Proton magnetic resonance spectroscopy and thought disorder in
Ronald R. Seese, Joseph O'Neill⁎, Matthew Hudkins, Prabha Siddarth, Jennifer Levitt, Ben Tseng,
Keng Nei Wu, Rochelle Caplan
Division of Child and Adolescent Psychiatry, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1759, United States
a b s t r a c ta r t i c l ei n f o
Received 2 July 2010
Received in revised form 5 July 2011
Accepted 9 July 2011
Available online 27 August 2011
Magnetic resonance spectroscopy
Objective: Although magnetic resonance spectroscopy has identified metabolic abnormalities in adult and
childhood schizophrenia, no prior studies have investigated the relationship between neurometabolites and
thought disorder. This study examined this association in language-related brain regions using proton
magnetic resonance spectroscopic imaging (1H MRSI).
Method: MRSI was acquired bilaterally from 28 youth with childhood-onset schizophrenia and 34 healthy
control subjects in inferior frontal, middle frontal, and superior temporal gyri at 1.5 T and short echo time
(TR/TE=1500/30 ms). CSF-corrected “total NAA” (tNAA; N-acetyl-aspartate+N-acetyl-aspartyl-glutamate),
glutamate+glutamine (Glx), creatine+phosphocreatine (Cr+PCr), choline compounds (Cho), and myo-
inositol (mI) were assayed in manually drawn regions-of-interest partitioned into gray matter, white matter,
and CSF and then coregistered with MRSI. Speech samples of all subjects were coded for thought disorder.
Results: In the schizophrenia group, the severity of formal thought disorder correlated significantly with tNAA
in the left inferior frontal and superior temporal gyri and with Cr+PCr in left superior temporal gyrus.
Conclusions: Neurometabolite concentrations in language-related brain regions are associated with thought
disorder in childhood-onset schizophrenia.
© 2011 Elsevier B.V. All rights reserved.
Proton magnetic resonance spectroscopy (1H MRS) is a non-
invasive, in vivo neuroimaging technique that interrogates specific
aspects of neurochemistry. As such, MRS offers possibilities to better
understand underlying abnormalities and to develop therapeutics for
brain-related illnesses like schizophrenia. Most MRS studies on
schizophrenia (reviewed in Steen et al., 2005) have focused on the
largest1H MRS peak thought to indicate neuronal integrity (Urenjak et
al., 1993; Demougeot et al., 2001). About three-quarters of this
resonance's intensity is generated by the amino acid N-acetyl-aspartate
(NAA); the remaining quarter is due to its derivative N-acetyl-aspartyl-
glutamate (NAAG) (Pouwels and Frahm, 1997; Edden et al., 2007). In
this paper, we refer to the combined peak “total NAA” (tNAA). Other
metabolites of interest in1H MRS include glutamate plus glutamine
(Glx), creatine plus phosphocreatine (Cr+PCr), choline compounds
(Cho), and myo-inositol (mI).
Several MRS studies have found that absolute tNAA levels and the
ratios, tNAA/Cr+PCr and tNAA/Cho, are below-normal in the hippo-
campus (Maier et al., 1995; Bertolino et al., 1996; Deicken et al., 1998,
1999), anterior cingulate cortex (Yamasue et al., 2002; Yasukawa et al.,
2005; Jessen et al., 2006), and dorsolateral prefrontal cortex (Bertolino
et al., 1996; Callicott et al., 2000; Molina et al., 2007; Zabala et al., 2007)
of adult schizophrenia patients. Similar to these findings in adults, MRS
studies in childhood schizophrenia demonstrated lower tNAA/Cr+PCr
in the hippocampus and dorsolateral prefrontal cortex bilaterally
compared to healthy control children (Bertolino et al., 1998) and
significantly lower tNAA in left dorsolateral prefrontal cortex compared
both to children experiencing first episodes of psychosis and to healthy
Cr+PCr and Cho in the anterior middle cingulate cortex, non-
cingulate frontal cortex, and caudate head (O'Neill et al., 2004).
Above-normal Glx was also found in the right medial frontal lobe in
children at high genetic risk for schizophrenia (Tibbo et al., 2004).
