Department of Psychiatry, University of Aachen and Tübingen, Germany and Section of Neuroimaging, Institute of Psychiatry and Guys, Kings and St Thomas School of Medicine, London, UK
Department of English Language and Literature, National University of Singapore
Section of Neuroimaging, Institute of Psychiatry and Guys, Kings and St Thomas School of Medicine, London, UK
Correspondence: Dr T. Kircher, Department of Psychiatry, University of Aachen, Pauwelstrasse 30, D-52076 Aachen, Germany. Tel: +49 (0)241 808 9640; fax: +49 (0)241 808 2401; e-mail: tkircher{at}ukaachen.de
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ABSTRACT |
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Aims To examine the neural correlates of syntax production in people with schizophrenia using functional magnetic resonance imaging (fMRI).
Method Six patients with schizophrenia and six healthy volunteers spoke about seven Rorschach inkblots for 3 min each while correlates of brain activation were measured with fMRI. Participants produced varying amounts of syntactically simple and complex sentences during each 3 min run. The number of simple and complex sentences was correlated separately with the BOLD contrast.
Results In the comparison between the control group and the patient group, the number of complex sentences produced was correlated with activation in the posterior portion of the right middle temporal (Brodmann area 21) and left superior frontal (BA10) gyriin the control group but not in the patients.
Conclusions The absence of activation in the right posterior temporal and left superior frontal cortex in patients with schizophrenia might contribute to the articulation of grammatically more simple speech in people with this disorder.
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INTRODUCTION |
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In this study we examined the neural correlates of syntax generation on a sentence level, using functional magnetic resonance imaging (fMRI) to observe participants articulating grammatically complex sentences. As syntactic processing in healthy individuals involves the inferior frontal and lateral temporal cortices (Kaan & Swaab, 2002), we predicted that the production of complex sentences would be correlated with activation in these areas in the control group, and that patients with schizophrenia would exhibit attenuated engagement of the left inferior frontal cortex and both left and right lateral temporal cortex.
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METHOD |
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During scanning, seven Rorschach inkblot plates were presented consecutively on a screen. Participants were asked to speak about whatever came to mind on viewing the inkblot, starting as soon as the stimulus appeared; they spoke freely and no prompting was given if they paused or stopped. Each of the seven plates was presented for 3 min (one run) with breaks of about 1 min between each presentation. The participants speech during scanning was recorded on a computer.
Linguistic analysis
Acoustic noise generated by image acquisition was filtered from the
recordings of the participants speech, which was transcribed verbatim
from these recordings and subsequently analysed from the transcripts. The
number of simple sentences (e.g. I see a moth) and sentences
with subordination (e.g. I see a moth that is blue) were
evaluated using Brief Syntactic Analysis
(Thomas et al,
1996a) by one of the authors (T.O.), who was masked to
the speakers identity. Brief Syntactic Analysis is a linguistic
analysis that rates spontaneous speech for syntactic complexity. In this
analysis, sentences were classified as one of the following:
Each 3 min scanning run was broken down into nine epochs of 20 s, and a total score for simple and complex sentences was obtained for each epoch.
Image acquisition and data analysis
The method of image acquisition and data analysis has been fully described
by Kircher et al
(2002). Gradient-echo
echoplanar MR images were acquired using a 1.5 T GE Signa System (General
Electric, Milwaukee, Wisconsin, USA): 14 planes, 60
T2*-weighted MR images; time to echo (TE) 40
ms, repetition time (TR) 3000 ms, =90°, in-plane resolution 3.1 mm,
slice thickness 7 mm, slice skip 0.7 mm.
For fMRI data analysis (Brammer et al, 1997), the behavioural data (number of simple and complex sentences per 20 s epoch in the two runs per individual with the highest variance and highest number of maxima and minima) were interpolated using a cubic spline to obtain a behavioural value corresponding to each fMRI volume acquired (one value per TR). The dependent variable (observed time series at each voxel) was regressed on the independent variable (number of simple and complex sentences). Further analysis was performed as described by Kircher et al (2002). For group comparisons, we computed a mask composed of all voxels activated at a stringent voxel-wise threshold (0.001) in either of the two groups or conditions that we needed to compare. We then carried out between-condition and between-group comparisons within this masked region to reduce the multiple comparison problem and thus enhance sensitivity. Comparison of groups was performed by computing the difference between the mean levels of activation at each voxel in standard space over all participants in each group. The significance of this difference was then assessed by reference to a null distribution obtained by repeated permutation of group membership and recomputation of the mean difference.
