were also tested. Finally, an effect for gender on the lateralisation index was tested for significance in the discordant and control twins separately, by means of a repeated-measures ANOVA. All results reported are based on two-tailed tests of statistical significance.
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RESULTS |
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Language activation
Discordant v. control twin pairs
For the lateralisation index a significant main effect for the discordant
v. control twin pairs (Group) was found
(F(1,22)=13.3, P<0.001). The main effect for
the first and second twins (Twin) was not significant
(F(1,22)=2.9, P=0.1), nor was the
TwinxGroup interaction (F(1,22)=2.0,
P=0.17). Differences in the lateralisation index are shown in
Fig. 1.
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Examples of the activation pattern in healthy and affected twin pairs are shown in Fig. 2. Summed language-related activation in the VOIs of the left hemisphere was similar in both groups (main effect for Group:F(1,22)=1.2, NS; main effect for Twin:F(1,22)=0.05, NS; TwinxGroup interaction:F(1,22)=0.03, NS). For the summed language-related activation in the VOIs of the right hemisphere, a significant main effect for Group was found (F(1,22)=5.0, P=0.02). No significant main effects for Twin (F(1,22)=0.17, NS) or GroupxTwin interaction were found for the activation of the right hemisphere (F(1,22)=0.34, NS). For the number of activated voxels in the separate VOIs the main effect for Group (F(9,198)=0.8, NS), the main effect for Twin (F(9,198)=0.04, NS) and the GroupxTwin interaction (F(9,198)=1.3, NS) were not significant. The mean activation per VOI for control participants, for probands with schizophrenia and for the probands' co-twins is shown in Fig. 3.
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Discordant twin pairs
Language lateralisation was not significantly lower in the twins with
schizophrenia compared with their co-twins: t=-1.9, d.f.=11,
P=0.09; in fact, there was a trend towards lower language
lateralisation in these co-twins.
Probands'co-twins v. control twins
Language lateralisation was significantly lower in the twins without
schizophrenia from the discordant pairs than in the control twins:
t=4.0, d.f.=22, P=0.001. This decreased lateralisation in
the probands' co-twins resulted from a trend towards increased language
activation in the right hemisphere of these co-twins compared with the control
twins (t=2.7, d.f.=22, P=0.1) whereas language activation in
the left hemisphere was similar in both groups (t=0.6, d.f.=22,
P=0.54). To preclude the possibility that the effect on
lateralisation reflected higher levels of psychopathological disorder in the
co-twins of the participants with schizophrenia rather than increased genetic
risk, the analyses were repeated after excluding the four co-twins with
psychiatric disorders. Results were essentially the same: the difference in
lateralisation index remained significant (t=4.4, d.f.=16,
P=0.003), there was a trend towards higher language activation of the
right hemisphere in the probands' co-twins compared with the control twins
(t=1.7, d.f.=17, P=0.1), and language activation levels of
the left hemisphere were equal in both groups (t=0.5, d.f.=17,
P=0.65).
Gender
No significant main effect for gender on the lateralisation index was found
in the discordant twin pairs, nor in the healthy twin pairs
(P>0.55).
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DISCUSSION |
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Comparison with other studies
Several functional imaging studies measured language activity patterns in
patients with schizophrenia (Lewis et
al, 1992; Frith et
al, 1995; McGuire et
al, 1996; Woodruff et
al, 1997; Curtis et
al, 1999; Artiges et
al, 2000; Spence et
al, 2000; Kircher et
al, 2001; Sommer et al,
2001a,
2003). Apart from the previous
studies of our group, five functional imaging studies have provided
information on language lateralisation. Lewis et al
(1992) reported decreased left
frontal activity in a single photon emission computed tomography (SPECT) study
of 25 people with schizophrenia during a verbal fluency task, resulting in
reversed frontal dominance. Woodruff et al
(1997) compared the fMRI
activation patterns of 15 people with schizophrenia with those of 8 healthy
participants while listening to speech. They found reduced activation of the
left superior temporal gyrus and increased activation of the right middle
temporal gyrus in the patients compared with the controls. Dye et al
(1999) found no difference in
positron emission tomography (PET) language activation patterns between 6
patients with schizophrenia and 10 healthy controls on a verbal fluency task.