Formal thought disorder, a symptom of childhood schizophrenia,
includes illogical reasoning and loosening of associations (Caplan et
al., 2000). Prior volumetric, functional magnetic resonance imaging
(fMRI), and H2
superior temporal (Shenton et al., 1992; McGuire et al., 1998;
Holinger et al., 1999; Kircher et al., 2003), middle frontal (Kircher et
al., 2003), and inferior frontal gyri (McGuire et al., 1998; Assaf et al.,
2006; Cerullo et al., 2007) in the thought disorder of adults with
schizophrenia. A recent fMRI study showed that the severity of
thought disorder in childhood schizophrenia was associated with
15O-PET studies demonstrated involvement of the
Schizophrenia Research 133 (2011) 82–90
⁎ Corresponding author at: Division of Child and Adolescent Psychiatry, Semel
Institute for Neuroscience and Human Behavior, 760 Westwood Plaza 58-227A, Box
175919, Los Angeles,CA 90024-1759, United States. Tel.: +1 310 825 5709; fax: +1 310
E-mail address: email@example.com (J. O'Neill).
0920-9964/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
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reduced cortical activity in the left inferior frontal gyrus and superior
prefrontal cortex and dorsal medial prefrontal cortex during the
semantic task, and in the insula during the syntactic task (Borofsky et
al., 2010). Combined, these studies suggest that cortical regions that
process language-related information may play a role in the thought
disorder of schizophrenia.
Thus, the exploratory proton magnetic resonance spectroscopy
investigation described here not only interrogated possible metabolite
differences in patients comparedtohealthy controls,but alsoexamined
the relationship between metabolite concentrations and severity of
thought disorder in childhood onset schizophrenia. We employed the
magnetic resonance spectroscopic imaging (MRSI) variety of MRS to
simultaneously examine multiple small (~1 cm3) volume elements
(“voxels”) each containing a high percentage of the targeted region-of-
interest (ROI) (Bertolino et al., 1999; Maudsley, 2002). Moreover, we
acquired MRSI at short-TE (30 ms), which allows for superior detection
of Glx and mI and also yields larger signal intensities for tNAA, Cr+PCr,
and Cho. We anticipated significantly different regional metabolite
levels in the superior temporal (Shenton et al., 1992; McGuire et al.,
1998; Holinger etal.,1999;Kircheret al., 2003), middlefrontal(Kircher
et al., 2003),andinferiorfrontal(McGuire etal.,1998;Assafetal.,2006;
healthy control subjects and that, within the schizophrenia group,
neurometabolite levels in these brain regions would vary in relation to
the severity of thought disorder.
The study included 28 children with schizophrenia (15 boys, 13
girls), aged 8.4–17.8 years (mean age±SD: 14.1±3.0), recruited from
community child psychiatryclinics.The28subjects werescreenedfrom
a total population of 207. Two additional subjects met all inclusion and
noexclusioncriteria,butcould not participatein the study becausethey
were severely ill and unable to get to or lie in the scanner. A
schizophrenia diagnosis was based on the Schedule for Affective
Disorders and Schizophrenia for School-Age Children, Present and
Lifetime Version (K-SADS-PL) (Kaufman et al., 1997), administered
2000). At the time of testing, the average duration of illness was
(mean±SD) 3.4±3.1 years. To be included in the study, these
children met DSM-IVcriteria for schizophrenia with onset of symptoms
by age 13. Exclusionary criteria included: (a) IQb70, (b) bilingualism,
(c) braces, (d) an underlying neurological disorder, (e) a metabolic
disorder, (f) a hearing disorder, (g) left handedness, and (h) psychosis
associated with an organic disorder or substance abuse. At the time of
the study, 23 patients were being treated with medications: 11 with
neuroleptics alone, 10 with neuroleptics plus non-neuroleptics, and 2
with non-neuroleptics alone. None of the healthy control subjects were
medicated. Neuroleptic dose was expressed as chlorpromazine equiv-
alents (CPZ) (mean±SD for schizophrenia group: 162.3±171.3).
6.4–17.2 years (mean age±SD: 11.5±2.9), who were recruited from
fourpublic and two private schoolsin the Los Angeles community. Both
healthy control and schizophrenia subjects completed face-to-face
evaluations and were screened for psychiatric, neurological, language,
and hearing disorders through a structured telephone interview with a
parent. We excluded any children manifesting symptoms of these
disorders in the past or after enrolling in the study.
