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Schizophrenia Research
D2/D3 dopamine receptor binding with [F-18]fallypride in
thalamus and cortex of patients with schizophrenia
Monte S. Buchsbaum a,c,e,*, Bradley T. Christian b,d, Douglas S. Lehrer b,c,
Tanjore K. Narayanan b, Bingzhi Shi b, Joseph Mantil b, Eileen Kemether a,
Terrence R. Oakes d, Jogeshwar Mukherjee b,e
a Department of Psychiatry, Mt. Sinai School of Medicine, 1 Gustave Levy Place, Box 1505, New York, NY 10029, USAb Boonshoft Schizophrenia Center/Wallace–Kettering Neuroscience Institute, USA
c Wright State University Department of Psychiatry, USAd Waisman Laboratory for Brain Imaging, University of Wisconsin-Madison, USA
e Department of Psychiatry and Human Behavior/University of California-Irvine (Dr. Buchsbaum emeritus), USA
Received 27 December 2005; received in revised form 11 March 2006; accepted 17 March 2006
Available online 19 May 2006
Abstract
Background: Abnormalities in the dopaminergic system are implicated in schizophrenia. [F-18]fallypride is a highly selective,
high affinity PET ligand well suited for measuring D2/D3 receptor availability in the extrastriatal regions of the brain
including thalamus, prefrontal, cingulate, and temporal cortex, brain regions implicated in schizophrenia with other imaging
modalities.
Methods: Resting [F-18]fallypride PET studies were acquired together with anatomical MRI for accurate coregistration and
image analysis on 15 drug naı̈ve schizophrenics (10 men, 5 women, mean age 28.5 years) and 15 matched controls (9 men, 6
women, mean age 27.4 years). Dopamine D2/D3 receptor levels were measured as binding potential (BP). The fallypride BP
images of each subject were spatially normalized and subsequently smoothed for group comparison. Measures of significance
between the schizophrenic and control groups were determined using statistical parametric mapping (SPM). The medial dorsal
nucleus and pulvinar were also traced on coregistered MRI for detailed assessment of BP in these regions.
Results: The thalamus of patients with schizophrenia had lower [F-18]fallypride BP than normal controls and this was the brain
area with the greatest difference (range �8.5% to �27.2%). Left medial dorsal nucleus and left pulvinar showed the greatest
decreases (�21.6% and �27.2% respectively). The patients with schizophrenia also demonstrated D2/D3 BP reduction in the
amygdala region, cingulate gyrus, and the temporal cortices.
Conclusions: These findings suggest that drug naı̈ve patients with schizophrenia have significant reductions in extrastratial D2/
D3 receptor availability. The reductions were most prominent in regions of the thalamus, replicating other studies both with
0920-9964/$ - see front matter D 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2006.03.042
* Corresponding author. Mount Sinai School of Medicine, Box 1505, 1 Gustave Levy Place, New York, NY 10029, USA. Tel.: +1 212 241
5294; fax: +1 212 423 0819.
E-mail address: [email protected] (M.S. Buchsbaum).
85 (2006) 232–244
M.S. Buchsbaum et al. / Schizophrenia Research 85 (2006) 232–244 233
high affinity D2/D3 ligands and consistent with FDG-PET studies, further supporting the hypothesis of thalamic abnormalities
in this patient population.
D 2006 Elsevier B.V. All rights reserved.
Keywords: Dopamine receptor; Thalamic association nuclei; Laterality; Limbic system
1. Introduction
The clinical efficacy of neuroleptics and their main
action of blocking D2 receptors suggested that PET
studies of dopamine receptor ligands would reveal
differences between patients with schizophrenia and
normal volunteers. The first study by Comar et al.
(1979) with [C-11]chlorpromazine revealed a wide-
spread pattern of cortical and subcortical uptake due
to nonspecific binding. Subsequent studies with more
specific ligands such as [C-11]methylspiperone
(Wong et al., 1986) and [C-11]raclopride (Farde et
al., 1990) focused exclusively on the striatum and
had variable results (see review (Tune et al., 1993)).
