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Neural Correlates of Formal Thought Disorder in Schizophrenia
Preliminary Findings From a Functional Magnetic Resonance Imaging Study
Tilo T. J. Kircher, MD, PhD;
P. F. Liddle, PhD, MRCPsych;
Michael J. Brammer, PhD;
Steve C. R. Williams, PhD;
Robin M. Murray, MD, MRCPsych;
Philip K. McGuire, MD, PhD, MRCPsych
Arch Gen Psychiatry. 2001;58:769-774.
ABSTRACT
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Background Formal thought disorder (FTD) is a core symptom of schizophrenia, but
its pathophysiology is little understood. We examined the neural correlates
of FTD using functional magnetic resonance imaging.
Methods Blood oxygenation level–dependent contrast was measured using
functional magnetic resonance imaging while 6 patients with schizophrenia
and 6 control subjects spoke about 7 Rorschach inkblots for 3 minutes each.
In patients, varying degrees of thought-disordered speech were elicited during
each "run." In a within-subject design, the severity of positive FTD was correlated
with the level of blood oxygenation level–dependent contrast in the
2 runs that showed the highest variance of FTD in each patient.
Results The severity of positive FTD in patients was negatively correlated (P<.001) with signal changes in the left superior and
middle temporal gyri. Positive correlations were evident in the cerebellar
vermis, the right caudate body, and the precentral gyrus.
Conclusions The severity of positive FTD was inversely correlated with the level
of activity in the Wernicke area, a region implicated in the production of
coherent speech. Reduced activity in this area might contribute to the articulation
of incoherent speech. Because of the small sample size, these findings should
be considered preliminary.
INTRODUCTION
FORMAL THOUGHT disorder (FTD) is regarded as one of the core features
of schizophrenia,1 yet little is known about
its pathophysiology. It can be subdivided into positive and negative FTD,
with the former characterized by incoherence, use of peculiar words, and distractibility
and the latter by a reduction in the amount and content of speech.2 These subtypes of FTD seem to have distinct clinical
and neuropsychologic correlates,3, 4
and their respective pathophysiologic mechanisms might thus be different.
Functional neuroimaging provides a means of investigating the pathophysiology
of FTD in vivo. To date, most studies5, 6, 7, 8, 9
have measured cerebral blood flow in patients with schizophrenia in the resting
state and have correlated this with the severity of positive FTD, assessed
outside the scanner. These investigations have linked the disorganization
syndrome (which predominantly comprises positive FTD) with the level of resting
activity in several regions, including the anterior cingulate, inferior frontal
and superior temporal gyri, and the caudate nucleus, although there has been
some inconsistency across studies.
An alternative approach is to scan patients while they are articulating
disorganized speech and examine the relationship between the severity of FTD
and brain activity "on-line." In the present study, patients produced varying
degrees of FTD as they were verbally describing Rorschach inkblots while regional
blood oxygenation level–dependent (BOLD) contrast was being continuously
measured using functional magnetic resonance imaging (fMRI). The relationship
between the severity of FTD and the BOLD response over time was examined within
each individual and in patients as a group. We predicted that the severity
of positive FTD in patients would be inversely correlated with activation
in the left superior temporal cortex.5, 10, 11, 12
SUBJECTS AND METHODS
SUBJECTS
Six men with schizophrenia (DSM-IV) were recruited
from the Maudsley and Bethlem Royal Hospitals, London, England. Patients were
selected if they were currently exhibiting prominent symptoms of positive
FTD, with relatively low levels of hallucinations and delusions. Forty-six
patients were assessed: 4 were not native speakers, 10 did not have high levels
of FTD at the time of scanning, 5 were left-handed, 6 were unable to complete
the task, 8 refused to participate, and 7 were too agitated or distractible
to tolerate scanning. A control group of healthy volunteers was matched for
sex, age, and demographic variables with the patient group. All subjects were
right-handed.13 Only subjects able to completed
3 "runs" of the task to be used during scanning and patients who articulated
positive FTD speech on these runs were included. Verbal IQ, immediate memory
recall, and attention were also assessed on the day of scanning using the
National Adult Reading Test,14 Digit Span,15 and the Continuous Performance Test,16
respectively. There were no significant differences between groups on these
measures or on sociodemographic variables (Table 1). The mean (SD) duration of illness in patients was 13.0
(9.9) years, and all were taking stable doses of typical antipsychotic medications
(mean [SD] dose in chlorpromazine equivalents, 1042 [738] mg/d).
