in the Frontal Lobe of Schizophrenic Patients: A
P
Chemical Shift Spectroscopic-Imaging Study
Hans-Peter Volz, Stefan Riehemann, Iris Maurer, Stefan Smesny, Monika Sommer,
Reinhard Rzanny, Werner Holstein, Jo¨rg Czekalla, and Heinrich Sauer
Background:
31Phosphorous magnetic resonance
spec-troscopy has been widely used to evaluate schizophrenic
patients in comparison to control subjects, because it
allows the investigation of both phospholipid and energy
metabolism in vivo; however, the results achieved so far
are inconsistent. Chemical shift imaging (CSI) has the
advantage that instead of only one or a few preselected
voxels the tissue of a whole brain slice can be examined.
The aim of the present investigation was to determine
whether the results of previous studies of our group,
showing that phosphodiesters (PDE) are decreased in the
frontal lobe of schizophrenic patients as compared to
control subjects, might be confirmed in an independent
unmedicated patient sample using the CSI technique.
Methods:
A carefully selected new cohort including 11
neuroleptic-free schizophrenic patients and 11 age- and
gender-matched healthy control subjects was recruited.
CSI was applied and an innovative analysis method for
CSI data based on a general linear model was used.
Results:
PDE, phosphocreatine, and adenosine
triphos-phate (ATP) were found to be significantly decreased in
the frontal lobe of patients with schizophrenia.
Conclusions:
Because PDE was decreased in
schizo-phrenic patients, the membrane phospholipid hypothesis
of schizophrenia could not be corroborated. Further
results indicate decreased ATP production in the frontal
lobe of patients with schizophrenia.
Biol Psychiatry
2000;47:954-961 ©
2000 Society of Biological Psychiatry
Key Words:
Schizophrenia,
31phosphorous magnetic
res-onance spectroscopy, chemical shift imaging,
phospho-lipid membrane hypothesis
Introduction
31
Phosphorous magnetic resonance spectroscopy (MRS) is
a noninvasive technique that allows in vivo evaluation of
phosphorous molecules in tissues (e.g., in brain tissue).
Two major independent groups of molecules containing
phosphor can be differentiated by MRS: the phospholipids
and the high-energy phosphates. The phospholipids
com-prise phosphomonoesters (PME), which in turn are mainly
composed of phosphocholine (PC), phosphoethanolamine
(PE), and L-phosphoserine (PS) on the one hand, and
phosphodiesters (PDE) on the other hand. The PDE peak
of the MR spectrum is a sum peak of
glycerol-3-phospho-choline (GPC), of glycerol-3-phosphoethanolamine (GPE),
and of mobile phospholipids present in the cell membrane
(Murphy et al 1989). PME are regarded as precursors of
membrane phospholipids, whereas PDE are believed to
represent products of membrane breakdown.
The high-energy phosphates comprise phosphocreatine
(PCr) and nucleoside triphosphates, mainly adenosine
triphosphate (ATP). Another metabolite important in
en-ergy metabolism that can be detected by MRS is inorganic
phosphate (Pi). PCr, ATP, and Pi are regarded as markers
of cellular energy metabolism and are believed to stay in
an equilibrium. As recently summarized by Magistretti et
al (1999), ATP consumption is directly linked to neuronal,
probably glutaminergic activity.
Thus, MRS allows the investigation of both cell
mem-brane turnover and cellular energy metabolism in the
tissues in vivo. It is therefore not surprising that MRS has
become a frequently applied spectroscopy technique in
schizophrenia research since the pioneering work of
Pet-tegrew et al in 1991.
The results obtained by MRS, however, are
inconsis-tent, both with respect to the amount of phospholipid
compounds and the markers of brain energy metabolism.
Pettegrew et al (1991) originally reported increased PDE
and decreased PME levels in neuroleptic-naive,
first-episode schizophrenic patients in the dorsolateral
prefron-tal cortex. They suggested that these alterations are
com-From the Department of Psychiatry (H-PV, SR, IM, SS, MS, HS) and Institute ofDiagnostic and Interventional Radiology (RR), University of Jena, Jena, and Lilly Deutschland GmbH, Bad Homburg (WH, JC), Germany.