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RESULTS |
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Head movement
Analysis of the estimated time series of displacements in three dimensions
revealed no evidence of major head motion in any individual. The maximum
amount of head movement in the three dimensions x, y and z
in the runs per patient was x=0.5 mm (s.d.=0.3), y=0.7 mm
(s.d.= 0.3), z=1.4 mm (s.d.=1.6) and in the controls it was
x=0.4 mm (s.d.=0.3), y=0.3 mm (s.d.=0.4) and z=0.8
mm (s.d.=0.8).
Cerebral activation
Control group
In the control group the number of simple sentences produced per 20 s
period was positively correlated (P<0.001) with the BOLD response
in the left thalamus and primary visual cortex. The main correlations for
complex sentences (P<0.001) were with responses in the posterior
part of the left middle temporal gyrus, Brodmann area (BA) 39, and in the
posterior portion of the right superior temporal sulcus, BA 21/22
(Table 1). Between-condition
differences in median correlation coefficient were examined using analysis of
variance (ANOVA) at each voxel with probability of type I error at
P<0.05. Significantly stronger correlations for complex
v. simple sentences were evident in the right posterior superior
temporal sulcus (BA 21) and the left superior frontal gyrus (BA 10;
Table 1).
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Patient group
In the patient group the number of simple sentences produced per 20 s
period was positively correlated (P<0.001) with the BOLD response
in the cerebellum bilaterally (vermal lobule VI;
Schmahmann et al,
1999). The main correlations for complex sentences
(P<0.001) were with responses in the middle temporal gyri
bilaterally (BA 21), in a part anterior and inferior to that activated in the
control group. Between-condition differences in median correlation coefficient
were examined using an ANOVA at each voxel. This indicated that there were
significantly stronger correlations for complex sentences than for simple
sentences with responses in the right middle temporal gyrus (BA 21;
P<0.05), again in a region anterior and inferior to the site of
the analogous differences in the control group
(Table 2;
Fig. 1).
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Differences in activations for simple sentences between groups
Signal changes correlating with simple sentences were compared between
groups (P<0.05). Participants in the control group activated the
left primary visual cortex and the thalamus more than the patients, whereas
those in the patient group engaged the right cerebellar cortex more than the
controls (Table 3).
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Differences in activations for complex sentences between groups
Signal changes correlating with complex sentences were compared between
groups (P<0.05). The control group activated the right posterior
middle temporal gyrus (BA 21) and the supramarginal gyrus (BA 40) more than
the patients, whereas the patient group engaged the left
fusiform/parahippocampal gyrus more than the controls
(Table 4,
Fig. 1).
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DISCUSSION |
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Syntax production in the control group
The rate of production of each sentence type was correlated with the BOLD
response in each group. In members of the control group there was a positive
correlation between the number of complex sentences and activation in the left
posterior middle temporal gyrus, which is part of Wernickes area, and
in the right superior temporal sulcus. Both these areas have consistently been
activated in functional imaging studies of syntax comprehension in healthy
volunteers (Kaan & Swaab,
2002). However, whereas previous studies investigated syntax in
the context of sentence comprehension, the neural correlates in our study were
those of syntactic production during continuous speech. We thus interpret the
signal changes in the left middle temporal gyrus and right superior temporal
sulcus as being related to the production of syntactically complex
sentences.
Syntax production in the patient group
In the patient group the production of complex sentences was also
correlated with bilateral activation in the temporal cortex, but in regions
anterior and inferior to those engaged in the controls. Direct comparison of
the correlations in the two groups revealed significantly greater activation
in the right posterior middle temporal gyrus, right supramarginal gyrus and
left superior frontal gyrus in the control group compared with the patients.
This weaker engagement of the posterior temporal cortex and adjacent inferior
parietal lobule may be related to the impairment in producing complex
sentences that we observed in the patients at the behavioural level. However,
we cannot entirely exclude the possibility that these functional differences
were related to semantic processing. Complex sentences are more complicated
than simple sentences in terms of syntax as well as their semantic content.
