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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: Monte.buchsbaum@mssm.edu (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) 232–244 239

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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