Address reprint requests to Hans-Peter Volz, M.D., University of Jena, Department of Psychiatry, Philosophenweg 3, D-07740 Jena, Germany.
Received August 4, 1999; revised December 13, 1999; accepted December 20, 1999.
patible either with premature aging or an exaggeration of
normal programmed regressive events occurring in the
frontal lobe. Later studies investigating phospholipids in
the frontal lobe, however, either could not confirm an
increase of PDE in schizophrenic patients (Fujimoto et al
1992; Shioiri et al 1994; Williamson et al 1991) or even
reported decreased PDE values in schizophrenic patients
(Volz et al 1997a, 1998). For PME, too, results were not
consistent: As summarized by Kegeles et al (1998), the
majority of studies investigating the frontal lobe reported
decreased PME levels in schizophrenia, whereas others
were not able to detect significant differences between
schizophrenic patients and control subjects. These
incon-sistencies are also characteristic of the results of the
measurements of high-energy metabolites. Conflicting
results were not only observed in the frontal, but also in
the temporal lobes. Several factors might be responsible
for these inconsistencies between studies: 1) different
patient samples (e.g., chronic vs. first episode
schizo-phrenic patients); 2) different medication status (e.g.,
drug-naive vs. long-term medicated patients); 3)
differ-ences in the used spectral analysis; 4) differdiffer-ences in the
MRS techniques regarding the use of different coils (e.g.,
surface coil, quadrature head coil) and regarding
acquisi-tion sequences (e.g., image selected in-vivo spectroscopy
[ISIS], depth-resolved surface coil spectroscopy [DRESS],
chemical shift imaging [CSI]); and 5) selection of
vol-ume(s) of interest (VOI) for analysis.
Among the different measurement techniques, CSI
pro-vides an advantage over DRESS since an entire slice
instead of a few preselected VOIs can be analyzed. So far,
however, the problem of how the entire information
provided by CSI can be used has not been resolved.
Investigators either selected specific VOIs (e.g., Deicken
et al 1994, 1995a, 1995b; Fukuzako et al 1994; Potwarka
et al 1999) or evaluated a high number of single regions
performing all possible comparisons (control subjects vs.
patients for every VOI for all MRS parameters) without
taking the problem of multiple testing into account (e.g.
Fujimoto et al 1992).
In the present study all image data obtained by a CSI
measurement were used without prior restrictions to
cer-tain VOIs. Instead of conventional statistical analysis, a
general linear model (GLM) was applied. The statistical
parametric maps obtained are the result of statistical
processes that are used to test hypotheses about regionally
specified effects in neuroimaging data (Friston et al 1991).
Most of the sets of statistical parametric maps—ranging
from an unpaired
t
test to linear regression—are based on
linear models. All these methods are special cases of the
GLM. One advantage of the GLM is its mathematical
simplicity. Irrespective of the complexity of the
experi-ment, the model uses only a small number of operational
equations. Furthermore, the GLM can be applied to any
method of constructing a statistical parametric map.
To exclude potential confounding factors, only those
schizophrenic patients who did not receive neuroleptic
medication were included and healthy control subjects
were carefully age and gender matched.
The aim of our study was to determine whether our
previous results of decreased PDE in schizophrenic frontal
lobe can be replicated in an independent unmedicated
patient sample by using both a different measurement
technique (CSI) and a new analysis technique (GLM).
Additionally, the status of high-energy phosphates and Pi
was determined.
Methods and Materials
Subjects
Eleven schizophrenic inpatients and 11 age- and gender-matched control subjects were included in the study. Ten of the patients had a diagnosis of schizophrenia (four paranoid type, three catatonic type, two residual type, one undifferentiated type) and one patient had a diagnosis of schizoaffective disorder according to DSM-IV criteria (American Psychiatric Association 1994). Diagnoses were made independently by the treating psychiatrist and by another experienced psychiatrist. Only if both diagnoses were the same and fulfilled the inclusion criteria was the respective patient included. At the end of the hospitalization period (mean duration: 9 weeks) the diagnoses were verified according to the hospital charts. The main demographic variables together with the individual wash-out and pretreatment data of the four pretreated patients are given in Tables 1 and 2.