In a PET study by Spence et al
(2000), 10 patients with
schizophrenia showed greater bilateral activation of the frontal areas on a
paced verbal fluency task at a qualitative level
(Crow, 2000). On formal
comparison, increased activation in the right hemisphere in the patients was
not statistically significant. Artiges et al
(2000) also observed reduced
lateralisation in 14 patients with schizophrenia using an unpaced verbal
fluency PET protocol. Decreased lateralisation was due to both decreased left
frontal language activity and increased language activity of the right-sided
frontal areas. However, an unpaced verbal fluency task may be problematic if
patients cannot generate enough words, as language activity will then not be
maintained throughout the task period, potentially resulting in reduced
language production and hence reduced language-related brain activity. Indeed,
decreased left frontal language activity was not detected when participants
with schizophrenia were compared with controls who had performed equally badly
(Frith et al, 1995; Curtis et al, 1999).
Although the decreased left-sided language activity described by Artiges
et al (2000) may
reflect low performance, increased language-related activity of the right
hemisphere in patients with schizophrenia cannot be explained by poor task
performance. Thus, increased language-language-related activity of the right
hemi-related sphere may be a functional characteristic of schizophrenia, or a
characteristic of the genetic predisposition for schizophrenia.
Language activation has not been studied previously with functional imaging techniques in monozygotic twin pairs with schizophrenia, but several studies used the dichotic listening paradigm to estimate language lateralisation in relatives of patients with schizophrenia. This method measures perceptual asymmetry of language stimuli, but provides no information on the involvement of each hemisphere in language processing. Ragland et al (1992) studied perceptual asymmetry in 18 monozygotic twin pairs discordant for schizophrenia and seven healthy twin pairs. In contrast to our results, Ragland et al found decreased language lateralisation in the affected twins compared with their unaffected co-twins, while lateralisation of the unaffected twins was not significantly different from that of the healthy twins. The difference between Ragland's study and ours may result from a lack of power in the former, since the standard deviation of their lateralisation indices was fairly large. Two groups studied language lateralisation with dichotic listening tests in other first-degree relatives of patients with schizophrenia. Grosh et al (1995) studied language lateralisation in 18 parents of people with schizophrenia. Lateralisation in the parents was significantly lower than in healthy controls, to a similar degree to that found in their affected offspring. Hallett et al (1986) assessed language lateralisation in 22 children whose parents had schizophrenia; consistent with the findings of Grosh et al (1995) and with the present study, significantly lower lateralisation was reported in children of patients compared with 22 children of unaffected parents.
Language activity in the right hemisphere
Our results suggest that increased activation in the contralateral
homologues of the language-related areas is not a necessary factor for
schizophrenia to develop, given the strong left cerebral dominance for
language in some of the people with schizophrenia in our sample. Neither is
increased language-related activation in homologue areas of the right
hemisphere sufficient to cause schizophrenia, given the absence of psychotic
symptoms in the unaffected co-twins of the patients. However, in combination
with other factors, more bilateral language activation might facilitate the
occurrence of language-related psychotic symptoms such as auditory verbal
hallucinations, thought insertion and thought disorder
(Nasrallah, 1985). Therefore,
it would be useful to gain more insight into the role of the right-sided
homologues of the language areas.
Current knowledge on the brain organisation for language functions is based on data from two different types of study (Binder et al, 1996). The first type establishes a link between language functions and brain organisation by associating disrupted function of a brain area with a change in linguistic behaviour, usually a deficit. Such studies identify a brain area as critical for a certain aspect of language, which means that aphasia results when a critical area is damaged. This type of study, which includes descriptions of different kinds of aphasia and their corresponding lesions, observations using the carotid amylobarbitone sodium (Wada) procedure and findings with intraoperative electrical stimulation, indicated that Broca's area (BA 44 and 45 of the left hemisphere) and Wernicke's area (the upper part of the superior temporal gyrus of the left hemisphere) are in most people critical language areas (Grodzinsky, 2000). The other type of study records physiological measures of brain activity while individuals are engaged in tasks that address certain language functions, using techniques such as PET and fMRI. Changes in physiological parameters during a language task may also be detected at sites that are not critical for that language function, but may be activated for non-specific supporting functions. Examples of areas that are frequently found to be activated during language tasks with functional imaging, but do not produce aphasia when lesioned, are the anterior cingulate gyrus and the superior frontal gyrus (Binder et al, 1997).
