Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 5361

Contents lists available at ScienceDirect

Progress in Neuro-Psychopharmacology & Biological

Psychiatry
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n p b p

Correlation between prepulse inhibition and cortical perfusion during an attentional

test in schizophrenia
A pilot study
V. Molina a,b,, C. Montes c, P. Tamayo d, R. Villa a, M. Isabel Osuna e, J. Prez a, C. Sancho b,f,
T. Lpez- Albuquerque g, A. Cardoso b, O. Castellano b, D.E. Lpez b
a

Department of Psychiatry, Hospital Clnico Universitario, Salamanca, Spain

Institute for Neuroscience of Castilla y Len, Universidad de Salamanca, Salamanca, Spain
c
Department of Medical Physics, Hospital Clnico Universitario, Salamanca, Spain
d
Department of Nuclear Medicine Hospital Clnico Universitario, Salamanca, Spain
e
Department of Psychiatry, Hospital Reina Sofa, Crdoba, Spain
f
Department of Physiology and Pharmacology, Universidad de Salamanca, Salamanca, Spain
g
Department of Neurology, Hospital Clnico Universitario, Salamanca, Spain
b

a r t i c l e

i n f o

Article history:
Received 29 April 2008
Received in revised form 23 September 2008
Accepted 9 October 2008
Available online 30 October 2008
Keywords:
Perfusion
Prepulse inhibition
Schizophrenia

a b s t r a c t
Background: Processes underlying cortical hypoactivation in schizophrenia are poorly understood but some
evidence suggests that a decient sensory ltering is associated with the condition. This ltering decit can
be studied by using measures of prepulse inhibition (PPI) of the startle reex.
Objective: To evaluate the contribution of sensory ltering decits to cortical hypoperfusion during an
attention test in schizophrenia.
Method: Measurements of PPI of the startle reex and perfusion during the performance of a Stroop test
(assessed with single photon emission tomography) were obtained in 10 acutely treated schizophrenia
patients (6 with recent onset, RO) and 16 control subjects. These measurements were compared between
patients and controls and the correlation between PPI and perfusion was evaluated within each group, using
Statistical Parametric Mapping.
Results: In comparison with normal subjects, the patients exhibited lower PPI, although the difference was
not statistically signicant. Perfusion was signicantly lower in the prefrontal and premotor regions of the
patients. In the patient group, a statistically signicant difference was observed between PPI and perfusion in
the parietal, premotor, and cingulate regions. When the associations were analyzed in the RO patients alone,
a positive correlation was also found between prefrontal perfusion and PPI, while anterior hippocampal
perfusion was inversely related to PPI.
Conclusions: These results support the notion that decient sensory-motor ltering is associated with
decreased cortical task-related activation in schizophrenia.
2008 Elsevier Inc. All rights reserved.

1. Introduction
Brain activity patterns as measured with positron emission
tomography (PET) or single photon-emission tomography (SPECT)
are consistently different between schizophrenia patients and healthy
Abbreviations: dB, decibels; DLPF, dorsolateral prefrontal; FWHM, full-width half
maximum; MBq, microbecquerels, ms, milliseconds; RO, recent onset; PANSS, positive
and negative symptoms scale; PET, positron emission tomography; PF, prefrontal; PPI,
prepulse inhibition; SD, standard deviation; SPECT, single photon emission computerized tomography; SPM, statistical parametric mapping; Tc-HMPAO, technetium
hexamethylene-propylenaminoxime.
Corresponding author. Department of Psychiatry, Hospital Clnico de Salamanca,
Paseo de San Vicente, 58-182, 37007 Salamanca, Spain. Fax: +34 923 291448.
E-mail address: vmolina@usal.es (V. Molina).
0278-5846/$ see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.pnpbp.2008.10.011

controls (Hill et al., 2004). This difference is usually reported as a

decreased activation of the regions involved in the performance of a
task, and can be found in different regions and conditions. For
example, hypoperfusion and hypometabolism have frequently been
described in the prefrontal (PF) areas associated with cognitive
activation (Andreasen et al., 1992), as well as in visual areas in the
resting condition (Andreasen et al., 1997; Desco et al., 2003). However,
hyperactive patterns may be also found, mainly in the limbic areas
(Molina et al., 2005).
The processes underlying such abnormal activation are still poorly
understood. One of the possible contributing causes is decient
sensory ltering, which could hinder task-related activation. Indeed,
there is support for such a gating deciency in schizophrenia, since
thalamic histology, volume and metabolism may be altered in this