This study was conducted in accordance with the policies of the
Human Subjects ProtectionCommittees of the Universityof California,
Los Angeles. Informed assent and consent were obtained from all
subjects and parents, respectively.
Structural MRI and1H MRSI were acquired together at 1.5 T with a
Siemens Sonata scanner using a standard quadrature head coil. Study
subjects were not sedated at the time of scanning. In addition to
localizer scout scans, structural MRI consisted of a pair of sagittal
spoiled gradient recalled (SPGR) sequences yielding high-resolution
T1-weighted whole-brain volumes. Two acquisitions were performed
separately and subsequently co-registered to each other and averaged
to diminish the contribution of any subject movement during
scanning. MRSI was acquired with PRESS (TR/TE=1500/30 ms,
NEX=4, slab thickness=9 mm, in-plane resolution=11×11 mm2)
from three slabs. Figs. 1–2 indicate slab positioning and anatomical
parameters used to make sure that all slabs were localized
approximately in the same brain regions across subjects. The first
two slabs (Fig. 1) were sagittal-oblique (roughly parallel to the
ipsilateral temple) in orientation and sampled the left and right peri-
Sylvian region including inferior frontal, superior temporal, and other
nearby cortex. The third slab (Fig. 2) was coronal-oblique and
sampled bilateral middle frontal (“dorsolateral prefrontal”) cortex,
mesial prefrontal cortex (pregenual anterior, anterior middle para-
cingulate cortex, or superior frontal cortex depending on individual
subject anatomy) and prefrontal white matter (mainly corona
radiata) lying in between. We excluded any subjects with clinically
relevant structural abnormalities.
Using software and protocols developed at the UCLA Laboratory of
Neuroimaging (Blanton et al., 2004; Taylor et al., 2005), regions-of-
interest (ROIs) consisting of cortex, superjacent sulcal CSF, and
subjacent white matter were sketched manually for bilateral inferior
frontal gyri (IFG), superior temporal gyri (STG), and middle frontal
gyri (MFG) using the sagittal T1-weighted MRI volume of each subject
in multiplanar view (Fig. 3). Independently, the entire brain was
segregated into gray matter, white matter, and CSF subvolumes
(Shattuck et al., 2001). By overlapping the ROIs with the whole-brain
gray matter, white matter, and CSF subvolumes, we divided each ROI
intothree separate “tissue-segmentedROIs.”All personnelinvolvedin
region measurement received extensive specialized training in
neuroanatomy. Intra- and interrater reliability were maintained at
an intraclass correlation coefficient of at least 0.90 for each ROI.
MRSI data were post-processed with the LCModel package
(Provencher, 2001), yielding metabolite values for major resonances
of tNAA (2.01 ppm), Glx (2.1–2.5 ppm), Cr+PCr (3.01 ppm), Cho
(3.24 ppm), and mI (3.54 ppm). Numerous minor metabolites,
particularly lipids and macromolecules, were included in the fit. Our
self-designed MRSI Voxel Picker (MVP) program(Fig. 4) (O'Neill et al.,
2006) was used for co-processing of MRI and MRSI data. For each
MRSI slab, MVP reconstructed the subject's whole-brain T1-weighted
gray matter, white matter, and CSF volumes, as well as the tissue-
segmented ROIs, which were manually delineated as described above,
into the space of the chosen MRSI slab. MVP then returned the tissue
content (both on whole-brain and ROI bases) and CSF-corrected
metabolite levels for each voxel in the slab and given ROI. Using
automated quality control features (aided by manual inspection), the
operator selected and averaged together all voxels within the ROI
meeting fixed tissue-content and spectral quality criteria. For each
ROI, values were averaged together for voxels containing at least 75%
by volume gray matter plus white matter, a signal-to-noise ratio of
three or greater, and a full width at half maximum (FWHM) less than
or equal to 0.1 ppm. Only metabolite peaks satisfying the LCModel
criterionof lessthan or equal to 20% standard deviationwere included
in the average. MVP implemented these quality-control criteria
automatically. Additionally, with the help of a guided user interface,
all voxels that passed these criteria were manually inspected by raters
blind to age, gender, and diagnosis. Voxels that showed significant
R.R. Seese et al. / Schizophrenia Research 133 (2011) 82–90
artifact (e.g., contaminating signals from proximal extracranial tissue)
were eliminated from analysis. Typically for both subject groups, 1–
4 voxels per ROI passed all quality-control criteria and were included
in the subject's average for that ROI.