Reading sentences involves the temporal cortex
(Kuperberg et al,
2000), and patients with schizophrenia show deficits in semantic
processing at the behavioural level (Bagner
et al, 2003). However, if semantic content were solely
responsible for the temporal activations, we would also expect at least small
signal changes in these areas for the correlations with simple sentences. An
increased number of simple sentences per unit of time also conveys increased
semantic content. We did not find such a correlation in either group and would
therefore suggest that, in line with recent research
(Kaan & Swaab, 2002), the
temporal activations reflect syntactic complexity.
The impaired posterior temporal activation we observed in the patients is in line with other data demonstrating structural and functional abnormalities in this area in schizophrenia. Thus, the production of thought-disordered speech in another study of the same patients correlated negatively with signal changes in the left superior temporal gyrus (Kircher et al, 2001b), and lateralisation changes in the same areas have been described during a sentence completion task, also in the same sample (Kircher et al, 2001a). The temporal cortices have been implicated in the generation of auditory verbal hallucinations (Dierks et al, 1999; Shergill et al, 2000). Structural imaging studies (for review, see Shenton et al, 2001) have described volumetric anomalies in the lateral temporal gyri in schizophrenia, particularly in patients with formal thought disorder. Our findings are also consistent with abnormalities in the planum temporale during simple acoustic processing, where abnormalities in lateralisation patterns have been described (Rockstroh et al, 1998; Kircher et al, 2004).
Frontal lobe
Apart from the temporal cortex, the only other region that was
significantly more correlated with complex rather than simple sentence
production in the control group was in the left prefrontal cortex, close to
the frontal pole (BA 10). This difference was not evident in the patient group
and direct contrast of the correlation maps for complex sentences in the two
groups revealed significantly greater activation in the controls than in the
patients. Other studies have found activation in the proximity of this region
during syntax comprehension in healthy volunteers
(Newman et al, 2001).
Although we predicted impaired differential engagement of the left inferior
frontal gyrus rather than this more anterior region in the two groups, these
observations suggest that this might also be related to impaired syntactic
processing in people with schizophrenia.
It has been proposed that Brocas area is involved in syntactic processing only when the demands on verbal working memory are high (Kaan & Swaab, 2002). Although the articulation of syntactically complex sentences might have engaged verbal working memory to a greater extent than simple sentences, the difference in the memory load might have been too small to lead to differential left inferior frontal activation. The absence of correlations between the production of complex sentences and the engagement of motor-related areas more generally may seem surprising, given that the participants were articulating speech; however, as they were speaking at a rate that was self-paced and felt natural for them, the demands on articulatory processing might have been relatively constant. Activation in motor areas might thus have been at ceiling and not have shown a measurable response to fluctuations in the amount of speech produced in association with the production of complex sentences (Kircher et al, 2002).
Methodological considerations
Although overt speech can be associated with artefacts in fMRI studies
secondary to articulation-related head movement
(Bullmore et al,
1999), we quantified head movement during image acquisition, and
found it to be minimal in both groups. Artefacts can also be introduced by air
volume changes in the pharynx during phonation. However, when scanning at 1.5
T these effects are likely to be small, except in areas close to the orbital
frontal cortex (Barch et al,
1999). Functional MRI is also associated with significant scanner
noise, but all our participants reported that they were able to hear
themselves speak during the task.
Concluding remarks
Our data implicate the left posterior superior temporal sulcus
(Wernickes area), the right posterior middle temporal gyrus and the
left prefrontal cortex in the production of syntactically complex sentences in
healthy individuals. Patients with schizophrenia failed to show this pattern
of activation, with significantly weaker engagement of the right temporal and
left prefrontal cortex, which may underlie the reduced production of
grammatically complex sentences in these patients. Language abnormalities seem
to be the only symptom that is genetically transmitted among relatives of
people with schizophrenia (Cardno et
al, 2001). The way in which language, genes, the brain and
schizophrenia relate to each other is a very intriguing question
(Crow, 2000) and needs further
investigation.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication September 17, 2003. Revision received March 5, 2004. Accepted for publication August 26, 2004.
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