The development of high-affinity ligands such as [C-
11]FLB 457 (Olsson et al., 1999) and [F-18]fall-
ypride (Mukherjee et al., 1999) opened the possibility
of examining other brain regions identified as
abnormal in functional activation imaging with
PET, SPECT, EEG, and fMRI (see recent reviews)
— the prefrontal cortex (Molina et al., 2005)
(Andreasen et al., 1997; Buchsbaum and Hazlett,
1998) (Eyler et al., 2004; Suzuki et al., 2005),
thalamus (Andreasen, 1997; Buchsbaum et al., 1996;
Hazlett et al., 2004), cingulate gyrus (Haznedar et al.,
2004; Quintana et al., 2004; Yasuno et al., 2005), and
temporal lobe (Eyler et al., 2004) (Eyler et al., 2004).
The medial dorsal nucleus (MDN), the largest
association nucleus in the thalamus, has its major
reciprocal connections with the prefrontal cortex, and
is thus a prime candidate region for a schizophrenia
diathesis. When thalamic nuclei were traced on
coregistered MRI, decreased metabolic rates were
found in the MDN in patients with schizophrenia in
comparison to normal controls (Hazlett et al., 2004).
This region is also known to have cell loss and
volume reduction in patients with schizophrenia in
postmortem studies (Byne et al., 2002; Danos et al.,
2005; Pakkenberg, 1992; Popken et al., 2000; Young
et al., 2000). In an early postmortem study, Oke
suggested elevated thalamic dopamine as important
in schizophrenia (Oke et al., 1992).
Autoradiographic and PET studies confirm moder-
ate density D2/D3 sites in the MDN. Epidepride
binding was about twice as high in the MDN than
lateral dorsal or geniculate nuclei in autoradiographic
studies (Rieck et al., 2004). PET studies have also
confirmed thalamic D2/D3 binding (Farde et al.,
1997; Mukherjee et al., 2002; Okubo et al., 1999;
Rieck et al., 2004; Sedvall and Farde, 1995; Suhara et
al., 2002; Talvik et al., 2003). There was markedly
higher D2/D3 binding in the MDN and anterior nuclei
of the thalamus than other thalamic areas (Okubo et
al., 1999) and nearly twice as high in medial than in
lateral thalamus in normal controls in PET measure-
ment with [C-11]FLB 457 (Talvik et al., 2003).
Several studies in patients with schizophrenia with
high affinity ligands have found low D2 binding in the
medial regions of the thalamus. After dividing the
thalamus into lateral and medial segments, low D2
binding was found in previously untreated patients
with schizophrenia (Talvik et al., 2003). Using
a thalamic map derived from our earlier report
(Buchsbaum et al., 1996), Yasuno found diminished
[C-11]FLB 457 binding in the ventral medial and
posterior subregions of the thalamus in 10 never
previously medicated schizophrenics in comparison to
19 normal controls (Yasuno et al., 2004). Another
PET study with [C-11]FLB 457 (Suhara et al., 2002)
found significantly decreased binding potential in the
anterior cingulate with a smaller effect in the whole
thalamus (3.31 in never previously medicated patients
and 3.58 in normals was p =0.06, approximate effect
size 0.79).
The goal of this work was to use the high affinity,
D2/D3 dopamine selective PET radioligand, [F-
18]fallypride to confirm and extend these earlier
findings in never-medicated patients with significance
probability mapping and anatomical tracing of the
major nuclei of the thalamus.
M.S. Buchsbaum et al. / Schizophrenia Research 85 (2006) 232–244234
2. Methods
2.1. Subjects
2.1.1. Schizophrenia and related conditions
Fifteen psychotic patients (10 men; 5 women;
mean age, 28.5; SD, 8.9; 15 right-handed) were
recruited from the greater Dayton, Ohio, area, and
were evenly divided between inpatients and out-
patients. After complete description of the study, all
subjects completed a verbal binformed consent post-
test.Q All participants passed this test and gave written
informed consent. Subjects underwent evaluation
using the Comprehensive Assessment of Symptoms
and History (CASH) (Andreasen et al., 1992) Brief
Psychiatric Rating Scale (BPRS, 18-item version) and
Table 1
Demographic and psychopathological data of healthy control subjects and
Parameter
Sex, no. M/F
Race, no. white/African American/Afro-Caribbean/ Mixed
Age, y ( p =71)
Education, y ( p =11)
Social classb p =66
Handedness, no. right/left-handed
Primary Diagnosis, DSM-IV (no. by diagnosis)
Schizophrenia, paranoid type
Schizophrenia, undifferentiated typec
Schizoaffective disorder
Schizophreniform disorderd
Secondary Diagnosis, DSM-IV (no. by diagnosis)
Alcohol abuse
Schizotypal personality disorder
Duration of illness, median/mean, wk
Locus of care at time of study, no. inpatient/outpatient
BPRS total score
GAF score (past month)
AIMSe, no. with total scoresN0 (mean score of positive subjects)
Medication status
Neuroleptic naı̈ve, number
Almost neuroleptic naı̈vef
a All figures represent mean values (standard deviation) unless otherwisb Hollingshead Two Factor Index of Social Position (Hollingshead and
represents data for 11 remaining ill subjects.c Two subjects initially diagnosed as schizophreniform were determinedd In both patients, symptoms fully remitted within six months; one pati
return of psychotic symptoms; the other patient relapsed almost two yeare Symptom scores are rated on a 0–5 scale, with 0=none, 1=questionaf Three previously-medicated subjects reported lifetime neuroleptic exp
evaluation; (2) one intramuscular haloperidol hydrochloride injection one
more than 10 in a single year, most recent dosage three weeks before study
the time of the study.