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V. Molina et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 5361

illness (Andreasen et al., 1994; Buchsbaum et al., 1996; Thune and

Pakkenberg, 2000), and sensory ltering is one of the key thalamic
functions (Steriade et al., 1997).
Prepulse modulation of the auditory startle reex (ASR) can be
used to measure sensory-motor gating (Geyer and Braff, 1987). ASR is
increasingly used as a measurement of the plasticity and changes that
occur during the processing of sensory-motor information (Koch and
Schnitzler, 1997). The prepulse inhibition (PPI) of ASR represents an
operational measure of information-protective pre-attentional
mechanisms. PPI is the normal inhibition of a startle response to an
intense, abrupt stimulus when it is preceded by a weak prepulse.
Over the past decades, many studies have reported lower PPI values in
schizophrenia (Geyer et al., 2001).
Sensory gating is a process that occurs earlier than cortical
activation, and hence it seems reasonable to propose that decits in
this process might contribute to cortical hypoactivation in schizophrenia. It therefore seems worthwhile to evaluate whether the
measurement of sensory ltering is correlated with cortical hypoactivation in schizophrenia. At least one research group has reported a
correlation between gating decits and cortical hypoactivation in that
illness (Kumari et al., 2003). However, cortical decits may, in turn,
contribute to a decrease in PPI in schizophrenia (Hazlett et al., 1998).
An association between PPI and cortical activation is also
suggested by the observation that greater PPI is related to superior
abilities in strategy formation and execution times (Bitsios et al.,
2006), as well as to better efciency in an attention task (Giakoumaki
et al., 2006). Recent results also suggest an association between
sensorimotor gating and working memory performance (Csomor et al,
2008).
Accordingly, if sensory-motor gating and cortical activation decits
are associated a relationship would be expected between the
percentage of PPI and perfusion in the areas involved in the task
where cortical activity is being studied. Evaluation of this possibility
would require an assessment in the same individuals of the
percentage of PPI and perfusion or metabolism during a cognitive
task. To accomplish this, in the present work we evaluated a group of
acutely treated schizophrenia patients with both PPI and perfusion
SPECT scans obtained during a Stroop test, which is expected to
activate the frontal and cingulate regions (Bush et al., 1998; Pardo
et al., 1990). On performing the three parts of the Stroop task, subjects
must successively read colour names written in black, to name
colours, and to name the ink colour in which a discrepant colour name
is written.
2. Patients and methods
2.1. Subjects
Our sample included 10 acutely treated patients (6 males)
diagnosed with paranoid schizophrenia by consensus between two
psychiatrists (VM, who was the treating clinician in all cases, and RV,
JP, or MO). For all of these patients, both PPI and SPECT data were
available. Moreover, 16 controls (7 males) were included. Among
them, 9 (4 males) had both PPI and SPECT and 7 (3 males) had only PPI
data available. Patient diagnosis was conrmed using the Structured
Clinical Interview for Diagnostic and Statistical Manual (SCID, patients'
version) and data obtained from clinical interviews, together with
information from the patients' families and the clinical staff. All
patients were in a short-term psychiatric unit for the treatment of
psychotic symptoms. The Positive and Negative Syndrome Scale (Kay
et al., 1987) was used to evaluate symptoms (Table 1).
Prior to their inclusion, 6 patients were neuroleptic-nave (NN),
and 4 were neuroleptic-free since they had quit their medication for
more than 1 month. In all cases, a short treatment with haloperidol
(5 mg/d) was given immediately after their admission to the
psychiatric ward. The duration of this treatment was between 24

Table 1
Demographic and cognitive data of patients and controls
Patients

Age
Male:female ratio
School years
Parental SES
Illness duration (years)
PANSS-positive
PANSS-negative
PANSS total
Stroop performance
(colour-incongruent
condition)
Stroop (word-reading
condition)

RO patients
(n = 6)

All patients
(n = 10)

Controls with Controls with

PPI and SPECT PPI
(n = 9)
(n = 16)

28.74 (8.61)
4:2
12.17 (4.73)
1.41 (0.61)
0.91 (0.79)
29.40 (3.59)
26.00 (10.19)
103.17 (19.21)
20.11 (9.22)

32.96 (7.46)
6:4
10.92 (4.89)
1.79 (0.91)
4.23 (3.15)
30.82 (3.70)
25.90 (9.63)
104.20 (19.88)
22.09 (8.27)

30.01 (9.24)
4:5
13.19 (3.60)
1.81 (1.09)

27.33 (8.65)
7:9
14.11 (4.08)
1.90 (1.02)

31.67 (8.03)

34.01 (9.17)

