Article

1646

Am J Psychiatry 157:10, October 2000

Selective Relationship Between

Prefrontal N-Acetylaspartate Measures

and Negative Symptoms in Schizophrenia

Joseph H. Callicott, M.D.

Alessandro Bertolino, M.D.

Michael F. Egan, M.D.

Venkata S. Mattay, M.D.

Frederick J.P. Langheim, B.S.

Daniel R. Weinberger, M.D.

Objective: Certain cognitive, behavioral,

and emotional deficits (so-called negative

symptoms) in patients with schizophrenia

have often been attributed to prefrontal

cortical pathology, but direct evidence for

a relationship between prefrontal neu-

ronal pathology and negative symptoms

has been lacking. The authors hypothe-

sized that an in vivo measure of prefron-

tal neuronal pathology (N-acetylaspartate

[NAA] levels) in patients with schizophre-

nia would predict negative symptoms.

Method: Proton magnetic resonance

spectroscopic imaging (

1

H-MRSI) and rating

scales for negative and positive symp-

toms were used to study 36 patients with

sc hiz o p hre nia . M a gne t ic res o na nc e

spectra were analyzed as metabolite ra-

tios, and parametric correlations were
performed.

Results: A regionally selective negative
correlation was found between prefrontal
NAA-creatine ratio and negative symptom
ratings in this group of patients with
schizophrenia.

Conclusions: Lower prefrontal NAA—
and by inference greater neuronal pathol-
ogy—predicted more severe negative
symptoms in patients with schizophrenia.
These data demonstrate a relationship
between an intraneuronal measure of
dorsolateral prefrontal cortex integrity
and negative symptoms in vivo and rep-
resent further evidence for the involve-
ment of the dorsolateral prefrontal cortex
in negative symptoms associated with
schizophrenia.

(Am J Psychiatry 2000; 157:1646–1651)

T

he early course of schizophrenia is often dominated

by florid psychotic symptoms such as hallucinations or
delusions (positive symptoms), but persistent difficulties
with emotional expression (flattened affect), social com-
munication (alogia), and motivation (avolition) often be-
come the most debilitating aspects of schizophrenia as
time passes (1–3). These latter, so-called negative symp-
toms are often most prominent in patients with schizo-
phrenia who have poorer premorbid adjustment, earlier
onset, and greater illness chronicity (4). Negative symp-
toms remain relatively unresponsive to most antipsy-
chotic medications (perhaps even to atypical drugs such
as clozapine) (5). Furthermore, negative symptoms inter-
fere with psychosocial rehabilitation efforts and often per-
sist unchanged (if not worsening) throughout the course
of the illness (6).

The persistent, invariant quality of negative symptoms

might lead one to predict that their etiopathogenesis might
be easier to identify than positive symptoms, which often
vary unpredictably in quality, duration, and amount. Be-
cause the negative symptoms in patients with schizophre-
nia are phenomenologically similar to the disruptions of
affect, cognition, and motivation in neurological patients
with frontal lobe lesions (7, 8), it has been speculated that

these symptoms arise from dysfunction of the frontal
lobes, particularly the dorsolateral prefrontal cortex (9–11).

Previous attempts to correlate negative symptoms with

indirect measures of cortical neuronal pathology—includ-
ing structural imaging, neuropsychological tests of dorso-
lateral prefrontal cortex function, regional cerebral blood
flow (rCBF), and evoked electrophysiological responses—
have had some success (e.g., reference 12), but replication
has been inconsistent. For example, frontal lobe structural
measurements have been found to predict negative symp-
toms in some studies (9, 13–16), but not others (17–21).

Patients with schizophrenia show greater impairments

on tests of cognition thought to rely on intact dorsolateral
prefrontal cortex function, such as the Wisconsin Card
Sorting Test (22–24) and working memory tasks (25), and
these deficits have been associated with negative symp-
toms (26–30). Moreover, in some reports, reduced dorso-
lateral prefrontal cortex blood flow at rest also predicted
greater negative symptoms (31–35). Neurophysiological
measures of dorsolateral prefrontal cortex function have
also been reported as abnormal in schizophrenia, includ-
ing abnormal eye tracking (36), abnormal EEG patterns
(37), and disruption of the normal coherence between the
dorsolateral prefrontal cortex and other brain regions (38).
A sizable functional neuroimaging literature, although at

Am J Psychiatry 157:10, October 2000

1647

CALLICOTT, BERTOLINO, EGAN, ET AL.

times contradictory (39), has largely reported reduced
physiological capacity of the dorsolateral prefrontal cortex
in response to cognitive challenge (e.g., references 40–44).

