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4, 1996
An In Vivo Proton Magnetic
Resonance Spectroscopy
Study of Schizophrenia
Patients
with a set of sagittal and coronal 'H by a Lorentzian-to-Gaussian transfor- rithm (Marquardt 1963). The a priori
MR images as shown in figure 1. The mation to enhance the apparent spec- knowledge included information on
dashed lines in figure 1 represent the tral resolution (Ferrige and Lindon chemical shifts, relative amplitudes,
anterior (a), posterior (b), lateral (c), 1978). The MR signal was then zero and linewidths of the peaks for each
and medial (d) surfaces of the three filled, Fourier transformed, and metabolite. The quantified 1 H
dimensional VOI (white box). The phased with Oth order and 1st order metabolites included NAA, gluta-
magnetic field homogeneity was (< one dwell period). No spline mate, glutamine, gamma-amino-
maximized with a global head shim function was applied to the baseline. butyric acid (GABA), aspartate, N-
followed by a localized shim on the The data were processed on a per- acetylaspartylglutamate (NAAG),
VOI. The interpulse repetition time sonal computer using the NMR-286 PCr + Cr, Chot, glucose, taurine,
was 1,500 ms, and 450 acquisitions software (Soft Pulse Software, Box scy//o-inositol, and two macromole-
were averaged. For each water sup- 504, Guelph, Ontario, N1H 6K9, cule resonances at 2.12 and 2.9 ppm
pressed 'H spectrum acquired, a Canada). (Kauppinen et al. 1992; Behar and
water unsuppressed ] H spectrum There is a direct relationship Ogino 1993; Behar et al. 1994; Stanley
was also collected (55 acquisitions) between the area under a spectral et al. 1995a). To calculate the relative
by setting the amplitudes of the peak and the concentration of the metabolite levels, the integral value
CHESS pulses to zero voltage. Fur- metabolite associated with that peak. of the phased water peak from the
ther details of the spectroscopy pro- Therefore, Gaussian functions were unsuppressed water 'H spectrum,
tocol are discussed by Stanley et al. fitted to each spectral peak between which represents the total MR visible
(1995a). 1.88 and 3.45 ppm (parts per million) water content in the VOI, was used
and the areas under the functions as an internal standard to normalize
Spectral Processing. The data files were used to calculate the 'H the metabolite peak areas (Chris-
were coded such that the operator metabolite levels. To resolve the issue tiansen et al. 1993). The quantified
had no knowledge of the subject's of quantifying complex 'H spectra areas of the spectral peaks were not
status. A time domain deconvolution with multiple peaks that overlap corrected for any attenuation due to
technique, QUALITY (de Graaf et al. each other (de Graaf and Bovee 1990; spin-spin (TJ or spin-lattice (T,)
1990), was first applied to the MR Provencher 1993; Stanley et al. relaxation; therefore the quoted rela-
signal to restore the spectral line- 1995a), a priori knowledge was incor- tive metabolite levels have arbitrary
shapes to pure Lorentzian. The time porated into a frequency domain units. Complete details on the imple-
domain signal was then multiplied nonlinear least-squares-fitting algo- mentation of the a priori knowledge
600 SCHIZOPHRENIA BULLETIN
Results
C)
A typical processed in vivo TH spec-
trum acquired from the left dorsolat-
eral prefrontal region of a control is
shown in figure 2. The spectrum con-
tains no dominating broad spectral
resonances that underlie the baseline
noise over the 1.88 to 3.45 ppm spec-
tral region. The signal-to-noise ratio
(i.e., the signal of the NAA peak at
2.02 ppm over the root mean square
of the noise) is approximately 80 (fig-
ure 2), which is adequate to reliably
quantify the spectrum (Stanley et al.
Sagittal and corona) 1H magnetic resonance Images with the 2 x 2 x 2 cm3 VOI (the white box) posi-
tioned In the left dorsolateraJ prefrontal region. The dotted lines in (a) and (b) represent position of the 1995a). The quantification of this
corona) Images In (c) and (d) while the dotted lines In (c) and (d) represent the position of the sagittal spectrum is displayed in figure 2b as
Images in (a) and (b). a sum of all spectral peaks of the
metabolites superimposed on the
into the fitting routine and on testing group (i.e., patient and control), age, acquired spectrum. The difference
the efficacy of quantifying in vivo 'H gender, education level, and parental between the two is shown as the
MR spectra has been reported by education level as independent pa- residual plot in figure 2b.