Abnormal Involuntary Movement Scale (AIMS)
(Psychopharmacology-Research-Branch, 1976), and
were diagnosed according to DSM-IV (American-
Psychiatric-Association, 1994) by a staff psychiatrist
(D.S.L.). Patients were neuroleptic naı̈ve (n =12) or
almost neuroleptic naı̈ve (n =3, defined in Table 1).
All patients were negative for drugs of abuse on a
urine screen at the time of the scan and smoking was
prohibited on the scan day. Subject characteristics are
summarized in Table 1. Following study evaluation,
all subjects were immediately referred for psychiatric
treatment.
2.1.2. Controls
Fifteen normal control subjects (9 men; 6 women;
mean age, 27.4; SD, 7.9; 14 right-handed) were age-
patients with schizophrenia
Controlsa (n =15) Patientsa (n =15)
9/6 10/5
12/0/2/1 12/3/0/0
27.4 (7.9) 28.5 (8.9)
14.7 (2.1) 13.3 (2.4)
33.1(7.8) 35.4 (18.0)
14/1 15/0
NA
7
4
2
2
1
1
NA 26/166 (257.3)
NA 7/8
NA 52.7 (9.1)
NA 30.3 (9.7)
2 (1.5)
NA
12
3
e specified.
Redlich, 1958); data for one ill subject was unobtainable; mean
at follow-up to be schizophrenic.
ent has remained continuously on antipsychotic medication without
s later after having been off of antipsychotics for one year.
ble, 2=mild, 3=moderate, 4=marked, and 5=severe symptoms.
osure of: (1) no more than five doses, several years prior to study
week prior to study; and, (3) 28 lifetime doses of risperidone, never
. All of these doses would have negligible pharmacological action at
M.S. Buchsbaum et al. / Schizophrenia Research 85 (2006) 232–244 235
and sex-matched to experimental subjects. Controls
underwent psychiatric assessment performed by a
staff psychiatrist (D.S.L.). Participating subjects had
no history of psychiatric illness, substance use
disorder, clinically significant head trauma, or neuro-
logical disease. Controls did not significantly differ
from ill subjects with respect to sex, age ( p =0.71),
race, handedness, education ( p=0.11), or family-of-
origin socioeconomic status ( p =0.66). Control sub-
ject characteristics are summarized in Table 1. The
results of PET scans measuring [F-18]fluorodeoxy-
glucose (FDG) uptake in the MDN of a subset of these
patients has recently been reported (Lehrer et al.,
2005).