2.2.2. Thought disorder
Formal thought disorder includes measures of impaired use of
language to formulate and organize thoughts and reflect higher-level
discourse deficits (Caplan et al., 2000). The listener has difficulty
making sense of the speech of children with formal thought disorder
because of unpredicted changes in the topic of conversation (e.g.,
loose associations) and unsound reasoning (e.g., illogical thinking).
The Story Game was administered to both control subjects and
patients to obtain adequate speech samples for rating formal thought
open-ended questions following each story. The children also chose to
Fig. 1. Sagittal-oblique (center), coronal (upper right), and axial-oblique (lower right) MRI depicting positioning of 9-mm thick MRSI slabs (one left hemisphere, one right) in peri-
Sylvian region. The PRESS volume was aligned parallel to the temple, set ~2 cm deep into the brain, sized to the subject's anatomy and rotated counterclockwise parallel to the
Sylvian fissure or beyond to sample inferior frontal (blue square) and superior temporal cortex. (Left)1H MR spectrum (TR/TE=1500/30 ms) from voxel sampled. Red trace is post-
acquisition fit of signal by scanner software; more precise fits were obtained offline using LCModel.
Fig. 2. Coronal-oblique (left), sagittal (right upper), and axial (right lower) MRI depicting positioning of 9-mm thick “dorsolateral prefrontal cortex” MRSI slab. The coronal-oblique
plane was acquired 43° counterclockwise to the genu-splenium line as seen in the sagittal plane. The PRESS volume was oriented parallel to the aforementioned coronal-oblique
plane then, in the sagittal plane, aligned parallel to the first cortical gyrus (paracingulate or superior frontal gyrus depending on subject) exterior to the rostral cingulate gyrus.
Within the coronal-oblique plane, the PRESS volume wasthen sized and positioned to encompassas much lateral cortex as possible without contacting extracranial lipids. In addition
to bilateral middle frontal (“dorsolateral prefrontal”) cortex, the PRESS volume samples medial prefrontal cortex and prefrontal white matter.
R.R. Seese et al. / Schizophrenia Research 133 (2011) 82–90
Two raters with no knowledge of the children's psychiatric
diagnosis coded videotapes of the Story Game with the Kiddie Formal
Thought Disorder Rating Scale (K-FTDS) which has operationalized
loose associations and illogical thinking for use in children (Caplan et
al., 1989). While speaking, the child with loose associations
unpredictably changes the topic of conversation without preparing
the listener for the upcoming change (i.e., Interviewer: What are
reasons not to like a kid? Child: I hate going to the beach). Illogical
thinking is coded when the child uses unsound reasoning during
causal (i.e., Interviewer: Why was the child in the story afraid? Child: I
am scared because my mother's name is Jane) and non-causal
utterances (i.e., Interviewer: What kind of mean things do kids do
to you? Child: They tease me. And then I know I am cool) or
contradicts him/herself (e.g., Interviewer: How did the story end?
Child: Peter woke up and was fast asleep).
Formal thought disorder scores are frequency counts of illogical
thinking and loose association ratings divided by the number of
sentences (clauses) made by the child. Higher loose associations and
illogical thinking scores represent more formal thought disorder. To
test for inter-rater reliability, the generalizability coefficients for
illogical thinking and kappa for loose associations were determined to
be 0.75 (SD=0.15) and 0.66 (SD=0.01), respectively (Caplan et al.,
The Wechsler Intelligence Scale for Children-III (Wechsler, 1974)
administered to both healthy control and schizophrenia subjects
generated Full Scale, Verbal and Performance IQ scores.