Seven of the patients had never been medicated with neuro-leptics before, and four had discontinued neuroleptic treatment for a mean of 4.360.4 days. Using gas chromatography–mass spectroscopy (detection limit 10 ng/mL), neuroleptics in plasma could not be detected in any patient prior to MRS. Patients were assessed using the Clinical Global Impression (CGI; National Institute of Mental Health 1970) and the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham 1962). Using the Edinburgh Table 1. Demographic Data of 11 Schizophrenic Patients and 11 Control Subjects
Duration of illness (years) 7.267.6 —
Range (years) 1–22
Values are given6SD. BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression.
aSeven of the patients were neuroleptic naive; data refer to the four patients
inventory (Oldfield 1971), all schizophrenic patients and 10 of the 11 control subjects were found to be right handed. The clinical interview was performed immediately before the MRS measurement. All control subjects were recruited by newspaper advertisements and were paid for their participation. Control subjects and patients were thoroughly investigated for symptoms of internal and neurological disease; control subjects or patients who had evidence of neurological disorders or who had first-degree relatives with such disorders were excluded from the study, as were subjects who had a history of substance abuse. Control subjects also underwent a psychiatric examination. Those who showed any psychiatric symptoms or had a history of psychiatric symptoms or had first-degree relatives suffering from a major psychiatric disorder were excluded. The study was approved by the ethical review board of the University of Jena. After a detailed description of the study protocol to the subjects, patients and control subjects gave written informed consent.
Method of
31P-MRS Chemical Shift Imaging
Two-dimensional 31P-CSI data were acquired with a
conven-tional magnetic resonance imaging (MRI) scanner at 1.5 T (Gyroscan ACSII, Philips, Hamburg, Germany) and a quadrature transmit/receive 31P head coil. Prior to the measurement, the
magnetic field homogeneity was improved by an automatic shim procedure including a volume indicated by the bold line in Figure 1. A PRESS sequence is used to measure the line broadening of the water signal. After shimming, the half-height line width (full width at half maximum) of the water signal had to be less than 15 Hz. Then, a phase-encoded image selective CSI sequence using free induction decay volume selection was applied. The Philips Gyroscan ACS II used has no option to adjust a preacquisition delay time; however, in the scan record the sample offset time was specified. For the CSI measurements, the offset time was Dt058.331024sec. An 838 CSI matrix was acquired with
a repetition time of 2000 msec, a sampling rate of 2 kHz, and a sampling time of 0.5 msec. Data were averaged over 16 mea-surements. To position the obliquely located slice (Figure 2) in a reproducable and reliable fashion, T1-weighted scout images
were recorded with the body coil of the scanner. On a midsagittal slice, the commissura anterior (CA) and commissura posterior (CP) were identified. The points where the line through CA and CP crosses the posterior cerebral surface and where a perpendic-ular to the CA–CP line through CA crosses the cerebral surface were identified. A line parallel to the line through these two reference points and crossing CP determined the location of the measured slice. The mean angles between the measured slice and the CA–PC line did not differ between both groups (mean angle in schizophrenic patients: 36.4°62.8°, in control subjects: 37.6° 64.2°,p5.56, Mann–WhitneyUtest). The acquired slice had a thickness of 4 cm, with 2 cm being located below and 2 cm above this line (Figure 2). In the transversal orientation, the size of the measured VOI was adjusted to the individual size of the brain. The mean size of the VOI was 18.4 3 18.43 4 cm3,
resulting in 8 3 8 voxels of about 19 cm3 each (Figure 1).