2.2. PET Scans
All subjects refrained from alcohol, smoking, and
caffeine 4 h before the PET scanning session. The
PET scans were acquired using an ECAT EXACT
HR+ scanner (Brix et al., 1997) in 3D mode. The
subjects were placed in the scanner in the supine
position, with the brain centered in the axial field of
view. A 5 minute transmission scan was first acquired
using a 68Ge/68Ga rod source to correct for the
attenuation of photons. The head was fixed with a
piece of surgical tape. Dynamic acquisition of the PET
dynamic data was initiated with the 30 s bolus
injection of [F-18]fallypride. The radiopharmaceutical
was produced according to previously reported
methods (Mukherjee et al., 1995) at high specific
activity (N2800 Ci/mmole) with a dose of 0.7 mCi/10
kg (range of 3.7–7.4 mCi). In an effort to increase
subject compliance and minimize subject discomfort,
a split session PET imaging protocol was imple-
mented during the uptake of radiotracer. A split
session PET involved 60 min of scanning (5 one-
minute frames, 5 two-minute frames, 9 five-minute
frames), 10-min break, and 50 min of scanning (10
five-minute frames) for a total PET imaging session of
2 h. The data were reconstructed using the ECAT v7.2
OSEM (3 iterations, 16 subsets) following the
corrections applied for attenuation, normalization,
and scatter. Prior to further data processing the
dynamic frames were spatially aligned using the
AIR 3.08 software (Woods et al., 1992) to correct
for patient motion. The cerebellum was used to
represent the reference region (with negligible specific
ligand-receptor binding) for the data analysis. Multi-
ple, circular regions of interest were placed over outer
lobules of the cerebellum, covering two 3.5 mm thick
transaxial planes.
2.3. Data analysis
2.3.1. Binding potential parametric image analysis
Parametric images of [F-18]fallypride binding
potential were generated to permit group comparison
over the entire volume of the brain using the SPM
software. For this work, apparent binding potential is
described as:
BP ¼ f2BmaxV ;
KD
where, f2 is the unbound fraction of radioligand in the
free cellular space, BmaxV is the available receptor
density, and KD is the equilibrium dissociation
constant.
The BP images reported here were calculated using
a multilinear variation (Ichise et al., 2002) of the
Logan (Logan et al., 1996) distribution volume ratio
(DVR). This multilinear method of BP calculation
was shown to be least sensitive to noise in the
dynamic PET data. This model employs the use of a
tissue reference region (cerebellum) to represent the
kinetics of unbound radioligand in the tissue (Cun-
ningham et al., 1991; Logan et al., 1996). Reference
tissue methods were also found suitable for mapping
of the thalamus with fallypride by Siessmeier et al.
(2005). The functional equation in the multilinear
form is given as:
Z T
0
C tð Þdt ¼ DVR
Z T
0
Cref tð Þdt þ Cref Tð Þk¯ 2
� �
þ bWC Tð Þ;
where C(t) is the PET measured time varying voxel
concentration, Cref(t) is the reference (cerebellum)
concentration, DVR is the distribution volume ratio,
k̄2 is the average tissue-to-plasma efflux constant
and bW is a constant of integration and T representing
the time midpoint of each PET frame. The advantage
of this method is that the integration of the tissue
concentration (C(t)) tends to reduce the parameter
bias introduced by the higher noise levels present in
M.S. Buchsbaum et al. / Schizophrenia Research 85 (2006) 232–244236
the voxel-by-voxel data. The apparent binding poten-
tial is then calculated as BP=DVR-1.
2.3.2. Statistical approach
Since we hypothesized a thalamic decrease in BP
we first evaluated the mean BP within targeted traced
regions of interest with repeated measures MANOVA
using the traditional p b0.05 criterion. Then to
document the exact shape of the thalamic area
showing significance, we examined significance
probability maps of the brain through the thalamic
level with threshold at p b0.005, uncorrected, using
the SPM package. Lastly we explored the entire brain
at a corrected p threshold level of 0.05 and with a
color bar scale indicating the p value between p b0.05
and the lowest p value. This allows readers to chose
the appropriate p value for their own application.
Other authors have published region of interest data
outside the thalamus including the anterior cingulate
cortex (Suhara et al., 2002) and temporal cortex
(Tuppurainen et al., 2003). Any replication needs to
be at p b0.05; it would introduce Type II bias if we
tested our own hypothesized region, the thalamus at
p b0.05 but required the anterior cingulate findings of
Suhara (Suhara et al., 2002) to be tested at 0.005 or
lower. Similarly, since we have already reported the
traced medial dorsal nucleus to be low in volume and
metabolic activity in two other samples (Byne et al.,
2001; Kemether et al., 2003), it would provide Type II
error bias to present only 0.005 rather than 0.05
significance probability mapping of the MDN.