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Table 1. Sociodemographic and Clinical Characteristics of Patient and
Control Groups
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Patients were clinically assessed (by T.T.J.K.) using the Schedule for
Affective Disorder and Schizophrenia–Lifetime version,18
the Scale for the Assessment of Positive Symptoms (SAPS),19
and the Scale for the Assessment of Negative Symptoms (SANS)20
the day of scanning, before collection of imaging data. Patients had high
levels of positive FTD (mean [SD] SAPS score, 3.83 [0.75]) and relatively
low levels of hallucinations (mean [SD] SAPS score, 0.33 [0.52]), delusions
(mean [SD] SAPS score, 0.83 [0.75]), and negative symptoms (total mean [SD]
SANS score, 3.33 [2.34]; total mean [SD] SAPS score, 6.17 [0.75]). Permission
for the study was obtained from the local ethics committee. After complete
description of the study to the subjects, written informed consent was obtained.
PROCEDURES
Subjects were given a standard set of verbal instructions about the
experiments and performed 3 trials of the task (using different stimuli from
those presented during scanning) on each of 2 occasions: 1 to 5 days before
and immediately before scanning. During scanning, stimuli (7 Rorschach inkblot
plates) were presented on a screen viewed by the subject via a mirror. These
inkblots were previously found to evoke positive FTD when patients with schizophrenia
were asked to describe them.21, 22
In the present study, subjects were asked to speak about whatever came to
mind on viewing the inkblot, starting as soon as the stimulus appeared, and
to maintain their gaze on the screen throughout the presentation. Subjects
spoke freely, and no prompting was given if they paused or stopped. Each plate
was presented for 3 minutes (1 run), with breaks of approximately 1 minute
between each presentation (total speech time, 21 minutes per subject). Subjects'
speech during scanning was recorded on a computer in digitized form using
a nonmetallic microphone positioned close to the mouth. Subjects wore customized
headphones that reduced the noise of image acquisition but still allowed them
to hear themselves speak.
Acoustic noise generated by image acquisition was filtered from recordings
of subjects' speech using commercially available software (Cool Edit 96; Syntrillium
Software Corp, Phoenix, Ariz). Subjects' speech was transcribed verbatim23 from these recordings and subsequently analyzed from
these transcripts. The severity of FTD was evaluated using the Thought and
Language Index24 by one of us (P.F.L.), who
was masked to subject identity. This scale includes 5 items that assess positive
FTD (looseness, peculiar word usage, peculiar sentence construction, peculiar
logic, and distractibility). Instances of disorder are scored 0.25, 0.50,
0.75, or 1 according to the degree of abnormality as specified in the scoring
guidelines. The reliability of the Thought and Language Index was established
in a study in which 5 raters scored transcripts of eight 1-minute speech samples
produced by each of 25 patients with schizophrenia.25
The intraclass correlation coefficient (CC) was 0.82 for the positive FTD
total (range, 0.60-0.93 for individual items).
Each 3-minute scanning run was broken down into nine 20-second epochs,
and a total score for positive Thought and Language Index items was obtained
for each epoch. The total number of words articulated during 20-second epochs
was used as a measure of the amount of speech produced in patients and control
subjects.
IMAGE ACQUISITION AND ANALYSIS
Gradient-echo echoplanar MRIs were acquired using a 1.5-T GE Signa System
(General Electric, Milwaukee, Wis) fitted with Advanced NMR hardware and software
(Advanced Nuclear Magnetic Resonance Systems, Wilmington, Mass). A quadrature
birdcage head coil was used for radiofrequency transmission and reception.