None of these indirect measures, however, speaks to the

integrity of prefrontal neurons per se; the different find-
ings might also reflect activity in prefrontal inputs. For ex-
ample, Sabri et al. (35) found that although negative symp-
toms correlated with bilateral frontal rCBF, negative
symptoms also correlated with bilateral temporal, cingu-
late, left parietal, basal ganglia, and thalamic rCBF at rest.

In contrast to the modest in vivo evidence for a rela-

tionship between negative symptoms and frontal lobe
dysfunction, evidence of dorsolateral prefrontal cortex
neuronal pathology is compelling. Postmortem neuro-
pathological human studies have found prefrontal gray
matter abnormalities, including reduced neuropil volume
with increased neuronal density in the dorsolateral pre-
frontal cortex (45), decreased inhibitory input from pre-
frontal chandelier cells onto dorsolateral prefrontal cortex
pyramidal neurons (46), and decreased abundance and
activity of interneurons (47, 48). In both medicated and
untreated patients with schizophrenia, studies using pro-
ton magnetic resonance spectroscopy (

1

H-MRS and

1

H-

MRSI) have repeatedly found evidence of dorsolateral pre-
frontal cortex neuronal pathology reflected in reduced
concentrations of the intraneuronal chemical N-acetylas-
partate (NAA) (49).

Based on

1

H-MRSI and postmortem evidence of dorso-

lateral prefrontal cortex neuronal pathology in schizo-
phrenia, we hypothesized that if negative symptoms arise
from such pathology, NAA measures should correlate with
negative symptom ratings. In particular, larger reductions
in dorsolateral prefrontal cortex NAA, and by inference
greater neuronal pathology, should predict more severe
negative symptoms. Since it is possible with

1

H-MRSI to

obtain NAA from many regions of brain, one would not
predict similar regional correlations between NAA and
negative symptoms if the cellular basis of the symptoms
were regionally selective.

Method

We studied 36 patients with schizophrenia diagnosed accord-

ing to DSM-IV criteria. There were six women (five were right-
handed) and 30 men (26 were right-handed) with a mean age of
34 years (SD=8). Patients were recruited from the inpatient wards
of the National Institute of Mental Health (NIMH) at St. Eliza-
beths Neuropsychiatric Research Hospital, Washington, D.C., and
the Warren Magnuson Clinical Center, Bethesda, Md. In addition,
patients were studied as part of the NIMH Clinical Brain Disor-
ders Branch Sibling Study of Schizophrenia, Bethesda, Md.

The majority of patients (30 of the 36) were receiving a stable

dose of antipsychotic medication at the time of scanning. The six
medication-free subjects had been off all medicines for a mini-
mum of 14 days. The remaining, medicated patients were evenly
divided between typical (N=15) and atypical (N=15) antipsychotic
treatment, with no acute change in dose for at least 14 days before
scanning. The patients studied were chosen from a larger group
of patients with schizophrenia on the basis of the presence of dor-

solateral prefrontal cortex regional NAA measures that were of
high quality as well as ratings that were obtained immediately af-
ter scanning.

Before participating, all subjects underwent a diagnostic inter-

view with the Structured Clinical Interview for DSM-IV (50). In
addition, patients completed a screening questionnaire regarding
past substance abuse and neurological illnesses followed by a full
neurological examination and a structural magnetic resonance
imaging (MRI) clinical examination. Exclusion criteria included
history of active or recent (less than 6 months) substance abuse,
history of clinically significant neurological illness, or abnormali-
ties on MRI examination. After discussion of the risks and bene-
fits of the MRI procedure and questioning to determine assent
and understanding of the MRI procedure, all subjects gave writ-
ten informed consent. The MRI protocol (91-M-0124) was ap-
proved by the institutional review board of the NIMH Intramural
Program.

For a comparison group, we used our database of healthy sub-

jects of similar age and sex. The comparison subjects were 28
women (27 were right-handed) and 45 men (34 were right-
handed) men with a mean age of 32.2 (SD=8.1). The same inclu-
sion and exclusion criteria were applied to all healthy comparison
subjects.

