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
54
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)
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).
55
56
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)
Voxel extent
4.49
3.94
3.78
415
133
272
3.90
3.82
55
51
Table 2
Mean values of the % of PPI (prepulse 75 dB)
Patients
Controls
RO patients
(n = 6)
All patients
(n = 10)
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.
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
44, 50, 60
40, 16, 68
0, 6, 44
38, 14, 46
4.08
4.05
3.99
3.51
84
60
84
79
18, 68, 44
14, 54, 16
48, 54, 10
4.56
3.96
3.64
68
79
54
58
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.
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.
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.
60
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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