75.28 (13.09)

79.36 (15.01)

89.16 (10.78)

88.70 (10.18)

Stroop performance was dened as the number of correct responses in 45 s in the wordcolour incongruent condition.
RO: recent onset; SES: socioeconomic status, according to the Hollingshead and
Frederick scale (see text).
Values are represented as means (SD).
Signicant difference between patients (n = 10) and controls (n = 16); (U = 21, z = 2.13,
p = 0.03; MannWhitney U test).

and 36 h, although it was withdrawn during the 12 h prior to SPECT

and PPI. Thus, the patients in our sample cannot be properly
considered as NN or neuroleptic-free at the time of the perfusion
and PPI exams, but rather should be considered minimally-treated
patients, and we shall henceforth refer to these as recent onset (RO)
patients.
Both data modes were acquired on the same or consecutive days
in the patients and on the same day in the controls. Benzodiazepines were allowed for insomnia (Lorazepam 2.5 mg) and 5
patients received this drug. After the PPI and SPECT examinations
had been performed, most patients received risperidone as their
only drug.
The healthy controls had no personal or familial psychiatric
antecedents. To match them with the patient group, it was ascertained
that none of the subjects had a college-level education, and efforts
were also made to match the parental school years. No differences in
age or parental socioeconomic status (SES) as dened by Hollingshead
and Frederick (1953) were observed between the patient and control
groups (Table 1). There were no signicant differences in parental
educational level between patients and controls.
The exclusion criteria for patients and controls were: any axis I
diagnosis other than schizophrenia for the patients or any axis I
diagnosis for the controls; any neurological illness, a history of cranial
trauma with loss of consciousness, past substance dependence,
excluding nicotine or caffeine; drug abuse during the previous
3 months (current consumption being ruled out by urinalysis);
signicant hearing loss and any current treatment with known actions
on the central nervous system. None of the patients or controls had
received mood-stabilizers, antidepressants, or depot neuroleptics over
the 6 months preceding the study. All patients and controls underwent a cautionary MRI scan to exclude any abnormality of neurological relevance as judged by an expert radiologist. Prior to PPI testing,
audiometric screening excluded individuals with a hearing impairment in both the patient and control groups (threshold N40 dB (A) at
1000 Hz).
After the subjects had been given detailed information about the
study, written informed consent was obtained from each of them and
from a rst-degree relative. The research and ethics boards of the
participating institutions endorsed the study.

V. Molina et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 5361

2.2. Scanning procedure

The SPECT procedure was performed in patients and controls with
the same scanner, following identical protocols. All subjects performed a Stroop test paradigm between 10 min before and 10 min
after a bolus intravenous injection of 740 MBq of 99mTc-HMPAO, and
scans were obtained 2030 min after the injection. For SPECT
acquisition, we used a dual-head rotating gamma camera (Axis,
Picker) tted with a fan-beam collimator. SPECT data were acquired
over 25 min in step-and-shoot mode (120 steps, 3 steps, 25 s/step)
using a symmetric window of 20% centred around 140 keV and a
128 128 matrix. Images were reconstructed with an iterative method
using a low-frequency pre-lter (order 5; cut-off 0.40 cm 1) and were
corrected for attenuation (Chang 0.09/cm). Sixty-four transaxial slices
were obtained. The SPECT study was performed after a fasting period
of more than 6 h. Coffee and psychoactive beverages were prohibited.
2.3. Cognitive assessment
The Stroop test is an attention task aimed at evaluating the
attentional capacity of subjects, and in particular their resistance to
interference, since in it they must name the colour of the ink in which
the name of a different colour is written. We used the standard version
of this test, with the presentation of 100 stimuli of each part (wordreading, colour and incongruent word-colour). The subjects were
instructed to perform the three parts successively several times, until
HMPAO uptake could be considered complete (20 min after its
injection), with a short resting period of 1 min between the
completion of each repetition (i.e., of each of the three parts of the
test). Performance was dened as the number of correct responses in
45 s in the word-colour incongruent condition in the rst completion.
2.4. PPI acquisition and processing
The acoustic startle test session aimed at measuring PPI consisted
of several parts, with a total acquisition time of about 1520 min.
During the session, the subjects were sitting comfortably in a doublewalled, sound-attenuated and slightly dark chamber. Ambient room
noise was measured using an ear coupler on the headphones.
First, the recording electrodes were placed on the orbicularis and
masseter muscles of the subjects. The subjects were then asked to remain
relaxed, with their eyes open. After emplacement of the electrodes, a
5 min acclimatising period began, with the cabin already closed. During
this period, a background, white noise of 60 dB was present, which was
also maintained for the rest of the session. The test itself consisted of 5
blocks of 2 different trials: pulse alone (105 dB, 50 ms bursts of white
noise), and acoustic startle stimuli preceded 50 ms by a prestimulus
(75 dB, 20 ms bursts of white noise, stimulus onset-asynchrony 70 ms).
The trials were presented binaurally through headphones (DR-531B-14;
Nihon Kohden America, Inc., USA). The sessions began and ended with a
block of three startle stimuli (pulse alone). Between these two blocks,
there were three blocks of 3 prepulsepulse and 1 pulse-alone trial,
presented in a pseudo-random order. The mean inter-trial intervals were
of 15 s and the interval between blocks was 120150 s.
EMG recordings of the orbicularis and masseter muscles were
taken with a Neuropack Kohden electromyograph (Nihon Kohden).
The bin-width for the electromyographic response was 300 ms,
including 50 ms of basal activity and the 100 ms following the
response, and was bandpass-ltered (11000 Hz).
The startle responses were averaged for each subject (response to
pulse alone) and were used as data for the statistical analyses. All the
results from the startle and PPI tests are reported as means SD. The
results of the PPI are reported as % PPI, calculated according to the
following formula:
% PPI = 100 [(magnitude of pulse alone magnitude of prepulse
pulse)/magnitude of pulse alone]