In each of 14 noncontiguous planes parallel to the intercommissural (AC-PC)
plane, 60 T2-weighted MRIs depicting BOLD contrast26
were acquired (echo time, 40 milliseconds; repetition time, 3000 milliseconds;  ,
90°; in-plane resolution, 3.1 mm; slice thickness, 7 mm; and slice skip,
0.7 mm). Head movement was limited by foam padding within the head coil and
a restraining band across the forehead. A 43-slice, high-resolution inversion
recovery echoplanar image of the whole brain was acquired in the AC-PC plane
(echo time, 73 milliseconds; inversion time, 180 milliseconds; repetition
time, 16 000 milliseconds; in-plane resolution, 1.5 mm; slice thickness,
3 mm; and slice skip, 0.3 mm).
Before analysis, the effects of small amounts of subject motion during
data acquisition were corrected using a 2-stage process involving realignment
and regression.27 In computing the correlation
between behavioral and imaging data, it was necessary to minimize the possibility
of spurious correlations leading to type I errors. Such effects are most likely
to occur if the behavioral data show a simple monotonic trend, which could
show apparent correlations with drifts in image intensity. To deal with this
possibility, the seven 3-minute runs of behavioral data (amount of positive
FTD and number of words produced) obtained from each individual were examined,
and the 2 runs with the highest intrarun variance and at least 2 maxima and
2 minima were selected for correlational analysis. Two runs were used because
all subjects had at least this number of runs showing clearly nonmonotonic
time and behavior characteristics.
The behavioral data were interpolated using a cubic spline to produce
smooth changes between discrete observations (20-second epochs) and obtain
an estimate of the behavioral value corresponding to each fMRI volume acquired
(one value per repetition time, 3 seconds). In the first analysis, the time
series at each voxel was correlated with the vector of the Thought and Language
Index score in patients, covarying for the number of words articulated per
epoch. Covariation was performed to control for activation related to speech
articulation and word retrieval. In the second analysis, applied in patients
and controls, the time series was correlated with the number of words produced
per epoch. In this analysis, we covaried for long speech pauses (>3 seconds)
because we were interested in the correlates of speech production as it varied
during continuous discourse (as opposed to the production of brief bursts
of speech).28, 29
After computing the correlation coefficient (CC) from the observed data,
correlational analysis was repeated 10 times after random permutation of the
time series at each voxel.30 This process resulted
in 10 estimates of the CC at each voxel for each individual after eliminating
the observed relationship between the behavioral and imaging data by the permutation
procedure. Ten was chosen as the number of randomizations to yield a null
distribution of sufficient size to test at all necessary P values. A typical image contains approximately 20 000 intracerebral
voxels. Ten permutations per voxel, after combining data across voxels, yields
approximately 200 000 estimates of CC using the null hypothesis that
there is no behaviorally determined change in fMRI signal intensity (BOLD
effect). The minimum testable P value with this distribution
is then 1 per 200 000, or .000005. The probability of any CC occurring
using the null hypothesis can be obtained by sampling this distribution at
the appropriate point. For example, for a P value
of .001, the value of the CC is found that is only exceeded by 0.1% of all
the values in the distribution control (20 error voxels over the whole brain).
Brammer27 and Bullmore30
and their colleagues showed that such techniques permit excellent nominal
type I error in fMRI activation mapping. The observed and permuted CC maps
for each of the 2 runs selected from each subject were then transformed into
the standard space of Talairach and Tournoux31
and smoothed by a 2-dimensional gaussian filter with full width at half maximum
of 7 mm. After smoothing, the mean of the 2 CC estimates for each subject
at each voxel in standard space was calculated.
Finally, as a measure of the overall group CC, the median of these subject
means was determined. Median statistics were chosen to minimize outlier effects
in small groups.27, 30 A null distribution
of median CCs was calculated by using identical computational steps on the
permuted data. Activated voxels (those exceeding the critical CC for the desired P value [see above]) were color coded according to a negative
or positive correlation and superimposed on an inversion recovery echo planar
imaging data set.27
RESULTS
The severity of positive FTD (per 20-second epoch, as rated with the
Thought Disorder Index) ranged from 0.5 to 48.5 points (mean [SD], 15.9 [15.9]
points) in patients and from 0.0 to 4.0 points (mean [SD], 1.2 [1.3] points)
in controls (difference, U = 4.5; P = .03). The amount of speech produced (number of words per 20-second
epoch) ranged from 0 to 59 (mean [SD], 29.3 [14.7]) in patients and from 11
to 76 (mean [SD], 45.8 [13.1]) in controls (difference, U = 5.5; P = .04).