Stanley et al. (1995a) rameters. This method enabled us to Instructions to perform specific
compare differences in the NAA, glu- physical or psychological tasks were
Statistical Analysis. A two-tailed t- tamate, glutamine, PCr + Cr, and not given to the subjects during the
test was performed to determine any Cho, levels between patient and con- collection of the data. Therefore, in
significant differences in age, educa- trol groups while adjusting for the general, the observed metabolite lev-
tion level, and parental education covariables of age, gender, education els reflect steady-state values at rest.
level when comparing the combined level, and parental education level. The absolute difference in metabolite
patients with the control group. The Probability values of < 0.05 were con- levels of NAA, glutamate, glutamine,
quantified ] H MR parameters were sidered statistically significant and a PCr + Cr, and Cho, between the three
modeled in a stepwise multiple threshold value of p = 0.2 was used to patient groups and controls is shown
regression analysis with subject enter or remove independent vari- in figure 3. In the controls, the coeffi-
VOL. 22, NO. 4, 1996 601
suppressed
a) water peak
y\ /^'<'W»^oAA/V»/*-vV'>***V«^^
Figure (a) contains a typical processed in vrvo 1H MR spectrum from the left dorsolateral prefrontal region acquired with the STEAM (stimulated echo acquisi-
tion mode) sequence (TE = 20 ms) and (b) shows the same spectrum with the frequency region expanded. The result of modeling the spectrum with a priori
The spectral peaks are N-acetyiaspartate (NAA), glutamate (G)u), glutamlne (Qln), gamma-amino-butyric acid (GABA), NAACHJ (methyl resonance from the
NAA molecule), aspartate (Asp), phosphocreatjne plus creatine (PCr + Cr), chollne-containing compounds (Cho,), glucose (Gte), myixnosrto) (myo-lns),
scyflo-inositol (scyflo-lns), and taurine (Tau). ppm = parts per million.
cients of variation for NAA, PCr + in vivo concentration levels resulted patients with the control group. The
Cr, and Cho, were approximately 10 in coefficients of variation i 30 per- glutamate levels tended to be greater
percent, and the coefficients of varia- cent (Stanley et al. 1995a), and there- in the acute medicated patients com-
tion for glutamate and glutamine fore these ^H metabolites were not pared with the controls; however,
were 22 and 33 percent, respectively. tested in the statistical analysis. this difference did not reach signifi-
Quantifying the metabolite levels of There were no significant differ- cance (p = 0.10 where age and gender
GABA, aspartate, NAAG, taurine, ences when comparing the ^H were the covariates). In the paired t-
scy//o-inositol, and glucose was con- metabolite levels of the first-episode, test for the eight drug-naive patients
sidered less reliable because their low drug-naive and acute medicated who were also examined as med-
602 SCHIZOPHRENIA BULLETIN
I— Controls
5 r
^SSI Drug-naive
Acute medicated
2 Chronic medicated
B II \
0) -1
0) -2
o
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CD
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-4
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< -5
NAA Glu Gin' PCr+Cr Cho.
NAA = AAacetytaspartate; Glu = glkitamate; Gin « glutamlne; PCr + Cr = phosphocreatine plus creatine; Cho, = choline-containing compounds; error bars
are ± 1 standard deviation.
'Values are relative to that of the controls (i.e., mean metabolite level of patient - mean metabolite level of controls).