55

Given the small number of subjects, in order to reduce the number

of comparisons we selected only the percentage of attenuation of the
amplitude of the startle reex response (% PPI) in the orbicularis
muscle as the variable to be assessed as an index of the sensory-motor
gating process. Other data obtained in the study, such as the acoustic
startle response (amplitude and latency), are not directly related to
pre-attentional or attentional processes, and were therefore not
analyzed in depth.
During at least the 3 h preceding PPI, neither the patients nor the
controls smoked, because the former had been admitted to the
hospital and the latter were also in hospital to undergo their SPECT
scans. Thus, the smoking abstinence period of the patients was longer
than 24 h in all cases.
2.5. Image analysis
SPECT images were analyzed with the SPM5 software package
(from the Welcome Dept. of Cognitive Neurology, London, UK)
(Frackowiak et al., 1997). Studies were transformed into a Talairach
stereotactic space (Talairach and Tournoux, 1988), warping each scan
to a reference template that already conformed to the standard space.
Images were reformatted to a nal voxel size of 2 2 2 mm and
smoothed using an isotropic Gaussian kernel of 12 12 12 mm
FWHM. The grey-level threshold was set to 0.8; i.e., only voxels with
an intensity level above 0.8 of the mean level for that scan were
included in the statistical analysis. Intensity normalization was carried
out using proportional scaling, hence assuming that global brain
metabolism was equal for each scan.
2.6. Statistical methods
The normality of the distribution of the variables was examined
using the KolmogorovSmirnoff test, and when it could not be
assumed non-parametric tests were used.
Performance in the Stroop test (number of correct responses in 45 s
in the word-incongruent condition) was compared between patients
and controls with a MannWhitney U test.
The signicance of the differences in %PPI and the startle response
between patients and controls was assessed using the MannWhitney
U test. We repeated the comparison between patients and the 16
controls with the available PPI data. In light of the differences in sex
distribution between the patients and controls, we had planned a
priori to corroborate that the same pattern of differences would be
present between male controls (n = 7) and male patients (n = 6).
In order to assess the clinical relevance of the PPI measurements,
we calculated the correlation coefcients between positive, negative,
and total symptoms scores in the PANSS and PPI using Spearman's rho.
With the same aim, we also calculated correlation coefcients
between the Stroop performance and PPI.
Following this, Statistical Parametric Mapping (SPM-5) was used to
assess perfusion differences between the patients and controls. Age
was included as a covariate in this model.
SPM was then used to evaluate the correlation between PPI and
perfusion across the brain. Correlations were calculated on a voxel-byvoxel basis, using the multiple regression design incorporated in the
SPM. These calculations were carried out separately in patients and
controls. In a second step, the calculations were repeated using the
Stroop performance as a covariate. Moreover, we repeated these
calculations using only the data in the RO group to conrm that if any
association was found it was not simply due to a residual effect of the
previous treatment in the chronic patients.
For all SPM analyses, the one-tailed signicance threshold was set
at p b .001, uncorrected with a minimum extent of 50 voxels, except for
the post-hoc analyses in the RO group. In this case, owing to the
limitation of the number of subjects we considered the results
signicant at p b .0025 and more than 50 voxels.