Because the VOI was adjusted to the individual size of the brain, one might speculate that the mean voxel volumes were different between both groups; however, this was not the case (mean voxel volume in schizophrenic patients: 181 6 13 cm3, control
subjects: 1866 8 cm3,p 5.47, Mann–Whitney Utest). The
slice covered the frontal, temporal, and occipital lobe, the cingulum, the thalamus, and the cerebellum.
The acquired time domain signals from each voxel were direct current corrected, zero filled to 2,048 data points, and exponen-tially multiplied (8 Hz). After Fourier transformation, an auto-matic zero- and first-order phase correction were applied. After this preprocessing, an iterative nonlinear last-square fit in the frequency domain was applied to the spectrum using the Pearch Research (PERCH) software (view online at http://www.uku.fi/ perch). Details of the fitting process and a figure of a typical simulated spectrum have already been published by Riehemann et al (1999b). The received values were converted into greyscale values and stored as CSIs. To minimize global distortions due to altered amplifier adjustments or varying shimming fields in different measurements, the greyscale values of each CSI were normalized for the mean total integrated area of the spectrum (Bottomley 1991; Rudin and Sauter 1992). This CSI preprocess-ing was based on the software Xunspec1 (Philips, Best, Nether-lands). Automatic calculation was established using batch pro-cessing and corresponding filter programs on a Sun workstation. No user interaction was necessary during the whole procedure of image generation. The resulting CSIs were finally converted into the “Analyze format.”
Statistical analysis of the CSI of the respective metabolites was performed by means of a general linear model (GLM) (Riehemann et al 1999a) implemented in the software package SPM96 (Statistical Parametric Mapping, version 96; Friston et al 1995). A subtractive GLM design allowing the detection of group differences was used. Two linear contrasts of effects in each voxel were used, the first contrast depicting higher values in control subjects compared to schizophrenic patients (or lower values in schizophrenic patients), the second contrast depicting higher values in schizophrenic brains. Each contrast resulted in a map of thetstatistic, which was transformed to the unit normal distribution and thresholded at 1.69, corresponding to p,.05. The obtained Z(1.69) map was finally overlaid on the corre-sponding anatomic image.
Table 2. Individual Data of the Four Pretreated Patients
Patient prothazine p.o. 5 days before measurement
2 5 Once 5 mg haloperidol IM 6 days before measurement
3 4 20 mg flupentixole decanoate IM 11 days before measurement
Results
The numbers of the voxels used in the text refer to those
marked on the grid overlaid on the corresponding
ana-tomic slice (see Figure 1). Tentative allocation of anaana-tomic
structures underlying each voxel is also given in Figure 1.
In the following only the voxel numbers will be referred
to.
In the frontal lobe, PDE was found to be decreased in
schizophrenic patients compared to control subjects in
voxel 13 (Figure 3a). PME was decreased in voxel 28
(Figure 3d). In the cerebellum, both PDE and PME were
PDE, ATP, or PCr in any of the regions examined. No
statistically significant group differences on Pi were
found.
Discussion
Phospholipids in Schizophrenic Brain Tissue
The present study revealed that alterations of phospholipid
levels were present throughout the brain in patients with
schizophrenia. Significant differences in comparision to
control subjects were observed in the frontal lobes, in the
region of the basal ganglia and in the cerebellum.
Our finding of decreased PDE in the right frontal lobe is
not in accordance with the majority of previous studies
reporting either increased or unchanged values in
schizo-phrenic patients (Deicken et al 1994; Fujimoto et al 1992;
Pettegrew et al 1991; Potwarka et al 1999; Shiori et al
1994, Stanley et al 1994, 1995; Williamson et al 1991).
These discrepancies may partly be due to methodological
differences, because increased PDE values in
schizophre-nia have mainly been reported in those studies where the
measured frontal VOIs included mostly grey and not white
matter. Because PDE and PME levels are higher in white
than in grey matter (Buchli et al 1994), one should rather
have expected PDE decreases in schizophrenic patients as
a result of studies investigating a relatively high amount of
white matter. Just the opposite is the case, however. Thus,
the results do not seem to be primarily dependent on the
localization methods used.