The mean (SD) maximum amount of head movement during data acquisition
in the x, y, and z dimensions
(in the 2 runs analyzed per subject) was as follows: x,
0.6 (0.2) voxels; y, 0.6 (0.3) voxels; and z, 1.6 (1.5) voxels in patients and x, 0.3 (0.2) voxels; y, 0.4 (0.4) voxels;
and z, 0.9 (0.7) voxels in controls.
In patients, the severity of positive FTD was positively correlated
with the BOLD response in the cerebellar vermis, the right body of caudate,
and the right precentral gyrus. Extensive negative correlations were evident
in the left superior temporal gyrus and to a lesser extent in the posterior
part of the middle temporal gyrus (Table
2, Figure 1).
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Table 2. Cerebral Areas That Correlate With the Severity of Positive
Formal Thought Disorder in 6 Patients With Schizophrenia (P .001)*
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Brain areas in which signal changes in 6 patients with schizophrenia
were correlated with positive formal thought disorder. Red voxels indicate
positive correlations (cerebellum and caudate); blue voxels, negative correlations
(middle and superior temporal gyri) (P<.001). The left side
of the brain is shown on the right side of the image. Talairach and Tournoux31 z coordinates are shown at the bottom
of each slice.
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The severity of FTD in controls was low, and there was little variation
over time, precluding detection of significant correlations with the BOLD
response.
In the control group, the amount of speech articulated was positively
correlated with the BOLD response in the left superior temporal gyrus (Brodmann
area [BA] 22 according to the atlas of Talairach and Tournoux31
[Tal]; Tal x, -49; Tal y, 0; and Tal z, -2; number of activated
voxels, 8). Negative correlations were evident in the fusiform gyri bilaterally
(BA 18/19; Tal x, 23; Tal y, -69;
Tal z, -13; number of activated voxels, 15;
and Tal x, -26; Tal y, -58;
Tal z, -7; number of activated voxels, 13)
and in the posterior cingulate cortex (BA 29/30; Tal x, 0; Tal y, -50; Tal z, 9; number of activated voxels, 11).
In patients, the amount of speech was positively correlated with signal
changes in the right superior temporal gyrus (BA 42; Tal x, 46; Tal y, -25; Tal z, 9; number of activated voxels, 17; BA 22; Tal x, 58; Tal y, -25; Tal. z, 4; number of activated voxels, 11) and inferior temporal gyrus (BA
20; Tal x, 40; Tal. y, -6;
Tal. z, -24; number of activated voxels, 17)
and the right cerebellar cortex (Tal x, 9; Tal y, -69; Tal z, -13;
number of activated voxels, 17). There was a negative correlation in the left
medial frontal (BA 10; Tal x, -14; Tal y, 42; Tal z, -7; number
of activated voxels, 18) and inferior frontal gyrus (BA 44/45; Tal x, -40; Tal y, 31; Tal z, 20; number of activated voxels, 7) and the right inferior frontal
gyrus (BA 44/45; Tal x, 46; Tal y, 19; Tal z, 9; number of activated voxels,
15) and cingulate gyrus (BA 24; Tal x, 9; Tal y, 47; Tal z, 9; number of activated
voxels, 9).
COMMENT
Schizophrenia is a phenomenologically heterogeneous disorder, and abnormal
brain activation could be related to a variety of different symptoms and cognitive
processes. In this study, we tried to minimize the impact of heterogeneity
by selecting a symptomatologically homogeneous group and by measuring a single
phenomenon as it varied over time within each subject. The patient thus served
as his own control, reducing potentially confounding effects of between-subject
differences in other symptoms, cognitive deficits, illness duration, medication
status, or IQ. Because the severity of FTD can vary with the amount of speech
produced, we also covaried for the number of words per epoch in the analysis;
the findings are thus independent of fluctuations in the rate of speech.