Metabolite spectra from multiple brain regions were acquired

by using

1

H-MRSI as previously described (51). A 1.5-tesla GE

Signa scanner (GE Medical Systems, Milwaukee) was used. The
technique acquires four 15-mm-thick oblique axial slices (TR=
2200 msec, TE=272 msec, voxel size=7.5

×

7.5

×

15 mm). All sub-

jects included in the analysis were free from substantial move-
ment artifact. Spectra were analyzed by using in-house software
(A. Barnett) and then converted to ratios for further analysis. Re-
gions of interest were then drawn by using T

1

-weighted scans ac-

quired immediately after the

1

H-MRSI acquisition with the group

identity blinded as described previously (49). Region of interest
analysis was used to quantify NAA, creatine (creatine plus phos-
phocreatine), and choline-containing compounds.

In addition to the dorsolateral prefrontal cortex, metabolite ra-

tios were obtained from the orbitofrontal cortex, hippocampal
area (inclusive of the amygdala), thalamus, putamen, anterior
and posterior cingulate, superior temporal gyrus, prefrontal
white matter, occipital cortex, and centrum semiovale for both
patients and healthy comparison subjects. Due to the oblique an-
gle of acquisition chosen to maximize coverage of the hippocam-
pal area, the parietal cortex was not imaged. Furthermore, where
metabolite ratios could not reliably be determined, they were not
entered into the statistical analyses (thus, the numbers are re-
ported separately for all correlations in addition to the p values).

Ratios of NAA to creatine, NAA to choline-containing com-

pounds, and choline-containing compounds to creatine were
used for the correlation analysis. To determine if there were re-
gional abnormalities in these ratios, the patients were compared
with the normal subjects (N=73) by using a three-way repeated
measures analysis of variance (ANOVA) with region of interest
and hemisphere as the repeated measures followed by post hoc
comparisons.

Following the MRI scanning session, subjects were rated with

the Scale for the Assessment of Negative Symptoms (SANS) (52)
and the Psychiatric Symptom Assessment Scale (53) by a psychia-
trist ( J.H.C.) who was blind to the

1

H-MRSI data. Because the

ANOVA did not identify a significant interaction of diagnosis by
region of interest by side, product moment correlations (r) were
computed between mean right and left hemisphere NAA-creatine
ratio, NAA-choline ratio, and choline-creatine ratio in each region
of interest and summary scores for the total SANS and the posi-
tive and negative subscales of the Psychiatric Symptom Assess-
ment Scale. On the basis of our previous hypotheses of selective
reduction in the dorsolateral prefrontal cortex (49), all analyses in

1648

Am J Psychiatry 157:10, October 2000

PREFRONTAL N-ACETYLASPARTATE

other regions were corrected by the method of Bonferroni to
avoid type I error (corrected p=0.0005 [0.05

÷

99] [three metabolite

ratios

×

11 regions of interest

×

three rating scales]). Within the

text, statistical significance for regions outside of the dorsolateral
prefrontal cortex will be reported as a corrected p.

Results

The patients with schizophrenia had significant bilateral

reductions in NAA/creatine (main effect for diagnosis: F=
5.7, df=1, 98, p=0.02; diagnosis by region: F=2.3, df=10, 908,
p=0.01; diagnosis by region by hemisphere: F=0.6, df=10,
908, p=0.80). Overall, post hoc comparisons revealed sig-
nificant reductions only in the dorsolateral prefrontal cor-
tex (F=4.7, df=1, 132, p=0.03) and hippocampal area (F=
13.6, df=1, 126, p

<

0.001), as found previously (54–57).

There were no other statistically significant regional differ-
ences found. On average, the patients were moderately af-
fected in terms of negative symptoms (SANS mean score=
17.6, SD=13.7, and Psychiatric Symptom Assessment Scale
negative subscale mean score=4.5, SD=3.1), and overall pa-
thology (Psychiatric Symptom Assessment Scale total
mean score=22.2, SD=11.1). These two rating instruments
were significantly correlated with each other (r=0.70, N=36,
p

≤

0.001). On the remaining items of the Psychiatric Symp-

tom Assessment Scale (i.e., positive symptoms), the pa-
tients were mildly to moderately ill (mean=16.2, SD=9.2).