A given voxel contains an admixture of grey and white
matter. Because in schizophrenic patients cortical grey
matter seems preferentially to be reduced (e.g., Falkai and
Bogerts 1986; Goldstein et al 1999; Suddath et al 1989),
the proportion of grey to white matter is in favour of white
matter in schizophrenic patients compared to control
subjects. As mentioned above, however, the relative
con-centration of PDE is about 40% higher in white compared
to grey matter (Buchli et al 1994). Therefore, the finding
of a reduced PDE cannot be explained solely by a
reduction of grey matter in schizophrenia.
The region of the basal ganglia has as yet only been
examined in two studies by MRS (Deicken et al 1995a;
Fujimoto et al 1992). Fujimoto et al (1992) reported
reduced PDE and increased PME on the left side in 16
neuroleptic-medicated schizophrenic patients as compared
to control subjects and interpreted these results as
indicat-ing higher anabolic activity of membrane phospholipids in
this region. Deicken et al (1995b), however, found no
differences in phospholipids in the basal ganglia when
comparing chronically ill, mostly neuroleptic-treated
pa-tients with control subjects. In the present study, PME was
lower in schizophrenic patients than in control subjects on
the left side, indicating decreased membrane anabolic
activity in schizophrenic patients, which is in contrast to
Fujimoto’s study. Because the patients included in our
study did not receive neuroleptics and those reported by
Fujimoto et al were long-term treated, the observed
differences might be due to an effect of neuroleptic
medication; however, previous studies addressing this
issue in the frontal lobes indicate that PDE increases rather
than decreases due to neuroleptic treatment (Volz et al
1999).
To our knowledge, this is the first study to examine
cerebellum by means of MRS in schizophrenic patients
compared to control subjects. In recent years, the
cerebel-lum has increasingly been suggested to play an important
role in the pathophysiology of schizophrenia (e.g.,
Katse-tos et al 1997). Thus, Andreasen et al (1998) attributed a
central role to the cerebellum in their model of “cognitive
dysmetria” as the underlying defect in schizophrenia. In
the right anterior cerebellar region, PDE was decreased in
patients with schizophrenia compared to control subjects;
however, in right cerebellar regions, schizophrenic
pa-Figure 2. T1-weighted scout image illustrating volume oftients showed lower PME values than control subjects.
These results cannot be explained as yet, but may point to
an alteration of phospholipid metabolism in patients with
schizophrenia, which is not restricted to the frontal lobe
but may include the cerebellum as well.
A reduction in PDE might also be due to an effect of
neuroleptic treatment via the inhibition of phospholipase
A
2(PLA
2) activity (Gattaz et al 1987, 1990). PLA
2leads
to the transformation of PC and PE to
lysophosphatidyl-choline and -ethanolamine, which are then further
de-graded to GPC and GPE, both major components of the
PDE peak. By inhibiting PLA
2activity, neuroleptics might
lower and thus normalize previously increased PDE levels
in medicated schizophrenic patients as suggested by
Stan-ley et al (1995). Neuroleptics have even been suggested to
cause a decrease of PDE in medicated patients compared
to control subjects (Volz et al 1997a, 1998); however,
PDE values were also reported to be lower in patients who
had not been medicated for 3 days up to 10 years (Volz et
al 1997b). In the present study, 7 out of 11 patients were
neuroleptic naive, a fact that speaks against a significant
influence of neuroleptic treatment on the measured PDE
values in schizophrenic patients.
The results confirm those of our earlier studies obtained
with a different measurement technique (ISIS) and a
conventional analyzing approach. They suggest that
mem-brane catabolism is decreased rather than increased in the
frontal lobes of schizophrenic patients. Therefore, our
findings do not confirm the original hypothesis of
in-creased membrane phospholipid metabolism (Pettegrew et
al 1991).