2.3.3. ROI based analysis
One of the authors with established reliability
(E.K.) traced the whole thalamus, MDN and pulvinar
on raw unresliced and coded MRI anatomical images
exactly as previously reported (Byne et al., 2001;
Kemether et al., 2003). These tracings were used to
create binary mask images. Unsmoothed fallypride
images were coregistered to these anatomical images
by first coregistering the early integrated fallypride
data (0–5 min) using the SPM registration algorithm
(Friston, 1995) then applying this transformation
matrix to the BP image as above. Binding potential
within these areas and the whole thalamus not
including the MDN or pulvinar were obtained by
applying the binary mask images to the [F-18]fally-
pride BP images.
2.3.4. Spatial normalization for exploratory signifi-
cance probability mapping
For many radiotracer studies, such as [O-15]water
and FDG, it is possible to directly transform an image
of integrated radiotracer uptake into a normalized
coordinate system. However, for [F-18]fallypride BP
images there are several preprocessing steps that need
to be performed. The highly selective D2/D3 binding
of [F-18]fallypride results in an image dominated with
striatal information and only limited information in
the cortical regions. As a result the current algorithms
for image coregistration and normalization fail when
trying to match [F-18]fallypride with MRI, FDG PET
or water PET. We have previously reported a
comparison of various methods to spatially normalize
the data (Christian et al., 2004). For the work reported
here, the following steps were undertaken to spatially
normalize the [F-18]fallypride BP images:
1. Create an image of the first several minutes of
[F-18]fallypride uptake (following the bolus), this
image represents primarily the delivery (i.e. un-
bound) of fallypride throughout the brain, also
mixed with significant bound fallypride in the high
D2/D3 density regions such as the striatum.
2. Spatially normalize the data from 1) to the
Montreal Neurological Institute (MNI) FDG tem-
plate, using 7�9�7 basis functions, 16 nonlinear
iterations.
3. Apply the transformation matrices from 2) to the
BP parametric images. Sum the transformed BP
images.
4. Spatially normalize the individual BP parametric
images to the image created in 3).
5. Sum the transformed images from 4) to create the
fallypride BP template. This template can then be
used for all spatial normalizations. The MNI image
dimensions were chosen for the size of the
bounding box of the output image.
6. Smooth all of the normalized images (8 mm filter)
before the application of SPM statistical analysis
but not for the application of the anatomical
tracings.
For many radioligands, the first several minutes of
tracer uptake in the brain represents primarily ligand
delivery, i.e. flow, thus a template representing blood
flow such as [O-15]water would be the most suitable.
Table 2
Mean thalamic nuclei binding potential
Structure Normals Patients with schizophrenia % change
Left Right Left Right Left Right
Medial dorsal 2.18 2.15 1.7a 1.84 �21.6% �14.4%Pulvinar 1.14 1.16 0.83b 1.04 �27.2% �10.3%Residual thalamus 2.57 2.36 2.25 2.16 �12.5% �8.5%a t =2.66, df =24, p =0.014.b t =3.54, df =24, p =0.0016.
M.S. Buchsbaum et al. / Schizophrenia Research 85 (2006) 232–244 237
However, with [F-18]fallypride, the binding in the
high D2/D3 receptor density regions such as the
striatum is so rapid, that the first several minutes of
PET data is actually dominated by radioligand in the
bound state (Christian et al., 2004). For this reason, we
have chosen to use the FDG template for the spatial
transformation of step 2) into standardized space.
2.3.5. SPM analysis
Following spatial normalization and spatial smooth-
ing (8 mm) of the [F-18]fallypride BP images,
statistical parametric maps of the groups was per-
formed using SPM2 (http://www.fil.ion.ucl.ac.uk/spm/
spm2.html). A schizophrenic and control group com-
parison was made using the two-sample t-test criterion.
There was no global scaling applied in the analysis, as
the BP images are directly comparable. The t-test
results were then displayed on the MNI template with a
color bar to indicate level of significance.
Fig. 1. [F-18]Fallypride binding potential in the brain, p b0.005 in
normalsNpatients with schizophrenia. Significant area is most prominent in
of the striatum. MNI z level from SPM program. Images shown in standa
3. Results
3.1. MDN and pulvinar
Patients with schizophrenia had lower BP in the
MDN (1.78F0.53) than normal volunteers (2.16F0.36; t=2.15, df =1,24, p =0.041, mean of left and
right sided ROI). This was also true for the pulvinar
(0.94F0.27 vs. 1.15F0.18, t =2.27, p=0.03). How-
ever the remainder of the thalamus after removal of
the areas of the medial dorsal and pulvinar showed
no significant group difference (2.21F0.92 vs.