There was a significant relationship between dorsolat-

eral prefrontal cortex NAA measures and negative symp-
toms. A negative correlation was found between dorsolat-
eral prefrontal cortex NAA/creatine and SANS total scores
(Table 1 and Figure 1) and the negative symptoms subscale
of the Psychiatric Symptom Assessment Scale (r=–0.43, N=
36, p=0.01). Neither dorsolateral prefrontal cortex NAA/
choline nor the dorsolateral prefrontal cortex choline/cre-
atine correlated with negative symptom measures.

Measures of positive symptoms did not correlate with

any regional measure of NAA/creatine, NAA/choline, or
choline/creatine. In spite of a between-group difference in

NAA/creatine in the hippocampal area, there were no sig-
nificant relationships between hippocampal area NAA/
creatine and negative symptoms. However, there were
negative correlations between SANS score and NAA/creat-
ine in regions outside of the dorsolateral prefrontal cortex
that share dense interconnectivity with the dorsolateral
prefrontal cortex, including the thalamus and anterior
cingulate (Table 1). Although these regional correlations
did not survive statistical correction for multiple compari-
sons, future studies aimed specifically at these regions
should be pursued.

Discussion

We found a regionally selective relationship between ev-

idence of dorsolateral prefrontal cortex neuronal pathol-
ogy (as reflected in NAA measures) and negative symptoms
in patients with schizophrenia. No regional measures pre-
dicted positive symptoms in this group of patients. These
patients showed significantly lower NAA in only two re-
gions—the dorsolateral prefrontal cortex and hippocam-
pal region—when compared with normal subjects. Al-
though hippocampal NAA measures were not found to
predict negative symptoms, we did find evidence of in-
volvement of a larger network in the production of nega-
tive symptoms. Specifically, the thalamus and anterior cin-
gulate were implicated by negative correlations between
NAA/creatine and negative symptom ratings (Table 1).

Because these regions did not differ significantly be-

tween patients and healthy comparison subjects in this
study, we cannot rule out the possibility that these repre-
sent spurious or secondary correlations. Nonetheless, their
relationship to negative symptoms may arise from their
dense interconnectivity with the dorsolateral prefrontal
cortex. As a post hoc test of this supposition, we performed

TABLE 1. Correlations Between Brain Regional NAA-Creat-
ine Ratio and Negative Symptoms in 36 Patients With
Schizophrenia

Region of Interest

Correlation of Regional

NAA-Creatine Ratio With Total
Score on Scale for Assessment

of Negative Symptoms

r

p

Corrected p

a

Thalamus (N=35)

–0.55

0.001

0.10

Putamen (N=35)

0.04

0.83

Hippocampal area (N=33)

–0.13

0.47

Superior temporal gyrus (N=35)

–0.25

0.15

Orbitofrontal cortex (N=36)

–0.17

0.31

Dorsolateral prefrontal cortex (N=36) –0.48

0.003

Anterior cingulate (N=36)

–0.50

0.002

0.20

Posterior cingulate (N=34)

–0.07

0.69

Occipital cortex (N=33)

–0.32

0.07

Frontal white matter (N=36)

–0.12

0.48

Centrum semiovale (N=35)

–0.40

0.02

1.00

a

Corrected for multiple comparisons in regions outside of the dorso-
lateral prefrontal cortex.

FIGURE 1. Relationship Between the Dorsolateral Prefron-
tal Cortex NAA-Creatine Ratio and Negative Symptoms in
36 Patients With Schizophrenia

a

a

The ratio is the mean of the right and left hemispheres. The dotted
lines indicate 95% confidence intervals (Table 1). Dorsolateral pre-
frontal cortex NAA was inversely related to negative symptoms (r=
–0.68, N=30, p

<

0.001). Some patients had overlapping values.

Ratio of N-Acetylaspartate to Creatine in

the Dorsolateral Prefrontal Cortex

2.0

–5

5

15

25

35

45

55

65

2.4

2.8

3.2

3.6

T

otal Scor

e on Scale f

o

r

Assessment of

Ne

g

a

tiv

e Symptoms

Am J Psychiatry 157:10, October 2000

1649

CALLICOTT, BERTOLINO, EGAN, ET AL.

a forward stepwise multiple regression that included the
dorsolateral prefrontal cortex, thalamus, and anterior cin-
gulate NAA/creatine. Partial correlations revealed that nei-
ther the thalamus (partial correlation=–0.30, p=0.10) nor
the anterior cingulate (partial correlation=–0.21, p=0.20)
predicted negative symptoms (according to SANS scores)
once the relationship between dorsolateral prefrontal cor-
tex NAA/creatine and SANS scores was factored out. None-
theless, these data suggest that multiple regions interact to
produce negative symptoms.