When their left hemisphere is anaesthetised during the Wada procedure, people who are right-handed are generally unable to speak or to read (Rasmussen & Milner, 1976). The left hemisphere can thus be defined as being critical for language. Aphasia is generally not present, however, after anaesthetising the right hemisphere of people who are right-handed; in these people, the right hemisphere thus appears not to contain critical language areas. In contrast, in approximately 30% of left-handed people tested, the right hemisphere does have critical language areas, since these people become aphasic after anaesthesis of the right hemisphere (Rasmussen & Milner, 1975). A common approach in aphasia and Wada test research is to classify participants into exclusively left dominance, bilateral language and exclusively right dominance categories (Binder et al, 1996). However, functional imaging studies show that there is considerable variation, even among healthy right-handed people, in the relative contribution of the right hemisphere to basic language tasks, varying on a continuum from almost exclusively left hemisphere activity to bilateral processing and in rare cases right cerebral dominance (Binder et al, 1997; Frost et al, 1999). Considering this, the increased language activation in the homologue areas of the right hemisphere in our discordant twin pairs can be interpreted in two ways. First, language functions of the discordant twin pairs may have a fundamentally different cortical organisation with a more bilateral distribution of critical language areas. Indirect support for this explanation is provided by structural MRI studies in schizophrenia, reporting decreased asymmetry of the Sylvian fissure and the planum temporale, though not all studies found significant differences (reviewed by Sommer et al, 2001b). Such a more bilateral distribution of critical language areas is frequently encountered in left-handed people (Pujol et al, 1999; Knecht et al, 2001). Possibly, twin pairs discordant for schizophrenia are similar to healthy left-handers, in that they also have a more bilateral cortical representation of language functions. However, the activation patterns of the discordant twin pairs argue against this explanation. In an earlier study by our group eight healthy left-handed people were scanned with the same protocol as in this study, and compared with eight healthy right-handed people (Ramsey et al, 2001). The left-handed participants indeed showed increased language activation of the right hemisphere, which can be assumed to arise from a more bilateral representation of critical language functions; however, language-related activation of the left hemisphere was decreased in these participants, i.e. they displayed a shift in language activation from the left to the right hemisphere. Other functional imaging studies comparing larger samples of left-handed and right-handed volunteers also found increased language activation of the right hemisphere in tandem with decreased language activation of the left hemisphere (Pujol et al, 1999; Knecht et al, 2000). In contrast to this activation pattern in healthy left-handers, both twins of the the discordant twin pairs in our study showed an additional increase in language activation of the right hemisphere, while left hemisphere language activation remained normal (i.e. high). Therefore, another interpretation of our data is more plausible, namely that language representation in the discordant twin pairs is not similar to that in healthy left-handers. Instead, the language activation pattern in the discordant twin pairs may reflect the use of additional cortical areas in the right hemisphere while the critical language areas are located at their regular sites in the left hemisphere. The additional activation of homologue areas in the right hemisphere is probably not essential for performing the word tasks, since the language areas of the left hemisphere show normal task-related activation. In fact, increased language activation of the right hemisphere areas may result from insufficient inhibition of these non-dominant areas.
Limitations
Theoretically, we cannot differentiate between genetic effects and the
effects of shared environmental influences on decreased language
lateralisation in the discordant twin pairs of this study, since the results
are not compared with findings in dizygotic discordant twin pairs. However,
for this type of research the comparison with dizygotic twin pairs may be less
effective, since environmental factors that are generally shared in both
monozygotic and dizygotic twin pairs - such as upbringing, nutrition,
education and sociocultural circumstances - are unlikely to have any effect on
cerebral dominance (Hicks &
Kinsbourne, 1976; Bryden &
Allard, 1981). An additional limitation of the study is that
performance was measured for only one of the two language tasks. One could
argue that patients did not perform the verb-generation task adequately.
However, this is unlikely, as one would then expect to find reduced brain
activity levels, which was not the case in the patients of this study.
Finally, the affected twins were a heterogene group. First, patients with both
schizophrenia and schizoaffective disorders were included. Furthermore,
symptom severity and type and dose of antipsychotic medication varied. All
three factors might have influenced the relative contribution of the right
hemisphere to language activity.
In summary, monozygotic twin pairs discordant for schizophrenia display lesser degrees of language lateralisation, caused by higher language-related activation in the homologue areas of the right hemisphere compared with healthy monozygotic twin pairs, whereas activation of the leftsided language-related areas is equal in both groups. Decreased language lateralisation in the discordant twin pairs may be a functional substrate of their genetic predisposition to develop psychotic symptoms of schizophrenia.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication January 27, 2003. Revision received May 21, 2003. Accepted for publication May 28, 2003.
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