2.47F0.46, t =0.89, p =0.37). The entire thalamus
did differ (1.34F .36 vs. 1.58 F21, t=2.12, p =0.04).
When the medial dorsal and pulvinar were entered
into a diagnostic group (normal, patient)� structure
(MDN, pulvinar)�hemisphere (right, left) there was a
main effect of group (F =5.17, df =1,24, p =0.032)
and a group�hemisphere interaction (F =5.58,
yellow on MNI anatomical brain background. Yellow indicates
medial dorsal and pulvinar with a third area in the posterior portion
rd orientation (image left is brain right hemisphere).
Fig. 2. 3D (orthogonal) view of [F-18]fallypride binding differences between normals and patients with schizophrenia. The color yellow
indicates normalsNpatients with schizophrenia. The second row with the p b0.05 probability level reveals areas in the cingulate (indicated by an
arrow in the first column) also found significant by Suhara et al., 2002). The SPM maps are overlaid on spatially normalized images of summed
data (0–5 min fallypride representing early radioligand delivery and binding for anatomical reference).
M.S. Buchsbaum et al. / Schizophrenia Research 85 (2006) 232–244238
df =1,24, p =0.027) indicating a larger left hemisphere
than right hemisphere difference between normals and
schizophrenics but higher order interactions with
diagnostic group were not significant (see Table 2).
Since low BP in the centromedian and posterior
subregions of the thalamus was found associated
with high BPRS positive symptoms earlier (Yasuno
et al., 2004), we examined the BPRS subscale
scores vs. right+ left BP value correlations in our
own data. There were significant negative correla-
tions (r b�0.55, p =0.05, two tailed, 0.47, 1 tailed
in replication) between whole thalamus and hostility
and suspiciousness (�0.59) and with positive
symptoms (�0.49) and between MDN and pulvinar
and hostility and suspiciousness (�0.81, �0.86respectively). However since this earlier report
(Yasuno et al., 2004) examined the centromedian
nucleus, which is outside our two traced nuclei, we
also examined the residual thalamus (outside the
Fig. 3. [F-18]Fallypride binding differences between normals and patient
with schizophrenia. In each row, three consecutive slices are presented w
extending from t =0 to the smallest value obtained in a map anywhere in th
3.5 and 4.0 are revealed in the region of the left medial dorsal nucleus of
anatomical MRI images from the SPM package. This allows an explorator
examining consistency with postmortem binding studies, SPECT studie
considered areas at a protected p value of the reader’s choice.
two traced nuclei) and found correlations with
BPRS Total (�0.51) positive symptoms (�0.73),hostility and suspiciousness (�0.69), and general
symptoms (�0.57). Thus, our data, associating
significantly more marked symptoms with low BP
in areas outside the medial dorsal, is quite consistent
with the previous report (Yasuno et al., 2004) and
appears to be more strongly contributed to by more
lateral thalamic structures. There were no significant
correlations with age for normals or patients
matching earlier results (Talvik et al., 2003).
3.2. Exploratory mapping
We present consecutive 2 mm slices through the
thalamus (Fig. 1) with p b0.005 threshold to explore
the spatial extent of the thalamic BP differences. Areas
of difference closely follow the traced areas in the
MDN and pulvinar with the area in the thalamus
s with schizophrenia. The color yellow indicates normalsNpatients
ith the threshold set at p b0.05 probability level and the color bar
e row. Thus in the second row, left column, z =12, t values between
the thalamus. The SPM maps are overlaid on spatially normalized
y survey of the brain from the viewpoint of a confirmatory analysis
s or other [F-18]fallypride studies to exploration of not otherwise
M.S. Buchsbaum et al. / Schizophrenia Research 85 (2006) 232–244240
outside of these areas not reaching the threshold. Fig. 2
presents the 3D orthogonal view with the two statistical
thresholds to reveal areas in the cingulate, frontal lobe
and temporal lobe which also differ in showing lower
BP and Fig. 3 presents a brain survey from z =24 down
to z =�24. Areas in the cingulate gyrus (rows 1–3,
z=26 through z =0) and temporal lobe (rows 4–5,
z=�12 to �24) show binding differences.
4. Discussion
We found decreased binding potential with [F-18]
fallypride, a D2/D3 high-affinity ligand in the MDN
and pulvinar regions of the thalamus in patients with
schizophrenia in comparison to normal controls.