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V. Molina et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 5361

3. Results

Table 3
Perfusion differences between the patients (n = 10) and controls (n = 9) with PPI and
SPECT data available (p b 0.001, regions greater than 50 voxels, uncorrected)

3.1. Comparisons between groups

Local maxima coordinates

3.1.1. Sex distribution

Although there were more males in the patient group, sex
distribution was not statistically signicant with respect to the 9
controls with PPI and SPECT available (2 = 2.55, df = 2, p = 0.12) nor
with respect to the 16 controls with PPI alone (2 = 1.70, df = 2, p = 0.18).
3.1.2. Cognitive performance
The patients performed well in the word-reading condition of the
Stroop test, but their performance was signicantly poorer than that
of the controls in the word-incongruent condition (Table 1).
3.1.3. Effect of prepulse on startle response
The startle response amplitude on the orbicularis muscle was
lower in the patients in comparison with the controls with PPI and
SPECT done and, at trend level, in comparison with all the controls
with available PPI data (Table 2).
The PPI value was lower in patients, but the difference did not
reach statistical signicance (Table 2). This was also the case of the
comparisons between the patients and the 16 controls with PPI data
available (Table 2).The same pattern was also found in a comparison
between the 7 male controls (PPI mean 64.12 23.34) and the 6 male
patients (PPI mean 48.01 28.60, U = 17.00, z = .95, p = 0.38) with
available PPI data. We repeated these comparisons using parametric
methods (Student's t) and the differences between patients and
controls were again not statistically signicant.
3.1.4. Perfusion
The schizophrenia patients showed lower perfusion values than
the controls (p b 0.001) in both the right and left premotor and right
dorsolateral (DLPF) regions. In the patients, smaller areas of
hyperactivity were detected in the cerebellar vermis and left inferior
PF regions (Table 3; Fig. 1). The same pattern was identied at
p b 0.0025 when the RO patients were compared with the healthy
controls (Fig. 1).
3.2. Correlation between PPI and clinical and cognitive scores
In the patients, the PPI values were signicantly related to negative
symptom scores (rho = 0.86, p b 0.01) and total symptom scores
(rho = 0.88, p b 0.01). There was no signicant correlation between
PPI and Stroop performance (rho = 0.43, p N 0.10).
3.3. Correlation between perfusion and PPI measures
In the controls, PPI was positively correlated with perfusion in the
upper parietal and occipital regions (Table 4; Fig. 2).

Voxel extent

Regions with higher activity in controls

Right dorsolateral
50, 18, 38
Right premotor
32, 6, 54
Left premotor
14, 4, 70

4.49
3.94
3.78

415
133
272

Regions with higher activity in patients

Cerebellum
0, 50, 22
Left orbitofrontal
28, 48, 6

3.90
3.82

55
51

Differences still signicant in the RO patients (n = 6) as compared to controls (n = 9),

at p b 0.0025.

In the patients, PPI was correlated with perfusion in the upper

right parietal lobe (Table 4; Fig. 2), similarly to the controls. Moreover,
in the patients PPI was also directly correlated with perfusion in the
middle cingulate and left premotor regions (Fig. 2). This pattern of
correlation was the same when the Stroop performance was
introduced as a covariate.
3.3.1. Correlations in the RO patients
When this correlation was evaluated in the RO patients alone (n = 6),
a positive correlation was also found between PPI and perfusion in the
right parietal and left premotor regions (p b 0.0025, Table 4; Fig. 2).
Moreover, in this subgroup a signicant negative correlation was also
found between perfusion in the anterior hippocampal region (coordinates 32, 8, 18, voxel extent= 389) and PPI (Fig. 3).
When Stroop performance was introduced as a covariate, the same
correlation pattern was found in the premotor and limbic areas of the RO
patients. Moreover, additional positive correlations emerged in the RO
group between PPI and perfusion in the medial prefrontal (coordinates
2, 48, 48, voxel extent = 102, z = 4.85), right DLPF(coordinates 24, 34, 52,
voxel extent = 84, z = 3.92) and right orbitofrontal (coordinates 28, 38,
20, voxel extent = 237, z = 4.51) regions (Fig. 4).
4. Discussion
In this work, the schizophrenia patients showed a signicant
correlation between the percentage of attenuation due to prepulse of
the startle reex (i.e., PPI) and perfusion measured during a Stroop test
in regions known to be activated by this task (middle cingulate and
parietal, and in the RO patients prefrontal, after including performance as a covariate). The patients showed the usual hypofrontal
pattern, their collaboration in the task presumably being normal, in
light of their performance data.
Previous neuroimaging results have shown that the Stroop test
activates the middle frontal and anterior cingulate (Bush et al., 1998;
Pardo et al., 1990), motor and premotor (Bush et al., 1998; Peterson
et al., 1999), as well as the parietal (Brown et al., 1999; Bush et al.,