2.2.4. Statistical analyses
A summary measure of formal thought disorder (“formal thought
disorder score”) was used in all analyses of the relationship of thought
disorder with MRSI neurometabolite levels, as previously described
(Caplan et al., 2006). Thought disorder data from healthy control and
schizophrenia subjects in all our studies (n=234 healthy control,
n=119 schizophrenia) were used to derive the formal thought
disorder score as follows. We computed a linear discriminant function
for formal thought disorder, using illogical thinking and loose
associations. Discriminant analysis develops a criterion (the discrim-
inant function) to classify each subject into one of two groups.
Employing a jackknife method to estimate the probability that each
subject has schizophrenia, we obtained scores between 0 and 1. This
process is analogous to the propensity score proposed by Rosenbaum
and Rubin (Rosenbaum and Rubin, 1983). The discriminant functions
were then applied to the subjects in the current study. Thus, every
subject was assigned a formal thought disorder score. The propensity
scores ranged from 0 to 1, with higher scores denoting greater
thought disorder in subjects. These scores were then used as a
continuous measure of the degree of thought disorder in the healthy
controls and schizophrenia subjects.
For each ROI – namely IFG, MFG and STG – percent gray and white
matter volumes, as compared to total volume of all tissues, including
CSF, in the MRSI voxels were compared between the schizophrenia and
control groups using univariate analysis of covariance (ANCOVA).
Gender and age were used as covariates since the schizophrenia group
was significantly older (14.1±3.0 vs. 11.5±2.9 years; t(61)=3.49,
χ2=0.55, p=0.46) than the healthy control group. Even though the
schizophrenia subjects had a significantly lower mean IQ score
(mean±SD, 86.1±17.7) than the healthy control group (113.1±
group comparisons, as reduced IQ reflects an illness effect (Gochman
et al., 2005).
MRSI is a data-rich field-mapping neuroimaging modality. In this
study MRSI yielded five metaboliteendpoints in each of the three ROIs
for both hemispheres, which raises an issue of multiple comparisons.
We addressed this issue by carrying out repeated-measures multi-
variate analyses of variance (R-MANOVAs) prior to comparing
metabolite levels in individual ROIs between schizophrenia and
healthy control groups. Separate R-MANOVAs were performed for
Fig. 3. Delineation of inferior frontal (top), superior temporal (bottom right), and middle frontal (bottom left) gyri. Figures adapted from Blanton et al. (2004) and Taylor et al. (2005).
R.R. Seese et al. / Schizophrenia Research 133 (2011) 82–90
each cerebral hemisphere, where ROI (IFG, MFG, STG) was used as the
within-subjects factor and diagnostic group (schizophrenia, healthy
control) was used as the between-subjects factor. R-MANOVAs were
carried out across the five metabolite measures tNAA, Glx, Cr+PCr,
Cho, and mI. Significant main effect of diagnosis or diagnosis-by-ROI
interactions in the R-MANOVAs were deemed sufficient cause to
compare the corresponding metabolite levels in post-hoc ANCOVAs
covarying gender and age within the individual ROIs.
Associations between formal thought disorder scores and MRSI
regional metabolite levels in the patient group were examined using R-
MANOVA omnibus tests across the five metabolites tNAA, Glx, Cr+PCr,
between-subjects factors, respectively. Post-hoc thought disorder-
metabolite correlations (age-partialed Spearman) were calculated
within individual ROIs. Age and thecurrentneuroleptic dose, expressed
influences on thought disorder (Caplan et al., 2000). An alpha level of
0.05 was considered to be statistically significant for all tests.
Univariate ANCOVAs of the percent of gray matter or white matter
volume in the MRSI voxel between schizophrenia and healthy control
alsodemonstrated nosignificant between-groupdifferencesfor either
set of metabolites in both hemispheres. Table 1 summarizes average
metabolitevalues in all cortical regions studied for both schizophrenia
and healthy control groups.
For the schizophrenia group, the R-MANOVA omnibus testing
demonstrated a significant multivariate main effect of formal thought
disorder (F5,13=6.2, pb0.005) in the left hemisphere. There were no
significant R-MANOVA findings in the right hemisphere of the schizo-
Fig. 5 and Table 2 summarize age-partialed Spearman correlations
between metabolite levels and formal thought disorder score for the
schizophrenia group. In the left hemisphere controlling for age and
CPZ equivalents, the severityof thought disorderwas significantly and
positively correlated with tNAA in the superior temporal and inferior
frontal gyri and with Cr+PCr in the superior temporal gyrus. These
correlations enjoyed omnibus protection for multiple comparisons.