These data are consistent with three other studies.
First, the reduced binding potential in the medial half
of the thalamus divided geometrically has been
reported in 9 never-medicated patients and 8 controls
using [C-11]FLB 457 (Talvik et al., 2003). These
findings were more prominent in the right medial area.
Second, in a study of 10 never-medicated patients
with schizophrenia and 19 normal controls also using
[C-11]FLB 457 (Yasuno et al., 2004), the central
medial and posterior regions of the thalamus were
found to have lower BP in patients; these regions were
identified using a thalamic template we developed and
are the regions identified as the MDN and pulvinar.
Third our findings are similar to a study (Suhara et al.,
2002) of 11 never-medicated patients and 18 normals
with [C-11]FLB 457 who showed a trend level
( p =0.06) effect for circular regions of interest placed
on the thalamus. In that study, normals had BP of
3.58F38 and patients 3.31F0.30 which showed an
F =3.90, p =0.06. The anterior cingulate was signif-
icantly lower ( p b0.02) in patients and the temporal
cortex was marginally lower ( p =0.16). Their cingu-
late cortex and temporal lobe values are replicated in
our p b0.05 maps (Figs. 2 and 3). The anterior
cingulate was also found significantly low in a second
FLB-457 study (Yasuno et al., 2005). The consistency
of these findings over the three studies with our
American sample as well as with patients in Sweden
and Japan is noteworthy. The striatum was not
analyzed in any of these studies and was not
considered here due to long equilibration times.
However, taken together with frontal and thalamic
findings, recent results with ligand imaging in the
caudate (Abi-Dargham et al., 2000; Hirvonen et al.,
2003) suggest that dopamine abnormalities may be
present in all parts of the fronto-stratio-thalamic
circuit. Both the cingulate (Choi et al., 2005; Haznedar
et al., 2004; Quintana et al., 2004; Yamasue et al.,
2004) and the temporal lobe (Yamasue et al., 2004)
(Whitford et al., 2005) (Loberg et al., 2004) are
regions for which we and others have recently
reported diminished functional activity and smaller
volume in patients with schizophrenia (see also review
(Shenton et al., 2001) and reviews in recent articles).
These findings were stronger in the left hemisphere
than the right (greater than 20% reduction in the left
medial thalamus and pulvinar). This difference is
greater than the test–retest variability of less than 10%
reported in our previous study in healthy volunteers
(Mukherjee et al., 2002). Earlier studies showed
stronger findings for the right medial thalamus (Talvik
et al., 2003) and two studies averaged right and left
sides (Suhara et al., 2002; Yasuno et al., 2004). Our
own MDN volumetric findings showed that the
decrease in volume was greater for schizophrenics
on the left than the right (Kemether et al., 2003), but
the diagnostic group asymmetry difference did not
reach statistical significance as in the current fall-
ypride results. These same patients did not show a
FDG activation asymmetry in the medial dorsal
nucleus (Lehrer et al., 2005) suggesting that any
asymmetry is not related to activation, although
subjects rested during the fallypride uptake so a
systematic behavioral bias in dopaminergic activity
cannot be ruled out. It should be noted that the low
values were not found for the remainder of the
thalamus outside the medial dorsal and pulvinar, a
larger volume containing other nuclei, suggesting
some anatomical specificity for the findings. The
use of a specific manually-traced coregistered MRI
template for the nuclei and thalamus and the actual
size of the medial dorsal nucleus and pulvinar (each
about 0.5 cc) minimize partial volume effects, but the
contribution of the third ventricle, typically about 1
mm wide at this point, cannot be fully excluded. Head
motion between the initial and final fallypride images
might blur or misposition the anatomical template and
fallypride image, but the specific localization of the
effect to the region of the medial dorsal nucleus with
ROI tracing, and the medial dorsal-pulvinar contour of
M.S. Buchsbaum et al. / Schizophrenia Research 85 (2006) 232–244 241
the matching SPM-identified regions tends to mitigate
against group differences in head motion (which
would tend to diminish normal-schizophrenia con-
trast) as a sole source of the effect.
When using a composite parameter such as BP to
serve as an index for receptor availability, Bmax,
several interpretations of the results can be made.