Table 2
Mean values of the % of PPI (prepulse 75 dB)
Patients

PPI values (%), masseter

PPI values (%), orbicularis
Amplitude of the startle response (V), masseter
Amplitude of the startle response (V), orbicularis

Controls

RO patients
(n = 6)

All patients
(n = 10)

Controls with PPI and SPECT

(n = 9)

Controls with PPI

(n = 16)

48.78 (29.56)
40.01 (27.45)
226.12 (149.33)
295.20 (102.17)

40.55 (30.11)
43.24 (28.27)
219.42 (128.56)
256.01 (122.78)

60.09 (26.67)
59.30 (27.1) U = 31.00, z = 1.14, p = 0.27
591.78 (860.12)
732.51 (744.21) U = 22.00, z = 2.09, p = 0.03

56.70 (29.51)
56.89 (26.9) U = 59.00, z = 1.10, p = 0.28
529.33 (692.01)
653.79 (737.22) U = 51.00, z = 1.89, p = 0.07

Prepulse inhibition values and of the response startle amplitude (V) obtained with a 105 dB pulse alone in patients and controls (both the whole group and the RO subgroup) and
controls, in the orbicularis occuli and masseter muscles. The statistics of the comparisons between the whole group of patients and, respectively, the whole group of controls and the
subgroup of controls with PPI and SPECT done are shown.
p b 0.05.

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57

Fig. 1. Top. Regions with signicantly lower perfusion in patients (n = 10) as compared to controls (n = 9) (p b .001). Bottom. Regions with signicantly lower perfusion in RO patients
(n = 6) as compared to controls (n = 9, p b .0025). In both cases, left and right premotor and right DLPF areas were hypoactive.

1998; Leung et al., 2000) regions. The percentage of PPI in our patients,
and also in the controls, was directly associated with the perfusion
values in these areas. Thus, our data are consistent with the hypothesis
that some factors underlying the usually lower PPI in schizophrenia,
such as a sensory ltering decit (Braff and Geyer, 1990; Geyer and
Braff, 1987), might interfere with task-related cortical activation in the
illness.
In the complete group of patients and in the RO subgroup, a lower
PPI was found as compared to the control subjects, although this
difference did not reach statistical signicance. Our patients showed a
decreased startle response as compared to controls, which might have
contributed to the observed lack of statistical signicance in the
decrease in PPI with respect to controls, although at least one other
group has reported a signicant decrease in PPI in schizophrenia,
along with a decreased startle response (Quednow et al., 2006).
Moreover, the magnitude of the PPI differences found in the present
study between the patients and controls (roughly one third less in the
patients than in the controls) is similar to the baseline magnitude
reported in other studies, despite the differences in the methods used
to elicit PPI (Quednow et al., 2006), and it lies within the range
described in studies of patients treated with olanzapine, risperidone,
or haloperidol (Wynn et al., 2007). For example, values of 68.5 22.0 of
PPI in controls and 32.1 48.3 have been reported in patients (Kumari
et al., 2003). Thus, it may be assumed that the lack of a signicant
difference in PPI between our patients and the controls may have been
due to the small sample size.
However, the lack of signicant differences in PPI may also have
been due to factors that increased the variance in the patients; notably
nicotine consumption or the treatment received previously. The latter
can reasonably be discarded since the pattern was very similar in the
RO subjects. As regards nicotine, its effects may be related to acute
consumption (Duncan et al., 2001; Postma et al., 2006) or abstinence.
The acute effects of nicotine on PPI were probably minimal in our
subjects since none of them smoked during the hours prior to the
study of PPI. In turn, abstinence would decrease PPI in schizophrenia
(George et al., 2006), and therefore would not account for the lack of a
signicant decrease in PPI in our patients. Nevertheless, an effect of
nicotine withdrawal on the degree of PPI reduction in our subjects
cannot be discarded, since it has been reported that healthy controls
scoring high on a scale measuring tolerance to nicotine withdrawal