High-Energy Phosphates and Pi in Schizophrenic
Brain Tissue
Alterations of ATP and PCr in schizophrenia were only
present in the frontal lobes of schizophrenic patients, not
in other brain regions investigated. The frontal lobes have
frequently been suggested to play a major role in the
pathogenesis of schizophrenia (i.e., in the concept of
hypofrontality). Previous MRS studies also reported on
decreased PCr (Deicken et al 1994; Fujimoto et al 1992);
however, Williamson et al (1991) and Kato et al (1994,
1995) reported on increased PCr values in the frontal lobe
of schizophrenic patients. PCr and PCr/ATP were
in-creased in neuroleptic treated patients compared to control
subjects, whereas there was no difference between
neuro-leptic-free schizophrenic patients and control subjects
(Volz et al 1997b, 1998). It was therefore hypothesized
that neuroleptics might lead to a decrease of energy
Figure 3. StatisticalZmaps showing group differ-ences between control subjects and schizophrenic patients. The Z(1.69) map is projected onto the corresponding anatomic slice positioned as de-scribed in the method section and as illustrated in Figures 1 and 2. All highlighted voxels indicate higher values in healthy control subjects com-pared to schizophrenic patients. Different color values of the highlighted voxels indicate differentdemanding processes in the frontal lobe. With respect to
Pi, the majority of studies did not show significant
differences between control subjects and patients with
schizophrenia (Kegeles et al 1998), whereas Stanley et al
(1995) and Potwarka et al (1999) found decreased values
in schizophrenic patients.
The results of the present study confirm those of our
earlier study using the ISIS and not the CSI technique. PCr
and ATP did not show an increase in schizophrenic
patients but even appeared to be decreased. This difference
may be due to the higher proportion of drug-naive patients
in the present group of schizophrenic patients (64%) than
in our earlier sample (20%). According to the present
results it might be hypothesized that in neuroleptic-naive
patients there is a reduction in PCr and ATP, whereas in
patients who have been neuroleptic free for a relatively
short time there are no differences compared to control
subjects, and in patients treated with neuroleptics over a
long time there is an increase in high-energy phosphates in
brain tissue.
Various studies including postmortem examinations and
functional imaging studies have demonstrated an
impair-ment of energy metabolism in schizophrenia. These
changes were interpreted as suggesting reduced demand
for metabolic energy in the cells. In the present study, ATP
and PCr were lower in schizophrenic frontal lobes than in
control subjects, whereas there was no change of Pi
concentration. Our results therefore indicate that rather
than a reduced demand for energy an abnormality in
energy generation may be present in brain tissue of
unmedicated schizophrenic patients. Our results are in
accordance with positron emission tomography (PET)
studies that revealed a decreased metabolism in the frontal
cortex of schizophrenic patients, which is generally
as-sumed not to be related to neuroleptic medication
(Asar-now et al 1990; Cohen et al 1988). Our findings are also
consistent with biochemical evidence: In brain tissue,
energy is generated almost exclusively through oxidative
phosphorylation by means of the mitochondrial respiratory
chain. Cavalier et al (1995) reported a 43% reduction of
activity of one enzyme complex of the mitochondrial
respiratory chain in patients with schizophrenia, which
might lead to an impairment of energy generation. Further
supporting evidence comes from studies examining brain
metabolism during tasks that normally raise glucose
utilisation levels. Neuroleptic-free schizophrenic patients
had only attenuated increase in glucose metabolic rate in
an auditory discrimination task as compared to control
subjects (Asarnow et al 1990; Cohen et al 1987).
In summary, our results with respect to phospholipids
confirm alterations, but do not corroborate the membrane
phospholipid hypothesis of schizophrenia. The second
major finding of decreased ATP and PCr (and no
differ-ences in Pi) in schizophrenic patients compared to control
subjects could be interpreted as a marker of altered
oxidative phosphorylation mechanisms in schizophrenia.
This study was supported by a grant of the Eli Lilly Company. The authors are grateful to Dr. K.-J. Ba¨r for his help in recruiting patients for this investigation and thank Mrs. I. Zierz for her excellent help in preparing the English manuscript.
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