Corroborating the findings of prior PET (McGuire et al., 1998), fMRI
et al., 1992; Holinger et al., 1999), this study demonstrated that
increased metabolite levels (tNAA and Cr+PCr) in language-related
were associated with formal thought disorder. We found no significant
metabolite differences between the schizophrenia and control groups.
Unlike many studies of adult subjects with schizophrenia, schizo-
phreniform disorder, or at risk for schizophrenia (Choe et al., 1994;
Bertolino et al., 1996; Deicken et al., 1997; Bertolino et al., 1998;
Fig. 4. Guided-user interface for the MRSI Voxel Picker (MVP) software package developed at UCLA. A high-resolution T1 weighted whole-brain MRI volume from a subject with
childhood schizophrenia (upper right) is co-registered with a PRESS MRSI voxel grid (green; PRESS volume outlined lightly in white) and an anatomic region of interest (blue) from
the same subject. The user selects an arbitrary MRSI voxel (maroon) and the matching LCModel-fit MR spectrum appears (lower right). Voxel volume% gray matter, white matter,
andCSF(forwhole-brainandregion-of-interest);LCModel-derivedQC-parametersandmetabolite levels;andlevelscorrectedforvoxelwhole-brainCSFcontent also appear(lowerleft).
Example is for MRSI (1.5 T, TR/TE=1500/30 ms) acquired in a bilateral “dorsolateral prefrontal cortex” (DLPFC) slab. Left middle frontal cortex (L-MFG-gm) is the highlighted region of
R.R. Seese et al. / Schizophrenia Research 133 (2011) 82–90
Cecil et al., 1999; Block et al., 2000; Callicott et al., 2000; Bertolino et al.,
2001; Bustillo et al., 2001; Bertolino et al., 2003; Molina et al., 2005;
Jessen et al., 2006; Molina et al., 2006), but similar to several other
Szulc et al., 2005; Rusch et al., 2008), we did not observe below-normal
pediatric studies of subjects with or at risk for schizophrenia or
schizophreniform disorders (reviewed in Mehler and Warnke, 2002)
with five finding below-normal tNAA (Bertolino et al., 1998; Brooks et
al., 1998; Hagino et al., 2002; Pae et al., 2004; Stanley et al., 2007) and
three reporting no abnormality (Bartha et al., 1999; Wood et al., 2003,
vary with the majority of other studies: subject age, chronicity, MRS
voxel location and tissue composition, and use of metabolite ratios.
In terms of age, Bertolino et al. (Bertolino et al., 1996) and our two
prior studies (Thomas et al., 1998; O'Neill et al., 2004) investigated
subjects. Findings of tNAA/Cr+PCr abnormalities in children with
schizophrenia (Bertolino et al., 1998), similar to those shown in adults,
might reflect both the older mean age (16.4±1.7 years) and smaller
sample size (N=14) of the subjects with schizophrenia compared to a
mean age of 14.1±3.0 years and larger sample size of 28 in our study.
Regarding the chronicity of the illness, our subjects might not have
been ill long enough for the development of the metabolite abnormal-
ities found in adult schizophrenia. In support of this explanation, two
studies (Molina et al., 2005, 2006) found tNAA/Cr+PCr and tNAA/Cho
deficits in chronically ill but not in first-episode schizophrenia. As for
medication effects, there is evidence that neuroleptics, especially
atypical antipsychotics, increase cortical NAA (Heimberg et al., 1998;
Ende et al., 2000; Bertolino et al., 2001; Braus et al., 2001, 2002; Molina
patients, may have masked tNAA deficits.