show signicantly less PPI than those who score low on that scale
(Kumari and Gray, 1999). Moreover, differences in the methods used to
elicit PPI may also be related to the lack of signicant differences in PPI
between patients and controls. For example, there are differences in
the level of background noise (60 dB in our study, as opposed to 70 dB
used by most laboratories whose studies have reported a signicant
decrease in PPI). The results obtained for one group without
background noise failed to reveal a PPI decit in schizophrenia
patients (Wynn et al., 2007). Nevertheless, using a background noise
of 60 dB, at least one group found decreased PPI in schizophrenia and
cannabis users during one of two conditions in which PPI was
determined in their study (Kedzior and Martin-Iverson, 2007).
Finally, another factor contributing to the lack of a signicantly
reduced PPI in our cases is related to the attentional modulation of PPI.
PPI is more robust when attending to than ignoring the prepulse, and
several groups have reported that the attentional modulation of PPI is
also impaired in schizophrenia and schizotypal patients (Dawson et al,
2000; Hazlett et al, 2007). Thus, it is conceivable that using an active
paradigm to measure PPI, our patients could have shown a statistically
signicant reduction in PPI. However, using passive paradigms such as
the one used here other groups have detected reduced PPI in
schizophrenia (Geyer et al., 2001).

Table 4
Correlations between PPI measured on orbicularis muscle and perfusion during a Stroop
test (p b 0.001, extent greater than 50 voxels) in patients and controls
Local maxima coordinates

Voxel extent

Patients: direct correlations

Right parietal
Left premotor
Middle cingulate
Left premotor

44, 50, 60
40, 16, 68
0, 6, 44
38, 14, 46

4.08
4.05
3.99
3.51

84
60
84
79

Controls: direct correlations

Right parietal
Left occipital
Left posterior temporal

18, 68, 44
14, 54, 16
48, 54, 10

4.56
3.96
3.64

68
79
54

No inverse associations were detected.

Correlations in the patients still signicant in the RO subgroup at p b 0.0025.

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V. Molina et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 5361

Fig. 2. Top (rows 1 and 2). Regions with a signicant correlation between PPI (orbitalis muscle) and perfusion during the Stroop test in the controls, n = 9 (p b .001). Perfusions in the
upper parietal and occipital regions were positively associated with PPI in this group. Middle (rows 3 to 5). Regions with a signicant correlation between PPI (orbitalis muscle) and
perfusion during the Stroop test in the patients, n = 10 (p b .001). Perfusion in the right upper parietal region was positively associated with PPI in this group. Bottom (row 6): Regions
with a signicant correlation between PPI (orbitalis muscle) and perfusion during the Stroop test in the RO patients, n = 6 (p b .0025) Perfusion in the right upper parietal region was
positively correlated with PPI in this group.

Our patients received a minimum treatment prior to the PPI and

SPECT studies. This was done to avoid the bias due to the inclusion
only of patients able to cooperate in imaging procedures. Dopamine

function may inuence PPI (Geyer et al., 2001), and in schizophrenia

important differences in dopamine transmission can be expected
between acute and remission states (Laruelle et al., 1999). It therefore

V. Molina et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 5361

59

Fig. 3. Regions with a signicant inverse correlation between PPI (orbitalis muscle) and perfusion during the Stroop test in the RO patients (n = 6, p b .0025). Inverse correlations were
found between the perfusion in the hippocampus and PPI in this group.

seems necessary to study acute psychotic patients, although this may

be unfeasible in most cases in which they have not undergone any
previous treatment. The minimum treatment with haloperidol that
our patients received prior to SPECT may have inuenced their brain
perfusion patterns, since with PET a decrease in frontal metabolism
has been reported after long-term treatments (Holcomb et al., 1996).
Regarding the acute administration of haloperidol to drug-free
schizophrenia patients, as used here, a widespread metabolic decrease
has been found 12 h after its administration in patients that did not
respond to the drug, but not in those who did respond (Bartlett et al.,
1998). Since there is no reason to assume that the patients in our study
would not have responded to haloperidol, this would suggest only a
weak effect on perfusion of the acute haloperidol doses administered
to our patients. This is also supported by the similar pattern of
hypofrontality described in NN patients under activation conditions
similar to those used here (Andreasen et al., 1992; Buchsbaum et al.,
1992). Thus, the effect of haloperidol may not be the only reason for
the hypofrontality observed in our patients as compared to controls.
Moreover, since the available data support the notion that haloperidol

does not modify PPI measurements, even after prolonged use,

previous minimal treatment with this drug is unlikely to account for
the association found here between cortical activation and sensorymotor gating.
Three studies from the same group have evaluated cerebral activity
correlates during a PPI paradigm in unmedicated chronic schizophrenia
patients and controls, using PET to assess cortical metabolism. Although
this is a different approach to the one used here, the results of these
studies point to the activation of frontal regions during PPI in the
controls but not in the patients (Hazlett and Buchsbaum, 2001; Hazlett
et al., 1998). In a more recent report, schizophrenia patients showed a
reduced activation of the prefrontal, caudate and thalamic regions
during the attentive PPI condition in comparison to controls (Hazlett
et al, 2008). This is coherent with the direct correlation observed in our
patients between frontal and cingulate perfusion and PPI and the lower
perfusion seen in the patients as compared to the controls. Taken
together, these data indicate that low PPI may be correlated with a lower
degree of frontal activation in schizophrenia patients than in controls. If
a decit in sensory gating in schizophrenia is assumed, this would also