For example, the decrease in [F-18]fallypride bind-
ing in the schizophrenia cohort could be attributed to
a decrease in D2/D3 receptor density or an increase
in endogenous dopamine competition or changes in
the apparent affinity (via KD). Following the
traditional dopamine theory, we postulate that the
decrease in [F-18]fallypride binding in the thalamus
of the schizophrenics may be due, at least in part, to
an increase in the endogenous dopamine concentra-
tion in the region of the synapse, thus competing
with the [F-18]fallypride for the binding sites. This
suggestion is consistent with findings in the striatum
of patients with schizophrenia by Abi-Dargham and
colleagues, reporting a baseline dopamine occupancy
of the D2/D3 receptor sites of 19% vs. 9% in
controls, using [I-123]IBZM before and after dopa-
mine depletion with a-MPT (Abi-Dargham et al.,
2000). However striatum-a-MPT depletion experi-
ments may not be directly applicable to our thalamus
findings and resolution of the question of 1) lower
apparent Bmax (receptor downregulation) or 2)
different radioligand or 3) increase in dopamine
concentration must await further study. Our results in
the thalamus appear to be largely attributable to D2
receptors since studies using quantitative autoradiog-
raphy with [(125)I]7-OH-PIPAT, a relatively specific
D3 agent, failed to demonstrate significant localiza-
tion in thalamus, temporal lobe, or cingulate (Stan-
wood et al., 2000).
Our current BP values are lower than those we
previously reported (Mukherjee et al., 2002) because
in that study we used circular regions of interest
placed over regions of peak intensity vs. MRI traced
over nuclei without reference to fallypride distribu-
tion. Comparing BPTs with [C-11]FLB 457 (Talvik et
al., 2003) reveals somewhat higher BP for [C-11]FLB
457 than for fallypride due to the differing kinetics of
the radioligands.
While the D2 receptor is the most prominent of the
dopamine receptors in the thalamus, it must be noted
that low levels of D3 receptors are also found in the
MDN (Gurevich and Joyce, 1999) and cannot be
excluded as a partial source of our effects. Examina-
tion of slices at z =�8 (Fig. 3, right column, 5th row)
suggests that differences in binding potential may also
extend into the nucleus accumbens, an area relatively
high in D3 receptors.
The findings reported here of dopamine receptor
change in the MDN of the thalamus in patients with
schizophrenia are noteworthy in replicating several
other receptor studies (Suhara et al., 2002; Talvik et
al., 2003; Yasuno et al., 2004). They are also
consistent with MRI volumetric reduction (Ananth
et al., 2002; Andreasen et al., 1994; Byne et al., 2001;
Kemether et al., 2003; Konick and Friedman, 2001),
reduced FDG uptake (Buchsbaum et al., 1996; Hazlett
et al., 2004; Lehrer et al., 2005) and postmortem
studies (Byne et al., 2002; Pakkenberg, 1990, 1992;
Young et al., 2000). These results, taken together with
the strong and well-documented connections between
the prefrontal regions and the MDN, implicate a
fronto-thalamic circuitry deficit as important in the
functional anatomy of schizophrenia.
Acknowledgements
This work was supported by the Boonshoft
Schizophrenia Center, the Wallace–Kettering Neuro-
science Center, and by a grant to Dr. Buchsbaum,
Anatomy and function of the thalamus in schizophre-
nia MH60023. The support of the United States Air
Force, Air Force Research Laboratory (AFRL/HEOP),
Air Force Materiel Command, under cooperative
agreement F33615-98-2-6002, for use of imaging
resources, is gratefully acknowledged. Marylin Brack-
ney, Dr. King-Wai Chu, Kelly Dunigan, Kerry
Kovacs, Candice Lee, Steve Mattmuller, Aaron
Murray, Maruthi Narayanan, and Tonya Perkins,
provided important technical support. Drs. Martin
Satter (Kettering Medical Center), Nathaniel Alpert
(Massachusetts General Hospital) and Chris Endres
(Johns Hopkins) furnished valuable discussions on the
analysis. MRI data were acquired by Dr. Mehdi
Adenih. The project was approved by the IRBs of
Kettering Medical Center, Wright State University
and Mount Sinai School of Medicine. Gerald M.
Szkotnicki, Executive Director, Wallace–Kettering
Neuroscience Institute, Charles F. Kettering Memorial
M.S. Buchsbaum et al. / Schizophrenia Research 85 (2006) 232–244242
Hospital provided critical facilitating administrative
and organizational support.
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