'Significantly different when comparing the chronic medicated patients and the controls (p » 0.013).
icated patients, glutamine levels (p = medicated patients (p = 0.013 where patients together, the length of ill-
0.020) and SAPS scores (p = 0.006) age, gender, education level, and ness, length of time on medication,
were both significantly reduced in parental education level were the equivalent dose of chlorpromazine,
the on-medication measures com- covariates). Age, education levels, and SANS and SAPS scores were not
pared with the premedication mea- and parental education levels of the significantly correlated (after apply-
sures. When comparing the metabo- patients with schizophrenia were not ing a Bonferroni correction for multi-
lite levels of the chronic medicated significantly different from the con- ple comparisons) with the levels of
patients and the control group, the trols. These results are summarized NAA, glutamate, glutamine, PCr +
only significant difference was the in table 1 and figures 3 and 4. Cr, or ChOj, except for a significant
increase in glutamine in the chronic Combining the schizophrenia positive correlation between the glu-
VOL. 22, NO. 4, 1996 603
famine level and the length of illness al. 1995a). While the function of NAA Involement of the Glutamatergic
(r = 0.53, p = 0.0007, figure 5). The in the central nervous system (CNS) System in Schizophrenia. Based on
glutamine level and age correlation has not been elucidated (Birken and in vitro studies, the glutamate con-
was not significant in the controls. Oldendorf 1989), it has been estab- centration in the frontal cortex is
lished that NAA is found exclusively approximately 9.0 mmol/kg wet
in mature neurons and neuronal weight (w. wt.) and the concentration
Discussion
processes (Matalon et al. 1988; Birken of glutamine is approximately two-
Assessing Neuronal Damage and and Oldendorf 1989; Urenjak et al. fold to threefold smaller (Perry et al.
Loss. NAA levels in the left dorso- 1993). Decreased NAA levels have 1971; Erecinska and Silver 1990).
lateral prefrontal region did not differ been observed by MRS in numerous Using the identical acquisition and
between any of the patient groups cerebral pathologies involving neu- processing protocol as this study, our
and the controls. In terms of the total ronal cell damage and loss (Arnold et group has reported glutamate and
concentration of free amino acids in al. 1990; Menon et al. 1990; Graham glutamine concentration levels in the
mammals, NAA is second only to et al. 1992; Klunk et al. 1992; Cendes left dorsolateral prefrontal region of
glutamate (Tallan 1957). This is et al. 1994). Recently, recovery of approximately 9.4 and 4.8 mmol/kg
reflected on the dominant spectral NAA levels has been reported in w. wt., respectively (Stanley et al.
feature of NAA (figure 2) that gives patients with acute CNS damage (De 1995a). This would suggest that the
rise to a reliable measure (Stanley et Stefano et al. 1995). The absence of a bulk of the in vivo concentration of
604 SCHIZOPHRENIA BULLETIN
10 -
c/T • _ o o
'c • o
13 • o
8 -
I
CO
• * * o
1CD
_ l
CD
I* o
o
0
iS
O *
o ^
' o
1 1 1 I 1 I . . . 1 . . . . 1 . . . . 1 . . . . 1 . . . . 1
0
0 10 15 20 25 30
Length of Illness (years)
Scatter plot of the glutamine levels of the drug-naive (*), acute medicated (O), and chronic medicated (0) patients. The solid Hne represents the regression
Bne ( r » 0.53, p = 0.0007).
glutamate and glutamine is observ- Silver 1990). The larger glutamate Attwell 1990). For instance, following
able with this short echo MRS tech- compartment has been described as a the release of glutamate by calcium-
nique. This observation is consistent slow turnover pool of glutamate (i.e., dependent exocytosis, excess gluta-
with the 'H MRS study by Kaup- the metabolic pool) derived from glu- mate is transported into glia and is
pinen and Williams (1991), in which cose precursors, and the smaller glu- subsequently converted to glutamine
79 percent of the total glutamate con- tamate compartment as a raster by glutamine synthetase. Following
centration was estimated as MR-visi- turnover pool of glutamate (i.e., the release from glial cells, glutamine
ble. Approximately 80 percent of the neurotransmitter pool) that serves as may then enter the presynaptic neu-
total glutamate concentration is a substrate to glutamine (Erecinska ron and serve as a precursor for
found in glutamatergic neurons and Silver 1990). Glutamine plays an glutamate by mitochondrial glu-
(large compartment) and approxi- important role in the recycling of the taminase. Overall, the localization of
mately 2 to 20 percent in glial cells neurotransmitter glutamate in the glutamine is found predominantly in
(small compartment) (Erecinska and smaller compartment (Nicholls and glial cells (Erecinska and Silver 1990;
VOL. 22, NO. 4, 1996 605