Fig. 4. Regions with a direct correlation between PPI and perfusion in the RO patients after including Stroop performance as a covariate in addition to the above-described direct
correlations. Medial frontal, right DLPF and right orbitofrontal perfusion directly correlated with PPI.

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V. Molina et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 5361

be coherent with decreased frontal activation under cognitive paradigms in patients with lower PPI. Those authors (Hazlett et al.,1998) also
described a positive correlation in their patients between metabolism in
prefrontal area 10 and PPI, equivalent to the correlation between
orbitofrontal perfusion and PPI in our RO patients, Another group
evaluated the association between perfusion as measured by fMRI and
tactile PPI in controls and schizophrenia subjects treated with conventional antipsychotics (Kumari et al., 2003). They found a lower degree of
PPI in the patients, accompanied by a blunted haemodynamic response
during the PPI task, in a complex set of regions encompassing frontal,
parietal, occipital, striatal, limbic and cerebellar locations. These results
are not easily comparable to ours, given the relevant changes that
classical antipsychotics exert on many of these regions, in particular the
basal ganglia (Buchsbaum et al., 1987; DeLisi et al., 1985). However, they
are consistent with the notion of the existence of an association between
PPI and cortical activation decits in schizophrenia.
Nevertheless, we cannot adequately identify the direction of that
association; i.e., we cannot state whether cortical dysfunction produces a
decit in PPI or whether sensory gating decits produce a ooding of the
cortex that impairs its activation. Sensory gating is an early process and
thus may be primary, but hypofrontality might also contribute to the
decrease in PPI in schizophrenia (Hazlett et al., 1998). Preclinical data also
show that the frontal depletion of dopamine impairs PPI in the rat (Bubser
and Koch, 1994), which could indicate the primary role of cortical decits.
We found an inverse correlation in the RO patients between limbic
perfusion and PPI: the greater the limbic perfusion, the lower the PPI.
Limbic hyperactivation has been described in schizophrenia patients
and has been related to prefrontal atrophy (Molina et al., 2005),
positive symptoms (Liddle et al., 1992; Molina et al., 2005), and
cognitive performance (Heckers et al., 1998). Together with the
correlation between PPI and low cortical activation, the association
between PPI and limbic hyperactivity supports the hypothesis that
sensory ltering decits may contribute to a disorganized activation
across the brain, as proposed for schizophrenia (Manoach, 2003). Such
an association was only detected in the RO patients, which suggests
the cancellation of such a correlation in treated patients.
Our study has several limitations; notably, the number of subjects.
This implies that the results can only be considered preliminary.
Another limitation is the different number of males and females in the
patient and control groups. Even within the same female subjects,
changes along the menstrual cycle may inuence PPI values
(Swerdlow et al., 1997). However, PPI decits in schizophrenia are
not restricted to males (Braff et al., 2005). In this latter study, female
patients and controls showed a similar pattern of differences at 54 dB
prepulse intensity (stimulus onset-asynchrony 30 and 120 ms) to that
found in the present one. Moreover, when we compared the male
patients and the male controls, the differences remained the same as
when the whole group was considered. Another limitation is related
to the state of acute psychosis of the patients, which could determine a
lower degree of collaboration. However, the patients' performance on
the Stroop test was good, as evidenced in the reading condition,
suggesting that in our cases acute psychosis was not associated with
poor collaboration in the test. Finally, we did not simultaneously
collect PPI and perfusion data. The future use of functional MRI may
help to overcome this problem, since it would allow a simultaneous
assessment of these parameters to be made, perhaps also during the
performance of an attention task.
In conclusion, sensory-motor gating measured with PPI and
cortical perfusion in some regions as measured with SPECT may be
positively correlated in schizophrenia.
Acknowledgements
Supported in part by a Grant from the Fondo de Investigaciones
Sanitarias (PI 040025), from the Spanish Ministry of Health and by the
Ministerio de Educacin y Ciencia (BFU2007-65210).

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