The shared variance between dorsolateral prefrontal

cortex pathology and negative symptoms was not large—
approximately 23%. A number of factors may have contrib-
uted to this modest predictive value. Both

1

H-MRSI and

psychiatric rating scales are inherently imprecise measures
(49, 52). In addition,

1

H-MRSI has a relatively low spatial

resolution (about 1.4 cc/voxel with our method). Finally,
although NAA is found almost exclusively within neurons
(58), the exact functional implications of reduced NAA lev-
els remain unclear. NAA is found in highest concentration
in pyramidal neurons in the dorsolateral prefrontal cortex
(59). In addition to serving as a storage form of aspartate,
NAA is in the metabolic pathway for glutamate and, al-
though not thought to be a neurotransmitter per se (60), is
capable of inducing calcium influx by means of N-methyl-

D

-aspartic acid receptors in vitro (61). Thus, the measure-

ment of NAA concentration in vivo is likely to reflect a
number of potentially variable factors.

NAA reductions are clearly linked to a number of neuro-

logical disorders involving neuronal pathology (60) and
may be reversed by treatment in some instances (62–64).
Thus, schizophrenia and its negative symptoms are not
likely caused by NAA reductions per se, but, rather, NAA
reductions are a marker for some other dorsolateral pre-
frontal cortex neuronal abnormality. NAA reductions are
also not likely the result of a gross loss of neurons in the
dorsolateral prefrontal cortex, given the wealth of post-
mortem human data suggesting that neuronal dropout is
not characteristic (65). To the extent that NAA concentra-
tions likely correlate with the overall volume of neuronal
soma and processes, the findings of reduced NAA mea-
sures are consistent with postmortem evidence of de-
creased neuropil and soma size (45, 66).

Reduced NAA measures in the dorsolateral prefrontal

cortex seem to predict a variety of phenomena associated
with manifest illness. In addition to the present findings,
dorsolateral prefrontal cortex NAA measures have been
found to predict activation within the distributed neural
network subserving working memory for patients with
schizophrenia (67), to predict baseline and amphetamine-
induced striatal dopamine levels (68, 69), and to predict
the loss of dorsolateral prefrontal cortex neuronal effi-
ciency during a parametric working memory task (70). This
particular predictive power of dorsolateral prefrontal cor-
tex NAA measures is both striking and puzzling. However,
given the widespread connectivity of dorsolateral prefron-

tal cortex neurons throughout the brain, these data may
collectively suggest that certain dorsolateral prefrontal cor-
tex neurons represent a population of effector neurons that
act within larger cortical networks to determine many of
the manifest state variables of schizophrenia.

In our patients, correlations between dorsolateral pre-

frontal cortex NAA measures and those in the thalamus
and anterior cingulate support the supposition of a larger
network, but this finding remains to be tested in future
data samples. If greater dorsolateral prefrontal cortex neu-
ronal pathology (lower NAA) can be used to predict greater
negative symptoms, then these data not only will lend cre-
dence to the supposition that negative symptoms arise
from dorsolateral prefrontal cortex neuronal pathology
but also may provide an additional clinical tool for the as-
sessment of neuropsychiatric patients.

Presented in preliminary form at the Fourth International Confer-

ence on Functional Mapping of the Human Brain, June 7–12, 1998,
Montreal. Received Oct. 12, 1999; revision received April 19, 2000;
accepted April 20, 2000. From the Clinical Brain Disorders Branch, In-
tramural Research Program, NIMH, National Institutes of Health. Ad-
dress reprint requests to Dr. Callicott, Clinical Brain Disorders Branch,
Intramural Research Program, NIMH, National Institutes of Health,
10 Center Dr., Rm. 4D-20, MSC 1389, Bethesda, MD 20892-1389;
[e-mail] (e-mail).

The authors thank Joseph Frank, M.D., Jeff Duyn, Ph.D., and Alan

Barnett, Ph.D., for providing expertise, equipment, and software for
the analysis of

1

H-MRSI data. They also thank the patients and staff

of the NIMH inpatient units and the NIMH Clinical Brain Disorders
Branch Sibling Study of Schizophrenia. Rebecca Rakow, B.S., Karin
Weidenhammer, B.S., and Philip Weissbrod, B.S., provided invaluable
assistance in data collection and analysis.

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