To our knowledge, this is the first study to use fMRI to examine brain
activity while subjects produced thought-disordered speech "on-line." Functional
MRI is associated with significant scanner noise, but all our participants
reported that they were able to hear themselves speak during the tasks. Although
we acquired hundreds of images in each participant, the total number of subjects
was small because such patients are difficult to recruit, and our results
should still be regarded as preliminary. Moreover, our patients are meant
to represent only a subset of the population with schizophrenia, and our results
might be specific to the production of FTD rather than the disorder as a whole.
Overt speech responses during fMRI might be associated with head movement,32 and artifacts in the orbital frontal cortex can be
introduced by changes in the pharynx during phonation (susceptibility induced
signal loss at the air-tissue border). However, (1) the main areas of activation
were far from this region; (2) we quantified head movement, and this was minimal;
and (3) at 1.5 T, when overt responses are continuous, these effects on grouped
data are likely to be small.33
The results confirmed our main prediction, that the severity of positive
FTD was negatively correlated with blood oxygenation level in the left superior
temporal gyrus. This observation, and the finding of positive correlations
in the right caudate, replicates the results from a previous positron emission
tomography study,10 which used a similar, although
less sophisticated, design. They are also consistent with data from structural
imaging studies (for a review, see Shapleske et al34
and Rajarethinam et al35), which described
volumetric anomalies in the left superior temporal gyrus in schizophrenia36, 37 and correlated the magnitude of the
reduction in left superior temporal gyrus volume with the severity of FTD.12, 33, 38, 39, 40
We also found a strong positive correlation between the severity of
FTD and signal changes in the cerebellar vermis. The cerebellum has been implicated
in normal somatosensory41 and verbal42 self-monitoring. Increased activation in the cerebellum
with increasing severity of FTD might be related to the detection of linguistic
errors in the patient's speech. However, because patients often seem to be
unaware of such errors,43 this neural response
might not be accompanied by detection of anomalies at the conscious level.
Key components of coherent discourse are discourse planning and self-monitoring
for (and correction of) verbal errors.44 In
controls, the amount of speech produced was positively correlated with activity
in the left superior temporal gyrus, consistent with its normal involvement
in these processes.45 This correlation between
speech production and left temporal activity was not evident in patients.
Moreover, when patients were articulating thought-disordered speech, they
showed a negative correlation with activity in the left superior temporal
region—opposite to what occurs during production of coherent speech.
This is consistent with the effects of lesions in this area, which lead to
Wernicke (jargon) aphasia, involving fluent but paragrammatical speech that
bears some resemblance to FTD. Cognitive models propose that defects in discourse
planning and verbal self-monitoring underlie the production of thought-disordered
speech in schizophrenia.46, 47
Malfunction of the left superior temporal gyrus during continuous discourse
might thus be associated with impairment of these processes and articulation
of the linguistic anomalies that characterize thought-disordered speech.
AUTHOR INFORMATION
Accepted for publication March 23, 2001.
This work was supported by grant Ki 588/1-1, 1-2 from the German Research
Foundation (Deutsche Forschungsgemeinschaft) (Dr Kircher).
We thank Edward Bullmore, PhD, MRCPsych, Chris Andrew, Mathias Bartels,
MD, PhD, Gerard Buchkremer, MD, PhD, and Andrew Simmons, PhD, for their help.
From the Section of Neuroimaging (Drs Kircher and McGuire), the Division
of Psychological Medicine (Dr Murray), the Department of Biostatistics and
Computing (Dr Brammer), and the Neuroimaging Research Unit (Dr Williams),
Institute of Psychiatry and GKT School of Medicine, De Crespigny Park, London;
the Department of Psychiatry, University of British Columbia, Vancouver (Dr
Liddle); and the Department of Psychiatry, University of Tuebingen, Tuebingen,
Germany (Dr Kircher).
Corresponding author: Tilo T. J. Kircher, MD, PhD, Department of
Psychiatry, University of Tuebingen, Osianderstr. 24, D-72076 Tuebingen, Germany
(e-mail: tilo.kircher{at}uni-tuebingen.de).
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