Voxel location and tissue composition may also help explain the
differences across studies. For example, the frontal cortical tNAA
deficits in several studies (Deicken et al., 1997; Heimberg et al., 1998;
Block et al., 2000; Pae et al., 2004; Jessen et al., 2006) included regions
outside of the middle frontal gyrus. Regarding tissue composition, in
many cases (Choe et al., 1994; Brooks et al., 1998; Lim et al., 1998;
Molina et al., 2005, 2006) the voxel included white matter. This is
relevant because two groups (Lim et al., 1998); (Bartha et al., 1999)
suggest that low tNAA/Cr+PCr in schizophrenia may be restricted to
white matter or due to higher voxel white matter content. We
Mean±SD regional metabolite values in childhood onset schizophrenia and healthy
Metabolite Left hemisphereRight hemisphere
Inferior frontal gyrus
Middle frontal gyrus
Superior temporal gyrus
Metabolite levels in Institutional Units (IU). No significant between-group differences
Fig. 5. Sample Spearman correlations between MRSI tNAA (NAA+NAAG; upper) and
Cr+PCr (lower) in left superior temporal gyrus (Institutional Units, IU) and formal
thought disorder controlling for age and chlorpromazine (CPZ) equivalents in
schizophrenia (blue diamonds) and control subjects (red squares). pb*0.05, **0.01
(after repeated-measures MANOVA). FTD = Formal Thought Disorder propensity score
between 0 and 1 represents the estimated probability that a subject will exhibit thought
Spearman correlations between MRSI metabolites and formal thought disorder score in
the childhood onset schizophrenia group.
Inferior frontal gyrus
Middle frontal gyrus
Superior temporal gyrus
tNAA: N-acetyl-aspartate+N-acetyl-aspartyl-glutamate, Glx: glutamate+glutamine,
Cr: creatine+phosphocreatine, Cho: choline compounds, mI: myo-inositol. Significant
correlations in bold are protected from multiple comparisons by repeated-measures
MANOVA, other significant correlations not protected. All correlations partialed for age,
correlations within the schizophrenia group also partialed for neuroleptic dose in
chlorpromazine (CPZ) equivalents.
R.R. Seese et al. / Schizophrenia Research 133 (2011) 82–90
delineated the middle frontal gyri of all the subjects in our study
according to a standardized procedure using voxels that contained
≥75% middle frontal gyrus. Moreover, volume percent gray matter
and white matter did not differ significantly between the patient and
healthy control groups in these voxels (data not shown). Thus,
metabolite values in our study may more accurately represent the
middle frontal gyrus and may be less influenced by between-group
differences in tissue content than those of other studies.
Additionally, many studies detecting tNAA deficits (Choe et al.,
1994; Cecil et al., 1999; Block et al., 2000; Callicott et al., 2000; Molina
et al., 2005; Jessen et al., 2006; Molina et al., 2006, 2007) expressed
their findings as the metabolite ratios tNAA/Cr+PCr and/or tNAA/
Cho. However, similar to our study, studies that found no metabolite
deficits (Bartha et al., 1999; Sigmundsson et al., 2003; Szulc et al.,
2005; Rusch et al., 2008) employed absolute metabolite analyses.
Effects observed with ratios can be attributable to either the numerator
or the denominator (e.g., to tNAA or to Cr+PCr). One group (Wood et
al., 2003), in fact, observed above-normal tNAA/Cr+PCr in adolescent
and adult subjects at ultra-high risk for schizophrenia, an effect they
attributed to Cr hypometabolism.
Overall, the inconsistent findings and methodological differences
across studies imply that frontal cortical tNAA may not necessarily be
diminished in childhood-onset schizophrenia. Our study of subjects
with childhood-onset schizophrenia acquired MRSI at high spatial
resolution and short-TE from voxels with carefully defined anatomic
localization and tissue composition. Its findings provide additional
evidence against below-normal tNAA levels in middle and inferior
frontal gyri and superior temporal gyri in pediatric schizophrenia.
Some studies have found cortical atrophy of the superior temporal
gyrus in adult schizophrenia (Shenton et al., 1992; Holinger et al.,
1999). Such atrophy, however, may occur through mechanisms that
do not necessarily imply a drop in tNAA, e.g., uniform loss of all
neurons and glia, selective loss of glia, and/or dehydration. Studies
with larger sample size are needed to replicate these results.
To our knowledge, this is the first study to investigate associations
between neurometabolites and thought disorder in schizophrenia. A
positive correlation was found between tNAA and thought disorder.
This is somewhat counterintuitive, as tNAA has been posited as a
neuronal marker (Urenjak et al., 1993; Demougeot et al., 2001) and
higher levels might be indicative of healthier neurons. As discussed
above, however, the presence of a tNAA deficit in schizophrenia is by
no means assured, particularly in children or early in the disease. The
significant correlations found in this study were illustrated in the left
superior temporal and inferior frontal gyri. This corroborates previous
structural and functional imaging work demonstrating that anatom-
ical and functional abnormalities in these language-related regions
are associated withthought disorder (Shentonet al., 1992; McGuire et
al., 1998; Holinger et al., 1999; Kircher et al., 2003; Assaf et al., 2006;
Cerullo et al., 2007). Functional MRI findings that normal topic
maintenance (the opposite of loose associations) and use of logical
reasoning(in contrast to illogical thinking)in conversation are related
to cortical activation of the same regions lend further support to the
finding that metabolites in these regions are correlated with thought
disorder (Caplan and Dapretto, 2001). All of the above observations
suggest that neurochemical imbalances in language-related cortical
regions are associated with illogical thinking and loosening of
associations in childhood-onset schizophrenia.
The specific role of tNAA and Cr+PCr, however, in thought
disorder requires extensive future biochemical investigation. NMDA
receptors are a necessary element for associative memory formation
(Tsien, 2000) and thus might be involved in the normal associative
chains engaged in thought and speech (Kircher, 2008; Hall et al.,
2009). Additionally, they have been proposed to be hypoactive in
schizophrenia (Coyle et al., 2002, 2003). NAAG, a component of the
tNAA peak (Pouwels and Frahm, 1997; Edden et al., 2007),
antagonizes NMDA receptors (Westbrook et al., 1986; Bergeron et
al., 2005), suggesting that future studies should delineate the
biochemistry of NAAG in schizophrenia. Specifically, microgliosis, an
already demonstrated phenomenon of schizophrenia (Bayer et al.,
1999; van Berckel et al., 2008), may contribute to the above NMDA
receptor antagonism since microglia contain high levels of NAAG
(Passani et al., 1998). PCr levels are also high in microglia (de Gannes
et al., 1998), which may help explain the observed Cr+PCr
association with thought disorder if the microglia are activated in
childhood onset schizophrenia. Thus, this study's correlations em-
phasize that the neurochemistry of language-related cortical regions
is associated with thought disorder, and they also suggest specific
biochemical pathways for future analysis.
Limitations of the study include residual partial voluming (even at
1.1 cm3voxel size) as well as the age and gender differences between
the schizophrenia and control subjects. Because the concentration of
NAA changes as the brain matures (Kadota et al., 2001), age and
gender differences (although statistically covaried) may contribute to
our findings. Psychotropic medication effects (as described above)
other than partialed-out CPZ equivalents, is a further limitation. Our
calculations of CPZ equivalents addressed atypical antipsychotic
doses, but it should be noted that the precise conversions for atypicals
to CPZ equivalents is disputed in the literature (Woods, 2003). While
IQ wasnot statistically covariedbecauseof its assumedillness effect, it
might have nevertheless influenced the study's findings because
lower IQ is related to below-normal tNAA (Jung et al., 1999), above-
normal Cho (Jung et al., 1999), and more thought disorder in adult
patients with schizophrenia (Willis-Shore et al., 2000). A further
limitation was MRSI acquisition at 1.5 T since acquisition at 3 T might
have enabled us to separately quantitate the NAA and NAAG peaks
with the aid of specialized pulse sequences (Edden et al., 2007).
Despite these limitations, the present findings highlight that neuro-
metabolite levels in language regions of the brain are associated with
formal thought disorder in childhood onset schizophrenia. Although
preliminary, they also imply a need to further investigate the possible
abnormal in the brain of schizophrenia patients with thought disorder.
Role of funding source
This study was supported by grants MH067187 (R.C.) and NS32070 (R.C.). The NIH
had no further role in the study design; in the collection, analysis and interpretation of
R.R.S., J.O.N., and R.C. designed the experiments, analyzed the data, and prepared
the manuscript. J.O.N. and P.S. performed statistical analyses. R.R.S., M.H., J.L., B.T., and
K.N.W. were involved with data acquisition and processing. All authors have
contributed to and have approved the final manuscript.
Conflict of interest
None of the authors declare any conflicts of interest with this study.
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